Azzindani/Open_Reaction_Data huggingface dataset:
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]=1OC)[C@H:13]1[NH:23][C@H:12]1[CH2:11]3.[NH2:26][CH2:27][C:28]([NH2:30])=[O:29]>C(O)C>[C:18](=[O:17])([OH:19])[NH2:20].[OH:17][CH2:16][CH:15]1[C:6]2[C:4](=[O:5])[C:3]([NH:26][CH2:27][C:28]([NH2:30])=[O:29])=[C:2]([CH3:1])[C:8](=[O:9])[C:7]=2[N:10]2[CH2:11][CH:12]3[NH:23][CH:13]3[C:14]12[O:21][CH3:22]
Reactant: NCC(N)=O
Reactant: COC1=C(C)C(=O)C2=C(C1=O)[C@@H](COC(N)=O)[C@@]1(OC)[C@H]3N[C@H]3CN21
Solvent: CCO
Product: COC12C(CO)C3=C(C(=O)C(C)=C(NCC(N)=O)C3=O)N1CC1NC12
Product: NC(=O)O
Temperature: 25 °C
Reaction time: 4 h
Yield: 56.8 %

Procedure:
A mixture of mitomycin A (40 mg, 0.11 mmol) and glycinamide (42 mg) in 3.5 ml of absolute ethanol was stirred at room temperature for 4 hours. The solvent was evaporated under reduced pressure and the residue was purified by preparative thin-layer chromatography using a pre-coated silica-gel plate (2 mm thickness) and a mixture of ethanol and ethyl acetate (1:3 by volume) as developing solvent. The blue zone was eluted with ethanol and evaporated under reduced pressure to give 12.8 mg (29.7% yield) of the desired product having a melting point of 124°-126° C. and providing the following analysis:
Reaction SMILES: [CH:1]1([C:7]2[S:11][C:10]([N:12]=[C:13]=[O:14])=[N:9][N:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:15]([NH:18][CH2:19][CH2:20][CH:21]=[O:22])[CH:16]=[CH2:17]>C1C=CC=CC=1>[CH2:15]([N:18]([CH2:19][CH2:20][CH:21]=[O:22])[C:13]([NH:12][C:10]1[S:11][C:7]([CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)=[N:8][N:9]=1)=[O:14])[CH:16]=[CH2:17]
Reactant: O=C=Nc1nnc(C2CCCCC2)s1
Reactant: C=CCNCCC=O
Solvent: c1ccccc1
Product: C=CCN(CCC=O)C(=O)Nc1nnc(C2CCCCC2)s1

Procedure:
A mixture of 5-cyclohexyl-1,3,4-thiadiazol-2-yl isocyanate dimer (0.05 mole), the dimethyl acetal of 3-allylaminopropionaldehyde (0.1 mole) and benzene (60 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer and reflux condenser. The reaction mixture is heated at reflux for a period of about 15 minutes. After this time the mixture is stripped of benzene under reduced pressure to yield a solid product as the residue. The residue is then recrystallized to yield the desired product the dimethyl acetal of 3-[1-allyl-3-(5-cyclohexyl-1,3,4-thiadiazol-2-yl)ureido]propionaldehyde.
Reaction SMILES: [C:1]12([O:11][CH2:12][C:13]3[NH:17][C:16]([CH:18]4[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]4)=[N:15][C:14]=3[C:24]([NH:26][C:27]3[CH:28]=[C:29]([CH:33]=[CH:34][CH:35]=3)[C:30](O)=[O:31])=[O:25])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.Cl.[CH2:37]([O:44][NH2:45])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1.C(N(CC)CC)C>>[CH2:37]([O:44][NH:45][C:30]([C:29]1[CH:28]=[C:27]([NH:26][C:24]([C:14]2[N:15]=[C:16]([CH:18]3[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]3)[NH:17][C:13]=2[CH2:12][O:11][C:1]23[CH2:2][CH:3]4[CH2:4][CH:5]([CH2:6][CH:7]([CH2:9]4)[CH2:8]2)[CH2:10]3)=[O:25])[CH:35]=[CH:34][CH:33]=1)=[O:31])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: O=C(O)c1cccc(NC(=O)c2nc(C3CCCCC3)[nH]c2COC23CC4CC(CC(C4)C2)C3)c1
Reactant: NOCc1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Product: O=C(NOCc1ccccc1)c1cccc(NC(=O)c2nc(C3CCCCC3)[nH]c2COC23CC4CC(CC(C4)C2)C3)c1
Yield: 82.2 %

