Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Na].CO.[OH:4][C:5]1[N:9]=[CH:8][N:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:6]=1.Br[CH:17]([CH2:23][CH2:24][CH3:25])[C:18]([O:20][CH2:21][CH3:22])=[O:19]>CS(C)=O>[CH2:21]([O:20][C:18]([CH:17]([O:4][C:5]1[N:9]=[CH:8][N:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:6]=1)[CH2:23][CH2:24][CH3:25])=[O:19])[CH3:22]
Reactant: CCCC(Br)C(=O)OCC
Reactant: Oc1ncn(-c2ccccc2)n1
Agent: [Na]
Solvent: CS(C)=O
Solvent: CO
Product: CCCC(Oc1ncn(-c2ccccc2)n1)C(=O)OCC

Procedure:
The synthesis was carried out substantially as shown above in Example 7, except that it was necessary to chromatograph the product as described in Example 8. The reactants were 0.7 g of sodium, 20 ml of methanol, 5 g of 3-hydroxy-1-phenyl-1,2,4-lH-triazole and 6.5 g of ethyl 2-bromopentanoate. The solvent was 80 ml of dimethylsulfoxide. Five g of the desired product, an oil, was obtained.
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[C:12]2[C:7](=[CH:8][C:9]([Cl:14])=[CH:10][C:11]=2[Cl:13])[NH:6][C@@H:5]([C:15]([O:17][CH3:18])=[O:16])[CH2:4]1.C(N(CC)CC)C.[CH3:26][S:27](Cl)(=[O:29])=[O:28]>ClCCl>[Cl:13][C:11]1[CH:10]=[C:9]([Cl:14])[CH:8]=[C:7]2[C:12]=1[C@@H:3]([NH:2][S:27]([CH3:26])(=[O:29])=[O:28])[CH2:4][C@H:5]([C:15]([O:17][CH3:18])=[O:16])[NH:6]2
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)[C@H]1C[C@H](N)c2c(Cl)cc(Cl)cc2N1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)[C@H]1C[C@H](NS(C)(=O)=O)c2c(Cl)cc(Cl)cc2N1
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.2 %

