Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:11][C:12](=[O:25])[C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)=[N:15][CH:14]=2)[CH:8]=[CH:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:26][O:27][C:28]([C@H:30]1[CH2:35][CH2:34][C@H:33]([C:36](O)=[O:37])[CH2:32][CH2:31]1)=[O:29].CCN=C=NCCCN(C)C>C(Cl)Cl>[CH3:26][O:27][C:28]([CH:30]1[CH2:35][CH2:34][CH:33]([C:36]([N:22]2[CH2:23][CH2:24][N:19]([C:16]3[CH:17]=[CH:18][C:13]([C:12](=[O:25])[NH:11][C:7]4[CH:8]=[CH:9][CH:10]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[CH:6]=4)=[CH:14][N:15]=3)[CH2:20][CH2:21]2)=[O:37])[CH2:32][CH2:31]1)=[O:29]
Reactant: COC(=O)[C@H]1CC[C@H](C(=O)O)CC1
Reactant: CC(C)(C)c1cccc(NC(=O)c2ccc(N3CCNCC3)nc2)c1
Agent: CCN=C=NCCCN(C)C
Solvent: ClCCl
Product: COC(=O)C1CCC(C(=O)N2CCN(c3ccc(C(=O)Nc4cccc(C(C)(C)C)c4)cn3)CC2)CC1
Reaction time: 8 h
Yield: 80 %

Procedure:
A mixture of N-(3-tert-butyl-phenyl)-6-piperazin-1-yl-nicotinamide (100 mg, 0.29 mmol) in CH2Cl2 (10 mL) was treated with trans-1,4-cyclohexane dicarboxylic acid monomethyl ester. (110 mg, 0.59 mmol) and EDCI (230 mg, 1.18 mmol) at room temperature. After stirring overnight the reaction mixture was partitioned between EtOAc and water. The organic layer was collected, dried over Na2SO4, filtered and concentrated. The residue was chromatographed on a silica gel column with 20-100% EtOAc in hexanes gradient to afford the product (120 mg, Yield: 80%). HRMS m/z calcd for C29H38N4O4 [M+H]+: 507.2966. Found: 507.2968.
Reaction SMILES: [C:1]1([P:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH2:27]Br)[CH:22]=1>C1(C)C=CC=CC=1>[Br-:20].[Br:20][C:21]1[CH:22]=[C:23]([CH2:27][P+:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:24]=[CH:25][CH:26]=1
Reactant: BrCc1cccc(Br)c1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: Brc1cccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)c1
Product: [Br-]
Temperature: 100 °C
Yield: 177.7 %

Procedure:
Triphenylphosphane (2.62 g, 10.0 mmol) was added to 1-bromo-3-(bromomethyl)benzene (2.5 g, 10.0 mmol) in toluene (15 mL) and the mixture heated in a microwave at 100° C. for about 1 h. The mixture was filtered to afford the title compound (4.55 g, 89%). LC-MS m/z 431 (cationic part)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N+:10]([O-:12])=[O:11])[C:5]=1[CH2:13]Br.CN(C)C=O.O.[N-:22]=[N+:23]=[N-:24].[Na+]>COC(C)(C)C>[CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N+:10]([O-:12])=[O:11])[C:5]=1[CH2:13][N:22]=[N+:23]=[N-:24]
Reactant: [N-]=[N+]=[N-]
Reactant: COC(=O)c1cccc([N+](=O)[O-])c1CBr
Agent: [Na+]
Solvent: COC(C)(C)C
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cccc([N+](=O)[O-])c1CN=[N+]=[N-]
Reaction time: 8 h
Yield: 89.6 %

Procedure:
10 g (36.5 mmol) of 2-(bromomethyl)-3-nitrobenzoic acid methyl ester is mixed with 36 ml of N,N-dimethylformamide and 24 ml of water. After 3.54 g of sodium azide is added, the batch is stirred overnight. The reaction mixture is diluted with methyl-tert butyl ether, and washed twice with water and once with brine. After drying on sodium sulfate, it is filtered, and the solvent is spun off. The desired azide is obtained in a yield of 89.6% (7.72 g) and further incorporated in crude form.
Reaction SMILES: [C:1]([CH2:3][C:4](O)=O)#[N:2].[CH3:7][NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26].C=O.[C:29](=O)=O>O1CCOCC1>[CH3:7][N:8]([CH2:29][C:3](=[CH2:4])[C:1]#[N:2])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: O=C=O
Reactant: CCCCCCCCCCCCCCCCCCNC
Reactant: N#CCC(=O)O
Agent: C=O
Solvent: C1COCCO1
Product: C=C(C#N)CN(C)CCCCCCCCCCCCCCCCCC

