Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([O:5][C:6]2[C:15]([C:16]3[CH:17]=[N:18][N:19]([CH:21]4[CH2:23][CH2:22]4)[CH:20]=3)=[CH:14][CH:13]=[C:12]3[C:7]=2[CH2:8][CH2:9][C@H:10]([CH3:27])[N:11]3[C:24](=[O:26])[CH3:25])[CH2:2]1.[CH3:28][C:29]([CH3:31])=O>>[CH:21]1([N:19]2[CH:20]=[C:16]([C:15]3[C:6]([O:5][CH:3]4[CH2:2][N:1]([CH:29]([CH3:31])[CH3:28])[CH2:4]4)=[C:7]4[C:12](=[CH:13][CH:14]=3)[N:11]([C:24](=[O:26])[CH3:25])[C@@H:10]([CH3:27])[CH2:9][CH2:8]4)[CH:17]=[N:18]2)[CH2:23][CH2:22]1
Reactant: CC(=O)N1c2ccc(-c3cnn(C4CC4)c3)c(OC3CNC3)c2CC[C@@H]1C
Reactant: CC(C)=O
Product: CC(=O)N1c2ccc(-c3cnn(C4CC4)c3)c(OC3CN(C(C)C)C3)c2CC[C@@H]1C

Procedure:
(S)-1-(6-(1-cyclopropyl-1H-pyrazol-4-yl)-5-(1-isopropylazetidin-3-yloxy)-2-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone was synthesized from (S)-1-(5-(azetidin-3-yloxy)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone and acetone according to the procedure outlined above for Example 40. 1H NMR (400 MHz, CD3OD) δ ppm 0.89-1.01 (m, 6H), 1.01-1.15 (m, 7H), 1.21-1.35 (m, 1H), 2.16 (s, 3H), 2.25-2.45 (m, 3H), 2.85-2.95 (m, 1H), 3.06 (t, J=7.20 Hz, 1H), 3.15 (t, J=7.20 Hz, 1H), 3.41-3.55 (m, 2H), 3.68-3.73 (m, 1H), 4.21-4.29 (m, 1H), 4.65-4.81 (m, 1H), 7.01-7.12 (m, 1H), 7.36 (d, J=8.00 Hz, 1H), 7.81 (s, 1H), 8.03 (s, 1H). MS (ESI, pos. ion) m/z 409 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:37])[NH:10][CH2:11][C@H:12]([N:28](C(OC(C)(C)C)=O)[CH3:29])[CH2:13][O:14][C:15](=[O:27])[NH:16][C:17]1[N:18]=[CH:19][C:20]2[C:25]([CH:26]=1)=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl>CO>[CH2:1]([O:8][C:9]([NH:10][CH2:11][C@H:12]([NH:28][CH3:29])[CH2:13][O:14][C:15](=[O:27])[NH:16][C:17]1[N:18]=[CH:19][C:20]2[C:25]([CH:26]=1)=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:37])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN(C(=O)OC(C)(C)C)[C@@H](CNC(=O)OCc1ccccc1)COC(=O)Nc1cc2ccccc2cn1
Agent: Cl
Solvent: CO
Product: CN[C@@H](CNC(=O)OCc1ccccc1)COC(=O)Nc1cc2ccccc2cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.7 %

Procedure:
To a solution of [(S)-2-(tert-Butoxycarbonyl-methyl-amino)-3-(isoquinolin-3-ylcarbamoyloxy)-propyl]-carbamic acid benzyl ester (4.58 g, 9.0 mmol) in MeOH (7.5 mL) was added HCl (4 N in 1,4-dioxane, 22.5 mL, 90.0 mmol). The mixture was stirred at RT for 2 h, concentrated, and re-dissolved in EtOAc. The organic mixture was washed with sat. NaHCO3, water, and brine, dried over Na2SO4, filtered, and concentrated to give Isoquinolin-3-yl-carbamic acid (S)-3-benzyloxycarbonylamino-2-methylamino-propyl ester (3.59 g), which was used without further purification. LRMS (M+H+) m/z 409.2.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([NH:9][CH:10]1[C:36](=[O:37])[N:12]2[CH:13]([C:20]([O:22][CH:23]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[O:21])[C:14]([CH:17]([OH:19])[CH3:18])=[CH:15][S:16][C@H:11]12)=[O:8].N1C=CC=CC=1.[C:44](OC(=O)C)(=[O:46])[CH3:45]>C(Cl)Cl>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([NH:9][CH:10]1[C:36](=[O:37])[N:12]2[CH:13]([C:20]([O:22][CH:23]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[O:21])[C:14]([CH:17]([O:19][C:44](=[O:46])[CH3:45])[CH3:18])=[CH:15][S:16][C@H:11]12)=[O:8]
