Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:21]=[CH:22][CH:23]=1)[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]([O:19]C)=[O:18])=[CH:14][CH:15]=2)[CH:10]=[CH:9]1)([O-:3])=[O:2].[OH-].[Na+].Cl>O1CCCC1.CO>[N+:1]([C:4]1[CH:5]=[C:6]([CH:21]=[CH:22][CH:23]=1)[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]([OH:19])=[O:18])=[CH:14][CH:15]=2)[CH:10]=[CH:9]1)([O-:3])=[O:2]
Reactant: COC(=O)c1ccc2c(ccn2Cc2cccc([N+](=O)[O-])c2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1ccc2c(ccn2Cc2cccc([N+](=O)[O-])c2)c1

Procedure:
To a solution of the methyl ester (Example 1) (12.5 g) in tetrahydrofuran (150 ml) and methanol (300 ml) was added 2N sodium hydroxide (78 ml). The reaction mixture was heated under reflux for 4 hours, then cooled. The volume was reduced in vacuo to approximately 100 ml. and the solution acidified with 5N hydrochloric acid. On cooling, the crystalline product was filtered off and dried in vacuo in the oven at 50° C. to give 1-(3-nitrobenzyl)indole-5-carboxylic acid (m.p. 251°-254° C.).
Reaction SMILES: [C:1]1([C:7]2[O:8][C:9]([C:15]([F:18])([F:17])[F:16])=[C:10]([C:12]([OH:14])=O)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:19][C:20]1[CH:21]=[N:22][C:23]([N:26]2[CH2:30][CH2:29][C@@H:28]([OH:31])[CH2:27]2)=[N:24][CH:25]=1>>[OH:31][C@@H:28]1[CH2:29][CH2:30][N:26]([C:23]2[N:24]=[CH:25][C:20]([NH:19][C:12]([C:10]3[N:11]=[C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[O:8][C:9]=3[C:15]([F:18])([F:17])[F:16])=[O:14])=[CH:21][N:22]=2)[CH2:27]1
Reactant: Nc1cnc(N2CC[C@@H](O)C2)nc1
Reactant: O=C(O)c1nc(-c2ccccc2)oc1C(F)(F)F
Product: O=C(Nc1cnc(N2CC[C@@H](O)C2)nc1)c1nc(-c2ccccc2)oc1C(F)(F)F

Procedure:
With a method similar to example 43 above, (R)-2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid-[2-(3-hydroxypyrrolidin-1-yl)pyrimidin-5-yl]amide was prepared from 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid and (R)—N-(5-aminopyrimidin-2-yl)-pyrrolidin-3-ol. LCMS calcd for C19H16F3N5O3 m/e 419.37, obsd 420.1 (ES, M+H).
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[C:4]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[N:5][CH:6]=[CH:7][CH:8]=1.[CH3:17][CH:18]1[CH2:23][CH2:22][CH:21]([CH2:24][C:25](O)=[O:26])[CH2:20][CH2:19]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C)C=O>[CH3:17][CH:18]1[CH2:23][CH2:22][CH:21]([CH2:24][C:25]([N:12]2[CH2:11][CH2:10][N:9]([C:4]3[C:3]([C:2]([F:1])([F:15])[F:16])=[CH:8][CH:7]=[CH:6][N:5]=3)[CH2:14][CH2:13]2)=[O:26])[CH2:20][CH2:19]1
Reactant: CC1CCC(CC(=O)O)CC1
Reactant: FC(F)(F)c1cccnc1N1CCNCC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: CC1CCC(CC(=O)N2CCN(c3ncccc3C(F)(F)F)CC2)CC1
Yield: 43 %

