Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][C:20]=1[CH:21]=[CH:22][C:23]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[NH:25][N:24]=1)[C:15]([OH:17])=[O:16].C(N(CC)CC)C.[N+:39](C1C=CC=C2C(OC(=O)C=12)=O)([O-:41])=[O:40]>C1(C)C(C)=CC=CC=1>[NH:25]1[C:26]2[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:23](/[CH:22]=[CH:21]/[C:20]2[CH:19]=[CH:18][C:14]([C:15]([OH:17])=[O:16])=[CH:13][C:12]=2[N:3]2[C:2](=[O:1])[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][C:9]=3[N+:39]([O-:41])=[O:40])[C:4]2=[O:11])=[N:24]1
Reactant: O=C1OC(=O)c2c1cccc2[N+](=O)[O-]
Reactant: O=C(O)c1ccc(C=Cc2n[nH]c3ccccc23)c(N2C(=O)c3ccccc3C2=O)c1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1C
Product: O=C(O)c1ccc(/C=C/c2n[nH]c3ccccc23)c(N2C(=O)c3cccc([N+](=O)[O-])c3C2=O)c1
Temperature: 140 °C

Procedure:
To 3-amino-4-[2-(1H-indazol-3-yl)vinyl]benzoic acid (1.7 g, 6.2 mmol) obtained in Step 2 of Example 276, xylene (55 mL), triethylamine (0.45 mL, 3.1 mmol), 3-nitrophthalic anhydride (1.4 g, 7.4 mmol), molecular sieves 3A (2.0 g) were added, followed by heating at 140° C. for 4 hours. Molecular sieves 3A was filtered off and the reaction mixture was acidified by hydrochloric acid (2 mol/L). The precipitated crystal was collected by filtration to obtain (E)-4-[2-(1H-indazol-3-yl)vinyl]-3-(4-nitro-1,3-dioxo-1,3-dihydroisoindol-2-yl)benzoic acid.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][O:9][NH2:10])[CH2:3][CH2:2]1.[NH2:11][C:12]1[N:13]=[C:14]([CH3:31])[C:15]2[C:21](=S)[NH:20][C@@H:19]([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=3[Br:30])[CH2:18][C:16]=2[N:17]=1>C1(C)C=CC=CC=1>[O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][O:9]/[N:10]=[C:21]2\[NH:20][C@@H:19]([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=3[Br:30])[CH2:18][C:16]3[N:17]=[C:12]([NH2:11])[N:13]=[C:14]([CH3:31])[C:15]\2=3)[CH2:3][CH2:2]1
Reactant: Cc1nc(N)nc2c1C(=S)N[C@@H](c1ccc(F)cc1Br)C2
Reactant: NOCCN1CCOCC1
Solvent: Cc1ccccc1
Product: Cc1nc(N)nc2c1/C(=N/OCCN1CCOCC1)N[C@@H](c1ccc(F)cc1Br)C2
Temperature: 25 °C
Yield: 100 %

Procedure:
To a solution of O-(2-morpholinoethyl)hydroxylamine (600 mg, 4.1 mmol) in anhydrous toluene (6 mL) was added (R)-2-amino-7-(2-bromo-4-fluorophenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidine-5(6H)-thione (0.150 g, 0.41 mmol) and mercuric acetate (II) (262 mg, 0.82 mmol). The resultant mixture was heated to 100° C. for 1 h. The reaction was allowed to cool to r.t. and filtered through a pad of Celite, rinsing with EtOAc and CH3OH. The filtrate was concentrated to provide a yellow-green oil, which was purified by preparative HPLC eluting with TFA/ACN/H2O. The fractions were concentrated to provide (R,Z)-2-amino-7-(2-bromo-4-fluorophenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-one O-2-morpholinoethyl oxime (196 mg, 0.41 mmol). [M+H] calc'd for C20H24BrFN6O2, 480. found, 480.
Reaction SMILES: [C:1]([OH:16])(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].C(C1NC=CN=1)(C1NC=CN=1)=O.[CH3:29][N:30]([NH2:32])[CH3:31]>O1CCCC1>[CH3:29][N:30]([CH3:31])[NH:32][C:1](=[O:16])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CN(C)N
Reactant: CCCCCCCCCCCCCC(=O)O
Agent: O=C(c1ncc[nH]1)c1ncc[nH]1
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCC(=O)NN(C)C

