Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH:11]([NH2:13])[CH3:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C([O:18][C:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C:27]1[CH:32]=[CH:31][C:30]([CH2:33][N:34]2[C:42]3[C:37](=[CH:38][C:39]([C:43](O)=[O:44])=[CH:40][CH:41]=3)[C:36]([CH3:46])=[C:35]2[CH3:47])=[CH:29][CH:28]=1)=[O:20])(C)(C)C>>[CH3:47][C:35]1[N:34]([CH2:33][C:30]2[CH:31]=[CH:32][C:27]([C:22]3[C:21]([C:19]([OH:20])=[O:18])=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:28][CH:29]=2)[C:42]2[C:37]([C:36]=1[CH3:46])=[CH:38][C:39]([C:43](=[O:44])[NH:13][CH:11]([C:1]1[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:4]=[CH:3][CH:2]=1)[CH3:12])=[CH:40][CH:41]=2
Reactant: CC(N)c1cccc2ccccc12
Reactant: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)OC(C)(C)C)cc2)c2ccc(C(=O)O)cc12
Product: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)O)cc2)c2ccc(C(=O)NC(C)c3cccc4ccccc34)cc12

Procedure:
The title compound was prepared following the same general protocol as described in Steps 8-9, Example 1, using 1-(naphthalen-1-yl)ethanamine and 1-((2′-(tert-butoxycarbonyl)biphenyl-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylic acid. LC-MS 553 (M+H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:18]([F:21])([F:20])[F:19])=[CH:4][C:5]([OH:17])=[C:6]([NH:8][C:9](=O)[C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)[CH:7]=1.O1CCCC1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:3]([C:18]([F:21])([F:20])[F:19])=[CH:4][C:5]2[O:17][C:9]([C:10]3[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=3)=[N:8][C:6]=2[CH:7]=1
Reactant: O=C(Nc1cc(Cl)c(C(F)(F)F)cc1O)c1ccncc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: FC(F)(F)c1cc2oc(-c3ccncc3)nc2cc1Cl
Reaction time: 1.5 h
Yield: 21.2 %

Procedure:
To a mixture of 0.55 g of N-[5-chloro-2-hydroxy-4-(trifluoromethyl)phenyl]isonicotinamide, 6 ml of tetrahydrofuran and 0.50 g of triphenylphosphine, 0.83 g of 40% toluene solution of diethyl azodicarboxylate was added dropwise at room temperature. The reaction mixture was stirred for 1.5 hours. The reaction mixture was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and the resultant crystals were washed with methanol to give 0.11 g of 5-chloro-2-(pyridin-4-yl)-6-(trifluoromethyl)benzoxazole (hereinafter, referred to as “active compound 78”).
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=2)[C:6](=[C:17](OCC)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:5]1=[O:27])(=O)C.[N:28]1([CH2:34][C:35]([N:37]([CH3:45])[C:38]2[CH:43]=[CH:42][C:41]([NH2:44])=[CH:40][CH:39]=2)=[O:36])[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1>>[N:28]1([CH2:34][C:35]([N:37]([C:38]2[CH:43]=[CH:42][C:41]([NH:44]/[C:17](=[C:6]3\[C:5](=[O:27])[NH:4][C:12]4[C:7]\3=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=4)/[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:40][CH:39]=2)[CH3:45])=[O:36])[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2cc(C(=O)OC)ccc21)c1ccccc1
Reactant: CN(C(=O)CN1CCOCC1)c1ccc(N)cc1
Product: COC(=O)c1ccc2c(c1)NC(=O)/C2=C(\Nc1ccc(N(C)C(=O)CN2CCOCC2)cc1)c1ccccc1

