Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([C:21]1[C:26]([OH:27])=[C:25]([O:28][CH3:29])[C:24]([O:30][CH3:31])=[CH:23][C:22]=1[CH3:32])=O.Cl(O)(=O)(=O)=O.[C:38](O)(=[O:40])[CH3:39]>CCOCC.[Pd]>[C:38]([O:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:21]1[C:26]([OH:27])=[C:25]([O:28][CH3:29])[C:24]([O:30][CH3:31])=[CH:23][C:22]=1[CH3:32])(=[O:40])[CH3:39]
Reactant: COc1cc(C)c(C(=O)CCCCCCCCCCCCCCCCCO)c(O)c1OC
Reactant: CC(=O)O
Agent: [Pd]
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: CCOCC
Product: COc1cc(C)c(CCCCCCCCCCCCCCCCCCOC(C)=O)c(O)c1OC

Procedure:
To a solution of 6-(18-hydroxy-1-oxooctadecyl)-2,3-dimethoxy-5-methylphenol (1.4 g) in acetic acid (30 ml) are added 5% palladium-on-carbon (50% hydrous) (0.5 g) and 70% perchloric acid (0.05 ml), and catalytic reduction is carried out at atmospheric temperature and pressure. After the absorption of hydrogen has subsided, the catalyst is filtered off and the filtrate is concentrated under reduced pressure, whereupon a colorless oil is obtained. This product is dissolved in ether and the ether layer is washed with 5% aqueous solution of sodium hydrogen carbonate and dried over anhydrous sodium sulfate. The solvent is then distilled off and the resultant crude crystals are recrystallized from hexane. The above procedure yields 6-(18-acetoxyoctadecyl)-2,3-dimethoxy-5-methylphenol (1.4 g) as colorless needles, m.p. 53° C.
Reaction SMILES: [N+](=[CH:3][C:4]1[CH2:5][S:6][C@@H:7]2[C@H:27]([NH:28][C:29](=[O:36])[CH2:30][C:31]3[S:32][CH:33]=[CH:34][CH:35]=3)[C:26](=[O:37])[N:8]2[C:9]=1[C:10]([O:12][CH:13]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])=[N-].[SH2:38]>ClCCl>[SH:38][CH2:3][C:4]1[CH2:5][S:6][C@@H:7]2[C@H:27]([NH:28][C:29](=[O:36])[CH2:30][C:31]3[S:32][CH:33]=[CH:34][CH:35]=3)[C:26](=[O:37])[N:8]2[C:9]=1[C:10]([O:12][CH:13]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)=[O:11]
Reactant: S
Reactant: [N-]=[N+]=CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](NC(=O)Cc3cccs3)[C@H]2SC1
Solvent: ClCCl
Product: O=C(Cc1cccs1)N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CS)CS[C@H]12

Procedure:
A solution of benzhydryl 3-diazomethyl-7β-(2-thienylacetamido)-ceph-3-em-4-carboxylate (9.0 × 10-4 mole), prepared by the process described in Example 2, in 5 ml. dichloromethane solvent is stirred at room temperature while a slow stream of hydrogen sulfide gas is bubbled in. The excess gas and solvent is removed in vacuo and the residue chromatographed over silica gel with chloroform:acetone (10:1) to give benzhydryl 3-mercaptomethyl-7β-(2-thienylacetamido)-ceph-3-em-4-carboxylate.
Reaction SMILES: Cl[CH2:2][C:3]([CH3:6])([OH:5])[CH3:4].C([O-])([O-])=O.[K+].[K+].[Br:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1.O>CN(C=O)C>[Br:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:2][C:3]([CH3:6])([OH:5])[CH3:4])=[CH:16][CH:15]=1
Reactant: Oc1ccc(Br)cc1
Reactant: CC(C)(O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(O)COc1ccc(Br)cc1
Temperature: 140 °C
Reaction time: 48 h

