Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]([N:11]1[C:19]2[CH2:18][CH2:17][CH2:16][CH:15](O)[C:14]=2[CH:13]=[N:12]1)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].[Br:21][C:22]1[C:30]2[C:25](=[N:26][CH:27]=[N:28][C:29]=2[NH:31][CH2:32][C:33]2[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][C:34]=2[O:41][CH3:42])[NH:24][N:23]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[Br:21][C:22]1[C:30]2[C:25](=[N:26][CH:27]=[N:28][C:29]=2[NH:31][CH2:32][C:33]2[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][C:34]=2[O:41][CH3:42])[N:24]([CH:15]2[CH2:16][CH2:17][CH2:18][C:19]3[N:11]([S:1]([C:4]4[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=4)(=[O:2])=[O:3])[N:12]=[CH:13][C:14]2=3)[N:23]=1
Reactant: Cc1ccc(S(=O)(=O)n2ncc3c2CCCC3O)cc1
Reactant: COc1ccc(CNc2ncnc3[nH]nc(Br)c23)c(OC)c1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1ccc(CNc2ncnc3c2c(Br)nn3C2CCCc3c2cnn3S(=O)(=O)c2ccc(C)cc2)c(OC)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 32.4 %

Procedure:
A solution of 1-tosyl-4,5,6,7-tetrahydro-1H-indazol-4-ol (4.05 g, 11.13 mmol), 3-bromo-N-(2,4-dimethoxybenzyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (3.9 g, 13.35 mmol) and PPh3 (4.38 g, 16.70 mmol) in dry THF (110 mL) at 0° C. was added dropwise DIAD (3.37 g, 16.70 mmol) over a period of 5 minutes under a nitrogen atmosphere, then the mixture was stirred at room temperature for 4 hours. Removed the solvent under reduced pressure and then extracted with DCM, the combined organic layer was washed with water, brine and dried over anhydrous Na2SO4. The organic layer was concentrated in vacuo and the residue was purified by preparative HPLC separation to afford 3-bromo-N-(2,4-dimethoxybenzyl)-1-(1-tosyl-4,5,6,7-tetrahydro-1H-indazol-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (2.3 g, yield 32.4%). MS-ESI (m/z): 640 (M+2)+ (Acq Method: 10-80AB_2 min; Rt: 1.357 min)
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[CH2:5]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:16]([S:21]([Cl:24])(=[O:23])=[O:22])=[CH:17][CH:18]=[CH:19][CH:20]=2)=[CH:11][CH:10]=1)[CH:6]([CH3:8])[CH3:7]>C(OC(=O)C)(=O)C>[CH2:5]([C:9]1[CH:10]=[CH:11][C:12]([C:15]2[C:16]([S:21]([Cl:24])(=[O:23])=[O:22])=[CH:17][CH:18]=[CH:19][CH:20]=2)=[CH:13][C:14]=1[N+:1]([O-:4])=[O:2])[CH:6]([CH3:8])[CH3:7]
Reactant: O=[N+]([O-])O
Reactant: CC(C)Cc1ccc(-c2ccccc2S(=O)(=O)Cl)cc1
Solvent: CC(=O)OC(C)=O
Product: CC(C)Cc1ccc(-c2ccccc2S(=O)(=O)Cl)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Fuming nitric acid (0.8 ml) was added over 10 minutes to a stirred solution of 4'-isobutyl-2-biphenylsulphonyl chloride (3.09 g) in acetic anhydride (18 ml) at -20° C. The solution was kept at -20° C. for 1.5 hours and then allowed to warm to ambient temperature. The solution was stirred for 1.5 hours and then added to ice (300 g) with vigorous stirring. The mixture was stirred for 30 minutes and extracted with ether (3×100 ml) while still below 10° C. The ethereal solution was dried (MgSO4) and the solvent was removed by evaporation. The resulting oil was purified by flash chromatography, eluting with ethyl acetate/hexane (1:9 v/v), to give 4'-isobutyl-3'-nitro-2-biphenylsulphonyl chloride (2.01 g); 1H NMR (CDCl3): 0.95 (d,6H), 1.9-2.05 (m,1H), 2.9 (d,2H), 7.35-7.5 (m,2H), 7.6 (d,1H), 7.7 (d,1H), 7.8 (t,1H), 8.0 (s,1H), 8.25 (d,1H); mass spectrum (EI): 353(M+).
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[CH:15]=[C:14]([C:19]([OH:24])([CH2:22][CH3:23])[CH2:20][CH3:21])[CH:13]=[CH:12]2)C1C=CC=CC=1.[H][H]>C(O)C>[CH2:20]([C:19]([C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][CH:13]=1)[CH:10]=[C:9]([OH:8])[CH:18]=[CH:17]2)([OH:24])[CH2:22][CH3:23])[CH3:21]
Reactant: [H][H]
Reactant: CCC(O)(CC)c1ccc2cc(OCc3ccccc3)ccc2c1
Solvent: CCO
Product: CCC(O)(CC)c1ccc2cc(O)ccc2c1
Yield: 87.2 %

