Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=1[C:16]1[C:21]([F:22])=[CH:20][N:19]=[C:18](Cl)[N:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:24][CH:25]([S:27]([CH2:30][C:31]1[CH:32]=[C:33]([CH:35]=[CH:36][CH:37]=1)[NH2:34])(=[O:29])=[O:28])[CH3:26]>>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=1[C:16]1[C:21]([F:22])=[CH:20][N:19]=[C:18]([NH:34][C:33]2[CH:35]=[CH:36][CH:37]=[C:31]([CH2:30][S:27]([CH:25]([CH3:26])[CH3:24])(=[O:29])=[O:28])[CH:32]=2)[N:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)S(=O)(=O)Cc1cccc(N)c1
Reactant: Fc1ccc(-c2nc(Cl)ncc2F)c(OCc2ccccc2)c1
Product: CC(C)S(=O)(=O)Cc1cccc(Nc2ncc(F)c(-c3ccc(F)cc3OCc3ccccc3)n2)c1

Procedure:
Example 5 was prepared under similar conditions as described in the preparation of Example 3 using 4-[2-(benzyloxy)-4-fluorophenyl]-2-chloro-5-fluoropyrimidine and 3-[(propan-2-ylsulfonyl)methyl]aniline (UkrOrgSynthesis Ltd.). The batch was purified by preparative HPLC.
Reaction SMILES: COC1C=CC(C[N:8]2[C:12]([CH2:13][CH2:14][C:15]3[N:25]=[C:18]4[C:19]([CH3:24])=[N:20][CH:21]=[C:22]([CH3:23])[N:17]4[N:16]=3)=[N:11][C:10]([N:26]3[CH2:30][CH2:29][CH2:28][CH2:27]3)=[N:9]2)=CC=1.FC(F)(F)C(O)=O.C1(OC)C=CC=CC=1>ClCCl>[CH3:23][C:22]1[N:17]2[N:16]=[C:15]([CH2:14][CH2:13][C:12]3[NH:8][N:9]=[C:10]([N:26]4[CH2:30][CH2:29][CH2:28][CH2:27]4)[N:11]=3)[N:25]=[C:18]2[C:19]([CH3:24])=[N:20][CH:21]=1
Reactant: COc1ccc(Cn2nc(N3CCCC3)nc2CCc2nc3c(C)ncc(C)n3n2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: Cc1ncc(C)n2nc(CCc3nc(N4CCCC4)n[nH]3)nc12
Yield: 67.3 %

Procedure:
2-(2-(1-(4-methoxybenzyl)-3-(pyrrolidin-1-yl)-1H-1,2,4-triazol-5-yl)ethyl)-5,8-dimethyl-[1,2,4]triazolo[1,5-a]pyrazine (13.6 mg, 31.4 μmol, Eq: 1.00) was stirred with trifluoroacetic acid (143 mg, 96.3 μl, 1.26 mmol, Eq: 40) and anisole (61.2 mg, 61.8 μl, 566 μmol, Eq: 18) in Dichloromethane (400 μl) overnight at room-temperature. The reaction mixture was extracted with aq. sodium borohydride sat. and dichloromethane three times, dried over magnesium sulfate, filtered and evaporated to give 5,8-Dimethyl-2-[2-(5-pyrrolidin-1-yl-2H-[1,2,4]triazol-3-yl)-ethyl]-[1,2,4]triazolo[1,5-a]pyrazine (6.6 mg, 67.2%) as off-white solid.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]3[N:12]=[N:13][N:14]([CH2:16][C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[CH:15]=3)[CH:9]=2)[N:4](C(OC(C)(C)C)=O)[N:3]=1.C(N(C(C)C)CC)(C)C.Br[CH2:40][CH2:41][CH2:42][C:43](Cl)=[O:44]>O1CCCC1>[CH2:16]([N:14]1[CH:15]=[C:11]([C:8]2[CH:9]=[C:10]3[C:5](=[CH:6][CH:7]=2)[NH:4][N:3]=[C:2]3[N:1]2[CH2:40][CH2:41][CH2:42][C:43]2=[O:44])[N:12]=[N:13]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C(Cl)CCCBr
Reactant: CC(C)(C)OC(=O)n1nc(N)c2cc(-c3cn(Cc4ccccc4)nn3)ccc21
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=C1CCCN1c1n[nH]c2ccc(-c3cn(Cc4ccccc4)nn3)cc12
Temperature: 60 °C
Reaction time: 16 h

