Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:6]2[O:7][C:8]3[CH:18]=[C:17]([N:19]([CH3:24])[S:20]([CH3:23])(=[O:22])=[O:21])[C:16](B4OC(C)(C)C(C)(C)O4)=[CH:15][C:9]=3[C:10]=2[C:11]([NH:13][CH3:14])=[O:12])[CH2:5][CH2:4][CH2:3][CH:2]=1.Cl[C:35]1[CH:36]=[CH:37][C:38]2[O:50][CH2:49][N:41]3[C:42]4[CH:43]=[CH:44][CH:45]=[CH:46][C:47]=4[CH:48]=[C:40]3[C:39]=2[N:51]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>O1CCOCC1.O>[C:1]1([C:6]2[O:7][C:8]3[CH:18]=[C:17]([N:19]([CH3:24])[S:20]([CH3:23])(=[O:22])=[O:21])[C:16]([C:35]4[CH:36]=[CH:37][C:38]5[O:50][CH2:49][N:41]6[C:42]7[CH:43]=[CH:44][CH:45]=[CH:46][C:47]=7[CH:48]=[C:40]6[C:39]=5[N:51]=4)=[CH:15][C:9]=3[C:10]=2[C:11]([NH:13][CH3:14])=[O:12])[CH2:5][CH2:4][CH2:3][CH:2]=1
Reactant: CNC(=O)c1c(C2=CCCC2)oc2cc(N(C)S(C)(=O)=O)c(B3OC(C)(C)C(C)(C)O3)cc12
Reactant: Clc1ccc2c(n1)-c1cc3ccccc3n1CO2
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CNC(=O)c1c(C2=CCCC2)oc2cc(N(C)S(C)(=O)=O)c(-c3ccc4c(n3)-c3cc5ccccc5n3CO4)cc12
Temperature: 110 °C
Reaction time: 2 h
Yield: 22.9 %

Procedure:
To a degassed solution of 2-(cyclopent-1-en-1-yl)-N-methyl-6-(N-methylmethylsulfonamido)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-3-carboxamide (110 mg, 0.23 mmol), 2-chloro-6H-pyrido[2′,3′:5,6][1,3]oxazino[3,4-a]indole (70 mg, 0.27 mmol), K3PO4(123 mg, 0.46 mmol) in 1,4-Dioxane (5 mL) and H2O (0.5 ml) was added Pd(dba)3 (5 mg) and X-Phos (5 mg) under N2, then the mixture was stirred at 110° C. for 2 hours. The reaction mixture was cooled to RT and filtered. The filtrate was washed with H2O, brine, extract with DCM, and dried over Na2SO4. After concentration, the residue was purified by prep-HPLC to give the product of 2-(cyclopent-1-en-1-yl)-N-methyl-6-(N-methylmethylsulfonamido)-5-(6H-pyrido[2′,3′:5,6][1,3]oxazino[3,4-a]indol-2-yl)benzofuran-3-carboxamide (30 mg, yield: 23%). 1H-NMR (CDCl3, 400 MHz) δ 7.88 (s, 1H), 7.69 (d, J=7.6 Hz, 1H), 7.56 (s, 1H), 7.47 (s, 2H), 7.27˜7.33 (m, 2H), 7.14˜7.20 (m, 2H), 6.74 (s, 1H), 6.10 (s, 1H), 5.99 (s, 2H), 3.32 (s, 3H), 3.01 (d, J=4.8 Hz, 3H), 2.83 (d, J=6.8 Hz, 2H), 2.73 (s, 3H), 2.62 (t, J=6.8 Hz, 2H), 2.00˜2.08 (m, 2H). MS (M+H)+: 569.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[CH:9][C:3]=1[O:4][CH2:5][C:6]([OH:8])=O.[NH2:17][C:18]1[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH2:31][N:32]([CH2:35][CH3:36])[CH2:33][CH3:34])=[CH:25][C:19]=1[C:20]([O:22][CH2:23][CH3:24])=[O:21]>>[Cl:1][C:2]1[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[CH:9][C:3]=1[O:4][CH2:5][C:6]([NH:17][C:18]1[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH2:31][N:32]([CH2:35][CH3:36])[CH2:33][CH3:34])=[CH:25][C:19]=1[C:20]([O:22][CH2:23][CH3:24])=[O:21])=[O:8]
Reactant: O=C(O)COc1ccc(C(F)(F)F)cc1Cl
Reactant: CCOC(=O)c1cc(OCCN(CC)CC)ccc1N
Product: CCOC(=O)c1cc(OCCN(CC)CC)ccc1NC(=O)COc1ccc(C(F)(F)F)cc1Cl

