Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][O:11][C@H:10]([CH2:14][N:15]2[C:19]3[CH:20]=[CH:21][C:22]([CH3:24])=[CH:23][C:18]=3[N:17]=[C:16]2[C:25]2[C:33]([F:34])=[CH:32][C:28]([C:29]([OH:31])=O)=[CH:27][C:26]=2[F:35])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:36][N+:37]1(C2N=C(OC)N=C(OC)N=2)CCOCC1.[Cl-].CN.C(O)C>CN(C=O)C>[F:34][C:33]1[CH:32]=[C:28]([C:29](=[O:31])[NH:37][CH3:36])[CH:27]=[C:26]([F:35])[C:25]=1[C:16]1[N:15]([CH2:14][C@H:10]2[O:11][CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[O:7])[CH2:9]2)[C:19]2[CH:20]=[CH:21][C:22]([CH3:24])=[CH:23][C:18]=2[N:17]=1
Reactant: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Reactant: Cc1ccc2c(c1)nc(-c1c(F)cc(C(=O)O)cc1F)n2C[C@@H]1CN(C(=O)OC(C)(C)C)CCO1
Agent: CN
Agent: [Cl-]
Solvent: CCO
Solvent: CN(C)C=O
Product: CNC(=O)c1cc(F)c(-c2nc3cc(C)ccc3n2C[C@@H]2CN(C(=O)OC(C)(C)C)CCO2)c(F)c1
Reaction time: 0.5 h
Yield: 100 %

Procedure:
(R)-4-(1-((4-(tert-butoxycarbonyl)morpholin-2-yl)methyl)-5-methyl-1H-benzo[d]imidazol-2-yl)-3,5-difluorobenzoic acid (750 mg, 1.54 mmol) was added to DMT-MM (408 mg, 1.69 mmol) in DMF (30.00 mL) under N2. The resulting suspension was stirred for 30 min. Afterward, methylamine 33% (by weight) solution in absolute ethanol (0.458 mL, 1.69 mmol) was added, and the mixture was stirred for 3 hr. The mixture was then concentrated under reduced pressure, and the resulting residue was dissolved in EtOAc and washed sequentially with water and brine. The organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure. The crude material was purified on preparative HPLC MS using the short high pH shallow gradient method (mobile phase: 30-50% B; A: H2O with 10 mM NH4CO3 and 0.375% NH4OH v/v; B: CH3CN; 10 min run; XBridge Prep C18 OBD, Waters reverse phase column; column size: 30×50 mm; and particle size 5 μm). This produced (S)-tert-butyl 2-((2-(2,6-difluoro-4-(methylcarbamoyl)phenyl)-5-methyl-1H-benzo[d]imidazol-1-yl)methyl)morpholine-4-carboxylate as an oil, which was used without further purification (1.4 g, >100% yield) in the next step. The oil was analyzed on analytical HPLC MS using the high pH gradient method (mobile phase: 5-95% B; A: H2O with 10 mM NH4CO3 and 0.375% NH4OH v/v; B: CH3CN; 2.25 min run; X-Bridge C18; column size: 2.1×30 mm, particle size: 5 μm). MS m/z 501.4 [M+H]+ (ESI), Rt 1.85 min.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:9]([OH:11])=O)=[N:4][C:5]([Br:8])=[CH:6][N:7]=1.[NH2:12][C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[NH2:1][C:2]1[C:3]([C:9]([NH:12][C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)=[O:11])=[N:4][C:5]([Br:8])=[CH:6][N:7]=1
Reactant: Nc1cccnc1
Reactant: Nc1ncc(Br)nc1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: Nc1ncc(Br)nc1C(=O)Nc1cccnc1
Yield: 79.3 %

