Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:9](OCCCC)(=O)[CH:10]=C.C>>[CH:2]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]=[CH2:10])=[CH2:1]
Reactant: C=CC(=O)OCCCC
Reactant: C=Cc1ccccc1
Agent: C
Product: C=Cc1ccccc1C=C

Procedure:
A monomer composition for core consisting of 78 parts of styrene and 22 parts of n-butyl acrylate (giving a copolymer having a calculated glass transition temperature of 50° C.), 7 parts of carbon black (`Printex 150T` trade name; produced by Degussa AG), 1 part of charge control agent (`Aizen Spilon Black TRH` trade name, produced by HODOGAYA Chemical Co.), 0.3 part of divinylbenzene, 0.8 part of poly-methacrylate macro-monomer (`AA6` trade name, glass transition temperature of 94° C., produced by TOA GOUSEI Chemical Industries Co., Ltd.), and 10 parts of penta-erythritol-tetra-stearate were dispersed with a homo mixer(TK Type, produced by TOKUSHUKIKAKOU Co.) of 12,000 rpm to obtain a core monomer mixture.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:9]=[C:10]([C:14](=[O:23])[CH2:15]CN3CCOCC3)[CH:11]=[CH:12][CH:13]=2)[CH:5]=[CH:4][N:3]=1.[C:24](N)(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[C:14]([C:10]1[CH:9]=[C:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:1][C:24](=[O:31])[C:25]3[CH:30]=[CH:29][C:28]([C:6]([CH3:8])([CH3:7])[CH3:5])=[CH:27][CH:26]=3)[CH:7]=2)[CH:13]=[CH:12][CH:11]=1)(=[O:23])[CH3:15]
Reactant: Nc1cc(-c2cccc(C(=O)CCN3CCOCC3)c2)ccn1
Reactant: NC(=O)c1ccccc1
Product: CC(=O)c1cccc(-c2ccnc(NC(=O)c3ccc(C(C)(C)C)cc3)c2)c1

Procedure:
According to the same procedure for the preparation of 1-[3-(2-Amino-pyridin-4-yl)-phenyl]-3-morpholin-4-yl-propan-1-one, 4-tert-Butyl-N-{4-3-(3-morpholin-4-yl-propionyl)-phenyl]-pyridin-2-yl}-benzamide (12 mg, 30%) was obtained from N-[4-(3-Acetyl-phenyl)-pyridin-2-yl]-4-tert-butyl-benzamide (36 mg, 0.1 mmol). MS: m/z 472.3 [MH+].
Reaction SMILES: [N:1]([O-])=O.[Na+].[NH2:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][NH:13][S:14]([CH3:17])(=[O:16])=[O:15])=[CH:8][CH:7]=1.C([O-])(=O)C.[Na+].S([O-])([O-])=O.[Na+].[Na+].[ClH:29]>O>[ClH:29].[NH:5]([C:6]1[CH:11]=[CH:10][C:9]([CH2:12][NH:13][S:14]([CH3:17])(=[O:16])=[O:15])=[CH:8][CH:7]=1)[NH2:1]
Reactant: CS(=O)(=O)NCc1ccc(N)cc1
Reactant: O=N[O-]
Agent: CC(=O)[O-]
Agent: Cl
Agent: O=S([O-])[O-]
Solvent: O
Product: CS(=O)(=O)NCc1ccc(NN)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of sodium nitrite (0.3 g) in water (3 ml) was added, over 15 min. to a stirred suspension of N-[(4-aminophenyl)methyl]methanesulphonamide (0.7 g ) in concentrated hydrochloric acid (3 ml) and water (4 ml) keeping the temperature below 0°. After 1 h, the resulting suspension was added, over 1 min. to a stirred, ice-cooled solution of sodium acetate (3.2 g) and sodium sulphite (1.8 g) in water (20 ml) containing ice (5 g). The orange mixture was stirred for a further 30 min. then at room temperature for 1.5 h, and then warmed on the steam bath for 20 min. The mixture was cooled, concentrated hydrochloric acid (15 ml) added and the mixture warmed on the steam bath for 0.5 h. The solvent was evaporated in vacuo and the residue re-evaporated with absolute ethanol (2×50 ml). The residue was extracted with absolute ethanol (50 ml). The extract was evaporated in vacuo and the residue re-evaporated with ethanol (20 ml) to leave a brown oil, which partially crystallised after standing overnight. Ethanol (1 ml) was added and the title compound filtered off as light tan crystals (0.1 g) m.p. 165°-70° (dec.)