Procedure:
3-{[5-(Adamantan-1-yloxymethyl)-2-cyclohexyl-1H-imidazole-4-carbonyl]-amino}-benzoic acid (Example 216) (910 mg, 1.90 mmol) was reacted with O-benzylhydroxylamine hydrochloride (455 mg, 2.85 mmol) in the presence of triethylamine (0.40 ml, 2.85 mmol) according to the procedure of Example 20, step d. The crude material was purified by flash column chromatography (silica, DCM/methanol 95:5) to afford a colourless foam (910 mg, 84%). 1H NMR (300MHz, CDCl3) 9.25 (1H, br s), 9.06 (1H, s), 8.64 (1H, s), 8.01 (1H, s), 7.84 (1H, m), 7.41 (6H, m), 5.06 (2H, s), 4.98 and 4.81 (2H, 2×s), 2.72 (1H, m), 2.19 (3H, br s), 2.07 (2H, m), 1.90-1.36 (20H, m).
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[O:15][C:8]([CH2:9][S:10][CH2:11][CH2:12]SC)=[CH:7][CH:6]=1)[CH3:3].[N+:16]([CH:19]=[C:20]([NH2:27])[NH:21][CH:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1)([O-:18])=[O:17]>>[CH3:1][N:2]([CH2:4][C:5]1[O:15][C:8]([CH2:9][S:10][CH2:11][CH2:12][NH:27][C:20]([NH:21][CH:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)=[CH:19][N+:16]([O-:18])=[O:17])=[CH:7][CH:6]=1)[CH3:3]
Reactant: CSCCSCc1ccc(CN(C)C)o1
Reactant: NC(=C[N+](=O)[O-])NC1CCCC1
Product: CN(C)Cc1ccc(CSCCNC(=C[N+](=O)[O-])NC2CCCC2)o1

Procedure:
24.54 grams of 2-[[5-[(dimethylamino)methyl]furfuryl]thio]ethylmethylsulphide are reacted with 42 grams of 2-nitro-N-cyclopentyl-1,1-ethenediamine at 80° C. for 3 hours. The mixture is cooled and the procedure described in Example 1 is followed. The product melts at 97°-103° C. Spectrophotometric analyses confirm its structure.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.I[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>>[C:7]1([N:1]2[CH:5]=[CH:4][CH:3]=[CH:2]2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: c1cc[nH]c1
Reactant: Ic1ccccc1
Product: c1ccc(-n2cccc2)cc1

Procedure:
Following General Procedure A (90° C., 30 hours), 1H-pyrrole (104 μL, 1.5 mmol) is coupled with iodo-benzene (112 μL, 1.0 mmol). The crude brown oil is purified by flash chromatography on silica gel (eluent: hexanes) to provide 130 mg (91% isolated yield) of the desired product as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][C:14]=1[F:15])[CH2:5][CH:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1.[O:16]=[C:17]1[NH:21][C:20]2[CH:22]=[CH:23][C:24]([NH:26][C:27](=[O:31])[C:28](O)=[O:29])=[CH:25][C:19]=2[O:18]1>>[F:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][C:14]=1[F:15])[CH2:5][CH:6]1[CH2:7][CH2:8][N:9]([C:28](=[O:29])[C:27]([NH:26][C:24]2[CH:23]=[CH:22][C:20]3[NH:21][C:17](=[O:16])[O:18][C:19]=3[CH:25]=2)=[O:31])[CH2:10][CH2:11]1
Reactant: O=C(O)C(=O)Nc1ccc2[nH]c(=O)oc2c1
Reactant: Fc1ccc(CC2CCNCC2)cc1F
Product: O=C(Nc1ccc2[nH]c(=O)oc2c1)C(=O)N1CCC(Cc2ccc(F)c(F)c2)CC1

