Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:3]([O:45][CH3:46])=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]1[S:13][CH:14]=[C:15]([CH:17]([CH3:19])[CH3:18])[N:16]=1)[CH:8]=[C:7]2[O:20][CH:21]1[CH2:38][CH:37]2[CH:23]([C:24](=[O:44])[N:25]([CH3:43])[CH2:26][CH2:27][CH2:28][CH2:29][CH:30]=[CH:31][CH:32]3[C:34]([C:40](O)=[O:41])([NH:35][C:36]2=[O:39])[CH2:33]3)[CH2:22]1.[CH:47]1([S:50]([NH2:53])(=[O:52])=[O:51])[CH2:49][CH2:48]1.ClC1C(OC)=CC=C2C=1N=C(C1SC=C(C(C)C)N=1)C=C2OC1CC2C(C(=O)N(C)CCCCC=CC3C(C(NS(C4CC4)(=O)=O)=O)(NC2=O)C3)C1>>[F:1][C:2]1[C:3]([O:45][CH3:46])=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]1[S:13][CH:14]=[C:15]([CH:17]([CH3:18])[CH3:19])[N:16]=1)[CH:8]=[C:7]2[O:20][CH:21]1[CH2:38][CH:37]2[CH:23]([C:24](=[O:44])[N:25]([CH3:43])[CH2:26][CH2:27][CH2:28][CH2:29][CH:30]=[CH:31][CH:32]3[C:34]([C:40]([NH:53][S:50]([CH:47]4[CH2:49][CH2:48]4)(=[O:52])=[O:51])=[O:41])([NH:35][C:36]2=[O:39])[CH2:33]3)[CH2:22]1
Reactant: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)O)CC5C=CCCCCN(C)C(=O)C4C3)cc(-c3nc(C(C)C)cs3)nc2c1F
Reactant: NS(=O)(=O)C1CC1
Agent: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)NS(=O)(=O)C6CC6)CC5C=CCCCCN(C)C(=O)C4C3)cc(-c3nc(C(C)C)cs3)nc2c1Cl
Product: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)NS(=O)(=O)C6CC6)CC5C=CCCCCN(C)C(=O)C4C3)cc(-c3nc(C(C)C)cs3)nc2c1F

Procedure:
The title compound was prepared from 17-[8-fluoro-2-(4-isopropylthiazole-2-yl)-7-methoxyquinolin-4-yloxy]-13-methyl-2,14-dioxo-3,13-diazatricyclo[13.3.0.04,6]-octadec-7-ene-4-carboxylic acid (73) and cyclopropylsulfonamide following the procedure reported for the preparation of N-[17-[8-chloro-2-(4-isopropylthiazole-2-yl)-7-methoxyquinolin-4-yloxy]-13-methyl-2,14-dioxo-3,13-diazatricyclo[13.3.0.04,6]-octadec-7-ene-4-carbonyl](cyclopropyl) sulfonamide (56): m/z=754 (M+H)+. NMR (CDCl3): 1H NMR (CDCl3): 0.75-1.52 (m, 15H), 1.64-2.05 (m, 4H), 2.77 (m, 1H), 2.41 (m, 2H), 2.59 (m, 2H), 2.92 (m, 2H), 3.04 (s, 3H), 3.19 (m, 1H), 3.40 (m, 2H), 4.07 (s, 3H), 4.60 (m, 1H), 5.05 (t, J=10.5 Hz, 1H), 5.37 (m, 1H), 5.66 (m, 1H), 6.17 (s, 1H), 7.07 (s, 1H), 7.54 (s, 1H), 7.86 (m, 1H), 10.77 (broad s, 1H).
Reaction SMILES: CN(C)C1N=CC([C:9]2[N:10]=[C:11]([CH2:36][CH3:37])[C:12]([NH:17][C@H:18]3[C@@H:22]([O:23][CH2:24][CH3:25])[CH2:21][N:20]([C:26]([O:28][CH2:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[O:27])[CH2:19]3)=[N:13][C:14]=2[CH2:15][CH3:16])=C(C)C=1.[CH3:40][C:41]1[CH:46]=[C:45]([O:47][CH3:48])[CH:44]=[CH:43][C:42]=1B(O)O>>[CH2:36]([C:11]1[C:12]([NH:17][C@H:18]2[C@@H:22]([O:23][CH2:24][CH3:25])[CH2:21][N:20]([C:26]([O:28][CH2:29][C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)=[O:27])[CH2:19]2)=[N:13][C:14]([CH2:15][CH3:16])=[C:9]([C:42]2[CH:43]=[CH:44][C:45]([O:47][CH3:48])=[CH:46][C:41]=2[CH3:40])[N:10]=1)[CH3:37]
Reactant: CCO[C@H]1CN(C(=O)OCc2ccccc2)C[C@H]1Nc1nc(CC)c(-c2cnc(N(C)C)cc2C)nc1CC
Reactant: COc1ccc(B(O)O)c(C)c1
Product: CCO[C@H]1CN(C(=O)OCc2ccccc2)C[C@H]1Nc1nc(CC)c(-c2ccc(OC)cc2C)nc1CC

