Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:5]([C:6]2[CH:7]=[C:8]([CH:25]=[CH:26][CH:27]=2)[O:9][C:10]2[CH:24]=[CH:23][C:13]3[N:14]4[CH2:22][CH2:21][CH2:20][CH:15]4[NH:16][S:17](=[O:19])(=[O:18])[C:12]=3[CH:11]=2)=[N:4][N:3]=[N:2]1.[CH2:28](O)C>>[CH3:28][N:1]1[C:5]([C:6]2[CH:7]=[C:8]([CH:25]=[CH:26][CH:27]=2)[O:9][C:10]2[CH:24]=[CH:23][C:13]3[N:14]4[CH2:22][CH2:21][CH2:20][C:15]4=[N:16][S:17](=[O:19])(=[O:18])[C:12]=3[CH:11]=2)=[N:4][NH:3][NH:2]1
Reactant: CCO
Reactant: O=S1(=O)NC2CCCN2c2ccc(Oc3cccc(-c4nnn[nH]4)c3)cc21
Product: CN1NNN=C1c1cccc(Oc2ccc3c(c2)S(=O)(=O)N=C2CCCN23)c1
Reaction time: 8 h

Procedure:
200 μl (0.39 mmol) of bis(tri-n-butyl)tin oxide are added to a suspension of the product obtained in Example 1 (300 mg, 0.78 mmol) in 20 ml of anhydrous ethanol and the solution is refluxed for 10 minutes. The ethanol is evaporated off, 1 ml of methyl iodide is added and stirring is carried out at ambient temperature overnight. The precipitate is filtered off to yield a mixture of the 1- and 2-methyl-2H-tetrazol isomers which is purified to yield the title product.
Reaction SMILES: C(N(C(C)C)CC)(C)C.[NH2:10][C:11]1[C:12]([C:27]([NH:29][C:30]2[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=2)=[O:28])=[N:13][C:14]([C:17]2[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][CH2:25][OH:26])=[CH:19][CH:18]=2)=[CH:15][N:16]=1.[CH3:36][S:37](Cl)(=[O:39])=[O:38]>ClCCl>[CH3:36][S:37]([O:26][CH2:25][CH2:24][CH2:23][C:20]1[CH:21]=[CH:22][C:17]([C:14]2[CH:15]=[N:16][C:11]([NH2:10])=[C:12]([C:27](=[O:28])[NH:29][C:30]3[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=3)[N:13]=2)=[CH:18][CH:19]=1)(=[O:39])=[O:38]
Reactant: Nc1ncc(-c2ccc(CCCO)cc2)nc1C(=O)Nc1cccnc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CS(=O)(=O)OCCCc1ccc(-c2cnc(N)c(C(=O)Nc3cccnc3)n2)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 91.9 %

Procedure:
Dichloromethane (200 mL) and diisopropylethylamine (2 g, 17.16 mmol) were added to the product of step (vii) (4 g, 11.46 mmol). The resulting solution was cooled to 0° C. and MsCl (2 g, 17.16 mmol) added dropwise. When the addition was completed, the resulting solution was stirred at 0° C. for 10 minutes and at room temperature for 2 hours. The reaction mixture was extracted with dichloromethane and washed with water (×3). The combined organic extract was dried over MgSO4, filtered and concentrated in vacuo, which afforded the subtitle compound (viii) as a yellow brown solid (4.5 g).
Reaction SMILES: [CH2:1]([SH:3])[CH3:2].O.C(=O)([O-])[O-].[K+].[K+].Cl[C:12]1[C:22](Cl)=[CH:21][C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[C:14]([CH3:24])[C:13]=1[C:25]1[O:29][N:28]=[C:27]([CH3:30])[CH:26]=1>CN(C=O)C>[CH2:1]([S:3][C:12]1[CH:22]=[CH:21][C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[C:14]([CH3:24])[C:13]=1[C:25]1[O:29][N:28]=[C:27]([CH3:30])[CH:26]=1)[CH3:2]
Reactant: CCS
Reactant: CCOC(=O)c1cc(Cl)c(Cl)c(-c2cc(C)no2)c1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(SCC)c(-c2cc(C)no2)c1C
Temperature: 0 °C
Yield: 43.2 %

