Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[K+].[CH3:3]I.[C:5]1([S:11]([NH:14][C:15]([C:17]2[CH:18]=[CH:19][C:20]3[N:24]=[C:23]([SH:25])[N:22]([CH2:26][C:27]4[CH:32]=[CH:31][C:30]([C:33]5[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=5)=[CH:29][CH:28]=4)[C:21]=3[CH:39]=2)=[O:16])(=[O:13])=[O:12])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.Cl>CO.O>[C:5]1([S:11]([NH:14][C:15]([C:17]2[CH:18]=[CH:19][C:20]3[N:24]=[C:23]([S:25][CH3:3])[N:22]([CH2:26][C:27]4[CH:28]=[CH:29][C:30]([C:33]5[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=5)=[CH:31][CH:32]=4)[C:21]=3[CH:39]=2)=[O:16])(=[O:13])=[O:12])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: O=C(NS(=O)(=O)c1ccccc1)c1ccc2nc(S)n(Cc3ccc(-c4ccccc4)cc3)c2c1
Reactant: CI
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CSc1nc2ccc(C(=O)NS(=O)(=O)c3ccccc3)cc2n1Cc1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.2 %

Procedure:
A 20% potassium hydroxide aqueous solution (0.323 g), 2 ml of water and 0.123 g of methyl iodide were added to a solution of 0.310 g of 6-benzenesulfonylcarbamoyl-1-(biphenyl-4-ylmethyl)-2-mercaptobenzimidazole in 5 ml of methanol in this order, and the mixture was stirred at room temperature for 2 hours. The reaction solution was adjusted to a pH of from 5 to 6 with 10% hydrochloric acid. The crystals precipitated were separated through filtration, and were dried to give 0.281 g of 6-benzenesulfonylcarbamoyl-1-(biphenyl-4-ylmethyl)-2-methylthio-benzimidazole (237).
Reaction SMILES: Cl[CH:2]=[CH:3][C:4]#[C:5][Si:6]([CH3:9])([CH3:8])[CH3:7].C(NCC)C.[C:15]1([O:21][C:22]([N:24]2[CH:37]([C:38]#[CH:39])[C:36]34[O:40][C:31]3([C:32](=[O:41])[CH2:33][CH2:34][CH2:35]4)[C:30]3[CH:29]=[CH:28][C:27]([O:42][C:43](=[O:48])[C:44]([CH3:47])([CH3:46])[CH3:45])=[CH:26][C:25]2=3)=[O:23])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C1C=CC=CC=1.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.[Cu]I>[C:15]1([O:21][C:22]([N:24]2[CH:37]([C:38]#[C:39]/[CH:2]=[CH:3]\[C:4]#[C:5][Si:6]([CH3:9])([CH3:8])[CH3:7])[C:36]34[O:40][C:31]3([C:32](=[O:41])[CH2:33][CH2:34][CH2:35]4)[C:30]3[CH:29]=[CH:28][C:27]([O:42][C:43](=[O:48])[C:44]([CH3:46])([CH3:45])[CH3:47])=[CH:26][C:25]2=3)=[O:23])[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: C#CC1N(C(=O)Oc2ccccc2)c2cc(OC(=O)C(C)(C)C)ccc2C23OC12CCCC3=O
Reactant: C[Si](C)(C)C#CC=CCl
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Solvent: CCNCC
Product: CC(C)(C)C(=O)Oc1ccc2c(c1)N(C(=O)Oc1ccccc1)C(C#C/C=C\C#C[Si](C)(C)C)C13CCCC(=O)C21O3
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 32 %