Procedure:
Coupling of 1-(3-(trifluoromethyl)pyridin-2-yl)piperazine (271 mg, 1.17 mmol) with 2-(4-methylcyclohexyl)acetic acid (100 mg, 0.64 mmol) was carried out according to a similar procedure described for example 19A using N,N-dimethylformamide (1 mL) as solvent and benzotriazole-1 yl-oxy-tris-(dimethylamino)-phosphonium hexafluorophosphate (700 mg, 1.56 mmol) as coupling agent. 1-[(4-methylcyclohexyl)acetyl]-4-[3-(trifluoromethyl)pyridin-2-yl]piperazine was obtained in 43% yield (102 mg) as colorless oil.
Reaction SMILES: [CH:1]([C:4]1[N:8]=[C:7]([CH:9]2[CH2:14][CH2:13][C:12](=O)[CH2:11][CH2:10]2)[O:6][N:5]=1)([CH3:3])[CH3:2].[C:16]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])(=[O:19])[NH:17][NH2:18]>>[C:21]([O:20][C:16]([NH:17][N:18]=[C:12]1[CH2:13][CH2:14][CH:9]([C:7]2[O:6][N:5]=[C:4]([CH:1]([CH3:3])[CH3:2])[N:8]=2)[CH2:10][CH2:11]1)=[O:19])([CH3:24])([CH3:23])[CH3:22]
Reactant: CC(C)(C)OC(=O)NN
Reactant: CC(C)c1noc(C2CCC(=O)CC2)n1
Product: CC(C)c1noc(C2CCC(=NNC(=O)OC(C)(C)C)CC2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.5 %

Procedure:
A mixture of 4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-cyclohexanone (Intermediate 11; 1.6 g, 7.7 mmol) and tert-butyl carbazate (1.12 g, 8.5 mmol) in hexanes (3 mL) was heated at reflux for 3 h, then allowed to cool to room temperature and stand overnight. The white solid was filtered off, washed with hexanes and held under high vacuum to give N′-[4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)cyclohexylidene]-hydrazinecarboxylic acid tert-butyl ester (1.9 g, 77%) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 1.22 (d, 6H, J=6.9 Hz), 1.41 (s, 9H), 1.60-1.76 (m, 2H), 1.98-2.20 (m, 2H), 2.25-2.36 (m, 2H), 2.75-2.84 (m, 1H), 2.96-3.06 (m, 1H), 3.24-3.35 (m, 2H), 9.62 (br s, 1H).
Reaction SMILES: [H-].[Na+].[N:3]1([CH2:8][CH2:9][O:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=2)[CH:7]=[CH:6][N:5]=[N:4]1.Cl[CH2:20][C:21]1[N:22]=[C:23]([CH:26]=[CH:27][C:28]2[CH:33]=[CH:32][C:31]([S:34]([F:39])([F:38])([F:37])([F:36])[F:35])=[CH:30][CH:29]=2)[O:24][CH:25]=1.O>CN(C=O)C>[F:37][S:34]([F:35])([F:36])([F:38])([F:39])[C:31]1[CH:32]=[CH:33][C:28](/[CH:27]=[CH:26]/[C:23]2[O:24][CH:25]=[C:21]([CH2:20][O:18][C:15]3[CH:14]=[CH:13][C:12]([CH2:11][O:10][CH2:9][CH2:8][N:3]4[CH:7]=[CH:6][N:5]=[N:4]4)=[CH:17][CH:16]=3)[N:22]=2)=[CH:29][CH:30]=1
Reactant: FS(F)(F)(F)(F)c1ccc(C=Cc2nc(CCl)co2)cc1
Reactant: Oc1ccc(COCCn2ccnn2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: FS(F)(F)(F)(F)c1ccc(/C=C/c2nc(COc3ccc(COCCn4ccnn4)cc3)co2)cc1
Reaction time: 0.25 h

