Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]([C:14]2[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:15]=2[F:22])[C:8]([CH:11]2[CH2:13][CH2:12]2)=[CH:9][CH:10]=1)=O.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[CH:11]1([C:8]2[C:7]([C:14]3[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:15]=3[F:22])=[CH:6][C:5]([CH2:3][OH:2])=[CH:10][CH:9]=2)[CH2:12][CH2:13]1
Reactant: COC(=O)c1ccc(C2CC2)c(-c2cc(OC)ccc2F)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(F)c(-c2cc(CO)ccc2C2CC2)c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 66.4 %

Procedure:
To a dry round bottom flask containing 13.3 (0.4 g, 1.328 mmol) under an argon atmosphere was added dry THF (6 mL). The resulting mixture was cooled to 0° C. After 15 minutes, lithium aluminum hydride (1.0 M solution in THF) (2.0 mL, 2.00 mmol) was carefully added at 0° C. Upon complete addition, the reaction was allowed to warm to room temperature. After 2 hours, the reaction was cooled in an ice bath, and then carefully quenched with water and diluted with EtOAc. The organic phase was washed with 2M HCl and then with brine. After drying over anhydrous magnesium sulfate, the organic solvent was removed under reduced pressure, and the residue was purified by flash chromatography (SiO2 gel 60, eluted with 0 to 40% EtOAc in hexanes) to yield a colorless oil 13.4 (0.24 g, 66% yield.).
Reaction SMILES: [NH2:1][C:2]1[C:10]2[CH:9]3[CH2:11][CH2:12][CH2:13][CH2:14][CH:8]3[O:7][C:6]=2[C:5](C(O)=O)=[CH:4][C:3]=1[Cl:18].C(N(CC)CC)C.C(OC(Cl)=O)C.Cl.Cl.NC1C2CCN(CC2)C1>C(Cl)(Cl)Cl.O>[NH2:1][C:2]1[C:10]2[CH:9]3[CH2:11][CH2:12][CH2:13][CH2:14][CH:8]3[O:7][C:6]=2[CH:5]=[CH:4][C:3]=1[Cl:18]
Reactant: Nc1c(Cl)cc(C(=O)O)c2c1C1CCCCC1O2
Agent: CCOC(=O)Cl
Agent: Cl
Agent: NC1CN2CCC1CC2
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Solvent: O
Product: Nc1c(Cl)ccc2c1C1CCCCC1O2
Reaction time: 2 h

Procedure:
To a cold solution of 0.3 g 1-amino-2-chloro-5a,6,7,8,9,9a-hexahydrodibenzofuran-4-carboxylic acid in 40 ml chloroform is added 0.3 g of triethylamine and then 0.2 g ethylchloroformate in 10 ml chloroform. Stirring is continued for 2 hours. This is then added to a cold mixture of 3 g 3-aminoquinuclidine dihydrochloride in 20 ml water containing 7.5 g K2CO3. Stirring is continued overnight. The reaction mixture is then diluted with chloroform, the two layers separated and the chloroform layer washed twice with water, dried over magnesium sulfate, filtered and evaporated to dryness to give 1-amino-2-chloro-5a,6,7,8,9,9a-hexahydrodibenzofuran-4-(N-1-azabicyclo [2.2.2.]oct-3-yl)carboxamide as an oily Product.
Reaction SMILES: COC1C=CC(C[N:8](CC2C=CC(OC)=CC=2)[C:9]2[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([C:16]3[C:17]([NH:24][C:25]4[CH:26]=[N:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=4)=[N:18][CH:19]=[C:20]([CH:23]=3)[CH:21]=O)[N:10]=2)=CC=1.[NH:44]1[CH2:47][CH:46]([NH:48]C(=O)OC(C)(C)C)[CH2:45]1>>[NH2:48][CH:46]1[CH2:45][N:44]([CH2:21][C:20]2[CH:23]=[C:16]([C:11]3[N:12]=[C:13]([CH3:15])[N:14]=[C:9]([NH2:8])[N:10]=3)[C:17]([NH:24][C:25]3[CH:26]=[N:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=3)=[N:18][CH:19]=2)[CH2:47]1
Reactant: CC(C)(C)OC(=O)NC1CNC1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(C=O)cnc3Nc3ccc(OC)nc3)n2)cc1
Product: COc1ccc(Nc2ncc(CN3CC(N)C3)cc2-c2nc(C)nc(N)n2)cn1

