Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([O:11][CH2:12][CH2:13][C@@H:14]2[CH2:16][C@@H:15]2[CH:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)=[N:9][CH:10]=1)(=[O:4])=[O:3].C(N(CC)CC)C.[C:30](Cl)(=[O:37])[O:31][CH2:32][C:33]([CH3:36])([CH3:35])[CH3:34]>ClCCl.[NH4+].[Cl-]>[CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([O:11][CH2:12][CH2:13][C@@H:14]2[CH2:16][C@@H:15]2[CH:17]2[CH2:22][CH2:21][N:20]([C:30]([O:31][CH2:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:37])[CH2:19][CH2:18]2)=[N:9][CH:10]=1)(=[O:3])=[O:4]
Reactant: CS(=O)(=O)c1ccc(OCC[C@@H]2C[C@@H]2C2CCNCC2)nc1
Reactant: CC(C)(C)COC(=O)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)COC(=O)N1CCC([C@H]2C[C@H]2CCOc2ccc(S(C)(=O)=O)cn2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 5-(methylsulfonyl)-2-(2-((1S,2R)-2-(piperidin-4-yl)cyclopropyl)ethoxy)pyridine (Step B, Example GJM10; 0.10 g, 0.32 mmol) in dichloromethane (3 mL) under a nitrogen atmosphere was added triethylamine (0.13 mL, 0.89 mmol) and neopentyl carbonochloridate (0.08 mL, 0.57 mmol). The resulting solution was stirred for 2 h at ambient temperature. The solution was diluted with saturated NH4Cl(aq.) (20 mL). The resulting layers were separated and the aqueous phase extracted with dichloromethane (3×15 mL). The combined organic extracts were washed with brine (20 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. Purification of the obtained residue by CombiFlash chromatography (12 g silica gel, 0 to 50% EtOAc in hexanes) provided the title compound as an off white semi-solid: 1H NMR (300 MHz, CDCl3) δ 8.72 (m, 1 h), 8.03 (m, 1H), 6.84 (m, 1H), 4.49 (m, 2H), 4.14 (m, 2H), 3.77 (s, 2H), 3.07 (s, 3H), 2.75 (m, 2H), 2.11 (m, 1H), 1.82-1.71 (m, 2H) 1.59-1.47 (m, 1H), 1.39-1.25 (m, 2H), 1.04-0.85 (m, 11H), 0.73-0.54 (m, 2H), −0.11 (q, J=4.8 Hz, 1H); MS (ESI) m/z 439 [M+H]+. GPR119 Human EC50: 2 nM
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[C:7]1[CH:12]=[C:11]([CH3:13])[C:10]([OH:14])=[C:9]([CH2:15][CH3:16])[CH:8]=1)([CH3:4])([CH3:3])[CH3:2].C(C1C=C(C(=N)NO)C=C(C)C=1O[CH2:23][C@@H:24]([OH:31])[CH2:25][NH:26][C:27](=[O:30])[CH2:28][OH:29])C>>[C:1]([O:5][C:6](=[O:17])[C:7]1[CH:12]=[C:11]([CH3:13])[C:10]([O:14][CH2:23][C@@H:24]([OH:31])[CH2:25][NH:26][C:27](=[O:30])[CH2:28][OH:29])=[C:9]([CH2:15][CH3:16])[CH:8]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCc1cc(C(=N)NO)cc(C)c1OC[C@@H](O)CNC(=O)CO
Reactant: CCc1cc(C(=O)OC(C)(C)C)cc(C)c1O
Product: CCc1cc(C(=O)OC(C)(C)C)cc(C)c1OC[C@@H](O)CNC(=O)CO

