Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[S:3][C:4](Br)=[N:5][N:6]=1.[CH2:8]1[C:11]2([CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]2)[CH2:10][NH:9]1.CCN(C(C)C)C(C)C>O1CCOCC1.O>[Br:1][C:2]1[S:3][C:4]([N:9]2[CH2:8][C:11]3([CH2:12][CH2:13][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:15][CH2:16]3)[CH2:10]2)=[N:5][N:6]=1
Reactant: Brc1nnc(Br)s1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CNC2
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CN(c1nnc(Br)s1)C2
Temperature: 120 °C
Yield: 87.8 %

Procedure:
A stirred suspension of 2,5-dibromo-1,3,4-thiadiazole (245 mg, 1.004 mmol), tert-butyl 2,7-diazaspiro[3.5]nonane-7-carboxylate (290 mg, 1.105 mmol) and DIPEA (702 μL, 1.02 mmol) in dioxane (2.5 mL) was heated at 120° C. for 1 hour. The reaction mixture was diluted with water (10 mL), extracted with DCM (20 mL), and the organic phase was concentrated onto silica gel. The crude material was purified by flash chromatography using a 24 g silica cartridge running an EtOAc/heptane gradient to afford the title compound as a yellow oil (343 mg, 88% yield). LC-MS: Rt 1.25 min; MS m/z 391.2 [M+2]+ [Method A]. 1H NMR (400 MHz, Chloroform-d) δ 3.87 (s, 4H), 3.34-3.43 (m, 4H), 1.73-1.85 (m, 4H), 1.46 (s, 9H).
Reaction SMILES: [CH2:1]1[C:11]2[N:10]3[C:12]4[CH:21]=[CH:20][N:19]=[CH:18][C:13]=4[C:14]4[CH2:15][CH2:16][CH:17]=[C:8]([C:9]=43)[CH:7]=[CH:6][C:5]=2[CH2:4][CH2:3][CH2:2]1.ClCCl.[CH:25]1([C:28](Cl)=[O:29])[CH2:27][CH2:26]1>C(N(CC)CC)C>[CH:25]1([C:28]([CH:3]2[CH2:4][C:5]3[CH:6]=[CH:7][C:8]4[C:9]5[N:10]([C:12]6[CH:21]=[CH:20][N:19]=[CH:18][C:13]=6[C:14]=5[CH2:15][CH2:16][CH:17]=4)[C:11]=3[CH2:1][CH2:2]2)=[O:29])[CH2:27][CH2:26]1
Reactant: O=C(Cl)C1CC1
Reactant: C1=CC2=C(CCCC2)n2c3c(c4cnccc42)CCC=C13
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(C1CC1)C1CCC2=C(C=CC3=CCCc4c3n2c2ccncc42)C1
Reaction time: 8 h

Procedure:
To a solution of 16.4 g of 1,2,3,4,8,9-hexahydropyrido[4',3':2,3]indolo[1,7-ab][1]benzazepine in 500 ml. of dichloromethane, 7.3 g. of cyclopropanecarbonyl chloride was added, followed by dropwise addition of 10 ml. of triethylamine. A mildly exothermic reaction took place, after which stirring of the mixture was continued at room temperature overnight. The mixture was then washed with 1N hydrochloric acid and water and dried over anhydrous sodium carbonate. On evaporation to dryness, crude 3-(cyclopropylcarbonyl)-1,2,3,4,8,9-hexahydropyrido[4',3':2,3]indolo[1,7-ab][1]benzazepine was obtained as a glassy product. Recrystallization from ethanol yielded the pure material, m.p. 154°-156° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH3:8])[CH:5]=[CH:4][CH:3]=1.[O-:9][Mn](=O)(=O)=O.[K+].[OH2:15]>>[Cl:1][C:2]1[N:7]=[C:6]([C:8]([OH:9])=[O:15])[CH:5]=[CH:4][CH:3]=1
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: O
Reactant: Cc1cccc(Cl)n1
Agent: [K+]
Product: O=C(O)c1cccc(Cl)n1
Temperature: 90 °C

