Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH2:11][C:10]([C:16]2[N:17]([CH3:43])[C:18]3[C:23]([N:24]=2)=[C:22]([N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)[N:21]=[C:20]([N:31]2[C:35]4[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=4[N:33]=[C:32]2[CH:40]([CH3:42])[CH3:41])[N:19]=3)([O:14][CH3:15])[CH2:9]1)=O)(C)(C)C.Cl>C(Cl)Cl.O1CCOCC1.CO>[CH:40]([C:32]1[N:31]([C:20]2[N:19]=[C:18]3[C:23]([N:24]=[C:16]([C:10]4([O:14][CH3:15])[CH2:11][CH2:12][CH2:13][NH:8][CH2:9]4)[N:17]3[CH3:43])=[C:22]([N:25]3[CH2:26][CH2:27][O:28][CH2:29][CH2:30]3)[N:21]=2)[C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=2[N:33]=1)([CH3:42])[CH3:41]
Reactant: COC1(c2nc3c(N4CCOCC4)nc(-n4c(C(C)C)nc5ccccc54)nc3n2C)CCCN(C(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Solvent: ClCCl
Product: COC1(c2nc3c(N4CCOCC4)nc(-n4c(C(C)C)nc5ccccc54)nc3n2C)CCCNC1
Reaction time: 1.5 h
Yield: 89.2 %

Procedure:
To a solution of 3-[2-(2-isopropylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purin-8-yl]-3-methoxypiperidine-1-carboxylic acid tert-butyl ester (2.47 g, 4.18 mmol) in DCM (100 mL) was added 4M HCl in dioxane (10 mL). The resulting mixture was allowed to stir for 2 h at r.t. before further 1.25M HCl in MeOH (20 mL) was added. The resulting mixture was allowed to stir for 1.5 h then concentrated in vacuo. The resulting residue was loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH and the product eluted with 2M NH3/MeOH affording 2-(2-Isopropylbenzoimidazol-1-yl)-8-(3-methoxypiperidin-3-yl)-9-methyl-6-morpholin-4-yl-9H-purine (1.83 g, 89%). LCMS (method H): RT 2.12 min [M+H]+ 491.4
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:14]([CH3:16])[CH3:15])[C:8]([OH:13])=[C:9]([CH:12]=1)[CH:10]=O)([CH3:4])([CH3:3])[CH3:2].[C:17]([C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[C:23]([CH:28]([CH3:30])[CH3:29])[CH:22]=1)([CH3:20])([CH3:19])[CH3:18].S(Cl)(Cl)=O>CO>[CH:10]([C:9]1[C:8]([OH:13])=[C:7]([CH:14]([CH3:15])[CH3:16])[CH:6]=[C:5]([C:1]([CH3:3])([CH3:2])[CH3:4])[CH:12]=1)([C:9]1[C:8]([OH:13])=[C:7]([CH:14]([CH3:16])[CH3:15])[CH:6]=[C:5]([C:1]([CH3:2])([CH3:4])[CH3:3])[CH:12]=1)[C:25]1[C:24]([OH:27])=[C:23]([CH:28]([CH3:30])[CH3:29])[CH:22]=[C:21]([C:17]([CH3:20])([CH3:19])[CH3:18])[CH:26]=1
Reactant: CC(C)c1cc(C(C)(C)C)ccc1O
Reactant: CC(C)c1cc(C(C)(C)C)cc(C=O)c1O
Solvent: O=S(Cl)Cl
Solvent: CO
Product: CC(C)c1cc(C(C)(C)C)cc(C(c2cc(C(C)(C)C)cc(C(C)C)c2O)c2cc(C(C)(C)C)cc(C(C)C)c2O)c1O
Temperature: 0 °C
Reaction time: 8 h
Yield: 96.5 %