Procedure:
690 mg (3 meq) of myristic acid and 486 mg (3 meq) of carbonyl diimidazole are reacted in a minimum volume of tetrahydrofuran at room temperature for 1 hour. Unsym-dimethylhydrazine (0.23 ml, 3 meq) is added and reacted overnight at room temperature. The reaction mixture is evaporated under reduced pressure, dried in vacuo and purified on a silica gel column using CH2Cl2 :CH3OH (5:1). The fractions having R6 0.76 on TLC S.G. CH2Cl2 :CH3OH (5:1) chlorine-peptide spray are combined, evaporated under reduced pressure and dried in vacuo to yield 185 mg of title compound having a m.p. of 63.5°-64.5° C.
Reaction SMILES: COC1C=C(C(C2C=CC(OC)=C(OC)C=2)=CC(OC)=O)C=CC=1OC.[CH3:27][O:28][C:29]1[CH:30]=[C:31]([CH:40]=[CH:41][C:42]=1[O:43][CH3:44])[C:32]([C:34]1[CH:39]=[CH:38][N:37]=[CH:36][CH:35]=1)=O.C(OP([CH2:53][C:54]#[N:55])(=O)OCC)C.C[Si](C)(C)[N-][Si](C)(C)C.[Li+]>CCCCCC>[CH3:27][O:28][C:29]1[CH:30]=[C:31]([C:32]([C:34]2[CH:39]=[CH:38][N:37]=[CH:36][CH:35]=2)=[CH:53][C:54]#[N:55])[CH:40]=[CH:41][C:42]=1[O:43][CH3:44]
Reactant: CCOP(=O)(CC#N)OCC
Reactant: COc1ccc(C(=O)c2ccncc2)cc1OC
Agent: COC(=O)C=C(c1ccc(OC)c(OC)c1)c1ccc(OC)c(OC)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CCCCCC
Product: COc1ccc(C(=CC#N)c2ccncc2)cc1OC

