Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:12]1[C:21]([CH3:22])=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]=1Cl)[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:4])([CH3:3])[CH3:2].CC1(C)C(C)(C)OB([C:32]2[CH:33]=[C:34]([N:38]3[CH2:41][CH2:40][CH2:39]3)[CH:35]=[CH:36][CH:37]=2)O1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C1COCC1>O>[N:38]1([C:34]2[CH:33]=[C:32]([C:13]3[C:14]4[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=4)[CH:20]=[C:21]([CH3:22])[C:12]=3[C@H:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH:37]=[CH:36][CH:35]=2)[CH2:41][CH2:40][CH2:39]1
Reactant: CC1(C)OB(c2cccc(N3CCC3)c2)OC1(C)C
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2ccccc2c1Cl
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2ccccc2c1-c1cccc(N2CCC2)c1
Temperature: 110 °C

Procedure:
A Smith process vial was charged with (S)-ethyl 2-tert-butoxy-2-(1-chloro-3-methylnaphthalen-2-yl)acetate (60.5 mg, 0.181 mmol), 1-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)azetidine (93.7 mg, 0.361 mmol), chloro(2-dicyclohexylphosphino-2′,6′-dimethoxy-1,1′-biphenyl)[2-(2-aminoethylphenyl)]Pd(II)methyl-t-butyl ether adduct (12.2 mg, 0.0181 mmol) and potassium phosphate (153 mg, 0.543 mmol), THF (2 mL) and water (1 mL) was added and mixture sparged with nitrogen for 10 minutes and then heated in microwave at 110° C. for 1 hour. The reaction mixture was diluted with ethyl acetate and washed with brine, dried (MgSO4), filtered, concentrated and purified by flash column chromatography (silica gel, ethyl acetate/hexanes) to the desired product containing some impurities that was used in the next step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:14][O:15][CH2:16][C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:39]=[CH:38][C:25]([CH2:26][N:27]5[CH2:30][CH:29]([C:31]([O:33]C(C)(C)C)=[O:32])[CH2:28]5)=[CH:24][CH:23]=4)[N:18]=3)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.CCOCC>FC(F)(F)C(O)=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:14][O:15][CH2:16][C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:23]=[CH:24][C:25]([CH2:26][N:27]5[CH2:30][CH:29]([C:31]([OH:33])=[O:32])[CH2:28]5)=[CH:38][CH:39]=4)[N:18]=3)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)C1CN(Cc2ccc(-c3noc(COCC4(c5ccc(F)cc5)CCCCC4)n3)cc2)C1
Solvent: CCOCC
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)C1CN(Cc2ccc(-c3noc(COCC4(c5ccc(F)cc5)CCCCC4)n3)cc2)C1
Yield: 0 %

Procedure:
A solution of tert-butyl 1-(4-(5-(((1-(4-fluorophenyl)cyclohexyl)methoxy)methyl)-1,2,4-oxadiazol-3-yl)benzyl)azetidine-3-carboxylate (37 mg, 69 mol) in trifluoroacetic acid (1.5 mL) was stirred at room temperature for 2 h. Trifluoroacetic acid was removed under reduced pressure, followed by co-evaporation with ether to obtain a solid which was stirred with ether (7 mL) for 3.5 h, filtered and dried to obtain 1-(4-(5-(((1-(4-fluorophenyl)cyclohexyl)methoxy)methyl)-1,2,4-oxadiazol-3-yl)benzyl) azetidine-3-carboxylic acid (26 mg, 63% yield) as a white solid. LC/MS: m/e 480.21 (M+H)+. 1H NMR (400 MHz, CD3OD): δ ppm 8.17 (d, J=8.03 Hz, 2H), 7.65 (d, J=7.78 Hz, 2H), 7.43 (dd, J=8.28, 5.52 Hz, 2H), 7.02 (t, J=8.53 Hz, 2H), 4.68 (s, 2H), 4.52 (s, 2H), 4.38 (d, J=7.53 Hz, 4H), 3.72 (ddd, J=16.63, 8.78, 8.47 Hz, 1H), 3.59 (s, 2H), 2.05-2.30 (m, 2H), 1.68-1.88 (m, 2H), 1.48-1.69 (m, 3H), 1.27-1.47 (m, 3H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[CH:10]=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[N:11]1([C:17]([C:19]2[CH:20]=[C:21](B(O)O)[CH:22]=[CH:23][CH:24]=2)=[O:18])[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1.C(=O)(O)[O-].[Na+]>O1CCOCC1.O.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>[NH:8]1[C:5]2=[N:6][CH:7]=[C:2]([C:23]3[CH:24]=[C:19]([C:17]([N:11]4[CH2:16][CH2:15][O:14][CH2:13][CH2:12]4)=[O:18])[CH:20]=[CH:21][CH:22]=3)[CH:3]=[C:4]2[CH:10]=[CH:9]1
Reactant: O=C(c1cccc(B(O)O)c1)N1CCOCC1
Reactant: Brc1cnc2[nH]ccc2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: O=C(c1cccc(-c2cnc3[nH]ccc3c2)c1)N1CCOCC1
Temperature: 110 °C
Reaction time: 15 h
Yield: 83.7 %

