Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[CH:14]=[CH:13][C:12]([N:15]2[C:19]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([F:28])[CH:21]=3)=[CH:18][N:17]=[CH:16]2)=[CH:11][CH:10]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:29]N1C(=O)CCC1=O>C(#N)C>[C:1]([NH:5][S:6]([C:9]1[CH:10]=[CH:11][C:12]([N:15]2[C:19]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([F:28])[CH:21]=3)=[C:18]([Cl:29])[N:17]=[CH:16]2)=[CH:13][CH:14]=1)(=[O:7])=[O:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C1CCC(=O)N1Cl
Reactant: COc1ccc(-c2cncn2-c2ccc(S(=O)(=O)NC(C)(C)C)cc2)cc1F
Solvent: CC#N
Product: COc1ccc(-c2c(Cl)ncn2-c2ccc(S(=O)(=O)NC(C)(C)C)cc2)cc1F
Reaction time: 0.17 h
Yield: 82 %

Procedure:
A mixture of N-tert-butyl-4-[5-(3-fluoro-4-methoxyphenyl)imidazol-1-yl]benzenesulfonamide (41.40 g, 103 mmol, obtained in example 3) and acetonitrile (840 mL) is heated at reflux and acetonitrile is added until complete dissolution (200 mL more). Next, N-chlorosuccinimide (15.0 g, 113 mmol) is added and the mixture is refluxed for 24 h. The solvent is removed and the residue is suspended in EtOAc and 1N HCl and is stirred for 10 min. The solid obtained is filtered and washed directly in the filter with 1N HCl, 1N NaOH, saturated NH4Cl solution, H2O and Et2O. A solid is obtained, which is dried in vacuo to give 37.0 g of the product as a creamy solid (yield: 82%).
Reaction SMILES: [N:1]1[CH:6]=[C:5]([OH:7])[CH:4]=[N:3][CH:2]=1.[H-].[Na+].F[C:11]1[CH:16]=[C:15]([I:17])[CH:14]=[CH:13][N:12]=1.O>CN(C=O)C>[I:17][C:15]1[CH:14]=[CH:13][N:12]=[C:11]([O:7][C:5]2[CH:6]=[N:1][CH:2]=[N:3][CH:4]=2)[CH:16]=1
Reactant: Fc1cc(I)ccn1
Reactant: Oc1cncnc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Ic1ccnc(Oc2cncnc2)c1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To 259 mg (26.9 mmol) pyrimidin-5-ol (J. Chem. Soc. 1956, 2033) in 200 mL DMF are added 108 mg (26.9 mmol) sodium hydride (60% dispersion in mineral oil). The mixture is stirred for 20 min at rt. After that time, 500 mg (22.4 mmol) 2-fluoro-4-iodopyridine are added and the mixture is stirred for 12 h at 80° C. Subsequently the mixture is poured into water and extracted with ethyl acetate (3×). The combined organic layers are washed with brine. After drying over sodium sulphate, the solvent is removed in vacuo and the residue is purified by column chromatography (silica gel; heptane/ethyl acetate, gradient 0-60%) to yield the desired product.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6]([C:8]1[CH:9]=[N:10][NH:11][C:12]=1[NH2:13])=[O:7])[CH3:4].[O:14]1[CH2:19][CH2:18][CH2:17][C:16]([CH:20]=O)=[CH:15]1>CN(C)C=O>[CH2:3]([O:5][C:6]([C:8]1[CH:9]=[N:10][N:11]2[CH:20]=[C:16]([CH2:17][CH2:18][CH2:19][OH:14])[CH:15]=[N:13][C:12]=12)=[O:7])[CH3:4]
Reactant: O=CC1=COCCC1
Reactant: CCOC(=O)c1cn[nH]c1N
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cnn2cc(CCCO)cnc12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 21.4 %

