Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C:9](=[O:25])[NH:10][C@@H:11]([CH3:24])[C:12]([C:14]1[CH:19]=[CH:18][C:17]([C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:16][CH:15]=1)=O)C1C=CC=CC=1.CC(O)C.[BH4-].[Na+]>C1(C)C=CC=CC=1.O>[C:20]([C:17]1[CH:16]=[CH:15][C:14]([C@@H:12]2[O:25][C:9](=[O:8])[NH:10][C@H:11]2[CH3:24])=[CH:19][CH:18]=1)([CH3:21])([CH3:22])[CH3:23]
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)c1ccc(C(C)(C)C)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: Cc1ccccc1
Solvent: O
Product: C[C@@H]1NC(=O)O[C@H]1c1ccc(C(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of 9 g (26.5 mmole) [(S)-2-(4-tert-butylphenyl)-1-methyl-2-oxoethyl]-carbamic acid benzyl ester o in 40 mL toluene and 10 mL 2-propanol was added dropwise a solution of 0.7 g (18.42 mmole) sodium borohydride in 2 mL water containing 1 drop 50% sodium hydroxide. The reaction mixture was stirred at room temperature for 15 hrs. The layers were separated and the organic phase was washed with 25 mL 10% sodium hydroxide. 2-Propanol was removed under reduced pressure and the remaining toluene solution was heated under reflux for 1 hr. The solvent was removed under reduced pressure. The residue was recrystallized from diethyl ether/hexane to provide (4S,5S)-5-(4-tert-butylphenyl)-4-methyl-oxazolidin-2-one p, 3 g; m.p. 199–200° C.
Reaction SMILES: C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N.[Br:15][C:16]1[CH:17]=[C:18]2[CH2:24][CH2:23][N:22]([Si:25]([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26])[C:19]2=[N:20][CH:21]=1.C([O-])(O)=O.[Na+]>C(Cl)Cl.P([O-])([O-])([O-])=O>[Br:15][C:16]1[CH:17]=[C:18]2[CH:24]=[CH:23][N:22]([Si:25]([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:26])[CH3:27])[C:19]2=[N:20][CH:21]=1
Reactant: CC(C)(C)[Si](C)(C)N1CCc2cc(Br)cnc21
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Agent: O=C([O-])O
Agent: O=P([O-])([O-])[O-]
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)n1ccc2cc(Br)cnc21
Reaction time: 0.5 h
Yield: 96.6 %

Procedure:
DDQ (about 380 mg, 1.68 mmol) was added in portions to a solution of 4 (525 mg, 1.68 mmol) in a mixture of CH2Cl2 (90 mL) and 0.2 M phosphate buffer pH 7 solution (910 μL) until full consumption of the starting material (TLC). Then, saturated aqueous NaHCO3 solution (22 mL) was added, and the reaction mixture stirred for 0.5 h. The organic layer was separated and the aqueous layer was extracted with CH2Cl2 (3×20 mL). The combined organic solutions were dried (MgSO4), concentrated and purified by SGC with hexane:CH2Cl2 as eluent (in gradient up to 20% CH2Cl2) to give 26 (505 mg, 97%) as a clear oil; 1H NMR (400 MHz, CDCl3) δ 0.62 (s, 6H), 0.93 (s, 9H), 6.47 (d, J=3.5 Hz, 1H), 7.24 (d, J=3.5 Hz, 1H), 7.97 (d, J=2.2 Hz, 1H), 8.28 (d, J=2.2 Hz, 1H).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:20]([O:27][C:28]([N:30]1[CH2:36][CH:35]([OH:37])[CH:34]([N:38]=[N+]=[N-])[CH2:33][CH2:32][CH:31]1[CH3:41])=[O:29])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C1COCC1.O.C1(C)C=CC=CC=1>[CH2:20]([O:27][C:28]([N:30]1[CH2:36][CH:35]([OH:37])[CH:34]([NH2:38])[CH2:33][CH2:32][CH:31]1[CH3:41])=[O:29])[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: CC1CCC(N=[N+]=[N-])C(O)CN1C(=O)OCc1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Solvent: O
Product: CC1CCC(N)C(O)CN1C(=O)OCc1ccccc1
Temperature: 45 °C

