Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][N:4]=[CH:5][C:6]1[CH2:7][S:8](=O)[C@@H:9]2[CH:16]([NH:17][C:18](=[O:25])[CH2:19][C:20]3[S:21][CH:22]=[CH:23][CH:24]=3)[C:15](=[O:26])[N:10]2[C:11]=1[C:12]([OH:14])=[O:13])[CH3:2].C(Cl)(=O)C>CN(C)C=O>[CH2:1]([O:3][N:4]=[CH:5][C:6]1[CH2:7][S:8][C@@H:9]2[CH:16]([NH:17][C:18](=[O:25])[CH2:19][C:20]3[S:21][CH:22]=[CH:23][CH:24]=3)[C:15](=[O:26])[N:10]2[C:11]=1[C:12]([OH:14])=[O:13])[CH3:2]
Reactant: CCON=CC1=C(C(=O)O)N2C(=O)C(NC(=O)Cc3cccs3)[C@H]2S(=O)C1
Solvent: CC(=O)Cl
Solvent: CN(C)C=O
Product: CCON=CC1=C(C(=O)O)N2C(=O)C(NC(=O)Cc3cccs3)[C@H]2SC1
Reaction time: 1.5 h

Procedure:
To a solution of 3-ethoxyiminomethyl-7-(2-thienylacetamido)-3-cephem-4-carboxylic acid-1-oxide (100 mg) in N,N-dimethylformamide (5 ml) is added stannous chloride (100 mg) at 0° C. under nitrogen atmosphere, and acetyl chloride (0.8 ml) is added dropwise to the stirred mixture. After 90 minutes, the reaction mixture is added a few piece of ice, and stirred for 10 minutes, and then extracted with ethyl acetate. The extract solution is washed with saturated saline solution and saturated aqueous sodium hydrogen carbonate, dried and evaporated to give residue which on recrystallization from a mixture of methylene chloride and ether gives 3-ethoxyiminomethyl-7-(2-thienylacetamido)-3-cephem-4-carboxylic acid. m.p. 177°-183° C. (decomp.).
Reaction SMILES: [C:1]1([C:7]2([CH2:12][O:13][CH2:14][C:15]3[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[C:17]([C:25]([F:28])([F:27])[F:26])[CH:16]=3)[CH2:11][CH:10]=[CH:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH2:29].OO.[OH-].[Na+]>C1COCC1.C(OCC)(=O)C>[F:28][C:25]([F:26])([F:27])[C:17]1[CH:16]=[C:15]([CH:20]=[C:19]([C:21]([F:22])([F:23])[F:24])[CH:18]=1)[CH2:14][O:13][CH2:12][C:7]1([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:11][CH2:10][CH:9]([OH:29])[CH2:8]1
Reactant: O
Reactant: FC(F)(F)c1cc(COCC2(c3ccccc3)CC=CC2)cc(C(F)(F)F)c1
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: OC1CCC(COCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)(c2ccccc2)C1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 1-(((1-phenylcyclopent-3-enyl)methoxy)methyl)-3,5-bis(trifluoromethyl)benzene (200 mg) in THF (0.55 mL) at 0° C. was added borane-tetrahydrofuran complex (1.0 M solution, 0.55 mL) dropwise, and the resulting solution was warmed to room temperature and stirred at room temperature for 12 h. The reaction mixture was cooled to 0° C., and water (1.0 mL) was added slowly followed by 30% hydrogen peroxide (0.19 mL) and 1 N sodium hydroxide (0.55 mL). The resulting solution was stirred at room temperature for 5 min, and ethyl acetate (2.0 mL) was added. The aqueous layer was extracted with ethyl acetate, the combined organic layers were dried over anhydrous sodium sulfate and filtered, and the filtrate was evaporated in vacuo. The residue was purified by preparative TLC eluting with 40% ethyl acetate/60% hexanes to give the title compound as an oily material. 1H NMR (400 MHz, CDCl3) δ 2.06 (m), 1.9-2.6 (m), 3.42 (s), 3.57 (q, J=8.8 Hz), 4.45 (s), 4.3-4.6 (m), 7.1-7.5 (m), 7.47 (s), 7.64 (s), 7.74 (s), and 7.76 (s).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:17](=[O:18])[C:12]3[CH2:13][CH2:14][CH2:15][CH2:16][C:11]=3[C:9]2=[O:10])=[C:4]([F:19])[CH:3]=1.[N+:20]([O-])([OH:22])=[O:21]>S(=O)(=O)(O)O>[Cl:1][C:2]1[C:7]([N+:20]([O-:22])=[O:21])=[CH:6][C:5]([N:8]2[C:9](=[O:10])[C:11]3[CH2:16][CH2:15][CH2:14][CH2:13][C:12]=3[C:17]2=[O:18])=[C:4]([F:19])[CH:3]=1
Reactant: O=[N+]([O-])O
Reactant: O=C1C2=C(CCCC2)C(=O)N1c1ccc(Cl)cc1F
Agent: O=S(=O)(O)O
Product: O=C1C2=C(CCCC2)C(=O)N1c1cc([N+](=O)[O-])c(Cl)cc1F
Temperature: -3 °C
Reaction time: 1.5 h
Yield: 101.9 %

