Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:18][CH2:19][CH2:20][N:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)=[CH:9][C:10]=2[N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[N:5]=[CH:4][N:3]=1.[Cl:26][C:27]1[C:32]([NH2:33])=[C:31]2[O:34][CH2:35][O:36][C:30]2=[CH:29][CH:28]=1>C(O)(C)C>[Cl:26][C:27]1[C:32]([NH:33][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:18][CH2:19][CH2:20][N:21]4[CH2:25][CH2:24][CH2:23][CH2:22]4)=[CH:9][C:10]=3[N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)[N:5]=[CH:4][N:3]=2)=[C:31]2[O:34][CH2:35][O:36][C:30]2=[CH:29][CH:28]=1
Reactant: Nc1c(Cl)ccc2c1OCO2
Reactant: Clc1ncnc2cc(OCCN3CCCC3)cc(N3CCOCC3)c12
Solvent: CC(C)O
Product: Clc1ccc2c(c1Nc1ncnc3cc(OCCN4CCCC4)cc(N4CCOCC4)c13)OCO2
Temperature: 80 °C
Yield: 9.4 %

Procedure:
A mixture of 4-chloro-5-morpholino-7-(2-pyrrolidin-1-ylethoxy)quinazoline (0.27 g), 6-chloro-2,3-methylenedioxyaniline (0.14 g) and isopropanol (4 ml) was stirred and heated to 80° C. for 1 hour. The mixture was evaporated and the residue was dissolved in a 49:1 mixture of methylene chloride and a saturated methanolic ammonia solution. The mixture was filtered and the filtrate was poured onto a column of silica and eluted with a 97:3 mixture of methylene chloride and a saturated methanolic ammonia solution. The material so obtained was triturated under diethyl ether. The resultant solid was isolated, washed with diethyl ether and dried under vacuum. There was thus obtained the title compound (0.035 g); NMR Spectrum: (CDCl3) 1.85 (br s, 4H), 2.65 (br s, 4H), 3.0 (m, 2H), 3.08 (m, 2H), 3.18 (d, 2H), 3.82 (m, 2H), 4.05 (m, 2H), 4.25 (m, 2H), 6.05 (s, 2), 6.75 (d, 1H), 6.95–7.1 (m, 3H), 8.52 (s, 1H); Mass Spectrum: M+H+ 498 and 500.
Reaction SMILES: C(O[C:5]1[C:6](=[O:18])[C:7](=[O:17])[C:8]=1[C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=1)(C)C.[CH3:19][C@@H:20]([NH2:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(O)C>[CH3:16][O:15][C:12]1[CH:11]=[CH:10][C:9]([C:8]2[C:7](=[O:17])[C:6](=[O:18])[C:5]=2[NH:27][C@@H:20]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH3:19])=[CH:14][CH:13]=1
Reactant: COc1ccc(-c2c(OC(C)C)c(=O)c2=O)cc1
Reactant: C[C@@H](N)c1ccccc1
Solvent: CCO
Product: COc1ccc(-c2c(N[C@H](C)c3ccccc3)c(=O)c2=O)cc1
Yield: 64.1 %

Procedure:
In a manner similar to Example 1, Step 2; 3-isopropoxy-4-(4-methoxy-phenyl)-cyclobut-3-ene-1,2-dione (150 g, 0.609 mmol) and (R)-(+)-α-methyl-benzylamine (180 μL, 0.914 mmol) in ethanol (1 mL) were converted to the title compound (120 mg, 64%) m.p.: 158.7-160.1° C.; 1H NMR (DMSO-d6) δ 9.28(d,1H), 8.04(ABq,2H), 7.35(m,5H), 7.10(ABq,2H), 3.83(s,3H), 1.64(d,3H); IR (KBr) 3260, 3060, 3030, 2970, 1770, 1720, 1600, 1560, 1520, 1440, 1410, 1380, 1340, 1310, 1260, 1220, 1180, 1120, 1100, 1025, 825, 700 cm−1; MS (m/z) 307 [M+], [α]25D−185.42° (c0.1049,THF).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=O)[CH2:6][CH2:5]2.C([O:16][N:17]=O)(C)(C)C.C([OH:21])C>>[Br:1][C:2]1[CH:3]=[C:4]2[C:8]([CH2:7][C:6](=[O:21])[C:5]2=[N:17][OH:16])=[CH:9][CH:10]=1
Reactant: CCO
Reactant: CC(C)(C)ON=O
Reactant: O=C1CCc2cc(Br)ccc21
Product: O=C1Cc2ccc(Br)cc2C1=NO
Temperature: 25 °C
Reaction time: 2 h
Yield: 76 %

Procedure:
A solution of 5-bromo-1-indanone (1.8 g, 8.5 mmol) in ethanol (150 ml) was cooled to 0° C., treated with t-butylnitrite (2.1 ml), stirred at room temperature for 2 hours, filtrated and washed the desired product with ether. The yield is 76%. MS (DCI/NH3) m/e 242 (M+1)+.
