Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=[O:46])[CH:5]([N:24]([CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[C:25]([C:27]1[CH:32]=[CH:31][C:30]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[CH:29][CH:28]=1)=[O:26])[CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][C:16]([C:19]([O:21]CC)=[O:20])([CH3:18])[CH3:17])=[CH:11][CH:10]=1)C.[OH-].[Na+].Cl>O1CCOCC1>[CH2:39]([N:24]([C:25]([C:27]1[CH:32]=[CH:31][C:30]([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)=[CH:29][CH:28]=1)=[O:26])[CH:5]([CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][C:16]([C:19]([OH:21])=[O:20])([CH3:18])[CH3:17])=[CH:11][CH:10]=1)[C:4]([OH:46])=[O:3])[C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1
Reactant: CCOC(=O)C(CCOc1ccc(OC(C)(C)C(=O)OCC)cc1)N(Cc1ccccc1)C(=O)c1ccc(-c2ccccc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CC(C)(Oc1ccc(OCCC(C(=O)O)N(Cc2ccccc2)C(=O)c2ccc(-c3ccccc3)cc2)cc1)C(=O)O
Temperature: 60 °C
Yield: 110.5 %

Procedure:
A sample of 2-[benzyl-(biphenyl-4-carbonyl)-amino]-4-[4-(1-ethoxycarbonyl-1-methyl-ethoxy)-phenoxy]-butyric acid ethyl ester (687 mg, 1.10 mmol) was dissolved in 5 mL of dioxane followed by addition of 5.0 N NaOH (2.3 mL, 11.6 mmol). The mixture was magnetically stirred and heated at 60° C. for 7 hours. The reaction mixture was allowed to cool to room temperature followed by addition of 1.0 N HCl (12 mL, 12 mmol) then partitioned by addition of methylene chloride (50 mL). The organic phase was separated, dried over sodium chloride and concentrated under reduced pressure to yield 690 mg (≈100%) of a glassy solid. HPLC RT1=2.24 min; 1H NMR (400 MHz, CDCl3) δ12.82 (broad s, 2H), 7.70-7.75 (m, 4H), 7.45-7.17 (m, 10H), 6.75-6.48 (m, 4H), 2.24-2.00 (m, 2H), 1.39 (s, 6H); MS (EI) 568.31 (M+H)+.
Reaction SMILES: [C:1]([C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH:6]=O)(=[O:3])[CH3:2].[CH3:12][N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C(O)(=O)C>C(Cl)Cl>[CH3:12][N:13]1[CH2:18][CH2:17][N:16]([CH2:6][C:5]2[CH:8]=[CH:9][CH:10]=[CH:11][C:4]=2[C:1](=[O:3])[CH3:2])[CH2:15][CH2:14]1
Reactant: CC(=O)c1ccccc1C=O
Reactant: CN1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(=O)c1ccccc1CN1CCN(C)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 67.6 %

Procedure:
A mixture of 2-acetyl-benzaldehyde (1 g, 6.75 mmol), N-methyl piperazine (878 mg, 8.76 mmol) and NaBH(OAc)3 (2.14 g, 10.12 mmol) in DCM (50 ml) was stirred at room temperature for 1 h and then acetic acid (526 mg, 8.76 mmol) was added. The resulting solution was stirred at room temperature overnight and then diluted with DCM and washed with 1 M Na2CO3. The organic phase was dried over Na2SO4 and evaporated in vacuo. The crude mixture was purified by column chromatography (eluent: DCM/MeOH/NH4OH 95:5:0.2) to give 1.06 g of 1-[2-(4-methyl-piperazin-1-ylmethyl)-phenyl]-ethanone.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([CH3:12])[CH:8]=[CH:7]2.[Li]CCCC.[CH3:18][C:19]1[C:20](=O)[CH:21]([CH3:26])[CH:22]([CH3:25])[C:23]=1[CH3:24].Cl>C1COCC1>[CH3:12][C:9]1[CH:8]=[CH:7][C:6]2[C:11](=[C:2]([C:20]3[CH:19]([CH3:18])[C:23]([CH3:24])=[C:22]([CH3:25])[C:21]=3[CH3:26])[CH:3]=[CH:4][CH:5]=2)[N:10]=1
Reactant: CC1=C(C)C(C)C(C)C1=O
Reactant: Cc1ccc2cccc(Br)c2n1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC1=C(C)C(C)C(c2cccc3ccc(C)nc23)=C1C
Temperature: 25 °C
Yield: 60.7 %

