Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[CH:12][C:13]1[CH:14]=[C:15]([CH:29]=[CH:30][CH:31]=1)[C:16]([NH:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]([OH:28])=O)=[O:17].Cl.C(N=C=NCCCN(C)C)C.O[C:45]1[C:53]2[N:52]=N[NH:50][C:49]=2[CH:48]=[CH:47][CH:46]=1.C(N(CC)CC)C.C1(N)C=CC=CC=1N>[Cl-].[Na+].O.CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[CH:12][C:13]1[CH:14]=[C:15]([CH:29]=[CH:30][CH:31]=1)[C:16]([NH:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]([NH:50][C:49]1[CH:48]=[CH:47][CH:46]=[CH:45][C:53]=1[NH2:52])=[O:28])=[O:17]
Reactant: Oc1cccc2[nH]nnc12
Reactant: O=C(O)CCCCCCCNC(=O)c1cccc(C=C2C(=O)Nc3ccc(F)cc32)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Nc1ccccc1N
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: Nc1ccccc1NC(=O)CCCCCCCNC(=O)c1cccc(C=C2C(=O)Nc3ccc(F)cc32)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 82.8 %

Procedure:
8-(3-((5-fluoro-2-oxoindolin-3-ylidene)methyl)benzamido)octanoic acid (424 mg, 1 mmol), and 8 ml of DMF were stirred at room temperature while 1-Ethyl-3-(3-dimethylamino-propyl)carbodiimide hydrochloride (394 mg, 2 mmol), hydroxybenzotriazole (162 mg, 1.2 mmol), triethylamine (404 mg, 4 mmol) and o-phenylenediamine (432 mg, 4 mmol) were added. The mixture was stirred for 24 hours at room temperature. The mixture was diluted with 400 mL of brine. The solids were collected by vacuum filtration, washed with water and dried under vacuum to give the title compound (426 mg, 83% yield) as a brown solid. LC-MS (m/z) 515 (M+1).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11].[C:15](Cl)(=[O:26])[O:16][C:17]1[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=1.CCN(C(C)C)C(C)C.O>CCOC(C)=O>[N+:23]([C:20]1[CH:21]=[CH:22][C:17]([O:16][C:15]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8](=[O:14])[O:9][C:10]([CH3:11])([CH3:13])[CH3:12])=[O:26])=[CH:18][CH:19]=1)([O-:25])=[O:24]
Reactant: CC(C)(C)OC(=O)NCCCCCN
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CC(C)(C)OC(=O)NCCCCCNC(=O)Oc1ccc([N+](=O)[O-])cc1

Procedure:
tert-Butyl 5-aminopentylcarbamate (2.02 g, 10 mmol) was dissolved in EtOAc, 4-nitrophenyl carbonochloridate (2.22 g, 11 mmol) was added, the mixture cooled on an icebath, DIEA (2.05 mL, 12 mmol) was added with stirring and the mixture gradually allowed to reach rt and stirred for 3 h. The mixture was transferred to a separatory funnel with EtOAc and H2O, and shaken. The organic phase was extracted with 1N HCl, H2O, 5% NA2CO3, H2O (three times), brine, dried over Mg2SO4, filtered and concentrated to yield compound 9.
Reaction SMILES: S(=O)(=O)(O)O.[N+:6]([O-:9])(O)=[O:7].[CH:10]1[C:15]([C:16]2[C:25](=[O:26])[C:24]3[CH:23]=[CH:22][C:21]([OH:27])=[CH:20][C:19]=3[O:18][CH:17]=2)=[CH:14][CH:13]=[C:12]([OH:28])[CH:11]=1.O>C(O)C>[OH:27][C:21]1[CH:20]=[C:19]2[C:24]([C:25](=[O:26])[C:16]([C:15]3[CH:10]=[CH:11][C:12]([OH:28])=[C:13]([N+:6]([O-:9])=[O:7])[CH:14]=3)=[CH:17][O:18]2)=[CH:23][CH:22]=1
Reactant: O=[N+]([O-])O
Reactant: O=c1c(-c2ccc(O)cc2)coc2cc(O)ccc12
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CCO
Product: O=c1c(-c2ccc(O)c([N+](=O)[O-])c2)coc2cc(O)ccc12