Procedure:
Prepared from 1-acetyl-3-(1-ethoxy-1-phenylmethylene)-6-methoxycarbonyl-2-indolinone and N-(morpholinyl-methylcarbonyl)-N-methyl-p-phenylenediamine Rf value: 0.5 (silica gel, methylene chloride/methanol=9:1) C30H30N4O5
Reaction SMILES: [N:1]([C@@H:4]([C@H:8]([C:17]1[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[CH:19][CH:18]=1)[C:9]1[CH:14]=[CH:13][C:12]([F:15])=[C:11]([F:16])[CH:10]=1)[C:5](O)=[O:6])=[N+]=[N-].[NH2:25][C:26]1[CH:56]=[CH:55][CH:54]=[C:53]([F:57])[C:27]=1[CH2:28][CH2:29][C@H:30]1[O:35][CH2:34][C@@H:33]([CH2:36][O:37][C:38](=[O:45])[NH:39][CH2:40][C:41]([F:44])([F:43])[F:42])[N:32](C(OC(C)(C)C)=O)[CH2:31]1>>[C:23]([C:20]1[CH:21]=[CH:22][C:17]([C@H:8]([C:9]2[CH:14]=[CH:13][C:12]([F:15])=[C:11]([F:16])[CH:10]=2)[C@@H:4]([C:5]([NH:25][C:26]2[CH:56]=[CH:55][CH:54]=[C:53]([F:57])[C:27]=2[CH2:28][CH2:29][C@H:30]2[O:35][CH2:34][C@@H:33]([CH2:36][O:37][C:38](=[O:45])[NH:39][CH2:40][C:41]([F:44])([F:43])[F:42])[NH:32][CH2:31]2)=[O:6])[NH2:1])=[CH:18][CH:19]=1)#[N:24]
Reactant: CC(C)(C)OC(=O)N1C[C@@H](CCc2c(N)cccc2F)OC[C@H]1COC(=O)NCC(F)(F)F
Reactant: N#Cc1ccc([C@H](c2ccc(F)c(F)c2)[C@H](N=[N+]=[N-])C(=O)O)cc1
Product: N#Cc1ccc([C@H](c2ccc(F)c(F)c2)[C@H](N)C(=O)Nc2cccc(F)c2CC[C@@H]2CN[C@H](COC(=O)NCC(F)(F)F)CO2)cc1

Procedure:
The title compound was prepared from the product of step 1 and the product of step 4 of Example 99 using the procedures given in steps 2-4 of Example 93. MS (ES) m/z=664 (M+H)+.
Reaction SMILES: [C:1]([C:3]([C:6]1[CH:7]=[C:8]([CH:42]=[CH:43][CH:44]=1)[C:9]([NH:11][C:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[C:14]([C:19](=[O:41])[CH2:20][S:21]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:13]=1)=[O:10])([CH3:5])[CH3:4])#[N:2].FC(F)(F)C(O)=O.C([SiH](CC)CC)C>C(Cl)Cl>[C:1]([C:3]([C:6]1[CH:7]=[C:8]([CH:42]=[CH:43][CH:44]=1)[C:9]([NH:11][C:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[C:14]([C:19](=[O:41])[CH2:20][SH:21])[CH:13]=1)=[O:10])([CH3:4])[CH3:5])#[N:2]
Reactant: Cc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1C(=O)CSC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1C(=O)CS
Yield: 25.2 %

