Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:3]=1[NH2:4].ClOC(C)(C)C.CO[CH:18](OC)[CH2:19][S:20][CH3:21].C(N(CC)CC)C>C(Cl)Cl.O>[Cl:1][C:2]1[CH:8]=[C:7]([F:9])[CH:6]=[C:5]2[C:3]=1[NH:4][CH:18]=[C:19]2[S:20][CH3:21]
Reactant: COC(CSC)OC
Reactant: Nc1ccc(F)cc1Cl
Agent: CC(C)(C)OCl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CSc1c[nH]c2c(Cl)cc(F)cc12
Reaction time: 3 h
Yield: 46.2 %

Procedure:
Following the procedure described in J.Amer.Chem.Soc. 96 (17), 5495 (1974) 2-chloro-4-fluoroaniline (1.45 g, 10 mmole) was dissolved in methylene chloride (35 ml) and stirred vigorously at −65° C. under nitrogen while freshly prepared t-butyl hypochlorite (1.08 g, 10 mmole) dissolved in 10 ml methylene chloride was added dropwise. Ten minutes after the completion of the addition a solution of 1,1-dimethoxy-2-methylsulfanyl-ethane (1.36 g, 10 mmole) dissolved in 10 ml methylene chloride was added slowly. The reaction mixture was stirred at −65° C. for 1 h after which time, triethyl amine (1.01 g, 10 mmole) dissolved in 10 ml methylene chloride was added and the temperature was allowed to rise to room temperature. Water was added and the organic layer was separated, dried over magnesium sulfate, filtered and evaporated to dryness. The oily residue was taken up in carbon tetrachloride (35 ml) containing triethylamine (2 ml) and refluxed overnight. The solvent was removed and replaced with ether (35 ml) and stirred in a two-phase system with 12 ml of 2N HCl for about 3 h. The ether layer was then separated, washed with bicarbonate solution, dried over magnesium sulfate, filtered and evaporated to dryness. Purification by chromatography on silica gel (1:9 ethyl acetate:hexane) afforded the pure 7-chloro-5-fluoro-3-methylsulfanyl-1H-indole (0.997 g, 46% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](I)[CH:5]=[C:4]([C:9]([F:12])([F:11])[F:10])[N:3]=1.[Cu](C#N)[C:14]#[N:15]>CN1CCCC1=O.O.CCOC(C)=O>[Cl:1][C:2]1[CH:7]=[C:6]([CH:5]=[C:4]([C:9]([F:12])([F:11])[F:10])[N:3]=1)[C:14]#[N:15]
Reactant: FC(F)(F)c1cc(I)cc(Cl)n1
Reactant: N#C[Cu]C#N
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: N#Cc1cc(Cl)nc(C(F)(F)F)c1
Temperature: 120 °C

Procedure:
2-Chloro-4-iodo-6-(trifluoromethyl)pyridine (0.50 g, 1.5 mmol, prepared according to the method described in European Journal of Organic Chemistry, (18) 3793-3798; 2004) and copper cyanide (0.52 g, 5.8 mmol) were mixed in N-methylpyrrolidinone (2 mL). The reaction vial was sealed and heated in the microwave to 120° C. for 10 minutes. The mixture was diluted with water and EtOAc and was filtered. The organic layer was washed with water (3×), followed by brine, dried over sodium sulfate and concentrated. Flash chromatography on silica gel, eluting with a gradient from 0-15% EtOAc in hexanes afforded product as a colorless oil (0.24 g, 64%).