Procedure:
20 ml of a mixture of concentrated sulfuric acid and nitric acid (3:1) are added dropwise to a solution of 1 g of daidzein in 200 ml of dry ethanol at room temperature while stirring vigorously. The mixture is stirred for another 2 hours, and 400 ml of water are then added. The compound precipitates, is filtered off with suction and washed with water until neutral. The yellow product is recrystallized from alcohol.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]3[C:11](=[O:17])[NH:12][CH2:13][CH2:14][C:15]=3[N:16]=2)=[CH:4][CH:3]=1.Br[C:19]1[CH:24]=[CH:23][C:22]([O:25][S:26]([C:29]2[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=2)(=[O:28])=[O:27])=[C:21]([O:36][CH3:37])[CH:20]=1.C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.CCOC(C)=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]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]3[C:11](=[O:17])[N:12]([C:19]4[CH:24]=[CH:23][C:22]([O:25][S:26]([C:29]5[CH:30]=[CH:31][C:32]([CH3:35])=[CH:33][CH:34]=5)(=[O:28])=[O:27])=[C:21]([O:36][CH3:37])[CH:20]=4)[CH2:13][CH2:14][C:15]=3[N:16]=2)=[CH:4][CH:3]=1
Reactant: COc1cc(Br)ccc1OS(=O)(=O)c1ccc(C)cc1
Reactant: O=C1NCCc2nc(-c3ccc(Cl)cc3)sc21
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: COc1cc(N2CCc3nc(-c4ccc(Cl)cc4)sc3C2=O)ccc1OS(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Yield: 59.7 %

Procedure:
Mix 2-(4-chloro-phenyl)-6,7-dihydro-5H-thiazolo[5,4-c]pyridin-4-one (128 mg, 0.48 mmol), toluene-4-sulfonic acid 4-bromo-2-methoxy-phenyl ester (218 mg, 0.61 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (17.2 mg, 0.030 mmol), Cs2CO3 (0.123 mg, 0.377 mmol) in dioxane (13 mL). Purge the solution with nitrogen for 30 min and then add tris(dibenzylideneacetone)dipalladium(0) (Pd2(dba)3) (6.7 mg, 0.0073 mmol). Stir the mixture at reflux overnight, then cool to room temperature. Dilute the mixture with EtOAc (50 mL) and wash with water (2×30 mL) and brine (30 mL). Dry, filter and concentrate the organic solution and purify the residue by flash chromatography, using a linear gradient of 100% hexanes to 80% EtoAc/hexanes as eluent, to give the title compound as a light brown solid (155 mg, 60%). MS (ES+) 541.0 (M+1)+. 1H NMR (CDCl3): δ 7.92 (d, 2H, J=8.4 Hz), 7.78 (d, 2H, J=8.4 Hz), 7.44 (d, 2H, J=8.8 Hz), 7.31 (d, 2H, J=8.4 Hz), 7.17 (d, 1H, J=8.8 Hz), 6.96 (d, 1H, J=2.6 Hz), 6.82 (dd, 1H, J=8.6, 2.4 Hz), 4.11 (t, 2H, J=6.8 Hz), 3.57 (s, 3H), 3.28 (t, 2H, J=6.8 Hz), 2.44 (s, 3H).
Reaction SMILES: [CH3:1][N:2]1[C:6]([NH:7][C:8]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[C:5]([NH:27][C:28](=O)[O:29]C2C=CC=CC=2)[CH:4]=[N:3]1.[NH2:37][CH:38]1[CH2:42][CH2:41][N:40]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[CH2:39]1.C(N(C(C)C)C(C)C)C>C(Cl)Cl>[CH3:1][N:2]1[C:6]([NH:7][C:8]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)=[C:5]([NH:27][C:28]([NH:37][CH:38]2[CH2:42][CH2:41][N:40]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[CH2:39]2)=[O:29])[CH:4]=[N:3]1
Reactant: CC(C)(C)OC(=O)N1CCC(N)C1
Reactant: Cn1ncc(NC(=O)Oc2ccccc2)c1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cn1ncc(NC(=O)NC2CCN(C(=O)OC(C)(C)C)C2)c1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Yield: 60.2 %