Procedure:
A solution of 3-(2-cyanopropan-2-yl)-N-(4-methyl-3-(2-(tritylthio)acetyl)phenyl)benzamide 114 (0.799 mmol, 475 mg), trifluoroacetic acid (40.4 mmol, 3 mL) and triethylsilane (0.799 mmol, 0.129 mL) in CH2Cl2 (10 mL) was stirred 1 h at room temperature. Evaporated to dryness and purified by chromatography (10% ethyl acetate in CH2Cl2) gave 3-(2-cyanopropan-2-yl)-N-(3-(2-mercaptoacetyl)-4-methylphenyl)benzamide 115 (71 mg, 25%). NMR (400 MHz, CDCl3) 1.79 (s, 6H), 2.51 (s, 3H), 3.93 (d, J=7.4 Hz, 2H), 7.30 (d, J=8.2 Hz, 1H), 7.54 (m, 2H), 7.72 (dq, J=7.8 Hz and 1.2 Hz, 1H), 7.80 (dt, J=7.8 Hz and 1.6 Hz, 1H), 7.90 (br s, 1H), 8.00 (t, J=2.0 Hz, 1H), 8.19 (d, J=2.0 Hz, 1H).
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[CH:9]=[CH:8][N:7]=[CH:6][C:5]=12>COCCO.[Pt](=O)=O>[N:1]1[CH:2]=[CH:3][N:4]2[CH2:9][CH2:8][NH:7][CH2:6][C:5]=12
Reactant: c1cn2ccnc2cn1
Agent: O=[Pt]=O
Solvent: COCCO
Product: c1cn2c(n1)CNCC2
Reaction time: 12 h
Yield: 38.7 %

Procedure:
Imidazo[1,2-a]pyrazine 4b (500 mg, 4.20 mmol) was dissolved in 5 mL of 2-methoxyethanol, followed by addition of platinum dioxide (100 mg, 0.36 mmol), and the reactor was purged with hydrogen for three times. After stirring for 12 hours, the reaction mixture was filtered. The filtrate was concentrated under reduced pressure to obtain 5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine 4c (200 mg, yield 38.7%) as a yellow oil.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:10][CH2:11][C:12]([F:15])([F:14])[F:13])[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[F:16][C:17]1[CH:44]=[C:43]([F:45])[CH:42]=[CH:41][C:18]=1[O:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][S:27]([CH2:30][CH3:31])(=[O:29])=[O:28])=[CH:22][C:21]=1B1OC(C)(C)C(C)(C)O1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[F:16][C:17]1[CH:44]=[C:43]([F:45])[CH:42]=[CH:41][C:18]=1[O:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][S:27]([CH2:30][CH3:31])(=[O:29])=[O:28])=[CH:22][C:21]=1[C:2]1[CH:3]=[C:4]([O:10][CH2:11][C:12]([F:15])([F:14])[F:13])[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1
Reactant: Cn1cc(Br)cc(OCC(F)(F)F)c1=O
Reactant: CCS(=O)(=O)Cc1ccc(Oc2ccc(F)cc2F)c(B2OC(C)(C)C(C)(C)O2)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: CCS(=O)(=O)Cc1ccc(Oc2ccc(F)cc2F)c(-c2cc(OCC(F)(F)F)c(=O)n(C)c2)c1
Temperature: 70 °C
Yield: 22.5 %

Procedure:
A mixture of 5-bromo-1-methyl-3-(2,2,2-trifluoroethoxy)pyridin-2-one (50 mg, 0.18 mmol), 2-[2-(2,4-difluorophenoxy)-5-(ethylsulfonylmethyl)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (88 mg, 0.20 mmol), Pd(dppf)Cl2 (11 mg) and K3PO4 (85 mg, 0.40 mmol) in dioxane (5 mL) and water (5 drops) was purged with nitrogen, capped, and heated to 70° C. for 8 h. After the mixture was filtered, the filtrate was concentrated in vacuo and purified by prep-HPLC to afford the title compound (21 mg, 22%) as a white solid. 1H NMR (CDCl3, 400 MHz) δ 7.41 (m, 2H) 7.35 (m, 1H) 7.30 (m, 1H) 7.07-6.96 (m, 2H) 6.92-6.87 (m, 1H) 6.80 (m, 1H), 4.51 (m, 2H) 4.21 (s, 2H) 3.69 (s, 3H) 2.97 (m, 2H) 1.44 (m, 3H). LCMS (M+H)+=518.
Reaction SMILES: C(OC([C:6]1[C:7]([NH:9][C:10](=[O:12])[CH:11]=1)=[O:8])=O)C.N[CH2:14][CH2:15][P:16](=[O:19])([OH:18])[OH:17].C(=O)([O-])[O-].[Na+].[Na+].S(=O)(=O)(O)O>O>[C:10]1(=[O:12])[N:9]([CH:15]([P:16]([OH:19])(=[O:17])[OH:18])[CH3:14])[C:7](=[O:8])[CH:6]=[CH:11]1
Reactant: CCOC(=O)C1=CC(=O)NC1=O
Reactant: NCCP(=O)(O)O
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: CC(N1C(=O)C=CC1=O)P(=O)(O)O
Reaction time: 0.33 h

