Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:28])[CH2:4][CH2:5][CH2:6][N:7]1[CH2:11][CH2:10][CH2:9][C@H:8]1[CH2:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)=[CH:16][CH:15]=1.[OH-].[Na+]>CO>[ClH:27].[Cl:27][C:24]1[CH:25]=[CH:26][C:21]([O:20][C:17]2[CH:18]=[CH:19][C:14]([O:13][CH2:12][C@@H:8]3[CH2:9][CH2:10][CH2:11][N:7]3[CH2:6][CH2:5][CH2:4][C:3]([OH:28])=[O:2])=[CH:15][CH:16]=2)=[CH:22][CH:23]=1
Reactant: COC(=O)CCCN1CCC[C@H]1COc1ccc(Oc2ccc(Cl)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cl
Product: O=C(O)CCCN1CCC[C@H]1COc1ccc(Oc2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of the product from step 5 (2.20 g, 5.45 mmol) in MeOH (22 mL) was added 2N NaOH (7.23 mL, 14.5 mmol). The resulting purplish-pink solution was stirred at ambient temperature overnight. The solvent was removed in vacuo. The crude oil was dissolved in water (45 mL) and the pH was adjusted to 7 with 2N HCl solution. The crude residue was extracted into ethyl acetate. The combined organic portions were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude product was purified by silica gel flash chromatography using MeOH/dichloromethane (gradient system) to give the free base of the title compound as a yellow oil. To the subsequent oil was added 2M HCl in diethyl ether (35 mL). The resulting mixture was stirred at ambient temperature for 2 hours. The solvents were decanted. The remaining white solid was triturated in diethyl ether (50 mL) for 1 hour. The slurry was filtered, washed with diethyl ether (25 mL×3) and dried in vacuo at 45° C. for 48 hours to afford the title compound as a white solid (0.84 g, 36%).
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]([C:5]1[CH:6]=[CH:7][C:8]([OH:16])=[C:9](CS(N)(=O)=O)[CH:10]=1)[OH:4].C(N(C(C)C)CC)(C)C.Br[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][O:33][CH2:34][CH2:35][CH2:36][CH2:37][C:38]1[CH:39]=[C:40]([S:44]([NH2:47])(=[O:46])=[O:45])[CH:41]=[CH:42][CH:43]=1>CN(C)C=O>[CH:8]([OH:16])=[O:33].[OH:4][C@H:3]([C:5]1[CH:6]=[CH:7][C:8]([OH:16])=[C:9]([NH:47][S:44]([CH3:40])(=[O:46])=[O:45])[CH:10]=1)[CH2:2][NH:1][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][O:33][CH2:34][CH2:35][CH2:36][CH2:37][C:38]1[CH:39]=[C:40]([S:44]([NH2:47])(=[O:46])=[O:45])[CH:41]=[CH:42][CH:43]=1
Reactant: NS(=O)(=O)c1cccc(CCCCOCCCCCCBr)c1
Reactant: NC[C@H](O)c1ccc(O)c(CS(N)(=O)=O)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CS(=O)(=O)Nc1cc([C@@H](O)CNCCCCCCOCCCCc2cccc(S(N)(=O)=O)c2)ccc1O
Product: O=CO
Yield: 18.1 %

