Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][C:23]=1[Cl:24])[CH2:5][N:6]([CH2:16][CH2:17]CC#N)[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([Cl:15])[CH:9]=1.[OH-:25].[Na+].[CH2:27]([OH:29])[CH3:28].Cl>O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][C:23]=1[Cl:24])[CH2:5][N:6]([CH2:16][CH2:17][CH2:28][C:27]([OH:25])=[O:29])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([Cl:15])[CH:9]=1
Reactant: N#CCCCN(Cc1ccc(Cl)c(Cl)c1)Cc1ccc(Cl)c(Cl)c1
Reactant: [OH-]
Reactant: CCO
Agent: Cl
Agent: [Na+]
Solvent: O
Product: O=C(O)CCCN(Cc1ccc(Cl)c(Cl)c1)Cc1ccc(Cl)c(Cl)c1

Procedure:
A mixture of 4-[N,N-bis-(3,4-dichlorobenzyl)amino]butyronitrile (1.95g), NaOH (2.0g) and ethanol (25ml) was stirred and heated to reflux for 6 hours under a nitrogen blanket. After cooling, the solvent was evaporated in vacuo to give a paste which was taken up in water (30ml), acidified with conc. HCl, stirred well and cooled in ice. The oil which had precipitated crystallised slowly. The crystals were filtered off, washed well with water, and recrystallised from dimethylformamide, diluted with a large volume of ether. The precipitated oil again crystallised slowly. The crystals were triturated with hot isopropanol, diluted with ether, collected by filtration and dried at 50°/1 mm to give the title compound as the hydrochloride salt. (1 .20g), m.p. 227-231° (decomp).
Reaction SMILES: [F:1][C:2]1[C:10]2[N:9]=[C:8]([C:11]([N:13]([CH2:31][CH:32]([CH3:34])[CH3:33])[C@@H:14]3[CH2:19][N:18]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:17][C@H:16]([C:27]([O:29]C)=[O:28])[CH2:15]3)=[O:12])[N:7]([CH2:35][CH2:36][CH2:37][CH2:38][O:39][CH3:40])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>O1CCCC1CO>[C:23]([O:22][C:20]([N:18]1[CH2:19][C@@H:14]([N:13]([C:11]([C:8]2[N:7]([CH2:35][CH2:36][CH2:37][CH2:38][O:39][CH3:40])[C:6]3[CH:5]=[CH:4][CH:3]=[C:2]([F:1])[C:10]=3[N:9]=2)=[O:12])[CH2:31][CH:32]([CH3:33])[CH3:34])[CH2:15][C@@H:16]([C:27]([OH:29])=[O:28])[CH2:17]1)=[O:21])([CH3:25])([CH3:26])[CH3:24]
Reactant: COCCCCn1c(C(=O)N(CC(C)C)[C@H]2C[C@@H](C(=O)OC)CN(C(=O)OC(C)(C)C)C2)nc2c(F)cccc21
Agent: [Na+]
Agent: [OH-]
Solvent: OCC1CCCO1
Product: COCCCCn1c(C(=O)N(CC(C)C)[C@H]2C[C@@H](C(=O)O)CN(C(=O)OC(C)(C)C)C2)nc2c(F)cccc21
Temperature: 45 °C
Reaction time: 4 h
Yield: 94.7 %

Procedure:
1-tert-Butyl 3-methyl(3R,5S)-5-{{{4-fluoro-1-(4-methoxybutyl)-1H-benzimidazol-2-yl}carbonyl}(2-methylpropyl)amino}piperidine-1,3-dicarboxylate (195 mg) was dissolved in tetrahydrofuran-methanol (1:2, 15 ml), 2M aqueous sodium hydroxide solution (1 ml) was added, and the mixture was stirred at 45° C. for 4 hr. The reaction mixture was concentrated under reduced pressure, neutralized with saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, concentration under reduced pressure to give the object product (180 mg).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3](B(O)O)[CH:2]=1.C([O-])([O-])=O.[Na+].[Na+].Cl[C:17]1[N:22]2[N:23]=[C:24]([NH2:26])[N:25]=[C:21]2[CH:20]=[C:19]([C:27]2[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=2)[CH:18]=1.C(Cl)Cl>C1(C)C=CC=CC=1>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:17]2[N:22]3[N:23]=[C:24]([NH2:26])[N:25]=[C:21]3[CH:20]=[C:19]([C:27]3[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=3)[CH:18]=2)[CH:2]=1
Reactant: OB(O)c1cccnc1
Reactant: Nc1nc2cc(-c3cccnc3)cc(Cl)n2n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: Nc1nc2cc(-c3cccnc3)cc(-c3cccnc3)n2n1