Procedure:
A mixture of Pd(PPh3)4 (185 mg, 0.16 mmol), 1-chloro-4-(trimethylsilyl)-but-1-en-3-yne (0.776 g, 4.89 mmol), and diethylamine (0.51 mL, 4.93 mmol) in degassed benzene (5 mL) was stirred at 25° C. for 15 minutes. The resultant solution was added to a mixture of Compound 230 (1.50 g, 3.26 mmol) and CuI (124 mg, 0.65 mmol) in degassed benzene (15 mL) via a syringe followed by stirring at 25° C. for one hour. The reaction mixture was quenched by saturated aqueous NH4Cl, extracted with ethyl ether (80 mL), washed with brine, dried over anhydrous Na2SO4, and concentrated in vacuo. Purification of the residue by flash column chromatography (silica gel, 25 percent ethyl ether in petroleum ether) provided a solid product Compound 231 (0.606 g, 32 percent): Rf =0.43 (silica, 50 percent ethyl ether in petroleum ether); IR (CHCl3) νmax 2964, 1721, 1494, 1378, 1305, 1270, 1253, 1202, 1181, 1122, 846 cm-1 ; 1H NMR (300 MHz, CDCl3) δ 8.40 (d, J=8.7 Hz, 1 H, H1), 7.44-7.10 (m, 6 H, H4 and aromatic), 6.99 (dd, J=8.7, 2.4 Hz, 1 H, H2), 5.98 (d, J=1.5 Hz, 1 H, H6), 5.84 (d, J=11.1 Hz, 1 H, olefinic), 5.69 (br d, J=11.1 Hz, 1 H, olefinic), 2.81-2.66 (m, 2 H, H9), 2.41-2.26 (m, 2 H, H7), 2.10-1.86 (m, 2 H, H8), 1.33 (s, 9 H, COC(CH3)3), 0.22 (s, 9 H, SiC(CH3)3); MS (FAB+) m/e (rel intensity) 582 (M+H, 100), 525 (13), 460 (48), 406 (8), 360 (6), 320 (8), 279 (25), 246 (5);HRMS for C34H36NO6Si (M+H), calcd 582.2312, found 582.2322.
Reaction SMILES: [C:1]([C:4]1[N:5]=[C:6]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)[S:7][CH:8]=1)([OH:3])=O.Cl.[CH2:23]([NH:25][CH:26]([CH3:35])[C:27]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:28])[CH3:24].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)C(C)C)C>CN(C)C=O>[CH2:23]([N:25]([CH:26]([CH3:35])[C:27](=[O:28])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:1]([C:4]1[N:5]=[C:6]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)[S:7][CH:8]=1)=[O:3])[CH3:24]
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc(C(=O)O)cs2)CC1
Reactant: CCNC(C)C(=O)c1ccccc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCN(C(=O)c1csc(C2CCN(C(=O)OC(C)(C)C)CC2)n1)C(C)C(=O)c1ccccc1

Procedure:
tert-Butyl 4-(4-carboxythiazol-2-yl)piperidine-1-carboxylate (6.5 mmol; 2.03 g) is dissolved in 40 ml of anhydrous dimethylformamide and placed under an inert atmosphere, and 2-(ethylamino)propiophenone hydrochloride (1 eq.; 6.5 mmol; 1.39 g), HBTU (1 eq.; 6.5 mmol; 2.47 g) and N-ethyldiisopropylamine (3.5 eq.; 22.75 mmol; 3.97 ml) are then added.
Reaction SMILES: [OH-].[NH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][P:10]([OH:19])([O:12][CH:13]([N+:15]([CH3:18])([CH3:17])[CH3:16])[CH3:14])=[O:11].C(N(CC)CC)C.C1C(=O)N(O[C:35]([CH2:37][CH2:38][S:39][S:40][C:41]2[N:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)=[O:36])C(=O)C1>CS(C)=O>[OH-:9].[N:46]1[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=1[S:40][S:39][CH2:38][CH2:37][C:35]([C:13]([O:12][P:10]([O:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][NH2:2])([OH:19])=[O:11])([N+:15]([CH3:17])([CH3:18])[CH3:16])[CH3:14])=[O:36]
Reactant: O=C(CCSSc1ccccn1)ON1C(=O)CCC1=O
Reactant: CC(OP(=O)(O)OCCCCCCN)[N+](C)(C)C
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CC(OP(=O)(O)OCCCCCCN)(C(=O)CCSSc1ccccn1)[N+](C)(C)C
Temperature: 25 °C