Procedure:
Treat a mixture of 3-(6-benzyloxynaphthalen-2-yl)pentan-3-ol (1.5 g, 4.68 mmol) and 5% PdlAl2CO3 (0.90 g) in ethanol (750 mL) with hydrogen at 60 psi for 8 h at RT. Filter the catalyst from the reaction mixture and concentrate the filtrate to give the title compound as a yellow solid (0.94 g, 87%). MS (ES) m/e 229 (M−1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9]N)=[CH:5][CH:4]=1.[C:11]1(=O)[CH2:16][CH2:15][CH2:14][C:13](=[O:17])[CH2:12]1>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:8]=[C:7]2[C:6](=[CH:5][CH:4]=1)[NH:9][C:11]1[CH2:16][CH2:15][CH2:14][C:13](=[O:17])[C:12]2=1
Reactant: O=C1CCCC(=O)C1
Reactant: COc1ccc(NN)cc1
Solvent: Cc1ccccc1
Product: COc1ccc2[nH]c3c(c2c1)C(=O)CCC3
Yield: 65.5 %

Procedure:
To a mixture of 4-methoxyphenyl hydrazine (0.359 g, 2.06 mmol) in toluene (30 mL) is added 1,3 cyclohexanedione (0.231 g, 2.06 mmol). The mixture is refluxed for 30 minutes. The toluene is removed under reduced pressure and the residue triturated in CH2Cl2: CH3OH (95:5). A white solid is filtered to give 0.2903 g (65%) of the title compound; IR (drift) 3160, 3141, 3114, 3064, 1619, 1588, 1474, 1434, 1277, 1215, 1140, 1015, 844, 802, 791 cm−1. MS (ESI+) for C13H13N1O2 m/z 216 (M+H)+. 1H NMR (DMSO-d6) δ2.08, 2.39, 2., 3.74, 6.74, 7.25, 7.43; Anal Calcd for C13H13NO2: C, 72.54; H, 6.09; N, 6.51. Found: C, 71.48; H, 6.06; N, 6.45.
Reaction SMILES: [C:1]([O:5][C:6](=[O:34])[C:7]1[CH:12]=[C:11]([O:13]CC2C=CC=CC=2)[C:10]([CH2:21][C:22]2([CH3:25])[CH2:24][O:23]2)=[C:9]([O:26]CC2C=CC=CC=2)[CH:8]=1)([CH3:4])([CH3:3])[CH3:2].CCN(CC)CC.C([O-])([O-])=O.[K+].[K+]>CO.[Pd]>[C:1]([O:5][C:6]([C:7]1[CH:12]=[C:11]([OH:13])[C:10]2[CH2:21][C:22]([CH2:24][OH:23])([CH3:25])[O:26][C:9]=2[CH:8]=1)=[O:34])([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(C)(C)OC(=O)c1cc(OCc2ccccc2)c(CC2(C)CO2)c(OCc2ccccc2)c1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)c1cc(O)c2c(c1)OC(C)(CO)C2
Temperature: 25 °C
Reaction time: 8 h
Yield: 18.7 %