Procedure:
A mixture of N-(4-chloro-2-fluorophenyl)-1-cyclohexene-1,2-dicarboximide (24.4 g, 86.7 mmol) in sulfuric acid is cooled to −3° C., treated dropwise with 70% nitric acid (6.7 mL, 104.0 mmol) while maintaining the temperature from 0° to 2° C., warmed to and stirred at room temperature for 90 minutes, and poured onto ice. The resultant aqueous mixture is filtered to obtain a solid. The solid is washed with water and air-dried overnight to give the title product as a white powder (28.68 g, mp 152-155° C.) which is identified by 1H, 13C and 19F NMR spectral analyses.
Reaction SMILES: [Cl:1]/[C:2](/[C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=1)=[CH:3]\[C@H:4]1[C@H:6]([C:7](O)=[O:8])[C:5]1([CH3:11])[CH3:10].S(Cl)([Cl:21])=O>C(Cl)(Cl)(Cl)Cl>[Cl:1]/[C:2](/[C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=1)=[CH:3]\[C@H:4]1[C@H:6]([C:7]([Cl:21])=[O:8])[C:5]1([CH3:11])[CH3:10]
Reactant: CC1(C)[C@@H](/C=C(\Cl)c2ccc(Cl)cc2)[C@@H]1C(=O)O
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)(Cl)Cl
Product: CC1(C)[C@@H](/C=C(\Cl)c2ccc(Cl)cc2)[C@@H]1C(=O)Cl
Yield: 96.9 %

Procedure:
1.0 g (0.0035 mol) of (±)-trans-3-(Z-2-chloro-2-(4-chloro-phenyl)-vinyl)-2,2-dimethyl-cyclopropanecarboxylic acid were dissolved in 20 ml of carbon tetrachloride, and 5 ml of thionyl chloride were added dropwise slowly at 25° C., while stirring. The mixture was then heated to the reflux temperature for 4 hours. After this reaction time, excess thionyl chloride and carbon tetrachloride were distilled off under a waterpump vacuum. Last residues of solvent were removed by brief incipient distillation at a bath temperature of 60° C./2 mm Hg. 1.03 g (96.9% of theory) of (±)-trans-3-(Z-2-chloro-2-(4-chloro-phenyl)-vinyl)-2,2-dimethyl-cyclopropanecarboxylic acid chloride were obtained as an oily liquid. ##STR21##
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:3][CH2:2]1.Cl.[NH2:22][C@@H:23]([CH2:29][CH:30]([CH3:32])[CH3:31])[C:24]([O:26][CH2:27][CH3:28])=[O:25]>>[CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([NH:22][C@@H:23]([CH2:29][CH:30]([CH3:31])[CH3:32])[C:24]([O:26][CH2:27][CH3:28])=[O:25])=[O:14])[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:2][CH2:3]1
Reactant: CCOC(=O)[C@@H](N)CC(C)C
Reactant: O=C(O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1
Agent: Cl
Product: CCOC(=O)[C@H](CC(C)C)NC(=O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1

