Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:11]=[CH:10][C:9]2[C:4](=[C:5]([OH:13])[CH:6]=[CH:7][C:8]=2[Cl:12])[N:3]=1.IC.[C:16](=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[Cl:1][C:2]1[N:11]=[CH:10][C:9]2[C:4](=[C:5]([O:13][CH3:16])[CH:6]=[CH:7][C:8]=2[Cl:12])[N:3]=1
Reactant: Oc1ccc(Cl)c2cnc(Cl)nc12
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CI
Product: COc1ccc(Cl)c2cnc(Cl)nc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2,5-dichloroquinazolin-8-ol (1 eq) (See example 32 for synthesis) in DMF was added iodomethane (3 eq) and potassium carbonate (3 eq). The reaction mixture was stirred at room temperature for overnight. Diluted with ethyl acetate and washed with water and brine and dried over sodium sulfate. Filtered, evaporated and dried to provide product as a yellow solid in quantitative yield. ES/MS m/z 229.0 (MH+). Proceed for next step.
Reaction SMILES: C([N:8]1[CH:12]=[C:11]([CH2:13][CH2:14][C:15]([OH:17])=[O:16])[N:10]=[N:9]1)C1C=CC=CC=1.[H][H]>CO.[Pd]>[NH:8]1[CH:12]=[C:11]([CH2:13][CH2:14][C:15]([OH:17])=[O:16])[N:10]=[N:9]1
Reactant: O=C(O)CCc1cn(Cc2ccccc2)nn1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: O=C(O)CCc1c[nH]nn1
Temperature: 60 °C
Reaction time: 16 h
Yield: 66.6 %

Procedure:
39 mg of palladium-on-charcoal at 10% are added to a solution containing 390 mg (1.7 mmol) of 3-(1-benzyl-1H[1,2,3]triazol-4-yl)propanoic acid in 3 ml of methanol. The reaction mixture is placed under 10 bar of hydrogen pressure and stirred at 60° C. for 16 hours. After filtration through celite, the solvents are evaporated off and the residue is purified by silica gel chromatography (eluent 95/5 dichloro-methane/methanol). 159.8 mg of 3-(1H[1,2,3]triazol-4-yl)propanoic acid are obtained in the form of a white powder with a yield of 67%.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]([OH:13])=O)=[CH:5][CH:4]=1)#[N:2].CN1CCOCC1.ClC(OCC(C)C)=O.[F:29][C:30]([F:45])([F:44])[C:31]([NH:33][C:34]1[CH:35]=[C:36]2[C:41](=[CH:42][CH:43]=1)[NH:40][CH2:39][CH2:38][CH2:37]2)=[O:32]>O1CCCC1.C(OCC)(=O)C>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([CH2:9][CH2:10][C:11]([N:40]2[C:41]3[C:36](=[CH:35][C:34]([NH:33][C:31](=[O:32])[C:30]([F:44])([F:45])[F:29])=[CH:43][CH:42]=3)[CH2:37][CH2:38][CH2:39]2)=[O:13])=[CH:7][CH:8]=1)#[N:2]
Reactant: O=C(Nc1ccc2c(c1)CCCN2)C(F)(F)F
Reactant: N#Cc1ccc(CCC(=O)O)cc1
Agent: CC(C)COC(=O)Cl
Solvent: CCOC(C)=O
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: N#Cc1ccc(CCC(=O)N2CCCc3cc(NC(=O)C(F)(F)F)ccc32)cc1
Temperature: -20 °C

Procedure:
10 g (0.057 mol) of 3-(4-cyano-phenyl)propionic acid and 6.6 g (0.065 mol) of N-methyl-morpholine are dissolved in 250 ml tetrahydrofuran and cooled to −20° C. Then 8.2 g (0.06 mol) of isobutyl chloroformate are added dropwise. 13.9 g (0.057 mol) of 6-(trifluoroacetylamino)-1,2,3,4-tetrahydro-quinoline in 200 ml tetrahydrofuran are then added and the solution is left to heat up to ambient temperature overnight. It is then diluted with 200 ml of ethyl acetate and washed with 2×80 ml of 0.5 N hydrochloric acid and then 100 ml of sodium hydrogen carbonate solution. The organic phase is dried over sodium sulphate and concentrated by evaporation in vacuo.
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[C:11]([CH3:16])[CH:10]=2)=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:17][C:18]([O:20]CC)=[O:19].[OH-].[Na+]>O>[NH2:1][C:2]1[C:7]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[C:11]([CH3:16])[CH:10]=2)=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:17][C:18]([OH:20])=[O:19]
Reactant: CCOC(=O)Cc1cccc(Oc2ccc(C)c(C)c2)c1N
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1ccc(Oc2cccc(CC(=O)O)c2N)cc1C
Yield: 72.4 %

