Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:3]=[C:4](SC)[NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N+:15]([O-:17])=[O:16])(=[O:8])=[O:7])#[N:2].[NH2:20][NH2:21]>C(#N)C>[NH2:2][C:1]1[NH:21][N:20]=[C:4]([NH:5][S:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N+:15]([O-:17])=[O:16])(=[O:8])=[O:7])[N:3]=1
Reactant: NN
Reactant: CSC(=NC#N)NS(=O)(=O)c1ccccc1[N+](=O)[O-]
Solvent: CC#N
Product: Nc1nc(NS(=O)(=O)c2ccccc2[N+](=O)[O-])n[nH]1
Reaction time: 216 h
Yield: 82.2 %

Procedure:
A suspension of 29.4 g (98.0 mmol) of N'-Cyano-N-(2-nitrophenylsulfonyl)-S-methylisothiourea in 100 ml of acetonitrile was treated with 6.2 ml (6.3 g, 0.20 mol) of anhydrous hydrazine. A mild exothermic reaction occurred as the reaction mixture became homogeneous. After stirring for 9 days the precipitated solid was collected by filtration and dried to afford 22.9 g of yellow solid. The crude product was recrystallized from HOAc to yield a total of 15.9 g (57 percent) of the desired product as a pale yellow solid, mp 255°-256° C. IR and 1H NMR spectra were consistent with the assigned structure.
Reaction SMILES: [CH3:1][C@H:2]1[C@@H:7]2[CH2:8][CH2:9][C:10]([CH3:12])=[CH:11][C@@H:6]2[C@H:5]([C:13]([C:15](O)=[O:16])=[CH2:14])[CH2:4][CH2:3]1.[N+](=C)=[N-]>CCOCC>[CH3:1][C@H:2]1[C@@H:7]2[CH2:8][CH2:9][C:10]([CH3:12])=[CH:11][C@@H:6]2[C@H:5]([C:13]([CH2:15][OH:16])=[CH2:14])[CH2:4][CH2:3]1
Reactant: C=C(C(=O)O)[C@@H]1CC[C@@H](C)[C@@H]2CCC(C)=C[C@@H]21
Agent: C=[N+]=[N-]
Solvent: CCOCC
Product: C=C(CO)[C@@H]1CC[C@@H](C)[C@@H]2CCC(C)=C[C@@H]21
Temperature: -60 °C
Reaction time: 1 h

Procedure:
Amorpha-4,11-diene-12-ol was prepared from 100 mg artemisinic acid. The acid was dissolved in 6 mL of dry ether and esterified by adding diazomethane and mixing for 1 hour. GC-MS analyses of the reaction mixture showed the methyl ester and another compound (3:1), probably the methyl ester that was not connected to a cyclopropyl group. After removal of ether, 8.6 mg of the mixture was dissolved in 20 mL of ether-TBF (1:1) and cooled at −60° C. under a flow of dry nitrogen for 2 hours. The mixture was subsequently stirred for 1 hour at −30° C. with an excess of LiAlH4, after which the reaction was stopped by the addition of Na2SO4.10H2O. The temperature was raised to room temperature, and the reaction mixture was stirred an additional half hour. After drying with MgSO4 overnight, the mixture was filtered through a Büichner funnel and the solvent removed. The desired alcohol was isolated and purified by preparative thin layer chromatography performed on silica gel plates, using a mixture of petroleum ether-ethyl acetate (3:1) as an eluent (Rf 0.7). Amorpha-4,11-diene-12-ol was obtained in an overall yield of 14% as a mixture with 4-amorphene-12-ol (9:1). 1H NMR (400 MHz, CDCl3): δ 0.87 (d, 3H, Me15, J=6.0 Hz), δ 1.50 (br s, 3H, Me14), δ 1.0–2.2 (m, 11H), δ 2.47 (m, 1H, H6), δ 4.10 (s, 2H, H12), δ 4.83 (br s, 1H, H13′), δ 5.04 (br s, 1H, H13), δ 5.18 (br s, 1H, H4). EIMS (70 eV) m/z: 220 [M]+ (6), 202 (35), 189 (66), 187 (34), 145 (40), 132 (52), 131 (36), 121 (100), 119 (81), 105 (51), 93 (74), 91 (70), 81 (47), 79 (77), 77 (50), 55 (41), 41 (47).
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][C:6]([S:10]([NH:13][C:14]3[CH:18]=[CH:17][S:16][C:15]=3[C:19]([O:21]C)=[O:20])(=[O:12])=[O:11])=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[OH-].[Na+]>O1CCCC1.CO>[CH2:1]1[C:9]2[C:4](=[CH:5][C:6]([S:10]([NH:13][C:14]3[CH:18]=[CH:17][S:16][C:15]=3[C:19]([OH:21])=[O:20])(=[O:11])=[O:12])=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: COC(=O)c1sccc1NS(=O)(=O)c1ccc2c(c1)CCC2
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1sccc1NS(=O)(=O)c1ccc2c(c1)CCC2
Temperature: 80 °C
Yield: 100.8 %

