Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:6]1[CH:11]=[CH:10][C:9]([Br:12])=[CH:8][N:7]=1)[CH2:4][OH:5].Cl[C:14](Cl)([O:16]C(=O)OC(Cl)(Cl)Cl)Cl>C(Cl)Cl>[Br:12][C:9]1[CH:10]=[CH:11][C:6]([C@@H:3]2[CH2:4][O:5][C:14](=[O:16])[NH:2]2)=[N:7][CH:8]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: N[C@@H](CO)c1ccc(Br)cn1
Agent: Cl
Solvent: ClCCl
Product: O=C1N[C@H](c2ccc(Br)cn2)CO1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 151.1 %

Procedure:
To a suspension of (R)-2-amino-2-(5-bromopyridin-2-yl)ethanol hydrogen chloride (4.97 g, 19.6 mmol) and TEA (9.02 mL, 64.7 mmol) in DCM (60 mL) at 0° C. was added a solution of triphosgene (2.91 g, 9.80 mmol) in DCM (20 mL) during 45 min. The resulting mixture was stirred at 0° C. for 15 min, then warmed to it and stirred for 1 h. The reaction was quenched with NH4Cl (15 mL) and stirred for 15 min. The aqueous layer was separated, basicified with Na2CO3, and extracted with DCM (×3). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated. The crude product was purified by a SiO2 column (0-80% EtOAc/Hexanes, Rf=0.15 in 50% EtOAc) to afford the titled compound as an off-white solid (3.60 g).
Reaction SMILES: [CH:1]1([N:5](C)[C:6](=[O:27])[C:7]2[CH:12]=[C:11](OC3C(C)=CC([N+]([O-])=O)=CC=3C)[CH:10]=[CH:9][C:8]=2[O:25]C)CCC1.B(Br)(Br)Br>C(Cl)Cl>[OH:25][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[C:6]([NH:5][CH3:1])=[O:27]
Reactant: COc1ccc(Oc2c(C)cc([N+](=O)[O-])cc2C)cc1C(=O)N(C)C1CCC1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CNC(=O)c1ccccc1O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of N-Cyclobutyl-5-(2,6-dimethyl-4-nitro-phenoxy)-2-methoxy-N-methyl-benzamide (1.65 grams, 4.3 mmol) in methylene chloride (35 mL) at room temperature was added slowly boron tribromide (1M in methylene chloride, 8.6 mL, 8.6 mmol). The resulting mixture was stirred at room temperature for 4 hours, and quenched by pouring into ice water (100 mL), stirred for 1 hour at room temperature, then extracted with methylene chloride (3 times 30 mL). The combined organic extracts were washed with saturated aqueous NaHCO3, brine, dried over Na2SO4, filtered, and concentrated to give 2-hydroxy-N-methyl benzamide as a brown solid which was subjected directly to hydrogenation without further purification. 1H NMR (400 MHz, CDCl3) δ9.43 (s, 1H), 8.00 (s, 2H), 6.97-6.93 (d+dd, 2H), 6.42 (d, 1H), 4.44 (m, 1H), 2.96 (s, 3H), 2.22 (s, 6H), 2.19-2.14 (m, 2H), 1.87-1.55 (m, 4H). MS (APCI+) Calc: 370.2, Found: 371.2 (M+1).
Reaction SMILES: [OH:1][C:2]([CH:11]([CH3:13])[CH3:12])=[CH:3][C:4](=O)[C:5]([O:7][CH2:8][CH3:9])=[O:6].Cl.[CH3:15][O:16][NH2:17].C(O)C>C(OCC)(=O)C>[CH3:15][O:16][N:17]=[C:4]([CH2:3][C:2](=[O:1])[CH:11]([CH3:13])[CH3:12])[C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CON
Reactant: CCOC(=O)C(=O)C=C(O)C(C)C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCOC(=O)C(CC(=O)C(C)C)=NOC
Temperature: 25 °C
Reaction time: 6 h
Yield: 92 %

