Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[N:8]=[C:7]([CH2:9][NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH:6]=[CH:5][CH:4]=1)#[N:2].[C:18](OC)(=[O:26])[C:19]1[C:20](=[CH:22][CH:23]=[CH:24][CH:25]=1)[SH:21].C(N(CC)CC)C>C1(C)C=CC=CC=1>[O:26]=[C:18]1[C:19]2[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=2[S:21][C:1]([C:3]2[N:8]=[C:7]([CH2:9][NH:10][C:11](=[O:17])[O:12][C:13]([CH3:14])([CH3:16])[CH3:15])[CH:6]=[CH:5][CH:4]=2)=[N:2]1
Reactant: COC(=O)c1ccccc1S
Reactant: CC(C)(C)OC(=O)NCc1cccc(C#N)n1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)NCc1cccc(-c2nc(=O)c3ccccc3s2)n1
Yield: 71.7 %

Procedure:
tert-Butyl (6-cyano-2-pyridyl)methylcarbamate (1.6 g, 6.8 mmol) and methyl thiosalicylate (1.8 g, 10.9 mmol) were dissolved in toluene (6 ml), and triethylamine (3.0 ml, 21.5 mmol) was added thereto. The mixture was refluxed for 20 hrs. After cooling, the precipitates were collected by filtration and dissolved in chloroform. The solution was subjected to a silica gel column chromatography. The fractions eluted with chloroform-methanol (20:1, v/v) were collected, concentrated and recrystallized from hexane-chloroform to give the titled compound (1.8 g, 72%) as pale yellow crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][NH:11][C@H:12]2[CH2:17][CH2:16][C@H:15]([C:18]3[CH:27]=[CH:26][C:21]4[NH:22][C:23](=[O:25])[O:24][C:20]=4[CH:19]=3)[CH2:14][CH2:13]2)=[CH:4][CH:3]=1.[BH-](OC(C)=O)(OC(C)=O)O[C:30](C)=O.[Na+].[OH-].[Na+]>CO.C(Cl)Cl.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][N:11]([CH3:30])[C@H:12]2[CH2:17][CH2:16][C@H:15]([C:18]3[CH:27]=[CH:26][C:21]4[NH:22][C:23](=[O:25])[O:24][C:20]=4[CH:19]=3)[CH2:14][CH2:13]2)=[CH:4][CH:3]=1
Reactant: O=c1[nH]c2ccc([C@H]3CC[C@H](NCCCc4ccc(Cl)cc4)CC3)cc2o1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Solvent: O
Product: CN(CCCc1ccc(Cl)cc1)[C@H]1CC[C@H](c2ccc3[nH]c(=O)oc3c2)CC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a stirred solution of 6-{trans-4-[3-(4-chlorophenyl)-propylamino]-cyclohexyl}-3H-benzoxazol-2-one (655 mg, 1.7 mmol) in MeOH (20 mL) and CH2Cl2 (25 mL) was added p-formaldehyde (0.70 mL of a 37 wt % solution in H2O, 8.5 mmol). The reaction mixture was warmed to dissolve compound the amine, and then stirred at room temperature for 15 minutes. NaBH(OAc)3 was added and stirring was continued for 12 hours. The reaction mixture was brought to pH 8 with solid NaOH, concentrated under reduced pressure, and purified by flash chromatography (silica, 95:4.5:0.5 CH2Cl2:MeOH:NH4OH). Formation of the HCl salt, followed by recrystallization (MeOH:Et2O) gave 6-(trans-4-{[3-(4-chlorophenyl)propyl]-methylamino}-cyclohexyl)-3H-benzoxazol-2-one (461 mg, 66%), as a white solid: mp 267-271° C.; IR (KBr): 2949, 1769, 1494, 1452 cm−1; 1H NMR (500 MHz, DMSO-d6): δ 11.50 (s, 1H), 10.39 (s, 1H), 7.37 (d, J=8 Hz, 2H), 7.30 (d, J=8 Hz, 2H), 7.16 (s, 1H), 7.00 (br s, 2H), 3.33-3.26 (m, 1H), 3.18-3.10 (m, 1H), 3.04-2.95 (m, 1H), 2.69 (d, J=5 Hz, 3H), 2.68-2.62 (m, 2H), 2.58-2.51 (m, 1H), 2.18-1.98 (m, 4H), 1.93-1.87 (m, 2H), 1.69-1.51 (m, 4H); HRMS-APCI (m/z): [M+H]+ calcd for C23H27ClN2O2, 399.1839; found, 399.1831; HPLC: method A, 6.35 minutes (98.6%); method B. 11.82 minutes (99.1%); Anal. Calcd for C23H27ClN2O2.HCl.0.25H2O: C, 62.80; H, 6.53; N, 6.37. Found: C, 62.94; H, 6.57; N, 6.21.
Reaction SMILES: Br[CH2:2][C:3]1[C:12]([C:13](=[O:19])[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[C:11]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([O:28][CH3:29])[CH:21]=2)[C:10]2[C:5](=[CH:6][C:7]([O:32][CH3:33])=[C:8]([O:30][CH3:31])[CH:9]=2)[N:4]=1.[CH2:34]([NH:36][CH2:37][CH3:38])[CH3:35]>>[CH2:34]([N:36]([CH2:2][C:3]1[C:12]([C:13](=[O:19])[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[C:11]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([O:28][CH3:29])[CH:21]=2)[C:10]2[C:5](=[CH:6][C:7]([O:32][CH3:33])=[C:8]([O:30][CH3:31])[CH:9]=2)[N:4]=1)[CH2:37][CH3:38])[CH3:35]
Reactant: CCCCCC(=O)c1c(CBr)nc2cc(OC)c(OC)cc2c1-c1ccc(OC)c(OC)c1
Reactant: CCNCC
Product: CCCCCC(=O)c1c(CN(CC)CC)nc2cc(OC)c(OC)cc2c1-c1ccc(OC)c(OC)c1

