Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH:7][C:8]2[C:13]([OH:14])=[CH:12][CH:11]=[CH:10][N:9]=2)[S:5][CH:6]=1.[ClH:15].Br[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[ClH:15].[ClH:15].[CH3:1][C:2]1[N:3]=[C:4]([NH:7][C:8]2[C:13]([O:14][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)=[CH:12][CH:11]=[CH:10][N:9]=2)[S:5][CH:6]=1
Reactant: BrCc1ccccn1
Reactant: Cc1csc(Nc2ncccc2O)n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1csc(Nc2ncccc2OCc2ccccn2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 142.9 %

Procedure:
A vial was charged with 2-(4-methylthiazol-2-ylamino)pyridin-3-ol (75 mg, 0.362 mmol), 2-(bromomethyl)pyridine hydrochloride (75.4 mg, 0.362 mmol), potassium carbonate (175 mg, 1.27 mmol), and DMF (3 mL), and the reaction mixture was stirred overnight at room temperature. The reaction mixture was then poured into water and extracted with ether. The organic layer was washed with brine, dried over sodium sulfate, filtered, concentrated, and purified over silica gel (80% EtOAc in hexanes). The residue was dissolved in 1:1 CH2Cl2:MeOH, and 2M HCl in ether was added. The solution was then concentrated to afford N-(4-methylthiazol-2-yl)-3-(pyridin-2-ylmethoxy)pyridin-2-amine dihydrochloride (96 mg, 71.4% yield) as a tan solid. 1H NMR (d6-DMSO) δ 8.77 (d, 1H), 8.19 (t, 1H), 8.07 (d, 1H), 8.04 (d, 1H), 7.67 (m, 2H), 7.16 (dd, 1H), 6.87 (s, 1H), 5.53 (s, 2H), 2.33 (s, 3H). Mass spectrum (apci) m/z=299 (M+H-2HCl).
Reaction SMILES: [CH2:1]([C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([Br:17])[CH:15]=2)[NH:10][C:9]=1[CH3:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CN(C=O)C>[CH2:19]([N:10]1[C:11]2[C:16](=[CH:15][C:14]([Br:17])=[CH:13][CH:12]=2)[C:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[C:9]1[CH3:18])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: BrCc1ccccc1
Reactant: Cc1[nH]c2ccc(Br)cc2c1Cc1ccccc1
Solvent: CN(C)C=O
Product: Cc1c(Cc2ccccc2)c2cc(Br)ccc2n1Cc1ccccc1

Procedure:
The desired product was prepared using a procedure similar to step 2 of example 3. Thus, 3-benzyl-5-bromo-2-methyl-1H-indole (1.651 g, 5.5 mmol) was reacted with k-t-butoxide (0.648 g, 5.775 mmol) and benzyl bromide (0.991 g, 5.775 mmol) in DMF (20 ml) to give the product (1.842 g, 4.719 mmol, 86%) as a viscous brown oil. 1H NMR (DMSO-d6) δ 2.33 (s, 3H), 4.03 (s, 2H), 5.42 (s, 2H), 6.95 (d, J=7.3 Hz, 2H), 7.10-7.14 (m, 2H), 7.18-7.29 (m, 7H), 7.34 (d, J=8.7 Hz, 1H), 7.53 (d, J=1.8 Hz, 1H); [ESI(+)], m/z 390/392 (M+H)+.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:14])[C@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[NH2:6].Cl[C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17].C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1>[CH3:2][O:3][C:4](=[O:14])[C@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[NH:6][C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17]
Reactant: COC(=O)[C@@H](N)Cc1ccccc1
Reactant: O=C(Cl)OCc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COC(=O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1
Reaction time: 3 h
Yield: 95.8 %

