Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:4](=[O:15])[C@@H:5]([CH3:14])[NH:6][C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])C.I[CH2:17][Cl:18].[Li+].CC([N-]C(C)C)C.Cl.[BH4-].[Na+]>C1COCC1.C1(C)C=CC=CC=1.CO.C(O)(=O)C.C1COCC1>[Cl:18][CH2:17][C@H:4]([OH:15])[C@H:5]([NH:6][C:7](=[O:8])[O:9][C:10]([CH3:11])([CH3:12])[CH3:13])[CH3:14]
Reactant: ClCI
Reactant: CCOC(=O)[C@@H](C)NC(=O)OC(C)(C)C
Agent: CC(C)[N-]C(C)C
Agent: Cl
Agent: [BH4-]
Solvent: C1CCOC1
Solvent: CO
Solvent: CC(=O)O
Product: C[C@@H](NC(=O)OC(C)(C)C)[C@@H](O)CCl
Temperature: -70 °C
Reaction time: 0.25 h
Yield: 81.1 %

Procedure:
Boc-D-alanine ethyl ester (4.9 g, 22.6 mMol) and iodochloromethane (15.9 g, 90.2 mMol) were dissolved in dry THF (50 ml), and the mixture was cooled to −70° C. To this solution was added dropwise a solution of freshly prepared LDA (115 mMol, 5.1 eq) in 1:1 THF/Hexanes (150 ml) at a rate which did not allow the temperature to rise above −65° C. After the addition was completed, the mixture was stirred for an additional 15 minutes, then a 1:1 solution of acetic acid/THF was added dropwise, at a rate which did not allow the temperature to rise above −65° C. After the addition was completed, the mixture was stirred for an additional 20 minutes, then allowed to warm to −20° C. The solution was diluted with toluene (60 ml) followed by an ice-cold aqueous 1% HCl solution (60 ml). The resulting mixture was stirred until all salts had dissolved, then the phases were separated. The organic phase was combined with an ice-cold aqueous 5% sodium bicarbonate solution, and the mixture was stirred for 10 minutes. The phases were separated, ethanol (60 ml) was added to the organic phase, and the mixture was cooled to −70° C. To this solution was added dropwise a solution of sodium borohydride (2.2 g, 58.6 mMol) in MeOH (60 ml), and the resulting mixture was stirred for two days at −70° C. The solution was allowed to come to 0° C., stirred for 3 hours, then carefully quenched with saturated sodium bicarbonate (30 ml) and water (30 ml). The mixture was stirred at 0° C. for 30 minutes, the organic solvents were stripped, the residue was diluted with 100 ml water, and the slurry was vigorously stirred for ten minutes. The resulting brown solids were collected by filtration, rinsed with water followed by hexanes, then dried under vacuum to yield 4.1 g of a brown solid, which was a 6:1 diasteromeric mixture by NMR. These solids were crystallized from methylcyclohexane to yield 2.1 g of brown needles containing only the desired diastereomer. NMR (300 MHz, CDCl3) δ 4.77 (b, 1H), 3.83-3.81 (m, 2H), 3.61 (dd, 1H, J=4, 7 Hz), 3.55-3.48 (m, 1H), 2.99 (b, 1H), 1.45 (s, 9H), 1.18 (d, 3H, J=7 Hz).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH2:17][O:18][C:19]2[CH:24]=[CH:23][C:22]([CH2:25][C@H:26]([O:32][CH2:33][CH3:34])[C:27]([O:29]CC)=[O:28])=[CH:21][CH:20]=2)=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Li+]>C1COCC1.O>[C:1]([O:5][C:6]([NH:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][CH2:16][CH2:17][O:18][C:19]2[CH:20]=[CH:21][C:22]([CH2:25][C@H:26]([O:32][CH2:33][CH3:34])[C:27]([OH:29])=[O:28])=[CH:23][CH:24]=2)=[CH:13][CH:14]=1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: CCOC(=O)[C@H](Cc1ccc(OCCCc2ccc(NC(=O)OC(C)(C)C)cc2)cc1)OCC
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCO[C@@H](Cc1ccc(OCCCc2ccc(NC(=O)OC(C)(C)C)cc2)cc1)C(=O)O
Reaction time: 4 h
Yield: 96 %

