Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4](Cl)[N:3]=1.CN(C=O)C.[NH2:17][C:18]1[CH:19]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:21]=[CH:22][CH:23]=1>C(O)CCC>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4]([NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:25])([F:26])[F:27])[CH:19]=2)[N:3]=1
Reactant: Clc1nc(Cl)c2[nH]cnc2n1
Reactant: Nc1cccc(C(F)(F)F)c1
Solvent: CN(C)C=O
Solvent: CCCCO
Product: FC(F)(F)c1cccc(Nc2nc(Cl)nc3nc[nH]c23)c1

Procedure:
1.9 g (10 mmol) of 2,6-dichloro-purine are stirred in 60 ml of butanol and 3 ml of DMF with 8.05 g (50 mmol) of 3-amino-benzotrifluoride at 60° C. for 3 h. On cooling, 2-chloro-6-(3-trifluoromethyl-phenyl-amino)-purine is obtained as a crystalline mass. This is filtered off and dried in vacuo; m.p. 248° C.; FAB-MS: (M+H)+=314; Rf=0.45 (CH2Cl2:methanol=95:5).
Reaction SMILES: [CH:1]([CH:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1)([CH3:3])[CH3:2].Cl.CS(O[CH2:16][CH2:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]#[C:26][C:27]2[CH:32]=[CH:31][C:30]([C:33]3[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][CH:34]=3)=[CH:29][N:28]=2)=[CH:21][C:20]=1[CH3:40])(=O)=O.C(N(C(C)C)C(C)C)C>CN(C=O)C>[Cl:39][C:36]1[CH:37]=[CH:38][C:33]([C:30]2[CH:31]=[CH:32][C:27]([C:26]#[C:25][C:22]3[CH:23]=[CH:24][C:19]([O:18][CH2:17][CH2:16][N:7]4[CH2:8][CH2:9][CH:4]([CH:1]([CH3:3])[CH3:2])[CH2:5][CH2:6]4)=[C:20]([CH3:40])[CH:21]=3)=[N:28][CH:29]=2)=[CH:34][CH:35]=1
Reactant: CC(C)C1CCNCC1
Reactant: Cc1cc(C#Cc2ccc(-c3ccc(Cl)cc3)cn2)ccc1OCCOS(C)(=O)=O
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(C#Cc2ccc(-c3ccc(Cl)cc3)cn2)ccc1OCCN1CCC(C(C)C)CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
164 mg (1.0 mmol) 4-isopropyl-piperidine (used as the hydrochloride) are added to a solution of 88 mg (0.2 mmol) 2-{4-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-2-methyl-phenoxy}-ethyl methanesulphonate and 0.34 mL (2 mmol) ethyldiisopropylamine in 1.8 mL DMF and the reaction mixture is stirred for 24 h at RT. It is filtered using an injection filter and the reaction mixture is purified by HPLC.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([N+:9]([O-:11])=[O:10])[C:3]=1[OH:12].[CH2:13]([CH:15]1[O:17][CH2:16]1)Cl.[OH-].[Na+].O>C(O)C>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([N+:9]([O-:11])=[O:10])[C:3]=1[O:12][CH2:13][CH:15]1[O:17][CH2:16]1
Reactant: ClCC1CO1
Reactant: O=[N+]([O-])c1cc(F)cc(F)c1O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=[N+]([O-])c1cc(F)cc(F)c1OCC1CO1
Temperature: 80 °C
Reaction time: 24 h

