Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](Cl)=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=[N:9]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH2:23]([NH2:27])[CH:24]([CH3:26])[CH3:25].O>CN(C=O)C>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:27][CH2:23][CH:24]([CH3:26])[CH3:25])=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1cnc2cc(Br)ccc2c1Cl
Reactant: CC(C)CN
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)CNc1c([N+](=O)[O-])cnc2cc(Br)ccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.5 %

Procedure:
To a suspension of 7-bromo-4-chloro-3-nitroquinoline (25.0 g, 87.0 mmol) in DMF (70 mL) was added triethylamine (18.2 mL, 130 mmol). A solution of iso-butylamine (9.50 mL, 95.7 mmol) in DMF (20 mL) was added dropwise. The viscous reaction mixture was stirred overnight at ambient temperature. Water (200 mL) was added and the mixture was stirred for 1 hour. A solid was isolated by filtration, washed with water, and dried in a vacuum oven overnight to yield 26.1 g of 7-bromo-N-(2-methylpropyl)-3-nitroquinolin-4-amine as a yellow powder.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][CH:8]=[CH:9][CH:10]=1)=[O:5])[CH3:2].[Cl-].[Al+3].[Cl-].[Cl-].[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][C:23](Cl)=[O:24])=[CH:18][CH:17]=1.C(O)C(N)(CO)CO>ClC(Cl)C>[CH2:1]([O:3][C:4]([C:6]1[NH:7][CH:8]=[C:9]([C:23](=[O:24])[CH2:22][C:19]2[CH:20]=[CH:21][C:16]([Cl:15])=[CH:17][CH:18]=2)[CH:10]=1)=[O:5])[CH3:2]
Reactant: O=C(Cl)Cc1ccc(Cl)cc1
Reactant: CCOC(=O)c1ccc[nH]1
Agent: NC(CO)(CO)CO
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC(Cl)Cl
Product: CCOC(=O)c1cc(C(=O)Cc2ccc(Cl)cc2)c[nH]1
Temperature: 60 °C
Yield: 48.4 %

Procedure:
Ethylpyrrole-2-carboxylate (1.0195 g, 7.33 mmol) in a minimal amount of dichloroethane was added to an ice cooled stirring mixture of aluminum chloride (1.934 g, 14.5 mmol) and 4-chlorobenzeneacetyl chloride (2.7841 g, 14.73 mmol) in dichloroethane (10.9 mL, 0.67 M) under N2. After stirring 10 min, the ice bath was removed, and the reaction was stirred at room temperature for 60 minutes, with little change by TLC (9:1 Hexanes:EtOAc): After heating to 60° C. for an additional hour, only a small quantity of starting material was left by TLC. The reaction was cooled to room temperature, PS-Trisamine™ resin (6.3954 g, 24.30 mmol) and dichloroethane (10 mL) were added, and the reaction was stirred for 3 hours. The reaction was then filtered through a glass-fritted funnel directly into ice water. The resin was rinsed with CH2Cl2, then the organic layers were removed, dried with Na2SO4, filtered, concentrated, and purified by silica gel chromatography (Combiflash column, 95:5 to 50:50 Hexanes:EtOAc) to obtain 1.0345 g (48.4%) 37 as a pale orange solid. Note. A small amount of CH2Cl2 was required to solubilize the crude product before placement on the silica column. 1H (CDCl3, 400 MHz): δ 10.07 (1H, broad s), 7.55-7.52 (1H, m), 7.33-7.30 (1H, m), 7.27 (2H, d, J=8.3 Hz), 7.14 (2H, d, J=8.3 Hz), 4.35 (2H, q, J=7.0 Hz), 4.04 (2H, s), 1.37 (3H, t, J=7.1 Hz) ppm. 13C (CDCl3, 100 MHz): δ 192.55, 160.97, 133.10, 132.75, 130.76, 128.69, 126.80, 126.25, 124.30, 114.95, 61.06, 45.79, 14.31 ppm. DEPT (CDCl3, 100 MHz): CH3 carbons: 14.31; CH2 carbons: 61.06, 45.79; CH carbons: 130.76, 128.69, 126.80, 114.96 ppm. HPLC: 10.049 min.
Reaction SMILES: [CH3:1][C:2]1[C:3]2[C:9](=O)[CH2:8][CH:7]([CH2:11][N+:12]([O-:14])=[O:13])[C:4]=2[S:5][CH:6]=1>C1COCC1>[CH3:1][C:2]1[C:3]2[CH2:9][CH2:8][CH:7]([CH2:11][N+:12]([O-:14])=[O:13])[C:4]=2[S:5][CH:6]=1
Reactant: Cc1csc2c1C(=O)CC2C[N+](=O)[O-]
Solvent: C1CCOC1
Product: Cc1csc2c1CCC2C[N+](=O)[O-]
Reaction time: 2 h
Yield: 56.4 %

