Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:15]2[CH:20]=[CH:19][C:18]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)=[CH:17][CH:16]=2)[C:9]([CH3:14])([CH3:13])[C:10](O)=[O:11])=[CH:4][CH:3]=1.Cl.CN(C)CCCN=C=NCC.CC1C2C(=CC=CC=2)C([C:50]2[N:51]=[C:52]([NH2:55])[S:53][CH:54]=2)=CC=1.C(N(C(C)C)CC)(C)C>CC#N>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([C:15]2[CH:20]=[CH:19][C:18]([N:21]3[CH2:22][CH2:23][O:24][CH2:25][CH2:26]3)=[CH:17][CH:16]=2)[C:9]([CH3:14])([CH3:13])[C:10]([NH:55][C:52]2[S:53][CH:54]=[CH:50][N:51]=2)=[O:11])=[CH:6][CH:7]=1
Reactant: CC(C)(C(=O)O)C(c1ccc(F)cc1)c1ccc(N2CCOCC2)cc1
Reactant: Cc1ccc(-c2csc(N)n2)c2ccccc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C(=O)Nc1nccs1)C(c1ccc(F)cc1)c1ccc(N2CCOCC2)cc1
Temperature: 75 °C
Reaction time: 0.08 h
Yield: 57.7 %

Procedure:
To a solution of the acid of Preparation 14a (51 mg, 0.142 mmol) in CH3CN (3 mL) were added 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (EDC) (48.3 mg, 0.213 mmol) and 1-hydroxy-7-benzotriazole (HOBt) (34 mg, 0.213 mmol). After stirring for 5 minutes, to the solution were added 4-(4-methyl-naphthalen-1-yl)-thiazol-2-ylamine (50.4 mg, 0.426 mmol) and diisopropylethyl amine (0.742 ml, 0.426 mmol). The reaction was heated at 75° C. for 12 hours. The reaction mixture was filtered, and purified by preparative HPLC to give the title compound of Example 222 as a white solid (36 mg, 58% yield). LC/MS (m/z) 440.17 [(M+H)+]; HPLC Rt: 3.12 min. 1H NMR (400 MHz, CDCl3): δ 7.34 (1H, m), 7.18-7.26 (5H, m), 6.79-6.93 (4H, m), 4.42 (1H, s), 3.78 (4H, m), 3.06 (4H, m), 1.34 (6H, s). LC/MS (m/z) 440.17 [(M+H)+]; HPLC Rt: 3.120 min.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[F:14])[N:5]=[CH:4][N:3]=1.[CH3:15][CH:16]([OH:20])[C:17]#[C:18][CH3:19].[H-].[Na+].O>CN(C)C=O>[F:14][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[C:6]1[CH:7]=[C:2]([O:20][CH:16]([CH3:15])[C:17]#[C:18][CH3:19])[N:3]=[CH:4][N:5]=1
Reactant: CC#CC(C)O
Reactant: Fc1ccccc1-c1cc(Cl)ncn1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC#CC(C)Oc1cc(-c2ccccc2F)ncn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.5 %

Procedure:
In 10 ml of N,N-dimethylformamide were dissolved 449 mg of 4-chloro-6-(2-fluorophenyl)pyrimidine and 272 mg of 3-pentyn-2-ol, to which 130 mg of sodium hydride (60% in oil) was added, followed by stirring at room temperature for 8 hours. The reaction mixture was then poured into water and extracted three times with ethyl acetate. The organic layers were combined, washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated. The resulting residue was subjected to silica gel column chromatography to give 510 mg of 4-(2-fluorophenyl)-6-(1-methyl-2-butynyloxy)pyrimidine (the present compound (151)).
Reaction SMILES: [P:1]([S:20][CH2:21][CH2:22][CH3:23])([O:17][CH2:18][CH3:19])([S:3][CH2:4][C:5]1[CH:10]=[C:9]([O:11][CH2:12][CH3:13])[N:8]=[C:7]([O:14][CH2:15][CH3:16])[N:6]=1)=O.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:25]>C1(C)C=CC=CC=1>[P:1]([O:17][CH2:18][CH3:19])([S:20][CH2:21][CH2:22][CH3:23])([S:3][CH2:4][C:5]1[CH:10]=[C:9]([O:11][CH2:12][CH3:13])[N:8]=[C:7]([O:14][CH2:15][CH3:16])[N:6]=1)=[S:25]
Reactant: CCCSP(=O)(OCC)SCc1cc(OCC)nc(OCC)n1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Solvent: Cc1ccccc1
Product: CCCSP(=S)(OCC)SCc1cc(OCC)nc(OCC)n1