Procedure:
Triphenylphosphine (1.94 g, 7.4 mmol) was added to a solution of racemic (2R,5S,6S)-5-azido-6-hydroxy-2-methyl-azepane-1-carboxylic acid benzyl ester (1.5 g, 4.93 mmol) in THF (185 ml) and H2O (0.7 ml), then was heated to 45 degrees C. overnight. The reaction mixture was then diluted with toluene (100 ml×2) and was azeotroped in vacuo by rotary evaporation twice. The resxulting oil was dissolved in MeOH and HCl in Et2O and the resulting salt was collected following filtration and was used in the next reaction without further purification (1.4 g, 90%).
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][C:7]1([C:13]2[CH:18]=[CH:17][C:16]([Sn](CCCC)(CCCC)CCCC)=[CH:15][CH:14]=2)[CH2:12][CH2:11][O:10][CH2:9][CH2:8]1)(=[O:3])[CH3:2].Br[C:33]1[N:34]=[C:35]([N:43]2[CH2:48][CH2:47][N:46]([CH2:49][CH3:50])[CH2:45][CH2:44]2)[C:36]2[C:41]([CH:42]=1)=[CH:40][CH:39]=[CH:38][CH:37]=2>C1(C)C(C)=CC=CC=1.C(OCC)(=O)C.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>[CH2:49]([N:46]1[CH2:45][CH2:44][N:43]([C:35]2[C:36]3[C:41](=[CH:40][CH:39]=[CH:38][CH:37]=3)[CH:42]=[C:33]([C:16]3[CH:15]=[CH:14][C:13]([C:7]4([CH2:6][CH2:5][O:4][C:1](=[O:3])[CH3:2])[CH2:8][CH2:9][O:10][CH2:11][CH2:12]4)=[CH:18][CH:17]=3)[N:34]=2)[CH2:48][CH2:47]1)[CH3:50]
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc(C2(CCOC(C)=O)CCOCC2)cc1
Reactant: CCN1CCN(c2nc(Br)cc3ccccc23)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1C
Solvent: CCOC(C)=O
Product: CCN1CCN(c2nc(-c3ccc(C4(CCOC(C)=O)CCOCC4)cc3)cc3ccccc23)CC1
Yield: 90.2 %

Procedure:
4-(2-Acetoxyethyl)-4-(4-tributylstannylphenyl)tetrahydropyran (2.20 g) and 3-bromo-1-(4-ethylpiperazin-1-yl)isoquinoline (0.83 g) were heated under reflux overnight in the presence of tetrakistriphenylphosphinepalladium(0) (0.12 g) in xylene in nitrogen atmosphere. After cooling, the reaction solution was diluted with ethyl acetate and filtered. The filtrate was extracted with 2N hydrochloric acid, and the resulting aqueous layer was washed with ethyl acetate, adjusted to pH 10 with a 8N aqueous solution of sodium hydroxide, and then extracted with ethyl acetate. The extract was washed with a 10% sodium carbonate and brine, and dried over magnesium sulfate. The solvent was evaporated, to give a mixture (1.14 g) of 1-(4-ethylpiperazin-1-yl)-3-{4-[4-(2-acetoxyethyl)tetrahydropyran-4-yl]phenyl}isoquinoline as a brown viscous oil and the starting material.
Reaction SMILES: [C:1]1([P:7]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[CH2:14][N:15]([CH3:17])[CH3:16])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:24]([N:28]=[N+]=[N-])(=[O:27])[O:25][CH3:26]>CCOCC>[CH3:16][N:15]([CH2:14][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[P:7](=[N:28][C:24](=[O:27])[O:25][CH3:26])([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[CH3:17]
Reactant: CN(C)Cc1ccccc1P(c1ccccc1)c1ccccc1
Reactant: COC(=O)N=[N+]=[N-]
Solvent: CCOCC
Product: COC(=O)N=P(c1ccccc1)(c1ccccc1)c1ccccc1CN(C)C