Procedure:
2-[(6-Aminohexoxyhydroxyphosphinyl)oxy-N,N,N-trimethylethanaminium hydroxide, inner salt (90 mg, 0.28 mmol) was dissolved in dry dimethyl sulphoxide (2 ml). Triethylamine (197 μl, 1.41 mmol) was added, followed by N-succinimidyl 3-(2-pyridyldithio)propionate (88 mg, 0.28 mmol). The mixture was stirred at ambient temperature for eighteen hours. The solvent was evaporated under vacuum at a temperature of 60° C. and re-evaporated from methanol. The residue was chromatographed on silica gel eluting with methanol. The relevant fractions were combined and evaporated to dryness to give 2[N(3-(2 pyridyldithio)propionyl)(6-aminohexoxyhydroxy
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:27]([F:30])([F:29])[F:28])=[N:4][N:5]([CH2:8][C:9]([N:11]2[CH2:16][CH2:15][C:14]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)([C:17](O)=[O:18])[CH2:13][CH2:12]2)=[O:10])[C:6]=1[CH3:7].[NH:31]1[CH2:35][CH2:34][CH2:33][CH2:32]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN1C(=O)CCC1>[Cl:1][C:2]1[C:3]([C:27]([F:30])([F:29])[F:28])=[N:4][N:5]([CH2:8][C:9]([N:11]2[CH2:16][CH2:15][C:14]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)([C:17]([N:31]3[CH2:35][CH2:34][CH2:33][CH2:32]3)=[O:18])[CH2:13][CH2:12]2)=[O:10])[C:6]=1[CH3:7]
Reactant: C1CCNC1
Reactant: Cc1c(Cl)c(C(F)(F)F)nn1CC(=O)N1CCC(C(=O)O)(c2ccc(Cl)cc2)CC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCCC1=O
Product: Cc1c(Cl)c(C(F)(F)F)nn1CC(=O)N1CCC(C(=O)N2CCCC2)(c2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a 4 mL vial was added 50 mg of 1-[2-(4-chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetyl]-4-(4-chloro-phenyl)-piperidine-4-carboxylic acid (0.11 mmol, 1.0 equiv), 11 μL of pyrrolidine (0.13 mmol, 1.2 equiv), 60 μL TEA (0.43 mmol, 4.00 equiv), 71 mg BOP (0.16 mmol, 1.5 equiv), and 500 μL NMP. The mixture was stirred overnight at room temperature and the crude product was purified by reversed phase HPLC (acetonitrile —H2O with 0.1% TFA as the eluent) to yield 2-(4-chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-1-[4-(4-chloro-phenyl)-4-(pyrrolidine-1-carbonyl)-piperidin-1-yl]-ethanone:.MS (ES) M+H expected=517.4, found=517.1.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]3[N:24]([CH3:25])[C:23]4[CH:26]=[CH:27][CH:28]=[CH:29][C:22]=4[N:21]=3)[CH:15]=2)[CH2:10][CH2:9]1)(C)(C)C.[Cl:31]CCl>CO.Cl.CCOCC>[ClH:31].[CH3:25][N:24]1[C:23]2[CH:26]=[CH:27][CH:28]=[CH:29][C:22]=2[N:21]=[C:20]1[C:16]1[CH:15]=[C:14]([N:11]2[CH2:12][CH2:13][CH:8]([NH2:7])[CH2:9][CH2:10]2)[CH:19]=[CH:18][CH:17]=1
Reactant: ClCCl
Reactant: Cn1c(-c2cccc(N3CCC(NC(=O)OC(C)(C)C)CC3)c2)nc2ccccc21
Agent: Cl
Solvent: CCOCC
Solvent: CO
Product: Cn1c(-c2cccc(N3CCC(N)CC3)c2)nc2ccccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of {1-[3-(1-Methyl-1H-benzoimidazol-2-yl)-phenyl]-piperidin-4-yl}-carbamic acid tert-butyl ester (2.00 g, 4.93 mmol) in dichloromethane (2 mL) and methanol (1 mL), 2M HCl in Et2O (25 mL) was added and the resulting mixture was stirred overnight at room temperature.
Reaction SMILES: [C:1]1([CH:9]=[CH:8][CH:7]=[C:5]([OH:6])[C:3]=1[OH:4])[OH:2].[CH:10](OC)(OC)[O:11][CH3:12].ClC(Cl)C>ClCCCl>[OH:2][C:1]1[C:3]2[O:4][CH:10]([O:11][CH3:12])[O:6][C:5]=2[CH:7]=[CH:8][CH:9]=1
Reactant: COC(OC)OC
Reactant: Oc1cccc(O)c1O
Solvent: ClCCCl
Solvent: CC(Cl)Cl
Product: COC1Oc2cccc(O)c2O1

