Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:14]([C:15]([O:17]CC=C)=[O:16])=[C:13]([CH3:21])[N:12]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=3)[C:11](=[O:32])[NH:10]2)=[C:5]([S:33]([CH2:36][CH2:37][OH:38])(=[O:35])=[O:34])[CH:4]=1)#[N:2].N1CCOCC1>C1COCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:14]([C:15]([OH:17])=[O:16])=[C:13]([CH3:21])[N:12]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:30])([F:31])[F:29])[CH:23]=3)[C:11](=[O:32])[NH:10]2)=[C:5]([S:33]([CH2:36][CH2:37][OH:38])(=[O:35])=[O:34])[CH:4]=1)#[N:2]
Reactant: C=CCOC(=O)C1=C(C)N(c2cccc(C(F)(F)F)c2)C(=O)NC1c1ccc(C#N)cc1S(=O)(=O)CCO
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: C1COCCN1
Product: CC1=C(C(=O)O)C(c2ccc(C#N)cc2S(=O)(=O)CCO)NC(=O)N1c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The reaction was carried out under argon. Allyl (rac)-4-[4-cyano-2-((2-hydroxyethyl)sulfonyl)phenyl]-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carboxylate (150 mg, 0.273 mmol) and morpholine (1.5 eq., 35.6 mg, 0.409 mmol) were initially charged in dry THF (4 ml) at RT. The reaction mixture was degassed repeatedly (evacuation followed by venting with argon). Under protective gas, tetrakis(triphenylphosphine)palladium(0) (0.05 eq., 15.8 mg, 0.014 mmol) was added, and the reaction mixture was stirred at RT for 1 h (HPLC control). The mixture was then concentrated, and the residue was taken up in ethyl acetate (60 ml). The organic phase was washed repeatedly with saturated ammonium chloride solution (3×20 ml), water (20 ml) and saturated sodium chloride solution (20 ml), dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by preparative HPLC (column: Gromsil C-18; mobile phase: acetonitrile/water+0.1% TFA 10:90→80:20). The title compound was obtained as a solid (60 mg, 43% of theory).
Reaction SMILES: [CH2:1](O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CN=C1.[I:39]I>ClCCl>[I:39][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: CCCCCCCCCCCCCO
Reactant: II
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCCCCCCCCCCCCI
Temperature: 0 °C
Reaction time: 3 h
Yield: 86.8 %

Procedure:
To a solution of tridecanol (1.08 g, 5.31 mmol) in dichloromethane (20 mL), triphenyl phosphine (1.53 g, 5.84 mmol) and imidazole (0.39 g, 5.84 mmol) were added and cooled to 0° C. I2 (1.48 g, 5.84 mmol) was added and the reaction mixture was stirred at room temperature for 3 h. After completion of starting materials, the reaction mixture was evaporated and diluted with hexane and passed through a Celite™ pad. The combined organic extracts were evaporated under reduced pressure to obtain the crude product which was purified by column chromatography (100-200 mesh silica gel, eluent hexane) to furnish iodotridecane (1.43 g, 84%) as a low melting solid.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]2[O:6][CH2:7][O:8][C:4]=2[C:3]=1[NH:11][C:12]1[C:20]2[C:19]3[CH2:21][NH:22][CH2:23][CH2:24][C:18]=3[NH:17][C:16]=2[N:15]=[CH:14][CH:13]=1.CCN(C(C)C)C(C)C.[CH:34]1([C:40](Cl)=[O:41])[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1>ClCCCl>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]2[O:6][CH2:7][O:8][C:4]=2[C:3]=1[NH:11][C:12]1[C:20]2[C:19]3[CH2:21][N:22]([C:40]([CH:34]4[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]4)=[O:41])[CH2:23][CH2:24][C:18]=3[NH:17][C:16]=2[N:15]=[CH:14][CH:13]=1
Reactant: O=C(Cl)C1CCCCC1
Reactant: Clc1ccc2c(c1Nc1ccnc3[nH]c4c(c13)CNCC4)OCO2
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(C1CCCCC1)N1CCc2[nH]c3nccc(Nc4c(Cl)ccc5c4OCO5)c3c2C1
Temperature: 25 °C
Yield: 43.2 %

