Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[C:11]([F:14])([F:13])[F:12].S(Cl)(Cl)=O.[CH3:19]O>>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH3:19])=[O:7])=[CH:4][C:3]=1[C:11]([F:12])([F:13])[F:14]
Reactant: O=C(O)c1ccc(Br)c(C(F)(F)F)c1
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccc(Br)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 94 %

Procedure:
To a suspension of 4-bromo-3-(trifluoromethyl)benzoic acid (Acceledev 000625, 15 g; 55.76 mmol) in MeOH (300 mL) at RT was added dropwise thionyl chloride (16.18 mL; 223.04 mmol) over 15 min. The reaction mixture was stirred at RT for 12 hours. The solvent was concentrated and the crude residue was diluted with EtOAc (500 mL). The organic layer was washed with a saturated aqueous solution of NaHCO3 (200 mL), water (200 mL), brine (200 mL), dried over MgSO4 and concentrated affording the title compound as an orange solid (14.80 g, 94%). 1H NMR (DMSO-d6, 300 MHz) δ 8.26 (m, 1H), 8.14-8.13 (m, 2H), 3.93 (s, 3H). HPLC (Method A) Rt 4.71 min (Purity: 99.0%).
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[CH:5]=[C:6]([NH:10][C:11]2[O:12][C:13]([C:16]3[CH:21]=[CH:20][C:19]([C:22]4[CH2:23][CH2:24][NH:25][CH2:26][CH:27]=4)=[CH:18][CH:17]=3)=[CH:14][N:15]=2)[CH:7]=[CH:8][CH:9]=1.CCN(C(C)C)C(C)C.Cl[C:38](=[O:44])[C:39]([O:41][CH2:42][CH3:43])=[O:40]>C(Cl)Cl>[CH2:42]([O:41][C:39](=[O:40])[C:38]([N:25]1[CH2:24][CH:23]=[C:22]([C:19]2[CH:20]=[CH:21][C:16]([C:13]3[O:12][C:11]([NH:10][C:6]4[CH:7]=[CH:8][CH:9]=[C:4]([Cl:3])[CH:5]=4)=[N:15][CH:14]=3)=[CH:17][CH:18]=2)[CH2:27][CH2:26]1)=[O:44])[CH3:43]
Reactant: Clc1cccc(Nc2ncc(-c3ccc(C4=CCNCC4)cc3)o2)c1
Reactant: CCOC(=O)C(=O)Cl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)C(=O)N1CC=C(c2ccc(-c3cnc(Nc4cccc(Cl)c4)o3)cc2)CC1
Reaction time: 0.08 h

Procedure:
To a solution of (3-chlorophenyl)-{5-[4-(1,2,3,6-tetrahydro-pyridin-4-yl)-phenyl]-oxazol-2-yl}-amine bis HCl salt (50 mg, 0.12 mmol) in DCM (1 mL) at 0° C. is added DIEA (0.052 mL, 0.3 mmol) and after stirring for 5 min, ethyl chlorooxoacetate (0.016 mL, 0.14 mmol) is added dropwise. The mixture is stirred for 2 h and the mixture is purified by RP-HPLC to give the title compound: 1H NMR (400 MHz, DMSO-D6) δ 1.30 (q, J=7.07 Hz, 3H) 2.58 (m, 2H) 3.55-3.90 (m, 2H) 4.07-4.20 (m, 1H) 4.32 (m, 2H) 6.21-6.29 (m, 1H) 7.00 (dd, J=7.45, 1.64 Hz, 1H) 7.34 (t, J=8.08 Hz, 1H) 7.47-7.60 (m, 6H) 7.86 (t, J=2.02 Hz, 1H); (M+H)+452.1.
Reaction SMILES: [N:1]1[O:2][N:3]=[C:4]2[CH:9]=[C:8]([CH2:10][CH2:11][N:12]3[CH2:17][CH2:16][NH:15][CH2:14][C:13]3=[O:18])[CH:7]=[CH:6][C:5]=12.Br[CH2:20][CH2:21][C:22]1[CH:31]=[CH:30][C:25]2[C:26](=[O:29])[O:27][CH2:28][C:24]=2[CH:23]=1.C(N(CC)CC)C.CN(C=O)C>CCOC(C)=O>[N:1]1[O:2][N:3]=[C:4]2[CH:9]=[C:8]([CH2:10][CH2:11][N:12]3[CH2:17][CH2:16][N:15]([CH2:20][CH2:21][C:22]4[CH:31]=[CH:30][C:25]5[C:26](=[O:29])[O:27][CH2:28][C:24]=5[CH:23]=4)[CH2:14][C:13]3=[O:18])[CH:7]=[CH:6][C:5]=12
Reactant: O=C1CNCCN1CCc1ccc2nonc2c1
Reactant: O=C1OCc2cc(CCBr)ccc21
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C1OCc2cc(CCN3CCN(CCc4ccc5nonc5c4)C(=O)C3)ccc21
Temperature: 60 °C