Procedure:
A 2.0 g portion of 2-(diphenylphosphino)-N,N-dimethylbenzenemethanamine was reacted with 4.0 ml of 1M methyl carbonazidate in ether as described in Example 1, giving 1.32 g of the desired product, mp 95°-97° C.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]2[C:8]([CH:30]3[CH2:33][CH2:32][CH2:31]3)=[N:9][N:10](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[C:4]=2[CH:3]=1.[CH2:34]([NH:38][C:39]([NH2:41])=[O:40])[CH2:35][CH2:36][CH3:37].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C([O-])([O-])=O.[Cs+].[Cs+].C(O)(C(F)(F)F)=O>CC([O-])=O.CC([O-])=O.[Pd+2].O1CCOCC1>[CH2:34]([NH:38][C:39]([NH:41][C:2]1[N:7]=[CH:6][C:5]2[C:8]([CH:30]3[CH2:31][CH2:32][CH2:33]3)=[N:9][NH:10][C:4]=2[CH:3]=1)=[O:40])[CH2:35][CH2:36][CH3:37]
Reactant: CCCCNC(N)=O
Reactant: Clc1cc2c(cn1)c(C1CCC1)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: O=C(O)C(F)(F)F
Solvent: C1COCCO1
Product: CCCCNC(=O)Nc1cc2[nH]nc(C3CCC3)c2cn1

Procedure:
In a manner similar to that described in Scheme 6 and Example 30, 6-chloro-3-cyclobutyl-1-trityl-1H-pyrazolo[4,3-c]pyridine was reacted with 1-butylurea, (Xantphos, Pd(OAc)2, Cs2CO3, dioxane, 80° C., overnight) and then deprotected with TFA to provide 1-butyl-3-(3-cyclobutyl-1H-pyrazolo[4,3-c]pyridin-6-yl)urea. MS ESI calc'd. for C15H21N5O[M+1]+ 288, found 288.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:15](Cl)=[N:16][CH:17]=[CH:18][CH:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:21][C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=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].C1([C-]2C(C3C=CC=CC=3)=C(C3C=CC=CC=3)C(C3C=CC=CC=3)=C2C2C=CC=CC=2)C=CC=CC=1.C(P(C(C)(C)C)[C-]1C=CC=C1)(C)(C)C.[Fe+2]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:15]([C:25]3[CH:26]=[CH:27][C:22]([F:21])=[CH:23][CH:24]=3)=[N:16][CH:17]=[CH:18][CH:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCN(c2cccnc2Cl)CC1
Reactant: OB(O)c1ccc(F)cc1
Agent: [Fe+2]
Agent: [Pd]
Agent: CC(C)(C)P([c-]1cccc1)C(C)(C)C
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCN(c2cccnc2-c2ccc(F)cc2)CC1
Temperature: 100 °C
Yield: 28 %

