Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].[NH:2]([C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]3[N:21]=[CH:20][NH:19][C:17]3=2)[N:12]=[C:11]([CH3:22])[CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C1(N)CCCCC1>CN(C)C=O>[ClH:1].[CH:3]1([NH:2][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]4[N:21]=[CH:20][NH:19][C:17]4=3)[N:12]=[C:11]([CH3:22])[CH:10]=2)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]1
Reactant: Cc1cc(Nc2ccccc2)c2c(ccc3nc[nH]c32)n1
Agent: Cl
Solvent: NC1CCCCC1
Solvent: CN(C)C=O
Product: Cc1cc(NC2CCCCC2)c2c(ccc3nc[nH]c32)n1

Procedure:
A solution of 22 g. (0.1 m.) of the compound of Example I, C., and 10 g. (0.1 m.) cyclohexylamine in 200 ml. of dimethylformamide was heated under reflux for 18 hours and filtered hot. The crystalline product which separated on cooling was filtered, washed with a little cold dimethylformamide then ether and air-dried to give 17 g. Recrystallization from 300 ml. of ethanol and 300 ml. of ether gave an analytical sample as white needles, m.p. 174°-178°.
Reaction SMILES: [Na:1].[CH3:2][C:3]1[C:4]([CH2:20][S:21]([C:23]2[NH:27][C:26]3[CH:28]=[CH:29][CH:30]=[CH:31][C:25]=3[N:24]=2)=[O:22])=[N:5][CH:6]=[CH:7][C:8]=1[O:9][CH2:10]CC1(CCC)OCCO1.ClC1C=C[N+]([O-])=C(C)C=1C.[F:42][CH2:43][C:44]1(CO)[O:48][CH2:47][CH2:46][O:45]1>>[Na:1].[F:42][CH2:43][C:44]1([CH2:10][O:9][C:8]2[CH:7]=[CH:6][N:5]=[C:4]([CH2:20][S:21]([C:23]3[NH:24][C:25]4[CH:31]=[CH:30][CH:29]=[CH:28][C:26]=4[N:27]=3)=[O:22])[C:3]=2[CH3:2])[O:48][CH2:47][CH2:46][O:45]1
Reactant: OCC1(CF)OCCO1
Reactant: CCCC1(CCOc2ccnc(CS(=O)c3nc4ccccc4[nH]3)c2C)OCCO1
Agent: Cc1c(Cl)cc[n+]([O-])c1C
Agent: [Na]
Product: Cc1c(OCC2(CF)OCCO2)ccnc1CS(=O)c1nc2ccccc2[nH]1
Yield: 8.2 %

Procedure:
The same procedure as in the steps (3c) to (3h) of Example 3 was repeated using 4-chloro-2,3-dimethylpyridine 1-oxide and (2-(fluoromethyl)-1,3-dioxolan-2-yl)methanol to obtain the title compound (140 mg, 6 steps 8.2%) as a light yellow solid.
Reaction SMILES: [OH:1][C:2]1[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([C:9]([Cl:12])([Cl:11])[Cl:10])[N:3]=1.C(N(CC)CC)C.[CH3:20][S:21](Cl)(=[O:23])=[O:22]>ClCCl>[CH3:20][S:21]([O:1][C:2]1[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([C:9]([Cl:12])([Cl:11])[Cl:10])[N:3]=1)(=[O:23])=[O:22]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1nc(O)nc(C(Cl)(Cl)Cl)n1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1nc(OS(C)(=O)=O)nc(C(Cl)(Cl)Cl)n1

