Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([CH2:8][N:9]2[CH:13]=[CH:12][N:11]=[C:10]2[C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[N:15]=2)[C:3]=1[CH2:21][CH2:22][CH3:23].[CH2:24]([NH2:26])[CH3:25]>>[CH2:24]([NH:26][C:2]1[C:3]([CH2:21][CH2:22][CH3:23])=[C:4]([CH2:8][N:9]2[CH:13]=[CH:12][N:11]=[C:10]2[C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[N:15]=2)[N:5]=[CH:6][N:7]=1)[CH3:25]
Reactant: CCN
Reactant: CCCc1c(Cl)ncnc1Cn1ccnc1-c1cccc(F)n1
Product: CCCc1c(Cn2ccnc2-c2cccc(F)n2)ncnc1NCC
Temperature: 70 °C

Procedure:
A mixture of 6-chloro-4-[2-(6-fluoro-pyridin-2-yl)-imidazol-1-ylmethyl]-5-propyl-pyrimidine (60 mg, 0.18 mmol) and ethylamine (2M in THF, 2 mL) is heated at 70° C. in a sealed tube overnight. Solvent is removed. Water (10 mL) and ethyl acetate (15 mL) are added. The layers are separated—the aqueous layer is extracted with ethyl acetate (2×20 mL) and the organic layers are combined. On drying, the solvent is removed in vacuo. Preparative TLC separation gives the title compound. LC-MS (M+1) 341.2 (retention time: 1.00 min).
Reaction SMILES: Br[C:2]1[C:3]([N:38]2[CH2:43][CH2:42][O:41][CH2:40][CH2:39]2)=[N:4][C:5]2[N:6]([N:25]=[CH:26][C:27]=2[C:28]2[CH:29]=[N:30][C:31]3[C:36]([CH:37]=2)=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:7]=1[N:8]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[CH2:9][O:10][CH2:11][CH2:12][Si:13]([CH3:16])([CH3:15])[CH3:14].[Sn]([C:57]#[N:58])(CCCC)(CCCC)CCCC>O1CCOCC1.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[CH3:14][Si:13]([CH3:16])([CH3:15])[CH2:12][CH2:11][O:10][CH2:9][N:8]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[C:7]1[N:6]2[N:25]=[CH:26][C:27]([C:28]3[CH:29]=[N:30][C:31]4[C:36]([CH:37]=3)=[CH:35][CH:34]=[CH:33][CH:32]=4)=[C:5]2[N:4]=[C:3]([N:38]2[CH2:43][CH2:42][O:41][CH2:40][CH2:39]2)[C:2]=1[C:57]#[N:58]
Reactant: C[Si](C)(C)CCOCN(COCC[Si](C)(C)C)c1c(Br)c(N2CCOCC2)nc2c(-c3cnc4ccccc4c3)cnn12
Reactant: CCCC[Sn](C#N)(CCCC)CCCC
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Solvent: C1COCCO1
Product: C[Si](C)(C)CCOCN(COCC[Si](C)(C)C)c1c(C#N)c(N2CCOCC2)nc2c(-c3cnc4ccccc4c3)cnn12
Temperature: 100 °C

Procedure:
A degassed mixture of 6-bromo-5-morpholino-3-(quinolin-3-yl)-N,N-bis((2-(trimethylsilyl)ethoxy)methyl)pyrazolo[1,5-a]pyrimidin-7-amine (35 mg, 0.051 mmoL), Bu3SnCN (32.3 mg, 0.10 mmoL), Pd[P(t-Bu)3]2 (5.2 mg, 0.010 mmoL) in Dioxane (3 mL) was heated at 100° C. overnight. The mixture was cooled to room temperature and the solvent was evaporated in vacuo. Purification by column chromatography afforded the titled compound. LCMS tR=2.76 Min (5 min run, UV254nm). Mass calculated for, M+ 631.3, observed LC/MS m/z 632.2 (M+H).
Reaction SMILES: C(OC([NH:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]2[C:21]([CH3:22])=[CH:20][N:19]=[C:18]([Cl:23])[N:17]=2)=[CH:11][C:10]=1[CH2:24][CH2:25][C:26]1[CH:27]=[C:28]([NH:32]C(=O)OC(C)(C)C)[CH:29]=[CH:30][CH:31]=1)=O)(C)(C)C.CO.[ClH:42]>O1CCOCC1>[ClH:23].[ClH:42].[ClH:23].[NH2:32][C:28]1[CH:27]=[C:26]([CH2:25][CH2:24][C:10]2[CH:11]=[C:12]([NH:15][C:16]3[C:21]([CH3:22])=[CH:20][N:19]=[C:18]([Cl:23])[N:17]=3)[CH:13]=[CH:14][C:9]=2[NH2:8])[CH:31]=[CH:30][CH:29]=1
Reactant: Cc1cnc(Cl)nc1Nc1ccc(NC(=O)OC(C)(C)C)c(CCc2cccc(NC(=O)OC(C)(C)C)c2)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: Cc1cnc(Cl)nc1Nc1ccc(N)c(CCc2cccc(N)c2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 90 %