Procedure:
3-(3,4-Dimethoxyphenyl)-3-pyridin-4-ylacrylonitrile was prepared analogously to methyl 3,3-bis-(3',4'-dimethoxyphenyl)acrylate using 4-(3,4-dimethoxybenzoyl)pyridine (1 g, 4 mmol), diethylcyanomethylphosphonate (0.73 mL, 4.4 mmol) and lithium hexamethyldisilazide (3.4 mL, 4.4 mmol, 1.3M) with a reaction time of 24 hours at room temperature. The crude product was slurried in 10 mL of hexane. The mixture was filtered, the solid was washed with hexane, air dried and then dried in vacuo to afford 0.91 g (85%) of a mixture of the E and Z isomers as an off white solid: mp 116-125° C.; 1H NMR (CDCl3) δ 8.80-8.63 (m, 4H), 7.40-7.20 (m, 4H), 7.04-6.74 (m, 6H), 5.81 (s, 1H), 5.70 (s, 1H), 3.94 (s, 3H), 3.92 (s, 3H), 3.87 (s, 3H), 3.84 (s, 3H); 13C NMR (CDCl3) δ 160.1, 157.0, 151.6, 151.1, 150.3, 149.2, 148.9, 146.7, 144.9, 129.6, 127.8, 123.7, 123.1, 122.7, 122.1, 117.4, 117.1, 112.3, 111.0, 110.5, 96.1, 94.8, 56.0, 56.0; Anal. Calcd for C16H14N2O2. Theoretical: C, 72.17; H, 5.30; N, 10.52. Found: C, 72.35; H, 5.43; N, 10.47.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(N(CC)CC)C.Br[CH2:15][C:16]1[N:17]=[CH:18][S:19][CH:20]=1>CN(C)C=O>[O:4]1[CH2:5][CH2:6][N:1]([CH2:15][C:16]2[N:17]=[CH:18][S:19][CH:20]=2)[CH2:2][CH2:3]1
Reactant: BrCc1cscn1
Reactant: C1COCCN1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: c1nc(CN2CCOCC2)cs1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-Methylthiazole (1.98 g), N-bromosuccinimide (3.56 g) and α,α′-azobisisobutyronitrile (164 mg) were dissolved in carbon tetrachloride (200 ml), and the solution was heated under reflux for 2 hours. After completion of the reaction, insoluble matter was removed by filtration, N,N-dimethylformamide (20 ml) was added to the filtrate, and carbon tetrachloride was distilled off under reduced pressure to obtain an N,N-dimethylformamide solution (about 20 ml) of 4-(bromomethyl)thiazole. Morpholine (871 μl), triethylamine (2.79 ml) and N,N-dimethylformamide (10 ml) were successively added to this N,N-dimethyl-formamide solution (about 10 ml) of 4-(bromomethyl)-thiazole, and the mixture was stirred overnight at room temperature. The solvent was distilled off under reduced pressure, dichloromethane and a saturated aqueous solution of sodium hydrogen carbonate were added to the residue and an organic layer was separated. The organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by column chromatography on silica gel (methanol:dichloromethane=1:19) to obtain the title compound (700 mg) as a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:14]2[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[C:16]([F:24])[CH:15]=2)=[N:4][C:5]([CH:8]2[CH2:13][CH2:12][CH2:11][NH:10][CH2:9]2)=[CH:6][N:7]=1.CCN(C(C)C)C(C)C.[C:34](Cl)(=[O:36])[CH3:35]>C(Cl)Cl>[C:34]([N:10]1[CH2:11][CH2:12][CH2:13][CH:8]([C:5]2[N:4]=[C:3]([C:14]3[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[C:16]([F:24])[CH:15]=3)[C:2]([NH2:1])=[N:7][CH:6]=2)[CH2:9]1)(=[O:36])[CH3:35]
Reactant: COC(=O)c1ccc(-c2nc(C3CCCNC3)cnc2N)cc1F
Reactant: CC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)c1ccc(-c2nc(C3CCCN(C(C)=O)C3)cnc2N)cc1F
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a mixture of methyl 4-(3-amino-6-(piperidin-3-yl)pyrazin-2-yl)-2-fluorobenzoate (55 mg, 0.166 mmol) (for synthesis, see example 34, Step 7) in DCM (3 mL) in ice bath was added DIEA (0.116 mL, 0.666 mmol) followed by acetyl chloride (0.012 mL, 0.166 mmol). The reaction mixture was stirred at 0° C. for 30 min. The reaction mixture was partitioned between DCM and water. The DCM layer was separated, washed with brine, dried over sodium sulfate, filtered and evaporated. The residue was proceeded to next step without purification (50 mg, 81%). LCMS (m/z): 373.3 (MH+), 0.666 min.
Reaction SMILES: [C:1]([OH:4])(=[O:3])[CH3:2].[CH3:5][O:6][C:7]1[CH:8]=[C:9]([C@H:16]([NH:29][C:30]2[CH:38]=[CH:37][C:33]([C:34]([NH2:36])=[NH:35])=[CH:32][CH:31]=2)[C:17]2[NH:21][C:20](=[O:22])[N:19]([C:23]3[N:28]=[CH:27][CH:26]=[CH:25][N:24]=3)[N:18]=2)[CH:10]=[C:11](COC)[CH:12]=1.[F:39][CH2:40][CH2:41][N:42]1C2C=C(C(NC3C=CC(C4N=C(C)ON=4)=CC=3)C#N)C=C(OC)C=2[O:45][CH2:44][C:43]1=[O:70]>>[C:1]([OH:4])(=[O:3])[CH3:2].[F:39][CH2:40][CH2:41][N:42]1[C:11]2[CH:10]=[C:9]([C@H:16]([NH:29][C:30]3[CH:38]=[CH:37][C:33]([C:34]([NH2:36])=[NH:35])=[CH:32][CH:31]=3)[C:17]3[NH:21][C:20](=[O:22])[N:19]([C:23]4[N:28]=[CH:27][CH:26]=[CH:25][N:24]=4)[N:18]=3)[CH:8]=[C:7]([O:6][CH3:5])[C:12]=2[O:45][CH2:44][C:43]1=[O:70]
Reactant: COc1cc(C(C#N)Nc2ccc(-c3noc(C)n3)cc2)cc2c1OCC(=O)N2CCF
Reactant: COCc1cc(OC)cc([C@H](Nc2ccc(C(=N)N)cc2)c2nn(-c3ncccn3)c(=O)[nH]2)c1
Solvent: CC(=O)O
Product: COc1cc([C@H](Nc2ccc(C(=N)N)cc2)c2nn(-c3ncccn3)c(=O)[nH]2)cc2c1OCC(=O)N2CCF

