Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Na].[CH2:2]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13](=[O:19])[C:14]3[S:18][CH:17]=[CH:16][CH:15]=3)=[CH:10][CH:11]=2)[CH2:6][C:5]1=[O:20])[CH3:3].[C:21](=O)([O:25]CC)[O:22][CH2:23][CH3:24].Cl>[Cl-].[Na+].O.C(Cl)Cl.C(O)C>[CH2:2]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13](=[O:19])[C:14]3[S:18][CH:17]=[CH:16][CH:15]=3)=[CH:10][CH:11]=2)[CH:6]([C:21]([O:22][CH2:23][CH3:24])=[O:25])[C:5]1=[O:20])[CH3:3]
Reactant: CCOC(=O)OCC
Reactant: CCN1C(=O)Cc2cc(C(=O)c3cccs3)ccc21
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)C1C(=O)N(CC)c2ccc(C(=O)c3cccs3)cc21
Yield: 54.4 %

Procedure:
To sodium ethoxide, formed by adding 2 g. of sodium metal to 58 ml. of ethanol, at 0° C. was added 7.84 g. (28.9 mmoles) of 1-ethyl-5-(2-thenoyl)oxindole followed by 10.24 g. (86.8 mmoles) of diethyl carbonate, and the reaction heated to 65° C. for 2 hours. The reaction mixture was poured into a cold mixture of 250 ml. 1N hydrochloric acid, 250 ml. of a saturated brine solution and 200 ml. of methylene chloride. The organic phase was separated, dried over magnesium sulfate and concentrated in vacuo. The residue was triturated with diethyl ether and filtered. The filtrate was substantially concentrated to dryness under vacuum to give the desired product, 5.4 g. (54.4% yield).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][Si:5]([CH3:10])([O:8][CH3:9])[O:6][CH3:7].[NH2:11][CH2:12][CH2:13][N:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1>>[CH3:10][Si:5]([O:8][CH3:9])([O:6][CH3:7])[CH2:4][CH2:3][CH2:2][NH:11][CH2:12][CH2:13][N:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1
Reactant: NCCN1CCNCC1
Reactant: CO[Si](C)(CCCCl)OC
Product: CO[Si](C)(CCCNCCN1CCNCC1)OC
Yield: 44.5 %

Procedure:
Starting with 182.7 g of chloropropylmethyldimethoxysilane and 79 g of 2-aminoethylpiperazine, the procedure described in Example 2 was used to prepare 75 g of the title compound, boiling point range 90°-110° C. at 5 mm Hg (34 kPa).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([NH:13][C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18](Br)[N:17]=2)=[O:15])[CH:8]=1)[CH3:2].[F:24][C:25]1[CH:26]=[C:27](B(O)O)[CH:28]=[CH:29][CH:30]=1>>[CH2:1]([O:3][C:4](=[O:23])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([NH:13][C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:29]3[CH:28]=[CH:27][CH:26]=[C:25]([F:24])[CH:30]=3)[N:17]=2)=[O:15])[CH:8]=1)[CH3:2]
Reactant: CCOC(=O)COc1cccc(NC(=O)c2cccc(Br)n2)c1
Reactant: OB(O)c1cccc(F)c1
Product: CCOC(=O)COc1cccc(NC(=O)c2cccc(-c3cccc(F)c3)n2)c1

