Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[C:5](=O)[CH2:6][C:7](=[O:20])/[CH:8]=[CH:9]/[C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([O:17][CH3:18])[C:11]=1[F:19])[CH3:2].C([O-])(=O)C.[NH4+:27]>CCO>[CH2:1]([O:3][C:4](=[O:22])/[C:5](/[NH2:27])=[CH:6]/[C:7](=[O:20])/[CH:8]=[CH:9]/[C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([O:17][CH3:18])[C:11]=1[F:19])[CH3:2]
Reactant: CCOC(=O)C(=O)CC(=O)/C=C/c1ccc(Cl)c(OC)c1F
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: CCO
Product: CCOC(=O)/C(N)=C/C(=O)/C=C/c1ccc(Cl)c(OC)c1F
Yield: 102.2 %

Procedure:
Using the procedure of Example 4, (E)-6-(4-chloro-2-fluoro-3-methoxyphenyl)-2,4-dioxo-hex-5-enoic acid ethyl ester (5; 37.8 g, 0.115 mol) and ammonium acetate (15.4 g, 0.2 mol) were allowed to react in EtOH (200 mL) to yield (2Z,5E)-2-amino-6-(4-chloro-2-fluoro-3-methoxyphenyl)-4-oxo-hexa-2,5-dienoic acid ethyl ester (10; 38.5 g, 92%, 90% pure by 1H NMR spectroscopy) as a dark orange solid. Treatment with silica gel (50 g) followed by eluting with 40% EtOAc/hexanes (400 mL) gave a yellow solid (25.3 g, 67%): mp 103-104° C.; 1H NMR (400 MHz, CDCl3) δ 9.44 (br s, 1H), 7.63 (d, J=16.1 Hz, 1H), 7.23 (dd, J=8.6, 7.0 Hz, 1H), 7.16 (dd, J=8.6, 1.6 Hz, 1H), 6.87 (d, J=16.1 Hz, 1H), 6.15 (s, 1H), 6.04 (br s, 1H), 4.37 (q, J=7.1 Hz, 2H), 3.98 (d, J=1.2 Hz, 3H), 1.40 (t, J=7.1 Hz, 3H); HRMS-ESI (m/z): calcd for C15H15ClFNO4, 327.067. found, 327.068.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N.[CH3:21][C:22]1[CH:40]=[CH:39][C:25]([O:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])=[CH:24][CH:23]=1>C(Cl)(Cl)(Cl)Cl>[Br:1][CH2:21][C:22]1[CH:40]=[CH:39][C:25]([O:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])=[CH:24][CH:23]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)Cc1ccccc1Oc1ccc(C)cc1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)Cc1ccccc1Oc1ccc(CBr)cc1
Temperature: 25 °C
Yield: 45.3 %

Procedure:
N-Bromosuccinimide (6.64 g) and azo(bisisobutyronitrile) (400 mg) were added to a solution of compound (B) (10.1 g) in carbon tetrachloride (100 ml). The mixture was heated under reflux for 20 hours and then cooled to ambient temperature. Insoluble material was removed by filtration and the filtrate was concentrated. The residue was purified by flash chromatography eluting with ethyl acetate/hexane (1:19 v/v), to give ethyl 2-(4-bromomethylphenoxy)phenylacetate (C) (5.9 g), as an oil; NMR (d6 -DMSO): 1.15(t, 3H), 4.1(q, 2H), 4.65(s, 2H), 6.0(s, 1H), 6.95(d, 2H), 7.3-7.5(m, 5H), 7.5-7.6(m, 2H).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[S:14][C:13]2[C:8](=[N:9][CH:10]=C[C:12]=2[O:15][C:16]2[CH:21]=[CH:20][C:19]([NH:22]C(NC(=O)CC3C=CC=CC=3)=S)=[CH:18][C:17]=2[F:35])[CH:7]=1.CCCCCCCCCCCC[NH2:48]>>[F:35][C:17]1[CH:18]=[C:19]([NH2:22])[CH:20]=[CH:21][C:16]=1[O:15][C:12]1[C:13]2[S:14][C:6]([C:2]3[S:1][CH:5]=[CH:4][N:3]=3)=[CH:7][C:8]=2[N:9]=[CH:10][N:48]=1
Reactant: O=C(Cc1ccccc1)NC(=S)Nc1ccc(Oc2ccnc3cc(-c4nccs4)sc23)c(F)c1
Reactant: CCCCCCCCCCCCN
Product: Nc1ccc(Oc2ncnc3cc(-c4nccs4)sc23)c(F)c1
Yield: 7 %