Procedure:
A mixture of 5-bromo-1H-pyrrolo[2,3-b]pyridine (3 g, 15 mmol), 3-(morpholine-4-carbonyl)phenylboronic acid (4 g, 18 mmol), sodium bicarbonate (4 g, 46 mmol), and tetrakis(triphenylphosphine)palladium(0) in dioxane/water (100 mL/20 mL) was stirred at 110° C. for 15 hours. The mixture was then poured into ice water and extracted with ethyl acetate (3×). The organic layers were combined, dried over sodium sulfate, filtered and concentrated to dryness. Silica gel chromatography of the crude product afforded (3-(1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)(morpholino)methanone (3.86 g, 84% yield) as yellow solids. MS: m/z 308.1 (M+H+).
Reaction SMILES: [F:1][C@H:2]1[C@H:8]([NH:9]C(=O)OC(C)(C)C)[CH2:7][CH2:6][C@@H:5]([C:17]2[N:21]([CH3:22])[N:20]=[CH:19][C:18]=2[N+:23]([O-])=O)[O:4][CH2:3]1.[F:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[C:33]1[S:34][CH:35]=[C:36]([C:38](O)=[O:39])[N:37]=1>>[NH2:9][C@H:8]1[C@H:2]([F:1])[CH2:3][O:4][C@H:5]([C:17]2[N:21]([CH3:22])[N:20]=[CH:19][C:18]=2[NH:23][C:38]([C:36]2[N:37]=[C:33]([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=3[F:26])[S:34][CH:35]=2)=[O:39])[CH2:6][CH2:7]1
Reactant: O=C(O)c1csc(-c2ccccc2F)n1
Reactant: Cn1ncc([N+](=O)[O-])c1[C@@H]1CC[C@@H](NC(=O)OC(C)(C)C)[C@H](F)CO1
Product: Cn1ncc(NC(=O)c2csc(-c3ccccc3F)n2)c1[C@@H]1CC[C@@H](N)[C@H](F)CO1

Procedure:
Following the procedure for Example 111 starting from tert-butyl ((3S,4R,7S)-3-fluoro-7-(1-methyl-4-nitro-1H-pyrazol-5-yl)oxepan-4-yl)carbamate (Intermediate 80), and replacing 5-((tert-butoxycarbonyl)amino)-2-(2,6-difluorophenyl)thiazole-4-carboxylic acid with 2-(2-fluorophenyl)thiazole-4-carboxylic acid (see Bioorg. Med. Chem. Lett. 2010, 20, 1758) gave 322. 1H NMR (400 MHz, DMSO-d6) δ 9.90 (s, 1H), 8.53 (s, 1H), 8.52-8.44 (m, 1H), 7.89 (s, 1H), 7.63-7.56 (m, 1H), 7.51-7.37 (m, 2H), 4.88 (dd, J=10.6, 3.6 Hz, 1H), 4.57-4.39 (m, 1H), 4.38-4.25 (m, 1H), 4.20-3.99 (m, 1H), 3.79 (s, 3H), 2.13-2.05 (m, 1H), 1.90-1.78 (m, 1H), 1.75 (d, J=9.6 Hz, 3H). LCMS (ES+) m/z 434 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8](Cl)=[O:9])[S:5][C:6]=1[Br:7].[C:11]([NH2:15])([CH3:14])([CH3:13])[CH3:12].O>C1(C)C=CC=CC=1>[C:11]([NH:15][C:8]([C:4]1[S:5][C:6]([Br:7])=[C:2]([Br:1])[CH:3]=1)=[O:9])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)N
Reactant: O=C(Cl)c1cc(Br)c(Br)s1
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)(C)NC(=O)c1cc(Br)c(Br)s1
Temperature: 50 °C
Reaction time: 1 h
Yield: 41.4 %

