Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[C:13]([C:15]2[O:16][CH:17]=[C:18]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[N:19]=2)[CH:12]=[CH:11][N:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].FC(F)(F)S(O[CH2:33][CH:34]([F:36])[F:35])(=O)=O>CN(C=O)C.C(OCC)(=O)C.O>[C:1]([O:5][C:6]([N:8]([CH2:33][CH:34]([F:36])[F:35])[C:9]1[CH:14]=[C:13]([C:15]2[O:16][CH:17]=[C:18]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[N:19]=2)[CH:12]=[CH:11][N:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=S(=O)(OCC(F)F)C(F)(F)F
Reactant: CCOC(=O)c1coc(-c2ccnc(NC(=O)OC(C)(C)C)c2)n1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1coc(-c2ccnc(N(CC(F)F)C(=O)OC(C)(C)C)c2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100.4 %

Procedure:
To a solution of ethyl 2-(2-((tert-butoxycarbonyl)amino)pyridin-4-yl)-1,3-oxazole-4-carboxylate (58 mg) in DMF (2 mL) was added a sodium hydride 60% dispersion in mineral oil (9.05 mg), and then 2,2-difluoroethyl trifluoromethanesulfonate (74.5 mg) was added thereto. The reaction mixture was stirred at room temperature for 30 min, and diluted with ethyl acetate, and water was added thereto. The organic layer was separated, washed with water and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (69.4 mg).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:12]=1[NH:11]C(=O)[C:9]2=[O:14])([O-:3])=[O:2].C(O)(=O)CC(CC(O)=O)(C(O)=O)[OH:18]>[OH-].[Na+].OO>[NH2:11][C:12]1[C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=[CH:7][C:8]=1[C:9]([OH:14])=[O:18]
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Reactant: O=C1Nc2c(cccc2[N+](=O)[O-])C1=O
Agent: OO
Agent: [Na+]
Agent: [OH-]
Product: Nc1c(C(=O)O)cccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 70 %

Procedure:
To a ice cold solution of 7-nitro-1H-indole-2,3-dione (9 g, 47 mmol) in 2 M aqueous sodium hydroxide (50 mL), 30% hydrogen peroxide (9 mL) was added drop wise. The mixture was warmed to room temperature and stirred overnight. The mixture was carefully acidified by addition of a saturated citric acid solution. The solid precipitate was collected by filtration, washed with water and dried in a vacuum oven to get 6 g of the required product as a yellow coloured solid (70%).
Reaction SMILES: Cl[CH2:2][C@H:3]([OH:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[N-:11]=[N+:12]=[N-:13].[Na+].CN(C=O)C>C1(C)C=CC=CC=1>[N:11]([CH2:2][C@H:3]([OH:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])=[N+:12]=[N-:13]
Reactant: CCOC(=O)C[C@@H](O)CCl
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: CCOC(=O)C[C@@H](O)CN=[N+]=[N-]
Temperature: 100 °C
Reaction time: 24 h
Yield: 79.4 %

Procedure:
In a 200 ml four-necked flask were charged 20.0 g (0.12 mol) of ethyl (R)-4-chloro-3-hydroxybutyrate, 15.6 g (0.24 mol) of sodium azide and 80 ml of DMF, and the reaction mixture was stirred for 24 hours at a reaction temperature of about 100° C. After cooling the reaction mixture, the reaction mixture was diluted with 100 ml of toluene, washed with 50 ml of water, and concentrated to give 16.5 g (79%) of the title compound.
Reaction SMILES: [C:1]1([C:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[O:9][C:8]=2[CH:16]([NH2:18])[CH3:17])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:20]1[N:28]=[CH:27][N:26]=[C:25]2[C:21]=1[N:22]=[CH:23][NH:24]2.CCN(C(C)C)C(C)C>C(O)CCC>[C:1]1([C:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[O:9][C:8]=2[CH:16]([NH:18][C:20]2[N:28]=[CH:27][N:26]=[C:25]3[C:21]=2[N:22]=[CH:23][NH:24]3)[CH3:17])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Clc1ncnc2[nH]cnc12
Reactant: CC(N)c1oc2ccccc2c1-c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: CC(Nc1ncnc2[nH]cnc12)c1oc2ccccc2c1-c1ccccc1
Temperature: 100 °C

