Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Na].Cl[C:3]1[C:7]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)=[N:6][O:5][N:4]=1.[CH2:14]([OH:18])[CH2:15][CH2:16][CH3:17]>>[CH2:14]([O:18][C:3]1[C:7]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)=[N:6][O:5][N:4]=1)[CH2:15][CH2:16][CH3:17]
Reactant: Clc1nonc1-c1cccnc1
Reactant: CCCCO
Agent: [Na]
Product: CCCCOc1nonc1-c1cccnc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of sodium (150 mg, 6.5 mmol) in 1-butanol (5 ml) was added 3-(3-chloro-1,2,5-oxadiazol-4-yl)pyridine (350 mg, 1.9 mmol). The mixture was stirred at 25° C. for 2 h and evaporated. The residue was dissolved in water and extracted with ether. The combined organic phases were dried and evaporated to give the title compound.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([C:10]#[N:11])[C:5](=[CH:8][CH:9]=1)[C:6]#[N:7].[BH:12]([OH:14])[OH:13]>>[C:10]([C:4]1[CH:3]=[C:2]([B:12]([OH:14])[OH:13])[CH:9]=[CH:8][C:5]=1[C:6]#[N:7])#[N:11]
Reactant: N#Cc1ccc(I)cc1C#N
Reactant: OBO
Product: N#Cc1ccc(B(O)O)cc1C#N

Procedure:
The title compound was prepared according to Preparation 102 using 4-iodophthalonitrile to provide a mixture of the boronic acid and boronic ester. The mixture was taken on to the next step as crude.
Reaction SMILES: [NH2:1][CH2:2][C:3]([OH:5])=[O:4].[Cl:6][C:7]1[C:17]([Cl:18])=[C:16]([C:19](=[O:24])[C:20](=[CH2:23])[CH2:21][CH3:22])[CH:15]=[CH:14][C:8]=1[O:9][CH2:10][C:11](Cl)=[O:12]>O1CCCC1>[Cl:6][C:7]1[C:17]([Cl:18])=[C:16]([C:19](=[O:24])[C:20](=[CH2:23])[CH2:21][CH3:22])[CH:15]=[CH:14][C:8]=1[O:9][CH2:10][C:11]([NH:1][CH2:2][C:3]([OH:5])=[O:4])=[O:12]
Reactant: C=C(CC)C(=O)c1ccc(OCC(=O)Cl)c(Cl)c1Cl
Reactant: NCC(=O)O
Solvent: C1CCOC1
Product: C=C(CC)C(=O)c1ccc(OCC(=O)NCC(=O)O)c(Cl)c1Cl
Temperature: 25 °C
Reaction time: 2.25 h

Procedure:
To a stirring suspension of finely ground glycine (6.01 g, 0.08 mole) in tetrahydrofuran (50 ml) was added, dropwise, the solution of [2,3-dichloro-4-(2-methylenebutyryl)phenoxy]acetyl chloride over a period of 15 minutes. The mixture was stirred at ambient temperature for 2.25 hours and then at reflux for one hour. The mixture was cooled, filtered and washed with tetrahydrofuran. The solid was suspended in water (60 ml), filtered, washed with water and dried to give 7.15 g of N-{[2,3-dichloro-4(2-methylenebutyryl)phenoxy]acetyl}glycine. Upon recrystallization from isopropyl alcohol, the product melted at 201.5°-202.5° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@H:12]([NH:13][CH3:14])[CH2:11][N:10]([C:15]([CH:17]3[CH2:22][CH2:21][N:20]([C:23]([C:25]4([CH3:28])[CH2:27][CH2:26]4)=[O:24])[CH2:19][CH2:18]3)=[O:16])[CH2:9]2)=[CH:4][CH:3]=1.Cl[C:30]([O:32][CH2:33][CH2:34][CH3:35])=[O:31]>>[CH2:33]([O:32][C:30](=[O:31])[N:13]([C@H:12]1[C@H:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH2:9][N:10]([C:15]([CH:17]2[CH2:22][CH2:21][N:20]([C:23]([C:25]3([CH3:28])[CH2:27][CH2:26]3)=[O:24])[CH2:19][CH2:18]2)=[O:16])[CH2:11]1)[CH3:14])[CH2:34][CH3:35]
Reactant: CCCOC(=O)Cl
Reactant: CN[C@@H]1CN(C(=O)C2CCN(C(=O)C3(C)CC3)CC2)C[C@H]1c1ccc(Cl)cc1
Product: CCCOC(=O)N(C)[C@@H]1CN(C(=O)C2CCN(C(=O)C3(C)CC3)CC2)C[C@H]1c1ccc(Cl)cc1

