Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:16]=4[Cl:23])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:24]([CH:26]2[CH2:28][CH2:27]2)[OH:25])=[CH:4][CH:3]=1.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.C(P(CCCC)CCCC)CCC.[F:60][C:61]([F:65])([F:64])[CH2:62]O>O1CCCC1>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:16]=4[Cl:23])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:24]([CH:26]2[CH2:28][CH2:27]2)[O:25][CH2:62][C:61]([F:65])([F:64])[F:60])=[CH:4][CH:3]=1
Reactant: OCC(F)(F)F
Reactant: COc1ccc(N2CCCn3c2nc2c(Cl)ccc(C(O)C4CC4)c23)c(Cl)c1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: COc1ccc(N2CCCn3c2nc2c(Cl)ccc(C(OCC(F)(F)F)C4CC4)c23)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 59.6 %

Procedure:
To a solution of [9-chloro-1-(2-chloro-4-methoxyphenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazol-6-yl](cyclopropyl)methanol (120 mg, 0.26 mmol), 1,1′-(azodicarbonyl)dipiperidine (131 mg, 0.52 mmol) in tetrahydrofuran (5.0 mL) was added tri(n-butyl)phosphine (0.130 mL, 0.52 mmol) at room temperature. After the mixture was stirred at room temperature for 10 min under nitrogen atmosphere, 2,2,2-trifluoroethanol (0.189 mL, 2.58 mmol) was added to the reaction mixture. The mixture was stirred at 60° C. for 5 hr under nitrogen atmosphere. The mixture was concentrated in vacuo and diethyl ether was added to the residue. The solid was removed by filtration and the filtrate was concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with a 10-25% ethyl acetate/n-hexane gradient mixture and recrystallization from ethyl acetate/n-hexane to give the title compound (77.4 mg, 0.155 mmol, 60%) as colorless crystals.
Reaction SMILES: Cl[C:2]1[C:3](=[O:23])[O:4][C:5]([CH2:14][CH2:15][CH2:16][CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)([CH:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)[CH2:6][C:7]=1[OH:8].ClC1C(=O)OC(CCC2CCCCC=2)(C2CCCC2)CC=1O.[Cl:46][C:47]1[CH:59]=[CH:58][C:50]2[N:51]([CH:55]([CH3:57])[CH3:56])[C:52]([SH:54])=[N:53][C:49]=2[CH:48]=1.N1C=CC(C2NC(S)=NN=2)=CC=1>>[Cl:46][C:47]1[CH:59]=[CH:58][C:50]2[N:51]([CH:55]([CH3:57])[CH3:56])[C:52]([S:54][C:2]3[C:3](=[O:23])[O:4][C:5]([CH2:14][CH2:15][CH2:16][CH:17]4[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]4)([CH:9]4[CH2:13][CH2:12][CH2:11][CH2:10]4)[CH2:6][C:7]=3[OH:8])=[N:53][C:49]=2[CH:48]=1
Reactant: CC(C)n1c(S)nc2cc(Cl)ccc21
Reactant: O=C1OC(CCCC2CCCCC2)(C2CCCC2)CC(O)=C1Cl
Agent: O=C1OC(CCC2=CCCCC2)(C2CCCC2)CC(O)=C1Cl
Agent: Sc1nnc(-c2ccncc2)[nH]1
Product: CC(C)n1c(SC2=C(O)CC(CCCC3CCCCC3)(C3CCCC3)OC2=O)nc2cc(Cl)ccc21