Reaction SMILES: C1CO[C:8]23OCCO[C:3]2([C@:4]2([CH2:27][CH2:26][C@H:25]4[C@@H:15]([CH2:16][C@H:17]([C:28]#[CH:29])[CH:18]5[C@:23]4([CH3:24])[CH2:22][CH2:21][CH2:20][CH2:19]5)[C@@H:6]2[CH2:7]3)[CH3:5])[O:2]1.C=C1C2[C@](C)(CCC(=[O:49])C2)[C@@H]2[C@H]([C@H]3[C@@](CC2)(C)C(=O)CC3)C1>>[C:28]([C@@H:17]1[CH:18]2[C@:23]([CH3:24])([CH2:22][CH2:21][C:20](=[O:49])[CH2:19]2)[C@@H:25]2[C@H:15]([C@H:6]3[C@@:4]([CH2:27][CH2:26]2)([CH3:5])[C:3](=[O:2])[CH2:8][CH2:7]3)[CH2:16]1)#[CH:29]
Reactant: C=C1C[C@@H]2[C@H](CC[C@]3(C)C(=O)CC[C@@H]23)[C@@]2(C)CCC(=O)CC12
Reactant: C#C[C@H]1C[C@@H]2[C@H](CC[C@@]3(C)[C@H]2CC24OCCOC23OCCO4)[C@@]2(C)CCCCC12
Product: C#C[C@H]1C[C@@H]2[C@H](CC[C@]3(C)C(=O)CC[C@@H]23)[C@@]2(C)CCC(=O)CC12
Yield: 46 %

Procedure:
The title compound II-am was prepared in 46% yield from 3,3:17,17-bis(ethylendioxy)-6α-ethynylandrostane by the procedure described for the preparation of 6-methyleneandrostane-3,17-dione (II-ac, Prepn. 13). The combined organic extracts were washed with H2O, dried over Na2SO4 and evaporated to dryness. The residue was purified by flash chromatography (SiO2, cyclohexane/CH2Cl2/acetone 80/10/10). 1H-NMR (300 MHz, acetone-d6, ppm from TMS): δ 2.69-0.78 (22H, m), 1.12 (3H, s), 0.87 (3H, s).
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][NH:13][CH2:12][CH:11]([NH:15][C:16](=[O:23])[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:10]2)=[CH:5][CH:4]=1.C(N(CC)CC)C.[C:33](Cl)(=[O:44])[O:34][C:35]1[CH:40]=[CH:39][C:38]([N+:41]([O-:43])=[O:42])=[CH:37][CH:36]=1.C(=O)(O)[O-].[Na+]>ClCCl.O>[C:17]1([C:16]([NH:15][CH:11]2[CH2:10][CH:9]([C:6]3[CH:5]=[CH:4][C:3]([C:2]([F:24])([F:1])[F:25])=[CH:8][CH:7]=3)[CH2:14][N:13]([C:33]([O:34][C:35]3[CH:36]=[CH:37][C:38]([N+:41]([O-:43])=[O:42])=[CH:39][CH:40]=3)=[O:44])[CH2:12]2)=[O:23])[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: O=C(NC1CNCC(c2ccc(C(F)(F)F)cc2)C1)c1ccccc1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NC1CC(c2ccc(C(F)(F)F)cc2)CN(C(=O)Oc2ccc([N+](=O)[O-])cc2)C1)c1ccccc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
At 0° C., 1.5 g (4.3 mmol) of N-{5-[4-(trifluoromethyl)phenyl]piperidin-3-yl}benzamide and 1.2 ml (1.1 mmol) of triethylamine were initially charged in 131 ml of dichloromethane, and 868 mg (4.3 mmol) of 4-nitrophenyl chlorocarbonate were added slowly. The mixture was stirred at 0° C. for 2 h and then warmed to RT. Water and saturated aqueous sodium bicarbonate solution were added, and the reaction mixture was extracted. The organic phase was concentrated under reduced pressure and purified by column chromatography (cyclohexane/ethyl acetate 1:2). Yield: 1.95 g (88% of theory)
