Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5]/[CH:6]=[CH:7]/[C:8]([CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[C:14]([O:19][CH3:20])[CH:13]=1)=[O:9].[Na].[C:22](O)(=[O:24])C>CO>[CH3:22][O:24][CH:6]([CH2:5][CH2:4][CH2:3][CH2:2][CH3:1])[CH2:7][C:8](=[O:9])[CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[C:14]([O:19][CH3:20])[CH:13]=1
Reactant: CC(=O)O
Reactant: CCCCC/C=C/C(=O)CCc1ccc(O)c(OC)c1
Agent: [Na]
Solvent: CO
Product: CCCCCC(CC(=O)CCc1ccc(O)c(OC)c1)OC
Reaction time: 4 h

Procedure:
A solution of [6]-shogaol (100 mg, 0.36 mmol) in methanol (5 mL) at 0° C. was treated with a solution of sodium (21 mg, 0.91 mmol) in methanol (1 mL). After 4.0 h, glacial acetic acid (0.5 mL) was added, and the solution was concentrated under reduced pressure. The residue was dissolved in water (5 mL), and extracted with ethyl acetate (5 mL×3). The organic phases were pooled, washed with water (5 mL×2) and brine (5 mL×1), dried over Na2SO4, and evaporated in vacuo. The residue was subjected to preparative TLC (hexane/EtOAc=4:1) to give the title compound M7 as a yellow oil (100 mg, yield 90%); 1H NMR (600 MHz, CDCl3) δ 6.69 (1H, d, J=1.6 Hz, H-2′), 6.82 (1H, d, J=8.1 Hz, H-5′), 6.66 (1H, dd, J=8.1, 1.6 Hz, H-6′), 2.75 (2H, m, H-1), 2.83 (2H, t, J=7.5 Hz, H-2), 2.64 (1H, dd, J=15.7, 7.6 Hz, H-4a), 2.40 (1H, dd, J=15.7, 4.7 Hz, H-4b), 3.66 (1H, m, H-5), 1.48 (1H, m, H-6a), 1.42 (1H, m, H-6b), 1.31-1.25 (6H, m, ranged from H-7 to H-9), 0.88 (3H, t, J=7.1 Hz, H-10), and 3.87 (3H, s, OMe-3′); positive APCIMS, m/z 309 [M+H]+.
Reaction SMILES: O=[C:2]1[CH2:6][CH2:5][C@@H:4]([C:7]2[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][CH:8]=2)[CH2:3]1.Cl.[F:16][C:17]1[CH:22]=[CH:21][C:20]([C@H:23]([NH2:25])[CH3:24])=[CH:19][C:18]=1[O:26][CH3:27]>>[F:16][C:17]1[CH:22]=[CH:21][C:20]([C@H:23]([NH:25][C@H:2]2[CH2:6][CH2:5][C@@H:4]([C:7]3[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][CH:8]=3)[CH2:3]2)[CH3:24])=[CH:19][C:18]=1[O:26][CH3:27]
Reactant: N#Cc1ccc([C@@H]2CCC(=O)C2)cc1
Reactant: COc1cc([C@@H](C)N)ccc1F
Agent: Cl
Product: COc1cc([C@@H](C)N[C@H]2CC[C@@H](c3ccc(C#N)cc3)C2)ccc1F