Reaction SMILES: [CH3:1][N:2](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Br:25][C:26]1[CH:27]=[C:28]2[C:35]([C:36](O)=[O:37])=[C:34]([C:39]3[CH:44]=[CH:43][C:42]([F:45])=[CH:41][CH:40]=3)[O:33][C:29]2=[N:30][C:31]=1[Cl:32].Cl.CN.CCN(C(C)C)C(C)C>CN(C=O)C.CCOC(C)=O.Cl>[Br:25][C:26]1[CH:27]=[C:28]2[C:35]([C:36]([NH:2][CH3:1])=[O:37])=[C:34]([C:39]3[CH:44]=[CH:43][C:42]([F:45])=[CH:41][CH:40]=3)[O:33][C:29]2=[N:30][C:31]=1[Cl:32]
Reactant: O=C(O)c1c(-c2ccc(F)cc2)oc2nc(Cl)c(Br)cc12
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2nc(Cl)c(Br)cc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 90 %

Procedure:
HATU (1.69 g, 4.45 mmol) was added to a stirring solution of 5-bromo-6-chloro-2-(4-fluorophenyl)furo[2,3-b]pyridine-3-carboxylic acid (1.1 g, 3.0 mmol), methylamine hydrochloride (1.00 g, 14.8 mmol), and DIEA (2.59 mL, 14.8 mmol) in a sealable tube in DMF (20 mL) at rt. The reaction tube was sealed and allowed to stir at rt for 2 hours. LCMS and TLC indicate complete conversion. The solution was then diluted with EtOAc (50 mL) and 1 M HCl (50 mL). The layers were separated and the aqueous layer was extracted with EtOAc (2×20 mL). The combined organic extracts were washed with water, brine, dried over Na2SO4, filtered and concentrated to give a tan solid. This solid was adsorbed onto SiO2 and eluted on silica gel with a 0-5% MeOH in DCM gradient over 40 CV (very slow gradient) to give 5-bromo-6-chloro-2-(4-fluorophenyl)-N-methylfuro[2,3-b]pyridine-3-carboxamide (1.1 g, 2.7 mmol, 92% yield) as a white fluffy solid. LCMS: m/e 385 (M+H)+ LCMS retention time: 3.04 min. (Column: Phenomenex-Luna 50×2.0 mm 3u. Solvent A=90% Water: 10% Methanol: 0.1% TFA. Solvent B=10% Water: 90% Methanol: 0.1% TFA. Start % B=0. Final % B=100. Gradient Time=4 min. Flow Rate=0.8 mL/min.). 1H NMR (500 MHz, CDCl3) δ ppm 8.50 (s, 1H), 7.89 (dd, J=9.0 Hz, 2H), 7.23 (dd, J=8.7 Hz, 2H), 5.85 (br s, 1H), 3.00 (d, J=4.8 Hz, 3H).
