Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1.[O-]S([O-])(=O)=O.[Na+].[Na+].O=[CH:18][C:19]([O:21][CH2:22][CH3:23])=[O:20]>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:6](/[N:7]=[CH:18]\[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:5][CH:4]=1
Reactant: COc1ccc(N)cc1
Reactant: CCOC(=O)C=O
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCOC(=O)/C=N\c1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 29.6 %

Procedure:
To a round bottom flask was added 4-methoxyaniline (10 g, 81 mmol), toluene (100 mL) and Na2SO4 (40 gm). Then a solution of ethyl 2-oxoacetate (8.29 gm, 81 mmol) in toluene (20 mL) was slowly added to the reaction over 45 min. The reaction was stirred at rt for an additional 30 min. Then, the Na2SO4 was filtered off and the filtrate was concentrated to give (Z)-ethyl 2-(4-methoxyphenylimino)acetate (5.0 g, 24 mmol, 30% yield) as a clear oil.
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH2:6][CH2:5]1.[Cl:28][C:29]1[CH:37]=[CH:36][C:32]([C:33](O)=[O:34])=[CH:31][CH:30]=1>>[Cl:28][C:29]1[CH:37]=[CH:36][C:32]([C:33]([NH:27][C@H:24]2[CH2:25][CH2:26][C@H:21]([CH2:20][CH2:19][N:16]3[CH2:17][CH2:18][N:13]([C:9]4[N:10]=[CH:11][CH:12]=[C:7]5[CH2:6][CH2:5][O:4][C:8]=45)[CH2:14][CH2:15]3)[CH2:22][CH2:23]2)=[O:34])=[CH:31][CH:30]=1
Reactant: O=C(O)c1ccc(Cl)cc1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3OCC4)CC2)CC1
Agent: Cl
Product: O=C(N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3OCC4)CC2)CC1)c1ccc(Cl)cc1

Procedure:
The title compound, white solid (111 mg, 95%), MS (ISP) m/z=469.4 [(M+H)+], mp 251.5° C., was prepared in accordance with the general method of example 6 from trans-4-{2-[4-(2,3-dihydro-furo[2,3-c]pyridin-7-yl)-piperazin-1-yl]-ethyl}-cyclohexylamine trihydrochloride (intermediate B) (110 mg, 0.25 mmol) and 4-chloro-benzoic acid.
Reaction SMILES: C[O:2][C:3](=[O:50])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][N:11]2[CH2:17][CH2:16][CH2:15][C@H:14]([N:18]([CH2:25][C:26]3[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[C:28]([C:36]([F:39])([F:38])[F:37])[CH:27]=3)[C:19]3[N:20]=[N:21][N:22]([CH3:24])[N:23]=3)[C:13]3[CH:40]=[C:41]([CH3:49])[C:42]([C:45]([F:48])([F:47])[F:46])=[C:43]([CH3:44])[C:12]2=3)=[CH:6][CH:5]=1.[OH-].[Na+]>CO.O.Cl>[F:34][C:32]([F:33])([F:35])[C:30]1[CH:31]=[C:26]([CH:27]=[C:28]([C:36]([F:39])([F:38])[F:37])[CH:29]=1)[CH2:25][N:18]([C:19]1[N:20]=[N:21][N:22]([CH3:24])[N:23]=1)[C@H:14]1[CH2:15][CH2:16][CH2:17][N:11]([CH2:10][C:7]2[CH:8]=[CH:9][C:4]([C:3]([OH:50])=[O:2])=[CH:5][CH:6]=2)[C:12]2[C:43]([CH3:44])=[C:42]([C:45]([F:46])([F:47])[F:48])[C:41]([CH3:49])=[CH:40][C:13]1=2
Reactant: COC(=O)c1ccc(CN2CCC[C@H](N(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)c3nnn(C)n3)c3cc(C)c(C(F)(F)F)c(C)c32)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1cc2c(c(C)c1C(F)(F)F)N(Cc1ccc(C(=O)O)cc1)CCC[C@@H]2N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1nnn(C)n1
Temperature: 60 °C

