Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:6]2[CH:7]=[N:8][C:9]([C:11]([O:13]C)=[O:12])=[CH:10][C:5]=2[N:4]([CH2:15][CH3:16])[CH:3]=1.Cl>CCO.[OH-].[Na+]>[Br:1][C:2]1[C:6]2[CH:7]=[N:8][C:9]([C:11]([OH:13])=[O:12])=[CH:10][C:5]=2[N:4]([CH2:15][CH3:16])[CH:3]=1
Reactant: CCn1cc(Br)c2cnc(C(=O)OC)cc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCn1cc(Br)c2cnc(C(=O)O)cc21
Temperature: 80 °C
Reaction time: 120 h
Yield: 90.9 %

Procedure:
A mixture of methyl 3-bromo-1-ethyl-1H-pyrrolo[3,2-c]pyridine-6-carboxylate (3A, 3.0 g, 11 mmol) in EtOH (10 ml) and 1N NaOH (10 ml) was stirred at 80° C. for 5 days. The reaction mixture was acidified with 1N HCl, concentrated in vacuo and dried to give 3-bromo-1-ethyl-1H-pyrrolo[3,2-c]pyridine-6-carboxylic acid (3B, 2.8 g, 10 mmol, 98% yield) as a pale brown powder. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.42 (t, J=7.20 Hz, 3H) 4.49 (q, J=7.33 Hz, 2H) 8.35 (s, 1H) 8.65 (s, 1H) 8.91 (s, 1H). 3F In a 200 ml round bottom flask, methyl 3-bromo-1-methyl-1H-pyrrolo[3,2-c]pyridine-6-carboxylate (3E, 8.5 g, 32 mmol) was dissolved THF (50 ml) NaOH (32 ml, 63 mmol) solution was added to the mixture and the stirring continued at room temperature overnight. Another equivalent of base was added and the mixture was warmed with water bath to complete the reaction. Volatiles were removed in vacuo and the residue was cooled in an ice bath and neutralized with dilute HCl to pH 4.0-4.5. The precipitated product was collected by filtration to give the product 3-bromo-1-methyl-1H-pyrrolo[3,2-c]pyridine-6-carboxylic acid (3F, 7.3 g, 91%).
Reaction SMILES: CS[C:3]1[N:8]=[C:7]([NH:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([Cl:19])[CH:12]=2)[C:6]([CH:20]=[O:21])=[CH:5][N:4]=1.Cl[C:23]1[CH:28]=CC=[C:25]([C:29]([O:31]O)=O)[CH:24]=1.C([N:35](CC)CC)C>C(Cl)(Cl)Cl.C(OCC)(=O)C>[OH:31][CH2:29][C@@H:25]1[CH2:24][CH2:23][CH2:28][N:35]1[C:3]1[N:8]=[C:7]([NH:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([Cl:19])[CH:12]=2)[C:6]([CH:20]=[O:21])=[CH:5][N:4]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COc1ccc(CNc2nc(SC)ncc2C=O)cc1Cl
Reactant: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Product: COc1ccc(CNc2nc(N3CCC[C@H]3CO)ncc2C=O)cc1Cl
Reaction time: 1 h

Procedure:
A solution of 2-methylthio-4-(3-chloro-4-methoxybenzylamino)-5-formylpyrimidine (prepared in Example 84-(2)) 2.057 g in chloroform 20 ml is treated at 0° C. for 30 minutes with m-chloroperbenzoic acid (80%) 1.468 g. L-(S)-Prolinol 0.901 g and then triethylamine 1.33 ml are added thereto. The reaction is carried out at 0° C. for 1 hour. The reaction mixture is elevated to room temperature, diluted with ethyl acetate, washed with an aqueous sodium hydrogen carbonate solution, water and a saturated sodium chloride solution, and dried over anhydrous sodium sulfate. The precipitate is filtered off and the filtrate is concentrated in vacuo to give (S)-2-(2-hydroxymethyl-1-pyrrolidinyl)-4-(3-chloro-4-methoxybenzylamino)-5-formylpyrimidine as a colorless amorphous, 1.9990 g. MS(m/z): 377(M+H)+
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].C([O-])(=O)C.[Na+].[Br:15]Br>C(O)(=O)C.[Fe]>[Br:15][C:3]1[C:2]([OH:1])=[CH:9][CH:8]=[CH:7][C:4]=1[CH:5]=[O:6]
Reactant: O=Cc1cccc(O)c1
Reactant: BrBr
Agent: [Fe]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: O=Cc1cccc(O)c1Br
Temperature: 25 °C
Reaction time: 2 h
Yield: 28 %