Procedure:
Ethoxy carbonyl maleimide, 169 mg, was added to 2-aminoethyl phosphonic acid, 125 mg, and sodium carbonate, 106 mg, in 1 ml of water at 0° C. The mixture was stirred for 20 minutes, then 4 ml of water was added and the mixture was stirred at room temperature for 1 hr. The solution was acidified to pH 5.5 with dilute sulfuric acid and concentrated in vacuo to 1 ml. The product was isolated by chromatography on three 1000μ reverse-phase TLC plates developed in water. Four bands were noted on examination of the developed plates under U.V. light. The third band at 15-16.7 cm from the origin was isolated; 100 mg of maleimidoethane phosphonic acid-sodium salt was recovered as an amorphous powder. The 200 MHZ NMR spectrum in D2O showed the maleimide hydrogens as a singlet at 7,2 ppm and the ethylene hydrogens as multiplets at 4.0 and 2.2 ppm.
Reaction SMILES: FC(F)(F)C([O-])=O.[CH3:8][C@@H:9]([NH:13][C:14]1[C:23]2[CH:24]=[CH:25][C:26]([F:28])=[CH:27][C:22]=2[C:21]2[C:20](=[O:29])[NH:19][CH:18]=[CH:17][C:16]=2[NH+:15]=1)[CH:10]([CH3:12])[CH3:11].C(N(CC)CC)C.[Br:37]NC(=O)CCC(N)=O>CN(C=O)C.CCOC(C)=O.C([O-])(O)=O.[Na+]>[Br:37][C:17]1[C:16]2[N:15]=[C:14]([NH:13][C@H:9]([CH3:8])[CH:10]([CH3:11])[CH3:12])[C:23]3[CH:24]=[CH:25][C:26]([F:28])=[CH:27][C:22]=3[C:21]=2[C:20](=[O:29])[NH:19][CH:18]=1
Reactant: NC(=O)CCC(=O)NBr
Reactant: CC(C)[C@@H](C)Nc1[nH+]c2cc[nH]c(=O)c2c2cc(F)ccc12
Agent: O=C([O-])C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)[C@@H](C)Nc1nc2c(Br)c[nH]c(=O)c2c2cc(F)ccc12
Reaction time: 2 h

Procedure:
To a solution of 6-{[(1R)-1,2-dimethylpropyl]amino}-9-fluoro-1-oxo-1,2-dihydrobenzo[c]-1,6-naphthyridin-5-ium trifluoroacetate (53 mg, 0.13 mmol) in DMF (3 mL) were added triethylamine (18 uL, 0.13 mmol) and N-bromosuccinamide (27 mg, 0.15 mmol). The solution was stirred for 2 hr then diluted with EtOAc and sat. NaHCO3. The organic layers were separated, dried with MgSO4, filtered, and concentrated. The resulting crude mixture was purified by silica column chromatography 100% Hex. to 100% EtOAC to afford 4-bromo-6-{[(1R)-1,2-dimethylpropyl]amino}-9-fluorobenzo[c]-1,6-naphthyridin-1(2H)-one. 1H NMR (600 MHz, CD3OD) δ 9.55 (d, 1H), 8.37 (m, 1H), 7.66 (s, 1H), 7.36 (m, 1H), 4.65 (m, 1H), 2.1 (m, 1H) 1.30 (d, 3H), 1.0 (m, 6H). LRMS (ESI) calc'd for (C17H18Br2FN3O) [M+H]+, 378.1; found 378.0.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][C:12]([N+:14]([O-:16])=[O:15])=[CH:13][C:8]=2[O:7][C:6]1=[O:17].[CH3:18][N:19]1[CH2:24][CH2:23][CH2:22][CH:21]([OH:25])[CH2:20]1>>[CH3:18][N:19]1[CH2:24][CH2:23][CH2:22][CH:21]([O:25][C:6]([N:5]2[C:9]3[CH:10]=[CH:11][C:12]([N+:14]([O-:16])=[O:15])=[CH:13][C:8]=3[O:7][CH2:2][CH2:3][CH2:4]2)=[O:17])[CH2:20]1
Reactant: O=c1oc2cc([N+](=O)[O-])ccc2n1CCCCl
Reactant: CN1CCCC(O)C1
Product: CN1CCCC(OC(=O)N2CCCOc3cc([N+](=O)[O-])ccc32)C1

