Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH2:3][C:4]([O:6][CH3:7])=[O:5])#[N:2].Br[CH2:9][CH2:10][O:11][CH2:12][CH2:13]Br.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[C:1]([C:3]1([C:4]([O:6][CH3:7])=[O:5])[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)#[N:2]
Reactant: COC(=O)CC#N
Reactant: BrCCOCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)C1(C#N)CCOCC1
Yield: 61.2 %

Procedure:
Methyl cyanoacetate (2.50 mL, 28.3 mmol) and 2-bromoethyl ether (4.63 mL, 36.8 mol) were dissolved in acetone (50 ml). To this, potassium carbonate (9.78 g, 70.8 mmol) was added and the mixture was heated to reflux for 8 hours. The reaction mixture was filtered and the mother liquid was concentrated. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=7/3) to give methyl 4-cyanotetrahydro-2H-pyran-4-carboxylate (2.93 g, yield: 61%).
Reaction SMILES: [CH2:1]([CH:4]([NH2:8])[CH2:5][CH:6]=[CH2:7])[CH:2]=[CH2:3].[Br:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]>CO>[Br-:9].[CH2:10]([NH2+:8][CH:4]([CH2:5][CH:6]=[CH2:7])[CH2:1][CH:2]=[CH2:3])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: C=CCC(N)CC=C
Reactant: CCCCCCCCCCBr
Solvent: CO
Product: C=CCC(CC=C)[NH2+]CCCCCCCCCC
Product: [Br-]
Temperature: 65 °C
Reaction time: 48 h
Yield: 78.4 %

Procedure:
Diallylmethylamine (33.3 g) and 1-bromodecane (66.6 g) were dissolved in 100 mL of methanol and the reaction mixture was stirred at 65° C. for 48 hours. After cooling to room temperature, the methanol was removed under reduced pressure. The residual viscous oil was precipitated into 800 mL of ether with rapid stirring. The ether layer was decanted and the residue was again treated with 500 mL of ether. After stirring for 15 minutes the solvent was removed and the oily residue was dried under vacuum at 35° C. for 48 hours, yielding 78 g of the product.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][C:28]=1[Cl:29])[CH2:5][S:6][C:7]1[C:17]2[CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][CH2:12][C:11]=2[CH:10]=[CH:9][C:8]=1[Cl:25].[NH:30]1[CH2:34][CH2:33][CH2:32][CH2:31]1>>[ClH:25].[Cl:25][C:8]1[CH:9]=[CH:10][C:11]2[CH2:12][CH2:13][NH:14][CH2:15][CH2:16][C:17]=2[C:7]=1[S:6][CH2:5][C:4]1[CH:26]=[CH:27][C:28]([Cl:29])=[C:2]([N:30]2[CH2:34][CH2:33][CH2:32][CH2:31]2)[CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(Cl)c(SCc3ccc(Cl)c(Br)c3)c2CC1
Reactant: C1CCNC1
Product: Cl
Product: Clc1ccc(CSc2c(Cl)ccc3c2CCNCC3)cc1N1CCCC1

Procedure:
Use a method similar to the Example 419, using 6-(3-bromo-4-chloro-benzylthio)-3-tert-butoxycarbonyl-7-chloro-2,3,4,5-tetrahydro-1H-benzo[d]azepine and pyrrolidine to give, after deprotection using a method similar to the General Procedure 1-4, the title compound as a white solid. MS (ES+) m/z: 407 (M+H)+.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][NH2:9])[CH:5]=[CH:4][N:3]=[CH:2]1.[CH3:10][C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][C:18]=1[CH3:19])[CH:14]=O.C([O:22][C:23](=O)[C:24](=[O:35])[CH2:25][C:26]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[NH:28][CH:27]=1)C>C(O)C>[CH3:10][C:11]1[CH:12]=[C:13]([CH:14]2[N:9]([CH2:8][CH2:7][CH2:6][N:1]3[CH:5]=[CH:4][N:3]=[CH:2]3)[C:23](=[O:22])[C:24]([OH:35])=[C:25]2[C:26]2[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[NH:28][CH:27]=2)[CH:16]=[CH:17][C:18]=1[CH3:19]
Reactant: CCOC(=O)C(=O)Cc1c[nH]c2ccccc12
Reactant: NCCCn1ccnc1
Reactant: Cc1ccc(C=O)cc1C
Solvent: CCO
Product: Cc1ccc(C2C(c3c[nH]c4ccccc34)=C(O)C(=O)N2CCCn2ccnc2)cc1C
Temperature: 50 °C
Reaction time: 24 h