Procedure:
A mixture of ethyl 2-[2-amino-3-(3,4-dimethylphenoxy)phenyl]acetate (3.2 g.), sodium hydroxide (0.9 g.) and water (50 ml.) was treated in a similar manner to that of Example 5-(2). The resultant residue was crystallized with a mixture of benzene and n-hexane to give 2-[2-amino-3-(3,4-dimethylphenoxy)phenyl]acetic acid (2.1 g.). mp 90° to 92° C.
Reaction SMILES: [C:1]([C@H:4]1[C@H:8]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([O:17][CH:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)[CH:10]=2)[CH2:7][N:6]([C:23]([O:25][CH3:26])=[O:24])[CH2:5]1)(O)=[O:2].C(N1C=CN=C1)([N:29]1C=CN=C1)=O>C(Cl)Cl>[NH2:29][C:1]([C@H:4]1[C@H:8]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([O:17][CH:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)[CH:10]=2)[CH2:7][N:6]([C:23]([O:25][CH3:26])=[O:24])[CH2:5]1)=[O:2]
Reactant: COC(=O)N1C[C@@H](C(=O)O)[C@H](c2ccc(OC)c(OC3CCCC3)c2)C1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: COC(=O)N1C[C@@H](C(N)=O)[C@H](c2ccc(OC)c(OC3CCCC3)c2)C1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 74 %

Procedure:
To a solution of trans-3-carboxy-4-(3-cyclopentoxy-4-methoxyphenyl)-1-(methoxycarbonyl)pyrrolidine (1.5 g, 4.1 mmol) in 11 mL of CH2Cl2 at 0° C. was added 1,1'-carbonyldiimidazole (736 mg, 4.5 mmol) in portions. The cooling bath was removed, and the solution was stirred at room temperature for 20 min. Ammonia gas was passed over the stirring solution for 4 min, and stirring was continued an additional 15 min. The solution was diluted with CH2Cl2 and poured into 1M H3PO4. The aqueous layer was extracted with CH2Cl2 (2×), and the combined organic layers were washed with brine, dried (MgSO4), filtered, and concentrated under reduced pressure to a pale yellow foam. Silica gel chromatography (8:1:1, CH2Cl2 :ethyl acetate:methanol) provided trans-3-aminocarbonyl-4-(3-cyclopentoxy-4-methoxyphenyl)-I-(methoxycarbonyl)pyrrolidine as a white solid (1.1 g, 76%), m.p. 130°-32° C. Anal. Calcd for C19H26N2O5 : C, 62.97; H, 7.23; N, 7.73. Found: C, 63.03; H, 7.28; N, 7.65.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][C:7]2[C:10]([CH2:14][CH2:15]Cl)=[C:11]([CH3:13])[S:12][C:6]=2[CH2:5]1)(=[O:3])[CH3:2].[Cl:17][C:18]1[CH:32]=[CH:31][C:21]2[N:22]=[C:23]([N:25]3[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]3)[S:24][C:20]=2[CH:19]=1.C([O-])(=O)C([O-])=O>>[C:1]([N:4]1[CH2:9][CH2:8][C:7]2[C:10]([CH2:14][CH2:15][N:28]3[CH2:29][CH2:30][N:25]([C:23]4[S:24][C:20]5[CH:19]=[C:18]([Cl:17])[CH:32]=[CH:31][C:21]=5[N:22]=4)[CH2:26][CH2:27]3)=[C:11]([CH3:13])[S:12][C:6]=2[CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCc2c(sc(C)c2CCCl)C1
Reactant: Clc1ccc2nc(N3CCNCC3)sc2c1
Agent: O=C([O-])C(=O)[O-]
Product: CC(=O)N1CCc2c(sc(C)c2CCN2CCN(c3nc4ccc(Cl)cc4s3)CC2)C1
Yield: 10.9 %