Procedure:
2 g (0.053 mol) of O-ethyl S-(2,6-diethoxy-4-pyrimidinylmethyl) S-(n-propyl) dithiophosphate (see Example 2) and 0.3 g (0.0145 mol) of phosphorus pentasulphide in 10 ml of toluene are left at 60° C. for 16 hours. The mixture is then diluted with 50 ml of toluene and the solution is washed once with 0.5N hydrochloric acid and twice with saturated sodium chloride solution. The solvent is subsequently removed by evaporation under reduced pressure and the resulting crude product is purified by chromatography on silica gel with 15% diethyl ether in n-hexane. There is obtained O-ethyl S-(2,6-diethoxy-4-pyrimidinylmethyl) S-(n-propyl) trithiophosphate as a yellow oil, nD23 1.5648.
Reaction SMILES: [CH3:1][C:2]([C:4]1[C:5]([OH:11])=[CH:6][CH:7]=[CH:8][C:9]=1[OH:10])=[O:3].S([O-])(O[CH3:16])(=O)=O.C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[CH3:1][C:2]([C:4]1[C:5]([O:11][CH3:16])=[CH:6][CH:7]=[CH:8][C:9]=1[OH:10])=[O:3]
Reactant: CC(=O)c1c(O)cccc1O
Reactant: COS(=O)(=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1cccc(O)c1C(C)=O
Yield: 60 %

Procedure:
A mixture of 25 mmoles of 2,6-dihydroxy acetophenone, 26 mmoles of methyl sulphate, 75 mmoles of K2CO3 and 60 ml of acetone are heated to reflux for 12 hours. Then the reaction medium is cooled, the mineral matter is separated by filtration and rinsed with dichloromethane. After evaporation of the organic phase and flash chromatography, the expected product is obtained in a practically quantitave way (mp =55° C).
Reaction SMILES: I[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18].NC(N)=[S:22].[OH-].[Na+].Cl>C(O)C>[SH:22][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18]
Reactant: NC(N)=S
Reactant: O=C(O)CCCCCCCCCCCCCCCI
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)CCCCCCCCCCCCCCCS
Temperature: 25 °C
Yield: 70 %

Procedure:
A mixture of 16-iodohexadecanoic acid (6) (4.0 g, 10.4 mmol) and thiourea (0.88 g, 1.1 equiv.) in ethanol (100 mL) was refluxed overnight under N2 atmosphere. The solution was cooled to room temperature. Sodium hydroxide (1.0 g in 10 mL of water) wad added and the mixture was further heated for 2 hr. After cooling to room temperature 1N HCl was added and the product was extracted using CH2Cl2. The organic extract was dried and evaporated to give a white solid Yield: 2.1 g (69%)
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:20]([O:21][C:22](=[O:24])[CH3:23])[C@@H:19]([O:25][C:26](=[O:28])[CH3:27])[C@@H:18]([CH2:29][O:30][C:31](=[O:33])[CH3:32])[O:17][C@H:6]1[O:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][O:13][CH2:14][CH2:15]Cl)(=[O:3])[CH3:2].[N-:34]=[N+:35]=[N-:36].[Na+]>[N+](CCCC)(CCCC)(CCCC)CCCC.[I-].CN(C=O)C.CCOC(C)=O>[C:1]([O:4][C@@H:5]1[C@@H:20]([O:21][C:22](=[O:24])[CH3:23])[C@@H:19]([O:25][C:26](=[O:28])[CH3:27])[C@@H:18]([CH2:29][O:30][C:31](=[O:33])[CH3:32])[O:17][C@H:6]1[O:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][O:13][CH2:14][CH2:15][N:34]=[N+:35]=[N-:36])(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@H]1O[C@@H](OCCOCCOCCCl)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Reactant: [N-]=[N+]=[N-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(=O)OC[C@H]1O[C@@H](OCCOCCOCCN=[N+]=[N-])[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Temperature: 25 °C
Yield: 84.4 %