Procedure:
Following the procedure for the preparation of benzyl (3R,4S)-3-({5-[6-(dimethylamino)-4-methylpyridin-3-yl]-3,6-diethylpyrazin-2-yl}amino)-4-ethoxypyrrolidine-1-carboxylate and but substituting 2-methyl-4-methoxy-phenyl boronic acid provided the title compound as an amorphous solid. 1H NMR (CDCl3) δ 1.04, 1.21, 2.04, 2.40, 2.65, 3.22˜3.26, 3.41, 3.52˜3.68, 3.75, 3.94, 4.03, 4.68, 5.08, 6.70, 6.74, 7.02, 7.28˜7.32; IR (liq.) 2971 (s), 2339 (w), 2166 (w), 2082 (w), 1957 (w), 1708 (s), 1564 (s), 1482 (s), 1420 (s), 1395 (s), 1349 (s), 1242 (s), 1169 (s), 1125 (s), 1096 (s) cm−1 HRMS (ESI) calcd for C30H38N4O4+H1 519.2971. found 519.2974.
Reaction SMILES: [CH3:1][N:2]1[C:6]([OH:7])=[C:5]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[CH:10]=2)[C:4]([CH3:16])=[N:3]1.[Cl:17][C:18]1[N:23]=[C:22](Cl)[CH:21]=[CH:20][N:19]=1.C(=O)([O-])[O-].[K+].[K+].O>C(#N)C>[CH3:1][N:2]1[C:6]([O:7][C:20]2[CH:21]=[CH:22][N:23]=[C:18]([Cl:17])[N:19]=2)=[C:5]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[CH:10]=2)[C:4]([CH3:16])=[N:3]1
Reactant: Clc1ccnc(Cl)n1
Reactant: Cc1cccc(Oc2c(C)nn(C)c2O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: Cc1cccc(Oc2c(C)nn(C)c2Oc2ccnc(Cl)n2)c1
Reaction time: 3 h
Yield: 87.7 %

Procedure:
In 10 ml of acetonitrile were dissolved 0.220 g (1.00 mmol) of 1,3-dimethyl-4-(3-methylphenoxy)-5-hydroxypyrazole, 0.220 g (1.50 mmol) of 2,4-dichloropyrimidine and 0.210 g (1.50 mmol) of potassium carbonate. Thus obtained solution was stirred for 3 hours with refluxing. After completing the reaction, the reaction solution was poured into water, extracted with ethyl acetate and dried. The organic layer was concentrated. The residue was purified by means of silica gel column chromatography (developing solution: ethyl acetate-hexane (1:1 v/v)) to give 0.29 g of 1,3-dimethyl-4-(3-methylphenoxy)-5-(2-chloropyrimidine-4-yloxy)pyrazole.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8](B(O)O)=[CH:9][C:4]=2[CH2:3][CH2:2]1.I[C:14]1[C:22]2[C:17](=[N:18][CH:19]=[N:20][C:21]=2[NH2:23])[N:16]([CH:24]([CH3:26])[CH3:25])[N:15]=1.C([O-])([O-])=O.[Na+].[Na+]>CCO.COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:14]3[C:22]4[C:17](=[N:18][CH:19]=[N:20][C:21]=4[NH2:23])[N:16]([CH:24]([CH3:26])[CH3:25])[N:15]=3)=[CH:9][C:4]=2[CH2:3][CH2:2]1
Reactant: OB(O)c1ccc2c(c1)CCO2
Reactant: CC(C)n1nc(I)c2c(N)ncnc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCO
Product: CC(C)n1nc(-c2ccc3c(c2)CCO3)c2c(N)ncnc21
Temperature: 80 °C
Yield: 53.2 %