Procedure:
To a solution of 125 (0.30 g; 0.89 mmol) in tetrahydrofuran (20 mL) and methanol (7 mL) was added aqueous sodium hydroxide (20 mL; 2N) and then heated at 80° C. for 16 hours. The reaction mixture was allowed to cool to room temperature and then extracted with diethyl ether (20 mL). The aqueous layer was separated and acidified with aqueous hydrochloric acid (15 mL; 2N) then extracted with ethyl acetate (2×20 mL). The combined organic phases were dried over magnesium sulfate, filtered, and concentrated under reduced pressure to yield the title product as an off-white solid (0.29 g).
Reaction SMILES: [Br-].[NH2:2][C:3]1[C:8]([CH2:9][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[C:7]([Cl:29])[C:6]([C:30]#[N:31])=[CH:5][CH:4]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[F:65][C:66]([F:73])([F:72])[CH2:67][CH2:68][C:69](O)=O>CN(C=O)C.C([O-])(O)=O.[Na+]>[Cl:29][C:7]1[C:6]([C:30]#[N:31])=[CH:5][CH:4]=[C:3]2[C:8]=1[CH:9]=[C:69]([CH2:68][CH2:67][C:66]([F:73])([F:72])[F:65])[NH:2]2
Reactant: O=C(O)CCC(F)(F)F
Reactant: N#Cc1ccc(N)c(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)c1Cl
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1ccc2[nH]c(CCC(F)(F)F)cc2c1Cl
Temperature: 25 °C

Procedure:
A solution of {[6-amino-3-cyano-2-(chloro)phenyl]methyl}(triphenyl) phosphonium bromide (Example 234A) (0.20 g, 0.39 mmol), HATU (0.157 g, 0.41 mmol), diisopropylethylamine (0.053 g, 0.41 mmol), and trifluoropropylcarboxylic acid (0.058 g, 0.41 mmol) in DMF (15 mL) was stirred at 100° C. for 24 h. After cooling to rt, the reaction was diluted with NaHCO3 (50 mL) and extracted with EtOAc (100 mL). The organic phase was washed with water and sat'd brine, dried (Na2SO4) and concentrated in vacuo. The residue was purified by flash chromatography (20-70% EtOAc-hexanes gradient) to afford the title compound as a light yellow solid: MS (ES) m/z 273 (M+1).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][N:7]([CH2:14][C:15]1[CH:23]=[CH:22][C:18]([C:19](O)=[O:20])=[CH:17][CH:16]=1)[CH2:8][C:9]1[NH:10][CH:11]=[CH:12][N:13]=1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.[C:46]([N:53]1[CH2:58][CH2:57][NH:56][CH2:55][CH2:54]1)([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47]>CN(C=O)C>[C:49]([O:48][C:46]([N:53]1[CH2:54][CH2:55][N:56]([C:19](=[O:20])[C:18]2[CH:22]=[CH:23][C:15]([CH2:14][N:7]([CH2:6][C:2]3[NH:1][CH:5]=[CH:4][N:3]=3)[CH2:8][C:9]3[NH:10][CH:11]=[CH:12][N:13]=3)=[CH:16][CH:17]=2)[CH2:57][CH2:58]1)=[O:47])([CH3:52])([CH3:51])[CH3:50]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=C(O)c1ccc(CN(Cc2ncc[nH]2)Cc2ncc[nH]2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(C(=O)c2ccc(CN(Cc3ncc[nH]3)Cc3ncc[nH]3)cc2)CC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 17.3 %

