Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[C:5]([S-:6])=[CH:4][N:3]=[N:2]1.[Na+].Cl[CH2:9][C:10]#[N:11]>ClCCl.CN(C)C=O>[S:1]1[C:5]([S:6][CH2:9][C:10]#[N:11])=[CH:4][N:3]=[N:2]1
Reactant: [S-]c1cnns1
Reactant: N#CCCl
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: N#CCSc1cnns1
Reaction time: 8 h

Procedure:
To a stirred solution of sodium 1,2,3-thiadiazol-5-thiolate (15 g) in dichloromethane (150 ml) and dimethylformamide (20 ml) was added chloroacetonitrile (4.76 ml) at room temperature. After stirring overnight, the precipitate was filtered off and the filtrate was poured into the mixture of water (30 ml) and dichloromethane (300 ml). The organic layer was separated, washed with brine and dried over magnesium sulfate. Evaporation of the solvent gave a residue, which was chromatographed on silica gel (450 ml) eluting with ethyl acetate to give (1,2,3-thiadiazol-5-yl)thioacetonitrile (10 g).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[Br:5][C:6]1[C:7]([OH:13])=[N:8][C:9]([CH3:12])=[CH:10][CH:11]=1>>[Br:5][C:6]1[C:7]([OH:13])=[N:8][C:9]([CH3:12])=[C:10]([N+:1]([O-:4])=[O:2])[CH:11]=1
Reactant: Cc1ccc(Br)c(O)n1
Reactant: O=[N+]([O-])O
Product: Cc1nc(O)c(Br)cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 3.5 h

Procedure:
In a 500 ml single-necked round-bottomed flask, 230 ml of a 65% ageous HNO3 solution is added and stirred under cooling (ice/water cooling bath). 7.00 g of 3-bromo-6-methyl-pyridin-2-ol 2 at ambient temperature is introduced portion-wise. Stirring is continued for 3.5 hours at ambient temperature. After pouring the mixture into 200 ml of an ice/water mixture (pH 1), the water phase is extracted with AcOEt. The organic phase is washed twice with water brought to pH 4 by adding ageous NaOH solution (pH meter), then dried over sodium sulfate, filtered and concentrated in vacuo to give 7.52 g of a yellow solid. This crude material is suspended in diethyl ether and stirred for 1 hour at ambient temperature, filtered, washed with the same solvent and dried to give 3.89 g of the compound as a yellow-orange solid (m.p. >220° C.).
Reaction SMILES: [BH4-].[Na+].[C:3]([O:7][C:8]([N:10]1[CH:14]2[CH:15]=[CH:16][CH:11]1[C:12]([S:17]([C:20]1[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=1)(=[O:19])=[O:18])=[CH:13]2)=[O:9])([CH3:6])([CH3:5])[CH3:4].Cl>C(O)C.C1COCC1.O.O.O.O.C([O-])(=O)C.[Ni+2].C([O-])(=O)C>[C:3]([O:7][C:8]([N:10]1[CH:14]2[CH2:15][CH2:16][CH:11]1[C:12]([S:17]([C:20]1[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=1)(=[O:18])=[O:19])=[CH:13]2)=[O:9])([CH3:6])([CH3:5])[CH3:4]
Reactant: Cc1ccc(S(=O)(=O)C2=CC3C=CC2N3C(=O)OC(C)(C)C)cc1
Agent: [Ni+2]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Solvent: CCO
Product: Cc1ccc(S(=O)(=O)C2=CC3CCC2N3C(=O)OC(C)(C)C)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 72.8 %

