Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[C:2]1([N:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[NH2:9])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1Br.CC([O-])(C)C.[Na+].C(NC(C)C)(C)C>CC([O-])=O.CC([O-])=O.[Pd+2].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>[C:2]1([N:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[NH:9][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[Cl:16])[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Clc1ccccc1Br
Reactant: NN(c1ccccc1)c1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: CC(C)NC(C)C
Product: Clc1ccccc1NN(c1ccccc1)c1ccccc1
Temperature: 80 °C
Yield: 74 %

Procedure:
1,1-Diphenylhydrazine hydrochloride (1.2 equiv., 0.6 mmol, 135 mg), 2-chlorobromobenzene (1.0 equiv., 0.5 mmol, 0.06 mL), Pd(OAc)2 (0.05 equiv, 0.025 mmol, 6 mg), BINAP (0.05 equiv., 0.025 mmol, 16 mg), and NaOtBu (1.4 equiv., 0.7 mmol, 67 mg) and diisopropylamine (2 mL) were added to an oven dried test tube which was capped with a septum and purged briefly with argon (Q 1 min.) and then heated to 80° C. for 5 hours. The reaction was then cooled to room temperature, diluted with Et2O (2 mL), filtered through Celite and concentrated under vacuum. The crude mixture was purified by flash column chromatography (2% EtOAc/Hex) to give the title product as a white solid (109 mg, 0.37 mmol, 74% yield).
Reaction SMILES: F[C:2]1[C:7](F)=[CH:6][C:5]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][C:10]=2[N:15]([CH2:32][CH2:33][S:34]([CH3:37])(=[O:36])=[O:35])C(=O)C2C=C(C(F)(F)F)N=C(C(F)(F)F)C=2)=[C:4]([O:38][CH3:39])C=1.COC1C(B(O)O)=CC=C[N:43]=1>C(Cl)Cl.CO>[CH3:37][S:34]([CH2:33][CH2:32][NH:15][C:10]1[CH:11]=[N:12][CH:13]=[CH:14][C:9]=1[C:5]1[C:4]([O:38][CH3:39])=[N:43][CH:2]=[CH:7][CH:6]=1)(=[O:36])=[O:35]
Reactant: COc1ncccc1B(O)O
Reactant: COc1cc(F)c(F)cc1-c1ccncc1N(CCS(C)(=O)=O)C(=O)c1cc(C(F)(F)F)nc(C(F)(F)F)c1
Solvent: ClCCl
Solvent: CO
Product: COc1ncccc1-c1ccncc1NCCS(C)(=O)=O

Procedure:
The title compound was prepared in analogy to example 72, from (4-iodo-pyridin-3-yl)-(2-methanesulfonyl-ethyl)-amine (example 158, intermediate b) and 2-methoxypyridine-3-boronic acid (CAS RN 163105-90-6) and using a gradient of CH2Cl2:methanol (100:0 to 85:15) for the chromatographic purification. Brown solid (89%). MS (ESI): m/z=308.11 [M+H]+.
Reaction SMILES: [Na].[K].CN(CCN(C)C)C.[CH2:11]=[CH:12][CH:13]=[CH2:14].[C:15]1([CH3:22])[C:16]([CH3:21])=[CH:17][CH:18]=[CH:19][CH:20]=1>O>[CH3:11][C:12]1[C:20]([CH2:19][CH2:18][CH2:17][CH:16]=[CH2:21])=[CH:15][CH:22]=[CH:14][CH:13]=1
Reactant: C=CC=C
Reactant: Cc1ccccc1C
Agent: CN(C)CCN(C)C
Agent: [K]
Agent: [Na]
Solvent: O
Product: C=CCCCc1ccccc1C
Yield: 59.7 %

