Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([C@H:12]2[CH2:17][CH2:16][C@H:15]([NH:18][CH2:19][CH2:20][O:21][CH3:22])[CH2:14][CH2:13]2)[N:5]2[CH:10]=[CH:9][N:8]=[C:7]([CH3:11])[C:6]=12.C(N(CC)CC)C.[C:30](Cl)(=[O:32])[CH3:31].O>ClCCl>[Br:1][C:2]1[N:3]=[C:4]([C@H:12]2[CH2:17][CH2:16][C@H:15]([N:18]([CH2:19][CH2:20][O:21][CH3:22])[C:30](=[O:32])[CH3:31])[CH2:14][CH2:13]2)[N:5]2[CH:10]=[CH:9][N:8]=[C:7]([CH3:11])[C:6]=12
Reactant: COCCN[C@H]1CC[C@H](c2nc(Br)c3c(C)nccn32)CC1
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: COCCN(C(C)=O)[C@H]1CC[C@H](c2nc(Br)c3c(C)nccn32)CC1

Procedure:
To (trans)-4-(1-bromo-8-methylimidazo[1,5-a]pyrazin-3-yl)-N-(2-methoxyethyl)cyclohexanamine (0.182 mmol, 67 mg) in dichloromethane (2 ml) and triethylamine (0.912 mmol, 0.127 ml) at 0° C. was added acetyl chloride (0.274 mmol, 0.020 ml). After stirring for 1 hour dichloromethane and water were added. The organic layer was separated, dried over a phase separation filter and concentrated in vacuo to give N-((trans)-4-(1-bromo-8-methylimidazo[1,5-a]pyrazin-3-yl)cyclohexyl)-N-(2-methoxyethyl)acetamide (72 mg).
Reaction SMILES: [N+:1]([C:4]1[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:5]=1[O:6][C:7]1[CH:23]=[CH:22][C:10]([O:11][CH:12]([CH3:21])[C:13](=[O:20])[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:9][CH:8]=1)([O-:3])=[O:2].[BH4-].[Na+]>C(O)C.C(Cl)Cl>[N+:1]([C:4]1[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:5]=1[O:6][C:7]1[CH:23]=[CH:22][C:10]([O:11][CH:12]([CH3:21])[CH:13]([OH:20])[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:9][CH:8]=1)([O-:3])=[O:2]
Reactant: CCOC(=O)CC(=O)C(C)Oc1ccc(Oc2ccc(Cl)cc2[N+](=O)[O-])cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCO
Product: CCOC(=O)CC(O)C(C)Oc1ccc(Oc2ccc(Cl)cc2[N+](=O)[O-])cc1
Reaction time: 0.33 h

Procedure:
To a solution of ethyl 4-[4-(2-nitro-4-chlorophenoxy)phenoxy]-3-oxopentanoate (600 mg) in absolute ethanol (10 ml) is added at 0°, NaBH4 (300 mg). After addition is complete, the reaction mixture is stirred for about 20 minutes. Then the solution is taken up in CH2Cl2, washed with brine, dried and evaporated to give ethyl 4-[4-(2-nitro-4-chlorophenoxy)phenoxy]-3-hydroxypentanoate.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][NH:4][C:5]([N:7]([CH3:17])[CH:8]1[O:14][C@H:13]([CH2:15][OH:16])[C@@H:11]([OH:12])[C@H:9]1[OH:10])=[O:6].C(=O)([O-])[O-].[Na+].[Na+].[N+:24]([O-])([N+]([O-])=O)=[O:25]>O1CCCC1.C(Cl)Cl>[Cl:1][CH2:2][CH2:3][N:4]([N:24]=[O:25])[C:5]([N:7]([CH3:17])[CH:8]1[O:14][C@H:13]([CH2:15][OH:16])[C@@H:11]([OH:12])[C@H:9]1[OH:10])=[O:6]
Reactant: CN(C(=O)NCCCl)C1O[C@H](CO)[C@@H](O)[C@H]1O
Reactant: O=[N+]([O-])[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: CN(C(=O)N(CCCl)N=O)C1O[C@H](CO)[C@@H](O)[C@H]1O
Yield: 70.2 %

