Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[C:14](O)=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([N:19](CC)CC)C.ClC(OCC)=O.N>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[C:14]#[N:19])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCCCC1C(=O)O
Reactant: CCN(CC)CC
Agent: CCOC(=O)Cl
Agent: N
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCCCC1C#N
Temperature: -20 °C
Yield: 80.4 %

Procedure:
Piperidine-1,2-dicarboxylic acid-1-tert-butyl ester (12.8 g, 55.6 mmol) and THF (170 mL) were added to a 500 mL round bottom flask equipped with stir bar. The solution was cooled to −20° C. and triethylamine (10.1 mL, 72.3 mmol) was added followed by ethyl chloroformate (5.32 mL, 55.6 mmol). The resulting white precipitate was left stirring at −10° C. for 1 h. Aqueous ammonia (22.6 mL, 1168 mmol) was added to the above reaction mixture and the clear reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated in vacuo and the isolated residue was dissolved in ethyl acetate (300 mL). The organic phase was successively washed with water (300 mL) and brine (200 mL), dried (sodium sulfate), filtered and concentrated in vacuo to isolate a clear gum. The gum was triturated with hexanes to isolate the title compound (9.4 g, 74%) as a white solid. 1H-NMR (CDCl3), δ(ppm): 6.03 (bs, 1H), 5.55 (bs, 1H), 4.77 (bs, 1H), 4.05 (bs, 1H), 2.81 (t, 1H), 2.27 (bs, 1H), 1.47 (m, 14H).
Reaction SMILES: [NH2:1][C@H:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH2:3][OH:4].[CH2:11]([O:18][C:19](ON1C(=O)CCC1=O)=[O:20])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>CN(C=O)C>[CH2:11]([O:18][C:19]([NH:1][C@H:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH2:3][OH:4])=[O:20])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Reactant: N[C@@H](CO)c1ccccc1
Solvent: CN(C)C=O
Product: O=C(N[C@@H](CO)c1ccccc1)OCc1ccccc1
Reaction time: 48 h

Procedure:
40.5 g (295 mol) of (R)-2-amino-2-phenylethanol were dissolved in 385 ml of absolute DMF. 73.5 g of N-(benzyloxycarbonyloxy)succinimide (295 mmol) were added at 0° C. with stirring and the mixture was stirred at 0° C. for 1 hour. The ice bath was removed and the batch was allowed to stand at room temperature for 48 hours. The reaction solution was concentrated in vacuo and the residue was then taken up in 500 ml of ethyl acetate. The organic phase was washed twice with 10% strength aqueous citric acid solution and once with water. It was dried over anhydrous sodium sulfate and concentrated. The crystalline crude product obtained (82.3 g) was dissolved again in ethyl acetate. The organic phase was washed twice with 10% strength aqueous citric acid solution and once with water and concentrated. The residue was then recrystallized from ethyl acetate/petroleum ether. Yield: 74.6 g (93.3%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:10]([CH:11]([OH:26])[C:12]3[CH:13]=[C:14]([NH:19][S:20]([CH2:23][CH2:24][CH3:25])(=[O:22])=[O:21])[CH:15]=[CH:16][C:17]=3[F:18])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>O1CCCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]([C:12]3[CH:13]=[C:14]([NH:19][S:20]([CH2:23][CH2:24][CH3:25])(=[O:22])=[O:21])[CH:15]=[CH:16][C:17]=3[F:18])=[O:26])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: CCCS(=O)(=O)Nc1ccc(F)c(C(O)c2c[nH]c3ncc(Br)cc23)c1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: C1CCOC1
Product: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)c2c[nH]c3ncc(Br)cc23)c1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To propane-1-sulfonic acid 3-[(5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)hydroxy-methyl]-4-fluoro-phenyl-amide (673, 55.0 mg, 0.12 mmol) in tetrahydrofuran (8.0 mL) was added Dess-Martin periodinane (70.0 mg, 0.17 mmol). The reaction was stirred at room temperature for 5 minutes. The reaction was concentrated with silica gel and purified with silica gel column chromatography eluting with 25% ethyl acetate in hexane to give an off-white solid (P-1403, 26.2 mg, 47%). MS (ESI) [M+H+]+=437.9, 439.9.