Procedure:
Ethyl (2S)-3-[4-(3-{4-[(tert-butoxycarbonyl)amino]phenyl}propoxy)phenyl]-2-ethoxypropanoate (350 mg, 0.742 mmol) was dissolved in THF (10 ml). Under stirring, lithium hydroxide in water (5 ml) was added. The mixture was stirred at room temperature and followed by HPLC. After 4 hours, the reaction was stopped. More lithium hydroxide (9 mg) was added. The mixture was stirred overnight. It was then evaporated in vacuum to remove THF. The residue was extracted with diethyl ether and then acidified with 10% hydrochloric acid, pH˜3, and extracted with ethyl acetate (×2). The organic phases were combined and washed with brine and dried with magnesium sulfate. The solvent was evaporated and white solid product (315 mg) was left, yield 96%.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][C@@H:10]([C:13](=[O:18])[CH2:14][CH:15]([CH3:17])[CH3:16])[C:9]1=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.N#N>CC(O)C>[CH2:1]([N:8]1[CH2:12][CH2:11][C@H:10]([C@@H:13]([OH:18])[CH2:14][CH:15]([CH3:16])[CH3:17])[C:9]1=[O:19])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)CC(=O)[C@@H]1CCN(Cc2ccccc2)C1=O
Agent: Cl
Agent: N#N
Solvent: CC(C)O
Product: CC(C)C[C@H](O)[C@H]1CCN(Cc2ccccc2)C1=O
Temperature: 65 °C
Reaction time: 17 h
Yield: 100 %