Procedure:
Starting from the nitro compound 150, following the procedure described above for the synthesis of compound 13a (via the intermediate amine 12, scheme 2, example 12), title compound 152a was obtained [via intermediate 3-fluoro-4-(6-(thiazol-2-yl)thieno[3,2-d]pyrimidin-4-yloxy)benzenamine (151)] in 7% yield. Characterization of 152a is provided in the Table 14.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:11][CH:12]=[CH:13][C:14]2[CH:15]=[CH:16][C:17]([O:23][CH2:24][O:25][CH3:26])=[C:18]([N+:20]([O-])=O)[CH:19]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[H][H]>C(OCC)(=O)C.[C].[Pd]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([CH2:11][CH2:12][CH2:13][C:14]2[CH:15]=[CH:16][C:17]([O:23][CH2:24][O:25][CH3:26])=[C:18]([CH:19]=2)[NH2:20])(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: [H][H]
Reactant: COCOc1ccc(C=CCS(=O)(=O)c2ccc(Cl)cc2)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COCOc1ccc(CCCS(=O)(=O)c2ccc(Cl)cc2)cc1N
Yield: 78.9 %

Procedure:
Under one atmosphere, a solution of 300 mg of 5-[3-(4-chlorophenylsulfonyl)-1-propenyl]-2-methoxymethoxy nitrobenzene in 8 ml of ethyl acetate and 500 mg of 10% palladium carbon added thereto were stirred in the presence of hydrogen gas. The resultant reaction mixture was filtered and then concentrated under a vacuum, to produce 220 mg of 5-[3-(4-chlorobenzenesulfonyl)propyl]-2-methoxymethoxy aniline in the form of a colorless oily substance. The yield was 73%. This product was put to use in its unpurified form in the following reaction.
Reaction SMILES: [Cl:1][C:2]1[C:3](F)=[CH:4][C:5]([F:22])=[C:6]([S:8]([N:11](COCC)[C:12]2[CH:17]=[CH:16][N:15]=[CH:14][N:13]=2)(=[O:10])=[O:9])[CH:7]=1.ClC1C(F)=CC(F)=C(S(/N=C2/N=CN(COCC)C=C/2)(=O)=O)C=1.[Cl:47][C:48]1[CH:53]=[CH:52][C:51]([OH:54])=[C:50]([C:55]2[N:59]([CH3:60])[N:58]=[CH:57][CH:56]=2)[CH:49]=1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.C(OCC)(=O)C>[Cl:1][C:2]1[C:3]([O:54][C:51]2[CH:52]=[CH:53][C:48]([Cl:47])=[CH:49][C:50]=2[C:55]2[N:59]([CH3:60])[N:58]=[CH:57][CH:56]=2)=[CH:4][C:5]([F:22])=[C:6]([S:8]([NH:11][C:12]2[CH:17]=[CH:16][N:15]=[CH:14][N:13]=2)(=[O:9])=[O:10])[CH:7]=1
Reactant: Cn1nccc1-c1cc(Cl)ccc1O
Reactant: CCOCN(c1ccncn1)S(=O)(=O)c1cc(Cl)c(F)cc1F
Agent: CCOCn1cc/c(=N\S(=O)(=O)c2cc(Cl)c(F)cc2F)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: Cn1nccc1-c1cc(Cl)ccc1Oc1cc(F)c(S(=O)(=O)Nc2ccncn2)cc1Cl
Temperature: 25 °C
Reaction time: 19 h
Yield: 27 %