Procedure:
The compound (500 mg) obtained in Example 2-2 was dissolved in DMF (10 ml) and added with WSCI hydrochloride (257 mg), HOBt (181 mg), and 1-Boc piperazine (manufactured by Aldrich Corporation) (249 mg), followed by stirring at room temperature for 3 days. After completion of the reaction, the solvent was distilled off and the residue was then dissolved in chloroform for extraction, followed by washing with distilled water, a 1 mol/l sodium hydroxide aqueous solution, and saturated saline solution. The resulting organic layer was dried with anhydrous sodium sulfate. The solvent was distilled off and the residue was then purified through silica gel column chromatography (chloroform/methanol/water), thereby obtaining the subject compound (111 mg) as a yellow oily substance.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][C:8](=[O:10])[CH3:9])=[CH:3][CH:2]=1.[C:11](#[N:15])/[CH:12]=[CH:13]/[CH3:14].C[O-].[Na+].[Na]>CO.C(Cl)Cl.C(O)(=O)C>[C:8]([CH:7]([C:4]1[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=1)[CH:13]([CH3:14])[CH2:12][C:11]#[N:15])(=[O:10])[CH3:9]
Reactant: C/C=C/C#N
Reactant: CC(=O)Cc1ccncc1
Agent: C[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: CO
Product: CC(=O)C(c1ccncc1)C(C)CC#N
Temperature: 100 °C
Reaction time: 0.08 h

Procedure:
To a stirred mixture mixture containing 59.6 g of 1-(4-pyridinyl)propanone and 100 ml of crotononitrile was added a solution of sodium methoxide in methanol obtained by adding 1 pellet of sodium shot to 20 ml of methanol. The reaction mixture was heated on a steam bath with stirring. After about 5 minutes, there was an exothermic reaction which raised the reaction temperature to 100° C. The resulting mixture was allowed to cool to room temperature and stand overnight (about 16 hours). To the reaction was added 100 ml of 10% acetic acid and 300 ml of methylene dichloride; and, the mixture was shaken well. The layers were separated and the methylene dichloride layer was dried over anhydrous magnesium sulfate and filtered. The methylene dichloride was distilled off in vacuo and the residual oil was distilled under vacuum using a small column to produce 85.0 g of 4-acetyl-3-methyl-4-(4-pyridinyl)butanenitrile, b.p. 130°-135° C. at 0.05 mm.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:15]=[C:16]([F:18])[CH:17]=1)[CH2:5][N:6]1[C:10]([C:11]([OH:13])=O)=[CH:9][N:8]=[C:7]1[SH:14].ON1C(=O)CCC1=O.C1(N=C=NC2CCCCC2)CCCCC1.[CH3:42][N:43]1[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]1>O1CCCC1>[F:18][C:16]1[CH:15]=[C:4]([CH:3]=[C:2]([F:1])[CH:17]=1)[CH2:5][N:6]1[C:10]([C:11]([N:46]2[CH2:47][CH2:48][N:43]([CH3:42])[CH2:44][CH2:45]2)=[O:13])=[CH:9][N:8]=[C:7]1[SH:14]
Reactant: O=C(O)c1cnc(S)n1Cc1cc(F)cc(F)c1
Reactant: CN1CCNCC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C1CCC(=O)N1O
Solvent: C1CCOC1
Product: CN1CCN(C(=O)c2cnc(S)n2Cc2cc(F)cc(F)c2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 1-(3,5-difluorobenzyl)-2-mercaptoimidazole-5-carboxylic acid (2.70 g, 0.01 moles) in tetrahydrofuran (25 ml) was added N-hydroxysuccinimide (1.27 g, 0.011 mole) followed by dropwise addition of dicyclohexylcarbodiimide (2.06 g, 0.01 mole) in tetrahydrofuran (30 ml). A solution of N-methylpiperazine (1.22 ml, 0.011 mole) in tetrahydrofuran (10 ml) was added and the mixture stirred at 25° C. for 2 hours and then at 40° C. for 16 hours. Additional N-methylpiperazine (1.0 ml, 0.009 mole) was added and the reaction mixture was stirred at 40° C. for 1.5 hours. The reaction mixture was filtered and the solvent removed under vacuum. The residue was dissolved in ethyl acetate and was washed with dilute sodium carbonate, water, and brine. The solution was dried and the solvent removed under vacuum. The resulting solid was triturated with ether and the product was filtered and dried to give a solid, m.p.: 243°-244° C. (2.10 g, 60%).
Reaction SMILES: [N:1]1([CH2:6][CH2:7][S:8]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)=[O:9])[CH:5]=[CH:4][N:3]=[N:2]1.[H-].[Na+].Cl[CH2:21][C:22]1[C:23]([CH3:38])=[N:24][C:25]([C:28]2[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][CH:29]=2)=[CH:26][CH:27]=1.O>CN(C)C=O>[CH3:38][C:23]1[C:22]([CH2:21][O:17][C:14]2[CH:13]=[CH:12][C:11]([CH2:10][S:8]([CH2:7][CH2:6][N:1]3[CH:5]=[CH:4][N:3]=[N:2]3)=[O:9])=[CH:16][CH:15]=2)=[CH:27][CH:26]=[C:25]([C:28]2[CH:33]=[CH:32][C:31]([C:34]([F:36])([F:37])[F:35])=[CH:30][CH:29]=2)[N:24]=1
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)ccc1CCl
Reactant: O=S(CCn1ccnn1)Cc1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1nc(-c2ccc(C(F)(F)F)cc2)ccc1COc1ccc(CS(=O)CCn2ccnn2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 51.9 %