Procedure:
The title compound was prepared analogously to Example C(4), where 3-Chloro-6-(3-cyclohexyl-propyl)-6-cyclopentyl-4-hydroxy-5,6-dihydro-pyran-2-one (described in Step 2 of example C(30) was substituted in place of 3-Chloro-6-(2-cyclohex-1-enyl-ethyl)-6-cyclopentyl-4-hydroxy-5,6-dihydro-pyran-2-one and 5-Chloro-1-isopropyl-2-mercapto benzimidazole was substituted in place of 5-Pyridin-4-yl-4H-[1,2,4]triazole-3-thiol of that example. 1H NMR (DMSO-d6): δ 0.63-1.39 (m, 23H), 1.38 (d, J=6.9, 6H), 1.70-1.73 (m, 2H), 2.14-2.20 (m, 1H), 2.39 (d, J=17.0, 1H), 2.71 (d, J=17.0, 1H), 4.58-4.67 (m, 1H), 6.96 (dd, J=8.6, 2.1, 1H), 7.17 (d, J=2.1, 1H), 7.49 (d, J=8.6, 1H) 12.9 (brs, 1H); Anal. Calcd. For C29H39ClN2O3S.0.5H2O: C, 64.48; H, 7.46; N, 5.19; Found: C, 64.69; H, 7.30; N, 5.15. ESIMS (MH+): 532.
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:13])[CH3:12])=[CH:6][CH:5]=1.CNCC1C=CC2C(=CC=CC=2)C=1CCC.[NH2:30][C:31]1[N:36]=[CH:35][C:34](/[CH:37]=[CH:38]/[C:39]([OH:41])=O)=[CH:33][CH:32]=1.Cl.CN1CC2C=C(/C=C/C(O)=O)C=NC=2NC(=O)C1>>[C:11]([NH:10][C:7]1[CH:8]=[CH:9][C:4]([CH2:3][N:2]([CH3:1])[C:39](=[O:41])/[CH:38]=[CH:37]/[C:34]2[CH:35]=[N:36][C:31]([NH2:30])=[CH:32][CH:33]=2)=[CH:5][CH:6]=1)(=[O:13])[CH3:12]
Reactant: Nc1ccc(/C=C/C(=O)O)cn1
Reactant: CNCc1ccc(NC(C)=O)cc1
Agent: CCCc1c(CNC)ccc2ccccc12
Agent: CN1CC(=O)Nc2ncc(/C=C/C(=O)O)cc2C1
Agent: Cl
Product: CC(=O)Nc1ccc(CN(C)C(=O)/C=C/c2ccc(N)nc2)cc1

Procedure:
According to the procedure of Example 1 (a), except substituting N-(4-methylaminomethyl-phenyl)acetamide for the methyl-(1-propyl-naphthalen-2-ylmethyl)amine, and substituting (E)-3-(6-amino-pyridin-3-yl)acrylic acid for the (E)-3-(4-methyl-2-oxo-2,3,4,5-tetrahydro-1H-pyrido[2,3-e][1,4]diazepin-7-yl)acrylic acid hydrochloride, the title compound was prepared as a pale yellow solid (200 mg, 25%): 1H NMR (300 MHz, DMSO-d6) δ 9.93 (s, 1H), 8.15-8.13 (m, 1H), 7.86-7.79 (m, 1H), 7.54-7.39 (m, 3H), 7.15 (s, 2H), 7.03-6.93 (m, 1H), 6.46 (s, 3H), 4.70-4.53 (m, 2H), 3.04-2.87 (m, 3H), 2.02 (s, 3H); MS (ESI) m/e 325 (M+H)+.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.CS(O[CH2:11][CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH2:21][C:22]2[N:23]=[C:24](/[CH:27]=[CH:28]/[C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[O:25][CH:26]=2)[CH:15]=1)(=O)=O>>[N:1]1([CH2:11][CH2:12][CH2:13][C:14]2[CH:15]=[C:16]([CH:17]=[CH:18][CH:19]=2)[O:20][CH2:21][C:22]2[N:23]=[C:24](/[CH:27]=[CH:28]/[C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[O:25][CH:26]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: CS(=O)(=O)OCCCc1cccc(OCc2coc(/C=C/c3ccccc3)n2)c1
Reactant: c1c[nH]cn1
Product: C(=C/c1nc(COc2cccc(CCCn3ccnc3)c2)co1)\c1ccccc1
Yield: 63 %

