Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[C:3]([NH:10][C@@H:11]2[CH2:15][CH2:14][O:13][CH2:12]2)=[N:4][C:5]([NH2:9])=[N:6][C:7]=1[CH3:8].[C:16]([O:20][CH2:21][CH3:22])(=[O:19])[CH:17]=[CH2:18].C(N(CC)CC)C>CN(C=O)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>[NH2:9][C:5]1[N:6]=[C:7]([CH3:8])[C:2](/[CH:18]=[CH:17]/[C:16]([O:20][CH2:21][CH3:22])=[O:19])=[C:3]([NH:10][C@@H:11]2[CH2:15][CH2:14][O:13][CH2:12]2)[N:4]=1
Reactant: C=CC(=O)OCC
Reactant: Cc1nc(N)nc(N[C@@H]2CCOC2)c1I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)/C=C/c1c(C)nc(N)nc1N[C@@H]1CCOC1
Temperature: 95 °C
Yield: 94 %

Procedure:
To a solution of (R)-5-iodo-6-methyl-N4-(tetrahydrofuran-3-yl)pyrimidine-2,4-diamine (4.53 g, 14.2 mmol), ethyl acrylate (4.25 g, 42.5 mmol) and triethylamine (4.30 g, 42.5 mmol) in DMF (150 mL) was added Pd(PPh3)4 (1.635 g, 10 mol %) under nitrogen at room temperature. The resulting mixture was heated to 95° C. for 18 h under a nitrogen atmosphere. After the reaction was complete by LC/MS, the resulting mixture was concentrated under reduced pressure and directly subjected to column chromatography purification to give (R,E)-ethyl 3-(2-amino-4-methyl-6-(tetrahydrofuran-3-ylamino)pyrimidin-5-yl)acrylate (3.90 g, 94% yield). MS (EI) for C14H20N4O: 293.2 (MH+).
Reaction SMILES: [CH3:1][C:2]([CH3:7])([CH3:6])[C:3]([NH2:5])=[O:4].C(Cl)(=O)[C:9](Cl)=[O:10].[NH2:14][C:15]1[N:20]=[C:19]([CH3:21])[C:18]([O:22][C:23]2[CH:28]=[CH:27][N:26]=[C:25]([NH:29][C:30](=[O:34])[CH:31]([CH3:33])[CH3:32])[CH:24]=2)=[CH:17][CH:16]=1>ClCCCl.C1COCC1>[C:30]([NH:29][C:25]1[CH:24]=[C:23]([O:22][C:18]2[CH:17]=[CH:16][C:15]([NH:14][C:9]([NH:5][C:3](=[O:4])[C:2]([CH3:7])([CH3:6])[CH3:1])=[O:10])=[N:20][C:19]=2[CH3:21])[CH:28]=[CH:27][N:26]=1)(=[O:34])[CH:31]([CH3:32])[CH3:33]
Reactant: CC(C)(C)C(N)=O
Reactant: O=C(Cl)C(=O)Cl
Reactant: Cc1nc(N)ccc1Oc1ccnc(NC(=O)C(C)C)c1
Solvent: C1CCOC1
Solvent: ClCCCl
Product: Cc1nc(NC(=O)NC(=O)C(C)(C)C)ccc1Oc1ccnc(NC(=O)C(C)C)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 43.7 %

