Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:6]=[CH:7][C:8]2[O:12][C:11]([C:13]3[CH:18]=[CH:17][N:16]=[CH:15][C:14]=3F)=[N:10][C:9]=2[CH:20]=1)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:27]([OH:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>O>[CH2:27]([O:34][C:14]1[CH:15]=[N:16][CH:17]=[CH:18][C:13]=1[C:11]1[O:12][C:8]2[CH:7]=[CH:6][C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:20][C:9]=2[N:10]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: CC(C)(C)c1ccc2oc(-c3ccncc3F)nc2c1
Reactant: OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CC(C)(C)c1ccc2oc(-c3ccncc3OCc3ccccc3)nc2c1
Temperature: 100 °C

Procedure:
A mixture of 2.07 g of 5-tert-butyl-2-(3-fluoropyridin-4-yl)benzoxazole, 4.23 g of potassium carbonate and 8 ml of benzyl alcohol was stirred while heating at 100° C. for 8.5 hours. The reaction mixture was cooled to room temperature, and then water was added to the reaction mixture, followed by extraction with ethyl acetate twice. The combined organic layers were washed with a saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 2.2 g of 2-(3-benzyloxypyridin-4-yl)-5-tert-butylbenzoxazole (hereinafter, referred to as “active compound 102”).
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[NH:8][CH:9]=1)(OC)=[O:2].[NH3:18]>CO>[C:1]([C:5]1[N:6]=[C:7]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[NH:8][CH:9]=1)(=[O:2])[NH2:18]
Reactant: N
Reactant: COC(=O)c1c[nH]c(-c2ccc(OC)cc2)n1
Solvent: CO
Product: COc1ccc(-c2nc(C(N)=O)c[nH]2)cc1
Temperature: 120 °C
Yield: 64.4 %

Procedure:
A mixture of 63 (21 g, 0.09 mol), CH3OH (700 ml) and NH3 (250 g) was heated in a sealed tube at 120° C. for 24 hours. After washing out the contents, the suspension was concentrated to dryness and the residue crystallized from CH3OH to yield 12.6 g (64%) of 64.
Reaction SMILES: [C:1]1([C:7]2[CH:16]=[CH:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>C(O)(=O)C.C(OCC)(=O)C>[C:1]1([CH:7]2[CH2:16][CH2:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[NH:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(-c2ccc3ccccc3n2)cc1
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: c1ccc(C2CCc3ccccc3N2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 97.5 %

Procedure:
A solution of 2-phenylquinoline, (0.248 g, 1.21 mmol) [Aldrich, cat. #299650] in acetic acid (6.0 mL) was treated with borane-pyridine complex (0.605 mL, 5.99 mmol) and stirred at room temperature for 18 h. The reaction mixture was diluted with ethyl acetate (50 mL) and washed with 3 M sodium hydroxide solution (70 mL), water (20 mL), and brine (20 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated to give a crude oil. Purification by flash column chromatography (100% hexanes to 25% ethyl acetate/hexanes) gave the desired product (0.247 g, 98%) as a racemic mixture. LCMS calculated for C15H16N (M+H)+: m/z=210.1. found: 210.1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:22][CH:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)[C:13]([NH:15][C:16]2[CH:20]=[CH:19][N:18]([CH3:21])[N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].C(Cl)(=O)C(Cl)=O.N1[C:39]([CH3:40])=[CH:38][CH:37]=[CH:36][C:35]=1[CH3:41].C(N1C=CC(N)=N1)CC1C=CC=CC=1>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:22][CH:23]2[CH2:24][CH2:25][CH2:26][CH2:27]2)[C:13]([NH:15][C:16]2[CH:20]=[CH:19][N:18]([CH2:21][CH2:41][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9]
Reactant: Cc1cccc(C)n1
Reactant: Cn1ccc(NC(=O)[C@H](CC2CCCC2)c2ccc(S(C)(=O)=O)c(Cl)c2)n1
Agent: Nc1ccn(CCc2ccccc2)n1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)Nc2ccn(CCc3ccccc3)n2)cc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 90 %

