Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:12]=[C:11]2[C@H:21]([NH:23][CH2:24][CH:25]2[CH2:30][CH2:29][N:28]([CH:31]([CH3:33])[CH3:32])[CH2:27][CH2:26]2)[CH3:22])=[CH:6][CH:5]=1)[CH3:2].[F:34][C:35]1[CH:40]=[CH:39][C:38]([CH2:41][C:42](O)=[O:43])=[CH:37][C:36]=1[C:45]([F:48])([F:47])[F:46].CN1CCOCC1.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(Cl)CCl>CN(C)C=O.ClCCl>[CH2:1]([O:3][C:4]1[CH:5]=[CH:6][C:7]([N:10]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:12]=[C:11]2[C@H:21]([N:23]([CH2:24][CH:25]2[CH2:30][CH2:29][N:28]([CH:31]([CH3:32])[CH3:33])[CH2:27][CH2:26]2)[C:42](=[O:43])[CH2:41][C:38]2[CH:39]=[CH:40][C:35]([F:34])=[C:36]([C:45]([F:46])([F:48])[F:47])[CH:37]=2)[CH3:22])=[CH:8][CH:9]=1)[CH3:2]
Reactant: O=C(O)Cc1ccc(F)c(C(F)(F)F)c1
Reactant: CCOc1ccc(-n2c([C@@H](C)NCC3CCN(C(C)C)CC3)nc3ccccc3c2=O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: ClCCCl
Product: CCOc1ccc(-n2c([C@@H](C)N(CC3CCN(C(C)C)CC3)C(=O)Cc3ccc(F)c(C(F)(F)F)c3)nc3ccccc3c2=O)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 57.1 %

Procedure:
To a mixture of 49.3 g A2 (0.11 mol, 1.00 equiv.) and 29.3 g 4-fluoro-3-(trifluoromethyl)phenylacetic acid (0.13 mol, 1.20 equiv.) in 120 mL N,N-dimethylformamide, DMF, and 40 mL dichloromethane at room temperature was added 12 mL N-methylmorpholine, NMM (0.11 mol, 1.00 equiv.) and 14.9 g 1-hydroxybenzotriazole, HOBT (0.11 mol, 1.00 equiv.). To the solution was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, EDC (0.22 mol, 2.00 equiv.) in two equivalent portions at a 5 min. interval. The reaction mixture was stirred at room temperature for 16 h then taken-up in 800 mL ethyl acetate and washed with saturated aqueous sodium bicarbonate and aqueous brine six times. The organic extract was dried over magnesium sulfate, filtered and concentrated in vacuo to afford a glassy solid. The product was purified by recrystallization from diethyl ether to yield 41 g of 1 as a colorless solid. 1H NMR (400 MHz; d6-DMSO; T=393 K): δ 0.92 (d, J=6.6 Hz, 6H), 0.95-1.20 (m, 2H), 1.35 (t, J=7.0 Hz, 3H), 1.32-1.50 (m, 2H), 1.50 (d, J=6.6 Hz, 3H), 1.58 (d, J=1.0 Hz, 1H), 1.85 (dd, J=10.3, 10.3 Hz, 1H), 1.99 (dd, J=11.4, 11.4 Hz, 1H), 2.52-2.68 (m, 2H), 2.75 (d, J=11.4 Hz, 1H), 2.88 (br s, 1H), 3.10 (dd, J=9.1, 14.8 Hz, 1H), 3.30 (dd, J=9.1, 13.7 Hz, 1H), 3.52 (br s, 1H), 4.09 (qt, J=7.0 Hz, 2H), 5.12 (qt, J=9.12 Hz, 1H), 7.00-7.13 (m, 2H), 7.18 (d, J=10.3 Hz, 1H), 7.30 (dd, J=10.3, 10.3 Hz, 1H), 7.33-7.48 (m, 3H), 7.57 (dd, J=9.5, 9.5 Hz, 1H), 7.72 (d, J=9.5 Hz, 1H), 7.87 (dd, J=9.5, 9.5 Hz, 1H), 8.15 (d, J=7.8 Hz, 1H) ppm; MS (ESI+) m/z=653.3 [M+H]+; Analytical calculated: 66.24%, C, 6.18% H, 11.64% F and 8.58% N. Found: 66.17% C, 6.05% H, 8.56% N, 11.59% F.
Reaction SMILES: OC(C)(C)[C:3]#[C:4][C:5]1[CH:6]=[C:7]([CH:16]=[CH:17][CH:18]=1)[C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:9].[OH-].[Na+]>C1(C)C=CC=CC=1>[C:4]([C:5]1[CH:6]=[C:7]([CH:16]=[CH:17][CH:18]=1)[C:8]([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)=[O:9])#[CH:3]
Reactant: CC(C)(O)C#Cc1cccc(C(=O)c2ccccc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: C#Cc1cccc(C(=O)c2ccccc2)c1
Temperature: 120 °C
Yield: 79.3 %

