Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([O-])([CH3:4])[CH3:3].[K+].[NH:7]1[C:13](=[O:14])C[CH2:11][CH2:10][C:9]2[CH:15]=[CH:16][CH:17]=[CH:18][C:8]1=2.BrCCC>C1COCC1.C([Li])CCCCC.O.Cl>[CH3:1][CH:2]([CH:4]1[C:13](=[O:14])[NH:7][C:8]2[CH:18]=[CH:17][CH:16]=[CH:15][C:9]=2[CH2:10][CH2:11]1)[CH3:3]
Reactant: CC(C)(C)[O-]
Reactant: O=C1CCCc2ccccc2N1
Agent: Cl
Agent: [K+]
Agent: [Li]CCCCCC
Solvent: O
Solvent: CCCBr
Solvent: C1CCOC1
Product: CC(C)C1CCc2ccccc2NC1=O
Temperature: 0 °C
Reaction time: 23 h
Yield: 46.2 %

Procedure:
29,01 g (0,253 mol) potassium tert-butylate is suspended in 227 ml of THF and 40 g (0,249 mol) 1,3,4,5-tetrahydro-benzo[b]azepin-2-one is added in portions at a temperature of −16°. At the same temperature 140,22 g (0,50 mol) of n-hexyllithium (33% in hexane) are added over the course of 30 min. Then a solution of 34,28 g (0,276 mol) 3-bromo propane in 21,8 ml THF is added at a temperature of −16°. After the solution has been stirred for 23 hours and meanwhile was allowed to reach room temperature, 150 g of water is added dropwise while stirring and cooling with ice water. The resulting mixture is acidified with 62 g hydrochloric acid (37%), the phases are separated and the organic phase is evaporated. 150 ml dichloromethane is added to the residue, the suspension is filtered and the filter is washed with additional 60 ml dichloromethane. The solution is concentrated and the crystals which precipitated on cooling to 0° over night are filtered off. The solid is recrystallized from 94,9 g 2-propanol. 23,3 g (0,115 mol) of 4,5-dihydro-3-(2-propyl)-1H-benzo[b]azepine-2-one is obtained [46,1%, HPLC 98,4 area %].
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH2:11]([O:14][C:15]([N:17]=[C:18]1[N:22]([CH3:23])[C@H:21]([CH2:24][OH:25])[CH2:20][CH2:19]1)=[O:16])[CH:12]=[CH2:13].C(N(CC)CC)C>ClCCl>[CH2:11]([O:14][C:15]([N:17]=[C:18]1[N:22]([CH3:23])[C@H:21]([CH:24]=[O:25])[CH2:20][CH2:19]1)=[O:16])[CH:12]=[CH2:13]
Reactant: C=CCOC(=O)N=C1CC[C@@H](CO)N1C
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CCOC(=O)N=C1CC[C@@H](C=O)N1C
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 73.7 %

Procedure:
To a solution of oxalyl chloride (0.52 ml) in dichloromethane (15 ml) was added dropwise dimethyl sulfoxide (0.60 ml) at -78° C. After stirring at -78° C. for 10 minutes, to the mixture was added dropwise a solution of (2S)-5-allyloxycarbonylimino-2-hydroxymethyl-1-methylpyrrolidine (0.63 g) in dichloromethane (10 ml). After stirring at -78° C. for 10 minutes, to the mixture was added dropwise triethylamine (2.1 ml) and the resulting mixture was allowed to warm to 0° C. The mixture was washed with water and brine, dried over magnesium sulfate, and evaporated. The residue was chromatographed on silica gel eluting with a mixture of acetone and dichloromethane (1:4 V/V) to give (2S)-5-allyloxycarbonylimino-2-formyl-1-methylpyrrolidine (0.46 g).
Reaction SMILES: Cl.[S:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[C:4]([N:11]2[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([NH2:25])=[C:21]([CH3:26])[CH:20]=3)[CH2:13][CH2:12]2)=[N:3]1.[CH3:27][C:28](=[CH2:32])[C:29](Cl)=[O:30]>>[S:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[C:4]([N:11]2[CH2:12][CH2:13][N:14]([CH2:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([NH:25][C:29](=[O:30])[C:28]([CH3:32])=[CH2:27])=[C:21]([CH3:26])[CH:20]=3)[CH2:15][CH2:16]2)=[N:3]1
Reactant: C=C(C)C(=O)Cl
Reactant: Cc1cc(CCN2CCN(c3nsc4ccccc34)CC2)ccc1N
Agent: Cl
Product: C=C(C)C(=O)Nc1ccc(CCN2CCN(c3nsc4ccccc34)CC2)cc1C
Yield: 72.8 %

Procedure:
Starting with 4-[2-(4-benzo[d]isothiazol-3-yl-piperazin-1-yl)-ethyl]-2-methyl-phenylamine hydrochloride (0.6 g, 1.702 mmol) and 2-methyl-acryloyl chloride (0.206 mL, 1.702 mmol) and following the procedure outlined in Example 512, N-{4-[2-(4-Benzo[d]isothiazol-3-yl-piperazin-1-yl)-ethyl]-2-methyl-phenyl}-2-methyl-acrylamide (0.521 g, 1.239 mmole) was obtained. Yield=73%. 100% purity at 254 nM; LCMS (APCI): 421.3 [M+H]+; 1H NMR (400 MHz, DMSO-d6) 811.17 (bs, 1H), 9.32 (s, 1H), 8.10 d, J=7.88 Hz, 1H), 8.07 (d, J=7.88 Hz, 1H), 7.55 (t, J=7.88 Hz, 1H), 7.43 (t, J=7.88 Hz, 1H), 7.19 (d, J=7.88 Hz, 1H), 7.11 (s, 1H), 7.05 (d, J=7.88 Hz, 1H), 5.80 (s, 1H), 5.44 (s, 1H), 4.05 (bd, J=12.08 Hz, 2H), 3.63 (bd, J=12.08 Hz, 2H), 3.51–3.32 (m, 5H), 3.31 (s, H2O), 3.29–3.22 (m, 1H), 3.07–2.98 (m, 2H), 2.12 (s, 3H), 1.90 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[C:18]([F:19])=[C:17]([F:20])[C:16]([C:21]#[C:22][Si](C)(C)C)=[CH:15][C:10]=1[C:11]([O:13][CH3:14])=[O:12].[OH:27]S(O)(=O)=O.O>CC(C)=O>[C:21]([C:16]1[C:17]([F:20])=[C:18]([F:19])[C:9]([NH:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])=[C:10]([CH:15]=1)[C:11]([O:13][CH3:14])=[O:12])(=[O:27])[CH3:22]
Reactant: O=S(=O)(O)O
Reactant: COC(=O)c1cc(C#C[Si](C)(C)C)c(F)c(F)c1Nc1ccccc1F
Solvent: O
Solvent: CC(C)=O
Product: COC(=O)c1cc(C(C)=O)c(F)c(F)c1Nc1ccccc1F

Procedure:
A mixture of methyl 2-(2-fluorophenylamino)-3,4-difluoro-5-((trimethylsilyl)ethynyl)benzoate (9 mmol, 3.5 g), HgSO4 (9 mmol, 2.67 g), and cone. H2SO4 (18 mmol, 0.96 ml) in acetone:H2O (70:12 ml) was refluxed at 65° C. overnight. The mixture was concentrated, diluted with EtOAc, and washed with water and brine. The organic fractions are combined, dried over MgSO4 and concentrated under reduced pressure. The crude material (brown solid) was triturated with MeOH and the precipitate was filtered, washed with additional MeOH and dried to yield the desired product in 60% (1.78 g).
Reaction SMILES: [N+](CCCC)(CCCC)(CCCC)CCCC.[F-].[N:19]1([C:25]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[N:27]([Si](C(C)C)(C(C)C)C(C)C)[CH:26]=2)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>C1COCC1.CCOC(C)=O>[N:19]1([C:25]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[NH:27][CH:26]=2)[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1cc(N2CCCCC2)c2ccccc21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: c1ccc2c(N3CCCCC3)c[nH]c2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 74 %

Procedure:
Add nBu4NF (1.0M in THF, 3.2 mL, 3.2 mmol) to a solution of 3-piperidin-1-yl-1-triisopropylsilanyl-1H-indole (835 mg, 2.34 mmol) in THF (10 mL). Stir the red solution at RT for 1 h, then dilute with EtOAc (40 mL) and wash with satd NaHCO3 (20 mL). Dry, filter, and concentrate the organic solution then purify the crude material by flash chromatography, using a linear gradient of 100% hexanes to 40% EtOAc/hexanes. Obtain the title compound (347 mg, 74%) as a grey solid. MS (ES+) 201.1 (M+1)+. 1H NMR (400 MHz, CDCl3): δ 7.65 (d, 1H, J=8.1), 7.59 (br s, 1H), 7.29 (d, 1H, J=8.4), 7.16 (t, 1H, J=7.5), 7.06 (t, 1H, J=7.9), 6.70 (s, 1H), 3.03 (m, 4H), 1.80 (m, 4H), 1.59 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH2:8][S:9][C:10]2[N:15]=[C:14]([OH:16])[CH:13]=[C:12]([CH3:17])[N:11]=2)=[CH:6][CH:5]=[C:4]([Cl:18])[N:3]=1.[CH2:19]([N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1)[CH3:20]>CS(C)=O>[Cl:1][C:2]1[C:7]([CH2:8][S:9][C:10]2[N:15]=[C:14]([OH:16])[CH:13]=[C:12]([CH3:17])[N:11]=2)=[CH:6][CH:5]=[C:4]([N:24]2[CH2:25][CH2:26][N:21]([CH2:19][CH3:20])[CH2:22][CH2:23]2)[N:3]=1.[Cl:18][C:4]1[N:3]=[C:2]([N:24]2[CH2:25][CH2:26][N:21]([CH2:19][CH3:20])[CH2:22][CH2:23]2)[C:7]([CH2:8][S:9][C:10]2[N:15]=[C:14]([OH:16])[CH:13]=[C:12]([CH3:17])[N:11]=2)=[CH:6][CH:5]=1
Reactant: CCN1CCNCC1
Reactant: Cc1cc(O)nc(SCc2ccc(Cl)nc2Cl)n1
Solvent: CS(C)=O
Product: CCN1CCN(c2ccc(CSc3nc(C)cc(O)n3)c(Cl)n2)CC1
Product: CCN1CCN(c2nc(Cl)ccc2CSc2nc(C)cc(O)n2)CC1

Procedure:
A mixture of 2-{[(2,6-dichloropyridin-3-yl)methyl]sulfanyl}-6-methylpyrimidin-4-ol (2.0 g, 6.61 mmol) and 1-ethylpiperazine (3.77 g, 26.88 mmol) was heated in DMSO (20 mL) at 90° C. overnight. After cooling, the mixture was extracted with ethyl acetate (2×100 mL). The organic layer was separated and washed with water and brine. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was evaporated to dryness and purified by CombiFlash chromatography using 0-20% dichloromethane:methanol to provide 2-({[2-chloro-6-(4-ethylpiperazin-1-yl)pyridin-3-yl]methyl}sulfanyl)-6-methylpyrimidin-4-ol (1H NMR (400 MHz, DMSO-d6): δ 1.02 (t, 3H), 2.18 (s, 3H), 2.31 (q, 2H), 2.56 (m, 4H), 3.42 (m, 4H), 4.30 (s, 2H), 6.01 (bs, 1H), 6.78 (d, J=8.4 Hz, 1H), 7.72 (d, J=8.4 Hz, 1H), LRMS (ES+) m/z 379.8) and 2-({[6-chloro-2-(4-ethylpiperazin-1-yl)pyridin-3-yl]methyl}sulfanyl)-6-methylpyrimidin-4-ol (1H NMR (400 MHz, DMSO-d6): δ 0.99 (t, 3H), 2.21 (s, 3H), 2.31 (q, 2H), 2.56 (m, 4H), 3.42 (m, 4H), 4.37 (s, 2H), 6.01 (bs, 1H), 7.06 (d, J=7.7 Hz, 1H), 7.77 (d, J=7.7 Hz, 1H), LRMS (ES+) m/z 379.8) as a white solid (1.73 g, 3:1 ratio, 69% yield).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH:4]([CH2:21][CH2:22][CH:23]([CH3:25])[CH3:24])[N:5]([S:7]([NH:10]C(OCC1C=CC=CC=1)=O)(=[O:9])=[O:8])[CH3:6].[CH3:27]O>[Pd]>[CH3:1][O:2][C:3](=[O:26])[CH:4]([CH2:21][CH2:22][CH:23]([CH3:24])[CH3:25])[NH:5][CH3:6].[CH3:1][O:2][C:3](=[O:26])[C:4]([CH2:21][CH2:22][CH3:23])([CH3:27])[NH:5][S:7]([NH2:10])(=[O:8])=[O:9]
Reactant: CO
Reactant: COC(=O)C(CCC(C)C)N(C)S(=O)(=O)NC(=O)OCc1ccccc1
Agent: [Pd]
Product: CCCC(C)(NS(N)(=O)=O)C(=O)OC
Product: CNC(CCC(C)C)C(=O)OC
Reaction time: 3.5 h

Procedure:
A solution of (N-carbobenzyloxyaminosulfonyl) -2- (3-methylbutyl)-sarcosine methyl ester (20.6 g, 53.17 mmol) in 200 ml of methanol under nitrogen was cooled to 0° C. and 1.5 g of 10% Pd/C was added. The mixture was placed into a Parr Apparatus and hydrogenated for 3.5 hours. The catalyst was removed on a pad of CELITE® and the filtrate was concentrated in vacuo to afford 13.24 g (98.6%) of N-aminosulfonyl) -2-(3-methylbutyl)-sarcosine methyl ester (Formula VII: R=CH3 ; R1 =H; R2 =(CH2)2CH(CH3)2 ; R3 =CH3 ) as an oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10]O)=[CH:6][C:5]=1[N+:12]([O-:14])=[O:13].C(N(CC)CC)C.C1(C)C=CC(S(Cl)(=O)=O)=CC=1.[NH:34]1[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1>ClCCl>[CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][N:34]2[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]2)=[CH:6][C:5]=1[N+:12]([O-:14])=[O:13]
Reactant: COC(=O)c1ccc(CO)cc1[N+](=O)[O-]
Reactant: C1CCNCC1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1ccc(CN2CCCCC2)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h
Yield: 45.5 %

Procedure:
To a solution of 4-hydroxymethyl-2-nitro-benzoic acid methyl ester (2.0 g, 9.47 mmol) in dry dichloromethane (80 mL) under argon, at room temperature, triethylamine (1.6 mL, 10.9 mmol, 1.15 eq.) and then p-toluenesulfonyl chloride (2.08 g, 10.9 mmol, 1.15 eq.) were added. The reaction mixture was stirred at room temperature for 1 h, then piperidine (1.6 mL, 18.94 mmol, 2 eq.) was added and the mixture stirred for additional 24 hours. The solvent was evaporated and the residue purified by flash chromatography on silica gel, using dichloromethane/ethanol 95:5 as eluant, affording 1.2 g of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:19]2[S:23][C:22]([C:24]([S:27]([NH2:30])(=[O:29])=[O:28])([CH3:26])[CH3:25])=[N:21][CH:20]=2)[CH:5]=[C:6]([NH:8][C:9]2[N:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:11][N:10]=2)[CH:7]=1.C(N(CC)CC)C.[C:38](Cl)(=[O:40])[CH3:39]>C(Cl)Cl.CO>[S:27]([C:24]([C:22]1[S:23][C:19]([C:4]2[CH:3]=[C:2]([NH:1][C:38](=[O:40])[CH3:39])[CH:7]=[C:6]([NH:8][C:9]3[N:14]=[C:13]([C:15]([F:16])([F:18])[F:17])[CH:12]=[CH:11][N:10]=3)[CH:5]=2)=[CH:20][N:21]=1)([CH3:26])[CH3:25])(=[O:29])(=[O:28])[NH2:30]
Reactant: CC(=O)Cl
Reactant: CC(C)(c1ncc(-c2cc(N)cc(Nc3nccc(C(F)(F)F)n3)c2)s1)S(N)(=O)=O
Solvent: CCN(CC)CC
Solvent: CO
Solvent: ClCCl
Product: CC(=O)Nc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnc(C(C)(C)S(N)(=O)=O)s2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 34.7 %

Procedure:
2-[5-(3-Amino-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]propane-2-sulfonamide (Example 71, 90 mg, 0.196 mmol) was suspended in CH2Cl2 (5 mL) with triethylamine (55 μL, 0.393 mmol), and acetyl chloride (28 μL, 0.393 mmol) was added. After stirring for 1 h at room temperature, additional acetyl chloride (28 μL, 0.393 mmol) and triethylamine (55 μL, 0.393 mmol) were added. After another 1 h at room temperature, the suspension was diluted with MeOH, silica was added, and the mixture was evaporated to dryness. Flash chromatography (dry load, 40-100% ethyl acetate in hexanes) afforded N-(3-[2-(2-sulfamoylpropan-2-yl)-1,3-thiazol-5-yl]-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}-phenyl)acetamide (34 mg, 35%) as a white solid. MS ESI: [M+H]+ m/z 501.0. 1H NMR (500 MHz, DMSO-d6) δ 10.35 (s, 1H), 10.07 (s, 1H), 8.82 (d, J=4.9, 1H), 7.94 (s, 1H), 7.91 (s, 1H), 7.83 (s, 1H), 7.61 (s, 1H), 7.29 (d, J=4.9, 1H), 7.05 (s, 2H), 2.05 (s, 3H), 1.79 (s, 6H). rhSYK activity=+++