Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].[CH2:10](O)[CH2:11][OH:12].C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]2[O:12][CH2:11][CH2:10][O:6]2)[CH:7]=[CH:8][CH:9]=1
Reactant: O=Cc1cccc(Br)c1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: Brc1cccc(C2OCCO2)c1
Yield: 96.8 %

Procedure:
3-Bromobenzaldehyde (4.00 g, 21.6 mmol), ethane-1,2-diol (6.03 mL, 108 mmol) and toluene-4-sulfonic acid monohydrate (186 mg, 1.08 mmol) were dissolved in toluene (80 mL), and the solution was stirred under reflux for 4 hours. An aqueous solution of saturated sodium bicarbonate was added to the reaction solution at 0° C., which was then extracted with ethyl acetate, the organic layer was washed with brine, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was evaporated in vacuo, the residue was purified by NH silica gel column chromatography (hexane:ethyl acetate=20:1), and the title compound (4.79 g, 20.9 mmol, 97%) was obtained as a colorless oil.
Reaction SMILES: [CH2:1]([N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][N:13]=2)[C:8]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=2)=[C:7]([NH:23][C:24]([NH:26][C:27]2[C:32]([CH:33]([CH3:35])[CH3:34])=[CH:31][C:30]([CH2:36][N:37]3C(=O)C4=CC=CC=C4C3=O)=[CH:29][C:28]=2[CH:48]([CH3:50])[CH3:49])=[O:25])[C:6]1=[O:51])[CH2:2][CH2:3][CH3:4].C(O)C.C(Cl)(Cl)Cl.O.NN>O>[CH2:1]([N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][N:13]=2)[C:8]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=2)=[C:7]([NH:23][C:24]([NH:26][C:27]2[C:28]([CH:48]([CH3:49])[CH3:50])=[CH:29][C:30]([CH2:36][NH2:37])=[CH:31][C:32]=2[CH:33]([CH3:35])[CH3:34])=[O:25])[C:6]1=[O:51])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCn1c(=O)c(NC(=O)Nc2c(C(C)C)cc(CN3C(=O)c4ccccc4C3=O)cc2C(C)C)c(-c2cccc(OC)c2)c2cccnc21
Agent: NN
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: CCO
Product: CCCCn1c(=O)c(NC(=O)Nc2c(C(C)C)cc(CN)cc2C(C)C)c(-c2cccc(OC)c2)c2cccnc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 80.7 %

Procedure:
To a solution of N-[1-butyl-4-(3-methoxyphenyl)-1,2-dihydro-2-oxo-1,8-naphthyridin-3-yl]-N′-(2,6-diisopropyl-4-phthalimidomethylphenyl)-urea (393 mg, 0.57 mmol) in a mixed solvent of ethanol/chloroform (10 ml) is added hydrazine monohydrate (0.033 ml, 0.68 mmol) at room temperature, and the mixture is stirred at room temperature for 2 hours. To the mixture is further added hydrazine monohydrate (0.14 ml, 3.4 mmol), and the mixture is stirred at room temperature for 4 days. To the mixture is added water, and the mixture is extracted with ethyl acetate. The organic layer is washed twice with an aqueous sodium hydrogen carbonate solution, and dried over anhydrous magnesium sulfate. The solvent is concentrated under reduced pressure, and the residue is purified by silica gel column chromatography to give the title compound (256 mg, 0.46 mmol).
Reaction SMILES: C(OC([N:8]1[CH2:18][CH2:17][C:11]2([CH2:15][NH:14][C:13](=[O:16])[CH2:12]2)[CH2:10][CH2:9]1)=O)(C)(C)C.Br[C:20]1[CH2:24][O:23][C:22](=[O:25])[CH:21]=1.O=C1OCC(N2CCCC3(CCNCC3)C2=O)=C1>>[O:25]=[C:22]1[O:23][CH2:24][C:20]([N:14]2[C:13](=[O:16])[CH2:12][C:11]3([CH2:10][CH2:9][NH:8][CH2:18][CH2:17]3)[CH2:15]2)=[CH:21]1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CNC(=O)C2
Reactant: O=C1C=C(Br)CO1
Agent: O=C1C=C(N2CCCC3(CCNCC3)C2=O)CO1
Product: O=C1C=C(N2CC3(CCNCC3)CC2=O)CO1

