Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH:12][NH2:13])[C:6]([O:14][CH3:15])=[N:5]2.[CH:16](OCC)(OCC)OCC>>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]1[CH:16]=[N:13][N:12]=[C:7]1[C:6]([O:14][CH3:15])=[N:5]2
Reactant: CCOC(OCC)OCC
Reactant: COc1nc2cc(F)ccc2nc1NN
Product: COc1nc2cc(F)ccc2n2cnnc12
Temperature: 100 °C
Reaction time: 8 h

Procedure:
A mixture consisting of 15 g. (0.072 mole) of 6-fluoro-2-hydrazino-3-methoxyquinoxaline and 250 ml. of triethyl orthoformate was heated with mechanical stirring in a preheated oil both at 100° C. overnight (~16 hours). The resulting mixture was then cooled to room temperature, and the precipitate which formed was subsequently recovered by means of suction filtration and washed with ethanol to ultimately afford 11.3 g (72%) of pure 7-fluoro-4-methoxy-[1,2,4]triazolo[4,3-a]quinoxaline, m.p. 245°-246° C. (decomp.).
Reaction SMILES: [CH2:1]([C:3]1[O:4][CH:5]=[C:6](/[CH:8]=[CH:9]/[C:10]2[C:11]([O:21]COC)=[N:12][N:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:14]=2)[N:7]=1)[CH3:2].[ClH:25]>CO>[ClH:25].[CH2:1]([C:3]1[O:4][CH:5]=[C:6](/[CH:8]=[CH:9]/[C:10]2[C:11]([OH:21])=[N:12][N:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:14]=2)[N:7]=1)[CH3:2]
Reactant: CCc1nc(/C=C/c2cn(-c3ccccc3)nc2OCOC)co1
Agent: Cl
Solvent: CO
Product: CCc1nc(/C=C/c2cn(-c3ccccc3)nc2O)co1
Temperature: 50 °C
Reaction time: 1 h
Yield: 90 %

Procedure:
To a solution of 2-ethyl-4-{(E)-2-[3-(methoxymethoxy)-1-phenyl-1H-pyrazol-4-yl]ethenyl}-1,3-oxazole (2.57 g) in methanol (30 mL) was added concentrated hydrochloric acid (1.33 mL) at room temperature, and the mixture was stirred at 50° C. for 1 hr. The reaction mixture was evaporated under reduced pressure, and the residue was washed with diethyl ether to give 4-[(E)-2-(2-ethyl-1,3-oxazol-4-yl)ethenyl]-1-phenyl-1H-pyrazol-3-ol.hydrochloride (2.00 g, yield 90%) as orange crystals. melting point: 157-159° C.
Reaction SMILES: CCCC[N+](CCCC)(CCCC)CCCC.[F-].[CH2:19]([O:51][C:52]1[CH:57]=[C:56]([O:58][CH3:59])[C:55]([C:60]([N:62]2[CH2:66][C:65](=[CH2:67])[CH2:64][CH:63]2[CH2:68][O:69][Si](C(C)(C)C)(C)C)=[O:61])=[CH:54][C:53]=1[N+:77]([O-:79])=[O:78])[CH2:20][CH2:21][O:22][C:23]1[CH:28]=[C:27]([O:29][CH3:30])[C:26]([C:31]([N:33]2[CH2:37][C:36](=[CH2:38])[CH2:35][CH:34]2[CH2:39][O:40][Si](C(C)(C)C)(C)C)=[O:32])=[CH:25][C:24]=1[N+:48]([O-:50])=[O:49].[NH4+].[Cl-]>C1COCC1>[CH2:21]([O:22][C:23]1[CH:28]=[C:27]([O:29][CH3:30])[C:26]([C:31]([N:33]2[CH2:37][C:36](=[CH2:38])[CH2:35][CH:34]2[CH2:39][OH:40])=[O:32])=[CH:25][C:24]=1[N+:48]([O-:50])=[O:49])[CH2:20][CH2:19][O:51][C:52]1[CH:57]=[C:56]([O:58][CH3:59])[C:55]([C:60]([N:62]2[CH2:66][C:65](=[CH2:67])[CH2:64][CH:63]2[CH2:68][OH:69])=[O:61])=[CH:54][C:53]=1[N+:77]([O-:79])=[O:78]
Reactant: C=C1CC(CO[Si](C)(C)C(C)(C)C)N(C(=O)c2cc([N+](=O)[O-])c(OCCCOc3cc(OC)c(C(=O)N4CC(=C)CC4CO[Si](C)(C)C(C)(C)C)cc3[N+](=O)[O-])cc2OC)C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [F-]
Solvent: C1CCOC1
Product: C=C1CC(CO)N(C(=O)c2cc([N+](=O)[O-])c(OCCCOc3cc(OC)c(C(=O)N4CC(=C)CC4CO)cc3[N+](=O)[O-])cc2OC)C1
Yield: 93.9 %