Procedure:
In substantially the same manner as in Working Example 8, imidazole was allowed to react with 3-[3-[2-[(E)-2-phenylethenyl]-4-oxazolylmethoxy]phenyl]propyl methanesulfonate to give 4-[3-[3-(1-imidazolyl)propyl]phenoxymethyl]-2-[(E)-2-phenylethenyl]oxazole. The yield was 63%. Recrystallization from ethyl acetate-hexane gave colorless prisms, mp 86-87° C.
Reaction SMILES: [OH:1][CH:2]1[CH2:8][CH2:7][CH2:6][S:5][C:4]2[CH:9]=[CH:10][S:11][C:3]1=2.C(N(C(C)C)CC)(C)C.[CH3:21][O:22][CH2:23][CH2:24][O:25][CH2:26]Cl>C(Cl)Cl>[CH3:21][O:22][CH2:23][CH2:24][O:25][CH2:26][O:1][CH:2]1[CH2:8][CH2:7][CH2:6][S:5][C:4]2[CH:9]=[CH:10][S:11][C:3]1=2
Reactant: OC1CCCSc2ccsc21
Reactant: COCCOCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COCCOCOC1CCCSc2ccsc21
Reaction time: 117 h
Yield: 81.8 %

Procedure:
To a solution of 8-hydroxy-5,6,7,8-tetrahydrothieno[3,2-b]thiepin (16.6 g, 0.089 mole) and diisopropylethylamine (18.1 g, 0.14 mole) in methylene chloride (185 ml) was added β-methoxyethoxymethyl chloride (17.5 g, 0.14 mole) over 10 minutes under nitrogen at ambient temperature. The solution was stirred for 117 hours and then washed with cold 0.5N HCl (2×100 ml), saturated sodium bicarbonate solution, twice with water and dried over sodium sulfate. The solvent was evaporated under reduced pressure and the residue was chromatographed on silica gel (2.5 kg), eluting with 20% ethyl acetate-hexane (v/v), to yield 19.97 g (82%) of oily product.
Reaction SMILES: [Cl:1][CH2:2][C:3](=[N:5][OH:6])[NH2:4].C(=O)(O)[O-].[Na+].[Cl:12][C:13]1[CH:21]=[CH:20][C:16]([C:17](Cl)=O)=[CH:15][CH:14]=1>CC(C)=O>[Cl:1][CH2:2][C:3]1[N:4]=[C:17]([C:16]2[CH:20]=[CH:21][C:13]([Cl:12])=[CH:14][CH:15]=2)[O:6][N:5]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: NC(CCl)=NO
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Product: ClCc1noc(-c2ccc(Cl)cc2)n1

