Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(NCCO)C1C=CC=CC=1.C([C@H]1OC1)Cl.[OH-:17].[Na+].C([N:26]1[CH2:31][CH2:30][O:29][CH:28]([CH2:32][OH:33])[CH2:27]1)C1C=CC=CC=1.C(N1CCCOCC1)C1C=CC=CC=1.OCC1OCCNC1.O1CCCNCC1.[N+:63]([C:66]1[CH:74]=[CH:73][C:69]([C:70]([OH:72])=[O:71])=[CH:68][CH:67]=1)([O-])=[O:64]>[C].[Pd].CO.O.CC(O)C>[N+:63]([C:66]1[CH:67]=[CH:68][C:69]([C:70]([OH:72])=[O:71])=[CH:73][CH:74]=1)([O-:64])=[O:17].[OH:33][CH2:32][C@@H:28]1[O:29][CH2:30][CH2:31][NH:26][CH2:27]1
Reactant: OCC1CN(Cc2ccccc2)CCO1
Reactant: [OH-]
Agent: [Pd]
Agent: C1CNCCOC1
Agent: ClC[C@@H]1CO1
Solvent: O
Solvent: CC(C)O
Solvent: CO
Product: OC[C@H]1CNCCO1
Temperature: 10 °C
Reaction time: 0.5 h

Procedure:
To a mixture of N-benzylethanolamine (302.4 g, 2.0 mol), 2-propanol (185 ml) and water (185 ml) was added dropwise at 15 to 25° C. (S)-epichlorohydrin (185.0 g, 2.0 mol, 99% ee). After reaction at 15 to 25° C. for 7 hr, aqueous 24% NaOH solution (NET 104 g, 2.6 mol) was added at 5 to 10° C. After reaction at 25° C. for 20 hr, the reaction mixture was concentrated under reduced pressure to evaporate 2-propanol. To the residue was added toluene (555 ml) and, after partitioning, the organic layer was concentrated under reduced pressure to give a mixture of N-benzyl-2-hydroxymethylmorpholine, N-benzyl-1,4-oxazepane and other byproducts (410.4 g, N-benzyl-2-hydroxymethylmorpholine:N-benzyl-1,4-oxazepane compound=75.2:24.8). To this mixture were added methanol (830 ml) and palladium carbon (40.0 g when dry), and the mixture was reacted under a hydrogen stream at 25° C. for 15 hr. Palladium carbon was filtered off, methanol was evaporated under reduced pressure to give a mixture of 2-hydroxymethylmorpholine and a 1,4-oxazepane compound (265.7 g, 2-hydroxymethylmorpholine:1,4-oxazepane compound=75.8:24.2). To the mixture (20.0 g) were added methanol (100 ml) and p-nitrobenzoic acid (25.2 g, 0.151 mol) and the mixture was stirred for 30 min. Then, methanol was evaporated under reduced pressure. To the residue was added 2-propanol (50 ml) and the mixture was subjected twice to azeotropic distillation with dehydrating. To the residue after azeotropic distillation with dehydrating was added ethyl acetate (100 ml) at 40° C., and the mixture was cooled to 10° C. After crystallization, the mixture was cooled to 0° C. and stirred for 1 hr. The crystals were collected by filtration, washed withed twice with ethyl acetate (25 ml) and dried (1 mmHg, 40° C.) to give (R)-2-hydroxymethylmorpholine p-nitrobenzoate (17.7 g) (yield from (S)-epichlorohydrin 41.3%). The obtained (R)-2-hydroxymethylmorpholine p-nitrobenzoate was analyzed by HPLC to find an optical purity of 99% ee.
Reaction SMILES: [Br:1][C:2]1[C:3](F)=[C:4]2[C:10]([NH:11][C:12]([C:14]3([CH3:17])[CH2:16][CH2:15]3)=[O:13])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[NH:19]1[CH2:24][CH2:23][CH2:22][C@@H:21]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[CH2:20]1>C(O)(CC)C>[Br:1][C:2]1[C:3]([N:19]2[CH2:24][CH2:23][CH2:22][C@@H:21]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:30])([CH3:29])[CH3:31])[CH2:20]2)=[C:4]2[C:10]([NH:11][C:12]([C:14]3([CH3:17])[CH2:16][CH2:15]3)=[O:13])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: CC1(C(=O)Nc2c[nH]c3ncc(Br)c(F)c23)CC1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCNC1
Solvent: CCC(C)O
Product: CC(C)(C)OC(=O)N[C@@H]1CCCN(c2c(Br)cnc3[nH]cc(NC(=O)C4(C)CC4)c23)C1
Yield: 52.1 %

