Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH2:17][CH2:16][C:5]2[NH:6][C:7]3[CH:8]=[CH:9][C:10]([C:13](=[O:15])[CH3:14])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[H-].[Na+].[O:20]1[CH2:22][CH:21]1[C:23]1[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=1>CN(C=O)C>[OH:20][CH:21]([C:23]1[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=1)[CH2:22][N:6]1[C:7]2[CH:8]=[CH:9][C:10]([C:13](=[O:15])[CH3:14])=[CH:11][C:12]=2[C:4]2[CH2:3][N:2]([CH3:1])[CH2:17][CH2:16][C:5]1=2
Reactant: CC(=O)c1ccc2[nH]c3c(c2c1)CN(C)CC3
Reactant: c1cc(C2CO2)ccn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)c1ccc2c(c1)c1c(n2CC(O)c2ccncc2)CCN(C)C1
Reaction time: 0.17 h
Yield: 4.9 %

Procedure:
To a stirred solution of 1-(2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indol-8-yl)ethanone (80 mg, 0.35 mmol) in DMF (2 mL) was added sodium hydride (60%, 42 mg, 1.05 mmol). After stirring for 10 min, a solution of 4-(oxiran-2-yl)pyridine (62 mg, 0.51 mmol) in DMF (1 mL) was added into the reaction mixture, and stirred at RT for 4 h. The reaction mixture was quenched with ice water and extracted with EtOAc. The organic layer was washed with water, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue obtain was purified by crystallization with ether to yield 1-(2,3,4,5-tetrahydro-5-(2-hydroxy-2-(pyridin-4-yl)ethyl)-2-methyl-1H-pyrido[4,3-b]indol-8-yl)ethanone (6 mg). 1H NMR (CDCl3, freebase) δ (ppm): 8.5 (d, 2H), 7.95 (s, 1H), 7.73 (d, 1H), 7.26 (d, 2H), 7.12 (d, 1H), 4.78 (t, 1H), 4.8 (d, 2H), 3.49 (m, 2H), 2.90 (m, 1H), 2.8 (q, 2H), 2.79 (s, 3H), 2.6 (m, 1H), 2.37 (s, 3H). Separation by chiral HPLC provided enantiomers 49a and 49b.
Reaction SMILES: [OH:1][C:2]12[CH2:9][CH2:8][C:5]([C:10]3[NH:18][C:17]4[C:16](SC)=[N:15][C:14](=[O:21])[N:13]([CH2:22][CH2:23][CH3:24])[C:12]=4[N:11]=3)([CH2:6][CH2:7]1)[CH2:4][CH2:3]2.[NH2:25][C@H:26]([CH2:29][CH3:30])[CH2:27][OH:28]>CS(C)=O>[OH:1][C:2]12[CH2:9][CH2:8][C:5]([C:10]3[NH:18][C:17]4[C:16]([NH:25][CH:26]([CH2:27][OH:28])[CH2:29][CH3:30])=[N:15][C:14](=[O:21])[N:13]([CH2:22][CH2:23][CH3:24])[C:12]=4[N:11]=3)([CH2:6][CH2:7]1)[CH2:4][CH2:3]2
Reactant: CC[C@@H](N)CO
Reactant: CCCn1c(=O)nc(SC)c2[nH]c(C34CCC(O)(CC3)CC4)nc21
Solvent: CS(C)=O
Product: CCCn1c(=O)nc(NC(CC)CO)c2[nH]c(C34CCC(O)(CC3)CC4)nc21
Temperature: 150 °C
Reaction time: 3 h

Procedure:
8-(4-Hydroxy-bicyclo[2.2.2]oct-1-yl)-6-methylsulfanyl-3-propyl-3,7-dihydro-purin-2-one (125 mg, 0.36 mmol) was dissolved in 3 mL of DMSO along with an excess of an appropriate amino alcohol (e.g., (R)-(−)-2-amino-1-butanol (0.24 mL, 7 eq) for compound 2). The resulting reaction mixture was stirred at 150° C. for 3 h. It was then cooled to rt and purified by preparative HPLC to afford 110 mg of the titled compound.
Reaction SMILES: [OH:1][C:2]1[C:3]([C:11](=[O:13])[CH3:12])=[CH:4][C:5]2[O:9][CH2:8][O:7][C:6]=2[CH:10]=1.C1N2CN3CN(C2)CN1C3.C1(C)C=CC=CC=1.FC(F)(F)[C:33](O)=[O:34]>>[C:11]([C:3]1[C:2]([OH:1])=[C:10]([CH:33]=[O:34])[C:6]2[O:7][CH2:8][O:9][C:5]=2[CH:4]=1)(=[O:13])[CH3:12]
Reactant: CC(=O)c1cc2c(cc1O)OCO2
Reactant: O=C(O)C(F)(F)F
Agent: C1N2CN3CN1CN(C2)C3
Solvent: Cc1ccccc1
Product: CC(=O)c1cc2c(c(C=O)c1O)OCO2
Temperature: 40 °C
Reaction time: 12 h
Yield: 6 %