Procedure:
20.0 g (92.73 mmol) of (L)-phenylalanine methyl ester hydrochloride was suspended in 93 ml of toluene, and 15.82 g (92.73 mmols) of benzyl chloroformate was added thereto. 130 ml of an aqueous solution of 1 M sodium carbonate was dropwise added thereto, while keeping it at 7° C. or lower, and stirred for 3 hours. After this was subjected to phase separation, the resulting organic layer was washed with 60 ml of 0.1 N hydrochloric acid and 60 ml of a saturated aqueous solution of sodium hydrogen carbonate, and then dried with anhydrous sodium sulfate. This was filtered and concentrated to obtain 28.75 g (96.8 wt. %, 88.81 mmol) of the above-entitled compound. The yield was 95.8%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N+:4]([O-:34])[CH:5]=[C:6]([Cl:33])[C:7]=1[CH2:8][C@@H:9]([C:18]1[CH:23]=[CH:22][C:21]([O:24][CH:25]([F:27])[F:26])=[C:20]([O:28]CC2CC2)[CH:19]=1)[O:10][C:11]([C:13]1[S:14][CH:15]=[CH:16][CH:17]=1)=[O:12].FC(F)(F)C(O)=O>C(Cl)Cl>[Cl:33][C:6]1[CH:5]=[N+:4]([O-:34])[CH:3]=[C:2]([Cl:1])[C:7]=1[CH2:8][C@@H:9]([C:18]1[CH:23]=[CH:22][C:21]([O:24][CH:25]([F:27])[F:26])=[C:20]([OH:28])[CH:19]=1)[O:10][C:11]([C:13]1[S:14][CH:15]=[CH:16][CH:17]=1)=[O:12]
Reactant: O=C(O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC2CC2)c1)c1cccs1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(O)c1)c1cccs1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 41.6 %

Procedure:
(S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(thiophene-2-carbonyloxy)ethyl)pyridine 1-oxide (180 mg, 0.339 mmol) (Compound 21), prepared as previously described in Example 5, Scheme 5, Table 3, was treated with trifluoroacetic acid (TFA) (4 mL, 51.9 mmol), and the resulting solution was stirred at room temperature for 2.5 hours. The reaction mixture was diluted with CH2Cl2 (40 mL) and washed with water (3×40 mL). The organic layer was died over Na2SO4 and evaporated to dryness. The residue was purified by chromatography on SiO2 (CH2Cl2:AcOEt=3:2) to afford (S)-3,5-dichloro-4-(2-(4-(difluoromethoxy)-3-hydroxyphenyl)-2-(thiophene-2-carbonyloxy)ethyl)pyridine 1-oxide (83) (67 mg, 0.141 mmol, 41.4% yield, MS/ESI+474.99 [MH]+)
Reaction SMILES: [CH:1]1([OH:4])[CH2:3][CH2:2]1.Cl[C:6]1[N:7]=[CH:8][C:9]([C:12]([O:14][CH3:15])=[O:13])=[N:10][CH:11]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[CH:1]1([O:4][C:6]2[N:7]=[CH:8][C:9]([C:12]([O:14][CH3:15])=[O:13])=[N:10][CH:11]=2)[CH2:3][CH2:2]1
Reactant: OC1CC1
Reactant: COC(=O)c1cnc(Cl)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cnc(OC2CC2)cn1
Temperature: 25 °C
Reaction time: 15 h
Yield: 54.3 %