Procedure:
To a suspension of trans-4-amino-5,7-dichloro-2-methoxycarbonyl-1,2,3,4-tetrahydroquinoline hydrochloride (0.15 g, 0.482 mmol) in dichloromethane (15 ml) was added triethylamine (0.14 ml, 1.01 mmol) and the mixture was stirred under an atmosphere of nitrogen at room temperature until dissolution was complete. To this solution was added methanesulphonyl chloride (0.039 ml, 0.50 mmol) and the resulting mixture was stirred at room temperature under an atmosphere of nitrogen for 2.5 h. A further portion of methanesulphonyl chloride (0.039 ml, 0.50 mmol) was added and stirring was continued for 2 h after which time more triethylamine (0.07 ml, 0.50 mmol) was added and the mixture was stirred for a further 18 hours. The solvent was removed in vacuo and the residue obtained was partitioned between dilute citric acid solution (50 ml) and ethyl acetate (100 ml). The organic layer was washed with saturated sodium hydrogen carbonate (2×50 ml), brine (1×50 ml), dried (MgSO4) and evaporated to give the title compound as colourless crystals (0.14 g, m.p. 143°-146° C.); δ (250 MHz, CDCl3) 1.69 (1H, m, CHACHBHCCHD), 2.90 (1H, dm, J=13.6 Hz, CHACHBHCCHD), 3.17 (3H, s, --SO2CH3), 3.83 3H, s, CO2CH3), 4.26 (2H, m, CHACHBHCCHD) and CHNHSO2CH3), 4.84 (1H, m, CHACHBHCCHD), 6.57 (1H, d, J=1.9 Hz, 6-H or 8-H), 6.73 (1H, d, J=1.9 Hz, 6-H or 8-H); m/e 353 (M+), 198 (100% M-NHSO2CH3, CO2CH3 and H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[N:10]1[C:14](=[O:15])[CH:13](Br)[C:12]([NH:17][C:18](=[O:39])[CH2:19][CH2:20][CH2:21][O:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]([CH2:32][CH3:33])([CH3:31])[CH3:30])=[CH:25][C:24]=2[C:34]([CH2:37][CH3:38])([CH3:36])[CH3:35])=[N:11]1.[CH3:40][C:41]1[CH:45]=[C:44]([CH3:46])[NH:43][N:42]=1>C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[N:10]1[C:14](=[O:15])[CH:13]([C:45]2[C:41]([CH3:40])=[N:42][NH:43][C:44]=2[CH3:46])[C:12]([NH:17][C:18](=[O:39])[CH2:19][CH2:20][CH2:21][O:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]([CH2:32][CH3:33])([CH3:31])[CH3:30])=[CH:25][C:24]=2[C:34]([CH2:37][CH3:38])([CH3:36])[CH3:35])=[N:11]1
Reactant: CCC(C)(C)c1ccc(OCCCC(=O)NC2=NN(c3c(Cl)cc(Cl)cc3Cl)C(=O)C2Br)c(C(C)(C)CC)c1
Reactant: Cc1cc(C)[nH]n1
Solvent: CCOC(C)=O
Product: CCC(C)(C)c1ccc(OCCCC(=O)NC2=NN(c3c(Cl)cc(Cl)cc3Cl)C(=O)C2c2c(C)n[nH]c2C)c(C(C)(C)CC)c1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
66 g of 1-(2,4,6-trichlorophenyl)-3-[4-(2,4-di-tert-amylphenoxy)butyramido]-4-bromo-5-oxo-2-pyrazoline and 27 g of 3,5-dimethylpyrazole were mixed well with each other in a mortar, then stirred for 2 hours under heating at 100° C. To the reaction mixture was added 1 liter of ethyl acetate followed by washing several times with water. The ethyl acetate layer was dried with anhydrous sodium sulfate and concentrated. Upon crystallization of the residue from ethyl acetate, 35 g of Coupler (1) was obtained. The melting point of the coupler was 207° to 209° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]([CH:7]=[CH:8][CH2:9]Cl)=[CH:5][CH:4]=1.[NH2:13][C:14]1[S:15][C:16]2[CH2:17][CH2:18][NH:19][CH2:20][CH2:21][C:22]=2[N:23]=1.C(=O)([O-])[O-].[K+].[K+].CCOCC>C(Cl)(Cl)Cl>[NH2:13][C:14]1[S:15][C:16]2[CH2:17][CH2:18][N:19]([CH2:9][CH:8]=[CH:7][C:6]3[CH:11]=[CH:12][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[CH2:20][CH2:21][C:22]=2[N:23]=1
Reactant: Nc1nc2c(s1)CCNCC2
Reactant: COc1ccc(C=CCCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: ClC(Cl)Cl
Product: COc1ccc(C=CCN2CCc3nc(N)sc3CC2)cc1
Yield: 10 %

Procedure:
Prepared from 4-methoxy-cinnamyl chloride and 1 equivalent of 2-amino-4,5,7,8-tetrahydro-6H-thiazolo[5,4-d]azepine in the presence of 1 equivalent of potassium carbonate in chloroform. Yield: 10% of theory, Melting point: 155-160° C. (ether).
Reaction SMILES: Cl[C:2]1[C:11]([C:12]#[N:13])=[C:10]2[C:5]([C:6](=[O:20])[C:7]([C:17]([OH:19])=[O:18])=[CH:8][N:9]2[CH:14]2[CH2:16][CH2:15]2)=[CH:4][C:3]=1[F:21].[C@@H:22]12[CH2:30][NH:29][CH2:28][C@@H:27]1[CH2:26][CH2:25][CH2:24][NH:23]2.N12CCN(CC1)CC2>CN(C)C=O.C(#N)C>[C:12]([C:11]1[C:2]([N:29]2[CH2:30][C@@H:22]3[C@@H:27]([CH2:26][CH2:25][CH2:24][NH:23]3)[CH2:28]2)=[C:3]([F:21])[CH:4]=[C:5]2[C:10]=1[N:9]([CH:14]1[CH2:16][CH2:15]1)[CH:8]=[C:7]([C:17]([OH:19])=[O:18])[C:6]2=[O:20])#[N:13]
Reactant: C1CN[C@@H]2CNC[C@@H]2C1
Reactant: N#Cc1c(Cl)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12
Agent: C1CN2CCN1CC2
Solvent: CN(C)C=O
Solvent: CC#N
Product: N#Cc1c(N2C[C@@H]3CCCN[C@@H]3C2)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12

