Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([OH:13])[CH:8]=[CH:9][C:10]=2[Cl:12])[N:5]=[CH:4][N:3]=1.O.C([O-])(O)=O.[Na+].[CH:20]([OH:23])([CH3:22])[CH3:21]>>[Cl:12][C:10]1[CH:9]=[CH:8][C:7]([OH:13])=[C:6]2[C:11]=1[C:2]([O:23][CH:20]([CH3:22])[CH3:21])=[N:3][CH:4]=[N:5]2
Reactant: Oc1ccc(Cl)c2c(Cl)ncnc12
Reactant: CC(C)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: CC(C)Oc1ncnc2c(O)ccc(Cl)c12
Temperature: 25 °C

Procedure:
A mixture of 4,5-dichloro-8-quinazolinol (3.0 g, 13.95 mmol) in isopropanol is heated at reflux for 30 minutes, cooled to room temperature and filtered to obtain a solid. The solid is mixed with water and saturated NaHCO3 solution. The resultant mixture is filtered and the filter cake is washed with water and dried to give the title product as an off-white solid, 1.71 g, mp 126°-126.5° C.
Reaction SMILES: [CH3:1][N:2](/[CH:4]=[C:5]1/[C:6](=O)[CH2:7][N:8]([C:10]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:9]/1)C.[CH3:30][C:31]1[CH:35]=C(N)[NH:33][N:32]=1.CC1C=C2N=C3CN(C(OC(C)(C)C)=O)CC3=CN2N=1>C(O)C>[CH3:35][C:31]1[CH:30]=[C:1]2[N:2]=[CH:4][C:5]3[CH2:9][N:8]([C:10]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)([C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=4)[C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH2:7][C:6]=3[N:33]2[N:32]=1
Reactant: CN(C)/C=C1\CN(C(c2ccccc2)(c2ccccc2)c2ccccc2)CC1=O
Reactant: Cc1cc(N)[nH]n1
Agent: Cc1cc2nc3c(cn2n1)CN(C(=O)OC(C)(C)C)C3
Solvent: CCO
Product: Cc1cc2ncc3c(n2n1)CN(C(c1ccccc1)(c1ccccc1)c1ccccc1)C3
Temperature: 25 °C

Procedure:
To a solution of 383 mg (1 mmol) of (4E)-4-[(dimethylamino)methylene]-1-tritylpyrrolidin-3-one in anhydrous ethanol (3 mL) was added 116 mg (1.2 mmol) of 3-methyl-1H-pyrazol-5-amine and the reaction mixture refluxed for 48 h. The mixture was cooled to ambient temperature and the solvent evaporated in vacuo to afford a 10:1 mixture of the title compound and tert-butyl 2-methyl-5H-pyrazolo[1,5-a]pyrrolo[3,4-d]pyrimidine-6(7H)-carboxylate. The resulting regioisomers were chromatographed on a Biotage Horizon® system (silica gel, 2 to 3% methanol/methylene chloride gradient) to yield the title compound and its regioisomer as tan solids. LC/MS 417.1 (M+1).
Reaction SMILES: [NH:1]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C@H:2]([C:10](O)=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[F-:20].N1C=CC=CC=1>C(Cl)Cl>[NH:1]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C@H:2]([C:10]([F:20])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: [F-]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)F

Procedure:
BOC-Phe (1 mmole) in dry CH2Cl2 under nitrogen is treated with cyannuric fluoride (8 mmol) and pyridine (1 mmole) to form the above-identified product.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH3:24])=[CH:5][C:6]=1[C:7](=[O:23])[C:8]1[CH:13]=[C:12]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:11]([OH:18])=[C:10]([C:19]([CH3:22])([CH3:21])[CH3:20])[CH:9]=1.[CH2:25](Cl)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[CH2:25]([N:3]1[C:4]([CH3:24])=[CH:5][C:6]([C:7](=[O:23])[C:8]2[CH:13]=[C:12]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:11]([OH:18])=[C:10]([C:19]([CH3:22])([CH3:21])[CH3:20])[CH:9]=2)=[C:2]1[CH3:1])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: ClCc1ccccc1
Reactant: Cc1cc(C(=O)c2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)c(C)[nH]1
Product: Cc1cc(C(=O)c2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)c(C)n1Cc1ccccc1

