Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([S:7](Cl)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[NH:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1>C1COCC1>[C:1]1([S:7]([N:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: C1CNCCN1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=S(=O)(c1ccccc1)N1CCNCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of benzenesulfonyl chloride (1 g, 5.66 mmol) in THF (20 mL) were sequentially added triethylamine (1.97 mL, 14.15 mmol) and piperazine (2.92 g, 33.9 mmol). The reaction was stirred at room temperature for 1 hour before it was extracted with ethyl acetate and washed with water and brine. The ethyl acetate extracts were dried over anhydrous magnesium sulfate and concentrated. The residue was chromatographed on silica gel (1:1 hexanes/ethyl acetate to 10/1 dichloromethane/methanol) to give 22 as a yellow oil.
Reaction SMILES: [C:1]([CH2:4][CH2:5][C:6]1[N:7]=[C:8]([F:30])[N:9]([C:11]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:10]=1)([OH:3])=O.C(N(CC)CC)C.ClC(OCC(C)C)=O.[Cl:46][C:47]1[CH:53]=[CH:52][C:50]([NH2:51])=[CH:49][CH:48]=1>C(Cl)Cl>[Cl:46][C:47]1[CH:53]=[CH:52][C:50]([NH:51][C:1]([CH2:4][CH2:5][C:6]2[N:7]=[C:8]([F:30])[N:9]([C:11]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:10]=2)=[O:3])=[CH:49][CH:48]=1
Reactant: Nc1ccc(Cl)cc1
Reactant: O=C(O)CCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c(F)n1
Agent: CC(C)COC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(CCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c(F)n1)Nc1ccc(Cl)cc1
Reaction time: 0.42 h

Procedure:
A solution of 4-(2-carboxyethyl)-2-fluoro-1-triphenylmethylimidazole in CH2Cl2 was treated with triethylamine. The mixture was cooled, isobutyl chloroformate added, and stirred for 25 min. 4-Chloroaniline was then added, and stirring continued for 1 hour. Extractive work-up, followed by chromatography, gave 4-[2-(4-chlorophenylcarbamoyl)ethyl]-2-fluoro-1-triphenylmethylimidazole, having the following n.m.r. spectrum in CDCl3 +d6DMSO: 2.4-2.75 (m, 4H); 6.25 (s, 1H); 6.9-7.65 (m, 19H); 9.9 (br s, 1H).
Reaction SMILES: C([N:8]1[CH2:12][CH2:11][C@H:10]([C@@H:13]([O:18][C:19]2[C:20]([CH3:27])=[N:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=2)[CH2:14][CH:15]([CH3:17])[CH3:16])[CH2:9]1)C1C=CC=CC=1>C(O)C.[Pd]>[CH3:26][O:25][C:22]1[N:21]=[C:20]([CH3:27])[C:19]([O:18][C@H:13]([C@H:10]2[CH2:11][CH2:12][NH:8][CH2:9]2)[CH2:14][CH:15]([CH3:17])[CH3:16])=[CH:24][CH:23]=1
Reactant: COc1ccc(O[C@@H](CC(C)C)[C@H]2CCN(Cc3ccccc3)C2)c(C)n1
Agent: [Pd]
Solvent: CCO
Product: COc1ccc(O[C@@H](CC(C)C)[C@H]2CCNC2)c(C)n1
Temperature: 60 °C
Reaction time: 24 h
Yield: 97.5 %