Procedure:
A solution of TBAF (3.98 mL of a 1M solution in THF, 3.98 mmol) was added to the bis-silyl ether 34 (1.41 g, 1.59 mmol) in THF (35 mL) at 0° C. (ice/acetone). The reaction mixture was allowed to warm to room temperature and after a further 30 minutes saturated NH4Cl (120 mL) was added. The aqueous solution was extracted with EtOAc (3×80 mL), washed with brine (80 mL), dried (MgSO4), filtered and evaporated in vacuo to give a dark orange oil which was purified by flash chromatography (97% CHCl3/MeOH) to provide the pure diol 35 as a light orange solid (0.98 g, 94%): [α]19D=−31.9° (c=0.09, CHCl3); 1H NMR (270 MHz, CDCl3) (Rotamers) δ 7.75 and 7.71 (s×2, 2Harom), 6.96 and 6.84 (s×2, 2Harom), 5.08, 5.02 and 4.88 (br s×3, 4H, NCH2C═CH2), 4.61-4.50 (m, 2H, NCHCH2OH), 4.35-4.33 (m, 4H, OCH2CH2CH2O), 4.02-3.65 (m, 14H, NCHCH2OH, NCH2C═CH2 and OCH3), 2.88-2.43 (m, 6H, NCH2C═CH2CH2 and OCH2CH2CH2O); 13C NMR (67.8 MHz, CDCl3) (Rotamers) δ 167.9 and 166.9 (NC═O), 154.9 and 154.3 (Cquat), 148.4 and 148.2 (Cquat), 143.3 and 142.6 (Cquat), 137.2 and 137.0 (Cquat), 127.6 and 127.3 (Cquat), 109.1 (C—Harom), 108.4 (NCH2C═CH2), 108.2 (C—Harom), 65.6 and 65.4 (OCH2CH2CH2O), 64.5 and 63.3 (NCHCH2OH), 60.5 and 60.0 (NCHCH2OH), 56.8 and 56.7 (OCH3), 52.9 (NCH2C═CH2), 35.0 and 34.3 (NCH2C═CH2CH2), 29.6 and 28.6 (OCH2CH2CH2O); MS (FAB) (Relative Intensity) 657 (M++1, 10), 639 (M-OH, 2), 612 (1), 544 (M-NCH2CCH2CH2CHCH2OH, 4), 539 (1), 449 (16), 433(9), 404 (8), 236 (32), 166 (65), 151 (81), 112 (82), 82 (100); IR (NUJOL7) 3600-3200 (br, OH), 2923, 2853, 2360, 1618, 1582, 1522 (NO2), 1459, 1408, 1375, 1335 (NO2), 1278, 1218, 1061, 908, 810, 757 cm−1.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][N:9]([CH3:14])[C:10]([NH:12][CH3:13])=[S:11])=[CH:4][CH:3]=1.[CH3:15]N(C)NCC1C=NC=CC=1.ClC1C(CN)=CC=C(Cl)N=1>>[CH3:15][S:11][C:10](=[N:12][CH3:13])[N:9]([CH2:8][C:5]1[CH:6]=[N:7][C:2]([Cl:1])=[CH:3][CH:4]=1)[CH3:14]
Reactant: CN(C)NCc1cccnc1
Reactant: CNC(=S)N(C)Cc1ccc(Cl)nc1
Agent: NCc1ccc(Cl)nc1Cl
Product: CN=C(SC)N(C)Cc1ccc(Cl)nc1

