Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([N:10]2[C:14]([CH2:15][CH2:16][CH:17]=O)=[CH:13][C:12]([CH2:19][CH2:20][CH2:21][CH3:22])=[N:11]2)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[F:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[F:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[N:30]1[CH2:35][CH2:34][N:33]([CH2:17][CH2:16][CH2:15][C:14]2[N:10]([C:6]3[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=3)[N:11]=[C:12]([CH2:19][CH2:20][CH2:21][CH3:22])[CH:13]=2)[CH2:32][CH2:31]1
Reactant: Fc1ccccc1N1CCNCC1
Reactant: CCCCc1cc(CCC=O)n(-c2cccc([N+](=O)[O-])c2)n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: CCCCc1cc(CCCN2CCN(c3ccccc3F)CC2)n(-c2cccc([N+](=O)[O-])c2)n1

Procedure:
218 mg (66.2%) of target compound was obtained by using a method same as in Example 1 by using 3-(1-(3-nitrophenyl)-3-butyl-1H-pyrazol-5-yl)propanal (213 mg, 0.707 mmol), 1-(2-fluorophenyl)piperazine (167 mL, 1.060 mmol), and NaBH(OAc)3 (198 mg, 0.936 mmol).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH:7]=O)=[CH:3][CH:2]=1.[CH2:9]([NH2:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.P(O)(O)O.[OH-].[Na+]>O>[CH2:9]([NH:16][CH2:7][C:4]1[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=Cc1ccncc1
Reactant: NCc1ccccc1
Agent: OP(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: c1ccc(CNCc2ccncc2)cc1
Yield: 74 %

Procedure:
To the imine from pyridine-4-carboxaldehyde and benzylamine (20 g; 0.1 mole) was added phosphorous acid (8.4 g; 0.1 mole) and the mixture heated at 110°-130° for 11/2 hours. After cooling to 90° water (150 ml) was added. The aqueous solution was basified with NaOH and extracted with benzene (3×100 ml). Evaporation of the solvent gave the N-benzyl(4-pyridyl) methylamine 14.9 g (74%). Nmr measurements, 1H and 13C, confirmed the structural assignment.
Reaction SMILES: [F:1][C:2]1[C:11]2[O:10][CH2:9][C@H:8]([NH:12][CH:13]([CH3:15])[CH3:14])[CH2:7][C:6]=2[C:5]([O:16][CH3:17])=[CH:4][CH:3]=1.[C:18]1(=O)[CH2:21][CH2:20][CH2:19]1.C([BH3-])#N.[Na+].C(O)(=O)C>CO>[CH:18]1([N:12]([C@@H:8]2[CH2:7][C:6]3[C:5]([O:16][CH3:17])=[CH:4][CH:3]=[C:2]([F:1])[C:11]=3[O:10][CH2:9]2)[CH:13]([CH3:15])[CH3:14])[CH2:21][CH2:20][CH2:19]1
Reactant: COc1ccc(F)c2c1C[C@@H](NC(C)C)CO2
Reactant: O=C1CCC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: COc1ccc(F)c2c1C[C@@H](N(C(C)C)C1CCC1)CO2
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.6 %