Procedure:
A mixture of pyrogallol (25 parts), trimethyl orthoformate (32 parts) and 1,2-dichloroethane (250 parts) was heated with continuous distillation of the solvent for 4 hours. The volume of solvent was kept constant by simultaneous addition of dichloroethane. The mixture was then washed three times with water and dried over sodium sulphate. Removal of the solvent under reduced pressure and distillation of the residue gave 4-hydroxy-2-methoxy-1,3-benzodioxole, boiling point 104°-105° C/1 mmHg.
Reaction SMILES: [N:1]([CH:4]([CH2:10][CH:11]([F:16])[C:12]([F:15])([F:14])[Cl:13])[C:5]([O:7][CH2:8][CH3:9])=[O:6])=[N+]=[N-].[H][H]>C(O)C.[Pd]>[NH2:1][CH:4]([CH2:10][CH:11]([F:16])[C:12]([F:14])([F:15])[Cl:13])[C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CCOC(=O)C(CC(F)C(F)(F)Cl)N=[N+]=[N-]
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)C(N)CC(F)C(F)(F)Cl
Yield: 72.2 %

Procedure:
Thereafter, 4.76 g (0.018 mol) of ethyl 2-azido-4,5,5-trifluoro-5-chloropentanoate was dissolved in 20 ml of ethanol. The resultant solution was placed in a three-neck round-bottom flask and 0.50 g of 5% palladium-containing activated carbon was added to the solution, and hydrogen was passed through the resultant mixture at a flow rate of 20 ml/min at room temperature for 22 hours. The catalyst was separated by filtration and the ethanol was expelled by distillation. By vacuum distilling the residual liquid, there was obtained 293 g (0.013 mol, yield of 69%) of ethyl 2-amino-4,5,5-trifluoro-5-chloropentanoate having b.p. 69° to 70° C./3 mm, nD20 1.4102, νNH2 3386 and 3318 cm-1 and νC=O 1733 cm-1.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([C:9]([OH:11])=O)=[CH:7][CH:6]=[CH:5][CH:4]=1.O=S(Cl)[Cl:14]>C(Cl)(Cl)Cl.CN(C=O)C>[C:9]([Cl:14])(=[O:11])[C:8]1[C:3]([O:2][CH3:1])=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=S(Cl)Cl
Reactant: COc1ccccc1C(=O)O
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: COc1ccccc1C(=O)Cl
Reaction time: 24 h
Yield: 95 %