Procedure:
A stirred solution of 1-{5-[(1R)-2-amino-1-hydroxyethyl]-2-hydroxyphenyl}methanesulfonamide (65 mg), diisopropylethylamine (0.06 ml) and 3-{4-[(6-bromohexyl)oxy]butyl}benzenesulfonamide (86 mg) in N,N-dimethylformamide (1 ml) under nitrogen was heated to 50° for 48 h. The mixture was cooled to 20°, the solvent evaporated in vacuo and the residue purified by mass-directed autopreparative HPLC to give the title compound (12 mg). LCMS RT=2.31 min ES+ve 558 (MH)+.
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[N:6][C:7]([CH3:22])=[CH:8][C:9]=2[NH:11][S:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=2)(=[O:14])=[O:13])[S:4][C:3]=1[C:23]1[CH:24]=[N:25][N:26](C(OC(C)(C)C)=O)[CH:27]=1.[CH3:35][O:36][C:37]1[CH:38]=[C:39](B2OC(C)(C)C(C)(C)O2)[CH:40]=[C:41]([O:43][CH3:44])[CH:42]=1.C(=O)([O-])[O-].[K+].[K+].O1CCOCC1>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.O.CN(C=O)C>[CH3:35][O:36][C:37]1[CH:38]=[C:39]([C:2]2[C:10]3[C:5](=[N:6][C:7]([CH3:22])=[CH:8][C:9]=3[NH:11][S:12]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=3)(=[O:13])=[O:14])[S:4][C:3]=2[C:23]2[CH:27]=[N:26][NH:25][CH:24]=2)[CH:40]=[C:41]([O:43][CH3:44])[CH:42]=1
Reactant: Cc1cc(NS(=O)(=O)c2cccc(Cl)c2)c2c(Br)c(-c3cnn(C(=O)OC(C)(C)C)c3)sc2n1
Reactant: COc1cc(OC)cc(B2OC(C)(C)C(C)(C)O2)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: C1COCCO1
Product: COc1cc(OC)cc(-c2c(-c3cn[nH]c3)sc3nc(C)cc(NS(=O)(=O)c4cccc(Cl)c4)c23)c1
Temperature: 110 °C
Yield: 48.6 %

Procedure:
A mixture of 1,1-dimethylethyl 4-(3-bromo-4-{[(3-chlorophenyl)sulfonyl]amino}-6-methylthieno[2,3-b]pyridin-2-yl)-1H-pyrazole-1-carboxylate (Description 75) (100 mg, 0.171 mmol), 3,5-dimethoxyphenylboronic acid pinacol ester (90 mg, 0.343 mmol), potassium carbonate (95 mg, 0.685 mmol) and tetrakis(triphenylphosphine)palladium(0) (3.96 mg, 3.43 μmol) were weighed into a microwave vial. 1,4-Dioxane (1.5 mL), DMF (0.75 mL) and water (0.38 mL) were added and the mixture heated in a microwave at 110° C. for 30 min. At this point, both reaction mixtures were combined and concentrated. The residue was passed through an SCX cartridge, eluting with MeOH (75 mL) and then with 2M NH3 in MeOH (100 mL). The basic methanolic solution was concentrated and purified by MDAP (acidic conditions), to give the title compound (45 mg). LCMS (A) m/z: 541 [M+1]+, Rt 1.26 min (acidic).
Reaction SMILES: [CH2:1]([N:8]1[C:12]2=[C:13]([N:18]3[CH2:27][CH2:26][C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[CH2:19]3)[N:14]=[C:15](Cl)[CH:16]=[C:11]2[C:10]([CH3:28])=[C:9]1[CH3:29])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[SH-:30].[Na+].O>CO>[CH2:1]([N:8]1[C:12]2=[C:13]([N:18]3[CH2:27][CH2:26][C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[CH2:19]3)[N:14]=[C:15]([SH:30])[CH:16]=[C:11]2[C:10]([CH3:28])=[C:9]1[CH3:29])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1c(C)n(Cc2ccccc2)c2c(N3CCc4ccccc4C3)nc(Cl)cc12
Reactant: [SH-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: Cc1c(C)n(Cc2ccccc2)c2c(N3CCc4ccccc4C3)nc(S)cc12
Reaction time: 0.5 h
Yield: 70.9 %

