Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C@@H:4]([NH2:12])[CH2:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.C(N(CC)C(C)C)(C)C.C([O:25][C:26](=O)/[CH:27]=[C:28](/[O:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[O:38][CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)\[CH2:29]Br)C>CN(C)C=O>[CH3:1][O:2][C:3](=[O:13])[C@@H:4]([N:12]1[CH2:29][C:28]([O:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2[O:38][CH2:39][C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=2)=[CH:27][C:26]1=[O:25])[CH2:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: COC(=O)[C@@H](N)CC1CCCCC1
Reactant: CCOC(=O)/C=C(\CBr)Oc1ccccc1OCc1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@H](CC1CCCCC1)N1CC(Oc2ccccc2OCc2ccccc2)=CC1=O
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 16 %

Procedure:
To a stirred solution of (S)-2-amino-3-cyclohexyl-propionic acid methyl ester (1.05 g, 0.006 mol) in N,N-dimethylformamide (8 mL) was added N,N-diisopropylethylamine (3.30 g, 0.026 mol) slowly at room temperature, under nitrogen. The resulting mixture was stirred for 5 min and then treated with (E)-3-(2-benzyloxy-phenoxy)-4-bromo-but-2-enoic acid ethyl ester (2.00 g, 0.005 mol) and the reaction mixture was heated at 110° C.-120° C. for 16 h. After this time, ice water was added and the resulting mixture was extracted with ethyl acetate. The combined organic layers were washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate and concentrated in vacuo. Purification by flash column chromatography (silica gel (100-200 mesh)) afforded (S)-2-[4-(2-benzyloxy-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-3-cyclohexyl-propionic acid methyl ester (360 mg, 14%) as a yellow oil.
Reaction SMILES: [CH:1]1([CH2:4][CH2:5][NH:6][C:7]([C:9]2[N:10]=[N:11][C:12](Cl)=[CH:13][CH:14]=2)=[O:8])[CH2:3][CH2:2]1.[N:16]1([C:22]([CH:24]2[C:26]([CH3:28])([CH3:27])[C:25]2([CH3:30])[CH3:29])=[O:23])[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1>>[CH:1]1([CH2:4][CH2:5][NH:6][C:7]([C:9]2[N:10]=[N:11][C:12]([N:19]3[CH2:20][CH2:21][N:16]([C:22]([CH:24]4[C:25]([CH3:30])([CH3:29])[C:26]4([CH3:28])[CH3:27])=[O:23])[CH2:17][CH2:18]3)=[CH:13][CH:14]=2)=[O:8])[CH2:3][CH2:2]1
Reactant: O=C(NCCC1CC1)c1ccc(Cl)nn1
Reactant: CC1(C)C(C(=O)N2CCNCC2)C1(C)C
Product: CC1(C)C(C(=O)N2CCN(c3ccc(C(=O)NCCC4CC4)nn3)CC2)C1(C)C

Procedure:
Following the procedure of Example 15, making variations only as required to use 6-chloropyridazine-3-carboxylic acid (2-cyclopropylethyl)amide in place of 6-chloropyridazine-3-carboxylic acid (2-cyclopropyl-2-hydroxyethyl)amide to react with piperazin-1-yl-(2,2,3,3-tetramethylcyclopropyl)methanone, the title compound was obtained as a white solid (35% yield). 1H NMR (400 MHz, CDCl3) δ 8.07, 8.01, 7.01, 3.91-3.89, 3.81-3.65, 3.57, 1.21, 1.19, 0.79-0.072, 0.49-0.46, 0.11-0.10. MS (ES+) m/z 400 (M+1).
Reaction SMILES: Cl[CH:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][O:5][C:4]2[CH:13]=[CH:14][C:15]([C:17]([O:19][CH3:20])=[O:18])=[CH:16][C:3]1=2.[CH:21]([NH2:23])=[O:22]>O>[CH:21]([NH:23][CH:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][O:5][C:4]2[CH:13]=[CH:14][C:15]([C:17]([O:19][CH3:20])=[O:18])=[CH:16][C:3]1=2)=[O:22]
Reactant: COC(=O)c1ccc2c(c1)C(Cl)c1ccccc1CO2
Reactant: NC=O
Solvent: O
Product: COC(=O)c1ccc2c(c1)C(NC=O)c1ccccc1CO2
Temperature: 110 °C
Yield: 90 %

