Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:10][CH2:11][CH:12]([OH:21])[CH:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:14]=2)=[CH:5][CH:4]=1.[H-].[Na+].[Cl:24][C:25]1[CH:26]=[C:27]([N:32]=[C:33]=[O:34])[CH:28]=[CH:29][C:30]=1[Cl:31].O>O1CCCC1>[Cl:24][C:25]1[CH:26]=[C:27]([NH:32][C:33]([O:21][CH:12]2[CH2:11][O:10][C:9]([C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=3)=[N:14][CH:13]2[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:34])[CH:28]=[CH:29][C:30]=1[Cl:31]
Reactant: COc1ccc(C2=NC(c3ccccc3)C(O)CO2)cc1
Reactant: O=C=Nc1ccc(Cl)c(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(C2=NC(c3ccccc3)C(OC(=O)Nc3ccc(Cl)c(Cl)c3)CO2)cc1
Reaction time: 0.5 h
Yield: 46.6 %

Procedure:
A solution of (4RS, 5RS)-2-(4-methoxyphenyl)-4-phenyl-5,6-dihydro-4H-1,3-oxazin-5-ol (1.42 g) in anhydrous tetrahydrofuran (15 cc) is added at a temperature in the region of 20° C. to an oily suspension (50% by weight; 0.27 g), maintained under an argon atmosphere, of sodium hydride in anhydrous tetrahydrofuran (15 cc), and the solution obtained is stirred for 30 minutes at this same temperature. A solution of 3,4-dichlorophenyl isocyanate (1.05 g) in anhydrous tetrahydrofuran (10 cc) is then added dropwise and stirring is continued for 4 hours at a temperature in the region of 20° C. Distilled water (20 cc) is then added and the mixture is extracted with dichloromethane (3×80 cc). The organic phases are combined, washed with distilled water (3×20 cc), dried over magnesium sulphate and concentrated to dryness under reduced pressure (2.7 kPa) at 40° C. The solid obtained is purified by chromatography on silica (0.063-0.2 mm; 300 g) contained in a column 3.5 cm in diameter (eluent: dichloromethane), collecting 30 cc fractions. Fractions 4 to 7 are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 40° C. The solid obtained is again purified by chromatography on silica (0.063-0.2 mm; 125 g) contained in a column 2 cm in diameter [eluent: cyclohexane/ethyl acetate (6:4 by volume)], collecting 20-cc fractions. The fractions 5 to 9 are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 40° C. After recrystallization in diisopropyl ether, (4RS, 5RS)-5-(3,4-dichlorophenylcarbamoyloxy)-2-(4-methoxyphenyl)-4-phenyl-5,6-dihydro-4H-1,3-oxazine (1.1 g), m.p. 130° C., is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10](C(O)=O)[C:11](=[O:22])[NH:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=2[Cl:21])=[CH:4][CH:3]=1.N1C2C(=CC=CC=2)C=CC=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[CH:10][C:11](=[O:22])[NH:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=2[Cl:21])=[CH:6][CH:7]=1
Reactant: O=C(O)c1cc(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)[nH]c1=O
Solvent: c1ccc2ncccc2c1
Product: O=c1ccc(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)[nH]1
Temperature: 235 °C

Procedure:
An oven-dried round bottom flask equipped with a magnetic stir bar and a reflux condenser was charged with 0.365 g (0.93 mmol) of 5-(4-chlorophenyl)-6-(2,4-dichlorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid from the product of Step A in Example 32 and 5 mL of freshly distilled quinoline. The reaction mixture was stirred and heated to 235° C. under a nitrogen atmosphere for 3 hours then cooled to room temperature. The reaction mixture was partitioned between excess EtOAc and 1N HCl, separated and the organic layer was extracted again twice with 1N HCl. The organic layer was washed with saturated brine, dried (MgSO4), filtered and evaporated in vacuo. The residual amorphous solid was used directly in the next step without further purification.
Reaction SMILES: C(O[C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9])(C)(C)C.[NH2:13][CH2:14][CH2:15][CH2:16][NH2:17]>C(Cl)Cl>[C:8]([O:7][C:6]([NH:13][CH2:14][CH2:15][CH2:16][NH2:17])=[O:12])([CH3:9])([CH3:10])[CH3:11]
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Reactant: NCCCN
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCCN
Temperature: 20 °C
Reaction time: 16 h