Reaction SMILES: [C:1]([CH2:3][CH:4]([OH:16])[CH2:5][C:6](=[O:15])[CH2:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])#[N:2].[BH4-].[Na+]>C(B(CC)CC)C.C1COCC1.CO.COCCOCCOCCOC>[C:1]([CH2:3][CH:4]([OH:16])[CH2:5][CH:6]([OH:15])[CH2:7][C:8]([O:10][C:11]([CH3:12])([CH3:14])[CH3:13])=[O:9])#[N:2]
Reactant: CC(C)(C)OC(=O)CC(=O)CC(O)CC#N
Agent: CCB(CC)CC
Agent: [BH4-]
Agent: [Na+]
Solvent: COCCOCCOCCOC
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)CC(O)CC(O)CC#N

Procedure:
Crude 5R 1,1-dimethylethyl 6-cyano-5-hydroxy-3-oxohexanoate (about 130 mmoles) from Step (1) is dissolved in 100 mL 1 M triethylborane in THF and 65 mL tetrahydrofuran, stirred for about 2 hours at room temperature, then cooled to −75° C.±20° C., and diluted with 25 mL methanol. Sodium borohydride (6 g) as a solution in triglyme (75 mL) is added slowly. After the addition, the reaction mixture is warmed to 20° C. to 25° C. The reaction mixture is quenched by the addition of 20 mL methanol and 8 g acetic acid and concentrated by vacuum distillation—saving the distillate. The residue is diluted with 100 mL water and 200 mL ethyl acetate, agitated, and the phases separated. The organic layer is concentrated by vacuum distillation—keeping this distillate separate from the first one. The residue is dissolved in 200 mL methanol and 10 mL acetic acid and concentrated by vacuum distillation. The residue is dissolved in 200 mL methanol and concentrated by vacuum distillation. The residue is dissolved in 200 mL methanol and concentrated by vacuum distillation. The residue is dissolved in ethyl acetate and concentrated by vacuum distillation resulting in crude [R-(R*,R*)]-1,1-dimethylethyl 6-cyano-3,5-dihydroxyhexanoate.
Reaction SMILES: [CH:1]([C:4]1([CH3:26])[C:8](=[O:9])[NH:7][C:6]([C:10]2[C:19]([C:20]([OH:22])=[O:21])=[CH:18][C:17]3[C:12](=[CH:13][CH:14]=[C:15]([N+:23]([O-])=O)[CH:16]=3)[N:11]=2)=[N:5]1)([CH3:3])[CH3:2]>[Pd].CO>[NH2:23][C:15]1[CH:16]=[C:17]2[C:12](=[CH:13][CH:14]=1)[N:11]=[C:10]([C:6]1[NH:7][C:8](=[O:9])[C:4]([CH:1]([CH3:2])[CH3:3])([CH3:26])[N:5]=1)[C:19]([C:20]([OH:22])=[O:21])=[CH:18]2
Reactant: CC(C)C1(C)N=C(c2nc3ccc([N+](=O)[O-])cc3cc2C(=O)O)NC1=O
Agent: [Pd]
Solvent: CO
Product: CC(C)C1(C)N=C(c2nc3ccc(N)cc3cc2C(=O)O)NC1=O
Yield: 0.1 %

Procedure:
To a solution of 2-(4-isopropyl-4-methyl-5-oxo-2 -imidazolin-2-yl)-6-nitro-3-quinolinecarboxylic acid (212 mg, 0,594 mmol) and methanol (100 mL), a 50 mg quantity of 10% palladium on carbon is added under argon. The mixture is allowed to shake under a hydrogen atmosphere (4 psi) for thirty minutes at room temperature, The catalyst is removed by filtration through diatomaceous earth and then the filtrate is concentrated in vacuo. The concentrate is partitioned between 100 mL portions of chloroform and water and the layers are separated. The organic layer is washed three times with water, dried over anhydrous sodium sulfate and concentrated in vacuo to give formula III 6-amino-2-(4-isopropyl-4-methyl-5-oxo-2-imidazolin2-yl)-3-quinolinecarboxylic acid as a yellow solid (170 mg). The purity of this material is determined by TLC on silica gel with chloroform, methanol and acetic acid (220:30:6) elution.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[F:9][C:10]([F:23])([O:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=1)[CH:18]=O)[CH:11]([F:13])[F:12].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClCCCl>[F:9][C:10]([F:23])([O:14][C:15]1[CH:16]=[C:17]([CH2:18][NH:1][C:2]2[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=2)[CH:20]=[CH:21][CH:22]=1)[CH:11]([F:12])[F:13]
Reactant: O=Cc1cccc(OC(F)(F)C(F)F)c1
Reactant: Nc1cccc(O)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: Oc1cccc(NCc2cccc(OC(F)(F)C(F)F)c2)c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 83.3 %

Procedure:
EX-20A) To a solution of 3-aminophenol (4.91 g, 45.0 mmol) and 3-(1,1,2,2-tetrafluoroethoxy)benzaldehyde (10.0 g, 45.0 mmol) in 100 mL of 1,2-dichloroethane was added sodium triacetoxyborohydride (14.28 g 67.5 mmol) and glacial acetic acid (2.7 mL, 47.3 mmol). The reaction mixture was stirred at room temperature for 6 h then quenched with water and extracted with dichloromethane. The organic layer was washed with saturated aqueous sodium bicarbonate, dried over MgSO4, and concentrated in vacuo to give 11.82 g (83%) of the desired 3-[[[3-(1,1,2,2-tetrafluoro-ethoxy)phenyl]methyl]amino]phenol product as a dark orange oil. 1H NMR (acetone-d6) δ 7.01-7.38 (m, 5H), 6.26-6.44 (m, 3H), 6.08 (t, 1H), 5.88 (tt, 1H), 4.34 (s, 2H).