Procedure:
A solution of 2,3-dihydro-1-benzofuran-5-ylboronic acid (38 mg, 0.23 mmol) in EtOH (1.65 ml) was added to a solution of 3-iodo-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (30 mg, 0.1 mmol) in DME (6 ml). Pd(PPh3)4 (30 mg, 0.03 mmol) and saturated Na2CO3 (0.95 ml) were added and the reaction was heated to 80° C. under an argon atmosphere overnight. After cooling, the reaction was extracted with saturated NaCl and CH2Cl2. Organic phases were combined, concentrated in vacuo and purified by RP-HPLC (MeCN:H2O:0.1% TFA) to yield BA95 (15.7 mg, 59% yield). ESI-MS (M+H)+ m/z calcd 296.1, found 296.1.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[CH:12]=[CH:11][C:10]([S:13]([NH2:16])(=[O:15])=[O:14])=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.Cl[C:18]1[CH:23]=[C:22]([N+:24]([O-:26])=[O:25])[CH:21]=[CH:20][N:19]=1>N1C=CC=CC=1>[N+:24]([C:22]1[CH:21]=[CH:20][N:19]=[C:18]([N:1]2[CH2:6][CH2:5][CH:4]([C:7]3[CH:12]=[CH:11][C:10]([S:13]([NH2:16])(=[O:14])=[O:15])=[CH:9][CH:8]=3)[CH2:3][CH2:2]2)[CH:23]=1)([O-:26])=[O:25]
Reactant: O=[N+]([O-])c1ccnc(Cl)c1
Reactant: NS(=O)(=O)c1ccc(C2CCNCC2)cc1
Solvent: c1ccncc1
Product: NS(=O)(=O)c1ccc(C2CCN(c3cc([N+](=O)[O-])ccn3)CC2)cc1

Procedure:
A solution of 4-(4-piperidinyl)benzensulphonamide [the product of Example 2(iii)] (0.46 g) and 2-chloro-4-nitropyridine (0.30 g) in pyridine (10 ml) was heated under reflux for 5 hours and then evaporated. The residue was partitioned between dichloromethane and 10% aqueous sodium carbonate solution. The aqueous layer was extracted several times with dichloromethane nd the combined organic extracts were dried (MgSO4) and evaporated. The residue was chromatographed on silica gel. Elution with dichloromethane/methanol (99:1) first gave impurity followed by the pure product. The product-containing fractions were combined and evaporated to give the title compound, (0.15 g), m.p. 215°-217°.
Reaction SMILES: [CH2:1]([N:5]1[C:9]2[CH2:10][O:11][CH2:12][C:8]=2[S:7][C:6]1=[NH:13])[CH2:2][CH2:3][CH3:4].[Cl:14][C:15]1[CH:16]=[CH:17][C:18]([O:24][CH3:25])=[C:19]([CH:23]=1)[C:20](O)=[O:21].ON1C2C=CC=CC=2N=N1.CCN=C=NCCCN(C)C.Cl.C(N(CC)CC)C>O1CCCC1>[CH2:1]([N:5]1[C:9]2[CH2:10][O:11][CH2:12][C:8]=2[S:7]/[C:6]/1=[N:13]\[C:20](=[O:21])[C:19]1[CH:23]=[C:15]([Cl:14])[CH:16]=[CH:17][C:18]=1[O:24][CH3:25])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCn1c2c(sc1=N)COC2
Reactant: COc1ccc(Cl)cc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCCn1c2c(s/c1=N\C(=O)c1cc(Cl)ccc1OC)COC2
Temperature: 80 °C
Reaction time: 2 h
Yield: 29.2 %