Procedure:
A solution of 3-methyl-6-(nitromethyl)-5,6-dihydro-4H-cyclopenta[b]thiophen-4-one (9.5 g) in 13H3.THF (400 mL) was stirred at room temperature overnight. TLC analysis indicated the consumption of starting material. The reaction mixture was acidified to pH 2 with 10% HCl and stirred for 2 h. The mixture was extracted with EtOAc (100 mL×3). The combined organic phase was dried with Na2SO4, and concentrated in vacuo. The crude product was purified by flash column chromatography to afford 5 g of title compound (yield: 56.4%).
Reaction SMILES: [H-].[Na+].O1CCCC1.[C:8]([O:12][C:13]([NH:15][C@H:16]1[CH2:21][CH2:20][C@H:19]([OH:22])[CH2:18][CH2:17]1)=[O:14])([CH3:11])([CH3:10])[CH3:9].Cl[C:24]1[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][N:25]=1>O.CS(C)=O>[C:8]([O:12][C:13]([NH:15][C@H:16]1[CH2:17][CH2:18][C@H:19]([O:22][C:24]2[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][N:25]=2)[CH2:20][CH2:21]1)=[O:14])([CH3:11])([CH3:9])[CH3:10]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](O)CC1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@H](Oc2ccc([N+](=O)[O-])cn2)CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
2.04 g of 60% sodium hydride was gradually added to 150 ml of a tetrahydrofuran solution containing 10.0 g of trans-4-(tert-butoxycarbonylamino)cyclohexanol and 7.35 g of 2-chloro-5-nitropyridine, and 30 mL of dimethylsulfoxide was further added thereto, and then, the mixture was stirred at room temperature for 1 day. The reaction mixture was poured into water and extracted with chloroform. The extract was washed with water and brine, dried over anhydrous sodium sulfate, and then, the solvent was removed under reduced pressure. The residue was applied to silica gel column chromatography (solvent: chloroform alone to chloroform-ethyl acetate (20:1)). The obtained powder crystals were suspended in ethyl acetate-hexane mixed solution and collected by filtration to obtain 12.20 g of trans-1-tert-butoxycarbonylamino-4-(5-nitro-2-pyridyloxy)-cyclohexane. To 10 ml of an ethanol suspension containing 800 mg of this compound was added 2 ml of 2N hydrochloric acid-dioxane solution, and the mixture was stirred at room temperature for 18 hours. The precipitates were collected by filtration to obtain 568 mg of trans-4-(5-nitro-2-pyridyloxy)cyclohexylamine.hydrochloride (Reference Example 9-1 in Table 6).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:31])=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][CH:9]2[C:28]([OH:30])=O)[CH:5]=[CH:6][CH:7]=1.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.[NH2:65][C:66]1[CH:71]=[CH:70][C:69]([C:72]2[NH:76][N:75]=[CH:74][N:73]=2)=[CH:68][CH:67]=1>C(Cl)Cl>[N:75]1[NH:76][C:72]([C:69]2[CH:70]=[CH:71][C:66]([NH:65][C:28]([CH:9]3[CH:8]([C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=4[F:31])[C:12]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=4[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:25])([CH3:27])[CH3:26])[NH:10]3)=[O:30])=[CH:67][CH:68]=2)=[N:73][CH:74]=1
Reactant: Nc1ccc(-c2ncn[nH]2)cc1
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
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)CC1NC(C(=O)Nc2ccc(-c3ncn[nH]3)cc2)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of rac (2R,3S,4R,5S)-3-(3-Chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (150 mg, 0.32 mmol) in methylene chloride (5 mL), HATU (Aldrich, 152 mg, 0.4 mmol) was added followed by the addition of DIPEA (0.1 mL) and 5-(4-amino-phenyl)-1H-[1,2,4]triazole (made above, 64 mg, 0.4 mmol). The mixture was stirred at rt for 2 hrs. The reaction was quenched with addition of water. The mixture was extracted with methylene chloride (2×10 mL) and the extracts were dried with magnesium sulfate. The solvent was removed and the residue was purified on an ISCO machine (40 g column, 70% EtOAc/hexanes) to give a white solid. 140 mg.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:8][CH3:9])=[N:6][CH:7]=1.C([Li])CCC.[CH3:15][O:16][C:17]1[N:22]=[CH:21][C:20]([C:23]#[N:24])=[CH:19][CH:18]=1.[BH4-].[Na+]>C1COCC1.CO>[CH3:9][O:8][C:5]1[N:6]=[CH:7][C:2]([CH:23]([C:20]2[CH:21]=[N:22][C:17]([O:16][CH3:15])=[CH:18][CH:19]=2)[NH2:24])=[CH:3][CH:4]=1
Reactant: COc1ccc(C#N)cn1
Reactant: COc1ccc(Br)cn1
Agent: [BH4-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(C(N)c2ccc(OC)nc2)cn1
Temperature: 25 °C
Reaction time: 0.42 h

