Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1([O:17][C:18](=[O:24])[NH:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH2:9][CH2:8][N:7]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[Cl-].[NH4+]>[O-]CC.[Na+]>[CH2:10]([N:7]1[CH2:8][CH2:9][C:4]2([O:17][C:18](=[O:24])[N:19]([C:20]([CH3:23])([CH3:22])[CH3:21])[C:1]2([OH:3])[CH3:2])[CH2:5][CH2:6]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CC(=O)C1(OC(=O)NC(C)(C)C)CCN(Cc2ccccc2)CC1
Agent: CC[O-]
Agent: [Cl-]
Agent: [NH4+]
Product: CC(C)(C)N1C(=O)OC2(CCN(Cc3ccccc3)CC2)C1(C)O
Reaction time: 3.5 h
Yield: 78 %

Procedure:
8.3 g of 4-acetyl-1-benzyl-4-tert-butylcarbamoyloxypiperidine are refluxed in 100 ml of an ethanolic sodium ethoxide solution of 0.1 mole/liter concentration under stirring for 3 to 4 hours. After cooling down and adding 10% by weight aqueous ammonium chloride solution to the reaction mixture the most part of the solvent is distilled off under reduced pressure. After adding water to the residue the precipitate is filtered off, washed to chloride-free with water, dried and finally recrystallized from benzene to give the title compound in 78% yield, m.p.: 179°-181° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]2[N:8]=[C:9]([C:26]3[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=3)[C:10]([C:11]3[N:16]=[C:15]([NH:17][CH:18]4[CH2:22][CH2:21][CH2:20][CH2:19]4)[N:14]=[C:13]([C:23]([OH:25])=[O:24])[CH:12]=3)=[C:6]2[CH:5]=[CH:4][CH:3]=1.[CH3:33][Si](C=[N+]=[N-])(C)C>CO>[Cl:1][C:2]1[N:7]2[N:8]=[C:9]([C:26]3[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=3)[C:10]([C:11]3[N:16]=[C:15]([NH:17][CH:18]4[CH2:22][CH2:21][CH2:20][CH2:19]4)[N:14]=[C:13]([C:23]([O:25][CH3:33])=[O:24])[CH:12]=3)=[C:6]2[CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1cc(-c2c(-c3ccc(F)cc3)nn3c(Cl)cccc23)nc(NC2CCCC2)n1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Product: COC(=O)c1cc(-c2c(-c3ccc(F)cc3)nn3c(Cl)cccc23)nc(NC2CCCC2)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 12.8 %

Procedure:
To a solution of 6-[7-chloro-2-(4-fluorophenyl)pyrazolo[1,5-α]pyridin-3-yl]-2-(cyclopentylamino)-4-pyrimidinecarboxylic acid (340 mg, 0.752 mmol) in methanol (20 mL) was added (trimethylsilyl)diazomethane (376 μL, 2.0 M in hexanes, 0.752 mmol). The reaction mixture was stirred at room temperature for 16 hours. Excess (trimethylsilyl)diazomethane was added and the reaction mixture was stirred 3 days. The reaction mixture was quenched with saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate. The organic layer was washed with water and brine, then dried over magnesium sulfate. Filtration and concentration followed by flash chromatography (49-1 to 29-1 dichloromethane-methanol) provided methyl 6-[7-chloro-2-(4-fluorophenyl)pyrazolo[1,5-α]pyridin-3-yl]-2-(cyclopentylamino)pyrimidine-4-carboxylate (45 mg, 13%). 1H NMR (CDCl3) δ 8.44 (d, 1H), 7.65 (m, 2H), 7.34 (t, 1H), 7.17 (t, 2H), 7.11 (d, 1H), 7.03 (s, 1H), 5.43 (br, 1H), 4.36 (m, 1H), 3.89 (s, 3H), 2.05 (m, 2H), 1.76–1.55 (m, 6H); MS m/z 466 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].Cl.[CH3:12][NH:13][O:14][CH3:15].N1C=CC=CC=1.O>ClCCl>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([N:13]([O:14][CH3:15])[CH3:12])=[O:5]
Reactant: O=C(Cl)c1ccccc1Cl
Reactant: CNOC
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: O
Product: CON(C)C(=O)c1ccccc1Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 85.2 %