Procedure:
To a solution of Example 17A (220 mg, 0.56 mmol) in tetrahydrofuran (10 mL) were added 5-chloro-2-methoxybenzoic acid (114 mg, 0.61 mmol, Aldrich), 1-hydroxybenzotriazole (93 mg, 0.61 mmol, Aldrich), N-(3-dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride (117 mg, 0.61 mmol) and triethylamine (0.23 mL, 1.7 mmol, Aldrich). The reaction mixture was stirred at 80° C. for 2 h, then cooled and quenched with saturated NaHCO3 (10 mL). The aqueous layer was extracted with EtOAc (3×20 mL). The combined organic extracts were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography using an Analogix® Intelliflash280 ™ (SiO2, 0-100% EtOAc in hexanes) to afford 60 mg (30%) of the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 0.92 (t, J=7.3 Hz, 3H), 1.33 (t, 2H), 1.74 (t, 2H), 3.80 (s, 3H), 4.10 (t, J=7.3 Hz, 2H), 4.87-5.08 (m, J=1.7 Hz, 4H), 7.13 (d, J=8.8 Hz, 1H), 7.47 (dd, J=8.8, 3.1 Hz, 1H), 7.75 (d, J=3.1 Hz, 1H); MS (ESI+) m/z 367 (M+H)+; Anal. Calculated C17H19ClN2O3S: C, 55.66; H, 5.22; N, 7.64. Found: C, 55.46; H, 5.03; N, 7.74.
Reaction SMILES: [C:1]1([S:11]([C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([O:23][CH:24]4[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]4)[CH:21]=3)[NH:16][N:15]=2)(=[O:13])=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[CH:30](=O)[CH2:31][CH2:32][CH3:33].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>ClCCCl.C(Cl)(Cl)Cl>[CH2:30]([N:27]1[CH2:28][CH2:29][CH:24]([O:23][C:20]2[CH:21]=[C:22]3[C:17](=[CH:18][CH:19]=2)[NH:16][N:15]=[C:14]3[S:11]([C:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:4]=[CH:3][CH:2]=2)(=[O:12])=[O:13])[CH2:25][CH2:26]1)[CH2:31][CH2:32][CH3:33]
Reactant: O=S(=O)(c1cccc2ccccc12)c1n[nH]c2ccc(OC3CCNCC3)cc12
Reactant: CCCC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CCCCN1CCC(Oc2ccc3[nH]nc(S(=O)(=O)c4cccc5ccccc45)c3c2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 40 %