Procedure:
The title compound was prepared from 3-oxo-2,8-diaza-spiro[4,5]decane-8-carboxylic acid tert-butyl ester and 4-bromofuran-2(5H)-one in two steps in an analogous fashion to that described for 2-(5-Oxo-2,5-dihydrofuran-3-yl)-2,9-diazaspiro[5.5]undecan-1-one (I-18) above. LC/MS: [(M+1)]+=237
Reaction SMILES: Cl.[CH3:2][Si:3]([CH3:29])([CH3:28])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][NH:18][C:19]1[CH:27]=[CH:26][C:22]([C:23](Cl)=[O:24])=[CH:21][CH:20]=1.[CH3:30][S:31]([NH2:34])(=[O:33])=[O:32]>N1C=CC=CC=1>[CH3:2][Si:3]([CH3:29])([CH3:28])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][NH:18][C:19]1[CH:27]=[CH:26][C:22]([C:23]([NH:34][S:31]([CH3:30])(=[O:33])=[O:32])=[O:24])=[CH:21][CH:20]=1
Reactant: CS(N)(=O)=O
Reactant: C[Si](C)(C)CCCCCCCCCCCCCCNc1ccc(C(=O)Cl)cc1
Agent: Cl
Solvent: c1ccncc1
Product: C[Si](C)(C)CCCCCCCCCCCCCCNc1ccc(C(=O)NS(C)(=O)=O)cc1

Procedure:
A solution of 12.3 g. of 4-[14-(trimethylsilyl)tetradecylamino]benzoyl chloride hydrochloride and 2.8 g. of methanesulfonamide in 150 ml. of pyridine is stirred at reflux for 2 hours and then evaporated in vacuo. The residue is partitioned between water and diethyl ether, the aqueous layer acidified with 1N hydrochloric acid, and the organic layer separated, dried with magnesium sulfate and evaporated. Crystallization of the residue affords the product as a white solid.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19](O)=[O:20])=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[C:4]=1[F:25])#[N:2].[F:26][CH:27]([F:37])[CH2:28][N:29]([CH3:36])[C@H:30]1[CH2:35][CH2:34][CH2:33][NH:32][CH2:31]1>>[F:37][CH:27]([F:26])[CH2:28][N:29]([CH3:36])[C@H:30]1[CH2:35][CH2:34][CH2:33][N:32]([C:19]([C:18]2[CH:22]=[CH:23][C:15]([N:12]3[C:13]([OH:14])=[C:9]([C:6]4[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[C:4]([F:25])[C:5]=4[CH3:24])[CH:10]=[N:11]3)=[N:16][CH:17]=2)=[O:20])[CH2:31]1
Reactant: Cc1c(-c2cnn(-c3ccc(C(=O)O)cn3)c2O)ccc(C#N)c1F
Reactant: CN(CC(F)F)[C@H]1CCCNC1
Product: Cc1c(-c2cnn(-c3ccc(C(=O)N4CCC[C@H](N(C)CC(F)F)C4)cn3)c2O)ccc(C#N)c1F

Procedure:
The title compound was prepared in a manner similar to Example 303 using 6-(4-(4-cyano-3-fluoro-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid and (S)—N-(2,2-difluoroethyl)-N-methylpiperidin-3-amine 1H NMR (400 MHz, DMSO-d6) δ ppm 1.41-1.93 (m, 3 H) 1.98-2.06 (m, 1 H) 2.33 (d, J=2.27 Hz, 3 H) 2.52-3.90 (m, 9 H) 4.26-4.73 (m, 1 H) 5.99-6.62 (m, 1 H) 7.63 (d, J=7.33 Hz, 1 H) 7.74 (t, J=7.58 Hz, 1 H) 8.08 (d, J=8.34 Hz, 1 H) 8.13-8.51 (m, 2 H) 8.54 (d, J=1.77 Hz, 1 H). ESI-MS m/z [M+H]+ 499.3.
Reaction SMILES: [Li+:1].[OH-].C([O:5][C:6]([C:8]1[O:9][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:11][N:12]=1)=[O:7])C>C1COCC1.CO.O>[Li+:1].[C:13]1([C:10]2[O:9][C:8]([C:6]([O-:7])=[O:5])=[N:12][N:11]=2)[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CCOC(=O)c1nnc(-c2ccccc2)o1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: O=C([O-])c1nnc(-c2ccccc2)o1
Reaction time: 1 h