Procedure:
To a stirred solution of nickel (II) acetate tetrahydrate (161 g, 647 mmol) in ethanol (400 mL) was added dropwise a solution of sodium borohydride (24.6 g, 1.54 mol) in ethanol (500 mL). This mixture was cooled to 0° C. and a solution of 7-tert-Butoxycarbonyl-2-p-tolylsulfonyl-7-azabicyclo[2.2.1]-hepta-2,5-diene (44.49 g, 128 mmol) in THF (300 mL) was added. Concentrated HCl (100 mL) was next added and the mixture allowed to stir overnight. After quenching the reaction with sodium bicarbonate, the mixture was filtered over a celite pad and extracted several times with ethyl acetate. The combined organic layers were dried with sodium sulfate, concentrated, then purified by flash chromatography with 4:1 hexane:ethyl acetate to give 7-tert-Butoxycarbonyl-2-p-tolylsulfonyl-7-azabicyclo[2.2.1]-hepta-2-ene (32.57 g, 73%) as a colorless solid.
Reaction SMILES: [N:1]([C:4]1[NH:5][C:6]([C:10]([OH:12])=O)=[C:7]([Cl:9])[N:8]=1)=[N+:2]=[N-:3].[NH2:13][CH2:14][C:15]1[C:16]([F:32])=[C:17]([O:22][C:23]2[CH:24]=[C:25]([CH:28]=[C:29]([Cl:31])[CH:30]=2)[C:26]#[N:27])[C:18]([Cl:21])=[CH:19][CH:20]=1.ON1C2C=CC=CC=2N=N1.C([O-])(O)=O.[Na+]>>[N:1]([C:4]1[NH:5][C:6]([C:10]([NH:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([O:22][C:23]3[CH:24]=[C:25]([C:26]#[N:27])[CH:28]=[C:29]([Cl:31])[CH:30]=3)[C:16]=2[F:32])=[O:12])=[C:7]([Cl:9])[N:8]=1)=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=Nc1nc(Cl)c(C(=O)O)[nH]1
Reactant: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc(CN)c2F)c1
Agent: O=C([O-])O
Agent: On1nnc2ccccc21
Agent: [Na+]
Product: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc(CNC(=O)c3[nH]c(N=[N+]=[N-])nc3Cl)c2F)c1

Procedure:
A solution of 2-azido-4-chloro-1H-imidazole-5-carboxylic acid (0.26 g, 1.4 mmol), 3-{[3-(aminomethyl)-6-chloro-2-fluorophenyl]oxy}-5-chlorobenzonitrile (0.44 g, 1.40 mmol), 1-Ethyl-3-(3-dimethyllaminopropyl)carbodiimide hydrochloride (0.32 g, 1.68 mmol) and N-hydroxybenzotriazole (0.28 g, 1.82 mmol) was stirred at RT overnight. NaHCO3 was added and the solution was extracted with 9:1 CH2Cl2:MeOH. The combined organic phase was dried (Na2SO4), filtered, and concentrated to give 2-azido-4-chloro-N-({4-chloro-3-[(3-chloro-5-cyanophenyl)oxy]-2-fluorophenyl}methyl)-1H-imidazole-5-carboxamide which was used without further purification after extraction. A solution of the above crude azide and catalytic Pd/CaCO3 (poisoned with lead) in EtOAc (20 mL) was then stirred under 50 psi hydrogen gas for 2 h. The solution was filtered through celite, evaporated and purified by silica gel chromatography (0-10% MeOH/CH2Cl2) to afford the title compound as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 10.95 (s, 1H), 7.82 (s, 1H), 7.77 (t, J=5.86 Hz, 1H), 7.48-7.54 (m, 2H), 7.46 (t, J=2.01 Hz, 1H), 7.34 (t, J=7.97 Hz, 1H), 5.82 (s, 2H), 4.49 (d, J=5.77 Hz, 2H). ES-LCMS: m/z 454.0, 456.0, 458.0 (M+1).
Reaction SMILES: C[O:2][C:3]([C@@H:5]1[C@H:9]([CH2:10][CH2:11][NH:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:8][CH2:7][N:6]1[C@H:21]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH3:22])=O.OC1C=CC=CN=1>C1COCC1.CCOCC>[CH2:13]([N:12]1[CH2:11][CH2:10][C@@H:9]2[CH2:8][CH2:7][N:6]([C@H:21]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH3:22])[C@@H:5]2[C:3]1=[O:2])[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: COC(=O)[C@@H]1[C@H](CCNCCc2ccccc2)CCN1[C@@H](C)c1ccccc1
Agent: Oc1ccccn1
Solvent: CCOCC
Solvent: C1CCOC1
Product: C[C@@H](c1ccccc1)N1CC[C@H]2CCN(CCc3ccccc3)C(=O)[C@H]21