Procedure:
A solution of 1-(6-hydroxybenzo[d][1,3]dioxol-5-yl)ethanone (1.5 g, 8.3 mmol) in trifluoroacetic acid (15 mL) was added with hexamethylenetetramine (1.7 g, 13 mmol), and the mixture was stirred at 40° C. for 12 hours. The reaction mixture was added with toluene, and then the solvent was evaporated under reduced pressure. The residue was dissolved in ethyl acetate, and the solution was successively washed with water, saturated aqueous sodium hydrogencarbonate, and saturated brine. The organic layer was dried over anhydrous magnesium sulfate, the solvent was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (eluted with chloroform/methanol (100:0→97:3)) to obtain 6-acetyl-5-hydroxybenzo[d][1,3]dioxole-4-carboxaldehyde (0.11 g, 6%).
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[N:8][N:7]([CH2:11][CH:12]3[CH2:14][CH2:13]3)[C:6]=2[CH:5]=[CH:4][C:3]=1[C:15]#[C:16][Si](C)(C)C.C(=O)([O-])[O-].[K+].[K+]>CO.C1COCC1>[Cl:1][C:2]1[C:10]2[N:9]=[N:8][N:7]([CH2:11][CH:12]3[CH2:13][CH2:14]3)[C:6]=2[CH:5]=[CH:4][C:3]=1[C:15]#[CH:16]
Reactant: C[Si](C)(C)C#Cc1ccc2c(nnn2CC2CC2)c1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CO
Product: C#Cc1ccc2c(nnn2CC2CC2)c1Cl
Reaction time: 18 h

Procedure:
A solution of 4-chloro-1-(cyclopropylmethyl)-5-[(trimethylsilyl)ethynyl]-1H-benzotriazole (0.72 g, 2.4 mmol) in MeOH (21 mL) and THF (2.1 mL) was treated with potassium carbonate (0.33 g, 2.4 mmol) and stirred for 18 hours. The mixture was concentrated in vacuo and the residue was dissolved in dichloromethane and washed with brine. The organic extracts were dried with magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel gradient chromatography (0-35% EtOAc in hexanes), providing the titled compound as a faint yellow oil: 1H-NMR (400 MHz, CDCl3) δ 7.60 (d, J=8.6 Hz, 1H), 7.43 (d, J=8.6 Hz, 1H), 4.52 (d, J=7.1 Hz, 2H), 3.44 (s, 1H), 1.36-1.43 (m, 1H), 0.66-0.71 (m, 2H), 0.48-0.52 (m, 2H) ppm; LRMS m/z (M+H) 234.1 [calculated for C12H11ClN3: 234.1].
Reaction SMILES: Br[CH2:2]/[CH:3]=[CH:4]/[C:5]([OH:7])=O.Cl.[O:9]1[CH2:15][CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.CCN(C(C)C)C(C)C.[Cl:25][C:26]1[CH:27]=[C:28]([NH:33][C:34]2[C:39]([C:40]#[N:41])=[CH:38][N:37]=[C:36]3[S:42][C:43]4[CH2:44][NH:45][CH2:46][CH2:47][C:48]=4[C:35]=23)[CH:29]=[CH:30][C:31]=1[Cl:32].CCN=C=NCCCN(C)C>C(Cl)Cl.O>[Cl:25][C:26]1[CH:27]=[C:28]([NH:33][C:34]2[C:39]([C:40]#[N:41])=[CH:38][N:37]=[C:36]3[S:42][C:43]4[CH2:44][N:45]([C:5](=[O:7])/[CH:4]=[CH:3]/[CH2:2][N:12]5[CH2:13][CH2:14][CH2:15][O:9][CH2:10][CH2:11]5)[CH2:46][CH2:47][C:48]=4[C:35]=23)[CH:29]=[CH:30][C:31]=1[Cl:32]
Reactant: N#Cc1cnc2sc3c(c2c1Nc1ccc(Cl)c(Cl)c1)CCNC3
Reactant: O=C(O)/C=C/CBr
Reactant: C1CNCCOC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1cnc2sc3c(c2c1Nc1ccc(Cl)c(Cl)c1)CCN(C(=O)/C=C/CN1CCCOCC1)C3
Temperature: 25 °C
Reaction time: 2 h
Yield: 16.7 %