Procedure:
The product was obtained according to general working method I starting from 1.00 g (3.567 mmol) (2-chloro-4-trifluoromethyl-phenoxy)-acetic acid (Z2b) and 0.908 g (3.567 mmol) ethyl 2-amino-5-(2-diethylamino-ethoxy)-benzoate (Z25c).
Reaction SMILES: [O:1]=[C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[C:13]2[CH:18]=[CH:17][C:16]([CH2:19][C:20]3[C:21](=[O:46])[N:22]([C@H:32]4[CH2:37][CH2:36][C@H:35]([O:38][CH2:39][CH:40]([OH:45])[C:41]([F:44])([F:43])[F:42])[CH2:34][CH2:33]4)[C:23]4[N:24]([N:29]=[CH:30][CH:31]=4)[C:25]=3[CH2:26][CH2:27][CH3:28])=[CH:15][CH:14]=2)[NH:3]1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C1=CC=CC=2)=O.C(OCC)(=O)C.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl.O>[O:1]=[C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[C:13]2[CH:14]=[CH:15][C:16]([CH2:19][C:20]3[C:21](=[O:46])[N:22]([C@H:32]4[CH2:33][CH2:34][C@H:35]([O:38][CH2:39][C:40](=[O:45])[C:41]([F:42])([F:44])[F:43])[CH2:36][CH2:37]4)[C:23]4[N:24]([N:29]=[CH:30][CH:31]=4)[C:25]=3[CH2:26][CH2:27][CH3:28])=[CH:17][CH:18]=2)[NH:3]1
Reactant: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n([C@H]2CC[C@H](OCC(O)C(F)(F)F)CC2)c2ccnn12
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n([C@H]2CC[C@H](OCC(=O)C(F)(F)F)CC2)c2ccnn12
Reaction time: 3 h

Procedure:
To a solution of 6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl-4-[trans-4-(3,3,3-trifluoro-2-hydroxypropoxy)cyclohexyl]pyrazolo[1,5-a]pyrimidin-5(4H)-one (0.14 g) in methylene chloride (2 mL) was added 1,1,1-tris(acetyloxy)-1,1-dihydro-1,2-benziodoxol-3-(1H)-one (0.14 g), and the mixture was stirred for 3 hr. Ethyl acetate, water and sodium thiosulfate were added to the reaction mixture, and the mixture was stirred for 30 min. After stirring, the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography to give the title compound as a colorless amorphous solid (0.098 g, 73%).
Reaction SMILES: O[C:2]1[N:7]=[C:6]2[C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=3[C:14](=[O:15])[C:5]2=[N:4][C:3]=1[C:16]#[N:17].O=P(Cl)(Cl)[Cl:20]>>[Cl:20][C:2]1[N:7]=[C:6]2[C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=3[C:14](=[O:15])[C:5]2=[N:4][C:3]=1[C:16]#[N:17]
Reactant: N#Cc1nc2c(nc1O)-c1ccccc1C2=O
Reactant: O=P(Cl)(Cl)Cl
Product: N#Cc1nc2c(nc1Cl)-c1ccccc1C2=O
Temperature: 100 °C
Reaction time: 17 h
Yield: 44 %