Procedure:
According to the same manner as that described in Example 1, 2-bromomethyl-4-(3,4-dimethoxyphenyl)-6,7-dimethoxy-3-hexanoylquinoline was reacted with diethylamine to give 2-(N,N-diethylaminomethyl)-4-(3,4-dimethoxyphenyl)-3-hexanoyl-6,7-dimethoxyquinoline. This compound was recrystallized from ethyl acetate - hexane to give colorless prisms. mp. 104°-106° C.
Reaction SMILES: C([NH:4][C:5]1[N:13]=[C:12]2[C:8]([N:9]=[CH:10][N:11]2[CH2:14][CH:15]([CH2:28][O:29][Si](C(C)(C)C)(C2C=CC=CC=2)C2C=CC=CC=2)/[CH:16]=[CH:17]/[P:18]([O:24][CH:25]([CH3:27])[CH3:26])([O:20][CH:21]([CH3:23])[CH3:22])=[O:19])=[C:7](Cl)[N:6]=1)(=O)C.[C:48](=O)(O)[O-:49].[Na+]>Cl>[NH2:4][C:5]1[N:13]=[C:12]2[C:8]([N:9]=[CH:10][N:11]2[CH2:14][CH:15]([CH2:28][OH:29])/[CH:16]=[CH:17]/[P:18]([O:20][CH:21]([CH3:23])[CH3:22])([O:24][CH:25]([CH3:27])[CH3:26])=[O:19])=[C:7]([O:49][CH3:48])[N:6]=1
Reactant: CC(=O)Nc1nc(Cl)c2ncn(CC(/C=C/P(=O)(OC(C)C)OC(C)C)CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)c2n1
Reactant: O=C([O-])O
Agent: Cl
Agent: [Na+]
Product: COc1nc(N)nc2c1ncn2CC(/C=C/P(=O)(OC(C)C)OC(C)C)CO
Yield: 72 %

