Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][C:4](=[O:6])[NH2:5].O.C1COCC1.C(N(CC)CC)C.[NH:23]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[C@H:24]([C:34](ON1C(=O)CCC1=O)=[O:35])[CH2:25][O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>O>[NH:23]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[C@H:24]([C:34]([NH:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][C:4](=[O:6])[NH2:5])=[O:35])[CH2:25][O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](COCc1ccccc1)C(=O)ON1C(=O)CCC1=O
Reactant: NC(=O)C[C@H](N)C(=O)O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)(C)OC(=O)N[C@@H](COCc1ccccc1)C(=O)N[C@@H](CC(N)=O)C(=O)O
Temperature: 25 °C
Reaction time: 20 h
Yield: 71.2 %

Procedure:
In 80 ml of H2O was suspended 4.50 g of H-Asn-OH.H2O, followed by addition of 80 ml of a THF solution containing 4.20 ml of triethylamine and 14.13 g of Boc-Ser(Bzl)-OSu under ice-cooling. The mixture was stirred at room temperature for 20 hours, after which the THF was distilled off. The residual aqueous solution was adjusted to pH 3 with 1M citric acid under ice-cooling and the resulting oily product was extracted with 200 ml of ethyl acetate. The extract was washed with 50 ml of saturated aqueous sodium chloride solution twice, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was treated with ether/petroleum ether (2:1) for solidification and the resultant powder was reprecipitated from methanol-isopropyl ether to give 8.74 g of Boc-Ser(Bzl)-Asn-OH (yield 71.2%).
Reaction SMILES: [Li+].[OH-].[O:3]=[C:4]1[N:10]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C@H:20]([CH2:41][C:42]3[CH:51]=[C:50]([CH3:52])[C:45]4[NH:46][C:47](=[O:49])[O:48][C:44]=4[CH:43]=3)[C:21]([N:23]3[CH2:28][CH2:27][CH:26]([CH:29]4[CH2:34][CH2:33][N:32]([CH2:35][C:36]([O:38]CC)=[O:37])[CH2:31][CH2:30]4)[CH2:25][CH2:24]3)=[O:22])=[O:18])[CH2:13][CH2:12]2)[CH2:9][CH2:8][C:7]2[CH:53]=[CH:54][CH:55]=[CH:56][C:6]=2[NH:5]1.Cl>O.C1COCC1>[O:3]=[C:4]1[N:10]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C@H:20]([CH2:41][C:42]3[CH:51]=[C:50]([CH3:52])[C:45]4[NH:46][C:47](=[O:49])[O:48][C:44]=4[CH:43]=3)[C:21]([N:23]3[CH2:28][CH2:27][CH:26]([CH:29]4[CH2:34][CH2:33][N:32]([CH2:35][C:36]([OH:38])=[O:37])[CH2:31][CH2:30]4)[CH2:25][CH2:24]3)=[O:22])=[O:18])[CH2:13][CH2:12]2)[CH2:9][CH2:8][C:7]2[CH:53]=[CH:54][CH:55]=[CH:56][C:6]=2[NH:5]1
Reactant: CCOC(=O)CN1CCC(C2CCN(C(=O)[C@@H](Cc3cc(C)c4[nH]c(=O)oc4c3)OC(=O)N3CCC(N4CCc5ccccc5NC4=O)CC3)CC2)CC1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)N2CCC(C3CCN(CC(=O)O)CC3)CC2)cc2oc(=O)[nH]c12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 39 mg (1.61 mmol) LiOH in 5 mL water was added to a solution of 240 mg (0.32 mmol) (R)-2-(1′-ethoxycarbonylmethyl-4,4′-bipiperidinyl-1-yl)-1-(4-methyl-2-oxo-2,3-dihydrobenzoxazol-6-ylmethyl)-2-oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate in 10 mL THF and the reaction solution was stirred for 1 h at RT. 1.61 mL of 1 M HCl was added and the mixture was evaporated down i.vac. The residue was combined with a little water, stirred, the water was decanted off and the residue was dried in the air.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([O:49][CH3:50])=[C:7]2[CH2:12][N:13]1[C:19](=[O:20])[C@@H:18]([NH:21][C:22](=[O:34])[C@@H:23]([N:25](C)[C:26](=O)OC(C)(C)C)[CH3:24])[C@H:17]([CH3:35])[N:16]([C:36](=[O:42])[CH2:37][S:38]([CH3:41])(=[O:40])=[O:39])[C:15]2[CH:43]=[CH:44][C:45]([C:47]#[N:48])=[CH:46][C:14]1=2.[C:51]([OH:57])([C:53]([F:56])([F:55])[F:54])=[O:52]>C(Cl)Cl>[F:54][C:53]([F:56])([F:55])[C:51]([OH:57])=[O:52].[Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([O:49][CH3:50])=[C:7]2[CH2:12][N:13]1[C:19](=[O:20])[C@@H:18]([NH:21][C:22](=[O:34])[C@@H:23]([NH:25][CH3:26])[CH3:24])[C@H:17]([CH3:35])[N:16]([C:36](=[O:42])[CH2:37][S:38]([CH3:41])(=[O:40])=[O:39])[C:15]2[CH:43]=[CH:44][C:45]([C:47]#[N:48])=[CH:46][C:14]1=2
Reactant: COc1ccc2c(Br)cccc2c1CN1C(=O)[C@@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)[C@H](C)N(C(=O)CS(C)(=O)=O)c2ccc(C#N)cc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN[C@@H](C)C(=O)N[C@@H]1C(=O)N(Cc2c(OC)ccc3c(Br)cccc23)c2cc(C#N)ccc2N(C(=O)CS(C)(=O)=O)[C@H]1C
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 99 %