Procedure:
Compound 3 was synthesized as described elsewhere with minor modifications.6 Briefly, a sample of 5-(tert-butyl)-2-hydroxy-3-isopropylbenzaldehyde (2) (5.08 g, 24.3 mmol) was combined with 2 equivalents of 4-(tert-butyl)-2-isopropylphenol (1) (9.17 g, 47.7 mmol) and 14 mL of methanol in a 100 mL schlenk flask. With a sodium carbonate trap connected to the reaction flask, the reaction mixture was cooled to 0° C. and thionyl chloride (11.4 mL, 157.7 mmol) was added dropwise causing an immediate change from orange/yellow to dark purple for the reaction mixture. The reaction was stirred overnight. The precipitate that was formed was collected by filtration. The residue was recrystallized from hexanes to afford 3 as a pale purple solid (6.88 g) in 48% yield with respect to the starting salicylaldehyde. 1H NMR (CDCl3-d) δ ppm 1.20 (27 H, s), 1.26 (18 H, d, J=6.9 Hz), 3.22 (3 H, spt, J=6.9 Hz), 4.91 (3 H, s), 5.83 (1 H, s), 6.81 (3 H, d, J=2.3 Hz), 7.18 (3 H, d, J=2.3 Hz). 13C-{1H} NMR, δ 22.7, 27.5, 31.4, 34.3, 41.8, 122.2, 123.7, 125.7, 135.0, 143.5, 148.9. Anal. calcd. for C40H58O3: C, 81.86; H, 9.96; N, 0.00. Found: C, 81.79; H, 10.32; N, 0.00.
Reaction SMILES: C([C:8]1[CH:16]=[CH:15][C:11]([C:12](O)=[O:13])=[CH:10][C:9]=1[C:17]([NH:19][C:20]1[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[C:22]([C:30]([F:33])([F:32])[F:31])[CH:21]=1)=[O:18])C1C=CC=CC=1.[NH:34]1[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1>>[CH2:12]([O:13][C:8]1[CH:16]=[CH:15][C:11]([C:12]([N:34]2[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]2)=[O:13])=[CH:10][C:9]=1[C:17]([NH:19][C:20]1[CH:25]=[C:24]([C:26]([F:28])([F:27])[F:29])[CH:23]=[C:22]([C:30]([F:31])([F:32])[F:33])[CH:21]=1)=[O:18])[C:11]1[CH:15]=[CH:16][CH:8]=[CH:9][CH:10]=1
Reactant: C1CCNCC1
Reactant: O=C(O)c1ccc(Cc2ccccc2)c(C(=O)Nc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1
Product: O=C(Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cc(C(=O)N2CCCCC2)ccc1OCc1ccccc1
Yield: 56.4 %

Procedure:
Using 4-benzyl-N-[3,5-bis(trifluoromethyl)phenyl]isophthalamic acid and piperidine as the raw materials, the same operation as the example 84(3) gave the title compound.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:13])=[CH:9][C:10]=2[F:12])[N:5]=[C:4](/[CH:14]=[CH:15]/[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:3]=1[CH3:22].[CH3:23][C:24]1([CH3:39])[C:28]2=[N:29][CH:30]=[C:31]([N:33]3[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)[CH:32]=[C:27]2[NH:26][CH2:25]1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.CC(C)([O-])C.[Na+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(C)C=CC=CC=1>[CH3:23][C:24]1([CH3:39])[C:28]2=[N:29][CH:30]=[C:31]([N:33]3[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)[CH:32]=[C:27]2[N:26]([C:2]2[C:11]3[C:6](=[CH:7][C:8]([F:13])=[CH:9][C:10]=3[F:12])[N:5]=[C:4](/[CH:14]=[CH:15]/[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:3]=2[CH3:22])[CH2:25]1
Reactant: Cc1c(/C=C/c2ccccc2)nc2cc(F)cc(F)c2c1Cl
Reactant: CC1(C)CNc2cc(N3CCOCC3)cnc21
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: Cc1ccccc1
Product: Cc1c(/C=C/c2ccccc2)nc2cc(F)cc(F)c2c1N1CC(C)(C)c2ncc(N3CCOCC3)cc21

