Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+](C1C=C([N+]([O-])=O)C=CC=1Cl)([O-])=O.[OH-].[Na+:15].[Cl-].[NH4+].[N+:18]([C:21]1[CH:26]=[C:25]([N+:27]([O-:29])=[O:28])[CH:24]=[CH:23][C:22]=1[O-:30])([O-])=O.[SH-].[Cl-].[Na+]>O>[NH2:18][C:21]1[CH:26]=[C:25]([N+:27]([O-:29])=[O:28])[CH:24]=[CH:23][C:22]=1[O-:30].[Na+:15]
Reactant: O=[N+]([O-])c1ccc([O-])c([N+](=O)[O-])c1
Agent: O=[N+]([O-])c1ccc(Cl)c([N+](=O)[O-])c1
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Product: Nc1cc([N+](=O)[O-])ccc1[O-]
Temperature: 90 °C

Procedure:
A suspension of 202.6 parts of 2,4-dinitrochlorobenzene in 300 parts of water and 7 parts of 32.6% strength sodium hydroxide solution is heated to about 90° C., and 256 parts of 32.6% strength sodium hydroxide solution are added at 90° to 95° C. in the course of about 3 hours, whilst stirring. The mixture is subsequently stirred at 90° to 95° C. for about 2 hours and 400 parts of water and 184 parts of ammonium chloride are added to the resulting 2,4-dinitrophenolate suspension, whereupon a pH value of 7.0 is established. 580 parts of a 31.9% strength hydrosulphide solution are then metered in at 70° to 75° C. in the course of about 45 minutes, whilst stirring continuously and continuously monitoring the pH value of the reduction batch, which rises to 8.6. The mixture is subsequently stirred at 70° to 75° C. for about 45 minutes. 40 parts of sodium chloride are then sprinkled in and the reaction mixture is then cooled to about 5° C. and filtered. 410 parts of a 39.6% strength aqueous press cake of sodium 2-amino-4-nitrophenolate, corresponding to 92% of the theoretical yield, are obtained. 410 parts of this press cake are introduced into 1,000 parts of water and are dissolved at pH ~1 with 225 parts of 30% strength aqueous hydrochloric acid. The sulphur is then filtered off and 116 parts of 32.6% strength sodium hydroxide solution are added to the aqueous solution of 2-amino-4-nitrophenol hydrochloride in order to establish a pH of 5. The yellow suspension of 2-amino-4-nitrophenol is subsequently stirred at 5° to 10° C. for about 1 hour and the product which has separated out is isolated by filtration. 324 parts of a 41.9% strength aqueous press cake of 2-amino-4-nitrophenol, corresponding to 135.8 parts of 100% pure 2-amino-4-nitrophenol (88% of theory, relative to 2,4-dinitrochlorobenzene) are obtained. A dried sample has a sulphur content of <0.1% and a melting point of 144° C.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH:7]([C:10]1[CH:15]=[C:14]([CH:16]([CH3:18])[CH3:17])[CH:13]=[C:12]([CH:19]([CH3:21])[CH3:20])[C:11]=1[CH2:22][C:23](O)=[O:24])([CH3:9])[CH3:8].[CH3:26][O:27][C:28](=[O:46])[C:29]1[CH:34]=[C:33]([CH:35]([CH3:37])[CH3:36])[C:32]([O:38][S:39](=[O:42])(=[O:41])[NH2:40])=[C:31]([CH:43]([CH3:45])[CH3:44])[CH:30]=1.C(N(CC)CC)C>C1(C)C=CC=CC=1.CN(C)C=O>[CH3:26][O:27][C:28](=[O:46])[C:29]1[CH:30]=[C:31]([CH:43]([CH3:45])[CH3:44])[C:32]([O:38][S:39](=[O:41])(=[O:42])[NH:40][C:23](=[O:24])[CH2:22][C:11]2[C:10]([CH:7]([CH3:8])[CH3:9])=[CH:15][C:14]([CH:16]([CH3:18])[CH3:17])=[CH:13][C:12]=2[CH:19]([CH3:21])[CH3:20])=[C:33]([CH:35]([CH3:37])[CH3:36])[CH:34]=1
Reactant: CC(C)c1cc(C(C)C)c(CC(=O)O)c(C(C)C)c1