Procedure:
A mixture of 3-pyridine boronic acid pinacolate ester (500 mg, 2.44 mmol), Na2CO3 (649 mg, 6.12 mmol) and 5-chloro-7-pyridin-3-yl-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine, which may be produced as in Example 1A, (500 mg, 2.04 mmol) in toluene (30 mL), ethanol (15 mL) and water (15 mL) was degassed by purging with N2 for 10 min. [PdCl2(dppf)].CH2Cl2 (56 mg, 0.082 mmol) was added and the mixture was brought to reflux for 36 h. The solvent was evaporated and the residue was extracted into hot EtOH/MeOH, filtered through Celite, and pre-adsorbed onto SiO2. Column chromatography (0-10% MeOH in CH2Cl2) afforded the product 5,7-di-pyridin-3-yl-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine as a solid. MS m/z 289 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[C:8]([N:15]([CH2:17][C:18]1([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1)[CH3:16])[N:7]=[C:6]2[NH2:30].Cl[C:32]([O:34][CH2:35][CH3:36])=[O:33].C(N(CC)CC)C>ClCCl.O>[CH2:35]([O:34][C:32]([N:21]1[CH2:20][CH2:19][C:18]([CH2:17][N:15]([C:8]2[N:7]=[C:6]([NH2:30])[C:5]3[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=3)[N:9]=2)[CH3:16])([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:23][CH2:22]1)=[O:33])[CH3:36]
Reactant: CCOC(=O)Cl
Reactant: COc1cc2nc(N(C)CC3(c4ccccc4)CCNCC3)nc(N)c2cc1OC
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)N1CCC(CN(C)c2nc(N)c3cc(OC)c(OC)cc3n2)(c2ccccc2)CC1

Procedure:
A solution of 6,7-dimethoxy-N2-(4-phenyl-piperidin-4-ylmethyl)-quinazoline-2,4-diamine 11 (375 mg), ethyl chloroformate, and triethylamine (250 μl) in dichloromethane (10 ml) was stirred at room temperature for 24 hours. The mixture was diluted with water and extracted with ethyl acetate. The product was chromatographed on silica gel to yield 4-{[(4-Amino-6,7-dimethoxy-quinazolin-2-yl)-methyl-amino]-methyl}-4-phenyl-piperidine-1-carboxylic acid ethyl ester 20, MS: 479 (M+).
Reaction SMILES: [NH:1]([C:14]([O:16][CH2:17][CH:18]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:24]2[C:19]1=[CH:20][CH:21]=[CH:22][CH:23]=2)=[O:15])[C@H:2]([C:11]([OH:13])=O)[CH2:3][C:4](=[O:10])[O:5][C:6]([CH3:9])([CH3:8])[CH3:7].C1CN([P+](ON2N=[N:55][C:50]3[CH:51]=[CH:52][CH:53]=[CH:54][C:49]2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1.[NH2:81][C@H:82]([C:93]([O:95][CH2:96][C:97]1[CH:102]=[CH:101][CH:100]=[CH:99][CH:98]=1)=[O:94])[CH2:83][C:84]1C2C(=CC=CC=2)N[CH:85]=1>C(Cl)Cl>[NH:1]([C:14]([O:16][CH2:17][CH:18]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:24]2[C:19]1=[CH:20][CH:21]=[CH:22][CH:23]=2)=[O:15])[C@H:2]([C:11]([NH:81][C@H:82]([C:93]([O:95][CH2:96][C:97]1[CH:102]=[CH:101][CH:100]=[CH:99][CH:98]=1)=[O:94])[CH2:83][C:84]1[C:49]2[C:50](=[CH:51][CH:52]=[CH:53][CH:54]=2)[NH:55][CH:85]=1)=[O:13])[CH2:3][C:4](=[O:10])[O:5][C:6]([CH3:8])([CH3:7])[CH3:9]
Reactant: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Reactant: CC(C)(C)OC(=O)C[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Reactant: N[C@@H](Cc1c[nH]c2ccccc12)C(=O)OCc1ccccc1
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)C[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 77.3 %