Procedure:
Into the reaction flask was added tert-butyl [3-(2-{2-[(tert-butoxycarbonyl)amino]-5-[(2-chloro-5-methylpyrimidin-4-yl)amino]phenyl}ethyl)phenyl]carbamate (0.25 g, 0.45 mmol), methanol (3 mL), and 4.0 M of hydrogen chloride in 1,4-dioxane (5 mL). The reaction mixture was stirred at rt for 16 h and concentrated to give the desired product (0.21 g, 90%). LCMS for C19H21ClN5 (M+H)+: m/z=354.1.
Reaction SMILES: [C:1]([O:4][C@H:5]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:6]([OH:8])=O)(=[O:3])[CH3:2].Cl.CN(C)CCCN=C=NCC.[O:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH:28]1[N:33]1[C:41]2[C:36](=[CH:37][C:38]([C:42]3[N:46]=[CH:45][N:44]([C:47]([C:60]4[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=4)([C:54]4[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=4)[C:48]4[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=4)[N:43]=3)=[CH:39][CH:40]=2)[C:35]([C:66]2[CH:67]=[C:68]([NH2:72])[CH:69]=[CH:70][CH:71]=2)=[N:34]1>ClCCl>[C:1]([O:4][C@@H:5]([C:6](=[O:8])[NH:72][C:68]1[CH:69]=[CH:70][CH:71]=[C:66]([C:35]2[C:36]3[C:41](=[CH:40][CH:39]=[C:38]([C:42]4[N:46]=[CH:45][N:44]([C:47]([C:48]5[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=5)([C:54]5[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=5)[C:60]5[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=5)[N:43]=4)[CH:37]=3)[N:33]([CH:28]3[CH2:29][CH2:30][CH2:31][CH2:32][O:27]3)[N:34]=2)[CH:67]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@@H](C(=O)O)c1ccccc1
Reactant: Nc1cccc(-c2nn(C3CCCCO3)c3ccc(-c4ncn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)cc23)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: CC(=O)O[C@@H](C(=O)Nc1cccc(-c2nn(C3CCCCO3)c3ccc(-c4ncn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)cc23)c1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (R)-2-acetoxy-2-phenylacetic acid (0.097 g, 0.498 mmol) in 2.0 mL of dichloromethane, was added 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride (EDCI) as a solid (0.100 g, 0.520 mmol). The solution was stirred at room temperature for 10 min before 3-{1-perhydro-2H-pyran-2-yl-5-[1-(triphenylmethyl)(1,2,4-triazol-3-yl)]-1H-indazol-3-yl}phenylamine (0.150 g, 0.248 mmol), dissolved in 1 mL of dichloromethane, was added. The reaction was stirred at room temperature for 2 hours. The reaction mixture was then partitioned between dichloromethane and water. (Yield not calculated) ES-MS (m/z) 779 [M+H]+.
Reaction SMILES: [CH3:1][N:2]([CH3:32])[C:3]1([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[CH:26]=2)[CH2:8][CH2:7][C:6](=[CH:9][C:10]([NH:12][CH:13]([CH3:24])[CH2:14][C:15]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[NH:17][CH:16]=2)=[O:11])[CH2:5][CH2:4]1>[Pd].CO>[CH3:32][N:2]([CH3:1])[C:3]1([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[CH:26]=2)[CH2:8][CH2:7][CH:6]([CH2:9][C:10]([NH:12][CH:13]([CH3:24])[CH2:14][C:15]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[NH:17][CH:16]=2)=[O:11])[CH2:5][CH2:4]1
Reactant: CC(Cc1c[nH]c2ccccc12)NC(=O)C=C1CCC(c2cccc(F)c2)(N(C)C)CC1
Agent: [Pd]
Solvent: CO
Product: CC(Cc1c[nH]c2ccccc12)NC(=O)CC1CCC(c2cccc(F)c2)(N(C)C)CC1
Reaction time: 15 h
Yield: 4 %