Procedure:
Likewise, using 2,5-dimethyl-3-(3,5-di-t-butyl-4-hydroxybenzoyl)pyrrole as compound "E" in this general reaction with benzyl chloride as "R--X" yields N-benzyl-2,5-dimethyl-3-(3,5-di-t-butyl-4-hydroxybenzoyl)pyrrole (a compound according to Formula X wherein: m is 0; n is 1; R is benzyl; Y is H; and X and Z are each methyl).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5](Cl)=[N:6][CH:7]=1.[CH3:9][C:10]1[NH:11][CH:12]=[C:13]([CH3:15])[N:14]=1.C([O-])([O-])=O.[K+].[K+].O>CN1C(=O)CCC1.CCOC(C)=O>[Br:1][C:2]1[CH:3]=[N:4][C:5]([N:11]2[CH:12]=[C:13]([CH3:15])[N:14]=[C:10]2[CH3:9])=[N:6][CH:7]=1
Reactant: Cc1c[nH]c(C)n1
Reactant: Clc1ncc(Br)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN1CCCC1=O
Product: Cc1cn(-c2ncc(Br)cn2)c(C)n1
Temperature: 80 °C
Reaction time: 8 h
Yield: 51 %

Procedure:
To a solution of 5-bromo-2-chloropyrimidine (0.3 g, 1.55 mmol) in NMP (15 mL) were added 2,4-dimethyl-1H-imidazole (0.224 g, 2.2 mmol) and K2CO3 (0.43 g, 3.1 mmol). The resulting solution was stirred at 80° C. overnight. After water (50 mL) and EtOAc (50 mL) were added, the mixture was extracted with EtOAc (3×50 mL). The combined organic layer was washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by pre-TLC to afford 5-bromo-2-(2,4-dimethyl-1H-imidazol-1-yl)-pyrimidine (0.2 g, 51%).
Reaction SMILES: [OH-].[Na+:2].[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([NH:14][C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23]3[CH:24]=[N:25][C:26]4[C:31]([CH:32]=3)=[CH:30][CH:29]=[CH:28][CH:27]=4)[CH:18]=2)=[O:16])=[C:8]([CH:13]=1)[C:9]([O:11]C)=[O:10]>C1COCC1>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([NH:14][C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23]3[CH:24]=[N:25][C:26]4[C:31]([CH:32]=3)=[CH:30][CH:29]=[CH:28][CH:27]=4)[CH:18]=2)=[O:16])=[C:8]([CH:13]=1)[C:9]([O-:11])=[O:10].[Na+:2]
Reactant: COC(=O)c1cc(Cl)ccc1NC(=O)c1cccc(-c2cnc3ccccc3c2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(Nc1ccc(Cl)cc1C(=O)[O-])c1cccc(-c2cnc3ccccc3c2)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 77 %

Procedure:
10 mL of THF and 1.3 mL of 1N aqueous sodium hydroxide solution were added to 340 mg (0.816 mmol) of methyl 5-chloro-2-({[3-(quinolin-3-yl)phenyl]carbonyl}amino)benzoate, and the mixture was stirred at room temperature for 1 day. The mixture was further stirred at 50° C. for 1 hour. THF was distilled off under reduced pressure, and water was added. Water-washing was then conducted, thereby giving 360 mg of the target sodium 5-chloro-2-({[3-(quinolin-3-yl)phenyl]carbonyl}amino)benzoate (yield: 77%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[C:9]([CH:11]=[CH:12][C:13](=[O:20])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:8]=[CH:7][C:4]=1[CH:5]=O.C(OP([CH2:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])(OCC)=O)C.[H-].[Na+]>C1COCC1>[C:33]([O:32][C:30](=[O:31])[CH:29]=[CH:5][C:4]1[CH:7]=[CH:8][C:9]([CH:11]=[CH:12][C:13](=[O:20])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:10][C:3]=1[O:2][CH3:1])([CH3:36])([CH3:35])[CH3:34]
Reactant: CCOP(=O)(CC(=O)OC(C)(C)C)OCC
Reactant: COc1cc(C=CC(=O)c2ccccc2)ccc1C=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cc(C=CC(=O)c2ccccc2)ccc1C=CC(=O)OC(C)(C)C
Yield: 84.2 %

