Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH:9]([NH:15][C@@H:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH3:17])[CH2:8][CH2:7][CH2:6][C:5]2=1.[ClH:24]>CO>[ClH:24].[CH3:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[C@H:9]([NH:15][C@@H:16]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH3:17])[CH2:8][CH2:7][CH2:6][C:5]2=1
Reactant: Cc1ccc2[nH]c3c(c2c1)CCCC3N[C@H](C)c1ccccc1
Agent: Cl
Solvent: CO
Product: Cc1ccc2[nH]c3c(c2c1)CCC[C@H]3N[C@H](C)c1ccccc1

Procedure:
(1R)-6-Methyl-N-[(1R)-1-phenylethyl]-2,3,4,9-tetrahydro-1H-carbazol-1-amine hydrochloride salt was prepared by separation of diastereomeric 6-methyl-N-[(1R)-1-phenylethyl]-2,3,4,9-tetrahydro-1H-carbazol-1-amine the free base by SFC (Berger Amino, 8% methanol, 1500 psi, 40° C., 2 mL/min, retention time: 8.7 min.) The oil obtained was converted to the HCl salt to give a white solid. [α]25=153 (c 0.23, MeOH); 1H-NMR (CD3OD): δ 7.63 (d, J=7.6 Hz, 2H), 7.55-7.46 (m, 3H), 7.29 (d, J=8.0 Hz, 1H), 7.27 (s, 1H), 7.02 (d, J=8.4 Hz, 1H), 4.75 (q, J=7.2 Hz, 1H), 4.43 (m, 1H), 2.85 (dt, J=16.4 Hz, J=4.0 Hz, 1H), 2.67 (dt, J=16.4 Hz, J=4.0 Hz, 1H), 2.40 (s, 3H), 2.11-1.96 (m, 4H), 1.71 (d, J=7.2 Hz, 3H); MS m/z 184 (M−121); Anal. Calcd. For C21H25BrN2Cl: C, 73.99; H, 7.39; N, 8.22. Found: C, 73.85; H, 7.38; N, 8.23.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([NH:7]C=O)=[N:4][C:3]=1/[C:10](=[N:65]/[O:66][CH:67]1[CH2:71][CH2:70][CH:69]=[CH:68]1)/[C:11]([NH:13][C@@H:14]1[C:63](=[O:64])[N:16]2[C:17]([C:47]([O:49][CH:50]([C:57]3[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=3)[C:51]3[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=3)=[O:48])=[C:18]([S:21][CH2:22][C:23]3[CH:24]=[N:25][N:26](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[CH:27]=3)[CH2:19][S:20][C@H:15]12)=[O:12].CO.Cl>O1CCCC1>[NH2:7][C:5]1[S:6][C:2]([Cl:1])=[C:3](/[C:10](=[N:65]/[O:66][CH:67]2[CH2:71][CH2:70][CH:69]=[CH:68]2)/[C:11]([NH:13][C@@H:14]2[C:63](=[O:64])[N:16]3[C:17]([C:47]([O:49][CH:50]([C:57]4[CH:58]=[CH:59][CH:60]=[CH:61][CH:62]=4)[C:51]4[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=4)=[O:48])=[C:18]([S:21][CH2:22][C:23]4[CH:27]=[N:26][NH:25][CH:24]=4)[CH2:19][S:20][C@H:15]23)=[O:12])[N:4]=1
Reactant: O=CNc1nc(/C(=N/OC2C=CCC2)C(=O)N[C@@H]2C(=O)N3C(C(=O)OC(c4ccccc4)c4ccccc4)=C(SCc4cnn(C(c5ccccc5)(c5ccccc5)c5ccccc5)c4)CS[C@H]23)c(Cl)s1
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Product: Nc1nc(/C(=N/OC2C=CCC2)C(=O)N[C@@H]2C(=O)N3C(C(=O)OC(c4ccccc4)c4ccccc4)=C(SCc4cn[nH]c4)CS[C@H]23)c(Cl)s1
Reaction time: 3 h
Yield: 63.1 %