Procedure:
41 mg of Fmoc-Asp(Ot-Bu)-OH was dissolved in 2 ml of methylene chloride, and the solution was cooled to 0° C. 78 mg of PyBOP, 20 mg of HOBt and 22 μl of NMM were added thereto in order and stirring was effected for 5 minutes, at 0° C. 2 ml of the methylene chloride solution containing 34 mg of H-Trp-OBzl (NO2) as obtained above was cooled to 0° C. and then added to the resulting reaction solution. Stirring was effected at 4° C. for 4 hours and at room temperature for 1 hour, the solvent was evaporated under reduced pressure, and the residue was purified with a silica gel column (manufactured by Merck Co., Kieselgel 60, 50 g, elution with chloroform:methanol=25:1), to obtain 53 mg of Fmoc-Asp(Ot-Bu)-Trp-OBzl (NO2). The obtained product was dissolved in 100 μl of DMF, 25 μl of piperidine was added. The mixture was then allowed to stand at room temperature for 10 minutes, and purified with a silica gel column (manufactured by Merck Co., Kieselgel 60, 50 g, elution with hexane:ethyl acetate=2:1), to obtain 1 mg of H-Asp(Ot-Bu)-Trp-OBzl (NO2).
Reaction SMILES: [C:1]([N:20]1[N:24]=[N:23][C:22]([CH2:25][CH2:26][CH2:27][CH2:28][N:29]2C(=O)C3C(=CC=CC=3)C2=O)=[N:21]1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.NN>CC(O)C.C1COCC1>[C:1]([N:20]1[N:24]=[N:23][C:22]([CH2:25][CH2:26][CH2:27][CH2:28][NH2:29])=[N:21]1)([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C1c2ccccc2C(=O)N1CCCCc1nnn(C(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: NN
Solvent: C1CCOC1
Solvent: CC(C)O
Product: NCCCCc1nnn(C(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 109.1 %

Procedure:
To a solution of 2-[4-(2-trityl-2H-tetrazol-5-yl)-butyl]-isoindole-1,3-dione (175 mg, 0.313 mmol) in 2-propanol/THF (2:1, 3.0 mL) was added hydrazine (30 mL, 0.939 mmol). The solution was stirred at ambient temperature for 16 h. White solid was filtered off and washed with DCM (5×). The filtrate and the washings were combined, concentrated, dissolved in DCM, washed with H2O (2×) and brine, dried over Na2SO4, and concentrated to give the title compound (131 mg, 97% yield) as a pale yellow oil.
Reaction SMILES: [NH2:1][C@@H:2]([CH3:7])[C:3]([O:5][CH3:6])=[O:4].Cl[C:9]1[N:14]=[C:13]([N:15]2[C@@H:19]([CH:20]([CH3:22])[CH3:21])[CH2:18][O:17][C:16]2=[O:23])[CH:12]=[CH:11][N:10]=1.CCN(C(C)C)C(C)C>O>[CH:20]([C@H:19]1[CH2:18][O:17][C:16](=[O:23])[N:15]1[C:13]1[CH:12]=[CH:11][N:10]=[C:9]([NH:1][C@@H:2]([CH3:7])[C:3]([O:5][CH3:6])=[O:4])[N:14]=1)([CH3:22])[CH3:21]
Reactant: COC(=O)[C@H](C)N
Reactant: CC(C)[C@H]1COC(=O)N1c1ccnc(Cl)n1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@H](C)Nc1nccc(N2C(=O)OC[C@@H]2C(C)C)n1
Temperature: 110 °C
Yield: 46.8 %