Procedure:
Charge a 400 mL stainless steel autoclave with 20% by weight Pd/C (10%, wet, 820 mg) followed by a solution of (S)-1-benzyl-3-((S)-1-(6-methoxy-2-methyl-3-pyridyloxy)-3-methylbutyl)-pyrrolidine (4.1 g, 11.126 mmoles) in ethanol (82 mL). Purge with H2 gas (3×50 PSI), then charge the vessel with H2 gas (50 PSI). Heat the reaction mixture to 60° C.1 and stir at 60° C. for 24 hours. The pressure of the vessel increases to ˜55 PSI at 60° C. and the vessel is refilled with H2 gas as needed. Allow the reaction mixture to cool to room temperature, filter through a medium fritted funnel charged with celite (wet with ethanol), and wash with ethanol (˜80 mL). Concentrate under reduced pressure to give (S)-3-((S)-1-(6-methoxy-2-methyl-3-pyridyloxy)-3-methylbutyl)-pyrrolidine as a light yellow oil (3.02 g, 10.848 mmoles, 97.5% yield). 1H NMR (300 MHz, CDCl3) δ 7.12 (d, 1H, J=8.79 Hz), 6.50 (d, 1H, 8.79 Hz), 4.2 (aq, 1H, Ja=7.03 Hz, Jb=5.27 Hz), 3.87 (s, 3H), 3.08-2.94 (m, 2H), 2.94-2.82 (m, 1H), 2.82-2.70 (m, 1H), 2.50-2.26 (m, 3H), 2.36 (s, 3H), 1.94-1.78 (m, 1H), 1.78-1.52 (m, 3H), 1.44-1.30 (m, 1H), 0.898 (at, 6H, Ja=6.45 Hz, Jb=7.03 Hz). LC/MS=279.3 (M+1).
Reaction SMILES: [CH:1]1([C:4]2[C:5]([N:11]3[CH2:16][CH2:15][N:14]([C:17]([C:19]4[CH:24]=[CH:23][C:22](I)=[CH:21][C:20]=4[F:26])=[O:18])[CH2:13][CH2:12]3)=[N:6][CH:7]=[C:8]([CH3:10])[CH:9]=2)[CH2:3][CH2:2]1.[CH3:27][C@@H:28]1[CH2:32][CH2:31][S:30](=[O:34])(=[O:33])[NH:29]1>>[CH:1]1([C:4]2[C:5]([N:11]3[CH2:16][CH2:15][N:14]([C:17]([C:19]4[CH:24]=[CH:23][C:22]([N:29]5[C@H:28]([CH3:27])[CH2:32][CH2:31][S:30]5(=[O:34])=[O:33])=[CH:21][C:20]=4[F:26])=[O:18])[CH2:13][CH2:12]3)=[N:6][CH:7]=[C:8]([CH3:10])[CH:9]=2)[CH2:3][CH2:2]1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(I)cc3F)CC2)c(C2CC2)c1
Reactant: C[C@@H]1CCS(=O)(=O)N1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4[C@H](C)CCS4(=O)=O)cc3F)CC2)c(C2CC2)c1
Yield: 45.7 %

Procedure:
Using [4-(3-cyclopropyl-5-methylpyridin-2-yl)piperazin-1-yl](2-fluoro-4-iodophenyl)methanone (627 mg) described in Preparation Example 183 and (R)-3-methylisothiazolidine 1,1-dioxide (182 mg) described in Preparation Example 2 and by the reaction and treatment in the same manner as in Example 1, the title compound (291 mg) was obtained.
Reaction SMILES: O[C@H](C(C)(C)C)[C@@H](N([C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:14][CH:13]=1)C(OC)=O)C(O)=O.O[C@@H:29]([C:51]([CH3:54])([CH3:53])[CH3:52])[C@@H:30]([N:34]([C:39]1C=CC(C2C=CC=CC=2)=CC=1)[C:35]([O:37]C)=[O:36])[C:31]([OH:33])=[O:32].CCN(CC)CC.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>C(Cl)Cl>[C:18]1([C:15]2[CH:14]=[CH:13][C:12]([O:37][C:35](=[O:36])[N:34]([CH3:39])[C@H:30]3[C:31](=[O:33])[O:32][C@@H:29]3[C:51]([CH3:54])([CH3:53])[CH3:52])=[CH:17][CH:16]=2)[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: COC(=O)N(c1ccc(-c2ccccc2)cc1)[C@@H](C(=O)O)[C@H](O)C(C)(C)C
Reactant: COC(=O)N(c1ccc(-c2ccccc2)cc1)[C@@H](C(=O)O)[C@@H](O)C(C)(C)C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C(=O)Oc1ccc(-c2ccccc2)cc1)[C@H]1C(=O)O[C@@H]1C(C)(C)C
Temperature: 0 °C
Reaction time: 15 h
Yield: 58 %