Procedure:
Into a 250-ml round-bottomed flask were placed 0.311 g of ethyl mercaptan, 0.018 g of water and 6 ml of DMF, and then 0.346 g of potassium carbonate and 0.314 g of ethyl 4,5-dichloro-2-methyl-3-(3-methylisoxazol-5-yl)benzoate were adder The resulting mixture was stirred with a magnetic stirrer at room temperature for 6 hours under the irradiation of 40W fluorescent light. The reaction solution was poured into 25 ml of ice-water, and extracted with 25 ml of diethyl ether. The organic layer was washed with water, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The obtained crude product was purified on silica gel column chromatography (elution with n-hexane/ethyl acetate=95/5) to give 0.132 g of the title compound as white crystals. Melting point: 39-40° C.
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][CH:10]=[CH:11][CH:12]=2)=[N:4]1)[CH3:2].[I:13]N1C(=O)CCC1=O.S([O-])([O-])(=O)=S.[Na+].[Na+].C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O>[CH2:1]([N:3]1[CH:7]=[C:6]([I:13])[C:5]([C:8]2[S:9][CH:10]=[CH:11][CH:12]=2)=[N:4]1)[CH3:2]
Reactant: CCn1ccc(-c2cccs2)n1
Reactant: O=C1CCC(=O)N1I
Agent: O=C([O-])[O-]
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCn1cc(I)c(-c2cccs2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 51.1 %

Procedure:
To a solution of 1-ethyl-3-(2-thienyl)-1H-pyrazole (13.5 mmol) in 45 mL dry N,N-dimethylformamide under argon atmosphere was added N-iodosuccinimide (14.1 mmol) in small portions. The reaction mixture was stirred overnight at room temperature. N-Iodosuccinimide (4.4 mmol) was added and stirring was continued for 24 h. 5% aqueous sodium thiosulfate solution and saturated aqueous sodium carbonate solution were added and the mixture was stirred at room temperature for 1 h, then extracted with ethyl acetate. The combined organic extracts were successively washed with water and brine, dried over MgSO4, filtered and concentrated. The residue was purified by chromatography on silica gel (toluene:ethyl acetate 100:0 to 0:100) to afford 2.10 g 1-ethyl-4-iodo-3-(2-thienyl)-1H-pyrazole (51% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:13]([C:14](O)=[O:15])=[C:12]([CH2:17][O:18][CH2:19][CH2:20][CH:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)[NH:11][C:10]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[C:33]1([CH:39]([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[CH2:40][CH2:41][NH2:42])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.CCN=C=NCCCN(C)C.Cl.ON1C2C=CC=CC=2N=N1>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:13]([C:14](=[O:15])[NH:42][CH2:41][CH2:40][CH:39]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)=[C:12]([CH2:17][O:18][CH2:19][CH2:20][CH:21]3[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]3)[NH:11][C:10]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[N:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)C1=C(COCCC2CCCCC2)NC(c2ccccc2)=NC1c1cccc(Cl)c1
Reactant: NCCC(c1ccccc1)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: O=C(NCCC(c1ccccc1)c1ccccc1)C1=C(COCCC2CCCCC2)NC(c2ccccc2)=NC1c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
60.0 mg (0.110 mmol) of 4-(3-chlorophenyl)-6-[(2-cyclohexylethoxy)methyl]-2-phenyl-1,4-dihydropyrimidine-5-carboxylic acid and 34.9 mg (0.165 mmol) of 3,3-diphenylpropylamine were dissolved in 10 ml of dichloromethane. 31.6 mg (0.165 mmol) of WSC hydrochloride and 16.8 mg (0.110 mmol) of 1-hydroxybenzotriazole (hereinafter referred to as “HOBT”) were added to the obtained solution under cooling with ice, and they were stirred at room temperature overnight. The reaction mixture was diluted with dichloromethane and then washed with saturated aqueous sodium hydrogencarbonate solution. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by the silica gel chromatography (hexane/ethyl acetate=3/1 to 1/1) to obtain the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:15]([O:17][CH2:18][CH2:19][CH2:20][O:21][C:22]4[CH:23]=[C:24]([CH:26]=[CH:27][CH:28]=4)[NH2:25])=[N:14][CH:13]=[N:12][C:11]=3[S:10][CH:9]=2)=[CH:4][CH:3]=1.[CH3:29][S:30](Cl)(=[O:32])=[O:31].C(N(C(C)C)CC)(C)C>ClCCl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:15]([O:17][CH2:18][CH2:19][CH2:20][O:21][C:22]4[CH:23]=[C:24]([NH:25][S:30]([CH3:29])(=[O:32])=[O:31])[CH:26]=[CH:27][CH:28]=4)=[N:14][CH:13]=[N:12][C:11]=3[S:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: Nc1cccc(OCCCOc2ncnc3scc(-c4ccc(F)cc4)c23)c1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CS(=O)(=O)Nc1cccc(OCCCOc2ncnc3scc(-c4ccc(F)cc4)c23)c1
Reaction time: 12 h
Yield: 38.5 %

