Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]([Cl:6])([Cl:5])[C:3]#[N:4].[CH2:7]([O:9][C:10](=[O:14])[CH2:11][C:12]#[N:13])[CH3:8]>C(O)C.C(N(CC)CC)C>[NH2:4]/[C:3](/[C:2]([Cl:6])([Cl:5])[Cl:1])=[C:11](/[C:12]#[N:13])\[C:10]([O:9][CH2:7][CH3:8])=[O:14]
Reactant: CCOC(=O)CC#N
Reactant: N#CC(Cl)(Cl)Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOC(=O)/C(C#N)=C(\N)C(Cl)(Cl)Cl
Temperature: 0 °C
Reaction time: 0.02 h
Yield: 87.3 %

Procedure:
To a mixture of trichloroacetonitrile (38 mL, 0.38 mol) and cyanoacetic acid ethyl ester (20 mL, 0.2 mol) in ethanol (63 mL) was added triethylamine (1 mL, 7 mmol). The reaction mixture began to turn red and an exotherm occurred after ˜1 minute. The reaction mixture was cooled to 0° C., then stirred for two hours while slowly warming to room temperature. The reaction mixture was concentrated in vacuo to a red oil, which was taken up in DCM, filtered through a plug of silica gel, and concentrated in vacuo to afford 44.95 g (90%) of (Z)-ethyl 3-amino-4,4,4-trichloro-2-cyanobut-2-enoate as a colorless oil that slowly solidified to a white solid. 1H NMR (400 MHz, CDCl3) δ 10.19 (s, 1H), 6.85 (s, 1H), 4.31 (q, J=7.1, 1H), 1.37 (t, J=7.1, 3H).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]([N:11]2[C:16](=[O:17])[C:15]([CH2:18][C:19]3[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=3)=[N:14][C:13]3[CH:25]=[CH:26][CH:27]=[N:28][C:12]2=3)[CH:8]=[CH:9][CH:10]=1)=[O:4].[ClH:29]>>[ClH:29].[C:3]([C:5]1[CH:6]=[C:7]([N:11]2[C:16](=[O:17])[C:15]([CH2:18][C:19]3[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=3)=[N:14][C:13]3[CH:25]=[CH:26][CH:27]=[N:28][C:12]2=3)[CH:8]=[CH:9][CH:10]=1)([OH:4])=[O:2]
Reactant: COC(=O)c1cccc(-n2c(=O)c(Cc3cccnc3)nc3cccnc32)c1
Agent: Cl
Product: O=C(O)c1cccc(-n2c(=O)c(Cc3cccnc3)nc3cccnc32)c1

Procedure:
A mixture of 4-(3-methoxycarbonylphenyl)-2-(3-pyridylmethyl)-3-oxo-3,4-dihydropyrido[2,3-b]pyrazine (0.29 g) and 4N hydrochloric acid (18 ml) was stirred under reflux for 2 hours. After evaporation of the solvent, crude residue was chromatographed on silica gel (29 g, chloroform-methanol 9:1 as eluent) and crystallized from methanol to afford 4-(3-carboxyphenyl)-2-(3-pyridylmethyl)-3-oxo-3,4-dihydropyrido[2,3-b]pyrazine.hydrochloride as colorless crystal (0.29 g)
Reaction SMILES: C(S[CH:5]1[N:8]([C:9](=[C:23]([O:30][C:31]2[C:40]3[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=3)[CH:34]=[CH:33][CH:32]=2)[C:24](=[O:29])[C:25]([CH3:28])([CH3:27])[CH3:26])[C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=2)=[S:11])[C:7](=[O:41])[CH2:6]1)C=C.[Cl:42]Cl>ClCCl.C(Cl)(Cl)(Cl)Cl>[Cl:42][CH:5]1[N:8]([C:9](=[C:23]([O:30][C:31]2[C:40]3[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=3)[CH:34]=[CH:33][CH:32]=2)[C:24](=[O:29])[C:25]([CH3:28])([CH3:27])[CH3:26])[C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=2)=[S:11])[C:7](=[O:41])[CH2:6]1
Reactant: C=CCSC1CC(=O)N1C(C(=S)OCc1ccc([N+](=O)[O-])cc1)=C(Oc1cccc2ccccc12)C(=O)C(C)(C)C
Reactant: ClCl
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClCCl
Product: CC(C)(C)C(=O)C(Oc1cccc2ccccc12)=C(C(=S)OCc1ccc([N+](=O)[O-])cc1)N1C(=O)CC1Cl
Temperature: 25 °C
Yield: 73.7 %

