Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([N:8]2[CH:12]=[CH:11][N:10]=[CH:9]2)[CH:3]=1.[Na].[CH3:14][OH:15]>>[N:8]1([C:4]2[CH:3]=[C:2]([O:15][CH3:14])[N:7]=[CH:6][N:5]=2)[CH:12]=[CH:11][N:10]=[CH:9]1
Reactant: CO
Reactant: Clc1cc(-n2ccnc2)ncn1
Agent: [Na]
Product: COc1cc(-n2ccnc2)ncn1

Procedure:
Following the procedure of Example 15, 180 mg of 6-chloro-4-(1-imidazolyl)pyrimidine was reacted with 23 mg of sodium metal and 2 ml of anhydrous methanol to yield 136 mg 4-(1-imidazolyl)-6-methoxypyrimidine, having a melting point of 152°-153° C., recrystallized from a mixture of n-hexane and ethyl acetate.
Reaction SMILES: C1CO[C:3]2([CH2:8][CH2:7][N:6]([C:9]([C:11]3[CH:12]=[C:13]4[C:18](=[CH:19][CH:20]=3)[NH:17][C:16](=[O:21])[CH2:15][CH2:14]4)=[O:10])[CH2:5][CH2:4]2)[O:2]1.Cl.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O>[O:2]=[C:3]1[CH2:8][CH2:7][N:6]([C:9]([C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][CH:20]=2)[NH:17][C:16](=[O:21])[CH2:15][CH2:14]3)=[O:10])[CH2:5][CH2:4]1
Reactant: O=C1CCc2cc(C(=O)N3CCC4(CC3)OCCO4)ccc2N1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: O=C1CCN(C(=O)c2ccc3c(c2)CCC(=O)N3)CC1
Temperature: 100 °C

Procedure:
46 Grams of 6-(4,4-ethylenedioxy-1-piperidylcarbonyl)-3,4-dihydrocarbostyril was dispersed in 400 ml of dioxane and 150 ml of water, then 15 ml of concentrated hydrochloric acid was added thereto and the whole mixture was heated at 100° C. for 7 hours with stirring. After the reaction mixture was allowed to stand for cooling, then was made alkaline by adding sodium carbonate, and the solvent was removed by evaporation. The residue thus obtained was extracted with chloroform, and the extract was dried with anhydrous sodium carbonate, and the solvent was removed by evaporation. The residue thus obtained was purified by means of a silica gel column chromatography (eluent: dichloromethane:methanol=10:1) to yield 37.6 g of 6-(4-oxo-1-piperidylcarbonyl)-3,4-dihydrocarbostyril.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.Cl[C:7]1[N:8]=[C:9]([NH:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:10]2[C:15]([CH3:16])=[C:14]([CH3:17])[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:10]3[C:15]([CH3:16])=[C:14]([CH3:17])[S:13][C:11]=3[N:12]=2)[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: Cc1sc2nc(Cl)nc(NCc3ccccc3)c2c1C
Reactant: c1nc[nH]n1
Product: Cc1sc2nc(-n3cncn3)nc(NCc3ccccc3)c2c1C

Procedure:
Following the procedure of Example 97, the reaction of 1,2,4-triazole with 2-chloro-5,6-dimethyl-4-benzylamino-thieno-[2,3-d]-pyrimidine gives 2-(1,2,4-triazol-1-yl)-5,6-dimethyl-4-benzylamino-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][CH:7]2[CH:9]([C:10]([OH:12])=[O:11])[C:8]2([CH3:14])[CH3:13])=[CH:4][CH:3]=1.C(=O)(O)[O-].[K+].CS(O[CH2:27][C:28]1[NH:29][CH:30]=[CH:31][C:32]=1[CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)(=O)=O>C1COCC1.CN(C=O)C.CCOCC>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH:7]2[CH:9]([C:10]([O:12][CH2:27][C:28]3[NH:29][CH:30]=[CH:31][C:32]=3[CH2:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)=[O:11])[C:8]2([CH3:13])[CH3:14])=[CH:15][CH:16]=1
Reactant: CS(=O)(=O)OCc1[nH]ccc1Cc1ccccc1
Reactant: CC1(C)C(Oc2ccc(F)cc2)C1C(=O)O
Agent: O=C([O-])O
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CC1(C)C(Oc2ccc(F)cc2)C1C(=O)OCc1[nH]ccc1Cc1ccccc1
Reaction time: 48 h