Procedure:
To a solution containing 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid (prepared as in PCT WO 2004/052869 A1, Example 1, 100 mg, 0.30 mmol) in methylene chloride (20 mL), was then added a 2.0 M solution of oxalylchloride in methylene chloride (181 μL, 0.36 mmol) at 0° C. and allowed to stir at 25° C. for 1 h, after which time 2,6-lutidine (70 μL, 0.61 mmol) was added to the solution at 0° C. After 1 h, the crude 1-phenethyl-1H-pyrazol-3-ylamine (0.42 mmol based on theory) was added and the reaction was allowed to proceed for 16 h. The reaction solution was washed with 1.0 M aqueous hydrochloric acid solution, dried over sodium sulfate, concentrated in vacuo and purified by ISCO flash column chromatography (Teledyne Isco RediSep Flash Column 10 g; 0% methanol/methylene chloride to 10% methanol/methylene chloride) to afford 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-(1-phenethyl-1H-pyrazol-3-yl)-propionamide (135 mg, 89%) as a white solid: ESI-LRMS m/e calcd for C26H30ClN3O3S [M+] 499.2, found 500.4 [M+H+]; 1H NMR (400 MHz, CDCl3) δ ppm 1.06-1.23 (m, 2H, CH2), 1.39-1.93 (m, 8H, 4×CH2), 2.09-2.33 (m, 1H, CH), 3.05 (t, J=7.2 Hz, 2H, ArCH2), 3.26 (s, 3H, SO2CH3), 3.60 (t, J=7.6 Hz, 1H, CH), 4.16 (t, J=7.2 Hz, 2H, NCH2), 6.58 (d, J=2.2 Hz, 1H, Ar), 7.00-7.05 (m, 3H, Ar), 7.16-7.29 (m, 3H, Ar), 7.47 (dd, Jo=8.1, Jm=1.6 Hz, 1H, Ar), 7.61 (d, Jm=1.6 Hz, 1H, Ar), 8.06 (d, Jo=8.1 Hz, 1H, Ar), 8.63 (s, 1H, NH).
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]2[N:23]3[C:18]([CH:19]=[N:20][C:21](O)=[N:22]3)=[CH:17][CH:16]=2)[CH:10]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].[N:25]1([CH2:31][CH2:32][N:33]2[CH:41]=[C:40]3[C:35]([CH:36]=[C:37]([NH2:42])[CH:38]=[CH:39]3)=[N:34]2)[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1.N1(CCN2C=C3C(C=CC(N)=C3)=N2)CCOCC1>>[C:1]([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]2[N:23]3[C:18]([CH:19]=[N:20][C:21]([NH:42][C:37]4[CH:38]=[CH:39][C:40]5[C:35]([CH:36]=4)=[N:34][N:33]([CH2:32][CH2:31][N:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)[CH:41]=5)=[N:22]3)=[CH:17][CH:16]=2)[CH:10]=1)(=[O:8])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: Nc1ccc2cn(CCN3CCOCC3)nc2c1
Reactant: CC(C)(C)NS(=O)(=O)c1cccc(-c2ccc3cnc(O)nn23)c1
Agent: Nc1ccc2nn(CCN3CCOCC3)cc2c1
Product: CC(C)(C)NS(=O)(=O)c1cccc(-c2ccc3cnc(Nc4ccc5cn(CCN6CCOCC6)nc5c4)nn23)c1

