Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:17]=[CH:16][C:15]2[C:10](=[C:11]([NH:18][C:19]([C:21]3[N:22]=[CH:23][S:24][CH:25]=3)=[O:20])[CH:12]=[CH:13][CH:14]=2)[N:9]=1.Cl[CH2:27][CH2:28][N:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[O:32]1[CH2:33][CH2:34][N:29]([CH2:28][CH2:27][O:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[C:11]([NH:18][C:19]([C:21]4[N:22]=[CH:23][S:24][CH:25]=4)=[O:20])[CH:12]=[CH:13][CH:14]=3)[N:9]=2)[CH2:30][CH2:31]1
Reactant: O=C(Nc1cccc2ccc(-c3ccccc3O)nc12)c1cscn1
Reactant: ClCCN1CCOCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=C(Nc1cccc2ccc(-c3ccccc3OCCN3CCOCC3)nc12)c1cscn1
Temperature: 200 °C

Procedure:
A solution of N-(2-(2-hydroxyphenyl)quinolin-8-yl)thiazole-4-carboxamide (0.1 g, 0.287 mmol), 4-(2-chloroethyl)morpholine (0.129 g, 0.862 mmol), and cesium carbonate (0.7 g, 2.15 mmol) in DMF (5 mL) was microwave heated (200° C.×2 hours). The crude material was filtered and purified by silica gel chromatography (gradient of 0 to 90% ethyl acetate in pentane). MS (ESI) calcd for C25H24N4O3S (m/z): 460.16. found: 461 [M+1].
Reaction SMILES: [Cl:1][C:2]1[C:10]2[O:9][C:8]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[O:7][C:6]=2[C:5]([Cl:23])=[CH:4][C:3]=1[CH2:24][OH:25].O[N:27]1[C:31](=[O:32])[C:30]2=[CH:33][CH:34]=[CH:35][CH:36]=[C:29]2[C:28]1=[O:37].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[Cl:1][C:2]1[C:10]2[O:9][C:8]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)([C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)[O:7][C:6]=2[C:5]([Cl:23])=[CH:4][C:3]=1[CH2:24][O:25][N:27]1[C:28](=[O:37])[C:29]2=[CH:36][CH:35]=[CH:34][CH:33]=[C:30]2[C:31]1=[O:32]
Reactant: OCc1cc(Cl)c2c(c1Cl)OC(c1ccccc1)(c1ccccc1)O2
Reactant: O=C1c2ccccc2C(=O)N1O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1OCc1cc(Cl)c2c(c1Cl)OC(c1ccccc1)(c1ccccc1)O2
Yield: 66.2 %

Procedure:
4,7-Dichloro-2,2-diphenyl-1,3-benzodioxol-5-methanol (250 mg) (0.67 mmol), 108 mg (0.67 mmol) of N-hydroxyphthalimide and 175 mg (0.67 mmol) of triphenylphosphine are suspended in 20 ml of absolute tetrahydrofuran. 128 mg (0.73 mmol) of diethyl azodicarboxylate are added dropwise at 0° C. while stirring. The mixture is stirred at 0° C. for 1 hour and at room temperature for 24 hours. Subsequently, the solvent is removed in a high vacuum. The residue is crystallized and recrystallized from ethanol/diethyl ether. There are obtained 230 mg of N-[(4,7-dichloro-2,2-diphenyl-1,3-benzodioxol-5-yl)methoxy]phthalimide as white crystals of m.p. 127°-129° C.
Reaction SMILES: Cl[S:2]([C:5]1[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[C:6]=1[C:7]([O:9][CH3:10])=[O:8])(=[O:4])=[O:3].[NH2:18][CH2:19][CH:20]([OH:22])[CH3:21].Cl>C1COCC1>[OH:22][CH:20]([CH3:21])[CH2:19][NH:18][S:2]([C:5]1[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[C:6]=1[C:7]([O:9][CH3:10])=[O:8])(=[O:4])=[O:3]
Reactant: COC(=O)c1c([N+](=O)[O-])cccc1S(=O)(=O)Cl
Reactant: CC(O)CN
Agent: Cl
Solvent: C1CCOC1
Product: COC(=O)c1c([N+](=O)[O-])cccc1S(=O)(=O)NCC(C)O
Temperature: 0 °C
Yield: 63.5 %