Procedure:
Under nitrogen atmosphere, to a stirred mixture of (2R*,3R*)-3-hydroxy-4,4-dimethyl-2-[(4-phenyl-phenyl)-methoxy-carbonylamino]-pentanoic acid and (2R*,3S*)-3-hydroxy-4,4-dimethyl-2-[(4-phenyl-phenyl)-methoxy-carbonylamino]-pentanoic acid (0.203 g, 0.55 mmol) in dry CH2Cl2 (25 mL), at 0° C., Et3N (0.23 mL, 1.65 mmol) and subsequently TBTU (0.21 g, 0.66 mmol) were added. The mixture was left stirring at 0° C. for 1 h and at rt for 15 h. The organics were then removed under reduced pressure, and the resulting crude product purified by column chromatography, using a Teledyne ISCO apparatus, eluting with Cy:AcOEt (from 90:10 to 80:20) to afford the pure title compound (0.063 g, 58%), as pure anti diastereoisomer, as white solid. MS (ESI) m/z: 371 [M−NH4]+; (ESI) m/z: 352 [M−H]−. 1H NMR (DMSO-d6) δ 0.95 (s, 9H), 4.37 (d, J=4.64 Hz, 1H), 4.83 (dd, J=4.65, 8.16 Hz, 1H), 5.14 (s, 2H), 7.32-7.56 (m, 5H), 7.60-7.75 (m, 4H), 8.25 (d, J=8.12 Hz, 1H).
Reaction SMILES: [Cl:1]Cl.[NH2:3][C:4]1[N:9]=[C:8](SC)[N:7]=[C:6]([C:12]([F:15])([F:14])[F:13])[N:5]=1.[OH-].[Na+]>C(O)(=O)C>[NH2:3][C:4]1[N:9]=[C:8]([Cl:1])[N:7]=[C:6]([C:12]([F:15])([F:14])[F:13])[N:5]=1
Reactant: ClCl
Reactant: CSc1nc(N)nc(C(F)(F)F)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: Nc1nc(Cl)nc(C(F)(F)F)n1
Temperature: 20 °C
Reaction time: 0.5 h
Yield: 60 %

Procedure:
Chlorine gas was passed into a solution of 21 g of 2-amino-4-methylthio-6-trifluoromethyl-1,3,5-triazine in 0.2 l glacial acetic acid at 20 to 25° C. (15 min). The reaction mixture was stirred for 30 min at approx. 20° C., sprayed for 1 hour with nitrogen gas at room temperature, poured into 1 l of ice-cold aqueous solution of 70 g of sodium hydroxide and stirred for 5 min. After extraction with ethyl acetate, the organic phase was washed with water and dried over magnesium sulfate, and the solvent was removed in vacuo. The crude product was purified by stirring in heptane. After filtration with suction and drying, 12 g (60%) of 2-amino-4-chloro-6-trifluoromethyl-1,3,5-triazine were obtained as a white powder (m.p. 109° C.); 1H NMR (CDCl3): δ=6.4 (s br., 2H).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:12]3[N:17]=[C:16]4[C:18]([C:21]([NH:23][CH2:24][C:25]5([OH:36])[CH2:28][N:27](C(OC(C)(C)C)=O)[CH2:26]5)=[O:22])=[CH:19][NH:20][C:15]4=[N:14][CH:13]=3)=[N:7][N:8]2[CH3:11])=[CH:4][CH:3]=1.[F:37][C:38]([F:43])([F:42])[C:39]([OH:41])=[O:40]>ClCCl>[F:37][C:38]([F:43])([F:42])[C:39]([OH:41])=[O:40].[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:12]3[N:17]=[C:16]4[C:18]([C:21]([NH:23][CH2:24][C:25]5([OH:36])[CH2:28][NH:27][CH2:26]5)=[O:22])=[CH:19][NH:20][C:15]4=[N:14][CH:13]=3)=[N:7][N:8]2[CH3:11])=[CH:4][CH:3]=1
Reactant: Cn1nc(-c2cnc3[nH]cc(C(=O)NCC4(O)CN(C(=O)OC(C)(C)C)C4)c3n2)c2ccc(F)cc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cn1nc(-c2cnc3[nH]cc(C(=O)NCC4(O)CNC4)c3n2)c2ccc(F)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 9 %

