Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:3][C@H:2]1[CH2:4][O:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH:8]=[CH:9][NH:10]2.[O:15]=[C:16]1[C:25]2([CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:18][CH2:17]1.[C:31]([OH:36])(=[O:35])[C:32]([OH:34])=[O:33].CO>C(OCC)(=O)C>[C:31]([OH:36])(=[O:35])[C:32]([OH:34])=[O:33].[NH:10]1[C:11]2[C:7](=[C:6]([O:5][CH2:4][C@@H:2]([OH:1])[CH2:3][N:28]3[CH2:27][CH2:26][C:25]4([C:24]5[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=5)[CH2:18][CH2:17][C:16]4=[O:15])[CH2:30][CH2:29]3)[CH:14]=[CH:13][CH:12]=2)[CH:8]=[CH:9]1
Reactant: O=C1CCc2ccccc2C12CCNCC2
Reactant: c1cc(OC[C@@H]2CO2)c2cc[nH]c2c1
Agent: O=C(O)C(=O)O
Solvent: CCOC(C)=O
Solvent: CO
Product: O=C1CCc2ccccc2C12CCN(C[C@H](O)COc1cccc3[nH]ccc13)CC2

Procedure:
The title compound was prepared in similar fashion from (S)-(+)-4-(oxiranylmethoxy)-1H-indole and 3,4-dihydro-2-oxospiro[naphthalene-1(2H),4'-piperidine]. The resulting free base was dissolved in ethyl acetate, and precipitated with one equivalent of oxalic acid in ethyl acetate in 68% overall yield. FDMS m/e=404 (M+ of free base). α[D]589 =-15.81 c=0.51, methanol).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]([C:19]3[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=3)[NH:12][C:13]=2[C:14]([O:16]CC)=[O:15])=[CH:5][CH:4]=1.N1C=CC(C=O)=CC=1.[OH-].[K+].Cl>CO>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[N:10]=[C:11]([C:19]3[CH:20]=[CH:21][N:22]=[CH:23][CH:24]=3)[NH:12][C:13]=2[C:14]([OH:16])=[O:15])=[CH:7][CH:8]=1
Reactant: CCOC(=O)c1[nH]c(-c2ccncc2)nc1-c1ccc(OC)cc1
Agent: Cl
Agent: O=Cc1ccncc1
Agent: [K+]
Solvent: CO
Product: COc1ccc(-c2nc(-c3ccncc3)[nH]c2C(=O)O)cc1
Temperature: 55 °C
Reaction time: 48 h

Procedure:
To a solution of ethyl 4-(4-methoxyphenyl)-2-(pyridin-4-yl)-1H-imidazole-5-carboxylate (0.089 g, 0.28 mmol, prepared (using pyridine-4-carboxaldehyde in place of benzaldehyde) according to the method outlined in Example A-1, step c), in methanol was added 1M aqueous potassium hydroxide (5 ml, 5.0 mmol) and the resulting mixture stirred at 55° C. for 48 hours. The solution was cooled to room temperature, neutralised by the addition of 0.5M aqueous HCl and extracted with DCM. The aqueous phase was then acidified by the addition of acetic acid and purified by SPE using MP-TsOH cartridges (2×1000 mg) to afford 4-(4-methoxyphenyl)-2-(pyridin-4-yl)-1H-imidazole-5-carboxylic acid (0.090 g) as an orange oil which was used without further purification. LCMS (2) Rt: 1.20 min; m/z (ES+) 296.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([O:13][CH:14]([CH3:16])[CH3:15])=[C:8]([C:17]([OH:19])=O)[CH:7]=[CH:6]2.C(Cl)(=O)C(Cl)=O.[NH4+:26].[OH-].O>C1COCC1.CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([O:13][CH:14]([CH3:16])[CH3:15])=[C:8]([C:17]([NH2:26])=[O:19])[CH:7]=[CH:6]2
Reactant: COc1ccc2c(OC(C)C)c(C(=O)O)ccc2c1
Reactant: [NH4+]
Agent: O=C(Cl)C(=O)Cl
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc2c(OC(C)C)c(C(N)=O)ccc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 74 %