Procedure:
The title compound was synthesized following an analogous procedure to Example 220 using 5-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-6-(6-methoxypyridin-3-ylamino)nicotinaldehyde (0.56 g, 0.969 mmol) and tert-butyl azetidin-3-ylcarbamate (Astatech, Bristol, Pa.) (0.250 g, 1.454 mmol). 1H NMR (400 MHz, d4-MeOH) δ 8.85 (d, 1H); 8.46 (d, J=2.54 Hz, 1H); 8.18 (d, J=2.35 Hz, 1H); 8.01 (dd, J=8.80, 2.74 Hz, 1H); 6.81 (d, J=8.80 Hz, 1H); 3.91 (s, 3H); 3.83-3.88 (m, 1H); 3.82 (s, 2H); 3.75 (t, J=7.92Hz, 2H); 3.36-3.40 (m, 2H); 2.47 (s, 3H). m/z (ESI, +ve ion) 394.0 (M+H)+.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[N:11][N:12]([CH3:14])[N:13]=2)=[CH:5][CH:4]=1.Cl.O.[NH:17]1[CH2:22][CH2:21][C:20](=[O:23])[CH2:19][CH2:18]1.C(N(CC)C(C)C)(C)C>CS(C)=O>[CH3:14][N:12]1[N:11]=[N:10][C:9]([C:6]2[CH:7]=[CH:8][C:3]([CH2:2][N:17]3[CH2:22][CH2:21][C:20](=[O:23])[CH2:19][CH2:18]3)=[CH:4][CH:5]=2)=[N:13]1
Reactant: O=C1CCNCC1
Reactant: Cn1nnc(-c2ccc(CBr)cc2)n1
Agent: Cl
Solvent: O
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: Cn1nnc(-c2ccc(CN3CCC(=O)CC3)cc2)n1
Temperature: 35 °C
Yield: 36.9 %

Procedure:
A solution of 23 grams (0.091 mole) of 5-[4-(bromomethyl)phenyl]-2-methyl-1,2,3,4-tetrazole, 14 grams (0.091 mole) of 4-piperidone monohydrate hydrochloride, and 47 mL (3 equivalents) of N,N-diisopropylethylamine in 200 mL of dimethylsulfoxide (DMSO) was stirred for about 3 days. The reaction was quenched by pouring the reaction mixture onto 400 mL of dilute, cold sodium hydroxide. The resultant solution was extracted one time with 300 mL of ethyl acetate. An emulsion formed, which was broken up by warming it to about 35° C. The organic layer was separated and concentrated under reduced pressure to a residue. The residue was purified with column chromatography on silica gel using 40:1 methylene chloride:methanol as an eluant. The appropriate fractions were combined and concentrated under reduced pressure, yielding 9.12 grams of the subject compound. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([C:14]([OH:16])=O)[CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[CH2:17]([O:19][C:20](=[O:30])[CH:21]=[CH:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([NH2:29])[CH:24]=1)[CH3:18]>>[CH2:17]([O:19][C:20](=[O:30])[CH:21]=[CH:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([NH:29][C:14]([C:12]2[CH:11]=[CH:10][CH:9]=[C:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)[N:13]=2)=[O:16])[CH:24]=1)[CH3:18]
Reactant: O=C(O)c1cccc(-c2cccc(Cl)c2)n1
Reactant: CCOC(=O)C=Cc1cccc(N)c1
Product: CCOC(=O)C=Cc1cccc(NC(=O)c2cccc(-c3cccc(Cl)c3)n2)c1