Procedure:
N-(5-Bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-1-methylcyclopropanecarboxamide (464 mg, 1.49 mmol) and (R)-tert-butyl piperidin-3-ylcarbamate (298 mg, 1.49 mmol) in s-BuOH (5 mL) were heated to 135° C. in a sealed tube for 24 hours. After cooling down, the residue was concentrated and purified by reverse phase chromatography (SP4, 25M, water/ACN 80/20→0/100, 30 CV) to yield (R)-tert-butyl 1-(5-bromo-3-(1-methylcyclopropanecarboxamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate (382 mg, 52.2% yield) as a solid.
Reaction SMILES: [CH2:1]([C:3]1[N:13]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][NH2:22])=[CH:16][CH:15]=2)[C:6]2=[N:7][C:8]([CH3:12])=[CH:9][C:10]([CH3:11])=[C:5]2[N:4]=1)[CH3:2].[C:23]1([CH3:35])[CH:28]=[CH:27][C:26]([S:29]([N:32]=[C:33]=[O:34])(=[O:31])=[O:30])=[CH:25][CH:24]=1>ClCCl>[CH2:1]([C:3]1[N:13]([C:14]2[CH:15]=[CH:16][C:17]([CH2:20][CH2:21][NH:22][C:33]([NH:32][S:29]([C:26]3[CH:27]=[CH:28][C:23]([CH3:35])=[CH:24][CH:25]=3)(=[O:31])=[O:30])=[O:34])=[CH:18][CH:19]=2)[C:6]2=[N:7][C:8]([CH3:12])=[CH:9][C:10]([CH3:11])=[C:5]2[N:4]=1)[CH3:2]
Reactant: CCc1nc2c(C)cc(C)nc2n1-c1ccc(CCN)cc1
Reactant: Cc1ccc(S(=O)(=O)N=C=O)cc1
Solvent: ClCCl
Product: CCc1nc2c(C)cc(C)nc2n1-c1ccc(CCNC(=O)NS(=O)(=O)c2ccc(C)cc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 55.9 %

Procedure:
To a solution of 2-[4-(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]ethylamine (step 9, 1.2 g, 4.0 mmol) in dichloromethane (15 mL) was added p-toluenesulfonyl isocyanate (805 mg, 4.0 mmol). The resulting mixture was stirred at room temperature for 3 h. After removal of solvent, the residue was purified by flash column chromatography on silica gel eluting with dichloromethane/methanol (20:1) to afford 1.10 g (56%) of the title compound as white solids: 1H-NMR (CDCl3) δ 7.85 (2H, d, J=8.2 Hz), 7.32 (2H, d, J=8.2 Hz), 7.23 (2H, d, J=8.4 Hz), 7.16 (2H, d, J=8.4 Hz), 6.91 (1H, s), 6.12 (1H, br. s), 3.55-3.46 (2H, m), 2.85 (2H, t, J=6.3 Hz), 2.74-2.64 (5H, m), 2.42 (3H, s), 2.41 (3H, s), 1.21 (3H, t, J=7.6 Hz).
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]([F:15])([C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=1)[C:4]([F:7])([F:6])[F:5].BrN1C(=[O:24])CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[N+](C(C)C)([O-])=O.[Na]>ClC(Cl)(Cl)Cl.C(O)C>[F:15][C:3]([C:8]1[CH:13]=[CH:12][C:11]([CH:14]=[O:24])=[CH:10][CH:9]=1)([C:4]([F:7])([F:6])[F:5])[C:2]([F:16])([F:17])[F:1]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(C(F)(C(F)(F)F)C(F)(F)F)cc1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Agent: [Na]
Solvent: CCO
Solvent: ClC(Cl)(Cl)Cl
Solvent: CC(C)[N+](=O)[O-]
Product: O=Cc1ccc(C(F)(C(F)(F)F)C(F)(F)F)cc1
Temperature: 0 °C
Reaction time: 72 h
Yield: 29.9 %