Procedure:
2-methoxy-4-(3-oxo-3-phenyl-propenyl)-benzaldehyde (550 mg, 2.07 mmol) was dissolved in THF (5 ml) and the resulting solution was added to a stirring mixture of tert-butyl diethylphosphonoacetate (603 mg, 2.27 mmol) and NaH (107 mg, 2.69 mmol, 60% oil dispersion) in THF (5 ml). After 15 minutes the reaction was quenched by the addition of water and partitioned between water and EtOAc. The organic extract was dried over Na2SO4 and evaporated under vacuo giving a crude that was purified by silica gel chromatography (EtOAc/petroleum ether 1:6). The collected fraction gave 635 mg of 3-[2-methoxy-4-(3-oxo-3-phenyl-propenyl)-phenyl]-acrylic acid tert-butyl ester as a yellow oil.
Reaction SMILES: FC(F)(F)C(O)=O.[F:8][C:9]1[CH:10]=[N:11][CH:12]=[C:13]([CH:18]=1)[C:14](Cl)=[N:15][OH:16].[C:19]([C:21]1[CH:22]=[C:23]([CH:25]=[CH:26][CH:27]=1)[NH2:24])#[CH:20].N>>[F:8][C:9]1[CH:18]=[C:13]([C:14]2[CH:20]=[C:19]([C:21]3[CH:22]=[C:23]([CH:25]=[CH:26][CH:27]=3)[NH2:24])[O:16][N:15]=2)[CH:12]=[N:11][CH:10]=1
Reactant: C#Cc1cccc(N)c1
Reactant: ON=C(Cl)c1cncc(F)c1
Agent: N
Solvent: O=C(O)C(F)(F)F
Product: Nc1cccc(-c2cc(-c3cncc(F)c3)no2)c1

Procedure:
The titled compound was prepared as the trifluoroacetic acid salt according to Method CD using the product of Example 28B (88 mg, 0.5 mmol) and 3-ethynylaniline (Aldrich, 59 mg, 0.5 mmol). 1H NMR (300 MHz, MeOH-d4) δ 6.82-6.91 (m, 1H), 7.13-7.49 (m, 4H), 8.16 (dt, J=9.2, 2.2 Hz, 1H), 8.60 (d, J=2.7 Hz, 1 H), 8.96 (s, 1H) ppm; MS (DCI/NH3) m/z 256 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[NH:13][CH:14]=2)[CH:5]=[CH:4][N:3]=1.F[C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[N:18]=1>>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[N:13]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[N:18]=3)[CH:14]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Fc1cccc(C(F)(F)F)n1
Reactant: Cc1nc(C#Cc2ccnc(Cl)c2)c[nH]1
Product: Cc1nc(C#Cc2ccnc(Cl)c2)cn1-c1cccc(C(F)(F)F)n1

Procedure:
The title compound, MS: m/e=363.1.1 (M+H+), was prepared in accordance with the general method of example 3 from 2-chloro-4-(2-methyl-1H-imidazol-4-ylethynyl)-pyridine and 2-fluoro-6-(trifluoromethyl)pyridine.
Reaction SMILES: C[Si](Br)(C)C.[CH2:6]([O:8][CH2:9][N:10]1[C:18]2[C:17](=[O:19])[N:16]([CH2:20][CH2:21][CH2:22][CH2:23][P:24](=[O:27])([O-:26])[O-:25])[C:15](=[O:28])[N:14]([CH3:29])[C:13]=2[N:12]=[CH:11]1)[CH3:7].CO.[NH3:32]>ClCCl>[CH2:6]([O:8][CH2:9][N:10]1[C:18]2[C:17](=[O:19])[N:16]([CH2:20][CH2:21][CH2:22][CH2:23][P:24](=[O:25])([O-:27])[O-:26])[C:15](=[O:28])[N:14]([CH3:29])[C:13]=2[N:12]=[CH:11]1)[CH3:7].[NH4+:32].[NH4+:10]
Reactant: N
Agent: CCOCn1cnc2c1c(=O)n(CCCCP(=O)([O-])[O-])c(=O)n2C
Agent: C[Si](C)(C)Br
Solvent: CO
Solvent: ClCCl
Product: [NH4+]
Temperature: 0 °C
Reaction time: 2 h