Procedure:
A mixture consisting of 12.62 g of 2,4-difluoro-6-nitrophenol, 36 ml of epichlorohydrin, 3.3 g of sodium hydroxide, 15 ml of water and 320 ml of ethanol was stirred at 80° C. for 24 hours. After cooling the reaction solution to room temperature, the insoluble matter was removed by filtration and the filtrate was concentrated to dryness under a reduced pressure. The resulting residue was dissolved in an ether-hexane (1:2) mixed solvent, washed with water and saturated brine and dried with anhydrous sodium sulfate, and then the solvent was evaporated under a reduced pressure. The residue was applied to a silica gel column chromatography and developed with an ethyl acetate-hexane (1:9) mixed solvent, and then the fractions containing the compound of interest were concentrated to obtain 11.28 g of the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]1[CH2:16][CH2:15][N:14]([C@H:17]2[CH2:22][CH2:21][C@@H:20]([NH:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:19][C@H:18]2[C:28]([O:30][CH3:31])=[O:29])[C:13]1=[O:32])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C=O.[BH-](OC(C)=O)(OC(C)=O)O[C:37](C)=O.[Na+]>C(Cl)Cl>[CH2:1]([O:8][C:9]([NH:11][C@H:12]1[CH2:16][CH2:15][N:14]([C@H:17]2[CH2:22][CH2:21][C@@H:20]([N:23]([C:24]([CH3:27])([CH3:26])[CH3:25])[CH3:37])[CH2:19][C@H:18]2[C:28]([O:30][CH3:31])=[O:29])[C:13]1=[O:32])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: COC(=O)[C@@H]1C[C@H](NC(C)(C)C)CC[C@@H]1N1CC[C@H](NC(=O)OCc2ccccc2)C1=O
Agent: C=O
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)[C@@H]1C[C@H](N(C)C(C)(C)C)CC[C@@H]1N1CC[C@H](NC(=O)OCc2ccccc2)C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 0.1 %

Procedure:
A solution of (1R,2S,5R)-methyl 2-((S)-3-(benzyloxycarbonylamino)-2-oxopyrrolidin-1-yl)-5-(tert-butylamino)cyclohexanecarboxylate (460 mg, 1.0 mol) (from Example 12b, Step 6 above) in CH2Cl2 was treated with a solution of 37% aq formaldehyde (1 ml) and NaBH(OAc)3 (436 mg, 2.0 mol) and stirred at room temperature overnight. The solution was diluted with CH2Cl2 (50 ml) and washed with 1 N NaOH, water, brine, concentrated in vacuo and the residue chromatographed (1:9:90 NH4OH:MeOH:CH2Cl2) to give 330 mg (70%) of (1R,2S,5R)-methyl 2-((S)-3-(benzyloxycarbonylamino)-2-oxopyrrolidin-1-yl)-5-(tert-butyl(methyl)amino)-cyclohexanecarboxylate. MS found: (M+H)+=460.49.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][C:9]=2[O:15][CH3:16])[C:5]([F:17])=[CH:4][N:3]=1.[CH3:18][C:19]1[CH:20]=[C:21]([CH:23]=[C:24]([CH2:26][S:27][CH3:28])[CH:25]=1)[NH2:22]>>[F:17][C:5]1[C:6]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][C:9]=2[O:15][CH3:16])=[N:7][C:2]([NH:22][C:21]2[CH:23]=[C:24]([CH2:26][S:27][CH3:28])[CH:25]=[C:19]([CH3:18])[CH:20]=2)=[N:3][CH:4]=1
Reactant: COc1cc(F)ccc1-c1nc(Cl)ncc1F
Reactant: CSCc1cc(C)cc(N)c1
Product: COc1cc(F)ccc1-c1nc(Nc2cc(C)cc(CSC)c2)ncc1F

Procedure:
Intermediate 58.3 was prepared under similar conditions as described in the preparation of Intermediate 20.1 using 2-chloro-5-fluoro-4-(4-fluoro-2-methoxyphenyl)pyrimidine and 3-methyl-5-[(methyl-sulfanyl)methyl]aniline. The batch was purified by chromatography (hexane/ethyl acetate 5% to 32%) to give the desired product.
Reaction SMILES: [CH3:1][CH:2]([NH2:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Br[CH2:11][CH2:12]O.Br>ClCCl>[CH3:1][CH:2]1[C:3]2[C:8](=[CH:7][CH:6]=[CH:5][CH:4]=2)[CH2:12][CH2:11][NH:9]1
Reactant: OCCBr
Reactant: CC(N)c1ccccc1
Agent: Br
Solvent: ClCCl
Product: CC1NCCc2ccccc21
Temperature: 51 °C
Reaction time: 50 h
Yield: 139 %