Reactant: COC(=O)c1cc(C(C)C)c(OS(N)(=O)=O)c(C(C)C)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: COC(=O)c1cc(C(C)C)c(OS(=O)(=O)NC(=O)Cc2c(C(C)C)cc(C(C)C)cc2C(C)C)c(C(C)C)c1
Reaction time: 8 h
Yield: 80.2 %

Procedure:
Oxalyl chloride (1.12 mL, 12.8 mmol) was added dropwise to a solution of 2,4,6-triisopropylphenyl acetic acid (3.05 g, 11.6 mmol) in 150 mL toluene with 4 drops of N,N-dimethylformamide as a catalyst. The resulting solution was stirred overnight and then concentrated in vacuo. The residue was re-dissolved in 150 mL dichloromethane. 3,5-Bis(1-methylethyl)-4-(sulfamoyloxy)benzoic acid methyl ester (3.48 g, 11.6 mmol) and triethylamine (4.0 mL) were added and the resulting mixture was stirred for 2 hours. Washed with 1 M HCl, dried the organic layer over magnesium sulfate, filtered, and concentrated to give an off-white foam. Recrystallized (hexanes) to give 5.21 g of the title compound as a white solid; mp 144-146° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][CH:9]=[C:10]2[CH2:13][C:14](Cl)=[O:15])=[CH:5][CH:4]=1.[NH3:17]>CCOCC>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][CH:9]=[C:10]2[CH2:13][C:14]([NH2:17])=[O:15])=[CH:5][CH:4]=1
Reactant: N
Reactant: COc1ccc2cccc(CC(=O)Cl)c2c1
Solvent: CCOCC
Product: COc1ccc2cccc(CC(N)=O)c2c1

Procedure:
The (7-methoxynaphth-1-yl)acetyl chloride obtained above is dissolved in 200 cm3 of anhydrous ether. After cooling the solution with the aid of an ice-salt bath, 200 cm3 of an aqueous concentrated ammonia solution are added, with stirring. The mixture is stirred for 30 minutes, and the resulting precipitate is suction filtered. The product is recrystallised in ethanol.
Reaction SMILES: Cl.COC1C2CC[C@H]3[C@H](CCN3CCCC[N:21]3[C:26](=[O:27])[CH2:25][C:24]([CH3:29])([CH3:28])[CH2:23][C:22]3=[O:30])C=2C=CC=1.Cl.N1C=CC=CC=1.[OH-].[NH4+]>C(Cl)Cl.C(OCC)(=O)C>[CH3:28][C:24]1([CH3:29])[CH2:25][C:26](=[O:27])[NH:21][C:22](=[O:30])[CH2:23]1
Reactant: COc1cccc2c1CC[C@H]1[C@@H]2CCN1CCCCN1C(=O)CC(C)(C)CC1=O
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC1(C)CC(=O)NC(=O)C1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
8.8 g (22.1 mmol) of rac-cis-1-[4-(6-methoxy-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]indol-3-yl)-butyl]-4,4-dimethyl-piperidine-2,6-dione hydrochloride were mixed well with 100 g of pyridine hydrochloride and stirred under an argon atmosphere in an oil bath for 4 hours at an oil bath temperature of 180°. After cooling the mixture was treated with ice-water, whereupon the brown solution was made alkaline with ammonium hydroxide solution and then extracted with methylene chloride. The organic phase was washed with water, dried over magnesium sulphate and evaporated. The brown oily product obtained (9.8 g) was chromatographed on a 30-fold amount of silica gel. The uniform eluates obtained in a thin-layer chromatogram using methylene chloride/ethyl acetate 1:1 were pooled and evaporated. The oil obtained crystallized after treatment with hexane. There were obtained 5.5 g (65%) of rac-cis-1-(6-hydroxy-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]indol-3-yl)-butyl]-4,4-dimethyl-piperidine-2,6-dione in the form of yellowish crystals of m.p. 131°-132°.
