Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:45])[CH2:3][C:4]([N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([NH:15][C:16]3[N:29]4[C:20](=[N:21][C:22]5[C:27]([C:28]4=[O:30])=[C:26]([F:31])[CH:25]=[CH:24][CH:23]=5)[C:19]4[CH:32]=[CH:33][N:34](S(C5C=CC(C)=CC=5)(=O)=O)[C:18]=4[N:17]=3)[CH:13]=2)[CH2:8][CH2:7]1)=[O:5].[CH3:46][NH2:47].C1COCC1.C(=O)(O)[O-].[Na+].CCOC(C)=O>O1CCCC1>[CH3:1][N:2]([CH3:45])[CH2:3][C:4]([N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([NH:15][C:16]3[NH:17][C:18]4=[N:34][CH:33]=[CH:32][C:19]4=[C:20]([NH:21][C:22]4[CH:23]=[CH:24][CH:25]=[C:26]([F:31])[C:27]=4[C:28]([NH:47][CH3:46])=[O:30])[N:29]=3)[CH:13]=2)[CH2:8][CH2:7]1)=[O:5]
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c2nc(Nc2ccc4c(c2)N(C(=O)CN(C)C)CC4)n2c(=O)c4c(F)cccc4nc32)cc1
Reactant: CN
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CNC(=O)c1c(F)cccc1Nc1nc(Nc2ccc3c(c2)N(C(=O)CN(C)C)CC3)[nH]c2nccc1-2
Temperature: 120 °C
Yield: 41.2 %

Procedure:
A suspension of 5-chloro-8-fluoro-3-[(4-methylphenyl)sulfonyl]pyrrolo[2′,3′:4,5]pyrimido[6,1-b]quinazolin-7(3H)-one hydrogen chloride (0.600 g, 1.252 mmol) and 1-[(dimethylamino)acetyl]-2,3-dihydro-1H-indol-6-amine (0.274 g, 1.252 mmol) was maintained at 70° C. in tetrahydrofuran (20 ml) in a pressure tube for 16 hours. The reaction was cooled, opened, concentrated under reduced pressure, and redissolved in methylene chloride/2,2,2-trifluoroethanol (ca 15 mL). Saturated sodium bicarbonate was added and all solids dissolve. The organic layer was dried over sodium sulfate, filtered, taken to a residue under reduced pressure, and triturated with diethyl ether to afford 5-{[1-(N,N-dimethylglycyl)-2,3-dihydro-1H-indol-6-yl]amino}-8-fluoro-3-[(4-methylphenyl)sulfonyl]pyrrolo[2′,3′:4,5]pyrimido[6,1-b]quinazolin-7(3H)-one (0.696 g, 1.112 mmol, 89%) as a yellow solid. A suspension of 5-{[1-(N,N-dimethylglycyl)-2,3-dihydro-1H-indol-6-yl]amino}-8-fluoro-3-[(4-methylphenyl)sulfonyl]pyrrolo[2′,3′:4,5]pyrimido[6,1-b]quinazolin-7(3H)-one (0.696 g, 1.112 mmol) in tetrahydrofuran (20 ml) was treated with 2.0M methyl amine/THF (3.34 ml, 6.67 mmol) and over 24 hours all solids dissolve. The solution was poured into saturated sodium bicarbonate/EtOAc and the organic layer was dried over sodium sulfate, filtered, and taken to a residue under reduced pressure. The residue was dissolved in 1,4-dioxane (8 ml)/2.0N NaOH (aq) (8 ml) and maintained at 120° C. under microwave heating for 12 minutes. The solution was cooled, poured into ethyl acetate/THF/saturated sodium chloride (aq) and the organic layer was dried over sodium sulfate, filtered, stripped onto celite, and purified by column chromatography to afford 2-[(2-{[1-(N,N-dimethylglycyl)-2,3-dihydro-1H-indol-6-yl]amino}-1H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]-6-fluoro-N-methylbenzamide (0.230 g, 0.458 mmol, 41.1%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.33 (s, 1H), 10.20 (s, 1H), 8.89 (s, 1H), 8.54 (d, J=7.62 Hz, 1H), 8.21 (s, 1H), 7.83 (d, J=7.22 Hz, 1H), 7.34-7.48 (m, 1H), 7.10 (d, J=8.23 Hz, 1H), 6.85-7.01 (m, 3H), 6.29 (dd, J=3.41, 1.81 Hz, 1H), 4.15 (t, J=8.23 Hz, 2H), 3.21 (s, 2H), 2.99-3.12 (m, 2H), 2.79 (d, J=4.61 Hz, 3H), 2.27 (s, 6H). ESIMS (M+H)+=503.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][CH:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15](Br)[CH:16]=2)[O:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].C([Li])CCC.CN([CH:28]=[O:29])C>C1COCC1>[C:1]([O:5][C:6](=[O:19])[NH:7][CH:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([CH:28]=[O:29])[CH:16]=2)[O:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(C)C=O