Procedure:
To 5-bromo-2-methoxypyridine (1.00 g, 5.32 mmol) in THF (20 mL) at −78° C. was added n-butyllithium (3.13 mL, 7.83 mmol, 2.5 M in hexane). The reaction was aged at −78° C. for about 25 min at which point the cold bath was removed. 6-methoxypyridine-3-carbonitrile (1.00 g, 7.46 mmol) in THF (10 mL) was added and the reaction aged for about 40 min warming to rt at which point the reaction was concentrated. The residue was diluted with MeOH (20 mL) and NaBH4 (0.282 g 7.46 mmol) was added. The reaction aged about 90 min at rt. The reaction was concentrated and diluted with EtOAc and aq HCl (15 mL, 2 M). The aq portion was extracted twice with EtOAc before adding aq NaOH (20 mL, 2M). The aq portion was then extracted three times with EtOAc. The combined organic portion was concentrated and the residue was purified by flash chromatography on silica gel gradient eluted with 0-100% EtOAc/hexane followed by 0-20% MeOH (containing 1.5% triethylamine)/EtOAc affording the title compound. HPLC/MS: 246 (M+1); Rt=1.61 min.
Reaction SMILES: [CH3:1][N:2]1[CH2:23][CH2:22][C:5]2[NH:6][C:7]3[C:8](/[CH:13]=[CH:14]/[C:15]4[CH:16]=[N:17][C:18]([CH3:21])=[CH:19][CH:20]=4)=[CH:9][CH:10]=[CH:11][C:12]=3[C:4]=2[CH2:3]1>O=[Pt]=O.C(O)C>[CH3:1][N:2]1[CH2:23][CH2:22][C:5]2[NH:6][C:7]3[C:8]([CH2:13][CH2:14][C:15]4[CH:16]=[N:17][C:18]([CH3:21])=[CH:19][CH:20]=4)=[CH:9][CH:10]=[CH:11][C:12]=3[C:4]=2[CH2:3]1
Reactant: Cc1ccc(/C=C/c2cccc3c4c([nH]c23)CCN(C)C4)cn1
Agent: O=[Pt]=O
Solvent: CCO
Product: Cc1ccc(CCc2cccc3c4c([nH]c23)CCN(C)C4)cn1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Adam's catalyst (PtO2, 17 mg, 0.075 mmol; Aldrich) was added to a solution of the product of Example 1C (170 mg, 0.56 mmol) in ethanol (20 mL). The reaction flask was evacuated and purged with nitrogen (3 cycles) then evacuated and purged with hydrogen (4 cycles), and the mixture was stirred under hydrogen (1 atm) at room temperature for 18 hours. The flask was evacuated and purged with nitrogen (3 cycles), and the reaction mixture was filtered. The filtrate was concentrated under vacuum, and the residue was purified by reverse-phase HPLC [Waters XBridge™ RP18 column, 5 μm, 30×100 mm, flow rate 40 mL/minute, 20-100% gradient of methanol in buffer (0.1 M aqueous ammonium bicarbonate, adjusted to pH 10 with ammonium hydroxide)] to afford the title compound: 1H NMR (300 MHz, methanol-d4) δ ppm 2.45 (s, 3H), 2.54 (s, 3H), 2.84-3.03 (m, 6H), 3.06-3.15 (m, 2H), 3.67 (s, 2H), 6.74-6.78 (m, 1H), 6.83-6.91 (m, 1H), 7.14 (d, J=7.9 Hz, 1H), 7.18 (dd, J=7.9, 1.2 Hz, 1H), 7.49 (dd, J=7.9, 2.0 Hz, 1H), 8.13 (d, J=2.0 Hz, 1H); MS (APCI) m/z 306 (M+H)−.
Reaction SMILES: [Cl:1][C:2]1([O:22][CH3:23])[CH:7]=[C:6]([O:8][CH3:9])[N:5]=[C:4]([C:10]([CH2:12][C:13]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:14])=[O:11])[NH:3]1.[BH4-].[Na+].[Cl-].[NH4+]>C(O)C>[Cl:1][C:2]1([O:22][CH3:23])[CH:7]=[C:6]([O:8][CH3:9])[N:5]=[C:4]([CH:10]([OH:11])[CH2:12][C:13]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:14])[NH:3]1
Reactant: COC1=CC(Cl)(OC)NC(C(=O)CC(=O)Nc2ccccc2)=N1
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Product: COC1=CC(Cl)(OC)NC(C(O)CC(=O)Nc2ccccc2)=N1
Temperature: 25 °C
Reaction time: 1 h
Yield: 68.6 %