Procedure:
A mixture of 1-(3-phenylbenzofuran-2-yl)ethylamine Example 24 (0.706 mmol), 6-chloro-9H-purine (213 mg, 1.38 mmol) and DIPEA (0.24 mL, 1.38 mmol) in n-butanol (5 mL) was heated at 100° C. for 18 h. After cooling to RT, volatiles were removed under reduced pressure and the resulting residue was purified by column chromatography (Si—PCC, gradient 0-5% MeOH in DCM) and then triturated from MeOH with water affording 103 as an off-white solid (107 mg, 43% over two steps). LCMS: RT 4.15 min [M+H]+ 356.1. 1H NMR (DMSO, 400 MHz): δ 8.21-7.95 (3H, m), 7.73-7.60 (3H, m), 7.58-7.49 (3H, m), 7.46-7.23 (3H, m), 5.84 (1H, s), 1.67 (3H, d, J=6.99 Hz)
Reaction SMILES: [OH-].[Na+].CO.[C:5]1([C:11]2[CH:16]=[C:15]([C:17]([O:19]C)=[O:18])[CH:14]=[C:13]([C:21]3[NH:25][N:24]=[N:23][N:22]=3)[N:12]=2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.Cl>O>[C:5]1([C:11]2[CH:16]=[C:15]([C:17]([OH:19])=[O:18])[CH:14]=[C:13]([C:21]3[NH:25][N:24]=[N:23][N:22]=3)[N:12]=2)[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: COC(=O)c1cc(-c2ccccc2)nc(-c2nnn[nH]2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1cc(-c2ccccc2)nc(-c2nnn[nH]2)c1
Temperature: 50 °C
Reaction time: 4 h

Procedure:
Aqueous 2 N sodium hydroxide solution (8.4 mL) was added to an MeOH (85 mL) solution of methyl 2-phenyl-6-(tetrazol-5-yl)pyridine-4-carboxylate (3.19 g), and stirred at 50° C. for 4 hours. With cooling with ice, 2N hydrochloric acid (16.8 mL) and water were added to it, the formed precipitate was taken out through filtration, washed with water and dried to obtain the title compound as a flesh-colored powder.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([OH:8])[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:15][CH2:16][CH2:17][CH3:18])[N:3]=1.[CH2:19]([NH2:22])[CH2:20][CH3:21]>C(O)C>[CH2:19]([NH:22][C:2]1[N:3]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:15][CH2:16][CH2:17][CH3:18])[NH:5][C:6](=[O:8])[CH:7]=1)[CH2:20][CH3:21]
Reactant: CCCN
Reactant: CCCOc1ccccc1-c1nc(O)cc(Cl)n1
Solvent: CCO
Product: CCCNc1cc(=O)[nH]c(-c2ccccc2OCCC)n1

Procedure:
4-Chloro-6-hydroxy-2-(2-propoxyphenyl)-pyrimidine (0.66 g), n-propylamine (1.8 g) and ethanol (20 ml) was heated at 90° C. in a pressure vessel for 16 hours. The cooled reaction mixture was evaporated under reduced pressure to yield an oil which solidified on washing with water. The residue was recrystallized from isopropanol:water to yield the title compound, 0.56 g, m.p. 172-3° C.
Reaction SMILES: [N:1]([CH2:4][CH2:5][C:6]1[N:7]=[CH:8][C:9]2[C:14]([CH:15]=1)=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>O1CCCC1>[NH2:1][CH2:4][CH2:5][C:6]1[N:7]=[CH:8][C:9]2[C:14]([CH:15]=1)=[CH:13][CH:12]=[CH:11][CH:10]=2
Reactant: [N-]=[N+]=NCCc1cc2ccccc2cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: NCCc1cc2ccccc2cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 55.4 %