Procedure:
Using the N-(6-chloro-3-pyridylmethyl)-N-methyl-N'-methylthiourea otained in (1), the procedure of Example 8 (2) was repeated to give S-methyl-N-(6-chloro-3-pyridylmethyl)-N-methyl-N'-methylisothiourea as oil.
Reaction SMILES: [C:1]1([CH3:18])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]1[CH2:16][CH2:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([OH:17])[CH:13]=2)[O:8]1.Cl[C:20]1[S:21][C:22]([C:25]([O:27][CH3:28])=[O:26])=[CH:23][N:24]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[CH3:28][O:27][C:25]([C:22]1[S:21][C:20]([O:17][C:12]2[CH:13]=[C:14]3[C:9](=[CH:10][CH:11]=2)[O:8][CH:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=2[CH3:18])[CH2:16][CH2:15]3)=[N:24][CH:23]=1)=[O:26]
Reactant: Cc1ccccc1C1CCc2cc(O)ccc2O1
Reactant: COC(=O)c1cnc(Cl)s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cnc(Oc2ccc3c(c2)CCC(c2ccccc2C)O3)s1
Temperature: 50 °C
Reaction time: 10 h
Yield: 97.6 %

Procedure:
A suspension of 2-o-Tolyl-chroman-6-ol (2.5 g, 10.4 mmol), methyl 2-chloro-thiazole-5-carboxylate (1.9 g, 10.6 mmol, 1.02 eq) and potassium carbonate (1.9 g, 1.3 eq) in dimethylformamide (30 ml) was stirred at 50° C. for 10 h. The suspension was cooled to room temperature and diluted with water. The aqueous layer was extracted with ethyl acetate and the combined organic layers washed with water, dried with sodium sulfate and filtered, and the solvent was removed under reduced pressure. The crude product was purified by column chromatography (silica gel; ethyl acetate/heptane gradient). The product was obtained as a pale yellow solid (3.87 g, 98%).
Reaction SMILES: [CH:1]1([N:7]([CH2:21]CC2C=CC=CC=2)[C:8](=[O:20])[NH:9][C:10]2[S:11][C:12]([S:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:13][N:14]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:29][CH:30]([CH3:34])[CH2:31]CN.C1(=O)CCCCC1>C(OC(=O)C)C>[CH:1]1([N:7]([CH2:21][C:30]([CH3:34])([CH3:31])[CH3:29])[C:8](=[O:20])[NH:9][C:10]2[S:11][C:12]([S:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:13][N:14]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)CSc1cnc(NC(=O)N(CCc2ccccc2)C2CCCCC2)s1
Reactant: CC(C)CCN
Solvent: O=C1CCCCC1
Solvent: CCOC(C)=O
Product: CC(C)(C)CN(C(=O)Nc1ncc(SCC(=O)O)s1)C1CCCCC1

Procedure:
Prepared as described for the synthesis of [2-(3-cyclohexyl-3-phenethyl-ureido)-thiazol-5-ylsulfanyl]-acetic acid, from 3,3-dimethyl-propylamine, cyclohexanone and 2-amino-thiazol-5-ylsulfanyl)-acetic acid ethyl ester.
Reaction SMILES: [C:1]([O:10]C)(=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[SH:4].[C:12]([C:14]1[N:19]=[C:18]([CH2:20][CH2:21][CH2:22][O:23][CH2:24][CH2:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH:17]=[CH:16][CH:15]=1)#[N:13].C(N(CC)CC)C>C1(C)C=CC=CC=1>[O:10]=[C:1]1[C:2]2[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=2[S:4][C:12]([C:14]2[N:19]=[C:18]([CH2:20][CH2:21][CH2:22][O:23][CH2:24][CH2:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH:17]=[CH:16][CH:15]=2)=[N:13]1
Reactant: COC(=O)c1ccccc1S
Reactant: CC(C)(C)OC(=O)CCOCCCc1cccc(C#N)n1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)CCOCCCc1cccc(-c2nc(=O)c3ccccc3s2)n1
Yield: 72.5 %

Procedure:
Methyl thiosalicylate (1.0 g, 6.1 mmol) and tert-butyl 3-[3-(6-cyano-2-pyridyl)propoxy]propanoate (1.6 g, 5.5 mmol) were dissolved in toluene (5.0 ml). Triethylamine (1.35 ml, 9.7 mmol) was added to the mixture and the mixture was refluxed for 14 hrs. The reaction mixture was subjected to a silica gel (110 g) column chromatography and eluted with hexane-ethyl acetate (3:2, v/v) to give the titled compound (1.7 g, 67%) as white crystals.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:8]=[C:9]([NH2:22])[CH:10]=[CH:11][C:12]=2[O:13][CH2:14][CH2:15][N:16]2[CH2:21][CH2:20][S:19][CH2:18][CH2:17]2)=[CH:5][CH:4]=[N:3]1.C(Cl)Cl.N1C=CC=CC=1.Cl[C:33]([O:35][CH:36]([CH3:38])[CH3:37])=[O:34]>CS(C)=O>[CH:36]([O:35][C:33](=[O:34])[NH:22][C:9]1[CH:10]=[CH:11][C:12]([O:13][CH2:14][CH2:15][N:16]2[CH2:17][CH2:18][S:19][CH2:20][CH2:21]2)=[C:7]([C:6]2[N:2]([CH3:1])[N:3]=[CH:4][CH:5]=2)[CH:8]=1)([CH3:38])[CH3:37]
Reactant: CC(C)OC(=O)Cl
Reactant: Cn1nccc1-c1cc(N)ccc1OCCN1CCSCC1
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: c1ccncc1
Product: CC(C)OC(=O)Nc1ccc(OCCN2CCSCC2)c(-c2ccnn2C)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84 %

