Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([C:10](Cl)(Cl)Cl)=[CH:6][CH:5]=1.[NH2:15][C:16]1[CH:17]=[C:18]([CH:22]=[CH:23][C:24]=1[OH:25])[C:19]([OH:21])=[O:20]>>[C:3]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:25][C:24]3[CH:23]=[CH:22][C:18]([C:19]([OH:21])=[O:20])=[CH:17][C:16]=3[N:15]=2)=[CH:6][CH:5]=1)([O:2][CH3:1])=[O:14]
Reactant: COC(=O)c1ccc(C(Cl)(Cl)Cl)cc1
Reactant: Nc1cc(C(=O)O)ccc1O
Product: COC(=O)c1ccc(-c2nc3cc(C(=O)O)ccc3o2)cc1
Temperature: 200 °C

Procedure:
In the apparatus described in Example 1, 12.7 g of 4-trichloromethylbenzoic acid methyl ester (0.05 mol) and 7.5 g of 3-amino-4-hydroxybenzoic acid (0.05 mol) were mixed and heated for 6 hours at 200° C. The reaction product after grinding in a mortar was extracted twice with 100 ml of CHCl3 and then, after drying, twice with 100 ml of water. 9.2 g of raw product remained, melting at 275° to 284° C (62% of the theory). After two recrystallizations with dimethyl formamide plus active charcoal and dimethylsulfoxide, the melting point was 291° to 293° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[OH:11].S(=O)(=O)(O)O.O.C([O-])(O)=O.[Na+].[CH3:23][CH2:24]O>CCOCC>[CH2:23]([O:7][C:6](=[O:8])[C:5]1[CH:9]=[CH:10][C:2]([Cl:1])=[C:3]([OH:11])[CH:4]=1)[CH3:24]
Reactant: CCO
Reactant: O=C(O)c1ccc(Cl)c(O)c1
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Product: CCOC(=O)c1ccc(Cl)c(O)c1

Procedure:
A solution of 4-chloro-3-hydroxy-benzoic acid (29.3 mmol) in EtOH (110 mL) is treated with conc. sulfuric acid (23.6 mL) and heated to reflux for 16 h. Water (600 mL), NaHCO3 (100 g) and ether (300 mL) are added successively, the layers are separated and the aqueous layer is extracted twice with ether. The combined organic layers are washed twice with brine, dried over MgSO4 and concentrated in vacuo to give the desired product which is used without further purification. 1H-NMR (CDCl3): δ=7.73 (s, 1H); 7.58 (d, J=8.3 Hz, 1H); 7.40 (d, J=8.3 Hz, 1H); 5.87 (s, 1H); 4.39 (q, J=7.0 Hz, 2H); 1.41 (t, J=7.0 Hz, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5](I)=[C:4]([CH3:10])[CH:3]=1.C([Li])CCC.[B:16](OC)([O:19]C)[O:17]C.Cl>O1CCCC1>[Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([B:16]([OH:19])[OH:17])=[C:4]([CH3:10])[CH:3]=1
Reactant: Cc1cc(Br)cc(C)c1I
Reactant: COB(OC)OC
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1cc(Br)cc(C)c1B(O)O
Temperature: -75 °C
Reaction time: 0.5 h
Yield: 43.7 %

Procedure:
To a solution of 4-bromo-2,6-dimethyl-1-iodobenzene (150 g, 0.48 mol) in tetrahydrofuran (1500 ml) at −75° C. is added n-butyl lithium (1.6 M in hexanes, 364 ml, 0.58 mol) dropwise maintaining the temperature of the reaction mixture below −70° C. When the addition is complete the mixture is stirred at −75° C. for an additional 30 minutes and then trimethyl borate (302 g, 2.9 mol) is added dropwise. After the addition is complete the reaction is stirred at −75° C. for 1 hour, then allowed to come to room temperature and stirred for 2 hours, followed by cooling in an ice bath and acidification with 0.5 N aqueous hydrochloric acid. The mixture is extracted with ethyl acetate (3×1000 ml) and the organic extracts are combined, washed with brine, dried over anhydrous sodium sulphate. The mixture is filtered and the filtrate is evaporated under reduced pressure. The residue is purified by column chromatography on silica gel to give 4-bromo-2,6-dimethylphenylboronic acid (48 g) as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:11]([NH2:12])=[CH:10][CH:9]=[C:8](Br)[N:7]=1)=[O:5])[CH3:2].[Cu][C:15]#[N:16]>CN(C=O)C>[CH2:1]([O:3][C:4]([C:6]1[C:11]([NH2:12])=[CH:10][CH:9]=[C:8]([C:15]#[N:16])[N:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1nc(Br)ccc1N
Reactant: N#C[Cu]
Solvent: CN(C)C=O
Product: CCOC(=O)c1nc(C#N)ccc1N
Yield: 26.6 %

