Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]([CH:4]1[C:10](=[O:11])[N:9]2[CH:5]1[CH2:6][C:7]([NH:22][CH2:23][CH2:24][CH3:25])=[C:8]2[C:12]([O:14]CC1C=CC=CC=1)=[O:13])[CH3:3].O.C(=O)(O)[O-].[Na+:31].C>O1CCOCC1.[Pd]>[OH:1][CH:2]([CH:4]1[C:10](=[O:11])[N:9]2[CH:5]1[CH2:6][C:7]([NH:22][CH2:23][CH2:24][CH3:25])=[C:8]2[C:12]([O-:14])=[O:13])[CH3:3].[Na+:31]
Reactant: CCCNC1=C(C(=O)OCc2ccccc2)N2C(=O)C(C(C)O)C2C1
Agent: [Pd]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CCCNC1=C(C(=O)[O-])N2C(=O)C(C(C)O)C2C1
Reaction time: 1 h

Procedure:
Benzyl 6-(1-hydroxyethyl)-3-propylamino-1-azabicyclo[3.2.0]hept-2-en-7-one-2-carboxylate (30 mg) is dissolved in dioxane (2 ml) and water (1 ml) containing sodium bicarbonate (7.5 mg). 10% palladium on powdered charcoal (30 mg) is added and the resulting mixture is hydrogenated at 40 psi for 1 hr. The catalyst is filtered off and washed with water (3 ml). The combined filtrate is extracted with ethyl acetate (3×2 ml), conc. in vacuo, and lyophilized to afford sodium 6-(1-hydroxyethyl)-3-propylamino-1-azabicyclo[3.2.0]hept-2-en-7-one-2-carboxylate.
Reaction SMILES: Cl.[NH2:2][C:3]1[N:4]=[CH:5][NH:6][C:7]=1[C:8]([NH2:10])=[O:9].CN(C)[CH:13]=[CH:14][C:15]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=1)=O.C([O-])(=O)C.[Na+]>C(O)(=O)C>[F:24][C:23]([F:25])([F:26])[C:19]1[CH:20]=[CH:21][CH:22]=[C:17]([C:15]2[N:4]3[CH:5]=[N:6][C:7]([C:8]([NH2:10])=[O:9])=[C:3]3[N:2]=[CH:13][CH:14]=2)[CH:18]=1
Reactant: NC(=O)c1[nH]cnc1N
Reactant: CN(C)C=CC(=O)c1cccc(C(F)(F)F)c1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Product: NC(=O)c1ncn2c(-c3cccc(C(F)(F)F)c3)ccnc12

Procedure:
A mixture of 1.62 g. of 4-amino-5-imidazolecarboxamide hydrochloride, 2.43 g. of 3-dimethylamino-3'-trifluoromethylacrylophenone and 0.82 g. of sodium acetate in 25 ml. of glacial acetic acid is refluxed for 15 hours and then evaporated to dryness. The residue is treated as described in Example 1, giving the desired product, m.p. 239°-240° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C@:4]([N:15]=[C:16]=[O:17])([CH3:14])[CH2:5][O:6][Si:7]([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8].[N+:19](=[C:21]1[N:25]=[CH:24][N:23]=[C:22]1[C:26]([NH2:28])=[O:27])=[N-:20]>CS(C)=O>[CH3:1][O:2][C:3](=[O:18])[C@:4]([N:15]1[C:16](=[O:17])[N:25]2[CH:24]=[N:23][C:22]([C:26](=[O:27])[NH2:28])=[C:21]2[N:19]=[N:20]1)([CH3:14])[CH2:5][O:6][Si:7]([C:10]([CH3:11])([CH3:12])[CH3:13])([CH3:9])[CH3:8]
Reactant: [N-]=[N+]=C1N=CN=C1C(N)=O
Reactant: COC(=O)[C@](C)(CO[Si](C)(C)C(C)(C)C)N=C=O
Solvent: CS(C)=O
Product: COC(=O)[C@](C)(CO[Si](C)(C)C(C)(C)C)n1nnc2c(C(N)=O)ncn2c1=O
Reaction time: 2 h