Procedure:
A solution of 46 g of di-tert-butyl-carbonate in 120 ml of methylene chloride was added at +5° C. without exceeding +10° C. to a solution of 36 ml of 1,3-diamino-propane in 160 ml of methylene chloride and after stirring for 16 hours at 20° C., the insoluble part was filtered off. The filtrate was evaporated to dryness under vacuum to obtain 63 g of residue which was chromatographed on silica (eluant: methanol with 2% ammonia) to obtain 23 g of the expected product melting at <60° C.
Reaction SMILES: Cl[C:2]1[C:7]([CH2:8][N:9]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)[C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:22][N:23]1[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=2[NH:25][C:24]1=[O:32].C([O-])(=O)C.[K+]>N1C=CC=CC=1.C([O-])(O)=O.[Na+].[Cu]>[N:12]1[CH:13]=[CH:14][CH:15]=[C:10]([N:9]([CH2:8][C:7]2[C:2]([N:25]3[C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=4[N:23]([CH3:22])[C:24]3=[O:32])=[N:3][CH:4]=[CH:5][CH:6]=2)[C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)[CH:11]=1
Reactant: Cn1c(=O)[nH]c2ccccc21
Reactant: Clc1ncccc1CN(c1cccnc1)c1cccnc1
Agent: [Cu]
Agent: CC(=O)[O-]
Agent: O=C([O-])O
Solvent: c1ccncc1
Product: Cn1c(=O)n(-c2ncccc2CN(c2cccnc2)c2cccnc2)c2ccccc21

Procedure:
To a solution of N-[(2-chloropyridin-3-yl)methyl]-N-pyridin-3-ylpyridin-3-amine (59 mg, 020 mmol) and 1-methyl-2-benzimidazolinone (45 mg, 0.30 mmol) in dry pyridine (1 mL) was added potassium acetate (51 mg, 0.512 mmol), cuprous chloride (11.6 mg, 0.117 mmol), and copper powder (31 mg, 0.487 mmol). This mixture was sealed and heated at 120 C for 4 days. The cooled reaction was diluted with NaHCO3 solution and the product extracted into methylene chloride. This solution was dried over anhydrous sodium sulfate, filtered, and the solvent evaporated This residue was subjected to chromatography on silica gel eluting with a 20-100% acetone/hexane gradient to give the title compound after trituration with diethyl ether as a white solid.
Reaction SMILES: [C:1](/[N:9]=[C:10](\SC)/[NH:11][C@H:12]([CH:28]([CH3:30])[CH3:29])[C:13]([N:15]1[CH2:20][CH2:19][CH:18]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)[CH2:17][CH2:16]1)=[O:14])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:33][NH2:34]>C1COCC1>[Cl:27][C:24]1[CH:25]=[CH:26][C:21]([CH:18]2[CH2:19][CH2:20][N:15]([C:13](=[O:14])[C@H:12]([NH:11][C:10]3[NH:34][N:33]=[C:1]([C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)[N:9]=3)[CH:28]([CH3:30])[CH3:29])[CH2:16][CH2:17]2)=[CH:22][CH:23]=1
Reactant: NN
Reactant: CS/C(=N\C(=O)c1ccccc1)N[C@@H](C(=O)N1CCC(c2ccc(Cl)cc2)CC1)C(C)C
Solvent: C1CCOC1
Product: CC(C)[C@@H](Nc1nc(-c2ccccc2)n[nH]1)C(=O)N1CCC(c2ccc(Cl)cc2)CC1
Temperature: 25 °C
Yield: 45.7 %