Procedure:
To a mixture of cyanacetic acid (2.6 g., 0.03 mole) and N-methyl-N-octadecylamine (8.4 g., 0.03 mole) in 25 ml. of dioxane at room temperature is added 38% aqueous formaldehyde (5.4 g., 0.06 mole) dropwise over about 2 minutes. The resultant mixture is then heated gently in a hot water bath until a clear solution is obtained and carbon dioxide is released vigorously (ca. 60° C. bath). When the evolution of carbon dioxide is complete, the mixture is allowed to cool, and the volatiles removed in vacuo to yield 9.2 g. of the substituted propenenitrile as an off-white solid.
Reaction SMILES: [NH2:1][C@H:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C@H:3]1[OH:11].C(=O)([O-])[O-].[K+].[K+].[CH2:18](I)[CH3:19].[C:21](#N)[CH3:22]>C(OCC)C>[CH2:21]([N:1]([CH2:18][CH3:19])[C@H:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C@H:3]1[OH:11])[CH3:22]
Reactant: CC#N
Reactant: N[C@H]1c2ccccc2C[C@H]1O
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Product: CCN(CC)[C@H]1c2ccccc2C[C@H]1O

Procedure:
A suspension of 15.09 grams (101 mmol) of (1S,2R)-1-amino-2-indanol, 33.72 grams (244 mmol) of potassium carbonate and 38.8 grams (249 mmol) of ethyl iodide in 100 ml of acetonitrile was refluxed for 3 hours. After cooling, the solid matter was removed through filtration and the filtrate was evaporated. The residue was dissolved in 4N hydrochloric acid and was washed three times using dichloromethane. The water layer was made basic with the aid of a 50% sodium hydroxide solution and was extracted with the aid of dichloromethane (3*25 ml). After drying (Na2SO4) and evaporation, the product was isolated as an oil. This oil was dissolved in diethyl ether and cooled, which caused the product to crystallise. Yield: 16.7 grams (81%) of a white solid substance. Melting point: 60-61° C. [α]20D +1.1 (c=1, methanol). 1H NMR (200 MHz, CDCl3): 1.02 (t, 6H), 2.24-2.57 (2*m, 4H), 2.65 (dd, 1H), 3.20 (dd, 1H), 4.22 (d, 1H), 4.29 (q, 1H), 4.7 (br s, 1H) and 7.10-7.27 (m, 4H). 13C NMR (50.31 MHz, CDCl3): 13.63 (q), 41.42 (t), 45.60 (t) 66.97 (d), 68.95 (d), 125.44 (d), 126.17 (d), 126.45 (d), 128.28 (d), 139.65(s) and 141.98 (s).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].CCN(CC)CC.Cl[C:24]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25]>C1COCC1.C(Cl)Cl>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH2:15][CH2:14][N:13]([C:24]([O:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[O:25])[CH2:12][CH2:11]2)=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(N2CCNCC2)cc1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(OCc1ccccc1)N1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 97.9 %

Procedure:
To a mixture of 1-(4-nitrophenyl)piperazine (5 g, 24.13 mmol) and Et3N (5.04 mL, 36.2 mmol) in THF (20 mL) was added benzyl chloroformate (3.79 mL, 26.5 mmol) portion-wise at 0° C. The reaction mixture was stirred at 0° C. for 1 h and then at rt for 2 h. The reaction mixture was diluted with CH2Cl2, washed with satd NaHCO3 and water, and concentrated to give 8.06 g of benzyl 4-(4-nitrophenyl)piperazine-1-carboxylate as yellow solid. LCMS: (M+H)+=342.15.
Reaction SMILES: C[O:2][C:3](=[O:31])[CH2:4][CH:5]([C:25]1[N:29]([CH3:30])[N:28]=[N:27][N:26]=1)[C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH:14]2[CH2:19][CH2:18][CH2:17][C:16]3([CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)[CH2:15]2)=[CH:8][CH:7]=1.O1CCCC1.[OH-].[Na+].Cl>O.CO>[CH3:30][N:29]1[C:25]([CH:5]([C:6]2[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH:14]3[CH2:19][CH2:18][CH2:17][C:16]4([CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]4)[CH2:15]3)=[CH:8][CH:7]=2)[CH2:4][C:3]([OH:31])=[O:2])=[N:26][N:27]=[N:28]1
Reactant: COC(=O)CC(c1ccc(OCC2CCCC3(CCCCC3)C2)cc1)c1nnnn1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: Cn1nnnc1C(CC(=O)O)c1ccc(OCC2CCCC3(CCCCC3)C2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 98.4 %

