Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N1C=CC=CC=1.[F:7][C:8]1[CH:17]=[C:16]2[C:11]([C@:12]([NH:21][C:22]([NH:24][C:25](=[O:32])[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[S:23])([CH3:20])[C@@H:13]([CH2:18]O)[CH2:14][O:15]2)=[CH:10][CH:9]=1.S(OS(C(F)(F)F)(=O)=O)(C(F)(F)F)(=O)=O.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C.C(Cl)Cl>[F:7][C:8]1[CH:9]=[CH:10][C:11]2[C@@:12]3([CH3:20])[N:21]=[C:22]([NH:24][C:25](=[O:32])[C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[S:23][CH2:18][C@H:13]3[CH2:14][O:15][C:16]=2[CH:17]=1
Reactant: C[C@@]1(NC(=S)NC(=O)c2ccccc2)c2ccc(F)cc2OC[C@@H]1CO
Agent: O=C([O-])O
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: C[C@]12N=C(NC(=O)c3ccccc3)SC[C@H]1COc1cc(F)ccc12
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
DCM (40 mL) and pyridine (0.539 mL, 6.67 mmol) were added to rel-N-(((3S,4S)-7-fluoro-3-(hydroxymethyl)-4-methylchroman-4-yl)carbamothioyl)benzamide from step F4 (832 mg, 2.22 mmol), under an atmosphere of dry nitrogen. The mixture was cooled to −78° C. Triflic anhydride (0.751 mL, 4.44 mmol) was slowly added to the reaction solution over 10 min. The resulting mixture was stirred for 15 min and then further stirred for 1 h while warming to 0° C. After adding ethyl acetate, a saturated solution of sodium bicarbonate was added. The mixture was extracted with ethyl acetate, the combined organic extracts were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was dissolved in dichloromethane and one drop of water and one drop of TFA was added. The reaction was stirred for 15 min, then concentrated in vacuo to afford rel-N-((4aR,10bS)-8-fluoro-10b-methyl-4,4a,5,10b-tetrahydrochromeno[4,3-d][1,3]thiazin-2-yl)benzamide. The crude product was used for subsequent chemistry without further purification. LCMS (M+H)+=357.2.
Reaction SMILES: C(OC([C:6](=[C:11]([C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:7][C:8]([OH:10])=[O:9])=O)C.Br>C(O)(=O)C>[F:24][C:21]1[CH:20]=[CH:19][C:18]([C:11]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[CH:6][CH2:7][C:8]([OH:10])=[O:9])=[CH:23][CH:22]=1
Reactant: CCOC(=O)C(CC(=O)O)=C(c1ccccc1)c1ccc(F)cc1
Agent: Br
Solvent: CC(=O)O
Product: O=C(O)CC=C(c1ccccc1)c1ccc(F)cc1
Yield: 47 %

Procedure:
3-Ethoxycarbonyl-4-(4-fluorophenyl)-4-phenylbut-3-enoic acid (47 g., 0.143 mole) was added to a mixture of glacial acetic acid (1000 ml.) and 48% aqueous hydrobromic acid (500 ml.), and the resulting mixture stirred at reflux for 16 hours. The reaction mixture was then concentrated under vacuum and the concentrate extracted with ether (3×500 ml.). The combined ether extract was extracted with 4% aqueous ammonium hydroxide (5×200 ml.). The combined aqueous extract was acidified with 6N hydrochloric acid to a pH of 6.5 and extracted again with ether (3×250 ml.). The combined ether extract was dried (MgSO4), filtered and evaporated under vacuum to an oil, which solidified on standing. Trituration with hexane gave 15 g. of the named product (47% yield, m.p. 98°-100° C., elemental analysis calculated: 74.99% C; 5.11% H; 7.41% F; found: 74.69% C; 5.40% H; 7.17% F).
Reaction SMILES: O[CH:2]([C:4]1[N:15]([C@@H:16]2[CH2:21][O:20][C@@H:19]([CH2:22][C:23]#[N:24])[CH2:18][CH2:17]2)[C:7]2=[C:8]3[S:14][CH:13]=[CH:12][C:9]3=[N:10][CH:11]=[C:6]2[N:5]=1)[CH3:3].[CH2:25]([N:27](CC)CC)C.CS(Cl)(=O)=O.[Cl-].C[NH3+]>C(Cl)Cl>[CH3:25][NH:27][CH:2]([C:4]1[N:15]([C@@H:16]2[CH2:21][O:20][C@@H:19]([CH2:22][C:23]#[N:24])[CH2:18][CH2:17]2)[C:7]2=[C:8]3[S:14][CH:13]=[CH:12][C:9]3=[N:10][CH:11]=[C:6]2[N:5]=1)[CH3:3]
Reactant: CC(O)c1nc2cnc3ccsc3c2n1[C@H]1CC[C@H](CC#N)OC1
Reactant: CCN(CC)CC
Agent: CS(=O)(=O)Cl
Agent: C[NH3+]
Agent: [Cl-]
Solvent: ClCCl
Product: CNC(C)c1nc2cnc3ccsc3c2n1[C@H]1CC[C@H](CC#N)OC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 19.1 %

