Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](#[N:5])[CH2:2][C:3]#[N:4].Br[CH2:7][CH2:8][C:9]([F:13])=[C:10]([F:12])[F:11].CC(C)([O-])C.[K+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O>[F:13][C:9](=[C:10]([F:12])[F:11])[CH2:8][CH2:7][CH:2]([C:1]#[N:5])[C:3]#[N:4]
Reactant: N#CCC#N
Reactant: FC(F)=C(F)CCBr
Agent: CC(C)(C)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Solvent: O
Product: N#CC(C#N)CCC(F)=C(F)F
Temperature: 0 °C
Yield: 14.2 %

Procedure:
First, 6.98 g of malononitrile, 681 mg of tetrabutylammonium bromide, and 10 g of 4-bromo-1,1,2-trifluoro-1-butene were mixed, and while stirring at 0° C. under an atmosphere of nitrogen, 5.92 g of potassium t-butoxide was slowly added. The mixture was further stirred at room temperature for 12 hours. Then, the reaction mixture was poured into water, followed by extraction with t-butyl methyl ether. The organic layer was washed with water, a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 1.31 g of (3,4,4-trifluoro-3-butenyl)malononitrile (the intermediate (17)).
Reaction SMILES: [CH2:1]([NH2:9])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[C:11]1[C:12]2[CH:25]=[C:24]([Cl:26])[S:23][C:13]=2[N:14]=[C:15](C2C=NC=CN=2)[N:16]=1>>[CH2:1]([NH:9][C:11]1[C:12]2[CH:25]=[C:24]([Cl:26])[S:23][C:13]=2[N:14]=[CH:15][N:16]=1)[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: Clc1cc2c(Cl)nc(-c3cnccn3)nc2s1
Reactant: NCCc1ccccc1
Product: Clc1cc2c(NCCc3ccccc3)ncnc2s1

Procedure:
With the procedure of Example 1, the reaction of phenethylamine with 4-chloro-2-(pyrazin-2-yl)-6-chloro-thieno-[2,3-d]-pyrimidine yields 2-pyrazin-2-yl)-4-phenethylamino-6-chloro-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[C:9]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][N:15]3[C:19](=[O:20])[CH2:18][S:17][C:16]3=[O:21])=[CH:8][CH:7]=[CH:6][C:5]=12.[CH:22](=O)[CH2:23][CH2:24][CH3:25].N1CCCCC1>C(O)C>[CH:22](=[C:18]1[S:17][C:16](=[O:21])[N:15]([CH2:14][CH2:13][CH2:12][CH2:11][O:10][C:9]2[N:4]3[CH:3]=[CH:2][N:1]=[C:5]3[CH:6]=[CH:7][CH:8]=2)[C:19]1=[O:20])[CH2:23][CH2:24][CH3:25]
Reactant: O=C1CSC(=O)N1CCCCOc1cccc2nccn12
Reactant: CCCC=O
Solvent: C1CCNCC1
Solvent: CCO
Product: CCCC=C1SC(=O)N(CCCCOc2cccc3nccn23)C1=O