Procedure:
The suspension of 3-hydroxybenzaldehyde (5 g, 0.04 mol), iron powder (172 mg, 3 mmol) and sodium acetate (6.72 g, 0.08 mol) in acetic acid (40 mL) was warmed until a clear solution was obtained and then cooled to room temperature. To this mixture was dropwise added a solution of bromine in glacial acetic acid (10 mL) over 15 min. After the addition, the reaction mixture was stirred for 2 h and then poured into ice-water. The resulting mixture was extracted with dichloromethane (3×50 mL). The combined extracts were dried over anhydrous Na2SO4 and concentrated. The residue was re-crystallized from dichloromethane to afford the product (2.3 g, yield 28%). 1H NMR (400 MHz, DMSO-d6 δ 10.30 (s, 1H), 7.54-7.51 (m, 1H), 7.39-7.35 (m, 1H), 7.31-7.27 (m, 1H), 5.90 (s, 1H).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[OH-].[K+].[CH3:13][CH:14]([C:21]#[N:22])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>N1C=CC=CC=1>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([CH3:13])[C:21]#[N:22])=[CH:3][CH:4]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(Cl)cc1
Reactant: CC(C#N)c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: c1ccncc1
Product: CC(C#N)(c1ccccc1)c1ccc([N+](=O)[O-])cc1
Temperature: 10 °C
Reaction time: 24 h

Procedure:
This compound is synthesized according to Makosza, et al with some modifications (Makosza, M., et al, Tetrahedron (1974), 30: 3723). A solution of 4-chloronitrobenzene (31.5 g, 0.2 mol) in pyridine (100 mL) is added dropwise to a vigorously stirred suspension of KOH (fine powder 70.0 g) and α-methylbenzylcyanide (26.2 g, 0.2 mol) in pyridine (150 mL), with the reaction temperature being maintained at 10° C. The reaction mixture is stirred for 24 hours at 25° C., and poured onto an excess of HCl-ice mixture. The acidic aqueous mixture is extracted with benzene, the organic phase washed with brine, dried (Na2SO4), and the benzene evaporated under vacuum. A crude product 42.5 g (84 wt %) results and is recrystallized from isopropanol-petroleum ether to give Compound 7 as white crystals,
Reaction SMILES: O[CH2:2][C:3]1[N:7]([C:8]2[CH:9]=[C:10]([C:14]3[CH2:20][C:19](=[O:21])[NH:18][C:17]4[CH:22]=[C:23]([C:28]([F:31])([F:30])[F:29])[C:24]([O:26][CH3:27])=[CH:25][C:16]=4[N:15]=3)[CH:11]=[CH:12][CH:13]=2)[N:6]=[N:5][CH:4]=1.O=S(Cl)Cl.[Na+].[I-].[NH:38]1[CH2:42][CH2:41][CH2:40][CH2:39]1.[Cl-]>C(Cl)Cl.CCOC(C)=O>[CH3:27][O:26][C:24]1[C:23]([C:28]([F:30])([F:31])[F:29])=[CH:22][C:17]2[NH:18][C:19](=[O:21])[CH2:20][C:14]([C:10]3[CH:11]=[CH:12][CH:13]=[C:8]([N:7]4[C:3]([CH2:2][N:38]5[CH2:42][CH2:41][CH2:40][CH2:39]5)=[CH:4][N:5]=[N:6]4)[CH:9]=3)=[N:15][C:16]=2[CH:25]=1
Reactant: COc1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-n3nncc3CO)c1)=N2
Reactant: C1CCNC1
Agent: [Cl-]
Agent: [I-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: COc1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-n3nncc3CN3CCCC3)c1)=N2

