Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(S([N:10]2[C:14]3[N:15]=[C:16]([Cl:20])[N:17]=[C:18]([Cl:19])[C:13]=3[CH:12]=[C:11]2[C:21]([OH:24])([CH3:23])[CH3:22])(=O)=O)C=CC=CC=1.[OH-].[Na+]>C(O)(C)C.O>[Cl:20][C:16]1[N:17]=[C:18]([Cl:19])[C:13]2[CH:12]=[C:11]([C:21]([OH:24])([CH3:22])[CH3:23])[NH:10][C:14]=2[N:15]=1
Reactant: CC(C)(O)c1cc2c(Cl)nc(Cl)nc2n1S(=O)(=O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)O
Product: CC(C)(O)c1cc2c(Cl)nc(Cl)nc2[nH]1
Temperature: 25 °C
Reaction time: 2 h
Yield: 61.8 %

Procedure:
Lithium diisopropylamide (2 mL, 4.0 mmol, 2 M in THF) was added dropwise to a solution of 7-benzenesulfonyl-2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidine (656 mg, 2.0 mmol) in anhydrous THF (15 mL) at −78° C. The resulting solution was stirred at −78° C. for 90 min, then acetone (0.4 mL, 5.5 mmol) was added and the reaction mixture was stirred at −78° C. for 30 min. The reaction mixture was quenched with saturated aqueous ammonium chloride and extracted with ethyl acetate. The combined organic extracts were dried (MgSO4) and concentrated in vacuo affording 2-(7-benzenesulfonyl-2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-propan-2-ol. To a solution of 2-(7-benzenesulfonyl-2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-propan-2-ol (2 mmol) in a mixture of isopropyl alcohol (11 mL) and water (3 mL) was added sodium hydroxide (6 mL, 36 mmol, 6M aqueous solution). The resulting mixture was stirred at RT for 2 h, then concentrated in vacuo. The resulting residue was purified by column chromatography (SiO2, gradient 0 to 40% ethyl acetate in cyclohexane) affording 2-(2,4-Dichloro-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-propan-2-ol (304 mg, 64%). LCMS (method A): RT=2.70 min, [M]−=244/246.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@H:9]([CH2:13][CH:14]2[CH2:16][CH2:15]2)[C:10]([NH2:12])=[O:11])[CH:5]=[N:4][C:3]=1[C:17]#[N:18].[NH2:19][C:20]1[CH:21]=[N:22][C:23]2[C:28]([CH:29]=1)=[CH:27][CH:26]=[CH:25][CH:24]=2.C([O-])([O-])=O.[K+].[K+].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>O1CCOCC1.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:17]([C:3]1[N:4]=[CH:5][C:6]([NH:8][C@H:9]([CH2:13][CH:14]2[CH2:16][CH2:15]2)[C:10]([NH2:12])=[O:11])=[N:7][C:2]=1[NH:19][C:20]1[CH:21]=[N:22][C:23]2[C:28]([CH:29]=1)=[CH:27][CH:26]=[CH:25][CH:24]=2)#[N:18]
Reactant: Nc1cnc2ccccc2c1
Reactant: N#Cc1ncc(N[C@H](CC2CC2)C(N)=O)nc1Cl
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: N#Cc1ncc(N[C@H](CC2CC2)C(N)=O)nc1Nc1cnc2ccccc2c1
Reaction time: 3 h
Yield: 43.9 %

