Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH2:6][C:5]([CH3:8])([CH3:7])[CH2:4][C:3]=1[CH:9]=O.[CH2:11]([O:13][C:14]([CH:16]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:15])[CH3:12]>C1C=CC=CC=1>[Cl:1][C:2]1[CH2:6][C:5]([CH3:7])([CH3:8])[CH2:4][C:3]=1/[CH:9]=[CH:16]/[C:14]([O:13][CH2:11][CH3:12])=[O:15]
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC1(C)CC(Cl)=C(C=O)C1
Solvent: c1ccccc1
Product: CCOC(=O)/C=C/C1=C(Cl)CC(C)(C)C1
Reaction time: 14 h
Yield: 36.4 %

Procedure:
The following two procedures were adapted from Organic Preparations and Procedures Int., 29(4):471-498. A 500-mL single neck round bottomed flask equipped with a magnetic stirrer and nitrogen inlet was charged with 2-chloro-4,4-dimethylcyclopent-1-enecarbaldehyde (38 g, 240 mmol) in benzene (240 mL). To the solution was added ethoxycarbonylmethylene triphenylphosphorane (84 g, 240 mmol). The mixture was stirred for 14 h. After that time, the solvent was evaporated and the residue was triturated with hexanes (2 L) to extract the product away from the PPh3 by-products. The organic layer was dried over sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography using a 100% hexane—1:1 hexane/ethyl acetate gradient to afford a 37% yield (20 g) of (E)-ethyl 3-(2-chloro-4,4-dimethylcyclopent-1-enyl)acrylate 107a.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:9]=[C:10]3[CH:16]=[CH:15][NH:14][C:11]3=[N:12][CH:13]=2)[CH:5]=[CH:4][C:3]=1[CH:17]1[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]1.[I:30]N1C(=O)CCC1=O>C(Cl)Cl>[F:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:9]=[C:10]3[C:16]([I:30])=[CH:15][NH:14][C:11]3=[N:12][CH:13]=2)[CH:5]=[CH:4][C:3]=1[CH:17]1[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(-c3cnc4[nH]ccc4c3)cc2F)CC1
Reactant: O=C1CCC(=O)N1I
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(-c3cnc4[nH]cc(I)c4c3)cc2F)CC1
Yield: 94.7 %

Procedure:
Using similar reaction conditions as described in step i of intermediate 1, tert-butyl 4-(2-fluoro-4-(1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)piperidine-1-carboxylate (320 mg, 0.810 mmol) was iodinated with N-iodosuccinimide (219 mg, 0.972 mmol) in DCM (20 ml) to afford 400 mg (94.7% yield) of the pure product. MS: m/z=522.1 (M+1).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[C:16]([O:25][CH2:26][CH3:27])(=[O:24])[C:17]1[C:18](=[CH:20][CH:21]=[CH:22][CH:23]=1)[OH:19]>CN(C)C1C=CN=CC=1.ClC1C=CC=CC=1Cl>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH3:15])[N:5]=[CH:4][CH:3]=[C:2]2[O:19][C:18]1[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=1[C:16]([O:25][CH2:26][CH3:27])=[O:24]
Reactant: COc1cc2nccc(Cl)c2cc1OC
Reactant: CCOC(=O)c1ccccc1O
Agent: CN(C)c1ccncc1
Solvent: Clc1ccccc1Cl
Product: CCOC(=O)c1ccccc1Oc1ccnc2cc(OC)c(OC)cc12
Temperature: 120 °C
Reaction time: 8 h
Yield: 63.3 %