Procedure:
76.61 g(630 mmole) of α-methylbenzylamine was dissolved in 77 ml of dichloromethane and 94.8 g(760 mmole) of 2-bromoethanol was added thereto. This mixture was stirred at 51° C. for 50 hours to complete the reaction. The reaction solution was concentrated under reduced pressure and 286.4 ml(2500 mmole) of 48% aqueous hydrobromic acid solution was added thereto and allowed to react at 126° C. for 30 minutes under refluxing. The reaction solution was then distilled for 2 hours under normal pressure at constant temperature and 250 ml of aqueous hydrobromic acid and water, the reaction by-product, was removed. The residue was dissolved in 350 ml of isopropyl alcohol with refluxing for 30 minutes, and this solution was cooled to 10° C. and then allowed to stand for 3 hours. The resulting solid product was filtered, washed with 50 ml of ethyl acetate and then dried to obtain 128.9 g of the title compound.
Reaction SMILES: [CH2:1]([C@H:3]1[CH2:8][C@H:7]2[C@H:9]3[C:18]([CH2:19][CH2:20][C@:5]2([CH3:6])[C@H:4]1[OH:22])=[C:17]1[C:12](=[CH:13][C:14](=[O:21])[CH2:15][CH2:16]1)[CH2:11][CH2:10]3)[CH3:2].[C:23]([O:30][CH2:31][C:32](Cl)=[O:33])(=[O:29])[CH2:24][CH2:25][CH2:26][CH2:27][CH3:28].C(OCC)(=O)C.C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1.CN(C)C1C=CN=CC=1>[CH2:1]([C@H:3]1[CH2:8][C@H:7]2[C@H:9]3[C:18]([CH2:19][CH2:20][C@:5]2([CH3:6])[C@H:4]1[O:22][C:32](=[O:33])[CH2:31][O:30][C:23](=[O:29])[CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[C:17]1[C:12](=[CH:13][C:14](=[O:21])[CH2:15][CH2:16]1)[CH2:11][CH2:10]3)[CH3:2]
Reactant: CCCCCC(=O)OCC(=O)Cl
Reactant: CC[C@H]1C[C@H]2[C@@H]3CCC4=CC(=O)CCC4=C3CC[C@]2(C)[C@H]1O
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CCCCCC(=O)OCC(=O)O[C@H]1[C@@H](CC)C[C@H]2[C@@H]3CCC4=CC(=O)CCC4=C3CC[C@@]21C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
In 20 ml of toluene are dissolved 1.5 g of 16β-ethyl-17β-hydroxy-4,9(10)-estradien-3-one and 1.92 g of 4-dimethylaminopyridine, and 1.6 ml of n-hexanoyloxyacetyl chloride is added. The mixture is stirred at 50°-60° C. for 3 hours. After cooling to 25° C., the mixture is poured into a mixture of ethyl acetate (200 ml) and saturated aqueous sodium hydrogen carbonate (50 ml). The organic layer is separated and the aqueous layer is extracted with ethyl acetate. These organic layers are combined, washed with water and saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent is then distilled off under reduced pressure and the residue is chromatographed on a silica gel column. Following passage of diisopropyl ether-n-hexane (1:1), elution is carried out with 1000 ml of a 3:2 mixture of the same solvents. The eluate is evaporated under reduced pressure to remove the solvent, giving 1.69 g of the above-identified compound as a light-yellow viscous oil.
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([C:10]([O:12][CH3:13])=[O:11])[C:4]=2[NH:3][CH:2]=1.[H-].[Na+].CI.[C:18](=O)([O-])O.[Na+]>CN(C)C=O>[CH3:18][N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([C:10]([O:12][CH3:13])=[O:11])[C:4]=2[N:3]=[CH:2]1
Reactant: O=C([O-])O
Reactant: COC(=O)c1cccc2nc[nH]c12
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)c1cccc2c1ncn2C
Temperature: 0 °C

Procedure:
1.39 g of methyl 3H-benzimidazole-4-carboxylate are dissolved under argon in 20 ml of N,N-dimethylformamide. The solution is cooled to 0° C. in an ice bath and admixed in portions with 0.299 g of sodium hydride (60% dispersion). 0.744 ml of methyl iodide is added and the reaction mixture is heated to 45° C. over 17 hours. The reaction mixture is subsequently poured onto 50 ml of saturated aqueous sodium hydrogencarbonate solution and extracted with 2:1 tetrahydrofuran/tert-butyl methyl ether (2×150 ml). The combined organic phases are washed with 50 ml each of saturated aqueous sodium hydrogencarbonate solution and water, dried over sodium sulphate, filtered and concentrated by evaporation. The title compound is obtained as a beige solid from the residue by means of flash chromatography (SiO2 60F). Rt=1.95.
Reaction SMILES: C[O:2][C:3]1[CH:29]=[CH:28][C:6]([CH2:7][C:8]2[C:12]3[C:13](=[O:27])[N:14]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[C:15]4[N:16]=[CH:17][CH:18]=[CH:19][C:20]=4[C:11]=3[NH:10][N:9]=2)=[CH:5][CH:4]=1.Br.O>C(O)(=O)C>[OH:2][C:3]1[CH:29]=[CH:28][C:6]([CH2:7][C:8]2[C:12]3[C:13](=[O:27])[N:14]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[C:15]4[N:16]=[CH:17][CH:18]=[CH:19][C:20]=4[C:11]=3[NH:10][N:9]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(Cc2n[nH]c3c2c(=O)n(-c2ccccc2)c2ncccc32)cc1
Agent: Br
Solvent: CC(=O)O
Solvent: O
Product: O=c1c2c(Cc3ccc(O)cc3)n[nH]c2c2cccnc2n1-c1ccccc1
Yield: 96.2 %

