Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[C:2]([C:6]1[C:10]([NH2:11])=[CH:9][S:8][CH:7]=1)([O:4][CH3:5])=[O:3].[Cl:12][CH2:13][C:14](Cl)=[O:15].C(N(CC)CC)C.O>C(Cl)Cl>[C:2]([C:6]1[C:10]([NH:11][C:14](=[O:15])[CH2:13][Cl:12])=[CH:9][S:8][CH:7]=1)([O:4][CH3:5])=[O:3]
Reactant: O=C(Cl)CCl
Reactant: COC(=O)c1cscc1N
Agent: Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1cscc1NC(=O)CCl

Procedure:
A suspension of 12.2 g (0.063 mol) of 3-carbomethoxy-4-aminothiophene hydrochloride in 100 ml of methylene chloride is treated with 10 ml (0.126 mol) of chloroacetyl chloride and subsequently dropwise with 17.6 ml (0.126 mol) of triethylamine, the temperature being held below 25° C. The solution is poured into water and extracted twice with 50 ml of methylene chloride each time. The combined methylene chloride extracts are washed three times with 50 ml of water each time, dried over magnesium sulphate and evaporated. After chromatography on silica gel using methylene chloride for the elution, there is obtained crystalline 3-carbomethoxy-4-[(chloroacetyl)amino]thiophene of melting point 98°-100° C.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]2[C:9](=[C:10]([CH3:12])[CH:11]=1)[C:8](=[O:13])[N:7]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=1)[CH2:6]2.Cl[CH2:27][CH2:28][N:29]([CH2:31][CH2:32]Cl)[CH3:30].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH3:12][C:10]1[CH:11]=[C:3]([CH2:2][N:1]2[CH2:32][CH2:31][N:29]([CH3:30])[CH2:28][CH2:27]2)[CH:4]=[C:5]2[C:9]=1[C:8](=[O:13])[N:7]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:23])[F:24])=[CH:17][CH:16]=1)[CH2:6]2
Reactant: Cc1cc(CN)cc2c1C(=O)N(Cc1ccc(OC(F)(F)F)cc1)C2
Reactant: CN(CCCl)CCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(CN2CCN(C)CC2)cc2c1C(=O)N(Cc1ccc(OC(F)(F)F)cc1)C2
Temperature: 110 °C
Reaction time: 16 h
Yield: 30.8 %

Procedure:
In sealed vial, a mixture of 5-aminomethyl-7-methyl-2-(4-trifluoromethoxy-benzyl)-2,3-dihydro-isoindol-1-one (0.104 g, 0.3 mmol), bis(2-chloro-ethyl)-methyl-amine (0.077 g, 0.4 mmol), and K2CO3 (0.083 g, 0.6 mmol) in DMF (3 mL) was stirred at 110° C. for 16 h. After this time, the GC-MS of the reaction mixture indicated the completion of reaction. The reaction was cooled to ambient temperature and the solids removed by filtration. The filtrate was concentrated. Silica gel column chromatography of the resulting material using 5:1 CHCl3-MeOH afforded 7-methyl-5-(4-methyl-piperazin-1-ylmethyl)-2-(4-trifluoromethoxy-benzyl)-2,3-dihydro-isoindol-1-one (0.040 g, 31%). 1H NMR (300 MHz, CDCl3): δ (ppm) 2.24 (s, 3H), 2.34-2.52 (m, 8H), 2.74 (s, 3H), 3.49 (s, 2H), 4.20 (s, 2H), 4.76 (s, 2H), 7.15-7.37 (m, 6H). GC-MS: m/z 433 (M)+.
Reaction SMILES: Br[C:2]1[C:3]2[C:4]3[CH:18]=[CH:17][S:16][C:5]=3[C:6](=[O:15])[NH:7][C:8]=2[C:9]([CH3:14])=[CH:10][C:11]=1[O:12][CH3:13].[F:19][C:20]1[CH:25]=[C:24](B2OC(C)(C)C(C)(C)O2)[CH:23]=[CH:22][C:21]=1[CH:35]([CH3:45])[CH2:36][NH:37][C:38](=[O:44])[O:39][C:40]([CH3:43])([CH3:42])[CH3:41]>>[F:19][C:20]1[CH:25]=[C:24]([C:2]2[C:3]3[C:4]4[CH:18]=[CH:17][S:16][C:5]=4[C:6](=[O:15])[NH:7][C:8]=3[C:9]([CH3:14])=[CH:10][C:11]=2[O:12][CH3:13])[CH:23]=[CH:22][C:21]=1[CH:35]([CH3:45])[CH2:36][NH:37][C:38](=[O:44])[O:39][C:40]([CH3:42])([CH3:41])[CH3:43]
Reactant: COc1cc(C)c2[nH]c(=O)c3sccc3c2c1Br
Reactant: CC(CNC(=O)OC(C)(C)C)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1F
Product: COc1cc(C)c2[nH]c(=O)c3sccc3c2c1-c1ccc(C(C)CNC(=O)OC(C)(C)C)c(F)c1
Yield: 27 %