Procedure:
14 mg (0.50 mmol) 95% sodium hydride were given to a solution of 110 mg (0.50 mmol) 4-(2-[1,2,3]Triazol-1-yl-ethoxymethyl)-phenol in 4.0 ml DMF and stirred for 15 min. 173 mg (0.50 mmol) 4-chloromethyl-2-[2-(4-pentafluorosulfanyl-phenyl)-vinyl]-oxazole were added and stirring continued at r.t. overnight. After addition of 10 ml water the resulting precipitate was washed twice with 10 ml water, 2×10 ml methanol, diethyl ether and dried at 45° C. in vacuum. Yield 155 mg (59%) colorless powder.
Reaction SMILES: C(OC([NH:8][CH2:9][C:10]([NH:12][C@H:13]1[C@@H:17]([CH3:18])[CH2:16][N:15]([C:19]2[C:28]([F:29])=[CH:27][C:26]3[C:30](=[O:36])[C:31]([C:33]([OH:35])=[O:34])=[CH:32][N:24]4[C:25]=3[C:20]=2[CH2:21][CH2:22][N:23]4[CH3:37])[CH2:14]1)=[O:11])=O)(C)(C)C.C(O)C.[ClH:41]>O1CCOCC1>[ClH:41].[NH2:8][CH2:9][C:10]([NH:12][C@H:13]1[C@@H:17]([CH3:18])[CH2:16][N:15]([C:19]2[C:28]([F:29])=[CH:27][C:26]3[C:30](=[O:36])[C:31]([C:33]([OH:35])=[O:34])=[CH:32][N:24]4[C:25]=3[C:20]=2[CH2:21][CH2:22][N:23]4[CH3:37])[CH2:14]1)=[O:11]
Reactant: C[C@H]1CN(c2c(F)cc3c(=O)c(C(=O)O)cn4c3c2CCN4C)C[C@H]1NC(=O)CNC(=O)OC(C)(C)C
Agent: Cl
Solvent: CCO
Solvent: C1COCCO1
Product: C[C@H]1CN(c2c(F)cc3c(=O)c(C(=O)O)cn4c3c2CCN4C)C[C@H]1NC(=O)CN
Temperature: 25 °C
Reaction time: 1 h
Yield: 49 %

Procedure:
750 mg (1.5 mmol) of the compound (84) obtained in Example 10 (1) was added to 10 ml of dioxane and 10 ml of ethanol, and then 2.5 ml of 4N hydrochloric acid solution in dioxane was added to the solution. The solution was stirred at room temperature for 1 hour, and the solvent was removed by distillation. The powder was filtered off and washed successively with ethanol and ether to obtain 324 mg of the subject compound (88) in a 49% yield. The result of the analysis of this compound was as follows.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:11]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)=O)=O)=[CH:5][CH:4]=1.[NH2:21][NH:22][C:23]([NH2:25])=[S:24]>C(O)(=O)C.O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:11]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)=[N:21][NH:22][C:23](=[S:24])[N:25]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(C(=O)C(=O)c2ccc(OC)cc2)cc1
Reactant: NNC(N)=S
Solvent: CC(=O)O
Solvent: O
Product: COc1ccc(-c2n[nH]c(=S)nc2-c2ccc(OC)cc2)cc1
Temperature: 25 °C
Yield: 62.1 %

Procedure:
A mixture of 4,4′-dimethoxybenzil (13.6 g, 50 mmol) and 6.06 g of thiosemicarbazide (66.5 mmol) in 50 mL of glacial acetic acid were stirred at room temperature then refluxed overnight. The cooled reaction mixture was diluted with 150 mL of water and filtered. The solids were washed with water and dried. The crude product was heated with 55 mL of ethyl acetate, cooled, filtered and dried to give 10.1 g of 5,6-bis-(4-methoxyphenyl)-1,2,4-triazin-3-thione, mp 228–232° C.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:21][S:22]([C:25]1[CH:30]=[CH:29][C:28]([O:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[CH:27][CH:26]=1)(=[O:24])=[O:23])[C:13]([NH:15][O:16]C(C)(C)C)=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(Cl)Cl.FC(F)(F)C(O)=O>[CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:21][S:22]([C:25]1[CH:26]=[CH:27][C:28]([O:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[CH:29][CH:30]=1)(=[O:23])=[O:24])[C:13]([NH:15][OH:16])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)ONC(=O)[C@H](CS(=O)(=O)c1ccc(Oc2ccccc2)cc1)NC(=O)OCc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(N[C@@H](CS(=O)(=O)c1ccc(Oc2ccccc2)cc1)C(=O)NO)OCc1ccccc1
Reaction time: 8 h
Yield: 37.3 %