Reactant: CC(C)(C)OC(=O)NC1CCOc2ccc(Br)cc21
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC1CCOc2ccc(C=O)cc21
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
(6-Bromo-chroman-4-yl)-carbamic acid tert-butyl ester (3.859 g, 11.76 mmol) was dissolved in THF (50 mL) and cooled to −78° C. n-Butyllithium (2.5 M) (11.76 mL, 29.40 mmol) was added drop-wise to the stirred solution. The reaction mixture was stirred at −78° C. for 30 min and DMF (4.55 mL, 58.8 mmol) was added drop-wise and the system was slowly warmed to RT overnight. The reaction was quenched with saturated aqueous NH4Cl solution and extracted with EtOAc. The combined organics were dried with MgSO4 and concentrated in vacuo to afford the crude compound, which was purified by flash column chromatography to furnish the pure title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N:17]2[C:21]([CH2:22][N:23]3C(=O)C4=CC=CC=C4C3=O)=[N:20][N:19]=[C:18]2[CH2:34][N:35]2C(=O)C3=CC=CC=C3C2=O)=[C:6]([CH:16]=1)[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[Cl:15])=O.O.NN>C(O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:17]3[C:18]([CH2:34][NH2:35])=[N:19][N:20]=[C:21]3[CH2:22][N:23]=[C:7]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[Cl:15])[C:6]=2[CH:16]=1
Reactant: O=C(c1ccccc1Cl)c1cc(F)ccc1-n1c(CN2C(=O)c3ccccc3C2=O)nnc1CN1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: O
Solvent: CCO
Product: NCc1nnc2n1-c1ccc(F)cc1C(c1ccccc1Cl)=NC2

Procedure:
In the manner given in Example 22, 5-fluoro-2'-chloro-2-[3,5-bis(phthalimidomethyl)-4H-1,2,4-triazol-4-yl]benzophenone in ethanol is heated with hydrazine hydrate to give 8-fluoro-1-(aminomethyl)-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine.
Reaction SMILES: CO.[C:3]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:22]([O:26][C:27]([NH:29][S:30]([NH:33][CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])(=[O:32])=[O:31])=[O:28])[CH2:23][CH2:24][CH3:25].CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[CH2:22]([O:26][C:27]([N:29]([CH3:3])[S:30]([NH:33][CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])(=[O:31])=[O:32])=[O:28])[CH2:23][CH2:24][CH3:25]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: CCCCOC(=O)NS(=O)(=O)NCC(=O)OCC
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Solvent: C1CCOC1
Solvent: CO
Product: CCCCOC(=O)N(C)S(=O)(=O)NCC(=O)OCC
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of methanol (8.5 mmol) and triphenylphosphine (2.6 g, 8.5 mol) in dry THF is added a solution of ethyl 2-((N-(butyloxycarbonyl)sulfamoyl)amino)acetate from the previous step (2.4 g, 8.5 mol) and DIAD (2.0 g, 8.5 mmol) in dry THF dropwise at 0° C. under N2 atmosphere. The mixture is stirred at 0° C. for 2 h, warmed to RT and is stirred overnight. After the solvent is removed in vacuo, the residue is purified by column chromatography to afford ethyl 2-((N-(butyloxycarbonyl)-N-methylsulfamoyl)amino)acetate.