Procedure:
In a 100 ml two-necked flask having a reflux condenser were charged 1.45 g (5.5 mmol) of 3-(3-hydroxy-3-methyl-1-butynyl)benzophenone and 230 mg (5.8 mmol) of NaOH (Kishida Chemical Co., Ltd.; 0.7 mm particles, 986) and air in the flask was replaced by Ar gas. 30 ml of toluene was added to the mixture and the mixture was heated at 120° C. under reflux for 0.5 hour. Toluene was added to the reaction mixture and the mixture was washed with a saturated aqueous ammonium chloride solution and dried over magnesium sulfate and the solvent was removed by distillation under reduced pressure using an evaporator. The resultant crude reaction product was purified by column chromatography (Hexane/AcOEt=30/1) using silica gel to obtain 0.9 g of 3-ethynylbenzophenone as orange solid. (Yield: 80%)
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[O:11]=[C:12]1[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]1.N1([C:30](=[O:38])[CH2:31][CH2:32][CH:33]2[CH2:37][CH2:36][CH2:35][O:34]2)C=CN=C1.C(O)(=O)C>C1(C)C=CC=CC=1.O>[O:11]=[C:12]1[CH2:13][CH2:14][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:16][CH:17]1[C:30](=[O:38])[CH2:31][CH2:32][CH:33]1[CH2:37][CH2:36][CH2:35][O:34]1
Reactant: O=C(CCC1CCCO1)n1ccnc1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(=O)C(C(=O)CCC2CCCO2)C1
Reaction time: 0.03 h
Yield: 38.9 %

Procedure:
Lithium bis(trimethylsilyl)amide (2.231 ml, 11.88 mmol) was added to a stirred solution of tert-butyl 4-oxopiperidine-1-carboxylate (1.127 g, 5.66 mmol) in toluene (3 mL) at 0° C. and the resulting mixture was stirred for 2 minutes. 1-(1H-Imidazol-1-yl)-3-(tetrahydrofuran-2-yl)propan-1-one (1.099 g, 5.66 mmol) in toluene (1 mL) was added and the reaction mixture was stirred for 5 minutes before it was quenched with acetic acid (0.972 ml, 16.97 mmol) in water (4 mL). The organic layer was separated and purified by silica flash chromatography using a gradient of ethyl acetate in heptane (0 to 40%) giving tert-butyl 4-oxo-3-(3-(tetrahydrofuran-2-yl)propanoyl)piperidine-1-carboxylate (0.717 g, 38.9%) as the product.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:4]=[CH:5][C:6]2[CH:12]=[CH:11][C:10](=[O:13])[NH:9][C:7]=2[N:8]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:21][CH:22]1[O:26][CH2:25][CH2:24][O:23]1.O>CN(C)C=O.C(Cl)(Cl)Cl>[O:23]1[CH2:24][CH2:25][O:26][CH:22]1[CH2:21][N:9]1[C:7]2[N:8]=[C:3]([O:2][CH3:1])[N:4]=[CH:5][C:6]=2[CH:12]=[CH:11][C:10]1=[O:13]
Reactant: COc1ncc2ccc(=O)[nH]c2n1
Reactant: BrCC1OCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Solvent: O
Product: COc1ncc2ccc(=O)n(CC3OCCO3)c2n1
Temperature: 70 °C
Reaction time: 1 h