Procedure:
To a solution of 3-(4-methoxybenzyl)-5-phenyl-1H-pyrazolo[4,3-c][1,8]naphthyridin-4 (5H)-one (100 mg, 0.26 mmol, prepared in Example 21) in acetic acid (1 ml) was added 47% hydrogen bromide (44 μl), and the mixture was heated under reflux. After additional 47% hydrogen bromide (144 μl) was added, the mixture was heated under reflux overnight. The reaction mixture was admixed with water, and filtered to give precipitates which were dried to afford 3-(4-hydroxybenzyl)-5-phenyl-1H-pyrazolo[4,3-c][1,8]-naphthyridin-4 (5H)-one (92.1 mg, 96%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH3:9])=[CH:7][N:6]=[C:5]([CH2:10][N:11]2[N:39]=[C:15]3[CH2:16][C:17](=O)[C:18]4[CH2:19][S:20][N:21]=[C:22]([N:23](C(OC(C)(C)C)=O)C(OC(C)(C)C)=O)[C:13]([C:14]=43)=[N:12]2)[C:4]=1[CH3:40].C([O-])(=O)C.[NH4+].C([BH3-])#[N:47].[Na+]>CO>[CH3:1][O:2][C:3]1[C:8]([CH3:9])=[CH:7][N:6]=[C:5]([CH2:10][N:11]2[N:39]=[C:15]3[CH2:16][CH:17]([NH2:47])[C:18]4[CH2:19][S:20][N:21]=[C:22]([NH2:23])[C:13]([C:14]=43)=[N:12]2)[C:4]=1[CH3:40]
Reactant: COc1c(C)cnc(CN2N=C3CC(=O)C4=C3C(=N2)C(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)=NSC4)c1C
Reactant: [BH3-]C#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Product: COc1c(C)cnc(CN2N=C3CC(N)C4=C3C(=N2)C(N)=NSC4)c1C
Temperature: 25 °C
Reaction time: 4 h
Yield: 43.3 %

Procedure:
A mixture composed of di-tert-butyl {2-[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]-8-oxo-2,7,8,9-tetrahydro-6-thia-1,2,3,5-tetraazabenzo[cd]azulen-4-yl}imidodicarbonate of Example 40 (50 mg), ammonium acetate (68 mg), molecular sieves 4A (50 mg) and methanol (1.5 ml) was stirred at room temperature for four hours. Sodium cyanoborohydride (12 mg) was added to the reaction mixture, followed by stirring at room temperature for three days. The insoluble matter in the reaction mixture was removed by filtration through Celite, followed by washing with methanol (4 ml) twice. The filtrate was concentrated under reduced pressure. Dichloromethane (2 ml) and trifluoroacetic acid (0.5 ml) were added to the resulting residue, and the mixture was stirred at room temperature for four hours. The reaction mixture was concentrated under reduced pressure. Diethyl ether (20 ml) was placed into the resulting residue, and the slurry was washed. Then, the solvent was removed by decantation. The resulting residue was purified by reversed phase liquid chromatography to obtain the title compound (14.1 mg, 43%) as a solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:29])=[C:6]([C@:8]([NH:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=2)([CH3:18])[CH2:9][O:10][Si:11]([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12])[CH:7]=1.C(N(CC)CC)C.[Cl:37][CH:38]([C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[C:39](Cl)=[O:40]>C(#N)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:29])=[C:6]([C@:8]([N:19]([CH2:20][C:21]2[CH:22]=[CH:23][C:24]([O:27][CH3:28])=[CH:25][CH:26]=2)[C:39](=[O:40])[CH:38]([Cl:37])[C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)([CH3:18])[CH2:9][O:10][Si:11]([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:12])[CH3:13])[CH:7]=1
Reactant: O=C(Cl)C(Cl)c1ccccc1
Reactant: COc1ccc(CN[C@@](C)(CO[Si](C)(C)C(C)(C)C)c2cc(Br)ccc2F)cc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COc1ccc(CN(C(=O)C(Cl)c2ccccc2)[C@@](C)(CO[Si](C)(C)C(C)(C)C)c2cc(Br)ccc2F)cc1
Temperature: 10 °C
Reaction time: 3 h

