Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][CH:2]([F:13])[O:3][C:4]1[C:5]([N+:10]([O-])=O)=[N:6][CH:7]=[CH:8][CH:9]=1.[Cl-].[NH4+]>C(O)C.O.[Fe]>[F:13][CH:2]([F:1])[O:3][C:4]1[C:5]([NH2:10])=[N:6][CH:7]=[CH:8][CH:9]=1
Reactant: O=[N+]([O-])c1ncccc1OC(F)F
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: Nc1ncccc1OC(F)F
Temperature: 90 °C
Yield: 546.2 %

Procedure:
To a stirred solution of 3-(difluoromethoxy)-2-nitropyridine (5 g, 2.63 mmol) and ammonium chloride (4.22 g, 78.9 mmol) in ethanol (40 mL) and water (30 mL) was added iron powder (7.34 g, 131.51 mmol). The reaction mixture was heated to 90° C. for 1 h. After cooling down the reaction mixture was filtered and the solid was washed with ethyl acetate. The mother liquid was concentrated to dryness in vacuo. The residue was diluted with water and extracted with ethyl acetate (3×70 mL). The combined organic layers were dried over sodium sulfate and concentrated to dryness in vacuo affording 3-(difluoromethoxy)pyridin-2-amine (2.3 g, 55%). The residue was used in next step directly without further purification. 1H NMR (400 MHz, DMSO-d6) δ 7.90 (dd, J1=4.8 Hz, J2=1.6 Hz, 1H), 7.28 (dd, J1=8.0 Hz, J2=0.8 Hz, 1H), 7.07 (t, J=74.0 Hz, 1H), 6.53 (dd, J1=8.0 Hz, J2=0.8 Hz, 1H), 6.01 (s, 2H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]#[C:8][CH2:9][CH2:10]O.[C:12]1(=[O:22])[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[N:14][NH:13]1>>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]#[C:8][CH2:9][CH2:10][N:13]1[N:14]=[CH:15][C:16]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:12]1=[O:22]
Reactant: O=c1[nH]ncc2ccccc12
Reactant: OCCC#Cc1ccccn1
Product: O=c1c2ccccc2cnn1CCC#Cc1ccccn1
Yield: 11449.3 %

Procedure:
The title compound was prepared in accordance with the general method of Example 3(B), from 4-(pyridin-2-yl)but-3-yn-1-ol (102 mg, 0.69 mmol, Example 3(A)) and phthalazin-1(2H)-one (152 mg, 1.04 mmol). The crude residue was purified by flash chromatography (DCM/MeOH 99:1 to 97:3) followed by bulb-to-bulb distillation (100° C., 0.1 mbar) to yield 22 mg (79 mmol, 11%) of 2-(4-(pyridin-2-yl)but-3-ynyl)phthalazin-1(2H)-one as a brown solid.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][N:8]([C:11]3[CH:18]=[CH:17][C:14]([CH:15]=O)=[CH:13][CH:12]=3)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[C:19]([O:27][CH2:28][CH3:29])(=[O:26])[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22].C([O-])(=O)C>C1(C)C=CC=CC=1>[CH2:24]([O:23][C:21](=[O:22])[C:20](=[CH:15][C:14]1[CH:17]=[CH:18][C:11]([N:8]2[CH2:9][CH2:10][C:5]3([O:4][CH2:3][CH2:2][O:1]3)[CH2:6][CH2:7]2)=[CH:12][CH:13]=1)[C:19]([O:27][CH2:28][CH3:29])=[O:26])[CH3:25]
Reactant: O=Cc1ccc(N2CCC3(CC2)OCCO3)cc1
Reactant: CCOC(=O)CC(=O)OCC
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Product: CCOC(=O)C(=Cc1ccc(N2CCC3(CC2)OCCO3)cc1)C(=O)OCC
Temperature: 25 °C