Procedure:
(5-Chloro-benzo[1,3]-dioxol-4-yl)-(6,7,8,9-tetrahydro-5H-dipyrido[2,3-b;3′,4′-d]pyrrol-4-yl)-amine (75 mg, 0.22 mmol) and DIEA (0.11 mL, 0.66 mmol) were dissolved in 1,2-dichloroethane (2 mL) and stirred at room temperature. Cyclohexanecarbonyl chloride (0.04 mL, 0.26 mmol) was added dropwise, and the reaction was stirred for 1 h at room temperature. The reaction was concentrated. The crude material was dissolved in DMSO (3 mL) and filtered. The filtrate was purified directly via prep-LC-MS to provide 71 (43 mg, 33% yield) as a white fluffy solid. LC-MS (M+H=453, obsd.=453).
Reaction SMILES: C(N(CC)CC)C.[NH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[OH:15].[C:16](=O)(OC(Cl)(Cl)Cl)[O:17]C(Cl)(Cl)Cl>ClCCl>[O:15]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[NH:8][C:16]1=[O:17]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: Nc1ccccc1O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=c1[nH]c2ccccc2o1
Reaction time: 0.5 h
Yield: 235.1 %

Procedure:
Triethylamine (27.0 mL) was added to a mixture of 2-aminophenol (10 g, 91.74 mmol) in dichloromethane (200 μL) at 5° C. This was followed by the addition of a solution of bis(trichloromethyl) carbonate (9.35 g, 31.48 mmol) in dichloromethane (40 mL), while maintaining the temperature below 10° C. The resulting solution was then maintained below 10° C. for 6 hours. The reaction mixture was then quenched by the addition of water (50 mL) and ethanol (20 mL). After 0.5 hours, the mixture was concentrated and then poured into 400 mL of water. After filtration, the filter cake was washed with hydrochloric acid (10%) and water to afford 10 g (48%) of benzo[d]oxazol-2(3H)-one as an off-white solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:8]([CH2:19][CH2:20][O:21][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23])[CH2:9][CH2:10][O:11][Si:12]([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13])[CH:5]=[CH:6][CH:7]=1.[CH3:29][N:30]([CH3:38])[C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([NH2:37])[CH:32]=1>>[CH3:29][N:30]([CH3:38])[C:31]1[CH:32]=[C:33]([NH:37][C:2]2[CH:3]=[C:4]([N:8]([CH2:19][CH2:20][O:21][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23])[CH2:9][CH2:10][O:11][Si:12]([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13])[CH:5]=[CH:6][CH:7]=2)[CH:34]=[CH:35][CH:36]=1
Reactant: CC(C)(C)[Si](C)(C)OCCN(CCO[Si](C)(C)C(C)(C)C)c1cccc(Br)c1
Reactant: CN(C)c1cccc(N)c1
Product: CN(C)c1cccc(Nc2cccc(N(CCO[Si](C)(C)C(C)(C)C)CCO[Si](C)(C)C(C)(C)C)c2)c1