Procedure:
A solution of 3-amino-6-bromo-pyridine-2-carboxylic acid ethyl ester (40 mg, 163 μmol) and copper(I) cyanide (29.2 mg, 326 μmol) in DMF (800 μL) was heated in the microwave at 220° C. for 8 min. The reaction mixture was filtered through diatomaceous filter-aid and the crude product was purified by preparative HPLC to afford the title compound as off-white solid (8.3 mg, 26.6%).
Reaction SMILES: [CH2:1]([NH:8][C:9]1[N:13]([CH2:14][CH2:15][CH2:16][N:17]2[C:21]([NH:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[C:20]([N+:30]([O-:32])=[O:31])[C:19](Br)=[N:18]2)[N:12]=[C:11](Br)[C:10]=1[N+:35]([O-:37])=[O:36])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:38]1(OB(O)O)[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1.C(=O)([O-])[O-].[K+].[K+]>COCCOC.O>[CH2:1]([NH:8][C:9]1[N:13]([CH2:14][CH2:15][CH2:16][N:17]2[C:21]([NH:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[C:20]([N+:30]([O-:32])=[O:31])[C:19]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)=[N:18]2)[N:12]=[C:11]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:10]=1[N+:35]([O-:37])=[O:36])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1c(Br)nn(CCCn2nc(Br)c([N+](=O)[O-])c2NCc2ccccc2)c1NCc1ccccc1
Reactant: OB(O)Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: O=[N+]([O-])c1c(-c2ccccc2)nn(CCCn2nc(-c3ccccc3)c([N+](=O)[O-])c2NCc2ccccc2)c1NCc1ccccc1
Yield: 81.8 %

Procedure:
3.7 g of 1,3-bis-(5-benzylamino-3-bromo-4-nitropyrazol-1-yl)propane from step 5.2 in 40 ml 1,2-dimethoxyethane are mixed under nitrogen with 3.8 g phenyl boric acid, 1.2 g of tetrakis(triphenylphosphin)palladium (0) and a solution of 8.3 g of potassium carbonate in 30 ml water. The resulting reaction mixture is subsequently heated under reflux under nitrogen. After five hours the reaction mixture is heated over silica gel (hyflo super-gel of Celite Co.), filtered and the filtrate cooled in an ice bath. The precipitate coming down is filtered, washed with water and recrystallized from 50 ml ethanol. After drying in vacuum at 60° C. one obtains 1.5 g of a yellow product.
Reaction SMILES: [N:1]1([CH:5]2[CH2:10][CH2:9][N:8]([C:11]([NH:13][C:14]3[CH:19]=[C:18]([O:20][C:21]4[CH:26]=[CH:25][C:24]([NH:27]C(=O)OCC5C=CC=CC=5)=[C:23]([F:38])[CH:22]=4)[CH:17]=[CH:16][N:15]=3)=[O:12])[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1>O1CCCC1.[C].[Pd]>[NH2:27][C:24]1[CH:25]=[CH:26][C:21]([O:20][C:18]2[CH:17]=[CH:16][N:15]=[C:14]([NH:13][C:11]([N:8]3[CH2:9][CH2:10][CH:5]([N:1]4[CH2:4][CH2:3][CH2:2]4)[CH2:6][CH2:7]3)=[O:12])[CH:19]=2)=[CH:22][C:23]=1[F:38]
Reactant: O=C(Nc1ccc(Oc2ccnc(NC(=O)N3CCC(N4CCC4)CC3)c2)cc1F)OCc1ccccc1
Agent: [Pd]
Solvent: C1CCOC1
Product: Nc1ccc(Oc2ccnc(NC(=O)N3CCC(N4CCC4)CC3)c2)cc1F
Temperature: 25 °C
Reaction time: 16 h