Procedure:
A suspension of 3-(1-naphthylsulfonyl)-5-(piperidin-4-yloxy)-1H-indazole (56.5 mg, 0.138 mmol) in 1,2-dichloroethane was treated sequentially with butyraldehyde (0.1 mL, 1 mmol) and acetic acid (0.1 mL, 2 mmol), stirred at ambient temperature for 3 hours, treated with sodium triacetoxyborohydride (46.5 mg, 0.220 mmol), stirred for 1 hour, 20 minutes under nitrogen at ambient temperatures, diluted with chloroform and poured into excess 1.0 N sodium hydroxide. The phases were separated. The organic phase was washed with brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo. The resultant residue was twice purified by flash chromatography using 0.25-0.5% ammonium hydroxide/2.5-5.0% methanol in chloroform to afford 5-(1-butylpiperidin-4-yloxy)-3-(1-naphthylsulfonyl)-1H-indazole as a light orange foam, 25.6 mg (40.0% yield). The foam was dispersed in methanol, treated with ethereal HCl and concentrated in vacuo at 83° C. for 25 hours to give the title product as an orange foam, 22.0 mg, Mass spectrum (+EI, [M+H]+) m/z 464. 1HNMR (500 MHz, DMSO-d6): δ14.16 (d, 1H, J=4.15 Hz), 9.86-9.98 (m*, 1H), 8.73 (dd, 1H, J=15.74 Hz and 8.42 Hz), 8.54-8.56 (m, 1H), 8.27 (d, 1H, J=8.29 Hz), 8.02-8.05 (m, 1H), 7.70-7.75 (m, 1H), 7.54-7.63 (m, 3H), 7.28-7.38 (s* and s*, 1H), 7.09-7.20 (m*, 1H), 4.60-4.80 (m*, 1H), 3.52-3.55 (m, 1H), 3.32-3.35 (m, 1H), 3.00-3.16 (m, 4H), 2.06-2.16 (m, 2H), 1.97-2.00 (m, 1H), 1.79-1.88 (m, 1H), 1.60-1.67 (m, 2H), 1.25-1.34 (m, 2H), 0.92-0.87 ppm (m, 3H). *Conformational isomers due to protonation of tertiary amine.
Reaction SMILES: [NH2:1][C:2]1[C:33]([Cl:34])=[CH:32][C:5]([C:6]([NH:8][CH2:9][CH:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][NH:22][CH2:23][C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[C:26]([Cl:31])[CH:25]=3)[CH2:12][CH2:11]2)=[O:7])=[C:4]([O:35][CH3:36])[CH:3]=1.[CH:37](=O)[CH3:38].C([BH3-])#N.[Na+]>>[NH2:1][C:2]1[C:33]([Cl:34])=[CH:32][C:5]([C:6]([NH:8][CH2:9][CH:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][N:22]([CH2:23][C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[C:26]([Cl:31])[CH:25]=3)[CH2:37][CH3:38])[CH2:12][CH2:11]2)=[O:7])=[C:4]([O:35][CH3:36])[CH:3]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCCCNCc2ccc(Cl)c(Cl)c2)CC1
Reactant: CC=O
Agent: [BH3-]C#N
Agent: [Na+]
Product: CCN(CCCCCCN1CCC(CNC(=O)c2cc(Cl)c(N)cc2OC)CC1)Cc1ccc(Cl)c(Cl)c1

Procedure:
4-Amino-5-chloro-N-((1-(6-(3,4-dichlorobenzylamino)hexyl)piperidin-4-yl)methyl)-2-methoxybenzamide (1.11 g) as starting compound, acetaldehyde (0.13 ml) and sodium cyanoborohydride (0.3 g) were reacted and treated in the same manner as in Example 136 to give 0.75 g of 4-amino-5-chloro-N-((1-(6-(N-(3,4-dichlorobenzyl)-N-ethylamino)hexyl)-piperidin-4-yl)methyl)-2-methoxybenzamide.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[CH:11][C:10]([N:13]2[C:18]3=[N:19][C:20]4[C:25]([Cl:26])=[CH:24][CH:23]=[C:22]([CH:27]([O:32][CH:33]([F:35])[F:34])[C:28]([F:31])([F:30])[F:29])[C:21]=4[N:17]3[CH2:16][CH2:15][CH2:14]2)=[C:9]([CH3:36])[N:8]=1)(=O)=O.[CH3:39][NH:40][CH3:41]>>[Cl:26][C:25]1[C:20]2[N:19]=[C:18]3[N:13]([C:10]4[CH:11]=[CH:12][C:7]([N:40]([CH3:41])[CH3:39])=[N:8][C:9]=4[CH3:36])[CH2:14][CH2:15][CH2:16][N:17]3[C:21]=2[C:22]([CH:27]([O:32][CH:33]([F:34])[F:35])[C:28]([F:29])([F:30])[F:31])=[CH:23][CH:24]=1
Reactant: CNC
Reactant: Cc1nc(OS(=O)(=O)C(F)(F)F)ccc1N1CCCn2c1nc1c(Cl)ccc(C(OC(F)F)C(F)(F)F)c12
Product: Cc1nc(N(C)C)ccc1N1CCCn2c1nc1c(Cl)ccc(C(OC(F)F)C(F)(F)F)c12
Temperature: 70 °C
Reaction time: 24 h
Yield: 67 %