Reaction SMILES: S(=O)(=O)(O)O.[C:6]1([CH:12]2[CH2:16][CH2:15][NH:14][CH2:13]2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[CH3:17][C:18](=[CH2:20])[CH3:19].O>C(Cl)(Cl)(Cl)Cl>[C:18]([C:9]1[CH:10]=[CH:11][C:6]([CH:12]2[CH2:16][CH2:15][NH:14][CH2:13]2)=[CH:7][CH:8]=1)([CH3:20])([CH3:19])[CH3:17]
Reactant: C=C(C)C
Reactant: c1ccc(C2CCNC2)cc1
Agent: O=S(=O)(O)O
Solvent: O
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)c1ccc(C2CCNC2)cc1
Reaction time: 0.25 h
Yield: 33 %

Procedure:
98 g (1 mole) of concentrated sulfuric acid were added dropwise to 29.4 g (0.2 mole) of 3-phenylpyrrolidine in 400 ml of carbon tetrachloride at 0°-5° C. After 15 minutes, 15.2 g (0.27 mole) of isobutylene were passed in gaseous form, the mixture was stirred for 1 hour at 0°-5° C. and hydrolysis was carried out with 400 ml of water at 20° C. The organic phase was separated off and the aqueous phase was extracted with twice 100 ml of dichloromethane. Working up of the organic phases gave 42 g of a crude product, which was fractionated under reduced pressure to give 13.4 g (33%) of a colorless oil of boiling point 84°-87° C./0.5 mbar.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[CH2:14][CH2:13][CH2:12][C@H:11]([C:15](O)=[O:16])[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].ClC(OCC(C)C)=O.[BH4-].[Na+].S([O-])(O)(=O)=O.[K+].C(=O)([O-])O.[Na+]>O1CCCC1.CO.C(N(CC)CC)C>[C:1]([O:5][C:6](=[O:7])[NH:8][C@H:9]1[CH2:14][CH2:13][CH2:12][C@@H:11]([CH2:15][OH:16])[CH2:10]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCC[C@H](C(=O)O)C1
Agent: CC(C)COC(=O)Cl
Agent: O=C([O-])O
Agent: O=S(=O)([O-])O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@H]1CCC[C@@H](CO)C1
Temperature: 0 °C
Yield: 66 %

Procedure:
To a solution of cis-3-[(tert-butoxycarbonyl)amino]-cyclohexanecarboxylic acid (500 mg) in tetrahydrofuran (5 ml) was added triethylamine (344 μl) and isobutyl chloroformate (320 μl) under stirring at 0° C. After stirring at 0° C. for 1 hour, sodium borohydride (233 mg) was added, and methanol (5 ml) was added dropwise under stirring at 0° C. After stirring at 0° C. for 1 hour, 10% aqueous potassium hydrogen sulfate (10 ml) was added and neutralized with saturated aqueous sodium hydrogencarbonate. and extracted with EtOAc. The organic layer was washed with water, brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by preparative thin layer chromatography on silica gel eluting with n-hexane:EtOAc=70:30 to 40:60 to give tert-butyl[cis-3-(hydroxymethyl)cyclohexyl]carbamate (311 mg) as a white powder.