Procedure:
The pyridyl bromide (166) (100 mg, 0.26 mmol) was coupled to 3-fluoro-phenylboronic acid (34 mg, 0.24 mmol) using Method E. During this reaction, partial hydrolysis occurred. The residue was extracted using Work-up E1 to give a mixture of acid and ester, which was used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C@H:13]([CH3:17])[C:14]([OH:16])=[O:15])[CH:7]=[CH:6]2.C([O-])(O)=O.[Na+].Br[CH2:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26]>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C@H:13]([CH3:17])[C:14]([O:16][CH2:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])=[O:15])[CH:7]=[CH:6]2
Reactant: COc1ccc2cc([C@H](C)C(=O)O)ccc2c1
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc2cc([C@H](C)C(=O)OCC(=O)OC(C)(C)C)ccc2c1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of (2S)-2-(6-methoxy(2-naphthyl))propanoic acid (naproxen, 3 g, 13.0 mmol), NaHCO3 (1.4 g, 16.7 mmol) and tert-butyl bromoacetate (5.08 g, 26.0 mmol) in DMF (30 mL) was stirred at room temperature for 2 days and the solvent was evaporated under high vacuo. The residue was then diluted with CH2Cl2, the solvent removed by filtration and the residue was recrystallized from a mixture of CH2Cl2/EtOAc/Hex to give the title compound as a white solid in quantitative yield. Mp 85-86° C. 1H NMR (300 MHz, CDCl3) δ 7.69-7.70 (m, 3H), 7.43 (dd, J=1.6 and 8.6 Hz, 1H), 7.10-7.15 (m, 2H), 4.47 (ABq, JAB=15.7 Hz, ΔvAB=40.7 Hz, 2H), 3.97 (q, J=7.2 Hz, 1H), 3.90 (s, 3H), 1.63 (d, J=7.2 Hz, 3H), 1.42 (s, 9H). 13C NMR (75 MHz, CDCl3) δ 174.2, 166.9, 157.8, 135.4, 133.9, 129.5, 129.1, 127.3, 126.5, 126.3, 119.1, 105.8, 82.5, 61.7, 55.5, 45.3, 28.1, 18.8. Mass spectrum (API-TIS) m/z 345 (MH+), 362 (MNH4+).
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[CH:3][CH:2]1[C:11]([O:13][CH2:14][CH3:15])=[O:12].C=O.[C:18]([BH3-])#N.[Li+].C(O)(=O)C>C(#N)C.C(OCC)C>[CH3:18][N:4]1[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[O:1][C:2]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:3]1
Reactant: [BH3-]C#N
Reactant: CCOC(=O)C1C=Nc2ccccc2O1
Agent: C=O
Agent: [Li+]
Solvent: CCOCC
Solvent: CC#N
Solvent: CC(=O)O
Product: CCOC(=O)C1=CN(C)c2ccccc2O1
Reaction time: 0.08 h
Yield: 95.2 %

Procedure:
Ethyl 1,4-benzoxazine-2-carboxylate (5.8g.) was disolved in acetonitrile (15ml.) under an atmosphere of argon. Formaldehyde (30ml. of a 37% aqueous solution) and lithium cyanoborohydride (4.67g.) were added, and the solution was stirred for 5 minutes. Glacial acetic acid (3.5ml.) was added dropwise and over a period of 10 minutes, and the solution was stirred at room temperature for 2 hours. More glacial acetic acid (3.5ml.) was added, and after 30 minutes the reaction mixture was poured into diethyl ether (200ml.), washed successively with 0.1N hydrochloric acid, sodium bicarbonate and brine, and was dried. The solvent was evaporated to give the crude 2-carboxyethyl-4-methyl-1,4-benzoxazine, which was purified by chromatography on silica gel (148g.). Elution with 10% ethyl acetate in toluene gave pure ethyl 4-methyl-1,4-benzoxazine-2-carboxylate (5.9g.) whose n.m.r. spectrum in deuteriochloroform showed the following features (δ values):-
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([N+:15]([O-])=O)=[CH:10][C:9]=2[CH3:18])=[O:5])[CH3:2].[H][H]>O1CCCC1.CO.[Pd]>[CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([NH2:15])=[CH:10][C:9]=2[CH3:18])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc2cc([N+](=O)[O-])cc(C)c2[nH]1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: CCOC(=O)c1cc2cc(N)cc(C)c2[nH]1