Procedure:
A solution of (R)-2-(benzyloxycarbonylamino)-N-tert-butoxy-3-(4-phenoxyphenylsulfonyl)-propionamide (1.2 g) obtained from Example 16 in methylene chloride (5 ml) was diluted with trifluoroacetic acid (30 ml). The solution was allowed to stand overnight, and solvent was removed under reduced pressure. This residue was chromatographed on silica gel, eluting with 10% methanol/methylene chloride to give (R)-2-(benzyloxycarbonylamino)-N-hydroxy-3-(4-phenoxyphenylsulfonyl)-propionamide (400 mg), m.p. 195-202° C.
Reaction SMILES: [C:1]([N:9]=[C:10]=[S:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:12][C@@:13]1([C:24]2[CH:29]=[C:28]([Br:30])[CH:27]=[CH:26][C:25]=2[F:31])[CH2:18][O:17][C@@H:16]([CH:19]2[CH2:21][CH2:20]2)[CH2:15][C@H:14]1[CH2:22][OH:23]>ClCCl>[Br:30][C:28]1[CH:27]=[CH:26][C:25]([F:31])=[C:24]([C@@:13]2([NH:12][C:10]([NH:9][C:1](=[O:8])[C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[S:11])[C@H:14]([CH2:22][OH:23])[CH2:15][C@H:16]([CH:19]3[CH2:20][CH2:21]3)[O:17][CH2:18]2)[CH:29]=1
Reactant: O=C(N=C=S)c1ccccc1
Reactant: N[C@@]1(c2cc(Br)ccc2F)CO[C@@H](C2CC2)C[C@H]1CO
Solvent: ClCCl
Product: O=C(NC(=S)N[C@@]1(c2cc(Br)ccc2F)CO[C@@H](C2CC2)C[C@H]1CO)c1ccccc1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
Benzoyl isothiocyanate (120 mg, 0.74 mmol) was added drop-wise to a solution of [(2R,4R,5S)-5-amino-5-(5-bromo-2-fluorophenyl)-2-cyclopropyltetrahydro-2H-pyran-4-yl]methanol (C56) (from the previous step, 225 mg, ≦0.78 mmol) in dichloromethane (25 mL) at 0° C. The reaction mixture was allowed to stir at 0° C. for 1.5 hours, then was warmed to room temperature and stirred overnight before concentrating in vacuo. Purification via silica gel chromatography (Gradient: 0% to 100% ethyl acetate in heptane) afforded the product as a solid. Yield: 127 mg, 26% over 2 steps LCMS m/z 454.3 [M+H+].
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[C:13]([C:18]([F:21])([F:20])[F:19])[CH:14]=[CH:15][CH:16]=3)[N:11]=[CH:10][C:9]=2[C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:23])[CH:5]=[CH:6][CH:7]=1.Br[CH2:31][C:32]1[O:33][C:34]([N+:37]([O-:39])=[O:38])=[CH:35][CH:36]=1>>[N+:37]([C:34]1[O:33][C:32]([CH2:31][O:1][C:2]2[CH:3]=[C:4]([C:8]3[C:17]4[C:12](=[C:13]([C:18]([F:21])([F:19])[F:20])[CH:14]=[CH:15][CH:16]=4)[N:11]=[CH:10][C:9]=3[C:22]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)=[O:23])[CH:5]=[CH:6][CH:7]=2)=[CH:36][CH:35]=1)([O-:39])=[O:38]
Reactant: O=C(c1ccccc1)c1cnc2c(C(F)(F)F)cccc2c1-c1cccc(O)c1
Reactant: O=[N+]([O-])c1ccc(CBr)o1
Product: O=C(c1ccccc1)c1cnc2c(C(F)(F)F)cccc2c1-c1cccc(OCc2ccc([N+](=O)[O-])o2)c1