Procedure:
A solution of 126 mg (mmol) 4-(2-[1,2,3]triazol-1-yl-ethanesulfinylmethyl)-phenol in 4.0 ml N,N-dimethylformamide was treated at 0° C. with 14 mg (0.55 mmol) of 95% sodium hydride and stirred at 0° C. for 30 min., then 143 mg (0.50 mmol) 3-chloromethyl-2-methyl-6-(4-trifluoromethyl-phenyl)-pyridine were added and stirring continued over night. After addition of 8 ml water, the precipitate was isolated, washed thoroughly with water, methanol/water 1:1, and a small amount of ether. The residue was purified by chromatography on silica (eluent: ethyl acetate/methanol 9:1) to give 130 mg (52%) of the title compound as white powder.
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[CH2:7][C@H:8]([C:18]1[O:22][N:21]=[C:20]([C:23](OCC)=[O:24])[N:19]=1)[CH2:9][CH2:10][CH2:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)([CH3:4])([CH3:3])[CH3:2].Cl.Cl.[NH:31]1[CH2:34][CH:33]([N:35]2[CH2:40][CH2:39][O:38][CH2:37][CH2:36]2)[CH2:32]1.C(N(CC)CC)C>C(O)C>[CH:12]1([CH2:11][CH2:10][CH2:9][C@@H:8]([C:18]2[O:22][N:21]=[C:20]([C:23]([N:31]3[CH2:34][CH:33]([N:35]4[CH2:40][CH2:39][O:38][CH2:37][CH2:36]4)[CH2:32]3)=[O:24])[N:19]=2)[CH2:7][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:28])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]1
Reactant: CCOC(=O)c1noc([C@H](CCCC2CCCCC2)CC(=O)OC(C)(C)C)n1
Reactant: C1CN(C2CNC2)CCO1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC(C)(C)OC(=O)C[C@@H](CCCC1CCCCC1)c1nc(C(=O)N2CC(N3CCOCC3)C2)no1
Yield: 105.9 %

Procedure:
A solution of ethyl 5-{(1R)-1-[2-(tert-butoxy)-2-oxoethyl]-4-cyclohexylbutyl}-1,2,4-oxadiazole-3-carboxylate (Preparation 3) (1.00 g, 2.54 mmol) in ethanol (10 ml) was treated with 4-(3-azetidinyl)morpholine dihydrochloride (2.72 g, 12.6 mmol) and triethylamine (2.56 g, 25 mmol) and the resulting mixture was heated under reflux under a nitrogen atmosphere for 24 hours. The solvent was removed under reduced pressure and the residue was partitioned between ethyl acetate and water. The layers were separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed sequentially with water and brine, dried over anhydrous sodium sulphate, filtered and the solvent removed under reduced pressure. The residue was purified by column chromatography on silica gel eluting with a gradient system of dichloromethane:methanol (97:3) gradually changing to dichloromethane:methanol (95:5) to afford the title compound as a colourless oil (1.32 g).
Reaction SMILES: [CH3:1][C:2]([CH3:27])([CH3:26])[C@H:3]([NH:8][C:9]([C:11]1[N:12]=[C:13]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:14]2[CH2:19][CH2:18][NH:17][CH2:16][C:15]=12)=[O:10])[C:4]([NH:6][CH3:7])=[O:5].C(O[C:31]1(O[Si](C)(C)C)[CH2:33][CH2:32]1)C.C([BH3-])#N.[Na+].C(O)(=O)C>CO>[CH:31]1([N:17]2[CH2:18][CH2:19][N:14]3[C:13]([C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=4)=[N:12][C:11]([C:9]([NH:8][C@@H:3]([C:2]([CH3:27])([CH3:26])[CH3:1])[C:4]([NH:6][CH3:7])=[O:5])=[O:10])=[C:15]3[CH2:16]2)[CH2:33][CH2:32]1
Reactant: CCOC1(O[Si](C)(C)C)CC1
Reactant: CNC(=O)[C@@H](NC(=O)c1nc(-c2ccccc2)n2c1CNCC2)C(C)(C)C
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CNC(=O)[C@@H](NC(=O)c1nc(-c2ccccc2)n2c1CN(C1CC1)CC2)C(C)(C)C
Temperature: 60 °C

