Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si]([O:18][CH:19]1[CH2:22][N:21]([C:23]2[S:24][CH:25]=[C:26]([CH2:28][NH:29][C:30]([C:32]3[S:33][CH:34]=[CH:35][CH:36]=3)=[O:31])[N:27]=2)[CH2:20]1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[OH:18][CH:19]1[CH2:22][N:21]([C:23]2[S:24][CH:25]=[C:26]([CH2:28][NH:29][C:30]([C:32]3[S:33][CH:34]=[CH:35][CH:36]=3)=[O:31])[N:27]=2)[CH2:20]1
Reactant: CC(C)(C)[Si](OC1CN(c2nc(CNC(=O)c3cccs3)cs2)C1)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: O=C(NCc1csc(N2CC(O)C2)n1)c1cccs1
Reaction time: 1 h
Yield: 47.4 %

Procedure:
To a solution of 3-t-butyldiphenylsilyloxy-1-[4-(thiophene-2-carbonylamino)methyl-1,3-thiazol-2-yl]azetidine (2.18 g, 4.08 mmol) (obtained as described in Reference Example 66(1)) in anhydrous tetrahydrofuran (110 ml) was added a solution of 1.0 M tetra-n-butylammonium fluoride in tetrahydrofuran (4.90 ml, 4.90 mmol) in an ice bath and the mixture was stirred in an ice bath for 1 hour. After checking the completion of the reaction, the mixture was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate solution. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using ethyl acetate:methanol (10:1) as the eluant to afford 3-hydroxy-1-[4-(thiophene-2-carbonylamino)methyl-1,3-thiazol-2-yl]azetidine (571 mg, yield 47%) as a white solid.
Reaction SMILES: [ClH:1].Cl.[C:3]([C:6]1[CH:15]=[C:14]2[C:9]([CH:10]=[CH:11][C:12]([CH2:16][N:17]([C:21]3[CH:26]=[CH:25][C:24]([O:27][CH:28]4[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]4)=[CH:23][CH:22]=3)[C:18](=[O:20])[CH3:19])=[CH:13]2)=[CH:8][CH:7]=1)(=[NH:5])[NH2:4].Cl.[C:35](=[NH:40])(OCC)[CH3:36].C(N(CC)CC)C>C(O)C>[ClH:1].[ClH:1].[C:35]([N:31]1[CH2:30][CH2:29][CH:28]([O:27][C:24]2[CH:25]=[CH:26][C:21]([N:17]([CH2:16][C:12]3[CH:11]=[CH:10][C:9]4[C:14](=[CH:15][C:6]([C:3](=[NH:4])[NH2:5])=[CH:7][CH:8]=4)[CH:13]=3)[C:18](=[O:20])[CH3:19])=[CH:22][CH:23]=2)[CH2:33][CH2:32]1)(=[NH:40])[CH3:36]
Reactant: CC(=O)N(Cc1ccc2ccc(C(=N)N)cc2c1)c1ccc(OC2CCNCC2)cc1
Reactant: CCOC(C)=N
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC(=N)N1CCC(Oc2ccc(N(Cc3ccc4ccc(C(=N)N)cc4c3)C(C)=O)cc2)CC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 197.7 %

Procedure:
N-[(7-Amidino-2-naphthyl)methyl]-N-[4-[(4-piperidyl)oxy]phenyl]acetamide dihydrochloride (56 mg) was dissolved in 2 ml of ethanol, 28 mg of ethyl acetoimidate hydrochloride and 36 mg of triethylamine were added to the solution, and the mixture was stirred at room temperature for 2 days. The reaction solution was evaporated, and the resulting residue was purified by an ODS (YMC-GEL ODS-A 120-230/70) column chromatography using methanol:water (2:98) as the eluent, followed by addition of a small amount of 1N hydrochloric acid and freeze-drying to give 60 mg of N-[4-[(1-acetoimidoyl-4-piperidyl)oxy]phenyl]-N-[(7-amidino-2-naphthyl)methyl]acetamide dihydrochloride.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:18])=[N:4][CH:5]=[C:6]([CH2:16][OH:17])[C:7]=1[CH:8]1[NH:12][CH:11]([C:13]([OH:15])=[O:14])[CH2:10][S:9]1.[C:19](OC(=O)C)(=[O:21])[CH3:20]>O>[C:19]([N:12]1[CH:11]([C:13]([OH:15])=[O:14])[CH2:10][S:9][CH:8]1[C:7]1[C:6]([CH2:16][OH:17])=[CH:5][N:4]=[C:3]([CH3:18])[C:2]=1[OH:1])(=[O:21])[CH3:20]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1ncc(CO)c(C2NC(C(=O)O)CS2)c1O
Solvent: O
Product: CC(=O)N1C(C(=O)O)CSC1c1c(CO)cnc(C)c1O
Temperature: 80 °C
Yield: 110.8 %

