Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](N1C=CN=C1)([N:3]1[CH:7]=[CH:6][N:5]=[CH:4]1)=[O:2].[CH3:13][C:14]1[N:15]=[C:16]([NH2:25])[S:17][C:18]=1[C:19]1[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=1>C(Cl)Cl>[CH3:13][C:14]1[N:15]=[C:16]([NH:25][C:1]([N:3]2[CH:7]=[CH:6][N:5]=[CH:4]2)=[O:2])[S:17][C:18]=1[C:19]1[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Cc1nc(N)sc1-c1ccncc1
Solvent: ClCCl
Product: Cc1nc(NC(=O)n2ccnc2)sc1-c1ccncc1
Temperature: 40 °C
Reaction time: 2.5 h

Procedure:
To a stirred solution of carbonyldiimidazole (3.91 g, 24.2 mmol) in DCM (150 ml) is added 4-methyl-5-pyridin-4-yl-thiazol-2-ylamine (prepared according to the method described in EP 117082 A2) (3.08 g, 16.1 mmol) in one portion. The suspension is stirred for 2.5 hours at 40° C. and the reaction mixture is then filtered and washed with DCM to afford the titled compound as a solid.
Reaction SMILES: C[O:2][C:3]([C@H:5]1[NH:18][C:17](=[S:19])[CH2:16][CH2:15][CH2:14][CH2:13][O:12][C:11](=[O:20])[C:10]2[C:21]([CH3:28])=[C:22]([O:26][CH3:27])[CH:23]=[C:24]([OH:25])[C:9]=2[CH2:8][S:7][CH2:6]1)=O>CO.C(N)CC>[CH2:17]([NH:18][C:3]([C@H:5]1[NH:18][C:17](=[S:19])[CH2:16][CH2:15][CH2:14][CH2:13][O:12][C:11](=[O:20])[C:10]2[C:21]([CH3:28])=[C:22]([O:26][CH3:27])[CH:23]=[C:24]([OH:25])[C:9]=2[CH2:8][S:7][CH2:6]1)=[O:2])[CH2:16][CH3:15]
Reactant: COC(=O)[C@@H]1CSCc2c(O)cc(OC)c(C)c2C(=O)OCCCCC(=S)N1
Solvent: CO
Solvent: CCCN
Product: CCCNC(=O)[C@@H]1CSCc2c(O)cc(OC)c(C)c2C(=O)OCCCCC(=S)N1
Temperature: 50 °C
Yield: 96.2 %

Procedure:
A solution of 43 mg of the product of Example 23 in a mixture of 0.5 ml of methanol and 0.5 ml of propylamine was heated to 50° C. for 6 h. The solution was evaporated in vacuo, the residue was dissolved in ethyl acetate and the solution was washed with 1N hydrochloric acid and water. The organic layer was dried over sodium sulfate and evaporated in vacuo, the residue was chromatographed on silica gel using ethyl acetate/hexane (1:2, v/v) as eluent, and the purified product was crystallized from ethyl acetate/hexane to afford 22 mg of (R)-16-hydroxy-14-methoxy-13-methyl-12-oxo-6-thioxo-1,3,4,5,6,7,8,9,10,12-decahydro-11,2,5-benzoxathiaazacyclotetradecine-4-carboxylic acid propylamide as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[S:12]([NH:15][C:16]1[CH:21]=[C:20]([O:22][C:23]2[S:24][C:25]3[CH:31]=[CH:30][C:29]([C:32]#[N:33])=[CH:28][C:26]=3[N:27]=2)[CH:19]=[C:18]([Cl:34])[CH:17]=1)(=[O:14])=[O:13].[N:35]([Si](C)(C)C)=[N+:36]=[N-:37].C([Sn](=O)CCCC)CCC.Cl>C1(C)C=CC=CC=1.CCOC(C)=O>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:10])([F:9])[F:11])[CH:5]=[CH:4][C:3]=1[S:12]([NH:15][C:16]1[CH:21]=[C:20]([O:22][C:23]2[S:24][C:25]3[CH:31]=[CH:30][C:29]([C:32]4[NH:37][N:36]=[N:35][N:33]=4)=[CH:28][C:26]=3[N:27]=2)[CH:19]=[C:18]([Cl:34])[CH:17]=1)(=[O:13])=[O:14]
Reactant: N#Cc1ccc2sc(Oc3cc(Cl)cc(NS(=O)(=O)c4ccc(C(F)(F)F)cc4Cl)c3)nc2c1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Agent: CCCC[Sn](=O)CCCC
Agent: Cl
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: O=S(=O)(Nc1cc(Cl)cc(Oc2nc3cc(-c4nnn[nH]4)ccc3s2)c1)c1ccc(C(F)(F)F)cc1Cl
Temperature: 90 °C
Yield: 85.1 %