Procedure:
To a solution of 2-hydroxy-4-methyl-6-trichloromethyl-[1,3,5]triazine (1.14 g, 5.0 mmol; J. Amer. Chem. Soc. 1956, 78, 2447) and triethylamine (0.51 g, 5.5 mmol) in dichloromethane was added methanesulfonyl chloride (0.57 g, 5.0 mmol) at 0° C. and stirred ford h then quenched in saturated aqueous sodium bicarbonate. The separated organic layer was washed once with saturated sodium chloride, dried over magnesium sulfate and filtered. The filtrate was evaporated to give the title compound of Example 242, Step A as an orange oil, 0.98 g (65%) which was used directly without any further purification. MS (CI) 291, 293 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:10]=[C:11]([N:18]3[CH:22]=[CH:21][N:20]=[C:19]3[CH3:23])[O:12][C:13]=2[CH2:14][CH2:15][CH2:16][OH:17])[CH:5]=[CH:6][C:7]=1[Cl:8].[CH3:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1O.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:10]=[C:11]([N:18]3[CH:22]=[CH:21][N:20]=[C:19]3[CH3:23])[O:12][C:13]=2[CH2:14][CH2:15][CH2:16][O:17][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[CH3:24])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: Cc1ccccc1O
Reactant: Cc1nccn1-c1nc(-c2ccc(Cl)c(Cl)c2)c(CCCO)o1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: Cc1ccccc1OCCCc1oc(-n2ccnc2C)nc1-c1ccc(Cl)c(Cl)c1
Reaction time: 1 h

Procedure:
To a mixture of 4-(3,4-dichlorophenyl)-2-(2-methyl-1-imidazolyl)-5-oxazolepropanol (352 mg), 2-methylphenol (216 mg), tributylphosphine (405 mg) and tetrahydrofuran (10 mL) was added 1,1′-(azodicarbonyl)dipiperidine (450 mg) at room temperature, and the mixture was stirred for 1 h. The reaction mixture was concentrated and the residue was subjected to silica gel column chromatography. The title compound was obtained as crystals from an eluate from ethyl acetate-hexane (2:3, v/v). Recrystallization from acetone-isopropyl ether gave colorless prism crystals (271 mg, 61%). melting point: 116-117° C.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:8]2[CH2:7][CH2:6][CH2:5][C:4]=2[C:3]=1[OH:11].C1N2CN3CN(C2)CN1C3.O.FC(F)(F)[C:25](O)=[O:26]>>[OH:11][C:3]1[C:4]2[CH2:5][CH2:6][CH2:7][C:8]=2[C:9]([CH:25]=[O:26])=[CH:10][C:2]=1[CH3:1]
Reactant: O=C(O)C(F)(F)F
Reactant: Cc1ccc2c(c1O)CCC2
Agent: C1N2CN3CN1CN(C2)C3
Solvent: O
Product: Cc1cc(C=O)c2c(c1O)CCC2
Temperature: 90 °C
Reaction time: 8 h

Procedure:
5-Methylindan-4-ol (4.50 g) and hexamethylenetetramine (4.26 g) were dissolved in trifluoroacetic acid (100 mL), and the mixture was stirred at 90° C. overnight. Water was added to the reaction mixture. After stirring for 30 min, the reaction mixture was extracted with ethyl acetate. The organic layer was washed with water, saturated sodium hydrogen carbonate and brine successively, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to give the title compound (4.76 g).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[C:5]2[S:10][C:9]([C:12]3[CH:13]=[C:14]([N:18]([CH3:22])[C:19](=[O:21])[CH3:20])[CH:15]=[CH:16][CH:17]=3)(I)[CH2:8][C:6]=2[N:7]=1.CC1(C)C(C)(C)OB([C:37]2[CH:45]=[CH:44][CH:43]=[C:42]3[C:38]=2[CH:39]=[N:40][NH:41]3)O1>>[NH:41]1[C:42]2[C:38](=[C:37]([C:2]3[N:3]=[C:4]([N:23]4[CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)[C:5]4[S:10][C:9]([C:12]5[CH:13]=[C:14]([N:18]([CH3:22])[C:19](=[O:21])[CH3:20])[CH:15]=[CH:16][CH:17]=5)=[CH:8][C:6]=4[N:7]=3)[CH:45]=[CH:44][CH:43]=2)[CH:39]=[N:40]1
Reactant: CC(=O)N(C)c1cccc(C2(I)Cc3nc(Cl)nc(N4CCOCC4)c3S2)c1
Reactant: CC1(C)OB(c2cccc3[nH]ncc23)OC1(C)C
Product: CC(=O)N(C)c1cccc(-c2cc3nc(-c4cccc5[nH]ncc45)nc(N4CCOCC4)c3s2)c1