Procedure:
A mixture of 1-[2-(2,1,3-Benzoxadiazol-5-yl)ethyl]piperazin-2-one (54 mg, 0.22 mmol), 5-(2-Bromoethyl)-2-benzofuran-1(3H)-one (105 mg, 0.44 mol), Triethylamine (0.15 mL, 1.1 mmol), and DMF (1.5 mL) was heated to 60° C. for 24 hours. The reaction was diluted with EtOAc, washed with water and brine, dried over MgSO4, and purified by prep-TLC (5% MeOH in DCM) to deliver the title product. LC-MS (IE, m/z): 407 [M+1]+.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([C:15]#[N:16])=[CH:11][CH:12]=[CH:13][CH:14]=2)=[CH:5][C:4]=1[C:17]([F:20])([F:19])[F:18])=[O:2].[BH4-].[Na+]>CO>[OH:2][CH2:1][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([C:15]#[N:16])=[CH:11][CH:12]=[CH:13][CH:14]=2)=[CH:5][C:4]=1[C:17]([F:18])([F:19])[F:20]
Reactant: N#Cc1ccccc1-c1ccc(C=O)c(C(F)(F)F)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: N#Cc1ccccc1-c1ccc(CO)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.2 %

Procedure:
To a solution (50 mL) of 4′-formyl-3′-(trifluoromethyl)biphenyl-2-carbonitrile (3.2 g) in methanol was added sodium borohydride (0.66 g), and the mixture was stirred at room temperature for 1 hr. After evaporation of the solvent under reduced pressure, the residue was extracted with water and ethyl acetate. The obtained ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (3.1 g, 95%).
Reaction SMILES: [O:1]1CCO[CH:2]1[C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]3[N:17]=[C:18]([C:26]4[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=4)[CH:19]=[C:20]([NH:21][CH2:22][CH:23]([CH3:25])[CH3:24])[C:15]3=[N:14][CH:13]=2)=[CH:8][CH:7]=1.Cl.C(=O)([O-])O>CC(C)=O>[CH2:22]([NH:21][C:20]1[C:15]2[N:16]([C:12]([C:9]3[CH:8]=[CH:7][C:6]([CH:2]=[O:1])=[CH:11][CH:10]=3)=[CH:13][N:14]=2)[N:17]=[C:18]([C:26]2[CH:27]=[CH:28][N:29]=[CH:30][CH:31]=2)[CH:19]=1)[CH:23]([CH3:25])[CH3:24]
Reactant: CC(C)CNc1cc(-c2ccncc2)nn2c(-c3ccc(C4OCCO4)cc3)cnc12
Agent: Cl
Agent: O=C([O-])O
Solvent: CC(C)=O
Product: CC(C)CNc1cc(-c2ccncc2)nn2c(-c3ccc(C=O)cc3)cnc12
Temperature: 23 °C
Reaction time: 2 h
Yield: 72.6 %

