Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:6]2[C:11]([CH:12]=[CH2:13])=[CH:10][CH:9]=[C:8]([C:14]([F:17])([F:16])[F:15])[N:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.CN1C=CN=C1.[CH2:24]([O:26][C:27](=[O:31])[CH:28]=[N+]=[N-])[CH3:25]>C1(C)C=CC=CC=1>[N:1]1([C:6]2[C:11]([CH:12]3[CH2:13][CH:28]3[C:27]([O:26][CH2:24][CH3:25])=[O:31])=[CH:10][CH:9]=[C:8]([C:14]([F:17])([F:15])[F:16])[N:7]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CCOC(=O)C=[N+]=[N-]
Reactant: C=Cc1ccc(C(F)(F)F)nc1N1CCCC1
Agent: Cn1ccnc1
Solvent: Cc1ccccc1
Product: CCOC(=O)C1CC1c1ccc(C(F)(F)F)nc1N1CCCC1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 92.1 %

Procedure:
To a THF (25 ml) suspension of methyltriphenylphosphonium bromide (3.8 g, 10.6 mmol) was added 1.60 M n-butyllithium in hexane solution (6.7 ml, 10.6 mmol) at 0° C. and the reaction was stirred for 30 minutes. Then the THF (5 ml) solution of the compound of Example 46C (1.3 g, 5.3 mmol) was added to at room temperature and stirred for 1 hour at room temperature. The reaction was quenched with saturated ammonium chloride aqueous solution, and the whole was extracted with EtOAc, dried over magnesium sulfate, and evaporated. The crude residue was purified by silica gel column chromatography, eluting with hexane/EtOAc (10:1), to give 2-pyrrolidin-1-yl-6-(trifluoromethyl)-3-vinylpyridine (1.03 g, 80%, trans). To a toluene (15 ml) solution of 2-pyrrolidin-1-yl-6-(trifluoromethyl)-3-vinylpyridine (1.03 g, 4.3 mmol), Co(TPP) (142 mg, 0.2 mmol) and 1-methyl-1H-imidazole (1.22 ml, 14.9 mmol), ethyldiazoacetate (1.0 ml, 8.5 mmol) was added and the mixture was stirred for 5 minutes at room temperature followed by additional stirring for 2 hour at 80° C. Then, evaporation and purification by silica gel column chromatography, eluting with hexane/EtOAc (20:1), gave ethyl 2-[2-pyrrolidin-1-yl-6-(trifluoromethyl)pyridin-3-yl]cyclopropanecarboxylate (1.3 g, 93%). To a THF (10 ml) solution of this compound (1.3 g, 4.0 mmol), 2M sodium hydroxide aqueous solution (15 ml) and MeOH (15 ml) were added and the mixture was stirred for 2 hours at room temperature. After the reaction was completed, the aqueous layer was extracted and then acidified with 2M HCl aqueous solution. The whole was extracted with EtOAc followed by evaporation to give the title compound (1.1 g, 92%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[C:8](I)[C:7]([C:11]([F:14])([F:13])[F:12])=[CH:6][C:5]=1[NH2:15].[CH3:17][N:18]1[C:22]([Sn](CCCC)(CCCC)CCCC)=[CH:21][C:20]([CH3:36])=[N:19]1>O1CCOCC1>[CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[C:8]([C:22]2[N:18]([CH3:17])[N:19]=[C:20]([CH3:36])[CH:21]=2)[C:7]([C:11]([F:14])([F:13])[F:12])=[CH:6][C:5]=1[NH2:15]
Reactant: COC(=O)c1cc(I)c(C(F)(F)F)cc1N
Reactant: CCCC[Sn](CCCC)(CCCC)c1cc(C)nn1C
Solvent: C1COCCO1
Product: COC(=O)c1cc(-c2cc(C)nn2C)c(C(F)(F)F)cc1N
Temperature: 80 °C
Reaction time: 18 h
Yield: 72 %