Procedure:
N-(3-(2-Chloro-6-iodo-4-morpholinothieno[3,2-d]pyrimidine-6-yl)phenyl)-N-methylacetamide (62 mg) was coupled to 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole 7 via General Procedure A to yield 352. MS (Q1) 485.2 (M)+
Reaction SMILES: Cl[Si](C)(C)C.[F:6][C:7]1[CH:8]=[C:9]([CH:16]=[C:17]([F:19])[CH:18]=1)[CH2:10][CH:11]([C:13]([OH:15])=[O:14])[NH2:12].C(N(C(C)C)C(C)C)C.[CH:29]1(/[CH:35]=[CH:36]/[C:37](Cl)=[O:38])[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1>ClCCl>[CH:29]1(/[CH:35]=[CH:36]/[C:37]([NH:12][C@H:11]([C:13]([OH:15])=[O:14])[CH2:10][C:9]2[CH:8]=[C:7]([F:6])[CH:18]=[C:17]([F:19])[CH:16]=2)=[O:38])[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1
Reactant: O=C(Cl)/C=C/C1CCCCC1
Reactant: NC(Cc1cc(F)cc(F)c1)C(=O)O
Agent: C[Si](C)(C)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(/C=C/C1CCCCC1)N[C@@H](Cc1cc(F)cc(F)c1)C(=O)O
Temperature: 0 °C
Reaction time: 8 h
Yield: 26 %

Procedure:
6.3 ml (49.7 mmol) of chlorotrimethylsilane are added to a solution of 5.0 g (24.9 mmol) of 3,5-difluoro-DL-phenylalanine in dichloromethane (150 ml) and the reaction mixture is heated to reflux for 1 h. After cooling to 0° C., 9.7 ml (55.9 mmol) of ethyldiisopropylamine are slowly added and then, dropwise, 4.29 g (24.9 mmol) of trans-3-cyclohexyl-2-propenoyl chloride. The reaction mixture is stirred overnight with slow warming to RT and remains standing at RT for two days. For working up, the mixture is evaporated to dryness in vacuo, the residue is taken up using diethyl ether and extracted with 2.5 pc. aq. sodium hydrogencarbonate solution (250 ml). The aqueous phase is extracted twice with diethyl ether. The combined organic phases are extracted a further three times with sodium hydrogencarbonate solution. The combined aqueous phases are brought to pH=2 using 1N aqueous hydrochloric acid and extracted three times with ethyl acetate. The combined ethyl acetate phases are dried over sodium sulfate, filtered, and the solvent is concentrated in vacuo. The residue (4.63 g) is washed by stirring with diethyl ether and filtered. 3.64 g (43% of th.) of colorless solid are obtained. The residue from the concentrated mother liquor and the residue from the concentrated diethyl ether phase of the alkaline extraction (see above), are taken up together in ethyl acetate and extracted with 1N hydrochloric acid. The organic phase is dried over sodium sulfate, filtered and concentrated. The residue is washed by stirring with diethyl ether and filtered off with suction. A further 2.18 g (26%) of product are isolated.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[CH:12]=[C:11]2[C:6]([N:7]=[C:8]([C:26]3[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=3)[C:9]([C:20]3[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=3)=[C:10]2[C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)=[N:5]1.[Cl:33][CH2:34][C:35](Cl)=[O:36]>>[F:19][C:16]1[CH:17]=[CH:18][C:13]([C:10]2[C:11]3[C:6](=[N:5][N:4]([CH2:3][CH2:2][NH:1][C:35](=[O:36])[CH2:34][Cl:33])[CH:12]=3)[N:7]=[C:8]([C:26]3[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=3)[C:9]=2[C:20]2[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=2)=[CH:14][CH:15]=1
Reactant: NCCn1cc2c(-c3ccc(F)cc3)c(-c3ccncc3)c(-c3ccc(F)cc3)nc2n1
Reactant: O=C(Cl)CCl
Product: O=C(CCl)NCCn1cc2c(-c3ccc(F)cc3)c(-c3ccncc3)c(-c3ccc(F)cc3)nc2n1