Procedure:
A mixture of 3.8 g (0.03 mol) of 6-chloro-2-methylpyridine and 10.45 g of KMnO4 in 380 ml of water is heated to 90° C. for 6 hours. The product is cooled, the pH is adjusted to approximately 4, water is evaporated off and the residue is taken up with ethanol. It is filtered and the ethanol is evaporated to produce 1.1 g of the compound referred to above.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[C:9]([CH3:15])([CH3:14])[CH2:8][N:7]([CH:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)[C:6]=2[N:21]=1.[NH2:22][C:23]1[CH:47]=[CH:46][C:26]([C:27]([NH:29][C@H:30]2[CH2:35][CH2:34][C@H:33]([N:36]3[CH2:41][CH2:40][N:39]([CH2:42][CH:43]4[CH2:45][CH2:44]4)[CH2:38][CH2:37]3)[CH2:32][CH2:31]2)=[O:28])=[CH:25][C:24]=1[O:48][CH3:49].C(O)(C(F)(F)F)=O.C1(N2CC(C)(C)C(=O)N(C)C3C=NC(NC4C=CC(C(O)=O)=CC=4OC)=NC2=3)CCCC1>>[CH:16]1([N:7]2[CH2:8][C:9]([CH3:15])([CH3:14])[C:10](=[O:13])[N:11]([CH3:12])[C:5]3[CH:4]=[N:3][C:2]([NH:22][C:23]4[CH:47]=[CH:46][C:26]([C:27]([NH:29][C@H:30]5[CH2:31][CH2:32][C@H:33]([N:36]6[CH2:41][CH2:40][N:39]([CH2:42][CH:43]7[CH2:45][CH2:44]7)[CH2:38][CH2:37]6)[CH2:34][CH2:35]5)=[O:28])=[CH:25][C:24]=4[O:48][CH3:49])=[N:21][C:6]2=3)[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: COc1cc(C(=O)N[C@H]2CC[C@H](N3CCN(CC4CC4)CC3)CC2)ccc1N
Reactant: CN1C(=O)C(C)(C)CN(C2CCCC2)c2nc(Cl)ncc21
Agent: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(C)(C)C(=O)N2C
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(C(=O)N[C@H]2CC[C@H](N3CCN(CC4CC4)CC3)CC2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(C)(C)C(=O)N2C

Procedure:
2-Chloro-9-cyclopentyl-5,7,7-trimethyl-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one (Intermediate 3) (0.13 g, 0.43 mmol, 1 eq), 4-amino-N-(trans-4-(4-(cyclopropylmethyl)piperazin-1-yl)cyclohexyl)-3-methoxybenzamide (Intermediate 11) (0.26 g, 0.67 mmol, 1.5 eq) and TFA (0.17 mL, 2.2 mmol, 5 eq) in TFE (3 mL) were heated together at 80° C. for 18 hours. Further quantity of Intermediate 6 (0.13 g) was added and the reaction further heated for 48 hours. RM was concentrated in vacuo and the residue was purified by flash column chromatography on silica eluting with 0→20% ammonia/MeOH in DCM gradient followed by preparative HPLC (Preparative—4) then finally preparative RP-HPLC-MS (Preparative—1) to give 4-(9-cyclopentyl-5,7,7-trimethyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-N-((trans)-4-(4-(cyclopropylmethyl)piperazin-1-yl)cyclohexyl)-3-methoxybenzamide (0.03 g, 7%).
Reaction SMILES: [OH:1][C:2]1[C:11]2[N:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]([C:12]([O:14][CH3:15])=[O:13])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH:23]([F:25])[F:24]>CN(C)C=O>[F:24][CH:23]([F:25])[O:1][C:2]1[C:11]2[N:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]([C:12]([O:14][CH3:15])=[O:13])=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc(O)c2ncccc12
Reactant: FC(F)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OC(F)F)c2ncccc12

