Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]1[C@H:8]([CH3:9])[CH2:7][N:6]([C:10]([N:12]2[CH2:19][C:18]3[C:17]([NH2:20])=[N:16][NH:15][C:14]=3[C:13]2([CH3:22])[CH3:21])=[O:11])[C@@H:5]([CH3:23])[CH2:4]1)[CH3:2].Cl[C:25]1[C:30]([F:31])=[CH:29][N:28]=[C:27]([O:32][CH3:33])[N:26]=1>C(O)(=O)C.O>[CH2:1]([N:3]1[C@H:8]([CH3:9])[CH2:7][N:6]([C:10]([N:12]2[CH2:19][C:18]3[C:17]([NH:20][C:25]4[C:30]([F:31])=[CH:29][N:28]=[C:27]([O:32][CH3:33])[N:26]=4)=[N:16][NH:15][C:14]=3[C:13]2([CH3:22])[CH3:21])=[O:11])[C@@H:5]([CH3:23])[CH2:4]1)[CH3:2]
Reactant: COc1ncc(F)c(Cl)n1
Reactant: CCN1C[C@H](C)N(C(=O)N2Cc3c(N)n[nH]c3C2(C)C)C[C@H]1C
Solvent: CC(=O)O
Solvent: O
Product: CCN1C[C@H](C)N(C(=O)N2Cc3c(Nc4nc(OC)ncc4F)n[nH]c3C2(C)C)C[C@H]1C

Procedure:
A solution of 5-{[(2S,5R)-4-ethyl-2,5-dimethylpiperazin-1-yl]carbonyl}-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-amine (289 mg, 0.9 mmol) and 4-chloro-5-fluoro-2-methoxypyrimidine (257 mg, 2 eq) in 5 mL of 50% acetic acid in water was heated in a microwave for 30 min at 80° C. Purification as described in Example A1 afforded the title compound AA1 as a white powder (13.1 mg, 3%). See Table 1 below for NMR data.
Reaction SMILES: [NH2:1][C:2]1[C:7]([S:8](Cl)(=[O:10])=[O:9])=[CH:6][C:5]([Br:12])=[CH:4][N:3]=1.[C:13]([NH2:17])([CH3:16])([CH3:15])[CH3:14]>C1COCC1>[NH2:1][C:2]1[C:7]([S:8]([NH:17][C:13]([CH3:16])([CH3:15])[CH3:14])(=[O:10])=[O:9])=[CH:6][C:5]([Br:12])=[CH:4][N:3]=1
Reactant: CC(C)(C)N
Reactant: Nc1ncc(Br)cc1S(=O)(=O)Cl
Solvent: C1CCOC1
Product: CC(C)(C)NS(=O)(=O)c1cc(Br)cnc1N
Temperature: 25 °C
Reaction time: 2 h
Yield: 49.6 %

Procedure:
2-amino-5-bromopyridine-3-sulfonyl chloride (15 g, 55 mmol) was dissolved in THF (125 mL) and at 0° C. t-butylamine (6.5 g, 111 mmol) was added and the reaction mixture was stirred at RT for 2 h. The reaction mixture was concentrated under reduced pressure to yield 2-amino-5-bromo-N-tert-butylpyridine-3-sulfonamide (8.4 g, 49%), which was used without further purification. LCMS Method Y: retention time 1.70 min, [M−1]=306.0.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1)([CH3:3])[CH3:2].[C:16]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:17]([CH:22]=O)=[CH:18][CH:19]=[CH:20][CH:21]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C1(C2C=CC=CC=2)C=CC=CC=1CN1CCN(C2C=CC=CC=2)CC1>>[C:16]1([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[CH2:22][N:13]1[CH2:12][CH2:11][N:10]([C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:1]([CH3:3])[CH3:2])[CH2:15][CH2:14]1
Reactant: O=Cc1ccccc1-c1ccccc1
Reactant: CC(C)c1ccccc1N1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: c1ccc(-c2ccccc2CN2CCN(c3ccccc3)CC2)cc1
Product: CC(C)c1ccccc1N1CCN(Cc2ccccc2-c2ccccc2)CC1