Procedure:
A mixture of (R)-2-(6-chloro-5-cyanopyrazin-2-ylamino)-3-cyclopropylpropanamide (78 mg, 0.293 mmol), 3-aminoquinoline (60 mg, 0.416 mmol), K2CO3 (70 mg, 0.507 mmol), BINAP (25 mg, 0.040 mmol) and Pd(OAc)2 (10 mg, 0.044 mmol) in dioxane (2 mL) was degassed with Ar, then was stirred at 110 C for 3 h. The mixture was concentrated in vacuo. The residue was purified by HPLC to give (R)-2-(5-cyano-6-(quinolin-3-ylamino)pyrazin-2-ylamino)-3-cyclopropylpropanamide (48 mg).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:9]=[C:8]([F:10])[C:7]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])=[C:6]([C:16]#[CH:17])[CH:5]=1.[CH3:18][O:19][CH2:20][CH2:21][O:22][C:23]1[C:28]([CH:29]=[CH:30][C:31](O)=[O:32])=[CH:27][CH:26]=[C:25]([C:34]([F:37])([F:36])[F:35])[N:24]=1>>[C:16]([C:6]1[CH:5]=[C:4]([CH:9]=[C:8]([F:10])[C:7]=1[NH:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH2:3][NH:2][C:31](=[O:32])[CH:30]=[CH:29][C:28]1[C:23]([O:22][CH2:21][CH2:20][O:19][CH3:18])=[N:24][C:25]([C:34]([F:36])([F:35])[F:37])=[CH:26][CH:27]=1)#[CH:17]
Reactant: C#Cc1cc(CN)cc(F)c1NS(C)(=O)=O
Reactant: COCCOc1nc(C(F)(F)F)ccc1C=CC(=O)O
Agent: Cl
Product: C#Cc1cc(CNC(=O)C=Cc2ccc(C(F)(F)F)nc2OCCOC)cc(F)c1NS(C)(=O)=O
Yield: 70.1 %

Procedure:
N-(4-Aminomethyl-2-ethynyl-6-fluoro-phenyl)-methanesulfonamide HCl salt (45 mg, 0.156 mmol) was reacted with 3-[2-(2-methoxy-ethoxy)-6-trifluoromethyl-pyridin-3-yl]-acrylic acid (38 mg, 0.13 mmol) to give the title compound (47 mg, 70%).
Reaction SMILES: [C:1]([OH:10])(=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([OH:8])=[O:7].[C:11]1([N:17]=[N:18][C:19]2[CH:24]=[CH:23][C:22](O)=[CH:21][CH:20]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C(Cl)(Cl)Cl>[C:11]1([N:17]=[N:18][C:19]2[CH:24]=[CH:23][C:22]([O:7][C:6](=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2][C:1]([O:10][C:22]3[CH:21]=[CH:20][C:19]([N:18]=[N:17][C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)=[CH:24][CH:23]=3)=[O:9])=[CH:21][CH:20]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C(O)CCCCC(=O)O
Reactant: Oc1ccc(N=Nc2ccccc2)cc1
Solvent: ClC(Cl)Cl
Product: O=C(CCCCC(=O)Oc1ccc(N=Nc2ccccc2)cc1)Oc1ccc(N=Nc2ccccc2)cc1
Reaction time: 4 h

Procedure:
164 g. of polyphosphoric acid ethyl ester is dissolved in 60 ml. of chloroform. A suspension of 14.86 g. of adipic acid and 40.0 g. of p-(phenylazo)-phenol in 340 ml. of chloroform is added to this solution. The reaction mixture is agitated for 4 hours. Then, 35 g. of adipic acid bis(4-phenylazophenyl)ester is obtained by vacuum-filtering the reaction mixture; this product is recrystallized from ethyl acetate. In this way, 30 g. of a pure compound is obtained, m.p. 176°-177° C.
Reaction SMILES: [CH2:1]([O:4][C:5](=[O:27])[C:6]1[C:11]([CH3:12])=[C:10]([O:13][CH3:14])[CH:9]=[C:8]([O:15][Si:16]([CH3:24])([CH3:23])[C:17]([CH3:22])([CH3:21])[CH:18]([CH3:20])[CH3:19])[C:7]=1[CH:25]=O)[CH:2]=[CH2:3].C(OC(=O)[NH:34][C@H:35]([C:38]1[O:42][N:41]=[C:40]([CH3:43])[N:39]=1)[CH2:36][SH:37])(C)(C)C.C([SiH](CC)CC)C>FC(F)(F)C(O)=O.ClCCl>[CH2:1]([O:4][C:5](=[O:27])[C:6]1[C:11]([CH3:12])=[C:10]([O:13][CH3:14])[CH:9]=[C:8]([O:15][Si:16]([CH3:23])([CH3:24])[C:17]([CH3:21])([CH3:22])[CH:18]([CH3:20])[CH3:19])[C:7]=1[CH2:25][S:37][CH2:36][C@H:35]([NH2:34])[C:38]1[O:42][N:41]=[C:40]([CH3:43])[N:39]=1)[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)c1c(C)c(OC)cc(O[Si](C)(C)C(C)(C)C(C)C)c1C=O
Reactant: Cc1noc([C@H](CS)NC(=O)OC(C)(C)C)n1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C=CCOC(=O)c1c(C)c(OC)cc(O[Si](C)(C)C(C)(C)C(C)C)c1CSC[C@H](N)c1nc(C)no1
Reaction time: 18 h
Yield: 74.9 %