Procedure:
Following the procedure of Example 1315, N-tert-butyl-3-(2-hydroxy-pyrrolo[2,1-f][1,2,4]triazin-7-yl)-benzenesulfonamide (114 mg, 0.330 mmol) was coupled in parallel fashion to 2-(2-morpholin-4-yl-ethyl)-2H-indazol-6-ylamine (57 mg, 0.23 mmol) and 2-(2-morpholin-4-yl-ethyl)-2H-indazol-5-ylamine (57 mg, 0.23 mmol). Products were purified by RP pHPLC as described in Example 1291c. Yield of TFA salt: 71 mg (62%); LC/MS: 575 (M+H); HPLC: 97% pure, RT=2.73 min; 1H NMR: (DMSO, δ) 9.68 (s, 1H), 9.08 (s, 1H), 8.73 (d, J=7.9, 1H), 8.42 (s, 1H), 8.38 (s, 1H), 8.19 (s, 1H), 7.87 (d, J=7.8, 1H), 7.77 (t, J=7.7, 1H), 7.72 (s, 1H), 7.69 (d, J=9.0, 1H), 7.36 (d, J=9.0, 1H), 7.25 (d, J=4.8, 1H), 7.04 (d, J=4.8, 1H), 4.85 (t, J=5.7, 2H), 3.85 (m, 4H), 3.80 (m, 2H), 3.30 (m, 4H), 1.13 (s, 9H).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][C:8]1([CH3:20])[O:17][C:16](=[O:18])[CH2:15][CH:14]2[CH:9]1[CH2:10][CH2:11][CH:12]([CH3:19])[CH2:13]2.Cl>CCOCC>[OH:18][CH2:16][CH2:15][CH:14]1[CH:9]([C:8]([OH:17])([CH3:7])[CH3:20])[CH2:10][CH2:11][CH:12]([CH3:19])[CH2:13]1
Reactant: CC1CCC2C(CC(=O)OC2(C)C)C1
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: CCOCC
Product: CC1CCC(C(C)(C)O)C(CCO)C1
Yield: 88.2 %

Procedure:
Into a four-mouth flask (volume: 100 ml), in which the inside was substituted by nitrogen, were supplied ether and lithium aluminum hydride (1.9 g; 51 mmol). To this mixture was added dropwise at room temperature an ether solution of 2,2,8-trimethyl-3-oxabicyclo-[4,4,0]- decan-4-one (1 g; 5.1 mmol) which had been separately prepared. The resultant mixture was allowed to react at the same temperature for 1 hour, and the reaction solution was poured into a 10% aqueous solution of hydrochloric acid for separation. The ether layer was separated, washed with brine, dried over anhydrous magnesium sulfate, and concentrated. The resultant crude product was purified by column chromatography on silica gel to give the title compound (3) (0.9 g; 4.5 mmol) (Theoretical yield: 88.2%). Analytical results on the title compound are given below.
Reaction SMILES: Cl[C:2]1[C:7]2[CH:8]=[CH:9][O:10][C:6]=2[CH:5]=[CH:4][N:3]=1.[NH:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1.O.ClCCl>C(O)C>[N:11]1([C:2]2[C:7]3[CH:8]=[CH:9][O:10][C:6]=3[CH:5]=[CH:4][N:3]=2)[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1
Reactant: Clc1nccc2occc12
Reactant: C1CNCCN1
Solvent: ClCCl
Solvent: O
Solvent: CCO
Product: c1cc2occc2c(N2CCNCC2)n1

