Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1.Cl.[Cl:15][C:16]1[CH:17]=[C:18]([S:23](Cl)(=[O:25])=[O:24])[CH:19]=[CH:20][C:21]=1[Cl:22].C(N(C(C)C)CC)(C)C>ClCCl>[Cl:15][C:16]1[CH:17]=[C:18]([S:23]([N:11]2[CH2:12][CH2:13][N:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[F:1])[CH2:9][CH2:10]2)(=[O:24])=[O:25])[CH:19]=[CH:20][C:21]=1[Cl:22]
Reactant: Fc1ccccc1N1CCNCC1
Reactant: O=S(=O)(Cl)c1ccc(Cl)c(Cl)c1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=S(=O)(c1ccc(Cl)c(Cl)c1)N1CCN(c2ccccc2F)CC1
Yield: 85.8 %

Procedure:
Sulfonylation of 1-(2-fluorophenyl)piperazine.HCl (325 mg, 1.5 mmol) with 3,4-dichlorobenzene-1-sulfonyl chloride (368.3 mg, 1.5 mmol) was carried out according to a similar procedure described for step 1A using anhydrous dichloromethane (3 mL) as solvent and diisopropylethylamine (0.575 mL, 3.3 mmol) as base. 1-[(3,4-dichlorophenyl)sulfonyl]-4-(2-fluorophenyl)piperazine was obtained in 85.8% yield (501 mg) as white solid.
Reaction SMILES: [F:1][C:2]([F:37])([F:36])[C:3]1[CH:4]=[C:5]([CH:29]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:31]=1)[CH2:6][CH2:7][C:8]1[N:12]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:11](=[O:20])[N:10]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[NH2:28])[N:9]=1.[C:38]1([S:44](Cl)(=[O:46])=[O:45])[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>>[F:37][C:2]([F:1])([F:36])[C:3]1[CH:4]=[C:5]([CH:29]=[C:30]([C:32]([F:33])([F:35])[F:34])[CH:31]=1)[CH2:6][CH2:7][C:8]1[N:12]([CH2:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:11](=[O:20])[N:10]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[NH:28][S:44]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)(=[O:46])=[O:45])[N:9]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Nc1ccccc1Cn1nc(CCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)n(Cc2ccccc2)c1=O
Product: O=c1n(Cc2ccccc2NS(=O)(=O)c2ccccc2)nc(CCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1Cc1ccccc1

Procedure:
Prepared by the method analogous to that described for Example 12 using the compound of Example 3 and benzenesulfonyl chloride. The title compound was isolated as a white solid (70%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C@@H:13]([CH3:14])[C@@H:12]([CH2:15][O:16][C:17]3[CH:24]=[CH:23][C:20]([C:21]#N)=[CH:19][CH:18]=3)[O:11][C:10]2=[O:25])=[CH:5][CH:4]=1.C(O)=[O:27]>[Ni]>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C@@H:13]([CH3:14])[C@@H:12]([CH2:15][O:16][C:17]3[CH:24]=[CH:23][C:20]([CH:21]=[O:27])=[CH:19][CH:18]=3)[O:11][C:10]2=[O:25])=[CH:5][CH:4]=1
Reactant: COc1ccc(N2C(=O)O[C@H](COc3ccc(C#N)cc3)[C@@H]2C)cc1
Reactant: O=CO
Agent: [Ni]
Product: COc1ccc(N2C(=O)O[C@H](COc3ccc(C=O)cc3)[C@@H]2C)cc1
Yield: 80 %