Procedure:
To an ice water cooled solution of 6-methoxy-1-(1-methylethoxy)-2-naphthalenecarboxylic acid (5.0 g, 19 mmol) in 50 mL of THF is added 2 drops of DMF followed by oxalyl chloride (2.8 g, 21 mmol). The solution is stirred a room temperature for 2 hours then poured onto 150 mL of aqueous NH4OH. An additional 700 mL of water is added and the resultant precipitate collected. Recrystallization from ethyl acetate provides 6-methoxy-1-(1-methylethoxy)-2-naphthalenecarboxamide in 74% yield; mp 183°-184° C.
Reaction SMILES: [F:1][C:2]1[CH:20]=[CH:19][CH:18]=[CH:17][C:3]=1[CH2:4][C:5]1[N:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]2=[C:7]([C:14]([NH2:16])=O)[N:6]=1.N1C=CC=CC=1.FC(F)(F)C(OC(=O)C(F)(F)F)=O.O>C1COCC1>[F:1][C:2]1[CH:20]=[CH:19][CH:18]=[CH:17][C:3]=1[CH2:4][C:5]1[N:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]2=[C:7]([C:14]#[N:16])[N:6]=1
Reactant: NC(=O)c1nc(Cc2ccccc2F)n2ccccc12
Solvent: C1CCOC1
Solvent: c1ccncc1
Solvent: O
Product: N#Cc1nc(Cc2ccccc2F)n2ccccc12
Temperature: 25 °C
Reaction time: 15 h

Procedure:
269 mg (1.00 mmol) of 3-(2-fluorobenzyl)imidazo[1,5-a]pyridine-1-carboxamide from example 17A are dissolved in 2.5 ml of THF, and 200 mg (2.50 mmol) of pyridine and 525 mg (2.50 mmol) of trifluoroacetic anhydride are added. The mixture is stirred at RT for 15 h, then water is added, and the mixture is extracted with ethyl acetate. The organic phase is washed with saturated sodium bicarbonate solution and 1 N hydrochloric acid, dried over sodium sulfate and concentrated. The crude product obtained (188 mg, 61% purity, 45% of theory) is reacted without further purification.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([P:9](=[O:26])([C:18]2[CH:23]=[CH:22][C:21]([O:24]C)=[CH:20][CH:19]=2)[C:10]2[CH:15]=[CH:14][C:13]([O:16]C)=[CH:12][CH:11]=2)=[CH:5][CH:4]=1.[K+].[Br-].S([O-])([O-])=O.[Na+].[Na+].CBr>Br>[OH:2][C:3]1[CH:4]=[CH:5][C:6]([P:9](=[O:26])([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)[C:18]2[CH:19]=[CH:20][C:21]([OH:24])=[CH:22][CH:23]=2)=[CH:7][CH:8]=1
Reactant: COc1ccc(P(=O)(c2ccc(OC)cc2)c2ccc(OC)cc2)cc1
Agent: Br
Agent: CBr
Agent: O=S([O-])[O-]
Product: O=P(c1ccc(O)cc1)(c1ccc(O)cc1)c1ccc(O)cc1
Temperature: 114 °C
Yield: 64.8 %

Procedure:
A reaction flask containing tris(4-methoxyphenyl)phosphine oxide (973.2 g) was charged with 48% aq HBr (2250 mL) and KBr (126.1 g). The flask was fitted with a sodium sulfite scrubber for containment of methyl bromide. The reaction mixture was heated to reflux (114° C.) and maintained at reflux until complete based on HPLC analysis. The product (Compound VIII) was worked up to give 558.5 g of tris(4-hydroxyphenyl)phosphine oxide (31P NMR (d6-DMSO): δ 27.6 (s); 1H NMR (d6-DMSO): δ 10.9 (s, 3H), 7.38 (m, 6H), 6.84 (m, 6H)).
Reaction SMILES: [Br:1][C:2]1[C:3]([C:9](=[O:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[C:4]([CH3:8])[S:5][C:6]=1[CH3:7].[BH4-].[BH4-].[BH4-].[BH4-].[Na+].[Na+].[Na+].[Na+]>O1CCCC1.C(O)C>[Br:1][C:2]1[C:3]([CH:9]([OH:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[C:4]([CH3:8])[S:5][C:6]=1[CH3:7]
Reactant: CCOC(=O)C(=O)c1c(C)sc(C)c1Br
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: CCOC(=O)C(O)c1c(C)sc(C)c1Br
Temperature: 0 °C
Reaction time: 1 h
Yield: 80.1 %