Procedure:
Carboxylic acid (136) (44 mg, 0.19 mmol) was coupled with aniline (60) (40 mg, 0.21 mmol) using Method D. The residue was purified by column chromatography eluting with a stepped gradient of 10-15% EtOAc in heptane to give the title compound.
Reaction SMILES: C(C(O)=[O:29])CC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F.ON1C(=O)CCC1=O.[CH:39]1([N:45]=[C:46]=[N:47][CH:48]2[CH2:53][CH2:52][CH2:51][CH2:50][CH2:49]2)[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]1>C(OCC)(=O)C>[C:46]([NH:45][CH:39]1[CH2:40][CH2:41][CH2:42][CH2:43][CH2:44]1)([NH:47][CH:48]1[CH2:53][CH2:52][CH2:51][CH2:50][CH2:49]1)=[O:29]
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: O=C(O)CCC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Agent: O=C1CCC(=O)N1O
Solvent: CCOC(C)=O
Product: O=C(NC1CCCCC1)NC1CCCCC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
2H,2H,3H,3H-Perfluoroundecanoic acid (1.354 g, 2.75 mmol), N-hydroxysuccinimide (348 mg, 3.02 mmol) and dicyclohexylcarbodiimide (622 mg, 3.02 mmol) were dissolved in ethyl acetate (120 ml) and stirred for 18 hours at ambient temperature. The white precipitate which formed (dicyclohexylurea, DCU) was filtered and the remaining solution was evaporated to dryness. The residue was recrystallised twice from ethyl acetate. Yield 1.00 g (62%) containing traces of DCU.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:23]=[CH:22][C:6]([CH2:7][C:8]2[O:9][C:10]3[CH:17]=[CH:16][C:15]([OH:18])=[C:14]([CH2:19][CH2:20][CH3:21])[C:11]=3[C:12]=2[CH3:13])=[CH:5][CH:4]=1.Cl[C:25]([O:27][CH2:28][CH3:29])=[O:26].C(N(CC)CC)C>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][C:8]2[O:9][C:10]3[CH:17]=[CH:16][C:15]([O:18][C:25]([O:27][CH2:28][CH3:29])=[O:26])=[C:14]([CH2:19][CH2:20][CH3:21])[C:11]=3[C:12]=2[CH3:13])=[CH:22][CH:23]=1
Reactant: CCOC(=O)Cl
Reactant: CCCc1c(O)ccc2oc(Cc3ccc(OC)cc3)c(C)c12
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCc1c(OC(=O)OCC)ccc2oc(Cc3ccc(OC)cc3)c(C)c12
Yield: 79 %

Procedure:
A solution of 2-(p-methoxybenzyl)-3-methyl-4-propyl-5-hydroxybenzofuran (1.2 gm, 3.87 mmoles), ethyl chloroformate (0.1 mL) and triethylamine (1.0 mL) in tetrahydrofuran (15 mL) was stirred at room temperature overnight. The volatiles were removed in vacuo. The residue was purified by chromatography on silica gel and eluted with 15% ethylacetate in hexane to yield 1.2 gm (79%) of 2-(p-methoxybenzyl)-3-methyl-4-propyl-5-ethoxycarbonyloxybenzofuran, mp. 51°-53° C.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:13]/[O:14][CH2:15][C:16](=[O:22])[N:17]([CH2:20][CH3:21])[CH2:18][CH3:19])/[C:8]([O:10]CC)=[O:9])[N:6]=1.O.[OH-].[Na+]>CO>[NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:13]/[O:14][CH2:15][C:16](=[O:22])[N:17]([CH2:20][CH3:21])[CH2:18][CH3:19])/[C:8]([OH:10])=[O:9])[N:6]=1
Reactant: CCOC(=O)/C(=N\OCC(=O)N(CC)CC)c1csc(N)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCN(CC)C(=O)CO/N=C(\C(=O)O)c1csc(N)n1
Yield: 402.7 %