Procedure:
Palladium-on-charcoal (5%, 40 mg) was added to a solution of 2-[4-dimethylamino-4-(3-fluorophenyl)-cyclohexylidene]-N-[2-(1H-indol-3-yl)-1-methylethyl]-acetamide (417 mg, 0.96 mmol) in abs. methanol (40 ml). The reaction mixture was hydrogenated at RT under a pressure of 3 bar for 15 h. The catalyst was separated off over Celite and the filtrate was concentrated. After separation of the residue by chromatography on silica gel G [50 g; EA/MeOH (10:1)-(5:1)], the less polar diastereoisomer of 2-[4-dimethylamino-4-(3-fluorophenyl)cyclohexyl]-N-[2-(1H-indol-3-yl)-1-methylethyl]acetamide was isolated in a yield of 4% (15 mg) and the more polar diastereoisomer of 2-[4-dimethylamino-4-(3-fluorophenyl)cyclohexyl]-N-[2-(1H-indol-3-yl)-1-methylethyl]acetamide was isolated in a yield of 41% (170.2 mg). Both products were colourless oils and diastereoisomerically pure.
Reaction SMILES: [C:1]([O:5][N:6]1[CH2:10][CH2:9][CH2:8][CH:7]1[C:11]#[N:12])([CH3:4])([CH3:3])[CH3:2].[N-:13]=[N+:14]=[N-:15].[Na+].[Cl-].[NH4+]>CN(C=O)C>[C:1]([O:5][N:6]1[CH2:10][CH2:9][CH2:8][CH:7]1[C:11]1[N:13]=[N:14][NH:15][N:12]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(C)ON1CCCC1C#N
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)ON1CCCC1c1nn[nH]n1
Temperature: 95 °C
Yield: 24.4 %

Procedure:
A mixture of tert-butyloxy-2-cyanopyrrolidine (3 g, 15.3 mmol), sodium azide (1.49 g, 23.0 mmol) and ammonium chloride (1.22 g, 23 mmol) in DMF (15 ml) were heated at 95° C. for 48 hours. The reaction was then partitioned between ethyl acetate and water. The organics were separated, dried (MgSO4) and the volatiles removed by evaporation. The residue was triturated with diethyl ether and collected by filtration to give the title compound (0.79 g, 22%) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])/[CH:4]=[CH:5]/[C:6]1[C:7]([CH3:18])=[N:8][O:9][C:10]=1[C:11]1[CH:16]=[CH:15][C:14](Br)=[CH:13][CH:12]=1.[CH2:20]([O:22][C:23]([C:25]1([C:28]2[CH:33]=[CH:32][C:31](B3OC(C)(C)C(C)(C)O3)=[CH:30][CH:29]=2)[CH2:27][CH2:26]1)=[O:24])[CH3:21]>>[CH2:20]([O:22][C:23]([C:25]1([C:28]2[CH:33]=[CH:32][C:31]([C:14]3[CH:15]=[CH:16][C:11]([C:10]4[O:9][N:8]=[C:7]([CH3:18])[C:6]=4/[CH:5]=[CH:4]/[C:3]([O:2][CH3:1])=[O:19])=[CH:12][CH:13]=3)=[CH:30][CH:29]=2)[CH2:26][CH2:27]1)=[O:24])[CH3:21]
Reactant: COC(=O)/C=C/c1c(C)noc1-c1ccc(Br)cc1
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4/C=C/C(=O)OC)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 3, Step 5, using (E)-3-[5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-acrylic acid methyl ester and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][CH:9]=[C:8]2[C:14](=[O:16])[CH3:15])=[O:4].C(O)CO.[OH-].[K+]>O1CCCC1>[C:14]([C:8]1[C:7]2[C:11](=[CH:12][CH:13]=[C:5]([C:3]([OH:4])=[O:2])[CH:6]=2)[NH:10][CH:9]=1)(=[O:16])[CH3:15]
Reactant: COC(=O)c1ccc2[nH]cc(C(C)=O)c2c1
Agent: [K+]
Agent: [OH-]
Solvent: OCCO
Solvent: C1CCOC1
Product: CC(=O)c1c[nH]c2ccc(C(=O)O)cc12
Temperature: 25 °C

