Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:29])[C@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:15](=[O:28])[N:16]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:17]=[C:18]([Cl:20])[CH:19]=2)=[CH:10][CH:9]=1)[NH2:6].[Cl:30][C:31]1[CH:39]=[CH:38][CH:37]=[C:36]([CH3:40])[C:32]=1[C:33](O)=[O:34].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH3:2][O:3][C:4](=[O:29])[C@H:5]([CH2:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]2[C:15](=[O:28])[N:16]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:17]=[C:18]([Cl:20])[CH:19]=2)=[CH:12][CH:13]=1)[NH:6][C:33]([C:32]1[C:36]([CH3:40])=[CH:37][CH:38]=[CH:39][C:31]=1[Cl:30])=[O:34]
Reactant: COC(=O)[C@@H](N)Cc1ccc(-c2cc(Cl)cn(Cc3ccccc3)c2=O)cc1
Reactant: Cc1cccc(Cl)c1C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)[C@H](Cc1ccc(-c2cc(Cl)cn(Cc3ccccc3)c2=O)cc1)NC(=O)c1c(C)cccc1Cl
Yield: 58.6 %

Procedure:
A solution of 4-(1-benzyl-5-chloro-2-oxo-3-pyridinyl)-L-phenylalanine methyl ester hydrochloride (100 mg, 0.23 mmol), 2-chloro-6-methylbenzoic acid (47 mg, 0.28 mmol), DIEA (200 μL, 1.2 mmol) and HBTU (133 mg, 0.35 mmol) in DMF (2 mL) was stirred at room temperature for 18 hr. The mixture was concentrated, the residue was dissolved in ethyl acetate (15 mL), was washed with 0.5 N HCl (1×5 mL), sat. NaHCO3 (1×5 mL), brine (1×5 mL) and was dried (MgSO4). The residue obtained upon evaporation was chromatographed on 25 g of silica gel, eluting with 45:55 ethyl acetate:hexane to give 4-(1-benzyl-5-chloro-2-oxo-3-pyridinyl)-N-[(2-chloro-6-methylphenyl)carbonyl]-L-phenylalanine methyl ester (74 mg, 58%). Obs. Mass 397.1313. Calcd. Mass 397.1320 (M+H)
Reaction SMILES: C(OC(=O)[NH:10][C@@H:11]([C@@H:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH3:15])[CH2:12][OH:13])C1C=CC=CC=1.[H][H].O>[Pd].CO>[NH2:10][C@@H:11]([C@@H:14]([O:16][C:17]([CH3:18])([CH3:20])[CH3:19])[CH3:15])[CH2:12][OH:13]
Reactant: [H][H]
Reactant: C[C@H](OC(C)(C)C)[C@@H](CO)NC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: O
Solvent: CO
Product: C[C@H](OC(C)(C)C)[C@H](N)CO
Temperature: 25 °C
Reaction time: 18 h
Yield: 87.1 %

Procedure:
To a round bottom flask containing benzyl((2R,3S)-3-(tert-butoxy)-1-hydroxybutan-2-yl)carbamate (5.27 g, 17.8 mmol) was added MeOH (100 mL). Solution was degassed with nitrogen for 15 min at which time palladium on carbon (0.95 g, 0.89 mmol) in MeOH (5 mL) was added. A hydrogen atmosphere was then inserted. Resulting reaction mixture allowed to stir 40 min at room temperature at atmospheric pressure when water (2 mL) was added and once again a hydrogen atmosphere was inserted at atmospheric pressure and the subsequent reaction mixture allowed to stir 18 hr at room temperature. The reaction mixture was filtered through a pad of celite and concentrated to a brown oil. Oil redissolved in toluene and concentrated to afford (2R,3S)-2-amino-3-(tert-butoxy)butan-1-ol (2.5 g, 15.5 mmol, 87% yield) as a brown oil. LCMS m/z 162.1 (M+H)+, Rt 0.41 min (Mass ion only, no UV peak).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][C:23]=1[O:24][CH2:25][C:26]1[N:27]=[C:28]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[O:29][C:30]=1[CH3:31])[CH2:6][O:7][C:8]1[CH:12]=[C:11]([CH:13]=O)[N:10]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:9]=1.C(OP([CH2:46][C:47]([O:49][CH2:50][CH3:51])=[O:48])(OCC)=O)C.CN(C)C=O.[H-].[Na+]>O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][C:23]=1[O:24][CH2:25][C:26]1[N:27]=[C:28]([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[O:29][C:30]=1[CH3:31])[CH2:6][O:7][C:8]1[CH:12]=[C:11](/[CH:13]=[CH:46]/[C:47]([O:49][CH2:50][CH3:51])=[O:48])[N:10]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:9]=1
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Reactant: COc1cc(COc2cc(C=O)n(-c3ccccc3)n2)ccc1OCc1nc(-c2ccccc2)oc1C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)/C=C/c1cc(OCc2ccc(OCc3nc(-c4ccccc4)oc3C)c(OC)c2)nn1-c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.1 %