Procedure:
The same procedure was carried out as in Examples (10c) to (10e), except that [4-(2-fluoroethyl)-8-methoxy-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-6-yl]-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylamino]acetonitrile was used instead of (3-methoxy-5-methoxymethylphenyl)-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylamino]acetonitrile in Example (10c), to give the first eluting enantiomer of the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=2)=[C:4]2[C:18]3[CH2:19][CH2:20][CH:21]([C:23](O)=[O:24])[CH2:22][C:17]=3[S:16][C:5]2=[N:6][C:7]=1[CH2:8][N:9]1[C:13](=[O:14])[CH2:12][CH2:11][C:10]1=[O:15].[NH:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1.Cl.CN(C)CCCN=C=NCC.CN(C=O)C>O>[Cl:1][C:2]1[C:3]([C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=2)=[C:4]2[C:18]3[CH2:19][CH2:20][CH:21]([C:23]([N:34]4[CH2:39][CH2:38][O:37][CH2:36][CH2:35]4)=[O:24])[CH2:22][C:17]=3[S:16][C:5]2=[N:6][C:7]=1[CH2:8][N:9]1[C:13](=[O:14])[CH2:12][CH2:11][C:10]1=[O:15]
Reactant: COc1ccc(-c2c(Cl)c(CN3C(=O)CCC3=O)nc3sc4c(c23)CCC(C(=O)O)C4)cc1
Reactant: C1COCCN1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(-c2c(Cl)c(CN3C(=O)CCC3=O)nc3sc4c(c23)CCC(C(=O)N2CCOCC2)C4)cc1
Temperature: 25 °C
Reaction time: 10 h
Yield: 455.1 %

Procedure:
A mixture of the compound obtained in Example 37 (500 mg), morpholine (99 mg), N,N-dimethylaminopyridine (13 mg), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (197 mg), and DMF (10 ml) was stirred at room temperature for 10 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO4), and then evaporated under reduced pressure to remove the solvent. The residue was subjected to column chromatography on silica gel to obtain 1-{[3-chloro-4-(4-methoxyphenyl)-7-[(4-morpholinyl)carbonyl]-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-2-yl]methyl}-2,5-pyrrolidinedione (2.6 g, 92%) from the eluates with ethyl acetate. It was recrystallized from chloroform-hexane. Colorless prisms. Melting point 170–171° C.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH2:10])[N:7]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl[C:18]([O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:19]>>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:18](=[O:19])[O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[N:7]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)[N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(Cl)Oc1ccccc1
Reactant: CC(C)(C)c1cc(N)n(-c2cccnc2)n1
Product: CC(C)(C)c1cc(NC(=O)Oc2ccccc2)n(-c2cccnc2)n1
Yield: 95.1 %

Procedure:
Following the procedure in Example 118A, 3-tert-butyl-1-(pyridin-3-yl)-1H-pyrazol-5-amine (665 mg, 3.08 mmol) and phenyl chloroformate (705 mg, 4.5 mmol) were reacted to give phenyl 3-tert-butyl-1-(pyridin-3-yl)-1H-pyrazol-5-ylcarbamate (984 mg, 2.93 mmol, 95%). 1H NMR (300 MHz, DMSO-d6) δ 7.42-7.39 (m, 3H), 7.30-7.26 (m, 5H), 6.85 (t, 1H), 6.82 (d, 2H), 1.21 (s, 9H); LC-MS (ESI) m/z 337 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:17]3[C:12](=[CH:13][C:14]([O:20][CH3:21])=[C:15]([O:18][CH3:19])[CH:16]=3)[CH2:11][CH:10]([CH2:22][OH:23])[O:9]2)[CH:5]=[CH:6][CH:7]=1.[C:24](OC(=O)C)(=[O:26])[CH3:25]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:17]3[C:12](=[CH:13][C:14]([O:20][CH3:21])=[C:15]([O:18][CH3:19])[CH:16]=3)[CH2:11][CH:10]([CH2:22][O:23][C:24](=[O:26])[CH3:25])[O:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc2c(cc1OC)C(c1cccc(Cl)c1)OC(CO)C2
Reactant: CC(=O)OC(C)=O
Product: COc1cc2c(cc1OC)C(c1cccc(Cl)c1)OC(COC(C)=O)C2
Reaction time: 3 h
Yield: 95 %