Procedure:
4-Chloro-6,7-dimethoxyquinoline (100 mg), ethyl salicylate (336 mg), and 4-dimethylaminopyridine (244 mg) were suspended in o-dichlorobenzene (1 ml), and the suspension was stirred at 120° C. overnight. The reaction solution was cooled to room temperature, and the solvent was removed by distillation under the reduced pressure. Water was then added to the residue, and the mixture was extracted with chloroform. The chloroform layer was washed with water and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by column chromatography using acetone-hexane to give the title compound (100 mg, yield 56%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:13](=[C:14]3[C:19]=1[CH:18]=[CH:17][CH:16]=[N:15]3)[NH:12][S:11](=[O:21])(=[O:20])[C:10]1[C:5]2=[CH:6][C:7](F)=[CH:8][CH:9]=1.[CH3:23][N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1>CN1C(=O)CCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:13](=[C:14]3[C:19]=1[CH:18]=[CH:17][CH:16]=[N:15]3)[NH:12][S:11](=[O:21])(=[O:20])[C:10]1[C:5]2=[CH:6][C:7]([N:27]2[CH2:28][CH2:29][N:24]([CH3:23])[CH2:25][CH2:26]2)=[CH:8][CH:9]=1
Reactant: CN1CCNCC1
Reactant: O=S1(=O)Nc2c(cc(Cl)c3cccnc23)-c2cc(F)ccc21
Solvent: CN1CCCC1=O
Product: CN1CCN(c2ccc3c(c2)-c2cc(Cl)c4cccnc4c2NS3(=O)=O)CC1
Yield: 28.1 %

Procedure:
In a similar fashion using route 51 general procedure 118, 12-chloro-9-fluoro-5H-6-thia-4,5-diaza-chrysene 6,6-dioxide 503 (100 mg, 0.3 mmol), 1-methyl piperazine (59 mg, 0.6 mmol) and NMP (2 ml) gave title compound (35 mg, 28%) after purification by column chromatography using DCM/MeOH (99.5:0.5) as the eluent.
Reaction SMILES: [C:1]([O:5]CC)(=O)[CH:2]=[CH2:3].[O-]CC.[Na+].C(O)C.[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][NH2:23])=[CH:18][CH:17]=1>C1(C)C=CC=CC=1>[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]2[CH2:3][CH2:2][C:1](=[O:5])[NH:23]2)=[CH:18][CH:17]=1
Reactant: NNc1ccc(Cl)cc1
Reactant: C=CC(=O)OCC
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: O=C1CCN(c2ccc(Cl)cc2)N1
Temperature: 40 °C
Reaction time: 1 h

Procedure:
90 g (0.9 mol) of ethyl acrylate are added dropwise at 40°-45° C. to a mixture of 15.9 g (234 mmol) of sodium ethoxide, 110 ml of ethanol, 110 ml of toluene and 25.7 g (180 mmol) of 4-chlorophenylhydrazine and the mixture is subsequently stirred for 1 hour at 40° C. The reaction mixture is evaporated to 100 ml and the residue is taken up in water. The resulting mixture is washed a number of times with toluene and the combined organic phases are extracted with 5% strength NaOH. The combined aqueous phases are adjusted to a pH of 6.5 and cooled to 10° C. The solid formed is filtered off with suction, washed with water and dried under reduced pressure.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[CH2:15][C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[NH:7][C:6]=2[CH2:5][NH:4]1.C(N(CC)CC)C.[CH2:23]([O:30][C:31](Cl)=[O:32])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CO>[CH2:23]([O:30][C:31]([N:4]1[C@H:3]([CH2:2][OH:1])[CH2:15][C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[NH:7][C:6]=2[CH2:5]1)=[O:32])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: OC[C@@H]1Cc2c([nH]c3ccccc23)CN1
Solvent: CCN(CC)CC
Solvent: CO
Product: O=C(OCc1ccccc1)N1Cc2[nH]c3ccccc3c2C[C@H]1CO
Reaction time: 3 h
Yield: 86 %

Procedure:
2.02 g of (3S)-3-hydroxymethyl-1,2,3,4-tetrahydro-β-carboline are dissolved in 24 ml of methanol, and 1.5 ml of triethylamine and 1.8 ml of benzyloxycarbonyl chloride are added dropwise to the mixture. The mixture is stirred at 5°-10° C. for 3 hours, and the mixture is evaporated to remove the solvent. The residue is dissolved in ethyl acetate. The solution is washed with water, a 0.5M citric acid solution and water, dried and then evaporated to remove the solvent. 2.90 g of (3S)-2-benzyloxycarbonyl-3-hydroxymethyl-1,2,3,4-tetrahydro-β-carboline are obtained as colorless oil. Yield: 86%
Reaction SMILES: [C:1](N1C=CC=CC1=O)(N1C=CC=CC1=O)=[S:2].[CH3:17][O:18][C:19]1[N:24]=[CH:23][C:22]([C:25]2[CH:30]=[C:29]([NH2:31])[N:28]=[CH:27][N:26]=2)=[CH:21][N:20]=1>ClCCl.CN(C)C=O>[N:31]([C:29]1[N:28]=[CH:27][N:26]=[C:25]([C:22]2[CH:21]=[N:20][C:19]([O:18][CH3:17])=[N:24][CH:23]=2)[CH:30]=1)=[C:1]=[S:2]
Reactant: O=c1ccccn1C(=S)n1ccccc1=O
Reactant: COc1ncc(-c2cc(N)ncn2)cn1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1ncc(-c2cc(N=C=S)ncn2)cn1
Temperature: 60 °C