Procedure:
1.0 g (5.0 mmol) of methyl 8-hydroxy-5-quinolinecarboxylate was dissolved in 20 ml of dimethylformamide, 0.76 g (5.5 mmol) of potassium carbonate was added and 14 g of chlorodifluoromethane were introduced at 40° C. over a period of 2 hours. Solid components were then filtered off, the solvent was removed and the residue was washed with water and dried. This gave 0.75 g of a brown powder;
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9](=[N:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[NH:10][C:11]1[CH:31]=[CH:30][C:14]([C:15]([O:17][C:18]2[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][CH2:26][C:27](O)=[O:28])=[CH:20][CH:19]=2)=[O:16])=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[C:41]([O:45][C:46]1[CH:61]=[CH:60][C:49]([CH2:50][C@@H:51]([C:53]([O:55][C:56]([CH3:59])([CH3:58])[CH3:57])=[O:54])[NH2:52])=[CH:48][CH:47]=1)([CH3:44])([CH3:43])[CH3:42].Cl.CN(C)CCCN=C=NCC.N1(O)C2C=CC=CC=2N=N1>CN(C)C=O.O.C(N(CC)CC)C>[C:36]([O:35][C:33]([NH:32][C:9](=[N:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[NH:10][C:11]1[CH:12]=[CH:13][C:14]([C:15]([O:17][C:18]2[CH:19]=[CH:20][C:21]([CH2:24][CH2:25][CH2:26][C:27]([NH:52][C@H:51]([C:53]([O:55][C:56]([CH3:59])([CH3:58])[CH3:57])=[O:54])[CH2:50][C:49]3[CH:60]=[CH:61][C:46]([O:45][C:41]([CH3:43])([CH3:42])[CH3:44])=[CH:47][CH:48]=3)=[O:28])=[CH:22][CH:23]=2)=[O:16])=[CH:30][CH:31]=1)=[O:34])([CH3:38])([CH3:39])[CH3:37]
Reactant: CC(C)(C)OC(=O)N=C(NC(=O)OC(C)(C)C)Nc1ccc(C(=O)Oc2ccc(CCCC(=O)O)cc2)cc1
Reactant: CC(C)(C)OC(=O)[C@@H](N)Cc1ccc(OC(C)(C)C)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N=C(NC(=O)OC(C)(C)C)Nc1ccc(C(=O)Oc2ccc(CCCC(=O)N[C@@H](Cc3ccc(OC(C)(C)C)cc3)C(=O)OC(C)(C)C)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.9 %

Procedure:
To a solution of 4-[4-({4-[N′,N″-bis(tert-butoxycarbonyl)carbamimidamido]benzoyl}oxy)phenyl]butanoic acid (250 mg) in N,N-dimethylformamide (5.00 mL) were added tert-butyl O-tert-butyl-L-tyrosinate hydrochloride (152 mg), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (88.5 mg), 1H-benzotriazol-1-ol (62.4 mg), and triethylamine (0.0643 mL), followed by stirring at room temperature overnight. To a reaction solution was added water, followed by extraction with ethyl acetate. The organic layer was washed with water and a saturated aqueous sodium chloride solution in this order, then dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain tert-butyl N-{4-[4-({4-[N′,N″-bis(tert-butoxycarbonyl)carbamimidamido]benzoyl}oxy)phenyl]butanoyl}-O-tert-butyl-L-tyrosinate (327 mg).
Reaction SMILES: [CH3:1][CH:2]([CH3:18])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[CH:7]=1)=[O:4].[CH2:19]=O.[F:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[C:28]1[CH:29]=[CH:30][CH:31]=[C:32]2[C:36]=1[NH:35][CH:34]=[CH:33]2>CC(O)=O.O1CCOCC1.O>[F:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[C:28]1[CH:29]=[CH:30][CH:31]=[C:32]2[C:36]=1[NH:35][CH:34]=[C:33]2[CH2:19][N:15]1[CH2:16][CH2:17][CH:12]([C:8]2[CH:7]=[C:6]([NH:5][C:3](=[O:4])[CH:2]([CH3:18])[CH3:1])[CH:11]=[CH:10][CH:9]=2)[CH2:13][CH2:14]1
Reactant: Fc1ccccc1-c1cccc2cc[nH]c12
Reactant: C=O
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Solvent: C1COCCO1
Solvent: CC(=O)O
Solvent: O
Product: CC(C)C(=O)Nc1cccc(C2CCN(Cc3c[nH]c4c(-c5ccccc5F)cccc34)CC2)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 126 %