Procedure:
Cyclopropanol (542 μL, 8.69 mmol) is added to a suspension of methyl 5-chloropyrazine-2-carboxylate (1.0 g, 5.79 mmol) and potassium carbonate (1.60 g, 11.59 mmol) in dimethylformamide (11.6 mL). The reaction mixture is stirred for 15 hours at room temperature then for 24 hours at 50° C. The reaction is cooled to ambient temperature, diluted with water, and extracted with ethyl acetate (3 times). The organic layers are combined, dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a brown oil. The crude product is purified by silica gel flash chromatography, eluting with ethyl acetate/hexane (0:100) to ethyl acetate/hexane (35:65) to give the title compound (610 mg, 54%). ES/MS (m/e): 195.0 (M+1).
Reaction SMILES: C([O:3][C:4](=[O:22])[C:5]1[CH:17]=[C:16]([O:18][CH:19]([CH3:21])[CH3:20])[CH:15]=[C:7]([C:8]([N:10]([CH3:14])[CH2:11][CH2:12][CH3:13])=[O:9])[CH:6]=1)C>[OH-].[Li+].C1COCC1.O>[CH:19]([O:18][C:16]1[CH:15]=[C:7]([C:8]([N:10]([CH3:14])[CH2:11][CH2:12][CH3:13])=[O:9])[CH:6]=[C:5]([CH:17]=1)[C:4]([OH:22])=[O:3])([CH3:21])[CH3:20]
Reactant: CCCN(C)C(=O)c1cc(OC(C)C)cc(C(=O)OCC)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCCN(C)C(=O)c1cc(OC(C)C)cc(C(=O)O)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 87.4 %

Procedure:
Dissolve crude 5-isopropoxy-N-methyl-N-propyl-isophthalamic acid ethyl ester (12.7 mmol) in 1 N lithium hydroxide (50 mL) and THF (50 mL). Stir at room temperature for 4 h. Dilute with water (100 mL). Wash with diethyl ether (3×30 mL), and acidify the aqueous layer with 5 N HCl to about pH=1. Extract with ethyl acetate to give the title compound (3.1 g, 87% over 2 steps).
Reaction SMILES: [OH-].[K+].C([O:5][C:6]([CH:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:15]=[C:16]3[C:21](=[C:22]([C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([O:30][C:31]([F:34])([F:33])[F:32])[CH:25]=4)[N:23]=2)[N:20]=[CH:19][CH:18]=[CH:17]3)[CH2:10][CH2:9]1)=[O:7])C.Cl>C(O)C.O>[F:34][C:31]([F:32])([F:33])[O:30][C:26]1[CH:25]=[C:24]([C:22]2[N:23]=[C:14]([CH:11]3[CH2:10][CH2:9][CH:8]([C:6]([OH:7])=[O:5])[CH2:13][CH2:12]3)[CH:15]=[C:16]3[C:21]=2[N:20]=[CH:19][CH:18]=[CH:17]3)[CH:29]=[CH:28][CH:27]=1
Reactant: CCOC(=O)C1CCC(c2cc3cccnc3c(-c3cccc(OC(F)(F)F)c3)n2)CC1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)C1CCC(c2cc3cccnc3c(-c3cccc(OC(F)(F)F)c3)n2)CC1
Temperature: 45 °C
Reaction time: 1 h
Yield: 93.5 %