Procedure:
By proceeding as described in the coupling general procedure, but starting from 1.85 g (3.8 mmol) of (3-bromo-phenyl)-bis-[2-(tert-butyldimethylsilanyloxy)ethyl]amine and 1.15 g (4.42 mmol) of N,N-dimethylbenzene-1,3-diamine, [3-(3-dimethylaminophenylamino)phenyl]-bis-[2-(tert-butyldimethylsilanyloxy)ethyl]amine is obtained as a pale yellow oil.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)[N:5]=[CH:4][N:3]=1.[OH:18][C:19]1[CH:28]=[C:27]2[C:22]([CH:23]=[CH:24][CH:25]=[N:26]2)=[CH:21][CH:20]=1.[H-].[Na+]>CN(C=O)C>[F:15][C:14]([F:17])([F:16])[C:11]1[CH:12]=[CH:13][C:8]([C:6]2[N:5]=[CH:4][N:3]=[C:2]([O:18][C:19]3[CH:28]=[C:27]4[C:22]([CH:23]=[CH:24][CH:25]=[N:26]4)=[CH:21][CH:20]=3)[CH:7]=2)=[CH:9][CH:10]=1
Reactant: FC(F)(F)c1ccc(-c2cc(Cl)ncn2)cc1
Reactant: Oc1ccc2cccnc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: FC(F)(F)c1ccc(-c2cc(Oc3ccc4cccnc4c3)ncn2)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a 250-mL, round-bottomed flask containing 4-chloro-6-(4-trifluoromethyl-phenyl)-pyrimidine, (Example 2(a), Method A), (2.5 g, 9.7 mmol) and 7-hydroxyquinoline (2.0 g, 14 mmol, Acros) in DMF (30 mL), was added NaH (5.4 g, 14 mmol, 60% in mineral oil, Aldrich) at room temperature The solution was then stirred at room temperature for 4 h. After the solvent was removed in vacuum, EtOAc (100 mL) and water (50 mL) were added to the residue. The solid precipitate was filtered and the filtrate was poured into a separatory funnel. The organic layer was separated, combined with the previously isolated solid, concentrated in vacuum, and purified by silica gel chromatography (2:1 hexanes/EtOAc). The purified product was dissolved in acetone (30 mL) and MeOH (10 mL), and to the solution was added water (30 mL) in small portions. The precipitated solid was filtered, washed with water (5 mL), and dried under vacuum at 50° C. for 48 h to furnish the title compound as a white solid. Mp: 178–180° C. MS (ESI, pos. ion) m/z: 368 (M+1). Anal. Calcd for C20H12F3N3O: C, 65.40; H, 3.29; N, 11.44. Found: C, 65.42; H, 3.23; N, 11.43.
Reaction SMILES: [N:1]1[CH:6]=[C:5]([NH2:7])[CH:4]=[N:3][CH:2]=1.N1C=CC=CC=1.Cl[C:15]([O:17][CH2:18][C:19]([Cl:22])([Cl:21])[Cl:20])=[O:16]>O1CCCC1>[N:1]1[CH:6]=[C:5]([NH:7][C:15](=[O:16])[O:17][CH2:18][C:19]([Cl:22])([Cl:21])[Cl:20])[CH:4]=[N:3][CH:2]=1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Reactant: Nc1cncnc1
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: O=C(Nc1cncnc1)OCC(Cl)(Cl)Cl
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 35.2 %

Procedure:
To a solution of pyrimidine-5-amine (100 mg, 1.05 mmol) and pyridine (0.255 ml, 3.15 mmol) in tetrahydrofuran (3 ml) was added 2,2,2-trichloroethyl chloroformate (0.217 ml, 1.58 mmol) with ice-cooling, the mixture was stirred for 30 minutes with ice-cooling, the reaction mixture was poured into ice-water and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate=1:1) to obtain the desired product (100 mg, 35.2%) as a solid.
Reaction SMILES: Cl.C([CH:7]1[C:12](=[O:13])[CH2:11][CH2:10][N:9]([CH2:14][CH3:15])[C:8]1=[O:16])(OCC)=O>>[CH2:14]([N:9]1[CH2:10][CH2:11][C:12](=[O:13])[CH2:7][C:8]1=[O:16])[CH3:15]
Reactant: CCOC(=O)C1C(=O)CCN(CC)C1=O
Agent: Cl
Product: CCN1CCC(=O)CC1=O
Yield: 69.6 %