Procedure:
After adding 10% palladium-carbon (26.2 mg) to a solution of benzyl [4-(2-{[4-(azetidin-1-yl)piperidine-1-carbonyl]amino}pyridin-4-yloxy)-2-fluorophenyl]carbamate (128 mg) in tetrahydrofuran (10 ml), the mixture was stirred for 16 hours at room temperature under a hydrogen atmosphere. The catalyst was filtered and washed with tetrahydrofuran (4 ml) to provide a solution of 4-(azetidin-1-yl)piperidine-1-carboxylic acid [4-(4-amino-3-fluorophenoxy)pyridin-2-yl]amide in tetrahydrofuran (approximately 14 ml)
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13](Cl)(=O)=O)=[CH:9][CH:8]=1)[CH3:2].[Sn].Cl.C(Cl)Cl>C(O)C.O1CCOCC1>[CH2:1]([O:3][C:4](=[O:17])[CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]([SH:13])=[CH:11][CH:12]=1)[CH3:2]
Reactant: CCOC(=O)COc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Agent: [Sn]
Solvent: CCO
Solvent: C1COCCO1
Solvent: ClCCl
Product: CCOC(=O)COc1ccc(S)cc1

Procedure:
To a mixture of (4-chlorosulfonyl-phenoxy)-acetic acid ethyl ester (0.98 g, 3.5 mmol) and tin powder (2.1 g) in ethanol (4.4 mL) is added HCl in dioxane (1.0 M, 4.4 mL) under nitrogen. The mixture is heated to reflux for 2 hrs, it is poured into ice and methylene chloride and filtered. The layers are separated and extracted with methylene chloride, dried and concentrated. The crude product is used for next step without purification.
Reaction SMILES: [C:1]([C:4]1[CH:13]=[C:12]([S:14][CH3:15])[C:11]2[C:6](=[CH:7][C:8]([Cl:16])=[CH:9][CH:10]=2)[N:5]=1)([OH:3])=O.[CH2:17]([O:19][C:20]([N:22]1[CH2:27][CH2:26][N:25]([C:28]([CH:30]([NH2:40])[CH2:31][CH2:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])=[O:29])[CH2:24][CH2:23]1)=[O:21])[CH3:18].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>C1COCC1.CN(C=O)C.C(OCC)(=O)C>[CH2:17]([O:19][C:20]([N:22]1[CH2:23][CH2:24][N:25]([C:28]([CH:30]([NH:40][C:1]([C:4]2[CH:13]=[C:12]([S:14][CH3:15])[C:11]3[C:6](=[CH:7][C:8]([Cl:16])=[CH:9][CH:10]=3)[N:5]=2)=[O:3])[CH2:31][CH2:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])=[O:29])[CH2:26][CH2:27]1)=[O:21])[CH3:18]
Reactant: CSc1cc(C(=O)O)nc2cc(Cl)ccc12
Reactant: CCOC(=O)N1CCN(C(=O)C(N)CCC(=O)OC(C)(C)C)CC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)N1CCN(C(=O)C(CCC(=O)OC(C)(C)C)NC(=O)c2cc(SC)c3ccc(Cl)cc3n2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 54.4 %

