Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1([F:49])[CH2:7][C@H:6]([O:8][C:9]2[C:14]([CH3:15])=[CH:13][C:12]([S:16]([N:19](CC3C=CC(OC)=CC=3OC)[C:20]3[CH:25]=[CH:24][N:23]=[CH:22][N:21]=3)(=[O:18])=[O:17])=[C:11]([F:37])[CH:10]=2)[C@@H:5]([C:38]2[N:42](COCCOC)[N:41]=[CH:40][CH:39]=2)[CH2:4][CH2:3]1.C([SiH](CC)CC)C>ClC(Cl)C.FC(F)(F)C(O)=O>[F:49][C:2]1([F:1])[CH2:7][C@H:6]([O:8][C:9]2[C:14]([CH3:15])=[CH:13][C:12]([S:16]([NH:19][C:20]3[CH:25]=[CH:24][N:23]=[CH:22][N:21]=3)(=[O:18])=[O:17])=[C:11]([F:37])[CH:10]=2)[C@@H:5]([C:38]2[NH:42][N:41]=[CH:40][CH:39]=2)[CH2:4][CH2:3]1
Reactant: COCCOCn1nccc1[C@H]1CCC(F)(F)C[C@@H]1Oc1cc(F)c(S(=O)(=O)N(Cc2ccc(OC)cc2OC)c2ccncn2)cc1C
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: CC(Cl)Cl
Product: Cc1cc(S(=O)(=O)Nc2ccncn2)c(F)cc1O[C@H]1CC(F)(F)CC[C@@H]1c1ccn[nH]1
Reaction time: 4 h
Yield: 71.1 %

Procedure:
To a solution of the 4-{[(1S*,2R*)-5,5-difluoro-2-{1-[(2-methoxyethoxy)methyl]-1H-pyrazol-5-yl}cyclohexyl]oxy}-N-(2,4-dimethoxybenzyl)-2-fluoro-5-methyl-N-(pyrimidin-4-yl)benzenesulfonamide (265 mg, 0.376 mmol) prepared in Example 155h and triethylsilane (0.50 mL) in dichloroethane (5.0 mL), trifluoroacetic acid (5.0 mL) was added at room temperature, and the reaction solution was stirred for 4 hours. The reaction solution was concentrated, then methanol (15 mL) and 6 M hydrochloric acid (5.0 mL) were added to the residue, and the reaction solution was stirred for 5 hours under heated reflux. To the reaction solution, an aqueous sodium hydrogencarbonate solution (50 mL) was added, followed by extraction five times with a dichloromethane/methanol (10:1) mixed solvent (50 mL). The thus obtained organic layer was dried over anhydrous sodium sulfate. After vacuum concentration, the residue was purified with silica gel chromatography (dichloromethane/methanol=10:1) to yield the title compound (125 mg, 71%) as a colorless solid.
Reaction SMILES: [N:1]([CH:4]([C:6]1[N:7]=[C:8]2[S:21][CH:20]=[CH:19][N:9]2[C:10](=[O:18])[C:11]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH3:5])=[N+]=[N-].CP(C)C.C(OCC)(=O)C>O1CCCC1.O>[NH2:1][CH:4]([C:6]1[N:7]=[C:8]2[S:21][CH:20]=[CH:19][N:9]2[C:10](=[O:18])[C:11]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH3:5]
Reactant: CC(N=[N+]=[N-])c1nc2sccn2c(=O)c1-c1ccccc1
Agent: CP(C)C
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: CC(N)c1nc2sccn2c(=O)c1-c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 62.2 %

Procedure:
To a stirred solution of 7-(1-azidoethyl)-6-phenyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one (0.23 g, 0.77 mmol) in tetrahydrofuran (5 mL) and water (1 mL) was added 1.00 M of trimethylphosphine in tetrahydrofuran (0.93 mL, 0.93 mmol) at room temperature, and the mixture was stirred at room temperature for 1 hour. To the mixture was added ethyl acetate, and the mixture was extracted with aqueous 1N HCl solution (three times). The combined extract was neutralized with solid NaHCO3 and extracted with dichloromethane (two times). The combined organic layer was washed with brine, dried over Na2SO4, and concentrated to give the desired compound (0.13 g, 62%). LCMS calculated for C14H14N3OS (M+H)+: m/z=272.1. Found: 272.0.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].C(N(CC)CC)C.FC(F)(F)S(O[Si:22]([CH3:25])([CH3:24])[CH3:23])(=O)=O>C1(C)C=CC=CC=1>[CH3:23][Si:22]([N:2]([CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])[Si:22]([CH3:25])([CH3:24])[CH3:23])([CH3:25])[CH3:24]
Reactant: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Reactant: CCOC(=O)CN
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCOC(=O)CN([Si](C)(C)C)[Si](C)(C)C
Temperature: 25 °C
Reaction time: 19 h