Procedure:
A solution of methyl 2-chlorosulfonyl-6-nitrobenzoate (2.80 g, 10 mmol) in 100 ml of THF was cooled in an ice-bath and stirred while a solution of 1-amino-2-propanol (1.65 g, 22 mmol) in 10 ml of THF was added dropwise over a period of 50 minutes. After stirring an additional 30 minutes in the ice-bath, the reaction mixture was acidified by the addition of 3 ml of 1.2N HCl. The THF was evaporated under reduced pressure and the residue taken up in 100 ml of ethyl acetate. After extracting with 4×20 ml of saturated NaCl solution, the ethyl acetate solution was dried over Na2SO4 and the solvent evaporated. The residue was crystallized from a mixture of ethyl acetate and hexane to give 2.02 g (63.5%) of yellow crystalline product, m.p., 93.5°-95°.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH2:7]([O:14][C:15]1[N:20]=[CH:19][C:18]([C:21]2[CH:26]=[CH:25][C:24]([CH2:27][C:28]([NH:30][C:31]3[CH:36]=[CH:35][C:34]([CH2:37][C:38]([CH3:45])([CH3:44])[C:39](OCC)=[O:40])=[C:33]([C:46]([F:49])([F:48])[F:47])[CH:32]=3)=[O:29])=[C:23]([F:50])[CH:22]=2)=[C:17]([O:51][CH2:52][CH3:53])[CH:16]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>C1COCC1>[CH2:7]([O:14][C:15]1[N:20]=[CH:19][C:18]([C:21]2[CH:26]=[CH:25][C:24]([CH2:27][C:28]([NH:30][C:31]3[CH:36]=[CH:35][C:34]([CH2:37][C:38]([CH3:45])([CH3:44])[CH2:39][OH:40])=[C:33]([C:46]([F:47])([F:49])[F:48])[CH:32]=3)=[O:29])=[C:23]([F:50])[CH:22]=2)=[C:17]([O:51][CH2:52][CH3:53])[CH:16]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CCOC(=O)C(C)(C)Cc1ccc(NC(=O)Cc2ccc(-c3cnc(OCc4ccccc4)cc3OCC)cc2F)cc1C(F)(F)F
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOc1cc(OCc2ccccc2)ncc1-c1ccc(CC(=O)Nc2ccc(CC(C)(C)CO)c(C(F)(F)F)c2)c(F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 20.9 %

Procedure:
LAH (17.45 mg, 0.460 mmol) was added to a solution of ethyl 3-(4-(2-(4-(6-(benzyloxy)-4-ethoxypyridin-3-yl)-2-fluorophenyl)acetamido)-2-(trifluoromethyl)phenyl)-2,2-dimethylpropanoate (100 mg, 0.153 mmol) in THF (5 mL). The reaction mixture was stirred at 25° C. for 1 h. The reaction was then extracted with EA (50 mL), washed with water and NaOH solution and dried over Na2SO4. The combined organic extracts were purified by preparative TLC (PE/EA=2:1, Rf=0.4) to yield a light yellow oil of 2-(4-(6-(benzyloxy)-4-ethoxypyridin-3-yl)-2-fluorophenyl)-N-(4-(3-hydroxy-2,2-dimethylpropyl)-3-(trifluoromethyl)phenyl)acetamide (20 mg, 0.032 mmol, 20.9% yield): 1H NMR (400 MHz, CD3OD) δ 7.94-8.03 (m, 2H) 7.77 (d, J=8.53 Hz, 1H) 7.46 (t, J=7.53 Hz, 3H) 7.36-7.43 (m, 3H) 7.27-7.35 (m, 3H) 6.52 (s, 1H) 5.38 (s, 2H) 3.83 (s, 2H) 2.81 (s, 2H) 2.03 (s, 4H) 1.40 (t, J=6.78 Hz, 3H) 1.26 (t, J=7.28 Hz, 3H) 0.82-0.90 (m, 6H); ES-LCMS m/z 611 (M+H).
Reaction SMILES: [CH3:1][C:2]([CH3:9])([CH3:8])[C:3](=O)[CH2:4][S:5][CH3:6].Cl.[NH2:11][OH:12].C(=O)([O-])[O-].[Na+].[Na+]>C(O)C.O>[CH3:1][C:2]([CH3:9])([CH3:8])[C:3](=[N:11][OH:12])[CH2:4][S:5][CH3:6]
Reactant: NO
Reactant: CSCC(=O)C(C)(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CSCC(=NO)C(C)(C)C