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:12][CH2:11][N:10]2[C:19](OC2C=CC([N+]([O-])=O)=CC=2)=[O:20])=[CH:5][CH:4]=1.[NH2:33][C:34]1[CH:41]=[CH:40][C:37]([C:38]#[N:39])=[C:36]([F:42])[CH:35]=1.[H-].[Na+].O>CC#N>[C:38]([C:37]1[CH:40]=[CH:41][C:34]([NH:33][C:19]([N:10]2[CH2:11][CH2:12][C:13]3[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=3)[C@H:9]2[C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:32])[F:31])=[CH:8][CH:7]=2)=[O:20])=[CH:35][C:36]=1[F:42])#[N:39]
Reactant: N#Cc1ccc(N)cc1F
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)N1CCc2ccccc2[C@H]1c1ccc(C(F)(F)F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: N#Cc1ccc(NC(=O)N2CCc3ccccc3[C@H]2c2ccc(C(F)(F)F)cc2)cc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (R)-4-nitrophenyl 1-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (70 mg, 158 μmol, example 88) in MeCN (0.5 mL) was added 4-amino-2-fluorobenzonitrile (65 mg, 475 μmol). The resulting mixture was then subjected to a microwave irradiation at 180° C. for 15 min. Then, sodium hydride, 60% dispersion in mineral oil (22 μL, 475 μmol) was added and the mixture was stirred at RT for overnight. Then, H2O (0.5 mL) was added and the solvents were removed. The residue was then dissolved in a solution of MeOH and DMSO (1:1, 1.0 mL). The solution mixture was then purified by preparative HPLC (0%-100% MeCN 0.1% TFA/H2O 0.1% TFA) to give the desired product, which was then dissolved in MeOH (1.0 mL). The solution was then washed through PL-HCO3 MP resin (polymerlabs, 200 mg/6 mL tube) and the resin was washed with MeOH (2×0.5 mL). The combined washings were then concentrated and dried under vacuum to give the title compound as a yellow solid. MS (ESI, positive ion) m/z: 440 (M+H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Cl[C:8]1[C:20]([F:21])=[CH:19][C:11]([CH2:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:10]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=2[F:30])[N:9]=1.C(Cl)(Cl)Cl.O>C(O)C.CCCCCC>[F:30][C:24]1[CH:25]=[C:26]([F:29])[CH:27]=[CH:28][C:23]=1[NH:22][C:10]1[N:9]=[C:8]([N:1]2[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]2)[C:20]([F:21])=[CH:19][C:11]=1[CH2:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: C1CNCCN1
Reactant: CCOC(=O)CCc1cc(F)c(Cl)nc1Nc1ccc(F)cc1F
Solvent: CCCCCC
Solvent: O
Solvent: ClC(Cl)Cl
Product: CCOC(=O)CCc1cc(F)c(N2CCNCC2)nc1Nc1ccc(F)cc1F
Yield: 41 %

Procedure:
In 1.5 ml of ethanol was dissolved 140 mg of anhydrous piperazine, and to the resulting solution was added 150 mg of ethyl 2-[6-chloro-2-(2,4-difluorophenylamino)-5-fluoronicotinyl]acetate in portions, and the resulting mixture was subjected to reaction at room temperature for 30 minutes. Subsequently, the reaction mixture was added to a mixture of 5 ml of chloroform and 5 ml of water, and the organic layer was separated, washed successively with 3 ml of water and 3 ml of saturated aqueous sodium chloride solution, and then dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure, and to the crystalline material thus obtained was added 2 ml of n-hexane, after which crystals were collected by filtration to obtain 70 mg (yield 41.2%) of ethyl 2-[2-(2,4-difluorophenylamino)-5-fluoro-6-(1-piperazinyl)nicotinyl]acetate