Procedure:
To a rt solution of tert-butyl(S)-1-((2S,3S)-5-((5-bromo-2-methoxynaphthalen-1-yl)methyl)-7-cyano-2-methyl-1-(2-(methylsulfonyl)acetyl)-4-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-ylamino)-1-oxopropan-2-yl(methyl)carbamate (68 mg, 88.2 μmol) in CH2Cl2 (353 μl) was added TFA (88.2 μl). The reaction was stirred at rt for 2.5 h, then concentrated, taken up in H2O, and lyophilized to provide (S)-N-((2S,3S)-5-((5-bromo-2-methoxynaphthalen-1-yl)methyl)-7-cyano-2-methyl-1-(2-(methylsulfonyl)acetyl)-4-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-yl)-2-(methylamino)propanamide 2,2,2-trifluoroacetate (68.6 mg, 99%) as a white solid. MS m/z 670/672 (MH)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:24]([O:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][C:31]([OH:33])=[O:32])=[CH:23][C:6]2[N:7]([C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=3)[C:8]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[N:9][C:5]=2[CH:4]=1.[C:34](=O)(O)[O-].[K+]>CO.S(=O)(=O)(O)O.O>[CH3:34][O:32][C:31](=[O:33])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][O:25][C:24]1[C:3]([O:2][CH3:1])=[CH:4][C:5]2[N:9]=[C:8]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[N:7]([C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=3)[C:6]=2[CH:23]=1
Reactant: COc1cc2nc(-c3ccccc3)n(-c3ccc(C)cc3)c2cc1OCCCCCC(=O)O
Reactant: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: O
Solvent: CO
Product: COC(=O)CCCCCOc1cc2c(cc1OC)nc(-c1ccccc1)n2-c1ccc(C)cc1
Reaction time: 2 h