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][CH:5]([C:8]([OH:10])=O)[CH2:4][CH2:3]1.Cl.[CH3:12][NH:13][O:14][CH3:15].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>ClCCl.O>[OH:1][CH:2]1[CH2:3][CH2:4][CH:5]([C:8]([N:13]([O:14][CH3:15])[CH3:12])=[O:10])[CH2:6][CH2:7]1
Reactant: O=C(O)C1CCC(O)CC1
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CON(C)C(=O)C1CCC(O)CC1
Yield: 69.8 %

Procedure:
4-Hydroxycyclohexanecarboxylic acid (10.0 g, 69.4 mmol) and N,O-dimethylhydroxylamine hydrochloride (8.80 g, 90.2 mmol) in dichloromethane (500 mL) was stirred with 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (17.3 g, 90.2 mmol), 1-hydroxybenzotriazole (12.2 g, 90.2 mmol) and N,N-diisopropylethylamine (24.2 mL, 139 mmol) at room temperature for one day. After addition of water, the reaction mixture was extracted with chloroform, and the organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=1/1 (v/v)→ethyl acetate) to give the title compound as a yellow oil (9.07 g, yield 70%).
Reaction SMILES: C(N(C(C)C)C(C)C)C.[F:10][C@H:11]1[CH2:28][C@@:26]2([CH3:27])[C@@H:22]([CH2:23][CH2:24][C@@H:25]2[OH:29])[C@H:21]2[C@H:12]1[C:13]1[CH:14]=[CH:15][C:16]([OH:56])=[CH:17][C:18]=1[CH2:19][C@H:20]2[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][N:35]([CH3:55])[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][C:42]([F:54])([F:53])[C:43]([F:52])([F:51])[C:44]([F:50])([F:49])[C:45]([F:48])([F:47])[F:46]>CS(C)=O.C(OCC)(=O)C>[F:10][C@H:11]1[CH2:28][C@@:26]2([CH3:27])[C@@H:22]([CH2:23][CH2:24][C:25]2=[O:29])[C@H:21]2[C@H:12]1[C:13]1[CH:14]=[CH:15][C:16]([OH:56])=[CH:17][C:18]=1[CH2:19][C@H:20]2[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][N:35]([CH3:55])[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][C:42]([F:53])([F:54])[C:43]([F:51])([F:52])[C:44]([F:49])([F:50])[C:45]([F:46])([F:47])[F:48]
Reactant: CN(CCCCCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)CCCCC[C@@H]1Cc2cc(O)ccc2[C@@H]2[C@@H]1[C@@H]1CC[C@H](O)[C@@]1(C)C[C@@H]2F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CN(CCCCCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)CCCCC[C@@H]1Cc2cc(O)ccc2[C@@H]2[C@@H]1[C@@H]1CCC(=O)[C@@]1(C)C[C@@H]2F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
1.5 ml of ethyldiisopropylamine is added in drops at 10° C. to a solution of 1.23 g of pyridine sulfur trioxide complex in 10 ml of dried dimethyl sulfoxide. Then, 1.72 g of 11β-fluoro-7α-{5-[methyl(7,7,8,8,9,9,10,10,10-nonafluorodecyl)amino]pentyl}-estra-1,3,5(10)-triene-3,17β-diol (compound No. Z9) as well as another 10 ml of dried dimethyl sulfoxide are added and stirred for 30 minutes at room temperature. Then, it is diluted with ethyl acetate, washed with saturated sodium bicarbonate solution, water and sodium chloride solution, dried on sodium sulfate, evaporated to the dry state in a vacuum and chromatographed on silica gel with dichloromethane/methanol. 11β-Fluoro-7α-{5-[methyl(7,7,8,8,9,9,10,10,10-nonafluorodecyl)amino]pentyl} estra-1,3,5(10)-trien-3-ol-17-one, [α]D=+58.2°, in chloroform, is obtained.