Procedure:
To a cooled mixture of {(2R,5S)-5-[2-(1-hydroxyethyl)-1H-imidazo[4,5-d]thieno[3,2-b]pyridin-1-yl]tetrahydro-2H-pyran-2-yl}acetonitrile (10.1 mg, 0.0295 mmol) and triethylamine (12 μL, 0.088 mmol) in methylene chloride (0.18 mL) was added methanesulfonyl chloride (2.7 μL, 0.035 mmol). The resulting mixture was allowed to warm to room temperature and stirred overnight. The mixture was diluted with dichloromethane and washed with water (2×). The layers were separated and the organic concentrated. To the concentrate was added methylene chloride (0.2 mL), triethylamine (18 μL), and methylammonium chloride (6.0 mg, 0.088 mmol). The resulting mixture was stirred at room temperature over the weekend (64 h) then heated to 40° C. for 3 h. The mixture was concentrated then purified using RP-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 30 mL/min) to give 2 mg (19%) of the desired product. LCMS calculated for C18H22N5OS (M+H)+: m/z=356.2. Found: 356.1.
Reaction SMILES: [F:1][C:2]([F:45])([F:44])[C:3]1[CH:4]=[C:5]([CH:37]=[C:38]([C:40]([F:43])([F:42])[F:41])[CH:39]=1)[CH2:6][N:7]([CH2:23][C:24]1[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[CH:26][C:25]=1[NH:34][CH2:35][CH3:36])[C:8]1[N:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:10][N:9]=1.[CH2:46]([N:48]([CH2:51]C)CC)[CH3:47].ClC(Cl)([O:56]C(=O)OC(Cl)(Cl)Cl)Cl>C(Cl)Cl>[F:43][C:40]([F:41])([F:42])[C:38]1[CH:37]=[C:5]([CH:4]=[C:3]([C:2]([F:1])([F:44])[F:45])[CH:39]=1)[CH2:6][N:7]([CH2:23][C:24]1[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[CH:26][C:25]=1[N:34]([CH2:35][CH3:36])[C:51]([NH:48][CH2:46][CH3:47])=[O:56])[C:8]1[N:9]=[CH:10][C:11]([O:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:12][N:13]=1
Reactant: CCNc1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ncc(OCCCC(=O)OCC)cn1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CCN(CC)CC
Solvent: ClCCl
Product: CCNC(=O)N(CC)c1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ncc(OCCCC(=O)OCC)cn1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Ethyl 4-{2-[(3,5-bis-trifluoromethyl-benzyl)-(2-ethylamino-5-trifluoromethyl-benzyl)-amino]-pyrimidin-5-yloxy}-butyrate (200 mg) and triethylamine (51 μl) are dissolved in methylene chloride (1 ml), and thereto is added triphosgene (36 mg) in a small amount at room temperature. The reaction solution is stirred at room temperature for 10 minutes and concentrated under reduced pressure. The residue is dissolved in tetrahydrofuran (1 ml) and therero is added a 2M ethylamine in tetrahydrofuran (1 ml) and the mixture is stirred at room temperature for 30 minutes. To the reaction solution are added ethyl acetate and a 1N-hydrochloric acid, and the mixture is separated, and the organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane:ethyl acetate=9:1→1:1) to give ethyl 4-(2-{(3,5-bis-trifluoromethyl-benzyl)-[2-(1,3-diethylureido)-5-trifluoromethyl-benzyl]-amino}-pyrimidin-5-yloxy)-butyrate (181 mg). MS (m/z): 724 [M+H]+
Reaction SMILES: C[O:2][C:3](=O)[CH:4]([CH3:20])[CH2:5][C@H:6]1[CH2:10][C:9](=[O:11])[N:8]([C@H:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH3:13])[CH2:7]1.[BH4-].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O.O>CCO>[OH:2][CH2:3][CH:4]([CH3:20])[CH2:5][C@@H:6]1[CH2:7][N:8]([C@H:12]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH3:13])[C:9](=[O:11])[CH2:10]1
Reactant: COC(=O)C(C)C[C@H]1CC(=O)N([C@@H](C)c2ccccc2)C1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC(CO)C[C@H]1CC(=O)N([C@@H](C)c2ccccc2)C1
Temperature: 0 °C
Yield: 58.5 %