Procedure:
The title compound was prepared from [4-(3-hydroxyphenyl)-8-(trifluoromethyl)quinolin-3-yl](phenyl)methanone and 2-Bromomethyl-5-nitro-furan following the procedure of Example 478: MS (ES) m/z 517.2.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH:26]([CH3:28])[CH3:27])=[CH:21][CH:20]=2)[C:7]2[C:12]([C:13]=1[C:14]([O:16][CH3:17])=[O:15])=[CH:11][C:10]([OH:18])=[CH:9][CH:8]=2)=[O:4].[Cl:29][C:30]1[CH:31]=[C:32](B(O)O)[CH:33]=[CH:34][CH:35]=1>>[CH3:1][O:2][C:3]([C:5]1[N:6]([C:19]2[CH:20]=[CH:21][C:22]([O:25][CH:26]([CH3:28])[CH3:27])=[CH:23][CH:24]=2)[C:7]2[C:12]([C:13]=1[C:14]([O:16][CH3:17])=[O:15])=[CH:11][C:10]([O:18][C:34]1[CH:33]=[CH:32][CH:31]=[C:30]([Cl:29])[CH:35]=1)=[CH:9][CH:8]=2)=[O:4]
Reactant: OB(O)c1cccc(Cl)c1
Reactant: COC(=O)c1c(C(=O)OC)n(-c2ccc(OC(C)C)cc2)c2ccc(O)cc12
Product: COC(=O)c1c(C(=O)OC)n(-c2ccc(OC(C)C)cc2)c2ccc(Oc3cccc(Cl)c3)cc12

Procedure:
The sub-title compound was prepared in accordance with step (a) Example 18 from 5-hydroxyindole-1-(4-isopropoxyphenyl)-2,3-dicarboxylic acid dimethyl ester (150 mg-0.39 mmol, see step (a) Example 19) and 3-chlorophenylboronic acid (120 mg, 0.78 mmol). Yield 93 mg (49%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][OH:4].[Cl:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8](Cl)[N:7]=1>N1C=CC=CC=1.C(OCC)(=O)C>[Cl:5][C:6]1[N:7]=[C:8]([NH:1][CH2:2][CH2:3][OH:4])[CH:9]=[CH:10][CH:11]=1
Reactant: Clc1cccc(Cl)n1
Reactant: NCCO
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: OCCNc1cccc(Cl)n1
Temperature: 100 °C
Yield: 98.7 %

Procedure:
2-Amino-ethanol (0.82 g, 13.5 mmol) was added to a solution of 2,6-dichloropyridine (2.0 g, 13.5 mmol) in pyridine (10 mL) at room temperature and then heated at 100° C. overnight. The reaction mixture was concentrated in vacuo to obtain a residue which was dissolved in ethyl acetate. The solution was washed with water, brine, dried over anhydrous sodium sulfate and evaporated in vacuo to afford 2-(6-chloro-pyridin-2-ylamino)-ethanol (2.3 g, 99%) as a white solid.
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:27])[C@@H:6]([OH:26])[C@@H:7]([N:11](CC2C=CC=CC=2)CC2C=CC=CC=2)[CH2:8][CH2:9][CH3:10])[CH2:3][CH2:2]1>CO.[OH-].[OH-].[Pd+2]>[NH2:11][C@@H:7]([CH2:8][CH2:9][CH3:10])[C@H:6]([OH:26])[C:5]([NH:4][CH:1]1[CH2:2][CH2:3]1)=[O:27]
Reactant: CCC[C@@H]([C@H](O)C(=O)NC1CC1)N(Cc1ccccc1)Cc1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CCC[C@H](N)[C@H](O)C(=O)NC1CC1
Reaction time: 2 h
Yield: 92.2 %