Procedure:
To a solution of 1.71 g (5.6 mmol) of 3-[4-(imidazo-[1,2-a]pyridin-5-yloxy)butyl]thiazolidine-2,4-dione and 0.51 ml (5.6 mmol) of n-butyraldehyde in 50 ml of ethanol, 0.05 ml (0.5 mmol) of piperidine was added, followed by refluxing for 2 hours. After the reaction mixture was cooled, the solvent was distilled off. The residue was dissolved in chloroform, washed with saturated aqueous sodium hydrogen carbonate and dried, after which the solvent was distilled off. The residue was purified by column chromatography (eluent, ethyl acetate) to yield 1.79 g (88.9%, yellow oily substance) of the desired product.
Reaction SMILES: C([N:8]1[CH2:31][CH:30]([CH:32]=[CH2:33])[O:29][C:10]2([CH2:15][CH2:14][N:13]([C:16]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH:25]([CH3:27])[CH3:26])=[C:20]([CH3:28])[CH:19]=3)=[O:17])[CH2:12][CH2:11]2)[CH2:9]1)C1C=CC=CC=1.C([O-])=O.[NH4+]>[Pd].CO>[CH2:32]([CH:30]1[O:29][C:10]2([CH2:15][CH2:14][N:13]([C:16]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH:25]([CH3:26])[CH3:27])=[C:20]([CH3:28])[CH:19]=3)=[O:17])[CH2:12][CH2:11]2)[CH2:9][NH:8][CH2:31]1)[CH3:33]
Reactant: C=CC1CN(Cc2ccccc2)CC2(CCN(C(=O)c3ccc(OC(C)C)c(C)c3)CC2)O1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: CCC1CNCC2(CCN(C(=O)c3ccc(OC(C)C)c(C)c3)CC2)O1
Temperature: 75 °C
Yield: 84.1 %

Procedure:
To (8-benzyl-10-vinyl-11-oxa-3,8-diazaspiro[5.5]undecan-3-yl)-(4-isopropoxy-3-methyl-phenyl)methanone (150 mg, 0.33 mmol), ammonium formate (74 mg, 1.17 mmol) and Pd (17 mg, 0.02 mmol) (10% on activated carbon) was added methanol (2 mL) and the reaction mixture was heated at 75° C. for 30 minutes. The reaction mixture was cooled, microfiltered and concentrated in vacuo, then diluted with DCM (20 mL), washed with aq. 1M NaOH (10 mL), extracted with DCM (120 mL), washed with brine (10 mL), dried over MgSO4 and concentrated in vacuo to give (10-ethyl-11-oxa-3,8-diazaspiro[5.5]undecan-3-yl)-(4-isopropoxy-3-methyl-phenyl)methanone (100 mg, 83%) as a colorless oil. ESI-MS m/z calc. 360.5. Found 361.3 (M+1)+; Retention time: 1.25 minutes (3 min run).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:10]([C:17]([OH:19])=O)=[CH:11][N:12]([CH3:16])[C:13](=[O:15])[CH:14]=2)=[C:4]([F:20])[CH:3]=1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.[CH:43]1([CH2:46][O:47][NH2:48])[CH2:45][CH2:44]1.CCN(CC)CC>CN(C=O)C.CCOC(C)=O>[CH:43]1([CH2:46][O:47][NH:48][C:17]([C:10]2[C:9]([NH:8][C:5]3[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][C:4]=3[F:20])=[CH:14][C:13](=[O:15])[N:12]([CH3:16])[CH:11]=2)=[O:19])[CH2:45][CH2:44]1
Reactant: NOCC1CC1
Reactant: Cn1cc(C(=O)O)c(Nc2ccc(Br)cc2F)cc1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: Cn1cc(C(=O)NOCC2CC2)c(Nc2ccc(Br)cc2F)cc1=O
Reaction time: 0.5 h
Yield: 88.4 %