Procedure:
3-(4-Fluorophenoxy)-2,2-dimethylcyclopropanecarboxylic acid (3.40 mmol) is stirred together with 0.34 g (3.40 mmol) potassium bicarbonate in 10 ml THF/DMF (1:1) for 15 minutes. Then 3.40 mmol of 3-benzylpyrrolylmethyl methanesulfonate in 5 ml THF/DMF (1:1) is added and the mixture stirred for approximately 48 hours. The reaction is diluted with ether, washed with water (3X) and sat. NaCl, dried and solvent is removed. The crude product is purified by preparative TLC developing with 10% ethyl acetate/hexane to yield 3-benzylpyrrolylmethyl 3-(4-fluorophenoxy)-2,2-dimethylcyclopropanecarboxylate.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.[H-].[Na+].[F:11][C:12]([F:26])([F:25])[C:13]([CH3:24])([C:20]([F:23])([F:22])[F:21])[CH2:14]OS(C)(=O)=O>CN(C=O)C.[I-].C([N+](CCCC)(CCCC)CCCC)CCC.O>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:14][C:13]([CH3:24])([C:12]([F:11])([F:25])[F:26])[C:20]([F:23])([F:22])[F:21])=[CH:4][CH:3]=1
Reactant: Cc1ccc(S)cc1
Reactant: CC(COS(C)(=O)=O)(C(F)(F)F)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [H-]
Agent: [I-]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(SCC(C)(C(F)(F)F)C(F)(F)F)cc1
Temperature: 150 °C
Reaction time: 8 h
Yield: 66.2 %

Procedure:
In a sealed tube dissolve 4-methylbenzenethiol (4.13 g, 33.2 mmol) in DMF (20 mL) at ambient temperature. Add portionwise with stirring sodium hydride (899 mg, 37.5 mmol) followed by tetrabutylammonium iodide (82 mg, 0.22 mmol) and a solution of methanesulfonic acid 3,3,3-trifluoro-2-methyl-2-trifluoromethylpropyl ester (6.16 g, 22.5 mmol) in DMF (10 mL). Stir at 150° C. overnight, cool the mixture to ambient temperature and dilute cautiously with water. Extract three times with EtOAc, dry over anhydrous Na2SO4, and concentrate in vacuo. Purify by chromatography on silica gel eluting with hexane to give the desired intermediate as a yellow oil (4.5 g, 62%).
Reaction SMILES: I[C:2]1[N:3]=[C:4]([CH:12]2[CH2:15][CH:14]([N:16]3[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]3)[CH2:13]2)[N:5]2[CH:10]=[CH:9][N:8]=[C:7]([NH2:11])[C:6]=12.[C:23]1([C:29]2[CH:38]=[C:37]([C:39]([F:42])([F:41])[F:40])[C:36]3[C:31](=[CH:32][C:33](B4OC(C)(C)C(C)(C)O4)=[CH:34][CH:35]=3)[N:30]=2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(=O)([O-])[O-].[Cs+].[Cs+].COCCOC>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>[CH3:22][N:19]1[CH2:20][CH2:21][N:16]([CH:14]2[CH2:15][CH:12]([C:4]3[N:5]4[CH:10]=[CH:9][N:8]=[C:7]([NH2:11])[C:6]4=[C:2]([C:33]4[CH:32]=[C:31]5[C:36]([C:37]([C:39]([F:42])([F:40])[F:41])=[CH:38][C:29]([C:23]6[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=6)=[N:30]5)=[CH:35][CH:34]=4)[N:3]=3)[CH2:13]2)[CH2:17][CH2:18]1
Reactant: CN1CCN(C2CC(c3nc(I)c4c(N)nccn34)C2)CC1
Reactant: CC1(C)OB(c2ccc3c(C(F)(F)F)cc(-c4ccccc4)nc3c2)OC1(C)C
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: [Cs+]
Solvent: COCCOC
Solvent: O
Product: CN1CCN(C2CC(c3nc(-c4ccc5c(C(F)(F)F)cc(-c6ccccc6)nc5c4)c4c(N)nccn34)C2)CC1
Temperature: 75 °C
Reaction time: 8 h