Procedure:
The reaction and procedure were conducted in a similar manner as in Example 24 using 0.2 g of 6-acetyl-3-(2-chloroethyl)-4,5,6,7-tetrahydro-2-methylthieno[2,3-c]pyridine and 0.2 g of 1-(6-chlorobenzothiazol-2-yl)piperazine to give 0.04 g of 6-acetyl-3-(2-(4-(6-chlorobenzothiazol-2-yl)piperazin-1-yl)ethyl)-4,5,6,7-tetrahydro-2-methylthieno[2,3-c]pyridine as an oil, m.p. 180° C. (decomposition) as an oxalate thereof.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[N:12][C:13]([NH2:17])=[N:14][CH:15]=3)[N:10]([CH3:18])[N:9]=2)=[CH:4][C:3]=1[F:19].C(=O)=O.CC(C)=O.[CH3:27][S:28](Cl)(=[O:30])=[O:29]>N1C=CC=CC=1.CCOC(C)=O>[NH2:17][C:13]1[N:12]=[C:11]2[N:10]([CH3:18])[N:9]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([NH:1][S:28]([CH3:27])(=[O:30])=[O:29])=[C:3]([F:19])[CH:4]=3)[C:16]2=[CH:15][N:14]=1
Reactant: Cn1nc(-c2ccc(N)c(F)c2)c2cnc(N)nc21
Reactant: CS(=O)(=O)Cl
Agent: O=C=O
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Solvent: c1ccncc1
Product: Cn1nc(-c2ccc(NS(C)(=O)=O)c(F)c2)c2cnc(N)nc21
Temperature: -10 °C
Reaction time: 0.5 h

Procedure:
3-(4-Amino-3-fluoro-phenyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-ylamine (Example 58) (0.13 g, 0.50 mmol) is dissolved in pyridine (1.5 ml) under an inert atmosphere of argon. The reaction mixture is cooled to −10° C. (dry ice/acetone bath) then methanesulfonyl chloride (0.078 ml, 0.75 mmol) is added drop wise over a period of 15 minutes. The reaction mixture is stirred at −10° C. for 30 minutes then allowed to warm to room temperature and stirred for further 3 hours. The reaction mixture is diluted with EtOAc (100 ml) and washed with water (3×40 ml) and brine (10 ml). The organic portion is dried over MgSO4, filtered and concentrated in vacuo. The resulting solid is triturated with hot EtOAc (plus few drops of MeOH), filtered and dried under vacuum at 50° C. for 3 hours to afford the title compound as an off-white solid.
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][CH2:5][CH2:4][C@@H:3]1[NH:7][C:8]1[C:13]([C:14]([O:16]CC)=[O:15])=[CH:12][N:11]=[C:10]([S:19][CH3:20])[N:9]=1.[OH-].[Na+]>C(O)C>[OH:1][C@H:2]1[CH2:6][CH2:5][CH2:4][C@@H:3]1[NH:7][C:8]1[C:13]([C:14]([OH:16])=[O:15])=[CH:12][N:11]=[C:10]([S:19][CH3:20])[N:9]=1
Reactant: CCOC(=O)c1cnc(SC)nc1N[C@H]1CCC[C@@H]1O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CSc1ncc(C(=O)O)c(N[C@H]2CCC[C@@H]2O)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.7 %