Reaction SMILES: Cl[C:2]1[C:3]2[CH2:11][CH2:10][N:9]([C:12]3[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][N:13]=3)[CH2:8][C:4]=2[N:5]=[CH:6][N:7]=1.[NH2:19][C:20]1[CH:28]=[C:27]2[C:23]([C:24]([CH3:31])([CH3:30])[C:25](=[O:29])[NH:26]2)=[CH:22][CH:21]=1.C(#N)C.C([O-])(O)=O.[Na+]>CCOC(C)=O>[Cl:18][C:17]1[C:12]([N:9]2[CH2:10][CH2:11][C:3]3[C:2]([NH:19][C:20]4[CH:28]=[C:27]5[C:23]([C:24]([CH3:31])([CH3:30])[C:25](=[O:29])[NH:26]5)=[CH:22][CH:21]=4)=[N:7][CH:6]=[N:5][C:4]=3[CH2:8]2)=[N:13][CH:14]=[CH:15][CH:16]=1
Reactant: CC1(C)C(=O)Nc2cc(N)ccc21
Reactant: Clc1cccnc1N1CCc2c(Cl)ncnc2C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CC1(C)C(=O)Nc2cc(Nc3ncnc4c3CCN(c3ncccc3Cl)C4)ccc21
Temperature: 180 °C
Yield: 66 %

Procedure:
A mixture of the 4-chloro-7-(3-chloropyridin-2-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine (50 mg, 0.18 mmol), 6-amino-3,3-dimethylindolin-2-one (63 mg, 0.36 mmol), and acetonitrile (3 mL) was heated in a sealed tube via at 180° C. for 60 min. The mixture was treated with EtOAc (50 mL) and sat. aq. solution of NaHCO3. The organic layer was separated and washed with brine, dried (Na2SO4), and evaporated. The residue was purified by flash chromatography over silica gel to give a light yellow solid (50 mg).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[C:12]([N:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1)=[O:13])[C:6]([OH:8])=O)#[CH:2].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)CC)(C)C.[Cl:50][C:51]1[CH:62]=[CH:61][C:54]2[N:55]=[C:56]([CH:58]([NH2:60])[CH3:59])[NH:57][C:53]=2[CH:52]=1.ClCl>O1CCCC1.ClCCl.C(O)C>[Cl:50][C:51]1[CH:62]=[CH:61][C:54]2[NH:55][C:56]([CH:58]([NH:60][C:6](=[O:8])[C:5]3[CH:9]=[CH:10][C:11]([C:12]([N:14]4[CH2:18][CH2:17][CH2:16][CH2:15]4)=[O:13])=[C:3]([C:1]#[CH:2])[CH:4]=3)[CH3:59])=[N:57][C:53]=2[CH:52]=1
Reactant: C#Cc1cc(C(=O)O)ccc1C(=O)N1CCCC1
Reactant: CC(N)c1nc2ccc(Cl)cc2[nH]1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: ClCl
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: C#Cc1cc(C(=O)NC(C)c2nc3cc(Cl)ccc3[nH]2)ccc1C(=O)N1CCCC1
Yield: 46 %

Procedure:
Prepared analogously to Example 1g from 3-ethynyl-4-(pyrrolidin-1-ylcarbonyl)benzoic acid, TBTU, diisopropylethylamine, and rac.-1-(5-chlorobenzimidazol-2-yl)ethylamine in tetrahydrofuran. Yield: 46%; Rf value: 0.48 (silica gel; dichloromethane/ethanol=9:1); C23H21ClN4O2 (420.90); mass spectrum: (M+H)+=421/423 (chlorine isotope).