Procedure:
To a solution of 2-Chloro-N-[3-chloro-5-(5-cyano-benzothiazol-2-yloxy)-phenyl]-4-trifluoromethyl-benzenesulfonamide (Example 286, 55 mg, 0.1 mmol) in 5 mL of toluene was added azidotrimethylsilane (Aldrich, 26 μL, 0.2 mmol) and dibutyltin oxide (Aldrich,3 mg, 0.01 mmol). The mixture was heated at 90° C. overnight till there was no starting material remained by TLC. Cooled to room temperature, 1N HCl and EtOAc was added. The mixture was extracted 3× with EtOAc (30 mL). The organic layers were washed twice with a brine solution (300 mL), dried over Na2SO4 and concentrated. The residue was purified by chromatography, eluted with 10% EtOAc/CH2Cl2 then 10% MeOH/CH2Cl2 to give 50 mg (85%) of product.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][C:3]=1[O:11][CH3:12].C(=O)(O)[O-].[Na+].[CH3:18][N:19](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.CN>>[NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:19][CH3:18])=[O:7])=[CH:4][C:3]=1[O:11][CH3:12]
Reactant: COc1cc(C(=O)O)ccc1N
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Product: CNC(=O)c1ccc(N)c(OC)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 63 %

Procedure:
To a solution of 4-amino-3-methoxybenzoic acid (1 equiv) in N—N-dimethylformamide (0.6 M) was added sodium bicarbonate (9.7 equiv), HATU (2 equiv) and methyl amine hydrochloride (10 equiv). The reaction mixture was stirred at room temperature overnight. The reaction mixture was poured on water and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel 100-200 mesh, 0-10% MeOH in DCM as eluent) to give the title compound. (Yield: 63%). MS (ESI) m/z 181 [M+1]1.
Reaction SMILES: [CH:1]1([NH:6][C:7]2[CH:23]=[CH:22][CH:21]=[CH:20][C:8]=2[CH2:9][S:10][C:11]2[NH:12][C:13]3[C:14]([N:19]=2)=[N:15][CH:16]=[CH:17][CH:18]=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.ClC1C=CC=C(C(OO)=[O:32])C=1>C(Cl)(Cl)Cl>[CH:1]1([NH:6][C:7]2[CH:23]=[CH:22][CH:21]=[CH:20][C:8]=2[CH2:9][S:10]([C:11]2[NH:12][C:13]3[C:14]([N:19]=2)=[N:15][CH:16]=[CH:17][CH:18]=3)=[O:32])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: c1ccc(NC2CCCC2)c(CSc2nc3ncccc3[nH]2)c1
Solvent: ClC(Cl)Cl
Product: O=S(Cc1ccccc1NC1CCCC1)c1nc2ncccc2[nH]1