Procedure:
A mixture of 5.0 g of ethyl 4-hydroxy-5-methyl-2-oxo-3-hexenoate, 2.46 g of O-methylhydroxylamine hydrochloride and 10 ml of ethanol was stirred at room temperature for 6 hours. After ethyl acetate was poured into the reaction mixture, the organic layer was washed with water and an aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain 5.32 g of ethyl 2-methoxyimino-5-methyl-4-oxohexanoate of the formula:
Reaction SMILES: [Cl:1][C:2]1[C:3](F)=[CH:4][C:5]([F:21])=[C:6]([S:8]([N:11]([CH2:18][O:19][CH3:20])[C:12]2[CH:17]=[CH:16][N:15]=[CH:14][N:13]=2)(=[O:10])=[O:9])[CH:7]=1.[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([OH:30])=[C:26]([C:31]2[C:32]([N+:42]([O-:44])=[O:43])=[N:33][N:34]([CH:36]3[CH2:41][CH2:40][CH2:39][CH2:38][O:37]3)[CH:35]=2)[CH:25]=1>>[Cl:1][C:2]1[C:3]([O:30][C:27]2[CH:28]=[CH:29][C:24]([Cl:23])=[CH:25][C:26]=2[C:31]2[C:32]([N+:42]([O-:44])=[O:43])=[N:33][N:34]([CH:36]3[CH2:41][CH2:40][CH2:39][CH2:38][O:37]3)[CH:35]=2)=[CH:4][C:5]([F:21])=[C:6]([S:8]([N:11]([CH2:18][O:19][CH3:20])[C:12]2[CH:17]=[CH:16][N:15]=[CH:14][N:13]=2)(=[O:10])=[O:9])[CH:7]=1
Reactant: COCN(c1ccncn1)S(=O)(=O)c1cc(Cl)c(F)cc1F
Reactant: O=[N+]([O-])c1nn(C2CCCCO2)cc1-c1cc(Cl)ccc1O
Product: COCN(c1ccncn1)S(=O)(=O)c1cc(Cl)c(Oc2ccc(Cl)cc2-c2cn(C3CCCCO3)nc2[N+](=O)[O-])cc1F

Procedure:
The title compound was prepared using the method described in Preparation 872 using 5-chloro-2,4-difluoro-N-(methoxymethyl)-N-pyrimidin-4-ylbenzenesulfonamide (Preparation 895) and 4-chloro-2-[3-nitro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl]phenol (Preparation 894). The product was purified on silica gel (hexane to 50% of 60% ethyl acetate gradient) to provide 82 mg of a colorless oil.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6](/[CH:8]=[N:9]/[C:10]2[C:15]([CH:16]([CH2:19][CH3:20])[CH2:17][CH3:18])=[CH:14][CH:13]=[CH:12][C:11]=2[CH:21]([CH2:24][CH3:25])[CH2:22][CH3:23])[CH:5]=[CH:4][CH:3]=1.[BH3-]C#N.[Na+].CC(O)=O.CO>O>[Br:1][C:2]1[N:7]=[C:6]([CH2:8][NH:9][C:10]2[C:15]([CH:16]([CH2:17][CH3:18])[CH2:19][CH3:20])=[CH:14][CH:13]=[CH:12][C:11]=2[CH:21]([CH2:22][CH3:23])[CH2:24][CH3:25])[CH:5]=[CH:4][CH:3]=1
Reactant: CCC(CC)c1cccc(C(CC)CC)c1/N=C/c1cccc(Br)n1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: CC(=O)O
Product: CCC(CC)c1cccc(C(CC)CC)c1NCc1cccc(Br)n1

