Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:9]2[C@@H:13]([CH2:14][NH:15][C:16]3[N:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][N:17]=3)[CH2:12][N:11]([C:26]([CH:28]3[CH2:33][CH2:32][N:31]([C:34]([C:36]4([CH3:39])[CH2:38][CH2:37]4)=[O:35])[CH2:30][CH2:29]3)=[O:27])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[H-].[Na+].[CH3:42]I>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:9]2[C@@H:13]([CH2:14][N:15]([CH3:42])[C:16]3[N:21]=[CH:20][C:19]([C:22]([F:24])([F:23])[F:25])=[CH:18][N:17]=3)[CH2:12][N:11]([C:26]([CH:28]3[CH2:29][CH2:30][N:31]([C:34]([C:36]4([CH3:39])[CH2:37][CH2:38]4)=[O:35])[CH2:32][CH2:33]3)=[O:27])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CI
Reactant: CC1(C(=O)N2CCC(C(=O)N3C[C@H](CNc4ncc(C(F)(F)F)cn4)[C@@H](c4ccc(Cl)c(Cl)c4)C3)CC2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C[C@H]1CN(C(=O)C2CCN(C(=O)C3(C)CC3)CC2)C[C@@H]1c1ccc(Cl)c(Cl)c1)c1ncc(C(F)(F)F)cn1
Yield: 62.2 %

Procedure:
{(3S,4S)-3-(3,4-Dichloro-phenyl)-4-[(5-trifluoromethyl-pyrimidin-2-ylamino)-methyl]-pyrrolidin-1-yl}-[1-(1-methyl-cyclopropanecarbonyl)-piperidin-4-yl]-methanone (30.0 mg, 0.051 mmol) were dissolved in DMF (1 mL) and treated with NaH (55% dispersion in oil) (2.5 mg, 0.056 mmol) at ambient temperature. After 5 min methyl iodide (3.5 μL, 0.056 mmol) were added and the reaction mixture was stirred over night. After quenching with water and extraction with ethyl acetate (3×10 mL) the combined organic phases were dried on sodium sulfate and filtered. After evaporation of the solvent the crude product was subjected to column chromatography (silica gel, ethyl acetate) to yield the title product (19 mg, 62%) as a colorless foam. ES-MS m/e: 598.3 (M+H+).
Reaction SMILES: [I:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=O)=[C:4]([O:11][CH3:12])[CH:3]=1.[NH:13]([C:15](=[S:17])[NH2:16])[NH2:14].P(Cl)(Cl)(Cl)=O>>[I:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]2[S:17][C:15]([NH2:16])=[N:13][N:14]=2)=[C:4]([O:11][CH3:12])[CH:3]=1
Reactant: NNC(N)=S
Reactant: COc1cc(I)ccc1C(=O)O
Solvent: O=P(Cl)(Cl)Cl
Product: COc1cc(I)ccc1-c1nnc(N)s1
Temperature: 78 °C
Reaction time: 1 h
Yield: 16.2 %

Procedure:
To an ice cooled mixture of 4-iodo-2-methoxybenzoic acid (6.178 g, 22.22 mmol) and hydrazinecarbothioamide (2.43 g, 26.7 mmol) was added phosphorous oxychloride (6.21 mL, 66.7 mmol) slowly. The mixture was heated at 78° C. overnight. After cooling to 0° C., ice water was added and the mixture was vigorously stirred for 1 hour. The resulting precipitate was filtered, washed with water, and re-suspended in saturated NaHCO3(aq) and water (1:1) for 1 hour. The solid was filtered, washed with water, and dried in vacuo to afford the crude compound. The crude material was purified by flash chromatography (MeOH/CH2Cl2) to afford the title compound (1.2 g, 16% yield). MS m/z 334.0 [M+H]+.
Reaction SMILES: [OH-].[Na+].O.[CH:4]1([NH:11][C:12]2[CH:17]=[CH:16][N:15]=[CH:14][C:13]=2[S:18]([NH2:21])(=[O:20])=[O:19])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1.[CH:22]1([N:29]=[C:30]=[O:31])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1>CC(C)=O>[CH:4]1([NH:11][C:12]2[CH:17]=[CH:16][N:15]=[CH:14][C:13]=2[S:18]([NH:21][C:30]([NH:29][CH:22]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)=[O:31])(=[O:20])=[O:19])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]1
Reactant: O=C=NC1CCCCCC1
Reactant: NS(=O)(=O)c1cnccc1NC1CCCCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Product: O=C(NC1CCCCCC1)NS(=O)(=O)c1cnccc1NC1CCCCCC1