Procedure:
Dissolve 4-(2-chloropyridin-3-yl)-piperazine-1-carboxylic acid t-butyl ester (2.7 g, 9.1 mmol) in toluene (30 mL). Add 4-fluorophenylboronic acid (1.92 g, 13.70 mmol) followed by bis(dibenzylideneacetone)palladium(0) (0.42 g, 0.46 mmol), 1,2,3,4,5-pentaphenyl-1′-(di-t-butylphosphino)ferrocene (CTC-Q-PHOS) (0.65 g, 0.91 mmol) and potassium phosphate (5.8 g, 27.3 mmol). Heat the reaction mixture at 100° C. for 23 hr. Cool to room temperature, concentrate and partition the residue between ethyl acetate and 1 N sodium hydroxide (pH=11). Dry (sodium sulfate), filter, concentrate and purify (silica gel chromatography, eluting with 20:80 ethyl acetate:hexanes), to give 4-[2-(4-fluorophenyl)-pyridin-3-yl]-piperazine-1-carboxylic acid t-butyl ester (28%). MS (ES): m/z=358 [M+H].
Reaction SMILES: C(OC(=O)[N:7]([C:37]1[CH:38]=[N:39][C:40]([O:43][CH2:44][CH3:45])=[CH:41][CH:42]=1)[C:8]1[CH:13]=[CH:12][C:11]([C:14]([C:16]2[C:24]3[C:19](=[N:20][CH:21]=[C:22]([CH3:25])[CH:23]=3)[N:18]([Si](C(C)C)(C(C)C)C(C)C)[CH:17]=2)=[O:15])=[C:10]([F:36])[N:9]=1)(C)(C)C.FC(F)(F)C(O)=O.C(=O)([O-])[O-].[K+].[K+]>ClCCCl>[CH2:44]([O:43][C:40]1[N:39]=[CH:38][C:37]([NH:7][C:8]2[N:9]=[C:10]([F:36])[C:11]([C:14]([C:16]3[C:24]4[C:19](=[N:20][CH:21]=[C:22]([CH3:25])[CH:23]=4)[NH:18][CH:17]=3)=[O:15])=[CH:12][CH:13]=2)=[CH:42][CH:41]=1)[CH3:45]
Reactant: CCOc1ccc(N(C(=O)OC(C)(C)C)c2ccc(C(=O)c3cn([Si](C(C)C)(C(C)C)C(C)C)c4ncc(C)cc34)c(F)n2)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOc1ccc(Nc2ccc(C(=O)c3c[nH]c4ncc(C)cc34)c(F)n2)cn1
Temperature: 80 °C
Reaction time: 2 h
Yield: 50.2 %

Procedure:
To (6-ethoxy-pyridin-3-yl)-[6-fluoro-5-(5-methyl-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-pyridin-2-yl]-carbamic acid tert-butyl ester (71, 0.200 g, 0.309 mmol) in 10 mL of 1,2-dichloroethane, trifluoroacetic acid (0.80 mL, 10.0 mmol) is added. The reaction is stirred at 80° C. for 2 hours, then poured into aqueous potassium carbonate and extracted with ethyl acetate. The organic layer is dried over sodium sulfate, filtered and the filtrate concentrated under vacuum. The resulting material is purified by silica gel column chromatography, eluting with 2-15% methanol in dichloromethane. Appropriate fractions are combined and concentrated under vacuum to provide the desired compound (P-3045, 60.7 mg). MS (ESI) [M+H+]+=391.9.
Reaction SMILES: [Br:1][C:2]1[C:7](=[O:8])[N:6]([C:9]2[CH:10]=[C:11]([CH:19]=[CH:20][C:21]=2[CH3:22])[C:12]([NH:14][C@H:15](C)[CH2:16][OH:17])=[O:13])[C:5]([CH3:23])=[N:4][C:3]=1[O:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][C:27]=1[F:33].NCCO>>[Br:1][C:2]1[C:7](=[O:8])[N:6]([C:9]2[CH:10]=[C:11]([CH:19]=[CH:20][C:21]=2[CH3:22])[C:12]([NH:14][CH2:15][CH2:16][OH:17])=[O:13])[C:5]([CH3:23])=[N:4][C:3]=1[O:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][C:27]=1[F:33]
Reactant: Cc1ccc(C(=O)N[C@H](C)CO)cc1-n1c(C)nc(OCc2ccc(F)cc2F)c(Br)c1=O
Solvent: NCCO
Product: Cc1ccc(C(=O)NCCO)cc1-n1c(C)nc(OCc2ccc(F)cc2F)c(Br)c1=O
Yield: 70 %