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9](=O)[CH2:10][NH:11][C:12]([CH3:18])([CH3:17])[C:13]([O:15]C)=O)[CH:5]=[C:6]([F:8])[CH:7]=1.Cl.[CH2:21]([O:23][C:24](=[O:27])[CH2:25][NH2:26])[CH3:22].CC(O)=O.[BH3-]C#N.[Na+]>CO>[F:8][C:6]1[CH:5]=[C:4]([CH:9]2[N:26]([CH2:25][C:24]([O:23][CH2:21][CH3:22])=[O:27])[C:13](=[O:15])[C:12]([CH3:18])([CH3:17])[NH:11][CH2:10]2)[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: CCOC(=O)CN
Reactant: COC(=O)C(C)(C)NCC(=O)c1cc(F)cc(F)c1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CCOC(=O)CN1C(=O)C(C)(C)NCC1c1cc(F)cc(F)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A mixture of methyl 2-{[2-(3,5-difluorophenyl)-2-oxoethyl]amino}-2-methylpropanoate from Step A (8.60 g, 31.7 mmol), glycine ethyl ester hydrochloride (44.3 g, 317 mmol), and AcOH (5.71 mL, 95 mmol) in MeOH (300 mL) was stirred at ambient temperature for 10 min. NaCNBH3 (2.39 g, 38.0 mmol) was added and the pH of the mixture was checked and adjusted to pH ˜5 as necessary. The reaction mixture was heated to 50° C. for 18 h. Additional AcOH (4 mL) was added and the reaction mixture was heated to 60° C. for 6 h then allowed to cool and concentrated in vacuo to a volume of ca. 150 mL. The resulting mixture was carefully quenched with saturated aqueous NaHCO3 (300 mL) and then extracted with CH2Cl2 (1 L). The organic extract was washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography, eluting with hexane:EtOAc—100:0 to 0:100, to give the title compound. MS: m/z=327 (M+1).
Reaction SMILES: Br.C([N:6]1[C:15](=[O:16])[C:14]2[C:9](=[CH:10][C:11]([CH3:41])=[C:12]([CH2:18][CH2:19][S:20]([N:23]3[CH2:40][CH2:39][C:26]4([N:30]=[C:29]([CH:31]5[CH2:36][CH2:35][CH:34]([CH3:37])[CH2:33][CH2:32]5)[NH:28][C:27]4=[O:38])[CH2:25][CH2:24]3)(=[O:22])=[O:21])[C:13]=2[CH3:17])[NH:8][C:7]1=[O:42])(C)(C)C>C(O)(=O)C>[CH3:17][C:13]1[C:12]([CH2:18][CH2:19][S:20]([N:23]2[CH2:40][CH2:39][C:26]3([N:30]=[C:29]([CH:31]4[CH2:32][CH2:33][CH:34]([CH3:37])[CH2:35][CH2:36]4)[NH:28][C:27]3=[O:38])[CH2:25][CH2:24]2)(=[O:22])=[O:21])=[C:11]([CH3:41])[CH:10]=[C:9]2[C:14]=1[C:15](=[O:16])[NH:6][C:7](=[O:42])[NH:8]2
Reactant: Cc1cc2[nH]c(=O)n(C(C)(C)C)c(=O)c2c(C)c1CCS(=O)(=O)N1CCC2(CC1)N=C(C1CCC(C)CC1)NC2=O
Agent: Br
Solvent: CC(=O)O
Product: Cc1cc2[nH]c(=O)[nH]c(=O)c2c(C)c1CCS(=O)(=O)N1CCC2(CC1)N=C(C1CCC(C)CC1)NC2=O
Temperature: 100 °C
Reaction time: 1 h
Yield: 66.4 %

Procedure:
An aqueous hydrogen bromide solution (80 μL) was added to a mixed solution of 3-tert-butyl-5,7-dimethyl-6-{2-[2-(4-methyl-cyclohexyl)-4-oxo-1,3,8-triaza-spiro[4.5]dec-1-ene-8-sulfonyl]-ethyl}-1H-quinazoline-2,4-dione (3.3 mg, 3.41 μmol) in acetic acid (80 μL), and the mixture was heated with stirring at 100° C. for one hour. The reaction solution was returned to room temperature and then concentrated under reduced pressure, and the resulting residue was purified by preparative TLC to give 5,7-dimethyl-6-{2-[2-(4-methyl-cyclohexyl)-4-oxo-1,3,8-triaza-spiro[4.5]dec-1-ene-8-sulfonyl]-ethyl}-1H-quinazoline-2,4-dione as a pale yellow solid (1.2 mg, 44%).