Procedure:
A solution of 2-chloroacetamidoxime (0.5 g) and sodium bicarbonate (0.78 g) in 10 mL of anhydrous acetone was treated with 4-chlorobenzoyl chloride (0.58 mL) at room temperature for 2 hours, concentrated in vacuo, dissolved in water and extracted with ethyl acetate. The organic layers were combined, dried with MgSO4 and concentrated to a semi-solid. This material was redissolved in toluene (50 mL). refluxed under nitrogen for 15 hours, cooled and absorbed on to silica gel. Chromatography using ethyl acetate:hexane (1:9) gave the pure title product as a light yellow solid, mp 79°-80° C. Mass spectrum m/e: 228 (M+), 1H NMR (250 MHz, CDCl3) δ 8.1 (d, 2H), 7.5 (d, 2H), 4.7 (s, 2H).
Reaction SMILES: [CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([O:13][N:14]=[C:15]2[CH2:20][CH2:19][N:18]([C:21]3[CH:26]=[C:25]([F:27])[C:24]([CH:28]4[S:33][CH2:32][CH2:31][CH2:30][S:29]4)=[CH:23][C:22]=3[F:34])[CH2:17][CH2:16]2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2].C1C=C(Cl)C=C(C(OO)=[O:43])C=1>C(Cl)Cl>[CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([O:13][N:14]=[C:15]2[CH2:20][CH2:19][N:18]([C:21]3[CH:26]=[C:25]([F:27])[C:24]([CH:28]4[S:33][CH2:32][CH2:31][CH2:30][S:29]4=[O:43])=[CH:23][C:22]=3[F:34])[CH2:17][CH2:16]2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2]
Reactant: CC(C)OC(=O)N1CCC(ON=C2CCN(c3cc(F)c(C4SCCCS4)cc3F)CC2)CC1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CC(C)OC(=O)N1CCC(ON=C2CCN(c3cc(F)c(C4SCCCS4=O)cc3F)CC2)CC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
21a (55 mg) was dissolved in 0.5 mL of DCM and cooled to −78° C. mCPBA (24 mg, 1 eq) in 1 mL of DCM was added and the mixture was stirred at room temperature for 2 days. The solution was washed with aqueous Na2CO3 twice then with water and the crude material obtained was purified on preparative HPLC to give 21-1 as a 15:85 mixture of diastereoisomers: LC-MS 530.2 (MH), tR=5.58 (Method 5). EC50: 143 nM.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:10]2[N:14]([C:15]3[CH:20]=[CH:19][N:18]=[C:17]([Cl:21])[CH:16]=3)[N:13]=[C:12]([C:22](O)=[O:23])[CH:11]=2)[CH:5]=[C:6]([O:8][CH3:9])[CH:7]=1.ClC1C=C(C2N(C3C=CC=CN=3)N=C(C([N:46]3[CH2:50][C:49](=[O:51])[NH:48][CH2:47]3)=O)C=2)C=C(F)C=1.Cl.N1C=CNC1=O>>[Br:1][C:2]1[CH:3]=[C:4]([C:10]2[N:14]([C:15]3[CH:20]=[CH:19][N:18]=[C:17]([Cl:21])[CH:16]=3)[N:13]=[C:12]([C:22]([N:46]3[CH2:50][C:49](=[O:51])[NH:48][CH2:47]3)=[O:23])[CH:11]=2)[CH:5]=[C:6]([O:8][CH3:9])[CH:7]=1
Reactant: COc1cc(Br)cc(-c2cc(C(=O)O)nn2-c2ccnc(Cl)c2)c1
Reactant: O=C1CN(C(=O)c2cc(-c3cc(F)cc(Cl)c3)n(-c3ccccn3)n2)CN1
Agent: Cl
Agent: O=c1[nH]cc[nH]1
Product: COc1cc(Br)cc(-c2cc(C(=O)N3CNC(=O)C3)nn2-c2ccnc(Cl)c2)c1

Procedure:
80 mg (0.20 mmol) of the compound of Example 51A is reacted analogously to the synthesis of the compound of Example 1 with 26 mg (0.22 mmol) of 4-imidazolinone-hydrochloride. 70 mg (75% of theory) of the title compound is obtained.
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]([OH:13])=[O:12])[CH:9]=2)[CH2:4][CH2:3][NH:2]1.C1C[O:17][CH2:16][CH2:15]1>>[C:16]([N:2]1[CH2:3][CH2:4][C:5]2[C:10](=[CH:9][C:8]([C:11]([OH:13])=[O:12])=[CH:7][CH:6]=2)[CH2:1]1)(=[O:17])[CH3:15]
Reactant: C1CCOC1
Reactant: O=C(O)c1ccc2c(c1)CNCC2
Product: CC(=O)N1CCc2ccc(C(=O)O)cc2C1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
30.6 g 1,2,3,4-tetrahydro-7-isoquinolinecarboxylic acid are dissolved in 383 ml THF 109 ml acetic acid anhydride are added and the mixture is stirred for 5 h at ambient temperature. The resulting solid is collected and dried. 12.1 g of a colorless solid are obtained.
Reaction SMILES: [CH:1]([NH:4][OH:5])([CH3:3])[CH3:2].[C:6]([C:10]1[CH:17]=[CH:16][C:13]([CH2:14]Cl)=[CH:12][CH:11]=1)([O:8][CH3:9])=[O:7].C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C>[CH:1]([N:4]([CH2:14][C:13]1[CH:12]=[CH:11][C:10]([C:6]([O:8][CH3:9])=[O:7])=[CH:17][CH:16]=1)[OH:5])([CH3:3])[CH3:2]
Reactant: CC(C)NO
Reactant: COC(=O)c1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(CN(O)C(C)C)cc1
Temperature: 60 °C
Reaction time: 20 h
Yield: 41.3 %