Procedure:
Potassium hydroxide (2M (aq), 2.5 ml) is added to a solution of 4-[8-(3-trifluoromethoxyphenyl)-[1,7]naphthyridin-6-yl]-cyclohexanecarboxylic acid ethyl ester (250 mg, 0.56 mmol) in ethanol (10 ml) and stirred 45° C. for 1 h. The reaction mixture is diluted with water and acidified with c.HCl to pH3. The mixture is stirred for 2 h. then filtered, and the filter cake washed with water to yield the product as a white powder (218 mg). MS (AP+) 417.65
Reaction SMILES: [CH:1]1([NH:7][C:8]2[C:13]([C:14]3[CH2:18][C:17]4([CH2:23][CH2:22][CH:21]([C:24]([O-:26])=[O:25])[CH2:20][CH2:19]4)[O:16][N:15]=3)=[CH:12][N:11]=[C:10]3[N:27]([CH2:30][CH3:31])[N:28]=[CH:29][C:9]=23)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Li+]>O1CCCC1.O>[CH:1]1([NH:7][C:8]2[C:13]([C:14]3[CH2:18][C:17]4([CH2:19][CH2:20][CH:21]([C:24]([OH:26])=[O:25])[CH2:22][CH2:23]4)[O:16][N:15]=3)=[CH:12][N:11]=[C:10]3[N:27]([CH2:30][CH3:31])[N:28]=[CH:29][C:9]=23)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCn1ncc2c(NC3CCCCC3)c(C3=NOC4(CCC(C(=O)[O-])CC4)C3)cnc21
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCn1ncc2c(NC3CCCCC3)c(C3=NOC4(CCC(C(=O)O)CC4)C3)cnc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Ethyl (cis or trans) 3-[4-(cyclohexylamino)-1-ethyl-1H-pyrazolo[3,4-b]pyridin-5-yl]-1-oxa-2-azaspiro[4.5]dec-2-ene-8-carboxylate (130 mg, 0.000286 mole) (example 9) was taken in tetrahydrofuran (5 ml). Aqueous lithium hydroxide (48 mg, 0.00147 mole) in 2 ml water was added to it. The reaction mixture was stirred at room temperature overnight. The solvent was removed under reduced pressure. The mixture was acidified with 3N hydrochloric acid to about pH of 6. The extraction was done with ethyl acetate. The organic layer was washed with water and brine, dried and concentrated under reduced pressure to get crude product. The title compound was purified by preparative thin layer chromatography.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N+:8]([O-:10])=[O:9])=[N:6][CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[C:17]([C:19]([C:22]1[CH:23]=[C:24]([CH:35]=[CH:36][CH:37]=1)[C:25]([NH:27][C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([OH:34])[CH:29]=1)=[O:26])([CH3:21])[CH3:20])#[N:18].O>CN(C)C=O>[C:17]([C:19]([C:22]1[CH:23]=[C:24]([CH:35]=[CH:36][CH:37]=1)[C:25]([NH:27][C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([O:34][C:2]2[CH:7]=[N:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=2)[CH:29]=1)=[O:26])([CH3:21])[CH3:20])#[N:18]
Reactant: CC(C)(C#N)c1cccc(C(=O)Nc2cccc(O)c2)c1
Reactant: O=[N+]([O-])c1ccc(Br)cn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C#N)c1cccc(C(=O)Nc2cccc(Oc3ccc([N+](=O)[O-])nc3)c2)c1
Temperature: 25 °C
Reaction time: 28 h
Yield: 66.7 %

Procedure:
To a solution of 5-bromo-2-nitropyridine (4.56 g, 22.4 mmol) and cesium carbonate (10.9 g, 33.6 mmol) in N,N-dimethylformamide (40 mL) was added dropwise a solution of 3-(1-cyano-1-methylethyl)-N-(3-hydroxyphenyl)benzamide (6.92 g, 24.6 mmol) in N,N-dimethylformamide (20 mL) over 30 min, and the mixture was stirred at room temperature for 28 hr. Cesium carbonate (3.63 g, 11.2 mmol) was added to the reaction mixture, and the mixture was further stirred with heating at 60° C. for 15 hr. Water (200 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate-hexane mixture (1:1, 200 mL, 3×50 mL). The combined organic layer was washed with saturated brine (30 mL) and dried over anhydrous magnesium sulfate. The insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (NH silica gel, hexane/ethyl acetate=90/10→50/50), and fractions containing the desired t product were concentrated under reduced pressure to give the title compound (6.01 g, 67%) as a yellow amorphous solid.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][C:3]=1[NH:10][C:11]1[NH:15][C:14]2[CH:16]=[CH:17][C:18]([N:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)=[CH:19][C:13]=2[N:12]=1.[CH:25]1([S:28](Cl)(=[O:30])=[O:29])[CH2:27][CH2:26]1>>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH:7][S:28]([CH:25]2[CH2:27][CH2:26]2)(=[O:30])=[O:29])=[CH:4][C:3]=1[NH:10][C:11]1[NH:15][C:14]2[CH:16]=[CH:17][C:18]([N:20]3[CH2:21][CH2:22][CH2:23][CH2:24]3)=[CH:19][C:13]=2[N:12]=1
Reactant: O=S(=O)(Cl)C1CC1
Reactant: NCc1ccc(Cl)c(Nc2nc3cc(N4CCCC4)ccc3[nH]2)c1
Product: O=S(=O)(NCc1ccc(Cl)c(Nc2nc3cc(N4CCCC4)ccc3[nH]2)c1)C1CC1
Reaction time: 8 h

