Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C@@H:4]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1)[NH:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7].[O:22]([C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(N(CC)CC)C>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH3:1][O:2][C:3](=[O:21])[C@H:4]([NH:5][C:6]([O:8][C:9]([CH3:12])([CH3:10])[CH3:11])=[O:7])[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][C:32]2[CH:33]=[CH:34][C:29]([O:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:30][CH:31]=2)=[CH:16][CH:15]=1
Reactant: COC(=O)[C@@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C
Reactant: OB(O)c1ccc(Oc2ccccc2)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)[C@@H](Cc1ccc(Oc2ccc(Oc3ccccc3)cc2)cc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 42 h
Yield: 38.2 %

Procedure:
To a solution of Boc-D-Tyrosine-Methyl ester (0.950 g, 3.217 mmol), 4-Phenoxyphenyl-boronic acid (0.688 g, 3.217 mmol), and triethylamine (228 mL, 16.083 mmol) in anhydrous dichloromethane (DCM) (79.2 mL) at room temperature under an atmosphere of nitrogen was added copper (II) acetate (0.445 g, 3.217 mmol), and the resulting mixture was stirred at room temperature for about 42 hours. The reaction mixture was washed with 60 mL of water and 20 mL of DCM and filtered. The DCM layer was then extracted. The aqueous layer was re-extracted with DCM (2×30 mL). The organic layers were combined, washed with 60 mL of brine, and seperated. Organic layer was dried over anhydrous Na2SO4, filtered, and the solvent was removed in vacuo to obtain the crude mixture, which was purified by silica gel flash chromatography, using EtOAc/hexane (gradient system), to obtain the product (0.57 g, 50%): 1H NMR (400 MHz, CDCL3): δ 1.42 (s, 9H), 1.59 (s, 1H), 2.99-3.11 (m, 2H), 3.67-3.73 (m, 3H), 4.57 (d, 1H, J=7.2 Hz), 4.99 (d, 1H, J=8 Hz), 6.92 (d, 2H, J=8.8 Hz), 6.99-7.01 (m, 5H), 7.07-7.10 (m, 3H), 7.31-7.35 (m, 2H).
Reaction SMILES: [OH:1]/[N:2]=[C:3](\Cl)/[CH:4]=[N:5]/O.S(Cl)(Cl)=O.[O:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1>>[CH2:13]([O:12][CH:16]1[O:1][N:2]=[C:3]([C:4]#[N:5])[CH2:15]1)[CH3:14]
Reactant: O/N=C(Cl)/C=N/O
Reactant: C1CCOC1
Solvent: O=S(Cl)Cl
Product: CCOC1CC(C#N)=NO1
Temperature: 2.5 °C
Reaction time: 6.5 h
Yield: 30.5 %

Procedure:
To a dried 10 L three-necked flask equipped with a thermometer controller, a mechanical stirrer, and a dropping funnel protected under nitrogen was charged 6966.7 g (7.3×) of tetrahydrofuran and 950.0 g (1.0×) of compound (1Z,2E)-N-hydroxy-2-(hydroxyimino)acetimidoyl chloride. The reaction mixture was cooled to 0-5° C. followed by drop wise addition of 1845.2 g (1.9×) thionyl chloride over 60˜90 minutes at 0-5° C. After addition, the reaction mixture was stirred at 10-15° C. for 6-7 hours and deemed complete by HPLC. The reaction mixture was then concentrated under vacuum at 15-20° C. to about 1.0 L (1.0×) followed by addition of a total of 950 g (0.9×) of tetrahydrofuran and distillation to remove residual thionyl chloride. The resulting mixture was added drop wise into a solution of 2755 g (2.9×) of ethoxyethene, 6764 g (7.12×) of tetrahydrofuran and 715.0 g (0.75×) of sodium carbonate in 3200.0 g (3.4×) of water over 30-40 minutes at 0-5° C. After addition, the reaction mixture was stirred at 0-5° C. for 1-2 hours and deemed complete by HPLC. The resulting mixture was separated and the aqueous layer was extracted with 1900 g (2.0×) of methyl t-butyl ether, and then the combined organic layer was dried with 380 g (0.4×) of sodium sulfate, filtered and then concentrated to give 549.7 g yellow oil (Assay 60.3%, purity 97.0%, yield 30.5%). 1H NMR (CDCl3, 400 MHz) δ 5.76 (dd, J=2.0 Hz, 4.8 Hz, 1H), 3.86˜3.90 (m, 1H), 3.60˜3.65 (m, 1H), 3.21 (dd, J=6.8 Hz, 11.2 Hz, 1H), 3.00 (dd, J=2.0 Hz, 16 Hz, 1H), 1.21 (T, J=6.8 Hz, 1H).
Reaction SMILES: [C:1]([C:3]1[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:5][O:6][C:7]=1[CH3:8])#[CH:2].[NH2:15][C:16]1[CH:17]=[N:18][C:19](Br)=[CH:20][CH:21]=1>>[CH3:8][C:7]1[O:6][N:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:3]=1[C:1]#[C:2][C:19]1[N:18]=[CH:17][C:16]([NH2:15])=[CH:21][CH:20]=1
Reactant: C#Cc1c(-c2ccccc2)noc1C
Reactant: Nc1ccc(Br)nc1
Product: Cc1onc(-c2ccccc2)c1C#Cc1ccc(N)cn1
Yield: 49 %