Procedure:
Using the equipment and procedure described in Example I a run was made using an alloy of 0.1% sodium and 0.1% potassium based on the weight of the xylene and another run with the same alloy was made adding 0.09% TMEDA. Both runs were made using butadiene having 155 ppm water which decreased activity but the effect of the amine cocatalyst is indicated by a trans:cis ratio 2.11 compared to 1.35 for the alloy alone, and by cumulative yield of 59.7% 5-OTP compared to 40% for the alloy alone. Other examples are listed in Table I.
Reaction SMILES: CS(Cl)(=O)=O.[CH3:6][O:7][C:8]1[CH:19]=[CH:18][CH2:17][C:16]2[C:9]=1[CH:10]=[C:11]1[C:15]=2[CH:14]=[N:13][N:12]1[CH2:20][CH:21](O)[CH3:22].C(N(CC)CC)C.[N-:31]=[N+:32]=[N-:33].[Na+].[Cl-].[Na+]>ClCCl.CN(C)C=O>[N:31]([CH:21]([CH3:22])[CH2:20][N:12]1[C:11]2=[CH:10][C:9]3[C:16]([CH2:17][CH:18]=[CH:19][C:8]=3[O:7][CH3:6])=[C:15]2[CH:14]=[N:13]1)=[N+:32]=[N-:33]
Reactant: COC1=C2C=c3c(cnn3CC(C)O)=C2CC=C1
Reactant: [N-]=[N+]=[N-]
Agent: CS(=O)(=O)Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COC1=C2C=c3c(cnn3CC(C)N=[N+]=[N-])=C2CC=C1
Yield: 87.3 %

Procedure:
0.6 ml (7.4 mmol) of methanesulfonyl chloride was added dropwise while stirring to a solution, cooled to 0° C., of 0.9 g (3.7 mmol) of (RS)-1-(7-methoxy-1,4-dihydro-indeno[2,1-c]pyrazol-1-yl)-propan-2-ol and 2 ml (14.8 mmol) of triethylamine in 40 ml of dichloromethane and the mixture was stirred at this temperature for a further 1.5 hours. The reaction mixture was subsequently diluted with 100 ml of dichloromethane, washed twice with 50 ml of saturated sodium hydrogen carbonate solution each time and the combined aqueous phases were extracted once with 50 ml of dichloromethane. The combined organic phases were washed with 50 ml of saturated sodium chloride solution, dried over magnesium sulfate and evaporated in a vacuum. The yellow oil obtained was dissolved in 40 ml of anhydrous dimethylformamide, treated with 0.48 g (7.4 mmol) of sodium azide and the reaction mixture was heated to 70° for 15 hours while stirring. After cooling, the solution was poured into 80 ml of semi-saturated sodium chloride solution and extracted twice with 80 ml of diethyl ether each time. The combined organic phases were washed once with 80 ml of water and once with 80 ml of saturated sodium chloride solution, dried over magnesium sulfate and the solution was concentrated in a vacuum. The brown oil obtained was purified by column chromatography on silica gel (ethyl acetate/toluene 1:1). 0.87 g (87%) of (RS)-1-(2-azido-propyl)-7-methoxy-1,4-dihydro-indeno[2,1-c]pyrazole was obtained as a light yellow oil.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1C(C1C=C(C)C=CC=1C1C=NN(C)C=1)=O.[CH3:25][C:26]1[N:31]=[C:30]([C:32]([OH:34])=O)[C:29]([N:35]2[CH:39]=[CH:38][CH:37]=[N:36]2)=[CH:28][CH:27]=1>>[NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:32]([C:30]1[C:29]([N:35]2[CH:39]=[CH:38][CH:37]=[N:36]2)=[CH:28][CH:27]=[C:26]([CH3:25])[N:31]=1)=[O:34]
Reactant: Cc1ccc(-n2cccn2)c(C(=O)O)n1
Reactant: Cc1ccc(-c2cnn(C)c2)c(C(=O)N2CCC[C@@H](C)[C@H]2CN)c1
Product: Cc1ccc(-n2cccn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CN)n1

Procedure:
The title compound was prepared following the same general protocol as described for ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(5-methyl-2-(1-methyl-1H-pyrazol-4-yl)phenyl)methanone in Example A1 using 6-methyl-3-(1H-pyrazol-1-yl)picolinic acid. MS (ESI) 314 (M+H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:29])[C:5]([CH2:7][C:8]1[CH:9]=[N:10][C:11]([N:14]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[N:12][CH:13]=1)=[CH2:6])[CH3:2].CCOC(C)=O.[C:36]([OH:39])(=[S:38])[CH3:37]>>[CH2:1]([O:3][C:4](=[O:29])[CH:5]([CH2:6][S:38][C:36](=[O:39])[CH3:37])[CH2:7][C:8]1[CH:9]=[N:10][C:11]([N:14]([C:15]([O:17][C:18]([CH3:19])([CH3:20])[CH3:21])=[O:16])[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])=[N:12][CH:13]=1)[CH3:2]
Reactant: C=C(Cc1cnc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nc1)C(=O)OCC
Reactant: CC(O)=S
Solvent: CCOC(C)=O
Product: CCOC(=O)C(CSC(C)=O)Cc1cnc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nc1
Temperature: 25 °C
Reaction time: 40 h
Yield: 89 %