Procedure:
To a stirred mixture of solution of diphenylmethyl 7β-[2-(5-chloro-2-formylaminothiazol-4-yl)-2-(Z)-(2-cyclopenten-1-yloxyimino)acetamido]-3-[(1-tritylpyrazol-4-yl)methylthio]-3-cephem-4-carboxylate (3.82 g) in the mixture of methanol (40 ml) and tetrahydrofurane (12 ml) was added dropwise conc. hydrochloric acid (i.56 ml) at room temperature. After the mixture was stirred for 3 hours, the solvent was evaporated in vacuo. The residue was diluted with the mixture of water and ethyl acetate while the pH was adjusted between 8.0 and 8.5 with saturated sodium hydrogen carbonate. The organic layer was collected, washed with water and brine and dried over magnesium sulfate. After evaporation of the solvent, the residue was purified on silica gel (eluent: dichloromethane-acetone) to afford diphenylmethyl 7β-[2-(2-amino-5-chlorothiazol-4-yl)-2-(Z)-(2-cyclopenten-1-yloxyimino)acetamido]-3-[(pyrazol-4-yl)methylthio]-3-cephem-4-carboxylate (1.77 g).
Reaction SMILES: [SH:1][CH2:2][CH2:3][OH:4].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O.[C:16]([N:19]1[CH2:23][CH2:22][CH2:21][CH:20]1[C:24]1[C:25]([O:39][C:40]2[CH:41]=[N:42][C:43](Cl)=[CH:44][CH:45]=2)=[CH:26][C:27]2[N:31]=[C:30]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=3)[NH:29][C:28]=2[CH:38]=1)(=[O:18])[CH3:17]>C(=O)(O)[O-].[Na+]>[C:16]([N:19]1[CH2:23][CH2:22][CH2:21][CH:20]1[C:24]1[C:25]([O:39][C:40]2[CH:45]=[CH:44][C:43]([S:1][CH2:2][CH2:3][OH:4])=[N:42][CH:41]=2)=[CH:26][C:27]2[N:31]=[C:30]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=3)[NH:29][C:28]=2[CH:38]=1)(=[O:18])[CH3:17]
Reactant: CC(=O)N1CCCC1c1cc2[nH]c(-c3ccccn3)nc2cc1Oc1ccc(Cl)nc1
Reactant: OCCS
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)N1CCCC1c1cc2[nH]c(-c3ccccn3)nc2cc1Oc1ccc(SCCO)nc1
Temperature: 120 °C
Reaction time: 5 h

Procedure:
20 mg of 2-mercaptoethanol and 10 mg of potassium carbonate were added in order to an N,N-dimethylformamide (1 ml) solution of 20 mg of 6-(1-acetylpyrrolidin-2-yl)-5-(6-chloropyridin-3-yl)oxy-2-pyridin-2-yl-1H-benzimidazole obtained in Example 504, and the reaction liquid was stirred at 120° C. for 5 hours. After cooled, the reaction liquid was diluted with aqueous saturated sodium bicarbonate, extracted with chloroform, and the organic layer was dried with anhydrous magnesium sulfate, and the solvent was evaporated away under reduced pressure. The resulting residue was purified through partitioning thin-layer chromatography (Kieselgel™ 60F254, Art 5744 (by Merck), chloroform/methanol=10/1) to obtain the entitled compound as a white solid.
Reaction SMILES: [NH:1]([C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24])[C@H:2]([C:13]([NH:15][C@H:16]([C:19]([O:21]C)=[O:20])[CH2:17][OH:18])=[O:14])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.CC1C(C2(C3C(C)=CC(O)=C(C(C)C)C=3)OC(=O)C3C2=CC=CC=3)=CC(C(C)C)=C(O)C=1.[OH-].[Na+]>O1CCOCC1.O>[NH:1]([C:23]([O:25][CH2:26][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)=[O:24])[C@H:2]([C:13]([NH:15][C@H:16]([C:19]([OH:21])=[O:20])[CH2:17][OH:18])=[O:14])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1
Reactant: COC(=O)[C@H](CO)NC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)OCc1ccccc1
Agent: Cc1cc(O)c(C(C)C)cc1C1(c2cc(C(C)C)c(O)cc2C)OC(=O)c2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: O=C(N[C@@H](Cc1c[nH]c2ccccc12)C(=O)N[C@@H](CO)C(=O)O)OCc1ccccc1