Procedure:
A solution of 2,2,2-trimethylacetamide (0.046 g, 0.454 mmol) in DCE (2 mL) was treated with oxalyl chloride (0.040 mL, 0.454 mmol), stirred at RT for 0.5 h, then heated at 75° C. for 1 h. The mixture was cooled to RT, added to a solution of N-(4-((6-amino-2-methylpyridin-3-yl)oxy)pyridin-2-yl)isobutyramide (0.10 g, 0.349 mmol) and TEA (0.1 mL, 0.70 mmol) in THF (2 mL) and stirred at RT for 1 h. The mixture was concentrated to dryness, the residue treated with EtOAc, washed with brine, dried over Na2SO4 and concentrated to dryness. The material was treated with EtOAc, allowed to stand at RT overnight and the resulting solid collected via filtration and dried to afford N-((5-((2-isobutyramidopyridin-4-yl)oxy)-6-methylpyridin-2-yl)carbamoyl)pivalamide (63 mg, 42%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 11.17 (s, 1H), 10.50 (s, 1H), 10.42 (br s, 1H), 8.18 (d, J=5.7 Hz, 1H), 7.92 (m, 1H), 7.63 (d, J=8.8 Hz, 1H), 7.60 (d, J=2.4 Hz, 1H), 6.66 (dd, J=5.7, 2.4 Hz, 1H), 2.69 (m, 1H), 2.24 (s, 3H), 1.22 (s, 9H), 1.02 (d, J=6.8 Hz, 6H); MS (ESI) m/z: 414.2 (M+H+).
Reaction SMILES: [C:1]1([CH:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[O:8][CH2:9][CH2:10]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:18][O:19][C:20]1[CH:21]=[C:22]([CH:26]2[CH2:30][CH2:29][NH:28][CH2:27]2)[CH:23]=[CH:24][CH:25]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN(C)C=O>[C:1]1([CH:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[O:8][CH2:9][CH2:10][N:28]2[CH2:29][CH2:30][CH:26]([C:22]3[CH:23]=[CH:24][CH:25]=[C:20]([O:19][CH3:18])[CH:21]=3)[CH2:27]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COc1cccc(C2CCNC2)c1
Reactant: BrCCOC(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cccc(C2CCN(CCOC(c3ccccc3)c3ccccc3)C2)c1
Temperature: 80 °C
Yield: 43 %

Procedure:
A solution of 17.5 g (60 mmole) of 1-(diphenylmethoxy)-2-bromoethane in 50 cm3 of dimethylformamide was added to a mixture of 10.6 g (60 mmole) of 3-(3-methoxyphenyl)pyrrolidine [prepared according to A. Ebnother and K. Hasspacher, Swiss Patent No. 526 536], 16.6 g (120 mmole) of potassium carbonate, 300 cm3 of dimethylformamide and a few potassium iodide crystals. The mixture was heated at 80° C. for 13 hours, and concentrated to dryness under reduced pressure after it returned to room temperature. The residue was taken up with 500 cm3 of 1N hydrochloric acid and extracted with ether. The aqueous acid phase was separated, basified with 10N sodium hydroxide solution, and extracted with methylene chloride. The organic solution was dried on sodium sulfate. The evaporation of the solvent provided an oily residue. Purification by silica gel filtration (eluent, hexane-ethyl acetate, 1/1) yielded 10 g of 1-[2-(diphenylmethoxy) ethyl]-3-(3-methoxyphenyl)pyrrolidine, which was dissolved in 100 cm3 of ether. To this solution was added a solution of 2.55 g (28.3 mmole) of oxalic acid in 30 cm3 of acetone. The oxalate precipitate was filtered and recrystallized from acetone.
Reaction SMILES: ClCCl.[N+:4]([C:7]1[CH:8]=[C:9]([S:14](Cl)(=[O:16])=[O:15])[CH:10]=[CH:11][C:12]=1[Cl:13])([O-:6])=[O:5].[CH2:18]([NH2:34])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]>C(N(CC)CC)C>[CH2:18]([NH:34][S:14]([C:9]1[CH:10]=[CH:11][C:12]([Cl:13])=[C:7]([N+:4]([O-:6])=[O:5])[CH:8]=1)(=[O:16])=[O:15])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]
Reactant: CCCCCCCCCCCCCCCCN
Reactant: O=[N+]([O-])c1cc(S(=O)(=O)Cl)ccc1Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCCCCNS(=O)(=O)c1ccc(Cl)c([N+](=O)[O-])c1