Procedure:
300 ml of a 10% aqueous hydrochloric acid solution was added to 36.0 g of 3-carboethoxy-1-ethylpiperidine-2,4-dione, and they were refluxed for 40 minutes and allowed to cool. The resulting mixture was subjected to extraction by chloroform. The resulting chloroform layer was water-washed, dried and concentrated to obtain 16.6 g of 1-ethylpiperidine-2,4-dione as a light yellow oily matter with an yield of 70%.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[C:11]([S-:13])#[N:12].[K+]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:12]=[C:11]=[S:13])=[O:7])=[CH:4][CH:3]=1
Reactant: N#C[S-]
Reactant: O=C(Cl)c1ccc(Cl)cc1
Agent: [K+]
Solvent: Cc1ccccc1
Product: O=C(N=C=S)c1ccc(Cl)cc1

Procedure:
A solution of 4-chlorobenzoyl chloride (127.1 ml) in 100 ml of dry toluene is added to a vigorously stirred suspension of dried KSCN (106.90 g) in about one liter of dried toluene. The reaction mixture is heated to reflux and after addition is completed the mixture is refluxed overnight. The reaction mixture is allowed to cool, KCl filtered and the filtrate evaporated leaving a reddish residue which solidifies on standing. The residue is vacuum distilled, using a steam filled condenser, yielding 152.4 g of a distillate, b.p. 88°-90° (0.350 torr).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[N:4][CH:5]=[C:6]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:7]=1.O.[C:21]([OH:25])(=[O:24])[CH:22]=O.[BH3-]C#N.[Na+]>CCO>[CH2:8]([C:6]1[CH:7]=[C:2]([NH:1][CH2:22][C:21]([OH:25])=[O:24])[C:3]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[N:4][CH:5]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=CC(=O)O
Reactant: CCOC(=O)c1ncc(Cc2ccccc2)cc1N
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1ncc(Cc2ccccc2)cc1NCC(=O)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of ethyl 3-amino-5-benzylpyridine-2-carboxylate (0.543 g, 2.12 mmol) and glyoxylic acid monohydrate (0.254 g, 2.76 mmol) in EtOH (6 mL) was heated at reflux for 1 h. The mixture was allowed to cool to rt and NaCNBH3 (266 mg, 4.23 mmol) was added. After stirring 2 h at rt, the reaction was quenched with water and the EtOH was removed at reduced pressure. The aqueous mixture was extracted with CH2Cl2 and the organic layers were dried and concentrated. Trituration of the remaining material with EtOAc/hexanes and filtration afforded the product as a beige solid: 1H NMR (d6-DMSO) δ 13.2 (1H, br), 7.92 (1H, br t, J=4.8 Hz), 7.76 (1H, s), 7.26 (4H, m), 7.17 (1H, t, J=7 Hz), 7.00 (1H, s), 4.24 (2H, q, J=7 Hz), 3.90 (2H, s), 3.86 (2H, br), 1.27 (3H, t, J=7 Hz).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C:12]([CH2:13][CH3:14])=[C:11](/[CH:15]=[CH:16]/[C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:10]=[N:9]2)[CH:5]=[C:4](Cl)[N:3]=1.Cl.[OH:24][CH:25]1[CH2:28][NH:27][CH2:26]1.C(N(CC)CC)C>C(O)C>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C:12]([CH2:13][CH3:14])=[C:11](/[CH:15]=[CH:16]/[C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:10]=[N:9]2)[CH:5]=[C:4]([N:27]2[CH2:28][CH:25]([OH:24])[CH2:26]2)[N:3]=1
Reactant: OC1CNC1
Reactant: CCOC(=O)/C=C/c1cnn(-c2cc(Cl)nc(N)n2)c1CC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCOC(=O)/C=C/c1cnn(-c2cc(N3CC(O)C3)nc(N)n2)c1CC

