Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11](OS(C)(=O)=O)[CH2:10][C@@H:9]1[CH2:18][OH:19])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:20]([O-:23])(=[S:22])[CH3:21].[K+].C(OCC)(=O)C.Cl>CN(C)C=O>[C:20]([S:22][C@@H:11]1[CH2:12][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[C@H:9]([CH2:18][OH:19])[CH2:10]1)(=[O:23])[CH3:21]
Reactant: CC([O-])=S
Reactant: CC(C)(C)OC(=O)N1C[C@@H](OS(C)(=O)=O)C[C@@H]1CO
Agent: Cl
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(=O)S[C@H]1C[C@@H](CO)N(C(=O)OC(C)(C)C)C1
Temperature: 0 °C
Yield: 86 %

Procedure:
A solution of (2R,4S)-1-t-butoxycarbonyl-4-methanesulfonyloxypyrrolidine-2-methanol (i.e., a substrate) (11.8 g: 40 mmole) and potassium thioacetate (5.94 g: 52 mmole) in dimethylformamide (120 ml) is stirred at 65° C. for 3.75 hours. The reaction mixture is mixed with ethyl acetate (330 ml), ice water (100 ml), and 1N-hydrochloric acid (20 ml) to adjust the aqueous layer at pH 4. The organic layer is taken, successively washed with water and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue is purified by silica gel chromatography (toluene-ethyl acetate=2:1) to give (2S,4S)-4-acetylthio-1-t-butoxycarbonylpyrrolidine-2-methanol (9.48 g). Yield: 86%. Pale orange colored oil.
Reaction SMILES: C[Si](C)(C)CCOCN(COCC[Si](C)(C)C)C1N2N=CC=C2N=C(C2CCC(=[CH:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])CC2)C=1.C[Si](C)(C)CCOCN(COCC[Si](C)(C)C)C1N2N=CC=C2N=C(C2CCCC(=O)C2)C=1.[CH3:72][Si:73]([CH3:104])([CH3:103])[CH2:74][CH2:75][O:76][CH2:77][N:78]([CH2:95][O:96][CH2:97][CH2:98][Si:99]([CH3:102])([CH3:101])[CH3:100])[C:79]1[N:84]2[N:85]=[CH:86][CH:87]=[C:83]2[N:82]=[C:81]([CH:88]2[CH2:93][CH2:92][C:91](=O)[CH2:90][CH2:89]2)[CH:80]=1>>[CH3:101][Si:99]([CH3:100])([CH3:102])[CH2:98][CH2:97][O:96][CH2:95][N:78]([CH2:77][O:76][CH2:75][CH2:74][Si:73]([CH3:72])([CH3:103])[CH3:104])[C:79]1[N:84]2[N:85]=[CH:86][CH:87]=[C:83]2[N:82]=[C:81]([CH:88]2[CH2:93][CH2:92][CH2:91][C:90](=[CH:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:89]2)[CH:80]=1
Reactant: CCOC(=O)C=C1CCC(c2cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n3nccc3n2)CC1
Reactant: C[Si](C)(C)CCOCN(COCC[Si](C)(C)C)c1cc(C2CCC(=O)CC2)nc2ccnn12
Agent: C[Si](C)(C)CCOCN(COCC[Si](C)(C)C)c1cc(C2CCCC(=O)C2)nc2ccnn12
Product: CCOC(=O)C=C1CCCC(c2cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n3nccc3n2)C1

Procedure:
Ethyl 2-(3-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)cyclohexylidene)acetate was synthesized in a manner similar to the synthesis of ethyl 2-(4-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)cyclohexylidene)acetate, but with 3-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)cyclohexanone substituted for 4-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)cyclohexanone.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][NH:5][C:6]=1[CH2:7][OH:8].CCN(C(C)C)C(C)C.[CH3:18][Si:19]([CH3:26])([CH3:25])[CH2:20][CH2:21][O:22][CH2:23]Cl>CN(C=O)C.[Cl-].[Na+].O.O.CCOC(C)=O>[CH3:1][C:2]1[N:3]([CH2:23][O:22][CH2:21][CH2:20][Si:19]([CH3:26])([CH3:25])[CH3:18])[CH:4]=[N:5][C:6]=1[CH2:7][OH:8]
Reactant: Cc1nc[nH]c1CO
Reactant: C[Si](C)(C)CCOCCl
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c(CO)ncn1COCC[Si](C)(C)C
Temperature: 25 °C
Yield: 55.7 %