Procedure:
To a solution of 2-carboxy-7-chloro-4-mercaptoquinoline HCl salt (75 mg, 0.31 mmol) in DMF (3 mL) was added Mel (0.0425 mL, 2.5 eq.) and cesium carbonate (340 mg, 3.5 eq.). The resulting reaction mixture was stirred at 70° C. overnight. The reaction mixture was diluted with ethyl acetate and washed with water, brine, and dried over sodium sulfate. The solvent was evaporated. Flash column chromatograpgy with 1%–2% MeOH in methylene chloride afforded 2-(methoxycarbonyl)-7-chloro-4-methylthioquinoline (40 mg). To 2-(methoxycarbonyl)-7-chloro-4-methylthioquinoline (40 mg) was added THF:H2O (2:1, 2 mL) and LiOH (10 mg, 1.5 eq.). The reaction mixture was stirred for 2 hours. The pH was adjusted to pH 4.5 with 1N HCl. Extraction with ethyl acetate, washing with brine, drying over sodium sulfate and evaporation gave 2-carboxy-7-chloro-4-methylthioquinoline (29 mg). To a solution of 2-carboxy-7-chloro-4-methylthioquinoline (29 mg) in THF (6 mL) and DMF (1 mL) was added 4-ethoxycarbonyl-1-(1-amino-3-(1,1-dimethylethoxycarbonyl)propyl)carbonylpiperazine (46 mg, 1.1 eq.), EDCI (28 mg, 1.2 eq.), and HOBt (18 mg, 1.1 eq.). The resulting reaction mixture was stirred at ambient temperature overnight. The reaction mixture was evaporated in vacuo to afford a crude product, which was dissolved in ethyl acetate, washed with saturated NaHCO3, 1M NaHSO4 and brine. The organic layer was evaporated. Flash column chromatography with 1%–3% MeOH in CH2Cl2 afforded the product, 2-[1-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-(1,1-dimethylethoxycarbonyl)propyl]aminocarbonyl-7-chloro-4-(methylthio)quinoline (36 mg). The product (32 mg) was treated with TFA:CH2Cl2 (1:1, 1 mL) at ambient temperature for 2 hours. The solvents were then evaporated to afford the desired product, 2-[1-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-carboxypropyl]aminocarbonyl-7-chloro-4-(methylthio)quinoline; NMR (CDCl3) 1.35 (t, 3), 2.10 (m, 1), 2.25 (m, 1), 2.55 (m, 2), 2.7 (s, 3), 3.4–3.9 (m, 8), 4.2 (q, 2), 5.3 (m, 1), 7.55 (d, 1), 7.9 (s, 1), 8.02 (d, 1), 8.15 (s, 1) ppm.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][C:15](OCC)=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C[OH:21].[BH4-].[Li+].O>C(OCC)C.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]([OH:21])[CH3:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CO
Reactant: CCOC(=O)CC1CCN(C(=O)OC(C)(C)C)CC1
Agent: [BH4-]
Agent: [Li+]
Solvent: O
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: CC(O)C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
In diethyl ether (20 ml) was dissolved ethyl N-tert-butoxycarbonyl-4-piperidineacetate (1.18 g) followed by addition of methanol (0.19 ml). Then, lithium borohydride (123 mg) was added under ice-cooling. The mixture was stirred at room temperature for 15 hours, after which time water was added under ice-cooling. The mixture was diluted with ethyl acetate, washed with aqueous NaCl solution, dried over MgSO4, and concentrated to provide the title compound as colorless oil (0.96 g). 1H-NMR (CDCl3) δ: 1.0-1.4(4H,m), 1.45(9H,s), 1.5-1.8(4H,m), 2.69(2H,t,J=13.3Hz), 3.6-3.8(2H,brm), 4.0-4.2(2H,brm).
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[N:14]=[C:13]([NH2:18])[C:12]([CH:19]([CH:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1)[CH2:20][CH2:21][CH:22]=[CH2:23])=[CH:11]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:30](OC(=O)C)(=[O:32])[CH3:31]>S(=O)(=O)(O)O.C(OCC)(=O)C>[O:1]([C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[N:14]=[C:13]([NH:18][C:30](=[O:32])[CH3:31])[C:12]([CH:19]([CH:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1)[CH2:20][CH2:21][CH:22]=[CH2:23])=[CH:11]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)OC(C)=O
Reactant: C=CCCC(c1cc2cc(Oc3ccccc3)ccc2nc1N)C1CCOCC1
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Product: C=CCCC(c1cc2cc(Oc3ccccc3)ccc2nc1NC(C)=O)C1CCOCC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a stirred solution of the solid isolated in Step D (5.08 g, 17.6 mmol) in acetic anhydride (20 mL), sulfuric acid (1 drop) was added. The reaction mixture was stirred at room temperature for four hours. The reaction mixture was then concentrated to yield a residue. The residue was dissolved in ethyl acetate (300 mL). The resulting solution was extracted with sodium hydroxide (1.0 N) solution twice, hydrochloric acid (1.0 N) once, and brine once, and then was dried over magnesium sulfate. The solution was filtered and concentrated to yield N-{6-phenoxy-3-[1-(tetrahydro-pyran-4-yl)-pent-4-enyl]-quinolin-2-yl}-acetamide as a yellow solid.
Reaction SMILES: C([Li])CCC.[CH2:6]([O:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:7]#[CH:8].B(F)(F)F.[CH3:22][CH2:23][O:24]CC.O1CC1.[Cl-].[NH4+]>C1COCC1>[C:12]1([CH2:11][CH2:10][O:9][CH2:6][C:7]#[C:8][CH2:22][CH2:23][OH:24])[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CCOCC
Reactant: C#CCOCCc1ccccc1
Agent: FB(F)F
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CO1
Solvent: C1CCOC1
Product: OCCC#CCOCCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
n-Butyl lithium (1.6M in hexane, 35 ml) was added to a stirred solution of the product of step (i) (8.0 g) in dry THF (50 ml) at -78° under nitrogen. Boron trifluoride etherate (6.8 ml) was added and the mixture was stirred at -78° for 30 min. Oxirane (7 ml) was added and the mixture was stirred at -78° for 1 h, treated with saturated saturated aqueous ammonium chloride (100 ml), allowed to warm to room temperature, and extracted with ER (2×100 ml). The organic extracts were washed with water and brine, dried and concentrated to an orange oil which was purified by FCC eluting with H-ER (2:1) to give the title compound as a pale yellow oil (3.95 g). T.l.c. (H-ER 2:1) Rf 0.10.
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][N:5]1[C:13](=[O:14])[C:12]2[C:7](=[N:8][CH:9]=[CH:10][CH:11]=2)[C:6]1=[O:15].P(Br)(Br)[Br:17]>C(#N)C>[Br:17][CH2:2][CH2:3][CH2:4][N:5]1[C:13](=[O:14])[C:12]2[C:7](=[N:8][CH:9]=[CH:10][CH:11]=2)[C:6]1=[O:15]
Reactant: O=C1c2cccnc2C(=O)N1CCCO
Reactant: BrP(Br)Br
Solvent: CC#N
Product: O=C1c2cccnc2C(=O)N1CCCBr
Yield: 83.8 %