Procedure:
Add 2.35 gm. of methyl 6,11-dihydro-11-chlorodibenz[b,e]oxepin-2-carboxylate to 20 ml. of formamide. Stir and heat the mixture at 110° C. for 3 hours. Cool to room temperature, dilute with water and separate the solids by filtration to obtain the title product (Yield 2.18 gm., 90%).
Reaction SMILES: C([O:3][C:4](=[O:25])[CH2:5][CH:6]1[CH2:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:16][CH2:17][CH2:18][CH2:19][NH:20][C:21]([NH2:23])=[NH:22])[CH:13]=2)[NH:8][C:7]1=[O:24])C.[OH-].[Na+].FC(F)(F)C(O)=O>C(O)C>[NH:20]([CH2:19][CH2:18][CH2:17][O:16][C:12]1[CH:13]=[C:14]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:24])[CH:6]([CH2:5][C:4]([OH:25])=[O:3])[CH2:15]2)[C:21]([NH2:23])=[NH:22]
Reactant: CCOC(=O)CC1Cc2cc(OCCCNC(=N)N)ccc2NC1=O
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: CCO
Product: N=C(N)NCCCOc1ccc2c(c1)CC(CC(=O)O)C(=O)N2
Temperature: 25 °C
Yield: 74.1 %

Procedure:
A solution of [6-(3-Guanidino-propoxy)-2-oxo-1,2,3,4-tetrahydro-quinolin-3-yl]-acetic acid ethyl ester (0.76 g, 1.6 mmol) in ethanol (7 mL) was treated with 0.5 N aqueous NaOH and heated at reflux for 3 h. The resulting precipitate was cooled to room temperature, treated with trifluoroacetic acid (1.5 mL) and the solution thus formed concentrated in vacuo to yield a clear, colorless oil. Purification by reverse phase HPLC gave the title compound (0.38 g, 55% yield) as a fluffy white solid.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]#[C:11][C:12]1([OH:25])[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Li]CCCC.[C:31](Cl)(=[O:34])[O:32][CH3:33]>C1COCC1>[C:21]([O:20][C:18]([N:15]1[CH2:16][CH2:17][C:12]([C:11]#[C:10][CH2:9][O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])([O:25][C:31]([O:32][CH3:33])=[O:34])[CH2:13][CH2:14]1)=[O:19])([CH3:24])([CH3:23])[CH3:22]
Reactant: COC(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCC(O)(C#CCO[Si](C)(C)C(C)(C)C)CC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COC(=O)OC1(C#CCO[Si](C)(C)C(C)(C)C)CCN(C(=O)OC(C)(C)C)CC1
Temperature: -78 °C
Reaction time: 1 h
Yield: 78.3 %