Procedure:
To a solution of 0.88 g of Compound [82], which had been obtained in Referential Example 12, dissolved in 25 ml of 80% aqueous formic acid, 1.8 g of Raney nickel were added, followed by heating under reflux for 1.5 hours. The reaction mixture was concentrated under reduced pressure. The residue so obtained was extracted with ethyl acetate. The extract was washed with aqueous sodium bicarbonate, dried over anhydrous magnesium sulfate and then filtered. The filtrate was concentrated under reduced pressure. The residue was purified by subjecting same to chromatography on a silica gel column using gradient elution with hexane-ethyl acetate, whereby 0.71 g of the title compound was obtained (yield: 80%).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:33])[CH2:15][NH:16][C:17]2[CH:22]=[C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[Cl:29])[C:20]([Cl:30])=[CH:19][C:18]=2[O:31][CH3:32])[CH2:10][CH2:9]1)=O)(C)(C)C.Cl.CO>C(Cl)Cl>[Cl:29][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1[C:21]1[C:20]([Cl:30])=[CH:19][C:18]([O:31][CH3:32])=[C:17]([NH:16][CH2:15][C:14]([N:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)=[O:33])[CH:22]=1
Reactant: COc1cc(Cl)c(-c2ccccc2Cl)cc1NCC(=O)N1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: COc1cc(Cl)c(-c2ccccc2Cl)cc1NCC(=O)N1CCNCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of tert-butyl-4-(2-(5-(2-chlorophenyl)-4-chloro-2-methoxyphenylamino)acetyl)piperazine-1-carboxylate (150 mg, 0.304 mmol) in DCM (2 mL), a solution of HCl in MeOH (10 mL, 29 mmol) was added. The mixture was stirred at room temperature for 1 h and then concentrated in vacuo to afford the crude product which was used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:14][CH2:15][CH2:16][OH:17])=[C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.N1C=CC=CC=1.[CH3:24][S:25](Cl)(=[O:27])=[O:26]>C(Cl)Cl>[CH3:24][S:25]([O:17][CH2:16][CH2:15][CH2:14][C:3]1[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)(=[O:27])=[O:26]
Reactant: CS(=O)(=O)Cl
Reactant: OCCCc1c(Cl)cccc1-c1ccccc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CS(=O)(=O)OCCCc1c(Cl)cccc1-c1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A stirred solution of 3-(3-chloro[1,1'biphenyl]-2-yl)-1-propanol (30.0 g, 0.12 mole) and pyridine (11.9 g, 0.15 mole) in methylene chloride (300 ml) was cooled to 0°. Methanesulfonyl chloride (13.9 g, 0.12 mole) was added dropwise to the mixture. After complete addition the mixture was allowed to warm to room temperature and stir for approximately 18 hours. The reaction mixture was diluted with ice water (50 grams) and washed successively with dilute hydrochloric acid (200 ml), saturated aqueous sodium chloride (700 ml) and dilute aqueous sodium hydroxide (200 ml). The organic phase was dried over anhydrous magnesium sulfate, filtered and the filtrate evaporated under reduced pressure to yield (3-chloro[1,1'-biphenyl]-2-yl)propanyl methylsulfonate as a brown oil.
Reaction SMILES: [CH:1]1([C:10]2[O:11][CH2:12][C:13](=[O:20])[C:14]=2[C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][NH:2]1.[NH:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][N:28]=2)[C:23]([CH:30]=O)=[CH:22]1.N1CCC[C@H]1C(O)=O>C(O)C>[NH:21]1[C:29]2=[N:28][CH:27]=[CH:26][CH:25]=[C:24]2[C:23]([CH:30]=[C:12]2[O:11][C:10]([CH:1]3[C:9]4[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=4)[CH2:3][NH:2]3)=[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:13]2=[O:20])=[CH:22]1
Reactant: O=Cc1c[nH]c2ncccc12
Reactant: CCOC(=O)C1=C(C2NCc3ccccc32)OCC1=O
Agent: O=C(O)[C@@H]1CCCN1
Solvent: CCO
Product: CCOC(=O)C1=C(C2NCc3ccccc32)OC(=Cc2c[nH]c3ncccc23)C1=O
Temperature: 25 °C
Yield: 28.5 %