Reaction SMILES: [CH:1]([C:4]1[N:5]=[C:6]([CH2:9][CH2:10][C:11]2[CH:32]=[CH:31][N:14]3[C:15](=[O:30])[C:16](/[CH:25]=[CH:26]/[C:27](O)=[O:28])=[C:17]([N:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)[N:18]=[C:13]3[CH:12]=2)[S:7][CH:8]=1)([CH3:3])[CH3:2].[C:33]([O:37][C:38]([NH:40][CH2:41][CH2:42][CH2:43][S:44]([NH2:47])(=[O:46])=[O:45])=[O:39])([CH3:36])([CH3:35])[CH3:34].Cl.C(N=C=NCCCN(C)C)C.C(OCC)(=O)C>CN(C)C=O.CCCCCC>[CH:1]([C:4]1[N:5]=[C:6]([CH2:9][CH2:10][C:11]2[CH:32]=[CH:31][N:14]3[C:15](=[O:30])[C:16](/[CH:25]=[CH:26]/[C:27]([NH:47][S:44]([CH2:43][CH2:42][CH2:41][NH:40][C:38]([O:37][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:39])(=[O:45])=[O:46])=[O:28])=[C:17]([N:19]4[CH2:20][CH2:21][O:22][CH2:23][CH2:24]4)[N:18]=[C:13]3[CH:12]=2)[S:7][CH:8]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1csc(CCc2ccn3c(=O)c(/C=C/C(=O)O)c(N4CCOCC4)nc3c2)n1
Reactant: CC(C)(C)OC(=O)NCCCS(N)(=O)=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CC(C)c1csc(CCc2ccn3c(=O)c(/C=C/C(=O)NS(=O)(=O)CCCNC(=O)OC(C)(C)C)c(N4CCOCC4)nc3c2)n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 40.7 %

Procedure:
(E)-3-{8-[2-(4-Isopropyl-1,3-thiazol-2-yl)ethyl]-2-morpholino-4-oxo-4H-pyrido -[1,2-a]pyrimidin-3-yl}-2-propenoic acid (53 mg) was dissolved in dimethylformamide (2 ml), added with 3-(N-tert-butoxycarbonylamino)propanesulfonamide (55 mg) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (67 mg), and the mixture was stirred at room temperature for 24 hours. The reaction solution was added with ethyl acetate and hexane, washed with 0.2 M hydrochloric acid, and dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (32 mg) as yellow powder.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[Br:7][C:8]1[CH:9]=[CH:10][C:11]([NH:14][C:15](=O)[CH:16]([N:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)[CH3:17])=[N:12][CH:13]=1.CCOC(C)=O.[OH-].[Na+]>C1COCC1.O>[Br:7][C:8]1[CH:9]=[CH:10][C:11]([NH:14][CH2:15][CH:16]([N:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)[CH3:17])=[N:12][CH:13]=1
Reactant: CC(C(=O)Nc1ccc(Br)cn1)N1CCCC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: CC(CNc1ccc(Br)cn1)N1CCCC1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
Under a nitrogen atmosphere 6.00 mL (6.00 mmol) 1 M lithium aluminium hydride solution in THF are added to a solution, cooled to 0° C., of 1.8 g (6.04 mmol) N-(5-bromo-pyridin-2-yl)-2-pyrrolidin-1-yl-propionamide in 30 mL THF, in such a way that the internal temperature does not exceed 4° C. The reaction solution is stirred for a further 20 min at 0° C. EtOAc is carefully added, the aluminium complex is decomposed with 0.2 mL water, then with 0.2 mL 15% sodium hydroxide solution solution and finally with 0.6 mL water. The precipitate formed is suction filtered and the filtrate is diluted with 50 mL EtOAc. The organic phase is washed with 30 mL saturated NaHCO3 solution and dried over MgSO4. The solvent is eliminated i.vac. and further purification is carried out by column chromatography on silica gel (EtOAc/MeOH/NH3 9:1:0.1).
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][C:3]=1[CH3:11].[CH:12]([C:14]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16][CH:15]=1)=[O:13]>COCCOC.C(=O)([O-])[O-].[Na+].[Na+].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd]>[CH:12]([C:14]1[CH:19]=[CH:18][C:17]([C:2]2[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][C:3]=2[CH3:11])=[CH:16][CH:15]=1)=[O:13]
Reactant: Cc1cc(C(N)=O)ccc1Br
Reactant: O=Cc1ccc(B(O)O)cc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: Cc1cc(C(N)=O)ccc1-c1ccc(C=O)cc1
Temperature: 95 °C
Yield: 95.3 %

Procedure:
4-Bromo-3-methyl-benzamide (15.02 g), 70 mmol), 4-formylphenylboronic acid (14.039, 91 mmol) and palladium tetrakis(triphenylphosphine) (5.03 g, 4 mmol) were combined in 1,2-dimethoxy ethane (5 ml) and 2M aqueous sodium carbonate (2.5 ml). After heating at 95° C. for 48 hours, the reaction mixture was cooled to ambient temperature and passed through a plug of Celite, rinsing with 1,2-dimethoxy ethane. The volatiles were removed under reduced pressure to yield 16 g of the title compound (I-4a) as a colorless solid.