Procedure:
2.7 g of 1-(2-chloroethyl)-3-methyl-3-D-ribofuranosylurea are dissolved in a mixture of 80 ml of tetrahydrofuran and 80 ml of methylene chloride, and 15 g of sodium carbonate anhydrate are added thereto. 5 g of nitrogen tetroxide gas are introduced into the mixture for 10 minutes under ice-cooling. The mixture is treated in the same manner as described in Example 2. 2.1 g of 1-(2-chloroethyl)-1-nitroso-3-methyl-3-ribofuranosylurea are thereby obtained as a yellow powder.
Reaction SMILES: CCN(C(C)C)C(C)C.[C:10]([O:14][C:15]([N:17]1[CH2:22][CH2:21][C@@H:20]([NH:23][C:24]2[C:25]3[N:26]([CH:33]=[C:34]([C:36]([OH:38])=O)[CH:35]=3)[N:27]=[CH:28][C:29]=2[C:30](=[O:32])[NH2:31])[C:19]([CH3:40])([CH3:39])[CH2:18]1)=[O:16])([CH3:13])([CH3:12])[CH3:11].F[P-](F)(F)(F)(F)F.[N:48]1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=[N:49]1.NN>CN(C)C=O.O>[C:30]([C:29]1[CH:28]=[N:27][N:26]2[CH:33]=[C:34]([C:36]([NH:48][NH2:49])=[O:38])[CH:35]=[C:25]2[C:24]=1[NH:23][C@@H:20]1[CH2:21][CH2:22][N:17]([C:15]([O:14][C:10]([CH3:13])([CH3:11])[CH3:12])=[O:16])[CH2:18][C:19]1([CH3:39])[CH3:40])(=[O:32])[NH2:31]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](Nc2c(C(N)=O)cnn3cc(C(=O)O)cc23)C(C)(C)C1
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: NN
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC[C@@H](Nc2c(C(N)=O)cnn3cc(C(=O)NN)cc23)C(C)(C)C1
Reaction time: 1 h
Yield: 76.1 %

Procedure:
Hunig's base (0.752 mL, 4.30 mmol) was added to a mixture of (R)-4-((1-(tert-butoxycarbonyl)-3,3-dimethylpiperidin-4-yl)amino)-3-carbamoylpyrrolo[1,2-b]pyridazine-6-carboxylic acid (619 mg, 1.435 mmol) and BOP (952 mg, 2.152 mmol) in N,N-dimethylformamide (4 mL). After 1 h at room temperature, hydrazine (0.225 mL, 7.17 mmol) was added. After additional 17 h at room temperature, the mixture was diluted with water to give a suspension. The precipitate was collected by filtration to give (R)-tert-butyl 4-((3-carbamoyl-6-(hydrazinecarbonyl)pyrrolo[1,2-b]pyridazin-4-yl)amino)-3,3-dimethylpiperidine-1-carboxylate (0.4863 g, 76% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 11.08 (d, J=9.2 Hz, 1H), 9.64 (s, 1H), 8.27 (s, 1H), 8.03 (d, J=1.5 Hz, 1H), 7.31 (d, J=1.5 Hz, 1H), 4.13-4.00 (m, 1H), 3.87 (br. s., 1H), 3.60 (d, J=13.2 Hz, 1H), 3.17 (d, J=7.9 Hz, 1H), 2.92 (br. s., 1H), 1.90 (dd, J=13.4, 3.5 Hz, 1H), 1.62-1.48 (m, 1H), 1.46-1.35 (m, 9H), 0.98 (s, 3H), 0.92 (s, 3H); LC retention time: 3.295 min (analytical HPLC Method H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[CH:21]=[C:20]([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)[CH:19]=[CH:18][C:12]=2[C:13]([O:15]CC)=[O:14])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[OH-].[Na+].Cl>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[CH:21]=[C:20]([C:22]3[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=3)[CH:19]=[CH:18][C:12]=2[C:13]([OH:15])=[O:14])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: CCOC(=O)c1ccc(-c2ccc(F)cc2)cc1-c1ccc(OC)c(OC)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc(-c2cc(-c3ccc(F)cc3)ccc2C(=O)O)cc1OC
Yield: 8.1 %