Procedure:
A solution of (2S,3R)-3-(2-Phenethylamino-ethyl)-1-((S)-1-phenyl-ethyl)-pyrrolidine-2 carboxylic acid methyl ester (400 mg, 1.05 mmol) and 2-hydroxyl pyridine (100 mg, 1.05 mmol) in THF (10 mL) is stirred at 40° C. for 24 hrs. The reaction is diluted with 50 mL of ether and washed with 2×120 mL of water. After dried and concentrated to give a pale liquid (350 mg, LC/MS shown a clean product only) without further purification for next step reaction.
Reaction SMILES: Cl.[S:2]1[C:6]2=[CH:7][CH:8]=[CH:9][NH:10][CH:5]2[CH2:4][CH2:3]1.[CH3:11][O:12][C:13](=[O:23])[CH:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[Cl:22])Br.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:11][O:12][C:13]([C@@H:14]([N:10]1[CH2:9][C:8]2[CH:7]=[CH:6][S:2][C:3]=2[CH2:4][CH2:5]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[Cl:22])=[O:23]
Reactant: C1=CNC2CCSC2=C1
Reactant: COC(=O)C(Br)c1ccccc1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)[C@H](c1ccccc1Cl)N1CCc2sccc2C1

Procedure:
Tetrahydrothienopyridine hydrochloride from Example 1 was reacted with α-bromo-2-chlorophenyl acetic acid methyl ester in acetone in the presence of potassium carbonate to give racemic clopidogrel. After inorganic salt filtration, the product was recovered as bisulfate, by addition of sulfuric acid.
Reaction SMILES: [OH:1][NH:2][C:3](=[NH:5])[CH3:4].[H-].[Na+].CO[C:10](=O)[CH:11]=[CH:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][Si](C(C)(C)C)(C)C)=[C:15]([O:27][Si](C(C)(C)C)(C)C)[CH:14]=1>O1CCCC1>[CH3:4][C:3]1[N:5]=[C:10]([CH:11]=[CH:12][C:13]2[CH:14]=[C:15]([OH:27])[C:16]([OH:19])=[CH:17][CH:18]=2)[O:1][N:2]=1
Reactant: COC(=O)C=Cc1ccc(O[Si](C)(C)C(C)(C)C)c(O[Si](C)(C)C(C)(C)C)c1
Reactant: CC(=N)NO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1noc(C=Cc2ccc(O)c(O)c2)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of N-hydroxy-acetamidine (0.17 g, 2.29 mmol) in dry tetrahydrofuran (5 mL) was added slowly into the suspension of 60% sodium hydride (0.14 g, 3.5 mmol) in dry tetrahydrofuran (5 mL) under nitrogen atmosphere at 0° C. to 10° C. The reaction mixture was stirred for 30 min at room temperature. 3-[3,4-Bis-(tert-butyl-dimethyl-silanyloxy)-phenyl]-acrylic acid methyl ester (compound of Example 1, Step 1; 0.5 g, 1.18 mmol) in dry tetrahydrofuran (5 mL) was added into the reaction mixture and heated at 60° C. for 8 h. The reaction mixture was cooled at 0° C. and quenched with MeOH (2 mL) to destroy excess sodium hydride. The reaction mixture was extracted with ethyl acetate (2×10 mL) and the combined organic layers were washed with water (2×10 mL) followed by brine (10 mL). The organic phase obtained was dried over anhydrous sodium sulphate and concentrated to dryness. The crude product obtained was purified by column chromatography (silica gel, chloroform-methanol) to afford the title compound.
Reaction SMILES: CN(C=O)C.[Cl:6][CH:7](Cl)[CH3:8].C(Cl)(=O)C(Cl)=O.[N:16]1[C:21]2[CH:22]=[CH:23][S:24]C=2C(=O)[NH:18][CH:17]=1>O>[Cl:6][C:7]1[C:8]2[S:24][CH:23]=[CH:22][C:21]=2[N:16]=[CH:17][N:18]=1
Reactant: CC(Cl)Cl
Reactant: O=c1[nH]cnc2ccsc12
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: O
Product: Clc1ncnc2ccsc12
Reaction time: 0.17 h
Yield: 82 %