Procedure:
690 mg (2.25 mmol) of 7-chloro-8-cyano-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid are stirred with 312 mg (2.47 mmol) of (1S,6S)-2,8-diazabicyclo[4.3.0]nonane and 504 mg (4.50 mmol) of 1,4-diazabicyclo[2.2.2]-octane (DABCO) in a mixture of 6.6 ml of dimethylformamide and 6.6 ml of acetonitrile at room temperature overnight. All the volatile components are removed in vacuo, the residue is taken up in water and the resulting solution is brought to pH 7 with dilute hydrochloric acid. The precipitate formed is filtered off with suction, the filtrate is extracted with methylene chloride and the combined organic phases are dried with sodium sulfate and concentrated in vacuo.
Reaction SMILES: [OH-].[Na+].[S:3]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([CH2:13][CH2:14][CH2:15][CH2:16][C:17]([O:19]C)=[O:18])[O:11][CH:12]=2)=[CH:4]1.Cl>O.CO>[S:3]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([CH2:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18])[O:11][CH:12]=2)=[CH:4]1
Reactant: COC(=O)CCCCc1nc(-c2ccsc2)co1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)CCCCc1nc(-c2ccsc2)co1
Temperature: 40 °C

Procedure:
Add solution of sodium hydroxide in water to a solution of methyl 5-(4-thiophen-3-yloxazol-2-yl)pentanoate in methanol at room temperature and heat the mixture at 40° C. for 2 hours. Adjust the pH of the mixture to 2 with 1 N HCl and extract with ethyl acetate. Wash the organic extract three times with water, dry over sodium sulfate and remove the solvent under reduced pressure. Triturate the residue with hexanes/ethyl acetate and collect the solids by filtration to provide the title compound: APCI mass spectrum m/z 252 [C12H13NO3S+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=O)=[CH:4][CH:3]=1.CC([NH2:18])(C)CO.C1(C)C(C)=CC=CC=1.[NH2-].[Li+]>>[NH2:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]2[O:8][CH2:9][CH2:10][N:18]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1ccc(N)cc1
Reactant: CC(C)(N)CO
Agent: [Li+]
Agent: [NH2-]
Solvent: Cc1ccccc1C
Product: Nc1ccc(C2=NCCO2)cc1

Procedure:
Ethyl p-aminobenzoate, 20.65 g (0.125 mol), 2-methyl-2-aminopropanol, 22.3 g (0.25 mol) 150 ml of xylene, and 0.25 g of lithium amide were combined and heated at the reflux temperature for 50 hr. The alcohol and water liberated was collected in a Dean-Stark trap, providing indication when the reaction was complete. The xylene solvent was removed and the viscous liquid was added to water to precipitate the product. After drying, a 15.5 g (65%) yield of the 4,4-dimethyl derivative of 4-aminophenyl oxazoline was obtained. The product was recrystallized from ethyl acetate, giving white, crystalline material with mp 172° C. FT-IR, with peaks centered at 3445 (NH), 1635 (—C═N—), and 1602 (phenyl) cm−1 confirmed the desired amino functionalized oxazoline. Following the Example 6 procedure, TDO was used to covert the aforesaid compound to the desired acetoacetamide. The structure of this new composition is as follows:
Reaction SMILES: [C:1]([OH:10])(=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[Cl-:11]>N1C=CC=CC=1>[C:1]([Cl:11])(=[O:10])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4]
Reactant: [Cl-]
Reactant: O=C(O)c1ccccc1O
Solvent: c1ccncc1
Product: O=C(Cl)c1ccccc1O

