Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]([C:17]3[CH:22]=[CH:21][N:20]=[C:19]([NH:23][CH:24]4[CH2:28][CH2:27][CH2:26][CH2:25]4)[N:18]=3)=[C:15]3[N:10]([C:11](SC)=[N:12][CH:13]=[CH:14]3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.ClC1C=C(C=CC=1)C(OO)=O.[CH:42]1([NH2:47])[CH2:46][CH2:45][CH2:44][CH2:43]1>ClCCl.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]([C:17]3[CH:22]=[CH:21][N:20]=[C:19]([NH:23][CH:24]4[CH2:28][CH2:27][CH2:26][CH2:25]4)[N:18]=3)=[C:15]3[N:10]([C:11]([NH:47][CH:42]4[CH2:46][CH2:45][CH2:44][CH2:43]4)=[N:12][CH:13]=[CH:14]3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: NC1CCCC1
Reactant: CSc1nccc2c(-c3ccnc(NC4CCCC4)n3)c(-c3cccc(Cl)c3)nn12
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Clc1cccc(-c2nn3c(NC4CCCC4)nccc3c2-c2ccnc(NC3CCCC3)n2)c1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 64.6 %

Procedure:
To a cold (0° C.) solution of 4-[2-(3-chlorophenyl)-7-(methylthio)pyrazolo[1,5-c]pyrimidin-3-yl]-N-cyclopentylpyrimidin-2-amine (40 mg, 0.0915 mmol) in dichloromethane (3 mL) was added m-chloroperoxybenzoic acid (24 mg, 0.139 mmol). The reaction mixture was stirred 1.5 hours at 0° C. then diluted with dichloromethane and washed with saturated aqueous sodium bicarbonate solution. The organic layer was washed with water and brine, then dried over magnesium sulfate. Filtration and concentration provided a crude oil which was heated in cyclopentylamine (2 mL, 20 mmol) at 85° C. in a sealed tube for 16 hours. The reaction mixture was diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate solution. The organic layer was washed with brine and dried over magnesium sulfate. Filtration and concentration followed by flash chromatography (4:1 to 3:1 hexanes:ethyl acetate) provided 2-(3-chlorophenyl)-N-cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]pyrazolo[1,5-c]pyrimidin-7-amine (28 mg, 65%) as a beige solid. Rf 0.27 (3:1 hexanes:ethyl acetate); 1H NMR (CDCl3) δ 8.09 (d, 1H), 7.78 (d, 1H), 7.71 (s, 1H), 7.51–7.35 (m, 4H), 6.41 (d, 1H), 6.30 (d, 1H), 5.15 (d, 1H), 4.53 (m, 1H), 4.29 (m, 1H), 2.20 (m, 2H), 2.04 (m, 2H), 1.83–1.50 (m, 12 H); MS m/z 474 (M+1).
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([OH:28])=O)=[C:24]([F:31])[C:23]=4[O:32][CH3:33])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:34][N:35]1[CH2:40][CH2:39][CH:38]([NH2:41])[CH2:37][CH2:36]1>>[CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([NH:41][CH:38]5[CH2:39][CH2:40][N:35]([CH3:34])[CH2:36][CH2:37]5)=[O:28])=[C:24]([F:31])[C:23]=4[O:32][CH3:33])=[N:20][C:7]2=3)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COc1c(Nc2ncc3c(n2)N(C2CCCC2)CC(F)(F)C(=O)N3C)ccc(C(=O)O)c1F
Reactant: CN1CCC(N)CC1
Product: COc1c(Nc2ncc3c(n2)N(C2CCCC2)CC(F)(F)C(=O)N3C)ccc(C(=O)NC2CCN(C)CC2)c1F