Procedure:
Charge a 400 mL stainless steel autoclave vessel with a solution of (S)-1-benzyl-3-(3-methylbutanoyl)pyrrolidin-2-one (20 g, 77.12 mmoles) in IPA (250 mL), followed by 35% HCl (6% compared to the substrate, 4.63 mmoles, M=36.4 g/mol, d=1.18 g/mL, 0.408 mL). Purged with N2 gas (5×˜50 PSI). Vent the vessel and quickly add (S)-Ru(OAc)2T-BINAP (250 mg, 0.2784 mmoles), while a stream of N2 flows over the top of the reaction mixture Immediately seal the autoclave and purge with N2 gas (5×˜50 PSI). Purge the vessel with H2 gas (5×60 PSI) and then charge of the vessel with H2 gas (60 PSI). Stir the reaction mixture at 65° C. overnight (˜16-18 hours). The pressure of the vessel increases to ˜70 PSI during this time and the vessel is refilled with H2 gas as needed and not kept at a constant pressure of 60 PSI over the course of the reaction. Cool to room temperature and concentrate under reduced pressure to give crude (R)-1-benzyl-3-((S)-1-hydroxy-3-methylbutyl)pyrrolidin-2-one as a dark brown oil that was taken onto the next step without further purification (21.6 g, 82.6 mmoles, ˜95-97% ee, >100% yield). 1H NMR (300 MHz, CDCl3) δ 7.38-7.18 (m, 5H), 4.48 (s, 2H), 4.34-4.22 (m, 1H), 3.28-3.14 (m, 2H), 2.63 (td, 1H, J=2.93, 9.37 Hz), 2.47 (d, 1H, J=5.86 Hz), 2.12-1.70 (m, 3H), 1.54-1.38 (m, 1H), 1.24-1.10 (m, 1H), 0.95 (d, 3H, J=3.51 Hz), 0.93 (d, 3H, J=2.93 Hz). GC/MS=262 (M+1).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]2[CH:11]=[C:10]([C:12]([N:14]([CH3:16])[CH3:15])=[O:13])[O:9][C:6]2=[N:7][CH:8]=1.[H-].[Na+].[CH3:19][O:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25]Cl)=[CH:23][CH:22]=1>CN(C=O)C>[CH3:19][O:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25][O:1][CH2:2][C:3]2[CH:4]=[C:5]3[CH:11]=[C:10]([C:12]([N:14]([CH3:16])[CH3:15])=[O:13])[O:9][C:6]3=[N:7][CH:8]=2)=[CH:23][CH:22]=1
Reactant: COc1ccc(CCl)cc1
Reactant: CN(C)C(=O)c1cc2cc(CO)cnc2o1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(COCc2cnc3oc(C(=O)N(C)C)cc3c2)cc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
An ice-cold solution of 5-(hydroxymethyl)-N,N-dimethylfuro[2,3-b]pyridine-2-carboxamide (4.2 g, 0.019 mol) in DMF (15 mL) was added dropwise to a suspension of sodium hydride (60% dispersion in mineral oil, 1.14 g, 0.0286 mol) in DMF (15 mL) at 0° C. After the resulting mixture was stirred at 0° C. for 15 min, 4-methoxybenzyl chloride (3.89 g, 286 mmol) was added. The reaction mixture was gradually warmed to 23° C., and stirred for 1 h. The excess of sodium hydride was carefully quenched with water (15 mL). The reaction mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, and concentrated. The residue was purified by flash chromatography on silcia gel eluting with 35% ethyl acetate in petroleum ether to give the title compound. MS: m/z=341.2 (M+1).
Reaction SMILES: O.[O:2]1[CH2:7][CH2:6][CH2:5][O:4][CH:3]1[C:8]1[CH:13]=[CH:12][C:11]([C:14]2[S:15][C:16]3[C:21]([N:22]=2)=[CH:20][CH:19]=[C:18]([C:23]2([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[CH2:28][CH2:27][CH:26]=[CH:25][CH2:24]2)[N:17]=3)=[C:10]([F:35])[CH:9]=1>[Pd].C1COCC1>[O:4]1[CH2:5][CH2:6][CH2:7][O:2][CH:3]1[C:8]1[CH:13]=[CH:12][C:11]([C:14]2[S:15][C:16]3[C:21]([N:22]=2)=[CH:20][CH:19]=[C:18]([C:23]2([C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=4)[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]2)[N:17]=3)=[C:10]([F:35])[CH:9]=1
Reactant: Fc1cc(C2OCCCO2)ccc1-c1nc2ccc(C3(c4ccccc4)CC=CCC3)nc2s1
Agent: [Pd]
Solvent: O
Solvent: C1CCOC1
Product: Fc1cc(C2OCCCO2)ccc1-c1nc2ccc(C3(c4ccccc4)CCCCC3)nc2s1
Reaction time: 36 h

Procedure:
A mixture of 10% palladium on carbon, 50% water wet (0.33 g, 0.31 mmol) and 2-(4-(1,3-dioxan-2-yl)-2-fluorophenyl)-5-(1-phenylcyclohex-3-enyl)thiazolo[5,4-b]pyridine (0.492 g, 1.0 mmol) under nitrogen was treated with 10 mL THF and exposed to 1 atm H2 gas via balloon. The reaction mixture was allowed to stir 36 h, then flush with nitrogen, filter, rinsing with DCM. The filtrate was concentrated in vacuo to give 2-(4-(1,3-dioxan-2-yl)-2-fluorophenyl)-5-(1-phenylcyclohexyl)thiazolo[5,4-b]pyridine as a light yellow solid. MS (ESI) m/z: Calculated: 474.2; Observed: 475.1 (M++1).
Reaction SMILES: Br[C:2]1[S:14][C:13]2[C:12]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[CH:6]([CH2:15][CH3:16])[N:5]([S:17]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=3)(=[O:19])=[O:18])[C:4]=2[CH:3]=1.[S:28]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29]1.C(=O)([O-])[O-].[K+].[K+]>C(COC)OC.C(Cl)Cl.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH2:15]([CH:6]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=2[C:13]2[S:14][C:2]([C:30]3[CH:31]=[CH:32][S:28][CH:29]=3)=[CH:3][C:4]=2[N:5]1[S:17]([C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1)(=[O:18])=[O:19])[CH3:16]
Reactant: OB(O)c1ccsc1
Reactant: CCC1c2ccccc2-c2sc(Br)cc2N1S(=O)(=O)c1ccc(OC)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: COCCOC
Solvent: ClCCl
Product: CCC1c2ccccc2-c2sc(-c3ccsc3)cc2N1S(=O)(=O)c1ccc(OC)cc1
Temperature: 75 °C
Yield: 71 %