Procedure:
To a solution of 1-chloro-2-methylpropan-2-ol (434.4 mg, 4 mmol) in DMF (10 mL) was added K2CO3 (552 mg, 4 mmol) and 4-bromophenol (346 mg, 2 mmol), the reaction was stirred at 140° C. for 48 hours. About of 10% 4-bromophenol was remained and the reaction was poured into 30 mL of water, extracted with EA (20 mL×3), washed with 30 mL of water and brine, concentrated and purified on TLC (EA:PE=1:3) to give yellow solid. MS (m/z): 196 (M−50)+
Reaction SMILES: [H-].[Na+].[Si:3]([O:10][CH2:11][CH2:12][OH:13])([C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:5])[CH3:4].[Cl:14][C:15]1[N:20]=[C:19]([C:21]2[C:22](F)=[N:23][CH:24]=[C:25]([Cl:27])[CH:26]=2)[C:18]2[N:29]([CH2:41][C@H:42]3[CH2:47][CH2:46][C@H:45]([CH3:48])[CH2:44][CH2:43]3)[C:30]([N:32]3[CH2:37][CH2:36][O:35][C@@H:34]4[CH2:38][CH2:39][CH2:40][C@@H:33]34)=[N:31][C:17]=2[CH:16]=1>CN(C=O)C>[Si:3]([O:10][CH2:11][CH2:12][O:13][C:22]1[C:21]([C:19]2[C:18]3[N:29]([CH2:41][C@H:42]4[CH2:47][CH2:46][C@H:45]([CH3:48])[CH2:44][CH2:43]4)[C:30]([N:32]4[CH2:37][CH2:36][O:35][C@@H:34]5[CH2:38][CH2:39][CH2:40][C@@H:33]45)=[N:31][C:17]=3[CH:16]=[C:15]([Cl:14])[N:20]=2)=[CH:26][C:25]([Cl:27])=[CH:24][N:23]=1)([C:6]([CH3:8])([CH3:9])[CH3:7])([CH3:5])[CH3:4]
Reactant: CC(C)(C)[Si](C)(C)OCCO
Reactant: C[C@H]1CC[C@H](Cn2c(N3CCO[C@@H]4CCC[C@H]43)nc3cc(Cl)nc(-c4cc(Cl)cnc4F)c32)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCCOc1ncc(Cl)cc1-c1nc(Cl)cc2nc(N3CCO[C@@H]4CCC[C@H]43)n(C[C@H]3CC[C@H](C)CC3)c12
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
NaH (24 mg, 0.6 mmol) was added to solution of 2-((tert-butyldimethylsilyl)oxy)ethanol (70 mg, 0.4 mmol) in DMF (1.0 mL) at 0° C., and the reaction was stirred at 0° C. for 30 minutes. A solution of 6-chloro-4-(5-chloro-2-fluoropyridin-3-yl)-2-[(trans)-hexahydrocyclopenta[b][1,4]oxazin-4(4aH)-yl]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridine (racemic, Example 18.1, Step 1; 100 mg, 0.2 mmol) was added, and the reaction was stirred at 0° C. for 30 minutes. The reaction was quenched by adding saturated aqueous NH4Cl solution and extracted using EtOAc. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated. Purification of the residue on a silica gel column with 0 to 50% EtOAc/hexane afforded 4-[2-(2-{[tert-butyl(dimethyl)silyl]oxy}ethoxy)-5-chloropyridin-3-yl]-6-chloro-2-[(trans)-hexahydrocyclopenta[b][1,4]oxazin-4(4aH)-yl]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridine (racemic). MS APCl calc'd. for C34H49Cl2N5O3Si [M+H]+ 674. found 674.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([CH2:8][C:9]([NH2:11])=[O:10])=[C:4]([NH:12][CH2:13][C:14]2[CH:19]=[C:18]([F:20])[CH:17]=[C:16]([F:21])[CH:15]=2)[CH:3]=1.[C:22]1([NH2:29])[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[NH2:28].CS(O)(=O)=O.C(Cl)(Cl)Cl>C1(OC2C=CC=CC=2)C=CC=CC=1>[NH2:28][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[NH:29][C:2]1[N:7]=[CH:6][C:5]([CH2:8][C:9]([NH2:11])=[O:10])=[C:4]([NH:12][CH2:13][C:14]2[CH:19]=[C:18]([F:20])[CH:17]=[C:16]([F:21])[CH:15]=2)[CH:3]=1
Reactant: Nc1ccccc1N
Reactant: NC(=O)Cc1cnc(Cl)cc1NCc1cc(F)cc(F)c1
Agent: CS(=O)(=O)O
Solvent: ClC(Cl)Cl
Solvent: c1ccc(Oc2ccccc2)cc1
Product: NC(=O)Cc1cnc(Nc2ccccc2N)cc1NCc1cc(F)cc(F)c1
Temperature: 180 °C
Reaction time: 0.5 h
Yield: 16.4 %