Procedure:
General procedure B was followed using 4-[(1R)-3-oxocyclopentyl]benzonitrile as the ketone and (1R)-1-(4-fluoro-3-methoxyphenyl)ethylamine hydrochloride as the amine. 1H NMR (300 MHz, DMSO) δ 7.76-7.69 (m, 2H), 7.44 (d, J=8.3 Hz, 2H), 7.15 (dd, J=8.6, 1.9 Hz, 1H), 7.09 (dd, J=11.5, 8.3 Hz, 1H), 6.88 (ddd, J=8.2, 4.5, 1.9 Hz, 1H), 3.82 (s, 3H), 3.75 (d, J=6.2 Hz, 1H), 3.07-2.85 (m, 2H), 2.23-2.03 (m, 2H), 2.00-1.54 (m, 3H), 1.40-1.19 (m, 1H), 1.23 (d, J=6.6 Hz, 3H).
Reaction SMILES: C([O:5][C:6]([CH2:8][CH:9]([NH:24][C:25]([CH:27]1[N:31]2[C:32](=[O:51])[CH:33]([NH:38][C:39]([C:41]3[CH:50]=[CH:49][C:48]4[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=4)[CH:42]=3)=[O:40])[CH2:34][CH:35]=[CH:36][CH2:37][CH:30]2[CH2:29][CH2:28]1)=[O:26])[C:10](=[O:23])[CH2:11][O:12][C:13](=[O:22])[C:14]1[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][C:15]=1[CH3:21])=[O:7])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[C:6]([CH2:8][CH:9]([NH:24][C:25]([CH:27]1[N:31]2[C:32](=[O:51])[CH:33]([NH:38][C:39]([C:41]3[CH:50]=[CH:49][C:48]4[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=4)[CH:42]=3)=[O:40])[CH2:34][CH:35]=[CH:36][CH2:37][CH:30]2[CH2:29][CH2:28]1)=[O:26])[C:10](=[O:23])[CH2:11][O:12][C:13](=[O:22])[C:14]1[C:15]([CH3:21])=[CH:16][CH:17]=[CH:18][C:19]=1[CH3:20])([OH:7])=[O:5]
Reactant: Cc1cccc(C)c1C(=O)OCC(=O)C(CC(=O)OC(C)(C)C)NC(=O)C1CCC2CC=CCC(NC(=O)c3ccc4ccccc4c3)C(=O)N21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cccc(C)c1C(=O)OCC(=O)C(CC(=O)O)NC(=O)C1CCC2CC=CCC(NC(=O)c3ccc4ccccc4c3)C(=O)N21
Reaction time: 2 h

Procedure:
To a solution of 2,6-dimethyl-benzoic acid 4-tert-butoxycarbonyl-3-({6-[(naphthalene-2-carbonyl)-amino]-5-oxo-1,2,3,5,6,7,10,10a-octahydro-pyrrolo[1,2-a]azocine-3-carbonyl}-amino)-2-oxo-butyl ester, 112, (188 mg 0.27 mmol) is treated with solution of trifluoroacetic acid (10 ml) and dichloromethane (10 ml). The mixture is stirred for 2 hours and solvent is removed in vacuo. The residue is purified over silica (dichloromethane/methanol 95:5) to afford 120 mg of the desired product as a white solid. 1H NMR (CDCl3): δ 8.32 (d, J=5.9 Hz, 1H), 7.84 (m, 4H), 7.71 (m, 1H), 7.51 (m, 2H), 7.23 (dd, J-16.1, 8.1 Hz, 1H), 7.04 (t, J=7.4 Hz, 1H), 5.87 (m, 2H), 5.65 (m, 2H), 5.13–4.80 (m, 3H), 4.51 (m, 1H), 4.24 (m, 1H), 3.02–2.86 (m, 4H), 2.37 (s, 6H), 2.43–1.83 (m, 5H). 13C NMR (CDCl3): δ 200.4, 200.1, 174.2, 172.9, 171.6, 171.4, 169.3, 167.6, 135.9, 135.1, 132.7, 131.2, 130.8, 129.9, 129.3, 128.7, 128.4, 128.3, 127.9, 127.0, 126.1, 125.7, 123.9, 66.9, 62.3, 61.7, 59.4, 59.1, 53.2, 52.9, 50.8, 35.3, 34.4, 34.2, 33.3, 32.2, 27.4, 26.9, 20.1. (excess carbons due to rotamers). ESI MS 639.69 (M+H).
Reaction SMILES: [Li]C(C)(C)C.[CH3:6][Si:7]([CH3:20])([CH3:19])[CH2:8][CH2:9][O:10][CH2:11][O:12][C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1.Cl[Si:22]([CH3:25])([CH3:24])[CH3:23].O>CCOCC>[CH3:23][Si:22]([CH3:25])([CH3:24])[C:18]1[CH:17]=[CH:16][N:15]=[CH:14][C:13]=1[O:12][CH2:11][O:10][CH2:9][CH2:8][Si:7]([CH3:20])([CH3:19])[CH3:6]
Reactant: C[Si](C)(C)Cl
Reactant: C[Si](C)(C)CCOCOc1cccnc1
Agent: [Li]C(C)(C)C
Solvent: O
Solvent: CCOCC
Product: C[Si](C)(C)CCOCOc1cnccc1[Si](C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 60 %

