Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:45])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][C:9]=1[C:18](=[O:44])[NH:19][C@H:20]1[CH2:24][CH2:23][N:22]([C@@H:25]([CH2:31][NH:32][C:33](OCC2C=CC=CC=2)=O)[C@@H:26]([OH:30])[C:27]#[C:28][CH3:29])[C:21]1=[O:43])([CH3:4])([CH3:3])[CH3:2].[CH3:46][C:47]1[CH:54]=[C:53]([CH3:55])[CH:52]=[CH:51][C:48]=1C=O.C([BH3-])#N.[Na+]>CO.[Pd]>[C:1]([O:5][C:6](=[O:45])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:16])([F:15])[F:17])=[CH:10][C:9]=1[C:18](=[O:44])[NH:19][C@H:20]1[CH2:24][CH2:23][N:22]([C@@H:25]([CH2:31][NH:32][CH2:33][C:48]2[CH:51]=[CH:52][C:53]([CH3:55])=[CH:54][C:47]=2[CH3:46])[C@@H:26]([OH:30])[CH2:27][CH2:28][CH3:29])[C:21]1=[O:43])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC#C[C@H](O)[C@H](CNC(=O)OCc1ccccc1)N1CC[C@H](NC(=O)c2cc(C(F)(F)F)ccc2NC(=O)OC(C)(C)C)C1=O
Reactant: Cc1ccc(C=O)c(C)c1
Agent: [Pd]
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CCC[C@H](O)[C@H](CNCc1ccc(C)cc1C)N1CC[C@H](NC(=O)c2cc(C(F)(F)F)ccc2NC(=O)OC(C)(C)C)C1=O
Temperature: 25 °C
Reaction time: 12 h

Procedure:
The compound (2-{(3S)-1-[(1S,2S)-1-(benzyloxycarbonylamino-methyl)-2-hydroxy-pent-3-ynyl]-2-oxo-pyrrolidin-3-ylcarbamoyl}-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (87 mg, 0.14 mmol) was dissolved in MeOH (4 mL). The resultant solution was charged with 5% Pd/C, Degussa style (10 mg), stirred under H2 (1 atm) for 12 h at RT, filtered, and concentrated in vacuo. The residue was redissolved in MeOH (4 mL). The resultant solution was charged sequentially with 2,4-dimethylbenzaldehyde (0.015 mL, 0.11 mmol) and sodium cyanoborohydride (10 mg), stirred for 12 h at RT, quenched with sat. NaHCO3, and extracted twice with EtOAc. The organic extracts were combined, washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo. Purification by reverse-phase HPLC afforded the title compound as a white powder after lyopholization (15 mg). MS found: (M+H)+=621.5.
Reaction SMILES: [CH3:1][C:2]1[S:17][C:5]2[N:6]=[C:7]3[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[CH:11][N:8]3[C:9](=[O:10])[C:4]=2[C:3]=1[CH3:18].[N-:19]=[N+:20]=[N-:21].[Na+].[Cl-].[NH4+].N1C=CC=CC=1>CN(C)C=O>[CH3:1][C:2]1[S:17][C:5]2[N:6]=[C:7]3[CH:14]=[CH:13][C:12]([C:15]4[NH:21][N:20]=[N:19][N:16]=4)=[CH:11][N:8]3[C:9](=[O:10])[C:4]=2[C:3]=1[CH3:18]
Reactant: Cc1sc2nc3ccc(C#N)cn3c(=O)c2c1C
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: Cc1sc2nc3ccc(-c4nnn[nH]4)cn3c(=O)c2c1C
Yield: 27.6 %