Procedure:
4.4 g (10 mmols) of Z-Trp-Ser-OMe were dissolved in 30 ml of dioxane/water (4:1) and mixed with a spatula tip of thymolphthaleine. The mixture was titrated, while stirring, with 1N NaOH until a constant blue color was obtained. 10 ml were consumed. 10 ml of 1N hydrochloric acid were added and the reaction mixture was evaporated. The residue was distributed between ethyl acetate and water. The ethyl acetate phase was dried with Na2SO4 and concentrated. The residue was triturated with petroleum ether. Yield: 3.2 g (75%). It was recrystallized from ethyl acetate/petroleum ether. Yield: 3 g (70%), melting point: 148° C.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[OH:24][C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][CH:33]=1)[NH:30][CH:29]=[CH:28]2>>[NH:30]1[C:31]2[C:27](=[CH:26][C:25]([O:24][C:2]3[C:11]4[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]5[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]5)=[C:9]([O:12][CH3:13])[CH:10]=4)[N:5]=[CH:4][N:3]=3)=[CH:33][CH:32]=2)[CH:28]=[CH:29]1
Reactant: COc1cc2c(Cl)ncnc2cc1OCCCN1CCCCC1
Reactant: Oc1ccc2[nH]ccc2c1
Product: COc1cc2c(Oc3ccc4[nH]ccc4c3)ncnc2cc1OCCCN1CCCCC1
Yield: 44.3 %

Procedure:
Using an analogous procedure to that described in Example 67, 4-chloro-6-methoxy-7-(3-piperidinopropoxy)quinazoline (100 mg), (prepared as described for the starting material in Example 67), was reacted with 5-hydroxyindole (48 mg, 0.36 mmol) to give 4-(indol-5-yloxy)-6-methoxy-7-(3-piperidinopropoxy)quinazoline (57 mg, 45%).
Reaction SMILES: S(Cl)([Cl:3])=O.[NH:5]1[CH:9]([C:10](O)=[O:11])[CH2:8][CH2:7][C:6]1=[O:13]>C(OCC)C>[NH:5]1[CH:9]([C:10]([Cl:3])=[O:11])[CH2:8][CH2:7][C:6]1=[O:13]
Reactant: O=S(Cl)Cl
Reactant: O=C1CCC(C(=O)O)N1
Solvent: CCOCC
Product: O=C1CCC(C(=O)Cl)N1
Reaction time: 8 h