Procedure:
2-Bromo-5-ethyl-4-[(4-methoxyphenyl)sulfonyl]-4,5-dihydrothieno[3,2-c]isoquinoline (1.02 g, 2.2 mmol), 3-thiopheneboronic acid (0.37 g, 2.9 mol), potassium carbonate (0.91 g, 6.6 mol) and [1.1′-bis(diphenylphosphino)ferrocene]dichloropalladium [II] (90 mg, 0.11 mmol) were combined in 40% aqueous dimethoxyethane (11 mL) and the mixture was heated to 75° C. After 3.5 h the mixture was cooled to 23° C., filtered through Celite and washed with ethyl acetate (125 mL). The filtrate was washed with 1 N aqueous sodium hydroxide and brine (125 mL each), dried (K2CO3), and concentrated in vacuo to give the crude product (0.91 g) as a tan solid which was taken up in methylene chloride (ca. 3 mL) and pre-adsorbed on silica gel (3 g). Flash chromatography on silica gel (27 g) eluting 25-, and then 50% methylene chloride-hexane gave the title compound (0.73 g, 71%, m.p. 182-84° C.) as a white solid which was pure enough for further use.
Reaction SMILES: [Cl:1][C:2]([Cl:41])([Cl:40])[CH2:3][O:4][C:5]([N:7](C(OCC(Cl)(Cl)Cl)=O)[C:8]1[C:9]([C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]3)=[CH:15][CH:14]=2)=[N:10][O:11][N:12]=1)=[O:6].[OH-].[Na+]>C1COCC1.[Cl-].[Na+].O>[Cl:40][C:2]([Cl:1])([Cl:41])[CH2:3][O:4][C:5]([NH:7][C:8]1[C:9]([C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH2:20][CH2:21][N:22]([C:25]([O:27][C:28]([CH3:29])([CH3:31])[CH3:30])=[O:26])[CH2:23][CH2:24]3)=[CH:15][CH:14]=2)=[N:10][O:11][N:12]=1)=[O:6]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(-c3nonc3N(C(=O)OCC(Cl)(Cl)Cl)C(=O)OCC(Cl)(Cl)Cl)cc2)CC1
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(-c3nonc3NC(=O)OCC(Cl)(Cl)Cl)cc2)CC1
Reaction time: 1 h

Procedure:
To tert-butyl 4-[4-(4-{bis[(2,2,2-trichloroethoxy)carbonyl]amino}-1,2,5-oxadiazol-3-yl)phenyl]piperazine-1-carboxylate (1.21 g, 1.74 mmol) in THF (25 mL) was added an aqueous solution of NaOH (1.0 M, 4.0 mL, 4.0 mmol) dropwise and the reaction mixture was stirred for 1 hour. The reaction was poured into brine and the product extracted with Et2O (2×), dried over Na2SO4, concentrated in vacuo and purified by flash chromatography over silica gel (EtOAc/Hex, 3/7) to afford tert-butyl 4-[4-(4-{[(2,2,2-trichloroethoxy)carbonyl]amino}-1,2,5-oxadiazol-3-yl)phenyl]piperazine-1-carboxylate.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:31])[C:7]([CH2:18][NH:19][C:20]([C:22]3[CH:23]=[C:24]4NC=NC4=N[CH:27]=3)=[O:21])=[CH:8][N:9]2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:4][CH:3]=1.[C:32]([O:36][C:37]([N:39]1[CH2:44]CC(C(O)=O)CC1)=[O:38])([CH3:35])([CH3:34])[CH3:33]>>[CH3:32][O:36][C:37]([C:8]1[N:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:10]2[C:5]([C:6](=[O:31])[C:7]=1[CH2:18][NH:19][C:20]([CH:22]1[CH2:23][CH2:24][N:39]([C:37]([O:36][C:32]([CH3:33])([CH3:34])[CH3:35])=[O:38])[CH2:44][CH2:27]1)=[O:21])=[CH:4][CH:3]=[C:2]([Cl:1])[CH:11]=2)=[O:38]
Reactant: O=C(NCc1cn(-c2ccccc2)c2cc(Cl)ccc2c1=O)c1cnc2nc[nH]c2c1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Product: COC(=O)c1c(CNC(=O)C2CCN(C(=O)OC(C)(C)C)CC2)c(=O)c2ccc(Cl)cc2n1-c1ccccc1