Procedure:
To a solution of ethyl 2-(4-bromo-2,5-dimethylthiophen-3-yl)-2-oxoacetate (28c) (1 g, 3.56 mmol) in tetrahydrofuran (22.5 mL) and ethanol (5.6 mL) cooled to 0° C. is added sodium tetraborohydride (121.2 mg, 3.20 mmol). The mixture is stirred at 0° C. for 1 hour. The mixture is quenched with HCl (1N) and extracted with ethyl acetate. The organic extract is washed with brine, dried over sodium sulfate, filtered and concentrated to afford the desired alcohol (28d) as a white solid (836 mg, 2.85 mmol, 89%) which was used without further purification.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C:9](=[O:26])[C:10]1[C:15]([C:16]([F:19])([F:18])[F:17])=[CH:14][C:13]([C:20]([F:23])([F:22])[F:21])=[CH:12][C:11]=1[O:24][CH3:25].Br[CH:28]([CH2:30][CH2:31][CH:32](Br)[CH3:33])[CH3:29]>>[CH3:33][CH:32]1[CH2:31][CH2:30][CH:28]([CH3:29])[N:1]1[CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[NH:8][C:9](=[O:26])[C:10]1[C:15]([C:16]([F:19])([F:18])[F:17])=[CH:14][C:13]([C:20]([F:21])([F:22])[F:23])=[CH:12][C:11]=1[O:24][CH3:25]
Reactant: CC(Br)CCC(C)Br
Reactant: COc1cc(C(F)(F)F)cc(C(F)(F)F)c1C(=O)N[C@@H]1CCCC[C@@H]1N
Product: COc1cc(C(F)(F)F)cc(C(F)(F)F)c1C(=O)NC1CCCCC1N1C(C)CCC1C

Procedure:
The title compound, MS: m/e=467.3 [(M+H)+], was prepared in accordance with the general method of example 10 from cis-N-(2-amino-cyclohexyl)-2-methoxy-4,6-bis-trifluoromethyl-benzamide (intermediate H) and 2,5-dibromohexane. The 3 diastereomers were not separated.
Reaction SMILES: [Mg].[CH2:2]([C@H:5]1[CH2:10][CH2:9][C@H:8]([C:11]2[CH:16]=[CH:15][C:14](Br)=[CH:13][CH:12]=2)[CH2:7][CH2:6]1)[CH2:3][CH3:4].[C:18](=[S:20])=[S:19].Cl>C1COCC1>[CH2:2]([C@H:5]1[CH2:10][CH2:9][C@H:8]([C:11]2[CH:16]=[CH:15][C:14]([C:18]([SH:20])=[S:19])=[CH:13][CH:12]=2)[CH2:7][CH2:6]1)[CH2:3][CH3:4]
Reactant: S=C=S
Reactant: CCC[C@H]1CC[C@H](c2ccc(Br)cc2)CC1
Agent: Cl
Agent: [Mg]
Solvent: C1CCOC1
Product: CCC[C@H]1CC[C@H](c2ccc(C(=S)S)cc2)CC1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a solution obtained by suspending 2.25 g (93 mmol) of magnesium in 50 mL of THF, a solution of 20.0 g (71 mmol) of 4-(trans-4-propylcyclohexyl)phenyl bromide in 100 mL of THF was added dropwise with stirring at the room temperature for 45 minutes and stirred with reflux for 30 minutes, to prepare a Grignard reagent. To the solution, 16.3 g (214 mmol) of carbon disulfide was added dropwise for 15 minutes at the room temperature and stirred for one night. To the reaction solution, 60 mL of 3 M hydrochloric acid was added to stop the reaction, extracted with ether, and dried with anhydrous magnesium sulfate. After filtering off magnesium sulfate, the filtrate was concentrated under reduced pressure, to obtain 3.50 g (yield 17.7%) of 4-(trans-4-propylcyclohexyl)phenyl dithiocarboxylic acid.
Reaction SMILES: CS(OS(C)(=O)=O)(=O)=O.[CH3:10][C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][C:18]=1[O:19][CH3:20])[CH2:14]O.C(N(C(C)C)CC)(C)C.[CH3:30][O:31][C:32](=[O:55])[C@H:33]([CH2:42][C:43]1[N:47]=[CH:46][N:45](C(OC(C)(C)C)=O)[CH:44]=1)[NH:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>ClCCl>[CH3:30][O:31][C:32](=[O:55])[C@H:33]([CH2:42][C:43]1[N:47]([CH2:14][C:13]2[CH:16]=[CH:17][C:18]([O:19][CH3:20])=[C:11]([CH3:10])[CH:12]=2)[CH:46]=[N:45][CH:44]=1)[NH:34][C:35]([O:37][C:38]([CH3:41])([CH3:39])[CH3:40])=[O:36]
Reactant: COC(=O)[C@H](Cc1cn(C(=O)OC(C)(C)C)cn1)NC(=O)OC(C)(C)C
Reactant: COc1ccc(CO)cc1C
Agent: CS(=O)(=O)OS(C)(=O)=O
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)[C@H](Cc1cncn1Cc1ccc(OC)c(C)c1)NC(=O)OC(C)(C)C
Temperature: -25 °C
Reaction time: 24 h