Procedure:
3-Imidazol-1-yl-propylamine (1 mmol) and 3,4-Dimethyl-benzaldehyde (1 mmol) were added to ethanol (5 ml). After 30 min 3-(1H-Indol-3-yl)-2-oxo-propionic acid ethyl ester (1 mmol) was added. The reaction was heated to 50° C. and stirred for 24 h. After evaporation of the solvent the residue was purified with chromatographic methods.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][C:19]=1[F:20])[O:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[C:11](=[O:15])[NH:10][C:9]2=[O:16].C(=O)([O-])[O-].[K+].[K+].CCC(=O)CC.Br[CH2:34][C:35]([O:37][CH3:38])=[O:36]>O>[CH3:38][O:37][C:35](=[O:36])[CH2:34][N:10]1[C:9](=[O:16])[C:8]2[C:12](=[CH:13][CH:14]=[C:6]([O:5][C:4]3[CH:17]=[CH:18][C:19]([F:20])=[C:2]([F:1])[CH:3]=3)[CH:7]=2)[C:11]1=[O:15]
Reactant: COC(=O)CBr
Reactant: O=C1NC(=O)c2cc(Oc3ccc(F)c(F)c3)ccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(=O)CC
Solvent: O
Product: COC(=O)CN1C(=O)c2ccc(Oc3ccc(F)c(F)c3)cc2C1=O
Temperature: 105 °C

Procedure:
To a pressure tube was added 5-(3,4-difluoro-phenoxy)-isoindole-1,3-dione (680 mg), potassium carbonate (1 g), 3-pentanone (20 ml), and methyl bromoacetate (295 μL). The resulting mixture was heated to 105° C. for 17 h. The reaction was diluted with 20 ml water and extracted with ethyl acetate (2×). The organic layer was dried and concentrated. The mixture was purified through silica gel chromatography with 4:1 hexanes/ethyl acetate and 3:1 hexanes/ethyl acetate to give 657 mg of the title compound.): 1H NMR (200 MHz, DMSO) δ 7.95 (d, J=9.0 Hz, 1H), 7.64-7.41 (m, 4H), 7.15-7.08 (m, 1H), 4.44 (s, 2H), 3.70 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:17])=[C:4]2[C:8](=[CH:9][C:10]=1[F:11])[C:7](=O)[CH:6]([CH2:13][CH2:14][CH2:15][CH3:16])[CH2:5]2.[OH-:18].[K+].C=C[C@@H]1[C@@H]2C[C@H]([C@@H](O)C3C4C(=CC=CC=4)N=CC=3)[N+](CC3C=CC(C(F)(F)F)=CC=3)(CC2)C1.[Br-].[CH:54]([C:56]([CH2:58][CH2:59][CH3:60])=[O:57])=[CH2:55]>C1(C)C=CC=CC=1.C(Cl)Cl>[NH2:1][C:2]1[C:3]([F:17])=[C:4]2[C:8](=[CH:9][C:10]=1[F:11])[C:7](=[O:18])[C:6]([CH2:13][CH2:14][CH2:15][CH3:16])([CH2:55][CH2:54][C:56](=[O:57])[CH2:58][CH2:59][CH3:60])[CH2:5]2
Reactant: [OH-]
Reactant: C=CC(=O)CCC
Reactant: CCCCC1Cc2c(cc(F)c(N)c2F)C1=O
Agent: C=C[C@H]1C[N+]2(Cc3ccc(C(F)(F)F)cc3)CC[C@H]1C[C@@H]2[C@@H](O)c1ccnc2ccccc12
Agent: [Br-]
Agent: [K+]
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CCCCC1(CCC(=O)CCC)Cc2c(cc(F)c(N)c2F)C1=O
Reaction time: 2 h