Procedure:
To a solution of 3-(2-azidoethyl)isoquinoline (Description 112; 5.6 g, 28.3 mmol) in anhydrous tetrahydrofuran (50 ml) was added triphenylphosphine (14.85 g, 56.6 mmol) and water (0.509 ml, 28.3 mmol), and the resulting mixture stirred at room temperature overnight. The mixture was loaded directly onto a Bond-elut SCX cartridge and eluted with methanol until TLC indicated complete elution of triphenylphosphine. The product was then eluted with 2.0M ammonia in methanol. The basic fractions were collected and evaporated to give the title compound (2.7 g, 55%).
Reaction SMILES: [C:1]([C:4]1[C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:8][N:7]([CH2:16][CH3:17])[C:6](=[O:18])[C:5]=1[N+:19]([O-])=O)(=[O:3])[CH3:2].N[C:23]1[O:27][N:26]=[C:25]([CH3:28])[CH:24]=1>C(O)C>[C:1]([C:4]1[C:9]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[N:8][N:7]([CH2:16][CH3:17])[C:6](=[O:18])[C:5]=1[NH:19][C:23]1[O:27][N:26]=[C:25]([CH3:28])[CH:24]=1)(=[O:3])[CH3:2]
Reactant: CCn1nc(-c2ccccc2)c(C(C)=O)c([N+](=O)[O-])c1=O
Reactant: Cc1cc(N)on1
Solvent: CCO
Product: CCn1nc(-c2ccccc2)c(C(C)=O)c(Nc2cc(C)no2)c1=O
Temperature: 50 °C
Reaction time: 96 h
Yield: 14.9 %

Procedure:
To a stirred solution of 200 mg (0.696 mmol) of 5-acetyl-2-ethyl-4-nitro-6-phenylpyridazin-3(2H)-one (Dal Piaz, V et al, J. Med. Chem. 1997, 40, 1417) in ethanol (10 mL), 5-amino-3-methylisoxazole (204 mg, 2.088 mmol) was added. The resulting mixture was stirred at 50° C. for four days. The solvent was evaporated and the residue purified by column chromatography (silica gel, hexane/ethyl acetate 2:1) to yield the title compound (35 mg, 14.9% yield).
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@H:35]([O:36][CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C@H:34]([O:44][C@@H:45]2[O:74][C@H:73]([CH3:75])[C@@H:64]([O:65][CH2:66][C:67]3[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=3)[C@H:55]([O:56][CH2:57][C:58]3[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=3)[C@H:46]2[O:47][CH2:48][C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)[C@@H:33]([CH2:76][O:77][CH2:78][C:79]2[CH:84]=[CH:83][CH:82]=[CH:81][CH:80]=2)[O:32][C@@H:10]1[O:11][C@@H:12]1[C@@H:19]2[C@@H:15]([N:16](C(OC)=O)[O:17][CH2:18]2)[CH2:14][C@H:13]1[O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+].[Cl-].[NH4+]>CO>[CH2:1]([O:8][C@@H:9]1[C@@H:35]([O:36][CH2:37][C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=2)[C@H:34]([O:44][C@@H:45]2[O:74][C@H:73]([CH3:75])[C@@H:64]([O:65][CH2:66][C:67]3[CH:68]=[CH:69][CH:70]=[CH:71][CH:72]=3)[C@H:55]([O:56][CH2:57][C:58]3[CH:59]=[CH:60][CH:61]=[CH:62][CH:63]=3)[C@H:46]2[O:47][CH2:48][C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)[C@@H:33]([CH2:76][O:77][CH2:78][C:79]2[CH:80]=[CH:81][CH:82]=[CH:83][CH:84]=2)[O:32][C@@H:10]1[O:11][C@@H:12]1[C@@H:19]2[C@@H:15]([NH:16][O:17][CH2:18]2)[CH2:14][C@H:13]1[O:24][CH2:25][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)N1OC[C@@H]2[C@@H](O[C@H]3O[C@H](COCc4ccccc4)[C@@H](O[C@@H]4O[C@H](C)[C@@H](OCc5ccccc5)[C@H](OCc5ccccc5)[C@H]4OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)[C@H](OCc3ccccc3)C[C@@H]21
Agent: [Cl-]
Agent: [K+]
Agent: [NH4+]
Solvent: CO
Product: C[C@H]1O[C@@H](O[C@H]2[C@H](OCc3ccccc3)[C@@H](OCc3ccccc3)[C@@H](O[C@@H]3[C@H]4CON[C@H]4C[C@H]3OCc3ccccc3)O[C@@H]2COCc2ccccc2)[C@H](OCc2ccccc2)[C@@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 90.2 %