Procedure:
A mixture of 5-{9-chloro-6-[1-(difluoromethoxy)-2,2,2-trifluoroethyl]-3,4-dihydropyrimido[1,2-a]benzimidazol-1(2H)-yl}-6-methylpyridin-2-yl trifluoromethanesulfonate (122.3 mg, 0.206 mmol) and dimethylamine (2.0 M tetrahydrofuran solution, 1.0 mL) was stirred at 70° C. for 24 hrs. The reaction mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with a 0-40% ethyl acetate/n-hexane gradient mixture. The resulting solid was recrystallized from ethyl acetate/n-hexane to give a title compound as a colorless powder (67.3 mg, 0.137 mmol, 67%).
Reaction SMILES: [C:1]([NH:4][NH:5][C:6](=[O:17])[C:7]1[CH:12]=[CH:11][C:10]([CH3:13])=[C:9]([N+:14]([O-:16])=[O:15])[CH:8]=1)(=O)[CH3:2]>C(OCC)(=O)C>[CH3:2][C:1]1[O:17][C:6]([C:7]2[CH:12]=[CH:11][C:10]([CH3:13])=[C:9]([N+:14]([O-:16])=[O:15])[CH:8]=2)=[N:5][N:4]=1
Reactant: CC(=O)NNC(=O)c1ccc(C)c([N+](=O)[O-])c1
Solvent: CCOC(C)=O
Product: Cc1nnc(-c2ccc(C)c([N+](=O)[O-])c2)o1
Temperature: 120 °C
Yield: 140.7 %

Procedure:
The compound (0.70 g, 2.95 mmol) obtained in step A and polyphosphoric acid (8.0 g) were mixed, and the mixture was stirred with heating at 120° C. After cooling to room temperature, the reaction mixture was poured into ice water, and diluted with ethyl acetate. The mixture was washed with water and saturated aqueous sodium hydrogen carbonate, and dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the solution was concentrated under reduced pressure to give the title compound (0.91 g) as a colorless solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12](Cl)[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[N+:19]([O-:21])=[O:20])([CH3:4])([CH3:3])[CH3:2].[CH3:23][NH:24][CH2:25][CH2:26][CH3:27].C(N(CC)CC)C>CS(C)=O>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([N:24]([CH3:23])[CH2:25][CH2:26][CH3:27])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[N+:19]([O-:21])=[O:20])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)Nc1cc(Cl)c(C(F)(F)F)cc1[N+](=O)[O-]
Reactant: CCCNC
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CCCN(C)c1cc(NC(=O)OC(C)(C)C)c([N+](=O)[O-])cc1C(F)(F)F

Procedure:
The title compound was prepared from (5-chloro-2-nitro-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example A1) (4.00 g, 11.7 mmol), N-methyl-propylamine (1.89 ml, 17.6 mmol) and triethylamine (5.73 ml, 41.1 mmol) in DMSO (30 mL) at RT according to the general procedure C. Obtained as a yellow solid (4.04 g, 91%).
Reaction SMILES: [Br:1][C:2]1[C:7]([CH2:8][CH:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[OH:10])=[CH:6][CH:5]=[CH:4][N:3]=1.[H-].[Na+].Br[CH2:20][C:21]([O:23][CH3:24])=[O:22]>CN(C=O)C>[Br:1][C:2]1[C:7]([CH2:8][CH:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[O:10][CH2:20][C:21]([O:23][CH3:24])=[O:22])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: OC(Cc1cccnc1Br)c1ccccc1
Reactant: COC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)COC(Cc1cccnc1Br)c1ccccc1
Temperature: 23 °C
Reaction time: 0.5 h