Procedure:
A solution of 20.4 g (0.14 mol) of 3,3-dimethyl-1-methylthio-2-butanone, 19.6 g (0.28 mol) of hydroxylamine hydrochloride and 14.8 g (0.14 mol) of anhydrous sodium carbonate in 140 ml of 95% ethanol and 80 ml of water was heated at reflux for 16 hr. The resulting nearly colorless solution was stripped of volatiles on a rotary evaporator to yield a two layered liquid residue. This residue was extracted with four portions of ethyl acetate. The organic extract was dried over magnesium sulfate, filtered from the drying agent and stripped of solvent. Distillation of the residue gave the desired product as a colorless liquid, b. 83° C./0.6 mm Hg, nD22 1.4989.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[CH:9]=[C:8]([C:15]#[C:16][C:17]([O:19]CC)=[O:18])[CH2:7][CH2:6]2.[OH-].[K+].Cl>CO.O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[CH:9]=[C:8]([C:15]#[C:16][C:17]([OH:19])=[O:18])[CH2:7][CH2:6]2
Reactant: CCOC(=O)C#CC1=Cc2cc(OC)c(OC)cc2CC1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COc1cc2c(cc1OC)CCC(C#CC(=O)O)=C2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 103.4 %

Procedure:
Added to a solution of 65.2 mg (0.23 mmol) of ethyl 3-(3,4-dihydro-6,7-dimethoxy-2-naphthyl)-2-propynoate synthesized by the process described in Referential Example 13 in methanol-tetrahydrofuran (1:1; 1 ml) was 0.5 ml (2.5 mmol) of a 5N aqueous solution of potassium hydroxide, and the mixture was stirred for 30 minutes at room temperature. A saturated saline solution and 0.25 ml (3.0 mmol) of concentrated hydrochloric acid were added to the reaction mixture to conduct extraction with chloroform. An organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The resultant concentrated residue was purified by column chromatography on silica gel to obtain 61.4 mg (quantitative) of 3-(3,4-dihydro-6,7-dimethoxy-2-naphthyl)-2-propynoic acid as a colorless amorphous powder.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2=[N:15][N:16]([CH2:18][CH3:19])[CH2:17][N:13]2[C:12]2[S:20](=[O:23])[CH2:21][CH2:22][C:11]=2[CH2:10][N:9]=1.[CH3:24][N:25]=[C:26]=[O:27]>C(Cl)(Cl)Cl>[CH3:24][NH:25][C:26]([CH:21]1[S:20](=[O:23])[C:12]2[N:13]3[CH2:17][N:16]([CH2:18][CH3:19])[N:15]=[C:14]3[C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])=[N:9][CH2:10][C:11]=2[CH2:22]1)=[O:27]
Reactant: CCN1CN2C(=N1)C(c1ccccc1Cl)=NCC1=C2S(=O)CC1
Reactant: CN=C=O
Solvent: ClC(Cl)Cl
Product: CCN1CN2C(=N1)C(c1ccccc1Cl)=NCC1=C2S(=O)C(C(=O)NC)C1

