Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[NH:8][C:9](=[O:18])[N:10]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C:3]=12.[N:19]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[C:20]=[O:21]>O1CCOCC1>[CH2:22]([NH:19][C:20]([N:8]1[C:4]2=[N:5][CH:6]=[CH:7][C:2]([CH3:1])=[C:3]2[N:10]([C:11]([O:13][C:14]([CH3:15])([CH3:17])[CH3:16])=[O:12])[C:9]1=[O:18])=[O:21])[CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: CCCCCCN=C=O
Reactant: Cc1ccnc2[nH]c(=O)n(C(=O)OC(C)(C)C)c12
Solvent: C1COCCO1
Product: CCCCCCNC(=O)n1c(=O)n(C(=O)OC(C)(C)C)c2c(C)ccnc21

Procedure:
Analogously to Example 1, tert-butyl 7-methyl-2-oxo-2,3-dihydroimidazo[4,5-b]pyridine-1-carboxylate (200 mg, 0.8 mmol) and 1-isocyanatohexane (113 mg, 0.88 mmol) were reacted in dioxane. Yield: 5 mg (2%), M+H+: 377.20.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][C:7]2[NH:8][C:9](=[O:11])[S:10][C:6]=2[CH:5]=1)([O-])=O>CCOC(C)=O.[Pd]>[NH2:1][C:4]1[CH:13]=[CH:12][C:7]2[NH:8][C:9](=[O:11])[S:10][C:6]=2[CH:5]=1
Reactant: O=c1[nH]c2ccc([N+](=O)[O-])cc2s1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Nc1ccc2[nH]c(=O)sc2c1
Yield: 96.3 %

Procedure:
A solution of 6-nitro-2-benzothiazolinone (98 mg, 0.50 mmol) in 20 ml of EtOAc with 10% Pd/C (˜20 mg) was stirred under H2 balloon for 4 h. The reaction mixture was filtered through celite eluting with EtOAc, concentrated under reduced pressure to give 80 mg of 6-amino-2-benzothiazolinone.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:10][CH3:11])[CH:9]=1)[CH:5]=O.[NH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.[BH4-].[Na+]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:10][CH3:11])[CH:9]=1)[CH2:5][N:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: COc1cc(Br)cc(C=O)c1
Reactant: C1CCNCC1
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Product: COc1cc(Br)cc(CN2CCCCC2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 68.8 %

Procedure:
To a pre-stirred solution of 3-bromo-5-methoxybenzaldehyde (0.56 g, 2.61 mmol) and piperidine (0.29 mL, 3.93 mmol) in DCM (10 mL) at 0° C. was added sodium borohydride (197 mg, 5.22 mmol) in portions. The reaction mixture was allowed to warm to ambient temperature and stirred for an additional 2 h. The reaction was quenched by the addition of water (30 mL) and extracted into ethyl acetate (75 mL) then washed with water (50 mL) then the organic phase was dried over anhydrous sodium sulfate, filtered and evaporated in vacuo to afford the title compound as a colourless oil (510 mg, 69%) that was used in the next step without further purification. 1H NMR (CDCl3, 400 MHz): 7.08-7.06 (m, 1H), 6.94-6.91 (m, 1H), 6.83-6.80 (s, 1H), 3.79 (s, 3H), 3.39 (s, 2H), 2.40-2.30 (s, 4H), 1.61-1.51 (m, 4H), 1.47-1.38 (m, 2H).
Reaction SMILES: [S:1]1[CH2:5][C:4](=[O:6])[NH:3][C:2]1=[O:7].[S:8]1[CH:12]=[CH:11][CH:10]=[C:9]1[CH:13]=O.N1CCCCC1>C(O)C>[S:8]1[CH:12]=[CH:11][CH:10]=[C:9]1[CH:13]=[C:5]1[S:1][C:2](=[O:7])[NH:3][C:4]1=[O:6]
Reactant: O=C1CSC(=O)N1
Reactant: O=Cc1cccs1
Solvent: C1CCNCC1
Solvent: CCO
Product: O=C1NC(=O)C(=Cc2cccs2)S1
Yield: 66.5 %