Procedure:
A solution of 4.4 g of 8-bromo-2-methylquinoline (20 mmol) in 50 ml of THF was cooled to −78° C., and 8.8 ml of n-BuLi (2.5 M in hexane, 22 mmol) was added dropwise while stirring. After ten minutes of stirring, 3.5 g of 2,3,4,5-tetramethylcyclopentenone (25 mmol) was added dropwise; the solution was heated to room temperature and then heated in reflux for one hour. The solution was cooled down; ice and hydrochloric acid to approximately pH 1 were added; and after neutralization with ammonia solution, the phases were separated and the aqueous phase was extracted with pentane. The combined organic extracts were dried, the pentane was removed in a vacuum, and the remaining brown oil was distilled in a high vacuum (boiling point: 115° C. at 0.01 mbar). A 60% yield (3.2 g) of 1-(2-methyl-8-quinolyl)-2,3,4,5-tetramethylcyclopentadiene in the form of yellow, viscous oil was obtained.
Reaction SMILES: [CH2:1]([N:8]1[CH2:19][C:18](=O)[NH:17][CH2:16][CH2:15][NH:14][CH2:13][CH2:12][NH:11][C:10](=O)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CSC>O1CCCC1>[CH2:1]([N:8]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15][NH:14][CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CN(Cc2ccccc2)CC(=O)NCCNCCN1
Solvent: CSC
Solvent: C1CCOC1
Product: c1ccc(CN2CCNCCNCCNCC2)cc1
Reaction time: 2 h

Procedure:
To a suspension of 890 mg (3.07 mmol) of 1-benzyl-3,11-dioxo-1,4,7,10-tetraazacyclododecane in tetrahydrofuran under nitrogen was added 2.64 ml of 8M borane-methyl sulfide complex (21.1 mol, 7 equivalents). The mixture was heated to reflux allowing the methyl sulfide to distill out of the reaction flask. After 2 hours, the reaction was quenched by the addition of 12 ml 1.8M hydrochloric acid in methanol and refluxed for an additional 3 hours. Volatiles were removed by evaporation, and the solid resuspended in methanol and reevaporated. The product was crystallized from methanol/ethyl acetate; yield 455 mg, 37%. Mass spectrum (CI): m/e 263 (M+H).
Reaction SMILES: C(OC([NH:11][CH:12]1[CH2:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]([C:22](=[O:40])[C:23]2[CH:28]=[CH:27][C:26]([NH:29][C:30](=[O:39])[C:31]3[CH:36]=[C:35]([Cl:37])[CH:34]=[C:33]([Cl:38])[CH:32]=3)=[CH:25][CH:24]=2)[CH2:13]1)=O)C1C=CC=CC=1.[H][H]>[Pd].C(O)(=O)C>[NH2:11][CH:12]1[CH2:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]([C:22](=[O:40])[C:23]2[CH:24]=[CH:25][C:26]([NH:29][C:30](=[O:39])[C:31]3[CH:36]=[C:35]([Cl:37])[CH:34]=[C:33]([Cl:38])[CH:32]=3)=[CH:27][CH:28]=2)[CH2:13]1
Reactant: O=C(NC1Cc2ccccc2N(C(=O)c2ccc(NC(=O)c3cc(Cl)cc(Cl)c3)cc2)C1)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)O
Product: NC1Cc2ccccc2N(C(=O)c2ccc(NC(=O)c3cc(Cl)cc(Cl)c3)cc2)C1
Yield: 63.3 %