Procedure:
To the ester 93 (4.82 g, 0.017 mol) in EtOH (100 mL) was added NaBH4 (3.7 g, 0.10 mol) and the mixture heated to reflux for 2.5hours. The solution was cooled to 0° C. and 1 M citric acid carefully added followed by water. The solution was concentrated to half volume added and extracted with ether. The combined organic extracts were dried (MgSO4) and concentrated. Flash chromatography (1:1 hexane/acetone) of the residue gave the product as an oil (2.6 g, 59%). MS m/z 262 (M+H, 100%).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][N:16]([CH2:28][C:29]#N)[CH2:17][CH2:18][CH2:19][CH2:20][N:21]([CH2:25][CH2:26][CH3:27])[CH2:22][CH2:23][CH3:24])=[CH:11][CH:10]=1)(C)(C)C.Cl.[O:33]1CCOC[CH2:34]1.C[OH:40]>>[CH3:34][O:33][C:29](=[O:40])[CH2:28][N:16]([CH2:15][C:12]1[CH:11]=[CH:10][C:9]([CH2:8][NH2:7])=[CH:14][CH:13]=1)[CH2:17][CH2:18][CH2:19][CH2:20][N:21]([CH2:22][CH2:23][CH3:24])[CH2:25][CH2:26][CH3:27]
Reactant: CCCN(CCC)CCCCN(CC#N)Cc1ccc(CNC(=O)OC(C)(C)C)cc1
Reactant: C1COCCO1
Reactant: CO
Agent: Cl
Product: CCCN(CCC)CCCCN(CC(=O)OC)Cc1ccc(CN)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The compound (265 mg) obtained in Example 63-1 was dissolved in anhydrous methanol (2.5 ml) and added with a 4 mol/l hydrogen chloride/dioxane solution (5.00 ml) and the whole was stirred overnight at room temperature. After completion of the reaction, the solvent was distilled off. The resultant was added with a saturated aqueous sodium hydrogen carbonate solution. The whole was subjected to extraction with chloroform and washed with a saturated saline solution. The organic layer was dried with anhydrous sodium sulfate. The solvent was distilled off, thereby obtaining the subject compound (161 mg) as a pale-yellow oily substance.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]([OH:14])=O)=[C:8]2[CH3:15].[CH3:16][O:17][CH2:18][CH2:19][N:20]([CH3:28])[C:21]1[CH:26]=[CH:25][C:24]([NH2:27])=[CH:23][N:22]=1>>[CH3:16][O:17][CH2:18][CH2:19][N:20]([CH3:28])[C:21]1[N:22]=[CH:23][C:24]([NH:27][C:12]([C:9]2[NH:10][C:11]3[C:7]([C:8]=2[CH3:15])=[CH:6][CH:5]=[CH:4][C:3]=3[O:2][CH3:1])=[O:14])=[CH:25][CH:26]=1
Reactant: COc1cccc2c(C)c(C(=O)O)[nH]c12
Reactant: COCCN(C)c1ccc(N)cn1
Product: COCCN(C)c1ccc(NC(=O)c2[nH]c3c(OC)cccc3c2C)cn1