Procedure:
To 90 ml of thionyl chloride was added dropwise 23.5 g of 2-pyrrolidone-5-carboxylic acid with stirring under ice-cooling, and the mixture was stirred for 30 minutes at 40°-50° C. After cooling of the reaction mixture, 200 ml of dry diethyl ether was added to the reaction mixture, and the reaction mixture was allowed to stand overnight in a freezing box. Precipitated crystals were collected by filtration, washed with dry diethyl ether, and dried in a desiccator to obtain 27 g of 2-pyrrolidone-5-carbonyl chloride. The obtained acid chloride was dissolved in 500 ml of dry chloroform, and to the solution were added 13.5 g of 2-pyridylmethanol with stirring at room temperature, and then the reaction mixture was heated under refluxing. After completion of the reaction, to the reaction mixture was added an aqueous sodium bicarbonate solution to make the solution basic at pH 9, and the reaction mixture was extracted with chloroform. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was recrystallized from benzene to obtain 16.2 g of 2-pyridylmethyl 2-pyrrolidone-5-carboxylate. (yield 60.0%)
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.CCCCCC.C([Li])CCC.[B:21](OC(C)C)([O:26]C(C)C)[O:22]C(C)C>O1CCCC1>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([B:21]([OH:26])[OH:22])=[CH:3][CH:4]=1
Reactant: COc1ccc(Br)cc1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COc1ccc(B(O)O)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 4-bromoanisole (2 g) in tetrahydrofuran (THF, 32 ml), which was cooled to -78° C., was added a hexane solution of n-butyllithium (0.83 M, 13.5 ml). The solution was stirred 15 minutes, at which time triisopropyl borate (8.6 ml) was added. The solution was stirred for 15 minutes, at which time the solution was allowed to warm to room temperature. Stirring was continued for 12 hrs. The solution was then washed into a hydrochloric acid solution (1M, 60 ml) with a small amount of THF. This solution was stirred an additional 2 hours, and was then extracted with ethyl acetate. The combined organic layers were washed with brine and dried over sodium sulfate, and the solvent was removed in vacuo to yield a white solid.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([O:9][CH3:10])[C:6]([F:11])=[CH:5][C:4]=1[C:12]1[CH:20]=[C:19]2[C:15]([C:16]([Sn](C)(C)C)=[N:17][N:18]2[CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][O:22]2)=[CH:14][CH:13]=1)[CH3:2].[C:31]([O:35][C:36]([N:38]1[CH2:44][CH2:43][C:42]2[N:45]=[C:46](I)[N:47]([CH2:48][O:49][CH2:50][CH2:51][Si:52]([CH3:55])([CH3:54])[CH3:53])[C:41]=2[CH2:40][CH2:39]1)=[O:37])([CH3:34])([CH3:33])[CH3:32]>C1(C)C=CC=CC=1.[Cu]I.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:31]([O:35][C:36]([N:38]1[CH2:44][CH2:43][C:42]2[N:45]=[C:46]([C:16]3[C:15]4[C:19](=[CH:20][C:12]([C:4]5[CH:5]=[C:6]([F:11])[C:7]([O:9][CH3:10])=[CH:8][C:3]=5[CH2:1][CH3:2])=[CH:13][CH:14]=4)[N:18]([CH:21]4[CH2:26][CH2:25][CH2:24][CH2:23][O:22]4)[N:17]=3)[N:47]([CH2:48][O:49][CH2:50][CH2:51][Si:52]([CH3:55])([CH3:54])[CH3:53])[C:41]=2[CH2:40][CH2:39]1)=[O:37])([CH3:34])([CH3:33])[CH3:32]
Reactant: CC(C)(C)OC(=O)N1CCc2nc(I)n(COCC[Si](C)(C)C)c2CC1
Reactant: CCc1cc(OC)c(F)cc1-c1ccc2c([Sn](C)(C)C)nn(C3CCCCO3)c2c1
Agent: [Cu]I
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CCc1cc(OC)c(F)cc1-c1ccc2c(-c3nc4c(n3COCC[Si](C)(C)C)CCN(C(=O)OC(C)(C)C)CC4)nn(C3CCCCO3)c2c1
Temperature: 100 °C
Yield: 57.5 %

Procedure:
To a solution of 6-(2-ethyl-5-fluoro-4-methoxy-phenyl)-1-(tetrahydro-pyran-2-yl)-3-trimethylstannanyl-1H-indazole (Preparation 18, 735 mg, 1.53 mmol) in toluene (6 mL) was added 2-iodo-1-(2-trimethylsilanyl-ethoxymethyl)-4,5,7,8-tetrahydro-1H-imidazo[4,5-d]azepine-6-carboxylic acid tert-butyl ester (Preparation 29, 829 mg, 1.68 mmol), copper (I) iodide (60 mg, 310 μmol) and tetrakis(triphenylphosphine) palladium(0) (173 mg, 150 μmol). The reaction mixture was degassed with nitrogen, heated at 100° C. for 18 hours, cooled to room temperature and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with 20% EtOAc in toluene to give the title compound as a foam (633 mg) in a 57% yield.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][CH2:5][N:4]([C@H:7]2[CH2:12][CH2:11][C@@H:10]([N:13]([C:15]([CH3:18])([CH3:17])[CH3:16])[CH3:14])[CH2:9][C@H:8]2[C:19]([O:21][CH3:22])=[O:20])[C:3]1=[O:23].[F:24][C:25]([F:36])([F:35])[C:26]1[CH:27]=[C:28]([CH:32]=[CH:33][CH:34]=1)[C:29](O)=[O:30].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(CC)CC>C(Cl)Cl>[C:15]([N:13]([CH3:14])[C@H:10]1[CH2:9][C@@H:8]([C:19]([O:21][CH3:22])=[O:20])[C@@H:7]([N:4]2[CH2:5][CH2:6][C@H:2]([NH:1][C:29](=[O:30])[C:28]3[CH:32]=[CH:33][CH:34]=[C:26]([C:25]([F:24])([F:35])[F:36])[CH:27]=3)[C:3]2=[O:23])[CH2:12][CH2:11]1)([CH3:18])([CH3:17])[CH3:16]
Reactant: O=C(O)c1cccc(C(F)(F)F)c1
Reactant: COC(=O)[C@@H]1C[C@H](N(C)C(C)(C)C)CC[C@@H]1N1CC[C@H](N)C1=O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)[C@@H]1C[C@H](N(C)C(C)(C)C)CC[C@@H]1N1CC[C@H](NC(=O)c2cccc(C(F)(F)F)c2)C1=O
Yield: 38 %