Procedure:
To a solution of 3-(2-methyl-2H-pyrazol-3-yl)-4-(2-thiomorpholin-4-yl-ethoxy)-phenylamine (0.14 g, 0.443 mmol) in 2.0 mL/1.0 mL DCM/Pyridine mixture was added isopropyl chloroformate (0.06 g, 0.487 mmol), and the reaction mixture was stirred at room temperature overnight. The DCM/Pyridine mixture was evaporated to give a brown residue. The residue was dissolved in 5.0 mL of DMSO and was subjected to purification on RP-HPLC. The proper fractions were collected and lyophilized to produce [3-(2-Methyl-2H-pyrazol-3-yl)-4-(2-thiomorpholin-4-yl-ethoxy)-phenyl]-carbamic acid isopropyl ester as a solid in 84% yield. LCMS m/z (%)=405 (M+H, 100). 1H NMR (400 MHz, Acetone-d6) δ: 8.58 (bs, 1H), 7.66 (dd, J=8.4 and 2.6 Hz, 1H), 7.55 (s, 1H), 7.47 (d, J=1.81 Hz, 1H), 7.28 (d, J=1.8 Hz, 1H), 7.16 (d, J=8.9 Hz, 1H), 6.05 (d, J=1.86 Hz, 1H), 4.92-4.98, (m, 1H), 4.53 (t, J=4.3 Hz, 2H), 3.72 (s, 3H), 3.59 (dd, J=9.63 and 4.86 Hz, 2H), 3.28-3.42 (m, 4H), 2.93-2.99 (m, 4H), 1.25 (d, J=6.12 Hz, 6H).
Reaction SMILES: [N:1]([CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][N:10]1C(=O)C2C(=CC=CC=2)C1=O)=[N+:2]=[N-:3].NN>CO>[N:1]([CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][NH2:10])=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=NCCOCCON1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: CO
Product: [N-]=[N+]=NCCOCCON
Temperature: 25 °C
Reaction time: 2 h
Yield: 58.8 %

Procedure:
To a solution of 2-(2-(2-azidoethoxy)ethoxy)isoindoline-1,3-dione (43 mg, 0.17 mmol) in 0.8 mL of methanol was added hydrazine (5.5 mg, 0.17 mmol), and the resulting mixture was allowed to stir at room temperature for 2 h. Solvent was removed under reduced pressure, the crude product was purified by silica gel column chromatography (hexanes: ethyl acetate 1:2) to afford O-(2-(2-azidoethoxy)ethyl)hydroxylamine (15 mg, 0.10 mmol, 60%) as colorless oil. 1H NMR (CDCl3, 500 MHz) δ (ppm): 3.38 (t, J=4.8 Hz, 2H), 3.65 (stack, 4H), 3.82 (t, J=4.2 Hz, 2H), 5.49 (s, br, 2H).
Reaction SMILES: CO[C:3](=[O:21])[C:4]([OH:20])=[CH:5][C:6](=[O:19])[N:7]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([F:17])=[C:13]([F:18])[CH:12]=1)[O:8][CH3:9].C=O.CN.ClC1C=C(C=CC=1Cl)[CH2:30][N:31](C)[C:32](C1CN(C)C(=O)C=1O)=O>>[F:18][C:13]1[CH:12]=[C:11]([CH:16]=[CH:15][C:14]=1[F:17])[CH2:10][N:7]([O:8][CH3:9])[C:6]([C:5]1[CH2:30][N:31]([CH3:32])[C:3](=[O:21])[C:4]=1[OH:20])=[O:19]
Reactant: CN1CC(C(=O)N(C)Cc2ccc(Cl)c(Cl)c2)=C(O)C1=O
Reactant: COC(=O)C(O)=CC(=O)N(Cc1ccc(F)c(F)c1)OC
Agent: C=O
Agent: CN
Product: CON(Cc1ccc(F)c(F)c1)C(=O)C1=C(O)C(=O)N(C)C1
Yield: 53 %