Procedure:
68.1 g of ethyl 2-(2-amino-4-thiazolyl)-2-[(Z)-[(diethylcarbamoyl)methoxy]imino]-acetate are dissolved in 2.8 l of methanol and 240 ml of water and the solution is treated with 230 ml of 1N aqueous sodium hydroxide solution. The methanol is removed under reduced pressure after 48 hours and the aqueous solution is washed with ethyl acetate. After the addition of 230 ml of 1N aqueous hydrochloric acid, the crystallized acid is filtered off and dried. There are obtained 250.8 g of 2-(2-amino-4-thiazolyl)-2-[(Z)-[(diethylcarbamoyl)methoxy]imino]-acetic acid of melting point 180° C.
Reaction SMILES: [CH2:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH2:4][CH2:3][N:2]1[C:14]1[N:19]=[CH:18][C:17]([C:20]([O:22]C)=[O:21])=[CH:16][N:15]=1.[OH-].[Li+].Cl>C1COCC1.O>[CH2:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH2:4][CH2:3][N:2]1[C:14]1[N:19]=[CH:18][C:17]([C:20]([OH:22])=[O:21])=[CH:16][N:15]=1
Reactant: COC(=O)c1cnc(N2CCc3c([nH]c4ccccc34)C2)nc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cnc(N2CCc3c([nH]c4ccccc34)C2)nc1
Reaction time: 4.5 h
Yield: 83.8 %

Procedure:
To a stirred solution of Example 8 (500 mg, mmol) in THF and water (10 mL, 1:1) was added lithium hydroxide (205 mg, mmol) at room temperature and the mixture was stirred for 4-5 hours. After completion, the reaction mixture was acidified using 1N hydrochloric acid. The mixture was extracted with EtOAc, washed with brine, the organics dried over sodium sulfate and concentrated to give 2-(1,3,4,9-tetrahydro-2H-b-carbolin-2-yl)pyrimidine-5-carboxylic acid (400 mg, 83% yield).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:11](=[O:12])[NH:10][C:9]3[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=3[NH:7][C:6]=2[CH:17]=1.[CH3:18][O:19][C:20]1[CH:25]=[C:24](B2OC(C)(C)C(C)(C)O2)[CH:23]=[CH:22][C:21]=1[OH:35].[F-].[Cs+]>COCCOC.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>[OH:35][C:21]1[CH:22]=[CH:23][C:24]([C:2]2[CH:3]=[CH:4][C:5]3[C:11](=[O:12])[NH:10][C:9]4[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=4[NH:7][C:6]=3[CH:17]=2)=[CH:25][C:20]=1[O:19][CH3:18]
Reactant: O=C1Nc2ccccc2Nc2cc(Br)ccc21
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccc1O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: CO
Solvent: COCCOC
Product: COc1cc(-c2ccc3c(c2)Nc2ccccc2NC3=O)ccc1O
Temperature: 25 °C
Yield: 81.2 %