Procedure:
Sodium hydride (60% suspension in mineral oil, 350 mg, 8.78 mmol) was added, at 0° C., to a solution of 5-amino-1H-pyrazole-4-carboxylic acid ethyl ester (1.4 g, 8.9 mmol) and 5,6-dihydro-4H-pyran-3-carbaldehyde (0.5 g, 4.5 mmol) in anhydrous N,N-dimethylformamide (10 mL) and the resulting mixture was stirred, at 0° C., for 30 minutes. The reaction mixture was stirred at room temperature overnight and then heated at 50° C. for 2 hours. The resulting mixture was partitioned between water and ethyl acetate and the organic layer was separated, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The crude residue was purified by flash chromatography to afford 0.24 g of 6-(3-hydroxy-propyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid ethyl ester as a white solid. MS=250 [M+H]+.
Reaction SMILES: [NH2:1][CH:2]1[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:4][C:3]1([F:15])[F:14].[CH3:16][S:17]([CH2:20][CH2:21][C:22](O)=[O:23])(=[O:19])=[O:18].CN1CCOCC1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[F:14][C:3]1([F:15])[CH:2]([NH:1][C:22](=[O:23])[CH2:21][CH2:20][S:17]([CH3:16])(=[O:19])=[O:18])[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:12])([CH3:11])[CH3:13])=[O:8])[CH2:4]1
Reactant: CS(=O)(=O)CCC(=O)O
Reactant: CC(C)(C)OC(=O)N1CC(N)C(F)(F)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC(NC(=O)CCS(C)(=O)=O)C(F)(F)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 75.7 %

Procedure:
To a reaction flask was added tert-butyl 4-amino-3,3-difluoropyrrolidine-1-carboxylate (1.36 g, 6.12 mmol), 3-(methylsulfonyl)propanoic acid (1.02 g, 6.73 mmol, 1.1 mol eq), DCM (31 mL, 0.4 M), NMM (1.35 mL, 12.2 mmol, 2 mol eq), HOBt (1.31 g, 9.2 mmol, 1.5 mol eq) and EDC-HCl (1.85 g, 9.2 mmol, 1.5 mol eq). The resulting suspension was stirred at ambient temperature under a nitrogen atmosphere for 2 hr. The reaction was diluted with DCM (80 mL), washed with aqueous NaHCO3 (2×30 mL) and the organic layer was dried over Na2SO4 and evaporated to give a residue that was purified via silica flash chromatography eluting with gradients from 100% heptane to 100% ethyl acetate to give the title product as a white foamy solid (1.65 g, 76% yield, >95% purity). 1H NMR (400 MHz, chloroform-d) δ ppm 6.45 (br. s., 1 H) 4.68-4.89 (m, 1 H) 3.94 (dd, J=10.70, 8.62 Hz, 1 H) 3.62-3.86 (m, 2 H) 3.43 (t, J=7.15 Hz, 2 H) 3.18 (br. s., 1 H) 2.97 (s, 3 H) 2.84 (td, J=7.15, 1.96 Hz, 2 H) 1.47 (s, 9 H). 19F NMR (376 MHz, chloroform-d) δ ppm −112.79-−110.52 (m, 1 F) −114.51-−113.30 (m, 1 F). m/z (APCI+) for C13H22F2N2O5S 257.1 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]3[CH:13]=[C:14]4[C:19]([C@@H:21]([OH:28])[C:22]5[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=5)([CH2:20][C:11]=3[CH:10]=[N:9]2)[CH2:18][N:17]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:16][CH2:15]4)=[CH:4][CH:3]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C1=CC=CC=2)=O.C(=O)([O-])O.[Na+]>ClCCl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12]3[CH:13]=[C:14]4[C@:19]([C:21](=[O:28])[C:22]5[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=5)([CH2:20][C:11]=3[CH:10]=[N:9]2)[CH2:18][N:17]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:16][CH2:15]4)=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC2=Cc3c(cnn3-c3ccc(F)cc3)CC2([C@@H](O)c2ccccn2)C1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC2=Cc3c(cnn3-c3ccc(F)cc3)C[C@]2(C(=O)c2ccccn2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 45.3 %