Procedure:
To a mixture of 3-{[3-methoxy-4-(5-methyl-2-phenyl-1,3-oxazol-4-ylmethoxy)benzyl]oxy}-1-phenyl-1H-pyrazole-5-carbaldehyde (600 mg), ethyl diethylphosphonoacetate (300 mg) and N,N-dimethylformamide (10 mL) was added sodium hydride (60% in oil, 52.0 mg) at 0° C., and the mixture was stirred overnight at room temperature. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed successively with dilute hydrochloric acid and saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give ethyl (E)-3-(3-{[3-methoxy-4-(5-methyl-2-phenyl-1,3-oxazol-4-ylmethoxy)benzyl]oxy}-1-phenyl-1H-pyrazol5-yl)-2-propenoate (590 mg, yield 86%) as colorless crystals from a fraction eluted with ethyl acetate-hexane (1:4, v/v). The crystals were recrystallized from ethyl acetate-hexane. melting point: 121-122° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([S:8][CH:9]([CH3:14])[C:10]([O:12]C)=[O:11])[CH:5]=[CH:6][CH:7]=1.C([Sn](CCCC)(CCCC)[C:20]1[CH:24]=[CH:23][S:22][CH:21]=1)CCC.BrC1C=CC=CC=1CC(OC)=S>>[S:22]1[CH:23]=[CH:24][C:20]([C:2]2[CH:3]=[C:4]([S:8][CH:9]([CH3:14])[C:10]([OH:12])=[O:11])[CH:5]=[CH:6][CH:7]=2)=[CH:21]1
Reactant: COC(=O)C(C)Sc1cccc(Br)c1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccsc1
Agent: COC(=S)Cc1ccccc1Br
Product: CC(Sc1cccc(-c2ccsc2)c1)C(=O)O

Procedure:
The same procedure as in Reference Example 6 was carried out using methyl 2-(3-bromophenylthio)propionate and tributyl(3-thienyl)tin in place of the starting methyl 2-bromophenylthioacetate and tributylphenylthin to give 2-[3-(3-thienyl)phenylthio]propionic acid.
Reaction SMILES: [OH-].[K+].[C:3]1([CH:10]=[CH:9][C:7]([OH:8])=[CH:6][CH:5]=1)[OH:4].Br[CH2:12][CH2:13][CH:14]=[CH2:15]>C(O)C>[CH2:15]([O:4][C:3]1[CH:10]=[CH:9][C:7]([OH:8])=[CH:6][CH:5]=1)[CH2:14][CH:13]=[CH2:12]
Reactant: C=CCCBr
Reactant: Oc1ccc(O)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: C=CCCOc1ccc(O)cc1