Procedure:
To a suspension of phenyl [1-methyl-5-(tritylamino)-1H-pyrazol-4-yl]carbamate (711 mg) and tert-butyl 3-amino-1-pyrrolidinecarboxylate (372 mg) in methylenechloride (15 ml) was added N-ethyldiisopropylamine (0.51 ml), and the mixture was stirred under reflux for 17 hours. The reaction mixture was washed successively with 10% aqueous citric acid solution, brine and saturated aqueous sodium hydrogen carbonate solution. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with 10% methanol/methylenechloride to give tert-butyl 3-[({[1-methyl-5-(tritylamino)-1H-pyrazol-4-yl]amino}carbonyl)amino]-1-pyrrolidinecarboxylate (511 mg) as a solid.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][CH2:10][N:11]([CH:21]([C:25]1[N:30]([CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:29](=[O:38])[C:28]2=[C:39]([Cl:42])[CH:40]=[CH:41][N:27]2[N:26]=1)[CH:22]1[CH2:24][CH2:23]1)[C:12](=[O:20])[C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=1)(C)(C)C.Cl.O1CCOCC1>>[ClH:19].[NH2:7][CH2:8][CH2:9][CH2:10][N:11]([CH:21]([C:25]1[N:30]([CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:29](=[O:38])[C:28]2=[C:39]([Cl:42])[CH:40]=[CH:41][N:27]2[N:26]=1)[CH:22]1[CH2:23][CH2:24]1)[C:12](=[O:20])[C:13]1[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=1
Reactant: CC(C)(C)OC(=O)NCCCN(C(=O)c1ccc(Cl)cc1)C(c1nn2ccc(Cl)c2c(=O)n1Cc1ccccc1)C1CC1
Agent: Cl
Solvent: C1COCCO1
Product: NCCCN(C(=O)c1ccc(Cl)cc1)C(c1nn2ccc(Cl)c2c(=O)n1Cc1ccccc1)C1CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 167 %

Procedure:
{3-[[(3-Benzyl-5-chloro-4-oxo-3,4-dihydro-pyrrolo[2,1-f][1,2,4]triazin-2-yl) cyclopropyl-methyl]-(4-chloro-benzoyl)-amino]-propyl}-carbamic acid tert-butyl ester (8 mg) was treated with 4 N HCl/dioxane (1 mL) and the resulting mixture stirred at room temperature for 18 h. The mixture was concentrated under high vacuum to give the title compound (6 mg) as a white solid: 1H NMR (DMSO-d6) δ −0.35 (m, 1H), 0.40 (m, 1H), 0.50 (m, 1H), 0.57 (m, 1H), 1.53 (m, 1H), 1.80 (m, 1H), 1.89 (m, 1H), 2.56 (m, 2H), 3.56 (m, 2H), 4.85 (m, 1H), 5.16 (m, 1H), 5.80 (m, 1H), 6.66 (m, 1H), 7.23 (bs, 3H), 7.25 (m, 2H), 7.30–7.40 (m, 4H), 7.46–7.49 (m, 3H), 7.56 (m, 1H), 7.99 (m, 1H); HRMS (ESI+) 524.1629 (M+H)+ for C27H28N5O2Cl2.
Reaction SMILES: [F:1][C:2]([F:48])([F:47])[O:3][C:4]1[CH:46]=[CH:45][C:7]([CH2:8][NH:9][C:10]([C@H:12]2[CH2:17][N:16]([C:18]3[S:19][C:20]4[C:25](Cl)=[N:24][C:23]([CH:27]5[CH2:29][CH2:28]5)=[N:22][C:21]=4[N:30]=3)[CH2:15][CH2:14][N:13]2[S:31]([C:34]2[CH:39]=[CH:38][C:37]([O:40][C:41]([F:44])([F:43])[F:42])=[CH:36][CH:35]=2)(=[O:33])=[O:32])=[O:11])=[CH:6][CH:5]=1.C([O-])=O.[NH4+].C(O)C>C(Cl)(Cl)Cl.[C].[Pd]>[F:48][C:2]([F:1])([F:47])[O:3][C:4]1[CH:46]=[CH:45][C:7]([CH2:8][NH:9][C:10]([C@H:12]2[CH2:17][N:16]([C:18]3[S:19][C:20]4[CH:25]=[N:24][C:23]([CH:27]5[CH2:29][CH2:28]5)=[N:22][C:21]=4[N:30]=3)[CH2:15][CH2:14][N:13]2[S:31]([C:34]2[CH:39]=[CH:38][C:37]([O:40][C:41]([F:42])([F:43])[F:44])=[CH:36][CH:35]=2)(=[O:32])=[O:33])=[O:11])=[CH:6][CH:5]=1
Reactant: O=C(NCc1ccc(OC(F)(F)F)cc1)[C@H]1CN(c2nc3nc(C4CC4)nc(Cl)c3s2)CCN1S(=O)(=O)c1ccc(OC(F)(F)F)cc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: O=C(NCc1ccc(OC(F)(F)F)cc1)[C@H]1CN(c2nc3nc(C4CC4)ncc3s2)CCN1S(=O)(=O)c1ccc(OC(F)(F)F)cc1
Reaction time: 0.5 h
Yield: 73.4 %