Procedure:
To a suspension of 0.50 g of 2-methoxypyrido(2,3-d)pyrimidin-7(8H)-one in 7.5 mL of N,N-dimethylformamide, 0.59 g of potassium carbonate was added at room temperature, the temperature was increased to 60 to 80° C., and the mixture was stirred for 1 hour. Thereto was added 0.35 mL of 2-bromomethyl-1,3-dioxolan at 80° C., the temperature of the reaction mixture was increased to 103° C., and the mixture was stirred for 3 hours 30 minutes. The reaction mixture was cooled to room temperature, and water and chloroform were added thereto. The organic layer was separated, and the aqueous layer was extracted with chloroform. The organic layer and the extract were combined, the resultant solution was washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The resultant residue was purified by silica gel column chromatography using an eluent of chloroform:methanol=75:1 to obtain 0.60 g of 8-(1,3-dioxolan-2-ylmethyl)-2-methoxypyrido(2,3-d)pyrimidin-7(8H)-one as a yellow solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[C:11]([C:12]([F:15])([F:14])[F:13])=[C:10]([C:16]([OH:18])=O)[CH:9]=[N:8]1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.O[NH:43][C:44](=[NH:53])[C:45]1[CH:50]=[CH:49][C:48]([CH2:51][OH:52])=[CH:47][CH:46]=1.Cl>CN(C=O)C.O>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[C:11]([C:12]([F:13])([F:14])[F:15])=[C:10]([C:16]2[O:18][N:53]=[C:44]([C:45]3[CH:50]=[CH:49][C:48]([CH2:51][OH:52])=[CH:47][CH:46]=3)[N:43]=2)[CH:9]=[N:8]1
Reactant: O=C(O)c1cnn(-c2ccccn2)c1C(F)(F)F
Reactant: N=C(NO)c1ccc(CO)cc1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: OCc1ccc(-c2noc(-c3cnn(-c4ccccn4)c3C(F)(F)F)n2)cc1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 58 %

Procedure:
To a solution of 1-(pyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid (2.57 g, 9.99 mmol) in DMF (30 mL) was added EDC (2.395 g, 12.49 mmol), HOBt (1.913 g, 12.49 mmol) and Hunig's Base (5.24 mL, 30.0 mmol). The reaction was stirred for 40 min. at room temperature, then N-hydroxy-4-(hydroxymethyl)benzimidamide, Int.2, (2.076 g, 12.49 mmol) was added. The reaction mixture was stirred at room temperature for 7 h, then additional EDC (2.395 g, 12.49 mmol), HOBt (1.913 g, 12.49 mmol) and Hunig's Base (5.24 mL, 30.0 mmol) were added. The reaction was heated to 60° C. for 2 h, then at 110° C. for 10 min. 1N aq. HCl was added to adjust the pH to 1, then 30 mL of water was added. The resulting precipitated product was collected by filtration and washed with water to afford (4-(5-(1-(pyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazol-4-yl)-1,2,4-oxadiazol-3-yl)phenyl)methanol (2.28 g, 5.83 mmol, 58%) as a light yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=3)([C:13]#[N:14])[CH:11]([CH2:22][C:23]([CH3:26])([CH3:25])[CH3:24])[NH:10][CH:9]2[C:27]([OH:29])=O)[CH:5]=[CH:6][CH:7]=1.[CH3:30][C:31]([CH3:35])([CH3:34])[CH2:32][NH2:33].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:30][C:31]([CH3:35])([CH3:34])[CH2:32][NH:33][C:27]([CH:9]1[CH:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[C:12]([C:15]2[CH:16]=[CH:17][C:18]([Cl:21])=[CH:19][CH:20]=2)([C:13]#[N:14])[CH:11]([CH2:22][C:23]([CH3:24])([CH3:25])[CH3:26])[NH:10]1)=[O:29]
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2)C1(C#N)c1ccc(Cl)cc1
Reactant: CC(C)(C)CN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)CNC(=O)C1NC(CC(C)(C)C)C(C#N)(c2ccc(Cl)cc2)C1c1cccc(Cl)c1
Yield: 24.6 %