Procedure:
To a solution of (S)-3-(tert-butyl-dimethyl-silanyloxy)-2-isocyanato-2-methyl-propionic acid methyl ester (510 mg, 1.86 mmol) in dry DMSO (1.5 mL) was added 5-diazoimidazole-4-carboxamide (135 g, 0.98 mmol) at room temperature under nitrogen. The reaction mixture was stirred for 2 hours whereupon it was poured onto crushed ice. The resultant white precipitate was collected by vacuum filtration. The filter cake was washed with water (2×1 reaction volume), EtOAc (1 reaction volume) and then Et2O (1 reaction volume) to give (S)-3-(tert-Butyl-dimethyl-silanyloxy)-2-(8-carbamoyl-4-oxo-imidazo[5,1-d][1,2,3,5]tetrazin-3-yl)-2-methyl-propionic acid methyl ester as a pale off white solid (140 mg, 34%). 1H NMR (400 MHz, d6-DMSO) δ ppm: 8.96 (CH, s, 1H), 7.91 (CONH2, s, 1H), 7.77 (CONH2, s, 1H), 5.77 (CH, dd, J=8.8 Hz, 5.6 Hz, 1H), 4.36 (CH2, dd, J=10.6 Hz, 5.6 Hz, 1H), 4.23 (CH2, dd, J=10.6 Hz, 8.8 Hz, 1H), 3.72 (CO2CH3, s, 3H), 0.72 (SiC(CH3)3, s, 9H), 0.03 (SiCH3, s, 3H), −0.06 (SiCH3, s, 3H).
Reaction SMILES: [CH3:1][N:2]([CH3:16])[C:3]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:8][CH2:7][C:6](=O)[CH2:5][CH2:4]1.[CH2:17]([NH2:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>O1CCCC1.C(O)(=O)C>[CH2:17]([NH:24][CH:6]1[CH2:7][CH2:8][C:3]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)([N:2]([CH3:16])[CH3:1])[CH2:4][CH2:5]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: NCc1ccccc1
Reactant: CN(C)C1(c2ccccc2)CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CN(C)C1(c2ccccc2)CCC(NCc2ccccc2)CC1

Procedure:
2.00 g 4-dimethylamino-4-phenyl-cyclohexanone were dissolved in 30 ml analytical grade tetrahydrofuran, and 986 mg benzylamine followed by 794 μl glacial acetic acid were added, while stirring in an ice-bath. 2.72 g sodium triacetoxyborohydride were then added in portions in the course of 15 minutes and the mixture was subsequently stirred for approx. 65 hours. For working up, 15 ml two molar sodium hydroxide solution were added dropwise (pH>10) and the mixture was extracted three times with 25 ml diethyl ether each time. The combined organic phases were then washed twice with 20 ml water each time, dried over sodium sulfate and filtered and the filtrate was concentrated. The crude product obtained was chromatographed over silica gel with diethyl ether with the addition of one percent by volume of aqueous ammonia solution (25 wt. %). 844 mg of the nonpolar diastereoisomer of N′-benzyl-N,N-dimethyl-1-phenyl-cyclohexane-1,4-diamine were obtained, and were converted into 843 mg of the corresponding hydrochloride by dissolving in 6.8 ml 2-butanone and addition of 27.1 μl water followed by 381 μl chlorotrimethylsilane and stirring overnight.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:20][C:21]1[CH:26]=[CH:25][C:24](Cl)=[CH:23][CH:22]=1)[CH2:3][NH:4][C:5]1[O:9][N:8]=[C:7]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[CH:16]=[N:15][CH:14]=[CH:13]3)[CH:6]=1.[C:28]1([CH2:34]CC#N)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>C(#N)C>[NH2:1][C@@H:2]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:3][NH:4][C:5]1[O:9][N:8]=[C:7]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[CH:16]=[N:15][CH:14]=[CH:13]3)[C:6]=1[CH2:34][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: N[C@H](CNc1cc(-c2ccc3cnccc3c2)no1)Cc1ccc(Cl)cc1
Reactant: N#CCCc1ccccc1
Solvent: CC#N
Product: N[C@H](CNc1onc(-c2ccc3cnccc3c2)c1Cc1ccccc1)Cc1ccccc1