Procedure:
(2E)-4-Bromobut-2-enoic acid (53 mg, 0.32 mmol) and 1,4-oxazepane hydrochloride (48 mg, 0.34 mmol) were dissolved in DCM (2.0 mL), and DIPEA (96 mg, 0.75 mmol) was added. The mixture was stirred at rt for 2 h. Subsequently, 4-[(3,4-dichlorophenyl)amino]-5,6,7,8-tetrahydrothieno[2,3-b:5,4-c′]dipyridine-3-carbonitrile from Example 88A (80 mg, 0.21 mmol), DIPEA (28 mg, 0.21 mmol) and EDCI (41 mg, 0.21 mmol) were added. The reaction mixture was stirred at rt overnight. Then, water was added, and the mixture was extracted three times with DCM. The combined organic layers were dried over sodium sulfate. The solvent was removed in vacuo, and the residue was purified by preparative HPLC to yield 19 mg (16%) of the title compound.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])([CH3:3])[CH3:2].[OH-].[K+]>C1C=CC=CC=1.O.[Fe-3](C#N)(C#N)(C#N)(C#N)(C#N)C#N.[K+].[K+].[K+]>[C:12]([C:9]1[C:10](=[O:11])[C:5]([C:1]([CH3:2])([CH3:3])[CH3:4])=[CH:6][C:7](=[CH:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:8]=1)([CH3:13])([CH3:14])[CH3:15]
Reactant: CCOC(=O)Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Agent: N#C[Fe-3](C#N)(C#N)(C#N)(C#N)C#N
Agent: [K+]
Agent: [OH-]
Solvent: c1ccccc1
Solvent: O
Product: CCOC(=O)C=C1C=C(C(C)(C)C)C(=O)C(C(C)(C)C)=C1
Temperature: 40 °C
Reaction time: 2 h