Procedure:
The title compound is prepared from 4-(3,4-difluoro-benzyl)-piperidine [J. Org. Chem., 64, 3763. (1999)] and N-(2-oxo-2,3-dihydro-benzoxazol-6-yl)-oxalamic acid (Example 43e) according to the method described in Example 43f. The residue is purified by column chromatography using Kieselgel 60 (Merck) as adsorbent and toluene:methanol=4:1 as eluent. Melting Point: 233° C. (isopropanol)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[CH2:12][CH2:13][C:14](=[O:17])[NH:15][N:16]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].CC(C)([O-])C.[K+].[C:24]([NH:32][C:33]1[CH:40]=[CH:39][C:36]([CH2:37]Cl)=[CH:35][CH:34]=1)(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[N:27][CH:26]=1>C1COCC1>[C:24]([NH:32][C:33]1[CH:40]=[CH:39][C:36]([CH2:37][N:15]2[C:14](=[O:17])[CH2:13][CH2:12][C:11]([C:5]3[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=3)=[N:16]2)=[CH:35][CH:34]=1)(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[N:27][CH:26]=1
Reactant: COc1ccc(C2=NNC(=O)CC2)cc1OC
Reactant: O=C(Nc1ccc(CCl)cc1)c1cccnc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COc1ccc(C2=NN(Cc3ccc(NC(=O)c4cccnc4)cc3)C(=O)CC2)cc1OC
Reaction time: 0.5 h

Procedure:
A suspension of 4.70 g of 6-(3,4-dimethoxyphenyl)-2,3,4,5-tetrahydropyridazin-3-one ("A") in 150 ml of THF is treated with 2.24 g of potassium tert-butoxide and the mixture is stirred for 30 minutes. 7.32 g of 4-nicotinoylaminobenzyl chloride is added and the mixture is subsequently stirred at room temperature for 10 hours. The solvent is removed and the residue is worked up in the customary manner. 2-(4-nicotinoylaminobenzyl)-6-(3,4-dimethoxyphenyl)-2,3,4,5-tetrahydropyridazin-3-one is obtained.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6](=[O:27])[CH:7]([C:12]2[CH:17]=[C:16]([O:18][CH2:19][CH:20]3[CH2:22][CH2:21]3)[C:15]([N+:23]([O-])=O)=[CH:14][C:13]=2[F:26])[CH2:8][CH:9]([CH3:11])[CH3:10])[CH2:3][CH2:2]1>CCO.[Pd]>[CH:1]1([CH2:4][O:5][C:6](=[O:27])[CH:7]([C:12]2[CH:17]=[C:16]([O:18][CH2:19][CH:20]3[CH2:21][CH2:22]3)[C:15]([NH2:23])=[CH:14][C:13]=2[F:26])[CH2:8][CH:9]([CH3:11])[CH3:10])[CH2:2][CH2:3]1
Reactant: CC(C)CC(C(=O)OCC1CC1)c1cc(OCC2CC2)c([N+](=O)[O-])cc1F
Agent: [Pd]
Solvent: CCO
Product: CC(C)CC(C(=O)OCC1CC1)c1cc(OCC2CC2)c(N)cc1F
Yield: 72 %