Procedure:
A solution of 3.5 g of 4-(heptafluoroisopropyl)-toluene (13.4 mmol) in 100 ml tetra-chloromethane was heated to reflux. Then 2.63 g of N-bromosuccinimide (14.8 mmol) and 326 mg of dibenzoyl peroxide (1.34 mmol) were added in small portions. After 5 h the mixture was cooled to 0° C., filtered and the solvent was evaporated. The remaining residue was dissolved in 15 ml ethanol and was added to a suspension that had been prepared by addition of 2-nitropropane (1.4 ml, 15.5 mmol) to a solution of 340 mg sodium (14.8 mmol) in ethanol. This mixture was stirred for 3 days. Then it was filtered, the solvent was removed and the remaining residue was dissolved in EtOAc and washed with 1 N sodium hydroxide solution, 1 N HCl solution, saturated NaHCO3 solution and with brine. The EtOAc layer was then dried with magnesium sulfate, filtered and concentrated. Purification of the residue (silica gel; c-hexane/EtOAc 10:1) gave 1.1 g (30%) of 4-(1,2,2,2-tetrafluoro-1-trifluoromethyl-ethyl)-benzaldehyde as a light yellow oil. 1H-NMR (CDCl3, 300 MHz): δ 7.82 (d, J=8 Hz, 2H), 8.03 (d, J=8 Hz, 2H), 10.11 (s, 1H).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7](=[O:24])[NH:8][C:9]2[CH:14]=[CH:13][N:12]3[N:15]=[C:16]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[N:17]=[C:11]3[CH:10]=2)=[C:5]([C:25]([OH:27])=O)[CH:4]=[N:3]1.[CH2:28]([NH:30][CH2:31][CH3:32])[CH3:29].CCCP(=O)=O>O1CCCC1>[CH2:28]([N:30]([CH2:31][CH3:32])[C:25]([C:5]1[CH:4]=[N:3][N:2]([CH3:1])[C:6]=1[C:7]([NH:8][C:9]1[CH:14]=[CH:13][N:12]2[N:15]=[C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:17]=[C:11]2[CH:10]=1)=[O:24])=[O:27])[CH3:29]
Reactant: Cn1ncc(C(=O)O)c1C(=O)Nc1ccn2nc(-c3ccccc3)nc2c1
Reactant: CCNCC
Agent: CCCP(=O)=O
Solvent: C1CCOC1
Product: CCN(CC)C(=O)c1cnn(C)c1C(=O)Nc1ccn2nc(-c3ccccc3)nc2c1
Temperature: 70 °C
Reaction time: 20 h
Yield: 80.7 %

Procedure:
A mixture of 1-methyl-5-(2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-ylcarbamoyl)-1H-pyrazole-4-carboxylic acid (100 mg, 276 μmol), diethylamine (142 μl, 1.38 mmol) and propylphosphonic anhydride (50% in ethyl acetate, 407 μl, 690 μmol) in tetrahydrofurane (7 ml) is stirred for 20 hours at 70° C. under nitrogen atmosphere. The solvent is evaporated and to the residue is added sat. aqueous sodium hydrogencarbonate solution. The mixture is stirred for 20 minutes while a white solid precipitates. The solid is collected by filtration, washed with diethylether and dried affording N4,N4-diethyl-1-methyl-N5-(2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1H-pyrazole-4,5-dicarboxamide (93 mg, 80.7%) as a white solid. mp.: 177-9° C. MS: m/z=418.3 (M+H+).
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:2][C:3]([CH3:5])=O.[CH:10]1([NH2:13])[CH2:12][CH2:11]1>>[CH2:8]([O:7][C:1](=[O:6])[CH:2]=[C:3]([NH:13][CH:10]1[CH2:12][CH2:11]1)[CH3:5])[CH3:9]
Reactant: NC1CC1
Reactant: CCOC(=O)CC(C)=O
Product: CCOC(=O)C=C(C)NC1CC1
Temperature: 40 °C
Reaction time: 3 h
Yield: 93.7 %