Procedure:
Add t-BuLi dropwise to a −78° C. solution of 3-(2-trimethylsilanyl-ethoxymethoxy)-pyridine (1.98 g, 8,8 mmol) in Et2O (25 mL, freshly distilled over Na0). After 1 hour, add chlorotrimethylsilane (1.33 mL, 10.5 mmol) dropwise and allow reaction to warm slowly to RT. After 1.5 hours, add water (5 mL) dropwise to quench. Wash with saturated NaHCO3 solution and brine. Dry the combined organic layers over MgSO4 and concentrate. Purify the residue by flash chromatography on silica gel eluting with 0-30% EtOAc/hexanes to afford the title compound (1.57 g, 60%) as yellow oil. MS(IS) 298 (M+1). TLC: Rf=0.38 (35% EtOAc/hexanes).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[N:14]=[C:13]([C:18]([O:20][CH3:21])=[O:19])[CH:12]=[CH:11]3)=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH:41]1([C:44]2[O:48][N:47]=[C:46]([C:49]3[C:54]([Cl:55])=[CH:53][N:52]=[CH:51][C:50]=3[Cl:56])[C:45]=2[CH2:57]O)[CH2:43][CH2:42]1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>ClCCl>[CH:41]1([C:44]2[O:48][N:47]=[C:46]([C:49]3[C:50]([Cl:56])=[CH:51][N:52]=[CH:53][C:54]=3[Cl:55])[C:45]=2[CH2:57][O:1][C:2]2[CH:7]=[CH:6][C:5]([C:8]3[CH:9]=[C:10]4[C:15](=[CH:16][CH:17]=3)[N:14]=[C:13]([C:18]([O:20][CH3:21])=[O:19])[CH:12]=[CH:11]4)=[CH:4][CH:3]=2)[CH2:43][CH2:42]1
Reactant: COC(=O)c1ccc2cc(-c3ccc(O)cc3)ccc2n1
Reactant: OCc1c(-c2c(Cl)cncc2Cl)noc1C1CC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)c1ccc2cc(-c3ccc(OCc4c(-c5c(Cl)cncc5Cl)noc4C4CC4)cc3)ccc2n1
Temperature: 90 °C
Reaction time: 8 h
Yield: 44.2 %

Procedure:
To a solution of methyl 6-(4-hydroxyphenyl)-2-quinolinecarboxylate (81 mg, 0.29 mmol), triphenylphosphine (84 mg, 0.32 mmol) and [5-cyclopropyl-3-(3,5-dichloro-4-pyridinyl)-4-isoxazolyl]methanol (83 mg, 0.29 mmol) in dichloromethane (2.5 mL) was added diisopropyl azodicarboxylate (0.058 mL, 0.32 mmol) dropwise. The solution was heated in a microwave reactor at 90° C. for 10 minutes and then allowed to stand overnight. The solution was adsorbed onto silica gel and purified by chromatography (silica gel, 0-1.25% methanol in chloroform gradient elution) to afford methyl 6-[4-({[5-cyclopropyl-3-(3,5-dichloro-4-pyridinyl)-4-isoxazolyl]methyl}oxy)phenyl]-2-quinolinecarboxylate (70 mg, 44%). 1H-NMR (400 MHz, CDCl3) δ 8.60 (s, 2H), 8.39-8.33 (m, 2H), 8.22 (d, J=9 Hz, 1H), 8.01-7.96 (m, 2H), 7.60 (d, J=9 Hz, 2H), 6.88 (d, J=9 Hz, 2H), 4.90 (s, 2H), 4.09 (s, 3H), 2.22-2.15 (m, 1H), 1.33-1.13 (m, 4H).
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5]2[CH:7]=[CH:8][C:9]([NH:11][C:12](=[O:16])[C:13]([OH:15])=O)=[CH:10][C:4]=2[S:3]1.[CH2:17]([CH:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(OCC)C>[CH2:17]([CH:24]1[CH2:29][CH2:28][N:27]([C:13](=[O:15])[C:12]([NH:11][C:9]2[CH:8]=[CH:7][C:5]3[NH:6][C:2](=[O:1])[S:3][C:4]=3[CH:10]=2)=[O:16])[CH2:26][CH2:25]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C(O)C(=O)Nc1ccc2[nH]c(=O)sc2c1
Reactant: c1ccc(CC2CCNCC2)cc1
Solvent: CCOCC
Product: O=C(Nc1ccc2[nH]c(=O)sc2c1)C(=O)N1CCC(Cc2ccccc2)CC1