Procedure:
To a solution of (S)-4-{5-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-7,9-dimethyl-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepin-1-ylmethyl}-benzoic acid methyl ester (0.1 mmol) in methanol (1 mL), add 4N sodium hydroxide (0.5 mL). Heat the mixture at 60° C. for 3 h. Dilute the cooled mixture with water and 1N HCl to bring the pH to 6-7 and extract with CH2Cl2 (3×15 mL). Combine the organic layers, dry over sodium sulfate, filter, and concentrate under reduced pressure to give a residue. Purify the residue by chromatography (elution with 5% methanol in EtOAc) to afford the title compound. MS (ES+): 701 (M+H).
Reaction SMILES: [OH:1][C:2]1[C:7]([C@@H:8]2[CH2:12][CH2:11][N:10]([CH3:13])[C@H:9]2[CH2:14][OH:15])=[C:6]([O:16][CH3:17])[CH:5]=[C:4]([O:18][CH3:19])[C:3]=1[C:20](=[O:22])[CH3:21].[Br:23][C:24]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][C:25]=1[C:26](OC)=O.[H-].[Na+]>CN(C=O)C>[Br:23][C:24]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][C:25]=1[C:26]1[O:1][C:2]2[C:3]([C:20](=[O:22])[CH:21]=1)=[C:4]([O:18][CH3:19])[CH:5]=[C:6]([O:16][CH3:17])[C:7]=2[C@@H:8]1[CH2:12][CH2:11][N:10]([CH3:13])[C@H:9]1[CH2:14][OH:15]
Reactant: COC(=O)c1cc(OC)ccc1Br
Reactant: COc1cc(OC)c([C@@H]2CCN(C)[C@H]2CO)c(O)c1C(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(Br)c(-c2cc(=O)c3c(OC)cc(OC)c([C@@H]4CCN(C)[C@H]4CO)c3o2)c1

Procedure:
Compound of example 6 (1.5 g, 4.85 mmol) in dry DMF (25 mL) was reacted with methyl 2-bromo-5-methoxybenzoate (3.11 g, 12.69 mmol) in the presence of NaH (50%, 1.16 g, 24.17 mmol) as described in example 16, to obtain the title compound.
Reaction SMILES: [C:1]([C:3]1[CH:35]=[CH:34][C:6]2[N:7]([C:12]3[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][NH:20][C:21]([NH:23][S:24]([C:27]4[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=4)(=[O:26])=[O:25])=[O:22])=[CH:14][CH:13]=3)[C:8]([CH2:10][CH3:11])=[N:9][C:5]=2[CH:4]=1)#[N:2].CS(C)=[O:38].OO.[OH-].[Na+]>O.CO>[CH2:10]([C:8]1[N:7]([C:12]2[CH:13]=[CH:14][C:15]([CH2:18][CH2:19][NH:20][C:21]([NH:23][S:24]([C:27]3[CH:28]=[CH:29][C:30]([CH3:33])=[CH:31][CH:32]=3)(=[O:25])=[O:26])=[O:22])=[CH:16][CH:17]=2)[C:6]2[CH:34]=[CH:35][C:3]([C:1]([NH2:2])=[O:38])=[CH:4][C:5]=2[N:9]=1)[CH3:11]
Reactant: CCc1nc2cc(C#N)ccc2n1-c1ccc(CCNC(=O)NS(=O)(=O)c2ccc(C)cc2)cc1
Reactant: CS(C)=O
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCc1nc2cc(C(N)=O)ccc2n1-c1ccc(CCNC(=O)NS(=O)(=O)c2ccc(C)cc2)cc1
Temperature: 50 °C
Reaction time: 4 h