Procedure:
A solution of 4-(1,4-dioxa-8-aza-spiro[4.5]dec-8-yl)-benzaldehyde (2.47, 10 mmol) (Taylor, E. C., Skotnicki, J. S. Synthesis, 1981, 606) and diethyl malonate (2.0 g, 12.5 mmol) in toluene (100 mL) containing a catalytic quantity of piperidineum acetate was refluxed for 18 hours. After cooling to room temperature the solution was washed with water, dried over sodium sulfate and concentrated. Purification by column chromatography on silica gel using ethyl acetate/hexanes as the eluent gave the title compound as a yellowish gum; 1H NMR (300 MHz, CDCl3) δ 1.28 (t, J=7.1 Hz, 3H), 1.29 (t, J=7.1 Hz, 3H), 1.79 (t, J=5.8 Hz, 4H), 3.46 (t, J=5.8 Hz, 4H), 4.27 (q, J=7.1 Hz, 2H), 4.31 (q, J=7.1 Hz, 2H), 6.85 (d, J=8.9 Hz, 2H), 7.33 (d, J=8.9 Hz, 2H), 7.61 (s, 1H); MS (ES) m/z: 390.0 (MH+); HRMS Calcd. for C21H27NO6 (MH+): 390.1911. Found: 390.1910.
Reaction SMILES: O1CCOCC1.[NH2:7][C:8]1[N:9]=[C:10]([CH3:22])[C:11]2[CH:17]=[C:16](Br)[C:15](=[O:19])[N:14]([CH2:20][CH3:21])[C:12]=2[N:13]=1.[CH3:23][C:24]1[C:25](B(O)O)=[CH:26][S:27][CH:28]=1.C([O-])([O-])=O.[K+].[K+]>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.O>[NH2:7][C:8]1[N:9]=[C:10]([CH3:22])[C:11]2[CH:17]=[C:16]([C:25]3[C:24]([CH3:23])=[CH:28][S:27][CH:26]=3)[C:15](=[O:19])[N:14]([CH2:20][CH3:21])[C:12]=2[N:13]=1
Reactant: CCn1c(=O)c(Br)cc2c(C)nc(N)nc21
Reactant: Cc1cscc1B(O)O
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: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CCn1c(=O)c(-c2cscc2C)cc2c(C)nc(N)nc21
Temperature: 100 °C
Yield: 54.5 %

Procedure:
A 3:1 solution of dioxane and water (4 mL) was added to a flask charged with 2-amino-6-bromo-8-ethyl-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one (0.140 g, 0.495 mmol) from above, 4-methylthiophene-3-boronic acid (0.140 g, 0.989 mmol), Pd(PPh3)4 (0.057 mg, 0.050 mmol), and K2CO3 (0.205 g, 1.48 mmol). The flask was flushed with nitrogen and fitted with a reflux condenser and heated to 100° C. After 12 hours the reaction was cooled to room temperature and diluted with ethyl acetate (70 mL) and washed with water. The aqueous phase was separated and washed with an additional amount of ethyl acetate (70 mL). The organic phases were combined and washed with brine, separated and dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified on SiO2 (1:1 methylene chloride:ethyl acetate) to give 2-Amino-8-ethyl-4-methyl-6-(4-methyl-3-thienyl)pyrido[2,3-d]pyrimidin-7(8H)-one (0.081 g, 55% yield) as an off-white solid: 1H NMR (400 MHz, DMSO-d6): δ 7.84 (s, 1H), 7.46 (d, J=4.0 Hz, 1H), 7.19 (m, 3H), 4.32 (q, J=8.0 Hz, 2H), 2.52 (s, 3H), 2.11 (bs, 3H), 1.19 (t, J=8.0 Hz, 3H); MS (EI) for C15H16N4OS: 301.1 (MH+).
Reaction SMILES: [Br:1][CH:2]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[CH:6][CH:5]=1)[CH3:3].[CH3:13]O>C1COCC1>[Br:1][CH:2]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([O:10][CH3:13])=[O:9])=[CH:6][CH:5]=1)[CH3:3]
Reactant: CC(Br)c1ccc(C(=O)O)cc1
Reactant: CO
Solvent: C1CCOC1
Product: COC(=O)c1ccc(C(C)Br)cc1
Temperature: 23 °C
Reaction time: 3 h