Procedure:
Prepared by Procedure D and Scheme N. A solution of 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide (23.3 mg, 0.0948 mmol) and 37 wt % aqueous formaldehyde (11.4 mg, 0.142 mmol) in 1.00 mL of HOAc:dioxane (1:4) was added to 7-(2-fluorophenyl)-1H-indole (20.0 mg, 0.0948 mmol) and the reaction mixture was stirred for 12 h at room temperature. The resulting mixture was diluted with H2O (10 mL). The aqueous layer was extracted with CH2Cl2 (3×10 mL). The combined organic extracts were washed with brine (10 mL), dried over MgSO4, and concentrated in vacuo. The residue was purified by preparative TLC on silica using 4% of NH3 (2.0 M in methanol) in CH2Cl2 to give the desired product (56.1 mg, 100%): 1H NMR (400 MHz, CDCl3) δ 8.58 (s, 1H), 7.73 (dd, 1H, J=2.8, 6.3 Hz), 7.69 (s, 1H), 7.53 (dt, 1H, J=1.8, 7.6 Hz), 7.44 (d, 1H, J=8.1 Hz), 7.38 (m, 2H), 7.32 (s, 1H), 7.27–7.21 (m, 4H), 7.17 (t, 1H, J=7.6 Hz), 6.88 (d, 1H, J=7.6 Hz), 3.92 (s, 2H); 3.20 (d, 1H, J=11.6 Hz), 2.51 (qt, 1H, J=6.7 Hz), 2.42 (m, 1H), 2.25 (dt, 2H, J=2.2, 11.6 Hz), 1.89–1.72 (m, 5H), 1.22 (d, 6H, J=7.3 Hz); ESMS m/e: 470.1 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[SH:8].[C:9]([C:12]1[CH:19]=[CH:18][C:15]([CH:16]=O)=[CH:14][CH:13]=1)([OH:11])=[O:10].CS(C)=O>O>[C:9]([C:12]1[CH:19]=[CH:18][C:15]([C:16]2[S:8][C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[N:1]=2)=[CH:14][CH:13]=1)([OH:11])=[O:10]
Reactant: O=Cc1ccc(C(=O)O)cc1
Reactant: Nc1ccccc1S
Solvent: O
Solvent: CS(C)=O
Product: O=C(O)c1ccc(-c2nc3ccccc3s2)cc1
Temperature: 145 °C
Reaction time: 3.5 h
Yield: 82 %

Procedure:
A mixture of 2-aminothiophenol (9.00 ml, 0.08 mol), 4-carboxybenzaldehyde (10.1 g, 0.07 mol) and DMSO (40 mL) was heated to 145° C., and held at this temperature for 3.5 hours. The reaction mixture was diluted with water, and separated solids were collected, dried and recrystallized from acetic acid; 14.15 g, (82% yield), white solid, m.p. 294.1-295.5° C. Mass Spectrum: m/z, 255 (M+), 238 (M—OH), 210 (M—COOH), 108. FT-IR (KBr; cm−1): 3051 (br; OH), 1684 (CO), 1609, 1424, 1407, 1291, 970, 756. Anal. Calcd for C14H9NO2S: C, 65.87; H, 3.55; N, 5.49; S, 12.56%. Found: C, 65.71; H, 3.96; N, 5.30; S, 12.66%. NMR: not available due to poor solubility.
Reaction SMILES: [CH3:1][N:2]1[C:6](=[O:7])[N:5]([CH3:8])[CH:4]([C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[C:11]([O:16][CH3:17])[CH:10]=2)[P:3]1(=[O:25])[O:18]C1C=CC=CC=1.C(#N)C.[OH2:29]>>[CH3:8][N:5]([CH:4]([P:3](=[O:25])([OH:18])[OH:29])[C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[C:11]([O:16][CH3:17])[CH:10]=1)[C:6]([NH:2][CH3:1])=[O:7]
Reactant: COc1cc(C2N(C)C(=O)N(C)P2(=O)Oc2ccccc2)ccc1O
Reactant: O
Solvent: CC#N
Product: CNC(=O)N(C)C(c1ccc(O)c(OC)c1)P(=O)(O)O

Procedure:
A solution of 10.0g of 1,4-dimethyl-3-(4-hydroxy-3-methoxyphenyl)-2-phenoxy-1,4,2-diazaphospholidin-5-one-2-oxide in 90g of acetonitrile and 10g of water was warmed at reflux for 0.5 hr, and then most of the solvent was allowed to evaporate. The residue was recrystallized twice from ethanol to give 4.6g of white solid: mp 183°-184° (dec); 31P nmr (CD3SOCD3) -18.6 ppm (d, J = 24Hz); 1H nmr δ 10.0 (broad, 3, Oh), 5.7 (d, 1, J = 24Hz, CH), 3.8 (s, 3, OCH3), 2.9 (s, 3, NCH3), 2.7 (s, 3, NCH3); 6.7-7.3 (m, 4, aryl and HN).
Reaction SMILES: [N:1]1([C:7]2[N:12]=[C:11]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[N:10]=[C:9]([C:19]3[CH:25]=[CH:24][C:22]([NH2:23])=[CH:21][CH:20]=3)[N:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.ClC(Cl)(O[C:30](=[O:36])OC(Cl)(Cl)Cl)Cl.C(N(CC)CC)C.[NH2:45][C:46]1[CH:51]=[CH:50][N:49]=[CH:48][CH:47]=1>C(Cl)Cl>[N:1]1([C:7]2[N:12]=[C:11]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[N:10]=[C:9]([C:19]3[CH:25]=[CH:24][C:22]([NH:23][C:30]([NH:45][C:46]4[CH:51]=[CH:50][N:49]=[CH:48][CH:47]=4)=[O:36])=[CH:21][CH:20]=3)[N:8]=2)[CH2:2][CH2:3][O:4][CH2:5][CH2:6]1
Reactant: Nc1ccc(-c2nc(N3CCOCC3)nc(N3CCOCC3)n2)cc1
Reactant: Nc1ccncc1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Nc1ccncc1)Nc1ccc(-c2nc(N3CCOCC3)nc(N3CCOCC3)n2)cc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 53.1 %