Procedure:
A mixture of 4-(4-bromo-2-fluorophenylamino)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid (0.078 g, 0.229 mmol), EDCl (0.13 g, 0.69 mmol), and HOBt (0.093 g, 0.69 mmol) in DMF (5 mL) was stirred for 30 minutes. O-Cyclopropylmethyl-hydroxylamine (0.060 g, 0.69 mmol) was added followed by Et3N (0.096 mL, 0.69 mmol). After 1 hour, the reaction mixture was diluted with EtOAc and washed with saturated NH4Cl solution, saturated NaHCO3 solution and brine. The organic layer was dried (MgSO4) and concentrated to yield 83 mg (89%) clean desired product. MS APCI (+) m/z 410, 412 (M+, Br pattern) detected; 1H NMR (400 mHz, DMSO-d6) δ 11.57 (s, 1H), 9.42 (s, 1H), 8.10 (s, 1H), 7.67 (d, 1H), 7.43 (m, 2H), 3.70 (d, 2H), 3.35 (s, 3H), 1.11 (m, 1H), 0.54 (m, 2H), 0.27 (m, 2H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9](=[O:11])[C:8]([CH3:13])([CH3:12])[C:7]=2[CH:14]=1)#[N:2].[CH3:15][NH:16][CH3:17]>C(OCC)C.C(O)C>[OH:10][C:6]1[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:14][C:7]=1[C:8]([CH3:13])([CH3:12])[C:9]([N:16]([CH3:17])[CH3:15])=[O:11]
Reactant: CNC
Reactant: CC1(C)C(=O)Oc2ccc(C#N)cc21
Solvent: CCOCC
Solvent: CCO
Product: CN(C)C(=O)C(C)(C)c1cc(C#N)ccc1O
Temperature: 25 °C

Procedure:
A suspension of 5-cyano-2,3-dihydro-3,3-dimethylbenzofuran-2-one (3.7 g), prepared as in Example 3, in diethyl ether (50 ml) was treated with a solution of dimethylamine in ethanol (8.6 ml of a 20.8% solution) portionwise with stirring at room temperature. The mixture was stirred for two hours, and the product was isolated by filtration, yield 4 g, mp 146°-148° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][S:10][CH2:11][CH:12]([C:16]([F:19])([F:18])[F:17])[C:13](Cl)=[O:14])=[CH:5][CH:4]=1.[O:20]=[C:21]1[CH2:25][NH:24][C@H:23]([C:26]([OH:28])=[O:27])[CH2:22]1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][S:10][CH2:11][CH:12]([C:16]([F:19])([F:18])[F:17])[C:13]([N:24]2[CH2:25][C:21](=[O:20])[CH2:22][C@H:23]2[C:26]([OH:28])=[O:27])=[O:14])=[CH:5][CH:4]=1
Reactant: O=C1CN[C@H](C(=O)O)C1
Reactant: COc1ccc(CSCC(C(=O)Cl)C(F)(F)F)cc1
Product: COc1ccc(CSCC(C(=O)N2CC(=O)C[C@H]2C(=O)O)C(F)(F)F)cc1

Procedure:
The 3-[[(4-methoxy)phenylmethyl]thio]-2-trifluoromethylpropionyl chloride from part (a) is reacted with 4-keto-L-proline to yield 1-[3-[[(4-methoxy)phenylmethyl]thio]-2-trifluoromethyl-1-oxopropyl]-4-oxo-L-proline.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[NH2:11][C:12]1[C:17]([OH:18])=[CH:16][CH:15]=[CH:14][N:13]=1.C([O-])([O-])=O.[K+].[K+].CC(C)([O-])C.[K+]>O.CN1CCCC1=O>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([NH:11][C:12]2[C:17]([OH:18])=[CH:16][CH:15]=[CH:14][N:13]=2)=[CH:3][CH:4]=1)([O-:10])=[O:9]
Reactant: Nc1ncccc1O
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: CC(C)(C)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN1CCCC1=O
Product: O=[N+]([O-])c1ccc(Nc2ncccc2O)cc1
Temperature: 60 °C
Reaction time: 6 h
Yield: 30.5 %