Procedure:
To a solution of the product of step (iv) (100 g, 0.45 mol) in DMF (350 mL) was added TEA (129 mL, 0.91 mol) and 3-aminopyridine (42.3 g, 0.45 mol). HATU (174 g, 0.45 mol) was added to the solution portionwise. The suspension was filtered, washed with water and dried under a reduced pressure to afford the subtitle compound (v) as a yellow solid (105 g).
Reaction SMILES: C1CCN2C(=NCCC2)CC1.[CH2:12]([O:14][C:15]([NH:17][C:18]([CH2:20][NH:21][C:22]1[CH:23]=[CH:24][C:25]([C:32]([O:34][CH3:35])=[O:33])=[C:26]([S:28]([NH2:31])(=[O:30])=[O:29])[CH:27]=1)=[S:19])=[O:16])[CH3:13].[CH3:36][O:37][C:38]1[CH:43]=[C:42]([O:44][CH3:45])[N:41]=[C:40]([NH:46][C:47](OC2C=CC=CC=2)=[O:48])[N:39]=1>C(#N)C>[CH3:45][O:44][C:42]1[CH:43]=[C:38]([O:37][CH3:36])[N:39]=[C:40]([NH:46][C:47]([NH:31][S:28]([C:26]2[CH:27]=[C:22]([NH:21][CH2:20][C:18]([NH:17][C:15]([O:14][CH2:12][CH3:13])=[O:16])=[S:19])[CH:23]=[CH:24][C:25]=2[C:32]([O:34][CH3:35])=[O:33])(=[O:29])=[O:30])=[O:48])[N:41]=1
Reactant: CCOC(=O)NC(=S)CNc1ccc(C(=O)OC)c(S(N)(=O)=O)c1
Reactant: COc1cc(OC)nc(NC(=O)Oc2ccccc2)n1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: CCOC(=O)NC(=S)CNc1ccc(C(=O)OC)c(S(=O)(=O)NC(=O)Nc2nc(OC)cc(OC)n2)c1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
1.2 ml of DBU is added to a suspension of 0.69 g (1.84 mmol) of 5-[N-(ethoxycarbonylaminothiocarbonyl)methylamino]-2-methoxycarbonylbenzenesulfonamide and 0.55 g (1.99 mmol) of 4,6-dimethoxy-2-phenoxycarbonylaminopyrimidine in 5 ml of acetonitrile. The mixture is stirred for 17 h at room temperature and the solvent is then removed by distillation. The residue is taken up in water and washed with diethyl ether. The aqueous phase is acidified with concentrated hydrochloric acid (pH=1) and produces a colorless precipitate, which is filtered off and induced to crystallize by stirring with a little methanol. The resulting product is 0.61 g (60% of theory) of N-[(4,6-dimethoxypyrimidin-2-yl)aminocarbonyl]-5-[N-(ethoxycarbonylaminothiocarbonyl)methylamino]-2-methoxycarbonylbenzenesulfonamide. m.p.: 144°-145° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:11]([N:13]2[C:26]3[CH:25]=[N:24][C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[C:17]=3[O:16][CH2:15][CH2:14]2)=[O:12])[CH:5]=[C:6]([Br:10])[C:7]=1[O:8]C.[Br-].[Li+].N1CCNCC1.Cl>CN(C)C=O.O>[Br:10][C:6]1[CH:5]=[C:4]([C:11]([N:13]2[C:26]3[CH:25]=[N:24][C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[C:17]=3[O:16][CH2:15][CH2:14]2)=[O:12])[CH:3]=[C:2]([Br:1])[C:7]=1[OH:8]
Reactant: COc1c(Br)cc(C(=O)N2CCOc3c2cnc2ccccc32)cc1Br
Agent: C1CNCCN1
Agent: Cl
Agent: [Br-]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(c1cc(Br)c(O)c(Br)c1)N1CCOc2c1cnc1ccccc21
Reaction time: 2 h

Procedure:
In a 10 ml flask, (3,5-dibromo-4-methoxy-phenyl)-(2,3-dihydro-4-oxa-1,9-diaza-phenanthren-1-yl)-methanone (30 mg, 0.063 mmol), lithium bromide (12 mg, 0.134 mmol) and piperazine (9 mg, 0.101 mmol) were dissolved in N,N-dimethyl formamide (3 ml), and then stirred at 100□ for 2 hours. After completion of the reaction by adding water dropwise, the mixture was adjusted to weak acidic condition (pH=6) by using 1N hydrochloric acid. The formed solid was filtered and washed with distilled water, and recrystallized from tetrahydrofuran and methanol to obtain the target compound 55, i.e., (3,5-dibromo-4-hydroxy-phenyl)-(2,3-dihydro-4-oxa-1,9-diaza-phenanthren-1-yl)-methanone, as yellow solid (10 mg, 34%).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5](B(O)O)[O:6][CH:7]=1)=[O:2].I[C:12]1[C:20]2[C:15](=[N:16][CH:17]=[N:18][C:19]=2[NH2:21])[N:14]([CH:22]([CH3:24])[CH3:23])[N:13]=1.C([O-])([O-])=O.[Na+].[Na+]>CCO.COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:21][C:19]1[N:18]=[CH:17][N:16]=[C:15]2[N:14]([CH:22]([CH3:24])[CH3:23])[N:13]=[C:12]([C:5]3[O:6][CH:7]=[C:3]([CH:1]=[O:2])[CH:4]=3)[C:20]=12
Reactant: O=Cc1coc(B(O)O)c1
Reactant: CC(C)n1nc(I)c2c(N)ncnc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCO
Product: CC(C)n1nc(-c2cc(C=O)co2)c2c(N)ncnc21
Temperature: 80 °C
Yield: 38.3 %