Procedure:
The title compound is prepared from N-(2-oxo-2,3-dihydro-benzothiazole-6-yl)-oxalamic acid and 4-benzylpiperidine according to the method described in Example 1c. Melting Point: 201-203° C. (diethylether)
Reaction SMILES: [OH:1][C:2]1[C:3]2[C:4]3[N:5]([N:13]=[C:14]([CH2:16][OH:17])[CH:15]=3)[C:6](=[O:12])[NH:7][C:8]=2[CH:9]=[CH:10][CH:11]=1.[CH3:18]I.Cl>[Na].CO>[OH:17][CH2:16][C:14]1[CH:15]=[C:4]2[N:5]([C:6](=[O:12])[NH:7][C:8]3[CH:9]=[CH:10][CH:11]=[C:2]([O:1][CH3:18])[C:3]=32)[N:13]=1
Reactant: CI
Reactant: O=c1[nH]c2cccc(O)c2c2cc(CO)nn12
Agent: Cl
Agent: [Na]
Solvent: CO
Product: COc1cccc2[nH]c(=O)n3nc(CO)cc3c12
Reaction time: 3 h

Procedure:
To 4.2 g of 10-hydroxy-2-(hydroxymethyl)pyrazolo[1,5-c]quinazoline-5(6H)-one in a solution of 0.58 g sodium dissolved in 100 ml dry methanol is added 2.9 g of methyl iodide. After stirring for 3 hours at 50°, the reaction is neutralized with one equivalent of 1 N hydrochloric acid, evaporated and the residue recrystallized from absolute ethanol to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C@H:9]1[C@H:14]([N+:15]([O-])=O)[CH2:13][C:12]([CH2:18][N:19]2[CH2:24][CH2:23][CH:22]([OH:25])[CH2:21][CH2:20]2)=[CH:11][CH2:10]1>[Zn].CO.C(O)(=O)C>[NH2:15][C@@H:14]1[CH2:13][C:12]([CH2:18][N:19]2[CH2:24][CH2:23][CH:22]([OH:25])[CH2:21][CH2:20]2)=[CH:11][CH2:10][C@H:9]1[C:3]1[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=1[Cl:1]
Reactant: O=[N+]([O-])[C@@H]1CC(CN2CCC(O)CC2)=CC[C@H]1c1ccc(Cl)cc1Cl
Agent: [Zn]
Solvent: CC(=O)O
Solvent: CO
Product: N[C@@H]1CC(CN2CCC(O)CC2)=CC[C@H]1c1ccc(Cl)cc1Cl
Yield: 75.8 %

Procedure:
To a solution of Example 16A (50 mg, 0.13 mmol) in mixture of methanol/acetic acid (0.5 mL/0.5 mL), Zn powder (85 mg, 1.3 mmol) was added at room temperature. The reaction mixture was stirred for thirty minutes, filtered, concentrated under reduced pressure and purified by high pressure liquid chromotography (eluting with 0-70% acetonitrile/water and 0.1% trifluoroacetic acid) to provide the title compound (35 mg, 76%). 1H NMR (300 MHz, methanol-d4) δ ppm 7.54-7.61 (m, 1H), 7.39-7.49 (m, 2H), 6.14-6.34 (m, 1H), 3.89-4.02 (m, 1H), 3.73-3.84 (m, 1H), 3.51-3.69 (m, 1H), 2.36-3.13 (m, 3H), 1.91-2.19 (m, 1H). MS (ESI) m/z 356 (M+H)+.
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[O:3].N[C:6]([NH:8][C:9](N)=[O:10])=[O:7]>>[NH:1]1[C:9](=[O:10])[NH:8][C:6](=[O:7])[NH:4][C:2]1=[O:3]
Reactant: NC(N)=O
Reactant: NC(=O)NC(N)=O
Product: O=c1[nH]c(=O)[nH]c(=O)[nH]1