Procedure:
Compound 2 (60 mg, 0.16 mmol) was dissolved in methanol and (1-ethoxycyclopropoxy)trimethylsilane (170 mg, 0.94 mmol) was added followed by sodium cyanoborohydride (46 mg, 0.73 mmol) and acetic acid (98 mg, 1.62 mmol). The reaction mixture was heated at 60° C. overnight, cooled down to room temperature, filtered and concentrated.
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[C:11](=[C:12](OS(C(F)(F)F)(=O)=O)[N:13]([CH:18]([CH3:20])[CH3:19])[N:14]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[CH3:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1B(O)O>>[CH:18]([N:13]1[C:12]([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=2[CH3:29])=[C:11]2[C:15]([CH2:16][CH2:17][NH:8][CH2:9][CH2:10]2)=[N:14]1)([CH3:19])[CH3:20]
Reactant: Cc1ccccc1B(O)O
Reactant: CC(C)n1nc2c(c1OS(=O)(=O)C(F)(F)F)CCN(C(=O)OC(C)(C)C)CC2
Product: Cc1ccccc1-c1c2c(nn1C(C)C)CCNCC2
Yield: 61.3 %

Procedure:
The title compound (80 mg) was prepared according to Example 189 using 207 mg of 2-isopropyl-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 189, Step A) and 198 mg of 2-methylphenylboronic acid. MS (ESI): exact mass calculated for C17H23N3, 269.19; found, m/z 270.5 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.45-7.40 (m, 2H), 7.36-7.33 (m, 1H), 7.19-7.18 (m, 1H), 4.66 (br s, 2H), 4.10 (m, 1H), 4.00-3.66 (m, 2H), 2.76-2.61 (m, 2H), 2.13 (s, 3H), 1.45-1.29 (m, 6H).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]=[CH:7][CH2:8][N:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12](=[O:19])[NH:11][C:10]1=[O:20])=[O:5])[CH3:2].[H][H]>O1CCCC1CO.[Pd]>[CH2:1]([O:3][C:4]([CH2:6][CH2:7][CH2:8][N:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12](=[O:19])[NH:11][C:10]1=[O:20])=[O:5])[CH3:2]
Reactant: [H][H]
Reactant: CCOC(=O)C=CCn1c(=O)[nH]c(=O)c2ccccc21
Agent: [Pd]
Solvent: OCC1CCCO1
Product: CCOC(=O)CCCn1c(=O)[nH]c(=O)c2ccccc21
Reaction time: 6 h
Yield: 94.6 %

Procedure:
To a solution of 1-(3-ethoxycarbonyl-2-propenyl)-2,4-(1H,3H)-quinazolinedione (5.50 g) in tetrahydrofuran-methanol (200 ml, 3:1 V/V) was added 10% palladium on carbon (550 mg). The mixture was stirred vigorously under atmospheric pressure of hydrogen. After 6 hours, the catalyst was filtered off, and the solvent was evaporated. 1-(3-Ethoxycarbonylpropyl)-2,4(1H,3H)-quinazolinedione (5.24 g) as a crystal was obtained by recrystallization from ethanol.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]2[NH:12][C@H:11]([C:13]([F:16])([F:15])[F:14])[CH2:10][CH2:9][N:5]2[C:6](=[O:8])[CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br.Br[CH2:25][C:26]([C:28]1[S:32][CH:31]=[N:30][C:29]=1[CH3:33])=[O:27]>C(#N)C>[Cl:1][C:2]1[N:3]=[C:4]2[N:12]([CH2:25][C:26]([C:28]3[S:32][CH:31]=[N:30][C:29]=3[CH3:33])=[O:27])[C@H:11]([C:13]([F:14])([F:15])[F:16])[CH2:10][CH2:9][N:5]2[C:6](=[O:8])[CH:7]=1
Reactant: O=c1cc(Cl)nc2n1CC[C@@H](C(F)(F)F)N2
Reactant: Cc1ncsc1C(=O)CBr
Agent: Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: Cc1ncsc1C(=O)CN1c2nc(Cl)cc(=O)n2CC[C@H]1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 81.8 %

