Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][NH2:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[CH3:14][O:15][C:16]1[CH:24]=[CH:23][C:19]([CH:20]2[O:22][CH2:21]2)=[CH:18][CH:17]=1>C(OCC)(=O)C.CCCCCC>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][NH:13][CH2:21][CH:20]([OH:22])[C:19]2[CH:23]=[CH:24][C:16]([O:15][CH3:14])=[CH:17][CH:18]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(CCN)cc1OC
Reactant: COc1ccc(C2CO2)cc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: COc1ccc(C(O)CNCCc2ccc(OC)c(OC)c2)cc1
Reaction time: 8 h

Procedure:
A mixture of 16 g. (88 mmole) of 3,4-dimethoxyphenylethylamine and 13.5 g. (88 mmole) of p-methoxystyrene oxide is heated with stirring under argon on a steam bath overnight. A sample is withdrawn from the reaction mixture and chromatographed on a silica column, eluting with benzene ethyl acetate to isolate the pure product in crystalline form. To the remainder of the reaction mixture is added 100 ml. of ethyl acetate-hexane (1:1) and seeded with the crystalline product, with stirring and chilling. Filtration furnishes the product N-[2-(3,4-dimethoxyphenyl)-ethyl]-2-hydroxy-2-(4-methoxyphenyl)ethylamine, m.p. 92° C.
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH2:6][CH2:5]1.[CH:28]1([CH2:32][C:33](O)=[O:34])[CH2:31][CH2:30][CH2:29]1>>[CH:28]1([CH2:32][C:33]([NH:27][C@H:24]2[CH2:25][CH2:26][C@H:21]([CH2:20][CH2:19][N:16]3[CH2:17][CH2:18][N:13]([C:9]4[N:10]=[CH:11][CH:12]=[C:7]5[CH2:6][CH2:5][O:4][C:8]=45)[CH2:14][CH2:15]3)[CH2:22][CH2:23]2)=[O:34])[CH2:31][CH2:30][CH2:29]1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3OCC4)CC2)CC1
Reactant: O=C(O)CC1CCC1
Agent: Cl
Product: O=C(CC1CCC1)N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3OCC4)CC2)CC1

Procedure:
The title compound, white solid (50 mg, 73%), MS (ISP) m/z=427.3 [(M+H)+], mp 147.5° C., was prepared in accordance with the general method of example 6 from trans-4-{2-[4-(2,3-dihydro-furo[2,3-c]pyridin-7-yl)-piperazin-1-yl]-ethyl}-cyclohexylamine trihydrochloride (intermediate B) (70.4 mg, 0.16 mmol) 2-cyclobutyl-acetic acid.
Reaction SMILES: Br[CH2:2][C:3]1[S:11][C:10]2[C:9]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)=[N:8][C:7]([Cl:18])=[N:6][C:5]=2[CH:4]=1.O.[C:20]([O:24][C:25](=[O:34])[N:26]([CH3:33])[CH:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1)([CH3:23])([CH3:22])[CH3:21].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[C:20]([O:24][C:25](=[O:34])[N:26]([CH:27]1[CH2:28][CH2:29][N:30]([CH2:2][C:3]2[S:11][C:10]3[C:9]([N:12]4[CH2:17][CH2:16][O:15][CH2:14][CH2:13]4)=[N:8][C:7]([Cl:18])=[N:6][C:5]=3[CH:4]=2)[CH2:31][CH2:32]1)[CH3:33])([CH3:23])([CH3:21])[CH3:22]
Reactant: CN(C(=O)OC(C)(C)C)C1CCNCC1
Reactant: Clc1nc(N2CCOCC2)c2sc(CBr)cc2n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CN(C(=O)OC(C)(C)C)C1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 62.1 %