Procedure:
The compound (363 mg, 0.32 mmol) synthesized in Example 6 (6j) was dissolved in methanol (8 mL) and 1N aqueous potassium hydroxide solution (4 mL) was added thereto, followed by stirring of the mixture at 80° C. for 8 hours. After cooling to room temperature, saturated aqueous ammonium chloride solution (15 mL) was added to the reaction mixture and the mixture was extracted with ethyl acetate (100 mL). After the organic layer was washed with saturated brine (10 mL) and dried with anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue was purified using silica gel flash column chromatography (hexane:ethyl acetate, 1.5:1-1:1, V/V) to obtain the desired title compound (313 mg, yield 91%) as pale yellow amorphous matter.
Reaction SMILES: C(OC(=O)C)(=O)C.[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([CH3:16])=[C:13]([CH:15]=1)[NH2:14].C([O-])(=O)C.[K+].[N:22](OC(C)(C)C)=O.O.[OH-].[Li+]>O.C1COCC1.CO.C1C=CC=CC=1>[Cl:8][C:9]1[CH:15]=[C:13]2[C:12]([CH:16]=[N:22][NH:14]2)=[CH:11][CH:10]=1
Reactant: Cc1ccc(Cl)cc1N
Reactant: CC(C)(C)ON=O
Agent: CC(=O)[O-]
Agent: [K+]
Agent: [Li+]
Solvent: CO
Solvent: c1ccccc1
Solvent: CC(=O)OC(C)=O
Product: Clc1ccc2cn[nH]c2c1
Temperature: 80 °C
Reaction time: 0.17 h

Procedure:
Acetic anhydride (10.0 mL, 106 mmol) was added dropwise to a benzene solution (110 mL) containing 5-chloro-2-methylaniline (5.0 g, 35.3 mmol) and potassium acetate (3.8 g, 38.7 mmol) at room temperature. After 10 minutes the reaction mixture, which had formed a thick white suspension, was heated to 80° C. Tert-butyl nitrite (6.99 mL, 90%, 53.0 mmol) was added over 20 minutes. The reaction mixture was kept at 80° C. overnight. The reaction was then cooled to room temperature and concentrated. The residue was dissolved in MeOH and stirred for 10 minutes. The solution was concentrated and to the residue was added MeOH (175 mL), THF (30 mL), water (60 mL) and lithium hydroxide monohydrate (8 g, 195 mmol). The solution was then stirred overnight at room temperature. The solution was then concentrated and the residue partitioned between EtOAc and 0.5 M NaOH aq. The aqueous phase was extracted twice with EtOAc. The combined organics were washed with brine, dried over MgSO4, filtered and concentrated to give the indicated product. The material was used in Step B without further purification. 1H NMR (400 MHz, CH3CN-d3): δ 11.20 (broad s, 1H); 8.01 (s, 1H); 7.75-7.70 (m, 1H); 7.60 (s, 1H); 7.13 (dd, J=8.6, 1.7 Hz, 1H). m/z=153.0 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8](C(=O)C(F)(F)F)[CH2:9][CH2:10][C:4]=2[C:3]=1[NH:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[N:28]=[C:29]([NH:32][C:33]([CH:35]3[CH2:37][CH2:36]3)=[O:34])[S:30][CH:31]=2)=[CH:23][CH:22]=1.N>CO>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][NH:8][CH2:9][CH2:10][C:4]=2[C:3]=1[NH:19][CH2:20][C:21]1[CH:22]=[CH:23][C:24]([C:27]2[N:28]=[C:29]([NH:32][C:33]([CH:35]3[CH2:37][CH2:36]3)=[O:34])[S:30][CH:31]=2)=[CH:25][CH:26]=1
Reactant: O=C(Nc1nc(-c2ccc(CNc3c(Cl)ccc4c3CCN(C(=O)C(F)(F)F)CC4)cc2)cs1)C1CC1
Agent: N
Solvent: CO
Product: O=C(Nc1nc(-c2ccc(CNc3c(Cl)ccc4c3CCNCC4)cc2)cs1)C1CC1
Reaction time: 0.5 h
Yield: 5.5 %