Procedure:
A solution of trimethylsillyldiazomethane in THF (2M, 49.1 mL, 98.3 mmol) was added dropwise to a solution of 4-(1-bromoethyl)benzoic acid (15 g, 66 mmol) in methanol (75 mL) and THF (75 mL) at 0° C. The resulting mixture was stirred at 23° C. for 3 h, then concentrated and partitioned between ethyl acetate and saturated aqueous sodium bicarbonate solution (2×). The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate, and concentrated to give the title compound. 1H NMR (400 MHz, CDCl3): δ 8.02 (d, 2H, J=8.5 Hz), 7.51 (d, 2H, J=8.2 Hz), 5.21 (q, 1H, J=6.7 Hz), 3.92 (s, 3H), 2.06 (d, 3H, J=7.0 Hz).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[F:10][C:11]1[CH:16]=[CH:15][C:14](B(O)O)=[CH:13][N:12]=1.N#N.C(=O)([O-])[O-].[Cs+].[Cs+]>O.O1CCOCC1>[F:10][C:11]1[N:12]=[CH:13][C:14]([C:2]2[C:7]([C:8]#[N:9])=[CH:6][CH:5]=[CH:4][N:3]=2)=[CH:15][CH:16]=1
Reactant: N#Cc1cccnc1Cl
Reactant: OB(O)c1ccc(F)nc1
Agent: N#N
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: N#Cc1cccnc1-c1ccc(F)nc1
Temperature: 90 °C
Reaction time: 2 h
Yield: 84.5 %

Procedure:
To an oven-dried, N2-purged, 250-mL, round-bottomed flask containing a magnetic stir bar were added the commercially available 2-chloro-3-cyanopyridine (1.25 g, 9.00 mmol), the commercially available 2-fluoropyridine-5-boronic acid (845 mg, 6.00 mmol), and dichlorobis(triphenylphosphine)pallalium(II) (211 mg, 0.300 mmol). The flask was sealed with a septum and purged with N2 atmosphere. Anhydrous dioxane (45 mL) and a N2-purged solution of cesium carbonate (5.86 g, 18.0 mmol) in water (45 mL) were added via syringe. The reaction mixture was heated to ˜90° C. in an oil bath and stirred for 2 hours. The reaction was monitored by LC-MS. After cooling to room temperature, the solvent/volatiles were removed by rotary evaporator to give a thick brown oil. Water (75 mL) was added and the mixture was transferred to a separatory funnel. The mixture was extracted with ethyl acetate (4×30 mL). The combined organic extracts were dried over magnesium sulfate, filtered, and concentrated by rotary evaporator to give a brown solid. The product was recrystallized from ethyl acetate/hexanes to give 1.01 g (84%) of the title compound as a tan powder. MS (ESI+) m/z 200.0 (M+H)+; 1H NMR (DMSO-d6) δ 7.43 (dd, J=8.6, 2.9 Hz, 1H), 7.70 (dd, J=8.1, 5.1 Hz, 1H), 8.49 (d, J=1.7 Hz, 1H), 8.51 (d, J=1.7 Hz, 1H), 8.74 (d, J=2.7 Hz, 1H), 8.98 (dd, J=4.7, 1.7 Hz, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH:11]1[CH2:14][N:13]([C:15]([C:17]2[O:18][C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[N:20][N:21]=2)=[O:16])[CH2:12]1)[CH:5]=O.FC(F)(F)C(O)=O.[CH2:35]([C:37]1([OH:41])[CH2:40][NH:39][CH2:38]1)[CH3:36]>>[CH2:35]([C:37]1([OH:41])[CH2:40][N:39]([CH2:5][C:4]2[CH:7]=[CH:8][C:9]([O:10][CH:11]3[CH2:14][N:13]([C:15]([C:17]4[O:18][C:19]([C:22]5[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=5)=[N:20][N:21]=4)=[O:16])[CH2:12]3)=[C:2]([CH3:1])[CH:3]=2)[CH2:38]1)[CH3:36]
Reactant: Cc1cc(C=O)ccc1OC1CN(C(=O)c2nnc(-c3ccccc3)o2)C1
Reactant: CCC1(O)CNC1
Solvent: O=C(O)C(F)(F)F
Product: CCC1(O)CN(Cc2ccc(OC3CN(C(=O)c4nnc(-c5ccccc5)o4)C3)c(C)c2)C1
Yield: 11 %