Procedure:
To a solution of (S)-methyl 2-aminopropanoate (270 mg, 2.0 mmol, 1.2 equv. in 10 ml of DMSO) and (S)-3-(2-chloropyrimidin-4-yl)-4-isopropyloxazolidin-2-one (430 mg, 1.8 mmol, 1.0 equv.) was added DIPEA (805 mg, 6.23 mmol, 3.5 equiv), and the reaction mixture was heated at 110° C. for 120 min. The reaction mixture was poured into water (40 ml) and extracted with EtOAc (2×30 mL) and washed with water (30 mL). After separation, the aqueous phase was extracted with EtOAc (3×8 mL). Combined organics were dried over Na2SO4, filtered and concentrated. Silica gel column chromatography (ethyl acetate in heptane 10 to 80%) to provide (S)-methyl 2-((4-((S)-4-isopropyl-2-oxooxazolidin-3-yl)pyrimidin-2-yl)amino)propanoate (260 mg, white solid) in 47.4% yield. LCMS m/z 309.1 (M+H)+ RT=1.53 min.
Reaction SMILES: [CH3:1][CH:2]([CH3:4])[O-:3].[Al+3].[CH3:6]C(C)[O-].[CH3:10]C(C)[O-].[CH3:14]CCC[O-].[CH3:19]CCC[O-].CCCC[O-].CCCC[O-].[Zr+4:34].[CH3:35][C:36]1[CH:41]=C(C)C=C[C:37]=1O>C1(C)C(C)=CC=CC=1>[CH3:6][C:1]1[CH:37]=[C:36]([CH3:41])[CH:35]=[CH:4][C:2]=1[O-:3].[Zr+4:34].[CH3:10][C:1]1[CH:37]=[C:36]([CH3:41])[CH:35]=[CH:4][C:2]=1[O-:3].[CH3:14][C:1]1[CH:37]=[C:36]([CH3:41])[CH:35]=[CH:4][C:2]=1[O-:3].[CH3:19][C:1]1[CH:37]=[C:36]([CH3:41])[CH:35]=[CH:4][C:2]=1[O-:3]
Reactant: CCCC[O-]
Reactant: Cc1ccc(O)c(C)c1
Reactant: CC(C)[O-]
Agent: [Zr+4]
Agent: [Al+3]
Solvent: Cc1ccccc1C
Product: Cc1ccc([O-])c(C)c1

Procedure:
instead of aluminum isopropoxide, 0.8 g of tetrabutyl zirconate (as a 30% solution in xylene) is added to the 2,4-dimethylphenol. Butyl alcohol and xylene are removed with heat and vacuum to yield zirconium 2,4-dimethylphenoxide, which upon addition of toluene and divinylbenzene and reaction in accordance with part A of Example I, functions as an alkylation catalyst, yielding a similar yield of the same styryl monomer.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:21])[C:10]([OH:20])([CH2:15][CH:16]=[C:17]([CH3:19])[CH3:18])[CH2:11][C:12]([OH:14])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:22]1C=CC=CC=1.[Si](C=[N+]=[N-])(C)(C)C>CO>[OH:20][C@:10]([CH2:15][CH:16]=[C:17]([CH3:18])[CH3:19])([CH2:11][C:12]([O:14][CH3:22])=[O:13])[C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:21]
Reactant: CC(C)=CCC(O)(CC(=O)O)C(=O)OCc1ccccc1
Reactant: c1ccccc1
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Product: COC(=O)C[C@](O)(CC=C(C)C)C(=O)OCc1ccccc1
Yield: 100 %