Procedure:
A suspension of Example 64A (200 mg, 0.51 mmol) and diisopropylethylamine (0.089 mL, 0.51 mmol) in tetrahydrofuran (5 mL) was stirred for about 15 minutes at ambient temperature then 4-bromobutanoyl chloride (0.059 mL, 0.51 mmol) was added. The reaction mixture was stirred for about 16 hours. The precipitate was removed by filtration and the filtrate concentrated under reduced pressure. The residue was taken up in acetonitrile (5 mL) and treated with diisopropylethylamine (0.089 mL, 0.51 mmol) and heated at about 60° C. for about 16 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was treated with hydrochloric acid (4 N in dioxane, 5 mL) and the reaction mixture stirred at room temperature for about 2 hours. The reaction mixture was concentrated under reduced pressure and the crude material was purified by reverse-phase HPLC using acetonitrile/water (0.05 M ammonium acetate) gradient elution method to afford the title compound as the acetate salt. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.84 (s, 1H), 8.56 (s, 1H), 8.49 (s, 1H), 7.84 (d, J=8.6 Hz, 1H), 7.51 (d, J=8.7 Hz, 1H), 7.29-7.46 (m, 5H), 5.64 (s, 2H), 3.96 (t, J=6.9 Hz, 2H), 2.56 (t, J=7.9 Hz, 2H), 2.25-2.12 (m, 2H). MS (ESI+) m/z 359 (M+H)+.
Reaction SMILES: CN(C)C(=O)C.[C:7]([O:16]CC)(=[O:15])[C:8]1[C:9](=[CH:11][CH:12]=[CH:13][CH:14]=1)[OH:10].C(=O)([O-])[O-].[K+].[K+].S(O[CH2:30][CH:31]([CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45])[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])(=O)(=O)C>C(OCC)(=O)C.O>[CH2:40]([CH:31]([CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[CH2:30][O:10][C:9]1[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=1[C:7]([OH:16])=[O:15])[CH2:41][CH2:42][CH2:43][CH2:44][CH3:45]
Reactant: CCOC(=O)c1ccccc1O
Reactant: CCCCCCCCC(CCCCCC)COS(C)(=O)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Solvent: CCOC(C)=O
Product: CCCCCCCCC(CCCCCC)COc1ccccc1C(=O)O
Reaction time: 2 h

Procedure:
300 ml of N,N-dimethylacetamide was added to 17.5 g of ethyl salicylate, and 34.6 g of potassium carbonate and then 32.1 of 2-hexyldecyl mesylate were added dropwise over about 30 min with stirring on a steam bath. After the addition the stirring was continued for 2 hours further under heating, and then the reaction mixture was cooled and transferred into a separately funnel. Then 300 ml of ethyl acetate and 1l of water were added for extraction. The ethyl acetate solution was washed with dilute hydrochloric acid, and then with an aqueous sodium hydrogencarbonate solution, and it was concentrated. 300 ml of ethanol was to the coil concentrate, to dissolve the concentrate, and a solution, of 12 g of sodium hydroxide in 50 ml of water was added dropwise thereto over about 10 min at room temperature with stirring. After the addition the stirring was continued for 1 hour further and 30 ml of concentrated hydrochloric acid diluted with 300 ml of water was added dropwise. The reaction liquid was transferred into a separately funnel, and 500 ml of water and 300 ml of ethyl acetate were added for extraction. The ethyl acetate solution was washed with 500 ml of water twice and then concentrated, to obtain 36.0 g of 2-(2-hexyldecyloxy)benzoic acid in the form of an oil.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]([OH:14])=[O:13])[C:6]([CH3:15])=[C:5]2[S:16][C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=1.C(=O)([O-])[O-].[Na+].[Na+].[C:30]1(B(O)O)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.[CH2:39](O)[CH3:40]>C1(C)C=CC=CC=1.O.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>[Cl:23][C:20]1[CH:21]=[CH:22][C:17]([S:16][C:5]2[C:4]3[C:8](=[CH:9][CH:10]=[C:2]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[CH:3]=3)[N:7]([CH2:11][C:12]([O:14][CH2:39][CH3:40])=[O:13])[C:6]=2[CH3:15])=[CH:18][CH:19]=1
Reactant: OB(O)c1ccccc1
Reactant: CCO
Reactant: Cc1c(Sc2ccc(Cl)cc2)c2cc(Br)ccc2n1CC(=O)O
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: Cc1ccccc1
Solvent: O
Product: CCOC(=O)Cn1c(C)c(Sc2ccc(Cl)cc2)c2cc(-c3ccccc3)ccc21