Procedure:
Using a similar protocol as described in Example 70 employing 74A and 70A as starting materials afforded 35 mg (11%) of 74 as a solid. 1H NMR (500 MHz, CDCl3): δ 0.95 (t, 3H), 1.78 (q, 2H), 2.24 (s, 3H), 3.01 (d, 2H), 3.31 (d, 2H), 3.57 (s, 2H), 4.35 (m, 1H), 4.68 (m, 1H), 4.75 (m, 1H), 5.07 (m, 1H), 5.12 (m, 1H), 6.45 (d, 1H), 7.06 (d, 1H), 7.11 (s, 1H), 7.52 (t, 2H), 7.60 (t, 1H), 8.16 (d, 1H), MS (APCI+) m/z 449 [M+H]+, LC purity: 97%.
Reaction SMILES: [C:1]([O:4][C:5](=[CH2:10])[C:6]([O:8][CH3:9])=[O:7])(=[O:3])[CH3:2].[H][H]>[B-](F)(F)(F)F.C1C2C=CC1C=C2.C1C2C=CC1C=C2.[Rh].PP.CO>[CH3:2][C:1]([O:4][C@@H:5]([CH3:10])[C:6]([O:8][CH3:9])=[O:7])=[O:3]
Reactant: C=C(OC(C)=O)C(=O)OC
Reactant: [H][H]
Agent: [Rh]
Agent: C1=CC2C=CC1C2
Agent: F[B-](F)(F)F
Solvent: CO
Product: COC(=O)[C@H](C)OC(C)=O
Temperature: 25 °C
Reaction time: 20 h

Procedure:
In a 50 ml Schlenk vessel, Rh(nbd)2BF4 (5.2 mg, 1 mol %) and the diphosphine ligand (1 mol %) were dissolved in MeOH (10 ml) under argon. After all of the rhodium complex had gone into solution, methyl 2-acetoxyacrylate (200 mg, 1.39 mmol) was added. The Schienk vessel was subsequently connected via a three-way stopcock with a hydrogen balloon and an oil pump and the inert gas atmosphere was replaced by hydrogen. The reaction mixture was stirred at room temperature for 20 h and the solvent was then distilled off in an oil pump vacuum. The residue was purified by bulb tube distillation. The ester (S)-8 was obtained as a colorless oil in quantitative yield.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[C:9]([F:15])([F:14])[CH2:8][N:7]([CH:16]3[CH2:19][CH2:18][CH2:17]3)[C:6]=2[N:20]=1.[NH2:21][C:22]1[CH:30]=[CH:29][C:25]([C:26]([OH:28])=[O:27])=[CH:24][C:23]=1[O:31][CH3:32]>C(O)C.O.Cl>[CH:16]1([N:7]2[CH2:8][C:9]([F:15])([F:14])[C:10](=[O:13])[N:11]([CH3:12])[C:5]3[CH:4]=[N:3][C:2]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([OH:28])=[O:27])=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:6]2=3)[CH2:19][CH2:18][CH2:17]1
Reactant: COc1cc(C(=O)O)ccc1N
Reactant: CN1C(=O)C(F)(F)CN(C2CCC2)c2nc(Cl)ncc21
Agent: Cl
Solvent: O
Solvent: CCO
Product: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCC1)CC(F)(F)C(=O)N2C
Yield: 52.4 %