Procedure:
In benzene (150 mL) was dissolved Intermediate 10 (6.7 g, 22.9 mmol) and this treated with a solution of potassium hydroxide (13.9 g [85%], 210 mmol) and potasium ferricyanide (K3Fe(CN)6) (15.2 g, 46 mmol) in water (150 mL). The mixture stirred under nitrogen atmosphere at 40° C. for 2 hours. The benzene layer then separated, washed with brine (100 mL) and dried over magnesium sulfate. The solvent was evaporated in vacuo to give a red oil, 6.1 g (92%), which was used as is.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:20]=[CH:21][C:22]=1[O:23][CH2:24][CH:25]([CH3:27])[CH3:26])[C:6]([NH:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:11]([C:12]([O:14]C)=[O:13])[C:10]=1[NH2:19])=O)#[N:2].[OH-].[Na+].Cl>C(O)(=O)C.CO>[C:1]([C:3]1[CH:4]=[C:5]([C:6]2[NH:8][C:9]3[CH:18]=[CH:17][CH:16]=[C:11]([C:12]([OH:14])=[O:13])[C:10]=3[N:19]=2)[CH:20]=[CH:21][C:22]=1[O:23][CH2:24][CH:25]([CH3:27])[CH3:26])#[N:2]
Reactant: COC(=O)c1cccc(NC(=O)c2ccc(OCC(C)C)c(C#N)c2)c1N
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)COc1ccc(-c2nc3c(C(=O)O)cccc3[nH]2)cc1C#N
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A solution of methyl 3-(3-cyano-4-isobutyloxybenzoylamino)anthranilate (341 mg, 0.93 mmol) in glacial acetic acid (10 mL) was heated under reflux for 2 hours, cooled, and placed under reduced pressure to distill the solvent off. To the residue was added a solution of sodium hydroxide (240 mg, 10 mmol) in methanol (20 mL), and the mixture was stirred for 5 hours at room temperature. The reaction mixture was made acidic by addition of aqueous 1M hydrochloric acid, and placed under reduced pressure to distill the solvent off. To the residue were added ethyl acetate and water. The organic portion was taken out, dried over anhydrous magnesium sulfate, and placed under reduced pressure to distill the solvent off. The residue was washed with hot toluene, to give 300 mg (yield 960) of the desired compound in the form of a pale yellow crystalline product.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[CH:6][C:7]([O:26][CH3:27])=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][C:11]=2[CH:20]2[O:24][C:23](=[O:25])[NH:22][CH2:21]2)[CH:9]=1)([CH3:3])[CH3:2].[H-].[Na+].[CH2:30](Br)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>CN(C=O)C.CCOC(C)=O.O>[CH2:30]([N:22]1[CH2:21][CH:20]([C:11]2[CH:12]=[C:13]([C:16]([F:17])([F:18])[F:19])[CH:14]=[CH:15][C:10]=2[C:8]2[CH:9]=[C:4]([CH:1]([CH3:3])[CH3:2])[CH:5]=[CH:6][C:7]=2[O:26][CH3:27])[O:24][C:23]1=[O:25])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: BrCc1ccccc1
Reactant: COc1ccc(C(C)C)cc1-c1ccc(C(F)(F)F)cc1C1CNC(=O)O1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(C(C)C)cc1-c1ccc(C(F)(F)F)cc1C1CN(Cc2ccccc2)C(=O)O1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a 0° C. solution of 44 mg of 5-[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]-1,3-oxazolidin-2-one in 1 mL of DMF was added 10 mg of sodium hydride. The mixture was stirred 10 min at room temperature, and then 24 mg of benzyl bromide was added. The mixture was stirred overnight at room temperature, then diluted with 15 mL of EtOAc and 5 mL of water. The phases were separated and the organic phase was washed with 5 mL each of water and brine, dried (Na2SO4), and concentrated. The residue was purified by flash chromatography on a Biotage Horizon, 25S column, eluting with 1 CV of hexanes, followed by a linear gradient of EtOAc in hexanes from 0 to 50% over 10 CV to provide the title compound. Mass spectrum (ESI) 470.1 (M+1). 1H NMR (500 MHz, CDCl3): δ 7.86, 7.76 (s, 1H), 7.62 (d, J=8 Hz, 1H), 7.14-7.40 (m, 7H), 7.01, 6.77 (d, J=2.5 Hz, 1H), 6.87, 6.83 (d, J=8.5 Hz, 1H), 5.45, 5.53 (m, 1H), 4.30-4.53 (m, 2H), 3.73, 3.55 (s, 3H), 3.48, 3.30 (m, 1H), 3.10, 2.96 (t, J˜8.5 Hz, 1H), 2.89, 2.82 (septet, J=7 Hz, 1H), 1.24, 1.16 (m, 6H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:10])[CH3:9])=[CH:4][N:3]=1.Br[CH2:12][C:13](=O)[C:14]([O:16][CH2:17][CH3:18])=[O:15]>>[CH:8]([C:5]1[CH:6]=[CH:7][C:2]2[N:3]([CH:12]=[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[N:1]=2)[CH:4]=1)([CH3:10])[CH3:9]
Reactant: CC(C)c1ccc(N)nc1
Reactant: CCOC(=O)C(=O)CBr
Product: CCOC(=O)c1cn2cc(C(C)C)ccc2n1

Procedure:
Ethyl 6-isopropylimidazo[1,2-a]pyridine-2-carboxylate is prepared by condensing 2-amino-5-isopropylpyridine (PCT Int. Appl. WO 2005028444) with ethyl 3-bromopyruvate according to the method described by J. G. Lombardino in J. Org. Chem. (1965), 30(7), 2403.
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:3]=1[CH2:4][N:5]1[C:17]2[CH:16]=[N:15][C:14]([CH2:18]O)=[CH:13][C:12]=2[C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2.S(Cl)([Cl:27])=O>C(Cl)Cl.C(O)C>[ClH:1].[Cl:27][CH2:18][C:14]1[N:15]=[CH:16][C:17]2[N:5]([CH2:4][C:3]3[CH:20]=[C:21]([Cl:24])[CH:22]=[CH:23][C:2]=3[Cl:1])[C:6]3[C:11]([C:12]=2[CH:13]=1)=[CH:10][CH:9]=[CH:8][CH:7]=3
Reactant: O=S(Cl)Cl
Reactant: OCc1cc2c3ccccc3n(Cc3cc(Cl)ccc3Cl)c2cn1
Solvent: CCO
Solvent: ClCCl
Product: Cl
Product: ClCc1cc2c3ccccc3n(Cc3cc(Cl)ccc3Cl)c2cn1
Temperature: 25 °C
Yield: 167.9 %