Procedure:
1-iodo-3-[3-(4-methyl-piperazin-1-yl)-cyclobutyl]-imidazo[1,5-a]pyrazin-8-ylamine (120 mg, 0.00029 mole), 2-phenyl-7-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-4-trifluoromethyl-quinoline (230 mg, 0.00058 mole), cesium carbonate (330 mg, 0.0010 mole), 1,2-dimethoxyethane (6 mL, 0.06 mole) and water (1 mL) were combined in a 25 ml round bottom flask with a magnetic stir bar. The flask was subjected to three vacuum, argon cycles and charged with tetrakis(triphenylphosphine)palladium(0) (35 mg, 0.000030 mole). The flask was subjected to three vacuum, argon cycles again. The reaction was stirred under argon at 75° C. (external temperature) overnight. The product mixture was concentrated in vacuo, then allowed to stand under vacuum for 1 h. The product mixture was then chromatographed on silica gel with methylene chloride, methanol, concentrated ammonium:hydroxide (140:10:1). Only the purest fractions were combined and concentration in vacuo, and placement under high vacuum for 30 minutes afforded the title compound as a yellow solid. The solid was re-crystallized from hexanes/ether to afford the title compound as a yellow solid; 1H NMR (CD3OD, 400 MHz) δ 2.14-2.62 (m, 15H), 2.78-2.82 (Q, 1H, J=7.9 Hz), 3.62-3.67 (Q, 1H, J=7.9H), 6.32 (bs, 2H), 7.12-7.14 (d, 1H, J=4.8 Hz), 7.58-7.64 (m, 4H), 8.16-8.22 (m, 2H), 8.39-8.42 (m, 3H), 8.48 (s, 1H); 19F NMR (DMSO, 400 MHz) δ 60.15; MS (ES+): 557.98 (10) [MH+]; HPLC TR 3.408 min. (100%) (polar—15 min).
Reaction SMILES: [CH3:1][N:2]([CH3:35])[CH2:3][CH2:4][CH2:5][S:6]([N:9]1[CH2:14][CH2:13][CH:12]([C:15]2[C:23]3[C:18](=[C:19]([C:32]([NH2:34])=[O:33])[CH:20]=[C:21]([C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([CH:30]=O)[CH:25]=4)[CH:22]=3)[NH:17][CH:16]=2)[CH2:11][CH2:10]1)(=[O:8])=[O:7].[CH2:36]([NH2:38])[CH3:37].C1COCC1.[BH4-].[Na+]>CO.C(Cl)Cl>[CH3:35][N:2]([CH3:1])[CH2:3][CH2:4][CH2:5][S:6]([N:9]1[CH2:10][CH2:11][CH:12]([C:15]2[C:23]3[C:18](=[C:19]([C:32]([NH2:34])=[O:33])[CH:20]=[C:21]([C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([CH2:30][NH:38][CH2:36][CH3:37])[CH:25]=4)[CH:22]=3)[NH:17][CH:16]=2)[CH2:13][CH2:14]1)(=[O:8])=[O:7]
Reactant: CN(C)CCCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cccc(C=O)c4)cc23)CC1
Reactant: CCN
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CO
Product: CCNCc1cccc(-c2cc(C(N)=O)c3[nH]cc(C4CCN(S(=O)(=O)CCCN(C)C)CC4)c3c2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 52 %