Procedure:
A solution of (1R,2S,5R)-methyl 2-((S)-3-amino-2-oxopyrrolidin-1-yl)-5-(tert-butyl(methyl) amino)-cyclohexanecarboxylate (58 mg, 0.18 mmol), 3-(trifluoromethyl)benzoic acid (42 mg, 0.22 mol), EDCI (30 mg, 0.21 mmol), HOBT (30 mg, 0.21 mmol), and Et3N (21 mg 0.21 mmol) in CH2Cl2 was stirred overnight at room temperature. The solution was washed with water and brine, concentrated in vacuo and the residue chromatographed on silica gel (3%-5%-10% (NH4OH/MeOH)/CH2Cl2) to give 34 mg of the title product, (1R,2S,5R)-methyl 5-(tert-butyl(methyl)amino)-2-((S)-2-oxo-3-(3-(trifluoromethyl)-benzamido)pyrrolidin-1-yl)cyclohexanecarboxylate, as a white solid. MS found: (M+H)+=498.40.
Reaction SMILES: C([O:3][C:4](=[O:35])[C@H:5]([OH:34])[CH2:6][C@H:7]([NH:23][C:24]([C:26]1[CH:30]=[C:29]([C:31](=[O:33])[CH3:32])[NH:28][N:27]=1)=[O:25])[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:16]=2[F:22])=[CH:11][CH:10]=1)C.[Li+].[OH-].O.CCO>>[C:31]([C:29]1[NH:28][N:27]=[C:26]([C:24]([NH:23][C@H:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:16]=3[F:22])=[CH:11][CH:10]=2)[CH2:6][C@@H:5]([OH:34])[C:4]([OH:35])=[O:3])=[O:25])[CH:30]=1)(=[O:33])[CH3:32]
Reactant: CCOC(=O)[C@H](O)C[C@@H](Cc1ccc(-c2cc(Cl)ccc2F)cc1)NC(=O)c1cc(C(C)=O)[nH]n1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(=O)c1cc(C(=O)N[C@H](Cc2ccc(-c3cc(Cl)ccc3F)cc2)C[C@@H](O)C(=O)O)n[nH]1
Yield: 16.3 %

Procedure:
(2R,4R)-4-[(5-Acetyl-1H-pyrazole-3-carbonyl)amino]-5-(5′-chloro-2′-fluorobiphenyl-4-yl)-2-hydroxypentanoic acid ethyl ester (75 mg, 150 μmol) was stirred at room temperature with LiOH (10.8 mg, 450 μmol) in water (450 μL, 25 mmol) and EtOH (450 μL, 7.7 mmol), overnight. The solvent was removed and the remaining material was purified by preparative HPLC to yield the title compound (11.6 mg) as a TFA salt.
Reaction SMILES: [CH:1]([N:3]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH2:4][C:5](O)=O)=O.[C:14]([O:18][CH2:19][CH3:20])(=[O:17])[C:15]#C.C(OC(=O)C)(=O)C>>[C:8]1([N:3]2[CH:4]=[CH:5][C:15]([C:14]([O:18][CH2:19][CH3:20])=[O:17])=[CH:1]2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=CN(CC(=O)O)c1ccccc1
Reactant: C#CC(=O)OCC
Solvent: CC(=O)OC(C)=O
Product: CCOC(=O)c1ccn(-c2ccccc2)c1
Yield: 89.6 %