Procedure:
A solution of 4a (3.85 g, 7.71 mmol), sodium azide (2.51 g, 38.58 mmol) and nBu4NI (5.7 g, 15.43 mmol) in anhydrous DMF (20 mL) was stirred at 90° C. for 24 hrs. The solution was cooled to r.t. then diluted with EtOAc (300 mL). The organic layer was washed with water (3×200 mL), dried (Na2SO4), filtered and evaporated under reduced pressure. The oily residue was purified by flash silica gel column chromatography (PE then PE/EtOAc 1:1) to afford 4 (3.29 g, 85%) as a pale yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[S:15][C:14]3=[N:16][CH:17]=[C:18](I)[N:13]3[N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].O1CCOCC1.[C:26]([C:28]1[CH:33]=[CH:32][C:31](B2OC(C)(C)C(C)(C)O2)=[CH:30][N:29]=1)#[N:27].C(=O)([O-])[O-].[K+].[K+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[S:15][C:14]3=[N:16][CH:17]=[C:18]([C:31]4[CH:32]=[CH:33][C:28]([C:26]#[N:27])=[N:29][CH:30]=4)[N:13]3[N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(-c2nn3c(I)cnc3s2)cc1OC
Reactant: CC1(C)OB(c2ccc(C#N)nc2)OC1(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc(-c2nn3c(-c4ccc(C#N)nc4)cnc3s2)cc1OC
Temperature: 120 °C
Yield: 26.6 %

Procedure:
A mixture of 2-(3,4-dimethoxy-phenyl)-5-iodo-imidazo[2,1-b][1,3,4]thiadiazole (0.10 g, 0.3 mmol, 1 eq), dioxane (5 mL), 2-cyanopyridine-5-boronic acid pinacol ester (0.155 g, 0.64 mmol, 2.5 eq), Pd(Ph3P)2Cl2 (0.018 g, 0.1 eq), potassium carbonate (0.178 g, 1.3 mmol, 5 eq), and water (2 mL) was heated in the microwave oven (120° C., 30 min) and was left to cool to RT. A precipitate formed that was filtered off (0.048 g) and washed with a mixture of Et2O and little MeOH to afford the desired product (white solid, 0.029 g, 31%). HPLC-MS: (5-100% B in 8 min, 0.8 mL/min, 50° C.): tR=5.37 min, [M+H]+ m/z 364.1; 1H NMR (300 MHz, DMSO) d 9.47-9.39 (m, 1H), 8.68 (dd, J=8.3, 2.3, 1H), 8.23-8.10 (m, 2H), 7.60 (dd, J=8.3, 2.3, 1H), 7.51 (d, J=2.1, 1H), 7.17 (d, J=8.5, 1H), 3.91 (s, 3H), 3.87 (s, 3H);
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C@H:16]2[CH2:21][N:20]([CH:22]3[CH2:25][CH2:24][CH2:23]3)[CH2:19][CH2:18][N:17]2[C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])=[O:15])[CH2:10][CH2:9]1)C1C=CC=CC=1.O>[Pd].C(O)C>[CH:22]1([N:20]2[CH2:19][CH2:18][N:17]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[C@@H:16]([C:14]([N:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)=[O:15])[CH2:21]2)[CH2:23][CH2:24][CH2:25]1
Reactant: CC(C)(C)OC(=O)N1CCN(C2CCC2)C[C@@H]1C(=O)N1CCN(Cc2ccccc2)CC1
Agent: [Pd]
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(C2CCC2)C[C@@H]1C(=O)N1CCNCC1
Temperature: 25 °C
Yield: 100.1 %