Procedure:
One liter of dichloromethane was mixed with 800 grams of 3-nitro 4-chlorobenzenesulfonyl chloride and a dichloromethane solution of 600 grams of hexadecylamine and 251 ml of triethylamine was added dropwise to the resulting mixture. After reaction, the reaction solvent was removed by distillation under reduced pressure, 3000 ml of methanol was added and a solution was obtained by heating. Crystals precipitated out on cooling this solution slowly. These crystals were recovered by filtration and dried.
Reaction SMILES: [CH:1]1([N:7]([C@H:29]2[CH2:34][CH2:33][C@H:32]([CH3:35])[CH2:31][CH2:30]2)[C:8](=[O:28])[NH:9][C:10]2[S:11][C:12]([S:15]([N:18](C)[CH2:19][C:20]([N:22]([CH2:25][CH3:26])[CH2:23][CH3:24])=[O:21])(=[O:17])=[O:16])=[CH:13][N:14]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C1(N([C@H]2CC[C@H](C)CC2)C(=O)NC2SC(S(NCC(O)=O)(=O)=[O:51])=CN=2)CCCCC1.N1CCOCC1>>[N:22]1([C:20](=[O:21])[CH2:19][NH:18][S:15]([C:12]2[S:11][C:10]([NH:9][C:8]([N:7]([CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)[C@H:29]3[CH2:30][CH2:31][C@H:32]([CH3:35])[CH2:33][CH2:34]3)=[O:28])=[N:14][CH:13]=2)(=[O:16])=[O:17])[CH2:23][CH2:24][O:51][CH2:26][CH2:25]1
Reactant: C[C@H]1CC[C@H](N(C(=O)Nc2ncc(S(=O)(=O)NCC(=O)O)s2)C2CCCCC2)CC1
Reactant: CCN(CC)C(=O)CN(C)S(=O)(=O)c1cnc(NC(=O)N(C2CCCCC2)[C@H]2CC[C@H](C)CC2)s1
Solvent: C1COCCN1
Product: C[C@H]1CC[C@H](N(C(=O)Nc2ncc(S(=O)(=O)NCC(=O)N3CCOCC3)s2)C2CCCCC2)CC1

Procedure:
The title compound was prepared in a similar manner to 2-({2-[3-cyclohexyl-3-(trans-4-methyl-cyclohexyl)-ureido]-thiazole-5-sulfonyl}-methyl-amino)-N,N-diethyl-acetamide using {2-[3-cyclohexyl-3-(trans-4-methyl-cyclohexyl)-ureido]-thiazole-5-sulfonylamino}-acetic acid and morpholine.
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([CH2:18][O:19][C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([C:27]([F:30])([F:29])[F:28])[CH:21]=3)[CH:14]=2)[CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O.CCN(C(C)C)C(C)C.[C:47]([O:51][C:52](=[O:55])[CH:53]=[CH2:54])([CH3:50])([CH3:49])[CH3:48]>C(Cl)Cl>[C:47]([O:51][C:52](=[O:55])[CH2:53][CH2:54][N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([CH2:18][O:19][C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([C:27]([F:29])([F:28])[F:30])[CH:21]=3)[CH:14]=2)[CH2:9]1)([CH3:50])([CH3:49])[CH3:48]
Reactant: CC(C)(C)OC(=O)N1CCc2cc(COc3ccc(Cl)c(C(F)(F)F)c3)ccc2C1
Reactant: C=CC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)OC(=O)CCN1CCc2cc(COc3ccc(Cl)c(C(F)(F)F)c3)ccc2C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 6-(4-chloro-3-trifluoromethyl-phenoxymethyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (70 mg, 0.158 mmol) in CH2Cl2 (1 mL) is added TFA(1 mL). The mixture is stirred at room temperature for 30 minutes. All the solvents are removed under reduced pressure. The mixture is dissolved in CH3OH (1.5 mL). Then DIEA (269 μL, 10 eq.) and acrylic acid tert-butyl ester (46 μL, 2 eq.) are added. The mixture is heated to 90° C. for 20 minutes using microwave irradiation. All the solvent is evaporated and the mixture is purified by column chromatography (silica gel, EtOAc/Hexane, gradient) to give 56 mg of 3-[6-(4-chloro-3-trifluoromethyl-phenoxymethyl)-3,4-dihydro-1H-isoquinolin-2-yl]-propionic acid tert-butyl ester.
Reaction SMILES: C([NH:5][S:6]([C:9]1[CH:10]=[C:11]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]3[N:26]=[C:25]([C:27]4[CH:32]=[CH:31][C:30]([Cl:33])=[C:29]([Cl:34])[CH:28]=4)[CH:24]=[C:23]([CH3:35])[N:22]=3)[CH:16]=2)[CH:12]=[CH:13][CH:14]=1)(=[O:8])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[Cl:34][C:29]1[CH:28]=[C:27]([C:25]2[CH:24]=[C:23]([CH3:35])[N:22]=[C:21]([C:17]3[CH:16]=[C:15]([C:11]4[CH:12]=[CH:13][CH:14]=[C:9]([S:6]([NH2:5])(=[O:8])=[O:7])[CH:10]=4)[CH:20]=[CH:19][CH:18]=3)[N:26]=2)[CH:32]=[CH:31][C:30]=1[Cl:33]
Reactant: Cc1cc(-c2ccc(Cl)c(Cl)c2)nc(-c2cccc(-c3cccc(S(=O)(=O)NC(C)(C)C)c3)c2)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(-c2ccc(Cl)c(Cl)c2)nc(-c2cccc(-c3cccc(S(N)(=O)=O)c3)c2)n1
Temperature: 25 °C
Reaction time: 15 h
Yield: 34 %