Procedure:
To water (1.06 ml) were added 2-[3-hydroxy-5-(hydroxymethyl)-2-methylpyridin-4-yl]thiazolidine-4-carboxylic acid (500 mg, 1.85 mmol) and acetic anhydride (1.06 ml, 11.1 mmol), and the mixture was heated at 80° C. for 1 hour. The reaction mixture was concentrated under reduced pressure, to the residue was added toluene (5 ml×3), and the mixture was concentrated under reduced pressure to give N-acetyl-2-[3-hydroxy-5-(hydroxymethyl)-2-methylpyridin-4-yl]thiazolidine-4-carboxylic acid as an amorphous solid (0.64 g).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][CH:20]=1)[CH2:5][CH2:6][NH:7][C:8](=[O:17])/[CH:9]=[CH:10]/[C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1.[C:21](OC(=O)C)(=[O:23])[CH3:22].C(OCC)(=O)C>N1C=CC=CC=1>[C:21]([O:1][C:2]1[CH:20]=[CH:19][CH:18]=[C:4]([CH2:5][CH2:6][NH:7][C:8](=[O:17])/[CH:9]=[CH:10]/[C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)[CH:3]=1)(=[O:23])[CH3:22]
Reactant: CC(=O)OC(C)=O
Reactant: O=C(/C=C/c1cccnc1)NCCc1cccc(O)c1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CC(=O)Oc1cccc(CCNC(=O)/C=C/c2cccnc2)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 82.6 %

Procedure:
(E)-N-(3-hydroxyphenethyl)-3-(3-pyridyl)-2-propenoic acid amide (600 mg, 2.24 mmol) obtained in Example 81 was dissolved in pyridine (4.0 ml) and acetic anhydride (0.40 ml, 4.24 mmol) was added under ice-cooling and stirred at room temperature for 1.5 hours. Ethyl acetate was added to the reaction mixture and the mixture was washed with water and dried over magnesium sulfate. The solvent was distilled out under reduced pressure, and the residue was purified by silica gel column chromatography (methanol:dichloromethane=1:30) and recrystallized to yield the titled compound (574 mg, 82%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:28])=[CH:4][C:5]([F:27])=[C:6]([C:8]2[C:9](=[O:26])[N:10]([CH2:24][CH3:25])[C:11]3[C:16]([CH:17]=2)=[CH:15][N:14]=[C:13]([NH:18][C:19](=[O:23])[CH2:20][C:21]#[N:22])[CH:12]=3)[CH:7]=1.C([O-])([O-])=O.[K+].[K+].Cl[C:36]([O:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)=[O:37]>C1COCC1>[C:21]([CH2:20][C:19]([NH:18][C:13]1[CH:12]=[C:11]2[C:16]([CH:17]=[C:8]([C:6]3[C:5]([F:27])=[CH:4][C:3]([F:28])=[C:2]([NH:1][C:36](=[O:37])[O:38][C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)[CH:7]=3)[C:9](=[O:26])[N:10]2[CH2:24][CH3:25])=[CH:15][N:14]=1)=[O:23])#[N:22]
Reactant: CCn1c(=O)c(-c2cc(N)c(F)cc2F)cc2cnc(NC(=O)CC#N)cc21
Reactant: O=C(Cl)Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCn1c(=O)c(-c2cc(NC(=O)Oc3ccccc3)c(F)cc2F)cc2cnc(NC(=O)CC#N)cc21
Temperature: 60 °C
Yield: 61.1 %