Procedure:
(R)-8-Fluoro-3-(N-isopropylamino)-5-methoxy-3,4-dihydro-2H-1-benzopyran (1.96 g, 8.19 mmol) was dissolved in anhydrous methanol (20 mL) and to this was cyclobutanone (6.1 mL, 81.9 mmol) added. The reaction was cooled (ice-bath) then sodium cyanoborohydride (2.0 g, 16.4 mmol) was added, the pH was adjusted to 4-5 with acetic acid, 3 Å molecular sieves were added and the reaction was allowed to stir at room temperature overnight. After 24 h the pH-was again adjusted to 4-5 and the reaction was allowed to stir for 3 more days. The reaction was filtered, solvent was removed in vacuo, the remains were taken into a 2M solution of NH3 and then extracted thrice with diethyl ether. The combined ether portions were dried (MgSO4) filtered, and the solvent removed in vacuo to give the crude residue. Chromatography on silica (eluent: 10% ethyl acetate/hexane) gave 1.60 g (77% yield) of the title compound as a clear oil. [α]21D =-95.1° (C=0.1; CHCl3). GC-MS (70 eV) M=293 (3%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[C:5](Cl)=[O:6].Br[C:13]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][C:14]=1[C:15]([OH:17])=[O:16]>>[CH3:23][O:22][C:19]1[CH:20]=[CH:21][C:13]([C:5](=[O:6])[C:4]2[CH:8]=[CH:9][CH:10]=[CH:11][C:3]=2[O:2][CH3:1])=[C:14]([CH:18]=1)[C:15]([OH:17])=[O:16]
Reactant: COc1ccc(Br)c(C(=O)O)c1
Reactant: COc1ccccc1C(=O)Cl
Product: COc1ccc(C(=O)c2ccccc2OC)c(C(=O)O)c1

Procedure:
This compound is obtained according to the procedure described in 1.1. by reacting 2-methoxybenzoyl chloride and 2-bromo-5-methoxybenzoic acid after halogen-lithium exchange. It is used in crude form in the following reaction.
Reaction SMILES: [NH2:1][C:2]1[S:6][N:5]=[C:4]([C:7]([Cl:10])([Cl:9])[Cl:8])[N:3]=1.[Cl:11][C:12]([Cl:17])([Cl:16])[C:13](Cl)=[O:14]>C1(C)C(C)=CC=CC=1>[Cl:11][C:12]([Cl:17])([Cl:16])[C:13]([NH:1][C:2]1[S:6][N:5]=[C:4]([C:7]([Cl:10])([Cl:9])[Cl:8])[N:3]=1)=[O:14]
Reactant: Nc1nc(C(Cl)(Cl)Cl)ns1
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Solvent: Cc1ccccc1C
Product: O=C(Nc1nc(C(Cl)(Cl)Cl)ns1)C(Cl)(Cl)Cl
Temperature: 120 °C
Yield: 86.8 %

Procedure:
To a solution of 10.9 grams (0.05 mole) 5-amino-3-trichloromethyl-1,2,4-thiadiazole in 200 milliliters xylene at 110° C. was added 18.2 grams (0.1 mole) trichloroacetyl chloride over 0.5 hour. After heating for an additional 20 hours at 120° C., the low boiling materials were distilled in vacuo to leave 15.8 grams (87% yield) of pure product as residue; m.p. 157.7° C.
Reaction SMILES: [CH3:1][N:2]([CH3:15])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][NH2:14].[O-:16][C:17]#[N:18].[K+].CO>Cl.O>[CH3:15][N:2]([CH3:1])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][NH:14][C:17]([NH2:18])=[O:16]
Reactant: N#C[O-]
Reactant: CN(C)CCCCCCCCCCCN
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CO
Product: CN(C)CCCCCCCCCCCNC(N)=O
Yield: 21.7 %

Procedure:
A solution of this amine (4.6 g) in dilute hydrochloric acid (40 ml) and concentrated hydrochloric acid (12 ml) was treated with potassium cyanate (7.0 g) in water (10 ml). The mixture was refluxed for 18 hours and the solvent removed leaving a white solid. To this methanol (10 ml) was added and the mixture filtered. The solvent was evaporated from the filtrate which was then chromatographed on a basic alumina column eluting with 10% methanol in chloroform, to give a yellow solid which was washed with ether to give N,N-dimethyl-N-(11-ureidoundecyl)amine as a white solid (1.2g).
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:17][C:18]1[S:32][C:21]2[N:22]([CH:29]([CH3:31])[CH3:30])[C:23](=[O:28])[N:24]([CH3:27])[C:25](=[O:26])[C:20]=2[CH:19]=1.O>CN(C)C=O>[N:1]1([CH2:17][C:18]2[S:32][C:21]3[N:22]([CH:29]([CH3:30])[CH3:31])[C:23](=[O:28])[N:24]([CH3:27])[C:25](=[O:26])[C:20]=3[CH:19]=2)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: CC(C)n1c(=O)n(C)c(=O)c2cc(CCl)sc21
Reactant: c1ccc2[nH]cnc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)n1c(=O)n(C)c(=O)c2cc(Cn3cnc4ccccc43)sc21
Reaction time: 48 h
Yield: 55.1 %