Procedure:
To a solution of 6-bromomethyl-2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine (85 mg, 0.244 mmol) in DMF (2 mL) were added water (13 μL), methyl-piperidin-4-yl-carbamic acid tert-butyl ester (105 mg, 0.489 mmol) and cesium carbonate (159 mg, 0.489 mmol). The resulting mixture was stirred at RT for 18 h. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge, washed with MeOH then eluted with 2 M NH3 in MeOH. The resultant residue was purified by column chromatography to give the title compound as a pale brown solid (73 mg, 62%).
Reaction SMILES: [OH:1][C:2]1[CH:14]=[C:13]2[C:5]([C:6]3[CH:7]=[CH:8][C:9]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:10][C:11]=3[NH:12]2)=[CH:4][CH:3]=1.CC1C=CC(S(O[CH2:34][CH2:35][O:36][CH2:37][CH2:38][O:39][CH2:40][CH2:41][F:42])(=O)=O)=CC=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN1C(=O)CCC1.CCOC(C)=O>[F:42][CH2:41][CH2:40][O:39][CH2:38][CH2:37][O:36][CH2:35][CH2:34][O:1][C:2]1[CH:14]=[C:13]2[C:5]([C:6]3[CH:7]=[CH:8][C:9]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:19])([CH3:21])[CH3:20])=[CH:10][C:11]=3[NH:12]2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc2c(c1)[nH]c1cc(O)ccc12
Reactant: Cc1ccc(S(=O)(=O)OCCOCCOCCF)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)Nc1ccc2c(c1)[nH]c1cc(OCCOCCOCCF)ccc12
Temperature: 25 °C
Reaction time: 15 h
Yield: 54.7 %

Procedure:
To tert-butyl 7-hydroxy-9H-carbazol-2-ylcarbamate (165 mg, 0.55 mmol) and 2-(2-(2-fluoroethoxy)ethoxy)ethyl 4-methylbenzenesulfonate (202 mg, 0.66 mmol) in 2 mL of NMP was added Cs2CO3 (179 mg, 0.55 mmol). The mixture was stirred at rt for 15 h under Ar atmosphere and diluted with EtOAc (50 mL). It was washed with water (3×50 mL) and dried over MgSO4. After solvent removal, the residue was chromatographed (hexane/EtOAc) to afford tert-butyl 7-(2-(2-(2-fluoroethoxy)ethoxy)ethoxy)-9H-carbazol-2-ylcarbamate as a white solid (130 mg, 55%). 1H NMR (400 MHz, CDCl3) δ 7.94 (s, 1H), 7.83-7.79 (m, 3H), 6.91 (d, J=2.0 Hz, 1H), 6.86 (dd, J=8.4, 2.0 Hz, 1H), 6.83 (dd, J=8.8, 2.4 Hz, 1H), 6.63 (s, 1H), 4.64 (m, 1H), 4.51 (m, 1H), 4.21 (m, 2H), 3.91 (m, 2H), 3.81-3.71 (m, 6H), 1.55 (s, 9H); MS (ESI) m/z 433 (M+H+).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=1)[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:20][C:21]1[CH:22]=[C:23]([C:27]([C:29]2[C:37]3[CH:36]=[N:35][CH:34]=[N:33][C:32]=3[N:31]([CH:38]([CH3:40])[CH3:39])[CH:30]=2)=[O:28])[CH:24]=[N:25][CH:26]=1.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1>N1C=CC=CC=1>[Cl:19][C:16]1[CH:17]=[CH:18][C:13]([CH:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[C:10]([NH:20][C:21]2[CH:26]=[N:25][CH:24]=[C:23]([C:27]([C:29]3[C:37]4[CH:36]=[N:35][CH:34]=[N:33][C:32]=4[N:31]([CH:38]([CH3:40])[CH3:39])[CH:30]=3)=[O:28])[CH:22]=2)=[O:12])=[CH:14][CH:15]=1
Reactant: CC(C)(C)OC(=O)NC(C(=O)O)c1ccc(Cl)cc1
Reactant: CC(C)n1cc(C(=O)c2cncc(N)c2)c2cncnc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: c1ccncc1
Product: CC(C)n1cc(C(=O)c2cncc(NC(=O)C(NC(=O)OC(C)(C)C)c3ccc(Cl)cc3)c2)c2cncnc21
Temperature: 50 °C
Yield: 49 %