Procedure:
2-(5-cyclopropylmethoxy-2-fluoro-4-nitro-phenyl)-4-methyl-pentanoic acid cyclopropylmethyl ester (10.0 g, 26.4 mmol) was dissolved in EtOH (200 mL) and hydrogenated at 50 psi, 25° C. for 24 h over 10% Pd—C (1 g). The mixture was filtered and the solvent evaporated to give crude a brown oi, which was purified by column chromatography over silica gel (Heptane-EtOAc gradient) to give 6.7 g, (72%) of 2-(5-cyclopropylmethoxy-2-fluoro-4-amino-phenyl)-4-methyl-pentanoic acid cyclopropylmethyl ester as a yellow oil. 1H NMR (300 MHz, CDCl3/TMS): δ 6.73 (d, J=6.9 Hz, 1H), 6.40 (d, J=11.0 Hz, 1H), 4.00-3.70 (m, 5H), 1.91-1.81 (m, 1H), 1.65-1.56 (m, 1H), 1.51-1.39 (m, 1H), 1.28-1.18 (m, 1H), 1.12-1.00 (m, 1H), 0.90 (d, J=6.6 Hz, 6H), 0.63-0.57 (m, 2H), 0.53-047 (m, 2H), 0.35-0.28 (m, 2H), 0.25-0.18 (m, 2H); 13C NMR (75 MHz, CDCl3/TMS): δ 174.2, 154.8 (d, 1JCF=236.0 Hz), 142.6, 136.6 (d, 3JCF=11.5 Hz), 114.1 (d, 2JCF=16.8 Hz), 111.6 (d, 3JCF=4.8 Hz), 101.6 (d, 2JCF=28.2 Hz), 73.8, 69.2, 42.1, 40.8, 25.9, 22.7, 22.2, 10.5, 9.8, 3.2.
Reaction SMILES: [Si]([O:8][C:9]1[CH:10]=[C:11]([NH:16][C:17]([NH:19][CH2:20][C:21]2[CH:22]=[C:23]3[C:27](=[CH:28][CH:29]=2)[C:26](=[O:30])[N:25]([CH:31]2[CH2:36][CH2:35][C:34](=[O:37])[NH:33][C:32]2=[O:38])[CH2:24]3)=[O:18])[CH:12]=[CH:13][C:14]=1[CH3:15])(C(C)(C)C)(C)C.[F-].[Cs+]>CN(C=O)C.O>[O:38]=[C:32]1[CH:31]([N:25]2[CH2:24][C:23]3[C:27](=[CH:28][CH:29]=[C:21]([CH2:20][NH:19][C:17]([NH:16][C:11]4[CH:12]=[CH:13][C:14]([CH3:15])=[C:9]([OH:8])[CH:10]=4)=[O:18])[CH:22]=3)[C:26]2=[O:30])[CH2:36][CH2:35][C:34](=[O:37])[NH:33]1
Reactant: Cc1ccc(NC(=O)NCc2ccc3c(c2)CN(C2CCC(=O)NC2=O)C3=O)cc1O[Si](C)(C)C(C)(C)C
Agent: [Cs+]
Agent: [F-]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(NC(=O)NCc2ccc3c(c2)CN(C2CCC(=O)NC2=O)C3=O)cc1O
Temperature: 70 °C

Procedure:
A mixture of 1-(3-(tert-butyldimethylsilyloxy)-4-methylphenyl)-3-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)urea (0.54 g, 1.0 mmol) and cesium fluoride (0.15 g, 1.0 mmol) in DMF (10 mL) is heated to 70° C. for 8 hrs. The mixture is cooled and diluted with water (10 mL). The solid precipitate is filtered, rinsed with water (10 mL), and dried under vacuum to provide the product.
Reaction SMILES: C(O[C:4](=[O:20])[CH:5]([NH:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][N:15]=[CH:14]2)[CH2:6][CH2:7][CH2:8][CH3:9])C.[C-]#[N:22].[K+]>N.CO>[NH:16]1[C:17]2[C:13](=[CH:12][C:11]([NH:10][CH:5]([CH2:6][CH2:7][CH2:8][CH3:9])[C:4]([NH2:22])=[O:20])=[CH:19][CH:18]=2)[CH:14]=[N:15]1
Reactant: CCCCC(Nc1ccc2[nH]ncc2c1)C(=O)OCC
Reactant: [C-]#N
Agent: N
Agent: [K+]
Solvent: CO
Product: CCCCC(Nc1ccc2[nH]ncc2c1)C(N)=O
Temperature: 25 °C
Yield: 724.5 %