Procedure:
The title compound was synthesized from 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-2-fluoro-3-methoxybenzoic acid and 1-methylpiperidin-4-amine as described in the General procedure for amide bond synthesis. The final compound was purified by reverse phase HPLC and basified to give the free base. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.37-1.66 (m, 7 H) 1.75 (m, 4 H) 1.82-2.04 (m, 4 H) 2.15 (m, 3 H) 2.66-2.81 (m, 2 H) 3.16 (s, 1 H) 3.70 (m, 1 H) 3.90 (s, 3 H) 4.05 (t, J=13.8 Hz, 2 H) 4.77 (m, 1 H) 7.24 (t, J=8.1 Hz, 1 H) 7.96-8.13 (m, 2 H) 8.26 (s, 1 H) 8.35 (s, 1 H). [M+H] calc'd for C27H34F3N7O3, 562; found 562.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:6]([F:10])=[CH:7][C:8]=1[Cl:9])[NH2:5].Cl[C:12]1[C:21]2[C:16](=[CH:17][C:18]([F:25])=[C:19]([N+:22]([O-:24])=[O:23])[CH:20]=2)[N:15]=[CH:14][N:13]=1>C(O)(C)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:5][C:12]2[C:21]3[C:16](=[CH:17][C:18]([F:25])=[C:19]([N+:22]([O-:24])=[O:23])[CH:20]=3)[N:15]=[CH:14][N:13]=2)[C:6]([F:10])=[CH:7][C:8]=1[Cl:9]
Reactant: Nc1cc(Cl)c(Cl)cc1F
Reactant: O=[N+]([O-])c1cc2c(Cl)ncnc2cc1F
Solvent: CC(C)O
Product: O=[N+]([O-])c1cc2c(Nc3cc(Cl)c(Cl)cc3F)ncnc2cc1F
Yield: 78 %

Procedure:
3,4-Dichloro-6-fluoroaniline (1 equivalent) was reacted with 4-chloro-7-fluoro-6-nitroquinazoline (3.5 equivalents), in iso-propylalcohol. After filtration, 4-[(3,4-dichloro-6-fluorophenyl)amino]-7-fluoro-6-nitroquinazoline was obtained in 78% yield.
Reaction SMILES: [CH2:1]([C:8]1[CH:30]=[CH:29][C:11]([O:12][CH2:13][CH2:14][CH2:15][N:16]2[C:20]([CH3:21])=[CH:19][CH:18]=[C:17]2[C:22]2[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O[C@@H:32]([CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[C:33]([O:35][CH2:36][CH3:37])=[O:34].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1(C)C=CC=CC=1.O>[CH2:1]([C:8]1[CH:30]=[CH:29][C:11]([O:12][CH2:13][CH2:14][CH2:15][N:16]2[C:20]([CH3:21])=[CH:19][CH:18]=[C:17]2[C:22]2[CH:23]=[CH:24][C:25]([O:28][C@H:32]([CH2:38][C:39]3[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=3)[C:33]([O:35][CH2:36][CH3:37])=[O:34])=[CH:26][CH:27]=2)=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)[C@@H](O)Cc1ccccc1
Reactant: Cc1ccc(-c2ccc(O)cc2)n1CCCOc1ccc(Cc2ccccc2)cc1
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)[C@@H](Cc1ccccc1)Oc1ccc(-c2ccc(C)n2CCCOc2ccc(Cc3ccccc3)cc2)cc1
Temperature: 80 °C
Reaction time: 12 h
Yield: 51.5 %

Procedure:
To a solution of 4-{1-[3-(4-benzylphenoxy)propyl]-5-methyl-1H-pyrrol-2-yl}phenol (910 mg, 2.29 mmol), ethyl (S)-2-hydroxy-3-phenylpropanoate (667 mg, 3.44 mmol) and triphenylphosphine (901 mg, 3.44 mmol) in toluene (2 ml) was added 1,1′-(azodicarbonyl)dipiperidine (867 mg, 3.44 mmol) and the mixture was stirred at 80° C. for 12 hours. The reaction solution was poured into water and the mixture was extracted with ethyl acetate. The extract was dried over magnesium sulfate anhydride, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=30:1) to give the object compound as an oily substance. 680 mg (yield: 51.5%)
Reaction SMILES: [CH2:1]([C:16]1[NH:17][C:18]2[C:23]([CH:24]=1)=[CH:22][C:21]([C:25]([OH:27])=[O:26])=[CH:20][CH:19]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].Cl.[CH3:29]O>C(OCC)C.O1CCCC1>[CH2:1]([C:16]1[NH:17][C:18]2[C:23]([CH:24]=1)=[CH:22][C:21]([C:25]([O:27][CH3:29])=[O:26])=[CH:20][CH:19]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: CO
Reactant: CCCCCCCCCCCCCCCc1cc2cc(C(=O)O)ccc2[nH]1
Agent: Cl
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCCc1cc2cc(C(=O)OC)ccc2[nH]1