Reaction SMILES: [N:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]([CH2:10][C:11]2[CH:22]=[CH:21][C:14]3[N:15]=[C:16](S(C)=O)[S:17][C:13]=3[CH:12]=2)[CH:2]=1.CCN(C(C)C)C(C)C.[NH2:32][C@@H:33]1[CH2:38][CH2:37][CH2:36][CH2:35][C@H:34]1[OH:39]>CC(N(C)C)=O.CCOC(C)=O>[N:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]([CH2:10][C:11]2[CH:22]=[CH:21][C:14]3[N:15]=[C:16]([NH:32][C@@H:33]4[CH2:38][CH2:37][CH2:36][CH2:35][C@H:34]4[OH:39])[S:17][C:13]=3[CH:12]=2)[CH:2]=1
Reactant: CS(=O)c1nc2ccc(Cn3cnc4cccnc43)cc2s1
Reactant: N[C@@H]1CCCC[C@H]1O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: O[C@@H]1CCCC[C@H]1Nc1nc2ccc(Cn3cnc4cccnc43)cc2s1
Temperature: 120 °C
Reaction time: 6 h

Procedure:
To a suspension of 6-((3H-imidazo[4,5-b]pyridin-3-yl)methyl)-2-(methylsulfinyl)benzo[d]thiazole (1.3 g, 3.96 mmol) from Step 5 of this Example in DMA (6 mL) were added DIEA (511 mg, 3.96 mmol) and (1R,2R)-2-aminocyclohexanol (1.36 g, 11.9 mmol) at rt. The reaction mixture was stirred in a sealed tube at 120° C. for 6 h. After cooling to rt, the mixture was diluted with 120 mL of EtOAc and washed with 120 mL of water. The organic layer was dried over MgSO4 and concentrated under reduced pressure. The crude product was purified on a silica gel column using a mixture of acetone-EtOAc (1:12, v/v) as eluent to give (1R,2R)-2-((6-((3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol as an off white solid (864 mg, 58%). 1H NMR (300 MHz, DMSO-d6) δ 8.60 (s, 1H), 8.38 (dd, J=1.3, 4.7 Hz, 1H), 8.09 (dd, J=1.2, 8.0 Hz, 1H), 7.95 (d, J=7.5 Hz, 1H), 7.67 (s, 1H), 7.17-7.35 (m, 3H), 5.49 (s, 2H), 4.73 (d, J=5.3 Hz, 1H), 3.52 (d, J=8.5 Hz, 1H), 3.32 (br s, 1H), 1.76-2.12 (m, 2H), 1.61 (br s, 2H), 1.07-1.38 (m, 4H). LCMS (ESI) m/z 380 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C@H:3]1[CH2:8][CH2:7][C@H:6]2[C@H:9]3[C@H:19]([CH2:20][CH2:21][C@:4]12[CH3:5])[C@:17]1([CH3:18])[C@H:12]([CH2:13][C:14](=[O:22])[CH2:15][CH2:16]1)[CH2:11][CH2:10]3.[CH2:23]([O:25][CH:26](OCC)[O:27][CH2:28][CH3:29])[CH3:24].B(F)(F)F.CCOCC>>[CH2:23]([O:25][CH:26]([O:27][CH2:28][CH3:29])[C@@H:15]1[CH2:16][C@@:17]2([CH3:18])[C@@H:12]([CH2:11][CH2:10][C@@H:9]3[C@@H:19]2[CH2:20][CH2:21][C@@:4]2([CH3:5])[C@H:6]3[CH2:7][CH2:8][C@@H:3]2[O:2][CH3:1])[CH2:13][C:14]1=[O:22])[CH3:24]
Reactant: CO[C@H]1CC[C@H]2[C@@H]3CC[C@H]4CC(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Reactant: CCOC(OCC)OCC
Agent: FB(F)F
Solvent: CCOCC
Product: CCOC(OCC)[C@@H]1C[C@@]2(C)[C@@H](CC[C@@H]3[C@@H]2CC[C@]2(C)[C@@H](OC)CC[C@@H]32)CC1=O
Yield: 117.7 %

Procedure:
By the method of part A of Example 20 (5α,17β)-17-methoxyandrostan-3-one (45.67 g., 0.15 mole) was diethoxymethylated using triethylorthoformate (55.0 ml., 49.0 g., 0.33 mole) and boron trifluoride etherate (50.0 ml., 57.7 g., 0.407 mole), affording (2α,5α,17β)-2-(diethoxymethyl)-17-methoxyandrostan-3-one (71.81 g.).