Procedure:
O-Anisic acid (0.38 mol) was suspended in 60 mL CHCl3 and 3 drops DMF. A single volume of SOCl2 (4 mole equiv.) was added at room temperature with vigorous reaction and the reaction was then refluxed. The reaction was monitored by IR for disappearance of the carboxylic acid carbonyl stretch at 1740 cm-1 and appearance of the acyl carbonyl stretch at 1780 cm-1. The reaction was judged complete after 24 hours. The solvent and excess reagent were removed via vacuum distillation (86 mmHg) affording the crude o-anisoyl chloride in >95% yield as an oil. The acid chloride was cooled, diluted with 50 mL CHCl3 and added dropwise to a chilled (ice/H2O) solution of TEA and t-butylamine (1.2 mole equiv. each) in 100 mL CHCl3. Once addition was complete, the cooling bath was removed and the mixture stood at ambient temperature. The mixture was washed 3×1.5N HCl, 2×0.5N NaOH, and 1× brine. The chloroform was dried on MgSO4, filtered, and concentrated in vacuo to approximately 93 g oil which was Kugelrohr distilled (110°/0.3 mmHg). The N-t-butyl-o-anisamide was obtained as a yellow oil in 95% yield.
Reaction SMILES: [C:1]([C:5]1[C:6]([S:19]C#N)=[CH:7][C:8]([CH3:18])=[C:9]([O:11][S:12](=[O:17])(=[O:16])[N:13]([CH3:15])[CH3:14])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].SC[C@H]([C@@H](CS)O)O.OP([O-])(O)=O.[K+]>CCO>[C:1]([C:5]1[C:6]([SH:19])=[CH:7][C:8]([CH3:18])=[C:9]([O:11][S:12](=[O:16])(=[O:17])[N:13]([CH3:14])[CH3:15])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cc(SC#N)c(C(C)(C)C)cc1OS(=O)(=O)N(C)C
Agent: O=P([O-])(O)O
Agent: O[C@H](CS)[C@H](O)CS
Agent: [K+]
Solvent: CCO
Product: Cc1cc(S)c(C(C)(C)C)cc1OS(=O)(=O)N(C)C

Procedure:
To a round bottom flask equipped with a magnetic stirrer and condenser were added 1.1 g (3.3 mmol) of dimethyl-sulfamic acid 5-tert-butyl-2-methyl-4-thiocyanato-phenyl ester (prepared in Example SSS), dithiothreitol (1.29 g, 8.35 mmol), EtOH (40 mL), and 0.02 M KH2PO4 buffer solution (5 mL), respectively. The reaction was refluxed overnight. The mixture was then quenched with H2O (250 mL) and extracted with a 1:1 mixture of hexanes:Et2O. The organic layer was again washed with H2O and brine, dried (MgSO4) and concentrated. The residue was dried under high vacuum to yield the title compound. 1H NMR (CDCl3) δ 1.45 (s, 9 H), 2.25 (s, 3 H), 3.02 (s, 6 H), 3.57 (s, 1 H), 7.01 (s, 1 H), 7.28 (s, 1 H).
Reaction SMILES: [CH3:1][NH:2][S:3]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10](=[O:15])[CH2:9]2)(=[O:5])=[O:4].[NH:16]1[C:20]2[CH:21]=[CH:22][C:23]([CH:25]=O)=[CH:24][C:19]=2[N:18]=[N:17]1>>[NH:16]1[C:20]2[CH:21]=[CH:22][C:23]([CH:25]=[C:9]3[C:8]4[C:12](=[CH:13][CH:14]=[C:6]([S:3]([NH:2][CH3:1])(=[O:5])=[O:4])[CH:7]=4)[NH:11][C:10]3=[O:15])=[CH:24][C:19]=2[N:18]=[N:17]1
Reactant: CNS(=O)(=O)c1ccc2c(c1)CC(=O)N2
Reactant: O=Cc1ccc2[nH]nnc2c1
Product: CNS(=O)(=O)c1ccc2c(c1)C(=Cc1ccc3[nH]nnc3c1)C(=O)N2
Yield: 25.5 %