Procedure:
9 g of 6-o-chlorophenyl-8-ethyl-1,2-dihydro-4H-s-triazolo [3,4-c]-thieno[2,3-e][1,4]diazepin-1-one is dissolved in 50 ml of chloroform, and 5 ml of methyl isocyanate is added, and the resulting mixture is refluxed for 8 hours. Then the chloroform is removed under reduced pressure, and the remaining jelly-like substance is treated with ligroin to give the title compound as white crystals. The product, when recrystallized from a mixture of ethanol and chloroform, shows a melting point of 193°-194° C.
Reaction SMILES: [H-].[Li+].[Cl:3][C:4]1[CH:21]=[CH:20][C:7]([NH:8][C:9]2[S:10][C:11]3[N:19]=[CH:18][CH:17]=[CH:16][C:12]=3[C:13](=[O:15])[N:14]=2)=[CH:6][CH:5]=1.Br[CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25]>CN(C=O)C>[Cl:3][C:4]1[CH:21]=[CH:20][C:7]([N:8]=[C:9]2[N:14]([CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:13](=[O:15])[C:12]3[CH:16]=[CH:17][CH:18]=[N:19][C:11]=3[S:10]2)=[CH:6][CH:5]=1
Reactant: O=c1nc(Nc2ccc(Cl)cc2)sc2ncccc12
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: CCOC(=O)Cn1c(=Nc2ccc(Cl)cc2)sc2ncccc2c1=O
Reaction time: 0.08 h
Yield: 63.1 %

Procedure:
In an atmosphere of argon, a mixture of 32 mg (4.0 mmol) of lithium hydride and 7 ml of DMF was put in a 100 ml flask. To the flask was then connected a dropping funnel which contained 1.0 g (3.5 mmol) of 2-(4-chloroanilino)-4H-pyrido[3,2-e]-1,3-thiazin-4-one and 12 ml of DMF. The solution of 2-(4-chloroanilino)-4H-pyrido[3,2-e]-1,3-thiazin-4-one was then added dropwise to the aforementioned mixture with stirring in 5 minutes. The mixture was further stirred for 20 minutes. To the mixture was then added a mixture of 605 mg of ethyl bromoacetate and 4 ml of DMF. The mixture was then stirred for 11 hours. After the termination of reaction, the mixture was concentrated under reduced pressure. The resulting residue was then extracted with water and ethyl acetate. The resulting organic phase was separated, washed with water and saturated brine, and then dried over sodium sulfate. The drying agent was then removed by filtration. The filtrate was then concentrated under reduced pressure. The resulting residue was then purified through silica gel column chromatography (eluant: 1/1 mixture of ethyl acetate and normal hexane). As a result, 830 mg of ethyl 2-[2-[(4-chlorophenyl)imino]-2,3-dihydro-4-oxo-4H-pyrido[3,2-e]-1,3-thiazin-3-yl]acetate was obtained as a low polarity substance, and 350 mg of ethyl 2-[N-(4-chlorophenyl)-N-(4-oxo-4H-pyrido[3,2-e]-1,3-thiazin-2-yl)amino]acetate was obtained as a high polarity substance.
Reaction SMILES: C([O:4][CH2:5][CH2:6][NH:7][C:8](=[O:25])[N:9]([CH3:24])[CH:10]1[C:23]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[O:17][C:16]2[C:11]1=[CH:12][CH:13]=[CH:14][CH:15]=2)(=O)C.[C-]#N.[K+]>CO>[OH:4][CH2:5][CH2:6][NH:7][C:8](=[O:25])[N:9]([CH3:24])[CH:10]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=2[O:17][C:18]2[C:23]1=[CH:22][CH:21]=[CH:20][CH:19]=2
Reactant: CC(=O)OCCNC(=O)N(C)C1c2ccccc2Oc2ccccc21
Agent: [C-]#N
Agent: [K+]
Solvent: CO
Product: CN(C(=O)NCCO)C1c2ccccc2Oc2ccccc21