Procedure:
To a solution of 2-chlorobenzoyl chloride (8 g, 46 mmol) in dichloromethane (200 mL) at 0° C. was added N,O-dimethylhydroxylamine hydrochloride (4.9 g, 50 mmol) followed by pyridine (11 mL, 137 mmol). The mixture was stirred at room temperature for 16 hours. Water was added to the reaction mixture and organic layer was washed with brine, dried over magnesium sulfate and concentrated. Purification by chromatography on silica gel gave 2-chloro-N-methoxy-N-methylbenzamide (21) (7.8 g, 39.2 mmol, 85%) as clear oil.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[C:8]([C:11]([F:14])([F:13])[F:12])[C:7]([C:15]#[N:16])=[CH:6][CH:5]=2.[CH3:17][O:18][CH2:19][CH2:20]Cl>>[CH3:1][C:2]1[N:3]([CH2:20][CH2:19][O:18][CH3:17])[C:4]2[C:9]([CH:10]=1)=[C:8]([C:11]([F:12])([F:14])[F:13])[C:7]([C:15]#[N:16])=[CH:6][CH:5]=2
Reactant: Cc1cc2c(C(F)(F)F)c(C#N)ccc2[nH]1
Reactant: COCCCl
Product: COCCn1c(C)cc2c(C(F)(F)F)c(C#N)ccc21

Procedure:
Synthesized as described in Example 4 using 2-methyl-4-(trifluoromethyl)-1H-indole-5-carbonitrile (Example 120) and 2-chloroethyl methyl ether: MS (ES) m/z 283 (M+1).
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:10]1[N:15]=[C:14]([NH:16][C:17]([C:19]2([C:22]3[CH:32]=[CH:31][C:25]4[O:26][C:27]([F:30])([F:29])[O:28][C:24]=4[CH:23]=3)[CH2:21][CH2:20]2)=[O:18])[CH:13]=[CH:12][C:11]=1[CH3:33]>>[CH2:1]([NH:8][C:10]1[N:15]=[C:14]([NH:16][C:17]([C:19]2([C:22]3[CH:32]=[CH:31][C:25]4[O:26][C:27]([F:30])([F:29])[O:28][C:24]=4[CH:23]=3)[CH2:20][CH2:21]2)=[O:18])[CH:13]=[CH:12][C:11]=1[CH3:33])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccc(NC(=O)C2(c3ccc4c(c3)OC(F)(F)O4)CC2)nc1Cl
Reactant: NCc1ccccc1
Product: Cc1ccc(NC(=O)C2(c3ccc4c(c3)OC(F)(F)O4)CC2)nc1NCc1ccccc1

Procedure:
To benzylamine (0.5 mL, 4.6 mmol) was added N-(6-chloro-5-methylpyridin-2-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide (37 mg, 0.1 mmol) and the reaction mixture was irradiated in the microwave at 170° C. for 60 minutes. The crude product purified by reverse-phase preparative liquid chromatography utilizing a gradient of 0-99% acetonitrile in water containing 0.05% trifluoracetic acid to yield the pure product. ESI-MS m/z calc. 437.4. found 438.3 (M+1)+; retention time 1.83 minutes.
Reaction SMILES: [F:1][C:2]1[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:3]=1[O:4][C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[C:7](/[CH:13]=C/N(C)C)[N:6]=1.O.I([O-])(=O)(=O)=[O:25].[Na+]>C1COCC1>[F:1][C:2]1[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:3]=1[O:4][C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[C:7]([CH:13]=[O:25])[N:6]=1
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: CN(C)/C=C/c1nc(Oc2ccc(F)cc2F)ccc1C#N
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: N#Cc1ccc(Oc2ccc(F)cc2F)nc1C=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
At RT, to the product of step 2 above in THF (70.00 mL) and water (70.00 mL) was added sodium periodate (8.9 g, 42 mmol) in one portion and the reaction mixture was allowed to stir at RT for 2 h, resulting in the formation of a yellow suspension. The suspension was passed through a flitted funnel, washing with THF (2×10 mL). The filtrate was concentrated under reduced pressure and the remaining mixture was extracted with DCM (2×30 mL). The organic layers were combined, dried over MgSO4, filtered and concentrated. Purification on the ISCO (40 g column, 20-60% EtOAc in hexanes) afforded 6-(2,4-difluorophenoxy)-2-formylnicotinonitrile as a light yellow crystalline solid. MS (ESI, pos.ion) m/z: M+1=261.0
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]2[N:9]=[C:10]([SH:12])[N:11]=[C:4]2[N:3]=1.[CH:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21]Br)=[CH:15][CH:14]=1>>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]2[N:9]=[C:10]([S:12][CH2:21][CH2:20][O:19][C:16]3[CH:17]=[CH:18][CH:13]=[CH:14][CH:15]=3)[N:11]=[C:4]2[N:3]=1
Reactant: Cc1cc(C)n2nc(S)nc2n1
Reactant: BrCCOc1ccccc1
Product: Cc1cc(C)n2nc(SCCOc3ccccc3)nc2n1
Yield: 65 %