Procedure:
(R,Z)-Methyl N′-benzoyl-N-(1-(4-(4-chlorophenyl)piperidin-1-yl)-3-methyl-1-oxobutan-2-yl)carbamimidothioate (47 mg, 0.1 mmol) was dissolved in THF (0.5 mL) and treated with anhydrous hydrazine (10 μL, 0.3 mmol). The reaction was stirred at rt. overnight. After this time, the THF was removed in vacuo and the resulting residue was dissolved in methanol and then purified by preparative HPLC to give (R)-1-(4-(4-chlorophenyl)piperidin-1-yl)-3-methyl-2-(3-phenyl-1H-1,2,4-triazol-5-ylamino)butan-1-one (20 mg, 45%). MS found: 438 (M+H).
Reaction SMILES: C(OC([NH:8][C@@H:9]([CH2:13][C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1)[C:10]([OH:12])=O)=O)(C)(C)C.[ClH:20].[CH3:21][NH:22][CH3:23].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[ClH:20].[NH2:8][C@@H:9]([CH2:13][C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1)[C:10]([N:22]([CH3:23])[CH3:21])=[O:12]
Reactant: CNC
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1cccnc1)C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)C(=O)[C@@H](N)Cc1cccnc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of (S)-2-tert-butoxycarbonylamino-3-pyridin-3-ylpropionic acid (500 mg, 1.88 mmol) in DMF (10 mL) was added dimethylamine hydrochloride (153 mg, 1.88 mmol), DIPEA (1.2 mL, 6.57 mmol) and TBTU (602 mg, 1.88 mol). The reaction mixture was stirred at rt for 16 h. The solvent was removed in vacuo and the residue dissolved in methanol (20 mL). To this was added 4M hydrochloric acid in dioxane (20 mL) and the reaction was stirred for 16 h at rt. The solvent was removed in vacuo and the residue was partitioned between water (100 mL) and ethyl acetate (2×100 mL). The aqueous layer was evaporated to dryness and the residue recrystallised from ethanol/ethoxyethanol (9:1), to give the title compound as a white solid. δH (CD3OD): 2.99 (3H, s), 3.06 (3H, s), 3.35-3.42 (1H, m), 3.45-3.53 (1H, m), 4.87-4.94 (1H, m), 8.04-8.10 (1H, m), 8.48-8.53 (1H, m), 8.84-8.90 (2H, m).
Reaction SMILES: [N:1]1([C:12]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:13])[CH2:6][CH2:5][CH2:4][CH:3]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:2]1.[CH3:22]N1C(=O)N(C)CCC1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].IC>C1COCC1>[CH3:22][C:3]1([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:4][CH2:5][CH2:6][N:1]([C:12]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:13])[CH2:2]1
Reactant: CCOC(=O)C1CCCN(C(=O)OCc2ccccc2)C1
Reactant: CN1CCCN(C)C1=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CI
Product: CCOC(=O)C1(C)CCCN(C(=O)OCc2ccccc2)C1
Temperature: -60 °C
Reaction time: 1 h
Yield: 75.2 %

Procedure:
To a solution of 1-benzyl 3-ethyl piperidine-1,3-dicarboxylate (2.107 g, 7.23 mmol) in dry THF (22 mL) and DMPU (1.4 mL, 1160 mmol) at −78° C. was added dropwise lithium bis(trimethylsilyl)amide (1.271 g, 7.59 mmol, 7.60 mL of 1M solution in THF). After addition, the reaction mixture was stirred at −60° C. for 1 h. Then iodomethane (0.520 mL, 8.32 mmol) in DMPU (0.344 mL, 2.86 mmol) was added dropwise. After addition, the reaction was stirred at −60° C. for 1.5 h, then slowly warmed up to −20° C. over approximately 1 hr. The reaction was quenched by the addition of saturated aqueous NH4Cl. The reaction solution was extracted with EtOAc (2×). The combined organics were washed with saturated aqueous NH4Cl and saturated aqueous NaCl. The organic layer was dried over Na2SO4, filtered and concentrated. The residue was purified using silica gel chromatography (ISCO system) eluting with a gradient of 0-30% EtOAc/Hex. The desired fractions were concentrated to give the product, benzyl 3-ethyl 3-methylpiperidine-1,3-dicarboxylate (1.66 gm, 5.44 mmol, 75.2% yield) as a light brown oil. Anal. Calcd. for C17H23NO4 m/z 305.3, found: 306.2 (M+H)+; 1H NMR (400 MHz, CDCl3) δ ppm 7.44-7.27 (m, 5H), 5.20-5.09 (m, 2H), 4.24-4.04 (m, 2H), 3.99 (d, J=13.19 Hz, 1H), 3.59 (br. s., 1H), 3.27 (d, J=7.15 Hz, 1H), 3.13 (d, J=12.64 Hz, 1H), 2.16-1.95 (m, 1H), 1.74-1.52 (m, 2H), 1.51-1.39 (m, 1H), 1.25-1.07 (m, 6H).
Reaction SMILES: Cl.C(O[C:7]([N:9](C)[C:10]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:11]=1[N+:18]([O-:20])=[O:19])=O)(C)(C)C>O1CCOCC1>[CH3:7][NH:9][C:10]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:11]=1[N+:18]([O-:20])=[O:19]
Reactant: COc1ccc([N+](=O)[O-])c(N(C)C(=O)OC(C)(C)C)c1
Agent: Cl
Solvent: C1COCCO1
Product: CNc1cc(OC)ccc1[N+](=O)[O-]
Reaction time: 2 h
Yield: 105.2 %