Procedure:
To a mixed solution of the compound (1.3 g) obtained in Step 6, ammonium formate (1.2 g) and ethanol (13 ml) was added 10% palladium carbon (1.3 g) at 80° C. After stirring at the same temperature for 30 min, ammonium formate (1.3 g) and 10% palladium carbon (0.50 g) were added. After stirring at 80° C. for 30 min, ammonium formate (1.2 g) and 10% palladium carbon (0.65 g) were further added. After stirring at the same temperature for 1.5 hr, the reaction mixture was allowed to return to room temperature and diluted with chloroform. The mixture was filtered through celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:chloroform=1:2) to give the title compound (0.91 g).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[CH3:12])[C:5]([NH:7][NH2:8])=[O:6].[CH3:13]OC(C1C=C(C2C=CC(NC(=O)C3C(F)=CC=CC=3F)=CC=2)C(C)=CC=1)=O>>[I:1][C:2]1[CH:3]=[C:4]([C:5]2[O:6][CH:13]=[N:8][N:7]=2)[CH:9]=[CH:10][C:11]=1[CH3:12]
Reactant: COC(=O)c1ccc(C)c(-c2ccc(NC(=O)c3c(F)cccc3F)cc2)c1
Reactant: Cc1ccc(C(=O)NN)cc1I
Product: Cc1ccc(-c2nnco2)cc1I

Procedure:
3-Iodo-4-methyl benzoic acid methyl ester was treated with hydrazine to form 3-Iodo-4-methyl benzoic acid hydrazide. 2-(3-Iodo-4-methyl-phenyl)-[1,3,4]oxadiazole was prepared from 3-iodo-4-methyl benzoic acid hydrazide according to a method analogous to that described in J. of Medicinal Chemistry (2001), 44(8): 1268-85, the entire teachings of which are incorporated herein by reference. Compounds 46, 68, 69, 70, and 71 were prepared via an amide coupling reaction analogous to that described in step A of the synthesis of Compound 1, followed by a Suzuki coupling reaction analogous to that described in step B of the synthesis of Compound 1. The amide coupling reaction and Suzuki coupling reaction are shown for Compound 69 in Scheme XX below:
Reaction SMILES: Cl.[C:2]([C:5]1[S:13][C:12]2[CH:11]=[N:10][C:9]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([CH:21]4[CH2:26][CH2:25][N:24](C(OC(C)(C)C)=O)[CH2:23][CH2:22]4)=[CH:17][C:16]=3[O:34][CH:35]([CH3:37])[CH3:36])=[N:8][C:7]=2[C:6]=1[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=1[O:44][CH3:45])(=[O:4])[NH2:3]>C(OCC)(=O)C>[CH3:45][O:44][C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][C:38]=1[C:6]1[C:7]2[N:8]=[C:9]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([CH:21]4[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]4)=[CH:17][C:16]=3[O:34][CH:35]([CH3:37])[CH3:36])[N:10]=[CH:11][C:12]=2[S:13][C:5]=1[C:2]([NH2:3])=[O:4]
Reactant: COc1ccccc1-c1c(C(N)=O)sc2cnc(Nc3ccc(C4CCN(C(=O)OC(C)(C)C)CC4)cc3OC(C)C)nc12
Agent: Cl
Solvent: CCOC(C)=O
Product: COc1ccccc1-c1c(C(N)=O)sc2cnc(Nc3ccc(C4CCNCC4)cc3OC(C)C)nc12
Temperature: 25 °C
Reaction time: 18 h
Yield: 71.5 %