Procedure:
A mixture of 5 g 7-methyl-5-nitro-1H-indole-2-carboxylic acid ethyl ester and 0.5 g Pd/C 10% in 200 ml tetrahydrofuran/methanol (3:1) was stirred for 5 h under a pressure of 3 bar of hydrogen. The catalyst was filtered and the mixture was evaporated under reduced pressure. The residue was purified by silica gel chromatography (SiO2; cyclohexane/ethyl acetate 75:25→50:50).
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][CH:9]=[C:6]([C:7]#[N:8])[C:5]=1[C:12]#[N:13])([O-])=O.C(=O)([O-])[O-].[K+].[K+].[CH3:20][N:21]1[CH2:26][CH2:25]N[CH2:23][CH2:22]1>O>[CH3:20][N:21]1[CH2:26][CH2:25][N:1]([C:4]2[CH:11]=[CH:10][CH:9]=[C:6]([C:7]#[N:8])[C:5]=2[C:12]#[N:13])[CH2:23][CH2:22]1
Reactant: N#Cc1cccc([N+](=O)[O-])c1C#N
Reactant: CN1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CN1CCN(c2cccc(C#N)c2C#N)CC1
Yield: 54 %

Procedure:
A mixture of 3-nitrophthalonitrile (2.121 g, 12.3 mmol), freshly dried potassium carbonate (5.45 g, 39 mmol) and N-methylpiperazine (12 mL) were heated at reflux for 2 h. The reaction mixture was poured into water (200 mL) to precipitate the product, which was filtered off and washed with water to give 5 as a beige powder (1.59 g, 54%).
Reaction SMILES: FC1C=CC=C(F)C=1[C:9]1[CH:10]=[C:11]2[C:15]3=[C:16]([CH2:18][NH:19][CH2:20][CH2:21][N:14]3[C@H:13]3[CH2:22][CH2:23][NH:24][CH2:25][C@@H:12]23)[CH:17]=1.[Cl:26][C:27]1[CH:32]=[C:31]([Cl:33])[CH:30]=[CH:29][C:28]=1B(O)O.[OH-].[Ba+2].[OH-]>COCCOC.C(OCC)(=O)C.O>[Cl:26][C:27]1[CH:32]=[C:31]([Cl:33])[CH:30]=[CH:29][C:28]=1[C:9]1[CH:10]=[C:11]2[C:15]3=[C:16]([CH2:18][NH:19][CH2:20][CH2:21][N:14]3[C@H:13]3[CH2:22][CH2:23][NH:24][CH2:25][C@@H:12]23)[CH:17]=1
Reactant: Fc1cccc(F)c1-c1cc2c3c(c1)[C@@H]1CNCC[C@@H]1N3CCNC2
Reactant: OB(O)c1ccc(Cl)cc1Cl
Agent: [Ba+2]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: Clc1ccc(-c2cc3c4c(c2)[C@@H]2CNCC[C@@H]2N4CCNC3)c(Cl)c1
Temperature: 90 °C
Reaction time: 1 h