Procedure:
In analogy to the procedure described for the synthesis of example 136, the title compound {(3S,4R)-4-(4-chloro-phenyl)-1-[1-(1-methyl-cyclopropanecarbonyl)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-methyl-carbamic acid propyl ester was prepared from [(3R,4S)-3-(4-chloro-phenyl)-4-methylamino-pyrrolidin-1-yl]-[1-(1-methyl-cyclopropanecarbonyl)-piperidin-4-yl]-methanone instead of 4-[(3R,4S)-3-(4-chloro-phenyl)-4-methylamino-pyrrolidine-1-carbonyl]-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-carbonitrile using propyl chloroformate instead of ethyl chloroformate and was obtained as a colorless foam. MS m/e: 490.4 [M]+.
Reaction SMILES: [CH:1]([N:4](CC)[CH:5](C)C)(C)C.[S:10]1[C:14]2[CH:15]=[C:16]([C:19]3([C:22]4[N:26]5[N:27]=[C:28]([C:31]6[CH:47]=[CH:46][C:34]([C:35]([NH:37][C@@H:38]([C:42]([CH3:45])([CH3:44])[CH3:43])[C:39]([OH:41])=O)=[O:36])=[CH:33][CH:32]=6)[CH:29]=[N:30][C:25]5=[N:24][N:23]=4)[CH2:21][CH2:20]3)[CH:17]=[CH:18][C:13]=2[N:12]=[CH:11]1.CNC.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C.CO>[S:10]1[C:14]2[CH:15]=[C:16]([C:19]3([C:22]4[N:26]5[N:27]=[C:28]([C:31]6[CH:32]=[CH:33][C:34]([C:35]([NH:37][C@H:38]([C:39]([N:4]([CH3:5])[CH3:1])=[O:41])[C:42]([CH3:45])([CH3:44])[CH3:43])=[O:36])=[CH:46][CH:47]=6)[CH:29]=[N:30][C:25]5=[N:24][N:23]=4)[CH2:21][CH2:20]3)[CH:17]=[CH:18][C:13]=2[N:12]=[CH:11]1
Reactant: CC(C)(C)[C@H](NC(=O)c1ccc(-c2cnc3nnc(C4(c5ccc6ncsc6c5)CC4)n3n2)cc1)C(=O)O
Reactant: CCN(C(C)C)C(C)C
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: CNC
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CO
Product: CN(C)C(=O)[C@@H](NC(=O)c1ccc(-c2cnc3nnc(C4(c5ccc6ncsc6c5)CC4)n3n2)cc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
N,N-Diisopropylethylamine (14 μL, 0.080 mmol) was added to a mixture of (2S)-2-[(4-{3-[1-(1,3-benzothiazol-6-yl)cyclopropyl][1,2,4]triazolo[4,3-b][1,2,4]triazin-6-yl}benzoyl)amino]-3,3-dimethylbutanoic acid (14 mg, 0.026 mmol), dimethylamine (0.034 mmol) and benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (14 mg, 0.032 mmol) in DMF (0.4 mL). The mixture was stirred at RT overnight. The residue was diluted with methanol, and purified by RP-HPLC (pH=10) to afford the desired product. Analytical LCMS: (M+H)+=555.1.
Reaction SMILES: [C:1]1([C:7]2[NH:8][C:9](=[O:27])[N:10]([CH2:18][C:19]3[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=3)[C:22]#[N:23])[C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:29][C:30]1[CH:39]=[C:38]2[C:33]([CH:34]=[CH:35][C:36]([C:40]#[N:41])=[CH:37]2)=[CH:32][CH:31]=1>>[C:22]([C:21]1[CH:20]=[C:19]([CH2:18][N:10]2[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[N:8]([CH2:29][C:30]3[CH:39]=[C:38]4[C:33]([CH:34]=[CH:35][C:36]([C:40]#[N:41])=[CH:37]4)=[CH:32][CH:31]=3)[C:9]2=[O:27])[CH:26]=[CH:25][CH:24]=1)#[N:23]
Reactant: N#Cc1ccc2ccc(CBr)cc2c1
Reactant: N#Cc1cccc(Cn2c(-c3ccccc3)c(-c3ccccc3)[nH]c2=O)c1
Product: N#Cc1cccc(Cn2c(-c3ccccc3)c(-c3ccccc3)n(Cc3ccc4ccc(C#N)cc4c3)c2=O)c1