Procedure:
To a solution of 63 mg (152 μmol) 3-[4-(1,3-dioxolan-2-yl)phenyl]-N-isobutyl-6-(pyridin-4-yl)imidazo[1,2-b]pyridazin-8-amine which was prepared according to intermediate example 13b, in 2.8 mL acetone were added 190 μL 4N hydrochloric acid and the mixture was stirred at 23° C. for 2 hours. Saturated hydrogen carbonate solution was added and the mixture was extracted with dichloromethane. The organic phase was dried over sodium sulfate. After filtration and removal of solvent the residue was purified by chromatography to give 41 mg (73%) of the title compound.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[NH:13][N:12]=[C:11]([C:14]([OH:16])=[O:15])[CH:10]=1.[C:17](=S)=[S:18].N1C=CC=CC=1.O>CO>[S:18]=[C:17]1[N:13]2[N:12]=[C:11]([C:14]([OH:16])=[O:15])[CH:10]=[C:9]2[C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[NH:2]1
Reactant: Nc1ccccc1-c1cc(C(=O)O)n[nH]1
Reactant: S=C=S
Agent: Cl
Solvent: O
Solvent: CO
Solvent: c1ccncc1
Product: O=C(O)c1cc2c3ccccc3[nH]c(=S)n2n1

Procedure:
A mixture of 600 mg (0.0025 mole) of 5-(2-aminophenyl)-1H-pyrazole-3-carboxylic acid hydrochloride, 1.98 ml of carbon disulfide, 3.2 ml of pyridine and 0.16 ml of water are refluxed under N2 for 40 hours. The reaction mixture is stripped to dryness and the solid obtained is taken up in 175 ml methanol and filtered while hot. The clear light-yellow filtrate is concentrated down to a volume of 80 ml and cooled. The cotton-like precipitates are filtered and dried in vacuo over a 72 hour period at 80°. Yield: 394.8 mg, m.p. 272°-273°, 64.4% recryst. yield.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[C:5]([CH:7]1[CH2:12][CH2:11][N:10]([CH3:13])[CH2:9][CH2:8]1)=[O:6].[F:17][C:18]([F:29])([F:28])[C:19]1[CH:20]=[C:21]([CH:25]=[CH:26][CH:27]=1)[C:22](Cl)=[O:23]>>[F:17][C:18]([F:28])([F:29])[C:19]1[CH:20]=[C:21]([CH:25]=[CH:26][CH:27]=1)[C:22]([NH:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[C:5]([CH:7]1[CH2:8][CH2:9][N:10]([CH3:13])[CH2:11][CH2:12]1)=[O:6])=[O:23]
Reactant: CN1CCC(C(=O)c2cccc(N)c2)CC1
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1
Product: CN1CCC(C(=O)c2cccc(NC(=O)c3cccc(C(F)(F)F)c3)c2)CC1
Yield: 99.1 %

Procedure:
Beginning with 4-[3-aminobenzoyl]-1-methylpiperidine (50 mg, 0.229 mmol) and 3-(trifluoromethyl)benzoyl chloride (104 μl, 0.687 mmol), 88.6 mg (99%) of the title compound were recovered.
Reaction SMILES: [OH-].[Na+].[CH3:3][C@@H:4]([N:11]1[CH2:15][CH2:14][C@@H:13]([CH2:16][OH:17])[CH2:12]1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.Br[CH2:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O.C1(C)C=CC=CC=1>[C:5]1([C@H:4]([N:11]2[CH2:15][CH2:14][C@@H:13]([CH2:16][O:17][CH2:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:12]2)[CH3:3])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: C[C@H](c1ccccc1)N1CC[C@@H](CO)C1
Reactant: CC(C)(C)OC(=O)CBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: C[C@H](c1ccccc1)N1CC[C@@H](COCC(=O)OC(C)(C)C)C1
Reaction time: 6.5 h