Procedure:
In a three-necked flask equipped with a dropping funnel, a mixture composed of potassium hydroxide (27 mmol) and hydroquinone (45 mmol) is dissolved in 400 ml of absolute ethanol by heating. Add 4-bromo-1-butene (Aldrich) (18 mmol) dropwise. Maintain at reflux for 4 hours. After being cooled and filtered the solvent is evaporated. The mixture is taken up in a solution of ice-cold water. That dissolves a part of the hydroquinone and leads to the appearance of a precipitate containing the desired product. Extract the product with ether. After three washings with water, the organic phase is dried over sodium sulfate then the solvent is evaporated. The phenyl is purified by chromatography on silica gel (eluent: heptane-ether 5/5). The yield of the reaction is of the order of 50%.
Reaction SMILES: [C@@H:1]([NH2:5])([CH2:3][CH3:4])[CH3:2].[CH2:6]([O:8][C:9](=[O:19])[C:10]1[CH:15]=[C:14]([O:16][CH3:17])[N:13]=[C:12](Cl)[CH:11]=1)[CH3:7].C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH2:6]([O:8][C:9](=[O:19])[C:10]1[CH:15]=[C:14]([O:16][CH3:17])[N:13]=[C:12]([NH:5][C@H:1]([CH2:3][CH3:4])[CH3:2])[CH:11]=1)[CH3:7]
Reactant: CC[C@H](C)N
Reactant: CCOC(=O)c1cc(Cl)nc(OC)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cc(N[C@@H](C)CC)nc(OC)c1
Temperature: 80 °C
Reaction time: 15 h
Yield: 93.3 %

Procedure:
Add (S)-sec-butyl amine (1.18 mL, 11.8 mmol) to a suspension of 2-chloro-6-methoxy-isonicotinic acid ethyl ester (1.69 g, 7.86 mmol), palladium acetate (0.088 g, 0.4 mmol), racemic 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (0.250 g, 0.4 mmol), and cesium carbonate (3.8 g, 11.8 mmol) in toluene (20 mL) at room temperature and stir 15 h at 80° C. Cool to room temperature, filter through a filtering agent, concentrate and purify (silica gel chromatography, eluting with 5:95 ethyl acetate:hexanes to give the title compound (1.85 g, 93%).
Reaction SMILES: C[O:2][C:3]1[C:4]([CH3:14])=[C:5]([CH:10]=[CH:11][C:12]=1[CH3:13])[C:6]([O:8][CH3:9])=[S:7].B(Br)(Br)Br.CO>C(Cl)Cl>[OH:2][C:3]1[C:4]([CH3:14])=[C:5]([CH:10]=[CH:11][C:12]=1[CH3:13])[C:6]([O:8][CH3:9])=[S:7]
Reactant: COC(=S)c1ccc(C)c(OC)c1C
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CO
Product: COC(=S)c1ccc(C)c(O)c1C
Temperature: 25 °C
Reaction time: 4 h
Yield: 106.5 %

Procedure:
10 g (0.044 mol) of methyl 3-methoxy-2-methyl-4-methylthiobenzoate was dissloved in 90 ml of methylene chloride, and the solution was added dropwise to 90 ml of methylene chloride containing 8.4 ml (0.088 mol) of boron tribromide at 5 to 10° C. After stirring at room temperature for 4 hours, 50 ml of methanol was added dropwise under ice cooling, and the solution was then washed with water and next a saturated sodium chloride solution. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure to obtain 9.2 g of methyl 3-hydroxy-2-methyl-4-methylthiobenzoate. Yield=98%.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([F:11])[C:5]([C:6]([NH2:8])=[O:7])=[C:4]([NH:12][C:13]2[N:18]=[C:17]([NH:19][C:20]3[CH:28]=[C:27]4[C:23]([CH2:24][CH2:25][N:26]4[C:29](=[O:34])[CH2:30][N:31]([CH3:33])[CH3:32])=[CH:22][C:21]=3[O:35][CH3:36])[NH:16][C:15]3=[N:37][CH:38]=[CH:39][C:14]=23)[CH:3]=1.[CH3:40]N>O1CCCC1>[Cl:1][C:2]1[CH:10]=[C:9]([F:11])[C:5]([C:6]([NH:8][CH3:40])=[O:7])=[C:4]([NH:12][C:13]2[N:18]=[C:17]([NH:19][C:20]3[CH:28]=[C:27]4[C:23]([CH2:24][CH2:25][N:26]4[C:29](=[O:34])[CH2:30][N:31]([CH3:32])[CH3:33])=[CH:22][C:21]=3[O:35][CH3:36])[NH:16][C:15]3=[N:37][CH:38]=[CH:39][C:14]=23)[CH:3]=1
Reactant: COc1cc2c(cc1Nc1nc(Nc3cc(Cl)cc(F)c3C(N)=O)c3ccnc-3[nH]1)N(C(=O)CN(C)C)CC2
Reactant: CN
Solvent: C1CCOC1
Product: CNC(=O)c1c(F)cc(Cl)cc1Nc1nc(Nc2cc3c(cc2OC)CCN3C(=O)CN(C)C)[nH]c2nccc1-2
Reaction time: 12 h

