Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][C:3]=1N.F[B-](F)(F)F.N(OC(C)(C)C)=O.[C:22]([Cu])#[N:23].[C-]#N.[Na+]>CCOCC.O>[Br:1][C:2]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][C:3]=1[C:22]#[N:23]
Reactant: N#C[Cu]
Reactant: Cc1ccc(N)c(Br)c1
Agent: CC(C)(C)ON=O
Agent: F[B-](F)(F)F
Agent: [C-]#N
Solvent: O
Solvent: CCOCC
Product: Cc1ccc(C#N)c(Br)c1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 54.3 %

Procedure:
To a solution of 2-bromo-4-methylaniline (558 mg, 3.0 mmol) in 30 mL of acetbnitrile was added tetrafluoroborate (600 μL of a 54% solution in Et2O, 4.35 mmol). The solution was cooled to about 0° C. and t-butyl nitrite (55 uL, 4.62 mmol) was added. After stirring for about 45 minutes, the solution was transferred to a solution of CuCN (800 mg, 8.93 mmol) and NaCN (1.47 g, 30 mmol) in 30 mL, of water cooled to 0° C. via cannula. The cold bath was removed. After stirring overnight, the aqueous solution was extracted with Et2O (2×). The combined organic solutions were washed with 1 M HCl, saturated sodium bicarbonate, water and brine, and then dried (Na2SO4), filtered and concentrated. The material was adsorbed onto 3 g of silica gel and purified by silica gel flash chromatography (4×15 cm column, 5-20 Et2O/pentane, over 48 min at 35 mL/min) to afford about 320 mg (1.63 mmol, 54%) of 2-bromo-4-methyl-benzonitrile as a colorless oil. GC/MS (EI): 195.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]2=[N+:6]([O-])[O:7][N:8]=[C:4]2[CH:3]=1.P(OCC)(OCC)OCC>C(O)C.CCCCCC>[Br:1][C:2]1[CH:11]=[CH:10][C:5]2=[N:6][O:7][N:8]=[C:4]2[CH:3]=1
Reactant: [O-][n+]1onc2cc(Br)ccc21
Agent: CCOP(OCC)OCC
Solvent: CCCCCC
Solvent: CCO
Product: Brc1ccc2nonc2c1
Temperature: 60 °C
Reaction time: 0.17 h
Yield: 70.7 %

Procedure:
To a stirred solution of 5-bromobenzo[c][1,2,5]oxadiazole 1-oxide (6.0 g, 28.436 mmol) in ethanol (60 mL) was added triethyl phosphite (6.2 mL, 34.123 mmol) at RT under an inert atmosphere. The reaction mixture was then heated at 60° C. for 1 h., cooled to RT, diluted with hexane (100 mL) and stirred for 10 min. The precipitated solid was filtered off and the filtrate was concentrated in vacuo to obtain the crude product. The crude material was purified via silica gel column chromatography to afford 5-bromobenzo[c][1,2,5]oxadiazole (4.0 g, 71%) as a light yellow solid.
Reaction SMILES: [C:1]([NH:11][C@@H:12]([C:16]([OH:18])=O)[CH:13]([CH3:15])[CH3:14])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].CN1CCOCC1.[NH2:26][CH2:27][CH:28]([O:31][CH3:32])[O:29][CH3:30]>C1COCC1>[CH3:30][O:29][CH:28]([O:31][CH3:32])[CH2:27][NH:26][C:16](=[O:18])[C@H:12]([NH:11][C:1](=[O:2])[O:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)[CH:13]([CH3:14])[CH3:15]
Reactant: CC(C)[C@@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: COC(CN)OC
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: COC(CNC(=O)[C@H](NC(=O)OCc1ccccc1)C(C)C)OC
Temperature: -15 °C
Reaction time: 0.5 h
Yield: 99.5 %

