Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]2[C@H:8]3[C@H:18]([CH2:19][CH2:20][C@:3]12[CH3:4])[C@:16]1([CH3:17])[C:11](=[CH:12][C:13](=[O:21])[CH2:14][CH2:15]1)[CH2:10][CH2:9]3.CS(C)=[O:24]>>[OH:24][C@@H:9]1[CH2:10][C:11]2[C@:16]([CH3:17])([CH2:15][CH2:14][C:13](=[O:21])[CH:12]=2)[C@@H:18]2[C@@H:8]1[C@H:5]1[C@@:3]([CH2:20][CH2:19]2)([CH3:4])[C@@H:2]([OH:1])[CH2:7][CH2:6]1
Reactant: C[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@]43C)[C@@H]1CC[C@@H]2O
Reactant: CS(C)=O
Product: C[C@]12CC[C@H]3[C@@H]([C@H](O)CC4=CC(=O)CC[C@@]43C)[C@@H]1CC[C@@H]2O
Temperature: 26.5 °C
Reaction time: 22 h

Procedure:
100 ml of the medium of Example 1 were inoculated with Mucor hiemalis FERM P-3800 and shaken at 26.5° C. for 22 hours. The culture was then treated with 50 mg of 17β-hydroxy-4-androsten-3one in 1 ml of dimethyl sulphoxide and incubated for 8 days. There were obtained from the culture filtrate 4.8 mg of 7α,17β-dihydroxy-4-androsten-3-one of melting point 191°-193° C.
Reaction SMILES: C([O:3][C:4](=[O:13])[C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[C:7]([NH2:12])[CH:6]=1)C.[Cl:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[C:16]=1[N:22]=[C:23]=S.C(N(CC)CC)C.CS(Cl)(=O)=O>ClCCl.CN(C)C1C=CN=CC=1>[Cl:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[C:16]=1[NH:22][C:23]1[NH:11][C:8]2[CH:9]=[CH:10][C:5]([C:4]([OH:3])=[O:13])=[CH:6][C:7]=2[N:12]=1
Reactant: CCOC(=O)c1ccc(N)c(N)c1
Reactant: S=C=Nc1c(Cl)cccc1Cl
Agent: CN(C)c1ccncc1
Agent: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(O)c1ccc2[nH]c(Nc3c(Cl)cccc3Cl)nc2c1
Reaction time: 8 h

Procedure:
To 3,4-diamino-benzoic acid ethyl ester (4.0 g, 22.2 mmol) in 100 mL dichloromethane was added 1,3-dichloro-2-isothiocyanato-benzene (4.5 g, 22 mmol) in 50 mL dichloromethane. After stirring overnight and refluxing for another 6 hrs, the solvent was evaporated. After adding 200 mL dichloromethane, triethylamine (7 mL, 50 mmol) and 4-dimethylaminopyridine (100 mg, 0.82 mmol) have been added, methanesulfonyl chloride (1.7 mL, 22 mmol) in 50 mL dichloromethane was added to the reaction mixture. After stirring for 2 h, another portion of methanesulfonyl chloride (1.7 mL, 22 mmol) was added. After stirring at room temperature overnight, the solvent was evaporated. The residue was mixed with 150 mL methanol and 40 mL 4N NaOH (aq), stirred over night, another 20 mL 4N NaOH (aq) added and refluxed for 2 h. The solvent was removed, the residue mixed with water and methanol and the mixture neutralized with 4 N HCl (aq). The mixture was filtered, washed with water and dried.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH2:10][C:11]2[C:16]([CH3:17])=[CH:15][CH:14]=[CH:13][C:12]=2[CH3:18])[C:4]=1[CH3:19].[C-:20]#[N:21].[Na+]>CN(C=O)C.CCOC(C)=O>[CH3:18][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]([CH3:17])[C:11]=1[CH2:10][O:9][C:5]1[C:4]([CH3:19])=[C:3]([CH2:2][C:20]#[N:21])[CH:8]=[CH:7][CH:6]=1
Reactant: Cc1cccc(C)c1COc1cccc(CBr)c1C
Reactant: [C-]#N
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1cccc(C)c1COc1cccc(CC#N)c1C