Procedure:
In the first step, salicylic acid is mixed with thionyl (or oxalyl) halide, most preferably chloride, (molar ratio in the general range of from 1:1 to 2:1) in an anhydrous, typically non-polar, solvent, in the presence of pyridine catalyst, at a temperature of from 20 to 45° C. for 0.5-2 hours. At the end of this reaction, salicylic acid chloride id obtained. Optionally, the solvent is distilled at least partially.
Reaction SMILES: [CH3:1][S:2][CH2:3][CH2:4]Cl.[OH:6][C:7]1[CH:16]=[C:15]2[C:10]([C:11]([O:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[N:12][CH:13]=[N:14]2)=[CH:9][C:8]=1[O:24][CH3:25].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:25][O:24][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][C:7]=1[O:6][CH2:4][CH2:3][S:2][CH3:1])[N:14]=[CH:13][N:12]=[C:11]2[O:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: COc1cc2c(Oc3ccccc3)ncnc2cc1O
Reactant: CSCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3ccccc3)ncnc2cc1OCCSC
Temperature: 110 °C
Yield: 53.9 %

Procedure:
2-Chloroethyl methyl sulphide (1.2 g, 10.9 mmol) was added to 7-hydroxy-6-methoxy-4-phenoxyquinazoline (2.25 g, 8.4 mmol), (prepared as described for the starting material in Example 16), and potassium carbonate (6.0 g, 43.4 mmol) in DMF (70 ml). The mixture was heated at 110° C. for 4 hours and allowed to cool. The mixture was filtered, and the volatiles were removed from the filtrate by evaporation. The residue was purified by column chromatography eluting with methylene chloride/methanol (96/4) to give 6-methoxy-7-(2-methylthioethoxy)4-phenoxyquinazoline (1.55 g, 54%).
Reaction SMILES: [C:1]([SiH2:5][O:6][C:7]([CH3:20])([CH3:19])[C:8]1[CH:9]=[C:10]([CH2:17][OH:18])[CH:11]=[C:12]([N+:14]([O-])=O)[CH:13]=1)([CH3:4])([CH3:3])[CH3:2]>C(O)C.[Pd]>[NH2:14][C:12]1[CH:11]=[C:10]([CH2:17][OH:18])[CH:9]=[C:8]([C:7]([CH3:20])([CH3:19])[O:6][SiH2:5][C:1]([CH3:2])([CH3:4])[CH3:3])[CH:13]=1
Reactant: CC(C)(C)[SiH2]OC(C)(C)c1cc(CO)cc([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)[SiH2]OC(C)(C)c1cc(N)cc(CO)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 107 %