Procedure:
To a solution of tert-butyl 4-(3-((tert-butyldimethylsilyl)oxy)prop-1-yn-1-yl)-4-hydroxypiperidine-1-carboxylate (500 mg, 1.353 mmol) in 30 mL of anhydrous THF was added dropwise n-BuLi (0.65 mL, 1.623 mmol) at −78° C. under N2. After stirring for 1 h at −78° C., methyl carbonochloridate (176.2 mg, 1.623 mmol) in THF (1 mL) was added dropwise to the above solution at −78° C. under N2. The resulting mixture was stirred at −78° C. under N2 for 2 h, then allowed to warm to r.t. and stirred for another 8 h. The reaction mixture was cooled to −78° C. and quenched by sat. NH4Cl aq., and the resulting mixture was extracted with EtOAc (50 mL, 30 mL). The combined organic phase was washed with brine, dried over anhy. Na2SO4 and concentrated in vacuo. Column chromatography (15% PE/EtOAc) afforded 453 mg of title compound. 1H NMR (CHLOROFORM-d) δ: 4.40 (s, 2H), 4.26-4.15 (m, 2H), 3.80-3.67 (m, 2H), 3.41-3.28 (m, 2H), 2.27-2.14 (m, 2H), 2.00 (ddd, J=13.1, 9.2, 3.9 Hz, 2H), 1.48 (s, 9H), 1.33 (t, J=7.1 Hz, 4H), 0.92 (s, 9H), 0.14 (s, 6H).
Reaction SMILES: O[CH:2]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[CH:19]=[CH:18][C:14]([C:15]([NH2:17])=[O:16])=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)[CH2:3][CH3:4].P(Br)(Br)[Br:21]>C(Cl)(Cl)Cl.O>[Br:21][CH:2]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[CH:19]=[CH:18][C:14]([C:15]([NH2:17])=[O:16])=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)[CH2:3][CH3:4]
Reactant: BrP(Br)Br
Reactant: CCC(O)c1ccc(-c2ccc(C(N)=O)cc2)cn1
Solvent: ClC(Cl)Cl
Solvent: O
Product: CCC(Br)c1ccc(-c2ccc(C(N)=O)cc2)cn1
Temperature: 25 °C
Yield: 96.4 %

Procedure:
To a solution of 4-(6-(1-hydroxypropyl)pyridin-3-yl)benzamide (0.1 g, 0.39 mmol) in chloroform (15 mL) was added PBr3 (0.316 g, 1.17 mmol) at 0-5° C. The solution was maintained at the same temperature for 1 h, was slowly warmed to rt and maintained at rt for another 2 h. The contents were diluted with water (75 mL) and chloroform (100 mL), the layers separated, the organic layer was washed with bicarbonate solution (2×30 mL), and the organic layer was dried over sodium sulphate and distilled off to get the crude product. The non-polar impurity was removed by pentane washings (2×7 mL) to provide 4-(6-(1-bromopropyl)pyridin-3-yl)benzamide (0.12 g, crude). LC-MS m/z calcd for [M+H]+ 321.03. found 321.0.
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[CH:2]1.ClC1C=CC=C(C(OO)=[O:18])C=1>COCCOC>[NH:1]1[C:5]2=[N+:6]([O-:18])[CH:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[CH:2]1
Reactant: c1cnc2[nH]ccc2c1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: COCCOC
Product: [O-][n+]1cccc2cc[nH]c21
Temperature: 25 °C
Reaction time: 2 h
Yield: 64.1 %

Procedure:
To a solution of 1H-pyrrolo[2,3-b]pyridine (495 mg) in 1,2-dimethoxyethane (20 mL) was added 3-chloroperbenzoic acid (1.48 g) at room temperature, and then the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was quenched with water, and extracted with chloroform. The obtained organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the titled compound (360 mg) as a white solid.
Reaction SMILES: C(OC(=O)[NH:10][CH:11]1[CH:18]2[CH:14]([O:15][C:16]([CH3:20])([CH3:19])[O:17]2)[CH:13]([O:21][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23])[CH2:12]1)C1C=CC=CC=1>CCO.[C].[Pd]>[Si:22]([O:21][CH:13]1[CH:14]2[O:15][C:16]([CH3:20])([CH3:19])[O:17][CH:18]2[CH:11]([NH2:10])[CH2:12]1)([C:25]([CH3:28])([CH3:26])[CH3:27])([CH3:23])[CH3:24]
Reactant: CC1(C)OC2C(NC(=O)OCc3ccccc3)CC(O[Si](C)(C)C(C)(C)C)C2O1
Agent: [Pd]
Solvent: CCO
Product: CC1(C)OC2C(N)CC(O[Si](C)(C)C(C)(C)C)C2O1
Reaction time: 8 h