Procedure:
A solution of 2-(2-bromopyridin-3-yl)-1-phenylethanol (2.5 g, 9.0 mmol) in anhydrous DMF (10 mL) was added dropwise to a suspension of sodium hydride (60% dispersion in mineral oil, 0.54 g, 13 mmol) in anhydrous DMF (10 mL) at 0° C., and the resulting mixture was stirred for 30 min. Methyl bromoacetate (1.03 mL, 10.7 mmol) was added, and the contents were warmed to 23° C. and stirred for 30 min, then partitioned between ethyl acetate and water (2×). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by flash chromatography on silica gel eluting with 20% ethyl acetate in petroleum ether to give the title compound. MS: m/z=352.0 (M+1).
Reaction SMILES: [C:1]([C@@H:3]1[C@@H:10]2[C@@H:6]([O:7][C:8]([CH3:12])([CH3:11])[O:9]2)[C@H:5]([O:13][CH3:14])[O:4]1)#[CH:2].C[Si]([N:19]=[N+:20]=[N-:21])(C)C>>[CH3:14][O:13][C@H:5]1[C@@H:6]2[O:7][C:8]([CH3:11])([CH3:12])[O:9][C@@H:10]2[C@@H:3]([C:1]2[CH:2]=[N:21][NH:20][N:19]=2)[O:4]1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: C#C[C@H]1O[C@@H](OC)[C@@H]2OC(C)(C)O[C@@H]21
Product: CO[C@@H]1O[C@H](c2cn[nH]n2)[C@H]2OC(C)(C)O[C@@H]12
Temperature: 25 °C

Procedure:
A solution of (3aR,4R,6R,6aR)-4-ethynyl-6-methoxy-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxole (Helv. Chim. Acta, 1980, 63(5), 1181) (0.55 g, 2.8 mmol), in trimethylsilylazide (5 ml) was heated at 120 □C. in a teflon lined bomb for 12 hours. The reaction mixture was allowed to cool to room temperature and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with a gradient system of dichloromethane gradually changing to dichloromethane:methanol (98:2 by volume) to give the title compound as a pale brown oil which solidified on standing (0.36 g).
Reaction SMILES: [Na].[CH2:2]([O:4][C:5]([C:7]1[C:8](=[O:18])[NH:9][C:10]2[C:15]([C:16]=1[NH2:17])=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:6])[CH3:3].CN(C)C=O.[CH2:24](Br)[CH:25]=[CH2:26]>O>[CH2:2]([O:4][C:5]([C:7]1[C:8](=[O:18])[N:9]([CH2:26][CH:25]=[CH2:24])[C:10]2[C:15]([C:16]=1[NH2:17])=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:6])[CH3:3]
Reactant: C=CCBr
Reactant: CCOC(=O)c1c(N)c2ccccc2[nH]c1=O
Agent: [Na]
Solvent: CN(C)C=O
Solvent: O
Product: C=CCn1c(=O)c(C(=O)OCC)c(N)c2ccccc21

Procedure:
To a solution containing 7.6 g. (0.03 mole) of the sodium salt of 4-amino-1,2-dihydro-2-oxo-3-quinolinecarboxylic acid ethyl ester in 50 ml. of dimethylformamide was added 4.8 g. (0.04 mole) of allyl bromide. The reaction mixture was heated on a steam bath for 1/2 hour. The reaction mixture was cooled in ice and poured into 500 ml. of water. The resulting precipitate was collected on a filter and recrystallized from ethyl acetate-petroleum ether giving 4.6 g. of product, m.p. 132°-134° C.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[C:20]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[O:28][CH3:29])=[C:19](Cl)[N:18]=[C:17]([N:31]3[CH2:36][CH2:35][N:34]([CH:37]([CH3:39])[CH3:38])[CH2:33][CH2:32]3)[N:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:40]([OH:44])[CH2:41][CH2:42][OH:43]>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[C:20]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[O:28][CH3:29])=[C:19]([O:43][CH2:42][CH2:41][CH2:40][OH:44])[N:18]=[C:17]([N:31]3[CH2:36][CH2:35][N:34]([CH:37]([CH3:39])[CH3:38])[CH2:33][CH2:32]3)[N:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccccc1Oc1c(Cl)nc(N2CCN(C(C)C)CC2)nc1NS(=O)(=O)c1ccc(C(C)(C)C)cc1
Reactant: OCCCO
Product: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)nc(N2CCN(C(C)C)CC2)nc1OCCCO