Reaction SMILES: [C:1]([C:4]1[S:5][CH:6]=[CH:7][CH:8]=1)(=O)[CH3:2].[C:9]([CH2:11][C:12]([O:14][CH3:15])=[O:13])#[N:10].C([O-])(=O)C.[NH4+].O>C(O)(=O)C.C1(C)C=CC=CC=1>[C:9](/[C:11](=[C:1](/[C:4]1[S:5][CH:6]=[CH:7][CH:8]=1)\[CH3:2])/[C:12]([O:14][CH3:15])=[O:13])#[N:10]
Reactant: CC(=O)c1cccs1
Reactant: COC(=O)CC#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: COC(=O)/C(C#N)=C(/C)c1cccs1
Yield: 40.1 %

Procedure:
400 g of 2-acetylthiophene, 314 g of methyl cyanoacetate and 48.8 g of ammonium acetate were dissolved in a mixture of 153 ml of acetic acid and 1.5 l of toluene, and the resulting reaction solution was refluxed under heating for 8 hours while water was removed. The reaction solution was washed sufficiently with water and then dried over anhydrous magnesium sulfate. Removal of the solvent by distillation was followed by vacuum distillation (b.p. 110°-140° C./0.05 mmHg) to give 263.4 g of methyl 2-cyano-3-(2-thienyl)crotonate. (Yield 40%)
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][O:15][C:16]2[CH:17]=[C:18]([O:26][S:27]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[Cl:36])(=[O:29])=[O:28])[CH:19]=[C:20]([C:22]([O:24][CH3:25])=[O:23])[CH:21]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O.Cl.[N:45]1(C(N)=N)C=CC=[N:46]1>C(Cl)Cl>[NH2:45][N:46]=[CH:6][N:8]1[CH2:9][CH2:10][CH:11]([CH2:14][O:15][C:16]2[CH:17]=[C:18]([O:26][S:27]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[Cl:36])(=[O:28])=[O:29])[CH:19]=[C:20]([C:22]([O:24][CH3:25])=[O:23])[CH:21]=2)[CH2:12][CH2:13]1
Reactant: COC(=O)c1cc(OCC2CCN(C(=O)OC(C)(C)C)CC2)cc(OS(=O)(=O)c2ccccc2Cl)c1
Reactant: N=C(N)n1cccn1
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1cc(OCC2CCN(C=NN)CC2)cc(OS(=O)(=O)c2ccccc2Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 20.2 %

Procedure:
2-Chlorobenzenesulfonic acid 3 -[[1-N-(tert-butoxycarbonyl)piperidin-4-yl]methoxy]-5-carbomethoxyphenyl ester (0.14 g, 0.26 mmol), as prepared in the preceding step, was treated with 2.5 mL of 25% trifluoroacetic acid in methylene chloride at ambient temperature for 15 min. The solvent was evaporated, the residue was azeotroped with acetonitrile (2 times), and placed under high vacuum. The residue was dissolved in methanol (3 mL) and treated with 1H-pyrazole-1-carboxamidine hydrochloride (0.057 g, 0.39 mmol) and N,N-duisopropylethylamine (0.136 mL, 0.78 mmol). The reaction mixture was stirred at ambient temperature overnight. An additional portion of 1H-pyrazole-1-carboxamidine hydrochloride (10 mg) was added to the reaction mixture and then was stirred for 6 h. The solvent was evaporated to dryness. The residue was triturated with hexane and ether. The residue was dissolved in acetonitrile and diluted with diethylether to produce a crystalline crop, which was collected by filtration to give 25.3 mg of solid. 1H-NMR (CDCl3 ; 300 MHz): δ 1.44-1.55 (m, 2H), 1.95-2.1 (m, 3H ), 3.11 (t, 2H ), 3.81 (d, 2H), 3.87 (s, 3H), 4.07 (d, 2H), 6.90 (t, 1H), 7.38 (m, 5H), 7.64 (m, 2H), 7.96 (m, 1H). Mass spectrum MADLDI-TOF) calcd. for C21H24N3O6SCl: 482.1 (M+H). Found 483.5.