Procedure:
A solution of 0.065 mol of 4-chlorofuro[3,2-c]pyridine and 5 equivalents of piperazine in 25 ml of ethanol is heated for 17 hours at 120° C. under an inert atmosphere. After cooling and concentration under reduced pressure, the residue obtained is stirred in the presence of 150 ml of water and 150 ml of dichloromethane. After decanting and extraction with dichloromethane, the organic phases are dried and filtered and then concentrated under reduced pressure, enabling the expected product to be isolated.
Reaction SMILES: CC(C)([O-])C.[K+].[NH:7]1[CH:11]=[CH:10][CH:9]=[N:8]1.[C:12]([O:16][C:17]([N:19]1[C:27]2[CH:26]=[C:25]([CH2:28]OS(C)(=O)=O)[N:24]=[CH:23][C:22]=2[C:21]([CH3:35])([CH3:34])[CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13].O>C1COCC1>[C:12]([O:16][C:17]([N:19]1[C:27]2[CH:26]=[C:25]([CH2:28][N:7]3[CH:11]=[CH:10][CH:9]=[N:8]3)[N:24]=[CH:23][C:22]=2[C:21]([CH3:35])([CH3:34])[CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13]
Reactant: c1cn[nH]c1
Reactant: CC(C)(C)OC(=O)N1CC(C)(C)c2cnc(COS(C)(=O)=O)cc21
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CC(C)(C)c2cnc(Cn3cccn3)cc21
Reaction time: 0.5 h
Yield: 52.1 %

Procedure:
To a solution of potassium tert-butoxide (0.090 g, 0.80 mmol) in anhydrous THF (4.0 mL) was added pyrazole (0.104 g, 1.52 mmol). The reaction was stirred for 30 min. 6-Methanesulfonyloxymethyl-3,3-dimethyl-2,3-dihydro-pyrrolo[3,2-c]pyridine-1-carboxylic acid tert-butyl ester (0.271 g, 0.76 mmol) was added at ambient temperature and the reaction was stirred for 1 h. A second equivalent of pyrazole (104 mg) was added, followed by potassium tert-butoxide (90 mg) and the reaction stirred for 1 h. Water (4.0 mL) was added and the reaction extracted with EtOAc (3×5.0 mL), washed with saturated brine solution (15 mL), dried over sodium sulfate, filtered and concentrated. Chromatography (SiO2, gradient elution, 0-100%, EtOAc/petrol then SiO2, gradient elution, 0-5%, MeOH/DCM). gave the title compound (0.13 g, 52%) as a pale yellow oil MS: [M+H]+=329.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]([CH2:7][CH:8]([OH:26])[CH:9]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[N+:17]([O-:19])=[O:18])[CH3:6])=[O:4].[H-].[Na+].O>CN(C=O)C>[N+:17]([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[O:10][CH:9]([CH:8]1[O:26][CH2:2][C:3](=[O:4])[N:5]([CH3:6])[CH2:7]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)([O-:19])=[O:18]
Reactant: CN(CC(O)C(Oc1ccccc1[N+](=O)[O-])c1ccccc1)C(=O)CCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CN1CC(C(Oc2ccccc2[N+](=O)[O-])c2ccccc2)OCC1=O
Temperature: 50 °C
Reaction time: 16 h
Yield: 80.6 %

Procedure:
To 24.7 g of N-chloroacetyl-N-methyl-2-hydroxy-3-phenyl-3-(2-nitro-phenoxy)-propylamine dissolved in 300 ml of anhydrous DMF there was added 3.5 g of 50% NaH in mineral oil. The reaction mixture was heated at 50° C. for 3 hours under stirring and then allowed to stand for 16 hours, then poured into 2 liters of water: a brown solid was separated and was filtered and purified by mixing with boiling 95% ETOH. There was obtained 18 g (Yield 80%) of 2-[α-(2-nitro-phenoxy)-benzyl]-4-methyl-morpholin-5-one, m.p. 192°-195° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1F)[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:10][CH:9]=1)=[O:6].[NH:23]1[CH2:27][CH2:26][C@@H:25]([OH:28])[CH2:24]1>CS(C)=O.CC(OC)(C)C.CCOC(C)=O>[Br:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[N:23]1[CH2:27][CH2:26][C@@H:25]([OH:28])[CH2:24]1)[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:10][CH:9]=1)=[O:6]
Reactant: O[C@@H]1CCNC1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1ccc(F)c(Br)c1
Solvent: COC(C)(C)C
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1ccc(N2CC[C@@H](O)C2)c(Br)c1
Temperature: 90 °C
Reaction time: 16 h