Procedure:
In a manner similar to the method described in Example 1e, rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (86.2 mg, 0.2 mmol) prepared in Example 1d was reacted with 2,2-dimethyl-propylamine (34.2 mg, 0.3 mmol), HATU (76 mg, 0.2 mmol) and iPr2NEt (0.1 mL, 0.55 mmol) in CH2Cl2 (2 mL) at rt overnight to give rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (2,2-dimethyl-propyl)-amide (24.6 mg, 24.6%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[N:7][C:6]([C:9]2[CH:10]=[N:11][CH:12]=[N:13][CH:14]=2)=[C:5]2[NH:15][CH:16]=[C:17]([C:18](=[O:22])[C:19]([OH:21])=O)[C:4]=12.Cl.[C:24]1([N:30]2[C:34]([N:35]3[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]3)=[N:33][N:32]=[N:31]2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C=O)C.C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:8]=[N:7][C:6]([C:9]2[CH:10]=[N:11][CH:12]=[N:13][CH:14]=2)=[C:5]2[NH:15][CH:16]=[C:17]([C:18](=[O:22])[C:19]([N:38]3[CH2:39][CH2:40][N:35]([C:34]4[N:30]([C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=5)[N:31]=[N:32][N:33]=4)[CH2:36][CH2:37]3)=[O:21])[C:4]=12
Reactant: COc1cnc(-c2cncnc2)c2[nH]cc(C(=O)C(=O)O)c12
Reactant: c1ccc(-n2nnnc2N2CCNCC2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1cnc(-c2cncnc2)c2[nH]cc(C(=O)C(=O)N3CCN(c4nnnn4-c4ccccc4)CC3)c12
Temperature: 25 °C
Reaction time: 4 h
Yield: 13.2 %

Procedure:
To a suspension of 2-(4-methoxy-7-(pyrimidin-5-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-oxoacetic acid (50 mg, 0.168 mmol), 1-(1-phenyl-1H-tetrazol-5-yl)piperazine hydrochloride (40.2 mg, 0.151 mmol) and 2-(1H-Benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (59.2 mg, 0.184 mmol) in DMF (1 ml) was added N,N-Diisopropylethylamine (0.146 ml, 0.838 mmol). The mixture was stirred at room temperature for 4 hours. The mixture was diluted with 150 ml of CH2Cl2 and washed with 5% NaHCO3 (30 ml), brine (30 ml). The organic layer was dried over Na2SO4 and concentrated to give a residue, which was purified by prep. HPLC to give 1-(4-methoxy-7-(pyrimidin-5-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-(4-(1-phenyl-1H-tetrazol-5-yl)piperazin-1-yl)ethane-1,2-dione (10 mg, 0.020 mmol, 11.68% yield) (light tan solid). LCMS: m/e 511.4 (M+H)+, ret time 1.25 min. 1H NMR (500 MHz, MeOD) δ ppm 9.30 (s, 1H) 9.17 (s, 2H) 8.38 (s, 1H) 8.16 (s, 1H) 7.58-7.65 (m, 5H) 4.09 (s, 3H) 3.80-3.83 (m, 2H) 3.57-3.60 (m, 2H) 3.38-3.42 (m, 2H) 3.31-3.33 (m, 2H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8](=[C:16]2[CH2:21][C:20]([CH3:23])([CH3:22])[CH2:19][C:18]([CH3:25])([CH3:24])[CH2:17]2)[C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[OH:26][CH2:27][C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1.C([O-])([O-])=O.[Na+].[Na+]>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.COCCOC>[OH:26][CH2:27][C:28]1[CH:33]=[CH:32][C:31]([C:2]2[CH:3]=[CH:4][C:5]([C:8](=[C:16]3[CH2:17][C:18]([CH3:25])([CH3:24])[CH2:19][C:20]([CH3:23])([CH3:22])[CH2:21]3)[C:9]3[CH:10]=[CH:11][C:12]([OH:15])=[CH:13][CH:14]=3)=[CH:6][CH:7]=2)=[CH:30][CH:29]=1
Reactant: OCc1ccc(B(O)O)cc1
Reactant: CC1(C)CC(=C(c2ccc(O)cc2)c2ccc(Br)cc2)CC(C)(C)C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CC1(C)CC(=C(c2ccc(O)cc2)c2ccc(-c3ccc(CO)cc3)cc2)CC(C)(C)C1
Temperature: 160 °C
Yield: 75 %