Procedure:
Cyanuric acid can be produced by heating urea or biuret in a solvent medium. During the process, particles of cyanuric acid are formed as a slurry in the hot solvent. Previous processes have employed operations to cool the reaction slurry and to separate the cyanuric acid from the slurry in which cyanuric acid was deposited on the cooling surfaces and the resulting product was discolored.
Reaction SMILES: [CH2:1]([S:3]([C:5]1[C:10]2[C:11]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=3)=[N:12][CH2:13][C:14](=S)[NH:15][C:9]=2[CH:8]=[CH:7][CH:6]=1)=[O:4])[CH3:2].[CH:27]([O:30][CH2:31][C:32]([NH:34][NH2:35])=O)([CH3:29])[CH3:28]>C(O)CCC>[CH2:1]([S:3]([C:5]1[C:10]2[C:11]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:24])[F:25])=[CH:19][CH:18]=3)=[N:12][CH2:13][C:14]3[N:15]([C:32]([CH2:31][O:30][CH:27]([CH3:29])[CH3:28])=[N:34][N:35]=3)[C:9]=2[CH:8]=[CH:7][CH:6]=1)=[O:4])[CH3:2]
Reactant: CC(C)OCC(=O)NN
Reactant: CCS(=O)c1cccc2c1C(c1ccc(C(F)(F)F)cc1)=NCC(=S)N2
Solvent: CCCCO
Product: CCS(=O)c1cccc2c1C(c1ccc(C(F)(F)F)cc1)=NCc1nnc(COC(C)C)n1-2

Procedure:
In the manner given in Example 1, a solution of 1,3-dihydro-6-ethylsulfinyl-5-[p-(trifluoromethyl)phenyl]-2H-1,4-benzodiazepine-2-thione in n-butyl alcohol was heated to reflux with isopropoxyacetic acid hydrazide to give 7-ethylsulfinyl-1-(isopropoxymethyl)-6-[p-(trifluoromethyl)phenyl]-4H-s-triazolo[4,3-a][1,4]benzodiazepine.
Reaction SMILES: FC(F)(F)[C:3]([OH:5])=[O:4].[CH3:8][O:9][C:10]1[C:11]([CH2:28][NH:29][CH3:30])=[C:12]2[C:16](=[CH:17][CH:18]=1)[N:15]([S:19]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)(=[O:21])=[O:20])[CH:14]=[CH:13]2>ClCCl>[CH3:8][O:9][C:10]1[C:11]([CH2:28][N:29]([CH3:30])[C:3](=[O:4])[O:5][C:11]([CH3:28])([CH3:12])[CH3:10])=[C:12]2[C:16](=[CH:17][CH:18]=1)[N:15]([S:19]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)(=[O:21])=[O:20])[CH:14]=[CH:13]2
Reactant: O=C(O)C(F)(F)F
Reactant: CNCc1c(OC)ccc2c1ccn2S(=O)(=O)c1ccccc1
Solvent: ClCCl
Product: COc1ccc2c(ccn2S(=O)(=O)c2ccccc2)c1CN(C)C(=O)OC(C)(C)C
Reaction time: 2 h

Procedure:
{[5-methoxy-1-(phenylsulfonyl)-1H-indol-4-yl]methyl}methylamine (0.627 g, 1.9 mmol; Example 144) was dissolved in dichloromethane (25 ml) and boc-anhydride (0.62 g, 2.8 mmol) was added. The mixture was stirred for 2 hours, washed with brine, dried (MgSO4) and evaporated. The crude product was purified through a plug of silica using 5% MeOH in dichloromethane as the eluent. Yield 0.628 g (78%). White solid. MS (ESI+) for C22H26N2O5S m/z 375 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[NH:6][C:5](=[O:7])[NH:4][C:3]1=[O:8].C(=O)([O-])[O-].[K+].[K+].[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CC(C)=O.C(OCC)(=O)C>[CH2:16]([N:4]1[C:3](=[O:8])[C:2]([CH3:9])([CH3:1])[NH:6][C:5]1=[O:7])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: BrCc1ccccc1
Reactant: CC1(C)NC(=O)NC1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: CC1(C)NC(=O)N(Cc2ccccc2)C1=O
Temperature: 25 °C
Yield: 91.3 %