Procedure:
To a solution of 1,1′-thiocarbonyldipyridin-2(1H)-one (0.832 g, 3.58 mmol) in dichloromethane/N,N-dimethylformamide at room temperature was added 2′-methoxy-4,5′-bipyrimidin-6-amine (0.56 g, 2.76 mmol). The orange mixture was heated at 60° C. for 18 hours. The LC/MS showed the desired product peak as the major peak. The deep orange mixture was purified by silica gel chromatography (0-40% ethyl acetate-hexanes) to afford 4-isothiocyanato-6-methoxypyrimidine (0.1 g, 0.408 mmol, 15% yield) as an orange solid. LCMS R.T.=2.29; [M+H]+=246.03.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[N:4]([C:8]([CH:27]3[CH2:30][C:29](=[CH2:31])[CH2:28]3)=[N:9][C:10]=2[C:11]2[CH:20]=[C:19]3[C:14]([CH:15]=[CH:16][C:17]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[N:18]3)=[CH:13][CH:12]=2)[CH:5]=[CH:6][N:7]=1.B1C2CCCC1CCC2.[OH-:41].[Na+].OO>C1COCC1.C(Cl)Cl>[Cl:1][C:2]1[C:3]2[N:4]([C:8]([CH:27]3[CH2:30][CH:29]([CH2:31][OH:41])[CH2:28]3)=[N:9][C:10]=2[C:11]2[CH:20]=[C:19]3[C:14]([CH:15]=[CH:16][C:17]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[N:18]3)=[CH:13][CH:12]=2)[CH:5]=[CH:6][N:7]=1
Reactant: [OH-]
Reactant: C=C1CC(c2nc(-c3ccc4ccc(-c5ccccc5)nc4c3)c3c(Cl)nccn23)C1
Agent: B1C2CCCC1CCC2
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: OCC1CC(c2nc(-c3ccc4ccc(-c5ccccc5)nc4c3)c3c(Cl)nccn23)C1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 7-[8-chloro-3-(3-methylenecyclobutyl)-imidazo[1,5-a]pyrazin-1-yl]-2-phenylquinoline (338 mg, 0.8 mmol) in dry THF (5 mL) was added 9-BBN (2.4 mL, 1.2 mmol, 0.5M in THF) dropwise at 0° C. under nitrogen atmosphere. The temperature was slowly warmed to rt overnight. The mixture was cooled to 0° C., and 3 mL 1N aq. NaOH and 0.6 mL 30% aq. H2O2 were added, the resulting mixture was stirred at 0° C. for 10 min, then rt for 30 min. The mixture was diluted with methylene chloride (30 mL), washed with brine (2×20 mL), and dried over anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure, and the crude material was purified by silica gel column chromatography (eluting with hexanes:EtOAc=50:50→100% ethyl acetate), to obtain the title compound as a yellow solid, a mixture of cis and trans isomers in the ratio of 5:1; MS (ES+): m/z 441/443 (3/1) [MH+]; 1H NMR (CDCl3, 400 MHz) δ 2.44-2.64 (m, 6H), 3.65-3.76 (m, 3H), 7.31, 7.33 (2×d, J=5.0 Hz, 1H, 1:5 ratio), 7.39-7.57 (m, 4H), 7.86-7.98 (m, 3H), 8.18 (m, 2H), 8.26 (d, J=8.6 Hz, 1H), 8.51, 8.53 (2×s, 1H, 5:1 ratio).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[S:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:25]=[CH:24][C:16]2[C:17]([CH3:23])([CH3:22])[O:18][C:19](=[O:21])[NH:20][C:15]=2[CH:14]=1.[OH:26]O>>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[S:7]([CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:25]=[CH:24][C:16]2[C:17]([CH3:22])([CH3:23])[O:18][C:19](=[O:21])[NH:20][C:15]=2[CH:14]=1)=[O:26]
Reactant: CC1(C)OC(=O)Nc2cc(OCCCCSc3ccccn3)ccc21
Reactant: OO
Product: CC1(C)OC(=O)Nc2cc(OCCCCS(=O)c3ccccn3)ccc21