Procedure:
To a solution of 13.8 g of 2-formyl-5-methoxy-6-methyl-3-[dimethyl-(1,1,2-trimethyl-propyl)-silanyloxy]-benzoic acid allyl ester in 38 ml of trifluoroacetic acid, cooled to 0° C., were added within 15 min a solution of 13.7 g of (R)-2-mercapto-1-(3-methyl-1,2,4-oxadiazol-5-yl)ethylcarbamic acid tert-butyl ester and 6.2 g of triethylsilane in 38 ml of dichloromethane. The solution was kept at 0° C. for 18 h and then evaporated in vacuo. The residue was taken up in ethyl acetate and the solution was successively washed with water; saturated sodium carbonate solution and brine, and dried over sodium sulfate. The solvent was evaporated in vacuo and the residue Was chromatographed on silica gel using ethyl acetate/hexane (1:3, v/v) as eluent to yield 14.1 g of (R)-2-[2-amino-2-(3-methyl-1,2,4-oxadiazol-5-yl)-ethylsulfanyl-methyl]-3-[dimethyl-(1,1,2-trimethyl-propyl)-silanyloxy]-5-methoxy-6-methylbenzoic acid allyl ester as a pale yellow oil.
Reaction SMILES: [C:1]([O:8][CH3:9])(=[O:7])[CH2:2][C:3]([O:5][CH3:6])=[O:4].[H-].[Na+].Br[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([CH:20]([O:24][CH2:25][CH3:26])[O:21][CH2:22][CH3:23])=[CH:16][CH:15]=1>CN(C=O)C>[CH2:25]([O:24][CH:20]([O:21][CH2:22][CH3:23])[C:17]1[CH:18]=[CH:19][C:14]([CH2:13][CH:2]([C:1]([O:8][CH3:9])=[O:7])[C:3]([O:5][CH3:6])=[O:4])=[CH:15][CH:16]=1)[CH3:26]
Reactant: COC(=O)CC(=O)OC
Reactant: CCOC(OCC)c1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(OCC)c1ccc(CC(C(=O)OC)C(=O)OC)cc1
Reaction time: 1 h

Procedure:
To a solution of dimethyl malonate (4.96 mL, 43 mmol) in DMF (80 mL) was added NaH (1.3 g 80% in mineral oil). After 20 min. a solution of 1-(bromomethyl)-4-(diethoxymethyl)benzene (2.37 g, 8.7 mmol) in DMF (5 mL) was added via double-tipped needle. After 1 h at 0° C., the reaction was quenched by the addition of saturated NH4Cl solution. The product was extracted with Et2O and the organic layer wash washed with H2O and brine. After drying (MgSO4) and filtration, the solvent was removed under vacuum. The crude was purified by flash chromatography (1:10 EtOAc/hexane) to yield a colorless oil (1:42 g).
Reaction SMILES: [CH3:1][NH:2][C:3]([C@@:5]1(N2C=NC3C2=NC(Cl)=NC=3Cl)[C@@H:12]2[C@@H:8]([O:9][C:10]([CH3:14])([CH3:13])[O:11]2)[CH2:7][S:6]1)=[O:4].Cl.IC1C=C(C=CC=1)CN.C(N(CC)CC)C>C(O)C>[CH3:1][NH:2][C:3]([CH:5]1[CH:12]2[CH:8]([O:9][C:10]([CH3:14])([CH3:13])[O:11]2)[CH2:7][S:6]1)=[O:4]
Reactant: CNC(=O)[C@]1(n2cnc3c(Cl)nc(Cl)nc32)SC[C@@H]2OC(C)(C)O[C@@H]21
Agent: Cl
Agent: NCc1cccc(I)c1
Solvent: CCO
Solvent: CCN(CC)CC
Product: CNC(=O)C1SCC2OC(C)(C)OC21
Temperature: 25 °C
Reaction time: 72 h