Procedure:
The title compound was synthesized in analogy to Example 1, using 6-(cyclopropylmethoxy)-5-(3,3-difluoroazetidin-1-yl)picolinic acid (Example 69 b) and (S)-ethyl 2-amino-4-methylpentanoate hydrochloride (CAN 2743-40-0) as starting materials. MS (EI): m/e=426.3 [M+H]+.
Reaction SMILES: C([Li])CCC.[CH3:6][O:7][CH:8]([O:15][CH3:16])[C:9]1[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=1.[F:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22]Cl)=[CH:20][CH:19]=1.[Cl-].[NH4+]>CCCCCC.O1CCCC1>[F:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22][C:8]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=2)([O:15][CH3:16])[O:7][CH3:6])=[CH:20][CH:19]=1
Reactant: Fc1ccc(CCl)cc1
Reactant: COC(OC)c1ccncc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COC(Cc1ccc(F)cc1)(OC)c1ccncc1
Reaction time: 0.5 h
Yield: 94.8 %

Procedure:
315 mL of n-butyllithium 1.6 M solution in hexane is added dropwise to a solution of 70.3 g (0.46 mole) of 4-dimethoxymethyl-pyridine in 1.4 L of tetrahydrofuran under nitrogen at −70° C. After 30 min. at −70° C., 73 g (0.505 mole) of 4-fluorobenzyl chloride in 280 mL of tetrahydrofuran is added dropwise. After 10 more min. at −70° C., the reaction mixture is allowed to reach room temperature and then stirred for 30 further min. The reaction mixture is poured into 2 L ammonium chloride solution and extracted with ethyl acetate. The organic phase is washed with water and dried over magnesium sulfate. After concentration the residue is purified by chromatography on silica gel (ethylacetate/hexane 1/1) to give 114 g of 4-[2-(4-Fluoro-phenyl)-1,1-dimethoxy-ethyl]-pyridine as yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:10](=[O:12])(=[O:11])[N:9]([CH3:13])[C:8]([C:14]([O:16]C)=O)=[C:7]([OH:18])[C:6]=2[CH:19]=1.[NH2:20][C:21]1[S:22][C:23]([CH3:26])=[CH:24][N:25]=1>C1(C)C(C)=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:10](=[O:11])(=[O:12])[N:9]([CH3:13])[C:8]([C:14]([NH:20][C:21]3[S:22][C:23]([CH3:26])=[CH:24][N:25]=3)=[O:16])=[C:7]([OH:18])[C:6]=2[CH:19]=1
Reactant: COC(=O)C1=C(O)c2cc(Cl)ccc2S(=O)(=O)N1C
Reactant: Cc1cnc(N)s1
Solvent: Cc1ccccc1C
Product: Cc1cnc(NC(=O)C2=C(O)c3cc(Cl)ccc3S(=O)(=O)N2C)s1
Yield: 77 %

Procedure:
5.0 gm (16.5 millimols) of methyl 6-chloro-4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxylate-1,1-dioxide and 2.1 gm (18.5 millimols) of 2-amino-5-methyl-thiazole were refluxed in 300 ml of anhydrous xylene for 24 hours in a Soxhlet-apparatus equipped with a 4-A-molecular sieve. After cooling, the crude product which had crystallized out was filtered off and recrystallized from dioxane. 4.9 gm (77% of theory) of 6-chloro-4-hydroxy-2-methyl-N-(5-methyl-2-thiazolyl)-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide were obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH:7]=[CH:8][NH:9]2)=[CH:5][CH:4]=1.ClS([N:16]=[C:17]=O)(=O)=O>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([C:17]#[N:16])=[CH:8][NH:9]2)=[CH:5][CH:4]=1
Reactant: O=C=NS(=O)(=O)Cl
Reactant: COc1ccc2cc[nH]c2c1
Solvent: CN(C)C=O
Product: COc1ccc2c(C#N)c[nH]c2c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 84.6 %