Procedure:
In a reactor were placed 1.00 g (3.0 m moles) of 4-chloro-2-(4,6-dimethoxypyrimidine-2-ylcarbonyl)acetanilide and 20 ml of ethanol. The reactor contents were cooled to 5° C. or less. Thereto was added 0.25 g (6.6 m moles) of sodium borohydride. The mixture was stirred at the same temperature for 1 hour. Then, the temperature was increased to room temperature. After the completion of the reaction, an aqueous ammonium chloride solution was added and the mixture was extracted with ethyl acetate. The organic layer was concentrated. The concentrate was purified by silica gel column chromatography (n-hexane/ethyl acetate=1/1) to obtain 0.69 g (2.0 m moles) of 4-chloro-2-(4,6-dimethoxypyrimidine-2-ylhydroxymethyl)acetanilide. Yield: 68%
Reaction SMILES: C(P1(=O)OP(=O)(CCC)OP(=O)(CCC)O1)CC.[Br:19][C:20]1[CH:25]=[C:24]([C:26]#[C:27][Si:28]([CH:35]([CH3:37])[CH3:36])([CH:32]([CH3:34])[CH3:33])[CH:29]([CH3:31])[CH3:30])[N:23]=[C:22]([NH2:38])[CH:21]=1.[CH3:39][N:40]([C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])[CH:41]([CH3:45])[C:42](O)=[O:43].C(=O)([O-])O.[Na+]>CCOC(C)=O.N1C=CC=CC=1>[C:49]([O:48][C:46](=[O:47])[N:40]([CH:41]([C:42](=[O:43])[NH:38][C:22]1[CH:21]=[C:20]([Br:19])[CH:25]=[C:24]([C:26]#[C:27][Si:28]([CH:32]([CH3:34])[CH3:33])([CH:35]([CH3:37])[CH3:36])[CH:29]([CH3:31])[CH3:30])[N:23]=1)[CH3:45])[CH3:39])([CH3:50])([CH3:51])[CH3:52]
Reactant: CC(C)[Si](C#Cc1cc(Br)cc(N)n1)(C(C)C)C(C)C
Reactant: CC(C(=O)O)N(C)C(=O)OC(C)(C)C
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CC(C(=O)Nc1cc(Br)cc(C#C[Si](C(C)C)(C(C)C)C(C)C)n1)N(C)C(=O)OC(C)(C)C
Reaction time: 3 h