Procedure:
TEA (0.189 mL, 1.35 mmol) was added to a solution of 2-(2-[N,N-bis(tert-butoxycarbonyl)amino]-pyrimidin-5-ylmethyl)-acrylic acid ethyl ester (0.53 g, 1.30 mmol) in thioacetic acid (13 mL) at 0° C. under argon. The mixture was stirred at room temperature for 40 h. EtOAc was added and the solution was washed with Na2CO3 and brine, dried and concentrated under reduced pressure. Flash chromatography (heptane/EtOAc, 5:1→1:1) gave 2-acetylsulfanylmethyl-3-(2-[N,N-bis(tert-butoxycarbonyl)amino]-pyrimidin-5-yl)-propionic acid ethyl ester(0.56 g, 89%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([NH:12][NH2:13])[CH2:9][N:8]=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[Cl:20])[C:6]=2[CH:21]=1.[C:22]([O:27][CH3:28])(=[O:26])[C:23]([CH3:25])=O>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([NH:12][N:13]=[C:23]([C:22]([O:27][CH3:28])=[O:26])[CH3:25])[CH2:9][N:8]=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[Cl:20])[C:6]=2[CH:21]=1
Reactant: NNC1=Nc2ccc(Br)cc2C(c2ccccc2Cl)=NC1
Reactant: COC(=O)C(C)=O
Product: COC(=O)C(C)=NNC1=Nc2ccc(Br)cc2C(c2ccccc2Cl)=NC1

Procedure:
In the manner given in Example 1, 7-bromo-2-hydrazino-5-(o-chlorophenyl)-3H-1,4-benzodiazepine can be stirred with methyl pyruvate at room temperature to give 7-bromo-2-[[1-(methoxycarbonyl)ethylidene]hydrazino]-5-(o-chlorophenyl)-3H-1,4-benzodiazepine.
Reaction SMILES: Br.[C:2]([C:5]1[C:15]2[CH2:14][CH2:13][NH:12][CH2:11][CH:10]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:9]=2[CH:8]=[C:7]([OH:22])[C:6]=1[OH:23])([OH:4])=[O:3].[ClH:24].[CH3:25]O>>[ClH:24].[C:2]([C:5]1[C:15]2[CH2:14][CH2:13][NH:12][CH2:11][CH:10]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:9]=2[CH:8]=[C:7]([OH:22])[C:6]=1[OH:23])([O:4][CH3:25])=[O:3]
Reactant: CO
Reactant: O=C(O)c1c(O)c(O)cc2c1CCNCC2c1ccccc1
Agent: Br
Agent: Cl
Product: COC(=O)c1c(O)c(O)cc2c1CCNCC2c1ccccc1

Procedure:
A mixture of 3.0 g (0.0079 mole) of 6-carboxy-7,8-dihydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrobromide in 200 ml of methanol saturated with hydrogen chloride gas was heated at reflux for 60 hours. The solvent was stripped off and the residue was triturated with ethyl acetate, then recrystallized from methanol-ethyl acetate to give 6-carbomethoxy-7,8-dihydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride, m.p. 216°-219° (dec.).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([S:19]([NH2:22])(=[O:21])=[O:20])=[CH:15][CH:14]=3)[N:11]=[C:10]([C:23]([F:26])([F:25])[F:24])[CH:9]=2)=[CH:4][CH:3]=1.C(O)(=O)C.[Cl:31]Cl>O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:14]=[CH:15][C:16]([S:19]([NH2:22])(=[O:21])=[O:20])=[CH:17][CH:18]=3)[N:11]=[C:10]([C:23]([F:24])([F:25])[F:26])[C:9]=2[Cl:31])=[CH:4][CH:3]=1
Reactant: ClCl
Reactant: NS(=O)(=O)c1ccc(-n2nc(C(F)(F)F)cc2-c2ccc(Cl)cc2)cc1
Solvent: O
Solvent: CC(=O)O
Product: NS(=O)(=O)c1ccc(-n2nc(C(F)(F)F)c(Cl)c2-c2ccc(Cl)cc2)cc1
Yield: 75 %