Procedure:
A 4.14 g portion of ethyl 3-[1-[2-amino-6-chloro-4-pyrimidinyl]-5-ethyl-4-pyrazolyl]-2-trans-propenoate was suspended in 150 ml of ethanol, mixed with 3.07 g of 3-hydroxyazetidine hydrochloride and 7.8 ml of triethylamine and then heated under reflux for 2 days. The reaction solution was allowed to stand at room temperature, and then the resulting precipitate was collected by filtration to obtain 4.10 g of the title compound as colorless crystals.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[N:10]=[C:9]([S:11][CH2:12][CH2:13][CH2:14][NH2:15])[CH:8]=[CH:7][CH:6]=1)[CH3:3].[CH3:16][S:17][C:18](SC)=[CH:19][N+:20]([O-:22])=[O:21]>C(#N)C>[CH3:1][N:2]([CH2:4][C:5]1[N:10]=[C:9]([S:11][CH2:12][CH2:13][CH2:14][NH:15][C:18]([S:17][CH3:16])=[CH:19][N+:20]([O-:22])=[O:21])[CH:8]=[CH:7][CH:6]=1)[CH3:3]
Reactant: CN(C)Cc1cccc(SCCCN)n1
Reactant: CSC(=C[N+](=O)[O-])SC
Solvent: CC#N
Product: CSC(=C[N+](=O)[O-])NCCCSc1cccc(CN(C)C)n1
Reaction time: 18 h
Yield: 73 %

Procedure:
A mixture of 3-(6-dimethylaminomethyl-2-pyridylthio)-propylamine (1.13 g, 0.005 mol) and 1,1-bis(methylthio)-2-nitroethene (0.86 g, 0.0052 mol) in acetonitrile (10 ml) is warmed briefly to effect solution and then allowed to stand at ambient temperature for 18 hours. The solvent is evaporated and the residue is chromotographed on silica gel (50 g) eluting with 3-7% methanol/chloroform to give 1.25 g of a glassy product.
Reaction SMILES: [Br:1][C:2]1[O:6][C:5]([C:7]2[C:11]3[CH:12]=[N:13][C:14]([C:17]([O:19]CC)=O)=[C:15]([OH:16])[C:10]=3[O:9][N:8]=2)=[CH:4][CH:3]=1.[NH2:22][CH2:23][C:24]([OH:26])=[O:25].[O-]CC.[Na+].Cl>CN(C=O)C.O>[Br:1][C:2]1[O:6][C:5]([C:7]2[C:11]3[CH:12]=[N:13][C:14]([C:17]([NH:22][CH2:23][C:24]([OH:26])=[O:25])=[O:19])=[C:15]([OH:16])[C:10]=3[O:9][N:8]=2)=[CH:4][CH:3]=1
Reactant: NCC(=O)O
Reactant: CCOC(=O)c1ncc2c(-c3ccc(Br)o3)noc2c1O
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(O)CNC(=O)c1ncc2c(-c3ccc(Br)o3)noc2c1O
Temperature: 25 °C
Yield: 92.2 %

Procedure:
Ethyl 3-(5-bromofuran-2-yl)-7-hydroxyisoxazolo[4,5-c]pyridine-6-carboxylate (62 mg, 0.176 mmol) was dissolved in 10 mL of DMF. Glycine (0.264 g, 3.51 mmol) and sodium ethoxide (0.179 g, 2.63 mmol) were added and the mixture was refluxed for 3 h. The mixture was cooled to room temperature and diluted with 70 mL of water. Concentrated hydrochloric acid was added dropwise until pH was 3. The resulting suspension was filtered and the solid was dried under vacuum to give 62 mg of the title compound. MS: (+) m/z 382, 384 (M+1, 79Br/81Br).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].S(=O)(=O)(O)O.[CH3:17][CH2:18]O>>[CH2:17]([O:5][C:4](=[O:6])[C:3]1[CH:7]=[C:8]([OH:11])[CH:9]=[CH:10][C:2]=1[Cl:1])[CH3:18]
Reactant: O=C(O)c1cc(O)ccc1Cl
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1cc(O)ccc1Cl