Procedure:
A solution of N-(3-(5-amino-2,4-difluorophenyl)-1-ethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-7-yl)-2-cyanoacetamide (0.5 g, 1.3 mmol) and K2CO3 (448 mg, 3.25 mmol) in THF (4 mL) was treated drop-wise with phenyl chloroformate (408 mg, 2.6 mmol) and heated at 60° C. overnight. The mixture was cooled to RT, concentrated to dryness, treated with water and extracted with EtOAc (2×). The combined organics were washed with brine, dried over Na2SO4, concentrated and purified via silica gel chromatography to afford phenyl (5-(7-(2-cyanoacetamido)-1-ethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2,4-difluorophenyl)carbamate (400 mg, 61% yield).
Reaction SMILES: [CH3:1][N:2]([CH3:20])[C:3]([C:5]1[N:14]([CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)[C:8]2[N:9]=[C:10](Cl)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4].C([Si](C)(C)[O:26][C@H:27]1[CH2:31][CH2:30][N:29](/[CH:32]=[CH:33]/[NH:34][C:35](=[NH:38])[CH:36]=[CH2:37])[CH2:28]1)(C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>>[CH3:1][N:2]([CH3:20])[C:3]([C:5]1[N:14]([CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)[C:8]2[N:9]=[C:10]([NH:38][C:35]3[CH:36]=[CH:37][C:32]([N:29]4[CH2:30][CH2:31][C@H:27]([OH:26])[CH2:28]4)=[CH:33][N:34]=3)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4]
Reactant: CN(C)C(=O)c1cc2cnc(Cl)nc2n1C1CCCC1
Reactant: C=CC(=N)N/C=C/N1CC[C@H](O[Si](C)(C)C(C)(C)C)C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Product: CN(C)C(=O)c1cc2cnc(Nc3ccc(N4CC[C@H](O)C4)cn3)nc2n1C1CCCC1
Yield: 64.3 %

Procedure:
Following Buchwald Method B, 2-chloro-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (101 mg, 0.35 mmol) and N-{(E)-2-[(S)-3-(tert-butyl-dimethyl-silanyloxy)-pyrrolidin-1-yl]-vinyl}-acrylamidine (153 mg, 0.52 mmol), followed by deprotection with TBAF to give 7-cyclopentyl-2-[5-((S)-3-hydroxy-pyrrolidin-1-yl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (98 mg, 65%). MS (ESI) m/z 436.3 (M+H)+
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:5]=[C:4]([CH3:13])[CH:3]=1>COCCOC.C([O-])([O-])=O.[K+].[K+].C(OCC)C.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>[CH2:11]([O:10][C:8]([C:6]1[CH:5]=[C:4]([CH3:13])[CH:3]=[C:2]([CH:3]=[C:4]([CH3:13])[CH3:5])[N:7]=1)=[O:9])[CH3:12]
Reactant: CCOC(=O)c1cc(C)cc(Cl)n1
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: [K+]
Solvent: CCOCC
Solvent: COCCOC
Product: CCOC(=O)c1cc(C)cc(C=C(C)C)n1
Temperature: 80 °C
Reaction time: 6 h
Yield: 64 %

