Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][C:10]([OH:12])=[O:11].S(=O)(=O)(O)O.[CH3:18][C:19](=[CH2:21])[CH3:20].C(=O)(O)[O-].[Na+]>O1CCOCC1.COC(C)(C)C>[C:19]([O:11][C:10](=[O:12])[CH2:9][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[CH2:2][Br:1])([CH3:21])([CH3:20])[CH3:18]
Reactant: C=C(C)C
Reactant: O=C(O)Cc1ccccc1CBr
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: COC(C)(C)C
Product: CC(C)(C)OC(=O)Cc1ccccc1CBr
Temperature: -15 °C
Reaction time: 4 h

Procedure:
To a solution of 80 g (0.349 mol) 2-bromomethylphenylacetic acid in 700 mL 1,4-dioxane in a 2 L heavy-walled flask was added 84 mL (1.571 mol) concentrated sulfuric acid at ambient temperature. The reaction mixture was chilled to −15° C., and 580 mL isobutylene was condensed directly into the reaction vessel. The sealed pressure flask was shaken mechanically at room temperature for 4 h (the pressure inside the flask rises to ca. 20 psi during this step). The mixture was carefully quenched by slowly pouring it into a 0-5° C. stirred mixture of 1.2 L tert-butyl methyl ether and 336 g (4.0 mol) solid sodium bicarbonate before slow dilution with 1.2 L ice-water. The separated organic phase was washed with 0.8 L brine, dried with sodium sulfate, filtered concentrated in vacuo to give an oil, which was used without further purification.
Reaction SMILES: [CH3:1][S:2]([C:5]1[C:6]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([S:23]([F:28])([F:27])([F:26])([F:25])[F:24])=[CH:19][CH:18]=2)=[CH:7][C:8]([CH3:15])=[C:9]([CH:14]=1)[C:10]([O:12]C)=[O:11])(=[O:4])=[O:3].[OH-].[Na+].O.Cl>CO>[CH3:1][S:2]([C:5]1[C:6]([NH:16][C:17]2[CH:18]=[CH:19][C:20]([S:23]([F:27])([F:28])([F:24])([F:25])[F:26])=[CH:21][CH:22]=2)=[CH:7][C:8]([CH3:15])=[C:9]([CH:14]=1)[C:10]([OH:12])=[O:11])(=[O:4])=[O:3]
Reactant: COC(=O)c1cc(S(C)(=O)=O)c(Nc2ccc(S(F)(F)(F)(F)F)cc2)cc1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1cc(Nc2ccc(S(F)(F)(F)(F)F)cc2)c(S(C)(=O)=O)cc1C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.4 %

Procedure:
70 mg of methyl 5-methanesulfonyl-2-methyl-4-(4-pentafluorosulfanyl-phenylamino)benzoate were dissolved in 2 ml of MeOH, and 0.12 ml of a 2N aqueous NaOH solution was added. The mixture was stirred at RT for 2 h and then left to stand at RT for 16 h. The reaction mixture was then poured into 50 ml of water, adjusted to pH=2 with aqueous HCl solution and stirred at RT for 30 minutes, and finally the product was filtered off with suction. 66 mg of colorless crystals were obtained, mp 106-109° C.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]([OH:14])=O)=[N:10][CH:11]=1)[C:2]#[C:3][CH3:4].[CH3:15][C:16]1[C:17]([NH2:31])=[N:18][C:19]2([C:29]3[C:24](=[CH:25][CH:26]=[C:27]([NH2:30])[CH:28]=3)[O:23][CH2:22][CH2:21]2)[N:20]=1>>[NH2:31][C:17]1[C:16]([CH3:15])=[N:20][C:19]2([C:29]3[C:24](=[CH:25][CH:26]=[C:27]([NH:30][C:12](=[O:14])[C:9]4[CH:8]=[CH:7][C:6]([O:5][CH2:1][C:2]#[C:3][CH3:4])=[CH:11][N:10]=4)[CH:28]=3)[O:23][CH2:22][CH2:21]2)[N:18]=1
Reactant: CC#CCOc1ccc(C(=O)O)nc1
Reactant: CC1=NC2(CCOc3ccc(N)cc32)N=C1N
Product: CC#CCOc1ccc(C(=O)Nc2ccc3c(c2)C2(CCO3)N=C(C)C(N)=N2)nc1
Yield: 15.5 %