Procedure:
A mixture of 3-bromo-4-fluoro-N-(4-(trifluoromethoxy)phenyl)benzamide (Stage 1.2, 100 mg, 0.264 mmol), (R)-pyrrolidin-3-ol (46.1 mg, 0.529 mmol) and TEA (147 μL, 1.058 mmol) in DMSO (199 μL) was stirred at 90° C. for 16 h. The RM was diluted with TBME/EtOAc (1:1) (30 mL), washed with 0.5 M HCl (3×5 mL) and brine (5 mL) and the solvent was evaporated off under reduced pressure to give a crude product that was purified by flash chromatography (RediSep® Silica gel column, 4 g, cyclohexane/EtOAc-EtOH+0.1% NH4OH (8:2), from 30% to 80% EtOAc-EtOH+0.1% NH4OH (8:2)) to yield the title compound as an off-white solid. UPLC-MS (condition 1) tR=2.83 min, m/z=444.9/446.9 [M+H]+, m/z=443.0/445.0 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.80-1.92 (m, 1H) 1.92-2.04 (m, 1H) 3.24-3.30 (m, 1H). 3.36-3.46 (m, 1H) 3.60-3.72 (m, 1H) 3.81 (dd, J=10.51, 4.65 Hz, 1H) 4.36 (d, J=2.69 Hz, 1H) 4.97 (d, J=3.42 Hz, 1H) 6.93 (d, J=8.80 Hz, 1H) 7.34 (d, J=8.56 Hz, 2H) 7.80-7.90 (m, 3H) 8.14 (d, J=1.96 Hz, 1H) 10.19 (s, 1H).
Reaction SMILES: N[C:2]1[N:7]([NH:8][C:9]2[C:14]([CH3:15])=[CH:13][CH:12]=[CH:11][C:10]=2[CH3:16])[C:6](=[O:17])[NH:5][C:4](=[O:18])[CH:3]=1.[ClH:19].[N+]([O-])([O-])=O.[Na+]>O>[Cl:19][C:2]1[N:7]([NH:8][C:9]2[C:14]([CH3:15])=[CH:13][CH:12]=[CH:11][C:10]=2[CH3:16])[C:6](=[O:17])[NH:5][C:4](=[O:18])[CH:3]=1
Reactant: Cl
Reactant: Cc1cccc(C)c1Nn1c(N)cc(=O)[nH]c1=O
Agent: O=[N+]([O-])[O-]
Agent: [Na+]
Solvent: O
Product: Cc1cccc(C)c1Nn1c(Cl)cc(=O)[nH]c1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To 1 mole of 6-amino-1-(2,6-dimethylanilino)-2,4-pyrimidinedione dissolved in 3 moles of dilute aqueous hydrochloric acid cooled to 0°-5° in an ice bath is slowly added 1.1 mole of sodium nitrate (dissolved in water at 5°) with rapid stirring. After addition is complete, add dropwise but rapidly 1.1 mole cuprous chloride dissolved in water. Stir for 30 minutes, then heat to 50° for 1 hour. The mixture is cooled to RT and filtered to obtain 6-chloro-1-(2,6-dimethyl anilino)-2,4-pyrimidinedione.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([C:11]([O:13][CH3:14])=[O:12])[CH:10]=1)[C:5](O)=[O:6].CSC.B>O1CCCC1>[Br:1][C:2]1[CH:10]=[C:9]([CH:8]=[C:4]([CH2:5][OH:6])[CH:3]=1)[C:11]([O:13][CH3:14])=[O:12]
Reactant: COC(=O)c1cc(Br)cc(C(=O)O)c1
Agent: B
Solvent: C1CCOC1
Solvent: CSC
Product: COC(=O)c1cc(Br)cc(CO)c1
Temperature: 50 °C