Procedure:
To a cooled and stirred solution of 3′-[4-(3,4-dichloro-phenyl)-6-methyl-pyrimidin-2-yl]-biphenyl-3-sulfonic acid tert-butylamide (0.54 g) in dichloromethane (6 mL) was added TFA (6 mL) and the reaction mixture was allowed to stir at room temperature for 15 h. The mixture was evaporated to dryness and saturated NaHCO3 solution (5 mL), diethyl ether and heptane were added. The mixture was stirred at room temperature for 1 h, the precipitate was collected by filtration, washed with water and heptane and dried. Further purification by flash-chromatography on silica gel (ethyl acetate/hexane) and crystallization (diethyl ether) yielded the title compound as a white solid (0.16, 34%). MS (ISP) 470.1 [(M+H)+]; mp 206.5° C.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1)#[N:2].Br[C:13]1[CH:14]=[CH:15][C:16]([O:21][CH2:22][CH3:23])=[C:17]([CH:20]=1)[CH:18]=[O:19]>>[CH2:22]([O:21][C:16]1[CH:15]=[CH:14][C:13]([C:6]2[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=2)=[CH:20][C:17]=1[CH:18]=[O:19])[CH3:23]
Reactant: CCOc1ccc(Br)cc1C=O
Reactant: N#Cc1ccc(B(O)O)cc1
Product: CCOc1ccc(-c2ccc(C#N)cc2)cc1C=O

Procedure:
4-cyanophenylboronic acid (500 mg, 3.40 mmol) is coupled to 5-bromo-2-ethoxybenzaldehyde (780 mg, 3.40 mmol) using Method A to give the title compound.
Reaction SMILES: [C:1]12([C:11]3[CH:21]=[CH:20][C:14]([O:15][CH2:16][C:17]([OH:19])=O)=[CH:13][CH:12]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[CH3:22][O:23][C:24](=[O:32])[C:25]1[CH:30]=[CH:29][N:28]=[C:27]([NH2:31])[CH:26]=1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>CN(C1C=CN=CC=1)C.CN(C=O)C.C(OCC)(=O)C>[CH3:22][O:23][C:24](=[O:32])[C:25]1[CH:30]=[CH:29][N:28]=[C:27]([NH:31][C:17](=[O:19])[CH2:16][O:15][C:14]2[CH:20]=[CH:21][C:11]([C:1]34[CH2:8][CH:7]5[CH2:6][CH:5]([CH2:4][CH:3]([CH2:9]5)[CH2:2]3)[CH2:10]4)=[CH:12][CH:13]=2)[CH:26]=1
Reactant: COC(=O)c1ccnc(N)c1
Reactant: O=C(O)COc1ccc(C23CC4CC(CC(C4)C2)C3)cc1
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1ccnc(NC(=O)COc2ccc(C34CC5CC(CC(C5)C3)C4)cc2)c1
Yield: 75.5 %