Procedure:
To a solution of 3-(1-{[3-(dimethylamino)propyl]sulfonyl}-4-piperidinyl)-5-(3-formylphenyl)-1H-indole-7-carboxamide (25 mg, 0.05 mmol) in MeOH/CH2Cl2 (1 mL/1 mL) was added 2M ethyl amine in THF (0.15 mL, 0.30 mmol). The reaction mixture was stirred at room temperature for 2 hours before NaBH4 (12 mg, 0.3 mmol) was added. The reaction mixture was stirred at room temperature overnight and evaporated all the solvent. The residue was purified by using a Gilson semi-preparative HPLC system, eluting with 10% B to 80% B, where A=H2O (0.1% trifluoroacetic acid) and B=CH3CN (0.1% trifluoroacetic acid) pumped at 25 mL/min to give the title compound (11 mg, 52%)
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]3[CH2:13][CH2:14][CH2:15][C:16]([C:18]([O:20]C)=[O:19])=[CH:17][C:10]=3[CH:9]=2)=[CH:4][CH:3]=1.[OH-].[Na+]>C(O)C.O1CCCC1>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:12][C:11]3[CH2:13][CH2:14][CH2:15][C:16]([C:18]([OH:20])=[O:19])=[CH:17][C:10]=3[CH:9]=2)=[CH:6][CH:7]=1
Reactant: COC(=O)C1=Cc2cc(-c3ccc(C)cc3)sc2CCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1ccc(-c2cc3c(s2)CCCC(C(=O)O)=C3)cc1
Reaction time: 120 h
Yield: 84.9 %

Procedure:
To a solution of methyl 2-(4-methylphenyl)-7,8-dihydro-6H-cyclohepta[b]thiophene-5-carboxylate (803 mg) in ethanol-tetrahydrofuran (5-10 ml) was added 2N sodium hydroxide (2 ml) at room temperature, and the mixture was stirred for 5 days and concentrated under reduced pressure. To the residue was added 1N hydrochloric acid (10 ml), and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried with magnesium sulfate and concentrated under reduced pressure to precipitate crystals, which were collected by filtration and washed with diisopropylether to give 2-(4-methylphenyl)-7,8-dihydro-6H-cyclohepta[b]thiophene-5-carboxylic acid (650 mg) as pale yellow crystals.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[NH:4][CH2:3][CH:2]1[CH2:11][O:12][CH:13]1[CH:18]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][CH2:28][O:29][CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[O:37][CH3:38])=[CH:21][CH:20]=2)[CH2:17][CH2:16][N:15]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:14]1.[CH3:46][O:47][CH2:48][CH2:49][CH2:50][C:51](Cl)=[O:52]>C(Cl)(Cl)Cl.C(N(CC)CC)C>[CH3:38][O:37][C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=1[CH2:30][O:29][CH2:28][CH2:27][CH2:26][O:25][C:22]1[CH:23]=[CH:24][C:19]([CH:18]2[CH2:17][CH2:16][N:15]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:14][CH:13]2[O:12][CH2:11][CH:2]2[CH2:3][N:4]([C:51](=[O:52])[CH2:50][CH2:49][CH2:48][O:47][CH3:46])[C:5]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[O:1]2)=[CH:20][CH:21]=1
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCC2CNc3ccccc3O2)cc1
Reactant: COCCCC(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COCCCC(=O)N1CC(COC2CN(C(=O)OC(C)(C)C)CCC2c2ccc(OCCCOCc3ccccc3OC)cc2)Oc2ccccc21
Reaction time: 0.5 h