Procedure:
A solution of 2-(n-pentadecyl)indole-5-carboxylic acid (15.0 g) in methanol (100 ml) containing aqueous hydrochloric acid (10 ml, of strength 36.5% w/v) was refluxed for 5 hours. After cooling, the mixture was dissolved in a mixture of diethyl ether and tetrahydrofuran (1:1). The solution was washed with water (2×50 ml), dried over sodium sulphate, evaporated in vacuo, and the residue was recrystallised from methanol to give methyl 2-(n-pentadecyl)indole-5-carboxylate (12.2 g), in the form of an off-white powder, m.p. 89°-92° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:29])[CH2:7][CH:6]([C:8]2[C:16]3[C:11](=[C:12]([C:24]([NH2:26])=[O:25])[CH:13]=[C:14]([C:17]4[CH:21]=[C:20]([CH:22]=O)[S:19][CH:18]=4)[CH:15]=3)[NH:10][CH:9]=2)[CH2:5][CH2:4][S:3]1(=[O:28])=[O:27].[CH3:30][NH:31][CH3:32].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CS(C)=O.C(O)(=O)C>[CH3:30][N:31]([CH2:22][C:20]1[S:19][CH:18]=[C:17]([C:14]2[CH:15]=[C:16]3[C:11](=[C:12]([C:24]([NH2:26])=[O:25])[CH:13]=2)[NH:10][CH:9]=[C:8]3[CH:6]2[CH2:5][CH2:4][S:3](=[O:27])(=[O:28])[C:2]([CH3:29])([CH3:1])[CH2:7]2)[CH:21]=1)[CH3:32]
Reactant: CNC
Reactant: CC1(C)CC(c2c[nH]c3c(C(N)=O)cc(-c4csc(C=O)c4)cc23)CCS1(=O)=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CS(C)=O
Product: CN(C)Cc1cc(-c2cc(C(N)=O)c3[nH]cc(C4CCS(=O)(=O)C(C)(C)C4)c3c2)cs1
Yield: 37.3 %

Procedure:
3-(2,2-Dimethyl-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-5-(5-formyl-3-thienyl)-1H-indole-7-carboxamide (30 mg, 0.070 mmol) was dissolved in dimethyl sulfoxide (1.5 mL) and put in a microwave vial. The mixture was stirred and 1-2 drops of acetic acid was added, dimethylamine (0.348 mL, 0.697 mmol) was added. The mixture was stirred 2 hours at 23° C., before adding sodium triacetoxyborohydride polymer bound (299 mg, 0.697 mmol). The vial was sealed using a silicon septum, and the mixture left stirring overnight at 23° C. The sodium triacetoxyborohydride polymer bound was removed by filtration (syringe filter 45 um). The product was purified by preparative HPLC(NH4OH buffer). The desired fractions were concentrated, giving 12 mg of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:11][C:12]2[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=2[F:19])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH:20]([O:22][CH2:23][CH2:24][CH2:25][CH2:26]O)=[CH2:21].C(C=P(CCCC)(CCCC)CCCC)#N>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:11]([C:12]2[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=2[F:19])[CH2:26][CH2:25][CH2:24][CH2:23][O:22][CH:20]=[CH2:21])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: C=COCCCCO
Reactant: O=S(=O)(Cc1cc(F)ccc1F)c1ccc(Cl)cc1
Agent: CCCCP(=CC#N)(CCCC)CCCC
Solvent: Cc1ccccc1
Product: C=COCCCCC(c1cc(F)ccc1F)S(=O)(=O)c1ccc(Cl)cc1