Procedure:
10 g (0.034 mol) of 4,5-dibromo-thiophene-2-carbonyl chloride in 100 ml of toluene are treated dropwise at room temperature with 5.0 g (0.068 mol) of tert-butyl-amine in 20 ml of toluene. The reaction mixture is then stirred at 50° C. for one hour, cooled to room temperature and treated with water. The organic phase is separated off, rewashed with water and concentrated under reduced pressure. After treating the residue with hexane, the crystalline residue which is deposited is filtered off and dried at 50° C. under reduced pressure. 4.8 g (41.4% of theory) of 4,5-dibromo-thiophene-2-carboxylic acid t-butyl-amide of melting point 190° C. are obtained.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[C:5]([O:10][CH3:11])[CH:4]=1)#[N:2].[ClH:12].[CH3:13][OH:14]>>[ClH:12].[CH3:13][O:14][N:2]=[CH:1][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[C:5]([O:10][CH3:11])[CH:4]=1
Reactant: CO
Reactant: COc1cc(C#N)ccc1O
Agent: Cl
Product: CON=Cc1ccc(O)c(OC)c1

Procedure:
In 50 ml of anhydrous methanol, was dissolved 7.5 g of 4-cyano-2-methoxyphenol. The solution was saturated with dried gaseous hydrogen chloride, while being cooled in ice and stirred, and then stirred overnight at room temperature to precipitate yellow crystals. After addition of ethyl ether, the crystals were collected by filtration, washed with ethyl ether and dried to obtain 9.4 g of 4-methoxyiminomethyl-2-methoxyphenol hydrochloride.
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3]1[CH:29]=[CH:28][CH:27]=[CH:26][C:4]=1[O:5][CH:6]1[CH2:11][CH2:10][N:9]([C:12]2[N:17]=[CH:16][C:15]([N:18]3[CH:22]=[C:21]([CH2:23][CH2:24][OH:25])[N:20]=[N:19]3)=[CH:14][N:13]=2)[CH2:8][CH2:7]1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>ClCCl>[F:30][C:2]([F:1])([F:31])[C:3]1[CH:29]=[CH:28][CH:27]=[CH:26][C:4]=1[O:5][CH:6]1[CH2:11][CH2:10][N:9]([C:12]2[N:17]=[CH:16][C:15]([N:18]3[CH:22]=[C:21]([CH2:23][CH:24]=[O:25])[N:20]=[N:19]3)=[CH:14][N:13]=2)[CH2:8][CH2:7]1
Reactant: OCCc1cn(-c2cnc(N3CCC(Oc4ccccc4C(F)(F)F)CC3)nc2)nn1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: O=CCc1cn(-c2cnc(N3CCC(Oc4ccccc4C(F)(F)F)CC3)nc2)nn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Into a 25-mL flask equipped with a magnetic stirbar was added 2-[1-(2-{4-[2-(trifluoromethyl)phenoxy]piperidin-1-yl}pyrimidin-5-yl)-1H-1,2,3-triazol-4-yl]ethanol (50 mg, 0.12 mmol) and dichloromethane (5 mL). To the solution was added Dess-Martin periodinane (59 mg, 0.14 mmol) and the reaction mixture stirred at room temperature for 1 h. The reaction mixture was concentrated and purified by column chromatography through silica gel, eluting with 60:40 Hexanes/EtOAc to 40:60 Hexanes/EtOAc, yielding the desired product as a yellow solid. MS (ESI, Q+) m/z 433 (M+1).
Reaction SMILES: [N:1]1([CH2:7][CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[O:16]1[CH2:18][CH:17]1[CH2:19]OS(C1C=CC=C([N+]([O-])=O)C=1)(=O)=O>>[O:16]1[CH2:18][CH:17]1[CH2:19][N:13]1[CH2:12][CH2:11][N:10]([CH2:9][CH2:8][CH2:7][N:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)[CH2:15][CH2:14]1
Reactant: C1CCN(CCCN2CCNCC2)CC1
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)OCC2CO2)c1
Product: C1CCN(CCCN2CCN(CC3CO3)CC2)CC1
Yield: 64 %