Procedure:
Palladium-carbon (10%) was added to a solution of benzyl((3aRS,4SR,6RS,6aRS)-6-{[tert-butyl(dimethyl)silyl]oxy}-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)carbamate in EtOH, for stirring overnight under hydrogen atmosphere, to obtain (3aRS,4SR,6RS,6aRS)-6-{[tert-butyl(dimethyl)silyl]oxy}-2,2-dimethyltetrahydro-3 aH-cyclopenta[d][1,3]dioxol-4-amine.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][NH:10][C:11]2[C:20]3[C:15](=[CH:16][C:17]([O:21][CH2:22][CH2:23][CH2:24][Cl:25])=[CH:18][CH:19]=3)[N:14]=[CH:13][N:12]=2)=[CH:4][CH:3]=1.[C:26]1([N:32]=[C:33]=[O:34])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C(Cl)Cl>[Cl:25][CH2:24][CH2:23][CH2:22][O:21][C:17]1[CH:16]=[C:15]2[C:20]([C:11]([NH:10][CH2:9][CH2:8][C:5]3[CH:6]=[CH:7][C:2]([NH:1][C:33]([NH:32][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)=[O:34])=[CH:3][CH:4]=3)=[N:12][CH:13]=[N:14]2)=[CH:19][CH:18]=1
Reactant: Nc1ccc(CCNc2ncnc3cc(OCCCCl)ccc23)cc1
Reactant: O=C=Nc1ccccc1
Solvent: ClCCl
Product: O=C(Nc1ccccc1)Nc1ccc(CCNc2ncnc3cc(OCCCCl)ccc23)cc1
Yield: 92.9 %

Procedure:
A solution of [2-(4-amino-phenyl)-ethyl]-[7-(3-chloro-propoxy)-quinazolin-4-yl]-amine (34 mg, 0.095 mmol) and phenyl isocyanate (17.0 mg, 0.143 mmol) in methylene chloride (8 mL) was stirred under nitrogen at room temperature overnight. The solid product formed was filtered to give the title compound as a solid (42 mg, 93%). 1H-NMR (300 MHz, d6-DMSO): δ 8.66 (s, 1H), 8.63 (s, 1H), 8.42 (s, 1H), 8.20 (t, 1H), 8.13 (d, J=9.0 Hz, 1H), 7.42-7.46 (m, 2H), 7.37 (d, J=8.4 Hz, 2H), 7.24-7.29 (m, 2H), 7.08-7.18 (m, 4H), 6.96 (t, 1H), 4.23 (t, 2H), 3.83 (t, 2H), 3.70 (q, 2H), 2.89 (t, 2H), 2.18-2.27 (m, 2H). LC-MS (ESI) m/z: 476.4 (M+1).
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:9]3[CH:10]=[CH:11][C:12]([S:14]([CH:17]4[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]4)(=[O:16])=[O:15])=[CH:13][C:8]=3[N:7]=[C:6]2[CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:3][CH2:2]1.C(N(CC)CC)C.[C:35]1([C:41](Cl)([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>ClCCl>[CH:1]1([CH2:4][N:5]2[C:9]3[CH:10]=[CH:11][C:12]([S:14]([CH:17]4[CH2:22][CH2:21][N:20]([C:41]([C:35]5[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=5)([C:48]5[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=5)[C:42]5[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=5)[CH2:19][CH2:18]4)(=[O:15])=[O:16])=[CH:13][C:8]=3[N:7]=[C:6]2[CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:2][CH2:3]1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)Cc1nc2cc(S(=O)(=O)C3CCNCC3)ccc2n1CC1CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)Cc1nc2cc(S(=O)(=O)C3CCN(C(c4ccccc4)(c4ccccc4)c4ccccc4)CC3)ccc2n1CC1CC1
Reaction time: 14 h
Yield: 93.7 %

Procedure:
To a solution of 1-(cyclopropylmethyl)-2-neopentyl-5-(piperidin-4-ylsulfonyl)-1H-benzo[d]imidazole (STEP D, 1.31 g, 3.36 mmol) and triethylamine (945 microL, 6.73 mmol) in dichloromethane (12 mL) was added triphenylmethyl chloride (1.22 g, 4.37 mmol) at room temperature. After stirring for 14 h, the mixture was diluted with dichloromethane and washed with saturated sodium bicarbonate aqueous solution. The organic layer was dried over sodium sulfate and concentrated in vacuo. The precipitate was washed with a mixture of diethyl ether and hexane (1:1) to give the title compound (1.99 g, 94%) as a white solid.
Reaction SMILES: CC(C)([O-])C.[K+].[CH3:7][C:8]([CH3:23])([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1)[C:9]([O:11]CC)=[O:10].Cl>O.O1CCCC1>[CH3:7][C:8]([CH3:23])([CH2:14][C:15]1[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=1)[C:9]([OH:11])=[O:10]
Reactant: CCOC(=O)C(C)(C)Cc1ccc(OC)cc1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(CC(C)(C)C(=O)O)cc1
Reaction time: 16 h
Yield: 96 %