Procedure:
2-Mercaptoimidazo[4,5-b]pyridine and 2-(N-cylopentylamino)benzyl chloride hydrochloride were reacted in an aqueous ethanol solution to obtain 2-[2-(N-cyclopentylamino)benzylthio[-imidazo[4,5-b]pyridine in the same manner as in Example 9-(2). The obtained 2-[2-(N-cyclopentylamino)benzylthio]imidazo[4,5-b]pyridine was oxidized by m-chloroperbenzoic acid in chloroform in the same manner in Example 9-(3) to give 2-[2-(N-cyclopentylamino)benzylsulfinyl]imidazo[4,5-b]pyridine as a pale yellow crystalline product. m.p.: 134° C. (decompn.)
Reaction SMILES: [C:1]([O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:20]=[CH:19][C:16]([CH:17]=[O:18])=[CH:15][CH:14]=1)(=[O:4])[CH:2]=[CH2:3].CC(=CC)C.Cl([O-])=[O:27].[Na+].P([O-])([O-])([O-])=O.[Na+].[Na+].[Na+]>O.C(O)(C)(C)C>[C:1]([O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:20]=[CH:19][C:16]([C:17]([OH:27])=[O:18])=[CH:15][CH:14]=1)(=[O:4])[CH:2]=[CH2:3]
Reactant: [O-][Cl+][O-]
Reactant: C=CC(=O)OCCCCCCOc1ccc(C=O)cc1
Agent: CC=C(C)C
Agent: O=P([O-])([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)(C)O
Product: C=CC(=O)OCCCCCCOc1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 65 %

Procedure:
In a 2 liter three-necked round-bottomed flask, fitted with a mechanical stirrer, dropping funnel, and ground glass stopper, were charged 4-(6'-acryloyloxyhexyloxy)benzaldehyde (from Example 12) (22 grams; 0.1 mole), tertiary-butyl alcohol (500 mL), and 2-methyl-2-butene (available from Aldrich Chemical Co., Milwaukee, Wis.) (232 grams; 3 moles). The reaction mixture was stirred at room temperature. Over two hours, a solution of sodium chlorite (available from Aldrich Chemical Co., Milwaukee, Wis.) (65 grams; 0.7 mole) and sodium phosphate, monobasic monohydrate (available from Aldrich Chemical Co., Milwaukee, Wis.) (75 grams; 0.5 mole) in water (300 mL) was added. The reaction mixture was stirred for 12 hours at ambient temperature at which time the organic solvents were concentrated by rotary evaporator. The residue was then dissolved in diethyl ether (500 mL) and the mixture was made acidic (pH~2) by addition of 4N HCl. The mixture was poured into a separatory funnel and the organic layer was processed. The residue was recrystallized from ethanol. Spectral analysis confirmed the presence of 4-(6'-acryloyloxyhexyloxy)benzoic acid. The crystals weighed 15 grams which represents a 65 percent yield based on starting material.
Reaction SMILES: [CH3:1][C:2]1[S:10][C:5]2=[CH:6][N:7]=[CH:8][CH:9]=[C:4]2[CH:3]=1.[N+:11]([O-])([OH:13])=[O:12].[OH-].[Na+].O.C([O-])(O)=O.[Na+]>OS(O)(=O)=O>[CH3:1][C:2]1[S:10][C:5]2=[CH:6][N:7]=[CH:8][CH:9]=[C:4]2[C:3]=1[N+:11]([O-:13])=[O:12]
Reactant: O=[N+]([O-])O
Reactant: Cc1cc2ccncc2s1
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: Cc1sc2cnccc2c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 18 h
Yield: 46 %

Procedure:
2-Methyl-thieno[2,3-c]pyridine (5.51 g, 36.9 mmol) was dissolved in concentrated H2SO4 (20 mL) at 0° C. Concentrated HNO3 (11.6 mL) was added dropwise over 15 min, followed by warming to RT. Stirred for 18 h at RT. The solution was poured over ice and adjusted pH to 7 with 50% NaOH/H2O and sat NaHCO3 solution. The solution was extracted with portions of CH2Cl2 (3×100 mL), dried (MgSO4) and condensed to yield the title compound as a bright yellow solid (3.27 g, 46%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH2:18][C:19]3[N:20]([CH3:24])C=[CH:22][N:23]=3)=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[N:10]=2)[CH:7]=1.FC1C=CC2[N:30](C(C=O)=C(C3C=CC(F)=CC=3)N=2)C=1.CN1C=NC=N1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH2:18][C:19]3[N:20]([CH3:24])[N:30]=[CH:22][N:23]=3)=[C:9]([C:11]3[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=3)[N:10]=2)[CH:7]=1
Reactant: Cn1ccnc1Cc1c(-c2ccc(F)cc2)nc2ccc(F)cn12
Reactant: O=Cc1c(-c2ccc(F)cc2)nc2ccc(F)cn12
Agent: Cn1cncn1
Product: Cn1ncnc1Cc1c(-c2ccc(F)cc2)nc2ccc(F)cn12
Yield: 53 %