Procedure:
A solution of 3-(3-{[5-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}propoxy)aniline (50 mg, 0.126 mmol) in dichloromethane (1.5 mL) was added to methanesulfonyl chloride (58 mg, 0.51 mmol) while stirring, followed by the addition of a solution of diisopropylethylamine (18 mg, 0.14 mmol) in dichloromethane (0.5 mL). Stirring was continued for 12 hours at room temperature and then the solvent was evaporated in vacuo. The residue was dissolved in ethyl acetate (30 mL), washed with sodium bicarbonate (2×25 mL) and the organic layer was isolated and concentrated. The product was purified by silica gel chromatography using 40% ethyl acetate in hexanes to give 23 mg (40%) of N-[3-(3-{[5-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}propoxy)phenyl]methanesulfonamide as a yellow solid. MS [M+H] 474.7. 1H NMR (400 MHz, CDCl3) δ (ppm) 8.65 (s, 1H), 7.42 (m, 2H), 7.23 (t, J=68.0 Hz, 1H), 7.22 (s, 1H), 7.06-7.01 (m, 2H), 6.76 (dd, J=8.0, 2.0 Hz, 1H), 6.68 (t, J=2.4 Hz, 1H), 6.58 (dd, J=8.0, 2.4 Hz, 1H), 6.32 (b, 1H), 4.58 (t, J=6.0 Hz, 2H), 3.01 (s, 3H), 2.07 (m, 2H).
Reaction SMILES: [CH2:1]([N:8]1[N:12]=[C:11]([CH:13]2[CH2:18][CH2:17][N:16]([C:19]3[CH:24]=[CH:23][C:22](/[N:25]=[CH:26]/[C:27]4[O:28][C:29]([N+:32]([O-:34])=[O:33])=[CH:30][CH:31]=4)=[CH:21][C:20]=3[F:35])[CH2:15][CH2:14]2)[O:10][C:9]1=[O:36])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([BH3-])#N.[Na+].C(=O)(O)[O-].[Na+]>CC(O)=O.CO>[CH2:1]([N:8]1[N:12]=[C:11]([CH:13]2[CH2:14][CH2:15][N:16]([C:19]3[CH:24]=[CH:23][C:22]([NH:25][CH2:26][C:27]4[O:28][C:29]([N+:32]([O-:34])=[O:33])=[CH:30][CH:31]=4)=[CH:21][C:20]=3[F:35])[CH2:17][CH2:18]2)[O:10][C:9]1=[O:36])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=c1oc(C2CCN(c3ccc(/N=C/c4ccc([N+](=O)[O-])o4)cc3F)CC2)nn1Cc1ccccc1
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: O=c1oc(C2CCN(c3ccc(NCc4ccc([N+](=O)[O-])o4)cc3F)CC2)nn1Cc1ccccc1
Yield: 83.9 %