Procedure:
Following General Procedure B, 9-bromo-8-methoxy-6-methylthieno[2,3-c]quinolin-4(5H)-one) (900 mg, 2.8 mmol) was reacted with ter-butyl 2-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propylcarbamate (1.3 g, 3.3 mmol) to afford the desired product (200 mg, 27%) as a yellow solid: ESI MS m/z 497 [C27H29FN2O4S+H]+.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[C:6]2=[C:7]([OH:11])[CH:8]=[CH:9][CH:10]=[C:5]2[O:4][CH2:3]1.CN(C=O)C.F[C:19]1[N:24]=[CH:23][C:22]([N:25]2[C:29](=[O:30])[NH:28][N:27]=[C:26]2[CH3:31])=[CH:21][CH:20]=1>>[CH3:1][C:2]1([CH3:12])[C:6]2[C:7]([O:11][C:19]3[N:24]=[CH:23][C:22]([N:25]4[C:26]([CH3:31])=[N:27][NH:28][C:29]4=[O:30])=[CH:21][CH:20]=3)=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3]1
Reactant: Cc1n[nH]c(=O)n1-c1ccc(F)nc1
Reactant: CC1(C)COc2cccc(O)c21
Solvent: CN(C)C=O
Product: Cc1n[nH]c(=O)n1-c1ccc(Oc2cccc3c2C(C)(C)CO3)nc1
Temperature: 110 °C
Reaction time: 8 h
Yield: 27.7 %

Procedure:
To a solution of 3,3-dimethyl-2H-benzofuran-4-ol (WO2012/076877 Intermediate 50, 30 mg, 0.18 mmol) in dry DMF (0.5 mL) dipotassium carbonate (50.5 mg, 0.36 mmol) and then 4-(6-fluoro-3-pyridyl)-3-methyl-1H-1,2,4-triazol-5-one (Intermediate 8, 24.8 mg, 0.128 mmol) were added and the reaction mixture was stirred for 8 hours at 110° C. The reaction was quenched with water (1 ml), diluted with brine (5 ml) and extracted with ethyl acetate (2×10 ml). The organic layer was dried (Na2SO4), filtered and evaporated and the residue was purified by flash chromatography (Biotage system) on silica gel using a SNAP 10 g as column and dichloromethane/methanol from 99.5:0.5 to 95:5 as eluent affording the title compound (12 mg) as yellow pale solid.
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[NH:16][C:17]1[N:25]=[C:24]2[C:20]([NH:21][C:22](=[O:34])[N:23]2[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[O:32][CH3:33])=[C:19]([C:35]([NH2:37])=[O:36])[N:18]=1)(C(C)(C)C)(C)C.[Si](OCC1C=CC=CC=1NC1N=C2C(NC(=O)N2C2C=CC=CC=2OC)=C(C(OCC)=O)N=1)(C(C)(C)C)(C)C>CO.N>[OH:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[NH:16][C:17]1[N:25]=[C:24]2[C:20]([NH:21][C:22](=[O:34])[N:23]2[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[O:32][CH3:33])=[C:19]([C:35]([NH2:37])=[O:36])[N:18]=1
Reactant: COc1ccccc1-n1c(=O)[nH]c2c(C(N)=O)nc(Nc3ccccc3CO[Si](C)(C)C(C)(C)C)nc21
Agent: CCOC(=O)c1nc(Nc2ccccc2CO[Si](C)(C)C(C)(C)C)nc2c1[nH]c(=O)n2-c1ccccc1OC
Agent: N
Solvent: CO
Product: COc1ccccc1-n1c(=O)[nH]c2c(C(N)=O)nc(Nc3ccccc3CO)nc21
Reaction time: 16 h
Yield: 90 %