Procedure:
The compound was synthesized according to the method described for Example A6 except reacting N-methyl-2-oxoindoline-5-sulfonamide (14 mg, 0.0618 mmol) with 1H-benzo[d][1,2,3]triazole-5-carbaldehyde (10 mg, 0.0680 mmol) to obtain 5.6 mg, 12% of the title compound as a mixture of (E) and (Z) isomers (69:21 by NMR). 1H NMR (400 MHz, d6-DMSO) δ 16.02, 16.00 (bs, 1H), 11.10, 11.15 (s, 1H), 8.55-8.10 (m, 2H), 7.95-7.80 (m, 3H), 7.77-7.60 (m, 1H), 7.27, 7.21 (q, J=5.2 Hz, 1H), 7.07, 7.03 (d, J=8.3 Hz, 1H), 2.44, 2.36 (s, 3H); MS ESI 356.1 [M+H]+, calcd for [C16H13N5O3S+H]+ 356.08.
Reaction SMILES: [Si]([O:18][CH2:19][C:20]1[CH:21]=[C:22]([CH:26]([S:34][CH2:35][CH2:36][C:37](=[O:41])[N:38]([CH3:40])[CH3:39])[S:27][CH2:28][CH2:29][C:30]([O:32][CH3:33])=[O:31])[CH:23]=[CH:24][CH:25]=1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C(OCC)(=O)C>C1COCC1>[OH:18][CH2:19][C:20]1[CH:21]=[C:22]([CH:26]([S:34][CH2:35][CH2:36][C:37](=[O:41])[N:38]([CH3:40])[CH3:39])[S:27][CH2:28][CH2:29][C:30]([O:32][CH3:33])=[O:31])[CH:23]=[CH:24][CH:25]=1
Reactant: COC(=O)CCSC(SCCC(=O)N(C)C)c1cccc(CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)CCSC(SCCC(=O)N(C)C)c1cccc(CO)c1

Procedure:
To a solution of (-)-methyl 5-(3-(t-butyldiphenylsilyloxymethyl)phenyl)-8-dimethylcarbamyl-4,6-dithiaoctanoate (step 5) (1.377 g, 2.26 mmol.) in THF (25 mL ) a t room temperature was slowly added tetra-n-butyl ammonium fluoride (1M) in THF (2.34 mL). The solution was stirred 2 hrs at room temperature Ethyl acetate was added to the reaction mixture, and the organic layer it was washed with brine (3×), dried over sodium sulfate, filtered and evaporated to dryness. Purification by flash chromatography using 40% acetone in hexane afforded the title compound.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].C(Cl)Cl.[C:10]1([C@H:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH2:19][CH2:18][NH:17]2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C(N(CC)CC)C>[C:10]1([C@H:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH2:19][CH2:18][N:17]2[C:2]([O:4][CH2:5][CH3:6])=[O:3])[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: CCOC(=O)Cl
Reactant: c1ccc([C@@H]2NCCc3ccccc32)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)N1CCc2ccccc2[C@@H]1c1ccccc1
Temperature: 27.5 °C
Reaction time: 1 h
Yield: 96.7 %