Procedure:
To a solution of DMF (170.3 μL, 2.2 mmol) and dichloroethane (1.2 mL) at 0° C. under N2, oxalyl chloride (279.2 mg, 3.2 mmol) is added slowly and stirred for 10 min. 3H-thieno[3,2-d]pyrimid-4-one (152.2 mg, 1.0 mmol) is added and refluxed for 5 h. The reaction mixture is poured into water and extracted with CH2Cl2. The organic layer is stripped under reduced pressure to yield 4-chlorothieno[3,2-d]pyrimidine (140 mg, 82%) as a yellow solid. 1H NMR (DMSO) δ 9.05 (1H, s), 8.62 (1H, d, J=5 Hz), 7.7 9 (1H, d, J=5 Hz)
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C@@H:3]([CH2:11][N:12]2[C:16]([CH2:17][C:18]3[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][CH:19]=3)=[CH:15][N:14]=[CH:13]2)[NH:2]1.[CH3:26][O:27][C:28]1[CH:29]=[C:30]([CH2:34][C:35](O)=[O:36])[CH:31]=[CH:32][CH:33]=1.ON1C2C=CC=CC=2N=N1.C(Cl)CCl.CN1CCOCC1>CN(C=O)C>[CH3:26][O:27][C:28]1[CH:29]=[C:30]([CH2:34][C:35]([N:2]2[C@H:3]([CH2:11][N:12]3[C:16]([CH2:17][C:18]4[CH:19]=[CH:20][C:21]([C:22]#[N:23])=[CH:24][CH:25]=4)=[CH:15][N:14]=[CH:13]3)[CH2:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH2:1]2)=[O:36])[CH:31]=[CH:32][CH:33]=1
Reactant: N#Cc1ccc(Cc2cncn2C[C@@H]2Cc3ccccc3CN2)cc1
Reactant: COc1cccc(CC(=O)O)c1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: COc1cccc(CC(=O)N2Cc3ccccc3C[C@H]2Cn2cncc2Cc2ccc(C#N)cc2)c1

Procedure:
The same proceedure as described in step D of Example 8 above was used to mix 4-{3-[(S)-1,2,3,4-tetrahydro-isoquinolin-3-yl-methyl]-3H-imidazol-4-yl-methyl}-benzonitrile (0.16 g, 0.487 mmol), 3-methoxyphenylacetic acid (0.081 g, 0.487 mmol), 1-hydroxybenzotriazole (0.075 g, 0.487 mmol), EDC (0.093 g, 0.487 mmol) and N-methylmorpholine (0.2 ml, 1.95 mmol) in 5 ml DMF. The title compound was obtained.
Reaction SMILES: Cl.[CH2:2]([C:4]1[N:5]=[C:6]([CH2:10][C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:12])[NH:7][C:8]=1[CH3:9])[CH3:3].C[O-].[Na+].[C:22](OC)(=[O:25])[C:23]#[CH:24]>>[C:11]([C:10]1[CH:24]=[CH:23][C:22](=[O:25])[N:7]2[C:8]([CH3:9])=[C:4]([CH2:2][CH3:3])[NH:5][C:6]=12)(=[O:12])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CCc1nc(CC(=O)c2ccccc2)[nH]c1C
Reactant: C#CC(=O)OC
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Product: CCc1[nH]c2c(C(=O)c3ccccc3)ccc(=O)n2c1C