Reaction SMILES: [SH:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[H-].[Na+:12]>COCCOC>[SH:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([O-:6])=[O:5].[Na+:12]
Reactant: O=C(O)c1ccccc1S
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: O=C([O-])c1ccccc1S
Temperature: 50 °C
Yield: 100 %

Procedure:
A solution of 2-mercaptobenzoic acid (15.4 g, 0.1 mole) in 50 ml of 1,2-dimethoxyethane (DME) was slowly added, with cooling, to a stirred suspension of 0.1 mole of sodium hydride in DME, the suspension having been prepared by washing 4.2 grams of a 57% oil dispersion with dry n-hexane (3 times) and replacing the last wash with dry 1,2-dimethoxyethane (50 ml). Cooling was necessary to maintain the temperature below 25°C. The resultant suspension was heated at 50°C for 2 hours, cooled to 0°C and filtered. The solid was washed well with cold DME (ca. 50 ml) and dried under vacuum overnight to yield sodium 2-mercaptobenzoate: 17.6 g (100% yield);
Reaction SMILES: CS(O[CH2:6][CH2:7][C@@H:8]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=1)(=O)=O.[N-:28]=[N+:29]=[N-:30].[Na+].O.CCOC(C)=O>CN(C=O)C>[N:28]([CH2:6][CH2:7][C@@H:8]([NH:20][C:21](=[O:22])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=1)=[N+:29]=[N-:30]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)N[C@H](CCOS(C)(=O)=O)Cc1ccc(C(F)(F)F)cc1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N[C@H](CCN=[N+]=[N-])Cc1ccc(C(F)(F)F)cc1
Temperature: 70 °C

Procedure:
(S)-3-(tert-Butoxycarbonylamino)-4-(4-(trifluoromethyl)phenyl)butyl methanesulfonate from the previous reaction was dissolved in 25 mL DMF and NaN3 (1.3 g, 20 mmol) was added. The mixture was heated to 70° C. for 4 hours and cooled back to room temperature. Water and EtOAc were added and the phases were separated. The aqueous phase was extracted with EtOAc (3×100 mL) and the combined organic layers were dried over MgSO4 and evaporated. Glass column chromatography (10% EtOAc in hexanes) provided the title compound as white solid. LCMS (API-ES) m/z (%): 259.0 (100%, M++H).