Procedure:
Ethyl 2-(3,4-dimethoxyphenyl)-4-(4-fluorophenyl)benzoate (2.8 g; 0.074 mole), absolute ethanol (50 ml) and 10N sodium hydroxide (2 ml) are introduced into a 100 ml flask. The mixture is taken to reflux temperature for two hours, then poured over 1N hydrochloric acid (150 ml). The precipitate is filtered on fritted glass, washed with water, then dried in the air. 2-(3,4-dimethoxyphenyl)-4-(4-fluorophenyl)benzoic acid (2.1 g; yield: 81%) is thus obtained in the form of a white solid of m.p. 210° C.
Reaction SMILES: [C:1]([CH2:3][CH:4]1[C:8]2[C:9]3[N:10]([N:13]=[C:14]([CH3:21])[C:15]=3[C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:11]=[CH:12][C:7]=2[CH2:6][CH2:5]1)#[N:2]>N.CO.[Co]>[NH2:2][CH2:1][CH2:3][CH:4]1[C:8]2[C:9]3[N:10]([N:13]=[C:14]([CH3:21])[C:15]=3[C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:11]=[CH:12][C:7]=2[CH2:6][CH2:5]1
Reactant: CCOC(=O)c1c(C)nn2ccc3c(c12)C(CC#N)CC3
Agent: [Co]
Agent: N
Solvent: CO
Product: CCOC(=O)c1c(C)nn2ccc3c(c12)C(CCN)CC3
Temperature: 25 °C
Reaction time: 14 h
Yield: 98.6 %

Procedure:
Ethyl 9-(cyanomethyl)-2-methyl-8,9-dihydro-7H-cyclopenta[c]pyrazolo[1,5-a]pyridine-1-carboxylate (145 mg, 0.512 mmol) and Raney cobalt (1.5 g) were suspended in 2M ammonia/methanol solution (50 mL), and the mixture was stirred under a hydrogen atmosphere at room temperature for 14 hr. The catalyst was filtered off through celite, and the filtrate was concentrated under reduced pressure to give the title compound (145 mg, yield 99%).
Reaction SMILES: C([Si](C)(C)[C:6]1[N:10]([CH3:11])[C:9]([C:12]([C:41]2[CH:46]=[CH:45][C:44]([Cl:47])=[CH:43][CH:42]=2)([OH:40])[C:13]2[CH:14]=[C:15]3[C:20](=[CH:21][CH:22]=2)[N:19]([CH2:23][CH:24]2[CH2:26][CH2:25]2)[C:18](=[O:27])[CH:17]=[C:16]3[C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([C:34]#[C:35][Si](C)(C)C)[CH:29]=2)=[CH:8][N:7]=1)(C)(C)C.O>C1COCC1.[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC>[Cl:47][C:44]1[CH:45]=[CH:46][C:41]([C:12]([OH:40])([C:9]2[N:10]([CH3:11])[CH:6]=[N:7][CH:8]=2)[C:13]2[CH:14]=[C:15]3[C:20](=[CH:21][CH:22]=2)[N:19]([CH2:23][CH:24]2[CH2:26][CH2:25]2)[C:18](=[O:27])[CH:17]=[C:16]3[C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([C:34]#[CH:35])[CH:29]=2)=[CH:42][CH:43]=1
Reactant: Cn1c(C(O)(c2ccc(Cl)cc2)c2ccc3c(c2)c(-c2cccc(C#C[Si](C)(C)C)c2)cc(=O)n3CC2CC2)cnc1[Si](C)(C)C(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: O
Product: C#Cc1cccc(-c2cc(=O)n(CC3CC3)c3ccc(C(O)(c4ccc(Cl)cc4)c4cncn4C)cc23)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 54.9 %