Procedure:
To a solution of ethyl 4-((1S,2S)-2-hydroxycyclopentylamino)-2-(methylthio)pyrimidine-5-carboxylate (1.3 g, 4.37 mmol) in ethanol (15 mL) was added aqueous sodium hydroxide solution (15 mL, 2 N), and the mixture was stirred for 1 h at room temperature. When the starting material was consumed, the reaction mixture was neutralized with saturated aqueous citric acid solution. The solids were collected by filtration and dried to give 4-((1S,2S)-2-hydroxycyclopentylamino)-2-(methylthio)pyrimidine-5-carboxylic acid (1.0 g, 3.7 mmol, yield 85%) as a white solid. MS (ESI): m/z 270.6 [M+1]+.
Reaction SMILES: O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[CH:24]1([C:27]([C:29]2[CH:53]=[CH:52][C:32]([O:33][C@@H:34]([C:37]3[O:41][N:40]=[C:39]([C:42]4[CH:50]=[CH:49][C:45]([C:46](O)=[O:47])=[C:44]([F:51])[CH:43]=4)[N:38]=3)[CH2:35][CH3:36])=[CH:31][CH:30]=2)=[O:28])[CH2:26][CH2:25]1.[NH2:54][C@H:55]1[C@H:59]([OH:60])[CH2:58][O:57][C:56]1=[O:61]>C(OCC)(=O)C.O.CN(C)C=O>[CH:24]1([C:27]([C:29]2[CH:30]=[CH:31][C:32]([O:33][C@@H:34]([C:37]3[O:41][N:40]=[C:39]([C:42]4[CH:50]=[CH:49][C:45]([C:46]([NH:54][C@H:55]5[C@H:59]([OH:60])[CH2:58][O:57][C:56]5=[O:61])=[O:47])=[C:44]([F:51])[CH:43]=4)[N:38]=3)[CH2:35][CH3:36])=[CH:52][CH:53]=2)=[O:28])[CH2:25][CH2:26]1
Reactant: N[C@@H]1C(=O)OC[C@H]1O
Reactant: CC[C@@H](Oc1ccc(C(=O)C2CC2)cc1)c1nc(-c2ccc(C(=O)O)c(F)c2)no1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC[C@@H](Oc1ccc(C(=O)C2CC2)cc1)c1nc(-c2ccc(C(=O)N[C@@H]3C(=O)OC[C@H]3O)c(F)c2)no1
Reaction time: 0.5 h
Yield: 38 %

Procedure:
1-Hydroxybenzotriazole monohydrate (46.1 mg, 0.301 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (57.7 mg, 0.301 mmol) were added to an N,N-dimethylformamide (0.5 mL) solution of the 4-(5-{(1R)-1-[4-(cyclopropylcarbonyl)phenoxy]propyl}-1,2,4-oxadiazol-3-yl)-2-fluorobenzoic acid synthesized in Reference Example 8 (103 mg, 0.252 mmol) at room temperature, and the mixture was stirred at the same temperature for 30 minutes. Subsequently, an N,N-dimethylformamide (1.0 mL) solution of the (3S,4S)-3-amino-4-hydroxydihydrofuran-2-(3H)-one synthesized in Reference Example 13 (44.2 mg) was added, and the mixture was further stirred at the same temperature for 30 minutes. Water was added to the reaction mixture, and the mixture was subjected to extraction twice with ethyl acetate. The organic layer thus obtained was washed with a saturated aqueous solution of sodium hydrogen carbonate and brine, and then was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=70:30→30:70, v/v) to give the title compound (48.5 mg, yield: 38%).
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[C:14]([F:16])[C:13]([F:17])=[CH:12][C:3]=1[C:4]([CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5].[CH:18]([O-])([O-])[O:19][CH2:20][CH3:21]>C(OC(=O)C)(=O)C>[Cl:1][C:2]1[CH:15]=[C:14]([F:16])[C:13]([F:17])=[CH:12][C:3]=1[C:4]([C:6](=[CH:18][O:19][CH2:20][CH3:21])[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5]
Reactant: CCOC([O-])[O-]
Reactant: CCOC(=O)CC(=O)c1cc(F)c(F)cc1Cl
Solvent: CC(=O)OC(C)=O
Product: CCOC=C(C(=O)OCC)C(=O)c1cc(F)c(F)cc1Cl
Yield: 98.7 %

Procedure:
Into a 200 cc glass reactor equipped with a stirrer, 26.3 g of ethyl 2-chloro-4,5-difluorobenzoylacetate, 23.7 g of ethyl ortho-formate and 40 ml of acetic anhydride were charged, and reacted at a reaction temperature of from 120° to 135° C. After completion of the reaction, the reaction mixture was concentrated by distillation under reduced pressure to obtain 31.5 g of the desired compound as the residue.
Reaction SMILES: [C:1]([C:3]1([CH3:17])[CH2:8][CH2:7][C:6]2[C:9]([CH3:16])=[C:10]([OH:15])[C:11]([CH3:14])=[C:12]([CH3:13])[C:5]=2[O:4]1)#[CH:2].I[C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=2)=[CH:21][CH:20]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C>C(#N)C>[CH3:17][C:3]1([C:1]#[C:2][C:19]2[CH:20]=[CH:21][C:22]([C:25]3[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=3)=[CH:23][CH:24]=2)[CH2:8][CH2:7][C:6]2[C:9]([CH3:16])=[C:10]([OH:15])[C:11]([CH3:14])=[C:12]([CH3:13])[C:5]=2[O:4]1
Reactant: Ic1ccc(-c2cccnc2)cc1
Reactant: C#CC1(C)CCc2c(C)c(O)c(C)c(C)c2O1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1c(C)c2c(c(C)c1O)CCC(C)(C#Cc1ccc(-c3cccnc3)cc1)O2
Reaction time: 3 h