Procedure:
65 mg (0.16 mmol) of (3aS,4R,6aR)-4-(2,6-dichloropurin-9-yl)-2,2-dimethyltetrahydrothieno[3,4-d][1,3]dioxole-4-carboxylic acid methyl amide from the aforementioned Experimental Example 10, 55 mg (0.20 mmol) of 3-iodobenzylamine hydrochloride, and 0.065 mL (0.46 mmol) of triethylamine were added to ethanol and stirred at ambient temperature for 3 days. The reaction mixture was distilled under reduced pressure to obtain a concentrate. The concentrate was purified by silica gel column chromatography using the eluant (hexane:ethyl acetate=1:1) to obtain 87 mg (yield: 90%) of (3aS,4R,6aR)-4-[2-chloro-6-(3-iodobenzylamino)purin-9-yl)]-2,2-dimethyltetrahydrothieno[3,4-d][1,3]dioxole-4-carboxylic acid methyl amide as a white foam.
Reaction SMILES: [CH2:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[NH:12][C:13]([C:15]2[N:19]3[CH:20]=[CH:21][C:22]([C:24]([N:26]4[CH2:31][CH2:30][N:29](C(OC(C)(C)C)=O)[CH2:28][CH2:27]4)=[O:25])=[CH:23][C:18]3=[N:17][CH:16]=2)=[O:14])[N:5]([CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[C:42]([CH3:46])[N:41]=2)[N:4]=1)[CH3:2].[ClH:47]>C(OCC)(=O)C>[ClH:47].[ClH:47].[CH2:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[NH:12][C:13]([C:15]2[N:19]3[CH:20]=[CH:21][C:22]([C:24]([N:26]4[CH2:27][CH2:28][NH:29][CH2:30][CH2:31]4)=[O:25])=[CH:23][C:18]3=[N:17][CH:16]=2)=[O:14])[N:5]([CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[C:42]([CH3:46])[N:41]=2)[N:4]=1)[CH3:2]
Reactant: CCc1nn(Cc2cccc(C)n2)c2cccc(NC(=O)c3cnc4cc(C(=O)N5CCN(C(=O)OC(C)(C)C)CC5)ccn34)c12
Agent: Cl
Solvent: CCOC(C)=O
Product: CCc1nn(Cc2cccc(C)n2)c2cccc(NC(=O)c3cnc4cc(C(=O)N5CCNCC5)ccn34)c12
Reaction time: 0.75 h

Procedure:
To a solution of tert-butyl 4-(3-(3-ethyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-ylcarbamoyl)imidazo[1,2-a]pyridine-7-carbonyl)piperazine-1-carboxylate (10.2 mg, 0.0164 mmol) in ethyl acetate (1 mL) was added hydrogen chloride (1 mL; 4M in dioxane) and the mixture was stirred for 45 minutes. The solvent was removed under reduced pressure and dried under high vacuum to give N-(3-ethyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl)-7-(piperazine-1-carbonyl)imidazo[1,2-a]pyridine-3-carboxamide dihydrochloride (9.5 mg). MS (APCI), positive scan, m/z=523.3 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:24]([F:27])([F:26])[F:25])[O:13][N:12]=[C:11]([C:14]3[CH:22]=[CH:21][C:17]([C:18]([NH2:20])=[O:19])=[C:16]([CH3:23])[CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[O:28]1[CH:32]=[CH:31][CH2:30][CH2:29]1.C(=O)([O-])O.[Na+]>ClCCl.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:24]([F:25])([F:27])[F:26])[O:13][N:12]=[C:11]([C:14]3[CH:22]=[CH:21][C:17]([C:18]([NH:20][CH:29]4[CH2:30][CH2:31][CH2:32][O:28]4)=[O:19])=[C:16]([CH3:23])[CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(N)=O
Reactant: C1=COCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)NC1CCCO1
Yield: 80.8 %