Procedure:
Prepared analogously to Example 2 from 7-[4-(2-pyridylmercapto)-butoxy]-4,4-dimethyl-4H-3,1-benzoxazin-2-one and hydrogen peroxide.
Reaction SMILES: [C:1]([OH:9])([OH:8])=[CH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].C([Si:14](C1C=CC=CC=1)(C1C=CC=CC=1)Cl)(C)(C)C.N1C=CN=C1>CN(C)C=O>[SiH3:14][O:8][C:1]([OH:9])=[CH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCC=C(O)O
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CCCCCC=C(O)O[SiH3]

Procedure:
A solution of 6 g of the diol 5, 6.5 ml of t-butyldiphenylchlorosilane and 3.4 g of imidazole in 120 ml of dimethylformamide (DMF) was stirred at 0° C. for 2 hours. The mixture was then concentrated under vacuum and the residue was dissolved in 300 ml of 5 hexanes: 1 EtOAc. The solution was washed with 150 ml of water and then 150 ml of saturated aqueous sodium chloride solution (brine). The organic phase was dried over sodium sulfate and concentrated under vacuum to provide the title compound.
Reaction SMILES: Br[CH:2]([CH3:7])[C:3]([O:5][CH3:6])=[O:4].[NH2:8][CH2:9][CH2:10][NH:11][C:12]1[N:17]=[C:16]([C:18]2[S:19][C:20]([C:23]3[S:24][CH:25]=[CH:26][CH:27]=3)=[CH:21][CH:22]=2)[CH:15]=[CH:14][N:13]=1.C(N(CC)C(C)C)(C)C.O>CN1CCCC1>[S:24]1[CH:25]=[CH:26][CH:27]=[C:23]1[C:20]1[S:19][C:18]([C:16]2[CH:15]=[CH:14][N:13]=[C:12]([NH:11][CH2:10][CH2:9][NH:8][CH:2]([CH3:7])[C:3]([O:5][CH3:6])=[O:4])[N:17]=2)=[CH:22][CH:21]=1
Reactant: COC(=O)C(C)Br
Reactant: NCCNc1nccc(-c2ccc(-c3cccs3)s2)n1
Agent: CN1CCCC1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C(C)NCCNc1nccc(-c2ccc(-c3cccs3)s2)n1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Methyl 2-bromopropanoate (182 mg, 1.09 mmol) was added to a mixture of N-(2-amino-ethyl)-4-(5-(thiophen-2-yl)thiophen-2-yl)pyrimidin-2-amine (300 mg, 0.99 mmol) and N,N-diisopropylethylamine (153 mg, 1.19 mmol) in 1-methylpyrrolidine (8 mL) at rt. After stirring at rt for 24 h, water (50 mL) was added and the mixture extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with brine (3×50 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give the title compound. MS (M+H)+ 389.
Reaction SMILES: [CH3:1][C:2]1([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:7][CH2:6][CH2:5][N:4](C(OCC2C=CC=CC=2)=O)[CH2:3]1>C(OCC)(=O)C.CO.[Pd]>[CH3:1][C:2]1([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:7][CH2:6][CH2:5][NH:4][CH2:3]1
Reactant: CCOC(=O)C1(C)CCCN(C(=O)OCc2ccccc2)C1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CCOC(=O)C1(C)CCCNC1
Reaction time: 1.5 h
Yield: 90.9 %