Procedure:
A mixture of 2.00 g (0.0066 mole) of 2-chloro-9-cyclobutyl-7,7-difluoro-5-methyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VII-1), 1.655 g (0.0099 mole) of 4-amino-3-methoxybenzoic acid and 200 mL of ethanol-water-hydrochloric acid (20:80:1) was refluxed for 18 hours, then concentrated under reduced pressure. The solid was washed with water and then purified by silica gel chromatography, eluting with dichloromethane-methanol-ammonium hydroxide (92:8:0.3) to give 1.500 g of 4-(9-cyclobutyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-benzoic acid (I-1).
Reaction SMILES: [F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([C:13]([CH3:34])([CH3:33])[C:14]([N:16]([C:18]2[CH:19]=[N:20][C:21](Cl)=[CH:22][C:23]=2[C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=2[CH3:31])[CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[OH:37][CH2:38][CH:39]1[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]1.[Cl-].[Li+].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.O>[F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([C:13]([CH3:34])([CH3:33])[C:14]([N:16]([C:18]2[C:23]([C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=3[CH3:31])=[CH:22][C:21]([N:42]3[CH2:43][CH2:44][CH:39]([CH2:38][OH:37])[CH2:40][CH2:41]3)=[N:20][CH:19]=2)[CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: Cc1cc(F)ccc1-c1cc(Cl)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: OCC1CCNCC1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: Cc1cc(F)ccc1-c1cc(N2CCC(CO)CC2)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 140 °C
Yield: 73.1 %

Procedure:
A mixture of 0.50 g (0.94 mmol) 2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-chloro-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-N-methyl-isobutyramide, 0.32 g (2.8 mmol) 4-(hydroxymethyl)piperidine, 0.12 g (2.8 mmol) lithium chloride and 0.39 g (2.8 mmol) potassium carbonate in 5 ml DMSO was heated at 140° C. for 24 h. After cooling to room temperature the reaction mixture was diluted with water and extracted with three portions of dichloromethane. The combined organic extracts were dried over sodium sulphate and concentrated. Flash column chromatography gave 0.42 g (74%) of the title compound as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH2:11]([N:15]1[C:23]2[N:22]=[C:21]([Cl:24])[NH:20][C:19]=2[C:18](=[O:25])[N:17]([CH2:26][CH2:27][CH2:28][CH2:29]/[C:30](=[N:33]/[H])/[NH:31]O)[C:16]1=[O:35])[CH2:12][CH2:13][CH3:14]>CS(C)=O>[CH2:11]([N:15]1[C:23]2[N:22]=[C:21]([Cl:24])[NH:20][C:19]=2[C:18](=[O:25])[N:17]([CH2:26][CH2:27][CH2:28][CH2:29][C:30]2[N:31]=[C:4]([C:3]3[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=3[F:1])[O:6][N:33]=2)[C:16]1=[O:35])[CH2:12][CH2:13][CH3:14]
Reactant: [H]/N=C(/CCCCn1c(=O)c2[nH]c(Cl)nc2n(CCCC)c1=O)NO
Reactant: O=C(O)c1ccccc1F
Solvent: CS(C)=O
Product: CCCCn1c(=O)n(CCCCc2noc(-c3ccccc3F)n2)c(=O)c2[nH]c(Cl)nc21
Temperature: 90 °C
Reaction time: 16 h
Yield: 28.6 %