Procedure:
To a stirred solution of 4-methyl-5-imidazolemethanol (587 mg, 3.96 mmol) in anhydrous DMF (13 mL) was added DIPEA (2.1 mL, 11.9 mmol) followed by 2-(trimethylsilyl)ethoxymethyl chloride (793 mg, 4.76 mmol). The resultant solution was heated to 80° C. for 3 h then cooled to room temperature. The reaction mixture was poured into brine (15 mL), and diluted with H2O (6 mL) and EtOAc (40 mL). The phases were mixed vigorously for 10 minutes and separated. The organic phase was washed with brine (4×20 mL), dried (Na2SO4), and concentrated under reduced pressure. Purification of the crude orange oil by flash chromatography on silica gel (CH2Cl2/MeOH/NH4OH, 95:4:1) provided [5-Methyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazol-4-yl]-methanol (535 mg, 56%) as a mixture of regioisomers.
Reaction SMILES: C([BH3-])#N.[Na+].[F:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH:8]=[C:9]([CH3:15])[NH:10]2.O.N>C(O)(=O)C>[F:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH2:8][CH:9]([CH3:15])[NH:10]2
Reactant: Cc1cc2c(F)cccc2[nH]1
Agent: N
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CC1Cc2c(F)cccc2N1
Temperature: 14 °C
Reaction time: 2 h
Yield: 75.3 %

Procedure:
3.63 g of sodium cyanoborohydride are gradually added to a solution of 2.87 g of 4-fluoro-2-methylindole in 98 ml of acetic acid under argon cooled to a temperature of about 14° C. The reaction mixture is left to warm up to ambient temperature. After 2 hours, the reaction mixture is poured into a mixture of water and ice, and is then treated with a 28% aqueous ammonia solution until the pH is 9. The mixture is then extracted twice with dichloromethane. The organic phases are combined, dried over anhydrous magnesium sulfate, filtered, and then concentrated to dryness under reduced pressure. The residue is purified on a 300 g silica column, elution being carried out with a 100/0 to 90/10 v/v heptane/ethyl acetate gradient. 2.19 g of 4-fluoro-2-methyl-2,3-dihydro-1H-indole are thus obtained in the form of a colorless oil, the characteristics of which are the following:
Reaction SMILES: [CH3:1][Si:2]([N:5]([Si:14]([CH3:17])([CH3:16])[CH3:15])[C:6]1[CH:7]=[C:8]([Mg]Cl)[CH:9]=[CH:10][CH:11]=1)([CH3:4])[CH3:3].C1COCC1.[CH:23]1[C:28]([Cl:29])=[CH:27][CH:26]=[C:25](Br)[CH:24]=1.S(=O)(=O)(O)O>C1COCC1.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]>[Cl:29][C:28]1[CH:23]=[CH:24][C:25]([C:8]2[CH:9]=[CH:10][CH:11]=[C:6]([N:5]([Si:14]([CH3:17])([CH3:16])[CH3:15])[Si:2]([CH3:4])([CH3:3])[CH3:1])[CH:7]=2)=[CH:26][CH:27]=1
Reactant: C[Si](C)(C)N(c1cccc([Mg]Cl)c1)[Si](C)(C)C
Reactant: Clc1ccc(Br)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=S(=O)(O)O
Solvent: C1CCOC1
Product: C[Si](C)(C)N(c1cccc(-c2ccc(Cl)cc2)c1)[Si](C)(C)C