Procedure:
A solution of [(R)-1-(5-bromo-2-fluoro-phenyl)-2-(tert-butyl-dimethyl-silanyloxy)-1-methyl-ethyl]-(4-methoxy-benzyl)-amine (1.035 g, 2.15 mmol) in acetonitrile (16 ml) was treated with triethylamine (0.36 ml, 2.57 mmol). The mixture was cooled to 10° C. and a solution of (RS)-2-chloro-2-phenyl-acetyl chloride (0.34 ml, 2.36 mmol) in acetonitrile (2 ml) was added slowly. The reaction mixture was allowed to warm to room temperature and was stirred for 3 hours. Because the transformation was not complete, triethylamine (0.33 ml, 2.36 mmol) was again added, the reaction mixture cooled to −5° C., then treated with a solution of (RS)-2-chloro-2-phenyl-acetyl chloride (0.31 ml, 2.15 mmol) in acetonitrile (1 ml). The reaction mixture was allowed to warm to room temperature and was stirred for 22 hours. Thereafter, the mixture was evaporated at reduced pressure and without further workup directly purified by chromatography on Silicycle-Si-amine column using a gradient of heptane and ethyl acetate=100/0 to 70/30 as the eluent. (RS)-N-[(R)-1-(5-bromo-2-fluoro-phenyl)-2-(tert-butyl-dimethyl-silanyloxy)-1-methyl-ethyl]-2-chloro-N-(4-methoxy-benzyl)-2-phenyl-acetamide was obtained as a white foam (1.068 g, 78% of theory). Mass (calculated) C31H38BrClFNO3 [635.09]; (found) [M+H]+=638, [M+2-H]+=636, [M+4-H]+=634.
Reaction SMILES: CN(C)C(N(C)C)=N.[C:9]([O:13][C:14]([CH:16](P(OC)(OC)=O)[C:17]([O:19][CH3:20])=[O:18])=[O:15])([CH3:12])([CH3:11])[CH3:10].[Cl:27][C:28]1[CH:35]=[CH:34][C:31]([CH:32]=O)=[CH:30][C:29]=1[F:36].O>C(Cl)Cl>[C:9]([O:13][C:14](/[C:16](=[CH:32]\[C:31]1[CH:34]=[CH:35][C:28]([Cl:27])=[C:29]([F:36])[CH:30]=1)/[C:17]([O:19][CH3:20])=[O:18])=[O:15])([CH3:10])([CH3:11])[CH3:12]
Reactant: COC(=O)C(C(=O)OC(C)(C)C)P(=O)(OC)OC
Reactant: O=Cc1ccc(Cl)c(F)c1
Agent: CN(C)C(=N)N(C)C
Solvent: O
Solvent: ClCCl
Product: COC(=O)/C(=C/c1ccc(Cl)c(F)c1)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 71.1 %

Procedure:
1,1,3,3-Tetramethylguanidine (2.11 mL, 16.8 mmol) was added to a 0° C. solution of methyl 2-(tert-butoxycarbonyl)-2-(dimethoxyphosphoryl)-acetate (5.00 g, 16.8 mmol) in DCM (70 mL). The reaction mixture stirred at 0° C. for 30 minutes, then a solution of 4-chloro-3-fluorobenzaldehyde (2.67 g, 16.8 mmol) in DCM (10 mL) was added by syringe. The reaction mixture was stirred for 10 minutes and then warmed to room temperature with continued stirring for 1 hour. H2O was then added, and the mixture was extracted with DCM. The combined extracts were dried (Na2SO4), filtered, and concentrated. The resulting solids were recrystallized from IPA to give (Z)-methyl 2-(tert-butoxycarbonyl)-3-(4-chloro-3-fluorophenyl)acrylate (3.76 g, 67.8% yield) as a white powder (2 crops). LCMS (APCI−) m/z 328 [M−H]−.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[OH:12].C(=O)([O-])[O-].[K+].[K+].[CH2:19](Br)[C:20]#[CH:21].O>C(#N)C>[Cl:1][C:2]1[C:3]([O:12][CH2:21][C:20]#[CH:19])=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([F:8])[CH:7]=1
Reactant: O=[N+]([O-])c1cc(O)c(Cl)cc1F
Reactant: C#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: C#CCOc1cc([N+](=O)[O-])c(F)cc1Cl
Temperature: 25 °C
Yield: 59 %