Procedure:
To a solution of 7.1 g of 4-nitrobenzyl 2-(4-allylthioazetidin-2-on-1-yl)-3-(1-naphthyloxy)-3-trimethylacetylthiopropenate in dichloromethane at -20° was added a solution of 23 mmol of chlorine in carbon tetrachloride. After 30 minutes the mixture was warmed to room temperature, evaporated in vacuo, and the residual oil was chromatographed over silica gel. Elution with hexane-ethyl acetate mixtures afforded 4.898 g of the title compound as a pale yellow foam (75% of the theoretical yield).
Reaction SMILES: [C:1]1([P:7](=[O:12])([O:10][CH3:11])OC)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:13][C:14](=[CH2:19])[C:15]([O:17][CH3:18])=[O:16].C1(O)C=CC=CC=1>>[C:1]1([P:7]([O:10][CH3:11])([CH2:19][CH:14]([Cl:13])[C:15]([O:17][CH3:18])=[O:16])=[O:12])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COP(=O)(OC)c1ccccc1
Reactant: C=C(Cl)C(=O)OC
Solvent: Oc1ccccc1
Product: COC(=O)C(Cl)CP(=O)(OC)c1ccccc1
Yield: 90.1 %

Procedure:
138 g of dimethyl phenylphosphonate are slowly added at 20° C. under nitrogen to a solution of 120.5 g of methyl 2-chloroacrylate and 94 g of phenol. After a reaction time of 3 hours at 70° C. phenetole is removed by vacuum distillation. The residue represents 267 g of crude product with a 93.0% purity, which corresponds to a theoretical yield of 90.1%.
Reaction SMILES: [F:1][C:2]1[C:3]([C:33]2[S:37][C:36]([C:38]3([OH:42])[CH2:41][CH2:40][CH2:39]3)=[N:35][CH:34]=2)=[C:4]2[CH:10]=[C:9]([C:11]3[CH:16]=[C:15]([O:17][CH3:18])[C:14]([O:19][CH3:20])=[C:13]([O:21][CH3:22])[CH:12]=3)[N:8](S(C3C=CC(C)=CC=3)(=O)=O)[C:5]2=[N:6][CH:7]=1.Cl>CO.[OH-].[Na+]>[F:1][C:2]1[C:3]([C:33]2[S:37][C:36]([C:38]3([OH:42])[CH2:41][CH2:40][CH2:39]3)=[N:35][CH:34]=2)=[C:4]2[CH:10]=[C:9]([C:11]3[CH:16]=[C:15]([O:17][CH3:18])[C:14]([O:19][CH3:20])=[C:13]([O:21][CH3:22])[CH:12]=3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: COc1cc(-c2cc3c(-c4cnc(C5(O)CCC5)s4)c(F)cnc3n2S(=O)(=O)c2ccc(C)cc2)cc(OC)c1OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1cc(-c2cc3c(-c4cnc(C5(O)CCC5)s4)c(F)cnc3[nH]2)cc(OC)c1OC
Temperature: 25 °C