Procedure:
The solution of 1-(bromomethyl)-3-(2,6-dimethylbenzyloxy)-2-methylbenzene (Step D, 4.28 g, 13.41 mmol) and NaCN (0.789 g, 16.10 mmol) in dry DMF (20 ml) was heated at 120° C. for 3 hours then cooled and diluted with EtOAc (50 ml). The organic layer was washed with water (30 ml), brine, dried over Na2SO4, filtered, concentrated, and purified by flash chromatography on a silica gel column (hex: ethyl acetate 4:1) to give the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[CH:19][C:18]([C:21]4[CH:22]=[C:23]([CH:27]=[CH:28][C:29]=4[CH3:30])[C:24](O)=[O:25])=[CH:17][C:11]=3[C:12]=2[C:13](=[O:16])[NH:14][CH3:15])=[CH:4][CH:3]=1.[CH3:31][C:32]1[N:33]=[CH:34][O:35][C:36]=1[C:37]1([NH2:40])[CH2:39][CH2:38]1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>ClCCl.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:9][C:10]3[CH:20]=[CH:19][C:18]([C:21]4[CH:22]=[C:23]([C:24](=[O:25])[NH:40][C:37]5([C:36]6[O:35][CH:34]=[N:33][C:32]=6[CH3:31])[CH2:39][CH2:38]5)[CH:27]=[CH:28][C:29]=4[CH3:30])=[CH:17][C:11]=3[C:12]=2[C:13]([NH:14][CH3:15])=[O:16])=[CH:6][CH:7]=1
Reactant: Cc1ncoc1C1(N)CC1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)O)ccc3C)cc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)NC4(c5ocnc5C)CC4)ccc3C)cc12
Temperature: 25 °C
Reaction time: 18 h

Procedure:
3-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-4-methylbenzoic acid (0.2 g, 0.5 mmol, 1 eq), 1-(4-methyloxazol-5-yl)cyclopropanamine (0.103 g, 0.74 mmol, 1.2 eq), EDCI.HCl (0.105 g, 0.54 mmol, 1.1 eq), HOBT (0.067 g, 0.5 mmol, 1.0 eq) and TEA (0.21 ml, 1.5 mmol, 3 eq) were dissolved in dichloromethane and the above mixture was stirred at room temperature for 18 h. The mixture was then added with water. The organic layer was separated, washed with water and concentrated to give the crude product which was purified by Prep. HPLC. Yield: 25 mg (25%) 1HNMR (400 MHz, DMSO-d6): δ 1.21 (broad s, 4H), 2.17 (s, 3H), 2.28 (s, 3H), 2.83 (d, J=4.8 Hz, 3H), 7.37-7.43 (m, 4H), 7.56 (d, J=1.6 Hz, 1H), 7.74-7.79 (m, 3H), 7.98-8.02 (m, 2H), 8.0 (s, 1H), 8.44-8.45 (m, 1H), 9.20 (s, 1H). LCMS: (ES+) m/z=524.2 (M+H)+
Reaction SMILES: CO[C:3]([CH:5]1[CH2:11][CH2:10][O:9][C:8]2[CH:12]=[C:13]([Cl:17])[C:14]([Cl:16])=[CH:15][C:7]=2[C:6]1=[O:18])=[O:4].[NH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=1>C1(C)C(C)=CC=CC=1>[N:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[NH:19][C:3]([CH:5]1[CH2:11][CH2:10][O:9][C:8]2[CH:12]=[C:13]([Cl:17])[C:14]([Cl:16])=[CH:15][C:7]=2[C:6]1=[O:18])=[O:4]
Reactant: Nc1ccccn1
Reactant: COC(=O)C1CCOc2cc(Cl)c(Cl)cc2C1=O
Solvent: Cc1ccccc1C
Product: O=C(Nc1ccccn1)C1CCOc2cc(Cl)c(Cl)cc2C1=O
Temperature: 25 °C
Yield: 14 %