Procedure:
To a solution of ethyl 6-chloro-4-methyl-pyridine-2-carboxylate (500 mg, 2.51 mmol) and 2,4,6-tris-(2-methyl-propenyl)-cyclotriboroxane pyridine complex (814 mg, 2.51 mmol) in DME (32 mL), 2 M aq. K2CO3 (12 mL) solution is added. The mixture is degassed and put under argon before Pd(PPh3)4 (52 mg, 0.045 mmol) is added. The mixture is stirred at 80° C. for 6 h before it is cooled to rt, diluted with diethyl ether (50 mL) and washed with sat. aq. NaHCO3 (2×30 mL) solution. The org. extract is dried over MgSO4, filtered and concentrated. The crude product is purified by CC on silica gel eluting with heptane:EA 9:1 to give 4-methyl-6-(2-methyl-propenyl)-pyridine-2-carboxylic acid ethyl ester (176 mg) as a yellow oil; 1H NMR (CDCl3): δ 1.45 (t, J=7.0 Hz, 3H), 1.97 (s, 3H), 2.12 (s, 3H), 2.42 (s, 3H), 4.46 (q, J=7.0 Hz, 2H), 6.41 (s, 1H), 7.17 (s, 1H), 7.75 (s, 1H).
Reaction SMILES: [OH:1][CH2:2][C:3]1O[CH:5]=[C:6]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][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][CH3:28])[C:7](=[O:9])[CH:8]=1.[CH2:29]([NH2:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>O>[CH2:29]([N:36]1[CH:5]=[C:6]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][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][CH3:28])[C:7](=[O:9])[CH:8]=[C:3]1[CH2:2][OH:1])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: CCCCCCCCCCCCCCCCCCOc1coc(CO)cc1=O
Reactant: NCc1ccccc1
Solvent: O
Product: CCCCCCCCCCCCCCCCCCOc1cn(Cc2ccccc2)c(CO)cc1=O
Temperature: 50 °C
Reaction time: 2 h

Procedure:
A mixture of 50.0 g (0.127 mole) 2-hydroxymethyl-5-octadecyloxy-4 pyranone and 70 mL benzylamine is stirred for 2 hours at 100°-110° C. After cooling to about 50° C., the dark solution is mixed with 400 mL water and stirred. The precipitate thus formed is filtered off, washed, dried and recrystallized from propan-2-ol with the addition of active charcoal, colorless crystals thereby being obtained; m.p. 120°-121° C.
Reaction SMILES: [S:1]1[C:5]([C:6]([OH:8])=O)=[CH:4][C:3]2[CH:9]=[CH:10][CH:11]=[CH:12][C:2]1=2.[NH2:13][C:14]1[CH:15]=[CH:16][C:17]([N:22]2[CH2:27][CH2:26][CH:25]([CH2:28][CH2:29][OH:30])[CH2:24][CH2:23]2)=[C:18]([CH:21]=1)[C:19]#[N:20]>>[C:19]([C:18]1[CH:21]=[C:14]([NH:13][C:6]([C:5]2[S:1][C:2]3[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=3[CH:4]=2)=[O:8])[CH:15]=[CH:16][C:17]=1[N:22]1[CH2:27][CH2:26][CH:25]([CH2:28][CH2:29][OH:30])[CH2:24][CH2:23]1)#[N:20]
Reactant: O=C(O)c1cc2ccccc2s1
Reactant: N#Cc1cc(N)ccc1N1CCC(CCO)CC1
Product: N#Cc1cc(NC(=O)c2cc3ccccc3s2)ccc1N1CCC(CCO)CC1
Yield: 34.6 %

Procedure:
By the reaction and treatment in the same manner as in Example 6 using benzo[b]thiophene-2-carboxylic acid (1.5 g) and 5-amino-2-[4-(2-hydroxyethyl)piperidin-1-yl]benzonitrile (1.4 g), the title compound (0.8 g) was obtained. melting point: 218° C.
Reaction SMILES: [O:1]=[C:2]([C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1)[CH2:3][CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].C=O.N1CCCC[CH2:19]1>C(OCC)(=O)C>[N:12]1[CH:13]=[CH:14][CH:15]=[C:10]([C:2]([C:3](=[CH2:19])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])=[O:1])[CH:11]=1
Reactant: CCOC(=O)CCC(=O)c1cccnc1
Reactant: C1CCNCC1
Agent: C=O
Solvent: CCOC(C)=O
Product: C=C(CC(=O)OCC)C(=O)c1cccnc1
Yield: 53.9 %

Procedure:
A solution of ethyl 4-oxo-4-(3-pyridyl)butanoate (4 g), 37% aqueous formaldehyde (2.46 g) and piperidine (2.46 g) was stirred at room temperature for 18 h. The reaction mixture was diluted with 200 mL of ethyl acetate and washed with water (2×100 mL). The reaction mixture was concentrated and dissolved in ethanol (10 mL) and treated with 4N HCl/dioxane (4 mL) at 80° C. for 12 h. The reaction mixture was diluted with ethyl acetate (200 mL), washed with water (2×100 mL), saturated sodium bicarbonate solution (2×100 mL), concentrated and purified on flash chromatography (20% Ethyl acetate to 80% ethyl acetate in hexane) to give 2.28 g of the title compound, ESMS (M+1)+220.
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[NH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1.C(N(CC)CC)C>C(Cl)(Cl)Cl>[N:8]1([CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: C1CCNCC1
Reactant: CCOC(=O)CBr
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCOC(=O)CN1CCCCC1
Reaction time: 2 h
Yield: 63.6 %