Procedure:
A solution of Cbz-D-Valine (500 g, 1.99 mol) and N-methylmorpholine (201.8 g, 1.99 mol) in anhydrous THF (8 L) was cooled to −15° C. and i-butyl chlorofomate (299 g, 2.19 mol) was added dropwise under stirring. After 30 min, a solution of 1-amino-2,2-dimethyoxyethane (209.5 g, 1.99 mol) in THF (1 L) was added slowly and the temperature was maintained at −15° C. for 2 h. The reaction mixture was washed with brine (2 L) and the organic phase was concentrated to remove the THF. The residue was diluted with EtOAc (4 L), washed with 1N aq HCl (2×2 L), sat. aq. NaHCO3 (2 L) and sat. aq. Na2CO3 (2 L) and brine (1.5 L). After drying over Na2SO4, the organic solvent was removed under reduce pressure to afford (R)-benzyl (1-((2,2-dimethoxyethyl)amino)-3-methyl-1-oxobutan-2-yl)carbamate as a white solid (670 g, yield 99.5%), which was used for next step without further purification. LC-MS m/z 360.9 [M+Na]+.
Reaction SMILES: [OH:1][NH:2][C:3]([CH3:10])([C:5]([CH3:9])([NH:7][OH:8])[CH3:6])[CH3:4].I([O-])(=O)(=O)=O.[Na+].C(Cl)(Cl)Cl.CO>O>[CH3:4][C:3]1([CH3:10])[C:5]([CH3:9])([CH3:6])[N+:7]([O-:8])=[N+:2]1[O-:1]
Reactant: CC(C)(NO)C(C)(C)NO
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: CO
Solvent: ClC(Cl)Cl
Solvent: O
Product: CC1(C)[N+]([O-])=[N+]([O-])C1(C)C

Procedure:
The product could also be obtained by oxidation of the dihydroxylamino precursor with sodium periodate. Thus, N,N'-dihydroxy 2,3-dimethyl-2,3-diaminobutane (1.5 g.) in water (50 ml.) was stirred for 30 min. with aqueous sodium periodate (4.5 g. in ca. 100 ml. water). The product precipitated out and was extracted with chloroform. The chloroform extract was washed with water, dried (MgSO4), and evaporated to give the product (800 mg., 65°) T.L.C. (silica, CHCl3 /MeOH:4/1) one spot, Rf 0.8).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9](OC)=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].NC1C=CC([F:24])=CC=1C(O)=O>>[NH2:1][C:2]1[CH:11]=[CH:10][C:9]([F:24])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1cc(OC)ccc1N
Reactant: Nc1ccc(F)cc1C(=O)O
Product: COC(=O)c1cc(F)ccc1N

Procedure:
In a manner similar to that described above for methyl 2-amino-5-methoxybenzoate, 7.82 g of 2-amino-5-fluorobenzoic acid was converted to i-f (40%): MS m/z═170 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:16]=[CH:15][C:6]([C:7]([N:9]2[CH2:13][CH2:12][S:11][C:10]2=S)=[O:8])=[C:5]([O:17][CH2:18][O:19][CH3:20])[CH:4]=1.[NH2:21]C1SCCN=1.[OH-].[Na+]>O1CCCC1>[CH3:1][O:2][C:3]1[CH:16]=[CH:15][C:6]([C:7]([NH:9][C:10]2[S:11][CH2:12][CH2:13][N:21]=2)=[O:8])=[C:5]([O:17][CH2:18][O:19][CH3:20])[CH:4]=1
Reactant: NC1=NCCS1
Reactant: COCOc1cc(OC)ccc1C(=O)N1CCSC1=S
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COCOc1cc(OC)ccc1C(=O)NC1=NCCS1
Reaction time: 20 h