Procedure:
3-Ethyl-4-[(S)-2-hydroxy-3-(2-hydroxy-acetylamino)-propoxy]-5-methyl-benzoic acid tert-butyl ester (5.94 g) is prepared starting from the above 3-ethyl-4-hydroxy-5-methyl-benzoic acid tert.butyl ester (6.53 g, 27.6 mmol) following the procedures given for N—((S)-3-[2-ethyl-4-(N-hydroxycarbamimidoyl)-6-methyl-phenoxy]-2-hydroxy-propyl)-2-hydroxy-acetamide; LC-MS: tR=0.87 min; [M+H]+=368.11; 1H NMR (CDCl3): δ1.17 (t, J=7.5 Hz, 3H), 1.53 (s, 9H), 2.28 (s, 3H), 2.66 (q, J=7.5 Hz, 2H), 3.17-3.26 (m, 1H), 3.38-3.46 (m, 1H), 3.65-3.75 (m, 2H), 3.83 (d, J=5.5 Hz, 2H), 3.91-3.97 (m, 1H), 5.28 (d, J=5.3 Hz, 1H), 5.54 (t, J=5.5 Hz, 1H), 7.59 (s, 1H), 7.60 (s, 1H), 7.68 (t, J=5.5 Hz, 1H).
Reaction SMILES: [CH3:1][C:2]([CH3:20])([CH2:16][CH2:17][CH:18]=[CH2:19])[CH2:3][O:4][C:5]([NH:7][C@@H:8]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:9]([OH:11])=O)=[O:6].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:54][N:55]([CH3:81])[C:56]1[CH:61]=[CH:60][C:59]([C:62]2[CH:67]=[CH:66][C:65]([C@@:68]3([O:77][CH3:78])[CH2:72][NH:71][C@H:70]([C:73]([O:75][CH3:76])=[O:74])[CH2:69]3)=[CH:64][CH:63]=2)=[C:58]([CH:79]=[CH2:80])[CH:57]=1>C(Cl)Cl>[CH3:81][N:55]([CH3:54])[C:56]1[CH:61]=[CH:60][C:59]([C:62]2[CH:63]=[CH:64][C:65]([C@@:68]3([O:77][CH3:78])[CH2:72][N:71]([C:9](=[O:11])[C@@H:8]([NH:7][C:5]([O:4][CH2:3][C:2]([CH3:1])([CH3:20])[CH2:16][CH2:17][CH:18]=[CH2:19])=[O:6])[C:12]([CH3:15])([CH3:14])[CH3:13])[C@H:70]([C:73]([O:75][CH3:76])=[O:74])[CH2:69]3)=[CH:66][CH:67]=2)=[C:58]([CH:79]=[CH2:80])[CH:57]=1
Reactant: C=CCCC(C)(C)COC(=O)N[C@H](C(=O)O)C(C)(C)C
Reactant: C=Cc1cc(N(C)C)ccc1-c1ccc([C@@]2(OC)CN[C@H](C(=O)OC)C2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=CCCC(C)(C)COC(=O)N[C@H](C(=O)N1C[C@](OC)(c2ccc(-c3ccc(N(C)C)cc3C=C)cc2)C[C@H]1C(=O)OC)C(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 64.8 %

Procedure:
(S)-2-((2,2-dimethylhex-5-enyloxy)carbonylamino)-3,3-dimethylbutanoic acid (62 mg, 0.217 mmol), DIEA (0.076 mL, 0.434 mmol) and HATU (61 mg, 0.159 mmol) were added to a solution of (2S,4R)-methyl 4-(4′-(dimethylamino)-2′-vinylbiphenyl-4-yl)-4-methoxypyrrolidine-2-carboxylate (55 mg, 0.145 mmol) in DCM (3 mL). The reaction was stirred at r.t. for 2 hrs. The reaction was evaporated and purified on the Biotage (10-45% EtOAc:Hex) to give (2S,4R)-methyl 4-(4′-(dimethylamino)-2′-vinylbiphenyl-4-yl)-1-((S)-2-((2,2-dimethylhex-5-enyloxy)carbonylamino)-3,3-dimethylbutanoyl)-4-methoxypyrrolidine-2-carboxylate (61 mg, 0.094 mmol, 65% yield) as a yellow oil. LCMS: rt=2.00 min. [M-OMe]+=616 and [M+H]+=648; Phenomenex-Luna C-18 (5μ) (3.0×50 mm); Solvent A=10% acetonitrile—90% water—0.1% TFA, Solvent B=90% acetonitrile—10% water—0.1% TFA; gradient 0% to 100% solvent B over 2 min. and then hold for 1 min.; 4 mL/min; inj. vol.=5 uL; wavelength=220.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:9]2[S:10][C:11]([C:15]([O:17]CC)=[O:16])=[C:12]([CH3:14])[N:13]=2)[CH:5]=[CH:6][C:7]=1[OH:8].C(=O)([O-])[O-].[K+].[K+].[CH2:26](Br)[CH:27]([CH3:29])[CH3:28].O>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]([C:9]2[S:10][C:11]([C:15]([OH:17])=[O:16])=[C:12]([CH3:14])[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:26][CH:27]([CH3:29])[CH3:28]
Reactant: CC(C)CBr
Reactant: CCOC(=O)c1sc(-c2ccc(O)c(Br)c2)nc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1nc(-c2ccc(OCC(C)C)c(Br)c2)sc1C(=O)O
Temperature: 70 °C
Reaction time: 24 h
Yield: 84.3 %