Procedure:
To a solution of tert-butyl 3-((2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[3,2-b]pyrazine-7-carboxamido)methyl)-3-hydroxyazetidine-1-carboxylate (86 mg, 0.16 mmol) in 3 mL of dichloromethane was added 3 mL of trifluoroacetic acid. The reaction mixture was stirred overnight at room temperature. After solvent evaporation, the residue was purified by preparative-HPLC (Gemini 5u C18 150×21.2 mm; inject volume: 3 mL/inj, flow rate: 20 mL/min; wavelength: 214 nm and 254 nm; the gradient conditions are: 40% acetonitrile/60% water (0.1% trifluoroacetic acid V/V) initially, and then proceed to 50% acetonitrile/50% water (0.1% trifluoroacetic acid V/V) in a linear fashion after just 9 min) to afford 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-N-((3-hydroxyazetidin-3-yl)methyl)-5H-pyrrolo[3,2-b]pyrazine-7-carboxamide trifluoroacetate (6 mg, 9%) as yellow solid. LCMS: (M+H)+=396; 1H NMR (300 MHz, CD3OD): δ 9.05 (s, 1H), 8.48-8.42 (m, 1H), 8.23 (s, 1H), 7.20 (d, 1H, J=9.0 Hz), 6.99 (t, 1H, J=9.3 Hz), 4.10-3.89 (m, 6H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:24])=[C:6]([C:8]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[C:16]=2[C:22]#[N:23])=[N:9]S(C(C)C)=O)[CH:7]=1.Br[C:26]1[CH:31]=[CH:30][N:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[CH:27]=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:24])=[C:6]([C:8]2([C:26]3[CH:31]=[CH:30][N:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[CH:27]=3)[C:15]3[C:16](=[C:17]([F:21])[CH:18]=[CH:19][CH:20]=3)[C:22]([NH2:23])=[N:9]2)[CH:7]=1
Reactant: FC(F)(F)c1cc(Br)ccn1
Reactant: CC(C)S(=O)N=C(c1cc(Br)ccc1F)c1cccc(F)c1C#N
Product: NC1=NC(c2ccnc(C(F)(F)F)c2)(c2cc(Br)ccc2F)c2cccc(F)c21
Yield: 90 %

Procedure:
The title compound was synthesized as described for example 11i in 90% yield starting from N-((5-bromo-2-fluorophenyl)(2-cyano-3-fluorophenyl)methylene)propane-2-sulfinamide (0.980 g, 2.38 mmol) and 4-bromo-2-(trifluoromethyl)pyridine (0.646 g, 2.86 mmol). Purification was achieved by flash chromatography using a gradient of 100% CH2Cl2 to 30% 0.1M NH3 in MeOH in CH2Cl2.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]([NH:5][C:6]1[C:14]2[C:9](=[N:10][CH:11]=[CH:12][N:13]=2)[S:8][C:7]=1[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[O:4].[C:22](=O)([O-])[O-].[K+].[K+].IC.[NH4+].[Cl-]>CC(C)=O>[F:21][C:2]([F:20])([F:1])[C:3]([N:5]([C:6]1[C:14]2[C:9](=[N:10][CH:11]=[CH:12][N:13]=2)[S:8][C:7]=1[C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH3:22])=[O:4]
Reactant: CCOC(=O)c1sc2nccnc2c1NC(=O)C(F)(F)F
Reactant: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Agent: [NH4+]
Solvent: CI
Solvent: CC(C)=O
Product: CCOC(=O)c1sc2nccnc2c1N(C)C(=O)C(F)(F)F
Temperature: 50 °C
Reaction time: 1 h
Yield: 94.5 %

Procedure:
To a solution of ethyl 7-(2,2,2-trifluoroacetamido)thieno[2,3-b]pyrazine-6-carboxylate 10 (9.22 g, 28.9 mmol) and potassium carbonate (7.98 g, 57.8 mmol) in acetone (140 mL) was added iodomethane (3.60 mL, 57.8 mmol). The reaction was stirred at 50° C. for 1 h. NH4Cl solution(aq) was added and extracted with EtOAc. Organic layer was washed with brine, dried and evaporated to give crude ethyl 7-(2,2,2-trifluoro-N-methylacetamido)thieno[2,3-b]pyrazine-6-carboxylate 11 (9.1 g, 95%). (m/z)=334 (M+H)+.
Reaction SMILES: ClCCl.[C:4]([O:8][C:9](C(C)(C)C)=[O:10])([CH3:7])([CH3:6])[CH3:5].[NH2:15][CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([S:24]([NH2:27])(=[O:26])=[O:25])=[CH:20][CH:19]=1>C(OCC)(=O)C>[S:24]([C:21]1[CH:20]=[CH:19][C:18]([CH2:17][CH2:16][NH:15][C:9](=[O:10])[O:8][C:4]([CH3:5])([CH3:6])[CH3:7])=[CH:23][CH:22]=1)(=[O:25])(=[O:26])[NH2:27]
Reactant: CC(C)(C)OC(=O)C(C)(C)C
Reactant: NCCc1ccc(S(N)(=O)=O)cc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NCCc1ccc(S(N)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 53.3 %