Procedure:
From 0.43 g (0.0017 mol) of 2,3-dimethyl-4-oxo-4H-pyrido[1,2-a]thieno[2,3-d]pyrimidine-7-carbonitrile (Example 32), 0.33 g (0.0051 mol) of sodium azide and 0.3 g (0.0056 mol) of ammonium chloride in 80 ml of dimethylformamide, following the procedure of Example 34, there is obtained 0.14 g of 2,3-dimethyl-7-(1H-tetrazol-5-yl)-4H-pyrido[1,2-a]thieno[2,3-d]pyrimidin-4-one with pyridine (1:0.6); mp 292°-294° C. (dec) after recrystallization from pyridine.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1)(=[O:3])[CH3:2].[CH2:10]([O:12][C:13](=[O:22])[CH:14](Br)[C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1)[CH3:11]>>[CH2:10]([O:12][C:13](=[O:22])[CH:14]([N:7]1[CH2:8][CH2:9][N:4]([C:1](=[O:3])[CH3:2])[CH2:5][CH2:6]1)[C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1)[CH3:11]
Reactant: CCOC(=O)C(Br)c1cccnc1
Reactant: CC(=O)N1CCNCC1
Product: CCOC(=O)C(c1cccnc1)N1CCN(C(C)=O)CC1
Yield: 60 %

Procedure:
N-acetyl-piperazine (3.7 g; 28.8 mmol; 2.8 equiv) was combined with bromo-pyridin-3-yl-acetic acid ethyl ester (approx. 2.5 g; 10 mmol). Purification on a 3×16 cm silica column using a 30% then 40% ethyl acetate/hexanes (v/v) mobile phase followed by a 2% methanol/dichloromethane (v/v) mobile phase resulted in 1.84 g light yellow oil (approx. 60% yield). MS(ES) calc'd: [M+H]+=292.2 m/z; [M+Na]+=314.2 m/z.
Reaction SMILES: [CH3:1][S:2][C:3]1[S:4][C:5]2[CH:11]=[C:10]([N+]([O-])=O)[CH:9]=[CH:8][C:6]=2[N:7]=1.[CH3:15][O:16][S:17]([C:20]1[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=1)(=[O:19])=[O:18]>CCOCC>[C:23]1([CH3:26])[CH:22]=[CH:21][C:20]([S:17]([O-:19])(=[O:16])=[O:18])=[CH:25][CH:24]=1.[CH3:15][N+:7]1[C:6]2[CH:8]=[CH:9][CH:10]=[CH:11][C:5]=2[S:4][C:3]=1[S:2][CH3:1]
Reactant: CSc1nc2ccc([N+](=O)[O-])cc2s1
Reactant: COS(=O)(=O)c1ccc(C)cc1
Solvent: CCOCC
Product: CSc1sc2ccccc2[n+]1C
Product: Cc1ccc(S(=O)(=O)[O-])cc1
Yield: 63.6 %

Procedure:
A mixture of 6-nitro-2-(methylthio)benzothiazole 7 (0.5 g, 2.2 mmol) and methyl-p-toluensulfonate (3.7 g, 20 mmol) was heated from 120° C. to 145° C. over one hour. To the cooled solution was added 30 mL of ether. The resulting amorphous solid was triturated with acetone to provide a pale mauve solid (0.57 g, 1.4 mmol, 63%).
Reaction SMILES: [C:1]([C:4]1[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][C:7]([O:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[C:6]([O:19][CH3:20])[CH:5]=1)([OH:3])=[O:2].O.[C:22]1(C)[CH:27]=CC(S(O)(=O)=O)=C[CH:23]=1.C(O)C=C>>[C:1]([C:4]1[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][C:7]([O:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[C:6]([O:19][CH3:20])[CH:5]=1)([OH:3])=[O:2].[CH3:27][CH:22]=[CH2:23]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: COc1cc(C(=O)O)c([N+](=O)[O-])cc1OCCC(=O)O
Solvent: C=CCO
Solvent: O
Product: C=CC