Procedure:
To the stirred solution of 5,5-dimethylhydantoin (7 g, 54.7 mmole) in dry acetone (150 mL) under nitrogen were added potassium carbonate (10.6 g, 76.8 mmole) and benzylbromide (11.2 g, 65.9 mmole) at room temperature. The reaction mixture was refluxed for 20 hr. The reaction mixture was cooled to room temperature and the solid was filtered off by suction filtration. The titrate was concentrated on a rotary evaporator to give a residue. The residue was diluted with ethyl acetate and washed with water and brine, dried over sodium sulfate and evaporated to give 10.9 g (yield=91.3 %) of 3-benzyl-5,5-dimethylhydantoin as a white solid, mp=101°-104° C. This intermediate was subjected to the next step without further purification.
Reaction SMILES: [Cl:1][CH2:2][C:3]([CH2:5]Cl)=[O:4].[F:7][C:8]1[C:13]([F:14])=[C:12]([F:15])[CH:11]=[CH:10][C:9]=1[NH:16][C:17](=[S:19])[S-:18].C([NH+](CC)CC)C>C(Cl)Cl>[F:7][C:8]1[C:13]([F:14])=[C:12]([F:15])[CH:11]=[CH:10][C:9]=1[NH:16][C:17](=[S:18])[S:19][CH2:5][C:3](=[O:4])[CH2:2][Cl:1]
Reactant: O=C(CCl)CCl
Reactant: Fc1ccc(NC(=S)[S-])c(F)c1F
Agent: CC[NH+](CC)CC
Solvent: ClCCl
Product: O=C(CCl)CSC(=S)Nc1ccc(F)c(F)c1F
Yield: 86.9 %

Procedure:
1,3-Dichloroacetone (2.0 g) is added to methylene chloride (100 ml), and thereto is added triethylammonium N-(2,3,4-trifluorophenyl)dithiocarbamate (cf. European Patent Publication 286089) (5.0 g) with stirring at 2° to 5° C. The mixture is stirred for additional 60 minutes and then washed with 3N hydrochloric acid and water in this order. The organic layer is dried over anhydrous sodium sulfate and distilled under reduced pressure to remove the solvent. The residue is crystallized from a mixture of hexane-ethyl acetate-ether to give the title compound (4.2 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:34]2[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=2)[O:10][CH:11]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:12]2[CH2:16][CH:15]([OH:17])[CH2:14][N:13]2[C:18](=[O:27])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][N:24]([CH3:26])[CH3:25])=[CH:5][CH:4]=1.[C:42]1(=[O:48])[O:47][C:45](=[O:46])[CH2:44][CH2:43]1.C(N(CC)CC)C>CN(C1C=CN=CC=1)C.ClCCl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:34]2[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=2)[O:10][CH:11]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:12]2[N:13]([C:18](=[O:27])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][N:24]([CH3:25])[CH3:26])[CH2:14][CH:15]([O:17][C:42](=[O:48])[CH2:43][CH2:44][C:45]([OH:47])=[O:46])[CH2:16]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(C(OC(c2ccccc2)C2CC(O)CN2C(=O)CCCCCN(C)C)c2ccc(OC)cc2)cc1
Reactant: O=C1CCC(=O)O1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(C(OC(c2ccccc2)C2CC(OC(=O)CCC(=O)O)CN2C(=O)CCCCCN(C)C)c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Referring to scheme 25, Compound 94 (1.2 g, 2 mmol) is mixed with succinic anhydride (0.200 g, 2 mmol) and DMAP (0.244 g, 13 mmol) and dried in a vacuum at 40° C. overnight. The mixture is dissolved in anhydrous dichloromethane (5 mL), triethylamine (0.476 g, 0.64 mL, 4 mmol) is added and the solution stirred at room temperature under argon atmosphere for 16 h. It is then diluted with dichloromethane (100 mL) and washed with ice cold aqueous citric acid (5% wt., 100 mL) and water (2×100 mL). The organic phase is dried over anhydrous sodium sulfate and concentrated to dryness. The crude product is purified by column chromatography to afford compound 96.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5](Br)=[C:6]2[C:10]=1[C:9](=[O:11])[NH:8][CH2:7]2.[C:13](=[O:16])([O-])[O-].[K+].[K+].O>C(COC)OC>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:10]2[CH:2]=[CH:3][CH:4]=[C:13]([OH:16])[CH:9]=2)=[C:6]2[C:10]=1[C:9](=[O:11])[NH:8][CH2:7]2
Reactant: O=C([O-])[O-]
Reactant: Nc1ccc(Br)c2c1C(=O)NC2
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: Nc1ccc(-c2cccc(O)c2)c2c1C(=O)NC2
Yield: 176.3 %