Procedure:
7,8-Dichloro-5-oxo-2,3,4,5-tetrahydro-benzo[b]oxepine-4-carboxylic acid methyl ester (0.2 mmol) and 2-aminopyridin (0.2 mmol) were dissolved in 1 ml xylene. Reaction was performed by microwave irradiation for one hour at 150° C. The solution obtained from this reaction was cooled to room temperature and extracted by 2 mol/l hydrochloric acid and ethyl acetate. The ethyl acetate extract was dried over sodiumsulfate and the solvent removed in vacuo. The remaining residue was purified via HPLC (Chromolith prep. RP18, Solvent A water:acetonitrile 90:10+0.1% formic acid, solvent B: water:acetonitrile 10:90+0.1% formic acid, flow: t=0 min 25 ml/min, t=1 min 50 ml/min, gradient: t=0 min 10% B, t=1 min 10% B, t=2 min 10% B, t=2.2 min 20% B, t=7.5 min 50% B, t=7.6 min 100% B, t=8.5 min 100% B). After evaporation of the solvent in vacuo 7,8-Dichloro-5-oxo-2,3,4,5-tetrahydro-benzo[b]oxepine-4-carboxylic acid pyridine-2-ylamide was obtained as a white powder in a yield of 14%. LC-MS: 1.9 min, 351.0 (MH+), 1H-NMR: (DMSO-d6, 500 MHz): □ [ppm]: 10.543 (s, 1H), 8.304 (s, 1H), 8.135 (d, 1H, J=8.1 Hz), 7.809 (t, 1H, J=7.6 Hz), 7.758 (s, 1H), 7.524 (s, 1H), 7.114 (s, 1H), 4.652 (m, 1H, J=2.8 Hz), 4.360 (t, 1H, J=8.9 Hz), 4.042 (m, 1H, J=4.9 Hz), 2.512 (m, 2H, J=1.8 Hz)
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:9][C:10]1[CH:11]=[N:12][CH:13]=[CH:14][C:15]=1/[CH:16]=[CH:17]/[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[BH4-].[Na+]>CN(C)C=O.C(O)C>[CH2:1]([N:12]1[CH2:13][CH2:14][C:15](/[CH:16]=[CH:17]/[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[C:10]([F:9])[CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Fc1cnccc1/C=C/c1ccccc1
Reactant: BrCc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCO
Product: FC1=C(/C=C/c2ccccc2)CCN(Cc2ccccc2)C1
Temperature: 90 °C
Reaction time: 1 h
Yield: 10.6 %

Procedure:
Benzyl bromide (0.45 ml, 3.8 mmol) was added to a solution of (E)-3-fluoro-4-(2-phenylethenyl)pyridine (0.6781 g, 3.40 mmol) in anhydrous dimethylformamide (5 ml) and the mixture stirred at 90° C. under nitrogen for 1 hour. The mixture was allowed to cool and diluted with ethanol (50 ml). Sodium borohydride (0.1580 g, 4.18 mmol) was added portionwise and the resulting reaction mixture stirred at room temperature for 2 hours. The mixture was concentrated in vacuo, water (100 ml) added and extracted with diethyl ether (2×100 ml). The extracts were washed with brine (100 ml), combined, dried (MgSO4) and concentrated in vacuo. Careful purification by first flash chromatography, eluting with ethyl acetate/petrol (60°-80°), followed by preparative layer chromatography, eluting with ethyl acetate/dichloromethane/petrol (60°-80°), gave the title compound (0.1058 g, 11%) as a pale yellow solid; δH (CDCl3) 2.43 (2H, m, tetrahydropyridinyl CH2), 2.69 (2H, m, tetrahydropyridinyl CH2), 3.18 (2H, br s, tetrahydropyridinyl CH2), 3.67 (2H, s, PhCH2N), 6.42 (1H, d, J 16.4Hz, CH=CHPh) and 7.20-7.49 (11H, m, CH=CHPh and ArH).
Reaction SMILES: [Br:1][CH2:2][CH2:3][OH:4].S(=O)(=O)(O)O.[CH:10](O)([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[CH:10]([O:4][CH2:3][CH2:2][Br:1])([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: OC(c1ccccc1)c1ccccc1
Reactant: OCCBr
Agent: O=S(=O)(O)O
Product: BrCCOC(c1ccccc1)c1ccccc1
Temperature: 100 °C