Procedure:
To a mixture of 4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)aniline (0.20 g 0.40 mmoles) in methylene chloride (80 mL) at 0° C. was added triphosgene (0.25 mg, 0.84 mmoles) and triethylamine (3 mL). The mixture was stirred for 20 minutes at 0° C. and 4-amino pyridine (0.10 g 0.83 mmoles) was added to the reaction mixture and stirred for another 2 hours at room temperature. The solvent was evaporated and the residue was submitted to the HPLC using acetonitrile/TFA as mobile phase to give 98.2 mg (36% yield) of 1-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-pyridin-4-ylurea. (M+H)=463.3.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:8][C:9](=[CH2:17])[CH2:10][CH2:11][CH2:12][C:13]([O:15][CH3:16])=[O:14]>>[OH:7][C:1]1[CH:6]=[CH:5][C:4]([C:9]([CH3:17])([CH3:8])[CH2:10][CH2:11][CH2:12][C:13]([O:15][CH3:16])=[O:14])=[CH:3][CH:2]=1
Reactant: Oc1ccccc1
Reactant: C=C(C)CCCC(=O)OC
Product: COC(=O)CCCC(C)(C)c1ccc(O)cc1

Procedure:
94 Parts of phenol, 14.2 parts of methyl 5-methyl-hex-5-enoate, and 5.0 parts of Fulmont 237® were stirred at 110° C. for 20 hours. The partly cooled reaction mixture was then filtered free of catalyst and distilled. After recovering 82 parts of phenol there was obtained methyl 5-(4-hydroxyphenyl)-5-methyl-hexanoate b0.85 167°-72° C. with the following percentage composition by weight.
Reaction SMILES: [CH:1]([C@H:14]1[CH2:20][C@H:19]2[C@H:17]([O:18]2)[CH2:16][O:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:21][O:22][C:23]1[CH:30]=[CH:29][C:26]([CH2:27][NH2:28])=[CH:25][CH:24]=1>C(O)C>[CH:1]([C@H:14]1[CH2:20][C@H:19]([OH:18])[C@@H:17]([NH:28][CH2:27][C:26]2[CH:29]=[CH:30][C:23]([O:22][CH3:21])=[CH:24][CH:25]=2)[CH2:16][O:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(C(c2ccccc2)[C@H]2C[C@@H]3O[C@@H]3CO2)cc1
Reactant: COc1ccc(CN)cc1
Solvent: CCO
Product: COc1ccc(CN[C@H]2CO[C@@H](C(c3ccccc3)c3ccccc3)C[C@@H]2O)cc1
Yield: 79.3 %