Procedure:
12.36 g of the thus produced N-(4-methoxy-2-methoxymethoxybenzoyl)thiazolidine-2-thion and 8.36 g of 2-aminothiazoline was dissolved in 150 ml of tetrahydrofuran, and the solution was agitated for 20 hours. To the solution was added 2N aqueous solution of sodium hydroxide. The mixture was extracted with methylene chloride and the extract was dried over anhydrous sodium sulfate. The solvent was distilled off in evacuated atomosphere, and the residue was subjected to column chromatography using silica gel. There was obtained 10.15 g of 2-(4-methoxy-2-methoxymethoxybenzoylamino)thiazoline from fractions eluted with methylene chloride.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5]2[NH:8][C:9]3[C:14]([C:4]=2[CH2:3]1)=[CH:13][CH:12]=[CH:11][N:10]=3.[H-].[Na+].CC1C=CC(S(O[CH2:28][CH2:29][C:30]2[CH:31]=[N:32][C:33]([CH3:36])=[CH:34][CH:35]=2)(=O)=O)=CC=1>CN(C=O)C.O>[CH3:1][N:2]1[CH2:7][CH2:6][C:5]2[N:8]([CH2:28][CH2:29][C:30]3[CH:31]=[N:32][C:33]([CH3:36])=[CH:34][CH:35]=3)[C:9]3[C:14]([C:4]=2[CH2:3]1)=[CH:13][CH:12]=[CH:11][N:10]=3
Reactant: Cc1ccc(S(=O)(=O)OCCc2ccc(C)nc2)cc1
Reactant: CN1CCc2[nH]c3ncccc3c2C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(CCn2c3c(c4cccnc42)CN(C)CC3)cn1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 27.5 %

Procedure:
To a solution of 6-methyl-6,7,8,9-tetrahydro-5H-pyrrolo[2,3-b:4,5-c′]dipyridine (200 mg, 1.068 mmol) in DMF (1 mL) was added a suspension of NaH (128.0 mg, 3.24 mmol) in DMF (1 mL). After stirring for 5 min. at RT, a solution of 2-(6-methylpyridin-3-yl)ethyl 4-methylbenzenesulfonate (932 mg, 3.204 mmol) in DMF (1 mL) was added dropwise into the reaction mixture and stirring continued for another 3 h. The progress of reaction was monitored by TLC and NMR. The reaction mixture was diluted with water (20 mL) and extracted with EtOAc (3×25 mL). The organic layer was washed with water (3×20 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford crude material, which was purified by silica gel flash chromatography eluting with 10% MeOH-DCM to yield 6-methyl-9-(2-(6-methylpyridin-3-yl)ethyl)-6,7,8,9-tetrahydro-5H-pyrrolo[2,3-b:4,5-c′]dipyridine (90 mg) as a free base. The free base was converted into tri-HCl salt by treatment with ethanolic HCl. 1H NMR (CD3OD, Tri-HCl salt) δ (ppm): 8.76 (s, 1H), 8.40 (m, 3H), 7.80 (d, 1H), 7.50 (t, 1H), 4.90-4.70 (m, 3H), 4.42 (m, 1H), 3.95 (m, 1H), 3.66 (m, 1H), 3.42-3.30 (m, 4H), 3.15 (s, 3H), 2.76 (s, 3H).
Reaction SMILES: [CH3:1][NH:2][C:3]1[N:11]=[CH:10][N:9]=[C:8]2[C:4]=1[N:5]=[CH:6][N:7]2[CH:12]=[CH2:13].I[C:15]1[CH:16]=[C:17]([NH:22][C:23](=[O:34])[C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=2)[CH:18]=[CH:19][C:20]=1[CH3:21].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)C(C)C)(C)C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O.CN(C=O)C>[CH3:21][C:20]1[CH:15]=[CH:16][C:17]([NH:22][C:23](=[O:34])[C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:31])([F:32])[F:33])[CH:25]=2)=[CH:18][C:19]=1/[CH:13]=[CH:12]/[N:7]1[CH:6]=[N:5][C:4]2[C:8]1=[N:9][CH:10]=[N:11][C:3]=2[NH:2][CH3:1]
Reactant: Cc1ccc(NC(=O)c2cccc(C(F)(F)F)c2)cc1I
Reactant: C=Cn1cnc2c(NC)ncnc21
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CNc1ncnc2c1ncn2/C=C/c1cc(NC(=O)c2cccc(C(F)(F)F)c2)ccc1C
Temperature: 110 °C
Reaction time: 15 h