Procedure:
40 mg of 6-[[5-methoxy-1-(4-methylphenyl)-2-phenyl-1H-benzimidazol-6-yl]oxy]hexanoic acid was dissolved in 2 ml of methanol, mixed with 1 drop of concentrated sulfuric acid, and the mixture was stirred for 2 hours. It was mixed with saturated potassium bicarbonate solution, diluted with water, extracted with ethyl acetate, the extracts were dried on sodium sulfate and concentrated by evaporation in a vacuum. The residue was crystallized from diisopropyl ether.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11]C)=[O:10])=[CH:7][C:6]=1[O:15][CH3:16])[CH3:3].Cl>CO.[OH-].[Na+]>[CH3:3][N:2]([CH2:4][C:5]1[CH:14]=[CH:13][C:8]([C:9]([OH:11])=[O:10])=[CH:7][C:6]=1[O:15][CH3:16])[CH3:1]
Reactant: COC(=O)c1ccc(CN(C)C)c(OC)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1cc(C(=O)O)ccc1CN(C)C
Temperature: 50 °C
Reaction time: 16 h

Procedure:
To a solution of methyl 4-dimethylaminomethyl-3-methoxy-benzoate (420 mg, 1.88 mmol) in MeOH (4 mL), 1 M aq. NaOH solution (2.5 mL) was added. The mixture was stirred at 50° C. for 2 h and at rt for 16 h before it was neutralised by adding 1 M aq. HCl (1.25 mL) and the solvent was evaporated. The residue was suspended in n-butanol (100 mL) and the mixture was refluxed for 1 h. The suspension was cooled to rt, filtered and the filtrate was concentrated and dried to give 4-dimethylaminomethyl-3-methoxy-benzoic acid as a colourless resin (380 mg). LC-MS*: tR=0.44 min, [M+1]+=210.32.
Reaction SMILES: [F:1][C:2]1[C:3]([O:17][CH3:18])=[C:4]([C:8]([CH3:16])([CH3:15])[CH2:9][C:10](=[O:14])[C:11]([OH:13])=[O:12])[CH:5]=[CH:6][CH:7]=1.S(=O)(=O)(O)O.[CH2:24](O)[CH3:25]>>[CH2:24]([O:12][C:11](=[O:13])[C:10](=[O:14])[CH2:9][C:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[C:3]=1[O:17][CH3:18])([CH3:16])[CH3:15])[CH3:25]
Reactant: CCO
Reactant: COc1c(F)cccc1C(C)(C)CC(=O)C(=O)O
Agent: O=S(=O)(O)O
Product: CCOC(=O)C(=O)CC(C)(C)c1cccc(F)c1OC
Yield: 90.6 %

Procedure:
4.14 g (16.28 mmol) of 4-(3-fluoro-2-methoxyphenyl)-4-methyl-2-oxo-pentanoic acid is dissolved in 97 ml of ethanol, mixed with 1.79 ml of sulfuric acid and refluxed for four hours. The ethanol is drawn off in a rotary evaporator, and the residue is carefully mixed with saturated sodium bicarbonate solution until a pH of 9 is reached. It is extracted twice with 100 ml each of ethyl acetate, and the combined organic extracts are washed with water and then with brine. After the desiccant is dried and filtered off, and after the solvent is spun in, the residue is chromatographed on silica gel (mobile solvent ethyl acetate/hexane). 4.16 g (90.6%) of the desired compound is isolated.
Reaction SMILES: [CH3:1][NH:2][S:3](Cl)(=[O:5])=[O:4].[NH2:7][C:8]1[C:9]([Cl:26])=[CH:10][C:11]([Cl:25])=[C:12]([C:14]2[C:18]([Cl:19])=[C:17]([O:20][CH:21]([F:23])[F:22])[N:16]([CH3:24])[N:15]=2)[CH:13]=1.C(N(CC)CC)C.N1C=CC=N1>O1CCCC1.C(OCC)(=O)C>[Cl:19][C:18]1[C:14]([C:12]2[CH:13]=[C:8]([NH:7][S:3]([NH:2][CH3:1])(=[O:5])=[O:4])[C:9]([Cl:26])=[CH:10][C:11]=2[Cl:25])=[N:15][N:16]([CH3:24])[C:17]=1[O:20][CH:21]([F:22])[F:23]
Reactant: Cn1nc(-c2cc(N)c(Cl)cc2Cl)c(Cl)c1OC(F)F
Reactant: CNS(=O)(=O)Cl
Agent: c1cn[nH]c1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CNS(=O)(=O)Nc1cc(-c2nn(C)c(OC(F)F)c2Cl)c(Cl)cc1Cl
Reaction time: 2 h
Yield: 71.7 %