Procedure:
To a solution of 20 g (171 mmol) of 2,4-thiazolidinedione and 16.0 ml (171 mmol) of 2-thiophenecarboxaldehyde in 350 ml of ethanol, 1.68 ml (17.1 mmol) of piperidine was added, and the mixture was heated under reflux for 5 hours. After cooling, the precipitated crystals were filtered and washed with cooled ethanol to give 24.03 g of the desired compound (66.6% yield, pale yellow crystals).
Reaction SMILES: [CH3:1][C:2]([CH3:36])([CH3:35])[C:3]([C:5]1[CH:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[O:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])[N:8]([C:22]2[CH:27]=[CH:26][C:25]([C:28]3[CH:32]=[CH:31][S:30][CH:29]=3)=[CH:24][CH:23]=2)[C:7](=[O:33])[C:6]=1O)=O.O.[NH2:38][NH2:39].C(=O)(O)[O-].[Na+]>C(O)(=O)C>[C:2]([C:3]1[C:5]2[CH:9]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[O:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])[N:8]([C:22]3[CH:27]=[CH:26][C:25]([C:28]4[CH:32]=[CH:31][S:30][CH:29]=4)=[CH:24][CH:23]=3)[C:7](=[O:33])[C:6]=2[NH:38][N:39]=1)([CH3:36])([CH3:35])[CH3:1]
Reactant: COC(=O)COc1ccccc1C1C(C(=O)C(C)(C)C)=C(O)C(=O)N1c1ccc(-c2ccsc2)cc1
Reactant: NN
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: COC(=O)COc1ccccc1C1c2c(C(C)(C)C)n[nH]c2C(=O)N1c1ccc(-c2ccsc2)cc1
Temperature: 95 °C
Reaction time: 1 h
Yield: 92.9 %

Procedure:
A mixture of 4-(2,2-dimethylpropionyl)-3-hydroxy-5-(2-methoxycarbonylmethyloxyphenyl)-1-(4-thiophene-3-ylphenyl)-1,5-dihydropyrrole-2-one (0.207 g, 0.41 mmol), hydrazine hydrate (0.022 mL, 0.45 mmol) and acetic acid (3.1 mL) was stirred at 95° C. for 1 hour. After the reaction was completed, saturated sodium bicarbonate solution was poured into the reaction mixture, and the mixture was extracted with chloroform. The extract was washed with brine, dried over anhydrous sodium sulphate, and then concentrated in vacuo. The resulting residue was triturated with ethyl ether and diisopropyl ether to give 3-t-butyl-5-(4-thiophene-3-ylphenyl)-4-(2-methoxycarbonylmethyloxyphenyl)-4,5-dihydro-1H-pyrrolo[3,4-c]pyrazole-6-one (0.191 g, yield: 93%) as pale brown solid.
Reaction SMILES: [C:1]([O:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)(=[O:6])[CH2:2][CH2:3][CH:4]=[CH2:5].C([O:16][CH2:17][CH2:18][CH2:19][CH3:20])=C>>[CH2:17]([O:16]/[CH:5]=[CH:4]\[CH2:3][CH2:2][C:1]([O:7][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)=[O:6])[CH2:18][CH2:19][CH3:20]
Reactant: C=CCCC(=O)Oc1ccccc1
Reactant: C=COCCCC
Product: CCCCO/C=C\CCC(=O)Oc1ccccc1
Reaction time: 2 h
Yield: 78.9 %