Procedure:
In argon atmosphere, a mixture of 11.2 g (28 mmol) of N-[(1E)-(6-bromopyridin-2-yl)methylene]-2,6-bis(1-ethylpropyl)aniline, 2.80 g (45 mmol) of NaBH3CN, 1 ml of AcOH and 230 ml of methanol was refluxed for 12 h. The obtained mixture was cooled, poured into 300 ml of water, and then crude product was extracted with 3×200 ml of ethyl acetate. The combined extract was dried over Na2SO4 and evaporated to dryness. Yield 10.3 g (93%) of yellow oil. Anal. calc. for C23H31BrN2: C, 65.50; H, 7.75; N, 6.94. Found: C, 65.36; H, 7.69; N, 6.82. 1H NMR (CDCl3): δ 7.52 (m, 1H, 4-H in Py), 7.41 (m, 1H, 3-H in Py), 7.38 (m, 1H, 5-H in Py), 7.03-7.08 (m, 1H, 4-H in dipentylphenyl), 6.97-6.99 (m, 2H, 3, 5-H in dipentylphenyl), 4.10 (s, 2H, CH2NH), 3.73 (br.s, 1H, NH), 2.86 (m, 2H, CHEt2), 1.70 (m, 4H, CH2Me), 1.49 (m, 4H, CH2Me), 0.79 (t, J=7.3 Hz, 12H, CH2Me).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[C:15]([C:16]([N:18]4[CH2:22][CH2:21][CH2:20][CH2:19]4)=[O:17])=[N:14][NH:13][C:12](=[O:23])[C:7]=3[N:8]([CH3:11])[C:9]=2[CH:10]=1.C(=O)([O-])[O-].[K+].[K+].Br[C:31]1[N:36]=[CH:35][CH:34]=[CH:33][N:32]=1>CN(C)C=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[C:15]([C:16]([N:18]4[CH2:22][CH2:21][CH2:20][CH2:19]4)=[O:17])=[N:14][N:13]([C:31]4[N:36]=[CH:35][CH:34]=[CH:33][N:32]=4)[C:12](=[O:23])[C:7]=3[N:8]([CH3:11])[C:9]=2[CH:10]=1
Reactant: Cn1c2cc(F)ccc2c2c(C(=O)N3CCCC3)n[nH]c(=O)c21
Reactant: Brc1ncccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cn1c2cc(F)ccc2c2c(C(=O)N3CCCC3)nn(-c3ncccn3)c(=O)c21

Procedure:
A solution of 0.24 g (0.73 mmol) of 1-[[7-fluoro-5-methyl-4-oxo-3,5-dihydro-4H-pyridazino[4,5-b]indol-1-yl]carbonyl]pyrrolidine (obtained in stage 5.1.), of 0.120 g (0.63 mmol) of cuprous iodide, of 0.15 g (1.09 mmol) of potassium carbonate and of 0.30 g (1.89 mmol) of 2-bromopyrimidine in 40 ml of N,N-dimethylformamide is heated at 150° C. for 16 h. The reaction mixture is cooled and concentrated under reduced pressure. Dichloromethane, water and a concentrated sodium hydroxide solution are added. The organic phase is separated by settling, filtered through Celite®, washed with water, dried over sodium sulphate, filtered and concentrated under reduced pressure. The residue is purified by chromatography on a column of silica gel (eluent: dichloromethane/ethyl acetate: 80/20 to 0/100; ethyl acetate/methanol: 100/0 to 90/10). The solid obtained is recrystallized from a dichloromethane/ethyl acetate mixture and washed with diethyl ether.
Reaction SMILES: I[C:2]1[C:3]([CH3:17])=[N:4][N:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][OH:16])=[CH:10][CH:9]=2)[C:6]=1[CH3:7].CC1(C)C(C)(C)OB([C:26]2[CH:31]=[CH:30][C:29]([NH:32][S:33]([CH3:36])(=[O:35])=[O:34])=[CH:28][CH:27]=2)O1>>[OH:16][CH2:15][CH2:14][C:11]1[CH:12]=[CH:13][C:8]([N:5]2[C:6]([CH3:7])=[C:2]([C:26]3[CH:27]=[CH:28][C:29]([NH:32][S:33]([CH3:36])(=[O:34])=[O:35])=[CH:30][CH:31]=3)[C:3]([CH3:17])=[N:4]2)=[CH:9][CH:10]=1
Reactant: CC1(C)OB(c2ccc(NS(C)(=O)=O)cc2)OC1(C)C
Reactant: Cc1nn(-c2ccc(CCO)cc2)c(C)c1I
Product: Cc1nn(-c2ccc(CCO)cc2)c(C)c1-c1ccc(NS(C)(=O)=O)cc1