Procedure:
A suspension of 5-chloro-N-(ethoxymethyl)-2,4-difluoro-N-pyrimidin-4-ylbenzenesulfonamide and 5-chloro-N-[(4E)-1-(ethoxymethyl)pyrimidin-4(1H)-ylidene]-2,4-difluorobenzenesulfonamide and 5-chloro-N-[(4E)-1-(ethoxymethyl)pyrimidin-4(1H)-ylidene]-2,4-difluorobenzenesulfonamide (Preparation 719) used as a mixture of three regioisomers, (64 mg, 0.18 mmol), 4-chloro-2-(1-methyl-1H-pyrazol-5-yl)phenol (Preparation 89) (37 mg, 0.18 mmol) and potassium carbonate (37 mg, 0.26 mmol) in dimethyl sulfoxide (1 mL) was stirred at room temperature for 19 hours then diluted with ethyl acetate (30 mL), washed with 1M aqueous sodium hydroxide, water, saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was taken up in trifluoroacetic acid (1 mL) and stirred for 3 hours then concentrated in vacuo. The residue was purified by reverse phase HPLC to give 29 mg (27%) of the desired product as a white solid.
Reaction SMILES: [C:1]([CH:5]1[CH2:10][CH2:9][C:8](=[CH:11][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH:18]=[C:17]([CH2:22][N:23]2[CH2:28][CH2:27][CH:26]([C:29]([O:31]CC)=[O:30])[CH2:25][CH2:24]2)[CH:16]=[CH:15]3)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].O.Cl>CO>[C:1]([CH:5]1[CH2:10][CH2:9][C:8](=[CH:11][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH:18]=[C:17]([CH2:22][N:23]2[CH2:24][CH2:25][CH:26]([C:29]([OH:31])=[O:30])[CH2:27][CH2:28]2)[CH:16]=[CH:15]3)[CH2:7][CH2:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)C1CCN(Cc2ccc3cc(C=C4CCC(C(C)(C)C)CC4)ccc3c2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)(C)C1CCC(=Cc2ccc3cc(CN4CCC(C(=O)O)CC4)ccc3c2)CC1
Temperature: 80 °C
Reaction time: 4 h
Yield: 75.8 %

Procedure:
To a solution of ethyl 1-((6-((4-tert-butylcyclohexylidene)methyl)naphthalen-2-yl)methyl)piperidine-4-carboxylate (50 mg, 0.11 mmol) in MeOH (3 mL) was added NaOH (22 mg, 0.55 mmol, 5.0 eq) and H2O (0.5 mL). The reaction mixture was stirred at 80° C. for 4 h. The pH of the solution was adjusted to 6 with 3 N HCl. The mixture was filtered and the yellow solid was the desired product 1-((6-((4-tert-butylcyclohexylidene)methyl)naphthalen-2-yl)methyl)piperidine-4-carboxylic acid (35 mg, yield: 81%). ESI-MS (M+1)+: 420.1. 1HNMR (400 MHz, CD3OD) δ: 7.86 (s, 1H), 7.83˜7.80 (m, 1H), 7.77-7.74 (m, 1H), 7.60 (br, 1H), 7.43 (d, J=8.4 Hz, 1H), 7.35˜7.32 (m, 1H), 6.30 (s, 1H), 4.29 (s, 2H), 3.33 (br, 2H), 2.97-2.94 (m, 3H), 2.42-2.38 (m, 2H), 2.20-2.03 (m, 1H), 2.03-2.00 (m, 2H), 1.89-1.80 (m, 5H), 1.22-1.12 (m, 3H), 0.80 (s, 9H). HPLC: 100%.
Reaction SMILES: [CH2:1]1[S:5][C@@H:4]([CH2:6][OH:7])[O:3][C@H:2]1[N:8]1[C:13](=[O:14])[N:12]=[C:11]([NH2:15])[C:10]([F:16])=[CH:9]1.CC#N.C([O-])(=O)CCC.C[O-].[Na+]>CO>[CH2:1]1[S:5][C@H:4]([CH2:6][OH:7])[O:3][C@@H:2]1[N:8]1[C:13](=[O:14])[N:12]=[C:11]([NH2:15])[C:10]([F:16])=[CH:9]1
Reactant: Nc1nc(=O)n([C@H]2CS[C@@H](CO)O2)cc1F
Agent: CCCC(=O)[O-]
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CC#N
Product: Nc1nc(=O)n([C@@H]2CS[C@H](CO)O2)cc1F
Reaction time: 20 h
Yield: 82 %