Procedure:
Following the general procedure, phenyl pent-4-enoate (50.0 mg, 0.284 mmol) was treated with butyl vinyl ether (284 mg, 2.84 mmol) and 2.5 mol % of in situ-generated complex la (71.0 μL, 0.10 M, 7.09 μmol; final substrate concentration=4.0 M) and allowed to stir for 2 h. The unpurified product is 98% Z (as determined by 400 MHz 1H NMR analysis). The resulting oil was purified by silica gel chromatography (50:1 hexanes:Et2O) to afford 8c (55.6 mg, 0.224 mmol, 79.0% yield, >98% Z isomer) as a colorless oil. IR (neat): 3040 (w), 2959 (m), 2933 (m), 2872 (m), 1759 (s), 1663 (m), 1594 (m), 1493 (m), 1374 (m), 1359 (m), 1272 (m), 1227 (m), 1195 (s), 1162 (s), 1130 (s), 1102 (s), 1072 (m); 1H NMR (400 MHz, CDCl3): δ 7.40-7.34 (2H, m), 7.25-7.19 (1H, m), 7.11-7.07 (2H, m), [diagnostic E isomer signal: 6.37 (1H, d, J=12.8 Hz)], 6.02 (1H, dt, J=6.0, 1.2 Hz), 4.43 (1H, td, J=6.8, 6.4 Hz), 3.75 (2H, t, J=6.4 Hz), 2.66-2.60 (2H, m), 2.56-2.49 (2H, m), 1.65-1.57 (2H, m), 1.46-1.35 (2H, m), 0.94 (3H, t, J=7.4 Hz); 13H NMR (100 MHz, CDCl3): δ 172.0, 150.9, 146.4, 129.4, 125.7, 121.7, 103.8, 72.2, 34.7, 32.0, 19.9, 19.1, 13.9; HRMS (ESI+) [M+H]+ calcd for C15H21O3: 249.1491, found: 249.1500.
Reaction SMILES: [CH:1]1([N:4]2[C:8]([N:9]3[CH2:15][CH2:14][CH2:13][C@@H:12]([NH:16][C:17](=[O:22])[C:18]([F:21])([F:20])[F:19])[CH2:11][CH2:10]3)=[C:7]([N+:23]([O-])=O)[CH:6]=[N:5]2)[CH2:3][CH2:2]1.[C:26]([O:30][C:31]([NH:33][C:34]1[S:38][C:37]([C:39]2[C:44]([F:45])=[CH:43][CH:42]=[CH:41][C:40]=2[F:46])=[N:36][C:35]=1[C:47](O)=[O:48])=[O:32])([CH3:29])([CH3:28])[CH3:27]>>[F:46][C:40]1[CH:41]=[CH:42][CH:43]=[C:44]([F:45])[C:39]=1[C:37]1[S:38][C:34]([NH:33][C:31](=[O:32])[O:30][C:26]([CH3:28])([CH3:27])[CH3:29])=[C:35]([C:47](=[O:48])[NH:23][C:7]2[CH:6]=[N:5][N:4]([CH:1]3[CH2:3][CH2:2]3)[C:8]=2[N:9]2[CH2:15][CH2:14][CH2:13][C@@H:12]([NH:16][C:17](=[O:22])[C:18]([F:21])([F:20])[F:19])[CH2:11][CH2:10]2)[N:36]=1
Reactant: O=C(N[C@@H]1CCCN(c2c([N+](=O)[O-])cnn2C2CC2)CC1)C(F)(F)F
Reactant: CC(C)(C)OC(=O)Nc1sc(-c2c(F)cccc2F)nc1C(=O)O
Product: CC(C)(C)OC(=O)Nc1sc(-c2c(F)cccc2F)nc1C(=O)Nc1cnn(C2CC2)c1N1CCC[C@@H](NC(=O)C(F)(F)F)CC1
Yield: 73 %

Procedure:
Following the procedure for Example 517 starting with (R)—N-(1-(1-cyclopropyl-4-nitro-1H-pyrazol-5-yl)azepan-4-yl)-2,2,2-trifluoroacetamide and 5-(tert-butoxycarbonylamino)-2-(2,6-difluorophenyl)thiazole-4-carboxylic acid gave (R)-tert-butyl 2-(2,6-difluorophenyl)-4-(1-cyclopropyl-5-(4-(2,2,2-trifluoroacetamido)azepan-1-yl)-1H-pyrazol-4-ylcarbamoyl)thiazol-5-ylcarbamate as a cream solid (142 mg, 73%). 1H-NMR (400 MHz, CDCl3) δ 10.40 (s, 1H), 8.76 (s, 1H), 7.87 (s, 1H), 7.41-7.34 (m, 1H), 7.10-7.00 (m, 2H), 6.39 (d, J=8 Hz, 1H), 4.25-4.15 (m, 1H), 3.45-3.36 (m, 3H), 3.35-3.15 (m, 2H), 2.25-2.12 (m, 1H), 2.10-1.70 (m, 5H), 1.55 (s, 9H), 1.35-1.15 (m, 2H), 1.10-1.00 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[CH2:4][CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[NH:8][C:7]1=[O:15].[CH3:17][C:18]1[CH:19]=[C:20]2[N:25]([C:26]=1[CH3:27])[CH:24]=[CH:23][CH:22]=[C:21]2[CH2:28]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1.[Al]>[CH3:1][O:2][C:3](=[O:16])[CH2:4][CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]([CH2:28][C:21]2[C:20]3[N:25]([C:26]([CH3:27])=[C:18]([CH3:17])[CH:19]=3)[CH:24]=[CH:23][CH:22]=2)[C:7]1=[O:15]
Reactant: COC(=O)CCn1c(=O)[nH]c2ccccc21
Reactant: Cc1cc2c(CO)cccn2c1C
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: [Al]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)CCn1c(=O)n(Cc2cccn3c(C)c(C)cc23)c2ccccc21
Reaction time: 0.08 h