Procedure:
To a solution of 0.813 g (3.94 mmol) 6-(3-hydroxypropyl)-5H-pyrrolo[3,4-b]pyridine-5,7(6H)-dione in 10 ml acetonitrile were added dropwise 0.854 g (3.15 mmol) PBr3 and the mixture was heated to reflux for 2 hours. The mixture was concentrated in vacuo and 6 ml of cold water were added to the residue. The precipitate was filtered, washed with cold water and dried in vacuo to get 0.71 g (71%) of the desired product as a light yellow powder. 1H-NMR (DMSO): 2.10-2.23 (m, 2H), 3.52-3.63 (m, 2H), 3.70-3.82 (m, 2H), 7.72-7.81 (m, 1H), 8.22-8.33 (m, 1H), 8.91-9.00 (m, 1H).
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][C:39]1[CH:44]=[CH:43][C:42]([Cl:45])=[CH:41][CH:40]=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][C:39]3[CH:44]=[CH:43][C:42]([Cl:45])=[CH:41][CH:40]=3)[CH2:10]2)=[CH:5][CH:4]=1)#[N:2]
Reactant: Cn1cc(CC(=O)N[C@@H]2CCCC[C@H]2N[C@H]2CCCN(c3ccc(C#N)cc3)C2)c2ccccc21
Reactant: O=C(Cl)OCc1ccc(Cl)cc1
Product: N#Cc1ccc(N2CCC[C@H](N[C@@H]3CCCC[C@H]3NC(=O)OCc3ccc(Cl)cc3)C2)cc1