Procedure:
340 mg of the phenol derivative prepared in step (1) was suspended in 5 ml of N,N-dimethylformamide, 690 mg of anhydrous potassium carbonate and 690 mg of isobutyl bromide were added thereto, and the mixture was stirred at 70° C. for 24 hours. After the completion of the reaction, the reaction product was poured into water, and the mixture was extracted with ether. The organic layer was concentrated to give a crystalline product. This product was hydrolyzed by a conventional process and purified by recrystallization to give 310 mg of 2-(3-bromo-4-isobutyloxyphenyl)-4-methyl-5-thiazolecarboxylic acid (yield: 78%).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([CH:11]=O)[CH:2]=1.[NH2:13][C:14]1[CH:29]=[CH:28][CH:27]=[CH:26][C:15]=1[C:16]([NH:18][C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=1)=[O:17]>CCO>[Cl:25][C:22]1[CH:23]=[CH:24][C:19]([N:18]2[C:16](=[O:17])[C:15]3[C:14](=[CH:29][CH:28]=[CH:27][CH:26]=3)[N:13]=[C:11]2[C:3]2[CH:2]=[N:1][C:10]3[C:5]([CH:4]=2)=[CH:6][CH:7]=[CH:8][CH:9]=3)=[CH:20][CH:21]=1
Reactant: O=Cc1cnc2ccccc2c1
Reactant: Nc1ccccc1C(=O)Nc1ccc(Cl)cc1
Solvent: CCO
Product: O=c1c2ccccc2nc(-c2cnc3ccccc3c2)n1-c1ccc(Cl)cc1
Yield: 14 %

Procedure:
3-Quinoline carboxaldehyde (0.41 mmol) and anhydrous CuCl2 (0.110 g, 0.82 mmol) were added to a solution of 2-amino-N-(4-chlorophenyl)benzamide (0.100 g, 0.41 mmol) in anhydrous EtOH (10 mL). The mixture was heated at reflux temperature for 4 hours and concentrated in vacuo. The residue was dissolved in EtOAc and washed with H2O and brine, dried (Na2SO4), filtered, and concentrated. Purification by flash chromatography on silica gel, eluting with 5% to 50% EtOAc in heptane, afforded the title compound as a white solid (14%). 1H-NMR (300 MHz, DMSO-d6): δ 8.83 (d, J=2.1 Hz, 1H), 8.45 (d, J=1.8 Hz, 1H), 8.24 (d, J=8.0 Hz, 1H), 7.88-8.03 (m, 3H), 7.74-7.88 (m, 2H), 7.56-7.73 (m, 2H), 7.52 (d, J=8.6 Hz, 2H), 7.40 (d, J=8.7 Hz, 2H). MS (APCI) m/z: 384 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]2[CH2:7][C:8](=S)[NH:9][N:10]=[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:5]=2[CH:4]=1.[NH2:21][CH2:22][C:23]1([CH3:28])OCCO1.O>COCCO>[CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]2[CH2:7][C:8]3[N:9]([C:23]([CH3:28])=[CH:22][N:21]=3)[N:10]=[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:5]=2[CH:4]=1
Reactant: CC1(CN)OCCO1
Reactant: COc1ccc2c(c1)C(c1ccccc1)=NNC(=S)C2
Solvent: COCCO
Solvent: O
Product: COc1ccc2c(c1)C(c1ccccc1)=Nn1c(C)cnc1C2

