Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.C([C:4]1[C:9]([OH:10])=[C:8]([CH2:11][OH:12])C(CO)=CN=1)=O.C(N(CC)CC)C.C([O:25][C:26](=[O:28])[CH3:27])(=O)C>O1CCCC1>[CH3:4][C:9]([CH2:8][C:11]([CH2:27][C:26]([OH:25])=[O:28])=[O:12])=[O:10]
Reactant: CC(=O)OC(C)=O
Reactant: O=Cc1ncc(CO)c(CO)c1O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)CC(=O)CC(=O)O
Reaction time: 1 h

Procedure:
A solution of one equivalent of 2-formyl-3-hydroxy-4,5-dihydroxymethylpyridine hydrochloride in 400 ml. anhydrous tetrahydrofuran is treated with four equivalents of triethylamine and aged for one hour at room temperature. Then three equivalents of acetic anhydride are introduced, and the reaction mixture is aged 4 hours at room temperature. The reaction mixture is concentrated under reduced pressure to a gum. This is treated with a mixture of 300 ml. of diethyl ether and 300 ml. of distilled water. After shaking well, the layers are separated and the ether layer is dried over magnesium sulfate. After evaporation to dryness, the desired triacetate is obtained as a viscous oil.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=1[O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH:12]=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:25]([O:27][CH:28]([O:31][CH2:32][CH3:33])[CH2:29][NH2:30])[CH3:26]>C1C=CC=CC=1>[CH2:25]([O:27][CH:28]([O:31][CH2:32][CH3:33])[CH2:29][N:30]=[CH:12][C:11]1[CH:14]=[CH:15][C:16]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:10]=1)[CH3:26]
Reactant: CCOC(CN)OCC
Reactant: O=Cc1ccc(OCc2ccccc2)c(OCc2ccccc2)c1
Solvent: c1ccccc1
Product: CCOC(CN=Cc1ccc(OCc2ccccc2)c(OCc2ccccc2)c1)OCC

Procedure:
73 g (0.172 mol) of 3,4-bis(benzyloxy)benzaldehyde was dissolved in 500 ml of benzene, and 25 ml (0.23 mol) of aminoacetaldehyde diethylacetal was added thereto. The mixture was stirred under reflux for 5 hours to remove the resulting water. The reaction solution was concentrated under reduced pressure to obtain a residue of 2-(N-[3,4-bis(benzyloxy)benzyliden]amino)acetaldehyde diethylacetal. This residue was dissolved in 700 ml of methanol, and 6.0 g (0.16 mol) of sodium borohydride was added thereto at room temperature. The mixture was stirred for 15 minutes. The reaction solution was concentrated under reduced pressure. The residue was dissolved in ethyl acetate, then washed with a saturated a sodium chloride aqueous solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a residue of 2-{N-[3,4-bis(benzyloxy)benzyl]amino}acetaldehyde diethylacetal. This residue was dissolved in 600 ml of dry tetrahydrofuran, and 39.8 g (0.21 mol) of p-toluenesulfonyl chloride and 59 ml (0.42 mol) of triethylamine were added. The mixture was stirred at room temperature for 17.5 hours. The reaction solution was concentrated under reduced pressure, and the residue was extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride aqueous solution, then dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (10% ethyl acetate/hexane), whereby 70 g (yield: 70.7%) of 2-{N-(P-tolylsulfonyl)-N-[3,4-bis(benzyloxy)benzyl]amino}acetaldehyde diethyl acetal was obtained.
Reaction SMILES: Cl.COC1C=CC(C[S:9][C@@H:10]2[CH2:14][N:13]([C:15]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=3)=[O:16])[C@H:12]([C:28]([NH:30][C@@H:31]3[CH2:35][CH2:34]N[CH2:32]3)=[O:29])[CH2:11]2)=CC=1.[N+:38]([C:41]1[CH:54]=[CH:53][C:44]([CH2:45][O:46][C:47]([NH:49][C:50](=[NH:52])[CH3:51])=[O:48])=[CH:43][CH:42]=1)([O-:40])=[O:39]>>[SH:9][C@@H:10]1[CH2:14][N:13]([C:15]([O:17][CH2:18][C:19]2[CH:20]=[CH:21][C:22]([N+:25]([O-:27])=[O:26])=[CH:23][CH:24]=2)=[O:16])[C@H:12]([C:28]([NH:30][C@@H:31]2[CH2:35][CH2:34][N:52]([C:50](=[N:49][C:47]([O:46][CH2:45][C:44]3[CH:43]=[CH:42][C:41]([N+:38]([O-:40])=[O:39])=[CH:54][CH:53]=3)=[O:48])[CH3:51])[CH2:32]2)=[O:29])[CH2:11]1
Reactant: COc1ccc(CS[C@H]2C[C@@H](C(=O)N[C@@H]3CCNC3)N(C(=O)OCc3ccc([N+](=O)[O-])cc3)C2)cc1
Reactant: CC(=N)NC(=O)OCc1ccc([N+](=O)[O-])cc1
Agent: Cl
Product: CC(=NC(=O)OCc1ccc([N+](=O)[O-])cc1)N1CC[C@@H](NC(=O)[C@@H]2C[C@H](S)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Yield: 53.1 %