Procedure:
About 6.02 g of ethyl glycinate hydrochloride, 14.39 g of triethylamine, and 10 ml of toluene were mixed in a round-bottom reaction flask cooled with an ice bath. To this mixture was added, in a dropwise fashion, a solution of 21.1 g of trimethylsilyl trifluoromethanesulfonate in 50 ml of toluene. The resulting mixture was stirred at room temperature for 19 hours to give a biphasic mixture. The top layer was transferred to another flask, and the bottom layer was extracted with 40 ml of toluene. The combined toluene solution was evaporated under vacuum. The residue was extracted with 100 ml of hexane, and the hexane layer was evaporated under vacuum, yielding ethyl [bis(trimethylsilyl)amino]acetate, also known as ethyl N,N-bis(trimethylsilyl)glycinate (BTMSEG), as a colorless liquid (9.23 g, 87% yield). The 1H NMR data (C6D6, 25° C., referenced to tetramethylsilane) of the product are listed as follows: δ 3.89 (quartet, 2 H, OCH2 protons), 3.51 (singlet, 2 H, NCH2 protons), 0.90 (triplet, 3 H, CH3 protons), 0.14 (singlet, 18H, Si—CH3 protons). From the 1H NMR data, the structure of the product was determined to be as follows:
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][N:6]=1.[NH2:7][C:8]1[C:27]([Cl:28])=[CH:26][C:11]([C:12]([NH:14][C@H:15]2[CH2:20][CH2:19][N:18]([CH2:21][CH2:22][NH2:23])[CH2:17][C@H:16]2[O:24][CH3:25])=[O:13])=[C:10]([O:29][CH3:30])[CH:9]=1>N1C=CC=CC=1>[NH2:7][C:8]1[C:27]([Cl:28])=[CH:26][C:11]([C:12]([NH:14][C@H:15]2[CH2:20][CH2:19][N:18]([CH2:21][CH2:22][NH:23][C:2]3[S:3][CH:4]=[CH:5][N:6]=3)[CH2:17][C@H:16]2[O:24][CH3:25])=[O:13])=[C:10]([O:29][CH3:30])[CH:9]=1
Reactant: Brc1nccs1
Reactant: COc1cc(N)c(Cl)cc1C(=O)N[C@H]1CCN(CCN)C[C@H]1OC
Solvent: c1ccncc1
Product: COc1cc(N)c(Cl)cc1C(=O)N[C@H]1CCN(CCNc2nccs2)C[C@H]1OC
Temperature: 60 °C
Reaction time: 1 h
Yield: 11 %

Procedure:
A mixture of 2 parts of 2-bromothiazole and 4.28 parts of cis-4-amino-N-[1-(2-aminoethyl)-3-methoxy-4-piperidinyl]-5-chloro-2-methoxybenzamide was stirred for one hour at 60° C. Ths mixture solidified. It was suspended in 10 parts of pyridine and stirring was continued overnight at reflux. The reaction mixture was evaporated. The residue was taken up in a saturated sodium carbonate solution. The product was extracted with trichloromethane. The extract was dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (93:7 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was converted into the hydrochloride salt in 2-propanol. The salt was filtered off and the free base was liberated in the conventional manner and extracted with trichloromethane. The extract was dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol, saturated with ammonia, (95:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from a mixture of acetonitrile and 2,2'-oxybispropane. The product was filtered off and dried, yielding 0.6 parts (11%) of cis-4-amino-5-chloro-2-methoxy-N-[3-methoxy-1-[2-(2-thiazolylamino)ethyl]-4-piperidinyl]benzamide; mp. 140.9° C. (compound 44).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7](Cl)[CH:6]=[C:5]2[C:13]([NH:15][C:16]1[C:17]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[N:18][O:19][C:20]=1[CH3:21])=[O:14].[NH2:28][C:29]1[CH:30]=[C:31]([OH:35])[CH:32]=[CH:33][CH:34]=1>C(O)C.C(N(CC)CC)C.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH:28][C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([OH:35])[CH:30]=1)[CH:6]=[C:5]2[C:13]([NH:15][C:16]1[C:17]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[N:18][O:19][C:20]=1[CH3:21])=[O:14]
Reactant: Nc1cccc(O)c1
Reactant: Cc1onc(-c2ccccc2)c1NC(=O)c1cc(Cl)nc2ccc(Br)cc12
Solvent: CCN(CC)CC
Solvent: CCO
Solvent: CCOC(C)=O
Product: Cc1onc(-c2ccccc2)c1NC(=O)c1cc(Nc2cccc(O)c2)nc2ccc(Br)cc12
Yield: 85.9 %