Procedure:
10% Palladium on carbon (900 mg) was added to tert-butyl (2R)-2-[(4-benzylpiperazin-1-yl)carbonyl]-4-cyclobutylpiperazine-1-carboxylate (5.12 g) and water (10 ml). Under an argon atmosphere, ethanol (250 ml) was added and the mixture stirred at room temperature under a hydrogen filled balloon. After 4 hours the catalyst was removed by filtration and washed with a small quantity of non-flammable solvent (dichloromethane). The combined filtrate was concentrated in vacuo, azeotroped once with toluene and dried under vacuum to give tert-butyl (2R)-4-cyclobutyl-2-(piperazin-1-ylcarbonyl)piperazine-1-carboxylate as an off-white foam (4.08 g).
Reaction SMILES: Cl[C:2]1[C:11]([N:12]([CH:14]([CH3:16])[CH3:15])[CH3:13])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:17]([O:19]C)=[O:18])[CH:8]=2)[N:3]=1.[NH:21]1[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[N:23]=[CH:22]1.C(O[K])(C)=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>[N:21]1([C:2]2[C:11]([N:12]([CH:14]([CH3:16])[CH3:15])[CH3:13])=[N:10][C:9]3[C:4](=[CH:5][CH:6]=[C:7]([C:17]([OH:19])=[O:18])[CH:8]=3)[N:3]=2)[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[N:23]=[CH:22]1
Reactant: COC(=O)c1ccc2nc(Cl)c(N(C)C(C)C)nc2c1
Reactant: c1ccc2[nH]cnc2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(=O)O[K]
Product: CC(C)N(C)c1nc2cc(C(=O)O)ccc2nc1-n1cnc2ccccc21
Temperature: 170 °C
Reaction time: 3 h
Yield: 7.3 %

Procedure:
The mixture of methyl 2-chloro-3-(isopropyl(methyl)amino)quinoxaline-6-carboxylate (200 mg, 0.68 mmol), 1H-benzo[d]imidazole (500 mg, 4.24 mmol), AcOK (200 mg, 2.05 mmol) and Pd(PPh3)4 (39 mg, 0.03 mmol) was stirred for 3 h at 170° C. and then purified by silica gel chromatography eluting with 2%-5% methanol in dichloromethane to afford 2-(1H-benzo[d]imidazol-1-yl)-3-(isopropyl(methyl)amino)quinoxaline-6-carboxylic acid as a yellow solid (18.0 mg, 7%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C@@H:10]([OH:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:17]I>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C@@H:10]([O:14][CH3:17])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CI
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](O)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CO[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C

Procedure:
To commercially available (R)-3-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (4.5 g, 22.36 mmol) in 60 ml DMF at 0° C. was added NaH (1.3 g, 33.54 mmol, 55-65 in mineral oil) under stirring in three portions under an argon atmosphere. After 20 min methyl iodide (4.76 g, 33.54 mmol) was added and the reaction was warmed to RT and stirred for another 3 h. After quenching with sat. aq NaHCO3-solution the mixture was extracted with ethyl acetate. The organic layer was washed with 1N KHSO4 and brine. The organic layer was dried with MgSO4, filtered and evaporated. The crude material was purified by chromatography on silica gel. Yield: 4.6 g, 96
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([OH:16])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.[NH2:48][CH2:49][CH2:50][O:51][C:52]([CH3:73])([CH3:72])[CH2:53][N:54]1[C:66]2[C:65]3[CH:64]=[CH:63][CH:62]=[CH:61][C:60]=3[N:59]=[C:58]([NH2:67])[C:57]=2[N:56]=[C:55]1[CH2:68][O:69][CH2:70][CH3:71]>CN(C=O)C>[NH2:67][C:58]1[C:57]2[N:56]=[C:55]([CH2:68][O:69][CH2:70][CH3:71])[N:54]([CH2:53][C:52]([CH3:73])([O:51][CH2:50][CH2:49][NH:48][C:14](=[O:16])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH3:72])[C:66]=2[C:65]2[CH:64]=[CH:63][CH:62]=[CH:61][C:60]=2[N:59]=1
Reactant: CCOCc1nc2c(N)nc3ccccc3c2n1CC(C)(C)OCCN
Reactant: CC(C)(C)OC(=O)NCCCCCC(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOCc1nc2c(N)nc3ccccc3c2n1CC(C)(C)OCCNC(=O)CCCCCNC(=O)OC(C)(C)C
Yield: 27.8 %