Procedure:
Following a procedure similar to that described in Preparation 23(iii) and 23(iv), but using 0.76 g of (2S,4S)-4-(4-methoxybenzylthio)-1-(4-nitrobenzyloxycarbonyl)-2-[(3R)-pyrrolidin-3-ylaminocarbonyl]pyrrolidine hydrochloride and 0.33 g of N-(4-nitrobenzyloxycarbonyl)acetamidine, 0.45 g of the title compound was obtained as a powder.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9]Br)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[NH:17]1[CH2:22][CH2:21][CH:20]([CH2:23][NH:24][C:25]([C:27]2[C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[N:29]([CH:36]([CH3:38])[CH3:37])[N:28]=2)=[O:26])[CH2:19][CH2:18]1.[ClH:39]>C(O)C.C(OCC)(=O)C>[ClH:39].[OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][N:17]2[CH2:22][CH2:21][CH:20]([CH2:23][NH:24][C:25]([C:27]3[C:35]4[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=4)[N:29]([CH:36]([CH3:38])[CH3:37])[N:28]=3)=[O:26])[CH2:19][CH2:18]2)=[CH:4][CH:3]=1
Reactant: Oc1ccc(CCBr)cc1
Reactant: CC(C)n1nc(C(=O)NCC2CCNCC2)c2ccccc21
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC(C)n1nc(C(=O)NCC2CCN(CCc3ccc(O)cc3)CC2)c2ccccc21

Procedure:
2-(4-hydroxyphenyl)ethyl bromide (prepared as described in Acta Chem. Scand. 21 (1) 53-62, 1967) (3.4 g, 0.017 moles) and anhydrous potassium carbonate (4.6 g, 0.033 moles) in absolute ethanol (100 ml) were added to a solution of N-(4-piperidinylmethyl)-1-isopropyl-1H-3 indazolecarboxamide (4.2 g, 0.014 moles), prepared as described in EP-A-0 975 623 in absolute ethanol (80 ml). The suspension thus obtained was stirred continuously under reflux for 16 hours. The suspension was filtered and the filtrate evaporated under reduced pressure. The residue thus obtained was then transformed into the corresponding hydrochloride salt by dissolution in ethyl acetate, addition of ethanolic hydrogen chloride and recrystallisation from absolute ethanol to give the desired product (2.2 g).
Reaction SMILES: [OH:1][C:2]1[CH2:6][O:5][C:4](=[O:7])[C:3]=1[C:8](=[O:25])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH:16]=[CH:17][C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=1.[H][H]>C(OCC)(=O)C.[Pd]>[OH:1][C:2]1[CH2:6][O:5][C:4](=[O:7])[C:3]=1[C:8](=[O:25])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]1[CH:19]=[CH:20][C:21]([Cl:24])=[CH:22][CH:23]=1
Reactant: O=C(CCCCCCCC=Cc1ccc(Cl)cc1)C1=C(O)COC1=O
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: O=C(CCCCCCCCCc1ccc(Cl)cc1)C1=C(O)COC1=O
Reaction time: 1.5 h
Yield: 66.2 %