Procedure:
LiOH (25 mg, 0.60 mmol) was added at room temperature to a stirred solution of 5-phenyl-[1,3,4]oxadiazole-2-carboxylic acid ethyl ester (60 mg, 0.275 mmol) in THF:MeOH:H2O (3:1:1, 5 mL) and the resulting mixture stirred for 1 hr. Removal of the volatiles by evaporation under reduced pressure afforded 5-phenyl-[1,3,4]oxadiazole-2-carboxylic acid lithium salt, which was used for the next step without further purification.
Reaction SMILES: Br.Br.[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)=[CH:7][CH:6]=1.Br[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH3:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([N:11]2[CH2:16][CH2:15][N:14]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)[CH2:13][CH2:12]2)=[CH:9][CH:10]=1
Reactant: Brc1ccccn1
Reactant: COc1ccc(N2CCNCC2)cc1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(N2CCN(c3ccccn3)CC2)cc1
Yield: 74 %

Procedure:
A mixture of 10.6 parts of 1-(4-methoxyphenyl)piperazine dihydrobromide, 7.9 parts of 2-bromopyridine, 8.4 parts of potassium carbonate and 90 parts of N,N-dimethylformamide is stirred and refluxed overnight. The reaction mixture is diluted with water and the product is extracted twice with benzene. The combined extracts are dried, filtered and evaporated. The residue is crystallized from 1,1'-oxybisbutane. The product is filtered off and dried, yielding 8 parts (74%) of 1-(4-methoxyphenyl)-4-(2-pyridinyl)piperazine; mp. 125.6° C.
Reaction SMILES: [Cl-].[Cl-].[Cl-].[Al+3].[C:5]1([C:11]2([C:14]([O:16][CH3:17])=[O:15])[CH2:13][CH2:12]2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[Cl:18][CH2:19][C:20](Cl)=[O:21].C(=S)=S>Cl>[Cl:18][CH2:19][C:20]([C:8]1[CH:9]=[CH:10][C:5]([C:11]2([C:14]([O:16][CH3:17])=[O:15])[CH2:13][CH2:12]2)=[CH:6][CH:7]=1)=[O:21]
Reactant: COC(=O)C1(c2ccccc2)CC1
Reactant: O=C(Cl)CCl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: COC(=O)C1(c2ccc(C(=O)CCl)cc2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Aluminum trichloride (7.9 g, 0.060 mol) was added in portions to a mixture of methyl 1-phenylcyclopropanecarboxylate (3.5 g, 0.020 mol) and chloroacetyl chloride (2.0 mL, 0.026 mol) in carbon disulfide (40 mL, 0.7 mol) at 15-25° C. and then the reaction mixture was stirred at room temperature for 2 hours. The mixture was poured into conc. HCl (10 mL) in ice (100 g) and then extracted with ether. The ether extract was washed with brine, dried and concentrated. The product was purified by CombiFlash using hexane/EtOAc (max. EA 20%). The final product was analyzed by 1H NMR, which showed that the product was a mixture of para and meta substituted isomers with a ratio of 3:2.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C@H:13]([O:17][CH3:18])[C:14]([OH:16])=[O:15])=[CH:8][CH:7]=1.[CH:19]1([C:24]2[CH:29]=[CH:28][C:27](O)=[CH:26][CH:25]=2)[CH2:23][CH2:22][CH2:21][CH2:20]1>>[CH:19]1([C:24]2[CH:25]=[CH:26][C:27]([O:1][CH2:2][CH2:3][CH2:4][O:5][C:6]3[CH:11]=[CH:10][C:9]([CH2:12][C@H:13]([O:17][CH3:18])[C:14]([OH:16])=[O:15])=[CH:8][CH:7]=3)=[CH:28][CH:29]=2)[CH2:20][CH2:21][CH2:22][CH2:23]1
Reactant: CO[C@@H](Cc1ccc(OCCCO)cc1)C(=O)O
Reactant: Oc1ccc(C2CCCC2)cc1
Product: CO[C@@H](Cc1ccc(OCCCOc2ccc(C3CCCC3)cc2)cc1)C(=O)O