Procedure:
The title compound was prepared from 4-[3-(5-hydroxymethyl-[1,2,3]triazol-1-yl)-phenyl]-7-methoxy-8-trifluoromethyl-1,3-dihydro-benzo[b][1,4]diazepin-2-one (Example 46) (86 mg, 0.2 mmol) by treatment with SOCl2 (0.044 mL, 0.6 mmol) in CH2Cl2 (2 mL) from 23° C. to reflux for 15 min, followed by evaporation to dryness. The crude chloride was dissolved in DMF (2 mL) and stirred with cat. amount of NaI and pyrrolidine (0.17 mL, 2.0 mmol) at 23° C. until tlc indicated complete conversion of the chloride. The reaction mixture was taken up in EtOAc, washed with water and brine, dried over Na2SO4. Removal of the solvent in vacuum left a yellow semisolid, which was purified by silica gel column chromatography. Obtained as a yellow solid (47 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][CH:9]([C:13]2[C:18]([Cl:19])=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:20])[C:10]([OH:12])=[O:11])[CH:5]=[CH:6][CH:7]=1.CN(C)P(N(C)C)(N(C)C)=O.[H-].[Na+].[CH2:34](I)[CH3:35]>C1C=CC=CC=1>[CH2:34]([N:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=1)[CH:9]([C:13]1[C:18]([Cl:19])=[CH:17][CH:16]=[CH:15][C:14]=1[Cl:20])[C:10]([OH:12])=[O:11])[CH3:35]
Reactant: O=C(O)C(Nc1cccc(Cl)c1)c1c(Cl)cccc1Cl
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCN(c1cccc(Cl)c1)C(C(=O)O)c1c(Cl)cccc1Cl
Reaction time: 0.5 h

Procedure:
To a stirred solution of 13.2 parts of N-(m-chlorophenyl)-2-(2,6-dichlorophenyl)glycine in 80 parts of hexamethylphosphoramide are added portionwise 2.1 parts of sodium hydride 50% and the whole is stirred for 30 minutes. Then there are added dropwise 6.9 parts of ethyl iodide and stirring is continued for 20 hours at room temperature. The reaction mixture is poured onto 320 parts of benzene. The organic layer is washed successively twice with 50 parts of water, twice with 50 parts of a sodium hydroxide solution 5% and again twice with 50 parts of water, dried, filtered and evaporated. The oily residue solidifies on standing at room temperature. The solid product is filtered off and crystallized from 2-propanol, yielding 8.9 parts of ethyl N-(m-chlorophenyl)-2-(2,6-dichlorophenyl)glycine; mp. 120.5° C.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Br)=[C:4]([F:10])[CH:3]=1.[CH3:11][S:12]([N:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1)(=[O:14])=[O:13].C([O-])([O-])=O.[K+].[K+]>C(#N)C>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][N:18]2[CH2:19][CH2:20][N:15]([S:12]([CH3:11])(=[O:14])=[O:13])[CH2:16][CH2:17]2)=[C:4]([F:10])[CH:3]=1
Reactant: CS(=O)(=O)N1CCNCC1
Reactant: Fc1cc(Br)ccc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CS(=O)(=O)N1CCN(Cc2ccc(Br)cc2F)CC1
Temperature: 40 °C
Reaction time: 18 h

Procedure:
A mixture of 4-bromo-2-fluorobenzyl bromide (30.4 g, 114 mmol, 1 eq), 1-methylsulfonylpiperazine (20.0 g, 114 mmol, 1 eq) and K2CO3 (31.6 g, 228 mmol, 2 eq) in acetonitrile (500 mL) was stirred at 40° C. for 18 h. The reaction mixture was allowed to cool to room temperature, the mixture was filtered through Celite, and washed with EtOAc. The filtrate was concentrated in vacuo to yield 1-(4-Bromo-2-fluoro-benzyl)-4-methanesulfonyl-piperazine (Intermediate 5).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[C:3]=1[C:10](=[O:12])[CH3:11].[CH3:13][Mg]Br.CCOCC>C1COCC1>[NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[C:3]=1[C:10]([OH:12])([CH3:13])[CH3:11]
Reactant: C[Mg]Br
Reactant: COc1cccc(N)c1C(C)=O
Solvent: C1CCOC1
Solvent: CCOCC
Product: COc1cccc(N)c1C(C)(C)O
Temperature: 0 °C