Procedure:
As described for example 11c, 4-ethynyl-5-methyl-3-phenyl-isoxazole (92 mg, 0.50 mmol) was converted (using 3-amino-6-bromopyridine instead of 2-chloro-4-iodopyridine) to the title compound (SiO2, heptane:ethyl acetate=95:5 to 0:100, 68 mg, 49%) which was obtained as a light brown foam. MS: m/e=276.3 [M+H]+.
Reaction SMILES: [OH-].[Na+].[CH3:3][O:4][C:5]1[CH:10]=[C:9]([CH3:11])[N:8]=[C:7]([C:12]([O:14]CC)=[O:13])[N:6]=1>C(O)C.O>[CH3:3][O:4][C:5]1[CH:10]=[C:9]([CH3:11])[N:8]=[C:7]([C:12]([OH:14])=[O:13])[N:6]=1
Reactant: CCOC(=O)c1nc(C)cc(OC)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COc1cc(C)nc(C(=O)O)n1
Reaction time: 12 h

Procedure:
A solution of 11.5 g of sodium hydroxide in 156 ml of ethanol and 78 ml of water is added to a stirred solution of 51.5 g of ethyl 4-methoxy-6-methylpyrimidine-2-carboxylate in 280 ml of ethanol. Stirring is continued for 12 hours at room temperature, and the sodium salt of the carboxylic acid, which has precipitated, is filtered off with suction. The sodium salt is transferred to a solution of 17.3 g of acetyl chloride in 220 ml of methanol, and the sodium chloride, which has precipitated, is filtered off with suction. The methanolic solution is evaporated on a rotary evaporator. This gives 30.9 g of 4-methoxy-6-methylpyrimidine-2-carboxylic acid of melting point 140°-141° C. as the residue.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](/[CH:11]=[CH:12]/[C:13]#[N:14])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[BH4-].[Na+].Cl>N1C=CC=CC=1.CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][C:13]#[N:14])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(/C=C/C#N)cc1OC
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: c1ccncc1
Product: COc1ccc(CCC#N)cc1OC
Temperature: 100 °C
Yield: 80.9 %

Procedure:
To a solution of 1 g (5.3 mmoles) of (2E)-3-(3,4-dimethoxyphenyl)prop-2-enenitrile in 9.3 mL of pyridine and 2.8 mL of methanol there is added, little by little, 0.24 g of NaBH4 (6.3 mmol, 1.2 eq.). The reaction mixture is heated at reflux (100° C.) for 9 hours. After cooling to ambient temperature, the reaction mixture is added to a solution of 9 mL of hydrochloric acid 37% in 24 g of ice. The solution is extracted twice with dichloromethane. The organic phases are collected and the solvent is evaporated off under reduced pressure to yield 0.82 g of a red-brown oil which crystallises.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([NH2:12])=[S:11])=[CH:5][CH:4]=1.Cl[CH2:14][CH:15]=O>CCO>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([NH:9][C:10]2[S:11][CH:14]=[CH:15][N:12]=2)=[CH:7][CH:8]=1
Reactant: COc1ccc(NC(N)=S)cc1
Reactant: O=CCCl
Solvent: CCO
Product: COc1ccc(Nc2nccs2)cc1
Temperature: 25 °C