Procedure:
A mixture of 3,5-bis-benzyloxy-4-(2-methyl-oxiranylmethyl)-benzoic acid tert-butyl ester (227b) (158 g, 0.343 mol), 10% Pd/C (15 g), Et3N (57.3 mL, 0.412 mol) and K2CO3 (56.94 g, 0.412 mol) in MeOH (1.5 L) was stirred under 760 mmHg of H2 at room temperature overnight. TLC (EtOAc/petroleum ether=1/3) showed that the reaction was complete. The mixture was filtered through Celite. The filtrate was concentrated and the residue was purified by column chromatography (EtOAc/petroleum ether=1/3) to give a brown oil. The brown oil was further purified by prep. HPLC to give the title compound (18 g, 18.7% yield) as a brown oil. 1H NMR (400 MHz, CDCl3): δ 6.98 (s, 1H), 6.82 (s, 1H), 3.67 (d, 1H), 3.56 (d, 1H), 2.80 (d, 1H), 1.48 (s, 9H), 1.35 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([C:11]2[C:16]([NH:17][C:18]([C:20]3[CH:25]=[CH:24][C:23]([C:26]#[N:27])=[CH:22][CH:21]=3)=[O:19])=[CH:15][CH:14]=[C:13]([OH:28])[CH:12]=2)=[O:10])=[N:6][CH:7]=1.C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:36][C:37]([O:39][CH2:40]C)=[O:38]>CN(C=O)C.CCOC(C)=O.O>[CH3:40][O:39][C:37](=[O:38])[CH2:36][O:28][C:13]1[CH:14]=[CH:15][C:16]([NH:17][C:18]([C:20]2[CH:25]=[CH:24][C:23]([C:26]#[N:27])=[CH:22][CH:21]=2)=[O:19])=[C:11]([C:9](=[O:10])[NH:8][C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=2)[CH:12]=1
Reactant: N#Cc1ccc(C(=O)Nc2ccc(O)cc2C(=O)Nc2ccc(Cl)cn2)cc1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)COc1ccc(NC(=O)c2ccc(C#N)cc2)c(C(=O)Nc2ccc(Cl)cn2)c1
Reaction time: 1 h
Yield: 115.8 %

Procedure:
To a mixture of compound N-(5-chloro(2-pyridyl)){6-[(4-cyanophenyl)-carbonylamino]-3-hydroxyphenyl}carboxamide (50 mg, 0.13 mmol) and Cs2CO3 (83 mg, 0.25 mmol) in DMF (1 mL) at room temperature was added ethyl bromoacetate (15 μL, 0.13 mmol). The mixture was stirred for 1 hour before diluted with EtOAc (20 mL) and water (10 mL). The organic layer was washed with brine dried and evaporated to give 70 mg of the crude compound, which was used without farther purification. MS found for C24H19ClN4O5 (M+H)+: 479.0.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH2:6]([N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(N(CC)CC)C>C(Cl)Cl>[CH2:6]([N:13]1[CH2:18][CH2:17][N:16]([S:2]([CH3:1])(=[O:4])=[O:3])[CH2:15][CH2:14]1)[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: CS(=O)(=O)Cl
Reactant: c1ccc(CN2CCNCC2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)N1CCN(Cc2ccccc2)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 87 %