Procedure:
A mixture of 1.15 g of rac-3,4-dihydro-2-ethynyl-2,5,7,8-tetramethyl-2H-1-benzopyran-6-ol, 1.14 g (4 mmol) of 3-(4-iodophenyl)pyridine, 0.2 g of triphenylphosphine, 50 mg of cuprous iodide, 1.5 ml of triethylamine and 20 ml of acetonitrile was degassed with argon for 10 minutes. Palladium acetate, 75 mg, was then added and stirring was continued for 3 hours. The reaction mixture was partitioned between methylene chloride and water. The organic layer was dried and evaporated. The residue was crystallized from ethyl acetate and recrystallized from methanol/ethyl acetate to give colorless crystals with m.p. 190°-192° C.
Reaction SMILES: [OH:1][CH:2]1[CH2:6][N:5]([CH2:7][C:8]([O-])=[O:9])[C:4](=[O:11])[CH2:3]1.[NH3:12]>>[OH:1][CH:2]1[CH2:6][N:5]([CH2:7][C:8]([NH2:12])=[O:9])[C:4](=[O:11])[CH2:3]1
Reactant: O=C([O-])CN1CC(O)CC1=O
Reactant: N
Product: NC(=O)CN1CC(O)CC1=O

Procedure:
reacting the 4-hydroxy-2-oxopyrrolidin-1-yl-acetate with ammonia to provide a 4-hydroxy-2-oxopyrrolidin-1-yl-acetamide.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([CH2:13][OH:14])[CH2:10][C:11]#[N:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:15][C:16]1[CH:17]=[CH:18][C:19]2[O:23][N:22]=[C:21](O)[C:20]=2[CH:25]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[C:1]([O:5][C:6]([NH:8][CH:9]([CH2:10][C:11]#[N:12])[CH2:13][O:14][C:21]1[C:20]2[CH:25]=[C:16]([Cl:15])[CH:17]=[CH:18][C:19]=2[O:23][N:22]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Oc1noc2ccc(Cl)cc12
Reactant: CC(C)(C)OC(=O)NC(CO)CC#N
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC(CC#N)COc1noc2ccc(Cl)cc12
Yield: 73.4 %

Procedure:
To a solution of 1.0 g of 3-tert-butoxycarbonylamino-4-hydroxybutyronitrile in 15 ml of tetrahydrofuran are added 0.85 g of 5-chloro-3-hydroxy-1,2-benzoisoxazole, 1.71 g of triphenylphosphine and 1.14 g of diethyl azodicarboxylate with ice-cooling, and they are subjected to reaction at room temperature for 24 hours. Thereafter, the solvent is removed by distillation under reduced pressure. The residue obtained is purified by a column chromatography [eluant:n-hexane:ethyl acetate=5:1], to obtain 1.29 g of 3-(2-tert-butoxycarbonylamino-3-cyanopropoxy)-5-chloro-1,2-benzoisoxazole having a melting point of 147.2°-147.9° C.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][CH:3]=1.CCN=C=NCCCN(C)C.Cl.Cl.C1C=CC2N(O)N=NC=2C=1.CCN(CC)CC.[C:41]([N:48]1[CH2:53][CH2:52][NH:51][CH2:50][CH2:49]1)([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42].[OH-].[Na+]>CN(C=O)C.CCOC(C)=O>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([N:51]2[CH2:50][CH2:49][N:48]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:53][CH2:52]2)=[O:8])=[CH:9][CH:10]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Nc1ccc(C(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCN(C(=O)c2ccc(N)cc2)CC1
Temperature: 25 °C
Reaction time: 21 h