Procedure:
The title compound was prepared according to the experimentals described for Example 1 above from 5,7-dimethyl-[1,2,4]-triazolo[1,5-a]pyrimidine-2-thiol and b-bromophenetole in 65% yield; EM (calc.): 300.1; MS (ESI) m/e: 301.1 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][CH:6]2[NH2:11].Cl[CH2:13][CH2:14][N:15]=[C:16]=[S:17]>C(OCC)C>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][CH:6]2[NH:11][C:16]1[S:17][CH2:13][CH2:14][N:15]=1
Reactant: S=C=NCCCl
Reactant: NC1CCc2c(Cl)cccc21
Solvent: CCOCC
Product: Clc1cccc2c1CCC2NC1=NCCS1
Reaction time: 2 h
Yield: 40.8 %

Procedure:
To a solution of 4-chloro-indan-1-ylamine (390 mg) in diethyl ether (20 ml) was added 1-chloro-2-isothiocyanatoethane (283 mg) at 0° C. and the solution stirred for 2 h at the same temperature. The reaction mixture was quenched with diluted sodium hydroxide solution and extracted with diethyl ether. The residue was purified on silica gel to yield 240 mg of the product (41%).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:14]=[C:13]2[C:8]([C@H:9]([N:21]([CH2:26][C:27]3[CH:32]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:30]=[C:29]([C:37]([F:40])([F:39])[F:38])[CH:28]=3)[C:22]([O:24][CH3:25])=[O:23])[CH2:10][C@H:11]([CH3:20])[N:12]2[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:7][C:6]=1[O:41][CH3:42])=O.[BH4-].[Na+].CO>O1CCCC1>[CH2:18]([O:17][C:15]([N:12]1[C:13]2[C:8](=[CH:7][C:6]([O:41][CH3:42])=[C:5]([CH2:3][OH:2])[CH:14]=2)[C@H:9]([N:21]([CH2:26][C:27]2[CH:28]=[C:29]([C:37]([F:38])([F:39])[F:40])[CH:30]=[C:31]([C:33]([F:35])([F:34])[F:36])[CH:32]=2)[C:22]([O:24][CH3:25])=[O:23])[CH2:10][C@@H:11]1[CH3:20])=[O:16])[CH3:19]
Reactant: CCOC(=O)N1c2cc(C(=O)OC)c(OC)cc2[C@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C(=O)OC)C[C@@H]1C
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CCOC(=O)N1c2cc(CO)c(OC)cc2[C@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C(=O)OC)C[C@@H]1C
Yield: 108 %

Procedure:
To a solution of cis-4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-6-methoxy-2-methyl-3,4-dihydro-2H-quinoline-1,7-dicarboxylic acid 1-ethyl ester 7-methyl ester (Example 13) (100 mg; 0.16 mmol) in 20 mL tetrahydrofuran was added sodium borohydride (62 mg; 1.6 mmol). The reaction was heated to reflux and methanol (40 mL) was added slowly. After an additional 30 min at reflux the reaction was concentrated and the residue was diluted with 20 ml H2O and extracted 3×50 mL of ethyl acetate. The combined extracts were dried (MgSO4), filtered, concentrated, and the residue was purified by chromatography (30-40% ethyl acetate:hexane) to afford 100 mg of the title product. 1H NMR (CDCl3) δ 1.1 (d, 3H), 1.3 (t, 3H), 3.75 (s, 3H), 6.4 (s, 1H), 7.4 (s, 1H), 7.7 (s, 2H), 7.8 (s, 1H).
Reaction SMILES: [BH4-].[Na+].[CH2:3]([O:10][C:11]1[C:16]2[NH:17][C:18](=[O:23])[C:19]([CH3:22])([CH3:21])[O:20][C:15]=2[C:14]([CH:24]([OH:39])[CH:25]=[N:26][C:27]([CH3:38])([CH3:37])[CH2:28][C:29]2[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=2)=[CH:13][CH:12]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.CC(C)=O.C(O)(=O)C>C(O)C.O>[CH2:3]([O:10][C:11]1[C:16]2[NH:17][C:18](=[O:23])[C:19]([CH3:21])([CH3:22])[O:20][C:15]=2[C:14]([CH:24]([OH:39])[CH2:25][NH:26][C:27]([CH3:38])([CH3:37])[CH2:28][C:29]2[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=2)=[CH:13][CH:12]=1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: COc1ccc(CC(C)(C)N=CC(O)c2ccc(OCc3ccccc3)c3c2OC(C)(C)C(=O)N3)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: CC(=O)O
Product: COc1ccc(CC(C)(C)NCC(O)c2ccc(OCc3ccccc3)c3c2OC(C)(C)C(=O)N3)cc1
Reaction time: 1 h