Procedure:
The title compound (15 mg, 16% yield) was prepared as described for Example 13a starting from 5-(but-2-ynyloxy)picolinic acid (Intermediate 19, 45 mg, 0.24 mmol) and 5′-methylspiro[chroman-4,2′-imidazole]-4′,6-diamine (Intermediate 30, 54.7 mg, 0.24 mmol): 1H NMR (500 MHz, CDCl3) δ ppm 1.87 (t, 3 H), 2.03 (m, 1 H), 2.30 (m, 1 H), 2.39 (m, 3 H), 4.50 (m, 1 H), 4.62 (m, 1 H), 4.76 (m, 2 H), 6.92 (d, 1 H), 6.98 (m, 1 H), 7.41 (dd, 1 H), 7.49 (m, 1 H), 8.18 (d, 1 H), 8.28 (d, 1 H), 9.61 (s, 1 H); MS (ES+) m/z 404 [M+H]+.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][CH:5]=1.Br[CH2:13][CH2:14][CH2:15][Cl:16]>CN(C)C=O>[Cl:16][CH2:15][CH2:14][CH2:13][O:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][CH:5]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: ClCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=Cc1ccc(OCCCCl)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 74.9 %

Procedure:
To a suspension of sodium hydride (50% in oil, 3.9 g, 82 mmol) in dimethylformamide (100 ml) was added p-hydroxybenzaldehyde (5.0 g, 41 mmol). The mixture was stirred at room temperature under an atmosphere of nitrogen for one hour, then treated dropwise with 1-bromo-3-chloropropane (8.1 ml, 82 mmol). The mixture was stirred at room temperature for 12 hours, quenched with methanol and filtered through Celite. The filtrate was dissolved in diethyl ether (500 ml), washed with water (3×200 ml) and dried over Na2SO4. The ether layer was concentrated to give 6.1 g (80% yield) of 4-chloropropoxybenzaldehyde as a yellow liquid. 1H NMR (CDCl3): δ 9.95 (s, 1H), 7.85 (d, J=8.1 Hz, 2H), 7.01 (d, J=8.1 Hz, 2H), 4.21 (t, J=5 Hz, 2H), 3.81 (t, J=5 Hz, 2H), 1.26 (m, 2H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][CH:3]=1.C([Li])CCC.[O:14]=[C:15]1[CH2:20][CH2:19][C:18]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)([C:21]#[N:22])[CH2:17][CH2:16]1.Cl>C1COCC1>[F:8][C:5]1[CH:6]=[CH:7][C:2]([C:15]2([OH:14])[CH2:20][CH2:19][C:18]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)([C:21]#[N:22])[CH2:17][CH2:16]2)=[CH:3][CH:4]=1
Reactant: N#CC1(c2ccccc2)CCC(=O)CC1
Reactant: Fc1ccc(Br)cc1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: N#CC1(c2ccccc2)CCC(O)(c2ccc(F)cc2)CC1
Temperature: -70 °C
Reaction time: 1 h
Yield: 93.1 %