Procedure:
Methanesulfonyl chloride (966 μl, 12.5 mmol) was added dropwise to a solution of 1-benzylpiperazine (2 g, 11.3 mmol) and triethylamine (1.74 ml, 12.5 mmol) in dry methylene chloride (30 ml) cooled at 0° C. After stirring for 1 hour at ambient temperature, the mixture was partitioned between water and methylene chloride. The organic layer was separated, washed with water, brine, dried (MgSO4) and evaporated. The residue was purified by column chromatography eluting with methylene chloride/ethyl acetate (7/3) to give 1-benzyl-4-methylsulfonylpiperazine (2.5 g, 87%).
Reaction SMILES: [C:1]([CH:5]1[CH2:10][C:9]([C:24]#[N:25])([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH2:20][CH:21]3[CH2:23][CH2:22]3)[CH:12]=2)[CH2:8][CH2:7][C:6]1=[O:26])([O:3][CH3:4])=[O:2].[H-].[Na+].Cl[CH2:30][O:31][CH3:32]>CN(C)P(=O)(N(C)C)N(C)C>[C:1]([C:5]1[CH2:10][C:9]([C:24]#[N:25])([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH2:20][CH:21]3[CH2:23][CH2:22]3)[CH:12]=2)[CH2:8][CH2:7][C:6]=1[O:26][CH2:30][O:31][CH3:32])([O:3][CH3:4])=[O:2]
Reactant: COCCl
Reactant: COC(=O)C1CC(C#N)(c2ccc(OC)c(OCC3CC3)c2)CCC1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: COCOC1=C(C(=O)OC)CC(C#N)(c2ccc(OC)c(OCC3CC3)c2)CC1
Reaction time: 4.5 h
Yield: 44.5 %

Procedure:
A solution of 2-carbomethoxy-4-cyano-4-(3-cyclopropylmethoxy-4-methoxyphenyl)cyclohexan-1-one (1.0 g, 2.8 mmol) and sodium hydride (80% dispersion in mineral oil, 0.09 g, 3.1 mmol) in dry hexamethylphosphoric triamide (8 mL) was stirred under an argon atmosphere at room temperature for 0.5 h. Chloromethylmethyl ether (0.26 mL, 3.4 mmol) was added and stirring was continued for 4.5 h. The mixture was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate, was extracted three times, the organic layer was dried (sodium sulfate) and the solvent was removed in vacuo. The product was purified by flash chromatography, eluting with 3:1 hexanes/ethyl acetate, to provide a white solid (0.5 g, 44%): m.p. 98°-99° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=3[Cl:21])[CH:11]=[C:10]([C:22]([F:25])([F:24])[F:23])[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[C:26]([NH:30][S:31]([C:34]1[CH:35]=[C:36](B(O)O)[CH:37]=[CH:38][CH:39]=1)(=[O:33])=[O:32])([CH3:29])([CH3:28])[CH3:27]>>[C:26]([NH:30][S:31]([C:34]1[CH:39]=[C:38]([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([C:8]3[N:13]=[C:12]([C:14]4[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=4[Cl:21])[CH:11]=[C:10]([C:22]([F:23])([F:25])[F:24])[N:9]=3)[CH:3]=2)[CH:37]=[CH:36][CH:35]=1)(=[O:33])=[O:32])([CH3:29])([CH3:27])[CH3:28]
Reactant: CC(C)(C)NS(=O)(=O)c1cccc(B(O)O)c1
Reactant: FC(F)(F)c1cc(-c2ccc(Cl)cc2Cl)nc(-c2cccc(Br)c2)n1
Product: CC(C)(C)NS(=O)(=O)c1cccc(-c2cccc(-c3nc(-c4ccc(Cl)cc4Cl)cc(C(F)(F)F)n3)c2)c1

Procedure:
3′-[4-(2,4-dichloro-phenyl)-6-trifluoromethyl-pyrimidin-2-yl]-biphenyl-3-sulfonic acid tert-butylamide was prepared from 2-(3-bromo-phenyl)-4-(2,4-dichloro-phenyl)-6-trifluoromethyl-pyrimidine (example E.106) (0.45 g, 1.0 mmol) and commercially available 3-(tert.-butylsulfamoyl)-phenylboronic acid (0.31 g, 1.2 mmol) according to the general procedure VI. Obtained as an off-white solid (0.36 g), which was subsequently deprotected.
Reaction SMILES: [C:1]([C:5]1[CH:39]=[CH:38][C:8]([C:9]([N:11]2[C@@H:15]([C:16]3[S:17][CH:18]=[CH:19][N:20]=3)[C@@H:14]([C:21]3[CH:26]=[N:25][CH:24]=[CH:23][N:22]=3)[CH2:13][C@@:12]2([CH2:34][CH:35]([CH3:37])[CH3:36])[C:27]([O:29]C(C)(C)C)=[O:28])=[O:10])=[CH:7][C:6]=1[CH2:40][CH3:41])([CH3:4])([CH3:3])[CH3:2].C(O)(C(F)(F)F)=O>>[C:1]([C:5]1[CH:39]=[CH:38][C:8]([C:9]([N:11]2[C@@H:15]([C:16]3[S:17][CH:18]=[CH:19][N:20]=3)[C@@H:14]([C:21]3[CH:26]=[N:25][CH:24]=[CH:23][N:22]=3)[CH2:13][C@@:12]2([CH2:34][CH:35]([CH3:36])[CH3:37])[C:27]([OH:29])=[O:28])=[O:10])=[CH:7][C:6]=1[CH2:40][CH3:41])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCc1cc(C(=O)N2[C@@H](c3nccs3)[C@@H](c3cnccn3)C[C@@]2(CC(C)C)C(=O)OC(C)(C)C)ccc1C(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: CCc1cc(C(=O)N2[C@@H](c3nccs3)[C@@H](c3cnccn3)C[C@@]2(CC(C)C)C(=O)O)ccc1C(C)(C)C