Procedure:
A pressure tube was charged with N-methyl-9-vinyl-9H-purin-6-amine (0.088 g, 0.5 mmol), N-(3-iodo-4-methylphenyl)-3-(trifluoromethyl)benzamide (0.20 g, 0.5 mmol), palladium acetate (0.05 eq), tri-(o-tolyl)phosphine (0.1 eq), and DMF (2 ml). The resulting solution was degassed by bubbling N2 for 10 minutes. N,N-Diisopropylethylamine (0.19 g, 1.5 mmol) was added and this solution was stirred at 110° C. for 15 h. Water was added and the aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate, concentrated on a rotavap, and then subjected to silica gel column chromatography (5% methanol/methylene chloride) yielding the desired product: MS [M+H]+ 453; m.p. 201° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([O:12][C:13]2[C:25]([F:26])=[CH:24][C:16]([C:17]([O:19]C(C)(C)C)=[O:18])=[CH:15][C:14]=2[F:27])[CH:5]=[N:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].[Li+].[OH-]>C1COCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]([O:12][C:13]2[C:14]([F:27])=[CH:15][C:16]([C:17]([OH:19])=[O:18])=[CH:24][C:25]=2[F:26])[CH:5]=[N:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10]
Reactant: CC(C)Oc1ncc(Oc2c(F)cc(C(=O)OC(C)(C)C)cc2F)cc1Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)Oc1ncc(Oc2c(F)cc(C(=O)O)cc2F)cc1Cl
Temperature: 50 °C
Yield: 93.9 %

Procedure:
tert-Butyl 4-[(5-chloro-6-isopropoxypyridin-3-yl)oxy]-3,5-difluorobenzoate (Preparation 145, 426 mg, 1.06 mmol) and LiOH (100 mg) were added to a solution of THF:water (1:1) and heated at 50° C. for 3 hours. The reaction was then quenched with aqueous 1M HCl and extracted with EtOAc. The combined organics were dried and concentrated in vacuo to afford the title compound as a white solid (342 mg, 94% yield):
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][CH:7]=1)[CH3:2].CC(C)([O-])C.[K+].[C:20]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])(=[O:23])[CH:21]=[CH2:22]>C1COCC1>[CH2:1]([O:3][C:4](=[O:13])[CH:5]([C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][CH:7]=1)[CH2:22][CH2:21][C:20]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH3:2]
Reactant: C=CC(=O)OC(C)(C)C
Reactant: CCOC(=O)Cc1ccc(Cl)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)C(CCC(=O)OC(C)(C)C)c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
The (4-chlorophenyl)-acetic acid ethyl ester (9.52 g, 47.9 mmol) was dissolved in 80 mL of THF, cooled to 0° C., and treated with potassium tert-butoxide (538 mg, 4.79 mmol). The resulting orange solution was allowed to stir for 15 minutes at 0° C., then cooled to −78° C. The tert-butyl acrylate (7.72 mL, 52.7 mmol) was added in three equal portions over ten minutes. The solution was allowed to stir overnight warming slowly to room temperature. The reaction solution was concentrated in vacuo, and the residue was partitioned between ethyl acetate and saturated NH4Cl solution. The aqueous was extracted with ethyl acetate, and the organics were combined. The organic was washed with brine, separated, dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by chromatography (silica gel eluted with 9:1 hexanes:EtOAc) to afford the 2-(4-chlorophenyl)-pentanedioic acid 5-tert-butyl ester 1-ethyl ester in greater than 80% purity (9.00 g, 57%). 1H NMR (CDCl3, 400 MHz) δ 7.31-7.21 (m, 4H), 4.13 (q, J=7.6 Hz, 2H), 3.58 (t, J=8.0 Hz, 1H), 2.27 (m, 1H), 2.16 (t, J=7.2 Hz, 2H), 2.04 (m, 1H), 1.43 (s, 9H), 1.21 (t, J=7.6 Hz, 3H).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([C:28]([F:31])([F:30])[F:29])=[N:8][N:9]([CH2:11][C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[CH2:17][C@@H:16]([NH:21][S:22]([CH:25]([CH3:27])[CH3:26])(=[O:24])=[O:23])[CH2:15]3)[CH:10]=1)=O)C.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[OH:3][CH2:4][C:6]1[C:7]([C:28]([F:29])([F:31])[F:30])=[N:8][N:9]([CH2:11][C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[CH2:17][C@@H:16]([NH:21][S:22]([CH:25]([CH3:27])[CH3:26])(=[O:24])=[O:23])[CH2:15]3)[CH:10]=1
Reactant: CCOC(=O)c1cn(Cc2ccc3c(c2)C[C@H](NS(=O)(=O)C(C)C)C3)nc1C(F)(F)F
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)S(=O)(=O)N[C@@H]1Cc2ccc(Cn3cc(CO)c(C(F)(F)F)n3)cc2C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 68.4 %