Procedure:
8.8 g of 1-bromo-4-fluorobenzene were dissolved in 50 ml of dry THF in a dried two-necked flask under an argon atmosphere, cooled to −70° C., and 32.2 ml of n-butyllithium solution (1.55 M in n-hexane) were slowly added dropwise so that the internal temperature did not exceed −65° C. The reaction mixture was stirred for 1 h at −70° C. Subsequently, 10.0 g of 4-oxo-1-phenylcyclohexanecarbonitrile in the form of a suspension in 50 ml of THF were slowly added dropwise so that the internal temperature did not exceed −65° C. The reaction solution was stirred further for 1 h at −70° C. and subsequently warmed to room temperature. It was stirred for 3 h at room temperature, the reaction mixture was added to ice water, cautiously acidified with 1 N hydrochloric acid and extracted three times with EA. The combined organic phases were dried over magnesium sulfate and the solvent was removed in vacuo. The crude product, a brown oil, was crystallized from toluene. 13.8 g of the title compound were obtained as a white solid.
Reaction SMILES: [C:1](#[N:4])[CH:2]=[CH2:3].N12CCCN=C1CCCCC2.[CH2:16]([N:23]1[C:27]2[CH:28]=[CH:29][C:30]3[N:31]([C:32]([CH3:35])=[N:33][N:34]=3)[C:26]=2[CH:25]=[C:24]1[C:36]1[NH:40][N:39]=[CH:38][CH:37]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(#N)C>[CH2:16]([N:23]1[C:27]2[CH:28]=[CH:29][C:30]3[N:31]([C:32]([CH3:35])=[N:33][N:34]=3)[C:26]=2[CH:25]=[C:24]1[C:36]1[CH:37]=[CH:38][N:39]([CH2:3][CH2:2][C:1]#[N:4])[N:40]=1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: Cc1nnc2ccc3c(cc(-c4ccn[nH]4)n3Cc3ccccc3)n12
Reactant: C=CC#N
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: Cc1nnc2ccc3c(cc(-c4ccn(CCC#N)n4)n3Cc3ccccc3)n12
Reaction time: 0.05 h

Procedure:
2-Propenenitrile (3.0 μL, 0.046 mmol, Aldrich) and 1,8-diazabicyclo[5.4.0]undec-7-ene (2.3 μL, 0.015 mmol) were added to a solution of 6-benzyl-1-methyl-7-(1H-pyrazol-5-yl)-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyridine (5.0 mg, 0.015 mmol, from Example 62) in acetonitrile (0.20 mL). After 3 minutes at room temperature, the reaction was found to be complete and was purified via preparative HPLC-MS (C18 eluting with a gradient of MeCN and H2O containing 0.15% NH4OH). Yield: (3.9 mg, 67%).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:8][S:7][C@H:6]([C:9]2[S:10][CH:11]=[CH:12][CH:13]=2)[CH2:5][N:4]([CH2:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C:3]1=[O:22].Br[CH:24]([CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][NH:37][C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[C:25]([O:27][CH2:28][CH3:29])=[O:26].C1C=CC=CC=1>C(OCC)(=O)C>[C:41]([O:40][C:38]([NH:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][C@@H:24]([NH:1][C@H:2]1[CH2:8][S:7][C@H:6]([C:9]2[S:10][CH:11]=[CH:12][CH:13]=2)[CH2:5][N:4]([CH2:14][C:15]([O:17][C:18]([CH3:19])([CH3:21])[CH3:20])=[O:16])[C:3]1=[O:22])[C:25]([O:27][CH2:28][CH3:29])=[O:26])=[O:39])([CH3:44])([CH3:43])[CH3:42]
Reactant: CC(C)(C)OC(=O)CN1C[C@@H](c2cccs2)SC[C@H](N)C1=O
Reactant: CCOC(=O)C(Br)CCCCCCCNC(=O)OC(C)(C)C
Solvent: CCOC(C)=O
Solvent: c1ccccc1
Product: CCOC(=O)[C@@H](CCCCCCCNC(=O)OC(C)(C)C)N[C@H]1CS[C@H](c2cccs2)CN(CC(=O)OC(C)(C)C)C1=O
Yield: 9.7 %