Procedure:
Benzimidazole (0.395 g) and potassium carbonate (1 g) were added to a stirred solution of 6-(chloromethyl)-3-methyl-1-(1-methylethyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (0.55 g) in anhydrous dimethylformamide (5 ml) at room temperature. After 2 days, water (50 ml) was added and the mixture was extracted with ethyl acetate (2×50 ml). The organic extracts were dried over anhydrous magnesium sulfate and filtered through a silica pad which was washed with ethyl acetate. The filtrate was evaporated and the residue was purified twice by normal-phase preparative HPLC with gradient dichloromethane/ethanol elution to give the title compound (0.394 g) as a foam.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[S:17][CH2:18][CH2:19][OH:20])=[N:9][N:10]=2)[CH:7]=1.CC1C=CC(S(O)(=O)=O)=CC=1.[O:32]1[CH:37]=[CH:36][CH2:35][CH2:34][CH2:33]1>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[S:17][CH2:18][CH2:19][O:20][CH:33]3[CH2:34][CH2:35][CH2:36][CH2:37][O:32]3)=[N:9][N:10]=2)[CH:7]=1
Reactant: C1=COCCC1
Reactant: OCCSc1ccccc1-c1nnc2ccc(F)cn12
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Product: Fc1ccc2nnc(-c3ccccc3SCCOC3CCCCO3)n2c1
Yield: 73.9 %

Procedure:
A solution of 2-[2-(6-fluoro-[1,2,4]triazolo[4,3-a]pyridin-3-yl)-phenylsulfanyl]-ethanol (400 mg, 1.38 mmol), 4-methylbenzenesulfonic acid (65 mg, 0.345 mmol) and 3,4-dihydro-2H-pyran (251 μL, 2.76 mmol) in DCM (5 mL) was stirred at RT under a nitrogen atmosphere for 36 h. The reaction mixture was diluted with DCM and extracted with sat. NaHCO3. The organic layer was dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by FCC using MeOH in DCM (0 to 5%) to give the title compound as a pale yellow oil (381 mg, 74%). LCMS (Method 3): Rt 3.10 min, m/z 374 [MH+]. 1H NMR (400 MHz, CDCl3): 1.49 (6 H, m), 3.01-3.02 (2 H, m), 3.42-3.59 (2 H, m), 3.80-3.80 (2 H, m), 4.52 (1 H, m), 7.34-7.35 (2 H, m), 7.55-7.55 (2 H, m), 7.67-7.68 (2 H, m), 7.90 (1 H, dd, J 9.97 and 4.82).
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH2:6][C:7](=[O:13])[NH:8]2.[NH:14]1[C:22]2[C:17](=[CH:18][C:19]([CH:23]=O)=[CH:20][CH:21]=2)[CH:16]=[CH:15]1>N1CCCCC1.C(O)C>[OH:1][CH2:2][CH2:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[C:6](=[CH:23][C:19]1[CH:18]=[C:17]3[C:22](=[CH:21][CH:20]=1)[NH:14][CH:15]=[CH:16]3)[C:7](=[O:13])[NH:8]2
Reactant: O=Cc1ccc2[nH]ccc2c1
Reactant: O=C1Cc2c(CCO)cccc2N1
Solvent: C1CCNCC1
Solvent: CCO
Product: O=C1Nc2cccc(CCO)c2C1=Cc1ccc2[nH]ccc2c1
Temperature: 90 °C
Yield: 71.7 %