Procedure:
A sealed tube containing 4-[(4-bromophenyl)(3,3,5,5-tetramethylcyclohexylidene)methyl]phenol (14) (0.20 g, 0.50 mmol), 4-(hydroxymethyl)phenyl boronic acid (0.16 g, 1.0 mmol), Pd(PPh3)4 (58 mg, 0.05 mmol), 2 M Na2CO3 (4 mL) and DME (4 mL) was heated at 160° C. for 25 min. Cooled to room temperature, the mixture was extracted with EtOAc. The EtOAc extracts were combined and washed with water, brine, dried over Na2SO4, filtered, and the filtrate was concentrated to give the crude product as dark brown oil. The crude product was purified by chromatography on a silica gel column eluted with a gradient from hexanes to 35% EtOAc in hexanes to give 0.16 g (75%) of the title compound (246) as pale yellow solid. mp 222-223° C. 1H NMR (400 MHz, DMSO-d6): δ 0.89 (s, 12H), 1.25 (s, 2H), 1.92 (s, 2H), 1.93 (s, 2H), 4.50 (d, J=5.7 Hz, 2H), 5.17 (t, J=5.7 Hz, 1H), 6.66 (d, J=8.4 Hz, 2H), 6.94 (d, J=8.5 Hz, 2H), 7.18 (d, J=8.1 Hz, 2H), 7.35 (d, J=8.1 Hz, 2H), 7.56 (d, J=8.2 Hz, 2H), 7.58 (d, J=8.0 Hz, 2H), 9.26 (s, 1H). LCMS (ESI): m/z 425 (M−H)−.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:15])[CH2:9][N:10]2[CH:14]=[N:13][CH:12]=[N:11]2)=[CH:4][CH:3]=1.[H-].[Na+].[CH2:18](Br)[CH2:19][CH2:20][CH3:21]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([O:15][CH2:18][CH2:19][CH2:20][CH3:21])[CH2:9][N:10]2[CH:14]=[N:13][CH:12]=[N:11]2)=[CH:4][CH:3]=1
Reactant: CCCCBr
Reactant: OC(Cn1cncn1)c1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Product: CCCCOC(Cn1cncn1)c1ccc(Cl)cc1