Procedure:
1.3 g of t-butyl α-[6(R)-amino-5-oxo-2(S)-(2-thienyl)perhydro-1,4-thiazepin-4-yl]acetate was treated with 1.73 g of ethyl 2-bromo-9-t-butoxycarbonylaminononanoate prepared as described in Preparation 4) in a similar manner to that described in Example 4. The product was then subjected to column chromatography through silica gel using a mixture of benzene and ethyl acetate in the ratio 5:1 by volume as the eluent. 237 mg of t-butyl α-{6(R)-[8-t-butoxycarbonylamino-1(R)-ethoxycarbonyloctylamino]-5-oxo-2(S)-(2-thienyl)perhydro-1,4-thiazepin-4-yl}acetate was obtained as a syrup from the fractions eluted first.
Reaction SMILES: [C:1]([N:8]1[C:16]2[CH:15]=[C:14]([O:17][C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=3[F:25])[N:13]=[CH:12][C:11]=2[C:10](I)=[N:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[Cl:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC=CC=1.CO.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:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[C:10]1[C:11]2[CH:12]=[N:13][C:14]([O:17][C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=3[F:25])=[CH:15][C:16]=2[N:8]([C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[N:9]=1
Reactant: CC(C)(C)OC(=O)n1nc(I)c2cnc(Oc3ccc(F)cc3F)cc21
Reactant: OB(O)c1ccccc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: c1ccccc1
Product: CC(C)(C)OC(=O)n1nc(-c2ccccc2Cl)c2cnc(Oc3ccc(F)cc3F)cc21
Yield: 66 %

Procedure:
A solution of 1-BOC-6-(2,4-difluorophenoxy)-3-iodo-1H-pyrazolo[4,3-c]pyridine (0.071 g) and 2-chlorophenylboronic acid in 5 mL of benzene and 1 mL of methanol was stirred at room temperature for 15 minutes. To this solution was added tetrakis(triphenylphosphine)palladium catalyst (52 mg) and 0.3 mL of 1 M sodium carbonate. The resulting mixture was heated to reflux for five hours, cooled, filtered and the organic layer was separated. The organic layer was washed, dried and concentrated. The residue was purified via chromatography using 5% ethyl acetate in hexane as the eluent to afford 45 mg of 3-(2-chlorophenyl)-6-(2,4-difluorophenoxy)-pyrazolo[4,3-c]pyridine-1-carboxylic acid, tert-butyl ester (66% yield). Mass. Spec. M+H=458.
Reaction SMILES: [O:1]=[C:2]1[CH:7]=[C:6]([CH2:8][C:9]2[C:10](=[O:16])[NH:11][C:12](=[S:15])[NH:13][CH:14]=2)[CH:5]=[CH:4][NH:3]1.[OH-].[K+].[CH3:19]I>C(O)C>[CH3:19][S:15][C:12]1[NH:13][CH:14]=[C:9]([CH2:8][C:6]2[CH:5]=[CH:4][NH:3][C:2](=[O:1])[CH:7]=2)[C:10](=[O:16])[N:11]=1
Reactant: O=c1cc(Cc2c[nH]c(=S)[nH]c2=O)cc[nH]1
Reactant: CI
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CSc1nc(=O)c(Cc2cc[nH]c(=O)c2)c[nH]1
Temperature: 80 °C
Reaction time: 1 h
Yield: 48.2 %