Procedure:
A mixture of ethyl acetoacetate (5.00 mL, 39.3 mmol) and cyclopropylamine (3.27 mL, 47.1 mmol) is stirred at 40° C. for 3 h. The mixture is concentrated under high vacuum overnight to give the title compound (6.23 g, 94%) of the as an oil, which is used without further purification in the next reaction.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][N:6]([C:21]2[C:26]([Cl:27])=[CH:25][C:24]([C:28]([F:31])([F:30])[F:29])=[CH:23][N:22]=2)[C:7]=1[CH:8]=[CH:9][C:10]([O:12][C:13]([C:16]([O:18]CC)=[O:17])(C)C)=[O:11])#[N:2]>FC(F)(F)C(O)=O>[C:1]([C:3]1[CH:4]=[N:5][N:6]([C:21]2[C:26]([Cl:27])=[CH:25][C:24]([C:28]([F:29])([F:31])[F:30])=[CH:23][N:22]=2)[C:7]=1[CH:8]=[CH:9][C:10]([O:12][CH2:13][C:16]([OH:18])=[O:17])=[O:11])#[N:2]
Reactant: CCOC(=O)C(C)(C)OC(=O)C=Cc1c(C#N)cnn1-c1ncc(C(F)(F)F)cc1Cl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1cnn(-c2ncc(C(F)(F)F)cc2Cl)c1C=CC(=O)OCC(=O)O
Yield: 103.4 %

Procedure:
A solution of 0.33 gram (0.0007 mole) of 1,1-dimethylethoxycarbonylmethyl 3-[4-cyano-1-(3-chloro-5-trifluoromethylpyridin-2-yl)-1H-pyrazol-5-yl]acrylate in 1.3 mL of trifluoroacetic acid was stirred at ambient temperature for one hour. After this time, the reaction mixture was concentrated under reduced pressure at a temperature of about 30° to 50° C. The resultant residue was taken up in toluene, and the concentration procedure was repeated. The residue was shaken with diethyl ether and water and then concentrated under reduced pressure at a temperature of about 45° C., yielding 0.29 gram of 90% pure carboxymethyl 3-[4-cyano-1-(3-chloro-5-trifluoromethylpyridin-2-yl)-1H-pyrazol-5-yl]acrylate. The nmr spectrum was consistent with the proposed structure.
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[C:8]([C:10]3[CH:11]=[C:12]([CH:17]=[CH:18][CH:19]=3)[C:13]([O:15][CH3:16])=[O:14])[CH:9]=[C:4]2[CH:3]=[N:2]1.C1C(=O)N([I:27])C(=O)C1>ClC(Cl)C>[I:27][C:3]1[C:4]2[C:5](=[N:6][CH:7]=[C:8]([C:10]3[CH:11]=[C:12]([CH:17]=[CH:18][CH:19]=3)[C:13]([O:15][CH3:16])=[O:14])[CH:9]=2)[NH:1][N:2]=1
Reactant: COC(=O)c1cccc(-c2cnc3[nH]ncc3c2)c1
Reactant: O=C1CCC(=O)N1I
Solvent: CC(Cl)Cl
Product: COC(=O)c1cccc(-c2cnc3[nH]nc(I)c3c2)c1
Temperature: 70 °C
Reaction time: 6 h
Yield: 40 %