Procedure:
To an ice-cold, stirred solution of 3-bromo-5-(methoxycarbonyl)benzoic acid (5.0 g, 19.3 mmol) in tetrahydrofuran (77.2 mL) is added borane dimethyl sulfide complex (10.6 mL, 2.0 M tetrahydrofuran, 21.1 mmol). The reaction mixture is heated at 50° C. for 2 h. The reaction mixture is quenched with methanol (50 mL) and concentrated under reduced pressure. Purification by flash column chromatography (silica, 50% ethyl acetate/hexanes) affords the title compound. 1H NMR (300 MHz, CDCl3) δ 8.03 (s, 1H), 7.90 (s, 1H), 7.69 (s, 1H), 4.69 (s, 1H), 3.91 (s, 3H), 2.83 (br s, 1H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:10][NH:11][C:12](=[O:14])[O-:13])[C:5]([O:8][CH3:9])=[N:6][CH:7]=1.[CH:15]([O-:17])=O.[Na+].[C]=O>CN(C)C=O.C(OCC)(=O)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH:15]([C:2]1[CH:3]=[C:4]([CH2:10][NH:11][C:12](=[O:14])[O:13][C:4]([CH3:10])([CH3:5])[CH3:3])[C:5]([O:8][CH3:9])=[N:6][CH:7]=1)=[O:17]
Reactant: O=C[O-]
Reactant: COc1ncc(Br)cc1CNC(=O)[O-]
Agent: [C]=O
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ncc(C=O)cc1CNC(=O)OC(C)(C)C
Yield: 77.6 %

Procedure:
1.009 g of N-[(5-bromo-2-methoxy-3-pyridyl)methyl]carbamate, 45 mg of dichlorobistriphenylphosphine palladium, 325 mg of sodium formate and 17 mg of triphenylphosphine were dissolved in 3 ml anhydrous N,N-dimethylformamide, followed by stirring at 110° C. for 2.5 hours in a carbon monoxide atmosphere. The reaction mixture was diluted with ethyl acetate, and the organic layer was washed with water and saturated aqueous sodium bicarbonate solution, dried over anhydrous magnesium sulfate and the solvent was evaporated. The residue was purified by silica gel column chromatography, to give 401 mg of tertiary butyl N-[(5-formyl-2-methoxy-3-pyridyl)methyl]carbamate was obtained from fractions eluted with hexane-ethyl acetate (3.5:1).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Cl:7][C:8]1[C:9]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:14]=2[N+:20]([O-:22])=[O:21])=[N:10][NH:11][CH:12]=1.[CH3:23][Si:24]([CH2:27]Cl)([CH3:26])[CH3:25]>CN(C)C=O.CCCCCCC.C(OCC)(=O)C>[CH3:23][Si:24]([CH2:27][N:11]1[CH:12]=[C:8]([Cl:7])[C:9]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:14]=2[N+:20]([O-:22])=[O:21])=[N:10]1)([CH3:26])[CH3:25]
Reactant: O=[N+]([O-])c1c(Cl)cccc1-c1n[nH]cc1Cl
Reactant: C[Si](C)(C)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Solvent: CN(C)C=O
Product: C[Si](C)(C)Cn1cc(Cl)c(-c2cccc(Cl)c2[N+](=O)[O-])n1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
0.85 g of anhydrous potassium carbonate is added to a solution of 1.30 g of 4-chloro-3-(2-nitro-3-chlorophenyl)pyrazole and 0.70 g of (trimethylsilyl)methyl chloride in 30 ml of N,N-dimethylformamide. The reaction mixture is stirred for 12 hours at room temperature and diluted with 100 ml of an ether/H2O (1/1) mixture. The ether phase is dried over MgSO4, and concentrated under reduced pressure. The residual oil is purified by liquid chromatography on a silica column (eluent: heptane/ethyl acetate [50/50]).
Reaction SMILES: [C:1]1([N:7]([CH2:9][CH2:10][CH3:11])[NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)(O)[O-].[Na+].C(O)(C)C.[S:21]([C:25]1[CH:26]=[C:27]([CH:31]=[CH:32][C:33]=1[Cl:34])[C:28](Cl)=[O:29])(=[O:24])(=[O:23])[NH2:22]>O>[CH2:9]([N:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[NH:8][C:28](=[O:29])[C:27]1[CH:31]=[CH:32][C:33]([Cl:34])=[C:25]([S:21](=[O:23])(=[O:24])[NH2:22])[CH:26]=1)[CH2:10][CH3:11]
Reactant: NS(=O)(=O)c1cc(C(=O)Cl)ccc1Cl
Reactant: CCCN(N)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Solvent: O
Product: CCCN(NC(=O)c1ccc(Cl)c(S(N)(=O)=O)c1)c1ccccc1
Temperature: 25 °C