Procedure:
N-isopropylhydroxylamine (13.74 g, 90%, 165 mmol), 4-carbomethoxybenzyl chloride (30.4 g, 165 mmol) and Na2CO3 (18.0 g, 170 mmol) were dissolved in DMF (150 mL) and stirred at 60° C. under Argon for 20 h. The reaction mixture was filtered, concentrated, diluted with CHCl3 (300 mL), washed with water (3×200 mL), dried with MgSO4, concentrated, dissolved in EtOAC (10 mL) and chromatographed on an Si gel eluting with 4:1 hexanes/EtOAc to give 15.2 g (41%) N-isopropyl-N-(4-carbomethoxybenzyl)-hydroxylamine. 1H NMR (DMSO-d6) δ 7.85 (d, J=8.2 Hz, 2), 7.43 (d, J=8.2 Hz, 2), 7.44 (s, 1), 3.80 (s, 3), 3.73 (s, 1), 2.85 (sept, J=6.3 Hz, 1), 1.02 (d, J=6.3 Hz, 6). 13C{1H} NMR (DMSO-d6) δ 166.2, 145.6, 129.0, 128.8, 127.8, 59.3, 56.8, 52.0, 18.4.
Reaction SMILES: [OH:1][CH:2]([CH2:6][C:7]1[CH:15]=[C:14]([CH3:16])[C:13]2[C:9](=[CH:10][N:11]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[N:12]=2)[CH:8]=1)[C:3]([OH:5])=O.[N:25]1([CH:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1.C(N(C(C)C)CC)(C)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>ClCCl.C(OCC)(=O)C>[OH:1][CH:2]([CH2:6][C:7]1[CH:15]=[C:14]([CH3:16])[C:13]2[C:9](=[CH:10][N:11]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:23])([CH3:22])[CH3:24])[N:12]=2)[CH:8]=1)[C:3]([N:34]1[CH2:35][CH2:36][CH:31]([N:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)[CH2:32][CH2:33]1)=[O:5]
Reactant: C1CCN(C2CCNCC2)CC1
Reactant: Cc1cc(CC(O)C(=O)O)cc2cn(COCC[Si](C)(C)C)nc12
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Cc1cc(CC(O)C(=O)N2CCC(N3CCCCC3)CC2)cc2cn(COCC[Si](C)(C)C)nc12
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To a solution of (±)-2-hydroxy-3-(7-methyl-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazol-5-yl)propanoic acid (100 mg, 0.29 mmol), 4-piperidinopiperidine (96.0 mg, 2.0 equiv), and diisopropylethylamine (0.10 mL, 0.57 mmol) in dichloromethane (3.6 mL) at 0° C. was added PyBOP® (156 mg, 0.30 mmol) in two portions. The reaction was stirred at 0° C. for 15 minutes and at room temperature overnight. The reaction was diluted with ethyl acetate, washed with water (2×), then brine, dried over magnesium sulfate, and concentrated. Column chromatography (4% to 10% methanol/dichloromethane) gave 130 mg (91%) as an oil. Mass spec.: 501.36 (MH)+.
Reaction SMILES: Cl.[NH2:2][C:3]1[C:8]2[N:9]=[C:10]([CH3:19])[N:11]([CH2:12][CH2:13][CH2:14][NH:15]C(=O)C)[C:7]=2[C:6]([CH3:20])=[C:5]([CH3:21])[N:4]=1>C(O)C>[NH2:15][CH2:14][CH2:13][CH2:12][N:11]1[C:7]2[C:6]([CH3:20])=[C:5]([CH3:21])[N:4]=[C:3]([NH2:2])[C:8]=2[N:9]=[C:10]1[CH3:19]
Reactant: CC(=O)NCCCn1c(C)nc2c(N)nc(C)c(C)c21
Agent: Cl
Solvent: CCO
Product: Cc1nc(N)c2nc(C)n(CCCN)c2c1C
Temperature: 25 °C
Reaction time: 48 h
Yield: 62.3 %