Procedure:
A solution of 5-amino-2-butyl-4,6-difluoro-1-indanone (0.25 g, 1.05 mmol) in toluene (5.5 mL) was treated with potassium hydroxide (0.1 g, 40% w/w), N-[4-(trifluoromethyl)benzy]cinchoninium bromide (0.112 g, 0.21 mmol), and propyl vinyl ketone (0.154 g, 1.57 mmol). The resulting solution was stirred under a nitrogen atmosphere for 2 hours. After being diluted with CH2Cl2, the mixture was filtered through a pad of silica gel and rinsed with EtOAc. The filtrate was evaporated under vacuum to afford crude 5-amino-2-butyl-4,6-difluoro-2-(3-oxohexyl)-1-indanone.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:17]2[O:18][CH:19]=[C:20]([CH2:22][CH:23](C(OC)=O)[C:24]([O:26][CH3:27])=[O:25])[N:21]=2)[CH:12]=[CH:13][C:14]=1[O:15][CH3:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl-].[Li+].O>CS(C)=O>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:17]2[O:18][CH:19]=[C:20]([CH2:22][CH2:23][C:24]([O:26][CH3:27])=[O:25])[N:21]=2)[CH:12]=[CH:13][C:14]=1[O:15][CH3:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)C(Cc1coc(-c2ccc(OC)c(OCc3ccccc3)c2)n1)C(=O)OC
Agent: [Cl-]
Agent: [Li+]
Solvent: O
Solvent: CS(C)=O
Product: COC(=O)CCc1coc(-c2ccc(OC)c(OCc3ccccc3)c2)n1
Temperature: 130 °C
Reaction time: 4 h

Procedure:
A 26.52 g quantity of the dimethyl 2-[2-(3-benzyloxy-4-methoxyphenyl)oxazol-4-ylmethyl]malonate obtained in Reference Example 47 was suspended in 53 ml of dimethyl sulfoxide, and 2.62 g of lithium chloride and 1.12 ml of purified water were added. The mixture was stirred at 130° C. for 4 hours. After the reaction mixture was allowed to cool, water was added and extraction with ethyl acetate was performed. The extract was dried over anhydrous magnesium sulfate, and the solvent was distilled off. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=3:1) to give 16 g of white powdery methyl 3-[2-(3-benzyloxy-4-methoxyphenyl)oxazol-4-yl]propionate.
Reaction SMILES: C([O:4][B:5](OC(C)C)[O:6]C(C)C)(C)C.[Cl:14][C:15]1[CH:20]=[C:19](I)[CH:18]=[CH:17][C:16]=1[O:22][C:23]([F:26])([F:25])[F:24]>C1(C)C=CC=CC=1>[Cl:14][C:15]1[CH:20]=[C:19]([B:5]([OH:6])[OH:4])[CH:18]=[CH:17][C:16]=1[O:22][C:23]([F:26])([F:25])[F:24]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: FC(F)(F)Oc1ccc(I)cc1Cl
Solvent: Cc1ccccc1
Product: OB(O)c1ccc(OC(F)(F)F)c(Cl)c1
Temperature: -78 °C
Reaction time: 3 h
Yield: 75.5 %

