Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([O:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:5]([NH:8][C:9]2[S:10][CH:11]=[C:12]([CH2:14][CH:15]3[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C:16]3=[O:27])[N:13]=2)=[N:6][CH:7]=1.[OH-:35].[Na+]>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([O:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:5]([NH:8][C:9]2[S:10][CH:11]=[C:12]([CH2:14][CH:15]([CH2:19][CH2:18][NH:17][C:20]([O:22][C:23]([CH3:25])([CH3:24])[CH3:26])=[O:21])[C:16]([OH:27])=[O:35])[N:13]=2)=[N:6][CH:7]=1
Reactant: [OH-]
Reactant: CC(C)(C)OC(=O)N1CCC(Cc2csc(Nc3ncc(Br)cc3Oc3ccccc3)n2)C1=O
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCCC(Cc1csc(Nc2ncc(Br)cc2Oc2ccccc2)n1)C(=O)O
Temperature: 55 °C
Reaction time: 3 h

Procedure:
tert-Butyl 3-((2-(5-bromo-3-phenoxypyridin-2-ylamino)thiazol-4-yl)methyl)-2-oxopyrrolidine-1-carboxylate (0.070 g, 0.128 mmol) (Example 393, Steps A-C) was dissolved in 1 mL of THF and sodium hydroxide (0.963 mL, 1.93 mmol) 2M solution was added. The resulting solution was heated to 55° C. and agitated for 3 hours. Reaction was quenched with 3 mL of 2M potassium hydrosulfate solution and extracted twice with ethyl acetate. The extracts were washed with water, brine, dried and evaporated to produce the title compound. 1H NMR (CDCl3) δ 1.40 (s, 9H), 1.60-1.74 (m, 2H), 2.64-3.08 (m, 5H), 4.65 (bs, 1H), 6.47 (s, 1H), 7.09-7.43 (m, 7H), 8.14 (s, 1H).
Reaction SMILES: ClCCl.[Br:4][C:5]1[CH:6]=[C:7]([NH:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][C:20]([F:25])([F:24])[CH:21]([F:23])[F:22])[CH:14]=2)[CH:8]=[CH:9][CH:10]=1.[F:26][C:27]([F:32])([F:31])[CH:28]1[O:30][CH2:29]1.C(S([O-])(=O)=O)(F)(F)F.C(S([O-])(=O)=O)(F)(F)F.C(S([O-])(=O)=O)(F)(F)F.[Yb+3]>C(OCC)C>[Br:4][C:5]1[CH:6]=[C:7]([N:11]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][C:20]([F:24])([F:25])[CH:21]([F:23])[F:22])[CH:14]=2)[CH2:29][CH:28]([OH:30])[C:27]([F:32])([F:31])[F:26])[CH:8]=[CH:9][CH:10]=1
Reactant: FC(F)C(F)(F)Oc1cccc(CNc2cccc(Br)c2)c1
Reactant: FC(F)(F)C1CO1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: ClCCl
Solvent: CCOCC
Product: OC(CN(Cc1cccc(OC(F)(F)C(F)F)c1)c1cccc(Br)c1)C(F)(F)F
Temperature: 25 °C
Reaction time: 24 h
Yield: 99 %

Procedure:
EX-220B) To a dichloromethane (9 mL) solution of the EX-220A amine (3.27 g, 8.65 mmol) was added 1,1,1-trifluoro-2,3-epoxypropane (0.968 mL, 11.3 mmol) and Yb(OTf)3 (0.536 g, 0.86 mmol). The cloudy mixture was stirred at room temperature for 24 hours, then diluted with diethyl ether. The organic layer was washed with water and brine, dried (MgSO4) and evaporated to yield 4.20 g (99%) of the desired 3-[(3-bromophenyl)-[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol product as a pale brown oil which can be used without further purification. The formation of the desired product was confirmed by the presence of the alcohol peak (δ1.5, d) in the 1H NMR spectrum (C6D6). An analytical sample was purified by silica gel chromatography eluting with 20% ethyl acetate in hexane to give the desired pure product as a yellow oil. FABMS m/z=491[M+H]+. 1H NMR (CDCl3) δ3.55-3.63 (m, 1H), 3.88 (dd, 1H), 4.36 (m, 1H), 4.69 (s, 2H), 5.914 (tt, 1H), 6.66 (dd, 1H), 6.92 (m, 2H), 7.06 (s, 1H), 7.09 (m, 3H), 7.36 (t, 1H).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[N:7][CH:6]=[CH:5][N:4]=1.Cl[C:10]1C(CCl)=CC=C(Cl)[N:11]=1>>[CH3:10][NH:11][CH2:2][C:3]1[CH:8]=[N:7][CH:6]=[CH:5][N:4]=1
Reactant: ClCc1cnccn1
Reactant: ClCc1ccc(Cl)nc1Cl
Product: CNCc1cnccn1