Procedure:
Concentrated hydrochloric acid (5 mL) was slowly added to a solution of N-[3-(4-amino-2,6,7-trimethyl-1H-imidazo[4,5-c]pyridin-1-yl)propyl]acetamide (15.94 g, 57.9 mmol) in absolute ethanol (100 mL). A precipitate formed immediately and the mixture thickened. Ethanol (50 mL) was added followed by the addition of concentrated hydrochloric acid (119.5 mL). The reaction mixture was heated at reflux for 2 days. The solvents were removed under reduced pressure. Water (250 mL) was added to the residue, solid potassium carbonate was added until the pH reached 7 at which time chloroform (250 mL) was added. Sodium carbonate addition was resumed until the pH reached 10, then 50% sodium hydroxide was added until the pH reached 14. The mixture was diluted with additional chloroform (500 mL) and then stirred at ambient temperature for 2 days. The organic layer was separated, dried with magnesium sulfate and then concentrated under reduced pressure. The residue was recrystallized from acetonitrile to provide 8.42 g of 1-(3-aminopropyl)-2,6,7-trimethyl-1H-imidazo[4,5-c]pyridin-4-amine as an off-white crystalline solid, m.p. 191.5-200° C. Analysis: Calculated for C12H19N5.0.25 H2O: %C, 60.61; %H, 8.26; %N, 29.45; Found: %C, 60.50; %H, 8.28; %N, 29.57.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])[CH2:7][CH2:6]1.C(N(CC)CC)C.CS(C)=O>O>[O:1]=[CH:2][CH2:3][O:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][CH2:14][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)=[O:12])[CH2:7][CH2:6]1
Reactant: O=C(OCc1ccccc1)N1CCC(OCCO)CC1
Solvent: CS(C)=O
Solvent: O
Solvent: CCN(CC)CC
Product: O=CCOC1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 68.1 %

Procedure:
To a mixture of benzyl 4-(2-hydroxyethoxy)piperidine-1-carboxylate (6.33 g), triethylamine (15.9 mL) and dimethyl sulfoxide (30 mL) were added dropwise a mixture of sulfur trioxide pyridine complex (10.8 g) and dimethyl sulfoxide (30 mL) at room temperature, and the obtained mixture was stirred at room temperature for 1 hr. Water was added thereto, and the obtained mixture was extracted with ethyl acetate. The extract was washed with 1M hydrochloric acid and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (4.28 g).
Reaction SMILES: [NH2:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][C:7]2[NH:15][C:14]3[C:13](=[O:16])[N:12]([CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[F:24])[C:11](=[O:25])[N:10]([CH2:26][CH2:27][CH2:28][CH3:29])[C:9]=3[N:8]=2)=[CH:4][CH:3]=1.[Cl:32][C:33]1[CH:34]=[C:35]([S:39](Cl)(=[O:41])=[O:40])[CH:36]=[CH:37][CH:38]=1>>[CH2:26]([N:10]1[C:9]2[N:8]=[C:7]([CH2:6][C:5]3[CH:4]=[CH:3][C:2]([NH:1][S:39]([C:35]4[CH:36]=[CH:37][CH:38]=[C:33]([Cl:32])[CH:34]=4)(=[O:41])=[O:40])=[CH:31][CH:30]=3)[NH:15][C:14]=2[C:13](=[O:16])[N:12]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[F:24])[C:11]1=[O:25])[CH2:27][CH2:28][CH3:29]
Reactant: O=S(=O)(Cl)c1cccc(Cl)c1
Reactant: CCCCn1c(=O)n(Cc2ccccc2F)c(=O)c2[nH]c(Cc3ccc(N)cc3)nc21
Product: CCCCn1c(=O)n(Cc2ccccc2F)c(=O)c2[nH]c(Cc3ccc(NS(=O)(=O)c4cccc(Cl)c4)cc3)nc21