Procedure:
To a mixture of commercially available 2-chloro-5-hydroxybenzoic acid (4 g, 23.18 mmol) in dry EtOH (90 mL), concentrated sulphuric acid (1 mL, 17.62 mmol) was added. The mixture was stirred under reflux overnight, then solvent evaporated under reduced pressure and the residue dissolved with DCM. A saturated solution of NaHCO3 was added, phases were separated, organics dried over sodium sulphate, filtered and evaporated to obtain 5 g of the corresponding 2-chloro-5-hydroxy-benzoic acid ethyl ester.
Reaction SMILES: [OH-].[NH4+:2].Cl[C:4]([CH:6]([CH3:28])[CH2:7][CH2:8][N:9]1[C:13]2[CH:14]=[CH:15][CH:16]=[C:17]([CH3:18])[C:12]=2[N:11]=[C:10]1[CH2:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=1)=[O:5]>CO>[C:4]([CH:6]([CH3:28])[CH2:7][CH2:8][N:9]1[C:13]2[CH:14]=[CH:15][CH:16]=[C:17]([CH3:18])[C:12]=2[N:11]=[C:10]1[CH2:19][O:20][C:21]1[CH:22]=[CH:23][C:24]([Cl:27])=[CH:25][CH:26]=1)(=[O:5])[NH2:2]
Reactant: [NH4+]
Reactant: Cc1cccc2c1nc(COc1ccc(Cl)cc1)n2CCC(C)C(=O)Cl
Agent: [OH-]
Solvent: CO
Product: Cc1cccc2c1nc(COc1ccc(Cl)cc1)n2CCC(C)C(N)=O
Temperature: 25 °C
Reaction time: 64 h
Yield: 73 %

Procedure:
In an ammonium hydroxide solution (28%, 10 ml) was placed 1-[3-(chlorocarbonyl)butyl]-2-[(4-chlorophenoxy)methyl]-4-methylbenzimidazole (400 mg, 1.0 mmol). To this mixture 10 ml of methanol were added, to enhance solubility and the mixture was stirred for about 64 hours at room temperature. The reaction mixture was then concentrated under reduced pressure to produce a tan foam. The crude material was further purified by flash silica gel chromatography, eluting with a gradient solvent of 19:1 ethyl acetate:methanol to 9:1 ethyl acetate:methanol. The fractions containing the desired material were combined and concentrated in vacuo to yield 300 mg (73%) of the desired title compound as a white foam.
Reaction SMILES: [C:1]([CH:5]([C:21]1[CH:26]=[CH:25][C:24]2[O:27][CH2:28][O:29][C:23]=2[CH:22]=1)[O:6][C:7]1[C:14]([CH2:15][CH2:16][CH3:17])=[CH:13][C:10]([CH2:11]O)=[CH:9][C:8]=1[CH2:18][CH2:19][CH3:20])([O:3][CH3:4])=[O:2].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(Br)(Br)(Br)[Br:50].CC#N>C1COCC1>[C:1]([CH:5]([C:21]1[CH:26]=[CH:25][C:24]2[O:27][CH2:28][O:29][C:23]=2[CH:22]=1)[O:6][C:7]1[C:14]([CH2:15][CH2:16][CH3:17])=[CH:13][C:10]([CH2:11][Br:50])=[CH:9][C:8]=1[CH2:18][CH2:19][CH3:20])([O:3][CH3:4])=[O:2]
Reactant: CCCc1cc(CO)cc(CCC)c1OC(C(=O)OC)c1ccc2c(c1)OCO2
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: C1CCOC1
Product: CCCc1cc(CBr)cc(CCC)c1OC(C(=O)OC)c1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 14 h
Yield: 89.1 %