Procedure:
10% Palladium-on-carbon (53 mg) was added to a magnetically stirred solution of [3-(tert-butyl-dimethyl-silanyloxymethyl)-5-nitro-phenyl]-methanol (535 mg, 1.80 mmol) in ethanol (20 mL). The heterogeneous mixture was purged twice using vacuum and dry nitrogen, then stirred at room temperature under hydrogen at atmospheric pressure. After three hours, the reaction mixture was filtered through a pad of Celite®. The pad was washed with ethanol (2×20 mL) and the filtrate was concentrated to give crude [3-amino-5-(tert-butyl-dimethyl-silanyloxymethyl)-phenyl]-methanol (515 mg) as an off-white solid, which was used directly in the next step without purification.
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:27][CH2:26][CH2:25][C@@H:24]([OH:28])[CH2:23]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[CH3:29][C:30]1[N:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1>>[OH:28][C@@H:24]1[CH2:25][CH2:26][CH2:27][N:22]([C:3]2[C:2]([C:33]3[CH:34]=[N:35][C:30]([CH3:29])=[CH:31][CH:32]=3)=[CH:21][C:6]([C:7]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=3)=[O:8])=[CH:5][N:4]=2)[CH2:23]1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CCC[C@@H](O)C2)c(Br)c1
Reactant: Cc1ccc(B(O)O)cn1
Product: Cc1ccc(-c2cc(C(=O)Nc3ccc(OC(F)(F)F)cc3)cnc2N2CCC[C@@H](O)C2)cn1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 118 using (R)-5-bromo-6-(3-hydroxypiperidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 121.1) and (6-methylpyridin-3-yl)boronic acid to afford a white solid. UPLC-MS (condition 1) tR=2.28 min, m/z=473.1 [M+H]+, m/z=471.2 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.18-1.39 (m, 2H) 1.53-1.62 (m, 1H) 1.77-1.86 (m, 1H) 2.54 (s, 3H) 2.55-2.62 (m, 1H) 2.68-2.77 (m, 1H) 3.42-3.51 (m, 2H) 3.55-3.63 (m, 1H) 4.72 (s, 1H) 7.36 (d, J=9.05 Hz, 2H) 7.40 (d, J=8.07 Hz, 1H) 7.83-7.88 (m, 2H) 7.92-7.98 (m, 1H) 8.07 (d, J=1.96 Hz, 1H) 8.67-8.72 (m, 1H) 8.75 (d, J=2.20 Hz, 1H) 10.29 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:9]=[N:10][C:11]2[N:12]([N:24]=[C:25]([NH2:32])[C:26]=2[C:27]([O:29][CH2:30][CH3:31])=[O:28])[C:13]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=1.Cl[CH2:34][CH2:35][CH2:36][CH2:37]Cl>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:9]=[N:10][C:11]2[N:12]([N:24]=[C:25]([N:32]3[CH2:37][CH2:36][CH2:35][CH2:34]3)[C:26]=2[C:27]([O:29][CH2:30][CH3:31])=[O:28])[C:13]=1[C:14]1[CH:15]=[CH:16][C:17]([C:20]([F:21])([F:23])[F:22])=[CH:18][CH:19]=1
Reactant: CCOC(=O)c1c(N)nn2c(-c3ccc(C(F)(F)F)cc3)c(-c3ccccc3Cl)cnc12
Reactant: ClCCCCCl
Product: CCOC(=O)c1c(N2CCCC2)nn2c(-c3ccc(C(F)(F)F)cc3)c(-c3ccccc3Cl)cnc12
Yield: 26 %

Procedure:
The compound obtained in Example 484 (2.1 g) and 1,4-dichlorobutane (2.9 g) were treated in the same manner as described in Example 43 to give 6-(2-chlorophenyl)-7-(4-trifluoromethylphenyl)-3-ethoxycarbonyl-2-(pyrrolidin-1-yl)pyrazolo[1,5-a]-pyrimidine (0.61 g, yield: 26%) as a yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[CH2:4][CH2:5][C:6]1[C:11]([OH:12])=[CH:10][CH:9]=[C:8]([C:13]#[C:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([O:23][CH3:24])=[O:22])[CH:16]=2)[N:7]=1.Br[CH2:27][CH2:28][CH2:29][CH2:30]/[CH:31]=[CH:32]/[C:33]1[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][CH:34]=1>>[CH3:1][O:2][C:3](=[O:25])[CH2:4][CH2:5][C:6]1[C:11]([O:12][CH2:27][CH2:28][CH2:29][CH2:30]/[CH:31]=[CH:32]/[C:33]2[CH:34]=[CH:35][C:36]([O:39][CH3:40])=[CH:37][CH:38]=2)=[CH:10][CH:9]=[C:8]([CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([O:23][CH3:24])=[O:22])[CH:16]=2)[N:7]=1
Reactant: COC(=O)CCc1nc(C#Cc2cccc(C(=O)OC)c2)ccc1O
Reactant: COc1ccc(/C=C/CCCCBr)cc1
Product: COC(=O)CCc1nc(CCc2cccc(C(=O)OC)c2)ccc1OCCCC/C=C/c1ccc(OC)cc1
Yield: 57.4 %