Procedure:
A mixture of 4-(2-hydroxy-ethyl)-1,3-dihydro-indol-2-one (39 mg, 0.22 mmol), 1H-indole-5-carbaldehyde (32 mg, 0.22 mmol) and 1 drop of piperidine in ethanol was heated at 90° C. for overnight and cooled to room temperature. The reaction mixture was concentrated and the residue was purified on silica gel column to give 48 mg (72%) of 4-(2-hydroxy-ethyl)-3-(1H-indol-5-ylmethylene)-1,3-dihydro-indol-2-one as a yellow solid.
Reaction SMILES: Cl.[S:2]1[C:6]2[CH2:7][CH2:8][CH2:9][C:5]=2[N:4]=[C:3]1[NH2:10].[C:11]12([C:21](Cl)=[O:22])[CH2:20][CH:15]3[CH2:16][CH:17]([CH2:19][CH:13]([CH2:14]3)[CH2:12]1)[CH2:18]2.C(N(CC)CC)C>CN(C)C1C=CN=CC=1.C1COCC1>[S:2]1[C:6]2[CH2:7][CH2:8][CH2:9][C:5]=2[N:4]=[C:3]1[NH:10][C:21]([C:11]12[CH2:20][CH:15]3[CH2:14][CH:13]([CH2:19][CH:17]([CH2:16]3)[CH2:18]1)[CH2:12]2)=[O:22]
Reactant: O=C(Cl)C12CC3CC(CC(C3)C1)C2
Reactant: Nc1nc2c(s1)CCC2
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(Nc1nc2c(s1)CCC2)C12CC3CC(CC(C3)C1)C2

Procedure:
A mixture of 5,6-dihydro-4H-cyclopentathiazole-2-ylamine hydrochloride (400 mg, 2.27 mmol), 1-adamantanecarbonyl chloride (540 mg, 2.72 mmol), 4-dimethylaminopyridine (100 mg, 0.82 mmol) and triethylamine (632 μL, 4.54 mmol) in 30 mL of THF was processed according to the method of Example 1A to afford the title compound: MS (DCI/NH3) m/z 303 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]2=[N:12][N:13]=[C:14]([C:15]3[CH:20]=[N:19][CH:18]=[CH:17][N:16]=3)[N:4]2[N:3]=1.[N:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[CH2:27][OH:28]>>[N:16]1[CH:17]=[CH:18][N:19]=[CH:20][C:15]=1[C:14]1[N:4]2[N:3]=[C:2]([O:28][CH2:27][C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][N:21]=3)[C:11]3[C:6]([C:5]2=[N:12][N:13]=1)=[CH:7][CH:8]=[CH:9][CH:10]=3
Reactant: Clc1nn2c(-c3cnccn3)nnc2c2ccccc12
Reactant: OCc1ccccn1
Product: c1ccc(COc2nn3c(-c4cnccn4)nnc3c3ccccc23)nc1

Procedure:
The title-compound was prepared from 6-chloro-3-(pyrazin-2-yl)-1,2,4-triazolo[3,4-a]phthalazine and 2-pyridylcarbinol using the procedure given for Example 98, 1H NMR (360 MHz, CDCl3) δ 5.77 (2H, s, CH2), 7.40 (1H, t, J=6.6 Hz, Ar—H), 7.71 (1H, d, J=7.8 Hz, Ar—H), 7.95-8.00 (2H, m, 2 of Ar—H), 8.08 (1H, t, J=7.6 Hz, Ar—H), 8.40 (1H, d, J=8.0 Hz, Ar—H), 8.70 (2H, m, 2 of Ar—H), 8.78 (1H, m, Ar—H), 8.88 (1H, s, Ar—H), 9.58 (1H, s, Ar—H); MS (ES30) m/e 356 [MH]+.
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[C:3]1[CH:7]=[CH:6][NH:5][N:4]=1.[N+]([O-])([O-])=O.[NH4+].[Ce].[Ce].[Br:17]Br>C(#N)C>[Br:17][C:7]1[C:3]([C:2]([F:9])([F:8])[F:1])=[N:4][NH:5][CH:6]=1
Reactant: BrBr
Reactant: FC(F)(F)c1cc[nH]n1
Agent: O=[N+]([O-])[O-]
Agent: [Ce]
Agent: [NH4+]
Solvent: CC#N
Product: FC(F)(F)c1n[nH]cc1Br
Yield: 169.9 %