Procedure:
To a solution of the product of example 25 part (ii) (0.5 g) in ethanol (0.8 ml) and toluene (3 ml) was added 2M sodium carbonate solution in water (1.4 ml), phenylboronic acid (0.131 g) and tetrakis(triphenylphosphine)palladium(0) (1.2 g). The reaction was heated to reflux for 2 hours, cooled and concentrated in vacuo. The residue was purified by flash column chromatography to give the subtitle compound (0.4 g). This was used in step (ii) without further characterisation.
Reaction SMILES: [OH:1][C@@:2]([C@@H:15]1[CH2:20][CH2:19][CH2:18][N:17]([C:21](Cl)=[O:22])[CH2:16]1)([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:3][CH2:4][CH2:5][CH2:6][O:7][CH3:8].[N:24]([CH2:27][C@@H:28]([NH2:36])[CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[N+:25]=[N-:26].C(N(CC)CC)C>C(Cl)Cl.CN(C1C=CN=CC=1)C>[N:24]([CH2:27][C@@H:28]([NH:36][C:21]([N:17]1[CH2:18][CH2:19][CH2:20][C@@H:15]([C@:2]([OH:1])([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:3][CH2:4][CH2:5][CH2:6][O:7][CH3:8])[CH2:16]1)=[O:22])[CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[N+:25]=[N-:26]
Reactant: [N-]=[N+]=NC[C@@H](N)Cc1ccccc1
Reactant: COCCCC[C@@](O)(c1ccccc1)[C@@H]1CCCN(C(=O)Cl)C1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COCCCC[C@@](O)(c1ccccc1)[C@@H]1CCCN(C(=O)N[C@H](CN=[N+]=[N-])Cc2ccccc2)C1
Reaction time: 12 h
Yield: 109.8 %