Procedure:
Prepared according to procedure Y by stirring (E)-4-chloro-5,7-difluoro-3-methyl-2-styrylquinoline (50 mg, 0.158 mmol), 4-(3,3-dimethyl-2,3-dihydro-1H-pyrrolo-[3,2-b]pyridin-6-yl)morpholine (37 mg, 0.158 mmol), Pd2dba3 (14.5 mg, 0.016 mmol), XPhos (15.1 mg, 0.032 mmol), sodium tert-butoxide (45.7 mg, 0.475 mmol), and toluene (1.6 mL) at 100° C. for 30 min. Purification by reverse-phase HPLC (0-70% acetonitrile in water) afforded 4-(3,3-dimethyl-6-(4-morpholinyl)-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-5,7-difluoro-3-methyl-2-((E)-2-phenylethenyl)quinoline as a yellow solid. 1H NMR (500 MHz, chloroform-d) δ ppm 8.08 (1H, d, J=15.4 Hz), 7.69 (2H, d, J=7.3 Hz), 7.61-7.66 (1H, m), 7.55 (1H, d, J=2.2 Hz), 7.52 (1H, d, J=15.4 Hz), 7.41-7.47 (2H, m), 7.39 (1H, m), 6.92 (1H, t, J=2.8 Hz), 5.67 (1H, d, J=2.2 Hz), 3.79-3.88 (1H, m), 3.70-3.79 (4H, m), 3.64 (1H, d, J=9.0 Hz), 2.95-3.07 (4H, m), 2.45 (3H, s), 1.55 (3H, s), 1.52 (3H, s). Mass Spectrum (ESI) m/e=513.2 (M+1).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:28]=[CH:27][C:12]([CH2:13][CH2:14][NH:15][C:16]2[CH:26]=[CH:25][C:19]([C:20]([O:22]CC)=[O:21])=[CH:18][CH:17]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+].C(O)C.O.Cl>O>[CH2:1]([O:8][C:9]1[CH:28]=[CH:27][C:12]([CH2:13][CH2:14][NH:15][C:16]2[CH:17]=[CH:18][C:19]([C:20]([OH:22])=[O:21])=[CH:25][CH:26]=2)=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1ccc(NCCc2ccc(OCc3ccccc3)cc2)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)c1ccc(NCCc2ccc(OCc3ccccc3)cc2)cc1

Procedure:
A mixture of 6.0 g. of ethyl p-[(p-benzyloxyphenethyl)amino]benzoate (prepared as described in Example 18) 6.0 g. of potassium hydroxide and 100 ml. of ethanol-water (9:1) is refluxed for 3.5 hours. The mixture is acidified while hot with concentrated hydrochloric acid, diluted with water, filtered and the solid washed with water to give tan crystals, m.p. 180°-185° C. Recrystallization from glacial acetic acid gives tan crystals, m.p. 187°-189° C.
Reaction SMILES: C(N(CC)CC)C.Cl[CH2:9][CH2:10][CH2:11]Cl.[Cl:13][SiH:14]([Cl:16])[Cl:15]>>[Cl:13][Si:14]([Cl:16])([Cl:15])[CH2:9][CH2:10][CH2:11][Si:14]([Cl:16])([Cl:15])[Cl:13]
Reactant: Cl[SiH](Cl)Cl
Reactant: ClCCCCl
Solvent: CCN(CC)CC
Product: Cl[Si](Cl)(Cl)CCC[Si](Cl)(Cl)Cl
Yield: 8.9 %

Procedure:
In the same apparatus and procedure as Example 1 above, 0.048 g (0.47 mmol) of triethylamine, 0.6 g (4.7 mmol) of 1,3-dichloropropane, and 3.18 g (23.5 mmol) of trichlorosilane were reacted at 200° C. for 15 hrs. The resulting mixture was distilled to give 0.13 g of 1,3-bis(trichlorosilyl)propane (yield; 9%).
Reaction SMILES: [F:1][CH:2]([F:12])[O:3][C:4]1[C:5]([CH3:11])=[C:6]([CH:8]=[CH:9][CH:10]=1)[NH2:7].Cl[C:14](Cl)([O:16]C(=O)OC(Cl)(Cl)Cl)Cl>C1(C)C=CC=CC=1>[F:1][CH:2]([F:12])[O:3][C:4]1[CH:10]=[CH:9][CH:8]=[C:6]([N:7]=[C:14]=[O:16])[C:5]=1[CH3:11]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: Cc1c(N)cccc1OC(F)F
Solvent: Cc1ccccc1
Product: Cc1c(N=C=O)cccc1OC(F)F
Yield: 200.1 %

