Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:11]=1)[C:6](Cl)=[O:7].[CH2:18]([N:25]1[CH2:30][CH2:29][NH:28][C@H:27]([CH2:31][C:32]2[CH:37]=[CH:36][C:35]([CH3:38])=[C:34]([O:39][CH3:40])[CH:33]=2)[CH2:26]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(N(CC)CC)C>ClCCl>[CH2:18]([N:25]1[CH2:30][CH2:29][N:28]([C:6](=[O:7])[C:5]2[CH:4]=[C:3]([C:2]([F:17])([F:16])[F:1])[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:9]=2)[C@H:27]([CH2:31][C:32]2[CH:37]=[CH:36][C:35]([CH3:38])=[C:34]([O:39][CH3:40])[CH:33]=2)[CH2:26]1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: COc1cc(C[C@@H]2CN(Cc3ccccc3)CCN2)ccc1C
Reactant: O=C(Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc(C[C@@H]2CN(Cc3ccccc3)CCN2C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)ccc1C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To an ice-cooled suspension of (3R)-1-benzyl-3-(3-methoxy-4-methylbenzyl)piperazine-2,5-dione (1.35 g) in tetrahydrofuran (22 ml) was added lithium aluminum hydride (0.378 g) at 5° C. or below under a nitrogen atmosphere. The mixture was stirred under reflux for 3 hours. After cooling the mixture to 5° C. or below, 2N sodium hydroxide was added to the mixture. After stirring the mixture for 30 minutes, insoluble matters were collected by filtration and washed with tetrahydrofuran. The filtrate and the washings were combined and the solvent was evaporated under reduced pressure to give (3R)-1-benzyl-3-(3-methoxy-4-methylbenzyl)piperazine in the form of an oily substance. A solution of 3,5-bis(trifluoromethyl)benzoyl chloride (0.80 ml) in dichloromethane (1 ml) was added dropwise to an ice-cooled solution of (3R)-1-benzyl-3-(3-methoxy-4-methylbenzyl)-piperazine obtained by the above process and triethylamine (0.84 ml) in dichloromethane (10 ml) at 5° C. or below over 5 minutes. After stirring at the same temperature for 30 minutes, the reaction mixture was washed with an aqueous sodium chloride solution and dried over magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography using a mixed solvent of hexane and ethyl acetate (4:1). Fractions containing the desired compound were collected and the solvent was evaporated under reduced pressure to give (2R)-4-benzyl-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(3-methoxy-4-methylbenzyl)-piperazine (1.92 g) in the form of an oily substance.
Reaction SMILES: O.[C:2]1([CH3:11])[CH:7]=[CH:6][C:5]([S:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[Na+].Br[CH2:14][CH2:15][CH:16]1[O:20][CH2:19][CH2:18][O:17]1.N>CN(C=O)C>[CH2:19]1[O:20][CH:16]([CH2:15][CH2:14][S:8]([C:5]2[CH:6]=[CH:7][C:2]([CH3:11])=[CH:3][CH:4]=2)(=[O:10])=[O:9])[O:17][CH2:18]1
Reactant: BrCCC1OCCO1
Reactant: Cc1ccc(S(=O)[O-])cc1
Agent: N
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(S(=O)(=O)CCC2OCCO2)cc1
Temperature: 0 °C
Yield: 65.9 %

Procedure:
A mixture of sodium 4-toluenesulphinate monohydrate (37.2 g, 0.19 mole) and 2-(2-bromoethyl)-1,3-dioxolane (20 ml, 0.17 mole) in dry DMF (100 ml) was stirred at room temperature for 64h, resulting in a homogenous solution. This was poured into ice/water (1 liter) containing conc. ammonia solution (100 ml) and stirred vigorously until a white precipitate formed. The solid was filtered off, washed with water, dried and recrystallised from propan-2-ol/ether to give the title compound (D24) as a white solid (28.7 g, 66%) m.p. 78°-80° C.
Reaction SMILES: O[C:2]1[N:7]=[CH:6][C:5]([C:8]([O:10][CH3:11])=[O:9])=[CH:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:17]1[S:18][CH:19]=[CH:20][CH:21]=1)CCC>C1(C)C=CC=CC=1.C(Cl)(Cl)Cl.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Pd]>[S:18]1[CH:19]=[CH:20][CH:21]=[C:17]1[C:2]1[N:7]=[CH:6][C:5]([C:8]([O:10][CH3:11])=[O:9])=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc(O)nc1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccs1
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: ClC(Cl)Cl
Product: COC(=O)c1ccc(-c2cccs2)nc1