Procedure:
From 2.69 g (15 mmol) of N-formyl-N-phenylglycine, 5.47 g (55.8 mmol) of ethyl propiolate and 15 ml of acetic anhydride, 2.894 g of the title compound were obtained in a similar manner as in Referential Example 3 (yield: 89.6%).
Reaction SMILES: [C:1]([N:5]1[CH2:10][CH2:9][C:8]([CH2:17][NH2:18])([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[F:19]C1C=CC=CC=1CC#N>>[C:1]([N:5]1[CH2:6][CH2:7][C:8]([CH2:17][NH2:18])([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[F:19])[CH2:9][CH2:10]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)N1CCC(CN)(c2ccccc2)CC1
Reactant: N#CCc1ccccc1F
Product: CC(C)(C)N1CCC(CN)(c2ccccc2F)CC1

Procedure:
The title material was prepared as described in the synthesis of (1-tert-butyl-4-phenylpiperidin-4-yl)methanamine (Synthesis of amines, Example H) using 2-(2-fluorophenyl)acetonitrile.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH:12]([C:14]3[C:15]([CH3:21])=[N:16][C:17]([CH3:20])=[CH:18][CH:19]=3)[OH:13])[CH:10]=2)[N:5]=[C:4]([O:22][CH3:23])[C:3]=1[CH2:24][C:25]1[CH:26]=[N:27][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:29][CH:30]=1.N#N>O=[Mn]=O.O1CCOCC1>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([C:14]3[C:15]([CH3:21])=[N:16][C:17]([CH3:20])=[CH:18][CH:19]=3)=[O:13])[CH:10]=2)[N:5]=[C:4]([O:22][CH3:23])[C:3]=1[CH2:24][C:25]1[CH:26]=[N:27][C:28]([C:31]([F:33])([F:32])[F:34])=[CH:29][CH:30]=1
Reactant: COc1nc2ccc(C(O)c3ccc(C)nc3C)cc2c(Cl)c1Cc1ccc(C(F)(F)F)nc1
Agent: O=[Mn]=O
Agent: N#N
Solvent: C1COCCO1
Product: COc1nc2ccc(C(=O)c3ccc(C)nc3C)cc2c(Cl)c1Cc1ccc(C(F)(F)F)nc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
(4-Chloro-2-methoxy-3-((6-(trifluoromethyl)pyridin-3-yl)methyl)quinolin-6-yl)(2,6-dimethylpyridin-3-yl)methanol (810 mg, 1.66 mmol, Intermediate 47: step a), 1,4-dioxane (8.5 mL) and activated MnO2 (724.4 mg, 8.332 mmol) were combined in a round-bottom flask and the mixture was heated to reflux under a positive pressure of N2. After 4 hours, the reaction was cooled to room temperature and filtered through Celite®, rinsing with dichloromethane. The filtrate was washed with water, and the aqueous layer was extracted with additional dichloromethane. The combined organic layers were dried (Na2SO4), filtered, and concentrated to dryness to provide the title compound which was used without further purification.
Reaction SMILES: ClC(Cl)(Cl)[C:3]([C:5]1[N:14]2[C:8]([CH2:9][N:10]([C:19]([C:21]3[CH:26]=[CH:25][C:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[O:33][CH3:34])=[C:23]([CH3:35])[CH:22]=3)=[O:20])[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH2:13]2)=[CH:7][CH:6]=1)=[O:4].[OH-].[Na+].Cl.C([O:43]CC)C.CCCCCC>CC(C)=O>[CH3:34][O:33][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=1[C:24]1[CH:25]=[CH:26][C:21]([C:19]([N:10]2[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH2:13][N:14]3[C:5]([C:3]([OH:43])=[O:4])=[CH:6][CH:7]=[C:8]3[CH2:9]2)=[O:20])=[CH:22][C:23]=1[CH3:35]
Reactant: CCOCC
Reactant: COc1ccccc1-c1ccc(C(=O)N2Cc3ccc(C(=O)C(Cl)(Cl)Cl)n3Cc3ccccc32)cc1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: CCCCCC
Product: COc1ccccc1-c1ccc(C(=O)N2Cc3ccc(C(=O)O)n3Cc3ccccc32)cc1C
Reaction time: 8 h