Procedure:
To a solution of ethyl 2-isoindolinyl-4-oxo-4,5-dihydrofuran-3-carboxylate (0.20 g, 0.70 mmol) which similarly prepared according to the procedure described in the Example 4, First step and 7-azaindole-3-carboxaldehyde (0.11 g, 0.70 mmol) in ethanol (10 mL), L-proline (0.0080 g, 0.070 mmol) was added at ambient temperature. The mixture was refluxed for 3 days. Cooled to ambient temperature, the precipitate was collected by filtration, washed with methanol then dried to afford the titled compound as solid (0.080 g, y. 27%).
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][C:10]([CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][CH:24]([NH:27][C:28]3[N:32]([CH2:33][CH2:34][O:35][CH2:36][CH3:37])[C:31]4[CH:38]=[CH:39][CH:40]=[CH:41][C:30]=4[N:29]=3)[CH2:23][CH2:22]2)([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:9]1)=O)(C)(C)C.Cl.O1CCOCC1>ClCCl>[CH2:36]([O:35][CH2:34][CH2:33][N:32]1[C:31]2[CH:38]=[CH:39][CH:40]=[CH:41][C:30]=2[N:29]=[C:28]1[NH:27][CH:24]1[CH2:25][CH2:26][N:21]([CH2:20][CH2:19][C:10]2([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:11][CH2:12][NH:8][CH2:9]2)[CH2:22][CH2:23]1)[CH3:37]
Reactant: CCOCCn1c(NC2CCN(CCC3(c4ccccc4)CCN(C(=O)OC(C)(C)C)C3)CC2)nc2ccccc21
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CCOCCn1c(NC2CCN(CCC3(c4ccccc4)CCNC3)CC2)nc2ccccc21
Reaction time: 24 h

Procedure:
Combine 1-(t-butoxycarbonyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl-amino)piperidin-1-yl)ethyl)-3-phenylpyrrolidine (10 mmol) and a solution of hydrochloric acid in dioxane (10 mL. 4 M, 40 mmol) in dichloromethane (150 mL). After 24 hours, evaporate in vacuo to give a residue. Partition the residue between with dichloromethane (300 mL) and a saturated aqueous solution of sodium bicarbonate. Separate the organic layer and extract with brine. Dry the organic layer over Na2SO4, filter, and evaporate in vacuo to give the title compound.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[C:5]2[S:10][C:9]([NH:11][CH2:12][CH2:13][OH:14])=[CH:8][C:6]=2[N:7]=1.CC1(C)C(C)(C)OB([C:29]2[CH:37]=[CH:36][CH:35]=[C:34]3[C:30]=2[CH:31]=[N:32][NH:33]3)O1>>[NH:33]1[C:34]2[C:30](=[C:29]([C:2]3[N:3]=[C:4]([N:15]4[CH2:20][CH2:19][O:18][CH2:17][CH2:16]4)[C:5]4[S:10][C:9]([NH:11][CH2:12][CH2:13][OH:14])=[CH:8][C:6]=4[N:7]=3)[CH:37]=[CH:36][CH:35]=2)[CH:31]=[N:32]1
Reactant: OCCNc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Reactant: CC1(C)OB(c2cccc3[nH]ncc23)OC1(C)C
Product: OCCNc1cc2nc(-c3cccc4[nH]ncc34)nc(N3CCOCC3)c2s1

Procedure:
2-(2-Chloro-4-morpholinothieno[3,2-d]pyrimidin-6-ylamino)ethanol (28 mg) was coupled to 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole 7 via General Procedure A. The product was purified by reverse phase HPLC to yield 21 mg of 226. MS (Q1) 397 (M)+
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:9])=[C:6]([OH:8])[CH:7]=1.C([O-])([O-])=O.[K+].[K+].[CH2:16](I)[CH3:17]>CN(C=O)C.CCOCC>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:9])=[C:6]([O:8][CH2:16][CH3:17])[CH:7]=1
Reactant: Oc1cc(Br)ccc1F
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CCOc1cc(Br)ccc1F
Temperature: 50 °C
Yield: 76.6 %