Procedure:
(R)-ethyl-1-((2-(1-methylethylsulfonamido)-2,3-dihydro-1H-inden-5-yl)methyl)-3-(trifluoromethyl)-1H-pyrazole-4-carboxylate (2.416 mmol, 1.11 g) was dissolved in THF (20 mL) and the vessel purged with nitrogen. Lithium aluminium hydride (1M, 4.83 mmol, 4.83 mL) was added dropwise and the mixture stirred at room temperature for 1 h. The reaction was quenched by addition of MeOH followed by water before concentration. The residue was partitioned between 1N HCl and EtOAc and the organic phase collected. The aqueous phase was further extracted with EtOAc (×2). Combined organics were dried and concentrated before purification on silica eluting with 30% EtOAc/iso-hexane followed by 50% EtOAc/iso-hexane. Desired fractions were collected and concentrated to give (R)—N-(5-((4-(hydroxymethyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)-2,3-dihydro-1 H-inden-2-yl)propane-2-sulfonamide as a colourless glass (0.690 g, 68.5%). MS (ESI): m/z [M+Na]+ 440.5
Reaction SMILES: [CH3:1][CH:2]([CH3:6])[C:3](Cl)=[O:4].[I:7][C:8]1[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=1[NH2:10]>>[I:7][C:8]1[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=1[NH:10][C:3](=[O:4])[CH:2]([CH3:6])[CH3:1]
Reactant: CC(C)C(=O)Cl
Reactant: Nc1ccccc1I
Product: CC(C)C(=O)Nc1ccccc1I

Procedure:
Prepared by Procedure Q1 using 2-methylpropanoyl chloride and 2-iodoaniline: ESMS m/e: 289.9 (M+H)+.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:10]1[CH2:15][CH2:14][CH:13]([CH2:16][CH2:17][CH2:18][CH2:19][NH:20][C:21](=[O:30])[CH:22]=[CH:23][C:24]2[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=2)[CH2:12][CH2:11]1.[OH-].[Na+]>ClCCl>[C:1]([N:10]1[CH2:15][CH2:14][CH:13]([CH2:16][CH2:17][CH2:18][CH2:19][NH:20][C:21](=[O:30])[CH:22]=[CH:23][C:24]2[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=2)[CH2:12][CH2:11]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(C=Cc1cccnc1)NCCCCC1CCNCC1
Reactant: O=C(Cl)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: O=C(C=Cc1cccnc1)NCCCCC1CCN(C(=O)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5.1 g (36.2 mMol) benzoyl chloride are dissolved in 150 ml abs. dichlormethane and cooled to ca 0° C. under moisture exclusion. 10.4 g (36.2 mmol) N-[4-(piperidin-4-yl)-butyl]-3-(pyridin-3-yl)-acrylamide (substance 14) are dissolved in 50 ml abs. dichlormethane and added dropwise under ice cooling. The mixture is stirred overnight at RT without further cooling. Subsequently, the suspension is added to 60 ml 2 M sodium hydroxide and extracted twice, each with 80 ml dichlormethane. The combined organic phases are washed twice, each with 60 ml water, dried over sodium sulfate and the solvent is removed under vacuum. The residue is chromatographically purified over silica gel with CHCl3/CH3OH (97/3 to 95/5) and recrystalized from 75 ml acetonitrile. Colorless crystals with a MP of 100–102° C. are recovered; yield: 9.8 g (69%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[CH:9])=[CH:4][CH:3]=1.[Cl:10][C:11]1[C:16](I)=[CH:15][N:14]=[CH:13][N:12]=1.C(N(CC)CC)C>ClCCl.[Cu](I)I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:10][C:11]1[C:16]([C:9]#[C:8][C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)=[CH:15][N:14]=[CH:13][N:12]=1
Reactant: C#Cc1ccc(Cl)cc1
Reactant: Clc1ncncc1I
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Clc1ccc(C#Cc2cncnc2Cl)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 11 %