Procedure:
A solution of (R)-3-((S)-1-hydroxy-5-methoxy-1-phenylpentyl)piperidine-1-carbonyl chloride (135 mg, 0.4 mmol) in CH2Cl2 (10 mL) was added to a solution of (S)-1-azido-3-phenylpropan-2-amine (156.3 mg, 0.73 mmol), triethylamine (0.6 mL, 4.3 mmol), and DMAP (16.6 mg, 0.13 mmol) in CH2Cl2. After stirring for 12 h, the reaction was taken up in CH2Cl2 (50 mL), washed with satd aq NaHCO3 (3×10 mL), and brine (3×10 mL), dried (Na2SO4), decanted, and stripped to afford (3R)—N—((S)-3-azido-1-phenylpropan-2-yl)-3-((S)-1-hydroxy-5-methoxy-1-phenylpentyl)piperidine-1-carboxamide (210.7 mg) as a brown residue (theoretical yield: 192.0 mg). MS ESI+ve m/z 502 (M+Na).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[CH:4](O)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.C(=O)([O-])[O-:14].[K+].[K+].[CH2:19]([O:21][C:22](=[O:27])[CH2:23][CH2:24][CH2:25]Br)[CH3:20]>CC(C)=O>[CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:14][CH2:25][CH2:24][CH2:23][C:22]([O:21][CH2:19][CH3:20])=[O:27])=[CH:7][CH:6]=1
Reactant: CCOC(=O)CCCBr
Reactant: COC(=O)C(O)c1ccccc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)CCCOc1ccc(CC(=O)OC)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
10 g (60.2 mmol) of hydroxyphenylacetic acid methyl ester (Aldrich) is dissolved in 75 ml of acetone. 18.4 g (133 mmol) of solid potassium carbonate is added. 17.8 ml (123 mmol) of 4-bromobutyric acid ethyl ester is added in drops under reflux within 15 minutes, and it is kept at this temperature for another 4 hours and stirred overnight at room temperature. Precipitate is filtered out, the solution is evaporated to the dry state, and it is chromatographed on silica gel (hexane/ethyl acetate 3:1). The fractions that contain the product are combined and concentrated by evaporation.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:13]([NH:15][C@@H:16]([C:22](=[O:24])[NH2:23])[CH2:17][CH2:18][C:19]([OH:21])=[O:20])=[O:14])[CH:10]([CH3:12])[CH3:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[C:26]1C=CC2N=NN(OS(C3C=CC(Cl)=CC=3)(=O)=O)C=2[CH:45]=1.C(O)C.C(OCC)(=O)C>CN(C=O)C>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:13]([NH:15][C@@H:16]([C:22](=[O:24])[NH2:23])[CH2:17][CH2:18][C:19]([O:21][CH2:26][CH3:45])=[O:20])=[O:14])[CH:10]([CH3:12])[CH3:11])=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: O=S(=O)(On1nnc2ccc(Cl)cc21)c1ccc(Cl)cc1
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@H](CCC(=O)O)C(N)=O
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: CN(C)C=O
Product: CCOC(=O)CC[C@@H](NC(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)C)C(N)=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 43.9 %

Procedure:
To a solution of t-butyloxycarbonyl-L-valyl-D-isoglutamine (1.73 g, 5 mmol) in DMF (5 ml) was added TEA (0.84 ml) and 6-chloro-1-p-chlorobenzenesulfonyloxybenzotriazole (2.06 g, 6 mmol) under cooling. After being stirred at room temperature for 4 hours, the mixture was cooled with ice again and ethanol (3 ml) and TEA (0.7 ml) were added. The mixture was stirred at room temperature for 24 hours. Ethyl acetate (100 ml) was added to the reaction mixture and the organic layer was then washed with a 5% aqueous sodium bicarbonate solution, 1 N hydrochloric acid and water successively. The mixture was then dried over anhydrous sodium sulfate and evaporated. The crystalline residue was recrystallized from ethyl acetate/petroleum ether to obtain ethyl t-butyloxycarbonyl-L-valyl-D-isoglutaminate (820 mg). m.p. 128°-129° C. [α]D23 +8.4° (C 0.5, DMF). Rf2 =0.72, Rf3 =0.28.
Reaction SMILES: C1([O:7][C:8](=O)[N:9]([C:19]2[CH:24]=[C:23]([O:25][C:26]3[CH:31]=[CH:30][C:29]([NH:32][C:33]([C:35]4([C:38](=[O:47])[NH:39][C:40]5[CH:45]=[CH:44][C:43]([F:46])=[CH:42][CH:41]=5)[CH2:37][CH2:36]4)=[O:34])=[CH:28][CH:27]=3)[CH:22]=[CH:21][N:20]=2)C(OC2C=CC=CC=2)=O)C=CC=CC=1.Cl.Cl.[N:51]1([CH:55]2[CH2:60][CH2:59][NH:58][CH2:57][CH2:56]2)[CH2:54][CH2:53][CH2:52]1.C(N(CC)CC)C.O>CN(C)C=O>[N:51]1([CH:55]2[CH2:60][CH2:59][N:58]([C:8]([NH:9][C:19]3[CH:24]=[C:23]([O:25][C:26]4[CH:27]=[CH:28][C:29]([NH:32][C:33]([C:35]5([C:38]([NH:39][C:40]6[CH:41]=[CH:42][C:43]([F:46])=[CH:44][CH:45]=6)=[O:47])[CH2:37][CH2:36]5)=[O:34])=[CH:30][CH:31]=4)[CH:22]=[CH:21][N:20]=3)=[O:7])[CH2:57][CH2:56]2)[CH2:54][CH2:53][CH2:52]1
Reactant: O=C(Oc1ccccc1)N(C(=O)Oc1ccccc1)c1cc(Oc2ccc(NC(=O)C3(C(=O)Nc4ccc(F)cc4)CC3)cc2)ccn1
Reactant: C1CN(C2CCNCC2)C1
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: O=C(Nc1cc(Oc2ccc(NC(=O)C3(C(=O)Nc4ccc(F)cc4)CC3)cc2)ccn1)N1CCC(N2CCC2)CC1
Reaction time: 62 h
Yield: 65 %