Procedure:
0.3 g of 4-fluoronitrobenzene, 0.468 g of 2-amino-3-hydroxypyridine, and 0.353 g of K2CO3 were added to a solution of 2.5 ml of N-methylpyrrolidinone. The reaction medium was heated at 60° C. for 1 hour and 0.286 g of potassium tert-butoxide was then added. Heating was then continued for 6 hours and, after cooling to room temperature, the reaction medium was poured into a water and ice mixture. The aqueous phase was extracted with ethyl acetate. The organic phase was dried over MgSO4 and then evaporated to dryness under vacuum. 0.15 g of 2-[(4-nitrophenyl)amino]pyrid-3-ol (3) was obtained.
Reaction SMILES: [C:1](O)(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[NH2:21][CH:22]([CH:25]([OH:41])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])[CH2:23][OH:24]>C(OCC)(=O)C.CCCCCCC>[C:1]([NH:21][CH:22]([CH:25]([OH:41])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])[CH2:23][OH:24])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCCCCCCCCCCCC(=O)O
Reactant: CCCCCCCCCCCCCCCC(O)C(N)CO
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: CCCCCCCCCCCCCCCCCC(=O)NC(CO)C(O)CCCCCCCCCCCCCCC
Yield: 72 %

Procedure:
6.2 g (0.022 mol) of stearic acid and 6 g (0.022 mol) of 2-aminooctadecane-1,3-diol were mixed in a tube and irradiated with the apparatus used in Example 1, under the same frequency and power conditions. After an irradiation of 18 minutes at 140° C.±5° C., the reaction mixture was solubilized in a mixture of 80 ml of ethyl acetate and 40 ml of heptane. The precipitate obtained was recrystallized from ethanol and 8.1 g of expected pure product were obtained with a yield of 72%.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([CH:6]=[CH:7][CH2:8][N:9]([CH3:14])[CH2:10][CH2:11][C:12]#[N:13])=[CH:4][CH:3]=1.[H-].[Na+].O>CN(C)P(=O)(N(C)C)N(C)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH:7]2[CH2:8][N:9]([CH3:14])[CH2:10][CH:11]2[C:12]#[N:13])=[CH:15][CH:16]=1
Reactant: CN(CC=Cc1ccc(Cl)cc1)CCC#N
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: O
Product: CN1CC(C#N)C(Cc2ccc(Cl)cc2)C1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
252 g of 3-[N-(p-chlorocinnamyl)-methylamino]propionitrile in 1 liter of hexamethylphosphoric acid triamide (HMPT) are added dropwise over a period of 11/4 hours at 0°-5° and in a nitrogen atmosphere to a suspension of 36 g of sodium hydride (80% in mineral oil) in 2 liter of HMPT, and the mixture stirred at room temperature for a period of 16 hours. Water is then added to the mixture with ice cooling, the mixture extracted with ether, the organic phase washed with water, dried over sodium sulphate and evaporated to yield 4-(p-chlorobenzyl)-1-methylpyrrolidin-3-carbonitrile. M.P. 170°-172° [hydrogen oxalate form].
Reaction SMILES: [S:1]([C:5]1[CH:6]=[C:7]([N:11]2[C:15]3=[N:16][CH:17]=[CH:18][C:19](B(O)O)=[C:14]3[CH:13]=[N:12]2)[CH:8]=[CH:9][CH:10]=1)(=[O:4])(=[O:3])[NH2:2].[NH2:23][C:24]1[C:29](Br)=[CH:28][N:27]=[CH:26][N:25]=1.C(=O)([O-])[O-].[Na+].[Na+]>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCO.COCCOC.O>[NH2:23][C:24]1[C:29]([C:19]2[CH:18]=[CH:17][N:16]=[C:15]3[N:11]([C:7]4[CH:6]=[C:5]([S:1]([NH2:2])(=[O:4])=[O:3])[CH:10]=[CH:9][CH:8]=4)[N:12]=[CH:13][C:14]=23)=[CH:28][N:27]=[CH:26][N:25]=1
Reactant: Nc1ncncc1Br
Reactant: NS(=O)(=O)c1cccc(-n2ncc3c(B(O)O)ccnc32)c1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: COCCOC
Solvent: O
Product: Nc1ncncc1-c1ccnc2c1cnn2-c1cccc(S(N)(=O)=O)c1
Temperature: 105 °C