Procedure:
A suspension of 5-(2-Oxo-1,2-dihydro-pyridin-4-ylmethyl)-2-thioxo-2,3-dihydro-1H-pyrimidin-4-one (640 mg, 2.72 mmol, 1 eq) and KOH, 85% (1.05 eq, 190 mg) in 15 ml of absolute ethanol was stirred with at 80° C. for 1 hour. In the suspension was then added MeI (1.1 eq, 187 μl) dropwise and the mixture was stirred for another 2 hours. The solvent was then evaporated. In the crude was added 10 ml of water and pH of the solution was adjusted to 5.5-6.5. The precipitate was collected, it was dried and obtained was 2-Methylsulfanyl-5-(2-oxo-1,2-dihydro-pyridin-4-ylmethyl)-1H-pyrimidin-4-one (394 mg, yield=48.2%, purity=83%) in form of white powder. MS: [M+H]+=250.15 1H NMR (300 MHz; DMSO-d6) δ/ppm 2.46 (s, 3H), 3.31 (s, 2H), 6.05-6.10 (m, 2H), 7.25 (d, J=6.6 Hz, 1H), 7.84 (s, 1H)
Reaction SMILES: [CH:1]([C:4]1[C:9]2[C:10](=[O:15])[NH:11][S:12](=[O:14])(=[O:13])[C:8]=2[CH:7]=[C:6]([O:16][CH3:17])[CH:5]=1)([CH3:3])[CH3:2].C(N(C(C)C)CC)(C)C.[C:27]([O:33][CH2:34]Cl)(=[O:32])[C:28]([CH3:31])([CH3:30])[CH3:29]>C(#N)C>[C:27]([O:33][CH2:34][N:11]1[C:10](=[O:15])[C:9]2[C:4]([CH:1]([CH3:3])[CH3:2])=[CH:5][C:6]([O:16][CH3:17])=[CH:7][C:8]=2[S:12]1(=[O:14])=[O:13])(=[O:32])[C:28]([CH3:31])([CH3:30])[CH3:29]
Reactant: COc1cc(C(C)C)c2c(c1)S(=O)(=O)NC2=O
Reactant: CC(C)(C)C(=O)OCCl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C(C)C)c2c(c1)S(=O)(=O)N(COC(=O)C(C)(C)C)C2=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 85.7 %

Procedure:
To a suspension of 4-isopropyl-6-methoxy-1,2-benzisothiazol-3(2H)-one 1,1-dioxide (1.020 kg, 4.2 mol) in 6 L of acetonitrile was added diisopropylethylamine (543 g, 4.2 mol) and the reaction mixture was stirred at ambient temperature for 30 minutes. At the end of this period, chloromethyl pivalate (633 g, 4.2 mol) was added in one portion and the resulting solution was refluxed on a steam bath for 20 hours. The acetonitrile was removed under vacuum and the residue was stirred with 6 L of water for 30 minutes. The off-white solid was collected by filtration, washed first with 6 L of water, followed by 3 L of hexane. The product was dried at 70° C. under vaccum for 18 hours to give 1.33 kg (91%) of 2-(pivaloyloxymethyl)-4-isopropyl-6-methoxy-1,2-benzisothiazol-3(2H)-one 1,1-dioxide, m.p. 178°-179° C.
Reaction SMILES: [O:1]1[CH2:18][CH:2]1[CH2:3][O:4][C:5]1[CH:6]=[C:7]([C:11]2[CH2:12][CH2:13][C:14](=[O:17])[NH:15][N:16]=2)[CH:8]=[CH:9][CH:10]=1.CO.[CH:21]([NH2:24])([CH3:23])[CH3:22]>CCOCC>[OH:1][CH:2]([CH2:18][NH:24][CH:21]([CH3:23])[CH3:22])[CH2:3][O:4][C:5]1[CH:6]=[C:7]([C:11]2[CH2:12][CH2:13][C:14](=[O:17])[NH:15][N:16]=2)[CH:8]=[CH:9][CH:10]=1
Reactant: CC(C)N
Reactant: O=C1CCC(c2cccc(OCC3CO3)c2)=NN1
Solvent: CCOCC
Solvent: CO
Product: CC(C)NCC(O)COc1cccc(C2=NNC(=O)CC2)c1
Yield: 95.8 %