Procedure:
3-{[(1-tert-butoxycarbonyl-piperidine-4-carbonyl)-amino]-methyl}-7-chloro-4-oxo-1-phenyl-1,4-dihydro-quinoline-2-carboxylic acid methyl ester was prepared starting from intermediate 1 and 1-tert-butoxycarbonyl-piperidine-4-carboxylic acid. MS calcd. for C29H33ClN3O6 [(M+H)+] 554.2, obsd. 554.1.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[N:6][C:7]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)=[C:8]([C:11]3[CH:16]=[CH:15][N:14]=[C:13]([S:17][CH3:18])[N:12]=3)[CH:9]=2)[NH:4][N:3]=1.[C:26](Cl)(=[O:28])[CH3:27]>>[F:25][C:22]1[CH:23]=[CH:24][C:19]([C:7]2[N:6]=[C:5]3[NH:4][N:3]=[C:2]([NH:1][C:26](=[O:28])[CH3:27])[C:10]3=[CH:9][C:8]=2[C:11]2[CH:16]=[CH:15][N:14]=[C:13]([S:17][CH3:18])[N:12]=2)=[CH:20][CH:21]=1
Reactant: CSc1nccc(-c2cc3c(N)n[nH]c3nc2-c2ccc(F)cc2)n1
Reactant: CC(=O)Cl
Product: CSc1nccc(-c2cc3c(NC(C)=O)n[nH]c3nc2-c2ccc(F)cc2)n1

Procedure:
Following a similar procedure to that described in example 245, but starting from 3-amino-6-(4-fluorophenyl)-5-(2-methylsulfanylpyrimidin-4-yl)pyrazolo[3,4-b]pyridine (obtained in example 180) and acetyl chloride, the title compound was obtained.
Reaction SMILES: [C:1]([O:5][C:6](=[O:41])[CH:7]([NH:13][C:14](=[O:40])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:8][CH2:9][C:10]([OH:12])=[O:11])([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.[B-](F)(F)(F)F.CN(C(O[N:64]1[C:69](=[O:70])[CH2:68][CH2:67][C:65]1=[O:66])=[N+](C)C)C>C1COCC1.C(#N)C>[O:66]=[C:65]1[CH2:67][CH2:68][C:69](=[O:70])[N:64]1[O:11][C:10](=[O:12])[CH2:9][CH2:8][CH:7]([NH:13][C:14](=[O:40])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:41]
Reactant: CC(C)(C)OC(=O)CCCCCCCCCCCCCCCCCCC(=O)NC(CCC(=O)O)C(=O)OC(C)(C)C
Reactant: CN(C)C(ON1C(=O)CCC1=O)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CCCCCCCCCCCCCCCCCCC(=O)NC(CCC(=O)ON1C(=O)CCC1=O)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.1 %

Procedure:
2-(19-tert-Butoxycarbonylnonadecanoylamino)pentanedioic acid 1-tert-butyl ester (6.52 g, 11.17 mmol) was dissolved in THF (100 mL), DIPEA (2.14 mL) was added followed by a solution of TSTU (3.70 g, 12.29 mmol) in acetonitrile (25 mL). The mixture was stirred overnight at RT, then it was evaporated resulting in a brownish residue which was recrystallised from acetonitrile. After cooling overnight at 5° C. a powder was formed. This was dissolved in THF and dried with MgSO4, filtered and evaporated to dryness to afford 6.17 g (81%) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[NH2:10])[C:5]#[N:6].[C:11](N1C=CN=C1)(N1C=CN=C1)=[O:12]>C1COCC1.CCOC(C)=O>[C:5]([C:4]1[CH:7]=[CH:8][C:9]2[NH:10][C:11](=[O:12])[NH:1][C:2]=2[CH:3]=1)#[N:6]
Reactant: N#Cc1ccc(N)c(N)c1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: N#Cc1ccc2[nH]c(=O)[nH]c2c1
Yield: 79.6 %