Procedure:
The 2-[(4-chlorophenyl)sulfonylmethyl]-1,4-difluorobenzene (0.94 g, 3.1 mmol) obtained in Example 5 was dissolved in toluene (30 ml). After addition of 4-vinyloxy-1-butanol (0.51 ml, 4.2 mmol) and cyanomethylenetri-n-butylphosphorane (1.0 g, 4.1 mmol), the resulting mixture was heated under reflux for 3 days under an argon atmosphere. The reaction mixture was allowed to cool down and then concentrated under reduced pressure. The residue thus obtained was purified by silica gel chromatography (hexane:ethyl acetate=10:1) to yield a white solid. The resulting white solid was washed with hexane, whereby the title compound (0.97 g, 78%) was obtained as a white powder.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C:5]1[C:15]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:14][CH:13]=[CH:12][C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8].C(N(CC)CC)C.[CH3:31][S:32](Cl)(=[O:34])=[O:33]>C(Cl)Cl>[CH3:31][S:32]([O:1][CH2:2][CH2:3][CH2:4][C:5]1[C:15]([O:16][CH2:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=[CH:12][C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8])(=[O:34])=[O:33]
Reactant: CS(=O)(=O)Cl
Reactant: CCOC(=O)c1cccc(OCc2ccccc2)c1CCCO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)c1cccc(OCc2ccccc2)c1CCCOS(C)(=O)=O
Temperature: 25 °C
Yield: 97.2 %

Procedure:
A solution of ethyl 2-(3-hydroxypropyl)-3-benzyloxybenzoate (10.19 g, 32.5 mmol), and triethyl amine (4.05 g, 40 mmol) in methylene chloride (100 ml) was cooled in an ice bath as methane sulfonyl chloride (2.79 ml, 36 mmol) was slowly added. The ice bath was removed and the reaction allowed to warm to room temperature over a 1 hr period. The mixture was diluted with water, and the methylene chloride layer was separated. The methylene chloride layer was washed with water twice, 1N HCl twice, and then filtered through a pad of silica gel to give a clear solution. This solution was concentrated in vacuo to give a clear oil (12.4 g, 98%).
Reaction SMILES: N#N.[C:3]([O:7][C:8](=[O:20])[NH:9][C@H:10]([C:12]1[CH:17]=[C:16]([CH3:18])[C:15](Br)=[CH:14][N:13]=1)[CH3:11])([CH3:6])([CH3:5])[CH3:4].[F:21][C:22]([F:33])([F:32])[C:23]1[CH:28]=[C:27](B(O)O)[CH:26]=[CH:25][N:24]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.CCOC(C)=O>[C:3]([O:7][C:8](=[O:20])[NH:9][C@H:10]([C:12]1[N:13]=[CH:14][C:15]([C:27]2[CH:26]=[CH:25][N:24]=[C:23]([C:22]([F:33])([F:32])[F:21])[CH:28]=2)=[C:16]([CH3:18])[CH:17]=1)[CH3:11])([CH3:6])([CH3:5])[CH3:4]
Reactant: OB(O)c1ccnc(C(F)(F)F)c1
Reactant: Cc1cc([C@H](C)NC(=O)OC(C)(C)C)ncc1Br
Agent: N#N
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: Cc1cc([C@H](C)NC(=O)OC(C)(C)C)ncc1-c1ccnc(C(F)(F)F)c1
Temperature: 90 °C
Reaction time: 16 h
Yield: 82.6 %