Procedure:
A solution of (E)-2-acetamido-9-[2-(t-butyldiphenylsilyloxy)methyl-4-(diisopropoxyphosphoryl)but-3-enyl]-6-chloropurine (330 mg, 473 μmol) in 7% methanolic hydrogen chloride (15 ml) was stirred at room temperature for 7 h. The solution was reduced to 1/3 volume then neutralised by addition of saturated sodium bicarbonate solution. The solvent was removed and the residue purified by column chromatography on silica gel eluting with dichloromethane-methanol (19:1, 6:1) to give (E)-2-amino-9-[4-(diisopropoxyphosphoryl)-2-(hydroxymethyl)but-3-enyl]-6-methoxypurine as a colourless gum (140 mg, 72%); λmax (EtOH) 249 (8,632) and 283 (9,086)nm; υmax (KBr) 3335, 2980, 1610, 1585, 1475, 1410, 1400 and 1250 cm-1 ; δH [(CD2)2SO] 1.10 (12H, m, CH(CH3)2), 3.02 (1H, m, CH), 3.50 (2H, t, J 5 Hz, CH2O), 3.94 (3H, s, CH3O), 4.10-4.40 (4H, m, CH2N and CH(CH3)2), 4.97 (1H, t, J 5 Hz, D2O exchangeable, OH), 5.61 (1H, dd, J 17 Hz and 20 Hz, PCH=CH), 6.43 (2H, br.s, D2O exchangeable, NH2), 6.50 (1H, ddd, J 8 Hz, 17 Hz and 22 Hz, PCH=CH), 7.80 (1H, s, H-8) (Found: MH+ 414. 1900). C17H28N5O5P requires MH+ 414.1906).
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([C:8]2[S:9][CH:10]=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)[N:12]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:19][N:20](C)C=O>C1(C)C=CC=CC=1.[C-]#N.[Zn+2].[C-]#N.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>[C:19]([C:2]1[CH:3]=[C:4]([C:8]2[S:9][CH:10]=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)[N:12]=2)[CH:5]=[CH:6][CH:7]=1)#[N:20]
Reactant: Ic1cccc(-c2nc(-c3ccccn3)cs2)c1
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: Cc1ccccc1
Product: N#Cc1cccc(-c2nc(-c3ccccn3)cs2)c1
Temperature: 80 °C
Yield: 30 %

Procedure:
A mixture of 2-(3-iodophenyl)-4-(pyridin-2-yl)-1,3-thiazole (130 mg, 0.36 mmol), zinc cyanide (117 mg, 1.0 mmol) and Pd(PPh3)4 (10 mg, 0.009 mmol) in N,N-dimethylformamide (2 mL) was heated overnight at 80° C. The mixture was cooled and diluted with toluene (5 mL). The organic solution was washed with 2N NH40H (2×10 mL). The mixture was then extracted with ethyl acetate and the organic extract was washed with brine. The organic solution was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Silica gel chromatography afforded 28 mg (30%) of 2-(3-cyanophenyl)-4-(pyridin-2-yl)-1,3-thiazole: 1H-NMR (CDCl3), δ ppm: 8.65 (d, 1H), 8.38 (s, 1H), 8.25 (m, 2H), 8.15 (s, 1H), 7.85 (m, 1H), 7.72 (m, 1H), 7.6 (t, 1H), 7.28 (m, 1H). GC/EI-MS gave m/z 263 (M+)
Reaction SMILES: [CH2:1]=[O:2].[C:3](=O)([O-])O.[Na+].[Br-].[C:9]1([CH:15]([C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)[O:16][C:17]([C:19]2[N:24]3[C:25](=[O:30])[C@@H:26]([NH:27]C=O)[C@H:23]3[S:22][CH2:21][C:20]=2[CH2:31][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[O:18])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C(Cl)Cl>[CH:1]([NH:27][C@@H:26]1[C:25](=[O:30])[N:24]2[C:19]([C:17]([O:16][CH:15]([C:51]3[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=3)[C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)=[O:18])=[C:20]([CH:31]=[CH2:3])[CH2:21][S:22][C@H:23]12)=[O:2]
Reactant: O=C([O-])O
Reactant: O=CN[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(C[P+](c3ccccc3)(c3ccccc3)c3ccccc3)CS[C@H]12
Reactant: C=O
Agent: [Br-]
Agent: [Na+]
Solvent: ClCCl
Product: C=CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](NC=O)[C@H]2SC1
Reaction time: 0.42 h