Procedure:
To a solution of 3-(1-methyl-1H-tetrazol-5-yl)-3-[4-(spiro[5.5]undec-2-ylmethoxy)-phenyl]-propionic acid methyl ester (41 mg) obtained in Step 8 in a mixed solvent of tetrahydrofuran (1 mL)-methanol (0.5 mL)-water (0.5 mL) was added 2N aqueous sodium hydroxide solution (0.144 mL), followed by stirring the reaction mixture at room temperature for 18 hours. Then, after addition of 1N aqueous hydrochloric acid solution (0.3 mL), the reaction mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried and concentrated. The residue was purified by thin-layer column chromatography on silica gel (acetic acid:ethyl acetate:chloroform (volume ratio)=0.1:1:10) to give 3-(1-methyl-1H-tetrazol-5-yl)-3-[4-(spiro[5.5]undec-2-ylmethoxy)-phenyl]-propionic acid (39 mg) as the desired compound.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][C:7]([OH:9])=[S:8].C(O[CH:14]1[NH:17][C:16](=[O:18])[CH2:15]1)(=O)C.N#N>[OH-].[K+].O>[CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][C:7]([O:9][CH:14]1[NH:17][C:16](=[O:18])[CH2:15]1)=[S:8]
Reactant: CC(=O)OC1CC(=O)N1
Reactant: COCCOCC(O)=S
Agent: N#N
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: COCCOCC(=S)OC1CC(=O)N1
Yield: 96 %

Procedure:
To a solution of 2-methoxyethoxythioacetic acid (990 mg.; 6.60 mmoles) in 1 N KOH (6.0 ml.) and water (30 ml.) was added in an ice-bath under nitrogen atmosphere 4-acetoxy-2-azetidinone (777 mg.; 6.00 mmoles). The reaction mixture was stirred at room temperature (N2) for 1 hr. and then extracted with methylene chloride (30 ml.×3). The extracts were washed with brine, dried (Na2SO4) and evaporated yielding 4-(2-methoxyethoxythioacetoxy)-2-azetidinone (1.26 g.; 5.76 mmoles; 96% yield) as a yellow oil. nmr (CDCl3): δppm 2.8-3.8 (2H, m, H-3), 3.40 (3H, s, --OCH3), 3.4-3.9 (4H, m, --CH2CH2 --O), 4.25 (2H, s, O=CCH2O--), 5.25 (1H, dd, J3-4 cis =5 Hz, J3-4 trans =3 Hz, H-4), 7.3 (1H, br.s, --NH), ir (neat): 3280 cm-1 (γN--H), 1770 (γc=o, β-lactam), 1690 (γc=o, thioester).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:14][C:15](=[O:17])[CH3:16])[CH:5]=[C:6]([C:10]([CH3:13])([CH3:12])[CH3:11])[C:7]=1[O:8][CH3:9].CC1(C)C(C)(C)OB([C:26]2[CH:27]=[C:28]3[C:33](=[CH:34][CH:35]=2)[CH:32]=[C:31]([NH:36][S:37]([CH3:40])(=[O:39])=[O:38])[CH:30]=[CH:29]3)O1>>[C:10]([C:6]1[CH:5]=[C:4]([NH:14][C:15](=[O:17])[CH3:16])[CH:3]=[C:2]([C:26]2[CH:35]=[CH:34][C:33]3[C:28](=[CH:29][CH:30]=[C:31]([NH:36][S:37]([CH3:40])(=[O:38])=[O:39])[CH:32]=3)[CH:27]=2)[C:7]=1[O:8][CH3:9])([CH3:13])([CH3:12])[CH3:11]
Reactant: COc1c(Br)cc(NC(C)=O)cc1C(C)(C)C
Reactant: CC1(C)OB(c2ccc3cc(NS(C)(=O)=O)ccc3c2)OC1(C)C
Product: COc1c(-c2ccc3cc(NS(C)(=O)=O)ccc3c2)cc(NC(C)=O)cc1C(C)(C)C
Temperature: 90 °C