Procedure:
A mixture of 3-(4-carboxy-2-methoxy-5-nitrophenoxy)propanoic acid (153) (20 g, 74.3 mmol) and p-toluene sulphonic acid monohydrate (2.3 g, 7.4 mmol) in allyl alcohol (240 mL, 3.5 mol) was refluxed for 7 hours then allowed to cool. The allyl alcohol was then removed in vacuo, and the residue triturated with dilute HCl acid and collected by filtration. This solid was taken up in EtOAc, and the resulting solution washed with water and brine and dried over sodium sulphate. Evaporation in vacuo afforded 154 as a white solid (19.27 g, 84%): mp 128-130° C.; 1H-NMR (CDCl3): δ2.92 (t, 2H, J=6.35 Hz); 3.94 (s, 3H); 4.38 (t, 2H, J=6.41 Hz); 4.65 (d, 2H, J=5.61 Hz); 5.27 (dd, 1H, J1=1.28 Hz, J2=19.42 Hz); 5.33 (dd, 1H, J1=1.28 Hz, J2=17.04 Hz); 5.92 (m, 1H); 7.15 (s, 1H); 7.45 (s, 1H); 13C NMR (67.8 MHz, CDCl3): δ34.1, 56.5, 65.0, 65.4, 108.5, 111.3, 118.3, 122.9, 131.8, 141.1, 149.1, 152.6, 167.1, 170.0; IR (Nujol); ν 1730, 1630, 1550, 1430, 1390, 1290, 1230, 1190, 1170, 1070, 1030, 1010 cm−1; MS (EI) m/z (relative intensity): 325 (M+., 19), 251 (3), 213 (2), 196 (3), 211 (3), 113 (19), 91 (4), 71 (9), 55 (6); HRMS: calcd. for C14H15NO8 325.0798, found 232.0773.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.[H-].[Na+].[CH2:13](Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.Cl>CN(C=O)C.O>[CH2:13]([N:7]1[C:8]2[C:4](=[CH:3][C:2]([Br:1])=[CH:10][CH:9]=2)[CH:5]=[CH:6]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Brc1ccc2[nH]ccc2c1
Reactant: BrCc1ccccc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Brc1ccc2c(ccn2Cc2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 77.7 %

Procedure:
A solution of 5-bromoindole (5.02 g, 25.6 mmol) in DMF (50 mL) was cooled in an ice bath. Sodium hydride (2.30 g of 60% dispersion in oil, 57.5 mmol) was added. After stirring for 40 minutes under nitrogen at room temperature, the reaction mixture was again cooled in an ice bath and benzyl bromide (6.7 mL, 56 mmol) was added. The reaction mixture was stirred for 2 hours, poured into excess water, acidified with 2N hydrochloric acid and extracted with ethyl acetate. The organic phase was washed with water and brine, dried over anhydrous magnesium sulfate and evaporated to dryness. The residue was purified by flash chromatography (Biotage apparatus) using hexane as an eluant. Dyring at 60° C. for 35 minutes yielded the title compound as a white solid (5.69 g, 78%), mp 93–95° C. Mass spectrum (+ESI, [M+H]+) m/z 286; 1HNMR (500 MHz, DMSO-d6): δ7.7 (d,1H, J=1.8 Hz), 7.55 (d, 1H, J=3.1 Hz), 7.4 (d, 1H, J=8.7 Hz), 7.15–7.30 (m, 6H), 6.45 (dd, 1H, J=3.2 Hz and 0.6 Hz), and 5.45 ppm (s, 2H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]2([C:15]3[S:19][C:18]([C:20](O)=[O:21])=[CH:17][CH:16]=3)[CH2:14][CH:13]=[CH:12][CH2:11]2)[CH:5]=[C:4]([CH3:23])[C:3]=1[C:24]1[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=1.Cl.[CH3:35][O:36][C:37](=[O:41])[CH2:38][CH2:39][NH2:40].O.ON1C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.Cl.CN(C)CCCN=C=NCC>CN(C=O)C.O>[CH3:35][O:36][C:37](=[O:41])[CH2:38][CH2:39][NH:40][C:20]([C:18]1[S:19][C:15]([C:10]2([CH2:9][O:8][C:6]3[CH:5]=[C:4]([CH3:23])[C:3]([C:24]4[CH:25]=[CH:26][C:27]([C:30]([F:32])([F:33])[F:31])=[CH:28][CH:29]=4)=[C:2]([CH3:1])[CH:7]=3)[CH2:11][CH:12]=[CH:13][CH2:14]2)=[CH:16][CH:17]=1)=[O:21]
Reactant: Cc1cc(OCC2(c3ccc(C(=O)O)s3)CC=CC2)cc(C)c1-c1ccc(C(F)(F)F)cc1
Reactant: COC(=O)CCN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)CCNC(=O)c1ccc(C2(COc3cc(C)c(-c4ccc(C(F)(F)F)cc4)c(C)c3)CC=CC2)s1
Yield: 65.4 %