Procedure:
40%-Aqueous formaldehyde solution (10 ml.) and 3%-sodium hydrogen carbonate solution (30 ml.) were added to a vigorously stirred solution of [4-diphenylmethoxycarbonyl-7β-formamidoceph-3-em-3-ylmethyl]-triphenylphosphonium bromide (1.875 g., 2.5 mmole) in methylene chloride (20 ml.). The two-phase mixture was stirred for 25 minutes and the organic phase was washed with 2N-hydrochloric acid and water (20 ml of each), dried (MgSO4), and evaporated to an orange foam (1.68 g.). This foam was chromatographed on Kieselgel G (Merck, 75 g.) with 10- and 17%-acetone in methylene chloride as eluants. The appropriate fractions were combined and evaporated to give the title ester as a pale-yellow crystalline solid (334 mg., 32%), m.p. 148° to 152° (decomp), [α]D23 - 66° (c 1.19; Me2SO), λmax. (EtOH) 295 nm (ε 9,350), νmax. (CHBr3), (NH), 1787 (azetidin-2-one), 1725 (CO2R), and 1696 and 1500 cm-1 (CONH), τ (CDCl3) 1.78 (1H, s; CHO), 2.4 to 2.8 (10 H, m; (C6H5)2CH), 2.96 (1H, dd, J 11 and 18 Hz; CH=CH2), 3.01 (1H, s; (C6H5)2CH), 3.29 (1H, d, J 9 Hz; NH), 4.12 (1H, dd, J 9 and 5 Hz; C7 -H), 4.55 (1H, d, J 18 Hz) and 4.72 (1H, d, J 11 Hz) (CH=CH2), 5.02 (1H, d, J 5 Hz; C6 -H), 6.34 and 6.57 (2H, AB-q, J 18 Hz; C2 -H2).
Reaction SMILES: C([NH:8][CH2:9][C:10](O)=[O:11])(OC(C)(C)C)=O.CN(C=O)C.Cl.[NH2:19][CH2:20][C:21]1[CH:22]=[CH:23][C:24]([F:46])=[C:25]([N:27]2[C:32]([CH3:33])=[CH:31][C:30]([O:34][CH2:35][C:36]3[CH:41]=[CH:40][C:39]([F:42])=[CH:38][C:37]=3[F:43])=[C:29]([Cl:44])[C:28]2=[O:45])[CH:26]=1.Cl>CO>[ClH:44].[Cl:44][C:29]1[C:28](=[O:45])[N:27]([C:25]2[CH:26]=[C:21]([CH:22]=[CH:23][C:24]=2[F:46])[CH2:20][NH:19][C:10](=[O:11])[CH2:9][NH2:8])[C:32]([CH3:33])=[CH:31][C:30]=1[O:34][CH2:35][C:36]1[CH:41]=[CH:40][C:39]([F:42])=[CH:38][C:37]=1[F:43]
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: Cc1cc(OCc2ccc(F)cc2F)c(Cl)c(=O)n1-c1cc(CN)ccc1F
Agent: Cl
Solvent: CO
Solvent: CN(C)C=O
Product: Cc1cc(OCc2ccc(F)cc2F)c(Cl)c(=O)n1-c1cc(CNC(=O)CN)ccc1F
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 130.1 %