Procedure:
A 100 mL three-necked round-bottomed flask equipped with reflux condenser, gas dispersion tube and provisions for magnetic stirring was charged with 4-[5(4-chlorophenyl)-3-trifluoromethyl-1H-pyrazol-1yl]benzenesulfonamide (500 mg, 1.2 mmol) and 50 mL of glacial acetic acid. The solution was stirred at room temperature and treated with a stream of chlorine gas for a period of 15 minutes. The solution was then stirred at room temperature for 1.25 hours and then diluted with 100 mL of water. The solution was then extracted three times with ether and the combined ethereal phase washed with brine, dried over anhyd. MgSO4, filtered, and concentrated in vacuo to give a white solid that was recrystallized from ether/petroleum ether to provide 390 mg, 75% of 4-[5-(4-chlorophenyl)-4-chloro-3-trifluoromethyl-1H-pyrazol-1-yl]benzenesulfonamide, mp 180°-182 ° C. 1H nmr (CDCl3 /300 MHz) 7.97(d, J=6.6 Hz, 2H), 7.49 (d, J=6.3 Hz, 2H), 7.45 (d, J=6.3 Hz, 2H), 7.25 (d, J=6.6 Hz, 2H), 5.78(brs, 2H).
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:8]2[CH2:28][N:27]([C:29](=[O:31])[CH3:30])[CH2:26][CH2:25][C:9]=2[N:10]=[C:11]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[O:24][CH:23]=[N:22][CH:21]=3)=[CH:16][CH:15]=2)[N:12]=1)(=O)=O.[CH:34]1([NH:37][CH2:38][CH2:39][C:40]#[N:41])[CH2:36][CH2:35]1>CS(C)=O>[C:29]([N:27]1[CH2:26][CH2:25][C:9]2[N:10]=[C:11]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[O:24][CH:23]=[N:22][CH:21]=4)=[CH:16][CH:15]=3)[N:12]=[C:7]([N:37]([CH:34]3[CH2:36][CH2:35]3)[CH2:38][CH2:39][C:40]#[N:41])[C:8]=2[CH2:28]1)(=[O:31])[CH3:30]
Reactant: N#CCCNC1CC1
Reactant: CC(=O)N1CCc2nc(Nc3ccc(-c4cnco4)cc3)nc(OS(=O)(=O)C(F)(F)F)c2C1
Solvent: CS(C)=O
Product: CC(=O)N1CCc2nc(Nc3ccc(-c4cnco4)cc3)nc(N(CCC#N)C3CC3)c2C1
Reaction time: 8 h
Yield: 49.9 %

Procedure:
6-Acetyl-2-(4-(oxazol-5-yl)phenylamino)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl trifluoromethanesulfonate (35 mg, 0.07 mmol, Example 26a) in DMSO (1 mL) was dispensed in a library plate. 3-(cyclopropylamino)propanenitrile (7.71 mg, 0.07 mmol) was added and it was left to shake overnight at 80° C. before filtered and purified by preparative HPLC to yield 3-((6-Acetyl-2-(4-(oxazol-5-yl)phenylamino)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl)(cyclopropyl)amino)propanenitrile (15.5 mg, 48%).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][C:24](=[C:27]3[C:33]4[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=4[CH2:31][CH2:30][N:29]4[C:38]([C:41]([OH:43])=[O:42])=[CH:39][N:40]=[C:28]34)[CH2:23][CH2:22]2)=[CH:15][CH:14]=1.Cl.CN(C)CCCN=C=NCC.[C:56]1([CH2:62]O)[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][N:21]2[CH2:22][CH2:23][C:24](=[C:27]3[C:33]4[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=4[CH2:31][CH2:30][N:29]4[C:38]([C:41]([O:43][CH2:62][C:56]5[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=5)=[O:42])=[CH:39][N:40]=[C:28]34)[CH2:25][CH2:26]2)=[CH:15][CH:14]=1
Reactant: OCc1ccccc1
Reactant: O=C(O)c1cnc2n1CCc1ccccc1C2=C1CCN(CCc2ccc(OCc3ccc4ccccc4n3)cc2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: O=C(OCc1ccccc1)c1cnc2n1CCc1ccccc1C2=C1CCN(CCc2ccc(OCc3ccc4ccccc4n3)cc2)CC1
Yield: 62.4 %