Procedure:
A solution of 4-Formylfuran-2-boronic acid (20 mg, 0.14 mmol) in EtOH (3.3 mL) was added to a solution of 3-iodo-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (40 mg, 0.13 mmol) in DME (12 mL). Pd(PPh3)4 (16 mg, 0.014 mmol) and saturated Na2CO3 (1.9 mL) were added and the reaction was heated to 80° C. under an argon atmosphere overnight. After cooling, the reaction was extracted with saturated NaCl and CH2Cl2. Organic phases were combined, concentrated in vacuo and purified by RP-HPLC (MeCN:H2O:0.1% TFA) to yield BA35 (13.5 mg, 39% yield). ESI-MS (M+H)+ m/z calcd 272.1, found 272.1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([CH:11]=[CH:12][CH2:13][CH2:14][CH2:15][CH3:16])=[CH:5]2.[H][H]>C(O)C.[Pd]>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[CH:5]2
Reactant: CCCCC=Cc1cc2cc(Cl)ccc2[nH]1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCCCCCc1cc2cc(Cl)ccc2[nH]1
Reaction time: 5 h

Procedure:
5-Chloro-2-hex-1-enyl-1H-indole was dissolved in ethanol and 10% palladium on carbon was added to the solution. The reaction flask was sealed and exposed to hydrogen gas under pressure and was stirred for 5 hours. Then the reaction mixture was filtered through Celite. The solvent was evaporated to give 5-Chloro-2-hexyl-1H-indole
Reaction SMILES: [CH:1]1([C:4]2[CH:9]=[C:8]([CH2:10][OH:11])[C:7]([O:12][CH:13]([CH3:15])[CH3:14])=[CH:6][C:5]=2[C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=2[F:23])[CH2:3][CH2:2]1>[O-2].[O-2].[Mn+4].C1(C)C=CC=CC=1>[CH:1]1([C:4]2[CH:9]=[C:8]([CH:10]=[O:11])[C:7]([O:12][CH:13]([CH3:15])[CH3:14])=[CH:6][C:5]=2[C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=2[F:23])[CH2:3][CH2:2]1
Reactant: CC(C)Oc1cc(-c2ccc(F)cc2F)c(C2CC2)cc1CO
Agent: [Mn+4]
Agent: [O-2]
Solvent: Cc1ccccc1
Product: CC(C)Oc1cc(-c2ccc(F)cc2F)c(C2CC2)cc1C=O
Temperature: 60 °C
Reaction time: 1 h
Yield: 89.5 %

Procedure:
Manganese dioxide (10.8 g) was added to a toluene (30 mL) solution of (2-cyclopropyl-2′,4′-difluoro-5-isopropoxybiphenyl-4-yl)methanol (3.97 g), and the mixture was stirred at 60° C. for 1 hour in a nitrogen atmosphere. The reaction mixture was filtered, and then, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain the title compound (3.53 g).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12]2[C:15]([S:20][C:21](=O)N(C)C)=[C:16]([Cl:19])[CH:17]=[CH:18][C:11]=2[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(OC(N1CCC2[C:40]([S:46][C:47](=O)N(C)C)=[C:41](Cl)[CH:42]=C(Cl)C=2CC1)=O)(C)(C)C.[OH-].[K+].ClCC1SC=CC=1>CO.CCOC(C)=O.O>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12]2[C:15]([S:20][CH2:21][C:47]3[S:46][CH:40]=[CH:41][CH:42]=3)=[C:16]([Cl:19])[CH:17]=[CH:18][C:11]=2[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(C)C(=O)Sc1c(Cl)cc(Cl)c2c1CCN(C(=O)OC(C)(C)C)CC2
Reactant: CN(C)C(=O)Sc1c(Cl)ccc2c1CCN(C(=O)OC(C)(C)C)CC2
Agent: ClCc1cccs1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCc2ccc(Cl)c(SCc3cccs3)c2CC1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 31 %