Procedure:
6-(tert-Butoxycarbonylamino)hexanoic acid (197 mg, 850 μmol) was combined with DMF (10.9 mL) to give a colorless solution. O-(Benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (TBTU, 300 mg, 936 μmol) and N,N-diisopropylethylamine (DIEA, 728 μl, 4.25 mmol) were added with stirring in an inert atmosphere. Then 1-(2-(2-aminoethoxy)-2-methylpropyl)-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-4-amine (Example 1c, 304 mg, 850 μmol) was added and the mixture was stirred for 2 hours at room temperature. The mixture was concentrated in vacuo, dissolved in ethyl acetate (5 mL), stirred for 1 min with cold sodium hydroxide solution (1 N) and dried by passing through ChemElut® (10 g). The organic phase was concentrated in vacuo again and the residue was purified by flash chromatography (silica gel, 10% methanol in dichloromethane) to give the title compound (0.135 g, 23%) as light brown oil; LC-MS (UV peak area, ESI) 83%, 571.5 (MH+).
Reaction SMILES: C(OC([NH:8][CH:9]([CH:17]([OH:28])[CH2:18][CH:19]([NH2:27])[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=O)(C)(C)C.FC(F)(F)C(O)=O.[OH-].[Na+]>C(Cl)Cl>[NH2:8][CH:9]([CH:17]([OH:28])[CH2:18][CH:19]([NH2:27])[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CC(C)(C)OC(=O)NC(Cc1ccccc1)C(O)CC(N)Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC(Cc1ccccc1)CC(O)C(N)Cc1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
(2RS,3RS,5RS)-2-tert-Butoxycarbonylamino-3-hydroxy-5-amino-1,6-diphenylhexane obtained in Example 39 (A) was dissolved in methylene chloride (1 ml), and trifluoroacetic acid (0.5 ml) was added at room temperature. After the mixture was stirred at room temperature for 3 hours, a 10% aqueous sodium hydroxide was added. After being extracted with methylene chloride, the mixture was dried over anhydrous sodium sulfate. After the desiccant was filtered off, the filtrate was concentrated under reduced pressure to give the desired compound as a colorless solid (3.2 mg).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([O:8][C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[O:15][CH:14]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:13][CH2:12]3)=[N:6][CH:7]=1.ClC1N=CC([CH2:32][N:33]([CH3:35])[CH3:34])=CC=1>>[CH3:32][N:33]([CH3:35])[CH2:34][C:2]1[CH:7]=[N:6][C:5]([O:8][C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[O:15][CH:14]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:13][CH2:12]3)=[CH:4][CH:3]=1
Reactant: Clc1ccc(Oc2ccc3c(c2)CCC(c2ccccc2)O3)nc1
Reactant: CN(C)Cc1ccc(Cl)nc1
Product: CN(C)Cc1ccc(Oc2ccc3c(c2)CCC(c2ccccc2)O3)nc1