Reactant: CC(O)C1=CS[C@@H]2C(NC(=O)Cc3cccs3)C(=O)N2C1C(=O)OC(c1ccccc1)c1ccccc1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)OC(C)C1=CS[C@@H]2C(NC(=O)Cc3cccs3)C(=O)N2C1C(=O)OC(c1ccccc1)c1ccccc1
Yield: 99 %

Procedure:
A solution of 0.535 g. of benzhydryl 7-(2-thienylacetamido)-3-(1-hydroxyethyl)-2-cephem-4-carboxylate, 6 ml. of pyridine, and 2 ml. of acetic anhydride in 30 ml. of methylene chloride was refluxed at 42° C. for 2 hours. The reaction mixture was then evaporated in vacuo to dryness, and the resulting residue was dissolved in ethyl acetate and washed with 1N.HCl and brine, and dried over anhydrous sodium sulfate. Evaporation in vacuo of the dried solution to dryness provided 0.571 g. (99 percent) of the title product as a white froth. The product was identical to that prepared above via the reaction of ketene with the cephem carbinol.
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[C:5]([CH:15]([S:24]([C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=2)(=[O:26])=[O:25])[C:16]2[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=2[F:23])=[CH:6][C:7]([NH:10][CH2:11][CH2:12][CH2:13][NH2:14])=[N:8][CH:9]=1.C(N(CC)CC)C.[C:41](N1C=CN=C1)(N1C=CN=C1)=[O:42].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C.O.C(Cl)Cl>[Cl:3][C:4]1[C:5]([CH:15]([S:24]([C:27]2[CH:28]=[CH:29][C:30]([Cl:33])=[CH:31][CH:32]=2)(=[O:25])=[O:26])[C:16]2[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=2[F:23])=[CH:6][C:7]([N:10]2[CH2:11][CH2:12][CH2:13][NH:14][C:41]2=[O:42])=[N:8][CH:9]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: NCCCNc1cc(C(c2cc(F)ccc2F)S(=O)(=O)c2ccc(Cl)cc2)c(Cl)cn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C1NCCCN1c1cc(C(c2cc(F)ccc2F)S(=O)(=O)c2ccc(Cl)cc2)c(Cl)cn1
Temperature: 50 °C
Reaction time: 17 h
Yield: 32.2 %

Procedure:
To a methylene chloride solution (5.0 ml) of the N-[5-chloro-4-[(4-chlorophenylsulfonyl)-(2,5-difluorophenyl)methyl]pyridin-2-yl]propane-1,3-diamine dihydrochloride (51 mg, 0.091 mmol) obtained in Example 173 were added triethylamine (51 μl, 0.36 mmol) and 1,1′-carbonyldiimidazole (16.2 mg, 0.10 mmol). The resulting mixture was stirred for 17 hours. To the reaction mixture was added ethyl acetate (80 ml). The resulting mixture was washed with water and brine, dried and concentrated under reduced pressure. The residue thus obtained was dissolved in dimethylformamide (1.0 ml). To the resulting solution was added potassium carbonate (27.2 mg, 0.2 mol), followed by stirring under heat at 50° C. for 24 hours. After cooling to room temperature, water was added to the reaction mixture. The resulting mixture was diluted with ethyl acetate (60 ml). The organic layer obtained by separation was washed with brine, dried and concentrated under reduced pressure. The residue thus obtained was purified by silica gel chromatography (hexane:ethyl acetate=1:2) to give the title compound (15 mg, 99%) as a white solid.