Procedure:
A suspension of 6 (671 mg, 3.0 mmol) in POCl3 (8.4 ml) was heated under stirring to 100° C. for 17 h. Excess of POCl3 was evaporated under reduced pressure and the crude was purified by flash chromatography on silica (CH2Cl2), affording 9 (320 mg, 44%) as yellow solid.
Reaction SMILES: [C:1]1([SH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[Br:10][C:11](Br)([F:13])[F:12].O>CN(C=O)C>[Br:10][C:11]([S:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)([F:13])[F:12]
Reactant: Sc1ccccc1
Reactant: FC(F)(Br)Br
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: FC(F)(Br)Sc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
In a three-necked round-bottomed flask placed under a nitrogen atmosphere, topped with a dry-ice condenser and a dropping funnel, thiophenol (10.2 ml, 100 mmol) was added dropwise, over 40 min at 0° C., to a suspension of NaH (6 g, 150 mmol) in anhydrous DMF (100 ml). The mixture was then stirred at 0° C. for 30 min then cooled to −50° C. Dibromodifluoromethane (27 ml, 300 mmol) was then added at −50° C. The mixture was then stirred for 3 h at this temperature, then 30 min at ambient temperature. Water (100 ml) was added to the reaction mixture, then the product was extracted with ethyl ether (3×100 ml). The organic phases were washed with water (3×100 ml) and dried over MgSO4. After evaporation of the solvent, the residue was purified by distillation under reduced pressure (97° C./34 mmHg) to give the product [(bromodifluoromethyl)sulfanyl]benzene in the form of a colorless liquid (15.3 g, 60%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:9]=[C:8]([N:10]2[CH2:14][CH2:13][CH2:12][C:11]2=[O:15])[CH:7]=[C:6](N)[CH:5]=1.[N-]=[N+]=[N-].[Na+].[OH2:22]>Cl.CO.CCOCC>[CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:9]=[C:8]([N:10]2[CH2:14][CH2:13][CH2:12][C:11]2=[O:15])[CH:7]=[C:6]([OH:22])[CH:5]=1
Reactant: COC(=O)c1cc(N)cc(N2CCCC2=O)c1
Reactant: O
Agent: Cl
Agent: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CO
Solvent: CCOCC
Product: COC(=O)c1cc(O)cc(N2CCCC2=O)c1
Temperature: 90 °C
Yield: 67 %

Procedure:
3-Amino-5-(2-oxo-pyrrolidin-1-yl)-benzoic acid methyl ester (D4a) (1.50 g, 6.4 mmol, 1 equiv) was dissolved in a mixture of 2N aqueous HCl solution (25 ml) and MeOH (50 ml) at 0° C. and treated portionwise with NaN3 (950 mg, 13.8 mmol, 2.2 equiv) over 20 min. H2O (50 ml) was added and the resulting mixture was heated at 90° C. for 45 min then cooled to room temperature and diluted with Et2O (300 ml). The two layers were separated and the organic phase was dried over MgSO4 and concentrated in vacuo to give 3-hydroxy-5-(2-oxo-pyrrolidin-1-yl)-benzoic acid methyl ester (D37) (1.0 g, 67%) as a tan solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:42])[C@@H:13]([NH:23][C:24]([C:26]2[CH:30]=[C:29]([O:31][CH2:32][C:33](O)=[O:34])[N:28]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[N:27]=2)=[O:25])[CH2:14][CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:8][CH2:7]1)=[O:5])[CH3:2].C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[CH2:62]([O:69][C:70]([C:72]1([NH2:76])[CH2:75][CH2:74][CH2:73]1)=[O:71])[C:63]1[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=1>CN(C=O)C.C(OCC)(=O)C.C(Cl)CCl>[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:42])[C@@H:13]([NH:23][C:24]([C:26]2[CH:30]=[C:29]([O:31][CH2:32][C:33](=[O:34])[NH:76][C:72]3([C:70]([O:69][CH2:62][C:63]4[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=4)=[O:71])[CH2:73][CH2:74][CH2:75]3)[N:28]([C:36]3[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=3)[N:27]=2)=[O:25])[CH2:14][CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: NC1(C(=O)OCc2ccccc2)CCC1
Reactant: CCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)c2cc(OCC(=O)O)n(-c3ccccc3)n2)CC1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)c2cc(OCC(=O)NC3(C(=O)OCc4ccccc4)CCC3)n(-c3ccccc3)n2)CC1

Procedure:
To a solution of 4.9 g 4-{(S)-4-tert-butoxycarbonyl-2-[(5-carboxymethoxy-1-phenyl-1H-pyrazole-3-carbonyl)-amino]-butyryl}-piperazine-1-carboxylic acid ethyl ester in 35 ml DMF were added 1.3 g HOBt, 1.6 g EDC, 2.7 ml DIPEA and 1.7 g 1-Amino-cyclobutanecarboxylic acid benzyl ester. After 12 h the mixture was diluted with ethyl acetate and subsequently extracted with aqueous LiCl (4% w/w), 0.1 M HCl and saturated aqueous NaHCO3. The organic layer was dried over MgSO4 and the solvent was removed under reduced pressure. The crude product thus obtained was used in the subsequent reaction. Yield: 4.7 g
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:18])[CH:8]=2)[N:3]=1.[CH3:19][NH:20][NH2:21]>O>[Cl:18][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([N:20]([CH3:19])[NH2:21])[N:11]=[C:10]2[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CNN
Reactant: Clc1ccc2nc(Cl)nc(-c3ccccc3)c2c1
Solvent: O
Product: CN(N)c1nc(-c2ccccc2)c2cc(Cl)ccc2n1
Yield: 79.1 %