Procedure:
0.01 mol of NaOH in solution in a minimum of water is added to a solution of 2.4 g of (4-(cycloheptylamino)pyrid-3-yl)sulphonamide in 80 cm3 of a mixture of water and acetone (1/1). Stirring is effected with a bar magnet and 2.1 g of cycloheptyl isocyanate are added. Stirring is continued while monitoring the progress of the reaction by thin layer chromatography. Evaporation is carried out in vacuo and the residue is taken up in 100 cm3 of 0.2N NaOH. After filtering, the pH of the solution is adjusted to 6.5 and the resulting precipitate is suction-filtered and then dried. The N-{[4-(cycloheptylamino)pyrid-3-yl]sulphonyl}-N'-(cycloheptyl)urea so obtained may optionally be recrystallised from an aqueous alcoholic solution.
Reaction SMILES: [CH2:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH2:4][C@@H:3]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[NH:2]1.C1C2NC3C(=CC=CC=3)C=2C[C@H](C(O)=O)N1>>[CH2:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH2:4][C@H:3]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[NH:2]1
Reactant: CCOC(=O)[C@@H]1Cc2c([nH]c3ccccc23)CN1
Agent: O=C(O)[C@H]1Cc2c([nH]c3ccccc23)CN1
Product: CCOC(=O)[C@H]1Cc2c([nH]c3ccccc23)CN1
Yield: 54 %

Procedure:
In the same manner as described above (1) using (3R)-1,2,3,4-tetrahydro-β-carboline-3-carboxylic acid, there is obtained the title compound (54%) as colorless needles, m.p. 126°-128° C.
Reaction SMILES: C([O-])(=O)C1C=CC=CC=1.[CH2:10]([N:12]([C:24]1[C:33]([CH3:34])=[CH:32][C:31]2[C:30]([CH3:36])([CH3:35])[CH2:29][CH:28]=[C:27]([C:37]([CH3:40])([CH3:39])[CH3:38])[C:26]=2[CH:25]=1)[C:13]1[CH:23]=[CH:22][C:16]([C:17]([O:19]CC)=[O:18])=[CH:15][CH:14]=1)[CH3:11]>>[CH2:10]([N:12]([C:24]1[C:33]([CH3:34])=[CH:32][C:31]2[C:30]([CH3:36])([CH3:35])[CH2:29][CH:28]=[C:27]([C:37]([CH3:38])([CH3:40])[CH3:39])[C:26]=2[CH:25]=1)[C:13]1[CH:14]=[CH:15][C:16]([C:17]([OH:19])=[O:18])=[CH:22][CH:23]=1)[CH3:11]
Reactant: CCOC(=O)c1ccc(N(CC)c2cc3c(cc2C)C(C)(C)CC=C3C(C)(C)C)cc1
Agent: O=C([O-])c1ccccc1
Product: CCN(c1ccc(C(=O)O)cc1)c1cc2c(cc1C)C(C)(C)CC=C2C(C)(C)C
Yield: 100 %

Procedure:
Following General Procedure E, 4-ethyl 4[ethyl(8-tert-butyl-3,5,5-trimethyl-5,6-dihydronaphthalen-2-yl)amino)]benzoate (Compound 22, 0.12 g, 0.27 mmol) was reacted to give 0.13 g (100%) of the title compound as an off-white solid.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:9])=[C:4]([NH2:8])[CH:5]=[CH:6][CH:7]=1.CCN(C(C)C)C(C)C.[C:19](Cl)(=[O:21])[CH3:20]>>[Br:1][C:2]1[C:3]([CH3:9])=[C:4]([NH:8][C:19](=[O:21])[CH3:20])[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1c(N)cccc1Br
Reactant: CC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)Nc1cccc(Br)c1C
Reaction time: 1 h
Yield: 88.1 %