Procedure:
At room temperature, to a mixture of 3-difluoromethoxy-2-methylaniline 6.4 g and toluene 100 ml was added triphosgene 5.48 g, and the resulting mixture was stirred with heating under reflux for one hour. The reaction mixture was concentrated under reduced pressure to give 1-difluoromethoxy-3-isocyanato-2-methylbenzene 7.36 g.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11](=[O:13])[C@@H:10]([NH:14][C:15](=[O:21])OC(C)(C)C)[C@H:9]([CH3:22])[N:8]([C:23](=[O:29])[CH2:24][S:25]([CH3:28])(=[O:27])=[O:26])[C:7]=2[CH:30]=1)#[N:2].[C:31]([N:38]([CH3:44])[C@H:39](C(O)=O)[CH3:40])([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32].C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>Cl.O1CCOCC1.CN(C=O)C.CCOC(C)=O>[C:1]([C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11](=[O:13])[C@@H:10]([NH:14][C:15](=[O:21])[C@@H:39]([N:38]([CH3:44])[C:31](=[O:32])[O:33][C:34]([CH3:36])([CH3:35])[CH3:37])[CH3:40])[C@H:9]([CH3:22])[N:8]([C:23](=[O:29])[CH2:24][S:25]([CH3:28])(=[O:26])=[O:27])[C:7]=2[CH:30]=1)#[N:2]
Reactant: C[C@H]1[C@H](NC(=O)OC(C)(C)C)C(=O)Nc2ccc(C#N)cc2N1C(=O)CS(C)(=O)=O
Reactant: C[C@@H](C(=O)O)N(C)C(=O)OC(C)(C)C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: C[C@@H](C(=O)N[C@@H]1C(=O)Nc2ccc(C#N)cc2N(C(=O)CS(C)(=O)=O)[C@H]1C)N(C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 74.4 %

Procedure:
A rt solution of tert-butyl(2S,3S)-8-cyano-2-methyl-1-(2-(methylsulfonyl)acetyl)-4-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-ylcarbamate (137 mg, 314 μmol) in 4 M HCl in dioxane (1.57 ml) was stirred for 2 h. The reaction was concentrated, taken up in in DMF (1.05 ml), and Boc-N-methyl-L-alanine (70.2 mg, 345 μmol), N,N-diisopropylethylamine (217 μl, 1.26 mmol), and HBTU (131 mg, 345 μmol) were added at 0° C. The reaction was stirred at rt for 30 min, then diluted with EtOAc, washed with H2O, sat. aq. NaHCO3, and sat. aq. NaCl, dried over Na2SO4, filtered, and concentrated. The crude material was purified by flash chromatography to provide tert-butyl(S)-1-((2S,3S)-8-cyano-2-methyl-1-(2-(methylsulfonyl)acetyl)-4-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-ylamino)-1-oxopropan-2-yl(methyl)carbamate (121.8 mg, 74%) as a white solid. MS m/z 544 (MNa)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C@H:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:12]([C:19]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)=[O:20])[C@@H:11]([CH3:28])[CH2:10]2)=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.[C:38](Cl)(=[O:40])[CH3:39]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:12]([C:19](=[O:20])[C:21]3[CH:22]=[CH:23][C:24]([F:27])=[CH:25][CH:26]=3)[CH:11]([CH3:28])[CH2:10]2)[C:38](=[O:40])[CH3:39])=[CH:4][CH:3]=1
Reactant: C[C@H]1C[C@@H](Nc2ccc(Cl)cc2)c2ccccc2N1C(=O)c1ccc(F)cc1
Reactant: CC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N(c1ccc(Cl)cc1)C1CC(C)N(C(=O)c2ccc(F)cc2)c2ccccc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 71 %