Procedure:
A mixture of 275 mg of 2,6-dichloro-4-phenylquinazoline (compound No. Ia1-3) and 461 mg of monomethylhydrazine was stirred at 85° C. for 30 minutes. The resulting reaction product was cooled and 200 ml of water was added thereto. Precipitated crystals were collected by filtration and the collected product was purified by column chromatography (ethyl acetate) to obtain 225 mg of the titled compound. Mp. 155.9° C. 1H NMR (CDCl3): 3.52 (3H, s), 4.65 (2H, s), 7.54-7.63 (5H, m), 7.70-7.74 (2H, m), 7.80 (1H, d, J=2.0 Hz).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[S:6]([NH:9][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]2[C:18]=1[NH:17][C:16]([C:19]([O:21]CC)=[O:20])=[CH:15]2)(=[O:8])=[O:7].[OH-].[Na+].O1CCCC1>C(O)C>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[S:6]([NH:9][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]2[C:18]=1[NH:17][C:16]([C:19]([OH:21])=[O:20])=[CH:15]2)(=[O:8])=[O:7]
Reactant: CCOC(=O)c1cc2cccc(NS(=O)(=O)c3cccs3)c2[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: O=C(O)c1cc2cccc(NS(=O)(=O)c3cccs3)c2[nH]1
Temperature: 50 °C
Reaction time: 8 h
Yield: 97.4 %

Procedure:
A mixture of ethyl 7-[(2-thienylsulfonyl)amino]-1H-indole-2-carboxylate (7.81 g), 8N aqueous sodium hydroxide solution (11.0 mL), tetrahydrofuran (20 mL) and ethanol (30 mL) was stirred at 50° C. overnight. The reaction mixture was concentrated, and water was added to the residue. The mixture was acidified with 10% aqueous citric acid solution, and the resulting crystals were filtrated, washed with water, and dried to give the title compound (7.00 g, yield 97%) as colorless crystals. melting point>268° C. (decomposition).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[N:15]([C:32]4[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=4)[C:16](=[O:31])[C:17]4[CH:22]=[N:21][N:20]([C:23]5[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=5)[C:26]#[N:27])[C:18]=4[N:19]=3)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.Cl.C(=O)([O-])[O-].[NH4+:44].[NH4+]>CO>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]([C:14]3[N:15]([C:32]4[CH:33]=[CH:34][C:35]([Cl:38])=[CH:36][CH:37]=4)[C:16](=[O:31])[C:17]4[CH:22]=[N:21][N:20]([C:23]5[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=5)[C:26]([NH2:44])=[NH:27])[C:18]=4[N:19]=3)=[CH:12][CH:13]=2)=[CH:4][CH:3]=1
Reactant: [NH4+]
Reactant: N#Cc1cccc(-n2ncc3c(=O)n(-c4ccc(Cl)cc4)c(-c4ccc(-c5ccc(N)nc5)cc4)nc32)c1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CO
Product: N=C(N)c1cccc(-n2ncc3c(=O)n(-c4ccc(Cl)cc4)c(-c4ccc(-c5ccc(N)nc5)cc4)nc32)c1