Procedure:
2-Fluorobenzoic acid (36 mg, 0.25 mmol) and CDl (45 mg, 0.28 mmol) were stirred in anhydrous DMSO (0.9 ml) at rt for 1 h. (1Z)-5-(3-Butyl-8-chloro-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)-N-hydroxypentanimidamide (100 mg, 0.28 mmol) was added and the mixture was stirred at 90° C. for 16 h. The mixture was purified by MDAP. The product fraction was combined and concentrated to give the title compound as a white solid (33 mg, 29%).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][N:6]2[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13].Cl[CH2:18][CH2:19][N:20]1[CH:25]=[C:24]([CH:26]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:23]=[CH:22][C:21]1=[O:39].O>CCO>[C:27]1([CH:26]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:24]2[CH:23]=[CH:22][C:21](=[O:39])[N:20]([CH2:19][CH2:18][NH:1][C:2]3[CH:10]=[CH:9][CH:8]=[C:7]4[C:3]=3[CH:4]=[CH:5][N:6]4[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:25]=2)[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: O=c1ccc(C(c2ccccc2)c2ccccc2)cn1CCCl
Reactant: CCOC(=O)Cn1ccc2c(N)cccc21
Solvent: CCO
Solvent: O
Product: CCOC(=O)Cn1ccc2c(NCCn3cc(C(c4ccccc4)c4ccccc4)ccc3=O)cccc21
Temperature: 50 °C
Reaction time: 24 h
Yield: 41.2 %

Procedure:
To a stirring solution of ethyl (4-amino-1H-indol-1-yl)acetate (94 mg) in EtOH (7 mL) was added 1-(2-chloroethyl)-5-(diphenylmethyl)-2(1H)-pyridinone (70 mg) at ambient temperature. The reaction mixture was warmed to 50° C. After 24 hours, to the mixture was added water and the resulting mixture was extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous sodium sulfate and evaporated in vacuo. The residue was purified by preparative thin-layer chromatography (chloroform:EtOAc=5:1) to give ethyl [4-({2-[5-(diphenylmethyl)-2-oxo-1(2H)-pyridinyl]ethyl}amino)-1H-indol-1-yl]acetate (45 mg).
Reaction SMILES: C(O[Si:5]([CH2:14][CH2:15][CH2:16][CH3:17])([CH2:10][CH2:11][CH2:12][CH3:13])[CH2:6][CH2:7][CH2:8][CH3:9])(=O)C.[C:18]([OH:23])(=[O:22])[C:19]([CH3:21])=[CH2:20]>>[C:18]([O:23][Si:5]([CH2:10][CH2:11][CH2:12][CH3:13])([CH2:14][CH2:15][CH2:16][CH3:17])[CH2:6][CH2:7][CH2:8][CH3:9])(=[O:22])[C:19]([CH3:21])=[CH2:20]
Reactant: C=C(C)C(=O)O
Reactant: CCCC[Si](CCCC)(CCCC)OC(C)=O
Product: C=C(C)C(=O)O[Si](CCCC)(CCCC)CCCC

Procedure:
4 g of acetoxytri-n-butylsilane and 1.33 g of commercial methacrylic acid (ATOFINA Norsocryl® MAA) are mixed at room temperature, acetic acid is then distilled under reduced pressure (45° C./13 hPa) to afford tri-n-butylsilyl methacrylate.
Reaction SMILES: [C:1]([O:5][C:6](=[O:42])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:29]=[CH:28][C:27](Br)=[CH:26][CH:25]=3)[O:21][C:22]=2[CH3:23])=[CH:11][C:10]=1[CH2:31][O:32][C:33](=[O:41])[NH:34][CH:35]1[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1)([CH3:4])([CH3:3])[CH3:2].C1(C)C=CC=CC=1.[NH:50]1[CH2:55][CH2:54][O:53][CH2:52][CH2:51]1.CC(C)([O-])C.[Na+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CCOC(C)=O>[C:1]([O:5][C:6](=[O:42])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:29]=[CH:28][C:27]([N:50]4[CH2:55][CH2:54][O:53][CH2:52][CH2:51]4)=[CH:26][CH:25]=3)[O:21][C:22]=2[CH3:23])=[CH:11][C:10]=1[CH2:31][O:32][C:33](=[O:41])[NH:34][CH:35]1[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: C1COCCN1
Reactant: Cc1oc(-c2ccc(Br)cc2)nc1CCOc1ccc(CCC(=O)OC(C)(C)C)c(COC(=O)NC2CCCCC2)c1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: Cc1oc(-c2ccc(N3CCOCC3)cc2)nc1CCOc1ccc(CCC(=O)OC(C)(C)C)c(COC(=O)NC2CCCCC2)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 19.1 %