Procedure:
23.19 g (69.2 mmoles) of 1-(3-chlorophenyl)-3-hydroxymethyl-6,7-dimethoxyisochromane are dissolved in 100 ml of acetic anhydride. The reaction mixture is boiled for 3 hours under reflux, then it is evaporated in vacuo, and three times 50 ml each of 99.5% ethanol are distilled off the residual gum in vacuo. Thus 24.8 g of crude 1-(3-chlorophenyl)-3-acetoxymethyl-6,7-dimethoxyisochromane are obtained. Yield: 95%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:10]([N+:16]([O-:18])=[O:17])=[N:11][CH:12]=[C:13](Br)[N:14]=1.[NH2:19][CH2:20][CH2:21][NH:22][C:23]1[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][N:24]=1.C(N(C(C)C)CC)(C)C>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:14]=[C:13]([NH:19][CH2:20][CH2:21][NH:22][C:23]2[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][N:24]=2)[CH:12]=[N:11][C:10]=1[N+:16]([O-:18])=[O:17]
Reactant: NCCNc1ccc([N+](=O)[O-])cn1
Reactant: O=[N+]([O-])c1ncc(Br)nc1-c1ccc(Cl)cc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(NCCNc2cnc([N+](=O)[O-])c(-c3ccc(Cl)cc3Cl)n2)nc1
Temperature: 80 °C
Reaction time: 12 h

Procedure:
To a solution of 3-(2,4-dichlorophenyl)-5-bromo-2-nitropyrazine (20 mg, 0.057 mmol) in DMF (1 ml), (2-aminoethyl)(5-nitro(2-pyridyl))amine (11.3 mg, 0.06 mmol) and diisopropylethyl amine (40 μl, 0.228 mmol) were added. The reaction mixture was stirred for 12 hours at 80° C. The crude mixture was concentrated in vacuo and subjected to column chromatography (5% methanol in methylene chloride) to afford the title compound as bright yellow solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=2[C:10]#[N:11])=[CH:4][CH:3]=1.C1C(=O)N([Br:23])C(=O)C1.N(C(C)(CC(C)C)C#N)=NC(C)(CC(C)C)C#N.O>ClCCl>[Br:23][CH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=2[C:10]#[N:11])=[CH:6][CH:7]=1
Reactant: Cc1ccc(-c2ccccc2C#N)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)CC(C)(C#N)N=NC(C)(C#N)CC(C)C
Solvent: ClCCl
Solvent: O
Product: N#Cc1ccccc1-c1ccc(CBr)cc1
Temperature: 47.5 °C
Reaction time: 5 h

Procedure:
A mixture of 2-(4-methylphenyl)benzonitrile [MPB] 23 g, NBS 22 g and 2,2′-azobis(2,4-dimethylvaleronitrile) 47 mg was suspended in dichloromethane 44 ml and the mixture was stirred at 45-50° C. for about 5 hours. To the reaction mixture was added water 46 ml and the organic layer was separated. This operation was conducted three times. The organic layer was concentrated and acetonitrile 50 ml was added to the concentrate. The solution was again concentrated and acetonitrile 50 ml was added to the concentrate to give acetonitrile solution of 2-(4-bromomethylphenyl)benzonitrile [BMB] (116 g; Yield based on the theoretical amount of (2-(4-bromomethylphenyl)benzonitrile: 84%).
Reaction SMILES: Cl[C:2]([O:4][CH:5]([CH3:7])[CH3:6])=[O:3].[CH3:8][O:9][C:10](=[O:19])[C:11]1[C:16]([CH3:17])=[CH:15][CH:14]=[CH:13][C:12]=1[NH2:18].N1C=CC=CC=1.Cl>ClCCl>[CH3:8][O:9][C:10](=[O:19])[C:11]1[C:16]([CH3:17])=[CH:15][CH:14]=[CH:13][C:12]=1[NH:18][C:2]([O:4][CH:5]([CH3:7])[CH3:6])=[O:3]
Reactant: COC(=O)c1c(C)cccc1N
Reactant: CC(C)OC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)c1c(C)cccc1NC(=O)OC(C)C
Temperature: 25 °C
Reaction time: 14 h
Yield: 76.4 %