Procedure:
N-(3-bromo-5-tert-butyl-4-methoxyphenyl)acetamide (24 mg, 0.08 mmol) and N-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalene-2-yl)methanesulfonamide (64 mg, 0.18 mmol), were reacted in the same manner as Example 43 Part C, heating in an oil bath at 90° C. for 18 hours to give crude product which was purified on an Isco 4 g silica cartridge eluting with 5% methanol/chloroform to give the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.39 (s, 9H), 2.02 (s, 3H), 3.06 (s, 3H), 3.16 (s, 3H), 7.34-7.76 (m, 5H), 7.84-8.00 (m, 3H), 9.91 (s, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2.C(=O)([O-])[O-].[K+].[K+].Br[CH:19]([CH2:29][O:30][CH3:31])[C:20]([NH:22][C:23]([CH3:28])([CH3:27])[C:24]#[C:25][CH3:26])=[O:21]>CN(C)C=O.O>[N:8]1[C:9]2[C:4](=[CH:3][C:2]([O:1][CH:19]([CH2:29][O:30][CH3:31])[C:20]([NH:22][C:23]([CH3:28])([C:24]#[C:25][CH3:26])[CH3:27])=[O:21])=[CH:11][CH:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC#CC(C)(C)NC(=O)C(Br)COC
Reactant: Oc1ccc2ncccc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC#CC(C)(C)NC(=O)C(COC)Oc1ccc2ncccc2c1
Temperature: 80 °C
Reaction time: 72 h
Yield: 29.5 %

Procedure:
6-Hydroxyquinoline (0.083 g), anhydrous potassium carbonate (0.087 g) and 2-bromo-N-(4-methylpent-2-yn-4-yl) 3-methoxypropionamide (0.150 g) in dry N,N-dimethylformamide (3 ml) were stirred and heated to 80° C. for 5 hours then stored for 72 hours at ambient temperature. The yellow suspension was diluted with water, extracted with ethyl acetate and the organic phase was separated then washed with water, dried over magnesium sulphate and evaporated under reduced pressure to a gum. The gum was fractionated by chromatography (silica; ethyl acetate:hexane, 3:2 by volume) to give the required product (0.055 g) as a colourless gum.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][N:6]=1.C([Al](CC(C)C)CC(C)C)C(C)C.[C:20]1([C:26]2[C:27]([OH:47])=[C:28]([C:42](OCC)=[O:43])[C:29]([C:38]([F:41])([F:40])[F:39])=[N:30][C:31]=2[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(Cl)Cl.C1(C)C=CC=CC=1>[C:20]1([C:26]2[C:27]([OH:47])=[C:28]([C:42]([NH:1][C:2]3[S:3][CH:4]=[CH:5][N:6]=3)=[O:43])[C:29]([C:38]([F:40])([F:41])[F:39])=[N:30][C:31]=2[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: Nc1nccs1
Reactant: CCOC(=O)c1c(C(F)(F)F)nc(-c2ccccc2)c(-c2ccccc2)c1O
Agent: CC(C)C[Al](CC(C)C)CC(C)C
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: O=C(Nc1nccs1)c1c(C(F)(F)F)nc(-c2ccccc2)c(-c2ccccc2)c1O
Reaction time: 0.33 h
Yield: 72 %