Procedure:
A mixture containing 2-amino-5-iodo-4-trifluoromethyl-benzoic acid methyl ester (1.0 g, 2.9 mmol), 1,3-dimethyl-5-tributylstannanyl-1H-pyrazole (1.34, 1.2 equiv) and bistriphenylphosphinedichloropalladium (207 mg, 0.1 equiv) in dioxane (15 mL) was stirred for 18 h at 80° C. Bistriphenylphosphinedichloropalladium (0.1 equiv) and another portion of the stannyl derivative (0.4 equiv) were added and the mixture was stirred for 24 h at 80° C. The mixture was evaporated to dryness. The crude product was purified by flash chromatography (hexanes to EtOAc/hexanes (1:1)) to provide 2-amino-5-(2,5-dimethyl-2H-pyrazol-3-yl)-4-trifluoromethyl-benzoic acid methyl ester (651 mg, 72%) as a yellow paste. (ESI-MS: m/z 314.2 [M+H]+, rt 5.12 min).
Reaction SMILES: C[O:2][C:3](=[O:32])[CH2:4][C@@H:5]([N:8]1[C:13](=[O:14])[C:12]2[N:15]=[CH:16][CH:17]=[CH:18][C:11]=2[N:10]([CH2:19][C:20]2[C:24]3[C:25]([CH3:30])=[CH:26][C:27]([CH3:29])=[CH:28][C:23]=3[S:22][N:21]=2)[C:9]1=[O:31])[CH2:6][CH3:7].[OH-].[Li+].C(O)(=O)C.O>O1CCOCC1>[CH3:30][C:25]1[C:24]2[C:20]([CH2:19][N:10]3[C:11]4[CH:18]=[CH:17][CH:16]=[N:15][C:12]=4[C:13](=[O:14])[N:8]([C@@H:5]([CH2:6][CH3:7])[CH2:4][C:3]([OH:32])=[O:2])[C:9]3=[O:31])=[N:21][S:22][C:23]=2[CH:28]=[C:27]([CH3:29])[CH:26]=1
Reactant: CC[C@@H](CC(=O)OC)n1c(=O)c2ncccc2n(Cc2nsc3cc(C)cc(C)c23)c1=O
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Solvent: CC(=O)O
Product: CC[C@@H](CC(=O)O)n1c(=O)c2ncccc2n(Cc2nsc3cc(C)cc(C)c23)c1=O
Reaction time: 3.5 h
Yield: 33.5 %

Procedure:
To a solution of 80 mg of (S)-3-[1-(4,6-dimethyl-benzo[d]isothiazol-3-ylmethyl)-2,4-dioxo-1,4-dihydro-2H-pyrido[3,2-d]pyrimidin-3-yl]-pentanoic acid methyl ester in 1,4-dioxane (2.5 mL) is added lithium hydroxide solution (11 mg of lithium hydroxide monohydrate in 0.5 mL of water) at room temperature. The solution is stirred at the same temperature for 3.5 h. Then 0.5 mL of acetic acid is added along with 25 mL of water. The mixture is extracted with ethyl acetate (3×50 mL). The combined organic layers are dried over sodium sulfate and concentrated. The residue is purified by flash chromatography on silica gel to give 26 mg (34%) of (S)-3-[1-(4,6-dimethyl-benzo[d]isothiazol-3-ylmethyl)-2,4-dioxo-1,4-dihydro-2H-pyrido[3,2-d]pyrimidin-3-yl]-pentanoic acid; LCMS (ESMS): m/z 439.12 (M+H+).
Reaction SMILES: [P:1]([O:5][C@@H:6]1[C@@H:10]([CH2:11][OH:12])[O:9][C@@H:8]([N:13]2[C:23]3[N:22]=[C:20]([NH2:21])[NH:19][C:17](=[O:18])[C:16]=3[N:15]=[CH:14]2)[C@@H:7]1[OH:24])(O)([OH:3])=[O:2].C(O)(C)(C)C.C1([N:36]=C=NC2CCCCC2)CCCCC1>O.N.C(N)=O>[P:1]([O:5][C@@H:6]1[C@@H:10]([CH2:11][OH:12])[O:9][C@@H:8]([N:13]2[C:23]3[N:22]=[C:20]([NH2:21])[NH:19][C:17](=[O:18])[C:16]=3[N:15]=[CH:14]2)[C@@H:7]1[OH:24])([NH2:36])(=[O:2])[OH:3]
Reactant: Nc1nc2c(ncn2[C@@H]2O[C@H](CO)[C@@H](OP(=O)(O)O)[C@H]2O)c(=O)[nH]1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Agent: N
Solvent: O
Solvent: NC=O
Solvent: CC(C)(C)O
Product: Nc1nc2c(ncn2[C@@H]2O[C@H](CO)[C@@H](OP(N)(=O)O)[C@H]2O)c(=O)[nH]1
Temperature: 80 °C
Reaction time: 8 h
Yield: 50 %