Procedure:
To 89 mg of 6-chloro-4-[(3,5-difluorobenzyl)amino]pyridine-3-carboxyamide (the compound of Example 20) suspended in 3 mL of diphenylether, 65 mg of 1,2-phenylenediamine and 144 mg of methanesulfonic acid were added, and stirred in a nitrogen atmosphere at 180° C. for 30 minutes. After cooling, chloroform was added to the reaction mixture to dissolve the deposit, washed with saturated sodium bicarbonate, and dried on anhydrous sodium sulfate. The solvent was evaporated, and the residue was purified by silica gel column chromatography (chloroform:methanol:ammonia water=10:1:0.1) to obtain 18 mg (yield 17%) of the title compound as a light brown powder.
Reaction SMILES: C([O:5][C:6]([CH:8]1[CH:14]([NH:15][S:16]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)(=[O:18])=[O:17])[CH2:13][CH:12]=[CH:11][CH2:10][N:9]1[S:26]([C:29]1[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=1)(=[O:28])=[O:27])=[O:7])(C)(C)C.C(OC(C1C(NC(OCC2C=CC=CC=2)=O)CC=CCN1S(C1C=CC(OC)=CC=1)(=O)=O)=O)(C)(C)C>>[CH3:36][O:35][C:32]1[CH:33]=[CH:34][C:29]([S:26]([N:9]2[CH2:10][CH:11]=[CH:12][CH2:13][CH:14]([NH:15][S:16]([CH2:19][C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)(=[O:18])=[O:17])[CH:8]2[C:6]([OH:7])=[O:5])(=[O:28])=[O:27])=[CH:30][CH:31]=1
Reactant: COc1ccc(S(=O)(=O)N2CC=CCC(NS(=O)(=O)Cc3ccccc3)C2C(=O)OC(C)(C)C)cc1
Agent: COc1ccc(S(=O)(=O)N2CC=CCC(NC(=O)OCc3ccccc3)C2C(=O)OC(C)(C)C)cc1
Product: COc1ccc(S(=O)(=O)N2CC=CCC(NS(=O)(=O)Cc3ccccc3)C2C(=O)O)cc1

Procedure:
1-(4-Methoxy-benzenesulfonyl)-3-(phenylmethanesulfonyl amino)-2,3,4,7-tetrahydro-1H-azepine-2-carboxylic acid tert-butyl ester (29 mg, 0.054 mmol) is reacted in the same manner as 3-Benzyloxycarbonylamino-1-(4-methoxy-benzenesulfonyl)-2,3,4,7-tetrahydro-1H-azepine-2-carboxylic acid tert-butyl ester: Cal. 479.5 found (M−H)+478.6. Cal. 498.6, found (MNH4)+498.1; 1H NMR (DMSO, 400 MHz), ppm: 7.85 (d, 2H), 7.38 (m, 5H) 7.01 (d, 2H), 5.5 (m, 2H) 4.45 (d, 2H), 4.30 (d, 2H), 4.15 (m, 2H), 4.00 (m, 1H), 3.90 (dd, 1H), 3.83 (s, 3H), 2.18 (m, 2H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:12]=[CH:13][CH:14]=1)[CH:7]=[CH:8][C:9]([OH:11])=[O:10])([O-])=O.[H][H]>C(O)(=O)C.CO.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]([CH2:7][CH2:8][C:9]([OH:11])=[O:10])[CH:12]=[CH:13][CH:14]=1
Reactant: [H][H]
Reactant: O=C(O)C=Cc1cccc([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CO
Product: Nc1cccc(CCC(=O)O)c1