Procedure:
20 mg of tetrabutylammonium bromide in 1 ml of water and then within 5 min. 20 g of 50% NaOH in water are added dropwise to a mixture of 2.05 g of (R)-1-[(R)-α-methylbenzyl]-3-pyrrolidinemethanol, 25 ml of toluene and 2.2 ml of tert.-butyl bromoacetate while stirring vigorously. After 6.5 hrs. the mixture is diluted with toluene, washed neutral with water, dried and evaporated in a vacuum. Chromatography on silica gel gives 2.1 g of tert.-butyl (R)-[1-(R)-[1-phenyl-ethyl]-pyrrolidin-3-ylmethoxy]-acetate, [α]D =+29.2°, (MeOH, c=1.0), MS: 319 (M)+.
Reaction SMILES: [C:1]([C:4]1[CH:11]=[CH:10][C:7]([C:8]#[N:9])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].CO.[BH4-].[Na+]>C1COCC1>[OH:3][CH:1]([C:4]1[CH:11]=[CH:10][C:7]([C:8]#[N:9])=[CH:6][CH:5]=1)[CH3:2]
Reactant: CC(=O)c1ccc(C#N)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CC(O)c1ccc(C#N)cc1
Reaction time: 0.5 h

Procedure:
4-Acetylbenzonitrile (3 g, 20.67 mmol) was dissolved in THF (5 mL) and MeOH (5 mL) and cooled to 0° C. NaBH4 (0.782 g, 20.67 mmol) was added slowly. The reaction aged at rt for 30 min and was concentrated. 2M aq HCl was added and the solution was extracted with EtOAc. The organic layer was washed with water, dried with Na2SO4, filtered and concentrated to provide the product.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH3:10])[CH:7]=[CH:8][CH:9]=1)([O-])=O.[OH-].[Na+]>[Zn].C(O)C>[CH3:10][C:6]1[CH:5]=[C:4]([NH2:1])[CH:9]=[CH:8][C:7]=1[C:7]1[CH:8]=[CH:9][C:4]([NH2:1])=[CH:5][C:6]=1[CH3:10]
Reactant: Cc1cccc([N+](=O)[O-])c1
Agent: [Na+]
Agent: [OH-]
Agent: [Zn]
Solvent: CCO
Product: Cc1cc(N)ccc1-c1ccc(N)cc1C
Temperature: 25 °C

Procedure:
A mixture of 40.0 grams, 0.30 moles, of m-nitrotoluene; 24 mL of a 20 percent aqueous solution of sodium hydroxide, and 120 mL ethanol is stirred and heated at gentle reflux. Zinc dust, 69.6 grams, is slowly added to keep the solution boiling without heating. Following addition of the zinc dust, the mixture is heated at reflux for about 4 hours. The hot mixture is filtered by suction, and the zinc residue is washed with ethanol. Concentrated hydrochloric acid is then slowly added to the filtrate. The precipitate formed is collected following filtration and redissolved in hot water. The aqueous solution is thereafter allowed to cool to room temperature and basified with a 20 percent aqueous solution of sodium hydroxide. The resulting DMB is an oil that is extracted with ethyl ether following its formation. Subsequent evaporation of the ethyl ether yields an oil containing 18.3 grams, 57.4 percent, of solids following cooling. Finally, the solid DMB is recrystallized from ethyl ether.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:11]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[O:12])[NH:8]2)=[CH:4][C:3]=1[O:19][CH:20]1[CH2:25][CH2:24][N:23]([CH:26]([CH3:28])[CH3:27])[CH2:22][CH2:21]1.[Cl:29][C:30]1[CH:35]=[C:34](B(O)O)[CH:33]=[CH:32][N:31]=1>>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:11]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[O:12])[N:8]2[C:34]2[CH:33]=[CH:32][N:31]=[C:30]([Cl:29])[CH:35]=2)=[CH:4][C:3]=1[O:19][CH:20]1[CH2:21][CH2:22][N:23]([CH:26]([CH3:28])[CH3:27])[CH2:24][CH2:25]1
Reactant: CC(C)N1CCC(Oc2cc3cc(C(=O)N4CCOCC4)[nH]c3cc2Br)CC1
Reactant: OB(O)c1ccnc(Cl)c1
Product: CC(C)N1CCC(Oc2cc3cc(C(=O)N4CCOCC4)n(-c4ccnc(Cl)c4)c3cc2Br)CC1