Procedure:
A solution of 6-[[2-(tert-Butyl-dimethyl-silanyl)-3-methyl-3H-imidazol-4-yl]-(4-chloro-phenyl)-hydroxy-methyl]-1-cyclopropylmethyl-4-(3-trimethylsilanylethynyl-phenyl)-1H-quinolin-2-one (4.50 g crude) in THF (100 mL) was treated with tetrabutylammonium chloride (1 M in THF, 10.0 mmol). The reaction mixture was stirred at room temperature for 12 hours, poured into H2O (200 mL), and extracted with ethyl acetate (3×100 mL). The combined organic extracts were washed with 1N HCl (100 mL), aqueous NaHCO3 (100 mL), and brine (100 mL), dried (MgSO4), filtered, and concentrated in vacuo to give a light green foam. Purification by flash column chromatography (silica, EtOAc:pet. ether:NH4OH 1:1:0.01) gave 6-[(4-Chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-1-cyclopropylmethyl-4-(3-ethynyl-phenyl)-1H-quinolin-2-one (1.82 g, 51%) as a yellow powder.
Reaction SMILES: [OH:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][C:7]2[N:11]([CH3:12])[N:10]=[C:9]([C:13]3[C:18]([F:19])=[CH:17][CH:16]=[CH:15][C:14]=3[F:20])[N:8]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl[C:30]1[C:35]([Cl:36])=[CH:34][C:33]([C:37]([F:40])([F:39])[F:38])=[CH:32][N:31]=1.O>CN(C=O)C>[Cl:36][C:35]1[C:30]([O:1][C:2]2[CH:3]=[CH:4][C:5]([CH2:6][C:7]3[N:11]([CH3:12])[N:10]=[C:9]([C:13]4[C:18]([F:19])=[CH:17][CH:16]=[CH:15][C:14]=4[F:20])[N:8]=3)=[CH:21][CH:22]=2)=[N:31][CH:32]=[C:33]([C:37]([F:39])([F:38])[F:40])[CH:34]=1
Reactant: FC(F)(F)c1cnc(Cl)c(Cl)c1
Reactant: Cn1nc(-c2c(F)cccc2F)nc1Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1nc(-c2c(F)cccc2F)nc1Cc1ccc(Oc2ncc(C(F)(F)F)cc2Cl)cc1
Temperature: 70 °C
Yield: 43.1 %

Procedure:
To a solution of 0.8 g of 5-(4-hydroxybenzyl)-3-(2,6-difluorophenyl)-1-methyl 1H-1,2,4-triazole in 10 ml of DMF at room temperature were added 0.4 g of anhydrous potassium carbonate and 0.63 g of 2,3-dichioro-5-trifluoromethylpyridine and then the suspension solution was heated to 70° C. or 1 hour. After cooling, the reaction mixture was poured into iced water and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried over magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel chromatography to afford 0.55 g of 5-(4-(3-chloro-5-trifluoromethylpyridin-2-yloxy)-benzyl)-3-(2,6-difluorophenyl)-1-methyl-1H-1,2,4-triazole.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[C:7]([NH2:12])=[N:8][CH:9]=[CH:10][CH:11]=2)[CH:3]=[N:2]1.[H-].[Na+].Cl[CH2:16][C:17]1[CH:30]=[CH:29][C:20]([CH2:21][O:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=2)=[CH:19][CH:18]=1>CN(C)C=O>[N:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1[O:22][CH2:21][C:20]1[CH:19]=[CH:18][C:17]([CH2:16][N:1]2[CH:5]=[C:4]([C:6]3[C:7]([NH2:12])=[N:8][CH:9]=[CH:10][CH:11]=3)[CH:3]=[N:2]2)=[CH:30][CH:29]=1
Reactant: Nc1ncccc1-c1cn[nH]c1
Reactant: ClCc1ccc(COc2ccccn2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Nc1ncccc1-c1cnn(Cc2ccc(COc3ccccn3)cc2)c1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 91.4 %