Reaction SMILES: C1N2CN3CN(C2)CN1C3.CCCCCCC=CCCC.[CH3:22][C:23]([CH3:43])([CH3:42])[CH2:24][C:25](=[O:41])[CH2:26][C@H:27]([C:31]1[O:32][CH2:33][C@@H:34]([C:36]([O:38][CH2:39][CH3:40])=[O:37])[N:35]=1)[CH2:28][CH:29]=[CH2:30]>ClCCl.[Cu](Br)Br>[CH3:42][C:23]([CH3:22])([CH3:43])[CH2:24][C:25](=[O:41])[CH2:26][C@H:27]([C:31]1[O:32][CH:33]=[C:34]([C:36]([O:38][CH2:39][CH3:40])=[O:37])[N:35]=1)[CH2:28][CH:29]=[CH2:30]
Reactant: C=CC[C@H](CC(=O)CC(C)(C)C)C1=N[C@H](C(=O)OCC)CO1
Agent: Br[Cu]Br
Agent: C1N2CN3CN1CN(C2)C3
Agent: CCCC=CCCCCCC
Solvent: ClCCl
Product: C=CC[C@H](CC(=O)CC(C)(C)C)c1nc(C(=O)OCC)co1
Temperature: 0 °C
Reaction time: 18 h
Yield: 66.3 %

Procedure:
A suspension of copper (II) bromide (50.6 g, 226.6 mmol) and hexamethylenetetramine (31.6 g, 225.5 mmol) in dichloromethane (250 ml), under a nitrogen atmosphere, was treated with 1,8-diazabicyco[5.4.0]undec-7-ene (33 ml, 220.7 mmol). The mixture was cooled to 0° C. and treated with a solution of ethyl (4S)-2-[(1R)-1-(4,4-dimethyl-2-oxopentyl)-3-butenyl]4,5-dihydro-1,3-oxazole-4-carboxylate (Preparation 114) (17.6 g, 56.4 mmol) in dichloromethane (250 ml) via a cannula. The reaction mixture was allowed to warm to room temperature and stirred for 18 hours. The solvent was removed under reduced pressure and the residue was azeotroped with ethyl acetate. The residue was dissolved in ethyl acetate and washed with a 1:1 mixture of 0.880 ammonia solution: saturated aqueous ammonium chloride solution (×2), water, hydrochloric acid (2M) (×3), saturated aqueous sodium hydrogen carbonate solution and brine. The solvent was removed under reduced pressure. The oil was purified by column chromatography on silica gel eluting with a solvent gradient of 95:5 (hexane:diethylether) gradually changing to 50:50 (hexane:diethylether) to afford the title compound as a colourless oil (11.5 g).