Procedure:
A mixture of Example 9 (116 mg, 0.4 mmol), 2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (150 mg, 0.6 mmol), Pd(PPh3)4 (23 mg, 0.02 mmol), and CsF (121 mg, 0.8 mmol) in DME (20 mL) and methanol (10 mL) was heated to reflux for 16 hours, cooled to room temperature, and partitioned between ethyl acetate and water. The organic layer was washed with brine, dried (MgSO4), filtered, and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel with 1:1 hexanes/ethyl acetate to provide 0.108 g (81%) of the desired product. MS (DCI) m/e 333 (M+H)+, 350 (M+NH4)+; 1H NMR (500 MHz, DMSO-d6) δ 9.90 (s, 1H), 8.02 (s, 1H), 7.62 (d, J=8.4 Hz, 1H), 7.24 (d, J=1.8 Hz, 1H), 7.15-7.18 (m, 2H), 7.08 (dd, J=8.1, 1.5 Hz, 1H), 6.97-7.02 (m, 5H), 3.86 (s, 3H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([O:7][C:8]2[S:9][C:10]3[CH:16]=[C:15]([C:17]4[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH:18]=4)[CH:14]=[CH:13][C:11]=3[N:12]=2)[CH2:3][CH2:2]1.Br[C:31]1[CH:36]=[N:35][C:34]([CH3:37])=[CH:33][N:32]=1.C(O[Na])(C)(C)C>C1(C)C=CC=CC=1.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>[CH3:37][C:34]1[N:35]=[CH:36][C:31]([N:1]2[CH2:6][CH2:5][CH:4]([O:7][C:8]3[S:9][C:10]4[CH:16]=[C:15]([C:17]5[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH:18]=5)[CH:14]=[CH:13][C:11]=4[N:12]=3)[CH2:3][CH2:2]2)=[N:32][CH:33]=1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2ccc3nc(OC4CCNCC4)sc3c2)CC1
Reactant: Cc1cnc(Br)cn1
Agent: [Pd]
Agent: CC(C)(C)O[Na]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1cnc(N2CCC(Oc3nc4ccc(C5=CCN(C(=O)OC(C)(C)C)CC5)cc4s3)CC2)cn1
Temperature: 80 °C
Reaction time: 8 h
Yield: 59.6 %

Procedure:
To a degassed solution of tert-butyl 4-(2-(piperidin-4-yloxy)benzo[d]thiazol-6-yl)-5,6-dihydropyridine-1(2H)-carboxylate (119.4 mg, 0.287 mmol), 2-bromo-5-methylpyrazine (99 mg, 0.575 mmol), t-BuONa (83 mg, 0.862 mmol), and BINAP (3.58 mg, 5.75 μmol) in toluene (2.5 mL) was added Pd2(dba)3 (15.79 mg, 0.017 mmol). The reaction mixture was stirred in a seal vial at 80° C. overnight, then at 90° C. for additional 2.5 h. The mixture was cooled to rt, diluted with water (10 mL), and extracted with EtOAc (3×5 mL). The combined organic layers were washed with brine (8 mL), dried (Na2SO4), and concentrated. The residue was purified by column chromatography (silica gel, hexanes-EtOAc gradient 0 to 70% EtOAc) to afford Compound 50B (86.6 mg, 0.171 mmol, 59% yield) as a light orange solid. 1H NMR (500 MHz, CDCl3) δ 8.11 (s, 1H), 7.97 (s, 1H), 7.62 (dd, J=9.9, 5.0 Hz, 2H), 7.40 (dd, J=8.5, 1.6 Hz, 1H), 6.04 (s, 1H), 5.44 (dt, J=7.6, 3.8 Hz, 1H), 4.09 (s, 2H), 3.97-3.84 (m, 2H), 3.65 (d, J=5.2 Hz, 2H), 3.57-3.43 (m, 2H), 2.55 (s, 2H), 2.41 (s, 3H), 2.28-2.13 (m, 2H), 2.08-1.94 (m, 2H), 1.50 (s, 9H). LCMS (m/z)=508 (M+H)+.
Reaction SMILES: [N+]([O-])([O-])=O.[Na+].[BrH:6].N[C:8]1[C:9]([CH3:16])=[C:10]([CH:13]=[CH:14][CH:15]=1)[CH2:11][OH:12]>O.[Cu]Br>[Br:6][C:8]1[C:9]([CH3:16])=[C:10]([CH:13]=[CH:14][CH:15]=1)[CH2:11][OH:12]
Reactant: Br
Reactant: Cc1c(N)cccc1CO
Agent: [Cu]Br
Agent: O=[N+]([O-])[O-]
Agent: [Na+]
Solvent: O
Product: Cc1c(Br)cccc1CO
Reaction time: 0.5 h