Procedure:
2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide (70 ml of a 50 wt.-% solution in EtOAc, 118 mmol) is added to a mixture of 4-bromo-6-{2-[tris(propan-2-yl)silyl]ethynyl}pyridin-2-amine B1 (10.4 g, 29.5 mmol), 2-[methyl-[(2-methylpropan-2-yl)oxycarbonyl]amino]propanoic acid (12 g, 59 mmol) and pyridine (20 ml) at −20° C. The mixture is stirred for 3 h at that temperature. 200 ml of a saturated aqueous sodium hydrogencarbonate solution is added and the mixture extracted with EtOAc. The combined organic layers are dried over MgSO4 and concentrated in vacuo. The product is purified by NP chromatography. Yield: 11.1 g (70%). HPLC-MS: M+H=538/540; tR=.2.05 min (METHOD—1).
Reaction SMILES: [CH2:1]([C@H:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:7](=[O:16])[C@H:6]([O:17][Si](C(C)(C)C)(C)C)[C@H:5]1[O:25][Si](C(C)(C)C)(C)C)[CH:2]=[CH2:3].C(O)(=O)[C@H]([C@@H](C(O)=O)O)O.Cl>C(O)C>[CH2:1]([C@H:4]1[N:8]([CH2:9][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:7](=[O:16])[C@H:6]([OH:17])[C@H:5]1[OH:25])[CH:2]=[CH2:3]
Reactant: C=CC[C@@H]1[C@H](O[Si](C)(C)C(C)(C)C)[C@@H](O[Si](C)(C)C(C)(C)C)C(=O)N1Cc1ccccc1
Agent: Cl
Agent: O=C(O)[C@@H](O)[C@H](O)C(=O)O
Solvent: CCO
Product: C=CC[C@@H]1[C@H](O)[C@@H](O)C(=O)N1Cc1ccccc1
Temperature: 50 °C
Reaction time: 48 h
Yield: 31.8 %

Procedure:
A mixture composed of 150 g of (3R*,4S*,5R*)-5-allyl-1-benzyl-3,4-bis(tert-butyldimethylsilyloxy)-2-pyrrolidinone which had been prepared according to the procedure described in J. Org. Chem. 60, 103-108 (1995) by using D-tartaric acid as the starting material, 500 ml of ethanol, and 20 ml of concentrated hydrochloric acid was heated to 50° C. and stirred for 2 days. After the reaction mixture was concentrated under reduced pressure, water was added to the resulting residue. This mixture was washed with n-hexane and then extracted with chloroform. After the extract was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. Then, ether and n-hexane were added to the resulting residue so as to crystallize the desired product. These crystals were collected by filtration to obtain 24.8 g of (3R*,4S*,5R*)-5-allyl-1-benzyl-3,4-dihydroxy-2-pyrrolidinone.
Reaction SMILES: [C:1]1(=[O:11])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][NH:2]1.[CH3:12][CH2:13]C(N)CCCCC>>[CH:10]1([C:1]([NH2:2])=[O:11])[C:5]2[C:6](=[CH:12][CH:13]=[CH:3][CH:4]=2)[CH2:7][CH2:8][CH2:9]1
Reactant: O=c1[nH]ccc2ccccc12
Reactant: CCCCCC(N)CC
Product: NC(=O)C1CCCc2ccccc21

Procedure:
A preferred process for preparing 2-(1-azabicyclo 2.2.2!oct-3-yl)-2,3,3a,4,5,6-hexahydro-1H-benz de!isoquinolin-1-one is that in which L is chloro and the 1-azabicyclo 2.2.2!oct-3-ylamine is (S)-1-azabicyclo 2.2.2!oct-3-ylamine and is reacted with the compound of Formula 5 to give N-(1-azabicyclo 2.2.2!oct-3S-yl)-1,2,3,4-tetrahydronaphthalen-1-ylcarboxamide; and preferably wherein the N-(1-azabicyclo 2.2.2!oct-3S-yl)-1,2,3,4-tetrahydronaphthalen-1-ylcarboxamide is then reduced as N-(1-azabicyclo 2.2.2!oct-3S-yl)-1,2,3,4-tetrahydronaphthalen-1S-ylcarboxamide.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:34])=[C:14]([C:29](OCC)=[O:30])[C:15](=[O:28])[N:16]3[CH2:19][CH2:20][N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][C:22]3=[O:27])=[N:11][CH:10]=2)=[CH:4][CH:3]=1.[NH2:35][CH:36]([CH:40]1[CH2:42][CH2:41]1)[CH2:37][CH2:38][OH:39]>>[CH:40]1([CH:36]([NH:35][C:29]([C:14]2[C:15](=[O:28])[N:16]([CH2:19][CH2:20][N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][C:22]3=[O:27])[C:17]3[C:12]([C:13]=2[OH:34])=[N:11][CH:10]=[C:9]([CH2:8][C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[CH:18]=3)=[O:30])[CH2:37][CH2:38][OH:39])[CH2:42][CH2:41]1
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCN2CCCCC2=O)c1=O
Reactant: NC(CCO)C1CC1
Product: O=C(NC(CCO)C1CC1)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCN2CCCCC2=O)c1=O