Procedure:
100 mg of the target compound (0.27 mmol, 49.1%) was obtained using 1-(2-isopropylphenyl)piperazine (223 mg, 1.09 mmol), biphenyl-2-carbaldehyde (100 mg, 0.55 mmol) and NaBH(OAc)3 (355 mg, 1.65 mmol) according to the synthesis method of Compound 1.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:26][CH2:25][C@@:24]2([CH3:27])[C@H:4]([CH2:5][CH2:6][C@@H:7]3[C:23]2=[CH:22][C:21](=[O:28])[C@@:20]2([CH3:29])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C@H:12]([CH3:19])[CH2:13][CH2:14][C:15]([O:17][CH3:18])=[O:16])[CH2:3]1.[CH3:30][CH2:31][O:32]C(C)=O>[Pd]>[C:31]([O:1][C@@H:2]1[CH2:26][CH2:25][C@@:24]2([CH3:27])[C@H:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:23]2[CH2:22][C:21](=[O:28])[C@@:20]2([CH3:29])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C@H:12]([CH3:19])[CH2:13][CH2:14][C:15]([O:17][CH3:18])=[O:16])[CH2:3]1)(=[O:32])[CH3:30]
Reactant: COC(=O)CC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC[C@@H]4C[C@H](O)CC[C@]4(C)C3=CC(=O)[C@]12C
Reactant: CCOC(C)=O
Agent: [Pd]
Product: COC(=O)CC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC[C@@H]4C[C@H](OC(C)=O)CC[C@]4(C)[C@H]3CC(=O)[C@]12C
Reaction time: 16 h
Yield: 80 %

Procedure:
10% Pd/C (900 mg) was added to a solution of compound 1.9a (2.0 g, 4.5 mmol) in EtOAc (150 mL) and the resulting slurry was hydrogenated in a Parr apparatus (50 psi) at 50° C. for 16 h. At this point the reaction was determined to be complete by TLC. The mixture was filtered through a small plug of Celite® and the solvent was removed under vacuum, providing compound 2.0a (1.6 g, 80% yield) as a white solid.
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:7])[C:4]#[C:5][CH3:6].Cl[C:9]1[CH:14]=[C:13]([N:15]([CH2:24][C:25]#[N:26])[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[C:17]=2[F:23])[N:12]=[CH:11][N:10]=1.[Cl-].[NH4+]>O1CCCC1>[CH2:3]([O:7][C:9]1[CH:14]=[C:13]([N:15]([CH2:24][C:25]#[N:26])[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[C:17]=2[F:23])[N:12]=[CH:11][N:10]=1)[C:4]#[C:5][CH3:6]
Reactant: N#CCN(c1cc(Cl)ncn1)c1cccc(F)c1F
Reactant: CC#CCO
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC#CCOc1cc(N(CC#N)c2cccc(F)c2F)ncn1
Temperature: 25 °C
Yield: 81.9 %

Procedure:
In 2 ml of tetrahydrofuran was suspended 0.05 g of sodium hydride (60% in oil), to which 0.6 ml of a tetrahydrofuran solution containing 0.07 g of 2-butyn-1-ol was slowly added dropwise with stirring at room temperature. The mixture was stirred at room temperature for 20 minutes, to which 0.6 ml of a tetrahydrofuran solution containing 0.24 g of 4-chloro-6-(N-cyanomethyl-N-(2,3-difluorophenyl)amino)pyrimidine was slowly added dropwise, followed by stirring at room temperature for 4 hours. The reaction mixture was then poured into a saturated aqueous ammonium chloride solution and extracted three times with chloroform. The chloroform layers were combined, washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated. The residue was subjected to silica gel column chromatography to give 0.22 g of 4-(2-butynyloxy)-6-(N-cyanomethyl-N-(2,3-difluorophenyl)amino)pyrimidine (the present compound (85)).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[S:10][CH:9]([C:11]([F:14])([F:13])[F:12])[C:8]([C:15]([O:17]CC)=[O:16])=[CH:7][C:6]=2[CH:20]=1.[OH-].[Na+]>C1COCC1.C(O)C>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[S:10][CH:9]([C:11]([F:13])([F:14])[F:12])[C:8]([C:15]([OH:17])=[O:16])=[CH:7][C:6]=2[CH:20]=1
Reactant: CCOC(=O)C1=Cc2cc(C)ccc2SC1C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1ccc2c(c1)C=C(C(=O)O)C(C(F)(F)F)S2
Temperature: 25 °C
Reaction time: 88 h
Yield: 28.4 %