Procedure:
After 4-amino-3-nitrobenzonitrile (3.26 g, 20 mmol) was treated with hydrogen in MeOH (300 mL) in the presence of 5% palladium on active carbon (1 g) at room temperature for 16 hours, the reaction mixture was filtered and the filtrate was concentrated to give 3,4-diaminobenzonitrile (2.4 g, 90% yield). A solution of 3,4-diaminobenzonitrile (2 g, 15 mmol) in THF (100 mL) was treated with carbonyldiimidazole (CDI, 3.2 g, 19 mmol) at room temperature for 18 hours. The mixture was diluted with EtOAc (150 mL), washed with 1N HCl (30 mL) and brine, and dried over MgSO4. Filtration and concentration gave 5-cyanobenzimidazolinone (1.9 g, 80%). 1H NMR (CD3OD) δ 7.40 (dd, J=8.1 Hz, J=1.5 Hz, 1H), 7.34 (d, J=1.5 Hz, 1H), 7.15 (d, J=8.1 Hz, 1H); MS: 160.1 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([CH:10](S(C)=O)SC)[C:7]([F:16])=[CH:6][C:3]=1[C:4]#[N:5].S(=O)(=O)(O)[OH:18].O>C1COCC1>[F:1][C:2]1[CH:9]=[C:8]([CH:10]=[O:18])[C:7]([F:16])=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: O=S(=O)(O)O
Reactant: CSC(c1cc(F)c(C#N)cc1F)S(C)=O
Solvent: C1CCOC1
Solvent: O
Product: N#Cc1cc(F)c(C=O)cc1F
Reaction time: 144 h

Procedure:
2,5-Difluoro-4-[(methylsulfinyl)(methylthio)methyl]benzonitrile (2.8 g, 0.0107 mol; see step (i) above) was dissolved in 100 mL of THF and 6.5 g of concentrated sulfuric acid was added. The mixture was left at room temperature for 6 days and subsequently poured into 500 mL of water. Extraction three times with diethyl ether followed and the combined ethereal phase washed several times with water, dried (Na2SO4) and evaporated. The crude product was flash chromatographed on silica gel using heptane:EtOAc (8:2). Yield: 1.2 g (67%). The position of the formyl group was established by use of 13C NMR. The carbon signals from the fluorinated carbons at 160.1 and 158.4 respectively were doublets and not quartets, which they would have been if the formyl group had been in the 2-position.
Reaction SMILES: N[C:2]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:3]=1[C:4]#[N:5].N(OC(C)(C)C)=O.C(I)[I:22]>>[I:22][C:2]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: ICI
Reactant: N#Cc1cc(C(F)(F)F)ccc1N
Agent: CC(C)(C)ON=O
Product: N#Cc1cc(C(F)(F)F)ccc1I
Temperature: 100 °C