Procedure:
The title compound was prepared according to Method C and the experimentals described for compound 199 from 6-fluoro-2-(4-fluorophenyl)imidazo[1,2-a]pyridine-3-carbaldehyde and 1-methyl-1H-1,2,4-triazole. (0.19 g, 53% yield). M/e+ 326.2 for C17H14F2N5 (M+H)+; 1H-NMR (500 MHz, DMSO-d6, δ) 8.55 (dd, J=5.0, 2.0 Hz, 1H), 7.72-7.68 (m, 4H), 7.40-7.36 (m, 1H), 7.31-7.27 (m, 2H), 4.64 (s, 2H), 3.86 (s, 3H).
Reaction SMILES: P([O-])([O-])([O-])=O.[K+].[K+].[K+].B1(CC2C=CC=CC=2)C2CCCC1CCC2.C1(P(C2CCCCC2)[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2[C:38]2[C:43](OC)=[CH:42][CH:41]=[CH:40][C:39]=2OC)CCCCC1.BrC1C=CC=C2[C:56]=1[C:57]([CH2:69][N:70]([CH:78]1[CH2:80][CH2:79]1)[C:71](=[O:77])[O:72][C:73]([CH3:76])([CH3:75])[CH3:74])=[CH:58][N:59]2[CH2:64][CH2:65][CH2:66][O:67][CH3:68]>CN(C)C=O.C(OCC)(=O)C.O1CCCC1>[CH2:33]([C:34]1[CH:35]=[CH:36][CH:37]=[C:32]2[C:56]=1[C:57]([CH2:69][N:70]([CH:78]1[CH2:79][CH2:80]1)[C:71](=[O:77])[O:72][C:73]([CH3:76])([CH3:75])[CH3:74])=[CH:58][N:59]2[CH2:64][CH2:65][CH2:66][O:67][CH3:68])[C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1
Reactant: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Reactant: COCCCn1cc(CN(C(=O)OC(C)(C)C)C2CC2)c2c(Br)cccc21
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Agent: c1ccc(CB2C3CCCC2CCC3)cc1
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COCCCn1cc(CN(C(=O)OC(C)(C)C)C2CC2)c2c(Cc3ccccc3)cccc21
Temperature: 80 °C
Reaction time: 3 h
Yield: 499.2 %

Procedure:
Potassium phosphate (498 mg), a 0.5M tetrahydrofuran-solution of B-benzyl-9-BBN (2.8 ml), palladium acetate(II) (21 mg), 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (38.5 mg) were added to a solution of tert-butyl {[4-bromo-1-(3-methoxypropyl)-1H-indol-3-yl]methyl}cyclopropylcarbamate (205 mg) in N,N-dimethylformamide (4.3 ml) and the mixture was stirred under argon atmosphere at 80° C. for 3 hours. The reaction mixture was diluted with ethyl acetate, washed with water and saturated brine successively, dried over magnesium sulfate and concentrated in vacuo. The resulted residue was purified with a silica gel column chromatography (eluting solvent: n-hexane/ethyl acetate=20/1 to 2/1) to give tert-butyl {[4-benzyl-1-(3-methoxypropyl)-1H-indol-3-yl]methyl}cyclopropylcarbamate (210 mg) as a yellow oil.
Reaction SMILES: [CH3:1][C:2]1[N:7]2[C:8](=[O:15])[C:9]([C:12]([OH:14])=O)=[CH:10][N:11]=[C:6]2[CH:5]=[CH:4][CH:3]=1.[CH2:16]([N:18](CC)[CH2:19][CH3:20])[CH3:17].ClC(OC)=O.N1CCCC1>C(Cl)(Cl)Cl>[CH3:1][C:2]1[N:7]2[C:8](=[O:15])[C:9]([C:12]([N:18]3[CH2:19][CH2:20][CH2:17][CH2:16]3)=[O:14])=[CH:10][N:11]=[C:6]2[CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cccc2ncc(C(=O)O)c(=O)n12
Reactant: CCN(CC)CC
Agent: COC(=O)Cl
Solvent: C1CCNC1
Solvent: ClC(Cl)Cl
Product: Cc1cccc2ncc(C(=O)N3CCCC3)c(=O)n12
Reaction time: 0.33 h
Yield: 32.3 %