Procedure:
The reaction according to Reference Example 11 was carried out using 2-chloromethylpyrazine in lieu of 2,6-dichloro-3-pyridylmethyl chloride to give the title compound as oil.
Reaction SMILES: [Sn](Cl)(Cl)(Cl)Cl.[CH3:6][O:7][C:8]1[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[C:10]([O:16][CH3:17])[CH:9]=1.[Cl:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23](Cl)=[O:24].Cl>C1C=CC=CC=1>[CH3:17][O:16][C:10]1[CH:9]=[C:8]([O:7][CH3:6])[CH:13]=[C:12]([O:14][CH3:15])[C:11]=1[C:23]([CH2:22][CH2:21][CH2:20][CH2:19][Cl:18])=[O:24]
Reactant: COc1cc(OC)cc(OC)c1
Reactant: O=C(Cl)CCCCCl
Agent: Cl
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: c1ccccc1
Product: COc1cc(OC)c(C(=O)CCCCCl)c(OC)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 91 g (0.384 mol) of tin tetrachloride in 112.5 ml of benzene is added over 1 h 30 min to a solution, maintained at about +5° C., of 50.4 g (0.3200 mol) of 1,3,5-trimethoxybenzene and 50.2 g (0.324 mol) of 5-chlorovaleryl chloride in 225 ml of benzene. The mixture is stirred overnight at room temperature and the reaction medium is poured into 325 ml of ice-cold water and 75 ml of 12N hydrochloric acid. The organic phase is separated out after settling has taken place, washed with water and dried over dry sodium sulphate.
Reaction SMILES: [Li]C(C)(C)C.CCCCC.Br[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[S:18]([N:21]([C:28]1[O:32][N:31]=[C:30]([CH3:33])[C:29]=1[CH3:34])[CH2:22][O:23][CH2:24][CH2:25][O:26][CH3:27])(=[O:20])=[O:19].C[O:36][B:37](OC)[O:38]C.Cl>C1COCC1>[B:37]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[S:18]([N:21]([C:28]1[O:32][N:31]=[C:30]([CH3:33])[C:29]=1[CH3:34])[CH2:22][O:23][CH2:24][CH2:25][O:26][CH3:27])(=[O:20])=[O:19])([OH:38])[OH:36]
Reactant: COB(OC)OC
Reactant: COCCOCN(c1onc(C)c1C)S(=O)(=O)c1ccccc1Br
Agent: Cl
Agent: [Li]C(C)(C)C
Solvent: CCCCC
Solvent: C1CCOC1
Product: COCCOCN(c1onc(C)c1C)S(=O)(=O)c1ccccc1B(O)O
Temperature: -100 °C
Reaction time: 0.08 h
Yield: 70.1 %