Procedure:
To a solution of (2S,3S)-N-cyclopropyl-3-(dibenzylamino)-2-hydroxyhexanamide (35.0 g) in methanol (350 mL) was carefully added palladium hydroxide on carbon (20% Pd(OH)2/C, 7.0 g), and the mixture was stirred under hydrogen at 50 psi for 2 hours. The mixture was filtered through Celite, and washed with methanol (150 mL). The solvent was evaporated under reduced pressure, to provide a light yellow solid, which was further washed with hexanes (2×75 mL), to give (2S,3S)-3-amino-N-cyclopropyl-2-hydroxyhexanamide (16.4 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:14]([F:17])([F:16])[F:15])[N:5]=[C:4]([NH:18][C:19]([C:21]2[O:25][N:24]=[C:23]([C:26]([CH3:29])([CH3:28])[CH3:27])[CH:22]=2)=[O:20])[C:3]=1[N+:30]([O-])=O.[Cl-].[NH4+]>CCO.O.[Fe]>[NH2:30][C:3]1[C:4]([NH:18][C:19]([C:21]2[O:25][N:24]=[C:23]([C:26]([CH3:29])([CH3:28])[CH3:27])[CH:22]=2)=[O:20])=[N:5][C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:14]([F:15])([F:16])[F:17])=[CH:7][C:2]=1[Cl:1]
Reactant: CC(C)(C)c1cc(C(=O)Nc2nc(-c3ccccc3C(F)(F)F)cc(Cl)c2[N+](=O)[O-])on1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: CC(C)(C)c1cc(C(=O)Nc2nc(-c3ccccc3C(F)(F)F)cc(Cl)c2N)on1
Temperature: 50 °C
Reaction time: 3 h

Procedure:
A solution of 3-tert-butyl-isoxazole-5-carboxylic acid [4-chloro-3-nitro-6-(2-trifluoromethyl-phenyl)-pyridin-2-yl]-amide (40.7 mg, 0.0868 mmol, prepared as described in STEP A above) in EtOH (5 mL) and water (2.5 mL) was treated with ammonium chloride (46.4 mg, 0.868 mmol) and iron powder (24.2 mg, 0.434 mmol), and the mixture was stirred at 50° C. for 3 h. The cooled mixture was concentrated in vacuo and partitioned between EtOAc (25 mL) and water (20 mL). The aqueous layer was extracted with EtOAc (20 mL). The combined organic extracts were dried over MgSO4 and concentrated in vacuo. The residue was purified on a 12-g SEPRA Si 50 SPE column (Flow rate=20 mL/min; Eluent=EtOAc-hexanes, 1:99 for 10 min, then 1:99 to 1:3 over 40 min) to yield 3-tert-butyl-isoxazole-5-carboxylic acid [3-amino-4-chloro-6-(2-trifluoromethyl-phenyl)-pyridin-2-yl]-amide as a yellow solid. Mass Spectrum (LCMS, ESI pos.): Calculated for C21H18N4O2ClF3: 439.1 (M+H); Measured: 439.1.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11]2[CH:16]=[CH:15][C:14]([F:17])=[C:13]([Cl:18])[CH:12]=2)=[CH:6][CH:5]=1)([O-])=O.[Cl-].[NH4+].O>C1COCC1.O.[Fe]>[Cl:18][C:13]1[CH:12]=[C:11]([O:10][C:7]2[CH:8]=[CH:9][C:4]([NH2:1])=[CH:5][CH:6]=2)[CH:16]=[CH:15][C:14]=1[F:17]
Reactant: O=[N+]([O-])c1ccc(Oc2ccc(F)c(Cl)c2)cc1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Product: Nc1ccc(Oc2ccc(F)c(Cl)c2)cc1
Yield: 97.6 %