Procedure:
A solution of 40.7 g of sodium nitrate in 300 ml of water is added dropwise to a mixture, cooled to 0° C., of 888 ml of water, 162 ml of 47% hydrobromic acid and 81.2 g of 3-amino-2-methylbenzyl alcohol. Stirring is carried out for 30 minutes at 0° C., after which a suspension of 168.7 9 of copper(I) bromide in 750 ml of water is added a little at a time at this temperature. The reaction mixture is stirred in succession for 1 hour at 10° C., for 1 hour at room temperature and for 2 hours at 100° C. After cooling, the reaction mixture is extracted several times with ether. The combined organic phases are washed with water, dried and evaporated down. Purification by column chromatogrpahy over silica gel using toluene as the mobile phase gives 64.2 g of 3-bromo-2-methylbenzyl alcohol (mp. 97°-100° C.).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][N:3]=1.[Cl:9][CH2:10][C:11](Cl)=[O:12]>>[Cl:9][CH2:10][C:11]([NH:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][N:3]=1)=[O:12]
Reactant: O=C(Cl)CCl
Reactant: Cc1ccnc(N)c1
Product: Cc1ccnc(NC(=O)CCl)c1
Yield: 74 %

Procedure:
The sub-titled compound (1.3 g, 74%, solid) was prepared by a similar procedure to that used to prepare Example 14f using 2-amino-4-methylpyridine in place of 2-amino-pyridine and adding the chloroacetyl chloride at room temperature rather than at 0° C.
Reaction SMILES: [C:1]([C:5]1[O:6][C:7]2[C:13]([S:14](Cl)(=[O:16])=[O:15])=[C:12]([Cl:18])[CH:11]=[CH:10][C:8]=2[N:9]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:26]([O:30][C:31](=[O:38])[NH:32][C@@H:33]1[CH2:37][CH2:36][NH:35][CH2:34]1)([CH3:29])([CH3:28])[CH3:27]>C1COCC1>[C:26]([O:30][C:31](=[O:38])[NH:32][C@@H:33]1[CH2:37][CH2:36][N:35]([S:14]([C:13]2[C:7]3[O:6][C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[N:9][C:8]=3[CH:10]=[CH:11][C:12]=2[Cl:18])(=[O:16])=[O:15])[CH2:34]1)([CH3:29])([CH3:27])[CH3:28]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCNC1
Reactant: CC(C)(C)c1nc2ccc(Cl)c(S(=O)(=O)Cl)c2o1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@@H]1CCN(S(=O)(=O)c2c(Cl)ccc3nc(C(C)(C)C)oc23)C1
Yield: 67.3 %

Procedure:
Following the general procedure for the synthesis of sulfonylamides outlined in example 51, 2-tert-butyl-6-chloro-benzooxazole-7-sulfonyl chloride (3.0 g, 9.74 mmol), triethylamine (1.63 mL, 11.7 mmol), and (R)-pyrrolidin-3-yl-carbamic acid tert-butyl ester (2.18 g, 11.7 mmol) were reacted in THF (30 mL) to afford the title compound (3.0 g, 67%). 1H NMR (CDCl3) • 7.77 (d, 1H, J=8.5 Hz), 7.48 (d, 1H, J=8.5 Hz), 4.67 (bm, 1H), 4.22 (bm, 1H), 3.66 (bm, 2H), 3.52 (bm, 1H), 3.41 (bm, 1H), 2.19 (bm, 1H), 1.90 (bm, 1H), 1.48 (s, 9H).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1.[N+:9]([C:12]1[CH:13]=[C:14](B(O)O)[CH:15]=[CH:16][CH:17]=1)([O-:11])=[O:10].C(COC)OC.C([O-])(O)=O.[Na+]>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.O>[Cl:8][C:6]1[CH:7]=[C:2]([C:16]2[CH:15]=[CH:14][CH:13]=[C:12]([N+:9]([O-:11])=[O:10])[CH:17]=2)[N:3]=[CH:4][N:5]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: O=[N+]([O-])c1cccc(B(O)O)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: O=[N+]([O-])c1cccc(-c2cc(Cl)ncn2)c1
Yield: 86.1 %