Procedure:
To a solution of appropriate (4-adamantan-1-yl-phenoxy)-acetic acid (150 mg, 0.523 mmol), 2-amino isonicotinic acid methyl ester (159.3 mg, 1.04 mmol) and DMAP (127.9 mg, 1.04 mmol) in DMF (6 ml) was added PyBOP (545 mg, 1.04 mmol) at room temperature and the resulting mixture was stirred until reaction completion as indicated by TLC. Reaction mixture was poured onto ice cold water, diluted with ethyl acetate, separated organic layer and sequentially washed with aqueous sodium bicarbonate, brine and water, and dried over anhydrous MgSO4. The solvent was filtered and evaporated under reduced pressure to afford a crude solid, which was purified by flash chromatography on silica gel (EtOAc:hexanes=1:9 to 1:1) to afford of 2-[2-(4-adamantan-1-yl-phenoxy)acetylamino]-isonicotinic acid methyl ester as a colorless solid (0.166 g, 75% yield).
Reaction SMILES: [F:1][C:2]1[CH:25]=[CH:24][CH:23]=[CH:22][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[C:7]([C:14]2[N:19]=[C:18]([NH2:20])[C:17]([NH2:21])=[CH:16][CH:15]=2)=[N:6]1.[CH3:26][CH:27]([CH3:35])[C:28](=O)[C:29](OCC)=[O:30].S(=O)(=O)(O)O>C(O)C>[F:1][C:2]1[CH:25]=[CH:24][CH:23]=[CH:22][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[C:7]([C:14]2[CH:15]=[CH:16][C:17]3[N:21]=[C:28]([CH:27]([CH3:35])[CH3:26])[C:29](=[O:30])[NH:20][C:18]=3[N:19]=2)=[N:6]1
Reactant: CCOC(=O)C(=O)C(C)C
Reactant: Nc1ccc(-c2nn(Cc3ccccc3F)c3ncccc23)nc1N
Agent: O=S(=O)(O)O
Solvent: CCO
Product: CC(C)c1nc2ccc(-c3nn(Cc4ccccc4F)c4ncccc34)nc2[nH]c1=O
Temperature: 25 °C

Procedure:
146 mg (0.435 mmol) of the compound from example 43A were initially charged in ethanol (8 ml), then 69 mg (0.48 mmol) of ethyl 3-methyl-2-oxobutanoate were added and the reaction mixture was heated to reflux overnight. Thereafter, a catalytic amount of conc. sulfuric acid was added and the mixture was again heated to reflux overnight. Subsequently, the mixture was cooled to RT, and the solid formed was filtered off, washed with methanol and dried under high vacuum. This gave 26 mg (14% of theory) of the title compound in solid form.
Reaction SMILES: [N:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[F:13])[C:7]([OH:9])=[O:8])=[N+:2]=[N-:3].[C:14]([C:16]1[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=1)#[CH:15].ClC1N=CC(C2N=NN(C3C=C(C=CC=3C)C(O)=O)C=2)=CC=1>>[F:13][C:12]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][C:4]=1[N:1]1[CH:15]=[C:14]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)[N:3]=[N:2]1
Reactant: C#Cc1cccnc1
Reactant: [N-]=[N+]=Nc1cc(C(=O)O)ccc1F
Agent: Cc1ccc(C(=O)O)cc1-n1cc(-c2ccc(Cl)nc2)nn1
Product: O=C(O)c1ccc(F)c(-n2cc(-c3cccnc3)nn2)c1