Procedure:
A mixture containing 20.4 g (0.1 mol) of 6-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-3-carboxylic acid and 15.5 ml (0.11 mol) of triethylamine in 600 ml of chloroform is cooled below -10° C. by ice-salt. A solution of 10 ml (0.1 mol) of methyl chloroformate dissolved in 50 ml of chloroform is dropped to the above mixture at -10° C. during 30 to 35 minutes. After stirring for 20 minutes, 9 g (0.11 mol) of pyrrolidine dissolved in 100 ml of chloroform are dropped to the above solution at a temperature between -5° C. and -8° C. during 1 hour. The reaction mixture is stirred at the same temperature for 1 hour, then allowed to stand overnight under cooling by ice. For working up, the reaction mixture is washed 3 times with 400 ml of 5% sodium hydrogen carbonate solution each, then 3 times with 400 ml of water each. The organic phase is dried over anhydrous sodium sulfate, filtered and evaporated. After suspending the oily residue in petroleum ether, 8.3 g (32.3%) of the named compound are obtained, which forms yellow crystals after recrystallization from ethanol, m.p.: 132°-134° C.
Reaction SMILES: [NH:1]([C:3]1[CH:8]=[C:7]([C:9]#[N:10])[CH:6]=[CH:5][N:4]=1)[NH2:2].[F:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18](=O)[CH2:19][C:20](OCC)=[O:21]>>[F:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]1[CH:19]=[C:20]([OH:21])[N:1]([C:3]2[CH:8]=[C:7]([C:9]#[N:10])[CH:6]=[CH:5][N:4]=2)[N:2]=1
Reactant: CCOC(=O)CC(=O)c1ccccc1F
Reactant: N#Cc1ccnc(NN)c1
Product: N#Cc1ccnc(-n2nc(-c3ccccc3F)cc2O)c1
Yield: 48 %

Procedure:
The title compound was prepared in 48% yield from 2-hydrazinylpyridine-4-carbonitrile (PREPARATION 2) and ethyl 3-(2-fluorophenyl)-3-oxopropanoate according to the procedure for the preparation of Example 3, part A. 1H NMR (300 MHz, DMSO-d6): δ 6.15-6.17 (1H, m), 7.13-7.41 (4H, m), 8.07-8.12 (1H, m), 8.34 (1H, s), 8.48-8.50 (1H, m), 11.64 (1H, s). [M+H] Calc'd for C15H9FN4O, 281. Found, 281.
Reaction SMILES: [C:1]([OH:12])(=[O:11])/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[CH:13]([S:16][CH2:17][CH2:18]O)([CH3:15])[CH3:14]>>[C:1]([O:12][CH2:18][CH2:17][S:16][CH:13]([CH3:15])[CH3:14])(=[O:11])/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCC/C=C/C(=O)O
Reactant: CC(C)SCCO
Product: CCCCCCC/C=C/C(=O)OCCSC(C)C

Procedure:
The same operation as in Example 1-1 or 1-2 was carried out using trans-2-decenoic acid and 2-(isopropylthio)ethanol as starting materials to give the aimed compound.
Reaction SMILES: [CH3:1][S:2]([N:5]([CH3:29])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12]1[N:20]2[C:15]([CH:16]=[N:17][C:18](OS(C(F)(F)F)(=O)=O)=[N:19]2)=[CH:14][CH:13]=1)(=[O:4])=[O:3].[CH3:30][O:31][C:32]1[CH:37]=[C:36]([CH2:38][N:39]2[CH2:44][CH2:43][O:42][CH2:41][CH2:40]2)[CH:35]=[CH:34][C:33]=1[NH2:45].C(N(CC)C(C)C)(C)C.COCC(O)C>>[CH3:30][O:31][C:32]1[CH:37]=[C:36]([CH2:38][N:39]2[CH2:40][CH2:41][O:42][CH2:43][CH2:44]2)[CH:35]=[CH:34][C:33]=1[NH:45][C:18]1[N:17]=[CH:16][C:15]2=[CH:14][CH:13]=[C:12]([C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=3[N:5]([CH3:29])[S:2]([CH3:1])(=[O:4])=[O:3])[N:20]2[N:19]=1
Reactant: CN(c1ccccc1-c1ccc2cnc(OS(=O)(=O)C(F)(F)F)nn12)S(C)(=O)=O
Reactant: COc1cc(CN2CCOCC2)ccc1N
Solvent: COCC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(CN2CCOCC2)ccc1Nc1ncc2ccc(-c3ccccc3N(C)S(C)(=O)=O)n2n1
Temperature: 120 °C
Yield: 45.1 %