Procedure:
1-(2-Amino-6-methoxyphenyl)ethanone (500 mg, 3.03 mmol) was dissolved in THF (7.5 mL) and cooled to 0° C. A 3M solution of Methyl magnesium bromide in Et2O (2.12 ml, 6.36 mmol) was added drop wise keeping the temperature below 10° C. The reaction was quenched with an aqueous saturated solution of NH4Cl (7.5 mL) keeping the temperature below 15° C. The mixture was diluted with water and ethyl acetate, two phases separated and the organic layer was washed twice with brine, dried over Na2SO4 and evaporated to dryness affording the title compound (500 mg) as light orange solid.
Reaction SMILES: C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[NH2:19][CH:20]1[CH2:25][CH2:24][CH2:23][N:22]([C:26]2[CH:27]=[C:28]([CH:33]=[CH:34][CH:35]=2)[C:29]([O:31][CH3:32])=[O:30])[CH2:21]1.[Cl:36][C:37]1[CH:42]=[CH:41][C:40]([C:43]2[S:44][C:45]([CH:49]=O)=[C:46]([CH3:48])[N:47]=2)=[CH:39][CH:38]=1.C(=O)(O)[O-].[Na+]>O1CCCC1>[Cl:36][C:37]1[CH:38]=[CH:39][C:40]([C:43]2[S:44][C:45]([CH2:49][NH:19][CH:20]3[CH2:25][CH2:24][CH2:23][N:22]([C:26]4[CH:27]=[C:28]([CH:33]=[CH:34][CH:35]=4)[C:29]([O:31][CH3:32])=[O:30])[CH2:21]3)=[C:46]([CH3:48])[N:47]=2)=[CH:41][CH:42]=1
Reactant: COC(=O)c1cccc(N2CCCC(N)C2)c1
Reactant: Cc1nc(-c2ccc(Cl)cc2)sc1C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: COC(=O)c1cccc(N2CCCC(NCc3sc(-c4ccc(Cl)cc4)nc3C)C2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 38.7 %

Procedure:
Acetic acid (0.0251 mL, 0.438 mmol) and sodium triacetoxyborohydride (97.7 mg, 0.438 mmol) were added to methyl 3-(3-aminopiperidin-1-yl)benzoate (79.0 mg, 0.337 mmol) and 2-(4-chlorophenyl)-4-methylthiazole-5-carboaldehyde (80.1 mg, 0.337 mmol) in tetrahydrofuran (5 mL). The reaction mixture was stirred at room temperature for 16 hours. Subsequently, a saturated aqueous sodium bicarbonate solution was added to make the mixture basic. The mixture was then extracted with ethyl acetate and the extract washed with brine, followed by drying over magnesium sulfate and evaporation of the solvent. Purification of the resulting residue by silica gel column chromatography (Chromatorex NH-DM2035 (Fuji Sylysia Chemical Co., Ltd.) hexane:ethyl acetate=5:1->2:1) gave 59.4 mg (39%) of the desired compound as a colorless oil.
Reaction SMILES: [H-].[Na+].[N:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[N:13]2[CH:14]=[C:15]([C:18]3[C:19]([C:42]4[CH:47]=[CH:46][C:45]([NH:48][C:49]([N:51]5[CH2:56][CH2:55][O:54][CH2:53][CH2:52]5)=[O:50])=[CH:44][CH:43]=4)=[N:20][N:21]([C:23]([C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH:22]=3)[CH:16]=[CH:17][C:12]2=[N:11][CH:10]=1.[CH3:57]I.O>CN(C)C=O.C(OCC)(=O)C>[CH3:57][N:48]([C:45]1[CH:44]=[CH:43][C:42]([C:19]2[C:18]([C:15]3[CH:16]=[CH:17][C:12]4[N:13]([C:9]([C:4]5[CH:5]=[CH:6][CH:7]=[CH:8][N:3]=5)=[CH:10][N:11]=4)[CH:14]=3)=[CH:22][N:21]([C:23]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[N:20]=2)=[CH:47][CH:46]=1)[C:49]([N:51]1[CH2:52][CH2:53][O:54][CH2:55][CH2:56]1)=[O:50]
Reactant: CI
Reactant: O=C(Nc1ccc(-c2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cc2-c2ccc3ncc(-c4ccccn4)n3c2)cc1)N1CCOCC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CN(C(=O)N1CCOCC1)c1ccc(-c2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cc2-c2ccc3ncc(-c4ccccn4)n3c2)cc1
Reaction time: 0.33 h