Procedure:
4-Fluoro-3-(4-pyridin-3-yl-[1,2,3]triazol-1-yl)-benzoic acid was prepared from 3-azido-4-fluoro benzoic acid (U.S. Ser. No. 04/102,492) and 3-ethynyl pyridine (Aldrich) in the same manner as 3-[4-(6-chloro-pyridin-3-yl)-1,2,3-triazol-1-yl]-4-methyl-benzoic acid (Example 1).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][N:6]=[C:5]([C:9]([OH:11])=O)[CH:4]=1)#[N:2].Br.Br.Br.[CH2:15]([C:17]1[C:18]([C:25]2[CH:33]=[C:32]3[C:28]([C:29]([C:34]4[NH:43][C:37]5[CH2:38][CH2:39][NH:40][CH2:41][CH2:42][C:36]=5[N:35]=4)=[N:30][NH:31]3)=[CH:27][CH:26]=2)=[CH:19][C:20]([F:24])=[C:21]([OH:23])[CH:22]=1)[CH3:16]>>[CH2:15]([C:17]1[CH:22]=[C:21]([OH:23])[C:20]([F:24])=[CH:19][C:18]=1[C:25]1[CH:33]=[C:32]2[C:28]([C:29]([C:34]3[NH:43][C:37]4[CH2:38][CH2:39][N:40]([C:9]([C:5]5[CH:4]=[C:3]([CH:8]=[CH:7][N:6]=5)[C:1]#[N:2])=[O:11])[CH2:41][CH2:42][C:36]=4[N:35]=3)=[N:30][NH:31]2)=[CH:27][CH:26]=1)[CH3:16]
Reactant: CCc1cc(O)c(F)cc1-c1ccc2c(-c3nc4c([nH]3)CCNCC4)n[nH]c2c1
Reactant: N#Cc1ccnc(C(=O)O)c1
Agent: Br
Product: CCc1cc(O)c(F)cc1-c1ccc2c(-c3nc4c([nH]3)CCN(C(=O)c3cc(C#N)ccn3)CC4)n[nH]c2c1
Yield: 15.6 %

Procedure:
The title compound was prepared from 4-cyano-pyridine-2-carboxylic acid (12.5 mg, 85 μmol) and 5-ethyl-2-fluoro-4-[3-(1,4,5,6,7,8-hexahydro-imidazo[4,5-d]azepin-2-yl)-1H-indazol-6-yl]-phenol trihydrobromide salt (Preparation 32, 50 mg, 80 μmol) using the method of Example 8. The crude material was purified by HPLC Method B to afford 6.5 mg of the title compound.
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].BrCCBr.Cl[Si](C)(C)C.[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:25]=[C:26]3[C:41](=[O:42])[CH2:40][C:39]([CH3:44])([CH3:43])[O:38][C:27]3=[N:28][C:29]=2[C:30]2[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][C:31]=2[Cl:37])=[CH:20][CH:19]=1>C1COCC1.CCOC(C)=O.[Zn]>[Cl:17][C:18]1[CH:19]=[CH:20][C:21]([C:24]2[CH:25]=[C:26]3[C:41]([CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4])([OH:42])[CH2:40][C:39]([CH3:44])([CH3:43])[O:38][C:27]3=[N:28][C:29]=2[C:30]2[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][C:31]=2[Cl:37])=[CH:22][CH:23]=1
Reactant: CC1(C)CC(=O)c2cc(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3Cl)nc2O1
Reactant: CCOC(=O)CBr
Agent: C[Si](C)(C)Cl
Agent: [Zn]
Solvent: C1CCOC1
Solvent: BrCCBr
Solvent: CCOC(C)=O
Product: CCOC(=O)CC1(O)CC(C)(C)Oc2nc(-c3ccc(Cl)cc3Cl)c(-c3ccc(Cl)cc3)cc21
Temperature: 65 °C