Procedure:
To a solution of 1.58 g (4.35 mmol) of 4-hydroxy-3-[10-(4-chlorophenyl)-1-oxodec-9-enyl]-2(5H)-furanone in 100 mL of ethyl acetate is added 250 mg of 5% palladium on carbon and subjected to atmospheric hydrogenation using a balloon to deliver the hydrogen. After 1.5 hours, the reaction is worked up by filtering through Solka Flok. The filtrate is washed with copious amounts of ethyl acetate and concentrated in vacuo to give 1.05 g (66%) of pure 4-hydroxy-3-[10-(4-chlorophenyl)1-oxodecyl]-2(5H)-furanone.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([SH:11])[CH:8]=[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:6]=1[OH:16])([CH3:4])([CH3:3])[CH3:2].[C:17]([C:19]1[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=1[CH2:21]Br)#[N:18].[OH-].[Na+].C(O)C>O>[C:12]([C:7]1[CH:8]=[C:9]([S:11][CH2:21][C:20]2[CH:23]=[CH:24][CH:25]=[CH:26][C:19]=2[C:17]#[N:18])[CH:10]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:6]=1[OH:16])([CH3:15])([CH3:14])[CH3:13]
Reactant: N#Cc1ccccc1CBr
Reactant: CC(C)(C)c1cc(S)cc(C(C)(C)C)c1O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)(C)c1cc(SCc2ccccc2C#N)cc(C(C)(C)C)c1O
Yield: 18.9 %

Procedure:
A solution of 2.00 g (8.39 mmole) of 2,6-di-t-butyl-4-mercaptophenol, 1.65 g (8.39 mmole) of o-cyanobenzyl bromide, 5 ml of 1.68N sodium hydroxide and 75 ml of ethanol was heated at reflux for 48 hours. The reaction mixture was poured into water and was extracted with diethyl ether. The ether extract was washed with water, dried with magnesium sulfate and evaporated to give the crude product as an oil. The oil was purified by silica gel chromatography, eluting with a mixture of ethyl acetate and hexane, followed by recrystallization from hexane to give 0.56 g of white 2,6-di-t-butyl-4-[(2-cyanophenyl) methylthio]phenol, m.p. 79°-82° C. Analysis: Calculated for C22H27NOS: %C, 74.7; %H, 7.7; %N, 4.0; Found: %C, 74.6; %H, 7.9; %N 3.6.
Reaction SMILES: [CH2:1]([N:12]1[CH:19]=[C:18]([CH2:20][C:21]2[CH:22]=[N:23][C:24]([O:27][CH2:28][CH3:29])=[N:25][CH:26]=2)[C:16](=[O:17])[NH:15][C:13]1=[S:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].C(N(C(C)C)CC)(C)C.[F:39][C:40]1[CH:47]=[CH:46][C:43]([CH2:44]Br)=[CH:42][CH:41]=1>C(Cl)Cl>[CH2:1]([N:12]1[CH:19]=[C:18]([CH2:20][C:21]2[CH:22]=[N:23][C:24]([O:27][CH2:28][CH3:29])=[N:25][CH:26]=2)[C:16](=[O:17])[N:15]=[C:13]1[S:14][CH2:44][C:43]1[CH:46]=[CH:47][C:40]([F:39])=[CH:41][CH:42]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: CCCCCCCCCCCn1cc(Cc2cnc(OCC)nc2)c(=O)[nH]c1=S
Reactant: Fc1ccc(CBr)cc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCCCCCCCCCn1cc(Cc2cnc(OCC)nc2)c(=O)nc1SCc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a mixture of 1-undecyl-5-(2-ethoxypyrimidin-5-ylmethyl)-2-thiouracil (5.0 g) and diisopropylethylamine (2.1 ml) in dry methylene chloride (200 ml) was added 4-fluorobenzyl bromide (1.5 ml) and the mixture stirred under argon at room temperature for 20 h. The solution was washed with 5% aqueous sodium bicarbonate and the organic layer was added directly to a silica gel column (200 g). Elution with ethyl acetate to 5% methanol in ethyl acetate gave the desired product (2.7 g). 1H-NMR (CDCl3) δ0.8-0.95 (3H,m), 1.15-1.4 (16H,m), 1.43 (3H,t), 1.55-1.8 (2H,m), 3.68 (2H,s), 3.71 (2H,t), 4.41 (2H,q), 4.47 (2H,s), 6.86 (1H,s), 6.9-7.1 (2H,m), 7.3-7.45 (2H,m), 8.45 (2H,d); MS (APCI+) found (M+1)=527; C29H39FN4O2S requires 526.
Reaction SMILES: [O:1]=[C:2]1[N:8]([CH2:9][C:10]([F:13])([F:12])[F:11])[CH2:7][CH2:6][NH:5][CH2:4][CH:3]1[NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18].[F:22][C:23]1[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:24]=1[CH:25]=O.C([BH3-])#N.[Na+].C(=O)(O)[O-].[Na+]>CO.C(O)(=O)C>[F:22][C:23]1[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:24]=1[CH2:25][N:5]1[CH2:4][CH:3]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:18])([CH3:20])[CH3:19])[C:2](=[O:1])[N:8]([CH2:9][C:10]([F:11])([F:12])[F:13])[CH2:7][CH2:6]1
Reactant: O=Cc1cccc(F)c1F
Reactant: CC(C)(C)OC(=O)NC1CNCCN(CC(F)(F)F)C1=O
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)(C)OC(=O)NC1CN(Cc2cccc(F)c2F)CCN(CC(F)(F)F)C1=O
Reaction time: 0.5 h
Yield: 88.6 %