Procedure:
The title compound was prepared according to the procedure described in step 1 of Example 12 from 2-[4-(4-iodo-3,5-dimethyl-1H-pyrazol-1-yl)phenyl]ethanol (step 2 of Example 11) and N-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methanesulfonamide: MS (EI) m/z 385 [M]+, 1H-NMR (CDCl3) δ 7.44-7.26 (8H, m), 3.92-3.90 (2H, br), 3.08 (3H, s), 2.94 (2H, t, J=6.6 Hz), 2.32 (3H, s), 2.29 (3H, s).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[C:12]1[C:20]2[C:15](=[N:16][C:17]([CH:21]=[CH2:22])=[CH:18][CH:19]=2)[CH2:14][O:13]1.[CH3:23][N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1>C(N(CC)CC)C>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[C:12]1[C:20]2[C:15](=[N:16][C:17]([CH2:21][CH2:22][N:27]3[CH2:28][CH2:29][N:24]([CH3:23])[CH2:25][CH2:26]3)=[CH:18][CH:19]=2)[CH2:14][O:13]1
Reactant: C=Cc1ccc2c(n1)COC2=C1C(=O)Nc2ccc(F)cc21
Reactant: CN1CCNCC1
Solvent: CCN(CC)CC
Product: CN1CCN(CCc2ccc3c(n2)COC3=C2C(=O)Nc3ccc(F)cc32)CC1
Temperature: 100 °C
Yield: 101.4 %

Procedure:
Following the method described in Example 19, 5-fluoro-3-(2-vinyl-7H-furo[3,4-b]pyridin-5-ylidene)-1,3-dihydro-indol-2-one (60 mg, 0.20 mmol) and N-methylpiperazine (300 mg, 3.00 mmol) are heated 100° C. for 2 h. The reaction mixture is cooled and treated with triethylamine (10 drops). The reaction mixture is loaded onto silica gel and purified by chromatography (silica gel, gradient elution, 2% MeOH/Chloroform to 20% MeOH/chloroform) to provide the title compound (80 mg, 100%) as a yellow solid.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([CH3:30])=[C:6]([CH:29]=1)[C:7]([NH:9][C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]([O:20][CH2:21][CH2:22][N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)=[CH:12][CH:11]=1)=[O:8].[NH:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1>>[CH3:30][C:5]1[CH:4]=[CH:3][C:2]([N:31]2[CH2:36][CH2:35][O:34][CH2:33][CH2:32]2)=[CH:29][C:6]=1[C:7]([NH:9][C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]([O:20][CH2:21][CH2:22][N:23]2[CH2:24][CH2:25][O:26][CH2:27][CH2:28]2)=[CH:12][CH:11]=1)=[O:8]
Reactant: C1COCCN1
Reactant: Cc1ccc(Br)cc1C(=O)Nc1ccc(OCCN2CCOCC2)c2ccccc12
Product: Cc1ccc(N2CCOCC2)cc1C(=O)Nc1ccc(OCCN2CCOCC2)c2ccccc12

Procedure:
Compound is formed by reacting 5-bromo-2-methyl-N-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-1-yl]-benzamide with morpholine under conditions described in general procedure B. 1H NMR (300 MHz, CDCl3) δ 8.33 (d, 1H, J=6.9), 7.85 (t, 2H, J=7.8), 7.61 (s, 1H), 7.54 (m, 2H), 7.34 (m, 2H), 7.19 (d, 1H, J=7.5), 6.88 (d, 1H, J=8.4), 4.33 (t, 2H, J=5.7), 3.88 (t, 4H, J=3.9), 3.75 (t, 4H, J=4.5), 2.95 (m, 6H), 2.66 (t, 4H, J=4.5), 2.63 (s, 3H). MS: 476.2 (M+1).
Reaction SMILES: NN1CCCC1.Cl[C:8]1[CH:13]=[C:12]([CH3:14])[N:11]=[C:10]([NH:15][C@H:16]2[C@H:20]([OH:21])[CH2:19][N:18]([C:22](=[O:35])[CH2:23][C:24]3[CH:29]=[CH:28][C:27]([O:30][C:31]([F:34])([F:33])[F:32])=[CH:26][CH:25]=3)[CH2:17]2)[CH:9]=1.[NH:36]1[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1.CC(C)([O-])C.[Na+].C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C>C(Cl)(Cl)Cl.CC([O-])=O.CC([O-])=O.[Pd+2].C1(C)C=CC=CC=1>[OH:21][C@H:20]1[C@H:16]([NH:15][C:10]2[CH:9]=[C:8]([N:36]3[CH2:41][CH2:40][O:39][CH2:38][CH2:37]3)[CH:13]=[C:12]([CH3:14])[N:11]=2)[CH2:17][N:18]([C:22](=[O:35])[CH2:23][C:24]2[CH:29]=[CH:28][C:27]([O:30][C:31]([F:34])([F:33])[F:32])=[CH:26][CH:25]=2)[CH2:19]1
Reactant: Cc1cc(Cl)cc(N[C@@H]2CN(C(=O)Cc3ccc(OC(F)(F)F)cc3)C[C@H]2O)n1
Reactant: C1COCCN1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Solvent: ClC(Cl)Cl
Solvent: Cc1ccccc1
Product: Cc1cc(N2CCOCC2)cc(N[C@@H]2CN(C(=O)Cc3ccc(OC(F)(F)F)cc3)C[C@H]2O)n1
Temperature: 100 °C