Reaction SMILES: O[C:2]1[C:3]2[C:8]([C:9]3C=CC=C[C:14]=3[CH:15]=1)=CC=CC=2.[C:16]([OH:20])(=[O:19])[CH:17]=[O:18]>ClCCCl.C1(C)C=CC(S(O)(=O)=O)=CC=1>[OH:18][CH:17]1[C:15]2[CH:14]=[CH:9][CH:8]=[CH:3][C:2]=2[O:19][C:16]1=[O:20]
Reactant: Oc1cc2ccccc2c2ccccc12
Reactant: O=CC(=O)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCCl
Product: O=C1Oc2ccccc2C1O
Yield: 79.2 %

Procedure:
4.9 g of 9-hydroxyphenanthrene, 4.1 g of 50% aqueous glyoxylic acid and 0.05 g of p-toluenesulfonic acid are heated for 2 h in 70 ml of 1,2-dichloroethane under a water separator. The precipitated solid is then cooled down, filtered off, washed with cold 1,2-dichloroethane and dried to leave 3.0 g of hydroxybenzofuranone, which is introduced in 20 ml of toluene as initial charge together with 1.5 ml of thionyl chloride and 3 drops of DMF and then gradually heated to 100° C. so that the evolution of HCl and SO2 remains lively, but still controllable. The reaction mixture is subsequently stirred at 100° C. for 1 h. About 20 ml of liquid are then distilled off to remove excess thionyl chloride. The residue is diluted with 10 ml of toluene and admixed at room temperature with 1.7 ml of triethylamine added dropwise. The thick blue reaction mixture is then refluxed for 2 h. The precipitated isoxindigo is filtered off after cooling down to room temperature, freed of the triethylamine hydrochloride by washing with water, dried and recrystallized from dichloromethane/ethanol to leave 1.3 g (47% of theory) of [3,3′]bi[1-oxacyclopenta[l]phenanthrenylidene]-2,2′dione of the formula:
Reaction SMILES: S(=O)(=O)(O)O.O.[Cl:7][C:8]1[CH:14]=[C:13]([O:15][CH3:16])[C:12]([SH:17])=[CH:11][C:9]=1[NH2:10].[CH3:18][O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[C:26](O)([CH3:28])[CH3:27]>O1CCCC1>[Cl:7][C:8]1[CH:14]=[C:13]([O:15][CH3:16])[C:12]([S:17][C:26]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[O:19][CH3:18])([CH3:28])[CH3:27])=[CH:11][C:9]=1[NH2:10]
Reactant: COc1cc(Cl)c(N)cc1S
Reactant: COc1ccccc1C(C)(C)O
Agent: O=S(=O)(O)O
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(Cl)c(N)cc1SC(C)(C)c1ccccc1OC
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 33.7 %

Procedure:
To concentrated sulfuric acid (6 mL) was added water (6 mL) under ice-cooling, and the mixture was stirred at the same temperature for 10 minutes. To the mixture was added a solution of 2-chloro-5-mercapto-4-methoxyaniline (0.5 g) and 2-(2-methoxyphenyl)-2-propanol (0.88 g) in tetrahydrofuran (6 mL), and the mixture was stirred at room temperature for 3 hours. The reaction mixture was poured into ice water, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water, a saturated aqueous sodium hydrogen carbonate solution and brine successively, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane−n-hexane/ethyl acetate=4/1) to give the title compound (0.3 g).