Procedure:
A mixture of tert-butyl 7-oxo-1-(2,2,2-trifluoroethyl)-1,4-diazepan-6-ylcarbamate (51 mg, 0.16 mmol), 2,3-difluorobenzaldehyde (0.053 mL, 0.49 mmol), and sodium cyanoborohydride (31 mg, 0.49 mmol) in methanol (5 mL) was adjusted to pH 4 with acetic acid. After 0.5 h, saturated aqueous sodium bicarbonate was added and the mixture was extracted with dichloromethane (3×). The combined organic extracts were dried over magnesium sulfate, filtered, and concentrated. Purification by silica gel chromatography [100% dichloromethane→95% dichloromethane/5% (10% ammonium hydroxide/methanol)] gave the title compound (62 mg). MS 438 (M+1).
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1)=[CH2:2].[NH:9]1[CH2:14][CH2:13][CH:12]([NH:15][C:16]2[O:17][C:18]3[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=3[N:20]=2)[CH2:11][CH2:10]1>C(O)CCC>[N:6]1[CH:7]=[CH:8][C:3]([CH2:1][CH2:2][N:9]2[CH2:10][CH2:11][CH:12]([NH:15][C:16]3[O:17][C:18]4[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=4[N:20]=3)[CH2:13][CH2:14]2)=[CH:4][CH:5]=1
Reactant: c1ccc2oc(NC3CCNCC3)nc2c1
Reactant: C=Cc1ccncc1
Solvent: CCCCO
Product: c1ccc2oc(NC3CCN(CCc4ccncc4)CC3)nc2c1
Yield: 62 %

Procedure:
A mixture of 3.2 parts of 4-(1-ethenyl)pyridine, 2.1 parts of N-(4-piperidinyl)-2-benzoxazolamine and 80 parts of 1-butanol was stirred and refluxed for 48 hours. The reaction mixture was evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (97:3 by volume) saturated with ammonia, as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from 2,2'-oxybispropane, yielding 2 parts (62%) of N-[1-[2-(4-pyridinyl)ethyl]-4-piperidinyl]-2-benzoxazolamine; mp. 146.9° C. (450).
Reaction SMILES: [C:1]([NH:9][CH:10]([C:18](=O)[CH3:19])[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.COC1C=CC(P2(=S)SP(=S)(C3C=CC(OC)=CC=3)[S:30]2)=CC=1>C1COCC1>[CH3:19][C:18]1[S:30][C:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[N:9][C:10]=1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CC(=O)C(NC(=O)c1ccccc1)C(=O)OC(C)(C)C
Solvent: C1CCOC1
Product: Cc1sc(-c2ccccc2)nc1C(=O)OC(C)(C)C
Yield: 62.1 %