Procedure:
A solution of [9-(2,5-dichlorobenzyl)-9H-β-carbolin-3-yl]methanol (7.14 g, 20 mmol) in anhydrous CH2Cl2 (100 mL) was cooled to 0° C. under nitrogen atmosphere, and thionyl chloride (2.5 g, 20.8 mmol) was added dropwise with stirring. The solution was allowed to warm to room temperature and stirred for another 15 hours. The reaction mixture was diluted with anhydrous ethanol (50 mL) and concentrated on a rotary evaporator to give a pale-yellow solid. The crude material was crystallized by addition of anhydrous ether, affording 6.92 grams (84%) of 3-chloromethyl-9-(2,5-dichlorobenzyl)-9H-β-carboline hydrochloride. This salt was converted to the free base by addition of aqueous Na2CO3 and then extracting the resulting mixture with CH2Cl2. The organic layer was dried (Na2SO4) and concentrated in vacuo to give 0.30 g (100%) of the free base as a pale yellow solid. 1H NMR (CDCl3) δ8.72 (s, 1H), 8.20 (d, J=7.9, 2.3 Hz, 1H), 8.18 (s, 1H), 7.60 (t,J=7 Hz, 1H), 7.38 (m, 3H), 7.20 (dd, J=8.3, 2.3 Hz, 1H), 6.55 (s, 1H), 5.65 (s, 2H), 4.92 (s, 2H); MS monoisotopic mass (calculated) 374.0, MH+(observed) 375.2, (MH+−HCl) 339.1.
Reaction SMILES: [CH3:1][C:2](OC(C)=O)=[O:3].[CH2:8]([O:15][C@@H:16]1[C@:20]([CH2:24][O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)([CH:21]([F:23])[F:22])[O:19][C@@H:18]([N:33]2[CH:38]=[CH:37][C:36](=[O:39])[NH:35][C:34]2=[O:40])[C@H:17]1[OH:41])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>N1C=CC=CC=1>[C:2]([O:41][C@H:17]1[C@H:16]([O:15][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C@:20]([CH2:24][O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)([CH:21]([F:22])[F:23])[O:19][C@H:18]1[N:33]1[CH:38]=[CH:37][C:36](=[O:39])[NH:35][C:34]1=[O:40])(=[O:3])[CH3:1]
Reactant: CC(=O)OC(C)=O
Reactant: O=c1ccn([C@@H]2O[C@@](COCc3ccccc3)(C(F)F)[C@@H](OCc3ccccc3)[C@@H]2O)c(=O)[nH]1
Solvent: c1ccncc1
Product: CC(=O)O[C@@H]1[C@H](n2ccc(=O)[nH]c2=O)O[C@@](COCc2ccccc2)(C(F)F)[C@H]1OCc1ccccc1
Temperature: 20 °C
Reaction time: 3 h
Yield: 88 %

Procedure:
Ac2O (0.5 mL) was added into a solution of compound 34 (0.114 g, 0.24 mmol) in dry pyridine (4 mL). The reaction mixture was stirred at 20° C. for 3 h and then quenched by saturated aqueous NaHCO3 solution (2 mL). The organic phase was extracted with dichloromethane and then evaporated to dryness under reduced pressure. Purification by silica gel chromatography [petroleum ether:ethyl acetate (4:1)] afforded 35 (0.12 g, 88%) as a white solid. LC-MS: (M+H)+=517.2
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9]C)=[O:8])=[CH:5][CH:4]=1.[CH3:13][O:14][C:15]1[CH:35]=[CH:34][C:18]([CH2:19][NH:20][S:21]([C:24]2[CH:33]=[CH:32][C:27]([C:28]([O:30]C)=[O:29])=[CH:26][CH:25]=2)(=[O:23])=[O:22])=[CH:17][CH:16]=1>>[C:28]([C:27]1[CH:26]=[CH:25][C:24]([S:21]([N:20]([CH2:2][C:3]2[CH:12]=[CH:11][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=2)[CH2:19][C:18]2[CH:17]=[CH:16][C:15]([O:14][CH3:13])=[CH:35][CH:34]=2)(=[O:23])=[O:22])=[CH:33][CH:32]=1)([OH:30])=[O:29]
Reactant: COC(=O)c1ccc(CBr)cc1
Reactant: COC(=O)c1ccc(S(=O)(=O)NCc2ccc(OC)cc2)cc1
Product: COc1ccc(CN(Cc2ccc(C(=O)O)cc2)S(=O)(=O)c2ccc(C(=O)O)cc2)cc1