Procedure:
To a mixture of 5-[1-(2,6-dimethyl-4′-trifluoromethyl-biphenyl-4-yloxymethyl)-cyclopent-3-enyl]-thiophene-2-carboxylic acid (0.204 g, 0.433 mmol), 3-amino-propionic acid methyl ester hydrochloride (0.0665 g, 0.476 mmol), and 1-hydroxybenzotriazole hydrate (HOBt, 0.0716 g, 0.530 mmol) in DMF (4.0 mL) is added N, N-diisopropylethylamine (0.240 mL, 1.37 mmol), then N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDCI, 0.106 g, 0.553 mmol) and stirred overnight. The reaction mixture is poured into H2O (10 mL) and extracted with EtOAc (3×10 mL). Combined organic extracts are washed with H2O, brine, dried over MgSO4, filtered, and concentrated. The residue is loaded onto silica gel and eluted using hexanes with an ethyl acetate gradient from 0% to 75% to provide 3-({5-[1-(2,6-dimethyl-4′-trifluoromethyl-biphenyl-4-yloxymethyl)-cyclopent-3-enyl]-thiophene-2-carbonyl}-amino)-propionic acid methyl ester (0.158 g, 65%) as a white foam. MS (ES): 556.3 [M−H]−.
Reaction SMILES: Br[C:2]1[C:3](=[O:18])[C:4]([CH3:17])([CH3:16])[O:5][C:6]=1[C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][CH:8]=1.CC1(C)C(C)(C)OB([C:27]2[CH:44]=[CH:43][C:30]([O:31][CH2:32][C:33]3[CH:42]=[CH:41][C:40]4[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=4)[N:34]=3)=[CH:29][CH:28]=2)O1.C([O-])([O-])=O.[Cs+].[Cs+]>C1(C)C=CC=CC=1.O>[CH3:16][C:4]1([CH3:17])[C:3](=[O:18])[C:2]([C:27]2[CH:28]=[CH:29][C:30]([O:31][CH2:32][C:33]3[CH:42]=[CH:41][C:40]4[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=4)[N:34]=3)=[CH:43][CH:44]=2)=[C:6]([C:7]2[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][CH:8]=2)[O:5]1
Reactant: CC1(C)OC(c2ccc([N+](=O)[O-])cc2)=C(Br)C1=O
Reactant: CC1(C)OB(c2ccc(OCc3ccc4ccccc4n3)cc2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: Cc1ccccc1
Product: CC1(C)OC(c2ccc([N+](=O)[O-])cc2)=C(c2ccc(OCc3ccc4ccccc4n3)cc2)C1=O
Yield: 53.6 %

Procedure:
A solution of 4-bromo-2,2-dimethyl-5-(4-nitrophenyl)furan-3(2H)-one (100 mg, 0.32 mmol, 1 eq), 2-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)methyl)quinoline (115 mg, 0.32 mmol, 1 eq), and Cs2CO3 (521 mg, 1.6 mmol, 5 eq) in toluene (7 mL) and water (2.5 mL) was degassed. Then Pd (dppf)Cl2 (52 mg, 0.06 mmol, 0.2 eq) was added under an inert atmosphere and the solution was again degassed. The reaction mixture was then refluxed for 3 h, filtered through a pad of Celite®, and the filtrate was diluted with EtOAc (30 mL). The combined organic layers were washed with water (20 mL) and brine (10 mL), dried over Na2SO4, filtered, and concentrated in vacuo to obtain the crude product. The crude material was purified via silica gel column chromatography (10% ethyl acetate in hexanes) to afford 2,2-dimethyl-5-(4-nitrophenyl)-4-(4-(quinolin-2-ylmethoxy)phenyl)furan-3(2H)-one (80 mg, 54%) as a solid. 1H NMR (400 MHz, d6-DMSO): δ 8.42 (d, J=8.5 Hz, 1 H), 8.27 (d, J=8.5 Hz, 2 H), 8.00 (t, J=7.9 Hz, 2 H), 7.82-7.76 (m, 3 H), 7.68 (d, J=8.5 Hz, 1 H), 7.61 (t, J=7.2 Hz, 1 H), 7.18 (d, J=8.7 Hz, 2 H), 7.10 (d, J=8.7 Hz, 2 H), 5.38 (s, 2 H), 1.48 (s, 6 H). MS: [M+H]: m/z=467.1. HPLC: 89%, Column: Acquity BEH—C-18, 50×2.1 mm, 1.7 um. Mobile Phase: 0.025% TFA in Water (A), AcN (B), Flow rate: 0.5 ml/min (Gradient).
Reaction SMILES: N[C:2]1[C:3]2[N:4]([N:10]=[C:11]([S:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:12]=2)[C:5]([Cl:9])=[CH:6][C:7]=1[Cl:8].N(OC(C)(C)C)=O.O1CCCC1>CCOCC>[CH2:14]([S:13][C:11]1[N:12]=[C:3]2[CH:2]=[C:7]([Cl:8])[CH:6]=[C:5]([Cl:9])[N:4]2[N:10]=1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: Nc1c(Cl)cc(Cl)n2nc(SCc3ccccc3)nc12
Agent: CC(C)(C)ON=O
Solvent: CCOCC
Solvent: C1CCOC1
Product: Clc1cc(Cl)n2nc(SCc3ccccc3)nc2c1