Procedure:
The tert-butyl ester from stage A was deprotected with TFA in a similar manner to that described in Example 1 to afford the title compound as a solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[CH:7]1[CH2:12][CH2:11][C:10](=O)[CH2:9][CH2:8]1.[NH:14]1[CH2:17][CH:16]([NH:18][C:19]([CH2:21][NH:22][C:23](=[O:34])[C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=2)=[O:20])[CH2:15]1>>[N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[CH:7]1[CH2:12][CH2:11][CH:10]([N:14]2[CH2:17][CH:16]([NH:18][C:19]([CH2:21][NH:22][C:23](=[O:34])[C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:31])[F:32])[CH:25]=3)=[O:20])[CH2:15]2)[CH2:9][CH2:8]1
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CNC1
Reactant: O=C1CCC(c2cnccn2)CC1
Product: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CN(C2CCC(c3cnccn3)CC2)C1

Procedure:
The title compounds were prepared as white solids from the reductive amination of 4-pyrazin-2-yl-cyclohexanone (as prepared in the previous step) and N-(azetidin-3-ylcarbamoylmethyl)-3-trifluoromethyl-benzamide using the procedure described in Step F of Example 1.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH3:14][O:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][C:25]=1[O:26][CH3:27])[CH2:22][NH:21][CH2:20][CH2:19]2>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:21]3[CH2:20][CH2:19][C:18]4[C:23](=[CH:24][C:25]([O:26][CH3:27])=[C:16]([O:15][CH3:14])[CH:17]=4)[CH2:22]3)=[O:13])[CH:10]=2)[CH:7]=1
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Reactant: COc1cc2c(cc1OC)CNCC2
Product: COc1cc2c(cc1OC)CN(C(=O)c1cc3ncc(Br)cn3n1)CC2

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 6,7-dimethoxy-1,2,3,4-tetrahydro-isoquinoline to provide the title compound as a solid.
Reaction SMILES: [CH3:1][O:2][P:3]([CH2:7][NH:8][S:9]([C:12]1[S:13][CH:14]=[CH:15][CH:16]=1)(=[O:11])=[O:10])(=[O:6])[O:4]C.[OH-].[Na+:18]>>[Na+:18].[CH3:1][O:2][P:3]([CH2:7][NH:8][S:9]([C:12]1[S:13][CH:14]=[CH:15][CH:16]=1)(=[O:11])=[O:10])(=[O:4])[O-:6]
Reactant: COP(=O)(CNS(=O)(=O)c1cccs1)OC
Agent: [Na+]
Agent: [OH-]
Product: COP(=O)([O-])CNS(=O)(=O)c1cccs1