Procedure:
Example 4 was prepared according to the general procedure of Example 1, except heating at 105° C. for 18 h and using the following materials: Intermediate 1B (32 mg, 0.101 mmol), 4-amino-5-bromopyrimidine (38.6 mg, 0.222 mmol), sodium carbonate (41.8 mg, 0.394 mmol), EtOH:DME:H2O (1.2:2.5:1.0 ratio) (1.0 mL) and tetrakis(triphenylphosphine) palladium(0) (18.6 mg, 0.016 mmol). The title compound was isolated as a white solid (4.3 mg, 11.6%). Purification was done by preparative HPLC (Condition A) using a Phenomenex Luna Axia 30×100 mm S10 column from 5% Solvent B to 100% Solvent B over 12 min, ret. T=4.7 min. 1H NMR (500 MHz, DMSO-d6) δ ppm 8.75-8.87 (2 H, m), 8.62-8.71 (1 H, m), 8.52 (1 H, s), 8.42 (1 H, s), 8.28 (1 H, s), 7.79-7.84 (2 H, m), 7.57 (2 H, s), 7.47 (1 H, d, J=4.88 Hz), 6.97 (2 H, br. s.) LC/MS (Condition B): ret. T=1.6 min, (M+H)+ 367.97. Analytical HPLC: (Condition A): >99%, ret. T=11.81 min, (Condition B): >99%, ret. T=13.74 min, (Condition C): >99%, ret. T=3.87 min, (Condition D): >99%, ret. T=4.18 min.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[CH:4]([N:11]1[C:16](=[O:17])[CH:15]=[C:14]([OH:18])[CH:13]=[N:12]1)[CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1.C(=O)([O-])[O-].[K+].[K+].Cl[C:27]1[N:32]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:30]=[CH:29][N:28]=1>CN(C)C=O>[CH3:1][O:2][C:3](=[O:19])[CH:4]([N:11]1[C:16](=[O:17])[CH:15]=[C:14]([O:18][C:27]2[N:32]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:30]=[CH:29][N:28]=2)[CH:13]=[N:12]1)[CH2:5][CH:6]1[CH2:7][CH2:8][CH2:9][CH2:10]1
Reactant: COC(=O)C(CC1CCCC1)n1ncc(O)cc1=O
Reactant: FC(F)(F)c1ccnc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)C(CC1CCCC1)n1ncc(Oc2nccc(C(F)(F)F)n2)cc1=O
Temperature: 110 °C
Reaction time: 1 h

Procedure:
A solution of 3-cyclopentyl-2-(4-hydroxy-6-oxo-6H-pyridazin-1-yl)-propionic acid methyl ester (3.0 g, 11.3 mmol) in N,N-dimethylformamide was treated with potassium carbonate (2.33 g, 16.9 mmol) and 2-chloro-4-trifluoromethyl-pyrimidine (3.1 g, 16.9 mmol). The reaction mixture was stirred at 110° C. for 1 h. At this time, the reaction was cooled to 25° C. and concentrated in vacuo. The residue was partitioned between water and ethyl acetate. The combined organics were washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, and concentrated in vacuo. Chromatography afforded 3-cyclopentyl-2-[6-oxo-4-(4-trifluoromethyl-pyrimidin-2-yloxy)-6H-pyridazin-1-yl]-propionic acid methyl ester as a light oil (4.0 g, 86%).
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[CH3:6][NH:7][CH2:8][C:9]1[C:18]2[O:17][C:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[C:15]([CH3:25])[C:14](=[O:26])[C:13]=2[CH:12]=[CH:11][CH:10]=1.C(N(CC)CC)C.O>ClCCCl>[CH3:6][N:7]([CH2:8][C:9]1[C:18]2[O:17][C:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[C:15]([CH3:25])[C:14](=[O:26])[C:13]=2[CH:12]=[CH:11][CH:10]=1)[C:3](=[O:4])[CH2:2][Cl:1]
Reactant: O=C(Cl)CCl
Reactant: CNCc1cccc2c(=O)c(C)c(-c3ccccc3)oc12
Solvent: ClCCCl
Solvent: O
Solvent: CCN(CC)CC
Product: Cc1c(-c2ccccc2)oc2c(CN(C)C(=O)CCl)cccc2c1=O
Reaction time: 2 h