Procedure:
To a solution of the product of Step B (0.53 g, 1.38 mMol) in dry THF (10 mL) were added Ph3P (0.49 g, 2.06 mMol), CBr4 (0.69 g, 2.06 mMol) and CH3CN (2 mL), and the mixture was stirred at room temperature for 14 h. At the end of this period, the reaction mixture was concentrated in vacuo to provide an oil, which was then purified by flash chromatography on silica-gel using ethyl acetate-hexane (1:9) to provide the titled product as a thick colorless oil (0.57 g).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[CH2:3][O:4][C:5]1[CH:11]=[CH:10][C:8]([NH2:9])=[CH:7][CH:6]=1.[S-:14][C:15]#[N:16].[K+].BrBr>C(O)(=O)C>[F:1][C:2]([F:12])([F:13])[CH2:3][O:4][C:5]1[CH:11]=[CH:10][C:8]2[N:9]=[C:15]([NH2:16])[S:14][C:7]=2[CH:6]=1
Reactant: N#C[S-]
Reactant: Nc1ccc(OCC(F)(F)F)cc1
Agent: BrBr
Agent: [K+]
Solvent: CC(=O)O
Product: Nc1nc2ccc(OCC(F)(F)F)cc2s1

Procedure:
The procedure is as in Example 1, starting with 4-(2,2,2-trifluoroethoxy)aniline, potassium thiocyanate and bromine in acetic acid, to obtain 6-(2,2,2-trifluoroethoxy)-2-benzothiazolamine, m.p. 134° C.
Reaction SMILES: [ClH:1].[CH3:2][C:3]1([CH3:28])[C:12](=[O:13])[CH:11]2[C:6](=[C:7]3[N:17]=[C:16]([C:18]4[CH:23]=[CH:22][C:21]([S:24][CH3:25])=[CH:20][C:19]=4[O:26][CH3:27])[N:15]=[C:8]3[C:9](=[O:14])[CH2:10]2)[CH:5]=[N:4]1.Br.[CH2:30]([N:32]([CH2:36][CH3:37])[CH2:33][CH2:34]Br)[CH3:31]>>[ClH:1].[ClH:1].[CH3:2][C:3]1([CH3:28])[C:12](=[O:13])[CH:11]2[C:6](=[C:7]3[N:17]=[C:16]([C:18]4[CH:23]=[CH:22][C:21]([S:24][CH3:25])=[CH:20][C:19]=4[O:26][CH3:27])[N:15]=[C:8]3[C:9](=[O:14])[CH:10]2[CH2:31][CH2:30][N:32]([CH2:36][CH3:37])[CH2:33][CH3:34])[CH:5]=[N:4]1
Reactant: CCN(CC)CCBr
Reactant: COc1cc(SC)ccc1C1=NC2=C3C=NC(C)(C)C(=O)C3CC(=O)C2=N1
Agent: Br
Agent: Cl
Product: CCN(CC)CCC1C(=O)C2=NC(c3ccc(SC)cc3OC)=NC2=C2C=NC(C)(C)C(=O)C21

Procedure:
Prepared analogously to Example 23 from 2.9 gm of 7,7-dimethyl-2-(2-methoxy-4-methylmercapto-phenyl)-5H,7H-imidazo[4,5-h]isoquinoline-4,6-dione hydrochloride and 2 gm of 2-diethylamino-ethyl bromide hydrobromide.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1OS(C(F)(F)F)(=O)=O.[CH3:27][C:28]1([CH2:34][O:35][C:36]2[CH:43]=[CH:42][C:39]([CH2:40][NH2:41])=[CH:38][CH:37]=2)[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1>O1CCOCC1>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1[NH:41][CH2:40][C:39]1[CH:42]=[CH:43][C:36]([O:35][CH2:34][C:28]2([CH3:27])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]2)=[CH:37][CH:38]=1
Reactant: CC1(COc2ccc(CN)cc2)CCCCC1
Reactant: O=C(N1CCc2ccc(Cl)c(OS(=O)(=O)C(F)(F)F)c2CC1)C(F)(F)F
Solvent: C1COCCO1
Product: CC1(COc2ccc(CNc3c(Cl)ccc4c3CCN(C(=O)C(F)(F)F)CC4)cc2)CCCCC1
Yield: 42.2 %