Procedure:
3-Nitro-7,8-dihydro-6H-5-oxa-9-aza-benzocycloheptene-9-carboxylic acid 1-methyl-piperidin-3-yl ester was prepared from 3-(3-chloro-propyl)-6-nitro-3H-benzoxazol-2-one and 1-methyl-piperidin-3-ol in an analogous manner to Example 1426a. Product isolated as a yellow oil (420 mg, 53%). LCMS (m/e) 336 (M+H); 1H-NMR (CDCl3, 400 MHz) δ 7.89-7.80 (m, 2H), 7.58-7.44 (m, 1H), 4.92-4.81 (m, 1H), 4.30-4.18 (m, 2H), 3.98-3.72 (m, 2H), 2.82-2.71 (m, 1H), 2.56-2.45 (m, 1H), 2.27 (s, 3H), 2.27-2.07 (m, 4H), 1.97-1.84 (m, 1H), 1.80-1.66 (m, 1H), 1.66-1.52 (m, 1H), 1.52-1.30 (m, 1H).
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[S:3].II.[N:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N:13]1[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][CH:21]2[CH2:26][CH2:25][C:24](=O)[CH2:23][CH2:22]2)[CH2:15][CH2:14]1.Cl>>[N:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N:13]1[CH2:14][CH2:15][N:16]([CH2:19][CH2:20][CH:21]2[CH2:26][CH2:25][C:24]3[N:1]=[C:2]([NH2:4])[S:3][C:23]=3[CH2:22]2)[CH2:17][CH2:18]1
Reactant: O=C1CCC(CCN2CCN(c3ccccn3)CC2)CC1
Reactant: NC(N)=S
Agent: Cl
Agent: II
Product: Nc1nc2c(s1)CC(CCN1CCN(c3ccccn3)CC1)CC2
Temperature: 150 °C
Reaction time: 0.5 h

Procedure:
Thiourea (7.56 g) and iodine (12.61 g) are mixed and stirred mechanically under a stream of nitrogen. To this mixture is added 4-[2-[4-(2-pyridinyl)-1-piperazinyl]ethyl]cyclohexanone (9.52 g) (Example J) and the temperature gradually increased to 150° C. Following 30 minutes at this temperature, the mixture is cooled to room temperature and treated with 250 ml of a 10% solution of hydrochloric acid. Some insoluble material is filtered, the filtrate made basic with ammonium hydroxide, and extracted with chloroform (2×500 ml). The combined organic extracts are dried over magnesium sulfate and concentrated. The crude reaction mixture is purified by MPLC (silica; 5% methanol, 95% chloroform) to give the title compound as a light yellow solid; mp 194°-197° C.
Reaction SMILES: Cl.[C:2]1([CH:8]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10][NH:9]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:16]1[N:21]([CH3:22])[C:20](=[O:23])[CH:19]=[C:18]([C:24]2[CH:29]=[CH:28][N:27]=[CH:26][N:25]=2)[N:17]=1.C(N(CC)CC)C.O>O1CCCC1>[C:2]1([CH:8]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10][N:9]2[C:16]2[N:21]([CH3:22])[C:20](=[O:23])[CH:19]=[C:18]([C:24]3[CH:29]=[CH:28][N:27]=[CH:26][N:25]=3)[N:17]=2)[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(C2CCOCCN2)cc1
Reactant: Cn1c(Cl)nc(-c2ccncn2)cc1=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: Cn1c(N2CCOCCC2c2ccccc2)nc(-c2ccncn2)cc1=O
Temperature: 150 °C
Reaction time: 0.25 h
Yield: 66.7 %