Procedure:
Prepared as in example 5-10 from methyl 4-(bromomethyl)benzoate and Methyl 4-(N-(4-methoxybenzyl)sulfamoyl)benzoate (example 5-10b). 1H NMR (400 MHz, DMSO-d6): δ, ppm: 3.65 (s, 3H), 4.24 (s, 2H), 4.33 (s, 2H), 6.71 (d, 2H, J=8 Hz), 6.95 (d, 2H, J=8 Hz), 7.14 (d, 2H, J=8 Hz). 7.73 (d, 2H, J=8 Hz), 7.89 (d, 2H, J=8 Hz), 8.06 (d, 2H, J=8 Hz).
Reaction SMILES: [C:1]1([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+:15].[H][H].[C:18](=[O:20])=[O:19]>O1CCCC1>[C:8]1([N:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:18](=[O:19])[O-:20])[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1.[Na+:15]
Reactant: O=C=O
Reactant: [H][H]
Reactant: c1ccc(Nc2ccccc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C([O-])N(c1ccccc1)c1ccccc1
Yield: 90 %

Procedure:
A solution of 16.9 grams diphenylamine (0.1 mole) in 100 ml tetrahydrofuran was added, dropwise and with stirring, to a suspension of 4.2 grams sodium hydride (57% in mineral oil, washed with pentane) in 400 ml tetrahydrofuran. After the evolution of hydrogen had ceased, dry CO2 was passed through the solution for 30 minutes. Evaporation of the tetrahydrofuran afforded 21.2 grams (90%) of the sodium N, N-diphenylcarbamate, as a greyish solid, m.p. > 250° C. This compound had the following structure: ##STR6##
Reaction SMILES: [Sn](Cl)(Cl)(Cl)Cl.[S:6]1[C:10]([CH2:11][C:12]2[O:16][C:15]([CH3:17])=[C:14]([CH3:18])[CH:13]=2)=[CH:9][C:8]2[CH:19]=[CH:20][CH:21]=[CH:22][C:7]1=2.[C:23](Cl)(=O)[C:24]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=1>C(=S)=S>[CH3:31][O:30][C:27]1[CH:28]=[CH:29][C:24]([C:23]2[C:9]3[C:8]4[C:7](=[CH:22][CH:21]=[CH:20][CH:19]=4)[S:6][C:10]=3[CH:11]=[C:12]3[O:16][C:15]([CH3:17])=[C:14]([CH3:18])[C:13]=23)=[CH:25][CH:26]=1
Reactant: Cc1cc(Cc2cc3ccccc3s2)oc1C
Reactant: COc1ccc(C(=O)Cl)cc1
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: S=C=S
Product: COc1ccc(-c2c3c(C)c(C)oc3cc3sc4ccccc4c23)cc1
Temperature: 0 °C
Yield: 18.8 %

Procedure:
Tin tetrachloride (7.6 mL, 65.2 mmol) was added dropwise to a −78° C., stirred solution of benzo[b]thiophen-2-yl-(2,3-dimethyl-furan-5-yl)-methane (3.96 g, 16.3 mmol) and anisoyl chloride (3.07 g, 17.93 mL) in carbon disulfide (100 mL) under a try N2 atmosphere over a period of 30 min. After the addition completed, the solution was allowed to warm to 0° C. After 9 h. the reaction mixture was carefully quenched with and further diluted with water (350 mL). Aqueous mixture was extracted with ethyl ether. The ethyl ether extracts were washed with water, 10% aqueous sodium bicarbonate and water and dried with brine. Silica gel (90 mL) was added. Solvents were removed and the silica adsorbate was flash chromatographed (eluent 99:1 petroleum ether:ethyl acetate) to provide the title compound as a light yellow solid (1.1 g, 25%): NMR (CDCl3); δ7.81 (s, 1H), 7.76 (d, J=8, Hz, 1H), 7.36-7.24 (m, 3H), 7.11-7.00 (m, 3H), 6.85 (d, J=8 Hz, 1H), 3.96 (s, 3H), 2.37 (s, 3H), 1.55 (s, 3H); MS (EI): [M+], 358.
Reaction SMILES: [C:1]1([C:6]2[CH:11]=[C:10]([F:12])[CH:9]=[CH:8][C:7]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH:2]=1>[Pd].CO>[CH:1]1([C:6]2[CH:11]=[C:10]([F:12])[CH:9]=[CH:8][C:7]=2[O:13][CH3:14])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COc1ccc(F)cc1C1=CCCC1
Agent: [Pd]
Solvent: CO
Product: COc1ccc(F)cc1C1CCCC1
Reaction time: 16 h
Yield: 88 %