Procedure:
Following the procedure of Example 9, Step 2, 1-p-chlorophenyl-2-(1,2,4-triazol-1-yl)-ethanol (2.23 g), sodium hydride (440 mg; 50%) and n-butyl bromide (1.37 g) were reacted to give the title compound as an oil. Analysis:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6](C(O[Si](C)(C)C)(C#N)[CH2:8][CH2:9][O:10]2)=[CH:5][CH:4]=1.[C:20]([OH:23])(=[O:22])[CH3:21]>Cl.ClCCl>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:21]([C:20]([OH:23])=[O:22])[CH2:8][CH2:9][O:10]2)=[CH:5][CH:4]=1
Reactant: COc1ccc2c(c1)OCCC2(C#N)O[Si](C)(C)C
Reactant: CC(=O)O
Agent: Cl
Solvent: ClCCl
Product: COc1ccc2c(c1)OCCC2C(=O)O
Temperature: 130 °C
Yield: 78.1 %

Procedure:
To 7-methoxy-4-(trimethylsilyloxy)-3,4-dihydro-2H-chromene-4-carbonitrile (1.62 g, 5.84 mmol) in acetic acid (15 mL) and HCl (15 mL) was added SnCl2 dihydrate (5.27 g, 23.4 mmol). The reaction was heated at 130° C. for 1 day. The reaction was cooled, diluted with dichloromethane (50 mL) and washed with water (50 mL) and brine (50 mL). The combined organic layers were dried over magnesium sulfate and concentrated. The residue was chromatographed over silica gel using a gradient of 0.5% MeOH/CH2Cl2 containing 0.5% acetic acid to 10% MeOH/CH2Cl2 containing 0.5% acetic acid to provide the title compound (0.95 g, 78.1% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:18]=[C:19](Br)[CH:20]=1)[C:5]([NH:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][O:13][CH2:14][CH2:15][O:16][CH3:17])=[O:6].C(N(CC)CC)C.[C:29]([Si:31]([CH:38]([CH3:40])[CH3:39])([CH:35]([CH3:37])[CH3:36])[CH:32]([CH3:34])[CH3:33])#[CH:30]>[Cu]I.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.C1COCC1>[NH2:1][C:2]1[CH:3]=[C:4]([CH:18]=[C:19]([C:30]#[C:29][Si:31]([CH:32]([CH3:34])[CH3:33])([CH:38]([CH3:40])[CH3:39])[CH:35]([CH3:37])[CH3:36])[CH:20]=1)[C:5]([NH:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][O:13][CH2:14][CH2:15][O:16][CH3:17])=[O:6]
Reactant: C#C[Si](C(C)C)(C(C)C)C(C)C
Reactant: COCCOCCOCCNC(=O)c1cc(N)cc(Br)c1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COCCOCCOCCNC(=O)c1cc(N)cc(C#C[Si](C(C)C)(C(C)C)C(C)C)c1
Temperature: 65 °C

Procedure:
To a 10 L flask under nitrogen was added the product from step (ii) above (700 g, 1.93 mol) and THF (5.59 L). This was followed by the addition of CuI (19.2 g, 0.1 mol), triethylamine (1.29 L, 9.27 mol) and ethynyltriisopropylsilane (389 g, 2.13 mol). The reaction was degassed and purged with nitrogen three times. Pd(PPh3)4 (125.5 g, 0.198 mol) was added and the reaction degassed and purged with nitrogen. The reaction was heated to 65° C. overnight, after which LC indicated 91% product and <1% starting material. The reaction mixture was concentrated in vacuo, then the residue was taken up in ethyl acetate (2 L) and put through a silica plug (2 kg), eluting with additional ethyl acetate (30 L). The product-containing fractions were concentrated in vacuo, then the crude product was dissolved in TBME (5 L) and extracted with 6 N HCl (5 L). The aqueous HCl phase was washed with TBME (2×5 L), before being basified with 6 N NaOH to pH 9-10. The product was then extracted with TBME (2×5 L), the organics were dried, filtered and concentrated in vacuo to give 635 g of the sub-title compound with a purity of >95% by 1H NMR (excluding solvents).
Reaction SMILES: [C:1]([N:4]1[C:13]2[CH:8]([CH2:9][CH2:10][CH2:11][CH:12]=2)[CH2:7][C:6](=[O:14])[N:5]1[C:15](=[O:17])[CH3:16])(=[O:3])[CH3:2].C(Cl)(=O)C.[CH3:22][O:23][CH:24](OC)OC>CN(C)C=O>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7](=[CH:22][O:23][CH3:24])[C:6](=[O:14])[N:5]1[C:15](=[O:17])[CH3:16])(=[O:3])[CH3:2]
Reactant: COC(OC)OC
Reactant: CC(=O)N1C(=O)CC2CCCC=C2N1C(C)=O
Solvent: CN(C)C=O
Solvent: CC(=O)Cl
Product: COC=C1C(=O)N(C(C)=O)N(C(C)=O)c2ccccc21
Temperature: 130 °C
Yield: 43.8 %