Reaction SMILES: [CH3:1][N:2]([CH3:17])[C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][CH:7]=[C:8]2[S:13](Cl)(=[O:15])=[O:14].[NH2:18][C:19]1[C:24]([O:25][CH3:26])=[N:23][C:22]([Br:27])=[CH:21][N:20]=1>N1C=CC=CC=1>[CH3:1][N:2]([CH3:17])[C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][CH:7]=[C:8]2[S:13]([NH:18][C:19]1[C:24]([O:25][CH3:26])=[N:23][C:22]([Br:27])=[CH:21][N:20]=1)(=[O:15])=[O:14]
Reactant: COc1nc(Br)cnc1N
Reactant: CN(C)c1cccc2c(S(=O)(=O)Cl)cccc12
Solvent: c1ccncc1
Product: COc1nc(Br)cnc1NS(=O)(=O)c1cccc2c(N(C)C)cccc12
Temperature: 80 °C
Reaction time: 1 h
Yield: 23.1 %

Procedure:
5-Dimethylamino-1-naphthalenesulphonyl chloride (15.2 g) and 2-amino-5-bromo-3-methoxypyrazine (obtained as described in Gazz. Chim. Ital. 1960, 90, 1807) (9.5 g) were mixed intimately in a mortar and pestle and added to pyridine (150 ml) at 0° C. The solution was kept at 0° C. for 1 hour and then heated at 80° C. for 18 hours. Volatile material was removed by evaporation and dichloromethane (250 ml) was added to the residue. Insoluble material was removed by filtration and the filtrate was washed with water (100 ml) and saturated sodium chloride solution (100 ml). The solution was treated with charcoal and dried (MgSO4). The solvent was removed by evaporation and the residue was purified by flash chromatography, eluting with ethyl acetate/hexane (1:4 v/v). The resulting solid was triturated with ether and recrystallised from ethanol to give 5-dimethylamino-N-(5-bromo-3-methoxy-2-pyrazinyl)-1-naphthalenesulphonamide (4.7 g), m.p. 166-167° C.; 1H NMR (d6 -DMSO): 2.8 (s,6H), 3.9 (s,3H), 7.2 (d,1H), 7.55-7.7 (d,2H), 7.8 (s,1H), 8.3 (d,1H), 8.4-8.5 (m,2H), 11.5 (s,1H); mass spectrum (+ve CI): 437 (M+H)+.
Reaction SMILES: [C:1]1([SH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[K+].[Cl:10][C:11]1[CH:12]=[CH:13][C:14]2[S:18][C:17](=[O:19])[N:16]([CH2:20][C:21](Cl)=[O:22])[C:15]=2[CH:24]=1>CC(C)=O>[Cl:10][C:11]1[CH:12]=[CH:13][C:14]2[S:18][C:17](=[O:19])[N:16]([CH2:20][C:21](=[O:22])[S:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[C:15]=2[CH:24]=1
Reactant: Sc1ccccc1
Reactant: O=C(Cl)Cn1c(=O)sc2ccc(Cl)cc21
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)=O
Product: O=C(Cn1c(=O)sc2ccc(Cl)cc21)Sc1ccccc1

Procedure:
A charge containing 0.1 moles of benzenethiol, 0.1 moles of 85% potassium hydroxide and 250 ml of acetone is stirred as in Example 1. To this mixture, 0.1 moles of 5-chloro-2-oxo-3-benzothiazolineacetyl chloride is added in one portion. The remaining steps of Example 1 are then followed. Analytical data is summarized in Table I, below.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]2[N:8]([C:9]=1[S:10]([NH2:13])(=[O:12])=[O:11])[CH2:7][CH2:6][S:5]2.[OH:14]O>C(O)(=O)C>[Cl:1][C:2]1[N:3]=[C:4]2[N:8]([C:9]=1[S:10]([NH2:13])(=[O:11])=[O:12])[CH2:7][CH2:6][S:5]2=[O:14]
Reactant: OO
Reactant: NS(=O)(=O)c1c(Cl)nc2n1CCS2
Solvent: CC(=O)O
Product: NS(=O)(=O)c1c(Cl)nc2n1CCS2=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 79.7 %

Procedure:
To a suspension of 2.0 g of 6-chloro-2,3-dihydroimidazo[2,1-b]thiazole-5-sulfonamide in 20 ml of acetic acid is add 2.2 g of 30% aqueous hydrogen peroxide, followed by stirring for 30 minutes at room temperature and further for 4 hours at 35°-45° C. Stirring is further maintained for 8 hours at room temperature, and the precipitated crystals are collected by filtration, washed with water and then dried to give 1.7 g of the title compound as colorless crystals. mp. 215°-217° C. (decomp.)