Procedure:
To a stirred solution of the 3-(2-oxo-2,3-dihydro-benzimidazol-1-yl)-propionic acid methyl ester (100 mg, 0.45 mmol) and (2,3-Dimethyl-indolizin-8-yl)-methanol (88 mg, 0.50 mmol) in THF (8 ml) was added triphenylphosphine (143 mg, 0.54 mmol) followed by DIAD (0.11 ml, 0.54 mmol, dropwise) at ambient temperature. After five minutes the reaction became dark brown and was consequently wrapped in aluminum foil. After stirring over night the reaction was treated with silica gel and concentrated. The remaining solid was purified via column chromatography (silica gel, 5-40% EtOAc/hexanes). The product-containing fractions were combined and concentrated to give the product which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:16][C:15]3[C:14](=[O:17])[N:13]([C:18]4[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]([OH:29])([CH3:28])[CH3:27])=[C:20]([CH2:30][CH3:31])[CH:19]=4)[CH:12]=[N:11][C:10]=3[CH:9]=2)=[CH:4][CH:3]=1.N1(C2C=CN=CC=2)CCCC1.[C:43]([O:47][C:48]([NH:50][CH2:51][C:52](O)=[O:53])=[O:49])([CH3:46])([CH3:45])[CH3:44].C(N=C=NC(C)C)(C)C.O.NN>C(Cl)Cl>[C:43]([O:47][C:48]([NH:50][CH2:51][C:52]([O:29][C:26]([CH3:27])([CH3:28])[CH2:25][O:24][C:21]1[CH:22]=[CH:23][C:18]([N:13]2[C:14](=[O:17])[C:15]3[S:16][C:8]([C:5]4[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=4)=[CH:9][C:10]=3[N:11]=[CH:12]2)=[CH:19][C:20]=1[CH2:30][CH3:31])=[O:53])=[O:49])([CH3:46])([CH3:45])[CH3:44]
Reactant: CCc1cc(-n2cnc3cc(-c4ccc(Cl)cc4)sc3c2=O)ccc1OCC(C)(C)O
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Agent: CC(C)N=C=NC(C)C
Agent: NN
Agent: c1cc(N2CCCC2)ccn1
Solvent: ClCCl
Solvent: O
Product: CCc1cc(-n2cnc3cc(-c4ccc(Cl)cc4)sc3c2=O)ccc1OCC(C)(C)OC(=O)CNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 106.1 %