Procedure:
A TEA solution (0.35 M in DMF, 0.1 mL) was added to a 4-Chloro-3-[5-(pyrrolidin-1-yl)-1H-benzimidazol-2-ylamino]-benzylamine solution (0.12 M in MeCN, 0.1 mL, prepared in analogy to example 4d) followed by a cyclopropylsulfonyl chloride solution (0.12 M in MeCN, 0.1 mL). The mixture was stirred overnight and filtered through basic alumina. The solids were washed with DMF/MeOH 9:1 and the combined filtrates were concentrated to give the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10](=O)[CH3:11])=[CH:5][CH:4]=1.[OH:13][CH:14]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[CH:18]=1)[CH2:15][NH2:16].[BH4-].[Na+]>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH:10]([NH:16][CH2:15][CH:14]([OH:13])[C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[CH:18]=2)[CH3:11])=[CH:5][CH:4]=1
Reactant: NCC(O)c1cccc(Cl)c1
Reactant: COc1ccc(CC(C)=O)cc1
Agent: [BH4-]
Agent: [Na+]
Product: COc1ccc(CC(C)NCC(O)c2cccc(Cl)c2)cc1

Procedure:
1-(4-Methoxyphenyl)propan-2-one (2.9 g) and 2-hydroxy-2-(3-chlorophenyl)ethanamine (3.03 g) were condensed and subsequently reduced with sodium borohydride (3.55 g) by an analogous procedure to that described in Example 1. The crude product was recrystallised from diethyl ether-hexane to give N-[2-(4-methoxyphenyl)-1-methylethyl]-2-hydroxy-2-(3-chlorophenyl)ethanamine, mp 80°-7° C., as a 45:55 mixture of diastereoisomers.
Reaction SMILES: [P:1]([O-:18])([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[O:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH:19](=[O:22])[CH2:20][CH3:21]>C(Cl)(Cl)Cl>[OH:22][CH:19]([P:1](=[O:18])([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[O:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH2:20][CH3:21]
Reactant: CCC=O
Reactant: [O-]P(OCc1ccccc1)OCc1ccccc1
Solvent: ClC(Cl)Cl
Product: CCC(O)P(=O)(OCc1ccccc1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The general method of F. Texier-Boullet and A. Foucaud [Synthesis, 1982, 916] was employed. A mixture of dibenzyl phosphite (31.13 ml, 0.14 mole) and propionaldehyde (10.21 ml, 1 equiv.) was stirred at room temperature and basic alumina (70 g) added in one portion. After standing overnight at room temperature chloroform was added and the alumina collected and washed with chloroform. The filtrate was evaporated to dryness and the resulting clear oil chromatographed on silica gel (600 g) with gradient elution (ether--5% methanol/ether). The title compound was obtained as a clear oil which solidified on standing (27.82 g, 64%). A sample was recrystallized from ether/pentane to give a white crystalline solid, m.p. 81°-82° C.
Reaction SMILES: Cl[C:2]1[S:3][C:4]([CH:8]([F:10])[F:9])=[CH:5][C:6]=1[Cl:7].C([Li])CCC.CN(C)[CH:18]=[O:19]>O1CCCC1>[Cl:7][C:6]1[CH:5]=[C:4]([CH:8]([F:10])[F:9])[S:3][C:2]=1[CH:18]=[O:19]
Reactant: FC(F)c1cc(Cl)c(Cl)s1
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=Cc1sc(C(F)F)cc1Cl
Reaction time: 2 h