Reaction SMILES: FC(F)(F)S([O:6][Si:7]([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8])(=O)=O.[F:16][C:17]1[CH:18]=[C:19]([C:23]2[N:24]([CH2:36][CH:37]([CH2:42]O)[CH2:38][C:39]([O-:41])=[O:40])[CH:25]=[C:26]3[C:31]=2[C:30](=[O:32])[N:29]([CH3:33])[C:28](=[O:34])[N:27]3[CH3:35])[CH:20]=[CH:21][CH:22]=1.[Na+].N1C(C)=CC=CC=1C.Cl.N1C=CC=CC=1>C(Cl)Cl.O>[Si:7]([O:6][CH2:42][CH:37]([CH2:36][N:24]1[C:23]([C:19]2[CH:20]=[CH:21][CH:22]=[C:17]([F:16])[CH:18]=2)=[C:31]2[C:26]([N:27]([CH3:35])[C:28](=[O:34])[N:29]([CH3:33])[C:30]2=[O:32])=[CH:25]1)[CH2:38][C:39]([OH:41])=[O:40])([C:10]([CH3:11])([CH3:12])[CH3:13])([CH3:8])[CH3:9]
Reactant: Cn1c(=O)c2c(-c3cccc(F)c3)n(CC(CO)CC(=O)[O-])cc2n(C)c1=O
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Agent: Cl
Agent: [Na+]
Solvent: Cc1cccc(C)n1
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cn1c(=O)c2c(-c3cccc(F)c3)n(CC(CO[Si](C)(C)C(C)(C)C)CC(=O)O)cc2n(C)c1=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of tert-butyldimethylsilyl trifluoromethanesulfonate (3.37 mL, 14.7 mmol) in DCM (5 mL) was added dropwise to a suspension of sodium 4-(5-(3-fluorophenyl)-1,3-dimethyl-2,4-dioxo-3,4-dihydro-1H-pyrrolo[3,4-d]pyrimidin-6(2H)-yl)-3-(hydroxymethyl)butanoate (1.51 g, 3.7 mmol) and 2,6-lutidine (2.57 mL, 22.0 mmol) in DCM (20 mL) at 0° C. The mixture was stirred at room temperature for 3 hours. Further portions of 2,6-lutidine (641 μL, 5.5 mmol) and tert-butyldimethylsilyl trifluoromethanesulfonate (843 μL, 3.7 mmol) were added and the mixture stirred for a further 2 hours. The reaction was diluted with DCM (50 mL), washed with water (2×25 mL) and 1M HCl(aq) (1×25 mL), the organic phase was dried over magnesium sulfate and evaporated under vacuum. The residue was suspended in methanol (25 mL) and pyridine hydrochloride (424 mg, 3.7 mmol) and water (2.5 mL) were added. The mixture was stirred at room temperature for 2 hours then concentrated under vacuum. The residue was dissolved in DCM (50 mL) and washed with 1M HCl (aq) (2×25 mL) and brine (1×25 mL). The organic phase was dried over magnesium sulfate and evaporated under vacuum. Trituration with diethyl ether afforded the title compound.
Reaction SMILES: [CH:1]([C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][CH:4]=1)=O.Cl.[C:12]([Si:16]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[O:17][C:18]1([CH3:22])[CH2:21][NH:20][CH2:19]1)([CH3:15])([CH3:14])[CH3:13].CO.CN(C=O)C.C([BH3-])#N.[Na+]>C(O)(=O)C>[C:12]([Si:16]([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)([C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)[O:17][C:18]1([CH3:22])[CH2:19][N:20]([CH2:1][C:3]2[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][CH:4]=2)[CH2:21]1)([CH3:13])([CH3:14])[CH3:15]
Reactant: N#Cc1ccc(C=O)cc1
Reactant: CC1(O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)CNC1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: CC1(O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)CN(Cc2ccc(C#N)cc2)C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 87.2 %

Procedure:
To a stirred solution of 4-formylbenzonitrile (68 mg, 0.51 mmol) and 3-(tert-Butyl-diphenyl-silanyloxy)-3-methyl-azetidine hydrochloride (188 mg, 0.51 mmol) in 1:1 MeOH/DMF (26 mL) was added acetic acid (catalytic). The reaction mixture was stirred under N2 at 0° C. for 1 h. Sodium cyanoborohydride (1M in THF, 0.6 mL, 0.57 mmol) was added and the reaction mixture stirred at RT, under N2 for 18 h. The reaction mixture was concentrated in vacuo, the residue suspended in H2O (10 mL), washed with CH2Cl2 (2×10 mL) and the solution passed through a phase separation cartridge. The combined organic layers were concentrated in vacuo and the crude residue purified by silica gel chromatography eluting with 100% isohexane and increasing the polarity 100% EtOAc to afford 4-[3-(tert-butyl-diphenyl-silanyloxy)-3-methyl-azetidin-1-ylmethyl]-benzonitrile as a colourless oil (196 mg, 86%).