Procedure:
Under the conditions of example 1 D, 1.24 g of 3-{3-hydroxy-6-[2-(3-methoxycarbonylphenyl)-ethinyl]-2-pyridyl}-propionic acid methyl ester is reacted with 970 mg of (1E)-6-bromo-1-(4-methoxyphenyl)-1-hexene, worked up, and the crude product is chromatographed on silica gel with hexane/0-7.5% ethyl acetate. 1.1 g of 3-{6-[2-(3-methoxycarbonylphenyl)-ethyl]-3-[6-(4-methoxyphenyl)-(5E)-5-hexenyloxy]-2-pyridyl}-propionic acid methyl ester is obtained as colorless oil.
Reaction SMILES: [CH2:1]([NH:8][CH:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH3:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.C(OC(=O)C)(=O)C>>[C:11]1([C:9](=[N:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH3:10])[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: CC(NCc1ccccc1)c1ccccc1
Solvent: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=NCc1ccccc1)c1ccccc1

Procedure:
Benzyl-(1-phenylethyl)amine, conversion>99%, ee 82% (GC, sample derivatised by treatment with acetic anhydride pyridine, Chirasil DEX CB, 25 m×0.25 mm, injector/detector 200° C., helium 20 psi, 170° C. for 40 minutes then ramp at 15° C./min to 200° C., retention times 29.71 minutes and 30.73 minutes).
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]2[S:6][C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=3[C:9](=O)[CH2:10][C:4]=2[CH:3]=1.[N:18]1([CH2:24][CH2:25][N:26]2[CH2:30][CH2:29][O:28][C:27]2=[O:31])[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1.C(=O)(O)[O-].[Na+]>C1C=CC=CC=1.[Ti](Cl)(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:17]=[CH:16][C:5]2[S:6][C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=3[C:9]([N:21]3[CH2:22][CH2:23][N:18]([CH2:24][CH2:25][N:26]4[CH2:30][CH2:29][O:28][C:27]4=[O:31])[CH2:19][CH2:20]3)=[CH:10][C:4]=2[CH:3]=1
Reactant: O=C1Cc2cc(Cl)ccc2Sc2ccccc21
Reactant: O=C1OCCN1CCN1CCNCC1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccccc1
Product: O=C1OCCN1CCN1CCN(C2=Cc3cc(Cl)ccc3Sc3ccccc32)CC1
Reaction time: 1 h

Procedure:
8.5 g of 2-chloro-10,11-dihydro-dibenzo[b,f]thiepin-10-one, 30 g of 3-[2-(1-piperazinyl)-ethyl]-2-oxazolidinone and 100 ml of benzene are treated dropwise under an argon atmosphere at 20° C with 5.2 g of titanium tetrachloride in 25 ml of benzene. The mixture is heated under reflux for 20 hours and subsequently poured on to a mixture of ice and aqueous sodium bicarbonate solution. The mixture is stirred for 1 hour and filtered through diatomaceous earth. The aqueous phase is separated and washed successively with benzene and chloroform. The organic phases are combined and washed successively with aqueous sodium chloride solution and water, dried, filtered and evaporated under reduced pressure. There is obtained 3-[2-[4-(2-chloro-dibenzo[b,f]thiepin-10-yl)-1-piperazinyl]-ethyl]-2-oxazolidinone as a red-brown viscous oil which, for the purpose of purification, is chromatographed on 100 g of silica dioxide [elution agent ethanol: methanol: concentrated ammonia (100:50:10)]. There is obtained a red-brown oil which is crystallised from acetone with the aid of active carbon. There are obtained beige-coloured crystals which are converted into the corresponding maleate (beige-coloured crystals) of melting point 232°-233° C (decomposition) by treatment with maleic acid in acetone.
Reaction SMILES: Br[CH:2]1[C:9]2[CH:10]=[C:11]([Cl:14])[CH:12]=[CH:13][C:8]=2[O:7][CH2:6][O:5][C:4]2[CH:15]=[CH:16][C:17]([Cl:19])=[CH:18][C:3]1=2.[Br:20][CH2:21][CH2:22][OH:23].C(=O)([O-])[O-].[K+].[K+]>ClCCl>[Br:20][CH2:21][CH2:22][O:23][CH:2]1[C:9]2[CH:10]=[C:11]([Cl:14])[CH:12]=[CH:13][C:8]=2[O:7][CH2:6][O:5][C:4]2[CH:15]=[CH:16][C:17]([Cl:19])=[CH:18][C:3]1=2
Reactant: OCCBr
Reactant: Clc1ccc2c(c1)C(Br)c1cc(Cl)ccc1OCO2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: Clc1ccc2c(c1)C(OCCBr)c1cc(Cl)ccc1OCO2
Temperature: 120 °C
Yield: 82.4 %