Procedure:
N-Methylaminosulfonyl chloride (0.22 g, 1.67 mmoles) was added dropwise to a solution of 3-(5-amino-2,4-dichlorophenyl)-4-chloro-5-difluoromethoxy-1-methyl-1H-pyrazole (0.44 g, 1.28 mmoles) and triethylamine (0.17 g, 1.67 mmoles) in 20 ml anhydrous tetrahydrofuran under cooling with ice to react with the pyrazole derivative. After the addition was finished, the reaction was continued further for 2 hours. Then ethyl acetate was added to the reaction product solution, and the mixture was washed with water. The separated organic layer was dehydrated, concentrated, and purified by recrystallization from a n-hexane-ether mixture, giving the title compound (0.40 g), m.p. 133.0° C., yield 71.7%.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[OH:9].Cl[CH2:11][C:12](Cl)=[O:13].C([O-])([O-])=O.[K+].[K+]>>[F:8][C:4]1[C:3]2[O:9][CH2:11][C:12](=[O:13])[NH:1][C:2]=2[CH:7]=[CH:6][CH:5]=1
Reactant: Nc1cccc(F)c1O
Reactant: O=C(Cl)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: O=C1COc2c(F)cccc2N1
Yield: 86.8 %

Procedure:
2-Amino-6-flourophenol (95MF2085) (0.256 g, 2.0 mmol), 2-chloroacetyl chloride (0.25 g, 2.2 mmol) and K2CO3 (0.583 g, 4.2 mmol) were mixed according to GP1 to give the title compound as a crude (95MF45) (0.29 g)
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([N+:11]([O-:13])=[O:12])[CH:3]=1.[F:14][C:15]1[CH:22]=[C:21]([I:23])[CH:20]=[CH:19][C:16]=1[CH2:17][NH2:18].C(OCC)(=O)C.Cl>O1CCCC1>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:18][CH2:17][C:16]2[CH:19]=[CH:20][C:21]([I:23])=[CH:22][C:15]=2[F:14])=[O:8])=[C:4]([N+:11]([O-:13])=[O:12])[CH:3]=1
Reactant: O=C(O)c1ccc(Br)cc1[N+](=O)[O-]
Reactant: NCc1ccc(I)cc1F
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C(NCc1ccc(I)cc1F)c1ccc(Br)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 4 h
Yield: 83.5 %

Procedure:
A mixture of 4-bromo-2-nitrobenzoic acid (3.0 g) and N,N'-carbonyldiimidazole (2.37 g) in tetrahydrofuran (30 ml) was stirred at room temperature for 4 hours. To this mixture was added a solution of 2-fluoro-4-iodobenzylamine (3.37 g) in tetrahydrofuran (10 ml), and the resulting mixture was stirred at room temperature overnight. The reaction mixture was poured into a mixture of ethyl acetate and 0.5N hydrochloric acid. The organic layer was separated, washed successively with water, aqueous sodium bicarbonate, water and saturated aqueous sodium chloride, and dried over magnesium sulfate. The solvent was removed in vacuo and the crystalline residue was recrystallized from a mixture of ethyl acetate and hexane to give 4-bromo-N-(2-fluoro-4-iodobenzyl)-2-nitrobenzamide (4.88 g).
Reaction SMILES: [C:1]([N:9]1[CH2:15][CH2:14][CH2:13][C:12]([Cl:17])([Cl:16])[CH2:11][C:10]1=[O:18])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:19](Cl)(=O)[CH2:20]CCCCCCC>>[C:1]([N:9]1[CH2:15][CH2:14][CH2:13][C:12]([Cl:16])([Cl:17])[CH2:11][C:10]1=[O:18])(=[O:8])[CH2:2][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:19][CH3:20]
Reactant: O=C1CC(Cl)(Cl)CCCN1C(=O)c1ccccc1
Reactant: CCCCCCCCC(=O)Cl
Product: CCCCCCCCC(=O)N1CCCC(Cl)(Cl)CC1=O