Procedure:
To a solution of 3-(1H-pyrazol-4-yl)-pyridin-2-ylamine (150 mg, 0.94 mmol) described in Manufacturing Example 32-1-4 in N,N-dimethylformamide (10 mL) was added sodium hydride (48.7 mg, 1.22 mmol, 60% in oil) on an ice bath (0° C.) under nitrogen atmosphere. Following 40 minutes of stirring at room temperature, 2-(4-chloromethyl-benzyloxy)-pyridine (228 mg, 0.98 mmol) described in Manufacturing Example 30-1-1 was added and stirred for 30 minutes at room temperature. The reaction mixture was partitioned into water and ethyl acetate at room temperature. The organic layer was washed with water and saturated aqueous sodium chloride, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under a reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate:heptane=2:1, then ethyl acetate) to obtain the title compound (307 mg, 92%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10](=[O:18])[CH:11]=[C:12]([CH:15]([F:17])[F:16])O[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:19]1([NH2:22])[CH2:21][CH2:20]1>CO.ClCCl.CCOCC>[CH2:1]([O:8][C:9]1[C:10](=[O:18])[CH:11]=[C:12]([CH:15]([F:16])[F:17])[N:22]([CH:19]2[CH2:21][CH2:20]2)[CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NC1CC1
Reactant: O=c1cc(C(F)F)occ1OCc1ccccc1
Solvent: CCOCC
Solvent: CO
Solvent: ClCCl
Product: O=c1cc(C(F)F)n(C2CC2)cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 7.5 h
Yield: 35.6 %

Procedure:
A mixture of 5-benzyloxy-2-difluoromethyl-pyran-4-one (4.0 g, 15.8 mmol) and cyclopropylamine (3.6 mL, 47.5 mmol) in methanol (40 mL) was stirred at room temperature for 7.5 hrs. The reaction mixture was concentrated in vacuo to obtain an oil. The oil was diluted with dichloromethane and ether, and a solid precipitated out. The solid was collected by suction filtration to afford 1.64 g of the title compound as the first crop. The filtrate was concentrated and then purified by column chromatography using a mixture of methanol and dichloromethane (1:20, v/v) as eluant. Fractions rich in the product were pooled together and evaporated to dryness, thereby affording a second crop (2.4 g). Crops 1 and 2 were combined to give 4.0 g (87%) of the title product. HPLC purity (peak area percent) is 98.8% at λ=280 nm using HPLC Method 1 as described above. 1H NMR (400 MHz, DMSO-D6) δ (ppm): 7.57 (s, 1H), 7.21-7.48 (m, 6H, 5ArH+CF2H), 6.44 (s, 1H), 5.05 (s, 2H, OCH2), 3.50-3.56 (m, 1H), 1.10-1.16 (m, 2H, CH2), 1.05-1.09 (m, 2H, CH2).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]1([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[CH3:31])[CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:32][C:33]([F:38])([F:37])[C:34]([OH:36])=[O:35]>ClCCl>[F:32][C:33]([F:38])([F:37])[C:34]([OH:36])=[O:35].[CH2:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]1([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[CH3:31])[CH2:17][NH:16][CH2:15]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccccc1C1(OCCCCOCc2ccccc2)CN(C(=O)OC(C)(C)C)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccccc1C1(OCCCCOCc2ccccc2)CNC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 101.6 %

Procedure:
1.43 g (3.36 mmol) of tert-butyl 3-(4-benzyloxybutoxy)-3-o-tolylazetidine-1-carboxylate are dissolved in 10 ml of dichloromethane. 4 ml (52 mmol) of trifluoroacetic acid are added dropwise and the mixture is stirred at room temperature for 1 hour and then concentrated to dryness. 1.5 g of 3-(4-benzyloxybutoxy)-3-o-tolylazetidine trifluoroacetate are obtained in the form of a colourless oil in quantitative yield.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[F:9][C:10]1[CH:11]=[C:12]([O:17][CH3:18])[CH:13]=[CH:14][C:15]=1[F:16].[C:19](O)(=[O:21])C.O>C1COCC1>[F:9][C:10]1[C:15]([F:16])=[CH:14][CH:13]=[C:12]([O:17][CH3:18])[C:11]=1[CH:19]=[O:21]
Reactant: CC(=O)O
Reactant: COc1ccc(F)c(F)c1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(F)c(F)c1C=O
Temperature: -75 °C
Reaction time: 1 h
Yield: 95 %