Procedure:
4,6-Dichloropyrimidine (5.58 g, 37.4 mmol) and 3-nitrophenylboronic acid (5.00 g, 27.2 mmol) were added to a stirred mixture of dimethoxyethane (112 mL) and water (17 mL), followed by the addition of NaHCO3 (6.28 g, 75 mmol) and (PPh3)2PdCl2 (0.787 g, 1.12 mmol) herein, and the reaction mixture was refluxed for 8 h. The solvent was removed under reduced pressure. The residue was taken up in CH2Cl2 (100 mL), and the resulting solution washed with water, dried over anhydrous K2CO3, filtered and the solvent removed under reduced pressure. The crude product was purified by column chropatography on silica (eluent CH2Cl2) to yield 4-chloro-6-(3-nitro-phenyl)-pyrimidine (5.52 g; 86%) as yellowish solid.
Reaction SMILES: [O-]CC.[Na+].[CH3:5][C:6]([CH:8]1[CH2:10][CH2:9]1)=[O:7].[CH:11]1([C:14](OC)=[O:15])[CH2:13][CH2:12]1>CS(C)=O>[CH:11]1([C:14](=[O:15])[CH2:5][C:6]([CH:8]2[CH2:10][CH2:9]2)=[O:7])[CH2:13][CH2:12]1
Reactant: COC(=O)C1CC1
Reactant: CC(=O)C1CC1
Agent: CC[O-]
Agent: [Na+]
Solvent: CS(C)=O
Product: O=C(CC(=O)C1CC1)C1CC1
Temperature: 60 °C

Procedure:
Sodium ethoxide (8 g, 117.64 mmol) was added to a solution of cyclopropyl methyl ketone (5 g, 59.4 mmol) and methyl cyclopropane carboxylate (12 ml, 118.9 mmol) in DMSO (30 mL). The resulting mixture was heated at 60° C. overnight and then cooled to 0° C. After quenching the reaction with 6N HCl, work-up (H2O/AcOEt) gave the title compound as a brown liquid which was used without any purification. 1H-NMR (δ ppm, CDCl3, 400 MHz): 16.05 (bs, 0.6H), 5.72 (s, 0.6H) 3.78 (s, 0.8H), 2.08-2.0 (m, 0.8H), 1.62-1.53 (m, 1.2H), 1.12-1.05 (m, 4H), 0.97-0.83 (m, 4H). MS (m/z): 153.2 [M+H]+.
Reaction SMILES: [CH:1](O)=O.[NH:4]([C:6]1[S:7][C:8]2[CH:14]=[CH:13][C:12]([CH3:15])=[C:11]([CH3:16])[C:9]=2[N:10]=1)[NH2:5]>O>[CH3:16][C:11]1[C:9]2[N:10]3[CH:1]=[N:5][N:4]=[C:6]3[S:7][C:8]=2[CH:14]=[CH:13][C:12]=1[CH3:15]
Reactant: O=CO
Reactant: Cc1ccc2sc(NN)nc2c1C
Solvent: O
Product: Cc1ccc2sc3nncn3c2c1C
Temperature: 25 °C