Procedure:
To pyridine (4 mL) in a sealed vessel was added 2-((tert-butoxycarbonyl)amino)-2-(4-chlorophenyl)acetic acid (67 mg, 0.24 mmol) (see Preparation 303), (5-aminopyridin-3-yl)(7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone (52 mg, 0.18 mmol) (see Preparation 95) and N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (105 mg, 0.28 mmol). The reaction was heated at 50° C. for 18 hours and then evaporated in vacuo and purified by column chromatography (gradient of 100:0 to 88:12 DCM:MeOH) to give the title compound in 49% yield, 64 mg. LCMS (basic): Rt=0.81 min; m/z 549 [M+H]+.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:15]([OH:17])=O)=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:14][CH2:13]2)[CH2:3][CH2:2]1.[NH2:18][C@H:19]1[CH2:23][CH2:22][O:21][C:20]1=[O:24]>>[O:24]=[C:20]1[C@@H:19]([NH:18][C:15]([C:7]2[CH:6]=[CH:5][C:4]([CH:1]3[CH2:2][CH2:3]3)=[C:9]([O:10][CH2:11][CH:12]3[CH2:13][CH2:14]3)[N:8]=2)=[O:17])[CH2:23][CH2:22][O:21]1
Reactant: N[C@H]1CCOC1=O
Reactant: O=C(O)c1ccc(C2CC2)c(OCC2CC2)n1
Product: O=C(N[C@H]1CCOC1=O)c1ccc(C2CC2)c(OCC2CC2)n1

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-cyclopropyl-6-cyclopropylmethyloxy-pyridine-2-carboxylic acid (Example 42a) and (35)-3-aminodihydro-2(3H)-furanone (CAN 2185-02-6) as starting materials; LC-MS (UV peak area/ESI) 100%, 317.1500 (M+H)+.
Reaction SMILES: CN([C:4]1[CH:9]=[CH:8][C:7]([N:10]=[C:11]2[CH:17]=[CH:16][C:14](=[O:15])[CH:13]=[CH:12]2)=[CH:6][CH:5]=1)C.C1([OH:24])C=CC=CC=1.[OH-].[Na+].C([O-])(=O)C.[Na+].Cl[O-].[Na+].Cl.NC1C=CC(N(C)C)=CC=1>O>[CH:6]1[C:7](=[N:10][C:11]2[CH:17]=[CH:16][C:14]([OH:15])=[CH:13][CH:12]=2)[CH:8]=[CH:9][C:4](=[O:24])[CH:5]=1
Reactant: CN(C)c1ccc(N=C2C=CC(=O)C=C2)cc1
Reactant: Oc1ccccc1
Agent: CC(=O)[O-]
Agent: CN(C)c1ccc(N)cc1
Agent: Cl
Solvent: O
Product: O=C1C=CC(=Nc2ccc(O)cc2)C=C1