Procedure:
To a solution of 23A (4.4 g, 23 mmol) and K2CO3 (6.4 g, 46 mmol) in DMF (30 mL) was added ethyl iodide (2.49 mL, 31 mmol) at rt. The mixture was heated at 50° C. for 2.0 h. After cooling to rt, it was diluted with ether, washed with water and brine, dried over MgSO4. The crude residue was purified by flash column chromatography (EtOAc:hexanes=1:5) to give 3.86 g (77%) of 32A as viscous oil.
Reaction SMILES: [CH2:1]([C:6]1[CH:15]=[CH:14][C:9]([C:10]([NH:12][NH2:13])=[O:11])=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH2:4][CH3:5].C(N(CC)CC)C.[CH2:23]([S:25][C:26]1[CH:34]=[CH:33][CH:32]=[CH:31][C:27]=1[C:28](Cl)=[O:29])[CH3:24]>C(Cl)Cl>[CH2:23]([S:25][C:26]1[CH:34]=[CH:33][CH:32]=[CH:31][C:27]=1[C:28]([NH:13][NH:12][C:10](=[O:11])[C:9]1[CH:8]=[CH:7][C:6]([CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])=[CH:15][CH:14]=1)=[O:29])[CH3:24]
Reactant: CCSc1ccccc1C(=O)Cl
Reactant: CCCCCc1ccc(C(=O)NN)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCc1ccc(C(=O)NNC(=O)c2ccccc2SCC)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirring solution of 4-pentylbenzohydrazide (1-C) (206 mg, 1.0 mmol) and triethylamine (153 μL, 1.1 mmol) in methylene chloride (5 mL) was added a solution of 2-(ethylthio)benzoyl chloride (1-B) (210 mg, 1.0 mmol) in methylene chloride (2.0 mL). After stirring at room temperature for 18 h, the mixture was diluted with methylene chloride and washed with water, 10% NaHCO3, brine, dried (MgSO4) and evaporated in vacuo to give 2-(ethylthio)-N′-(4-pentylbenzoyl)benzohydrazide (1-D). MS m/z 371 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([C:20]2[CH:25]=[CH:24][C:23]([O:26]CC3C=CC=CC=3)=[CH:22][CH:21]=2)[CH2:15][CH2:16][CH:17]([CH3:19])[CH3:18])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>C1COCC1.CO.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([C:20]2[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=2)[CH2:15][CH2:16][CH:17]([CH3:18])[CH3:19])[CH2:10][CH2:9]1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)CCN(c1ccc(OCc2ccccc2)cc1)C1CCN(C(=O)OC(C)(C)C)CC1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)CCN(c1ccc(O)cc1)C1CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 15 h
Yield: 82 %

Procedure:
4-[(4-Benzyloxy-phenyl)-(3-methyl-butyl)-amino]-piperidine-1-carboxylic acid tert-butyl ester (9.59 g, 21.2 mmol) was dissolved in 1:1 THF/MeOH (100 mL), treated with 20% Pd/C (1.0 g), and shaken under an atmosphere of H2 (47 psi) for 15 hours. The reaction was filtered and the solution was concentrated. The crude material was chromatographed on silica gel eluting with 4:1 hexane/EtOAc to give 6.3 g (82%) of the desired product.
Reaction SMILES: C([O:4][C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C@@H:7]([CH2:8][CH2:9][C@:10]3([CH3:46])[C@@H:19]2[CH2:18][CH2:17][C@H:16]2[C@@:11]3([CH3:45])[CH2:12][CH2:13][C@@:14]3([C:30](=[O:44])[NH:31][C@H:32]4[CH2:36][C@@H:35]([CH2:37][N:38]5[CH2:43][CH2:42][O:41][CH2:40][CH2:39]5)[CH:34]=[CH:33]4)[CH2:26][CH2:25][C@@H:24]([C:27]([CH3:29])=[CH2:28])[C@@H:15]32)[C:6]1([CH3:48])[CH3:47])(=O)C.C1COCC1.[OH-].[Na+]>CO>[OH:4][C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C@@H:7]([CH2:8][CH2:9][C@:10]3([CH3:46])[C@@H:19]2[CH2:18][CH2:17][C@H:16]2[C@@:11]3([CH3:45])[CH2:12][CH2:13][C@@:14]3([C:30]([NH:31][C@H:32]4[CH2:36][C@@H:35]([CH2:37][N:38]5[CH2:39][CH2:40][O:41][CH2:42][CH2:43]5)[CH:34]=[CH:33]4)=[O:44])[CH2:26][CH2:25][C@@H:24]([C:27]([CH3:29])=[CH2:28])[C@@H:15]32)[C:6]1([CH3:48])[CH3:47]
Reactant: C=C(C)[C@@H]1CC[C@]2(C(=O)N[C@@H]3C=C[C@H](CN4CCOCC4)C3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](OC(C)=O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: C=C(C)[C@@H]1CC[C@]2(C(=O)N[C@@H]3C=C[C@H](CN4CCOCC4)C3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 25 °C
Reaction time: 6 h
Yield: 67.9 %