Reaction SMILES: [O:1]=[C:2]1[C:6](=[CH:7][C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH2:15][C:16](O)=[O:17])[CH:9]=2)[S:5][C:4](=[S:19])[N:3]1[NH:20][C:21]1[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[S:23](=[O:31])(=[O:30])[N:22]=1.[CH2:32](N)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.O[N:41]1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O>[O:1]=[C:2]1[C:6](=[CH:7][C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH:15]([CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C:16]([NH2:41])=[O:17])[CH:9]=2)[S:5][C:4](=[S:19])[N:3]1[NH:20][C:21]1[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[S:23](=[O:31])(=[O:30])[N:22]=1
Reactant: O=C(O)COc1cccc(C=C2SC(=S)N(NC3=NS(=O)(=O)c4ccccc43)C2=O)c1
Reactant: On1nnc2ccccc21
Reactant: NCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Product: NC(=O)C(Cc1ccccc1)Oc1cccc(C=C2SC(=S)N(NC3=NS(=O)(=O)c4ccccc43)C2=O)c1
Temperature: 0 °C
Yield: 84.2 %

Procedure:
To a solution of 3-[(4-oxo-5-(3-(carboxymethyloxy)benzylidene)-2-thioxothiazolidin-3-yl)amino]-1,2-benzothiazole 1,1-dioxide (34 mg) obtained in Example 174 and benzylamine (8 mg) in N,N-dimethylformamide (1 ml) were added 1-hydroxybenzotriazole (10 mg) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (14 mg) with stirring under ice cooling, and the mixture was stirred overnight at room temperature. The reaction mixture was poured into ice water (20 ml), and the mixture was extracted with ethyl acetate (30 ml). The extract was washed successively with 0.5M aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 3-[(4-oxo-5-(3-(benzyl aminocarbonylmethyloxy)benzylidene)-2-thioxothiazolidin-3-yl)amino]-1,2-benzothiazole 1,1-dioxide (34 mg).
Reaction SMILES: [SH:1][CH2:2][C@H:3]([NH:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=1)[C:4]([OH:6])=[O:5].[C:17]([O-])([O-])=[O:18].[K+].[K+].C1N=CN(C(N2C=NC=C2)=O)C=1.C(OC(C)C)(=O)C>C(#N)C.O>[CH3:16][O:15][C:12]1[CH:11]=[CH:10][C:9]([CH2:8][N:7]2[C@H:3]([C:4]([OH:6])=[O:5])[CH2:2][S:1][C:17]2=[O:18])=[CH:14][CH:13]=1
Reactant: O=C([O-])[O-]
Reactant: COc1ccc(CN[C@@H](CS)C(=O)O)cc1
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [K+]
Solvent: O
Solvent: CC#N
Solvent: CC(=O)OC(C)C
Product: COc1ccc(CN2C(=O)SC[C@H]2C(=O)O)cc1
Temperature: 40 °C
Yield: 69.9 %

Procedure:
A 22 L three-necked round bottom flask fitted with an internal temperature probe and a mechanical stirrer was charged with the title compound from Example 2 (400.0 g, 1.66 mol), K2CO3 (480.0 g, 3.47 mol) and water (2.8 L). The mixture was heated at 40° C. while stirring until it became homogeneous and was then cooled to room temperature. A solution of N,N-carbonyldiimidazole (400.0 g, 222.47 mol) in acetonitrile (2.8 L) was added dropwise at a rate that maintained an internal reaction temperature less than 30° C. The reaction was monitored by HPLC and was complete upon the disappearance of the starting material (about 15 minutes). The acetonitrile was removed by heating at 40° C. and 80-100 torr. Isopropyl acetate (200 mL) was added and the pH of the mixture was adjusted to 2 with 3 M H2SO4. The biphasic mixture was filtered, and the organic phase was isolated. Additional isopropyl acetate was added and the solution was dried by azeotropic distillation. The reaction volume was reduced further until a precipitate began to form. The yellow precipitate was isolated by filtration and dried at 50° C. overnight to afford the title compound (310 g, 70%).