Procedure:
A 1.7 M solution of t-BuLi in pentane (5.0 ml; 8.50 mmol) was added over ~10 minutes to a solution of 2-bromo-N-(3,4-dimethyl-5-isoxazolyl)-N-[(2-methoxyethoxy)methyl]benzenesulfonamide (1.62 g; 3.86 mmol) in THF at -100° C. The temperature was kept below -80° C. during the addition. After stirring 5 minutes at -100° C., trimethylborate (0.53 ml; 4.63 mmol) was added in one portion and the reaction mixture was allowed to warm to room temperature over several hours. At this time, 15 ml of 10% HCl was added and the mixture was extracted with methylene chloride (3×50 ml). The combined organic layers were washed with water (50 ml) and brine (50 ml). Drying (MgSO4), and concentration afforded a yellow oil. The residue was then partitioned between ether (50 ml) and 0.5 N NaOH (20 ml). The ether layer was extracted with 10 ml of 0.5N NaOH. The combined basic layers were washed with ether (50 ml), acidified to pH ~1.5 with saturated KHSO4 solution and extracted with methylene chloride (3×50 ml). Drying (MgSO4) and concentration afforded 1.04 g (70%) of the title product of this step as a light yellow foamy oil.
Reaction SMILES: [N:1]1[CH2:6][CH2:5][CH2:4][NH:3][C:2]=1[NH:7][CH2:8][CH2:9][CH2:10][O:11][C:12]1[CH:13]=[CH:14][C:15]2[CH2:21][CH:20]([CH2:22][C:23]([O:25]CC)=[O:24])[C:19]3[CH:28]=[CH:29][CH:30]=[CH:31][C:18]=3[CH2:17][C:16]=2[CH:32]=1.O.[OH-].[Li+].C1COCC1>O>[N:1]1[CH2:6][CH2:5][CH2:4][NH:3][C:2]=1[NH:7][CH2:8][CH2:9][CH2:10][O:11][C:12]1[CH:13]=[CH:14][C:15]2[CH2:21][CH:20]([CH2:22][C:23]([OH:25])=[O:24])[C:19]3[CH:28]=[CH:29][CH:30]=[CH:31][C:18]=3[CH2:17][C:16]=2[CH:32]=1
Reactant: CCOC(=O)CC1Cc2ccc(OCCCNC3=NCCCN3)cc2Cc2ccccc21
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)CC1Cc2ccc(OCCCNC3=NCCCN3)cc2Cc2ccccc21
Yield: 98.8 %

Procedure:
A solution of ethyl (±)-10,11-dihydro-3-[3-(3,4,5,6-tetrahydropyrimid-2-ylamino)-1-propyloxy]-5H-dibenzo[a,d]cycloheptene-10-acetate (0.17 g, 0.36 mmol), lithium hydroxide monohydrate (0.042 g, 1 mmol), THF (3 mL), and water (10 mL) was stirred at room temperature for 20 hr, then was concentrated. The residue was dissolved in water, and the solution was brought to pH 4 with 3 N HCl. The resulting solution was kept in the refrigerator overnight, then the supernatant was decanted away from the solid. The solid was dried in vacuum to give the title compound (0.145 g, 91%) as a tan solid: MS (ES) 408.3 (M+H)+. Anal. Calcd for C24H29N3O3.1.3 HCl: C, 63.37; H,6.71; N, 9.23. Found: C, 63.67; H, 6.84; N, 9.46.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[CH:4][N:3]=1.[Cl:9][C:10]1[CH:11]=[C:12](B(O)O)[CH:13]=[CH:14][CH:15]=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.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:9][C:10]1[CH:15]=[C:14]([C:2]2[CH:7]=[C:6]([NH2:8])[CH:5]=[CH:4][N:3]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: Nc1ccnc(Cl)c1
Reactant: OB(O)c1cccc(Cl)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: [K+]
Solvent: C1COCCO1
Product: Nc1ccnc(-c2cccc(Cl)c2)c1
Temperature: 120 °C
Yield: 47.1 %