Procedure:
In a similar manner to Step 1 of Example 152, 7-amino-4-bromoisoindolinone (150 mg, 0.661 mmol) was dissolved in dimethoxyethane (10.5 mL), and the solution was treated with 3-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)phenol (291 mg, 1.32 mmol), [bis(diphenylphosphino)ferrocene]dichloropalladium (43 mg, 0.053 mmol), potassium carbonate (455 mg, 3.31 mmol) and water (0.24 mL), followed by purification by slurry using chloroform to obtain 7-amino-4-(3-hydroxyphenyl)isoindolinone (140 mg, yield 88%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N+:4]([O-:11])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].CNC.O.[CH3:16][N:17]([CH3:20])[CH:18]=O>>[CH3:16][N:17]([CH3:20])/[CH:18]=[CH:1]/[C:2]1[CH:3]=[N+:4]([O-:11])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: CN(C)C=O
Reactant: Cc1c[n+]([O-])ccc1[N+](=O)[O-]
Agent: CNC
Solvent: O
Product: CN(C)/C=C/c1c[n+]([O-])ccc1[N+](=O)[O-]
Temperature: 90 °C
Reaction time: 15 h
Yield: 50 %

Procedure:
To the stirred solution of 3-methyl-4-nitropyridine 1-oxide (600 mg, 3.8 mmol, Step b) in dimethylformamide was added dimethylformamide and dimethylamine (1.14 mL, 8.5 mmol) drop wise at room temperature. After complete addition, the reaction mixture was stirred at 90° C. for 15 hours. The reaction mixture was poured on cold water and the precipitated solid was filtered, washed with water and dried to get (E)-N,N-dimethyl-2-(4-nitro-1-oxidopyridin-3-yl)ethenamine (470 mg, 50%).
Reaction SMILES: [C:1]([O:4][C@H:5]1[C:14]2[C:9](=[N:10][C:11]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:13]=2)[NH:8][CH2:7][CH2:6]1)(=[O:3])[CH3:2].O=[CH:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.O>[C:1]([O:4][C@H:5]1[C:14]2[C:9](=[N:10][C:11]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:13]=2)[N:8]([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH2:7][CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@@H]1CCNc2nc(-c3ccccc3)c(-c3ccccc3)nc21
Reactant: CCOC(=O)CCCCCC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: ClCCCl
Product: CCOC(=O)CCCCCCN1CC[C@@H](OC(C)=O)c2nc(-c3ccccc3)c(-c3ccccc3)nc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (R)-2,3-diphenyl-5,6,7,8-tetrahydropyrido[2,3-b]pyrazin-8-yl acetate (Intermediate HBR) in DCE (7 ml) was added ethyl 7-oxoheptanoate (71.8 mg, 0.417 mmol) followed by sodium triacetoxyborohydride (236 mg, 1.112 mmol). The reaction mixture was left to stir at room temperature overnight under an atmosphere of nitrogen. A further portion of ethyl 7-oxoheptanoate (6 equivalents) was added and the reaction mixture was left to stir at RT for 4 days. The mixture was diluted with water (20 ml) and extracted with EtOAc (3×20 ml). The combined organic extracts were dried over MgSO4, filtered and concentrated in vacuo. The resulting crude product was purified by chromatography on silica eluting with 0-40% EtOAc/iso-hexane to afford the title compound;
Reaction SMILES: [CH3:1][C:2]1[C:8](=[O:9])[C:7]2[N:10]3[C@@:14]([O:21][CH3:22])([C@H:15]([CH2:16][O:17][C:18]([NH2:20])=[O:19])[C:6]=2[C:4](=[O:5])[C:3]=1N)[C@H:13]1[NH:23][C@H:12]1[CH2:11]3.Cl.CCCCCC.[OH-:32].[Na+]>CCOCC>[CH3:1][C:2]1[C:3](=[O:32])[C:4](=[O:5])[C:6]2[C@@H:15]([CH2:16][O:17][C:18]([NH2:20])=[O:19])[C@@:14]3([O:21][CH3:22])[C@H:13]4[NH:23][C@H:12]4[CH2:11][N:10]3[C:7]=2[C:8]=1[OH:9]
Reactant: CO[C@@]12[C@H](COC(N)=O)C3=C(C(=O)C(C)=C(N)C3=O)N1C[C@@H]1N[C@@H]12
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: CCOCC
Solvent: CCCCCC
Product: CO[C@@]12[C@H](COC(N)=O)C3=C(C(O)=C(C)C(=O)C3=O)N1C[C@@H]1N[C@@H]12
Temperature: 25 °C
Reaction time: 30 h
Yield: 63 %