Procedure:
A mixture of 2,4-dichloro-6-methylpyridine 1-oxide (200 mg), 1-((3R,4R)-3-amino-4-hydroxypyrrolidin-1-yl)-2-(4-trifluoromethoxyphenyl)ethanone (340 mg), and n-butanol (0.6 mL) was stirred at 130° C. for 10 h. The reaction mixture was concentrated under reduced pressure, the residue was purified by silica gel column chromatography (NH silica gel, ethyl acetate−ethyl acetate/methanol=20:1), and then the resulting solids were washed with hexane and diethyl ether to obtain 1-((3R,4R)-3-(4-chloro-6-methylpyridin-2-ylamino)-4-hydroxypyrrolidin-1-yl)-2-(4-trifluoromethoxyphenyl)ethanone (75 mg). (2) A mixture of 1-((3R,4R)-3-(4-chloro-6-methylpyridin-2-ylamino)-4-hydroxypyrrolidin-1-yl)-2-(4-trifluoromethoxyphenyl)ethanone (68 mg), morpholine (0.02 mL), sodium t-butoxide (42 mg), Pd(OAc)2 (1 mg), 2-(di-t-butylphosphino)biphenyl (3 mg), and toluene (1 mL) was heated at 100° C. for 10 h. The mixture was cooled to room temperature, then the reaction mixture was diluted with chloroform, insoluble matters were removed by Celite filtration, and then the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (NH silica gel, ethyl acetate, and silica gel, hexane/acetone=1:1) to obtain the title compound (8 mg).
Reaction SMILES: C(OC([NH:11][C@H:12]1[CH2:16][CH2:15][N:14]([C@H:17]2[CH2:22][CH2:21][C@@H:20]([N:23]([C:25]([CH3:28])([CH3:27])[CH3:26])[CH3:24])[CH2:19][C@H:18]2[C:29]([O:31][CH3:32])=[O:30])[C:13]1=[O:33])=O)C1C=CC=CC=1>CO.[Pd]>[NH2:11][C@H:12]1[CH2:16][CH2:15][N:14]([C@H:17]2[CH2:22][CH2:21][C@@H:20]([N:23]([C:25]([CH3:28])([CH3:27])[CH3:26])[CH3:24])[CH2:19][C@H:18]2[C:29]([O:31][CH3:32])=[O:30])[C:13]1=[O:33]
Reactant: COC(=O)[C@@H]1C[C@H](N(C)C(C)(C)C)CC[C@@H]1N1CC[C@H](NC(=O)OCc2ccccc2)C1=O
Agent: [Pd]
Solvent: CO
Product: COC(=O)[C@@H]1C[C@H](N(C)C(C)(C)C)CC[C@@H]1N1CC[C@H](N)C1=O
Yield: 94.5 %