Procedure:
2.47 g of the product of Stage B were cooled to -60° C. in 20 ml of tetrahydrofuran and 9.2 ml of n-butyllithium were added. The mixture was stirred for 2 hours and 1.4 ml of dimethylformamide and 3 ml of tetrahydrofuran were added. The mixture was stirred for 30 minutes at -60° C., allowed to return to room temperature and the synthesis was continued as shown in Stage A to obtain 0.9 g of the expected product.
Reaction SMILES: C(Cl)Cl.[Br:4][C:5]1[C:6]([Cl:16])=[CH:7][C:8]([F:15])=[C:9]([S:11](Cl)(=[O:13])=[O:12])[CH:10]=1.[CH3:17][O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[NH:25][CH3:26].C(N(CC)CC)C>O>[Br:4][C:5]1[C:6]([Cl:16])=[CH:7][C:8]([F:15])=[C:9]([S:11]([N:25]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[O:18][CH3:17])[CH3:26])(=[O:13])=[O:12])[CH:10]=1
Reactant: CNc1ccccc1OC
Reactant: O=S(=O)(Cl)c1cc(Br)c(Cl)cc1F
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccccc1N(C)S(=O)(=O)c1cc(Br)c(Cl)cc1F
Reaction time: 16 h
Yield: 61.5 %

Procedure:
To a solution of DCM (36 mL) containing 5-bromo-4-chloro-2-fluoro-benzenesulfonyl chloride (5.5 g, 17.9 mmol) was added (2-methoxy-phenyl)-methyl-amine (2.6 g, 18.8 mmol) and triethylamine (7.1 mL, 53.7 mmol). The mixture was stirred for 16 hrs. 100 mL of DCM and 100 mL of water were added. The organic layer was separated, washed with water (2×50 mL) and dried over MgSO4. Concentration and purification by silica gel column chromatography eluting with hexane/ethyl acetate (9/1 to 5/1) yielded 5-bromo-4-chloro-2-fluoro-N-(2-methoxy-phenyl)-N-methyl-benzenesulfonamide as a white solid (4.5 g). MS: 408.0 (M+H)+; tR=8.83 min (method 2). NMR (CDCl3), δ, 7.925 (1H, d, J=6.9 Hz), 7.257-7.367 (3H, m), 6.959 (1H, m), 6.831 (1H, d, m), 3.490 (3H, s), 3.339 (3H, d, J=2.4 Hz).
Reaction SMILES: [OH-].[Na+].[F:3][C:4]1[CH:9]=[C:8]([I:10])[CH:7]=[CH:6][C:5]=1[NH:11][C:12]1[CH:13]=[N:14][CH:15]=[C:16]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[F:33])[C:17]=1[C:18]1[N:19]=[N:20][NH:21][C:22]=1[Si](C)(C)C>CO>[F:3][C:4]1[CH:9]=[C:8]([I:10])[CH:7]=[CH:6][C:5]=1[NH:11][C:12]1[CH:13]=[N:14][CH:15]=[C:16]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[F:33])[C:17]=1[C:18]1[N:19]=[N:20][NH:21][CH:22]=1
Reactant: C[Si](C)(C)c1[nH]nnc1-c1c(Nc2ccc(I)cc2F)cncc1-c1ccccc1F
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Fc1cc(I)ccc1Nc1cncc(-c2ccccc2F)c1-c1c[nH]nn1
Temperature: 50 °C
Reaction time: 8 h
Yield: 63.1 %