Procedure:
3-Benzyl-5-[1-(2-fluoro-4-[(E)-1-(5-nitro-2-furyl)methylidene]aminophenyl)-4-piperidyl]-2,3-dihydro-1,3,4-oxadiazol-2-one (9 h, 0.49 g, 1 mmol) on reduction with sodiumcyanoborohydride (0.12 g, 2 mmol) in the presence of catalytic amount of CH3COOH (3 drops) in methanol at 0° C. for 12 h. After completion of the reaction as indicated by TLC, the reaction mixture is neutralized with sodium bi carbonate and extracted into chloroform. The crude product thus obtained was purified by column chromatography using ethyl acetate-hexane (8:2) as eluant to obtain product 3-benzyl-5-[1-(2-fluoro-4-[(5-nitro-2-furyl)methyl]aminophenyl)-4-piperidyl]-2,3-dihydro-1,3,4-oxadiazol-2-one (10 h, 414 mg, 84%).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]#[C:11][CH3:12])[N:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[F:19][C:20]1[CH:25]=[C:24]([F:26])[CH:23]=[C:22]([F:27])[C:21]=1[OH:28].[Cl-].[NH4+]>CN(C)C=O>[CH2:9]([O:8][C:6]1[CH:7]=[C:2]([O:28][C:21]2[C:20]([F:19])=[CH:25][C:24]([F:26])=[CH:23][C:22]=2[F:27])[N:3]=[CH:4][N:5]=1)[C:10]#[C:11][CH3:12]
Reactant: CC#CCOc1cc(Cl)ncn1
Reactant: Oc1c(F)cc(F)cc1F
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC#CCOc1cc(Oc2c(F)cc(F)cc2F)ncn1
Temperature: 60 °C
Reaction time: 7 h
Yield: 93.1 %