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]=[C:16]=[O:17])=[CH:11][CH:10]=1.[Cl-].[CH3:19][O:20][C:21]1([O:42][CH3:43])[CH2:25][NH2+:24][C@@H:23]([C:26](=[O:41])[NH:27][C:28]2[CH:33]=[CH:32][C:31]([N:34]3[CH:39]=[CH:38][CH:37]=[CH:36][C:35]3=[O:40])=[CH:30][CH:29]=2)[CH2:22]1>ClCCl>[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]([N:24]2[CH2:25][C:21]([O:42][CH3:43])([O:20][CH3:19])[CH2:22][C@@H:23]2[C:26]([NH:27][C:28]2[CH:33]=[CH:32][C:31]([N:34]3[CH:39]=[CH:38][CH:37]=[CH:36][C:35]3=[O:40])=[CH:30][CH:29]=2)=[O:41])=[O:17])=[CH:11][CH:10]=1
Reactant: O=C=Nc1ccc(Cl)cc1
Reactant: COC1(OC)C[NH2+][C@@H](C(=O)Nc2ccc(-n3ccccc3=O)cc2)C1
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC1(OC)C[C@H](C(=O)Nc2ccc(-n3ccccc3=O)cc2)N(C(=O)Nc2ccc(Cl)cc2)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
6.1 12.2 g (122 mmol) of chromium(VI) oxide are added to a mixture, held at 0° C., of 22 ml of pyridine and 50 ml of dichloromethane, and the mixture is stirred at the same temperature for 30 minutes. The solution is allowed to warm to room temperature, and a solution of 5.00 g of cis-Boc-4-hydroxy-D-proline in 80 ml of dichloromethane is added dropwise over the course of 5 minutes. After stirring at room temperature for 1 hour, the solution is filtered, and the filtrate is evaporated. The residue is partitioned between 1N HCl and tert-butyl methyl ether. The organic phase is dried over sodium sulfate, evaporated and recrystallised from diethyl ether/petroleum ether, giving Boc-4-keto-D-proline as a colourless solid; ESI 130. 6.2 742 mg (3.00 mmol) of ethyl 2-ethoxy-1,2-dihydroquinoline-1-carboxylate (EEDQ) are added to a suspension of 459 mg (2.00 mmol) of Boc-4-keto-D-proline and 372 mg (2.00 mmol) of 1-(4-aminophenyl)-1H-pyridin-2-one in 25 ml of toluene, and the mixture is stirred at room temperature for 18 hours. 200 ml of tert-butyl methyl ether are added, and the precipitate formed is filtered off. 200 ml of petroleum ether are added to the filtrate, and the resultant precipitate is filtered off, giving tert-butyl (R)-4-oxo-2-[4-(2-oxo-2H-pyridin-1-yl)phenylcarbamoyl]pyrrolidine-1-carboxylate as a brownish solid; ESI 398. 6.3 10 ml of methanol are added to a suspension of 400 mg (1.01 mmol) of tert-butyl (R)-4-oxo-2-[4-(2-oxo-2H-pyridin-1-yl)phenyl-carbamoyl]pyrrolidine-1-carboxylate in 5 ml of 4N HCl in dioxane, and the mixture is stirred at room temperature for one hour. The reaction mixture is evaporated, giving (R)-4,4-dimethoxy-2-[4-(2-oxo-2H-pyridin-1-yl)phenyl-carbamoyl]pyrrolidinium chloride as a brownish solid; ESI 344. 6.4 0.12 ml of triethylamine and 127 mg (0.830 mmol) of 4-chloro-phenyl isocyanate are added to a solution of 250 mg (0.658 mmol) of (R)-4,4-dimethoxy-2-[4-(2-oxo-2H-pyridin-1-yl)phenylcarbamoyl]pyrrolidinium chloride in 10 ml of dichloromethane. After stirring at room temperature for one hour, the reaction mixture is evaporated, and the residue is chromatographed on a silica-gel column with dichloromethane/methanol 95:5 as eluent, giving 1-N-[(4-chlorophenyl)]-2-N-{[4-(2-oxo-2H-pyridin-1-yl)phenyl]}-(R)-4,4-dimethoxypyrrolidine-1,2-dicarboxamide (“A7”) as a colourless solid; ESI 497.
Reaction SMILES: [C:1]([C:4]1[CH:14]=[CH:13][C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][CH:5]=1)(=O)[CH3:2].[C:15]([CH:19]1[CH2:24][CH2:23][CH:22]([NH2:25])[CH2:21][CH2:20]1)([CH3:18])([CH3:17])[CH3:16].[BH4-].[Na+]>C(O)C.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[C:15]([C@H:19]1[CH2:20][CH2:21][C@H:22]([NH:25][CH:1]([C:4]2[CH:14]=[CH:13][C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][CH:5]=2)[CH3:2])[CH2:23][CH2:24]1)([CH3:18])([CH3:16])[CH3:17]
Reactant: CCOC(=O)c1ccc(C(C)=O)cc1
Reactant: CC(C)(C)C1CCC(N)CC1
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: [BH4-]
Solvent: CCO
Product: CCOC(=O)c1ccc(C(C)N[C@H]2CC[C@H](C(C)(C)C)CC2)cc1
Temperature: 25 °C
Reaction time: 10 h

Procedure:
A mixture of ethyl 4-acetylbenzoate (3.00 g, 15.6 mmol), titanium (IV) isopropoxide (9.30 mL, 31.2 mmol), 4-tert-butylcyclohexyl amine (4.85 g, 31.2 mmol) in absolute ethanol (100 mL) was stirred under nitrogen at room temperature for 10 h. Sodium borohydride (0.88 g, 23.4 mmol) was then added and the resulting mixture was stirred for an additional 8 h at room temperature. The reaction was quenched by pouring into aqueous ammonia (2N, 225 mL). The resulting inorganic precipitate was filtered off and washed with dichloromethane (100 mL). The organic layer was separated and the remaining aqueous layer was extracted once with dichloromethane (100 mL). The combined organic extracts were dried over Na2SO4, filtered and concentrated. Chromatography (20% EtOAc in Hexane) afforded ethyl 4-{1-[(trans-4-tert-butylcyclohexyl)amino]ethyl}benzoate. HPLC/MS: m/z=332.3 (M+1), Rt=2.74 min. 1HNMR (500 MHz, CDCl3): δ 8.01 (2H, d, J=8.1 Hz), 7.38 (2H, d, J=8.0 Hz), 4.37 (2H, q, J=7.1 Hz), 4.02 (1H, q, J=6.6 Hz), 2.18-2.06 (2H, m), 1.77-1.67 (4H, m), 1.39 (3H, t, J=7.1 Hz), 1.32 (3H, d, J=6.5 Hz), 1.22 (1H, br s), 1.09-0.85 (4H, m), 0.79 (9H, s).