Procedure:
A solution of 3-bromo-2-methyl-phenylamine (4.1 g, 21.9 mmol) was treated with DIEA (8.4 mL, 48 mmol) and chilled to zero degrees. Acetyl chloride (1.7 mL, 24.1 mmol) was added dropwise via syringe. Reaction was allowed to return to room temperature and stir for 1 hour. Reaction was then poured onto water and washed once. Organic phase was evaporated to off-white solids. Trituration with hexanes afforded title compound as white solids (4.4 g, 89%).
Reaction SMILES: [CH3:1][N:2]([C@@H:10]1[CH2:14][C@H:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C@@H:12]([CH2:21][N:22]2[CH2:27][CH2:26][CH:25]([N:28]([C:32]([O:34][CH2:35][C:36]3[CH:41]=[CH:40][C:39]([N+:42]([O-:44])=[O:43])=[CH:38][CH:37]=3)=[O:33])[CH2:29][CH:30]=[CH2:31])[CH2:24][CH2:23]2)[CH2:11]1)C(OC(C)(C)C)=O.[C:45](Cl)(=[O:52])[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1>>[CH3:1][N:2]([C@@H:10]1[CH2:14][C@H:13]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[C@@H:12]([CH2:21][N:22]2[CH2:23][CH2:24][CH:25]([N:28]([C:32]([O:34][CH2:35][C:36]3[CH:37]=[CH:38][C:39]([N+:42]([O-:44])=[O:43])=[CH:40][CH:41]=3)=[O:33])[CH2:29][CH:30]=[CH2:31])[CH2:26][CH2:27]2)[CH2:11]1)[C:45]([C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)=[O:52]
Reactant: O=C(Cl)c1ccccc1
Reactant: C=CCN(C(=O)OCc1ccc([N+](=O)[O-])cc1)C1CCN(C[C@H]2C[C@H](N(C)C(=O)OC(C)(C)C)C[C@@H]2c2ccccc2)CC1
Product: C=CCN(C(=O)OCc1ccc([N+](=O)[O-])cc1)C1CCN(C[C@H]2C[C@H](N(C)C(=O)c3ccccc3)C[C@@H]2c2ccccc2)CC1

Procedure:
Using essentially the same procedure as in Example 16, Step A and B but substituting 1-(R)-(N-(methyl)-N-(t-butoxycarbonyl)amino)-3-(S)-((4-(N-(4-nitrobenzyloxycarbonyl)-N-(allyl)amino)piperidin-1-yl)methyl)-4-(S)-phenylcyclopentane from Example 29, Step H in Step A and benzoyl chloride in Step B, the title compound was prepared.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([NH2:15])[CH:13]=2)[CH:8]=[CH:7]1)[CH3:2].[F:17][C:18]([F:34])([F:33])[O:19][C:20]1[CH:21]=[C:22]([C:26]#[C:27][CH2:28][CH2:29][C:30](O)=[O:31])[CH:23]=[CH:24][CH:25]=1.Cl.CN(C)CCCN=C=NCC>CN(C)C1C=CN=CC=1.ClCCl>[CH2:1]([O:3][C:4](=[O:16])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([NH:15][C:30](=[O:31])[CH2:29][CH2:28][C:27]#[C:26][C:22]3[CH:23]=[CH:24][CH:25]=[C:20]([O:19][C:18]([F:33])([F:34])[F:17])[CH:21]=3)[CH:13]=2)[CH:8]=[CH:7]1)[CH3:2]
Reactant: O=C(O)CCC#Cc1cccc(OC(F)(F)F)c1
Reactant: CCOC(=O)Cn1ccc2ccc(N)cc21
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CCOC(=O)Cn1ccc2ccc(NC(=O)CCC#Cc3cccc(OC(F)(F)F)c3)cc21
Temperature: 25 °C
Reaction time: 14 h
Yield: 75 %