Procedure:
500 mg of 8-methoxy-1-(phenyl)-4,5-dihydro-3H-2,3-benzodiazepine-4-thione is stirred in 1.5 ml of ethylene glycol monomethyl ether (Cellosolve®) and 548 mg of 2-aminomethyl-2-methyl-1,3-dioxolane while argon is passing through it for 10 hours at 60° C. After filtration and washing with cold ethanol and diisopropyl ether, 550 mg of imino compound, which is dissolved in 10 ml of ethanol, mixed with 10 ml of concentrated hydrochloric acid and refluxed for 3 hours, is obtained. It is added to water, set at pH 11 and extracted with ethyl acetate. The ethyl acetate phase is washed with water, dried, filtered and concentrated by evaporation. After recrystallization from ethyl acetate/diisopropyl ether, 240 mg of 8-methoxy-3-methyl-6-phenyl-11H-imidazo[1,2-c][2,3]benzodiazepine with a melting point of 140° C. is obtained.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][NH:8][CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.C([O-])([O-])=O.[K+].[K+].Br[CH2:18][C:19]1[CH:31]=[CH:30][C:22]([C:23]([N:25]([CH2:28][CH3:29])[CH2:26][CH3:27])=[O:24])=[CH:21][CH:20]=1.O>C(#N)C>[O:1]1[C:5]2([CH2:10][CH2:9][N:8]([CH2:18][C:19]3[CH:31]=[CH:30][C:22]([C:23]([N:25]([CH2:28][CH3:29])[CH2:26][CH3:27])=[O:24])=[CH:21][CH:20]=3)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1
Reactant: C1CC2(CCN1)OCCO2
Reactant: CCN(CC)C(=O)c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CCN(CC)C(=O)c1ccc(CN2CCC3(CC2)OCCO3)cc1
Reaction time: 16 h
Yield: 96 %

Procedure:
1,4-Dioxa-8-azaspiro[4.5]-decane (200 mmol, 28.6 g, 25.6 mL) is dissolved in 160 ml of dry acetonitrile under nitrogen and treated with K2CO3 (220 mmol, 30.3 g) followed by dropwise addition over 1.5 hours of 4-(bromomethyl)-N,N-diethylbenzamide (200 mmol, 54.01 g) as a solution in 81 mL of acetonitrile. After 16 hours, the reaction mixture is poured into 250 mL of water and extracted twice with 150 mL of methylene chloride. The pooled extracts were washed with 250 mL of brine, dried over Na2SO4 and concentrated in vacuo affording 63.9 g (192 mmol, 96% yield) of the product as a yellow-orange oil.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([OH:8])[NH:6][N:7]=1)[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH:16]([CH3:27])[C:17]([C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=1[Cl:26])=[O:18]>CN(C=O)C>[Cl:26][C:20]1[CH:21]=[C:22]([Cl:25])[CH:23]=[CH:24][C:19]=1[C:17](=[O:18])[CH:16]([O:8][C:5]1[NH:6][N:7]=[C:3]([CH2:1][CH3:2])[CH:4]=1)[CH3:27]
Reactant: CCc1cc(O)[nH]n1
Reactant: CC(Br)C(=O)c1ccc(Cl)cc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCc1cc(OC(C)C(=O)c2ccc(Cl)cc2Cl)[nH]n1
Temperature: 50 °C
Reaction time: 0.08 h