Procedure:
3.22 g of 2-aminothiazole were cooled to +2° C. in 80 ml of methylene chloride, and while maintaining the temperature between +2° and +5° C. 17.9 ml of triisobutyl aluminium in toluene (0.9M) were added and stirred for 20 minutes. 2.5 g of the product of Step D were then introduced all at once into the mixture and the temperature was brought up progressively to reflux and kept there for 24 hours then lowered to the ambient. The mixture was concentrated to dryness under reduced pressure and 50 ml of water and 50 ml of 2N hydrochloric acid were added to the residue. The mixture was triturated and the precipitate was separated and washed abundantly with water. While still humid, the latter was dissolved in tetrahydrofuran and the solution was dried and concentrated under reduced pressure. The 2.6 g of residue were triturated in ether, separated and dried to obtain 2.05 g of product melting at 256° C. After crystallizing from acetonitrile, 1.48 g of the expected product melted at 256° C.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9](OC)[CH:10]=2)[N:5]=[CH:4][C:3]=1C(OCC)=O.FC1C=CC(NN)=CC=1.C1([O:34]C2C=CC=CC=2)C=CC=CC=1.C1(C2C=CC=CC=2)C=CC=CC=1>C(OCC)C>[ClH:1].[N:5]1[C:6]2[C:11]([CH2:10][CH:9]=[CH:8][CH:7]=2)=[CH:2][C:3](=[O:34])[CH:4]=1
Reactant: CCOC(=O)c1cnc2ccc(OC)cc2c1Cl
Reactant: c1ccc(Oc2ccccc2)cc1
Agent: NNc1ccc(F)cc1
Solvent: c1ccc(-c2ccccc2)cc1
Solvent: CCOCC
Product: Cl
Product: O=C1C=NC2=CC=CCC2=C1
Temperature: 25 °C

Procedure:
The mixture of 2.7 g of ethyl 4-chloro-6-methoxyquinolin-3-carboxylate, 1.4 g of p-fluorophenylhydrazine and 20 ml of eutectic diphenyl ether-biphenyl is heated to 160°-165° for 4 hours, then cooled to room temperature and diluted with diethyl ether. The precipitated crystalline product is collected, washed thoroughly with diethyl ether and dried, to yield the 2-(p-fluorophenyl)-8-methoxypyrazolo]4,3-c]quinolin-3(5H)-one hydrochloride melting at 322°-324°.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:26][CH3:27])=[C:6]([CH:25]=1)[C:7]([NH:9][CH:10]1[CH:19](O)[C:18]2[C:13](=[CH:14][C:15]([O:21][CH3:22])=[CH:16][CH:17]=2)[O:12][C:11]1([CH3:24])[CH3:23])=[O:8]>C(Cl)Cl.C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:26][CH3:27])=[C:6]([CH:25]=1)[C:7]([NH:9][CH:10]1[CH2:19][C:18]2[C:13](=[CH:14][C:15]([O:21][CH3:22])=[CH:16][CH:17]=2)[O:12][C:11]1([CH3:23])[CH3:24])=[O:8]
Reactant: COc1ccc2c(c1)OC(C)(C)C(NC(=O)c1cc(F)ccc1OC)C2O
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COc1ccc2c(c1)OC(C)(C)C(NC(=O)c1cc(F)ccc1OC)C2

Procedure:
A reduction was carried out analogously to Example 15e using 18.8 g (50 mmol) of 3-(5-fluoro-2-methoxybenzamido)-2,2-dimethyl-7-methoxy-4-chromanol. After chromatography over a silica gel column using methylene chloride/ethyl acetate 95:5, the 3-(5-fluoro-2-methoxybenzamido)-2,2-dimethyl-7-methoxychroman was obtained as an oil.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH:4]=[CH:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11](=[O:16])[CH2:10][CH2:9]2.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>O1CCOCC1.C(Cl)(Cl)Cl.CO>[Cl:1][CH2:2][CH2:3][CH:4]=[CH:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11](=[O:16])[CH:10]=[CH:9]2
Reactant: O=C1CCc2cc(C=CCCCl)ccc2N1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: ClC(Cl)Cl
Solvent: CO
Solvent: C1COCCO1
Product: O=c1ccc2cc(C=CCCCl)ccc2[nH]1