Procedure:
A 25 mL round bottomed flask equipped with stirbar and nitrogen inlet was charged with boc-glycine (105 mg, 0.6 mmol) and 8 mL of DMF. The mixture was cooled to 0° C. and isboutylchloroformate (77.5 μL, 0.6 mmol) was added and stirred for 20 min. 1-[5-(aminomethyl)-2-fluorophenyl]-3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin-2(1H)-one hydrochloride (250 mg, 0.6 mmol) was added and stirred for 3 h. After completion of the reaction by LC-MS, concentrated HCl (2 mL) and 2 mL of methanol was added to remove the boc group. The reaction was stirred for 24 h, neutralized with 2M NaOH and extracted with ethyl acetate. The organic phase was dried with Na2SO4 and concentrated in vacuo to obtain (196 mg, 66%) of the desired product as a the HCl salt. 1H NMR (400 MHz, (CD3OD) δ 7.6 (q, J=8 and 6.5 Hz, 1H), 7.5 (m, 1H), 7.3 (m, 2H), 7.0 (m, 2H), 6.63 (s, 1H), 5.35 (s, 2H), 4.4 (q, J=15 and 13.6 Hz, 2H), 3.7 (s, 2H), 2.05 (s, 3H) ppm. ES-HRMS m/z 466.1157 (M+H calcd for C22H20ClF3N3O3 requires 466.1140).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:27])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10](=[O:17])[N:9]2[CH:18]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=2)[CH3:19])=[CH:4][CH:3]=1.[CH2:28](O)[CH2:29][CH2:30][CH2:31][OH:32]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([O:27][CH2:28][CH2:29][CH2:30][CH2:31][OH:32])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10](=[O:17])[N:9]2[CH:18]([C:20]2[CH:21]=[CH:22][C:23]([Cl:26])=[CH:24][CH:25]=2)[CH3:19])=[CH:4][CH:3]=1
Reactant: CC(c1ccc(Cl)cc1)N1C(=O)c2ccccc2C1(O)c1ccc(Cl)cc1
Reactant: OCCCCO
Product: CC(c1ccc(Cl)cc1)N1C(=O)c2ccccc2C1(OCCCCO)c1ccc(Cl)cc1
Yield: 37.6 %

Procedure:
The named compound was synthesised from 3-(4-chlorophenyl)-2-[1-(4-chlorophenyl)-ethyl]-3-hydroxy-2,3-dihydroisoindol-1-one (498 mg, 1.37 mmol, 1 equiv.) and 1,4-butanediol (616 mg, 6.85 mmol, 5 equiv.) using General Procedure A and obtained as a pale yellow oil (242 mg, 51%). 1H NMR (300 MHz, CDCl3): 7.87-7.83 (m, 1H, C(O)═C═CH), 7.53-7.46 (m, 2H, Ar—H), 7.07-7.03 (m, 9H, Ar—H), 4.41 (q, J=7.2 Hz, 1H, N—CH), 3.70 (m, 2H, HO—CH2), 3.29-3.25 and 3.01-2.95 (m, 2H, OCH2), 1.86 (d, J=7.2 Hz, 3H, CH3), 1.77-1.68 (m, 4H, CH2). 13C NMR (75 MHz, CDCl3): 168.31, 145.26, 141.47, 137.76, 134.79, 133.15, 133.06, 132.84, 130.20, 129.67, 128.75, 128.41, 128.27, 123.71, 123.27, 95.44, 63.35, 62.89, 52.49, 29.96, 26.48, 20.08. m/z (ES): 470 [M+H]+. HPLC: Rt=3.76 min. Anal.: calc. for C26H25Cl2NO3: C, 66.39; H, 5.36; N, 2.98. Found: C, 66.33; H, 5.25; N, 2.46.
Reaction SMILES: [CH:1]([C:3]1[N:4]=[C:5]([F:27])[N:6]([C:8]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:7]=1)=O.Cl.[NH2:29][OH:30].N1C=CC=CC=1>C(O)C>[F:27][C:5]1[N:6]([C:8]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:7]=[C:3]([CH:1]=[N:29][OH:30])[N:4]=1
Reactant: NO
Reactant: O=Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c(F)n1
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Product: ON=Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c(F)n1
Reaction time: 18 h