Procedure:
To 2 ml of N,N-dimethylformamide were added 0.2 g of 4-chloro-6-(2-butynyloxy)pyrimidine, 0.23 g of potassium carbonate, and 0.19 g of 2,4,6-trifluorophenol, followed by stirring at 60° C. for 7 hours. The reaction mixture was then left for cooling to room temperature and poured into a saturated aqueous ammonium chloride solution, which was extracted three times with chloroform. The chloroform layers were combined, washed with diluted hydrochloric acid and then with water, and dried over anhydrous magnesium sulfate and then concentrated. The residue was subjected to silica gel column chromatography to give 0.3 g of 4-(2-butynyloxy)-6-(2,4,6-trifluorophenoxy)pyrimidine (the present compound (45)), m.p.: 60.3° C.
Reaction SMILES: [C:1]([C:5]1[CH:12]=[C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])[CH:10]=[C:9]([OH:17])[C:6]=1[CH:7]=O)([CH3:4])([CH3:3])[CH3:2].[CH3:18][NH2:19].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>ClCCCl.C(O)(=O)C>[C:1]([C:5]1[C:6]([CH2:7][NH:19][CH3:18])=[C:9]([OH:17])[CH:10]=[C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])[CH:12]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CN
Reactant: CC(C)(C)c1cc(O)c(C=O)c(C(C)(C)C)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CNCc1c(O)cc(C(C)(C)C)cc1C(C)(C)C
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A mixture of 0.234 g (1.00 mmol) of the product of Step A, 3 mL of 2 N methylamine in TMF, and 0.5 mL acetic acid dissolved in 4.0 mL 1,2-dichloroethane was stirred at room temperature for 5 h. Sodium triacetoxyborohydride (0.422 g; 2.0 mmol) and 10 mL of 1,2-dichloroethane was then added and the resulting mixture was stirred overnight at room temperature. The reaction mixture was then treated with excess saturated aqueous NaHCO3. The aqueous layer was separated and extracted with CH2Cl2, the organic layers were combined, dried (Na2SO4), filtered, and evaporated. The residue was purified on a silica gel flash chromatography column eluted with CH2Cl2-MeOH—NH4OH (95:5:0.5). Evaporation of the purified fractions and drying in vacuo afforded the title compound. HPLC/MS: 250.2 (M+1); Rt=2.5 min.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:22]2[S:26][C:25]([C:27]3([O:31][CH2:32][C:33]4[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][CH:34]=4)[CH2:30][O:29][CH2:28]3)=[N:24][CH:23]=2)=[C:4]2[CH:10]=[C:9](I)[N:8]([S:12]([C:15]3[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:5]2=[N:6][CH:7]=1.[N:41]1([CH2:46][CH2:47][N:48]2[CH:52]=[C:51](B3OC(C)(C)C(C)(C)O3)[CH:50]=[N:49]2)[CH2:45][CH2:44][CH2:43][CH2:42]1.C(=O)(O)[O-]>CN(C)C=O.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>[Cl:1][C:2]1[C:3]([C:22]2[S:26][C:25]([C:27]3([O:31][CH2:32][C:33]4[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][CH:34]=4)[CH2:30][O:29][CH2:28]3)=[N:24][CH:23]=2)=[C:4]2[CH:10]=[C:9]([C:51]3[CH:50]=[N:49][N:48]([CH2:47][CH2:46][N:41]4[CH2:45][CH2:44][CH2:43][CH2:42]4)[CH:52]=3)[N:8]([S:12]([C:15]3[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:5]2=[N:6][CH:7]=1
Reactant: COc1ccc(COC2(c3ncc(-c4c(Cl)cnc5c4cc(I)n5S(=O)(=O)c4ccc(C)cc4)s3)COC2)cc1
Reactant: CC1(C)OB(c2cnn(CCN3CCCC3)c2)OC1(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Solvent: CN(C)C=O
Product: COc1ccc(COC2(c3ncc(-c4c(Cl)cnc5c4cc(-c4cnn(CCN6CCCC6)c4)n5S(=O)(=O)c4ccc(C)cc4)s3)COC2)cc1
Temperature: 70 °C

Procedure:
To a stirred ambient solution of 5-(5-chloro-2-iodo-1-tosyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-(3-(4-methoxybenzyloxy)oxetan-3-yl)thiazole (Example 11G) (300 mg, 0.424 mmol) and 1-(2-(pyrrolidin-1-yl)ethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (Example 20A) (173 mg, 0.593 mmol) in N,N-dimethylformamide (3.97 mL) was added saturated aqueous bicarbonate solution (1.32 mL) followed by bis(triphenylphosphine)palladium dichloride (20.8 mg, 0.030 mmol). The mixture was heated to 70° C. for 4 hours, cooled to room temperature, and then quenched by the addition of water and ethyl acetate. The layers were separated, and the aqueous layer was extracted with additional ethyl acetate. The combined organics were dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel, eluting with a gradient of 0 to 10% methanol in dichloromethane, to afford the title compound. MS ESI(+) m/z 745.1 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][CH:10]=[C:11]([CH2:13][CH2:14][NH:15][C:16](=[O:21])[C:17]([F:20])([F:19])[F:18])[N:12]=2)=[CH:4][CH:3]=1.[CH3:22][N:23](C=O)C>[C-]#N.[C-]#N.[Zn+2].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[C:22]([C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][CH:10]=[C:11]([CH2:13][CH2:14][NH:15][C:16](=[O:21])[C:17]([F:20])([F:19])[F:18])[N:12]=2)=[CH:4][CH:3]=1)#[N:23]
Reactant: CN(C)C=O
Reactant: O=C(NCCc1coc(-c2ccc(Br)cc2)n1)C(F)(F)F
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [C-]#N
Product: N#Cc1ccc(-c2nc(CCNC(=O)C(F)(F)F)co2)cc1
Temperature: 150 °C