Procedure:
A vigorously stirred mixture of 14.0 g (0.1 mol) 1-phenyl-1-n-propylhydrazine, 8.4 g (0.1 mol) sodium bicarbonate, and 100 ml isopropanol was chilled to 0°-5° C., 23 g (0.09 mol) 3-sulfamoyl-4-chlorobenzoyl chloride was added in one portion, and the reaction mixture was allowed to stir for several hours, gradually warming to room temperature. Dilution with water and refrigeration overnight yielded solid material which was collected and recrystallized from acetone/water, mp. 102° C. (d).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][CH2:9][O:10][C:11]2[CH:20]=[C:19]3[C:14]([C:15](=O)[NH:16][CH:17]=[N:18]3)=[CH:13][CH:12]=2)[CH2:3][CH2:2]1.S(Cl)([Cl:24])=O>CN(C=O)C>[Cl:24][C:15]1[C:14]2[C:19](=[CH:20][C:11]([O:10][CH2:9][CH2:8][CH2:7][N:4]3[CH2:5][CH2:6][O:1][CH2:2][CH2:3]3)=[CH:12][CH:13]=2)[N:18]=[CH:17][N:16]=1
Reactant: O=S(Cl)Cl
Reactant: O=c1[nH]cnc2cc(OCCCN3CCOCC3)ccc12
Solvent: CN(C)C=O
Product: Clc1ncnc2cc(OCCCN3CCOCC3)ccc12
Reaction time: 0.17 h
Yield: 80 %

Procedure:
A mixture of 7-(3-morpholinopropoxy)-3,4-dihydroquinazolin-4-one (500 mg, 1.7 mmol), thionyl chloride (10 ml) and DMF (0.1 ml) was heated at reflux for 2 hours. The volatiles were removed by evaporation and the residue azeotroped with toluene. The crude product was partitioned between methylene chloride (50 ml) and saturated aqueous sodium hydrogen carbonate solution (50 ml) and the mixture was stirred for 10 minutes. The organic phase was separated and the aqueous phase extracted with methylene chloride. The combined extracts were dried (MgSO4) and the solvent removed by evaporation to give 4-chloro-7-(3-morpholinopropoxy)quinazoline (425 mg, 80%).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH2:5][CH:4]([NH:8][C:9]2[CH2:13][S:12][C:11](=[O:14])[N:10]=2)[C:3]1=[O:15].[F:16][C:17]([F:38])([F:37])[C:18]1[CH:32]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:30]=[CH:29][C:19]=1[CH2:20][N:21]1[CH2:26][CH2:25][CH:24]([CH:27]=O)[CH2:23][CH2:22]1.C([O-])(=O)C.[NH2+]1CCCCC1>CC(O)C>[F:38][C:17]([F:16])([F:37])[C:18]1[CH:32]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:30]=[CH:29][C:19]=1[CH2:20][N:21]1[CH2:26][CH2:25][CH:24](/[CH:27]=[C:13]2/[C:9]([NH:8][CH:4]3[CH2:5][CH2:6][CH2:7][N:2]([CH3:1])[C:3]3=[O:15])=[N:10][C:11](=[O:14])[S:12]/2)[CH2:23][CH2:22]1
Reactant: CN1CCCC(NC2=NC(=O)SC2)C1=O
Reactant: O=CC1CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)CC1
Agent: C1CC[NH2+]CC1
Agent: CC(=O)[O-]
Solvent: CC(C)O
Product: CN1CCCC(NC2=NC(=O)S/C2=C\C2CCN(Cc3ccc(C(F)(F)F)cc3C(F)(F)F)CC2)C1=O
Temperature: 60 °C
Reaction time: 8 h
Yield: 29.8 %