Procedure:
In a manner similar to Preparation 2 above, 3-[(2,3-dihydro-4,5-diphenyl-2-oxo-1H-imidazol-1-yl) methyl]benzonitrile was reacted with 7-(bromomethyl)-naphthalene-2-carbonitrile to give 7-[[3-(3-cyanophenyl)methyl-2,3-dihydro-4,5-diphenyl-2-oxo-1H-imidazol-1-yl]methyl]naphthalene-2-carbonitrile; NMR (CDCl3) 8.05 (s,1), 7.9 (d,1), 7.85 (d,1), 7.55 (m,3), 7.4 (m,2), 7.2 (m,9), 7.0 (m,3), 5.1 (s,2), 4.95 (s,2) ppm.
Reaction SMILES: [C:1]([O:4][C@H:5]([CH3:33])[CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:19](=[O:20])[C:18]2[N:17]([CH2:21][CH2:22]NC(OC(C)(C)C)=O)[C:16](Br)=[N:15][C:14]=2[N:13]([CH3:32])[C:11]1=[O:12])(=[O:3])[CH3:2].FC(F)(F)C(O)=O.ClCCl.C(=O)([O-])[O-].[K+].[K+].[C:50](#[N:52])C>>[C:1]([O:4][C@H:5]([CH3:33])[CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:19](=[O:20])[C:18]2[N:17]3[CH2:21][CH2:22][CH2:50][NH:52][C:16]3=[N:15][C:14]=2[N:13]([CH3:32])[C:11]1=[O:12])(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@H](C)CCCCn1c(=O)c2c(nc(Br)n2CCNC(=O)OC(C)(C)C)n(C)c1=O
Reactant: CC#N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(=O)O[C@H](C)CCCCn1c(=O)c2c(nc3n2CCCN3)n(C)c1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 88 %

Procedure:
(R)-1-(5-acetoxyhexyl)-8-bromo-7-(2-(N-tert-butoxycarbonylamino)ethyl)-3-methylxanthine (6.10 g, 11.2 mmol) was added to a solution of trifluoroacetic acid (50 ml) and dichloromethane (50 ml) and stirred at room temperature for 3 hours. Concentration under reduced pressure provided an oil to which was added acetonitrile (30 ml) followed by potassium carbonate (13.8 g, 100 mmol). The mixture was stirred at 650° C. for 3 hours and filtered to remove solids. The filtrate was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel eluting with ethyl acetate-methanol (4:1) to provide (R)-3-(5-acetoxyhexyl)-1-methyl-6,7,8,9-tetrahydro-pyrimido[2,1-f]purine-2,4(1H,3H)-dione (3.58 g, 88% yield) as a white powder.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([N:12]2[C:16]3[CH:17]=[C:18]([F:21])[CH:19]=[CH:20][C:15]=3[N:14]=[C:13]2[C@@H:22]([NH2:24])[CH3:23])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[C:26]1[N:34]=[CH:33][N:32]=[C:31]2[C:27]=1[N:28]=[CH:29][N:30]2C1CCCCO1.CCN(C(C)C)C(C)C>C(O)CCC>[F:21][C:18]1[CH:19]=[CH:20][C:15]2[N:14]=[C:13]([CH:22]([NH:24][C:26]3[N:34]=[CH:33][N:32]=[C:31]4[C:27]=3[N:28]=[CH:29][NH:30]4)[CH3:23])[N:12]([CH:10]3[CH2:9][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:11]3)[C:16]=2[CH:17]=1
Reactant: Clc1ncnc2c1ncn2C1CCCCO1
Reactant: C[C@H](N)c1nc2ccc(F)cc2n1C1CN(C(=O)OC(C)(C)C)C1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: CC(Nc1ncnc2[nH]cnc12)c1nc2ccc(F)cc2n1C1CN(C(=O)OC(C)(C)C)C1
Temperature: 90 °C
Yield: 45 %