Procedure:
Into an 8-dram vial, Trifluoro-methanesulfonic acid 7-[2-(methanesulfonyl-methyl-amino)-phenyl]-pyrrolo[2,1-f][1,2,4]triazin-2-yl ester (88.0 mg, 0.195 mmol), 2-Methoxy-4-morpholin-4-ylmethyl-phenylamine (0.174 g, 0.782 mmol), N,N-Diisopropylethylamine (0.136 mL, 0.782 mmol), and 1-Methoxy-2-propanol (0.880 mL, 9.00 mmol) were added. The reaction mixture was heated at 120° C. for 4 hours. The solvent was removed under vacuum. The reaction mixture was purified via HPLC reverse phase chromatography with 0.1% TFA in Water and 0.1% TFA in ACN. The collected fractions were concentrated under vacuum to give a glassy solid. The solid was triturated with Et2O to give N-{2-[2-(2-Methoxy-4-morpholin-4-ylmethyl-phenylamino)-pyrrolo[2,1-f][1,2,4]triazin-7-yl]-phenyl}-N-methyl-methanesulfonamide as a yellow solid (46 mg, 37%). LCMS (E/I+) 523.15 (M+H). NMR 1H (DMSO-d6)-9.61 (s, 1H), 8.13 (d, 1H, J=8.58 Hz), 7.95-8.00 (m, 1H), 7.86 (s, 1H), 7.66-7.70 (m, 1H), 7.53-7.58 (m, 1H), 7.16 (d, 1H, J=1.72 Hz), 7.04 (d, 1H, J=4.66 Hz), 7.01 (d, 1H, J=4.66 Hz), 6.96 (d, 1H, J=8.58 Hz), 4.29 (d, 2H, J=3.50 Hz), 3.86-4.04 (m, 5H), 3.61 (t, 2H, J=11.67 Hz), 3.20 (d, 2H, J=12.84 Hz), 3.00-3.15 (m, 5H), 2.88 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][C:5](N)=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.[C-:12]#[N:13].[Na+]>[O-]S([O-])(=O)=O.[Cu+2]>[CH3:1][C:2]1[CH:8]=[CH:7][C:5]([C:12]#[N:13])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1
Reactant: [C-]#N
Reactant: Cc1ccc(N)c([N+](=O)[O-])c1
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Product: Cc1ccc(C#N)c([N+](=O)[O-])c1

Procedure:
11.75 g (77.2 mmol) of 4-methyl-2-nitroaniline underwent a Sandmeyer reaction in a conventional process by diazotization and substitution with NaCN and CuSO4 to give 9.6 g of crude 4-methyl-2-nitrobenzonitrile.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[C:7]([C:9]2[CH:10]=[C:11]3[CH:27]=[N:26][NH:25][C:12]3=[N:13][C:14]=2[C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=2)[CH:6]=[CH:5][N:4]=1.Br[CH2:29][CH2:30][CH2:31][O:32][CH:33]1[CH2:38][CH2:37][CH2:36][CH2:35][O:34]1>>[CH3:1][S:2][C:3]1[N:8]=[C:7]([C:9]2[C:14]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:23])([F:22])[F:24])[CH:16]=3)=[N:13][C:12]3=[N:25][N:26]([CH2:29][CH2:30][CH2:31][O:32][CH:33]4[CH2:38][CH2:37][CH2:36][CH2:35][O:34]4)[CH:27]=[C:11]3[CH:10]=2)[CH:6]=[CH:5][N:4]=1
Reactant: CSc1nccc(-c2cc3cn[nH]c3nc2-c2cccc(C(F)(F)F)c2)n1
Reactant: BrCCCOC1CCCCO1
Product: CSc1nccc(-c2cc3cn(CCCOC4CCCCO4)nc3nc2-c2cccc(C(F)(F)F)c2)n1