Procedure:
This compound was synthesized in an analogous manner to N-((S)-2-amino-3-(4-chlorophenyl)propyl)-3-(isoquinolin-6-yl)isoxazol-5-amine starting with commercial available 3-phenylpropionitrile (commercially available from Acros Organics Order Number 17399) instead of acetonitrile. MS m/z: 435 (M+1); 1H NMR (400 MHz, CD3OD) δ ppm 9.43 (br s, 1H), 8.50 (br s, 1H), 8.23 (d, J=8.6, 1H), 8.06 (s, 1H), 7.89 (d, J=9.0, 1H), 7.87 (d, J=9.8, 1H), 7.15-7.42 (m, 10H), 3.89 (s, 2H), 3.70 (m, 1H), 3.57-3.62 (m, 2H), 3.02 (d, J=7.04 Hz, 2H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)([C:14](O)=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH3:23]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)([C:14]([NH2:23])=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: N
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)(c2cccnc2)CC1
Product: CC(C)(C)OC(=O)N1CCC(C(N)=O)(c2cccnc2)CC1

Procedure:
Prepare by the method of example 20.8 using 1-tert-butoxycarbonyl-4-(pyridin-3-yl)-piperidine-4-carboxylic acid (4.0 mmol) and NH3 (gas). Purify to give the title compound.
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]([CH3:10])([CH2:7][O:8][CH3:9])[CH2:5][OH:6].IC.[CH3:13]CO>CCOCC>[CH3:9][O:8][CH2:7][C:4]([NH2:3])([CH2:5][O:6][CH3:13])[CH3:10]
Reactant: CCO
Reactant: COCC(C)(N)CO
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: CCOCC
Product: COCC(C)(N)COC
Reaction time: 1 h
Yield: 68.3 %

Procedure:
To a 3-necked 3 L RB flask equipped with overhead stirrer, condenser and N2 inlet line was added NaH (Morton Thiokol, Inc. - Alfa Products, 60% in mineral oil, 44 g, 1.1 mol). After washing with hexane (3×200 mL), dry THF (1.1 L) was added to the flask. After cooling to 0°, 2-amino-3-methoxy-2-methyl-1-propanol (61C, 119.16 g, 1.0 mol) was added dropwise to the flask at such a rate that the reaction temperature remained below 30°. The resulting slurry was cooled to 0°. Iodomethane (Aldrich, 141.94 g, 1.0 mol, 62.25 mL) was added dropwise to the mixture at such a rate that the reaction temperature remained below 30°. After the mixture was stirred for 1 h, EtOH (25 mL) was added to quench the reaction. The volume of the reaction was reduced to 200 mL. This material was diluted to 2 L with Et2O, filtered and the solvent removed. Fractional distillation of this material gave 91.02 g (68.3% yield of 1,1-bis-(methoxymethyl)ethylamine, bp 146°-149°, (C,H,N).
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[CH:9]=[CH:10][C:11]([O:16][CH3:17])=[C:12]([CH:15]=1)[CH:13]=O.[C:18]([O:22][C:23](=[O:33])[N:24]([CH:26]1[CH2:31][CH2:30][CH:29]([NH2:32])[CH2:28][CH2:27]1)[CH3:25])([CH3:21])([CH3:20])[CH3:19]>>[C:18]([O:22][C:23](=[O:33])[N:24]([CH:26]1[CH2:27][CH2:28][CH:29]([NH:32][CH2:13][C:12]2[CH:15]=[C:8]([C:7]3[CH:6]=[CH:5][N:4]=[CH:3][C:2]=3[F:1])[CH:9]=[CH:10][C:11]=2[O:16][CH3:17])[CH2:30][CH2:31]1)[CH3:25])([CH3:21])([CH3:19])[CH3:20]
Reactant: CN(C(=O)OC(C)(C)C)C1CCC(N)CC1
Reactant: COc1ccc(-c2ccncc2F)cc1C=O
Product: COc1ccc(-c2ccncc2F)cc1CNC1CCC(N(C)C(=O)OC(C)(C)C)CC1