Procedure:
1-(5-(5-fluoro-1-tosyl-2-(3,4,5-trimethoxyphenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)thiazol-2-yl)cyclobutanol (Example 90A) (103 mg, 0.169 mmol) in methanol (2.50 mL) and 2N aqueous sodium hydroxide solution (830 μL) was heated by microwave irradiation (Biotage, Initiator) to 120° C. for 30 minutes. The reaction was cooled to room temperature, and the pH was adjusted to ˜3 with 10% aqueous HCl solution. The resulting solution was purified by reverse phase high performance liquid chromatography (RP HPLC, eluting with a gradient of 5% B in A to 75% B in A over 25 minutes, wherein A is water containing 0.1% v/v ammonium acetate and B is acetonitrile) to give the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 12.48 (bs, 1H), 8.80 (s, 1H), 8.29 (d, J=2.0 Hz, 1H), 8.37 (m, 3H), 6.69 (s, 1H), 3.91 (s, 6H), 3.71 (s, 3H), 2.64-2.55 (m, 2H), 2.45-2.35 (m, 2H), 2.05-1.92 (m, 2H); MS ESI(+) m/z 456.1 [M+H]+.
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:17])[C:7]([C:14]([OH:16])=[O:15])=[CH:8][N:9]2[CH2:12][CH3:13])=[CH:4][C:3]=1[F:18].C(OC([NH:26][C@H:27]1[C@@H:31]([CH3:32])[CH2:30][NH:29][CH2:28]1)=O)(C)(C)C.C1CCN2C(=NCCC2)CC1>C(#N)C>[NH2:26][C@H:27]1[C@@H:31]([CH3:32])[CH2:30][N:29]([C:2]2[CH:11]=[C:10]3[C:5]([C:6](=[O:17])[C:7]([C:14]([OH:16])=[O:15])=[CH:8][N:9]3[CH2:12][CH3:13])=[CH:4][C:3]=2[F:18])[CH2:28]1
Reactant: C[C@H]1CNC[C@H]1NC(=O)OC(C)(C)C
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(Cl)cc21
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3C[C@@H](N)[C@@H](C)C3)cc21
Yield: 0.6 %

Procedure:
A mixture of 7-chloro-1-ethyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (1.0 g), cis-3-t-butoxycarbonylamino-4-methylpyrrolidine (0.89 g), DBU (0.62 g) and anhydrous acetonitrile (30 ml) was refluxed for 27 hours. Then, the reacting mixture was treated as described in example 33 and recrystallized from chloroform-methanol-concentrated aqueous ammonia (20:20:1) to give the title compound (0.008 g) as white powder, mp 300~° C. (decompd.).
Reaction SMILES: [CH:1]1([CH:7]([NH:19][C:20]2[CH:21]=[CH:22][C:23]([C:26]([NH:28][CH2:29][CH2:30][C:31]([O:33]CC)=[O:32])=[O:27])=[N:24][CH:25]=2)[C:8]2[O:9][C:10]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:11]=3[C:12]=2[CH3:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O1CCCC1.[OH-].[Na+]>C(O)C>[CH:1]1([CH:7]([NH:19][C:20]2[CH:21]=[CH:22][C:23]([C:26]([NH:28][CH2:29][CH2:30][C:31]([OH:33])=[O:32])=[O:27])=[N:24][CH:25]=2)[C:8]2[O:9][C:10]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:11]=3[C:12]=2[CH3:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)CCNC(=O)c1ccc(NC(c2oc3ccc(F)cc3c2C)C2CCCCC2)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1c(C(Nc2ccc(C(=O)NCCC(=O)O)nc2)C2CCCCC2)oc2ccc(F)cc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.3 %

Procedure:
To a mixture of ethyl 3-{[(5-{[cyclohexyl(5-fluoro-3-methyl-1-benzofuran-2-yl)methyl]amino}pyridin-2-yl)carbonyl]amino}propanoate (361 mg) synthesized above, tetrahydrofuran (5 mL) and ethanol (5 mL) was added 1N aqueous sodium hydroxide solution (2.00 mL), and the mixture was stirred at room temperature for 1 hr, and concentrated under reduced pressure. The residue was dissolved in water (10 mL), and 1N hydrochloric acid (2.00 mL) was added at 0° C. The resulting precipitate was collected by filtration to give the title object compound (324 mg, 95%) as a white solid.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.[C:6]1(=[O:11])[CH2:10][CH2:9][CH:8]=[CH:7]1.O>C(Cl)Cl>[N:1]1([CH:8]2[CH2:9][CH2:10][C:6](=[O:11])[CH2:7]2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: O=C1C=CCC1
Reactant: c1cn[nH]c1
Solvent: O
Solvent: ClCCl
Product: O=C1CCC(n2cccn2)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93.9 %