Procedure:
2-Amino-5-(trifluoromethyl)benzonitrile (3.06 g, 16.45 mmol) was suspended in CH2I2 (36 mL) and t-butyl nitrite (3.9 mL, 32.9 mmol) was added dropwise by syringe. The reaction was heated slowly to 100° C. and was maintained at this temperature for 30 minutes. The reaction was then cooled to room temperature, diluted with hexanes (200 mL), loaded on a silica gel column, and purified with 100% hexanes to 15% EtOAc/hexanes. The resulting product, 2-iodo-5-(trifluoromethyl)benzonitrile was contaminated with minor impurities which were removed by silica gel chromatography with 25% CH2Cl2/hexanes. 2-Iodo-5-(trifluoromethyl)benzonitrile was obtained as a white solid. Rf=0.44 (15% EtOAc/hexanes). 1H NMR (CDCl3, 500 MHz) δ 8.10 (d, J=8.5 Hz, 1H), 7.85 (d, J=1.8 Hz, 1H), 7.52 (dd, J=8.5, 1.8 Hz, 1H).
Reaction SMILES: C(O)(C(F)(F)F)=O.[F:8][C:9]1[CH:10]=[C:11]([N:22]2[CH2:26][C@H:25]([CH2:27][NH:28][C:29](=O)[O:30]C(C)(C)C)[O:24][C:23]2=[O:36])[CH:12]=[CH:13][C:14]=1[N:15]1[CH:20]=[CH:19][C:18](=[O:21])[CH2:17][CH2:16]1.[Cl:37][CH:38]([Cl:44])C(OCC)=O>ClC(Cl)C>[Cl:37][CH:38]([Cl:44])[C:29]([NH:28][CH2:27][CH:25]1[O:24][C:23](=[O:36])[N:22]([C:11]2[CH:12]=[CH:13][C:14]([N:15]3[CH:20]=[CH:19][C:18](=[O:21])[CH2:17][CH2:16]3)=[C:9]([F:8])[CH:10]=2)[CH2:26]1)=[O:30]
Reactant: CCOC(=O)C(Cl)Cl
Reactant: CC(C)(C)OC(=O)NC[C@H]1CN(c2ccc(N3C=CC(=O)CC3)c(F)c2)C(=O)O1
Solvent: O=C(O)C(F)(F)F
Solvent: CC(Cl)Cl
Product: O=C1C=CN(c2ccc(N3CC(CNC(=O)C(Cl)Cl)OC3=O)cc2F)CC1
Reaction time: 1.5 h

Procedure:
TFA (0.75 mL) is added to a solution of the carbamate from Step 6 of Example 3 (100 mg, 0.247 mmol) in dichloroethane (3.0 mL). This solution is stirred for 1.5 h., and the solvent is removed under vacuum. The residue is dissolved in MeOH (4.0 mL). TEA (105 mg, 1 mmol) is added to the mixture, followed by adding ethyl dichloroacetate (77 mg, 0.49 mmol). The mixture is stirred at r.t. for 16 h. Solvent is removed under vacuum, and the crude product purified by silica gel column chromatography (gradient 1% to 2% MeOH in DCM). MS (m/z): 417 [M+1]+. 1H NMR (300 MHz, DMSO-d6) δ 9.17 (t, J=5.5 Hz, 1H), 7.79 (d, J=14.3 Hz, 1H), 7.69–7.48 (m, 3 H), 6.67 (s, 1H), 5.17 (d, J=7.7 Hz, 1H), 5.05–4.99 (m, 1H), 4.35 (t, J=9.1 Hz, 1H), 4.06 (t, J=7.7 Hz, 3H), 3.93 (dd, J=6.0 and 9.3 Hz, 1H), 3.74–3.72 (m, 2H), 3.51–3.49 (m, 2H).
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)[CH:5]=[CH:4][N:3]=[N:2]1.CN(C)C=O.[H-].[Na+].Cl[CH2:25][C:26]1[N:27]=[C:28]([CH:31]=[CH:32][C:33]2[CH:43]=[CH:42][C:36]3[O:37][C:38]([F:41])([F:40])[O:39][C:35]=3[CH:34]=2)[O:29][CH:30]=1>O>[F:41][C:38]1([F:40])[O:37][C:36]2[CH:42]=[CH:43][C:33]([CH:32]=[CH:31][C:28]3[O:29][CH:30]=[C:26]([CH2:25][O:16][C:13]4[CH:12]=[CH:11][C:10]([CH2:9][CH2:8][CH2:7][CH2:6][N:1]5[CH:5]=[CH:4][N:3]=[N:2]5)=[CH:15][CH:14]=4)[N:27]=3)=[CH:34][C:35]=2[O:39]1
Reactant: FC1(F)Oc2ccc(C=Cc3nc(CCl)co3)cc2O1
Reactant: Oc1ccc(CCCCn2ccnn2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: FC1(F)Oc2ccc(C=Cc3nc(COc4ccc(CCCCn5ccnn5)cc4)co3)cc2O1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 87.4 %