Procedure:
N-(2-(2-(4-Bromophenyl)oxazol-4-yl)ethyl)-2,2,2-trifluoroacetamide (200 mg, 0.55 mmol) was dissolved in dry DMF (10 mL) and the solution was purged with argon for 10 min. Zn(CN)2 (97 mg, 0.83 mmol) and PdCl2(dppf) (302 mg, 0.04 mmol) were added to the reaction mixture and heated to 150° C. for 48 h. The reaction mixture was filtered through Celite and the filtrate was concentrated under reduced pressure. The residue was diluted with water and the product was extracted with EtOAc. The combined extracts were dried over anhydrous sodium sulfate and concentrated under reduced pressure to get N-(2-(2-(4-cyanophenyl)oxazol-4-yl)ethyl)-2,2,2-trifluoroacetamide (150 mg), which was used for the next step without further purification. MS (ESI) m/z: Calculated for C14H10F3N3O2: 309.07. found: 307.9 (M−H)−.
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20](SCCC)=[N:19][C:18]4=[O:26])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:29]([F:32])([F:31])[F:30])[CH:3]=1.[NH:33]1[C:37]2([CH2:42][CH2:41][NH:40][CH2:39][CH2:38]2)[C:36](=[O:43])[NH:35][CH2:34]1>>[Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20]([N:40]5[CH2:39][CH2:38][C:37]6([NH:33][CH2:34][NH:35][C:36]6=[O:43])[CH2:42][CH2:41]5)=[N:19][C:18]4=[O:26])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:29]([F:32])([F:30])[F:31])[CH:3]=1
Reactant: O=C1NCNC12CCNCC2
Reactant: CCCSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Product: O=C1N=C(N2CCC3(CC2)NCNC3=O)SC1=Cc1ccc2c(cnn2Cc2ccc(Cl)cc2C(F)(F)F)c1

Procedure:
8-{5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-1,3,8-triaza-spiro[4.5]decan-4-one was prepared from 5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-propylsulfanyl-thiazol-4-one and 1,3,8-Triaza-spiro[4.5]decan-4-one following General Procedure B.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[C:7]([N+:18]([O-])=O)=[C:8]([CH:13]=[CH:14][C:15]=2[O:16][CH3:17])[C:9]([O:11][CH3:12])=[O:10])[CH2:3][CH2:2]1>[Pd].CO>[NH2:18][C:7]1[C:6]([O:5][CH2:4][CH:1]2[CH2:3][CH2:2]2)=[C:15]([O:16][CH3:17])[CH:14]=[CH:13][C:8]=1[C:9]([O:11][CH3:12])=[O:10]
Reactant: COC(=O)c1ccc(OC)c(OCC2CC2)c1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1ccc(OC)c(OCC2CC2)c1N
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.2 %

Procedure:
A mixture of methyl 3-(cyclopropylmethoxy)-4-methoxy-2-nitrobenzoate (128 g, 0.46 mol), 10% Pd/C (110 g, 103 mmol Pd), and methanol (1 L) was stirred overnight at room temperature under an atmosphere of H2. The resulting mixture was filtered and concentrated to give 110 g of methyl 2-amino-3-(cyclopropylmethoxy)-4-methoxybenzoate as a white solid. MS (ESI): 252.1.
Reaction SMILES: [C:1]([O:5][P:6]([O:13][CH2:14][CH2:15][N:16]([CH2:27][CH3:28])C(=O)OCC1C=CC=CC=1)([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[P:6]([O:13][CH2:14][CH2:15][NH:16][CH2:27][CH3:28])([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])([O:8][C:9]([CH3:10])([CH3:11])[CH3:12])=[O:7]
Reactant: CCN(CCOP(=O)(OC(C)(C)C)OC(C)(C)C)C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CCNCCOP(=O)(OC(C)(C)C)OC(C)(C)C
Reaction time: 8 h
Yield: 93.4 %