Procedure:
A solution of 0.33 g of tert-butyl 3-(3,4-dihydro-2H-benzo[1,4]oxazin-2(R,S)-ylmethoxy)-4-{4-[3-(2-methoxybenzyloxy)propoxy]phenyl}piperidine-1-carboxylate in 40 ml of chloroform and 0.23 ml of triethylamine is admixed at room temperature with 0.23 g of 4-methoxybutyryl chloride and stirred over 30 minutes. The reaction mixture is washed successively with 1N HCl and 1N NaOH, dried over sodium sulphate and concentrated by evaporation. The title compound is obtained as a colourless oil from the residue by means of flash chromatography (SiO2 60F). Rf=0.27 (1:1.5 EtOAc-heptane); Rt=6.05.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:5]=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[N:3]=1.CC1(C)C(C)(C)OB([C:28]2[CH:33]=[CH:32][C:31]([CH2:34][C:35]([OH:37])=[O:36])=[CH:30][CH:29]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.C(OCC)(=O)C.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:17]1[CH2:18][CH2:19][N:14]([C:4]2[N:5]=[C:6]([N:8]3[CH2:13][CH2:12][O:11][CH2:10][CH2:9]3)[N:7]=[C:2]([C:28]3[CH:33]=[CH:32][C:31]([CH2:34][C:35]([OH:37])=[O:36])=[CH:30][CH:29]=3)[N:3]=2)[CH2:15][CH2:16]1
Reactant: Clc1nc(N2CCOCC2)nc(N2CCOCC2)n1
Reactant: CC1(C)OB(c2ccc(CC(=O)O)cc2)OC1(C)C
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: [Na+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: O=C(O)Cc1ccc(-c2nc(N3CCOCC3)nc(N3CCOCC3)n2)cc1
Yield: 18 %

Procedure:
A mixture of 4,4′-(6-chloro-1,3,5-triazine-2,4-diyl)dimorpholine (285 mg, 1.0 mmol), 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetic acid. (315 mg, 1.2 mmol) and tetrakis(triphenylphosphine)palladium (0) (58 mg, 0.05 mmol) in 2M sodium carbonate aqueous solution (3 mL, 8 mmol) and 20 mL of DME was stirred at 80° C. for 2 hr. Then the reaction mixture was diluted with 50 mL of ethyl acetate and extracted with 1N NaOH (50 mL, three times)). The combined aqueous layers were neutralized to pH=6. Then the aqueous solution was extracted with ethyl acetate (50 mL, three times). The combined organic layers were washed with saturated sodium carbonate and brine. Then the organic layer was dried over anhydrous sodium sulfate and concentrated to give 2-(4-(4,6-dimorpholino-1,3,5-triazin-2-yl)phenyl)acetic acid (68 mg, 18% yield). HPLC: Rt=2.04 min; MS 386 [M+H].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH3:29])[C:9]([C:11]1[S:28][C:14]2[C:15]3[CH:23]=[CH:22][C:21]([C:24](OC)=[O:25])=[CH:20][C:16]=3[O:17][CH2:18][CH2:19][C:13]=2[CH:12]=1)=[O:10].[CH3:30][NH:31][CH3:32]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH3:29])[C:9]([C:11]1[S:28][C:14]2[C:15]3[CH:23]=[CH:22][C:21]([C:24]([N:31]([CH3:32])[CH3:30])=[O:25])=[CH:20][C:16]=3[O:17][CH2:18][CH2:19][C:13]=2[CH:12]=1)=[O:10]
Reactant: COC(=O)c1ccc2c(c1)OCCc1cc(C(=O)N(C)c3ccccc3Cl)sc1-2
Reactant: CNC
Product: CN(C)C(=O)c1ccc2c(c1)OCCc1cc(C(=O)N(C)c3ccccc3Cl)sc1-2