Procedure:
The same method as employed in the preparation of Intermediate 1 but starting from 1-(3-piperidin-1-ylpropyl)piperazine and (±)-3-nitro-benzenesulfonic acid oxiranylmethyl ester gives after flash chromatography the title compound as an orange oil in a 64% yield.
Reaction SMILES: [N+:1]([C:4]1[CH:20]=[CH:19][C:7]([C:8]([NH:10][C:11]2[C:16]([CH3:17])=[CH:15][CH:14]=[CH:13][C:12]=2[CH3:18])=[O:9])=[CH:6][CH:5]=1)([O-])=O>C(O)C.[Pd]>[NH2:1][C:4]1[CH:20]=[CH:19][C:7]([C:8]([NH:10][C:11]2[C:16]([CH3:17])=[CH:15][CH:14]=[CH:13][C:12]=2[CH3:18])=[O:9])=[CH:6][CH:5]=1
Reactant: Cc1cccc(C)c1NC(=O)c1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CCO
Product: Cc1cccc(C)c1NC(=O)c1ccc(N)cc1
Reaction time: 3 h
Yield: 49.5 %

Procedure:
A solution of 5.0 g of 4-nitro-N-(2,6-dimethylphenyl) benzamide in 250 ml of ethanol was added to a Paar hydrogenation bottle along with 250 mg of 5% palladium on carbon. The mixture was subjected to low pressure hydrogenation (45 psi) for three hours. The mixture was filtered through celite and the filtrate was evaporated in vacuo. The resulting residue was purified by (crystallization from benzene-petroleum ether) [column chromatography over silica gel using a step-wise solvent gradient of petroleum ether and diethyl ether] to provide 2.2 g of the desired title product, m.p. 212°-215° C.
Reaction SMILES: [C:1](=[O:19])([S:3][CH2:4][C@H:5]1[CH2:10][CH2:9][C@H:8]([NH:11]C(OC(C)(C)C)=O)[CH2:7][CH2:6]1)[CH3:2].[F:20][C:21]([F:26])([F:25])[C:22]([OH:24])=[O:23]>C(Cl)Cl>[F:20][C:21]([F:26])([F:25])[C:22]([OH:24])=[O:23].[NH2:11][C@H:8]1[CH2:7][CH2:6][C@H:5]([CH2:4][SH:3]=[C:1]([OH:19])[CH3:2])[CH2:10][CH2:9]1
Reactant: CC(=O)SC[C@H]1CC[C@H](NC(=O)OC(C)(C)C)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(O)=[SH]C[C@H]1CC[C@H](N)CC1
Yield: 98.9 %

Procedure:
A mixture of S-({trans-4-[(tert-Butoxycarbonyl)amino]cyclohexyl}methyl) ethanethioate (0.20 g, 0.70 mmol) in methylene chloride (1.6 mL) was treated with trifluoroacetic acid (0.54 mL, 7.0 mmol) at room temperature for 2 h. The reaction mixture was evaporated to dryness to give the desired product (0.21 g, 100%). LCMS calculated for C9H18NOS (M+H)+: m/z=188.1. Found: 188.1.
Reaction SMILES: C([N:4]1[CH2:9][CH:8]=[C:7]([C:10]2[CH:19]=[C:18]3[C:13]([C:14](=[O:28])[C:15]([C:23]([O:25]CC)=[O:24])=[CH:16][N:17]3[CH:20]3[CH2:22][CH2:21]3)=[CH:12][C:11]=2[F:29])[CH2:6][CH2:5]1)(=O)C>Cl>[CH:20]1([N:17]2[C:18]3[C:13](=[CH:12][C:11]([F:29])=[C:10]([C:7]4[CH2:8][CH2:9][NH:4][CH2:5][CH:6]=4)[CH:19]=3)[C:14](=[O:28])[C:15]([C:23]([OH:25])=[O:24])=[CH:16]2)[CH2:21][CH2:22]1
Reactant: CCOC(=O)c1cn(C2CC2)c2cc(C3=CCN(C(C)=O)CC3)c(F)cc2c1=O
Agent: Cl
Product: O=C(O)c1cn(C2CC2)c2cc(C3=CCNCC3)c(F)cc2c1=O