Procedure:
To a solution of 5-ethyl-2H-pyrazol-3-ol (4.40 g, 39.2 mmol) in DMF (40 ml) is added cesium carbonate (13.42 g, 41.2 mmol) and the reaction mixture is heated to 50° C. After 5 minutes, 2-bromo-1-(2,4-dichloro-phenyl)-propan-1-one (Intermediate AA) (11.62 g, 41.2 mmol) in DMF (60 ml) is added slowly (addition time 10 minutes, initially yellow) and the reaction is stirred for a further 45 minutes giving a tan solution which is allowed to cool to RT. The reaction mixture is partitioned between EtOAc (150 ml) and 1N Na2CO3 (400 ml) and extracted with EtOAc (4×75 ml). The combined organic extracts are washed with H2O (1×200 ml) and brine (250 ml), dried (Na2SO4), filtered and concentrated in vacuo to yield a brown oil. The residue is pre-absorbed (dissolved in dichloromethane) onto silica gel and purified via Flashmaster (SiO2 340 g Snap cartridge column) eluting with 4:1 iso-hexane/EtOAc to 2:1 iso-hexane/EtOAc to yield the title compound as a pale yellow solid MS: m/z 313.12 [M+H]+
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11]/[C:12](=[CH:18]\[C:19]1[N:20]=[CH:21][N:22]([C@H:24]2[CH2:29][CH2:28][C@@H:27]([OH:30])[CH2:26][CH2:25]2)[CH:23]=1)/[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[C:51]1[CH:56]=[CH:55][N:54]=[CH:53][CH:52]=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1.C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11]/[C:12](=[CH:18]\[C:19]1[N:20]=[CH:21][N:22]([C@H:24]2[CH2:25][CH2:26][C@H:27]([O:30][C:51]3[CH:56]=[CH:55][N:54]=[CH:53][CH:52]=3)[CH2:28][CH2:29]2)[CH:23]=1)/[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: Oc1ccncc1
Reactant: CCOC(=O)/C(=C/c1cn([C@H]2CC[C@@H](O)CC2)cn1)CCCNC(=O)OC(C)(C)C
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCOC(=O)/C(=C/c1cn([C@H]2CC[C@H](Oc3ccncc3)CC2)cn1)CCCNC(=O)OC(C)(C)C
Temperature: 55 °C
Reaction time: 5.5 h

Procedure:
The compound (170 mg) obtained in Step 2 of Example 37 was dissolved in tetrahydrofuran (6 mL). To the solution, triphenylphosphine (137 mg), 4-hydroxypyridine (50 mg), and a 40% solution of diisopropyl azodicarboxylate in toluene (276 μL) were added, and the mixture was stirred at 55° C. for 5.5 hours. The solvent in the reaction solution was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluting solvent: hexane/ethyl acetate=7/3-ethyl acetate) to obtain the title compound (51 mg).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][N:15]([CH2:23][CH3:24])[C:16]2[C:21]([NH2:22])=[CH:20][CH:19]=[CH:18][N:17]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:25](=O)[CH3:26].C([BH3-])#N.[Na+].[OH-].[Na+]>CO>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][N:15]([CH2:23][CH3:24])[C:16]2[C:21]([NH:22][CH2:25][CH3:26])=[CH:20][CH:19]=[CH:18][N:17]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCN(CC1CCN(Cc2ccccc2)CC1)c1ncccc1N
Reactant: CC=O
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCNc1cccnc1N(CC)CC1CCN(Cc2ccccc2)CC1
Reaction time: 1 h

Procedure:
1-Benzyl-4-[N-ethyl-N-(3-amino-2-pyridinyl)amino]methylpiperidine (EXAMPLE 177, 2.35 g, 7.27 mmol) is dissolved in 18 ml methanol and cooled to 0°. Acetaldehyde (0.45 ml, 8.0 mmol) and sodium cyanoborohydride (685 mg, 10.9 mmol) is added. The mixture is stirred at 0° for one hr, then warmed to 20°-25°. Acetaldehyde and sodium cyanoborohydride are added in the same amounts as above two more times, cooling to 0° before and warming to 20°-25° after each addition. The mixture is poured into 1N sodium hydroxide, extracted with chloroform, dried over sodium sulfate, filtered and concentrated. Flash column chromatography (silica gel, 100 g; methanol/chloroform (5/95)), gives the title compound, NMR (300 MHz, CD3OD) 7.58, 7.31, 6.98, 3.49, 3.18, 3.00, 2.87. 1.93, 1.70, 1.40, 1.15 and 1.01δ.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[N:13]1[N:17]=[C:16]([CH:18]=O)[CH:15]=[N:14]1.[CH3:20][S:21][CH2:22][S:23]([CH3:25])=[O:24]>O1CCCC1.CO>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[N:13]1[N:17]=[C:16]([CH:18]=[C:22]([S:21][CH3:20])[S:23]([CH3:25])=[O:24])[CH:15]=[N:14]1
Reactant: O=Cc1cnn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)n1
Reactant: CSCS(C)=O
Solvent: CO
Solvent: C1CCOC1
Product: CSC(=Cc1cnn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)n1)S(C)=O