Procedure:
In analogy to the procedure described for the synthesis of example 6, the title compound was synthesized from [6-bromo-5-(1-isopropyl-piperidin-4-yloxy)-1H-indol-2-yl]-morpholin-4-yl-methanone (example 41, step 6) and 2-chloropyridine-4-boronic acid. The title compound was obtained in 12% yield as light yellow oil. MS (m/e): 561.4 (MH+, 100%).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8].[CH2:10](Br)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8]
Reactant: O=C(O)CCCCCBr
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(CCCCCBr)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.2 %

Procedure:
A mixture of 50.0 g of 6-bromohexanoic acid, 88 g of benzyl bromide, and 69 g of potassium carbonate in 500 ml of dimethylformamide was stirred overnight at room temperature. The reaction mixture was filtered, concentrated, and the residue was taken up in ether, washed with water and dried over sodium sulfate. The residue obtained after evaporation was distilled to give 63 g (85%) of benzyl 6-bromohexanoate.
Reaction SMILES: [CH3:1][NH:2][C:3]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][C:6]([C:7]([OH:9])=O)=[C:5]([N:15]2[CH2:20][CH2:19][CH:18]([C:21]([F:24])([F:23])[F:22])[CH2:17][CH2:16]2)[N:4]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C1COCC1.[F:52][C:53]([F:62])([F:61])[C@H:54]1[CH2:59][CH2:58][C@H:57]([NH2:60])[CH2:56][CH2:55]1>O.CN(C=O)C>[F:52][C:53]([F:61])([F:62])[C@H:54]1[CH2:55][CH2:56][C@H:57]([NH:60][C:7](=[O:9])[C:6]2[CH:10]=[C:11]([N+:12]([O-:14])=[O:13])[C:3]([NH:2][CH3:1])=[N:4][C:5]=2[N:15]2[CH2:20][CH2:19][CH:18]([C:21]([F:23])([F:24])[F:22])[CH2:17][CH2:16]2)[CH2:58][CH2:59]1
Reactant: N[C@H]1CC[C@H](C(F)(F)F)CC1
Reactant: CNc1nc(N2CCC(C(F)(F)F)CC2)c(C(=O)O)cc1[N+](=O)[O-]
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: C1CCOC1
Product: CNc1nc(N2CCC(C(F)(F)F)CC2)c(C(=O)N[C@H]2CC[C@H](C(F)(F)F)CC2)cc1[N+](=O)[O-]
Reaction time: 0.08 h

Procedure:
A mixture of 6-methylamino-5-nitro-2-(4-trifluoromethyl-piperidinyl)-nicotinic acid (570 mg, 1.64 mmol), TBTU (540 mg, 1.68 mmol), TEA (1.00 mL, 7.2 mmol), THF (10 mL) and DMF (5 mL) are stirred for 5 min. Then trans-4-trifluoromethyl-cyclohexylamine (335 mg, 1.65 mmol) is added and it is stirred for 30 min. Water is added, the mixture is concentrated and the precipitate is filtered, washed with water and dried at 55° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]1.Cl[CH2:9][CH2:10][CH2:11][O:12][CH2:13][CH3:14]>>[CH2:13]([O:12][CH2:11][CH2:10][CH2:9][N:1]1[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]1)[CH3:14]
Reactant: O=C1CCNCC1
Reactant: CCOCCCCl
Product: CCOCCCN1CCC(=O)CC1