Procedure:
A suspension of 150 mg (0.591 mmol) of (8S)-2-chloro-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one and 578.13 mg (1.77 mmol) of cesium carbonate in 10 mL of acetonitrile is stirred for 15 minutes at room temperature. 213.64 mg (0.709 mmol) of 2-bromo-1-(4-methylthiazol-5-yl)ethanone hydrobromide are then added. After stirring overnight at room temperature, the reaction mixture is evaporated and the residue is taken up in water and extracted with ethyl acetate. The organic phase is dried over magnesium sulfate and evaporated to dryness to give 190 mg of (8S)-2-chloro-9-[2-(4-methylthiazol-5-yl)-2-oxoethyl]-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one, corresponding to the following characteristics:
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[C:7](Br)[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH:16]1[CH2:19][CH2:18][CH2:17]1)=[O:14].[CH3:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][C:23]=1B(O)O>>[NH2:1][C:2]1[C:11]2[C:6](=[C:7]([C:23]3[CH:24]=[C:25]([CH3:28])[CH:26]=[CH:27][C:22]=3[O:21][CH3:20])[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH:16]1[CH2:19][CH2:18][CH2:17]1)=[O:14]
Reactant: Nc1c(C(=O)NC2CCC2)nnc2c(Br)cccc12
Reactant: COc1ccc(C)cc1B(O)O
Product: COc1ccc(C)cc1-c1cccc2c(N)c(C(=O)NC3CCC3)nnc12
Yield: 57.4 %

Procedure:
Using Method A, 4-amino-8-bromo-N-cyclobutyl-cinnoline-3-carboxamide (145 mg) and 2-methoxy-5-methyl-phenyl boronic acid (186 mg) were reacted to afford the title compound (94 mg) as white solid. 1H NMR (500 MHz, DMSO-d6) δ 9.20 (d, 1H), 8.38 (d, 1H), 7.76-7.66 (m, 2H), 7.20 (m, 1H), 7.07 (m, 1H), 7.00 (m, 1H), 4.50 (m, 1H), 3.58 (s, 3H), 2.29 (s, 3H), 2.26-2.10(m, 4H), 1.72-1.62 (m, 2H). MS APCI, m/z=363 (M+H).
Reaction SMILES: [Cl-].[Cl:2][C:3]1[S:7][C:6]([CH3:8])=[C:5]([Cl:9])[C:4]=1[CH2:10][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[CH:30]([C:32]([CH3:44])=[CH:33][CH:34]=[CH:35][C:36]([CH3:43])=[CH:37][C:38]([O:40][CH2:41][CH3:42])=[O:39])=O>C1OCCC1>[CH2:41]([O:40][C:38](=[O:39])[CH:37]=[C:36]([CH3:43])/[CH:35]=[CH:34]/[CH:33]=[C:32]([CH3:44])[CH:30]=[CH:10][C:4]1[C:5]([Cl:9])=[C:6]([CH3:8])[S:7][C:3]=1[Cl:2])[CH3:42]
Reactant: Cc1sc(Cl)c(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)c1Cl
Reactant: CCOC(=O)C=C(C)C=CC=C(C)C=O
Agent: [Cl-]
Solvent: C1CCOC1
Product: CCOC(=O)C=C(C)/C=C/C=C(C)C=Cc1c(Cl)sc(C)c1Cl