Procedure:
To a suspension of 5-phenyl-[1,4]oxazepane hydrochloride (0.07 g, 0.33 mmol) and 2-chloro-3-methyl-6-(pyrimidin-4-yl)-3H-pyrimidin-4-one (0.07 g, 0.30 mmol) in tetrahydrofuran (2 mL) in a sealed tube was added triethylamine (0.14 mL) at room temperature. The mixture was heated to 150° C. under microwave irradiation and stirred for 15 min. After cooling to room temperature, the reaction mixture was poured into water and extracted with chloroform. The extracts were dried over anhydrous sodium sulfate and concentrated. The residue was purified by flash column chromatography on silica gel (chloroform/methano=10/1 as an eluant) to yield 2-(5-phenyl-[1,4]oxazepane-4-yl)-3-methyl-6-pyrimidin-4-yl-3H-pyrimidin-4-one (A071) (0.07 g, 0.20 mmol, 66%) as a white solid.
Reaction SMILES: [C:1]([C:9]1[NH:10][CH:11]=[CH:12][CH:13]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH:15]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:16]([O:18][CH2:19][CH3:20])=[O:17]>C(O)(=O)C.C(OCC)C.O.O.C([O-])(=O)C.[Mn+3].C([O-])(=O)C.C([O-])(=O)C>[C:1]([C:9]1[NH:10][C:11]([CH2:15][C:16]([O:18][CH:15]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:16]([O:18][CH2:19][CH3:20])=[O:17])=[O:17])=[CH:12][CH:13]=1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(Cl)C(=O)OCC
Reactant: O=C(c1ccccc1)c1ccc[nH]1
Agent: [Mn+3]
Agent: CC(=O)[O-]
Solvent: O
Solvent: CC(=O)O
Solvent: CCOCC
Product: CCOC(=O)C(OC(=O)Cc1ccc(C(=O)c2ccccc2)[nH]1)C(=O)OCC
Temperature: 80 °C
Reaction time: 4 h
Yield: 150.8 %

Procedure:
A mixture of 2-benzoylpyrrole (855 mg, 5 mmol), diethyl chloromalonate (973 mg, 5 mmol) and manganese(III) acetate dihydrate (4560 mg, 15 mmol) in acetic acid (30 mL) was stirred at 80° C. for four hours. The reaction was cooled to room temperature, diluted with diethyl ether and filtered. The filtrate was washed with 10% aqueous sodium hydroxide and saturated aqueous sodium chloride, dried (Na2SO4), and concentrated under reduced pressure. The residue was purified by column chromatography on silica (70-30, hexanes-ethyl acetate) to provide 1.46 g (75%) of diethyl (5-benzoylpyrrol-2-yl)acetoxymethane-dicarboxylate.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[C:7]([N+:9]([O-])=O)[CH:6]=[CH:5][C:4]=1[S:12]([NH:15][C:16]1[CH:17]=[CH:18][C:19]2[CH2:23][O:22][B:21]([OH:24])[C:20]=2[CH:25]=1)(=[O:14])=[O:13])#[N:2]>CO.[Ni]>[NH2:9][C:7]1[CH:6]=[CH:5][C:4]([S:12]([NH:15][C:16]2[CH:17]=[CH:18][C:19]3[CH2:23][O:22][B:21]([OH:24])[C:20]=3[CH:25]=2)(=[O:13])=[O:14])=[C:3]([CH2:1][NH2:2])[CH:8]=1
Reactant: N#Cc1cc([N+](=O)[O-])ccc1S(=O)(=O)Nc1ccc2c(c1)B(O)OC2
Agent: [Ni]
Solvent: CO
Product: NCc1cc(N)ccc1S(=O)(=O)Nc1ccc2c(c1)B(O)OC2
Temperature: 25 °C
Reaction time: 20 h
Yield: 75 %