Procedure:
A suspension of 100 g (0.52 moles) of 3-nitrocinnamic acid in 800 ml glacial acetic acid and 100 ml of methanol was hydrogenated at 50 pounds per square inch over 2.5 g 10% palladium on carbon until four equivalents of hydrogen were absorbed. The catalyst was filtered off, the filtrates combined and the solvent was concentrated in vacuo leaving a brown glass of 3-aminobenzenepropanoic acid. To this was added 1 liter of ethanolic hydrochloric acid which was brought to reflux for five hours. The solvent was evaporated off in vacuo leaving a purple solid. Recrystallization from ethyl acetate yielded 88.0 g of ethyl 3-aminobenzenepropanoate hydrochloride, mp 132°-135° C., (74% yield).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]([C:6]1[N:7]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:8]2[C:13]([C:14](=[O:18])[C:15]=1[CH2:16][NH2:17])=[CH:12][CH:11]=[C:10](Cl)[CH:9]=2)=[O:5].[C:26](Cl)(=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[CH3:2][O:3][C:4]([C:6]1[N:7]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:8]2[C:13]([C:14](=[O:18])[C:15]=1[CH2:16][NH:17][C:26](=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:5]
Reactant: O=C(Cl)c1ccccc1
Reactant: COC(=O)c1c(CN)c(=O)c2ccc(Cl)cc2n1-c1ccccc1
Agent: Cl
Product: COC(=O)c1c(CNC(=O)c2ccccc2)c(=O)c2ccccc2n1-c1ccccc1

Procedure:
3-(Benzoylamino-methyl)-4-oxo-1-phenyl-1,4-dihydro-quinoline-2-carboxylic acid methyl ester was prepared starting from an over-reduced batch of intermediate I and benzoyl chloride. MS calcd. for C25H21N2O4 [(M+H)+] 413.1, obsd. 412.9
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][C:5]([CH2:12][C:13]([C:27]([O:29][CH2:30][CH3:31])=[O:28])([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:14][C:15]([O:17]C(C)(C)C)=[O:16])=[CH:4][C:3]=1[Cl:32].C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:1][C:2]1[C:7]([C:8]([F:9])([F:10])[F:11])=[CH:6][C:5]([CH2:12][C:13]([C:22]([O:24][CH2:25][CH3:26])=[O:23])([C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:14][C:15]([OH:17])=[O:16])=[CH:4][C:3]=1[Cl:32]
Reactant: CCOC(=O)C(CC(=O)OC(C)(C)C)(Cc1cc(Cl)c(N)c(C(F)(F)F)c1)C(=O)OCC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)C(CC(=O)O)(Cc1cc(Cl)c(N)c(C(F)(F)F)c1)C(=O)OCC
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 30.0 g (62.25 mmol) tert. butyl 4-(4-amino-3-chloro-5-trifluoromethyl-phenyl)-3,3-bis-ethoxycarbonyl-butyrate (Intermediate product 65) in 200 mL CH2Cl2 was added 20 mL TFA while cooling with ice and the mixture was stirred for 16 hours at RT. The reaction mixture was evaporated i. vac. and the residue recrystallised from petroleum ether. The precipitate was filtered off, washed with petroleum ether and dried.
Reaction SMILES: C1C[O:37][C:3]([CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])([CH2:4][CH2:5][C@H:6]2[C@H:10]([O:11]C3CCCCO3)[CH2:9][C:8](=[O:18])[C@@H:7]2[CH2:19]/[CH:20]=[CH:21]\[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]([O-:29])=[O:28])O1.C(O)(=O)C.[CH2:43]1[CH2:47]OC[CH2:44]1>O>[OH:11][C@@H:10]1[CH2:9][C:8](=[O:18])[C@H:7]([CH2:19]/[CH:20]=[CH:21]\[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]([O:29][CH:43]([CH3:47])[CH3:44])=[O:28])[C@H:6]1[CH2:5][CH2:4][C:3](=[O:37])[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36]
Reactant: C1CCOC1
Reactant: CCCCCCCC1(CC[C@H]2[C@H](OC3CCCCO3)CC(=O)[C@@H]2C/C=C\CCCCCC(=O)[O-])OCCO1
Solvent: O
Solvent: CC(=O)O
Product: CCCCCCCC(=O)CC[C@H]1[C@H](O)CC(=O)[C@@H]1C/C=C\CCCCCC(=O)OC(C)C
Reaction time: 3 h