Procedure:
A suspension of 10.83 g. (22.6 mmol) of (2,4-dichloro-5-methyl-3-thenyl)triphenyl phosphonium chloride and 5.15 g. (24.8 mmol) of ethyl 7-formyl-3-methyl-2,4,6-octatrienoate in 350 ml. of butylene oxide was heated to 70° C. for 4.5 hrs. The resulting clear solution was cooled, poured into 500 ml. of a methanol/water mixture (6:4) and extracted with hexane. The combined hexane extracts were washed with methanol/water (6:4), dried and evaporated. The resulting crude material was purified by chromatography (silica gel, hexane/ethyl acetate = 4:1) to yield after recrystallization from hexane, all trans-3,7-dimethyl-9-(2,4-dichloro-5-methyl-3-thienyl)-2,4,6,8-nonatetraenoic acid ethyl ester, m.p. 99°-100° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH:12]([N:15]([CH3:17])[CH3:16])[C:13]#N)[CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C([N-]C(C)C)(C)C.[Li+].C(NC(C)C)(C)C.C([Li])CCC.C=[O:39].[BH4-].[Na+]>O1CCCC1.CCCCCC.Cl.O.CO>[ClH:1].[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH:12]([N:15]([CH3:17])[CH3:16])[CH2:13][OH:39])[CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: C=O
Reactant: CN(C)C(C#N)C1(c2ccc(Cl)cc2)CCC1
Agent: CC(C)[N-]C(C)C
Agent: Cl
Agent: [BH4-]
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CC(C)NC(C)C
Product: CN(C)C(CO)C1(c2ccc(Cl)cc2)CCC1
Reaction time: 72 h

Procedure:
A solution of 2-[1-(4-chlorophenyl)cyclobutyl]-2-dimethylaminoacetonitrile (4.7 g prepared as described in Example A) in dry tetrahydrofuran (20 ml) was added at -20° C. to lithium diisopropylamide [prepared by adding a solution of diisopropylamine (2.02 g) in dry tetrahydrofuran (30 ml) to a 2.7M solution of butyllithium in hexane (7.5 ml) at -10° C⟧ Formaldehye vapour produced by heating paraformaldehyde to 180° C. was passed into the resulting solution at -50° C. until the colour changed from red-brown to pale yellow. Methanol (50 ml) was added and sodium borohydride (6 g) added portionwise with stirring. Stirring was continued for 3 days and then water (50 ml) and excess dilute hydrochloric acid were added. Methanol was removed by evaporation in vacuo to leave a solution which was basified and extracted with ether. Removal of the ether after drying yielded an oil which was dissolved in 5N hydrochloric acid (8 ml) and water (50 ml). The solution was evaporated and the residue dried by azeotropic distillation with propan-2-ol. The residue was crystallised from acetone to give 2-[1-(4-chlorophenyl)cyclobutyl]-2-dimethylaminoethanol hydrochloride (m.p. 230°-231° C.). A solution of this compound in the form of its free base (1.01 g) in dry tetrahydrofuran (10 ml) was added dropwise to a stirred mixture of sodium hydride (0.35 g, 50% suspension in mineral oil) and dry tetrahydrofuran (10 ml) under nitrogen. Stirring was continued until hydrogen evolution had ceased and the mixture was heated at 40°-45° C. for 20 minutes. After cooling to 20° C. a solution of iodomethane (0.6 g) in dry tetrahydrofuran (5 ml) was added and the mixture heated under reflux for two hours. Water (20 ml) was added dropwise to the cooled reaction mixture which was then extracted with ether and the extract washed with water. The ether extract was dried and evaporated and the residue was dissolved in propan-2-ol (15 ml). Concentrated hydrochloric acid (2 ml) was added and the mixture evaporated to dryness to give a solid which was recrystallised from ethyl acetate to give N,N-dimethyl-1-[1-(4-chlorophenyl)cyclobutyl]-2-methoxyethylamine hydrochloride (m.p. 180°-185° C.).
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1.[C:23]1([S:29]([CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]Cl)=[O:30])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:13][CH2:14][N:15]([CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][S:29]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[O:30])[CH2:16][CH2:17]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCNCC1
Reactant: O=S(CCCCCCl)c1ccccc1
Agent: Cl
Product: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCCS(=O)c2ccccc2)CC1

Procedure:
4-Amino-5-chloro-2-methoxy-N-(piperidin-4-ylmethyl)benzamide dihydrochloride as starting compound and 5-phenylsulfinylpentyl chloride were reacted and treated in the same manner as in Example 199 to give 4-amino-5-chloro-2-methoxy-N-((1-(5-phenylsulfinylpentyl)piperidin-4-yl)methyl)benzamide.