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([CH:19]2[CH2:21][CH2:20]2)=[N:8][C:9]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[CH:10][C:11]=1[CH3:12])=[O:5])C.[OH-].[Na+]>CO.O1CCCC1>[CH:19]1([C:7]2[C:6]([C:4]([OH:5])=[O:3])=[C:11]([CH3:12])[CH:10]=[C:9]([N:13]3[CH2:14][CH2:15][O:16][CH2:17][CH2:18]3)[N:8]=2)[CH2:21][CH2:20]1
Reactant: CCOC(=O)c1c(C)cc(N2CCOCC2)nc1C1CC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cc(N2CCOCC2)nc(C2CC2)c1C(=O)O
Yield: 68.5 %

Procedure:
A solution of 2-cyclopropyl-4-methyl-6-morpholin-4-yl-pyridine-3-carboxylic acid ethyl ester (16.8 g, 57.8 mmol) in methanol-tetrahydrofuran (1:1) (90 ml) is treated for 3 days with a 2M aqueous solution of sodium hydroxide at reflux. The organic solvent is distilled off and the aqueous layer treated with 2M hydrochloric acid, and extracted with ethyl acetate. The combined organic layers are dried over magnesium sulphate and evaporated to dryness. The crude product is purified by flash chromatography (silica gel, 75% ethyl acetate/cyclohexane) to yield 2-cyclopropyl-4-methyl-6-morpholin-4-yl-pyridine-3-carboxylic acid (10.4 g, 39.6 mmol, 69%).
Reaction SMILES: [Na].[NH2:2][C:3]1[C:8]([C:9](=[O:16])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:17][C:18]([OH:20])=[O:19].CN(C)C=O.[CH2:26](I)[CH3:27]>O>[NH2:2][C:3]1[C:8]([C:9](=[O:16])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:17][C:18]([O:20][CH2:26][CH3:27])=[O:19]
Reactant: CCI
Reactant: Nc1c(CC(=O)O)cccc1C(=O)c1ccccc1
Agent: [Na]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)Cc1cccc(C(=O)c2ccccc2)c1N
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 2.5 g. (0.009 mole) of the sodium salt of 2-amino-3-benzoylphenylacetic acid in 25 ml. of dry dimethylformamide was treated with 5.0 g. (0.035 mole) of ethyl iodide. The mixture was stirred two hours at room temperature using a magnetic stirrer. The mixture was diluted with water and the aqueous solution extracted several times with ethyl ether. The combined extracts were washed with water, dried over sodium sulfate and concentrated under vacuum to a yellow solid. The solid was recrystallized from absolute ethanol to give 1.7 gms. (61.0%) of yellow needles which melted at 77°-78° C.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=O.[F:11][C:12]1([F:18])[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>CN(C=O)C.C(OCC)(=O)C>[F:11][C:12]1([F:18])[CH2:17][CH2:16][N:15]([C:5]([C:4]2[CH:8]=[CH:9][CH:10]=[C:2]([I:1])[CH:3]=2)=[O:7])[CH2:14][CH2:13]1
Reactant: FC1(F)CCNCC1
Reactant: O=C(O)c1cccc(I)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1cccc(I)c1)N1CCC(F)(F)CC1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of 3-iodobenzoic acid 1 (482 mg, 1.94 mmol) in DMF (6 mL) was added 4,4-difluoropiperidine 2 (259 mg, 2.14 mmol), HATU (886 mg, 2.33 mmol) and diisopropylethylamine (750 mg, 5.81 mmol). The reaction mixture was stirred at room temperature for 1.5 hours. Ethyl acetate (100 mL) was added and the organic layer was washed with 1 N sodium hydroxide solution, 1 N hydrochloric acid, water and brine. The organic layer was dried over anhydrous sodium sulfate. The organic solvent was evaporated under reduced pressure. The crude product was purified by flash column chromatography to afford the desired 4,4-difluoro-1-[(3-iodophenyl)carbonyl]piperidine compound 77-1 (362 mg, 1.03 mmol).