Procedure:
Synthesized as for N-benzoyl-3,3-chlorocaprolactam (Example IX) using nonanoyl chloride (Aldrich) in place of benzoyl chloride.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([F:18])=[C:14]([F:19])[CH:13]=2)=[CH:4][N:3]=1.[C:20]([Cu])#[N:21].[C-]#N.[Na+]>CN1C(=O)CCC1.CCOC(C)=O>[F:19][C:14]1[CH:13]=[C:12]([CH2:11][C:5]2[CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]([C:20]#[N:21])=[N:3][CH:4]=2)[CH:17]=[CH:16][C:15]=1[F:18]
Reactant: N#C[Cu]
Reactant: O=[N+]([O-])c1cc(Cc2ccc(F)c(F)c2)cnc1Cl
Agent: [C-]#N
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: N#Cc1ncc(Cc2ccc(F)c(F)c2)cc1[N+](=O)[O-]
Temperature: 170 °C

Procedure:
To a solution of 2-chloro-5-[(3,4-difluorophenyl)methyl]-3-nitropyridine (10.88 g, 38.22 mmol) in NMP (50 ml), was added CuCN (10.27 g, 0.115 mmol) and NaCN (1.02 g). Heated in the microwave at 170° C. for 1 h and the resulting mixture was diluted with EtOAc and filtered through Celite. Water was added to the filtrate and the organic layer was washed with water and brine, dried and concentrated in vacuo. The resulting product was purified by chromatography on silica gel, eluting with 0-25% EtOAc/hexanes to afford an amber oil. 1H NMR (CDCl3) δ 8.82 (1H, s), 8.31 (1H, s), 7.22-7.15 (1H, m), 7.03-6.98 (1H, m), 6.94-6.90 (1H, m), 4.16 (2H, s).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH2:12][CH:13]([NH:19][C:20](=[O:46])[CH:21]([N:25]([C:27](=[O:45])[CH:28]([NH:37]C(OC(C)(C)C)=O)[CH2:29][C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=2)[CH3:26])[CH:22]([CH3:24])[CH3:23])[C:14]2[O:18][N:17]=[CH:16][N:15]=2)[CH:8]=[CH:9][C:10]=1[OH:11])([CH3:4])([CH3:3])[CH3:2]>C(Cl)Cl.C(O)(C(F)(F)F)=O>[C:1]([C:5]1[CH:6]=[C:7]([CH2:12][CH:13]([NH:19][C:20](=[O:46])[CH:21]([N:25]([C:27](=[O:45])[CH:28]([NH2:37])[CH2:29][C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=2)[CH3:26])[CH:22]([CH3:24])[CH3:23])[C:14]2[O:18][N:17]=[CH:16][N:15]=2)[CH:8]=[CH:9][C:10]=1[OH:11])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)C(C(=O)NC(Cc1ccc(O)c(C(C)(C)C)c1)c1ncno1)N(C)C(=O)C(Cc1ccc(F)cc1)NC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)C(C(=O)NC(Cc1ccc(O)c(C(C)(C)C)c1)c1ncno1)N(C)C(=O)C(N)Cc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.7 %