Procedure:
Dichloromethane (4 mL) and di-tert-butylcarboxylic acid (218 mg, 1.0 mmol) were added to 4-(2-aminoethyl)benzenesulfonamide (200 mg, 1.0 mmol) and the mixture was stirred at room temperature for 1.5 hours. Ethyl acetate (100 mL) was added to the reaction mixture and the solid was collected by filtration. Thus, tert-butyl 4-sulfamoylphenethylcarbamate (Compound GI) (160 mg, yield: 53%) was obtained.
Reaction SMILES: O=S(Cl)Cl.[I:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=[O:11])=[CH:8][CH:7]=1.[CH3:15]O>>[I:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([O:12][CH3:15])=[O:11])=[CH:8][CH:7]=1
Reactant: CO
Reactant: O=C(O)c1ccc(I)cc1
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccc(I)cc1

Procedure:
2.95 ml of SOCl2 were added to a suspension of 10 g of 4-iodobenzoic acid in 100 ml of methanol and the refluxed for 24 hours and then evaporated under reduced pressure until 10.49 g of a dry extract were obtained corresponding to the expected product with a Rf=0.55 (cyclohexane/ethyl acetate 80/20).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:14]=[C:13]([OH:15])[CH:12]=[C:11]([CH:16]([CH3:18])[CH3:17])[N:10]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[Br-].Br[CH2:21][C:22]1[CH:31]=[CH:30][C:25]([C:26]([O:28]C)=[O:27])=[CH:24][CH:23]=1>>[Cl:8][C:6]1[CH:5]=[C:4]([C:9]2[N:14]=[C:13]([O:15][CH2:21][C:22]3[CH:31]=[CH:30][C:25]([C:26]([OH:28])=[O:27])=[CH:24][CH:23]=3)[CH:12]=[C:11]([CH:16]([CH3:18])[CH3:17])[N:10]=2)[CH:3]=[C:2]([Cl:1])[CH:7]=1
Reactant: CC(C)c1cc(O)nc(-c2cc(Cl)cc(Cl)c2)n1
Reactant: COC(=O)c1ccc(CBr)cc1
Agent: [Br-]
Product: CC(C)c1cc(OCc2ccc(C(=O)O)cc2)nc(-c2cc(Cl)cc(Cl)c2)n1

Procedure:
The title compound was prepared from 2-(3,5-dichloro-phenyl)-6-isopropyl-pyrimidin-4-ol (which was obtained in Intermediate 6) and methyl 4-(bromomethyl)benzoate bromide according to Method A and Method B; LC retention time 4.11 min; MS: m/z (ESI) 415 (M−H).
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[CH2:11]([O:18][C:19]1[CH:31]=[CH:30][C:22]([O:23][CH:24]([CH3:29])[C:25](OC)=[O:26])=[CH:21][CH:20]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(O)(=O)C>C1(C)C=CC=CC=1>[CH2:11]([O:18][C:19]1[CH:20]=[CH:21][C:22]([O:23][CH:24]([CH3:29])[CH:25]=[O:26])=[CH:30][CH:31]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: COC(=O)C(C)Oc1ccc(OCc2ccccc2)cc1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: CC(C=O)Oc1ccc(OCc2ccccc2)cc1
Temperature: -65 °C
Reaction time: 5 h
Yield: 42.5 %