Procedure:
A solution of 6 ml of chloracetyl chloride in 60 ml of 1,2-dichloroethane was added dropwise at -5° to 0° C. to a solution of 20 g of Intermediate XX and 10 ml of triethylamine in 200 ml of 1,2-dichloroethane. After stirring at 20°-25° C. for 2 hours, 150 ml of water was added to the reaction mixture and the phases were separated. The organic phase was washed with water and dried on anhydrous sodium sulfate. The solvent was removed in vacuo, and the residue was crystallized from ethanol to give 22.5 g of the title compound, m.p. 146°-148° C.
Reaction SMILES: [N:1]1([S:7]([NH:10][C:11]([C:13]2[CH2:17][CH:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:15]([C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=3)[N:14]=2)=O)(=[O:9])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.P(Cl)(Cl)(Cl)(Cl)Cl.Cl.C[CH2:39][N:40](C(C)C)C(C)C>ClC1C=CC=CC=1>[N:1]1([S:7]([NH:10][C:11]([C:13]2[CH2:17][CH:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:15]([C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=3)[N:14]=2)=[N:40][CH3:39])(=[O:9])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(NS(=O)(=O)N1CCCCC1)C1=NN(c2ccc(Cl)cc2)C(c2ccccc2)C1
Reactant: CCN(C(C)C)C(C)C
Agent: Cl
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: Clc1ccccc1
Product: CN=C(NS(=O)(=O)N1CCCCC1)C1=NN(c2ccc(Cl)cc2)C(c2ccccc2)C1
Temperature: 140 °C
Yield: 48.7 %

Procedure:
Part B: A stirred mixture of N-[(piperidin-1-yl)sulfonyl]-1-(4-chlorophenyl)-5-phenyl-4,5-dihydro-(1H)-pyrazole-3-carboxamide (2.23 gram, 5 mmol), PCl5 (1.15 g, 5.5 mmol) and chlorobenzene (50 ml) is heated for 90 minutes at 140° C. After cooling the mixture to room temperature, followed by concentration in vacuo, the residue is dissolved in dichloromethane and methylamine.HCl (0.34 g, 5 mmol) and DIPEA (1.74 ml, 10 mmol) are successively added. The resulting mixture is stirred for 1 hour at room temperature, twice washed with water, dried over MgSO4, filtered and concentrated in vacuo. The resulting residue is further purified by flash chromatography (silica gel, dichloromethane), followed by crystallization from diisopropyl ether to give N-[(piperidin-1-yl)sulfonyl]-N′-methyl-1-(4-chlorophenyl)-5-phenyl-4,5-dihydro-(1H)-pyrazole-3-carboxamidine (1.12 gram, 49% yield). Melting point: 141-144° C. Rf (silica gel, diethyl ether=0.2).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:18]2[CH2:21][C:20]([F:23])([F:22])[CH2:19]2)[C:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[C:6]=2[N:7]=1.[Cl:24][C:25]1[N:29]=[CH:28][N:27]([C:30]2[CH:36]=[CH:35][C:33]([NH2:34])=[CH:32][C:31]=2[O:37][CH3:38])[N:26]=1.C(O)(=O)C>C1COCC1.CO>[Cl:24][C:25]1[N:29]=[CH:28][N:27]([C:30]2[CH:36]=[CH:35][C:33]([NH:34][C:2]3[N:3]=[C:4]([N:18]4[CH2:19][C:20]([F:23])([F:22])[CH2:21]4)[C:5]4[CH2:10][CH2:9][CH:8]([C:11]5[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=5)[C:6]=4[N:7]=3)=[CH:32][C:31]=2[O:37][CH3:38])[N:26]=1
Reactant: Fc1ccc(C2CCc3c2nc(Cl)nc3N2CC(F)(F)C2)cc1
Reactant: COc1cc(N)ccc1-n1cnc(Cl)n1
Solvent: CC(=O)O
Solvent: CO
Solvent: C1CCOC1
Product: COc1cc(Nc2nc3c(c(N4CC(F)(F)C4)n2)CCC3c2ccc(F)cc2)ccc1-n1cnc(Cl)n1
Temperature: 100 °C
Reaction time: 8 h
Yield: 49.2 %