Procedure:
Potassium tert-butoxide (38.0 g, 0.34 mol) was added to a solution of ethyl 2,2-dimethyl-3-(4-methoxyphenyl)propanoate (40.0 g, 0.17 mol) in a mixture of water (4 mL) and tetrahydrofuran (800 mL) at room temperature and stirred for 16 h. The pH of the reaction mixture was adjusted to ˜2 with 2 N HCl (250 mL) and extracted with EtOAc (800 mL). Aqueous layer was saturated with NaCl and extracted again with EtOAc (800 mL). The combined organic layers were washed with brine (350 mL), dried over Na2SO4, and concentrated to afford 34.0 g (96%) of 2,2-dimethyl-3-(4-methoxyphenyl)propanoic acid as a gummy oil; 1H NMR (200 MHz, CDCl3) δ 7.08 (d, J=8.4 Hz, 2H), 6.80 (d, J=8.4 Hz, 2H), 3.78 (s, 3H), 2.83 (s, 2H), 1.19 (s, 6H).
Reaction SMILES: C([N:14]1[CH2:17][C:16]([NH:19][C:20]2[CH:21]=[C:22]3[C:31](=[CH:32][C:33]=2[C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[O:30][CH2:29][C:28]2[N:23]3[CH:24]([CH3:41])[C:25](=[O:40])[NH:26][N:27]=2)([CH3:18])[CH2:15]1)(C1C=CC=CC=1)C1C=CC=CC=1>C1COCC1.CO.Cl.[OH-].[OH-].[Pd+2]>[CH3:41][CH:24]1[N:23]2[C:28]([CH2:29][O:30][C:31]3[C:22]2=[CH:21][C:20]([NH:19][C:16]2([CH3:18])[CH2:17][NH:14][CH2:15]2)=[C:33]([C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH:32]=3)=[N:27][NH:26][C:25]1=[O:40]
Reactant: CC1C(=O)NN=C2COc3cc(-c4ccccc4)c(NC4(C)CN(C(c5ccccc5)c5ccccc5)C4)cc3N21
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC1C(=O)NN=C2COc3cc(-c4ccccc4)c(NC4(C)CNC4)cc3N21
Temperature: 50 °C
Yield: 139.8 %

Procedure:
To a solution of 6-(1-benzhydryl-3-methyl-azetidin-3-ylamino)-4-methyl-7-phenyl-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one (Example #79, Step C, 0.10 g, 0.18 mmol) in THF (20 mL), MeOH (20 mL) and aqueous HCl (12N, 0.3 mL) was added Pd(OH)2/C (10%, 0.02 g, 0.014 mmol) and the solution was heated at 50° C. under an atmosphere of H2 (55 psi) for 4 h. The reaction mixture was cooled to ambient temperature and filtered. The filtrate was evaporated in vacuo to give 4-methyl-6-(3-methyl-azetidin-3-ylamino)-7-phenyl-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one (0.095 g, 57% pure, 82%), which was used in the next step directly without further purification. LC/MS (Table 1, Method 2) Rt=0.890 min; MS m/z: 378 [M+H]+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[N:8]([C:16]3[CH:21]=[CH:20][C:19]([S:22]([NH2:25])(=[O:24])=[O:23])=[CH:18][CH:17]=3)[CH:9]=[C:10]([C:12]([F:15])([F:14])[F:13])[N:11]=2)[CH:2]=1.[C:26](OC(=O)C)(=[O:28])[CH3:27].C(N(CC)CC)C>CN(C)C1C=CN=CC=1.O>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[N:8]([C:16]3[CH:21]=[CH:20][C:19]([S:22]([NH:25][C:26](=[O:28])[CH3:27])(=[O:23])=[O:24])=[CH:18][CH:17]=3)[CH:9]=[C:10]([C:12]([F:13])([F:14])[F:15])[N:11]=2)[CH:2]=1
Reactant: NS(=O)(=O)c1ccc(-n2cc(C(F)(F)F)nc2-c2cccnc2)cc1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: O
Product: CC(=O)NS(=O)(=O)c1ccc(-n2cc(C(F)(F)F)nc2-c2cccnc2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 89.6 %