Procedure:
A solution of tert-butyl 2-benzamido-3-oxobutanoate (842 mg, 3.04 mmol) and 2,4-bis(4-methoxyphenyl)-1,3,2,4-dithiadiphosphetane 2,4-disulfide (Lawesson's reagent) (1.88 g 6.07 mmol) in THF (20 ml) was heated at reflux for 6 h. The mixture was evaporated in vacuo and purified by flash chromatography to give tert-butyl 5-methyl-2-phenylthiazole-4-carboxylate as a yellow solid (520 mg, 62% yield).
Reaction SMILES: [CH2:1]([OH:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[Cl:14][S:15]([N:18]=[C:19]=[O:20])(=[O:17])=[O:16]>CCOCC>[CH2:1]([O:13][C:19](=[O:20])[NH:18][S:15]([Cl:14])(=[O:17])=[O:16])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: O=C=NS(=O)(=O)Cl
Reactant: CCCCCCCCCCCCO
Solvent: CCOCC
Product: CCCCCCCCCCCCOC(=O)NS(=O)(=O)Cl
Reaction time: 2 h
Yield: 111.3 %

Procedure:
A solution of n-dodecyl alcohol (107 g, 52.4 mmoles) in 100 mL Et2O was added dropwise to a solution of chlorosulfonyl isocyanate (5.0 mL, 57.4 mmoles) in 100 mL Et2O at -15° C. under an atmosphere of N2. The resulting mixture was stirred for 2 hours and concentrated in vacuo. The residue was triturated with cold hexanes to give a white solid which was collected by filtration to give 19.12 g of a white solid, mp 62°-63° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8](Cl)=[CH:7][CH:6]=2.ClC1C=C2C(=CC=1)N=C([C:29](OCC)=[O:30])C(=O)N2>>[Cl:1][C:2]1[C:3]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([O:30][CH3:29])=[CH:7][CH:6]=2
Reactant: CCOC(=O)c1nc2ccc(Cl)cc2nc1Cl
Reactant: CCOC(=O)c1nc2ccc(Cl)cc2[nH]c1=O
Product: CCOC(=O)c1nc2ccc(OC)cc2nc1Cl

Procedure:
In a similar manner, 3,6-dichloro-2-quinoxalinecarboxylic acid, ethyl ester, m.p. 63°-65°, was prepared from 6-chloro-3,4-dihydro-3-oxo-2-quinoxalinecarboxylic acid, ethyl ester (Example 12a) (73%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([OH:10])=[O:9])=[CH:6][CH:7]=1.[Cl-:11].[Al+3].[Cl-:13].[Cl-]>C(Cl)Cl>[Cl:11][C:3]1[CH:4]=[C:5]([CH:6]=[C:7]([Cl:13])[C:2]=1[CH3:1])[C:8]([OH:10])=[O:9]
Reactant: Cc1ccc(C(=O)O)cc1
Reactant: [Cl-]
Agent: [Al+3]
Solvent: ClCCl
Product: Cc1c(Cl)cc(C(=O)O)cc1Cl
Reaction time: 4 h

Procedure:
To a solution of p-toluic acid (95.0 g,0.698 mole) in methylene chloride (1 liter), was added aluminum chloride (260.0 g,1.948 mole), portionwise, while keeping the reaction temperature below 10° C. When the addition was completed, chlorine gas was bubbled in at such a rate as to keep the temperature below 10° C. The reaction was followed by GLC. After about 4 hours most of the starting material had been converted to the expected compound. The resulting mixture was poured into ice and concentrated hydrochloric acid, and then extracted with ethyl acetate several times. The combined organic layers were washed with water and then dried over anhydrous sodium sulfate. Removing the solvent in the rotavap yielded the crude product as a white solid. Recrystalization from acetone/water yielded 3,5-dichloro-4-methylbenzoic acid with minor impurities 115.4 g (81% yield of product).
Reaction SMILES: [O:1]=[S:2]1(=[O:28])[CH2:7][CH2:6][CH:5]([CH2:8][C:9]2[C:17]3[C:12](=[C:13]([C:25]([NH2:27])=[O:26])[CH:14]=[C:15]([C:18]4[CH:22]=[C:21]([CH:23]=O)[S:20][CH:19]=4)[CH:16]=3)[NH:11][CH:10]=2)[CH2:4][CH2:3]1.[NH:29]1[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C>CS(C)=O>[O:28]=[S:2]1(=[O:1])[CH2:3][CH2:4][CH:5]([CH2:8][C:9]2[C:17]3[C:12](=[C:13]([C:25]([NH2:27])=[O:26])[CH:14]=[C:15]([C:18]4[CH:22]=[C:21]([CH2:23][N:29]5[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]5)[S:20][CH:19]=4)[CH:16]=3)[NH:11][CH:10]=2)[CH2:6][CH2:7]1
Reactant: C1CCCNCC1
Reactant: NC(=O)c1cc(-c2csc(C=O)c2)cc2c(CC3CCS(=O)(=O)CC3)c[nH]c12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Solvent: CC(=O)O
Solvent: CS(C)=O
Product: NC(=O)c1cc(-c2csc(CN3CCCCCC3)c2)cc2c(CC3CCS(=O)(=O)CC3)c[nH]c12
Yield: 10.6 %