Procedure:
With a procedure similar to the example above, 7-methoxy-3-methyl-1H-indole-2-carboxylic acid {6-[(2-methoxy-ethyl)-methyl-amino]-pyridin-3-yl}-amide was prepared from 7-methoxy-3-methyl-1H-indole-2-carboxylic acid and N2-(2-methoxy-ethyl)-N2-methyl-pyridine-2,5-diamine. LCMS calcd for C20H24N4O3 (m/e) 368, obsd 369 (M+H).
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[NH:3].[CH2:5]([C:7]1[CH:15]=[C:14]([S:16][C:17]2[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=2)[C:13]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:12][C:8]=1[C:9](Cl)=[O:10])[CH3:6].C(C1C=C(Cl)C(S(C)(=O)=O)=CC=1C(O)=O)C.SC1C=CN=CC=1.O(C)[Na].O=S(Cl)Cl>>[NH2:3][C:2]([NH2:4])=[N:1][C:9](=[O:10])[C:8]1[CH:12]=[C:13]([S:23]([CH3:26])(=[O:25])=[O:24])[C:14]([S:16][C:17]2[CH:18]=[CH:19][N:20]=[CH:21][CH:22]=2)=[CH:15][C:7]=1[CH2:5][CH3:6]
Reactant: CCc1cc(Sc2ccncc2)c(S(C)(=O)=O)cc1C(=O)Cl
Reactant: N=C(N)N
Agent: CCc1cc(Cl)c(S(C)(=O)=O)cc1C(=O)O
Agent: CO[Na]
Agent: Sc1ccncc1
Solvent: O=S(Cl)Cl
Product: CCc1cc(Sc2ccncc2)c(S(C)(=O)=O)cc1C(=O)N=C(N)N

Procedure:
In analogy to Example 1, the reaction of guanidine with 2-ethyl-4-(4-pyridylthio)-5-methylsulfonylbenzoyl chloride [obtainable by reacting 2-ethyl-4-chloro-5-methylsulfonylbenzoic acid with 4-mercaptopyridine in the presence of NaOCH3 at 180° followed by chlorination with SOCl2 ] gives N-diaminomethylene-2-ethyl-4-(4-pyridylthio)-5-methylsulfonylbenzamide.
Reaction SMILES: [Br-].[CH3:2]OC[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CC(C)([O-])C.[K+].[CH:30]([CH:32]1[CH2:37][CH2:36][CH:35]([C:38]([O:40][CH3:41])=[O:39])[CH2:34][CH2:33]1)=O.O>O1CCCC1>[CH:30]([CH:32]1[CH2:37][CH2:36][CH:35]([C:38]([O:40][CH3:41])=[O:39])[CH2:34][CH2:33]1)=[CH2:2]
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COC(=O)C1CCC(C=O)CC1
Agent: CC(C)(C)[O-]
Agent: [Br-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: C=CC1CCC(C(=O)OC)CC1
Reaction time: 0.5 h

Procedure:
297.4 g of methoxymethyltriphenylphosphonium bromide was dispersed in 900 mL of tetrahydrofuran (THF) and 95.6 g potassium t-butoxide was added at −8° C. in 3 minutes. After stirring for 30 minutes, all of methyl 4-formylcyclohexanecarboxylate was dissolved in 270 mL of THF and the resulting solution was added dropwise at −6 to 4° C. over 50 minutes. After stirring at 0 to 4° C. for 30 minutes, 15 mL of water was added. The solvent of the reaction mixture was distilled off under reduced pressure and 500 mL of hexane was added, followed by stirring at room temperature for 30 minutes. The precipitate was filtered and the precipitate was suspended and washed again with 500 mL of hexane. After combining with the hexane filtrate, the mixture was washed in turn with a mixed solution of methanol and water (1:1), water, and saturated saline. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure to obtain 81.2 g of an oily substance. The oily substance was distilled under reduced pressure to obtain 57.3 g of methyl 4-vinylclohexanecarboxylate. A boiling point was 122 to 127° C./48 hPa. The gas chromatography analysis revealed that, the resulting substance is a mixture of a cis isomer and a trans isomer in a mixing ratio of 26:74.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]([CH3:15])([CH3:14])[CH3:13])(=[O:10])=[O:9])=[CH:4][C:3]=1[CH3:16].[CH3:17][N:18](C=O)C>CCOC(C)=O.[C-]#N.[Zn+2].[C-]#N.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>[C:12]([NH:11][S:8]([C:5]1[CH:6]=[CH:7][C:2]([C:17]#[N:18])=[C:3]([CH3:16])[CH:4]=1)(=[O:10])=[O:9])([CH3:15])([CH3:14])[CH3:13]
Reactant: Cc1cc(S(=O)(=O)NC(C)(C)C)ccc1Br
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: CCOC(C)=O
Product: Cc1cc(S(=O)(=O)NC(C)(C)C)ccc1C#N
Temperature: 120 °C