Procedure:
2-(2-((tert-Butyldimethylsilyloxy)methyl)phenylamino)-9-(2-methoxyphenyl)-8-oxo-8,9-dihydro-7H-purine-6-carboxamide. Ethyl 2-(2-((tert-butyldimethylsilyloxy)methyl)phenyl-amino)-9-(2-methoxyphenyl)-8-oxo-8,9-dihydro-7H-purine-6-carboxylate (0.190 g, 3.97 mmol) was dissolved in methanol (15 mL) and saturated with ammonia gas according to General Procedure G. After 16 h, the solution was condensed under reduced pressure to afford the title compound (0.150 g, 90%). MS (ESI) m/z 521.6. [M+1]+.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]1[CH:19]=[CH:18][C:17]([CH2:20][N:21]2[C:25]([C:26]#[N:27])=[C:24]([C:28](=[O:32])[CH2:29][CH2:30][CH3:31])[N:23]=[C:22]2[CH2:33][CH2:34][CH2:35][CH3:36])=[CH:16][CH:15]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+]>C(O)C>[C:1]([O:5][C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]1[CH:19]=[CH:18][C:17]([CH2:20][N:21]2[C:25]([C:26]#[N:27])=[C:24]([CH:28]([OH:32])[CH2:29][CH2:30][CH3:31])[N:23]=[C:22]2[CH2:33][CH2:34][CH2:35][CH3:36])=[CH:16][CH:15]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCCc1nc(C(=O)CCC)c(C#N)n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CCCCc1nc(C(O)CCC)c(C#N)n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1

Procedure:
Following a procedure similar to that described in Example 45(b), but using 0.99 g of 1-[(2'-t-butoxycarbonylbiphenyl-4-yl)methyl-2-butyl-4-butyrylimidazole-5-carbonitrile [prepared as described in step (a) above] and 0.077 g of sodium borohydride in 20 ml of ethanol, 0.88 g of the title compound was obtained as a viscous oil.
Reaction SMILES: NC1[S:3][C:4]2[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:5]=2[N:6]=1.[OH-].[K+]>C(O)(=O)C>[NH2:6][C:5]1[CH:7]=[CH:8][C:9]([O:11][CH3:12])=[CH:10][C:4]=1[SH:3]
Reactant: COc1ccc2nc(N)sc2c1
Agent: [K+]
Agent: [OH-]
Solvent: CC(=O)O
Product: COc1ccc(N)c(S)c1
Reaction time: 1 h
Yield: 81 %

Procedure:
A solution of 2-amino-6-methoxybenzothiazole (36 g, 200 mmol; Aldrich Chemical Co.) and 400 ml 30% aqueous potassium hydroxide was refluxed for 16 h. The dark solution was cooled to 0° C. and neutralized to pH 6 with 50% aqueous acetic acid and stirred for 1 h. The resulting slurry was filtered and the product collected on the filter paper and dried (25.29 g, 81% yield). 1H NMR (DMSO-d6) δ 6.91-6.44 (m, 3H), 5.90 (br s, 2H). 3.52 (s, 3H). MS Da/e=154 (M-H).
Reaction SMILES: [NH2:1][C:2]1[C:7]2=[C:8]([C:14]3[CH:19]=[CH:18][C:17]([NH:20][C:21]([NH:23][C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[N:25]=4)=[O:22])=[CH:16][CH:15]=3)[CH:9]=[C:10]([C:11](O)=[O:12])[N:6]2[N:5]=[CH:4][N:3]=1.[F:34][C:35]([F:39])([F:38])[CH2:36][NH2:37].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CN1CCOCC1>CN(C=O)C>[NH2:1][C:2]1[C:7]2=[C:8]([C:14]3[CH:15]=[CH:16][C:17]([NH:20][C:21]([NH:23][C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:32])([F:33])[F:31])[N:25]=4)=[O:22])=[CH:18][CH:19]=3)[CH:9]=[C:10]([C:11]([NH:37][CH2:36][C:35]([F:39])([F:38])[F:34])=[O:12])[N:6]2[N:5]=[CH:4][N:3]=1
Reactant: Nc1ncnn2c(C(=O)O)cc(-c3ccc(NC(=O)Nc4cccc(C(F)(F)F)n4)cc3)c12
Reactant: NCC(F)(F)F
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: Nc1ncnn2c(C(=O)NCC(F)(F)F)cc(-c3ccc(NC(=O)Nc4cccc(C(F)(F)F)n4)cc3)c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 46.2 %