Procedure:
1-(3-Ethoxypropyl)-4-piperidone is prepared from 4-piperidone and 1-chloro-3-ethoxypropane essentially as described above in Example 38, Scheme C, step a.
Reaction SMILES: C(SCCCCCC[NH2:27])(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.Cl[C:29]([O:31][C:32]1[CH:37]=[CH:36][C:35]([N+:38]([O-:40])=[O:39])=[CH:34][CH:33]=1)=[O:30].CCN(C(C)C)C(C)C.C(O)(=O)C>C1COCC1>[C:29](=[O:30])([O:31][C:32]1[CH:37]=[CH:36][C:35]([N+:38]([O-:40])=[O:39])=[CH:34][CH:33]=1)[NH2:27]
Reactant: NCCCCCCSC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)O
Product: NC(=O)Oc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 69.9 %

Procedure:
6-(Tritylthio)hexane-1-amine (1.21 g, 3.22 mmol) and p-nitrophenyl chloroformate (0.78 g, 3.86 mmol) were suspended in dry THF (15 mL). DIEA (841 μL, 4.83 mmol) was added, and the resulting solution was stirred at room temperature for 2 h. After acidification by addition of acetic acid the solvent was evaporated under reduced pressure, and the residue was purified by RP-HPLC. 1.21 g (2.25 mmol) p-nitrophenyl carbamate were obtained after lyophilisation.
Reaction SMILES: [C:1]1([N:7]2[C:11]([CH:12]=[O:13])=[C:10]3[C:14]([CH3:21])([C:19]#[N:20])[CH2:15][C:16]([CH3:18])([CH3:17])[C:9]3=[C:8]2[CH3:22])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Mn]([O-])(=O)(=O)=O.[K+].C1(N2C([C:40](O)=[O:41])=C3C(C)(C#N)CC(C)(C)C3=C2C)C=CC=CC=1.[H-].[Na+].CI>O.N1C=CC=CC=1>[C:1]1([N:7]2[C:11]([C:12]([O:41][CH3:40])=[O:13])=[C:10]3[C:14]([CH3:21])([C:19]#[N:20])[CH2:15][C:16]([CH3:17])([CH3:18])[C:9]3=[C:8]2[CH3:22])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Cc1c2c(c(C(=O)O)n1-c1ccccc1)C(C)(C#N)CC2(C)C
Reactant: Cc1c2c(c(C=O)n1-c1ccccc1)C(C)(C#N)CC2(C)C
Agent: O=[Mn](=O)(=O)[O-]
Agent: [H-]
Agent: [K+]
Solvent: c1ccncc1
Solvent: CI
Solvent: O
Product: COC(=O)c1c2c(c(C)n1-c1ccccc1)C(C)(C)CC2(C)C#N

Procedure:
Following a procedure similar to that described in Example 13C, 17.48 g. (0.06 mole) of 2-phenyl-3-formyl-2,4,5,6-tetrahydro-1,4,6,6-tetrmethylcyclopenta[c]pyrrole-4-carbonitrile was oxidized with 18.9 g. (0.12 mole) of potassium permanganate in 120 ml. of pyridine and 90 ml. of water to give 4.03 g. of 2-phenyl-3-carboxy-2,4,5,6-tetrahydro-1,4,6,6tetramethylcyclopenta[c]pyrrole-4-carbonitrile which was esterified by reaction of 9.83 g. (0.032 mole) of the acid with 1.713 g. (0.035 mole) of a 50% mineral oil dispersion of sodium hydride followed by 2.23 ml. (0.036 mole) of methyl iodide. There was thus obtained 4.18 of 2-phenyl-3-carbomethoxy-2,4,5,6-tetrahydro-1,4,6,6-tetramethylcyclopenta[c]pyrrole-4-carbonitrile.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH2:6][CH2:5]2.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:20][CH2:21][CH2:22][Cl:23]>C(#N)C.C(Cl)(Cl)Cl>[Cl:23][CH2:22][CH2:21][CH2:20][O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH2:6][CH2:5]2
Reactant: O=C1CCc2cc(O)ccc2N1
Reactant: ClCCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClC(Cl)Cl
Solvent: CC#N
Product: O=C1CCc2cc(OCCCCl)ccc2N1
Temperature: 110 °C
Reaction time: 4 h
Yield: 57.2 %