Procedure:
The solution of 6-bromo-2-chloro-N-(5-methyl-3-phenylisoxazol-4-yl)-4-quinolinecarboxamide (50 mg) and 3-aminophenol (50 mg) in ethanol (2 mL) and triethylamine (0.1 mL) was microwaved at 170° C. for one hour. The reaction mixture was then diluted with ethyl acetate (60 mL). The organic solution was washed with water (60 mL), 1N HCl aqueous solution (2×60 mL), separated, dried, evaporated and re-crystallized from ethyl acetate and hexanes to give 6-bromo-2-(3-hydroxyphenyl)amino-N-(5-methyl-3-phenylisoxazol-4-yl)-4-quinolinecarboxamide (50 mg) as a yellow solid. 1H NMR (acetone-d6): δ 2.53 (s, 3H), 6.72 (d, J=6.9 Hz, 1H), 7.15 (d, J=7.8 Hz, 1H), 7.26 (t, J=7.8 Hz, 1H), 7.51 (m, 4H), 7.60 (s, 1H), 7.78 (m, 3H), 7.87 (d, J=9.0 Hz, 1H), 8.15 (d, J=2.1 Hz, 1H), 8.70 (br, 1H), 9.77 (br, 1H); LCMS: ret. time: 25.49 min.; purity: 1100%; MS (m/e): 514.91 (M+).
Reaction SMILES: [CH:1]1([CH2:6][C@H:7]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([S:28][CH3:29])[CH:23]=2)[C:8](N([C@H](C)[C@H](O)C2C=CC=CC=2)C)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.S(=O)(=O)(O)[OH:31].C(Cl)Cl>O1CCOCC1.O>[CH:1]1([CH2:6][C@H:7]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([S:28][CH3:29])[CH:23]=2)[C:8]([OH:9])=[O:31])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=S(=O)(O)O
Reactant: CSc1cccc([C@@H](CC2CCCC2)C(=O)N(C)[C@H](C)[C@H](O)c2ccccc2)c1
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: O
Product: CSc1cccc([C@@H](CC2CCCC2)C(=O)O)c1
Temperature: 110 °C
Reaction time: 18 h
Yield: 96 %

Procedure:
To a stirred solution of (R)-3-cyclopentyl-N-((1R,2R)-2-hydroxy-1-methyl-2-phenyl-ethyl)-N-methyl-2-(3-methylsulfanyl-phenyl)-propionamide (1.16 g, 2.82 mmol) in 1,4-dioxane (10 mL) was added 9 N aqueous sulfuric acid (10 mL) and the reaction was stirred at 110° C. for 18 h. The reaction was cooled to 25° C. and diluted with water (25 mL) and poured into methylene chloride (30 mL). The layers were separated and the aqueous layer was extracted with methylene chloride (2×30 mL). The combined methylene chloride layers were washed with water and saturated sodium chloride solution and then dried over magnesium sulfate. Filtration and concentration afforded the crude product which was purified by ISCO flash column chromatography (Teledyne Isco RediSep Flash Column 40 g; 0% ethyl acetate/hexanes to 50% ethyl acetate/hexanes) to yield (R)-3-cyclopentyl-2-(3-methylsulfanyl-phenyl)-propionic acid (712 mg, 96%) as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[C:4]([CH3:12])[CH:3]=1.[CH2:13]([N:15](C(C)C)[CH:16](C)C)[CH3:14].CNCC>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:15]([CH2:13][CH3:14])[CH3:16])(=[O:10])=[O:9])=[C:4]([CH3:12])[CH:3]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: Cc1cc(Br)ccc1S(=O)(=O)Cl
Agent: CCNC
Solvent: ClCCl
Product: CCN(C)S(=O)(=O)c1ccc(Br)cc1C
Reaction time: 2 h
Yield: 83.8 %