Procedure:
0.6 g sodium borohydride are added at ambient temperature to a solution of 8.6 g (17 mmol) 5-benzyloxy-8-{1-hydroxy-2-[2-(4-methoxy-phenyl)-1,1-dimethyl-ethylimino]-ethyl}-2,2-dimethyl-4H-benzo[1,4]oxazin-3-one in 80 mL ethanol and the mixture is stirred for one hour. The reaction mixture is combined with 20 mL acetone, stirred for 30 minutes, diluted with 50 ml of water and acidified with glacial acetic acid. After the organic solvents have been distilled off ethyl acetate is added to the aqueous residue. It is acidified with conc. hydrochloric acid and diluted with diethyl ether. The product precipitated as the hydrochloride is suction filtered and washed with acetone and diethyl ether. Yield: 8.4 g (91%, hydrochloride); melting range=215-218° C.
Reaction SMILES: Br[CH2:2][C:3]1[NH:8][C:7]([C:9]2[S:10][CH:11]=[CH:12][N:13]=2)=[N:6][CH:5]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=2[Cl:21])[C:4]=1[C:22]([O:24][CH2:25][CH3:26])=[O:23].Cl.[NH:28]1[CH2:33][CH2:32][O:31][CH:30]([CH2:34][C:35]([OH:37])=[O:36])[CH2:29]1>>[Cl:21][C:15]1[CH:16]=[C:17]([Cl:20])[CH:18]=[CH:19][C:14]=1[CH:5]1[N:6]=[C:7]([C:9]2[S:10][CH:11]=[CH:12][N:13]=2)[NH:8][C:3]([CH2:2][N:28]2[CH2:33][CH2:32][O:31][CH:30]([CH2:34][C:35]([OH:37])=[O:36])[CH2:29]2)=[C:4]1[C:22]([O:24][CH2:25][CH3:26])=[O:23]
Reactant: CCOC(=O)C1=C(CBr)NC(c2nccs2)=NC1c1ccc(Cl)cc1Cl
Reactant: O=C(O)CC1CNCCO1
Agent: Cl
Product: CCOC(=O)C1=C(CN2CCOC(CC(=O)O)C2)NC(c2nccs2)=NC1c1ccc(Cl)cc1Cl
Yield: 48.7 %

Procedure:
Ethyl 6-(bromomethyl)-4-(2,4-dichlorophenyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate (0.65 g, 1.37 mmol) was reacted with 2-(morpholin-2-yl)acetic acid hydrochloride (0.3 g, 1.65 mmol) according to the procedure as described in Example 3 to give the title compound as a yellow solid (0.36 g, 49%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]23[CH2:18][CH2:17][CH2:16][CH2:15][CH:14]2[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]3=[O:19])[N:3]=[CH:2]1.[OH-].[Na+].[BH4-].[Na+].Cl>C(O)C.O>[NH:1]1[CH:5]=[C:4]([C:6]23[CH2:18][CH2:17][CH2:16][CH2:15][CH:14]2[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]3[OH:19])[N:3]=[CH:2]1
Reactant: O=C1c2ccccc2C2CCCCC12c1c[nH]cn1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: OC1c2ccccc2C2CCCCC12c1c[nH]cn1
Temperature: 40 °C
Reaction time: 0.08 h