Procedure:
A solution of (1R,2S,5R)-methyl 2-((S)-3-(benzyloxycarbonylamino)-2-oxopyrrolidin-1-yl)-5-(tert-butyl(methyl)amino)cyclohexanecarboxylate (330 mg, 0.65 mmol) in methanol was treated with 100 mg of 10% Pd/C and hydrogenated at 55 psi of H2 in a Parr shaker overnight. The catalyst was filtered and the filtrate concentrated in vacuo to give 200 mg of (1R,2S,5R)-methyl 2-((S)-3-amino-2-oxopyrrolidin-1-yl)-5-(tert-butyl(methyl) amino)-cyclohexanecarboxylate as a white solid. This was used without further purification. MS found: (M+H)+=326.50
Reaction SMILES: [O:1]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([C:16]1[O:17][C:18]([CH2:21][O:22]CC2C=CC=CC=2)=[N:19][N:20]=1)=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1CC=CCC=1>CC(O)=O.CO.[Pd]>[OH:22][CH2:21][C:18]1[O:17][C:16]([C:14](=[O:15])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][O:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[N:20][N:19]=1
Reactant: O=C(CCCCCCOc1ccccc1)c1nnc(COCc2ccccc2)o1
Agent: [Pd]
Solvent: CO
Solvent: CC(=O)O
Solvent: C1=CCC=CC1
Product: O=C(CCCCCCOc1ccccc1)c1nnc(CO)o1
Reaction time: 2 h
Yield: 25 %

Procedure:
To a stirred suspension of 73.1 (80 mg, 0.2 mmol) and Pd/C (160 mg) in AcOH/MeOH (1:10 mixture, 5 mL) at 45° C. was added 1,4-cyclohexadiene (304 mg, 4 mmol) over a period of 30 min. The mixture was stirred for an additional 2 h at the same temperature. The catalyst was removed by filtration through celite and the filtrate was evaporated under reduced pressure. The residue was purified through a column of silica, eluting with 45% ethyl acetate in petroleum ether to give 74.1 as a white solid (m p 83-85° C.) in 25% yield (15 mg).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[C:7]3[CH:14]=[CH:13][N:12]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[C:8]=3[N:9]=[CH:10][N:11]=2)[CH:3]=[N:2]1.C(#N)C.[N:26]1([C:32]2[CH:33]=[C:34](/[CH:38]=[CH:39]/[C:40]#[N:41])[CH:35]=[N:36][CH:37]=2)[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1.C1CCN2C(=NCCC2)CC1>>[N:26]1([C:32]2[CH:33]=[C:34]([CH:38]([N:1]3[CH:5]=[C:4]([C:6]4[C:7]5[CH:14]=[CH:13][N:12]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[C:8]=5[N:9]=[CH:10][N:11]=4)[CH:3]=[N:2]3)[CH2:39][C:40]#[N:41])[CH:35]=[N:36][CH:37]=2)[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cn[nH]c3)ncnc21
Reactant: N#C/C=C/c1cncc(N2CCOCC2)c1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C(CC#N)c4cncc(N5CCOCC5)c4)c3)ncnc21
Reaction time: 8 h
Yield: 125.6 %

Procedure:
To a solution of 4-(1H-pyrazol-4-yl)-7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]-pyrimidine (120 mg, 0.00038 mol) in ACN (10 mL, 0.2 mol) and (2E)-3-(5-morpholin-4-ylpyridin-3-yl)acrylonitrile (70 mg, 0.0003 mol) (mixture of isomers), DBU (50 μL, 0.0003 mol) was added and the resulting mixture was stirred overnight. The mixture was partitioned between water and ethyl acetate. The combined organic layers were washed with saturated sodium chloride, dried over magnesium sulfate, filtered and concentrated to give 3-(5-morpholin-4-ylpyridin-3-yl)-3-[4-(7-[2-(trimethylsilyl)-ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile (200 mg, 100%) as a crude product; L/MS=531 (M+1).
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:13]=[C:9]([C:10]([OH:12])=O)[C:8]([NH2:14])=[CH:7][CH:6]=1)([CH3:3])[CH3:2].Cl[C:16]1[CH:21]=[CH:20][C:19]([C:22]#[N:23])=[CH:18][N:17]=1.[I-].[K+].COCCOCCOCCOC>>[C:22]([C:19]1[CH:20]=[CH:21][C:16]2[N:17]([CH:18]=1)[C:10](=[O:12])[C:9]1[C:8](=[CH:7][CH:6]=[C:5]([O:4][CH:1]([CH3:2])[CH3:3])[CH:13]=1)[N:14]=2)#[N:23]
Reactant: N#Cc1ccc(Cl)nc1
Reactant: CC(C)Oc1ccc(N)c(C(=O)O)c1
Agent: [I-]
Agent: [K+]
Solvent: COCCOCCOCCOC
Product: CC(C)Oc1ccc2nc3ccc(C#N)cn3c(=O)c2c1