Procedure:
To prepare the starting material N,N-Dimethylindoaniline (Phenol Blue III)-A solution of 0.075 mole of phenol, 4 g (0.1 mole) of sodium hydroxide, and 8 g (0.06 mole) of sodium acetate in 250 c.c of water was stirred mechanically in a salt-ice bath in such a way as to maintain a temperature of 0° to 5° during the reaction. Two dropping funnels were put in place, one containing 100 cc (0.1 mole) of 5% sodium hypochlorite, the other a solution of 0.05 mole of p-aminodimethylaniline hydrochloride in 100 cc of water. The two solutions were then added simultaneously in the course of forty-five to sixty minutes. The solution became blue after the addition of a few drops of the reagents and the dye soon began to separate. Stirring was then continued for fifteen minutes after completion of the addition and the product was then collected and washed several times with water; the dark blue filtrate, probably containing phenol-indophenol formed by alkaline hydrolysis of the product was discarded. The crude dye was crystallized from ethyl acetate, giving fine, intense violet needles, m.p. 161° [as reported by Gnelm and Bots J. Prakt. Chem., 69:162 (1904)] Yield 7.2 g (63%). This is generally the method of Gnelm and Bots, Supra [see also Heller Ann 392:16 (1912) and Cohen and Phillips, Suppl. No. 74 U.S. Pub. Health Reports 1929]. 1.1 6 g N,N-Dimethylindoaniline (J.A.C.S., 61, 376/1939, see above) are added to a solution of 7 g. sodium hydroxide in 250 ml. water. While stirring vigorously, sodium dithionite is added portionwise thereto until the blue colour has disappeared. The solution is filtered, the filtrate is cooled to about 5° C. and mixed dropwise with glacial acetic acid, until the precipitate has come out completely. The precipitate is filtered off and dissolved in 25 ml. concentrated hydrochloric acid. The solution is treated with carbon, filtered and evaporated. The residue is recrystallised from ethanol. There are obtained 3.1 g. (51% of theory) 4-dimethylamino-4'-hydroxydiphenylamine. 1.2 2.6 g. of the leuko coloured material obtained in 1.1, 8.83 g. 2-acetamido-3,4,6-tri-O-acetyl-2-deoxy-α-D-glucosyl chloride and 4.21 g. benzyltriethylammonium bromide are added to a mixture of 125 ml. chloroform and 125 ml. water. The mixture is vigorously stirred, mixed with 8.7 g. potassium carbonate and boiled under reflux for 6 hours, whereby after 3 hours, 4.4 g. of the halogenase and 4.3 g. potassium carbonate are added thereto. The chloroform phase is separated off, dried with anhydrous sodium sulphate and evaporated.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([O:14][CH3:15])[C:11]=1[O:12][CH3:13])[C:6]([Cl:8])=[O:7].[NH2:16][C:17]([CH3:21])([CH3:20])[CH2:18][OH:19].S(Cl)(Cl)=O.[OH-].[Na+]>C(Cl)Cl>[CH3:15][O:14][C:10]1[CH:9]=[C:5]([CH:4]=[C:3]([O:2][CH3:1])[C:11]=1[O:12][CH3:13])[C:6]([Cl:8])=[O:7].[CH3:20][C:17]1([CH3:21])[CH2:18][O:19][C:6]([C:5]2[CH:9]=[C:10]([O:14][CH3:15])[C:11]([O:12][CH3:13])=[C:3]([O:2][CH3:1])[CH:4]=2)=[N:16]1
Reactant: CC(C)(N)CO
Agent: COc1cc(C(=O)Cl)cc(OC)c1OC
Agent: [Na+]
Agent: [OH-]
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: COc1cc(C2=NC(C)(C)CO2)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A solution of 16.2 g (70 mmoles) of 3,4,5-trimethoxybenzoyl chloride (compound 1) in 40 ml of dry methylene chloride was added dropwise to a solution of 12.5 g (140 mmoles) of 2-amino-2-methyl-1-propanol in 50 ml of dry methylene chloride under cooling in an ice-bath for 30 minutes. After completion of the addition, the mixture was stirred for additional 45 minutes and the reaction solution was filtered through a glass filter. The filtered cake was washed with methylene chloride and the filtrate was combined with the washing, which was followed by concentration in vacuo. The residue was dissolved in 30 ml of dry toluene, and 6.64 ml (91.0 mmoles) of thionyl chloride was added dropwise thereto under cooling in an ice-bath. The mixture was allowed to warm to room temperature, while being stirred for additional 45 minutes. Subsequently, 20 g of ice and aqueous sodium hydroxide (18 g of NaOH in 60 ml of water) were added to the mixture and then the mixture was extracted with toluene. The extract was washed with water and brine and dried over anhydrous magnesium sulfate. After concentration in vacuo, the residue was crystallized from 70 ml of n-hexane to give 16.8 g (90.6% from compound 1) of the desired compound. Melting point: 87°-89° C.
Reaction SMILES: F[C:2]1[C:10]([F:11])=[C:9]([F:12])[C:8]([F:13])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[OH-:14].[Na+]>CN1CCN(C)C1=O>[F:11][C:10]1[C:9]([F:12])=[C:8]([F:13])[CH:7]=[C:3]([C:4]([OH:6])=[O:5])[C:2]=1[OH:14]
Reactant: [OH-]
Reactant: O=C(O)c1cc(F)c(F)c(F)c1F
Agent: [Na+]
Solvent: CN1CCN(C)C1=O
Product: O=C(O)c1cc(F)c(F)c(F)c1O
Temperature: 130 °C
Reaction time: 3 h
Yield: 29.7 %

Procedure:
3.88 g (0.02 mole) of 2,3,4,5-tetrafluorobenzoic acid, 3.23 g (0.08 mole) of powdery 99% sodium hydroxide and 40 ml of 1,3-dimethyl-2-imidazolidinone were fed into a 200-ml four-necked flask provided with a thermometer, a stirrer and a reflux condenser. The mixture was stirred at 130° C. for 3 hours to give rise to a reaction. Then, the same post-treatment as in Example 1 was conducted to obtain 1.14 g of 3,4,5-trifluorosalicylic acid. The isolated yield was 29.7% relative to the 2,3,4,5-tetrafluorobenzoic acid used.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[C:17](=[O:18])[NH:16][C:15]2[C:10]1=[N:11][C:12]([NH:24][CH2:25][C@@H:26]1[CH2:30][CH2:29][CH2:28][NH:27]1)=[N:13][C:14]=2[C:19]([O:21]CC)=O.C(OC([N:38]1CCC[C@H]1CNC1N=C2C(NC(=O)N2C2C=CC=CC=2OC)=C(C(OCC)=O)N=1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[C:17](=[O:18])[NH:16][C:15]2[C:10]1=[N:11][C:12]([NH:24][CH2:25][C@@H:26]1[CH2:30][CH2:29][CH2:28][NH:27]1)=[N:13][C:14]=2[C:19]([NH2:38])=[O:21]
Reactant: CCOC(=O)c1nc(NC[C@@H]2CCCN2C(=O)OC(C)(C)C)nc2c1[nH]c(=O)n2-c1ccccc1OC
Reactant: CCOC(=O)c1nc(NC[C@@H]2CCCN2)nc2c1[nH]c(=O)n2-c1ccccc1OC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccccc1-n1c(=O)[nH]c2c(C(N)=O)nc(NC[C@@H]3CCCN3)nc21
Yield: 100 %