Procedure:
To a solution of 2-chloro-4-(3,3-difluoroazetidin-1-yl)-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine (Preparation Ha) (170 mg, 0.500 mmol) and 4-(3-chloro-1H-1,2,4-triazol-1-yl)-3-methoxyaniline (Preparation F) (146 mg, 0.650 mmol) in THF (1498 μL) was added Acetic Acid (1498 μL). The resulting mixture was heated to 100° C. and stirred overnight. The reaction mixture was then concentrated in vacuo. MeOH was added to the residue which resulted in a suspension. This was filtered to give a solid which was taken up in hot MeOH and filtered. The filtrate was then concentrated in vacuo to give N-(4-(3-chloro-1H-1,2,4-triazol-1-yl)-3-methoxyphenyl)-4-(3,3-difluoroazetidin-1-yl)-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-amine (racemate) (130 mg, 49.22% yield) as a yellow solid. LC-MS (M+H)+=528.1. 1H NMR (500 MHz, MeOD) δ ppm 8.81 (1H, s), 7.65 (1H, d, J=8.55 Hz), 7.59 (1H, s), 7.29-7.36 (2H, m), 7.11-7.21 (3H, m), 4.87-4.88 (4H, m), 4.47 (1H, s), 3.91 (3H, s), 3.11-3.19 (1H, m), 2.99-3.08 (1H, m), 2.77 (1H, dddd, J=13.47, 8.96, 4.43, 4.27 Hz), 2.13 (1H, dq, J=8.89, 6.70 Hz).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([OH:14])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[N:15]1([CH2:20][CH2:21][CH2:22]O)[CH2:19][CH2:18][CH2:17][CH2:16]1>>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:22][CH2:21][CH2:20][N:15]3[CH2:19][CH2:18][CH2:17][CH2:16]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1
Reactant: COc1cc2c(Cl)ncnc2cc1O
Reactant: OCCCN1CCCC1
Product: COc1cc2c(Cl)ncnc2cc1OCCCN1CCCC1

Procedure:
The compound was synthesised according to GP 4 from 4-chloro-7-hydroxy-6-methoxy-quinazoline and 3-Pyrrolidin-1-yl-propan-1-ol. LC/ESI-MS: m/z=322 [M+H].
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([F:10])=[C:6]([OH:11])[CH:5]=1.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21]O)=[CH:16][CH:15]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>O1CCCC1>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([F:10])=[C:6]([O:11][CH2:21][CH2:20][C:17]2[CH:18]=[CH:19][C:14]([Cl:13])=[CH:15][CH:16]=2)[CH:5]=1
Reactant: OCCc1ccc(Cl)cc1
Reactant: COC(=O)c1ccc(F)c(O)c1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1ccc(F)c(OCCc2ccc(Cl)cc2)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
0.5 g (2.94 mmol) of 4-Fluoro-3-hydroxy-benzoic acid methyl ester was dissolved in 30 ml of anhydrous tetrahydrofuran. To this solution was added 0.506 g (3.23 mmol) of 2-(4-chloro-phenyl)-ethanol, 2.93 g (equivalent to 8.8 mmol PPh3) of triphenylphosphine derivatized polystyrene and 1.53 g (8.8 mmol) of DEAD. The solution was shaken for 16 h at RT. The polymer was filtered off and washed with tetrahydrofuran. The solvent was removed under reduced pressure. The residue was taken-up in ethyl acetate/n-heptane (1/5) and the insoluble residue was removed by filtration. The solvent was removed under reduced pressure. The residue was chromatographed on silica gel eluting with ethyl acetate/n-heptane (1/5).
Reaction SMILES: [CH3:1][C:2]1([CH2:5][CH2:6][CH2:7][CH:8]([CH3:10])[CH3:9])[CH2:4][O:3]1.CC(C)[O-].[Al+3].CC(C)[O-].CC(C)[O-].C(O)(C)C>C1(C)C=CC=CC=1>[CH3:1][C:2](=[CH:5][CH2:6][CH2:7][CH:8]([CH3:10])[CH3:9])[CH2:4][OH:3]
Reactant: CC(C)CCCC1(C)CO1
Agent: CC(C)[O-]
Agent: [Al+3]
Solvent: Cc1ccccc1
Solvent: CC(C)O
Product: CC(=CCCC(C)C)CO
Temperature: 25 °C
Yield: 93 %