Procedure:
Triisopropylborate (0.76 mL, 3.29 mmol) and iodide 54 (815 mg, 2.53 mmol) were successively added via syringe to a mixture of anhydrous toluene (4 mL) and anhydrous distilled THF (1 mL) under N2 and the mixture was cooled to −78° C. n-Butyllithium (1.08 mL of a 2.5 M solution in hexanes, 2.70 mmol) was added drop-wise over 75 min to the stirred solution (at −78° C.), and the mixture was stirred at −78° C. for an additional 3 h, and then slowly warmed to −20° C. (over 1.5H). 2N HCl (2.6 mL) was added and the mixture was stirred at room temperature for 30 min, and then diluted with water (40 mL) and extracted with EtOAc (5×50 mL). The extracts were washed with brine (50 mL) and then evaporated to dryness. The residue was triturated in pentane (˜3-4 mL), cooled to −78° C., and rapidly filtered cold (washing with pentane cooled to −78° C.) to give 3-chloro-4-(trifluoromethoxy)phenylboronic acid (55) (459 mg, 76%) as a white solid (a 1:1 mixture of the trimeric boroxine and the boronic acid by NMR): mp 202-204° C.; 1H NMR (CDCl3) δ 8.26 (d, J=1.5 Hz, 3H, boroxine), 8.12 (dd, J=8.2, 1.5 Hz, 3H, boroxine), 7.85 (d, J=1.5 Hz, 1H, boronic acid), 7.65 (dd, J=8.2, 1.6 Hz, 1H, boronic acid), 7.48 (dq, J=8.2, 1.5 Hz, 3H, boroxine), 7.35 (dq, J=8.2, 1.5 Hz, 1H, boronic acid), 4.57 (s, 2H, boronic acid).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][CH:10]=[C:11]([C:13]3[N:17]([CH:18]([CH3:20])[CH3:19])[N:16]=[C:15]([CH3:21])[N:14]=3)[N:12]=2)=[C:4]([F:22])[CH:3]=1.C1(=O)O[CH2:26][CH2:25][O:24]1.CO>C1(C)C=CC=CC=1.C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH2:26][CH2:25][OH:24])[CH:10]=[C:11]([C:13]3[N:17]([CH:18]([CH3:19])[CH3:20])[N:16]=[C:15]([CH3:21])[N:14]=3)[N:12]=2)=[C:4]([F:22])[CH:3]=1
Reactant: Cc1nc(-c2c[nH]c(-c3ccc(Br)cc3F)n2)n(C(C)C)n1
Reactant: O=C1OCCO1
Solvent: CO
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: Cc1nc(-c2cn(CCO)c(-c3ccc(Br)cc3F)n2)n(C(C)C)n1
Yield: 71 %

Procedure:
A suspension of 5-[2-(4-bromo-2-fluoro-phenyl)-1H-imidazol-4-yl]-1-isopropyl-3-methyl-1H-[1,2,4]triazole (2.9 g, 7.96 mmol) in toluene (50 mL) was treated with ethylene carbonate (25 mL) and heated at reflux for 5 h. The cooled reaction mixture was diluted with DCM and passed through a pad of silica eluting with DCM then 20% methanol in DCM. Methanolic fractions were combined and concentrated in vacuo to give a pale tan solid. The solid was triturated in diethyl ether to give 2-[2-(4-Bromo-2-fluoro-phenyl)-4-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-imidazol-1-yl]-ethanol as a white solid (2.3 g, 71%). LCMS: RT=2.85 min, [M+H]+=408/410. 1H NMR 400 MHz (CDCl3) δ: 8.16 (1H, s), 7.67-7.20 (3H, m), 5.83 (1H, m), 4.05 (2H, t, J=5.10 Hz), 3.92 (2H, t, J=5.10 Hz), 2.44 (3H, s), 1.50 (6H, d, J=6.65 Hz).
Reaction SMILES: [CH:1]1([C:5]2[C:13]([C:14]3[NH:18][C:17]([O:19][CH3:20])=[N:16][N:15]=3)=[CH:12][C:8]([C:9]([OH:11])=O)=[C:7]([CH3:21])[CH:6]=2)[CH2:4][CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[NH:53]1[CH2:58][CH2:57][CH:56]([C:59]2[CH:66]=[CH:65][C:62]([C:63]#[N:64])=[CH:61][CH:60]=2)[CH2:55][CH2:54]1>CN(C)C=O.C(OCC)(=O)C>[CH:1]1([C:5]2[C:13]([C:14]3[NH:18][C:17]([O:19][CH3:20])=[N:16][N:15]=3)=[CH:12][C:8]([C:9]([N:53]3[CH2:58][CH2:57][CH:56]([C:59]4[CH:66]=[CH:65][C:62]([C:63]#[N:64])=[CH:61][CH:60]=4)[CH2:55][CH2:54]3)=[O:11])=[C:7]([CH3:21])[CH:6]=2)[CH2:2][CH2:3][CH2:4]1
Reactant: COc1nnc(-c2cc(C(=O)O)c(C)cc2C2CCC2)[nH]1
Reactant: N#Cc1ccc(C2CCNCC2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1nnc(-c2cc(C(=O)N3CCC(c4ccc(C#N)cc4)CC3)c(C)cc2C2CCC2)[nH]1
Yield: 23049 %