Procedure:
N'-2-Acetoxyethyl-N-methyl-N-9-xanthenylurea (2.1 g.), methanol (20 ml.) and potassium cyanide (50 mg.) were refluxed for 20 minutes and then evaporated to dryness. Recrystallisation of the residue from benzene and then from methylene chloride gave N'-(2-hydroxyethyl)-N-methyl-N-9-xanthenylurea as a hydrate, m.p. 130°-132°C.
Reaction SMILES: [S:1]1[CH:5]=[C:4]([CH:6]=O)[C:3]2[CH:8]=[CH:9][CH:10]=[CH:11][C:2]1=2.[S:12]1[CH:16]=[CH:15][CH:14]=[C:13]1[CH2:17][C:18]#[N:19]>>[S:1]1[CH:5]=[C:4](/[CH:6]=[C:17](/[C:13]2[S:12][CH:16]=[CH:15][CH:14]=2)\[C:18]#[N:19])[C:3]2[CH:8]=[CH:9][CH:10]=[CH:11][C:2]1=2
Reactant: O=Cc1csc2ccccc12
Reactant: N#CCc1cccs1
Product: N#C/C(=C\c1csc2ccccc12)c1cccs1
Yield: 30 %

Procedure:
Benzo[b]thiophene-3-carboxaldehyde (81 mg) was condensed with 2-thiopheneacetonitrile (62 mg) through Method B (production step 3), to thereby yield the target product (yield: 40 mg, 30%).
Reaction SMILES: CC(O[CH2:5][C:6]1[CH2:27][S:26][C@@H:9]2[C@H:10]([NH:13][C:14](/[C:16](/[C:20]3[N:24]=[C:23]([NH2:25])[S:22][CH:21]=3)=[N:17]\[O:18][CH3:19])=[O:15])[C:11](=[O:12])[N:8]2[C:7]=1[C:28]([OH:30])=[O:29])=O.[N-:31]=[N+:32]=[N-:33].[Na+].[I-].[Na+]>P([O-])([O-])([O-])=O>[N:31]([CH2:5][C:6]1[CH2:27][S:26][C@@H:9]2[CH:10]([NH:13][C:14](=[O:15])/[C:16](/[C:20]3[N:24]=[C:23]([NH2:25])[S:22][CH:21]=3)=[N:17]\[O:18][CH3:19])[C:11](=[O:12])[N:8]2[C:7]=1[C:28]([OH:30])=[O:29])=[N+:32]=[N-:33]
Reactant: CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)O)=C(COC(C)=O)CS[C@H]12)c1csc(N)n1
Reactant: [N-]=[N+]=[N-]
Agent: O=P([O-])([O-])[O-]
Agent: [I-]
Agent: [Na+]
Product: CO/N=C(\C(=O)NC1C(=O)N2C(C(=O)O)=C(CN=[N+]=[N-])CS[C@H]12)c1csc(N)n1
Reaction time: 4.5 h