Procedure:
8-Amino-2-benzylthio-5,7-dichloro[1,2,4]triazolo[1,5-a]pyridine (25.8 g, 0.079 mol), t-butyl nitrite (18.9 mL, 16.4 g, 0.158 mol) and tetrahydrofuran (1.5 L) were combined and heated at reflux with stirring. Gas evolution began immediately and stopped after a few minutes, but the reaction was heated at reflux for an hour. The volatiles were removed by evaporation under reduced pressure and the residue obtained was chromatographed on silica gel eluting with dichloromethane. The product fractions were concentrated by evaporation under reduced pressure and the residue obtained was mixed with ether. The insoluble solid material was collected by filtration. The ether filtrate was concentrated by evaporation under reduced pressure and the residue was rechromatographed on silica gel eluting with 10 percent ethyl acetate in hexane. The product fractions were concentrated by evaporation under reduced pressure and the residue obtained was combined with the insoluble solid material obtained before to obtain 12.2 g (50 percent of theory) of the title compound as a red-brown powder melting at 88°-89° C.
Reaction SMILES: [CH2:1]([N:3]([CH2:21][CH3:22])[CH2:4][CH2:5][NH:6][C:7]([C:9]1[NH:10][C:11]2[C:16]([C:17](=O)[CH:18]=1)=[CH:15][C:14]([I:20])=[CH:13][CH:12]=2)=[O:8])[CH3:2].[Cl:23]C1C2C(=CC=C(I)C=2)N=CC=1C(NCCN(CC)CC)=O>>[Cl:23][C:17]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([I:20])[CH:15]=2)[N:10]=[C:9]([C:7]([NH:6][CH2:5][CH2:4][N:3]([CH2:21][CH3:22])[CH2:1][CH3:2])=[O:8])[CH:18]=1
Reactant: CCN(CC)CCNC(=O)c1cc(=O)c2cc(I)ccc2[nH]1
Reactant: CCN(CC)CCNC(=O)c1cnc2ccc(I)cc2c1Cl
Product: CCN(CC)CCNC(=O)c1cc(Cl)c2cc(I)ccc2n1
Yield: 91 %

Procedure:
This compound was prepared, starting from compound 104 (0.34 g, 0.82 mmol), according to the procedure developed for compound 95. Reaction time at 100° C.: 15 min; the purification was performed using column chromatography (Al2O3, CH2Cl2/EtOH, 99/1, v/v) to give compound 105 (323 mg, 0.75 mmol) as a beige solid. Yield 91%; Rf (Al2O3, CH2Cl2/EtOH, 99/1, v/v) 0.42; mp 64-66° C.: IR (KBr) ν 1182, 1297, 1386, 1479, 1518, 1691, 2811, 2965, 3354 cm−1; 1H NMR (200 MHz, CDCl3) δ 1.11 (t, 6H, J=7.1 Hz), 2.66 (q, 4H, J=7.1 Hz), 2.75 (t, 2H, J=6.2 Hz), 3.60 (q, 2H, J=6.1 Hz), 7.82 (d, 1H, J=8.9 Hz), 8.03 (dd, 1H, J=1.8, 8.9 Hz), 8.36 (s, 1H), 8.56 (m, 1H), 8.64 (d, 1H, J=1.8 Hz); ESI-MS m/z 431.8 [M+H]+.
Reaction SMILES: [OH:1][CH:2]([C:7]1[C:8]([I:18])=[C:9]2[CH:16]=[CH:15][N:14]([CH3:17])[C:10]2=[N:11][C:12]=1[CH3:13])[C:3]([O:5][CH3:6])=[O:4].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[O-]S([O-])(=S)=O.[Na+].[Na+].C(OCC)(=O)C>ClCCl>[I:18][C:8]1[C:7]([C:2](=[O:1])[C:3]([O:5][CH3:6])=[O:4])=[C:12]([CH3:13])[N:11]=[C:10]2[N:14]([CH3:17])[CH:15]=[CH:16][C:9]=12
Reactant: COC(=O)C(O)c1c(C)nc2c(ccn2C)c1I
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COC(=O)C(=O)c1c(C)nc2c(ccn2C)c1I
Temperature: 25 °C
Reaction time: 18 h
Yield: 80.5 %