Procedure:
To a mixture of 2-[4-(5-cyano-2-ethyl-1H-benzimidazol-1-yl)phenyl]ethanol (step 4 of Example 82, 200 mg, 0.68 mmol), DMSO (0.06 mL, 0.82 mmol) and methanol (10 mL) was added 30% aqueous solution of hydrogen peroxide (0.12 mL, 1.0 mmol) and 0.2 M aqueous NaOH (0.06 mL). The mixture was stirred at 50° C. for 4 h, then cooled. The mixture was poured into water (50 mL) and extracted with ethyl acetate (100 mL). The organic layer was washed with 2N aqueous NaOH (50 mL) and brine (50 mL), then dried (Na2SO4), and concentrated to afford the title compound as pale yellow solids: 1H-NMR (CDCl3) δ 8.23 (1H, d, J=1.1 Hz), 7.96 (1H, br.s), 7.76 (1H, dd, J=1.1 Hz, 8.4 Hz), 7.42-7.51 (4H, m), 7.25 (1H, br.s), 7.09 (1H, d, J=8.4 Hz), 3.70 (2H, t, J=6.6 Hz), 2.85 (2H, t, J=6.9 Hz), 2.76 (2H, q, J=7.4 Hz), 1.24 (3H, t, J=7.4 Hz).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.[F:32][C:33]1[CH:34]=[CH:35][C:36]2[O:40][N:39]=[C:38]([OH:41])[C:37]=2[CH:42]=1.[C:43]([O:47][C:48]([NH:50][CH2:51][CH2:52]O)=[O:49])([CH3:46])([CH3:45])[CH3:44]>O1CCCC1>[C:43]([O:47][C:48]([NH:50][CH2:51][CH2:52][O:41][C:38]1[C:37]2[CH:42]=[C:33]([F:32])[CH:34]=[CH:35][C:36]=2[O:40][N:39]=1)=[O:49])([CH3:46])([CH3:45])[CH3:44]
Reactant: CC(C)(C)OC(=O)NCCO
Reactant: Oc1noc2ccc(F)cc12
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCCOc1noc2ccc(F)cc12
Reaction time: 0.25 h
Yield: 60.1 %

Procedure:
To a solution of triphenylphosphine (0.87 g) in tetrahydrofuran (20 ml) was added diethyl azodicarboxylate (0.57 g) at 5° C. and the mixture was stirred at the same temperature for 15 minutes. Then 5-fluoro-3-hydroxy-1,2-benzisoxazole (0.46 g) was added and the mixture was stirred at the same temperature for 15 minutes followed by addition of N-t-butoxycarbonyl ethanolamine (0.48 g) and stirring at room temperature for 24 hours. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography with cyclohexane/ethyl acetate (9/1) as an eluent, to give the title compound (0.53 g, 60%) as a colorless powder.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:10]2[C:15]([F:16])=[CH:14][C:13]([C:17]([OH:20])([CH3:19])[CH3:18])=[CH:12][C:11]=2[F:21])=[CH:5][C:6]=1[C:7]([NH2:9])=[O:8].Br[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([C:29]2[CH2:30][CH2:31][O:32][CH2:33][CH:34]=2)[N:24]=1>>[F:16][C:15]1[CH:14]=[C:13]([C:17]([OH:20])([CH3:18])[CH3:19])[CH:12]=[C:11]([F:21])[C:10]=1[C:4]1[S:3][C:2]([NH:1][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([C:29]3[CH2:30][CH2:31][O:32][CH2:33][CH:34]=3)[N:24]=2)=[C:6]([C:7]([NH2:9])=[O:8])[CH:5]=1
Reactant: CC(C)(O)c1cc(F)c(-c2cc(C(N)=O)c(N)s2)c(F)c1
Reactant: Brc1cccc(C2=CCOCC2)n1
Product: CC(C)(O)c1cc(F)c(-c2cc(C(N)=O)c(Nc3cccc(C4=CCOCC4)n3)s2)c(F)c1

Procedure:
The title compound was prepared by using the procedure listed in Example 1 with 2-amino-5-[2,6-difluoro-4-(1-hydroxy-1-methylethyl)phenyl]thiophene-3-carboxamide (0.24 g, 0.75 mmol) and 2-bromo-6-(3,6-dihydro-2H-pyran-4-yl)pyridine (0.18 g, 0.74 mmol) as the starting materials.
Reaction SMILES: [CH2:1]([N:3]([CH:18]1[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]1)[C:4]1[C:5]([CH3:17])=[C:6]([CH:10]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:12]=1)[C:7]([OH:9])=O)[CH3:2].Cl.Cl.[NH2:27][CH2:28][C:29]1[C:30](=[O:40])[NH:31][C:32]([CH3:39])=[CH:33][C:34]=1[C:35]([F:38])([F:37])[F:36].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CS(C)=O>[CH2:1]([N:3]([CH:18]1[CH2:19][CH2:20][N:21]([CH3:24])[CH2:22][CH2:23]1)[C:4]1[C:5]([CH3:17])=[C:6]([CH:10]=[C:11]([C:13]([F:15])([F:16])[F:14])[CH:12]=1)[C:7]([NH:27][CH2:28][C:29]1[C:30](=[O:40])[NH:31][C:32]([CH3:39])=[CH:33][C:34]=1[C:35]([F:36])([F:37])[F:38])=[O:9])[CH3:2]
Reactant: Cc1cc(C(F)(F)F)c(CN)c(=O)[nH]1
Reactant: CCN(c1cc(C(F)(F)F)cc(C(=O)O)c1C)C1CCN(C)CC1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CCN(c1cc(C(F)(F)F)cc(C(=O)NCc2c(C(F)(F)F)cc(C)[nH]c2=O)c1C)C1CCN(C)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 45 %