Procedure:
0.686 g (3.16 mmol) methyl-3-acetylindole-5-carboxylate are dissolved under heat in 10 ml tetrahydrofurane and 10 ml ethylene glycol and mixed with 7.08 g (0.13 mol) potassium hydroxide. Having stirred under reflux for 30 minutes, the reaction mixture is cooled to room temperature. The tetrahydrofurane is removed on the rotary evaporator and the solution is acidified under ice cooling with 20 ml 6N hydrochloric acid. The precipitated light violet precipitate is sucked off and dried.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]([OH:10])([CH3:9])[C:5]([F:8])([F:7])[F:6].[Br:12][C:13]1[CH:14]=[C:15]([C:19](=[O:23])[CH:20]=[N+]=[N-])[CH:16]=[CH:17][CH:18]=1>C(Cl)Cl.C(O)(C(F)(F)F)=O.C(O)(C(F)(F)F)=O.C(O)(C(F)(F)F)=O.C(O)(C(F)(F)F)=O.[Rh].[Rh]>[CH3:1][O:2][C:3](=[O:11])[C:4]([O:10][CH2:20][C:19]([C:15]1[CH:16]=[CH:17][CH:18]=[C:13]([Br:12])[CH:14]=1)=[O:23])([CH3:9])[C:5]([F:7])([F:6])[F:8]
Reactant: COC(=O)C(C)(O)C(F)(F)F
Reactant: [N-]=[N+]=CC(=O)c1cccc(Br)c1
Agent: [Rh]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)C(C)(OCC(=O)c1cccc(Br)c1)C(F)(F)F

Procedure:
To a solution of 3,3,3-trifluoro-2-hydroxy-2-methyl-propionic acid methyl ester (22.94 g, 133 mmol) in CH2Cl2 (400 ml) was added rhodium(II) trifluoroacetate dimer (0.439 g, 0.667 mmol). After cooling to 0° C. a solution of 1-(3-bromo-phenyl)-2-diazo-ethanone (15.0 g, 66.7 mmol) dissolved in CH2Cl2 (100 ml) was added over a period of 2 h. The reaction mixture was concentrated and the title compound was obtained after flash-chromatography on silica gel (toluene) as a yellow oil: TLC (toluene/EtOAc 10:1): Rf=0.45; HPLC RtH5=1.352 min; 1H NMR (360 MHz, CDCl3): δ 8.15 (s, 1H), 7.94 (d, 1H), 7.76 (d, 1H), 7.40 (t, 1H), 4.87 (s, 2H), 3.89 (s, 3H), 1.72 (s, 3H); ESIMS: 386, 388 [(M+NH4)+].
Reaction SMILES: [Br:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:6]=1[C:14]1[N:18]([CH3:19])[N:17]=[CH:16][CH:15]=1.[Cl:20]N1C(=O)CCC1=O>CN(C=O)C>[Br:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:6]=1[C:14]1[N:18]([CH3:19])[N:17]=[CH:16][C:15]=1[Cl:20]
Reactant: Cn1nccc1-c1cc([N+](=O)[O-])ccc1OCCBr
Reactant: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Product: Cn1ncc(Cl)c1-c1cc([N+](=O)[O-])ccc1OCCBr
Temperature: 100 °C
Reaction time: 0.33 h
Yield: 89 %