Procedure:
To 7-chloro-6-{4-[2-(cyclopropanecarbonyl-amino)-thiazol-4-yl]-benzylamino}-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (0.310 g, 5.648 mmol) at room temperature, add 2M ammonia in methanol (18 mL). After stirring for 30 min, add 7M ammonia in methanol (124 mL) to the reaction mixture. After stirring at room temperature overnight, concentrate the reaction mixture in vacuo and elute the residue through a SCX column (20 g). Dissolve the residue in DCM and load the solution on to a RediSep® column (40 g). Purify by preparative liquid chromatography (0:1 to 1:9 2M ammonia in methanol/DCM over 33 min, 1:9 to 1:4 2M ammonia in methanol/DCM over 33 min; 35 mL/min) to afford 7-chloro-6-{4-[2-(cyclopropanecarbonyl-amino)-thiazol-4-yl]-benzylamino}-2,3,4,5-tetrahydro-1H-benzo[d]azepine (0.140 g, 55%) as a white foam. MS (ES+) m/z: 453.1 (M+H)+.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([O:11][CH:12]([CH2:16][CH3:17])[C:13]([OH:15])=O)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[NH2:18][C:19]([CH3:32])([CH3:31])[C:20]#[C:21][CH2:22][O:23][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25].Cl.CN(C)CCCN=C=NCC.CCCCCC.C(OCC)(=O)C>CN(C)C1C=CN=CC=1.ClCCl>[N:1]1[C:10]2[C:5](=[CH:6][C:7]([O:11][CH:12]([CH2:16][CH3:17])[C:13]([NH:18][C:19]([CH3:32])([CH3:31])[C:20]#[C:21][CH2:22][O:23][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:25])[CH3:26])=[O:15])=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: CCC(Oc1ccc2ncccc2c1)C(=O)O
Reactant: CC(C)(N)C#CCO[Si](C)(C)C(C)(C)C
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCC(Oc1ccc2ncccc2c1)C(=O)NC(C)(C)C#CCO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 10.9 %

Procedure:
2-(6-Quinolinyloxy)butyric acid (0.61 g), 4-amino-1-tert-butyldimethylsilyloxy-4-methylpent-2-yne (0.57 g) and 4-dimethylaminopyridine (0.010 g) in dry dichloromethane (10 ml) were stirred and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.53 g) was added. The mixture was stirred at ambient temperature for 3.5 hours, stored for 2 days, diluted with dichloromethane, washed with saturated aqueous sodium hydrogen carbonate (twice) and then with water. The organic phase was dried over magnesium sulphate and evaporated under reduced pressure to give a yellow oil. The oil was fractionated by chromatography (silica; hexane/ethyl acetate, 3:1 by volume) to give a gum that was triturated with hexane to give the required product (0.12 g) as a colourless solid, m.p. 78–80° C.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][NH:10][C:9]1=[N:13]C#N)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N1CCNC1=N)C1C=CC=CC=1.Br[C:30]1[S:31][C:32]([C:36]([NH:38][CH2:39][C:40]2[CH:45]=[CH:44][C:43]([F:46])=[CH:42][CH:41]=2)=[O:37])=[C:33]([CH3:35])[N:34]=1>>[CH2:1]([N:8]1[CH2:12][CH2:11][N:10]([C:30]2[S:31][C:32]([C:36]([NH:38][CH2:39][C:40]3[CH:45]=[CH:44][C:43]([F:46])=[CH:42][CH:41]=3)=[O:37])=[C:33]([CH3:35])[N:34]=2)[C:9]1=[NH:13])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#CN=C1NCCN1Cc1ccccc1
Reactant: Cc1nc(Br)sc1C(=O)NCc1ccc(F)cc1
Agent: N=C1NCCN1Cc1ccccc1
Product: Cc1nc(N2CCN(Cc3ccccc3)C2=N)sc1C(=O)NCc1ccc(F)cc1
Yield: 7 %

Procedure:
Following the procedure as described in Example 27, making variations as required to replace N-(1-benzylimidazolidin-2-ylidene)cyanamide with 1-benzylimidazolidin-2-imine to react with 2-bromo-N-(4-fluorobenzyl)-4-methylthiazole-5-carboxamide, the title compound was obtained as a colorless solid in 7% yield: mp 142-144° C. (ethyl acetate/hexanes); 1H NMR (300 MHz, DMSO-d6) δ 8.35 (br s, 1H), 8.16 (t, J=5.9 Hz, 1H), 7.36-7.23 (m, 7H), 7.13-7.07 (m, 2H), 4.45 (s, 2H), 4.29 (d, J=5.9 Hz, 2H), 3.56-3.50 (m, 2H), 3.32-3.26 (m, 2H), 2.41 (s, 3H); 13C NMR (75 MHz, DMSO-d6) δ 163.1, 162.4, 159.9, 159.0, 152.8, 137.4, 136.5, 129.6, 129.0, 128.1, 127.7, 115.5, 115.2, 47.6, 45.2, 42.3, 40.9, 17.8; MS (ES+) m/z 424.2 (M+1).
Reaction SMILES: [CH:1]([NH:4][C:5]([NH2:7])=[S:6])([CH3:3])[CH3:2].Br[CH2:9][C:10](=O)[C:11]([O:13][CH2:14][CH3:15])=[O:12]>C(O)C>[CH:1]([NH:4][C:5]1[S:6][CH:9]=[C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[N:7]=1)([CH3:3])[CH3:2]
Reactant: CC(C)NC(N)=S
Reactant: CCOC(=O)C(=O)CBr
Solvent: CCO
Product: CCOC(=O)c1csc(NC(C)C)n1