Procedure:
In a solution of 1.25 g of 4-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl]-2-methyl benzoic acid amide synthesized in Step 1 of Synthetic Example 19 and 0.32 g of 2,3-dihydrofuran in 30 mL of dichloromethane, 0.01 g of p-toluene sulfonic acid monohydrate was added at room temperature with stirring, and stirred at room temperature for 3 days. After the completion of the reaction, 30 mL of saturated sodium hydrogen carbonate aqueous solution was added in the reaction mixture, extracted with ethyl acetate (30 mL×2), the organic phase was dehydrated with and dried over saturated sodium chloride aqueous solution and then anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified with silica gel column chromatography that was eluated with ethyl acetate-hexane (1:1) to obtain 1.18 g of the aimed product as colorless resinous substance.
Reaction SMILES: C(OC([NH:11][C@H:12]([C@@H:14]([OH:30])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH3:13])=O)C1C=CC=CC=1>CO.[Pd]>[NH2:11][C@H:12]([C@@H:14]([OH:30])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH3:13]
Reactant: CCCCCCCCCCCCCCC[C@H](O)[C@H](C)NC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CCCCCCCCCCCCCCC[C@H](O)[C@H](C)N
Reaction time: 8 h
Yield: 88.7 %

Procedure:
To a solution of N-benzyloxycarbonylamine 90 (330 mg, 0.79 mmol) in MeOH (40 mL) at room temperature, Pd—C (10% wt, 100 mg, 0.09 mmol) was added. The mixture was purged with a stream of dry Ar, and then H2. The reaction was stirred overnight under a H2 atmosphere (1 atm). The catalyst was filtered off through a 0.45 μm teflon filter in polypropylene housing, washing the filter with MeOH (50 mL) and the solvent was evaporated in vacuo. The crude was purified by column chromatography on silica (90:10 CH2Cl2/MeOH to 100% MeOH) to obtain aminoalcohol 91 as a white solid (200 mg, 89% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:14]=1[NH:13][C:12]1[CH2:11][CH2:10][CH2:9][C:8](=[O:15])[C:7]2=1.CCCCC.[H-].[Na+].[CH2:23](Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CN(C=O)C>[CH2:23]([N:13]1[C:12]2[CH2:11][CH2:10][CH2:9][C:8](=[O:15])[C:7]=2[C:6]2[C:14]1=[C:2]([Cl:1])[CH:3]=[CH:4][CH:5]=2)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=C1CCCc2[nH]c3c(Cl)cccc3c21
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCCCC
Product: O=C1CCCc2c1c1cccc(Cl)c1n2Cc1ccccc1
Reaction time: 0.5 h
Yield: 68.1 %