Procedure:
Three millimoles of guanosine-3'-monophosphate were dissolved in a mixture of 7.5 ml of 2 N ammonia water and 5 ml of formamide, the solution was combined with 20 ml of tertiary butanol that contained 15 millimoles of dicyclohexyl carbodiimide, and the resulting mixture was heated at 80° C. for a period of 9 to 10 hours with care taken to prevent evaporation of the solvent. After the reaction, the mixture was left to stand overnight at room temperature, the precipitate was filtered off, the filtrate was concentrated under vacuum to remove the tertiary butanol, and the residue was extracted with ether. The aqueous layer was recovered, concentrated under vacuum, and the residue was treated with acetone to give a crystal of guanosine-3'-monophosphoramidate in a yield of about 50%. The crystal was heated under vacuum at 100° C. for a period of 3 to 4 hours until it was dehydrated thoroughly.
Reaction SMILES: [CH2:1]([O:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:25]C)[N:12]2[CH2:15][CH2:16][CH2:17][CH2:18][CH:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)=[C:8]([NH2:27])[N:7]=1)[CH2:2][CH2:3][CH3:4].I[CH2:29][CH2:30][CH:31]1[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1>>[NH2:27][C:8]1[N:7]=[C:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])[N:14]=[C:13]2[C:9]=1[NH:10][C:11](=[O:25])[N:12]2[CH2:15][CH2:16][CH2:17][CH2:18][CH:19]1[CH2:20][CH2:21][N:22]([CH2:29][CH2:30][CH:31]2[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]2)[CH2:23][CH2:24]1
Reactant: CCCCOc1nc(N)c2nc(OC)n(CCCCC3CCNCC3)c2n1
Reactant: ICCC1CCCCC1
Product: CCCCOc1nc(N)c2[nH]c(=O)n(CCCCC3CCN(CCC4CCCCC4)CC3)c2n1

Procedure:
Prepared similarly to Example 80 from 2-(butyloxy)-8-(methyloxy)-9-[4-(4-piperidinyl)butyl]-9H-purin-6-amine and (2-iodoethyl)cyclohexane.
Reaction SMILES: [C:1]([OH:25])(=[O:24])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]#[C:11][C:12]#[C:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23].CO.[CH:28](Cl)(Cl)Cl>S(=O)(=O)(O)O.C(O)C>[C:1]([O:25][CH3:28])(=[O:24])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]#[C:11][C:12]#[C:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: ClC(Cl)Cl
Reactant: CCCCCCCCCCC#CC#CCCCCCCCCC(=O)O
Agent: O=S(=O)(O)O
Solvent: CO
Solvent: CCO
Product: CCCCCCCCCCC#CC#CCCCCCCCCC(=O)OC
Temperature: 25 °C