Procedure:
To 2-bromoethanol (40.7 g, 326 mmol) was added conc. sulfuric acid (9.96 g, 102 mmol) under ice-cooling while stirring. Thereto was added benzhydrol (12.0 g, 65.1 mmol), and the mixture was heated at 100° C. for 15 minutes. The reaction mixture was allowed to stand for cooling, poured into ice-cold water and extracted with ether. The organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate and saturated brine, dried over anhydrous magnesium sulfate and evaporated. The thus-obtained liquid was distilled under reduced pressure to give the title compound (3). Yield 13.9 g (73%). b.p. 125°-165° C./2.5 mmHg.
Reaction SMILES: [C:1]([N:4]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[O:15][C:16]3[C:24]([F:25])=[C:23]([CH3:26])[C:22]([F:27])=[C:21]([NH2:28])[C:17]=3[C:18](=[O:20])[CH:19]=2)=[CH:10][C:9]=1[F:29])[CH2:5][CH2:6][CH3:7])(=[O:3])[CH3:2].[H-].[Na+].I[CH2:33][CH2:34][CH2:35][CH2:36][CH3:37].O>CN(C)C=O>[C:1]([N:4]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[O:15][C:16]3[C:24]([F:25])=[C:23]([CH3:26])[C:22]([F:27])=[C:21]([NH:28][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[C:17]=3[C:18](=[O:20])[CH:19]=2)=[CH:10][C:9]=1[F:29])[CH2:5][CH2:6][CH3:7])(=[O:3])[CH3:2]
Reactant: CCCCCI
Reactant: CCCN(C(C)=O)c1ccc(-c2cc(=O)c3c(N)c(F)c(C)c(F)c3o2)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCNc1c(F)c(C)c(F)c2oc(-c3ccc(N(CCC)C(C)=O)c(F)c3)cc(=O)c12
Temperature: 25 °C
Reaction time: 6 h
Yield: 26 %

Procedure:
299 mg (0.740mmol) of the above 2-[4-[N-acetyl-N-(1-propyl)amino]-3-fluorophenyl]-5-amino-6,8-difluoro-7-methyl-4H-1-benzopyran-4-one was dissolved in 10 mL of dimethylformamide under argon atmosphere, 60 mg (1.5 mmol) of sodium hydride (60% oil dispersion) and 0.98 mL (7.4 mmol) of 1-iodopentane were added under ice-cooling and the mixture was stirred at room temperature for 6 hours. Water was added to the reaction solution and the mixture was extracted once with ethyl acetate. The organic layer was washed once with water and once with an aqueous saturated solution of sodium chloride and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (chloroform) to give 91.2 mg of 2-[4-[N-acetyl-N-(1-propyl)amino]-3-fluorophenyl]-6,8-difluoro-7-methyl-5-(1-pentylamino)-4H-1-benzopyran-4-one (yield: 26%).
Reaction SMILES: Br[CH2:2][C:3]([NH2:5])=[O:4].[SH:6][C:7]1[CH:16]=[CH:15][C:10]([C:11]([O:13][CH3:14])=[O:12])=[CH:9][CH:8]=1>>[NH2:5][C:3](=[O:4])[CH2:2][S:6][C:7]1[CH:8]=[CH:9][C:10]([C:11]([O:13][CH3:14])=[O:12])=[CH:15][CH:16]=1
Reactant: NC(=O)CBr
Reactant: COC(=O)c1ccc(S)cc1
Product: COC(=O)c1ccc(SCC(N)=O)cc1

Procedure:
2.5 g of 2-bromoacetamide was reacted with methyl 4-mercaptobenzoate via Procedure Q to afford methyl 4-(2-amino-2-oxoethylthio)benzoate. 2.6 g of methyl 4-(2-amino-2-oxoethylthio)benzoate was reacted via Procedure R to give methyl 4-(2-amino-2-oxoethylsulfonyl)benzoate. 1 g of methyl 4-(2-amino-2-oxoethylsulfonyl)benzoate was hydrolyzed via Procedure M to give 4-(2-amino-2-oxoethylsulfonyl)benzoic acid. 150 mg of 4-chloro-3-(pyridin-2-yl)aniline was coupled to 4-(2-amino-2-oxoethylsulfonyl)benzoic acid via Procedure G. The product was purified on reverse phase HPLC to yield 4-(2-amino-2-oxoethylsulfonyl)-N-(4-chloro-3-(pyridin-2-yl)phenyl)benzamide. MS (Q1) 430.2 (M)+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:12]=[CH:11][O:10][C:9]=2[CH3:13])[CH:5]=[CH:4][N:3]=1.[CH3:14][C@H:15]1[O:20][C@@H:19]([CH3:21])[CH2:18][NH:17][CH2:16]1.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[CH3:21][C@H:19]1[O:20][C@@H:15]([CH3:14])[CH2:16][N:17]([C:2]2[N:7]=[C:6]([C:8]3[CH:12]=[CH:11][O:10][C:9]=3[CH3:13])[CH:5]=[CH:4][N:3]=2)[CH2:18]1
Reactant: Cc1occc1-c1ccnc(Cl)n1
Reactant: C[C@@H]1CNC[C@H](C)O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: Cc1occc1-c1ccnc(N2C[C@@H](C)O[C@@H](C)C2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.7 %