Procedure:
A mixture of compound 7 (3 g) and N,N-dimethyl-4-pyridinamine (1.22 g) in DCM (100 ml) was stirred till complete dissolution. 1-(3-Dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (1.8 g) was added portionwise and the mixture was stirred at room temperature for 15 minutes. A solution of benzenemethanol (0.54 g) in DCM was added. The mixture was stirred at room temperature overnight. The solvent was evaporated. The residue was purified over silica gel on a glass filter (eluent: CH2Cl2/CH3OH 97/3 to 95/5). The pure fractions were collected and the solvent was evaporated. The residue was crystallized from ACN. The precipitate was filtered off and dried, yielding 2.06 g (62%) of phenylmethyl 6,11-dihydro-11-[1-[2-[4-(2-quinolinylmethoxy)phenyl]ethyl]-4-piperidinylidene]-5H-imidazo[2,1-b][3]benzazepine-3-carboxylate (compound 9). In a similar way, but replacing the alcohol by ammonia or dimethylamine, compound 55 (compound ) and compound 56 (compound) respectively were synthesized.
Reaction SMILES: CO[C:3]1[C:8]([O:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[Cl:16])=[CH:7][CH:6]=[CH:5][C:4]=1[CH:17]([CH2:21][CH2:22][CH3:23])[C:18]([OH:20])=[O:19]>C(OC(=O)C)(=O)C.I>[CH2:21]([CH:17]1[C:4]2[CH:5]=[CH:6][CH:7]=[C:8]([O:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[Cl:16])[C:3]=2[O:19][C:18]1=[O:20])[CH2:22][CH3:23]
Reactant: CCCC(C(=O)O)c1cccc(Oc2ccccc2Cl)c1OC
Agent: I
Solvent: CC(=O)OC(C)=O
Product: CCCC1C(=O)Oc2c(Oc3ccccc3Cl)cccc21
Yield: 43.7 %

Procedure:
A solution of 2-[2-methoxy-3-(2-chlorophenoxy)phenyl]valeric acid (3.8 g) in acetic anhydride (10 ml) and hydriodic acid (55-58%, 20 ml) were treated in a similar manner to that of Example 14-(8) to give 3-n-propyl-7-(2-chlorophenoxy)-2,3-dihydrobenzofuran-2-one (1.5 g). mp 51°-53° C.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.Cl[CH2:11][CH2:12][C:13]([CH3:16])([CH3:15])[CH3:14].[I-].[Na+].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[CH3:14][C:13]([CH3:16])([CH3:15])[CH2:12][CH2:11][O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: CC(C)(C)CCCl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Solvent: CN(C)C=O
Product: CC(C)(C)CCOc1ccc(C=O)cc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 77.4 %

Procedure:
A suspension of 4-hydroxybenzaldehyde (200 mg, 1.64 mmol), 1-chloro-3,3-dimethylbutane (395 mg, 1.97 mmol), sodium iodide (24 mg, 0.16 mmol), and cesium carbonate (800 mg, 2.46 mmol) in anhydrous dimethylformamide (5 mL) was stirred at 80° C. overnight. After cooling to room temperature, solids were filtered and washed with ether. The filtrate was washed with 2 N sodium hydroxide (2×20 mL), water (20 mL), and brine (20 mL), dried over magnesium sulfate, filtered, and concentrated to give 4-(3,3-dimethylbutoxyl)benzaldehyde (262 mg, 78% crude) as a pale yellow oil that was used without further purification or characterization.
Reaction SMILES: [CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([C:21]3[NH:25][C:24]([C:26]4[N:31]=[CH:30][C:29]([CH:32]=[O:33])=[CH:28][CH:27]=4)=[CH:23][CH:22]=3)[CH2:14][CH:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.[Mn]([O-])(=O)(=O)=[O:35].[K+].S([O-])([O-])=O.[Na+].[Na+]>CC(C)=O>[CH:1]1([S:4]([C:7]2[CH:8]=[CH:9][C:10]([CH:13]([C:21]3[NH:25][C:24]([C:26]4[N:31]=[CH:30][C:29]([C:32]([OH:35])=[O:33])=[CH:28][CH:27]=4)=[CH:23][CH:22]=3)[CH2:14][CH:15]3[CH2:16][CH2:17][O:18][CH2:19][CH2:20]3)=[CH:11][CH:12]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1
Reactant: O=Cc1ccc(-c2ccc(C(CC3CCOCC3)c3ccc(S(=O)(=O)C4CC4)cc3)[nH]2)nc1
Reactant: O=[Mn](=O)(=O)[O-]
Agent: O=S([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CC(C)=O
Product: O=C(O)c1ccc(-c2ccc(C(CC3CCOCC3)c3ccc(S(=O)(=O)C4CC4)cc3)[nH]2)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 48.3 %