Procedure:
A mixture of (4-methoxy-phenyl)-thiourea (3.0 g, 16.5 mmol) and a 45% aqueous solution of chloroacetaldehyde (12 mL, 82.4 mmol, 5.0 equiv) in EtOH (23 mL) is heated to reflux for 1 h. The resulting dark orange solution is allowed to cool to RT and concentrated in vacuo. NaHCO3 is then added to the oily residue until CO2 evolution subsides and a beige precipitate forms. The product is collected by vacuum filtration, washed thoroughly with water (600 mL), and dried in vacuo. Title compound: ES-MS: 207.0 [M+H]+; single peak at tR=5.32 min (System 1); Rf=0.17 (CH2Cl2/MeOH, 95/5).
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([NH:10][C@H:11]1[CH2:20][CH2:19][C:18]2[C:13](=[CH:14][C:15]([OH:21])=[CH:16][CH:17]=2)[CH2:12]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].Br[CH2:23][C:24]([NH2:26])=[O:25].O>CN(C=O)C>[C:3]([O:7][C:8]([NH:10][C@H:11]1[CH2:20][CH2:19][C:18]2[C:13](=[CH:14][C:15]([O:21][CH2:23][C:24]([NH2:26])=[O:25])=[CH:16][CH:17]=2)[CH2:12]1)=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: NC(=O)CBr
Reactant: CC(C)(C)OC(=O)N[C@H]1CCc2ccc(O)cc2C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N[C@H]1CCc2ccc(OCC(N)=O)cc2C1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
0.16 g of 60% NaH (0.004 mole) and 3.5 ml of anhydrous DMF were stirred at ambient temperature in a stream of nitrogen and 1 g (0.0038 mole) of (2S)-2-tert-butoxycarbonylamino-7-hydroxy-tetralin in 9 ml of anhydrous DMF and 0.52 g (0.0038 mole) of 2-bromoacetamide in 2.5 ml of anhydrous DMF were added. It was stirred at ambient temperature for 6 hours then the mixture was poured into water. The precipitated product was filtered and the product of the heading was then obtained.
Reaction SMILES: [C:1]1(=[O:8])[NH:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C=O.[C:11]([O-])([O-])=[O:12].[K+].[K+].C(N1CCCCCC1=O)O>>[CH2:11]([CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:1]1=[O:8])[OH:12]
Reactant: O=C1CCCCCN1
Reactant: O=C([O-])[O-]
Agent: C=O
Agent: O=C1CCCCCN1CO
Agent: [K+]
Product: O=C1NCCCCC1CO
Temperature: 50 °C
Reaction time: 2 h

Procedure:
1,130 g (10.00 mol) of 6-caprolactam, 306.1 g (10.00 mol) of 98% purity paraformaldehyde and 6.91 g (0.05 mol) of ground K2CO3 were brought to reaction. Apart from the catalyst, a clear solution was present. After 2 hours, the mixture was cooled to 50° C.; a few grains of pure N-methylol-caprolactam were added as seed crystals. 1,428 g of methylolcaprolactam (=99.9% of the theoretical yield) were obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=3)([C:13]#[N:14])[CH:11]([CH2:22][C:23]([CH3:26])([CH3:25])[CH3:24])[NH:10][CH:9]2[C:27]([OH:29])=O)[CH:5]=[CH:6][CH:7]=1.[N:30]1([CH2:36][CH2:37][NH2:38])[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[N:30]1([CH2:36][CH2:37][NH:38][C:27]([CH:9]2[CH:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)[C:12]([C:15]3[CH:16]=[CH:17][C:18]([Cl:21])=[CH:19][CH:20]=3)([C:13]#[N:14])[CH:11]([CH2:22][C:23]([CH3:26])([CH3:25])[CH3:24])[NH:10]2)=[O:29])[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2)C1(C#N)c1ccc(Cl)cc1
Reactant: NCCN1CCNCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)CC1NC(C(=O)NCCN2CCNCC2)C(c2cccc(Cl)c2)C1(C#N)c1ccc(Cl)cc1
Yield: 42.3 %