Procedure:
A solution of lithium diisopropylamide, 2M in TBF/n-heptane (171 mL, 341 mmol) was further diluted with dry THF (250 mL) and cooled under nitrogen to −75° C. 3,4-Difluoroanisole (46.8 g, 325 mmol) in dry THF (100 mL) was added dropwise and the mixture stirred at −75° C. for 1 h. Dry N,N-dimethylformnamide (27.6 mL, 358 mmol) was added dropwise and the mixture stirred for 10 mins at −70° C. Acetic acid (30 mL) and water (400 mL) were added, warming the temperature to 10° C. Extracted into diethyl ether (2×300 mL). Combined extracts were washed with water (250 mL), aqueous hydrochloric acid (0.2 N, 400 mL) and brine (2×250 mL), dried (MgSO4) and the solvent evaporated in vacuo to give a red/orange oil which crystallised. Purification was by recrystallisation from diethyl ether/petroleum ether 40-60 to give (53.0g, 95%) of solid; δH (300 MHz, CDCl3) 10.40 (1H, s, CHO), 7.37 (1H, q, ArH), 6.71 (1H, m, ArH), and 3.93 (3H, s OCH3).
Reaction SMILES: Br[CH2:2][C:3](=O)[C:4]([O:6][CH2:7][CH3:8])=[O:5].[NH2:10][C:11]1[N:21]=[CH:20][CH:19]=[CH:18][C:12]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14]>C(C(C)=O)C>[CH2:7]([O:6][C:4]([C:3]1[N:10]=[C:11]2[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:18][CH:19]=[CH:20][N:21]2[CH:2]=1)=[O:5])[CH3:8]
Reactant: CCOC(=O)C(=O)CBr
Reactant: CCOC(=O)c1cccnc1N
Solvent: CCC(C)=O
Product: CCOC(=O)c1cn2cccc(C(=O)OCC)c2n1
Temperature: 25 °C
Yield: 26.7 %

Procedure:
A mixture of ethyl bromopyruvate (2.3 g, 10.2 m mol and ethyl 2-aminonicotinate (1.7 g, 10 m mol) in methyl ethyl ketone (17 ml) was refluxed for 5 hours. After completion of the reaction, the mixture was cooled to room temperature and distilled under reduced pressure to remove the solvent. The residue to which saturated sodium hydrogen carbonate aqueous solution (50 ml) was added was extracted with chloroform (100 ml×3). The extract was washed with water, dried over MgSO4 and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (eluent: ethyl acetate) to give the object compound (0.7 g, yield 26.7%) as crystals. m.p. 97° C.
Reaction SMILES: [Li]CCCC.Br[C:7]1[CH:8]=[CH:9][C:10]([Cl:15])=[C:11]([Cl:14])[C:12]=1[Cl:13].[F:16][C:17]([F:24])([F:23])[C:18](OCC)=[O:19]>C(OCC)C>[F:16][C:17]([F:24])([F:23])[C:18]([C:8]1[CH:9]=[C:10]([Cl:15])[C:11]([Cl:14])=[C:12]([Cl:13])[CH:7]=1)=[O:19]
Reactant: CCOC(=O)C(F)(F)F
Reactant: Clc1ccc(Br)c(Cl)c1Cl
Agent: [Li]CCCC
Solvent: CCOCC
Product: O=C(c1cc(Cl)c(Cl)c(Cl)c1)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
n-BuLi (16.5 ml, 2.5M in hexane) is added over 20 minutes to a solution of 5-bromo-1,2,6-trichloro-benzene (10.2 g) in diethyl ether (150 ml) under nitrogen at −78° C. After 20 minutes at −78° C., a solution of ethyl trifluoroacetate (5.15 ml) in diethyl ether (50 ml) is added over 15 minutes to the reaction mixture. After 40 minutes at −78° C., the reaction mixture is slowly warmed up to room temperature and then quenched with a saturated aqueous solution of NH4Cl. The aqueous phase is extracted three times with diethyl ether. The combined organic phases are dried over Na2SO4 and concentrated in vacuo. The crude product is purified by vacuum distillation to yield 2,2,2-trifluoro-1-(3,4,5-trichloro-phenyl)-ethanone (9.20 g) as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]#[N:10])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[CH3:14][O:15][C:16]([N:18]=[C:19]=[S:20])=[O:17]>CC(C)=O>[CH3:14][O:15][C:16]([NH:18][C:19](=[S:20])[NH:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]#[N:10])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12])=[O:17]
Reactant: COC(=O)N=C=S
Reactant: N#CSc1ccc(N)c([N+](=O)[O-])c1
Solvent: CC(C)=O
Product: COC(=O)NC(=S)Nc1ccc(SC#N)cc1[N+](=O)[O-]