Procedure:
Ethyl bromoacetate (8.5 g, 50.9 mmol) was added dropwise to a stirred solution of piperidine (4.3 g, 50.5 mmol) and triethylamine (5.5 g, 54.4 mmol) in chloroform (20 ml) at such a rate as to maintain a gentle reflux. After the addition was complete stirring was continued for 2 hours and the reaction mixture washed with water (20 ml×3). The chloroform layer was dried (MgSO4) filtered and the solvent evaporated to leave a yellow oil. This oil was passed through a short column of silica eluting with a CH2Cl2/Pet Ether 40:60 mixture (1:1). Removal of the solvent from the resulting solution gave the required product as a pale yellow oil (Yield 5.5 g, 64%).
Reaction SMILES: [H-].[Na+].[C:3]([CH2:5][C:6]([NH2:8])=[O:7])#[N:4].F[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[N+:16]([O-:18])=[O:17].Cl>CN(C=O)C>[C:3]([CH:5]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[N+:16]([O-:18])=[O:17])[C:6]([NH2:8])=[O:7])#[N:4]
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: N#CCC(N)=O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#CC(C(N)=O)c1ccccc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
7.1 448 g of NaH are introduced into 9 l of DMF, then 967 g of cyanoacetamide are added in portions over the course of 1 hour at 2-8° with strong ice cooling and under a nitrogen atmosphere. The mixture is stirred for a further 30 minutes, 600 ml of 1-fluoro-2-nitrobenzene are added, and the mixture is stirred for a further 2 hours. The mixture is poured into 50 l of ice-water, acidified using 3 l of conc. HCl and subjected to further conventional work-up, giving 956 g of 2-cyano-2-(2-nitrophenyl)acetamide (“GA”), m.p. 172-174°.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:24](O)=[O:25])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.C(Cl)(=O)OCC.[NH2:40][C:41]1[CH:46]=[CH:45][N:44]=[CH:43][N:42]=1>O1CCCC1>[N:44]1[CH:45]=[CH:46][C:41]([NH:40][C:24](=[O:25])[CH:9]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:12]=2)[NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])=[N:42][CH:43]=1
Reactant: Nc1ccncn1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1cccc(Oc2ccccc2)c1)C(=O)O
Agent: CCOC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NC(Cc1cccc(Oc2ccccc2)c1)C(=O)Nc1ccncn1
Reaction time: 0.5 h
Yield: 136.8 %

Procedure:
N-(t-butoxycarbonyl)-3-phenoxyphenylalanine (1 g) was dissolved in dry tetrahydrofuran (30 ml) and triethylamine (2 ml) was added thereto. Thereafter, ethyl chlorocarbonate (0.3 g) was added under ice-cooling, followed by stirring for 30 minutes. To this solution, 4-aminopyrimidine (0.24 g) was added, followed by stirring at room temperature for 10 hours. After distilling off the solvent, the residue was extracted with ethyl acetate, followed by washing with water. After drying, the solvent was distilled off to obtain N-(t-butoxycarbonyl)-3-phenoxy-DL-phenylalanine 4-pyrimidylamide (I) (1.5 g), which was confirmed as a substantially pure product by an NMR analysis, in the form of a white powder.
Reaction SMILES: OO.[Br:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([C:13]1([C:18]#[N:19])[CH2:17][CH2:16][CH2:15][CH2:14]1)(=[O:12])=[O:11].C([O-])([O-])=[O:21].[K+].[K+].CS(C)=O>O>[Br:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([C:13]1([C:18]([NH2:19])=[O:21])[CH2:17][CH2:16][CH2:15][CH2:14]1)(=[O:12])=[O:11]
Reactant: O=C([O-])[O-]
Reactant: N#CC1(S(=O)(=O)c2ccccc2Br)CCCC1
Agent: OO
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: NC(=O)C1(S(=O)(=O)c2ccccc2Br)CCCC1
Reaction time: 0.5 h
Yield: 88.5 %