Reaction SMILES: [NH2:1][C:2](=[O:41])[CH2:3][C:4]1[CH:40]=[CH:39][CH:38]=[CH:37][C:5]=1[CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][N:11]=[C:10]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([N:21]3[CH2:26][CH2:25][N:24](C(OCC4C=CC=CC=4)=O)[CH2:23][CH2:22]3)=[CH:17][CH:16]=2)[N:9]=1.C1CCCCC1>CN(C=O)C.C(Cl)Cl.[Pd]>[N:21]1([C:18]2[CH:17]=[CH:16][C:15]([NH:14][C:10]3[N:9]=[C:8]([CH2:7][CH2:6][C:5]4[CH:37]=[CH:38][CH:39]=[CH:40][C:4]=4[CH2:3][C:2]([NH2:1])=[O:41])[CH:13]=[CH:12][N:11]=3)=[CH:20][CH:19]=2)[CH2:22][CH2:23][NH:24][CH2:25][CH2:26]1
Reactant: NC(=O)Cc1ccccc1CCc1ccnc(Nc2ccc(N3CCN(C(=O)OCc4ccccc4)CC3)cc2)n1
Agent: [Pd]
Solvent: CN(C)C=O
Solvent: C1CCCCC1
Solvent: ClCCl
Product: NC(=O)Cc1ccccc1CCc1ccnc(Nc2ccc(N3CCNCC3)cc2)n1
Temperature: 25 °C
Reaction time: 19 h
Yield: 2.6 %

Procedure:
To a solution of benzyl 4-(4-((4-(2-(2-amino-2-oxoethyl)phenethyl)pyrimidin-2-yl)amino)phenyl)piperazine-1-carboxylate (A6) (73 mg, 0.13 mmol) in DMF (5 mL) under nitrogen, was added a slurry of 10% Pd/C (20 mg) in DMF. The resulting mixture was stirred under an atmosphere of hydrogen at room temperature for 19 hours then filtered through a 2.0 PFTE filter. The filtrate was evaporated in vacuo and the residue was loaded onto a SCX (5 g) column using MeOH. The column was washed with 2 column volumes of MeOH followed by 3 column volumes of 1% MeNH2 in MeOH. The 1% MeNH2 in MeOH filtrate was evaporated in vacuo to give a pale brown oil which was taken up in DCM (0.5 mL) and cyclohexane (1 mL) and sonicated. The resulting precipitate was filtered and the filter cake dried in vacuo to give the title compound 1 as a white solid (1.4 mg, 90% purity). 1H-NMR: (400 MHz, d4-MeOH) δ 8.22-8.16 (m, 1H), 7.57-7.48 (m, 2H), 7.20 (m, 4H), 7.01-6.93 (m, 2H), 6.60 (dd, J=5.0, 2.8 Hz, 1H), 3.63 (d, J=2.3 Hz, 2H), 3.18-3.12 (m, 4H), 3.09 (dd, J=9.2, 6.4 Hz, 5H), 2.93-2.83 (m, 3H). LC-MS Method A: rt 4.305 min; m/z 417.2 [m+H]+.