Procedure:
A solution of 4-cyclobutyl-5-(5-methoxy-4H-1,2,4-triazol-3-yl)-2-methylbenzoic acid (compound 222.3, 60 mg, 0.2 μmol), DIEA (0.11 ml, 0.63 mmol), HOBT (53 mg, 0.32 mmol, with 20% water), EDCI (60 mg, 0.32 mmol) and 4-(piperidin-4-yl)benzonitrile hydrochloride (compound 1.5, 47 mg, 0.21 mmol) in N,N-dimethylformamide (3 mL) was stirred overnight at room temperature. The reaction mixture was then diluted with 50 mL of ethyl acetate and washed with 2×20 mL of brine. The mixture was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was applied onto a silica gel prep-TLC plate and developed using ethyl acetate/hexanes (1:1) to yield 21.0 mg (22%) of the title compound as a white solid. m/z (ES+) 456 (M+H)+. 1H NMR (400 MHz, Chloroform-d) 611.54-10.86 (br s, 1H), 7.60 (d, 2H), 7.38-7.20 (m, 4H), 5.04-4.92 (m, 1H), 4.06 (s, 3H), 4.14-4.00 (m, 1H), 3.62 (d, 1H), 3.15-3.03 (m, 1H), 2.93-2.76 (m, 2H), 2.38 and 2.30 (2 singlets, amide rotamers, ArCH3, 3H), 2.34-2.22 (m, 1H), 2.20-2.06 (m, 2H), 2.05-1.84 (m, 3H), 1.61-1.45 (m, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[F:10])[C:5]#N.[OH2:11]>[Ni].C(O)=O>[Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[F:10])[CH:5]=[O:11]
Reactant: N#Cc1ccc(F)c(Br)c1
Reactant: O
Agent: [Ni]
Solvent: O=CO
Product: O=Cc1ccc(F)c(Br)c1
Yield: 85 %