Procedure:
A mixture of 2-cyano-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)-4-nitrobenzenesulfonamide (3.6 g, crude, 10 mmol), NH3H2O (50 mL) and Raney Ni (3 g) in MeOH (500 mL) was stirred under 50 PSI H2 at room temperature for 20 hrs. The mixture was filtered and the filtrate was concentrated. The residue was purified by prep-HPLC (column: Luna 300×50.0 mm, 10 u; liquid phase: [A-H2O+0.025% TFA; B-MeCN] B %: 10%-45%, 25 min) to give 4-amino-2-(aminomethyl)-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)benzenesulfonamide (2.5 g, 55%) as TFA salt. 1H NMR DMSO 400 MHz δ10.05 (s, 1H), 8.16 (s, 3H), 7.47 (d, J=4.8 Hz, 1H), 7.42 (d, J=5.6 Hz, 1H), 7.23 (d, J=8.4 Hz, 1H), 7.10 (q, 1H), 6.54 (s, 1H), 6.47 (q, 1H), 4.86 (s, 2H), 4.12 (d, J=5.6 Hz, 1H).
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]#[CH:13])[CH:10]=2)[O:5][CH2:4][CH2:3]1.[Li].Cl[C:17]1[CH:27]=[CH:26][C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:19][N:18]=1>O1CCCC1.CCCCCC>[CH3:1][C:2]1([CH3:14])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]#[C:13][C:17]3[CH:27]=[CH:26][C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:19][N:18]=3)[CH:10]=2)[O:5][CH2:4][CH2:3]1
Reactant: CCOC(=O)c1ccc(Cl)nc1
Reactant: C#Cc1ccc2c(c1)C(C)(C)CCO2
Agent: [Li]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(C)(C)CCO3)nc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
Reaction vessels used in this procedure were flame dried under vacuum and all operations were carried out in an oxygen-free, argon or nitrogen atmosphere. To a solution of 509.4 mg (2.74 mmol) of 4,4-dimethyl-6-ethynylchroman in 4 ml of dry tetrahydrofuran at 0° C. was added dropwise 1.72 ml of 1.6M (2.75 mmol) of n-buryl lithium in hexane. Stirring was commenced at 0° C. for 30 minutes and at room temperature for 15 minutes, after which the solution was cooled again to 0° C. and then treated with a solution of 380 mg (2.79 mmol) of fused zinc chloride in 5 ml of dry tetrahydrofuran using a double ended needle. The resulting solution was stirred at 0° C. for 1 hour and then at room temperature for 15 minutes. A solution of 628.6 mg (2.74 mmol) of ethyl 6-chloronicotinate in 4 ml of dry tetrahydrofuran was transferred by double ended needle into a suspension of 380 mg (0.33 mmol) of tetrakistriphenylphosphine palladium in 5 ml dry tetrahydrofuran and mixture stirred at room temperature for 15 minutes and then treated by double ended needle with the solution of alkynylzinc prepared above. The mixture was stirred at room temperature for 20 hours and then quenched with ice and 30 ml of 3N hydrogen chloride. The mixture was extracted with (MgSO4). Solvent was removed in vacuo and the residue further 3×75 ml ether and ether extracts were combined and washed successively with saturated NaHCO3 and saturated NaCl and then dried purified by flash chromatography (silica; 10% ethyl acetate in hexane) to give the title compound as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([O:13][CH2:14]C)=[O:12])=[CH:5]2.[Mg]>>[CH3:14][O:13][C:11]([CH:6]1[CH2:5][C:4]2[C:8](=[CH:9][CH:10]=[C:2]([Cl:1])[CH:3]=2)[NH:7]1)=[O:12]
Reactant: CCOC(=O)c1cc2cc(Cl)ccc2[nH]1
Agent: [Mg]
Product: COC(=O)C1Cc2cc(Cl)ccc2N1