Procedure:
To a solution of 1-methyl-3-[(2-oxo-2,5-dihydro-1,3-thiazol-4-yl)amino]piperidin-2-one (220 mg) and 1-[2,4-bis(trifluoromethyl)benzyl]piperidine-4-carbaldehyde (339 mg) in 2-propanol (5 mL) was added piperidinium acetate (141 mg) at room temperature. The reaction mixture was stirred at 60° C. overnight, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane) and recrystallized from ethyl acetate/heptane to give the title compound (158 mg).
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[C:7]([O:11][C:12]([N:14]1[CH2:21][CH:20]2[CH:16]([CH2:17][NH:18][CH2:19]2)[CH2:15]1)=[O:13])([CH3:10])([CH3:9])[CH3:8].[F:22][C:23]1[CH:31]=[CH:30][CH:29]=[C:28]([N:32]2[N:36]=[CH:35][CH:34]=[N:33]2)[C:24]=1[C:25](Cl)=[O:26]>C1(C)C=CC=CC=1>[C:7]([O:11][C:12]([N:14]1[CH2:15][CH:16]2[CH:20]([CH2:19][N:18]([C:25](=[O:26])[C:24]3[C:28]([N:32]4[N:33]=[CH:34][CH:35]=[N:36]4)=[CH:29][CH:30]=[CH:31][C:23]=3[F:22])[CH2:17]2)[CH2:21]1)=[O:13])([CH3:10])([CH3:8])[CH3:9]
Reactant: CC(C)(C)OC(=O)N1CC2CNCC2C1
Reactant: O=C(Cl)c1c(F)cccc1-n1nccn1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CC2CN(C(=O)c3c(F)cccc3-n3nccn3)CC2C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 76.8 %

Procedure:
In a 3-neck round bottom 100 mL flask was added toluene (8.5 mL), aqueous sodium carbonate (1.42 g in 10.7 mL water), and Intermediate 15 (0.905 mg, 4.26 mmol). The biphasic mixture was cooled to 0° C. After cooling to 0° C., 2-fluoro-6-[1,2,3]triazol-2-yl-benzoyl chloride was poured over the stirring biphasic mixture of amine and aqueous sodium carbonate. An exotherm was observed. The mixture was allowed to warm to room temperature. After 1 h, a sample of the organic layer was quenched into methanol and a small amount of acid chloride was determined to remain (observed as its methyl ester). Additional amine (˜50 mg) was added and the mixture was stirred overnight at room temperature. At the end of this period, the layers were separated and 100 mL of methanol were added to the organic layer. The organic was concentrated and purified using flash column chromatography (FCC), gradient of 5-50% of a solution of 10% MeOH, 0.1% NH4OH in DCM/DCM. The desired fractions were combined and concentrated to provide a white foamy solid (1.327 g, 76.8%). MS (ESI): mass calculated for C20H24FN5O3, 401.44, m/z found 346.2 [M+H-56]+. 1H NMR (400 MHz, CDCl3): 7.91-7.73 (m, 3H), 7.53-7.39 (m, 1H), 7.18-7.06 (m, 1H), 4.00-2.76 (m, 10H), 1.52-1.33 (m, 9H).