Procedure:
To 3-benzyloxycarbonylamino-1-[4-(3,5-dichlorobenzoylamino)benzoyl]-1,2,3,4-tetrahydroquinoline (3.3 g) are added acetic acid (40 ml) and 10% Pd-C (0.4 g) and the reaction mixture is subjected to catalytic reduction at ordinary temperature under atmospheric pressure of hydrogen. One hour thereafter, the catalyst is removed by filtration and the filtrate is concentrated. The resulting residue is purified by silica gel column chromatography (eluent; dichloromethane:methanol=20:1), and recrystallized from ethanol to give 3-amino-1-[4-(3,5-dichlorobenzoylamino)benzoyl]-1,2,3,4-tetrahydroquinoline (1.6 g) as white powder, m.p. 207°-210° C.
Reaction SMILES: [Br:1][C:2]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][C:3]=1[O:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]2[N:12]=[CH:13][C:14]([C:17]3[N:21]([CH2:22][C:23]([O:25]CC)=[O:24])[N:20]=[N:19][N:18]=3)=[N:15][CH:16]=2)[CH2:7][CH2:6]1.CO.[OH-].[Na+].Cl>C1COCC1.C(OCC)(=O)C>[Br:1][C:2]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][C:3]=1[O:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]2[N:12]=[CH:13][C:14]([C:17]3[N:21]([CH2:22][C:23]([OH:25])=[O:24])[N:20]=[N:19][N:18]=3)=[N:15][CH:16]=2)[CH2:7][CH2:6]1
Reactant: CCOC(=O)Cn1nnnc1-c1cnc(N2CCC(Oc3cc(F)ccc3Br)CC2)cn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)Cn1nnnc1-c1cnc(N2CCC(Oc3cc(F)ccc3Br)CC2)cn1
Reaction time: 2 h

Procedure:
To a solution of ethyl (5-{5-[4-(2-bromo-5-fluorophenoxy)piperidin-1-yl]pyrazin-2-yl}-1H-tetrazol-1-yl)acetate (Isomer A) from Step 7 (0.067 g, 0,132 mmol) in THF (2 mL) and MeOH (2 mL) was added 1 N NaOH (2 mL). After approximately 2 h, ethyl acetate and 1 N HCl were added to the reaction mixture. The organic phase was separated, dried over sodium sulfate and evaporated to give the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:33])[C:10]1[CH:15]=[C:14](Br)[C:13]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:12][C:11]=1[O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:34](N)[CH2:35][CH2:36]C>CC(O)C.O.O>[CH2:1]([O:8][C:9](=[O:33])[C:10]1[CH:15]=[C:14]([C:35]([CH3:36])=[CH2:34])[C:13]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:12][C:11]=1[O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCCN
Reactant: O=C(OCc1ccccc1)c1cc(Br)c(OCc2ccccc2)cc1OCc1ccccc1
Solvent: O
Solvent: CC(C)O
Product: C=C(C)c1cc(C(=O)OCc2ccccc2)c(OCc2ccccc2)cc1OCc1ccccc1
Yield: 119.5 %

Procedure:
A mixture of 2,4-bis-benzyloxy-5-bromo-benzoic acid benzyl ester (10.0 g, 20 mmol), potassium isopropenyl trifluoroborate (4.0 g, 27.2 mmol) and n-butylamine (6.0 mL, 60 mmol) in 2-propanol/water (2:1, 200 mL) was purged with N2 for 5 minutes. To this mixture was added [1,1′-bis(diphenyl-phosphino)ferrocene]dichloropalladium(II) (816 mg, 1.09 mmol) and the mixture was heated at reflux for 20 h. The mixture was allowed to cool to ambient then diluted with water (400 mL) and extracted with EtOAc (2×300 mL). The combined organic extracts were washed with 1M aqueous HCl, brine, dried (MgSO4), filtered through a plug of Celite and the filtrate reduced in vacuo to give the title compound (11.1 g) as a brown gum.
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[N+:10]([O-])=O.C[O:14][C:15](=O)[CH2:16][NH2:17].Cl.C([O-])(O)=O.[Na+]>CCO.CO.[Pd]>[C:6]([C:5]1[CH:4]=[C:3]2[C:2]([NH:17][CH2:16][C:15](=[O:14])[NH:10]2)=[CH:9][CH:8]=1)#[N:7]
Reactant: N#Cc1ccc(Cl)c([N+](=O)[O-])c1
Reactant: COC(=O)CN
Agent: [Pd]
Agent: Cl
Agent: O=C([O-])O
Solvent: CO
Solvent: CCO
Product: N#Cc1ccc2c(c1)NC(=O)CN2
Yield: 112.6 %