Procedure:
A solution of (R)-tert-butyl 1-(4-fluorophenyl)-4a-(R/S)-(hydroxy(pyridin-2-yl)methyl)-4a,5,7,8-tetrahydro-1H-pyrazolo[3,4-g]isoquinoline-6(4H)-carboxylate (410 mg, 0.86 mmol) in dry dichloromethane (10 mL) was treated with 1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3(1H)-one (547 mg, 1.29 mmol; Dess-Martin periodinane) and the reaction mixture was stirred for 1 hour at room temperature. The reaction mixture was cooled and treated with saturated sodium hydrogen carbonate solution (20 mL) followed by dichloromethane (10 mL). The mixture was stirred for 10 minutes and the phases were separated. The aqueous phase was extracted with further dichloromethane (×2) and the combined organic phases dried over sodium sulfate. The solids were removed by filtration, the filtrate was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel (gradient: 20-40% ethyl acetate in cyclohexane) to afford (R)-tert-butyl 1-(4-fluorophenyl)-4a-picolinoyl-4a,5,7,8-tetrahydro-1H-pyrazolo[3,4-g]isoquinoline-6(4H)-carboxylate as a pale yellow foam (185 mg). LCMS (Method B, ESI): RT 4.13 min, m+H=475.5; 1H NMR (400 MHz, CDCl3): δ 8.68 (d, J=4.8 Hz, 2 H); 7.44-7.45 (m, 5 H); 7.15-7.16 (m, 3 H); 6.51 (s, 2 H); 2.83 (br s, 5 H); 2.49 (s, 1 H); 1.43 (s, 9 H).
Reaction SMILES: [Na].[NH:2]1[C:6]([C:7]2[CH:8]=[CH:9][C:10]3[C:11](=[O:23])[C:12]4[C:17]([S:18](=[O:22])(=[O:21])[C:19]=3[CH:20]=2)=[CH:16][CH:15]=[CH:14][CH:13]=4)=[N:5][N:4]=[N:3]1.Br[CH2:25][C:26]([O:28]CC)=[O:27]>C(O)C>[C:26]([CH2:25][N:4]1[N:3]=[N:2][C:6]([C:7]2[CH:8]=[CH:9][C:10]3[C:11](=[O:23])[C:12]4[C:17]([S:18](=[O:21])(=[O:22])[C:19]=3[CH:20]=2)=[CH:16][CH:15]=[CH:14][CH:13]=4)=[N:5]1)([OH:28])=[O:27]
Reactant: CCOC(=O)CBr
Reactant: O=C1c2ccccc2S(=O)(=O)c2cc(-c3nnn[nH]3)ccc21
Agent: [Na]
Solvent: CCO
Product: O=C(O)Cn1nnc(-c2ccc3c(c2)S(=O)(=O)c2ccccc2C3=O)n1
Reaction time: 2 h

Procedure:
Sodium (0.46 g) was dissolved in ethanol (20 ml) and 3-(5-tetrazolyl)thioxanthone-10,10-dioxide (6.24 g) was added. Ethyl bromoacetate (3.34 g) was added to the mixture, which was boiled under reflux for 1.5 hours. The ester intermediate was deposited during this time, and after cooling was filtered off, washed with water and dried, m.p. 194°-195° C. The ester was boiled with concentrated hydrochloric acid (40 ml) and acetic acid (120 ml) for 2 hr. On cooling 3-(2-carboxymethyl-5-tetrazolyl)thioxanthone-10,10-dioxide crystallised out, and was filtered off, recrystallised from acetic acid, and dried, m.p. 252° C. with decomposition.
Reaction SMILES: [C:1]([CH2:8][N:9]1[CH2:22][CH2:21][CH2:20][NH:19][CH2:18][CH2:17][N:16]([CH2:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:15][CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH3:31]I>C(Cl)(Cl)Cl>[C:24]([CH2:23][N:16]1[CH2:15][CH2:14][CH2:13][NH:12][CH2:11][CH2:10][N:9]([CH2:8][C:1]([O:3][C:4]([CH3:6])([CH3:5])[CH3:7])=[O:2])[CH2:22][CH2:21][CH2:20][N:19]([CH3:31])[CH2:18][CH2:17]1)([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25]
Reactant: CC(C)(C)OC(=O)CN1CCCNCCN(CC(=O)OC(C)(C)C)CCCNCC1
Reactant: CI
Solvent: ClC(Cl)Cl
Product: CN1CCCN(CC(=O)OC(C)(C)C)CCNCCCN(CC(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 100.3 %