Procedure:
A solution of 2-(1H-indazol-5-ylamino)-hexanoic acid ethyl ester (1.0 g, 3.63 mmol) and KCN (0.026 g, 0.363 mmol) in 7N NH3 in methanol (10.4 mL) was heated at 80° C. in a sealed tube. After 96 ours the reaction mixture was cooled to ambient temperature, concentrated in vacuo, and purified by chromatography (silica, 0 to 10% MeOH in DCM) to furnish 2-(1H-indazol-5-ylamino)-hexanoic acid amide (0.647 g, 2.63 mmol, 72%) as a foam.
Reaction SMILES: CN1CCOCC1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Cl:32][C:33]1[CH:34]=[C:35]2[C:39](=[C:40]([C:42]([OH:44])=O)[CH:41]=1)[NH:38][CH:37]=[CH:36]2.[F:45][C:46]1[CH:51]=[CH:50][C:49]([CH2:52][CH2:53][NH:54][CH2:55][C:56]2[CH:61]=[CH:60][C:59]([C:62]([F:65])([F:64])[F:63])=[CH:58][CH:57]=2)=[CH:48][CH:47]=1>CN(C=O)C.O>[F:45][C:46]1[CH:51]=[CH:50][C:49]([CH2:52][CH2:53][N:54]([CH2:55][C:56]2[CH:61]=[CH:60][C:59]([C:62]([F:63])([F:64])[F:65])=[CH:58][CH:57]=2)[C:42]([C:40]2[CH:41]=[C:33]([Cl:32])[CH:34]=[C:35]3[C:39]=2[NH:38][CH:37]=[CH:36]3)=[O:44])=[CH:48][CH:47]=1
Reactant: Fc1ccc(CCNCc2ccc(C(F)(F)F)cc2)cc1
Reactant: O=C(O)c1cc(Cl)cc2cc[nH]c12
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Solvent: O
Product: O=C(c1cc(Cl)cc2cc[nH]c12)N(CCc1ccc(F)cc1)Cc1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Yield: 93.7 %

Procedure:
121 mg (1.2 mmol) of N-methyl morpholine and then 227 mg (0.6 mmol) of HBTU were added to 78 mg (0.40 mmol) of 5-chloro-1H-indol-7-carboxylic acid and 142 mg (0.48 mmol) of [2-(4-fluoro-phenyl)-ethyl]-(4-trifluoromethyl-benzyl)-amine dissolved in 4 ml DMF at rt under nitrogen. The reaction mixture was stirred at rt over night. Water was added and the reaction mixture was extracted twice with EtOAc. The combined organic layers were washed once with 1N aqueous HCl solution, once with saturated aqueous NaHCO3 solution and once with saturated aqueous NaCl. Solution, dried over sodium sulfate, filtered and the solvent was evaporated. The residue was purified by column chromatography (20 g silica gel; heptane/EtOAc 7:3) to yield 178 mg (94%) product as a yellow viscous oil. MS (ISP) 475.1 (M+H)+.
Reaction SMILES: [Li+].[OH-].[O:3]=[C:4]1[N:10]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C@@H:20]([C:30]([O:32]C)=[O:31])[CH2:21][C:22]3[CH:27]=[CH:26][C:25]([CH3:28])=[C:24]([Cl:29])[CH:23]=3)=[O:18])[CH2:13][CH2:12]2)[CH2:9][CH2:8][C:7]2[CH:34]=[CH:35][CH:36]=[CH:37][C:6]=2[NH:5]1>O.C1COCC1>[O:3]=[C:4]1[N:10]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C@@H:20]([C:30]([OH:32])=[O:31])[CH2:21][C:22]3[CH:27]=[CH:26][C:25]([CH3:28])=[C:24]([Cl:29])[CH:23]=3)=[O:18])[CH2:13][CH2:12]2)[CH2:9][CH2:8][C:7]2[CH:34]=[CH:35][CH:36]=[CH:37][C:6]=2[NH:5]1
Reactant: COC(=O)[C@@H](Cc1ccc(C)c(Cl)c1)OC(=O)N1CCC(N2CCc3ccccc3NC2=O)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)O)cc1Cl
Temperature: 25 °C
Reaction time: 7 h

Procedure:
A solution of 0.34 g (14.2 mmol) LiOH in 20 mL water was added to a solution of 3.38 g (6.76 mmol) of (R)-2-(3-chloro-4-methyl-phenyl)-1-methoxycarbonyl-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate in 30 mL THF and the reaction mixture was stirred for 7 h at RT. The mixture was evaporated down i.vac., diluted with 80 mL water, the aqueous phase was extracted twice with 50 mL diethyl ether, the aqueous phase was acidified with 4 M HCl and stirred for 30 min. The precipitated product was suction filtered, washed with water and dried.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[CH2:18][C:17]2[C:12](=[N:13]C(SC)=[N:15][CH:16]=2)[NH:11][C:10]1=[O:21].ClC1C=CC=C(C(OO)=[O:30])C=1.[CH3:33][S:34]([CH3:36])=[O:35].C(=O)(O)[O-].[Na+]>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[CH2:18][C:17]2[C:12](=[N:13][C:33]([S:34]([CH3:36])(=[O:30])=[O:35])=[N:15][CH:16]=2)[NH:11][C:10]1=[O:21]
Reactant: CSc1ncc2c(n1)NC(=O)N(c1c(Cl)cccc1Cl)C2
Reactant: CS(C)=O
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CS(=O)(=O)c1ncc2c(n1)NC(=O)N(c1c(Cl)cccc1Cl)C2
Reaction time: 18 h
Yield: 100 %