Procedure:
A mixture of 4-amino-5-{4-[({[6-(trifluoromethyl)pyridin-2-yl]amino}carbonyl)amino]phenyl}pyrrolo[2,1-f][1,2,4]triazine-7-carboxylic acid (30.0 mg, 0.066 mmol), 2,2,2-trifluoroethylamine (32.5 mg, 0.33 mmol), benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (58.0 mg, 0.13 mmol), and 4-methylmorpholine (13.3 mg, 0.13 mmol) in DMF (2 mL) was stirred at rt overnight. The crude reaction mixture was purified directly by HPLC using a gradient of 30-90% MeCN in water to afford 16.4 mg (36%) of the title compound as a white solid. 1H-NMR (DMSO-d6) δ 9.88 (s, 1H), 9.73 (s, 1H), 9.40 (t, J=6.6 Hz, 1H), 8.34 (bs, 1H), 8.18 (s, 1H), 8.05 to 7.98 (m, 2H), 7.58 (d, J=8.6 Hz, 2H), 7.51-7.49 (m, 1H), 7.44 (d, J=8.7 Hz, 2H), 7.24 (s, 1H), 5.94 (bs, 1H), 4.33-4.24 (m, 2H); MS [M+H]+=539.0; LCMS RT=3.24 min.
Reaction SMILES: Cl[C:2]1[C:3]2[N:11]([CH3:12])[CH:10]=[C:9]([C:13]3[C:18]([CH3:19])=[CH:17][C:16]([O:20][CH3:21])=[CH:15][C:14]=3[CH3:22])[C:4]=2[N:5]=[C:6]([CH3:8])[N:7]=1.[NH2:23][CH2:24][CH2:25][NH:26][C:27](=[O:37])[CH2:28][C:29]1[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=1.O>CN1C(=O)CCC1>[CH3:36][O:35][C:32]1[CH:31]=[CH:30][C:29]([CH2:28][C:27]([NH:26][CH2:25][CH2:24][NH:23][C:2]2[C:3]3[N:11]([CH3:12])[CH:10]=[C:9]([C:13]4[C:18]([CH3:19])=[CH:17][C:16]([O:20][CH3:21])=[CH:15][C:14]=4[CH3:22])[C:4]=3[N:5]=[C:6]([CH3:8])[N:7]=2)=[O:37])=[CH:34][CH:33]=1
Reactant: COc1ccc(CC(=O)NCCN)cc1
Reactant: COc1cc(C)c(-c2cn(C)c3c(Cl)nc(C)nc23)c(C)c1
Solvent: CN1CCCC1=O
Solvent: O
Product: COc1ccc(CC(=O)NCCNc2nc(C)nc3c(-c4c(C)cc(OC)cc4C)cn(C)c23)cc1