Procedure:
To a solution of methyl 3-(1H-pyrazolo[3,4-b]pyridin-5-yl)benzoate (1.65 g, 6.52 mmol) in dichloroethane (40 mL) was added NIS (1.81 g, 8.04 mmol) and the mixture was stirred at 70° C. for 6 hours. The solvent was removed by reduced pressure and the crude product was purified by silica gel chromatography to afforded methyl 3-(3-iodo-1H-pyrazolo[3,4-b]pyridin-5-yl)benzoate (9) (988 mg, 40% yield). MS: m/z 379.9 (M+H+).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([NH:11][C:12]([CH:14]2[CH2:18][CH:17]([O:19][C:20]3[C:29]4[C:24](=[C:25]([CH3:32])[C:26]([O:30][CH3:31])=[CH:27][CH:28]=4)[N:23]=[C:22]([C:33]4[CH:38]=[CH:37][CH:36]=[C:35]([CH3:39])[N:34]=4)[CH:21]=3)[CH2:16][CH:15]2[C:40](=[O:49])[N:41]([CH2:43][CH2:44][CH2:45][CH2:46]C=C)[CH3:42])=[O:13])[CH2:8][CH:7]1[CH:9]=[CH2:10])=[O:5])[CH3:2]>ClCCCl>[CH2:1]([O:3][C:4]([C:6]12[CH2:8][CH:7]1[CH:9]=[CH:10][CH2:46][CH2:45][CH2:44][CH2:43][N:41]([CH3:42])[C:40](=[O:49])[CH:15]1[CH:14]([CH2:18][CH:17]([O:19][C:20]3[C:29]4[C:24](=[C:25]([CH3:32])[C:26]([O:30][CH3:31])=[CH:27][CH:28]=4)[N:23]=[C:22]([C:33]4[CH:38]=[CH:37][CH:36]=[C:35]([CH3:39])[N:34]=4)[CH:21]=3)[CH2:16]1)[C:12](=[O:13])[NH:11]2)=[O:5])[CH3:2]
Reactant: C=CCCCCN(C)C(=O)C1CC(Oc2cc(-c3cccc(C)n3)nc3c(C)c(OC)ccc23)CC1C(=O)NC1(C(=O)OCC)CC1C=C
Solvent: ClCCCl
Product: CCOC(=O)C12CC1C=CCCCCN(C)C(=O)C1CC(Oc3cc(-c4cccc(C)n4)nc4c(C)c(OC)ccc34)CC1C(=O)N2
Temperature: 25 °C
Yield: 58.6 %

Procedure:
1-{2-(Hex-5-enylmethylcarbamoyl)-4-[2-(6-methyl-2-pyridyl)-7-methoxy-8-methyl-quinolin-4-yloxy]cyclopentanecarbonyl}amino-2-vinylcyclopropanecarboxylic acid ethyl ester (100, 250 mg, 0.37 mmol) was dissolved in dry 1,2-dichloroethane (250 mL). Then, nitrogen gas was bubbled through the solution for 30 min before Hoveyda-Grubbs 2nd generation (25 mg) was added. The resulting solution was refluxed overnight, then cooled down to room temperature and evaporated. The residue was purified by column chromatography on silica gel (gradient AcOEt/Heptane, 3:7 to 5:5) to give 139 mg (58%) of the title compound 101.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:13]([NH:14][C:15](=[O:23])OC2C=CC=CC=2)=[N:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1)[CH3:2].[CH2:24]([O:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[N:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1)[CH3:25]>>[CH2:1]([O:3][C:4]1[C:13]([NH:14][C:15]([N:36]2[CH2:35][CH2:34][N:33]([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=3[O:26][CH2:24][CH3:25])[CH2:38][CH2:37]2)=[O:23])=[N:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1)[CH3:2]
Reactant: CCOc1nc2ccccc2nc1NC(=O)Oc1ccccc1
Reactant: CCOc1ccccc1N1CCNCC1
Product: CCOc1ccccc1N1CCN(C(=O)Nc2nc3ccccc3nc2OCC)CC1
Yield: 76.5 %

Procedure:
Phenyl N-(2-ethoxyquinoxalin-3-yl)carbamate and 1-(2-ethoxyphenyl)-piperazine were reacted by the same way with the example 36 to obtain the titled compound.
Reaction SMILES: CO.[OH-].[K+].[C:5](I)([C:8]([C:11]([C:14]([C:17]([C:20]([F:23])([F:22])[F:21])([F:19])[F:18])([F:16])[F:15])([F:13])[F:12])([F:10])[F:9])([F:7])[F:6]>[Br-].C([P+](CCCC)(CCCC)CCCC)CCC.O>[CH:5]([C:8]([C:11]([C:14]([C:17]([C:20]([F:21])([F:22])[F:23])([F:18])[F:19])([F:15])[F:16])([F:13])[F:12])([F:10])[F:9])([F:7])[F:6]
Reactant: FC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)I
Agent: CCCC[P+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: FC(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.1 %