Procedure:
A solution of 220 mg (0.64 mmol) of 3-(2,6-dichlorophenyl)-7-methylthio-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-one in 10 ml of dichloromethane was treated with 440 mg (1.28 mmol) of 3-chloroperbenzoic acid (50% w/w in water) and stirred for 18 hours. 0.2 ml of dimethyl sulfoxide was added. After a further 15 minutes 15 ml of saturated aqueous sodium bicarbonate solution were added. The phases were separated and then the organic phase was washed with 30 ml of saturated aqueous sodium bicarbonate solution, dried over magnesium sulfate and evaporated to give 250 mg (100%) of 3-(2,6-dichlorophenyl)-7-methanesulfonyl-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one as a white solid.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][NH:4][C:5]([N:7]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1)[CH:8]1[O:16][CH2:15][C@H:13]([OH:14])[C@H:11]([OH:12])[C@H:9]1[OH:10])=[O:6].[N+:26]([O-])([N+]([O-])=O)=[O:27]>>[Cl:1][CH2:2][CH2:3][N:4]([N:26]=[O:27])[C:5]([N:7]([CH2:17][C:18]1[CH:19]=[CH:20][C:21]([O:24][CH3:25])=[CH:22][CH:23]=1)[CH:8]1[O:16][CH2:15][C@H:13]([OH:14])[C@H:11]([OH:12])[C@H:9]1[OH:10])=[O:6]
Reactant: O=[N+]([O-])[N+](=O)[O-]
Reactant: COc1ccc(CN(C(=O)NCCCl)C2OC[C@H](O)[C@H](O)[C@H]2O)cc1
Product: COc1ccc(CN(C(=O)N(CCCl)N=O)C2OC[C@H](O)[C@H](O)[C@H]2O)cc1
Yield: 62.7 %

Procedure:
3.7 g of 1-(2-chloroethyl)-3-(p-methoxybenzyl)-3-(L-arabinopyranosyl)urea and 5.0 g of nitrogen tetroxide gas are treated in the same manner as described in Example 31-(2). 2.5 g of 1-(2-chloroethyl)-1-nitroso-3-(p-methoxybenzyl)-3-(L-arabinopyranosyl)urea are thereby obtained as yellow caramel.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:9]([O:11][CH3:12])=[O:10])[NH:7][CH:8]=1)([O-:3])=[O:2].I[CH3:14]>>[CH3:14][N:7]1[CH:8]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=[C:6]1[C:9]([O:11][CH3:12])=[O:10]
Reactant: COC(=O)c1cc([N+](=O)[O-])c[nH]1
Reactant: CI
Product: COC(=O)c1cc([N+](=O)[O-])cn1C
Yield: 89 %

Procedure:
Following the basic procedure of Example 25(d), by reacting 2.9 g (17 mmol) of methyl 4-nitro-2-pyrrolecarboxylate with 1.1 ml of iodomethane, 2.8 g (89%) of the expected compound of melting point 122°-124° C. were obtained.
Reaction SMILES: [C:1]([C:4]1[C:5]([N:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)=[C:6]2[CH:12]=[N:11][N:10](CC3OC=CC=3)[C:7]2=[N:8][CH:9]=1)(=[O:3])[CH3:2].S(=O)(=O)(O)O>>[C:1]([C:4]1[C:5]([N:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)=[C:6]2[CH:12]=[N:11][NH:10][C:7]2=[N:8][CH:9]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1cnc2c(cnn2Cc2ccco2)c1N1CCCCC1
Agent: O=S(=O)(O)O
Product: CC(=O)c1cnc2[nH]ncc2c1N1CCCCC1

