Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][CH2:10][N:11]1[CH2:16][CH2:15][CH:14]([N:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[CH2:13][CH2:12]1)(C)(C)C.[ClH:24]>O1CCOCC1.C(OCC)C>[ClH:24].[ClH:24].[ClH:24].[N:17]1([CH:14]2[CH2:15][CH2:16][N:11]([CH2:10][CH2:9][CH2:8][NH2:7])[CH2:12][CH2:13]2)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: CC(C)(C)OC(=O)NCCCN1CCC(N2CCCCC2)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: NCCCN1CCC(N2CCCCC2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92 %

Procedure:
A mixture of (3-[1,4′]bipiperidinyl-1′-yl-propyl)-carbamic acid tert-butyl ester (2.15 g, 6.6 mmol), dry dioxane (40 mL) and 6.5 N hydrogen chloride in dioxane (22 mL) was stirred at room temperature overnight, then diluted with diethyl ether and stirred at 0° C. for 1 h. The precipitated crystals were filtered off, washed with diethyl ether and dried to yield 2.03 g (92%) of the title compound as a beige solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[C:5]([NH2:8])=[N:6][CH:7]=1.FC(F)(F)C(F)(F)C(F)(F)C([O:18][C:19](=O)[C:20]([F:29])([F:28])[C:21]([F:27])([F:26])[C:22]([F:25])([F:24])[F:23])=O>>[Cl:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[C:5]([NH:8][C:19](=[O:18])[C:20]([F:28])([F:29])[C:21]([F:26])([F:27])[C:22]([F:25])([F:24])[F:23])=[N:6][CH:7]=1
Reactant: Nc1ncc(Cl)cc1[N+](=O)[O-]
Reactant: O=C(OC(=O)C(F)(F)C(F)(F)C(F)(F)F)C(F)(F)C(F)(F)C(F)(F)F
Product: O=C(Nc1ncc(Cl)cc1[N+](=O)[O-])C(F)(F)C(F)(F)C(F)(F)F

Procedure:
5-Chloro-3-nitro-2-aminopyridine is reacted with heptafluorobutyric anhydride to obtain 5-chloro-3-nitro-2-(heptafluorobutyramido)pyridine which when hydrogenated yields 6-chloro-1-hydroxy-2-(heptafluoro-n-propyl)-1H-imidazo(4,5-b)-pyridine.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[C:7]([C:12]([OH:14])=[O:13])[CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][NH:3]1.S(=O)(=O)(O)O.[OH-].[Na+].[CH3:22]O>>[O:1]=[C:2]1[C:11]2[C:6](=[C:7]([C:12]([O:14][CH3:22])=[O:13])[CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][NH:3]1
Reactant: O=C(O)c1cccc2c(=O)[nH]cnc12
Reactant: CO
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: COC(=O)c1cccc2c(=O)[nH]cnc12
Temperature: 25 °C
Yield: 94 %

Procedure:
4-oxo-3,4-dihydroquinazoline-8-carboxylic acid (5.0 g, 26.3 mmol) was treated with a solution of sulfuric acid ((1.2 equivalents) in anhydrous MeOH (100 mL) under refluxing for 2 days. After cooling to rt, 2N NaOH solution was added to the reaction mixture to adjust pH˜8. After removal of MeOH, methyl ester was collected by filtration, and washing with water and ethyl acetate as pale yellow solid in 94% yield. 1HNMR (in DMSO): 3.84 (s, 3H), 7.42 (t, J=7.6 Hz, 1H), 7.85 (d, J=6.9 Hz, 1H), 8.16 (s, 1H), 8.20 (d, J=7.8 Hz, 1H). Mass: M+H+: 205.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([S:8][CH3:9])[N:3]=1.[NH3:10]>CO>[CH3:9][S:8][C:4]1[N:3]=[C:2]([NH2:10])[CH:7]=[CH:6][N:5]=1
Reactant: CSc1nccc(Cl)n1
Reactant: N
Solvent: CO
Product: CSc1nccc(N)n1
Reaction time: 48 h

Procedure:
A mixture of 4-chloro-2-methylsulfanylpyrimidine (8 g) and 7N ammonia in methanol (100 mL) at 100° C. was stirred for 2 days in a sealed tube, cooled, concentrated, treated with water, and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous sodium sulfate, and concentrated. The concentrate was triturated with ethyl ether and filtered. 1H NMR (300 MHz, CDCl3) δ 8.06 (d, 1H), 6.12 (d, 1H), 4.83 (s, 2H), 2.51 (s, 3H).
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH2:26][CH3:27])[CH2:23][CH2:22][C:21]([C:28]([NH:30][C:31]4[CH:36]=[CH:35][C:34]([S:37][CH2:38][CH2:39][N:40]5[CH:44]=[N:43][N:42]=[CH:41]5)=[CH:33][CH:32]=4)=[O:29])=[CH:20][C:19]=3[CH:45]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].ClC1C=CC=C(C(OO)=[O:54])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH2:26][CH3:27])[CH2:23][CH2:22][C:21]([C:28]([NH:30][C:31]4[CH:32]=[CH:33][C:34]([S:37]([CH2:38][CH2:39][N:40]5[CH:41]=[N:42][N:43]=[CH:44]5)=[O:54])=[CH:35][CH:36]=4)=[O:29])=[CH:20][C:19]=3[CH:45]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(SCCn4cnnc4)cc2)CCN3CCC)cc1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(S(=O)CCn4cnnc4)cc2)CCN3CCC)cc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 87.8 %

Procedure:
To a solution of 7-[4-(2-butoxyethoxy)phenyl]-N-[4-(4H-1,2,4-triazol-4-ylethylthio)phenyl]-1-propyl-2,3-dihydro-1H-benzazepine-4-carboxamide (1.0 g) in dichloromethane (20 ml) was added dropwise a solution of 3-chloroperbenzoic acid (70%, 0.43 g) in dichloromethane (10 ml) at −78° C., and the mixture was stirred for 1 hour at −78° C. To the reaction solution was added sodium thiosulfate solution at room temperature and the mixture was stirred for several minutes. The mixture was extracted with ethyl acetate, and the organic layer was washed with sodium bicarbonate solution and saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The obtained residue was separated and purified by column chromatography (basic silica gel, ethanol:ethyl acetate 1:20→1:9), to give 7-[4-(2-butoxyethoxy)phenyl]-N-[4-(4H-1,2,4-triazol-4-ylethylsulfinyl)phenyl]-1-propyl-2,3-dihydro-1H-benzazepine-4-carboxamide (Compound 157) (0.90 g) as yellow amorphous.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:11])[CH2:5][C:6](=[O:10])[CH:7]([F:9])[F:8])[CH3:2].S([N:22]=[N+:23]=[N-])(C1C=CC(C)=CC=1)(=O)=O>>[N+:22](=[C:5]([C:6](=[O:10])[CH:7]([F:9])[F:8])[C:4]([O:3][CH2:1][CH3:2])=[O:11])=[N-:23]
Reactant: CCOC(=O)CC(=O)C(F)F
Reactant: Cc1ccc(S(=O)(=O)N=[N+]=[N-])cc1
Product: CCOC(=O)C(=[N+]=[N-])C(=O)C(F)F

Procedure:
This compound was synthesised from 4,4-difluoro-3-oxo-butyric acid ethyl ester (CAS 352-24-9) and polymer-bound tosylazide using similar conditions as described in Intermediate 1-7. The crude was used directly in next step.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][C:10]([OH:12])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:13][C@@H:14]1[CH2:23][CH2:22][C:21]2[C:16](=[C:17]([N:24]3[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]3)[CH:18]=[CH:19][CH:20]=2)[CH2:15]1.C(N(CC)CC)C>S(Cl)(Cl)=O.C(Cl)Cl>[CH3:30][N:27]1[CH2:28][CH2:29][N:24]([C:17]2[CH:18]=[CH:19][CH:20]=[C:21]3[C:16]=2[CH2:15][C@H:14]([NH:13][C:10](=[O:12])[CH2:9][CH2:8][CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:23][CH2:22]3)[CH2:25][CH2:26]1
Reactant: CN1CCN(c2cccc3c2C[C@H](N)CC3)CC1
Reactant: O=C(O)CCCc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O=S(Cl)Cl
Product: CN1CCN(c2cccc3c2C[C@H](NC(=O)CCCc2ccccc2)CC3)CC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
4-Phenylbutyric acid (1.0 g, 6.1 mmol) was dissolved in thionyl chloride (15 mL) and heated at reflux for 1 h. The excess of thionyl chloride was evaporated in vacuo, the residue was treated with toluene and again the solvent was removed in vacuo. Crude acid chloride (86 mg, 0.47 mmol) was dissolved in methylene chloride (5 mL) and added dropwise to an ice-cooled solution of (R)-2-amino-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydronaphthalene (110 mg, 0.45 mmol) and triethylamine (93 μL, 0.68 mmol) in methylene chloride (15 mL). After the addition, the reaction was allowed to stir at ambient temperature for 15 min and was then washed with water. The phases were separated and the organic phase was dried (Na2SO4), filtered and evaporated in vacuo to give a crude product which was purified on a silica gel column using chloroform/ethanol saturated with NH3 (100:4) as the eluent. Yield: 150 mg (82%) of the title compound as white crystals: mp 137-139° C.; [α]21D+8.4° (c 0.50, chloroform); EIMS (70 eV) m/z (relative intensity) 391 (23, M+).
Reaction SMILES: [Cl:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:27])[N:19]([CH2:23][C:24](O)=O)[C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[C:9]([Cl:28])=[N:8]2)=[C:4]([C:31]([F:34])([F:33])[F:32])[CH:3]=1.[CH3:35][N:36]1C[CH2:39][CH2:38][C@H:37]1CO>>[Cl:28][C:9]1[C:10]2[C:15](=[CH:14][CH:13]=[C:12](/[CH:16]=[C:17]3/[C:18](=[O:27])[N:19]([CH2:23][C@@H:24]4[CH2:39][CH2:38][CH2:37][N:36]4[CH3:35])[C:20](=[O:22])[S:21]/3)[CH:11]=2)[N:7]([CH2:6][C:5]2[CH:29]=[CH:30][C:2]([Cl:1])=[CH:3][C:4]=2[C:31]([F:34])([F:32])[F:33])[N:8]=1
Reactant: O=C(O)CN1C(=O)S/C(=C\c2ccc3c(c2)c(Cl)nn3Cc2ccc(Cl)cc2C(F)(F)F)C1=O
Reactant: CN1CCC[C@H]1CO
Product: CN1CCC[C@H]1CN1C(=O)S/C(=C\c2ccc3c(c2)c(Cl)nn3Cc2ccc(Cl)cc2C(F)(F)F)C1=O

Procedure:
(5Z)-5-({3-Chloro-1-[4-chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}-methylidene)-3-{[(2S)-1-methylpyrrolidin-2-yl]methyl}-1,3-thiazolidine-2,4-dione was prepared from [(5Z)-5-({3-chloro-1-[4-chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2,4-dioxo-1,3-thiazolidine (from Example 287) and (2S)-(−)-1-methyl-2-pyrrolidinemethanol following General Procedure J.
Reaction SMILES: [CH2:1]1COC23OCCOC2([C@]2(CC[C@H]4[C@@H](C[C@H](CNC=O)C5[C@]4(C)CCCC5)[C@@H]2C3)C)[O:2]1.[C:32]([C@@H:34]1[CH:51]2[C@:46]([CH3:53])([CH2:47][CH2:48][C:49](=[O:52])[CH2:50]2)[C@@H:45]2[C@H:36]([C@H:37]3[C@@:41]([CH2:43][CH2:44]2)([CH3:42])[C:40](=[O:54])[CH2:39][CH2:38]3)[CH2:35]1)#[N:33]>>[CH:1]([NH:33][CH2:32][C@@H:34]1[CH:51]2[C@:46]([CH3:53])([CH2:47][CH2:48][C:49](=[O:52])[CH2:50]2)[C@@H:45]2[C@H:36]([C@H:37]3[C@@:41]([CH2:43][CH2:44]2)([CH3:42])[C:40](=[O:54])[CH2:39][CH2:38]3)[CH2:35]1)=[O:2]
Reactant: C[C@]12CCCCC1[C@@H](CNC=O)C[C@@H]1[C@@H]2CC[C@@]2(C)[C@H]1CC13OCCOC12OCCO3
Reactant: C[C@]12CCC(=O)CC1[C@@H](C#N)C[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Product: C[C@]12CCC(=O)CC1[C@@H](CNC=O)C[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Yield: 92 %

Procedure:
The title compound II-bl was prepared in 92% yield from 3,3:17,17-bis(ethylendioxy)-6α-formamidomethylandrostane by the procedure described above for the preparation of 6α-cyanoandrostane-3,17-dione (II-ac, Prepn. 3). 1H-NMR (300 MHz, DMSO, ppm from TMS): δ 7.99 (0.9H, s), 7.94 (0.9H, m), 7.88 (0.1H, d), 7.67 (0.1H, m), 3.15 (1H, m), 2.87 (1H, m), 2.40-1.00 (21H, m), 0.98 (3H, s), 0.79 (3H, s).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:12]=[CH:11][S:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[Br:13]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:13][CH2:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:12]=[CH:11][S:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cccc(-c2ccsc2)c1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: BrCc1cccc(-c2ccsc2)c1
Yield: 61.4 %

Procedure:
A stirred solution of 9.8 g (0.056 mol) of 3-(3-methylphenyl)thiophene in 250 mL of carbon tetrachloride was heated to reflux, and 0.5 g of benzoyl peroxide was added. Heating was continued, and after five minutes an additional 0.5 g of benzoyl peroxide and 10 g of N-bromosuccinimide were added. Upon complete addition, the reaction mixture was heated under reflux for an additional 2.5 hours, then cooled in an ice-water bath for one hour. The reaction mixture was filtered, and the filter cake washed with 50 mL of carbon tetrachloride. The wash and filtrate were combined, and the whole was washed with 200 mL of a saturated aqueous solution of sodium chloride. The organic layer was dried with magnesium sulfate, filtered, and the filtrate concentrated under reduced pressure to give a residual oil. The residual oil was subjected to distillation under reduced pressure using a Kugelrohr distilling system to give 8.7 g of 3-(3-bromomethylphenyl)thiophene, b.p. 95°-150° C./0.1 mm.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][C:17]=1[CH3:18])[C:5]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[OH:14])=O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([C:5]2[O:14][C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=3[N:7]=2)[CH:15]=[CH:16][C:17]=1[CH3:18]
Reactant: Cc1ccc(C(=O)Nc2ccccc2O)cc1Br
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: Cc1ccc(-c2nc3ccccc3o2)cc1Br
Temperature: 25 °C

Procedure:
A mixture of 3-bromo-N-(2-hydroxyphenyl)-4-methylbenzamide (554 mg, 1.8 mmol), p-toluenesulfonic acid (2.41 g, 12.7 mmol) and toluene (50 mL) was refluxed for 4 h, cooled to rt, and filtered through a Celite pad. The filtrate was evaporated to dryness and the residue was purified by flash chromatography on silica gel using a gradient of EtOAc:hexanes (0 to 30 min:0 to 15% EtOAc) to afford 2-(3-bromo-4-methylphenyl)-1,3-benzoxazole as a colorless solid. MS (ESI) 288 (M+).
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10]CC)[C:5]=1[OH:13])CC.C1(C2C=CC=C(C3C=CC=CC=3)C=2O)C=CC=CC=1>>[CH3:1][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:5]=1[OH:13]
Reactant: CCCc1cccc(CCC)c1O
Agent: Oc1c(-c2ccccc2)cccc1-c1ccccc1
Product: Cc1cccc(C)c1O

Procedure:
2,6-diaurylphenol; 2,6-dipropylphenol; 2,6-diphenylphenol;
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]([CH:15]2[CH2:17][CH2:16]2)[NH:9][S:10]([CH2:13][CH3:14])(=[O:12])=[O:11])[CH:5]=[N:6][CH:7]=1.[Cl:18][C:19]1[CH:26]=[C:25](B2OC(C)(C)C(C)(C)O2)[CH:24]=[CH:23][C:20]=1[C:21]#[N:22].C(=O)([O-])[O-].[Na+].[Na+].C(Cl)Cl>CN(C=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:18][C:19]1[CH:26]=[C:25]([C:2]2[CH:3]=[C:4]([CH:8]([CH:15]3[CH2:17][CH2:16]3)[NH:9][S:10]([CH2:13][CH3:14])(=[O:12])=[O:11])[CH:5]=[N:6][CH:7]=2)[CH:24]=[CH:23][C:20]=1[C:21]#[N:22]
Reactant: CC1(C)OB(c2ccc(C#N)c(Cl)c2)OC1(C)C
Reactant: CCS(=O)(=O)NC(c1cncc(Br)c1)C1CC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCS(=O)(=O)NC(c1cncc(-c2ccc(C#N)c(Cl)c2)c1)C1CC1
Yield: 84.9 %

Procedure:
A mixture of N-((5-bromopyridin-3-yl)(cyclopropyl)methyl)ethanesulfonamide (5 g, 15.66 mmol), 2-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile (as prepared in Example 1, step 1; 4.13 g, 15.66 mmol), sodium carbonate (15.66 mL, 31.3 mmol) and PdCl2(dppf).CH2Cl2 adduct (0.320 g, 0.392 mmol) in DMF (100 mL) was heated to 100° C. for 25 min. After concentration, the residue was dissolved into CH2Cl2 and filtered through a pad of Na2SO4. The solution was absorbed into celite and concentrated. The residue was purified by flash column (ethyl acetate/heptane, 30%-50%-80%, v/v) and yielded the title compound as a colorless solid (5.0 g). Chiral separation by chiral HPLC (Chiralpak AD-H using Supercritical fluid chromatography. 25% Methanol at 65 grams per minute with supercritical CO2) afforded enantiomer 1 (S)—N-((5-(3-chloro-4-cyanophenyl)pyridin-3-yl)(cyclopropyl)methyl)ethanesulfonamide (retention time=3 min), and enantiomer 2 (R)—N-((5-(3-chloro-4-cyanophenyl)pyridin-3-yl)(cyclopropyl)methyl)ethanesulfonamide (retention time=4 min). ESI-MS m/z: 376.2 [M+H]+, 1H NMR (400 MHz, CDCl3): δ 0.37-0.40 (m, 1H), 0.51-0.55 (m, 1H), 0.57-0.68 (m, 1H), 0.70-0.77 (m, 1H), 1.15-1.27 (m, 3H), 2.70-2.88 (m, 2H), 3.85 (dd, J=5 Hz, 9 Hz, 1H), 4.68 (d, J=5 Hz, 1H), 7.53 (dd, J=1.5 Hz, 8 Hz, 1H), 7.67 (d, J=1.5 Hz, 1H), 7.73 (d, J=8 Hz, 1H), 7.80 (t, J=2 Hz, 1H), 8.67 (d, J=2 Hz, 1H), 8.72 (d, J=2 Hz, 1H).
Reaction SMILES: [CH:1]1([C:4]2[CH:9]=[CH:8][C:7]([C@H:10]3[C@H:15]([OH:16])[C@@H:14]([OH:17])[C@H:13]([OH:18])[C@@H:12]([CH2:19][OH:20])[O:11]3)=[CH:6][C:5]=2[CH2:21][C:22]2[CH:31]=[CH:30][C:25]3[O:26][CH2:27][CH2:28][O:29][C:24]=3[CH:23]=2)[CH2:3][CH2:2]1.Cl[C:33]([O:35][CH3:36])=[O:34]>N1C(C)=CC(C)=CC=1C.C(Cl)Cl>[CH3:36][O:35][C:33](=[O:34])[O:20][CH2:19][C@@H:12]1[C@@H:13]([OH:18])[C@H:14]([OH:17])[C@@H:15]([OH:16])[C@H:10]([C:7]2[CH:8]=[CH:9][C:4]([CH:1]3[CH2:3][CH2:2]3)=[C:5]([CH2:21][C:22]3[CH:31]=[CH:30][C:25]4[O:26][CH2:27][CH2:28][O:29][C:24]=4[CH:23]=3)[CH:6]=2)[O:11]1
Reactant: OC[C@H]1O[C@@H](c2ccc(C3CC3)c(Cc3ccc4c(c3)OCCO4)c2)[C@H](O)[C@@H](O)[C@@H]1O
Reactant: COC(=O)Cl
Solvent: Cc1cc(C)nc(C)c1
Solvent: ClCCl
Product: COC(=O)OC[C@H]1O[C@@H](c2ccc(C3CC3)c(Cc3ccc4c(c3)OCCO4)c2)[C@H](O)[C@@H](O)[C@@H]1O
Temperature: 0 °C
Reaction time: 1 h
Yield: 107.7 %

Procedure:
To a stirred solution of (2S,3R,4R,5S,6R)-2-[4-Cyclopropyl-3-(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-phenyl]-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol (Intermediate 3, 890 mg, 2.1 mmol) in collidine (7 ml) was added a solution of methyl chloroformate (0.21 ml, 2.5 mmol) in DCM (0.5 ml) at −40° C. After stirring for 1 h at same temperature, it was stirred at room temperature for 1.5 h. Reaction mixture was poured into ice cold 10% HCl solution and extracted with ethyl acetate (2×10 ml). Combined organic layers were washed with brine (10 ml), dried over sodium sulfate, concentrated and purified by silica gel column chromatography to give 1.1 g of carbonic acid (2R,3S,4R,5R,6S)-6-[4-cyclopropyl-3-(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-phenyl]-3,4,5-trihydroxy-tetrahydro-pyran-2-ylmethyl ester methyl ester as a white solid.
Reaction SMILES: [C:1]([O:24]C)(=[O:23])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].[OH-].[K+:27]>CO>[C:1]([O-:24])(=[O:23])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].[K+:27]
Reactant: CCCCCCCCCCCCCCCCCCCCCC(=O)OC
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CCCCCCCCCCCCCCCCCCCCCC(=O)[O-]

Procedure:
Methyl behenate (0.375 moles/mole of sucrose to be used in Step B) is saponified by stirring at reflux in methanol containing an equivalent amount of KOH. The reaction is stirred with heating until all methyl ester has been converted to soap as indicated by infrared analysis. The soap solution is used, as is in the next reaction step.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)O)=[CH:4][CH:3]=1.[NH:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]1=[O:23].OS(O)(=O)=O.O>C(Cl)Cl>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)[C:21]2[CH:20]=[CH:19][C:18](=[O:23])[NH:17][CH:22]=2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(C(O)c2ccc(C)cc2)cc1
Reactant: O=c1cccc[nH]1
Agent: O=S(=O)(O)O
Solvent: ClCCl
Solvent: O
Product: Cc1ccc(C(c2ccc(C)cc2)c2ccc(=O)[nH]c2)cc1
Temperature: 180 °C
Yield: 13.8 %

Procedure:
A mixture of bis(4-methylphenyl)methanol (5 g), and pyridin-2(1H)-one (6.72 g) was stirred at 180° C. To the solution was added concentrated H2SO4 (0.07 mL), and the mixture was stirred at 250° C. for 2 hours. Water (15 mL) and DCM (15 mL) were poured into the reaction mixture. The organic layer was washed with water and brine, dried over anhydrous MgSO4, filtered and evaporated in vacuo. The residue was purified by silica gel column chromatography (n-hexane:EtOAc). The desired fractions were collected and evaporated in vacuo, and the residue was washed with MeCN and dried in vacuo to give 5-[bis(4-methylphenyl)methyl]pyridin-2(1H)-one (0.94 g) as white crystals.
Reaction SMILES: [NH:1]1[CH2:5][CH:4]=[CH:3][CH2:2]1.C(N(CC)C(C)C)(C)C.Cl[C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17]>C(Cl)(Cl)Cl>[N:1]1([C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:17])[CH2:5][CH:4]=[CH:3][CH2:2]1
Reactant: C1=CCNC1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(OCc1ccccc1)N1CC=CC1
Temperature: 25 °C
Reaction time: 15 h
Yield: 97.1 %

Procedure:
A mixture of 3-pyrroline (9.1 g), N,N-diisopropylethylamine (28 mL), and chloroform (46 mL) was ice-cooled, benzyl chloroformate (26 g) was added dropwise, and then the mixture was stirred at room temperature for 15 h. The reaction solution was diluted with chloroform, washed with saturated aqueous sodium hydrogencarbonate, saturated aqueous ammonium chloride, and saturated brine, and then dried with anhydrous sodium sulfate. The desiccant was removed by filtration, then the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=7:3) to obtain benzyl 2,5-dihydropyrrole-1-carboxylate (26 g).
Reaction SMILES: [CH2:1]([C:8]1[C:9](=[O:36])[NH:10][C:11](=[O:35])[N:12]([CH2:14][O:15][CH:16]([CH2:26][O:27]CC2C=CC=CC=2)[CH2:17][O:18]CC2C=CC=CC=2)[CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(O)(=O)C.Cl.[Pd]>[CH2:1]([C:8]1[C:9](=[O:36])[NH:10][C:11](=[O:35])[N:12]([CH2:14][O:15][CH:16]([CH2:17][OH:18])[CH2:26][OH:27])[CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=c1[nH]c(=O)n(COC(COCc2ccccc2)COCc2ccccc2)cc1Cc1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: CC(=O)O
Product: O=c1[nH]c(=O)n(COC(CO)CO)cc1Cc1ccccc1
Yield: 78.1 %

Procedure:
2 g (4.6 mmol) of 3a prepared as above was dissolved in 100 ml of glacial acetic acid and 0.2 ml of concentrated HCl. 5% Palladium on charcoal (1 g) was then added and the reaction mixture hydrogenated under 50 lbs pressure. After the theoretical amount of hydrogen had been absorbed, the solution was filtered and evaporated to dryness. The residue was placed on a silica gel column and eluted with methylene chloride-methanol (12:1) to give 1.1 g of 4a (87%). It was isolated as an oil and dried under vacuum over P2O5 for several days. UV (pH 1): λ max 266 nm (9400); pH 11: λ max 266 nm (6400). NMR(DMSO-d6): δ3.47 (s, 4H, CH2OH), 3.52 (s, 3H, CH2 at C5 and tert. H), 4.66 (t, 2H, OH) 5.20 (s, 2H, CH2 at N1), 7.24 (s, 5H, ArH), 7.65(s, 1H, C6 -H), 11.33 (s, 1H, NH).
Reaction SMILES: Cl[C:2]1[C:7]([F:8])=[C:6]([O:9][CH2:10][C:11]#[C:12][CH2:13][CH3:14])[N:5]=[CH:4][N:3]=1.[CH3:15][CH:16]1[CH2:20][CH2:19][CH:18]([CH3:21])[NH:17]1>>[CH3:15][CH:16]1[CH2:20][CH2:19][CH:18]([CH3:21])[N:17]1[C:2]1[C:7]([F:8])=[C:6]([O:9][CH2:10][C:11]#[C:12][CH2:13][CH3:14])[N:5]=[CH:4][N:3]=1
Reactant: CCC#CCOc1ncnc(Cl)c1F
Reactant: CC1CCC(C)N1
Product: CCC#CCOc1ncnc(N2C(C)CCC2C)c1F
Reaction time: 13 h
Yield: 46.4 %

Procedure:
0.2 g of 4-chloro-5-fluoro-6-(2-pentynyloxy)pyrimidine and 0.2 g of 2,5-dimethylpyrrolidine were mixed and left for 13 hours at room temperature. The reaction mixture was subjected to silica gel column chromatography to obtain 0.12 g of 4-(2,5-dimethyl-1-pyrrolidinyl)-5-fluoro-6-(2-pentynyloxy)pyrimidine (hereinafter, referred to as Compound (13)).
Reaction SMILES: [CH3:1][C@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[CH:8]=[C:9]([NH:13][C:14]2[C:15]3[N:43]=[CH:42][S:41][C:16]=3[N:17]=[C:18]([C:20]3[CH:21]=[C:22]([CH:38]=[CH:39][CH:40]=3)[CH2:23][NH:24][CH:25]3[CH2:30][CH2:29][N:28](C(OC(C)(C)C)=O)[CH2:27][CH2:26]3)[N:19]=2)[CH:10]=[CH:11][CH:12]=1.[F:44][C:45]([F:50])([F:49])[C:46]([OH:48])=[O:47]>C(Cl)Cl>[F:44][C:45]([F:50])([F:49])[C:46]([OH:48])=[O:47].[CH3:1][C@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[CH:8]=[C:9]([NH:13][C:14]2[C:15]3[N:43]=[CH:42][S:41][C:16]=3[N:17]=[C:18]([C:20]3[CH:40]=[CH:39][CH:38]=[C:22]([CH2:23][NH:24][CH:25]4[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]4)[CH:21]=3)[N:19]=2)[CH:10]=[CH:11][CH:12]=1
Reactant: C[C@H]1CCCN1c1cccc(Nc2nc(-c3cccc(CNC4CCN(C(=O)OC(C)(C)C)CC4)c3)nc3scnc23)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@H]1CCCN1c1cccc(Nc2nc(-c3cccc(CNC4CCNCC4)c3)nc3scnc23)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 43 %

Procedure:
To a stirred solution of (S)-tert-butyl 4-(3-(7-(3-(2-methylpyrrolidin-1-yl)phenylamino)thiazolo[5,4-d]pyrimidin-5-yl)benzylamino)piperidine-1-carboxylate (110 mg, 0.184 mmol) in 2 mL of DCM was added 2 mL of 2,2,2-trifluoroacetic acid. The solution was stirred at room temperature overnight. The mixture was washed with NaHCO3(aq.), the organic layer was concentrated. The residue was purified by preparative HPLC (Gemini 5u C18 150×21.2 mm; inject volume: 3 ml/inj, flow rate: 20 ml/min; wavelength: 214 nm and 254 nm; the gradient conditions are: 40% acetonitrile/60% water (0.1% TFA V/V) initially, and then proceed to 55% acetonitrile/45% water (0.1% TFA V/V) in a linear fashion after just 9 min.) to give (S)—N-(3-(2-methylpyrrolidin-1-yl)phenyl)-5-(3-((piperidin-4-ylamino)methyl)phenyl)thiazolo[5,4-d]pyrimidin-7-amine 2,2,2-trifluoroacetate (40 mg, 43%) as an oil. 1H NMR (300 MHz, DMSO): δ 9.18 (s, 1H), 8.60 (s, 1H), 8.51 (dd, 1H, J1=7.5 Hz, J2=1.2 Hz), 7.92 (s, 1H), 7.84 (brs, 1H), 7.68-7.52 (m, 3H), 7.15 (brs, 1H), 4.40 (s, 2H), 4.08-4.01 (m, 2H), 3.87-3.85 (m, 1H), 3.64-3.55 (m, 4H), 3.17-3.08 (m, 2H), 2.48-2.21 (m, 5H), 2.03-1.87 (m, 3 h), 1.34 (d, 3H, J=6.3 Hz). LC-MS: 250 [M/2+H]+, 500 [M+H]+, tR=1.20 min. HPLC: 100% at 214 nm, 100% at 254 nm, tR=4.59 min.