Procedure:
To a solution of acid 75 (175.2 mg, 0.599 mmol, 1.00 equiv) in 7:2 PhH:MeOH (6.0 mL) was added a 2.0 M solution of TMSCHN2 (449 μL, 0.899 mmol, 1.50 equiv.). After the resulting gas evolution had subsided, the solvent was removed by rotary evaporation to yield methyl ester 77 (183.7 mg, 100%) as a clear, colorless oil. Rf=0.55 (2:1 hex:EtOAc); 1H NMR (500 MHz, CDCl3) δ 7.36 (m, 5H, aryl H), 5.23 (d, 1H, J=12.1 Hz, PhCH2), 5.19 (d, 1H, J=12.1 Hz, PhCH2), 5.08 (m, 1H, vinyl H), 3.68 (s, 1H, OH), 3.62 (s, 3H, OCH3), 2.95 (d, 1H, J=16.2 Hz, C(O)CH2), 2.72 (d, 1H, J=16.3 Hz, C(O)CH2), 2.41 (m, 2H, CHCH2), 1.67 (s, 3H, C(CH3)2), 1.54 (s, 3H, C(CH3)2); 13C NMR (125 MHz, CDCl3) δ 174.84, 171.43, 136.54, 135.46, 128.70, 128.66, 128.60, 116.75, 75.65, 67.79, 51.93, 42.81, 38.11, 26.06, 18.09; IR (neat film) 3514 (m), 3034 (w), 2955 (m), 1742 (s), 1498 (w), 1439 (s), 753 (m), 699 (m) cm−1; LRMS (ESI) calc'd for C17H22O5Na (M+Na+) 329.2; found 329.1.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:14]([F:15])=[CH:13][C:12]([NH:16][C:17](=[O:24])[CH2:18][C:19]([O:21]CC)=[O:20])=[C:11]([F:25])[CH:10]=2)[CH:5]=[CH:4][N:3]=1.C(OC1C=CC(NC2N=CN=C(OC3C=CC(NC(=O)CC(NC4C=CC(F)=CC=4)=O)=CC=3F)C=2)=CC=1)C1C=CC=CC=1>>[NH2:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:14]([F:15])=[CH:13][C:12]([NH:16][C:17](=[O:24])[CH2:18][C:19]([OH:21])=[O:20])=[C:11]([F:25])[CH:10]=2)[CH:5]=[CH:4][N:3]=1
Reactant: CCOC(=O)CC(=O)Nc1cc(F)c(Oc2ccnc(N)c2)cc1F
Agent: O=C(CC(=O)Nc1ccc(Oc2cc(Nc3ccc(OCc4ccccc4)cc3)ncn2)c(F)c1)Nc1ccc(F)cc1
Product: Nc1cc(Oc2cc(F)c(NC(=O)CC(=O)O)cc2F)ccn1
Yield: 0 %

Procedure:
Ethyl 3-(4-(2-aminopyridin-4-yloxy)-2,5-difluorophenylamino)-3-oxopropanoate (0.24 g, 0.68 mmol) was converted to the title compound (0.039 mg, 18%) in a manner similar to the preparation of Compound B of Example 116. HRMS (ESI+), Calcd.: 324.0796 (M+H)+. found: 324.0795 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[O:9][CH3:10].[CH3:11][O:12]C(Cl)Cl>ClCCl.[Ti](Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[C:3]([O:9][CH3:10])=[CH:4][C:5]([F:8])=[C:6]([CH:7]=1)[CH:11]=[O:12]
Reactant: COc1cc(F)ccc1Br
Reactant: COC(Cl)Cl
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: COc1cc(F)c(C=O)cc1Br
Temperature: 25 °C
Reaction time: 4.5 h