Procedure:
Following Example 47 and General Procedure C, methyl 2-((2-chlorophenyl)(methyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-8-carboxylate 138 and dimethylamine gave 101. MS: (ESI+) 441.1.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH2:10][CH2:11][C:12]([C:14]2[S:21][C:20]([CH3:22])=[C:19]3[C:15]=2[CH2:16][C@H:17]2[C:23]([CH3:25])([CH3:24])[C@H:18]23)=[O:13])[CH:5]=[C:6]([CH3:9])[C:7]=1[OH:8].[CH2:26]([CH:28]1[O:30][CH2:29]1)Cl>C(O)(C)C.[OH-].[Na+].C(OCC)C>[CH3:9][C:6]1[CH:5]=[C:4]([CH2:10][CH2:11][C:12]([C:14]2[S:21][C:20]([CH3:22])=[C:19]3[C:15]=2[CH2:16][C@H:17]2[C:23]([CH3:25])([CH3:24])[C@H:18]23)=[O:13])[CH:3]=[C:2]([CH3:1])[C:7]=1[O:8][CH2:26][CH:28]1[CH2:29][O:30]1
Reactant: ClCC1CO1
Reactant: Cc1cc(CCC(=O)c2sc(C)c3c2C[C@@H]2[C@H]3C2(C)C)cc(C)c1O
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CC(C)O
Product: Cc1cc(CCC(=O)c2sc(C)c3c2C[C@@H]2[C@H]3C2(C)C)cc(C)c1OCC1CO1
Temperature: 25 °C
Reaction time: 18 h
Yield: 74.3 %

Procedure:
A solution of 3-(3,5-dimethyl-4-hydroxy-phenyl)-1-((1aS,5aR)-1,1,2-trimethyl-1,1a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalen-4-yl)-propan-1-one (2.00 g, 5.64 mmol, Intermediate 10) in isopropanol (20 mL) and 3 N aq. NaOH (12 mL) is treated with epichlorohydrine (2.12 g, 16.92 mmol). The dark red reaction mixture is stirred at rt for 18 h. The mixture is diluted with diethyl ether (250 mL) and washed with sat. aq. NaHCO3 followed by water. The organic layer is dried over MgSO4 and evaporated. The crude product is purified by CC on silica gel eluting with heptane:EA 4:1 to give 3-(3,5-dimethyl-4-oxiranylmethoxy-phenyl)-1-((1aS,5aR)-1,1,2-trimethyl-1,1a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalen-4-yl)-propan-1-one (1.72 g, mixture of diastereoisomers) as a pale yellow oil; LC-MS: tR=1.16 min, [M+1]+=411.17; 1H NMR (CDCl3): δ 6.85 (s, 2H), 4.04-3.97 (m, 1H), 3.77-3.69 (s, 1H), 3.52-3.44 and 3.38-3.32 (2m, 1H), 3.05-2.84 (m, 6H), 2.79 (d, J=18.8 Hz, 1H), 2.72-2.68 (m, 1H), 2.38 (s, 3H), 2.26 (s, 6H), 1.92-1.86 (m, 2H), 1.11 (s, 3H), 0.71 (s, 3H).
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:18])=[C:4]2[C:9](=[C:10]([CH3:13])[C:11]=1[CH3:12])[O:8][C:7]([CH3:17])([C:14]([OH:16])=O)[CH2:6][CH2:5]2.C1N=CN(C(N2C=NC=C2)=O)C=1.[NH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][OH:37]>>[OH:1][C:2]1[C:3]([CH3:18])=[C:4]2[C:9](=[C:10]([CH3:13])[C:11]=1[CH3:12])[O:8][C:7]([CH3:17])([C:14]([NH:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][OH:37])=[O:16])[CH2:6][CH2:5]2
Reactant: NCCCCCO
Reactant: Cc1c(C)c2c(c(C)c1O)CCC(C)(C(=O)O)O2
Agent: O=C(n1ccnc1)n1ccnc1
Product: Cc1c(C)c2c(c(C)c1O)CCC(C)(C(=O)NCCCCCO)O2
Yield: 70.5 %