Procedure:
750 ml of a 4 N solution of hydrogen chloride in 1,4-dioxane were added to 52 g of N-t-butoxycarbonyl-N-methyl-5-methoxy-2-nitroaniline [prepared as described in step (c) above] at room temperature, and the resulting mixture was stirred for 2 hours. At the end of this time, the reaction mixture was freed from the solvent by distillation under reduced pressure, and the resulting residue was mixed with water and ethyl acetate. The mixture was then neutralized by the addition of sodium hydrogencarbonate, after which it was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. On distilling off the solvent, there were obtained 35.3 g of the title compound, melting at 107-110° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[N+:19]([O-])([OH:21])=[O:20]>C(O)(=O)C>[CH3:10][O:9][C:8]1[C:3]([O:2][CH3:1])=[CH:4][C:5]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17])=[C:6]([N+:19]([O-:21])=[O:20])[CH:7]=1
Reactant: O=[N+]([O-])O
Reactant: COc1ccc(CCCCCC(=O)O)cc1OC
Solvent: CC(=O)O
Product: COc1cc(CCCCCC(=O)O)c([N+](=O)[O-])cc1OC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 6-(3,4-dimethoxyphenyl)hexanoic acid (2.7 g) in acetic acid (10 ml) was added nitric acid (5.4 ml of a 2 M solution in acetic acid) and the mixture stirred at room temperature for one hour. The mixture was evaporated and the product used as such for the next step. Yield: 3.2 g.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:19]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=3)[N:18]=[C:17]([NH:28][C:29](=[O:33])[N:30]([CH3:32])[CH3:31])[CH:16]=2)=[CH:11][CH:10]=1)C1C=CC=CC=1.C([O-])=O.[NH4+]>CCO.C1COCC1.O.[Pd]>[OH:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[N:19]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=3)[N:18]=[C:17]([NH:28][C:29](=[O:33])[N:30]([CH3:32])[CH3:31])[CH:16]=2)=[CH:13][CH:14]=1
Reactant: COc1ccc(-n2nc(NC(=O)N(C)C)cc2-c2ccc(OCc3ccccc3)cc2)cc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCO
Product: COc1ccc(-n2nc(NC(=O)N(C)C)cc2-c2ccc(O)cc2)cc1
Yield: 58.6 %

Procedure:
To a solution of N′-[5-[4-(benzyloxy)phenyl]-1-(4-methoxy-phenyl)-1H-pyrazol-3-yl]-N,N-dimethylurea (1.19 g) in EtOH (10 ml) and THF (10 ml) were added a solution of ammonium formate (509 mg) in H2O (2 ml) and 10% Pd-C 50% wet (150 mg). The mixture was refluxed for 1 hour. The catalyst was filtered off through a celite pad and the pad was washed with EtOH. The filtrate and combined washings were concentrated in vacuo. To the residue were added AcOEt and H2O. White precipitates were appeared and collected and washed with H2O and IPE successively to give N′-[5-(4-hydroxyphenyl)-1-(4-methoxyphenyl)-1H-pyrazol-3-yl]-N,N-dimethylurea (555 mg) as a white powder.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][NH2:7].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC.[CH2:39]([S:41][C:42]1[C:51]([C:52](O)=[O:53])=[C:50]([CH3:55])[C:49]2[C:44](=[CH:45][C:46]([C:56]([F:59])([F:58])[F:57])=[CH:47][CH:48]=2)[N:43]=1)[CH3:40]>C1COCC1.CCCCCC>[CH2:39]([S:41][C:42]1[C:51]([C:52]([NH:7][CH2:6][C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)=[O:53])=[C:50]([CH3:55])[C:49]2[C:44](=[CH:45][C:46]([C:56]([F:59])([F:57])[F:58])=[CH:47][CH:48]=2)[N:43]=1)[CH3:40]
Reactant: NCc1cccs1
Reactant: CCSc1nc2cc(C(F)(F)F)ccc2c(C)c1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCSc1nc2cc(C(F)(F)F)ccc2c(C)c1C(=O)NCc1cccs1
Temperature: 50 °C
Yield: 63.8 %