Procedure:
To a 0° C. solution of 4-bromo-2-methylbenzenesulfonyl chloride (1.00 g, 3.71 mmol) in CH2Cl2 (10 mL) was added N-ethyldiisopropylamine (0.71 mL, 4.31 mmol) and N-methylethylamine (0.96 mL, 11.13 mmol). The cold bath was removed and the reaction was stirred for 2 h. At completion, the reaction was concentrated, and the crude material was dissolved in CH2Cl2 (20 mL). The mixture was washed with 0.5 N aqueous HCl (3×10 mL), sat. aq. NaHCO3 (2×10 mL), water (10 mL), and saturated aqueous NaCl (5 mL), dried (Na2SO4), and concentrated to give 4-bromo-N-ethyl-2,N-dimethyl-benzenesulfonamide (0.91 g, 3.11 mmol, 85% yield). This material was directly dissolved in 1,4-dioxane (10 mL) and treated with bisboron pinacol ester (0.87 g, 3.43 mmol), PdCl2(dppf)-DCM (69 mg, 0.093 mmol), and KOAc (0.92 g, 9.34 mmol). The reaction was heated at 85° C. for 2 h. At completion, the reaction was cooled to room temperature and concentrated. The crude material was treated with CH2Cl2 (30 mL) and water (10 mL). The organic layer was washed with water (2×10 mL) and brine (5 mL), dried over Na2SO4 and concentrated. The crude material was purified by flash chromatography over silica gel (5-20% EtOAc:hexane eluent) to give N-ethyl-2,N-dimethyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzenesulfonamide (0.64 g, 60% yield). 1H NMR (300 MHz, MeOH) δ ppm 7.80-7.88 (m, 1H), 7.68-7.77 (m, 2H), 3.26 (q, J=7.12 Hz, 2H), 2.83 (s, 3H), 2.61 (s, 3H), 1.37 (s, 12H), 1.17 (t, J=7.15 Hz, 3H). MS (EI) m/z: 340 [M+H]+. HPLC (Sunfire C18 4.6 mm×50 mm, 10-90% MeCN:10 mM aq NH4OAc, 2 min gradient) tR=2.48 min, 91% integrated area.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([C:8]2[N:12]([CH3:13])[C:11]([CH2:14][C:15]3[CH:21]=[CH:20][C:18]([NH2:19])=[CH:17][CH:16]=3)=[CH:10][C:9]=2[CH3:22])=[O:7])=[CH:4][CH:3]=1.[C:25](N1C=CN=C1)([N:27]1[CH:31]=[CH:30]N=C1)=[O:26].C(CN)[OH:38]>CN(C=O)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([C:8]2[N:12]([CH3:13])[C:11]([CH2:14][C:15]3[CH:16]=[CH:17][C:18]([NH:19][C:25]([NH:27][CH2:31][CH2:30][OH:38])=[O:26])=[CH:20][CH:21]=3)=[CH:10][C:9]=2[CH3:22])=[O:7])=[CH:23][CH:24]=1
Reactant: NCCO
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Cc1cc(Cc2ccc(N)cc2)n(C)c1C(=O)c1ccc(Cl)cc1
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(Cc2ccc(NC(=O)NCCO)cc2)n(C)c1C(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 57.3 %