Procedure:
A 1 mL microvial under a nitrogen atmosphere was charged with 3-(4-{2-[2-(4-bromophenyl)-5-methyloxazol-4-yl]ethoxy}-2-cyclohexylcarbamoyloxymethylphenyl)-propionic acid tert-butyl ester (0.30 g, 0.468 mmol; Example 39), anhydrous toluene (0.5 mL), and then morpholine (0.053 mL, 0.61 mmol). Tris(dibenzylideneacetone)-dipalladium(0) (0.004 g, 0.0044 mmol), 2-(di-tert-butylphosphine)biphenyl (0.006 g, 0.020 mmol), and sodium tert-butoxide (0.063 g, 0.655 mmol) were added sequentially. The mixture was stirred at ambient temperature under a nitrogen atmosphere for 5 h and was poured into EtOAc (50 mL). The organic layer was washed with brine (2×), dried (Na2SO4), and concentrated to a dark yellow oil. This crude product was purified using radial chromatography (EtOAc:hexanes 15:85 to 50:50) to give a yellow oil (0.058 g, 19%). 1H NMR (400 MHz, CDCl3) 1.07-1.18 (m, 3H), 1.29-1.40 (m, 1H), 1.42 (s, 9H), 1.52-1.70 (m, 4H), 1.91-1.93 (m, 2H), 2.34 (s, 3H), 2.46 (t, J=8.1 Hz, 2H), 2.87 (t, J=7.8 Hz, 2H), 2.94 (t, J=6.8 Hz, 2H), 3.24 (t, J=4.9 Hz, 4H), 3.48-3.50 (m, 1H), 3.86 (t, J=4.9 Hz, 4H), 4.20 (t, J=6.6 Hz, 2H), 5.07 (s, 2H), 6.79 (dd, J=8.6, 2.7 Hz, 1H), 6.85-6.93 (m, 3H), 7.09 (d, J=8.3 Hz, 1H), 7.87 (dd, J=11.5, 2.7 Hz, 2H). MS (ES) m/e 648 (M+1).
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:2][C:3]([O-:5])=O.[K+].[Mg+2].[Cl-].[Cl-].C(N(CC)CC)C.[F:21][C:22]1[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][C:23]=1C(Cl)=O.Cl>C(OCC)(=O)C>[F:21][C:22]1[CH:23]=[CH:27][C:28]([C:31]([F:32])([F:33])[F:34])=[CH:29][C:30]=1[C:3](=[O:5])[CH2:2][C:1]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: O=C(Cl)c1cc(C(F)(F)F)ccc1F
Reactant: CCOC(=O)CC(=O)[O-]
Agent: Cl
Agent: [Cl-]
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCOC(=O)CC(=O)c1cc(C(F)(F)F)ccc1F
Temperature: 40 °C