Procedure:
6 mg sodium hydride was suspended in 2 mL N,N-dimethylformamide, then 3 mL of 64 mg morpholine-4-carboxylic acid {4-[4-(3-pyridin-2-ylimidazo[1,2-a]-pyridin-6-yl)-1-trityl-1H-pyrazol-3-yl]phenyl}amide (compound in Example 357) in N,N-dimethylformamide was added thereto under ice-coolingd water in a stream of nitrogen, and the reaction solution was returned to room temperature and stirred for 20 minutes. 7 μL methyl iodide was added thereto under ice-cooling and stirred for 20 minutes. Water and ethyl acetate were added to the reaction solution, and the organic layer was separated and dried over anhydrous sodium sulfate. The solvent was evaporated, and the resulting residue was purified by NH silica gel column chromatography (ethyl acetate/hexane) to give 55 mg of the title compound as a colorless amorphous.
Reaction SMILES: CN1C(=O)CCC1.Br[C:9]1[CH:10]=[CH:11][C:12]([N+:15]([O-:17])=[O:16])=[N:13][CH:14]=1.[CH3:18][Si:19]([C:22]#[CH:23])([CH3:21])[CH3:20].C(N(CC)C(C)C)(C)C>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I.O>[N+:15]([C:12]1[CH:11]=[CH:10][C:9]([C:23]#[C:22][Si:19]([CH3:21])([CH3:20])[CH3:18])=[CH:14][N:13]=1)([O-:17])=[O:16]
Reactant: O=[N+]([O-])c1ccc(Br)cn1
Reactant: C#C[Si](C)(C)C
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: C[Si](C)(C)C#Cc1ccc([N+](=O)[O-])nc1
Temperature: 65 °C
Reaction time: 4 h

Procedure:
To a NMP solution (20 mL) of 5-bromo-2-nitropyridine (1.00 g, 4.93 mmol) were added trimethylsilyl acetylene (1.4 mL), tetrakis(triphenylphosphine)palladium(0) (110 mg), copper(I) iodide (38 mg), and N,N-diisopropylethylamine (1.7 mL) at room temperature, which was stirred under a nitrogen atmosphere for 4 hours at 65° C. Water was added at 0° C. to the reaction solution, which was then extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and filtered, after which the solvent was evaporated from the filtrate under a reduced pressure. The residue was purified by silica gel column chromatography (heptane:ethyl acetate=6:1) to obtain the titled compound (490 mg).
Reaction SMILES: [N:1]1([CH2:7][C:8]2[S:12][C:11]([C:13]3[O:14][C:15]4[CH:21]=[CH:20][C:19]([N+:22]([O-])=O)=[CH:18][C:16]=4[N:17]=3)=[CH:10][CH:9]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.O.C(=O)([O-])[O-].[Ca+2].[C:31](Cl)(Cl)=[S:32]>O1CCCC1.C(Cl)(Cl)Cl.[Pt]=O>[N:22]([C:19]1[CH:20]=[CH:21][C:15]2[O:14][C:13]([C:11]3[S:12][C:8]([CH2:7][N:1]4[CH2:6][CH2:5][O:4][CH2:3][CH2:2]4)=[CH:9][CH:10]=3)=[N:17][C:16]=2[CH:18]=1)=[C:31]=[S:32]
Reactant: O=[N+]([O-])c1ccc2oc(-c3ccc(CN4CCOCC4)s3)nc2c1
Reactant: S=C(Cl)Cl
Agent: O=[Pt]
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: C1CCOC1
Solvent: O
Solvent: ClC(Cl)Cl
Product: S=C=Nc1ccc2oc(-c3ccc(CN4CCOCC4)s3)nc2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 21.3 %