Procedure:
8-Chloro-1,2,3,9-tetrahydro-4H-carbazol-4-one (0.2019 g, 0.92 mmol) is added to a slurry of pentane-washed NaH (0.0275 g, 0.68 mmol) in DMF (1 mL) and after stirring 22 min benzyl bromide (0.13 mL, 0.0011 mol) is added. Starting material remained after 30 min, so additional NaH (0.0140 g, 0.35 mmol) and DMF (1 mL) are added and the mixture is allowed to stir overnight. The mixture is then partitioned between aq. sodium bicarbonate and ethyl acetate and the organic layer is dried over sodium sulfate and concentrated to dryness. The resulting solids are recrystallized from 30% ethyl acetate/hexane and dichloromethane to give 0.1942 g (68%) of the title compound; mp 161-162° C.; MS (ESI+) for C19H16ClNO m/z 310.1 (M+H)+; IR (drift) 1644, 1605, 1538, 1484, 1462, 1447, 1425, 1357, 1188, 1106, 793, 784, 737, 725, 699 cm−1; 1H NMR (CDCl3) δ2.22, 2.59, 2.85, 5.82, 6.95, 7.18, 7.28, 8.28. Anal. Calcd for C19H16ClNO: C, 73.66; H, 5.20; N, 4.52. Found: C, 73.41; H, 5.17; N, 4.57.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:8]([NH:11][CH2:12][C:13]2[S:14][C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([S:24]([CH3:27])(=[O:26])=[O:25])[CH:19]=3)=[CH:16][CH:17]=2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].[CH2:30](Br)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>CN(C)C(=O)C>[CH2:30]([N:11]([CH2:12][C:13]1[S:14][C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([S:24]([CH3:27])(=[O:26])=[O:25])[CH:19]=2)=[CH:16][CH:17]=1)[S:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=1)(=[O:9])=[O:10])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: BrCc1ccccc1
Reactant: CS(=O)(=O)c1cccc(-c2ccc(CNS(=O)(=O)c3cccc(Cl)c3)s2)c1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CS(=O)(=O)c1cccc(-c2ccc(CN(Cc3ccccc3)S(=O)(=O)c3cccc(Cl)c3)s2)c1

Procedure:
In analogy to example 1, step 2, 3-chloro-N-[5-(3-methanesulfonyl-phenyl)-thiophen-2-ylmethyl]-benzenesulfonamide was reacted with sodium hydride in N,N-dimethylacetamide at 0° C. followed by reaction with benzyl bromide at r.t. overnight to give N-benzyl-3-chloro-N-[5-(3-methanesulfonyl-phenyl)-thiophen-2-ylmethyl]-benzenesulfonamide as an off-white solid. MS: 549.3 ([M+NH4]+)
Reaction SMILES: [OH:1][CH2:2][C:3]([N:5]1[CH2:10][CH2:9][NH:8][C:7](=[O:11])[C:6]1([CH3:13])[CH3:12])=[O:4].[H-].[Na+].CC1C=CC(S(O[C:27](=[CH:32][C:33]#[N:34])[C:28]([F:31])([F:30])[F:29])(=O)=O)=CC=1>CN(C=O)C>[NH2:34][C:33]1[CH:32]=[C:27]([C:28]([F:31])([F:30])[F:29])[O:1][C:2]=1[C:3]([N:5]1[CH2:10][CH2:9][NH:8][C:7](=[O:11])[C:6]1([CH3:13])[CH3:12])=[O:4]
Reactant: Cc1ccc(S(=O)(=O)OC(=CC#N)C(F)(F)F)cc1
Reactant: CC1(C)C(=O)NCCN1C(=O)CO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1(C)C(=O)NCCN1C(=O)c1oc(C(F)(F)F)cc1N
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 6.8 %