Procedure:
To a solution of cefotaxime (5.24 g.) in phosphate buffer (pH 6.4, 440 ml.) was added sodium azide (2.86 g.) and sodium iodide (1.65 g.) and the mixture was immersed in a 70° bath with stirring for 4.5 hours. The solvent was evaporated to the point of precipitation and then the pH adjusted to 2.5 with 2N aqueous HCl. The resulting precipitate was collected, washed with water, acetone and ether and dried over P2O5 to give 3-azidomethyl-7-[2-(2-aminothiazol-4-yl)-2-((Z)-methoxyimino)acetamido]ceph-3-em-4-carboxylic acid in quantative yield, having the following n.m.r. in solvent A: 3.4 (d, 1H); 3.7 (d, 1H); 3.86 (s, 3H); 3.95 (d, 1H); 4.4 (d, 1H); 5.15 (d, 1H); 5.78 (d, 1H); 6.75 (s, 1H).
Reaction SMILES: [CH2:1]1C2C(=CC=CC=2)C[C:2]1=[O:10].[C:11]1([CH3:17])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[CH:2]1([OH:10])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:17][CH2:1]1
Reactant: O=C1Cc2ccccc2C1
Reactant: Cc1ccccc1
Product: OC1CCc2ccccc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A 3-neck 500 mL round-bottomed flask fitted with a condenser and an addition funnel was charged with 2.62 g (0.11 mol) of Mg turnings and 20 mL of anhydrous diethyl ether. Slow addition of a solution of 25.10 g (0.09 mol) of 3,5-bis(trifluoromethyl) bromobenzene in diethyl ether (100 mL), followed by refluxing for 30 min, gave a brown-grey solution of the aryl Grignard reagent. The solution was cooled to room temperature (RT), filtered over a plug of Celite and evacuated to yield a brown oil. Toluene (40 mL) was added and the suspension cooled to 0° C. whereupon a solution of 2-indanone (9.22 g, 0.07 mol) in toluene (60 mL) was added dropwise to give a tan-brown slurry. This mixture was warmed to room temperature and stirred for an additional 3 hours. After cooling to 0° C. it was quenched with 150 mL of water, hexane (200 mL) added and the reaction mixture neutralized with 5 M HCl. The organic layer was separated, and the aqueous layer was extracted with two 50-mL portions of hexane. The combined organic layers were washed with two 50-mL portions of brine and dried over anhydrous magnesium sulfate. After filtration over Celite, the solvent was removed under vacuo yielding 21.5 g (89% based on 2-indanone) of 2-(bis-3,5-trifluoromethylphenyl) indanol as an off-white solid. 1H NMR (CDCl3, 23 C, 400 MHz): d 8.05 (s, 2H), 7.80 (s, 1H), 7.5-7.0 (M, 4H), 3.41 (m, 4H), 2.21 (s, 1H, OH). Under argon, this alcohol (21.5 g, 0.06 mol) and p-toluene-sulfonic acid monohydrate (800 mg) were dissolved in toluene (250 mL) and the solution was heated to reflux for 6 hours to afford 14.4 g, (70%) of 2-(bis-3,5(trifluoromethyl)-phenyl) indene upon recrystallization from diethyl ether/hexane at −18 C. 1H NMR (CDCl3, 23° C., 400 MHz): d 8.01 (s, 2H), Arf), 7.75 (s, 1H, Arf), 7.52 (d, J=7 Hz, 1H), 7.47 (d, J=7 Hz, 1H), 7.43 (s, 1H), 7.33 (dd, 2J=7 Hz, 1H), 7.27 (dd, 2J=7 Hz, 1H), 2.83 (s, 2H). 13C NMR (CDCl3, 23 C, 100 MHz): L144.3 (s), 143.1 (s), 138.0 (s), 132.1 (q, 2JC—F=33 Hz), 130.1 (d, JC—H=167 Hz), 127.0 (dd), JC—H=160 Hz, 2JC—H=7 Hz), 126.0 (dd, JC—H=159 Hz, 2JC—H=7 Hz)m 125.2 (brd, JC—H=162 Hz), 123.9 (dd, JC—H=156 Hz, 2JC—H=9 Hz), 123.4 (q, JC—F=273 Hz, CF3), 121.8 (dd, Jc-H=160 Hz, 2JC—H=8 Hz), 120.6 (brd, JC—H=167 Hz), 38.9 (td, JC—H=127 Hz, JC—H=7 Hz, CH2). C,H analysis: Anal. Found (Calcd): C, 62.45 (62-20); H 3.01 (3.07).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][O:8][C:9]1[C:21]2[CH2:20][CH2:19][C@H:18]3[C@H:14]([CH2:15][C:16](=O)[N:17]3[CH2:22][CH2:23][CH:24]([CH3:26])[CH3:25])[C:13]=2[CH:12]=[CH:11][CH:10]=1.[OH-].[Na+].[O-]S([O-])(=O)=O.[Na+].[Na+]>C1COCC1.O>[CH3:7][O:8][C:9]1[C:21]2[CH2:20][CH2:19][C@H:18]3[C@H:14]([CH2:15][CH2:16][N:17]3[CH2:22][CH2:23][CH:24]([CH3:26])[CH3:25])[C:13]=2[CH:12]=[CH:11][CH:10]=1
Reactant: COc1cccc2c1CC[C@H]1[C@@H]2CC(=O)N1CCC(C)C
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Product: COc1cccc2c1CC[C@H]1[C@@H]2CCN1CCC(C)C
Yield: 91.1 %