Procedure:
A mixture of 4-[2-(pyridin-3-yl)-4-(trifluoromethyl)-1H-imidazol-1-yl]benzenesulfonamide (0.5 g, 1.36 mmol), acetic anhydride (0.42 g, 4.1 mmol), 4-dimethylaminopyridine (DMAP) (0.083 g, 0.68 mmol) and triethylamine (0.17 g, 1.6 mmol) was stirred at room temperature for 16 hours. The reaction mixture was diluted with 50 mL of water and extracted with ethyl acetate. The organic layer was washed with water, brine, dried over magnesium sulfate and filtered. The filtrate was concentrated under vacuum and the residue was recrystallized from ethyl acetate and hexane to afford 0.5 g (90%) of N-[[4-[2-(3-pyridinyl)-4-(trifluoromethyl)-1H-imidazol-1-yl]phenyl]sulfonyl]acetamide as a colorless solid: mp (DSC): 244-246 _C. Anal. Calc'd. for C17H13F3N4O3S: C, 49.76; H, 3.19; N, 13.65; S, 7.81. Found: C, 49.66; H, 3.06; N, 13.53; S, 8.11.
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][CH2:5][N:4]([C:7]2[C:15]3[C:14]4[CH:16]=[C:17]([C:20]#[N:21])[N:18]=[CH:19][C:13]=4[N:12]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:11]=3[N:10]=[CH:9][CH:8]=2)[CH2:3]1.[Cl:30]N1C(=O)CCC1=O>C(#N)C.C(O)(C)C>[Cl:30][C:8]1[CH:9]=[N:10][C:11]2[N:12]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:13]3[CH:19]=[N:18][C:17]([C:20]#[N:21])=[CH:16][C:14]=3[C:15]=2[C:7]=1[N:4]1[CH2:5][CH2:6][C@H:2]([OH:1])[CH2:3]1
Reactant: O=C1CCC(=O)N1Cl
Reactant: C[Si](C)(C)CCOCn1c2cnc(C#N)cc2c2c(N3CC[C@H](O)C3)ccnc21
Solvent: CC(C)O
Solvent: CC#N
Product: C[Si](C)(C)CCOCn1c2cnc(C#N)cc2c2c(N3CC[C@H](O)C3)c(Cl)cnc21
Temperature: 35 °C
Reaction time: 5 h

Procedure:
A mixture of (S)-4-(3-hydroxypyrrolidin-1-yl)-9-((2-(trimethylsilyl)ethoxy)methyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile (140 mg, 0.34 mmol) and N-chlorosuccinimide (137 mg, 1.02 mmol) in acetonitrile (1.3 mL) and isopropyl alcohol (0.4 mL) was stirred at 35° C. for 5 hours. The cooled reaction mixture was quenched with saturated aqueous sodium thiosulfate (1 mL), diluted with ethyl acetate (50 mL), and washed with water (20 mL). The organic layer was separated, dried over sodium sulfate, filtered, concentrated in vacuo, and purified by flash chromatography (silica, 4 g, ISCO, 0-50% ethyl acetate in heptane) to afford the title compound as a pale yellow solid, which was used in the next step without any further purification (100 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:21]([C:24]2[C:29]([F:30])=[CH:28][CH:27]=[CH:26][N:25]=2)=[CH:20][C:3]=1[C:4]([NH:6][C:7]1[N:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:10]=[C:9]([C:18]#[N:19])[CH:8]=1)=[O:5].C([O-])([O-])=[O:32].[K+].[K+].OO>CS(C)=O.O.Cl>[Cl:1][C:2]1[CH:23]=[CH:22][C:21]([C:24]2[C:29]([F:30])=[CH:28][CH:27]=[CH:26][N:25]=2)=[CH:20][C:3]=1[C:4]([NH:6][C:7]1[N:11]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:10]=[C:9]([C:18]([NH2:19])=[O:32])[CH:8]=1)=[O:5]
Reactant: N#Cc1cc(NC(=O)c2cc(-c3ncccc3F)ccc2Cl)n(-c2ccccc2)n1
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: NC(=O)c1cc(NC(=O)c2cc(-c3ncccc3F)ccc2Cl)n(-c2ccccc2)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 50.5 %