Procedure:
17.0 g of a 50% strength alkaline suspension of Raney nickel were filtered under a nitrogen atmosphere and the material on the filter was washed until neutral. The Raney nickel obtained by this method was suspended in 150 ml of formic acid. 20.0 g (0.1 mole) of 3-bromo-4-fluoro-benzonitrile were added to this suspension. The mixture was heated at 80° to 90° C. for 3 to 5 hours and the reaction mixture was then cooled and poured into 300 ml of water. After filtering, the filtrate was twice extracted with, in each case, 200 ml of toluene. The toluene phase was dried over sodium sulphate and then concentrated. 17.2 g (85% of theory) of 3-bromo-4-fluoro-benzaldehyde with a boiling point of 63°-65° C./0.3 mm Hg were obtained.
Reaction SMILES: [CH2:1]([CH:8]1[NH:13][CH2:12][CH2:11][N:10]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:27]([F:30])([F:29])[F:28])=[CH:17][CH:16]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:31][N:32]=[C:33]=[O:34]>ClCCl>[CH3:31][NH:32][C:33]([N:13]1[CH2:12][CH2:11][N:10]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:27]([F:30])([F:28])[F:29])=[CH:17][CH:16]=2)[CH2:9][CH:8]1[CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:34]
Reactant: FC(F)(F)c1ccccc1-c1ccc(CN2CCNC(Cc3ccccc3)C2)cc1
Reactant: CN=C=O
Solvent: ClCCl
Product: CNC(=O)N1CCN(Cc2ccc(-c3ccccc3C(F)(F)F)cc2)CC1Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
This compound could be made in the following manner: 100 mg of 3-benzyl-1-(2′-trifluoromethyl-biphenyl-4-ylmethyl)-piperazine would be dissolved in dichloromethane, 1.1 equiv. methylisocyanate would be added. The reaction would be shaken at room temperature overnight. The reaction would be concentrated in vacuo. The residue would be diluted with DCM, washed with 1M aqueous sodium hydroxide solution, then dried over sodium sulfate, filtered and concentrated in vacuo. The crude residue would be purified by column chromatography to afford the title compound as free base. Addition of 1 equiv. of 1M HCl in dioxane and concentratation in vacuo would afford the title compound as hydrochloride salt.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:7]2.[S:16]1[CH:20]=[CH:19][CH:18]=[C:17]1[C:21](O)=[O:22].C(N(C(C)C)C(C)C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>C(OCC)(=O)C.CN(C)C=O>[S:16]1[CH:20]=[CH:19][CH:18]=[C:17]1[C:21]([NH:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:7]2)=[O:22]
Reactant: O=C(O)c1cccs1
Reactant: CCOC(=O)c1cc2cccc(N)c2[nH]1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2cccc(NC(=O)c3cccs3)c2[nH]1
Temperature: 60 °C
Reaction time: 18 h
Yield: 82.8 %

Procedure:
A mixture of ethyl 7-amino-1H-indole-2-carboxylate (0.40 g), thiophene-2-carboxylic acid (0.28 g), ethyldiisopropylamine (0.75 mL), O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.82 g) and N,N-dimethylformamide (10 mL) was stirred at 60° C. for 18 hr. The reaction mixture was diluted with ethyl acetate, washed with aqueous citric acid solution, aqueous sodium hydrogencarbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (ethyl acetate:hexane=3:97-3:7) to give the title compound (510 mg, yield 83%) as a pale-yellow amorphous solid.
Reaction SMILES: [OH-].[K+].[OH:3][C:4]1[CH:9]=[CH:8][C:7]([P:10]([O:21][CH2:22][CH3:23])([CH2:12][P:13]([O:18][CH2:19][CH3:20])([O:15][CH2:16][CH3:17])=[O:14])=[O:11])=[CH:6][C:5]=1[C:24]([CH3:30])([CH3:29])[CH2:25][C:26]([OH:28])=[O:27].[CH2:31](Br)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>C(#N)C>[OH:3][C:4]1[CH:9]=[CH:8][C:7]([P:10]([O:21][CH2:22][CH3:23])([CH2:12][P:13]([O:18][CH2:19][CH3:20])([O:15][CH2:16][CH3:17])=[O:14])=[O:11])=[CH:6][C:5]=1[C:24]([CH3:30])([CH3:29])[CH2:25][C:26]([O:28][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:27]
Reactant: BrCc1ccccc1
Reactant: CCOP(=O)(CP(=O)(OCC)c1ccc(O)c(C(C)(C)CC(=O)O)c1)OCC
Agent: [K+]
Agent: [OH-]
Solvent: CC#N
Product: CCOP(=O)(CP(=O)(OCC)c1ccc(O)c(C(C)(C)CC(=O)OCc2ccccc2)c1)OCC
Temperature: 25 °C
Reaction time: 2 h
Yield: 48 %