Procedure:
Potassium ethyl malonate (10.2 g, 60 mmol), MgCl2 (6.3 g, 66 mmol), and triethylamine (28 ml, 200 mmol) were suspended in dry ethyl acetate (200 ml) and heated to 40° C. for 15 hr. A solution of 2-fluoro-5-trifluoromethylbenzoyl chloride (10 g, 44.1 mmol) in ethyl acetate (40 ml) was dropped in slowly (in about one hour). After another hour, the mixture was treated with 2N HCl (200 ml). The organic layer was washed with 0.5 N HCl 2×, 5% K2CO3 2×, brine 2×, and dried over Na2SO4. Evaporation of the solvent and vacuum drying afforded ethyl 3-[2-fluoro-5-(trifluoromethyl)phenyl]-3-oxopropanoate as a pale yellow oil. NMR (500 MHz, CDCl3) δ: 1.25 (t, J=7.4 Hz, 3H); 1.32*; 4.00 (d, JF-H=3 Hz, 2H); 4.21 (q, J=7.4 Hz, 2H); 5.8*; 7.22*; 7.29 (t, J=10.3 Hz, 1H); 7.66*; 7.82 (br, 1H); 8.14*; 8.24 (d, J=6.4 Hz, 1H). Enol form* exists in about 35%.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[O:3][C:4]1[CH:5]=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([C:16](O)=[O:17])=[CH:12][N:11]=2)[CH:7]=[CH:8][CH:9]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[F:20][C:2]([F:1])([F:19])[O:3][C:4]1[CH:5]=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][OH:17])=[CH:12][N:11]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: O=C(O)c1ccc(-c2cccc(OC(F)(F)F)c2)nc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCc1ccc(-c2cccc(OC(F)(F)F)c2)nc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 2-(3-trifluoromethoxyphenyl)-5-carboxy pyridine (2.0 g, 7.06 mmol) in tetrahydrofuran (15 mL) at 0° C. was added 1.0M lithium aluminum hydride in tetrahydrofuran (7.07 mL, 7.07 mmol) over 10 minutes. The reaction was allowed to stir at ambient temperature for 4 hours, cooled to 0° C., and quenched by dropwise addition of saturated Na2SO4 (1.0 mL). The reaction was diluted with diethylether, filtered through a pad of Celite and the filtrate evaporated in vacuo. The residue was chromatographed (silica gel, 50% EtOAc in hexanes) to afford the title compound.
Reaction SMILES: [ClH:1].[NH2:2][C:3]1[C:4]([C:8](=[N:10][OH:11])N)=[N:5][O:6][N:7]=1.N([O-])=O.[Na+]>O>[NH2:2][C:3]1[C:4]([C:8]([Cl:1])=[N:10][OH:11])=[N:5][O:6][N:7]=1
Reactant: NC(=NO)c1nonc1N
Reactant: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: Nc1nonc1C(Cl)=NO
Temperature: 2.5 °C
Reaction time: 1.5 h
Yield: 21 %

Procedure:
A solution of 3 M of hydrogen chloride in water (190 mL) was treated with 4-amino-N′-hydroxy-1,2,5-oxadiazole-3-carboximidamide [J. Heterocycl. Chem. (1965), 2, 253] (7.3 g, 0.051 mol) at 0° C. The reaction mixture was treated with enough 12 M hydrogen chloride (˜19 mL) to dissolve the solid and then treated with a solution of sodium nitrite (4.4 g, 0.063 mol) in water (24 mL) dropwise while maintaining an internal temperature at 0-5° C. with an ice/brine bath. The reaction mixture was stirred at 0° C. for 1.5 h and filtered to yield a beige solid. Purification of the crude mixture by preparative HPLC gave the desired product (1.7 g, 21%) as an off-white solid.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([CH3:11])[CH:3]=1.[CH3:12]O>Cl>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH3:12])=[O:7])=[C:4]([CH3:11])[CH:3]=1
Reactant: CO
Reactant: Cc1cc(Br)ccc1C(=O)O
Agent: Cl
Product: COC(=O)c1ccc(Br)cc1C
Yield: 100 %

Procedure:
A solution of 4-bromo-2-methyl benzoic acid (1.0 g, 4.7 mmol) in methanol (24 mL) was treated with 20 drops of HCl, heated at reflux for 6 hours, and concentrated to provide the desired product (1.07 g, 100%).