Procedure:
At 0° C., 3-[6-[4-(6-amino-pyridin-3-yl)-phenyl]-5-(4-chloro-phenyl)-4-oxo-4,5-dihydro-pyrazolo[3,4-d]pyrimidin-1-yl]-benzonitrile (prepared as described in example 28, 0.325 g, 0.629 mmol) is added to methanol saturated with hydrogen chloride gas (7 mL) with stirring. The reaction mixture is allowed to reach rt and stirred there for 24 h. The reaction mixture is then concentrated to a dry residue. It is taken in dry methanol (6 mL) and ammonium carbonate (0.593 g, 3.77 mmol) is added. After stirring at rt for 16 h, the reaction mixture is concentrated and the residue obtained is purified by preparative HPLC to afford 3-[6-[4-(6-ammo-pyridin-3-yl)-phenyl]-5-(4-chloro-phenyl)-4-oxo-4,5-dihydro-pyrazolo[3,4-d]pyrimidin-1-yl]-benzamidine. 1H NMR (Acetone-d6, 400 MHz) δ 11.32 (br, 2H), 8.88 (br, 2H), 8.72 (m, 2H), 8.40 (s, 1H), 8.25 (m, 2H), 7.95 (m, 2H), 7.83 (m, 1H), 7.65 (m, 5H), 7.45 (m, 4H), 7.14 (d, 1H); LC-MS calculated for C29H21ClN8O (M+H+) 533.2, found 533.1.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][C:4]=1C.N([O-])=[O:12].[Na+]>>[CH3:9][C:7]1[CH:8]=[C:3]([OH:2])[C:4](=[CH:5][CH:6]=1)[OH:12]
Reactant: O=N[O-]
Reactant: COc1cc(C)ccc1C
Agent: [Na+]
Product: Cc1ccc(O)c(O)c1
Temperature: 2.5 °C
Reaction time: 5 h
Yield: 65.7 %

Procedure:
To an ice-cold concentrated nitric acid (200 mL) was added slowly under stirring over a period of 20 minutes 2-methoxy-1,4-dimethylbenzene (25 g, 184 mmol). To this cold reaction mixture, sodium nitrite (38 g, 552 mmol) was added slowly in lots over a period of 1 h while maintaining the temperature below 2° C. The reaction mixture was stirred at between 0-5° C. for 5 h. The reaction mass was poured into ice-cold water (1000 mL), and the precipitated solid was filtered, washed with cold water (100 mL) and dried. The crude solid was crystallized from ethanol and water (7:1) to yield compound 1 (15 g, 45%).
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([O:10][C:11](=[O:33])[CH:12]([O:30][CH2:31][CH3:32])[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=2)=[CH:16][CH:15]=1)[CH3:9].[CH:34]([S:37](Cl)(=[O:39])=[O:38])([CH3:36])[CH3:35].O>ClCCl>[CH2:8]([O:10][C:11](=[O:33])[CH:12]([O:30][CH2:31][CH3:32])[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][C:23]2[CH:24]=[CH:25][C:26]([O:29][S:37]([CH:34]([CH3:36])[CH3:35])(=[O:39])=[O:38])=[CH:27][CH:28]=2)=[CH:16][CH:15]=1)[CH3:9]
Reactant: CCOC(=O)C(Cc1ccc(OCCc2ccc(O)cc2)cc1)OCC
Reactant: CC(C)S(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)C(Cc1ccc(OCCc2ccc(OS(=O)(=O)C(C)C)cc2)cc1)OCC
Temperature: 25 °C
Yield: 90.1 %

Procedure:
Triethylamine (0.64 g; 6.28 mmole) was slowly added to a solution of 2-ethoxy-3-{4-[2-(4-hydroxyphenyl)ethoxy]phenyl}propanoic acid ethyl ester (1.5 g; 4.18 mmole) in dry dichloromethane (20 ml). After cooling to 0° C. isopropylsulfonyl chloride (0.9 g; 6.28 mmole) was added slowly. The reaction mixture was stirred over night at room temperature, water was added and the mixture was extracted with dichloromethane. The organic phase was washed with hydrochloric acid (1M) and sodium bicarbonate solution, dried (magnesium sulfate) and evaporated in vacuo to give 1.75 g (yield 90%) of 2-ethoxy-3-(4-{2-[4-(2-propanesulfonyloxy)phenyl]ethoxy}phenyl)propanoic acid ethyl ester.
Reaction SMILES: [N+:1]([C:4]1[CH:16]=[C:15]2[C:7]([C:8]3[CH2:9][CH2:10][N:11]([CH2:20][CH2:21][CH3:22])[CH2:12][C:13]=3[N:14]2C(=O)C)=[CH:6][CH:5]=1)([O-])=O.[Sn](Cl)Cl>CO>[CH2:20]([N:11]1[CH2:10][CH2:9][C:8]2[C:7]3[C:15](=[CH:16][C:4]([NH2:1])=[CH:5][CH:6]=3)[NH:14][C:13]=2[CH2:12]1)[CH2:21][CH3:22]
Reactant: CCCN1CCc2c(n(C(C)=O)c3cc([N+](=O)[O-])ccc23)C1
Agent: Cl[Sn]Cl
Solvent: CO
Product: CCCN1CCc2c([nH]c3cc(N)ccc23)C1
Yield: 46.9 %