Procedure:
The compound (45) (0.311 g) was dissolved in a mixed solvent (5 ml) consisting of acetic acid, THF and water (2:1:1) and kept at 50° C. for 3 hours. The resultant mixture was worked up with the conventional procedure and the residue was subjected to silicagel column chromatography to give the titled compound (46). Yield: 0.156 g (66%). Compound (46) [Q1 =Q2 =H, Rb-Rc=hexyl, P3 =isopropyl]NMR(CDCl3)δ: 0.86 (t,3H,J=6.5 Hz), 1.20 (d,6H,J=6 Hz), 1.23-2.75 (m,33H), 4.20 (m,1H), 4.99 (Hept,1H,J=6 Hz), 5.15-5.50 (m,2H)
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1.[C@@H:10]12[C:19](=O)[O:18][C:16](=[O:17])[C@@H:11]1[CH2:12][CH:13]=[CH:14][CH2:15]2.[BH4-].[Na+].Cl>O.CC(O)C>[OH:18][CH2:19][CH:10]1[CH:11]([C:16]([NH:1][CH2:2][CH2:3][N:4]2[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]2)=[O:17])[CH2:12][CH:13]=[CH:14][CH2:15]1
Reactant: O=C1OC(=O)[C@@H]2CC=CC[C@H]12
Reactant: NCCN1CCCCC1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)O
Product: O=C(NCCN1CCCCC1)C1CC=CCC1CO
Temperature: 140 °C
Reaction time: 6 h

Procedure:
N-(2-Aminoethyl)piperidine (2.11 g) was added to cis-4-cyclohexene-1,2-dicarboxylic anhydride (2.50 g) and stirred for 6 hours at 140° C. The reaction mixture was suspended into a mixed solution of 2-propanol (125 ml) and water (21 ml) and then sodium borohydride (3.12 g) was added thereto at room temperature. After being stirred for 68 hours at room temperature, the reaction mixture was acidified with dilute hydrochloric acid and then concentrated. The residue was adjusted to pH 9 with saturated sodium hydrogencarbonate aqueous solution and 1N sodium hydroxide, and then extracted with ethyl acetate. The extract was washed with saturated brine, dried over sodium sulfate anhydride, and concentrated, thereby yielding a crude (3.34 g) containing the entitled compound as brown syrup.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[O:3][C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][CH:5]=1.O=[C:14]1[CH2:19][CH2:18][N:17]([C@H:20]([CH3:24])[CH2:21][C:22]#[N:23])[CH2:16][CH2:15]1>>[NH2:23][CH2:22][CH2:21][C@H:20]([N:17]1[CH2:18][CH2:19][CH:14]([NH:8][C:7]2[CH:9]=[CH:10][C:4]([O:3][C:2]([F:11])([F:12])[F:1])=[CH:5][CH:6]=2)[CH2:15][CH2:16]1)[CH3:24]
Reactant: Nc1ccc(OC(F)(F)F)cc1
Reactant: C[C@H](CC#N)N1CCC(=O)CC1
Product: C[C@H](CCN)N1CCC(Nc2ccc(OC(F)(F)F)cc2)CC1