Procedure:
0.5 mol of a 25% strength by weight 3-bis(trimethylsilyl)aminophenyl-magnesium chloride/THF solution is added dropwise in the course of 30 minutes to a boiling solution of 0.5 mol of 1,4-bromochlorobenzene and 0.0025 g of Pd(dppf)Cl2 *CH2Cl2 in 100 ml THF. After stirring under reflux for four hours, the mixture is hydrolyzed with dilute sulfuric acid (conversion 99%, selectivity 97%). The organic phase is freed from the solvent by distillation. The crude 4-chloro-3'-bis(trimethylsilyl)aminobiphenyl thus obtained is recrystallized from isopropanol.
Reaction SMILES: [CH:1]([C:3]1[N:12]=[CH:11][C:10]([CH:13]=[CH2:14])=[CH:9][C:4]=1[C:5]([O:7]C)=O)=[CH2:2].[CH3:15][O:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21][NH2:22])=[CH:19][CH:18]=1>CC(N(C)C)=O>[CH3:15][O:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21][N:22]2[CH2:2][CH2:1][C:3]3[N:12]=[CH:11][C:10]([CH:13]=[CH2:14])=[CH:9][C:4]=3[C:5]2=[O:7])=[CH:19][CH:18]=1
Reactant: C=Cc1cnc(C=C)c(C(=O)OC)c1
Reactant: COc1ccc(CN)cc1
Solvent: CC(=O)N(C)C
Product: C=Cc1cnc2c(c1)C(=O)N(Cc1ccc(OC)cc1)CC2
Temperature: 150 °C
Yield: 91.5 %

Procedure:
Methyl 2,5-divinylnicotinate (2.1 g, 11.1 mmol) was combined with p-methoxybenzylamine (2 mL, 15 mmol) and dimethylacetamide (7 mL) and heated for 20 min in a microwave reactor at 150° C. The reaction mixture was concentrated and purified over silica gel (0-100% EtOAc/hexanes) using automated chromatography. The product containing fractions were combined and evaporated under reduced pressure to give the compound (2.99 g, 92%). LC-MS (M+H)=295.1.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[C:17]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[C:9]([NH2:18])[C:8]=2[N:7]=[C:6]1[CH3:19].[N:20]1([C:26](Cl)=[O:27])[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1>>[NH2:18][C:9]1[C:8]2[N:7]=[C:6]([CH3:19])[N:5]([CH2:4][CH2:3][CH2:2][NH:1][C:26]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)=[O:27])[C:17]=2[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:10]=1
Reactant: O=C(Cl)N1CCOCC1
Reactant: Cc1nc2c(N)nc3ccccc3c2n1CCCN
Product: Cc1nc2c(N)nc3ccccc3c2n1CCCNC(=O)N1CCOCC1
Yield: 47 %

Procedure:
Using the general method of Example 150 except that the reaction was run at 0° C, 1-(3-aminopropyl)-2-methyl-1H-imidazo[4,5-c]quinolin-4-amine (2.0 g, 7.8 mmol) was reacted with 4-morpholinecarbonyl chloride (1.17 g, 7.8 mmol) to provide 1.35 g of N-[3-(4-amino-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)propyl]morpholine-4-carboxamide as a white solid, m.p. 226.0-228.0° C. Analysis: Calculated for C19H24N6O2: %C, 61.94; %H, 6.57; %N, 22.81; Found: %C, 61.67; %H, 6.46; %N, 22.74.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:9](I)=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[CH3:13][C:14]1[CH:15]=[C:16](B(O)O)[CH:17]=[N:18][CH:19]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.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]>[Br:1][C:2]1[CH:11]=[CH:10][C:9]([C:16]2[CH:17]=[N:18][CH:19]=[C:14]([CH3:13])[CH:15]=2)=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1cc(I)ccc1Br
Reactant: Cc1cncc(B(O)O)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: COC(=O)c1cc(-c2cncc(C)c2)ccc1Br
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of methyl 2-bromo-5-iodobenzoate (2-2, 2.0 g, 5.87 mmol, 1.0 equiv), 5-methylpyridine-3-boronic acid (0.803 g, 5.87 mmol, 1.0 equiv), Cs2CO3 (6.69 g, 20.53 mmol, 3.5 equiv) and PdCl2(dppf) (0.429 g, 0.587 mmol, 0.1 equiv) was made in DMF (30 mL) and stirred at room temperature overnight. The reaction mixture was partitioned between EtOAc and water. The layers were separated and the aqueous layer extracted with ethyl acetate. The combined organics were washed with saturated sodium bicarbonate solution and brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by normal phase column chromatography (25 to 75% EtOAc in hexanes) to afford the product (2-3) as a solid. ESI+ MS [M+H]+ C14H12BrNO2: 307.8 found, 307.1 required.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([Cl:26])[C:7]2[N:8]([CH:23]=[N:24][CH:25]=2)[C:9]=1[N:10]1[CH2:15][CH2:14][N:13]([C:16](OC(C)(C)C)=O)[CH2:12][CH2:11]1)(=[O:3])[CH3:2].Cl.[C:28]1(=O)[CH2:31]C[CH2:29]1.C([BH3-])#N.[Na+]>O1CCOCC1.C(#N)C.O1CCCC1>[Cl:26][C:6]1[C:7]2[N:8]([CH:23]=[N:24][CH:25]=2)[C:9]([N:10]2[CH2:15][CH2:14][N:13]([CH:16]3[CH2:31][CH2:28][CH2:29]3)[CH2:12][CH2:11]2)=[C:4]([C:1](=[O:3])[CH3:2])[CH:5]=1
Reactant: CC(=O)c1cc(Cl)c2cncn2c1N1CCN(C(=O)OC(C)(C)C)CC1
Reactant: O=C1CCC1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC#N
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: CC(=O)c1cc(Cl)c2cncn2c1N1CCN(C2CCC2)CC1
Reaction time: 0.5 h
Yield: 62.2 %