Reaction SMILES: C[Si](C)(C)[N-][Si](C)(C)C.[Li+].[O:11]=[C:12]1[CH2:21][CH2:20][C@@:19]2([C:22]([O:24][CH3:25])=[O:23])[C:14]([CH2:15][CH2:16][N:17]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:18]2)=[CH:13]1.[CH:33](OCC(F)(F)F)=[O:34].Cl>CCOCC.C(OCC)(=O)C.O>[OH:34]/[CH:33]=[C:21]1\[C:12](=[O:11])[CH:13]=[C:14]2[C@:19]([C:22]([O:24][CH3:25])=[O:23])([CH2:20]\1)[CH2:18][N:17]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:16][CH2:15]2
Reactant: COC(=O)[C@]12CCC(=O)C=C1CCN(C(=O)OC(C)(C)C)C2
Reactant: O=COCC(F)(F)F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: COC(=O)[C@]12C/C(=C/O)C(=O)C=C1CCN(C(=O)OC(C)(C)C)C2
Temperature: -78 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
Lithium hexamethyldisilazide (12.93 ml, 12.93 mmol) was added to diethyl ether (20 mL) at −78° C. (R)-2-tert-butyl 8a-methyl 6-oxo-3,4,6,7,8,8a-hexahydroisoquinoline-2,8a(1H)-dicarboxylate (WO2005087769) (1.0 g, 3.23 mmol) in ether (5 mL) was added followed by the addition of 2,2,2-trifluoroethyl formate (2.51 ml, 25.9 mmol) after 20 minutes. The reaction was stirred at −78° C. for 2 hours then allowed to slowly warm to room temperature. 1M hydrochloric acid (8 mL) was added, followed by water (10 mL) and ethyl acetate (10 mL). The organic phase was separated, washed with brine, dried (magnesium sulfate) and solvent removed to give (R,Z)-2-tert-butyl 8a-methyl 7-(hydroxymethylene)-6-oxo-3,4,6,7,8,8a-hexahydroisoquinoline-2,8a(1H)-dicarboxylate (1.09 g) as a yellow oil. LCMS (Method F, ES-API): RT 1.99 min, m−H=336.
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=O.NS(O)(=O)=O.[C:24]([O:30][C:31](C)(C)[CH3:32])(=[O:29])[CH2:25][C:26]([CH3:28])=O>C(OCC)(=O)C>[CH3:28][C:26]1[C:25]([C:24]([O:30][CH2:31][CH3:32])=[O:29])=[C:4]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:3]2[C:2](=[CH:15][CH:14]=[C:13]([N+:16]([O-:18])=[O:17])[CH:12]=2)[N:1]=1
Reactant: CC(=O)CC(=O)OC(C)(C)C
Reactant: Nc1ccc([N+](=O)[O-])cc1C(=O)c1ccccc1
Agent: NS(=O)(=O)O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1c(C)nc2ccc([N+](=O)[O-])cc2c1-c1ccccc1
Temperature: 120 °C
Reaction time: 12 h
Yield: 76.1 %

Procedure:
A mixture of 2-amino-5-nitrobenzophenone (1 g, 4.1 mmol), H2NSO3H (40 mg) and tert-butyl acetoacetate (1.3 ml, 10.3 mmol) was stirred for 12 h at 120° C. under N2. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and washed with water. The organic layer was dried (MgSO4) and concentrated in vacuo to give a solid, which was recrystallised from EtOH to give a pale orange solid (1.05 g, 76%). 1H NMR (300 MHz, CDCl3) δ 8.41-8.5(m, 2H, 8.15 (d, J=9 Hz, 1H), 7.52-7.55(m, 3H), 7.3-7.4 (m, 2H), 2.82(s, 3H), 1.24(s, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH:13]=[CH:14][C:15]([S:17][C:18]([CH3:25])([CH3:24])[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:16][C:11]=3[O:10][N:9]=2)=[CH:4][CH:3]=1.OO.C(O)=[O:29]>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH:13]=[CH:14][C:15]([S:17]([C:18]([CH3:24])([CH3:25])[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[O:29])=[CH:16][C:11]=3[O:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(C)(C)Sc1ccc2c(-c3ccc(Cl)cc3)noc2c1
Reactant: O=CO
Agent: OO
Solvent: ClCCl
Product: CCOC(=O)C(C)(C)S(=O)c1ccc2c(-c3ccc(Cl)cc3)noc2c1
Reaction time: 0.75 h
Yield: 52 %

Procedure:
3.0 g (8.0 mmole) of ethyl 2-[[3-(4-chlorophenyl)-1,2-benzisoxazol-6-yl]thio]-2-methylpropionate was combined in a flask with 0.91 g (1 eq.) of a 30% H2O2 solution, 10 ml of formic acid and 50 ml of dichloromethane. The mixture was briskly stirred and the reaction monitored by TLC. After 45 minutes, 1 ml more of a 30% H2O2 solution was added to consume the remaining starting material. The reaction was stopped when the TLC showed the starting material was consumed (at which point oxidation of the product to the sulfone will begin) and the reaction mixture was diluted with 3N HCl. The dichloromethane layer was separated, washed with 3N HCl, water, and a saturated salt solution, dried over sodium sulfate and evaporated to an oil. The oil was crystallized by adding methanol and the resulting solid was collected and recrystallized from methanol to yield 1.6 g (52%) of ethyl 2-[ [3-(4-chlorophenyl)-1,2-benzisoxazol-6yl-]sulfinyl]-2-methylpropionate, m.p. 89° C.