Procedure:
Prepared from 8-(4-amino-benzyl)-3-butyl-1-(2-fluoro-benzyl)-3,7-dihydro-purine-2,6-dione and 3-chloro-benzenesulfonyl chloride. Purity (ELSD, based on MW=596.1)=90%.
Reaction SMILES: [CH:1]1([S:7]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17]([C:19]3[CH2:20][CH2:21][O:22][C:23]4[CH:29]=[CH:28][C:27]([C:30]5[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=5)=[CH:26][C:24]=4[CH:25]=3)=[O:18])=[CH:12][CH:11]=2)=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.ClC1C=CC=C(C(OO)=[O:45])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)(Cl)Cl>[CH:1]1([S:7]([CH2:9][C:10]2[CH:11]=[CH:12][C:13]([NH:16][C:17]([C:19]3[CH2:20][CH2:21][O:22][C:23]4[CH:29]=[CH:28][C:27]([C:30]5[CH:31]=[CH:32][C:33]([CH3:36])=[CH:34][CH:35]=5)=[CH:26][C:24]=4[CH:25]=3)=[O:18])=[CH:14][CH:15]=2)(=[O:45])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CS(=O)C4CCCCC4)cc2)CCO3)cc1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CS(=O)(=O)C4CCCCC4)cc2)CCO3)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 82 %

Procedure:
To a solution of N-(4-(cyclohexylsulfinylmethyl)-phenyl)-7-(4-methylphenyl)-2,3-dihydro-1-benzoxepine-4-carboxamide (0.13 g) in chloroform (45 ml) was added 70% m-chloroperbenzoic acid (mCPBA) (0.097 g) under ice-cooling, and the mixture was stirred at room temperature for 30 minutes. To the mixture was added sodium thiosulfate solution, and the mixture was washed with sodium hydrogen carbonate solution and water, and dried with anhydrous magnesium sulfate. Under reduced pressure, the solvent was evaporated to give crude crystals, which were recrystallized from ethanol-hexane to give N-(4-(cyclohexylsulfonylmethyl)phenyl)-7-(4-methylphenyl)-2,3-dihydro-1-benzoxepine-4-carboxamide (Compound 107) (0.11 g) as colorless crystals.
Reaction SMILES: CSC.ClN1C(=O)CCC1=O.[CH:12]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][OH:22])([CH3:14])[CH3:13].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH:12]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH:21]=[O:22])([CH3:14])[CH3:13]
Reactant: CC(C)OCCCCCCO
Agent: O=C1CCC(=O)N1Cl
Solvent: CCN(CC)CC
Solvent: CSC
Solvent: Cc1ccccc1
Product: CC(C)OCCCCCC=O
Reaction time: 1.5 h