Procedure:
A solution of 6-methoxyindole (10.0 g, 68.0 mmol) in DMF (120 mL) was cooled to 0° C. and treated with chlorosulfonyl isocyanate (7.72 mL, 88.4 mmol). After the addition, the reaction mixture was stirred at this temperature for 1 h. The dark solution was poured into ice water (600 mL) and the light brown solid was collected by filtration, washed with additional H2O and dried to afford 9.9 g (85%) of 6-methoxy-1H-indole-3-carbonitrile as a light brown solid.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH:9]1[C:14]1[N:19]=[C:18]([CH:20]2[CH2:25][NH:24][CH2:23][CH2:22][N:21]2[CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:17]=[C:16](Cl)[N:15]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:34][NH2:35]>O1CCOCC1>[CH2:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH:9]1[C:14]1[N:19]=[C:18]([CH:20]2[CH2:25][NH:24][CH2:23][CH2:22][N:21]2[CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:17]=[C:16]([NH:34][NH2:35])[N:15]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Clc1cc(C2CNCCN2Cc2ccccc2)nc(C2CNCCN2Cc2ccccc2)n1
Reactant: NN
Solvent: C1COCCO1
Product: NNc1cc(C2CNCCN2Cc2ccccc2)nc(C2CNCCN2Cc2ccccc2)n1
Yield: 96.4 %

Procedure:
A solution of 2,4-di(N-benzylpiperazinyl)-6-chloropyrimidine (48.4 g, 104 mmol), hydrazine (96 g, 3 mol), in p-dioxane (1000 mL) was heated at 75° C. for 16 hours. The reaction was concentrated, dissolved in CH2Cl21 washed with H2O, and dried (MgSO4). Filtration and concentration of the resulting solution gave 46 g (97%) of the title compound as a foam. 1H NMR (CDCl3) δ 2.44 (m, 8H, piperazine), 3.52-3.59 (m, 8H, piperazine), 3.71 (m, 4H, CH2), 5.22 (s, 1H, C5H), 5.72 (bs, 2H, NH2)1 7.30 (m, 10H, Ar).
Reaction SMILES: [C:1]1([CH2:9][OH:10])[CH:6]=[CH:5][C:4]([CH2:7]O)=[CH:3][CH:2]=1.S(Cl)([Cl:13])=O.C(=O)(O)[O-].[Na+].Cl>C(Cl)(Cl)Cl>[OH:10][CH2:9][C:1]1[CH:6]=[CH:5][C:4]([CH2:7][Cl:13])=[CH:3][CH:2]=1
Reactant: OCc1ccc(CO)cc1
Reactant: O=S(Cl)Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: OCc1ccc(CCl)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 75 %