Procedure:
Following the synthetic protocol described in Method C′; {4-[5-(3-Fluoro-pyridin-4-yl)-2-methoxy-benzylamino]-cyclohexyl}-methyl-carbamic acid tert-butyl ester is prepared starting from 5-(3-Fluoro-pyridin-4-yl)-2-methoxy-benzaldehyde and (4-Amino-cyclohexyl)-methyl-carbamic acid tert-butyl ester. The desired product is isolated in 67%.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][N:9]2[C:21]3[CH2:20][N:19]([C:22]4[N:27]=[CH:26][C:25]([C:28](O)=[O:29])=[CH:24][N:23]=4)[CH2:18][CH2:17][C:16]=3[C:15]3[C:10]2=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[NH2:61][O:62][CH:63]1[CH2:68][CH2:67][CH2:66][CH2:65][O:64]1>C(Cl)Cl>[O:64]1[CH2:65][CH2:66][CH2:67][CH2:68][CH:63]1[O:62][NH:61][C:28]([C:25]1[CH:24]=[N:23][C:22]([N:19]2[CH2:18][CH2:17][C:16]3[C:15]4[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=4)[N:9]([CH2:8][CH2:7][N:1]4[CH2:2][CH2:3][O:4][CH2:5][CH2:6]4)[C:21]=3[CH2:20]2)=[N:27][CH:26]=1)=[O:29]
Reactant: NOC1CCCCO1
Reactant: O=C(O)c1cnc(N2CCc3c(n(CCN4CCOCC4)c4ccccc34)C2)nc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NOC1CCCCO1)c1cnc(N2CCc3c(n(CCN4CCOCC4)c4ccccc34)C2)nc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 23.3 %

Procedure:
To a solution of 2-[9-(2-morpholin-4-ylethyl)-1,3,4,9-tetrahydro-2H-b-carbolin-2-yl]pyrimidine-5-carboxylic acid (160 mg, 0.39 mmol) in DCM (20 mL) were added EDCI (170 mg, 0.88 mmol), HOBT (90 mg, 0.66 mmol), DIEA (152 mg, 1.17 mmol) and NH2OTHP (47 mg, 0.4 mmol) under nitrogen atmosphere. The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure and the residue obtained was purified by column chromatography using EtOAc in hexanes (50%) to obtain N-(tetrahydro-2H-pyran-2-yloxy)-2-[9-(2-morpholin-4-ylethyl)-1,3,4,9-tetrahydro-2H-b-carbolin-2-yl]pyrimidine-5-carboxamide (46 mg, 23% yield). 1H NMR (200 MHz, CDCl3) ppm: 8.75 (s, 2H), 7.50 (d, 1H, J=7.0 Hz), 7.30 (m, 1H), 7.16 (m, 2H), 5.13 (s, 2H), 5.04 (s, 1H), 4.24 (m, 4H), 4.00 (m, 1H), 3.69 (m, 4H), 2.91 (m, 2H), 2.70 (m, 2H), 2.49 (m, 4H), 1.85 (m, 2H), 1.47 (m, 5H); m/e=506 (M+1).
Reaction SMILES: [O:1]1[CH2:3][C@@H:2]1[CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]2[S:13][C:12]([CH3:14])=[N:11][C:10]=2[CH:15]=1.[NH:16]1[CH2:21][CH2:20][C:19](=[O:22])[CH2:18][CH2:17]1.[Cl-].C(N(C(C)C)CC)(C)C>C(O)C>[OH:1][C@@H:2]([CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]2[S:13][C:12]([CH3:14])=[N:11][C:10]=2[CH:15]=1)[CH2:3][N:16]1[CH2:21][CH2:20][C:19](=[O:22])[CH2:18][CH2:17]1
Reactant: O=C1CCNCC1
Reactant: Cc1nc2cc(OC[C@H]3CO3)ccc2s1
Agent: [Cl-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: Cc1nc2cc(OC[C@H](O)CN3CCC(=O)CC3)ccc2s1