Procedure:
The 5'-O-butyrate of (+)-FTC (0.47 mmol, 149 mg) was dissolved in 16 mL of a solution of 4:1 pH 8 buffer:CH3CN. The clear solution was stirred and treated with 26 mg of pig liver esterase (PLE-A). The progress of the reaction was monitored by HPLC (FIG. 4). After 20 hours (52% conversion), the reaction mixture was extracted with 2×80 mL of CHCl3 and 80 mL of ethyl acetate. The organic layer extracts were combined, dried over anhydrous MgSO4, filtered, and concentrated by rotary evaporation. The resulting residue was eluted on 2×1000 m pTLC plates using ethyl acetate as eluant (double elution) to give, after isolation, 53 mg (36% based on starting material) of FTC butyrate which was determined to have 98% enantiomeric excess (e.e.) by HPLC analysis. The enantiomerically-enriched butyrate was then treated with 1.6 mL of methanol followed by 0.38 mmol (20 mg) of sodium methoxide. The resulting mixture was stirred at room temperature, and the progress of the reaction was monitored by HPLC. The reaction was completed within 30 minutes. The solvent was removed by rotary evaporation to give a crude white solid (76 mg) that was eluted on a 1000 m pTLC using 5:1 ethyl acetate:ethanol. (-)-FTC was isolated as a white solid (33 mg; 82% yield). HPLC analysis of the FTC as its 5'-O-acetate derivative showed 97% e.e.; [α](20,D) -120.5° (c=0.88; abs. ethanol).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH3:9])[CH:5]=[C:6]([OH:8])[CH:7]=1.[C:10]([O-])([O-])=O.[K+].[K+].CI>CC(C)=O>[CH3:9][C:4]1[CH:5]=[C:6]([O:8][CH3:10])[CH:7]=[C:2]([OH:1])[CH:3]=1
Reactant: Cc1cc(O)cc(O)c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: COc1cc(C)cc(O)c1
Yield: 80 %

Procedure:
1 mmol of 3,5-Dihydroxy-toluene was taken in 3 mL of acetone, and then 3 mmol of K2CO3 was added and stirred for several minutes. Then, a solution of CH3I (3 mmol) in 10 ml of acetone was added from a pressure-equalizing dropping funnel, and the reaction was monitored by TLC. Upon completion, the reaction mixture was filtered to remove K2CO3, and evaporated by a rotatory evaporator to remove acetone. The mixture was then purified by column chromatography to give 5-methyl-3-methoxy-phenol (80%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16](S(C)=O)[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:30]=[CH:31][C:32]=3[CH3:33])[C:22]([NH:24][C:25]3[S:26][CH:27]=[CH:28][N:29]=3)=[O:23])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:37].[CH3:38][N:39]([CH3:45])[CH2:40][CH2:41][CH2:42][NH:43][CH3:44]>>[F:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([N:43]([CH2:42][CH2:41][CH2:40][N:39]([CH3:45])[CH3:38])[CH3:44])[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:30]=[CH:31][C:32]=3[CH3:33])[C:22]([NH:24][C:25]3[S:26][CH:27]=[CH:28][N:29]=3)=[O:23])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:37]
Reactant: CNCCCN(C)C
Reactant: Cc1ccc(C(=O)Nc2nccs2)cc1-c1nc(S(C)=O)nc2c1ccc(=O)n2-c1c(F)cccc1F
Product: Cc1ccc(C(=O)Nc2nccs2)cc1-c1nc(N(C)CCCN(C)C)nc2c1ccc(=O)n2-c1c(F)cccc1F