Procedure:
To a stirred mixture of 4-formyl-2-fluoro-1-triphenylmethylimidazole (0.356 g.) and hydroxylamine hydrochloride (0.035 g.) in ethanol (4 ml.) was added pyridine (0.2 ml.). Stirring was continued at ambient temperature for 18 hours and the precipitated solid was filtered to give 2-fluoro-4-hydroxyiminomethyl-1-triphenylmethylimidazole, m.p. 147°-149°. Further amounts of product could be isolated from the mother liquors.
Reaction SMILES: [CH2:1]([N:5]1[C:9](=[O:10])[C:8](Cl)=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[S:6]1(=[O:19])=[O:18])[CH2:2][CH2:3][CH3:4].[NH2:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][OH:28])=[CH:23][CH:22]=1>CN(C=O)C>[CH2:1]([N:5]1[C:9](=[O:10])[C:8]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([CH2:27][OH:28])=[CH:23][CH:22]=2)=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[S:6]1(=[O:19])=[O:18])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN1C(=O)C(Cl)=C(c2ccccc2)S1(=O)=O
Reactant: Nc1ccc(CO)cc1
Solvent: CN(C)C=O
Product: CCCCN1C(=O)C(Nc2ccc(CO)cc2)=C(c2ccccc2)S1(=O)=O
Temperature: 140 °C
Yield: 4.7 %

Procedure:
2-Butyl-4-chloro-5-phenylisothiazol-3(2H)-one 1,1-dioxide (110 mg, 0.331 mmol) was dissolved in dry DMF (0.5 mL) under nitrogen atmosphere. (4-Aminophenyl)methanol (122 mg, 0.991 mmol) was added and the reaction mixture was heated in a microwave reactor for 25 mins at 140° C. The crude product was purified by preparative HPLC affording the title compound (6 mg, 4.7%). 1H NMR (500 MHz, CD3CN): δ 1.00 (t, 3H), 1.43-1.52 (m, 2H), 1.78-1.85 (m, 2H), 3.03 (t, 1H), 3.75 (t, 2H), 4.40 (d, 2H), 6.77 (d, 2H), 6.97 (d, 2H), 7.13-7.19 (m, 4H), 7.24-7.28 (m, 1H), 7.76 (bs, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:7](=[O:9])[CH3:8])[S:5][CH:6]=1.[Br-:10].[Br-].[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC>CO.ClCCl>[Br:10][CH2:8][C:7]([C:4]1[S:5][CH:6]=[C:2]([Br:1])[CH:3]=1)=[O:9]
Reactant: CC(=O)c1cc(Br)cs1
Reactant: [Br-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: ClCCl
Solvent: CO
Product: O=C(CBr)c1cc(Br)cs1