Procedure:
10,12-tricosadiynoic acid (10 gm., GFS Chemicals) was dissolved in a solution containing 10 ml methanol (HPLC grade) and 10 ml chloroform (HPLC grade). The solution was stirred at room temperature and 10 drops of neat sulfuric acid was added drop wise. The solution was warmed to 100° F. for 2 hour. The reaction mixture was purified using column chromatography. The product (MeTDA) was dried using a Rotovap and the material stored in a chloroform solution. The solid form of MeTDA was very unstable to polymerization and therefore kept dissolved in organic solutions. Alcoholic solutions of MePDA and MeTDA: Solids MePDA or MeTDA were dissolved in reagent grade ethanol to a concentration of 150 mg/ml. A residual polymer was removed by filtration through Whatman No. 1 filter paper. The solutions were held at room temperature or slightly above (70-75° F.) to avoid crystallization or precipitation.
Reaction SMILES: ClC1C=CC=CC=1CCCN1C(=O)C(CN2CCN(C)CC2)=CC(C2C=CC3OCCC=3C=2)=N1.[C:35]([C:38]1[C:39](=[O:63])[N:40]([CH2:53][CH2:54][CH2:55][C:56]2[CH:61]=[CH:60][C:59]([Cl:62])=[CH:58][CH:57]=2)[N:41]=[C:42]([C:44]2[CH:45]=[CH:46][C:47]3[O:51][CH2:50][CH2:49][C:48]=3[CH:52]=2)[CH:43]=1)(O)=[O:36]>>[Cl:62][C:59]1[CH:60]=[CH:61][C:56]([CH2:55][CH2:54][CH2:53][N:40]2[C:39](=[O:63])[C:38]([CH2:35][OH:36])=[CH:43][C:42]([C:44]3[CH:45]=[CH:46][C:47]4[O:51][CH2:50][CH2:49][C:48]=4[CH:52]=3)=[N:41]2)=[CH:57][CH:58]=1
Reactant: O=C(O)c1cc(-c2ccc3c(c2)CCO3)nn(CCCc2ccc(Cl)cc2)c1=O
Agent: CN1CCN(Cc2cc(-c3ccc4c(c3)CCO4)nn(CCCc3ccccc3Cl)c2=O)CC1
Product: O=c1c(CO)cc(-c2ccc3c(c2)CCO3)nn1CCCc1ccc(Cl)cc1
Yield: 53.3 %

Procedure:
The general procedure of Example 1 (4) was carried out by use of 4-carboxy-2-[3-(4-chlorophenyl)propyl]-6-(2,3-dihydro-1-benzofuran-5-yl)-2H-pyridazin-3-one, to thereby yield the title compound as a yellow oil (yield: 53.3%).
Reaction SMILES: I[C:2]1[S:3][C:4]([CH3:8])=[C:5]([CH3:7])[N:6]=1.[NH:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1>>[CH3:7][C:5]1[N:6]=[C:2]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[S:3][C:4]=1[CH3:8]
Reactant: Cc1nc(I)sc1C
Reactant: C1CNCCN1
Product: Cc1nc(N2CCNCC2)sc1C
Yield: 25 %

Procedure:
Prepared in analogy to example 2 (b) from 2-iodo-4,5-dimethyl-thiazole and piperazine. The crude material was purified by chromatography (SiO2, methanol/dichloromethane) to yield the title compound as a yellow crystalline solid (yield 25%). MS (m/e): 198.3 (M+H+, 100%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([O:13][CH3:14])=[C:5]([CH3:15])[C:4]=1/[CH:16]=[C:17](\[CH3:23])/[C:18]([O:20]CC)=[O:19].COC1C2C(=CC=CC=2)C(OC)=CC=1/C=C(\C)/C(O)=O>CC(C)=O>[CH3:1][O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([O:13][CH3:14])=[C:5]([CH3:15])[C:4]=1/[CH:16]=[C:17](\[CH3:23])/[C:18]([OH:20])=[O:19]
Reactant: CCOC(=O)/C(C)=C/c1c(C)c(OC)c2ccccc2c1OC
Agent: COc1cc(/C=C(\C)C(=O)O)c(OC)c2ccccc12
Solvent: CC(C)=O
Product: COc1c(C)c(/C=C(\C)C(=O)O)c(OC)c2ccccc12

Procedure:
Compound 99a was prepared from 98a (0.176 g, 0.560 mmol) as described above for 29a to give 0.134 g (0.468 mmol, 83%) of the product as a light yellow solid following flash chromatography (3:17 acetone:hexanes 0.5% AcOH) and recrystallization from Et2O/hexanes.
Reaction SMILES: N#N.[CH2:3]([N:10]1[CH2:14][CH2:13][C@H:12]([C@@H:15]([OH:20])[CH2:16][CH:17]([CH3:19])[CH3:18])[CH2:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[H-].[Na+].[Cl:23][C:24]1[N:29]=[C:28]([CH3:30])[C:27](F)=[CH:26][CH:25]=1>CC(N(C)C)=O>[CH2:3]([N:10]1[CH2:14][CH2:13][C@H:12]([C@@H:15]([O:20][C:27]2[C:28]([CH3:30])=[N:29][C:24]([Cl:23])=[CH:25][CH:26]=2)[CH2:16][CH:17]([CH3:18])[CH3:19])[CH2:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: Cc1nc(Cl)ccc1F
Reactant: CC(C)C[C@H](O)[C@H]1CCN(Cc2ccccc2)C1
Agent: N#N
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: Cc1nc(Cl)ccc1O[C@@H](CC(C)C)[C@H]1CCN(Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 67 %