Procedure:
The title compound was prepared from 3-[8-(2,6-difluorophenyl)-2-(methylsulfinyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl]-4-methyl-N-1,3-thiazol-2-ylbenzamide and N,N,N′-trimethyl-1,3-propanediamine by following the procedures in Example 79c. LC-MS m/z 590 (M+H)+; 1H-NMR (MeOD) 1.70 (m, 2 H), 2.04 (m, 2 H), 2.20 (s, 6 H), 2.36 (s, 3 H), 2.89-3.21 (m, 3 H), 3.36-3.70 (m, 2 H), 6.36 (d, J=8.4 Hz, 1 H), 7.16 (m, 1 H), 7.27 (m, 2 H), 7.50 (m, 2 H), 7.59 (m, 2 H), 8.01 (s, 1 H), 8.13 (m, 1 H).
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[CH:2]=[CH2:3].C(N(CC)CC)C.[CH3:14][C:15]([C:18]1[CH:23]=[C:22]([SH:24])[CH:21]=[C:20]([C:25]([CH3:28])([CH3:27])[CH3:26])[C:19]=1[OH:29])([CH3:17])[CH3:16]>C(#N)C>[CH3:28][C:25]([C:20]1[CH:21]=[C:22]([S:24][CH2:3][CH2:2][C:1]([O:5][CH3:6])=[O:4])[CH:23]=[C:18]([C:15]([CH3:17])([CH3:16])[CH3:14])[C:19]=1[OH:29])([CH3:26])[CH3:27]
Reactant: CC(C)(C)c1cc(S)cc(C(C)(C)C)c1O
Reactant: C=CC(=O)OC
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COC(=O)CCSc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Reaction time: 1.5 h

Procedure:
Methyl acrylate (1.1 g, 12.6 mmol) and triethylamine (0.5 mL, 0.4 mmol) are sequentially added to a room temperature solution of 2,6-bis(1,1-dimethylethyl)-4-mercaptophenol (3.0 g, 12.6 mmol) in acetonitrile (6 mL). The reaction is stirred for 1.5 hours and then evaporated under high vacuum to give 3.7 g (90%) of the crude product. A small portion is chromatographed on a silica column with ethyl acetate/hexane (1/9) to afford an analytically pure sample of methyl 3-[[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]thio]propanoate, mp 64.0°-66.0° C.
Reaction SMILES: [C:1]([CH:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:19]=[CH:18][C:14]([CH:15]=[N:16]O)=[CH:13][C:12]=2[N:20]2[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][CH2:28][CH3:29])[CH2:22][CH2:21]2)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].C1(S(Cl)(=O)=O)C=CC=CC=1.N1C=CC=CC=1>O1CCCC1>[C:1]([CH:5]1[CH2:6][CH2:7][CH:8]([C:11]2[CH:19]=[CH:18][C:14]([C:15]#[N:16])=[CH:13][C:12]=2[N:20]2[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][CH2:28][CH3:29])[CH2:22][CH2:21]2)[CH2:9][CH2:10]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCCN1CCN(c2cc(C=NO)ccc2C2CCC(C(C)(C)C)CC2)CC1
Agent: O=S(=O)(Cl)c1ccccc1
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CCCCN1CCN(c2cc(C#N)ccc2C2CCC(C(C)(C)C)CC2)CC1
Yield: 74.7 %