Procedure:
Into a 1 l four-necked flask equipped with a stirrer, a reflux condenser, a dropping funnel and a thermometer, 200 cc of methanol, 74.3 g (1.1 mols) of 85% potassium hydroxide and 1 g of tetrabutylphosphonium bromide were charged. The reactor was heated to bring the internal temperature to 60° C. Then, 223 g (0.5 mol) of C6F13I was dropwise added thereto over a period of one hour. After completion of the dropwise addition, heating and refluxing were continued for tow hours. The conversion at that time was 98.1%. The heating and refluxing were further continued for two hours. Then, the reactor was cooled to room temperature, and 200 g of water was added to dissolve precipitated potassium iodide. The crude reaction solution was separated into two layers, and the fluorocarbon layer (lower layer) was further washed with 300 g of water to recover the fluorocarbon. Thus, 157 g of C6F13H having a purity of 99.1%, was obtained.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[CH2:6][O:5][C:4]([C:7]2[C:8]([CH3:14])=[C:9]([NH2:13])[CH:10]=[CH:11][CH:12]=2)=[N:3]1.C(N(CC)CC)C.[CH3:23][C:24]1[CH:39]=[CH:38][C:37]([CH3:40])=[CH:36][C:25]=1[O:26][CH2:27][CH2:28][CH2:29][C:30]([CH3:35])([CH3:34])[C:31](Cl)=[O:32]>ClCCl>[CH3:1][C:2]1([CH3:15])[CH2:6][O:5][C:4]([C:7]2[C:8]([CH3:14])=[C:9]([NH:13][C:31](=[O:32])[C:30]([CH3:34])([CH3:35])[CH2:29][CH2:28][CH2:27][O:26][C:25]3[CH:36]=[C:37]([CH3:40])[CH:38]=[CH:39][C:24]=3[CH3:23])[CH:10]=[CH:11][CH:12]=2)=[N:3]1
Reactant: Cc1c(N)cccc1C1=NC(C)(C)CO1
Reactant: Cc1ccc(C)c(OCCCC(C)(C)C(=O)Cl)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(C)c(OCCCC(C)(C)C(=O)Nc2cccc(C3=NC(C)(C)CO3)c2C)c1
Yield: 59.6 %

Procedure:
To a solution of 10.2 g (0.05 mol) of 3-(4,5-dihydro-4,4-dimethyl-2-oxazolyl)-2-methylbenzenamine and 10 ml of triethylamine in dichloromethane is added 13.4 g (0.05 mol) of 5-(2,5-dimethylphenoxy)-2,2-dimethylpentanoyl chloride (U.S. Pat. No. 4,285,951). The mixture is worked up, chromatographed over silica gel and eluted with toluene-diethyl ether (2:1) to give 13 g of N-[3-(4,5-dihydro-4,4-dimethyl-2-oxazolyl)-2-methylphenyl]-5-(2,5-dimethylphenoxy)-2,2-dimethylpentanamide; mp 51°-52° C.
Reaction SMILES: [OH:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)[CH:5]=[CH:4][CH:3]=1.[Mg+2].[Cl-].[Cl-].C(N(CC)CC)C.[CH2:31]=[O:32]>CC#N.CCOC(C)=O>[CH:31]([C:3]1[CH:4]=[CH:5][C:6]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)=[N:7][C:2]=1[OH:1])=[O:32]
Reactant: CC(C)(C)OC(=O)N1CCN(c2cccc(O)n2)CC1
Reactant: C=O
Agent: [Cl-]
Agent: [Mg+2]
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(C=O)c(O)n2)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 39 %