Procedure:
A solution of 2-(1-benzyl-5-chloro-2,3-dimethyl-1H-pyrrolo[2,3-c]pyridin-7-yl)-1,2,3,4-tetrahydroisoquinoline (100 mg, 0.24 mmol) prepared in Example 658 and sodium hydrosulfide (26.7 mg, 0.48 mmol) in methanol (2 ml) was refluxed for 2 hours. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was dried on anhydrous magnesium sulfate and then concentrated under reduced pressure. Water was added to the resulting solid. The reaction mixture was stirred for 30 minutes and then filtered. The resulting solid washed with water 3 times and then dried to give 68 mg of the titled compound as a pale yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16](S(C)=O)[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:28]=[CH:29][C:30]=3[CH3:31])[C:22]([NH:24][CH:25]([CH3:27])[CH3:26])=[O:23])[C:13]=2[CH2:12][NH:11][C:10]1=[O:35].[CH3:36][CH:37]([NH:39][CH2:40][CH2:41][NH2:42])[CH3:38]>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([NH:42][CH2:41][CH2:40][NH:39][CH:37]([CH3:38])[CH3:36])[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:28]=[CH:29][C:30]=3[CH3:31])[C:22]([NH:24][CH:25]([CH3:27])[CH3:26])=[O:23])[C:13]=2[CH2:12][NH:11][C:10]1=[O:35]
Reactant: Cc1ccc(C(=O)NC(C)C)cc1-c1nc(S(C)=O)nc2c1CNC(=O)N2c1c(F)cccc1F
Reactant: CC(C)NCCN
Solvent: C1CCOC1
Product: Cc1ccc(C(=O)NC(C)C)cc1-c1nc(NCCNC(C)C)nc2c1CNC(=O)N2c1c(F)cccc1F
Yield: 71.3 %

Procedure:
To a solution of compound 3-[8-(2,6-difluorophenyl)-2-(methylsulfinyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methyl-N-(1-methylethyl)benzamide (30 mg, 0.06 mmol) in THF (3 mL) was added N-(1-methylethyl)-1,2-ethanediamine (0.019 mL, 0.15 mmol). The resultant solution was stirred at room temperature over night. The result mixture was concentrated. CombiFlash chromatography (mobile phase DCM/DCM[90]+MeOH [7]+NH4OH[3]) provided the title compound as a white solid (23 mg, 71%). LC-MS m/z 538 (M+H)+; 1H-NMR (MeOD) δ 1.00 (d, 3H), 1.27 (d, 3H), 2.30 (s, 3H), 2.58 (m, 2H), 2.70 (m, 1H), 3.25 (m, 2H), 4.07 (s, 2H), 4.23 (m, 1H), 7.16 (m, 2H), 7.44 (d, 1H), 7.50 (m, 1H), 7.69 (s, 1H), 7.85 (d, 1H).
Reaction SMILES: [C:1]([C@@:4]1([CH3:15])[CH2:8][CH2:7][C@@H:6]([C:9]([O:11][CH3:12])=[O:10])[C:5]1([CH3:14])[CH3:13])(=O)[NH2:2].N1C(Cl)=NC(Cl)=NC=1Cl>CN(C=O)C>[C:1]([C@@:4]1([CH3:15])[CH2:8][CH2:7][C@@H:6]([C:9]([O:11][CH3:12])=[O:10])[C:5]1([CH3:14])[CH3:13])#[N:2]
Reactant: COC(=O)[C@@H]1CC[C@](C)(C(N)=O)C1(C)C
Agent: Clc1nc(Cl)nc(Cl)n1
Solvent: CN(C)C=O
Product: COC(=O)[C@@H]1CC[C@](C)(C#N)C1(C)C
Reaction time: 14 h
Yield: 90.7 %