Procedure:
To a solution of compound (5) (2.33 g, 5.43 mmol) in dry chloroform (50 ml) was added methyl iodide (6.78 ml, 15.43 g, 108.72 mmol). After stirring at an ambient temperature for 24 hours, the solvent was removed from the reaction mixture under reduced pressure. The residue was purified via column chromatography on silica using chloroform/isopropyl amine (20:2) as an eluent, to obtain compound (31) as a clear oil (2.41 g, 84% yield). 1H NMR (500 MHz, CDCl3): δ 3.27-3.25 (dd, 4H), 2.84-2.43 (m, 16H), 2.16 (s, 3H), 1.73-1.59 (m, 4H), 1.45 (s, 18H); 13C NMR (125 MHz, CDCl3): δ 170.94, 170.68, 80.57, 55.99, 55.93, 54.80, 53.77, 53.40, 52.26, 50.11, 48.34, 47.41, 47.17, 41.88, 28.18, 25.59, 25.00; HRMS (FAB) calculated for C23H47N4O4: 443.3597 [(M+H)+], measured value: 443.3600 [(M+H)+].
Reaction SMILES: [NH2:1][C:2]1[N:6]=[C:5]([C:7]([O:9][CH3:10])=[O:8])[NH:4][N:3]=1.O=[C:12]([CH:19]([CH3:21])[CH3:20])[CH2:13][C:14](OCC)=[O:15].Cl>C(O)(=O)C>[OH:15][C:14]1[N:3]2[N:4]=[C:5]([C:7]([O:9][CH3:10])=[O:8])[N:6]=[C:2]2[N:1]=[C:12]([CH:19]([CH3:21])[CH3:20])[CH:13]=1
Reactant: COC(=O)c1nc(N)n[nH]1
Reactant: CCOC(=O)CC(=O)C(C)C
Agent: Cl
Solvent: CC(=O)O
Product: COC(=O)c1nc2nc(C(C)C)cc(O)n2n1
Temperature: 25 °C
Yield: 55.6 %

Procedure:
A mixture of 3-amino-5-methoxycarbonyl-s-triazole (60 g) and ethyl 3-oxo-4-methylvalerate (65 g) in 600 ml of acetic acid was refluxed for five hours, the reaction mixture was cooled to room temperature, its pH was lowered to 1 to 2 with concentrated hydrochloric acid, and the separated crystals were recrystallized from ethanol, affording 54 g of the objective compound as colorless crystals.
Reaction SMILES: [H-].[Na+].[CH2:3]([CH:10]1[CH2:14][CH2:13][NH:12][CH2:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[Cl:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][CH:20]=[C:19]2[CH2:25][CH2:26][NH:27][C:28](=O)[O:29]C1C=CC=CC=1>C1COCC1>[CH2:3]([CH:10]1[CH2:14][CH2:13][N:12]([C:28]([NH:27][CH2:26][CH2:25][C:19]2[C:18]3[C:22](=[CH:23][CH:24]=[C:16]([Cl:15])[CH:17]=3)[NH:21][CH:20]=2)=[O:29])[CH2:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: c1ccc(CC2CCNC2)cc1
Reactant: O=C(NCCc1c[nH]c2ccc(Cl)cc12)Oc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)N1CCC(Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 32.1 %