Procedure:
A solution of 10.8 g methanesulfonic anhydride in 120 mL dichloromethane is chilled to -50° C. and treated dropwise with a solution of 9.4 g 3-methyl-4-methoxybenzyl alcohol, 10.8 mL diisopropylethylamine and 80 mL dichloromethane. The resulting solution is warmed to -25° C. over 30 min and treated dropwise with 20.0 g N,1-bis-BOC-histidine methyl ester dissolved in 125 mL dichloromethane. The mixture is then allowed to warm to 25° C. over 4 hr, stirring at this temperature 24 hr. The reaction mixture is poured into 700 mL 0.25M, pH=7 potassium phosphate buffer and the organic layer is separated, dried and evaporated. Chromatography on silica gel, eluting with chloroformmethanol (99:1) gives 3-(3-methyl-4-methoxyphenyl)methyl-N-BOC-histidine methyl ester as a gum. NMR (CDCl3) 1.43 (s, 9H, t-Bu).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][N:11]=[C:10]([NH:13][C:14]([CH:16]3[CH2:24][C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH2:17]3)=[O:15])[CH:9]=2)=[CH:4][CH:3]=1.[CH2:25](C([Sn])=C(CCCC)CCCC)[CH2:26]CC.O1C=CC=C1P(C1OC=CC=1)C1OC=CC=1.[Cl-].[Li+]>CN1CCCC1=O.C(OCC)(=O)C.CCCCCC>[CH2:17]1[C:18]2[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:24][CH:16]1[C:14]([NH:13][C:10]1[CH:9]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([CH:25]=[CH2:26])=[CH:3][CH:4]=2)[NH:12][N:11]=1)=[O:15]
Reactant: O=C(Nc1cc(-c2ccc(Br)cc2)[nH]n1)C1Cc2ccccc2C1
Reactant: CCCCC([Sn])=C(CCCC)CCCC
Agent: [Cl-]
Agent: [Li+]
Agent: c1coc(P(c2ccco2)c2ccco2)c1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: CN1CCCC1=O
Product: C=Cc1ccc(-c2cc(NC(=O)C3Cc4ccccc4C3)n[nH]2)cc1