Procedure:
An aqueous KOH solution (0.14 g, 2.5 mmol) was added to a stirring solution of 121 (1.1 g, 2.5 mmol) in acetonitrile (5 mL). After 10 min the solvent was evaporated under reduced pressure and the residue was dried under vacuum for 1 hr. The pale yellow solid was resuspended in DMF (10 mL) followed by the addition of benzylbromide (330 μL, 2.8 eq). The resulting solution was stirred at room temperature for 2 hr. The mixture was diluted with EtOAC (80 mL) and washed with H2O and saturated aqueous NaCl, followed by drying over Na2SO4. The crude product was purified by silica gel chromatography (0-10% methanol in CH2Cl2) on a Biotage™ flash chromatography system, resulting in 122 as a pale yellow liquid (0.64 g, 48%): 1H NMR (400 MHz, CDCl3) δ 1.23 (t, J=7.1, 3H), 1.26 (t, J=7.1, 3H), 1.30 (t, J=7.1, 3H), 1.45 (s, 3H), 1.49 (s, 3H), 2.60 (dd, J=17.4, 20.9, 2H), 3.00 (AB q, J=14.0, 2H), 3.78-3.88 (m, 2H), 3.99-4.15 (m, 4H), 4.93 (s, 2H), 6.75-6.78 (m, 1H), 7.14 (dd, J=2.0, 7.5, 2H), 7.25-7.31 (m, 3H), 7.58 (ddd, J=1.4, 8.0, 11.9, 1H), 7.64 (d, J=13.4, 1H): 31P (162 MHz, CDCl3) δ 21.04 (d, J=4.6, 1 P), 36.00 (d, J=4.6, 1 P).
Reaction SMILES: [O:1]=[C:2]1[N:8]([CH2:9][C:10]([N:12]([CH:21]([CH3:23])[CH3:22])[C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)=[O:11])[C:7]2[CH:24]=[CH:25][CH:26]=[CH:27][C:6]=2[N:5]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:4](=[O:34])[CH2:3]1.Br[CH2:36][C:37]1[CH:46]=[CH:45][C:44]2[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=2)[CH:38]=1>CN(C=O)C.C1(C)C=CC=CC=1>[CH:21]([N:12]([C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1)[C:10](=[O:11])[CH2:9][N:8]1[C:2](=[O:1])[CH:3]([CH2:36][C:37]2[CH:46]=[CH:45][C:44]3[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=3)[CH:38]=2)[C:4](=[O:34])[N:5]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:6]2[CH:27]=[CH:26][CH:25]=[CH:24][C:7]1=2)([CH3:23])[CH3:22]
Reactant: BrCc1ccc2ccccc2c1
Reactant: COc1ccc(N(C(=O)CN2C(=O)CC(=O)N(c3ccccc3)c3ccccc32)C(C)C)cc1
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: COc1ccc(N(C(=O)CN2C(=O)C(Cc3ccc4ccccc4c3)C(=O)N(c3ccccc3)c3ccccc32)C(C)C)cc1
Reaction time: 0.17 h
Yield: 78.6 %

Procedure:
To a stirring solution of 300 mg (0.66 mmol) of 2-(2,4-Dioxo-5-phenyl-2,3,4,5-tetrahydro-benzo[b][1,4]diazepin-1-yl)-N-isopropyl-N-(4-methoxy-phenyl) acetamide, prepared as in Intermediate 4, in 10 mL DMF at 0° C. is added dropwise over 5 min 1.45 mL (0.72 mmol, 1.1 equiv) of a 0.5M solution of KN(TMS)2 in toluene. The resulting solution is stirred 10 min, and then a solution of 160 mg (0.72 mmol, 1.1 equiv) of 2-bromomethylnaphthalene in 3 mL DMF is added. The resulting solution is stirred 2 h at RT and then quenched with 5 mL of H2O. The reaction mixture is poured into 50 mL of Et2O and extracted with H2O (2×50 mL). The organic layer is separated, dried (MgSO4), and the solvents removed in vacuo. Purification of the material by silica gel MPLC on an Si60 column using hexane/EtOAc 2/1 as eluent followed by lyophilization in acetonitrile/H2O afforded 310 mg of the title compound as a white amorphous solid: 1H NMR (CDCl3, 300 MHz) δ7.80-7.70 (m, 3H), 7.45-6.93 (m, 16H), 6.84 (dd, 1H, J=1.2, 8.3), 5.04 (m, 1H), 4.35 (d, 1H, J=16.3), 4.13 (d, 1H, J=16.3), 3.85 (s, 3H), 3.68 (m, 2H), 3.48 (dd, 1H, J=4.6, 13.7), 1.09 (d, 6H, J=6.8); low resolution MS (FAB)m/e 598 (MH+), 597 (M+), 433.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:9][CH2:10][C@@H:11]2[CH2:14][CH2:13][N:12]2[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH:5]=[N:6][C:7]=1[Cl:8].[CH:22]([Sn](CCCC)(CCCC)CCCC)=[CH2:23]>C1(C)C=CC=CC=1.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>[Cl:8][C:7]1[C:2]([CH:22]=[CH2:23])=[CH:3][C:4]([O:9][CH2:10][C@@H:11]2[CH2:14][CH2:13][N:12]2[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[CH:5][N:6]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@H]1COc1cnc(Cl)c(Br)c1
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: C=Cc1cc(OC[C@@H]2CCN2C(=O)OC(C)(C)C)cnc1Cl
Temperature: 95 °C
Yield: 84 %