Procedure:
Add isopropyl chloroformate (19.8 mL, 19.8 mmol, 1.0 M in toluene) dropwise to a solution of 2-Amino-6-methyl-benzoic acid methyl ester (3.27 g, 19.8 mmol) and pyridine (4.0 mL, 50 mmol) in dichloromethane (39 mL) at 0° C. under an atmosphere of nitrogen and stir at room temperature for 14 h. Add 1M HCl and separate the layers. Extract the aqueous layer with dichloromethane. Dry the organic layer over anhydrous sodium sulfate, filter, and remove the solvent under reduced pressure. Purify the residue by flash chromatography, eluting with hexanes/ethyl acetate, to afford the title compound (3.80 g, 76%): 1H NMR (CDCl3) δ 1.29 (d, J=6.5 Hz, 6H), 2.43 (s, 3H), 3.94 (s, 3H), 5.00 (septuplet, J=6.5 Hz, 1H), 6.90 (d, J=8.1 Hz, 1H), 7.32 (t, J=8.1 Hz, 1H), 8.07 (d, J=8.1 Hz, 1H), 8.86 (brs, 1H). MS (ES+): 252 (M+H).
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH3:5])[CH3:2].C(=O)([O-])[O-].[Na+].[Na+].[CH2:12]([C:16]1[CH2:17][C:18]2[C:23]([C:24]=1Br)=[CH:22][C:21]1[O:26][CH2:27][O:28][C:20]=1[CH:19]=2)[CH2:13][CH2:14][CH3:15].C(=O)([O-])O.[Na+]>CS(C)=O>[CH2:12]([C:16]1[CH2:17][C:18]2[C:23]([C:24]=1[N:3]([CH2:4][CH3:5])[CH2:1][CH3:2])=[CH:22][C:21]1[O:26][CH2:27][O:28][C:20]=1[CH:19]=2)[CH2:13][CH2:14][CH3:15]
Reactant: CCCCC1=C(Br)c2cc3c(cc2C1)OCO3
Reactant: CCNCC
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CCCCC1=C(N(CC)CC)c2cc3c(cc2C1)OCO3
Reaction time: 5 h
Yield: 65 %