Procedure:
To a stirred solution of 3-[ethyl(1-methylpiperidin-4-yl)amino]-2-methyl-5-(trifluoromethyl)benzoic acid (crude material, ˜0.313 mmol) and 3-(aminomethyl)-6-methyl-4-(trifluoromethyl)-1,2-dihydropyridin-2-one hydrochloride HCl salt (100 mg, 0.91 mmol) in DMSO (2.4 mL) was added PyBOP (248 mg, 1.05 mmol) and hunig base (166 ul, 2.10 mmol). The reaction mixture was stirred at rt for 16 hours. The reaction mixture was quenched with water and resulting precipitate was collected. The solid was triturated from ethylacetate/hexane. The resulting solid was purified by silica gel column chromatography (NH—SiO2 ethylacetate/MeOH=10/1+10% triethylamine). The crude compound was triturated from ethylacetate/hexane, and dried to give the titled compound as a white solid (75.0 mg, 44% yield). 1H-NMR (400 MHz, CDCl3) δppm; 7.32 (s, 1H), 7.26 (s, 1H), 6.86-6.89 (m, 1H), 6.34 (s, 1H), 4.73 (d, J=6.4 Hz, 2H), 3.08 (q, J=7.2 Hz, 2H), 2.80-2.85 (m, 2H), 2.70-2.78 (m, 1H), 2.37 (s, 3H), 2.35 (s, 3H), 2.24 (s, 3H), 1.85-1.89 (m, 2H), 1.69-1.72 (m, 4H), 0.84 (t, J=7.2 Hz, 3H); MS (ES) [M+H] 533.1, [M+Na] 555.2; HPLC 95.8% purity.
Reaction SMILES: [N:1]1([CH2:6][C:7]2[CH:12]=[CH:11][C:10]([CH:13]3[CH2:16][CH:15]([CH2:17][OH:18])[CH2:14]3)=[CH:9][CH:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[C:26]1([CH3:36])[CH:31]=[CH:30][C:29]([S:32](Cl)(=[O:34])=[O:33])=[CH:28][CH:27]=1>ClCCl.CN(C)C1C=CN=CC=1>[N:1]1([CH2:6][C:7]2[CH:12]=[CH:11][C:10]([CH:13]3[CH2:14][CH:15]([CH2:17][O:18][S:32]([C:29]4[CH:30]=[CH:31][C:26]([CH3:36])=[CH:27][CH:28]=4)(=[O:34])=[O:33])[CH2:16]3)=[CH:9][CH:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: OCC1CC(c2ccc(CN3CCCC3)cc2)C1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)OCC2CC(c3ccc(CN4CCCC4)cc3)C2)cc1
Yield: 89.2 %