Procedure:
To 5-bromo-6-chloro-3-(1-t-butyloxycarbonyl-2-(S)-azetidinylmethoxy)pyridine from Example 17 above (1.00 g, 2.65 mmol) in toluene (30 mL) was added tetrakis(triphenylphosphine)palladium(0) (93 mg, 0.081 mmol) and vinyltributyltin (0.93 mL, 3.18 mmol). The mixture heated at 95° C. overnight, then the volatile components were removed in vacuo. The residue was chromatographed (silica gel; CH2Cl2/MeOH, 100:2) to afford 2-chloro-3-vinyl-5-(1-t-butyloxycarbonyl-(2S)-azetidinylmethoxy)pyridine as an oil (720 mg, 84%): 1H NMR (CDCl3, 300 MHz) δ1.42 (s, 9H), 2.33 (m, 2H), 3.89 (t, J=8.5 Hz, 2H), 4.14 (m, 1H), 4.36 (m, 1H), 4.52 (m, 1H), 5.50 (d, J=10.9 Hz, 1H), 5.80 (d, J=17 Hz, 1H), 6.98 (dd, J=17.6 Hz, J=11.2 Hz, 1H), 7.44 (d, J=2.7 Hz, 1H), 8.02 (d, J=2.7 Hz, 1H); MS (CI/NH3) m/z: 325 (M+H)+. This product was treated with TFA in CH2Cl2 to give, following extractive work-up, the free base of the title compound. The free amine was converted to the hydrochloride salt by treatment with a solution of HCl in diethyl ether to give the title compound as a light yellow hygroscopic solid: mp 121° C. (dec); MS (CI/NH3): m/z 225 (M+H+), 242 (M+NH4+). Anal. Calcd for C11H13ClN2O.1.1 HCl: C, 49.90; H, 5.37; N, 10.58. Found: C, 49.84; H, 5.25; N, 10.27.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH2:8]O)[N:5]=[C:4]([C:10]([O:12][CH3:13])=[O:11])[CH:3]=1.S(Cl)([Cl:16])=O.C1(C)C=CC=CC=1>ClCCl>[Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][Cl:16])[N:5]=[C:4]([C:10]([O:12][CH3:13])=[O:11])[CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: COC(=O)c1cc(Cl)cc(CO)n1
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: COC(=O)c1cc(Cl)cc(CCl)n1
Reaction time: 0.67 h

Procedure:
To a solution of methyl 4-chloro-6-(hydroxymethyl)-2-pyridinecarboxylate (166 mg, Ref: Kittika et al., Tetrahedron, 44 (10), 2821, (1988)) in dry dichloromethane (3 ml) was added thionyl chloride (66 μl). The solution was stirred for 40 minutes. LC/MS indication reaction completion. Solvent was removed u.r.p. (under reduced pressure) to give a white solid. Toluene (˜2 ml) added then removed u.r.p. The residue was dried in vacuo to give a white solid. (175 mg, 97%). LC/MS [MH+]=220/222, Rt=2.51 min. Title compound obtained as the free base.