Procedure:
8.4 g of 1-bromo-4-fluoro-2-methoxy-benzene obtained in Production Example II-1-a was dissolved in 200 ml of dichloromethane. 21 ml of titanium tetrachloride and 5.6 ml of dichloromethyl methyl ether were added at 0° C. in nitrogen atmosphere, followed by stirring at room temperature for 4.5 hours. Then, the reaction mixture was gradually poured onto ice-water, and extracted with diethyl ether for two times. The organic layer was sequentially washed with each one portion of water, saturated aqueous sodium hydrogencarbonate solution and water, dried over magnesium sulfate and the solvent was evaporated, to give 9.44 g of the title compound as white crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]([CH3:12])=[C:10]2[C:6]([C:7](=[O:13])[O:8][CH2:9]2)=[C:5]([O:14][S:15]([C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=2)(=[O:17])=[O:16])[C:4]=1[CH2:25][CH:26]=[C:27]([CH3:30])[CH:28]=[O:29].[CH:31]([Mg]Br)=[CH2:32]>O1CCCC1.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[C:11]([CH3:12])=[C:10]2[C:6]([C:7](=[O:13])[O:8][CH2:9]2)=[C:5]([O:14][S:15]([C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=2)(=[O:17])=[O:16])[C:4]=1[CH2:25][CH:26]=[C:27]([CH3:30])[CH:28]([OH:29])[CH:31]=[CH2:32]
Reactant: COc1c(C)c2c(c(OS(=O)(=O)c3ccc(C)cc3)c1CC=C(C)C=O)C(=O)OC2
Reactant: C=C[Mg]Br
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C=CC(O)C(C)=CCc1c(OC)c(C)c2c(c1OS(=O)(=O)c1ccc(C)cc1)C(=O)OC2
Reaction time: 0.5 h

Procedure:
To a solution of 4-(1,3-dihydro-6-methoxy-7-methyl-3-oxo-4-p-toluenesulfonyloxy-5-isobenzofuranyl)-2-methylbut-2-enaldehyde (0.90 g) in tetrahydrofuran (40 mL) was added vinylmagnesium bromide (4.5 mL of a 1M solution in tetrahydrofuran). After stirring for 0.5 hours, the reaction was diluted with ethyl acetate nd washed successively with aqueous ammonium chloride and brine. Drying over magnesium sulfate was followed by filtration and solvent removal to leave a residual oil, 6-(1,3-dihydro-6-methoxy-7-methyl-3-oxo-4-p-toluenesulfonyloxy-5-isobenzofuranyl)-3-hydroxy-4-methylhexa-1,4-diene, which was carried on without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:11][C:12]([O:14][CH3:15])=[O:13])[CH:5]=[CH:6][C:7]=1[N+:8]([O-])=O.C(O[Na])(C)=O.O.O.O.CC(O)=O>CO.O>[NH2:8][C:7]1[CH:6]=[CH:5][C:4]([CH2:11][C:12]([O:14][CH3:15])=[O:13])=[CH:3][C:2]=1[Cl:1]
Reactant: COC(=O)Cc1ccc([N+](=O)[O-])c(Cl)c1
Agent: CC(=O)O[Na]
Solvent: CC(=O)O
Solvent: CO
Solvent: O
Product: COC(=O)Cc1ccc(N)c(Cl)c1
Temperature: 110 °C
Yield: 48.3 %