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:9]2[N:10]=[CH:11][S:12][C:8]=2[CH:7]=[CH:6][CH:5]=1)[CH3:2].C(O[C:18](=O)[NH:19][C@H:20]1[CH2:25][CH2:24][C@H:23]([C:26](=[O:31])N(OC)C)[CH2:22][CH2:21]1)(C)(C)C.[O:33]=[C:34]1[NH:39][C:38]2[CH:40]=[C:41](C=O)[CH:42]=[CH:43][C:37]=2[S:36][CH2:35]1>>[CH2:1]([O:3][C:4]1[C:9]2[N:10]=[C:11]([C:26]([C@H:23]3[CH2:22][CH2:21][C@H:20]([NH:19][CH2:18][C:41]4[CH:42]=[CH:43][C:37]5[S:36][CH2:35][C:34](=[O:33])[NH:39][C:38]=5[CH:40]=4)[CH2:25][CH2:24]3)=[O:31])[S:12][C:8]=2[CH:7]=[CH:6][CH:5]=1)[CH3:2]
Reactant: CCOc1cccc2scnc12
Reactant: CON(C)C(=O)[C@H]1CC[C@H](NC(=O)OC(C)(C)C)CC1
Reactant: O=Cc1ccc2c(c1)NC(=O)CS2
Product: CCOc1cccc2sc(C(=O)[C@H]3CC[C@H](NCc4ccc5c(c4)NC(=O)CS5)CC3)nc12

Procedure:
Using 4-ethoxy-benzothiazole (5 mmol), [trans-4-(methoxy-methyl-carbamoyl)-cyclohexyl]-carbamic acid tert-butyl ester (2.5 mmol) and 3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carbaldehyde (0.3 mmol) according to the same protocol as that described for example 1, steps 1.a to 1.c, the title compound was obtained as a yellow solid (15 mg).
Reaction SMILES: O.O.[Sn](Cl)Cl.[CH2:6]([NH:10][C:11]1[CH:16]=[C:15]([Br:17])[CH:14]=[CH:13][C:12]=1[N+:18]([O-])=O)[CH:7]([CH3:9])[CH3:8].C(=O)(O)[O-].[Na+].[N:26]#[C:27]Br>O.C(O)C.C(OCC)(=O)C>[CH2:6]([N:10]1[C:11]2[CH:16]=[C:15]([Br:17])[CH:14]=[CH:13][C:12]=2[N:18]=[C:27]1[NH2:26])[CH:7]([CH3:9])[CH3:8]
Reactant: N#CBr
Reactant: CC(C)CNc1cc(Br)ccc1[N+](=O)[O-]
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCO
Product: CC(C)Cn1c(N)nc2ccc(Br)cc21
Temperature: 70 °C
Reaction time: 2 h
Yield: 86.4 %

Procedure:
Add tin(II) chloride dihydrate (245.5 g, 1.09 mol) to a solution of N-[isobutyl]2-nitro-5-bromoaniline (49.5 g, 0.180 mol) in 2:1 ethyl acetate:ethanol (900 mL). Stir at 70° C. for 2 hours. Pour the reaction mixture into a slurry of ice in water and treat with saturated aqueous sodium bicarbonate. Add ethyl acetate (250 mL) and wash the organic phase sequentially with water (2×600 mL) and saturated aqueous sodium chloride (2×600 mL). Dry over magnesium sulfate and concentrate under reduced pressure. Dissolve the residue in ethanol (600 mL). Add cyanogen bromide (32.6 g, 0.31 mol) and stir at room temperature for 15 hours. Add saturated aqueous sodium carbonate (500 mL) and extract with ethyl acetate (600 mL). Wash the organic phase sequentially with water (2×400 mL) and saturated aqueous sodium chloride (2×400 mL). Dry over magnesium sulfate and concentrate under reduced pressure. Suspend the residue in diethyl ether (300 mL), stir for 15 minutes, filter, and dried under reduced pressure to provide the desired compound as a light brown solid (41.7 g, 86% yield).