Procedure:
A mixture of 5-[2-(2-bromo-ethoxy)-5-nitro-phenyl]-1-methyl-1H-pyrazole (470 mg, 1.44 mmole), and N-chlorosuccinimide (1.44 mmole, 1.0 eq) in 2 mL of DMF was stirred at 100° C. for 20 minutes in the Microwave. The mixture was quenched with water, extract with ethyl acetate, and dried in vacuo give the title compound as a yellow solid (462 mg, 89%). 1H NMR (400 MHz, CDCl3) δ 3.61 (t, 2H), 3.78 (s, 3H), 4.44 (t, 2H), 7.13 (d, 1H), 7.57 (s, 1H), 8.23 (s, 1H), 8.40 (d, 1H). Exact mass calculated for C12H1181BrClN3O3 359.0, found 362.0 (MH+).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:29]=[CH:28][C:13]2[N:14]([CH:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)[C:15]([C:17]3[O:18][CH:19]=[CH:20][CH:21]=3)=[N:16][C:12]=2[CH:11]=1.[H][H]>CO.C(OCC)(=O)C.[C].[Pd]>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:29]=[CH:28][C:13]2[N:14]([CH:22]3[CH2:23][CH2:24][O:25][CH2:26][CH2:27]3)[C:15]([CH:17]3[CH2:21][CH2:20][CH2:19][O:18]3)=[N:16][C:12]=2[CH:11]=1
Reactant: [H][H]
Reactant: c1coc(-c2nc3cc(-c4nc5ccccc5o4)ccc3n2C2CCOCC2)c1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: c1ccc2oc(-c3ccc4c(c3)nc(C3CCCO3)n4C3CCOCC3)nc2c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 34.5 %

Procedure:
To a solution of 5-(benzoxazol-2-yl)-2-(furan-2-yl)-1-(tetrahydropyran-4-yl)benzimidazole (see Working Example 63) (90 mg, 0.234 mmol) in methanol/ethyl acetate (1:1, 6 mL) was added 10% palladium-carbon (20 mg), a hydrogen atmosphere was substituted in the flask, and this was stirred at room temperature for 20 hours. After the reaction was complete, this was filtered through Celite and the filtrate was concentrated. The residue obtained was purified by silica gel column chromatography to yield the title compound (31.4 mg, 34% yield) as a colorless amorphous mass.
Reaction SMILES: CC1(C)[O:9][C:8](=[O:10])[C:5]2([CH2:7][CH2:6]2)[C:4](=[O:11])O1.[F:13][C:14]1[CH:15]=[C:16]([CH:18]=[C:19]([F:21])[CH:20]=1)[NH2:17]>C(O)C>[F:13][C:14]1[CH:15]=[C:16]([N:17]2[CH2:6][CH2:7][CH:5]([C:8]([OH:9])=[O:10])[C:4]2=[O:11])[CH:18]=[C:19]([F:21])[CH:20]=1
Reactant: Nc1cc(F)cc(F)c1
Reactant: CC1(C)OC(=O)C2(CC2)C(=O)O1
Solvent: CCO
Product: O=C(O)C1CCN(c2cc(F)cc(F)c2)C1=O
Yield: 47.8 %

Procedure:
This compound was prepared according to general method 1 starting from 6,6-dimethyl-5,7-dioxaspiro[2.5]octane-4,8-dione (0.250 g; 1.45 mmol) and 3,5-difluoroaniline (0.575 g; 4.36 mmol) in ethanol (3 mL). 1-(3,5-difluorophenyl)-2-oxopyrrolidine-3-carboxylic acid 0.167 g (48%) was obtained as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:21]#[N:22])=[C:6]([C:8]2[C:13]([F:14])=[CH:12][N:11]([CH:15]([CH3:19])[C:16](O)=[O:17])[C:10](=[O:20])[CH:9]=2)[CH:7]=1.[NH2:23][C:24]1[CH:36]=[CH:35][C:27]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])=[CH:26][CH:25]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:21]#[N:22])=[C:6]([C:8]2[C:13]([F:14])=[CH:12][N:11]([CH:15]([CH3:19])[C:16]([NH:23][C:24]3[CH:36]=[CH:35][C:27]([C:28]([O:30][C:31]([CH3:32])([CH3:33])[CH3:34])=[O:29])=[CH:26][CH:25]=3)=[O:17])[C:10](=[O:20])[CH:9]=2)[CH:7]=1
Reactant: CC(C)(C)OC(=O)c1ccc(N)cc1
Reactant: CC(C(=O)O)n1cc(F)c(-c2cc(Cl)ccc2C#N)cc1=O
Product: CC(C(=O)Nc1ccc(C(=O)OC(C)(C)C)cc1)n1cc(F)c(-c2cc(Cl)ccc2C#N)cc1=O