Procedure:
[4-(4-{[1-(4-Fluorophenylcarbamoyl)cyclopropanecarbonyl]amino}phenoxy)pyridin-2-yl]-N-(phenoxycarbonyl)carbamic acid phenyl ester (50 mg) was dissolved in N,N-dimethylformamide (1.0 ml), and 4-(azetidin-1-yl)piperidine dihydrochloride (82.9 mg), triethylamine (0.0782 ml) and water (0.100 ml) were added thereto in this order, followed by stirring for 62 hr. The reaction mixture was partitioned between ethyl acetate (50 ml) and a saturated aqueous solution of sodium hydrogencarbonate (20 ml). The separated organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate (20 ml), water (20 ml) and brine (20 ml) in this order, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the resultant residue was purified by silica gel column chromatography (Fuji Silysia NH, eluent; ethyl acetate, then ethyl acetate:methanol=95:5). Fractions containing the target compound were concentrated under reduced pressure, and the resultant residue was suspended in diethyl ether (2 ml) and hexane (4 ml). The solid was collected by filtration and dried under aeration to provide the titled compound as white powder (28.8 mg, 65.1%).
Reaction SMILES: [CH3:1][C:2]([CH3:21])([CH3:20])[C:3]([C:5]1[O:6][C:7]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:8]=2[C:9]=1[CH2:10][C:11]([OH:13])=O)=[O:4].C1C=CC2N(O)N=NC=2C=1.[CH2:32]([C@H:35]1[CH2:39][CH2:38][C@H:37]([CH2:40][CH2:41][CH3:42])[NH:36]1)[CH2:33][CH3:34].CCN(C(C)C)C(C)C>CN(C=O)C.C(Cl)CCl>[CH2:32]([C@H:35]1[CH2:39][CH2:38][C@H:37]([CH2:40][CH2:41][CH3:42])[N:36]1[C:11](=[O:13])[CH2:10][C:9]1[C:8]2[CH:14]=[C:15]([O:18][CH3:19])[CH:16]=[CH:17][C:7]=2[O:6][C:5]=1[C:3](=[O:4])[C:2]([CH3:20])([CH3:1])[CH3:21])[CH2:33][CH3:34]
Reactant: CCC[C@H]1CC[C@H](CCC)N1
Reactant: COc1ccc2oc(C(=O)C(C)(C)C)c(CC(=O)O)c2c1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: CCC[C@H]1CC[C@H](CCC)N1C(=O)Cc1c(C(=O)C(C)(C)C)oc2ccc(OC)cc12
Temperature: 40 °C