Procedure:
2-Chloropyridin-4-amine (200 mg, 1.556 mmol), 3-chlorophenylboronic acid (243 mg, 1.556 mmol) and Pd(PPh3)4 (450 mg, 0.389 mmol) were combined in dioxane (4 mL) and saturated K2CO3 solution (2 mL). The mixture was heated at 120° C. for 30 minutes in a microwave. The solvent was removed to give a residue which was purified by silica column chromatography eluting with a gradient of 0-5% methanol in dichloromethane to give the title compound as light yellow oil (150 mg, 47.1% yield).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([N:10]2[C:14]3[C:15](=[O:28])[N:16]([C:20]4[CH:25]=[CH:24][C:23]([I:26])=[CH:22][C:21]=4[F:27])[CH2:17][CH2:18][CH2:19][C:13]=3[C:12]([C:29]([F:32])([F:31])[F:30])=[N:11]2)[CH:6]=[CH:7][C:8]=1[F:9])#[N:2].BrN1C(=O)CCC1=O.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)(Cl)Cl>[C:1]([C:3]1[CH:4]=[C:5]([N:10]2[C:14]3[C:15](=[O:28])[N:16]([C:20]4[CH:25]=[CH:24][C:23]([I:26])=[CH:22][C:21]=4[F:27])[CH2:17][CH:18]=[CH:19][C:13]=3[C:12]([C:29]([F:31])([F:30])[F:32])=[N:11]2)[CH:6]=[CH:7][C:8]=1[F:9])#[N:2]
Reactant: N#Cc1cc(-n2nc(C(F)(F)F)c3c2C(=O)N(c2ccc(I)cc2F)CCC3)ccc1F
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: N#Cc1cc(-n2nc(C(F)(F)F)c3c2C(=O)N(c2ccc(I)cc2F)CC=C3)ccc1F

Procedure:
1-(3-Cyano-4-fluorophenyl)-3-trifluoromethyl-7-(2-fluoro-4-iodophenyl)-4,5,6,7-tetrahydropyrazolo-[3,4-c]azepin-8-one prepared by the same methods as shown in Example 40 (0.50 g, 0.90 mmol), N-bromosuccinimide (0.19 g, 1.08 mmol), and AIBN (9.0 mg) were refluxed with 50 mL of CCl4 under N2 for 2 h. The reaction mixture was cooled and filtered through Celite. The filtrate was concentrated to a brown solid. It was then dissolved in 20 mL of THF and 1, 8-diazabicyclo[5, 4, 0]unden-7-ene (DBU, 0.14 mL) was added. The mixture was refluxed for 12 h. The solvent was removed. It was dissolved in EtOAc and washed with water and brine, dried over MgSO4 and concentrated. Flash chromatography on silica gel with 15% EtOAc in hexane gave 0.21 g of 1-(3-Cyano-4-fluorophenyl)-3-trifluoromethyl-7-(2-fluoro-4-iodophenyl)-6,7-dihydropyrazolo-[3,4-c]azepin-8-one. The title compound was then prepared from 1-(3-Cyano-4-fluorophenyl)-3-trifluoromethyl-7-(2-fluoro-4-iodophenyl)-6,7-dihydropyrazolo-[3,4-c]azepin-8-one by the same methods shown in Example 40. LRMS (ES+): 603.2, (M+H)+. 1H NMR (CDCl3) 7.82 (d, 1H), 7.73 (m, 2H), 7.54-7.35 (m, 4H), 7.09 (dd, 4H), 6.46 (m, 1H), 4.34 (s, 2H), 4.32 (d, 2H), 3.86 (bs, 2H), 3.59 (m, 2H), 2.58 (m, 2H), 2.01 (m, 2H), 1.85 (m, 2H).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][N:7]=[C:6]([Cl:10])[CH:5]=1)(=[O:3])[CH3:2].CCCCCC.C(O[CH:20](OCC)[N:21]([CH3:23])[CH3:22])C>>[CH3:20][N:21]([CH3:23])[CH:22]=[CH:2][C:1]([C:4]1[CH:9]=[CH:8][N:7]=[C:6]([Cl:10])[CH:5]=1)=[O:3]
Reactant: CCOC(OCC)N(C)C
Reactant: CC(=O)c1ccnc(Cl)c1
Solvent: CCCCCC
Product: CN(C)C=CC(=O)c1ccnc(Cl)c1
Temperature: 25 °C