Procedure:
2.0 G. of 1-amino-2-nitro-4-thiocyanatobenzene in 20 ml. acetone is treated with 3.0 g. methoxycarbonyl isothiocyanate at room temperature for 9 days. The solution is concentrated and the residue triturated with methanol and recrystallized from acetone, yielding 1-(3-methoxycarbonyl-2-thioureido)- 2-nitro-4-thiocyanatobenzene.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH2:16]([O:18][C:19](=[O:23])[CH:20](Br)[CH3:21])[CH3:17].C(O)(C)C>CC(C)=O>[CH:6]([C:5]1[CH:8]=[CH:9][C:2]([O:1][CH:20]([CH3:21])[C:19]([O:18][CH2:16][CH3:17])=[O:23])=[CH:3][CH:4]=1)=[O:7]
Reactant: CCOC(=O)C(C)Br
Reactant: O=Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CC(C)O
Product: CCOC(=O)C(C)Oc1ccc(C=O)cc1
Yield: 83 %

Procedure:
The compound was prepared according to general procedure E with 4-hydroxybenzaldehyde (3.3 mmol) in dry acetone (15 ml), anhydrous K2CO3 (4.3 mmol), and ethyl-2 bromopropionate (3.6 mmol) at reflux for 2 h45. Isopropanol was added and evaporated by azeotropic distillation with ethyl-2-bromopropionate. 609 mg of pure compound were obtained (83% yield). 1H NMR (250 MHz, CDCl3): δ 1.10 (t, J=7.1 Hz, 3H), 1.52 (d, J=6.8 Hz, 3H), 4.10 (q, J=7.1 Hz, 2H), 4.76 (q, J=6.8 Hz, 1H) 6.85 (d, J=8.7 Hz 2H), 7.70 (d, J=8.9 Hz, 2H), 9.74 (s, 1H) 13C NMR (63 MHz, CDCl3): δ 14.0, 18.2, 61.4, 72.4, 115.1, 130.4, 131.8, 162.4, 171.1, 190.5
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:43]=[CH:42][C:41]([C:44]#[N:45])=[CH:40][C:10]=1[O:11][C:12]1[N:17]=[C:16]([NH:18][CH2:19][C:20]([O:22]CC)=O)[C:15]([N+:25]([O-])=O)=[C:14]([O:28][C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([C:35]([N:37]([CH3:39])[CH3:38])=[O:36])[CH:30]=2)[N:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>[Zn].O1CCCC1>[CH2:1]([O:8][C:9]1[CH:43]=[CH:42][C:41]([C:44]#[N:45])=[CH:40][C:10]=1[O:11][C:12]1[NH:17][C:16]2[C:15](=[C:14]([O:28][C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([C:35]([N:37]([CH3:39])[CH3:38])=[O:36])[CH:30]=3)[N:13]=1)[NH:25][C:20](=[O:22])[CH2:19][N:18]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)CNc1nc(Oc2cc(C#N)ccc2OCc2ccccc2)nc(Oc2cccc(C(=O)N(C)C)c2)c1[N+](=O)[O-]
Agent: [Zn]
Solvent: C1CCOC1
Product: CN(C)C(=O)c1cccc(OC2=C3NC(=O)CN=C3NC(Oc3cc(C#N)ccc3OCc3ccccc3)=N2)c1
Temperature: 70 °C
Yield: 139.8 %