Procedure:
This compound was prepared from ethyl 7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1-[2-(2-oxo-1-piperidinyl)ethyl]-1,2-dihydro-1,5-naphthyridine-3-carboxylate and 3-amino-3-cyclopropyl-1-propanol using methods similar to Example 563 to provide an off-white solid: 1H NMR (300 MHz, DMSO-d6) δ ppm 0.24-0.34 (m, 2 H), 0.38-0.46 (m, 1 H), 0.52 (t, J=8.74 Hz, 1 H), 1.00-1.11 (m, 1 H), 1.54-1.67 (m, 4 H), 1.75-1.88 (m, 2 H), 2.04 (s, 2 H), 3.28 (t, J=5.69 Hz, 3 H), 3.46-3.60 (m, 5 H), 4.17 (s, 2 H), 4.41 (t, J=6.95 Hz, 2 H), 7.11-7.17 (m, 2 H), 7.38-7.45 (m, 2 H), 8.22 (s, 1 H), 8.56 (d, J=1.47 Hz, 1 H), 10.36 (d, J=8.63 Hz, 1 H), 17.23 (s, 1 H); ES+ MS: 537 (M+H+).
Reaction SMILES: C([Li])CCC.[CH3:6][C:7]1[CH:12]=[C:11]([CH3:13])[CH:10]=[CH:9][C:8]=1[C:14]1[O:15][CH2:16][C:17]([CH3:20])([CH3:19])[N:18]=1.Br[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH2:29][CH3:30])[CH:24]=1>CCCC(C)C.O1CCCC1>[CH2:29]([C:25]1[CH:24]=[C:23]([CH2:22][CH2:6][C:7]2[CH:12]=[C:11]([CH3:13])[CH:10]=[CH:9][C:8]=2[C:14]2[O:15][CH2:16][C:17]([CH3:20])([CH3:19])[N:18]=2)[CH:28]=[CH:27][CH:26]=1)[CH3:30]
Reactant: CCc1cccc(CBr)c1
Reactant: Cc1ccc(C2=NC(C)(C)CO2)c(C)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCC(C)C
Product: CCc1cccc(CCc2cc(C)ccc2C2=NC(C)(C)CO2)c1
Reaction time: 1 h

Procedure:
n-Butyllithium (16.8 ml of a 2.5M solution in isohexane) was added dropwise to a stirred solution of the product of step (iii) (8.13 g) in dry tetrahydrofuran (ISOml) at 0° C. under nitrogen. After 1 hour, the product of step (ii) (8.0 g) in tetrahydrofliran (60 ml) was added. After 1 hour, the reaction was quenched with aqueous ammonium chloride and partitioned between ethyl acetate and water. The organic solution was dried (MgSO4) and evaporated. Purification was by chromatography eluting with 5% ethyl acetate in isohexane. Yield 4.93 g.
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=1)[CH:11]=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:16]([O:18][C:19]([CH:21]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:20])[CH3:17]>O1CCOCC1.C(OCC)(=O)C.CCCCCCC.C(OCC)(=O)C>[O:1]([C:8]1[CH:9]=[C:10]([CH:11]=[CH:21][C:19]([O:18][CH2:16][CH3:17])=[O:20])[CH:13]=[CH:14][CH:15]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1cccc(Oc2ccccc2)c1
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: CCCCCCC
Product: CCOC(=O)C=Cc1cccc(Oc2ccccc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.5 %