Procedure:
0.98 g (0.02593 mol) of lithium aluminum hydride was suspended in 50 ml of THF under argon. A solution of 3.61 g (0.01297 mol) of rac-cis-1,3,3a,4,5,9b-hexahydro-6-methoxy-3-(3-methyl-butyl)-2H-benzo[e]indol-2-one in 50 ml of THF was added dropwise thereto and the mixture was boiled under reflux for 2 hours. 1.0 ml of water, 1.0 ml of a 4N aqueous NaOH solution and 3.0 ml of water were cautiously added dropwise thereto in succession, whereupon the mixture was boiled at reflux until a complete white precipitate had resulted. After the addition of dry Na2SO4, filtration and concentration there was obtained an oil which was chromatographed over silica gel with cyclohexane/ethyl acetate 1:1. There were obtained 3.23 g (94%) of oily rac-cis-2,3,3a,4,5,9b-hexahydro-6-methoxy-3-(3-methyl-butyl)-1H-benzo[e]indole.
Reaction SMILES: [CH3:1][C:2]([C:11]([F:14])([F:13])[F:12])([CH:9]=[CH2:10])[CH2:3][C:4](OCC)=[O:5].[H-].[H-].[H-].[H-].[Li+].[Al+3]>C(OCC)C>[CH3:1][C:2]([C:11]([F:12])([F:14])[F:13])([CH:9]=[CH2:10])[CH2:3][CH2:4][OH:5]
Reactant: C=CC(C)(CC(=O)OCC)C(F)(F)F
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: C=CC(C)(CCO)C(F)(F)F
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Ethyl 3-methyl-3-(trifluoromethyl)pent-4-enoate (5 g, 23.8 mmol) in diethyl ether (20 mL) was added dropwise to a suspension of LAH (291 mg, 1.67 mmol) in diethyl ether (80 mL). After stirring at −78° C. for 30 min and at 0° C. for a further 30 min, the reaction mixture was quenched with sodium potassium tartrate and stirred vigorously until layers separated. The aqueous phase was extracted with diethyl ether. The combined ethereal layers were dried (magnesium sulfate) and concentrated in vacuo to afford 3-methyl-3-(trifluoromethyl)pent-4-en-1-ol which was used in the subsequent step without further purification.
Reaction SMILES: [S:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([NH:10][CH2:11][CH2:12][CH2:13][NH2:14])=[N:2]1.C(N(C(C)C)CC)(C)C.[CH3:24][O:25][C:26]1[CH:34]=[CH:33][C:29]([C:30](Cl)=[O:31])=[CH:28][CH:27]=1>C(Cl)Cl>[S:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([NH:10][CH2:11][CH2:12][CH2:13][NH:14][C:30](=[O:31])[C:29]2[CH:33]=[CH:34][C:26]([O:25][CH3:24])=[CH:27][CH:28]=2)=[N:2]1
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: NCCCNc1nsc2ncccc12
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(C(=O)NCCCNc2nsc3ncccc23)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 32.9 %

Procedure:
N1-(Isothiazolo[5,4-b]pyridin-3-yl)propane-1,3-diamine (100 mg, 0.48 mmol) was dissolved in anhydrous methylene chloride with diisopropylethylamine (0.23 mL, 1.34 mmol). The mixture was cooled in an ice-bath under nitrogen and a solution of 4-methoxybenzoyl chloride (98 mg, 0.58 mmol) in methylene chloride (5 mL) was added drop-wise. After the addition was completed the ice-bath was removed and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with methylene chloride and then washed successively with saturated sodium bicarbonate solution and brine. The organic solution was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by prep-scale reverse phase high performance liquid chromatography to yield N-(3-(isothiazolo[5,4-b]pyridin-3-ylamino)propyl)-4-methoxybenzamide (54 mg). 1H NMR (300 MHz, DMSO-d6): 8.68 (d, 1H), 8.55 (t, 1H), 8.45 (d, 1H), 8.18 (s, 1H), 7.82-7.85 (m, 2H), 7.41 (dd, 1H), 7.26-7.36 (m, 2H), 3.95 (s, 3H), 3.40-3.42 (dd, 2H), 3.39-3.40 (dd, 2H), 1.82-1.95 ppm (m, 2H). MW=342 confirmed by LC-MS, tr=10.82 min (Method Y) MH+=343.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([C:15]3(O)[CH2:19][CH2:18][S:17][CH2:16]3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:15]3[CH2:19][CH2:18][S:17][CH2:16]3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1ccc(C2(O)CCSC2)cc1OC1CCCC1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc(C2CCSC2)cc1OC1CCCC1
Reaction time: 3.5 h
Yield: 48.2 %