Procedure:
To a solution of 1,2-diacetyltetrahydrocinnolin-3-one (0.34 g, 1.5 mmol) in N,N-dimethylformamide (3.6 mL) is added acetyl chloride (5 mL) and trimethylorthoformate (0.64 mL, 6.0 mmol). The mixture is heated at reflux in a 130° C. oil bath for 12 hours under a nitrogen atmosphere and then is allowed to cool to room temperature. The reaction mixture is purified in three batches via semi-preparative HPLC (Prodigy ODS3 column, 5% MeCN/95% water/0.01% trifluoroacetic acid to 100% acetonitrile over 1 hour at 10 mL/min) to give 1,2-diacetyl-4-methoxymethylene-1,4-dihydro-2H-cinnolin-3-one (0.18 g).
Reaction SMILES: [H-].[Na+].[N:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[NH:5][CH:4]=1.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[N:20]1[CH2:25][CH2:24][N:23]([C:26](=[O:35])[CH:27](Cl)[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:22][CH2:21]1>CN(C)C=O>[CH3:12][O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[N:20]1[CH2:21][CH2:22][N:23]([C:26](=[O:35])[CH:27]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[N:3]2[C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=3[N:5]=[CH:4]2)[CH2:24][CH2:25]1
Reactant: COc1ccccc1N1CCN(C(=O)C(Cl)c2ccccc2)CC1
Reactant: c1ccc2[nH]cnc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccccc1N1CCN(C(=O)C(c2ccccc2)n2cnc3ccccc32)CC1
Reaction time: 0.5 h
Yield: 104.9 %

Procedure:
A mixture of sodium hydride (0.47 g of 80% dispersion) in dry dimethyl formamide (10 ml) at 0°-5° C. was treated with benzimidazole (1.584 g) and the mixture stirred for 30 mins. A solution of 1-(2-methoxyphenyl)-4-(2-chloro-1-oxo-2-phenylethyl) piperazine (4.624 g) in dry DMF (20 ml) was added and the mixture was stirred at 90° C. for 5 hrs then at ambient temperature overnight. The suspension was filtered and the solvent evaporated under vacuum. The residue, in dichloromethane was washed well with water and dried over magnesium sulphate, to give 6 g of an oil. The crude product was purified by dry column flash chromatography to give the title compound (2.4 g).
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]([C:6]([C:8]2[CH:18]=[CH:17][CH:16]=[CH:15][C:9]=2[C:10](OCC)=[O:11])=O)=[CH:4][N:3]=1.O.[NH2:22][NH2:23]>C(O)C>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([C:6]2[C:8]3[C:9](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:10](=[O:11])[NH:23][N:22]=2)=[CH:19][CH:20]=1
Reactant: NN
Reactant: CCOC(=O)c1ccccc1C(=O)c1ccc(Cl)nc1
Solvent: O
Solvent: CCO
Product: O=c1[nH]nc(-c2ccc(Cl)nc2)c2ccccc12
Temperature: 75 °C
Reaction time: 1 h