Procedure:
9a-(1H-Imidazol-4-yl)-1,2,3,4,4a,9a-hexahydrofluoren-9-one (0.41 g) was dissolved in ethanol (10 ml). 48% NaOH solution (0.003 ml) and NaBH4 (0.06 g) was added and the mixture was heated at 40° C. for 12 hours. Water (2.5 ml) was added and the mixture was cooled to the ambient temperature. HCl (0.3 ml of 30% HCl in 1 ml H2O) was added and the mixture was stirred for 5 minutes. NaOH (0.2 ml of 48% NaOH in 5 ml H2O) was then added and the solvents were evaporated. The residue was mixed with water (30 ml) and extracted with CH2Cl2 (3×30 ml) and evaporated. The crude product was purified by flash chromatography using methylene chloride/methanol (95:5) as eluent. The yield was 0.26 g.
Reaction SMILES: [CH3:1][CH:2]1[CH2:8][C:7]2[CH:9]=[C:10]3[O:15][CH2:14][O:13][C:11]3=[CH:12][C:6]=2[C:5]([C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=2)=[N:4][N:3]1[C:25](=[S:27])[NH2:26].[CH2:28](OC(OCC)CBr)[CH3:29].CN(C)C=O>O>[CH3:1][CH:2]1[CH2:8][C:7]2[CH:9]=[C:10]3[O:15][CH2:14][O:13][C:11]3=[CH:12][C:6]=2[C:5]([C:16]2[CH:17]=[CH:18][C:19]([N+:22]([O-:24])=[O:23])=[CH:20][CH:21]=2)=[N:4][N:3]1[C:25]1[S:27][CH:28]=[CH:29][N:26]=1
Reactant: CC1Cc2cc3c(cc2C(c2ccc([N+](=O)[O-])cc2)=NN1C(N)=S)OCO3
Reactant: CCOC(CBr)OCC
Solvent: CN(C)C=O
Solvent: O
Product: CC1Cc2cc3c(cc2C(c2ccc([N+](=O)[O-])cc2)=NN1c1nccs1)OCO3
Temperature: 80 °C
Reaction time: 0.67 h
Yield: 80 %

Procedure:
A mixture of 1.00 g (2.60 mmol) of the starting material I, 2.54 g (12.89 mmol) of bromoacetaldehyde diethyl acetal and 10 ml of dimethylformamide was stirred at 80° C. for 40 min. Then the reaction mixture was diluted with water and the crude product obtained was recrystallized from ethanol to yield 0.85 g (80%) of the title compound. Mp.: 145-150° C.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]([N:11]2[CH:15]=[CH:14][CH:13]=[CH:12]2)=[CH:7][C:3]=1[C:4]([OH:6])=O.[F:16][C:17]([F:30])([F:29])[C:18]1[CH:19]=[C:20]([CH:22]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:24]=1)[NH2:21]>>[F:16][C:17]([F:29])([F:30])[C:18]1[CH:19]=[C:20]([NH:21][C:4](=[O:6])[C:3]2[CH:7]=[C:8]([N:11]3[CH:15]=[CH:14][CH:13]=[CH:12]3)[CH:9]=[CH:10][C:2]=2[OH:1])[CH:22]=[C:23]([C:25]([F:26])([F:28])[F:27])[CH:24]=1
Reactant: Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: O=C(O)c1cc(-n2cccc2)ccc1O
Product: O=C(Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cc(-n2cccc2)ccc1O
Yield: 57.8 %

Procedure:
Using 2-hydroxy-5-(pyrrol-1-yl)benzoic acid and 3,5-bis(trifluoromethyl)-aniline as the raw materials, the same operation as the example 16 gave the title compound.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][C:4](=[CH:7][CH2:8][C@H:9]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C@@H:10]([CH2:14][CH:15]([CH3:17])[CH3:16])[C:11]([OH:13])=[O:12])[CH2:3][CH2:2]1.[H][H]>CO.[Pd]>[O:1]1[CH2:2][CH2:3][CH:4]([CH2:7][CH2:8][C@H:9]([C:18]([O:20][C:21]([CH3:23])([CH3:22])[CH3:24])=[O:19])[C@@H:10]([CH2:14][CH:15]([CH3:17])[CH3:16])[C:11]([OH:13])=[O:12])[CH2:5][CH2:6]1
Reactant: [H][H]
Reactant: CC(C)C[C@@H](C(=O)O)[C@H](CC=C1CCOCC1)C(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CO
Product: CC(C)C[C@@H](C(=O)O)[C@H](CCC1CCOCC1)C(=O)OC(C)(C)C
Yield: 82.9 %