Procedure:
The diester (vii) was treated with sodium hydroxide according to the procedure described in Example 46, step 5, to produce the title compound: 1H NMR (300 MHz, CD3OD) δH 7.65 (dd, J=4.8, 1.2 Hz, 1 H), 7.62 (dd, J=3.6, 1.2 Hz, 1 H), 7.15 (dd, J=4.8, 3.6 Hz, 1 H), 3.55 (d, J=9.3 Hz, 3 H), 3.04 (d, J=13.8 Hz, 2 H); 31P NMR: (121 MHz, CD3OD) δP 17.60; 13C NMR (75 MHz, CD3OD) δC 141.77, 132.98, 132.90, 128.43, 52.02, 40.11, (d, J=147.2 Hz).
Reaction SMILES: C([O:3][C:4]([C:6]1[S:15][C:14]2[C:13]3[CH:16]=[CH:17][CH:18]=[CH:19][C:12]=3[O:11][CH2:10][CH2:9][C:8]=2[N:7]=1)=[O:5])C.[OH-].[Na+].O>C1COCC1>[S:15]1[C:14]2[C:13]3[CH:16]=[CH:17][CH:18]=[CH:19][C:12]=3[O:11][CH2:10][CH2:9][C:8]=2[N:7]=[C:6]1[C:4]([OH:5])=[O:3]
Reactant: CCOC(=O)c1nc2c(s1)-c1ccccc1OCC2
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1nc2c(s1)-c1ccccc1OCC2
Temperature: 25 °C
Reaction time: 3 h
Yield: 61.7 %

Procedure:
A solution of 4,5-dihydro-6-oxa-1-thia-3-aza-benzo[e]azulene-2-carboxylic acid ethyl ester (1 eq, 1.9 mmol, 530 mg), and sodium hydroxide (5 eq, 9.6 mmol, 385 mg), in THF (5 ml) and water (5 ml) was allowed to stir at RT for 3 hrs. Reaction concentrated in vacuo and the solid washed with water to give 4,5-dihydro-6-oxa-1-thia-3-aza-benzo[e]azulene-2-carboxylic acid (290 mg, yield 58%).
Reaction SMILES: Br[C:2]1[N:6]2[C:7]3[CH:19]=[CH:18][CH:17]=[N:16][C:8]=3[NH:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[C:5]2=[N:4][C:3]=1[CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(O)C.C(=O)(O)[O-].[Na+].CC1(C)C(C)(C)OB([C:44]2[CH:49]=[CH:48][C:47]([C:50]3([NH:54][C:55](=[O:61])[O:56][C:57]([CH3:60])([CH3:59])[CH3:58])[CH2:53][CH2:52][CH2:51]3)=[CH:46][CH:45]=2)O1>C1(C)C=CC=CC=1>[CH2:20]([C:3]1[N:4]=[C:5]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[NH:9][C:8]3[N:16]=[CH:17][CH:18]=[CH:19][C:7]=3[N:6]2[C:2]=1[C:44]1[CH:45]=[CH:46][C:47]([C:50]2([NH:54][C:55](=[O:61])[O:56][C:57]([CH3:59])([CH3:58])[CH3:60])[CH2:51][CH2:52][CH2:53]2)=[CH:48][CH:49]=1)[CH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CCC1
Reactant: Brc1c(CCc2ccccc2)nc2n1-c1cccnc1Nc1ccccc1-2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(CCc4ccccc4)nc4n3-c3cccnc3Nc3ccccc3-4)cc2)CCC1
Temperature: 100 °C
Reaction time: 8 h
Yield: 15.2 %