Procedure:
A stirred mixture of 6-[3-(2,3-epoxypropoxy)phenyl]-4,5-dihydro-3(2H)-pyridazinone (10 g, 0.04 mole), methanol (100 ml), and isopropylamine (20.8 ml, 0.24 mole) was heated under reflux for 90 minutes. Evaporation of the solution under reduced pressure gave a white solid which, when treated with ether, gave crude 6-[3-(2-hydroxy-3-isopropylaminopropoxy)phenyl]-4,5-dihydro-3(2H)-pyridazinone (11.7 g, 94%, m.p. 137°-141° C). The hemisulphate, recrystallised from aqueous methanol-ether, had m.p. 256°-258° C.
Reaction SMILES: [CH2:1]([N:8]1[C:12]2=[C:13]([N:20]3[CH2:29][CH2:28][C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH2:21]3)[N:14]=[C:15]([C:17]([OH:19])=[O:18])[CH:16]=[C:11]2[C:10]([CH3:30])=[C:9]1[CH3:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+].I[CH3:35].O>CN(C)C=O>[CH3:35][O:18][C:17]([C:15]1[CH:16]=[C:11]2[C:10]([CH3:30])=[C:9]([CH3:31])[N:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[C:12]2=[C:13]([N:20]2[CH2:29][CH2:28][C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH2:21]2)[N:14]=1)=[O:19]
Reactant: CI
Reactant: Cc1c(C)n(Cc2ccccc2)c2c(N3CCc4ccccc4C3)nc(C(=O)O)cc12
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cc2c(C)c(C)n(Cc3ccccc3)c2c(N2CCc3ccccc3C2)n1
Yield: 35 %

Procedure:
A solution of 1-benzyl-7-(3,4-dihydro-1H-isoquinolin-2-yl)-2,3-dimethyl-1H-pyrrolo[2,3-c]pyridin-5-carboxylic acid (20 mg, 0.05 mmol) prepared in Example 733, potassium hydroxide (10.1 mg, 0.07 mmol) and iodomethane (4.3 μl, 0.07 mmol) in anhydrous N,N-dimethylformamide (1 ml) was stirred for 10 hours at room temperature. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was dried on anhydrous magnesium sulfate and then concentrated under reduced pressure. The resulting residue was purified with silica gel column chromatography (ethyl acetate/n-hexane=1/10, v/v) to give the titled compound as a white solid. (Yield: 35%)
Reaction SMILES: [C:1](NCCCl)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH3:12][CH2:13][N:14](CC)CC.C(Cl)Cl>CN(C=O)C>[C:1]([CH2:12][CH2:13][NH2:14])([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2]
Reactant: CCN(CC)CC
Reactant: CC(C)(C)OC(=O)NCCCl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CCN

Procedure:
Compounds of formula IX may be prepared according to Scheme V. Alkylation of the secondary amine in a compound of formula VII or formula VIIa with 2-(N-Boc amino)ethyl chloride (prepared according to the procedure of Tanaka (Chem. Pharm. Bull. 1988, 36, 3125) in the presence of Et3N in a solvent such as CH2Cl2 or DMF gives the N-Boc ethylamine derivative of formula XI. Removal of the Boc group is accomplished by treatment with TFA in a solvent such as CH2Cl2 to give naphthyl-8-azabicyclo[3.2.1]octene/naphthyl-8-azabicyclo[3.2.1]octane of formula IX.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=2)[N:9]2[CH2:12][CH:11]([C:13]([C:15]3[CH:20]=[C:19]([F:21])[CH:18]=[C:17]([F:22])[CH:16]=3)=[O:14])[CH2:10]2)=[CH:4][CH:3]=1.[C:30]([Mg]Cl)([CH3:33])([CH3:32])[CH3:31].CCOCC.[OH-].[Na+]>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:23]2[CH:24]=[CH:25][C:26]([Cl:29])=[CH:27][CH:28]=2)[N:9]2[CH2:12][CH:11]([C:13]([C:15]3[CH:20]=[C:19]([F:21])[CH:18]=[C:17]([F:22])[CH:16]=3)([OH:14])[C:30]([CH3:33])([CH3:32])[CH3:31])[CH2:10]2)=[CH:4][CH:3]=1
Reactant: O=C(c1cc(F)cc(F)c1)C1CN(C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)C1
Reactant: CC(C)(C)[Mg]Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)(C)C(O)(c1cc(F)cc(F)c1)C1CN(C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)C1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of 120 mg (0.278 mmol) of {1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}(3,5-difluorophenyl)methanone (Example 19, Step 4) in 3 mL of THF, 0.35 mL (0.69 mmol) of tert-butyl magnesium chloride (2M in THF) was added and stirred for 1 h at −78° C. Then to the reaction mixture was added 30 μL of ether and 5 mL of 7 mL of qNaHCO3. The pH was adjusted to 8-9 with 2N NaOH. The water layer was extracted with CH2Cl2 (3×30 mL). The combined organic layer was dried over Na2SO4 and concentrated. The residue was purified by silica gel chromatography with hexanes/ethyl acetate to afford of the title compound as a white solid; 1H-NMR (CDCl3) δ 0.88 (s, 9H), 2.46 (t, J=7.2 Hz, 1H), 2.97 (s, 1H), 3.05 (t, J=7.6 Hz, 1H), 3.31-3.39 (m, 2H), 3.42 (m, 1H), 4.25 (s, 1H), 6.56 (m, 2H), 6.68 (m, 1H), 7.24-7.36 (m, 8H); Mass Spectrum m/e=490 (M+1 35Cl, 35Cl) and 492 (M+1 35Cl, 37Cl).
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH2:11][C@@H:10]2[C@@H:6]([CH2:7][C:8]3(OCC[O:12]3)[CH2:9]2)[CH:5]=1>CC(C)=O.O.Cl.[Cl-].[Na+]>[OH:1][CH2:2][CH2:3][C:4]1[CH2:11][C@@H:10]2[C@@H:6]([CH2:7][C:8](=[O:12])[CH2:9]2)[CH:5]=1
Reactant: OCCC1=C[C@@H]2CC3(C[C@@H]2C1)OCCO3
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: O=C1C[C@@H]2CC(CCO)=C[C@@H]2C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.1 %