Procedure:
The compound is prepared as described in example 20 with 200 mg (0.76 mmol) of 2-(4-Ethyl-5-methyl-1H-imidazol-2-yl)-1-phenylethanone hydrochloride (example XVII), 50 mg (0.92 mmol) of sodium methylate and 63.5 mg (0.76 mmol) methyl propiolate.
Reaction SMILES: [NH:1](C(OCC1C=CC=CC=1)=O)[C@H:2]([C:15]([NH:17][C@H:18]([C:26]([NH:28][C@H:29]([C:35]([NH:37][C@H:38]([C:47]([NH:49][C@H:50]([C:58]([O:60][CH3:61])=[O:59])[CH2:51][C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1)=[O:48])[CH2:39][C:40](=[O:46])[O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:36])[CH2:30][CH2:31][C:32](=[O:34])[NH2:33])=[O:27])[C@@H:19]([CH3:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:16])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:6][CH:5]=1.[H][H]>[Pd].CO>[NH2:1][C@H:2]([C:15]([NH:17][C@H:18]([C:26]([NH:28][C@H:29]([C:35]([NH:37][C@H:38]([C:47]([NH:49][C@H:50]([C:58]([O:60][CH3:61])=[O:59])[CH2:51][C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1)=[O:48])[CH2:39][C:40](=[O:46])[O:41][C:42]([CH3:43])([CH3:44])[CH3:45])=[O:36])[CH2:30][CH2:31][C:32](=[O:34])[NH2:33])=[O:27])[C@@H:19]([CH3:25])[O:20][C:21]([CH3:24])([CH3:22])[CH3:23])=[O:16])[CH2:3][C:4]1[CH:5]=[CH:6][C:7]([O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[CH:8][CH:9]=1
Reactant: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(=O)OC(C)(C)C)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](NC(=O)[C@H](Cc1ccc(OC(C)(C)C)cc1)NC(=O)OCc1ccccc1)[C@@H](C)OC(C)(C)C
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(=O)OC(C)(C)C)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](NC(=O)[C@@H](N)Cc1ccc(OC(C)(C)C)cc1)[C@@H](C)OC(C)(C)C

Procedure:
4.0 g of Z-Tyr(tBu)-Thr(tBu)-Gln-Asp(OtBu)-Phe-OCH3 in 100 ml of absolute pre-hydrogenated N,N-dimethylformamide are decarbobenzoxylated with hydrogen at room temperature with the addition of 1.4 g of 10 % strength palladium on charcoal. After completion of the hydrogen uptake the mixture is diluted with 400 ml of methanol, filtered and evaporated in vacuo. The colourless solid residue is used for the next stage without further purification.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].[S:9]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15]O)=[CH:10]1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[I:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH2:15][CH2:14][C:11]1[CH:12]=[CH:13][S:9][CH:10]=1
Reactant: Oc1ccccc1I
Reactant: OCCc1ccsc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Solvent: C1CCOC1
Product: Ic1ccccc1OCCc1ccsc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred solution of 2-iodophenol (6.7 g, 30.6 mmol), 2-(3-thienyl)ethanol (3.57 g, 27.8 mol) and triphenylphosphene (8.00 g, 30.6 mmol) in THF, was slowly added a solution of DEAD (4.8 ml, 30.6 mmol). Reaction mixture was stirred at room temperature for 3 hours. Purification on silica gave 3-[2-(2-iodo-phenoxy)-ethyl]-thiophene. A mixture of 3-[2-(2-iodo-phenoxy)-ethyl]-thiophene (1.55 g, 4.69 mmol), palladium(II) acetate (105 mg, 0.47 mmol), potassium carbonate (3.2 g, 23.45 mmol), triphenylphosphene (246 mg, 0.94 mmol) and tetraethylammonium chloride (1.3 g, 4.69 mmol) in DMF was microwaved at 100° C. for 1 hour. The reaction was diluted with dichloromethane and filtered through celite. The filtrate was washed with water, dried (MgSO4), and concentrated in-vacuo. Purification on silica gave 4,5-dihydrobenzo[b]thieno[2,3-d]oxepine.
Reaction SMILES: [OH:1][C@H:2]1[C@H:6]([CH3:7])[CH2:5][C@@H:4]([C:8]([O:10]CC2C=CC=CC=2)=[O:9])[CH2:3]1.O[C@@H]1[C@@H](C)C[C@H](C(OCC2C=CC=CC=2)=O)C1.O[C@H]1[C@H](C)C[C@@H](C(O)=O)C1>CO.[OH-].[OH-].[Pd+2]>[OH:1][C@@H:2]1[C@@H:6]([CH3:7])[CH2:5][C@H:4]([C:8]([OH:10])=[O:9])[CH2:3]1
Reactant: C[C@@H]1C[C@@H](C(=O)OCc2ccccc2)C[C@H]1O
Agent: [Pd+2]
Agent: C[C@@H]1C[C@@H](C(=O)O)C[C@H]1O
Agent: C[C@H]1C[C@H](C(=O)OCc2ccccc2)C[C@@H]1O
Solvent: CO
Product: C[C@H]1C[C@H](C(=O)O)C[C@@H]1O
Reaction time: 8 h
Yield: 98 %