Procedure:
To a solution of (2S,4R)-[4-(4-chloro-phenylamino)-2-methyl-3,4-dihydro-2H-quinolin-1-yl]-(4-fluoro-phenyl)-methanone (250 mg, 0.636 mmol) in acetyl chloride (5 mL) was added diisopropylethylamine (120 uL, 0.70 mmol). The mixture was stirred at rt 4 h. The mixture was concentrated under reduced pressure, dissolved in ethyl acetate, washed with sat. aqueous sodium bicarbonate, brine and dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (25/75 hexanes/ethyl acetate gradient) to afford pure N-(4-chloro-phenyl)-N-[1-(4-fluoro-benzoyl)-2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl]-acetamide (200 mg, 71%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:30]=[C:11]3[N:12]=[C:13]([CH3:29])[C:14]([C@H:23]([OH:28])[C:24]([O:26][CH3:27])=[O:25])=[C:15]([C:16]4[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=4)[N:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1.C(O[C:35]([CH3:38])([CH3:37])[CH3:36])(=O)C.Cl(O)(=O)(=O)=O>C(Cl)Cl.CCOCC>[C:35]([O:28][C@@H:23]([C:14]1[C:13]([CH3:29])=[N:12][C:11]2[N:10]([N:9]=[C:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)[CH:30]=2)[C:15]=1[C:16]1[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=1)[C:24]([O:26][CH3:27])=[O:25])([CH3:38])([CH3:37])[CH3:36]
Reactant: COC(=O)[C@@H](O)c1c(C)nc2cc(-c3cccc(Cl)c3)nn2c1-c1ccc(F)cc1
Reactant: CC(=O)OC(C)(C)C
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: CCOCC
Solvent: ClCCl
Product: COC(=O)[C@@H](OC(C)(C)C)c1c(C)nc2cc(-c3cccc(Cl)c3)nn2c1-c1ccc(F)cc1
Reaction time: 2 h
Yield: 70.2 %

Procedure:
To a stirred solution of (S)-methyl 2-(2-(3-chlorophenyl)-7-(4-fluorophenyl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-hydroxyacetate (0.06 g, 0.141 mmol) and tert-butyl acetate (0.952 ml, 7.04 mmol) in CH2Cl2 (3 mL) was added 70% perchloric acid (0.036 ml, 0.423 mmol) at rt. After 2 h, the reaction was diluted with Et2O (50 mL), washed with sat. Na2CO3 (2×5 mL), dried (Na2SO4), filtered and concentrated to give yellow solid which was purified by prep-HPLC to afford (S)-methyl 2-(tert-butoxy)-2-(2-(3-chlorophenyl)-7-(4-fluorophenyl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)acetate (0.0478 g, 0.099 mmol, 70.4% yield) as while solid. 1H NMR (500 MHz, CDCl3) δ: 7.83 (s, 1H), 7.77-7.69 (m, 2H), 7.67-7.62 (m, 1H), 7.35-7.26 (m, 4H), 6.87 (s, 1H), 5.07 (s, 1H), 3.81 (s, 3H), 2.66 (s, 3H), 0.96 (s, 9H). LCMS (M+H) calcd for C26H26ClFN3O3: 482.16. found: 482.3.
Reaction SMILES: [C:1]1([CH3:8])[C:6]([OH:7])=[CH:5][CH:4]=[CH:3][CH:2]=1.[S-:9][C:10]#[N:11].[Na+].[Br-].[Na+].BrBr.C(=O)(O)[O-].[Na+]>CO>[CH3:8][C:1]1[CH:2]=[C:3]([S:9][C:10]#[N:11])[CH:4]=[CH:5][C:6]=1[OH:7]
Reactant: N#C[S-]
Reactant: Cc1ccccc1O
Agent: BrBr
Agent: O=C([O-])O
Agent: [Br-]
Solvent: CO
Product: Cc1cc(SC#N)ccc1O
Temperature: 0 °C
Reaction time: 1 h
Yield: 69.8 %

Procedure:
To a 500 ml three-necked flask were added sequentially with agitation o-cresol (15 g, 138.7 mmol), sodium thiocyanate (NaSCN, 34 g, 419.3 mmol), sodium bromide (NaBr, 16 g, 155.5 mmol) and methanol (200 ml). The mixture was cooled to 0° C., and then a solution of bromine (8.6 ml, 167 mmol) in methanol (30 ml) was added dropwise thereinto. After 1 hour of stirring at 0° C., the mixture was warmed up to room temperature and then stirred for another 4 hours at room temperature. After the reaction was completed, a 200 ml saturated aqueous solution of sodium bicarbonate (NaHCO3) was added to the reaction mixture and stirred for 10 min. The mixture was extracted with ethyl acetate (2×500 ml). The combined organic layer was dried over anhydrous magnesium sulfate, filtrated, concentrated under reduced pressure to give yellow oil. Silica gel column chromatography purification (silica-gel H: 300-400 mesh; petroleum ether/ethyl acetate=8:1 v/v) was performed to yield 3-methyl-4-hydroxy-phenyl thiocyanic acid as a white solid (16 g, yield: 69.8%).
Reaction SMILES: [C:1]([O:7][CH3:8])(=[O:6])[CH2:2][C:3]([CH3:5])=O.[CH3:9][NH2:10]>CO>[CH3:8][O:7][C:1](=[O:6])[CH:2]=[C:3]([NH:10][CH3:9])[CH3:5]
Reactant: CN
Reactant: COC(=O)CC(C)=O
Solvent: CO
Product: CNC(C)=CC(=O)OC
Reaction time: 1 h