Procedure:
To 1-(4-bromothiophen-2-yl)ethanone (10 g, 48.8 mmol) in methanol (98 mL) and dichloromethane (163 mL) is added tetra-n-butylammonium tribromide (28.8 g, 58.5 mmol). The reaction mixture is concentrated under reduced pressure at 50° C. to give a residue which is purified by silica gel chromatography, eluting with dichloromethane to give crude 2-bromo-1-(4-bromo-2-thienyl)ethanone. To a solution of the crude 2-bromo-1-(4-bromo-2-thienyl)ethanone in acetonitrile (200 ml) is added potassium carbonate (20.2 g, 146 mmol) and diallylamine (9.48 g, 97.5 mmol). The reaction is stirred at room temperature for 2 hours. Water is added and the solution is extracted with ethyl acetate. The organic phases are combined, dried over sodium sulfate, filtered, and concentrated under reduced pressure to give the crude title compound. ES/MS (m/e): (79Br/81Br) 300/302 (M+H).
Reaction SMILES: [CH:1]1([C:7]([OH:9])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[NH:31]1[CH2:34][CH:33]([C:35]([N:37]2[CH2:43][CH2:42][CH2:41][N:40]([CH:44]3[CH2:47][CH2:46][CH2:45]3)[CH2:39][CH2:38]2)=[O:36])[CH2:32]1.CCN(C(C)C)C(C)C>C(Cl)Cl.CN(C=O)C.C(Cl)Cl>[CH:44]1([N:40]2[CH2:41][CH2:42][CH2:43][N:37]([C:35]([CH:33]3[CH2:32][N:31]([C:7]([CH:1]4[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]4)=[O:9])[CH2:34]3)=[O:36])[CH2:38][CH2:39]2)[CH2:47][CH2:46][CH2:45]1
Reactant: O=C(C1CNC1)N1CCCN(C2CCC2)CC1
Reactant: O=C(O)C1CCCCC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(C1CN(C(=O)C2CCCCC2)C1)N1CCCN(C2CCC2)CC1
Yield: 82.2 %

Procedure:
To a stirred solution of cyclohexanecarboxylic acid (10.8 mg, 0.084 mmol) in DCM/DMF (1.1 ml) was added HOBt (11.4 mg, 0.084 mmol) and EDCI (16.1 mg, 0.084 mmol). After 10 mins a solution of 1-(azetidin-3-ylcarbonyl)-4-cyclobutyl-1,4-diazepane (20 mg, 0.084 mmol) in DCM (1 ml) and DIPEA (0.01 ml, 0.084 mmol) was added dropwise. After 15 h the solvent was evaporated at reduced pressure and purified by silica FCC (eluting with 99:1 to 95:5 gradient of DCM/2M NH3 in MeOH) to give the title compound (24 mg, 82% yield) as brown oil.
Reaction SMILES: [CH3:1][C:2]([CH3:14])([O:5][C:6]1[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[CH:8][CH:7]=1)[C:3]#[CH:4].I[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1.O.C(OCC)(=O)C>C(NCC)C.[Cu]I.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:1][C:2]([CH3:14])([O:5][C:6]1[CH:7]=[CH:8][C:9]([C:10]#[N:11])=[CH:12][CH:13]=1)[C:3]#[C:4][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1
Reactant: Ic1ccccn1
Reactant: C#CC(C)(C)Oc1ccc(C#N)cc1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCNCC
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C#Cc1ccccn1)Oc1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 88.2 %

Procedure:
53 mg of copper(I) iodide, 293 mg of triphenylphosphine and 99 mg of palladium(II) chloride were dissolved in 320 ml of diethylamine. 10.4 g of 4-(1,1-dimethyl-2-propynyloxy)benzonitrile and 11.5 g of 2-iodopyridine were added and the mixture was stirred at room temperature under a nitrogen atmosphere for 3 days. Water and ethyl acetate were added and the organic phase was separated, dried over sodium sulphate and evaporated. The residue was chromatographed on silica gel using ethyl acetate/petroleum ether (1:3) and then ethyl acetate/petroleum ether (1:2) for the elution to give 12.98 g of 4-[1,1-dimethyl-3-(2-pyridyl)-2-propynyloxy]benzonitrile in the form of an oil.
Reaction SMILES: [CH3:1][C:2]1[O:13][C:5]2[CH2:6][N:7]([CH3:12])[CH2:8][CH2:9][CH:10]([OH:11])[C:4]=2[CH:3]=1.[CH2:14]([NH:16][C:17]([C:19]1[CH:24]=[CH:23][C:22](F)=[C:21]([Cl:26])[CH:20]=1)=[O:18])[CH3:15]>>[ClH:26].[CH2:14]([NH:16][C:17]([C:19]1[CH:24]=[CH:23][C:22]([O:11][CH:10]2[CH2:9][CH2:8][N:7]([CH3:12])[CH2:6][C:5]3[O:13][C:2]([CH3:1])=[CH:3][C:4]2=3)=[C:21]([Cl:26])[CH:20]=1)=[O:18])[CH3:15]
Reactant: Cc1cc2c(o1)CN(C)CCC2O
Reactant: CCNC(=O)c1ccc(F)c(Cl)c1
Product: CCNC(=O)c1ccc(OC2CCN(C)Cc3oc(C)cc32)c(Cl)c1
Product: Cl