Procedure:
(1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-((1S,4R)-4-(morpholinomethyl)cyclopent-2-enylcarbamoyl)-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysen-9-yl acetate (Example 21, 0.22 g) in MeOH:THF (8:8 ml) and cooled the contents to 0° C. then sodium hydroxide (0.05 g in 4 ml water) was added and the contents were stirred for about 6 hours at room temperature then completion of the reaction was monitored by TLC. The reaction mixture was evaporated under reduced pressure, the residue was taken in water and extracted with DCM. The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using 5% methanol in DCM as eluent to furnish the title compound (0.14 g) as a white solid. 1H NMR (300 MHz, CDCl3): 0.88-0.96 (m, 9H); 1.25-1.39 (m, 11H); 1.43-1.88 (m, 24H); 2.21-2.47 (m, 8H); 2.86-3.10 (m, 3H); 3.15-3.72 (m, 7H); 4.60 (s, 1H); 4.74 (s, 1H); 5.52-5.55 (m, 1H); 5.69-5.70 (m, 1H); 5.72-5.91 (m, 1H); ES Mass: 620 (100%), [M+1] 621; HPLC: 96.98%.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[F:12])[NH:8][C:7](=O)[C:6]([CH3:14])=[N:5]2.O=P(Cl)(Cl)[Cl:17]>CN(C)C1C=CN=CC=1>[Cl:17][C:7]1[C:6]([CH3:14])=[N:5][C:4]2[C:9](=[CH:10][C:11]([F:12])=[C:2]([F:1])[CH:3]=2)[N:8]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1nc2cc(F)c(F)cc2[nH]c1=O
Agent: CN(C)c1ccncc1
Product: Cc1nc2cc(F)c(F)cc2nc1Cl

Procedure:
6,7-Difluoro-3-methyl-1H-quinoxalin-2-one (2 g, prepared from 4,5-difluoro-1,2-phenylene-diamine and pyruvic acid according to general procedure (A), step 1) was mixed with POCl3 (20 ml) and 4-dimethylaminopyridine (10 mol %) and the mixture was refluxed for 2 hours. The mixture was allowed to cool and poured onto ice (300 ml), filtered and washed with water to afford the title compound.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[S:8](=O)(=[O:11])([OH:10])[OH:9]>>[CH:6]1[C:1]([OH:7])=[CH:2][CH:3]=[C:4]([S:8]([OH:11])(=[O:10])=[O:9])[CH:5]=1
Reactant: O=S(=O)(O)O
Reactant: Oc1ccccc1
Product: O=S(=O)(O)c1ccc(O)cc1
Temperature: 100 °C

Procedure:
To a three-neck flask, fitted with a mechanical stirrer, thermometer, and condenser were added 94 g phenol and 98 g concentrated sulfuric acid and the mixture was stirred and heated at 100° C. for two hours under nitrogen atmosphere to form phenolsulfonic acid. To this reaction mixture were added 193 g water and 37 g calcium hydroxide and this mixture was stirred and heated at 95° C. for two hours. The reaction mixture was filtered to remove precipitated calcium sulfate to yield a 39.4% aqueous solution of the phenolsulfonic acid calcium salt. A portion of this salt solution (98 g containing 38.6 g salt), 70 g 4,4'-dihydroxydiphenylsulfone, 38.5 g of 37% aqueous formaldehyde, and 7.4 g calcium hydroxide were reacted for 15 hours at 97° C. under nitrogen atmosphere to form the substantially sulfonic acid-free, water-soluble sulfonated 4,4'-dihydroxydiphenylsulfone-formaldehyde calcium salt. This calcium salt product was diluted to 30% solids using 106 g water and the pH was adjusted to 7.6 with 3.5 g calcium hydroxide.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([C:8]([OH:10])=[O:9])=[CH:5][S:6][CH:7]=1.S(Cl)([Cl:14])(=O)=O>C(Cl)(Cl)Cl>[Cl:14][C:7]1[S:6][CH:5]=[C:4]([C:8]([OH:10])=[O:9])[C:3]=1[O:2][CH3:1]
Reactant: O=S(=O)(Cl)Cl
Reactant: COc1cscc1C(=O)O
Solvent: ClC(Cl)Cl
Product: COc1c(C(=O)O)csc1Cl