Procedure:
54 mg (purity 90%, 0.15 mmol) of 2-[4-(5-chloro-2-cyanophenyl)-5-fluoro-2-oxopyridin-1(2H)-yl]propanoic acid (racemate) and 1.1 eq. of tert-butyl 4-aminobenzoate were reacted according to General Method 5A. Yield: 51 mg (67% of theory)
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7]([O-:10])(=[O:9])=[O:8])=[CH:3][CH:2]=1.C([O:16][C:17]1[CH:22]=[CH:21][C:20]([S+:23]([C:30]2[CH:35]=[CH:34][C:33]([O:36]C(C)(C)C)=[CH:32][CH:31]=2)[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:19][CH:18]=1)(C)(C)C.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[C:1]1([CH3:11])[CH:2]=[CH:3][C:4]([S:7]([O-:10])(=[O:8])=[O:9])=[CH:5][CH:6]=1.[OH:16][C:17]1[CH:22]=[CH:21][C:20]([S+:23]([C:30]2[CH:31]=[CH:32][C:33]([OH:36])=[CH:34][CH:35]=2)[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:19][CH:18]=1
Reactant: CC(C)(C)Oc1ccc([S+](c2ccccc2)c2ccc(OC(C)(C)C)cc2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Solvent: CO
Product: Oc1ccc([S+](c2ccccc2)c2ccc(O)cc2)cc1
Yield: 100 %