Procedure:
To a 4:1 mixture of 3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-1H-benzo[d]azepine and 3-tert-butoxycarbonyl-7,9-dichloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-benzo[d]azepine (108 mg, 0.281 mmol) in methanol (3 ml), add potassium hydroxide pellets (504 mg, 9.0 mmol) and heat the mixture 2 h at 50° C. Cool the reaction to ambient temperature, add 2-chloromethylthiophene (186 μL, 1.406 mmol), and continue stirring for 30 min. Dilute with EtOAc and water. Separate the layers and extract the aqueous layer three times with EtOAc, dry over anhydrous Na2SO4, and concentrate in vacuo. Purify by chromatography on silica gel eluting with hexane/EtOAc (19:1) to give 3-tert-butoxycarbonyl-7-chloro-6-(thiophen-2-ylmethylthio)-2,3,4,5-tetrahydro-benzo[d]azepine as a colorless oil (36 mg, 31%).
Reaction SMILES: [C:1]([C:5]1[S:9][C:8]([C:10]2[S:11][CH:12]=[CH:13][CH:14]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(=O)=O.CC(C)=O.C([Li])CCC.[B:27](OC)([O:30]C)[O:28]C>C1COCC1>[C:1]([C:5]1[S:9][C:8]([C:10]2[S:11][C:12]([B:27]([OH:30])[OH:28])=[CH:13][CH:14]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COB(OC)OC
Reactant: CC(C)(C)c1ccc(-c2cccs2)s1
Agent: O=C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)=O
Product: CC(C)(C)c1ccc(-c2ccc(B(O)O)s2)s1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 96 %

Procedure:
In a flame-dried, 500 mL round bottom flask, 5-(t-butyl)-2,2′-bithiophene (from U152-001, 13 g, 58.5 mmol) was dissolved in anhydrous THF (200 mL) and the solution was cooled to −78° C. (dry ice/acetone). n-butyl lithium (2.5 M in hexanes, 25.7 mL, 64.3 mmol) was added dropwise over a period of 10 minutes, and the resulting green solution was allowed to stir for 15 minutes. Trimethyl borate (19.6 mL, 175 mmol) was added dropwise over a period of 10 minutes, and the resulting light yellow solution was stirred for 2 hours at −78° C., then allowed to warm to room temperature and stirred for 1 hour. The reaction was quenched by pouring it into 10% HCl (500 mL). The organic phase was separated and the aqueous phase extracted with ether (250 mL). The combined organics were washed with water (500 mL), dried over MgSO4, filtered and solvent removed by rotary evaporation. The resulting green solid was dried under vacuum to afford 15 g (96% yield), which was used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([C:9]#[C:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[C:17]([F:20])([F:19])[F:18])[CH:3]=1.[CH2:21]([O:23][C:24](=[O:29])[CH2:25][C:26](Cl)=[O:27])[CH3:22]>>[CH2:21]([O:23][C:24](=[O:29])[CH2:25][C:26]([NH:6][C:5]1[CH:7]=[CH:8][C:2]([Cl:1])=[CH:3][C:4]=1[C:9]#[C:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]([F:18])([F:19])[F:20])=[O:27])[CH3:22]
Reactant: Nc1ccc(Cl)cc1C#Cc1ccccc1C(F)(F)F
Reactant: CCOC(=O)CC(=O)Cl
Product: CCOC(=O)CC(=O)Nc1ccc(Cl)cc1C#Cc1ccccc1C(F)(F)F

Procedure:
The title compound was prepared in analogy to example 29 step A from 4-chloro-2-((2-(trifluoromethyl)phenyl)ethynyl)aniline (200 mg, 0.68 mmol) and chlorocarbonyl-acetic acid ethyl ester (128 μl, 1.01 mmol). Off white solid (213 mg, 77%). MS (ESI): 410 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:8]([C:17]2[CH:22]=[CH:21][C:20]([N+:23]([O-])=O)=[CH:19][CH:18]=2)[C:7]=1[CH3:26])=[O:5])[CH3:2].C(OCC)(=O)C>C(O)C.[Pd]>[CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:8]([C:17]2[CH:18]=[CH:19][C:20]([NH2:23])=[CH:21][CH:22]=2)[C:7]=1[CH3:26])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc(-c2ccccc2)n(-c2ccc([N+](=O)[O-])cc2)c1C
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cc(-c2ccccc2)n(-c2ccc(N)cc2)c1C