Procedure:
3.4 ml (0.026 mol) of trimethylsilyl bromide were slowly added dropwise at 0° C., under an argon atmosphere, to a solution of 4.16 g (0.01 mol) of [4-(7-ethoxymethyl-3-methylxanthin-1-yl)butyl]phosphonate in 5 ml of dichloromethane. The solution was stirred at 0° C. for 1 hour and at room temperature for 2 hours. The dichloromethane was then evaporated and the oily residue which remained was dried in a bulb tube in an oil pump vacuum to remove excess trimethylsilyl bromide and ethyl bromide formed. The residue was taken up in a little methanol and treated with 1 ml of concentrated ammonia solution and stirred at room temperature for 2 hours. After evaporating the solvent, the diammonium salt was crystallized from a methanoltdiisopropyl ether mixture.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[C:5]2[CH:11]1[CH2:14][CH2:13][CH2:12]1.[H-].[Na+].Cl[CH2:18][C:19]#[N:20]>>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:18][C:19]#[N:20])[N:6]=[C:5]2[CH:11]1[CH2:14][CH2:13][CH2:12]1
Reactant: Brc1ccc2[nH]nc(C3CCC3)c2c1
Reactant: N#CCCl
Agent: [H-]
Agent: [Na+]
Product: N#CCn1nc(C2CCC2)c2cc(Br)ccc21
Yield: 61.4 %

Procedure:
The title compound was prepared by the method outlined for Preparative Example 59 using 5-bromo-3-cyclobutyl-1H-indazole intermediate (225 mg, 0.898 mmol), NaH (41 mg, 1.02 mmol), and chloroacetonitrile (78 mg, 1.03 mmol) to afford titled compound as an off-white solid (160 mg, 62%). 1H NMR (DMSO-d6) 7.99 (s, 1H), 7.72 (d, J=8.8, 1H), 7.62 (d, J=8.8, 1H), 5.74 (s, 2H), 3.91 (pent, J=8.8, 1H), 2.38-2.32 (m, 4H), 2.08-2.06 (m, 1H), 1.95 (m, 1H). LC/MS (Method B) 3.99 min, [M+1]+ 290/292].
Reaction SMILES: [Si:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:17]([C:19]3[CH:20]=[CH:21][C:22]([Cl:36])=[C:23]([S:25]([NH:28][Si:29]([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:31])[CH3:30])(=[O:27])=[O:26])[CH:24]=3)=[O:18])[CH:15]=2)[CH:10]=[CH:9]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Br:37]N1C(=O)CCC1=O>O1CCCC1.C(OCC)C>[Br:37][C:10]1[C:11]2[C:16](=[CH:15][C:14]([C:17]([C:19]3[CH:20]=[CH:21][C:22]([Cl:36])=[C:23]([S:25]([NH:28][Si:29]([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:30])[CH3:31])(=[O:27])=[O:26])[CH:24]=3)=[O:18])=[CH:13][CH:12]=2)[N:8]([Si:1]([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2])[CH:9]=1
Reactant: CC(C)(C)[Si](C)(C)NS(=O)(=O)c1cc(C(=O)c2ccc3ccn([Si](C)(C)C(C)(C)C)c3c2)ccc1Cl
Reactant: O=C1CCC(=O)N1Br
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)(C)[Si](C)(C)NS(=O)(=O)c1cc(C(=O)c2ccc3c(Br)cn([Si](C)(C)C(C)(C)C)c3c2)ccc1Cl
Reaction time: 6 h

Procedure:
A solution of 1.7 g of 5-[1-(tert-butyldimethylsilyl)-1H-indole-6-carbonyl]-2-chloro-N-(tert-butyldimethylsilyl)-benzenesulfonamide in tetrahydrofuran (110 mL) at −78° C. is treated with 0.564 g of N-bromosuccinimide. After 6 h at −78° C. the temperature is allowed to reach room temperature. The reaction mixture is taken up in diethyl ether, washed with water and dried (magnesium sulfate). The solvent is evaporated and the residue is triturated under sonication with diisopropylether to give 5-[3-bromo-1-(tert-butyldimethylsilyl)-1H-indole-6-carbonyl]-2-chloro-N-(tert-butyldimethylsilyl)-benzenesulfonamide as a tan powder. MS (m/z): 643 (M+1); Rf 0.90 (95:5 methylene chloride/methanol).
Reaction SMILES: [CH:1]1([N:7]([CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[C:8]([NH:10][C:11]2[S:12][C:13]([CH:16]=O)=[CH:14][N:15]=2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[CH3:25][S:26]([N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1)(=[O:28])=[O:27].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[CH:1]1([N:7]([CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[C:8]([NH:10][C:11]2[S:12][C:13]([CH2:16][N:32]3[CH2:33][CH2:34][N:29]([S:26]([CH3:25])(=[O:28])=[O:27])[CH2:30][CH2:31]3)=[CH:14][N:15]=2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=Cc1cnc(NC(=O)N(C2CCCCC2)C2CCCCC2)s1
Reactant: CS(=O)(=O)N1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Product: CS(=O)(=O)N1CCN(Cc2cnc(NC(=O)N(C3CCCCC3)C3CCCCC3)s2)CC1
Yield: 38.6 %