Procedure:
tert-Butyl 4-(6-acetyl-8-chloroimidazo[1,5-a]pyridine-5-yl)piperazine-1-carboxylate (33 mg, 0.087 mmol) was treated with a solution of 4 M hydrogen chloride in 1,4-dioxane (1.0 mL) and evaporated to dryness. Cyclobutanone (13 μL, 0.18 mmol), tetrahydrofuran (0.5 mL) and acetonitrile (0.5 mL) were added and the mixture was stirred for 30 minutes. Sodium cyanoborohydride (17 mg, 0.26 mmol) was added and was stirred for 4 hours. Purification by preparative LCMS (pH 10) gave the desired compound (18 mg, 61%). LCMS calculated for C17H22ClN4O (M+H)+: m/z=333.1. found: 332.9.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]1[CH2:16][O:15][NH:14][C:13]1=[O:17])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl[C:26]1([C:38]([O:40][CH2:41][C:42]2[CH:47]=[CH:46][C:45]([N+:48]([O-:50])=[O:49])=[CH:44][CH:43]=2)=[O:39])[CH2:30][CH:29]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:28](=[O:37])[O:27]1>ClCCl>[CH2:1]([O:8][C:9]([NH:11][C@H:12]1[CH2:16][O:15][N:14]([C:26]2([C:38]([O:40][CH2:41][C:42]3[CH:43]=[CH:44][C:45]([N+:48]([O-:50])=[O:49])=[CH:46][CH:47]=3)=[O:39])[CH2:30][CH:29]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:28](=[O:37])[O:27]2)[C:13]1=[O:17])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1OC(Cl)(C(=O)OCc2ccc([N+](=O)[O-])cc2)CC1c1ccccc1
Reactant: O=C(N[C@H]1CONC1=O)OCc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(N[C@H]1CON(C2(C(=O)OCc3ccc([N+](=O)[O-])cc3)CC(c3ccccc3)C(=O)O2)C1=O)OCc1ccccc1
Yield: 68.9 %