Procedure:
2-Methyl-1-(4-nitro-phenyl)-5-phenyl-1H-pyrrole-3-carboxylic acid ethyl ester of Example 33 (2 mmol, 0.8 g) was dissolved 50% solution of ethyl acetate in ethanol, and treated with Pd/C (0.088 g). The mixture was hydrogenated with H2 (g) at 45 psi. Upon completion of the reaction, the mixture was filtered through Celite and the solvents removed under vacuum. This material was purified over silica gel to yield the named product.
Reaction SMILES: [C:1](#[N:3])[CH3:2].C([Li])CCC.[Cl:9][C:10]1[CH:11]=[C:12]([C:17](=[O:28])[CH2:18][O:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)[CH:13]=[CH:14][C:15]=1[Cl:16]>CCCCCC.C1COCC1.O>[Cl:9][C:10]1[CH:11]=[C:12]([C:17]([OH:28])([CH2:18][O:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)[CH2:2][C:1]#[N:3])[CH:13]=[CH:14][C:15]=1[Cl:16]
Reactant: CC#N
Reactant: COc1ccc(OCC(=O)c2ccc(Cl)c(Cl)c2)cc1
Agent: [Li]CCCC
Solvent: O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COc1ccc(OCC(O)(CC#N)c2ccc(Cl)c(Cl)c2)cc1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a mixed solution of acetonitrile (3.54 mL) and THF (30 mL) was added dropwise a solution of n-butyllithium in hexane (1.6 M, 42.1 ml), and the mixture was stirred at −78° C. for 30 min. To the reaction mixture was added dropwise a solution of 1-(3,4-dichlorophenyl)-2-(4-methoxyphenoxy)ethanone (14 g) in THF (45 mL), and the mixture was stirred at −78° C. for 10 min, and then stirred for 1 hr while warming to room temperature. The reaction mixture was diluted with water, and the mixture was extracted with ethyl acetate. The obtained extract was washed with brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (11.73 g).
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][CH2:11][CH2:12][OH:13])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].O[C:15]1[CH:23]=[CH:22][C:18]([C:19]([NH2:21])=[O:20])=[CH:17][CH:16]=1.N(C(OCC)=O)=NC(OCC)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[C:1]([N:4]1[CH2:5][CH2:6][CH:7]([O:10][CH2:11][CH2:12][O:13][C:15]2[CH:23]=[CH:22][C:18]([C:19]([NH2:21])=[O:20])=[CH:17][CH:16]=2)[CH2:8][CH2:9]1)(=[O:3])[CH3:2]
Reactant: NC(=O)c1ccc(O)cc1
Reactant: CC(=O)N1CCC(OCCO)CC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(=O)N1CCC(OCCOc2ccc(C(N)=O)cc2)CC1
Yield: 44 %

Procedure:
N-Acetyl-4-(2-hydroxyethoxy)piperidine (1.0 g.), 4-hydroxybenzamide (0.82 g.), diethyl azodicarboxylate (1.12 g.) and triphenylphosphine (1.68 g.) in tetrahydrofuran (30 ml.) were stirred at room temperature for 66 hours. The precipitated solid was collected and dried to give 4-[2-(N-acetyl-4-piperidyloxy)ethoxy]benzamide (0.72 g.), m.p. 154°-155° C.
Reaction SMILES: I[C@@:2]1([N:11]2[CH:18]=[CH:17][C:15](=[O:16])[NH:14][C:12]2=[O:13])[O:10][C@H:7]([CH2:8][OH:9])[C@@H:5](O)[C@H:3]1O.[CH2:19]([NH:22][C:23](=[O:28])[C:24]([F:27])([F:26])[F:25])[C:20]#[CH:21].CO>ClCCl>[F:25][C:24]([F:27])([F:26])[C:23]([NH:22][CH2:19][C:20]#[C:21][C:17]1[C:15](=[O:16])[NH:14][C:12](=[O:13])[N:11]([CH:18]=1)[C@@H:2]1[O:10][C@H:7]([CH2:8][OH:9])[CH2:5][CH2:3]1)=[O:28]
Reactant: C#CCNC(=O)C(F)(F)F
Reactant: O=c1ccn([C@]2(I)O[C@H](CO)[C@@H](O)[C@H]2O)c(=O)[nH]1
Solvent: ClCCl
Solvent: CO
Product: O=C(NCC#Cc1cn([C@H]2CC[C@@H](CO)O2)c(=O)[nH]c1=O)C(F)(F)F