Procedure:
A solution of 2.0 g of (methyl 6-hydroxypyridine-3-carboxylate, o-triflate) and 5.23 g of 2-(tributylstannyl)thiophene in 50 ml of dry toluene is stirred under nitrogen at reflux for 16 hours in the presence of tetrakis(triphenylphosphine)palladium(O). The reaction mixture is diluted with 50 ml of chloroform and filtered through a pad of diatomaceous earth. The filtrate is evaporated in vacuo to a residue which is extracted and decanted (2×100 ml) with 1:1 ether:petroleum ether. The combined extracts are evaporated in vacuo to give 1.6 g of the desired product as a residue.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][O:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14](=[O:47])[CH2:15][N:16]1[C:25](=[O:26])[C:24]2[N:23]([CH2:27][CH:28]=[C:29]([CH3:31])[CH3:30])[C:22]([N:32]3[CH2:37][CH2:36][CH2:35][CH:34]([NH:38]C(OC(C)(C)C)=O)[CH2:33]3)=[N:21][C:20]=2[N:19]([CH3:46])[C:17]1=[O:18])=[O:5])[CH3:2].FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([O:3][C:4]([CH2:6][O:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14](=[O:47])[CH2:15][N:16]1[C:25](=[O:26])[C:24]2[N:23]([CH2:27][CH:28]=[C:29]([CH3:30])[CH3:31])[C:22]([N:32]3[CH2:37][CH2:36][CH2:35][CH:34]([NH2:38])[CH2:33]3)=[N:21][C:20]=2[N:19]([CH3:46])[C:17]1=[O:18])=[O:5])[CH3:2]
Reactant: CCOC(=O)COc1ccccc1C(=O)Cn1c(=O)c2c(nc(N3CCCC(NC(=O)OC(C)(C)C)C3)n2CC=C(C)C)n(C)c1=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)COc1ccccc1C(=O)Cn1c(=O)c2c(nc(N3CCCC(N)C3)n2CC=C(C)C)n(C)c1=O
Temperature: 25 °C

Procedure:
A solution of 209 mg of 1-(2-{2-[(ethoxycarbonyl)methoxy]-phenyl}-2-oxo-ethyl)-3-methyl-7-(3-methyl-2-buten-1-yl)-8-[3-(tert.-butyloxycarbonylamino) -piperidin-1-yl]-xanthine in 4 ml methylene chloride is combined with 1 ml of trifluoroacetic acid and stirred for half an hour at ambient temperature. For working up the reaction mixture is diluted with methylene chloride and washed with saturated potassium carbonate solution. The organic phase is dried, evaporated down and chromatographed through a silica gel column with methylene chloride/methanol (1:0 to 4:1) as eluant.
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14])([CH3:4])([CH3:3])[CH3:2].[B-](F)(F)(F)F.CN(C(O[N:30]1[C:35](=[O:36])[CH2:34][CH2:33][C:31]1=[O:32])=[N+](C)C)C.CCN(C(C)C)C(C)C>C1COCC1>[O:32]=[C:31]1[CH2:33][CH2:34][C:35](=[O:36])[N:30]1[O:14][C:13](=[O:15])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:16]
Reactant: CN(C)C(ON1C(=O)CCC1=O)=[N+](C)C
Reactant: CC(C)(C)OC(=O)CCCCCCC(=O)O
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CCCCCCC(=O)ON1C(=O)CCC1=O

Procedure:
Octanedioic acid mono-tert-butyl ester (3.14 g, 13.63 mmol) was dissolved in THF (100 mL). TSTU (4.9 g, 16.3 mmol) was added and pH was adjusted to 8.5 with DIPEA (2.85 mL).
Reaction SMILES: [CH:1]12[CH2:10][CH:7]([CH2:8][CH2:9]1)[C:6]1[CH:5]=[C:4]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[NH:3][C:2]2=1.[H-].[Na+].Br[CH2:19][C:20]#[N:21].O>CN(C=O)C>[C:20]([CH2:19][N:3]1[C:4]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:5][C:6]2[CH:7]3[CH2:10][CH:1]([CH2:9][CH2:8]3)[C:2]1=2)#[N:21]
Reactant: N#CCBr
Reactant: CCOC(=O)c1cc2c([nH]1)C1CCC2C1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2c(n1CC#N)C1CCC2C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 72.9 %