Procedure:
Prepared as described in general procedure (P) using 1,1-dicyclohexyl-3-(5-formyl-thiazol-2-yl)-urea (50 mg, 0.15 mmol), 4-methanesulfonyl-piperazine hydrochloride (45 mg, 0.23 mmol) and sodium triacetoxyborohydride (40 mg, 0.19 mmol) to afford 28 mg (38%) of the desired product after purification.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[CH2:8][CH:9]([C:11]1[C:12](F)=[N:13][CH:14]=[CH:15][CH:16]=1)[OH:10].CC(C)([O-])C.[K+].[Na+].[Cl-].O.Cl>C1COCC1>[N:13]1[C:12]2[NH:1][C:2]3[CH:7]=[CH:6][N:5]=[CH:4][C:3]=3[CH2:8][CH:9]([OH:10])[C:11]=2[CH:16]=[CH:15][CH:14]=1
Reactant: Nc1ccncc1CC(O)c1cccnc1F
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: O
Product: OC1Cc2cnccc2Nc2ncccc21
Temperature: -78 °C
Reaction time: 3 h
Yield: 89.9 %

Procedure:
2-(4-Aminopyridin-3-yl)-1-(2-fluoropyridin-3-yl)ethanol (6.00 mmol, Intermediate D-4) was dissolved in THF (200 mL) under an atmosphere of nitrogen. The solution was cooled to −78° C., then a solution of potassium tert-butoxide (36.0 mL, 1.0 M in THF, 36.0 mmol) was added dropwise. The mixture turned orange/red, then became darker brown. After the addition, the mixture was slowly warmed to 0° C. After stirring for 3 hours at 0° C., the reaction mixture was poured into a cold solution of saturated NaCl/water and HCl (2.0 mL, 12 M, 24 mmol) and stirred (pH ˜13) and then extracted 3× with ethyl acetate. The combined extracts were washed with brine, dried over Na2SO4, filtered, and concentrated. The crude product was adsorbed onto silica gel and then chromatographed on silica gel eluting with 10% methanol/CH2Cl2 to give the desired product as a white solid (1.15 g, 89%).
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]1[CH2:11][C:10]([C:12]#[C:13][Si](C)(C)C)=[CH:9][CH:8]1[C:18]([O:20]C)=O)=[O:6])[CH:2]=[CH2:3].[BH4-].[Na+].C(O)(=[O:26])C>O1CCCC1.C(O)C.C(OCC)(=O)C.O>[CH2:1]([O:4][C:5]([N:7]1[CH2:11][C:10]([C:12](=[O:26])[CH3:13])=[CH:9][CH:8]1[CH2:18][OH:20])=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)N1CC(C#C[Si](C)(C)C)=CC1C(=O)OC
Reactant: CC(=O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: O
Product: C=CCOC(=O)N1CC(C(C)=O)=CC1CO
Temperature: 5 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1-allyloxycarbonyl-2-methoxycarbonyl-4-trimethylsilylethynyl-3-pyrroline (2.9 g) in tetrahydrofuran (9 ml) and ethanol (36 ml), previously cooled to 5° C., was slowly added sodium borohydride (713 mg) while the internal temperature was maintained below 10° C. The mixture was stirred at 5° C. for 30 minutes and, then, at room temperature for one hour. After decomposition of the sodium borohydride with addition of a small amount of acetic acid, the reaction mixture was diluted with ethyl acetate and water. The aqueous layer was extracted with ethyl acetate twice. The organic layers were combined, washed successively with 1N hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution, water and aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. The solvent was then distilled off under reduced pressure. To the residue were added tetrahydrofuran (26 ml), water (5 ml), mercuric sulfate (280 mg) and sulfuric acid (2 drops) and the mixture was stirred at room temperature for 1 day. After completion of the reaction, saturated aqueous sodium hydrogen carbonate solution and ethyl acetate were added. The aqueous layer was then separated and extracted with ethyl acetate twice. The organic layers were combined, washed successively with 1N hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution, water and aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. Finally the solvent was distilled off under reduced pressure to give 1-allyloxycarbonyl-4-acetyl-2-hydroxymethyl-3-pyrroline (2.50 g).
Reaction SMILES: [C:1](Cl)(=[O:6])[CH:2]=[CH:3][CH2:4][CH3:5].[CH3:8][C:9]1[C@H:14]2[C:15]([CH3:17])([CH3:16])[C@H:12]([CH2:13]2)[CH2:11][CH:10]=1>C(Cl)CCl.[Cl-].[Zn+2].[Cl-]>[CH2:4]([CH:3]1[C:12]2([C:15]([CH3:17])=[CH2:16])[CH2:13][CH:14]([C:9]([CH3:8])=[CH:10][CH2:11]2)[C:1](=[O:6])[CH2:2]1)[CH3:5]
Reactant: CCC=CC(=O)Cl
Reactant: CC1=CC[C@H]2C[C@@H]1C2(C)C
Agent: [Cl-]
Agent: [Zn+2]
Solvent: ClCCCl
Product: C=C(C)C12CC=C(C)C(C1)C(=O)CC2CC
Temperature: 30 °C
Reaction time: 0.5 h
Yield: 12.9 %