Procedure:
To a solution of 6-(4-chlorophenyl)-3-(3-ethyl-4-(2-hydroxy-2-methylpropoxy)-phenyl)thieno[3,2-d]pyrimidin-4(3H)-one (0.96 g, 2.11 mmol), 4-pyrrolidinopyridine (0.31 g, 2.11 mmol) and N-(tert-butoxycarbonyl)glycine (1.11 g, 6.33 mmol) in 20 mL of CH2Cl2 heated at reflux was added diisopropylcarbodiimide (0.98 mL; 6.33 mmol) over 3 h via syringe pump. The suspension was heated at reflux for 1 h and additional N-(tert-butoxycarbonyl)glycine (0.55 g, 3.17 mmol) was added followed by diisopropylcarbodiimide (0.55 mL, 3.17 mmol) over 2 hrs via syringe pump. The suspension heated at reflux for 1 h and cooled to rt. Hydrazine monohydrate (0.34 mL, 7.01 mmol) was added and the suspension stirred at rt for 2 h. The suspension was cooled to 0° C., filtered and the filtrate washed with cold, 1N HCl, cold, dilute NaHCO3 solution, dried over anhydrous MgSO4, filtered and the filtrate concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, EtOAc/Hexanes, 0:100 to 1:1 gradient) to afford 1.37 g (100%) of the title compound as an off-white solid. 1H NMR (CDCl3) δ 1.24 (t, 3H), 1.45 (s, 9H), 1.64 (s, 6H), 2.68-2.73 (m, 2H), 3.85 (d, J=4.95 Hz, 2H), 4.18 (s, 2H), 4.98 (br s, 1H), 6.92 (d, J=9.35 Hz, 1H), 7.20-7.22 (m, 2H), 7.44 (d, J=8.79 Hz, 2H), 7.53 (s, 1H), 7.66 (d, J=8.25 Hz, 2H), 8.13 (s, 1H); 13C NMR (CDCl3) δ 13.68, 23.39, 23.67, 28.28, 42.87, 72.72, 79.86, 81.86, 111.48, 120.82, 123.25, 125.42, 127.62, 129.42, 129.67, 131.54, 134.25, 135.59, 148.29, 151.50, 155.58, 156.69, 156.92, 157.37, 169.47; HPLC (Method #1) 4.80 min retention time; LCMS (ES): m/z 612 [M+H]+.
Reaction SMILES: [C:1]1([N:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:13]1[CH2:19][S:16](=[O:18])(=[O:17])[O:15][CH2:14]1>CC(C)=O>[C:1]1([N:7]2[CH2:12][CH2:11][N:10]([CH2:14][CH2:13][CH2:19][S:16]([OH:18])(=[O:17])=[O:15])[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: O=S1(=O)CCCO1
Solvent: CC(C)=O
Product: O=S(=O)(O)CCCN1CCN(c2ccccc2)CC1
Temperature: 25 °C

Procedure:
To a solution of 1-phenylpiperazine (2.0 g, 1.9 mL, 12.3 mmol) in acetone (20 mL) was added 1,3-propane sultone (1.53 g, 12.9 mmol). The mixture was stirred at reflux for 2 hours. The reaction mixture was cooled to room temperature. The solid was collected by filtration, washed with acetone (2×25 mL) and dried in vacuo. This allowed the isolation of compound K, 3.04 g (87%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH:11]([CH3:13])[CH3:12])=[C:6]([N+:14]([O-])=O)[CH:5]=1>CO.CCOC(C)=O.[Pd]>[CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH:11]([CH3:13])[CH3:12])=[C:6]([NH2:14])[CH:5]=1
Reactant: COC(=O)c1ccc(NC(C)C)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(NC(C)C)c(N)c1
Yield: 89 %

Procedure:
3-Amino-4-isopropylamino-benzoic acid methyl ester (700.0 mg) was prepared by following General Procedure B starting from 4-isopropylamino-3-nitro-benzoic acid methyl ester (900.0 mg) and Pd/C (20% by weight, 180.0 mg) in MeOH:EtOAc (1:1, 10.0 mL). The crude product was used in the next step without further purification.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[C:5]([NH2:14])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([CH3:7])[CH3:6].[OH-].[Na+].C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1>[CH3:6][C:5]([NH:14][C:1](=[O:3])[CH3:2])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH3:7]
Reactant: CC(=O)Cl
Reactant: CC(C)(N)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC(=O)NC(C)(C)c1ccccc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 86.7 %