Procedure:
To a solution of 4-chloro-3-nitrobenzonitrile (18.3 g, 100 mmol) and glycine methyl ester•hydrochloride (12.3 g, 100 mmol) in EtOH (150 mL) was added NaHCO3 (25.2 g, 300 mmol), and the resulting mixture was refluxed for 16 hours. The mixture was filtered and the filtrate was concentrated. The resulting residue was partitioned in EtOAc and water. The organic layer was neutralized with 1N HCl to pH 7 and then washed with brine, dried over MgSO4, and concentrated to give a crude (25 g). A solution of the crude was hydrogenated in MeOH (500 mL) in the presence of 10% Pd on carbon (1.5 g) at room temperature for 6 hours. The mixture was filtered and the filtrate was concentrated to give more of the same product (19.5 g, 100%). 1H NMR (DMSO-d6) δ 10.50 (s, 1H), 7.15 (dd, J=8.1 Hz, J=1.8 Hz, 1H), 6.94 (d, J=1.6 Hz, 1H), 6.93 (s, 1H), 6.68 (d, J=8.4 Hz, 1H), 3.90 (d, J=1.1 Hz, 2H); MS(CI) m/z 191 (M+NH4).
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]([CH:6]=[C:7]2[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[CH:8]2[C:14]([O:16][CH3:17])=[O:15])=[CH:4][CH:3]=1.[Na]>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C:7]2[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]=2[C:14]([O:16][CH3:17])=[O:15])=[CH:18][CH:19]=1
Reactant: COC(=O)C1C(=Cc2ccc(Cl)cc2)CCC1(C)C
Agent: [Na]
Solvent: CO
Product: COC(=O)C1=C(Cc2ccc(Cl)cc2)CCC1(C)C

Procedure:
The crude 1-(4-chlorobenzylidene)-3,3-dimethyl-2-methoxycarbonylcyclopentane obtained in Example 2 was refluxed in methanol (20 ml) containing dissolved sodium (0.3 g) for 15 minutes to give 1-(4-chlorobenzyl)-3,3-dimethyl-2-methoxycarbonylcyclopent-1-ene as an oil.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([CH3:18])=[C:6]([CH:17]=1)[CH2:7][N:8]1[C:12]([O:13][CH3:14])=[N:11][N:10]([CH3:15])[C:9]1=[O:16].[CH2:19]([C:26]#[CH:27])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C>C(#N)C.C(OC(C)(C)C)(C)(C)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[C:20]1([CH2:19][C:26]#[C:27][C:2]2[CH:3]=[CH:4][C:5]([CH3:18])=[C:6]([CH:17]=2)[CH2:7][N:8]2[C:12]([O:13][CH3:14])=[N:11][N:10]([CH3:15])[C:9]2=[O:16])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: COc1nn(C)c(=O)n1Cc1cc(Br)ccc1C
Reactant: C#CCc1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: CC(C)(C)OC(C)(C)C
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COc1nn(C)c(=O)n1Cc1cc(C#CCc2ccccc2)ccc1C
Temperature: 25 °C
Yield: 51.4 %

Procedure:
A mixture of 437 mg (1.4 mmol) of 4-(5-bromo-2-methylbenzyl)-5-methoxy-2-methyl-2,4-dihydro-3H-1,2,4-triazol-3-one (the compound 299 of the present invention), 325 mg (2.8 mol) of benzylacetylene, 41 mg (0.058 mmol) of PdCl2(PPh3)2, 33 mg (0.17 mmol) of copper (I) iodide, 82 mg (0.31 mmol) of triphenylphosphine and 0.80 g of triethylamine in 4 ml of acetonitrile was heated under reflux under an atmosphere of nitrogen for 9 hours. After cooling to room temperature, the reaction mixture was diluted with tert-butyl ether, washed with water, dried and concentrated. The residue was subjected to silica gel column chromatography (eluted with hexane:ethyl acetate=2:1) to obtain 0.25 g of 4-{5-(3-phenyl-l-propynyl)-2-methylbenzyl}-5-methoxy-2-methyl-2,4-dihydro-3H-1,2,4-triazol-3-one (the compound 535 of the present invention).
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[C:10]([C:11]([NH:13][CH:14]([CH3:16])[CH3:15])=[O:12])=[CH:9][N:8]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[C:5]2=[N:6][CH:7]=1.C(C1CN(C(=O)[C@H](NC(C2C3C(=NC=C([C:46]4[C:54]5[C:49](=[CH:50][C:51]([Cl:55])=[CH:52][CH:53]=5)[N:48](C)[N:47]=4)N=3)NC=2)=O)C)C1)#N>CN(C=O)C.C(OCC)(=O)C.[Cl-].[NH4+].[Cu]I.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:55][C:51]1[CH:50]=[C:49]2[C:54]([C:46]([C:2]3[N:3]=[C:4]4[C:10]([C:11]([NH:13][CH:14]([CH3:16])[CH3:15])=[O:12])=[CH:9][N:8]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[C:5]4=[N:6][CH:7]=3)=[N:47][NH:48]2)=[CH:53][CH:52]=1
Reactant: CC(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Br)nc12
Reactant: C[C@@H](NC(=O)c1c[nH]c2ncc(-c3nn(C)c4cc(Cl)ccc34)nc12)C(=O)N1CC(C#N)C1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3n[nH]c4cc(Cl)ccc34)nc12
Temperature: 80 °C
Yield: 23.6 %