Procedure:
(S)-Ethyl 9-(2-methoxyphenyl)-8-oxo-2-(pyrrolidin-2-ylmethylamino)-8,9-dihydro-7H-purine-6-carboxylate. (S)-Ethyl 2-((1-(tert-butoxycarbonyl)pyrrolidin-2-yl)methylamino)-9-(2-methoxyphenyl)-8-oxo-8,9-dihydro-7H-purine-6-carboxylate (0.352 g, 0.687 mmol) was dissolved in dichloromethane (3 mL) and trifluoroacetic acid (1 mL) was added. The solution was stirred for two h and condensed under reduced pressure to afford the crude title compound (0.400 g, >100%). MS (ESI) m/z 413.1 [M+1]+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[NH:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([CH2:14][OH:15])[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.C(=O)([O-])O.[Na+]>ClCCl>[C:1]([O:5][C:6](=[O:16])[NH:7][C@H:8]1[CH2:9][CH2:10][C@H:11]([CH:14]=[O:15])[CH2:12][CH2:13]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](CO)CC1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@H](C=O)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a dichloromethane (30 mL) solution of the compound (1.6 g) obtained in Example 22, a Dess-Martin reagent (3.97 g) was added at 0° C. The reaction solution was stirred at room temperature for 16 hours. To the reaction solution, an aqueous saturated sodium hydrogen carbonate solution (50 mL) was added, and then aqueous layer was extracted with dichloromethane. The combined organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. After removing the anhydrous sodium sulfate by filtration, the filtrate was concentrated. The residue was purified by silica gel chromatography (n-hexane:ethyl acetate=1:0→8:2) to obtain the title compound (1.60 g) having the following physical properties.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[C@@H:14]([O:15][CH2:16][C:17]3[CH:18]=[CH:19][C:20]4[O:25][CH2:24][CH2:23][N:22]([CH2:26][CH2:27][CH2:28][O:29][CH3:30])[C:21]=4[CH:31]=3)[CH2:13][N:12]([S:32]([C:35]3[CH:40]=[CH:39][C:38]([CH3:41])=[CH:37][CH:36]=3)(=[O:34])=[O:33])[C@H:11]([CH2:42][C:43]([CH3:48])([CH3:47])[C:44](O)=[O:45])[CH2:10]2)=[CH:5][CH:4]=1.[CH2:49]([NH2:55])[C@H:50]1[O:54][CH2:53][CH2:52][CH2:51]1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[C@@H:14]([O:15][CH2:16][C:17]3[CH:18]=[CH:19][C:20]4[O:25][CH2:24][CH2:23][N:22]([CH2:26][CH2:27][CH2:28][O:29][CH3:30])[C:21]=4[CH:31]=3)[CH2:13][N:12]([S:32]([C:35]3[CH:40]=[CH:39][C:38]([CH3:41])=[CH:37][CH:36]=3)(=[O:34])=[O:33])[C@H:11]([CH2:42][C:43]([CH3:48])([CH3:47])[C:44]([NH:55][CH2:49][C@@H:50]3[CH2:51][CH2:52][CH2:53][O:54]3)=[O:45])[CH2:10]2)=[CH:5][CH:4]=1
Reactant: NC[C@@H]1CCCO1
Reactant: COCCCN1CCOc2ccc(CO[C@H]3CN(S(=O)(=O)c4ccc(C)cc4)[C@H](CC(C)(C)C(=O)O)C[C@@H]3c3ccc(OC)cc3)cc21
Product: COCCCN1CCOc2ccc(CO[C@H]3CN(S(=O)(=O)c4ccc(C)cc4)[C@H](CC(C)(C)C(=O)NC[C@@H]4CCCO4)C[C@@H]3c3ccc(OC)cc3)cc21