Procedure:
Benzyl 2-(di-tert-butoxyphosphoryloxy)ethyl(ethyl)carbamate (INTERMEDIATE 48, 0.9 g, 2.17 mmol) was dissolved in methanol (5 ml), and 5% Pd on charcoal (0.10 g) was added. The reaction mixture was stirred at r.t under a hydrogen atmosphere overnight. The reaction mixture was filtered and concentrated in vacuo to give the title compound (0.57 g, yield: 94%).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[CH2:9][O:8][C:7]([CH3:14])([CH3:13])[C:6]=2[CH:15]=1.Br[C:17]1[C:18]([F:25])=[C:19]([CH:22]=[CH:23][CH:24]=1)[C:20]#[N:21]>>[CH3:13][C:7]1([CH3:14])[C:6]2[CH:15]=[C:2]([C:24]3[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[C:18]([F:25])[CH:17]=3)[CH:3]=[CH:4][C:5]=2[NH:11][C:10](=[O:12])[CH2:9][O:8]1
Reactant: CC1(C)OCC(=O)Nc2ccc(Br)cc21
Reactant: N#Cc1cccc(Br)c1F
Product: CC1(C)OCC(=O)Nc2ccc(-c3ccc(C#N)c(F)c3)cc21

Procedure:
Prepared from 7-bromo-5,5-dimethyl-1,5-dihydro-4,1-benzoxazepin-2(3H)-one and 3-bromo-2-fluorobenzonitrile generally according to the coupling procedure described in examples 82 and 1. 1H NMR (DMSO-d6): δ 10.08 (s, 1H), 7.92-7.99 (m, 2H), 7.77-7.79 (m, 1H), 7.64-7.69 (m, 2H), 7.22 (d, J=8.39 Hz, 1H), 4.28 (s, 2H), 1.62 (s, 6H). MS (ESI) m/z 311 ([M+H]+); MS (ESI) m/z 309 ([M−H]−).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:23]=[C:22]3[C:18]([C:19]([C:36]4[CH:45]=[CH:44][C:43]5[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=5)[CH:37]=4)=[N:20][N:21]3S(C3C(C)=CC(C)=CC=3C)(=O)=O)=[CH:17][CH:16]=2)=[CH:11][C:10]=1[O:46][CH3:47])C1C=CC=CC=1.C(OC1C=CC(C2C=C3C(C(C4C=CC5C(=CC=CC=5)C=4)=NN3)=CC=2)=CC=1OC)C1C=CC=CC=1>C(OCC)(=O)C.CCCCCC>[CH:37]1[C:38]2[C:43](=[CH:42][CH:41]=[CH:40][CH:39]=2)[CH:44]=[CH:45][C:36]=1[C:19]1[C:18]2[C:22](=[CH:23][C:15]([C:12]3[CH:13]=[CH:14][C:9]([OH:8])=[C:10]([O:46][CH3:47])[CH:11]=3)=[CH:16][CH:17]=2)[NH:21][N:20]=1
Reactant: COc1cc(-c2ccc3c(-c4ccc5ccccc5c4)nn(S(=O)(=O)c4c(C)cc(C)cc4C)c3c2)ccc1OCc1ccccc1
Agent: COc1cc(-c2ccc3c(-c4ccc5ccccc5c4)n[nH]c3c2)ccc1OCc1ccccc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: COc1cc(-c2ccc3c(-c4ccc5ccccc5c4)n[nH]c3c2)ccc1O