Procedure:
NaOH (50 μL, 2.0 M in H2O, 0.09 mmol) was added to a solution of (2-fluoro-4-iodo-phenyl)-[5-(2-fluoro-phenyl)-4-(5-trimethylsilanyl-1H-[1,2,3]triazol-4-yl)-pyridin-3-yl]-amine (10 mg, 0.02 mmol) in MeOH (1 mL), and stirred overnight at 50° C. The reaction was quenched with satd. NH4Cl, diluted with EtOAc, and filtered through an Extrelut column. The column was washed with EtOAc, and the filtrate was concentrated. The crude product was purified via Biotage eluting with a gradient of 0 to 75% EtOAc in hexanes to afford the desired product (6 mg, 69%) as a yellow solid. LC-MS (M+H=476, obsd.=476). 1H NMR: δ 8.51 (s, 1H), 8.19 (s, 1H), 7.62 (dd, 1H), 7.44 (m, 1H), 7.38 (m, 2H), 7.28 (m, 2H), 7.19 (t, 1H), 6.99 (s, 1H).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:8][CH2:7][C:6]2[CH:9]=[CH:10][CH:11]=[CH:12][C:5]=2[NH:4][C:3]1=[O:13].[CH:14](=O)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.FC(F)(F)C(O)=O.C([BH3-])#N.[Na+]>CO>[CH2:14]([NH:1][C@@H:2]1[CH2:8][CH2:7][C:6]2[CH:9]=[CH:10][CH:11]=[CH:12][C:5]=2[NH:4][C:3]1=[O:13])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=Cc1ccccc1
Reactant: N[C@@H]1CCc2ccccc2NC1=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: O=C1Nc2ccccc2CC[C@H]1NCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 51.3 %

Procedure:
A solution of 528 mg (3.0 mmol) of 3(R)-amino-2,3,4,5-tetrahydro-1H-1-benzazepin-2-one (Example 1, Step B) in 45 mL of absolute methanol at room temperature was treated with 4.5 g of powdered 3A molecular sieves followed by dropwise addition of a solution of 954 mg (9.0 mmol, 3 eq.) of benzaldehyde in 15 mL of methanol. The pH of the mixture was adjusted to 7 by addition of trifluoroacetic acid then stirred at room temperature for 2 hours. Sodium cyanoborohydride (18 mL of 1.0M THF solution; 18 mmol, 6 eq.) was added and the mixture stirred at room temperature for 18 hours. The mixture was filtered and the filtrate treated with 3 mL of trifluoroacetic acid with stirring for 3 hours, then all volatiles removed under vacuum and the residue dissolved in 50 mL of ethyl acetate. The ethyl acetate solution was washed with water (3×15 mL), saturated aqueous sodium bicarbonate (2×15 mL) and 15 mL of brine then dried over magnesium sulfate, filtered and solvents removed under vacuum. The residue was purified by chromatography on silica, eluting with ethyl acetate/hexane (70:30), to afford 410 mg (1.54 mmol, 51%) of the product. 1H NMR (200 MHz,CDCl3): 2.05 (m,1H), 2.5-3.0 (m,3H), 3.37 (dd;7,11 Hz;1H), 3.57 (d,12 Hz,1H), 3.90 (d,12 Hz,1H), 7.05 (d,8 Hz,1H), 7.1-7.4 (m,8H), 7.75 (br s,1H). FAB-MS: calculated for C17H18N2O 266; found 267 (M+H,75%).
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([CH:6]=[CH:7][C:8](=[O:14])[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][CH:3]=1>[PdH2]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH2:7][C:8](=[O:14])[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:15][CH:16]=1
Reactant: CCOC(=O)C(=O)C=Cc1ccc(Cl)cc1
Agent: [PdH2]
Product: CCOC(=O)C(=O)CCc1ccc(Cl)cc1
Reaction time: 2 h