Procedure:
Into a solution of 167c (3.0 g, 14.6 mmol) in anhydrous DMF (30 mL) was added NaH (880 mg, 22 mmol). The mixture was stirred at room temperature for 30 minutes. 2-Bromoacetonitrile (3.5 g, 29.3 mmol) was added and the resulting mixture was heated at 65° C. for 1 hour. It was then stirred at room temperature overnight. After reaction water (30 mL) was added and the resulting mixture was extracted with ethyl acetate (200 mL×3). The combined organic phase was evaporated under reduced pressure to dryness. The residue was purified by silica-gel column chromatography eluting with 20:1 methylene chloride/methanol to afford 167d as a brown solid (2.6 g, 72%). MS: [M+H]+ 245.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:23])[N:10]([C@H:12]2[CH2:17][CH2:16][C@H:15]([CH2:18][S:19][CH2:20][CH2:21]Cl)[CH2:14][CH2:13]2)[CH3:11])=[CH:4][CH:3]=1.[Na+].[I-].[CH2:26]([NH:28][CH2:29][CH2:30][OH:31])[CH3:27]>CC(N(C)C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:23])[N:10]([C@H:12]2[CH2:17][CH2:16][C@H:15]([CH2:18][S:19][CH2:20][CH2:21][N:28]([CH2:26][CH3:27])[CH2:29][CH2:30][OH:31])[CH2:14][CH2:13]2)[CH3:11])=[CH:4][CH:3]=1
Reactant: CCNCCO
Reactant: CN(C(=O)Oc1ccc(Cl)cc1)[C@H]1CC[C@H](CSCCCl)CC1
Agent: [I-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CCN(CCO)CCSC[C@H]1CC[C@H](N(C)C(=O)Oc2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 94 mg (0.25 mmol) of trans-[4-(2-Chloro-ethylsulfanylmethyl)-cyclohexyl]-methyl-carbamic acid 4-chloro-phenyl ester in 1 ml DMA was treated with a catalytic amount of NaI and with 0.05 ml (0.5 mmol) of 2-ethylaminoethanol and stirred at RT for 16 h. The reaction mixture was stirred for 1 week, adding every day twice 0.05 ml (0.5 mmol) of 2-ethylaminoethanol. The solution was concentrated and the residual oil was extracted with aqueous sat. NaHCO3/Et2O (3×). The organic phases were washed with aqueous 10% NaCl solution and dried over Na2SO4 to yield after flash column chromatography on silica gel (CH2Cl2/MeOH 95:5) 40 mg (39%) of trans-(4-{2-[Ethyl-(2-hydroxy-ethyl)-amino]-ethylsulfanylmethyl}-cyclohexyl)-methyl-carbamic acid 4-chloro-phenyl ester, MS: 429 (MH+, 1Cl).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[N:12]3[N:19]=[CH:20][C:21]([C:22]#[CH:23])=[C:11]3[N:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].Br[C:25]1[S:29][C:28]([S:30]([NH2:33])(=[O:32])=[O:31])=[CH:27][CH:26]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[C:13]([C:15]([F:16])([F:17])[F:18])[N:12]3[N:19]=[CH:20][C:21]([C:22]#[C:23][C:25]4[S:29][C:28]([S:30]([NH2:33])(=[O:32])=[O:31])=[CH:27][CH:26]=4)=[C:11]3[N:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: NS(=O)(=O)c1ccc(Br)s1
Reactant: C#Cc1cnn2c(C(F)(F)F)cc(-c3ccc(Cl)c(Cl)c3)nc12
Product: NS(=O)(=O)c1ccc(C#Cc2cnn3c(C(F)(F)F)cc(-c4ccc(Cl)c(Cl)c4)nc23)s1