Procedure:
2-(2-Benzyloxy-5-cyanophenoxy)-4-(ethoxycarbonylmethyl)amino-5-nitro-6-(3-(dimethylaminocarbonyl)phenoxy)pyrimidine (1.1 g, 1.80 mmol), a compound of formula (H), and granular zinc (0.5 g) were mixed with tetrahydrofuran (50 mL) and 10% aqueous HCI (10 mL). The reaction mixture was heated for 30 minutes at 70° C. The volatiles were evaporated. Saturated aqueous NaHCO3 was added and the solution extracted with ethyl acetate (300 mL). The organic layer was dried (Na2SO4) and evaporated to afford 1.35 g of 2-(2-benzyloxy-5-cyanophenoxy)-4-(3-(dimethylaminocarbonyl)phenoxy)-1,7-dihydro-6(5H)-pteridinone, a compound of formula (J).
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:17][CH:16]=1)=O)(C)(C)C.Cl>O1CCOCC1>[C:22]1([NH:21][C:18]2[CH:19]=[CH:20][C:15]([O:14][CH2:13][C@H:9]3[CH2:10][CH2:11][CH2:12][NH:8]3)=[CH:16][CH:17]=2)[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1ccc(Nc2ccccc2)cc1
Agent: Cl
Solvent: C1COCCO1
Product: c1ccc(Nc2ccc(OC[C@H]3CCCN3)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.1 %

Procedure:
To the product from step 1 (155 mg, 0.421 mmol) was added 4M HCl in dioxane (6 mL) and the resulting mixture was stirred at rt for 2 h. The solvent was removed in vacuo to obtain the title product as a solid (104 mg, 72%); MS; m/z 268 (M+H): LCMS (UV) 99%; 1H NMR (400 MHz, CD3OD) δ 1.86-1.96 (m, 1H), 2.06-2.18 (m, 2H), 2.23-2.31 (m, 1H), 3.32-3.39 (m, 2H), 3.99-4.12 (m, 2H), 4.30-4.33 (m, 1H), 6.92-7.01 (m, 3H), 7.07 (d, 2H, J=7.6 Hz), 7.16 (d, 2H, J=8.4 Hz); 7.26 (t, 2H, J=15.2 Hz)
Reaction SMILES: C([N:8]1[CH2:12][CH2:11][C@H:10]([O:13][S:14]([CH3:17])(=[O:16])=[O:15])[CH2:9]1)C1C=CC=CC=1.[ClH:18].[H][H]>[C].[Pd].C(O)C>[ClH:18].[CH3:17][S:14]([O:13][C@H:10]1[CH2:11][CH2:12][NH:8][CH2:9]1)(=[O:16])=[O:15]
Reactant: [H][H]
Reactant: CS(=O)(=O)O[C@H]1CCN(Cc2ccccc2)C1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: CS(=O)(=O)O[C@H]1CCNC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixed solution obtained by mixing 2.3 g of 100% pure (S)-1-benzyl-3-methanesulfonyloxypyrrolidine with 3.0 ml of ethanol and adding dropwise 1.00 ml of 35% aqueous hydrochloric acid thereto with cooling on an ice-water bath was charged, together with 300 mg of moist 5% palladium-carbon (water content 52% by weight), into an autoclave, hydrogen was introduced thereinto and the autoclave was heated to raise the temperature to 60 and the pressure to 203 kPa, and the reaction was allowed to proceed for 4 hours. Hydrogen absorption came to an end in 3.2 hours after the start of hydrogen introduction. After completion of the reaction, the reaction mixture was cooled to room temperature and depressurized. The reaction mixture was taken out, the catalyst was filtered off, and the filtrate obtained was concentrated under reduced pressure and further dried under vacuum to give 2.4 g (yield: 84 mole percent) of (S)-3-methanesulfonyloxypyrrolidine hydrochloride.