Reaction SMILES: [Br-].[F:2][CH2:3][CH2:4][CH2:5]P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CC(C)([O-])C.[K+].[F:31][C:32]1[CH:33]=[C:34]([CH:39]2[CH2:44][CH2:43][C:42](=O)[CH2:41][CH2:40]2)[CH:35]=[C:36]([F:38])[CH:37]=1.O>C1COCC1>[F:31][C:32]1[CH:33]=[C:34]([CH:39]2[CH2:44][CH2:43][CH:42]([CH2:5][CH2:4][CH2:3][F:2])[CH2:41][CH2:40]2)[CH:35]=[C:36]([F:38])[CH:37]=1
Reactant: FCCC[PH](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C1CCC(c2cc(F)cc(F)c2)CC1
Agent: CC(C)(C)[O-]
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: FCCCC1CCC(c2cc(F)cc(F)c2)CC1
Temperature: 0 °C
Reaction time: 3 h
Yield: 21.4 %

Procedure:
THF in an amount of 100 ml was added to 12.5 g (31.0 mmol) of the 3-fluoropropyltriphenylphosphine bromide synthesized in the first step, and cooled down to 0° C. under nitrogen gas atmosphere. Solution of 3.4 g (31.0 mmol) of potassium-t-butoxide in 30 ml of THF was added thereto and stirred for 3 hours. To this reaction product was added dropwise a solution of 5.0 g (23.8 mmol) of the 4-(3,5-difluorophenyl)cyclohexanone synthesized in the second step in 50 ml of THF at 0° C., stirred at the temperature as it was for 1 hour, warmed up to room temperature, and then stirred for further 4 hours. Water in an amount of 100 ml was added to the reaction product, the product was extracted with ethyl acetate, the extract was washed with saturated aqueous sodium bicarbonate solution and water in turn, and then the organic layer was dried over magnesium sulfate. The solvent was distilled off under a reduced pressure and the residue was purified by column chromatography treatment using toluene as eluent. The purified product was subjected to hydrogenation in ethanol in the presence of 5% Pd/C catalyst. After termination of the reaction, the catalyst was filtered off, the ethanol was distilled off under a reduced pressure to obtain 1.3 g (5.1 mmol) of 4-(3,5-difluorophenyl)-1-(3-fluoropropyl)cyclohexane. Yield of this product from 4-(3,5-difluorophenyl)cyclohexanone was 21%.
Reaction SMILES: C(OC([N:6]1[CH2:11][CH2:10][N:9]([CH:12]2[C:18]3[CH:19]=[C:20]([CH3:23])[CH:21]=[CH:22][C:17]=3[O:16][C:15]3[CH:24]=[CH:25][C:26]([CH3:28])=[CH:27][C:14]=3[CH2:13]2)[CH2:8][CH2:7]1)=O)C.[OH-].[K+].C(O)CO>O>[CH3:28][C:26]1[CH:25]=[CH:24][C:15]2[O:16][C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][C:18]=3[CH:12]([N:9]3[CH2:10][CH2:11][NH:6][CH2:7][CH2:8]3)[CH2:13][C:14]=2[CH:27]=1
Reactant: CCOC(=O)N1CCN(C2Cc3cc(C)ccc3Oc3ccc(C)cc32)CC1
Agent: [K+]
Agent: [OH-]
Solvent: OCCO
Solvent: O
Product: Cc1ccc2c(c1)CC(N1CCNCC1)c1cc(C)ccc1O2

Procedure:
22.0 G. of 4-[10,11-dihydro-2,8-dimethyl-dibenz[b,f]oxepin-10-yl]-1-piperazinecarboxylic acid ethyl ester and 22 g. of potassium hydroxide are stirred in 320 ml. of ethyleneglycol and 1.5 ml. of water for 90 minutes at 160° C. After cooling, the mixture is diluted with 1.3 liters of water and extracted three times with ether. The ethereal extracts are washed twice with saturated sodium chloride solution, dried over sodium sulfate, evaporated in vacuo, and there is obtained crude 1-[10,11-dihydro-2,8-dimethyl-dibenz[b,f]oxepin-10-yl]-piperazine as an oil.