Procedure:
The residue obtained from concentration of the filtrates generated from the synthesis of 4-chloro-2-[(2-{[1-(N,N-dimethylglycyl)-5-(methyloxy)-2,3-dihydro-1H-indol-6-yl]amino}-1H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]-6-fluorobenzamide above were dissolved in tetrahydrofuran (10 mL) and 2.0M methyl amine in THF (5 mL) was added. The resulting solution was stirred for 12 hours and then concentrated to a residue under reduced pressure. The solids were dissolved in 1,4-dioxane (8 mL) and added to a microwave vial with 2.0N sodium hydroxide (8 mL). The mixture was maintained with rapid stirring under microwave irradiation at 120° C. for 8 minutes, cooled, poured into ethyl acetate/tetrahydrofuran/saturated sodium bicarbonate, and the organic layer was dried over sodium sulfate, taken to a residue under reduced pressure, and purified by chromatography on SiO2 to afford 4-chloro-2-[(2-{[1-(N,N-dimethylglycyl)-5-(methyloxy)-2,3-dihydro-1H-indol-6-yl]amino}-1H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]-6-fluoro-N-methylbenzamide (0.078 g); 1H NMR (400 MHz, DMSO-d6) δ ppm 11.31 (s, 1H), 10.53 (s, 1H), 8.62 (d, J=2.57 Hz, 1H), 8.49-8.56 (m, 2H), 7.67 (s, 1H), 7.05 (dd, J=10.26, 1.83 Hz, 1H), 6.96-7.00 (m, 1H), 6.95 (s, 1H), 6.21-6.28 (m, 1H), 4.13 (t, J=8.43 Hz, 2H), 3.76 (s, 3H), 3.13 (s, 2H), 3.09 (t, J=8.62 Hz, 2H), 2.80 (d, J=4.77 Hz, 3H), 2.21 (s, 6H). ESIMS (M+H)+=567.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[O:16]1[CH2:19][C:18](=O)[CH2:17]1.[BH3-]C#N.[Na+]>CO.[Cl-].[Zn+2].[Cl-]>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH2:15][CH2:14][N:13]([CH:18]3[CH2:19][O:16][CH2:17]3)[CH2:12][CH2:11]2)=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=C1COC1
Reactant: O=[N+]([O-])c1ccc(N2CCNCC2)cc1
Agent: [BH3-]C#N
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Product: O=[N+]([O-])c1ccc(N2CCN(C3COC3)CC2)cc1
Temperature: 50 °C
Reaction time: 5 h
Yield: 76.1 %