Procedure:
To a flask charged with 2-cyclopentenyl-4-fluoro-1-methoxybenzene (1500 mg, 4.68 mmol) and 10% Pd/C (50 mg) under inert atmosphere was added methanol. The reaction was stirred under H2 atmosphere for 16 h, then filtered and concentrated. Purification by silica gel chromatography (0-30% ethyl acetate/hexanes) provided 2-cyclopentyl-4-fluoro-1-methoxybenzene (800 mg, 88% yield). 1H NMR (400.0 MHz, DMSO-d6) δ 6.96 (dd, J=3.0, 9.9 Hz, 1H), 6.88-6.76 (m, 2H), 3.83 (s, 3H), 3.35 (q, J=8.5 Hz, 1H), 2.09-2.01 (m, 2H), 1.86-1.66 (m, 4H), 1.59-1.50 (m, 2H).
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[N:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]2=[N:6][C:5]=1[C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=1.[NH:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22](=[O:29])[NH:21]1>>[Cl:19][C:16]1[CH:17]=[CH:18][C:13]([C:5]2[N:6]=[C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][N:8]3[C:4]=2[CH2:3][N:21]2[C:22](=[O:29])[C:23]3[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=3)[NH:20]2)=[CH:14][CH:15]=1
Reactant: O=c1[nH][nH]c2ccccc12
Reactant: ClCc1c(-c2ccc(Cl)cc2)nc2ccccn12
Agent: Cl
Product: O=c1c2ccccc2[nH]n1Cc1c(-c2ccc(Cl)cc2)nc2ccccn12

Procedure:
The title compound was prepared according to Method B and the experimentals described for compound 91 from 3-(chloromethyl)-2-(4-chlorophenyl)imidazo[1,2-a]pyridine hydrochloride and 1H-indazol-3(2H)-one. M/e+ 375 for C21H16ClN4O (M+H)+; 1H-NMR (400 MHz, CDCl3) δ 11.11 (bs, 1H), 8.16 (d, J=6.9 Hz, 1H), 8.01 (d, J=7.7 Hz, 1H), 7.64 (m, 1H), 7.55 (d, J=8.4 Hz, 2H), 7.50 (d, J=8.4 Hz, 1H), 7.30 (t, J=7.3 Hz, 1H), 7.15 (d, J=8.4 Hz, 2H), 6.75 (t, J=7.7 Hz, 1H), 6.60 (t, J=7.7 Hz, 1H), 6.27 (d, J=8.4 Hz, 1H), 5.34 (s, 2H) ppm.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[N:3]=1.C([Mg]Cl)(C)C.[CH2:14]([Sn:18](Cl)([CH2:23][CH2:24][CH2:25][CH3:26])[CH2:19][CH2:20][CH2:21][CH3:22])[CH2:15][CH2:16][CH3:17]>C1COCC1>[Br:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Sn:18]([CH2:19][CH2:20][CH2:21][CH3:22])([CH2:23][CH2:24][CH2:25][CH3:26])[CH2:14][CH2:15][CH2:16][CH3:17])[N:3]=1
Reactant: Brc1cccc(Br)n1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1cccc(Br)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 39.2 %