Procedure:
Ethyl chloroformate (5.61 g) was slowly added to a mixture of methylene chloride (100 ml), (1S)-1-phenyl-1,2,3,4-tetrahydroisoquinoline (10 g) and triethylamine (5.32 g) at 5-15° C. over a period of 30 min. Thereafter, the reaction mass was warmed to 25-30° C. and stirred at 25-30° C. for 1 h. The reaction solution was sequentially washed with water (50 ml), 3% w/w hydrochloric acid (50 ml), water (50 ml) and 5% w/w aqueous sodium chloride (50 ml) at 25-30° C. The solvent was removed under reduced pressure at 30-40° C. to produce (1S)-ethyl 1-phenyl-1,2,3,4-tetrahydro-2-isoquinolinecarboxylate (13.0 g) as a pale yellow oil. Chromatographic Purity (By HPLC): 99.22%.
Reaction SMILES: [H][H].C([N:10]1[CH2:15][CH:14]=[C:13]([C:16]2[C:17]([OH:28])=[N:18][C:19]3[C:24]([CH:25]=2)=[CH:23][C:22]([O:26][CH3:27])=[CH:21][CH:20]=3)[CH2:12][CH2:11]1)C1C=CC=CC=1.C1COCC1>[Pd].CO>[CH3:27][O:26][C:22]1[CH:23]=[C:24]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:28])[C:16]([CH:13]1[CH2:14][CH2:15][NH:10][CH2:11][CH2:12]1)=[CH:25]2
Reactant: [H][H]
Reactant: COc1ccc2nc(O)c(C3=CCN(Cc4ccccc4)CC3)cc2c1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc2[nH]c(=O)c(C3CCNCC3)cc2c1
Reaction time: 2 h

Procedure:
In a hydrogen atmosphere 160 mg (0.46 mmol) 3-(1-benzyl-1,2,3,6-tetrahydro-pyridin-4-yl)-6-methoxy-quinolin-2-ol and 20 mg palladium on charcoal (10%) in 30 mL MeOH were hydrogenated for 17.5 h at 50° C. at 50 psi. Then another 10 mL THF and catalyst were added and the mixture was hydrogenated for a further 2 h. Catalyst was added again and the mixture was hydrogenated overnight at 50° C. in a hydrogen atmosphere of 60 psi. After filtration of the reaction mixture the filter cake was washed with DMF and the filtrate was evaporated down. The residue was added to EtOAc, triturated with PE and filtered. The precipitate was washed with diisopropylether and dried.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@@H:3]1[N:8]1[C:12]2=[C:13]3[CH:19]=[CH:18][N:17](COCC[Si](C)(C)C)[C:14]3=[N:15][CH:16]=[C:11]2[N:10]([CH2:28][C:29]#[N:30])[C:9]1=[O:31].B(F)(F)F.CCOCC.C([O-])(=O)C.[Na+]>ClCCl>[CH3:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@@H:3]1[N:8]1[C:12]2=[C:13]3[CH:19]=[CH:18][NH:17][C:14]3=[N:15][CH:16]=[C:11]2[N:10]([CH2:28][C:29]#[N:30])[C:9]1=[O:31]
Reactant: C[C@@H]1CCCC[C@@H]1n1c(=O)n(CC#N)c2cnc3c(ccn3COCC[Si](C)(C)C)c21
Agent: CC(=O)[O-]
Agent: FB(F)F
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOCC
Product: C[C@@H]1CCCC[C@@H]1n1c(=O)n(CC#N)c2cnc3[nH]ccc3c21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 22.7 %

Procedure:
To a solution of {1-[(1S,2R)-2-methylcyclohexyl]-2-oxo-6-{[2-(trimethylsilyl)ethoxy]methyl}-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-3(2H)-yl}acetonitrile (25 mg) in dichloromethane (1 mL) was added boron trifluoride etherate (35.7 μl) dropwise at 4° C. The mixture was stirred at ambient temperature for 0.5 hour. To the mixture was added 5.5M sodium acetate aqueous solution (0.207 mL) and the mixture was stirred at 80° C. for 4 hours. The mixture was extracted with chloroform and washed with water. The extract was dried over MgSO4, filtrated and concentrated under reduced pressure. The residue was purified by column chromatography on NH silica gel with EtOAc and n-hexane (50:50 to 95:5) to give {1-[(1S,2R)-2-methylcyclohexyl]-2-oxo-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-3(2H)-yl}acetonitrile (4 mg) as a white powder.
Reaction SMILES: [C:1]1([C:7]2[N:11]=[C:10]([N:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[S:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[CH2:25]1[O:33][C:32]2[CH:31]=[CH:30][C:29]([N:34]=[C:35]=[O:36])=[CH:28][C:27]=2[O:26]1>O1CCCC1>[O:33]1[C:32]2[CH:31]=[CH:30][C:29]([NH:34][C:35]([N:15]3[CH2:16][CH2:17][N:12]([C:10]4[S:9][N:8]=[C:7]([C:1]5[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=5)[N:11]=4)[CH2:13][CH2:14]3)=[O:36])=[CH:28][C:27]=2[O:26][CH2:25]1
Reactant: O=C=Nc1ccc2c(c1)OCO2
Reactant: c1ccc(-c2nsc(N3CCNCC3)n2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc2c(c1)OCO2)N1CCN(c2nc(-c3ccccc3)ns2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.9 %