Procedure:
5-(4-Bromophenyl)-3-(2-indanyl)carbonylaminopyrazole (106.5 mg), tributylvinyltin (0.25 ml), a tris(dibenzylideneacetone)dipalladium chloroform complex (17.1 mg), tri-2-furylphosphine (34.4 mg) and lithium chloride (34.0 mg) were dissolved in N-methylpyrrolidone (2 ml) with heating, and the resultant mixture was heated at 80° C. overnight. After allowing to cool, the reaction solution was diluted with ethyl acetate-hexane (1:1, 100 ml), washed with saturated aqueous potassium fluoride solution (100 ml×2) and then dried over anhydrous magnesium sulfate. The solvent was distilled away under a reduced pressure. The resultant residue was purified by column chromatography on silica gel (ethyl acetate:hexane=1:1) and then crystallized from chloroform to obtain the title compound (70.2 mg) as white crystals (melting point: 193-195° C.).
Reaction SMILES: C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[NH2:19][C:20]1[CH:40]=[C:39]([C:41]2[N:45]=[C:44]([CH3:46])[O:43][N:42]=2)[CH:38]=[CH:37][C:21]=1[CH2:22][NH:23][C:24](=[O:36])[C:25]1[CH:30]=[C:29]([O:31][CH3:32])[C:28]([CH3:33])=[C:27]([O:34][CH3:35])[CH:26]=1.[C:47]1([CH2:53][CH:54]=O)[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1>ClCCCl>[CH3:35][O:34][C:27]1[CH:26]=[C:25]([CH:30]=[C:29]([O:31][CH3:32])[C:28]=1[CH3:33])[C:24]([NH:23][CH2:22][C:21]1[CH:37]=[CH:38][C:39]([C:41]2[N:45]=[C:44]([CH3:46])[O:43][N:42]=2)=[CH:40][C:20]=1[NH:19][CH2:54][CH2:53][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)=[O:36]
Reactant: COc1cc(C(=O)NCc2ccc(-c3noc(C)n3)cc2N)cc(OC)c1C
Reactant: O=CCc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: COc1cc(C(=O)NCc2ccc(-c3noc(C)n3)cc2NCCc2ccccc2)cc(OC)c1C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Acetic acid (0.040 mL, 5 eq) and sodium triacetoxyborohydride (42 mg, 0.20 mmol) were added to a suspension of compound 1g (50 mg, 0.13 mmol) and phenylacetaldehyde (0.020 mg, 2 eq) in DCE (1.5 mL). The reaction was stirred at rt for 16 h and concentrated on a rotary evaporator. The residue was purified by preparative tlc (silica gel, 1:1 ethyl acetate/hexane) to afford compound 9a. ESI-MS m/e 487.3 (M+1).
Reaction SMILES: [OH:1][CH:2]([CH2:9][O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH2:3][O:4][P:5](=[O:8])([OH:7])[OH:6].S(Cl)(Cl)=O.N1C=CC=CC=1.C([N:40](C(CC1C=CC=CC=1)=O)[C@H:41]([C:44]([OH:46])=[O:45])[CH2:42]O)C1C=CC=CC=1>C(Cl)(Cl)Cl.[Pd].O>[NH2:40][CH:41]([C:44]([OH:46])=[O:45])[CH2:42][O:8][P:5](=[O:6])([OH:7])[O:4][CH2:3][CH:2]([OH:1])[CH2:9][O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCCCCCCCCCCCOCC(O)COP(=O)(O)O
Reactant: O=C(O)[C@H](CO)N(Cc1ccccc1)C(=O)Cc1ccccc1
Agent: [Pd]
Solvent: O=S(Cl)Cl
Solvent: c1ccncc1
Solvent: O
Product: CCCCCCCCCCCCOCC(O)COP(=O)(O)OCC(N)C(=O)O
Temperature: 0 °C
Reaction time: 4 h
Yield: 31 %