Procedure:
NaH in mineral oil (60%) (12.20 mg) was added to a mixture of 3-benzylpyrrolidine (0.085 g; 0.508 mmol) in THF (2 mL) and stirred at room temperature for 10 minutes. Phenyl 2-(5-chloro-1H-indol-3-yl)ethylcarbamate (0.080 g; 0.245 mmol) in THF (2 mL) was added to the above mixture and stirred at room temperature overnight. The crude material was purified by preparative HPLC (method 2) to yield 0.03 g (31%) of 3-benzyl-N-(2-(5-chloro-1H-indol-3-yl)ethyl)pyrrolidine-1-carboxamide as a white solid.
Reaction SMILES: Cl[C:2]1[C:7]2[C:8]([CH3:12])=[C:9]([CH3:11])[NH:10][C:6]=2[CH:5]=[CH:4][N:3]=1.[F:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18][NH2:19])=[CH:16][CH:15]=1>>[CH3:11][C:9]1[NH:10][C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:19][CH2:18][C:17]3[CH:20]=[CH:21][C:14]([F:13])=[CH:15][CH:16]=3)[C:7]=2[C:8]=1[CH3:12]
Reactant: NCc1ccc(F)cc1
Reactant: Cc1[nH]c2ccnc(Cl)c2c1C
Product: Cc1[nH]c2ccnc(NCc3ccc(F)cc3)c2c1C
Temperature: 160 °C
Reaction time: 12 h
Yield: 83.2 %

Procedure:
A mixture of 4-chloro-2,3-dimethyl-1H-pyrrolo[3,2-c]pyridine (1.16 g, 6.43 mmol) prepared in Preparation 1 and 4-fluorobenzylamine (3 ml, 26.2 mmol) was stirred for 12 hours at 160° C. The reaction mixture was cooled to room temperature and purified with silica gel column chromatography (ethyl acetate: 100%) to give the titled compound as a white solid. (Yield: 83.2%)
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.Br[C:9]1[CH:10]=[N:11][C:12]([N:15]2[CH2:20][CH2:19][CH:18]([C:21]3[C:30]([CH:31]([F:42])[C:32]4[CH:37]=[CH:36][C:35]([C:38]([F:41])([F:40])[F:39])=[CH:34][CH:33]=4)=[C:29]([CH:43]4[CH2:48][CH2:47][C:46]([F:50])([F:49])[CH2:45][CH2:44]4)[C:28]4[CH:27]([O:51]CC5C=CC(OC)=CC=5)[CH2:26][C:25]([CH3:62])([CH3:61])[CH2:24][C:23]=4[N:22]=3)[CH2:17][CH2:16]2)=[N:13][CH:14]=1>>[F:50][C:46]1([F:49])[CH2:47][CH2:48][CH:43]([C:29]2[C:28]3[CH:27]([OH:51])[CH2:26][C:25]([CH3:61])([CH3:62])[CH2:24][C:23]=3[N:22]=[C:21]([CH:18]3[CH2:19][CH2:20][N:15]([C:12]4[N:13]=[CH:14][C:9]([N:5]5[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]5)=[CH:10][N:11]=4)[CH2:16][CH2:17]3)[C:30]=2[CH:31]([F:42])[C:32]2[CH:33]=[CH:34][C:35]([C:38]([F:40])([F:41])[F:39])=[CH:36][CH:37]=2)[CH2:44][CH2:45]1
Reactant: CN1CCNCC1
Reactant: COc1ccc(COC2CC(C)(C)Cc3nc(C4CCN(c5ncc(Br)cn5)CC4)c(C(F)c4ccc(C(F)(F)F)cc4)c(C4CCC(F)(F)CC4)c32)cc1
Product: CN1CCN(c2cnc(N3CCC(c4nc5c(c(C6CCC(F)(F)CC6)c4C(F)c4ccc(C(F)(F)F)cc4)C(O)CC(C)(C)C5)CC3)nc2)CC1