Procedure:
A mixture of 4-acetyl-2-chloro-pyridine (1.72 g, 11 mmol) in N,N-dimethyl formamide diethyl acetal (10 mL) is heated to reflux for 1 hour and cooled to room temperature before adding hexane (8 mL). The solid is collected by filtration, washed with hexane and dried to give 3-dimethylamino-1-(2-chloro-4-pyridyl)-2-propen-1-one (1.70 g); ESI-MS (m/z): 211.0 (M++H).
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[CH:7]2.[CH3:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18]Br)=[CH:16][CH:15]=1>CN(C=O)C>[Br:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH2:13][C:14]1[CH:21]=[CH:20][C:17]([CH3:18])=[CH:16][CH:15]=1)[CH:8]=[CH:7]2
Reactant: Brc1ccc2[nH]ccc2c1
Reactant: Cc1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(Cn2ccc3cc(Br)ccc32)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
NaH (60%, 2.53 g, 63.1 mmol) was added portionwise to a stirring solution of 5-bromoindole (8.25 g, 42.1 mmol) in DMF (80 mL) at 0° C. under a nitrogen atmosphere over a period of 10 min. The mixture was then warmed up to room temperature. After the reaction mixture was stirred at room temperature for 1 hour, 4-methylbenzyl bromide (12.0 g, 63.1 mmol) was added and the mixture was stirred at room temperature overnight. The reaction was quenched with aqueous ammonium chloride and diluted with water. The aqueous phase was extracted with ethyl acetate. The organic extract was washed with water and brine, then dried over anhydrous magnesium sulfate. This mixture was concentrated to give a crude oil (14.1 g, 71%). Crystallization from petroleum ether afforded the title compound as a white solid, m.p: 56-57° C. Mass spectrum (APCI, [M+H]+) m/z 300. 1HNMR (400 MHz, DMSO-d6): δ 7.73 (s, 1H), 7.53 (s, 1H), 7.40 (d, 1H, J=8.9 Hz), 7.18 (d, 1H, J=10.5 Hz), 7.09 (d, 2H, J=8.2 Hz), 7.07 (d, 2H, J=8.2 Hz), 6.45 (s, 1H), 5.35 (s, 2H), and 2.22 ppm (s, 3H). Elemental Analysis for C16H14BrN: Calculated: C, 64.02; H, 4.70; N, 4.67. Found: C, 63.66; H, 4.59; N, 4.71.
Reaction SMILES: [Mg].[CH2:2]([O:4][CH2:5][CH2:6][CH2:7]Br)[CH3:3].[NH2:9][C:10]1[CH:11]=[CH:12][C:13]2[CH:19]=[CH:18][C:17]3[CH:20]=[CH:21][CH:22]=[CH:23][C:16]=3[C:15](=[O:24])[C:14]=2[CH:25]=1.[Cl-].[NH4+]>O1CCCC1>[NH2:9][C:10]1[CH:11]=[CH:12][C:13]2[CH:19]=[CH:18][C:17]3[CH:20]=[CH:21][CH:22]=[CH:23][C:16]=3[C:15]([CH2:7][CH2:6][CH2:5][O:4][CH2:2][CH3:3])([OH:24])[C:14]=2[CH:25]=1
Reactant: CCOCCCBr
Reactant: Nc1ccc2ccc3ccccc3c(=O)c2c1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCOCCCC1(O)c2ccccc2C=Cc2ccc(N)cc21
Reaction time: 0.25 h

Procedure:
Magnesium turnings (6.2 g., 0.255 mole) covered with dry tetrahydrofuran (30 ml.) in carefully-dried apparatus are treated with a solution of 3-ethoxypropylbromide (42.5 g., 0.255 mole) added dropwise to maintain reflux. After preparation of the Grignard reagent according to standard procedures, the mixture is cooled, and 16 g. (0.072 mole) of 3-amino-5H-dibenzo[a,d]cyclohepten-5-one added in portions over 5 minutes. The reaction is stirred 15 minutes, then poured into 200 ml. of saturated aqueous ammonium chloride. The layers are separated, and the aqueous layer extracted once with ether. The ether layer, combined with the original organic phase, is washed once with water, dried over sodium sulfate, and evaporated in vacuo to give the title compound in essentially quantitative yield.
Reaction SMILES: C([O:3][C:4](=[O:23])[C:5]([CH3:22])([O:14][C:15]1[CH:16]=[C:17]([CH3:21])[CH:18]=[CH:19][CH:20]=1)[CH2:6][C:7]1[CH:12]=[CH:11][C:10](O)=[CH:9][CH:8]=1)C.[C:24]1([C:30]2[O:31][C:32]([CH3:48])=[C:33]([CH2:35][CH2:36][O:37]S(C3C=CC(C)=CC=3)(=O)=O)[N:34]=2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH3:22][C:5]([O:14][C:15]1[CH:16]=[C:17]([CH3:21])[CH:18]=[CH:19][CH:20]=1)([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:37][CH2:36][CH2:35][C:33]2[N:34]=[C:30]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[O:31][C:32]=2[CH3:48])=[CH:9][CH:8]=1)[C:4]([OH:23])=[O:3]
Reactant: CCOC(=O)C(C)(Cc1ccc(O)cc1)Oc1cccc(C)c1
Reactant: Cc1ccc(S(=O)(=O)OCCc2nc(-c3ccccc3)oc2C)cc1
Product: Cc1cccc(OC(C)(Cc2ccc(OCCc3nc(-c4ccccc4)oc3C)cc2)C(=O)O)c1