Procedure:
To a solution of 5-[((2R)oxiran-2-yl)methoxy]-2-methylbenzothiazole (2.0 g, 9.25 mmol) and piperidin-4-one, chloride (1.25 g, 9.25 mmol) in ethanol was added diisopropylethylamine (1.6 ml, 9.0 mmol). The mixture was heated to reflux for 16 hours. The solvent was removed and the residue purified by column chromatography (10:1 DCM:MeOH) followed by preparative TLC (10:1 DCM:MeOH) to yield 1-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperidin-4-one.
Reaction SMILES: F[C:2]1[CH:14]=[C:13]([NH2:15])[CH:12]=[CH:11][C:3]=1[CH:4]=[CH:5][C:6]([O:8][CH2:9][CH3:10])=[O:7].Br[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32].C(=O)([O-])[O-].[K+].[K+]>CN(C)P(N(C)C)(N(C)C)=O.O>[CH2:32]([NH:15][C:13]1[CH:12]=[CH:11][C:3]([CH:4]=[CH:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:2][CH:14]=1)[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH3:17]
Reactant: CCOC(=O)C=Cc1ccc(N)cc1F
Reactant: CCCCCCCCCCCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCCCCCCCCCCCCCCCNc1ccc(C=CC(=O)OCC)cc1
Temperature: 60 °C

Procedure:
A mixture of ethyl 2-fluoro-4-aminocinnamate, one equivalent of 1-bromohexadecane and one equivalent of anhydrous potassium carbonate in hexamethylphosphoramide is heated for 20 hours at 60° C. The mixture is then cooled, diluted with water and extracted with ether. The combined ether extracts are dried, filtered and evaporated to provide ethyl 4-hexadecylaminocinnamate. The ester is hydrolyzed with sodium hydroxide in a 1:9 water:ethanol solution at steam bath temperatures for 10 hours. The hot solution is then acidified with acetic acid, cooled and filtered and the solid is washed with water. Recrystallization from chloroform yields 2-fluoro-4-(hexadecylamino)cinnamic acid.
Reaction SMILES: [OH:1][N:2]=[C:3]([C:5]1[C:9]([NH:10][CH2:11][CH2:12][O:13][CH3:14])=[N:8][O:7][N:6]=1)N.[ClH:15].[Cl-].[Na+].N([O-])=O.[Na+]>C(OCC)(=O)C.O>[OH:1][N:2]=[C:3]([Cl:15])[C:5]1[C:9]([NH:10][CH2:11][CH2:12][O:13][CH3:14])=[N:8][O:7][N:6]=1
Reactant: Cl
Reactant: COCCNc1nonc1C(N)=NO
Agent: O=N[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: COCCNc1nonc1C(Cl)=NO
Temperature: 5.5 °C
Reaction time: 2 h
Yield: 100.1 %

Procedure:
At room temperature N′-hydroxy-4-[(2-methoxyethyl)amino]-1,2,5-oxadiazole-3-carboximidamide (50.0 g, 0.226 mol) was dissolved in 6.0 M hydrochloric acid aqueous solution (250 mL, 1.5 mol). Sodium chloride (39.5 g, 0.676 mol) was added followed by water (250 mL) and ethyl acetate (250 mL). At 3-5° C. a previously prepared aqueous solution (100 mL) of sodium nitrite (15.0 g, 0.217 mol) was added slowly over 1 hr. The reaction was stirred at 3-8° C. for 2 hours and then room temperature over the weekend. LCMS indicated reaction completed. The reaction solution was extracted with ethyl acetate (2×200 mL). The combined ethyl acetate solution was dried over sodium sulfate and concentrated to give the desired product (49.9 g, 126%) as a crude white solid. LCMS for C6H10ClN4O3 (M+H)+: m/z=221.0. 1H NMR (400 MHz, DMSO-d6): δ 13.43 (s, 1H), 5.85 (t, J=5.6 Hz, 1H), 3.50 (t, J=5.6 Hz, 2H), 3.37 (dd, J=10.8, 5.6 Hz, 2H), 3.25 (s, 3H).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[C:11]([I:12])=[C:10](S(C)=O)[N:9]=[C:8]([NH2:16])[N:7]=1.[CH3:17][NH2:18]>C1COCC1.C(O)C>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:7]=[C:8]([NH2:16])[N:9]=[C:10]([NH:18][CH3:17])[C:11]=1[I:12]
Reactant: CS(=O)c1nc(N)nc(-c2ccco2)c1I
Reactant: CN
Solvent: CCO
Solvent: C1CCOC1
Product: CNc1nc(N)nc(-c2ccco2)c1I