Reaction SMILES: N1CCOCC1.[O:7]1[CH:11]=[CH:10][C:9]([CH:12]=[O:13])=[CH:8]1.C([Li])(CC)C.[CH3:19][Si:20](Cl)([CH3:22])[CH3:21].Cl>CCCCCC.O1CCCC1.C1CCCCC1>[CH3:19][Si:20]([CH3:22])([CH3:21])[C:11]1[O:7][CH:8]=[C:9]([CH:12]=[O:13])[CH:10]=1
Reactant: C[Si](C)(C)Cl
Reactant: O=Cc1ccoc1
Agent: Cl
Agent: [Li]C(C)CC
Solvent: C1CCCCC1
Solvent: CCCCCC
Solvent: C1CCOC1
Product: C[Si](C)(C)c1cc(C=O)co1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
N-Butyl lithium (a 2.5 M solution in hexane; 28.8 ml, 72 mmol) was added to a solution of morpholine (6.28 ml, 72 mmol) in tetrahydrofuran (700 ml) at -78° under argon. After 20 minutes. 3-furaldehyde (7.0 g, 72 mmol) was added. After another 20 minutes, sec-butyl lithium (a 1.3 M solution in cyclohexane; 55.4 ml, 72 mmol) was added dropwise and stirring continued at -78° for 7 hours before trimethylsilyl chloride (27 ml, 21.6 mmol) was added. Stirring was continued overnight (14 hours) while the cooling bath was allowed to attain room temperature. The solution was poured into ice cold 10% (v/v) hydrochloric acid (200 ml) and after stirring at 0° for 10 minutes, the layers were separated. The aqueous phase was extracted with diethyl ether. All the organic phases were combined, dried (magnesium sulfate) and evaporated down to give a light brown oil, which was purified by flash chromatography on silica using 2% ethyl ether/hexane. Fractions with Rf of about 0.30 (silica, 10% ethyl ether/hexane) on evaporation gave the title aldehyde as a light yellow oil, b.p. 48°-50°/0.25 torr.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:11][CH2:10][C:9]2[C:4](=[C:5]([N:12]3[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]3)[CH:6]=[CH:7][CH:8]=2)[CH2:3]1.C(N(CC)CC)C.[F:26][C:27]([F:38])([F:37])[C:28]1[CH:29]=[C:30]([CH:34]=[CH:35][CH:36]=1)[C:31](Cl)=[O:32]>C(Cl)Cl>[CH3:18][N:15]1[CH2:16][CH2:17][N:12]([C:5]2[CH:6]=[CH:7][CH:8]=[C:9]3[C:4]=2[CH2:3][C@H:2]([NH:1][C:31](=[O:32])[C:30]2[CH:34]=[CH:35][CH:36]=[C:28]([C:27]([F:26])([F:37])[F:38])[CH:29]=2)[CH2:11][CH2:10]3)[CH2:13][CH2:14]1
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1
Reactant: CN1CCN(c2cccc3c2C[C@H](N)CC3)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN1CCN(c2cccc3c2C[C@H](NC(=O)c2cccc(C(F)(F)F)c2)CC3)CC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To an ice-cooled solution of (R)-2-amino-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydronaphthalene (100 mg, 0.42 mmol) and triethylamine (88 μL, 0.63 mmol) in methylene chloride (15 mL) was added dropwise 3-(trifluoromethyl)benzoyl chloride (93 mg, 0.44 mmol) in methylene chloride (5 mL). After the addition, the reaction was allowed to stir at ambient temperature for 15 min and was then washed with water. The phases were separated and the organic phase was dried (Na2SO4), filtered and evaporated in vacuo to give a crude product which was purified on a silica gel column using chloroform/ethanol saturated with NH3 (100:4) as the eluent. Yield: 130 mg (71%) of the title compound as a viscous oil: [α]21D −25° (c 1.0, chloroform); EIMS (70 eV) m/z (relative intensity) 417 (25, M+).