Procedure:
A mixture of methyl 3-chloro-4-nitrophenylacetate (10.9 g, 47.5 mmol), reduced iron powder (8.58 g, 153.6 mmol), AcONa.3H2O (6.05 g, 44.5 mmol) and AcOH (17.6 ml) in MeOH/H2O (100/400 ml) was heated at 110° C. for 1 h. After cooled to room temperature, the reaction mixture was filtered through Celite and the filtered cake was washed with MeOH. The combined filtrate were evaporated and extracted with EtOAc. The combined extracts were washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue was chromatographed on silica gel [150 g, CHCl3/EtOAc (10/1)] to give methyl 4-amino-3-chlorophenylacetate (4.58 g, 48%) as a red oil. 1H-NMR (CDCl3) δ3.49 (s, 2H), 3.68 (s, 3H), 4.01 (br, 2H), 6.70 (d, J=7.4 Hz, 1H), 6.96 (dd, J=8.1, 2.0 Hz, 1H), 7.17 (d, J=2.0 Hz, 1H).
Reaction SMILES: [CH:1]1([N:7]([CH2:24][CH:25]2[CH2:27][CH2:26]2)[C:8]2[N:13]=[CH:12][N:11]=[C:10]([C:14]([NH:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[CH3:23])=[O:15])[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:28][S:29](O)(=[O:31])=[O:30]>C(Cl)Cl>[CH:1]1([N:7]([CH2:24][CH:25]2[CH2:27][CH2:26]2)[C:8]2[N:13]=[CH:12][N:11]=[C:10]([C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([S:29]([Cl:28])(=[O:31])=[O:30])=[CH:19][C:18]=3[CH3:23])=[O:15])[CH:9]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: Cc1ccccc1NC(=O)c1cc(N(CC2CC2)C2CCCCC2)ncn1
Reactant: O=S(=O)(O)Cl
Solvent: ClCCl
Product: Cc1cc(S(=O)(=O)Cl)ccc1NC(=O)c1cc(N(CC2CC2)C2CCCCC2)ncn1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A cooled (−78° C.) solution of 6-[cyclohexyl(cyclopropylmethyl)amino]-N-(2-methylphenyl)pyrimidine-4-carboxamide (Intermediate 19; 2.70 g; 7.41 mmol) in DCM (27 ml) was treated dropwise with a solution of chlorosulfonic acid (2.48 ml; 37.0 mmol) in DCM (2 mL). The reaction mixture was allowed to warm to RT, then it was stirred at RT for 16 hours. The solution was cooled again (−78° C.) and treated with a second aliquot of chlorosulfonic acid (0.99 ml; 14.8 mmol) and the reaction mixture was stirred at RT for 4 h. The mixture was cooled to 5° C. and a mixture of ice/water was carefully added.
Reaction SMILES: O.[OH-].[Li+].[C:4]([O:8][C:9]([NH:11][CH2:12][CH2:13][N:14]([CH3:44])[C@@H:15]1[CH2:22][N:21]2[C:23]3[CH:24]=[C:25]([C:36]([O:38]C)=[O:37])[CH:26]=[CH:27][C:28]=3[C:29]([CH:30]3[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]3)=[C:20]2[C:19]2[CH:40]=[CH:41][CH:42]=[CH:43][C:18]=2[O:17][CH2:16]1)=[O:10])([CH3:7])([CH3:6])[CH3:5]>CO.C1COCC1.O>[C:4]([O:8][C:9]([NH:11][CH2:12][CH2:13][N:14]([CH3:44])[C@@H:15]1[CH2:22][N:21]2[C:23]3[CH:24]=[C:25]([C:36]([OH:38])=[O:37])[CH:26]=[CH:27][C:28]=3[C:29]([CH:30]3[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]3)=[C:20]2[C:19]2[CH:40]=[CH:41][CH:42]=[CH:43][C:18]=2[O:17][CH2:16]1)=[O:10])([CH3:7])([CH3:6])[CH3:5]
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)C[C@@H](N(C)CCNC(=O)OC(C)(C)C)COc1ccccc1-3
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CN(CCNC(=O)OC(C)(C)C)[C@H]1COc2ccccc2-c2c(C3CCCCC3)c3ccc(C(=O)O)cc3n2C1
Temperature: 60 °C
Yield: 98 %