Procedure:
A mixture of 3-[2-((S)-1-aminoethyl)-6-fluorobenzoimidazol-1-yl]azetidine-1-carboxylic acid tert-butyl ester (354 mg, 1.05 mmol), 6-chloro-9-(tetrahydropyran-2-yl)-9H-purine (278 mg, 1.16 mmol) and DIPEA (0.41 mL, 3.18 mmol) in n-butanol (1.4 mL) was heated at 90° C. in a sealed vial for 16 h. After cooling to RT, the volatiles were removed under reduced pressure and the resulting residue loaded onto an Isolute® SCX-2 cartridge and washed with MeOH followed by 2M NH3/MeOH. The basic fractions were combined, concentrated in vacuo and the resulting residue was purified by column chromatography (Si—PCC, gradient 0-5% MeOH in DCM) to afford 377 as a white solid (214 mg, 71%). LCMS (Method K): RT 3.59 min [M+H]+ 453.1. 1H NMR (DMSO-d6, 400 MHz): δ 12.43 (1H, s), 8.23 (1H, br s), 8.14 (1H, br s), 7.96 (1H, d, J=7.67 Hz), 7.68 (1H, dd, J=8.83, 5.02 Hz), 7.36 (1H, dd, J=9.41, 2.45 Hz), 7.11 (1H, td, J=9.29, 2.36 Hz), 5.79 (1H, br s), 5.70-5.60 (1H, m), 4.48-4.34 (2H, m), 4.31-4.19 (2H, m), 1.65 (3H, d, J=6.67 Hz), 1.44 (9H, s)
Reaction SMILES: [C:1](=[O:25])([O:3][CH:4]1[C:13]2[CH:12]=[C:11]3[O:14][CH:15]([CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[O:16][C:10]3=[CH:9][C:8]=2[NH:7][CH:6]([CH3:24])[CH2:5]1)[NH2:2].N1C=CC=CC=1.[C:32](Cl)(=[O:34])[CH3:33].Cl>ClCCl>[C:1](=[O:25])([O:3][CH:4]1[C:13]2[CH:12]=[C:11]3[O:14][CH:15]([CH2:17][C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)[O:16][C:10]3=[CH:9][C:8]=2[N:7]([C:32](=[O:34])[CH3:33])[CH:6]([CH3:24])[CH2:5]1)[NH2:2]
Reactant: CC(=O)Cl
Reactant: CC1CC(OC(N)=O)c2cc3c(cc2N1)OC(Cc1ccccc1)O3
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)N1c2cc3c(cc2C(OC(N)=O)CC1C)OC(Cc1ccccc1)O3
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 48.5 %