Procedure:
From 4-furan-2-yl-5-iodo-6-methanesulfinyl-pyrimidin-2-yl-amine and methylamine in THF/ethanol. ES-MS m/e (%): 317 (M+H+, 100).
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([C:5]2[CH:6]=[N:7][CH:8]=[CH:9][CH:10]=2)[CH2:2]1.C(N(C(C)C)CC)(C)C.[N:20]([C:23]1[CH:32]=[CH:31][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][CH:24]=1)=[C:21]=[O:22]>ClCCl>[N:7]1[CH:8]=[CH:9][CH:10]=[C:5]([CH:3]2[CH2:4][N:1]([C:21]([NH:20][C:23]3[CH:32]=[CH:31][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][CH:24]=3)=[O:22])[CH2:2]2)[CH:6]=1
Reactant: COC(=O)c1ccc(N=C=O)cc1
Reactant: c1cncc(C2CNC2)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)c1ccc(NC(=O)N2CC(c3cccnc3)C2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a 20 mL vial was added 3-(azetidin-3-yl)pyridine, bistrifluoroacetic acid (75 mg, 0.207 mmol) and diisopropylethylamine (0.109 ml, 0.622 mmol) in dichloromethane (2072 μl. Methyl 4-isocyanatobenzoate (47.7 mg, 0.269 mmol) was added, and the mixture was stirred at room temperature for 2 hours and concentrated by rotary evaporation. The residue was purified by regular phase chromatography to give the title compound. 1H NMR (300 MHz, DMSO-d6) δ 8.90 (s, 1H), 8.57 (d, J=2.1 Hz, 1H), 8.48 (dd, J=4.8, 1.6 Hz, 1H), 7.91-7.82 (m, 3H), 7.71-7.64 (m, 2H), 7.41 (ddd, J=7.9, 4.7, 0.8 Hz, 1H), 4.42 (t, J=8.4 Hz, 2H), 4.05-3.96 (m, 2H), 3.89 (dt, J=8.1, 7.0 Hz, 1H), 3.81 (s, 1H); MS (ESI(+)) m/e 312 (M+H).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([I:16])=[CH:12][C:11]=2[F:17])[C:5]([NH2:18])=[CH:4][CH:3]=1.[Cl:19][C:20]1[N:24]([CH3:25])[N:23]=[C:22]([CH3:26])[C:21]=1[S:27](Cl)(=[O:29])=[O:28]>>[Cl:19][C:20]1[N:24]([CH3:25])[N:23]=[C:22]([CH3:26])[C:21]=1[S:27]([NH:18][C:5]1[CH:4]=[CH:3][C:2]([F:1])=[C:7]([F:8])[C:6]=1[NH:9][C:10]1[CH:15]=[CH:14][C:13]([I:16])=[CH:12][C:11]=1[F:17])(=[O:28])=[O:29]
Reactant: Cc1nn(C)c(Cl)c1S(=O)(=O)Cl
Reactant: Nc1ccc(F)c(F)c1Nc1ccc(I)cc1F
Product: Cc1nn(C)c(Cl)c1S(=O)(=O)Nc1ccc(F)c(F)c1Nc1ccc(I)cc1F