Procedure:
The title compound was prepared from (2S)-3-[4-(3-Hydroxy-propoxy)-phenyl]-2-methoxy-propionic acid linked to Wang's Resin (Example 94, Step D) via Mitsunobu coupling with 4-cyclopentylphenol and cleavage from the resin (Standard Procedure G) gave an oily solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:10]=[N:11][C:12]3[C:17]([CH:18]=2)=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:5]=[CH:4][N:3]=1.[CH3:19][O:20][C:21]1[CH:22]=[C:23]([CH:25]=[C:26]([O:28][CH3:29])[CH:27]=1)[NH2:24].N(CC)(CC)CC.FC(C(O)=O)(F)F>CS(C)=O>[N:11]1[C:12]2[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:18]=[C:9]([NH:8][C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:24][C:23]3[CH:25]=[C:26]([O:28][CH3:29])[CH:27]=[C:21]([O:20][CH3:19])[CH:22]=3)[N:7]=2)[CH:10]=1
Reactant: COc1cc(N)cc(OC)c1
Reactant: Clc1nccc(Nc2cnc3ccccc3c2)n1
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: COc1cc(Nc2nccc(Nc3cnc4ccccc4c3)n2)cc(OC)c1
Temperature: 100 °C

Procedure:
A mixture of (2-chloro-pyrimidin-4-yl)-quinolin-3-yl-amine (70 mg 0.272 mmol) and 3,5-dimethoxyaniline (42 mg, 0.274 mmol) was suspended in a sealed tube with 0.3 mL of a solution of DMSO containing Et3N-TFA (50 mg). The resulting mixture was heated at 100° C. for 3 h, cooled to RT, diluted with 0.4 mL DMSO and purified via preparative HPLC to give N4-quinolin-3-yl-N2-(3,5-dimethoxyphenyl)pyrimidine-2,4-diamine as a yellow solid. M+H—374. Calc'd for C21H19N5O2: 373.414.
Reaction SMILES: C(O)(=O)C(O)=O.[F:7][C:8]([F:21])([F:20])[C:9]1[CH:10]=[C:11]([CH:17]=[CH:18][CH:19]=1)[O:12][CH:13]1[CH2:16][NH:15][CH2:14]1.C(N(CC)CC)C.[C:29]1([N:35]=[C:36]=[O:37])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>O1CCCC1.O>[C:29]1([NH:35][C:36]([N:15]2[CH2:16][CH:13]([O:12][C:11]3[CH:17]=[CH:18][CH:19]=[C:9]([C:8]([F:7])([F:20])[F:21])[CH:10]=3)[CH2:14]2)=[O:37])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: O=C=Nc1ccccc1
Reactant: FC(F)(F)c1cccc(OC2CNC2)c1
Agent: O=C(O)C(=O)O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: O=C(Nc1ccccc1)N1CC(Oc2cccc(C(F)(F)F)c2)C1
Reaction time: 16 h
Yield: 78.8 %

Procedure:
A stirred slurry of 6.2 g (0.02 mole) of 3-[3-(trifluoromethyl)phenoxy]azetidine oxalate in 60 ml of tetrahydrofuran was treated with 5 ml of triethylamine followed by 2.62 g (0.022 mole) of phenyl isocyanate and stirring continued for 16 hr. The reaction mixture was diluted with water until an oil separated which quickly solidified. The aqueous tetrahydrofuran was decanted and the solid residue recrystallized from ethanol-water to yield 5.3 g (80.1%) of white crystals, m.p. 137°-138° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:17]([OH:19])=O)=[N:4][O:5][C:6]=1[C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.Cl.[NH2:45][C@@H:46]1[CH2:51][CH2:50][C@H:49]([OH:52])[CH2:48][CH2:47]1.C(N(CC)CC)C>C(#N)C>[Cl:1][C:2]1[C:3]([C:17]([NH:45][C@H:46]2[CH2:51][CH2:50][C@@H:49]([OH:52])[CH2:48][CH2:47]2)=[O:19])=[N:4][O:5][C:6]=1[C:7]1[CH:8]=[CH:9][C:10]([C:13]([F:14])([F:15])[F:16])=[CH:11][CH:12]=1
Reactant: N[C@H]1CC[C@@H](O)CC1
Reactant: O=C(O)c1noc(-c2ccc(C(F)(F)F)cc2)c1Cl
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O=C(N[C@H]1CC[C@@H](O)CC1)c1noc(-c2ccc(C(F)(F)F)cc2)c1Cl
Temperature: 150 °C
Reaction time: 0.17 h