Procedure:
Dichlorophosphoridate was obtained by using 100.0 g (0.29 mol) of mono(2-hydroxy-3-lauryloxypropyl) phosphoric acid and 105.0 g (0.88 mol) of thionyl chloride. Then, 55.4 g (0.70 mol) of pyridine and 179.6 g (0.52 mol) of benzyl-N-benzylcarbonyl serine were dissolved in 100 ml of chloroform and stirred at 0° C. for 4 hours. Then, the reaction temperature was raised to room temperature and agitation was effected for 4 hours. After the reaction was completed, 100 ml of water were added and stirred at 20° C. for one hour. Then, the solvent was distilled off and the residue was extracted from ethylether. The thus obtained residue was dissolved in methanol and hydrogen was blown while refluxing methanol by heating to effect hydrogenation reaction for about 10 hours at a normal pressure by using a palladium/carbon catalyst at a normal pressure. After the reaction was completed, the residue obtained by distilling off methanol was purified on silica gel column chromatography (eluent/chloroform:methanol=90:10), to obtain 39.7 g of aimed 2-amino-2-carboxyethyl-(2-hydroxy-3-lauryloxypropyl) phosphoric acid as a white solid (0.09 mol, yield 32.0%).
Reaction SMILES: N[CH2:2][C:3]([OH:5])=[O:4].[CH:6](=[O:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.COC(OC)OC>CN(C=O)C.C(N(CC)CC)C>[C:3]1(=[O:4])[O:5][C:6](=[O:13])[C:7]2=[CH:12][CH:11]=[CH:10][CH:9]=[C:8]2[CH2:2]1
Reactant: NCC(=O)O
Reactant: O=Cc1ccccc1
Solvent: COC(OC)OC
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C1Cc2ccccc2C(=O)O1
Reaction time: 3 h

Procedure:
The teabag containing glycine on resin was placed in a 20 mL bottle and treated with a solution of benzaldehyde (0.508 mL, 5 mmoles) and anhydrous trimethylorthoformate (1.094 mL, 10 mmoles) in anhydrous DMF (9 mL). After shaking for 3 hours, the packet was washed with anhydrous DMF (3×8 mL). A solution of homophthalic anhydride (801 mg, 5 mmoles) and triethylamine (0.044 mL, 0.3 mmoles) was prepared in DMF (10 mL) and added to the teabag. After shaking at room temperature for 16 hours the packet was washed with DMF (6×30 mL) and DCM (4×30 mL) and dried at room temperature.
Reaction SMILES: [C:1]([O:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][CH:11]([C:13]1[CH:25]=[CH:24][C:16]([CH2:17][C:18]2[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=2)=[CH:15][CH:14]=1)O)([CH3:4])([CH3:3])[CH3:2].S(Cl)(Cl)=O.C1CCN2C(=NCCC2)CC1.Cl>C(Cl)Cl.CN(C)C=O.C1(C)C=CC=CC=1.O>[C:1]([O:5][CH2:6][CH2:7][O:8][CH2:9][CH:10]=[CH:11][C:13]1[CH:25]=[CH:24][C:16]([CH2:17][C:18]2[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=2)=[CH:15][CH:14]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OCCOCCC(O)c1ccc(Cc2cccnc2)cc1
Agent: Cl
Solvent: O=S(Cl)Cl
Solvent: O
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)(C)OCCOCC=Cc1ccc(Cc2cccnc2)cc1
Yield: 75 %