Procedure:
1,4-benzenedimethanol (13.8 g, 0.10 mole) was dispersed in chloroform (100 mL) in a 500 mL three-neck round bottom flask equipped with a magnetic stirring bar, an addition funnel, a nitrogen inlet and a gas scrubber. The mixture was cooled to 0° C. in an ice bath. Thionyl chloride (13.1 g, 0.11 mole) dissolved in chloroform (10 mL) was added dropwise over ten minutes with rapid stirring to the cooled mixture. As the addition proceeded, the mixture largely cleared. During the addition step, and for one hour thereafter, the reaction flask was swept with nitrogen which was then passed through the scrubber before venting to the atmosphere. The nitrogen was turned off and the scrubber disconnected. The mixture was allowed to come to room temperature and stirring was continued for 20 hours. Sufficient sodium bicarbonate was added to neutralize any residual hydrogen chloride. The mixture was filtered through a coarse glass frit and the solvent removed under reduced pressure at 35° C. A sample of the residue was chromatographed on silica gel (200 g) with an ethyl acetate:hexane (2:3) solvent. p-Hydroxymethyl- benzyl chloride was obtained in 75% yield (11.64 g). The product had a melting point of 58°-60° C. NMR spectral data were as follows: 1H NMR (CDCl3, 300 MHz): δ 7.3 (m, 4H), 4.70 (s, 2H), 4.59 (s, 2H), 1.67 (s, 1H); 13C NMR (CDCl3, 75 MHz, ppm) 141.372, 135.995, 128.876, 127.366, 64.927, 46.121.
Reaction SMILES: [C:1]([C:4]1[CH:26]=[CH:25][C:7]([O:8][CH2:9][CH2:10][CH2:11][S:12][C:13]2[CH:18]=[CH:17][C:16]([C:19](=[O:24])[CH2:20][CH2:21][C:22]#[N:23])=[CH:15][CH:14]=2)=[C:6]([CH2:27][CH2:28][CH3:29])[C:5]=1[OH:30])(=[O:3])[CH3:2].C([Sn]([N:44]=[N+:45]=[N-:46])(CCCC)CCCC)CCC>C1COCC1.CCOCC.Cl>[C:1]([C:4]1[CH:26]=[CH:25][C:7]([O:8][CH2:9][CH2:10][CH2:11][S:12][C:13]2[CH:18]=[CH:17][C:16]([C:19](=[O:24])[CH2:20][CH2:21][C:22]3[NH:46][N:45]=[N:44][N:23]=3)=[CH:15][CH:14]=2)=[C:6]([CH2:27][CH2:28][CH3:29])[C:5]=1[OH:30])(=[O:3])[CH3:2]
Reactant: CCCC[Sn](CCCC)(CCCC)N=[N+]=[N-]
Reactant: CCCc1c(OCCCSc2ccc(C(=O)CCC#N)cc2)ccc(C(C)=O)c1O
Agent: Cl
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCCc1c(OCCCSc2ccc(C(=O)CCc3nnn[nH]3)cc2)ccc(C(C)=O)c1O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The nitrile from Example 40, Step E, (1.0 g, 2.35 mmole) and tri-n-butyltin azide (1.0 g, 3.0 mmole) in dry THF (20 ml) were stirred at 70° for 48 hours, and then heated at reflux for 24 hours. The reaction mixture was cooled to room temperature, diluted with ether (20 ml) and concentrated HCl was added. After 1 hour, the solution was filtered, the solid was washed with ether and dried to yield the title compound.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH2:6]([O:13][C:14]1[CH:15]=[CH:16][C:17]2[O:21][CH:20]=[CH:19][C:18]=2[C:22]=1[C:23]([CH3:26])([CH3:25])[CH3:24])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.O.CN(C)[CH:30]=[O:31]>>[CH2:6]([O:13][C:14]1[CH:15]=[CH:16][C:17]2[O:21][C:20]([CH:30]=[O:31])=[CH:19][C:18]=2[C:22]=1[C:23]([CH3:26])([CH3:25])[CH3:24])[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: CN(C)C=O
Reactant: CC(C)(C)c1c(OCc2ccccc2)ccc2occc12
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: CC(C)(C)c1c(OCc2ccccc2)ccc2oc(C=O)cc12
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 36 %