Procedure:
A mixture of ethyl 2-bromoacetate (0.334 mL 3.01 mmol), 1,2-dibromoethane (0.02 mL, 0.23 mmol), Zn powder (0.227 g, 3.47 mmol) and THF (2.5 mL) was heated to 65° C. for 2 min before cooling to rt. Chlorotrimethylsilane (0.015 mL, 0.116 mmol) was added and the reaction was stirred for 5 min at which point the product of Example 1 (1 g, 2.315 mmol) in THF 10 mL was added. The reaction was heated to 70° C. After 1 h the reaction was cooled to rt. The reaction was diluted with EtOAc and washed with 2 M aq HCl and brine. The concentrated residue was purified by flash chromatography on silica gel gradient eluted with 0-10% EtOAc in CH2Cl2 affording the product (LC-2) HPLC/MS: 520.2 (M+1), 522.2 (M+3); Rt=3.97 min.
Reaction SMILES: Cl.[CH3:2][NH:3][CH3:4].O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[C:28]([C@@H:31]1[CH2:36][CH2:35][C@@H:34]([NH:37][C:38]([C:40]2[NH:41][C:42]3[C:47]([CH:48]=2)=[CH:46][C:45]([Cl:49])=[CH:44][CH:43]=3)=[O:39])[C@@H:33]([NH:50][C:51]([C:53]2[S:54][C:55]3[CH2:56][N:57]([CH3:62])[CH2:58][CH2:59][C:60]=3[N:61]=2)=[O:52])[CH2:32]1)(O)=[O:29]>C(Cl)(Cl)Cl.C(N(CC)CC)C>[ClH:49].[Cl:49][C:45]1[CH:46]=[C:47]2[C:42](=[CH:43][CH:44]=1)[NH:41][C:40]([C:38]([NH:37][C@@H:34]1[CH2:35][CH2:36][C@@H:31]([C:28](=[O:29])[N:3]([CH3:4])[CH3:2])[CH2:32][C@@H:33]1[NH:50][C:51]([C:53]1[S:54][C:55]3[CH2:56][N:57]([CH3:62])[CH2:58][CH2:59][C:60]=3[N:61]=1)=[O:52])=[O:39])=[CH:48]2
Reactant: CNC
Reactant: CN1CCc2nc(C(=O)N[C@H]3C[C@H](C(=O)O)CC[C@H]3NC(=O)c3cc4cc(Cl)ccc4[nH]3)sc2C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: CCN(CC)CC
Product: CN1CCc2nc(C(=O)N[C@H]3C[C@H](C(=O)N(C)C)CC[C@H]3NC(=O)c3cc4cc(Cl)ccc4[nH]3)sc2C1
Reaction time: 72 h
Yield: 118.7 %

Procedure:
Triethylamine (0.25 ml), dimethylamine hydrochloride (133 mg), 1-hydroxybenzotriazole monohydrate (53 mg) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (75 mg) were added to a chloroform suspension (10 ml) of (1R*,2S*,4R*)-4-carboxy-N1-[(5-chloroindol-2-yl)carbonyl]-N2-[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-1,2-cyclohexanediamine (168 mg), and the mixture was stirred for 72 hours. The solvent was distilled off under reduced pressure, and water was added to the residue to conduct extraction with chloroform. The resultant organic layer was washed with saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resultant residue was purified by column chromatography on silica gel (dichloromethane:methanol=93:7). The thus-obtained colorless solid (135 mg) was suspended in ethanol (5 ml), to which 1N hydrochloric acid (0.5 ml) was added. The mixture was stirred for 2 hours, and the solvent was distilled off to obtain the title compound (112 mg) as colorless powder.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@@:8]1([CH2:12][N:13]2[CH:17]=[N:16][CH:15]=[N:14]2)[C@H:10]([CH3:11])[O:9]1.[N:18]1([C:23]2[CH:28]=[CH:27][C:26]([N:29]3[CH:33]=[CH:32][NH:31][C:30]3=[O:34])=[CH:25][CH:24]=2)[CH:22]=[N:21][CH:20]=[N:19]1.C(=O)([O-])[O-].[Cs+].[Cs+].CS(C)=O>C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@@:8]([OH:9])([CH2:12][N:13]1[CH:17]=[N:16][CH:15]=[N:14]1)[C@H:10]([N:31]1[CH:32]=[CH:33][N:29]([C:26]2[CH:25]=[CH:24][C:23]([N:18]3[CH:22]=[N:21][CH:20]=[N:19]3)=[CH:28][CH:27]=2)[C:30]1=[O:34])[CH3:11]
Reactant: C[C@@H]1O[C@@]1(Cn1cncn1)c1ccccc1F
Reactant: O=c1[nH]ccn1-c1ccc(-n2cncn2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: C[C@@H](n1ccn(-c2ccc(-n3cncn3)cc2)c1=O)[C@](O)(Cn1cncn1)c1ccccc1F
Temperature: 100 °C
Reaction time: 17 h
Yield: 10.2 %