Procedure:
The title compound was prepared from 3-(4-hydroxy-phenyl)-2-methyl-2-m-tolyloxy-propionic acid ethyl ester and toluene-4-sulfonic acid 2-(2-phenyl-5-methyl-oxazol-4-yl)-ethyl ester using Standard Procedure (B). 1H NMR (400 MHz, CDCl3) δ 8.04-8.01 (m, 2H), 7.47-7.45 (m, 3H), 7.18 (d, 2H, J=8.60 Hz), 7.13 (t, 1H, J=7.82 Hz), 6.87-6.85 (m, 1H), 6.82 (d, 2H, J=8.60 Hz), 6.74-6.67 (m, 2H), 4.23 (t, 2H, J=6.26 Hz), 3.24 (d, 1H, J=13.69 Hz), 3.12 (d, 1H, J=13.69 Hz), 3.06 (t, 2H, J=6.26 Hz), 2.41 (s, 3H), 2.29 (s, 3H), 1.42 (s, 3H); HRMS (ES+) m/z exact mass calcd for C29H30O5 472.2124, found 472.2098.
Reaction SMILES: [OH2:1].[OH-].[Li+].[F:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[O:16][C:15](=[O:17])[C:14]3=[CH:18][CH:19]=[C:20]([CH3:21])[N:13]3[CH2:12]2)=[CH:7][CH:6]=1.Cl>O.C1COCC1.CCOC(C)=O>[F:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]([OH:16])[CH2:12][N:13]2[C:20]([CH3:21])=[CH:19][CH:18]=[C:14]2[C:15]([OH:1])=[O:17])=[CH:7][CH:6]=1
Reactant: O
Reactant: Cc1ccc2n1CC(c1ccc(F)cc1)OC2=O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1ccc(C(=O)O)n1CC(O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 100.2 %

Procedure:
A solution of lithium hydroxide hydrate (103 mg, 2.4 mmol) in water (1 mL) was added to a solution of 3-(4-fluorophenyl)-6-methyl-3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazin-1-one (200 mg, 0.8 mmol) in THF (9 mL) at room temperature. The reaction was stirred at room temperature for 2 days. The reaction mixture was then diluted with EtOAc (20 mL) and acidified to approx. pH 2 with 1 M HCl (aq). The organic layer was separated and the aqueous layer extracted further with EtOAc (2×20 mL). The combined organic layers were washed with water, dried (MgSO4), filtered and concentrated in vacuo to give 1-[2-(4-fluorophenyl)-2-hydroxyethyl]-5-methyl-1H-pyrrole-2-carboxylic acid as an off-white solid (211 mg, 98%). 1H NMR (400 MHz, CD3OD): δ 2.07 (s, 3H), 4.31 (dd, 1H, J 13.7, 7.9 Hz), 4.42 (dd, 1H, J 13.7, 4.9 Hz), 4.99 (dd, 1H, J 7.7, 5.1 Hz), 5.85 (dd, 1H, J 3.9, 0.7 Hz), 6.92 (d, 1H, J 3.9 Hz), 6.97-7.06 (m, 2H), 7.34 (dd, 2H, J 8.5, 5.5 Hz).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([CH3:18])[C:5]2[CH:11]=[C:10](Br)[C:9](=[O:13])[N:8]([CH:14]3[CH2:17][CH2:16][CH2:15]3)[C:6]=2[N:7]=1.[C:19]([Cu])#[N:20]>CN1C(=O)CCC1.[Cl-].[Na+].O>[NH2:1][C:2]1[N:3]=[C:4]([CH3:18])[C:5]2[CH:11]=[C:10]([C:19]#[N:20])[C:9](=[O:13])[N:8]([CH:14]3[CH2:17][CH2:16][CH2:15]3)[C:6]=2[N:7]=1
Reactant: N#C[Cu]
Reactant: Cc1nc(N)nc2c1cc(Br)c(=O)n2C1CCC1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CN1CCCC1=O
Product: Cc1nc(N)nc2c1cc(C#N)c(=O)n2C1CCC1
Temperature: 220 °C
Yield: 78.3 %