Procedure:
To a stirred solution of 2-bromo-N-isopropyl-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (289 mg, 700 μmol) and 6-chloro-3-(tributylstannyl)-1H-indazole (see Example 4, 2.01 g, 4.55 mmol) in DMF at 20° C. was added copper(I) iodide (25.1 mg, 280 μmol) and then the mixture degassed with bubbling Argon for 15 min. Tetrakis(triphenylphosphine)palladium(0) (80.9 mg, 70.0 μmol) was added then the reaction mixture was heated to 80° C. After 15 h the mixture was cooled and diluted with ethyl acetate and saturated aqueous saturated ammonium chloride solution. The organic layer was separated and washed with brine, then dried (sodium sulfate), filtered and concentrated in vacuo. The residue was purified by chromatography (silica, 40 g Analogix column, 20-50% ethyl acetate in hexanes, gradient over 15 min) to give 2-(6-chloro-1H-indazol-3-yl)-N-isopropyl-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (0.080 g) as a light brown oil. This was approximately 75% pure by 1H NMR with a single, major impurity tentatively assigned as 6,6′-dichloro-1H,1′H-[3,3′]biindazolyl and was used directly in the next step without further purification. MS (M−H)−=483; 1H NMR (CDCl3) δ: 8.41 (s, 1H), 8.35 (s, 1H), 8.07 (br. s, 1H), 7.64-7.77 (m, 2H), 7.52 (s, 1H), 7.16 (d, J=8.7 Hz, 1H), 5.64 (s, 2H), 4.23-4.47 (m, 1H), 3.45-3.58 (m, 2H), 1.34 (d, J=6.4 Hz, 6H), 0.93 (s, 2H), −0.05 (s, 9H)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:23])[C:15]1[CH:20]=[CH:19][C:18]([CH2:21]Cl)=[CH:17][CH:16]=1.[CH2:24]([NH2:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.[I-].[Na+]>C1COCC1>[CH2:24]([NH:31][CH2:21][C:18]1[CH:19]=[CH:20][C:15]([C:14]([NH:13][CH2:12][CH2:11][C:5]2[C:4]3[C:8](=[CH:9][CH:10]=[C:2]([Cl:1])[CH:3]=3)[NH:7][CH:6]=2)=[O:23])=[CH:16][CH:17]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1ccc(CCl)cc1
Reactant: NCc1ccccc1
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1ccc(CNCc2ccccc2)cc1
Yield: 60.4 %

Procedure:
4-((Benzylamino)methyl)-N-(2-(5-chloro-1H-indol-3-yl)ethyl)benzamide was prepared following Method C starting from N-(2-(5-chloro-1H-indol-3-yl)ethyl)-4-(chloromethyl)benzamide (0.070 g; 0.202 mmol), benzylamine (0.0997 mL; 0.907 mmol) and sodium iodide (0.153 g; 1.01 mmol) in THF (3 mL), under a microwave irradiation at 150° C. for 5 minutes. Flash chromatography on silica gel (eluent 2 to 10% methanol in dichloromethane) furnished 0.051 g (61%) of the title compound as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH:8]=1)N.N([O-])=O.[Na+].[I-:16].[K+]>Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([I:16])[CH:8]=1
Reactant: Nc1cc(F)ccc1[N+](=O)[O-]
Reactant: [I-]
Agent: Cl
Agent: O=N[O-]
Agent: [K+]
Product: O=[N+]([O-])c1ccc(F)cc1I
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.1 %