Procedure:
Dimethyl-[6-(2-phenylchroman-6-yloxy)pyridin-3-ylmethyl]amine was prepared as described for 5-Chloro-2-(2-phenylchroman-6-yloxy)pyridine in Example 61, but replacing 2,5-dichloropyridine with (6-chloropyridin-3-ylmethyl)dimethylamine. 1H NMR (400 MHz, CDCl3) δ: 8.03 (d, 1H, J 2.3 Hz), 7.65 (dd, 1H, J 8.4, 2.3 Hz), 7.44-7.32 (m, 5H), 6.92-6.88 (m, 3H), 6.84 (d, 1H, J 8.4 Hz), 5.05 (dd, 1H, J 10.2, 2.3 Hz), 3.36 (s, 2H), 3.02 (m, 1H), 2.80 (m, 1H), 2.23 (s, 1H), 2.19 (m, 1H), 2.10 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH3:13])[C:11]([C:14]([N:16]([O:18][CH3:19])[CH3:17])=[O:15])=[C:10]([C:20]3[CH:25]=[CH:24][C:23]([S:26](=[O:29])(=[O:28])[NH2:27])=[CH:22][CH:21]=3)[C:9]=2[CH3:30])=[CH:4][CH:3]=1.[CH3:31][N:32]([CH:34]=O)[CH3:33]>C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH3:13])[C:11]([C:14]([N:16]([O:18][CH3:19])[CH3:17])=[O:15])=[C:10]([C:20]3[CH:25]=[CH:24][C:23]([S:26](=[O:28])(=[O:29])[N:27]=[CH:31][N:32]([CH3:34])[CH3:33])=[CH:22][CH:21]=3)[C:9]=2[CH3:30])=[CH:4][CH:3]=1
Reactant: CON(C)C(=O)c1c(-c2ccc(S(N)(=O)=O)cc2)c(C)c(-c2ccc(Cl)cc2)n1C
Reactant: CN(C)C=O
Solvent: CCOC(C)=O
Product: CON(C)C(=O)c1c(-c2ccc(S(=O)(=O)N=CN(C)C)cc2)c(C)c(-c2ccc(Cl)cc2)n1C
Temperature: 25 °C
Reaction time: 15 h
Yield: 82.19 %

Procedure:
To a stirred solution of 5-(4-chlorophenyl)-N-methoxy-N,1,4-trimethyl-3-(4-sulfamoylphenyl)-1H-pyrrole-2-carboxamide (compound 49φ, 0.650 g, 1.45 mmol) in ethyl acetate (12 ml) was added DMF (0.65 ml) and DMF acetal (0.207 g, 0.233 ml, 1.74 mmol) sequentially at room temperature. The reaction mixture was then stirred at room temperature for 15 hr under a nitrogen atmosphere. The progress of the reaction was monitored by TLC. The precipitated out product was filtered and washed with ether (10 ml) to obtain the title compound (0.600 g, 82.19%).
Reaction SMILES: [Cl:1]C1C=C(OC)C(OC)=CC=1C1N=C(C2C=C(C(OC)=S)SC=2C)SC=1.[Cl:27][C:28]1[CH:36]=[C:35]([O:37][CH3:38])[C:34]([O:39][CH3:40])=[CH:33][C:29]=1[C:30](O)=[O:31].P(Cl)(Cl)(Cl)(Cl)Cl>>[Cl:27][C:28]1[CH:36]=[C:35]([O:37][CH3:38])[C:34]([O:39][CH3:40])=[CH:33][C:29]=1[C:30]([Cl:1])=[O:31]
Reactant: COC(=S)c1cc(-c2nc(-c3cc(OC)c(OC)cc3Cl)cs2)c(C)s1
Reactant: COc1cc(Cl)c(C(=O)O)cc1OC
Agent: ClP(Cl)(Cl)(Cl)Cl
Product: COc1cc(Cl)c(C(=O)Cl)cc1OC
Temperature: 120 °C
Yield: 96 %