Procedure:
Using general procedure A with 4-(trifluoromethoxy)-aniline (0.21 mL, 1.55 mmol) and (R)-3-(4-oxo-piperidin-1-yl]-butyronitrile (310 mg, 1.87 mmol) followed by general procedure J afforded [1-((R)-3-amino-1-methyl-propyl)-piperidin-4-yl]-(4-trifluoromethoxy-phenyl)-amine as a white solid (277 mg, 55% over 2 steps).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH:10]1[CH2:15][NH:14][CH2:13][CH2:12][NH:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[S:23]1[CH:27]=[CH:26][CH:25]=[C:24]1[S:28](Cl)(=[O:30])=[O:29]>C(Cl)Cl>[CH2:1]([O:8][CH2:9][CH:10]1[NH:11][CH2:12][CH2:13][N:14]([S:28]([C:24]2[S:23][CH:27]=[CH:26][CH:25]=2)(=[O:30])=[O:29])[CH2:15]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc(COCC2CNCCN2)cc1
Reactant: O=S(=O)(Cl)c1cccs1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=S(=O)(c1cccs1)N1CCNC(COCc2ccccc2)C1
Temperature: 0 °C
Reaction time: 2 h
Yield: 50.3 %

Procedure:
A 250 mL round-bottomed flask was charged with 2-(benzyloxymethyl)piperazine (2.10 g, 10.1 mmol), triethylamine (1.42 mL, 10.2 mmol) and CH2Cl2 (50 mL). After cooling to 0° C., 2-thiophenesulfonyl chloride (1.84 g, 10.1 mmol, Sigma-Aldrich, St. Louis, Mo.) was added slowly via syringe. After 2 h, the mixture was concentrated and diluted with EtOAc (200 mL). The organic solution was washed with 1 N HCl (2×50 mL) and the combined acidic layers made basic with Na2CO3. The resulting basic solution was extracted with EtOAc (3×100 mL) and the combined organic layers were dried (MgSO4), filtered and concentrated to give 3-(benzyloxymethyl)-1-(thiophen-2-ylsulfonyl)piperazine (1.79 g) as a yellow tar.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([CH:14]2[N:18]([CH2:19][CH2:20][CH2:21]O)[C:17](=[O:23])[CH2:16][S:15]2)[CH:7]=[C:8]([CH:11]([CH3:13])[CH3:12])[C:9]=1[OH:10])([CH3:3])[CH3:2].S(Cl)([Cl:26])=O>ClCCl>[CH:1]([C:4]1[CH:5]=[C:6]([CH:14]2[N:18]([CH2:19][CH2:20][CH2:21][Cl:26])[C:17](=[O:23])[CH2:16][S:15]2)[CH:7]=[C:8]([CH:11]([CH3:13])[CH3:12])[C:9]=1[OH:10])([CH3:3])[CH3:2]
Reactant: O=S(Cl)Cl
Reactant: CC(C)c1cc(C2SCC(=O)N2CCCO)cc(C(C)C)c1O
Solvent: ClCCl
Product: CC(C)c1cc(C2SCC(=O)N2CCCCl)cc(C(C)C)c1O
Yield: 60.2 %

Procedure:
To a dichloromethane (50 ml) solution of the 2-(3,5-diisopropyl-4-hydroxyphenyl)-3-(3-hydroxypropyl)-1,3-thiazolidin-4-one (1.97 g) obtained in Reference Example 1 was added thionyl chloride (1.04 g) under a nitrogen atmosphere, then the mixture was refluxed for 1 hour. The solvent was evaporated under reduced pressure, and to the residue were added brine and chloroform. The organic layer was separated and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent; dichloromethane) to afford 1.25 g (60%) of the title compound as pale yellow crystals. mp 105-106° C. NMR (CDCl3, 60 MHz) δ: 1.23 (12H, d, J=6.6 Hz), 1.5-2.1 (2H, m), 2.6-3.8 (6H, m), 3.67 (2H, brs), 5.20 (1H, s), 5.50 (1H, brs), 6.88 (2H, s)
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([Br:16])=[N:7][N:8]([CH:13]([CH3:15])[CH3:14])[C:9]2=[O:12])=[CH:4][CH:3]=1.[C:17]([O-])([O-])=O.[K+].[K+].CI>O1CCCC1>[CH3:17][O:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([Br:16])=[N:7][N:8]([CH:13]([CH3:14])[CH3:15])[C:9]2=[O:12])=[CH:4][CH:3]=1
Reactant: CC(C)n1nc(Br)c2ccc(O)cc2c1=O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CI
Product: COc1ccc2c(Br)nn(C(C)C)c(=O)c2c1
Yield: 76.9 %