Procedure:
Reactions similar to those of the first step of Example 5 and Example 7 were performed except for using 1-methyl piperazine instead of morpholine, and from 120 mg (0.144 mmol) of (−)-2-[1-(5-Bromopyrimidin-2-yl)piperidin-4-yl]-4-(4,4-difluorocyclohexyl)-3-{fluoro[4-(trifluoromethyl)phenyl]methyl}-5-[(4-methoxybenzyl)oxy]-7,7-dimethyl-5,6,7,8-tetrahydroquinoline, which was prepared by a method similar to that of Reference Example 11, 36 mg of the title compound was obtained as a light yellow solid (yield: 34%).
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:10](=[O:11])[N:9]2[C@@H:5]1[C@@H:6]([CH3:53])[C:7]([S:25][C@@H:26]1[CH2:30][CH2:29][O:28][C@@H:27]1[CH2:31][NH:32][C:33](=[O:52])[C@@H:34]([NH:38]C(OCC1C=CC([N+]([O-])=O)=CC=1)=O)[CH:35]([CH3:37])[CH3:36])=[C:8]2[C:12]([O:14]CC1C=CC([N+]([O-])=O)=CC=1)=[O:13])[CH3:3].O>C(OCC)(=O)C.[Pd]>[NH2:38][C@@H:34]([CH:35]([CH3:37])[CH3:36])[C:33]([NH:32][CH2:31][C@@H:27]1[C@H:26]([S:25][C:7]2[C@H:6]([CH3:53])[C@H:5]3[N:9]([C:10](=[O:11])[C@@H:4]3[C@H:2]([OH:1])[CH3:3])[C:8]=2[C:12]([OH:14])=[O:13])[CH2:30][CH2:29][O:28]1)=[O:52]
Reactant: CC(C)[C@H](NC(=O)OCc1ccc([N+](=O)[O-])cc1)C(=O)NC[C@H]1OCC[C@H]1SC1=C(C(=O)OCc2ccc([N+](=O)[O-])cc2)N2C(=O)[C@H]([C@@H](C)O)[C@H]2[C@H]1C
Agent: [Pd]
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)[C@H](N)C(=O)NC[C@H]1OCC[C@H]1SC1=C(C(=O)O)N2C(=O)[C@H]([C@@H](C)O)[C@H]2[C@H]1C
Reaction time: 20 h
Yield: 77.7 %

Procedure:
To a mixture of 5.064 g of 4-nitrobenzyl (4R,5S, 6S)-6-[(1R)-1-hydroxyethyl]-4-methyl-3-{[(2R,3R)-2-({[(2S)-3-methyl-2-({[(4-nitrobenzyl)oxy]carbonyl}amino)-butanoyl]amino}methyl)tetrahydrofuran-3-yl]thio}-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate in 120 ml of ethyl acetate is added 5 ml of water, (about a 4% water:ethyl acetate biphasic solvent mixture) and after standing for about 5 minutes, gives a clear biphasic solvent mixture. An additional 55 ml of water is added followed by 2.5 g of 10% palladium-on-carbon. The reaction mixture is then hydrogenated in a Parr apparatus at 54 psi for 20 hours. The mixture is transferred to a separatory funnel and 100 ml of water is added. The aqueous layer is separated and the ethyl acetate layer washed with 20 ml of water. The combined aqueous layers are filtered through a pad of diatomaceous earth and the pad washed with an additional 30 ml of water. The combined aqueous layers are washed with 200 ml of ethyl acetate and lyophilized to afford 2.3 g(78%) of the desired product. MS (ES), m/z:442.3 (M+H)+, 98.9% area percent pure by analytical HPLC.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][CH2:12][C@H:11]([NH:15][C@@H:16]3[CH2:21][CH2:20][CH2:19][CH2:18][C@H:17]3[NH:22]C(=O)CC3C4C(=CC=CC=4)N(C)C=3)[CH2:10]2)=[CH:5][CH:4]=1)#[N:2].[C:36](Cl)(=[O:46])[O:37][CH2:38][CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][CH2:12][C@H:11]([NH:15][C@@H:16]3[CH2:21][CH2:20][CH2:19][CH2:18][C@H:17]3[NH:22][C:36](=[O:46])[O:37][CH2:38][CH2:39][C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[CH2:10]2)=[CH:5][CH:4]=1)#[N:2]
Reactant: O=C(Cl)OCCc1ccccc1
Reactant: Cn1cc(CC(=O)N[C@@H]2CCCC[C@H]2N[C@H]2CCCN(c3ccc(C#N)cc3)C2)c2ccccc21
Product: N#Cc1ccc(N2CCC[C@H](N[C@@H]3CCCC[C@H]3NC(=O)OCCc3ccccc3)C2)cc1