Procedure:
Following a similar procedure to that described in reference example 1 section a, but starting from 2-(2-aminoethyl)-4,6-bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridine (obtained in example 90) and chloroacetyl chloride, the title compound was obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:10](I)=[CH:9][N:8]([S:12]([C:15]3[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:5]2=[N:6][CH:7]=1.[N:22]1[CH:27]=[CH:26][CH:25]=[C:24](B(O)O)[CH:23]=1.C(#N)C.C([O-])([O-])=O.[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.ClCCl>[Br:1][C:2]1[CH:3]=[C:4]2[C:10]([C:24]3[CH:23]=[N:22][CH:27]=[CH:26][CH:25]=3)=[CH:9][N:8]([S:12]([C:15]3[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:5]2=[N:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(I)c3cc(Br)cnc32)cc1
Reactant: OB(O)c1cccnc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CC#N
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cccnc3)c3cc(Br)cnc32)cc1
Temperature: 60 °C

Procedure:
To a screw top reaction tube was placed 5-bromo-3-iodo-1-tosyl-1H-pyrrolo[2,3-b]pyridine (1.2 g, 2.52 mmol, prepared according to WO2011/149950), pyridin-3-ylboronic acid (371 mg, 3.02 mmol) and trans-dichlorobis(triphenylphosphine)palladium (II) (177 mg, 0.25 mmol). Degassed acetonitrile (16 mL) and 1 N Na2CO3 (16 mL) was added and the reaction tube was purged with argon, sealed and heated at 60° C. for 2 h. The reaction was cooled, filtered through a Celite pad and concentrated under reduced pressure. The residue was partitioned between EtOAc/water and extracted. The organic layer was washed with brine, dried over Na2SO4 and concentrated to give a solid. Trituration of the solid with hexanes and dichloromethane gave the desired compound. LCMS-ESI+: calc'd for C19H14BrN3O2S: 428.0 (M+H+); found: 428.2 (M+H+).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH:15]=O)[CH2:10][C:11]([O:13][CH3:14])=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:17]([NH2:19])[CH3:18]>>[CH2:17]([N:19]([CH2:15][CH:9]([NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:10][C:11]([O:13][CH3:14])=[O:12])[CH2:15][CH:9]([NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:7])[CH2:10][C:11]([O:13][CH3:14])=[O:12])[CH3:18]
Reactant: COC(=O)C[C@@H](C=O)NC(=O)OC(C)(C)C
Reactant: CCN
Product: CCN(CC(CC(=O)OC)NC(=O)OC(C)(C)C)CC(CC(=O)OC)NC(=O)OC(C)(C)C