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]([CH2:8]Cl)=[O:7])(=[O:3])[CH3:2].[CH3:10][C:11]1[CH:16]=[CH:15][C:14]([SH:17])=[CH:13][CH:12]=1.C(N(CC)CC)C>COC(C)(C)C>[C:1]([O:4][CH2:5][C:6]([CH2:8][S:17][C:14]1[CH:15]=[CH:16][C:11]([CH3:10])=[CH:12][CH:13]=1)=[O:7])(=[O:3])[CH3:2]
Reactant: CC(=O)OCC(=O)CCl
Reactant: Cc1ccc(S)cc1
Solvent: COC(C)(C)C
Solvent: CCN(CC)CC
Product: CC(=O)OCC(=O)CSc1ccc(C)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97.6 %

Procedure:
To a solution of 1-acetoxy-3-chloroacetone (5.0 g, 33.2 mmol) and 4-methylthiophenol (4.12 g, 33.2 mmol) in tert-butyl methyl ether (100 ml) was slowly added triethylamine (5.1 ml, 36.6 mmol) under ice-cooling. The solution was stirred at room temperature for 30 minutes. The reaction solution was washed with water, saturated aqueous sodium hydrogen carbonate solution, then saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=7:3) to give 7.72 g of 1-acetoxy-3-(4-methylphenylthio)acetone (yield: 97%) as oil.
Reaction SMILES: [CH2:1]([N:3]([CH2:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][NH:23][CH2:24][C:25]2[NH:26][CH:27]=[CH:28][N:29]=2)=[CH:18][CH:17]=1)[CH2:4][CH2:5][CH2:6][CH2:7][N:8]([CH2:12][CH2:13][CH3:14])[CH2:9][CH2:10][CH3:11])[CH3:2].C([BH3-])#N.[Na+].C(O)(=O)C.[CH3:38][N:39]1[CH:43]=[CH:42][N:41]=[C:40]1[CH:44]=O>CO>[CH2:1]([N:3]([CH2:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][N:23]([CH2:24][C:25]2[NH:29][CH:28]=[CH:27][N:26]=2)[CH2:44][C:40]2[N:39]([CH3:38])[CH:43]=[CH:42][N:41]=2)=[CH:18][CH:17]=1)[CH2:4][CH2:5][CH2:6][CH2:7][N:8]([CH2:9][CH2:10][CH3:11])[CH2:12][CH2:13][CH3:14])[CH3:2]
Reactant: CCCN(CCC)CCCCN(CC)Cc1ccc(CNCc2ncc[nH]2)cc1
Reactant: Cn1ccnc1C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CCCN(CCC)CCCCN(CC)Cc1ccc(CN(Cc2ncc[nH]2)Cc2nccn2C)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.2 %

Procedure:
The compound (317 mg) obtained in Example 23-7 was dissolved in anhydrous methanol (6.0 ml) and added with sodium cyanoborohydride (74.8 mg), acetic acid (1.00 ml), and 1-methyl-2-imidazole carboxaldehyde (105 mg) and the whole was stirred overnight at room temperature under a nitrogen atmosphere. After completion of the reaction, the solvent was distilled off and the resultant was dissolved in chloroform and added with a 1 mol/l sodium hydroxide aqueous solution. The whole was stirred for a while and subjected to extraction with chloroform, followed by washing with a saturated aqueous sodium hydrogen carbonate solution and a saturated saline solution. The organic layer obtained was dried with anhydrous sodium sulfate. The solvent was distilled off. The residue was purified through silica gel column chromatography (chloroform/ethyl acetate) and treated with hydrochloric acid, thereby obtaining a hydrochloride (318 mg) of the subject compound as a white solid.