Procedure:
[Step 3] 675 mg (approx. 1.98 mmol) of the benzyl-6-methyl-5,6,7,8-tetrahydro[1,3]dioxolo[4,5-g]quinolin-8-yl carbamate were dissolved in 15 mL of dichloromethane followed by adding 313 mg (4.0 mmol) of pyridine. 234 mg (3.0 mmol) of acetyl chloride were further added followed by stirring for 30 minutes at room temperature. Following completion of the reaction, aqueous hydrochloric acid (1 mol/L) was added followed by extraction with chloroform. The organic phase was washed with water and then dehydrated with anhydrous sodium sulfate. The solution was concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography (n-hexane:ethyl acetate 2:1) to obtain 367 mg of benzyl-5-acetyl-6-methyl-5,6,7,8-tetrahydro-[1,3]dioxolo[4,5-g]quinolin-8-yl carbamate in the form of a pale brown oil (56%, 2 steps).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([NH:11][C:12]2[N:17]=[C:16]([O:18][C:19]3[CH:27]=[CH:26][CH:25]=[C:24]4[C:20]=3[C:21](=[O:29])[N:22]([CH3:28])[CH2:23]4)[C:15]([Cl:30])=[CH:14][N:13]=2)[C:8]([O:31][CH3:32])=[CH:7][C:3]=1[C:4](O)=[O:5].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C.[CH3:64][N:65]1[CH2:70][CH2:69][CH:68]([NH2:71])[CH2:67][CH2:66]1>CN(C=O)C>[Cl:1][C:2]1[CH:10]=[C:9]([NH:11][C:12]2[N:17]=[C:16]([O:18][C:19]3[CH:27]=[CH:26][CH:25]=[C:24]4[C:20]=3[C:21](=[O:29])[N:22]([CH3:28])[CH2:23]4)[C:15]([Cl:30])=[CH:14][N:13]=2)[C:8]([O:31][CH3:32])=[CH:7][C:3]=1[C:4]([NH:71][CH:68]1[CH2:69][CH2:70][N:65]([CH3:64])[CH2:66][CH2:67]1)=[O:5]
Reactant: CN1CCC(N)CC1
Reactant: COc1cc(C(=O)O)c(Cl)cc1Nc1ncc(Cl)c(Oc2cccc3c2C(=O)N(C)C3)n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cc(C(=O)NC2CCN(C)CC2)c(Cl)cc1Nc1ncc(Cl)c(Oc2cccc3c2C(=O)N(C)C3)n1
Reaction time: 0.08 h

Procedure:
2-chloro-4-[5-chloro-4-(2-methyl-3-oxo-2,3-dihydro-1H-isoindol-4-yloxy)-pyrimidin-2-ylamino]-5-methoxy-benzoic acid (65 mg), TBTU (60 mg) and DIPEA (0.1 mL) are suspended in DMF (0.50 mL) and stirred for 5 min. 1-methylpiperidin-4-amine (18 mg) is added and the reaction mixture is stirred for a further 20 min. The reaction mixture is purified by HPLC without working up. (IC50=1 nmol).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([O:10][C:11]2[CH:20]=[CH:19][C:18]3[CH2:17][CH:16]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[CH2:15][CH2:14][C:13]=3[CH:12]=2)=[N:8][CH:9]=1)([O-:3])=[O:2].[OH:27]C1C=C2C(=CC=1)C(=O)C(C1C=CC=CC=1)CC2.ClC1C=CC([N+]([O-])=O)=CN=1.[F-].[K+]>>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([O:10][C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][CH:20]=2)[C:17](=[O:27])[CH:16]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:15][CH2:14]3)=[N:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(Oc2ccc3c(c2)CCC(c2ccccc2)C3)nc1
Reactant: O=C1c2ccc(O)cc2CCC1c1ccccc1
Agent: O=[N+]([O-])c1ccc(Cl)nc1
Agent: [F-]
Agent: [K+]
Product: O=C1c2ccc(Oc3ccc([N+](=O)[O-])cn3)cc2CCC1c1ccccc1