Procedure:
Under ice-cooling, 26.2 ml of phosphorus oxychloride was added dropwise to 17 ml of N,N-dimethylformamide, followed by a solution of 40.0 g of 5-benzyloxy-4-t-butylbenzofuran in 10 ml of N,N-dimethylformamide. After stirring at room temperature for 20 minutes, the mixture was heated at 80° C. for 2 hours. After cooling, the reaction solution was poured into water and extracted with ethyl acetate. The extracted layers were washed with a saturated aqueous sodium bicarbonate solution and then water, dried over anhydrous magnesium sulfate, and then concentrated. The concentrate was purified by silica gel column chromatography (in n-hexane containing 10%ethyl acetate) to give 16.2 g of 5-benzyloxy-4-t-butyl-2-formylbenzofuran as a pale yellow solid (yield 36%).
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[N:17]=[C:16]([NH:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([CH3:25])[CH:20]=3)[C:15]([C:26]([NH2:28])=[O:27])=[CH:14][N:13]=2)=[CH:7][CH:6]=1.[O-:29][C:30]#[N:31].[K+]>C(O)(=O)C>[CH3:25][C:21]1[CH:20]=[C:19]([NH:18][C:16]2[C:15]([C:26]([NH2:28])=[O:27])=[CH:14][N:13]=[C:12]([NH:11][C:8]3[CH:9]=[CH:10][C:5]([CH2:4][NH:3][C:30]([NH2:31])=[O:29])=[CH:6][CH:7]=3)[N:17]=2)[CH:24]=[CH:23][CH:22]=1
Reactant: Cc1cccc(Nc2nc(Nc3ccc(CN)cc3)ncc2C(N)=O)c1
Reactant: N#C[O-]
Agent: Cl
Agent: [K+]
Solvent: CC(=O)O
Product: Cc1cccc(Nc2nc(Nc3ccc(CNC(N)=O)cc3)ncc2C(N)=O)c1
Reaction time: 6 h
Yield: 32.3 %

Procedure:
A 20 ml acetic acid-10 ml THF mixed solution containing 500 mg of 2-{[4-(aminomethyl)phenyl]amino}-4-[(3-methylphenyl)-amino]pyrimidine-5-carboxamide dihydrochloride was mixed with 5.76 g of potassium cyanate, which was added by dividing into 6 portions, at room temperature, followed by stirring for 6 hours. The reaction mixture was concentrated and then poured into water, and the precipitated solid was collected by filtration and washed with acetonitrile. The resulting solid was purified by a silica gel column chromatography (chloroform:methanol) to obtain 150 mg of 4-[(3-methylphenyl)amino]-2-[(4-ureidomethylphenyl)amino]pyrimidine-5-carboxamide as a pale yellow solid.
Reaction SMILES: [O:1]([CH2:8][CH:9]([OH:30])[CH2:10][NH:11][CH:12]([CH3:29])[CH2:13][O:14][C:15]1[CH:28]=[CH:27][C:18]([CH2:19][CH:20]2[S:24][C:23](=[O:25])[NH:22][C:21]2=[O:26])=[CH:17][CH:16]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C)[CH:33]=[O:34]>>[O:1]([CH2:8][CH:9]1[O:30][C:33](=[O:34])[N:11]([CH:12]([CH3:29])[CH2:13][O:14][C:15]2[CH:28]=[CH:27][C:18]([CH2:19][CH:20]3[S:24][C:23](=[O:25])[NH:22][C:21]3=[O:26])=[CH:17][CH:16]=2)[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(C)C=O
Reactant: CC(COc1ccc(CC2SC(=O)NC2=O)cc1)NCC(O)COc1ccccc1
Product: CC(COc1ccc(CC2SC(=O)NC2=O)cc1)N1CC(COc2ccccc2)OC1=O
Temperature: 25 °C
Reaction time: 5 h