Procedure:
A 1M solution of hydrochloric acid in ethyl acetate (90 ml) is added slowly to a mixture of 536 mg of 2-methylpropan-2-yl 4-[4-{[6-carbamoyl-7-(2-methoxyphenyl)thieno[3,2-d]pyrimidin-2-yl]amino}-3-(propan-2-yloxy)phenyl]piperidine-1-carboxylate in 5 ml of cold ethyl acetate in an ice bath. After the addition, the mixture is stirred at ambient temperature for 18 h, and then the precipitate is filtered off and rinsed with ether. The solid is suspended in 60 ml of water and 40 ml of a 1M sodium hydroxide solution are added and the mixture is left to stir for 5 min. The mixture is extracted three times with 100 ml of ethyl acetate. The organic phases are washed with 50 ml of water and then with 50 ml of a saturated sodium chloride solution. The organic phases are dried over magnesium sulfate, filtered and concentrated under vacuum. The residue is taken up with ether and the solid is filtered off and dried under vacuum, so as to obtain 321 mg of 7-(2-methoxyphenyl)-2-{[4-(piperidin-4-yl)-2-(propan-2-yloxy)phenyl]amino}thieno[3,2-d]pyrimidine-6-carboxamide in the form of a yellow solid.
Reaction SMILES: [Na].[NH2:2][C:3]([NH2:5])=[S:4].N[C:7]([C:11]1[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][CH:12]=1)=[CH:8][C:9]#[N:10].Cl>S([O-])([O-])(=O)=O.[Cu+2].O.C(O)C>[NH2:10][C:9]1[NH:5][C:3](=[S:4])[N:2]=[C:7]([C:11]2[CH:12]=[CH:13][C:14]([Br:17])=[CH:15][CH:16]=2)[CH:8]=1
Reactant: N#CC=C(N)c1ccc(Br)cc1
Reactant: NC(N)=S
Agent: [Cu+2]
Agent: Cl
Agent: O=S(=O)([O-])[O-]
Solvent: CCO
Solvent: O
Product: Nc1cc(-c2ccc(Br)cc2)nc(=S)[nH]1
Reaction time: 0.08 h
Yield: 110.8 %