Procedure:
A suspension of 1-benzyl 3-ethyl 3-methylpiperidine-1,3-dicarboxylate (3.945 g, 12.92 mmol) and 5% Pd/C (800 mg) in ethyl acetate (20 mL) and methanol (20.00 mL) was vigorously stirred under a hydrogen balloon for 1.5 hr. The reaction mixture was filtered to remove the catalyst and the filtrate was concentrated to dryness to give the desired crude product ethyl 3-methylpiperidine-3-carboxylate (2.010 g, 11.74 mmol, 91% yield) as a colorless oily residue. Anal. Calcd. for C9H17NO2 m/z 171.2, found: 172.2 (M+H)+; 1H NMR (400 MHz, CDCl3) δ ppm 4.25-4.06 (m, 2 H), 3.31 (d, J=13.19 Hz, 1 H), 2.93 (d, J=13.19 Hz, 1 H), 2.59 (d, J=10.44 Hz, 1 H), 2.41 (d, J=13.19 Hz, 1 H), 2.23-2.11 (m, 1 H), 1.68 (br. s., 1 H), 1.52 (t, J=3.85 Hz, 1 H), 1.46-1.31 (m, 2 H), 1.27 (t, J=7.15 Hz, 3 H), 1.10 (s, 3H).
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]([C:9]1[CH:14]=[CH:13][C:12]([CH2:15]O)=[C:11]([CH2:17][CH2:18][CH3:19])[CH:10]=1)([OH:8])[C:4]([F:7])([F:6])[F:5].C(N(CC)CC)C.CS(Cl)(=O)=O.[CH:34]1([CH2:37][NH:38][C:39]([NH:41][C:42]2[CH:47]=[CH:46][C:45]([C:48]([N:50]3[CH2:55][CH2:54][NH:53][CH2:52][CH2:51]3)=[O:49])=[CH:44][CH:43]=2)=[O:40])[CH2:36][CH2:35]1.C(=O)([O-])[O-].[K+].[K+]>ClCCl>[CH:34]1([CH2:37][NH:38][C:39]([NH:41][C:42]2[CH:43]=[CH:44][C:45]([C:48]([N:50]3[CH2:55][CH2:54][N:53]([CH2:15][C:12]4[CH:13]=[CH:14][C:9]([C:3]([OH:8])([C:4]([F:5])([F:6])[F:7])[C:2]([F:21])([F:20])[F:1])=[CH:10][C:11]=4[CH2:17][CH2:18][CH3:19])[CH2:52][CH2:51]3)=[O:49])=[CH:46][CH:47]=2)=[O:40])[CH2:35][CH2:36]1
Reactant: O=C(NCC1CC1)Nc1ccc(C(=O)N2CCNCC2)cc1
Reactant: CCCc1cc(C(O)(C(F)(F)F)C(F)(F)F)ccc1CO
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCc1cc(C(O)(C(F)(F)F)C(F)(F)F)ccc1CN1CCN(C(=O)c2ccc(NC(=O)NCC3CC3)cc2)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 20.6 %

Procedure:
1,1,1,3,3,3-Hexafluoro-2-(4-(hydroxymethyl)-3-propylphenyl)propan-2-ol (0.509 mmol, 161 mg) was dissolved in dichloromethane (4 mL) and triethylamine (1.527 mmol, 155 mg) was added. The mixture was cooled to 0° C. before the addition of methanesulfonyl chloride (0.611 mmol, 70.0 mg). The mixture was stirred at 0° C. for 1 hour before warming to room temperature and stirring for 1 hour. The reaction mixture was diluted with dichloromethane (50 mL) and washed with water (2×10 mL). The organic phase was dried over magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure. The resulting residue was dissolved in acetonitrile (4 mL) and 1-(cyclopropylmethyl)-3-(4-(piperazine-1-carbonyl)phenyl)urea (0.510 mmol, 154 mg) was added followed by potassium carbonate (1.529 mmol, 211 mg). The mixture was heated to reflux for 16 hours. The mixture was cooled, diluted with dichloromethane (50 mL) and washed with water (2×20 mL). The organic phase was dried over magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by HPLC and treated with strong cation exchange column chromatography to afford the title compound (63 mg). MS (ESI) m/z 601.3 [M+H]+
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:33])[CH:5]([N:16]([CH:30]1[CH2:32][CH2:31]1)[C:17](=O)[C:18]1[CH:23]=[CH:22][C:21]([O:24][C:25]([F:28])([F:27])[F:26])=[CH:20][CH:19]=1)[C:6]([C:8]1[CH:9]=[N:10][C:11]([S:14][CH3:15])=[N:12][CH:13]=1)=O)[CH3:2].FC(F)(F)C([O-])=O.[NH4+:41]>>[CH2:1]([O:3][C:4]([C:5]1[N:16]([CH:30]2[CH2:31][CH2:32]2)[C:17]([C:18]2[CH:19]=[CH:20][C:21]([O:24][C:25]([F:26])([F:28])[F:27])=[CH:22][CH:23]=2)=[N:41][C:6]=1[C:8]1[CH:9]=[N:10][C:11]([S:14][CH3:15])=[N:12][CH:13]=1)=[O:33])[CH3:2]
Reactant: [NH4+]
Reactant: CCOC(=O)C(C(=O)c1cnc(SC)nc1)N(C(=O)c1ccc(OC(F)(F)F)cc1)C1CC1
Agent: O=C([O-])C(F)(F)F
Product: CCOC(=O)c1c(-c2cnc(SC)nc2)nc(-c2ccc(OC(F)(F)F)cc2)n1C1CC1