Reaction SMILES: [O-]P([O-])([O-])=O.[K+].[K+].[K+].CO[C:11]1[CH:12]=[CH:13][CH:14]=[C:15](OC)[C:16]=1[C:17]1C=CC=CC=1P(C1CCCCC1)C1CCCCC1.[Cl:38][C:39]1[C:44]([OH:45])=[CH:43][CH:42]=[C:41](I)[N:40]=1.B1(CC2C=CC=CC=2)C2CCCC1CCC2>C1COCC1.CCOC(C)=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:17]([C:41]1[N:40]=[C:39]([Cl:38])[C:44]([OH:45])=[CH:43][CH:42]=1)[C:16]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Reactant: Oc1ccc(I)nc1Cl
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=P([O-])([O-])[O-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Oc1ccc(Cc2ccccc2)nc1Cl
Temperature: 80 °C

Procedure:
A mixture of K3PO4 (12 g, 55 mmol), S-Phos (0.45 g, 1.1 mmol), and palladium acetate (0.21 g, 0.91 mmol) in THF (55 mL) was prepared in a sealed tube. The mixture was treated with 2-chloro-6-iodopyridin-3-ol (4.67 g, 18 mmol) and β-benzyl-9-BBN (0.5M solution in THF, 73 mL, 37 mmol) and heated to 80° C. for 2 h. The crude mixture was diluted with EtOAc, washed with 2M aqueous NaOH, brine, dried over MgSO4, and evaporated. Purification by flash chromatography (EtOAc/hexanes) gave 6-benzyl-2-chloropyridin-3-ol. 1H NMR (300 MHz, CDCl3) δ ppm 7.11-7.41 (m, 6H), 6.94 (d, J=8.2 Hz, 1H), 5.49 (br. s, 1H), 4.06 (s, 2H). MS (ESI) m/z: Calculated; 219.1 Observed: 220.0 (M++1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N:12]1[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]1)[N:8]([NH:19][CH3:20])[CH:7]=[C:6]([C:21]([OH:23])=[O:22])[C:5]2=[O:24].[C:25](OC=O)(=[O:27])C.C(OC(=O)C)(=O)C>C(O)=O>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N:12]1[CH2:13][CH2:14][N:15]([CH3:18])[CH2:16][CH2:17]1)[N:8]([NH:19][CH2:20][CH:25]=[O:27])[CH:7]=[C:6]([C:21]([OH:23])=[O:22])[C:5]2=[O:24]
Reactant: CNn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCN(C)CC3)cc21
Reactant: CC(=O)OC=O
Solvent: CC(=O)OC(C)=O
Solvent: O=CO
Product: CN1CCN(c2cc3c(cc2F)c(=O)c(C(=O)O)cn3NCC=O)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
6-Fluoro-methylamino-1,4-dihydro-7-(4-methyl-1-piperazinyl)-4-oxo-3-quinolinecarboxylic acid (Example 1) (2.7 g) was added to mixed formic-acetic anhydride prepared from 3.9 g of 96% formic acid and 8.3 g of acetic anhydride. The reaction mixture was stirred at room temperature for 16 hours and then concentrated in vacuo. The solid residue was dissolved in 50 ml of water and the solution made basic with pyridine. The solid product was collected by filtration and recrystallized from acetonitrile to give 2.0 g of 6-fluoro-1-(N-formylmethylamino)-1,4-dihydro-7-(4-methyl-1-piperazinyl)-4-oxo-3-quinolinecarboxylic acid, cream-colored powder, m.p. 252°-253° C. (decompn.).
Reaction SMILES: Cl.[Br:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]([CH2:14][C@@H:15]3[CH2:19][CH2:18][NH:17][CH2:16]3)=[N:12][NH:11][C:10]2=[O:20])=[CH:5][CH:4]=1.C(N(CC)C(C)C)(C)C.[C:30](Cl)(=[O:33])[CH2:31][CH3:32]>ClCCl>[Br:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]([CH2:14][C@@H:15]3[CH2:19][CH2:18][N:17]([C:30](=[O:33])[CH2:31][CH3:32])[CH2:16]3)=[N:12][NH:11][C:10]2=[O:20])=[CH:5][CH:4]=1
Reactant: O=c1[nH]nc(C[C@@H]2CCNC2)n1-c1ccc(Br)cc1
Reactant: CCC(=O)Cl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCC(=O)N1CC[C@@H](Cc2n[nH]c(=O)n2-c2ccc(Br)cc2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 61.7 %

Procedure:
In a 4 mL screwcap vial was placed 4-(4-bromophenyl)-5-[(3S)-3-pyrrolidinylmethyl]-2,4-dihydro-3H-1,2,4-triazol-3-one hydrochloride (0.278 mmol). Added to the vial were dichloromethane (2 mL) and N,N-diisopropylethylamine (0.859 mmol). The vial contents were stirred for 1 min, at which point propanoyl chloride (0.319 mmol) was added. The vial was capped and the contents were stirred at room temperature for 2 h. The reaction was quenched with saturated aq NH4Cl (1 mL) and the solution was stirred vigorously for 1 min. The separation of the two layers occurred upon settling of the solution. The organic layer was removed, dried over sodium sulfate, filtered, and concentrated in vacuo. Silica gel chromatography (0-10% methanol:ethyl acetate) was utilized to purify the title compound (65 mg, 61% yield). MS(ES)+ m/e 379.1, 380.8 [M+H]+.