Procedure:
This compound was prepared from ethyl 5-chloroindole-2-carboxylate as described in example 1. However this time 5-6 equivalence of magnesium turnings were used instead of 2-3 eq. of magnesium turnings.
Reaction SMILES: C(OC([N:8]1[CH2:24][CH2:23][C@@H:11]2[N:12]([CH3:22])[C:13]3[C:14]([C:20]#[N:21])=[CH:15][C:16](Br)=[CH:17][C:18]=3[C@@H:10]2[CH2:9]1)=O)(C)(C)C.[Br-].[F:26][C:27]1[CH:34]=[CH:33][C:32]([F:35])=[CH:31][C:28]=1[CH2:29][Zn+]>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>[F:26][C:27]1[CH:34]=[CH:33][C:32]([F:35])=[CH:31][C:28]=1[CH2:29][C:16]1[CH:17]=[C:18]2[C:13](=[C:14]([C:20]#[N:21])[CH:15]=1)[N:12]([CH3:22])[C@H:11]1[CH2:23][CH2:24][NH:8][CH2:9][C@@H:10]21
Reactant: Fc1ccc(F)c(C[Zn+])c1
Reactant: CN1c2c(C#N)cc(Br)cc2[C@@H]2CN(C(=O)OC(C)(C)C)CC[C@@H]21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Product: CN1c2c(C#N)cc(Cc3cc(F)ccc3F)cc2[C@@H]2CNCC[C@@H]21

Procedure:
Following the general procedure for Examples 127–146, the title compound was prepared (18 mg, 53%) as a light yellow oil using (4aS,9bR)-8-bromo-6-cyano-5-methyl-1,3,4,4a,5,9b-hexahydro-pyrido[4,3-b]indole-2-carboxylic acid tert-butyl ester (Example 158, 40 mg, 0.10 mmol), 2,5-difluoro-benzylzinc bromide (0.5 M in THF, 2.5 mole equivalent) and Pd(PPh3)4 (0.06 mole equivalent).: MS (ESI): 340 (base, M+H).
Reaction SMILES: O.Cl.[CH3:3][O:4][C:5](=[O:15])[C@H:6]([CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[NH2:7].[C:16](=[O:19])([O-])[O-:17].[Na+].[Na+]>CO>[CH3:3][O:4][C:5](=[O:15])[C@H:6]([CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[NH:7][C:16]([O:17][C:9]([CH3:14])([CH3:10])[CH3:8])=[O:19]
Reactant: O=C([O-])[O-]
Reactant: COC(=O)[C@@H](N)Cc1ccccc1
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COC(=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Temperature: 40 °C
Reaction time: 6 h
Yield: 188.7 %

Procedure:
To a mixed solvent of methanol (50 ml) and water (100 ml) were added L-phenylalanine methyl ester hydrochloride (21.6 g), sodium carbonate (11.64 g), and a solution of di-tert-butoxydicarbonate (21.8 g) in methanol (100 ml). The resulting mixture was heated to 40° C., followed by stirring for 6 hours. The reaction mixture was concentrated to remove the methanol. The concentrate was extracted by adding ethyl acetate and water. The resulting ethyl acetate layer was washed with 0.1 N hydrochloric acid, water, an aqueous sodium hydrogencarbonate solution and a saturated solution of sodium chloride. The ethyl acetate layer after washed was dried over anhydrous magnesium sulfate. The magnesium sulfate was filtered off. The solvent was distilled off under reduced pressure to give the target N-tert-butoxycarbonyl-L-phenylalanine methyl ester (26.4 g) in a yield of 95%.