Procedure:
Methyl 4-[4-(2-chloro-4,5-dimethoxyphenyl)(1,3-thiazol-2-yl)]-5-methylthiothiophene-2-carboxylate: 2-Chloro-4,5-dimethoxybenzoic acid (0.5 g, 2.3 mmol) and PCl5 (0.54 g, 2.6 mmol) were placed in a round bottomed flask fitted with a reflux condenser. The mixture was heated in an oil bath at 120° C. for 70 min. The mixture was allowed to cool and the formed phosphorus oxychloride was removed under vacuum to give 0.52 g (96%) of 2-chloro-4,5-dimethoxybenzoyl chloride as a solid. 2-Chloro-4,5-dimethoxybenzoyl chloride (0.52 g, 2.2 mmol) was treated in a manner similar to that for Example 32 step (a) to give 2-bromo-1-(2-chloro-4,5-dimethoxyphenyl)ethan-1-one. The dry solid (0.65 g, 2.2 mmol) was dissolved in acetone (25 ml). To this solution 5-(methoxycarbonyl)-2-(methylthio)-thiophene-3-thiocarboxamide (0.55 g, 2.2 mmol) was added and heated at reflux for 5 h. At this point the solid that precipitated was filtered off and washed with acetone and dried under vacuum to give 0.53 g (54%) of methyl 4-[4-(2-chloro-4,5-dimethoxyphenyl)(1,3-thiazol-2-yl)]-5-methylthiothiophene-2-carboxylate. 1H-NMR (DMSO-d6; 300 MHz) δ 2.73 (s, 3H), 3.83 (s, 3H), 3.84 (s, 3H), 3.85 (s, 3H), 7.13 (s, 1H), 7.69 (s, 1H), 8.13 (s, 1H), 8.17 (s, 1H).
Reaction SMILES: [N:1]1([C:6]2[C:7]([C:12]([NH:14][C@H:15]3[CH2:19][CH2:18][CH2:17][C@@H:16]3[NH:20][C:21]3[CH:26]=[N:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][N:22]=3)=[O:13])=N[CH:9]=[CH:10][CH:11]=2)[CH:5]=[CH:4][CH:3]=[N:2]1.BrC1C=CC=[C:53]([O:57][CH3:58])C=1C(N[C@H]1CCC[C@@H]1NC1C=NC(C(F)(F)F)=CN=1)=O.N1C=CC=N1>>[CH3:53][O:57][C:58]1[CH:9]=[CH:10][CH:11]=[C:6]([N:1]2[CH:5]=[CH:4][CH:3]=[N:2]2)[C:7]=1[C:12]([NH:14][C@H:15]1[CH2:19][CH2:18][CH2:17][C@@H:16]1[NH:20][C:21]1[CH:26]=[N:25][C:24]([C:27]([F:28])([F:30])[F:29])=[CH:23][N:22]=1)=[O:13]
Reactant: O=C(N[C@H]1CCC[C@@H]1Nc1cnc(C(F)(F)F)cn1)c1ncccc1-n1cccn1
Reactant: COc1cccc(Br)c1C(=O)N[C@H]1CCC[C@@H]1Nc1cnc(C(F)(F)F)cn1
Agent: c1cn[nH]c1
Product: COc1cccc(-n2cccn2)c1C(=O)N[C@H]1CCC[C@@H]1Nc1cnc(C(F)(F)F)cn1

Procedure:
Prepared according to the procedure for 3-(1H-pyrazol-1-yl)-N-[(1S,2S)-2-{[5-(trifluoromethyl)pyrazin-2-yl]amino}cyclopentyl]pyridine-2-carboxamide (Example 43) from 2-bromo-6-methoxy-N-[(1S,2S)-2-{[5-(trifluoromethyl)pyrazin-2-yl]amino}cyclopentyl]benzamide (Example 49; 100 mg, 0.218 mmol) and 1H-pyrazole (30 mg, 0.435 mmol) to afford the title compound.
Reaction SMILES: [CH:1](=O)[CH:2]([CH3:4])[CH3:3].[CH:6]([NH2:19])([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C1C=CC=CC=1>O>[CH:1](=[N:19][CH:6]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: NC(c1ccccc1)c1ccccc1
Reactant: CC(C)C=O
Solvent: O
Solvent: c1ccccc1
Product: CC(C)C=NC(c1ccccc1)c1ccccc1