Procedure:
At 30° C., a mixture of 7.35 g of 2-pentenoyl chloride (62 mmol) and 1.7 g of zinc chloride (12 mmol, 0.2 eq.) in 85 ml ethylene chloride was treated dropwise within 20 min. with a solution of 19.4 g of (−)-alpha-pinene (142 mmol, 2 eq.) in 20 ml ethylene dichloride. The reaction mixture was then stirred at 30° C. for 30 min., then at 50° C. for 2 h, and finally at 80° C. for 1 h. After cooling, the reaction mixture was washed with aq. sat. NaCl soln. and aq. sat. NaHCO3 soln. The aq. phases were extracted with Et2O, dried (Na2SO4), and concentrated. FC (SiO2, hexane/Et2O 20:1) of the crude (26 g) gave 1.74 g (13%) of compound 2. The boiling point of the end product is 95° C. at 0.06 torr (0.08 mbar).
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20](SCC)=[N:19][C:18]4=[O:25])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:28]([F:31])([F:30])[F:29])[CH:3]=1.[F:32][CH:33]([F:41])[CH2:34][N:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1>>[Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20]([N:38]5[CH2:39][CH2:40][N:35]([CH2:34][CH:33]([F:41])[F:32])[CH2:36][CH2:37]5)=[N:19][C:18]4=[O:25])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:28]([F:30])([F:29])[F:31])[CH:3]=1
Reactant: FC(F)CN1CCNCC1
Reactant: CCSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Product: O=C1N=C(N2CCN(CC(F)F)CC2)SC1=Cc1ccc2c(cnn2Cc2ccc(Cl)cc2C(F)(F)F)c1

Procedure:
5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-[4-(2,2-difluoro-ethyl)-piperazin-1-yl]-thiazol-4-one was prepared from 5-[1-(4-chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazol-4-one and 1-(2,2-difluoro-ethyl)piperazine following General Procedure C.
Reaction SMILES: C1(C)C=CC(S([O-])(=O)=O)=CC=1.[CH3:12][C:13]1[S:14][C:15]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[C:16]([CH3:20])[N+:17]=1[CH2:18][CH3:19].[Cl:26][C:27]([Cl:38])([Cl:37])[C:28]1[CH:36]=[CH:35][C:31]([C:32](Cl)=[O:33])=[CH:30][CH:29]=1>>[Cl:26][C:27]([Cl:37])([Cl:38])[C:28]1[CH:36]=[CH:35][C:31]([C:32]([CH:12]=[C:13]2[N:17]([CH2:18][CH3:19])[C:16]([CH3:20])=[C:15]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[S:14]2)=[O:33])=[CH:30][CH:29]=1
Reactant: O=C(Cl)c1ccc(C(Cl)(Cl)Cl)cc1
Reactant: CCOC(=O)c1sc(C)[n+](CC)c1C
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Product: CCOC(=O)C1=C(C)N(CC)C(=CC(=O)c2ccc(C(Cl)(Cl)Cl)cc2)S1