Procedure:
The title compound was prepared in a similar manner as described for (±)3-[5-bromo-4-[(2,4-difluorobenzyl)oxy]-2-methyl-6-oxopyrimidin-1(6H)-yl]-N-[(1R)-2-hydroxy-1-methylethyl]-4-methylbenzamide substituting R-2-amino-1-propanol with 2-aminoethanol. Yield 70%. 1H NMR (CD3OD/400 MHz) δ 7.91 (d, 1H,J=1.6 Hz, & 6.4 Hz), 7.68 (d, 1H, J=2.0 Hx), 7.60 (m, 1H), 7.54 (d, 1H, J=8.0 Hz), 7.01 (m, 2H), 5.57 (abq, 2H), 3.67 (t, 2H, J=6.0 Hz), 3.49(t, 2H, J=6.0 Hz), 2.17 (s, 3H), and 2.13 (s, 3H); ES-HRMS m/z 508.0659 (M+H calcd for C22H21N3O4F2Br requires 508.0678). 19F NMR (CD3OD/400 MHz) −111.85(m) and −115.90 (m).
Reaction SMILES: [Br:1][CH:2]([C:4]1[C:5](=O)[NH:6][C:7]2[C:12]([N:13]=1)=[CH:11][CH:10]=[C:9]([F:14])[CH:8]=2)[CH3:3].P(Cl)(Cl)([Cl:18])=O>>[Br:1][CH:2]([C:4]1[C:5]([Cl:18])=[N:6][C:7]2[C:12](=[CH:11][CH:10]=[C:9]([F:14])[CH:8]=2)[N:13]=1)[CH3:3]
Reactant: CC(Br)c1nc2ccc(F)cc2[nH]c1=O
Reactant: O=P(Cl)(Cl)Cl
Product: CC(Br)c1nc2ccc(F)cc2nc1Cl
Temperature: 100 °C
Reaction time: 2 h
Yield: 92.8 %

Procedure:
A heterogeneous mixture of 3-(1-bromoethyl)-7-fluoroquinoxalin-2(1H)-one (58.86 g, 217.1 mmol) and phosphorous oxychloride (198.8 ml, 2171 mmol) in a 1 L round bottom flask was stirred at 100° C. for 2 h. The mixture was heterogeneous in the beginning of the reaction and then homogeneous black solution over 1 h. After 2 h, the mixture was cooled to rt and concentrated under reduced pressure. To the black residue was carefully added ice (˜400 ml) in portions and then water (200 ml) with stirring. The mixture was neutralized with NH4OH (200 ml) and ice (˜200 ml) with stirring. The resulting precipitate was collected by filtration, rinsed with water (1 L), and dried under high vacuum overnight to give 2-(1-bromoethyl)-3-chloro-6-fluoroquinoxaline (58.31 g, 92.8% yield) including 3-chloro-2-(1-chloroethyl)-6-fluoroquinoxaline as a brown solid. 1H NMR (400 MHz, DMSO-d6), ratio of bromoethyl analog and chloroethyl analog=2.5:1 Mass Spectrum (ESI) m/e=288.9 [M+H(79Br)]+ and 291.0 [M+H (81Br)]+
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[C:5]1[CH:10]=[C:9]([F:11])[C:8]([O:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]#[N:20])=[CH:15][CH:14]=2)=[N:7][C:6]=1Cl)[CH3:2].[F:23][C:24]([F:34])([F:33])[O:25][C:26]1[CH:27]=[C:28]([OH:32])[CH:29]=[CH:30][CH:31]=1>>[CH2:1]([O:3][C:4](=[O:22])[C:5]1[CH:10]=[C:9]([F:11])[C:8]([O:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]#[N:20])=[CH:15][CH:14]=2)=[N:7][C:6]=1[O:32][C:28]1[CH:29]=[CH:30][CH:31]=[C:26]([O:25][C:24]([F:23])([F:33])[F:34])[CH:27]=1)[CH3:2]
Reactant: CCOC(=O)c1cc(F)c(Oc2ccc(C#N)cc2)nc1Cl
Reactant: Oc1cccc(OC(F)(F)F)c1
Product: CCOC(=O)c1cc(F)c(Oc2ccc(C#N)cc2)nc1Oc1cccc(OC(F)(F)F)c1
Yield: 52 %