Procedure:
The reaction described in Preparation 42 was repeated, but using 3.7 g of isopropylthiourea, 7.4 g of ethyl bromopyruvate and 50 ml of ethanol, giving the title compound as a pale yellow oil.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[F:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]=[CH:15][C:16]2[C:17]([NH:24][CH3:25])=[N:18][C:19]([S:22][CH3:23])=[N:20][CH:21]=2)=[CH:10][C:9]=1[N+:26]([O-:28])=[O:27].[OH-].[Na+]>C1COCC1>[F:7][C:8]1[CH:13]=[CH:12][C:11]([NH:14][CH2:15][C:16]2[C:17]([NH:24][CH3:25])=[N:18][C:19]([S:22][CH3:23])=[N:20][CH:21]=2)=[CH:10][C:9]=1[N+:26]([O-:28])=[O:27]
Reactant: CNc1nc(SC)ncc1C=Nc1ccc(F)c([N+](=O)[O-])c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CNc1nc(SC)ncc1CNc1ccc(F)c([N+](=O)[O-])c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 56 %

Procedure:
To a suspension of LiAlH4 (1.3 g, 34 mmol) in anhydrous THF at 0° C. was added the above 5-((4-fluoro-3-nitrophenylimino)methyl)-N-methyl-2-(methylthio)pyrimidin-4-amine portionwise over 20 min. After the addition was complete, the mixture was stirred at 0° C. for 30 min. Aqueous 10% NaOH (2 mL) was added and the resultant precipitate was removed by filtration. The filtrate was concentrated under reduced pressure to give 5-((4-fluoro-3-nitrophenylamino)methyl)-N-methyl-2-(methylthio)pyrimidin-4-amine (6.0 g, 56% yield) as a brown solid. 1H NMR (300 MHz, DMSO-d6): δ 7.84 (s, 1 H), 7.28 (dd, J=6.6, 8.4 Hz, 1 H), 7.17 (m, 1 H), 7.03 (m, 1 H), 6.42 (t, J=3.9 Hz, 1 H), 4.00 (d, J=3.9 Hz, 2 H), 2.82 (d, J=4.8 Hz, 3 H), 2.39 (s, 3 H); MS (ESI) m/z: 324.1 (M+H+).
Reaction SMILES: Cl.[NH2:2][C:3]1[C:12]2[CH2:11][CH2:10][CH2:9][CH2:8][C:7]=2[C:6]([C:13]#[N:14])=[CH:5][CH:4]=1.[C:15]([O-])(O)=[O:16].[Na+].C(Cl)(Cl)=O.C1(C)C=CC=CC=1>C(Cl)Cl>[N:2]([C:3]1[C:12]2[CH2:11][CH2:10][CH2:9][CH2:8][C:7]=2[C:6]([C:13]#[N:14])=[CH:5][CH:4]=1)=[C:15]=[O:16]
Reactant: N#Cc1ccc(N)c2c1CCCC2
Reactant: O=C([O-])O
Agent: Cl
Agent: O=C(Cl)Cl
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: N#Cc1ccc(N=C=O)c2c1CCCC2
Temperature: 0 °C
Reaction time: 2 h
Yield: 99.8 %

Procedure:
To a stirring suspension of compound 2D (0.10 g, 0.48 mmol) and NaHCO3 (0.404 g, 4.80 mmol) in CH2Cl2 (4 mL) cooled to 0° C. was rapidly added a solution of phosgene (20%) in toluene (0.95 mL, 4.32 mmol). After addition, the mixture was stirred at rt for 2 h, then filtered to remove the solid. The filtrate was concentrated under reduced pressure, the resulting solid residue dried under vacuum for 1 h to afford compound 2E (95 mg) as a light yellow solid.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14]SC1=S)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:17][CH2:18][CH2:19][CH2:20]CCN>C(Cl)Cl>[CH2:1]([O:8][C:9]([NH:11][CH2:15][CH2:14][CH2:20][CH2:19][CH2:18][NH2:17])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(OCc1ccccc1)N1CCSC1=S
Reactant: NCCCCCN
Solvent: ClCCl
Product: NCCCCCNC(=O)OCc1ccccc1
Reaction time: 3 h
Yield: 63.1 %