Procedure:
To a solution of 5-fluoro-2-nitroaniline (70.0 g, 448 mmol) in HCl (350 mL, 37% in water) at 0° C. was added sodium nitrite (32.2 g, 469 mmol, in 100 mL water) dropwise. The mixture was stirred for 1 h at which time, potassium iodide (82.0 g, 490 mmol, in 100 mL H2O) was added dropwise. The mixture was stirred at rt for 2 h and then extracted with EtOAc. The organic layer was washed with brine, dried (MgSO4) and purified by flash chromatography to provide the title compound (98.6 g, 368 mmol, 83%). 1H NMR (400 MHz, CDCl3) δ ppm 7.15-7.23 (m, 1H), 7.75 (dd, J=3.50 Hz, J=7.60 Hz, 1H), 7.97 (dd, J=1.6 Hz, J=8.8 Hz, 1H).
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:27])[F:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:29][C:30]1[CH:31]=[CH:32][C:33]([C:38]([F:41])([F:40])[F:39])=[C:34]([CH:37]=1)[CH:35]=O>>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH:24][CH2:35][C:34]3[CH:37]=[C:30]([F:29])[CH:31]=[CH:32][C:33]=3[C:38]([F:40])([F:39])[F:41])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:26])[F:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1cc(F)ccc1C(F)(F)F
Reactant: Nc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Product: Fc1ccc(C(F)(F)F)c(CNc2cccc(-c3c(Cc4ccccc4)cnc4c(C(F)(F)F)cccc34)c2)c1

Procedure:
The title compound was prepared from {3-[3-benzyl-8-(trifluoromethyl)quinolin-4-yl]phenyl}amine and 5-fluoro-2-trifluoromethyl-benzaldehyde according to the procedure of Example 66. MS (ESI) m/z 555.
Reaction SMILES: ClS([C:5]1[CH:9]=[CH:8][S:7][C:6]=1C)(=O)=O.S1C=CC=C1.[Cl:16][S:17](O)(=[O:19])=[O:18].P(Cl)(Cl)(Cl)(Cl)Cl>>[Cl:16][S:17]([C:6]1[S:7][CH:8]=[CH:9][CH:5]=1)(=[O:19])=[O:18]
Reactant: Cc1sccc1S(=O)(=O)Cl
Reactant: O=S(=O)(O)Cl
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: c1ccsc1
Product: O=S(=O)(Cl)c1cccs1
Yield: 70 %

Procedure:
This compound was produced as described for chlorosulfonyl-methylthiophene in J. org. Chem. 33, 1357 (1968) from thiophene, chlorosulfonic acid and PCl5. The yield was 70%. The substance was a low melting solid.
Reaction SMILES: [CH2:1]1[O:13][C:12]2[CH:11]=[C:10]3[C:5]([CH2:6][CH2:7][C:8](=O)[CH2:9]3)=[CH:4][C:3]=2[O:2]1.[N:15]1[CH:20]=[CH:19][CH:18]=[N:17][C:16]=1[N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1.C1(C)C(S(O)(=O)=O)=CC=CC=1>C1(C)C=CC=CC=1>[CH2:1]1[O:13][C:12]2[CH:11]=[C:10]3[C:5]([CH2:6][CH2:7][C:8]([N:24]4[CH2:25][CH2:26][N:21]([C:16]5[N:15]=[CH:20][CH:19]=[CH:18][N:17]=5)[CH2:22][CH2:23]4)=[CH:9]3)=[CH:4][C:3]=2[O:2]1
Reactant: c1cnc(N2CCNCC2)nc1
Reactant: O=C1CCc2cc3c(cc2C1)OCO3
Agent: Cc1ccccc1S(=O)(=O)O
Solvent: Cc1ccccc1
Product: C1=C(N2CCN(c3ncccn3)CC2)CCc2cc3c(cc21)OCO3
Yield: 95.2 %