Procedure:
2-Chloro-4-(2-methyl-3-furanyl)pyrimidine (686 mg, 3.52 mmol), cis-2,6-dimethylmorpholine (447 mg, 3.88 mmol) and potassium carbonate (536 mg, 3.88 mmol) were added together in ethanol (16 mL) and the resulting mixture was heated under reflux for 4 hours. A further quantity of cis-2,6-dimethylmorpholine (122 mg, 1.057 mmol) and potassium carbonate (146 mg, 1.057 mmol) were added and the resulting mixture was heated under reflux for 4 hours. The reaction mixture was allowed to cool to room temperature and left to stand overnight. The reaction mixture was filtered, the filtrate evaporated under reduced pressure and the residue purified by SP4 Biotage column chromatography eluting with a gradient of 0-30% ethyl acetate and iso-hexane. Product containing fractions were combined and evaporated under reduced pressure to give the title compound (737 mg, 2.70 mmol, 76% yield) as a colourless oil. LC/MS [M+H]+=274.
Reaction SMILES: [CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[C:3]([CH:14]=[CH:15][C:16]([OH:18])=[O:17])[N:2]=1.S(=O)(=O)(O)O.[OH-].[NH4+].[CH2:26](O)[CH3:27]>>[CH2:26]([O:17][C:16](=[O:18])[CH:15]=[CH:14][C:3]1[N:2]=[CH:1][C:13]2[NH:12][C:11]3[C:6]([C:5]=2[CH:4]=1)=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH3:27]
Reactant: CCO
Reactant: O=C(O)C=Cc1cc2c(cn1)[nH]c1ccccc12
Agent: O=S(=O)(O)O
Agent: [NH4+]
Agent: [OH-]
Product: CCOC(=O)C=Cc1cc2c(cn1)[nH]c1ccccc12
Temperature: 0 °C

Procedure:
A mixture of 2.3 g of 3-(3-beta-carbolinyl)acrylic-acid, 70 ml of 99% ethanol, and 10 ml of concentrated sulfuric acid is boiled at the reflux for 5 h. After cooling, the reaction mixture is placed in an ice mixture of 100 g of ice and 40 ml of concentrated ammonium hydroxide. The reaction product is filtered off. 2.2 g of ethyl-3-(3-beta-carbolinyl)-acrylate with a m.p. of 132°-134° C. is obtained.
Reaction SMILES: [F:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:6]=1[F:12])=[O:4].O.S(Cl)([Cl:17])(=O)=O>>[F:1][CH:2]([Cl:17])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:6]=1[F:12])=[O:4]
Reactant: O=S(=O)(Cl)Cl
Reactant: O=C(CF)c1ccc(F)cc1F
Solvent: O
Product: O=C(c1ccc(F)cc1F)C(F)Cl