Procedure:
A mixture of pyrazole (6.85 g, 100 mmol), 2-cyclopenten-1-one (19.3 g, 235 mmol) and ScCl3 (1.42 g, 9.38 mmol) in anhydrous CH2Cl2 (3 mL) was stirred at room temperature for 30 min. The reaction mixture was poured into water and then extracted with CH2Cl2. The organic layer was washed with brine, and dried over anhyd Na2SO4 followed by the removal of solvent. The crude product was purified by column chromatography (Hexane/EtOAc=4/1) to yield 3-(1H-pyrazol-1-yl)cyclopentan-1-one (14.1 g, 94%) as yellow oil.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[N:8]=[C:7]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-:22])=[O:21])[CH:15]=1)[N:6]=[C:5]2[NH:23][C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][CH:32]=1)[N:29]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[N:28]=[CH:27]2.Cl[CH2:41][CH2:42][CH2:43][N:44]1[CH2:49][CH2:48][O:47][CH2:46][CH2:45]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH3:13][O:12][C:11]1[CH:10]=[C:9]2[C:4]([C:5]([NH:23][C:24]3[CH:25]=[C:26]4[C:30](=[CH:31][CH:32]=3)[N:29]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[N:28]=[CH:27]4)=[N:6][C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-:22])=[O:21])[CH:15]=3)=[N:8]2)=[CH:3][C:2]=1[O:1][CH2:41][CH2:42][CH2:43][N:44]1[CH2:49][CH2:48][O:47][CH2:46][CH2:45]1
Reactant: COc1cc2nc(-c3cccc([N+](=O)[O-])c3)nc(Nc3ccc4c(cnn4C(=O)OC(C)(C)C)c3)c2cc1O
Reactant: ClCCCN1CCOCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2nc(-c3cccc([N+](=O)[O-])c3)nc(Nc3ccc4c(cnn4C(=O)OC(C)(C)C)c3)c2cc1OCCCN1CCOCC1
Temperature: 80 °C

Procedure:
A mixture of tert-Butyl 5-(6-hydroxy-7-methoxy-2-(3-nitrophenyl)quinazolin-4-ylamino)-1H-indazole-1-carboxylate (0.70 g, 1.32 mmol), 4-(3-chloropropyl)morpholine (0.32 g, 1.96 mmol) and K2CO3 (1.33 g, 9.62 mmol) in DMF (10 mL) was heated at 80° C. for 2.5 h. The mixture was allowed to cool to RT and the volatiles were removed in vacuo. The crude product was purified by column chromatography (SiO2, CH2Cl2 97:3 to 94:6 to 90:10) to give the desired compound tert-butyl 5-(7-methoxy-6-(3-morpholinopropoxy)-2-(3-nitrophenyl)quinazolin-4-ylamino)-1H-indazole-1-carboxylate. HPLC retention time (5.76 min).
Reaction SMILES: Cl[C:2]1[C:3]2[S:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[C:4]=2[N:5]=[N:6][N:7]=1.[CH3:15][O-:16].[Na+]>CO>[CH3:15][O:16][C:2]1[C:3]2[S:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[C:4]=2[N:5]=[N:6][N:7]=1
Reactant: Clc1nnnc2c1sc1ccccc12
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1nnnc2c1sc1ccccc12