Procedure:
To a flask charged with 600 mL of absolute ethanol was dissolved sodium (14.86 g, 646.5 mmol) with a catalytic amount of copper(II)sulfate (10 mg). The reaction volume was reduced by half under reduced pressure and thiourea (49.22 g, 646.5 mmol) and 3-amino-3-(4-bromophenyl)acrylonitrile (38.46 g, 172.4 mmol) were added at ambient temperature and the reaction mixture was fitted with a condenser and heated to reflux over the weekend. Water (400 mL) was added and the mixture was made acidic with concentrated aqueous hydrochloric acid to a pH=7. The reaction mixture was allowed to stir for 5 minutes and the resulting solids were collected by means of vacuum filtration and afforded 6-amino-4-(4-bromophenyl)pyrimidine-2(1H)-thione (53.90 g, 191.0 mmol, 110.8% yield). MS (apci) m/z=282.0 (M+H).
Reaction SMILES: [CH:1]1([C:4]2[N:9]3[N:10]=[CH:11][C:12]([C:13]([OH:15])=O)=[C:8]3[N:7]=[C:6]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)[CH:5]=2)[CH2:3][CH2:2]1.[CH3:26][S:27]([C:30]1[CH:31]=[C:32]([NH2:36])[CH:33]=[CH:34][CH:35]=1)(=[O:29])=[O:28]>>[CH3:26][S:27]([C:30]1[CH:31]=[C:32]([NH:36][C:13]([C:12]2[CH:11]=[N:10][N:9]3[C:4]([CH:1]4[CH2:3][CH2:2]4)=[CH:5][C:6]([C:16]4[CH:21]=[CH:20][C:19]([C:22]([F:23])([F:24])[F:25])=[CH:18][CH:17]=4)=[N:7][C:8]=23)=[O:15])[CH:33]=[CH:34][CH:35]=1)(=[O:28])=[O:29]
Reactant: CS(=O)(=O)c1cccc(N)c1
Reactant: O=C(O)c1cnn2c(C3CC3)cc(-c3ccc(C(F)(F)F)cc3)nc12
Product: CS(=O)(=O)c1cccc(NC(=O)c2cnn3c(C4CC4)cc(-c4ccc(C(F)(F)F)cc4)nc23)c1

Procedure:
The title compound was prepared from 7-cyclopropyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.29) and 3-methanesulfonyl-phenylamine according to general procedure II. Pale-yellow solid. MS (ISP) 501.3 [(M+H)+]; mp 231-234° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[C:6]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([CH3:26])[N:21]=3)[N:13]=[C:12]2[CH3:27])[CH:5]=1.[Cl:29]N1C(=O)CCC1=O>C(O)(C)C.ClC(Cl)C(O)=O>[CH3:1][O:2][C:3](=[O:28])[C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[C:6]([N:11]2[C:16](=[O:17])[C:15]([Cl:29])=[C:14]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([CH3:26])[N:21]=3)[N:13]=[C:12]2[CH3:27])[CH:5]=1
Reactant: COC(=O)c1ccc(C)c(-n2c(C)nc(OCc3cccc(C)n3)cc2=O)c1
Reactant: O=C1CCC(=O)N1Cl
Agent: O=C(O)C(Cl)Cl
Solvent: CC(C)O
Product: COC(=O)c1ccc(C)c(-n2c(C)nc(OCc3cccc(C)n3)c(Cl)c2=O)c1
Temperature: 60 °C

Procedure:
To a solution of 4-methyl-3-[2-methyl-4-(6-methyl-pyridin-2-ylmethoxy)-6-oxo-6H-pyrimidin-1-yl]-benzoic acid methyl ester from Step A, of Example 13 (100 mg, 0.26 mmol) in isopropanol (1 mL) was added N-chlorosuccinimide (39 mg, 0.29 mmol) and 1 drops of dichloroacetic acid. The solution was heated at 60° C. for two hours. The solution was concentrated in vacuo and the residue was partitioned between ethyl acetate and water. The organic layer was washed with water and brine and dried over magnesium sulfate. The slurry was filtered and concentrated to provide the chlorinated product as colorless oil (120 mg, quantitative yield). MS (M+H): 414
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH:7]=[O:8])=[CH:5][N:6]=1.C([O-])([O-])=O.[K+].[K+].Cl.Cl[CH2:17][CH2:18][N:19]([CH2:21][CH2:22]Cl)[CH3:20]>CN(C=O)C>[CH3:20][N:19]1[CH2:21][CH2:22][N:1]([C:2]2[S:3][C:4]([CH:7]=[O:8])=[CH:5][N:6]=2)[CH2:17][CH2:18]1
Reactant: Nc1ncc(C=O)s1
Reactant: CN(CCCl)CCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN1CCN(c2ncc(C=O)s2)CC1
Temperature: 90 °C
Reaction time: 1 h
Yield: 50.9 %