Procedure:
To a stirred solution of 7-Hydroxy-2-Isopropyl-4-bromo-2H-phthalazin-1-one (0.4 g, 1.4 mmol) in tetrahydrofuran (THF) (5 ml) were added successively, K2CO3 (0.59 g, 4.3 mmol) and methyl iodide (0.22 g, 1.55 mmol) and the mixture was heated to reflux for 24 hours. After this time, LC-MS indicated complete consumption of starting material, and the reaction mixture was concentrated under vacuum. The residue was re-dissolved in ethyl acetate (50 ml) and washed with water (2×30 ml), the organic layer was dried (MgSO4), filtered and concentrated under vacuum to give the title compound (0.32 g, 76% yield) as an orange powder.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:14]=[C:13]2[C:9]([C:10]([CH:18]=[O:19])=[C:11]([CH:15]([CH3:17])[CH3:16])[NH:12]2)=[CH:8][CH:7]=1)=[O:5])[CH3:2].C([O-])([O-])=O.[K+].[K+].Br[CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=1>CN(C=O)C.CCOC(C)=O>[CH:18]([C:10]1[C:9]2[C:13](=[CH:14][C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])=[CH:7][CH:8]=2)[N:12]([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=2)[C:11]=1[CH:15]([CH3:16])[CH3:17])=[O:19]
Reactant: BrCc1ccccn1
Reactant: CCOC(=O)c1ccc2c(C=O)c(C(C)C)[nH]c2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ccc2c(C=O)c(C(C)C)n(Cc3ccccn3)c2c1
Temperature: 60 °C
Reaction time: 5 h

Procedure:
Following General Procedure C, ethyl3-formyl-2-isopropyl-1H-indole-6-carboxylate (Compound 34, 278 mg, 1.07 mmol) in DMF (15 ml) was added K2CO3 (590 mg, 4.28 mmol) and 2-(bromomethyl)pyridine (914 mg, 5.35 mmol). The reaction was stirred at 60° C. for 5 h, diluted with EtOAc, washed with H2O, brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by chromatography on silica gel (0→35% EtOAc-hexanes) to yield the title compound as a yellow oil.
Reaction SMILES: BrC1SC2C(O)=CC(C)=CC=2N=1.C(N(CC)CC)C.[Cl-:20].C(OCC)(=O)C=O.Br[C:29]1[S:30][C:31]2[C:37]([OH:38])=[C:36]([CH:39]([OH:45])[C:40]([O:42][CH2:43][CH3:44])=[O:41])[C:35]([CH3:46])=[CH:34][C:32]=2[N:33]=1>ClCCl>[Cl:20][C:29]1[S:30][C:31]2[C:37]([OH:38])=[C:36]([CH:39]([OH:45])[C:40]([O:42][CH2:43][CH3:44])=[O:41])[C:35]([CH3:46])=[CH:34][C:32]=2[N:33]=1
Reactant: CCOC(=O)C(O)c1c(C)cc2nc(Br)sc2c1O
Reactant: [Cl-]
Agent: CCOC(=O)C=O
Agent: Cc1cc(O)c2sc(Br)nc2c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)C(O)c1c(C)cc2nc(Cl)sc2c1O
Reaction time: 0.5 h