Procedure:
N2 was bubbled through a solution of (S)-tert-butyl(1-(5-bromo-4-methylpyridin-2-yl)ethyl)carbamate (200 mg, 0.635 mmol), (2-(trifluoromethyl)pyridin-4-yl)boronic acid (145 mg, 0.761 mmol) and Na2CO3 (2.0 M, 635 μl, 1.269 mmol) in dioxane for 5 min. Cl2Pd(dppf) (CH2Cl2 adduct) (51.8 mg, 0.063 mmol) was added. The reaction mixture was stirred at 90° C. for 16 hr. The mixture was diluted with EtOAc, washed with water, brine, dried over Na2SO4, filtered, concentrated and purified through flash column chromatography (0-100% EtOAc/Heptane) to give 200 mg (S)-tert-butyl(1-(4-methyl-2′-(trifluoromethyl)-[3,4′-bipyridin]-6-yl)ethyl)carbamate as a white solid. 1H NMR (400 MHz, CDCl3) δ 8.83 (d, J=4.9 Hz, 1H), 8.36 (s, 1H), 7.66 (s, 1H), 7.51-7.42 (m, 1H), 7.21 (s, 1H), 5.60 (d, J=7.7 Hz, 1H), 4.87 (p, J=6.9 Hz, 1H), 2.30 (s, 3H), 1.48 (d, J=6.9 Hz, 3H), 1.45 (s, 9H). MS m/z 382.3 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:21]=[CH:20][C:19]3[CH2:18][CH2:17][CH2:16][C:15](=O)[C:14]=3[C:13]=2[C:23]([OH:25])=[O:24])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[BH3-]C#[N:28].[Na+].C([O-])(=O)C.[NH4+]>CO>[NH2:28][CH:15]1[C:14]2[C:13]([C:23]([OH:25])=[O:24])=[C:12]([NH:11][S:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)(=[O:10])=[O:9])[CH:21]=[CH:20][C:19]=2[CH2:18][CH2:17][CH2:16]1
Reactant: O=C1CCCc2ccc(NS(=O)(=O)c3ccc(F)cc3)c(C(=O)O)c21
Reactant: [BH3-]C#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Product: NC1CCCc2ccc(NS(=O)(=O)c3ccc(F)cc3)c(C(=O)O)c21

Procedure:
A mixture of Example 103B (20 mg, 0.055 mmol), NaCNBH3 (17.2 mg, 0.275 mmol), and ammonium acetate (42 mg, 0.55 mmol) in methanol (5 mL) was heated to reflux overnight and concentrated. The concentrate was purified by reverse-phase HPLC to provide the desired product. MS (ESI) m/e 363 (M−H)−; 1H NMR (300 MHz, DMSO-d6) δ 8.4 (br s, 2H), 7.66 (m, 2H), 7.36 (m, 2H), 7.25 (d, 1H), 7.14 (d, 1H), 4.42 (br s, 1H), 2.65 (m, 2H), 2.06 (m, 2H), 1.68 (m, 2H).
Reaction SMILES: [C:1]([C:3]([C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=1)[C:9]([OH:11])=O)([CH3:5])[CH3:4])#[N:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[Br:48][C:49]1[CH:55]=[CH:54][C:52]([NH2:53])=[CH:51][C:50]=1[N+:56]([O-:58])=[O:57]>CN(C=O)C>[Br:48][C:49]1[CH:55]=[CH:54][C:52]([NH:53][C:9](=[O:11])[C:8]2[CH:12]=[CH:13][CH:14]=[C:6]([C:3]([C:1]#[N:2])([CH3:4])[CH3:5])[CH:7]=2)=[CH:51][C:50]=1[N+:56]([O-:58])=[O:57]
Reactant: Nc1ccc(Br)c([N+](=O)[O-])c1
Reactant: CC(C)(C#N)c1cccc(C(=O)O)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C#N)c1cccc(C(=O)Nc2ccc(Br)c([N+](=O)[O-])c2)c1
Temperature: 60 °C
Reaction time: 8 h
Yield: 249.8 %