Procedure:
To a solution of 2-chloro-N-(3-cyano-1-phenyl-1H-pyrazol-5-yl)-5-(3-fluoropyridin-2-yl)benzamide (Example 90, 100 mg, 0.24 mmol) in DMSO (3 mL) was added K2CO3 (66 mg, 0.48 mmol) and H2O2 (30% aqueous solution, 1.5 mL) and the reaction was stirred at room temperature for 18 hours. The reaction was diluted with water (1 mL), and 2M aqueous HCl (3 mL) was added resulting in precipitation of a white solid. The solid was filtered, washed with water and dried to afford the title compound as a colourless solid (52.8 mg, 51%).
Reaction SMILES: [Cl:1][C:2]([Cl:7])([Cl:6])[C:3](Cl)=[O:4].[Cl:8][C:9]1[C:10]([F:21])=[C:11]([CH:18]=[CH:19][CH:20]=1)/[CH:12]=[CH:13]/[C:14](=[N:16]O)[NH2:15].N1C=CC=CC=1.Cl.N1C=CC=CC=1>C(Cl)(Cl)Cl>[Cl:8][C:9]1[C:10]([F:21])=[C:11]([CH:18]=[CH:19][CH:20]=1)/[CH:12]=[CH:13]/[C:14]1[N:16]=[C:3]([C:2]([Cl:7])([Cl:6])[Cl:1])[O:4][N:15]=1
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Reactant: NC(/C=C/c1cccc(Cl)c1F)=NO
Agent: Cl
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: Fc1c(Cl)cccc1/C=C/c1noc(C(Cl)(Cl)Cl)n1
Reaction time: 1 h
Yield: 48.7 %

Procedure:
12.7 g (0.07 mol) of trichloroacetyl chloride are added dropwise to a suspension of 6.4 g (0.03 mol) of (E)-3-chloro-2-fluoro-cinnamamide oxime in 90 ml of chloroform and 6 ml (0.07 mol) of dry pyridine. During this process the temperature of the reaction mixture rises slightly. Stirring is subsequently continued for 1 hour, and the pyridine hydrochloride which separates out in this process is filtered off and washed with chloroform. The filtrate is concentrated in vacuo and the solid which remains is recrystallised. 5.0 g (48.7 % of theory) of (E)-3-(3-chloro-2-fluoro-styryl)-5-trichloromethyl-1,2,4-oxadiazole are obtained.
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3]([CH:18]=[N:19][C:20]1[C:28]([CH3:29])=[CH:27][CH:26]=[C:25]2[C:21]=1[CH:22]=[N:23][NH:24]2)([OH:17])[CH2:4][C:5]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[C:9]=1[O:15]C)([CH3:7])[CH3:6].B(Br)(Br)Br.C(=O)(O)[O-].[Na+].C(OCC)(=O)C>ClCCl>[CH3:29][C:28]1[C:20]([NH:19][CH:18]2[C:13]3[CH:12]=[CH:11][C:10]([F:14])=[C:9]([OH:15])[C:8]=3[C:5]([CH3:6])([CH3:7])[CH2:4][C:3]2([C:2]([F:31])([F:30])[F:1])[OH:17])=[C:21]2[C:25](=[CH:26][CH:27]=1)[NH:24][N:23]=[CH:22]2
Reactant: COc1c(F)cccc1C(C)(C)CC(O)(C=Nc1c(C)ccc2[nH]ncc12)C(F)(F)F
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Cc1ccc2[nH]ncc2c1NC1c2ccc(F)c(O)c2C(C)(C)CC1(O)C(F)(F)F
Reaction time: 4 h