Procedure:
Mitomycin C (2.2 g, 6.6 mmoles) was dissolved in 140 ml 0.1N methanolic NaOH (50%) and the reaction mixture was stirred at room temperature for 30 hours. The solution was then adjusted to ca. pH 4.0 with 1N HCl and extracted with ethyl acetate (4×500 ml). The combined ethyl acetate extracts were dried (Na2SO4) and evaporated under reduced pressure at about 30° to 35° C. to obtain a solid residue, which upon dissolving in ether and treating with excess hexane afforded a purple precipitate. The precipitate was collected and air dried to afford the title compound as a fine purple powder (1.4 g, 63%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([NH:16]CCCC)=[C:8]([C:13](=O)[CH3:14])[C:9]([OH:12])=[N:10][CH:11]=1)=[O:5])[CH3:2].O.[NH2:22]N>C(O)(=O)C>[CH2:1]([O:3][C:4]([C:6]1[C:7]2[NH:16][N:22]=[C:13]([CH3:14])[C:8]=2[C:9]([OH:12])=[N:10][CH:11]=1)=[O:5])[CH3:2]
Reactant: NN
Reactant: CCCCNc1c(C(=O)OCC)cnc(O)c1C(C)=O
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)c1cnc(O)c2c(C)n[nH]c12

Procedure:
8.4 g. of 3-acetyl-4-butylamino-2-hydroxypyridine-5-carboxylic acid ethyl ester (0.03 mol.) are dissolved in 20 ml. of acetic acid, 3 ml. of hydrazine-hydrate are added and the mixture is refluxed for 5 hours. After this time, the solvent is removed in vacuo and the crystalline precipitate of 4-hydroxy-3-methyl-1H-pyrazolo[4,3-c]pyridine-7-carboxylic acid ethyl ester is recrystallized from acetic acid, yield 5.1 g. (77%), m.p. 310°.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[S:10]([CH3:13])(=[O:12])=[O:11])[CH:5]=O.[N+:14]([CH2:17][CH3:18])([O-:16])=[O:15].C([O-])(=O)C.[NH4+]>C(Cl)(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:17]([N+:14]([O-:16])=[O:15])[CH3:18])[CH:7]=[CH:8][C:9]=1[S:10]([CH3:13])(=[O:12])=[O:11]
Reactant: CS(=O)(=O)c1ccc(C=O)cc1F
Reactant: CC[N+](=O)[O-]
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: ClC(Cl)Cl
Product: CC(=Cc1ccc(S(C)(=O)=O)c(F)c1)[N+](=O)[O-]

Procedure:
A stirred mixture of 3-fluoro-4-methanesulfonyl-benzaldehyde (Example AA1) (24 g, 0.119 mol), nitroethane (70 ml, 0.97 mol) and ammonium acetate (2.75 g, 35 mmol) is heated at reflux under argon for 24 hours. The mixture is concentrated to give an oil which is dissolved in chloroform (200 ml) and washed with water (2×200 ml), followed by brine (100 ml). The organic extract is dried (MgSO4), filtered and the solvent removed to give the product as an orange oil. This was used immediately in the next step.