Procedure:
To a solution of 2-[5-(4-morpholinylmethyl)-2-thienyl]-5-nitrobenzoxazole (1.75 g, 0.005 mole) in 50 ml of tetrahydrofuran, 0.2 g of platinum oxide is added. The mixture is hydrogenated at 50 psi over a period of 3 hours. The catalyst is removed by filtration and the solvent is evaporated under vacuum yielding an oil. The oil is dissolved in 25 ml of chloroform and added slowly to the following mixture at 10° C: water 25 ml; calcium carbonate 1.2 g, 0.012 mole; thiophosgene 0.6 g, 0.005 mole; and chloroform 25 ml. The reaction mixture is then stirred overnight at room temperature. The chloroform layer is separated, dried over anhydrous magnesium sulfate and evaporated under vacuum yielding a solid. Crystallization from petroleum ether yields 0.380 g of the title compound, melting point 135°-138° C.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[CH:16][CH:15]=2)[O:11][CH2:10][C:9]1=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO>C1COCC1>[CH2:1]([N:8]1[CH2:9][CH2:10][O:11][CH:12]([C:14]2[CH:15]=[CH:16][C:17]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[CH:18][CH:19]=2)[CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCCCCCCOc1ccc(C2CN(Cc3ccccc3)C(=O)CO2)cc1
Solvent: CO
Solvent: C1CCOC1
Product: CCCCCCCCOc1ccc(C2CN(Cc3ccccc3)CCO2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.8 %

Procedure:
To a solution of 4-benzyl-6-(4-octyloxy-phenyl)-morpholin-3-one (22.22 g; 56.2 mmol) in THF (400 mL) was added borane-THF complex (1M, 140.4 mL; 140.4 mmol) dropwise, at 0° C. After 1 hour the mixture was allowed to warm to RT and stirred for another 2 hours. To the reaction mixture was added MeOH (30 mL), at 0° C., and the resulting mixture was stirred at RT for 30 minutes, and subsequently concentrated in vacuo. The residue was suspended in MeOH (300 mL.) and 1 M aqueous NaOH (112 mL) was added and heated under reflux for 1 hour. The resulting mixture was concentrated in vacuo and the residue was partitioned between EtOAc and 5% aqueous NaHCO3-solution. The organic layer was dried (Na2SO4), filtered, and concentrated in vacuo to afford 4-benzyl-2-(4-octyloxy-phenyl)-morpholine (20.33 g), which was used as such in the next step.
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([OH:28])=O)=[CH:24][C:23]=4[CH3:31])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.ON1C2C=CC=CC=2N=N1.F[P-](F)(F)(F)(F)F.CN(C(N(C)C)=[N+]1C2C=CC=CC=2[N+]([O-])=N1)C.C(N(C(C)C)CC)(C)C.[NH2:75][CH:76]1[CH2:81][CH2:80][N:79]([C:82]([O:84][C:85]([CH3:88])([CH3:87])[CH3:86])=[O:83])[CH2:78][CH2:77]1>CN(C)C=O>[C:85]([O:84][C:82]([N:79]1[CH2:80][CH2:81][CH:76]([NH:75][C:26](=[O:28])[C:25]2[CH:29]=[CH:30][C:22]([NH:21][C:19]3[N:18]=[CH:17][C:8]4[N:9]([CH3:16])[C:10](=[O:15])[C:11]([F:13])([F:14])[CH2:12][N:6]([CH:1]5[CH2:2][CH2:3][CH2:4][CH2:5]5)[C:7]=4[N:20]=3)=[C:23]([CH3:31])[CH:24]=2)[CH2:77][CH2:78]1)=[O:83])([CH3:88])([CH3:86])[CH3:87]
Reactant: Cc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Agent: CN(C)C(N(C)C)=[N+]1N=[N+]([O-])c2ccccc21
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(C(=O)NC2CCN(C(=O)OC(C)(C)C)CC2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Reaction time: 0.17 h
Yield: 90.5 %