Procedure:
A 1.5 molar solution of diisobutylaluminum hydride in toluene (138 mL, 0.207 mol) is added dropwise to a mixture of methyl 2-[p-(benzyloxy)phenoxy]propionate (56.4 g, 0.197 mol) in toluene at -65° C. under a nitrogen atmosphere. The reaction mixture is stirred at -65° C. for 5 hours. Acetic acid (70 mL) is added dropwise and the reaction mixture is warmed to room temperature, diluted with hexanes, washed with 10% hydrochloric acid solution and water, dried and concentrated in vacuo to obtain an oil. Flash chromatography of the oil using silica gel and eluting with a 1:1 methylene chloride/hexanes solution gives the title product as a white solid (21.44 g, mp 50°-51° C.).
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[C:4]2[S:10][CH:9]=[CH:8][C:5]2=[N:6][CH:7]=1.[F:12][C:13]1[CH:28]=[C:27]([N+:29]([O-:31])=[O:30])[CH:26]=[CH:25][C:14]=1[O:15]C1N=CC=C2C=CNC=12>>[Br:1][C:2]1[C:3]([O:15][C:14]2[CH:25]=[CH:26][C:27]([N+:29]([O-:31])=[O:30])=[CH:28][C:13]=2[F:12])=[C:4]2[S:10][CH:9]=[CH:8][C:5]2=[N:6][CH:7]=1
Reactant: O=[N+]([O-])c1ccc(Oc2nccc3cc[nH]c23)c(F)c1
Reactant: Clc1c(Br)cnc2ccsc12
Product: O=[N+]([O-])c1ccc(Oc2c(Br)cnc3ccsc23)c(F)c1
Yield: 61 %

Procedure:
Starting from the compound 271 and following the procedure described above for the synthesis of compound 260 (scheme 59, example 218, step 2), title compound 272 was obtained in 61% yield as an off-white solid. MS (m/z): 368.9 (M+H).
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[C:10]([C:11]([NH:13][CH2:14][C:15]3[C:16]([OH:23])=[N:17][C:18]([CH3:22])=[CH:19][C:20]=3[CH3:21])=[O:12])=[C:9]([CH3:24])[N:8]([C@@H:25]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH3:26])[C:6]=2[N:7]=1.[CH3:33][NH2:34]>>[OH:23][C:16]1[C:15]([CH2:14][NH:13][C:11]([C:10]2[C:5]3[CH:4]=[N:3][C:2]([NH:34][CH3:33])=[N:7][C:6]=3[N:8]([C@@H:25]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH3:26])[C:9]=2[CH3:24])=[O:12])=[C:20]([CH3:21])[CH:19]=[C:18]([CH3:22])[N:17]=1
Reactant: CN
Reactant: Cc1cc(C)c(CNC(=O)c2c(C)n([C@H](C)c3ccccc3)c3nc(Cl)ncc23)c(O)n1
Product: CNc1ncc2c(C(=O)NCc3c(C)cc(C)nc3O)c(C)n([C@H](C)c3ccccc3)c2n1
Yield: 34 %

Procedure:
A solution of (R)-2-chloro-N-((2-hydroxy-4,6-dimethylpyridin-3-yl)methyl)-6-methyl-7-(1-phenyl ethyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide (30 mg, 0.07 mmol) in methylamine (1 M in tetrahydrofuran, 3 mL) was stirred at 150° C. for 30 minutes under microwave (pressure: 17.2 bar, equipment power: 150 W). The mixture was concentrated in vacuo and purified by column chromatography (silica gel, dichloromethane/methanol=10:1) to afford (R)—N-((2-hydroxy-4,6-dimethylpyridin-3-yl)methyl)-6-methyl-2-(methylamino)-7-(1-phenylethyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide (10 mg, 34%). LRMS (M+H+) m/z: calcd 444.23. found 444. HPLC purity (214 nm): 92%. 1H NMR (300 MHz, CD3OD): δ 8.55 (s, 1H), 7.30-7.23 (m, 5H), 6.15-6.10 (m, 2H), 4.47 (s, 2H), 2.90 (s, 3H), 2.40 (s, 3H), 2.38 (s, 3H), 2.24 (s, 3H), 2.03 (d, J=7.2 Hz, 3H).
Reaction SMILES: Cl.[C:2]1([CH3:10])[CH:7]=[CH:6][C:5]([NH:8]N)=[CH:4][CH:3]=1.Cl.[CH2:12]([N:14]1[CH2:19][CH2:18][C:17](=O)[CH2:16][CH2:15]1)[CH3:13]>C(O)C>[CH2:12]([N:14]1[CH2:19][CH2:18][C:17]2[NH:8][C:5]3[CH:4]=[CH:3][C:2]([CH3:10])=[CH:7][C:6]=3[C:16]=2[CH2:15]1)[CH3:13]
Reactant: Cc1ccc(NN)cc1
Reactant: CCN1CCC(=O)CC1
Agent: Cl
Solvent: CCO
Product: CCN1CCc2[nH]c3ccc(C)cc3c2C1
Temperature: 80 °C
Yield: 91.4 %