Procedure:
4-Chlorobenzyl (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) (60 mg, 0.20 mmol) and 4-chlorobenzyl carbonochloridate (68 mg, 0.22 mmol) according to General Procedure H to give 25 mg (26.6%) of white solid. Anal. Calcd. for C26H31ClN4O2 m/z 466.2, found: 467.2 (M+H)+; 1H NMR (400 MHz, CD3OD) δ ppm 7.48 (d, J=8.9 Hz, 2H), 7.30 (s, 4H), 6.98 (d, J=9 Hz, 2H), 4.99 (m, 2H), 3.70 (m, 1H), 3.57 (m, 1H), 3.29 (m, 1H), 2.98 (m, 1H), 2.75 (m, 1H), 2.68 (m, 1H), 2.50 (m, 1H), 2.04 (m, 1H), 1.91 (m, 2H), 1.77 (m, 3H), 1.64 (m, 1H), 1.32 (m, 5H), 1.21 (m, 1H).
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[CH:3]([NH:5][CH2:6][CH2:7][OH:8])[CH3:4].C(N(C(C)C)CC)(C)C.[Si:20](Cl)([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21].O>ClCCl>[Si:20]([O:8][CH2:7][CH2:6][NH:5][CH:3]([CH3:4])[C:2]([F:10])([F:9])[F:1])([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21]
Reactant: CC(NCCO)C(F)(F)F
Reactant: CC(C)(C)[Si](C)(C)Cl
Solvent: ClCCl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CC(NCCO[Si](C)(C)C(C)(C)C)C(F)(F)F
Reaction time: 16 h
Yield: 37.1 %

Procedure:
To a stirred solution of 2-(1,1,1-trifluoropropan-2-ylamino)ethanol (40) (5.50 g, 35.0 mmol, Eq: 1.00) in dichloromethane (100 ml) were added diisopropylethylamine (6.33 g, 8.56 ml, 49.0 mmol, Eq: 1.4) followed by tert-butyldimethylsilyl chloride (5.8 g, 38.5 mmol, Eq: 1.1) at room temperature under a nitrogen atmosphere. The resulting solution was stirred for 16 hrs and then it was poured into water (100 ml) and the organic layer was separated, washed with brine, dried (MgSO4), concentrated, and chromatographed (silica gel, gradient 0 to 10% ethyl acetate-hexane) to obtain N-(2-(tert-butyldimethylsilyloxy)ethyl)-1,1,1-trifluoropropan-2-amine (41) (oil, 3.52 g, 13.0 mmol, 37.1% yield).
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:8][OH:9])[C:3]=1[O:10][CH3:11].N([O-])=[O:13].[Na+]>S(=O)(=O)(O)O>[OH:13][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:8][OH:9])[C:3]=1[O:10][CH3:11]
Reactant: COc1c(N)ccnc1CO
Reactant: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: COc1c(O)ccnc1CO

Procedure:
4-Amino-2-hydroxymethyl-3-methoxypyridine is diazotised in dilute sulphuric acid with sodium nitrite and the diazonium compound is warmed to give 4-hydroxy-2-hydroxymethyl-3-methoxypyridine which may be demethylated with hydrobromic acid.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][N:12]1[CH2:17][CH2:16][N:15]([CH2:18][C:19]([N:21]2[C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=3[C:25](=[O:32])[NH:24][C:23]3[CH:33]=[CH:34][CH:35]=[N:36][C:22]2=3)=[O:20])[CH2:14][CH2:13]1.[C:37]1([N:46]=[C:47]=[S:48])[CH:42]=[CH:41][CH:40]=[C:39]([N:43]=[C:44]=[S:45])[CH:38]=1.C(OCC)(=O)C>CN(C=O)C>[N:43]([C:39]1[CH:38]=[C:37]([NH:46][C:47]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][N:15]([CH2:18][C:19]([N:21]3[C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=4[C:25](=[O:32])[NH:24][C:23]4[CH:33]=[CH:34][CH:35]=[N:36][C:22]3=4)=[O:20])[CH2:14][CH2:13]2)=[S:48])[CH:42]=[CH:41][CH:40]=1)=[C:44]=[S:45]
Reactant: NCCCCCCCCCCN1CCN(CC(=O)N2c3ccccc3C(=O)Nc3cccnc32)CC1
Reactant: S=C=Nc1cccc(N=C=S)c1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C1Nc2cccnc2N(C(=O)CN2CCN(CCCCCCCCCCNC(=S)Nc3cccc(N=C=S)c3)CC2)c2ccccc21
Reaction time: 0.5 h
Yield: 51.2 %