Procedure:
2.5 Grams of 6-(4-chloro-1-butenyl)-3,4-dihydrocarbostyril and 2.3 g of DDQ (2,3-dichloro-5,6-dicyanobenzoquinone) were mixed in 160 ml of dioxane and the mixture was refluxed by heating for 6 hours. Further, 1.1 of DDQ was added to the reaction mixture and the mixture was refluxed by heating for 3 hours. The reaction mixture was cooled and the precipitates thus formed were removed by filtration and the motor liquor was concentrated under a reduced pressure to obtain a residue. The residue was dissolved in a mixture of 100 ml of chloroform with 5 ml of methanol and the solution was padded through a silica gel column for removing the unreacted DDQ. The residue was recrystallized from methanol to obtain 1.6 g of 6-(4-chloro-1-butenyl)carbostyril in yellow needle-like crystals. Melting point: 215°-218° C.
Reaction SMILES: F[C:2](F)(F)[C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH:6]=O.[CH3:13][CH:14]([CH3:33])[CH:15]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:16]([NH:18][C@@H:19]1[C@@H:26]2[C@@H:22]([CH2:23][NH:24][CH2:25]2)[CH2:21][CH2:20]1)=[O:17].[CH:34]1(C(C2CCCCC2)C(N[C@@H]2[C@H]3[C@H](CNC3)CC2)=O)CCCCC1>>[CH3:2][C:3]1[CH:10]=[CH:9][CH:8]=[C:5]([CH3:6])[C:4]=1[CH2:34][N:24]1[CH2:25][C@@H:26]2[C@@H:19]([NH:18][C:16](=[O:17])[CH:15]([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:14]([CH3:33])[CH3:13])[CH2:20][CH2:21][C@@H:22]2[CH2:23]1
Reactant: O=C(N[C@H]1CC[C@H]2CNC[C@H]21)C(C1CCCCC1)C1CCCCC1
Reactant: O=Cc1cccc(C(F)(F)F)c1
Reactant: CC(C)C(C(=O)N[C@H]1CC[C@@H]2CNC[C@@H]21)c1ccccc1
Product: Cc1cccc(C)c1CN1C[C@H]2CC[C@H](NC(=O)C(c3ccccc3)C(C)C)[C@H]2C1

Procedure:
The title compound was prepared by substituting 2,6-dimethylbenzaldehyde for 3-(trifluoromethyl)benzaldehyde and 3-methyl-N-[(3aR,4S,6aS)-octahydrocyclopenta[c]pyrrol-4-yl]-2-phenylbutanamide from Example 83 Step A for 2,2-dicyclohexyl-N-[(3aS,4S,6aR)-octahydrocyclopenta[c]pyrrol-4-yl]acetamide in the procedure described for Example 54: 1H NMR (500 MHz, pyridine-d5) δ ppm 8.54-8.50 (m, J=6.7, 1H), 7.65-7.60 (m, 2H), 7.32 (t, J=7.1, 2H), 7.28-7.23 (m, 1H), 7.11 (dd, J=6.2, 14.3, 1H), 7.04 (t, J=8.3, 2H), 4.27-4.19 (m, 1H), 3.57 (d, J=12.5, 0.5H), 3.44 (dd, J=12.5, 15.5, 1H), 3.34 (d, J=12.5, 0.5H), 3.20 (d, J=10.4, 1H), 2.92 (d, J=5.9, 0.5H), 2.68-2.58 (m, J=10.2, 18.3, 1H), 2.55-2.51 (m, J=4.5, 1H), 2.48-2.42 (m, 0.5H), 2.39 (s, 3H), 2.34 (s, 3H), 2.32-2.18 (m, 3H), 2.07 (td, J=6.6, 12.6, 0.5H), 1.87-1.73 (m, 1H), 1.72-1.62 (m, 1H), 1.33 (dd, J=19.1, 78.6, 2.5H), 1.19 (dd, J=4.9, 6.3, 3H), 0.69 (d, J=6.6, 3H); MS (ESI+) m/z 405 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)[N:3]=1.[Cl:22][C:23]1[CH:28]=[C:27](I)[CH:26]=[CH:25][N:24]=1>C([Mg]Cl)(C)C.[Cl-].[Cl-].[Zn+2]>[Cl:22][C:23]1[CH:28]=[C:27]([C:2]2[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([C:12]3[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=3)[N:3]=2)[CH:26]=[CH:25][N:24]=1
Reactant: Clc1cc(I)ccn1
Reactant: FC(F)(F)c1ccc(-c2cc(C(F)(F)F)cc(Br)n2)cc1
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [Zn+2]
Product: FC(F)(F)c1ccc(-c2cc(C(F)(F)F)cc(-c3ccnc(Cl)c3)n2)cc1