Procedure:
3-[(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methyl]-5-(5-formyl-3-thienyl)-1H-indole-7-carboxamide (30 mg, 0.072 mmol), hexahydro-1H-azepine (71.4 mg, 0.720 mmol, 10 eq), acetic acid (0.4 μL, 0.007 mmol, 0.1 eq) were dissolved in DMSO (2 mL) in a 5 mL A-vial reaction tube. The mixture was stirred in VX-2500 Multi-Tube Vortexer for overnight at room temperature. MP-triacetoxyborohydride (309 mg, 0.72 mmol, 10 eq) was then added and the mixture was stirred again in VX-2500 Multi-Tube Vortexer for overnight at room temperature. The reaction mixture was filtered through a polypropylene cartridge (10 mL tube) on Bohdan Miniblock in a reaction tube and was then concentrated and purified by Gilson HPLC with a water-acetonitrile with 0.1% TFA buffer. The desired product fractions were combined and concentrated in a Glas-Col evaporator, giving 3.8 mg (9.5%) of the title compound.
Reaction SMILES: [C:1]([C:3]1([CH3:17])[CH2:8][CH2:7][C:6]2[C:9]([CH3:16])=[C:10]([OH:15])[C:11]([CH3:14])=[C:12]([CH3:13])[C:5]=2[O:4]1)#[CH:2].I[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C>C(#N)C>[CH3:17][C:3]1([C:1]#[C:2][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:8][CH2:7][C:6]2[C:9]([CH3:16])=[C:10]([OH:15])[C:11]([CH3:14])=[C:12]([CH3:13])[C:5]=2[O:4]1
Reactant: C#CC1(C)CCc2c(C)c(O)c(C)c(C)c2O1
Reactant: Ic1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1c(C)c2c(c(C)c1O)CCC(C)(C#Cc1ccccc1)O2
Reaction time: 3 h
Yield: 68.5 %

Procedure:
A mixture of 2.3 g (10 mmol) of rac-3,4-dihydro-2-ethynyl-2,5,7,8-tetramethyl-2H-1-benzopyran-6-ol, 3.06 g (15 mmol) of iodobenzene, 0.39 g of triphenylphosphine, 95 mg of cuprous iodide, 3 ml of triethylamine and 100 ml of acetonitrile was degassed with argon for 10 minutes. Palladium acetate, 110 mg (0.5 mmol), was then added and stirring under argon was continued for 3 hours. The reaction mixture was evaporated under reduced pressure and the residue was partitioned between methylene chloride and saturated aqueous sodium bicarbonate solution. The organic phase was separated, dried over sodium sulfate and evaporated. The crude product was chromatographed over 100 g of silica gel (Merck 70-230 mesh) using methylene chloride for elution. The clean fractions were combined and evaporated and the residue was crystallized from hexane to yield 2.1 g (68%) of rac-3,4-dihydro-2,5,7,8-tetramethyl2-(phenylethynyl)-2H-1-benzopyran-6-ol with m.p. 109°-111° C. The analytical sample was recrystallized from hexane and had m.p. 111°-113° C. Anal. Calcd. for C21H22O2 : C, 82.32; H, 7.24 Found: C, 82.02; H, 7.30
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10](=[O:19])[CH:11]=[CH:12]C1C=CC=CC=1.[Cl-].[Cl-].[Cl-].[Al+3]>>[F:8][C:6]1[CH:5]=[C:4]2[C:3](=[C:2]([F:1])[CH:7]=1)[N:9]=[C:10]([OH:19])[CH:11]=[CH:12]2
Reactant: O=C(C=Cc1ccccc1)Nc1ccc(F)cc1F
Agent: [Al+3]
Agent: [Cl-]
Product: Oc1ccc2cc(F)cc(F)c2n1
Temperature: 160 °C