Procedure:
A solution of 3-(3-cyclopentyloxy-4-methoxyphenyl)-3-hydroxytetrahydrothiophene (2.94 g; which is prepared as described in Example 14) and triethylsilane (2.7 mL) in dichloromethane (30 mL) under a nitrogen atmosphere is treated with trifluoroacetic acid (2.3 mL) during 15 minutes. The mixture is stirred for 3.5 hours and then it is allowed to stand for 2 days. The mixture is diluted with dichloromethane (150 mL) and the solution is washed with saturated aqueous sodium bicarbonate solution (2×25 mL), brine (2×25 mL) and water (2×25 mL). The solution is dried over magnesium sulphate, the solvent is removed and the oily residue is subjected to flash chromatography, using a mixture of pentane and ethyl acetate (19:1 v/v) as eluent, to give 3-(3-cyclopentyloxy-4-methoxyphenyl)tetrahydrothiophene (1.34 g) in the form of a pale yellow oil.
Reaction SMILES: Br[C:2]1[C:3]([C:12]#[N:13])=[N:4][C:5]([O:10][CH3:11])=[C:6]([O:8][CH3:9])[CH:7]=1.[C:14]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:19]=[CH:18][CH:17]=[C:16](B(O)O)[CH:15]=1.[Na+].O.S(C1C=C(P(C2C=CC=C(S([O-])(=O)=O)C=2)C2C=CC=C(S([O-])(=O)=O)C=2)C=CC=1)([O-])(=O)=O.[Na+].[Na+].C(NC(C)C)(C)C>CN(C=O)C.CC([O-])=O.CC([O-])=O.[Pd+2].O>[C:14]1([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:19]=[CH:18][CH:17]=[C:16]([C:2]2[C:3]([C:12]#[N:13])=[N:4][C:5]([O:10][CH3:11])=[C:6]([O:8][CH3:9])[CH:7]=2)[CH:15]=1
Reactant: COc1cc(Br)c(C#N)nc1OC
Reactant: OB(O)c1cccc(-c2ccccc2)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=S(=O)([O-])c1cccc(P(c2cccc(S(=O)(=O)[O-])c2)c2cccc(S(=O)(=O)[O-])c2)c1
Solvent: CC(C)NC(C)C
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(-c2cccc(-c3ccccc3)c2)c(C#N)nc1OC
Temperature: 65 °C
Reaction time: 5 h
Yield: 88.9 %

Procedure:
To a mixture of 3-bromo-5,6-dimethoxypyridine-2-carbonitrile (31 mg, 0.128 mmol), 3-biphenylboronic acid (30 mg, 0.153 mmol), Pd(OAc)2 (5.7 mg, 0.026 mmol) and tris(3-sulfonatophenyl)phosphine hydrate sodium salt (49 mg, 0.077 mmol) in DMF (1 mL), under argon, were added diisopropylamine (0.045 mL, 0.319 mmol) and H2O (0.25 mL). Stirred at 65° C. for 5 h. Purification by preparative HPLC (10-75% CH3CN/H2O over 20 min, 0.05% added TFA) afforded 36 mg (89%) of 3-(biphenyl-3-yl)-5,6-dimethoxypyridine-2-carbonitrile as a white solid. LC/MS (M+H)+ 317.1.