Procedure:
To a solution of 4-aminobenzoic acid (0.411 g, 3.00 mmol) in DMF (5.0 mL) at room temperature was added EDCl.HCl (0.862 g, 4.50 mmol), HOBt (0.608 g, 4.50 mmol), Et3N (0.835 mL, 6.00 mmol) and N-Boc piperazine (0.671 g, 3.60 mmol). The resulting mixture was stirred at room temperature for 21 hours then 2 M aqueous NaOH was added to adjust the pH to >10. EtOAc was added then the layers separated and the organic layer dried over MgSO4. The volatiles were removed under reduced pressure and the residue was purified by silica gel chromatography (Biotage Isolera, 40 g SiO2 cartridge, 50-90% EtOAc in petroleum benzine 40-60° C.) to give the title compound A21 as a white solid (0.530 g, 56%); LCMS-A: rt 5.079 min; m/z 250.1 [(M-t-Bu)+H]+, 206.1 [(M-Boc)+H]+.
Reaction SMILES: [O:1]1[CH2:20][CH:2]1[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[NH:12][CH:13]=[C:14]([C:16]([F:19])([F:18])[F:17])[N:15]=2)=[CH:7][CH:6]=1>C(N)(C)C>[CH:14]([NH:15][CH2:20][CH:2]([OH:1])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[NH:12][CH:13]=[C:14]([C:16]([F:19])([F:18])[F:17])[N:15]=2)=[CH:7][CH:6]=1)([CH3:16])[CH3:13]
Reactant: FC(F)(F)c1c[nH]c(-c2ccc(OCC3CO3)cc2)n1
Solvent: CC(C)N
Product: CC(C)NCC(O)COc1ccc(-c2nc(C(F)(F)F)c[nH]2)cc1
Reaction time: 16 h

Procedure:
A solution of 2-[4-(2.3-epoxypropoxy)phenyl]-4-trifluoromethylimidazole (1 g) in isopropylamine (10 ml.) is heated 7 hours at reflux and then allowed to stand 16 hours at room temperature. The excess isopropylamine is removed by distillation at atmospheric pressure and the residue is triturated with nitromethane to yield a solid. After filtration and recrystallization from acetonitrile, 0.6 g. of 2-[4-(3-isopropylamino-2-hydroxypropoxy)phenyl]-4-trifluoromethylimidazole is obtained, m.p. 173°-173.5° C.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([C:6]([N:12]([CH3:14])[CH3:13])=[N:7][N:8]2[CH3:11])=[CH:4][CH:3]=1.C(Cl)Cl.CC(O)=O.CC([O-])=O.[K+].Br[C:28]1[S:29][C:30]2[C:36]([C:37]3[CH:42]=[CH:41][C:40]([Cl:43])=[CH:39][CH:38]=3)=[C:35]([C@H:44]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])[C:45]([O:47]CC)=[O:46])[C:34]([CH3:55])=[CH:33][C:31]=2[N:32]=1.C([O-])([O-])=O.[K+].[K+].[OH-].[Na+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].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.CCO.O1CCOCC1>[C:51]([O:50][C@@H:44]([C:35]1[C:34]([CH3:55])=[CH:33][C:31]2[N:32]=[C:28]([C:2]3[CH:10]=[C:9]4[C:5]([C:6]([N:12]([CH3:14])[CH3:13])=[N:7][N:8]4[CH3:11])=[CH:4][CH:3]=3)[S:29][C:30]=2[C:36]=1[C:37]1[CH:38]=[CH:39][C:40]([Cl:43])=[CH:41][CH:42]=1)[C:45]([OH:47])=[O:46])([CH3:54])([CH3:52])[CH3:53]
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(Br)sc2c1-c1ccc(Cl)cc1
Reactant: CN(C)c1nn(C)c2cc(Br)ccc12
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CC(=O)O
Solvent: C1COCCO1
Solvent: CCO
Product: Cc1cc2nc(-c3ccc4c(N(C)C)nn(C)c4c3)sc2c(-c2ccc(Cl)cc2)c1[C@H](OC(C)(C)C)C(=O)O
Temperature: 100 °C