Procedure:
A mixture of (6-amino-indol-1-yl)-acetic acid ethyl ester (100 mg, 0.46 mmol; WO 2003041714 A1), 5-(3-trifluoromethoxy-phenyl)-pent-4-ynoic acid (115 mg, 0.44 mmol), 1-[3-(dimethylamino)-propyl]-3-ethylcarbodiimide hydrochloride (90 mg, 0.46 mmol) and 4-(dimethylamino)pyridine (57 mg, 0.46 mmol) in dichloromethane (1.5 ml) was stirred for 14 h at ambient temperature. The reaction mixture was diluted with dichloromethane, successively washed with 1 N HCl, brine, 1 N NaOH and brine, and dried over sodium sulfate. The solvent was removed under reduced pressure and the residue purified by flash chromatography (silica gel, heptane/AcOEt) to give 152 mg (0.33 mmol, 72%) of the title compound as off-white crystals.
Reaction SMILES: Cl[C:2](=[O:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[C:9]([C:13]1[CH:19]=[C:18]([C:20]([CH3:23])([CH3:22])[CH3:21])[CH:17]=[C:16]([C:24]([CH3:27])([CH3:26])[CH3:25])[C:14]=1[NH2:15])([CH3:12])([CH3:11])[CH3:10]>C(N(CC)CC)C.ClCCl>[CH2:6]([O:5][C:3](=[O:4])[C:2]([NH:15][C:14]1[C:16]([C:24]([CH3:25])([CH3:26])[CH3:27])=[CH:17][C:18]([C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:19][C:13]=1[C:9]([CH3:12])([CH3:11])[CH3:10])=[O:8])[CH3:7]
Reactant: CCOC(=O)C(=O)Cl
Reactant: CC(C)(C)c1cc(C(C)(C)C)c(N)c(C(C)(C)C)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)C(=O)Nc1c(C(C)(C)C)cc(C(C)(C)C)cc1C(C)(C)C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
In a 500 mL round bottom flask, 2,4,6-tri-tert-butylaniline (2.0 g) and 2.6 mL triethylamine were dissolved in dichloromethane (50 mL) and cooled to 0° C. A mixture of ethyl chloroglyoxylate (0.85 mL) and dichloromethane (33 mL) was slowly added via dropping funnel, after which the mixture was stirred at 0° C. for 1 h, and then at 25° C. for 3 h. The resultant mixture was quenched with 100 mL of water. The aqueous layer was extracted with 100 mL of dichloromethane. The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure (20 mm Hg). The residue was purified by flash chromatography (silica; hexane/EtOAc; linear gradient). The N-(2,4,6-tri-tert-butylphenyl)oxalamic acid ethyl ester so obtained (201.5 mg) was reacted with excess hydrazine hydrate (81 μL) in 5 mL of EtOH at 50° C. for 14 h. The resultant solid was isolated by filtration and washed with EtOH to obtain compound a38.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([N:14]([CH3:16])[CH3:15])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH3:17][CH2:18][CH2:19][CH2:20][O:21][C:22]1[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][CH:23]=1>>[CH2:20]([O:21][C:22]1[CH:23]=[CH:24][C:25]([C:26]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([N:8]3[CH2:9][CH2:10][CH:11]([N:14]([CH3:16])[CH3:15])[CH2:12][CH2:13]3)=[CH:4][CH:3]=2)=[O:27])=[CH:29][CH:30]=1)[CH2:19][CH2:18][CH3:17]
Reactant: CN(C)C1CCN(c2ccc(N)cc2)CC1
Reactant: CCCCOc1ccc(C(=O)O)cc1
Product: CCCCOc1ccc(C(=O)Nc2ccc(N3CCC(N(C)C)CC3)cc2)cc1