Procedure:
An 0° C. solution of methyl 2-hydroxy-2-(4-iodo-1,6-dimethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)acetate (12.0 g, 33.3 mmol) in dichloromethane (DCM) (120 mL) was treated with Dess-Martin periodinane (19.84 g, 46.8 mmol) in one portion and warmed to ambient temperature. After 18 h, sat. aq. Na2S2O3 was added and the reaction mixture was stirred for 20 min. Ethyl acetate was added and the layers partitioned. The organic phase was washed with sat. aq. NaHCO3, brine, dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by ISCO (0-30% EtOAc-hexanes) to afford methyl 2-(4-iodo-1,6-dimethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-oxoacetate (9.6 g, 26.8 mmol, 74.5% yield) as light yellow solid: 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.58 (s, 3H) 3.86 (s, 3H) 3.93 (s, 3H) 6.35 (d, J=3.52 Hz, 1H) 7.22 (d, 1H). LC/MS (m/z) ES+=359.9 (M+1)+
Reaction SMILES: [CH3:1][O-:2].[Na+].[CH3:4][C:5]1([CH3:22])[C@@H:7]([CH:8](Br)[C:9](=O)[CH2:10]Br)[C@H:6]1[C:14]([O:16][CH2:17][C:18]([Cl:21])([Cl:20])[Cl:19])=[O:15].[OH2:23].Cl>CO>[CH3:4][C:5]1([CH3:22])[C@@H:7](/[CH:8]=[CH:9]\[C:10]([O:2][CH3:1])=[O:23])[C@H:6]1[C:14]([O:16][CH2:17][C:18]([Cl:21])([Cl:20])[Cl:19])=[O:15]
Reactant: O
Reactant: CC1(C)[C@H](C(=O)OCC(Cl)(Cl)Cl)[C@@H]1C(Br)C(=O)CBr
Reactant: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COC(=O)/C=C\[C@H]1[C@@H](C(=O)OCC(Cl)(Cl)Cl)C1(C)C
Reaction time: 16 h

Procedure:
10 ml of methanol and 0.724 g of sodium methylate were mixed together under an inert gas atmosphere and 4 g of the product of Step A of Example 12 in 30 ml of methanol were added slowly at 0°,+5° C. The mixture was stirred for 16 hours at about +5° C. and was poured into a mixture of water and ice to which 15 ml of 2N hydrochloric acid had been added. After stirring for 15 minutes, extraction was carried out with methylene chloride. The organic phase was washed with water, dried and evaporated to dryness. The residue was chromatographed on silica, eluting with a methylene chloride - cyclohexane mixture (1-1) to obtain 0.879 g of the expected product.
Reaction SMILES: CC([O-])=O.[Na+].[Br:6][C:7]1[CH:16]=[C:15]2[C:10]([C:11](=O)[CH2:12][CH2:13][O:14]2)=[CH:9][CH:8]=1.Cl.[OH:19][NH2:20]>O.CCO>[Br:6][C:7]1[CH:16]=[C:15]2[C:10]([C:11](=[N:20][OH:19])[CH2:12][CH2:13][O:14]2)=[CH:9][CH:8]=1
Reactant: NO
Reactant: O=C1CCOc2cc(Br)ccc21
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: ON=C1CCOc2cc(Br)ccc21
Temperature: 25 °C