Procedure:
To a stirred solution of 23.4 g (0.188 mole) of 3-phenoxybenzaldehyde in 175 mL of 1,4-dioxane was added 45.2 grams (0.130 mole) of ethoxycarbonylmethylenetriphenylphosphorane in one portion. The reaction was allowed to stir at ambient temperature overnight. The solvent was evaporated under reduced pressure, leaving a residue which was dissolved in ethyl acetate. Approximately 30 grams of silica gel was mixed with this solution. This solvent was evaporated under reduced pressure, and the silica gel was placed in a sintered glass filter. The silica gel was eluted with 1000 mL of heptane/ethyl acetate (3:1). The solvent was evaporated under reduced pressure, leaving an oil. This oil was dissolved in 150 mL of heptane/ethyl acetate (9:1), treated with 15 grams of silica gel, and filtered. The filtrate was evaporated under reduced pressure, leaving 26.7 grams of ethyl 3-(3-phenoxyphenyl)acrylate as an oil. The nmr spectrum was consistent with the proposed structure.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]2[CH:10]=[C:9]([CH:11]([OH:13])[CH3:12])[N:8]([CH:14]([CH2:17][CH3:18])[CH2:15][CH3:16])[C:6]=2[N:7]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[CH:10]=[C:9]([C:11](=[O:13])[CH3:12])[N:8]([CH:14]([CH2:15][CH3:16])[CH2:17][CH3:18])[C:6]=2[N:7]=1
Reactant: CCC(CC)n1c(C(C)O)cc2cnc(Cl)nc21
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: CCC(CC)n1c(C(C)=O)cc2cnc(Cl)nc21
Reaction time: 1 h
Yield: 109.1 %

Procedure:
To a solution of 1-[2-chloro-7-(1-ethyl-propyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-ethanol (61 mg, 0.2 mmol) in CH2Cl2 (2 mL) is added Dess-Martin periodinane (242 mg, 0.5 mmol). The reaction mixture is stirred for 1 h, quenched with 10% NaS2O3:saturated NaHCO3 (1:1) aqueous solution, and extracted with CH2Cl2. The extracts are washed with water and brine, dried over Na2SO4, and concentrated in vacuo. The residue is purified by flash chromatography (SiO2, EtOAc/Hexane 1:3) to afford 58 mg of 1-[2-chloro-7-(1-ethyl-propyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-ethanone.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH2:27][CH2:28][NH2:29])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[CH:30](=O)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH2:27][CH2:28][NH:29][CH2:30][C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)=[CH:17][CH:16]=3)=[CH:13][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: O=Cc1ccccc1
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4CCN)cc3)cc2)CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4CCNCc4ccccc4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 21, Step 1, using 1-{4′-[4-(2-amino-ethyl)-3-methyl-isoxazol-5-yl]-biphenyl-4-yl}-cyclopropanecarboxylic acid ethyl ester and benzaldehyde.
Reaction SMILES: C(OC([N:8]1[C:17]2[C:12](=[CH:13][C:14](Br)=[CH:15][N:16]=2)[CH2:11][CH2:10][CH2:9]1)=O)(C)(C)C.[C:19]([O:23]CC1C=CC=CC=1)(=[O:22])[CH:20]=[CH2:21].CCN(C(C)C)C(C)C.N#N>C(#N)CC.CC([O-])=O.CC([O-])=O.[Pd+2].CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>[N:16]1[C:17]2[NH:8][CH2:9][CH2:10][CH2:11][C:12]=2[CH:13]=[C:14](/[CH:21]=[CH:20]/[C:19]([OH:23])=[O:22])[CH:15]=1
Reactant: CC(C)(C)OC(=O)N1CCCc2cc(Br)cnc21
Reactant: C=CC(=O)OCc1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCC#N
Solvent: CCN(C(C)C)C(C)C
Product: O=C(O)/C=C/c1cnc2c(c1)CCCN2
Temperature: 25 °C
Yield: 103.9 %

Procedure:
A solution of 1-(tert-butoxycarbonyl)-6-bromo-1,2,3,4-tetrahydro-1,8-naphthyridine (1.79 g, 5.70 mmole), benzyl acrylate (1.11 g, 6.84 mmole), Pd(OAc)2 (65 mg, 0.29 mmole), P(o-tolyl)3 (173 mg, 0.57 mmole), and (i-Pr)2NEt (2.5 mL, 14.25 mmole) in propionitrile (30 mL) was degassed (3×N2/vacuum) then heated to reflux. After 18 hr the mixture was cooled to RT and concentrated. Flash chromatography on silica gel (25% EtOAc/hexanes) gave the title compound (1.21 g, 54%) as a yellow solid: 1H NMR (400 MHz, CDCl3) δ 8.44 (s,1H), 7.65 (d, J=16.0 Hz,1H), 7.53 (s,1H), 7.40 (m, 5H), 6.43 (d, J=16.0 Hz,1H), 5.25 (s, 2H). 3.77 (m, 2H), 2.75 (t, 16.5 Hz, 2H), 1.93 (m, 2H), 1.54 (s, 9H)