Procedure:
Charge a 200 mL round bottom flask equipped with a Claisen adaptor, thermal couple and N2 inlet with (S)-1-benzyl-3-((S)-1-hydroxy-3-methylbutyl)-pyrrolidine (5.69 g, 23 mmoles) and DMA (58 mL). Add NaH (1.29 g, 32.2 mmoles) in one portion with stirring and stir at room temperature for 1 hour. Add 6-chloro-3-fluoro-2-methylpyridine (3.52 g, 24.15 mmoles) in one portion with stirring and then stir at room temperature for 24 hours. Quench the reaction mixture with H2O (120 mL) and extract with MTBE (120 mL). Wash the organic layer with H2O (2×60 mL), followed by brine (60 mL), and then dry over Na2SO4. Filter, concentrate, and then purify the crude material (in toluene) by loading onto silica (225 g, wet with toluene) and eluting with the following: hexanes (2×500 mL), 15% MTBE/hexanes (16×500 mL), 50% MTBE/hexanes (8×500 mL). Concentrate the appropriate fractions to give (S)-1-benzyl-3-((S)-1-(6-chloro-2-methyl-3-pyridyloxy)-3-methylbutyl)-pyrrolidine as a light yellow oil (5.77 g, 15.47 mmoles, 67% yield, purity >98%). 1H NMR (300 MHz, CDCl3) δ 7.38-7.20 (m, 5H), 7.06 (s, 2H), 4.32-4.20 (m, 1H), 3.68-3.48 (m, 2H) 2.78-2.64 (m, 2H), 2.64-2.30 (m, 2H), 2.42 (s, 3H), 2.28-2.20 (m, 1H), 2.05-1.85 (m, 1H), 1.82-1.52 (m, 4H), 1.48-1.34 (m, 1H), 0.92 (d, 3H, J=6.45 Hz), 0.88 (d, 3H, J=6.45 Hz). LC/MS=373.2 (M), 375.3 (M+2).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][N:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[F:25])[CH2:15][CH2:14]3)=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.Cl[CH2:27][CH2:28][N:29]([CH3:31])[CH3:30]>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][N:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[F:25])[CH2:15][CH2:14]3)=[O:12])=[CH:7][N:8]2[CH2:27][CH2:28][N:29]([CH3:31])[CH3:30])=[CH:4][CH:3]=1
Reactant: CN(C)CCCl
Reactant: O=C(c1c[nH]c2cc(Cl)ccc12)N1CCN(c2ccccc2F)CC1
Product: CN(C)CCn1cc(C(=O)N2CCN(c3ccccc3F)CC2)c2ccc(Cl)cc21

Procedure:
Following general procedure II, the alkylation of (6-chloro-1H-indol-3-yl)-[4-(2-fluoro-phenyl)-piperazin-1-yl]-methanone (preparation described herein), with (commercially available) (2-chloro-ethyl)-dimethyl-amine gave the title compound.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=1[CH:14]1[CH2:23][CH2:22][C:21]2[CH:20]=[C:19]([O:24]C(=O)C(C)(C)C)[CH:18]=[CH:17][C:16]=2[CH2:15]1)[CH3:2].Cl.[N:32]1([CH2:39][CH2:40][CH2:41][C:42]2[CH:50]=[CH:49][C:45]([C:46](O)=O)=[CH:44][CH:43]=2)[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1>>[N:32]1([CH2:39][CH2:40][CH2:41][C:42]2[CH:50]=[CH:49][C:45]([CH2:46][CH2:2][CH2:1][NH:3][C:4]3[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=3[CH:14]3[CH2:23][CH2:22][C:21]4[CH:20]=[C:19]([OH:24])[CH:18]=[CH:17][C:16]=4[CH2:15]3)=[CH:44][CH:43]=2)[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1
Reactant: CCNc1cc(OC)c(OC)cc1C1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Reactant: O=C(O)c1ccc(CCCN2CCCCCC2)cc1
Agent: Cl
Product: COc1cc(NCCCc2ccc(CCCN3CCCCCC3)cc2)c(C2CCc3cc(O)ccc3C2)cc1OC
Yield: 44.3 %