Procedure:
To a solution of methyl acetoacetate (29.4 g, 253 mmol) in MeOH (30 mL) was added methylamine (33% w/w in EtOH, 48 mL, 385 mmol) dropwise at room temperature. The reaction was stirred for 1 hour then concentrated and dried to give the title compound as a white crystalline solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[C:9]1[C:17]2[O:16][CH:15]([CH2:18]OS(C3C=CC(C)=CC=3)(=O)=O)[CH2:14][C:13]=2[CH:12]=[C:11]([O:30][CH3:31])[CH:10]=1.[CH3:32][NH2:33]>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[C:9]1[C:17]2[O:16][CH:15]([CH2:18][NH:33][CH3:32])[CH2:14][C:13]=2[CH:12]=[C:11]([O:30][CH3:31])[CH:10]=1
Reactant: CN
Reactant: COc1cc2c(c(-c3cc(C)ccc3C)c1)OC(COS(=O)(=O)c1ccc(C)cc1)C2
Product: CNCC1Cc2cc(OC)cc(-c3cc(C)ccc3C)c2O1

Procedure:
The title compound was prepared (0.064 g, 62%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-{[7-(2,5-dimethylphenyl)-5-methoxy-2,3-dihydro-1-benzofuran-2-yl]methyl}4-methylbenzenesulfonate (0.135 g, 0.31 mmol) and methylamine (0.096 g, 3.1 mmol). mp 202-204° C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[C:6]([NH2:11])[CH:5]=1)([O-:3])=[O:2].[F:12][C:13]1[CH:21]=[CH:20][CH:19]=[CH:18][C:14]=1[C:15](O)=O.[K+].[Br-]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[F:12][C:13]1[CH:21]=[CH:20][CH:19]=[CH:18][C:14]=1[C:15]1[NH:11][C:6]2[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:9]=[CH:8][C:7]=2[N:10]=1
Reactant: O=C(O)c1ccccc1F
Reactant: Nc1ccc([N+](=O)[O-])cc1N
Agent: [Br-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1ccc2nc(-c3ccccc3F)[nH]c2c1
Yield: 15 %

Procedure:
Prepared from 4-nitrophenylenediamine and 2-fluorobenzoic acid, in a manner similar to that of Example 31b. Yield: 15%; Rf (7/3 toluene/ethyl acetate): 0.55; IR (KBr): 2996, 1625, 1520, 1479, 1340 cm−1; 1H-NMR (d6-DMSO) 8.5-8.0 (m, 3H); 7.2-7.9 (m, 4H).
Reaction SMILES: C(OC(=O)[NH:7]/[C:8](=[N:34]\C(OC(C)(C)C)=O)/[CH:9]1[NH:21][CH2:20][C:18]2=[C:19]3[C:14](=[C:15]([C:30]([F:33])([F:32])[F:31])[C:16]([CH2:22][CH2:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[CH:17]2)[CH:13]=[CH:12][N:11]3[CH2:10]1)(C)(C)C.Cl>C(Cl)Cl.O1CCOCC1>[CH2:22]([C:16]1[C:15]([C:30]([F:33])([F:32])[F:31])=[C:14]2[C:19]3=[C:18]([CH2:20][NH:21][CH:9]([C:8](=[NH:7])[NH2:34])[CH2:10][N:11]3[CH:12]=[CH:13]2)[CH:17]=1)[CH2:23][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: CC(C)(C)OC(=O)/N=C(\NC(=O)OC(C)(C)C)C1Cn2ccc3c(C(F)(F)F)c(CCc4ccccc4)cc(c32)CN1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: N=C(N)C1Cn2ccc3c(C(F)(F)F)c(CCc4ccccc4)cc(c32)CN1
Temperature: 25 °C
Reaction time: 8 h
Yield: 51.8 %