Procedure:
An acetonitrile solution (20 ml) of 3-trifluoromethyl-1H-pyrazole (1.0 g), dicerium ammonium nitrate (2.0 g) and bromine (0.7 g) was refluxed for 2 hours. After cooling, the reaction solution was washed with saturated aqueous solution of sodium thiosulfate and saturated aqueous solution of sodium chloride. After drying the organic layer with magnesium sulfate, the solvent was distilled off under the reduced pressure to obtain 4-bromo-3-trifluoromethyl-1H-pyrazole (1.6 g).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12]([CH:14]([NH:19][C:20]([C:22]2[CH:31]=[C:30]([O:32][CH3:33])[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[N:23]=2)=[O:21])[CH2:15][C:16](O)=[O:17])=[O:13])[CH2:8][CH2:7]1)=[O:5])[CH3:2].Cl.C([O:39][C:40](=[O:43])[CH2:41][NH2:42])(C)(C)C.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>O1CCCC1>[CH2:1]([O:3][C:4]([N:6]1[CH2:7][CH2:8][N:9]([C:12]([CH:14]([NH:19][C:20]([C:22]2[CH:31]=[C:30]([O:32][CH3:33])[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[N:23]=2)=[O:21])[CH2:15][C:16]([NH:42][CH2:41][C:40]([OH:43])=[O:39])=[O:17])=[O:13])[CH2:10][CH2:11]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCN(C(=O)C(CC(=O)O)NC(=O)c2cc(OC)c3ccccc3n2)CC1
Reactant: CC(C)(C)OC(=O)CN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCOC(=O)N1CCN(C(=O)C(CC(=O)NCC(=O)O)NC(=O)c2cc(OC)c3ccccc3n2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-[1-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-2-carboxyethyl]aminocarbonyl-4-methoxyquinoline (50 mg, 0.11 mmol) in tetrahydrofuran (THF) (2 mL) was added glycine t-butyl ester hydrochloride (20 mg, 0.12 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDCI) (23 mg, 0.12 mmol), 1-hydroxybenzotriazole (HOBT) (16 mg, 0.12 mmol) and diisopropylethylamine (DIEA) (0.16 g, 0.12 mmol). The reaction was stirred at ambient temperature overnight. The resultant solution was partitioned between water and ethyl acetate. The organic layer was concentrated in vacuo to afford 2-[1-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-2-(((carboxy)methyl)aminocarbonyl)ethyl]aminocarbonyl-4-methoxyquinoline as an oil.
Reaction SMILES: [CH2:1]([Li])CCC.[C:6]1([CH:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:13]=O)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C(OCC)C>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[C:6]1([CH:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:13]=[CH2:1])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: [Li]CCCC
Reactant: O=CC(c1ccccc1)c1ccccc1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: CCOCC
Solvent: C1CCOC1
Product: C=CC(c1ccccc1)c1ccccc1
Yield: 21.3 %