Procedure:
2-chloro-6-(4-cyano phenoxy)-5-fluoro nicotinic acid ethyl ester (2.4 g, 7.49 mmol) and 3-trifluoromethoxyphenol (1.33 g, 7.49 mmol) were coupled using the procedure of Example 17(b) to afford 1.8 g of the required product. 1H NMR (DMSO-d6): δ 1.35 (3H, t), 4.4 (2H, q), 7.22 (2H, d), 7.3 (3H, d), 7.34 (1H, m), 7.54 (2H, d), 8.38 (1H, d).
Reaction SMILES: [CH2:1]([O:3][CH:4]([C:10]([O-:12])=O)[C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH3:2].[Br:13][C:14]1[CH:20]=[CH:19][C:17]([NH2:18])=[CH:16][CH:15]=1.C1(N=C=NC2CCCCC2)CCCCC1>>[Br:13][C:14]1[CH:20]=[CH:19][C:17]([NH:18][C:10](=[O:12])[CH:4]([O:3][CH2:1][CH3:2])[C:5]([O:7][CH2:8][CH3:9])=[O:6])=[CH:16][CH:15]=1
Reactant: Nc1ccc(Br)cc1
Reactant: CCOC(=O)C(OCC)C(=O)[O-]
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Product: CCOC(=O)C(OCC)C(=O)Nc1ccc(Br)cc1
Yield: 20 %

Procedure:
Mono-ethyl ethoxymalonate (1.44 grams, 0.01 mole), prepared in Example LXVIII Part A, 4-bromoaniline (1.41 grams, 0.01 mole) and 1,3-dicyclohexylcarbodiimide (1.68 grams, 0.01 mole) were reacted in a manner similar to that described in Example LVII to give 0.79 gram (0.002 mole) of ethyl 3-[(4-bromophenyl)amino]-2-ethoxy-3-oxopropanoate having a melting point of 59° C.-64° C. An analytical sample recrystallized from hexane-ethyl acetate had a melting point of 62° C.-64° C.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([CH2:8][N:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][C:17]=3[F:19])[C:12](=[O:20])[C:11]([C:21]([OH:23])=[O:22])=[CH:10]2)=[CH:4][CH:3]=1.[NH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1>CS(C)=O>[F:19][C:17]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:18]=1[N:9]([CH2:8][C:5]1[N:6]=[N:7][C:2]([N:24]3[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]3)=[CH:3][CH:4]=1)[CH:10]=[C:11]([C:21]([OH:23])=[O:22])[C:12]2=[O:20]
Reactant: C1CCNCC1
Reactant: O=C(O)c1cn(Cc2ccc(Cl)nn2)c2c(F)cccc2c1=O
Solvent: CS(C)=O
Product: O=C(O)c1cn(Cc2ccc(N3CCCCC3)nn2)c2c(F)cccc2c1=O

Procedure:
To a solution of 1-[(6-chloropyridazin-3-yl)methyl]-8-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (0.040 g, 0.12 mmol) in 1 mL of DMSO was added piperidine (0.015 mL, 0.16 mmol). The reaction mixture was irradiated in the microwave at 100° C. for 10 minutes, and purified via reverse phase HPLC to provide the title compound that gave a proton NMR spectra consistent with theory and a mass ion (ES+) of 383.1 for M+H+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8](F)[CH:9]=1)[C:5]#[N:6].[OH:11][CH2:12][CH:13]1[CH2:15][CH2:14]1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>>[Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:11][CH2:12][CH:13]2[CH2:15][CH2:14]2)[CH:9]=1)[C:5]#[N:6]
Reactant: N#Cc1cc(F)cc(Br)c1
Reactant: OCC1CC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Product: N#Cc1cc(Br)cc(OCC2CC2)c1
Yield: 84 %

Procedure:
In analogy to the procedure described in WO2007060448, the reaction of 3-bromo-5-fluorobenzonitrile with hydroxymethylcyclopropane using sodium bis(trimethylsilyl)amide as the base yielded the title compound as a white solid (yield: 84% of theory). TLC: Rf: 0.55 (silica gel:heptane:ethyl acetate=6:1, UV, 254 nm).
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[N:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][C:10]=1[CH2:19][O:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25]O)=[CH:23][CH:22]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[N:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][C:10]=1[CH2:19][O:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25][Cl:1])=[CH:23][CH:22]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: OCc1ccc(OCc2ccc3ccccc3n2)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: ClCc1ccc(OCc2ccc3ccccc3n2)cc1
Reaction time: 1.5 h