Procedure:
To a mixture of 0.060 g (0.139 mmole) of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methyl-benzoic acid (I-184) and 8 mL of dimethylformamide was added 0.0282 g (0.209 mmole) of 1-hydroxybenzotriazole, 0.079 g (0.208 mmole) of 1-[bis(dimethylamino)methylene]-1H-benzotriazolium-3-oxide hexafluorophosphate and 0.072 g (0.555 mmole) of diisopropylethylamine. The mixture was stirred for 10 minutes, then 0.0417 g (0.208 mmole) of 4-amino-1-Boc-piperidine was added. The reaction mixture was stirred for 2 hours and then concentrated under reduced pressure. The residue was dissolved in 80 mL of ethyl acetate and washed three times with 10 mL of 1M sodium hydroxide, twice with 15 mL of brine, dried, filtered and concentrated under reduced pressure. Purification by silica gel chromatography, eluting with dichloromethane-methanol (gradient, 95:5-90:10) gave 0.0772 g of 4-[4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methyl-benzoylamino]-piperidine-1-carboxylic acid tert-butyl ester (I-191) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[C:10]([N:18]3[CH:22]=[C:21](I)[N:20]=[CH:19]3)[N:9]=2)=[CH:4][CH:3]=1.[N:24]1[CH:29]=[CH:28][CH:27]=[C:26](B(O)O)[CH:25]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[C:10]([N:18]3[CH:22]=[C:21]([C:26]4[CH:25]=[N:24][CH:29]=[CH:28][CH:27]=4)[N:20]=[CH:19]3)[N:9]=2)=[CH:4][CH:3]=1
Reactant: OB(O)c1cccnc1
Reactant: FC(F)(F)c1cc(-c2ccc(Cl)cc2)nc(-n2cnc(I)c2)c1
Product: FC(F)(F)c1cc(-c2ccc(Cl)cc2)nc(-n2cnc(-c3cccnc3)c2)c1

Procedure:
The title compound was prepared from 2-(4-chloro-phenyl)-6-(4-iodo-imidazol-1-yl)-4-trifluoromethyl-pyridine (example E.19) (0.45 g, 1.0 mmol) and commercially available 3-pyridineboronic acid (0.32 g, 2.6 mmol) according to the general procedure VI. Obtained as a white solid (0.011 g, 3%). MS (ISP) 401.2 [(M+H)+] and 403 [(M+2+H)+].
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.F[C:13]1[CH:20]=[CH:19][C:16]([CH:17]=[O:18])=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[F:1][C:2]([F:10])([F:11])[C:3]1[CH:4]=[CH:5][C:6]([O:9][C:13]2[CH:20]=[CH:19][C:16]([CH:17]=[O:18])=[CH:15][CH:14]=2)=[CH:7][CH:8]=1
Reactant: Oc1ccc(C(F)(F)F)cc1
Reactant: O=Cc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=Cc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1
Temperature: 150 °C
Reaction time: 3 h

Procedure:
A mixture of 4-(trifluoromethyl)phenol (4.86 g, 1 equiv), 4-fluorobenzaldehyde (3.22 mL, 1 equiv), potassium carbonate (4.15 g, 1 equiv) and dimethylformamide (60 mL) was stirred at 150° C. under argon for 3 hours, then poured into ice/water. The precipitate was filtered off, washed with water, then extracted with hot ethanol. Undissolved solid was removed by filtration, and the filtrate evaporated and purified by chromatography on silica. 1H-NMR (CDCl3) δ 7.14 (4H,m), 7.66 (2H,m), 7.90 (2H,m), 9.97 (1H,s); MS (APCI+) found (M+1)=267; C14H9F3O2 requires 266.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][CH:4]=1)#[CH:2].O>C(OCC)(=O)C>[CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][CH:4]=1)[CH3:2]
Reactant: C#Cc1ccc(OC)cc1
Solvent: O
Solvent: CCOC(C)=O
Product: CCc1ccc(OC)cc1
Reaction time: 0.5 h
Yield: 70 %

Procedure:
64.8 μL (0.50 mmol) of 4-ethynyl-1-methoxybenzene (12), 270 μL (15 mmol) of distilled water and stainless steel balls (50 pieces) were placed in the vessel of the planetary ball mill, which was then closed, and agitated by operating the planetary ball mill for 12 hours at 800 rpm (reversed every 30 minutes). After the lapse of 12 hours, 10 mL of ethyl acetate was added to the vessel of the ball mill to provide a solution containing the reaction mixture, which was then filtered with celite. The operation was repeated 5 times to provide a filtrate, which was then concentrated, thereby providing 47.0 mg (0.35 mmol) of 4-ethyl-1-methoxybenzene (13). The yield was 69%. The reaction is expressed by the following scheme.