Procedure:
A solution of 0.80 g (2.01 mmol) of ethyl 7-(1-acetyl-1,2,3,6-tetrahydro-4-pyridyl)-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylate in 50 ml of 6 N hydrochloric acid was heated on a steam bath for 2.75 hours. The mixture was evaporated to dryness, redissolved in water, filtered and titrated to pH 7 with dilute sodium hydroxide. The precipitated title compound was filtered and dried.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([C:9]([N:11]2[C:19]3[C:14](=[CH:15][C:16]([F:20])=[CH:17][CH:18]=3)[CH2:13][CH2:12]2)=[O:10])[CH:3]=1.[CH3:21][O:22][C:23]1[CH:24]=[CH:25][C:26]2[NH:32][C:31](=[O:33])[N:30]([CH:34]3[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]3)[CH2:29][CH2:28][C:27]=2[CH:40]=1.C(=O)([O-])[O-].[K+].[K+]>CN1C(=O)CCC1>[F:20][C:16]1[CH:15]=[C:14]2[C:19](=[CH:18][CH:17]=1)[N:11]([C:9]([C:4]1[N:5]=[C:6]([CH3:8])[CH:7]=[C:2]([N:37]3[CH2:36][CH2:35][CH:34]([N:30]4[CH2:29][CH2:28][C:27]5[CH:40]=[C:23]([O:22][CH3:21])[CH:24]=[CH:25][C:26]=5[NH:32][C:31]4=[O:33])[CH2:39][CH2:38]3)[CH:3]=1)=[O:10])[CH2:12][CH2:13]2
Reactant: COc1ccc2c(c1)CCN(C1CCNCC1)C(=O)N2
Reactant: Cc1cc(Cl)cc(C(=O)N2CCc3cc(F)ccc32)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: COc1ccc2c(c1)CCN(C1CCN(c3cc(C)nc(C(=O)N4CCc5cc(F)ccc54)c3)CC1)C(=O)N2

Procedure:
125 mg (0.43 mmol) (4-chloro-6-methyl-pyridin-2-yl)-(5-fluoro-2,3-dihydro-indol-1-yl)-methanone, 118 mg (0.43 mmol) 7-methoxy-3-piperidin-4-yl-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one and 89 mg (0.65 mmol) potassium carbonate in 2.0 mL NMP were stirred for 10 h at 130° C. Then the reaction mixture was purified by preparative HPLC-MS. The product-containing fractions were combined and freeze-dried.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([CH2:8][N:9]([C:15]2[C:20]([N+:21]([O-])=O)=[CH:19][N:18]=[C:17]([Cl:24])[N:16]=2)[CH:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)[CH2:7][CH2:6]1)=[O:4]>[Pd].C(OCC)(=O)C>[CH3:1][O:2][C:3]([C:5]1([CH2:8][N:9]([C:15]2[C:20]([NH2:21])=[CH:19][N:18]=[C:17]([Cl:24])[N:16]=2)[CH:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)[CH2:6][CH2:7]1)=[O:4]
Reactant: COC(=O)C1(CN(c2nc(Cl)ncc2[N+](=O)[O-])C2CCCC2)CC1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COC(=O)C1(CN(c2nc(Cl)ncc2N)C2CCCC2)CC1
Yield: 88 %