Procedure:
To 4-methoxythiophene-3-carboxylic acid (3.16 g) in chloroform (10 ml) was added freshly distilled sulphuryl chloride (1.8 ml). After the exothermic reaction had subsided the product was extracted into 2N NaOH and washed with chloroform. The aqueous solution was acidified with 2N HCl and extracted into dichloromethane, washed with water, dried over magnesium sulphate and the solvent evaporated. The product was crystallised from dichloromethane/n-hexane.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([F:10])[C:8]=1[F:9])[NH2:5].[Br:11][C:12]1[CH:13]=[CH:14][C:15]2[N:16]([CH:18]=[C:19]([C:21](OCC)=[O:22])[N:20]=2)[CH:17]=1>>[Br:11][C:12]1[CH:13]=[CH:14][C:15]2[N:16]([CH:18]=[C:19]([C:21]([NH:5][C:4]3[CH:3]=[C:2]([F:1])[C:8]([F:9])=[C:7]([F:10])[CH:6]=3)=[O:22])[N:20]=2)[CH:17]=1
Reactant: CCOC(=O)c1cn2cc(Br)ccc2n1
Reactant: Nc1cc(F)c(F)c(F)c1
Product: O=C(Nc1cc(F)c(F)c(F)c1)c1cn2cc(Br)ccc2n1

Procedure:
The title compound was prepared by using procedures analogous to those described for the synthesis of Intermediate I, using 3,4,5-trifluoroaniline and ethyl 6-bromoimidazo[1,2-a]pyridine-2-carboxylate as starting materials.
Reaction SMILES: S1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:7]=[C:8]2[C:14]([C:15]3[CH:16]=[C:17]([CH:38]=[CH:39][CH:40]=3)[CH2:18][NH:19][C:20]([C:22]3[C:23](=[O:37])[N:24]([CH2:28][C:29]4[CH:34]=[CH:33][C:32]([F:35])=[C:31]([F:36])[CH:30]=4)[CH:25]=[CH:26][CH:27]=3)=[O:21])=[CH:13][NH:12][C:9]2=[N:10][CH:11]=1.BrC1[O:43]C=CC=1.[Br-]>[Pd]>[O:43]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:7]=[C:8]2[C:14]([C:15]3[CH:16]=[C:17]([CH:38]=[CH:39][CH:40]=3)[CH2:18][NH:19][C:20]([C:22]3[C:23](=[O:37])[N:24]([CH2:28][C:29]4[CH:34]=[CH:33][C:32]([F:35])=[C:31]([F:36])[CH:30]=4)[CH:25]=[CH:26][CH:27]=3)=[O:21])=[CH:13][NH:12][C:9]2=[N:10][CH:11]=1
Reactant: O=C(NCc1cccc(-c2c[nH]c3ncc(-c4cccs4)cc23)c1)c1cccn(Cc2ccc(F)c(F)c2)c1=O
Reactant: Brc1ccco1
Agent: [Pd]
Agent: [Br-]
Product: O=C(NCc1cccc(-c2c[nH]c3ncc(-c4ccco4)cc23)c1)c1cccn(Cc2ccc(F)c(F)c2)c1=O