Procedure:
3-[(3,4-Difluorobenzyl)-methoxy-carbamoyl]-2-hydroxy-acrylic acid methyl ester (Compound 54-D) was treated with paraformaldehyde and methylamine as described in the preparation of Compound 12 to and gave the title compound as a white solid (53% yield); mp 146–147° C. 1HNMR 400 MHz (CDCl3) δ (ppm): 3.11 (3H, s, NCH3), 3.74 (3H, s, OCH3), 4.16 (2H, s, NCH2), 4.79 (2H, s, NCH2), 7.06–7.19 (3H, m, aromatics). Anal. calcd for C14H14F2N2O4: C, 53.84; H, 4.51; N, 8.97. Found: C, 53.82; H, 4.41; N, 8.87.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:5]=1[OH:13])[CH3:2].[Br:14][CH2:15][CH2:16][CH2:17]O.C(P(CCCC)CCCC)CCC.CCOC(/N=N/C(OCC)=O)=O>O1CCCC1.C1(C)C=CC=CC=1>[Br:14][CH2:15][CH2:16][CH2:17][O:13][C:5]1[CH:6]=[C:7]([N+:10]([O-:12])=[O:11])[CH:8]=[CH:9][C:4]=1[NH:3][CH2:1][CH3:2]
Reactant: CCNc1ccc([N+](=O)[O-])cc1O
Reactant: OCCCBr
Agent: CCCCP(CCCC)CCCC
Agent: CCOC(=O)/N=N/C(=O)OCC
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCNc1ccc([N+](=O)[O-])cc1OCCCBr
Reaction time: 8 h

Procedure:
2-Ethylamino-5-nitro-phenol (2.50 g, 13.7 mmol) was azeotroped with toluene to ensure dryness, then dissolved in Tetrahydrofuran (300 mL). 3-Bromo-1-propanol (1.50 mL, 16.6 mmol), Tributylphosphine (5.5 mL, 22 mmol), and 40% w/w DEAD in Toluene (40:60, Diethyl Azodicarboxylate:Toluene, 9.6 g) were added, and the reaction was stirred under an atmosphere of Nitrogen overnight. Solvent was partially removed (300 mL removed) and the mixture was diluted with 300 mL EtOAc, then washed with satd. sodium bicarbonate (100 mL), water (2×100 mL) and brine (100 mL). The organics were dried over sodium sulfate and conc. onto 15 g SiO2 and chromatographed (ISCO, 120 g, 0-30% EtOAc:Hex) to afford [2-(3-Bromo-propoxy)-4-nitro-phenyl]-ethyl-amine as a yellow solid. [2-(3-Bromo-propoxy)-4-nitro-phenyl]-ethyl-amine was dissolved in Tetrahydrofuran (200 mL) and Sodium hydride, 60% disp. in mineral oil 0.55 g) was added. After 2 h, no reaction was observed, so N,N-Dimethylformamide (10 mL) was added. After overnight stirring, the reaction was near completion and was quenched with water, diluted with 500 mL ether then washed with water (50 mL), satd. sodium bicarbonate (2×50 mL) and brine (100 mL), dried over sodium sulfate and conc. in vacuo onto 8 g SiO2, then chromatographed (ISCO, 0-30% EtOAc:Hex, 120 g SiO2). The isolated product was ˜85% purity, with the alkyl bromide as the major impurity. The mixture was redissolved in DMF (20 mL). Potassium tert-Butoxide (0.23 g, 2.0 mmol) was added and the mixture stirred under nitrogen for 1 h, then water (100 mL) was added. The precipitate was cooled for 20 min, then collected by filtration, washing with water (2×50 mL) to give 9-Ethyl-3-nitro-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocycloheptene (1.99 g, 48%). 1H-NMR (CDCl3): 7.83 (dd, 1H, J=2.5, 8.4 Hz), 7.72 (d, 1H, J=2.5 Hz), 6.61 (d, 1H, J=8.4 Hz), 4.25 (t, 2H, J=6.4 Hz), 3.60 (t, 2H, J=5.4 Hz), 3.38 (q, 2H, J=7.2 Hz), 2.11 (m, 2H), 1.25 (t, 3H, J=7.2 Hz).
Reaction SMILES: [BH4-].[Na+].[CH:3]1([C:6]([C:8]2[N:12]([CH3:13])[C:11]3[CH:14]=[C:15]([N:18]4[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]5[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=5)=[CH:20][C:19]4=[O:33])[CH:16]=[CH:17][C:10]=3[N:9]=2)=[O:7])[CH2:5][CH2:4]1.CO>C1COCC1>[CH:3]1([CH:6]([OH:7])[C:8]2[N:12]([CH3:13])[C:11]3[CH:14]=[C:15]([N:18]4[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]5[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=5)=[CH:20][C:19]4=[O:33])[CH:16]=[CH:17][C:10]=3[N:9]=2)[CH2:5][CH2:4]1
Reactant: Cn1c(C(=O)C2CC2)nc2ccc(-n3ccc(OCc4ccc(F)cc4)cc3=O)cc21
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: Cn1c(C(O)C2CC2)nc2ccc(-n3ccc(OCc4ccc(F)cc4)cc3=O)cc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 79.4 %