Procedure:
Lithium hydroxide monohydrate (4.4 eq) was added to a solution of methyl (7R)-7-[{2-[(tert-butoxycarbonyl)amino]ethyl}(methyl)amino]-14-cyclohexyl-7,8-dihydro-6H-indolo[1,2-e][1,5]benzoxazocine-11-carboxylate (0.02 M) in MeOH/THF/H2O (1/1/1). The reaction was heated at 60° C. for 4 h prior to introducing further lithium hydroxide monohydrate (5 eq) and continuing heating for 2 h. The reaction was allowed to cool to RT, and the solvent volume reduced in vacuo. The residue was partitioned between 1N HCl (aq) and EtOAc, extracting the aqueous fraction a further two times with EtOAc. The combined organics were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo to afford the product as an off white foam (98%). (ES+) m/z 548 (M+H)+
Reaction SMILES: Br[CH2:2][CH:3]1[CH2:16][C:15]2[C:14]3[C:9](=[CH:10][CH:11]=[C:12]([O:18][CH3:19])[C:13]=3[F:17])[N:8]=[CH:7][C:6]=2[O:5][CH2:4]1.C(OC([N:27]1[CH2:32][CH2:31][CH:30]([NH2:33])[CH2:29][CH2:28]1)=O)(C)(C)C.[O:34]=[C:35]1[NH:40][C:39]2[CH:41]=[C:42]([C:45](O)=[O:46])[CH:43]=[CH:44][C:38]=2[S:37][CH2:36]1>>[F:17][C:13]1[C:12]([O:18][CH3:19])=[CH:11][CH:10]=[C:9]2[C:14]=1[C:15]1[CH2:16][CH:3]([CH2:2][N:27]3[CH2:28][CH2:29][CH:30]([NH:33][C:45]([C:42]4[CH:43]=[CH:44][C:38]5[S:37][CH2:36][C:35](=[O:34])[NH:40][C:39]=5[CH:41]=4)=[O:46])[CH2:31][CH2:32]3)[CH2:4][O:5][C:6]=1[CH:7]=[N:8]2
Reactant: O=C1CSc2ccc(C(=O)O)cc2N1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: COc1ccc2ncc3c(c2c1F)CC(CBr)CO3
Product: COc1ccc2ncc3c(c2c1F)CC(CN1CCC(NC(=O)c2ccc4c(c2)NC(=O)CS4)CC1)CO3

Procedure:
The titled compound is prepared as a white lyophilized powder following Scheme 1 and in analogy to Example 1 using 3-bromomethyl-5-fluoro-6-methoxy-3,4-dihydro-2H-1-oxa-9-aza-phenanthrene, 4-amino-piperidine-1-carboxylic acid tert-butyl ester and 3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid as starting material.
Reaction SMILES: C([Mg]Br)C.CCOCC.[CH:10]1([C:13]#[CH:14])[CH2:12][CH2:11]1.[C:15]([O:21][C@H:22]([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[C:23]([NH:25][C:26]1[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][C:27]=1[C:33](=[O:38])[C:34]([F:37])([F:36])[F:35])=[O:24])(=[O:20])[C:16]([CH3:19])([CH3:18])[CH3:17].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1>[C:15]([O:21][C@H:22]([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[C:23]([NH:25][C:26]1[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][C:27]=1[C@@:33]([OH:38])([C:14]#[C:13][CH:10]1[CH2:12][CH2:11]1)[C:34]([F:36])([F:37])[F:35])=[O:24])(=[O:20])[C:16]([CH3:19])([CH3:18])[CH3:17]
Reactant: CC(C)(C)C(=O)O[C@@H](C(=O)Nc1ccc(Cl)cc1C(=O)C(F)(F)F)c1ccccc1
Reactant: C#CC1CC1
Agent: CC[Mg]Br
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)O[C@@H](C(=O)Nc1ccc(Cl)cc1[C@@](O)(C#CC1CC1)C(F)(F)F)c1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Ethylmagnesium bromide 3 M in ether (2 mL, 6.2 mmol) was added slowly to a solution of cyclopropyl acetylene (0.41 g, 6.2 mmol) in THF (5 mL) in an ice-bath under argon. The mixture was stirred at 0° C. for 1 hour and then 40° C. for 2 hours. Then (R)-2-(4-chloro-2-(2,2,2-trifluoroacetyl)phenylamino)-2-oxo-1-phenylethyl pivalate (12, 0.55 g, 1.24 mmol) in THF (2 mL) was added slowly in an ice-bath. The mixture was stirred at 0° C. for 1.5 hours. 10% Citric acid was added to quench the reaction. The organic layer was washed with water and then evaporated to dryness to give (R)-2-(4-chloro-2-((S)-4-cyclopropyl-1,1,1-trifluoro-2-hydroxybut-3-yn-2-yl)phenylamino)-2-oxo-1-phenylethyl pivalate (13). This solid was shown to be 35.9% de by chiral HPLC. The pure product was isolated by chromatography.