Procedure:
5-Acetyl-1-(2-furanyl)methyl-4-piperidino-1H-pyrazolo[3,4-b]pyridine is treated with concentrated sulfuric acid according to the procedure in Example 4 to obtain 5-acetyl-4-piperidino-1H-pyrazolo[3,4-b]pyridine.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1Cl)=[CH:13][CH:12]=[CH:11][C:10]=2[O:17][CH3:18])=[O:5])[CH3:2].[CH:19]1([NH2:23])[CH2:22][CH2:21][CH2:20]1>>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:23][CH:19]1[CH2:22][CH2:21][CH2:20]1)=[CH:13][CH:12]=[CH:11][C:10]=2[O:17][CH3:18])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnc2c(OC)cccc2c1Cl
Reactant: NC1CCC1
Product: CCOC(=O)c1cnc2c(OC)cccc2c1NC1CCC1

Procedure:
4-Chloro-8-methoxy-quinoline-3-carboxylic acid ethyl ester (300 mg, 1.13 mmol) was treated with cyclobutylamine following general procedure B to afford 4-cyclobutylamino-8-methoxy-quinoline-3-carboxylic acid ethyl ester (240 mg). Thus obtained amino-ester was hydrolyzed to the corresponding acid using general procedure D and then transformed into the corresponding ethylamide (170 mg) following general procedure E.
Reaction SMILES: C(O)(=O)C.[F:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17](/[CH:20]=[CH:21]/[N+:22]([O-:24])=[O:23])=[CH:16][CH:15]=2)[CH:7]=1.[BH4-].[Na+]>CS(C)=O>[F:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]([O:12][CH2:13][C:14]2[CH:15]=[CH:16][C:17]([CH2:20][CH2:21][N+:22]([O-:24])=[O:23])=[CH:18][CH:19]=2)[CH:7]=1
Reactant: O=[N+]([O-])/C=C/c1ccc(COc2cc(F)ccn2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CS(C)=O
Product: O=[N+]([O-])CCc1ccc(COc2cc(F)ccn2)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 55.4 %

Procedure:
To an acetic acid (1.7 mL) and dimethyl sulfoxide (29 mL) solution of 4-fluoro-2-(4-((E)-2-nitro-vinyl)-benzyloxy)-pyridine (1.72 g, 6.27 mmol) described in Manufacturing Example 59-1-3 was added sodium borohydride (380 mg, 10 mmol) at room temperature while cooling appropriately. This mixture was stirred for 5 hours at room temperature. This mixture was partitioned into ethyl acetate and water. The organic layer was separated, washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure, and the residue was purified by silica gel column chromatography (heptane:ethyl acetate=4:1-1:1) to obtain the title compound (960 mg, 55%).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][C:6]=1[C:7]([NH2:9])=[O:8].[F:10][C:11]1[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=1[C:13](Cl)=[O:14]>N1C=CC=CC=1>[F:10][C:11]1[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=1[C:13]([NH:1][C:2]1[S:3][CH:4]=[CH:5][C:6]=1[C:7]([NH2:9])=[O:8])=[O:14]
Reactant: NC(=O)c1ccsc1N
Reactant: O=C(Cl)c1ccccc1F
Solvent: c1ccncc1
Product: NC(=O)c1ccsc1NC(=O)c1ccccc1F
Temperature: 0 °C
Reaction time: 8 h
Yield: 77 %