Procedure:
To a mixture of 2-bromo-5-methylbenzo[d]thiazol-7-ol (2.48 g, 10.16 mmol) in dichloromethane (100 mL) at 0° C. was added triethylamine (1.42 mL, 10.16 mmol) to give a clear solution. Titaniuim(IV) chloride (1.0M in CH2Cl2, 10.67 mL, 10.67 mmol) was added slowly to give an orange reaction mixture that was stirred for 30 minutes. A solution of cracked ethyl glyoxalate (1.04 g, 10.16 mmol) in CH2Cl2 (1 mL) was added over 2 minutes and reaction mixture was stirred at room temperature for 2.5 h. Reaction mixture was quenched with Rochelle's salt and stirred at room temperature for 2 h, diluted with CH2Cl2, and aqueous layer extracted with CH2Cl2 (2×). The combined organic layer was dried (MgSO4), filtered and concentrated. Purification by CombiFlash (40 g, 0 to 30% EtOAc/Hex) gave product contaminated with ethyl 2-(2-bromo-7-hydroxy-5-methylbenzo[d]thiazol-6-yl)-2-hydroxyacetate. LCMS-ESI+: calc'd for C12H13ClNO3S: 302.8 (M+H+); Found: 302.1 (M+H+).
Reaction SMILES: [CH:1]([OH:3])=O.C(OC(=O)C)(=O)C.[NH2:11][CH2:12][C:13]1[N:14]2[CH:21]=[N:20][CH:19]=[C:15]2[S:16][C:17]=1[CH3:18].C(=O)([O-])[O-].[K+].[K+]>ClCCl>[CH:1]([NH:11][CH2:12][C:13]1[N:14]2[CH:21]=[N:20][CH:19]=[C:15]2[S:16][C:17]=1[CH3:18])=[O:3]
Reactant: O=CO
Reactant: Cc1sc2cncn2c1CN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)OC(C)=O
Solvent: ClCCl
Product: Cc1sc2cncn2c1CNC=O
Reaction time: 1 h

Procedure:
A mixture of 0.94 ml of formic acid and 0.47 ml of acetic anhydride which had been beforehand reacted with each other at 50° C. for 30 minutes was added at room temperature to 5 ml of a dry dichloromethane solution containing 167 mg of 3-aminomethyl-2-methylimidazo[5,1-b]thiazole, and the mixture was then stirred at the same temperature for 1 hour. Then, an aqueous potassium carbonate solution was added to the reaction solution to alkalify the same. The organic layer was separated, and the aqueous layer was further extracted five times with dichloromethane. The combined organic layer was dried over anhydrous sodium sulfate and then filtered, and the solvent was evaporated under reduced pressure to obtain 117 mg of the title compound.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([C:12]3[O:13][C:14]4[CH:20]=[C:19]([OH:21])[CH:18]=[CH:17][C:15]=4[N:16]=3)=[CH:8][C:7]=2[F:22])[CH2:3][CH2:2]1.O[CH2:24][C@@H:25]([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[CH3:26].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(C)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([C:12]3[O:13][C:14]4[CH:20]=[C:19]([O:21][CH2:26][C@@H:25]([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:31])([CH3:33])[CH3:32])[CH3:24])[CH:18]=[CH:17][C:15]=4[N:16]=3)=[CH:8][C:7]=2[F:22])[CH2:2][CH2:3]1
Reactant: C[C@@H](CO)NC(=O)OC(C)(C)C
Reactant: Oc1ccc2nc(-c3ccc(OCC4CC4)c(F)c3)oc2c1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: C[C@@H](COc1ccc2nc(-c3ccc(OCC4CC4)c(F)c3)oc2c1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 48.8 %

Procedure:
To a solution of 2-(4-(cyclopropylmethoxy)-3-fluorophenyl)-1,3-benzoxazol-6-ol (1.00 g), tert-butyl ((2S)-1-hydroxypropan-2-yl)carbamate (0.878 g) and triphenylphosphine (1.32 g) in THF (10 mL) was added dropwise diisopropyl azodicarboxylate toluene solution (1.9 M, 2.64 mL), and the mixture was stirred at room temperature for 16 hr. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (NH, hexane/ethyl acetate) to give the title compound (0.744 g). 1H NMR (300 MHz, CDCl3) δ 0.35-0.45 (2H, m), 0.63-0.76 (2H, m), 1.29-1.39 (4H, m), 1.46 (9H, s), 3.91-4.02 (4H, m), 4.04-4.18 (1H, m), 4.70-4.85 (1H, m), 6.95 (1H, dd, J=8.7, 2.3 Hz), 7.04 (1H, t, J=8.3 Hz), 7.10 (1H, d, J=2.3 Hz), 7.60 (1H, d, J=8.7 Hz), 7.84-8.01 (2H, m).