Procedure:
A 2.2 g. portion of the product of Example 1 was stirred at reflux temperature in 100 ml. of methanol with 0.7 g. of sodium methoxide for one hour. When the reaction mixture was cooled, the product, 1.9 g. of 4-methoxy[1]-benzothieno[3,2-d]-v-triazine, m.p. 165°-167° C., crystallized and needed no further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:17](=[O:18])[C:16]2[C:11](=[N:12][C:13](S(C)=O)=[N:14][CH:15]=2)[N:10]2[CH:22]=[CH:23][N:24]=[C:9]12.[NH2:25][C:26]1[CH:31]=[CH:30][C:29]([CH:32]2[CH2:36][CH2:35][N:34](C(OC(C)(C)C)=O)[CH2:33]2)=[CH:28][CH:27]=1.[F:44][C:45]([F:50])([F:49])[C:46]([OH:48])=[O:47]>C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:17](=[O:18])[C:16]2[CH:15]=[N:14][C:13]([NH:25][C:26]3[CH:27]=[CH:28][C:29]([CH:32]4[CH2:36][CH2:35][NH:34][CH2:33]4)=[CH:30][CH:31]=3)=[N:12][C:11]=2[N:10]2[CH:22]=[CH:23][N:24]=[C:9]12.[F:44][C:45]([F:50])([F:49])[C:46]([OH:48])=[O:47]
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(N)cc2)C1
Reactant: CS(=O)c1ncc2c(=O)n(-c3ccccc3Cl)c3nccn3c2n1
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: O=c1c2cnc(Nc3ccc(C4CCNC4)cc3)nc2n2ccnc2n1-c1ccccc1Cl
Temperature: 35 °C
Reaction time: 5 h

Procedure:
A mixture of Example 1E (0.048 g, 0.133 mmol) and tert-butyl 3-(4-aminophenyl)pyrrolidine-1-carboxylate (0.056 g, 0.213 mmol) was heated in a capped vial at 90° C. for 1 hour. The reaction mixture was treated with ethyl acetate and washed with saturated aqueous NaHCO3. The organic layer was dried over MgSO4, filtered, and concentrated. The residue was dissolved in CH2Cl2 (2 mL) and treated with trifluoroacetic acid (0.103 ml, 1.334 mmol). The mixture was stirred at 35° C. for 5 hrs, concentrated, and purified by HPLC (see protocol in Example 1F) to provide the title compound as a trifluoroacetic acid salt. 1H NMR (500 MHz, CD3OD) δ 2.24-2.05 (m, 1H), 2.49 (dtd, J=10.2, 7.1, 3.1 Hz, 1H), 3.21 (dd, J=24.8, 13.8 Hz, 1H), 3.46-3.37 (m, 1H), 3.61-3.52 (m, 2H), 3.73 (dd, J=11.4, 7.9 Hz, 1H), 7.07 (d, J=1.8 Hz, 1H), 7.40-7.39 (m, 2H), 7.62-7.51 (m, 3H), 7.73-7.66 (m, 1H), 7.86-7.81 (m, 3H), 9.15 (s, 1H). MS (ESI+) m/z 458.2 (M+H)+.
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][C:10]([N+:13]([O-])=O)=[CH:9][C:8]=2[C:16]#[C:17][C:18]2[CH:19]=[C:20]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[CH:21]=[CH:22][CH:23]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1>CO.[Pd]>[NH2:13][C:10]1[CH:11]=[CH:12][C:7]([N:1]2[CH2:2][CH2:3][O:4][CH2:5][CH2:6]2)=[C:8]([CH2:16][CH2:17][C:18]2[CH:19]=[C:20]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[CH:21]=[CH:22][CH:23]=2)[CH:9]=1
Reactant: CC(C)(C)OC(=O)Nc1cccc(C#Cc2cc([N+](=O)[O-])ccc2N2CCOCC2)c1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)Nc1cccc(CCc2cc(N)ccc2N2CCOCC2)c1
Reaction time: 48 h
Yield: 93.5 %