Procedure:
Methyltriphenylphosphonium bromide (4 g, 11.12 mmol) was added over a 15-min period to a mixture of butyllithium (7.3 ml of 1.6 M solution in THF, 11.76 mmol) and dry THF (50 ml) with stirring and under nitrogen atmosphere. The reaction mixture was stirred for 2 h at room temperature and the mixture was then recooled to −78° C. A solution of diphenylacetaldehyde (2.2 g, 11.12 mmol) in dry THF (10 ml) was added to the above mixture over a 15-min period. The reaction mixture was stirred for 24 h at room temperature, followed by addition of ethyl ether (200 ml), and the reaction mixture was then filtered. The ether extracts were washed with water (3×50 ml), brine (100 ml) and dried over anhydrous sodium sulfate. The crude material was purified by flash chromatography on silical gel (Hexane:Ethyl ether=9:1) to give pure 3,3-diphenylpropene 460 mg (46%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:14][CH2:15][C:16]([C:18]2[S:19][C:20]([CH3:29])=[C:21]3[CH2:26][C:25]([CH3:28])([CH3:27])[CH2:24][CH2:23][C:22]=23)=[O:17])[CH:5]=[C:6]([O:12][CH3:13])[C:7]=1[O:8][CH2:9][CH2:10][OH:11].CCN(C(C)C)C(C)C.[CH3:39][S:40](Cl)(=[O:42])=[O:41]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:14][CH2:15][C:16](=[O:17])[C:18]2[S:19][C:20]([CH3:29])=[C:21]3[CH2:26][C:25]([CH3:27])([CH3:28])[CH2:24][CH2:23][C:22]=23)[CH:5]=[C:6]([O:12][CH3:13])[C:7]=1[O:8][CH2:9][CH2:10][O:11][S:40]([CH3:39])(=[O:42])=[O:41]
Reactant: COc1cc(CCC(=O)c2sc(C)c3c2CCC(C)(C)C3)cc(Cl)c1OCCO
Reactant: CS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1cc(CCC(=O)c2sc(C)c3c2CCC(C)(C)C3)cc(Cl)c1OCCOS(C)(=O)=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 88.8 %

Procedure:
To a solution of 3-[3-chloro-4-(2-hydroxyethoxy)-5-methoxy-phenyl]-1-(3,5,5-trimethyl-4,5,6,7-tetrahydro-benzo[c]thiophen-1-yl)-propan-1-one (160 mg, 0.40 mmol) in DCM (10 mL) and DIPEA (0.11 mL, 0.64 mmol) is added methane sulfonylchloride (0.04 mL, 0.48 mmol) at 0° C. The reaction mixture is stirred at 0° C. for 30 min. The reaction mixture is diluted with DCM, washed with 0.1 N aq. NaOH followed by 10% aq. citric acid solution, dried over MgSO4 and evaporated to give methanesulfonic acid 2-{2-chloro-6-methoxy-4-[3-oxo-3-(3,5,5-trimethyl-4,5,6,7-tetrahydro-benzo[c]thiophen-1-yl)-propyl]-phenoxy}-ethyl ester (183 mg) as a yellow oil; LC-MS: tR=1.15 min, [M+1]+=515.15.
Reaction SMILES: [OH:1][C:2]1([C:18]([F:21])([F:20])[F:19])[CH2:6][S:5][C:4]([NH:7][C:8]2[CH:9]=[C:10]([C:14]([O:16][CH3:17])=O)[S:11][C:12]=2[CH3:13])=[N:3]1.NC(NC1C=C(C(OC)=S)SC=1C)=[S:24].BrCC(C(F)(F)F)=O>>[OH:1][C:2]1([C:18]([F:21])([F:20])[F:19])[CH2:6][S:5][C:4]([NH:7][C:8]2[CH:9]=[C:10]([C:14]([O:16][CH3:17])=[S:24])[S:11][C:12]=2[CH3:13])=[N:3]1
Reactant: COC(=S)c1cc(NC(N)=S)c(C)s1
Reactant: COC(=O)c1cc(NC2=NC(O)(C(F)(F)F)CS2)c(C)s1
Agent: O=C(CBr)C(F)(F)F
Product: COC(=S)c1cc(NC2=NC(O)(C(F)(F)F)CS2)c(C)s1
Yield: 54 %