Procedure:
Heat a solution of 4-chloro-7-(4-methoxy-2,6-dimethyl-phenyl)-2,5-dimethyl-5H-pyrrolo[3,2-d]pyrimidine (120 mg, 0.38 mmol) and N-(2-amino-ethyl)-2-(4-methoxy-phenyl)-acetamide (125 mg) in NMP (2 mL) for 14 h at 130° C. Pour into water (5 mL) and extract with EtOAc (2×10 mL). Dry the combined organic extracts over Na2SO4, filter, and concentrate under reduced pressure to obtain the title compound which is used without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:20]3[CH2:19][C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[C:12]=3[C:11]([C:21]#[N:22])=[C:10]([N:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)[CH:9]=2)=[CH:4][CH:3]=1.[H-].[Na+].C1C[O:34]CC1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:20]3[C:19](=[O:34])[C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[C:12]=3[C:11]([C:21]#[N:22])=[C:10]([N:23]3[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]3)[CH:9]=2)=[CH:6][CH:7]=1
Reactant: N#Cc1c(N2CCCCC2)cc(-c2ccc(F)cc2)c2c1-c1ccccc1C2
Reactant: C1CCOC1
Agent: [H-]
Agent: [Na+]
Product: N#Cc1c(N2CCCCC2)cc(-c2ccc(F)cc2)c2c1-c1ccccc1C2=O
Temperature: 25 °C
Yield: 91 %

Procedure:
A solution of 1-(4-fluorophenyl)-3-(piperidin-1-yl)-9H-fluorene-4-carbonitrile (368 mg) in THF was added sodium hydride (38 mg) and was stirred at room temperature for less than five minutes. After completion, the reaction solvent was evaporated under vacuum and the crude solid obtained was quenched with ice water and subsequently neutralized by dilute HCl. The precipitate thus obtained was filtered and purified on a silica gel column using ethyl acetate-hexane as eluent. Yellow solid; yield 91%; mp 180-182° C.; ESMS 383 (M++1); IR (KBr) 1707 cm−1 (CO), 2219 (CN); 1H NMR (300 MHz, CDCl3) δ 1.69-1.75 (m, 2H, CH2), 1.80-1.89 (m, 4H, 2CH2), 3.39-3.44 (m, 4H, 2CH2), 6.63 (s, 1H, ArH), 7.16 (t, J=8.6 Hz, 2H, ArH), 7.41 (t, J=7.6 Hz, 1H, ArH), 7.46-7.53 (m, 2H, ArH), 7.56-7.65 (m, 2H, ArH), 8.37 (d, J=7.6 Hz, 1H, ArH).
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][CH2:4][CH:3]1[C:7]([O:9][CH2:10][CH3:11])=[O:8].C1N=C(N)C2N=CN([C@@H]3O[C@H](COP(OP(OC[C@H]4O[C@@H](N5C=C(C(N)=O)CC=C5)[C@H](O)[C@@H]4O)(O)=O)(O)=O)[C@@H](O)[C@H]3OP(O)(O)=O)C=2N=1.P([O-])([O-])([O-])=O.O=C[C@@H]([C@H]([C@@H]([C@@H](CO)O)O)O)O.C1C=[N+]([C@@H]2O[C@H](COP(OP(OC[C@H]3O[C@@H](N4C5N=CN=C(N)C=5N=C4)[C@H](OP(O)(O)=O)[C@@H]3O)(O)=O)(O)=O)[C@@H](O)[C@H]2O)C=C(C(N)=O)C=1>>[OH:1][CH:2]1[CH2:6][CH2:5][CH2:4][CH:3]1[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: CCOC(=O)C1CCCC1=O
Agent: NC(=O)C1=CN([C@@H]2O[C@H](COP(=O)(O)OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](OP(=O)(O)O)[C@@H]3O)[C@@H](O)[C@H]2O)C=CC1
Agent: NC(=O)c1ccc[n+]([C@@H]2O[C@H](COP(=O)(O)OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](OP(=O)(O)O)[C@@H]3O)[C@@H](O)[C@H]2O)c1
Agent: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Product: CCOC(=O)C1CCCC1O
Reaction time: 6 h