Procedure:
NaOAc (3.78 g, 46.2 mmol) in H2O (30 mL) was added to a soln of 7-bromo 4-chromanone (3.5 g, 15.4 mmol) and hydroxyl-amine hydrochloride (1.75 g, 23.1 mmol) in EtOH (70 ml). The reaction was heated at reflux for 2 h, cooled to room temperature, and concentrated. The residue was diluted with H2O and a precipitate was filtered to give 7-bromochroman-4-one oxime obtained as the needle like crystals 3.5 g (98%). LCMS 244 (M+2H) RT=1.7 min (Condition 2); 1H NMR (DMSO-d6) 11.37 (s, OH, 1H), 7.76-7.70 (d, 1H), 7.09-7.13 (d, 2H), 4.16-4.20 (t, 2H), 2.79-2.83 (t, 2H).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:17]=[C:18]5[C:22](=[CH:23][CH:24]=4)[N:21]([CH2:25][CH2:26][C:27]#[N:28])[CH:20]([C:29]([CH3:32])([CH3:31])[CH3:30])[CH2:19]5)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.[NH4+].[Cl-].[N-:35]=[N+:36]=[N-:37].[Na+]>CN(C=O)C>[N:28]1[NH:35][N:36]=[N:37][C:27]=1[CH2:26][CH2:25][N:21]1[C:22]2[C:18](=[CH:17][C:16]([NH:15][C:13]([C:10]3([C:8]4[CH:7]=[CH:6][C:5]5[O:1][CH2:2][O:3][C:4]=5[CH:9]=4)[CH2:12][CH2:11]3)=[O:14])=[CH:24][CH:23]=2)[CH:19]=[C:20]1[C:29]([CH3:32])([CH3:31])[CH3:30]
Reactant: CC(C)(C)C1Cc2cc(NC(=O)C3(c4ccc5c(c4)OCO5)CC3)ccc2N1CCC#N
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)c1cc2cc(NC(=O)C3(c4ccc5c(c4)OCO5)CC3)ccc2n1CCc1nn[nH]n1
Temperature: 110 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1-(benzo[d][1,3]dioxol-5-yl)-N-(2-tert-butyl-1-(2-cyano-ethyl)indolin-5-yl)cyclopropanecarboxamide (50 mg, 0.12 mmol) in anhydrous DMF (2.6 mL) was added NH4Cl (230 mg, 4.3 mmol) and NaN3 (280 mg, 4.3 mmol). The reaction mixture was stirred for 30 min at 110° C. in the microwave, filtrated, and purified by preparative HPLC. The solid residue was dissolved in CDCl3 (3 mL) and briefly (2 to 4 min) exposed to daylight, which initiated a color change (purple). After 2 h of stirring open to the atmosphere at room temperature, the solvent was removed and the residue was purified by preparative HPLC to give N-(1-(2-(2H-tetrazol-5-yl)ethyl)-2-tert-butyl-1H-indol-5-yl)-1-(benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide. MS (ESI) m/e (M+H+) 473.0.
Reaction SMILES: [C:1]([Cl:6])(=O)[C:2](Cl)=[O:3].[C:7]([N:11]1C(=O)C(O)=[C:13]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[S:12]1(=[O:25])=[O:24])([CH3:10])([CH3:9])[CH3:8].CN(C=O)C>C(Cl)Cl>[C:7]([N:11]1[C:2](=[O:3])[C:1]([Cl:6])=[C:13]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[S:12]1(=[O:25])=[O:24])([CH3:10])([CH3:8])[CH3:9]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC(C)(C)N1C(=O)C(O)=C(c2ccccc2)S1(=O)=O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)(C)N1C(=O)C(Cl)=C(c2ccccc2)S1(=O)=O
Temperature: 50 °C
Yield: 480.1 %