Procedure:
In a 25 ml flask are added 0.5 g of 2-aminothiazole-5-carboxaldehyde, 1.35 g of K2CO3 in 5 ml of DMF. After dissolution, 0.901 g of 2-chloro-N-(2-chloroethyl)-N-methylethanamine hydrochloride are added. The mixture is left at room temperature for 1 h then heated to 90° C. for 5 h. Next, the mixture is evaporated, dissolved in 100 ml of water, and the aqueous phase is extracted three times with ethyl acetate. The organic phases are combined, washed with sodium chloride saturated solution, dried over sodium sulfate, filtered, and evaporated to yield 420 mg (50%) of 2-(4-methylpiperazin-1-yl)thiazole-5-carboxaldehyde.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9](OCC)=[O:10])[CH:5]=[CH:6][CH:7]=1.[H-].C([Al+]CC(C)C)C(C)C>>[Br:1][C:2]1[CH:3]=[C:4]([CH2:8][CH:9]=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)Cc1cccc(Br)c1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Product: O=CCc1cccc(Br)c1

Procedure:
Important starting materials for the synthesis of the preferred compounds of the invention are 6-bromo-1,2,3,4-tetrahydro-1,1-dimethylnaphthalene (Compound F), 7-bromo-3,4-dihydro-4,4-dimethylnaphthalen-1-one (Compound G), and the isomeric bromo compound, 6-bromo-3,4-dihydro-4,4-dimethylnaphthalen-1(2H)-one (Compound H). Compound G can be obtained as described in J. Med. Chem. 1995, 38, 4764-4767, and as shown in Reaction Scheme 1. Thus, referring now specifically to Reaction Scheme 1, ethyl 3-bromophenylacetate (Compound B, made by esterification of 3-bromophenylacetic acid) is reduced with diisobutylaluminum hydride (DIBAL H) to yield (3-bromophenyl)acetaldehyde. (3-Bromophenyl)acetaldehyde is reacted in a Wittig reaction with (carbethoxymethylene)triphenylphosphorane to provide a mixture of E and Z ethyl 4-(3-bromophenyl)but-2-enoates. The latter compounds are hydrogenated to yield ethyl 4-(3-bromophenyl)butanoate (Compound D). Compound D is reacted with the Grignard reagent derived from methylbromide to give the tertiary alcohol 5-(3-bromophenyl)-2-methylpentan-2-ol (Compound E) (It should be apparent to those skilled in the art, that the choice of the Grignard reagent used in this reaction step determines the nature of the R1 substituent in the resulting compounds of the invention.) Compound E is then treated with acid to cyclize it and to form 6-bromo-1,2,3,4-tetrahydro-1,1-dimethylnaphthalene (Compound F). Compound F is oxidized with chromium trioxde to yield 7-bromo-3,4-dihydro-4,4-dimethylnaphthalen-1(2H)-one (Compound G). The isomeric compound, 6-bromo-3,4-dihydro-4,4-dimethylnaphthalen-1(2H)-one (Compound H) can be obtained, starting with ethyl (4-bromophenyl)acetate, in accordance with the sequence of reactions illustrated in Reaction Scheme 1 for Compound G. 6-Bromo-3,4-dihydro-4,4-dimethylnaphthalen-1(2H)-one (Compound H) can also be obtained in accordance with the published literature procedure: Mathur et al. Tetrahedron, 41, 1509-1516 (1985).
Reaction SMILES: N1C=CN=C1.[NH2:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][CH2:15][OH:16])=[CH:9][CH:8]=1.[C:17]([Si:21](Cl)([CH3:23])[CH3:22])([CH3:20])([CH3:19])[CH3:18]>O1CCCC1>[Si:21]([O:16][CH2:15][CH2:14][CH2:13][C:10]1[CH:9]=[CH:8][C:7]([NH2:6])=[CH:12][CH:11]=1)([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:23])[CH3:22]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Nc1ccc(CCCO)cc1
Agent: c1c[nH]cn1
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCCCc1ccc(N)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 100.6 %