Procedure:
Production of Compound(64): In 6 ml of dichloromethane was suspended 280 mg of (4S)-4-benzyloxycarbonylamino-3-isoxazolidinone. To the suspension were added, under ice-cooling and stirring, 0.36 ml of triethylamine and 490 mg of the Compound (63) obtained in Example 63 dissolved in 1 ml of dichloromethane. The reaction was solution stirred at room temperature for 30 minutes, which was washed with water and dried (MgSO4). The solvent was evaporated off, and the residue was chromatographed on silica gel, followed by elution with hexane-ethylacetate (3:1) to give 470 mg of the subject Compound (64) as colorless oily product. The IR and NMR spectra of this product were in agreement with those of the Compound (64) obtained in Example 64.
Reaction SMILES: C1C[C@H](C(O)=O)CC[C@H]1CN.[CH3:12][CH:13]([CH3:33])[C:14]([O:16][C@@H:17]([O:19][C:20]([NH:22][CH2:23][C@H:24]1[CH2:29][CH2:28][C@H:27]([C:30]([OH:32])=[O:31])[CH2:26][CH2:25]1)=[O:21])[CH3:18])=[O:15].C(=O)(O)[O-].[Na+:38].C(#N)C>O>[CH3:12][CH:13]([CH3:33])[C:14]([O:16][C@@H:17]([O:19][C:20]([NH:22][CH2:23][C@H:24]1[CH2:25][CH2:26][C@H:27]([C:30]([O-:32])=[O:31])[CH2:28][CH2:29]1)=[O:21])[CH3:18])=[O:15].[Na+:38]
Reactant: CC(C)C(=O)O[C@H](C)OC(=O)NC[C@H]1CC[C@H](C(=O)O)CC1
Agent: NC[C@H]1CC[C@H](C(=O)O)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: CC(C)C(=O)O[C@H](C)OC(=O)NC[C@H]1CC[C@H](C(=O)[O-])CC1

Procedure:
Following the general procedure for the formation of the corresponding sodium carboxylates of acyloxyalkyl carbamates of tranexamic acid, 90.0 mg (0.2854 mmol) of (+)-trans-4-({[(1S)-1-(2-methylpropanoyloxy)ethoxy]carbonylamino}methyl)-cyclohexanecarboxylic acid 15 was reacted with 24.0 mg (0.2854 mmol) of sodium bicarbonate (NaHCO3) in 4 mL of a mixture of acetonitrile and water (1:1) to yield 96.3 mg (quant.) of the title compound 16 as a colorless powder. The enantiomeric excesses were determined with an analytical Waters 2690/ZQ LC/MS apparatus using a ChiralPak AD-RH column, an isocratic eluent consisting of 30% acetonitrile/70% water/0.05% formic acid, and a flowrate of 60 μL/min (Rf=12.1 min; e.e.=98.5%). 1H NMR (400 MHz, DMSO-d6): δ=0.72-0.84 (br. m, 2H), 1.057 (d, J=6.4 Hz, 3H), 1.059 (d, J=6.8 Hz, 3H), 1.20-1.32 (br. m, 3H), 1.38 (d, J=5.2 Hz, 3H), 1.59-1.73 (br. m, 3H), 1.75-1.83 (m, 2H), 2.43-2.53 (m, 1H), 2.72-2.84 (br. m, 2H), 6.62 (q, J=5.6 Hz, 1H), 7.42 (t, J=5.6 Hz, 1H). MS (EST) m/z 338.16 (M+Na)+; 314.12 (M−H)−.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:25][CH3:26])=[C:6]([C@H:8]2[CH2:12][CH2:11][CH2:10][N:9]2[C:13]2[CH:18]=[CH:17][N:16]3[N:19]=[CH:20][C:21]([C:22]([OH:24])=O)=[C:15]3[N:14]=2)[CH:7]=1.[NH2:27][CH2:28][C@@H:29]([OH:32])[CH2:30][OH:31]>CO.CCOC(C)=O>[OH:32][C@@H:29]([CH2:30][OH:31])[CH2:28][NH:27][C:22]([C:21]1[CH:20]=[N:19][N:16]2[CH:17]=[CH:18][C:13]([N:9]3[CH2:10][CH2:11][CH2:12][C@@H:8]3[C:6]3[CH:7]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=3[O:25][CH3:26])=[N:14][C:15]=12)=[O:24]
Reactant: NC[C@@H](O)CO
Reactant: COc1ccc(F)cc1[C@H]1CCCN1c1ccn2ncc(C(=O)O)c2n1
Solvent: CCOC(C)=O
Solvent: CO
Product: COc1ccc(F)cc1[C@H]1CCCN1c1ccn2ncc(C(=O)NC[C@@H](O)CO)c2n1
Yield: 46 %