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[C:5]([Cl:12])=[CH:4][CH:3]=1.[OH:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:12][C:5]1[CH:4]=[CH:3][C:2]([O:22][C:19]2[CH:20]=[CH:21][C:16]([CH2:15][CH2:14][OH:13])=[CH:17][CH:18]=2)=[N:7][C:6]=1[C:8]([F:11])([F:10])[F:9]
Reactant: FC(F)(F)c1nc(Br)ccc1Cl
Reactant: OCCc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: OCCc1ccc(Oc2ccc(Cl)c(C(F)(F)F)n2)cc1
Temperature: 110 °C
Yield: 8.2 %

Procedure:
To the solution of 6-bromo-3-chloro-2-(trifluoromethyl)pyridine (2 g, 7.68 mmol) and 4-(2-hydroxyethyl)phenol (1.061 g, 7.68 mmol) in DMF (30 mL) was added K2CO3 (1.592 g, 11.52 mmol). The mixture was heated at 110° C. for 2 h. Purification via reverse phase flash chromatography afforded the title compound (200 mg, 8.2% yield) as brown solid. LCMS: rt=3.14 min, [M+H+]=318
Reaction SMILES: [CH:1]([C:3]1[CH:18]=[CH:17][C:6]([O:7][C:8]2[CH:9]=[CH:10][C:11]([C:14]([NH2:16])=[O:15])=[N:12][CH:13]=2)=[CH:5][CH:4]=1)=O.[F:19][C:20]1[CH:28]=[CH:27][C:23]([CH2:24][CH2:25][NH2:26])=[CH:22][CH:21]=1.[BH4-].[Na+]>CO>[F:19][C:20]1[CH:28]=[CH:27][C:23]([CH2:24][CH2:25][NH:26][CH2:1][C:3]2[CH:18]=[CH:17][C:6]([O:7][C:8]3[CH:9]=[CH:10][C:11]([C:14]([NH2:16])=[O:15])=[N:12][CH:13]=3)=[CH:5][CH:4]=2)=[CH:22][CH:21]=1
Reactant: NCCc1ccc(F)cc1
Reactant: NC(=O)c1ccc(Oc2ccc(C=O)cc2)cn1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: NC(=O)c1ccc(Oc2ccc(CNCCc3ccc(F)cc3)cc2)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.4 %

Procedure:
Suspend 5-(4-formylphenoxy)pyridine-2-carboxamide (0.0271 g, 0.112 mmol) In methanol (2.1 mL). Add 4-fluorophenethylamine (0.015 mL, 0.112 mmol) and 3 Å molecular sieves. Stir at room temperature overnight. Add NaBH4 (in small excess) and stir for additional 3 hour-s. Load the reaction mixture directly onto a 5 g SCX column. Wash the column with methanol and elute with 2.0 M NH3 in methanol. Purify by flash chromatography, eluting with 70% ethyl acetate, 5% (2.0 M NH3 in methanol) and 25% hexanes to give the title compound (0.0370 g, 90.5%): TOF MS ES+ 366.2 (M+H)+, base peak TOF MS ES+ 227.1 (M-NHCH2CH2C6H4F)+, HRMS calcd for C21H21N3O2F 366.1618 (M+H)+, found 366.1621, time 0.42 min; HPLC [YMC-Pack Pro C-18 (150×4.6 mm, S-5 microm), 0.1% TFA/acetonitrile in 0.1% TFA/water at 1.0 mL/min, 5-95°/over 19 min], tR=10.2 min, 100% purity.