Procedure:
According to the general procedure B, 5,6-difluoro-N1-(2-fluoro-4-iodophenyl)benzene-1,2-diamine (0.182 mmol) was reacted with 5-chloro-1,3-dimethyl-1H-pyrazole-4-sulfonyl chloride (0.5 mmol) to obtain 5-chloro-N-(3,4-difluoro-2-(2-fluoro-4-iodophenylamino) phenyl)-1,3-dimethyl-1H-pyrazole-4-sulfonamide. 1H NMR (300 MHz, CDCl3)) δ 2.1 (s, 3H), 3.6 (s, 3H), 5.8 (s, 1H), 5.95 (dt, 1H), 7.0 (q, 1H), 7.2 (d, 1H), 7.3 (m, 2H), 7.4 (dd, 1H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([CH2:15][C:16]([C:18]2[CH:23]=[CH:22][C:21]([CH2:24]Br)=[C:20]([F:26])[CH:19]=2)=[O:17])[C:11](=[O:27])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:28][C:29]1([CH3:35])[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1>>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([CH2:15][C:16]([C:18]2[CH:23]=[CH:22][C:21]([CH2:24][N:32]3[CH2:33][CH2:34][C:29]([OH:28])([CH3:35])[CH2:30][CH2:31]3)=[C:20]([F:26])[CH:19]=2)=[O:17])[C:11](=[O:27])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1(O)CCNCC1
Reactant: O=C(Cn1ccc(OCc2ccccc2)cc1=O)c1ccc(CBr)c(F)c1
Product: CC1(O)CCN(Cc2ccc(C(=O)Cn3ccc(OCc4ccccc4)cc3=O)cc2F)CC1

Procedure:
4-Benzyloxy-1-{2-[3-fluoro-4-(4-hydroxy-4-methyl-piperidin-1-ylmethyl)-phenyl]-2-oxo-ethyl}-1H-pyridin-2-one is prepared as example 1.1b from 105 mg (0.24 mmol) 4-benzyloxy-1-[2-(4-bromomethyl-3-fluoro-phenyl)-2-oxo-ethyl]-1H-pyridin-2-one (preparation 16 h) and 84 mg (0.73 mmol) 4-hydroxy-4 methyl-piperidine.
Reaction SMILES: [C:1]([C:3]1[C:8](=[O:9])[CH:7]=[CH:6][N:5]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=2)[N:4]=1)#[CH:2].[OH:20][N:21]=[C:22](Cl)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.CCN(CC)CC>C1COCC1>[C:23]1([C:22]2[C:1]([C:3]3[C:8](=[O:9])[CH:7]=[CH:6][N:5]([C:10]4[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=4)[N:4]=3)=[CH:2][O:20][N:21]=2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: ON=C(Cl)c1ccccc1
Reactant: C#Cc1nn(-c2cccc(C(F)(F)F)c2)ccc1=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=c1ccn(-c2cccc(C(F)(F)F)c2)nc1-c1conc1-c1ccccc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 55 %

Procedure:
To a solution of 3-ethynyl-1-[3-(trifluoromethyl)phenyl]pyridazin-4(1H)-one (104 mg, 0.391 mmol) and N-hydroxybenzenecarboximidoyl chloride (122 mg, 0.782 mmol) in THF (5 mL) was added Et3N (0.108 mL, 0.782 mmol) at 0° C. The suspension was stirred at room temperature for 14 h. The reaction was quenched with water. The mixture was extracted with AcOEt, washed with brine, dried over Na2SO4, filtered, concentrated in vacuo, purified by column chromatography on silica gel (hexane/AcOEt=50/50 to 0/100) and on basic silica gel (hexane/AcOEt=50/50 to 43/57) and crystallized with AcOEt/heptane to yield the title compound (82.4 mg, 55% yield) as a white solid: mp 217-219° C. 1H NMR (DMSO-d6, 300 MHz): δ ppm 6.87 (1H, d, J=8.0 Hz), 7.50-7.59 (3H, m), 7.86-7.92 (2H, m), 7.94-8.02 (3H, m), 8.15-8.26 (2H, m), 9.09 (1H, d, J=8.2 Hz). Anal. Calcd for C20H12F3N3O2: C, 62.67; H, 3.16; N, 10.96. Found: C, 62.60; H, 3.19; N, 10.95.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.[Cl:12][C:13]1[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=1[S:20](Cl)(=[O:22])=[O:21]>CN(C1C=CN=CC=1)C>[Cl:12][C:13]1[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=1[S:20]([NH:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2)(=[O:22])=[O:21]
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1Cl
Reactant: Nc1cccc2cccnc12
Agent: CN(C)c1ccncc1
Product: O=S(=O)(Nc1cccc2cccnc12)c1ccc(Cl)cc1Cl
Yield: 103.4 %