Procedure:
The product from Example 16A and ethylamine were processed as described in Example 7B to provide the title compound.
Reaction SMILES: [C:1]1([O:7][C:8]([N:10]2[CH:23]([C:24]#[CH:25])[C:22]34O[C:17]3([CH:18]([O:27][Si](C(C)(C)C)(C)C)[CH2:19][CH2:20][CH2:21]4)[C:16]3[CH:15]=[CH:14][C:13]([O:35][C:36](=[O:41])[C:37]([CH3:40])([CH3:39])[CH3:38])=[CH:12][C:11]2=3)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.B(F)(F)F.CCOCC>C(Cl)(Cl)Cl>[C:1]1([O:7][C:8]([N:10]2[CH:23]([C:24]#[CH:25])[C:22]3[CH2:21][CH2:20][CH2:19][C:18](=[O:27])[C:17]=3[C:16]3[CH:15]=[CH:14][C:13]([O:35][C:36](=[O:41])[C:37]([CH3:39])([CH3:38])[CH3:40])=[CH:12][C:11]2=3)=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C#CC1N(C(=O)Oc2ccccc2)c2cc(OC(=O)C(C)(C)C)ccc2C23OC12CCCC3O[Si](C)(C)C(C)(C)C
Agent: FB(F)F
Solvent: ClC(Cl)Cl
Solvent: CCOCC
Product: C#CC1C2=C(C(=O)CCC2)c2ccc(OC(=O)C(C)(C)C)cc2N1C(=O)Oc1ccccc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 72.5 %

Procedure:
To a solution of Compound 228 (7.0 g, 12.16 mmol) in wet CHCl3 (100 mL) was added BF3.OEt2 (7.48 mL, 60.82 mmol). The mixture was stirred at 25° C. (1. 5 hours) until TLC indicated complete conversion of Compound 228. Silica gel (10.0 g) was added to the reaction mixture followed by stirring at 25° C. for another 12 hours. Silica gel was filtered off through Celite and washed with ethyl ether (100 mL). The solvent was removed in vacuo, and the residue was purified by flash column chromatography (silica gel, 10 percent ethyl ether in benzene) to provide Compound 229 (3.91 g, 73 percent). A more polar component (about 1.0 g) was also isolated which could not be converted to Compound 229 in the presence of silica gel for prolonging reaction time. Compound 229: white solid; mp 140°-142° C.; Rf =0.44 (silica, 10 percent ethyl ether in benzene); IR (CHCl3) νmax 3305, 2977, 1737 (shoulder), 1720, 1705, 1684, 1607, 1577, 1495, 1382, 1306, 1201, 1178, 1122 cm-1 ; 1H NMR (300 MHz, CDCl3) δ 8.25 (d, J=8.7 Hz, 1 H, H1), 7.43-7.35 (m, 3 H, H4 and aromatic), 7.28-7.16 (m, 3 H, aromatic), 6.98 (dd, J=8.7, 2.4 Hz, 1 H, H2), 5.86 (d, J=2.4 Hz, 1 H, H6), 2.87-2.51 (m, 4 H, H7 and H9 ), 2.26 (d, J=2.4 Hz, 1 H, acetylenic), 2.24-2.08 (m, 2 H, H8), 1.33 (s, 9 H, COC(CH3)3); MS (FAB+) m/e (rel intensity) 444 (M+H, 82), 350 (15), 266 (20), 238 (15); HRMS for C27H26NO5 (M+H), calcd 444.1811, found 444.1842.
Reaction SMILES: [H-].[Na+].[CH:3]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[NH:19][CH:18]=[C:17]([CH:20]=[O:21])[CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.[N:22]1[CH:27]=[CH:26][CH:25]=[C:24]([S:28](Cl)(=[O:30])=[O:29])[CH:23]=1>O1CCCC1>[CH:3]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[N:19]([S:28]([C:24]4[CH:23]=[N:22][CH:27]=[CH:26][CH:25]=4)(=[O:30])=[O:29])[CH:18]=[C:17]([CH:20]=[O:21])[CH:16]=3)=[CH:11][CH:10]=2)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]1
Reactant: O=Cc1c[nH]c(-c2ccc(C3CCCCC3)cc2)c1
Reactant: O=S(=O)(Cl)c1cccnc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=Cc1cc(-c2ccc(C3CCCCC3)cc2)n(S(=O)(=O)c2cccnc2)c1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 98.2 %