Procedure:
A mixture of 4-bromo-N-tert-butyl-3-methylbenzenesulfonamide (1.207 g) and zinc cyanide (0.976 g) in DMF (8 ml) was purged with N2 for 20 min. Then PdCl2(dppf) was added. The reaction mixture was heated at 120° C. for 4 hours and showed no reaction. Pd(PPh3)4 was added and the reaction mixture was stirred at 120° C. over the weekend. The reaction mixture was diluted with EtOAc and washed with 5% LiCl solution (2×). The combined organic layers were dried (MgSO4), concentrated and purified by silica gel column chromatography to give 1.227 g N-tert-butyl-4-cyano-3-methylbenzenesulfonamide as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH2:11][N:12]2[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH:14]([CH3:25])[CH2:13]2)[C:5]2[O:9][CH:8]=[CH:7][C:6]=2[CH:10]=1.[F:26][C:27]([F:39])([F:38])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[S:34]([Cl:37])(=[O:36])=[O:35]>>[ClH:37].[ClH:37].[CH3:25][CH:14]1[NH:15][CH2:16][CH2:17][N:12]([CH2:11][C:4]2[C:5]3[O:9][CH:8]=[CH:7][C:6]=3[CH:10]=[C:2]([NH:1][S:34]([C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=3[C:27]([F:26])([F:38])[F:39])(=[O:36])=[O:35])[CH:3]=2)[CH2:13]1
Reactant: CC1CN(Cc2cc(N)cc3ccoc23)CCN1C(=O)OC(C)(C)C
Reactant: O=S(=O)(Cl)c1ccccc1C(F)(F)F
Product: CC1CN(Cc2cc(NS(=O)(=O)c3ccccc3C(F)(F)F)cc3ccoc23)CCN1
Product: Cl
Yield: 53.6 %

Procedure:
The title compound was prepared according to the procedure of Example 115, Step 4, starting from tert-butyl 4-[(5-amino-1-benzofuran-7-yl)methyl]-2-methylpiperazine-1-carboxylate (41 mg crude starting material, 0.11 mmol; obtained in Example 115, Step 3) and 2-(trifluoromethyl)benzenesulfonyl chloride (25 μL, 0.17 mmol). The title compound (24 mg, 44%) was obtained as an off-white solid. HPLC 98%, RT=1.56 min (System A; 10-97% MeCN over 3 min), 97%, RT=1.37 min (System B; 10-97% MeCN over 3 min). 1H NMR (400 MHz, methanol-d4) δ ppm 1.41 (d, J=6.53 Hz, 3H) 3.36-3.44 (m, J=13.30, 12.05 Hz, 1H) 3.47-3.78 (m, 5H) 3.81-3.94 (m, 1H) 4.74 (s, 2H) 6.88 (d, J=2.26 Hz, 1H) 7.41 (d, J=2.01 Hz, 1H) 7.53 (d, J=2.26 Hz, 1H) 7.68-7.76 (m, 2H) 7.88 (d, J=2.01 Hz, 1H) 7.90-7.95 (m, J=6.90, 2.13 Hz, 1H) 8.09-8.13 (m, 1H). MS (ESI+) for C21H22F3N3O3S m/z 454 (M+H)+.
Reaction SMILES: Br[C:2]1[C:12]2[O:11][CH2:10][CH2:9][N:8]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.C([Li])CCC.CCCCCC.[C:31]1(=[O:36])[CH2:35][CH2:34][CH2:33][CH2:32]1.[Cl-].[NH4+]>O1CCCC1>[OH:36][C:31]1([C:2]2[C:12]3[O:11][CH2:10][CH2:9][N:8]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:7][C:6]=3[CH:5]=[CH:4][CH:3]=2)[CH2:35][CH2:34][CH2:33][CH2:32]1
Reactant: CC(C)(C)OC(=O)N1CCOc2c(Br)cccc2C1
Reactant: O=C1CCCC1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCOc2c(cccc2C2(O)CCCC2)C1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 14.9 %