Procedure:
(1R,4R,6S)-4-benzhydryl-3,7-dioxa-bicyclo[4.1.0]-heptane 28c (0.02 g, 0.075 mmol) was reacted with p-methoxybenzylamine (0.21 g, 1.50 mmol) in ethanol (Procedure E) to yield (2R,4S,5S)-2-benzhydryl-5-(4-methoxy-benzylamino)-tetrahydropyran-4-ol (+)-29a 0.024 g (80%, [α]D=(+)72.8, c=1, MeOH). The 1HNMR and 13CNMR were identical with (2S,4R,5R)-2-benzhydryl-5-(4-methoxy-benzylamino)-tetrahydropyran-4-ol.
Reaction SMILES: [CH3:1][N:2]([CH3:11])[C:3]1[CH:4]=[C:5]([O:9][CH3:10])[CH:6]=[CH:7][CH:8]=1.C([Li])CCC.[B:17](OC)([O:20]C)[O:18]C>C1COCC1>[CH3:10][O:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([N:2]([CH3:11])[CH3:1])[C:4]=1[B:17]([OH:20])[OH:18]
Reactant: COc1cccc(N(C)C)c1
Reactant: COB(OC)OC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1cccc(N(C)C)c1B(O)O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 5.3 g (35 mmol) of 3-dimethylamino-anisole in 25 mL of dry THF at −78° C. was added 19 mL (47 mmol) of a 2.5M solution of n-butyl lithium in hexanes. The reaction mixture was stirred for 1 hour before removing the ice bath and warming to room temperature for 90 minutes. The solution was cooled to −78° C., treated with 8.75 g (84 mmol) of trimethyl orthoborate, and then stirred for one hour before warming to room temperature for one hour. The reaction was quenched by the addition of 20 mL of water and sufficient acetic acid to neutralize the mixture. The reaction mixture was extracted with ethyl acetate (3×30 mL), and the combined organic extracts were extracted with 1N NaOH solution (4×15 mL). The combined aqueous extracts were acidified with acetic acid and extracted with EtOAc (3×20 mL). The organic phase was washed with brine, dried over anhydrous MgSO4, filtered and concentrated in vacuo to give 2-methoxy-6-dimethylamino-phenylboronic acid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH:7](O)[CH3:8])=[CH:3][CH:2]=1.Cl[Si:11]([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12].N1C=CN=C1.C(OCC)(=[O:25])C.CCCCCC>CN(C)C=O>[Si:11]([O:25][CH2:8][CH2:7][C:4]1[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12]
Reactant: CCOC(C)=O
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CC(O)c1ccncc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: CC(C)(C)[Si](C)(C)OCCc1ccncc1

Procedure:
A solution of 16.3 g of 4-pyridylethanol, 21.8 g of chloro-tert-butyl-dimethylsilane and 10.9 g of imidazole in 150 ml of dimethylformamide is stirred 1 hour at room temperature. The product is isolated by extraction into ethyl acetate/hexane (1:1) and washed 4 times with 400 ml of water; the extract is filtered through silica gel and concentrated in vacuo to yield 4-(tert-butyl-dimethylsilyloxyethyl)-pyridine.
Reaction SMILES: [CH2:1]([NH:10][C:11]([NH:13][C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1)=[O:12])/[CH:2]=[CH:3]/[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[H-].[Na+].Cl[CH2:23][CH2:24]OS(C1C=CC(C)=CC=1)(=O)=O>CN(C)C=O>[CH2:1]([N:10]1[CH2:24][CH2:23][N:13]([C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)[C:11]1=[O:12])/[CH:2]=[CH:3]/[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: Cc1ccc(S(=O)(=O)OCCCl)cc1
Reactant: O=C(NC/C=C/c1ccccc1)Nc1cccnc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1N(C/C=C/c2ccccc2)CCN1c1cccnc1
Reaction time: 0.5 h
Yield: 59.6 %

Procedure:
To a solution of 2.51 g of (E)-N-cinnamyl-N'-(3-pyridyl) urea dissolved in 30 ml of dimethylformamide, 990 mg of sodium hydride (60% oily dispersion) was added under ice-cooling and the mixture was stirred for 30 minutes. To the mixture was added 2.8 g of 1-chloro-2-p-toluenesulfonyloxyethane and the mixture was stirred under ice-cooling for 6 hours. After distilling dimethylformamide off under reduced pressure, the residue was diluted with water and extracted with chloroform. The chloroform layer was washed with water, dried and then the solvent was distilled off. The residue was purified by silica gel column chromatography (solvent: chloroform-methanol=30:1) and recrystalliezed from ethanol to give 1.65 g of (E)-1-cinnamyl-3-(3-pyridyl)-2-imidazolidinone.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][C:3]=1[C:4](O)=[O:5].[CH3:12][NH:13][O:14][CH3:15].CCN(CC)CC.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][C:3]=1[C:4]([N:13]([O:14][CH3:15])[CH3:12])=[O:5]
Reactant: Cc1ccc(Cl)c(C(=O)O)c1
Reactant: CNOC
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CON(C)C(=O)c1cc(C)ccc1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 95 %