Procedure:
6-(5-Nitro-pyridin-2-yloxy)-2-phenyl-3,4-dihydro-2H-naphthalen-1-one was prepared as described for 5-nitro-2-(6-phenyl-5,6,7,8-tetrahydro-naphthalen-2-yloxy)-pyridine in Example 5(d) using 50 mg 6-hydroxy-2-phenyl-3,4-dihydro-2H-naphthalen-1-one, 33 mg 2-chloro-5-nitropyridine and 37 mg potassium fluoride. 1H NMR (400 MHz, d6-DMSO) δ: 9.07 (d, 1H, J 2.8 Hz), 8.68 (dd, 1H, J 9.0, 2.9), 8.01 (d, 1H, J 8.5), 7.37 (d, 1H, J 9.1 Hz), 7.21-7.38 (m, 7H), 3.96-4.04 (m, 1H), 3.15-3.23 (m, 1H), 2.98-3.04 (m, 1H), 2.39-2.48 (m, 1H), 2.25-2.31 (m, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2([C:19]#[N:20])[CH2:14][CH2:13][C:12]3([O:18][CH2:17][CH2:16][O:15]3)[CH2:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=1.[OH-].[K+].C([OH:25])C>O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2([C:19](=[O:25])[NH2:20])[CH2:10][CH2:11][C:12]3([O:15][CH2:16][CH2:17][O:18]3)[CH2:13][CH2:14]2)[CH:6]=[CH:7][CH:8]=1
Reactant: CCO
Reactant: COc1cccc(C2(C#N)CCC3(CC2)OCCO3)c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: COc1cccc(C2(C(N)=O)CCC3(CC2)OCCO3)c1

Procedure:
A mixture of 3.5 g of 4-(3-methoxyphenyl)-4-cyano-1,1-ethylenedioxy-cyclohexane, 70 ml of 5 % aqueous potassium hydroxide and 70 ml of ethanol is refluxed for 22 hours. After cooling, the mixture is diluted with water, and then extracted with chloroform. The chloroform extract is dried and evaporated to remove solvent. The residue thus obtained is recrystallized from a mixture of ethylacetate and n-hexane. 2.32 g of 4-(3-methoxyphenyl)-4-carbamoyl-1,1-ethylenedioxy-cyclohexane are obtained. M.p. 135° - 138°C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C@@H:4]([NH2:12])[CH2:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.C(N(CC)C(C)C)(C)C.C([O:25][C:26](=O)[CH:27]=[C:28]([O:31][C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([Cl:38])[C:33]=1[Cl:39])[CH2:29]Br)C>CN(C)C=O>[CH3:1][O:2][C:3](=[O:13])[C@@H:4]([N:12]1[CH2:29][C:28]([O:31][C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([Cl:38])[C:33]=2[Cl:39])=[CH:27][C:26]1=[O:25])[CH2:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: COC(=O)[C@@H](N)CC1CCCCC1
Reactant: CCOC(=O)C=C(CBr)Oc1cccc(Cl)c1Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@H](CC1CCCCC1)N1CC(Oc2cccc(Cl)c2Cl)=CC1=O
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 16.2 %

Procedure:
To a stirred solution of (S)-2-amino-3-cyclohexyl-propionic acid methyl ester (1.15 g, 0.062 mol) in N,N-dimethylformamide (5 mL) was added N,N-diisopropylethylamine (3.63 g, 0.282 mol) slowly at room temperature, under nitrogen. The resulting mixture was stirred for 5 min and then treated with 4-bromo-3-(2,3-dichloro-phenoxy)-but-2-enoic acid ethyl ester (2.0 g, 0.006 mol) and the reaction mixture was heated at 110° C.-120° C. for 16 h. After this time, ice water was added and the resulting mixture was extracted with ethyl acetate. The combined organic layers were washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate and concentrated in vacuo. Purification using flash column chromatography (silica gel (100-200 mesh)) afforded (S)-3-cyclohexyl-2-[4-(2,3-dichloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-propionic acid methyl ester (0.40 g, 17%) as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([OH:11])[CH2:7][CH2:6]1.C(N(CC)CC)C.[C:23]1([CH3:32])[CH:28]=[CH:27][C:26]([C:29](Cl)=[O:30])=[CH:25][CH:24]=1>C1(C)C=CC=CC=1>[CH3:32][C:23]1[CH:28]=[CH:27][C:26]([C:29]([O:11][CH:8]2[CH2:9][CH2:10][N:5]([CH2:4][C:3]3[CH:12]=[CH:13][CH:14]=[CH:15][C:2]=3[Cl:1])[CH2:6][CH2:7]2)=[O:30])=[CH:25][CH:24]=1
Reactant: Cc1ccc(C(=O)Cl)cc1
Reactant: OC1CCN(Cc2ccccc2Cl)CC1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: Cc1ccc(C(=O)OC2CCN(Cc3ccccc3Cl)CC2)cc1
Yield: 43.6 %