Procedure:
The ester from Step 2 (0.55 g 1.8 mmol) was dissolved in THF (1.5 mL) and ethanol (1.5 mL), treated with 2.5 N sodium hydroxide (1.5 mL, 3.8 mmol), and stirred at room temperature for 88 hours. The reaction mixture was concentrated in vacuo, acidified with 3 N HCl, filtered, and recrystallized from diethyl ether/petroleum ether to yield the title compound as a yellow solid (0.14 g, 28%): mp 180.8-184.2° C. 1H NMR (acetone-d6/300 MHz) 7.95 (s, 1H), 7.42 (s, 1H), 7.31 (d, 1H, J=8.1 Hz), 7.25 (d, 1H, J=8.1 Hz), 4.94 (q, 1H, J=8.7 Hz), 2.34 (s, 3H). FABLRMS m/z 281 (M+Li). EIHRMS m/z 274.0250 (M+, Calc'd 274.0275). Anal. Calc'd for C12H9F3O2S: C, 52.55; H, 3.31. Found: C, 52.54; F;, 3.35.
Reaction SMILES: F[C:2]1[C:10]2[S:9][C:8]([I:11])=[N:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.FC1C(F)=CC=CC=1N.[Br:21]C1C(Br)=CC=CC=1N>>[Br:21][C:2]1[C:10]2[S:9][C:8]([I:11])=[N:7][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: Nc1cccc(Br)c1Br
Reactant: Fc1cccc2nc(I)sc12
Agent: Nc1cccc(F)c1F
Product: Brc1cccc2nc(I)sc12

Procedure:
The title compound was prepared following the route for 7-fluoro-2-iodo-1,3-benzothiazole from 2,3-difluoroaniline, starting from 2,3-dibromoaniline (prepared according to J. Org. Chem. 1990, 55(9), 2739) and conducting the first step at 95° C. for 4 h.
Reaction SMILES: [Cl:1][C:2]1[C:11]([CH2:12][C:13]2[CH:18]=[CH:17][C:16](SC)=[CH:15][CH:14]=2)=[C:10]([Cl:21])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:22]([C:30]3[C:31]([CH3:37])=[N:32][C:33]([CH3:36])=[CH:34][CH:35]=3)([C:24]3[N:28]([CH3:29])[N:27]=[N:26][CH:25]=3)[OH:23])[CH:8]=2)[N:3]=1.ClC1C=CC=C(C(OO)=O)C=1.[CH3:49][S:50]([O-:53])(=O)=[O:51].CS(C1C=CC=C[N+]=1[O-])(=O)=O.BrP(Br)Br.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.C(Cl)Cl>[Cl:1][C:2]1[C:11]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([S:50]([CH3:49])(=[O:53])=[O:51])=[CH:17][CH:18]=2)=[C:10]([Cl:21])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:22]([C:30]3[C:31]([CH3:37])=[N:32][C:33]([CH3:36])=[CH:34][CH:35]=3)([C:24]3[N:28]([CH3:29])[N:27]=[N:26][CH:25]=3)[OH:23])[CH:8]=2)[N:3]=1
Reactant: CSc1ccc(Cc2c(Cl)nc3ccc(C(O)(c4ccc(C)nc4C)c4cnnn4C)cc3c2Cl)cc1
Reactant: CS(=O)(=O)[O-]
Agent: BrP(Br)Br
Agent: CS(=O)(=O)c1cccc[n+]1[O-]
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1ccc(C(O)(c2ccc3nc(Cl)c(Cc4ccc(S(C)(=O)=O)cc4)c(Cl)c3c2)c2cnnn2C)c(C)n1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
A suspension of (2,4-dichloro-3-(4-(methylthio)benzyl)quinolin-6-yl)(2,6-dimethylpyridin-3-yl)(1-methyl-1H-1,2,3-triazol-5-yl)methanol (1.10 g, 2.00 mmol, Example 95), 3-chloroperbenzoic acid (˜77%, 1.62 g, 7.23 mmol) and DCM (100 mL) was stirred at room temperature for 2.5 hours, during which it became a clear solution. LCMS showed mainly methylsulfonate product and methylsulfonyl pyridine-oxide by-product. To the mixture was added tribromophosphine (1.0 M in DCM, 3.2 mL, 3.2 mmol) dropwise (a white suspension formed at the end of the addition). DMF (10 mL) was then added and the suspension dissolved. After stirring for ˜30 minutes, additional tribromophosphine (1.0 M in DCM, 3.2 mL, 3.2 mmol) was added. After stirring for 1 hour, 1 M K2CO3 (aqueous) was added, the organic layer was separated. The aqueous layer was further extracted with DCM. The combined organic phases were washed with 1 M K2CO3 (aqueous), and the aqueous layer was back extracted with DCM. The organic phase was dried (Na2SO4), filtered, and concentrated. The residue was purified by flash column chromatography (silica gel, 30-100% EtOAc in heptanes, 10% MeOH in DCM) to provide the title compound. 1H NMR (400 MHz, CHLOROFORM-d) δ 8.25 (d, J=2.02 Hz, 1H), 8.02 (d, J=9.09 Hz, 1H), 7.93 (br. s., 1H), 7.86 (d, J=8.59 Hz, 2H), 7.58 (dd, J=2.27, 8.84 Hz, 1H), 7.44 (d, J=8.59 Hz, 2H), 6.91-6.98 (m, 2H), 6.87 (s, 1H), 4.61 (s, 2H), 3.94 (s, 3H), 3.03 (s, 3H), 2.54 (s, 3H), 2.36 (s, 3H); MS m/e 582.2 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:24])[N:5]([CH:12]1[CH2:17][CH:16]([O:18]C(=O)C)[C:15](=[O:22])[NH:14][C:13]1=[O:23])[C:6]2=[O:11].C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:24])[N:5]([CH:12]1[CH2:17][CH:16]([OH:18])[C:15](=[O:22])[NH:14][C:13]1=[O:23])[C:6]2=[O:11]
Reactant: CC(=O)OC1CC(N2C(=O)c3cccc(N)c3C2=O)C(=O)NC1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Product: Nc1cccc2c1C(=O)N(C1CC(O)C(=O)NC1=O)C2=O

Procedure:
A solution of 3-(4-amino-1,3-dioxoisoindolin-2-yl)-2,6-dioxo-5-acetoxypiperidine (1 g, 3.5 mmol) and p-toluenesulfonic acid (0.33 g, 1.8 mmol) in methanol (10 mL) is heated at reflux for 5 hours and the solvent is then removed in vacuo to give 4-amino-2-(5-hydroxy-2,6-dioxopiperid-3-yl)isoindoline-1,3-dione which can be further purified by column chromatography.
Reaction SMILES: [CH2:1]1[CH2:15][CH2:14][CH2:13][CH:12]=[CH:11][CH:10]2[CH:6]([CH2:7][O:8][CH2:9]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C([O-])(=[O:18])C.[Na+].C(OO)(=O)C.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH:10]12[CH2:9][O:8][CH2:7][CH:6]1[CH2:5][CH2:4][CH2:3][CH2:2][CH2:1][CH2:15][CH2:14][CH2:13][CH:12]1[CH:11]2[O:18]1
Reactant: C1=CC2COCC2CCCCCCCC1
Reactant: CC(=O)[O-]
Agent: C1=C\C2COCC2CCCCCCCC/1
Agent: CC(=O)OO
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: C1CCCCC2OC2C2COCC2CCC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 271 %

Procedure:
Muscogene (478 g, 2.4 mol), sodium acetate (63 g, 0.76 mol) and ethyl acetate (500 mL) were charged into a flask. The reaction was cooled to 0° C. While the temperature was maintained at 0° C., peracetic acid (32%, 500 mL, 2.38 mol) was dropped in over an hour and the reaction mixture was stirred for another 2 hours. Saturated sodium carbonate solution (100 mL) and toluene (50 mL) were added. The organic layer was separated and washed with brine (200 mL). The crude was purified to provide 3,15-dioxa-tricyclo[11.3.0.0*2,4*]hexadecane (462 g, ˜85% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]2[NH:15][CH:14]([C:16]([N:18]3[CH2:23][CH2:22][N:21]([CH2:24][CH2:25][CH2:26][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[CH2:20][CH2:19]3)=[O:17])[CH2:13][S:12]2)[CH:6]=[N:7][C:8]=1[O:9]C.Cl>C(OCC)(=O)C.O1CCOCC1>[CH3:1][O:2][CH:3]1[C:8](=[O:9])[N:7]=[CH:6][C:5]([CH:11]2[NH:15][CH:14]([C:16]([N:18]3[CH2:19][CH2:20][N:21]([CH2:24][CH2:25][CH2:26][C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=4)[CH2:22][CH2:23]3)=[O:17])[CH2:13][S:12]2)=[CH:4]1
Reactant: COc1cc(C2NC(C(=O)N3CCN(CCCc4ccccc4)CC3)CS2)cnc1OC
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COC1C=C(C2NC(C(=O)N3CCN(CCCc4ccccc4)CC3)CS2)C=NC1=O
Yield: 29.7 %

Procedure:
1-[2-(5,6-Dimethoxy-3-pyridyl)thiazolidin-4-ylcarbonyl]-4-(3-phenylpropyl)piperazine (730 mg) was dissolved in 25 ml of ethyl acetate. To the solution was added with stirring at room temperature 2N hydrogen chloride solution in dioxane. The resultant powder was collected by filtration and dissolved in saturated sodium carbonate solution. Ethyl acetate was added, the organic layer was separated and washed with water, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (silica gel 25 ml; 10% methanol-ethyl acetate) to give 210 mg of 1-[2-(5-methoxy-6 oxo 5,6-dihydro-3-pyridyl)thiazolidin-4-ylcarbonyl]-4-(3-phenylpropyl)piperazine.
Reaction SMILES: [C:1]([O:7][CH2:8][O:9][C:10]([C:12]1[N:16]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[C:30]([O:32]C(C)(C)C)=[O:31])=[CH:20][CH:19]=2)[C:15]([CH2:37][CH2:38][CH3:39])=[N:14][C:13]=1[C:40]([OH:43])([CH3:42])[CH3:41])=[O:11])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].Cl>O1CCOCC1>[C:30]([C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=1[C:21]1[CH:20]=[CH:19][C:18]([CH2:17][N:16]2[C:12]([C:10]([O:9][CH2:8][O:7][C:1](=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3])=[O:11])=[C:13]([C:40]([OH:43])([CH3:42])[CH3:41])[N:14]=[C:15]2[CH2:37][CH2:38][CH3:39])=[CH:23][CH:22]=1)([OH:32])=[O:31]
Reactant: CCCc1nc(C(C)(C)O)c(C(=O)OCOC(=O)C(C)(C)C)n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Agent: Cl
Solvent: C1COCCO1
Product: CCCc1nc(C(C)(C)O)c(C(=O)OCOC(=O)C(C)(C)C)n1Cc1ccc(-c2ccccc2C(=O)O)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 109.1 %

Procedure:
A mixture of 6.6 g of pivaloyloxymethyl-1-[(2'-t-butoxycarbonylbiphenyl-4-yl)methyl]-4-(1-hydroxy-1-methylethyl)-2-propylimidazole-5-carboxylate [prepared as described in step (c) above] and 57 ml of a 4N solution of hydrogen chloride in dioxane was stirred at room temperature for 4 hours. At the end of this time, the reaction mixture was concentrated by evaporation under reduced pressure, and the residue was triturated with ethyl acetate to crystallize it, giving 6.52 g of the title compound as the hydrochloride, melting at 170°-173° C.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2(O)[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([Cl:25])[CH:23]=3)[NH:18][C:17]2=[O:26])=[C:12]([O:28][CH3:29])[CH:11]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].FC(F)(F)C(O)=O.[OH:37][C@H:38]1[CH2:42][NH:41][C@H:40]([C:43]([N:45]([CH3:47])[CH3:46])=[O:44])[CH2:39]1>>[Si:1]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2([N:41]3[CH2:42][C@H:38]([OH:37])[CH2:39][C@H:40]3[C:43]([N:45]([CH3:47])[CH3:46])=[O:44])[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([Cl:25])[CH:23]=3)[NH:18][C:17]2=[O:26])=[C:12]([O:28][CH3:29])[CH:11]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: COc1cc(CO[Si](C)(C)C(C)(C)C)ccc1C1(O)C(=O)Nc2ccc(Cl)cc21
Reactant: CN(C)C(=O)[C@@H]1C[C@@H](O)CN1
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(CO[Si](C)(C)C(C)(C)C)ccc1C1(N2C[C@H](O)C[C@H]2C(=O)N(C)C)C(=O)Nc2ccc(Cl)cc21

Procedure:
With 1.64 g of the compound obtained in Step 237-3 and (4R)-4-hydroxy-N,N-dimethyl-L-prolinamide trifluoroacetate (5.67 mmol) as starting materials, respectively 901 mg (Isomer A: colorless solid) and 288 mg (Isomer B: colorless amorphous) of two species of diastereoisomers of the title compound were obtained by a similar method to Step 28-2.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([C@@H:13]2[C:18]([C:19]#[N:20])=[C:17]([CH3:21])[N:16]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=3)[C:15](=[O:32])[NH:14]2)=[C:7]([S:9](Cl)(=[O:11])=[O:10])[CH:8]=1)#[N:2].[NH:33]1[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1>ClCCl>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([C@@H:13]2[C:18]([C:19]#[N:20])=[C:17]([CH3:21])[N:16]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=3)[C:15](=[O:32])[NH:14]2)=[C:7]([S:9]([N:33]2[CH2:38][CH2:37][O:36][CH2:35][CH2:34]2)(=[O:11])=[O:10])[CH:8]=1)#[N:2]
Reactant: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2S(=O)(=O)Cl)NC(=O)N1c1cccc(C(F)(F)F)c1
Reactant: C1COCCN1
Solvent: ClCCl
Product: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2S(=O)(=O)N2CCOCC2)NC(=O)N1c1cccc(C(F)(F)F)c1
Reaction time: 8 h

Procedure:
Under an atmosphere of argon protective gas, 5-cyano-2-{(4S)-5-cyano-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidin-4-yl}benzenesulfonyl chloride (20 mg, 42 μmol) was dissolved in absolute dichloromethane (2.5 ml), morpholine (7.3 μl, 83 μmol; 2 eq.) was added at room temperature and the mixture was stirred overnight. The reaction mixture was then concentrated under reduced pressure and the residue was purified by preparative HPLC (column: Gromsil C-18, 10 μm; mobile phase: acetonitrile/water+0.1% TFA 10:90→90:10). This gave a colorless amorphous solid (8.6 mg, 35% of theory).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH:11]1[C:20]2[C:15](=[CH:16][C:17]([O:21][CH3:22])=[CH:18][CH:19]=2)[O:14][CH2:13][C:12]1([CH3:29])[C:23]1[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=1.C(N(CC)CC)C.[CH3:37][S:38](Cl)(=[O:40])=[O:39].[NH4+].[Cl-]>C(Cl)Cl>[CH3:37][S:38]([O:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH:11]1[C:20]2[C:15](=[CH:16][C:17]([O:21][CH3:22])=[CH:18][CH:19]=2)[O:14][CH2:13][C:12]1([CH3:29])[C:23]1[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=1)(=[O:40])=[O:39]
Reactant: COc1ccc2c(c1)OCC(C)(c1ccncc1)C2CCCCCCCCCO
Reactant: CS(=O)(=O)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc2c(c1)OCC(C)(c1ccncc1)C2CCCCCCCCCOS(C)(=O)=O
Reaction time: 0.5 h
Yield: 380.3 %

Procedure:
To a solution of 4-(9-hydroxynonyl)-7-methoxy-3-methyl-3-(4-pyridyl)chroman (108 mg, 0.272 mmol) in methylene chloride (2 mL) were added under ice-cooling triethylamine (0.057 mL, 0.41 mmol) and methanesulfonyl chloride (0.032 ml, 0.41 mmol), which was then stirred for 30 minutes. After the reaction was completed, saturated aqueous NH4Cl solution was added, the resulting mixture was then extracted with methylene chloride and washed with saturated saline solution. The organic layer was dried over magnesium sulfate, and the solvent was removed under reduced pressure. The residue was subjected to silica gel column chromatography (n-hexane:ethyl acetate=1:1) to give 4-(9-methanesulfonyloxynonyl)-7-methoxy-3-methyl-3-(4-pyridyl)chroman (492 mg, yield 38%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N:8]2[C:12]3=[N:13][CH:14]=[CH:15][CH:16]=[C:11]3[NH:10][C:9]2=[O:17])[N:3]=1.[CH3:18][C:19]([CH3:21])=O.[OH-].[K+].C(Br)C=C>O>[CH2:21]([N:10]1[C:11]2[C:12](=[N:13][CH:14]=[CH:15][CH:16]=2)[N:8]([C:4]2[N:3]=[C:2]([CH3:1])[CH:7]=[CH:6][CH:5]=2)[C:9]1=[O:17])[CH:19]=[CH2:18]
Reactant: CC(C)=O
Reactant: Cc1cccc(-n2c(=O)[nH]c3cccnc32)n1
Agent: [K+]
Agent: [OH-]
Solvent: C=CCBr
Solvent: O
Product: C=CCn1c(=O)n(-c2cccc(C)n2)c2ncccc21
Reaction time: 8 h