Procedure:
The title compound was prepared from 2-[cyclopropyl-(4-trifluoromethoxy-benzoyl)-amino]-3-(2-methylsulfanyl-pyrimidin-5-yl)-3-oxo-propionic acid ethyl ester in direct analogy to intermediate 8B, by reaction with ammonium trifluoroacetate. MS: 465.1 (MH+).
Reaction SMILES: [CH:1]1([CH2:4][S:5][C:6]2[CH:15]=[C:14]3[C:9]([CH:10]=[CH:11][CH:12]=[C:13]3[CH2:16][CH2:17][NH:18][C:19](=[O:24])[CH2:20][CH2:21][CH2:22][Cl:23])=[CH:8][CH:7]=2)[CH2:3][CH2:2]1.I([O-])(=O)(=O)=[O:26].[Na+]>>[CH:1]1([CH2:4][S:5]([C:6]2[CH:15]=[C:14]3[C:9]([CH:10]=[CH:11][CH:12]=[C:13]3[CH2:16][CH2:17][NH:18][C:19](=[O:24])[CH2:20][CH2:21][CH2:22][Cl:23])=[CH:8][CH:7]=2)=[O:26])[CH2:3][CH2:2]1
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: O=C(CCCCl)NCCc1cccc2ccc(SCC3CC3)cc12
Agent: [Na+]
Product: O=C(CCCCl)NCCc1cccc2ccc(S(=O)CC3CC3)cc12
Temperature: 2.5 °C
Reaction time: 8 h

Procedure:
The product obtained in Example 43 (10 mmol) is added to an aqueous 0.5M sodium periodate solution (21 ml, 10.5 mmol) at 0° C. Stirring at 0-5° C. is carried out overnight. The solution is filtered and the filtrate is extracted with chloroform. The organic phase is dried over magnesium sulphate and is concentrated under reduced pressure. The residue is chromatographed on silica gel to yield the title compound.
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[C:5](Cl)(=[O:7])[CH3:6].[Cl:9][C:10]1[CH:15]=[C:14]([O:16]C)[CH:13]=[CH:12][C:11]=1[O:18][CH3:19].Cl>C(Cl)Cl>[Cl:9][C:10]1[C:11]([O:18][CH3:19])=[CH:12][C:13]([C:5](=[O:7])[CH3:6])=[C:14]([OH:16])[CH:15]=1
Reactant: CC(=O)Cl
Reactant: COc1ccc(OC)c(Cl)c1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COc1cc(C(C)=O)c(O)cc1Cl
Temperature: 25 °C
Yield: 527.3 %

Procedure:
To a mixture of AlCl3 (8.89 g, 59 mmol) in CH2Cl2 at −10° C. was added acetyl chloride (4.1 ml, 58 mmol) drop-wise while maintaining the internal temperature below 0° C. After 20 min 2-Chloro-1,4-dimethoxybenzene (10.0 g, 8.3 mmol) was dissolved in 8 ml CH2Cl2 and added to the above solution drop-wise while maintaining the internal temperature below 0° C. After 20 min the mixture was warmed to room temperature for 1 hour then warmed to reflux. After 21 h the solution was cooled, poured over a mixture of ice and concentrated HCl and extracted with dichloromethane. The combined organics were concentrated in vacuo and recrystallized from H2O/EtOH to afford 1-(4-chloro-2-hydroxy-5-methoxy-phenyl)-ethanone (8.78 g, 85%) as a solid.
Reaction SMILES: [Br:1][C:2]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:3]=1[O:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]#[N:12])[CH2:7][CH2:6]1.Cl.[NH2:19][OH:20].C([O-])([O-])=O.[Na+].[Na+]>CCO.O>[Br:1][C:2]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:3]=1[O:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11](=[N:19][OH:20])[NH2:12])[CH2:7][CH2:6]1
Reactant: NO
Reactant: N#CN1CCC(Oc2cc(F)ccc2Br)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: NC(=NO)N1CCC(Oc2cc(F)ccc2Br)CC1
Temperature: 80 °C