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@H:16]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C@@H:15]([CH2:25][O:26][Si:27]([C:40]([CH3:43])([CH3:42])[CH3:41])([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:14][C@@H:11]([O:12][CH3:13])[C@@H:10]1[O:44]CC1C=CC(Cl)=CC=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CNC1C=CC=CC=1.CC([O-])(C)C.[Na+].Cl[Sn](Cl)(Cl)Cl>CC([O-])=O.CC([O-])=O.[Pd+2]>[CH2:1]([O:8][C@H:9]1[C@H:16]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C@@H:15]([CH2:25][O:26][Si:27]([C:40]([CH3:42])([CH3:41])[CH3:43])([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[O:14][C@@H:11]([O:12][CH3:13])[C@@H:10]1[OH:44])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CO[C@@H]1O[C@H](CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccc(Cl)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: CNc1ccccc1
Product: CO[C@@H]1O[C@H](CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1O
Yield: 80.5 %

Procedure:
The general procedure C using 23 (56.8 mg, 0.077 mmol), N-methylaniline (10 μL, 0.092 mmol), Pd(OAc)2 (0.7 mg, 0.003 mmol), (o-biphenyl)P(t-Bu)2 (1.8 mg, 0.006 mmol) and NaOtBu (10.4 mg, 0.11 mmol) for 12 h at room temperature afforded a yellow oil. Cleavage of the aminated intermediate with SnCl4 (92 μL 1.0 M in CH2Cl2, 0.092 mmol) using general procedure D gave 38.0 mg (81%) of 29 as a colorless oil after purification by flash column chromatography on silica gel (25% EtOAc/Hexanes). [α]24D: −13.60 (c 6.02, CH2Cl2); IR (thin film) 3456, 3070, 2930, 1113, 1055 cm−1; 1H-NMR (CDCl3) δ 7.89 (dd, J=0.6, 6.7 Hz, 2H), 7.83 (dd, J=0.9, 6.7 Hz, 2H), 7.54-7.33 (m, 16H), 5.0 (d, J=11.3 Hz, 1H), 5.04 (d, J=11.0 Hz, 1H), 5.01 (d, J=11.0 Hz, 1H), 4.84 (d, J=11.0 Hz, 1H), 4.32 (d, J=7.6 Hz, 1H), 4.10-4.04 (m, 2H), 3.91 (dd, J=9.2, 9.2 Hz, 1H), 3.76-3.67 (m, 5H), 3.51-3.46 (m, 1H), 2.83 (br s, 1H), 1.18 (s, 9H); 13C-NMR (CDCl3) δ 138.9, 138.4, 136.2, 135.8, 133.9, 133.3, 129.9, 128.8, 128.7, 128.3, 128.2, 128.0, 127.8, 103.8, 84.8, 77.7, 76.2, 75.6, 75.4, 75.0, 62.9, 56.9, 27.0, 19.6; FAB MS m/z (M+Na)+: calcd 635.2805, obsd 635.2804.