Procedure:
To a solution of 2,2,2-trichloro-1-{10-[(2′-methoxy-2-methyl-[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl} ethanone of Step D (2.0 g, 3.6 mmol) in acetone (20 mL) was added 2.5 N sodium hydroxide (2.9 mL, 7.25 mmol). After stirring overnight, the reaction mixture was acidified with 2 N hydrochloric acid (4.0 mL, 8.0 mmol) then concentrated in vacuo. The residue was partitioned between ethyl acetate and water. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give a brown solid. Trituration with diethyl ether-hexane provided 1.4 g of the desired product as a white solid, m.p. 174-184° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:13]([OH:15])=[O:14])=[C:6]2[C:11]=1[S:10](=O)[CH2:9][CH2:8][NH:7]2.C(OCC)(=O)C>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:13]([OH:15])=[O:14])=[C:6]2[C:11]=1[S:10][CH2:9][CH2:8][NH:7]2
Reactant: O=C(O)c1ccc(Cl)c2c1NCCS2=O
Solvent: CO
Solvent: CCOC(C)=O
Product: O=C(O)c1ccc(Cl)c2c1NCCS2
Yield: 19.3 %

Procedure:
A mixture of 8-chloro-3,4-dihydro-2H-1,4-benzothiazine-5-carboxylic acid-1-oxide (2.5 g) and stannous chloride dihydrate (4.51 g) in methanol (20 ml) was refluxed for 21 hours. To the reaction mixture was added ethyl acetate (200 ml), washed with water and dried over anhydrous sodium sulfate. After concentrated under reduced pressure, the resulting residue was purified by silica gel column chromatography eluting with dichloromethaneethanol (9:1) to give the title compound (450 mg, 19.6%). This compound was recrystallized from ethanol to give yellow needles, mp 220° C.
Reaction SMILES: [Br:1][C:2]1[CH:15]=[C:14]([CH3:16])[C:5]([O:6][CH:7]([CH3:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:4]([CH3:17])[CH:3]=1.BrC1C=C(C)C(O)=C(C)C=1.[N+:28]([O-])([OH:30])=[O:29]>S(=O)(=O)(O)O.O>[Br:1][C:2]1[CH:15]=[C:14]([CH3:16])[C:5]([O:6][CH:7]([CH3:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:4]([CH3:17])[C:3]=1[N+:28]([O-:30])=[O:29]
Reactant: O=[N+]([O-])O
Reactant: CCOC(=O)C(C)Oc1c(C)cc(Br)cc1C
Agent: Cc1cc(Br)cc(C)c1O
Agent: O=S(=O)(O)O
Solvent: O
Product: CCOC(=O)C(C)Oc1c(C)cc(Br)c([N+](=O)[O-])c1C

Procedure:
Ethyl 2-(4-bromo-2,6-dimethylphenoxy)propanoate (92.8 g, 307 mmole), prepared by the method of Example 1 from 4-bromo-2,6-dimethylphenol, was dissolved in 320 ml of cold (-10°) concentrated sulfuric acid. While maintaining the temperature below 0°, 22.4 ml of 70% nitric acid was added slowly. After fifteen minutes the reaction mixture was poured onto ice and diluted to 1.0 l with water, then extracted with two portions of diethyl ether. The organic portion was washed repeatedly with aqueous sodium bicarbonate and then with water. The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo to dryness. Chromatography on silica gel (ethyl acetate-hexane eluent) afforded the title compound. Structure assignment was supported by nmr and infrared spectra.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][N:3]=1.[NH2:11][C:12]1[CH:13]=[CH:14][C:15]([O:18][CH3:19])=[N:16][CH:17]=1>>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([C:6]([NH:11][C:12]2[CH:13]=[CH:14][C:15]([O:18][CH3:19])=[N:16][CH:17]=2)=[O:7])=[CH:9][CH:10]=1
Reactant: O=C(Cl)c1ccc(Cl)nc1
Reactant: COc1ccc(N)cn1
Product: COc1ccc(NC(=O)c2ccc(Cl)nc2)cn1