Procedure:
Use a method similar to the General Procedure 5-2 to couple 7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine (200 mg, 0.47 mmol) with 4-(1-methyl-cyclohexylmethoxy)-benzylamine (120 mg, 0.51 mmol) in anhydrous 1,4-dioxane (7 mL). Purify the crude mixture by chromatography on silica gel eluting with isohexane/EtOAc (19:1 to 4:1 gradient) to obtain 7-chloro-6-[4-(1-methyl-cyclohexylmethoxy)-benzylamino]-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (101 mg, 39%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:18]([CH:20]3[CH2:24][CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21]3)=O)[CH2:14][CH2:13]2)=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8].B.Cl>C1COCC1.CO>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH:20]3[CH2:24][CH2:23][NH:22][CH2:21]3)[CH2:14][CH2:13]2)=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)N2CCN(C(=O)Nc3ccc(Cl)c(Cl)c3)CC2)C1
Agent: B
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Product: O=C(Nc1ccc(Cl)c(Cl)c1)N1CCN(CC2CCNC2)CC1
Yield: 17.2 %

Procedure:
To a stirred solution of tert-butyl 3-[(4-{[(3,4-dichlorophenyl)amino]carbonyl}piperazin-1-yl)carbonyl]pyrrolidine-1-carboxylate (3.39 g, 7.19 mmol) in THF (60 ml) was added a 1M solution of borane in THF (21.6 ml, 21.6 mmol) and the reaction heated to reflux for 4 hours. The cooled reaction mixture was then cautiously quenched by addition of methanol then solvents removed in vacuo to give a white solid. To this was then added saturated HCl in methanol (150 ml) and heated to reflux for 1 hour. The reaction mixture was then evaporated to dryness, partitioned between 2M NaOH and DCM, extracted twice, combined organics dried (Na2SO4), filtered and evaporated to a colorless oil. This was then purified on Isco™ Companion (40 g column: 20% methanolic ammonia/DCM) to give the product N-(3,4-dichlorophenyl)-4-(pyrrolidin-3-ylmethyl)piperazine-1-carboxamide as a white foam (444 mg, 1.24 mmol, 17%).
Reaction SMILES: [CH2:1]([CH:3]1[CH2:12][C:11]2[C:6](=[CH:7][C:8]([N+:13]([O-])=O)=[CH:9][CH:10]=2)[CH:5]=[N:4]1)[CH3:2].[ClH:16].C(O)(C)C>CO.[Pd]>[ClH:16].[ClH:16].[CH2:1]([CH:3]1[CH2:12][C:11]2[C:6](=[CH:7][C:8]([NH2:13])=[CH:9][CH:10]=2)[CH2:5][NH:4]1)[CH3:2]
Reactant: CCC1Cc2ccc([N+](=O)[O-])cc2C=N1
Agent: [Pd]
Agent: Cl
Solvent: CC(C)O
Solvent: CO
Product: CCC1Cc2ccc(N)cc2CN1

Procedure:
To a pressure bottle charged with 3-ethyl-7-nitro-3,4-dihydroisoquinoline (3.6 g, 17 mmols) dissolved in methanol (100 ml) and saturated isopropanol-HCl (20 ml) was added 10% Pd-C (250 mg), and the reaction hydrogenated for 1 h. The catalyst was removed by filtration and the solvent evaporated to yield 3-ethyl-1,2,3,4-tetrahydroisoquinolin-7-amine dihydrochloride (4.3 g).