Procedure:
Analogous to Preparation Example 1 B, the 2,4-dimethyl-3-ethyl-5-ethoxycarbonyl-thiazolium p-toluene-sulfonate is reacted with p-trichloromethylbenzoyl chloride to give 2-(p-trichloromethyl-benzoylmethylene)-3-ethyl-4-methyl-5-ethoxycarbonylthiazoline.
Reaction SMILES: [ClH:1].O1CCOCC1.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([C@H:15]([C:25]([N:27]2[CH2:32][CH2:31][N:30]([C:33]3[C:34]4[C@H:41]([CH3:42])[CH2:40][CH2:39][C:35]=4[N:36]=[CH:37][N:38]=3)[CH2:29][CH2:28]2)=[O:26])[CH2:16][NH:17]C(=O)OC(C)(C)C)=[CH:11][CH:10]=1>O1CCOCC1>[ClH:8].[ClH:1].[NH2:17][CH2:16][C@H:15]([C:12]1[CH:13]=[CH:14][C:9]([Cl:8])=[CH:10][CH:11]=1)[C:25]([N:27]1[CH2:28][CH2:29][N:30]([C:33]2[C:34]3[C@H:41]([CH3:42])[CH2:40][CH2:39][C:35]=3[N:36]=[CH:37][N:38]=2)[CH2:31][CH2:32]1)=[O:26]
Reactant: C[C@@H]1CCc2ncnc(N3CCN(C(=O)[C@H](CNC(=O)OC(C)(C)C)c4ccc(Cl)cc4)CC3)c21
Agent: Cl
Solvent: C1COCCO1
Product: C[C@@H]1CCc2ncnc(N3CCN(C(=O)[C@H](CN)c4ccc(Cl)cc4)CC3)c21
Temperature: 25 °C
Reaction time: 16 h
Yield: 157.4 %

Procedure:
4M HCl/dioxane (0.860 ml, 3.44 mmol) was added to a solution of tert-butyl (S)-2-(4-chlorophenyl)-3-(4-((R)-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-oxopropylcarbamate (0.043 g, 0.0860 mmol) in dioxane (1.2 mL). The reaction mixture was stirred at room temperature overnight (16 hours), after which it was concentrated and dried on high vacuum line. The resulting residue was dissolved in minimal MeOH, and the product was triturated by the addition of ether. The resulting solids were isolated by filtration through Varian quantitative membrane filter paper with nitrogen pressure, rinsed with ether, dried with nitrogen pressure, and further dried in vacuo to give (S)-3-amino-2-(4-chlorophenyl)-1-(4-((R)-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one dihydrochloride (0.032 g, 78.7% yield) as a white powder. LC/MS (APCI+) m/z 400 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.Br[CH2:9][C:10]([C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=1)=O.C(=O)(O)[O-].[Na+]>CCO>[N+:18]([C:15]1[CH:16]=[CH:17][C:12]([C:10]2[N:1]=[C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][N:3]3[CH:9]=2)=[CH:13][CH:14]=1)([O-:20])=[O:19]
Reactant: O=C(CBr)c1ccc([N+](=O)[O-])cc1
Reactant: Nc1ccccn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: O=[N+]([O-])c1ccc(-c2cn3ccccc3n2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 55.1 %

Procedure:
A mixture of 2-aminopyridine (0.20 g, 2.11 mmol) and 2-bromo-4′-nitroacetophenone (0.5 g, 2.05 mmol) in EtOH (25 ml) was heated under reflux for 18 h. The reaction mixture was allowed to cool and sodium bicarbonate (88 mg, 1.05 mmol) was added and heating was continued for 2 h. On cooling to room temperature, the solvent was removed under reduced pressure and the residue was dissolved in DCM (40 ml), washed with water (40 ml), and dried (Na2SO4). The solvent was removed under reduced pressure to give a brown solid which was purified by flash chromatography (15:1 DCM/MeOH) to give the title compound (0.27 g, 54%) as a yellow solid.