Procedure:
The procedure described in Synthesis Example 3 was repeated by use of 4-t-butyl-N-[6-chloro-2-(4-isopropyl -piperazinyl)-5-(2-methoxyphenoxy)-4-pyrimidinyl]-benzenesulfonamide and 1,3-propanediol, to thereby obtain the title compound as a pale yellow oil.
Reaction SMILES: [CH3:1][N:2]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]2[N:14]=[N:15][C:16](Cl)=[CH:17][CH:18]=2)[CH:8]=1)[C:3](=[O:6])[CH2:4][CH3:5].[CH3:20][NH:21][C:22](=S)[NH:23][NH2:24]>C(O)C>[CH3:1][N:2]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]2[CH:18]=[CH:17][C:16]3[N:15]([C:22]([NH:21][CH3:20])=[N:23][N:24]=3)[N:14]=2)[CH:8]=1)[C:3](=[O:6])[CH2:4][CH3:5]
Reactant: CNC(=S)NN
Reactant: CCC(=O)N(C)c1cccc(-c2ccc(Cl)nn2)c1
Solvent: CCO
Product: CCC(=O)N(C)c1cccc(-c2ccc3nnc(NC)n3n2)c1
Yield: 16 %

Procedure:
A solution of 5.0 g of N-methyl-N-[3-(6-chloro-3-pyridazinyl)phenyl]propanamide and 3.8 g 4-methylthiosemicarbazide in 200 ml ethanol was refluxed for 18 hours. The mixture was then treated and the product chromatographed as described in Example 70. Recrystallization of the product from dichloromethane-hexane afforded 0.9 g yellow powder, mp 212°-213° C.
Reaction SMILES: [I:1][C:2]1[CH:13]=[CH:12][C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:10](=O)[C:4]=2[CH:3]=1.N1C=CC=CC=1.Cl.[CH3:21][O:22][NH2:23]>CO>[CH3:21][O:22][N:23]=[C:10]1[C:4]2[CH:3]=[C:2]([I:1])[CH:13]=[CH:12][C:5]=2[CH2:6][CH2:7][CH2:8][CH2:9]1
Reactant: O=C1CCCCc2ccc(I)cc21
Reactant: CON
Agent: Cl
Solvent: c1ccncc1
Solvent: CO
Product: CON=C1CCCCc2ccc(I)cc21
Temperature: 20 °C
Reaction time: 16 h
Yield: 97 %

Procedure:
To a stirred suspension of 3-iodo-6,7,8,9-tetrahydrobenzocylohepten-5-one prepared as described in example P3a (0.806 g; 2.82 mmol) in methanol (5.7 ml) was added pyridine (0.7 ml; 9.02 mmol) followed by a portion wise addition of methoxyamine hydrochloride (0.754 g; 9.02 mmol). The reaction mixture was stirred at 20° C. for 16 h under nitrogen. The solvent was removed in vacuo to afford 0.86 g (97% of theory) of crude 3-iodo-6,7,8,9-tetrahydrobenzocylohepten-5-one-O-methyl-oxime E/Z-mixture as a brown oil.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([C:16]([O:18][CH3:19])=[O:17])=[N:11][C:12]([OH:15])=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:20](Br)[CH3:21].C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[CH2:1]([O:8][C:9]1[C:10]([C:16]([O:18][CH3:19])=[O:17])=[N:11][C:12]([O:15][CH2:20][CH3:21])=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1nc(O)ccc1OCc1ccccc1
Reactant: CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOc1ccc(OCc2ccccc2)c(C(=O)OC)n1

Procedure:
5.0 g (19 mmol) of methyl 3-benzyloxy-6-hydroxypicolinate, 2.1 g (19 mmol) of ethyl bromide and 2.9 g (21 mmol) of potassium carbonate were added to 100 ml of DMF, and the resultant mixture was reacted at 80° C. for 5 hours. After the reaction, the reaction content was poured into water, and was extracted with ethyl acetate, washed with water, dried and concentrated. The residue thus obtained was purified by column chromatography to obtain an aimed compound.