Procedure:
Synthesized from pivalic acid 6-(2-ethylamino-4,5-dimethoxyphenyl)-5,6,7,8-tetrahydronaphthalen-2-yl ester (50 mg) and 4-(3-azepan-1-ylpropyl)benzoic acid hydrochloride (100 mg) according to an analogous synthetic method to Example 337 described below, the title compound (30 mg) was obtained.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8](=[CH2:12])[C:9]([NH2:11])=[O:10].[C:13](OC(=O)C)(=[O:15])[CH3:14].CN(C1C=CC=CN=1)C>N1C=CC=CC=1>[C:13]([O:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8](=[CH2:12])[C:9]([NH2:11])=[O:10])(=[O:15])[CH3:14]
Reactant: CC(=O)OC(C)=O
Reactant: C=C(CCCCCCO)C(N)=O
Agent: CN(C)c1ccccn1
Solvent: c1ccncc1
Product: C=C(CCCCCCOC(C)=O)C(N)=O
Reaction time: 8 h

Procedure:
6-Hydroxyhexylacrylamide (4.00 gm, 23.4 mmole), acetic anhydride (4.41 mL, 46.8 mmole) and dimethylamino pyridine (23.3 mg, 2.3 mmole) were dissolved in 15 mL of pyridine and were allowed to react at room temperature for 4 hours. After evaporation of the solvents the residue was dissolved in 100 mL of ethyl acetate and was washed with N HCl and brine. After drying over Na2SO4 the organic solution was filtered and the solvent was removed in vacuo to yield a yellow syrup. Crystallisation was induced by adding and evaporating benzene followed by hexane. Crude yield: 4.84 gm, mp 38°-45° C. 3.5 gm of this crude product was dissolved in 20 mL of EtOAc, decolorised with charcoal and was dropped into 200 mL of hexane. On stirring the material crystallised. After sitting at 4° C. overnight the product was collected. Yield 2.50 gm (71% recrystallised) mp 43°-43.5° C. TLC Rf 0.47 (CHCl3 :MeOH 9:1). NRM:δ(CDCl3) 6.67 (br s, 1 H, NH), 5.5-6.4 (M, 3 H, CH2 =CH--), 4.03 (tr, J=6 Hz, 2 H, CH2O) 3.30 (br q, 3 H, CH2N), 2.02 (s,3 H, COCH3), 1.4 (m, 8 H, (CH2)4). Analysis: C11H19NO3 requires C, 61.95%; H, 898%; N, 6.56%. Found: C, 62.09%; H, 9.09%; N, 6.51%.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]([CH3:13])([CH3:12])[CH2:10][CH2:9][C:8](=[O:14])[N:7]([CH2:15][CH:16]([CH3:18])[CH3:17])[C:6]=2[CH:19]=1.Cl[C:21]1[N:26]=[C:25]([NH:27][C:28]2[CH:33]=[CH:32][C:31]([N:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)=[CH:30][C:29]=2[O:40][CH3:41])[C:24]([Cl:42])=[CH:23][N:22]=1>>[Cl:42][C:24]1[C:25]([NH:27][C:28]2[CH:33]=[CH:32][C:31]([N:34]3[CH2:35][CH2:36][O:37][CH2:38][CH2:39]3)=[CH:30][C:29]=2[O:40][CH3:41])=[N:26][C:21]([NH:1][C:2]2[CH:3]=[CH:4][C:5]3[C:11]([CH3:12])([CH3:13])[CH2:10][CH2:9][C:8](=[O:14])[N:7]([CH2:15][CH:16]([CH3:17])[CH3:18])[C:6]=3[CH:19]=2)=[N:22][CH:23]=1
Reactant: CC(C)CN1C(=O)CCC(C)(C)c2ccc(N)cc21
Reactant: COc1cc(N2CCOCC2)ccc1Nc1nc(Cl)ncc1Cl
Product: COc1cc(N2CCOCC2)ccc1Nc1nc(Nc2ccc3c(c2)N(CC(C)C)C(=O)CCC3(C)C)ncc1Cl