Procedure:
To a solution containing 300 mg of diethylamine and 430 mg of sodium carbonate in 6 ml of dimethylsulfoxide, 600 mg of 2-n-butyl-3-bromo-5,6-methylenedioxyindene was added at room temperature. The reaction mixture was stirred for 5 hours. After completion of the reaction, the reaction mixture was added with a saturated aqueous solution of sodium hydrogencarbonate and then extracted with ether. The ethereal layer was washed with water, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: a 10:1 mixture of n-hexane and ether) to give 380 mg of an oily substance (yield: 65%).
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:22])([F:21])[CH2:17]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][CH3:15])[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(N2CCC(F)(F)C2)C2N=NNC=2N=1)(C)(C)C.BrCC1[CH:50]=[C:49]([F:51])[CH:48]=[CH:47][C:46]=1[Cl:52]>>[C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:21])([F:22])[CH2:17]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[CH:50]=[C:49]([F:51])[CH:48]=[CH:47][C:46]=3[Cl:52])[C:9]=2[N:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: Fc1ccc(Cl)c(CBr)c1
Reactant: CCn1nnc2c(N3CCC(F)(F)C3)nc(C(C)(C)C)nc21
Agent: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1
Product: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nnn(Cc3cc(F)ccc3Cl)c2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3-ethyl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 61), the title compound was prepared from 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 2-(bromomethyl)-1-chloro-4-fluorobenzene and isolated as light-yellow gum. MS(m/e): 425.3 (MH+).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.[N+:12]([O-])([OH:14])=[O:13].[N+]([O-])(O)=O.C(O)(=O)C>C(O)(=O)C>[N+:12]([C:7]1[CH:6]=[C:5]([CH2:8][C:9]([OH:11])=[O:10])[CH:4]=[CH:3][C:2]=1[OH:1])([O-:14])=[O:13]
Reactant: O=C(O)Cc1ccc(O)cc1
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Product: O=C(O)Cc1ccc(O)c([N+](=O)[O-])c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
In a first step, carried out according to Humel in Synth. Commun. 15, pages 1081-88 (1985), to a magnetically stirred solution of 100 g (0.65 mole) of 4-hydroxyphenyl acetic acid in 250 ml of glacial acetic acid was added dropwise a mixture of 40 ml of nitric acid (1.4 specific gravity) and 60 ml glacial acetic acid. The glacial acetic acid was warmed to about 45° C. to completely dissolve the 4-hydroxyphenyl acetic acid. Following addition of the nitric acid/acetic acid mixture, stirring of the resulting mixture was continued for one hour at 25° C. and then the flask was chilled in ice water for one hour. The resulting crystals were washed with cold water and air-dried at room temperature, the reaction providing 65% of the theoretical yield of 3-nitro 4-hydroxyphenyl acetic acid.
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]3[N:19]=[CH:18][C:17]4=[CH:20][CH:21]=[C:22]([C:23]5[CH:31]=[CH:30][C:26]([C:27](O)=[O:28])=[CH:25][CH:24]=5)[N:16]4[N:15]=3)=[CH:9][CH:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.CN(C)C=O.ON1C2C=CC=CC=2N=N1.CN1CCOCC1.[CH3:54][S:55]([CH2:58][CH2:59][NH2:60])(=[O:57])=[O:56].Cl.Cl.CN(C)CCCN=C=NCC>>[CH3:54][S:55]([CH2:58][CH2:59][NH:60][C:27](=[O:28])[C:26]1[CH:30]=[CH:31][C:23]([C:22]2[N:16]3[C:17]([CH:18]=[N:19][C:14]([NH:13][C:10]4[CH:9]=[CH:8][C:7]([N:1]5[CH2:6][CH2:5][O:4][CH2:3][CH2:2]5)=[CH:12][CH:11]=4)=[N:15]3)=[CH:20][CH:21]=2)=[CH:24][CH:25]=1)(=[O:57])=[O:56]
Reactant: O=C(O)c1ccc(-c2ccc3cnc(Nc4ccc(N5CCOCC5)cc4)nn23)cc1
Reactant: CS(=O)(=O)CCN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CS(=O)(=O)CCNC(=O)c1ccc(-c2ccc3cnc(Nc4ccc(N5CCOCC5)cc4)nn23)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Into a 30 mL vial, 4-[2-(4-Morpholin-4-yl-phenylamino)-pyrrolo[2,1-f][1,2,4]triazin-7-yl]-benzoic acid (104 mg, 0.251 mmol), N,N-Dimethylformamide (2.08 mL, 26.9 mmol; Supplier=EMD), 1-Hydroxybenzotriazole (41 mg, 0.30 mmol), 4-Methylmorpholine (33.1 uL, 0.301 mmol), [B] 2-Methanesulfonyl-ethylamine; hydrochloride (0.0601 g, 0.376 mmol), and N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.0577 g, 0.301 mmol) were added. The reaction was stirred at room temperature overnight. The reaction was partitioned with sat'd NaHCO3. The precipitate was filtered and washed with water to afford N-(2-Methanesulfonyl-ethyl)-4-[2-(4-morpholin-4-yl-phenylamino)-pyrrolo[2,1-f][1,2,4]triazin-7-yl]-benzamide as a yellow solid. MP 241-242° C. LCMS (E/I+) 521.00M+H). NMR 1H (DSMO-d6)-9.34 (d, 1H, J=2.00), 8.97 (s, 1H), 8.60 (d, 1H, J=8.21 Hz), 8.79 (t, 1H, J=5.72 Hz), 8.34 (d, 2H, J=8.52 Hz), 7.97 (d, 2H, J=8.52 Hz), 7.65 (d, 2H, J=9.00 Hz), 7.28 (d, 1H, J=4.80 Hz), 6.94-7.00 (m, 3H), 3.65-3.80 (m, 6H), 3.41 (t, 2H, J=6.88 Hz), 3.03-3.12 (m, 7H).
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:9][C:10]([CH3:16])=[CH:11][C:12]([O:14][CH3:15])=[O:13]>CO.O>[CH3:9][C:10]([NH:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)([CH3:16])[CH2:11][C:12]([O:14][CH3:15])=[O:13]
Reactant: NCc1ccccc1
Reactant: COC(=O)C=C(C)C
Solvent: CO
Solvent: O
Product: COC(=O)CC(C)(C)NCc1ccccc1
Temperature: 55 °C
Yield: 27.6 %

Procedure:
To a solution of benzylamine (10.0 mL, 91.6 mmol) in 95% MeOH-water (180 mL) was added methyl 3-methyl-2-butenoate (12.3 mL, 100.8 mmol). The solution was heated at 55° C. and stirred for 2 weeks. The solution was then cooled to room temperature, concentrated in vacuo, and the residue purified by gradient silica gel chromatography (0% to 100% EtOAc in hexanes; 1% Et3N) to provide methyl 3-methyl-3-[(phenylmethyl)amino]butanoate (5.5893 g, 28%) as a pale yellow oil. LCMS: (M+H)+: 222.1.