Procedure:
Solid N-chlorosuccinimide (16.69 g) was added in portions to a stirred solution of 4-(quinolin-2-ylmethoxy)benzyl alcohol (26.58 g) and triphenylphosphine (32.89 g) in dichloromethane (600 ml) at 0°-5° C. The mixture was stirred for a further 1.5 hours at 0°-5° C. and then purified rapidly by pouring the mixture onto flash silica and eluting with petroleum spirit 40°-60° C.-diethyl ether (2:1) under vacuum.
Reaction SMILES: [CH3:1][S:2]([CH:5]([S:7]([O-:10])(=O)=[O:8])[CH3:6])(=[O:4])=[O:3].[Na+].P(Cl)(Cl)(Cl)(Cl)[Cl:13].Cl>ClCCl>[CH3:1][S:2]([CH:5]([S:7]([Cl:13])(=[O:10])=[O:8])[CH3:6])(=[O:4])=[O:3]
Reactant: CC(S(C)(=O)=O)S(=O)(=O)[O-]
Reactant: ClP(Cl)(Cl)(Cl)Cl
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Product: CC(S(C)(=O)=O)S(=O)(=O)Cl
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A mixture of 5 g of sodium 1-(methylsulfonyl)ethanesulfonate (Formula II, X=R=CH3, Y=Na) and 5.34 g of phosphorus pentachloride was stirred under an inert atmosphere at room temperature. After about 20 minutes, the evolution of hydrogen chloride and the generation of heat were observed, and shortly thereafter the mixture became liquid. The mixture was maintained at 80°-100° C. overnight, cooled, and diluted with dichloromethane. The mixture was filtered, the residue was washed with dichloromethane, and the solvent was evaporated from the dichloromethane solution (combined portions) with a stream of nitrogen. The residual oil was concentrated further with a vacuum pump: weight of oil, 3.8 g. The mass spectrum and the proton NMR showed that this material was principally 1-(methylsulfonyl)ethanesulfonyl chloride (Formula III, R=X=CH3 and Z=Cl): MS (electron-impact, direct-probe temperature 20° C.), m/e 207 (M+1), 171 (M - Cl); 1H NMR (300.6 MHz, CDCl3), δ2.07 (d, CH3CH), 3.32 (s, CH 3 SO2), 4.84 (q, CHCH3). The infrared spectrum (KBr) included strong bands at 1375, 1325, 1170, 1150, 960, 760, 715, 595, 535, 505, 490 cm-1.
Reaction SMILES: Br[C:2]1[C:10]2[NH:9][C:8]3[CH:11]4[CH2:17][CH2:16][N:14]([CH2:15][C:7]=3[C:6]=2[CH:5]=[CH:4][CH:3]=1)[CH2:13][CH2:12]4.[CH:18]([C:20]1[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=1)=[CH2:19].[O-]S([O-])(=O)=O.[Mg+2]>>[N:23]1[CH:24]=[CH:25][C:20](/[CH:18]=[CH:19]/[C:2]2[C:10]3[NH:9][C:8]4[CH:11]5[CH2:17][CH2:16][N:14]([CH2:15][C:7]=4[C:6]=3[CH:5]=[CH:4][CH:3]=2)[CH2:13][CH2:12]5)=[CH:21][CH:22]=1
Reactant: C=Cc1ccncc1
Reactant: Brc1cccc2c3c([nH]c12)C1CCN(CC1)C3
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Product: C(=C/c1cccc2c3c([nH]c12)C1CCN(CC1)C3)\c1ccncc1