Procedure:
In a manner similar to the method described in Example 1e, rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (82.2 mg, 0.20 mmol) prepared in Example 1d was reacted with 2-piperazin-1-yl-ethylamine (38.7 mg, 0.30 mmol), HATU (76.0 mg, 0.20 mmol) and iPr2NEt (38.8 mg, 0.30 mmol) in CH2Cl2 (2 mL) at rt overnight to give rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (2-piperazin-1-yl-ethyl)-amide (45.9 mg, 58.0%). HRMS (ES+) m/z Calcd for C29H37Cl2N5O+H [(M+H)+]: 542.2448. found: 542.2445.
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9](=[O:43])[NH:10][CH2:11][CH2:12][CH2:13][NH:14][C:15]2[C:20]([CH2:21][O:22][Si](C(C)(C)C)(C)C)=[CH:19][N:18]=[C:17]([NH:30][C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([NH:37][C:38]([NH:40][CH2:41][CH3:42])=[O:39])[CH:32]=3)[N:16]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O-])(O)=O.[Na+].C(OCC)(=O)C>C(O)C.Cl>[CH2:41]([NH:40][C:38]([NH:37][C:33]1[CH:32]=[C:31]([NH:30][C:17]2[N:16]=[C:15]([NH:14][CH2:13][CH2:12][CH2:11][NH:10][C:9](=[O:43])[O:8][CH2:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[C:20]([CH2:21][OH:22])=[CH:19][N:18]=2)[CH:36]=[CH:35][CH:34]=1)=[O:39])[CH3:42]
Reactant: CCNC(=O)Nc1cccc(Nc2ncc(CO[Si](C)(C)C(C)(C)C)c(NCCCNC(=O)OCc3ccccc3)n2)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCNC(=O)Nc1cccc(Nc2ncc(CO)c(NCCCNC(=O)OCc3ccccc3)n2)c1

Procedure:
Phenylmethyl[3-[[5-[[[(1,1-dimethylethyl)dimethylsilyl]oxy]methyl]-2-[[3[[(ethylamino)carbonyl]amino]phenyl]amino]pyrimidin-4-yl]amino]propyl]carbamate (145 mg) were stirred in a mixture of ethanol (10 ml) and hydrochloric acid (4 n; 1 ml) for 3 h at room temperature. Then halfconcentrated NaHCO3-solution and ethyl acetate were added.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH2:9][C:10]#[CH:11])=[CH:6][C:5]([N:12]2[C:16](Cl)=[C:15]([C:18]#[N:19])[N:14]([CH2:20][CH2:21][CH3:22])[C:13]2=[O:23])=[C:4]([F:24])[CH:3]=1.[C-:25]#[N:26].[K+]>CN(C)C=O>[Cl:1][C:2]1[C:7]([O:8][CH2:9][C:10]#[CH:11])=[CH:6][C:5]([N:12]2[C:16]([C:25]#[N:26])=[C:15]([C:18]#[N:19])[N:14]([CH2:20][CH2:21][CH3:22])[C:13]2=[O:23])=[C:4]([F:24])[CH:3]=1
Reactant: C#CCOc1cc(-n2c(Cl)c(C#N)n(CCC)c2=O)c(F)cc1Cl
Reactant: [C-]#N
Agent: [K+]
Solvent: CN(C)C=O
Product: C#CCOc1cc(-n2c(C#N)c(C#N)n(CCC)c2=O)c(F)cc1Cl

Procedure:
The product of Example 4, 1-(4-chlorophenyl)-5-chloro-4-cyano-3-phenyl-1,3-dihydro-2H-imidazol-2-one (V) (0.94 g, 2.8 mmol) was stirred in 25 mL dimethylformamide. To this mixture was added KCN (0.6 g, 8.5 mmol) and the resulting mixture was heated to reflux for ten minutes. The mixture was then allowed to cool, poured onto water, extracted with ethyl acetate, dried, filtered, and evaporated via standard techniques. Recrystallization with ethyl acetate/heptane gave 0.5 g of 1-(4-chlorophenyl)-4,5-dicyano-3-phenyl-1,3-dihydro-2H-imidazol-2-one (VI) as an orange solid (m.p. 182°-4° C.).
Reaction SMILES: [Cl-].[Cl-].[Cl-].[Al+3].[C:5](Cl)(=[O:7])[CH3:6].[CH3:9][CH2:10][CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1>C(=S)=S>[CH3:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:5]([CH3:6])=[O:7])=[CH:14][CH:13]=1
Reactant: CC(=O)Cl
Reactant: CCCc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: CCCc1ccc(C(C)=O)cc1
Reaction time: 8 h