Procedure:
4-(2-Hydroxyacetyl)-3,3-dimethylpiperazin-2-one (0.090 g, 0.48 mmol) and sodium hydride (60%, 0.040 g, 0.97 mmol) were dissolved in 3 mL DMF and stirred at 25° C. for 30 min. To the resulting, cooled (0° C.) mixture was added drop-wise 3-cyano-1,1,1-trifluoroprop-2-en-2-yl 4-methylbenzenesulfonate (0.16 g, 0.56 mmol). The reaction was gradually warmed up to 25° C., stirred for an additional 2 hours, 2 additional equivalents of sodium hydride were added and the mixture stirred for another additional 4 hours. The reaction mixture was quenched with water, extracted with ethyl acetate, the combined organic layers dried, the solvent eliminated under vacuum and the crude product purified by preparative thin layer chromatography. (silicagel, dichloromethane:methanol 95:5) to afford 0.010 g of 4-(4-amino-2-(trifluoromethyl)furan-5-carbonyl)-3,3-dimethylpiperazin-2-one.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:41])[C:10]2[CH:15]=[CH:14][C:13]([S:16][C:17]3[CH:22]=[CH:21][C:20]([NH:23][CH2:24][CH2:25][CH3:26])=[CH:19][CH:18]=3)=[C:12]([NH:27][C:28]3[C:29]4[CH:37]=[CH:36][C:35]([CH:38]([CH3:40])[CH3:39])=[N:34][C:30]=4[N:31]=[CH:32][N:33]=3)[CH:11]=2)=[N:6][CH:7]=1.[C:42](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C=O>ClCCl.CO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:41])[C:10]2[CH:15]=[CH:14][C:13]([S:16][C:17]3[CH:18]=[CH:19][C:20]([N:23]([CH3:42])[CH2:24][CH2:25][CH3:26])=[CH:21][CH:22]=3)=[C:12]([NH:27][C:28]3[C:29]4[CH:37]=[CH:36][C:35]([CH:38]([CH3:40])[CH3:39])=[N:34][C:30]=4[N:31]=[CH:32][N:33]=3)[CH:11]=2)=[N:6][CH:7]=1
Reactant: CCCNc1ccc(Sc2ccc(C(=O)Nc3ccc(Br)cn3)cc2Nc2ncnc3nc(C(C)C)ccc23)cc1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: CCCN(C)c1ccc(Sc2ccc(C(=O)Nc3ccc(Br)cn3)cc2Nc2ncnc3nc(C(C)C)ccc23)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To the product from Example 290 and sodium triacetoxyborohydride in 9/1 dichloromethane/methanol was added excess formaldehyde (37% in water). The mixture was stirred at room temperature for 2 hours and evaporated. The residue was purified by reverse phase preparative HPLC with the AA method to provide the title compound. 1H NMR (300 MHz, DMSO-D6) δ ppm: 0.88 (t, J=7.35 Hz, 3 H) 1.34 (d, J=6.99 Hz, 6 H) 1.54 (m, 2 H) 2.93 (s, 3 H) 3.25 (m, 3 H) 6.75 (d, J=9.19 Hz, 2 H) 6.85 (d, J=7.72 Hz, 1 H) 7.27 (d, J=8.82 Hz, 2 H) 7.63 (d, J=8.46 Hz, 1 H) 7.87 (d, J=8.46 Hz, 1 H) 8.04 (d, J=2.57 Hz, 1 H) 8.07 (d, J=2.21 Hz, 1 H) 8.17 (m, 1 H) 8.49 (d, J=2.21 Hz, 1 H) 8.58 (s, 1 H) 8.88 (d, J=8.82 Hz, 1 H) 10.13 (s, 1 H) 10.91 (s, 1 H); MS (ESI+) m/z 642/644 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:35]=[CH:34][C:33]([F:36])=[CH:32][C:3]=1[CH2:4][O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]2[CH2:20][CH2:19][N:18]([C:21]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[O:22])[CH2:17][CH:16]2[OH:31])=[CH:11][CH:10]=1.Cl[CH2:38][C:39]1[CH:40]=[CH:41][C:42]2[O:47][CH2:46][C:45](=[O:48])[N:44]([CH2:49][CH2:50][CH2:51][O:52][CH3:53])[C:43]=2[CH:54]=1>>[F:1][C:2]1[CH:35]=[CH:34][C:33]([F:36])=[CH:32][C:3]=1[CH2:4][O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]2[CH2:20][CH2:19][N:18]([C:21]([O:23][CH2:24][C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)=[O:22])[CH2:17][CH:16]2[O:31][CH2:38][C:39]2[CH:40]=[CH:41][C:42]3[O:47][CH2:46][C:45](=[O:48])[N:44]([CH2:49][CH2:50][CH2:51][O:52][CH3:53])[C:43]=3[CH:54]=2)=[CH:11][CH:10]=1
Reactant: COCCCN1C(=O)COc2ccc(CCl)cc21
Reactant: O=C(OCc1ccccc1)N1CCC(c2ccc(OCCOCc3cc(F)ccc3F)cc2)C(O)C1
Product: COCCCN1C(=O)COc2ccc(COC3CN(C(=O)OCc4ccccc4)CCC3c3ccc(OCCOCc4cc(F)ccc4F)cc3)cc21