Procedure:
To a suspension of 3-bromo-2-phenethyl-9H-benzo[f]imidazo[1,2-d]pyrido[2,3-b][1,4]diazepine (0.197 g, 1 eq.) in a mixture of toluene (10 mL), ethanol (10 mL), and saturated sodium bicarbonate (4 mL) was added tert-butyl (1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)cyclobutyl)carbamate (0.353 g, 2 eq.). The reaction was degassed (nitrogen) for 5 minutes and tetrakis(triphenylphosphine)palladium(0) added (0.054 g). The reaction was again degassed for 5 minutes and stirred at 100° C. overnight. The reaction mixture was cooled to room temperature and poured onto water (100 mL). The aqueous phase was extracted with dichloromethane (2×100 mL) and the organic extracts were combined and washed with brine (1×100 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. Purification by column chromatography (10-60% ethyl acetate in hexanes) gave tert-butyl (1-(4-(2-phenethyl-9H-benzo[f]imidazo[1,2-d]pyrido[2,3-b][1,4]diazepin-3-yl)phenyl)cyclobutyl)carbamate (0.042 g, 15%) as a yellow solid. LCMS: 584 [M+H].
Reaction SMILES: [Li+].[OH-].C([O:5][C:6]([C:8]1[C:9]([O:23][CH2:24][CH3:25])=[N:10][C:11]2[C:16]([C:17]=1[CH3:18])=[CH:15][CH:14]=[C:13]([C:19]([F:22])([F:21])[F:20])[CH:12]=2)=[O:7])C>CO.C1COCC1>[CH2:24]([O:23][C:9]1[C:8]([C:6]([OH:7])=[O:5])=[C:17]([CH3:18])[C:16]2[C:11](=[CH:12][C:13]([C:19]([F:22])([F:20])[F:21])=[CH:14][CH:15]=2)[N:10]=1)[CH3:25]
Reactant: CCOC(=O)c1c(OCC)nc2cc(C(F)(F)F)ccc2c1C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCOc1nc2cc(C(F)(F)F)ccc2c(C)c1C(=O)O
Temperature: 60 °C
Yield: 94.8 %

Procedure:
2M aq. LiOH sol. (38 ml) was added to a solution of 5.1 g (15.5 mmol) 2-ethoxy-4-methyl-7-(trifluoromethyl)quinoline-3-carboxylic acid ethyl ester in a MeOH/THF mixture (in each case 38 ml) and subsequently heated to 60° C. for 16 h. The organic solvents were removed as far as possible in a vacuum and the obtained aqueous solution was washed with EtOAc, set at pH 2 with 2M hydrochloric acid and diluted with EtOAc. The organic phase was separated and washed with brine, dried over MgSO4 and concentrated in a vacuum. 4.4 g (14.7 mmol, 95%) 2-ethoxy-4-methyl-7-(trifluoromethyl)quinoline-3-carboxylic acid was obtained as a residue. The raw product was further converted without additional purification.
Reaction SMILES: C([Mg]Cl)(C)C.I[C:7]1[CH:35]=[CH:34][C:10]([CH2:11][O:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([O:21][Si](C)(C)C)=[CH2:20])=[C:15]([O:26][Si](C)(C)C)[C:14]=2[CH2:31][CH2:32][CH3:33])=[CH:9][CH:8]=1.[CH:36]([C:38]1[CH:39]=[C:40]([CH:43]=[CH:44][N:45]=1)[C:41]#[N:42])=[O:37].Cl>O1CCCC1.O>[C:19]([C:16]1[CH:17]=[CH:18][C:13]([O:12][CH2:11][C:10]2[CH:34]=[CH:35][C:7]([CH:36]([OH:37])[C:38]3[CH:39]=[C:40]([CH:43]=[CH:44][N:45]=3)[C:41]#[N:42])=[CH:8][CH:9]=2)=[C:14]([CH2:31][CH2:32][CH3:33])[C:15]=1[OH:26])(=[O:21])[CH3:20]
Reactant: C=C(O[Si](C)(C)C)c1ccc(OCc2ccc(I)cc2)c(CCC)c1O[Si](C)(C)C
Reactant: N#Cc1ccnc(C=O)c1
Agent: CC(C)[Mg]Cl
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: CCCc1c(OCc2ccc(C(O)c3cc(C#N)ccn3)cc2)ccc(C(C)=O)c1O
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 75.9 %