Procedure:
4-{5-(4-Chlorobenzoyl)-1,4-dimethyl-1H-pyrrol-2-ylmethyl}aniline (0.33 g, 0.98 mmol) and 1,1'-carbonyldiimidazole (0.4 g, 2.46 mmol) were dissolved in DMF, and the reaction mixture was stirred at room temperature for 1 h. Ethanolamine (0.3 ml, 4.91 mmol) was added and after 1.5 h the mixture was diluted with water. The product was extracted into ethyl acetate, and the organic layer was dried over MgSO4 and then concentrated under vacuum. Purification by flash chromatography (ethyl acetate), followed by recrystallization from hexane-chloroform gave 1-{4-[5-(4-chlorobenzoyl)-1,4-dimethyl-1H-pyrrol-2-ylmethyl]phenyl}-3-(2-hydroxyethyl)urea (239 mg, 57%) as a solid, mp 209.6-210.2° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:15]([SH:18])[CH2:16][SH:17])[CH:6]=[C:7]([O:13][CH3:14])[C:8]=1[O:9][CH2:10]OC.[CH3:19][O:20][C:21]1[CH:22]=[C:23]([CH:26]=[C:27]([I:31])[C:28]=1[O:29][CH3:30])[CH:24]=O.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.C1C=CC=CC=1>C1C=CC=CC=1.O>[CH3:19][O:20][C:21]1[CH:22]=[C:23]([C@H:24]2[S:18][C@H:15]([C:5]3[CH:6]=[C:7]([O:13][CH3:14])[C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=3)[CH2:16][S:17]2)[CH:26]=[C:27]([I:31])[C:28]=1[O:29][CH3:30]
Reactant: COc1cc(C=O)cc(I)c1OC
Reactant: COCOc1c(OC)cc(C(S)CS)cc1OC
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: O
Solvent: c1ccccc1
Product: COc1cc([C@@H]2SC[C@@H](c3cc(OC)c(OC)c(OC)c3)S2)cc(I)c1OC

Procedure:
1-(3,4,5-trimethoxyphenyl)-1,2-ethanedithiol (39) (FIG. 19) (1.404 g,5.40 mmole), 3,4-dimethoxy-5-iodobenzaldehyde (41) (FIG. 22) (1.30 g, 4.45 mmole) and 0.542 g of pyridinium para-toluenesulfonate was added to 50 ml dry benzene and refluxed with Dean-Stark removal of the benzene- water azeotrope for 12 hours. The benzene was removed in vacuo, and the remaining oil redissolved in ethyl acetate. The organic layer was washed with 10% NaHCO3 and H2O. The organic layer was dried over MgSO4, and evaporated in vacuo to an oil which was purified by flash column chromatography with 2:1 hex/ethyl acetate as eluent. The product mixture contains a 1.0/1.0 cis/trans ratio (2.38 g, 100%). The trans isomer can be isolated by recrystallization from methanol.
Reaction SMILES: OCCCCCCCC[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[O:17].C(C(CCCCCC)CO)CCCCCCCCC.[O-2].[Mg+2]>>[CH2:26]1[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16](=[O:17])[O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]1
Reactant: CCCCCCCCOC(=O)CCCCCCCCCCCCCCO
Agent: CCCCCCCCCCC(CO)CCCCCC
Agent: [Mg+2]
Agent: [O-2]
Product: O=C1CCCCCCCCCCCCCCO1
Yield: 3 %

Procedure:
A 26.7 g (72.0 mmol) portion of octyl 15-hydroxypentadecanoate, 20.1 g (154 mmol) of 2-decyl-1-octanol and 1.5 g of magnesium oxide were put into the same apparatus of Inventive Example 1 and the reaction was carried out under conditions of 230 to 250° C. and 1.3 kPa to 130 Pa while distilling out the distillate to obtain 26.9 g of a colorless and transparent liquid distillate 5 hours thereafter. This contained 0.5 g of cyclopentadecanolide (yield 3%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH2:11]O)=[CH:5][C:4]=1[CH3:13].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:33]N1C(=O)CCC1=O>C(Cl)Cl>[Br:33][CH2:11][CH2:10][CH2:9][C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[C:4]([CH3:13])[CH:5]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1ccc(CCCO)cc1C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1ccc(CCCBr)cc1C
Reaction time: 2 h
Yield: 69 %

Procedure:
Compound 42-3 (860 mg) was dissolved in methylene chloride (30 ml), triphenylphosphine (1.39 g) and N-bromosuccinimide (0.934 g) were added under ice-cooling, and the mixture was stirred under ice-cooling for 2 hr, and at room temperature for 2 hr. The reaction mixture was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. Diethyl ether (50 ml) was added, and the precipitated triphenylphosphine oxide was filtered off. The concentrate of the filtrate was purified by silica gel column chromatography (hexane alone) to give the object product (800 mg) as a colorless oil.
Reaction SMILES: Br[C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[CH:4][C:3]=1[O:10][CH3:11].[S:12](Cl)([Cl:15])(=[O:14])=[O:13]>>[CH3:11][O:10][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([O:8][CH3:9])[C:2]=1[S:12]([Cl:15])(=[O:14])=[O:13]
Reactant: O=S(=O)(Cl)Cl
Reactant: COc1cccc(OC)c1Br
Product: COc1cccc(OC)c1S(=O)(=O)Cl