Procedure:
To a mixture of t-butyl 4-(6-hydroxypyridin-2-yl)piperazine-1-carboxylate (8.4 g, 30 mmol) and MgCl2 (5.8 g, 60 mmol) in CH3CN (100 mL) was added triethylamine (25.2 mL, 150 mmol). After the mixture was stirred for 10 minutes at ambient temperature, paraformaldehyde (9.0 g, 300 mmol) was added to the mixture. The mixture was stirred for 18 hours at 60° C., and then cooled to room temperature. The mixture was then diluted with EtOAc (500 mL) and washed with 1 M Rochelle salt solution (200 mL) and saturated NH4Cl solution (200 mL). The organic layer was concentrated under reduced pressure and purified by column chromatography (30%-50% EtOAc/hexanes) to yield 3.6 g (39%) of t-butyl 4-(5-formyl-6-hydroxypyridin-2-yl)piperazine-1-carboxylate as white solid. MS m/z 308.2 [M+H]+; 1H NMR (500 MHz, CDCl3) δ (ppm) 12.35 (1H, br), 9.55 (1H, s), 7.66 (1H, d, J=8.51 Hz), 6.26 (1H, d, J=8.83 Hz), 3.79 (4H, m), 3.56 (4H, m), 1.51 (9H, s).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][NH:8][C:9]([C:11]1[CH:20]=[C:19]2[C:14]([CH2:15][CH2:16][NH:17][CH2:18]2)=[CH:13][CH:12]=1)=[O:10].[CH3:21][C:22]1[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][CH:23]=1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C=O)C.C(N(CC)CC)C>[CH3:21][C:22]1[CH:30]=[CH:29][C:25]([C:26]([N:17]2[CH2:16][CH2:15][C:14]3[C:19](=[CH:20][C:11]([C:9]([NH:8][O:7][CH:2]4[CH2:3][CH2:4][CH2:5][CH2:6][O:1]4)=[O:10])=[CH:12][CH:13]=3)[CH2:18]2)=[O:27])=[CH:24][CH:23]=1
Reactant: Cc1ccc(C(=O)O)cc1
Reactant: O=C(NOC1CCCCO1)c1ccc2c(c1)CNCC2
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)N2CCc3ccc(C(=O)NOC4CCCCO4)cc3C2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 27 %

Procedure:
A mixture of 200 mg N-(tetrahydro-2H-pyran-2-yloxy)-1,2,3,4-tetrahydroisoquinoline-7-carboxamide, 108 mg 4-methylbenzoic acid, 98 mg HOBt, 278 mg EDC, 0.6 ml triethylamine and 8 ml DMF is stirred overnight at ambient temperature. The mixture is evaporated. The residue is purified by silica gel flash chromatography. 77 mg of the title compound are obtained after drying as colorless foam.
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][N:13]=2)=[CH:7][CH:6]=1)=[O:3].[F:22][C:23]([F:37])([F:36])[C:24]1[C:25]([N:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)=[N:26][CH:27]=[CH:28][CH:29]=1.[K+].[Br-]>>[F:19][C:18]([F:21])([F:20])[C:15]1[CH:16]=[CH:17][C:12]([O:11][C:8]2[CH:9]=[CH:10][C:5]([O:4][C:2]([N:33]3[CH2:34][CH2:35][N:30]([C:25]4[C:24]([C:23]([F:37])([F:22])[F:36])=[CH:29][CH:28]=[CH:27][N:26]=4)[CH2:31][CH2:32]3)=[O:3])=[CH:6][CH:7]=2)=[N:13][CH:14]=1
Reactant: FC(F)(F)c1cccnc1N1CCNCC1
Reactant: O=C(Cl)Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1
Agent: [Br-]
Agent: [K+]
Product: O=C(Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1)N1CCN(c2ncccc2C(F)(F)F)CC1
Yield: 25 %