Procedure:
The asymmetric reduction of ethyl 2-oxocyclopentanecarboxylate was carried out by using this reductase (1). Namely, 4 ml of the reaction mixture containing the reductase (1) (2U), NADPH (0.8 μmol), ethyl 2-oxocyclopentanecarboxylate (100 μmol, 16 mg), phosphate buffer solution (pH 7.0, 400 μmol), glucose dehydrogenase [manufactured by Sigma, Co., U.S.A.; 2U (wherein 1U is defined as the amount of the enzyme which reduces 1 μmol of NADP+ per 1 minute in the presence of glucose)] and glucose (100 μmol) was incubated at 30° C. with gentle shaking to promote the enzymatic reaction. After 6 hour-incubation, the reaction mixture was extracted according to the same manner as in Example 3. The extract was analyzed by gas chromatography described in Example 1. As a result, the yield of the cis isomer was 15.9 mg (reduction yield >99%), and neither the remaining substrate nor the trans isomer was detected. On the other hand, the extract above was distilled off according to the the same manner as in Example 3 to obtain the reduction product, ethyl 2-hydroxycyclopentane-carboxylate. The resulting reduction product was analyzed by high performance liquid chromatography as described in Example 1. As a result, only the cis 2 isomer was detected and no other isomers were detected.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([C:9]([F:12])([F:11])[F:10])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:20][CH2:21][OH:22]>C(#N)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:20][CH2:21][OH:22])=[C:4]([C:9]([F:10])([F:11])[F:12])[CH:3]=1
Reactant: OCCBr
Reactant: Oc1ccc(Br)cc1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: OCCOc1ccc(Br)cc1C(F)(F)F

Procedure:
4-Bromo-2-(trifluoromethyl)phenol (83 mmol, 20 g), potassium carbonate (166 mmol, 22.94 g) and 2-bromoethanol (124 mmol, 8.79 mL, 15.56 g) were combined and heated to reflux for overnight in Acetonitrile (200 mL). The reaction mixture was washed with water, 0.5M NaOH, dried over sodium sulfate and concentrated in vacuo. The resulting residue was taken up in hot heptane (300 mL) and allowed to crystallise. The solid was filtered off to afford 2-(4-bromo-2-(trifluoromethyl)-phenoxy)ethanol. (20.74 g)
Reaction SMILES: [OH:1][CH:2]1[CH2:6][CH2:5][N:4]([CH3:7])[CH2:3]1.C(N(CC)CC)C.[CH3:15][C:16]1[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1>C(Cl)Cl>[CH3:15][C:16]1[CH:21]=[CH:20][C:19]([S:22]([O:1][CH:2]2[CH2:6][CH2:5][N:4]([CH3:7])[CH2:3]2)(=[O:24])=[O:23])=[CH:18][CH:17]=1
Reactant: CN1CCC(O)C1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)OC2CCN(C)C2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 75.1 %

Procedure:
To a mixture of 3.0 g (0.03 mole) of 3-hydroxy-1-methylpyrrolidine, 3.1 g (0.03 mole) of triethylamine, and 25 mL of methylene chloride was added 5.6 g (0.03 mole) of 4-methylphenylsulfonyl chloride, and the reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated to a residue. The residue was dissolved in ether, the solution filtered, and the filtrate concentrated to give 5.75 g of product as an oil.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([NH:7][CH2:8][CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:3][N:2]=1.O=C1CCC(=O)N1[O:22][C:23](=O)[O:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=1>CN(C=O)C>[F:32][C:29]1[CH:28]=[CH:27][C:26]([CH2:25][O:24][C:23]([N:12]2[CH2:11][CH2:10][CH:9]([CH2:8][NH:7][C:4]3[CH:5]=[CH:6][N:1]=[N:2][CH:3]=3)[CH2:14][CH2:13]2)=[O:22])=[CH:31][CH:30]=1
Reactant: c1cc(NCC2CCNCC2)cnn1
Reactant: O=C(OCc1ccc(F)cc1)ON1C(=O)CCC1=O
Solvent: CN(C)C=O
Product: O=C(OCc1ccc(F)cc1)N1CCC(CNc2ccnnc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 4-[(pyridazin-4-ylamino)-methyl]-piperidine (0.20 g, 1.04 mmol, from EXAMPLE 66, Step 1) in DMF (3 mL) was added carbonic acid-4-fluoro-benzyl ester 2,5-dioxo-pyrrolidin-1-yl ester (0.28 g, 1.04 mmol). The resulting reaction solution was stirred at rt for 0.5 h, then concentrated in vacuo. The residue was purified by silica gel chromatography (1-7 (10% NH4OH in MeOH)/99-93 CH2Cl2) to give 4-[(pyridazin-4-ylamino)-methyl]-piperidine-1-carboxylic acid-4-fluoro-benzyl ester. M.S.(M+1):345.29
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C@H:17]1[O:21][C:20](=[O:22])[C@H:19]([C:23]2([OH:29])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)[CH2:18]1)[CH2:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:30][NH2:31]>CO>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)[C@@H:17]([OH:21])[CH2:18][C@@H:19]([C:23]1([OH:29])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1)[C:20]([NH:31][CH3:30])=[O:22])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@@H](CC1CCCCC1)[C@@H]1C[C@@H](C2(O)CCCCC2)C(=O)O1
Reactant: CN
Solvent: CO
Product: CNC(=O)[C@@H](C[C@H](O)[C@H](CC1CCCCC1)NC(=O)OC(C)(C)C)C1(O)CCCCC1
Reaction time: 8 h
Yield: 97 %