Procedure:
tert-butyl (±)Cis-bromo-4-oxo-1,2,3,4,7b, 10,11,11 a-octahydro[1,4]diazepino[6,7,1-hi]pyrido[4,3-b]indol-9(8H)-carboxylate from EXAMPLE 70, Part E (150 mg, 0.356 mmol), 2,4-dichlorophenylboronic acid (82 mg, 0.430 mmol) and barium hydroxide (170 mg, 0.540 mmol) were dissolved in DME (7 mL) and water (4 mL), and degassed for 10 minutes under nitrogen. Tetrakis (triphenylphosphine)palladium (0) (10 mg, 0.007 mmol) was added and the reaction was heated to 90° C. for 13 h. The reaction was cooled to room temperature and diluted with ethyl acetate (20 mL) and water (20 mL). The organic layer was separated and dried over magnesium sulfate, filtered and concentrated under reduced pressure to give an oil. The oil was purified by silica gel column chromatography (13% ethyl acetate, hexanes).). Fractions were collected, concentrated to a solid, then dissolved in 20% TFA/CHCl3 and stirred for 1 hour. The reaction solution was cooled to 0° C. in an ice bath, and basified to pH=10 with concentrated NH4OH. This was extracted with CHCl3 (3×15 ml), organics collected, dried over MgSO4 and concentrated under reduced pressure to give to give the title compound. 1H NMR (CDCl3, 300 MHz): δ 7.52 (d, 1H, J=1.8 Hz), 7.44 (d, 1H, J=1.8 Hz), 7.26-7.20 (m, 2H), 6.45 (s, 1H), 4.34 (t, 2H, J=9.2 Hz), 4.14-4.06 (m, 2H), 3.18-2.95 (m, 3H), 2.88-2.75 (m, 3H), 2.14 (s-br, 1H), 1.96-1.79 (m, 2H) ppm.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+:9]([O-])=O)[C:5]([OH:8])=[N:6][CH:7]=1.O.O.[Sn](Cl)(Cl)(Cl)Cl>C(OCC)(=O)C>[NH2:9][C:4]1[C:5]([OH:8])=[N:6][CH:7]=[C:2]([Br:1])[CH:3]=1
Reactant: O=[N+]([O-])c1cc(Br)cnc1O
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: O
Solvent: CCOC(C)=O
Product: Nc1cc(Br)cnc1O
Temperature: 50 °C
Yield: 66.7 %

Procedure:
A mixture of 5-bromo-3-nitropyridin-2-ol (1.26 g, 4.6 mmol) and tin chloride dihydrate (3.91 g, 17.3 mmol) in ethyl acetate (19.3 mL) was heated at 50° C. for 20 h. The reaction mixture was cooled to room temperature and diluted with ethyl acetate (100 mL) and washed with brine. The aqueous layer was separated and extracted with ethyl acetate (5×50 mL). The combined organic layers were dried with sodium sulfate, filtered and concentrated in vacuo to give a black solid 580 mg (53%), which was used without further purification.
Reaction SMILES: [CH2:1]([O:8][C:9]([O:11]N1C(=O)CCC1=O)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:19][C@@H:20]([C:33]([OH:35])=[O:34])[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[CH:24][CH:23]=1.C(N(CC)CC)C>CN(C)C=O>[NH:19]([C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:11])[C@@H:20]([C:33]([OH:35])=[O:34])[CH2:21][C:22]1[CH:23]=[CH:24][C:25]([O:28][C:29]([CH3:32])([CH3:30])[CH3:31])=[CH:26][CH:27]=1
Reactant: CC(C)(C)Oc1ccc(C[C@@H](N)C(=O)O)cc1
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)Oc1ccc(C[C@@H](NC(=O)OCc2ccccc2)C(=O)O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
N-benzyloxycarbonyloxysuccinimide (5.75 g) was added to a suspension of D-Tyr(tBu)-OH (5.0 g) in N,N-dimethyl formamide (40 ml). The pH of the solution was adjusted to 8 using triethylamine. The reaction mixture was stirred overnight at room temperature and then evaporated to dryness in vacuo. The residue was dissolved in dichloromethane and diluted with ice water. The pH of the water layer was adjusted to pH 2.5 with 2 N hydrogen chloride. The organic layer was seperated and the aqueous phase was extracted with dichloromethane. The organic layers were combined and washed with water, dried over sodium sulfate and concentrated. Yield: 9.95 g. TLC: Rf=0.31, heptane/ethyl acetate 1/1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]([OH:13])=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8].[C:14]([O-])([O-])=O.[Cs+].[Cs+].CI>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]([O:13][CH3:14])=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C(O)C=Cc1ccc(Cl)c(Cl)c1
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)C=Cc1ccc(Cl)c(Cl)c1
Reaction time: 0.25 h