Procedure:
2,6-Dimethoxybenzenesulfonyl chloride was prepared from 2-bromo-1,3-dimethoxybenzene according to the procedure in Example 1, Step 1. The reaction gave a mixture of sulfonyl chloride and another product as a white solid.
Reaction SMILES: [C:1]([C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[C:5]([OH:10])[CH:4]=1)#[N:2].[Br:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[N:18]=[C:19]=[S:20]>C(O)C>[C:1]([C:3]1[CH:9]=[CH:8][C:6]([NH:7][C:19]([NH:18][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[Br:11])=[S:20])=[C:5]([OH:10])[CH:4]=1)#[N:2]
Reactant: S=C=Nc1ccccc1Br
Reactant: N#Cc1ccc(N)c(O)c1
Solvent: CCO
Product: N#Cc1ccc(NC(=S)Nc2ccccc2Br)c(O)c1
Reaction time: 24 h
Yield: 76.6 %

Procedure:
To a solution of 4-cyano-2-hydroxyl aniline (1.0 g, 7.5 mmol) in ethanol (20 mL) was added 2-bromophenylisothiocyanate (1.0 mL, 7.5 mmol). After 24 h, the reaction mixture was concentrated under reduced pressure to give 2.0 g (77%) of N-(4-cyano-2-hydroxyphenyl)-N′-(2-bromophenyl) thiourea as a yellow solid which required no further purification. 1H NMR (400 MHz, DMSO) δ 10.8 (s, 1H), 10.1 (s, 1H), 9.6 (s, 1H), 8.7 (d, 1H), 7.7 (d, 1H), 7.6 (d, 1H), 7.4 (t, 1H), 7.25 (d, 1H and d, 2H); MS(EI) m/e 229 (100), 348 (75 (M+)), 462 (30), 695 (10).
Reaction SMILES: [Br-].[C:2]([C:5]1[CH:6]=[N+:7]([CH2:11][CH2:12][CH2:13][C:14](=[O:24])[NH:15][CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:8]=[CH:9][CH:10]=1)(=[O:4])[NH2:3].S(S([O-])=O)([O-])=O.[Na+].[Na+]>>[C:2]([C:5]1[CH2:10][CH:9]=[CH:8][N:7]([CH2:11][CH2:12][CH2:13][C:14](=[O:24])[NH:15][CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:6]=1)(=[O:4])[NH2:3]
Reactant: NC(=O)c1ccc[n+](CCCC(=O)NCCc2ccccc2)c1
Agent: O=S([O-])S(=O)[O-]
Agent: [Br-]
Agent: [Na+]
Product: NC(=O)C1=CN(CCCC(=O)NCCc2ccccc2)C=CC1
Yield: 70.2 %

Procedure:
The product of Example 125 (3.92 g, 0.01 mol) was reduced with sodium dithionite (6.96 g, 0.04 mol) according to the procedure of Example 126. A yield of 2.2 g (65%) of the title compound was obtained as an orange-yellow amorphous powder, m.p. 55°-60° C. UV max (methanol) 358 nm; IR (CHCl3) 3325 (NH), 1682 (CO), 1645 (CO) cm-1. Anal. calc. for C18H23N3O2.3/4H2O: C,66.07; H,7.49; N,12.85. Found: C,66.05; H,7.56; N,12.84. The structure of the product was further confirmed by PMR to be: ##STR1526##
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]3[N:15]=[C:16]([N:24]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[CH2:25][CH2:26][OH:27])[C:17]4[CH2:23][NH:22][CH2:21][CH2:20][C:18]=4[N:19]=3)=[CH:9][CH:8]=2)[CH:4]=[N:3]1.[C:34](O)(=O)C.C=O.C([BH3-])#N.[Na+]>CO>[CH3:34][N:22]1[CH2:21][CH2:20][C:18]2[N:19]=[C:14]([NH:13][C:10]3[CH:9]=[CH:8][C:7]([C:5]4[CH:4]=[N:3][N:2]([CH3:1])[CH:6]=4)=[CH:12][CH:11]=3)[N:15]=[C:16]([N:24]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH2:25][CH2:26][OH:27])[C:17]=2[CH2:23]1
Reactant: Cn1cc(-c2ccc(Nc3nc4c(c(N(CCO)c5ccccc5)n3)CNCC4)cc2)cn1
Reactant: CC(=O)O
Agent: C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CN1CCc2nc(Nc3ccc(-c4cnn(C)c4)cc3)nc(N(CCO)c3ccccc3)c2C1
Yield: 107.6 %