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[N:7]([C:14]1[N:18]([CH3:19])[C:17]2[CH:20]=[CH:21][C:22]([N:24]([C:26]3[CH:31]=[CH:30][N:29]=[C:28]([Cl:32])[N:27]=3)[CH3:25])=[CH:23][C:16]=2[N:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:34][C:35]1[CH:36]=[C:37]([S:41]([NH2:44])(=[O:43])=[O:42])[CH:38]=[CH:39][CH:40]=1>C(O)C.Cl>[ClH:32].[C:1]([O:5][C:6](=[O:33])[N:7]([C:14]1[N:18]([CH3:19])[C:17]2[CH:20]=[CH:21][C:22]([N:24]([CH3:25])[C:26]3[CH:31]=[CH:30][N:29]=[C:28]([NH:34][C:35]4[CH:40]=[CH:39][CH:38]=[C:37]([S:41](=[O:43])(=[O:42])[NH2:44])[CH:36]=4)[N:27]=3)=[CH:23][C:16]=2[N:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(c1ccc2c(c1)nc(N(C(=O)OC(C)(C)C)c1ccccc1)n2C)c1ccnc(Cl)n1
Reactant: Nc1cccc(S(N)(=O)=O)c1
Agent: Cl
Solvent: CCO
Product: CN(c1ccc2c(c1)nc(N(C(=O)OC(C)(C)C)c1ccccc1)n2C)c1ccnc(Nc2cccc(S(N)(=O)=O)c2)n1
Temperature: 70 °C
Reaction time: 20 h

Procedure:
To a solution of {5-[(2-Chloro-pyrimidin-4-yl)-methyl-amino]-1-methyl-1H-benzoimidazol-2-yl}-phenyl-carbamic acid tert-butyl ester (100 mg, 0.22 mmol) and 3-amino-benzenesulfonamide (38 mg, 0.22 mmol) in ethanol was added HCl (1 drop, 1M in diethyl ether), and the reaction was heated to 70° C. After 20 h, the reaction was filtered to give the title compound as a white solid. 1H NMR (300 MHz, d6-DMSO+NaHCO3) δ 10.15 (s, 1H), 8.44 (s, 1H), 7.84 (d, J=6.6 Hz, 1H), 7.72 (d, J=8.4 Hz, 2H), 7.61 (s, 1H), 7.27-7.39 (m, 10H), 5.79 (d, J=5.1 Hz, 1H), 3.78 (s, 3H), 3.51 (s, 3H), 1.41 (s, 9H). MS (ESI) m/z=601 [M+H]+.
Reaction SMILES: C(O[CH2:5][C:6]1[C:11]([CH3:12])=[C:10]([O:13][CH2:14][CH3:15])[CH:9]=[CH:8][N:7]=1)(=O)C.S(Cl)(Cl)=O.[SH:20][C:21]1[NH:22][C:23]2[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=2[N:25]=1.C[O-].[Na+]>C(Cl)(Cl)Cl.CO>[CH2:14]([O:13][C:10]1[CH:9]=[CH:8][N:7]=[C:6]([CH2:5][S:20][C:21]2[NH:25][C:24]3[CH:26]=[CH:27][CH:28]=[CH:29][C:23]=3[N:22]=2)[C:11]=1[CH3:12])[CH3:15]
Reactant: Sc1nc2ccccc2[nH]1
Reactant: CCOc1ccnc(COC(C)=O)c1C
Agent: C[O-]
Agent: [Na+]
Solvent: O=S(Cl)Cl
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CCOc1ccnc(CSc2nc3ccccc3[nH]2)c1C
Yield: 18.3 %

Procedure:
10.7 g of 2-acetoxymethyl-3-methyl-4-ethoxy-pyridine was dissolved in chloroform, and 28.2 g (4 eq.) of thionyl chloride was added. The mixture was heated to reflux for one hour and then concentrated, and a residue resulting therefrom was dissolved in methanol. The solution was added in advance to 8.4 g (1 eq.) of 2-mercaptobenzimidazole, 71 mL of a 28% sodium methoxide solution, and 150 mL of methanol, and the mixture was heated to reflux for one hour. Methanol was distilled off, and ice and ethyl acetate were added to the residue, to wash the residue by suspending. Produced crystals were collected by filtration and dissolved in methanol, and the solution was dried over anhydrous magnesium sulfate. Subsequently, the methanol solution was concentrated to dryness, and the resultant was dissolved in chloroform. The chloroform layer was dried over magnesium sulfate and then concentrated to dryness, to obtain an amorphous solid. The solid was washed by suspending in ethyl acetate, to obtain 2.8 g of colorless crystals. Total yield 7.9% (purity by HPLC: 98.2%).