Procedure:
5,11-Dihydro-11-[(4-[10-aminodecyl]-1-piperazinyl)acetyl]-6H-pyrido[2,3-b][1,4]-benzodiazepine-6-one (2.8 mg, 5.7 μmol) was dissolved in 0.2 mL DMF and treated with 1,3-phenylenediisothiocyanate (6 mg, 31 μmol). After 0.5 h, ethyl acetate (1 mL) and petroleum ether (3 mL) were added, and the cloudy mixture was stored at 4° C. overnight. The supernatant was decanted from the oily residue. The residue solidified upon trituration with dry ether to give 2.0 mg (51% yield) of pure product (Rf =0.35, silica, chloroform:methanol:acetic acid, 85:10:5, by volume). FAB-MS spectrum showed a parent ion peak at 685 m/z (m+1).
Reaction SMILES: [I-].CS[C:4]1[S:5][CH2:6][C@@H:7]2[CH2:16][C:15]3[C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=[CH:11][C:10]=3[CH2:9][N+:8]=12.[NH2:20][C:21]1[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=1>N1C=CC=CC=1>[N+:17]([C:14]1[C:15]2[CH2:16][C@H:7]3[CH2:6][S:5][C:4](=[N:20][C:21]4[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=4)[N:8]3[CH2:9][C:10]=2[CH:11]=[CH:12][CH:13]=1)([O-:19])=[O:18]
Reactant: Nc1cccnc1
Reactant: CSC1=[N+]2Cc3cccc([N+](=O)[O-])c3C[C@H]2CS1
Agent: [I-]
Solvent: c1ccncc1
Product: O=[N+]([O-])c1cccc2c1C[C@H]1CSC(=Nc3cccnc3)N1C2
Reaction time: 6 h
Yield: 81.3 %

Procedure:
(S)-3-Methylthio-9-nitro-1,5,10,10a-tetrahydrothiazolo[3,4-b]isoquinolinium iodide (6 g.) is added to a solution of 3-aminopyridine (3 g.) in pyridine (100 cc.). After 6 hours at a temperature of about 20° C., the mixture is concentrated to dryness under reduced pressure (25 mm. Hg). The residue is dissolved in a mixture consisting of methylene chloride (300 cc.) and water (200 cc.). The organic phase is decanted, washed with water (3 × 200 cc.), dried over magnesium sulphate, filtered and then concentrated to dryness. The residue obtained is recrystallised from acetonitrile (40 cc.) to give (S)-9-nitro-3-(pyrid-3-ylimino)-1,5,10,10a-tetrahydrothiazolo[3,4-b]isoquinoline (3.9 g.) in the form of white crystals melting at 144° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C:11]([F:14])([F:13])[CH2:10][CH:9]1[C:15](O)=[O:16])=[O:7])([CH3:4])([CH3:3])[CH3:2]>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:12][C:11]([F:13])([F:14])[CH2:10][C@H:9]1[CH2:15][OH:16])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CC(F)(F)CC1C(=O)O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC(F)(F)C[C@H]1CO
Temperature: 25 °C
Yield: 84.3 %

Procedure:
To a solution of 4,4-difluoro-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester (Compound 2a) (1.5 g; 6.0 mmol) in tetrahydrofuran (15 mL) was added borane-dimethylsulfide complex (3.79 mL; 7.58 mmol) dropwise at ambient temperature. The reaction mixture was refluxed for 2 h. The resultant mixture was allowed to cool to room temperature. The mixture was partitioned between EtOAc and H2O. The organic phase was washed with H2O, and then dried over Na2SO4. The mixture was filtered and the filtrate was evaporated under reduced pressure to give the crude material. The crude material was purified by flash column chromatography (SiO2), eluting with a heptane-EtOAc gradient to afford Compound 2b (1.2 g; 84% yield) as a colorless oil. 1H-NMR (400 MHz, CDCl3): δ4.08-4.23 (m, 2H), 3.61-3.87 (m, 4H), 2.45-2.57 (m, 1H), 2.15 (br.s, 1H), 1.49 (s, 9H).