Procedure:
Iodouridine 21 was coupled for 3 hours to N-propargyltrifluoroacetamide following the general method given in Example 5C. Chromatography with a 0-5% methanol in dichloromethane gradient afforded material which was homogeneous by TLC, but which was difficult to dry. After co-evaporating the chromatographed product several times with chloroform and vacuum-drying, 536.5 mg of alkynylamino nucleoside 22 was obtained as a white foam. This material was homogeneous by TLC and was pure by NMR except for a small amount (39 mole %; corrected yield 66%) of chloroform.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([CH:40]([CH3:42])[CH3:41])[CH2:10][O:11][C:12](=[O:39])[CH:13]([NH:26][S:27]([C:30]1[C:35]([CH3:36])=[CH:34][C:33]([CH3:37])=[CH:32][C:31]=1[CH3:38])(=[O:29])=[O:28])[CH2:14][NH:15]C(OCC1C=CC=CC=1)=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CO>[Pd]>[C:1]([O:5][C:6]([NH:8][CH:9]([CH:40]([CH3:42])[CH3:41])[CH2:10][O:11][C:12](=[O:39])[CH:13]([NH:26][S:27]([C:30]1[C:31]([CH3:38])=[CH:32][C:33]([CH3:37])=[CH:34][C:35]=1[CH3:36])(=[O:29])=[O:28])[CH2:14][NH2:15])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cc(C)c(S(=O)(=O)NC(CNC(=O)OCc2ccccc2)C(=O)OCC(NC(=O)OC(C)(C)C)C(C)C)c(C)c1
Agent: [Pd]
Solvent: CO
Product: Cc1cc(C)c(S(=O)(=O)NC(CN)C(=O)OCC(NC(=O)OC(C)(C)C)C(C)C)c(C)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 56 %

Procedure:
To a mixture of 3-Benzyloxycarbonylamino-2-(2,4,6-trimethyl-benzenesulfonylamino)-propionic acid 2-tert-butoxycarbonylamino-3-methyl-butyl ester (Z-1) (280 mg, 0.46 mmol methanol (70 ml), was added Pd/C. The reaction was stirred under hydrogen atmosphere overnight at room temperature. Catalyst was removed by filtration and the solvent was evaporated. Purification of the residue on silica gel (1:2 hexane:EtOAc) gave 120 mg (56%) of pure 3-Amino-2-(2,4,6-trimethyl-benzenesulfonylamino)-propionic acid 2-tert-butoxycarbonylamino-3-methyl-butyl ester (Z-2).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]([C:12]2[C:13]([C:18]3[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:19]=3[OH:25])=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:9]=[CH:10][CH:11]=1)=[O:5])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:33][CH2:34][CH:35]([CH3:37])[CH3:36].O>CN(C=O)C>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]([C:12]2[C:13]([C:18]3[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:19]=3[O:25][CH2:33][CH2:34][CH:35]([CH3:37])[CH3:36])=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:9]=[CH:10][CH:11]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cccc(-c2ccccc2-c2cc(Cl)ccc2O)c1
Reactant: CC(C)CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cccc(-c2ccccc2-c2cc(Cl)ccc2OCCC(C)C)c1
Yield: 76 %