Procedure:
A solution of 274 mg (0.67 mmoles) of (3S, 5S)-5-[(1S)-1-(N-t-butoxycarbonylamino)-2-cyclohexylethyl]-3-(1-hydroxycyclohexyl)dihydrofuran-2(3H)-one (prepared as described in Preparation 22) in 10 ml of methanol was saturated with gaseous methylamine by passing the gas through the solution whilst ice-cooling, and then the flask containing the reaction mixture was stoppered tightly, and allowed to stand at room temperature overnight. The reaction mixture was then concentrated by evaporation under reduced pressure, and the residue was purified by medium pressure silica gel column chromatography (using a 20:1 by volume mixture of methylene chloride and methanol as eluent), followed by recrystallization from hexane, to give 286 mg (yield 97%) of the title compound as white crystals, melting at 175°-177° C.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][NH:7]C(=O)C(F)(F)F)=[CH:4][C:3]=1[C:16]1[NH:20][C:19](=[O:21])[N:18]([C:22]2[CH:23]=[N:24][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:26][CH:27]=2)[N:17]=1.[OH-].[K+].C1COCC1>O>[NH2:7][CH2:6][C:5]1[CH:14]=[CH:15][C:2]([Cl:1])=[C:3]([C:16]2[NH:20][C:19](=[O:21])[N:18]([C:22]3[CH:23]=[N:24][C:25]([C:28]([F:30])([F:29])[F:31])=[CH:26][CH:27]=3)[N:17]=2)[CH:4]=1
Reactant: O=C(NCc1ccc(Cl)c(-c2nn(-c3ccc(C(F)(F)F)nc3)c(=O)[nH]2)c1)C(F)(F)F
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: NCc1ccc(Cl)c(-c2nn(-c3ccc(C(F)(F)F)nc3)c(=O)[nH]2)c1
Yield: 110.2 %

Procedure:
The title compound was prepared according to the procedure described in Intermediate-66 by using N-(4-chloro-3-(1-(6-(trifluoromethyl)pyridin-3-yl)-4,5-dihydro-5-oxo-1H-1,2,4-triazol-3-yl)benzyl)-2,2,2-trifluoroacetamide (0.400 g), KOH (0.400 g), THF (5.0 mL), and water (5 mL) to afford 0.350 g of the desired product.
Reaction SMILES: N1C=CC=CC=1.[CH3:7][C:8]1([OH:18])[CH:15]2[CH2:16][CH:11]3[CH2:12][CH:13]([CH2:17][CH:9]1[CH2:10]3)[CH2:14]2.[C:19](Cl)(=[O:23])[C:20]([CH3:22])=[CH2:21]>C1COCC1>[C:19]([O:18][C:8]1([CH3:7])[CH:9]2[CH2:17][CH:13]3[CH2:12][CH:11]([CH2:16][CH:15]1[CH2:14]3)[CH2:10]2)(=[O:23])[C:20]([CH3:22])=[CH2:21]
Reactant: C=C(C)C(=O)Cl
Reactant: CC1(O)C2CC3CC(C2)CC1C3
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: C=C(C)C(=O)OC1(C)C2CC3CC(C2)CC1C3
Yield: 39 %