Procedure:
To a stirring solution of [3-(4-pyrrolidin-1-ylmethyl-phenyl)-cyclobutyl]-methanol (0.56 g, 2.3 mmol) prepared above in 5 mL of dichlormethane was added triethyl amine (1.6 mL, 2.7 mmol) followed by 4-(dimethyl amino)pyridine (2.8 mg, 0.23 mmol) and p-toluene sulfonyl chloride (0.52 g, 2.7 mmol). After 1 hr the reaction was quenched with a saturated aqueous solution of NaHCO3. The reaction was diluted and extracted with dichloromethane. The organic layers were dried over magnesium sulfate, filtered through a fritted funnel, and concentrated under reduced pressure. Purification of this material was accomplished by flash column chromatography, using a 40 g ISCO column, eluting with a gradient of 4%, 6%, and 10% MeOH/CH2Cl2. The product containing fractions were collected and concentrate under reduced pressure to give the title compound (0.82 g, 93% yield) as a colorless oil and a mixture of cis:trans isomers.
Reaction SMILES: [C:1]([C:4]1[N:9]=[N:8][C:7]([NH:10][C@@H:11]2[CH2:16][CH2:15][O:14][CH2:13][C@@H:12]2[NH:17]C(=O)OC(C)(C)C)=[CH:6][C:5]=1[NH:25][C:26]1[CH:31]=[C:30]([CH3:32])[CH:29]=[C:28]([CH2:33][CH2:34][CH3:35])[N:27]=1)(=[O:3])[NH2:2].FC(F)(F)C(O)=O>ClCCl>[NH2:17][C@@H:12]1[C@H:11]([NH:10][C:7]2[N:8]=[N:9][C:4]([C:1]([NH2:2])=[O:3])=[C:5]([NH:25][C:26]3[CH:31]=[C:30]([CH3:32])[CH:29]=[C:28]([CH2:33][CH2:34][CH3:35])[N:27]=3)[CH:6]=2)[CH2:16][CH2:15][O:14][CH2:13]1
Reactant: CCCc1cc(C)cc(Nc2cc(N[C@@H]3CCOC[C@@H]3NC(=O)OC(C)(C)C)nnc2C(N)=O)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCc1cc(C)cc(Nc2cc(N[C@@H]3CCOC[C@@H]3N)nnc2C(N)=O)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 32.7 %

Procedure:
To a solution of tert-butyl (3R,4R)-4-(6-carbamoyl-5-(4-methyl-6-propylpyridin-2-ylamino)pyridazin-3-ylamino)tetrahydro-2H-pyran-3-ylcarbamate (27 mg, 55.6 μmol) in dichloromethane (1 mL) was added trifluoroacetic acid (127 mg, 85.7 μL, 1.11 mmol) and the mixture stirred at room temperature for 16 h. The mixture was concentrated in vacuo and then the residue was diluted with dichloromethane and 25% aqueous NH4OH. The mixture was washed with water (2×), then the organic phase was collected, concentrated in vacuo, and purified by chromatography (silica, 1 to 10% of a 99.5:0.5 methanol:NH4OH solution in dichloromethane) to give 6-((3R,4R)-3-aminotetrahydro-2H-pyran-4-ylamino)-4-(4-methyl-6-propylpyridin-2-ylamino)pyridazine-3-carboxamide (7 mg, 18.2 μmol, 33%) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.61 (s, 1H), 8.38 (s, 1H), 8.10 (s, 1H), 7.68 (s, 1H), 6.98 (d, J=5.8 Hz, 1H), 6.71 (s, 1H), 6.61 (s, 1H), 4.08 (q, J=5.5 Hz, 1H), 3.92 (d, J=9.9 Hz, 1H), 3.81 (d, J=12.2 Hz, 1H), 3.59 (d, J=11.7 Hz, 1H), 3.47 (t, J=11.8 Hz, 1H), 3.28 (s, 1H), 3.17 (d, J=5.0 Hz, 2H), 2.67 (t, J=7.8 Hz, 1H), 2.33 (s, 1H), 2.26 (s, 3H), 1.72 (m, 3H), 1.23 (s, 1H), 0.93 (t, J=7.4 Hz, 3H); MS (EI/CI) m/z: 386.2 [M+H].
Reaction SMILES: [SH:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.Cl[CH2:10][CH:11]([O:14][CH3:15])[O:12][CH3:13].O.[Cl-].[NH4+]>CN(C)C=O>[CH3:13][O:12][CH:11]([O:14][CH3:15])[CH2:10][S:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1
Reactant: COC(CCl)OC
Reactant: Oc1cccc(S)c1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(CSc1cccc(O)c1)OC
Reaction time: 3 h

Procedure:
The S-sodium salt of 3-mercaptophenol prepared in Example 7 was dissolved in dimethylformamide (25 ml) and charged under nitrogen gas into a glass reaction vessel equipped with a mechanical stirrer, thermometer and addition funnel. The solution was heated to a temperature of 45 to 50° C., and 1-chloro-2,2-dimethoxyethane (3.15 grams) was added with stirring. After the addition was completed, stirring was continued for a period of about 3 hours. After this time the reaction mixture was poured into water (150 ml), and the resulting mixture was carefully neutralized with ammonium chloride. The mixture was then extracted with chloroform and the organic phase was separated. The organic portion was washed with water and then dried with phase separation paper. The dried solution was then stripped of solvent, leaving an oil. This oil was distilled, and the fraction boiling at 138° to 144° C. at 0.04 mm of Hg pressure was collected to yield the desired product 3-(2,2-dimethoxyethylthio)phenol.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:4][CH:3]=1.[Li]CCCC.CN([CH:28]=[O:29])C.O>C1COCC1>[CH:28]([C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:4][CH:3]=1)=[O:29]
Reactant: CC(C)(C)OC(=O)Nc1ccc(Br)c2ccccc12
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)Nc1ccc(C=O)c2ccccc12
Temperature: -78 °C
Reaction time: 1 h
Yield: 87.1 %