Procedure:
To a solution of tert-butyl 9-bromo-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (200 mg, 0.605 mmol) in tetrahydrofuran (4 ml) was added dropwise 1.6 M solution of n-butyllithium in hexane (0.396 ml, 0.634 mmol) at −78° C., and the mixture was stirred at −78° C. for 10 min. A solution of cyclopentanone (0.0696 ml, 0.787 mmol) in tetrahydrofuran (2 ml) was added dropwise, and the mixture was stirred at 78° C. for 2 hr. The reaction mixture was poured into saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1) to give the desired product (30.0 mg, 14.9%) as an oil.
Reaction SMILES: Br[C:2]1[C:23]([N:24]2[CH2:29][CH2:28][N:27]([CH:30]3[CH2:33][CH2:32][CH2:31]3)[CH2:26][CH2:25]2)=[CH:22][C:5]2[C:6]([CH3:21])([CH3:20])[C:7]3[NH:8][C:9]4[C:14]([C:15]=3[C:16](=[O:17])[C:4]=2[CH:3]=1)=[CH:13][CH:12]=[C:11]([C:18]#[N:19])[CH:10]=4.[CH3:34]B1OB(C)OB(C)O1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH:30]1([N:27]2[CH2:26][CH2:25][N:24]([C:23]3[C:2]([CH3:34])=[CH:3][C:4]4[C:16](=[O:17])[C:15]5[C:14]6[C:9](=[CH:10][C:11]([C:18]#[N:19])=[CH:12][CH:13]=6)[NH:8][C:7]=5[C:6]([CH3:21])([CH3:20])[C:5]=4[CH:22]=3)[CH2:29][CH2:28]2)[CH2:33][CH2:32][CH2:31]1
Reactant: CC1(C)c2cc(N3CCN(C4CCC4)CC3)c(Br)cc2C(=O)c2c1[nH]c1cc(C#N)ccc21
Reactant: CB1OB(C)OB(C)O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc2c(cc1N1CCN(C3CCC3)CC1)C(C)(C)c1[nH]c3cc(C#N)ccc3c1C2=O
Temperature: 100 °C
Reaction time: 24 h
Yield: 59.6 %

Procedure:
Under nitrogen atmosphere, to the N,N-dimethyl formamide (1.5 ml) solution of 9-bromo-8-(4-cyclobutyl-piperazin-1-yl)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile (Compound F4-10, 50 mg, 0.099 mmol), trimethyl boroxine (12 mg, 0.1 eq.), tetrakis triphenylphosphine palladium (39 mg, 0.2 eq.), and potassium carbonate (41 mg, 3.0 eq.) were added, and the mixture was stirred at 100° C. for 24 hr. Upon the completion of the reaction, distilled water was added to the reaction solution, which was then extracted with ethyl acetate. The organic layer was washed with brine and dried over sodium sulfate. The drying agent was removed by filtration and the residues obtained after concentration under reduced pressure were purified by silica gel column chromatography (ethyl acetate/methanol) to obtain the title compound (25 mg, 58%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][CH:17]=1)[C:5]([N:7]1[CH2:13][CH2:12][CH2:11][CH2:10]C[C:8]1=[O:14])=[O:6].C1(=O)NCCCC1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][CH:17]=1)[C:5]([N:7]1[CH2:13][CH2:12][CH2:11][CH2:10][C:8]1=[O:14])=[O:6]
Reactant: O=C1CCCCCN1C(=O)c1cccc(Cl)c1
Agent: O=C1CCCCN1
Product: O=C1CCCCN1C(=O)c1cccc(Cl)c1

Procedure:
Synthesized as for N-(3-chloroobenzoyl)caprolactam (Example XXVII) using valerolactam (Aldrich) in place of caprolactam.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[CH2:5][CH2:6][C:7]3[CH:16]=[CH:15][CH:14]=[CH:13][C:8]=3[C:9](=O)[C:10]=2[N:11]=1.[CH:17](Br)=[CH2:18].[OH:20][C:21]1[CH:22]=C(B(O)O)[CH:24]=[CH:25][CH:26]=1>>[CH3:1][C:2]1[O:3][C:4]2[CH2:5][CH2:6][C:7]3[CH:16]=[CH:15][CH:14]=[CH:13][C:8]=3[C:9](=[CH:24][C:25]3[CH:26]=[C:21]([OH:20])[CH:22]=[CH:17][CH:18]=3)[C:10]=2[N:11]=1
Reactant: OB(O)c1cccc(O)c1
Reactant: C=CBr
Reactant: Cc1nc2c(o1)CCc1ccccc1C2=O
Product: Cc1nc2c(o1)CCc1ccccc1C2=Cc1cccc(O)c1