Procedure:
Solid N-(2,4-difluorophenyl)cinnamamide (13.2 g, 50.7 mmol) was pre-mixed with aluminum trichloride (20.29 g, 152.2 mmol) and the mixture was heated to 160° C. under gently flowing nitrogen gas for 80 minutes. The reaction was cooled and quenched with ice, and the resultant beige solid was collected by filtration, washed with water and air-dried to a light tan solid (9.89 g).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6](Cl)[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[CH3:12][N:13]1[CH:17]=[CH:16][N:15]=[C:14]1[SH:18].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[NH2:1][C:2]1[CH:7]=[C:6]([S:18][C:14]2[N:13]([CH3:12])[CH:17]=[CH:16][N:15]=2)[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10]
Reactant: Cn1ccnc1S
Reactant: Nc1cc(Cl)ccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1ccnc1Sc1ccc([N+](=O)[O-])c(N)c1

Procedure:
A mixture of 2.5 G. of 2-amino-4-chloro-1-nitrobenzene, 3.4 g. of 1-methyl-2-mercapto-imidazole and 4.2 g. potassium carbonate in 20 ml. dimethylformamide is heated overnight at 110°-120° C., then cooled, and poured into water. The product is filtered off and recrystallized from aqueous methanol to give 2-amino-4-(1-methylimidazol-2-ylthio)-1-nitrobenzene.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:7]=[C:6]([C:8]2[N:9]=[CH:10][N:11]3[C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=4[C:15](=[O:22])[N:14]([CH3:23])[CH2:13][C:12]=23)[O:5][N:4]=1.[CH2:24](Br)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(N(C(C)C)C(C)C)C>C(Cl)Cl>[CH2:24]([NH:1][CH2:2][C:3]1[N:7]=[C:6]([C:8]2[N:9]=[CH:10][N:11]3[C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=4[C:15](=[O:22])[N:14]([CH3:23])[CH2:13][C:12]=23)[O:5][N:4]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: BrCc1ccccc1
Reactant: CN1Cc2c(-c3nc(CN)no3)ncn2-c2ccccc2C1=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CN1Cc2c(-c3nc(CNCc4ccccc4)no3)ncn2-c2ccccc2C1=O

Procedure:
0.93 g (3 mmol) of 3-(3-aminomethyl-1,2,4-oxadiazol-5-yl)-5-methyl-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepin-6-one was stirred at room temperature overnight with 0.51 g (3 mmol) of benzyl bromide and 0.52 g (4 mmol) of N-ethyldiisopropylamine in 10 ml of methylene chloride. By evaporation of the solvent and chromatography of the residue on silica gel while eluting with ethyl acetate/methanol 6/1 there was obtained 3-(3-benzylaminomethyl-1,2,4-oxadiazol-5-yl)-5-methyl-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepin-6-one, which was converted into the hydrochloride (0.25 g: 17%) of m.p. 195°-198°.
Reaction SMILES: [F:1][C:2]1[CH:17]=[CH:16][C:5]2[C:6](=O)[C:7]3[C:8]([CH2:13][CH2:14][C:4]=2[CH:3]=1)=[N:9][CH:10]=[CH:11][CH:12]=3.[CH3:18][Mg]Br.[Cl-].[NH4+]>O1CCCC1>[F:1][C:2]1[CH:17]=[CH:16][C:5]2[C:6](=[CH2:18])[C:7]3[C:8]([CH2:13][CH2:14][C:4]=2[CH:3]=1)=[N:9][CH:10]=[CH:11][CH:12]=3
Reactant: O=C1c2ccc(F)cc2CCc2ncccc21
Reactant: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: C=C1c2ccc(F)cc2CCc2ncccc21
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Chill a mixture of 8-fluoro-10,11-dihydro-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one (1.3 g, 5.7 mmol) and dry tetrahydrofuran (50 mL) to 0° C. Treat this mixture with methyl magnesium bromide(3.0M solution in diethyl ether, 5.7 mL, 17.2 mmol). Remove cooling and stir the admixture at room temperature for 15 min. Quench the reaction, while cooling with an ice-water bath, by adding saturated aqueous ammonium chloride solution (50 mL). Separate the layers and extract the aqueous layer with methylene chloride (2×50 mL). Dry the combined organic layers with magnesium sulfate, filter and concentrate to provide the intermediate product as a thick crude oil.