Procedure:
17.84 g of the product of Step A in solution in 100 ml of methylene chloride were added to 16.4 g of 1,5-diamino-pentane in solution in 85 ml of methylene chloride and after stirring for 3 hours and concentration to dryness, the residue was chromatographed (eluant: methanol-ammonia 99-1) to obtain 10.5 g of the expected product.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:6]([CH:14]=[CH2:15])[CH:5]=1)([O-])=O>CO>[NH2:1][C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:6]([CH2:14][CH3:15])[CH:5]=1
Reactant: C=Cc1cc([N+](=O)[O-])ccc1C(=O)OC
Solvent: CO
Product: CCc1cc(N)ccc1C(=O)OC
Yield: 18.5 %

Procedure:
15.0 g (72.3 mmol) of methyl 4-nitro-2-vinylbenzoate in 150 ml of methanol were hydrogenated in an autoclave at 5 bar for 15 hours. The solution was filtered through kieselguhr, the solvent was distilled off under reduced pressure, and the residue was chromatographed using silica gel with cyclohexane/ethyl acetate (ratio 3:1) as the eluent. 2.4 g (24% of theory) of methyl 4-amino-2-ethylbenzoate were obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([Cl:11])=[O:10].[S:12](=[O:15])(=[O:14])=[O:13].C(Cl)(Cl)Cl>ClCCl.ClC(Cl)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([S:12]([OH:15])(=[O:14])=[O:13])[C:9]([Cl:11])=[O:10]
Reactant: O=C(Cl)Cc1ccccc1Cl
Reactant: O=S(=O)=O
Solvent: CC(Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: O=C(Cl)C(c1ccccc1Cl)S(=O)(=O)O
Temperature: 25 °C

Procedure:
A solution of 2-(2-chlorophenyl)acetyl chloride (1.89 g, 10 mmole) in dichloromethane (20 ml) was treated with a suspension of sulphur trioxide--dioxane complex (15 mmole) in dichloroethane at 0° C. The mixture was stirred at room temperature for eighteen hours and evaporated to afford a yellow gum. νmax. (CHCl3) 1800 cm-1.
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[CH2:7]/[N:8]=[CH:9]/[CH2:10][C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:4])([CH3:3])[CH3:2].[Cl:16][C:17]1[CH:22]=[CH:21][C:20](/[C:23](=[CH:26]/[C:27]2[CH:32]=[C:31]([Cl:33])[CH:30]=[CH:29][C:28]=2[O:34][CH3:35])/[C:24]#[N:25])=[C:19]([F:36])[CH:18]=1.C(N(CC)CC)C>ClCCl>[C:1]([O:5][C:6]([CH:7]1[CH:26]([C:27]2[CH:32]=[C:31]([Cl:33])[CH:30]=[CH:29][C:28]=2[O:34][CH3:35])[C:23]([C:20]2[CH:21]=[CH:22][C:17]([Cl:16])=[CH:18][C:19]=2[F:36])([C:24]#[N:25])[CH:9]([CH2:10][C:11]([CH3:14])([CH3:13])[CH3:12])[NH:8]1)=[O:15])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)C/C=N/CC(=O)OC(C)(C)C
Reactant: COc1ccc(Cl)cc1/C=C(\C#N)c1ccc(Cl)cc1F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(Cl)cc1C1C(C(=O)OC(C)(C)C)NC(CC(C)(C)C)C1(C#N)c1ccc(Cl)cc1F
Yield: 14 %

Procedure:
In a manner similar to the method described in Example 1c, [3-methyl-but-(E)-ylideneamino]-acetic acid tert-butyl ester prepared in Example 1a (1.1 g, 5 mmol) was reacted with (Z)-2-(4-chloro-2-fluoro-phenyl)-3-(5-chloro-2-methoxy-phenyl)-acrylonitrile (1.28 g, 4 mmol) prepared in Example 85a, AgF (0.76 g, 6 mmol), and triethylamine (1.38 mL, 10 mmol) in dichloromethane (100 mL) at room temperature for 18 h to give rac-(2R,3S,4R,5S)-4-(4-chloro-2-fluoro-phenyl)-3-(5-chloro-2-methoxy-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid tert-butyl ester as a white foam (0.3 g, 14%).