Procedure:
0.451 g (0.002 mol) of 1-(2-chloro-benzyl)-piperidin-4-ol and 1.23 ml (0.0088 mol) of triethylamine were dissolved in 4 ml of toluene, treated with 0.331 ml (0.0025 mol) of p-toluoyl chloride and boiled at reflux for 18 hrs. The reaction mixture was concentrated and the residue was chromatographed over silica gel with ethyl acetate/hexane (1:1→1:2). 0.3 g (44%) of 1-(2-chloro-benzyl)-piperidin-4-yl 4-methyl-benzoate was obtained as a colorless oil.
Reaction SMILES: C([C:3]1[CH:16]=[CH:15][C:6]([O:7][CH:8]([CH3:14])[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:5][CH:4]=1)=O.C1(C)C=CC=CC=1.C(OO)(=[O:26])C>O>[OH:26][C:3]1[CH:16]=[CH:15][C:6]([O:7][CH:8]([CH3:14])[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:5][CH:4]=1
Reactant: CC(=O)OO
Reactant: CCOC(=O)C(C)Oc1ccc(C=O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)C(C)Oc1ccc(O)cc1
Temperature: 25 °C
Yield: 77.5 %

Procedure:
While stirring a mixture of 22.5 g of ethyl 2-(4-formylphenoxy)propionate ([α]D25 =+51.5°) and 60 g of toluene at room temperature, 22.8 g of 40% peracetic acid was dropwise added. After stirring at 20° to 30° C. for 2 hours and at 50° C. for 2 hours, 0.2 g of water was added, and the mixture was stirred for 2 hours. After cooling the reaction mixture to room temperature, 40 g of water was added. The aqueous layer was separated. The organic layer was washed with 40 g of water, followed by washing twice with 40 g of a 5% sodium hydrogen carbonate aqueous solution, then with 40 g of a 5% sodium hydrogen sulfite aqueous solution and further with 40 g of water. Then, the reaction mixture was concentrated by distilling off toluene under reduced pressure, and subjected to distillation under reduced pressure, whereby 16.5 g of (+)-ethyl 2-(4-hydroxyphenoxy)propionate was obtained as a colorless transparent liquid. The boiling point was from 130° to 140° C./1 mmHg.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:8]2[CH:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:11][C:10](=[O:18])[NH:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.S(=O)(=O)(O)O.S(OOS([O-])(=O)=O)([O-])(=O)=O.[K+].[K+]>C(#N)C>[Cl:1][C:2]1[C:3]([N:8]2[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:11][C:10](=[O:18])[NH:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C1CC(=O)NN1c1ncccc1Cl
Agent: O=S(=O)(O)O
Agent: O=S(=O)([O-])OOS(=O)(=O)[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)c1cc(=O)[nH]n1-c1ncccc1Cl
Yield: 15.7 %