Procedure:
The title compound was prepared with a procedure analogous to that used to prepare example 381 by combining 8-Amino-1-isobutyl-5,5-dimethyl-1,3,4,5-tetrahydro-benzo[b]azepin-2-one and (2,5-Dichloro-pyrimidin-4-yl)-(2-methoxy-4-morpholin-4-yl-phenyl)-amine to yield a colorless solid (9%). LCMS: m/z=579.59 (M+H+), 1H NMR (400 MHz, CDCl3) δ 8.22 (d, 1H, J=8.8 Hz), 8.05 (d, 1H, J=1.0 Hz), 7.67 (bs, 1H), 7.62 (bs, 1H), 7.22 (m, 3H), 6.55 (d, 1H, J=1.5 Hz), 6.48 (dd, 1H, J=8.8, 1.5 Hz), 3.93 (s, 3H), 3.90 (m, 4H), 3.16 (m, 4H), 2.36 (m, 5H), 2.05 (m, 2H), 1.35 (s, 6H), 0.97 (d, 6H, J=6.6 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]([O:22][C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)=[C:6]([CH:21]=1)[C:7]([NH:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17](O)([CH3:19])[CH3:18])=[CH:13][CH:12]=1)=[O:8].C[Si]([C:34]#[N:35])(C)C.[Sn](Cl)(Cl)(Cl)Cl.C(=O)([O-])[O-].[K+].[K+].O.O.[F-].[K+]>ClCCl.O>[Cl:1][C:2]1[CH:3]=[N:4][C:5]([O:22][C:23]2[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=2)=[C:6]([CH:21]=1)[C:7]([NH:9][CH2:10][C:11]1[CH:12]=[CH:13][C:14]([C:17]([C:34]#[N:35])([CH3:19])[CH3:18])=[CH:15][CH:16]=1)=[O:8]
Reactant: CC(C)(O)c1ccc(CNC(=O)c2cc(Cl)cnc2Oc2ccc(F)cc2)cc1
Reactant: C[Si](C)(C)C#N
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [F-]
Solvent: O
Solvent: ClCCl
Product: CC(C)(C#N)c1ccc(CNC(=O)c2cc(Cl)cnc2Oc2ccc(F)cc2)cc1
Temperature: 0 °C

Procedure:
5-Chloro-2-(4-fluoro-phenoxy)-N-[4-(1-hydroxy-1-methyl-ethyl)-benzyl]-nicotinamide (1.61 g) was dissolved in anhydrous dichloromethane (40 mL) and cooled to 0° C. in an ice bath. Trimethylsilyl cyanide (7.8 mL) was added, followed by tin(IV)chloride (1.0 M solution in dichloromethane; 1.6 mL) added slowly over 15 min. The reaction mixture was sealed under nitrogen and allowed to warm slowly to ambient temperature overnight while stirring. Potassium carbonate (7.56 g), potassium fluoride dihydrate (0.902 g), and water (1.95 mL) were then added. The resulting mixture was stirred for 90 min, then silica gel (3.22 g) was added and the slurry stirred for another 30 minutes. The solids were removed by filtration and the filtrate concentrated to dryness in vacuo to yield the crude title compound (0.850 g).
Reaction SMILES: Br[C:2]1[C:3]([F:11])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].[N:12]1([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1>>[C:21]([O:20][C:18]([N:12]1[CH2:17][CH2:16][N:15]([C:2]2[C:3]([F:11])=[C:4]([CH:8]=[CH:9][CH:10]=2)[C:5]([OH:7])=[O:6])[CH2:14][CH2:13]1)=[O:19])([CH3:24])([CH3:22])[CH3:23]
Reactant: O=C(O)c1cccc(Br)c1F
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Product: CC(C)(C)OC(=O)N1CCN(c2cccc(C(=O)O)c2F)CC1