Procedure:
To a solution of 2-((2-tertbutoxycarbonylamino-3-(4-fluorophenyl)propionyl)-N-methylamino)-3-methylbutyric acid 2-(3-t-butyl-4-hydroxyphenyl)-1-(1,2,4-oxadiazol-5-yl)ethylamide (440 mg) in methylene chloride (5 ml), TFA (1 ml) was added under cooling with ice. The mixture was stirred at room temperature for 1 hour and evaporated to remove the solvent under reduced pressure; the thus obtained residue was subjected to silica gel column chromatography (developing solvent: methylene chloride:methanol=15:1), giving the titled compound (370 mg, 99%).
Reaction SMILES: [CH3:1][C:2]([CH3:16])=[CH:3][CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:9]([O:10][CH2:11][CH2:12][OH:13])=[CH:8][CH:7]=1.[H-].[Na+].[CH2:19]([N:21]=[C:22]=[S:23])[CH3:20]>>[CH2:19]([NH:21][C:22](=[S:23])[O:13][CH2:12][CH2:11][O:10][C:9]1[CH:14]=[CH:15][C:6]([O:5][CH2:4][CH:3]=[C:2]([CH3:16])[CH3:1])=[CH:7][CH:8]=1)[CH3:20]
Reactant: CC(C)=CCOc1ccc(OCCO)cc1
Reactant: CCN=C=S
Agent: [H-]
Agent: [Na+]
Product: CCNC(=S)OCCOc1ccc(OCC=C(C)C)cc1

Procedure:
In the same manner, 2-[4-(3-methyl-2-butenoxy)phenoxy]-ethanol is reacted with sodium hydride and ethyl isothiocyanate to yield O-2-[4-(3-methyl-2butenoxy)phenoxy]ethyl N-ethylthiocarbamate (compound 37, Table A).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([NH:10][CH:11]3[CH2:16][CH2:15][C:14](=O)[CH2:13][CH2:12]3)=[CH:7][CH:8]=2)[CH:3]=[N:2]1.[CH2:18]([NH2:20])[CH3:19].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].Cl.CO>CO>[CH2:18]([NH:20][CH:14]1[CH2:15][CH2:16][CH:11]([NH:10][C:6]2[CH:5]=[C:4]3[C:9](=[CH:8][CH:7]=2)[NH:1][N:2]=[CH:3]3)[CH2:12][CH2:13]1)[CH3:19]
Reactant: CCN
Reactant: O=C1CCC(Nc2ccc3[nH]ncc3c2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CCNC1CCC(Nc2ccc3[nH]ncc3c2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 15.6 %

Procedure:
4-(1H-5-Indazolylamino)-1-cyclohexanone (intermediate 3) (57 mg) and ethylamine (23 mg) were dissolved in methanol (1 ml), and sodium triacetoxyborohydride (105 mg) was added by portions to the solution at room temperature. The reaction mixture was stirred at room temperature for 18 hr. Hydrochloric acid-methanol was then added thereto, and the reaction mixture was stirred and was then concentrated. The residue was purified by HPLC [0.5% aqueous trifluoroacetic acid solution/acetonitrile] to give an anti-form compound (10 mg) and a syn-form compound (10 mg).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[O:9]1[CH2:13][CH2:12][O:11][CH:10]1[C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=1)[CH2:17]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl.C(N(CC)CC)C>[O:9]1[CH2:13][CH2:12][O:11][CH:10]1[C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=1)[CH2:17][Br:1]
Reactant: OCc1cccc(C2OCCO2)c1
Reactant: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: BrCc1cccc(C2OCCO2)c1
Temperature: -5 °C
Reaction time: 2 h