Procedure:
To a mixture of 117c (2.0 g, 8.23 mmol), zinc chloride (2.2 g, 16.4 mmol), oxetan-3-one (1.18 g, 16.4 mmol) in methanol (80 mL) was added NaBH3CN (1.02 g, 16.4 mmol). The mixture was stirred at 50° C. for 5 hours. The mixture was then concentrated under reduced pressure and the residue was diluted with water (100 mL). It was extracted with dichloromethane (3×100 mL) and the combined organic layer was concentrated under reduced pressure. The residue was purified by silica-gel column chromatography eluting with 4:1 petroleum ether/ethyl acetate to afford 117d (1.65 g, 76%) as a yellow solid. MS: [M+H]+ 264.
Reaction SMILES: [NH2:1][CH:2]1[CH2:8][CH2:7][C:6]2[CH:9]=[CH:10][CH:11]=[CH:12][C:5]=2[N:4]([CH2:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C:3]1=[O:21].[CH2:22]([O:29][C:30]([N:32]1[CH2:37][CH2:36][CH:35]([CH2:38][CH2:39][CH2:40][CH2:41][CH:42](OS(C)(=O)=O)[C:43]([O:45][CH2:46][CH3:47])=[O:44])[CH2:34][CH2:33]1)=[O:31])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(OCC)(=O)C>[CH2:22]([O:29][C:30]([N:32]1[CH2:33][CH2:34][CH:35]([CH2:38][CH2:39][CH2:40][CH2:41][CH:42]([NH:1][CH:2]2[CH2:8][CH2:7][C:6]3[CH:9]=[CH:10][CH:11]=[CH:12][C:5]=3[N:4]([CH2:13][C:14]([O:16][C:17]([CH3:18])([CH3:20])[CH3:19])=[O:15])[C:3]2=[O:21])[C:43]([O:45][CH2:46][CH3:47])=[O:44])[CH2:36][CH2:37]1)=[O:31])[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: CC(C)(C)OC(=O)CN1C(=O)C(N)CCc2ccccc21
Reactant: CCOC(=O)C(CCCCC1CCN(C(=O)OCc2ccccc2)CC1)OS(C)(=O)=O
Solvent: CCOC(C)=O
Product: CCOC(=O)C(CCCCC1CCN(C(=O)OCc2ccccc2)CC1)NC1CCc2ccccc2N(CC(=O)OC(C)(C)C)C1=O
Temperature: 90 °C
Yield: 51 %

Procedure:
A mixture of 1.75 g of tert-butyl 3-amino-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine-1-acetate and 1.1 g of ethyl 6-(1-benzyloxycarbonyl-4-piperidyl)-2-methanesulfonyloxyhexanoate is heated at 90° C. for 24 hours. After cooling, the reaction solution is diluted with 200 ml of ethyl acetate, and the resulting solution is washed with 30 ml of 5% aqueous phosphoric acid and water, successively, and dried over anhydrous magnesium sulfate. After the solvent is distilled off under reduced pressure, the residue is separated and purified by silica gel column chromatography (hexane:ethyl acetate=2:1), whereby the first fraction yields 0.8 g of tert-butyl 3(RS)-[5-(1-benzyloxycarbonyl-4-piperidyl)-1(SR)-ethoxycarbonylpentyl]amino-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine-1-acetate as a colorless oil.
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([N:11]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[N:13]=[CH:12]2)[CH:8]=[CH:7][N:6]=1)(=O)=O.[I:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=1)[CH2:24][NH2:25]>>[I:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=1)[CH2:24][NH:25][C:5]1[N:10]=[C:9]([N:11]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[N:13]=[CH:12]2)[CH:8]=[CH:7][N:6]=1
Reactant: CS(=O)(=O)c1nccc(-n2cnc3ccccc32)n1
Reactant: NCc1cccc(I)c1
Product: Ic1cccc(CNc2nccc(-n3cnc4ccccc43)n2)c1