Procedure:
Cool a solution of 3-(3,4-dichlorophenyl)-2-propeneoic acid (100 g, 461 mmol) in dry DMF (500 mL) to 0° C. and treat with Cs2CO3 (100 g, 307 mmol). Stir the resulting off-white slurry for 15 min., then add CH3I (33 mL, 530 mmol) via syringe. After 1 h, add additional DMF (250 mL) and stir the slurry for 14 h, then partition between ethyl acetate (EtOAc) (1.5 L) and half saturated aqueous NaHCO3 (500 mL). Separate the organic layer and extract the aqueous layer with EtOAc (1 L, 500 mL). Wash the combined organic layers with half saturated aqueous NaHCO3 (500 mL) and water (5×500 mL), then dry over Na2 SO4 and concentrate to obtain methyl 3-(3,4-dichlorophenyl)-2-propenoate, 105.4 g (456 mmol, 99%, as light brown needles.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[C:7]([NH2:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[OH2:13]>>[NH2:11][C@@H:8]([C:9]1[NH:11][C:8]2[CH:9]=[CH:10][C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])=[CH:6][C:7]=2[N:12]=1)[CH2:7][CH2:6][OH:13]
Reactant: O
Reactant: CC(C)(C)c1ccc(N)c(N)c1
Product: CC(C)(C)c1ccc2[nH]c([C@H](N)CCO)nc2c1

Procedure:
The title compound was prepared using Method 4 Steps 1 and 2 followed by the method described for Example 140 using 4-tert-butyl-1,2-diaminobenzene and N-α-t-Butyloxylcarbonyl-O-benzyl-D-homoserine. The residue was diluted with water and washed with EtOAc. Dilute aqueous LiOH solution was added to pH=10 and extracted with EtOAc. The organic layer was collected, dried over Na2SO4 and concentrated in vacuo (56 mg, 79%).
Reaction SMILES: BrBr.C([C:8]1([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:12][CH2:11][CH2:10][C:9]1=[O:13])(OCC)=O>C(Cl)(Cl)Cl>[C:20]([CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][C:8]1[C:9](=[O:13])[CH2:10][CH2:11][CH:12]=1)([O:22][CH2:23][CH3:24])=[O:21]
Reactant: CCOC(=O)CCCCCCC1(C(=O)OCC)CCCC1=O
Agent: BrBr
Solvent: ClC(Cl)Cl
Product: CCOC(=O)CCCCCCC1=CCCC1=O

Procedure:
Under agitation at 20° , 48 g. of Br2, dissolved in 500 ml. of CHCl3, is added dropwise within 2 hours to a solution of 100 g. of 2-carbethoxy-2-(6-carbethoxyhexyl)-cyclopentanone in 1 l. of CHCl3. The solvent is distilled off, the residue is taken up in a mixture of 4 l. of ethanol, l kg. of H2SO4 (density: 1.84), and 100 ml. of H2O, refluxed for 18 hours under N2 and poured on 10 kg. of ice after cooling. The reaction mixture is extracted three times with respectively 5 l. of ether, the combined ether extracts are dried over Na2SO4, the solvent is distilled off, and chromatographic purification of the residue (silica gel/petroleum ether : ether =1 : 1) yields 2-(6-carbethoxyhexyl)- 2-cyclopentenone.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:10])=[C:4]([O:8]C)[CH:5]=[CH:6][CH:7]=1>S(=O)(=O)(O)O>[Cl:1][C:2]1[C:3]([CH3:10])=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1
Reactant: COc1cccc(Cl)c1C
Agent: O=S(=O)(O)O
Product: Cc1c(O)cccc1Cl