Procedure:
Solid N-bromosuccinimide (10.4 g., 58 mmol) was added in small portions to a stirred solution of 3-(1,3-dioxolan-2-yl)benzyl alcohol (9.6 g., 53 mmol) and triphenylphosphine (16.7 g., 64 mmol) in dichloromethane (250 ml) at ca. -5° C. The yellow solution was stirred for a further 2 hours at -5° C. then added to a suspension of silica (50 g) in dichloromethane (250 ml) and triethylamine (2.5 ml). The mixture was evaporated and the residual silica was placed on the top of a silica column (250 g) and eluted with ethyl acetate-hexane (1:4) to give the product as a pale solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[C@H:7]([NH2:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.[CH3:25][N:26]([CH3:30])[C:27](Cl)=[O:28]>CN(C=O)C>[CH3:25][N:26]([CH3:30])[C:27](=[O:28])[NH:14][C@H:7]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:15]
Reactant: CN(C)C(=O)Cl
Reactant: CC(C)(C)OC(=O)[C@H](N)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)C(=O)N[C@@H](C(=O)OC(C)(C)C)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred solution of (R)-tert-butyl-2-amino-2-phenylacetate (1.0 g, 4.10 mmol) and Hunig's base (1.79 mL, 10.25 mmol) in DMF (40 mL) was added dimethylcarbamoyl chloride (0.38 mL, 4.18 mmol) dropwise over 10 minutes. After stirring at room temperature for 3 hours, the reaction was concentrated under reduced pressure and the resulting residue was dissolved in ethyl acetate. The organic layer was washed with H2O, 1N aq. HCl and brine, dried (MgSO4), filtered and concentrated under reduced pressure. (R)-tert-butyl 2-(3,3-dimethylureido)-2-phenylacetate was obtained as a white solid (0.86 g; 75%) and used without further purification. 1H NMR (500 MHz, DMSO-d6) δ ppm 1.33 (s, 9H) 2.82 (s, 6H) 5.17 (d, J=7.63 Hz, 1H) 6.55 (d, J=7.32 Hz, 1H) 7.24-7.41 (m, 5H). LC-MS: Anal. Calcd. for C15H22N2O3 278.16 found 279.23 (M+H)+; HPLC PHENOMENEX® Luna C-18 4.6×50 mm, 0 to 100% B over 4 minutes, 1 minute hold time, A=90% water, 10% methanol, 0.1% TFA, B=10% water, 90% methanol, 0.1% TFA, RT=2.26 min, 97% homogeneity index.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4]Br.[OH-].[K+].[O:8]1[CH2:12][CH2:11][NH:10][C:9]1=[O:13]>CS(C)=O.CCOCC.O>[Br:1][CH2:2][CH2:3][CH2:4][N:10]1[CH2:11][CH2:12][O:8][C:9]1=[O:13]
Reactant: BrCCCBr
Reactant: O=C1NCCO1
Agent: [K+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CS(C)=O
Solvent: O
Product: O=C1OCCN1CCCBr
Temperature: 20 °C
Reaction time: 4 h

Procedure:
To a cooled solution (15-20° C.) of 1,3-dibromopropane (6.4 mL, 63.05 mmol) in dry DMSO (5 mL) was added ground KOH (0.920 g, 16.40 mmol). 2-Oxazolidinone (1.100 g, 12.63 mmol) was added in small amounts over 5 min, and the reaction was stirred for 4 hr at 20° C. The mixture was diluted with ether (100 mL) and H2O (20 mL), and the aqueous phase was extracted with ether (3×50 mL). After drying with MgSO4, the crude product was purified by flash chromatography using a step gradient (25% EtOAc/75% hexanes to 50% EtOAc/50% hexanes) to give N-(3′-bromopropyl)-2-oxazolidinone, 17 (1.48 g, 56%). IR (neat) 1747 cm−1; 1H NMR (CDCl3) δ 4.30 (2H, t, J=7.2 Hz), 3.57 (2H, t, J=8.2 Hz), 3.33-3.43 (4H, q), 2.03-2.17 (2H, m); 13C NMR (CDCl3) δ 158.4, 61.7, 45.0, 43.0, 30.4, 29.9; HRMS (FAB+) m/z: calcd for C6H10NO2Br, 207.9972; found, 207.9957.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:8]2[C:9]([F:16])=[C:10]([OH:15])[C:11]([CH3:14])=[CH:12][CH:13]=2)=[N:6][CH:7]=1.[C:17]([Si](OC1C(F)=CC=CC=1CC)(C)C)(C)(C)C>>[NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:8]2[C:9]([F:16])=[C:10]([OH:15])[C:11]([CH2:14][CH3:17])=[CH:12][CH:13]=2)=[N:6][CH:7]=1
Reactant: CCc1cccc(F)c1O[Si](C)(C)C(C)(C)C
Reactant: Cc1ccc(-c2cnc(N)cn2)c(F)c1O
Product: CCc1ccc(-c2cnc(N)cn2)c(F)c1O