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.P(Cl)(Cl)(Cl)=O.C(N(CC)CC)C.[CH3:18][C:19]1[N:27]2[C:22]([C:23](=O)[NH:24][CH:25]=[N:26]2)=[C:21]([C:29]2[CH:30]=[N:31][N:32]([CH3:41])[C:33]=2[C:34]2[CH:39]=[CH:38][C:37]([CH3:40])=[CH:36][CH:35]=2)[N:20]=1>ClCCl>[CH3:18][C:19]1[N:27]2[C:22]([C:23]([N:1]3[CH:5]=[N:4][CH:3]=[N:2]3)=[N:24][CH:25]=[N:26]2)=[C:21]([C:29]2[CH:30]=[N:31][N:32]([CH3:41])[C:33]=2[C:34]2[CH:39]=[CH:38][C:37]([CH3:40])=[CH:36][CH:35]=2)[N:20]=1
Reactant: Cc1ccc(-c2c(-c3nc(C)n4nc[nH]c(=O)c34)cnn2C)cc1
Reactant: c1nc[nH]n1
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(-c2c(-c3nc(C)n4ncnc(-n5cncn5)c34)cnn2C)cc1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
1H-1,2,4-Triazole (162 mg, 2.34 mmol) was pulverized, mixed with dichloromethane (4.0 mL) and cooled to 0° C. Phosphorus oxychloride (58.2 μL, 0.624 mmol) was added, followed after 1 minute by the drop-wise addition of triethylamine (0.349 mL, 2.50 mmol). After 10 minutes at 0° C., the ice bath was removed; 5 minutes later, 7-methyl-5-[1-methyl-5-(4-methylphenyl)-1H-pyrazol-4-yl]imidazo[5,1-f][1,2,4]triazin-4(3H)-one (50 mg, 0.16 mmol) was added. The reaction mixture was maintained at room temperature for 4 hours, then cooled to 0° C. and quenched with water, then treated with saturated aqueous sodium bicarbonate solution. The mixture was extracted with ethyl acetate, and the combined organic layers were washed with water, washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, and concentrated in vacuo. This crude material was taken directly to the following step. LCMS m/z 372.5 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 2.27 (br s, 3H), 2.70 (s, 3H), 3.73 (s, 3H), 6.86 (br d, J=8.2 Hz, 2H), 7.06 (br d, J=8.0 Hz, 2H), 7.37 (s 1H), 8.14 (s, 1H), 8.53 (s, 1H), 8.84 (s, 1H).
Reaction SMILES: [CH:1]1([OH:13])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Br[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].[H-].[Na+]>>[CH2:15]([O:13][CH:1]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: CCCCCCBr
Reactant: OC1CCCCCCCCCCC1
Agent: [H-]
Agent: [Na+]
Product: CCCCCCOC1CCCCCCCCCCC1
Reaction time: 0 h

Procedure:
Cyclododecanol (20.0 g, 0.11 tool), 1-bromohexane (120.0 g, 0.727 mol), and 60% sodium hydride in mineral oil (5.6 g, 0.14 mol) prepared as in Example 1 were refluxed for 2 hours. A 28.4 g sample (96%) was isolated as in Example 1. GC showed 99% one component; bp 109°-111° C. at 0.03 min. IR (neat, cm-1) 28 38, 2868, 1470, 1452, 1354, 1100 (C-O-C); 13C NMR (ppm, CDC13) 76.90 (α-ring carbon), 68.64 (α-chain carbon), 31.81, 30.31, 2 9.06, 26.00, 24.78, 24.31, 23.29, 22.71, 20.78, 14.10; MS, m/z (relative intensity) 268 (M+,1.1), 225(0.03), 211(0.2), 197(1.0), 183(0.4), 138(2.4), 124(3.6), 111(4.5), 110(6.4), 97(2.0), 96(19.9), 83(15.4), 82(46.5), 69(16.1), 68(17.1), 55(34.2), 54(6.2), 43(100.0), 41(40.3), 39(14.8). Anal calcd for C18H36O:C,80.53; H,13.52. Found: C, 80.77; H, 13.33.