Procedure:
To a suspension of ethyl 2-(3-chloro-2-pyridinyl)-5-oxo-3-pyrazolidinecarboxylate (i.e. product of Example 8, Step A) (27 g, 100 mmol) stirred in dry acetonitrile (200 mL) was added sulfuric acid (20 g, 200 mmol) in one portion. The reaction mixture thinned to form a pale green, nearly clear solution before thickening again to form a pale yellow suspension. Potassium persulfate (33 g, 120 mmol) was added in one portion, and then the reaction mixture was heated at gentle reflux for 3.5 hours. After cooling using an ice bath, a precipitate of white solid was removed by filtration and discarded. The filtrate was diluted with water (400 mL) and then extracted three times with ethyl ether (700 mL total). Concentration of the combined ether extracts to a reduced volume (75 mL) caused precipitation of an off-white solid (3.75 g), which was collected by filtration. The ether mother liquor was further concentrated to yield a second crop of an off-white precipitate (4.2 g), which was also collected by filtration. An off-white solid also precipitated from the aqueous phase; this solid (4.5 g) was collected by filtration to provide a combined total of 12.45 g of the title compound.
Reaction SMILES: [O:1]=[C:2]1[CH:7]([C:8](=[O:11])[CH2:9][CH3:10])[C:6](=[O:12])[CH2:5][CH:4]([C:13]#[N:14])[CH2:3]1.[CH2:15]([SH:17])[CH3:16].[ClH:18]>C(OCC)C>[ClH:18].[O:12]=[C:6]1[CH:7]([C:8](=[O:11])[CH2:9][CH3:10])[C:2](=[O:1])[CH2:3][CH:4]([C:13]([S:17][CH2:15][CH3:16])=[NH:14])[CH2:5]1
Reactant: CCC(=O)C1C(=O)CC(C#N)CC1=O
Reactant: CCS
Agent: Cl
Solvent: CCOCC
Product: CCSC(=N)C1CC(=O)C(C(=O)CC)C(=O)C1

Procedure:
19.3 g (0.1 mol) of 3,5-dioxo-4-propionylcyclohexanecarbonitrile and 6.5 g (0.105 mol) of ethyl mercaptan were dissolved in 800 ml of dry diethyl ether and reacted with hydrogen chloride as described in Example 2.1: 20.7 g (71% of theory) of compound 2.2 [melting point 180°-185° C. (decomposition)].
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[C:15]=2[F:21])=[CH:10][C:9]=1[NH:22][C:23](=[O:35])[CH2:24][C:25]([C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([C:33]#[N:34])[CH:28]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:21][C:15]1[C:16]([F:20])=[CH:17][CH:18]=[CH:19][C:14]=1[C:11]1[CH:12]=[CH:13][C:8]2[N:7]=[C:25]([C:27]3[CH:28]=[C:29]([CH:30]=[CH:31][CH:32]=3)[C:33]#[N:34])[CH2:24][C:23](=[O:35])[NH:22][C:9]=2[CH:10]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2cccc(F)c2F)cc1NC(=O)CC(=O)c1cccc(C#N)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1cccc(C2=Nc3ccc(-c4cccc(F)c4F)cc3NC(=O)C2)c1
Yield: 88 %

Procedure:
Prepared from {3-[3-(3-cyano-phenyl)-3-oxo-propionylamino]-2′,3′-difluoro-biphenyl-4-yl}-carbamic acid tert.-butyl ester (Example K8) (35 mg, 0.07 mmol) by treatment with TFA in CH2Cl2 according to the general procedure M. Obtained as a grey solid (23 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([N+:11]([O-:13])=[O:12])[CH:10]=1)[C:5]([OH:7])=[O:6].[C:14]1(=O)[O:20][C:18](=[O:19])[CH2:17][CH2:16][CH2:15]1.S(=O)(=O)(O)O>>[C:14]1(=[O:20])[N:1]([C:2]2[CH:3]=[C:4]([CH:8]=[C:9]([N+:11]([O-:13])=[O:12])[CH:10]=2)[C:5]([OH:7])=[O:6])[C:18](=[O:19])[CH2:17][CH2:16][CH2:15]1
Reactant: O=C1CCCC(=O)O1
Reactant: Nc1cc(C(=O)O)cc([N+](=O)[O-])c1
Agent: O=S(=O)(O)O
Product: O=C(O)c1cc(N2C(=O)CCCC2=O)cc([N+](=O)[O-])c1

Procedure:
3-Glutarimido-5-nitrobenzoic Acid [D; Y is CH2CH2CH2, Z is OH] was prepared by heating a mixture of 18.2 g. of 3-amino-5-nitrobenzoic acid, 45.6 g. of glutaric anhydride and 0.5 ml. of concentrated sulfuric acid on a steam bath for two hours. The product was isolated and recrystallized from aqueous dimethylformamide to give 3-glutarimido-5-nitrobenzoic acid, pale yellow prisms, m.p. above 300° C.