Reaction SMILES: C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C([O-])(=O)C.[Na+].[Cl:28][C:29]1[C:34]([C:35]2[CH:40]=[CH:39][CH:38]=[C:37]([NH:41][C:42]3[C:47](I)=[CH:46][N:45]=[CH:44][N:43]=3)[CH:36]=2)=[CH:33][C:32]([C:49]([NH:51][C:52]2[CH:57]=[CH:56][CH:55]=[C:54]([C:58]([F:61])([F:60])[F:59])[CH:53]=2)=[O:50])=[CH:31][CH:30]=1>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:28][C:29]1[CH:30]=[CH:31][C:32]([C:49]([NH:51][C:52]2[CH:57]=[CH:56][CH:55]=[C:54]([C:58]([F:61])([F:60])[F:59])[CH:53]=2)=[O:50])=[CH:33][C:34]=1[C:35]1[CH:36]=[C:37]2[C:38]([C:47]3[CH:46]=[N:45][CH:44]=[N:43][C:42]=3[NH:41]2)=[CH:39][CH:40]=1
Reactant: O=C(Nc1cccc(C(F)(F)F)c1)c1ccc(Cl)c(-c2cccc(Nc3ncncc3I)c2)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CN(C)C=O
Product: O=C(Nc1cccc(C(F)(F)F)c1)c1ccc(Cl)c(-c2ccc3c(c2)[nH]c2ncncc23)c1
Temperature: 20 °C
Reaction time: 0.08 h

Procedure:
tri-o-Tolylphosphine (2.0E1 mg, 0.064 mmol) was stirred in DMF (2 mL). The mixture was degassed by bubbling nitrogen through it until all additions were complete. To the mixture was added palladium acetate (7.2 mg, 0.032 mmol), and the resulting mixture was stirred at 20° C. for 5 min. To the resulting mixture was added sodium acetate (39.5 mg, 0.482 mmol) and 6-chloro-3′-[(5-iodopyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]biphenyl-3-carboxamide (0.191 g, 0.321 mmol). The resulting mixture was heated to reflux. After 4 h, LCMS showed complete reaction to give the desired product, M+H 467; and small amounts of reduction product (M+H 469) and de-chlorination product (M+H 433). The product was isolated by prep HPLC using a 30 mm×100 mm C18 column; 35% CH3CN—H2O (0.1% TFA), 1.5 min, to 55% at 6 min; 60 mL/min; detector set at 285 nm; retention time, 4.9 min; retention time of the de-chlorination product, 4.5 min. The HPLC fractions were freeze-dried to yield product TFA salt, a white solid; 1H NMR (DMSO-d6) δ 13.0 (s, 1H, NH); 10.7 (s, 1H, amide NH); 9.63 (s, 1H, NH); 9.11 (s, 1H); 8.44 (d, 1H); 8.36 (s, 1H); 8.27 (s, 1H); 8.09 (d, 1H); 8.02 (t, 2H); 7.95 (s, 1H); 7.84 (d, 1H); 7.70 (t, 1H); 7.62 (t, 1H); 7.47 (d, 1H).