Procedure:
Acetyl chloride (62 g) was dropwise added to a solution (1 l) of cumylamine (90 g) and a 48% aqueous solution of sodium hydroxide (70 ml) in toluene under ice-cooling and the mixture was stirred at room temperature for 5 hours. After completion of the reaction, the mixture was neutralized with a saturated aqueous solution of potassium carbonate and extracted with ethyl acetate. The extract was washed with water and dried. The solvent was distilled away under reduced pressure to give 102.3 g of N-(1-methyl-1-phenylethyl)acetamide.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([CH:9](O)[CH3:10])=[CH:4][N:3]=1.P(Cl)(Cl)([Cl:14])=O.C(N(C(C)C)CC)(C)C>C1(C)C=CC=CC=1>[Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([CH:9]([Cl:14])[CH3:10])=[CH:4][N:3]=1
Reactant: CC(O)c1cnc(Cl)nc1Cl
Reactant: O=P(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: CC(Cl)c1cnc(Cl)nc1Cl
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a solution of (±)-1-(2,4-dichloro-pyrimidin-5-yl)-ethanol (1.27 g, 6.60 mmol) (from Example 1a supra) in phosphorus oxychloride (5.0 mL, 53.11 mmol) (Aldrich), at 0° C., was added diisopropylethyl-amine (2.60 mL, 14.78 mmol) (Aldrich). The reaction was stirred at 0° C. for 5 minutes, at ambient temperature for 15 minutes and then at 115° C. for 3 hours. The reaction was cooled to room temperature, diluted with toluene (10 mL) and the mixture was then poured into ice (15 g). After stirring for 10 minutes, the layers were separated and the aqueous extract was back washed with toluene. The combined organic extracts were dried over anhydrous sodium sulfate, filtered, and concentrated. Purification by flash chromatography (Biotage, 40M, 10:90 to 15:85 ethyl acetate-hexanes gradient) gave (±)-2,4-dichloro-5-(1-chloroethyl)-pyrimidine as an oil. (Yield 1.233 g; 88.3%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([S:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[N:15]=2)=[CH:11][C:10]([C:21](OCC)=[O:22])=[N:9]1.[H-].C([Al+]CC(C)C)C(C)C.[OH-].[Na+]>O1CCCC1.C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([S:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[N:15]=2)=[CH:11][C:10]([CH:21]=[O:22])=[N:9]1
Reactant: CCOC(=O)c1cc(Sc2cccc(C)n2)n(-c2ccccc2Cl)n1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: Cc1cccc(Sc2cc(C=O)nn2-c2ccccc2Cl)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 74.4 %

Procedure:
To a solution of ethyl 1-(2-chlorophenyl)-5-[(6-methylpyridin-2-yl)thio]-1H-pyrazole-3-carboxylate (640 mg) in tetrahydrofuran (10 mL) was added a 1.5 mol/L solution (4.6 mL) of diisobutylaluminum hydride in toluene at −78° C. and the mixture was stirred at the same temperature for 30 min. 1 mol/L Aqueous sodium hydroxide solution was added to the reaction mixture, insoluble materials were filtered off, and the filtrate was extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. To a solution of the residue in toluene (7 mL) was added manganese dioxide (968 mg) and the mixture was stirred at 80° C. for 1 hr. The reaction mixture was cooled to room temperature and filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate=2:1) to give the title compound as a yellow oil (yield 420 mg, yield 74%).
Reaction SMILES: [N:1]1([C:7]2[N:16]=[C:15]([NH2:17])[C:14]3[C:9](=[CH:10][C:11]([O:20][CH3:21])=[C:12]([O:18][CH3:19])[CH:13]=3)[N:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[C:22]1([N:28]=[C:29]=[S:30])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>O1CCOCC1>[C:22]1([NH:28][C:29]([N:4]2[CH2:5][CH2:6][N:1]([C:7]3[N:16]=[C:15]([NH2:17])[C:14]4[C:9](=[CH:10][C:11]([O:20][CH3:21])=[C:12]([O:18][CH3:19])[CH:13]=4)[N:8]=3)[CH2:2][CH2:3]2)=[S:30])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: COc1cc2nc(N3CCNCC3)nc(N)c2cc1OC
Reactant: S=C=Nc1ccccc1
Solvent: C1COCCO1
Product: COc1cc2nc(N3CCN(C(=S)Nc4ccccc4)CC3)nc(N)c2cc1OC
Reaction time: 8 h
Yield: 69.9 %