Procedure:
To a solution of tert-butyl 4-bromonaphthalen-1-ylcarbamate (29) (3.00 g, 9.31 mmol) in THF (100 mL) at −78° C. under nitrogen was added n-BuLi (1.6M in hexane, 20.4 mL, 32.6 mmol) and the reaction mixture was stirred at −78° C. for 1 hr. Neat DMF (4.50 mL, 58.1 mmol) was added and the reaction mixture was stirred at −78° C. for 1 hr, then warmed to RT and stirred for a further 1 hr. Water (5 mL) was added and the mixture was partitioned between ethyl acetate (100 mL) and water (100 mL). The organic phase was washed with brine, dried (MgSO4) and evaporated in vacuo. The residue was triturated with isohexane to afford the title compound (30) as a beige solid (2.20 g, 87%): m/z 272 (M+H)+ (ES)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C:10](=[O:26])[C:11]2[C:16]([CH3:17])=[CH:15][C:14]([N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[CH:13][C:12]=2[O:24]C)=[CH:4][CH:3]=1.B(Br)(Br)Br.O>ClCCl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C:10](=[O:26])[C:11]2[C:16]([CH3:17])=[CH:15][C:14]([N:18]3[CH2:19][CH2:20][O:21][CH2:22][CH2:23]3)=[CH:13][C:12]=2[OH:24])=[CH:4][CH:3]=1
Reactant: COc1cc(N2CCOCC2)cc(C)c1C(=O)NCc1ccc(F)cc1
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: Cc1cc(N2CCOCC2)cc(O)c1C(=O)NCc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 37 %

Procedure:
To a solution of N-[(4-fluorophenyl)-methyl]-2-methoxy-6-methyl-4-morpholin-4-yl-benzamide (2.50 g, 6.98 mmol) in dichloromethane (70 ml) is added neat boron tribromide (0.99 ml, 10.3 mmol) at −78° C. The temperature is slowly raised to RT over a period of 30 min and stirred for 1 h at RT. The reaction mixture is poured onto cold water and extracted with dichloromethane (3×50 ml). The combined organic layers are washed with brine (30 ml), dried over sodium sulfate and evaporated to dryness. The crude material is purified by column chromatography (silica gel, 25% ethyl acetate/hexane) affording N-[(4-fluorophenyl)-methyl]-2-hydroxy-6-methyl-4-morpholin-4-yl-benzamide (0.90 g, 2.58 mmol, 37%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:14][CH2:15][NH2:16])[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH:17](=O)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(Cl)Cl>[CH2:17]([NH:16][CH2:15][CH2:14][C:8]1([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: NCCC1(c2ccc(F)cc2)CCOCC1
Reactant: O=Cc1ccccc1
Solvent: ClCCl
Product: Fc1ccc(C2(CCNCc3ccccc3)CCOCC2)cc1
Reaction time: 8 h