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Br[C:21]1[N:29]2[C:24]([CH:25]=[N:26][C:27]([S:30][CH3:31])=[N:28]2)=[CH:23][CH:22]=1.Cl.[NH2:33][C:34]1[CH:35]=[C:36](B(O)O)[CH:37]=[CH:38][CH:39]=1.C(=O)([O-])[O-].[Na+].[Na+].Cl>O1CCCC1.C(O)C.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:31][S:30][C:27]1[N:26]=[CH:25][C:24]2=[CH:23][CH:22]=[C:21]([C:38]3[CH:39]=[C:34]([NH2:33])[CH:35]=[CH:36][CH:37]=3)[N:29]2[N:28]=1
Reactant: CSc1ncc2ccc(Br)n2n1
Reactant: Nc1cccc(B(O)O)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: CSc1ncc2ccc(-c3cccc(N)c3)n2n1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 39.1 %

Procedure:
Palladium Acetate (0.37 g, 0.0016 mol) and Triphenylphosphine (0.54 g, 0.0020 mol) were dissolved in Tetrahydrofuran (25 mL) and the mixture was allowed to stir at room temperature for 10 minutes. 7-Bromo-2-methylsulfanyl-pyrrolo[2,1-f][1,2,4]triazine (1.95 g, 0.00799 mol) and 3-Aminophenylboronic acid hydrochloride (2.84 g, 0.0164 mol) were added followed by 2.00 M of Sodium carbonate in Water (20.0 mL, 0.0400 mol) and Ethanol (25 mL). The reaction mixture was then heated at 75° C. and was allowed to stir overnight. The reaction mixture was diluted with water (40 mL), cooled and acidified with 12M HCl, then washed twice with EtOAc (50 mL). The org. wash was extracted with 3M HCl (3×30 mL) and the combined aq. extr. washed with EtOAc (2×50 mL). The aq. was then basified with 5N NaOH to pH 9, then extracted with DCM (4×30 mL). The DCM extr. was washed with brine (50 mL) and dried over sodium sulfate before conc. in vacuo. The residue was applied to a 25 g ISCO preload cartridge and purified on the ISCO (40 g, 5-40% EtOAc:Hex). Clean product was isolated from select fractions to afford 3-(2-Methylsulfanyl-pyrrolo[2,1-f][1,2,4]triazin-7-yl)-phenylamine (0.80 g, 39%).
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[C:9]([O:13][C:14]([NH:16][N:17]=[C:18]1[C:26]2[C:21](=[CH:22][C:23]([O:27][CH3:28])=[CH:24][CH:25]=2)[CH2:20][CH2:19]1)=[O:15])([CH3:12])([CH3:11])[CH3:10].[S:29]1[CH:33]=[CH:32][CH:31]=[C:30]1[C:34](OCC)=O.FC(F)(F)C(O)=O>CCCCCCC.C1COCC1.C(C1C=CC=CC=1)C.O1CCCC1.ClCCl>[CH3:28][O:27][C:23]1[CH:22]=[C:21]2[C:26](=[CH:25][CH:24]=1)[C:18]1[NH:17][N:16]([C:14]([O:13][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:15])[CH:34]([C:30]3[S:29][CH:33]=[CH:32][CH:31]=3)[C:19]=1[CH2:20]2
Reactant: CCOC(=O)c1cccs1
Reactant: COc1ccc2c(c1)CCC2=NNC(=O)OC(C)(C)C
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CCc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: CCCCCCC
Product: COc1ccc2c(c1)CC1=C2NN(C(=O)OC(C)(C)C)C1c1cccs1
Temperature: 25 °C

Procedure:
Lithium diisopropylamide (27.2 ml of a 2.0M solution in heptane/THF/ethylbenzene) was added dropwise to a stirred solution of 5-methoxyindan-1-one tert-butyloxycarbonylhydrazone (5.0 g) in tetrahydrofuran (150 ml) at −78° C. under nitrogen with stirring. After the addition was complete the mixture was stirred for 1.5 hours at −78° C. and then a solution of ethyl thiophen-2-carboxylate (3.39 g) in tetrahydrofuran (25 ml) was added dropwise. The mixture was stirred at −78° C. for 1.5 hours and then allowed to warm to ambient temperature. After 30 minutes the reaction mixture was quenched by the addition of saturated ammonium chloride solution and the layers were separated. The aqueous phase was extracted with ether. The combined organic phases were washed with 2M hydrochloric acid, dried, filtered and evaporated to give a residue which was dissolved in dichloromethane (100 ml) and trifluoroacetic acid (0.35 ml) was added. The mixture was stirred under a nitrogen atmosphere at ambient temperature and then purified by flash column chromatography using ethyl acetate/petroleum ether b.p 60-80° C. (4:1) as the mobile phase to give 6-methoxy-2-tert-butyloxycarbonyl-3-(2-thienyl)-1,4-dihydroindeno[1,2-c]pyrazole.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]([NH:13][CH:14]1[C:21](=[O:22])[N:20]2[CH:23]([C:26](O)=[O:27])[CH2:24][CH2:25][CH:19]2[CH2:18][CH:17]=[CH:16][CH2:15]1)=[O:12].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1.[CH2:57]([O:64][C:65](=[O:78])[CH2:66][CH:67]([NH2:77])[CH2:68][O:69][Si:70]([C:73]([CH3:76])([CH3:75])[CH3:74])([CH3:72])[CH3:71])[C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=1>C1COCC1.O>[CH2:57]([O:64][C:65](=[O:78])[CH2:66][CH:67]([NH:77][C:26]([CH:23]1[N:20]2[C:21](=[O:22])[CH:14]([NH:13][C:11]([C:2]3[CH:3]=[CH:4][C:5]4[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=4)[CH:1]=3)=[O:12])[CH2:15][CH:16]=[CH:17][CH2:18][CH:19]2[CH2:25][CH2:24]1)=[O:27])[CH2:68][O:69][Si:70]([C:73]([CH3:74])([CH3:75])[CH3:76])([CH3:72])[CH3:71])[C:58]1[CH:59]=[CH:60][CH:61]=[CH:62][CH:63]=1
Reactant: CC(C)(C)[Si](C)(C)OCC(N)CC(=O)OCc1ccccc1
Reactant: O=C(NC1CC=CCC2CCC(C(=O)O)N2C1=O)c1ccc2ccccc2c1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCC(CC(=O)OCc1ccccc1)NC(=O)C1CCC2CC=CCC(NC(=O)c3ccc4ccccc4c3)C(=O)N21
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 67.9 %

Procedure:
A solution containing 6-[(Naphthalene-2-carbonyl)-amino]-5-oxo-1,2,3,5,6,7,10,10a-octahydro-pyrrolo[1,2-a]azocine-3-carboxylic acid (425 mg, 1.12 mmol), EDCI (240 mg, 1.25 mmol), HOBt (170 mg, 1.25 mmol), and NMM (0.15 mL, 1.25 mmol) in THF (15 mL) is stirred at rt for 20 min. A solution of 3-Amino-4-(tert-butyl-dimethyl-silanyloxy)-butyric acid benzyl ester (400 mg, 1.25 mmol, prepared by methods outlined in Chem. Pharm. Bull. 1999, 47, 11–21) in 5 mL of THF is added and the solution is stirred at rt for 12 h. The solution is poured into water and the aqueous solution is extracted with EtOAc. The combined organic extracts are washed with saturated NaHCO3 and brine, dried (Na2SO4), filtered, concentrated, and purified by flash chromatography on silica gel (hexane/EtOAc) to yield 520 mg of desired product. 1H NMR (CDCl3) δ 8.33 (s, 1H), 7.88 (m, 4H), 7.56 (m, 3H), 7.36 (m, 4H), 7.14 (d, J=8.4 Hz, 1H), 5.86 (m, 1H), 5.75 (m, 1H), 5.46 (m, 1H), 5.13 (s, 2H), 4.63 (d, J=7.5 Hz, 1H), 4.40 (m, 1H), 5.75 (m, 1H), 5.46 (m, 1H), 5.13 (s, 2H), 4.63 (d, J=13.5 Hz, 1H), 2.94 (m, 1H), 2.75–2.56 (m, 2H), 2.37–2.21 (m, 2H), 2.10–1.70 (m, 3H), 0.93 (s, 9H), 0.08 (s, 3H), 0.07 (s, 3H).