Procedure:
211 mg of N,N'-carbonyldiimidazole were added to a solution of 500 mg of 5-{4-[2-(3-phenoxy-2-hydroxypropylamino)propoxy]benzyl}thiazolidine-2,4-dione (prepared as described in Example 3) in 5 ml of anhydrous dimethylformamide, whilst ice-cooling, and the mixture was then stirred at room temperature for 5 hours. At the end of this time, the dimethylformamide was removed from the reaction mixture by evaporation under reduced pressure, and water was added to the resulting residue, which was then extracted with ethyl acetate. The extract was further washed with an aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The ethyl acetate was removed from the extract by evaporation under reduced pressure, and the resulting residue was purified by silica gel column chromatography, using a gradient elution method, with mixtures of ethyl acetate and hexane ranging from 1:1 to 2:1 by volume as the eluent, to give 410 mg of the title compound, melting at 54° C. to 56° C.
Reaction SMILES: [NH2:1][C:2]1[NH:6][CH:5]=[N:4][C:3]=1[C:7]([NH2:9])=[O:8].[CH2:10]([O:14][C:15]1[N:20]=[C:19]([CH:21]=O)[CH:18]=[CH:17][CH:16]=1)[CH2:11][CH2:12][CH3:13].C(O)(=O)C.C([BH3-])#N.[Na+]>C(O)C>[CH2:10]([O:14][C:15]1[N:20]=[C:19]([CH2:21][NH:1][C:2]2[N:6]=[CH:5][NH:4][C:3]=2[C:7]([NH2:9])=[O:8])[CH:18]=[CH:17][CH:16]=1)[CH2:11][CH2:12][CH3:13]
Reactant: NC(=O)c1nc[nH]c1N
Reactant: CCCCOc1cccc(C=O)n1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Product: CCCCOc1cccc(CNc2nc[nH]c2C(N)=O)n1
Reaction time: 2 h

Procedure:
5-Aminoimidazole-4-carboxamide (0.30 g, 2.4 mmol) was added to the solution of 6-butoxypyridine-2-carbaldehyde (0.43 mg, 2.4 mmol, obtained from Example 17(d)) in anhydrous ethanol (30 mL) and the reaction mixture was refluxed. After 2 h, the reaction mixture was concentrated in vacuo. The light pink solid was suspended in anhydrous ethanol (25 mL), and acetic acid (0.27 mL, 4.8 mmol) was added. After 1.5 h, sodium cyanoborohydride (0.30 g, 4.8 mmol) was added to the mixture. After stirring o.n. at ambient temperature, the reaction mixture was concentrated in vacuo. The resulting 1.2 g of crude title compound was used in the next step without further purification. MS (ESI) m/z 290 (M+1)
Reaction SMILES: Br[C:2]1[N:6]([CH3:7])[N:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[O:11]=[C:12]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14][NH:13]1>>[CH3:7][N:6]1[C:2]([N:13]2[C:12](=[O:11])[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]2)=[C:3]([N+:8]([O-:10])=[O:9])[CH:4]=[N:5]1
Reactant: CC(C)(C)OC(=O)N1CCNC(=O)CC1
Reactant: Cn1ncc([N+](=O)[O-])c1Br
Product: Cn1ncc([N+](=O)[O-])c1N1CCN(C(=O)OC(C)(C)C)CCC1=O
Yield: 33 %

Procedure:
Following the procedure for Intermediate 202 starting from 5-bromo-1-methyl-4-nitro-1H-pyrazole and tert-butyl 5-oxo-1,4-diazepane-1-carboxylate gave tert-butyl 4-(1-methyl-4-nitro-1H-pyrazol-5-yl)-5-oxo-1,4-diazepane-1-carboxylate as a brown gum (136 mg, 33%). 1H NMR (400 MHz, d4-MeOD) δ 8.18 (s, 1H), 4.04-3.72 (m, 5H), 3.90-3.62 (m, 4H), 3.02-2.86 (m, 2H), 1.52 (s, 9H).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:3]=1[C:4]([OH:6])=[O:5].[CH3:12][Si](C=[N+]=[N-])(C)C>C(OC(=O)C)C.C(O)C>[CH3:12][O:5][C:4](=[O:6])[C:3]1[C:7]([CH3:11])=[CH:8][CH:9]=[CH:10][C:2]=1[NH2:1]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: Cc1cccc(N)c1C(=O)O
Solvent: CCO
Solvent: CCOC(C)=O
Product: COC(=O)c1c(C)cccc1N
Reaction time: 0.5 h
Yield: 100.9 %