Procedure:
A solution of tert-butyl {3-[(2-morpholin-4-yl-5-nitrophenyl)ethynyl]phenyl}carbamate (0.33 g, 0.78 mmol) in methanol (20 mL) was degassed with nitrogen, treated with 10% palladium on carbon (wet Degussa type) (0.33 g, 100 wt %), degassed with nitrogen, and shaken under an atmosphere of hydrogen (50 psi) for 48 h. The reaction mixture was filtered over celite and the filtrate concentrated to give the desired product (0.29 g, 92%) which was used without further purification. LCMS for C23H32N3O3 (M+H)+: m/z=398.1.
Reaction SMILES: C(OC([NH:8][C:9]1[CH:29]=[CH:28][CH:27]=[C:26]([CH3:30])[C:10]=1[CH2:11][O:12][C:13]1[C:14]2[N:15]([C:19]([CH2:23][C:24]#[CH:25])=[C:20]([CH3:22])[N:21]=2)[CH:16]=[CH:17][CH:18]=1)=O)(C)(C)C.[Cl-]>C(O)C.C(OCC)C>[NH2:8][C:9]1[CH:29]=[CH:28][CH:27]=[C:26]([CH3:30])[C:10]=1[CH2:11][O:12][C:13]1[C:14]2[N:15]([C:19]([CH2:23][C:24]#[CH:25])=[C:20]([CH3:22])[N:21]=2)[CH:16]=[CH:17][CH:18]=1
Reactant: C#CCc1c(C)nc2c(OCc3c(C)cccc3NC(=O)OC(C)(C)C)cccn12
Agent: [Cl-]
Solvent: CCO
Solvent: CCOCC
Product: C#CCc1c(C)nc2c(OCc3c(C)cccc3N)cccn12
Temperature: 25 °C
Reaction time: 3 h
Yield: 74.1 %

Procedure:
To a solution of 8-(2-t-butoxycarbonylamino-6-methylbenzyloxy)-2-methyl-3-(2-propynyl)imidazo[1,2-a]pyridine (1.04 g) in ethanol (15.5 ml) was added dropwise 25% ethanolichydrogen chloride (8.4 ml) with ice-cooling. After being stirred for 3 hours at ambient temperature, the mixture was diluted with diethyl ether. The resulting precipitates were collected by filtration, treated with a saturated aqueous solution of sodium hydrogen carbonate and extracted with methylene chloride. The extract was washed with water, dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was triturated with diethyl ether to give 8-(2-amino-6-methylbenzyloxy)-2-methyl-3-(2-propynyl)imidazo[1,2-a]pyridine (0.58 g).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([F:8])=[N:6][CH:7]=1.C([Mg]Cl)(C)C.Cl.[NH2:15][C:16]1[N:27]=[CH:26][C:25]([Br:28])=[CH:24][C:17]=1[C:18](N(OC)C)=[O:19]>C1COCC1>[NH2:15][C:16]1[C:17]([C:18]([C:2]2[CH:7]=[N:6][C:5]([F:8])=[CH:4][CH:3]=2)=[O:19])=[CH:24][C:25]([Br:28])=[CH:26][N:27]=1
Reactant: CON(C)C(=O)c1cc(Br)cnc1N
Reactant: Fc1ccc(Br)cn1
Agent: CC(C)[Mg]Cl
Agent: Cl
Solvent: C1CCOC1
Product: Nc1ncc(Br)cc1C(=O)c1ccc(F)nc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 43.5 %

Procedure:
To a solution of 5-bromo-2-fluoropyridine (5.6 ml, 54.2 mmol) in THF (50 ml) at 0° C. under nitrogen was added dropwise a 2 M solution of iso-propylmagnesium chloride in THF (27 ml) over a period of 10 minutes. The ice bath was removed and the reaction mixture was stirred at room temperature for 2 hours. The resulting slurry was added dropwise via cannula to a solution of 2-amino-5-bromo-N-methoxy-N-methyl-nicotinamide hydrochloride (3.0 g, 11.5 mmol) in THF (50 ml) at room temperature under nitrogenover a period of 30 minutes. After stirring for 3 hours, the reaction was quenched by addition of a saturated aqueous solution of ammonium chloride (50 ml) at 0° C. and the mixture was stirred at room temperature for another 20 minutes. Water was added and the mixture was extracted with ethyl acetate (three times). The combined organic layers were dried over sodium sulfate, then filtered and concentrated. Crystallization from methanol (ca. 60 ml) afforded the title compound as dark yellow crystals (1.48 g, 49% yield). 1H NMR (DMSO-d6): δ 8.49 (s, 1H), 8.34 (d, J=1.5 Hz, 1H), 8.23 (dt, J=2.5, 8.0 Hz, 1H), 7.81 (d, J=2.5 Hz, 1H), 7.74 (broad s, 2H), 7.36 (dd, J=2.0, 8.0 Hz, 1H); MS: m/z 295.9, 297.9 [MH]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:18]=[CH:19][C:20]([CH2:23][N:24]4[CH2:27][CH:26]([C:28]([O:30]C)=[O:29])[CH2:25]4)=[N:21][CH:22]=3)[N:13]=2)[CH:5]=[CH:6][C:7]=1[CH2:8][CH:9]([CH3:11])[CH3:10].[OH-].[Na+]>>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:18]=[CH:19][C:20]([CH2:23][N:24]4[CH2:25][CH:26]([C:28]([OH:30])=[O:29])[CH2:27]4)=[N:21][CH:22]=3)[N:13]=2)[CH:5]=[CH:6][C:7]=1[CH2:8][CH:9]([CH3:10])[CH3:11]
Reactant: COC(=O)C1CN(Cc2ccc(-c3noc(-c4ccc(CC(C)C)c(Cl)c4)n3)cn2)C1
Agent: [Na+]
Agent: [OH-]
Product: CC(C)Cc1ccc(-c2nc(-c3ccc(CN4CC(C(=O)O)C4)nc3)no2)cc1Cl
Yield: 87.8 %