Procedure:
7.5 cc (0.132 mol) of dimethyl sulphide are added dropwise at 0°, whilst stirring and under nitrogen, to a solution of 13.4 g (0.10 mol) of N-chlorosuccinimide in 250 cc of absolute toluene. A white precipitate is formed. The reaction mixture is subsequently cooled to -25° and a solution of 8.0 g (0.05 mol) of 6-isopropoxyhexanol in 25 cc of absolute toluene is added over the course of 15 minutes. After stirring at -25° for 90 minutes, a solution of 7.5 g (0.074 mol) of triethylamine in 25 cc of toluene is added over the course of 15 minutes to the white suspension. The cooling bath is then separated and after 10 minutes 500 cc of ether are added. The organic phase is washed with 1% aqueous hydrochloric acid, water and saturated sodium chloride solution, dried over magnesium sulphate and evaporated at 30° /20 mm Hg. After fractional distillation almost pure 6-isopropoxyhexanol is obtained (B.P. 90-93° /15 mm Hg). Said compound may be used for the production of 1-(7-isopropoxy-1-heptenyl)-4 -nitrobenzene without further purification.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([O:12]CC1C=CC=CC=1)=[O:11].[H-].[Na+].Br[CH:23]([CH3:32])[CH2:24][CH2:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28].ClC1C=CC=CC=1C(C1C=C(CC)SC=1N1C(C)=NN=C1CNC(C1N(CCCCCC(OCC)=O)C2C(C=1)=CC=CC=2)=O)=O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.NCC1N(C2SC(CC)=CC=2C(=O)C2C=CC=CC=2Cl)C(C)=NN=1.CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F>C(N(CC)CC)C.CN(C=O)C>[CH2:30]([O:29][C:27]([CH2:26][CH2:25][CH2:24][CH2:23][CH2:32][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([OH:12])=[O:11])=[O:28])[CH3:31]
Reactant: CCOC(=O)CCCC(C)Br
Reactant: O=C(OCc1ccccc1)c1cc2ccccc2[nH]1
Agent: CCOC(=O)CCCCCn1c(C(=O)NCc2nnc(C)n2-c2sc(CC)cc2C(=O)c2ccccc2Cl)cc2ccccc21
Agent: CCc1cc(C(=O)c2ccccc2Cl)c(-n2c(C)nnc2CN)s1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)CCCCCn1c(C(=O)O)cc2ccccc21

Procedure:
1-(5-Ethoxycarbonylpentyl)indole-2-carboxylic acid was prepared using benzyl indole-2-carboxylate, DMF, sodium hydride (60% in oil) and ethyl 5-bromohexanoate, and ethyl 6-(2-((4-(3-(2-chlorobenzoyl)-5-ethylthiophen-2-yl)-5-methyl[1,2,4]triazol-3-yl)methylcarbamoyl)indol-1-yl)hexanoate was synthesized in the same manner as in Example 186 using 3-aminomethyl-4-(3-(2-chlorobenzoyl)-5-ethylthiophen-2-yl)-5-methyl[1,2,4]triazole di-p-toluenesulfonate, triethylamine and Bop reagent.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([CH:6]([C:11]([O:13]C)=[O:12])[C:7]([O:9]C)=[O:8])=[CH:2]1.[OH-].[Na+].CO>O>[S:1]1[CH:5]=[CH:4][C:3]([CH:6]([C:7]([OH:9])=[O:8])[C:11]([OH:13])=[O:12])=[CH:2]1
Reactant: COC(=O)C(C(=O)OC)c1ccsc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)C(C(=O)O)c1ccsc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 75 %

Procedure:
Dimethyl 3-thienylmalonate, unpurified from the above reaction, (0.0385 kg, 0.18 mole) was added dropwise over 10 minutes to a stirred solution of sodium hydroxide (0.0157 kg, 0.39 mole) in water (0.065 dm3) maintaining the temperature between 10°-20°. The resulting solution was stirred at ambient temperature for 1 hour and the methanol (formed in the hydrolysis) distilled under reduced pressure (Buchi, to ≤50°). The concentrate was cooled to 10°, 4-methyl-2-pentanone (0.040 dm3) added and the pH adjusted to 5.0 with concentrated hydrochloric acid. The mixture was separated, the aqueous phase acidified to pH 3.0 (conc. HCl) and the solution extracted with dichloromethane (2×0.02 dm3). After separation the aqueous phase was acidified to pH 1.0 (conc. HCl) and the solution extracted with diethyl ether (2×0.05 dm3). The ethereal extract was treated with charcoal and dried over magnesium sulphate (0.01 kg). Filtration and evaporation of the filtrate gave a pale yellow gum that on trituration with dichloromethane (0.03 dm3) yielded 3-thienylmalonic acid as a white powder 0.025 kg (75%), m.p. 138°-139°.