Procedure:
The title compound was prepared from 5-(3,4-dichloro-phenyl)-3-ethynyl-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine (example C.9) (89 mg, 0.25 mmol) and 5-bromo-thiophene-2-sulfonic acid amide (61 mg, 0.25 mmol) according to general procedure II. Obtained as a yellow solid (42 mg, 32%). MS (ISP) 517.0 [(M+H)+]; mp 231–232° C.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].Br[C:8]1[S:9][CH:10]=[CH:11][N:12]=1.[I:13][C:14]1[CH:15]=[C:16]([OH:20])[CH:17]=[CH:18][CH:19]=1.O>CN(C=O)C>[I:13][C:14]1[CH:15]=[C:16]([CH:17]=[CH:18][CH:19]=1)[O:20][C:8]1[S:9][CH:10]=[CH:11][N:12]=1
Reactant: Oc1cccc(I)c1
Reactant: Brc1nccs1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: Ic1cccc(Oc2nccs2)c1
Temperature: 135 °C
Reaction time: 8 h
Yield: 72.3 %

Procedure:
Cesium carbonate (4.52 g, 13.87 mmol) was added to 2-bromo-1,3-thiazole (1.90 g, 11.6 mmol) and 3-iodophenol (2.54 g, 11.5 mmol) in anhydrous DMF (30 mL). The reaction was heated to 135° C. and stirred at this temperature overnight. The reaction was allowed to cool, then was poured into water (100 mL), and extracted with EtOAc (3×100 mL). The combined organics were washed with brine (100 mL), dried (MgSO4), filtered, and concentrated. The crude product was purified via flash chromatography using a Varian SF15-24 g column and an eluent of EtOAc in hexanes (0-10%) to afford the title compound as a yellow oil (2.52 g, 71.8%). MS (LCMS) m/z 304.1 (M+1).
Reaction SMILES: F[C:2]1[C:8]([F:9])=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].ClC1C=CC2[S:18][C:17]([SH:19])=NC=2C=1>>[F:9][C:8]1[C:2]2[S:18][C:17]([SH:19])=[N:4][C:3]=2[CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cccc(F)c1F
Reactant: Sc1nc2cc(Cl)ccc2s1
Product: Fc1cccc2nc(S)sc12
Temperature: 90 °C

Procedure:
The title compound was prepared from 2,3-difluoroaniline as described for 5-chloro-2-mercaptobenzothiazole except that in the first step the reaction mixture was heated to 90° C. for 4 h.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][NH:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][S:19][CH2:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:13]=2)=[CH:4][CH:3]=1.[Cl:28][C:29]1[C:30]([OH:40])=[C:31]([S:36](Cl)(=[O:38])=[O:37])[CH:32]=[C:33]([Cl:35])[CH:34]=1.C(N(CC)C(C)C)(C)C>C1COCC1>[Cl:28][C:29]1[C:30]([OH:40])=[C:31]([S:36]([N:10]([CH2:9][CH2:8][C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][S:19][CH2:20][CH2:21][C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:13]=2)(=[O:38])=[O:37])[CH:32]=[C:33]([Cl:35])[CH:34]=1
Reactant: Fc1ccc(CCNCc2cccc(CSCCc3ccccc3)c2)cc1
Reactant: O=S(=O)(Cl)c1cc(Cl)cc(Cl)c1O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=S(=O)(c1cc(Cl)cc(Cl)c1O)N(CCc1ccc(F)cc1)Cc1cccc(CSCCc2ccccc2)c1
Reaction time: 1.5 h
Yield: 44.9 %

Procedure:
To a solution of 2-(4-fluorophenyl)-N-(3-(phenethylthiomethyl)benzyl)ethanamine (70 mg, 0.184 mmol) in THF (3 mL) were added 3,5-dichloro-2-hydroxybenzenesulfonyl chloride (63 mg, 0.24 mmol) and N,N-diisopropylethylamine (0.1 mL, 0.55 mmol). The resulting reaction mixture was stirred at it for 1.5 h. The reaction mixture was concentrated and the residue was dissolved in MeOH. The mixture was purified by preparative HPLC. Fractions containing the desired product were combined, concentrated in vacuo and lyophilized to give the title compound (50 mg, 44%) as a white solid. 1H NMR (CDCl3) δ 9.15 (s, 1H), 7.55 (d, J=4.0 Hz, 1H), 7.45 (d, J=4.0 Hz, 1H), 7.34-7.15 (m, 9H), 6.98-6.89 (m, 4H), 4.40 (s, 2H), 3.70 (s, 2H), 3.35 (t, J=8.0 Hz, 2H), 2.86 (t, J=4.0 Hz, 2H), 2.69-2.63 (m, 4H). MS (ESI): 602.0 (M−H)−.
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][O:6][CH2:7][CH2:8][C:9]#[N:10])[CH3:2].[NH2:11][OH:12]>CCO>[CH2:1]([O:3][CH2:4][CH2:5][O:6][CH2:7][CH2:8][C:9](=[N:11][OH:12])[NH2:10])[CH3:2]
Reactant: NO
Reactant: CCOCCOCCC#N
Solvent: CCO
Product: CCOCCOCCC(N)=NO
Yield: 97.3 %