Procedure:
Sodium borohydride (10.9 mg) was added to a solution of 1-(2-(cyclopropylcarbonyl)-1-methyl-1H-benzimidazol-6-yl)-4-((4-fluorobenzyl)oxy)pyridin-2(1H)-one (60.0 mg) in THF (2 ml)-MeOH (0.2 ml) at room temperature. The mixture was stirred at room temperature for 30 min. The mixture was quenched with water and extracted with EtOAc/THF twice. The organic layer was separated, washed with brine, dried over MgSO4 and concentrated in vacuo. The solid was washed with Et2O to give the title compound (47.9 mg) as a white solid.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][C:13]([C:17]([OH:19])=O)=[CH:14][CH:15]=3)[C:10]([C:20]([CH:22]3[C:24]([CH3:26])([CH3:25])[C:23]3([CH3:28])[CH3:27])=[O:21])=[CH:9]2)[CH2:3][CH2:2]1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH2:41]([NH2:48])[CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47]>CCOC(C)=O.C1COCC1>[CH2:41]([NH:48][C:17]([C:13]1[CH:12]=[C:11]2[C:16](=[CH:15][CH:14]=1)[N:8]([CH2:7][CH:4]1[CH2:3][CH2:2][O:1][CH2:6][CH2:5]1)[CH:9]=[C:10]2[C:20]([CH:22]1[C:23]([CH3:27])([CH3:28])[C:24]1([CH3:25])[CH3:26])=[O:21])=[O:19])[CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47]
Reactant: CC1(C)C(C(=O)c2cn(CC3CCOCC3)c3ccc(C(=O)O)cc23)C1(C)C
Reactant: CCCCCCCN
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCCCCCNC(=O)c1ccc2c(c1)c(C(=O)C1C(C)(C)C1(C)C)cn2CC1CCOCC1
Yield: 20 %

Procedure:
A mixture 1-(tetrahydro-2H-pyran-4-ylmethyl)-3-[(2,2,3,3-tetramethylcyclopropyl)carbonyl]-1H-indole-5-carboxylic acid (0.10 g, 0.26 mmol, the minor product of Example 114B), 1,1′-carbonyldimidazole (55 mg, 0.34 mmol) and heptylamine (50 μL, 0.34 mmol) in 4 mL of EtOAc and 3 mL of THF was processed as described in Example 93 to provide the title compound (25 mg, 0.052 mmol, 20% yield). 1H NMR (MeOH-d4, 300 MHz) δ ppm 0.87-0.95 (m, 3H), 1.34 (s, 12H), 1.37-1.43 (m, 7H), 1.43-1.51 (m, 6H), 1.58-1.71 (m, 2H), 2.13-2.27 (m, 1H), 2.18 (s, 1H), 3.32-3.37 (m, 2H), 3.40 (t, J=7.1 Hz, 2H), 3.87-3.97 (m, 2H), 4.19 (d, J=7.1 Hz, 2H), 7.58 (d, J=8.8 Hz, 1H), 7.75 (dd, J=8.6, 1.9 Hz, 1H), 8.16 (s, 1H), 8.77 (d, J=1.7 Hz, 1H); MS (DCI/NH3) m/z 481 (M+H)+; Anal. Calculated for C30H44N2O3.0.2H2O: C, 74.40; H, 9.24; N, 5.78. Found: C, 74.43; H, 9.00; N, 5.81.
Reaction SMILES: [N:1]1[S:5][N:4]=[C:3]2[C:6]([C:10]([C:12]3[N:13]=[CH:14][N:15](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[CH:16]=3)=O)=[CH:7][CH:8]=[CH:9][C:2]=12.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>C(Cl)Cl>[NH:15]1[CH:16]=[C:12]([CH2:10][C:6]2[C:3]3=[N:4][S:5][N:1]=[C:2]3[CH:9]=[CH:8][CH:7]=2)[N:13]=[CH:14]1
Reactant: O=C(c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1)c1cccc2nsnc12
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: c1cc(Cc2c[nH]cn2)c2nsnc2c1