Procedure:
The title compound was prepared from 6-chloronicotinoyl chloride and 5-amino-2-methoxypyridine as a pink solid as described in Example 1. 1H NMR (CDCl3): 8.87 (d, J=2.1, 1H), 8.28 (d, J=3.0, 1H), 8.20-8.17 (m, 1H), 7.99-7.96 (m, 1H), 7.67 (s, 1H), 7.49 (d, J=8.7, 1H), 6.81 (d, J=8.7, 1H), 3.95 (s, 3H).
Reaction SMILES: C[O:2][C:3]([C:5]1[S:9][C:8]([N:10]2[C:14]3[CH:15]=[C:16]([O:21][CH3:22])[C:17]([O:19][CH3:20])=[CH:18][C:13]=3[N:12]=[CH:11]2)=[N:7][C:6]=1Br)=[O:4].[CH3:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1B(O)O>>[CH3:20][O:19][C:17]1[C:16]([O:21][CH3:22])=[CH:15][C:14]2[N:10]([C:8]3[S:9][C:5]([C:3]([OH:2])=[O:4])=[C:6]([C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=4[CH3:24])[N:7]=3)[CH:11]=[N:12][C:13]=2[CH:18]=1
Reactant: COC(=O)c1sc(-n2cnc3cc(OC)c(OC)cc32)nc1Br
Reactant: Cc1ccccc1B(O)O
Product: COc1cc2ncn(-c3nc(-c4ccccc4C)c(C(=O)O)s3)c2cc1OC
Yield: 56.9 %

Procedure:
In a similar manner as described for Example 26, 4-bromo-2-(5,6-dimethoxy-benzoimidazol-1-yl)-thiazole-5-carboxylic acid methyl ester (40 mg, 0.1 mmol) and 2-methylphenylboronic acid (20.4 mg, 0.15 mmol) gave 2-(5,6-Dimethoxy-benzoimidazol-1-yl)-4-o-tolyl-thiazole-5-carboxylic acid (22.5 mg, 57%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 13.43 (br.s., 1 H); 8.82 (s, 1 H); 7.68 (s, 1 H); 7.41 (d, 1 H); 7.40 (s, 1 H); 7.31-7.39 (m, 2 H); 7.27 (td, 1 H); 3.85 (s, 3 H); 3.81 (s, 3 H); 2.29 (s, 3 H). MS m/z 396 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([CH3:13])([CH3:12])[CH:10]=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:14][CH:15]([SiH3])[CH:16]=C(C)C>C(Cl)Cl.Cl[Ti](Cl)(Cl)Cl>[C:1]([O:5][C:6]([NH:8][C:9]([CH3:13])([CH3:12])[CH:10]([OH:11])[CH2:16][CH:15]=[CH2:14])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C=O)NC(=O)OC(C)(C)C
Reactant: CC(C)=CC(C)[SiH3]
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: C=CCC(O)C(C)(C)NC(=O)OC(C)(C)C
Reaction time: 0.17 h

Procedure:
To a solution of the product of step b (20 mmol, 3.74 g) in 20 ml of CH2Cl2 at -78° C., 22 ml of a solution 1 M of TiCl4 in CH2Cl2 is added. After 10 min, trimethyallylsilane (22 mmol, 3.5 ml) in 20 ml of CH2Cl2 is added. After one hour the reaction is quenched with water. The organic layer is separated and extracted with CH2Cl2 (3×25 ml). The solution is anhydrified (Na2SO4) and after concentration 1.14 g of product is obtained.