Procedure:
To a solution of 2-[4-(4-fluorophenyl)oxan-4-yl]ethan-1-amine (250 mg, 1.12 mmol) in anhydrous CH2Cl2 (5 ml) and NA2SO4 (159 mg, 1.12 mmol) at rt was added benzaldehyde (0.17 ml, 1.68 mmol). The reaction was stirred overnight. The reaction mixture was filtered and concentrated. The residue was dissolved in 5 ml MeOH at 0° C. and NaBH4 added in one portion (51 mg, 1.34 mmol). The reaction was stirred at 0° C. for 1 h. The solution was then quenched with H2O (10 ml), extracted with CH2Cl2 (3×20 ml), washed with brine (10 ml) and dried over NA2SO4. Purified by normal phase SiO2 chromatography (0 to 10% MeOH/CH2Cl2) to give benzyl({2-[4-(4-fluorophenyl)oxan-4-yl]ethyl})amine as a colorless oil (200 mg, 60%, m/z: 314.2 [M+H]+ observed).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8](S(C3C=CC(C)=CC=3)(=O)=O)[C:9]([C:11]3[CH2:12][CH2:13][N:14]([S:17]([CH3:20])(=[O:19])=[O:18])[CH2:15][CH:16]=3)=[CH:10][C:3]=12.[OH-].[Na+]>O1CCOCC1.O>[Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[NH:8][C:9]([C:11]3[CH2:16][CH2:15][N:14]([S:17]([CH3:20])(=[O:19])=[O:18])[CH2:13][CH:12]=3)=[CH:10][C:3]=12
Reactant: Cc1ccc(S(=O)(=O)n2c(C3=CCN(S(C)(=O)=O)CC3)cc3c(Br)ccnc32)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CS(=O)(=O)N1CC=C(c2cc3c(Br)ccnc3[nH]2)CC1
Temperature: 60 °C
Reaction time: 12 h

Procedure:
To a solution of Example 220E (6.5 g, 12.73 mmol) in 1,4-dioxane (50 mL) was added a solution of sodium hydroxide (1.528 g, 38.2 mmol) in water (5 mL) and the mixture was stirred at 60° C. for 12 hours. The mixture was concentrated and the residue was suspended in water and N,N-dimethylformamide. The mixture was filtered and the solid was washed with ethyl acetate to give the title compound. MS (CI) m/z 356 (M+H)+.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.I[C:11]1[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=1.C([O-])([O-])=O.[K+].[K+]>CN1CCCC1=O.O.[Cu]>[CH3:17][C:14]1[CH:15]=[CH:16][C:11]([N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[CH:3]=[CH:2]2)=[CH:12][CH:13]=1
Reactant: c1ccc2[nH]ccc2c1
Reactant: Cc1ccc(I)cc1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN1CCCC1=O
Product: Cc1ccc(-n2ccc3ccccc32)cc1
Temperature: 150 °C
Yield: 79.1 %

Procedure:
A mixture of 1-H-indole (58.5 mg, 0.500 mmol), 1-iodo-4-methylbenzene (0.218 g, 1.00 mmol), copper powder (32.0 mg, 0.500 mmol), and K2CO3 (0.138 g, 1.00 mmol) in 1-methyl-2-pyrrolidinone (1.00 mL) was heated at 150° C. for 12 h under argon. The resulting mixture was diluted with H2O (6 mL). The aqueous layer was extracted with CH2Cl2 (3×10 mL). The combined organic extracts were washed with brine (10 mL), dried over MgSO4, and concentrated in vacuo. The residue was purified by preparative TLC using EtOAc:hexane (1:4) to give the desired product (82.0 mg, 79.0%): 1H NMR (400 MHz, CDCl3) δ 7.67 (d, 1H, J=7.7 Hz), 7.52 (d, 1H, J=7.4 Hz), 7.38 (d, 2H, J=8.4 Hz), 7.34–7.29 (m, 3H), 7.21 (t, 1H, J=7.0 Hz), 7.15 (t, 1H, J=7.0 Hz), 6.66 (d, 1H, J=3.3 Hz), 2.43 (s, 3H); ESMS m/e: 208.0 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:11]([CH3:12])=[CH:10][C:9]([NH2:13])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[C:14]1([S:20](Cl)(=[O:22])=[O:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CN(C1C=CN=CC=1)C>[Cl:1][C:2]1[C:11]([CH3:12])=[CH:10][C:9]([NH:13][S:20]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:22])=[O:21])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Cc1cc(N)c2ncccc2c1Cl
Agent: CN(C)c1ccncc1
Product: Cc1cc(NS(=O)(=O)c2ccccc2)c2ncccc2c1Cl
Yield: 39.8 %

Procedure:
In a similar fashion using route 14 general procedure 27, 5-chloro-6-methylquinolin-8-amine (Intermediate 51) (160 mg, 0.83 mmol), benzenesulfonyl chloride (175 mg, 0.99 mmol) and DMAP (cat.) gave the title compound (110 mg, 40%) after purification by column chromatography with n-hexane/EtOAc (1:1), followed by DCM/MeOH (99:1) as the eluent.