Procedure:
A mixture of 16.7 g. of 5-isopropoxyanthranilic acid, 10.0 g. of 2-chloro-5-cyanopyridine and 0.01 g. of potassium iodide in 30 ml. of triglyme was heated to a bath temperature of 150° overnight under a stream of argon. On cooling, the mixture was triturated with ethanol and water. A gummy solid was collected, dissolved in hot ethyl acetate, filtered and the filtrate was evaporated to give 8.4 g. of crude product (38% yield). Two recrystallizations of this solid from dimethylformamide-acetic acid-water give pure 8-cyano-2-isopropoxy-11-oxo-11H-pyrido[2,1-b]quinazoline, mp 234°-236°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[NH2:6].[F:12][C:13]1[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:14]=1>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:6][S:19]([C:16]2[CH:17]=[CH:18][C:13]([F:12])=[CH:14][CH:15]=2)(=[O:21])=[O:20])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Reactant: COc1ccc(N)cc1OC
Solvent: c1ccncc1
Product: COc1ccc(NS(=O)(=O)c2ccc(F)cc2)cc1OC
Reaction time: 8 h

Procedure:
3,4-Dimethoxyaniline(1.01 g, 6.99 mM) was added to a solution of 4-Fluorobenzenesulfonyl chloride (1.50 g, 7.69 mM) in anhydrous pyridine(10 ml). The reaction was stirred overnight. The reaction was quenched with 1N HClaq. (20 ml) and washed with ethyl acetate(3×20 ml). The organic extracts were combined, dried(sodium sulfate), solids filtered off and concentrated. The desired product was isolated using silica gel flash chromatography of 1.30 g as a yellow solid. H1 NMR(CDCl3) δ 3.79(s, 3H), 3.86(s, 3H), 6.50(d, 1H), J=4.71 Hz), 6.68(d, 1H, J=2.64 Hz), 6.71 (d, 1H, J=2.76 Hz), 7.11 (d, 2H, J=8.67 Hz), 7.75(m, 2H). MS(ES) m/z 328.9; (M+NH4+); HRMS for (MH+) C14H14SFNO4: 260.1511.
Reaction SMILES: [CH3:1][N:2]([CH3:20])[CH2:3][CH2:4][CH2:5][NH:6][C:7]1[CH:16]=[CH:15][C:10]([C:11]([NH:13][CH3:14])=[O:12])=[CH:9][C:8]=1[N+:17]([O-])=O>C(O)C.[C].[Pd]>[NH2:17][C:8]1[CH:9]=[C:10]([CH:15]=[CH:16][C:7]=1[NH:6][CH2:5][CH2:4][CH2:3][N:2]([CH3:20])[CH3:1])[C:11]([NH:13][CH3:14])=[O:12]
Reactant: CNC(=O)c1ccc(NCCCN(C)C)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CCO
Product: CNC(=O)c1ccc(NCCCN(C)C)c(N)c1
Temperature: 25 °C
Reaction time: 14 h
Yield: 97.1 %

Procedure:
10% of palladium-carbon (0.40 g) was added to a solution containing 4-{[3-(dimethylamino)propyl]amino}-N-methyl-3-nitrobenzamide (1.88 g) in ethanol (30 ml) and the mixture was stirred for 14 hours under a hydrogen gas atmosphere at room temperature. After the catalyst was removed out by filtration, the filtrate was concentrated, thereby yielding the entitled compound (1.63 g) as purple solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[CH:5]=[CH:6][C:7]([OH:9])=O.P(Cl)(OCC)(OCC)=O.C(N(CC)CC)C.[CH3:29][N:30]([CH3:41])[CH2:31][CH2:32][NH:33][C@H:34]1[CH2:39][CH2:38][C@H:37]([CH3:40])[CH2:36][CH2:35]1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:29][N:30]([CH3:41])[CH2:31][CH2:32][N:33]([C@H:34]1[CH2:35][CH2:36][C@H:37]([CH3:40])[CH2:38][CH2:39]1)[C:7](=[O:9])[CH:6]=[CH:5][C:4]1[CH:10]=[CH:11][CH:12]=[C:2]([Cl:1])[CH:3]=1
Reactant: CN(C)CCN[C@H]1CC[C@H](C)CC1
Reactant: O=C(O)C=Cc1cccc(Cl)c1
Agent: CCOP(=O)(Cl)OCC
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C)CCN(C(=O)C=Cc1cccc(Cl)c1)[C@H]1CC[C@H](C)CC1