Procedure:
To a stirred suspension of 4-chloro-5-(4-(trifluoromethyl)phenyl)isoxazole-3-carboxylic acid (50 mg, 0.17 mmol) in acetonitrile (2 mL) was added O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (85 mg, 0.22 mmol), followed by cis-4-aminocyclohexanol hydrochloride (26 mg, 0.17 mmol). Triethylamine (52 mg, 0.51 mmol) was added before heating in the microwave at 150° C. for 10 minutes. After 10 minutes, the solvent was removed in vacuo, and the residue was partitioned between water and dichloromethane. The aqueous layer was separated and extracted with dichloromethane (3×10 mL), the combined organic extracts were dried with MgSO4, filtered and the solvent removed in vacuo. The residue was purified by preparative HPLC to afford the title compound: (26 mg, 0.067 mmol).
Reaction SMILES: [S:1](Cl)([CH3:4])(=[O:3])=[O:2].N1C=CC=CC=1.[CH3:12][O:13][C:14]1[N:19]=[CH:18][C:17]([C:20]2[S:21][C:22]3[CH:28]=[C:27]([NH2:29])[CH:26]=[CH:25][C:23]=3[N:24]=2)=[CH:16][CH:15]=1>C(Cl)Cl.CCCCCC>[CH3:12][O:13][C:14]1[N:19]=[CH:18][C:17]([C:20]2[S:21][C:22]3[CH:28]=[C:27]([NH:29][S:1]([CH3:4])(=[O:3])=[O:2])[CH:26]=[CH:25][C:23]=3[N:24]=2)=[CH:16][CH:15]=1
Reactant: CS(=O)(=O)Cl
Reactant: COc1ccc(-c2nc3ccc(N)cc3s2)cn1
Solvent: CCCCCC
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1ccc(-c2nc3ccc(NS(C)(=O)=O)cc3s2)cn1
Temperature: 25 °C
Reaction time: 144 h
Yield: 70.2 %

Procedure:
Mesylchloride (3 μL, 0.037 mmol) and pyridine (3 μL, 0.037 mmol) was added to a sol. 2-(6-methoxypyridin-3-yl)-1,3-benzothiazol-6-amine (9 mg, 0.034 mmol) in DCM (1 mL). The r.m. was stirred at r.t. for 6 days. A few drops of hexane was added and the precipitated solid was collected and dried in vacuo. The crude product was purified by flash column chromatography (20 to 100% ethyl acetate in heptane), to give the title compound (8 mg) as an off-white solid. 1H NMR δ 9.84 (s, 1H) 8.63 (d, 1H) 8.11 (dd, 1H) 7.77 (d, 1H) 7.71 (d, 1H) 7.14 (dd, 1H) 6.79 (d, 1H) 3.73 (s, 3H) 2.82 (s, 3H); MS m/z (M+H) 336, (M−H) 334.
Reaction SMILES: N[C:2]1[N:6]([C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][CH:15]=2)[N:12]([C:16]([O:18][C:19](C)([CH3:21])C)=[O:17])[N:11]=[CH:10]3)[N:5]=[C:4]([C:23]([CH3:26])([CH3:25])[CH3:24])[CH:3]=1.[C:27](Cl)([O:29][CH2:30][C:31]([Cl:34])([Cl:33])[Cl:32])=[O:28].C([O-])(O)=O.[Na+].[CH3:41][CH2:42]OC(C)=O>>[C:23]([C:4]1[CH:3]=[C:2]([C:27]([O:29][CH2:30][C:31]([Cl:34])([Cl:33])[Cl:32])=[O:28])[N:6]([C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][CH:15]=2)[N:12]([C:16]([O:18][CH2:19][CH2:21][CH2:41][CH3:42])=[O:17])[N:11]=[CH:10]3)[N:5]=1)([CH3:25])([CH3:26])[CH3:24]
Reactant: CCOC(C)=O
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Reactant: CC(C)(C)OC(=O)n1ncc2cc(-n3nc(C(C)(C)C)cc3N)ccc21
Agent: O=C([O-])O
Agent: [Na+]
Product: CCCCOC(=O)n1ncc2cc(-n3nc(C(C)(C)C)cc3C(=O)OCC(Cl)(Cl)Cl)ccc21
Reaction time: 3 h
Yield: 97 %