Procedure:
3.1 g (0.02 mol) of 3-chloro-2-methylanisole are heated in 20 ml of 50% sulphuric acid for 18 hours with reflux. After cooling, the reaction mixture is extracted three times with dichloromethane, dried over sodium sulphate and concentrated to dryness under reduced pressure. 3-Chloro-2-methylphenol is obtained as a solid (2.9 g, content by HPLC: 11.7%, 12% of theory).
Reaction SMILES: Cl[C:2]1[C:3]([F:22])=[CH:4][N:5]2[C:10]([C:11]=1[CH3:12])=[C:9]([CH:13]1[CH2:15][CH2:14]1)[CH:8]=[C:7]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:6]2=[O:21].[N:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1>>[N:23]1[CH:28]=[CH:27][C:26]([C:2]2[C:3]([F:22])=[CH:4][N:5]3[C:10]([C:11]=2[CH3:12])=[C:9]([CH:13]2[CH2:15][CH2:14]2)[CH:8]=[C:7]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:6]3=[O:21])=[CH:25][CH:24]=1
Reactant: CCOC(=O)c1cc(C2CC2)c2c(C)c(Cl)c(F)cn2c1=O
Reactant: OB(O)c1ccncc1
Product: CCOC(=O)c1cc(C2CC2)c2c(C)c(-c3ccncc3)c(F)cn2c1=O

Procedure:
Ethyl 8-(pyridin-4-yl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylate was prepared according to General Procedure A from ethyl 8-chloro-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylate (100 mg, 0.34 mmol) and pyridin-4-yl-boronic acid (52.1 mg, 0.42 mmol). Purification by flash silica column chromatography (DCM:MeOH) (1:0 to 9:1) afforded quantitatively the title compound as a yellow solid.
Reaction SMILES: N1C=CC=CC=1.ClCCl.[O:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH:11]1[O:16][C@H:17]1[CH2:22][CH2:21][C@H:20]2[C@H:23]3[C@H:33]([CH2:34][CH2:35][C@:18]12[CH3:19])[C@:31]1([CH3:32])[C@H:26]([C@@H:27]([OH:36])[CH2:28][CH2:29][CH2:30]1)[CH2:25][CH2:24]3>O.[O-2].[O-2].[O-2].[Cr+6]>[O:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH:11]1[O:16][C@H:17]1[CH2:22][CH2:21][C@H:20]2[C@H:23]3[C@H:33]([CH2:34][CH2:35][C@:18]12[CH3:19])[C@:31]1([CH3:32])[C@H:26]([C:27](=[O:36])[CH2:28][CH2:29][CH2:30]1)[CH2:25][CH2:24]3
Reactant: C[C@]12CCC[C@H](O)[C@@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](OC3CCCCO3)CC[C@@H]12
Agent: [Cr+6]
Agent: [O-2]
Solvent: O
Solvent: ClCCl
Solvent: c1ccncc1
Product: C[C@]12CCCC(=O)[C@@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](OC3CCCCO3)CC[C@@H]12

Procedure:
To 0.42 ml. of dry pyridine and 6.3 ml. of dry dichloromethane was slowly added 0.264 g. of chromium trioxide and the mixture was stirred for 15 min. at room temperature. To the mixture was added a solution of 175 mg. of the product of Step D in 0.7 ml. of dichloromethane and the resulting mixture was stirred for 20 min. at room temperature. The mixture was diluted with water, extracted with ethyl ether, and washed with 2.5 N sodium hydroxide, water, and brine. The mixture was then dried and evaporated to a clear oil.
Reaction SMILES: [CH:1]1([C:7]2[C:15]3[C:14](=[O:16])[NH:13][C:12]([C:17]4[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=4)=[N:11][C:10]=3[N:9]([CH3:27])[N:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:28][N:29]1[CH2:35][CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1>>[CH:1]1([C:7]2[C:15]3[C:14](=[O:16])[NH:13][C:12]([C:17]4[CH:22]=[CH:21][C:20]([S:23]([N:32]5[CH2:33][CH2:34][CH2:35][N:29]([CH3:28])[CH2:30][CH2:31]5)(=[O:25])=[O:24])=[CH:19][CH:18]=4)=[N:11][C:10]=3[N:9]([CH3:27])[N:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cn1nc(C2CCCCC2)c2c(=O)[nH]c(-c3ccc(S(=O)(=O)Cl)cc3)nc21
Reactant: CN1CCCNCC1
Product: CN1CCCN(S(=O)(=O)c2ccc(-c3nc4c(c(C5CCCCC5)nn4C)c(=O)[nH]3)cc2)CC1
Yield: 45 %