Procedure:
134 μl (1.3 mmol) thiophenemethanamine, 438 mg (1.1 mmol) HATU and 420 μl (3.0 mmol) NEt3 were added in succession to a solution of 330 mg (1.05 mmol) 2-(ethylthio)-4-methyl-7-(trifluoromethyl)quinoline-3-carboxylic acid (VVV08) in THF (8 ml) and the mixture was then heated for 24 h at 50° C. Then it was diluted with EE and washed with a 4M aqueous NH4Cl solution, a 1M aqueous Na2CO3 solution and brine. The organic phase was dried over MgSO4 and then filtered through a silica layer. Column chromatography (hexane/EE 7:3) of the residue yielded 277 mg (0.67 mmol, 65%) 2-ethylsulfanyl-4-methyl-N-(thiophen-2-yl-methyl)-7-(trifluoromethyl)-quinoline-3-carboxamide. MS: m/z 411.1 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[C:11]3[C:16]4=[C:17]([C@@H:19]5[CH2:24][NH:23][CH2:22][CH2:21][C@@H:20]5[N:15]4[CH2:14][CH2:13][CH2:12]3)[CH:18]=2)=[C:5]([C:25]([F:28])([F:27])[F:26])[CH:4]=1.Br[CH2:30][CH:31]([F:33])[F:32].N>>[F:32][CH:31]([F:33])[CH2:30][N:23]1[CH2:22][CH2:21][C@@H:20]2[N:15]3[C:16]4[C:11](=[CH:10][C:9]([C:6]5[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][C:5]=5[C:25]([F:28])([F:26])[F:27])=[CH:18][C:17]=4[C@@H:19]2[CH2:24]1)[CH2:12][CH2:13][CH2:14]3
Reactant: FC(F)CBr
Reactant: COc1ccc(-c2cc3c4c(c2)[C@@H]2CNCC[C@@H]2N4CCC3)c(C(F)(F)F)c1
Agent: N
Product: COc1ccc(-c2cc3c4c(c2)[C@@H]2CN(CC(F)F)CC[C@@H]2N4CCC3)c(C(F)(F)F)c1

Procedure:
The title compound was prepared by the method of Example 382 as a yellow oil (27 mg, 77%) from (7aS,11aR)-2-[4-methoxy-2-(trifluoromethyl)phenyl]-5,6,7a,8,9,10,11,11a-octahydro-4H-pyrido[3′,4′:4,5]pyrrolo[3,2,1-ij]quinoline (30 mg, 0.077 mmol) and 2-bromo-1,1-difluoroethane (35 mg, 0.23 mmol). MS (CI, NH3): 453.1 (base, M+H).
Reaction SMILES: Cl[CH2:2][C:3]1[S:7][C:6]([N:8]2[CH:14](C)[CH2:13][C:12]3[CH:16]=[C:17]4[O:22][CH2:21][O:20][C:18]4=[CH:19][C:11]=3[C:10]([C:23]3[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=3)=[N:9]2)=[N:5][N:4]=1.[CH:32]1([NH2:35])[CH2:34][CH2:33]1.[Cl-].[Na+]>CN(C)C=O>[CH:32]1([NH:35][CH2:2][C:3]2[S:7][C:6]([N:8]3[CH2:14][CH2:13][C:12]4[CH:16]=[C:17]5[O:22][CH2:21][O:20][C:18]5=[CH:19][C:11]=4[C:10]([C:23]4[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=4)=[N:9]3)=[N:5][N:4]=2)[CH2:34][CH2:33]1
Reactant: CC1Cc2cc3c(cc2C(c2ccc([N+](=O)[O-])cc2)=NN1c1nnc(CCl)s1)OCO3
Reactant: NC1CC1
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(C2=NN(c3nnc(CNC4CC4)s3)CCc3cc4c(cc32)OCO4)cc1
Temperature: 75 °C
Reaction time: 1 h
Yield: 87.5 %