Procedure:
1,1,1-Trifluoro-4-(3-fluoro-2-methoxyphenyl)-4-methyl-2-[(5-methyl-1H-indazol-4-ylimino)-methyl]-pentan-2-ol (150 mg, 0.34 mmol) is mixed with boron tribromide (3.40 ml of a 1 M solution in dichloromethane, 3.4 mmol) at room temperature. After 4 hours at room temperature, the reaction mixture is allowed to stand overnight at −30° C., then saturated sodium bicarbonate solution and ethyl acetate are added. It is extracted with ethyl acetate, and the combined organic phases are washed with saturated sodium chloride solution and dried on sodium sulfate. After the solvent is removed in a vacuum as well as purification by means of preparative thin-layer chromatography on silica gel with hexane/ethyl acetate (50% ethyl acetate), 56 mg (39% of theory) of the product is obtained.
Reaction SMILES: [H-].[Na+].[CH3:3][C@@H:4]([CH2:15][CH2:16][CH2:17][CH3:18])[C:5]([NH:7][C@@H:8]([CH2:12][CH:13]=[CH2:14])[C:9]([OH:11])=[O:10])=[O:6].I[CH3:20]>C1COCC1>[CH3:20][N:7]([C@@H:8]([CH2:12][CH:13]=[CH2:14])[C:9]([OH:11])=[O:10])[C:5](=[O:6])[C@H:4]([CH3:3])[CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: C=CC[C@H](NC(=O)[C@@H](C)CCCC)C(=O)O
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CC[C@@H](C(=O)O)N(C)C(=O)[C@H](C)CCCC
Temperature: 25 °C
Reaction time: 18 h
Yield: 80 %

Procedure:
Step D (3): General procedure: Sodium hydride (60% dispersion in mineral oil, 231 mg, 5.79 mmol) was carefully added portionwise to a solution of (S)-2-((S)-2-methylhexanamido)pent-4-enoic acid (diastereomer A from Step D (2), 440 mg, 1.93 mmol) and iodomethane (961 μL, 15.4 mmol) in THF (25 mL) at 0° C. The resulting mixture was allowed to warm to rt and stirred overnight (18 h). The reaction was chilled to 0° C. and quenched with EtOAc. The mixture was diluted with water and poured into 1 N NaOH. The aqueous layer was extracted with diethyl ether. The aqueous layer was then acidified with 1 N HCl and extracted with EtOAc. The second organic extract was sequentially washed with aqueous sodium bisulfite solution and brine solution. The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo to provide 370 mg (80% yield) of the title compound (diastereomer A) as a clear viscous oil. Diastereomer B from Step D (2) was subject to the same procedure to afford 580 mg (97% yield) of the title compound (diastereomer B) as a clear viscous oil. Data for diastereomer A: LRMS (M−H)−=240.1 1H NMR (500 MHz, CDCl3) δ ppm 0.82-0.90 (m, 3H) 1.05-1.13 (m, 3H) 1.17-1.42 (m, 5H) 1.62-1.73 (m, 1H) 2.52-2.61 (m, 1H) 2.63-2.87 (m, 2H) 2.99 (d, J=3.36 Hz, 3H) 5.00-5.16 (m, 3H) 5.64-5.76 (m, 1H). Data for diastereomer B: LRMS (M−H)−=240.2; 1H NMR (500 MHz, CDCl3) δ ppm 0.82-0.90 (m, 3H) 1.10 (dd, J=11.29, 6.71 Hz, 3H) 1.17-1.43 (m, 5H) 1.60-1.75 (m, 1H) 2.52-2.83 (m, 3H) 2.99 (d, J=3.05 Hz, 3H) 5.01-5.16 (m, 3H) 5.63-5.77 (m, 1H).