Procedure:
A solution of 12 milliliters of formic acid (97-100 percent) and 3.5 grams of 2-hydrazino-4,5-dimethylbenzothiazole was refluxed for 24 hours with stirring. The reaction mixture was then cooled to room temperature and poured into water. The 5,6-dimethyl-s-triazole(3,4-b)benzothiazole compound precipitated and was separated by filtration, 2.6 grams, m.p. 226-8° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)=[N:9][CH:10]=[C:4]2[CH:3]=1.C([Li])CCC.[CH3:23][C:24]1([CH3:45])[O:28][CH:27]([CH2:29][N:30]2[C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[C:32]([C:39](=[O:44])[C:40]([F:43])([F:42])[F:41])=[CH:31]2)[CH2:26][O:25]1>C1COCC1>[CH3:23][C:24]1([CH3:45])[O:28][CH:27]([CH2:29][N:30]2[C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[C:32]([C:39]([C:2]3[CH:7]=[CH:6][N:5]4[C:8]([C:11]5[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=5)=[N:9][CH:10]=[C:4]4[CH:3]=3)([OH:44])[C:40]([F:43])([F:42])[F:41])=[CH:31]2)[CH2:26][O:25]1
Reactant: CC1(C)OCC(Cn2cc(C(=O)C(F)(F)F)c3ccccc32)O1
Reactant: Fc1ccc(-c2ncc3cc(Br)ccn23)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC1(C)OCC(Cn2cc(C(O)(c3ccn4c(-c5ccc(F)cc5)ncc4c3)C(F)(F)F)c3ccccc32)O1
Reaction time: 0.03 h
Yield: 33.7 %

Procedure:
To a chilled (−78° C.) solution of 7-bromo-3-(4-fluorophenyl)imidazo[1,5-a]pyridine (160 mg, 0.55 mmol) in anhydrous THF (3 mL) was added n-butyllithium (275 μL of a 2.5 M solution in hexanes, 0.69 mmol). After 2 minutes, a chilled (−78° C.) solution of 1-[1-(2,2-dimethyl-1,3-dioxolan-4-ylmethyl)-1H-indol-3-yl]-2,2,2-trifluoroethanone (240 mg, 0.73 mmol) in 1 mL of THF was added. After 60 minutes, the mixture was quenched with brine (50 mL) and extracted with ethyl acetate. The combined organic layers were washed with water, dried over anhydrous sodium sulfate, and concentrated in vacuo to afford a yellow oil. The residue was purified by column chromatography over silica gel eluting with 0-75% ethyl acetate in hexanes and fractions corresponding to a MS m/z 540 (MH+) peak were pooled and concentrated in vacuo to afford 100 mg of the title compound as a light yellow solid.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][CH:13]([C:15]([O:17][CH3:18])=[O:16])[CH2:12][CH2:11][NH:10]2)=[CH:5][C:4]=1[F:19].CCN(C(C)C)C(C)C.[C:29](Cl)(=[O:32])[O:30][CH3:31]>C(Cl)Cl>[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][CH:13]([C:15]([O:17][CH3:18])=[O:16])[CH2:12][CH2:11][N:10]2[C:29]([O:30][CH3:31])=[O:32])=[CH:5][C:4]=1[F:19]
Reactant: COC(=O)Cl
Reactant: COC(=O)C1CCNC(c2ccc(Cl)c(F)c2)C1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)C1CCN(C(=O)OC)C(c2ccc(Cl)c(F)c2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.6 %

Procedure:
Methyl 2-(4-chloro-3-fluorophenyl)piperidine-4-carboxylate hydrochloride (1.639 g, 5.32 mmol) and DIPEA (2.316 mL, 13.30 mmol) were dissolved in DCM (10 mL). Methyl carbonochloridate (0.503 mL, 6.38 mmol) was added dropwise and the reaction stirred at room temperature for 2 h. The reaction mixture was diluted with DCM (100 mL) and washed with 0.1 M HCl (2×75 mL), sat. NaHCO3 (100 mL), dried through a phase separator and evaporated in vacuo yielding dimethyl 2-(4-chloro-3-fluorophenyl)piperidine-1,4-dicarboxylate (1.625 g, 93%) as a colorless oil. MS m/z 330 (M+H)+