Procedure:
(2R,3S)-2-(2-fluorophenyl)-3-methyl-2-(1H-1,2,4-triazol-1-yl)methyloxirane (2.24 g), 1-[4-(1H-1,2,4-triazol-1-yl)phenyl]-2(1H,3H)-imidazolone (2.17 g) and cesium carbonate (powder: 7.76 g) were added to dimethylsulfoxide (100 ml), and the mixture was heated with stirring at 100° C. for 17 hours. After being cooled, the reaction solution was diluted with ethyl acetate (200 ml). Ice water (200 ml) was added thereto to separate the ethyl acetate layer. The aqueous layer was extracted with ethyl acetate (100 ml). The ethyl acetate layers were combined and washed with 0.5N-sodium hydroxide (100 ml), 1N-hydrochloric acid (100 ml×2) and a saturated aqueous solution of sodium chloride (100 ml) successively. The ethyl acetate layer was dried over anhydrous magnesium sulfate and distilled under reduced pressure to remove the solvent. The residue was purified by silica gel chromatography (eluent: ethyl acetate/acetone=4/1) to give 1-[(1R,2R)-2-(2-fluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]-3-[4-[1H-1,2,4-triazol-1-yl)phenyl]-2(1H,3H)-imidazolone (Compound 38; 0.45 g).
Reaction SMILES: N12[CH2:8][CH2:7][CH:4](CC1)[C@@H:3]([O:9][C:10](=[O:26])[C@H:11]([NH:18][C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)C2.[Cl:27][CH2:28][C:29]([C:31]1[S:32][CH:33]=[CH:34][CH:35]=1)=[O:30]>CC#N>[Cl-:27].[F:25][C:22]1[CH:21]=[CH:20][C:19]([NH:18][CH:11]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:10](=[O:26])[O:9][C@@H:3]2[CH2:4][CH:7]3[CH2:8][CH2:19][N+:18]2([CH2:28][C:29](=[O:30])[C:31]2[S:32][CH:33]=[CH:34][CH:35]=2)[CH2:11][CH2:10]3)=[CH:24][CH:23]=1
Reactant: O=C(O[C@H]1CN2CCC1CC2)[C@H](Nc1ccc(F)cc1)c1ccccc1
Reactant: O=C(CCl)c1cccs1
Solvent: CC#N
Product: O=C(C[N+]12CCC(CC1)C[C@H]2OC(=O)C(Nc1ccc(F)cc1)c1ccccc1)c1cccs1
Product: [Cl-]
Temperature: 100 °C
Yield: 72.1 %

Procedure:
To a solution of (R)-(4-fluoro-phenylamino)-phenyl-acetic acid (R)-(1-aza-bicyclo[2.2.2]oct-3-yl)ester (C254) (200 mg, 0.56 mmol) in CH3CN (2 mL), is added 2-chloro-1-(thiophen-2-yl)ethanone (100 mg, 0.62 mmol). The reaction is heated at 100° C. for 1 hour under MW irradiation. The solvent is evaporated and the crude is purified by flash chromatography (DCM/MeOH=9/1) recovering the title compound as a white solid (104 mg, 36% yield, chloride salt, single diastereoisomer).
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:6]=[C:7]([OH:16])[C:8](=[CH:14][CH:15]=1)[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[N+]=[N-].[ClH:17].[H][H]>[Pd].CO>[ClH:17].[NH2:1][CH2:4][C:5]1[CH:6]=[C:7]([OH:16])[C:8](=[CH:14][CH:15]=1)[C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: [H][H]
Reactant: CCOC(=O)c1ccc(CN=[N+]=[N-])cc1O
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CCOC(=O)c1ccc(CN)cc1O
Yield: 71 %

Procedure:
Palladium on carbon (0.5 g; 10% [w/w]) was added to a 1L hydrogenation flask under a nitrogen atmosphere. The crude ethyl 4-azidomethylsalicylate was dissolved in methanol (200 mL) and transferred to the hydrogenation flask. Concentrated-aqueous hydrochloric acid (2 mL) was then added, and the flask was affixed to the Parr hydrogenator. The reaction mixture was shaken under 35 psi of hydrogen for 4 hours at room temperature. The mixture was then filtered through Celite to remove the catalyst, and the filtrate was evaporated to dryness to afford an off-white solid. Finally, this solid was crystallized from EtOH to afford 3.1 g (71% yield) of ethyl 4-aminomethylsalicylate hydrochloride (m.p. 240°-241 ° C.).