Procedure:
A suspension of 6-hydroxy-3,4-dihydroquinolin-2(1H)-one (50 g), cesium carbonate (150 g) and 1-bromo-3-chloropropane (58 g) in acetonitrile (300 mL) was stirred at 110° C. for 4 hours. The reaction mixture was cooled to room temperature, diluted with chloroform and filtered to remove insoluble materials. The filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluting solvent: chloroform→chloroform/methanol=4/1), and the resulting solid was subjected to recrystallization from ethanol to give the titled compound (42 g, 68%) as a colorless solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:10]=[CH:9][NH:8][C:7]=1[CH3:11])=[O:5])[CH3:2].Br[CH2:13][CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1>>[CH2:1]([O:3][C:4]([C:6]1[CH:10]=[CH:9][N:8]([CH2:13][CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[C:7]=1[CH3:11])=[O:5])[CH3:2]
Reactant: BrCC1CCCCC1
Reactant: CCOC(=O)c1cc[nH]c1C
Product: CCOC(=O)c1ccn(CC2CCCCC2)c1C

Procedure:
Prepared from 2-methyl-1H-pyrrole-3-carboxylic acid ethyl ester, example 96(a), and (bromomethyl)cyclohexane under conditions analogous to experimental example 96(b). 1H NMR (200 MHz, CDCl3) δ 6.50 (1H, d, J=3.2 Hz), 6.43 (1H, d, J=3.2 Hz), 4.23 (2H, q, J=7.0 Hz), 3.62 (2H, d, J=6.6 Hz), 2.50 (3H, s), 1.78-0.88 (11H, m), and 1.33 (3H, t, J=7.0 Hz).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][CH:9]=1)[NH2:6])#[N:2].C[O:11][C:12]([C:14]#[C:15][C:16](OC)=[O:17])=[O:13].[OH-].[Na+].Cl>CO.C1(OC2C=CC=CC=2)C=CC=CC=1.O>[C:1]([C:3]1[CH:9]=[CH:8][CH:7]=[C:5]2[C:4]=1[C:16](=[O:17])[CH:15]=[C:14]([C:12]([OH:13])=[O:11])[NH:6]2)#[N:2]
Reactant: COC(=O)C#CC(=O)OC
Reactant: N#Cc1cccc(N)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: O
Solvent: CO
Product: N#Cc1cccc2[nH]c(C(=O)O)cc(=O)c12
Yield: 0.5 %

Procedure:
3-Cyanoaniline (21.3 g, 0.18 mol) and dimethylacetylene dicarboxylate (10.9 ml, 0.12 mol) were dissolved in dry methanol and heated at reflux for 14 h. After cooling, the solvent was removed in vacuo and the residue partitioned between diethyl ether and 1N hydrochloric acid. The organic layer was dried (Na2SO4), filtered and concentrated in vacuo to leave an oil which was heated in diphenyl ether (100 ml) at 250° C. for 15 minutes. On cooling, a solid precipated which was collected and recrystallised successively from acetic acid/diethyl ether, then from pyridine, to give a pure material by t.l.c. (0.165 g). This was dissolved in water (20 ml) and methanol (10 ml) with sodium hydroxide (0.13 g) and the solution heated at 100° C. for 2 h. Addition of 1N hydrochloric acid caused precipitation of a white solid which was collected by filtration and washed successively with water, ethanol and diethyl ether to give 5-cyano-4-oxo-1,4-dihydroquinoline-2-carboxylic acid (0.14 g) m.p. 278°-279° C., δ (360 MHz, NAOD) 6.96 (1H, s, 3-H), 7.64 (1H, dd, 7-H), 7.83 (1H, dd, 6-H) and 8.05 (1H, dd, 8-H). (Found: C, 60.23; H, 3.03; N, 12.46%. C11H6N2O3. 0.3H2O requires C, 60.17; H, 3.03; N, 12.78%).
Reaction SMILES: [CH:1]1(B(O)O)[CH2:3][CH2:2]1.Br[C:8]1[N:13]=[CH:12][C:11]([C:14]2([C:22]#[N:23])[CH2:19][CH2:18][C:17]([F:21])([F:20])[CH2:16][CH2:15]2)=[CH:10][CH:9]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.[Cl-].[NH4+]>C1(C)C=CC=CC=1.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH:1]1([C:8]2[N:13]=[CH:12][C:11]([C:14]3([C:22]#[N:23])[CH2:15][CH2:16][C:17]([F:20])([F:21])[CH2:18][CH2:19]3)=[CH:10][CH:9]=2)[CH2:3][CH2:2]1
Reactant: N#CC1(c2ccc(Br)nc2)CCC(F)(F)CC1
Reactant: OB(O)C1CC1
Agent: [Pd+2]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: CC(=O)[O-]
Solvent: O
Solvent: Cc1ccccc1
Product: N#CC1(c2ccc(C3CC3)nc2)CCC(F)(F)CC1
Temperature: 110 °C
Yield: 41.6 %