Reaction SMILES: [H-].NN.C1(=O)[N:8]([CH2:9][CH2:10][CH2:11][S:12][C:13]2[O:14][CH:15]=[CH:16][N:17]=2)C(=O)C2=CC=CC=C12>C(O)C>[NH2:8][CH2:9][CH2:10][CH2:11][S:12][C:13]1[O:14][CH:15]=[CH:16][N:17]=1
Reactant: O=C1c2ccccc2C(=O)N1CCCSc1ncco1
Agent: NN
Agent: [H-]
Solvent: CCO
Product: NCCCSc1ncco1

Procedure:
Hydrazine hydride (5.3 g.) was added carefully to a solution of 2-(3-phthalimidopropylthio)oxazole (10. g.) in ethanol (173 ml.) with stirring. The solution was then heated under reflux for 25 minutes. After cooling, and filtration from phthalhydrazide, the filtrate was concentrated under reduced pressure and the residue was re-evaporated with ethanol to yield crude 2-(3-aminopropylthio)oxazole which was washed twice with ether and dissolved in ethanol (60 ml.). Methyl isothiocyanate (2.54 g.) was added and the solution was heated under reflux for 30 minutes. Following cooling and filtration from insoluble material, the filtrate was concentrated to an oil which was chromatographed on a column of silica gel with ethyl acetate as eluant. The product obtained crystallised from ethanol-ether-n-hexane to give N-methyl-N'-[3-(2-oxazolylthio)propyl]thiourea (2.4 g.), m.p. 43°-45°. (Found: C, 41.7; H, 5.9; N, 18.3; S, 27.5. C8H13N3OS2 requires: C, 41.5; H, 5.7; N 18.2; S, 27.7).
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:14][CH3:15])[CH:11]=2)[N:6]1[C:16](=[O:28])[C@@H:17]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:18][CH3:19])=[O:4].[OH-].[Na+].ClCCl>CO.O>[C:24]([O:23][C:21]([NH:20][C@@H:17]([CH2:18][CH3:19])[C:16]([N:6]1[C:7]2[C:12](=[CH:11][C:10]([O:14][CH3:15])=[CH:9][CH:8]=2)[CH2:13][CH:5]1[C:3]([OH:4])=[O:2])=[O:28])=[O:22])([CH3:27])([CH3:26])[CH3:25]
Reactant: CC[C@H](NC(=O)OC(C)(C)C)C(=O)N1c2ccc(OC)cc2CC1C(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: ClCCl
Product: CC[C@H](NC(=O)OC(C)(C)C)C(=O)N1c2ccc(OC)cc2CC1C(=O)O
Temperature: 7.5 °C
Reaction time: 4 h

Procedure:
To the solution of 1-(N-t-butoxycarbonyl-2(S)-aminobutyryl)-5-methoxyindoline-2(R/S)-carboxylic acid methyl ester (1.3 g, 3.3 mmol) in methanol (20 ml), was added sodium hydroxide(0.265 g, 6.6 mmol) in water (10 ml). The solution was stirred at 5 to 10° C. for 4 hours. The mixture was poured into dichloromethane (40 ml), and washed with cold potassium hydrogen sulphate (3×20 ml), and water (20 ml). The organic layer was dried over sodium sulphate, and evaporated to provide a white foam which was pure enough for the next step.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[CH2:10][CH:9]=[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)[N:7]2[N:21]=[CH:22][C:23]([C:24]#[N:25])=[C:6]12)=[O:4].[F:26][C:27]1[CH:39]=[CH:38][CH:37]=[CH:36][C:28]=1[CH2:29][N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1.C(N(CC)CC)C>O1CCCC1.O>[F:26][C:27]1[CH:39]=[CH:38][CH:37]=[CH:36][C:28]=1[CH2:29][N:30]1[CH2:31][CH2:32][N:33]([CH2:2][C:3]([N:5]2[CH2:10][CH:9]=[C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=3)[N:7]3[N:21]=[CH:22][C:23]([C:24]#[N:25])=[C:6]23)=[O:4])[CH2:34][CH2:35]1
Reactant: Fc1ccccc1CN1CCNCC1