Procedure:
Using 1.1 g of 3-chlorocinnamic acid, 1.4 ml of diethyl chlorophosphate, 1.4 ml of triethylamine, 60 ml of methylene chloride, 1.4 ml of N-(2-dimethylaminoethyl)-trans-4-methylcyclohexylamine (Example 78), and 0.25 g of 4-dimethylaminopyridine, a reaction similar to that conducted in Example 81 was carried out. As a result, 2.06 g of N-(2-dimethylaminoethyl)-N-(trans-4-methylcyclohexyl)-3-chlorocinnamamide (a compound of the present invention) was obtained as white crystal, which had the following physiochemical properties:
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4]Cl.[CH3:10][N:11]1[CH2:16][CH2:15][C:14](=[O:17])[CH2:13][CH2:12]1>>[CH3:10][N:11]1[CH2:16][CH2:15][C:14]([CH2:4][C:3]2[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=2[F:1])([OH:17])[CH2:13][CH2:12]1
Reactant: Fc1ccccc1CCl
Reactant: CN1CCC(=O)CC1
Product: CN1CCC(O)(Cc2ccccc2F)CC1

Procedure:
A sample of 2-fluorobenzyl chloride is converted to its Grignard reagent as described in Example 1 and is reacted with a sample of N-methyl-4-piperidone to provide 1-methyl-4-(2-fluorobenzyl)-4-piperidinol, mp 93°-95° C., after two recrystallizations.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]([N:8]([CH3:19])[C:9](=[O:18])[O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C@@H:4]([CH3:7])[CH2:5][CH3:6].C(N(CC)CC)C.O.COC(C)(C)C>CS(C)=O>[CH3:19][N:8]([C@@H:3]([C@@H:4]([CH3:7])[CH2:5][CH3:6])[CH:2]=[O:1])[C:9](=[O:18])[O:10][CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CC[C@H](C)[C@@H](CO)N(C)C(=O)OCc1ccccc1
Solvent: CS(C)=O
Solvent: O
Solvent: COC(C)(C)C
Product: CC[C@H](C)[C@@H](C=O)N(C)C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 18 h
Yield: 86.9 %

Procedure:
To a solution of #1 (8.27 g, 31.2 mmol, 1 eq.) in dimethyl sulfoxide (41.35 mL, 0.75 M), was added triethylamine (8.70 mL, 64.0 mmol, 2.05 eq.) and the mixture was cooled to 0° C. Sulfur trioxide pyridine complex (10.18 g, 63.96 mmol, 2.05 eq.) was then added portion-wise, while keeping the internal temperature below 8° C. The reaction was allowed to reach room temperature and was stirred for 18 hours. The reaction was poured into water (100 mL) and tert-butyl methyl ether (100 mL). The aqueous layer was back-extracted with tert-butyl methyl ether (50 mL) and the combined organic layers were washed with brine (100 mL), dried over magnesium sulfate, filtered, concentrated in vacuo and purified by silica gel chromatography (Gradient: 10% to 60% ethyl acetate in heptane) to provide #2 (7.14 g, 87%) as a colorless oil. 1H NMR (400 MHz, DMSO-d6), presumed to be a mixture of rotamers, characteristic signals: δ 9.61 (s, 1H), 7.26-7.42 (m, 5H), 5.01-5.13 (m, 2H), 4.04-4.12 (m, 1H), 2.86 and 2.82 (2 s, total 3H), 1.94-2.11 (br m, 1H), 1.26-1.42 (br m, 1H).