Procedure:
Crushed anhydrous aluminium trichloride (1.28 mole) was suspended in dry carbon disulphide (348 ml). Acetylchloride (1.1 mole) and n-propylbenzene (1.0 mole) was dissolved in dry carbon disulphide (348 ml) and added to the suspension of aluminium trichloride under anhydrous conditions. The mixture was then left to stir overnight. The solvent was distilled from the reaction mixture and the viscous residue poured onto crushed ice and stirred for 0.5 hours. The product was extracted into ether and the extract washed with water and dried (Na2SO4). The ether was removed by distillation and the oily residue distilled. The product had mpt 132° C. at 0.1 mm Hg.
Reaction SMILES: C(N(C(C)C)C(C)C)C.[CH:10]1([C:15](Cl)=[O:16])[CH2:14][CH2:13][CH2:12][CH2:11]1.[Cl:18][C:19]1[C:20]([F:29])=[C:21]2[C:27]([NH2:28])=[CH:26][NH:25][C:22]2=[N:23][CH:24]=1>C1COCC1>[Cl:18][C:19]1[C:20]([F:29])=[C:21]2[C:27]([NH:28][C:15]([CH:10]3[CH2:14][CH2:13][CH2:12][CH2:11]3)=[O:16])=[CH:26][NH:25][C:22]2=[N:23][CH:24]=1
Reactant: O=C(Cl)C1CCCC1
Reactant: Nc1c[nH]c2ncc(Cl)c(F)c12
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1c[nH]c2ncc(Cl)c(F)c12)C1CCCC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 61.1 %

Procedure:
N-Ethyl-N-isopropylpropan-2-amine (279 mg, 2.16 mmol) followed by cyclopentanecarbonyl chloride (143 mg, 1.08 mmol) were added dropwise to 5-chloro-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-amine (200 mg, 1.08 mmol) in THF (10 mL) at 0° C. The reaction mixture was stirred at 0° C. for 1 hour and then concentrated to dryness. The residue was triturated in water and then filtered. The solid was washed with ACN and dried under vacuum to provide N-(5-chloro-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopentanecarboxamide (186 mg, 61% yield) as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH3:38])[C:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)([CH3:13])[N:11]([C:21](Cl)=[O:22])[C:10]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([O:33][CH3:34])([CH3:32])[CH3:31])=[CH:26][C:25]=3[O:35][CH2:36][CH3:37])=[N:9]2)=[CH:4][CH:3]=1.Cl.Cl.[CH3:41][S:42]([CH2:45][CH2:46][CH2:47][N:48]1[CH2:53][CH2:52][NH:51][CH2:50][CH2:49]1)(=[O:44])=[O:43]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([CH3:38])[C:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)([CH3:13])[N:11]([C:21]([N:51]3[CH2:50][CH2:49][N:48]([CH2:47][CH2:46][CH2:45][S:42]([CH3:41])(=[O:43])=[O:44])[CH2:53][CH2:52]3)=[O:22])[C:10]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([O:33][CH3:34])([CH3:31])[CH3:32])=[CH:26][C:25]=3[O:35][CH2:36][CH3:37])=[N:9]2)=[CH:6][CH:7]=1
Reactant: CCOc1cc(C(C)(C)OC)ccc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1C(=O)Cl
Reactant: CS(=O)(=O)CCCN1CCNCC1
Agent: Cl
Product: CCOc1cc(C(C)(C)OC)ccc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(CCCS(C)(=O)=O)CC1

Procedure:
In a manner analogous to the method described in example 5, 4,5-bis-(4-chloro-phenyl)-2-[2-ethoxy-4-(1-methoxy-1-methyl-ethyl)-phenyl]-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride was reacted with 1-(3-methanesulfonyl-propyl)-piperazine dihydrochloride (prepared as described in Fotouhi, N. et al. WO 2005110996) to give the title compound as a racemic mixture. The enantiomers were then separated by supercritical fluid chromatography (Berger Instrument Multi-Gram II, Daicel ChiralPak OD-H 3×25 cm, 35° C. at 100 bar, eluting with 30% methanol in carbon dioxide). HR-MS (ES, m/z) calculated for C38H49N4O5SCl2 [(M+H)+] 743.2795, observed 743.2795.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH:6]=1.Br[CH2:15][C:16](=O)[C:17]([O:19][CH2:20][CH3:21])=[O:18].C>C(O)C>[CH2:4]1[C:5]2[C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[NH:7][C:6]=2[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:15][NH:2][CH2:3]1
Reactant: NCCc1c[nH]c2ccccc12
Reactant: CCOC(=O)C(=O)CBr
Agent: Cl
Solvent: CCO
Product: CCOC(=O)C1=CNCCc2c1[nH]c1ccccc21