Procedure:
The title compound (0.12 g) was synthesized in a yield of 90% as a white crystalline solid by conducting the reaction similar to that mentioned in Example 3 (3e) using methyl 1-({5-[5-(3-chloro-4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]pyridin-2-yl}methyl)azetidine-3-carboxylate (0.14 g, 0.32 mmol) that was obtained in Example 26 (26b) and a 1 N aqueous solution of sodium hydroxide (0.96 mL, 0.96 mmol).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=[O:14])=[CH:11][C:10]=1[O:17][CH3:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[I:19]I>FC(F)(F)C([O-])=O.[Ag+].C(Cl)Cl>[CH2:1]([O:8][C:9]1[C:10]([O:17][CH3:18])=[CH:11][C:12]([CH:13]=[O:14])=[C:15]([I:19])[CH:16]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: II
Reactant: COc1cc(C=O)ccc1OCc1ccccc1
Agent: [Ag+]
Agent: O=C([O-])C(F)(F)F
Solvent: ClCCl
Product: COc1cc(C=O)c(I)cc1OCc1ccccc1
Reaction time: 2 h
Yield: 86.9 %

Procedure:
To a mixture of 4-benzyloxy-3-methoxybenzaldehyde (10 g), silver trifluoroacetate (11.4 g) and methylene chloride (105 mL) was added iodine (13.1 g) at room temperature. After stirring for 2 hours, the mixture was passed through a layer of Celite (registered mark). The filtrate was washed with an aqueous solution of sodium hydrogen sulfite and brine successively, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was triturated with methanol:water=4:1 to give the title compound (13.2 g).
Reaction SMILES: [CH:1]([C:4]1[CH:11]=[CH:10][CH:9]=[C:8]([CH3:12])[C:5]=1[CH:6]=[O:7])([CH3:3])[CH3:2].[BH4-].[Na+]>CO>[CH:1]([C:4]1[CH:11]=[CH:10][CH:9]=[C:8]([CH3:12])[C:5]=1[CH2:6][OH:7])([CH3:3])[CH3:2]
Reactant: Cc1cccc(C(C)C)c1C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Cc1cccc(C(C)C)c1CO
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.5 %

Procedure:
To a solution of 2-isopropyl-6-methylbenzaldehyd (1.75 g, 10.8 mmol) in methanol (15 ml) was added sodium borohydride (0.35 g, 9.5 mmol) and the mixture was stirred 1 h. at room temperature. The solvent was evaporated under reduced pressure and to the residue was added hexane and water. The organic layer was separated and evaporated under reduced pressure to give 1.73 g (98%) of the title compound as an oil.
Reaction SMILES: [I:1][C:2]1[CH:12]=[N:11][C:5]2[NH:6][CH2:7][C:8](=[O:10])[NH:9][C:4]=2[CH:3]=1.[Cl:13][C:14]1[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][C:15]=1[CH2:16]Br>>[Cl:13][C:14]1[CH:21]=[CH:20][C:19]([C:22]([F:23])([F:24])[F:25])=[CH:18][C:15]=1[CH2:16][N:9]1[C:8](=[O:10])[CH2:7][NH:6][C:5]2[N:11]=[CH:12][C:2]([I:1])=[CH:3][C:4]1=2
Reactant: FC(F)(F)c1ccc(Cl)c(CBr)c1
Reactant: O=C1CNc2ncc(I)cc2N1
Product: O=C1CNc2ncc(I)cc2N1Cc1cc(C(F)(F)F)ccc1Cl
Yield: 39 %