Procedure:
A mixture of 2.20 g (0.00679 mole) of 1-{[(2-chloro-5-nitro-pyrimidin-4-yl)-cyclopentyl-amino]-methyl}-cyclopropanecarboxylic acid methyl ester (IV-53), 0.75 g of 5% palladium on carbon catalyst, and 80 mL of ethyl acetate was stirred under an atmosphere of hydrogen until the reaction was complete. The resulting mixture was filtered through Celite and the combined filtrate was concentrated under reduced pressure to give 1.94 g of 1-{[(5-amino-2-chloro-pyrimidin-4-yl)-cyclopentyl-amino]-methyl}-cyclopropanecarboxylic acid methyl ester (V-53) as an off-white solid.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:10]=[C:9]([NH:11][CH2:12][CH2:13][C:14]([F:17])([F:16])[F:15])[CH:8]=[CH:7][C:4]=1[C:5]#[N:6].Br[CH:21]([CH3:29])[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23]>>[C:5]([C:4]1[CH:7]=[CH:8][C:9]([N:11]([CH2:12][CH2:13][C:14]([F:17])([F:16])[F:15])[C@H:21]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH3:29])=[CH:10][C:3]=1[C:2]([F:18])([F:19])[F:1])#[N:6]
Reactant: N#Cc1ccc(NCCC(F)(F)F)cc1C(F)(F)F
Reactant: CC(Br)C(=O)OC(C)(C)C
Product: C[C@@H](C(=O)OC(C)(C)C)N(CCC(F)(F)F)c1ccc(C#N)c(C(F)(F)F)c1

Procedure:
Synthesized as described in example 1B using 2-(trifluoromethyl)-4-[(3,3,3-trifluoropropyl)amino]benzonitrile and 1,1-dimethylethyl 2-bromopropanoate. 1H NMR (400 MHz, CDCl3) δ 7.67 (d, J=8.8 Hz, 1H), 7.0 (d, J=2.6 Hz, 1H), 6.85 (dd, J=8.8, 2.6 Hz, 1H), 4.37 (q, J=7.3 Hz, 1H), 3.74 (t, J=8.1 Hz, 2H), 2.62-2.38 (m, 2H), 1.61 (d, J=7.3 Hz, 3H), 1.45 (s, 9H).
Reaction SMILES: Br.C([O:9][C:10]1[CH:27]=[CH:26][C:13]([C:14]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=2)=[O:15])=[CH:12][C:11]=1[O:28][CH3:29])C1C=CC=CC=1>C(O)(=O)C>[OH:9][C:10]1[CH:27]=[CH:26][C:13]([C:14]([C:16]2[CH:17]=[CH:18][C:19]([C:22]([F:24])([F:25])[F:23])=[CH:20][CH:21]=2)=[O:15])=[CH:12][C:11]=1[O:28][CH3:29]
Reactant: COc1cc(C(=O)c2ccc(C(F)(F)F)cc2)ccc1OCc1ccccc1
Agent: Br
Solvent: CC(=O)O
Product: COc1cc(C(=O)c2ccc(C(F)(F)F)cc2)ccc1O
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
70 ml. of 33 percent hydrobromic acid in acetic acid are added within 15 minutes at 10° to 20 g of 4-(benzyloxy)-3-methoxy-4'-(trifluoromethyl)benzophenone (dissolved in 150 ml of methylene chloride). After stirring at 20° for 1.5 hours, the reaction mixture is poured into 600 ml. of ice-water; the methylene chloride phase is separated and the aqueous phase is extracted twice more with 100 ml. of methylene chloride. The combined methylene chloride phases are washed with 600 ml of water, dried over sodium sulfate and evaporated. The residue is chromatographed on 150 g of silica gel with methylene chloride. After recrystallization from methylene chloride/hexane, there is obtained 4-hydroxy-3-methoxy-4'-(trifluoromethyl)benzophenone of melting point 97°.
Reaction SMILES: [F:1][C:2]1[CH:13]=[C:6]2[C:7]([O:9][C:10](=[O:12])[NH:11][C:5]2=[CH:4][CH:3]=1)=O.[CH2:14]1[C@@H:17](C(O)=O)[NH:16][CH2:15]1>CS(C)=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[C@@H:15]3[CH2:14][CH2:17][N:16]3[C:7](=[O:9])[C:6]=2[CH:13]=1
Reactant: O=C(O)[C@@H]1CCN1
Reactant: O=c1[nH]c2ccc(F)cc2c(=O)o1
Solvent: CS(C)=O
Product: O=C1Nc2ccc(F)cc2C(=O)N2CC[C@@H]12