Procedure:
The same reaction procedure as in Example 49 was performed, except that the compound obtained in Example 181 was used in place of the compound obtained in Example 48, and N-methyl-1,4-diazacycloheptane was used in place of N-methylpiperazine. In this manner, 110 mg (45%) of the captioned compound was obtained.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][O:17][CH3:18])=[C:9]([C:12]#[N:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[F:19][C:20]1[C:28]([OH:29])=[CH:27][CH:26]=[C:25]2[C:21]=1[CH:22]=[C:23]([CH3:30])[NH:24]2>CN(C=O)C>[C:12]([C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH2:15][CH2:16][O:17][CH3:18])[N:5]=[CH:4][CH:3]=[C:2]2[O:29][C:28]1[C:20]([F:19])=[C:21]2[C:25](=[CH:26][CH:27]=1)[NH:24][C:23]([CH3:30])=[CH:22]2)#[N:13]
Reactant: Cc1cc2c(F)c(O)ccc2[nH]1
Reactant: COCCOc1cc2nccc(Cl)c2cc1C#N
Solvent: CN(C)C=O
Product: COCCOc1cc2nccc(Oc3ccc4[nH]c(C)cc4c3F)c2cc1C#N
Yield: 57.2 %

Procedure:
Using an analogous procedure to that described in Example 12, 4-chloro-6-cyano-7-(2-methoxyethoxy)quinoline (200 mg, 0.76 mmol) was reacted with 4-fluoro-5-hydroxy-2-methylindole (150 mg, 0.91 mmol), (prepared as described for the starting material in Example 11), in DMF (6 ml) to give 6-cyano-4-(4-fluoro-2-methylindol-5-yloxy)-7-(2-methoxyethoxy)quinoline (170 mg, 57%).
Reaction SMILES: C([C:7]1[N:12]2[C:13]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:14]=3[C:15]([C:18]3[C:23]([F:24])=[CH:22][CH:21]=[CH:20][C:19]=3[F:25])=[N:16][CH2:17][C:11]2=[N:10][C:9](=[O:31])[CH:8]=1)(OCCC)=O.[I-].[Li+]>N1C=CC=CC=1>[Cl:30][C:27]1[CH:28]=[CH:29][C:13]2[N:12]3[CH:7]=[CH:8][C:9](=[O:31])[N:10]=[C:11]3[CH2:17][N:16]=[C:15]([C:18]3[C:23]([F:24])=[CH:22][CH:21]=[CH:20][C:19]=3[F:25])[C:14]=2[CH:26]=1
Reactant: CCCOC(=O)c1cc(=O)nc2n1-c1ccc(Cl)cc1C(c1c(F)cccc1F)=NC2
Agent: [I-]
Agent: [Li+]
Solvent: c1ccncc1
Product: O=c1ccn2c(n1)CN=C(c1c(F)cccc1F)c1cc(Cl)ccc1-2