Procedure:
Sodium hydride (60% in oil, 68 mg) was added to a solution of 5-(4-cyclohexylphenyl)-1H-pyrrole-3-carbaldehyde (0.17 g) in tetrahydrofuran (12 mL) at room temperature. The mixture was stirred for 20 min, 3-pyridinesulfonyl chloride (0.19 g) was added, and the mixture was stirred at room temperature for 3 hr. The reaction mixture was poured into ice water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate=3:2→2:1) to give the title compound as crystals (yield 0.26 g, 97%).
Reaction SMILES: [N+:1]([C:4]1[C:5]([C:9]([OH:11])=O)=[N:6][NH:7][CH:8]=1)([O-:3])=[O:2].[NH2:12][C@H:13]1[CH2:18][CH2:17][C@H:16]([OH:19])[CH2:15][CH2:14]1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.C(Cl)Cl>[OH:19][CH:16]1[CH2:17][CH2:18][CH:13]([NH:12][C:9]([C:5]2[C:4]([N+:1]([O-:3])=[O:2])=[CH:8][NH:7][N:6]=2)=[O:11])[CH2:14][CH2:15]1
Reactant: N[C@H]1CC[C@H](O)CC1
Reactant: O=C(O)c1n[nH]cc1[N+](=O)[O-]
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(NC1CCC(O)CC1)c1n[nH]cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 16 h
Yield: 24.2 %

Procedure:
A mixture of 4-nitro-3-pyrazolecarboxylic acid (4.98 g, 31.7 mmol), trans 4-aminocyclohexanol (3.65 g, 31.7 mmol), EDAC (6.68 g, 34.8 mmol) and HOBt (4.7 g, 34.8 mmol) in DMF (120 ml) was stirred at ambient temperature for 16 hours. The mixture was reduced in vacuo, the residue taken up in CH2Cl2 and washed successively with 5% citric acid, saturated aqueous sodium bicarbonate, water and brine. The product was found to be mainly in the citric acid wash, which was basified and extracted with EtOAc. The organic layer was dried over MgSO4, filtered and evaporated to give a white solid, which was triturated with CHCl3 to give 1.95 g of 4-nitro-1H-pyrazole-3-carboxylic acid 4-hydroxy-cyclohexylamide. (LC/MS: Rt 1.62, [M+H]+ 255).
Reaction SMILES: [CH3:1][N:2]([CH3:9])[CH2:3][CH2:4][C:5](OC)=[O:6].[NH2:10][NH2:11]>C(O)C>[NH2:10][NH:11][C:5](=[O:6])[CH2:4][CH2:3][N:2]([CH3:9])[CH3:1]
Reactant: NN
Reactant: COC(=O)CCN(C)C
Solvent: CCO
Product: CN(C)CCC(=O)NN

Procedure:
To a solution of methyl 3-(dimethylamino)propanoate (1.0 g, 7.62 mmol) in 1 mL of anhydrous ethanol was added anhydrous hydrazine (0.370 mL, 7.62 mmol). The solution was heated to reflux temperature overnight. The solvent was then removed under reduced pressure. (quantitative yield): 1H NMR (CDCl3) δ 9.49 (br s, 1H), 3.88 (br s, 2H), 2.53-2.52 (m, 2H), 2.44-2.36 (m, 2H), 2.24 (s, 6H); ES-MS (m/z) 132 [M+H]+.
Reaction SMILES: [Cl-].[Na+].[CH3:3][O:4][CH:5]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1)[C:6]([NH2:8])=O.P(Cl)(Cl)(Cl)=O.[OH-].[Na+]>ClCCCl>[CH3:3][O:4][CH:5]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1)[C:6]#[N:8]
Reactant: COC(C(N)=O)c1ccccn1
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCCl
Product: COC(C#N)c1ccccn1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To 20 ml. of dry 1,2-dichloroethane containing 2.0 g. of sodium chloride is added 3.32 g. of 2-methoxy-2-(2-pyridyl)acetamide. After stirring at room temperature for 15 minutes, 1.7 ml. of phosphorus oxychloride is added. The solution is refluxed for 18 hours. The solution is then cooled and made basic with 10% aqueous sodium hydroxide solution. The aqueous phase is extracted three times with chloroform and the combined chloroform extracts are washed three times with water and once with brine and dried over magnesium sulfate. Filtration, removal of solvent and distillation in vacuo gives 2-methoxy-2-(2-pyridyl)acetonitrile, b.p. 72°-76°C./0.2 mm.
Reaction SMILES: [CH3:1][CH:2]([CH2:6][CH2:7][CH2:8][CH:9]([CH3:11])[CH3:10])[CH2:3][CH2:4][OH:5].[C:12](OCC)(=[O:16])[CH:13]([CH3:15])[OH:14]>>[C:12]([O:5][CH2:4][CH2:3][CH:2]([CH3:1])[CH2:6][CH2:7][CH2:8][CH:9]([CH3:11])[CH3:10])(=[O:16])[CH:13]([CH3:15])[OH:14]
Reactant: CCOC(=O)C(C)O
Reactant: CC(C)CCCC(C)CCO
Product: CC(C)CCCC(C)CCOC(=O)C(C)O
Temperature: 60 °C
Yield: 62.2 %