Procedure:
A 30% H2O2 solution (1.6 mL) was added drop-wise at rt to a mixture of 1-(2-bromophenylsulfonyl)cyclopentanecarbonitrile (1.6 g, 5.1 mmol), K2CO3 (2.1 g, 15 mmol), and DMSO (5 mL). The mixture was stirred for 30 min before diluting with water (40 mL) and isolating the precipitate via vacuum filtration. The precipitate was washed with water and air-dried to give the title compound (1.5 g, 89%). MS (ESI): mass calcd. for C12H19NO3S, 330.99; m/z found, 331.9 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 7.99-7.95 (m, 1H), 7.89-7.84 (m, 1H), 7.64-7.51 (m, 4H), 2.41-2.25 (m, 4H), 1.78-1.66 (m, 2H), 1.58-1.45 (m, 2H).
Reaction SMILES: C[O:2][C:3](=[O:30])[C:4]1[CH:9]=[C:8]([CH3:10])[CH:7]=[C:6]([CH3:11])[C:5]=1[N:12]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[S:13]([C:16]1[CH:21]=[CH:20][C:19](F)=[CH:18][CH:17]=1)(=[O:15])=[O:14].[CH2:31]([OH:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.[H-].[Na+]>CN(C=O)C>[CH2:23]([N:12]([S:13]([C:16]1[CH:21]=[CH:20][C:19]([O:38][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[CH:18][CH:17]=1)(=[O:15])=[O:14])[C:5]1[C:6]([CH3:11])=[CH:7][C:8]([CH3:10])=[CH:9][C:4]=1[C:3]([OH:2])=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: OCc1ccccc1
Reactant: COC(=O)c1cc(C)cc(C)c1N(Cc1ccccc1)S(=O)(=O)c1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(C)c(N(Cc2ccccc2)S(=O)(=O)c2ccc(OCc3ccccc3)cc2)c(C(=O)O)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 73.5 %

Procedure:
To a solution of 0.50 g (1.171 mmol) of the product of Example 65 in 10 mL of DMF was added 0.485 mL (4.684 mmol) of benzyl alcohol and 0.187 g (4.684 mmol) of 60% sodium hydride. The eaction mixture was stirred for 18 h at room temperature and the quenched with 5% HCl solution. The resulting mixture was extracted with ether and the combined organics were washed with water, dried over MgSO4, filtered and concentrated in vacuo. The residue was dissolved 10 mL of MeOH-THF (1:1) and 4.7 mL of 1N sodium hydroxide solution was added. The resulting mixture was heated to reflux for 18 h and then cooled to room temperature, acidified with 5% HCl and extracted with EtOAc. The combined organics were washed with water and brine, dried over MgSO4, filtered and concentrated in vacuo. Triturion of the residue with edter provided 0.432 g (74%) of the desired product as a white solid. Electrospray Mass Spec: 502.3 (M+H)+.
Reaction SMILES: [C:1]([N:4]1[CH2:13][CH2:12][C:11]2[C:6](=[CH:7][C:8]([Cl:14])=[CH:9][CH:10]=2)[CH2:5]1)(=[O:3])[CH3:2].S(=O)(=O)(O)O.[N+:20]([O-])([O-:22])=[O:21].[K+]>>[C:1]([N:4]1[CH2:13][CH2:12][C:11]2[C:6](=[CH:7][C:8]([Cl:14])=[C:9]([N+:20]([O-:22])=[O:21])[CH:10]=2)[CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCc2ccc(Cl)cc2C1
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: CC(=O)N1CCc2cc([N+](=O)[O-])c(Cl)cc2C1
Reaction time: 1 h