Procedure:
The title compound was prepared in an analogous way to 3-(5-aminopyrazin-2-yl)-2-fluoro-6-methylphenol in Steps B-D of Intermediate J using tert-butyl(2-ethyl-6-fluorophenoxy)dimethylsilane. 1H NMR (500 MHz, CD3OD) δ 8.26 (dd, J=2.3, 1.5, 1H), 8.02 (d, J=1.5, 1H), 7.12 (dd, J=8.0, 7.3, 1H), 6.99-6.93 (m, 1H), 2.68 (q, J=7.5, 2H), 1.21 (t, J=7.5, 3H).
Reaction SMILES: [F:1][C:2]1[C:3]([C:24]2[CH2:29][CH2:28][CH2:27][C:26](=O)[CH:25]=2)=[N:4][C:5]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[CH:14][CH:13]=2)=[C:6]([CH:10]=1)[C:7]([NH2:9])=[O:8].C([O-])(=O)C.[NH4+:35].[BH4-].[Na+].CO>CN(C=O)C.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[NH2:35][CH:26]1[CH2:27][CH2:28][CH2:29][C:24]([C:3]2[C:2]([F:1])=[CH:10][C:6]([C:7]([NH2:9])=[O:8])=[C:5]([NH:11][C:12]3[CH:17]=[CH:16][C:15]([N:18]4[CH2:23][CH2:22][O:21][CH2:20][CH2:19]4)=[CH:14][CH:13]=3)[N:4]=2)=[CH:25]1
Reactant: NC(=O)c1cc(F)c(C2=CC(=O)CCC2)nc1Nc1ccc(N2CCOCC2)cc1
Reactant: [NH4+]
Agent: [Ti+4]
Agent: CC(=O)[O-]
Agent: CC(C)[O-]
Solvent: CO
Solvent: CN(C)C=O
Product: NC(=O)c1cc(F)c(C2=CC(N)CCC2)nc1Nc1ccc(N2CCOCC2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 8.7 %

Procedure:
A solution of 5-fluoro-2-(4-morpholinophenylamino)-6-(3-oxocyclohex-1-enyl)nicotinamide (1.2 g, 2.92 mmol), ammonium acetate (2.254 g, 29.2 mmol) and titanium(IV) isopropoxide (2.57 mL, 8.77 mmol) in DMF (0.8 mL) was stirred at rt overnight. To the above solution were added sodium borohydride (0.221 g, 5.85 mmol) and 0.2 mL of MeOH. Violent bubbling occurred and the reaction mixture became warm. The reaction mixture was stirred at rt for 1 h. To the reaction mixture was added 1N NaOH (10 mL). A precipitate formed and was filtered through CELITE®, washed with a mixture of methylene chloride, and MeOH (50% each cosolvent) many times until the filter cake was white. The filtrate was washed with water; the aqueous fraction was back extracted 3 times with methylene chloride. The combined organic fractions were concentrated and the residue was purified by MPLC (ISCO, 5%-20% gradient ammonia/methanol/methylene chloride, 40 g silica gel column) to yield 105 mg of product as a yellow solid.