Procedure:
A solution of Z-tert-butyl(((tert-butoxycarbonyl)imino)(6-phenethyl-7-(trifluoromethyl)-3,4-dihydro-[1,4]diazepino[6,7,1-hi]indol-2(1H)-yl)methyl)carbamate (74 mg, 0.13 mmol) in CH2Cl2 (5 mL) was treated with 4M HCl in 1,4-dioxane (12 mL) and the resulting mixture was stirred at room temperature overnight. Evaporation of the solvent and trituration with diethyl ether yielded 6-phenethyl-7-(trifluoromethyl)-3,4-dihydro-[1,4]diazepino[6,7,1-hi]indole-2(1H)-carboximidamide (26 mg).
Reaction SMILES: C[O:2][C:3](=[O:27])[C@H:4]([CH2:6][O:7][C:8]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:20]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[C:14]2[C:9]1=[CH:10][CH:11]=[CH:12][CH:13]=2)[NH2:5].[OH-].[Na+]>CO>[C:21]1([C:8]2([O:7][CH2:6][C@@H:4]([C:3]([OH:27])=[O:2])[NH2:5])[C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=3[C:15]3[C:20]2=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: COC(=O)[C@@H](N)COC1(c2ccccc2)c2ccccc2-c2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: N[C@@H](COC1(c2ccccc2)c2ccccc2-c2ccccc21)C(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.2 %

Procedure:
To a solution of 6.4 g (17.8 mmol) of O-(9-phenyl-9H-fluoren-9-yl)-L-serine methyl ester from step 2 in methanol (20 mL) was added 20% sodium hydroxide (10 mL) and the mixture stirred at room temperature for 1 h. Most of the methanol was evaporated under vacuo, the residue suspended in water (200 mL) and extracted with diethyl ether (2×50 mL). The alkaline aqueous phase was added dropwise into 20% acetic acid (30 mL) with stirring and cooling with an ice bath, the white precipitate was filtered, washed with water and dried in vacuo over P2O5 to give 5.3 g (yield 90%) of O-(9-phenyl-9H-fluoren-9-yl)-L-serine as a white powder. 13C NMR (DMSO-d6, 75 MHz) δ: 167.0, 146.4, 146.1, 143.3, 140.3, 140.0, 129.4, 129.2, 128.4, 128.2, 128.0, 127.2, 125.6, 125.5, 125.1, 120.5, 120.4, 88.4, 63.2, 54.8.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][C@@H:9]([OH:12])[C@H:8]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:7]1)=[O:5])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:38][C:39]1[CH:44]=[CH:43][C:42](O)=[CH:41][CH:40]=1.N(C(OCC)=O)=NC(OCC)=O>C1C=CC=CC=1>[Br:38][C:39]1[CH:44]=[CH:43][C:42]([O:12][C@H:9]2[CH2:10][CH2:11][N:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH2:7][C@H:8]2[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[CH:41][CH:40]=1
Reactant: CCOC(=O)N1CC[C@@H](O)[C@H](c2ccccc2)C1
Reactant: Oc1ccc(Br)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Product: CCOC(=O)N1CC[C@H](Oc2ccc(Br)cc2)[C@H](c2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 6.26 g of trans-1-ethoxycarbonyl-3-phenyl-4-piperidinol, 7.21 g of triphenylphosphine, 4.76 g of 4-bromophenol and 250 ml of benzene is added dropwise, at 5° C. under nitrogen, a solution of 4.79 g of diethyl azocarboxylate in 250 ml of benzene. After the addition is complete, the mixture is stirred at room temperature overnight. The reaction mixture is processed according to the procedure of Example 75 to give product as a gum.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]=O)[CH:5]=[N:6][CH:7]=1.Br[C:11]1[CH:12]=[C:13](CO)[CH:14]=[N:15][CH:16]=1>C(Cl)(Cl)Cl.O=[Mn]=O>[N:15]1([CH2:4][CH2:3][C:2]#[C:7][C:2]2[CH:7]=[N:6][CH:5]=[C:4]([CH2:8][N:15]3[CH2:16][CH2:11][CH2:12][CH2:13][CH2:14]3)[CH:3]=2)[CH2:16][CH2:11][CH2:12][CH2:13][CH2:14]1
Reactant: O=Cc1cncc(Br)c1
Reactant: OCc1cncc(Br)c1
Agent: O=[Mn]=O
Solvent: ClC(Cl)Cl
Product: C(#Cc1cncc(CN2CCCCC2)c1)CCN1CCCCC1
Yield: 51 %