Reaction SMILES: [Cl:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[S:7][C:6]=2[C:5]([OH:17])=[CH:4][CH:3]=1.COC1C2[C:32](=[O:34])[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)SC=2C(OC)=CC=1.C(=O)([O-])[O-].[K+].[K+].C(Cl)(=O)C1C=CC=CC=1>O.CC(=O)CC>[C:32]([O:17][C:5]1[C:6]2[S:7][C:8]3[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=3)[C:14](=[O:16])[C:15]=2[C:2]([Cl:1])=[CH:3][CH:4]=1)(=[O:34])[C:31]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: O=c1c2ccccc2sc2c(O)ccc(Cl)c12
Reactant: COc1ccc(OC)c2c(=O)c3ccccc3sc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: O=C(Cl)c1ccccc1
Solvent: O
Product: O=C(Oc1ccc(Cl)c2c(=O)c3ccccc3sc12)c1ccccc1
Yield: 74 %

Procedure:
1-Chloro-4-hydroxythioxanthone as prepared in Example 1 (6.6 g), potassium carbonate (4.1 g), 2-butanone (60 ml) and water (6 ml) were heated under reflux. Benzoyl chloride (5.3 g) was added over 20 minutes and the mixture heated under reflux for 3 hours. A solid precipitated from solution during the heating period. The mixture was cooled, quenched with water (120 ml), the solid filtered and recrystallised from 2-butanone with a charcoal treatment. The title compound (6.8 g; 74.0%) was obtained of mp 177°-78°. Analysis C20H11ClO3S=366.81 Requires C 65.48% H 3.02% Cl 9.67% S 8.74% Found C 65.46% H 3.13% Cl 9.77% S 8.70%
Reaction SMILES: [C:1]([OH:7])([C:3]([F:6])([F:5])[F:4])=[O:2].C[Si](C)(C)CCOC[N:14]1[C:18]2[N:19]=[CH:20][N:21]=[C:22]([C:23]3[CH:24]=[N:25][N:26]([CH:28]4[CH2:33][CH2:32][C:31](=[CH:34][C:35]#[N:36])[CH2:30][CH2:29]4)[CH:27]=3)[C:17]=2[CH:16]=[CH:15]1.[OH-].[NH4+]>CC#N.O>[F:4][C:3]([F:6])([F:5])[C:1]([OH:7])=[O:2].[N:19]1[C:18]2[NH:14][CH:15]=[CH:16][C:17]=2[C:22]([C:23]2[CH:24]=[N:25][N:26]([CH:28]3[CH2:29][CH2:30][C:31](=[CH:34][C:35]#[N:36])[CH2:32][CH2:33]3)[CH:27]=2)=[N:21][CH:20]=1
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C4CCC(=CC#N)CC4)c3)ncnc21
Agent: [NH4+]
Agent: [OH-]
Solvent: CC#N
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: N#CC=C1CCC(n2cc(-c3ncnc4[nH]ccc34)cn2)CC1
Reaction time: 16 h

Procedure:
A solution of TFA (0.5 mL, 0.006 mol) and 4-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclohexylideneacetonitrile (22.7 mg, 0.0000522 mol), was stirred for 1.5 h. The solution was then concentrated using a rotary evaporator to remove TFA. LCMS analysis showed conversion to the hydroxymethyl intermediate, M+H 335. Methanol was added; and the methanol mixture was concentrated again using a rotary evaporator. The resulting residue was dissolved in methanol (1 mL) and ammonium hydroxide (0.25 mL, 0.0064 mol) was added. The resulting solution was stirred for 16 h. LCMS analysis showed complete de-protection. The solution was then concentrated using a rotary evaporator. The product was isolated by prep HPLC using a 30 mm×100 mm C18 column; 18% CH3CN—H2O (0.1% TFA), 1 min, to 35% at 6 min; 60 mL/min; detector set at 254 nm; retention time, 4.4 min. The eluate was freeze dried. yield 7.6 mg of a white solid (TFA salt; racemic; 34.6%). 1H NMR (d6DMSO) δ 12.9 (br s, 1H, NH); 8.9 (s, 2H); 8.5 (s, 1H); 7.8 (m, 1H); 7.3 (m, 1H); 5.6 (s, 1H, olefin); 4.6 (m, 1H, NCH); 2.8 (m, 1H); 2.6 (m, 1H); 2.5 (m, 2H); 2.3 (m, 2H) 2.0 (m, 2H). MS (ES) 305 (M+1).