Procedure:
Oxalyl chloride (3.39 g, 2.71 mmol) was added dropwise to a solution of 2-tert-butyl-4-hydroxy-5-phenylisothiazol-3(2H)-one 1,1-dioxide (5 g, 17.77 mol) and DMF (15 mL) in DCM (220 mL) at 0° C. The reaction mixture was heated at 50° C. for 4 h, concentrated and the residue was diluted with EtOAc and washed with water, then brine and evaporated. The residue was purified by silica gel column chromatography, using a 98:2 mixture of petroleum ether and EtOAc as eluant. The product containing fractions were evaporated, the residue was triturated in petroleum ether and the solvent was decanted to give the title compound (3.9 g, 74%) as a solid; 1H NMR (500 MHz, CDCl3): δ 7.97-7.92 (m, 2H), 7.61-7.51 (m, 3H), 1.75 (s, 9H); 13C NMR (125 MHz, CDCl3): δ 156.5, 142.8, 132.3, 129.3, 128.8, 123.4, 63.0, 27.7.
Reaction SMILES: [Cl:1][CH2:2][C:3]1[C:4]([CH2:9][Cl:10])=[CH:5][CH:6]=[CH:7][CH:8]=1.[CH2:11]([P:13]([CH2:16][CH3:17])[CH2:14][CH3:15])[CH3:12].[Cl-].C([PH+](CC)CC)C>C1(C)C=CC=CC=1>[Cl-:1].[Cl:10][CH2:9][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[CH2:2][P+:13]([CH2:16][CH3:17])([CH2:14][CH3:15])[CH2:11][CH3:12]
Reactant: ClCc1ccccc1CCl
Reactant: CCP(CC)CC
Agent: CC[PH+](CC)CC
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: CC[P+](CC)(CC)Cc1ccccc1CCl

Procedure:
To a mixture of α,α'-dichloro-o-xylene (15.0 g, 86.0 mmol) in toluene (200 ml) was added triethylphosphine (6.3 ml, 43.0 mmol) under argon gas. The reaction mixture was stirred for several days at room temperature under argon after which time the triethylphosphonium chloride salt had crystallized out of solution. The crystals were filtered and washed with toluene (3×50 mL) and pentane (3×50 mL) and dried: 1H NMR (CDCl3) δ 1.15-1.26 (dt, 9H), 2.58-2.69 (m, 6H), 4.39-4.44 (d, 2H), 4.87 (s, 2H), 7.31-7.34 (dd, 2H), 7.43-7.46 (dd, 1H), 7.50-7.54 (m, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[N:17]=[C:16]([NH:18][C:19]3[CH:20]=[C:21]4[C:25](=[CH:26][CH:27]=3)[N:24]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[N:23]=[CH:22]4)[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[N:35]1([C:41](Cl)=[O:42])[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1.CCN(CC)CC.[Cl-]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[N:35]1([C:41]([NH:1][C:2]2[CH:3]=[C:4]([C:8]3[N:17]=[C:16]([NH:18][C:19]4[CH:20]=[C:21]5[C:25](=[CH:26][CH:27]=4)[N:24]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[N:23]=[CH:22]5)[C:15]4[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=4)[N:9]=3)[CH:5]=[CH:6][CH:7]=2)=[O:42])[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1
Reactant: O=C(Cl)N1CCOCC1
Reactant: CC(C)(C)OC(=O)n1ncc2cc(Nc3nc(-c4cccc(N)c4)nc4ccccc34)ccc21
Agent: CN(C)c1ccncc1
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)n1ncc2cc(Nc3nc(-c4cccc(NC(=O)N5CCOCC5)c4)nc4ccccc34)ccc21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a suspension of tert-butyl 5-(2-(3-aminophenyl)quinazolin-4-ylamino)-1H-indazole-1-carboxylate (100 mg, 0.22 mmol) and morpholine-4-carbonyl chloride (51 μL, 0.44 mmol,) in CH2Cl2 (2 mL) was added Et3N (61 μL, 0.44 mmol) and catalytic amount of DMAP. The reaction mixture was stirred at RT for 2 h after which 2 equivalents each of morpholine-4-carbonyl chloride and Et3N were added. After 2 h of stirring another 2 equivalents of both the chloride and Et3N were added and continued to stir at ambient temperature for 16 hours. The reaction was concentrated in vacuo and the residue was purified by flash chromatography on silica (12:1 CH2Cl2:MeOH). The product tert-butyl 5-(2-(3-(morpholine-4-carboxamido)phenyl)quinazolin-4-ylamino)-1H-indazole-1-carboxylate was isolated. (80 mg, 65%)