Procedure:
To a solution of 6-(5-{1-[4-(cyclopropylsulfonyl)phenyl]-2-(tetrahydro-2H-pyran-4-yl)ethyl}-1H-pyrrol-2-yl)pyridine-3-carbaldehyde (100 mg) in acetone (5 mL) was added an aqueous solution (1 mL) of potassium permanganate (45.0 mg), and the mixture was stirred overnight at room temperature. To the reaction mixture was added sodium sulfite, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated to give the title compound (50.0 mg, yield 49%) as a pale-yellow amorphous solid. MS: 481 (MH+).
Reaction SMILES: [CH2:1]([S:15][CH2:16][CH2:17][C:18]([OH:20])=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].S(Cl)([Cl:23])=O>>[CH2:1]([S:15][CH2:16][CH2:17][C:18]([Cl:23])=[O:20])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCCCCCCCCCCCSCCC(=O)O
Reactant: O=S(Cl)Cl
Product: CCCCCCCCCCCCCCSCCC(=O)Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture consisting of 3-(tetradecylthio)propionic acid (3.02 g) and thionyl chloride (20 ml) was stirred for 30 minutes at room temperature and then evaporated under a reduced pressure to obtain 3-(tetradecylthio)propionyl chloride. The thus obtained 3-(tetradecylthio)propionyl chloride was dissolved in toluene (5 ml) and added dropwise to a mixture consisting of 2,6-diisopropylaniline (1.77 g), triethylamine (2.1 ml) and toluene (20 ml), followed by 1 hour of stirring at room temperature. The reaction mixture was washed with 3% hydrochloric acid, 10% sodium hydroxide solution and saturated brine successively and then dried on anhydrous magnesium sulfate. After removing the solvent by distillation under a reduced pressure, the resulting residue was subjected to a silica gel column chromatography (developing solvent; ethyl acetate:hexane=1:5) and then to crystallization using isopropyl ether, thereby obtaining the title compound (2.55 g) in the form of colorless needle crystals.
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][CH:5]1[O:9][N:8]=[C:7]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:6]1.I[CH2:16][CH3:17]>CN(C=O)C>[CH2:16]([O:3][CH2:4][CH:5]1[O:9][N:8]=[C:7]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:6]1)[CH3:17]
Reactant: CCOC(=O)C1=NOC(CO)C1
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOCC1CC(C(=O)OCC)=NO1
Temperature: 25 °C
Reaction time: 2 h
Yield: 40.1 %

Procedure:
Sodium hydride (0.141 g; 3.51 mmol) was added to a solution of ethyl 5-(hydroxymethyl)-4,5-dihydroisoxazole-3-carboxylate (0.338 g; 1.76 mmol) in DMF (3 mL) in an ice bath. The mixture was stirred for 10 min before addition of iodoethane (0.430 mL; 5.27 mmol). The ice bath was removed and the mixture was stirred at room temperature for 2 h. After evaporation, the residue was partitioned between brine and dichloromethane and the solution extracted with dichloromethane. Organic extracts were evaporated and the residue was purified by flash chromatography on silica gel (eluent: 1-6% ethyl acetate in dichloromethane) to afford 0.142 g (40%) of ethyl 5-(ethoxymethyl)-4,5-dihydroisoxazole-3-carboxylate.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.[Br:12]Br>C(Cl)(Cl)Cl.CO>[Br:12][C:11]1[CH:10]=[C:5]([CH:4]=[CH:3][C:2]=1[OH:1])[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)c1ccc(O)cc1
Reactant: BrBr
Solvent: ClC(Cl)Cl
Solvent: CO
Product: COC(=O)c1ccc(O)c(Br)c1
Reaction time: 2 h