Procedure:
In the manner given in Example 32, 1-carbopropoxy-9-chloro-7-(2,6-difluorophenyl)pyrimido[1,2-a][1,4]benzodiazepine-3(5H)-one was heated in pyridine with lithium iodide to give 9-chloro-7-(2,6-difluorophenyl)pyrimido[1,2-a][1,4]benzodiazepin-3(5H)-one.
Reaction SMILES: [C:1]([C:4]1[N:9]=[CH:8][C:7]([C:10]2([C:18]#[N:19])[CH2:15][CH2:14][C:13]([F:17])([F:16])[CH2:12][CH2:11]2)=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[CH3:20][Mg]Br.CCOCC>C1COCC1>[F:17][C:13]1([F:16])[CH2:12][CH2:11][C:10]([C:7]2[CH:8]=[N:9][C:4]([C:1]([OH:3])([CH3:20])[CH3:2])=[CH:5][CH:6]=2)([C:18]#[N:19])[CH2:15][CH2:14]1
Reactant: C[Mg]Br
Reactant: CC(=O)c1ccc(C2(C#N)CCC(F)(F)CC2)cn1
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)(O)c1ccc(C2(C#N)CCC(F)(F)CC2)cn1
Temperature: -50 °C
Reaction time: 3 h
Yield: 48 %

Procedure:
A solution of 1-(6-acetyl-pyridin-3-yl)-4,4-difluoro-cyclohexanecarbonitrile (17 mg, 0.064 mmol) in THF (1.2 mL) was cooled at −50° C. and treated with a 3.0 M solution of methylmagnesium bromide in ether (110 μL, 0.32 mmol). After stirring at −50° C. for 3 hours, the reaction was quenched by adding saturated aqueous ammonium chloride (5 mL) and stirred at room temperature for a few minutes. AcOEt (5 mL) was added and the biphasic mixture was stirred vigorously for a few seconds. The layers were separated and the aqueous layer was extracted again with AcOEt (5 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was then purified by preparative TLC, eluting with 60% AcOEt in hexanes to afford 4,4-difluoro-1-[6-(1-hydroxy-1-methyl-ethyl)-pyridin-3-yl]-cyclohexanecarbonitrile as a colorless oil (8.7 mg, 48%). LC-MS (m/z) 280.0 (MH+); tR=1.11.
Reaction SMILES: [F:1][C:2]1[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[C:3]=1[C:4]([NH:6][C:7]1[CH:11]=[CH:10][N:9]([CH2:12][C:13]2[CH:18]=[C:17](I)[CH:16]=[CH:15][C:14]=2[C:20]([F:23])([F:22])[F:21])[N:8]=1)=[O:5].[Cl-].[CH3:30][Zn+]>C1COCC1>[F:1][C:2]1[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[C:3]=1[C:4]([NH:6][C:7]1[CH:11]=[CH:10][N:9]([CH2:12][C:13]2[CH:18]=[C:17]([CH3:30])[CH:16]=[CH:15][C:14]=2[C:20]([F:23])([F:22])[F:21])[N:8]=1)=[O:5]
Reactant: C[Zn+]
Reactant: O=C(Nc1ccn(Cc2cc(I)ccc2C(F)(F)F)n1)c1c(F)cccc1F
Agent: [Cl-]
Solvent: C1CCOC1
Product: Cc1ccc(C(F)(F)F)c(Cn2ccc(NC(=O)c3c(F)cccc3F)n2)c1
Temperature: 80 °C
Reaction time: 4 h

Procedure:
To a solution of 2,6-difluoro-N-(1-{[5-iodo-2-(trifluoromethyl)phenyl]methyl}-1H-pyrazol-3-yl)benzamide (for a preparation see Example 102)(80 mg, 0.158 mmol) in THF (1 ml) was added tetrakis(triphenyl-phosphine)palladium(0) (25 mg, 0.022 mmol, Aldrich). To the solution was added 2.0 M methylzinc chloride in THF (0.5 mL, 1.0 mmol, Aldrich) and the mixture stirred at 80° C. under nitrogen for 4 h. The solvent was removed in vacuo and the residue diluted with methanol:DMSO (1:1, 2 ml). The suspension was filtered and purified by MDAP on Sunfire C18 column (Method B) using Acetonitrile-Water with a Formic acid modifier. The solvent was evaporated in vacuo to give the title compound as a white solid (26.3 mg); LCMS: (System 4) MH+=396, tRET=3.00 min.