Procedure:
2-Amino-thiophene-3-carboxylic acid amide (8.73 g, 61.4 mmole) was dissolved in pyridine (100 ml) cooled to 0° C. and 2-fluorobenzoyl chloride was added dropwise over 20 min, then reaction was allowed to warm to room temperature with stirring overnight. The pyridine was removed under vacuum, added dichloromethane and water. Product precipitated as a grey solid and was washed with dilute hydrochloric acid, water and air dried. The dichloromethane layer was separated, washed with dilute hydrochloric acid, and water, dried over sodium sulfate (anh.) and solvent removed to give a total of 12.45 g product (77% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][C:14]=1[Cl:15])[N:11](S(C1C=CC(C)=CC=1)(=O)=O)[C:10]1[C:9]([C:31]([F:34])([F:33])[F:32])([O:26][Si](C)(C)C)[CH:8]([CH3:35])[CH2:7][CH2:6][C:5]2=1.[OH-].[K+].CCO>C1COCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][C:14]=1[Cl:15])[NH:11][C:10]1[C:9]([C:31]([F:32])([F:33])[F:34])([OH:26])[CH:8]([CH3:35])[CH2:7][CH2:6][C:5]2=1
Reactant: Cc1ccc(S(=O)(=O)n2c3c(c4cc(Cl)c(Cl)cc42)CCC(C)C3(O[Si](C)(C)C)C(F)(F)F)cc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: CC1CCc2c([nH]c3cc(Cl)c(Cl)cc23)C1(O)C(F)(F)F
Temperature: 60 °C
Yield: 28.4 %

Procedure:
6,7-Dichloro-2-methyl-9-tosyl-1-(trifluoromethyl)-1-(trimethylsilyloxy)-2,3,4,9-tetrahydro-1H-carbazole (0.13 g, 0.26 mmol) was dissolved in THF (10 mL) and KOH (0.070 g, 1 mmol) in water (10 mL) was added followed by EtOH (3 mL). The reaction mixture was heated to 60° C. for 4 h, diluted with water (10 mL) and extracted with EtOAc (2×50 mL). The combined organic extracts were dried over Na2SO4 and concentrated under reduced pressure. The crude material was purified by column chromatography [EtOAc-hexane (1:4) as eluant] to give the title compound (0.025 g, 28%) 1H NMR (500 MHz, CDCl3, δ in ppm) (mixture of two diastereomers) 8.22 (br s, 1H), 8.15 (bs, 1H), 7.60 (s, 1H), 7.47 (s, 1H), 2.82-2.63 (m, 2H), 2.51 (s, 1H), 2.46-2.43 (m, 1H), 2.33 (s, 1H), 2.28 (s, 1H), 2.14-2.10 (m, 2H), 2.03-1.98 (m, 1H), 1.82-1.79 (m, 1H), 1.22-1.20 (m, 3H).
Reaction SMILES: [OH:1]OS([O-])=O.[K+].[O:7]=[C:8]([N:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1)[CH:9]([C:14]1[CH:21]=[CH:20][C:17]([CH:18]=[O:19])=[CH:16][CH:15]=1)[CH2:10][CH2:11][CH2:12][CH3:13]>CN(C=O)C>[O:7]=[C:8]([N:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1)[CH:9]([C:14]1[CH:15]=[CH:16][C:17]([C:18]([OH:1])=[O:19])=[CH:20][CH:21]=1)[CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: O=S([O-])OO
Reactant: CCCCC(C(=O)N1CCCCC1)c1ccc(C=O)cc1
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCC(C(=O)N1CCCCC1)c1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 64 %

Procedure:
Oxone (257 mg, 0.42 mmol) was added to a stirred solution of 4-(1-oxo-1-(piperidin-1-yl)hexan-2-yl)benzaldehyde (100 mg, 0.35 mmol) in DMF (5 mL) and the resulting mixture was stirred at room temperature for 16 hours. The DMF was removed in vacuo and the resulting residue was purified by flash column chromatography (50% EtOAc/hexane, Rf=0.4) to afford the desired compound as a pale yellow solid (68 mg. 64%). MP=142° C. 1H NMR (400 MHz, CDCl3) 0.86 (t, J=7 Hz, 3H); 1.05 (m, 1H); 1.15 (m, 1H); 1.2-1.6 (multiple signals, 8H); 1.71 (m, 1H); 2.10 (m, 1H); 3.33-3.43 (m, 3H); 3.69 (m, 1H); 3.77 (t, J=7 Hz, 1H); 7.38 (d, J=8.4 Hz, 2H); 8.02 (d, J=8.4 Hz, 2H). 13C NMR (75 MHz, CDCl3) 13.98, 22.68, 24.50, 25.55, 26.16, 30.04, 34.60, 43.32, 46.68, 48.82, 128.04, 130.50, 153.75, 170.59. HRMS (ESI+1 ion) m/z calcd for C18H26NO3 304.1907. found 304.1917.