Procedure:
To a solution of 3-chloro-4-fluorophenyl 4-nitrophenyl ether (Intermediate 7, 2.48 g) in THF/water (40 mL/10 mL) was added Fe power (11.2 g, 200 mmol) and ammonium chloride (10.7 g, 200 mmol and the mixture was heated at reflux for 4 hours. After filtration, the solvent was concentrated to give a residue and poured into 50 mL of water. The mixture was extracted with ethyl acetate (3 times 50 mL) and the combined organic phases were washed and dried over magnesium sulphate. Removal of the solvent afforded the title compound (2.15 g) which was directly used in the next step.
Reaction SMILES: Cl.[NH:2]1[CH2:5][CH:4]([OH:6])[CH2:3]1.Br[CH2:8][CH2:9][CH2:10][Cl:11].C([O-])([O-])=O.[Cs+].[Cs+]>C(#N)C.CCOC(C)=O>[Cl:11][CH2:10][CH2:9][CH2:8][N:2]1[CH2:5][CH:4]([OH:6])[CH2:3]1
Reactant: ClCCCBr
Reactant: OC1CNC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: OC1CN(CCCCl)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 37.5 %

Procedure:
In a 25 mL round-bottomed flask were mixed with stirring azetidin-3-ol hydrochloride (available from Beta Pharma, 250 mg, 2.28 mmol) and 1-bromo-3-chloropropane (719 mg, 4.56 mmol.0) in acetonitrile (5 mL) to the suspension was added Cs2CO3 (1.86 g, 5.7 mmol.50). The mixture was stirred at 25° C. for 18 h, then diluted with 15 mL of EtOAc and filtered to remove solids. Filtrate was evaporated and residue purified by chromatography (40 g column, 50 μm from Analogix, 0 to 5% over 20 min (MeOH containing 10% ammonium hydroxide)/dichloromethane (developing TLC in an iodine chamber) to give 1-(3-chloropropyl)azetidin-3-ol (128 mg, 856 μmol, 37.5%) as a clear dense liquid. 1H NMR (CDCl3) δ: 4.25-4.53 (m, 2H), 3.36-3.68 (m, 4H), 2.82-3.04 (m, 2H), 2.58 (t, J=7.2 Hz, 2H), 1.80 (quin, J=6.8 Hz, 2H).
Reaction SMILES: [CH:1]([O:4][C:5]1[C:13]([CH3:14])=[CH:12][CH:11]=[CH:10][C:6]=1[C:7]([OH:9])=O)([CH3:3])[CH3:2].[CH2:15]([O:17][C:18]([C:20]1([NH2:30])[CH2:29][C:23]2=[C:24]([CH3:28])[S:25][C:26]([CH3:27])=[C:22]2[CH2:21]1)=[O:19])[CH3:16].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH2:15]([O:17][C:18]([C:20]1([NH:30][C:7](=[O:9])[C:6]2[CH:10]=[CH:11][CH:12]=[C:13]([CH3:14])[C:5]=2[O:4][CH:1]([CH3:2])[CH3:3])[CH2:21][C:22]2=[C:26]([CH3:27])[S:25][C:24]([CH3:28])=[C:23]2[CH2:29]1)=[O:19])[CH3:16]
Reactant: Cc1cccc(C(=O)O)c1OC(C)C
Reactant: CCOC(=O)C1(N)Cc2c(C)sc(C)c2C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)C1(NC(=O)c2cccc(C)c2OC(C)C)Cc2c(C)sc(C)c2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.6 %