Procedure:
To 1-(7-nitro-2-propyl-1,2,3,4-tetrahydro-beta-carbolin-9-yl)-ethanone (1.2 g, 2.79 mmol, 70% purity) in methanol (50 ml) was added tin dichloride (5.03 g, 22.3 mmol) and the reaction mixture was refluxed for 3 h. The solvent was removed, the residue treated with 1 N aqueous sodium hydroxide and ethyl acetate, filtered through celite, the phases separated and the aqueous phase extracted twice with ethyl acetate. The combined organic phases were dried over magnesium sulfate, filtered, and evaporated to dryness to yield 700 mg of crude product. The crude product was purified with silica gel chromatography with ethyl acetate/methanol (95:5) as eluent to give the desired product (300 mg, 45% yield).
Reaction SMILES: [BrH:1].[OH:2][C:3]1[C:16]2[CH2:15][CH2:14][C@H:13]3[C@@H:8]([CH2:9][CH2:10][CH2:11][NH:12]3)[C:7]=2[CH:6]=[CH:5][CH:4]=1.[C:17](Cl)(=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19]>FC(F)(F)C(O)=O>[BrH:1].[C:17]([O:2][C:3]1[C:16]2[CH2:15][CH2:14][C@H:13]3[C@@H:8]([CH2:9][CH2:10][CH2:11][NH:12]3)[C:7]=2[CH:6]=[CH:5][CH:4]=1)(=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19]
Reactant: CC(C)(C)C(=O)Cl
Reactant: Oc1cccc2c1CC[C@@H]1NCCC[C@@H]21
Agent: Br
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)C(=O)Oc1cccc2c1CC[C@@H]1NCCC[C@@H]21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(±)-trans-7-Hydroxy-1,2,3,4,4a,5,6,10b-octahydrobenzo(f)quinoline hydrobromide (50 mg, 0.17 mmol) was dissolved in trifluoroacetic acid (1 ml). Pivaloyl chloride (0.2 ml) was added and the mixture was stirred at room temperature overnight. After evaporation of the solvent, the residue was partitioned between H2O and CH2Cl2. The organic layer was concentrated and applied to a SiO2 column and the product was eluted with CH2Cl2 -MeOH. Fractions containing the product were collected. The solvent was evaporated yielding 20 mg of an oil. GC-MS: M+ at m/e 287.
Reaction SMILES: Cl[C:2]1[CH2:7][C:6]([CH3:9])([CH3:8])[CH2:5][CH2:4][C:3]=1[CH:10]=[O:11].C([O-])([O-])=O.[K+].[K+].[Cl:18][C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1.C([O-])(O)=O.[Na+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1.C(#N)C>[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([C:2]2[CH2:7][C:6]([CH3:9])([CH3:8])[CH2:5][CH2:4][C:3]=2[CH:10]=[O:11])=[CH:21][CH:20]=1
Reactant: CC1(C)CCC(C=O)=C(Cl)C1
Reactant: OB(O)c1ccc(Cl)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: CC#N
Product: CC1(C)CCC(C=O)=C(c2ccc(Cl)cc2)C1
Temperature: 20 °C
Reaction time: 0.08 h
Yield: 86.6 %