Procedure:
Except where indicated, 1-(3,4-Difluoro-benzyl)-2-oxo-1,2-dihydro-pyridine-3-carboxylic acid 3-(5-furan-2-yl-1H-pyrrolo[2,3-b]pyridin-3-yl)-benzylamide was synthesized as per Example 95, 1-(3,4-Difluoro-benzyl)-2-oxo-1,2-dihydro-pyridine-3-carboxylic acid 3-(5-thiophen-2-yl-1H-pyrrolo[2,3-b]pyridin-3-yl)-benzylamide using 2-Bromo-furan as bromide in the second palladium coupling, to yield the product. 1H NMR (400 MHz, CDCl3-MeOH-d4) ppm 10.237 (m, 1H) 8.813 (s, 1H) 8.594 (s, 1H) 8.510 (d, J=7.0 Hz, 1H) 7.669 (s, 1H) 7.587 (s, 1H) 7.543 (d, J=6.1 Hz, 1H) 7.508 (s, 1H) 7.490-7.391 (m, 2H) 7.346 (d, J=6.7 Hz, 1H) 7.132-7.014 (m, 2H) 6.991-6.925 (m, 1H) 6.868 (d, J=2.9 Hz, 1H) 6.495 (m, 1H) 6.440 (t, J=6.7 Hz, 1H) 5.079 (s, 2H) 4.677 (m, 2H); MS m/z=537.31 M+H.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]1=2.[N+:15]([C:18]1[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=1[C:20](Cl)=[O:21])([O-:17])=[O:16].[Al+3].[Cl-].[Cl-].[Cl-].O>ClCCl>[CH3:12][C:9]1([CH3:13])[CH2:10][CH2:11][C:2]([CH3:14])([CH3:1])[C:3]2[CH:4]=[C:5]([C:20]([C:19]3[CH:23]=[CH:24][CH:25]=[CH:26][C:18]=3[N+:15]([O-:17])=[O:16])=[O:21])[CH:6]=[CH:7][C:8]1=2
Reactant: CC1(C)CCC(C)(C)c2ccccc21
Reactant: O=C(Cl)c1ccccc1[N+](=O)[O-]
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Product: CC1(C)CCC(C)(C)c2cc(C(=O)c3ccccc3[N+](=O)[O-])ccc21
Yield: 44 %

Procedure:
5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthalene (10.0 g, 53.2 mmol) and o-nitrobenzoic acid chloride (9.4 g, 50.5 mmol) were dissolved in dichloromethane (50 ml), and the mixture was added with AlCl3 (14.3 g) portionwise and then heated under reflux for 1 hour and 30 minutes. The reaction mixture was poured into water and extracted with dichloromethane and dried, and then the solvent was evaporated to give a crude product (21.59 g). This product was purified by silica gel column chromatography (AcOEt:n-hexane=1:10) to give (5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl) carbonyl-2-nitrobenzene (Compound 37, 7.5 g, 42%). This product was further recrystallized from n-hexane.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](=[O:12])[NH:9]2)=[N:4][CH:3]=1.[H-].[Na+].[CH2:15](I)[CH:16]=[CH2:17].O>CN(C=O)C>[F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](=[O:12])[N:9]2[CH2:17][CH:16]=[CH2:15])=[N:4][CH:3]=1
Reactant: C=CCI
Reactant: O=c1ccc2ncc(F)cc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CCn1c(=O)ccc2ncc(F)cc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 63 %

Procedure:
7-Fluoro-1,5-naphthyridin-2(1H)-one (2.152 g, 13.122 mmol) was suspended in dry DMF (40 ml) under argon at 0° C., and the stirred suspension was treated with sodium hydride (1.155 g of a 60% w:w dispersion in oil, 2.2 eq.) added in portions. The suspension was allowed to warm to rt. After stirring for 30 mins at rt, the mixture was treated with allyl iodide (2.67 ml, 2.2 eq) and then stirred for a further 30 min before addition of water (100 ml). The mixture was then extracted with DCM (3×200 ml). The organic extracts were combined, dried over anhydrous magnesium sulphate, filtered and evaporated to give a residue which was purified by column chromatography on silica with a 0-10% methanol in DCM gradient to give the desired product as a light brown solid (1.683 g, 63%).