Reaction SMILES: [CH3:1][NH:2][C:3]([CH:5]1[CH2:10][N:9]([S:11]([C:14]2[S:18][C:17]3[CH:19]=[C:20]([C:23]#[C:24][Si](C)(C)C)[CH:21]=[CH:22][C:16]=3[CH:15]=2)(=[O:13])=[O:12])[CH2:8][CH2:7][N:6]1[C:29]([C:31]1[S:32][C:33]2[CH2:34][NH:35][CH:36]([CH3:40])[CH2:37][C:38]=2[N:39]=1)=[O:30])=[O:4].[OH-].[Na+].[Cl-].[NH4+].C(=O)(O)[O-].[Na+]>O1CCCC1.CO.C(Cl)Cl.CCCCCC>[C:23]([C:20]1[CH:21]=[CH:22][C:16]2[CH:15]=[C:14]([S:11]([N:9]3[CH2:8][CH2:7][N:6]([C:29]([C:31]4[S:32][C:33]5[CH2:34][NH:35][CH:36]([CH3:40])[CH2:37][C:38]=5[N:39]=4)=[O:30])[CH:5]([C:3](=[O:4])[NH:2][CH3:1])[CH2:10]3)(=[O:13])=[O:12])[S:18][C:17]=2[CH:19]=1)#[CH:24]
Reactant: CNC(=O)C1CN(S(=O)(=O)c2cc3ccc(C#C[Si](C)(C)C)cc3s2)CCN1C(=O)c1nc2c(s1)CNC(C)C2
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCCCCC
Solvent: CO
Solvent: C1CCOC1
Product: C#Cc1ccc2cc(S(=O)(=O)N3CCN(C(=O)c4nc5c(s4)CNC(C)C5)C(C(=O)NC)C3)sc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 103.2 %

Procedure:
In a mixed solvent of tetrahydrofuran (0.5 ml) and methanol (0.5 ml) was dissolved 2-(N-methylcarbamoyl)-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-4-[(6-trimethylsilylethynylbenzo[b]thien-2-yl)sulfonyl]piperazine (90 mg), followed by the addition of a 1N aqueous solution (0.3 ml) of sodium hydroxide. The resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was made weakly acidic with a saturated aqueous solution of ammonium chloride and then made weakly alkaline with a saturated aqueous solution of sodium bicarbonate. The solution was extracted (four times) with methylene chloride. The organic layers were combined, dried over anhydrous sodium sulfate and distilled under reduced pressure to remove the solvent. The residue was purified by preparative thin-layer chromatography (methanol:methylene chloride=1:9). Similar reaction and post treatment were repeated three times and the purified products were combined, followed by purification through Sephadex LH-20 (elution with methanol). The amorphous substance thus obtained was dissolved in methylene chloride. Hexane was added dropwise to the resulting solution, whereby the title compound (82 mg) was obtained as a light gray solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([Cl:19])=[CH:4][C:5]2[O:10][CH2:9][C:8](=[O:11])[N:7]([CH2:12][C:13]([O:15]CC)=[O:14])[C:6]=2[CH:18]=1.[Li+].[OH-]>C1COCC1.O>[Cl:1][C:2]1[C:3]([Cl:19])=[CH:4][C:5]2[O:10][CH2:9][C:8](=[O:11])[N:7]([CH2:12][C:13]([OH:15])=[O:14])[C:6]=2[CH:18]=1
Reactant: CCOC(=O)CN1C(=O)COc2cc(Cl)c(Cl)cc21
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)CN1C(=O)COc2cc(Cl)c(Cl)cc21
Temperature: 25 °C
Yield: 123.3 %

Procedure:
Ethyl (6,7-dichloro-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl)acetate (22.0 g, 0.072 mol) was suspended in 400 mL of THF and treated with LiOH (3.46 g, 0.144 mol) dissolved in 80 mL of water at room temperature. The reaction was magnetically stirred and maintained at room temperature for 20 hours. The reaction was then quenched with 30 mL of concentrated HCl and stirred for 20 minutes. HPLC (Eclipse XDB-C18, 4.6×250 mm, 5 micron, 1-99% CH3CN/H2O with 0.1% trifluoroacetic acid) showed that all of the starting material (Rt=7.5 min) was gone and that a single product (Rt=6.0 min) had formed. The solvent was removed by rotary evaporation to give an off-white solid that was further dried under high vacuum to give 24.5 g of a mixture of the title compound (77 % by mass) and LiCl (23% by mass) which was used in subsequent reactions without further purification. Actual product yield is 18.9 g (0.068 mol, 95%). MS (ES) m/e 276 [M+H]+.