Procedure:
2-Methanesulfonyl-4-[benzimidazol-1-yl]pyrimidine was reacted with 3-iodobenzylamine according to the procedure described in EXAMPLE 1, Step C to afford the title compound. Mass Spectrum (ESI): m/e 428.1 (M+1). 1H NMR (500 MHz, CDCl3): δ 8.59 (s, 1H); 8.44 (d, J=4.7 Hz, 1H); 8.02 (br s, 1H); 7.86 (m, 1H); 7.79 (s, 1H); 7.65 (d, J=7.8 Hz, 1H); 7.38 (m, 3H); 7.12 (t, J=7.8 Hz, 1H), 6.87 (d, J=5.3 Hz, 1H); 5.78 (br s, 1H); 4.71 (d, J=5.9 Hz, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][C:23]=1[O:24][CH3:25])[CH2:5][NH:6][C:7]1[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:11][N:10]=[C:9](S(C)=O)[N:8]=1.C(N(CC)CC)C.[NH:33]1[CH2:39][CH2:38][CH2:37][C@H:34]1[CH2:35][OH:36]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][C:23]=1[O:24][CH3:25])[CH2:5][NH:6][C:7]1[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:11][N:10]=[C:9]([N:33]2[CH2:39][CH2:38][CH2:37][C@H:34]2[CH2:35][OH:36])[N:8]=1
Reactant: CCOC(=O)c1cnc(S(C)=O)nc1NCc1ccc(OC)c(Cl)c1
Reactant: OC[C@@H]1CCCN1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)c1cnc(N2CCC[C@H]2CO)nc1NCc1ccc(OC)c(Cl)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
In the solution of ethyl 4-((3-chloro-4-methoxybenzyl)amino)-2-methanesulfinyl-5-pyrimidine carboxylate in DCM was added triethylamine (4.24 g, 42 mmol). The mixture was cooled in an ice bath, then was added L-prolinol (2.2 g, 19.8 mmol) dropwise. The reaction mixture was stirred at ambient temperature for 3 h. The reaction was monitored by LC-MS. After the completion of the reaction, the reaction mixture was washed with water, dilute hydrochloric acid, sodium bicarbonate aqueous solution and brine, each once. The organic phase was dried over sodium sulfate and concentrated until the solvent was removed. The product was used in subsequent procedures without further purification.
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[NH:7][C:8]1[CH2:9][O:10][CH2:11][CH2:12][C:13]([C:18]2[CH:23]=[C:22]([NH2:24])[CH:21]=[CH:20][C:19]=2[F:25])([CH:15]([F:17])[F:16])[N:14]=1)([CH3:4])([CH3:3])[CH3:2]>CCCCCCC.C(O)C>[C:1]([O:5][C:6](=[O:26])[NH:7][C:8]1[CH2:9][O:10][CH2:11][CH2:12][C@:13]([C:18]2[CH:23]=[C:22]([NH2:24])[CH:21]=[CH:20][C:19]=2[F:25])([CH:15]([F:17])[F:16])[N:14]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1=NC(c2cc(N)ccc2F)(C(F)F)CCOC1
Solvent: CCO
Solvent: CCCCCCC
Product: CC(C)(C)OC(=O)NC1=N[C@@](c2cc(N)ccc2F)(C(F)F)CCOC1
Yield: 50 %

Procedure:
Racemic [5-(5-amino-2-fluoro-phenyl)-5-difluoromethyl-2,5,6,7-tetrahydro-[1,4]oxazepin-3-yl]-carbamic acid tert-butyl ester (1.62 g, 4.04 mmol) was separated via a VWR prep HPLC System on a Chiralpak AD 20 um 4×50×100 (4×SMB columns) column; eluent: heptane/ethanol 70/30; flow=65 ml/min; UV detection at 220 nm. As a result, 754 mg of the desired title compound ((S)-isomer) was obtained as the first eluting isomer. Purity: >99.5% ee.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([Cl:12])[C:3]=1[C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[N:19]=[C:18]([NH:23][C@H:24]1[C@@H:28]([NH:29]C(OCC[Si](C)(C)C)=O)[CH2:27][N:26]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:25]1)[N:17]=[CH:16]2.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1.CO.ClCCl>[NH2:29][C@@H:28]1[C@H:24]([NH:23][C:18]2[N:17]=[CH:16][C:15]3[C:20](=[CH:21][CH:22]=[C:13]([C:3]4[C:2]([Cl:1])=[C:7]([O:8][CH3:9])[CH:6]=[C:5]([O:10][CH3:11])[C:4]=4[Cl:12])[CH:14]=3)[N:19]=2)[CH2:25][N:26]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:27]1
Reactant: COc1cc(OC)c(Cl)c(-c2ccc3nc(N[C@@H]4CN(C(=O)OC(C)(C)C)C[C@@H]4NC(=O)OCC[Si](C)(C)C)ncc3c2)c1Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CO
Product: COc1cc(OC)c(Cl)c(-c2ccc3nc(N[C@@H]4CN(C(=O)OC(C)(C)C)C[C@@H]4N)ncc3c2)c1Cl
Yield: 95.8 %