Procedure:
To a solution of 2-chloro-4-fluoro-5-nitrophenol (19.1 g) in acetonitrile (100 ml), there was added anhydrous potassium carbonate (8 g). After stirring at room temperature for several minutes, propargyl bromide (14 g) was added thereto, and the resultant mixture was heated under reflux for 3 hours. After being allowed to cool to room temperature, water was added thereto, and the reaction mixture was extracted with ether. The ether extract was washed with a 5% aqueous sodium hydroxide solution and water in this order, dried over anhydrous magnesium sulfate and subjected to filtration. The filtrate was concentrated under reduced pressure, and the residue was recrystallized from ethanol to obtain 13.5 g of 4-chloro-2-fluoro-5-(2-propynyloxy)nitrobenzene. M.P., 88°-89° C.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]2[C:8]([C:11]([OH:13])=O)=[CH:9][NH:10][C:5]2=[N:4][CH:3]=1.[CH3:14][C:15]1([NH2:18])C[CH2:16]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C1COCC1>[Br:1][C:2]1[N:7]=[C:6]2[C:8]([C:11]([NH:18][CH:15]([CH3:16])[CH3:14])=[O:13])=[CH:9][NH:10][C:5]2=[N:4][CH:3]=1
Reactant: CC1(N)CC1
Reactant: O=C(O)c1c[nH]c2ncc(Br)nc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Product: CC(C)NC(=O)c1c[nH]c2ncc(Br)nc12
Reaction time: 4 h
Yield: 42.9 %

Procedure:
A mixture of 2-bromo-5H-pyrrolo[3,2-b]pyrazine-7-carboxylic acid (250 mg, 1.03 mmol), 1-methylcyclopropanamine (150 mg, 2.2 mmol) and HATU (456 mg, 1.2 mmol) in 20 mL of dry THF was stirred for 4 hours. The reaction mixture was evaporated to dryness, the residue suspended in 20 mL of 0.5 N HCl, product extracted with ethyl acetate (3×50 mL), organics combined dried with sodium sulfate, filtered and concentrated. The residue was triturated with petroleum ether (2 mL) then decanted and dried to give 2-bromo-N-isopropyl-5H-pyrrolo[3,2-b]pyrazine-7-carboxamide (125 mg, crude). LCMS: (M+H)+=285/287.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=O)[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[C:4]([C:16]([NH2:18])=[O:17])[CH:3]=1.C1COCC1.CC[O-].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(O)C>[NH2:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:6][CH:7]=1)[N:8]=[C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[NH:18][C:16]2=[O:17]
Reactant: CCOC(=O)C(=O)Nc1ccc(N)cc1C(N)=O
Agent: CC[O-]
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Product: CCOC(=O)c1nc2ccc(N)cc2c(=O)[nH]1
Temperature: 25 °C
Reaction time: 12 h
Yield: 40.6 %

Procedure:
To a solution of ethyl {[4-amino-2-(aminocarbonyl)phenyl]amino}(oxo)acetate (1.96 g) in a mixed solvent of THF (60 ml)-ethanol (30 mL) was added dropwise sodium ethylate (20% ethanol solution, 2.82 g), and the mixture was stirred at room temperature for 12 hr. 10% Aqueous citric acid solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried and concentrated, and the obtained crude crystals were washed with diisopropyl ether to give the title compound (738 mg).
Reaction SMILES: Br[CH2:2][C:3]1[S:7][CH:6]=[N:5][C:4]=1[C:8](=[O:10])[CH3:9].[SH:11][C:12]1[N:17]=[C:16]([OH:18])[CH:15]=[C:14]([C:19]([F:22])([F:21])[F:20])[N:13]=1.C(N(CC)CC)C>C(O)C>[C:8]([C:4]1[N:5]=[CH:6][S:7][C:3]=1[CH2:2][S:11][C:12]1[N:17]=[C:16]([OH:18])[CH:15]=[C:14]([C:19]([F:22])([F:20])[F:21])[N:13]=1)(=[O:10])[CH3:9]
Reactant: CC(=O)c1ncsc1CBr
Reactant: Oc1cc(C(F)(F)F)nc(S)n1
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC(=O)c1ncsc1CSc1nc(O)cc(C(F)(F)F)n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 34.4 %