Procedure:
A mixture of 4-(2-bromo-5-fluorophenoxy)piperidine-1-carbonitrile (1.6 g, 5.3 mmol), hydroxylamine hydrochloride (1.1 g, 16.1 mmol) and Na2CO3 (2.3 g, 92 mmol) in EtOH/water 4:1 (26 ml) was heated at 80° C. for 1 h. The solvent was evaporated. The residue was acidified with 6N HCl and washed with Et2O (2×10 mL). The aqueous layer was made basic with solid Na2CO3 and extracted with EtOAc (3×20 mL). The combined organic fractions were dried over Na2SO4 and the solvent was evaporated under reduced pressure to give the title compound as a foam which was used in the next step without further purification. MS: m/z 332, 334 (MH+).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][CH:21]2[C:26](=[O:27])[NH:25][C:24](=[O:28])[NH:23][C:22]2=[O:29])=[CH:15][CH:14]=1>>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][C:21]2([C:2]3[C:11]4[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=4)[N:5]=[CH:4][CH:3]=3)[C:22](=[O:29])[NH:23][C:24](=[O:28])[NH:25][C:26]2=[O:27])=[CH:15][CH:14]=1
Reactant: O=C1NC(=O)C(CCc2ccc(Cl)cc2)C(=O)N1
Reactant: Clc1ccnc2ccccc12
Product: O=C1NC(=O)C(CCc2ccc(Cl)cc2)(c2ccnc3ccccc23)C(=O)N1
Temperature: 150 °C

Procedure:
A mixture of 3.63 g of 4-chloroquinoline and 5.3 g of 5-[2-(4-chlorophenyl)ethyl]barbituric acid was heated to 150° C. for 11/4 hours, to form 5-[2-(4-chlorophenyl)ethyl]-5-(4-quinolinyl)barbituric acid. This compound was hydrolyzed, without isolation, by adding 4 g of NaOH in 40 ml of water and refluxing for four hours. The mixture was cooled, acidified with HCl and refluxed for several hours, cooled, and neutralized with dilute NaOH. The desired product was extracted into CH2Cl2, which was then filtered through phase separating paper and evaporated to dryness. The residue was absorbed onto silica gel and chromatographed over silica gel using CH2Cl2. Fractions containing product were combined to give 2.69 g of crystalline material. This was recrystallized from a petroleum ether/CH2Cl2 mixture to give 2.35 g of the title product. Yield: 39%. M.P. 97° C.
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:5]([C:6](=O)[CH2:7]Cl)=[CH:4][CH:3]=1.[NH2:12][C:13]1[S:14][CH2:15][CH2:16][N:17]=1.C(O)C>O>[F:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]2[N:12]=[C:13]3[N:17]([CH:7]=2)[CH2:16][CH2:15][S:14]3)=[CH:4][CH:3]=1
Reactant: NC1=NCCS1
Reactant: O=C(CCl)c1ccc(F)cc1
Solvent: CCO
Solvent: O
Product: Fc1ccc(-c2cn3c(n2)SCC3)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99 %

Procedure:
A mixture of 51.6 g (0.3 mol) of 4-fluorophenacylchloride, 33.66 g (0.33 mol) of 2-aminothiazoline and 200 ml of ethanol was heated at reflux for 2 hours. The mixture was cooled to room temperature at which point 300 ml of water was added. After a reflux period of 2 hours, the mixture was concentrated to remove about 190 ml of aqueous alcohol. The pH of the residue was adjusted to about 2 with 10% hydrochloric acid (10 ml). The solid product was separated and dried to give 65.4 g (85%) of 6-(4-fluorophenyl)-2,3-dihydroimidazo[2,1-b]thiazole, m.p. 116°-118°.