Reactant: N#Cc1cnn2c1N(C(=O)CCl)CC=C2c1cccc(C(F)(F)F)c1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: N#Cc1cnn2c1N(C(=O)CN1CCN(Cc3ccccc3F)CC1)CC=C2c1cccc(C(F)(F)F)c1

Procedure:
A mixture of 6.3 g of 4-(chloroacetyl)-4,5-dihydro-7-[3-(trifluoromethyl)phenyl]pyrazolo[1,5-a]pyrimidine-3-carbonitrile, 3.7 of 2-fluorobenzyl piperazine and 4.1 g of triethylamine in 250 ml of tetrahydrofuran was stirred under reflux for 18 hours, then cooled and diluted with 500 ml of water. The resulting solid was collected, washed with water, dried, then heated to solution in 200 ml of ethyl acetate, filtered and refrigerated. The resulting solid was collected, washed with hexane and dried, giving 7.1 g of the desired product, mp 188°-190° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:18][OH:19])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[C:13]([F:15])[C:12]([F:16])=[C:11]([F:17])[CH:10]=1.[H-].[Na+].Cl[C:23]1[CH:24]=[C:25]2[N:32]([CH3:33])[CH2:31][CH2:30][N:26]2[C:27](=[O:29])[N:28]=1>C1COCC1.CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:10]=[C:11]([F:17])[C:12]([F:16])=[C:13]([F:15])[CH:14]=1)[CH2:18][O:19][C:23]1[CH:24]=[C:25]2[N:32]([CH3:33])[CH2:31][CH2:30][N:26]2[C:27](=[O:29])[N:28]=1
Reactant: CN1CCn2c1cc(Cl)nc2=O
Reactant: OCc1ccc(Oc2cc(F)c(F)c(F)c2)c(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CN1CCn2c1cc(OCc1ccc(Oc3cc(F)c(F)c(F)c3)c(F)c1)nc2=O

Procedure:
Prepared in a manner similar to that described for E1 using (3-fluoro-4-(3,4,5-trifluorophenoxy)phenyl)methanol in THF (6 mL), sodium hydride (0.013 g, 0.323 mmol) and 7-chloro-1-methyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one (0.040 g, 0.216 mmol) in DMF (1 mL).
Reaction SMILES: [C:1]([N:5]1[CH2:10][CH2:9][N:8]([CH2:11][C:12]2[CH:13]=[C:14](B(O)O)[CH:15]=[CH:16][CH:17]=2)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[Na+].[Na+].Br[C:28]1[CH:29]=[C:30]([C:34]2[CH:39]=[C:38]([NH:40][CH:41]3[CH2:45][CH2:44][CH2:43][CH2:42]3)[N:37]=[C:36]([C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][N:47]=3)[CH:35]=2)[CH:31]=[N:32][CH:33]=1>COCCOC.C(Cl)Cl.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[C:1]([N:5]1[CH2:10][CH2:9][N:8]([CH2:11][C:12]2[CH:13]=[C:14]([C:28]3[CH:29]=[C:30]([C:34]4[CH:39]=[C:38]([NH:40][CH:41]5[CH2:45][CH2:44][CH2:43][CH2:42]5)[N:37]=[C:36]([C:46]5[CH:51]=[CH:50][CH:49]=[CH:48][N:47]=5)[CH:35]=4)[CH:31]=[N:32][CH:33]=3)[CH:15]=[CH:16][CH:17]=2)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)N1CCN(Cc2cccc(B(O)O)c2)CC1
Reactant: Brc1cncc(-c2cc(NC3CCCC3)nc(-c3ccccn3)c2)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: COCCOC
Product: CC(C)(C)N1CCN(Cc2cccc(-c3cncc(-c4cc(NC5CCCC5)nc(-c5ccccn5)c4)c3)c2)CC1

Procedure:
To a solution of 3-(4-tert-Butyl-piperazin-1-ylmethyl)-phenyl boronic acid (Intermediate B11) (1.1 eq, 0.195 mmol, 54 mg) and 2M Na2CO3 (2.0 eq, 0.354 mmol, 0.18 ml) in DME (1 ml) is added (5″-Bromo-[2,2′;4′,3″]terpyridin-6′-yl)-cyclopentylamine (1 eq, 0.177 mmol, 70 mg) followed by [1,1′-Bis(diphenylphosphino)-ferrocene]dichloropalladium (II), complex with DCM (0.1 eq, 0.0177 mmol, 13 mg). The reaction mixture is heated using microwave radiation at 90° C. for 90 mins. The reaction