Procedure:
14.4 parts of isobutyraldehyde was added to 36.6 parts of benzhydrylamine in 100 parts of dry benzene at room temperature with stirring. The cloudy mixture was heated to reflux with water-separation for 4 hours. On cooling the solution was filtered to remove a small amount of solid and evaporated to give isobutylidenebenzhydrylamine.
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[CH3:10][O:11][C:12]1[CH:17]=[CH:16][C:15](B(O)O)=[CH:14][CH:13]=1.[F-].[K+]>C1COCC1>[CH:6]([C:5]1[CH:8]=[CH:9][C:2]([C:15]2[CH:16]=[CH:17][C:12]([O:11][CH3:10])=[CH:13][CH:14]=2)=[CH:3][CH:4]=1)=[O:7]
Reactant: COc1ccc(B(O)O)cc1
Reactant: O=Cc1ccc(Cl)cc1
Agent: [F-]
Agent: [K+]
Solvent: C1CCOC1
Product: COc1ccc(-c2ccc(C=O)cc2)cc1
Yield: 95.2 %

Procedure:
4-Chlorobenzaldehyde (141 mg, 1.00 mmol) reacted with 4-methoxyphenylboronic acid (200 mg, 1.32 mmol) using 1/2 mol % of Pd(OAc)2/Ph5FcP(t-Bu)2 and KF (180 mg, 3.10 mmol) in THF (2 ml) at 50° C. to give the title compound (202 mg, 94%) as a solid: 1H-NMR (400 MHz, CDCl3): δ. 13C{1H}-NMR (100 MHz, CDCl3): δ 191.90, 160.78, 146.77, 134.63, 132.03, 130.31, 128.48, 127.04, 114.45, 55.38.: GC/MS (EI): m/z 212 (M+).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([Cl:12])[CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.C([Li])CCC.[C:18](OCC)(=[O:24])[C:19]([O:21][CH2:22][CH3:23])=[O:20]>O1CCCC1>[Cl:12][C:4]1[CH:5]=[C:6]2[C:11](=[C:2]([C:18](=[O:24])[C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:3]=1)[N:10]=[CH:9][CH:8]=[CH:7]2
Reactant: CCOC(=O)C(=O)OCC
Reactant: Clc1cc(Br)c2ncccc2c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOC(=O)C(=O)c1cc(Cl)cc2cccnc12
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
8-Bromo-6-chloroquinoline [J. Het. Chem. 6, pp. 243-245 (1969); 6 g., 0.025 mole]in 50 ml. of tetrahydrofuran was added dropwise over a 10 minute period to a mixture of butyl lithium (2.3 M in hexane, 12.2 ml., 0.028 mole) and 40 ml. of tetrahydrofuran held at -70° C. After an additional 30 minutes at this temperature, a cold (0° C.) solution of diethyl oxalate (14.6 g, 0.10 mole) in 50 ml. of tetrahydrofuran was added dropwise. The reaction mixture was maintained at 0° C. for 1 hour, then quenched at 0°-5° C. with glacial acetic acid (17 ml.) in 50 ml. of tetrahydrofuran. After warming to room temperature the quenched mixture was poured into 500 m1. of water and then diluted with 500 ml. of ethyl acetate and 500 ml. of saturated sodium bicarbonate. The organic layer was separated, washed with 500 ml. of fresh bicarbonate, dried over anhydrous magnesium sulfate, filtered, and evaporated to an oil. Trituration with two 100 ml. portions of hexane gave the title product (2.3 g., m.p. 107°-110° C.; m/e 265/263).