Procedure:
A mixture of 23.7 g (0.131 mol) of 5-fluoro-isatoic acid anhydride, 13.23 g (0.131 mol) of L-azetidine-2-carboxylic acid and 150 ml of dimethyl sulphoxide is heated to 90° for 3 hours, subsequently evaporated in a high vacuum and the residue is heated in a high vacuum for 17 hours. By recrystallization from methanol there is obtained (S)-6-fluoro-1,10a-dihydroazeto[2,1-c][1,4]benzodiazepine-4,10(2H,9H)-dione of melting point 216°-217°.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1)[CH:6]=[O:7].[H][H]>[Ni].C1(C)C=CC=CC=1>[F:1][C:2]([F:15])([F:16])[C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([C:11]([F:14])([F:12])[F:13])[CH:10]=1)[CH2:6][OH:7]
Reactant: [H][H]
Reactant: O=Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: [Ni]
Solvent: Cc1ccccc1
Product: OCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 7.5 h
Yield: 82.5 %

Procedure:
37 g of 3,5-bis(trifluoromethyl)benzaldehyde and 4 g of Raney nickel together with 150 ml of toluene were placed in a reaction vessel at room temperature. The vessel was pressurized with 30 bar of hydrogen gas and the mixture was hydrogenated at 50° C. for 7.5 hours while stirring. The mixture was subsequently cooled to room temperature, depressurized and the catalyst was filtered off. The filtrate was evaporated and the crude product obtained in this way was distilled at 17 mbar. 3,5-bis(trifluoro-methyl)benzyl alcohol having a boiling point of 97° C. was obtained in a yield of 31.5 g and a purity of 97.7%. This corresponds to a yield of 82.5% of theory.
Reaction SMILES: FC(F)(F)[C:3]([C:5]1[C:13]2[C:8](=[CH:9][C:10]([CH3:14])=[CH:11][CH:12]=2)[N:7]([CH:15]([CH3:17])[CH3:16])[CH:6]=1)=[O:4].[OH-:20].[Na+]>>[CH:15]([N:7]1[C:8]2[C:13](=[CH:12][CH:11]=[C:10]([CH3:14])[CH:9]=2)[C:5]([C:3]([OH:4])=[O:20])=[CH:6]1)([CH3:17])[CH3:16]
Reactant: [OH-]
Reactant: Cc1ccc2c(C(=O)C(F)(F)F)cn(C(C)C)c2c1
Agent: [Na+]
Product: Cc1ccc2c(C(=O)O)cn(C(C)C)c2c1
Temperature: 25 °C
Yield: 98 %

Procedure:
A solution of 2,2,2-trifluoro-1-(1-isopropyl-6-methyl-1H-indol-3-yl)-ethanone (1.50 g, 5.57 mmol) in a 20% aqueous sodium hydroxide solution (20 mL) was heated at 110° C. for 18 h. At this time, the reaction was cooled to 25° C., partitioned between water (150 mL) and ethyl acetate (150 mL), and then treated with a 1N aqueous hydrochloric acid solution (50 mL). The organic layer was washed with a saturated aqueous sodium bicarbonate solution (1×50 mL), water (1×50 mL), and a saturated aqueous sodium chloride solution (1×50 mL). The organic layer was then dried over magnesium sulfate, filtered, and concentrated in vacuo to afford 1-isopropyl-6-methyl-1H-indole-3-carboxylic acid (1.19 g, 98%) as a yellow solid: mp 185-186° C.; EI-HRMS m/e calcd for C13H15NO2 (M+) 217.1103, found 217.1110.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]([C:12]2[CH:13]=[N:14][C:15]([O:18]C)=[CH:16][CH:17]=2)=[O:11])=[C:4]([F:20])[CH:3]=1.Cl>O1CCOCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]([C:12]2[CH:17]=[CH:16][C:15](=[O:18])[NH:14][CH:13]=2)=[O:11])=[C:4]([F:20])[CH:3]=1
Reactant: COc1ccc(C(=O)/C=C/c2ccc(Cl)cc2F)cn1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(/C=C/c1ccc(Cl)cc1F)c1ccc(=O)[nH]c1