Procedure:
In the similar fashion using route 14 general procedure 27, 8-aminoquinoline (100 mg, 0.69 mmol), 2,4-dichlorobenzenesulfonyl chloride (200 mg, 0.83 mmol) and DMAP (cat.) gave the title compound (252 mg, 100%) after purification by column chromatography with DCM as the eluent.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[C:9]2[CH:12]2[CH2:17][CH2:16][CH2:15][N:14]([CH3:18])[CH2:13]2)=[CH:4][CH:3]=1.Cl[C:20]1[C:25]([N+:26]([O-:28])=[O:27])=[CH:24][CH:23]=[CH:22][N:21]=1.N1C(C)=CC(C)=CC=1C>CN(C)C=O>[N+:26]([C:25]1[C:20]([NH:1][C:2]2[CH:11]=[C:10]3[C:5]([CH:6]=[CH:7][CH:8]=[C:9]3[CH:12]3[CH2:17][CH2:16][CH2:15][N:14]([CH3:18])[CH2:13]3)=[CH:4][CH:3]=2)=[N:21][CH:22]=[CH:23][CH:24]=1)([O-:28])=[O:27]
Reactant: CN1CCCC(c2cccc3ccc(N)cc23)C1
Reactant: O=[N+]([O-])c1cccnc1Cl
Solvent: Cc1cc(C)nc(C)c1
Solvent: CN(C)C=O
Product: CN1CCCC(c2cccc3ccc(Nc4ncccc4[N+](=O)[O-])cc23)C1

Procedure:
A mixture of 7-amino-1-(1-methyl-3-piperidinyl)-naphthalene (0.252 g, 1.05 mmol from Example 61 ), 2-chloro-3-nitropyridine (0.333 g, 2.1 mmol) and collidine (0.139 mL, 1.05 mmol) in dimethylformamide (10 mL) was refluxed overnight. The reaction was concentrated at reduced pressure and the residue was taken up in methylene chloride. The organic phase was washed with 0.5N sodium hydroxide and brine, dried, concentrated onto silica gel and flash chromatographed (1×3 inches). Elution proceeded as follows: 50% ethyl acetate/hexane (500 mL) unweighed forrun; 75% ethyl acetate/hexane (400 mL) and ethyl acetate (100 mL) 0.151 g (51%) of red oil product. A sample crystallized from ether gave the title compound as red crystals. mp 107°-108° C. Analysis calculated for C21H22N4O2 ; C, 69.59; H, 6.12; N, 15.46. Found: C, 69.30; H, 5.91; N, 14.92.
Reaction SMILES: CON(C)[C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:12]=[C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]#[N:24])[CH:14]=[CH:15][CH:16]=2)[CH:10]=1)=[O:5].Br[C:27]1[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=1>>[F:33][C:30]1[CH:31]=[CH:32][C:27]([C:4]([C:6]2[N:7]=[CH:8][N:9]([C:11]3[CH:12]=[C:13]([C:17]4[C:18]([C:23]#[N:24])=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH:14]=[CH:15][CH:16]=3)[CH:10]=2)=[O:5])=[CH:28][CH:29]=1
Reactant: CON(C)C(=O)c1cn(-c2cccc(-c3ccccc3C#N)c2)cn1
Reactant: Fc1ccc(Br)cc1
Product: N#Cc1ccccc1-c1cccc(-n2cnc(C(=O)c3ccc(F)cc3)c2)c1

Procedure:
This compound is prepared by method C using compound 12d and 1-bromo-4-fluorobenzene.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[NH:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[CH3:20][O:21][CH2:22][C:23](O)=O>>[CH3:20][O:21][CH2:22][C:23]1[N:12]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:11]2[C:10]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[N:4]=[CH:3][C:2]=2[N:1]=1
Reactant: Nc1cnc2ccccc2c1NCc1ccccc1
Reactant: COCC(=O)O
Product: COCc1nc2cnc3ccccc3c2n1Cc1ccccc1

Procedure:
Using the general method of Example 91, 3-amino-4-(phenylmethylamino)quinoline (4.0 g, 16 mmol) was reacted with methoxyacetic acid (3.7 mL) to provide 4.4 g of the desired product as a solid. The structure was confirmed by nuclear magnetic resonance spectroscopy.