Procedure:
Dissolve a mixture of 17 mg [2-(2,2-dimethylpropanoyl)-5-methoxy-1-benzofuran-3-yl]acetic acid from the Step B Example 1 and 18.5 mg HOBt in 1 mL dry DMF. Add 13.7 mg trans-2,5-dipropylpyrrolidine from the Step D above followed by 23.0 mg EDC and 35 μL DIEA. This solution was heated at 40° C. for 2 hours. It was purified directly on RP-HPLC using 70-100% MeCN gradient. The fractions containing pure product were pooled and lyophilized to give the title compound. LC-MS: 4.58 min. (m/Z 428.3, 344.2, 450.3).
Reaction SMILES: C([C:4]1[C:5]([OH:17])=[CH:6][C:7]2C[CH2:9][CH2:10][CH:11]([CH2:14][CH2:15][CH3:16])[C:12]=2[CH:13]=1)(=O)C.[OH-].S(OC)([O:22][CH3:23])(=O)=O>>[CH3:23][O:22][C:16]1[CH:9]=[CH:10][C:11]([C:12]2[CH:13]=[CH:4][C:5]([OH:17])=[CH:6][CH:7]=2)=[CH:14][CH:15]=1
Reactant: CCCC1CCCc2cc(O)c(C(C)=O)cc21
Reactant: COS(=O)(=O)OC
Agent: [OH-]
Product: COc1ccc(-c2ccc(O)cc2)cc1

Procedure:
4,4'-Dihydroxydiphenyl (1) (32 g 0.17 mol) was dissolved in 2M solution hydroxide solution (0.34 mol) and dimethyl sulphate (22 g 0.175 mol) was added slowly with stirring over half an hour. The sodium salt of the required product was filtered off and dried. The yield was 24 g. The sodium salt of the phenol (24 g) was treated with acetyl chloride (150 cm3), filtered and excess acetyl chloride removed. Work up gave 4- methoxy-4'-acetoxydiphenyl (4) (22 g).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH2:8][C@H:9]1[CH2:15][CH2:14][CH2:13][CH2:12][N:11]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2OC)[C:10]1=[O:24].C(NC1C=CC=[C:31]([O:35]C)C=1)C=C>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH2:8][C@H:9]1[CH2:15][CH2:14][CH2:13][CH2:12][N:11]([C:16]2[CH:17]=[CH:18][CH:19]=[C:20]([O:35][CH3:31])[CH:21]=2)[C:10]1=[O:24]
Reactant: C=CCNc1cccc(OC)c1
Reactant: COc1ccccc1N1CCCC[C@H](N)C1=O
Solvent: O=C(O)C(F)(F)F
Product: COc1cccc(N2CCCC[C@H](N)C2=O)c1

Procedure:
(S)-3-Amino-1-(3-methoxyphenyl)azepan-2-one trifluoroacetate (143 mg, 0.411 mmol) was synthesized as described for the preparation of Intermediate 62 using N-allyl-3-methoxyaniline in step A.
Reaction SMILES: [CH3:1][C:2]([CH:4](O)[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[CH2:3].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCCCC>O1CCCC1.C(Cl)(Cl)(Cl)Cl>[CH3:3][C:2]([C:4]#[C:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[CH2:1]
Reactant: C=C(C)C(O)Cc1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: C1CCOC1
Solvent: CCCCC
Product: C=C(C)C#Cc1ccccc1

Procedure:
A solution of 100 mmol of 2-methyl-4-phenylbut-1-en-3-ol (16.02 g) in 90 mL of tetrahydrofuran and 210 mL of carbon tetrachloride was mixed with 300 mmol (78.70 g) of dry triphenylphosphine. The solution was heated to boiling under reflux for 2 hours, whereupon a precipitate formed. After cooling, 400 mL of pentane was added and the precipitate was separated by filtration. The solvent was removed from the filtrate under reduced pressure and the residue was fractionally distilled to give 2-methyl-4-phenylbut-1-en-3-yne havng the formula: ##STR27##
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:26]#N)[C:15]=2[O:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)[C:10]([CH3:28])=[C:9]1[CH3:29])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-:30].[K+].[OH2:32]>C(O)C>[CH2:1]([N:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:26]([OH:32])=[O:30])[C:15]=2[O:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)[C:10]([CH3:28])=[C:9]1[CH3:29])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [OH-]
Reactant: O
Reactant: Cc1c(C)n(Cc2ccccc2)c2c(OCc3ccc(F)cc3)c(C#N)cnc12
Agent: [K+]
Solvent: CCO
Product: Cc1c(C)n(Cc2ccccc2)c2c(OCc3ccc(F)cc3)c(C(=O)O)cnc12