Procedure:
A mixture of the crude product of 4-(4-t-butylcyclohexyl)-3-(4-butylpiperazin-1-yl)benzaldehydeoxime produced in Example (101c) (269 mg), benzenesulfonyl chloride (0,11 mL, 0.862 mmol), pyridine (0.11 ml, 1.36 mmol) and tetrahydrofuran (15 mL) was refluxed for 4 hours and 30 minutes. After then distilling off tetrahydrofuran partially in the reaction mixture under reduced pressure, chloroform was added and the mixture was further refluxed for 1 hour. The reaction mixture was concentrated under reduced pressure, the obtained residue was poured into ice water, and then ethyl acetate and saturated aqueous solution of ammonium chloride were added and extraction was performed with ethyl acetate. The separated organic layer was washed twice with saturated aqueous ammonium chloride and once with brine, and then dried over anhydrous sodium sulfate. The desiccant was filtered off, and the filtrate was concentrated under reduced pressure to give a residue, which was purified by NH silica gel column chromatography (ethyl acetate/hexane, followed by ethyl acetate/methanol), to give 192 mg of the title compound as an ochre oil.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:8]=[CH:7][C:6](/[CH:9]=[CH:10]/[C:11](OCC)=[O:12])=[CH:5][CH:4]=1.[H-].C([Al+]CC(C)C)C(C)C>CCOCC.CCCCCC>[F:1][C:2]([F:16])([F:17])[C:3]1[CH:4]=[CH:5][C:6](/[CH:9]=[CH:10]/[CH2:11][OH:12])=[CH:7][CH:8]=1
Reactant: CCOC(=O)/C=C/c1ccc(C(F)(F)F)cc1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: CCCCCC
Solvent: CCOCC
Product: OC/C=C/c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 74.2 %

Procedure:
(E)-Ethyl 3-(4-(trifluoromethyl)phenyl)acrylate (25.00 g, 102 mmol) in 100 mL ether was cooled in an ice-water bath. To this solution, di-iso-butylaluminum hydride (205 mL, 205 mmol) in hexane was added. After addition, the ice-water bath was removed. After 2 hours of stirring at room temperature, the reaction mixture was diluted with 200 mL diethyl ether, cooled to 0° C. and quenched with careful addition of 200 mL brine and 200 mL of 5.0 M HCl. The aqueous solution was extracted twice with diethyl ether (200 mL each time). The combined organic phases were washed with brine and dried over sodium sulfate. The product was chromatographed eluting with 20% EtOAc in hexane. After removing the solvent, a white solid was obtained as the desired product (15.3 g, yield=74%). 1H NMR (400 MHz, CD3OD) δ ppm 4.28 (dd, J=5.28, 1.57 Hz, 2H) 6.55 (dt, J=15.94, 5.23 Hz, 1H) 6.67-6.75 (m, 1H) 7.58-7.67 (m, 4H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([I:13])[C:11]=1[OH:12])[C:5]([O:7][CH3:8])=[O:6].C(=O)(O)[O-].[Na+].Cl[CH2:20][C:21](Cl)=[O:22]>CC(CC(C)C)=O.O>[I:13][C:10]1[C:11]2[O:12][CH2:20][C:21](=[O:22])[NH:1][C:2]=2[CH:3]=[C:4]([C:5]([O:7][CH3:8])=[O:6])[CH:9]=1
Reactant: COC(=O)c1cc(N)c(O)c(I)c1
Reactant: O=C(Cl)CCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)CC(C)C
Product: COC(=O)c1cc(I)c2c(c1)NC(=O)CO2
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.8 %

Procedure:
To an ice-cold, stirred solution of Methyl 3-amino-4-hydroxy-5-iodobenzoate (2.3 g) and sodium bicarbonate (1.5 g) in 1:1 isobutyl methyl ketone/water (80 mL) was added chloroacetyl chloride (1.1 g), and the reaction mixture was stirred for 1 h. The mixture was warmed to room temperature and heated at reflux for 18 h. After overnight, a beige solid formed. The mixture was filtered, and washed with water and hexanes to give 2.4 g of the title compound: 1H NMR (300 MHz, DMSO-d6) δ 10.98, 7.89, 7.47, 4.79, 3.82.
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]3([CH2:14][CH2:13]3)[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[NH2:64][N:65]1[CH2:70][CH2:69][O:68][CH2:67][CH2:66]1>C(Cl)Cl>[CH:1]1([N:6]2[CH2:12][C:11]3([CH2:14][CH2:13]3)[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([NH:64][N:65]5[CH2:70][CH2:69][O:68][CH2:67][CH2:66]5)=[O:27])=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: NN1CCOCC1
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC1(CC1)C(=O)N2C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C(=O)NN2CCOCC2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC1(CC1)C(=O)N2C
Temperature: 25 °C
Reaction time: 16 h
Yield: 45.3 %