Procedure:
A mixture of 5 ml of dimethylformamide, 0.44 g (0.96 mmol) of (±)-7-(5-chloromethyl-1,3,4-thiadiazol-2-yl)-8-methyl-5-(4-nitrophenyl)-8,9-dihydro-7H-1,3-dioxolo[4,5-h][2,3]benzodiazepine (Example 34) and 0.37 ml (5.31 mmol) of cyclopropylamine was stirred at 70-80° C. for 1 h. Then the reaction mixture was poured into 20% sodium chloride solution and, the precipitated crude product was extracted into ethyl acetate. The solution was washed with water, dried and after evaporation yielded 0.39 g (85%) of the title compound, as solid foam.
Reaction SMILES: [CH2:1]([O:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:24]C)[N:12]2[CH2:15][CH2:16][CH2:17][CH:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)=[C:8]([NH2:26])[N:7]=1)[CH2:2][CH2:3][CH3:4].I[CH2:28][CH:29]1[CH2:33][CH2:32][CH2:31][CH2:30]1>>[NH2:26][C:8]1[N:7]=[C:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])[N:14]=[C:13]2[C:9]=1[NH:10][C:11](=[O:24])[N:12]2[CH2:15][CH2:16][CH2:17][CH:18]1[CH2:19][CH2:20][N:21]([CH2:28][CH:29]2[CH2:33][CH2:32][CH2:31][CH2:30]2)[CH2:22][CH2:23]1
Reactant: CCCCOc1nc(N)c2nc(OC)n(CCCC3CCNCC3)c2n1
Reactant: ICC1CCCC1
Product: CCCCOc1nc(N)c2[nH]c(=O)n(CCCC3CCN(CC4CCCC4)CC3)c2n1

Procedure:
Prepared similarly to Example 14 from 2-(butyloxy)-8-(methyloxy)-9-[3-(4-piperidinyl)propyl]-9H-purin-6-amine and (iodomethyl)cyclopentane.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:16]=[C:15]3[C:11]([CH2:12][N:13]([C@@H:18]([CH:23]([CH3:25])[CH3:24])[C:19]([O:21][CH3:22])=[O:20])[C:14]3=[O:17])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[Cl:26][C:27]1[CH:28]=[CH:29][C:30]([O:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[C:31]([N:33]=[C:34]=[O:35])[CH:32]=1>>[Cl:26][C:27]1[CH:28]=[CH:29][C:30]([O:36][C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)=[C:31]([NH:33][C:34](=[O:35])[NH:1][C:2]2[CH:3]=[CH:4][C:5]([C:8]3[CH:16]=[C:15]4[C:11]([CH2:12][N:13]([C@@H:18]([CH:23]([CH3:25])[CH3:24])[C:19]([O:21][CH3:22])=[O:20])[C:14]4=[O:17])=[CH:10][CH:9]=3)=[CH:6][CH:7]=2)[CH:32]=1
Reactant: O=C=Nc1cc(Cl)ccc1Oc1ccccc1
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(N)cc3)cc2C1=O
Product: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)Nc4cc(Cl)ccc4Oc4ccccc4)cc3)cc2C1=O

Procedure:
The compound of example 45 was prepared analogous to compound of example 7 by reaction of compound of example 6 with 5-chloro-2-phenoxy phenyl isocyanate.
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[C:11]([C:18]#[N:19])[CH:12]=[CH:13][CH:14]=2)[CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[C:18]([C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:10]=1[CH2:9][NH:8][CH2:17][CH2:16]2)#[N:19]
Reactant: CC(C)(C)OC(=O)N1CCc2cccc(C#N)c2C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1cccc2c1CNCC2
Temperature: 40 °C
Reaction time: 16 h
Yield: 105.4 %

Procedure:
A mixture of 2-t-butyloxycarbonyl-8-cyano-1,2,3,4-tetrahydroisoquinoline (1.4 g, 5.4 mmol) and trifluoroacetic acid (2 ml) in dichloromethane (20m1) was stirred at 40° C. for 16 h. Mixture was evaporated in vacuo and the resulting residue partitioned between dichloromethane and saturated potassium carbonate solution. The aqueous layer was extracted with more dichloromethane (2×100 ml). The combined organic extracts were dried (Na2SO4) and evaporated in vacuo to afford the desired product as an amber oil (0.9 g, 100%).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[C:16](=[O:33])[NH:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20](B2OC(C)(C)C(C)(C)O2)[CH:19]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:35]1[CH:36]=[C:37]([CH:41]=[CH:42][CH:43]=1)[CH2:38][NH:39][CH3:40].CN(C=O)C>CO.C([O-])(O)=O.[Na+]>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[C:16](=[O:33])[NH:17][C:18]1[CH:19]=[C:20]([C:35]2[CH:43]=[CH:42][CH:41]=[C:37]([CH2:38][NH:39][CH3:40])[CH:36]=2)[CH:21]=[CH:22][CH:23]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CNCc1cccc(Br)c1
Reactant: CC1(C)OB(c2cccc(NC(=O)[C@@H]3CCCN3C(=O)OCc3ccccc3)c2)OC1(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: CNCc1cccc(-c2cccc(NC(=O)[C@@H]3CCCN3C(=O)OCc3ccccc3)c2)c1
Temperature: 70 °C