Procedure:
A mixture of Novozym 435 (2.81 g), molecular sieves (23.17 g), 3,7-dimethyl-1-octanol (4.64 g), and ethyl lactate (14.78 g) in a 250 mL beaker was maintained at 60° C. in a convection oven for 28 hours. Upon work-up, 4.2 g of 3,7-dimethyl-1-octyl lactate (62% yield) was obtained as an amber-colored liquid. The purity of the product was >96% as assessed by HPLC-RI.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:31]=[CH:30][C:9]([C:10]([NH:12][NH:13][C:14](=O)[C:15]2[CH:20]=[CH:19][C:18]([N:21]3[CH2:25][CH2:24][CH:23]([N:26]([CH3:28])[CH3:27])[CH2:22]3)=[CH:17][CH:16]=2)=O)=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:41])=CC=1>C1(C)C=CC=CC=1>[CH2:1]([O:5][C:6]1[CH:31]=[CH:30][C:9]([C:10]2[S:41][C:14]([C:15]3[CH:20]=[CH:19][C:18]([N:21]4[CH2:25][CH2:24][CH:23]([N:26]([CH3:28])[CH3:27])[CH2:22]4)=[CH:17][CH:16]=3)=[N:13][N:12]=2)=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CCCCOc1ccc(C(=O)NNC(=O)c2ccc(N3CCC(N(C)C)C3)cc2)cc1
Solvent: Cc1ccccc1
Product: CCCCOc1ccc(-c2nnc(-c3ccc(N4CCC(N(C)C)C4)cc3)s2)cc1

Procedure:
A mixture of N′-(4-butoxybenzoyl)-4-(3-dimethylaminopyrrolidin-1-yl)benzo-hydrazide (100 mg), Lawesson's reagent (191 mg) and toluene (5 ml) was boiled under reflux for 4 hours. Volatiles were removed, and the residue was purified by preparative HPLC. The product with the molecular weight of 422.60 (C24H30N4OS) was obtained in this way; MS (ESI): 423 (M+H+).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]2[CH2:13][CH2:14][C:15](=[O:18])[NH:16][N:17]=2)=[CH:4][CH:3]=1.[CH2:19]([CH:21]1[O:23][CH2:22]1)Cl.N1CCCCC1.[OH-].[Na+]>ClCCl>[O:23]1[CH2:22][CH:21]1[CH2:19][O:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]2[CH2:13][CH2:14][C:15](=[O:18])[NH:16][N:17]=2)=[CH:4][CH:3]=1
Reactant: O=C1CCC(c2ccc(O)c3ccccc23)=NN1
Reactant: ClCC1CO1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCNCC1
Solvent: ClCCl
Product: O=C1CCC(c2ccc(OCC3CO3)c3ccccc23)=NN1
Yield: 71.7 %