Procedure:
To a solution of (1R,3S)-methyl 3-carbamoyl-2,2,3-trimethylcyclopentane carboxylate (4.49 g, 21.05 mmol) in DMF (35 ml) at room temperature was added cyanuric chloride (2.329 g, 12.63 mmol). The reaction mixture was stirred for 14 hrs. The reaction solution was partitioned between water and ethyl acetate. The ethyl acetate extracts were combined, washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure, yielding (1R,3S)-methyl 3-cyano-2,2,3-trimethylcyclopentanecarboxylate (3.73 g, 19.10 mmol, 91% yield) as a white solid. ESI-MS m/z 218.2 ([M+H]+).
Reaction SMILES: [F:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[N:9]([C:16]3[S:17][C:18]([C:22](O)=[O:23])=[C:19]([CH3:21])[N:20]=3)[C:8]2=[O:25])=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[CH2:60]([NH2:67])[C:61]1[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=1>CN(C)C=O>[CH2:60]([NH:67][C:22]([C:18]1[S:17][C:16]([N:9]2[C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:7]([CH2:6][C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:27][CH:26]=3)[C:8]2=[O:25])=[N:20][C:19]=1[CH3:21])=[O:23])[C:61]1[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=1
Reactant: Cc1nc(-n2c(=O)n(Cc3ccc(F)cc3)c3ccccc32)sc1C(=O)O
Reactant: NCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1nc(-n2c(=O)n(Cc3ccc(F)cc3)c3ccccc32)sc1C(=O)NCc1ccccc1
Reaction time: 0.17 h

Procedure:
To a solution of 2-(3-(4-fluorobenzyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-4-methylthiazole-5-carboxylic acid in N,N-dimethylformamide is added N,N-diisopropylethylamine, followed by the addition of 1-hydroxybenzotriazole monohydrate and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride. The resulting mixture is stirred for 10 minutes and followed by the addition of benzylamine at ambient temperature. After stirred at ambient temperature for an additional 17 h, the mixture is concentrated in vacuo. The residue is poured into a saturated aqueous solution of sodium bicarbonate and then extracted with ethyl acetate. The organic layer is washed with saturated aqueous sodium bicarbonate solution, water and brine, dried over sodium sulfate, and filtered. The filtrate is concentrated and purified by column chromatography to afford the title compound.
Reaction SMILES: [Cl:1][C:2]1[S:18][C:5]2[NH:6][C:7](=[O:17])[C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[C:9]([OH:10])[C:4]=2[C:3]=1[C:19]1[C:20]([OH:29])=[C:21]2[C:26](=[CH:27][CH:28]=1)[CH2:25][CH2:24][CH2:23][CH2:22]2.C[O-].[Na+:32].O>CO.O1CCCC1>[Cl:1][C:2]1[S:18][C:5]2[NH:6][C:7](=[O:17])[C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[C:9]([O-:10])[C:4]=2[C:3]=1[C:19]1[C:20]([OH:29])=[C:21]2[C:26](=[CH:27][CH:28]=1)[CH2:25][CH2:24][CH2:23][CH2:22]2.[Na+:32]
Reactant: O=c1[nH]c2sc(Cl)c(-c3ccc4c(c3O)CCCC4)c2c(O)c1-c1ccccc1
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: O=c1[nH]c2sc(Cl)c(-c3ccc4c(c3O)CCCC4)c2c([O-])c1-c1ccccc1

Procedure:
2-chloro-4-hydroxy-3-(5-hydroxytetralin-6-yl)-5-phenyl-7H-thieno[2,3-b]pyridin-6-one (4.0 g, 9.44 mmol) was dissolved in a mixture of methanol/tetrahydrofuran (25 ml/25 mL). Sodium methoxide solution (30% in methanol) (1.75 mL, 9.44 mmol) was slowly added followed by water (15 ml). Organic solvents were removed under reduced pressure. The remaining aqueous solution was lyophilized to give a grey solid (4.80 g, 100%, compound crystallized with 4 water molecules).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[NH2:6].[F:12][C:13]1[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:14]=1>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:6][S:19]([C:16]2[CH:17]=[CH:18][C:13]([F:12])=[CH:14][CH:15]=2)(=[O:21])=[O:20])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: COc1ccc(N)cc1OC
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Solvent: c1ccncc1
Product: COc1ccc(NS(=O)(=O)c2ccc(F)cc2)cc1OC
Reaction time: 8 h