Procedure:
([1-(4-Aminophenyl)piperidin-4-yl]dimethylamine) was reacted with 4-4-butoxybenzoic acid by method E. This resulted in the product with the molecular weight of 395.55 (C24H33N3O2); MS (ESI): 396 (M+H+).
Reaction SMILES: [NH2:1][C@H:2]([C@@H:10]([OH:28])[CH2:11][C@@H:12]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[N+](C1C=CC([O:38][C:39]([O:41][CH2:42][C:43]2[S:47][CH:46]=[N:45][CH:44]=2)=O)=CC=1)([O-])=O>CN(C=O)C>[C:24]([O:23][C:21]([NH:20][C@@H:12]([CH2:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[CH2:11][C@H:10]([OH:28])[C@@H:2]([NH:1][C:39]([O:41][CH2:42][C:43]1[S:47][CH:46]=[N:45][CH:44]=1)=[O:38])[CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1)=[O:22])([CH3:25])([CH3:27])[CH3:26]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C[C@H](O)[C@@H](N)Cc1ccccc1
Reactant: O=C(OCc1cncs1)Oc1ccc([N+](=O)[O-])cc1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)OCc1cncs1
Reaction time: 4 h
Yield: 79.6 %

Procedure:
The product of Example 68D (6.0g, 15.6 mmoles) was dissolved in 60 mL of DMF under nitrogen atmosphere. To this stirred solution at room temperature was added 5-(p-nitrophenyloxycarbonyloxymethyl)thiazole (4.67 g , 15.6 mmole) and the resulting solution was stirred for 4 h. The solvent was removed under reduced pressure by rotary evaporation and the residue dissolved in 150 mL EtOAc. This solution was washed with 5×75 mL 1N NaOH solution, 100 mL brine, dried over Na2SO4. The solvent was removed to afford 8.02 g of a slightly yellowish oil. This material was crystallized from 30 mL EtOAc and 40 mL hexane to afford 6.53 g (80%) of the desired product as a white solid. mp 118°-120 ° C. H 1NMR (CDCl3) δ8.79 (s, 1H), 7.83 (s, 1H), 7.30-7.15 (m, 8H), 7.08 (m, 2H), 5.23 (s, 2H), 5.14 (d, 1H, J=9 Hz), 4.52 (m, 1H), 3.92-3.72 (m, 3H), 3.65 (m, 1H), 2.85 (d-apparent, 2H, J=7.5 Hz), 2.72 (d-apparent, 2H, J=7 Hz), 1.61 (m, 2H), 1.38 (s, 9H). CIMS m/z (526) (M+H)+, 543 (M+18)+.
Reaction SMILES: BrBr.C(Cl)(Cl)(Cl)Cl.N1C2C(=CC=CC=2)C=CC=1.[CH3:18][S:19][C:20]1[CH:25]=[CH:24][C:23]([NH:26][C:27](=[O:36])[O:28][CH2:29][C:30]2[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=2)=[CH:22][CH:21]=1.[OH2:37]>C(O)(=O)C>[CH3:18][S:19]([C:20]1[CH:25]=[CH:24][C:23]([NH:26][C:27](=[O:36])[O:28][CH2:29][C:30]2[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=2)=[CH:22][CH:21]=1)=[O:37]
Reactant: CSc1ccc(NC(=O)OCc2cccnc2)cc1
Reactant: O
Agent: BrBr
Solvent: c1ccc2ncccc2c1
Solvent: CC(=O)O
Solvent: ClC(Cl)(Cl)Cl
Product: CS(=O)c1ccc(NC(=O)OCc2cccnc2)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 34 %