Procedure:
Prepared by the method of Example 1, using (R)-5-(2-(5-fluoro-2-methoxyphenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (Preparation G) and (R)-3-aminopropane-1,2-diol (2.0 equiv). The crude material was purified by SiO2 column chromatography, eluting with EtOAc then 10% MeOH-EtOAc to afford the title compound as a white solid (46% yield). MS (apci) m/z=430.1 (M+H).
Reaction SMILES: Br[C:2]1[C:3]([CH3:21])=[C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)[C:5]2[N:6]([N:8]=[CH:9][N:10]=2)[CH:7]=1.C([Sn](CCCC)(CCCC)[C:27]1[N:31]([C:32]2[CH:39]=[CH:38][C:35]([C:36]#[N:37])=[CH:34][CH:33]=2)[N:30]=[CH:29][CH:28]=1)CCC>>[CH3:21][C:3]1[C:2]([C:27]2[N:31]([C:32]3[CH:39]=[CH:38][C:35]([C:36]#[N:37])=[CH:34][CH:33]=3)[N:30]=[CH:29][CH:28]=2)=[CH:7][N:6]2[N:8]=[CH:9][N:10]=[C:5]2[C:4]=1[C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccnn1-c1ccc(C#N)cc1
Reactant: Cc1c(Br)cn2ncnc2c1-c1cccc(C(F)(F)F)c1
Product: Cc1c(-c2ccnn2-c2ccc(C#N)cc2)cn2ncnc2c1-c1cccc(C(F)(F)F)c1

Procedure:
The title compound was prepared from 6-bromo-7-methyl-8-(3-trifluoromethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridine (Int. 6, 100 mg, 0.281 mmol) and 4-(5-tributylstannanyl-pyrazol-1-yl)-benzonitrile (Int. 3, 193 mg, 0.421 mmol) using a similar method to that used in Example 1 (Step 4) (91 mg).
Reaction SMILES: Cl.[NH2:2][C:3]1[N:4]=[C:5](O)[C:6]2[S:11][C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[C:7]=2[N:8]=1.O=P(Cl)(Cl)[Cl:19].CN(C)C1C=CC=CC=1>[NH4+].[OH-]>[Cl:19][C:5]1[C:6]2[S:11][C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[C:7]=2[N:8]=[C:3]([NH2:2])[N:4]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Nc1nc(O)c2sc3ccccc3c2n1
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: CN(C)c1ccccc1
Product: Nc1nc(Cl)c2sc3ccccc3c2n1
Temperature: 110 °C
Yield: 52 %

Procedure:
A suspension of 2-amino-benzo[4,5]thieno[3,2-d]pyrimidin-4-ol hydrochloride (179 mg, 0.7 mmol), POCl3 (1.5 mL), and N,N-dimethylaniline (0.15 mL) was heated at 110° C. for 3 h. The mixture was cooled to rt and the resulting suspension was added dropwise to a 0° C. solution of aq. NH4OH (19 g/L; 30 mL). The suspension was filtered and the collected solid dried to yield 87 mg (52%) of a crude solid, which was immediately used without purification.
Reaction SMILES: C([NH:3][C:4]([NH:16][CH2:17][CH2:18][NH2:19])=[N:5][CH2:6][CH2:7][S:8][CH2:9][C:10]1[NH:14][CH:13]=[N:12][C:11]=1[CH3:15])#N.[ClH:20]>>[ClH:20].[ClH:20].[ClH:20].[NH2:19][CH2:18][CH2:17][NH:16][C:4]([NH:5][CH2:6][CH2:7][S:8][CH2:9][C:10]1[NH:14][CH:13]=[N:12][C:11]=1[CH3:15])=[NH:3]
Reactant: Cc1nc[nH]c1CSCCN=C(NC#N)NCCN
Agent: Cl
Product: Cc1nc[nH]c1CSCCNC(=N)NCCN