Procedure:
Add isopropyl magnesium chloride (2M solution in tetrahydrofuran, 2.98 mL, 5.95 mmol) to a solution of 1-(4-iodo-benzyloxy)-2-propyl-3-trimethylsilanyloxy-4-(1-trimethylsilanyloxy-vinyl)-benzene (3.00 g, 5.41 mmol) in tetrahydrofuran (0.1M) cooled to 0° C. After 15 minutes, warm reaction to room temperature. After 1 hour, cool the reaction to −78° C. Add a solution of 2-formyl-isonicotinonitrile (612 mg, 5.95 mmol) in tetrahydrofuran (10 mL) via syringe. After 1 hour, warm the reaction to room temperature. Add 10% hydrochloric acid (30 mL). After 5 minutes, pour the reaction into water and extract with ethyl acetate. Combine organics, dry with sodium sulfate, filter and concentrate under reduced pressure to give a residue. Purify the residue by flash chromatography eluting with methanol:dichlormethane followed by trituration with acetonitrile to yield the title product as a white solid (1.71 g, 76%): 1H NMR (CDCl3) δ 0.95 (t, 3H), 1.56 (sextet, 2H), 2.56 (s, 3H), 2.69 (t, 2H), 4.50 (d, 1H), 5.16 (s, 2H), 5.84 (d, 1H), 6.46 (d, 1H), 7.41 (m, 4H), 7.51 (s, 1H), 7.55 (d, 1H), 8.76 (d, 1H), 12.74 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][CH:13]([OH:16])[CH2:14][Cl:15])(=[O:10])=[O:9])=[CH:4][CH:3]=1.N1C=CN=C1.[C:22]([Si:26](Cl)([CH3:28])[CH3:27])([CH3:25])([CH3:24])[CH3:23].C(=O)([O-])O.[Na+]>CN(C=O)C>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][CH:13]([O:16][Si:26]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:28])[CH3:27])[CH2:14][Cl:15])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)OCC(O)CCl)cc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: O=C([O-])O
Agent: [Na+]
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)OCC(CCl)O[Si](C)(C)C(C)(C)C)cc1
Reaction time: 64 h
Yield: 81.5 %

Procedure:
To a mixture of 3-chloro-2-hydroxypropyl 4-methylbenzenesulfonate (17.4 g) and imidazole (13.4 g) in DMF (130 mL) was added tert-butyl(chloro)dimethylsilane (14.9 g), and the mixture was stirred for 64 hr. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with hexane. The extract was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (20.3 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH2:13][CH3:14])[O:8][C:7]([CH3:16])([CH3:15])[CH2:6][C:5]2=[O:17].S(Cl)([Cl:21])(=O)=O>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([Cl:21])[C:11]=1[O:12][CH2:13][CH3:14])[O:8][C:7]([CH3:16])([CH3:15])[CH2:6][C:5]2=[O:17]
Reactant: O=S(=O)(Cl)Cl
Reactant: CCOc1cc2c(cc1Br)C(=O)CC(C)(C)O2
Solvent: ClCCl
Product: CCOc1c(Br)cc2c(c1Cl)OC(C)(C)CC2=O

Procedure:
Following General Procedure B, 6-bromo-7-ethoxy-2,2-dimethyl-chroman-4-one (Compound 5, 2.8 g, 9.33 mmol) and sulfuryl chloride (1.51 g, 11.2 mmol) in dichloromethane were reacted to yield the title compound as a colorless oil.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18](Br)=[CH:17][CH:16]=2)=[O:12])=[CH:6][CH:5]=1)[CH3:2].[C:22](C#N)#[N:23].N1C=CC=CC=1.CN1CCCC1=O>Cl>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:22]#[N:23])=[CH:17][CH:16]=2)=[O:12])=[CH:6][CH:5]=1)[CH3:2]
Reactant: CCOc1ccc(CC(=O)OCc2ccc(Br)cc2)cc1
Reactant: N#CC#N
Agent: Cl
Solvent: c1ccncc1
Solvent: CN1CCCC1=O
Product: CCOc1ccc(CC(=O)OCc2ccc(C#N)cc2)cc1

Procedure:
A mixture of 34.9 g of p-bromobenzyl p-ethoxyphenylacetate (obtainable by esterification), 10 g of Cu2 (CN)2, 120 ml of pyridine and 60 ml of N-methylpyrrolidone is heated at 150° for 2 hours. The mixture is cooled; a solution of 120 g of FeCl3.6H2O in 600 ml of 20% hydrochloric acid is added; and the mixture is warmed at 70° for 1.5 hours while stirring and worked up in a customary manner to give p-cyanobenzyl p-ethoxyphenylacetate, m.p. 59°, c.p. -40°.