Procedure:
A mixture of tryptamine hydrochloride (1.96 g, 10 mmol), ethyl 3-bromopyruvate (1.67 mL, 1.2 equiv) and decolorizing charcoal (0.5 g) in absolute ethanol was heated to reflux under nitrogen overnight. TEA was added and the reaction mixture was heated to reflux for another 7.5 hours. After cooling, charcoal was removed by filtration and washed with ethanol. The filtrate was concentrated under vacuum and diluted with water (20 mL). It was then extracted by EtOAc (3×30 mL) and the combined organic layers were washed with brine and dried over MgSO4. Evaporation of solvent and recrystallization from DCM-Hexane gave the title compound (1.17 g). 1H-NMR (CDCl3): δ 10.49 (1 H, br s), 7.79 (1H, d), 7.43 (1H, d), 7.43 (1 H, d), 7.06 (2H, m), 5.27 (1H, br s), 4.29 (2H, q) 3.58 (2H, m), 3.17 (2H, m), 1.36 (3H, t); MS (ES): 257 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][C:10](=[O:28])[CH:11]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:12][CH:13]=[CH:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[CH:16]=2)=[CH:4][CH:3]=1.[C:29]([O:33]C)(=[O:32])[CH:30]=[CH2:31]>CO.C(COC)OC>[CH3:21][C:17]1[CH:16]=[C:15]([CH:20]=[CH:19][CH:18]=1)[CH:14]=[CH:13][CH2:12][C:11]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([C:10](=[O:28])[CH:9]=[CH:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)[CH2:31][CH2:30][C:29]([OH:33])=[O:32]
Reactant: Cc1cccc(C=CCC(C(=O)C=Cc2ccc(Cl)cc2)c2ccccc2)c1
Reactant: C=CC(=O)OC
Solvent: CO
Solvent: COCCOC
Product: Cc1cccc(C=CCC(CCC(=O)O)(C(=O)C=Cc2ccc(Cl)cc2)c2ccccc2)c1
Reaction time: 96 h

Procedure:
Triton B (2 ml., 40% in MeOH) is added to a stirred solution of 1-(p-chlorophenyl)-4-phenyl-7-(m-methylphenyl)-1,6-heptadien-3-one (19.33 g., 0.05 mole) in glyme (250 ml.) followed by the addition of methyl acrylate (4.73 g., 0.055 mole) in glyme (50 ml.). The solution is stirred for 96 hours and the solvent is removed under reduced pressure. The residue is suspended in methanol (700 ml.) and a 20% sodium hydroxide solution (35 ml.) is added. After an additional 24 hours, the methanol is evaporated in vacuo and the residue is dissolved in water. Extraction with ether removes unreacted ketone. The aqueous solution is acidified and the solid that separates is collected, washed well with water, and air-dried, yield 9.78 g., m.p. 135°-144°C. Recyrstallization from butyl chloride produces material with m.p. 154°-155°C.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:12]=[CH:11][CH:10]=[CH:9][C:6]=1[C:7]#[N:8].[H-].[Na+].[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CN(C=O)C.O>[CH2:15]([O:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:12]=[CH:11][CH:10]=[CH:9][C:6]=1[C:7]#[N:8])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: BrCc1ccccc1
Reactant: N#Cc1ccccc1CCCO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1ccccc1CCCOCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 2-(3-hydroxypropyl)benzonitrile (Example 323c, 3.83 g) in DMF (40 mL) under nitrogen was treated with 60% Sodium hydride (1.140 g) and stirred at room temperature for 1 h before adding benzyl bromide (2.83 mL). The resulting solution was stirred at 20° C. for 60 h. The reaction mixture was diluted with water (200 mL), and extracted with ethyl acetate (200 mL). The organic was dried (MgSO4), filtered and evaporated. The residue was purified (SiO2 chromatography eluting with 30% diethyl ether in isohexane). Pure fractions were evaporated to dryness to afford the subtitle compound as an oil (2.3 g).
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:18])[C:7]([C:15]([OH:17])=[O:16])=[C:8]3[S:14][CH2:13][CH2:12][N:9]32)=[CH:4][C:3]=1[F:19].[CH3:20][N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>N1C=CC=CC=1>[F:19][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:2]=1[N:24]1[CH2:25][CH2:26][N:21]([CH3:20])[CH2:22][CH2:23]1)[N:9]1[CH2:12][CH2:13][S:14][C:8]1=[C:7]([C:15]([OH:17])=[O:16])[C:6]2=[O:18]
Reactant: O=C(O)c1c2n(c3cc(Cl)c(F)cc3c1=O)CCS2
Reactant: CN1CCNCC1
Solvent: c1ccncc1
Product: CN1CCN(c2cc3c(cc2F)c(=O)c(C(=O)O)c2n3CCS2)CC1
Temperature: 25 °C