Procedure:
A mixture of 12-bromo-2,10-dichloro-12H-5,7-dioxa-dibenzo[a,d]cyclooctene (900 mg, 2.5 mmol), 2-bromoethanol (3.75 g, 30 mmol) and potassium carbonate (1.0 g, 7.2 mmol) in dichloromethane (10 mL) was heated at 120° C. for 4 h. The reaction mixture was concentrated in vacuo, added water (25 mL) and the product extracted with ethyl acetate (3×25 mL). The combined organic phases were dried (MgSO4), filtered and evaporated to give 832 mg (82%) of 12-(2-bromo-ethoxy)-2,10-dichloro-12H-5,7-dioxa-dibenzo[a,d]cyclooctene.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][C:10]([OH:12])=[O:11].Cl.[CH3:14]O>>[CH3:14][O:11][C:10](=[O:12])[CH2:9][C:3]1[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=1[Cl:8]
Reactant: CO
Reactant: O=C(O)Cc1c(Cl)cccc1Cl
Agent: Cl
Product: COC(=O)Cc1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 18 h

Procedure:
(2,6-Dichlorophenyl)acetic acid (2.55 g) was dissolved in anhydrous MeOH (60 mL) and HCl (gas) was passed through the mixture and the resulting solution was stirred at room temperature for 18 h. The solvent was then evaporated to give (2,6-dichlorophenyl)acetic acid methyl ester (2.7 g).
Reaction SMILES: [Br:1]Br.[C:3]([C:6]1[N:7]=[C:8]([CH2:11][NH:12][C:13](=[O:15])[CH3:14])[S:9][CH:10]=1)(=[O:5])[CH3:4]>C(O)(=O)C.O>[C:13]([NH:12][CH2:11][C:8]1[S:9][CH:10]=[C:6]([C:3](=[O:5])[CH2:4][Br:1])[N:7]=1)(=[O:15])[CH3:14]
Reactant: BrBr
Reactant: CC(=O)NCc1nc(C(C)=O)cs1
Solvent: CC(=O)O
Solvent: O
Product: CC(=O)NCc1nc(C(=O)CBr)cs1
Temperature: 70 °C