Procedure:
To a cooled mixture of 2-chloro-5-methyl-benzoic acid (1 g, mmol), N,O-dimethylhydroxylamine (860 mg, 8.82 mmol) and Et3N (3.27 mL) in CH2Cl2 (10 mL) was added 1-propane phosphonic acid cyclic anhydride (4.49 mL, 7.05 mmol; 50 wt % solution in EtOAc) dropwise and stirred at room temperature for 3 h. The reaction mixture was filtered, washed with CH2Cl2 (mL), evaporated to dryness and subjected to column chromatography (SiO2, 40% EtOAc-hexanes) to obtain 2-chloro-N-methoxy-5,N-dimethyl-benzamide (1.19 g) as white crystalline solid in 95% yield. ESMS m/z (relative intensity): 214.1 (M+H)+ (100).
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:7]([C:9]1C=CC=CC=1)[CH3:8]>O>[C:1]1([CH:7]([CH3:9])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCc1ccccc1
Reactant: c1ccccc1
Solvent: O
Product: CC(C)c1ccccc1

Procedure:
The benzene column 140 receives feed from the bottoms of the depropanizer column 130 in the line 136 after it is mixed with transalkylation effluent in a line 152. The benzene column 140 produces a benzene column overhead stream comprising benzene in a line 142 and a benzene column bottom stream comprising ethylbenzene and PEBs in a line 144. The overhead benzene stream in the line 142 may be provided with a water concentration of about 50 to about 150 wppm and a temperature of at least about 120° C. and preferably greater than 125° C. and no more than about 170° C. The depropanizer intermediate stream in the line 132 has similar properties, and is combined with stream 142 and delivered to a hot adsorbent vessel 160 by line 161. The hot adsorbent vessel 160 contains a bed of acidic molecular sieve adsorbent for the removal of ONCs, including nitrites from the mixed benzene stream in the line 161. The denitrogenated benzene effluent in a line 164 is delivered to both the alkylation reactor 120 by the line 102 and to a transalkylation reactor 150 by a line 166. The benzene stream in the line 166 is mixed with an intermediate stream comprising diisopropylbenzene (DIB) in a line 168 from a heavies column 190. The mixture of benzene and DIB in a line 154 are delivered to the transalkylation reactor 150. The DIB transalkylates with benzene over a transalkylation catalyst bed 156 in the transalkylation reactor 150 to produce cumene. Transalkylation effluent in the line 152 has a greater concentration of cumene and a smaller concentration of benzene and DIB than in the line 154.
Reaction SMILES: Cl[C:2]1[C:7]2[CH2:8][C:9](=[O:17])[C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[S:12][C:6]=2[CH:5]=[CH:4][CH:3]=1.[Cu](C#N)[C:19]#[N:20].CN1CCCC1=O.N>S([O-])([O-])(=O)=O.[Cu+2].O>[C:19]([C:2]1[C:7]2[CH2:8][C:9](=[O:17])[C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[S:12][C:6]=2[CH:5]=[CH:4][CH:3]=1)#[N:20]
Reactant: N#C[Cu]C#N
Reactant: O=C1Cc2c(Cl)cccc2Sc2ccccc21
Agent: [Cu+2]
Agent: N
Agent: O=S(=O)([O-])[O-]
Solvent: O
Solvent: CN1CCCC1=O
Product: N#Cc1cccc2c1CC(=O)c1ccccc1S2
Temperature: 200 °C
Reaction time: 8 h
Yield: 27.9 %

Procedure:
The mixture of 2.6 g of 9-chloro-10,11-dihydro-11-oxo-dibenzo[b,f]thiepin, 2.0 g of copper cyanide, 0.1 g of anhydrous copper sulfate and 50 ml of N-methyl pyrrolidone was heated with stirring at 200° C. overnight in a flask equipped with a tube packed with silica gel. After cooling, to the reaction mixture were added 100 ml of conc. aqueous ammonia and 200 ml of water, and the resulting mixture was extracted with benzene. The extract was washed with water, diluted hydrochloric acid and then water, which was dried over potassium sulfate and the solvent was evaporated therefrom. The residue thus obtained was chromatographed on 200 g of silica gel, and eluted with chloroform/methanol (50/1). 0.6 g of the starting material was recovered from a first eluate. Recrystallization of the residue of a second eluate from benzene gave 0.7 g of 9-cyano-10,11-dihydro-11-oxo-dibenzo[b,f]thiepin as pale yellow prismatic crystals having a melting point of 165°-167° C.