Procedure:
To a solution of 2-isopropoxy-3-methyl-benzoic acid (300 mg, 1.54 mmol), 5-amino-1,3-dimethyl-5,6-dihydro-4H-cyclopenta[c]thiophene-5-carboxylic acid ethyl ester (443 mg, 1.85 mmol), HATU (878 g, 2.31 mmol) in anhydrous DMF (10 mL) is added DIPEA (382 μL, 2.31 mmol). The resulting solution is stirred at RT overnight. After the removal of DMF in vacuo, the residue is dissolved in EtOAc (70 mL) and washed with water (1×10 mL) and brine (2×10 mL). The organic layer is dried over anhydrous Na2SO4 and concentrated in vacuo. The residue is purified by flash column chromatography (115 g silica gel, gradient elution: 5%-50% EtOAc in heptane) to give a pure product (88) as a pale yellow solid (599 mg, 95%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[NH:4][CH:5]([C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16]1[NH:17][C:18]([C:21]#[CH:22])=[CH:19][N:20]=1)=[O:10])[CH:6]([CH3:8])[CH3:7].[CH3:24][O:25][C:26](=[O:57])[NH:27][CH:28]([C:32]([N:34]1[CH2:38][CH2:37][CH2:36][CH:35]1[C:39]1[NH:40][C:41]([C:44]2[CH:49]=[CH:48][C:47]([C:50]3[CH:55]=[CH:54][C:53](Br)=[CH:52][CH:51]=3)=[CH:46][CH:45]=2)=[CH:42][N:43]=1)=[O:33])[CH:29]([CH3:31])[CH3:30].C(N(CC)CC)C>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I>[CH3:24][O:25][C:26](=[O:57])[NH:27][CH:28]([C:32]([N:34]1[CH2:38][CH2:37][CH2:36][CH:35]1[C:39]1[NH:40][C:41]([C:44]2[CH:49]=[CH:48][C:47]([C:50]3[CH:55]=[CH:54][C:53]([C:22]#[C:21][C:18]4[NH:17][C:16]([CH:12]5[CH2:13][CH2:14][CH2:15][N:11]5[C:9](=[O:10])[CH:5]([NH:4][C:3]([O:2][CH3:1])=[O:23])[CH:6]([CH3:8])[CH3:7])=[N:20][CH:19]=4)=[CH:52][CH:51]=3)=[CH:46][CH:45]=2)=[CH:42][N:43]=1)=[O:33])[CH:29]([CH3:31])[CH3:30]
Reactant: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc(-c3ccc(Br)cc3)cc2)[nH]1)C(C)C
Reactant: C#Cc1cnc(C2CCCN2C(=O)C(NC(=O)OC)C(C)C)[nH]1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)NC(C(=O)N1CCCC1c1ncc(C#Cc2ccc(-c3ccc(-c4cnc(C5CCCN5C(=O)C(NC(=O)OC)C(C)C)[nH]4)cc3)cc2)[nH]1)C(C)C
Temperature: 80 °C
Reaction time: 15 h
Yield: 12.3 %

Procedure:
{1-[2-(5-Ethynyl-1H-imidazol-2-yl)-pyrrolidine-1-carbonyl]-2-methyl-propyl}-carbamic acid methyl ester (44 mg, 0.138 mmol), (1-{2-[5-(4′-Bromo-biphenyl-4-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (67 mg, 0.128 mmol), Pd(PPh3)4 (15 mg, 0.0128 mmol), CuI (2 mg, 0.0128 mmol) and triethylamine (0.180 mL, 1.28 mmol) were suspended in DMF (2 mL) and the mixture was degassed for 10 min with nitrogen. The reaction mixture was stirred at 80° C. for 15 hours then cooled to RT. Formic acid (0.1 mL) and water (1 mL) were added and the mixture was purified by reverse phase preparative HPLC, giving (1-{2-[5-(4′-{2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-ylethynyl}-biphenyl-4-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (12 mg, 12%). 1H NMR (MeOH-d4, 400 MHz) 7.73 (d, J=8.4 Hz, 2H), 7.66-7.64 (m, 4H), 7.52 (d, J=8.2 Hz, 2H), 7.35 (s, 1H), 7.24 (s, 1H), 6.98 (m, 2H), 5.18 (m, 1H), 5.11 (m, 1H), 4.26-4.19 (m, 2H), 4.01-3.80 (m, 4H), 3.65 (s, 6H), 2.37-2.01 (m, 10H), 1.00-0.88 (m, 12H); MS (ESI) m/z 763 [M+H]+.