Procedure:
Phenethyl(1R,2R)-2-((S)-1-(4-cyanophenyl)piperidin-3-ylamino)cyclohexylcarbamate was synthesized using 4-((S)-3-((1R,2R)-2-aminocyclohexylamino)piperidin-1-yl)benzonitrile (from intermediate D, Example 10) (50 mg, 0.17 mmol) and phenethyl carbonochloridate (52.9 mg, 0.18 mmol) according to General Procedure H to give 60 mg (80.4%) of pale yellow solid. Anal. Calcd. for C27H34N4O2 m/z 446.3, found: 447.2 (M+H)+; 1H NMR (400 MHz, DMSO-d6) δ ppm 7.54 (d, J=9 Hz, 2H), 7.24 (m, 5H), 6.98 (d, J=7 Hz, 3H), 4.13 (t, J=6.8 Hz, 2H), 3.89 (d, J=12.6 Hz, 1H), 3.76 (d, J=12.5 Hz, 1H), 3.05 (bs, 1H), 2.82 (m, 3H), 1.90 (m, 1H), 1.80 (m, 2H), 1.68 (m, 1H), 1.61 (m, 2H), 1.46 (m, 1H), 1.18-1.2 (m, 4H), 1.01 (m, 1H).
Reaction SMILES: C([O:8][C:9]1[CH:10]=[CH:11][C:12]([O:15][C:16]2[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][CH:24]([NH:26][C:27](=[O:29])[CH3:28])[CH3:25])=[CH:18][CH:17]=2)=[N:13][CH:14]=1)C1C=CC=CC=1.[H][H]>C(O)C.[Pd]>[OH:8][C:9]1[CH:10]=[CH:11][C:12]([O:15][C:16]2[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][CH:24]([NH:26][C:27](=[O:29])[CH3:28])[CH3:25])=[CH:18][CH:17]=2)=[N:13][CH:14]=1
Reactant: CC(=O)NC(C)CCc1ccc(Oc2ccc(OCc3ccccc3)cn2)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CC(=O)NC(C)CCc1ccc(Oc2ccc(O)cn2)cc1

Procedure:
N-{3-[4-(5-Benzyloxypyridin-2-yloxy)phenyl]-1-methylpropyl}acetamide (344 mg, 881 μmol) were dissolved in 20 ml of ethanol. Addition of 93 mg of palladium/carbon was followed by hydrogenation under a pressure of 5 bar of hydrogen at room temperature for 16 h. The catalyst was filtered off and the filtrate was concentrated. Yield: 220 mg (83%), M+H+: 301.13.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][C:23]([S:26]([CH2:29][CH3:30])(=[O:28])=[O:27])=[CH:22][CH:21]=3)=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O.[OH-].[Na+]>C(Cl)Cl>[CH2:29]([S:26]([C:23]1[CH:24]=[CH:25][C:20]([C:17]2[CH:18]=[CH:19][C:14]([CH:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)=[N:15][CH:16]=2)=[CH:21][CH:22]=1)(=[O:28])=[O:27])[CH3:30]
Reactant: CCS(=O)(=O)c1ccc(-c2ccc(C3CCN(C(=O)OC(C)(C)C)CC3)nc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCS(=O)(=O)c1ccc(-c2ccc(C3CCNCC3)nc2)cc1
Reaction time: 4 h
Yield: 83.5 %