Procedure:
7-Iodo-3,4-dihydro-1H-pyrido[2,3-b]pyrazin-2-one (924 mg) was reacted with 2-chloro-5-(trifluoromethyl)benzyl bromide as in General Procedure 1 to give the title compound as a white solid (39% yield). M.p. 252-253° C., LCMS: m/z=468.02 (M+H+), 1H-NMR (DMSO-d6, 400 MHz) δ 4.16 (d, J=1.2 Hz, 2H), 5.16 (s, 2H), 7.20 (s, 1H), 7.26 (d, J=1.3 Hz, 1H), 7.42 (s, 1H), 7.71 (dd, J=8.3 Hz, 1.5 Hz, 1H), 7.77 (d, J=8.6 Hz, 1H), 7.83 (d, J=1.5 Hz, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][C:8](=O)[NH:7][C:6]=2[C:12]=1[CH3:13]>O1CCCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][CH2:8][NH:7][C:6]=2[C:12]=1[CH3:13]
Reactant: Cc1c(Br)ccc2c1NC(=O)CO2
Solvent: C1CCOC1
Product: Cc1c(Br)ccc2c1NCCO2
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
An ice cold mixture of 6-bromo-5-methyl-2H-1,4-benzoxazin-3(4H)-one (3.05 g, 12.59 mmol) in tetrahydrofuran (THF) (40 mL) was treated with borane tetrahydrofuran complex (1.0 M solution in tetrahydrofuran (18.88 mL, 18.88 mmol) and the mixture was stirred at ambient temperature for 150 minutes. The mixture was cooled to 0° C. and then quenched slowly with 1N NaOH (30 mL). The mixture was extracted with ethyl acetate, then washed with 1N NaOH, dried over sodium sulfate, filtered and then concentrated to a thick dark brown oil. The material was purified on silica gel (95:4:1 dichloromethane/methanol/ammonium hydroxide, gradient) to afford an off-white solid: 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 6.87 (d, J=8.6 Hz, 1 H), 6.57 (d, J=8.8 Hz, 1 H), 4.31-4.15 (m, 2 H), 3.56-3.38 (m, 2 H), 2.22 (s, 3 H); LC/MS (m/z) ES+=228 (M+1).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7]([OH:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.F[C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[C:18]([CH3:25])[C:17]=1[F:26]>CCOC(C)=O>[CH2:7]([O:14][C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[C:18]([CH3:25])[C:17]=1[F:26])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: OCc1ccccc1
Reactant: Cc1c([N+](=O)[O-])ccc(F)c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: Cc1c([N+](=O)[O-])ccc(OCc2ccccc2)c1F
Temperature: 180 °C

Procedure:
To a suspension of potassium carbonate (19.2 g, 138 mmol) and benzyl alcohol (22 mL) is added 1,2-difluoro-3-methyl-4-nitrobenzene (12 g, 69 mmol, ref. WO2007121416) and the mixture is heated to 180° C. for 2 h. The reaction mixture is then diluted with EtOAc and washed with water. The organic layer is concentrated and the residue is separated with FCC (EtOAc/heptane from 0 to 20%) to give 1-benzyloxy-2-fluoro-3-methyl-4-nitrobenzene. 1H NMR (400 MHz, MeOD) δ ppm 7.87 (dd, J=9.35, 2.02 Hz, 1 H), 7.44-7.47 (m, 2 H), 7.32-7.41 (m, 3 H), 7.17 (t, J=8.72 Hz, 1 H), 5.26 (s, 2 H), 2.49 (d, J=2.78 Hz, 3 H).