Procedure:
Analogously to Method D, 0.430 g of benzyl 4-{4-[2-(2,5-difluorobenzyloxy)ethoxy]phenyl}-3-hydroxypiperidine-1-carboxylate and 0.261 g of 6-chloromethyl-4-(3-methoxypropyl)-4H-benzo[1,4]oxazin-3-one are reacted. The title compound is obtained as a colourless oil. Rf=0.10 (1:1 EtOAc-heptane). Rt=5.72.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][C:5]1([CH2:17][OH:18])[CH:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:9][CH:8]=[CH:7][CH2:6]1.CC(C)=[O:21].OS(O)(=O)=O.O=[Cr](=O)=O.C(O)(C)C>CC(C)=O>[Cl:1][CH2:2][CH2:3][CH2:4][C:5]1([C:17]([OH:21])=[O:18])[CH:10]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:9][CH:8]=[CH:7][CH2:6]1
Reactant: OCC1(CCCCl)CC=CCC1c1ccccc1
Reactant: CC(C)=O
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CC(C)O
Product: O=C(O)C1(CCCCl)CC=CCC1c1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 87 %

Procedure:
Ethyl 1-(3-chloropropyl)-6-phenyl-3-cyclohexene-1-carboxylate (8.65 g, 29.4 mmol) dissolved in toluene (200 ml) was added dropwise to a 1.0M stock solution of diisobutylaluminum hydride (DIBAL, 2.2 equiv., 64.6 ml). The contents were stirred for 16 hrs. under N2 at ambient temperature. The reaction was then chilled to 0° C. and water (100 ml) added. The resulting precipitate was filtered off and the filtrate was dried over MgSO4, filtered, and concentrated in vacuo to afford 7.21 g (92% yield) of 1-(3-chloropropyl)-6-phenyl-3-cyclohexene-1-methanol as a clear mobile oil. Infrared spectroscopy indicated the disappearance of an ester carbonyl band and the appearance of hydroxyl stretching between 3200-3400 cm-1. To this alcohol (27 mmol) dissolved in acetone (100 ml) and cooled to 0° C. was added Jones reagent (2.67M, 2.0 equiv., 20.3 ml). The contents were stirred for 2 hr. at which time isopropyl alcohol (20 ml) was added to quench unreacted Jones reagent. The solution was concentrated in vacuo. The residue was washed with water and extracted three times with 100 ml of ethyl ether. The combined organic extracts were dried over MgSO4, filtered through celite and concentrated in vacuo to afford 1-(3-chloropropyl)-6-phenyl-3-cyclohexene-1-carboxylic acid (4.95 g, 87% yield) as a clear viscous oil. Infrared spectroscopy indicated the appearance of the carboxyl stretch at 1700 cm-1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:22]=[CH:21][C:6]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[C:10]=2[CH:18]([OH:20])[CH3:19])=[CH:5][CH:4]=1.C[N+]1([O-])CCOCC1>ClCCl.[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[C:10]=2[C:18](=[O:20])[CH3:19])=[CH:21][CH:22]=1
Reactant: COc1ccc(COc2cccc([N+](=O)[O-])c2C(C)O)cc1
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: ClCCl
Product: COc1ccc(COc2cccc([N+](=O)[O-])c2C(C)=O)cc1
Temperature: 0 °C
Reaction time: 12 h
Yield: 80.1 %

Procedure:
To a cooled (0° C.), stirred solution of 1-{2-[(4-methoxybenzyl)oxy]-6-nitro-phenyl}ethanol (0.20 g, 0.659 mmol) in dichloromethane (20 mL) were added molecular sieves 4A (1 g), N-methylmorpholine N-oxide (0.15 g, 1.319 mmol) and tetra-n-propylammonium perruthenate (0.01 g). The mixture was stirred at room temperature for 12 hrs. The reaction mixture was filtered on Celite®, and the filtrate was diluted with ethyl acetate. The organic phase was washed with saturated aqueous ammonium chloride solution and dried over Na2SO4, filtered and concentrated under reduced pressure to give 1-{2-[(4-methoxybenzyl)oxy]-6-nitrophenyl}ethanone as a white solid (0.159 g, yield; 80%). The residue was used for the next step without further purification.