Procedure:
A solution of 3-(2-ethoxyethoxy)propanenitrile (1 g, 7 mmol) and NH2OH (50% in water, 0.64 cm3, 10.5 mmol) in EtOH (10 cm3) were heated to reflux for 24 hours, after which the solvent and excess hydroxylamine were removed by rotary evaporator. The residue was freeze-dried and kept in high vacuum line for several hours to give 3(2-ethoxyethoxy)N′-hydroxypropanimidamide (1.2 g, 97.6%) as a colourless oil.
Reaction SMILES: CCN(C(C)C)C(C)C.Cl.Cl.[CH3:12][C@H:13]1[C:21]2[C:20]([N:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)=[N:19][CH:18]=[N:17][C:16]=2[C:15]([CH3:29])([OH:28])[CH2:14]1.[C:30]([O:34][C:35]([N:37]([CH:50]([CH3:52])[CH3:51])[CH2:38][CH:39]([C:43]1[CH:48]=[CH:47][C:46]([Cl:49])=[CH:45][CH:44]=1)[C:40](O)=[O:41])=[O:36])([CH3:33])([CH3:32])[CH3:31].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1>C(Cl)Cl>[Cl:49][C:46]1[CH:47]=[CH:48][C:43]([CH:39]([C:40]([N:25]2[CH2:24][CH2:23][N:22]([C:20]3[C:21]4[C@H:13]([CH3:12])[CH2:14][C:15]([OH:28])([CH3:29])[C:16]=4[N:17]=[CH:18][N:19]=3)[CH2:27][CH2:26]2)=[O:41])[CH2:38][N:37]([CH:50]([CH3:51])[CH3:52])[C:35](=[O:36])[O:34][C:30]([CH3:32])([CH3:31])[CH3:33])=[CH:44][CH:45]=1
Reactant: C[C@@H]1CC(C)(O)c2ncnc(N3CCNCC3)c21
Reactant: CC(C)N(CC(C(=O)O)c1ccc(Cl)cc1)C(=O)OC(C)(C)C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)N(CC(C(=O)N1CCN(c2ncnc3c2[C@H](C)CC3(C)O)CC1)c1ccc(Cl)cc1)C(=O)OC(C)(C)C
Reaction time: 1 h
Yield: 100.1 %

Procedure:
A solution of tert-butyl 4-((5R)-7-hydroxy-5,7-dimethyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazine-1-carboxylate (28 mg, 0.080 mmol) in DCM (6 mL) was added to a 4.0M HCl solution in dioxane (1.4 mL, 5.63 mmol). The mixture was stirred at room temperature for 4 hours. A 4.0M HCl solution in dioxane (1.4 mL, 5.63 mmol) from a different bottle was added. The resulting mixture was stirred for 18 hours. The solvents were removed in vacuo to give (5R)-5,7-dimethyl-4-(piperazin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-ol dihydrochloride. DIPEA (41.5 mg, 0.321 mmol) was added to a suspension of this (5R)-5,7-dimethyl-4-(piperazin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-ol dihydrochloride (25.8 mg, 0.0803 mmol), 3-(tert-butoxycarbonyl(isopropyl)amino)-2-(4-chlorophenyl)propanoic acid (32.9 mg, 0.0964 mmol), and O-(1H-benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (36.6 mg, 0.0964 mmol) in CH2Cl2 (6 mL) at room temperature. The resulting mixture was stirred for 1 hour. The solvent was removed in vacuo. The residue was purified by a silica cartridge (5.0 g) eluted by EtOAc to give tert-butyl 2-(4-chlorophenyl)-3-(4-((5R)-7-hydroxy-5,7-dimethyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-oxopropyl(isopropyl)carbamate (46 mg, 100%) as a gel. LCMS (APCI+) [M-Boc+H]+ 472.2; Rt: 3.51 min.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([S:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:22])[C:5]([NH:8][C:9]2[S:10][CH:11]=[C:12]([CH3:14])[N:13]=2)=[N:6][CH:7]=1.[SH:23][CH2:24][CH2:25][C:26]([O:28][CH3:29])=[O:27]>>[Cl:22][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[S:15][C:4]1[CH:3]=[C:2]([S:23][CH2:24][CH2:25][C:26]([O:28][CH3:29])=[O:27])[CH:7]=[N:6][C:5]=1[NH:8][C:9]1[S:10][CH:11]=[C:12]([CH3:14])[N:13]=1
Reactant: COC(=O)CCS
Reactant: Cc1csc(Nc2ncc(Br)cc2Sc2ccccc2Cl)n1
Product: COC(=O)CCSc1cnc(Nc2nc(C)cs2)c(Sc2ccccc2Cl)c1