Procedure:
A racemic mixture of (1R,3R,4R)-benzyl 3-hydroxy-4-methylcyclopentanecarboxylate and (1S,3S,4S)-benzyl 3-hydroxy-4-methylcyclopentanecarboxylate (217 mg, 0.463 mmol) and palladium hydroxide on carbon (65.0 mg, 0.463 mmol) in methanol (10 mL) was degassed under vacuum/nitrogen, and the mixture was hydrogenated overnight at 50 psi. The catalyst was removed by filtration and rinsed with methanol. The filtrates were combined and concentrated in-vacuo to yield a racemic mixture of (1R,3R,4R)-3-hydroxy-4-methylcyclopentanecarboxylic acid and (1S,3S,4S)-3-hydroxy-4-methylcyclopentanecarboxylic acid (131 mg, 0.454 mmol, 98% yield) as a colorless oil which solidified upon standing overnight.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:11])[CH:5]=[C:6]([F:10])[C:7]=1[CH2:8][OH:9].[CH2:12](Br)[CH3:13]>>[Cl:1][C:2]1[CH:3]=[C:4]([O:11][CH2:12][CH3:13])[CH:5]=[C:6]([F:10])[C:7]=1[CH2:8][OH:9]
Reactant: CCBr
Reactant: OCc1c(F)cc(O)cc1Cl
Product: CCOc1cc(F)c(CO)c(Cl)c1
Yield: 60 %

Procedure:
This compound was prepared from 3-chloro-5-fluoro-4-hydroxymethyl-phenol and ethylbromide according to the procedure described in Example 179 to give the product as a yellowish oil (209 mg, 60%); MS (EI): 204.1 (M)+.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:14]=[CH:13][N:12]=[C:11]3[N:15]([S:18]([C:21]4[CH:27]=[CH:26][C:24]([CH3:25])=[CH:23][CH:22]=4)(=[O:20])=[O:19])[CH:16]=[CH:17][C:10]=23)O1.Cl[C:30]1[N:39]=[CH:38][C:37]2[NH:36][CH2:35][CH:34]3[CH2:40][O:41][CH2:42][CH2:43][N:33]3[C:32]=2[N:31]=1>O1CCOCC1.C([O-])(O)=O.[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]>[S:18]([N:15]1[C:11]2=[N:12][CH:13]=[CH:14][C:9]([C:30]3[N:39]=[CH:38][C:37]4[NH:36][CH2:35][CH:34]5[CH2:40][O:41][CH2:42][CH2:43][N:33]5[C:32]=4[N:31]=3)=[C:10]2[CH:17]=[CH:16]1)([C:21]1[CH:22]=[CH:23][C:24]([CH3:25])=[CH:26][CH:27]=1)(=[O:19])=[O:20]
Reactant: Clc1ncc2c(n1)N1CCOCC1CN2
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(B4OC(C)(C)C(C)(C)O4)ccnc32)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])O
Solvent: C1COCCO1
Product: Cc1ccc(S(=O)(=O)n2ccc3c(-c4ncc5c(n4)N4CCOCC4CN5)ccnc32)cc1