Procedure:
5-(4-Ethanesulfonylphenyl)-3′,4′,5′,6′-tetrahydro-2′H-[2,4′]bipyridinyl-1′-carboxylic acid tert-butyl ester (0.76 g, 1.675 mmol) was dissolved in DCM (12 mL) and TFA (4 mL) was added. The reaction mixture was stirred for 4 hours. 1N NaOH (20 mL) was added and the DCM phase was washed and dried with Na2CO3, filtered and evaporation gave 462 mg (79%) white crystalline compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]#[C:10][C:11]#[CH:12])=[CH:5][CH:4]=1.[F:13][C:14]([F:27])([F:26])[C:15]1[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][C:16]=1I.C1C=CC=CC=1>C(N(CC)CC)C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Cu]Cl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]#[C:10][C:11]#[C:12][C:16]2[CH:17]=[C:18]([C:21]([F:24])([F:23])[F:22])[CH:19]=[CH:20][C:15]=2[C:14]([F:13])([F:26])[F:27])=[CH:5][CH:4]=1
Reactant: C#CC#Cc1ccc(OC)cc1
Reactant: FC(F)(F)c1ccc(C(F)(F)F)c(I)c1
Agent: Cl[Cu]
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: COc1ccc(C#CC#Cc2cc(C(F)(F)F)ccc2C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 13 h
Yield: 61.7 %

Procedure:
1100 mg of the 1-(4-methoxyphenyl)-1,3-butadiyne obtained and 2700 mg of 2,5-bis(trifluoromethyl) iodobenzene were then dissolved in 50 ml of triethylamine, and 50 mg of bis(triphenylphosphine)palladium (II) chloride and 14 mg of copper (I) chloride were then rapidly added to the reaction mixture. After the solution had been stirred at room temperature for 13 hours, 50 ml of benzene were added to the reaction mixture, and the precipitates produced were then filtered off. After the solvent had been evaporated, the residue was neutralized by 1N hydrochloric acid and subjected to extraction with 50 ml of benzene three times. The organic layer was dried over magnesium sulfate, and the solvent was then evaporated. The residue was purified by silica-gel column chromatography using hexane as an eluent to obtain 1600 mg of 1-(4-methoxyphenyl)-4-[2,5-bis(trifluoromethyl)phenyl]-1,3-butadiyne. This compound was a needle-like white crystal having a melting point of from 86° to 88° C.
Reaction SMILES: [C:1](=[O:4])([O-])[O-].[Cs+].[Cs+].O=[C:8]1[NH:17][CH:16]([C:18]2[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][C:19]=2[S:26]([CH3:29])(=[O:28])=[O:27])[C:15]2[C:14](=[O:30])[CH2:13][CH2:12][CH2:11][C:10]=2[N:9]1[C:31]1[CH:36]=[CH:35][N:34]=[C:33]([C:37]([F:40])([F:39])[F:38])[CH:32]=1.C(OCC)(=O)C>CN(C)C=O>[CH3:8][N:17]1[CH:16]([C:18]2[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][C:19]=2[S:26]([CH3:29])(=[O:27])=[O:28])[C:15]2[C:14](=[O:30])[CH2:13][CH2:12][CH2:11][C:10]=2[N:9]([C:31]2[CH:36]=[CH:35][N:34]=[C:33]([C:37]([F:40])([F:38])[F:39])[CH:32]=2)[C:1]1=[O:4]
Reactant: O=C([O-])[O-]
Reactant: CS(=O)(=O)c1cc(C#N)ccc1C1NC(=O)N(c2ccnc(C(F)(F)F)c2)C2=C1C(=O)CCC2
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CN1C(=O)N(c2ccnc(C(F)(F)F)c2)C2=C(C(=O)CCC2)C1c1ccc(C#N)cc1S(C)(=O)=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Cesium carbonate (265 mg, 0.82 mmol) and methyl idodide (51 μL, 0.82 mmol) are added to a solution of 4-(2,5-dioxo-1-(2-(trifluoromethyl)pyridin-4-yl)-1,2,3,4,5,6,7,8-octahydroquinazolin-4-yl)-3-(methylsulfonyl)benzonitrile (example 57, 200 mg, 0.41 mmol) in N,N-dimethylformamide (3 mL), and the mixture is stirred at room temperature for 2 h. Ethyl acetate is added, and the mixture is extracted three times with water. The organic phase is dried over Mg2SO4 and concentrated under reduced pressure. The residue is it) purified by flash chromatography on silica (gradient dichloromethane/methanol 99:1 to 97:3). Yield: 134 mg; ESI mass spectrum [M+H]+=505; Retention time HPLC: 0.60 min (X012_S02).