Procedure:
A solution of 5.8 g (0.01 mol) of bis(p-tert-butoxyphenyl)phenylsulfonium p-toluenesulfonate and 0.95 g (0.005 mol) of p-toluenesulfonic acid in 35 g of methanol was heated at 60° C. for 5 hours with stirring. The reaction mixture was evaporated in vacuo. The residual oil was washed two times with 200 g of diethyl ether. The amount of this crude product was 4.7 g (100% yield). Without further purification, the crude product was used in subsequent reaction.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10]([NH:12][CH2:13][CH:14]2[CH2:19][CH:18]([OH:20])[CH2:17][N:16]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:15]2)[C:9]2[C:4](=[N:5][CH:6]=[CH:7][N:8]=2)[CH:3]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>ClCCl.C(OCC)(=O)C>[Cl:1][C:2]1[N:11]=[C:10]([NH:12][CH2:13][CH:14]2[CH2:19][C:18](=[O:20])[CH2:17][N:16]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:15]2)[C:9]2[C:4](=[N:5][CH:6]=[CH:7][N:8]=2)[CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CC(O)CC(CNc2nc(Cl)cc3nccnc23)C1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC(=O)CC(CNc2nc(Cl)cc3nccnc23)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of tert-butyl 3-((7-chloropyrido[4,3-b]pyrazin-5-ylamino)methyl)-5-hydroxypiperidine-1-carboxylate (1.97 g, 5.0 mmol) in dichloromethane was added Dess-Martin periodinane (2.54 g, 6.0 mmol) at room temperature. The reaction mixture was stirred at room temperature overnight, then diluted with ethyl acetate, washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give the title compound.
Reaction SMILES: FC(F)(F)S(O[C@@H:7]1[C:11]([CH3:13])([CH3:12])[CH2:10][O:9][C:8]1=[O:14])(=O)=O.[N-:17]=[N+:18]=[N-:19].C([N+](CCCC)(CCCC)CCCC)CCC>C(Cl)Cl.CCOC(C)=O>[N:17]([C@H:7]1[C:11]([CH3:13])([CH3:12])[CH2:10][O:9][C:8]1=[O:14])=[N+:18]=[N-:19]
Reactant: CC1(C)COC(=O)[C@@H]1OS(=O)(=O)C(F)(F)F
Reactant: [N-]=[N+]=[N-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC1(C)COC(=O)[C@H]1N=[N+]=[N-]
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of (R)-4,4-dimethyl-2-oxotetrahydrofuran-3-yl trifluoromethanesulfonate (10 g) in DCM (10 mL) was added tetra-n-butylammonium azide (11.1 g). The reaction mixture was stirred at rt for 16 hr. The reaction was diluted with EtOAc, washed with water, sat. NaHCO3, citric acid, water, and sat. NaCl, dried over anhydrous Na2SO4, filtered and concentrated to yield an oil. The crude product was purified by silica gel chromatography (0-100% EtOAc in hexane) to yield (S)-3-azido-4,4-dimethyldihydrofuran-2(3H)-one as a white solid. 1H NMR (400 MHz, CHLOROFORM-d) ppm 3.87-4.02 (3H, m), 1.17 (3H, s), 1.02 (3H, s).
Reaction SMILES: [C:1](O)(=[O:6])[CH2:2][CH2:3][CH:4]=[CH2:5].C(N(CC)CC)C.ClC(OCC(C)C)=O.[CH3:23][O:24][C:25](=[O:52])[CH2:26][CH2:27][C@H:28]([C@@H:30]1[C@:47]2([CH3:48])[C@H:33]([C@H:34]3[C@H:44]([CH2:45][C@@H:46]2[OH:49])[C@:42]2([CH3:43])[C@@H:37]([CH2:38][C@@H:39]([NH2:50])[CH2:40][CH2:41]2)[CH2:36][C@H:35]3[OH:51])[CH2:32][CH2:31]1)[CH3:29]>C1COCC1>[CH3:23][O:24][C:25](=[O:52])[CH2:26][CH2:27][C@H:28]([C@@H:30]1[C@:47]2([CH3:48])[C@H:33]([C@H:34]3[C@H:44]([CH2:45][C@@H:46]2[OH:49])[C@:42]2([CH3:43])[C@@H:37]([CH2:38][C@@H:39]([NH:50][C:1](=[O:6])[CH2:2][CH2:3][CH:4]=[CH2:5])[CH2:40][CH2:41]2)[CH2:36][C@H:35]3[OH:51])[CH2:32][CH2:31]1)[CH3:29]
Reactant: C=CCCC(=O)O
Reactant: COC(=O)CC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3[C@H](O)C[C@@H]4C[C@@H](N)CC[C@]4(C)[C@H]3C[C@H](O)[C@]12C
Agent: CC(C)COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C=CCCC(=O)N[C@H]1CC[C@@]2(C)[C@@H](C1)C[C@@H](O)[C@@H]1[C@@H]2C[C@H](O)[C@]2(C)[C@@H]([C@H](C)CCC(=O)OC)CC[C@@H]12

Procedure:
A solution of 4-pentenoic acid (marketed product) and triethylamine in THF was added drop by drop, under nitrogen and at 5° C., to isobutyl chloroformate and subsequently with a solution of (3β,5β,7α,12α)-3-amino-7,12-dihydroxy-cholan-24-oic acid methyl ester (prepared according to the procedure described in EXAMPLE 5) in THF. When the reaction was over, solvent was evaporated and the residue was taken up with H2O and AcOEt. The organic phase was separated, washed with H2O, dried over Na2SO4 and evaporated under reduced pressure. The residue was purified by flash chromatography to obtain the desired product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])/[C:5]/2=[C:12](/[C:17]#[N:18])\[C:13]([O:15][CH3:16])=[O:14].[N+:19]([CH3:22])([O-:21])=[O:20].N1CCCCC1>C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2([CH:12]([C:17]#[N:18])[C:13]([O:15][CH3:16])=[O:14])[CH2:22][N+:19]([O-:21])=[O:20]
Reactant: COC(=O)/C(C#N)=C1\C(=O)Nc2ccc(Cl)cc21
Reactant: C[N+](=O)[O-]
Solvent: CCOC(C)=O
Solvent: C1CCNCC1
Product: COC(=O)C(C#N)C1(C[N+](=O)[O-])C(=O)Nc2ccc(Cl)cc21
Reaction time: 3 h
Yield: 73.8 %