Procedure:
The title compound was prepared in a manner similar to EXAMPLE 2 using 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine (PREPARATION x2, 527 mg, 1.324 mmol), 2-chloro-5,6,6a,7,9,10-hexahydro-[1,4]oxazino[3,4-h]pteridine (150 mg, 0.662 mmol), and PdCl2(dppf) (38.7 mg, 0.053 mmol) in dioxane (3.5 mL) and aqueous saturated NaHCO3 (0.8 mL).
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[CH:6][C:7]([NH:10][C@H:11]3[CH2:15][CH2:14][CH2:13][C@@H:12]3[NH:16][C:17](=[O:29])[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[N:24]3[N:28]=[CH:27][CH:26]=[N:25]3)=[N:8][CH:9]=2)[CH2:3][CH2:2]1.BrC1N=CC(N[C@H]2CCC[C@@H]2NC(=O)C2C=CC=CC=2N2N=CC=N2)=NC=1.ClC1N=CC(N[C@H]2CCC[C@@H]2NC(=O)C2C=CC=CC=2N2N=CC=N2)=NC=1.CC1(C)C(C)(C)OB(C(C)=C)O1>>[CH3:3][CH:1]([C:4]1[N:5]=[CH:6][C:7]([NH:10][C@H:11]2[CH2:15][CH2:14][CH2:13][C@@H:12]2[NH:16][C:17](=[O:29])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[N:24]2[N:28]=[CH:27][CH:26]=[N:25]2)=[N:8][CH:9]=1)[CH3:2]
Reactant: O=C(N[C@H]1CCC[C@@H]1Nc1cnc(C2CC2)cn1)c1ccccc1-n1nccn1
Agent: C=C(C)B1OC(C)(C)C(C)(C)O1
Agent: O=C(N[C@H]1CCC[C@@H]1Nc1cnc(Br)cn1)c1ccccc1-n1nccn1
Agent: O=C(N[C@H]1CCC[C@@H]1Nc1cnc(Cl)cn1)c1ccccc1-n1nccn1
Product: CC(C)c1cnc(N[C@H]2CCC[C@@H]2NC(=O)c2ccccc2-n2nccn2)cn1
Reaction time: 2 h

Procedure:
Prepared according to the procedure for N-[(1S,2S)-2-[(5-cyclopropylpyrazin-2-yl)amino]cyclopentyl]-2-(2H-1,2,3-triazol-2-yl)benzamide (Example 112) from N-[(1S,2S)-2-[(5-bromopyrazin-2-yl)amino]cyclopentyl]-2-(2H-1,2,3-triazol-2-yl)benzamide and N-[(1S,2S)-2-[(5-chloropyrazin-2-yl)amino]cyclopentyl]-2-(2H-1,2,3-triazol-2-yl)benzamide (Intermediate 30a and 30b; 100 mg, 0.23 mmol) and 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (CAS number 126726-62-3; 165 mg, 0.98 mmol) except this was purified only by column chromatography (silica, 0-100% ethyl acetate/petrol) and then was dissolved in ethanol (2.5 ml). To this was then added palladium on carbon (10% wt, 50% wet) (26 mg, 0.025 mmol) and the resulting mixture was stirred under a balloon of hydrogen gas for 2 hours. The reaction was filtered through diatomaceous earth (commercially sold under the trade mark “Celite”) and concentrated in vacuo. This was purified by column chromatography (basic silica, 0-100% ethyl acetate/petrol) to afford the title compound.
Reaction SMILES: [Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([OH:9])=[CH:4][C:3]=1[CH3:10].[H-].[Na+].[O:13]=[S:14]1(=[O:26])[CH2:18][CH2:17][CH2:16][N:15]1[CH2:19][CH2:20]OS(C)(=O)=O>>[Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([O:9][CH2:20][CH2:19][N:15]2[CH2:16][CH2:17][CH2:18][S:14]2(=[O:26])=[O:13])=[CH:4][C:3]=1[CH3:10]
Reactant: CS(=O)(=O)OCCN1CCCS1(=O)=O
Reactant: Cc1cc(O)cc(C)c1Br
Agent: [H-]
Agent: [Na+]
Product: Cc1cc(OCCN2CCCS2(=O)=O)cc(C)c1Br
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
4-Bromo-3,5-dimethylphenol (1.25 g, 6.17 mmol) and sodium hydride (60% on mineral oil, 160 mg, 3.95 mmol) are suspended in dry N,N-dimethylacetate (25 mL) and stirred for 30 minutes at room temperature. Methanesulfonic acid 2-(1,1-dioxo-isothiazolidin-2-yl)-ethyl ester (Patent EP1479684 A1, 600 mg, 2.47 mmol;) is added and the mixture stirred at 80° C. for 5 hours. The mixture is concentrated under vacuum, diluted with water and extracted with ethyl acetate. The organic phase is dried and the solvent removed. The residue is purified by flash chromatography (0-50% ethyl acetate in cyclohexane) to give the title compound. (Yield: 350 mg).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH:7]([CH2:12][C:13]([OH:15])=[O:14])[C:8]2=[O:11])=[CH:4][CH:3]=1.CO.O1CCCC1.[BH4-].[Na+]>O>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH:7]([CH2:12][C:13]([OH:15])=[O:14])[CH:8]2[OH:11])=[CH:4][CH:3]=1
Reactant: O=C(O)CC1Cc2ccc(Br)cc2C1=O
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)CC1Cc2ccc(Br)cc2C1O
Reaction time: 0.75 h