Procedure:
3,4-Dimethoxyaniline(1.01 g, 6.99 mM) was added to a solution of 4-Fluorobenzenesulfonyl chloride (1.50 g, 7.69 mM) in anhydrous pyridine(10 ml). The reaction was stirred overnight. The reaction was quenched with 1N HClaq.(20 ml) and washed with ethyl acetate(3×20 ml). The organic extracts were combined, dried(sodium sulfate), solids filtered off and concentrated. The desired product was isolated using silica gel flash chromatography of 1.30 g as a yellow solid. H1 NMR(CDCl3) δ 3.79(s, 3H), 3.86(s, 3H), 6.50(d, 1H, J=4.71 Hz), 6.68(d, 1H, J=2.64 Hz), 6.71(d, 1H, J=2.76 Hz), 7.11(d, 2H, J=8.67 Hz), 7.75(m, 2H). MS(ES) m/z 328.9; (M+NH4+); HRMS for (MH+) C14H14SFNO4: 260.1511.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12](=[O:13])[CH2:11][S:10]/[C:9]/1=[N:14]\[CH:15]([CH3:17])[CH3:16].[O:18]1[C:23]2[CH:24]=[CH:25][C:26]([CH:28]=O)=[CH:27][C:22]=2[O:21][CH2:20][CH2:19]1.C([O-])(=O)C.[Na+]>C(O)(=O)C>[O:18]1[C:23]2[CH:24]=[CH:25][C:26](/[CH:28]=[C:11]3/[C:12](=[O:13])[N:8]([C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=4[CH3:1])/[C:9](=[N:14]/[CH:15]([CH3:17])[CH3:16])/[S:10]/3)=[CH:27][C:22]=2[O:21][CH2:20][CH2:19]1
Reactant: O=Cc1ccc2c(c1)OCCO2
Reactant: Cc1ccccc1N1C(=O)CS/C1=N\C(C)C
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: Cc1ccccc1N1C(=O)/C(=C/c2ccc3c(c2)OCCO3)S/C1=N\C(C)C
Temperature: 25 °C

Procedure:
A solution of 3-(2-methyl phenyl)-2-[(Z)-isopropylimino]-thiazolidin-4-one (50 mg, 0.200 mmol), 2,3-dihydro-benzo[1,4]dioxine-6-carbaldehyde (49 mg, 0.300 mmol) and sodium acetate (33 mg, 0.400 mmol) in acetic acid (1 mL) is stirred at 110° C. for 5 h. The reaction mixture is cooled to rt and subjected to prep. HPLC purification. The product containing fractions are evaporated and dried to give 5-(2,3-dihydro-benzo[1,4]dioxin-6-ylmeth-(Z)-yl idene)-2-[(Z)-isopropylimino]-3-o-tolyl-thiazolidin-4-one.
Reaction SMILES: [NH:1]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C@H:2]([C:19]([OH:21])=[O:20])[CH2:3][C:4]1[N:8]=[CH:7][N:6]([S:9]([C:12]2[CH:18]=[CH:17][C:15]([CH3:16])=[CH:14][CH:13]=2)(=[O:11])=[O:10])[CH:5]=1.C[O:30][C:31](=O)[C@H:32]([CH2:34][CH:35]1[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1)[NH2:33].[BH4-].[Li+]>C1COCC1.C(O)C>[NH:1]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C@H:2]([C:19]([OH:21])=[O:20])[CH2:3][C:4]1[N:8]=[CH:7][N:6]([S:9]([C:12]2[CH:13]=[CH:14][C:15]([CH3:16])=[CH:17][CH:18]=2)(=[O:11])=[O:10])[CH:5]=1.[CH:35]1([CH2:34][C@@H:32]([CH2:31][OH:30])[NH2:33])[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1
Reactant: COC(=O)[C@@H](N)CC1CCCCC1
Agent: Cc1ccc(S(=O)(=O)n2cnc(C[C@H](NC(=O)OC(C)(C)C)C(=O)O)c2)cc1
Agent: [BH4-]
Agent: [Li+]
Solvent: CCO
Solvent: C1CCOC1
Product: N[C@H](CO)CC1CCCCC1