Procedure:
To a solution of 2-amino-6-bromo-8-cyclobutyl-4-methyl-8H-pyrido[2,3-d]pyrimidin-7-one (371 mg, 1.20 mmol) in NMP (4 mL) was added CuCN (480 mg, 5.36 mmol). The mixture was sealed and heated at 220° C. for 30 min using microwave irradiation. The mixture was poured into brine and filtered to give a solid. The aqueous phase was extracted with t-butyl methyl ether (3 times), dried and evaporated. The combined solid was purification by flash chromatography, using 0 to 3% MeOH/CHCl3, to give the title compound (240 mg, 78%).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH3:7][C:8]1[O:12][C:11]([Si:13]([CH2:18][CH3:19])([CH2:16][CH3:17])[CH2:14][CH3:15])=[CH:10][C:9]=1[CH:20]=[O:21]>O1CCCC1>[CH3:7][C:8]1[O:12][C:11]([Si:13]([CH2:18][CH3:19])([CH2:16][CH3:17])[CH2:14][CH3:15])=[CH:10][C:9]=1[CH2:20][OH:21]
Reactant: CC[Si](CC)(CC)c1cc(C=O)c(C)o1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC[Si](CC)(CC)c1cc(CO)c(C)o1
Temperature: 25 °C

Procedure:
LiAlH4 (1.0M solution in hexane, 0.51 ml, 0.51 mmol) was added dropwise to a solution of 5-methyl-2-triethylsilyl-4 -furaldehyde (230 mg, 1.03 mmol) in tetrahydrofuran (15 ml) at 0 degrees under argon. The stirring solution was allowed to warm to room temperature gradually over 1/2 hour. The reaction was quenched with 10% aqueous HCl and the organics were extracted into ethyl ether. The combined fractins were washed with H2O and brine. Evaporation of the dried (magnesium sulfate) extracts gave an oil which was purified by filtration through silica using 10% ethyl ether/hexanes to give the title compound.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([CH:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:11]=2)[OH:9])[CH:5]=[CH:4][CH:3]=1.C(O)(=O)C>O.[O-2].[O-2].[O-2].[Cr+6]>[Br:1][C:2]1[N:7]=[C:6]([C:8](=[O:9])[C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:11]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: OC(c1cccc(Oc2ccccc2)c1)c1cccc(Br)n1
Agent: [Cr+6]
Agent: [O-2]
Solvent: CC(=O)O
Solvent: O
Product: O=C(c1cccc(Oc2ccccc2)c1)c1cccc(Br)n1
Reaction time: 1 h