Procedure:
To a stirring suspension of tert-butyl 5-(5-amino-3-tert-butyl-1H-pyrazol-1-yl)-1H-indazole-1-carboxylate (see WO 2006/071940A2, 0.250 g, 0.70 mmol) and Troc-Cl (0.10 ml, 0.74 mmol) in EtOAc (7 ml) at RT was added sat'd. NaHCO3 (2.9 ml, 2.1 mmol). After 3 h, the completed reaction was diluted with hexanes (35 ml) and filtered. The solid was rinsed well with hexanes and dried to afford tent-butyl 5-(3-tert-butyl-5-((2,2,2-trichloroethoxy)carbonyl)-1H-pyrazol-1-yl)-1H-indazole-1-carboxylate (0.36 g, 97% yield). MS (ESI) m/z: 532.0 (M+H+).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([CH3:12])[C:3]=1[OH:13].[C:14](=O)([O-])[O-].[Cs+].[Cs+].IC>CN(C)C=O.C(OCC)(=O)C>[Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([CH3:12])[C:3]=1[O:13][CH3:14]
Reactant: COC(=O)c1ccc(Br)c(O)c1C
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)c1ccc(Br)c(OC)c1C
Yield: 70.4 %

Procedure:
A solution of methyl 4-bromo-3-hydroxy-2-methylbenzoate (610 mg, 2.5 mmol), cesium carbonate (1.22 g, 3.7 mmol) and iodomethane (162 μl, 2.6 mmol) in dimethylformamide (5 mL) was stirred at room temperature for 15 hours. The mixture was diluted with ethyl acetate, then washed with 5% aqueous lithium chloride then brine and dried over anhydrous sodium sulfate. Filtration and concentration afforded an orange residue, which was purified by silica gel column chromatography. Eluting with 15% diethyl ether in hexane, purified fractions were pooled and concentrated to afford 455 mg, 1.76 mmol (71%) of methyl 4-bromo-2-methyl-3-(methyloxy)benzoate as a colorless residue. 1H NMR (400 MHz, CDCl3): 7.52 (d, 1H), 7.43 (d, 1H), 3.88 (s, 3H), 3.80 (s, 3H), 2.55 (s, 3H). MS (EI) for C10H1BrO3: 260 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:16]=[C:17]([C:28](O)=[O:29])[N:18]([CH3:27])[C:19]=2[C:20]2[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=2)=[CH:11][CH:10]=1>>[C:2]1([NH:1][C:28]([C:17]2[N:18]([CH3:27])[C:19]([C:20]3[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=3)=[C:15]([C:12]3[CH:11]=[CH:10][C:9]([CH3:8])=[CH:14][CH:13]=3)[N:16]=2)=[O:29])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccccc1
Reactant: Cc1ccc(-c2nc(C(=O)O)n(C)c2-c2ccc(C)cc2)cc1
Product: Cc1ccc(-c2nc(C(=O)Nc3ccccc3)n(C)c2-c2ccc(C)cc2)cc1

Procedure:
Using essentially the same procedure as Example 9, Step B, but using aniline (0.020 mL), 4,5-di-(4-methylphenyl)-1-methylimidazole-2-carboxylic acid (25 mg, 0.08 mmol) from Example 9, Step A was converted to the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]=[CH:7]2.[N+:12]([O-])([O-:14])=[O:13].[K+]>OS(O)(=O)=O>[Br:1][C:2]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]=[CH:7]2
Reactant: O=[N+]([O-])[O-]
Reactant: Brc1cccc2cnccc12
Agent: O=S(=O)(O)O
Agent: [K+]
Product: O=[N+]([O-])c1ccc(Br)c2ccncc12
Temperature: 20 °C

Procedure:
Into a 500 mL 3-necked round bottom flask was placed a solution of 5-bromoisoquinoline (22.24 g, 106.87 mmol) in H2SO4 (120 mL). This was followed by the addition of a solution of KNO3 (15.1 g, 149.36 mmol) in H2SO4 (100 mL), which was added dropwise with stirring, while cooling to a temperature of 20° C. over a time period of 1 hour. The resulting solution was allowed to react, with stirring, for 1 hour while the temperature was maintained at room temperature. The reaction progress was monitored by TLC (ethyl acetate/petroleum ether=1:5). The reaction mixture was then quenched by the adding 600 mL of H2O/ice. Adjustment of the pH to 8-10 was accomplished by the addition of NH3. H2O (30%). A filtration was performed. The filter cake was washed 2 times with 500 mL of H2O. The solid was dried in an oven under reduced pressure. This resulted in 25.59 g (90%) of 5-bromo-8-nitroisoquinoline as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]#[CH:10].[F:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16][SH:17])=[CH:14][CH:13]=1.[Na]>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1/[CH:9]=[CH:10]\[CH:16]([S:17][CH:16](/[CH:10]=[CH:9]\[C:3]1[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=1[Cl:1])[C:15]1[CH:18]=[CH:19][C:12]([F:11])=[CH:13][CH:14]=1)[C:15]1[CH:18]=[CH:19][C:12]([F:11])=[CH:13][CH:14]=1
Reactant: Fc1ccc(CS)cc1
Reactant: C#Cc1ccc(Cl)cc1Cl
Agent: [Na]
Product: Fc1ccc(C(/C=C\c2ccc(Cl)cc2Cl)SC(/C=C\c2ccc(Cl)cc2Cl)c2ccc(F)cc2)cc1