Procedure:
To the ethyl p-chlorobenzalpyruvate from step B (23.6 g, 0.1 moL) was added 0.1 g of the palladium catalyst from Example 1. The reactor was pressurized to 10 psi with H2 for two hours after which time the catalyst was removed by filtration and the ethyl 4-(p-chlorophenyl)-2-ketobutanoate isolated by vacuum concentration in quantitative yield. 3H NMR (CDCl3) δ: 1.1 (t, 3H), 3.8 (m, 4H), 4.0 (q, 2H), 7.1 (s, 4H), IR (film) cm-1 : 3450w, 3075-2875s, 1750s, 1710s, 1600m, 675s.
Reaction SMILES: [CH2:1]1[C@@H:10]2[C@H:5]([CH2:6][CH2:7][C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=32)[CH2:4][NH:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[N+:21]([C:24]1[CH:32]=[CH:31][C:27]([CH2:28][CH2:29]Br)=[CH:26][CH:25]=1)([O-:23])=[O:22]>CN(C=O)C>[N+:21]([C:24]1[CH:32]=[CH:31][C:27]([CH2:28][CH2:29][N:3]2[CH2:2][CH2:1][C@@H:10]3[C@H:5]([CH2:6][CH2:7][C:8]4[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=43)[CH2:4]2)=[CH:26][CH:25]=1)([O-:23])=[O:22]
Reactant: c1ccc2c(c1)CC[C@@H]1CNCC[C@@H]21
Reactant: O=[N+]([O-])c1ccc(CCBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(CCN2CC[C@H]3c4ccccc4CC[C@@H]3C2)cc1
Yield: 37.2 %

Procedure:
Following the procedure of Example 3, step 4, 0.300 g (1.60 mmol) of crude trans-1,2,3,4,4a,5,6,10b-octahydrobenz[f]isoquinoline in 10 ml of anhydrous DMF was reacted with 0.244 g (1.77 mmol) of anhydrous potassium carbonate and 0.369 g (1.60 mmol) of 4-nitrophenethyl bromide. Chromatography on flash silica, eluting with 50-100% ethyl acetate/petroleum ether, then on a Lobar column, eluting with 50% ethyl acetate/petroleum ether, afforded 0.200 g (37%) of the title product as a white solid. The hydrochloride salt was made using ethereal hydrogen chloride. Upon evaporation of the solvent the title product hydrochloride was obtained as a white solid, m.p. 232°-233° C. (dec). NMR δ(CDCl3) 1.50 (1H, m), 1.86-1.91 (1H, m), 2.28-2.61 (5H, m), 2.86-3.06 (3H, m), 3.24-3.26 (2H, m), 3.49-3.52 (2H, m), 3.66 (1H, m), 3.85 (1H, m), 7.10-7.19 (4H, m), 7.49 (2H, d, J=8.6 Hz), 8.19 (2H, d, J=8.6 Hz). m/z (CI+, NH3) 307 (M-NO+H)+, 200 (M-CH2C6H4NO2)+, 188.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([NH:9][C:10]([C:12]2[S:13][CH:14]=[CH:15][CH:16]=2)=[O:11])[CH:6]=[CH:7][CH:8]=1)#[CH:2].Br[C:18]1[CH:19]=[N:20][CH:21]=[C:22]([CH:35]=1)[C:23]([N:25]=[S@@:26]([CH3:34])(=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24]>>[CH3:34][S@:26](=[O:33])([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[N:25][C:23](=[O:24])[C:22]1[CH:35]=[C:18]([C:2]#[C:1][C:3]2[CH:8]=[CH:7][CH:6]=[C:5]([NH:9][C:10]([C:12]3[S:13][CH:14]=[CH:15][CH:16]=3)=[O:11])[CH:4]=2)[CH:19]=[N:20][CH:21]=1
Reactant: C[S@@](=O)(=NC(=O)c1cncc(Br)c1)c1ccccc1
Reactant: C#Cc1cccc(NC(=O)c2cccs2)c1
Product: C[S@@](=O)(=NC(=O)c1cncc(C#Cc2cccc(NC(=O)c3cccs3)c2)c1)c1ccccc1
Yield: 31.2 %

Procedure:
In a manner similar to that described in Example 449, thiophene-2-carboxylic acid (3-ethynyl-phenyl)-amide (0.100 g, 0.443 mmol) and (S)-5-bromo-N-[methyl(oxo)phenyl-λ6-sulfanylidene]nicotinamide (100 mg, 0.295 mmol) were reacted to give the title compound as a solid (44 mg, 0.092 mmol, 31%).