Procedure:
3.00 g of 3-(2-hydroxyethyl)-7,7-ethylenedioxy-cis-bicyclo[3,3,0]oct-2-ene (prepared as described in Preparation 43) were dissolved in a mixture of 30 ml of acetone and 12 ml of water, and 0.5 ml of concentrated hydrochloric acid was added to the solution. The mixture was stirred for 1 hour at room temperature, after which it was diluted with a saturated aqueous solution of sodium chloride, and extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The solvent was removed by evaporation under reduced pressure, and the resulting residue (2.61 g) was purified by silica gel column chromatography. 1.97 g of the title compound was obtained in the form of an oil from the fractions eluted with hexane containing from 35 to 45% by volume of ethyl acetate.
Reaction SMILES: S(Cl)([Cl:3])=O.[Na+].[OH:6][C:7]1[CH:12]=[CH:11][C:10]([S:13]([O-:16])(=O)=[O:14])=[CH:9][CH:8]=1>C(Cl)Cl.CN(C=O)C>[OH:6][C:7]1[CH:12]=[CH:11][C:10]([S:13]([Cl:3])(=[O:16])=[O:14])=[CH:9][CH:8]=1
Reactant: O=S(Cl)Cl
Reactant: O=S(=O)([O-])c1ccc(O)cc1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=S(=O)(Cl)c1ccc(O)cc1
Temperature: 65 °C
Reaction time: 6 h
Yield: 98.9 %