Procedure:
2-((2-(4-(1-Methyl-1H-pyrazol-4-yl)phenylamino)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl)(phenyl)amino)ethanol (40 mg, 0.09 mmol) was dissolved in methanol (2 mL). Acetic acid (1.037 μL, 0.02 mmol) was added followed by formaldehyde (0.014 mL, 0.18 mmol). The reaction mixture was stirred at room temperature for 30 minutes before sodium cyanoborohydride (11.39 mg, 0.18 mmol) was added. After 20 minutes the solvent was evaporated under reduced pressure, the crude dissolved in few drops of DMF and acetonitrile, filtered and purified by preparative HPLC yielding 2-((6-methyl-2-(4-(1-methyl-1H-pyrazol-4-yl)phenylamino)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl)(phenyl)amino)ethanol (9.8 mg, 21%) as acetic acid salt. MS (ESI) (M+H) m/z 456;
Reaction SMILES: [CH2:1]([O:3][CH2:4][N:5]1[C:9]([CH:10]([OH:20])[C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[C:13]([Cl:18])[C:12]=2[Cl:19])=[CH:8][CH:7]=[N:6]1)[CH3:2].Br[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24]>>[CH2:1]([O:3][CH2:4][N:5]1[C:9]([CH:10]([OH:20])[C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[C:13]([Cl:18])[C:12]=2[Cl:19])=[CH:8][CH:7]=[N:6]1)[CH3:2]
Reactant: CCOC(=O)CBr
Reactant: CCOCn1nccc1C(O)c1ccc(O)c(Cl)c1Cl
Product: CCOCn1nccc1C(O)c1ccc(OCC(=O)OCC)c(Cl)c1Cl
Yield: 98 %

Procedure:
634 mg of α-(1-ethoxymethyl-5-pyrazolyl)-2,3-dichloro-4-hydroxybenzylalcohol and 367 mg of ethyl bromoacetate are treated in the same manner as described in Example 1 to give 790 mg of α-(1-ethoxymethyl-5-pyrazolyl)-2,3-dichloro-4-ethoxycarbonylmethoxybenzylalcohol.
Reaction SMILES: [OH:1][CH:2]([CH2:16][NH:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:3][O:4][C:5]1[C:13]2[NH:12][C:11](=[O:14])[NH:10][C:9]=2[C:8]([CH3:15])=[CH:7][CH:6]=1.C[O-].[Na+].[C:25](N=[N+]=[N-])(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.[ClH:36]>CN(C)C=O>[ClH:36].[C:25]([O:1][CH:2]([CH2:16][NH:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:3][O:4][C:5]1[C:13]2[NH:12][C:11](=[O:14])[NH:10][C:9]=2[C:8]([CH3:15])=[CH:7][CH:6]=1)(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: Cc1ccc(OCC(O)CNC(C)(C)C)c2[nH]c(=O)[nH]c12
Reactant: [N-]=[N+]=NC(=O)c1ccccc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(OCC(CNC(C)(C)C)OC(=O)c2ccccc2)c2[nH]c(=O)[nH]c12

Procedure:
4-(2-Hydroxy-3-tert.-butylaminopropoxy)-7-methyl-2-benzimidazolinone (prepared from the hydrochloride (see Example 3) and methanolic sodium methylate solution) is stirred for 5 days at ambient temperature with an equimolar amount of benzoic acid azide in dimethylformamide. The crystalline precipitate obtained is mixed with ethereal hydrochloric acid and, after evaporation, recrystallised from ethanol to give 4-[2-benzoyloxy-3-tert.-butylaminopropoxy]-7-methyl-2-benzimidazolinone hydrochloride; m.p. 216°-218° C.