Procedure:
To a 250 mL pressure bottle were charged 2-chloro-4,4-dimethylcyclohex-1-enecarbaldehyde (10.00 g), tetrabutylammonium bromide (18.67 g), and acetonitrile (10 mL). The mixture was stirred at 20° C. for 5 min. 21.0 wt % K2CO3 aq. solution (76.0 g) was added. The mixture was stirred at room temperature (rt) for NLT 5 min. followed by addition of 4-chlorophenylboronic acid (9.53 g) all at once. The mixture was evacuated and purged with N2 for three times. Palladium acetate (66 mg, 0.5 mol %) was added all at once under N2. The reaction mixture was evacuated and purged with N2 for three times (an orange colored mixture). The bottle was back filled with N2 and heated to ˜35° C. in an oil bath (bath temp ˜35° C.). The mixture was stirred at 30° C. overnight (15 hours). The reaction mixture was cooled to RT, and pulled IP sample from the upper organic phase for reaction completion, typically starting material <2% (orange colored mixture). Toluene (100 mL) and 5% NaHCO3-2% L-Cysteine aq. solution (100 mL) were added. The mixture was stirred at 20° C. for 60 min. The mixture was filtered through a pad of Celite to remove black solid, rinsing the flask and pad with toluene (10 mL). The upper organic phase was washed with 5% NaHCO3 aq. solution-2% L-Cysteine (100 mL) once more. The upper organic phase was washed with 25% brine (100 mL). The organic layer (105.0 g) was assayed (118.8 mg/g, 12.47 g product assayed, 87% assayed yield), and concentrated to ˜1/3 volume (˜35 mL). The product solution was directly used in the next step without isolation. However, an analytical sample was obtained by removal of solvent to give a brown oil. 1HNMR (CDCl3): δ 1.00 (s, 6H), 1.49 (t, J=6.6 Hz, 2H), 2.28 (t, J=2.1 Hz, 2H), 2.38 (m, 2H), 7.13 (m, 2H), 7.34 (m, 2H), 9.47 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([OH:8])=O.[NH:12]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[N:14]=[C:13]1[C:21]1[C:25]([NH2:26])=[CH:24][NH:23][N:22]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>CS(C)=O.O>[NH:14]1[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[N:12]=[C:13]1[C:21]1[C:25]([NH:26][C:6](=[O:8])[C:5]2[CH:9]=[CH:10][CH:11]=[C:3]([O:2][CH3:1])[CH:4]=2)=[CH:24][NH:23][N:22]=1
Reactant: Nc1c[nH]nc1-c1nc2ccccc2[nH]1
Reactant: COc1cccc(C(=O)O)c1
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCCl
Solvent: CS(C)=O
Product: COc1cccc(C(=O)Nc2c[nH]nc2-c2nc3ccccc3[nH]2)c1
Yield: 12.6 %

Procedure:
A mixture of 3-methoxybenzoic acid (84 mg, 0.55 mmol), 3-(1H-benzimidazol-2-yl)-1H-pyrazol-4-ylamine (100 mg, 0.50 mmol), EDC (116 mg, 0.60 mmol) and HOBt (81 mg, 0.60 mmol) was stirred at ambient temperature in DMSO (3 ml) for 20 h. The reaction mixture was poured into water (30 ml) and the resultant solid was collected by filtration and purified by flash column chromatography [SiO2, (dichloromethane 120 ml, methanol 15, acetic acid 3 ml, water 2 ml (DMAW 120)] to yield N-[3-(1H-Benzimidazol-2-yl)-1H-pyrazol-4-yl]-3-methoxy-benzamide as a pale pink-gray solid (21 mg, 13%). (LC/MS: Rt 3.81, [M+H]+ 334.03).
Reaction SMILES: [OH-].[K+].[CH3:3][S:4]([O:7][CH:8]([CH3:14])[C:9]([O:11]CC)=[O:10])(=[O:6])=[O:5].Cl>O>[CH3:3][S:4]([O:7][CH:8]([CH3:14])[C:9]([OH:11])=[O:10])(=[O:6])=[O:5]
Reactant: CCOC(=O)C(C)OS(C)(=O)=O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: CC(OS(C)(=O)=O)C(=O)O
Yield: 95.4 %

Procedure:
5.02 G (89.5 mmol) of potassium hydroxide was dissolved in 50 ml of water and stirred at 10°-20° C. 14.46 G (73.70 mmol) of the ethyl (-)-2-methanesulfonyloxypropionate obtained in Example 1 was added to this, and the mixture was stirred at the same temperature for 5 hours. Concentrated hydrochloric acid was added to bring the pH below 1, and extraction was performed with ethyl acetate (30 ml, 3 times). Anhydrous sodium sulfate and anhydrous magnesium sulfate were added in sequence to dry the extract, which was then vacuum concentrated, and 11.83 g of (-)-2-methanesulfonyloxypropionic acid was obtained in the form of crystals of mp 65°-72° C. Yield 95.4%.