Procedure:
A solution of 0.397 g of 4-tert-butyl hydrogen 3(S)-[(tetrahydro-2H-pyran-4-ylidene)ethyl]-2(R)-isobutylsuccinate in 10 ml of methanol was shaken in a hydrogen atmosphere in the presence of 0.196 g of 10% palladium on charcoal catalyst until no further uptake of hydrogen was observed. The catalyst was filtered off and the filtrate was evaporated. There was obtained 0.331 g of 4-tert-butyl hydrogen 3(S)-[(tetrahydro-2H-pyran-4-yl)ethyl]-2(R)-isobutylsuccinate in the form of a colourless gum.
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:14][CH2:15][CH2:16][C:17]#[N:18].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>C(O)CCC.O1CCOCC1>[C:1]1([CH:7]2[CH2:8][CH2:9][N:10]([CH2:14][CH2:15][CH2:16][C:17]#[N:18])[CH2:11][CH2:12]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: c1ccc(C2CCNCC2)cc1
Reactant: N#CCCCBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: CCCCO
Product: N#CCCCN1CCC(c2ccccc2)CC1
Temperature: 25 °C
Yield: 53.7 %

Procedure:
A suspension of 4-phenylpiperidine (5.20 g, 32.2 mmol, 1.00 equiv), 4-bromobutyronitrile (4.81 mL, 48.4 mmol, 1.50 equiv), potassium carbonate (11.14 g, 80.6 mmol, 2.50 equiv), and potassium iodide (266 mg, 12.9 mmol, 0.4 equiv) in n-butanol (60 mL) and 1,4-dioxane (60 mL) was stirred at reflux under argon for 48 hours. The mixture was cooled to room temperature and concentrated. The residue was purified by flash chromatography (SiO2, MeOH—EtOAc 1:19) to afford 3.95 g of 4-(4-phenylpiperidin-1-yl)butyronitrile (white solid, 53%), which was characterized spectroscopically.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]([C:11]2[CH:12]=[N:13][NH:14][CH:15]=2)=[O:10])[CH:5]=[CH:4][C:3]=1[C@@H:16]1[O:21][CH2:20][CH2:19][N:18]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:17]1.Cl[C:30]1[CH:35]=[C:34]([C:36]([F:39])([F:38])[F:37])[N:33]=[CH:32][N:31]=1>CS(C)=O>[F:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]([C:11]2[CH:12]=[N:13][N:14]([C:30]3[CH:35]=[C:34]([C:36]([F:39])([F:38])[F:37])[N:33]=[CH:32][N:31]=3)[CH:15]=2)=[O:10])[CH:5]=[CH:4][C:3]=1[C@@H:16]1[O:21][CH2:20][CH2:19][N:18]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:17]1
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(NC(=O)c3cn[nH]c3)cc2F)C1
Reactant: FC(F)(F)c1cc(Cl)ncn1
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(NC(=O)c3cnn(-c4cc(C(F)(F)F)ncn4)c3)cc2F)C1
Temperature: 120 °C
Reaction time: 1 h

Procedure:
Under N2, (S)-tert-butyl 2-(2-fluoro-4-(1H-pyrazole-4-carboxamido)phenyl)morpholine-4-carboxylate (60 mg, 154 μmol, Eq: 1.00), 4-chloro-6-(trifluoromethyl)-pyrimidine (CAS 37552-81-1) (28 mg, 154 μmol, Eq: 1.00) and were combined in DMSO (2 ml). The orange solution was stirred at 120° C. over 1 hour. Control with TLC: the reaction was finished. At RT, the RM was partitioned between water and EtOAc; extracted; the organic layer was washed with water and brine; dried over MgSO4; filtered; concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 10 g, 15% to 60% EtOAc in heptane). Yellow solid (41 mg). MS: 535.7 ([M−H]−)
Reaction SMILES: [C:1]1([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH:6]=[CH:5][C:4]([C@@:7]2([O:34][CH3:35])[CH2:11][N:10]([C:12](=[O:29])[C@@H:13]([NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH:19]=[CH2:20])[C@H:9]([C:30]([O:32]C)=[O:31])[CH2:8]2)=[CH:3][CH:2]=1.O.[OH-].[Li+]>C1COCC1.CO.O>[C:1]1([C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH:2]=[CH:3][C:4]([C@@:7]2([O:34][CH3:35])[CH2:11][N:10]([C:12](=[O:29])[C@@H:13]([NH:21][C:22]([O:24][C:25]([CH3:26])([CH3:27])[CH3:28])=[O:23])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH:19]=[CH2:20])[C@H:9]([C:30]([OH:32])=[O:31])[CH2:8]2)=[CH:5][CH:6]=1
Reactant: C=CCCCCC[C@H](NC(=O)OC(C)(C)C)C(=O)N1C[C@](OC)(c2ccc(-c3ccccc3)cc2)C[C@H]1C(=O)OC
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: C=CCCCCC[C@H](NC(=O)OC(C)(C)C)C(=O)N1C[C@](OC)(c2ccc(-c3ccccc3)cc2)C[C@H]1C(=O)O
Temperature: 25 °C
Reaction time: 18 h
Yield: 91.4 %