Procedure:
A solution of benzo[1,2,5]thiadiazol-4-yl-(1-trityl-1H-imidazol-4-yl)-methanone (Intermediate L3) (500 mg, 1.12 mmol) in methylene chloride (2 mL) was treated with triethylsilane (8 mL), and trifluoroacetic acid (8 mL) at rt for 48 h. This mixture was evaporated under vacuum and quenched with a ˜7M NH3-MeOH solution. The solvent was exchanged with CH2Cl2. The solution was concentrated onto silica gel and purified by chromatography, eluting with 3% NH3-MeOH:CH2Cl2 to give 4-(1H-imidazol-4-ylmethyl)-benzo[1,2,5]thiadiazole (Intermediate L4). 4-(1H-imidazol-4-ylmethyl)-benzo[1,2,5]thiadiazole (Intermediate L4) was subjected to the appropriate process steps in Method A to produce 4-benzo[1,2,5]thiadiazol-4-ylmethyl-1,3-dihydro-imidazole-2-thione (Compound 16).
Reaction SMILES: [CH3:1]OS(OC)(=O)=O.[CH3:8][C:9]1[O:15][CH:14]=[CH:13][C:11](=[O:12])[C:10]=1[OH:16]>[OH-].[K+]>[CH3:1][O:16][C:10]1[C:11](=[O:12])[CH:13]=[CH:14][O:15][C:9]=1[CH3:8]
Reactant: COS(=O)(=O)OC
Reactant: Cc1occc(=O)c1O
Agent: [K+]
Agent: [OH-]
Product: COc1c(C)occc1=O
Yield: 36749.8 %

Procedure:
Dimethylsulphate (3.8 ml, 5.05 g, 0.04 mmol) was added to a solution of maltol (5.0 g, 0.04 mmol) in 10% aqueous potassium hydroxide (22.5 ml). After stirring for 5h the reaction mixture was extracted into CH2Cl2 (x3). The organic extract was dried (MgSO4) and concentrated under reduced pressure. The residue was chromatographed on silica gel 60 eluting with 60% ethyl acetate in hexane to give the title compound (2.06 g, 37%) as a pale yellow oil; νmax (film) 3080, 1620, and 1580 cm-1 ; δH (CDCl3) 2.3 (3H, s), 3.8 (3H, s), 6.3 (1H, d, J 6 Hz), 7.6 (1H, d, J 6 Hz).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]([C@H:8]2[O:12][C@@H:11]([CH2:13][O:14]C(=O)C3C=CC=CC=3)[S:10][CH2:9]2)[C:4](=[O:23])[N:3]=1>CO>[NH2:1][C:2]1[CH:7]=[CH:6][N:5]([C@H:8]2[O:12][C@@H:11]([CH2:13][OH:14])[S:10][CH2:9]2)[C:4](=[O:23])[N:3]=1
Reactant: Nc1ccn([C@@H]2CS[C@H](COC(=O)c3ccccc3)O2)c(=O)n1
Solvent: CO
Product: Nc1ccn([C@@H]2CS[C@H](CO)O2)c(=O)n1
Yield: 90.4 %