Procedure:
A solution of 2,2',4'-trifluoroacetophenone (1.60 g; 9.2 mM) in sulphuryl chloride (4 ml) was heated at 75° for 18 hours. The mixture was then cooled and iced-water (40 ml) was added. The product was extracted into ether (80 ml), which was washed with water and aqueous sodium bicarbonate solution, and then dried over magnesium sulphate. Evaporation yielded the desired product as a colourless, intensely lachrymatory liquid (2.0 g; 100%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:22][C:23]([O:25][CH3:26])=[O:24])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:18]=[CH:17][C:12]2[NH:13][C:14]([CH3:16])=[N:15][C:11]=2[C:10]=1[N+:19]([O-])=O.O.O.[Sn](Cl)(Cl)(Cl)Cl>C(OCC)(=O)C>[NH2:19][C:10]1[C:11]2[N:15]=[C:14]([CH3:16])[NH:13][C:12]=2[CH:17]=[CH:18][C:9]=1[O:8][C:7]1[CH:6]=[CH:5][C:4]([CH2:22][C:23]([O:25][CH3:26])=[O:24])=[CH:3][C:2]=1[Cl:1]
Reactant: COC(=O)Cc1ccc(Oc2ccc3[nH]c(C)nc3c2[N+](=O)[O-])c(Cl)c1
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)Cc1ccc(Oc2ccc3[nH]c(C)nc3c2N)c(Cl)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Under an N2 atmosphere, methyl 2-(3-chloro-4-(2-methyl-4-nitro-1H-benzo[d]imidazol-5-yloxy)phenyl)acetate (0.226 g, 0.601 mmol) was dissolved in ethyl acetate and tin chloride dihydrate (0.543 g, 2.41 mmol) was added. The reaction was allowed to stir at room temperature for 16 h. The reaction was diluted with ethyl acetate and washed with a 10% NaHCO3 (aq) solution. The aqueous layer was washed with additional ethyl acetate. The organics were combined, dried (Na2SO4), filtered, and concentrated in vacuo, and the title compound isolated. LC-MS ESI (pos.) m/z: 346.0 (M+H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[C:12]([CH3:25])=[N:13][N:14]([CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=4)[C:15]=3[CH3:16])=[CH:9][N:8]([S:26]([C:29]3[CH:35]=[CH:34][C:32]([CH3:33])=[CH:31][CH:30]=3)(=[O:28])=[O:27])[C:5]2=[N:6][CH:7]=1.[CH3:36][O:37][C:38]1[CH:43]=[CH:42][C:41](B2OC(C)(C)C(C)(C)O2)=[CH:40][C:39]=1[NH:53][S:54]([CH3:57])(=[O:56])=[O:55].C(=O)([O-])[O-].[Na+].[Na+]>>[F:24][C:20]1[CH:19]=[C:18]([CH:23]=[CH:22][CH:21]=1)[CH2:17][N:14]1[C:15]([CH3:16])=[C:11]([C:10]2[C:4]3[C:5](=[N:6][CH:7]=[C:2]([C:41]4[CH:42]=[CH:43][C:38]([O:37][CH3:36])=[C:39]([NH:53][S:54]([CH3:57])(=[O:55])=[O:56])[CH:40]=4)[CH:3]=3)[N:8]([S:26]([C:29]3[CH:30]=[CH:31][C:32]([CH3:33])=[CH:34][CH:35]=3)(=[O:27])=[O:28])[CH:9]=2)[C:12]([CH3:25])=[N:13]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3c(C)nn(Cc4cccc(F)c4)c3C)c3cc(Br)cnc32)cc1
Reactant: COc1ccc(B2OC(C)(C)C(C)(C)O2)cc1NS(C)(=O)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: COc1ccc(-c2cnc3c(c2)c(-c2c(C)nn(Cc4cccc(F)c4)c2C)cn3S(=O)(=O)c2ccc(C)cc2)cc1NS(C)(=O)=O
Yield: 95.8 %

Procedure:
Using similar reaction conditions as described in step-ii of example-1, 5-bromo-3-(1-(3-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine (300 mg, 0.542 mmol) was coupled with N-(2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methane sulfonamide (intermediate-17) (212 mg, 0.650 mmol) in sodium carbonate (172 mg, 1.62 mmol), 1,2-methoxyethane (15 mL). This afforded 350 mg of the crude titled compound.
Reaction SMILES: C([O:3][C:4](=[O:31])[C:5]([O:8][C:9]1[N:30]=[CH:29][C:12]2[C:13]3[N:17]([CH2:18][CH2:19][O:20][C:11]=2[CH:10]=1)[CH:16]=[C:15]([C:21]1[N:22]([CH:26]([CH3:28])[CH3:27])[N:23]=[CH:24][N:25]=1)[N:14]=3)([CH3:7])[CH3:6])C.O.O.[OH-].[Li+].Cl>CO>[CH:26]([N:22]1[C:21]([C:15]2[N:14]=[C:13]3[N:17]([CH2:18][CH2:19][O:20][C:11]4[CH:10]=[C:9]([O:8][C:5]([CH3:7])([CH3:6])[C:4]([OH:31])=[O:3])[N:30]=[CH:29][C:12]=43)[CH:16]=2)=[N:25][CH:24]=[N:23]1)([CH3:28])[CH3:27]
Reactant: CCOC(=O)C(C)(C)Oc1cc2c(cn1)-c1nc(-c3ncnn3C(C)C)cn1CCO2
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1cnc(OC(C)(C)C(=O)O)cc1OCC2
Temperature: 50 °C