Procedure:
According to general procedure D, 110 mg of 3-[(2S,4R,5R)-4-(4-methoxy-phenyl)-5-[4-(3-methoxy-propyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-1-(toluene-4-sulfonyl)-piperidin-2-yl]-2,2-dimethyl-propionic acid (from example 65b) and 20 mg (S)-tetrahydrofurfurylamine are used to afford the title compound as a yellow oil. Rf=0.35 (EtOAc-heptane 8:1); Rt=5.12.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:27]=[CH:26][C:6]([CH2:7][N:8]([CH2:15][CH2:16][N:17]([CH3:25])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][NH2:24])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)=[CH:5][CH:4]=1.CS[C:30]([NH:35][CH2:36][CH2:37][CH2:38][O:39][C:40]1[CH:45]=[CH:44][CH:43]=[C:42]([CH2:46][N:47]2[CH2:52][CH2:51][CH2:50][CH2:49][CH2:48]2)[CH:41]=1)=[CH:31][N+:32]([O-:34])=[O:33]>>[CH3:1][O:2][C:3]1[CH:27]=[CH:26][C:6]([CH2:7][N:8]([CH2:15][CH2:16][N:17]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][NH:24][C:30]([NH:35][CH2:36][CH2:37][CH2:38][O:39][C:40]2[CH:45]=[CH:44][CH:43]=[C:42]([CH2:46][N:47]3[CH2:52][CH2:51][CH2:50][CH2:49][CH2:48]3)[CH:41]=2)=[CH:31][N+:32]([O-:34])=[O:33])[CH3:25])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(CN(CCN(C)CCCCCCN)c2ccccn2)cc1
Reactant: CSC(=C[N+](=O)[O-])NCCCOc1cccc(CN2CCCCC2)c1
Product: COc1ccc(CN(CCN(C)CCCCCCNC(=C[N+](=O)[O-])NCCCOc2cccc(CN3CCCCC3)c2)c2ccccn2)cc1

Procedure:
Preparation is effected analogously to Example 22, using 0.54 g (1.45 mmol) of N-[2-[N-(4-methoxybenzyl)-N-(2-pyridyl)amino]ethyl]-N-methyl-1,6-hexanediamine and the equimolar amount of 1-methylthio-1-[3-[3-(piperidinomethyl)phenoxy]propyl]amino-2-nitroethene as starting materials. Working up by chromatography analogously to Example 22 yields the purified title compound in the form of a viscous oil; MS (+FAB method): m/z (rel. int. [%])=688 ([M+H]+, 5), 121 (100). For further analysis, a portion of the compound is converted into the tartaric acid salt in an ethanol/ether solvent mixture; m.p.: 73° C. (ethanol/ether).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[C:10]([N:13]1[CH2:18][CH2:17][C:16](=O)[CH:15]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:14]1)(=[O:12])[CH3:11]>>[C:10]([N:13]1[CH2:18][CH2:17][C@H:16]([N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[CH2:3][CH2:2]2)[C@H:15]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:14]1)(=[O:12])[CH3:11]
Reactant: CCOC(=O)C1CN(C(C)=O)CCC1=O
Reactant: c1ccc2c(c1)CCN2
Product: CCOC(=O)[C@@H]1CN(C(C)=O)CC[C@@H]1N1CCc2ccccc21
Yield: 21.5 %

Procedure:
Indoline (12.5 g), ethyl 1-acetyl-4-oxo-3-piperidinecarboxylate (22.3 g) and triacetoxylated sodium borohydride (48.7 g) were treated as in Example 1 to give the title compound (7.12 g) as a pale yellow powder (yield: 22%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[C:14]([CH3:16])[CH:13]=[CH:12][C:11]=2[O:17][CH3:18])=[O:9])=[CH:6][N:5]=[C:4]([S:19][CH2:20][CH3:21])[N:3]=1.ClC1C=C(C=CC=1)C(OO)=[O:27]>C(Cl)(Cl)Cl.C(Cl)Cl>[NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[C:14]([CH3:16])[CH:13]=[CH:12][C:11]=2[O:17][CH3:18])=[O:9])=[CH:6][N:5]=[C:4]([S:19]([CH2:20][CH3:21])=[O:27])[N:3]=1
Reactant: CCSc1ncc(C(=O)c2cc(C)ccc2OC)c(N)n1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: CCS(=O)c1ncc(C(=O)c2cc(C)ccc2OC)c(N)n1
Reaction time: 1 h