Procedure:
The procedure of Comparative Example 1 was repeated with the proviso that under the cooling conditions, 24 ml of pyridine was slowly dropwise added to a mixture of 22.6 g (0.136 mole) of 2-methyl-2-adamantanol, 130 ml of THF and 26.6 g of methacrylic chloride. The raw product was purified on a column of silica gel to obtain 12.1 g of the target product, i.e., 2-methyl-2-adamantyl methacrylate, (yield: 39.0%). It was confirmed that the product contained a remarkable amount of impurities.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]([CH:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1)=[O:10].[C:17]([O:21][C:22](=[O:33])[NH:23][C@H:24]1[CH2:29][CH2:28][C@H:27]([CH2:30][CH:31]=O)[CH2:26][CH2:25]1)([CH3:20])([CH3:19])[CH3:18]>>[C:17]([O:21][C:22](=[O:33])[NH:23][C@H:24]1[CH2:25][CH2:26][C@H:27]([CH2:30][CH2:31][N:14]2[CH2:13][CH2:12][CH:11]([C:9](=[O:10])[C:3]3[CH:4]=[C:5]([Cl:8])[CH:6]=[CH:7][C:2]=3[Cl:1])[CH2:16][CH2:15]2)[CH2:28][CH2:29]1)([CH3:20])([CH3:19])[CH3:18]
Reactant: O=C(c1cc(Cl)ccc1Cl)C1CCNCC1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](CC=O)CC1
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@H](CCN2CCC(C(=O)c3cc(Cl)ccc3Cl)CC2)CC1

Procedure:
The title compound was prepared as described on example 1 from (2,5-Dichloro-phenyl)-piperidin-4-yl-methanone and Trans-[4-(2-Oxo-ethyl)-cyclohexyl]-carbamic acid tert-butyl ester (m/e): 483.5 (M+H+)
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][C:5]#[N:6].[NH:7]1[CH2:12][CH2:11][O:10][CH2:9][CH2:8]1.O1CCCC1>C(OCC)C>[O:10]1[CH2:11][CH2:12][N:7]([CH2:2][CH2:3][CH2:4][C:5]#[N:6])[CH2:8][CH2:9]1
Reactant: N#CCCCBr
Reactant: C1COCCN1
Solvent: C1CCOC1
Solvent: CCOCC
Product: N#CCCCN1CCOCC1
Yield: 90.2 %

Procedure:
A mixture of 10.0 g of 4-bromobutyronitrile, 14.7 g of morpholine and 40 g of tetrahydrofuran was heated under reflux for 10 hours. The reaction solution was cooled, diluted with diethyl ether, filtered, and concentrated in vacuum. Purification by vacuum distillation yielded 9.4 g of 4-morpholinobutyronitrile (boiling point: 85° C./50 Pa, yield: 91%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6](F)[CH:5]=[C:4]([Cl:9])[CH:3]=1.[OH:10][C:11]1[CH:12]=[N:13][CH:14]=[N:15][CH:16]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Br:1][C:2]1[CH:7]=[C:6]([CH:5]=[C:4]([Cl:9])[CH:3]=1)[O:10][C:11]1[CH:12]=[N:13][CH:14]=[N:15][CH:16]=1
Reactant: Fc1cc(Cl)cc(Br)c1
Reactant: Oc1cncnc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Clc1cc(Br)cc(Oc2cncnc2)c1
Yield: 53.6 %

Procedure:
1-Bromo-3-chloro-5-fluorobenzene (1.0 g, 4.8 mmol, 1.0 eq), 5-hydroxypyrimidine (454 mg, 5.02 mmol, 1.05 eq), K2CO3 (792 mg, 5.73 mmol, 1.20 eq) and DMF (15 mL) were added to a microwave vial and microwaved at 200° C. for 30 minutes. The reaction was filtered and concentrated on silica gel (5 g). The silica gel was loaded on top a fresh bed of silica gel and washed with 50% ethyl acetate/hexane. The solvents were removed in vacuo and the crude mixture was purified by flash chromatography on silica gel afforded 735 mg (43%) of the title compound as a golden oil: 1H NMR (400 MHz, DMSO-d6) δ 9.07 (s, 1H), 8.73 (s, 2H), 7.58 (t, J=1.7 Hz, 1H), 7.43 (t, J=1.9 Hz, 1H), 7.35 (t, J=2.0 Hz, 1H); ES-MS [M+1]+: 285.0.