Procedure:
In 3 ml of methylene chloride was dissolved 630 mg of 3-[p-[3-(2-tert-butoxyethyl)oxy-1-hydroxypropyl]benzyl]pyridine, and to the resulting solution was added 0.27 ml of thionyl chloride with ice-cooling, after which the resulting mixture was subjected to reaction at room temperature for 30 minutes. The solvent and the excessive thionyl chloride were removed by distillation under reduced pressure, and the residue thus obtained was dissolved in 3 ml of N,N-dimethylformamide, and 1.38 ml of DBU was added to the resulting solution, after which the resulting mixture was subjected to reaction at a temperature of 110° to 115° C. for 2 hours. To the reaction mixture were added 10 ml of water and 10 ml of toluene, and the pH of the mixture was adjusted to 7.5 with 2N hydrochloric acid. The organic layer was separated, washed with 5 ml of water, and then dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure, and the residue thus obtained was purified by a column chromatography [Wako Silica Gel C-200, eluant: toluene:ethyl acetate (10:1 by volume)] to obtain 450 mg (yield 75.0%) of colorless, oily 3-[p-[3-(2-tert-butoxyethyl)oxy-1-propenyl]benzyl]pyridine.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([NH:13][C@@H:14]1[CH2:19][CH2:18][C@H:17]([C:20]([O:22]CC)=[O:21])[CH2:16][C@H:15]1[NH:25][C:26]([C:28]1[S:29][C:30]3[CH2:31][N:32]([CH3:37])[CH2:33][CH2:34][C:35]=3[N:36]=1)=[O:27])=[O:12])=[CH:5]2.C(O)C.[OH-].[Na+].Cl>O1CCCC1>[C:20]([C@H:17]1[CH2:18][CH2:19][C@@H:14]([NH:13][C:11]([C:6]2[NH:7][C:8]3[C:4]([CH:5]=2)=[CH:3][C:2]([Cl:1])=[CH:10][CH:9]=3)=[O:12])[C@H:15]([NH:25][C:26]([C:28]2[S:29][C:30]3[CH2:31][N:32]([CH3:37])[CH2:33][CH2:34][C:35]=3[N:36]=2)=[O:27])[CH2:16]1)([OH:22])=[O:21]
Reactant: CCOC(=O)[C@H]1CC[C@@H](NC(=O)c2cc3cc(Cl)ccc3[nH]2)[C@H](NC(=O)c2nc3c(s2)CN(C)CC3)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CN1CCc2nc(C(=O)N[C@@H]3C[C@@H](C(=O)O)CC[C@H]3NC(=O)c3cc4cc(Cl)ccc4[nH]3)sc2C1
Reaction time: 12 h
Yield: 65.7 %

Procedure:
(1R*,2R*,4S*)-N1-[(5-Chloroindol-2-yl)carbonyl]-4-ethoxycarbonyl-N2-[(5-methyl-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-2-yl)carbonyl]-1,2-cyclohexane-diamine (244 mg) was suspended in a mixed solvent of ethanol (8 ml) and tetrahydrofuran (5 ml), and a 1N aqueous solution (0.9 ml) of sodium hydroxide was added at room temperature to stir the mixture for 12 hours. After adding 1N hydrochloric acid (0.9 ml), the solvent was distilled off under reduced pressure, and the residue was washed with water and ether to obtain the title compound (152 mg) as a colorless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:6]([CH:7]=[O:8])[C:5]([OH:10])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:18][CH2:19][O:20][Si:21]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22]>CN(C)C=O.C(OCC)(=O)C>[C:24]([Si:21]([CH3:23])([CH3:22])[O:20][CH2:19][CH2:18][O:10][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:9][C:6]=1[CH:7]=[O:8])([CH3:27])([CH3:26])[CH3:25]
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Reactant: O=Cc1cc(Cl)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCCOc1ccc(Cl)cc1C=O
Temperature: 60 °C
Yield: 99.2 %

Procedure:
To a solution of 5-chlorosalicylaldehyde (5 g, 32 mmol) (Aldrich) in N,N-dimethylformamide (40 mL) was added K2CO3 (20 g, 145 mmol), and (2-bromo-ethoxy)-tert-butyl-dimethyl-silane (10 g, 42 mmol, Aldrich). The reaction mixture was heated at 60° C. for 18 h. The crude was cooled to room temperature, diluted with ethyl acetate, washed with water, brine. The organic layer was separated, concentrated, and the residue was purified by chromatography (EtOAc:Hexanes=1:8, then 1:4) to give 2-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-5-chloro-benzaldehyde as a white solid (Yield 10 g, 99%).
Reaction SMILES: [O:1]1[CH2:3][C@H:2]1[CH2:4][O:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH:8]=[CH:9][NH:10]2.[Cl:15][C:16]1[CH:30]=[CH:29][C:19]2[S:20][C:21]([C:23]3[CH2:24][CH2:25][NH:26][CH2:27][CH:28]=3)=[CH:22][C:18]=2[CH:17]=1.C(O)C>CS(C)=O>[Cl:15][C:16]1[CH:30]=[CH:29][C:19]2[S:20][C:21]([C:23]3[CH2:24][CH2:25][N:26]([CH2:3][C@H:2]([OH:1])[CH2:4][O:5][C:6]4[CH:14]=[CH:13][CH:12]=[C:11]5[C:7]=4[CH:8]=[CH:9][NH:10]5)[CH2:27][CH:28]=3)=[CH:22][C:18]=2[CH:17]=1
Reactant: Clc1ccc2sc(C3=CCNCC3)cc2c1
Reactant: c1cc(OC[C@@H]2CO2)c2cc[nH]c2c1
Solvent: CCO
Solvent: CS(C)=O
Product: O[C@H](COc1cccc2[nH]ccc12)CN1CC=C(c2cc3cc(Cl)ccc3s2)CC1