Procedure:
5-Bromo-pyridine-3-carbaldehyde. (5-Bromo-pyridin-3-yl)-methanol (1.13 g, 6.00 mmol) was dissolved in CHCl3 (40 mL) and treated with MnO2 (3.60 g). The reaction mixture was heated at reflux temperature for 3 h. The hot reaction mixture was filtered through a pad of diatomaceous earth and the filtrate was concentrated to yield the title compound (0.570 g, 51%).
Reaction SMILES: [CH2:1]([C@@H:8]([CH2:12][CH2:13][C@H:14]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:15]([NH:17][C@H:18]1[CH2:24][CH2:23][S:22][C@H:21]2[CH2:25][CH2:26][CH2:27][C@@H:28]([C:29]([O:31][CH3:32])=[O:30])[N:20]2[C:19]1=[O:33])=[O:16])[C:9](O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:41][C@H:42]1[CH2:48][CH:47]=[CH:46][CH2:45][N:44]([CH2:49][C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)[C:43]1=[O:56]>>[CH2:34]([C@@H:14]([CH2:13][CH2:12][C@H:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:9]([NH:41][C@H:42]1[CH2:48][CH:47]=[CH:46][CH2:45][N:44]([CH2:49][C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)[C:43]1=[O:56])=[O:10])[C:15]([NH:17][C@H:18]1[CH2:24][CH2:23][S:22][C@H:21]2[CH2:25][CH2:26][CH2:27][C@@H:28]([C:29]([O:31][CH3:32])=[O:30])[N:20]2[C:19]1=[O:33])=[O:16])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: COC(=O)[C@@H]1CCC[C@@H]2SCC[C@H](NC(=O)[C@H](CC[C@H](Cc3ccccc3)C(=O)O)Cc3ccccc3)C(=O)N21
Reactant: N[C@H]1CC=CCN(Cc2ccccc2)C1=O
Product: COC(=O)[C@@H]1CCC[C@@H]2SCC[C@H](NC(=O)[C@H](CC[C@H](Cc3ccccc3)C(=O)N[C@H]3CC=CCN(Cc4ccccc4)C3=O)Cc3ccccc3)C(=O)N21

Procedure:
(4S,7S,10aS)-Methyl 4-((2R,5R)-2,5-dibenzyl-6-((S,Z)-1-benzyl-2-oxo-2,3,4,7-tetrahydro-1H-azepin-3-ylamino)-6-oxohexanamido)-5-oxooctahydro-2H-pyrido[2,1-b][1,3]thiazepine-7-carboxylate was synthesized as described in General Procedure H using Intermediate 23 (11 mg, 0.019 mmol) and Intermediate 51 (5.9 mg, 0.027 mmol) to give a white solid (10 mg, 68% yield). Anal. Calcd. for C44H52N4O6S m/z 764.4. found: 765.2 (M+H)+; 1H NMR (400 MHz, CDCl3) δ ppm 7.41-7.06 (m, 16H), 6.96 (d, J=7.1 Hz, 1H), 5.67-5.48 (m, 2H), 5.34 (t, J=4.6 Hz, 1H), 5.18-5.06 (m, 2H), 5.05-4.93 (m, 1H), 4.61 (dd, J=51.2, 15.0 Hz, 2H), 4.34 (d, J=17.6 Hz, 1H), 3.67 (s, 3H), 3.33 (dd, J=17.6, 6.8 Hz, 1H), 3.14 (t, J=11.4 Hz, 1H), 2.91-2.64 (m, 4H), 2.51-2.14 (m, 6H), 2.02 (d, J=4.4 Hz, 2H), 1.89-1.44 (m, 9H).