Procedure:
A solution of 5 g chromium trioxide in 10 ml water is added to a mixture of 20 g 6-bromo-α-(3-phenoxyphenyl)-2-pyridinemethanol (see Ex. 18) and 70 ml glacial acetic acid. After stirring for 1 hr. at room temperature, the reaction mixture is added to ice:water and extracted with chloroform. The organic layer is washed with 2.5N NaOH, then with water, dried (Na2SO4) and solvent removed. Yield: 15.4 g of the title product, m.p. 65°-6° C. (from methanol); Br 22.87 (22.56).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([O:8][C:9]2[CH:10]=[CH:11][C:12]([CH3:25])=[C:13]([NH:15][C:16]([C:18]3[N:22]([CH3:23])[N:21]=[C:20]([CH3:24])[CH:19]=3)=[O:17])[CH:14]=2)=[CH:4][CH:3]=1.[N:26]([C:29]([O:31][CH2:32][CH3:33])=[O:30])=[C:27]=[S:28].CS(C)=O>O>[CH3:23][N:22]1[C:18]([C:16]([NH:15][C:13]2[CH:14]=[C:9]([CH:10]=[CH:11][C:12]=2[CH3:25])[O:8][C:5]2[CH:4]=[CH:3][C:2]([NH:1][C:27]([NH:26][C:29](=[O:30])[O:31][CH2:32][CH3:33])=[S:28])=[N:7][CH:6]=2)=[O:17])=[CH:19][C:20]([CH3:24])=[N:21]1
Reactant: CCOC(=O)N=C=S
Reactant: Cc1cc(C(=O)Nc2cc(Oc3ccc(N)nc3)ccc2C)n(C)n1
Solvent: O
Solvent: CS(C)=O
Product: CCOC(=O)NC(=S)Nc1ccc(Oc2ccc(C)c(NC(=O)c3cc(C)nn3C)c2)cn1
Temperature: 25 °C
Reaction time: 15 h
Yield: 94.3 %

Procedure:
A mixture of N-{5-[(6-aminopyridin-3-yl)oxy]-2-methylphenyl}-1,3-dimethyl-1H-pyrazole-5-carboxamide (214 mg, 0.634 mmol), ethyl isothiocyanatoformate (108 mg, 0.824 mmol) and DMSO (5 mL) was stirred at room temperature for 15 hr. The reaction mixture was diluted with water and extracted with ethyl acetate (×3). The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and filtrated. The filtrate was concentrated under reduced pressure, and the residue was collected by filtration and washed with ethyl acetate-hexane to give ethyl ({[5-(3-{[(1,3-dimethyl-1H-pyrazol-5-yl) carbonyl]amino}-4-methylphenoxy)pyridin-2-yl]amino}carbonothioyl)carbamate (280 mg, 94%) as a white solid. A mixture of ethyl ({[5-(3-{[(1,3-dimethyl-1H-pyrazol-5-yl)carbonyl]amino}-4-methylphenoxy)pyridin-2-yl]amino}carbonothioyl)carbamate (270 mg, 0.576 mmol) thus-obtained, hydroxylammonium chloride (280 mg, 4.03 mmol), N,N-diisopropylethylamine (502 μL, 2.88 mmol), ethanol (10 mL) and methanol (10 mL) was stirred at 80° C. for 8 hr. The reaction mixture was diluted with water and extracted with ethyl acetate (×3). The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and filtrated. The filtrate was concentrated under reduced pressure, and the residue was collected by filtration and washed with ethyl acetate-hexane to give the title compound (164 mg, 75%) as a white solid.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:12])=[N:4][C:5]([NH2:11])=[C:6]([N+:8]([O-])=O)[CH:7]=1.Cl>C(O)C.O.[Fe]>[Br:1][C:2]1[C:3]([CH3:12])=[N:4][C:5]([NH2:11])=[C:6]([NH2:8])[CH:7]=1
Reactant: Cc1nc(N)c([N+](=O)[O-])cc1Br
Agent: [Fe]
Agent: Cl
Solvent: CCO
Solvent: O
Product: Cc1nc(N)c(N)cc1Br
Reaction time: 1 h
Yield: 98.4 %

Procedure:
7.7 g (33.2 mmole) of the compound obtained in step 2 was dissolved in a mixture of 27 ml of ethanol and 7 ml of water and to the resulting solution were added 20 g (0.36 mole) of iron powder and 0.33 ml of conc. hydrochloric acid. The resultant was refluxed with stirring for 1 hour, filtered through Cellite to remove the remaining iron powder and washed with ethanol (50 ml×3). The filtrate was concentrated under reduced pressure and the residue was dissolved in ethyl acetate. The resultant was passed through silica gel and concentrated under reduced pressure to obtain 6.6 g of the title compound (yield 98%).