Procedure:
A solution of (S)-2-[3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylcarbamoyl]-pyrrolidine-1-carboxylic acid benzyl ester (89.7 mg, 0.20 mmol), (3-bromo-benzyl)-methyl-amine (43.4 mg, 0.22 mmol), and Pd[P(Ph)3]4 (15.4 mg, 6.7 mol %) in methanol (2 mL), NaHCO3 (sat. aq., 300 μL), and DMF (400 μL) was degassed and heated to 70° C. overnight in a sealed vial. The reaction was cooled, filtered, and purified by reverse phase HPLC to give the desired product. The product was then converted to the HCl salt. After dissolving the product in a minimum amount of acetonitrile and cooling the solution in dry ice, 2.0M HCl in diethyl ether was added until precipitate crashed out of solution. The mixture was centrifuged, and the liquid was decanted. Additional cold diethyl ether was added, and the mixture was again centrifuged and the liquid decanted. The resulting solid was dried to give the HCl salt of the desired product. Yield 5.9 mg. MS: 444.2 (M+H+); H1 NMR (DMSO-d6): δ (ppm) 1.80-2.02 (m, 3H), 2.17-2.35 (m, 1H), 2.53-2.64 (t, 3H), 3.39-3.57 (m, 2H), 4.15-4.23 (t, 2H), 4.33-4.44 (m, 1H), 4.60-5.12 (m, 2H), 7.02-7.76 (m, 12H), 8.06-8.12 (m, 1H), 8.78-8.93 (s, 1H), 10.10-10.25 (s, 1H).
Reaction SMILES: [CH2:1]([C:3]1[C:4]([C:12]([O:14]C)=O)=[C:5]([N:9]=[C:10]=[S:11])[S:6][C:7]=1[CH3:8])[CH3:2].[CH3:16][C:17]1[N:21]([CH2:22][CH2:23][CH2:24][NH2:25])[CH:20]=[N:19][CH:18]=1>>[CH2:1]([C:3]1[C:4]2[C:12](=[O:14])[N:25]([CH2:24][CH2:23][CH2:22][N:21]3[C:17]([CH3:16])=[CH:18][N:19]=[CH:20]3)[C:10](=[S:11])[NH:9][C:5]=2[S:6][C:7]=1[CH3:8])[CH3:2]
Reactant: CCc1c(C)sc(N=C=S)c1C(=O)OC
Reactant: Cc1cncn1CCCN
Product: CCc1c(C)sc2[nH]c(=S)n(CCCn3cncc3C)c(=O)c12

Procedure:
The compound was synthesized starting from methyl 4-ethyl-2-isothiocyanato-5-methylthiophene-3-carboxylate (0.10 g, 0.41 mmol) and 3-(5-methyl-1H-imidazol-1-yl)propan-1-amine (5) (0.058 g, 0.41 mmol) as described above.
Reaction SMILES: C1(C(C2C=CC=CC=2)[N:8]2[CH2:11][CH:10]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:9]2)C=CC=CC=1.Cl.O1CCOCC1.[H][H]>CO>[NH:8]1[CH2:11][CH:10]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:17])([CH3:16])[CH3:18])[CH2:9]1
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)NC1CN(C(c2ccccc2)c2ccccc2)C1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)NC1CNC1

Procedure:
A solution of 1,1-dimethylethyl [1-(diphenylmethyl)-3-azetidinyl]carbamate in MeOH (10 mL) was treated with of 4.0 N HCl/dioxane (1 mL) and then reacted overnight with hydrogen gas at 50 psi. The reaction mixture was then filtered through a pad of Celite, concentrated and the crude residue was used without further purification.