Procedure:
A solution of 2,4-dichlorophenylacetylene (0.02 mol), 4-fluorobenzyl mercaptan (0.02 mol) and metallic sodium (0.02 g atom) is subjected to the General Procedure to form (Z)-2,4-dichlorostyryl-4-fluorobenzylsulfide. The title compound is obtained following oxidation of the sulfide, according to the General Procedure.
Reaction SMILES: ClCCl.[OH-].[Na+].Cl.[CH3:7][NH:8][OH:9].[Br:10][CH:11]([CH2:15][CH2:16]Br)[C:12](Cl)=[O:13]>O>[Br:10][CH:11]1[CH2:15][CH2:16][O:9][N:8]([CH3:7])[C:12]1=[O:13]
Reactant: CNO
Reactant: O=C(Cl)C(Br)CCBr
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: CN1OCCC(Br)C1=O
Temperature: 5 °C
Reaction time: 2 h

Procedure:
A mixture of 65 mL of dichloromethane and 2.6 g (33 mmol) of 50% aqueous sodium hydroxide in 8 mL of water was treated with 2.5 g (30 mmol) of N-methylhydroxylamine hydrochloride. After cooling to 5° C., 8.5 g (32 mmol) of 2,4-dibromobutyryl chloride* was added dropwise, with the temperature maintained at 5° to 8° C. An additional 2.6 g of 50% aqueous sodium hydroxide was added, and the mixture was stirred for 2 hours at 5° C. A final 2.6 g of 50% aqueous sodium hydroxide was added, and the mixture was stirred at room temperature for 18 hours. The organic layer was separated, and the aqueous layer was extracted with dichloromethane. The combined organic layers were dried (anhydrous magnesium sulfate) and evaporated.
Reaction SMILES: [OH:1][C@@H:2]1[C@H:6]2[N:7](C(OCC3C4C=CC=CC=4C4C3=CC=CC=4)=O)[CH2:8][C@H:9]([O:10][CH3:11])[C@H:5]2[O:4][CH2:3]1.[H][H]>[Pd].C(O)C>[CH3:11][O:10][C@H:9]1[CH2:8][NH:7][C@@H:6]2[C@@H:2]([OH:1])[CH2:3][O:4][C@H:5]12
Reactant: [H][H]
Reactant: CO[C@H]1CN(C(=O)OCC2c3ccccc3-c3ccccc32)[C@H]2[C@@H]1OC[C@@H]2O
Agent: [Pd]
Solvent: CCO
Product: CO[C@H]1CN[C@H]2[C@@H]1OC[C@@H]2O
Reaction time: 1.5 h

Procedure:
(3R,3aR,6S,6aS)-(9H-Fluoren-9-yl)methyl 3-hydroxy-6-methoxytetrahydro-2H-furo[3,2-b]pyrrole-4(5H)-carboxylate (6b). Ethanol (15 mL) was added dropwise to a mixture of 10% palladium on charcoal (30 mg) and anti-(31) (315 mg, 1.07 mmol) under an atmosphere of argon. The argon was replaced by hydrogen then the suspension was stirred for 1.5 hours then 10% palladium on charcoal (30 mg) was added. The mixture was stirred for 2 hours then 10% palladium on charcoal (50 mg) was added. The mixture was stirred for 4.5 hours then filtered through celite in vacuo. The filter cake was washed with ethanol then the solvents removed in vacuo from the filtrate to obtain the crude (3R,3aR,6S,6aS)-6-methoxyhexahydro-2H-furo[3,2-b]pyrrol-3-ol which was used without further purification.