Procedure:
Prepared according to the method of Example 13 from N-(5-bromo-3-(2-chlorophenylthio)pyridin-2-yl)-4-methylthiazol-2-amine (prepared according to Example 47) and methyl 3-mercaptopropanoate. 1H NMR (CDCl3) δ 9.01 (bs, 1H), 8.52 (d, 1H), 7.95 (d, 1H), 7.40 (dd, 1H), 7.16-7.06 (m, 2H), 6.66 (dd, 1H), 6.46 (s, 1H), 3.68 (s, 3H), 3.07 (t, 2H), 2.61 (t, 2H), 2.32 (s, 3H); Mass spectrum (esi) m/z=452.1 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH2:10][C:11](=[O:17])[NH:12]3)[CH:5]=[CH:6][CH:7]=1.[CH3:18][C@H:19]1[NH:24][C@@H:23]([CH3:25])[CH2:22][N:21]([C:26]([C:28]2[C:29]([CH3:36])=[C:30]([CH:34]=O)[NH:31][C:32]=2[CH3:33])=[O:27])[CH2:20]1>C(O)C.N1CCCCC1>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[C:10](=[CH:34][C:30]2[NH:31][C:32]([CH3:33])=[C:28]([C:26]([N:21]4[CH2:20][C@H:19]([CH3:18])[NH:24][C@H:23]([CH3:25])[CH2:22]4)=[O:27])[C:29]=2[CH3:36])[C:11](=[O:17])[NH:12]3)[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1[nH]c(C=O)c(C)c1C(=O)N1C[C@@H](C)N[C@@H](C)C1
Reactant: O=C1Cc2c(cccc2-c2cccc(Br)c2)N1
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1[nH]c(C=C2C(=O)Nc3cccc(-c4cccc(Br)c4)c32)c(C)c1C(=O)N1C[C@@H](C)N[C@@H](C)C1
Temperature: 25 °C
Reaction time: 72 h
Yield: 71.2 %

Procedure:
To a solution of 4-(3-bromo-phenyl)-1,3-dihydro-indol-2-one (72 mg, 0.25 mmol) and 4-[(cis)-3,5-dimethyl-piperazine-1-carbonyl)-3,5-dimethyl-1H-pyrrole-2-carbaldehyde (68.5 mg, 0.25 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. The reaction solution was evaporated, and purified on a silica gel column eluting with MeOH—CH2Cl2 5:95 to provide pure product 4-(3-bromo-phenyl)-3-[4-[(cis)-3,5-dimethyl-piperazine-1-carbonyl)-3,5-dimethyl-1H-pyrrol-2-ylmethylene]-1,3-dihydro-indol-2-one as a yellow solid (95 mg, 70%).
Reaction SMILES: [CH2:1]=[C:2]([CH:6]([O:11][C:12](=[O:14])[CH3:13])[C:7]([Cl:10])([Cl:9])[Cl:8])[C:3]([O-:5])=[O:4].[CH2:15]=[C:16]([CH:20](O)[C:21](Cl)(Cl)Cl)C([O-])=O.[BH4-].[Na+].CC(=CC(Cl)(Cl)Cl)C(OCCCC)=O>O1CCCC1>[CH3:1][CH:2]([CH:6]([O:11][C:12](=[O:14])[CH3:13])[C:7]([Cl:9])([Cl:10])[Cl:8])[C:3]([O:5][CH2:15][CH2:16][CH2:20][CH3:21])=[O:4]
Reactant: C=C(C(=O)[O-])C(OC(C)=O)C(Cl)(Cl)Cl
Reactant: C=C(C(=O)[O-])C(O)C(Cl)(Cl)Cl
Agent: CCCCOC(=O)C(C)=CC(Cl)(Cl)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCOC(=O)C(C)C(OC(C)=O)C(Cl)(Cl)Cl
Temperature: 70 °C