Procedure:
In 20 ml of dioxane, there was dissolved 0.87 g. (3 mmole) of 2-piperazino-4-amino-6,7-dimethoxyquinazoline. To the resultant solution was added dropwise a solution of 0.41 g. (3 mmole) of phenylisothiocyanate dissolved in 10 ml of dioxane at room temperature. The mixture was further stirred overnight. After evaporation of the solvent, the residue was chromatographed on silica gel and eluted with 20% dioxane-chloroform to obtain 0.89 g. of the desired product.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH2:8][OH:9])[CH:5]=[CH:4][N:3]=1.[CH:10]([NH2:13])([CH3:12])[CH3:11]>O1CCOCC1.C(Cl)Cl>[CH:10]([NH:13][C:2]1[CH:7]=[C:6]([CH2:8][OH:9])[CH:5]=[CH:4][N:3]=1)([CH3:12])[CH3:11]
Reactant: CC(C)N
Reactant: OCc1ccnc(Br)c1
Solvent: C1COCCO1
Solvent: ClCCl
Product: CC(C)Nc1cc(CO)ccn1
Temperature: 110 °C

Procedure:
A mixture of (2-bromo-pyridin-4-yl)-methanol (500 mg, 2.66 mmol), isopropylamine (0.45 mL, 5.32 mmol), NatOBu (790 mg, 7.98 mmol) and Pd(tBu3P)2 (136 mg, 0.26 mmol) in 1,4-dioxane (5 mL) is heated in a microwave reactor at 110° C. for 45 min. The reaction is diluted with DCM (50 mL) and washed with saturated aqueous NH4Cl. The organic layer is removed, dried over anhydrous Na2SO4, and concentrated in vacuo to give the title compound that is used without further purification. MS (ESI) m/z 167.1 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][N:11]([CH3:34])[C:12]2[N:17]=[C:16]([N:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)[N:15]=[C:14]([NH:24][CH2:25][CH2:26][C:27]3[CH:32]=[CH:31][C:30]([OH:33])=[CH:29][CH:28]=3)[N:13]=2)=[CH:4][CH:3]=1.Cl.[N:36]1[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1[C:42](Cl)=[O:43]>C(Cl)Cl.CCOC(C)=O.CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][N:11]([CH3:34])[C:12]2[N:17]=[C:16]([N:18]3[CH2:19][CH2:20][N:21]([C:42]([C:37]4[CH:38]=[CH:39][CH:40]=[CH:41][N:36]=4)=[O:43])[CH2:22][CH2:23]3)[N:15]=[C:14]([NH:24][CH2:25][CH2:26][C:27]3[CH:28]=[CH:29][C:30]([OH:33])=[CH:31][CH:32]=3)[N:13]=2)=[CH:4][CH:3]=1
Reactant: CN(CCCc1ccc(Cl)cc1)c1nc(NCCc2ccc(O)cc2)nc(N2CCNCC2)n1
Reactant: O=C(Cl)c1ccccn1
Agent: Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CO
Product: CN(CCCc1ccc(Cl)cc1)c1nc(NCCc2ccc(O)cc2)nc(N2CCN(C(=O)c3ccccn3)CC2)n1
Yield: 46 %