Procedure:
A solution of 3.8 g of 6,7-methylenedioxy-2-tetralone and 3.3 g of 1-(2-pyrimidinyl) piperazine in 100 ml of anhydrous toluene was boiled for 30 minutes in the presence of 100 mg of p.toluenesulphonic acid, in a Dean and Stark apparatus. When the theoretical quantity of water was collected, the solution was cooled and washed with twice 20 ml of water. The solution was then decanted off, and the solvent was evaporated under reduced pressure. The residue was taken up with petroleum ether, and there were obtained 6.4 g of 1-(6,7-methylenedioxy-3,4-dihydro-2-naphthyl)-4-(2-pyrimidinyl) piperazine, beige crystals melting at 155°-160° C.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([CH2:7][CH2:8][O:9][CH2:10][CH2:11][NH2:12])=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl[S:21]([CH2:24][CH2:25][C:26]([O:28][CH3:29])=[O:27])(=[O:23])=[O:22]>ClCCl>[CH3:1][C:2]1[S:6][C:5]([CH2:7][CH2:8][O:9][CH2:10][CH2:11][NH:12][S:21]([CH2:24][CH2:25][C:26]([O:28][CH3:29])=[O:27])(=[O:23])=[O:22])=[CH:4][CH:3]=1
Reactant: Cc1ccc(CCOCCN)s1
Reactant: COC(=O)CCS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)CCS(=O)(=O)NCCOCCc1ccc(C)s1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The product of step c) as the hydrochloride salt (1.50 g) was stirred under nitrogen in dichloromethane (25 ml). Triethylamine (2.21 ml) was added followed by methyl 3-(chlorosulphonyl)propanoate (1.18 g). The mixture was stirred at room temperature overnight. The solution was diluted with a further amount of dichloromethane and the organics washed with dilute hydrochloric acid then water, then dried (MgSO4). The mixture was filtered and the volatiles removed in vacuo to give the subtitle compound as an oil (1.4 g).
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][N:3]=1.Cl.Cl[CH2:10][C:11]1[CH:12]=[N+:13]([O-:17])[CH:14]=[CH:15][CH:16]=1>C(O)C>[CH:15]1[CH:14]=[N+:13]([O-:17])[CH:12]=[C:11]([CH2:10][S:1][C:2]2[CH:7]=[CH:6][N:5]=[CH:4][N:3]=2)[CH:16]=1
Reactant: Sc1ccncn1
Reactant: [O-][n+]1cccc(CCl)c1
Agent: Cl
Solvent: CCO
Product: [O-][n+]1cccc(CSc2ccncn2)c1
Temperature: 25 °C
Yield: 70 %

Procedure:
11.2 g (0.1 moles) 4-mercaptopyrimidine is dissolved in 100 ml ethanol containing 10.8 g sodium methoxide. 18 g (0.1 moles) 3-chloromethylpyridine-N-oxide hydrochloride is added; the mixture is heated under reflux for about one hours. The solution is cooled to ambient temperature, the sodium chloride filtered off, and the filtrate evaporated under vacuum to eliminate the solvent. The residue is crystallized from ethyl acetate to give 15.35 g of product (M.P.=105°-108° C.; yield=70%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](=[O:11])(=[O:10])[NH2:9])=[CH:4][C:3]=1[S:12]([NH2:15])(=[O:14])=[O:13].[CH:16]1([CH:22]=O)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1>>[CH:16]1([CH:22]2[NH:1][C:2]3[CH:7]=[CH:6][C:5]([S:8](=[O:10])(=[O:11])[NH2:9])=[CH:4][C:3]=3[S:12](=[O:14])(=[O:13])[NH:15]2)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: Nc1ccc(S(N)(=O)=O)cc1S(N)(=O)=O
Reactant: O=CC1CCCCC1
Product: NS(=O)(=O)c1ccc2c(c1)S(=O)(=O)NC(C1CCCCC1)N2

Procedure:
2-Amino-5-sulfamoylbenzenesulfonamide (see compound 101) was transformed by Method G (using cyclohexanecarboxaldehyde). M.p. 252-254° C.
Reaction SMILES: ClC(OCC)=O.[OH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10][C:9]=1[C:18](O)=O.C(=O)([O-])N.[BH4-].[Na+]>O1CCCC1.O.C(N(CC)CC)C>[CH3:18][C:9]1[CH:10]=[CH:11][C:12]2[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:8]=1[OH:7]
Reactant: O=C(O)c1ccc2ccccc2c1O
Agent: CCOC(=O)Cl
Agent: NC(=O)[O-]
Agent: [BH4-]
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc2ccccc2c1O
Reaction time: 1 h
Yield: 69.2 %

Procedure:
Minami et al (Chem. Pharm. Bull., 27(3), 816-820, 1979) disclose the following reaction scheme: ethyl chloroformate was added, at a temperature of 0°-5° C. and over a period of 1 hour, to a solution of 1-hydroxy-2-naphthoic acid and triethylamine in tetrahydrofuran whereby the correspondence carbamate was produced. The reaction mixture was added to a solution of sodium borohydride in water, with stirring, at a temperature of 5° to 15° C., and over a period of 1 hour. Extraction with ether gave 2-methyl-1-naphthol in a yield of 69.2%.