Reaction SMILES: Cl[CH2:2][CH:3]([OH:11])[CH2:4][N:5]1[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1.[NH3:12]>CO>[NH2:12][CH2:2][CH:3]([OH:11])[CH2:4][N:5]1[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1
Reactant: N
Reactant: OC(CCl)CN1CCOCC1
Solvent: CO
Product: NCC(O)CN1CCOCC1
Yield: 91 %

Procedure:
1-Chloro-3-morpholin-4-yl-propan-2-ol (2.0 g, 11 mmol) was treated with the solution of NH3 in methanol (25% by weight, 20 mL) at room temperature. Nitrogen was bulbbed into the reaction mixture to remove the ammonia. Evaporation of solvent gave the hydrogen chloride salt of 1-amino-3-morpholin-4-yl-propan-2-ol (2.0 g, 91%). 1H NMR (DMSO-d6) δ 2.30 (d, J=6.0 Hz, 2H), 2.36 (m, 4H, NCH2), 2.65 (dd, J=8.4, 12.8 Hz, 1H), 2.91 (dd, J=3.6, 12.8 Hz, 1H), 3.52 (m, 4H, OCH2), 3.87 (m, 1H, CH), 5.32 (s, 1H, OH), 8.02 (brs., 3H, NH3+). MS (m/z) 161.1 (M+1).
Reaction SMILES: Cl[CH2:2][C:3]1[N:8]=[C:7]([C:9]([NH:11][C:12]2[CH:20]=[C:19]([C:21]3[CH:29]=[CH:28][CH:27]=[C:26]4[C:22]=3[CH:23]=[CH:24][NH:25]4)[CH:18]=[C:17]3[C:13]=2[CH:14]=[N:15][N:16]3S(C2C=CC=CC=2)(=O)=O)=[O:10])[CH:6]=[CH:5][CH:4]=1.[NH:39]1[CH2:44][CH2:43][S:42](=[O:46])(=[O:45])[CH2:41][CH2:40]1.[I-].[Na+].CCN(C(C)C)C(C)C.Cl>CC#N>[O:45]=[S:42]1(=[O:46])[CH2:43][CH2:44][N:39]([CH2:2][C:3]2[N:8]=[C:7]([C:9]([NH:11][C:12]3[CH:20]=[C:19]([C:21]4[CH:29]=[CH:28][CH:27]=[C:26]5[C:22]=4[CH:23]=[CH:24][NH:25]5)[CH:18]=[C:17]4[C:13]=3[CH:14]=[N:15][NH:16]4)=[O:10])[CH:6]=[CH:5][CH:4]=2)[CH2:40][CH2:41]1
Reactant: O=S1(=O)CCNCC1
Reactant: O=C(Nc1cc(-c2cccc3[nH]ccc23)cc2c1cnn2S(=O)(=O)c1ccccc1)c1cccc(CCl)n1
Agent: Cl
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1cc(-c2cccc3[nH]ccc23)cc2[nH]ncc12)c1cccc(CN2CCS(=O)(=O)CC2)n1
Temperature: 70 °C
Reaction time: 2 h

Procedure:
6-(Chloromethyl)-N-[6-(1H-indol-4-yl)-1-(phenylsulfonyl)-1H-indazol-4-yl]-2-pyridinecarboxamide (75 mg), thiomorpholine 1,1-dioxide (25 mg) and sodium iodide (25 mg) were added to a small round-bottomed flask followed by MeCN (2 ml) and DIPEA (0.048 ml). The reaction mixture was heated at 70° C. for 18 h. The reaction was cooled to RT and the solvent was removed under a stream of nitrogen. The residue was suspended in IPA (2 ml) and 2M NaOH (aq) (1 ml) was added. The mixture was stirred at RT for 2 h, heated to 50° C. for 1 h, then cooled to RT to remain stirring overnight. The reaction was heated to 60° C. for 1 h. Then 2M NaOH (aq) (0.5 ml) was added and reaction was stirred at 60° C. for 2 h. The reaction was neutralised with 2M HCl (aq.) and the solvent was removed in vacuo. The residue was dissolved in DMSO (3 ml), filtered and purified by MDAP (method K). The product-containing fractions were evaporated under a stream of nitrogen and the residues were taken up in methanol, combined and blown down to give title compound, 24 mg.