Procedure:
The title compound was prepared from 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl chloroformate and 1-(3-trifluoromethyl-pyridin-2-yl)-piperazine, yield 25%. White crystals, m.p. 131-132° C.; HPLC-MS: m/z: 513 (M+1) at Rt=5.0 min.; IR (KBr): ν 1722 (C═O) cm−1.
Reaction SMILES: N1C=CC(N)=NC1=O.[F:9][C:10]1[CH:11]=[C:12](B(O)O)[CH:13]=[CH:14][CH:15]=1.NC1C=CN(C2C=CC(F)=CC=2)C(=O)N=1.[Cl:34][CH2:35][C:36]1[N:37]=[C:38]2[CH:43]=[CH:42][N:41](C3C=CC(F)=CC=3)[C:40](=[O:51])[N:39]2[CH:52]=1>>[Cl:34][CH2:35][C:36]1[N:37]=[C:38]2[CH:43]=[CH:42][N:41]([C:12]3[CH:13]=[CH:14][CH:15]=[C:10]([F:9])[CH:11]=3)[C:40](=[O:51])[N:39]2[CH:52]=1
Reactant: O=c1n(-c2ccc(F)cc2)ccc2nc(CCl)cn12
Reactant: OB(O)c1cccc(F)c1
Agent: Nc1cc[nH]c(=O)n1
Agent: Nc1ccn(-c2ccc(F)cc2)c(=O)n1
Product: O=c1n(-c2cccc(F)c2)ccc2nc(CCl)cn12

Procedure:
2-chloromethyl-6-(3-fluoro-phenyl)-6H-imidazo[1,2-c]pyrimidin-5-one was prepared from cytosine and 3-fluorophenylboronic acid using the methods as described above for the preparation of 4-amino-1-(4-fluoro-phenyl)-1H-pyrimidin-2-one and 2-chloromethyl-6-(4-fluoro-phenyl)-6H-imidazo[1,2-c]pyrimidin-5-one.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[N:13][N:12](C2CCCCO2)[C:11](=[O:21])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl>CO>[CH2:1]([O:8][C:9]1[CH:14]=[N:13][NH:12][C:11](=[O:21])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=c1cc(OCc2ccccc2)cnn1C1CCCCO1
Agent: Cl
Solvent: CO
Product: O=c1cc(OCc2ccccc2)cn[nH]1
Temperature: 25 °C
Reaction time: 10 h

Procedure:
To 500 mg (1.75 mmol) 5-benzyloxy-2-(tetrahydro-pyran-2-yl)-2H-pyridazin-3-one (preparation 5b) in 10 mL MeOH is added 8.73 mL (8.73 mmol) 1M aqueous HCl solution and the reaction mixture is stirred overnight at RT and 10 h at reflux. MeOH is evaporated, to the residual aqueous phase is added saturated aqueous NaHCO3-solution until the solution is basic. The aqueous phase is extracted with EtOAc, the combined organic phase is washed with water, dried over MgSO4, filtered and evaporated to afford the product.
Reaction SMILES: [OH:1][C@H:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C@H:3]1[NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15].[O:19]1[CH:24]=[CH:23][CH2:22][CH2:21][CH2:20]1>C(Cl)Cl.C(OCC)(=O)C.[NH+]1C=CC=CC=1.C1(C)C=CC(S([O-])(=O)=O)=CC=1>[O:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH:20]1[O:1][C@H:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C@H:3]1[NH:11][C:12](=[O:18])[O:13][C:14]([CH3:15])([CH3:17])[CH3:16]
Reactant: C1=COCCC1
Reactant: CC(C)(C)OC(=O)N[C@@H]1c2ccccc2C[C@@H]1O
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H]1c2ccccc2C[C@@H]1OC1CCCCO1
Temperature: 25 °C
Reaction time: 4 h
Yield: 95 %

Procedure:
tert-Butyl [(1R,2S)-2-hydroxy-2,3-dihydro-1H-inden-1-yl]carbamate (Method 15, 7.0 g, 28.1 mmol) and 3,4-dihydro-2H-pyran (4.7 g, 56.2 mmol) dissolved in DCM (50 mL). 4-Toluene sulphonic acid pyridinium salt (100 mg) was added and the reaction stirred for 4 hours at ambient temperature. The reaction was diluted with ethyl acetate (100 mL), washed with water (2×50 mL), brine (50 mL) and dried (MgSO4). The volatiles were removed by evaporation under reduced pressure to give the title compound (8.9 g, 95%) as an oil.