Procedure:
A mixture of ethyl 2-(6-chloronicotinoyl)benzoate (0.599 g, 2.1 mmol) and hydrazine hydrate (0.35 mL, 6.2 mmol) in ethanol (6 mL) was stirred at 75° C. for 1 hour, concentrated, and azeotroped with toluene to provide the title compound, which was used without purification: 1H NMR (300 MHz, DMSO-d6) δ 13.01 (s, 1H), 8.65 (dd, J=2.7, 0.6, 1H), 8.44-8.25 (m, 1H), 8.13 (dd, J=8.3, 2.5, 1H), 8.08-7.82 (m, 2H), 7.82-7.59 (m, 2H).
Reaction SMILES: C([C:5](C(C)(C)C)([O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16](=[O:37])[CH2:17][N:18]([C:20](=[O:36])[CH2:21][CH2:22][CH:23]2[CH2:28][CH2:27][N:26](C(OC(C)(C)C)=O)[CH2:25][CH2:24]2)C)=[CH:12][C:11]=1[O:38][CH2:39][C:40]([O-:42])=[O:41])[C:6]([O-:8])=[O:7])(C)(C)C>FC(F)(F)C(O)=O>[NH:26]1[CH2:27][CH2:28][CH:23]([CH2:22][CH2:21][C:20]([NH:18][CH2:17][C:16]([C:13]2[CH:14]=[CH:15][C:10]([O:9][CH2:5][C:6]([OH:8])=[O:7])=[C:11]([O:38][CH2:39][C:40]([OH:42])=[O:41])[CH:12]=2)=[O:37])=[O:36])[CH2:24][CH2:25]1
Reactant: CN(CC(=O)c1ccc(OC(C(=O)[O-])(C(C)(C)C)C(C)(C)C)c(OCC(=O)[O-])c1)C(=O)CCC1CCN(C(=O)OC(C)(C)C)CC1
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)COc1ccc(C(=O)CNC(=O)CCC2CCNCC2)cc1OCC(=O)O
Yield: 121.2 %

Procedure:
The compound prepared in (a) (480 mg) was dissolved in 5 ml of trifluoroacetic acid and treated in the same manner as described in Example 9(b) to give the title compound (380 mg).
Reaction SMILES: C([NH:6][C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][C:8]=1[C:16]#[C:17][C:18]([CH3:24])(C)[C:19](OC)=O)(=O)CCC.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>CN(C=O)C>[CH:18]([C:17]1[NH:6][C:7]2[C:8]([CH:16]=1)=[CH:9][C:10]([N+:13]([O-:15])=[O:14])=[CH:11][CH:12]=2)([CH3:24])[CH3:19]
Reactant: CCCC(=O)Nc1ccc([N+](=O)[O-])cc1C#CC(C)(C)C(=O)OC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CN(C)C=O
Product: CC(C)c1cc2cc([N+](=O)[O-])ccc2[nH]1
Temperature: 70 °C
Yield: 32.6 %

Procedure:
A mixture of methyl 4-(2-butyramido-5-nitrophenyl)-2,2-dimethylbut-3-ynoate (0.50 g, 1.5 mmol) and TBAF (790 mg, 3.0 mmol) in DMF (20 mL) was heated at 70° C. for 24 h. The reaction mixture was cooled to room temperature and poured into ice water. The mixture was extracted with ether (30 mL×3). The combined organic layers were dried over anhydrous Na2SO4 and evaporated under reduced pressure to give a residue, which was purified by column chromatography on silica gel (petroleum ether/ethyl acetate=20/1) to give 2-isopropyl-5-nitro-1H-indole (100 mg, 33%). 1H NMR (400 MHz, CDCl3) δ 8.68 (s, 1H), 8.25 (br s, 1H), 8.21 (dd, J=2.4, 10.0 Hz, 1H), 7.32 (d, J=8.8 Hz, 1H), 6.41 (s, 1H), 3.07-3.14 (m, 1H), 1.39 (d, J=6.8 Hz, 6H).