Procedure:
A solution of 3-(2-cyanopropan-2-yl)benzoic acid 3 (436 mg, 2.304 mmol), HATU (1.051 g, 2.76 mmol) and DIPEA (0.762 mL, 4.61 mmol) in DMF (9 mL) was stirred 15 min at rt. 4-bromo-3-nitroaniline (200 mg, 0.922 mmol) was added and stirred overnight at 60° C. The reaction mixture was cooled to rt and extracted with CH2Cl2. Organic layer was washed (3×) with water, dried and evaporated. Purification by chromatography heptane:EtOAc (1:1) gave N-(4-bromo-3-nitrophenyl)-3-(2-cyanopropan-2-yl)benzamide 61 (894 mg, 89%). (m/z)=388 and 390 (M+H)+.
Reaction SMILES: C(N(CC)CC)C.[CH:8](=[O:12])/[CH:9]=[CH:10]/[CH3:11].[C:13]1([Si:19]([CH3:22])([CH3:21])Cl)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>[Cl-].[Zn+2].[Cl-].C1(C)C=CC=CC=1>[CH:8]([O:12][Si:19]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([CH3:22])[CH3:21])=[CH:9][CH:10]=[CH2:11]
Reactant: C[Si](C)(Cl)c1ccccc1
Reactant: C/C=C/C=O
Agent: [Cl-]
Agent: [Zn+2]
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: C=CC=CO[Si](C)(C)c1ccccc1
Temperature: 25 °C
Yield: 59 %

Procedure:
A 250 mL flask, fitted with a magnetic stirrer, a reflux condenser and an addition funnel, was charged with zinc chloride (0.25 g, 1.83 mmol, anhydrous), triethylamine (36.2 mL, 0.260M, distilled from CaH2), crotonaldehyde (21.0 mL, 0.257M, dried over MgSO4 and distilled), and toluene (35 mL, distilled from sodium). 42 mL of phenyldimethyl chlorosilane (0.254M) were added dropwise via the addition funnel over one hour with stirring. The resulting mixture was heated slowly to about 65° and maintained at 65°-75° for a total of 6.5 hours with stirring. The mixture was cooled to ambient temperature and filtered to remove precipitated triethylamine hydrochloride (32 g, 92%) which was rinsed on the filter with 35 mL of dry toluene. The resulting filtrate and rinse were combined and distilled on a water pump at about 110 mm to remove solvent and unreacted starting materials. The resulting residue was distilled on an oil pump to give (1,3-butadienyloxy)phenyldimethylsilane (30.9 g, 59%) as a colorless liquid boiling at 57.8°-59.0°/0.10 mm (13 Pa).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]([N:13]3[CH2:17][CH2:16][C@@H:15]([OH:18])[CH2:14]3)=[O:12])[S:10][C:3]=12.[CH:19]1([NH:22][C:23]([C:25]2[C:33]3[C:28](=[CH:29][C:30]([OH:34])=[CH:31][CH:32]=3)[N:27]([CH3:35])[C:26]=2[CH3:36])=[O:24])[CH2:21][CH2:20]1.C([O-])([O-])=O.[Cs+].[Cs+]>>[CH:19]1([NH:22][C:23]([C:25]2[C:33]3[C:28](=[CH:29][C:30]([O:34][C:2]4[CH:7]=[CH:6][N:5]=[C:4]5[CH:8]=[C:9]([C:11]([N:13]6[CH2:17][CH2:16][C@@H:15]([OH:18])[CH2:14]6)=[O:12])[S:10][C:3]=45)=[CH:31][CH:32]=3)[N:27]([CH3:35])[C:26]=2[CH3:36])=[O:24])[CH2:20][CH2:21]1
Reactant: O=C(c1cc2nccc(Cl)c2s1)N1CC[C@@H](O)C1
Reactant: Cc1c(C(=O)NC2CC2)c2ccc(O)cc2n1C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: Cc1c(C(=O)NC2CC2)c2ccc(Oc3ccnc4cc(C(=O)N5CC[C@@H](O)C5)sc34)cc2n1C