Procedure:
The title compound was prepared from 2-bromo-4-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-pyridine (example A.19) (1.11 g, 3.0 mmol), commercially available 2-chloro-4-iodo-pyridine [CAS No. 153034-86-7] (740 mg, 3.1 mmol) and i-PrMgCl/ZnCl2 according to the general procedure IVc protocol a. Obtained as a white solid (0.601 g, 50%). MS (ISP) 403.3 [(M+H)+] and 405.2 [(M+2+H)+].
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[N:10][C:11]([N:14]3[CH2:19][CH2:18][C:17]([CH2:25][CH3:26])([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:16][CH2:15]3)=[N:12][CH:13]=2)=[CH:4][C:3]=1[N+:27]([O-:29])=[O:28].[Br:30]Br>C(O)(=O)C>[NH2:1][C:2]1[C:3]([N+:27]([O-:29])=[O:28])=[CH:4][C:5]([C:8]2[CH:9]=[N:10][C:11]([N:14]3[CH2:19][CH2:18][C:17]([CH2:25][CH3:26])([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:16][CH2:15]3)=[N:12][CH:13]=2)=[CH:6][C:7]=1[Br:30]
Reactant: BrBr
Reactant: CCOC(=O)C1(CC)CCN(c2ncc(-c3ccc(N)c([N+](=O)[O-])c3)cn2)CC1
Solvent: CC(=O)O
Product: CCOC(=O)C1(CC)CCN(c2ncc(-c3cc(Br)c(N)c([N+](=O)[O-])c3)cn2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 77.9 %

Procedure:
To solution of ethyl 1-(5-(4-amino-3-nitrophenyl)pyrimidin-2-yl)-4-ethylpiperidine-4-carboxylate (6.0 g, 15.02 mmol) in acetic acid (60.0 mL) was added bromine (0.85 mL, 16.52 mmol) dropwise at rt and the mixture then stirred at rt for 16 h. After completion of reaction the mixture was poured into 100 mL of ice-cold water, extracted with EtOAc (3×150 mL) and the combined organic layer washed with brine, dried over anhydrous Na2SO4, filtered and evaporated under reduced pressure. The crude residue was purified over 100-200 M silica-gel column chromatography using 10% EtOAc:Hexane to obtain the product as a beige solid (5.60 g, 78%). 1H NMR (CDCl3): δ 8.66 (s, 2H), 8.18 (s, 2H), 7.21 (br s, 2H), 4.39-4.43 (m, 2H), 4.13-4.18 (m, 2H), 3.06-3.11 (m, 2H), 2.04-2.08 (m, 2H), 1.50-1.52 (m, 2H), 1.38-1.39 (m, 2H), 1.21 (t, J=7.60 Hz, 3H) and 0.75 (t, J=7.60 Hz, 3H). MS: 478.11 [M+H]+, 81%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[C:22]([OH:24])=O)[C:5]([NH:7][CH2:8][C:9]1[NH:13][C:12]2[CH:14]=[CH:15][C:16]([Cl:18])=[CH:17][C:11]=2[N:10]=1)=[O:6].CN(C(O[N:33]1N=[N:40][C:35]2[CH:36]=[CH:37][CH:38]=C[C:34]1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)CC)(C)C.C(OC(NCC1CCCN1)=O)(C)(C)C.FC(F)(F)C(O)=O.ClCl>CN(C=O)C>[NH2:33][CH2:34][CH:35]1[CH2:36][CH2:37][CH2:38][N:40]1[C:22]([C:21]1[CH:20]=[CH:19][C:4]([C:5]([NH:7][CH2:8][C:9]2[NH:13][C:12]3[CH:14]=[CH:15][C:16]([Cl:18])=[CH:17][C:11]=3[N:10]=2)=[O:6])=[CH:3][C:2]=1[Cl:1])=[O:24]
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: O=C(NCc1nc2cc(Cl)ccc2[nH]1)c1ccc(C(=O)O)c(Cl)c1
Agent: CC(C)(C)OC(=O)NCC1CCCN1
Agent: ClCl
Agent: F[B-](F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: NCC1CCCN1C(=O)c1ccc(C(=O)NCc2nc3cc(Cl)ccc3[nH]2)cc1Cl
Yield: 47 %

Procedure:
Prepared analogously to Example 1g from 3-chloro-N-(5-chloro-1H-benzimidazol-2-ylmethyl)-4-carboxybenzamide, TBTU, diisopropylethylamine, and rac.-2-tert-butoxycarbonylaminomethylpyrrolidine in DMF followed by treatment with trifluoroacetic acid analogously to Example 17. Yield: 47%; C21H21Cl2N5O2 (446.34); mass spectrum: (M+H)+=446/448/450 (chlorine isotope).