Procedure:
A mixture of tert-butyl (3R,4S)-3-((6-(2,6-dichloro-3,5-dimethoxyphenyl)quinazolin-2-yl)amino)-4-(((2-(trimethylsilyl)ethoxy)carbonyl)amino)pyrrolidine-1-carboxylate (2.77 g, 4.1 mmol) and 1M TBAF in THF (6.1 mL, 6.1 mmol) was stirred in THF (27 mL) at 50° C. for 4 h and then 16 h at room temperature. The reaction mixture was diluted with 10% methanol in dichloromethane (100 mL) and washed with water (50 mL). The aqueous layer was then extracted with fresh dichloromethane (3×20 mL). The combined organic layers were washed with saturated brine solution, dried over sodium sulfate, filtered, concentrated down, and dried to yield tert-butyl (3S,4R)-3-amino-4-((6-(2,6-dichloro-3,5-dimethoxyphenyl)quinazolin-2-yl)amino)pyrrolidine-1-carboxylate as a yellow solid (2.1 g, 94%).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH2:11][C@H:10]([NH:14][CH3:15])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:17]1[N:22]=[CH:21][N:20]=[C:19]2[N:23]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31])[N:24]=[CH:25][C:18]=12.CCN(C(C)C)C(C)C>CN(C=O)C.CCOC(C)=O>[CH2:1]([N:8]1[CH2:13][CH2:12][CH2:11][C@H:10]([N:14]([CH3:15])[C:17]2[N:22]=[CH:21][N:20]=[C:19]3[N:23]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31])[N:24]=[CH:25][C:18]=23)[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN[C@H]1CCCN(Cc2ccccc2)C1
Reactant: C[Si](C)(C)CCOCn1ncc2c(Cl)ncnc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CN(c1ncnc2c1cnn2COCC[Si](C)(C)C)[C@H]1CCCN(Cc2ccccc2)C1
Temperature: 60 °C
Reaction time: 8 h
Yield: 50.6 %

Procedure:
To a solution of (S)-1-benzyl-N-methylpiperidin-3-amine (500 mg, 2.4 mmol) and 4-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-d]pyrimidine (697 mg, 2.4 mmol) in DMF (10 mL), DIEA (1.26 g, 9.7 mmol) was added and the reaction mixture was stirred at 60° C. overnight. After reaction was completed as indicated by TLC, the reaction mixture was diluted with EtOAc (40 mL) and was washed with water (3×20 mL). The EtOAc layer was then dried over Na2SO4 and evaporated in vacuo to give a residue that was purified by column chromatography (silica gel, gradient EtOAc in hexanes) to afford the titled intermediate (550 mg, 49%). 1H NMR (400 MHz, CD3OD): δ 8.26 (s, 1H), 8.15 (bs, 1H), 7.32 (m, 3H), 7.22 (m, 2H), 5.67 (s, 2H), 3.61 (t, J=9.2 Hz, 2H), 3.57 (m, 2H), 3.31 (s, 3H), 2.95 (m, 2H), 2.24 (m, 1H), 2.03 (m, 2H), 1.80 (m, 4H), 0.86 (m, 2H), 0.07 (s, 9H). LC-MS: m/z [M+1]=453.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[F:11])[CH2:7][C:6]([NH:15][C:16](=[O:27])[C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[C:18]=1[CH:24]=[CH:25][CH3:26])([C:12]([OH:14])=[O:13])[CH2:5]2>CCO.[Pd]>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[F:11])[CH2:7][C:6]([NH:15][C:16](=[O:27])[C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[C:18]=1[CH2:24][CH2:25][CH3:26])([C:12]([OH:14])=[O:13])[CH2:5]2
Reactant: CC=Cc1c(C)cccc1C(=O)NC1(C(=O)O)Cc2cc(F)c(F)cc2C1
Agent: [Pd]
Solvent: CCO
Product: CCCc1c(C)cccc1C(=O)NC1(C(=O)O)Cc2cc(F)c(F)cc2C1
Temperature: 25 °C
Yield: 71.4 %