Procedure:
1-Benzyl-7-(4-fluorobenzyloxy)-2,3-dimethyl-1H-pyrrolo[3,2-b]pyridine-6-carbonitrile (500 mg, 1.30 mmol) prepared in Example 276 was diluted with a mixture of ethanol (8 ml) and water (2 ml). Potassium hydroxide (650 mg, 13.0 mmol) was added to the solution, which was then refluxed for 24 hours. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The separated organic layer was dried on anhydrous magnesium sulfate and then concentrated under reduced pressure. The resulting residue was purified with silica gel column chromatography (ethyl acetate/methanol=5/1, (v/v)) to give 280 mg of the titled compound as a white solid.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]2[N:20]([CH3:21])[C:19]3[CH:22]=[CH:23][CH:24]=[CH:25][C:18]=3[N:17]=2)=[CH:11][CH:10]=1)C1C=CC=CC=1.C(O)(=O)C>C1COCC1.CO.[OH-].[OH-].[Pd+2]>[CH3:21][N:20]1[C:19]2[CH:22]=[CH:23][CH:24]=[CH:25][C:18]=2[N:17]=[C:16]1[NH:15][C:12]1[CH:13]=[CH:14][C:9]([OH:8])=[CH:10][CH:11]=1
Reactant: Cn1c(Nc2ccc(OCc3ccccc3)cc2)nc2ccccc21
Agent: [Pd+2]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: CO
Product: Cn1c(Nc2ccc(O)cc2)nc2ccccc21
Reaction time: 3 h

Procedure:
To a solution of compound (4-benzyloxy-phenyl)-(1-methyl-1H-benzoimidazol-2-yl)-amine (1.8 g, 5.4 mmol) in 18 mL of THF and 18 mL of MeOH was added Pd(OH)2 (0.36 g, 20%) and 9 mL of acetic acid. The resulting mixture was kept and kept at 50 psi H2 atmosphere for 3 h. The reaction mixture was then filtered over a cake of Celite™. The filtrate was concentrated and purified by silica gel column chromatography (EtOAc/hexane) to get desired product 4-(1-methyl-1H-benzoimidazol-2-ylamino)-phenol. [M+1]=240
Reaction SMILES: Cl[C:2]1[C:7]([C:8]2[N:13]=[CH:12][N:11]=[C:10]([NH:14][CH3:15])[N:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[F:16][C:17]1[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][C:18]=1[C:19]([OH:21])=[O:20].CS(C)=O>O>[F:16][C:17]1[CH:25]=[CH:24][C:23]([O:26][C:2]2[C:7]([C:8]3[N:9]=[C:10]([NH:14][CH3:15])[N:11]=[CH:12][N:13]=3)=[CH:6][CH:5]=[CH:4][N:3]=2)=[CH:22][C:18]=1[C:19]([OH:21])=[O:20]
Reactant: O=C(O)c1cc(O)ccc1F
Reactant: CNc1ncnc(-c2cccnc2Cl)n1
Solvent: O
Solvent: CS(C)=O
Product: CNc1ncnc(-c2cccnc2Oc2ccc(F)c(C(=O)O)c2)n1
Temperature: 130 °C