Procedure:
4-(9′-Cyclopentyl-5′-methyl-6′-oxo-5′,6′,8′,9′-tetrahydrospiro[cyclopropane-1,7′-pyrimido[4,5-b][1,4]diazepine]-2′-ylamino)-3-methoxybenzoic acid (Intermediate 5) (50 mg, 0.11 mmol, 1 eq), DIPEA (38 μL, 0.23 mmol, 2 eq) and TBTU (40 mg, 0.12 mmol, 1.1 eq) were added to 5 mL DCM and the resulting solution stirred at rt for 15 min before the addition of 4-aminomorpholine (12 mg, 0.14 mmol, 1.2 eq). The RM was then stirred at rt for 16 hours before concentrating in vacuo and purifying by preparative RP-HPLC-MS (Preparative—1) to provide 4-(9′-cyclopentyl-5′-methyl-6′-oxo-5′,6′,8′,9′-tetrahydrospiro[cyclopropane-1,7′-pyrimido[4,5-b][1,4]diazepine]-2′-ylamino)-3-methoxy-N-morpholinobenzamide (26 mg, 44%).
Reaction SMILES: C(OC(N([CH2:16][C:17]1[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:18]=1[Br:24])C(OC(C)(C)C)=O)=O)(C)(C)C.[Br:25]C1C=CC(Cl)=CC=1C.C1C(=O)N(Br)C(=O)C1>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:24][C:18]1[CH:19]=[CH:20][C:21]([Cl:23])=[CH:22][C:17]=1[CH2:16][Br:25]
Reactant: CC(C)(C)OC(=O)N(Cc1cc(Cl)ccc1Br)C(=O)OC(C)(C)C
Reactant: Cc1cc(Cl)ccc1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Agent: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: Clc1ccc(Br)c(CBr)c1
Temperature: 80 °C

Procedure:
N,N-bis(tert-butoxycarbonyl)-2-bromo-5-chlorobenzylamine: To 1-bromo-4-chloro-2-methylbenzene (3.3 g, 16.06 mmol) in CCl4 (30 mL) were added NBS (3.43 g, 19.27 mmol) and benzoyl peroxide (10 mg, 0.041 mmol). The reaction was heated 80° C. overnight, then filtered and purified by flash chromatography to give 1-bromo-2-bromomethyl-4-chloro-benzene (4.5 g). 1HNMR (400 MHz, CDCl3) δ: 4.53 (s, 2 H) 7.15 (dd, J=8.59, 2.27 Hz, 1 H), 7.40-7.47 (m, 1 H), 7.49 (d, J=8.59 Hz, 1 H). This intermediate was combined with di-tert-butyl imidodicarbonate (3.49 g, 16.06 mmol) and cesium carbonate (5.23 g, 16.06 mmol) in DMF (16 mL) and stirred overnight. The reaction was partitioned with EtOAc/water and extracted with EtOAc. The combined organic layers were washed with water and brine, dried (MgSO4), and evaporated. The resulting residue was purified by flash chromatography to give 126A (3.4 g). 1HNMR (400 MHz, CDCl3) δ: 1.43-1.51 (m, 18 H), 4.82 (s, 2 H), 7.08-7.18 (m, 1 H), 7.39-7.53 (m, 2 H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:36])[CH:4]([NH:25]C(OCC1C=CC=CC=1)=O)[CH2:5][C:6]1[CH:14]=[C:13]([CH3:15])[C:12]2[C:8](=[CH:9][N:10]([S:16]([CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])(=[O:18])=[O:17])[N:11]=2)[CH:7]=1.[H][H]>[Pd].CO>[CH3:1][O:2][C:3](=[O:36])[C@H:4]([NH2:25])[CH2:5][C:6]1[CH:14]=[C:13]([CH3:15])[C:12]2[C:8](=[CH:9][N:10]([S:16]([CH2:19][CH2:20][Si:21]([CH3:22])([CH3:24])[CH3:23])(=[O:17])=[O:18])[N:11]=2)[CH:7]=1
Reactant: [H][H]
Reactant: COC(=O)C(Cc1cc(C)c2nn(S(=O)(=O)CC[Si](C)(C)C)cc2c1)NC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: COC(=O)[C@H](N)Cc1cc(C)c2nn(S(=O)(=O)CC[Si](C)(C)C)cc2c1
Yield: 100 %