Reaction SMILES: [CH:1]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][CH:13]([CH2:15][CH3:16])[CH3:14])=[CH:8][CH:7]=1)([CH2:3][CH3:4])[CH3:2].[Na].[CH2:18]([CH:20]([CH2:23][CH2:24][CH2:25][CH3:26])[CH:21]=O)[CH3:19]>ClCCl>[CH:13]([N:12]([CH2:21][CH:20]([CH2:18][CH3:19])[CH2:23][CH2:24][CH2:25][CH3:26])[C:9]1[CH:8]=[CH:7][C:6]([N:5]([CH:1]([CH2:3][CH3:4])[CH3:2])[CH2:21][CH:20]([CH2:18][CH3:19])[CH2:23][CH2:24][CH2:25][CH3:26])=[CH:11][CH:10]=1)([CH2:15][CH3:16])[CH3:14]
Reactant: CCCCC(C=O)CC
Reactant: CCC(C)Nc1ccc(NC(C)CC)cc1
Agent: [Na]
Solvent: ClCCl
Product: CCCCC(CC)CN(c1ccc(N(CC(CC)CCCC)C(C)CC)cc1)C(C)CC
Temperature: 25 °C
Reaction time: 15 h
Yield: 86.5 %

Procedure:
N,N′-di-sec-butyl-p-phenylenediamine (20.8 g, 94 mmol) and sodium triacetoxyhydroborate (60.0 g, 283 mmol) in dichloromethane (500 ml) was treated with 2-ethylhexanal (30.3 g, 236 mmol) and stirred at room temperature for 15 hours. TLC showed the reaction complete and the reaction mixture was decanted to a beaker and quenched by addition of saturated aqueous NaHCO3 and stirred until effervescence ceased. The organic phase was separated and washed twice with water, once with brine and then dried (MgSO4), filtered and concentrated in vaccuo to afford a red oil. The product was chromatographed (eluent 5% ethyl acetate in heptane). Relevant fractions were collected and concentrated to afford a red oil (36.16 g, 82% yield).
Reaction SMILES: [CH2:1]1[O:3][CH2:2]1.[NH2:4][C:5]1[CH:6]=[C:7]([CH:12]=[CH:13][CH:14]=1)[C:8]([O:10][CH3:11])=[O:9].[C:15](O)(=[O:17])[CH3:16]>O>[OH:17][CH2:15][CH2:16][N:4]([C:5]1[CH:6]=[C:7]([CH:12]=[CH:13][CH:14]=1)[C:8]([O:10][CH3:11])=[O:9])[CH2:2][CH2:1][OH:3]
Reactant: CC(=O)O
Reactant: C1CO1
Reactant: COC(=O)c1cccc(N)c1
Solvent: O
Product: COC(=O)c1cccc(N(CCO)CCO)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Ethylene oxide (16 mL, 330 mmol) was added rapidly via a cold syringe to a solution of methyl 3-aminobenzoate (5.0g, 33 mmol), glacial acetic acid (40 mL), and water (40 mL) with stirring at 0 ° C. under nitrogen beneath a dry ice/acetone condenser. After 1 h, the cold bath was removed and the reaction stirred for 43 h at room temperature. Water was added, and the mixture neutralized by adding solid sodium bicarbonate portionwise. After a series of EtOAc/H2O extractions, the crude product was isolated by concentration under reduced pressure. Purification by chromatography on silica gel, eluting with 0% to 5% MeOH in EtOAc, and evaporation yielded an oil (6.9 g). IR(neat): cm-1 3340, 1718. 1H NMR(300 MHz, CDCl3): 7.38-6.87 (m, 4H), 3.90-3.85 (m, 7H), 3.65-3.59 (m, 4H), 3.27 (s, 2H). HR-MS: Calc'd. 240.1236, Found 240.1237.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([C:9]2[C:10]([OH:20])=[CH:11][CH:12]=[C:13]([C:15]3[NH:19][N:18]=[N:17][N:16]=3)[CH:14]=2)[CH:6]=[CH:7][CH:8]=1.C(N(CC)CC)C.[C:28]([N:32]=[C:33]=[O:34])([CH3:31])([CH3:30])[CH3:29].[C:35](OCC)(=[O:37])C>CN(C)C=O.O>[C:28]([NH:32][C:33]([NH:1][CH2:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:14]=[C:13]([C:15]3[NH:19][N:18]=[N:17][N:16]=3)[CH:12]=[C:11]([CH:35]=[O:37])[C:10]=2[OH:20])[CH:6]=[CH:7][CH:8]=1)=[O:34])([CH3:31])([CH3:30])[CH3:29]
Reactant: CC(C)(C)N=C=O
Reactant: NCc1cccc(-c2cc(-c3nnn[nH]3)ccc2O)c1
Reactant: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)NC(=O)NCc1cccc(-c2cc(-c3nnn[nH]3)cc(C=O)c2O)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
3′-aminomethyl-5-(1H-tetrazol-5-yl)-biphenyl-2-ol (0.31 g, 1.16 mmol) was dissolved in dimethylformamide (10 mL) and the solution was treated with triethylamine (0.8 mL, 5.8 mmol) and tert-butylisocyanate (0.14 mL, 1.27 mmol). The mixture was stirred at room temperature for 2 hours. Workup with ethyl acetate and water, followed by drying afforded 0.56 g (quant.) of the crude 1-tert-butyl-3-[2′-hydroxy-5′-(1H-tetrazol-5-yl)-biphenyl-3-ylmethyl]-urea.