Procedure:
To [4-(2-chloro-pyridin-3-yl)-[1,3,5]triazin-2-yl]-methyl-amine (6.90 g, 31.1 mmol), 2-fluoro-5-hydroxybenzoic acid (4.9 g, 31.1 mmol) and Cs2CO2 (20.3 g, 62.2 mmol) was added DMSO (25 mL). The mixture was heated overnight at 130° C. in a sealed tube. The cooled mixture was diluted with water and extracted with EtOAc. The aqueous layer was acidified (pH˜4) with TFA and the resulting solid was filtered, washed with water and dried to yield 2-fluoro-5-[3-(4-methylamino-[1,3,5]triazin-2-yl)-pyridin-2-yloxy]-benzoic acid. MS m/z=342 [M+1]+. Calc'd for C16H12FN5O3: 341.30.
Reaction SMILES: Cl.[CH2:2]([N:5]1[C:10](=[O:11])[C:9]2[CH2:12][NH:13][CH2:14][CH2:15][C:8]=2[NH:7][C:6]1=[O:16])[C:3]#[CH:4].C(N(CC)CC)C.[Cl:24][C:25]1[CH:33]=[CH:32][C:28]([C:29](Cl)=[O:30])=[CH:27][CH:26]=1.O>C(Cl)Cl>[Cl:24][C:25]1[CH:33]=[CH:32][C:28]([C:29]([N:13]2[CH2:14][CH2:15][C:8]3[NH:7][C:6](=[O:16])[N:5]([CH2:2][C:3]#[CH:4])[C:10](=[O:11])[C:9]=3[CH2:12]2)=[O:30])=[CH:27][CH:26]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: C#CCn1c(=O)[nH]c2c(c1=O)CNCC2
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C#CCn1c(=O)[nH]c2c(c1=O)CN(C(=O)c1ccc(Cl)cc1)CC2

Procedure:
3-propargyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-2,4-dione hydrochloride (790 mg) was suspended in methylene chloride, triethylamine (0.95 ml) and 4-chlorobenzoyl chloride (0.42 ml) were added under ice cooling and the resultant mixture was stirred at the same temperature for 30 minutes. To the reaction solution, water was added and the resultant mixture was concentrated. To the residue, diethyl ether was added and insoluble matter was separated by filtration to obtain the titled compound (894 mg) as a white powder. The resultant compound was used in a next reaction without further purifying.
Reaction SMILES: [CH:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8][NH2:9])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[C:12](Cl)(Cl)=[O:13].CCN(C(C)C)C(C)C.[NH2:25][C:26]1[CH:35]=[CH:34][CH:33]=[C:32]2[C:27]=1[CH:28]=[C:29]([CH3:36])[N:30]=[CH:31]2>C1(C)C=CC=CC=1>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:8][NH:9][C:12]([NH:25][C:26]2[CH:35]=[CH:34][CH:33]=[C:32]3[C:27]=2[CH:28]=[C:29]([CH3:36])[N:30]=[CH:31]3)=[O:13])=[CH:10][CH:11]=1)([CH3:3])[CH3:2]
Reactant: Cc1cc2c(N)cccc2cn1
Reactant: CC(C)c1ccc(CN)cc1
Reactant: O=C(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: Cc1cc2c(NC(=O)NCc3ccc(C(C)C)cc3)cccc2cn1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
4-Isopropylbenzylamine (748 mg, 5.02 mmol) in toluene (20 mL) was refluxed with 20% w/v phosgene solution in toluene (3 mL) overnight. The mixture was cooled to room temperature and concentrated in vacuo. The residue was taken up in toluene (20 mL) and was treated with DIEA (4 mL) and 5-amino-3-methylisoquinoline (500 mg, 3.16 mmol). The reaction mixture was stirred was at 80° C. for 6 hours. After cooling to room temperature, a precipitate formed which was collected by filtration and purified by silica gel chromatography (98:2 CH2Cl2:CH3OH) to provide the title compound. The corresponding hydrochloride salt was formed by treatment with methanolic HCl. 1H NMR (300 MHz, DMSO-d6) δ 9.16 (s, 1H), 8.60 (s, 1H), 8.24 (dd, 1H, J=7.5 Hz, 1.0 Hz), 7.74 (s, 1H), 7.68 (d, 1H, J=8.2 Hz), 7.50 (t, 1H, J=8.0 Hz), 7.22-7.30 (m, 4H), 6.99 (t, 1H, 5.6 Hz), 4.32 (d, 2H, J=7.8 Hz), 2.88 (m, 1H), 2.64 (s, 3H), 1.20 (d, 6H, J=6.8 Hz); MS (ESI+) m/z 334 (M+H).