Procedure:
The extract is dried over MgSO4 and evaporated to dryness in vacuo to quantitatively obtain 3-cyclohexylalanine methyl ester [16a] as an oil. The product is then, without further purification, dissolved in dichloromethane (50 ml). To the solution are added Boc-His(Ts).DCHA [8a](10.7 g, 18.11 mmol, 1.3 eq) and diethyl cyanophosphonate (2.95 g, 18.1 mmol, 1.3 eq), and the mixture is stirred for 1.5 hours at room temperature. The reaction mixture is subjected to silica gel chromatography (SiO2 :300 g, CH2Cl2 :MeOH=99:1) to give a purified Boc-His(Ts)-3-cyclohexylalanine methyl ester [17a] (7.43 g, 93%) as an oil. To a solution of the dipeptide ester [17a](3.0 g, 5.2mmol) in THF (6 ml) and ethanol (6 ml) is added a 2N solution of lithium borohydride in THF (3 ml, 6 mmol) with stirring and ice-cooling. After 20 minutes stirring, the mixture is allowed to react at room temperature for additional one hour. The solvent is removed in vacuo and the residue added ice water and saturated aqueous ammonium chloride is extracted with dichloromethane (20 ml×3). The organic layer is washed with saturated aqueous sodium chloride, dried over MgSO4, evaporated to dryness in vacuo and the residue is purified by silica gel chromatography (SiO2 : 200 g, CH2Cl2 :MeOH=98:2) to obtain Boc-His(Ts)-3-cyclohexyl-alaninol [18a] (2.06 g, 72%) as an oil.
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH:8][CH:9]=O)=[C:6]([NH:11][O:12][CH2:13][CH2:14][CH2:15][P:16]([O:21][CH2:22][CH3:23])([O:18][CH2:19][CH3:20])=[O:17])[N:5]=[C:4]([NH:24][CH:25]=[O:26])[N:3]=1.N>C(OC(OCC)OCC)(=O)C.CO>[Cl:1][C:2]1[N:3]=[C:4]([NH:24][CH:25]=[O:26])[N:5]=[C:6]2[C:7]=1[N:8]=[CH:9][N:11]2[O:12][CH2:13][CH2:14][CH2:15][P:16]([O:21][CH2:22][CH3:23])([O:18][CH2:19][CH3:20])=[O:17]
Reactant: CCOP(=O)(CCCONc1nc(NC=O)nc(Cl)c1NC=O)OCC
Agent: CCOC(OCC)OC(C)=O
Agent: N
Solvent: CO
Product: CCOP(=O)(CCCOn1cnc2c(Cl)nc(NC=O)nc21)OCC
Reaction time: 1 h