Procedure:
Bromine (2.2 g) was added slowly to a solution of 4-acetyl-2-acetylaminomethylthiazole (2.2 g) in acetic acid (20 ml) and water (20 ml), and the mixture was heated at 70° C. for 4 hours. The solvent was removed under reduced pressure to give crude product of 2-acetylaminomethyl-4-bromoacetylthiazole. The above residue was dissolved in ethanol (50 ml). Diaminomethylenethiourea (1.3 g) was added to the solution and the mixture was refluxed for 4 hours. The solvent was removed under reduced pressure. The residue was dissolved in water and then the solution was alkalized with a saturated aqueous potassium carbonate solution. The resulting precipitate was collected by filtration. The filtrate was extracted by ethyl acetate and then the solvent was removed under reduced pressure. The residue and the precipitate were chromatographed on an alumina column eluting with a mixture of chloroform and methanol (10:1). Recrystallization from water afforded 4-(2-acetylaminomethylthiazol-4-yl)-2-(diaminomethyleneamino)thiazole (430 mg).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.Cl.[F:12][C:13]1[CH:18]=[CH:17][C:16]([N:19]([CH3:28])[C:20]([C@H:22]2[CH2:27][CH2:26][CH2:25][NH:24][CH2:23]2)=[O:21])=[CH:15][CH:14]=1.C(N(CC)CC)C>ClCCl>[F:12][C:13]1[CH:14]=[CH:15][C:16]([N:19]([CH3:28])[C:20]([C@H:22]2[CH2:27][CH2:26][CH2:25][N:24]([C:6](=[O:7])[C:5]3[CH:9]=[CH:10][C:2]([F:1])=[CH:3][CH:4]=3)[CH2:23]2)=[O:21])=[CH:17][CH:18]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: CN(C(=O)[C@H]1CCCNC1)c1ccc(F)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C(=O)[C@H]1CCCN(C(=O)c2ccc(F)cc2)C1)c1ccc(F)cc1
Reaction time: 2 h
Yield: 84.4 %

Procedure:
4-Fluorobenzoyl chloride (47 mL, 0.40 mmol) was added at 0° C. to a solution of (S)-piperidine-3-carboxylic acid (4-fluoro-phenyl)-methyl-amide hydrochloride (0.11 g, 0.40 mmol) and triethylamine (112 mL, 0.80 mmol) in dichloromethane (3 mL), under nitrogen atmosphere. The reaction mixture was kept under stiffing at R.T. for 2 h, the solvent was evaporated and the residue was diluted with water and ethyl acetate. The phases were separated and the organic layer was washed with HCl 1N (10 mL), with Na2CO3 2M (aq.) (10 mL) and with brine (10 mL). The organic layer was dried over sodium sulphate and concentrated under reduced pressure to give 0.121 g of (S)-1-(4-fluoro-benzoyl)-piperidine-3-carboxylic acid (4-fluoro-phenyl)-methyl-amide as a gummy solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[C:13]([C:18]([F:21])([F:20])[F:19])[CH:14]=[CH:15][CH:16]=3)[N:11]=[CH:10][C:9]=2[C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:23])[CH:5]=[CH:6][CH:7]=1.[CH2:30]([N:33]1[C:37](=[O:38])[C:36](=[CH:39][C:40]2[CH:47]=[CH:46][C:43]([CH:44]=O)=[CH:42][CH:41]=2)[S:35][C:34]1=[S:48])[CH:31]=[CH2:32]>>[CH2:30]([N:33]1[C:37](=[O:38])[C:36](=[CH:39][C:40]2[CH:41]=[CH:42][C:43]([CH2:44][NH:1][C:2]3[CH:7]=[CH:6][CH:5]=[C:4]([C:8]4[C:17]5[C:12](=[C:13]([C:18]([F:21])([F:19])[F:20])[CH:14]=[CH:15][CH:16]=5)[N:11]=[CH:10][C:9]=4[C:22](=[O:23])[C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=4)[CH:3]=3)=[CH:46][CH:47]=2)[S:35][C:34]1=[S:48])[CH:31]=[CH2:32]
Reactant: Nc1cccc(-c2c(C(=O)c3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Reactant: C=CCN1C(=O)C(=Cc2ccc(C=O)cc2)SC1=S
Product: C=CCN1C(=O)C(=Cc2ccc(CNc3cccc(-c4c(C(=O)c5ccccc5)cnc5c(C(F)(F)F)cccc45)c3)cc2)SC1=S

Procedure:
The title compound was prepared from [4-(3-amino-phenyl)-8-trifluoromethyl-quinolin-3-yl]-phenyl-methanone and 4-(3-allyl-4-oxo-2-thioxo-thiazolidin-5-ylidenemethyl)-benzaldehyde according to the procedure of Example 66. MS (ES) m/z 663.8.