Procedure:
Quinoline-bromine complex was prepared by adding 3.2 g. (0.02 mole) of bromine in 50 ml. of CCl4 to a solution of 2.6 g. (0.02 mole) of quinoline in 50 ml. of CCl4. A yellow solid separated which was filtered off and air-dried. The yield was 3.5 g. (60%). To a solution of 2.7 g. (0.01 mole) of 3-pyridylmethyl N-(4'-methylthiophenyl)carbamate in 100 ml. of 70% aqueous acetic acid was added, portionwise, 2.7 g. (0.01 mole) of the quinoline-bromine complex. The mixture was stirred at ambient temperature for 15 min. and poured into 100 ml. of water. A negligible amount of solid formed and was removed by filtration. The filtrate was made alkaline with 25% aqueous NaOH, and a white precipitate formed which was filtered off and recrystallized from aqueous ethanol. There was obtained 0.5 g. of recrystallized product, melting at 118° - 121°C., which proved to be a mixture of two components by thin layer chromatography. The filtrate was concentrated to near-dryness, and yielded after oven drying in vacuo 1 g. of a white solid melting at 139° - 143° C. This was a 34% yield of 3-pyridylmethyl N-(4'-methylsulfinylphenyl)-carbamate.
Reaction SMILES: [F:1][C:2]([F:9])([F:8])/[CH:3]=[CH:4]/[C:5](O)=[O:6].C(Cl)(=O)C(Cl)=O.[CH3:16][O:17][C:18]1[N:23]=[C:22]([CH3:24])[C:21]([NH:25][CH2:26][CH2:27][NH2:28])=[CH:20][CH:19]=1.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[F:1][C:2]([F:9])([F:8])/[CH:3]=[CH:4]/[C:5]([NH:28][CH2:27][CH2:26][NH:25][C:21]1[C:22]([CH3:24])=[N:23][C:18]([O:17][CH3:16])=[CH:19][CH:20]=1)=[O:6]
Reactant: O=C(O)/C=C/C(F)(F)F
Reactant: COc1ccc(NCCN)c(C)n1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccc(NCCNC(=O)/C=C/C(F)(F)F)c(C)n1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 23.3 %

Procedure:
(E)-4,4,4-Trifluorobut-2-enoic acid (33 mg, 0.23 mmol) was dissolved in DCM (1 ml containing one drop of dimethyl formamide), oxalyl chloride was added (20 μl, 0.23 mmol) and the solution was stirred at room temperature for 15 minutes. This solution was added to a solution of N-(6-methoxy-2-methyl-3-pyridyl)ethane-1,2-diamine (27 mg, 0.15 mmol) and diisopropylethylamine (88 μl, 0.5 mmol) in DCM (2 ml) and the resulting mixture was stirred at room temperature for three hours. The volatiles were removed under reduced pressure and the residue was purified by preparative HPLC (Waters XBridge, gradient of water containing 0.1% NH3 and 10% to 100% acetonitrile) to yield 10.5 mg of a solid (0.035 mmol, 23%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[CH2:4][CH2:5][CH2:6][CH2:7][C:8]1[O:9][C:10]([C:13]2[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=2[O:20]C)=[CH:11][N:12]=1.B(Br)(Br)Br>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:22])[CH2:4][CH2:5][CH2:6][CH2:7][C:8]1[O:9][C:10]([C:13]2[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=2[OH:20])=[CH:11][N:12]=1
Reactant: COC(=O)CCCCc1ncc(-c2cc(Cl)ccc2OC)o1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: COC(=O)CCCCc1ncc(-c2cc(Cl)ccc2O)o1
Temperature: -78 °C
Reaction time: 27 h
Yield: 81.7 %

Procedure:
Dissolve 5-[5-(5-chloro-2-methoxy-phenyl)-oxazol-2-yl]-pentanoic acid methyl ester (4.174 g, 12.89 mmol) in 50 mL of CH2Cl2 and cool the solution to −78° C. Add boron tribromide (48.9 mL of a 1M solution in CH2Cl2) dropwise to the reaction and allow it to warm to ambient temperature and allow it to stir for 27 hours. Cool the reaction to −78° C. and quench it by adding 100 mL of MeOH dropwise to the reaction mixture. Allow the reaction to warm to ambient temperature and stir for 19 hours. Concentrate the reaction mixture in vacuo. Dissolve the residue in CH2Cl2 and wash it with saturated aqueous NaHCO3 and brine. Dry the organic layer with MgSO4. Filter off the drying agent and concentrate in vacuo to afford a crude residue. Purify the residue using silica gel chromotagraphy eluting with hexanes/ethyl acetate mixtures to afford 3.26 g of the titled product (82%): mass spectrum: m/z=310.09 (M+H).
Reaction SMILES: C(=N[OH:9])C1C=CC=CC=1.CN(C=O)C.[H-].[Na+].O1CCOCC1.[C:23]([C:25]([C:28]1[C:33]([C:34]#[C:35][C:36]([O:38][CH2:39][CH3:40])=[O:37])=[CH:32][CH:31]=[CH:30][N:29]=1)([CH3:27])[CH3:26])#[N:24]>>[OH:9][C:34]1[C:33]2[CH:32]=[CH:31][CH:30]=[N:29][C:28]=2[C:25]([CH3:27])([CH3:26])[C:23](=[NH:24])[C:35]=1[C:36]([O:38][CH2:39][CH3:40])=[O:37]
Reactant: CCOC(=O)C#Cc1cccnc1C(C)(C)C#N
Reactant: ON=Cc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: CCOC(=O)C1=C(O)c2cccnc2C(C)(C)C1=N
Reaction time: 0.5 h