Procedure:
This material was prepared by the reaction of (7-chloro-thieno [3,2-b]pyridin-2-yl)-((R)-3-hydroxy-pyrrolidin-1-yl)-methanone 4a with 6-hydroxy-1,2-dimethyl-1H-indole-3-carboxylic acid cyclopropylamide 20b and Cs2CO3 in a manner as previously described for example 1. 1H NMR (300 MHz, CD3OD) δ8.50 (1H, d, J=5.5 Hz), 7.93 (1H, d, J=17.33 Hz), 7.80 (1H, d, J=8.6 Hz), 7.39 (1H, d, J=2.1 Hz), 7.05 (1H, dd, J=2.1, 8.6 Hz), 6.71 (1H, d, J=5.5 Hz), 4.54 (1H, bs), 4.11-4.00 (2H, m), 3.85-3.72 (6H, m), 2.93-2.86 (1H, m), 2.66 (3H, s), 2.19-2.07 (2H, m), 0.90-0.84 (2H, m), 0.76-0.68 (2H, m). LCMS (ESI+) [M+H]/z Calc'd 491, found 491.
Reaction SMILES: [NH2:1][C:2]1[C:6]([C:7]#[N:8])=[CH:5][NH:4][N:3]=1.CN(C)[CH:11]=[C:12]([CH3:25])[C:13]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=1)=O>C(O)(=O)C>[CH3:25][C:12]1[CH:11]=[N:1][C:2]2[N:3]([N:4]=[CH:5][C:6]=2[C:7]#[N:8])[C:13]=1[C:15]1[CH:16]=[C:17]([C:21]([F:22])([F:23])[F:24])[CH:18]=[CH:19][CH:20]=1
Reactant: CC(=CN(C)C)C(=O)c1cccc(C(F)(F)F)c1
Reactant: N#Cc1c[nH]nc1N
Solvent: CC(=O)O
Product: Cc1cnc2c(C#N)cnn2c1-c1cccc(C(F)(F)F)c1

Procedure:
A mixture of 1.08 g. of 3-aminopyrazole-4-carbonitrile, 25 ml. of glacial acetic acid and 2.57 g. of 3-dimethylamino-2-methyl-3'-(trifluoromethyl)acrylophenone is refluxed for 8 hours and then evaporated to a crystalline solid. A methylene chloride solution of this solid is treated as described in Example 1, giving the desired product, m.p. 191°-193° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([NH2:23])[C:7](=[O:22])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][C:11]([Cl:21])=[CH:10][CH:9]=2)=[O:4].[O:24]1[CH:28]=[CH:27][C:26]([CH:29]=O)=[CH:25]1>>[CH3:1][O:2][C:3]([C:5]1[N:6]([N:23]=[CH:29][C:26]2[CH:27]=[CH:28][O:24][CH:25]=2)[C:7](=[O:22])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][C:11]([Cl:21])=[CH:10][CH:9]=2)=[O:4]
Reactant: COC(=O)c1c(-c2ccccc2)c2cc(Cl)ccc2c(=O)n1N
Reactant: O=Cc1ccoc1
Product: COC(=O)c1c(-c2ccccc2)c2cc(Cl)ccc2c(=O)n1N=Cc1ccoc1

Procedure:
The present compound was synthesized by a method similar to that in Example 210 and using 2-amino-6-chloro-1-oxo-4-phenyl-1,2-dihydroisoquinoline-3-carboxylic acid methyl ester (210 mg) and furan-3-carbaldehyde. A colorless powder (130 mg).
Reaction SMILES: [CH2:1]([S:3][C:4]1[NH:5][C:6](=O)[C:7]2[S:12][C:11]3[N:13]=[C:14]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[CH:15]=[C:16]([CH3:17])[C:10]=3[C:8]=2[N:9]=1)[CH3:2].O=P(Cl)(Cl)[Cl:27].C(=O)([O-])O.[Na+]>>[Cl:27][C:6]1[C:7]2[S:12][C:11]3[N:13]=[C:14]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[CH:15]=[C:16]([CH3:17])[C:10]=3[C:8]=2[N:9]=[C:4]([S:3][CH2:1][CH3:2])[N:5]=1
Reactant: CCSc1nc2c(sc3nc(-c4ccccc4)cc(C)c32)c(=O)[nH]1
Reactant: O=P(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: CCSc1nc(Cl)c2sc3nc(-c4ccccc4)cc(C)c3c2n1
Temperature: 0 °C
Yield: 22.3 %