Procedure:
Using a procedure suggested by S. Terao, et al., Synthesis, 467 (1979), a mixture of 521 mg (3.66 mmoles) of 2-methyl-2-[4-methylpentyl]oxirane (produced in accordance with Example XV) and 1.73 g (8.47 mmoles of aluminum isopropoxide in 10 mL of toluene was heated at reflux for 3.75 hours. [Note: On a larger scale, the isopropyl alcohol formed during the reaction can be continuously removed by fractional distillation, thereby enabling one to use considerably less aluminum isopropoxide to effect this isomerization.] After cooling to room temperature, the reaction mixture was treated with 15 mL of 2M aqueous hydrochloric acid to decompose the aluminum complex. The mixture was subsequently diluted with 25 mL of ether and 30 mL of 10% aqueous sodium chloride. After separating the layers, the organic layer was washed in successive order with 10% aqueous sodium chloride (1×25 mL) and saturated brine (1×25 mL), and then was dried over anhydrous sodium sulfate and filtered. Removal of the volatile organic solvents by evaporation at reduced pressure afforded, after evaporative distillation, 482 mg (93% yield) of the named allylic alcohols: boiling point 58°-71° C. (bath temperature, 0.20 mm). Proton NMR analysis indicated that the product was a 2:1 mixture of 6-methyl-2-methylene-1-heptanol and 2,6-dimethyl-2-hepten-1-ol respectively, accompanied by approximately 10% of what appeared to be a saturated C-9 alcohol (2,6-dimethyl-1-heptanol). 2,6-Dimethyl-2-hepten-1-ol was characterized by two singlets at δ4.09 (CH2OH, E stereoisomer), and 3.94 (CH2OH, Z stereoisomer), and two triplets at δ5.37 and 5.24 (vinyl H, Z and E stereoisomers). The corresponding signals for 6-methyl-2-methylene-1-heptanol appeared as singlets at δ4.02 (CH2OH), 4.97 (one vinyl H), and 4.81 (the second vinyl H).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([CH:8]([CH:12]=[CH2:13])[C:9]([NH2:11])=[S:10])[CH:5]=[CH:4][CH:3]=1.[CH2:14](N)[CH:15]=[CH2:16]>>[CH2:16]([NH:11][C:9](=[S:10])[CH:8]([C:6]1[CH:5]=[CH:4][CH:3]=[C:2]([CH3:1])[N:7]=1)[CH:12]=[CH2:13])[CH:15]=[CH2:14]
Reactant: C=CCN
Reactant: C=CC(C(N)=S)c1cccc(C)n1
Product: C=CCNC(=S)C(C=C)c1cccc(C)n1

Procedure:
Reacting 2-(6-methyl-2-pyridyl)-3-thiobutenamide with allylamine by the procedure of Example 7 gives N-allyl-2-(6-methyl-2-pyridyl)-3-thiobutenamide.