Procedure:
A vial was charged with 6-bromo-N,N,1-trimethyl-1H-indazol-3-amine (102 mg, 0.402 mmol), bis-pinacolatodiboron (112 mg, 0.442 mmol), PdCl2(dppf).DCM (33 mg, 40 μmol), glacial AcOH (25 μL, 0.44 mmol), KOAc (130 mg, 1.33 mmol), and dioxane (2.0 mL). The reaction was heated to 100° C. for 30 min. To this reaction was added (S)-ethyl 2-(2-bromo-7-(4-chlorophenyl)-5-methylbenzo[d]thiazol-6-yl)-2-tert-butoxyacetate (150 mg, 0.302 mmol), 2 M aq K2CO3 (884 μL), and Pd(PPh3)4 (46 mg, 40 mop. The reaction was heated for another 1 h at 100° C. Finally, EtOH (absolute, 1.7 mL) and 2 M aqueous NaOH (884 μL) were added. The reaction was heated to 100° C. for another 1 h. The reaction was cooled to 23° C., and filtered (0.45 micron teflon syringe filter). The filtrate was purified by reverse phase HPLC, eluting by 5-100% acetonitrile in H2O with 0.1% TFA to give the desired product. LCMS-ESI+: calc'd for C30H31ClN4O3S: 563.2, 565.2 (M+H+); Found: 563.2, 565.2 (M+H+). 1H NMR (400 MHz, CD3OD): δ 8.01 (s, 1H), 7.93 (d, J=8.6 Hz, 1H), 7.84 (s, 1H), 7.69 (dd, J=6.3, 3.2 Hz, 1H), 7.65 (dd, J=8.6, 1.2 Hz, 1H), 7.62-7.56 (m, 3H), 5.26 (s, 1H), 3.90 (s, 3H), 3.12 (s, 6H), 2.61 (d, J=4.8 Hz, 3H), 0.98 (d, J=4.1 Hz, 9H).
Reaction SMILES: Cl[C:2]1[C:7]2[N:8]=[C:9]([CH3:22])[N:10]([C:11]3[CH:16]=[CH:15][C:14]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:13][N:12]=3)[C:6]=2[CH:5]=[CH:4][N:3]=1.[O-2].[Mg+2]>C(O)C.[Pd]>[CH2:20]([O:19][C:17]([C:14]1[CH:15]=[CH:16][C:11]([N:10]2[C:6]3[CH:5]=[CH:4][N:3]=[CH:2][C:7]=3[N:8]=[C:9]2[CH3:22])=[N:12][CH:13]=1)=[O:18])[CH3:21]
Reactant: CCOC(=O)c1ccc(-n2c(C)nc3c(Cl)nccc32)nc1
Agent: [Pd]
Agent: [Mg+2]
Agent: [O-2]
Solvent: CCO
Product: CCOC(=O)c1ccc(-n2c(C)nc3cnccc32)nc1
Reaction time: 30 h
Yield: 96 %

Procedure:
A solution of 4-chloro-1-(5-ethoxycarbonylpyrid-2-yl)-2-methylimidazo[4,5-c]pyridine in ethanol (100 ml) was hydrogenated over 30% palladium on carbon (3 g) and magnesium oxide (0.8 g) at 50 p.s.i. (345 kPa) for 30 hours. The mixture was filtered through Arbocel filter aid and the filter cake washed with boiling ethanol (6×50 ml). The filtrate was concentrated under reduced pressure yielding the title compound as a white foam, (2.75 g, 96%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH:12]2[CH2:20][C:19]3[C:14](=[CH:15][CH:16]=[C:17]([C:21]([C:30]4[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=4)=[CH:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]([OH:29])=[O:28])[CH:18]=3)[CH2:13]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1>[Pt]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH:12]2[CH2:20][C:19]3[C:14](=[CH:15][CH:16]=[C:17]([CH:21]([C:30]4[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=4)[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]([OH:29])=[O:28])[CH:18]=3)[CH2:13]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=C(O)CCCCC=C(c1cccnc1)c1ccc2c(c1)CC(NS(=O)(=O)c1ccc(Cl)cc1)C2
Agent: [Pt]
Product: O=C(O)CCCCCC(c1cccnc1)c1ccc2c(c1)CC(NS(=O)(=O)c1ccc(Cl)cc1)C2

Procedure:
Prepared analogously to Example 19 by reduction of 7-(2-(4-chlorobenzenesulphonylamino)indan-5-yl)-7-(3-pyridyl)hept-6-enoic acid with platinum/charcoal.