Procedure:
To a mixture of 1-[5-(bromomethyl)-1,3-thiazol-4-yl]ethan-1-one (615 mg, 2.8 mmol) and 2-sulfanyl-6-(trifluoromethyl)pyrimidin-4-ol (255 mg, 1.3 mmol) in absolute ethanol (25 mL) at 0° C. was added triethylamine (725 μL, 5.2 mmol). The mixture was stirred at room temperature for 4 hours. The mixture was evaporated, and the solid residue was treated with diethyl ether (50 mL). The solid salts were removed by filtration. The filtrate was recovered and evaporated. The crude product was purified by flash chromatography (0-10% MeOH/CH2Cl2 and 0-5% MeOH/CH2Cl2), affording 2-{[(4-acetyl-1,3-thiazol-5-yl)methyl]sulfanyl}-6-(trifluoromethyl)pyrimidin-4-ol (150 mg, 34%); 1H NMR (500 MHz, DMSO-d6): δ 2.71 (s, 3H), 4.82 (s, 2H), 6.58 (s, 1H), 8.99 (s, 1H); M+ 336.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([C:12]2[CH:13]=[N:14][O:15][C:16]=2[CH3:17])=[O:11])=[CH:5][CH:4]=1.[OH-].[Na+].Cl>CO.O>[F:1][C:2]([F:18])([F:19])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:11])/[C:12](/[C:13]#[N:14])=[C:16](\[OH:15])/[CH3:17])=[CH:5][CH:4]=1
Reactant: Cc1oncc1C(=O)Nc1ccc(C(F)(F)F)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: C/C(O)=C(\C#N)C(=O)Nc1ccc(C(F)(F)F)cc1
Reaction time: 0.5 h

Procedure:
0.1 mol of N-(4-trifluoromethylphenyl)-5-methylisoxazole-4-carboxamide is dissolved in 100 ml of methanol and treated at +10° C. with a solution of 0.11 mol (4.4 g) of sodium hydroxide in 100 ml of water. The mixture is stirred for 30 minutes and, after diluting with water, is acidified with concentrated hydrochloric acid. The precipitated crop of crystals is filtered off with suction, washed with water and dried in air. The yield is 24.4 g of N-(4-trifluoromethylphenyl)-2-cyano-3-hydroxycrotonamide (compound 2). Melting point from methanol 205° to 206° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]2=[CH:8][CH:9]=[C:10]([CH:11]3[CH2:16][CH2:15][CH2:14][N:13]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:12]3)[N:6]2[N:5]=[CH:4][N:3]=1.[Br:24]N1C(C)(C)C(=O)N(Br)C1=O>CN(C=O)C.C(O)(=O)C>[NH2:1][C:2]1[C:7]2=[C:8]([Br:24])[CH:9]=[C:10]([CH:11]3[CH2:16][CH2:15][CH2:14][N:13]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:12]3)[N:6]2[N:5]=[CH:4][N:3]=1
Reactant: CC1(C)C(=O)N(Br)C(=O)N1Br
Reactant: CC(C)(C)OC(=O)N1CCCC(c2ccc3c(N)ncnn23)C1
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCCC(c2cc(Br)c3c(N)ncnn23)C1
Temperature: -20 °C
Reaction time: 1.5 h
Yield: 192.9 %

Procedure:
To a cooled (−20° C.) solution tert-butyl 3-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)piperidine-1-carboxylate (891 mg, 2.81 mmol) in DMF (8.7 mL) and acetic acid (7.0 mL) was added 1,3-dibromo-5,5-dimethylhydantoin (401 mg, 1.40 mmol) in 3 portions over 10 min. The mixture was allowed to stir at −20° C. for 90 min. The reaction was quenched with the addition 5% aqueous K2CO3 (20 mL) and was allowed to warm to rt. The mixture was extracted with ethyl acetate (3×20 mL). The combined organics were washed with brine, dried (Na2SO4) and evaporated to provide 1.07 g (96%) of the desired product. ES-MS m/z 396.06 [M+H]+, HPLC RT (min) 3.05.