Procedure:
A solution of 4-chloro-6-[[3-(diethoxyphosphoryl)-propoxy]amino]-2,5-diformamidopyrimidine (1.1 g, 2.7 mmol) in diethoxymethyl acetate (15 ml) was heated at 120° C. for 2 hours. The solution was then cooled, evaporated to dryness under reduced pressure and the residue obtained dissolved in methanol (10 ml) and 880 ammonia (1 ml). After standing at ambient temperature for 1 hr, the solvent was removed. The residue was chromatographed on silica gel (dichloromethane-methanol (98:2) as eluant) to give the title compound as a colorless oil which crystallised on standing, mp. 121°-124°, (1.01 g, 95%). IR: υmax (KBr) 1700, 1618, 1577, 1506, 1439, 1405, 1383, 1328, 1259, 1242, 1226, 1165, 1052, 1024, 972, 918 cm-1. 1H NMR: δH ((CD3)2SO) 1.21 (6H, t, J=7Hz, (O--CH2CH3)2), 1.75-2.1 (4H, m, CH2CH2P), 3.99 (4H, m, (OCH2CH3)2), 4.47 (2H, t, J=6Hz, N--OCH2), 8.83 (1Y, s, H--8), 9.37 (1H, s, CHO), 11.30 (1H, bs, D2O exchangeable, NHCHO). Found: C, 39.82; H, 4.96; N, 17.65%. C13H19N5O5ClP requires: C, 39.85; H, 4.89; N, 17.88%. m/z: C13H20N5O5PCl requires: 392.0890. Observed: 392.0888 (MH+).
Reaction SMILES: [C:1](=O)(OC(Cl)(Cl)Cl)[O:2]C(Cl)(Cl)Cl.[CH3:13][N:14]1[CH2:18][CH2:17][C@H:16]([NH2:19])[CH2:15]1.[CH3:20][O:21][C:22]1[CH:23]=[CH:24][CH:25]=[C:26]2[C:31]=1[CH:30]([NH:32][C:33]1[CH:42]=[CH:41][C:40]3[C:35](=[CH:36][CH:37]=[C:38]([NH2:43])[CH:39]=3)[N:34]=1)[CH2:29][CH2:28][CH2:27]2>>[CH3:20][O:21][C:22]1[CH:23]=[CH:24][CH:25]=[C:26]2[C:31]=1[CH:30]([NH:32][C:33]1[CH:42]=[CH:41][C:40]3[C:35](=[CH:36][CH:37]=[C:38]([NH:43][C:1]([NH:19][C@H:16]4[CH2:17][CH2:18][N:14]([CH3:13])[CH2:15]4)=[O:2])[CH:39]=3)[N:34]=1)[CH2:29][CH2:28][CH2:27]2
Reactant: COc1cccc2c1C(Nc1ccc3cc(N)ccc3n1)CCC2
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CN1CC[C@H](N)C1
Product: COc1cccc2c1C(Nc1ccc3cc(NC(=O)N[C@H]4CCN(C)C4)ccc3n1)CCC2

Procedure:
The title compound was prepared in accordance with the general method 4 described in example 16 from bis(trichloromethyl) carbonate, (3S)-1-methyl-3-pyrrolidinamine (CAS no. 214357-95-6) and rac-N2-(8-methoxy-1,2,3,4-tetrahydro-naphthalen-1-yl)-quinoline-2,6-diamine; MS: m/e=446.2 (M+H+).
Reaction SMILES: [CH:1]1([S:4]([NH:7][C@@H:8]2[CH2:12][C@H:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C@H:10]([CH2:18][CH3:19])[CH2:9]2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.NC1CC(C(OCC)=O)C(CC)C1.C1(S(Cl)(=O)=O)CC1>>[CH:1]1([S:4]([NH:7][CH:8]2[CH2:12][CH:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:10]([CH2:18][CH3:19])[CH2:9]2)(=[O:6])=[O:5])[CH2:2][CH2:3]1
Reactant: CCOC(=O)[C@H]1C[C@@H](NS(=O)(=O)C2CC2)C[C@H]1CC
Agent: CCOC(=O)C1CC(N)CC1CC
Agent: O=S(=O)(Cl)C1CC1
Product: CCOC(=O)C1CC(NS(=O)(=O)C2CC2)CC1CC

Procedure:
The precursor to Preparation #Z.1, (1S,2R,4S)-ethyl 4-(cyclopropanesulfonamido)-2-ethylcyclopentane-carboxylate, was prepared (as shown in Scheme B) by initially reacting ethyl 4-amino-2-ethylcyclopentanecarboxylate (Preparation #Y.1) with the commercially available cyclopropanesulfonyl chloride, following the conditions given in General Procedure K, to give ethyl 4-(cyclopropanesulfonamido)-2-ethylcyclopentane-carboxylate as a mixture of stereoisomers. This mixture of stereoisomers is separated as described in General Procedure AA, using the conditions from Method 1 in Table 2, to give the precursor to Preparation #Z.1, (1S,2R,4S)-ethyl 4-(cyclopropanesulfonamido)-2-ethylcyclopentane-carboxylate as a single enantiomer with a retention time of 9.5 minutes and a negative optical rotation. The reaction sequence to synthesize the precursor to Preparation #Z.1, (1S,2R,4S)-ethyl 4-(cyclopropanesulfonamido)-2-ethylcyclopentane-carboxylate, (detailed above) is consequently translated in the preparations and examples section to: (1S,2R,4S)-ethyl 4-(cyclopropanesulfonamido)-2-ethylcyclopentane-carboxylate (prepared using K from Preparation #Y.1 and cyclopropanesulfonyl chloride, AA [Table 2, Method 1, Rt=9.5 min, or =negative]). Hence the Preparation #Z.1 would be written as: Preparation #Z.1 was prepared from (1S,2R,4S)-ethyl 4-(cyclopropanesulfonamido)-2-ethylcyclopentane carboxylate (prepared using K from Preparation #Y.1 and cyclopropanesulfonyl chloride, AA [Table 2, Method 1, Rt=9.5 min, or =negative]) using General Procedure Z.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11]Cl)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[Cl:14][CH2:15]CCCN>>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:15][Cl:14])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: NCCCCCl
Reactant: CC(C)(C)OC(=O)NCCCCl
Agent: Cl
Product: CC(C)(C)OC(=O)NCCCCCl