Procedure:
The title compound was prepared in a fashion similar to that described in Example 1 using (S)-(+)-4-(oxiranylmethoxy)-1H-indole (0.075 g, 0.042 mmol), and 5-chloro-2-(1,2,3,6-tetrahydropyridin-4-yl)benzo[b]thiophene (0.100 g, 0.042 mmol) using ethanol as reaction solvent. Yield 0.103 g (58%) of an orange oil. FDMS m/e=438 (M+ of free base). α[D]589 =+7.3 (c=0.95, dimethylsulfoxide)
Reaction SMILES: N1C=CN=C1.[C:6]([Si:10]([CH3:13])([CH3:12])Cl)([CH3:9])([CH3:8])[CH3:7].[F:14][C:15]1[CH:16]=[CH:17][C:18]([O:25][CH3:26])=[C:19]([C@@H:21]([CH3:24])[CH2:22][OH:23])[CH:20]=1>C(Cl)Cl.CCOC(C)=O>[C:6]([Si:10]([O:23][CH2:22][C@@H:21]([C:19]1[CH:20]=[C:15]([F:14])[CH:16]=[CH:17][C:18]=1[O:25][CH3:26])[CH3:24])([CH3:13])[CH3:12])([CH3:9])([CH3:8])[CH3:7]
Reactant: COc1ccc(F)cc1[C@@H](C)CO
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COc1ccc(F)cc1[C@@H](C)CO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Imidazole (3.55 g, 52.1 mmol) and tert-butyldimethylchlorosilane (10.21 g, 33.9 mmol) were added to a solution of 25A (4.8 g, 26.1 mmol) in CH2Cl2 (125 mL) and stirred overnight at rt. The reaction mixture was diluted with EtOAc (150 mL), washed with water and brine, dried over Na2SO4 and concentrated in vacuo. The crude product was purified by flash chromatography (loading in chloroform, 0% to 20% ethyl acetate in hexane) to yield 25B as a clear oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH:10](S(C)=O)SC)=[CH:5][CH:4]=1.C([OH:18])C.C([O-])([O-])OCC>S(=O)(=O)(O)O.O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH:10]=[O:18])=[CH:5][CH:4]=1
Reactant: CCO
Reactant: COc1ccc(CC(SC)S(C)=O)cc1
Agent: CCOC([O-])[O-]
Agent: O=S(=O)(O)O
Solvent: O
Product: COc1ccc(CC=O)cc1

Procedure:
764 mg. of methyl 2-(p-methoxyphenyl)-1-methylthioethyl sulfoxide was dissolved in 6 ml. of ethanol, and with the addition of 1.03 ml. of ethyl orthoformate and 5 drops of concentrated sulfuric acid, the solution was stirred for 27 hours at room temperature. 10 ml. of water was added, and the reaction mixture was extracted with methylene chloride. The product was dried with anhydrous sodium sulfate, and concentrated at reduced pressure to give a diethyl acetal of p-methoxyphenylacetaldehyde. 5 ml. of ether was added to the acetal, and 20 ml. of 0.25 N dilute sulfuric acid was further added. The mixture was stirred for 12 hours at room temperature. The stirred mixture was then extracted with ether, and the ether layer was dried with anhydrous sodium sulfate, followed by concentration at reduced pressure. The residue was subjected to column chromatography to give 386 mg of p-methoxyphenylacetaldehyde as a colorless liquid. Yield 82%.