Procedure:
Methyl 4-{[4-hydroxy-4-(trifluoromethyl)(1,3-thiazolin-2-yl)]amino}-5-methylthiophene-2-carboxylate: Using a procedure similar to Example 204, step (a), 56 mg (0.21 mmol) of methyl 4-[(aminothioxomethyl)amino]-5-methylthiothiophene-2-carboxylate was allowed to react with 40 mg (0.21 mmol) of bromotrifluoroacetone (Aldrich Chemical Co., Milwaukee, Wis.) to afford 40.3 mg (54%) of methyl 4-{[4-hydroxy-4-(trifluoromethyl)(1,3-thiazolin-2-yl)]amino}-5-methylthiothiophene-2-carboxylate. Mass spectrum (ESI, m/z): Calcd. for C11H11F3N2O3S3, 373.00 (M+H), found 373.0.
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][CH2:16][CH2:17][CH3:18])=[O:14].[F:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH3:27])[C:21]=1B(O)O>>[NH2:1][C:2]1[C:11]2[C:6](=[C:7]([C:21]3[C:22]([O:26][CH3:27])=[CH:23][CH:24]=[CH:25][C:20]=3[F:19])[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH2:16][CH2:17][CH3:18])=[O:14]
Reactant: COc1cccc(F)c1B(O)O
Reactant: CCCNC(=O)c1nnc2c(Br)cccc2c1N
Product: CCCNC(=O)c1nnc2c(-c3c(F)cccc3OC)cccc2c1N
Yield: 42.5 %

Procedure:
Using method A, 4-amino-8-bromo-N-propyl-cinnoline-3-carboxamide (150 mg, 0.485 mmol) and 2-fluoro-6-methoxy-phenylboronic acid (170 mg, 1.000 mmol) were reacted to afford the title compound (73 mg, 42% yield) as a white solid. 1H NMR (300 MHz, CDCl3) δ 8.54 (br, 1H), 7.93 (m, 1H), 7.78-7.69 (m, 2H), 7.42-7.31 (m, 1H), 6.89-6.80 (m, 2H), 3.70 (s, 3H), 3.44 (apparent quartet, J=7.0 Hz, 2H), 1.64 (apparent sextet, J=7.0 Hz, 2H), 0.99 (t, J=7.0 Hz, 3H). MS APCI, m/z=355 (M+H). HPLC 1.68 min.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][N:10]=1)[C:5]([OH:7])=O.[CH:11]([N:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1)([CH3:13])[CH3:12]>>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]([N:17]2[CH2:18][CH2:19][N:14]([CH:11]([CH3:13])[CH3:12])[CH2:15][CH2:16]2)=[O:7])[CH:8]=[CH:9][N:10]=1
Reactant: O=C(O)c1ccnc(Cl)c1
Reactant: CC(C)N1CCNCC1
Product: CC(C)N1CCN(C(=O)c2ccnc(Cl)c2)CC1

Procedure:
The title compound was prepared in a manner similar to that described in Step A of Example 9 using 2-chloro-isonicotinic acid and 1-isopropyl-piperazine.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10]([CH3:12])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[CH2:13]([NH2:16])[CH2:14][CH3:15].C(=O)([O-])[O-].[Na+].[Na+].Cl>C(OCC)C.C(O)C>[ClH:1].[CH3:7][O:6][C:4](=[O:5])[C:3]1[CH:8]=[CH:9][C:10]([CH3:12])=[N:11][C:2]=1[NH:16][CH2:13][CH2:14][CH3:15]
Reactant: CCCN
Reactant: COC(=O)c1ccc(C)nc1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CCO
Product: CCCNc1nc(C)ccc1C(=O)OC