Procedure:
A mixture of 0.6 g of 1-chloro-4-ethynylbenzene, 1.44 g of 4-chloro-5-iodopyrimidine (J. Chem. Soc. Perkins Trans. I, 1977,621, Allen et al), 7.0 cc of triethylamine, 58 mg of copper iodide and 108 mg of dichlorobis(triphenylphosphine)palladium II was stirred at room temperature under nitrogen for 18 hours. The reaction mixture was evaporated in vacuo. The resulting tan solid was partitioned between water and dichloromethane and the organic extracts washed twice with water, dried over sodium sulfate and evaporated to give a dark brown solid, 1.57 g. The solid was redissolved in dichloromethane and hexanes added to give 120 mg of a beige powder after filtration. The filtrate was purified by column chromatography on silica gel using 1:1 ethyl acetate/dichloromethane as the eluant. The middle rf spot fractions (silica gel TLC in 1:1) were pooled and evaporated to give 0.8 g of a yellow solid, 4-chloro-5-(4-chlorophenylethynyl)-pyrimidine
Reaction SMILES: C(O[C:5]1([C:11]#[CH:12])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1)(=O)C.[NH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.C(OCC)C.CCCCCC>O1CCCC1.[Cu](Cl)Cl>[C:11]([C:5]1([N:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]1)#[CH:12]
Reactant: C#CC1(OC(C)=O)CCCCC1
Reactant: C1CCNCC1
Agent: Cl[Cu]Cl
Solvent: CCCCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: C#CC1(N2CCCCC2)CCCCC1
Temperature: 95 °C
Reaction time: 2 h

Procedure:
7.0 g of 1-acetoxy-1-ethynylcyclohexane (Production Example 17) was dissolved in 140 ml of tetrahydrofuran, and after 20.8 ml of piperidine was added dropwise thereto at room temperature, 208 mg of copper chloride (I) was added to the resulting yellow transparent solution. The resulting mixture was stirred in an oil bath at 95° C. for 2 hours. The reaction mixture was left to stand to cool to room temperature, 200 ml of diethyl ether was added thereto and extracted with 100 ml of an aqueous 2 N hydrochloric solution twice. After addition of about 200 ml of ice to the resultant acidic solution, sodium hydroxide was added to the solution until the solution became basic (pH=10). The solution was extracted with 100 ml of dichloromethane twice. The organic layer was dried over anhydrous magnesium sulfate. The solvent was removed, to give a brown solid. To the solid was added hexane and washed, and the solid was collected by filtration, to give 700 mg of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:10]([F:22])=[C:11]3[N:20]=[CH:19][N:18]([CH3:21])[C:12]3=[N:13][C:14]=2[C:15](O)=[O:16])=[C:4]([F:23])[CH:3]=1.C1C=CC2N(O)[N:31]=[N:30]C=2C=1.CCN=C=NCCCN(C)C.NN>CCOC(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:10]([F:22])=[C:11]3[N:20]=[CH:19][N:18]([CH3:21])[C:12]3=[N:13][C:14]=2[C:15]([NH:30][NH2:31])=[O:16])=[C:4]([F:23])[CH:3]=1
Reactant: Cn1cnc2c(F)c(Nc3ccc(Br)cc3F)c(C(=O)O)nc21
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: NN
Solvent: CCOC(C)=O
Product: Cn1cnc2c(F)c(Nc3ccc(Br)cc3F)c(C(=O)NN)nc21
Reaction time: 1 h