Procedure:
3-(4-(tert-butoxycarbonyl)piperazin-1-yl)-2-fluorobenzoic acid was synthesised following the procedure in Example 2 (Step ii) using 3-bromo-2-fluorobenzoic acid and tert-butyl piperazine-1-carboxylate.
Reaction SMILES: [BH4-].[Na+].[Cl-].[Cl-].[Cl-].[Ce+3].[CH3:7][C:8](=[CH:12][CH2:13][CH:14]1[CH2:19][CH:18]2[C:16]([CH3:20])([CH2:17]2)[C:15]1([CH3:22])[CH3:21])[C:9](=[O:11])[CH3:10].O>CO>[CH3:7][C:8](=[CH:12][CH2:13][CH:14]1[CH2:19][CH:18]2[C:16]([CH3:20])([CH2:17]2)[C:15]1([CH3:21])[CH3:22])[CH:9]([OH:11])[CH3:10]
Reactant: CC(=O)C(C)=CCC1CC2CC2(C)C1(C)C
Agent: [BH4-]
Agent: [Ce+3]
Agent: [Cl-]
Solvent: CO
Solvent: O
Product: CC(=CCC1CC2CC2(C)C1(C)C)C(C)O
Yield: 58.5 %

Procedure:
0.37 g (10 mmol) of sodium borohydride was added portionwise with cooling to the solution of 3.7 g (10 mmol) of cerium trichloride and 2.0 g (10 mmol) of 3-methyl-5-(1,2,2-trimethylbicyclo[3.1.0]hex-3-yl)pent-3-en-2-one in 25 ml of methanol. After 5 more minutes water was added and the mixture extracted with diethyl ether, dried (MgSO4) and evaporated in vacuo. Purification by flash chromatography on silica gel (eluent: hexane/MTBE 9:1) gave 1.3 g (58% yield) of 3-methyl-5-(1,2,2-trimethylbicyclo[3.1.0]hex-3-yl)pent-3-en-2-ol.
Reaction SMILES: [NH2:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[OH-].[Na+]>C(OC(C)(C)C)(=O)C.O>[CH3:3][C:4]([O:11][C:10](=[O:12])[C@H:2]([CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[NH2:1])([CH3:9])[CH3:5]
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)OC(C)(C)C
Product: CC(C)(C)OC(=O)[C@@H](N)Cc1ccccc1
Yield: 64 %

Procedure:
A solution of L-phenylalanine (62.6 g; 379 mol) in tert-butyl acetate (320 mL) cooled on an ice bath and stirred vigorously is slowly added with 70% aqueous HClO4 (35 mL, 407 mol). After stirring for 11 days at room temperature, the mixture is diluted with 100 mL of water and cooled on an ice bath. The mixture is basified with 5 N NaOH to precipitate a white solid (unreacted phenylalanine) which is filtered off. The mixture is then extracted with EtOAc (4×200 mL), the organic phases are combined and washed with water (2×200 mL) and 5% Na2CO3 (300 mL). After drying over Na2SO4 and carefully removing the solvent under vacuum, the desired compound is obtained as a colourless oil (53.53 g; 242 mol), which needs no further purifications and is stored at −18° C.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][N:3]=[C:2]1[CH:6]1[C:15]2[CH:14]=[CH:13][CH:12]=[C:11]([C:16]#[N:17])[C:10]=2[CH2:9][CH2:8][O:7]1.C(N)(=[O:20])C.C1COCC1>Cl[Zn]Cl.O>[NH:3]1[CH2:4][CH2:5][N:1]=[C:2]1[CH:6]1[C:15]2[CH:14]=[CH:13][CH:12]=[C:11]([C:16]([NH2:17])=[O:20])[C:10]=2[CH2:9][CH2:8][O:7]1
Reactant: N#Cc1cccc2c1CCOC2C1=NCCN1
Reactant: CC(N)=O
Agent: Cl[Zn]Cl
Solvent: O
Solvent: C1CCOC1
Product: NC(=O)c1cccc2c1CCOC2C1=NCCN1

Procedure:
The mixture of 1-(4,5-dihydro-1H-imidazol-2-yl)isochroman-5-carbonitrile (example 5, 75 mg), acetamide (39 mg), zink chloride (45 mg), THF (0.5 ml) and water (0.5 ml) was heated in a microwave reactor for 50 seconds at 320 W. The title compound was purified by applying method A. (Yield 15 mg).