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:16]([O-])=O)=[C:6]([C:8]([C:10]2[N:11]([CH3:15])[N:12]=[N:13][CH:14]=2)=[O:9])[CH:7]=1.Cl>CO>[NH2:16][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][C:6]=1[C:8]([C:10]1[N:11]([CH3:15])[N:12]=[N:13][CH:14]=1)=[O:9]
Reactant: Cn1nncc1C(=O)c1cc(Cl)ccc1[N+](=O)[O-]
Agent: Cl
Solvent: CO
Product: Cn1nncc1C(=O)c1cc(Cl)ccc1N
Temperature: 100 °C

Procedure:
To 31 mg (0.12 mmol) of (5-Chloro-2-nitro-phenyl)-(3-methyl-[1,2,3]triazol4-yl)-methanone in 1.5 ml of methanol were added 0.05 ml of 12M HCl and 200 mg (0.89 mmol) of stannous (II) chloride monohydrate, and the mixture was heated at 100° C. for four hours. The mixture was then cooled to ambient temperature, partitioned between 1M NaOH and ethyl acetate, and the phases were separated. The ethyl acetate phase was washed once each with water and brine, dried over Na2SO4, filtered, and concentrated in vacuo to a solid. The solid was chromatographed to give the title product as a yellow solid.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:18]3[C:13](=[C:14]([CH2:19][N:20]4[CH2:25][CH2:24][N:23](C(OC(C)(C)C)=O)[CH:22]([C:33]([O:35][CH3:36])=[O:34])[CH2:21]4)[CH:15]=[CH:16][CH:17]=3)[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:37]([OH:43])([C:39]([F:42])([F:41])[F:40])=[O:38]>ClCCl>[F:40][C:39]([F:42])([F:41])[C:37]([OH:43])=[O:38].[F:40][C:39]([F:42])([F:41])[C:37]([OH:43])=[O:38].[C:1]1([S:7]([N:10]2[C:18]3[C:13](=[C:14]([CH2:19][N:20]4[CH2:25][CH2:24][NH:23][CH:22]([C:33]([O:35][CH3:36])=[O:34])[CH2:21]4)[CH:15]=[CH:16][CH:17]=3)[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)C1CN(Cc2cccc3c2ccn3S(=O)(=O)c2ccccc2)CCN1C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)C1CN(Cc2cccc3c2ccn3S(=O)(=O)c2ccccc2)CCN1
Reaction time: 1 h

Procedure:
1-tert-Butyl 2-methyl 4-{[1-(phenylsulfonyl)-1H-indol-4-yl]methyl}piperazine-1,2-dicarboxylate (0.013 g, 0.025 mmol, Intermediate 50) was dissolved in dichloromethane (1 mL) and TFA (0.5 mL) was added. The mixture was stirred for 1 h and evaporated. Yield: 16 mg (100%). Colorless oil. MS (electronspray; [M+H]+) m/z 414.6.