Procedure:
A suspension of cyclopropylboronic acid (0.94 g, 11 mmol), 1-(6-bromo-pyridin-3-yl)-4,4-difluoro-cyclohexanecarbonitrile (1.10 g, 3.67 mmol) and potassium phosphate tribasic (2.30 g, 10.8 mmol) in a mixture of toluene (16 mL) and water (4 mL) at room temperature was purged with nitrogen gas for 1 hour. Then palladium acetate (31 mg, 0.14 mmol) and tricyclohexylphosphine (51 mg, 0.18 mmol) were added and the mixture was heated at 110° C. for 18 hours. After cooling to room temperature a saturated aqueous solution of ammonium chloride was added, followed by water. The organic layer was separated and the aqueous layer was extracted again three times with AcOEt. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was then purified by silica gel chromatography to afford 1-(6-cyclopropyl-pyridin-3-yl)-4,4-difluoro-cyclohexanecarbonitrile (400 mg, 27%). LC-MS (m/z) 263.0 (MH+). 11-1 NMR (400 MHz, CDCl3) δ ppm 8.59 (d, J=2.5 Hz, 1 H), 7.64 (dd, J=8.3, 2.5 Hz, 1 H), 7.19 (d, J=8.3 Hz, 1 H), 2.00-2.39 (m, 9 H), 0.99-1.06 (m, 4 H).
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[CH:7]=[C:6]([CH3:8])[CH2:5][CH2:4][CH:3]1[C:9](=O)[CH3:10].N1C=CC=CC=1.Cl.[CH3:20][O:21][NH2:22]>CO>[CH3:20][O:21][N:22]=[C:9]([CH:3]1[CH2:4][CH2:5][C:6]([CH3:8])=[CH:7][C:2]1([CH3:12])[CH3:1])[CH3:10]
Reactant: CON
Reactant: CC(=O)C1CCC(C)=CC1(C)C
Agent: Cl
Solvent: c1ccncc1
Solvent: CO
Product: CON=C(C)C1CCC(C)=CC1(C)C
Temperature: 24 °C
Reaction time: 16 h
Yield: 92.4 %

Procedure:
To a stirred solution of 1-(2,2,4-trimethyl-cyclohex-3-enyl)-ethanone (162 g; 0.97 mol), prepared as described in example P4, in methanol (500 ml) was added pyridine (160 ml; 1.95 mol) followed by a portionwise addition of methoxyamine hydrochloride (142 g; 1.70 mol). The reaction mixture was stirred at 24° C. for 16 hours under nitrogen atmosphere. Methanol was removed under reduced pressure, the residue poured in water (600 ml) and 1N hydrochloric acid was added (100 ml). The solution was extracted with dichloromethane (3×300 ml). Combined organic layers were washed with brine (500 ml) and dried over sodium sulfate. The solvent was removed in vacuo to afford 175 g (92% of theory) of 1-(2,2,4-trimethyl-cyclohex-3-enyl)-ethanone O-methyl-oxime as a clear red oil.