Procedure:
In analogy to example 162, step 2, (E)-3-(4-chloro-2-fluorophenyl)-1-(6-methoxypyridin-3-yl)prop-2-en-1-one (example 237, step 1) was reacted with concentrated aqueous HCl in 1,4-dioxane to give the title compound as an colourless solid, MS (ESI+): m/z=278.0 [M+H]+.
Reaction SMILES: C(O)(=O)C.N[CH:6]([OH:12])[CH2:7][C:8]([O:10][CH3:11])=[O:9].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[CH2:27]([O:34][C:35]1[C:36]([CH2:65][CH3:66])=[C:37]([CH2:55][CH2:56][NH:57][CH:58]([OH:64])CC(OC)=O)[C:38]([C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)=[C:39]([O:41][CH2:42][C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[CH:40]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>ClCCCl>[CH2:27]([O:34][C:35]1[C:36]([CH2:65][CH3:66])=[C:37]([CH2:55][CH2:56][N:57]2[CH:7]([C:8]([O:10][CH3:11])=[O:9])[CH2:6][O:12][C:58]2=[O:64])[C:38]([C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)=[C:39]([O:41][CH2:42][C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[CH:40]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: CCc1c(OCc2ccccc2)cc(OCc2ccccc2)c(-c2ccccc2)c1CCNC(O)CC(=O)OC
Reactant: COC(=O)CC(N)O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CCc1c(OCc2ccccc2)cc(OCc2ccccc2)c(-c2ccccc2)c1CCN1C(=O)OCC1C(=O)OC
Yield: 63 %

Procedure:
In the same manner as in the step 1 in Example 316, methyl 3-{2-[3,5-bis(benzyloxy)-2-ethyl-6-phenylphenyl]ethylamino}-3-hydroxypropionate was obtained from 2-[3,5-bis(benzyloxy)-2-ethyl-6-phenylphenyl]ethanal (280 mg, 0.64 mmol) obtained in the step 1 in Example 218, using acetic acid (0.6 mL), methyl 3-amino-3-hydroxypropionate (150 mg, 0.97 mmol), sodium triacetoxyborohydride (270 mg, 1.3 mmol) and 1,2-dichloroethane (6.0 mL). Then, in the same manner as in the step 2 in Example 315, methyl 3-{2-[3,5-bis(benzyloxy)-2-ethyl-6-phenylphenyl]ethyl}-2-oxo-1,3-oxazolidine-4-carboxylate (230 mg, 63%) was obtained from methyl 3-{2-[3,5-bis(benzyloxy)-2-ethyl-6-phenylphenyl]ethylamino}-3-hydroxypropionate obtained in the above.
Reaction SMILES: [CH2:1]([C:3]1[N:4]([CH2:9][CH2:10][NH2:11])[CH:5]=[C:6]([I:8])[N:7]=1)[CH3:2].[F:12][C:13]([F:25])([F:24])[C:14]1[CH:15]=[C:16]([CH:21]=[CH:22][CH:23]=1)[O:17][CH2:18][CH:19]=O>>[CH2:1]([C:3]1[N:4]2[CH2:9][CH2:10][NH:11][CH:19]([CH2:18][O:17][C:16]3[CH:21]=[CH:22][CH:23]=[C:14]([C:13]([F:12])([F:24])[F:25])[CH:15]=3)[C:5]2=[C:6]([I:8])[N:7]=1)[CH3:2]
Reactant: O=CCOc1cccc(C(F)(F)F)c1
Reactant: CCc1nc(I)cn1CCN
Product: CCc1nc(I)c2n1CCNC2COc1cccc(C(F)(F)F)c1

Procedure:
According to the general procedure (GP10), microwave-assisted Pictet-Spengler reaction (60 W; 140° C.; 6.5 bars; 10 min.) between 2-(2-ethyl-4-iodo-imidazol-1-yl)-ethylamine (3.880 mmol) and (3-trifluoromethyl-phenoxy)-acetaldehyde (0.792 g; 3.880 mmol) afforded 3-ethyl-1-iodo-8-(3-trifluoromethyl-phenoxymethyl)-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine.