Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:14][C@H:15]([CH2:41][O:42][C:43](=[O:55])[CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH3:54])[CH2:16][S:17][CH2:18][C@@H:19]([C:38](O)=[O:39])[NH:20][C:21](=[O:37])[O:22][CH2:23][CH:24]1[C:36]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[C:30]2[C:25]1=[CH:26][CH:27]=[CH:28][CH:29]=2)(=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[NH2:56][CH2:57][CH2:58][C:59]1[CH:76]=[CH:75][C:62]([O:63][CH2:64][CH2:65][CH2:66][P:67](=[O:74])([O:71][CH2:72][CH3:73])[O:68][CH2:69][CH3:70])=[CH:61][CH:60]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl.C(OCC)(=O)C>[C:43]([O:42][CH2:41][C@@H:15]([O:14][C:1](=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[CH2:16][S:17][CH2:18][C@H:19]([NH:20][C:21]([O:22][CH2:23][CH:24]1[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:30]=2[C:31]2[C:36]1=[CH:35][CH:34]=[CH:33][CH:32]=2)=[O:37])[C:38]([NH:56][CH2:57][CH2:58][C:59]1[CH:60]=[CH:61][C:62]([O:63][CH2:64][CH2:65][CH2:66][P:67]([O:68][CH2:69][CH3:70])([O:71][CH2:72][CH3:73])=[O:74])=[CH:75][CH:76]=1)=[O:39])(=[O:55])[CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH3:54]
Reactant: CCCCCCCCCCCC(=O)OC[C@H](CSC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O)OC(=O)CCCCCCCCCCC
Reactant: CCOP(=O)(CCCOc1ccc(CCN)cc1)OCC
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCCCCCCCCCCC(=O)OC[C@H](CSC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)NCCc1ccc(OCCCP(=O)(OCC)OCC)cc1)OC(=O)CCCCCCCCCCC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (5R,9R)-9-(dodecanoyloxy)-1-(9H-fluoren-9-yl)-3,12-dioxo-2,11-dioxa-7-thia-4-azatricosane-5-carboxylic acid (6, 1 eq) in DCM (0.1 M) was added diethyl 3-(4-(2-aminoethyl)phenoxy)propylphosphonate (1.1 eq), DIEA (2.5 equiv) and HBTU (1.1 eq). The reaction mixture was then stirred at room temperature for 2 hours. The mixture was diluted with ethyl acetate, and washed with 5% citric acid three times, saturated NaHCO3 solution twice, water and brine. The organic layer was dried over anhydrous Na2SO4, and concentrated en vaccuo. The crude mixture was purified by flash chromatography on a COMBIFLASH® system (ISCO) using 60-100% EtOAc/Hex to give the product.
Reaction SMILES: [BH4-].[Na+].[N+:3]([C:6]1[CH:13]=[C:12]([O:14][CH3:15])[C:11]([O:16][CH3:17])=[C:10]([O:18][CH3:19])[C:7]=1[CH:8]=[O:9])([O-:5])=[O:4]>>[OH:9][CH2:8][C:7]1[C:10]([O:18][CH3:19])=[C:11]([O:16][CH3:17])[C:12]([O:14][CH3:15])=[CH:13][C:6]=1[N+:3]([O-:5])=[O:4]
Reactant: COc1cc([N+](=O)[O-])c(C=O)c(OC)c1OC
Agent: [BH4-]
Agent: [Na+]
Product: COc1cc([N+](=O)[O-])c(CO)c(OC)c1OC
Reaction time: 0.17 h
Yield: 90.9 %

Procedure:
Sodium borohydride (4.44 g. 0.12 mol) was added portionwise to a suspension of 2-nitro-4,5,6-trimethoxybenzaldehyde (24.2 g, 0.1 mol) in 200 ml during 0.5 hours at 5-10 ° C. in an ice-bath. The mixture was stirred for an additional 10 minutes, and the excess of NaBH4 was destroyed by addition of acetic acid. The mixture was then concentrated in vacuo to dryness, and the solid residue was triturated with water. The solid was collected by filtration, washed with water and recrystallized from ethanol to give 22.1 g (90.9%) of 2-hydroxymethyl-1-nitro-3,4,5-trimethoxybenzene; mp 69-70° C. 1H-NMR (CDCl3): δ2.89 (1H, b, exchangeable, OH) 3.94, 3.96, and 3.97 (each 3H, s, 3×OMe), 4.78 (2h, s, CH2), 7.38 (1H, s, H-6). Analyses: Calculated for C10H13NO6 : C, 49.38; H, 5.39; N, 5.76. Found: C, 49.44; H, 5.43; N, 5.79.
Reaction SMILES: [Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([CH2:9][CH2:10][CH2:11][OH:12])=[CH:4][C:3]=1[CH3:13].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.C(O)(C)C>ClCCl>[Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([CH2:9][CH2:10][CH:11]=[O:12])=[CH:4][C:3]=1[CH3:13]
Reactant: Cc1cc(CCCO)cc(C)c1Br
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: CC(C)O
Solvent: ClCCl
Product: Cc1cc(CCC=O)cc(C)c1Br
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 3-(4-bromo-3,5-dimethylphenyl)propan-1-ol (250 mg) in dichloromethane (5 mL) is added at 0° C. 1,1-dihydro-1,1,1-triacetoxy-1,2-benziodoxol-3(1H)-on (Dess-Martin periodinan, 2.7 mL of a 15% solution in dichloromethane). The mixture is stirred for 12 hours at room temperature, cooled to 0° C. and 1,1-dihydro-1,1,1-triacetoxy-1,2-benziodoxol-3(1H)-on (Dess-Martin periodinan, 1.6 mL of a 15% solution in dichloromethane) is added. After stirring for 4 hours isopropanol (5 mL) is added, the mixture is stirred for 15 minutes and the solvents are evaporated in vacuo. The residue is chromatographed on silica gel (cyclohexane/ethyl acetate 99:1→70:30) to give the title compound. Yield: 120 mg; LC (method 8): tR=0.38 min; Mass spectrum (ESI−): m/z=239 [M−H]−.
Reaction SMILES: [C:1]1(=O)[CH2:6][CH2:5][CH2:4][C:3](=[O:7])[CH2:2]1.[NH2:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=1.C(O)(=O)C>C(OCC)(=O)C>[F:19][C:16]([F:17])([F:18])[C:12]1[CH:11]=[C:10]([NH:9][C:1]2[CH2:6][CH2:5][CH2:4][C:3](=[O:7])[CH:2]=2)[CH:15]=[CH:14][N:13]=1
Reactant: Nc1ccnc(C(F)(F)F)c1
Reactant: O=C1CCCC(=O)C1
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: O=C1C=C(Nc2ccnc(C(F)(F)F)c2)CCC1
Temperature: 130 °C

Procedure:
A mixture of cyclohexane-1,3-dione (2.00 g, 17.8 mmol), 4-amino-2-trifluormethylpyridine (2.89 g, 17.8 mmol) and glacial acetic acid (10 mL) is heated at 130° C. for 4 h. The mixture cooled at room temperature, diluted with ethyl acetate and extracted three times with water. The phases are separated, and the aqueous layer is extracted with ethyl acetate. The combined organic layers are dried over Na2SO4 and concentreated under reduced pressure. The residue is purified by flash chromatography on silica (gradient dichloromethane/is methanol 95:5). Yield: 940 mg; ESI mass spectrum [M+H]+=257; Retention time HPLC: 0.80 min (V011_S01).
Reaction SMILES: [CH3:1][O:2][CH:3]([O:29][CH3:30])[C:4]1[CH:23]=[CH:22][C:7]([O:8][CH2:9][CH2:10]C23C=CC=CC2C(NC3=O)=O)=[C:6]([O:24][CH3:25])[C:5]=1[N+:26]([O-:28])=[O:27].O.[NH2:32]N.O>C(O)C>[CH3:1][O:2][CH:3]([O:29][CH3:30])[C:4]1[CH:23]=[CH:22][C:7]([O:8][CH2:9][CH2:10][NH2:32])=[C:6]([O:24][CH3:25])[C:5]=1[N+:26]([O-:28])=[O:27]
Reactant: NN
Reactant: COc1c(OCCC23C=CC=CC2C(=O)NC3=O)ccc(C(OC)OC)c1[N+](=O)[O-]
Solvent: O
Solvent: CCO
Product: COc1c(OCCN)ccc(C(OC)OC)c1[N+](=O)[O-]
Temperature: 25 °C
Yield: 116.4 %

Procedure:
A solution of 2-[2-(4-dimethoxymethyl-2-methoxy-3-nitrophenoxy)ethyl]phtalimide (0.05 g, 0.12 mmol) obtained in Step 2 in ethanol (1.0 mL) was added with hydrazine monohydrate (6.4 μL, 0.13 mmol) and heated under reflux for 3 hours. The reaction mixture was cooled to room temperature and added with water, followed by extracting with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure to obtain 2-(4-dimethoxymethyl-2-methoxy-3-nitrophenoxy)ethylamine (0.04 g, 100%).
Reaction SMILES: C(O)(=O)C.[C:5]([O:9][C:10]([NH:12][C:13]1[N:18]=[CH:17][C:16]([CH2:19][CH:20]([CH:28]([S:45][CH2:46][C:47]2[CH:52]=[CH:51][C:50]([O:53][CH3:54])=[CH:49][CH:48]=2)[CH2:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([O:37][Si](C(C)(C)C)(C)C)[CH:32]=2)[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[CH:15][CH:14]=1)=[O:11])([CH3:8])([CH3:7])[CH3:6].C([Si](OC1C=CC=C(I)C=1)(C)C)(C)(C)C.O.O.O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1.CCOC(C)=O>[C:5]([O:9][C:10]([NH:12][C:13]1[N:18]=[CH:17][C:16]([CH2:19][CH:20]([CH:28]([S:45][CH2:46][C:47]2[CH:52]=[CH:51][C:50]([O:53][CH3:54])=[CH:49][CH:48]=2)[CH2:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([OH:37])[CH:32]=2)[C:21]([O:23][C:24]([CH3:25])([CH3:26])[CH3:27])=[O:22])=[CH:15][CH:14]=1)=[O:11])([CH3:6])([CH3:7])[CH3:8]
Reactant: COc1ccc(CSC(CCc2cccc(O[Si](C)(C)C(C)(C)C)c2)C(Cc2ccc(NC(=O)OC(C)(C)C)nc2)C(=O)OC(C)(C)C)cc1
Agent: CC(C)(C)[Si](C)(C)Oc1cccc(I)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: COc1ccc(CSC(CCc2cccc(O)c2)C(Cc2ccc(NC(=O)OC(C)(C)C)nc2)C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 98 %

Procedure:
Glacial acetic acid (190 μL, 3.3 mmoL) was added to a solution of tert-butyl 2-({6-[(tert-butoxycarbonyl)amino]pyridin-3-yl}methyl)-5-(3-{[tert-butyl(dimethyl)silyl]oxy}phenyl)-3-[(4-methoxybenzyl)thio]pentanoate (800 mg, 0.89 mmol, synthesised according to the procedure for Example 1, starting from tert-butyl(3-iodophenoxy)dimethylsilane) in dry THF (10 mL). Tetrabutylammonium fluoride trihydrate (489 mg, 1.5 mmol) was added and the mixture was stirred for 12 h at room temperature. EtOAc (150 mL) was added and the solution was washed with saturated aqueous NaHCO3, water and brine, dried and concentrated. Flash chromatography (CH2Cl2/EtOAc, 10:1) gave tert-butyl 2-({6-[(tert-butoxycarbonyl)amino]pyridin-3-yl}methyl)-5-(3-hydroxyphenyl)-3-[(4-methoxybenzyl)thio]pentanoate (660 mg, 98%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[NH:7][CH:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].Br[CH2:22][CH:23]=[C:24]([CH3:26])[CH3:25]>C1COCC1>[C:1]([O:5][C:6](=[O:14])[NH:7][CH:8]1[CH2:13][CH2:12][N:11]([CH2:22][CH:23]=[C:24]([CH3:26])[CH3:25])[CH2:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)=CCBr
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)=CCN1CCC(NC(=O)OC(C)(C)C)CC1
Reaction time: 2 h

Procedure:
To 0.75 g (3.75 mmol) Piperidin-4-yl-carbamic acid tert-butyl ester and 0.78 g (5.62 mmol) K2CO3 in 5 mL THF was added drop wise 0.65 mL (5.62 mmol) of 1-Bromo-3-methyl-but-2-ene and stirring was continued for 2 h at room temperature. The reaction mixture was filtered, the filtrate was concentrated and the residue purified by column chromatography (silica, EtOAc).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:54])[C@@H:9]([CH3:53])[C:10]([NH:12][C@H:13]([C:31]([N:33]1[C@H:37]([C:38](=[O:50])[NH:39][C@H:40]2[C:49]3[C:44](=[CH:45][CH:46]=[CH:47][CH:48]=3)[CH2:43][CH2:42][CH2:41]2)[CH2:36][Si:35]([CH3:52])([CH3:51])[CH2:34]1)=[O:32])[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:26]=[CH:25][C:24]([C:27]([O:29]C)=[O:28])=[CH:23][CH:22]=2)=[CH:17][CH:16]=1)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li+].[OH-].Cl>C1COCC1.CO>[C:1]([O:5][C:6]([N:8]([CH3:54])[C@@H:9]([CH3:53])[C:10]([NH:12][C@H:13]([C:31]([N:33]1[C@H:37]([C:38](=[O:50])[NH:39][C@H:40]2[C:49]3[C:44](=[CH:45][CH:46]=[CH:47][CH:48]=3)[CH2:43][CH2:42][CH2:41]2)[CH2:36][Si:35]([CH3:51])([CH3:52])[CH2:34]1)=[O:32])[CH2:14][C:15]1[CH:16]=[CH:17][C:18]([C:21]2[CH:26]=[CH:25][C:24]([C:27]([OH:29])=[O:28])=[CH:23][CH:22]=2)=[CH:19][CH:20]=1)=[O:11])=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: COC(=O)c1ccc(-c2ccc(C[C@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)C(=O)N3C[Si](C)(C)C[C@H]3C(=O)N[C@@H]3CCCc4ccccc43)cc2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: C[C@@H](C(=O)N[C@@H](Cc1ccc(-c2ccc(C(=O)O)cc2)cc1)C(=O)N1C[Si](C)(C)C[C@H]1C(=O)N[C@@H]1CCCc2ccccc21)N(C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of methyl 4′-((S)-2-((S)-2-((tert-butoxycarbonyl)(methyl)amino)propanamido)-3-((R)-3,3-dimethyl-5-(((R)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)-1,3-azasilolidin-1-yl)-3-oxopropyl)-[1,1′-biphenyl]-4-carboxylate (40 mg, 0.053 mmol) in THF (1 mL) and MeOH (0.5 mL) was added LiOH solution (0.48 mL, 0.95 mmol). The resulting mixture was stirred at rt overnight and acidified (1N HCl) to pH 1. The resulting mixture was extracted with ethyl acetate (2×). The organic layer was separated, dried over MgSO4 and concentrated in vacuo to give the title compound. MS(ESI+) m/z 741.5 (M+H)+.
Reaction SMILES: [CH3:1][CH2:2][N:3]([CH2:6][CH2:7][NH:8][C:9]([C:11]1[C:15]([CH3:16])=[C:14](/[CH:17]=[C:18]2/[C:19]3[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=3[NH:26][C:27]/2=[O:28])[NH:13][C:12]=1[CH3:29])=[O:10])[CH2:4][CH3:5].[C:30]([OH:38])(=[O:37])[CH:31]([CH2:33][C:34]([OH:36])=[O:35])[OH:32].C1(C)C=CC=CC=1>CN1CCCC1=O>[CH3:1][CH2:2][N:3]([CH2:6][CH2:7][NH:8][C:9]([C:11]1[C:15]([CH3:16])=[C:14](/[CH:17]=[C:18]2/[C:19]3[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=3[NH:26][C:27]/2=[O:28])[NH:13][C:12]=1[CH3:29])=[O:10])[CH2:4][CH3:5].[CH2:33]([C:34]([OH:36])=[O:35])[C@H:31]([OH:32])[C:30]([OH:38])=[O:37]
Reactant: O=C(O)CC(O)C(=O)O
Agent: CCN(CC)CCNC(=O)c1c(C)[nH]c(/C=C2\C(=O)Nc3ccc(F)cc32)c1C
Solvent: CN1CCCC1=O
Solvent: Cc1ccccc1
Product: O=C(O)C[C@H](O)C(=O)O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
1 g of sunitinib base was dissolved in 3 ml of N-methyl pyrrolidone, at RT 0.336 g of Malic acid added (as a solid): the solution was heated to 40° C. than 15 ml of toluene was added and precipitation was observed. The suspension was kept at 40° C. for 1 hour than cooled to 0° C., filtered and washed with toluene. Dried at 60° C. under vacuum for 16 h.
Reaction SMILES: C(OC([N:8]1[CH2:44][CH2:43][C:11]2([N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:14][N:13]([CH2:22][C:23]3[N:33]([CH2:34][CH2:35][CH:36]4[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]4)[C:26]4[N:27]=[C:28]([C:31]#[N:32])[N:29]=[CH:30][C:25]=4[CH:24]=3)[C:12]2=[O:42])[CH2:10][CH2:9]1)=O)(C)(C)C.[F:45][C:46]([F:51])([F:50])[C:47]([OH:49])=[O:48]>ClCCl>[F:45][C:46]([F:51])([F:50])[C:47]([OH:49])=[O:48].[CH:36]1([CH2:35][CH2:34][N:33]2[C:26]3[N:27]=[C:28]([C:31]#[N:32])[N:29]=[CH:30][C:25]=3[CH:24]=[C:23]2[CH2:22][N:13]2[C:12](=[O:42])[C:11]3([CH2:43][CH2:44][NH:8][CH2:9][CH2:10]3)[N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:14]2)[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)C(=O)N(Cc1cc3cnc(C#N)nc3n1CCC1CCCCC1)CN2c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1ncc2cc(CN3CN(c4ccccc4)C4(CCNCC4)C3=O)n(CCC3CCCCC3)c2n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 3-[2-cyano-7-(2-cyclohexyl-ethyl)-7H-pyrrolo[2,3-d]pyrimidin-6-ylmethyl]4-oxo-1-phenyl-1,3,8-triaza-spiro[4.5]decane-8-carboxylic acid tert-butyl ester (340 mg, 0.56 mmol) in dichloromethane (5 ml), trifluoroacetic acid (5 ml) is added. After stirring for 1 h at room temperature, solvent is evaporated down to give 7-(2-cyclohexyl-ethyl)-6-(4-oxo-1-phenyl-1,3,8-triaza-spiro[4.5]dec-3-ylmethyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile trifluoroacetic acid salt in quant yield.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.[OH-].[Na+].Br[CH2:14][CH3:15].[Cl-].[NH4+]>C1C=CC=CC=1.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.ClCCl.O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:14][CH3:15])[CH:6]=[CH:5]2
Reactant: CCBr
Reactant: Clc1ccc2[nH]ccc2c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Cl-]
Solvent: O
Solvent: c1ccccc1
Solvent: ClCCl
Product: CCn1ccc2cc(Cl)ccc21
Temperature: 25 °C
Reaction time: 40 h

Procedure:
In benzene (10 ml), 5-chloroindole (1.52 g) was dissolved, followed by the addition of a 50% aqueous solution of sodium hydroxide (10 ml), tetrabutylammonium bromide (161 mg) and bromoethane (1.64 g). The resulting mixture was stirred at room temperature for 40 hours. After the addition of a saturated aqueous solution of ammonium chloride to the reaction mixture, water and dichloromethane were added to separate the organic layer. After the organic layer was dried over anhydrous sodium sulfate, the residue obtained by distilling off the solvent under reduced pressure was purified by chromatography on a silica gel column (ethyl acetate:hexane 1:20), whereby the title compound (1.68 g, 93%) was obtained as colorless crystals.
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(C)(c1ncc(-c2cc(N)cc(Nc3nccc(C(F)(F)F)n3)c2)s1)S(N)(=O)=O
Reactant: CC(=O)Cl
Solvent: CO
Solvent: CCN(CC)CC
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=+++
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@@H:10]([NH:32][C:33](=[O:45])[C:34]([NH:37]C(=O)OC(C)(C)C)([CH3:36])[CH3:35])[C:11]([N:13]1[CH2:31][CH2:30][CH2:29][C:15]2([C:19](=[O:20])[N:18]([CH3:21])[CH2:17][CH:16]2[C:22]2[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=2)[CH2:14]1)=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O.[OH-].[Na+]>C(Cl)Cl>[NH2:37][C:34]([CH3:36])([CH3:35])[C:33]([NH:32][C@H:10]([CH2:9][O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:11]([N:13]1[CH2:31][CH2:30][CH2:29][C:15]2([C:19](=[O:20])[N:18]([CH3:21])[CH2:17][CH:16]2[C:22]2[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=2)[CH2:14]1)=[O:12])=[O:45]
Reactant: Cc1ccc(C2CN(C)C(=O)C23CCCN(C(=O)[C@@H](COCc2ccccc2)NC(=O)C(C)(C)NC(=O)OC(C)(C)C)C3)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1ccc(C2CN(C)C(=O)C23CCCN(C(=O)[C@@H](COCc2ccccc2)NC(=O)C(C)(C)N)C3)cc1
Temperature: 7.5 °C
Reaction time: 8 h

Procedure:
To a stirred solution of tert-butyl 1-((2R)-3-(benzyloxy)-1-(2-methyl-1-oxo-4-p-tolyl-2,7-diazaspiro[4.5]decan-7-yl)-1-oxopropan-2-ylamino)-2-methyl-1-oxopropan-2-ylcarbamate (302 mg, 0.486 mmol) in DCM (3 ml) was added TFA (562 I, 7.30 mmol) at 5° C. The reaction mixture was then left to stir at 5-10° C. overnight. The reaction mixture was added to 2M NaOH (2 ml) and extracted with DCM (3×5 ml). The extracts were washed with brine (5 ml), dried (MgSO4) and concentrated to give the mixture of diastereomers. The desired isomer was isolated via SFC chromatography.
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[C:7]2[CH:8]=[C:9]([C:12]3[NH:16][C:15]([C:17]#[N:18])=[CH:14][CH:13]=3)[CH:10]=[CH:11][C:6]=2[NH:5][C:4](=O)[O:3]1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:30])=CC=1.COCCOC>C(#N)C>[CH3:1][C:2]1([CH3:20])[C:7]2[CH:8]=[C:9]([C:12]3[NH:16][C:15]([C:17]#[N:18])=[CH:14][CH:13]=3)[CH:10]=[CH:11][C:6]=2[NH:5][C:4](=[S:30])[O:3]1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CC1(C)OC(=O)Nc2ccc(-c3ccc(C#N)[nH]3)cc21
Solvent: COCCOC
Solvent: CC#N
Product: CC1(C)OC(=S)Nc2ccc(-c3ccc(C#N)[nH]3)cc21

Procedure:
5-(4,4-Dimethyl-2-oxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)-1H-pyrrole-2-carbonitrile (14.5 kg), Lawesson's Reagent (12.1 kg, 1.16 eq.), DME (215 kg), and acetonitrile (8.96 kg) were combined and heated to reflux for at least 4 hours at less than 16 hours to form unpurified 5-(4,4-dimethyl-2-thioxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)-1H-pyrrole-2-carbonitrile. The mixture was cooled to 18 to 28° C., quenched with water (276 kg), cooled to 10 to 20° C., stirred for at least 30 minutes, and the resulting slurry collected via filtration.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].S(=O)(=O)(O)O.[CH2:10]([P:17](=[O:24])([CH2:21][CH2:22][CH3:23])[CH2:18][CH2:19][CH3:20])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.N>>[N+:1]([C:14]1[CH:15]=[CH:16][C:11]([CH2:10][P:17](=[O:24])([CH2:18][CH2:19][CH3:20])[CH2:21][CH2:22][CH3:23])=[CH:12][CH:13]=1)([O-:4])=[O:2]
Reactant: CCCP(=O)(CCC)Cc1ccccc1
Reactant: O=[N+]([O-])O
Agent: N
Agent: O=S(=O)(O)O
Product: CCCP(=O)(CCC)Cc1ccc([N+](=O)[O-])cc1
Temperature: 60 °C
Reaction time: 1.5 h

Procedure:
To a mixture of nitric acid (3.6 ml) and concentrated sulfuric acid (22 ml) was added benzyldipropylphosphineoxide (10.75 g) at 0° C., and the mixture was stirred at 60° C. for 1.5 hours. The reaction mixture was added to ice-water, and ammonia solution was added to the mixture to neutralize the solution, which was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried with magnesium sulfate and concentrated. The residue was separated and purified with column chromatography (ethyl acetate/ethanol=9:1→4:1) to give 4-nitrobenzyldipropylphosphine oxide (3.77 g) as pale yellow crystals.
Reaction SMILES: Cl.[C:2]([C:4]1[CH:9]=[CH:8][C:7]([NH:10]N)=[CH:6][CH:5]=1)#[N:3].C([O-])(=O)C.[Na+].[C:17]1(=[O:34])[N:21]([CH:22]2[CH2:27][CH2:26][C:25](=O)[CH2:24][CH2:23]2)[C:20](=[O:29])[C:19]2=[CH:30][CH:31]=[CH:32][CH:33]=[C:18]12>C(O)(=O)C>[C:20]1(=[O:29])[N:21]([CH:22]2[CH2:23][C:24]3[C:8]4[C:7](=[CH:6][CH:5]=[C:4]([C:2]#[N:3])[CH:9]=4)[NH:10][C:25]=3[CH2:26][CH2:27]2)[C:17](=[O:34])[C:18]2=[CH:33][CH:32]=[CH:31][CH:30]=[C:19]12
Reactant: O=C1CCC(N2C(=O)c3ccccc3C2=O)CC1
Reactant: N#Cc1ccc(NN)cc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Product: N#Cc1ccc2[nH]c3c(c2c1)CC(N1C(=O)c2ccccc2C1=O)CC3

Procedure:
4-Cyanophenyl hydrazine hydrochloride (4.41 g, 0.026 mole) was dissolved in acetic acid (100 ml) and sodium acetate (2 g) was added. 4-Phthalimido cyclohexanone (6.4 g, 0.026 mole) was added and the mixture heated under reflux overnight. The solvent was removed in vacuo and the residue triturated with methanol to give 3-phthalimido-6-cyano-1,2,3,4-tetrahydrocarbazole as a beige solid, (5.3 g).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[S:3]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:16])[CH2:13][C:14]#[N:15])=[CH:7][CH:6]=1)=[O:4].[H-].[Na+].[CH:21]1([C:24](Cl)=[O:25])[CH2:23][CH2:22]1.Cl.O>C1COCC1.N1C=CN=C1>[F:18][C:2]([F:17])([F:1])[S:3]([C:5]1[CH:6]=[CH:7][C:8]([NH:11][C:12](=[O:16])[C:13]([C:14]#[N:15])=[C:24]([CH:21]2[CH2:23][CH2:22]2)[OH:25])=[CH:9][CH:10]=1)=[O:4]
Reactant: N#CCC(=O)Nc1ccc(S(=O)C(F)(F)F)cc1
Reactant: O=C(Cl)C1CC1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: N#CC(C(=O)Nc1ccc(S(=O)C(F)(F)F)cc1)=C(O)C1CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 65.9 %

Procedure:
3.1 g (0.0112 mole) of N-(4'-trifluoromethylsulfinyl-phenyl)-cyanoacetamide in 100 ml of anhydrous THF and 10 mg of catalytic imidazole and 0.75 g (0.0246 mole) of sodium hydride (80% oil dispersion) were stirred at room temperature for 90 minutes and then 1.32 ml (0.0146 mole) of cyclopropylcarbonyl chloride were added dropwise. The solution was stirred at room temperature for 10 minutes, was poured into a 1M HCl/water mixture and was filtered. The product was dissolved in dichloromethane and chromatographed on a short silica column (dichloromethane) to obtain 2.54 g (66% yield) of N-(4'-trifluoromethylsulfinyl-phenyl)-2-cyano-3-cyclopropyl-3-hydroxy-prop-2-enamide melting at 155°-157° C.