Procedure:
Prepare the corresponding ketone (2-methyl-9,10-dihydro-1-oxa-3-aza-benzo[f]azulen-4-one) as described by E. E. Galantay, et al, J. Med. Chem. (17) 1316-1327 (1974) and convert to the corresponding Z-isomer of the vinyl bromide using procedures essentially as described in Preparations 23 and 24. Then, following procedures essentially as described in Example 219, combine the ketone with 3-hydroxyphenyl boronic acid (207 mg, 1.5 mmmol). Purify the crude product using column chromatography (15% EtOAc/hexane to 30% EtOAc/hexane) to give 26 mg title compound, MS (ES) 304 (M+1). HPLC shows 93% purity at t=2.48 min.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([CH3:27])([CH3:26])[CH2:10][C:11]([NH:13][C@@H:14]1[CH2:20][CH2:19][C:18]2[CH:21]=[CH:22][CH:23]=[CH:24][C:17]=2[NH:16][C:15]1=[O:25])=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Br[CH2:31][C:32]1[CH:37]=[CH:36][C:35]([C:38]2[C:39]([C:44]#[N:45])=[CH:40][CH:41]=[CH:42][CH:43]=2)=[CH:34][CH:33]=1.[Br-]>CN(C)C=O>[C:44]([C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][C:38]=1[C:35]1[CH:34]=[CH:33][C:32]([CH2:31][N:16]2[C:17]3[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=3[CH2:19][CH2:20][C@@H:14]([NH:13][C:11](=[O:12])[CH2:10][C:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:2])[CH3:3])([CH3:27])[CH3:26])[C:15]2=[O:25])=[CH:37][CH:36]=1)#[N:45]
Reactant: CC(C)(CC(=O)N[C@@H]1CCc2ccccc2NC1=O)NC(=O)OC(C)(C)C
Reactant: N#Cc1ccccc1-c1ccc(CBr)cc1
Agent: [Br-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(CC(=O)N[C@@H]1CCc2ccccc2N(Cc2ccc(-c3ccccc3C#N)cc2)C1=O)NC(=O)OC(C)(C)C
Reaction time: 1 h
Yield: 90.2 %

Procedure:
To a solution of 0.83 g (2.21 mmol) of 3-t-butoxycarbonylamino-3-methyl-N-[2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-3(R)-yl]-butanamide (Example 57, Step A) in 6 mL of dry dimethylformamide at room temperature under nitrogen was added 97 mg of 60% sodium hydride dispersion in oil (58 mg NaH, 2.43 mmol, 1.1 eq). After stirring for 1 hour, a solution of 780 mg (2.88 mmol, 1.3 eq) of 4'-bromomethyl-1,1'-biphenyl-2-nitrile (Step C) in 2.0 mL of dimethylformamide was added via cannula. The flask which originally contained the bromide was washed with 1 mL of dry dimethylformamide which was then added to the reaction mixture via cannula. After stirring at room temperature for 3 hours, the reaction was diluted with 200mL of ethyl acetate, washed with 50 mL of water and 50 mL of brine. The organic layer was separated, dried over magnesium sulfate, filtered and the solvent removed under vacuum. The residue was purified by flash chromatography on silica gel, eluting with ethyl acetate/hexane (6:4), to afford 1.13 g (90%) of the product as a white foam. 1H NMR (200MHz,CDCl3); 1.32 (s,3H), 1.40 (s,12H), 1.85 (m,1H), 2.35-2.70 (m,5H), 4.52 (m,1H), 4.90 (d,12Hz,1H), 5.21 (d,12Hz,1H), 6.70 (d,5Hz,1H), 7.10-7.65 (m,12H), 7.72 (d,6Hz,1H). FAB-MS: calculated for C34H38N4O4 566; found 567 (M+H).