Procedure:
A mixture of 1 g. of 1,3-dihydro-3-(2-methylpyridin-6-yl)imidazo[4,5-b]pyridin-2-one in 100 ml. of acetone and 450 mg. of powdered potassium hydroxide was stirred 10 minutes and 1.1 g. of allyl bromide was added. After refluxing for 1.5 hours, the mixture was allowed to stand overnight at room temperature. The mixture was diluted with water and the acetone was evaporated causing crystallization of 325 mg. of 1-allyl-1,3-dihydro-3-(2-methylpyridin-6yl)imidazo[4,5-b]pyridin-2-one, m.p. 111°-112° C.
Reaction SMILES: [BH4-].[Na+].[NH2:3][C:4]1[CH:14]=[CH:13][C:7]([CH:8]=[CH:9][C:10](O)=[O:11])=[CH:6][CH:5]=1>CO>[NH2:3][C:4]1[CH:5]=[CH:6][C:7]([CH:8]=[CH:9][CH2:10][OH:11])=[CH:13][CH:14]=1
Reactant: Nc1ccc(C=CC(=O)O)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Nc1ccc(C=CCO)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To 72.0 g of sodium borohydride in 1.5 l. of methanol, with ice cooling, is added 16.30 g of p-amino-cinnamic acid in 500 ml of methanol, maintaining the temperature between 10° -15° C. Subsequent to the addition, the mixture is stirred for four hours at room temperature and then worked up to give p-aminocinnamyl alcohol.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:12]1[C:35]([CH3:36])=[CH:34][C:15]2[N:16]=[C:17]([C:19]3[S:20][CH:21]=[C:22]([C:24]4[CH:25]=[C:26]5[C:30](=[CH:31][CH:32]=4)[N:29]([CH3:33])[N:28]=[CH:27]5)[N:23]=3)[S:18][C:14]=2[C:13]=1[C:37]1[CH:42]=[CH:41][C:40]([Cl:43])=[CH:39][CH:38]=1)[C:7]([O:9]CC)=[O:8])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>C1COCC1.O>[C:1]([O:5][C@@H:6]([C:12]1[C:35]([CH3:36])=[CH:34][C:15]2[N:16]=[C:17]([C:19]3[S:20][CH:21]=[C:22]([C:24]4[CH:25]=[C:26]5[C:30](=[CH:31][CH:32]=4)[N:29]([CH3:33])[N:28]=[CH:27]5)[N:23]=3)[S:18][C:14]=2[C:13]=1[C:37]1[CH:38]=[CH:39][C:40]([Cl:43])=[CH:41][CH:42]=1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3nc(-c4ccc5c(cnn5C)c4)cs3)sc2c1-c1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc2nc(-c3nc(-c4ccc5c(cnn5C)c4)cs3)sc2c(-c2ccc(Cl)cc2)c1[C@H](OC(C)(C)C)C(=O)O
Temperature: 40 °C
Reaction time: 17 h

Procedure:
In a 25 mL round bottom flask, (S)-ethyl 2-tert-butoxy-2-(7-(4-chlorophenyl)-5-methyl-2-(4-(1-methyl-1H-indazol-5-yl)thiazol-2-yl)benzo[d]thiazol-6-yl)acetate (74 mg, 0.117 mmol) was dissolved in THF (3 mL) EtOH (2 mL) and water (1 mL). Then aqueous NaOH (2N) (1.17 mL) was added. The reaction mixture was stirred at 40° C. in oil bath for 17 h. The resulting reaction mixture was concentrated and purified on Gilson reverse phase preparative HPLC with 0-95% acetonitrile (with 0.1% TFA) in water (with 0.1% TFA) to afford product as a TFA salt. LCMS-ESI+: calc'd for: C31H27ClN4O3S2: 603.1, 605.1, 604.1 (M+H+); found: 603.2, 605.2, 604.0 (M+H+).1H NMR (400 MHz, CD3OD) δ 8.36 (d, J=1.2 Hz, 1H), 8.06-7.98 (m, 3H), 7.82 (s, 1H), 7.70 (dd, J=7.9, 2.4 Hz, 1H), 7.66-7.52 (m, 4H), 5.28 (s, 1H), 4.05 (s, 3H), 2.61 (s, 3H), 0.98 (s, 9H).
Reaction SMILES: Cl[CH2:2][C:3](=[O:5])[CH3:4].[I-].[Na+].[CH:8]1([C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=2)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH:8]1([C:14]2[CH:15]=[CH:16][C:17]([O:20][CH2:2][C:3](=[O:5])[CH3:4])=[CH:18][CH:19]=2)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]1
Reactant: Oc1ccc(C2CCCCC2)cc1
Reactant: CC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(=O)COc1ccc(C2CCCCC2)cc1
Reaction time: 1 h

Procedure:
Freshly distilled chloroacetone (31 ml) was added to a solution of sodium iodide (1.0 g) in dry acetone (50 ml). The mixture was allowed to stand for 1 hour at room temperature and then added over 1 hour to a stirred, refluxing mixture of 4-(cyclohexyl)phenol (52.8 g) and anhydrous potassium carbonate (52 g) in dry acetone (100 ml). The stirred mixture was heated under reflux for a further 5 hours, filtered and evaporated to a brown oil which crystallised from ether-petroleum spirit (40°-60° C.) to give 1-[4-(cyclohexyl)phenoxy]-2-propanone (mp 58° C.).