Procedure:
N-Cyano-N'-(2-aminoethyl)-N"-[2-((4-methyl-5-imidazolyl)methylthio)ethyl]guanidine (1.0 g) (see Example 10) and 1N hydrochloric acid (20 ml) were refluxed together for 6 hours. Evaporation and recrystallisation from methanol/isopropanol gave the title compound (0.6 g), m.p. 195°-196° C.
Reaction SMILES: O.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl.[C:16]([O:20][C:21]([NH:23][CH2:24][C@@:25]1([CH2:43][C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[CH2:31][C@H:30]2[C@@H:26]1[CH:27]=[C:28]([CH2:32][O:33]CC1C=CC(OC)=CC=1)[CH2:29]2)=[O:22])([CH3:19])([CH3:18])[CH3:17]>C(Cl)Cl>[C:16]([O:20][C:21]([NH:23][CH2:24][C@@:25]1([CH2:43][C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[CH2:31][C@H:30]2[C@@H:26]1[CH:27]=[C:28]([CH2:32][OH:33])[CH2:29]2)=[O:22])([CH3:19])([CH3:18])[CH3:17]
Reactant: COc1ccc(COCC2=C[C@H]3[C@@H](C2)C[C@@]3(CNC(=O)OC(C)(C)C)CC(=O)OC(C)(C)C)cc1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)C[C@]1(CNC(=O)OC(C)(C)C)C[C@@H]2CC(CO)=C[C@@H]21
Temperature: 0 °C

Procedure:
Water (1.4 mL) and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (831 mg, 3.66 mmol) were added to a methylene chloride solution (25 mL) of tert-butyl(±)-[(1R,5R,6R)-6-{[(tert-butoxycarbonyl)amino]methyl}-3-{[(4-methoxybenzyl)oxy]methyl}bicyclo[3.2.0]hept-3-en-6-yl]acetate (1.19 g, 2.44 mmol) with stirring at 0° C. The mixture was stirred at this temperature 0° C. for 1 hour and further stirred at room temperature for 1 hour. Then, the reaction was terminated by the addition of a saturated aqueous solution of sodium bicarbonate, followed by extraction with methylene chloride. The organic layer was washed with water, a saturated aqueous solution of sodium bicarbonate, and saturated saline and dried over anhydrous sodium sulfate. The residue was filtered and concentrated under reduced pressure. Then, the obtained crude product was purified by silica gel column chromatography to obtain the compound of interest as an oil substance (571 mg, 64%).
Reaction SMILES: [F:1][C:2]([F:14])([CH3:13])[CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[CH:11]=[CH:10][C:9]([NH2:12])=[N:8]1.[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20](/[CH:23]=[CH:24]/[C:25](O)=[O:26])=[CH:19][CH:18]=1>>[F:14][C:2]([F:1])([CH3:13])[CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[CH:11]=[CH:10][C:9]([NH:12][C:25](=[O:26])/[CH:24]=[CH:23]/[C:20]2[CH:21]=[CH:22][C:17]([O:16][CH3:15])=[CH:18][CH:19]=2)=[N:8]1
Reactant: COc1ccc(/C=C/C(=O)O)cc1
Reactant: CC(F)(F)CCCCn1ccc(N)n1
Product: COc1ccc(/C=C/C(=O)Nc2ccn(CCCCC(C)(F)F)n2)cc1

Procedure:
Following general procedure B, starting from 1-(5,5-difluoro-hexyl)-1H-pyrazol-3-ylamine and (E)-3-(4-methoxy-phenyl)-acrylic acid. LC-MS-conditions 05b: tR=1.08 min; [M+H]+=364.29.
Reaction SMILES: CN(C=O)C.C(=O)([O-])[O-].[K+].[K+].[OH:12][C:13]1[CH:20]=[CH:19][C:16]([CH:17]=[O:18])=[CH:15][CH:14]=1.[CH:21]1([CH2:27]Br)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1>O>[CH:21]1([CH2:27][O:12][C:13]2[CH:20]=[CH:19][C:16]([CH:17]=[O:18])=[CH:15][CH:14]=2)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: O=Cc1ccc(O)cc1
Reactant: BrCC1CCCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1ccc(OCC2CCCCC2)cc1
Yield: 63 %