Procedure:
A stirred mixture of 37.1 g. (0.2 mole) of methyl 2-chloro-6-methyl-nicotinate, 11.8 g. (0.02 mole) of propylamine and 21.2 g. (0.02 mole) of sodium carbonate in 200 ml. of ethanol was heated under reflux for 5 hours. The mixture was filtered and the filtrate was evaporated in a rotary evaporator. The residue was triturated with 200 ml. of water and was extracted with 100 ml. of diethyl ether. The ether layer was dried over magnesium sulfate, filtered and was evaporated to give 31 g. of an oil. A small amount of this oil was dissolved in diethyl ether and was acidified with an etheral hydrochloric acid solution. On cooling, the oil which separated crystallized to yield 6-methyl-2-propylaminonicotinic acid methyl ester, hydrochloride. The solid was collected and was recrystallized from ethyl acetate to give the analytical sample, m.p. 113°-15° C.
Reaction SMILES: Br[CH2:2][C:3]([CH:5]1[CH2:10][CH2:9][N:8]([C:11](=[O:18])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:7][CH2:6]1)=O.[NH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=1>C(O)C>[C:11]([N:8]1[CH2:9][CH2:10][CH:5]([C:3]2[N:19]=[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][N:21]3[CH:2]=2)[CH2:6][CH2:7]1)(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C(CBr)C1CCN(C(=O)c2ccccc2)CC1
Reactant: Nc1ccccn1
Solvent: CCO
Product: O=C(c1ccccc1)N1CCC(c2cn3ccccc3n2)CC1
Yield: 49.5 %

Procedure:
To a solution of 160 mg of 2-bromo-1-(1-benzoyl-4-piperidyl)-1-ethanone (prepared in analogy with Example 523, Step A) in 6 mL ethanol was added 59 mg of 2-aminopyridine. After refluxing for 18 hours, the solvent was evaporated. The mixture was partitioned between EtOAc and saturated sodium bicarbonate solution. Aqueous layer was extracted with EtOAc (3×). The combined organic phase was washed with brine, dried over MgSO4 and concentrated. The residue was purified by flash chromatography with 100% EtOAc followed by 10% MeOH in EtOAc to give 78 mg of a solid: 1H NMR (500 MHz, CDCl3) δ1.80 (d, 2H), 2.16 (d, 2H), 3.17 (m, 3H), 3.87 (br, 1H), 4.85 (br, 1H), 6.76 (t, J=6.8 Hz,1H). 7.15 (m,1H), 7.37(s, 1H), 7.42(m, 5H), 7. 55(d, J=9.1 Hz, 1H), 8.08 (d, J=6.9 Hz,1H).
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[CH:24][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=[C:16]3[S:20][C:19](SC)=[N:18][C:17]3=[O:23])=[CH:12][CH:13]=2)[CH:8]=[N:7]1.[CH2:34]([N:36]1[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1)[CH3:35]>>[F:1][C:2]([F:32])([F:33])[C:3]1[CH:27]=[C:26]([C:28]([F:31])([F:29])[F:30])[CH:25]=[CH:24][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=[C:16]3[S:20][C:19]([N:39]4[CH2:40][CH2:41][N:36]([CH2:34][CH3:35])[CH2:37][CH2:38]4)=[N:18][C:17]3=[O:23])=[CH:12][CH:13]=2)[CH:8]=[N:7]1
Reactant: CSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(C(F)(F)F)cc3C(F)(F)F)c2)S1
Reactant: CCN1CCNCC1
Product: CCN1CCN(C2=NC(=O)C(=Cc3ccc4c(cnn4Cc4ccc(C(F)(F)F)cc4C(F)(F)F)c3)S2)CC1

Procedure:
5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(4-ethyl-piperazin-1-yl)-thiazol-4-one was prepared from 5-[1-(2,4-bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-methylsulfanyl-thiazol-4-one and 1-ethyl-piperazine following General Procedure C.