Reaction SMILES: [Br:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][C:19]3[N:20]=[C:21]([CH:24]([CH3:26])[CH3:25])[O:22][CH:23]=3)[CH2:14][CH2:13]2)=[C:4]([N+:9]([O-])=O)[C:5]([NH2:8])=[N:6][CH:7]=1.CCO.[O:30]1[CH2:35][CH2:34][N:33]([CH2:36][C:37]2[CH:44]=[CH:43][C:40]([CH:41]=O)=[CH:39][CH:38]=2)[CH2:32][CH2:31]1.[O-]S(S([O-])=O)=O.[Na+].[Na+]>CN(C=O)C>[Br:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][C:19]3[N:20]=[C:21]([CH:24]([CH3:26])[CH3:25])[O:22][CH:23]=3)[CH2:14][CH2:13]2)=[C:4]2[N:9]=[C:41]([C:40]3[CH:39]=[CH:38][C:37]([CH2:36][N:33]4[CH2:34][CH2:35][O:30][CH2:31][CH2:32]4)=[CH:44][CH:43]=3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: O=Cc1ccc(CN2CCOCC2)cc1
Reactant: CC(C)c1nc(CN2CCN(c3c(Br)cnc(N)c3[N+](=O)[O-])CC2)co1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CN(C)C=O
Product: CC(C)c1nc(CN2CCN(c3c(Br)cnc4[nH]c(-c5ccc(CN6CCOCC6)cc5)nc34)CC2)co1
Temperature: 85 °C

Procedure:
To a mixture of 5-bromo-4-(4-((2-isopropyloxazol-4-yl)methyl)piperazin-1-yl)-3-nitropyridin-2-amine (0.065 g, 0.15 mmol), EtOH (0.85 mL), and DMF (0.15 mL), was added 4-(morpholinomethyl)benzaldehyde (0.040 g, 0.19 mmol) followed by a freshly prepared aqueous solution of Na2S2O4 (1M; 0.49 mL, 0.49 mmol). The reaction mixture was heated at 85° C. for 24 h, then allowed to cool to room temperature and the solvents were removed in vacuo. The residue was purified by column chromatography on a Biotage SP1 system eluting with methanol (10-30%) in ethyl acetate. The title compound was isolated as a pale yellow solid (0.002 g, 2.4%) after trituration with ether; 1H-NMR (500 Mz, DMSO-d6): δ 1.27 (d, J=7 Hz, 6H, iPr—CH3), 2.38 (m, 4H), 2.65 (m, 4H), 3.05 (m, 1H, iPr—CH), 3.44 (s, 2H, NCH2), 3.54 (s, 2H, NCH2), 3.59 (t, J=4.5 Hz, 4H), 3.66 (m, 4H), 7.47 (d, J=7.5 Hz, 2H, ArH), 7.87 (s, 1H, oxazole 5-H), 8.14 (d, J=8.0 Hz, 2H, ArH), 8.23 (s, 1H, imidazo[4,5-b]pyridine 5-H), 13.49 (br s, 1H, imidazo[4,5-b]pyridine N—H); LC (Method B)-MS (ESI, m/z) 2.43 min—580/582 [(M+H)+, Br isotopic pattern]. ESI-HRMS: Found: 580.2036, calculated for C28H35BrN7O2 (M+H)+: 580.2035.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([S:13]([C:16]3[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=3)(=[O:15])=[O:14])[CH:11]=[C:10]([CH2:22][N:23](C)[C:24](=O)OC(C)(C)C)[CH:9]=2)=[CH:4][CH:3]=1.FC(F)(F)C(O)=O.C(=O)([O-])O.[Na+].[Cl:44]CCl>>[ClH:44].[ClH:44].[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]([S:13]([C:16]3[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=3)(=[O:15])=[O:14])[CH:11]=[C:10]([CH2:22][NH:23][CH3:24])[CH:9]=2)=[CH:6][CH:7]=1
Reactant: CN(Cc1cc(-c2ccc(F)cc2)n(S(=O)(=O)c2cccnc2)c1)C(=O)OC(C)(C)C
Reactant: ClCCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: CNCc1cc(-c2ccc(F)cc2)n(S(=O)(=O)c2cccnc2)c1
Product: Cl
Temperature: 25 °C
Reaction time: 3 h

Procedure:
tert-Butyl {[5-(4-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate (293 mg) was dissolved in dichloromethane (1 mL), trifluoroacetic acid (1 mL) was added at 0° C., and the mixture was stirred at room temperature for 3 hr. The reaction solution was basified by adding dropwise to a 6% aqueous sodium hydrogencarbonate solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (eluent: hexane-ethyl acetate=1:1→1:9) to give a free salt of the title compound as a pale-yellow oil. The obtained free salt was dissolved in ethyl acetate (5 mL), a 4 mol/L hydrogen chloride-ethyl acetate solution (1 mL) was added, and the mixture was concentrated under reduced pressure. The residue was recrystallized from ethyl acetate-ethanol to give the title compound as colorless crystals (yield 110 mg, 40%).
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Cl[CH2:12][C:13](=[O:20])[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16].Cl>C(OCC)C.O>[CH2:1]([O:8][CH2:12][C:13](=[O:20])[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)CC(=O)CCl
Reactant: OCc1ccccc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Product: CCOC(=O)CC(=O)COCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Benzyl alcohol (19.7 g, 182.3 mmol) was slowly added to a suspension of sodium hydride (15.9 g 55% in mineral oil, 364.5 mmol) in anhydrous diethyl ether (116 mL) and the resulting mixture was stirred at room temperature for 1 hour. It was then diluted with some diethyl ether to ensure good stirring. Ethyl 4-chloro-3-oxobutanoate (12.3 mL, 91.1 mmol) was then slowly added and the mixture was stirred at room temperature overnight. The reaction mixture was cooled with an ice bath and then diluted with cold water and diethyl ether pH was adjusted to 4 with 5 N HCl and it was extracted three times with diethyl ether containing some ethyl acetate. The combined organic phases were dried over Na2SO4 and it was concentrated to dryness, thus obtaining the title compound with quantitative yield as a crude product that was used as such in the following step.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[N:12]1[CH2:17][CH2:16][O:15][C:14]2[CH:18]=[CH:19][CH:20]=[CH:21][C:13]1=2.[Cl:22][S:23](O)(=[O:25])=[O:24]>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[N:12]1[CH2:17][CH2:16][O:15][C:14]2[CH:18]=[C:19]([S:23]([Cl:22])(=[O:25])=[O:24])[CH:20]=[CH:21][C:13]1=2
Reactant: FC(F)(F)c1ccc(N2CCOc3ccccc32)c(Br)c1
Reactant: O=S(=O)(O)Cl
Solvent: ClCCl
Product: O=S(=O)(Cl)c1ccc2c(c1)OCCN2c1ccc(C(F)(F)F)cc1Br

Procedure:
A solution of INTERMEDIATE B (1.325 g, 3.70 mmol) in DCM (7.40 mL) was cooled to 0° C. in an ice-water bath, and chlorosulfonic acid (1.230 mL, 18.50 mmol) was added dropwise. The resulting solution was stirred at RT for 4 hours until complete conversion to the desired product occurred. The reaction mixture was then slowly added dropwise to well-stirred ice water and subsequently neutralized to a pH of about 7 with saturated aqueous sodium bicarbonate solution. After extraction with EtOAc (×3), the combined organics were washed with water and brine, dried over magnesium sulfate, filtered and concentrated to provide INTERMEDIATE C. The material was taken forward without further purification. m/z (ESI) 477.8 (M+Na)+.