Procedure:
To a solution of p-tolylhydrazine hydrochloride (5.0 g, 31.5 mmol) in Ethanol (150 mL) was added 1-ethylpiperidin-4-one hydrochloride (4.0 g, 24.5 mmol) and heated at 80° C. for 16 h. After completion of the reaction (monitored by LCMS). The reaction mixture was concentrated to dryness and basified with aq. saturated NaHCO3, extracted with EtOAc, the organic layer was separated dried over sodium sulfate and concentrated under vacuum to obtain 4.8 g (Yield 71.0%) of 2-ethyl-8-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole. 1H NMR (CDCl3, free base) δ (ppm) 7.7 (bs, 1H), 7.2-7.1 (m, 2H), 6.9 (d, 1H), 3.8 (s, 2H), 2.9 (s, 4H), 2.7 (q, 2H), 2.4 (s, 3H), 1.2 (t, 3H).
Reaction SMILES: [I:1][C:2]#[C:3][C:4]1[CH:8]=[CH:7][S:6][CH:5]=1.[F:9][C:10]([F:22])([F:21])[C:11]1[CH:12]=[C:13]([CH:18]=[CH:19][CH:20]=1)[CH2:14][N:15]=[N+:16]=[N-:17]>>[I:1][C:2]1[N:15]([CH2:14][C:13]2[CH:18]=[CH:19][CH:20]=[C:11]([C:10]([F:9])([F:22])[F:21])[CH:12]=2)[N:16]=[N:17][C:3]=1[C:4]1[CH:8]=[CH:7][S:6][CH:5]=1
Reactant: [N-]=[N+]=NCc1cccc(C(F)(F)F)c1
Reactant: IC#Cc1ccsc1
Product: FC(F)(F)c1cccc(Cn2nnc(-c3ccsc3)c2I)c1