Procedure:
Following a similar procedure to that described in examples 6 and 7, but starting from 5-[2-(methylsulfanyl)pyrimidin-4-yl]-6-[3-(trifluoromethyl)phenyl]-1H-pyrazolo[3,4-b]pyridine (obtained in example 126) and 2-(3-bromopropoxy)tetrahydropyran, the title compound was obtained.
Reaction SMILES: [C:1]([N:4]1[CH2:7][C:6]2([CH2:16][C:15](=[O:17])[C:14]3[C:9](=[CH:10][CH:11]=[C:12](/[CH:18]=[CH:19]/[C:20](O)=[O:21])[CH:13]=3)[O:8]2)[CH2:5]1)(=[O:3])[CH3:2].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[NH2:37][O:38][CH:39]1[CH2:44][CH2:43][CH2:42][CH2:41][O:40]1>C(Cl)Cl>[C:1]([N:4]1[CH2:7][C:6]2([CH2:16][C:15](=[O:17])[C:14]3[C:9](=[CH:10][CH:11]=[C:12](/[CH:18]=[CH:19]/[C:20]([NH:37][O:38][CH:39]4[CH2:44][CH2:43][CH2:42][CH2:41][O:40]4)=[O:21])[CH:13]=3)[O:8]2)[CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CC2(CC(=O)c3cc(/C=C/C(=O)O)ccc3O2)C1
Reactant: NOC1CCCCO1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: ClCCl
Product: CC(=O)N1CC2(CC(=O)c3cc(/C=C/C(=O)NOC4CCCCO4)ccc3O2)C1
Yield: 30 %

Procedure:
A suspension of (E)-3-[1′-acetyl-4-oxo-spiro(chromane-2,3′-azetidine)-6-yl]-acrylic acid (100 mg, 0.30 mmol) in DCM (3 ml) was treated with TEA (0.060 ml, 0.49 mmol) and then with EDC (94 mg, 0.49 mmol), HOBt (67 mg, 0.49 mmol) and NH2OTHP (50 mg, 0.43 mmol) following the procedure described in Example 30, Step B, giving (E)-3-[1′-acetyl-4-oxo-spiro(chromane-2,3′-azetidine)-6-yl]-N-(tetrahydro-pyran-2-yloxy)-acrylamide (36 mg) as a white solid.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]([F:12])[C:5]2[C:6](=[O:9])[O:7][CH2:8][C:4]=2[CH:3]=1.[CH:13]([B-](F)(F)F)=[CH2:14].[K+]>CCO.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]>[F:12][C:10]1[C:5]2[C:6](=[O:9])[O:7][CH2:8][C:4]=2[CH:3]=[C:2]([CH:13]=[CH2:14])[CH:11]=1
Reactant: C=C[B-](F)(F)F
Reactant: O=C1OCc2cc(Br)cc(F)c21
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [K+]
Solvent: CCO
Product: C=Cc1cc(F)c2c(c1)COC2=O

Procedure:
A mixture of 5-bromo-7-fluoro-2-benzofuran-1(3H)-one (4.6 g, 20.0 mmol), potassium vinyltrifluoroborate (2.9 g, 22 mmol) and Pd(dppf)2Cl2 (0.5 g) in 40 mL of EtOH and 40 mL of TEA was refluxed under Ar for 4 hours. After concentration, the residue was purified by column chromatography (PE:EtOAc=20:1) to afford 7-fluoro-5-vinyl-2-benzofuran-1(3H)-one.
Reaction SMILES: F.[Si]([O:9][CH2:10][C:11]([N:14]1[CH2:18][CH:17]([CH2:19][O:20][C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[CH:22]=2)[O:16][C:15]1=[O:28])([CH3:13])[CH3:12])(C(C)(C)C)(C)C>C(#N)C>[Cl:27][C:23]1[CH:22]=[C:21]([CH:26]=[CH:25][CH:24]=1)[O:20][CH2:19][CH:17]1[O:16][C:15](=[O:28])[N:14]([C:11]([CH3:13])([CH3:12])[CH2:10][OH:9])[CH2:18]1
Reactant: CC(C)(CO[Si](C)(C)C(C)(C)C)N1CC(COc2cccc(Cl)c2)OC1=O
Agent: F
Solvent: CC#N
Product: CC(C)(CO)N1CC(COc2cccc(Cl)c2)OC1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.5 %