Procedure:
1.23 g (3.5 mmol) 2-ethylthio-9-methyl-7-phenyl-pyrido[3′,2′:4,5]-thieno[3,2-d]pyrimidin-4-one is refluxed in 10 ml (10.9 mol) phosphoroxychloride for 6 h. Then, the product is poured onto about 100 g ice water and neutralized with saturated sodium hydrogen carbonate solution. The precipitate is sucked off, washed with about 100 ml water, dried and purified by means of flash chromatography (dichloromethane/petroleum ether 5:1). 0.29 g (22%) 4-chloro-2-ethylthio-9-methyl-7-phenyl-pyrido[3′,2′:4,5]thieno[3,2-d]pyrimidine is obtained.
Reaction SMILES: [ClH:1].[NH2:2][NH:3][C:4](=[NH:7])[NH:5][NH2:6].O.[CH3:9][C:10]1([CH3:19])[CH2:15][C:14](=O)[CH2:13][C:12]([CH3:18])([CH3:17])[NH:11]1>C(O)C>[ClH:1].[CH3:9][C:10]1([CH3:19])[CH2:15][C:14](=[N:2][NH:3][C:4]([NH:5][N:6]=[C:14]2[CH2:13][C:12]([CH3:18])([CH3:17])[NH:11][C:10]([CH3:19])([CH3:9])[CH2:15]2)=[NH:7])[CH2:13][C:12]([CH3:18])([CH3:17])[NH:11]1
Reactant: CC1(C)CC(=O)CC(C)(C)N1
Reactant: N=C(NN)NN
Agent: Cl
Solvent: O
Solvent: CCO
Product: CC1(C)CC(=NNC(=N)NN=C2CC(C)(C)NC(C)(C)C2)CC(C)(C)N1
Temperature: 25 °C
Yield: 50 %

Procedure:
A solution of diaminoguanidine hydrochloride (6.28 grams; 0.05 mole) and 2,2,6,6-tetramethyl-4-piperidone monohydrate (17.3 grams; 0.10 mole) in 200 mls. of ethanol 2B was refluxed for a period of 15 hours while stirring. The resulting slurry was cooled to 25° C. and the solid was separated to obtain 10.0 grams of crude 1,3-bis[(2,2,6,6-tetramethyl-4-piperidylidene)amino]guanidine hydrochloride. Recrystallization of the crude hydrochloride from ethanol 2B gave 8.9 grams of white solid, m.p. 210°-220° C. (dec).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C:4]([NH:14][C:15](=[O:17])[CH3:16])=[C:5](OS(C)(=O)=O)[CH2:6][O:7][CH3:8].C(NCC)C>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:18])/[C:4](/[NH:14][C:15](=[O:17])[CH3:16])=[CH:5]/[CH2:6][O:7][CH3:8]
Reactant: COCC(OS(C)(=O)=O)=C(NC(C)=O)C(=O)OC
Solvent: CCNCC
Solvent: ClCCl
Product: COC/C=C(\NC(C)=O)C(=O)OC

Procedure:
A solution consisting of 27.6 g (0.098 mol) of mesylate 9, 20.5 ml of diethylamine and 250 ml of methylene chloride was heated at reflux temperature for 2 hrs under an atmosphere of argon. The resultant solution was cooled, concentrated in vacuo and the residue filtered through a column of silica gel (125 g) using ethyl acetate as the eluent. The fractions containing product (as determined by thin layer chromatography) were combined and concentrated in vacuo. Crystallization of the residue from ether/petroleum ether (bp 35°-60°) yielded Z-2-acetamido-4-methoxy-2-butenoic acid methyl ester (4) identical to the material obtained by the previous method (Examples 1 and 2). The mother liquors from the crystallization of 4 were concentrated in vacuo to yield an oil which contained a 1:1 mixture of 4 and E-2-acetamido-4-methoxy-2-butenoic acid methyl ester (5).