Procedure:
Synthesized from 3-(iodoethynyl)thiophene and 3-trifluoromethyl-benzylazide using general procedure; 0.994 g, 2.284 mmol, 99%; mp=153-158° C. (dec.); IR (υ[cm−1]) 3121, 1326, 1194, 1163, 1096, 1075, 853, 792, 702; 1H NMR (600 MHz, CDCl3) δ=7.97-7.93 (m, 1H), 7.75 (d, J=5.0, 1H), 7.59 (d, J=7.7, 2H), 7.58 (s, 1H), 7.47 (t, J=7.7, 1H), 7.45-7.38 (m, 2H), 5.69 (s, 2H); 13C NMR (151 MHz, CDCl3) δ=147.5, 135.4, 131.6 (q, J=32.7), 131.3, 131.0, 129.8, 126.7, 126.2, 125.7 (q, J=3.7), 124.9 (q, J=3.8), 123.9 (q, J=272.4), 123.5, 76.0, 53.9; HRMS (ESI-TOF) (m/z): [M+H]+ calcd for C14H10F3IN3S, 435.9587; found 435.9586.
Reaction SMILES: [C:1]([CH:9]1[C:13](=O)[N:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:11]=[C:10]1[CH3:21])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])O.[Na+].P(Cl)(Cl)([Cl:29])=O>>[Cl:29][C:13]1[N:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:11]=[C:10]([CH3:21])[C:9]=1[C:1]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:8]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CC1=NN(c2ccccc2)C(=O)C1C(=O)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1nn(-c2ccccc2)c(Cl)c1C(=O)c1ccccc1
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
A solution containing 2.0 g of 4-benzoyl-3-methyl-1-phenyl-2-pyrazolin-5-one (commercially available e.g. Aldrich 15,660-4) in 4 ml of phosphorus oxychloride was stirred under nitrogen at 100° C. for 30 min. The mixture was poured into 40 ml of saturated sodium hydrogen carbonate solution and extracted three times with 30 ml of dichloromethane. Combined extracts were dried over magnesium sulphate, filtered and evaporated to give 2.0 g of (5-chloro-3-methyl-1-phenyl-1H-pyrazol-4-yl)-phenyl-methanone as a yellow oil which was used without further purification.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.FC(F)(F)C(O)=O.[OH:20][CH:21]1[CH2:26][CH2:25][N:24]([C:27]2[N:32]=[CH:31][C:30]([C:33]3([C:36]([N:38]4[CH2:42][CH2:41][C@@:40]5([C:46]6[CH:47]=[CH:48][CH:49]=[CH:50][C:45]=6[C:44](=[O:51])[O:43]5)[CH2:39]4)=[O:37])[CH2:35][CH2:34]3)=[CH:29][CH:28]=2)[CH2:23][CH2:22]1.[N:52]1[CH:57]=[CH:56][C:55](O)=[CH:54][CH:53]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O1CCCC1>>[N:52]1[CH:57]=[CH:56][C:55]([O:20][CH:21]2[CH2:22][CH2:23][N:24]([C:27]3[N:32]=[CH:31][C:30]([C:33]4([C:36]([N:38]5[CH2:42][CH2:41][C@@:40]6([C:46]7[CH:47]=[CH:48][CH:49]=[CH:50][C:45]=7[C:44](=[O:51])[O:43]6)[CH2:39]5)=[O:37])[CH2:34][CH2:35]4)=[CH:29][CH:28]=3)[CH2:25][CH2:26]2)=[CH:54][CH:53]=1
Reactant: Oc1ccncc1
Reactant: O=C1O[C@]2(CCN(C(=O)C3(c4ccc(N5CCC(O)CC5)nc4)CC3)C2)c2ccccc21
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: O=C1O[C@]2(CCN(C(=O)C3(c4ccc(N5CCC(Oc6ccncc6)CC5)nc4)CC3)C2)c2ccccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Diethyl azodicarboxylate (3.0×10−1 μL, 0.00019 mol) was added to a mixture of (1R)-1′-({1-[6-(4-hydroxypiperidin-1-yl)pyridin-3-yl]cyclopropyl}carbonyl)-3H-spiro[2-benzofuran-1,3′-pyrrolidin]-3-one trifluoroacetate (salt) (42 mg, 0.000077 mol, example 172), 4-pyridinol (18 mg, 0.00019 mol) and triphenylphosphine (5.0×10−1 mg, 0.00019 mol) in tetrahydrofuran (1.0 mL, 0.012 mol). The reaction mixture was stirred at room temperature overnight. The crude product was purified by prep-LCMS. LC/MS: 511.2 (M+H+).
Reaction SMILES: O=O.[C:3]([NH:11][C:12](=[CH:17][N:18]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]([O:15][CH3:16])=[O:14])(=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>>[C:3]([NH:11][C@@H:12]([CH2:17][N:18]([C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[C:13]([O:15][CH3:16])=[O:14])(=[O:10])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: COC(=O)C(=CN(c1ccccc1)c1ccccc1)NC(=O)c1ccccc1
Agent: O=O
Product: COC(=O)[C@H](CN(c1ccccc1)c1ccccc1)NC(=O)c1ccccc1

Procedure:
With exclusion exclusion of oxygen and moisture, an ampule was charged with 100 mg of methyl 2-benzoylamino-3-diphenylaminoacrylate (0.255 mmol) and 1.9 mg (0.0026 mmol, 0.01 equivalent) of [(S,S)-Et-FerroTANE-Rh]BF4. After purging with argon, 5 ml of oxygen-free methanol were added. The ampule was sealed gas-tight and hydrogenated in an autoclave at 20 bar of hydrogen pressure for 24 h. The autoclave was decompressed and purged with nitrogen. The conversion of the hydrogenation was determined by HPLC. The enantioselectivity was determined by HPLC on chiral phase by the method described in Example 4. The [(R,R)-Et-FerroTANE-Rh]BF4 catalyst afforded the corresponding R derivative in the same yield and enantiomeric purity.