Procedure:
To a 50 mL round bottomed flask was added 1H-imidazole (59.4 mg, 0.873 mmol), 3-(4-aminophenyl)propan-1-ol 120 mg, 0.794 mmol) and Tetrahydrofuran (THF) (5 mL). To this solution was added tert-butylchlorodimethylsilane (132 mg, 0.873 mmol), and this was left to stir for 2 days, under nitrogen at room temperature. Another 0.5 eq of tert-butylchlorodimethylsilane was added to the reaction and the reaction was left to stir for another 2 hours. After this, reaction was stopped and the suspension concentrated down on a Biotage V10 evaporator, and then the product extracted to the organic phase of an aqueous work up between ethyl acetate (10 mL) and water (10 mL). The organic phase was then passed through a hydrophobic frit, and concentrated in vacuo, leaving the crude product (212 mg, 100%). LCMS (M+1): 266, RT 1.14 mins.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH3:29])=[C:5]([C:23]([O:25][CH:26]([CH3:28])[CH3:27])=[O:24])[CH:6]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([NH:21][OH:22])[CH:16]=2)[C:7]=1[C:8]([O:10][CH2:11][CH2:12][O:13][CH3:14])=[O:9].[N+:30]([C:33]1[CH:40]=[CH:39][C:36]([CH:37]=O)=[CH:35][CH:34]=1)([O-:32])=[O:31]>>[CH3:1][C:2]1[NH:3][C:4]([CH3:29])=[C:5]([C:23]([O:25][CH:26]([CH3:27])[CH3:28])=[O:24])[CH:6]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([N:21](=[CH:37][C:36]3[CH:39]=[CH:40][C:33]([N+:30]([O-:32])=[O:31])=[CH:34][CH:35]=3)=[O:22])[CH:16]=2)[C:7]=1[C:8]([O:10][CH2:11][CH2:12][O:13][CH3:14])=[O:9]
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Reactant: COCCOC(=O)C1=C(C)NC(C)=C(C(=O)OC(C)C)C1c1cccc(NO)c1
Agent: COCCOC(=O)C1=C(C)NC(C)=C(C(=O)OC(C)C)C1c1cccc(/[N+]([O-])=C/c2ccc([N+](=O)[O-])cc2)c1
Product: COCCOC(=O)C1=C(C)NC(C)=C(C(=O)OC(C)C)C1c1cccc([N+]([O-])=Cc2ccc([N+](=O)[O-])cc2)c1

Procedure:
The reaction of hydroxylamine 55 (0.80 g, 2 mmol) with 4-nitrobenzaldehyde (58) (0.30 g, 2 mmol) afforded, after workup, a yellow oil. The crude product was purified by flash chromatography with 1:1 ethyl acetate/hexane as the eluant to obtain 0.76 g (1.42 mmol, 71%) of 69 as a yellow oil. The oil crystallized from ethyl acetate-pentane to yield red crystalline solid: mp 148°-150° C.; IR (CH2Cl2) 3435, 29980, 1695, 1620, 1598, 1545, 1520, 1470, 1342, 1215, 1102, 858; 1H NMR (CDCl3) δ 1.08 (d, J=6.2 Hz, 3H), 1.19 (d, J=6.2 Hz, 3H), 2.25 (s, 6H), 3.28 (s, 3H), 3.55 (t, J=4.8 Hz, 2H), 4.16 (m, 2H), 4.92 (septet, J=6.2 Hz, 1H), 5.06 (s, 1H), 6.66 (s, 1H), 7.27-8.51 (m, 9H); 13C NMR (CDCl3) δ 19.78, 19.88, 22.45, 22.68, 40.60, 59.26, 63.36, 67.79, 71.19, 103.34, 104.16, 119.97, 122.05, 124.43, 129.24, 129.84, 131.23, 132.97, 137.03, 145.36, 146.17, 148.45, 149.23, 150.50, 167.46, 167.94. Anal. Calcd for C28H31N3O8 : C, 62.57; H, 5.77. Found: C, 62.76, H, 5.82.