Procedure:
A solution of (4-amino-2-ethylsulfanyl-pyrimidin-5-yl)-(2-methoxy-5-methyl-phenyl)-methanone, 571 mg, 1.885 mmol, Example 324) in chloroform (16 mL) was cooled to −15° C. and treated with 3-chloroperoxybenzoic acid (503.7 mg, ˜2.25 mmol, ˜70% purity from Aldrich) and the reaction was stirred at the same temperature for 1 hour. The reaction mixture was diluted with methylene chloride (20 mL) and washed with 10% aqueous sodium thiosulfate (2×5 mL), 10% aqueous sodium carbonate (2×5 mL), brine, dried and concentrated to give (4-amino-2-ethanesulfinyl-pyrimidin-5-yl)-(2-methoxy-5-methyl-phenyl)-methanone as a white solid. MS (M+H)+: 320.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][O:15][C:16]2[CH:17]=[C:18]([O:22][S:23]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[Cl:32])(=[O:25])=[O:24])[CH:19]=[CH:20][CH:21]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl>O1CCOCC1>[NH:8]1[CH2:13][CH2:12][CH:11]([CH2:14][O:15][C:16]2[CH:17]=[C:18]([O:22][S:23]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[Cl:32])(=[O:24])=[O:25])[CH:19]=[CH:20][CH:21]=2)[CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCC(COc2cccc(OS(=O)(=O)c3ccccc3Cl)c2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: O=S(=O)(Oc1cccc(OCC2CCNCC2)c1)c1ccccc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 78.6 %

Procedure:
2-Chlorobenzenesulfonic acid 3 -[[N-(tert-butoxycarbonyl)piperidin-4-yl]-methoxy]phenyl ester (565 mg, 1.2 mmol), as prepared in the preceding step, was treated with 30 mL of 4N HCl in 1,4-dioxan and stirred at room temperature for 2 h. After removing the solvent in vacuo, the residue was purified by flash column chromatography (5% methanol in methylene chloride to 5% methanol in methylene chloride saturated with NH3) to give the title compound as a white foam (360 mg, 79%). 1H-NMR (300 MHz, CDCl3) δ 1.50 (m, 2H), 1.91 (m, 3H), 2.77 (t, 2H), 3.33 (d, 2H), 3.73 (d, 2H), 4.44 (bs, 1H), 6.69 (m, 2H), 6.77 (dd, 1H), 7.16 (t, 1H), 7.37 (t, 1H), 7.62 (m, 2H), 7.95 (dd, 1H). Mass spectrum (MALDI-TOF, sinapinic acid matrix) calcd. for C18H20NO4SCl: 382.1 (M+H), 404.1 (M+Na). Found: 382.1, 404.5.
Reaction SMILES: [CH2:1]([C:3]1[S:12][C:6]2[N:7]=[CH:8][N:9]=[C:10](O)[C:5]=2[CH:4]=1)[CH3:2].O=P(Cl)(Cl)[Cl:15]>O1CCCCO1>[Cl:15][C:10]1[C:5]2[CH:4]=[C:3]([CH2:1][CH3:2])[S:12][C:6]=2[N:7]=[CH:8][N:9]=1
Reactant: CCc1cc2c(O)ncnc2s1
Reactant: O=P(Cl)(Cl)Cl
Agent: C1CCOOC1
Product: CCc1cc2c(Cl)ncnc2s1
Yield: 64 %

Procedure:
To a solution of 6-ethylthieno[2,3-d]pyrimidin-4-ol (10 g, 55.49 mmol, 1.00 equiv) in 1,2-dioxane (100 mL) was added POCl3 (30 mL) and heated to reflux for 4 hr. After completion of the reaction, the reaction mixture was concentrated under vacuum and then quenched with water/ice. The resulting solution was extracted with 3×200 mL of ethyl acetate: The combined organic layers were washed with brine, dried over anhydrous sodium sulfateand concentrated under vacuum. The residue was purified on a silica gel column with ethyl acetate/petroleum ether (1/10) to give 7 g (64%) of 4-chloro-6-ethylthieno[2,3-d]pyrimidine as a yellow solid. MS (ES, m/z): 382 (M+H+).