Procedure:
Methyl 4-hydroxybenzoate (25.00 g) was dissolved in chloroform (225 mL) and methanol (25 mL), and a chloroform (30 mL) solution of bromine (8.5 mL) was added dropwise to the solution, and then the mixture was stirred for 2 hours. The reaction solution was diluted with chloroform, washed with water, an aqueous 10% sodium thiosulfate solution and saturated brine and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound (37.81 g) as a colorless crystal.
Reaction SMILES: [NH:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4](=[O:5])[C:2]1=[O:3].[H-].[Na+].Br[CH2:15][C:16]1[C:17]2[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:18]=2[S:19][CH:20]=1>O1CCOCC1>[Cl:25][C:23]1[CH:22]=[CH:21][C:18]2[S:19][CH:20]=[C:16]([CH2:15][N:1]3[C:11]4[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=4)[C:4](=[O:5])[C:2]3=[O:3])[C:17]=2[CH:24]=1
Reactant: Clc1ccc2scc(CBr)c2c1
Reactant: O=C1Nc2ccccc2C1=O
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: O=C1C(=O)N(Cc2csc3ccc(Cl)cc23)c2ccccc21
Reaction time: 0.08 h
Yield: 44.7 %

Procedure:
A solution of isatin (125 mg, 0.85 mmol) in anhydrous dioxane (10 mL) was added dropwise to a solution of sodium hydride (60% dispersion in mineral oil, 25 mg, 0.62 mmol) in anhydrous dioxane (10 mL) at 0° C. under argon. The mixture was allowed to stir for 5 minutes and then a solution of 3-(bromomethyl)-5-chlorobenzo[b]thiophene (267 mg, 1.02 mmol) in dioxane (10 mL) was added dropwise to the reaction mixture. The reaction mixture was heated at reflux under argon for 16 h and concentrated in vacuo. The crude material was purified by preparative TLC using 1:24 methanol in chloroform as the eluent, giving the desired product as a yellow solid (125 mg, 0.38 mmol, 45%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=O)[C:5]([OH:11])=[CH:4][CH:3]=1.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([NH2:20])[CH:15]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([CH:10]=1)[C:7]([NH:20][C:16]1[CH:17]=[CH:18][CH:19]=[C:14]([O:13][CH3:12])[CH:15]=1)=[O:9]
Reactant: COc1cccc(N)c1
Reactant: O=C(O)c1cc(Cl)ccc1O
Product: COc1cccc(NC(=O)c2cc(Cl)ccc2O)c1

Procedure:
This material was prepared according to the method of Example 1 using 5-chlorosalicylic acid and m-anisidine, with reagents and solvents employed in similar molar ratios. 1HNMR (500 MHz, DMSO-d6): δ 3.72 (s, 3H), 6.74 (m, 1H), 7.09 (m, 1H), 7.26 (br m, 2H), 7.40 (br s, 1H), 7.47 (m, 1H), 7.88 (m, 1H), 10.34 (s, 1H).
Reaction SMILES: [CH2:1]([N:4]([CH2:8][C:9]([N:11]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[NH:15][C:14](=S)[C:13]2[CH:23]=[CH:24][CH:25]=[N:26][C:12]1=2)=[O:10])[CH2:5][CH2:6][CH3:7])[CH2:2][CH3:3].[C:27](OCC)(=[O:30])[NH:28][NH2:29]>>[CH2:1]([N:4]([CH2:8][C:9]([N:11]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[N:15]2[C:27](=[O:30])[NH:28][N:29]=[C:14]2[C:13]2[CH:23]=[CH:24][CH:25]=[N:26][C:12]1=2)=[O:10])[CH2:5][CH2:6][CH3:7])[CH2:2][CH3:3]
Reactant: CCCN(CCC)CC(=O)N1c2ccccc2NC(=S)c2cccnc21
Reactant: CCOC(=O)NN
Product: CCCN(CCC)CC(=O)N1c2ccccc2-n2c(n[nH]c2=O)-c2cccnc21

Procedure:
In the manner given in Example 13, 6,11-dihydro-11-[(dipropylamino)acetyl]5H-pyrido[2,3-b][1,5]benzodiazepin-5-thione is heated to about 200° C. with ethyl carbazate to give 2,9-dihydro-9-[(dipropylamino)acetyl]-3H-pyrido-[3,2-c]-s-triazolo[4,3-a][1,5]benzodiazepin-3-one.