Procedure:
5,6-Difluoro-2-[3-methyl-2-(-propenyl)-benzoylamino]-indan-2-carboxylic acid (160) (110 mg, 0.30 mmol) is dissolved in absolute EtOH (15 mL) by heating. The resulting solution is cooled to RT and catalyst, Pd—C (5 wt. % Pd, 64 mg, 3.0% mmol) is added under argon. The resulting reaction mixture is moved to the Paar apparatus to run hydrogenation: 55 psi, 50° C., overnight. The catalyst is removed by filtration through a pre-column (10 g silica gel) and washed with EtOH. The combined EtOH solution is concentrated in vacuo. The residue is purified by HPLC to give a pure product (161) as white solid (80 mg, 71%).
Reaction SMILES: C([O:8][C@H:9]1[C@H:15]([O:16]CC2C=CC=CC=2)[C@@H:14]([O:24]CC2C=CC=CC=2)[C@:13]2([C:33]3[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]4[CH:46]=[CH:45][C:44]([O:47][CH2:48][CH3:49])=[CH:43][CH:42]=4)[CH:34]=3)[O:32][C@:10]1([CH:50]1[CH2:52][O:51]1)[CH2:11][O:12]2)C1C=CC=CC=1.ClC1C=CC=CC=1Cl>[Pd].CO.O1CCCC1>[Cl:39][C:36]1[CH:37]=[CH:38][C:33]([C@@:13]23[O:32][C@@:10]([CH:50]4[CH2:52][O:51]4)([CH2:11][O:12]2)[C@@H:9]([OH:8])[C@H:15]([OH:16])[C@H:14]3[OH:24])=[CH:34][C:35]=1[CH2:40][C:41]1[CH:46]=[CH:45][C:44]([O:47][CH2:48][CH3:49])=[CH:43][CH:42]=1
Reactant: CCOc1ccc(Cc2cc([C@]34OC[C@@](C5CO5)(O3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]4OCc3ccccc3)ccc2Cl)cc1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Solvent: Clc1ccccc1Cl
Product: CCOc1ccc(Cc2cc([C@]34OC[C@](C5CO5)(O3)[C@@H](O)[C@H](O)[C@H]4O)ccc2Cl)cc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of (1S,2S,3S,4R,5S)-2,3,4-tribenzyloxy-5-[4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]-1-(oxiran-2-yl)-6,8-dioxabicyclo[3.2.1]octane 10a (310 mg, 0.43 mmol, obtained from the synthetic method described in step 1 example 10) in a methanol/tetrahydrofuran mixture (v/v=4/1, 15 mL) were added o-dichlorobenzene (0.25 mL, 2.15 mmol) and 10% Pd/C (30 mg, 0.03 mmol) at room temperature. The mixture was stirred under H2 at room temperature for 6 hours and filtered. The filter cake was washed with an ethyl acetate/tetrahydrofuran mixture (v/v=4/1, 10 mL×2) and the filtrate was concentrated in vacuo. The residue was purified by silica gel chromatography eluted with PE/EtOAc(v/v)=1/1 to give the title compound 26 as a white solid (34 mg, 17.6%, HPLC: 97.5%). The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 449.1[M+H]+; and 1H NMR (400 MHz, DMSO-d6) δ(ppm): 7.38 (m, 2H), 7.27 (m, 1H), 7.09 (d, 2H), 6.83 (d, 2H), 5.54 (d, 1H), 5.10 (d, 1H), 4.99 (d, 1H), 3.97 (m, 5H), 3.45 (t, 1H), 3.40 (m, 2H), 3.26 (m, 3H), 2.78 (t, 1H), 1.29 (t, 3H).