Procedure:
To a solution of 1-(3-phenyl-1,2,4-thiadiazol-5-yl)piperazine (200 mg, 0.812 mmol) and triethylamine (0.113 ml, 0.812 mmol) in tetrahydrofuran (2 ml) was added 3,4-(methylenedioxy)phenyl isocyanate (199 mg, 1.22 mmol) at room temperature, and the mixture was stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure. The residue was recrystallized from a mixed solvent of hexane and tetrahydrofuran to give 239 mg (71.9%) of the desired product as a solid.
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:7](CC2C=CC([N+]([O-])=O)=CC=2)[C:6]([O:18][CH3:19])=[N:5][CH:4]=1.[C:20]([C:23]1[CH:47]=[CH:46][CH:45]=[CH:44][C:24]=1[C:25]([NH:27][C:28]1[CH:43]=[CH:42][C:31]([CH2:32]N2C(CO)=CN=C2OC)=[CH:30][CH:29]=1)=[O:26])([OH:22])=[O:21]>>[C:20]([C:23]1[CH:47]=[CH:46][CH:45]=[CH:44][C:24]=1[C:25]([NH:27][C:28]1[CH:29]=[CH:30][C:31]([CH2:32][C:4]2[N:5]=[C:6]([O:18][CH3:19])[NH:7][C:3]=2[CH2:2][OH:1])=[CH:42][CH:43]=1)=[O:26])([OH:22])=[O:21]
Reactant: COc1ncc(CO)n1Cc1ccc([N+](=O)[O-])cc1
Reactant: COc1ncc(CO)n1Cc1ccc(NC(=O)c2ccccc2C(=O)O)cc1
Product: COc1nc(Cc2ccc(NC(=O)c3ccccc3C(=O)O)cc2)c(CO)[nH]1

Procedure:
By repeating Example 72, Parts C and D, but substituting 5-hydroxymethyl-2-methoxy-1-(4-nitrobenzyl)imidazole as starting material in Part C, the compound 1-[4-(2-carboxybenzamido)benzyl]-5-hydroxymethyl-2-methoxyimidazole can be prepared.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:31]=[CH:32][C:33]=1[O:34][CH3:35])[CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([O:18][CH3:19])=[C:14]([OH:17])[CH:15]=2)[CH2:10][CH2:9][N:8]1[CH2:20][C:21]([NH:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22].[CH2:36](Br)[CH2:37][CH2:38][CH3:39]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:31]=[CH:32][C:33]=1[O:34][CH3:35])[CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([O:18][CH3:19])=[C:14]([O:17][CH2:36][CH2:37][CH2:38][CH3:39])[CH:15]=2)[CH2:10][CH2:9][N:8]1[CH2:20][C:21]([NH:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22]
Reactant: CCCCBr
Reactant: COc1cc2c(cc1O)C(Cc1ccc(OC)c(OC)c1)N(CC(=O)NCc1ccccc1)CC2
Product: CCCCOc1cc2c(cc1OC)CCN(CC(=O)NCc1ccccc1)C2Cc1ccc(OC)c(OC)c1

Procedure:
prepared by reaction of 2-[1-(3,4-dimethoxy-benzyl)-7-hydroxy-6-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-benzyl-acetamide with butyl bromide