Procedure:
To a solution of 2.6-dibromopyridine (5.0 g, 21.1 mmol) in dry THF (50 ml) at 0° C. was added iso-propyl magnesium chloride (11.6 ml, 23.21 mmol) dropwise for 20 min. The reaction was stirred at RT for 2 h, then cooled to 0° C. Tri-butyl tin chloride (7.55 g, 23.21 mmol) was added dropwise in 15 min. The mixture was stirred at RT for 12 h. The reaction was quenched with 10% NH4Cl solution and was extracted with EtOAc. The combined organic layers were washed with brine, dried, and concentrated. The residue was purified with silica gel chromatography to give 2-bromo-6-(tributylstannyl)pyridine (3.7 g, 40.3%). MS (ESI, pos. ion) m/z: 448 (M+1); 1H-NMR (CDCl3, 300 MHz) δ 7.3-7.5 (3H, m), 1.5-1.7 (6H, m), 1.3-1.4 (6H, m), 1.1-1.25 (6H, q), 0.7-0.9 (9H, q).
Reaction SMILES: [CH2:1]([C@@:3]12[CH2:28][CH2:27][C@@:26]([C:30]([F:33])([F:32])[F:31])([OH:29])[CH2:25][C@H:4]1[CH2:5][CH2:6][CH2:7][C:8]1[C:9]2=[CH:10][C:11]2[CH:12]=[N:13][N:14]([C:17]3[CH:22]=[CH:21][C:20]([S:23][CH3:24])=[CH:19][CH:18]=3)[C:15]=2[CH:16]=1)[CH3:2].[OH2:34].ClC1C=C(C=CC=1)C(OO)=[O:40]>CC(C)=O>[CH2:1]([C@@:3]12[CH2:28][CH2:27][C@@:26]([C:30]([F:33])([F:32])[F:31])([OH:29])[CH2:25][C@H:4]1[CH2:5][CH2:6][CH2:7][C:8]1[C:9]2=[CH:10][C:11]2[CH:12]=[N:13][N:14]([C:17]3[CH:18]=[CH:19][C:20]([S:23]([CH3:24])(=[O:40])=[O:34])=[CH:21][CH:22]=3)[C:15]=2[CH:16]=1)[CH3:2]
Reactant: CC[C@@]12CC[C@](O)(C(F)(F)F)C[C@H]1CCCc1cc3c(cnn3-c3ccc(SC)cc3)cc12
Reactant: O
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CC(C)=O
Product: CC[C@@]12CC[C@](O)(C(F)(F)F)C[C@H]1CCCc1cc3c(cnn3-c3ccc(S(C)(=O)=O)cc3)cc12

Procedure:
(3R,4aR,12bR)-12b-Ethyl-9-(4-(methylthio)phenyl)-3-(trifluoromethyl)-1,2,3,4,4a,5,6,7,9,12b-decahydrobenzo[6,7]cyclohepta[1,2-f]indazol-3-ol (11, R1=4-(Methylthio)phenyl, R2=Ethyl, R3=Trifluoromethyl) (230 mg, 0.485 mmol) in acetone (10 mL) and water (2 mL) was treated with 3-chlorobenzoperoxoic acid (543 mg, 2.42 mmol) at rt. After 30 min the mixture was concentrated under reduced pressure then the material was partitioned between sat. aq. NaHCO3 (15 mL), water (15 mL) and EtOAc (30 mL). The organic layer was washed with brine (10 mL), dried over MgSO4 and filtered. The filtrate was concentrated under reduced pressure then the material was purified on silica gel (12 g) using 0-40% EtOAc in DCM. Product fractions were concentrated under reduced pressure then triturated with Et2O (1.5 mL) in heptane (20 mL). The solids were collected by filtration and dried to yield (3R,4aR,12bR)-12b-ethyl-9-(4-(methylsulfonyl)phenyl)-3-(trifluoromethyl)-1,2,3,4,4a,5,6,7,9,12b-decahydrobenzo[6,7]cyclohepta[1,2-f]indazol-3-ol (11, R1=4-(Methylsulfonyl)phenyl, R2=Ethyl, R3=Trifluoromethyl) (110.6 mg, 45.0%); LC/MS, method 2, Rt=2.43 min, MS m/z 507 (M+H)+. 1H NMR (400 MHz, DMSO) δ 8.37 (d, J=0.8 Hz, 1H), 8.14-8.06 (m, 4H), 7.88 (s, 1H), 7.80 (s, 1H), 5.86 (s, 1H), 3.30 (s, 3H), 3.28-3.22 (m, 1H), 3.02-2.97 (m, 1H), 2.29-2.20 (m, 1H), 2.16-1.98 (m, 4H), 1.93-1.75 (m, 2H), 1.73-1.54 (m, 5H), 1.41-1.30 (m, 1H), 0.44 (t, J=7.3 Hz, 3H).