Procedure:
The same method as in Example 3 was conducted using 2,7-dimethyl-5,6,7,8-tetrahydro-4H-furo[2,3-c]azepin-4-ol (Reference Example 20) instead of 6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-4-ol (Reference Example 6) and was conducted using 4-ethylcarbamoyl-2-chloro-1-fluorobenzene instead of 1,3-difluorobenzene to give the objective compound.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][N+:3]=1[O-].ClC1N=C(C[O:19][C:20](=[O:22])[CH3:21])C=CC=1>>[C:20]([O:22][CH2:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][N:3]=1)(=[O:19])[CH3:21]
Reactant: CC(=O)OCc1cccc(Cl)n1
Reactant: COc1cc[n+]([O-])c(C)c1
Product: COc1ccnc(COC(C)=O)c1

Procedure:
Starting with 2-methyl-4-methoxypyridine-1-oxide (2.1 g) in the procedure of Part (ii) afforded 2.5 g of 2-acetoxymethyl-4-methoxypyridine which was contaminated with about 25% of 5-acetoxy-2-methyl-4-methoxypyridine. This mixture was dissolved in methanol (10 ml) containing 1.118 g (20.7 mmole) sodium methoxide and stirred at reflux for one hour. The methanol was evaporated in vacuo, the residue diluted with water, neutralized with dilute hydrochloric acid and extracted with chloroform. The organic layer was washed with brine, dried (MgSO4) and concentrated in vacuo to give 853 mg (41%) 2-hydroxymethyl-4-methoxypyridine. 1H-NMR(CDCl3)ppm (delta): 3.9 (s, 3H), 4.72 (s, 2H), 5.35 (bs, 1H), 6.7 (dd, 1H), 6.95 (d, 1H), 8.3 (d, 1H).
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]([F:24])([F:23])[F:22])[CH:15]=2)[N:8]=1)=O.[NH:26]([C:28]1[CH:29]=[C:30]([CH:34]=[CH:35][CH:36]=1)[C:31]([NH2:33])=[O:32])N>C(O)(=O)C>[O:13]=[C:12]1[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]([F:24])([F:23])[F:22])[CH:15]=2)[N:8]=[C:7]1[C:5]1[N:26]([C:28]2[CH:29]=[C:30]([CH:34]=[CH:35][CH:36]=2)[C:31]([NH2:33])=[O:32])[N:2]=[CH:3][CH:4]=1
Reactant: CN(C)/C=C/C(=O)c1nn(-c2cccc(OC(F)(F)F)c2)ccc1=O
Reactant: NNc1cccc(C(N)=O)c1
Solvent: CC(=O)O
Product: NC(=O)c1cccc(-n2nccc2-c2nn(-c3cccc(OC(F)(F)F)c3)ccc2=O)c1

Procedure:
3-((E)-3-Dimethylamino-acryloyl)-1-(3-trifluoromethoxy-phenyl)-1H-pyridazin-4-one (A-6) and 3-hydrazino-benzamide (2 eq) were dissolved in a sealed tube in acetic acid and irradiated in MW at 120° C. for 15 min. The solvent of the reaction mixture was removed and the crude product was purified by preparative HPLC yielding the desired product.