Procedure:
The title compound was prepared in 46% yield via the procedure outlined for Example 3 using 4-(2-{[4-[[3-(4-chlorophenyl)propyl](methyl)amino]-6-(1-piperazinyl)-1,3,5-triazin-2-yl]amino}ethyl)phenol and picolinoyl chloride hydrochloride to give a white glass: 1H NMR (CDCl3, 300 MHz) δ 8.65 (bs, 1H), 7.83 (t, 1H, J=7.5), 7.72 (d, 1H, J=7.5), 7.40 (t, 1H, J=5.7), 7.24-7.21 (m, 2H), 7.12-7.04 (m, 4H), 6.73 (d, 2H, J=8.1), 3.96-3.78 (m, 4H), 3.75-3.55 (m, 6H), 3.10 (s, 3H), 2.80 (t, 2H, J=6.6), 2.65-2.60 (m, 2H), 1.95-1.89 (m, 2H); low resolution MS (ES+) m/e 588 (MH+); TLC (CH2Cl2/EtOAc/MeOH (5:5:1)): Rf=0.62.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2/[C:11](=[CH:19]/[C:20]2[NH:21][CH:22]=[CH:23][CH:24]=2)/[C:12](=[O:18])[NH:13]3)[CH:6]=[CH:7][CH:8]=1.CCN(CC)CC.[N+:32]([C:35]1[CH:36]=[C:37]([CH:41]=[CH:42][CH:43]=1)[C:38](Cl)=[O:39])([O-:34])=[O:33]>C(Cl)(Cl)Cl>[O:18]=[C:12]1[NH:13][C:14]2[C:10](/[C:11]/1=[CH:19]/[C:20]1[NH:21][CH:22]=[CH:23][CH:24]=1)=[C:9]([C:5]1[CH:4]=[C:3]([NH:2][C:38](=[O:39])[C:37]3[CH:41]=[CH:42][CH:43]=[C:35]([N+:32]([O-:34])=[O:33])[CH:36]=3)[CH:8]=[CH:7][CH:6]=1)[CH:17]=[CH:16][CH:15]=2
Reactant: Nc1cccc(-c2cccc3c2/C(=C/c2ccc[nH]2)C(=O)N3)c1
Reactant: O=C(Cl)c1cccc([N+](=O)[O-])c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: O=C1Nc2cccc(-c3cccc(NC(=O)c4cccc([N+](=O)[O-])c4)c3)c2/C1=C/c1ccc[nH]1
Temperature: 25 °C
Reaction time: 7 h
Yield: 86 %

Procedure:
A solution of (Z)-4-(3-aminophenyl)-1,3-dihydro-3-[(1H-pyrrol-2-yl)methylene]-2H-indol-2-one hydrochloride (40 mg, 0.1 18 mmol) (from Example 5 supra) and Et3N (33 μL , 0.237 mmol) in 3 mL of chloroform was cooled to −78° C. and then treated with 3-nitrobenzoyl chloride (24 mg, 0.129 mmol) (Aldrich). The reaction mixture was then stirred at room temperature under a nitrogen atmosphere for 7 h. The reaction mixture was then concentrated in vacuo. The resulting yellow solid was dissolved in ethanol, and re-precipitated by the addition of distilled water to yield pure (Z)-N-[3-[2,3-dihydro-2-oxo-3-[(1H-pyrrol-2-yl)methylene]-1H-indol-4-yl]-phenyl]-3-nitrobenzamide (yield: 50 mg, 94%) as a yellow solid (mp 265-266° C.).
Reaction SMILES: [N:1](=[C:3]1[CH2:7][CH2:6][CH:5]([C:8]2[CH:17]=[C:16]3[C:11]([C:12](=[O:24])[C:13]([C:21]([OH:23])=[O:22])=[CH:14][N:15]3[CH:18]3[CH2:20][CH2:19]3)=[CH:10][C:9]=2[F:25])[CH2:4]1)O.[H][H].[ClH:28]>[Ni].CN(C)C=O>[ClH:28].[NH2:1][CH:3]1[CH2:7][CH2:6][CH:5]([C:8]2[CH:17]=[C:16]3[C:11]([C:12](=[O:24])[C:13]([C:21]([OH:23])=[O:22])=[CH:14][N:15]3[CH:18]3[CH2:19][CH2:20]3)=[CH:10][C:9]=2[F:25])[CH2:4]1
Reactant: [H][H]
Reactant: O=C(O)c1cn(C2CC2)c2cc(C3CCC(=NO)C3)c(F)cc2c1=O
Agent: [Ni]
Agent: Cl
Solvent: CN(C)C=O
Product: NC1CCC(c2cc3c(cc2F)c(=O)c(C(=O)O)cn3C2CC2)C1
Yield: 71.4 %

Procedure:
A suspension of 17.2 g (50 mmol) of 7-[(3-oximino)cyclopentyl]-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, 3.0 g of Raney-nickel and 300 ml of N,N-dimethylformamide was shaken in a hydrogen atmosphere at 45-50 psi for 24 hours. After removing the catalyst by filtration through Celite and addition of 100 ml of 6.0 M hydrochloric acid (60 mmol), the mixture was evaporated in high vacuo at 50° . The residue was triturated with a mixture of 200 ml of ethanol/ether (1:1) and the solid was removed by filtration, washed with ethanol/ether (1:1) and dried in vacuo to give 13.1 g of the title compound.