Procedure:
A mixture of 5-chloro-2-hydroxy-[1,1′;2′,1″]terphenyl-3″-carboxylic acid ethyl ester (50 mg, 0.14 mmol), potassium carbonate (48 mg, 0.35 mmol), and 1-bromo-3-methylbutane (23.5 mg, 0.15 mmol) was heated in N,N′-dimethylformamide (3 ml) at 90° C. for 4 hours. The reaction mixture was then poured into water and extracted with ethyl acetate; the organic layers were dried over MgSO4 and evaporated. The residue was chromatographed through a SPE column using 10% ethyl acetate in iso-hexane as eluent to yield the title compound as a white solid (45 mg, 75%).
Reaction SMILES: [H-].[Na+].C(O[C:6]([C:8]1[NH:9][C:10]2[C:15]([CH:16]=1)=[CH:14][CH:13]=[CH:12][C:11]=2[O:17][C:18]([F:21])([F:20])[F:19])=[O:7])C.C(OC([N:29]1[CH2:33][C@H:32]([CH3:34])OS1(=O)=O)=O)(C)(C)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O.C([O-])([O-])=O.[K+].[K+]>CN(C)C=O>[CH3:34][C@H:32]1[N:9]2[C:10]3[C:11]([O:17][C:18]([F:19])([F:20])[F:21])=[CH:12][CH:13]=[CH:14][C:15]=3[CH:16]=[C:8]2[C:6](=[O:7])[NH:29][CH2:33]1
Reactant: CCOC(=O)c1cc2cccc(OC(F)(F)F)c2[nH]1
Reactant: C[C@H]1CN(C(=O)OC(C)(C)C)S(=O)(=O)O1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [H-]
Solvent: CN(C)C=O
Product: C[C@@H]1CNC(=O)c2cc3cccc(OC(F)(F)F)c3n21
Temperature: 0 °C
Reaction time: 36 h
Yield: 5.6 %

Procedure:
Sodium hydride (280 mg of a 60% dispersion in mineral oil, 7 mmol) was added to a solution of 7-trifluoromethoxy-1H-indole-2-carboxylic acid ethyl ester (1.53 g, 5.6 mmol) and (S)-5-methyl-2,2-dioxo-[1,2,3]oxathiazolidine-3-carboxylic acid tert-butyl ester (1.53 g, 6.45 mmol) in N,N-dimethylformamide (15 mL) at 0° C. The solution was allowed to reach room temperature and stirred 36 h. Further amounts of sodium hydride (56 mg) and (S)-5-methyl-2,2-dioxo-[1,2,3]oxathiazolidine-3-carboxylic acid tert-butyl ester (306 mg) were added to complete the reaction. To the solution was added 10% aq. citric acid solution and the mixture stirred 1 h at room temperature. The organics were extracted with ethyl acetate (2×), the combined organic phases washed with sat. aq. NaHCO3 solution and brine, dried (Na2SO4), and evaporated. The residue was dissolved in dichloromethane (25 mL), cooled to 0° C. and treated with trifluoroacetic acid (12 mL). After removal of the ice bath, the solution was stirred for 30 min and evaporated under reduced pressure. The residue was taken up in methanol (20 mL) and K2CO3 (2.52 g, 19.5 mmol) added, and the mixture stirred 15 h at room temperature. The mixture was filtered, the filtrate diluted with ethyl acetate, washed with water, dried (Na2SO4) and evaporated. The residue was purified by column chromatography on silica gel (hexane/ethyl acetate gradient) to afford the product as a pale yellow foam (89 mg, 64%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=3)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[Cl:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25]Br)=[CH:23][CH:22]=1.[I-].[K+].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:25][C:24]3[CH:27]=[CH:28][C:21]([Cl:20])=[CH:22][CH:23]=3)([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=3)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1
Reactant: Clc1ccc(CBr)cc1
Reactant: COc1cccc(C2C(=O)Nc3cc(Cl)ccc32)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: COc1cccc(C2(Cc3ccc(Cl)cc3)C(=O)Nc3cc(Cl)ccc32)c1
Temperature: 60 °C

Procedure:
A mixture of rac-6-chloro-3-(3-methoxy-phenyl)-1,3-dihydro-indol-2-one (0.16 g, 0.6 mmol) (from Example 6b supra), 4-chlorobenzyl bromide (0.15 g, 0.7 mmol) (Lancaster), potassium iodide (0.12 g, 0.71 mmol) and potassium carbonate (0.18 g, 1.3 mmol) in acetone (5 mL) was heated at 60° C. for 6 hours in a capped pressure tube. After cooling, mixture was diluted with ethyl acetate (50 mL) and extracted with water (2×50 mL) and brine (50 mL). Aqueous layers were back washed with ethyl acetate (50 mL). Organic layers were combined, dried (MgSO4), filtered and concentrated. Residue was recrystallized from dichloromethane-hexanes to give rac-6-chloro-3-(4-chloro-benzyl)-3-(3-methoxy-phenyl)-1,3-dihydro-indol-2-one as white crystals. (Yield 0.18 g, 75.3%).