Procedure:
A mixture of 1 gram (3.3 mmol) of 8-chloro-7-fluoro-5-oxo-1,2-dihydro-5H-thiazolo(3,2-a)-quinoline-4-carboxylic acid, 1.65 g. (0.0165 mol) of N-methylpiperazine and 20 ml of pyridine was heated to reflux. After twelve hours, 1.65 g. (0.0165 mol) of N-methylpiperazine was added thereto again and the heating to reflux was continued for twelve hours. When the reaction was completed, the mixture was allowed to cool to a room temperature, crystals separated out therefrom were collected by filtration, washed with pyridine and ether and air dried to give the title compound. Yellow powdery crystals. Yield 720 mg (60 percent).
Reaction SMILES: [NH2:1][C:2](=[O:72])[C@H:3]([CH2:65][C:66]1[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=1)[NH:4][C:5](=[O:64])[C@H:6]([CH2:51][NH:52][C:53](=[O:63])[CH2:54][NH:55][C:56]1[S:57][C:58]([CH:61]=[O:62])=[CH:59][N:60]=1)[NH:7][C:8](=[O:50])[CH2:9][NH:10][C:11](=[O:49])[C@H:12]([CH3:48])[NH:13][C:14](=[O:47])[C@H:15]([CH3:46])[NH:16][C:17](=[O:45])[C@@H:18]([NH:27][C:28](=[O:44])[O:29][CH2:30][CH:31]1[C:43]2[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=2[C:37]2[C:32]1=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=1.[BH4-].[Na+]>CCO.O>[NH2:1][C:2](=[O:72])[C@H:3]([CH2:65][C:66]1[CH:67]=[CH:68][CH:69]=[CH:70][CH:71]=1)[NH:4][C:5](=[O:64])[C@H:6]([CH2:51][NH:52][C:53](=[O:63])[CH2:54][NH:55][C:56]1[S:57][C:58]([CH2:61][OH:62])=[CH:59][N:60]=1)[NH:7][C:8](=[O:50])[CH2:9][NH:10][C:11](=[O:49])[C@H:12]([CH3:48])[NH:13][C:14](=[O:47])[C@H:15]([CH3:46])[NH:16][C:17](=[O:45])[C@@H:18]([NH:27][C:28](=[O:44])[O:29][CH2:30][CH:31]1[C:43]2[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=2[C:37]2[C:32]1=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=1
Reactant: C[C@H](NC(=O)[C@H](C)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)NCC(=O)N[C@@H](CNC(=O)CNc1ncc(C=O)s1)C(=O)N[C@@H](Cc1ccccc1)C(N)=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: C[C@H](NC(=O)[C@H](C)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)NCC(=O)N[C@@H](CNC(=O)CNc1ncc(CO)s1)C(=O)N[C@@H](Cc1ccccc1)C(N)=O
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
Following the procedure as described in Example 32, except using material from Example 87 (16 mg, 0.014 mmol), EtOH/H2O (4:1) (5 mL), sodium borohydride (6.3 mg, 0.167 mmol) and stirring at room temp for 2.5 h, the title compound is isolated (quantitative yield) that is used crude in the next step. LC/MS (Condition A): ret. T=3.37 min, (2M+Na) 1005.75.