Procedure:
2-Benzyloxycarbonylamino-3-[7-methyl-2-(2-trimethylsilanyl-ethanesulfonyl)-2H-indazol-5-yl]-propionic acid methyl ester, (1.35 g, 2.54 mmol) and 10% palladium on carbon (135 mg) in methanol (40 mL) were agitated for 3.0 h under 55 psi hydrogen using a Parr apparatus. The reaction mixture was purged with 3 vacuum/nitrogen purge cycles. The reaction mixture was then filtered through a pad of celite and the pad was rinsed with several portions of methanol. The methanol filtrate was evaporated to give the title compound (1.01 g, quantitative yield) as a sticky gum. 1H-NMR (CDCl3, 300 MHz) δ 8.45 (s, 1H), 7.29 (s, 1H), 6.97 (s, 1H), 3.79-3.73 (m, 1H), 3.73 (s, 3H), 3.56-3.50 (m, 2H), 5.12 (dd, J=13.5, 5.12 Hz, 1H), 4.85 (dd, J=13.5, 8.1 Hz, 1H), 2.58 (s, 3H), 0.87-0.81 (m, 2H), 0.01 (s, 9H). 13C-NMR (CDCl3, 75 MHz) δ 175.5, 151.8, 133.7, 129.9, 129.4, 125.0, 121.3, 117.9, 55.5, 52.1, 51.1, 41.4, 17.1, 9.8, −2.1. Mass spec.: 398 (MH)+.
Reaction SMILES: [C:1]([NH:9][C:10]1[S:11][CH2:12][CH:13]2[CH2:18][N:17]([C:19]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[O:20])[CH2:16][C:14]2([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[N:15]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO.C(#N)C.CN(C)CC>C(=O)=O>[C:1]([NH:9][C:10]1[S:11][CH2:12][C@@H:13]2[CH2:18][N:17]([C:19]([O:21][CH2:22][C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)=[O:20])[CH2:16][C@:14]2([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[N:15]=1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(NC1=NC2(c3ccccc3)CN(C(=O)OCc3ccccc3)CC2CS1)c1ccccc1
Agent: CCN(C)C
Agent: O=C=O
Solvent: CO
Solvent: CC#N
Product: O=C(NC1=N[C@@]2(c3ccccc3)CN(C(=O)OCc3ccccc3)C[C@H]2CS1)c1ccccc1
Yield: 37.4 %

Procedure:
Racemic benzyl 2-benzamido-7a-phenyl-4,4a,5,7-tetrahydropyrrolo[3,4-d][1,3]thiazine-6-carboxylate (30 g, 63 mmol) is chirally purified by SFC: (Column: Chiralpak IC 2.1×25 cm; eluent: 40% methanol/acetonitrile (8/2) with 0.2% dimethylethyl amine in CO2; flow: 70 mL/min at UV 284 nm). The second eluting isomer is the title compound (11.1 g, 37%, >98% ee). Chiral analysis of the isolated isomer 2: Chiralpak IC 0.46×10 cm, 5 μm; eluent: 40% methanol/acetonitrile (8/2) with 0.2% dimethyl ethyl amine in CO2; flow: 5 mL/min at UV 215 nm. Rt=3.2 minutes. [α]D20=−88 (C=1.0, methanol), ES/MS (m/e) 372 (M+H)