Procedure:
A suspension of (cis)-4-amino-1-(2-benzoyloxymethyl-1,3-oxathiolan-5-yl)-(1H)-pyrimidin-2-one (Intermediate 3) (8.19 g) and Amberlite IRA-400 (OH) resin (8.24 g) in methanol (250 ml) was stirred and heated to reflux for 11/4 h. Solids were removed by filtration then washed with methanol. The combined filtrates were evaporated. The residue was triturated with ethyl acetate (80 ml). The resulting white solid was collected by filtration to give the title product (5.09 g), 1H NMR (DMSO-d6) 3.04 (1H), 3.40 (1H), 3.73 (2H), 5.18 (1H), 5.29 (1H), 5.73 (1H), 6.21 (1H), 7.19 (2H), 7,81 (1H).
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][CH:19]([C:35]#[N:36])[C:20]([N:22]([CH:32]2[CH2:34][CH2:33]2)[CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[C:25]=2[Cl:31])=[O:21])=[CH:14][CH:13]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:37][Si]([N-][Si](C)(C)C)(C)C.[K+].IC>C1COCC1>[Si:1]([O:8][CH2:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][C:19]([C:35]#[N:36])([CH3:37])[C:20]([N:22]([CH:32]2[CH2:34][CH2:33]2)[CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[C:25]=2[Cl:31])=[O:21])=[CH:14][CH:13]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OCCCc1ccc(CC(C#N)C(=O)N(Cc2cccc(Cl)c2Cl)C2CC2)cc1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Solvent: CI
Product: CC(C#N)(Cc1ccc(CCCO[Si](C)(C)C(C)(C)C)cc1)C(=O)N(Cc1cccc(Cl)c1Cl)C1CC1
Temperature: -40 °C
Reaction time: 0.25 h

Procedure:
To a solution of 3-[4-(3-{[tert-butyl(dimethyl)silyl]oxy}propyl)phenyl]-2-cyano-N-cyclopropyl-N-(2,3-dichlorobenzyl)propanamide (prepared as detailed in Example 14, 1 eq.) in THF (0.1 M) was added, at −78° C., potassium bis(trimethylsilyl)amide (15% w/w toluene solution, 1 eq.). The resulting yellow suspension was stirred at −78° C. for 15 min and at −40° C. for 15 min. Iodomethane (1 eq.) was then added and the reaction mixture was slowly warmed to RT over 14 h. The reaction was quenched with sat. aq. NH4Cl and extracted with ether. The combined organic extracts were washed with H2O and brine, dried over MgSO4 and filtered. Concentration of the filtrate in vacuo afforded a pale yellow oil. Purification of the crude product thus obtained by way of column chromatography (SiO2, 10:1→1:1 (v/v) Hex:EtOAc) afforded the title compound as a colorless oil.
Reaction SMILES: [NH2:1][C@H:2]([CH:5]([CH3:7])[CH3:6])[CH2:3]O.[CH3:8][S:9](Cl)(=[O:11])=[O:10]>>[CH:5]([C@@H:2]1[CH2:3][CH2:8][S:9](=[O:11])(=[O:10])[NH:1]1)([CH3:7])[CH3:6]
Reactant: CC(C)[C@@H](N)CO
Reactant: CS(=O)(=O)Cl
Product: CC(C)[C@@H]1CCS(=O)(=O)N1

Procedure:
Using (R)-2-amino-3-methyl-1-butanol (5.0 g) and methanesulfonyl chloride (7.7 mL) and by the reaction and treatment in the same manner as in Preparation Example 1, the title compound (3.48 g) was obtained.
Reaction SMILES: [I-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CCCCCC.[CH2:28]([Li])[CH2:29][CH2:30][CH3:31].C[C:34]1[O:35][C:36]([C:43](OC)(OC)[CH2:44]C)=[C:37](C)[C:38](=[O:41])[C:39]=1[CH3:40]>CCOCC>[CH3:28][CH:29]1[CH:30]([CH3:31])[C:34](=[O:35])[C:39]([CH3:40])=[C:38]([CH:37]=[CH:36][CH2:43][CH3:44])[O:41]1
Reactant: CCC(OC)(OC)c1oc(C)c(C)c(=O)c1C
Reactant: [Li]CCCC
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [I-]
Solvent: CCCCCC
Solvent: CCOCC
Product: CCC=CC1=C(C)C(=O)C(C)C(C)O1
Temperature: 0 °C
Reaction time: 1 h
Yield: 56 %

Procedure:
40.4 g (0.1 moles) of methyltriphenylphosphonium iodide were suspended in 400 ml of anhydrous ether under argon gas flow. After cooling the mixture to 0° C., 90 ml (0.15 moles) of a hexane solution of n-butyl lithium were dripped. 19.6 g (0.1 moles) of 2,3-dihydro-2,3,5-trimethyl-6-(2-methyl-1-oxoethyl)-4H-pyran-4-on obtained in Example 3 were added dripwise to the mixture solution, and the mixture was agitated for 1 hour to obtain 10.1 g of 2,3-dihydro-2,3,5-trimethyl-6-(3-methyl-1-propenyl)-4H-pyran-4-one. The yield was 56%.