Procedure:
Following the amide coupling procedure described in protocol A, 497 mg 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid (1.98 mmol), 370 mg CDI (2.28 mmol) and 239 mg 5-aminopentanol (2.2 mmol) produced 468 mg of 6-hydroxy-N-(5-hydroxypentyl)-2,5,7,8-tetramethylchroman-2-carboxamide as a pale brown solid.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([S:7](Cl)(=[O:9])=[O:8])=[CH:4][CH:3]=1.[NH2:11][C:12]1[O:16][N:15]=[C:14]([CH3:17])[CH:13]=1>>[CH3:17][C:14]1[CH:13]=[C:12]([NH:11][S:7]([C:5]2[S:6][C:2]([Br:1])=[CH:3][CH:4]=2)(=[O:9])=[O:8])[O:16][N:15]=1
Reactant: Cc1cc(N)on1
Reactant: O=S(=O)(Cl)c1ccc(Br)s1
Product: Cc1cc(NS(=O)(=O)c2ccc(Br)s2)on1

Procedure:
N-(3-methyl-5-isoxazolyl)-5-bromothiophene-2-sulfonamide was prepared in the same manner as described in Example 14 from 5-bromothiophene-2-sulfonyl chloride and 5-amino-3-methyl isoxazole. Purification was achieved by extraction of the crude sulfonamide into aqueous 2N NaOH, washing of the aqueous layer with ethyl acetate and acidification, using concentrated HCl, to pH ~2. Re-extraction into ethyl acetate was followed by washing of the organic material with water, brine and drying over magnesium sulfate. After evaporation of solvents, a brownish solid remained which was sufficiently pure to use in the next step.
Reaction SMILES: Br[C:2]1[N:10]2[C:5]([C:6]([N:12]([CH2:22][CH3:23])[CH2:13][C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)=[N:7][C:8]([Cl:11])=[N:9]2)=[N:4][CH:3]=1.[Cu][C:25]#[N:26]>CN1C(=O)CCC1>[Cl:11][C:8]1[N:7]=[C:6]([N:12]([CH2:22][CH3:23])[CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[C:5]2=[N:4][CH:3]=[C:2]([C:25]#[N:26])[N:10]2[N:9]=1
Reactant: N#C[Cu]
Reactant: CCN(Cc1ccc(OC)cc1)c1nc(Cl)nn2c(Br)cnc12
Solvent: CN1CCCC1=O
Product: CCN(Cc1ccc(OC)cc1)c1nc(Cl)nn2c(C#N)cnc12
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 101.9 %

Procedure:
(I10B): To an oven dried 500 ml round bottom flask was added 7-bromo-2-chloro-N-ethyl-N-(4-methoxybenzyl)imidazo[2,1-f][1,2,4]triazin-4-amine (12.5 g, 31.5 mmol) and copper(i) cyanide (9.0 g, 100 mmol). The flask was caped under nitrogen and NMP (250 mL) was added. The mixture stirred 5 min at 25° C. and the flask was evacuated and back-filled with nitrogen 3×. The reaction stirred at 135° C. (oil bath) 21 hr. The reaction cooled to 25° C., diluted with ethyl acetate (500 ml) and filter through edit bed. The bed was washed with EtoAc 3×100 ml and the filtrate washed with water 1×300 ml and brine 3×150 ml. The organics dried with sodium sulphate and remove solvent. The material was crystallized from IPA and filtered to afford 2-chloro-4-(ethyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (11 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:16])=[C:6]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)[CH:7]=1.[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCCC1>[CH2:17]([O:15][C:12]1[CH:13]=[CH:14][C:9]([CH2:8][C:6]2[CH:7]=[C:2]([Br:1])[CH:3]=[CH:4][C:5]=2[Cl:16])=[CH:10][CH:11]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: BrCc1ccccc1
Reactant: Oc1ccc(Cc2cc(Br)ccc2Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: Clc1ccc(Br)cc1Cc1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 70.4 %