Procedure:
To 250 ml of DMF containing about 200 g of anhydrous potassium carbonate (1.5M) was added 122 g of 4-hydroxybenzaldehyde and 177 g of cyclohexylmethylbromide. The mixture was heated to reflux temperature and maintained overnight, after which was poured into cold water and extracted with ethyl acetate. The extracts were dried and evaporated under reduced pressure to yield the desired subtitled intermediate (63% yield), b.p. 133°-138° C.
Reaction SMILES: [N:1]1[N:2]([CH2:6][C:7]([OH:9])=O)[N:3]=[CH:4][CH:5]=1.[Cl:10][C:11]1[CH:39]=[CH:38][C:14]([CH2:15][C@H:16]2[CH2:20][NH:19][C@H:18]([C:21]([NH:23][C:24]3[CH:29]=[CH:28][C:27]([O:30][C:31]4[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=4)=[CH:26][CH:25]=3)=[O:22])[CH2:17]2)=[CH:13][CH:12]=1>>[N:3]1[N:2]([CH2:6][C:7]([N:19]2[CH2:20][C@H:16]([CH2:15][C:14]3[CH:38]=[CH:39][C:11]([Cl:10])=[CH:12][CH:13]=3)[CH2:17][C@H:18]2[C:21]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([O:30][C:31]3[CH:32]=[CH:33][C:34]([F:37])=[CH:35][CH:36]=3)=[CH:26][CH:25]=2)=[O:22])=[O:9])[N:1]=[CH:5][CH:4]=1
Reactant: O=C(O)Cn1nccn1
Reactant: O=C(Nc1ccc(Oc2ccc(F)cc2)cc1)[C@@H]1C[C@@H](Cc2ccc(Cl)cc2)CN1
Product: O=C(Nc1ccc(Oc2ccc(F)cc2)cc1)[C@@H]1C[C@@H](Cc2ccc(Cl)cc2)CN1C(=O)Cn1nccn1

Procedure:
Proceeding as in Example 1, but substituting 2-(2H-1,2,3-triazol-2-yl)acetic acid and (2S,4R)-4-(4-chlorobenzyl)-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide, gave Compound 227, (2S,4R)-1-(2-(2H-1,2,3-triazol-2-yl)acetyl)-4-(4-chlorobenzyl)-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide. 1H-NMR (400 MHz, CDCl3): δ 9.14 (s, 1H), 7.72 (s, 1H), 7.42 (d, 2H), 7.29-7.26 (m, 2H), 7.12 (d, 2H), 7.00 (t, 2H), 6.94-6.89 (m, 4H), 5.28 (d, 2H), 4.85 (d, 1H), 3.51 (t, 1H), 3.15 (t, 1H), 2.96-2.85 (m, 2H), 2.68-2.62 (m, 2H), 1.70-1.61 (m, 1H). MS (EI) for C28H25ClFN5O3 found 534.2 (MH+).
Reaction SMILES: [CH2:1]([C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[C:13]([CH2:18][CH:19]4[CH2:22][N:21]([C:23]([CH3:29])([CH3:28])[C:24](OC)=[O:25])[CH2:20]4)[N:14]3[CH3:17])=[C:10]([N:30]3[CH2:35][CH2:34][O:33][CH2:32][CH2:31]3)[N:9]=2)[C:6]2[CH:36]=[CH:37][CH:38]=[CH:39][C:5]=2[N:4]=1)[CH3:2].[H-].[Al+3].[Li+].[H-].[H-].[H-]>>[CH2:1]([C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[C:13]([CH2:18][CH:19]4[CH2:20][N:21]([C:23]([CH3:29])([CH3:28])[CH2:24][OH:25])[CH2:22]4)[N:14]3[CH3:17])=[C:10]([N:30]3[CH2:35][CH2:34][O:33][CH2:32][CH2:31]3)[N:9]=2)[C:6]2[CH:36]=[CH:37][CH:38]=[CH:39][C:5]=2[N:4]=1)[CH3:2]
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CC3CN(C(C)(C)C(=O)OC)C3)n(C)c2n1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CC3CN(C(C)(C)CO)C3)n(C)c2n1

Procedure:
Following the procedure for 509, methyl 2-(3-((2-(2-ethyl-1H-benzo[d]imidazol-1-yl)-9-methyl-6-morpholino-9H-purin-8-yl)methyl)azetidin-1-yl)-2-methylpropanoate was reduced with lithium aluminum hydride to give 533. LCMS m/z: 253.2 (2M+H+)