Procedure:
A solution of benzaldehyde oxime (0.6 g, 5 mmol) in dry DMF (10 mL, 129 mmol) was added to a stirred suspension of 60% NaH (0.2 g, 5 mmol) in dry 1,4-dioxane (10 mL, 117 mmol) under a nitrogen atmosphere at room temperature. After 0.5 hours, a solution of the ethyl 3-(2-(2-cyanopropan-2-yl)pyridin-3-yl)propiolate (0.98 g, 4 mmol) in dry DMF (10 mL, 129 mmol) was added, and the solution was stirred for 30 minutes. The solvent was removed under vacuum, and water was added to the residue. The product was extracted with EtOAc. The organic layer was washed with water (3×) and then with saturated NH4Cl and brine (3× each) and dried over MgSO4. The resulting mixture was concentrated in vacuo to give a light-yellow crystalline solid/yellow oil. The yellow residue was washed with hexane providing the product as a yellow solid which was filtered off (0.65 g, 62%). MS (m/z)=261 (M+H)+. Calculated for C14H16N2O3 260.3.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[CH2:4][NH:5][C:6]1[S:7][CH2:8][C:9](=[O:11])[N:10]=1.C(O[Na])(C)=O.[CH:21]([C:23]1[N:24]=[C:25]2[C:30](=[CH:31][CH:32]=1)[N:29]=[CH:28][C:27]([C:33]#[N:34])=[C:26]2[O:35][CH:36]([CH3:38])[CH3:37])=O>CC(O)=O>[Cl:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[CH2:4][NH:5][C:6]1[S:7][C:8](=[CH:21][C:23]2[N:24]=[C:25]3[C:30](=[CH:31][CH:32]=2)[N:29]=[CH:28][C:27]([C:33]#[N:34])=[C:26]3[O:35][CH:36]([CH3:38])[CH3:37])[C:9](=[O:11])[N:10]=1
Reactant: CC(C)Oc1c(C#N)cnc2ccc(C=O)nc12
Reactant: O=C1CSC(NCc2ccccc2Cl)=N1
Agent: CC(=O)O[Na]
Solvent: CC(=O)O
Product: CC(C)Oc1c(C#N)cnc2ccc(C=C3SC(NCc4ccccc4Cl)=NC3=O)nc12
Temperature: 90 °C
Yield: 35.3 %