Procedure:
To a solution of (2S,4R)-methyl 4-(biphenyl-4-yl)-1-((S)-2-(tert-butoxycarbonylamino)non-8-enoyl)-4-methoxypyrrolidine-2-carboxylate (166 mg, 0.294 mmol) in THF (2 mL) and MeOH (2 mL) was added a pre-made solution of lithium hydroxide monohydrate (37 mg, 0.882 mmol) in water (2 mL). This cloudy solution was stirred at rt for 18 h, and then concentrated in vacuo. The residue was dissolved in water and acidified with 1N HCl to pH 2. This aqueous solution was extracted with EtOAc. The organic phase was washed with 5% citric acid and brine, dried over MgSO4, filtered, and concentrated in vacuo to give 148 mg (91%) of (2S,4R)-4-(biphenyl-4-yl)-1-((S)-2-(tert-butoxycarbonylamino)non-8-enoyl)-4-methoxypyrrolidine-2-carboxylic acid as a white solid. No further purification was undertaken.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C:13]([OH:15])=[O:14])[CH:10]([CH3:12])[CH3:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:22](Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>CN(C)C=O>[CH2:22]([O:14][C:13](=[O:15])[C@@H:9]([CH:10]([CH3:11])[CH3:12])[NH:8][C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:7])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CC(C)[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)[C@@H](NC(=O)OC(C)(C)C)C(=O)OCc1ccccc1
Reaction time: 8 h
Yield: 98.6 %

Procedure:
N-Tert-butoxycarbonyl-D-valine (70 g, 0.32 mol) and cesium carbonate (200.2 g, 0.615 mol) were stirred in dry dimethylformamide (550 mL). Benzyl bromide (40.32 mL, 0.336 mol) was added and the reaction mixture was stirred overnight. The material was concentrated on the roto-evaporator and the residue was dissolved in methylene chloride (200 mL) and the methylene chloride layer was washed with water and brine, dried over magnesium sulfate and concentrated to give N-tert-butoxycarbonyl-D-valine benzyl ester (97 g) as a viscous oil.
Reaction SMILES: [OH-].[K+].[Cl:3][C:4]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:5]=1[CH:6]=O.[CH3:13][CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][C:15]1=[O:20]>O>[CH3:13][CH:14]1[CH2:19][CH2:18][CH2:17][C:16](=[CH:6][C:5]2[CH:8]=[CH:9][C:10]([Cl:12])=[CH:11][C:4]=2[Cl:3])[C:15]1=[O:20]
Reactant: CC1CCCCC1=O
Reactant: O=Cc1ccc(Cl)cc1Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: CC1CCCC(=Cc2ccc(Cl)cc2Cl)C1=O
Temperature: 150 °C
Reaction time: 10 h
Yield: 86 %

Procedure:
A solution of 1.5 g of 85% strength aqueous potassium hydroxide solution in 135 ml of water was charged to a 0.31 stainless-steel autoclave, and then 47.5 g of 2,4-dichlorobenzaldehyde and 30.5 g of 2-methylcyclohexanone were added, and the mixture was subsequently heated to 150° C. under the intrinsic pressure (to 3.8 bar). Stirring was subsequently carried out at this temperature for 10 hours. After cooling to room temperature, the suspension was filtered with suction and the solid product was washed to neutrality with water and dried in a vacuum oven at 55° C. In this way 62.8 g of 2-methyl-6-(2,4-dichlorobenzylidene)-cyclohexanone (99.5% pure) were obtained. This corresponds to a yield of 86% of theory.