Procedure:
The product of Example 1B (100 mg, 0.34 mmol), 4-vinylpyridine (144 mg, 1.37 mmol; Aldrich) and MgSO4 (83 mg, 0.69 mmol) were combined and processed as described in Example 1D to provide the title compound: 1H NMR (400 MHz, methanol-d4) δ ppm 1.97-2.22 (m, 4 H), 3.03-3.12 (m, 2 H), 3.13-3.18 (m, 1 H), 3.21-3.29 (m, 2 H), 4.24 (s, 2 H), 7.04 (t, J=7.6 Hz, 1 H), 7.24 (d, J=16.5 Hz, 1 H), 7.31 (dd, J=7.8, 0.8 Hz, 1 H), 7.44 (d, J=7.6 Hz, 1 H), 7.59-7.69 (m, 2 H), 7.94 (d, J=16.5 Hz, 1 H), 8.46-8.50 (m, 2 H); MS (APCI) m/z 316 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][NH:10]C(OC(C)(C)C)=O)=[CH:5][CH:4]=1.[F:20][C:21]([F:40])([F:39])[C:22]([NH:24][CH2:25][C:26]1[C:27]([CH3:38])=[C:28]([C:34]([CH3:37])=[CH:35][CH:36]=1)[C:29]([N:31]=[C:32]=[O:33])=O)=[O:23].FC(F)(F)C(O)=O>C(Cl)Cl>[F:1][C:2]([F:18])([F:19])[C:3]1[CH:4]=[CH:5][C:6]([N:9]2[C:32](=[O:33])[NH:31][C:29]([C:28]3[C:27]([CH3:38])=[C:26]([CH:36]=[CH:35][C:34]=3[CH3:37])[CH2:25][NH:24][C:22](=[O:23])[C:21]([F:40])([F:39])[F:20])=[N:10]2)=[CH:7][CH:8]=1
Reactant: CC(C)(C)OC(=O)NNc1ccc(C(F)(F)F)cc1
Reactant: Cc1ccc(CNC(=O)C(F)(F)F)c(C)c1C(=O)N=C=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1ccc(CNC(=O)C(F)(F)F)c(C)c1-c1nn(-c2ccc(C(F)(F)F)cc2)c(=O)[nH]1
Yield: 45.9 %

Procedure:
The title compound was prepared according to the procedure described in Example-83 by using tert-butyl 2-(4-(trifluoromethyl)phenyl)hydrazinecarboxylate (Intermediate-53, 1.00 g, 3.63 mmol), 3-((2,2,2-trifluoroacetamido)methyl)-2,6-dimethylbenzoyl isocyanate (Intermediate-65, 1.00 g, 3.33 mmol), DCM (20 mL), trifluoro acetic acid (5.0 mL) to afford 0.700 g of the desired product. 1H NMR (400 MHz, DMSO d6): δ 2.20 (s, 3H), 2.22 (s, 3H), 4.40 (d, J=4.2 Hz, 2H), 7.21 (d, J=6.0 Hz, 1H), 7.29 (d, J=6.0 Hz, 1H), 7.82 (d, J=6.6 Hz, 1H), 8.17 (d, J=6.6 Hz, 1H), 9.95 (t, J=6.9 Hz, 1H), 12.32 (br s, 1H); MS (m/z): 457.26 (M−H)−.
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:12]3[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[CH2:14][CH:13]3[CH3:21])=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1>C1(OC2C=CC=CC=2)C=CC=CC=1.[Pd]>[CH3:21][C:13]1[N:12]([C:6]2[C:5]3[C:10](=[CH:11][CH:2]=[CH:3][CH:4]=3)[N:9]=[CH:8][CH:7]=2)[C:20]2[C:15]([CH:14]=1)=[CH:16][CH:17]=[CH:18][CH:19]=2
Reactant: CC1Cc2ccccc2N1c1ccnc2cc(Cl)ccc12
Agent: [Pd]
Solvent: c1ccc(Oc2ccccc2)cc1
Product: Cc1cc2ccccc2n1-c1ccnc2ccccc12

Procedure:
A solution of 7-chloro-4-(2-methylindolin-1-yl)quinoline (17g.) in diphenyl ether (50ml.) containing 10% w/w palladium on charcoal catalyst (6.5g.) was heated under reflux for 3 hours. The mixture was cooled and filtered, and the solid residue was extracted with hot chloroform (3 × 50ml.; ca 60° C.). The chloroform was evaporated in vacuo from the extract. The residue was chromatographed on a column of chromatographic silica gel (column dimensions: 20 × 3.5cm.) using a 1:3 v/v mixture of diethyl ether and petroleum ether (b.p. 40°-60° C.) as eluant. The solvents were evaporated in vacuo from the eluate to give 4-(2-methylindol-1-yl)quinoline, m.p. 78°-80° C.