Procedure:
To a mixture of 2-(2-chloro-benzylamino)-thiazol-4-one (48.1 mg, 0.20 mmol) (prepared as described below), AcONa (160 mg, 1.95 mmol), molecular sieves, and 6-formyl-4-isopropoxy-[1,5]naphthyridine-3-carbonitrile (53.1 mg, 0.22 mmol, (see Example 1) in a sealed tube was added AcOH (0.3 mL). The reaction mixture was heated to 85-95° C. (oil bath) for 1.5 h. The reaction mixture was then cooled to r.t. and triturated with water. The solid was collected by filtration and washed with water. The solid was then suspended in hot MeOH (50 mL) and filtered again. The filtrate was concentrated to give a brown solid: 120.3 mg, which was purified by Biotage flash column (1%-6% MeOH in CH2Cl2) to give 6-[2-(2-chloro-benzylamino)-4-oxo-4H-thiazol-5-ylidenemethyl]-4-isopropoxy-[1,5]naphthyridine-3-carbonitrile as a yellowish solid (32.8 mg, 35.3%). HR-ES (+) m/e calcd for C23H18ClN5O2S (M+H)+ 464.0943. found 464.0943.
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)Cl.[C:7]1([CH:13]2[NH:19][C:18](=[O:20])[CH2:17][CH2:16][CH2:15][CH2:14]2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.N1C=CC=CC=1.[Br-:27].[Br-].[Br-].[Br-].C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1>C(Cl)Cl>[Br:27][CH:17]1[CH2:16][CH2:15][CH2:14][CH:13]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:19][C:18]1=[O:20]
Reactant: O=C1CCCCC(c2ccccc2)N1
Reactant: [Br-]
Agent: C[N+](C)(C)c1ccccc1
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C1NC(c2ccccc2)CCCC1Br
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a 250 ml round-bottomed flask equipped with N2 inlet were added 5.12 g (24.6 mmol) phosphorus pentachloride and 45 ml methylene chloride. To the stirring mixture cooled to 0° C. was added dropwise over 20 minutes, a solution of 4.65 g (24.6 mmol) 7-phenyl-hexahydroazepin-2-one and 3.98 ml (49.2 mmol) pyridine in 40 ml methylene chloride. To the stirring mixture at 0° C. was then added 9.25 g (24.6 mmol) phenyltrimethylammonium bromide tribromide. The reaction was then allowed to warm to room temperature and stirred for 3 hours. It was then evaporated, taken up in tetrahydrofuran, quenched with water, evaporated, and partitioned between water and methylene chloride. The organic layer was washed with water and saturated aqueous sodium bisulfite, dried over sodium sulfate, and evaporated. The residue was chromatographed on silica gel with ethyl acetate/hexane as eluent to afford the product as an oil, 4.0 g (61%).
Reaction SMILES: [NH2:1][CH:2]([C:5]1[C:6](=[O:17])[NH:7][C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:9][N:10]=1)[CH2:3][CH3:4].C(N(CC)CC)C.[C:25]([C@@H:29]1[CH2:34][CH2:33][C@H:32]([C:35](Cl)=O)[CH2:31][CH2:30]1)([CH3:28])([CH3:27])[CH3:26].O=P(Cl)(Cl)Cl.[OH-].[Na+]>ClC(Cl)C.ClCCl.O>[C:25]([C@@H:29]1[CH2:30][CH2:31][C@H:32]([C:35]2[N:10]3[C:5]([C:6](=[O:17])[NH:7][C:8]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)=[N:9]3)=[C:2]([CH2:3][CH3:4])[N:1]=2)[CH2:33][CH2:34]1)([CH3:28])([CH3:26])[CH3:27]
Reactant: CC(C)(C)[C@H]1CC[C@@H](C(=O)Cl)CC1
Reactant: CCC(N)c1nnc(-c2ccccc2)[nH]c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(Cl)Cl
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCl
Product: CCc1nc([C@H]2CC[C@@H](C(C)(C)C)CC2)n2nc(-c3ccccc3)[nH]c(=O)c12
Temperature: 25 °C

Procedure:
20.45 g (0.09 mol) 6-(1-Aminopropyl)-3-phenyl-1,2,4-triazin-5(4H)-one (Example 34A) are dissolved in dichloroethane, 502 g (5.08 mol) triethylamine and 19.8 g (0.10 mol) cis-4-tert-butylcyclohexanecarbonyl chloride are added. The solution is stirred at reflux for three hours, then 20.42 g (0.13 mol) phosphoroxychloride are added. The solution is stirred at reflux for another 4 hours and, after cooling down to room temperature, water, sodium hydroxide and then dichloromethane are added. The organic phase is evaporated to dryness in vacuo, and the residue triturated with diethylether and filtrated. The solid is dissolved in methanol (75%)/dichloromethane (25%), the dichloromethane is evaporated in vacuo, and the crystallized product is filtered and dried.