Procedure:
A solution of 31.4 ml (430 mmol) of thionyl chloride and 0.2 ml (2.58 mmol) of DMF was quickly added to 10 g (43 mmol) of 4-hydroxybenzenesulfonic acid sodium salt under N2 atmosphere. The resulting mixture is stirred at 65° C. for 6 h. At the end of this time, the mobile, nearly homogenous reaction mixture is poured on ice with vigorous stirring. An oily lower layer is produced and which is dissolved in 100 ml of CH2Cl2. The aqueous layer is extracted with CH2Cl2 and the combined organic solution is dried over MgSO4 and concentrated under reduced pressure to give 8.19 g of 4-hydroxybenzenesulfonyl chloride; NMR (CDCl3): 5.3 (br s, 1H), 7.01 (d, 2H, J=9.08 Hz), 7.94 (d, 2H, J=9.08 Hz).
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([NH2:13])=[CH:10][CH:11]=2)[C:6]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[N:5]1)(=[O:3])[CH3:2].C(N(CC)CC)C.Cl.[CH3:28][O:29][C:30](=[O:40])[C:31]1[CH:39]=[CH:38][C:34]([C:35](O)=[O:36])=[CH:33][CH:32]=1>CN(C)C1C=CN=CC=1.ClCCl>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([NH:13][C:35]([C:34]3[CH:38]=[CH:39][C:31]([C:30]([O:29][CH3:28])=[O:40])=[CH:32][CH:33]=3)=[O:36])=[CH:10][CH:11]=2)[C:6]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[N:5]1)(=[O:3])[CH3:2]
Reactant: COC(=O)c1ccc(C(=O)O)cc1
Reactant: CC(=O)n1nc(-c2ccccc2)c2cc(N)ccc21
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(C(=O)Nc2ccc3c(c2)c(-c2ccccc2)nn3C(C)=O)cc1
Reaction time: 18 h
Yield: 74.2 %

Procedure:
To a flask containing 1-acetyl-5-amino-3-phenyl-1H-indazole (300 mg, 1.2 mmol) was added dichloromethane (10 mL), 4-(dimethylamino)pyridine (75 mg, 0.6 mmol) and triethylamine (180 mg, 1.8 mmol). The mixture was allowed to stir for ten minutes. Terephthalic acid monomethyl ester hydrochloride (285 mg, 1.44 mmol) was then added and stirring continued for 18 hours. The mixture was quenched with 5% sodium bicarbonate and extracted with dichloromethane. The extracts were dried using sodium sulfate, filtered and condensed to give a solid. The solid was recrystallized in ethanol to give the title compound (368 mg, 75%/; yield). ES-MS (m/z) 414 [M+1]+.
Reaction SMILES: [NH:1]([C:3]1[S:4][C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[N:7]=1)[NH2:2].[OH-].[K+].[C:14](=S)=[S:15]>C(O)C>[N:1]1[N:2]=[C:14]([SH:15])[N:7]2[C:6]3[CH:8]=[CH:9][CH:10]=[CH:11][C:5]=3[S:4][C:3]=12
Reactant: NNc1nc2ccccc2s1
Reactant: S=C=S
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: Sc1nnc2sc3ccccc3n12

Procedure:
2-Hydrazinobenzothiazole (300 grams), potassium hydroxide (100 grams), and 225 milliliters of carbon disulfide were refluxed for 60 hours in 5500 milliliters of ethanol. A light yellow solid began precipitating out shortly after the beginning of reflux. The solid was collected by filtration and dissolved in water to which 1500 milliliters of 0.5N hydrochloric acid were added. The mixture thickened; the desired s-triazolo(3,4-b)benzothiazole-3-thiol product was collected by filtration, m.p., 242° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2(O)[CH2:13][CH2:12][C:11]([CH3:15])([CH3:14])[CH2:10][CH:9]2[CH:16](OCC)[O:17]CC)=[CH:4][CH:3]=1.Cl>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH2:13][CH2:12][C:11]([CH3:14])([CH3:15])[CH2:10][C:9]=2[CH:16]=[O:17])=[CH:6][CH:7]=1
Reactant: CCOC(OCC)C1CC(C)(C)CCC1(O)c1ccc(Cl)cc1
Agent: Cl
Product: CC1(C)CCC(c2ccc(Cl)cc2)=C(C=O)C1

Procedure:
reacting the 1-(4-chlorophenyl)-2-(diethoxymethyl)-4,4-dimethylcyclohexanol and aqueous hydrochloric acid at about 50° C. to 80° C. to provide 2-(4-chlorophenyl)-5,5-dimethylcyclohex-1-ene-1-carbaldehyde and isolating or not isolating the 2-(4-chlorophenyl)-5,5-dimethylcyclohex-1-ene-1-carbaldehyde.