Procedure:
1236.1 g of crude 2-methylene-3-acetoxy-4,4,4-trichlorobutyrate (91.3%) containing about 2.5% 2-methylene-3-hydroxy-4,4,4-trichlorobutyrate and 747 ml of tetrahydrofuran was charged to a 2-liter flask equipped with a reflux condenser, magnetic stir bar, and a thermometer. 38.0 g of sodium borohydride was added in three portions to the stirred solution. The reaction temperature rose to 32° C. The reaction was heated slowly to 70° C. for three hours. NMR indicated 80% of the starting material was converted into product, butyl 2-methyl-4,4,4-trichlorobut-2-enoate. The reaction was heated for another six hours at 80° C. and the reaction was quenched by removal of tetrahydrofuran and addition of water. The organic layer was separated and GC analysis showed the presence of 79.2% butyl 2-methyl-4,4,4-trichlorobut-2-enoate, 1% butyl 2-methyl-2,4,4-trichlorobut-3-enoate, 6.6% unreacted starting material, butyl 2-methylene-3-acetoxy-4,4,4-trichlorobutyrate, 3% 1-o butyl 2-methyl-3-acetoxy-4,4,4-trichlorobutyrate, and 0.5% butyl 2-methylene-3-hydroxy-4,4,4-trichlorobutyrate. Hydrogenated product, butyl 2-methyl-3-acetoxy-4,4,4-trichlorobutyrate, was formed owing to the presence of water or traces of other protonic solvents in the reaction system.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][C:16]2[N:17]=[C:18]([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)[O:19][C:20]=2[CH3:21])=[CH:9][CH:8]=1)[C:3]([OH:5])=[O:4].[F:29][C:30]1[CH:35]=[CH:34][C:33]([C:36](=[O:42])[CH2:37][C:38](=O)[CH2:39][CH3:40])=[CH:32][CH:31]=1>>[CH2:39](/[C:38](/[NH:1][C@@H:2]([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][CH2:14][CH2:15][C:16]2[N:17]=[C:18]([C:22]3[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=3)[O:19][C:20]=2[CH3:21])=[CH:11][CH:12]=1)[C:3]([OH:5])=[O:4])=[CH:37]/[C:36]([C:33]1[CH:32]=[CH:31][C:30]([F:29])=[CH:35][CH:34]=1)=[O:42])[CH3:40]
Reactant: Cc1oc(-c2ccc(F)cc2)nc1CCOc1ccc(C[C@H](N)C(=O)O)cc1
Reactant: CCC(=O)CC(=O)c1ccc(F)cc1
Product: CC/C(=C/C(=O)c1ccc(F)cc1)N[C@@H](Cc1ccc(OCCc2nc(-c3ccc(F)cc3)oc2C)cc1)C(=O)O

Procedure:
The title compound was prepared (as described above for the preparation of Example 2) from 500 mg (1.56 mmol) of Intermediate 46 and 315 mg (1.56 mmol) of Intermediate 32 to yield 412 mg of Example 9: TLC (DCM/MeOH, 4/1): Rf=0.53; 1H NMR (DMSO-d6, 300 MHz) δ11.53 (d, 1H, J=9.3), 7.99 (m, 2H), 7.95 (m, 2H), 7.39 (t, 2H, J=8.7), 7.26 (t, 2H, J=8.7), 7.17 (d, 2H, J=8.1), 6.86 (d, 2H, J=8.1), 5.60 (s, 1H), 4.20 (t, 2H, J=6.6), 4.12 (m, 1H), 3.21 (m, 2H), 2.94 (t, 2H, J=6.6), 2.78 (dd, 1H, J=13.8, 8.4), 2.38 (s, 3H), 2.05 (m, 2H), 0.96 (t, 3H, J=7.5); low resolution MS (ES+)m/e 561.4 (MH+).