Procedure:
6-(4-Benzyloxy-3-methoxy-phenyl)-3-naphthalen-2-yl-1-(2,4,6-trimethyl-benzenesulfonyl)-1H-indazole was converted to 6-(4-benzyloxy-3-methoxy-phenyl)-3-naphthalen-2-yl-1H-indazole as described in Example 1(a), step (ix). Rf sm 0.40, p 0.17 (ethyl acetate-hexane 3:7); 1H NMR (CDCl3) δ 8.40 (s, 1H), 8.12 (d, 1H, J=8.5 Hz), 8.10 (dd, 1H, J=1.6, 8.4 Hz), 7.93 (d, 1H, J=8.3 Hz), 7.88 (m, 2H), 7.61 (m, 1H) 7.56 (s, 1H), 7.43 (m, 5H), 7.30 (m, 3H), 7.15 (d, 1H, J=2.0 Hz), 7.08 (dd, 1H, J=2.1, 8.3 Hz), 6.91 (d, 1H, J=8.3 Hz), 5.16 (s, 2H), 3.91 (s, 3H).
Reaction SMILES: N.[Li].[CH:3]#[CH:4].[Si](O[CH2:13][CH:14]1[CH2:19][CH2:18][CH:17]([CH2:20][O:21]S(C2C=CC(C)=CC=2)(=O)=O)[CH2:16][CH2:15]1)(C(C)(C)C)(C)C>CS(C)=O.C1COCC1>[CH2:13]([CH:14]1[CH2:15][CH2:16][CH:17]([CH2:20][OH:21])[CH2:18][CH2:19]1)[C:3]#[CH:4]
Reactant: C#C
Reactant: Cc1ccc(S(=O)(=O)OCC2CCC(CO[Si](C)(C)C(C)(C)C)CC2)cc1
Agent: N
Agent: [Li]
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: C#CCC1CCC(CO)CC1
Temperature: -78 °C
Reaction time: 1 h
Yield: 93 %

Procedure:
A 3-neck 250 mL-flask equipped with a gas inlet tube and dry-ice condenser was cooled to −78° C. and charged with liquid ammonia (40 mL). To the reaction mixture was added lithium wire (600 mg, 86.4 mmol) generating a deep blue solution. The mixture was allowed to stir for 1 hour. Acetylene, passed through a charcoal drying tube, was added to the ammonia until all the lithium had reacted and the solution turned colorless, at which time the flow of acetylene was stopped, the acetylene-inlet tube and condenser removed and the flask outfitted with a thermometer. DMSO (20 mL) was added and the ammonia evaporated with a warm water bath until the mixture reached a temperature of 30° C. The solution was stirred at this temperature for 2 hours until the solution stopped bubbling. The mixture was cooled to 5° C. and compound 84 (11.25 g, 27.3 mmol), in DMSO (10 mL), was added. The temperature was maintained at 5° C. The mixture was allowed to stir at 5° C. for 0.5 hours. Then the solution was gradually warmed to room temperature and stirred for an additional 18 hours. The brown/black reaction mixture was poured slowly over ice (300 g) and extracted with ether (4×100 mL), dried with anhydrous sodium sulfate, and concentrated in vacuo to yield a yellow oil. The oil was subsequently dissolved in THF (200 mL) and changed to a brownish color upon addition of TBAF hydrate (11.20 g, 35.5 mmol). The solution was allowed to stir for 24 hours 2 under N2 atmosphere. After stirring, the reaction was quenched with water (200 mL) and extracted with ether (3×100 mL). The ether extracts were combined and concentrated in vacuo. The crude product was purified by chromatography, on a silica gel column, eluting with 1:1 ether/petroleum ether to yield 86 (3.91 g, 93%) as a yellow oil. 1H NMR (CDCl3) δ 3.45 (d, J=6.2, 2H), 2.10 (d, J=6.2, 2H), 1.9 (s, 1H), 1.94-1.69 (m, 4H), 1.52-1.34 (m, 2H), 1.16-0.83 (m, 4H); 13C NMR (CDCl3) δ 83.8, 69.5, 69.0, 40.8, 37.7, 32.3, 29.7, 26.5.