Procedure:
A mixture of 6-(4-hydroxy-1-naphthyl)-4,5-dihydro-3(2H)-pyridazinone (0.5 g, 0.002 mole), epichlorohydrin (2g, 0.02 mole), and piperidine (0.02 g) was heated on a steam bath for 1.5 hours. Evaporation under reduced pressure gave an oil which was dissolved in dichloromethane and shaken with dilute sodium hydroxide (5 ml). The organic phase was washed with water, dried and evaporated to an oil which with ethanol-ether gave crystalline 6-[4-(2,3-epoxypropoxy)-1-naphthyl]-4,5-dihydro-3(2H)-pyridazinone (0.425 g, 69%, m.p. 151°-155°C). Crystallisation from ethanol gave the pure epoxide, m.p. 153.5°-155.5°C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10](Cl)(=[O:12])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[OH:14][CH2:15][CH:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1.C1COCC1.C(N(C(C)C)CC)(C)C>>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([N:19]2[CH2:20][CH2:21][CH:16]([CH2:15][OH:14])[CH2:17][CH2:18]2)(=[O:12])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: OCC1CCNCC1
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(S(=O)(=O)N2CCC(CO)CC2)cc1

Procedure:
Prepared in identical fashion to the 4-carboxamide analog by reacting 4-nitrobenzenesulfonyl chloride with 4-hydroxymethylpiperidine in THF containing 1 equivalent of diisopropyethylamine overnight at ambient temperature.
Reaction SMILES: C[O:2][C:3](=[O:45])[CH2:4][C:5]1[CH:6]=[C:7]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([C:22]3[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][CH:30]([O:35][Si](C(C)(C)C)(C)C)[C:31]([CH3:34])([CH3:33])[CH3:32])=[C:24]([CH3:43])[CH:23]=3)([CH2:20][CH3:21])[CH2:18][CH3:19])=[CH:13][C:12]=2[CH3:44])[CH:8]=[CH:9][CH:10]=1>ClCCl.FC(F)(F)C(O)=O>[CH2:18]([C:17]([C:14]1[CH:15]=[CH:16][C:11]([C:7]2[CH:8]=[CH:9][CH:10]=[C:5]([CH2:4][C:3]([OH:45])=[O:2])[CH:6]=2)=[C:12]([CH3:44])[CH:13]=1)([C:22]1[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][CH:30]([OH:35])[C:31]([CH3:33])([CH3:34])[CH3:32])=[C:24]([CH3:43])[CH:23]=1)[CH2:20][CH3:21])[CH3:19]
Reactant: CCC(CC)(c1ccc(CCC(O[Si](C)(C)C(C)(C)C)C(C)(C)C)c(C)c1)c1ccc(-c2cccc(CC(=O)OC)c2)c(C)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCC(CC)(c1ccc(CCC(O)C(C)(C)C)c(C)c1)c1ccc(-c2cccc(CC(=O)O)c2)c(C)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 80.6 %

Procedure:
[4′-(1-{4-[3-(t-Butyl-dimethyl-silanyloxy)-4,4-dimethyl-pentyl]-3-methyl-phenyl}-1-ethyl-propyl)-2′-methyl-biphenyl-3-yl]-acetic acid methyl ester (Example 66-(1); 36 mg, 0.057 mmol) was dissolved in dichloromethane/trifluoroacetic acid=1/5 (1 mL), and the solution was stirred at room temperature for three hours. The reaction mixture was concentrated under reduced pressure, and then the residue was purified by silica gel chromatography (hexane only to hexane/ethyl acetate=1/1). The product was dissolved in methanol/tetrahydrofuran=1/1 (1 mL). A 1 N sodium hydroxide aqueous solution (0.1 mL) was added, and the mixture was stirred at room temperature for one hour. A 30% sodium dihydrogenphosphate aqueous solution (0.3 mL) was added to the reaction mixture, and then the reaction mixture was concentrated under reduced pressure. The residue was purified by preparative TLC (hexane/ethyl acetate=1/1) to give the title compound (23 mg, 80%).