Procedure:
To a solution of 6-(4-bromo-2-fluorophenylamino)-7-fluoro-3-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (1.00 equivalent) and HOBt (3.00 equivalents) is added EDCI (3.00 equivalents) at room temperature. After stirring for 1 hour, hydrazine (3.00 equivalents) and TEA (3.00 equivalents) are added. The reaction mixture is stirred for 1 hour and diluted with EtOAc. The resulting mixture is washed with saturated aqueous NH4Cl, brine, saturated aqueous NaHCO3, and brine. The organic layer is dried over MgSO4, filtered, and concentrated in vacuo to give the crude material that is used directly without further purification.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][C@H:6]([OH:25])/[CH:7]=[CH:8]/[C@@H:9]1[C@@H:13]([CH2:14]/[CH:15]=[CH:16]\[CH2:17][CH2:18][CH2:19][C:20]([OH:22])=[O:21])[C@@H:12]([OH:23])[CH2:11][C@H:10]1[OH:24].CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O.C(O)(C)C.O>CC(C)=O.C(OCC)C>[CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][C@H:6]([OH:25])/[CH:7]=[CH:8]/[C@H:9]1[C:10](=[O:24])[CH2:11][C@H:12]([OH:23])[C@@H:13]1[CH2:14]/[CH:15]=[CH:16]\[CH2:17][CH2:18][CH2:19][C:20]([OH:22])=[O:21]
Reactant: CCCCC[C@H](O)/C=C/[C@@H]1[C@@H](C/C=C\CCCC(=O)O)[C@@H](O)C[C@H]1O
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CCOCC
Solvent: CC(C)O
Solvent: CC(C)=O
Product: CCCCC[C@H](O)/C=C/[C@H]1C(=O)C[C@H](O)[C@@H]1C/C=C\CCCC(=O)O
Reaction time: 0.5 h

Procedure:
PGF2α, 15-(tetrahydropyranyl ether) (2g.) in acetone (75 ml.) is cooled to -45° C. and thereafter treated with 1.2 ml. of the Jones reagent. The mixture is stirred for 30 min. at -35° to -45° C. and thereafter treated with 0.5 ml. of isopropanol and stirred an additional 15 min. The reaction mixture is then poured into a mixture of ice, water, and diethyl ether. The mixture is then extracted with diethyl ether and the combined etheral extracts washed with brine, and dried over sodium sulfate. After filtration removal of solvent proceeds by rotary evaporation. Crude product (1.8 g.) thereby obtained is chromatographed on 360 g. of acid washed silica gel eluting with 45 percent ethyl acetate in hexane. PGD2 15 -(tetrahydropyranyl ether) (800 mg.) is thereby obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[O:13][C:11](=[O:12])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[OH-:14].[Na+].Cl>O>[OH:13][CH:8]([C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1)[CH2:9][CH2:10][C:11]([OH:12])=[O:14]
Reactant: [OH-]
Reactant: O=C1CCC(c2ccc(F)cc2)O1
Agent: Cl
Agent: [Na+]
Solvent: O
Product: O=C(O)CCC(O)c1ccc(F)cc1
Temperature: 0 °C
Yield: 93 %

Procedure:
Commercial γ-(p-fluorophenyl)-γ-butyrolactone, 18.0 g. (0.10 mole) was added to a solution of 14.0 g. (0.35 mole) of sodium hydroxide in 100 ml. of water and the mixture heated at reflux for 40 minutes. After cooling to 0° C., 70 ml of 6 N hydrochloric acid was added at 0°-15° C. for one hour. The white solid which formed was filtered, washed with pentane and air dried to afford racemic-4-hydroxy-4-(p-fluorophenyl)butyric acid, 18.43 g., (93% yield). When heated to temperatures of about 100° C., the hydroxy acid was converted back to the starting lactone.