Procedure:
To a solution of 4-[(5-bromo-2-chloro-phenyl)methyl]phenol 17b (2.0 g, 6.72 mmol, obtained from the synthetic method described in step 1 of example 17) and benzyl bromide (1.36 mL, 11.4 mmol) in tetrahydrofuran (20 mL) was added potassium carbonate (1.86 g, 13.4 mmol) at room temperature. The mixture was stirred at room temperature for 12 hours. The reaction mixture was quenched with saturated aqueous ammonium chloride and extracted with ethyl acetate (50 mL×3). The combined organic layers were washed with saturated aqueous sodium chloride (50 mL×2), dried over anhydrous sodium sulfate and filtered. The filtrated was concentrated in vacuo and the residue was purified by silica gel chromatography eluted with PE/EtOAc(v/v)=20/1 to give the title compound 25c as a white solid (1.83 g, 70.4%).
Reaction SMILES: C[CH2:2][N:3]([CH2:6][CH3:7])[CH2:4][CH3:5].BrC/C=[CH:11]/[C:12]([O:14][CH2:15][CH3:16])=[O:13].CC1CN1>C1COCC1.CCOC(C)=O>[CH2:15]([O:14][C:12](=[O:13])/[CH:11]=[CH:7]/[CH2:6][N:3]1[CH2:2][CH:4]1[CH3:5])[CH3:16]
Reactant: CCOC(=O)/C=C/CBr
Reactant: CCN(CC)CC
Agent: CC1CN1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)/C=C/CN1CC1C
Reaction time: 60 h

Procedure:
Add 10 mL of NEt3 to a solution of 9.2 mL of ethyl 4-bromocrotonate and 4 mL of 2-methylaziridine in 100 mL of THF. Stir for 60 h, during which time a white precipitate forms. Dilute the reaction mixture with 300 mL of EtOAc and wash with water and then with brine. Dry the organic solution over MgSO4, filter, and concentrate in vacuo to yield 6.7 g of crude product. Purify by flash chromatography (silica gel, 1:4 hexane/EtOAc) to yield 5.2 g of E-4-(2-methyl-1-aziridinyl)-2-butenoic acid ethyl ester.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[C:7]1([CH:13]2[CH:21]3[CH:17]([CH2:18][NH:19][CH2:20]3)[CH2:16][C:15]3[CH:22]=[CH:23][CH:24]=[CH:25][C:14]2=3)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH2:26]1[CH2:28][CH:27]1[C:29](N)=O.[OH-].[Na+]>O1CCCC1>[CH:27]1([CH2:29][N:19]2[CH2:18][CH:17]3[CH:21]([CH:13]([C:7]4[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=4)[C:14]4[CH:25]=[CH:24][CH:23]=[CH:22][C:15]=4[CH2:16]3)[CH2:20]2)[CH2:28][CH2:26]1
Reactant: c1ccc(C2c3ccccc3CC3CNCC32)cc1
Reactant: NC(=O)C1CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: c1ccc(C2c3ccccc3CC3CN(CC4CC4)CC32)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1 g of lithium aluminium hydride is added portionwise to a warm solution of 8.6 g of (3aRS,4SR,9aSR)-3a,4,9,9a-tetrahydro-4-phenyl-benz[f]-isoindoline-2-cyclopropylcarboxylic acid amide in 100 cc of tetrahydrofuran. The mixture is stirred at room temperature for 1 hour, is then decomposed with a 2 N caustic soda solution and filtered. The concentrated filtrate is reduced to a paste with silica gel in benzene/ethyl acetate (1:1), filtration and concentration by evaporation are effected, whereby the title compound, having a M.P. of 65-68° (after crystallization from pentane), is obtained.