Procedure:
7 ml of a 5% w/v solution of hydrogen fluoride in acetonitrile were added dropwise to a solution of 3.84 g of 3-(2-t-butyldimethylsilyloxy-1,1-dimethylethyl)-5-(3-chlorophenoxymethyl)oxazolidin-2-one (prepared as described in Preparation 106) in 40 ml of acetonitrile, and then the mixture was stirred at room temperature for 1 hour. At the end of this time, the solvent was removed from the reaction mixture by evaporation under reduced pressure to give 2.71 g of the title compound, melting at 81° C. to 82° C.
Reaction SMILES: [F:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][CH:7]2[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH2:9][N:8]2[CH2:17][CH2:18][CH2:19][NH2:20])=[CH:4][CH:3]=1.[CH2:23]([C:25]1[CH:30]=[CH:29][C:28]([N:31]=[C:32]=[O:33])=[CH:27][CH:26]=1)[CH3:24]>>[CH2:23]([C:25]1[CH:30]=[CH:29][C:28]([NH:31][C:32]([NH:20][CH2:19][CH2:18][CH2:17][N:8]2[CH:7]([CH2:6][C:5]3[CH:21]=[CH:22][C:2]([F:1])=[CH:3][CH:4]=3)[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH2:9]2)=[O:33])=[CH:27][CH:26]=1)[CH3:24]
Reactant: NCCCN1Cc2ccccc2CC1Cc1ccc(F)cc1
Reactant: CCc1ccc(N=C=O)cc1
Product: CCc1ccc(NC(=O)NCCCN2Cc3ccccc3CC2Cc2ccc(F)cc2)cc1

Procedure:
The reaction and treatment were carried out in the same manner as in Example 208 using 3-[3-(4-fluorobenzyl)-3,4-dihydroisoquinolin-2(1H)-yl]propanamine obtained in Example 214-b) as a starting material, and using 4-ethylphenyl isocyanate instead of phenyl isocyanate to obtain a title compound as a pale yellow amorphous substance.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[C:11]([F:14])([F:13])[F:12].S(Cl)(Cl)=O.[NH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1O.C(N(C(C)C)CC)(C)C.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1COCC1.C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]2[O:8][C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[N:19]=2)=[CH:4][C:3]=1[C:11]([F:14])([F:13])[F:12]
Reactant: Nc1ccccc1O
Reactant: Cc1ccc(C(=O)O)cc1C(F)(F)F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: Cc1ccc(-c2nc3ccccc3o2)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 4-methyl-3-(trifluoromethyl)benzoic acid (1.0 g, 4.9 mmol) and thionyl chloride (15 mL) was refluxed for 3 h and then stirred at rt overnight. The excess thionyl chloride was removed in vacuo, the residue was dissolved in THF (20 mL), and it was added to a cooled (0° C.) solution of 2-aminophenol (0.53 g, 4.9 mmol) and diisopropylethylamine (1.0 mL, 5.9 mmol) in anhydrous THF (15 mL). The resulting brownish mixture was stirred at rt for 3 h. The solvent was then removed and p-toluenesulfonic acid (3.7 g, 19.6 mmol) and toluene (20 mL) were added to the dark oil. The mixture was then refluxed for 3 h and the mixture was cooled to rt. The excess p-toluenesulfonic acid was filtered through Celite and the filtrate was evaporated to dryness. The crude was purified by flash chromatography on silica gel eluting with EtOAc:hexanes (1:9) to afford 2-[4-methyl-3-(trifluoromethyl)phenyl]-1,3-benzoxazole as a colorless solid.