Procedure:
Dissolve 2-Amino-6-methyl-benzoic acid (3.00 g, 19.8 mmol) in ethylacetate (100 mL) and ethanol (100 mL) and add (trimethylsilyl) diazomethane (19.8 mL, 39.7 mmol, 2M in hexane) at room temperature and stir the solution for 1 h 30 min. Remove the solvent under reduced pressure to afford the title compound (3.30 g, quantitative). 1H NMR (CDCl3, 300 MHz) δ 2.43 (s, 3H), 3.89 (s, 3H), 5.11 (brs, 2H), 6.52 (m, 2H), 7.08 (t, J=7.7 Hz, 1H). MS (ES+): 166 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[C:5]([F:11])=[CH:4][C:3]=1[OH:12].[NH4+].[Cl-]>C1COCC1.CO.[Zn]>[NH2:8][C:6]1[C:5]([F:11])=[CH:4][C:3]([OH:12])=[C:2]([Cl:1])[CH:7]=1
Reactant: O=[N+]([O-])c1cc(Cl)c(O)cc1F
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CO
Solvent: C1CCOC1
Product: Nc1cc(Cl)c(O)cc1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96.7 %

Procedure:
Zinc dust (10 g, 160 mmol) was added portion wise to a solution of 2-chloro-5-fluoro-4-nitro-phenol (3.0 g, 16 mmol) and NH4Cl (8.4 g, 160 mmol) in THF (150 mL) and MeOH (150 mL) and the mixture was stirred at RT for 0.5 h. The reaction mixture was filtered, and the filter cake was washed with EtOAc (3×50 mL). The combined filtrate was washed with brine (3×100 mL), dried over Na2SO4 and concentrated to provide 4-amino-2-chloro-5-fluorophenol (2.5 g, 100% yield). 1H NMR (400 MHz, DMSO-d6): δ 9.39 (s, 1H), 6.76 (d, J=9.2 Hz, 1H), 6.65 (d, J=12.4 Hz, 1H), 4.70 (s, 2H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:14]=[CH:15][C:16]=1[NH:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([N:24]2[CH2:29][CH2:28][N:27]([CH2:30][C:31]([O:33]CC3C=CC=CC=3)=[O:32])[CH2:26][CH2:25]2)[CH:19]=1)[C:7]([O:9][CH2:10][CH2:11][O:12][CH3:13])=[O:8])([O-])=O.C([O-])=O.[NH4+]>O1CCCC1.CN(C=O)C.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]([CH:14]=[CH:15][C:16]=1[NH:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([N:24]2[CH2:29][CH2:28][N:27]([CH2:30][C:31]([OH:33])=[O:32])[CH2:26][CH2:25]2)[CH:19]=1)[C:7]([O:9][CH2:10][CH2:11][O:12][CH3:13])=[O:8]
Reactant: COCCOC(=O)c1ccc(Nc2cccc(N3CCN(CC(=O)OCc4ccccc4)CC3)c2)c([N+](=O)[O-])c1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COCCOC(=O)c1ccc(Nc2cccc(N3CCN(CC(=O)O)CC3)c2)c(N)c1

Procedure:
To a solution of 2-methoxyethyl 3-nitro-4-(3-(4-(benzyloxy-carbonyl-methyl)-1-piperazinyl)-phenylamino)-benzoate (3d) (3.5 g; 6.4 mmol) in a mixture of tetrahydrofurane (50 ml) and DMF (5 ml) was added palladium catalyst (0.9 g, 5% Pd on activated carbon) and ammonium formiate (0.8 g; 12.6 mmol) and the mixture was heated to reflux for 2 hours. The cooled mixture was filtered through celite and the solvent was removed under reduced pressure to leave 2d, quantitatively.