Procedure:
This compound, employed as the starting material in example 2, is prepared by following substantially the same procedure described above under (a) but using 4-chloro-butylamine hydrochloride instead of 3-chloro-propylamine hydrochloride.
Reaction SMILES: [CH2:1]([N:5]1[C:13](=[O:14])[N:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]2=[N:6]1)[CH2:2][C:3]#[CH:4].Br[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1>>[N:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[C:4]#[C:3][CH2:2][CH2:1][N:5]1[C:13](=[O:14])[N:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]2=[N:6]1
Reactant: C#CCCn1nc2ccccn2c1=O
Reactant: Brc1ccccn1
Product: O=c1n(CCC#Cc2ccccn2)nc2ccccn12
Yield: 23513.5 %

Procedure:
The title compound was prepared in accordance with the general method of Example 1, from 2-(but-3-ynyl)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one (70 mg, 0.37 mmol) and 2-bromopyridine (65 mg, 0.41 mmol). The crude residue was purified by flash chromatography (DCM/MeOH 98:2) to yield 23 mg (87 mmol, 23%) of 2-(4-(pyridin-2-yl)but-3-ynyl)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one as a yellow solid (M.P.=95.5-96° C.).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:8][CH:9]([NH:11][CH2:12][CH2:13][CH:14]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH3:10])[CH:5]=[CH:6][CH:7]=1.CS(C)=O.[OH-].[Na+].[Cl:33][C:34]1[CH:41]=[CH:40][C:37]([CH2:38]Cl)=[CH:36][CH:35]=1>O>[ClH:33].[Cl:33][C:34]1[CH:41]=[CH:40][C:37]([CH2:38][O:1][C:2]2[CH:3]=[C:4]([CH2:8][CH:9]([NH:11][CH2:12][CH2:13][CH:14]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH3:10])[CH:5]=[CH:6][CH:7]=2)=[CH:36][CH:35]=1
Reactant: ClCc1ccc(Cl)cc1
Reactant: CC(Cc1cccc(O)c1)NCCC(c1ccccc1)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: CC(Cc1cccc(OCc2ccc(Cl)cc2)c1)NCCC(c1ccccc1)c1ccccc1
Product: Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
The mixture of 17.3 g of 1-(3-hydroxyphenyl)-2-(3,3-diphenylpropylamino)-propane, 100 ml of dimethylsulfoxide and 5 ml of 10 N-aqueous sodium hydroxide is stirred at room temperature for 1/2 hour, combined with 8.05 g of 4-chlorobenzyl chloride and stirred 16 hours longer. It is poured into water, extracted with ethyl acetate, the extract washed with saturated aqueous sodium chloride, dried and evaporated. The residue is taken up in diethyl ether, the solution acidified with isopropanolic hydrogen chloride, the precipitate collected and washed with diethyl ether, to yield the 1-[3-(4-chlorobenzyloxy)-phenyl]-2-(3,3-diphenylpropylamino)-propane hydrochloride melting at 184°-189°.