Procedure:
A solution of 20.9 g. (0.1 mole) of 2-acetyl-7-chloro-1,2,3,4-tetrahydroisoquinoline in 100 ml. of concentrated sulfuric acid is treated with 10 g. (0.1 mole) of potassium nitrate dissolved in 150 ml. of concentrated sulfuric acid. The mixture is stirred for one hour, quenched on ice, made alkaline with ammonium hydroxide and filtered to yield 2-acetyl-7-chloro-6-nitro-1,2,3,4-tetrahydroisoquinoline.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]#[C:8][CH2:9][CH2:10][CH2:11][CH2:12][OH:13])[CH:2]=1.C(OCC)(=O)C>[Pd].C(O)C>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3](/[CH:7]=[CH:8]\[CH2:9][CH2:10][CH2:11][CH2:12][OH:13])[CH:2]=1
Reactant: OCCCCC#Cc1cccnc1
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: OCCCC/C=C\c1cccnc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 45.9 %

Procedure:
6-(3-Pyridyl)-1-hex-5-ynol (0.15 g, 0.86 mmol) was added to a stirred suspension of 10% palladium on charcoal (20 mg) in ethanol. The reaction was stirred at room temperature under hydrogen for 24 h. The mixture was filtered through celite and evaporated to give a clear oil. Column chromatography (flash silica gel; ethyl acetate) gave Z-6-(3-pyridyl)-1-hex-5-enol (70 mg, 46%).
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[C:11]([C:13]2[CH:18]=[CH:17][N:16]=[C:15]([C:19]3[CH:25]=[C:24]([N:26]4[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]4)[CH:23]=[CH:22][C:20]=3[NH2:21])[CH:14]=2)[N:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:32][N:33]([CH2:45][CH2:46][N:47]1[CH2:52][CH2:51][O:50][CH2:49][CH2:48]1)[C:34]([C:36]1[CH:37]=[C:38]([CH:42]=[CH:43][CH:44]=1)[C:39](O)=[O:40])=[O:35].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>CN(C=O)C>[CH2:1]([N:8]1[CH:12]=[C:11]([C:13]2[CH:18]=[CH:17][N:16]=[C:15]([C:19]3[CH:25]=[C:24]([N:26]4[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]4)[CH:23]=[CH:22][C:20]=3[NH:21][C:39](=[O:40])[C:38]3[CH:42]=[CH:43][CH:44]=[C:36]([C:34]([N:33]([CH3:32])[CH2:45][CH2:46][N:47]4[CH2:48][CH2:49][O:50][CH2:51][CH2:52]4)=[O:35])[CH:37]=3)[CH:14]=2)[N:10]=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ccc(N2CCCCC2)cc1-c1cc(-c2cn(Cc3ccccc3)nn2)ccn1
Reactant: CN(CCN1CCOCC1)C(=O)c1cccc(C(=O)O)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(CCN1CCOCC1)C(=O)c1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2-c2cc(-c3cn(Cc4ccccc4)nn3)ccn2)c1
Yield: 37.6 %

Procedure:
A solution of 22 mg of 2-(4-(1-benzyl-1H-1,2,3-triazol-4-yl)pyridin-2-yl)-4-(piperidin-1-yl)aniline 24d, 15.2 mg of 3-(methyl(2-morpholinoethyl)carbamoyl)benzoic acid, 22.6 mg of HATU, and 27.9 mg of diisopropylethylamine in 0.3 mL of DMF was stirred for 1 h. The solution was filtered and the product was isolated from the filtrate by reverse phase chromatography eluting with 0.05% TFA in a water/acetonitrile gradient. This procedure gave 13.4 mg of product. 1H NMR (400 MHz, DMSO-d6, ppm): δ 8.97 (s, 1H), 8.78 (d, J=5.0 Hz, 1H), 8.35 (s, 1H), 8.32-8.26 (m, 1H), 8.03-7.94 (m, 2H), 7.91 (d, J=5.2 Hz, 1H), 7.70-7.50 (m, 3H), 7.35 (mj, 4H), 7.28-7.19 (m, 1H), 5.69 (s, 2H), 4.09-3.90 (m, 3H), 3.85-3.76 (m, 2H), 3.71-3.53 (m, 4H), 2.91 (s, 3H), 1.69 (s, 4H), 1.55 (s, 2H). MS (ESI, m/z) 685.3 [M+H]+.