Procedure:
6-Bromo-2-carboxymethyl-1-indanone (139 g, 650 mmol), methanol (1100 mL), and tetrahydrofuran (200 mL) were stirred at 0° C. Sodium borohydride (9.30 g, 245 mmol) was added in portions over 45 minutes and stirred another 45 minutes. More sodium borohydride (12.4 g, 326 mmol) was added in portions over 45 minutes and stirred another 60 minutes. Water was added and the solvent was removed under vacuum at 35° C. The residue was partitioned between diethyl ether and water. The organic layer was washed with water and brine and then dried over sodium sulfate. Flash chromatography of the crude product on a 30×7 cm silica gel column, eluting with dichloromethane/ethyl acetate/hexane (1:2:5), yielded an orange wax (99.6 g, 57%). 1H-NMR (300 MHz, CDCl3) (a ratio of approximately 1:1 cis to trans diastereomers) 7.55 (s, 0.43H), 7.51 (s, 0.57H), 7.39 (t, 0.57H, J=8.1), 7.39 (t, 0.43H, J=8.1), 7.13 (d, 0.43H, J=8.1), 7.08 (d, 0.57H, J=8.1), 5.44 (d, 0.57H, J=6.9), 5.30 (d, 0.43H, J=6.0), 3.79 (s, 1.71H), 3.77 (s, 1.29H), 3.45-2.95 (m, 3H), 2.87 (s, 1H).
Reaction SMILES: Cl[C:2]1[C:7]([CH3:8])=[CH:6][C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1.[CH3:12][NH2:13]>CCO>[CH3:12][NH:13][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1
Reactant: CN
Reactant: Cc1cc([N+](=O)[O-])cnc1Cl
Solvent: CCO
Product: CNc1ncc([N+](=O)[O-])cc1C
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
2-Chloro-3-methyl-5-nitropyridine (5.00 g, 29.0 mmol) was added portion wise to a cooled (0° C.) 35% solution of methylamine in EtOH (20 mL) and the reaction was allowed to warm to rt. After approximately 5 min an exotherm and gas evolution was observed and the reaction mixture solidified. EtOH (10 mL) was added and the reaction mixture was stirred at rt for 20 min, then diluted with ice/water (30 mL) and cooled to 0° C. The mixture was stirred vigorously for 15 min and then allowed to stand for 17 h. A solid was isolated by filtration, washed with H2O and dried in vacuo to yield N,3-dimethyl-5-nitropyridin-2-amine (4.44 g) which was used without further purification. A mixture of N,3-dimethyl-5-nitropyridin-2-amine (4.44 g, 26.6 mmol), Boc2O (11.6 g, 53.1 mmol) and 4-(dimethylamino)pyridine (649 mg, 5.31 mmol) in MeCN (230 mL) was stirred at 75° C. for 21 h. Further Boc2O (2.32 g, 10.6 mmol) was added and heating at 75° C. was continued for 24 h, before cooling to rt. Imidazole (5.06 g, 74.4 mmol) was added and the mixture concentrated in vacuo. Purification by gradient flash chromatography eluting with 5-20% EtOAc in heptane yielded the title compound (6.20 g, 23.2 mmol) as a yellow oil which solidified upon standing.