mixture is dissolved in DCM and washed with water. The organic layer is washed with brine, dried over drying agent MgSO4, filtered and the organic solvent is reduced in vacuo. The crude residue is purified by reverse phase column chromatography (Isolute™ C18, 0-20% acetonitrile in water—0.1% TFA). The appropriate fractions by HPLC are combined and concentrated in vacuo. The resulting residue is dissolved in MeOH and loaded onto a SCX-2 cartridge eluting with MeOH followed by 2M NH3 in MeOH. The methanolic ammonia fractions are combined, concentrated in vacuo and dried under vacuum to afford the title compound; [M+H]+ 547.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH:5]([NH:8][C:9]([CH2:11][CH2:12][CH2:13][CH3:14])=[O:10])[C:6]#[N:7])[CH3:2].[CH3:16][O:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22][SH:23])=[CH:20][CH:19]=1.C(N(CC)CC)C>C(O)C>[NH2:7][C:6]([S:23][CH2:22][C:21]1[CH:24]=[CH:25][C:18]([O:17][CH3:16])=[CH:19][CH:20]=1)=[C:5]([NH:8][C:9]([CH2:11][CH2:12][CH2:13][CH3:14])=[O:10])[C:4]([O:3][CH2:1][CH3:2])=[O:15]
Reactant: CCCCC(=O)NC(C#N)C(=O)OCC
Reactant: COc1ccc(CS)cc1
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCCCC(=O)NC(C(=O)OCC)=C(N)SCc1ccc(OC)cc1

Procedure:
3 g of the product obtained in Stage 1 above, 4 ml of paramethoxybenzylmercaptan, 0.2 ml of triethylamine and 5 ml of ethanol are mixed together.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][S:10][C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=2)=[CH:5][C:4]=1[O:18][CH3:19].N1C2C(=CC=C3C=2N=CC=C3)C=CC=1.C([Li])CCC.CCCCCC.Br[CH2:46][CH2:47][CH2:48][Cl:49]>O1CCCC1.C(OCC)(=O)C>[Cl:49][CH2:48][CH2:47][CH2:46][CH:9]([C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[C:4]([O:18][CH3:19])[CH:5]=1)[S:10][C:11]1[CH:12]=[CH:13][C:14]([CH3:17])=[CH:15][CH:16]=1
Reactant: ClCCCBr
Reactant: COc1ccc(CSc2ccc(C)cc2)cc1OC
Agent: [Li]CCCC
Agent: c1cnc2c(c1)ccc1cccnc12
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: COc1ccc(C(CCCCl)Sc2ccc(C)cc2)cc1OC
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a solution of 13.72 g of 1,2-dimethoxy-4-[[(4-methylphenyl)thio]methyl]benzene and a crystal of phenanthroline in 250 mL of tetrahydrofuran (dried over 3A sieves), under nitrogen at -78° C. is added 21.0 mL of 2.5M n-butyl lithium/hexane via a syringe. After 10 minutes, the brown solution is warmed to 0° C. for 1 hour, then it is recooled to -78° C. and 8.02 mL of 1-bromo-3-chloropropane is added via syringe. The reaction is permitted to warm to room temperature overnight. To the now light yellow reaction mixture is added 10 mL of ethyl acetate and the resulting solution concentrated in yacuo. The residue is partitioned between ethyl acetate and water, the organic phase dried (sodium sulfate) and concentrated in vacuo to a yellow oil. Purification by chromatography on silica gel with gradient elution progressing from hexane to chloroform to methyl alcohol, repeated three times, affords 16.47 g of the desired product as a yellow oil. MS(CI): m/z 227 and 229(MH+ (-TolSH)). Calcd for C19H23ClO2S 1/8H2O: C=63.80, H=6.59, Cl=11.15, S=8.95 Found C=63.68, H=6.44, Cl=10.89, S=8.98