Procedure:
To a solution of 2-[2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a,9-triaza-benzo[e]azulen-8-yloxy]-2-methyl-propionic acid ethyl ester (103 mg, 0.24 mmol) in methanol (5 mL) was added water (0.5 mL) and lithium hydroxide monohydrate (19 mg, 0.48 mmol). The reaction mixture was heated at 50° C. for 16 h then HCl (1N, aq.) added until pH˜4. The reaction mixture was concentrated in vacuo to give 2-[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a,9-triaza-benzo[e]azulen-8-yloxy]-2-methyl-propionic acid as a yellow solid. LCMS: RT=2.88 min, [M+H]+=399
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.[Li]CCCC.[C:15]([O:19][C:20](=[O:34])[NH:21][C@H:22]1[CH2:27][CH2:26][C@H:25]([C:28](=[O:33])N(OC)C)[CH2:24][CH2:23]1)([CH3:18])([CH3:17])[CH3:16].O>C1COCC1>[C:15]([O:19][C:20](=[O:34])[NH:21][CH:22]1[CH2:23][CH2:24][CH:25]([C:28]([C:2]2[S:1][C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[N:3]=2)=[O:33])[CH2:26][CH2:27]1)([CH3:18])([CH3:16])[CH3:17]
Reactant: CON(C)C(=O)[C@H]1CC[C@H](NC(=O)OC(C)(C)C)CC1
Reactant: c1ccc2scnc2c1
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC1CCC(C(=O)c2nc3ccccc3s2)CC1
Yield: 82.1 %

Procedure:
To a solution of benzothiazole (675 mg, 0.55 ml, 5 mmol) in THF (20 ml) at −78° C. was added dropwise n-BuLi (2.5M in Hex, 2 ml) such that the temperature did not exceed −70° C. The brown solution was stirred at this temperature for 15 min before dropwise addition of a solution of [trans-4-(methoxy-methyl-carbamoyl)-cyclohexyl]-carbamic acid tert-butyl ester (716 mg, 2.5 mmol, prepared according to WO 03/053933) in THF (2 ml). The temperature was kept below −70° C. The brown solution was then gradually allowed to reach RT (over 3 h). Mixture was poured into water and extracted with EtOAc. The combined organic extracts were washed with brine and dried over MgSO4 and concentrated under reduced pressure. The residue was purified by chromatography over SiO2 (Hex/EtOAc 4:1 then DCM). The relevant fractions were pooled, evaporated under reduced pressure, digested with Hex and filtered to give 740 mg (82%) of [4-(benzothiazole-2-carbonyl)-cyclohexyl]-carbamic acid tert-butyl ester.
Reaction SMILES: [C:1](#[N:3])[CH3:2].C([Li])CCC.[CH2:9]([O:16][C:17]1[CH:25]=[CH:24][C:20]([C:21](Cl)=[O:22])=[C:19]([F:26])[CH:18]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[Cl-].[NH4+]>C1COCC1>[CH2:9]([O:16][C:17]1[CH:25]=[CH:24][C:20]([C:21](=[O:22])[CH2:2][C:1]#[N:3])=[C:19]([F:26])[CH:18]=1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: O=C(Cl)c1ccc(OCc2ccccc2)cc1F
Reactant: CC#N
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: N#CCC(=O)c1ccc(OCc2ccccc2)cc1F
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 79 %

Procedure:
Acetonitrile (1.66 mL, 31.7 mmol) was dissolved in dry THF (40 mL) and the mixture was cooled to −78 C. Butyllithium (2.5 M, 9.5 mL, 23.8 mmol) was added dropwise, and the resulting reaction mixture was stirred for 15 minutes. A solution of 4-(benzyloxy)-2-fluorobenzoyl chloride (2.1 g, 7.93 mmol) in THF was then added dropwise to the reaction mixture, and the resulting reaction mixture was stirred at −78 C for 40 minutes. Saturated ammonium chloride solution was then added carefully to the reaction mixture, and the resulting mixture was allowed to warm to room temperature. Next, the mixture was partitioned between water and EtOAc, and the organic portion was washed further with brine, then dried over sodium sulfate, and concentrated onto silica gel and purified by chromatography (gradient: 9:1 EtOAc:hexanes to 1:1 EtOAc:hexanes to 100% ethyl acetate) to give the title compound in 79% yield.