Procedure:
A suspension of methyl (2Z)-(5-chloro-2-oxo-1,2-dihydro-3H-indol-3-ylidene)(cyano)acetate, intermediate 1 (10.000 g; 38.1 mmol) in dry nitromethane (61 ml; 1.14 mol) was treated with piperidine (189 μl; 1.90 mmol). After stirring for 3 hours, the mixture was diluted with ethyl acetate and filtered through silica. Evaporation of the solvent gave methyl [5-chloro-3-(nitromethyl)-2-oxo-2,3-dihydro-1H-indol-3-yl](cyano)acetate as an oil (9.1 g, 73.8%). This was a mixture of diastereomers which was sufficiently pure for subsequent reaction (HPLC purity 97%). MS (ESI+): 324.2; MS (ESI−): 322.2
Reaction SMILES: Cl.[C:2]([O:6][C:7](=[O:14])[C@H:8]([C@H:10]([CH2:12][CH3:13])[CH3:11])[NH2:9])([CH3:5])([CH3:4])[CH3:3].C(N(CC)CC)C.[C:22](Cl)(=[O:31])[C:23]1[C:24]([O:29][CH3:30])=[CH:25][CH:26]=[CH:27][CH:28]=1>C(Cl)Cl>[C:2]([O:6][C:7](=[O:14])[C@@H:8]([NH:9][C:22](=[O:31])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[O:29][CH3:30])[CH:10]([CH3:11])[CH2:12][CH3:13])([CH3:4])([CH3:5])[CH3:3]
Reactant: CC[C@H](C)[C@H](N)C(=O)OC(C)(C)C
Reactant: COc1ccccc1C(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC(C)[C@H](NC(=O)c1ccccc1OC)C(=O)OC(C)(C)C
Yield: 47.5 %

Procedure:
L-Isoleucine tertbutyl ester hydrochloride (500 mg, 2.23 mmol) was dissolved in CH2Cl2 (10 ml). Triethylamine (600 g, 6.0 mmol) and 2-anisoyl chloride (456 mg, 2.68 mmol) were added. After 18 h at room temperature the solvent was removed in vacuo and the residue was taken up in ethyl acetate (100 ml). This solution was washed with 0.3M KHSO4, sat. NaHCO3, water and brine, dried (Na2SO4) and evaporated in vacuo. The residue was purified by flash chromatography (eluant: 60% Pet. ether, 40% ethyl acetate) to give a colourless oil identified as the title compound (341 mg, 1.06 mmol, 48%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([S:8]([N:11]=[CH:12][N:13]([CH3:15])[CH3:14])(=[O:10])=[O:9])=[CH:6][C:5]([CH2:16][NH:17][CH:18]2[CH2:23][CH:22]([CH3:24])[CH2:21][C:20]([CH3:26])([CH3:25])[CH2:19]2)=[CH:4][CH:3]=1.[CH3:27][S:28](Cl)(=[O:30])=[O:29].N1C=CC=CC=1>C(Cl)Cl>[Cl:1][C:2]1[C:7]([S:8]([N:11]=[CH:12][N:13]([CH3:15])[CH3:14])(=[O:10])=[O:9])=[CH:6][C:5]([CH2:16][N:17]([CH:18]2[CH2:23][CH:22]([CH3:24])[CH2:21][C:20]([CH3:25])([CH3:26])[CH2:19]2)[S:28]([CH3:27])(=[O:30])=[O:29])=[CH:4][CH:3]=1
Reactant: CC1CC(NCc2ccc(Cl)c(S(=O)(=O)N=CN(C)C)c2)CC(C)(C)C1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC1CC(N(Cc2ccc(Cl)c(S(=O)(=O)N=CN(C)C)c2)S(C)(=O)=O)CC(C)(C)C1

Procedure:
This compound is obtained as an oil by reacting 6-chloro-N-dimethylaminomethylene-3-[(3,3,5-trimethylcyclohexylamino)methyl]benzenesulfonamide with methanesulfonyl chloride in methylene chloride in the presence of pyridine as auxiliary base and by purification by column chromatography (silica gel, methylene chloride:methanol=95:5).