Procedure:
To a solution of 0.217 g (1.00 mmol) 4-(4-[1,2,3]Triazol-1-yl-butyl)-phenol in 4 ml N,N-dimethyl formamide 40 mg (1.00 mmol) of NaH (60% dispersion in mineral oil) were added and the mixture stirred for 15 min at room temperature. Subsequently 0.3 g (1.00 mmol) 4-chloromethyl-2-[2-(2,2-difluoro-benzo[1,3]dioxol-5-yl)-vinyl]-oxazole were added and stirring continued for 12 h. 20 ml of water were added, the resulting precipitate collected, washed with water (2×), methanol/water (1:1), ether (3×) and dried in vacuo yielding 0.42 g (87%) 1-[4-(4-{2-[2-(2,2-Difluoro-benzo[1,3]dioxol-5-yl)-vinyl]-oxazol-4-ylmethoxy}-phenyl)-butyl]-1H-[1,2,3]triazole as white solid.
Reaction SMILES: [CH2:1]([N:3]([CH2:7][CH3:8])[CH2:4][CH2:5][NH2:6])[CH3:2].C[Al](C)C.CCCCCCC.[I:20][C:21]1[CH:22]=[C:23]2[C:28](=[CH:29][CH:30]=1)[NH:27][C:26]([C:31](OC)=[O:32])=[CH:25][C:24]2=[O:35].N1C2C(=CC=CC=2)C=CC=1>ClCCl.C(O)C.O>[CH2:1]([N:3]([CH2:7][CH3:8])[CH2:4][CH2:5][NH:6][C:31]([C:26]1[NH:27][C:28]2[C:23]([C:24](=[O:35])[CH:25]=1)=[CH:22][C:21]([I:20])=[CH:30][CH:29]=2)=[O:32])[CH3:2]
Reactant: COC(=O)c1cc(=O)c2cc(I)ccc2[nH]1
Reactant: CCN(CC)CCN
Agent: C[Al](C)C
Solvent: ClCCl
Solvent: CCCCCCC
Solvent: CCO
Product: CCN(CC)CCNC(=O)c1cc(=O)c2cc(I)ccc2[nH]1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 78.2 %

Procedure:
To a stirred solution of N,N-diethylethylenediamine (483 μL, 3.42 mmol) in anhydrous dichloromethane (50 mL) was added, at 0° C., under argon, a 2.0 M trimethylaluminium solution in heptane (1.71 mL, 3.42 mmol). After 10 min, methyl 6-iodo-4-oxo-1,4-dihydroquinoline-2-carboxylate (103) (800 mg, 2.43 mmol) (Deng, Y.; Curran, P. J.; Shipps, G. W. Jr.; Zhao, L.; Siddiqui, M. A.: Popovici-Muller, J.; Duca, J. S.; Kruza, A. W.; Fischmann, T. O.; Madison, V. S.; Zhang, R.; Mcnemar, C. W.; Mayhood, T. W.; Windsor, W. T.; Lees, E. M.; Parry, D. Novel high affinity quinoline-based kinase ligands. Patent WO2007/022241, 2007) was added and the mixture was refluxed for 12 h. After cooling to room temperature, water (40 mL) and ethanol (100 mL) were added. The precipitate was then filtered and washed with ethanol (5×10 mL). The filtrate volume was reduced to 20 mL by evaporation under reduce pressure and the precipitate formed was filtered and washed with diethylether (10 mL) to give compound 104 (784 mg, 1.90 mmol) as a beige solid. Yield 78%; mp 345-347° C. (dec.); IR (KBr) ν 1507, 1594, 1622, 1665, 2963, 3241 cm−1; 1H NMR (200 MHz, DMSO-d6) δ 0.96 (t, 6H, J=7.0 Hz), 2.53 (m, 6H), 3.34 (q, 2H, J=6.3 Hz), 6.83 (s, 1H), 7.72 (d, 1H, J=8.8 Hz), 7.94 (dd, 1H, J=2.0, 8.8 Hz), 8.36 (d, 1H, J=2.0 Hz), 8.91 (t, 1H, J=5.3 Hz); ESI-MS m/z 413.8 [M+H]+.