Procedure:
2-(2,6-Dichloro-4-trifluoromethylphenyl)-2H-1,2,3-triazole-4-carboxaldehyde [15 g) and methyl methylthiomethyl sulphoxide (6 ml) were heated under reflux in tetrahydrofuran (100 ml) containing Triton B solution (6 ml; 40% in methanol) for 12 hours. The mixture was worked up to give 2-(2,6-dichloro-4-trifluoromethylphenyl)-4-(2-methylthio-2-methylsulphinylvinyl)- 2H-1,2,3-triazole, m.p. 122°-123°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:15][CH2:16][C:17]([N:19]2[CH2:24][CH2:23][N:22]([CH2:25][C:26]3[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=3)[CH2:21][CH:20]2[CH3:33])=[O:18])=[C:6]([N:8]([C:13]#[N:14])[C:9](=[NH:12])SC)[CH:7]=1.[OH-].[NH4+:35]>CCO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:15][CH2:16][C:17]([N:19]2[CH2:24][CH2:23][N:22]([CH2:25][C:26]3[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=3)[CH2:21][C@H:20]2[CH3:33])=[O:18])=[C:6]([N:8]([C:13]#[N:14])[C:9]([NH2:35])=[NH:12])[CH:7]=1
Reactant: CSC(=N)N(C#N)c1cc(Cl)ccc1OCC(=O)N1CCN(Cc2ccc(F)cc2)CC1C
Reactant: [NH4+]
Agent: [OH-]
Solvent: CCO
Product: C[C@@H]1CN(Cc2ccc(F)cc2)CCN1C(=O)COc1ccc(Cl)cc1N(C#N)C(=N)N
Temperature: 60 °C
Reaction time: 8 h

Procedure:
To a solution of 1-(5-chloro-2-{2-[4-(4-fluoro-benzyl)-2-methyl-piperazin-1-yl]-2-oxo-ethoxy}-phenyl)-N-cyano-S-methyl-isothiourea (0.045 g, 0.092 mmol) in EtOH (1 mL) was added ammonium hydroxide (0.100 mL) and the resulting solution was shaken at 60° C. overnight. The crude reaction mixture was purified directly via radial chromatography (2 mm plate) to give the title compound (0.027 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:19]=[CH:20][C:21]=1[O:22][CH2:23][C:24]1[N:25]=[C:26]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[O:27][C:28]=1[CH3:29])[CH2:6][O:7][C:8]1[C:12]([C:13]([O:15]CC)=[O:14])=[CH:11][N:10]([CH3:18])[N:9]=1.[OH-].[Na+].O1CCCC1.Cl>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:19]=[CH:20][C:21]=1[O:22][CH2:23][C:24]1[N:25]=[C:26]([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[O:27][C:28]=1[CH3:29])[CH2:6][O:7][C:8]1[C:12]([C:13]([OH:15])=[O:14])=[CH:11][N:10]([CH3:18])[N:9]=1
Reactant: CCOC(=O)c1cn(C)nc1OCc1ccc(OCc2nc(-c3ccccc3)oc2C)c(OC)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: COc1cc(COc2nn(C)cc2C(=O)O)ccc1OCc1nc(-c2ccccc2)oc1C
Temperature: 60 °C
Reaction time: 5 h
Yield: 93 %

Procedure:
A mixture of ethyl 3-{[3-methoxy-4-(5-methyl-2-phenyl-1,3-oxazol-4-ylmethoxy)benzyl]oxy}-1-methyl-1H-pyrazole-4-carboxylate (400 mg), 1N aqueous sodium hydroxide solution (3 mL), tetrahydrofuran (5 mL) and ethanol (5 mL) was stirred at 60° C. for 5 hrs. To the reaction mixture was added 1N hydrochloric acid (3 mL), and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The obtained colorless crystals were collected by filtration to give 3-{[3-methoxy-4-(5-methyl-2-phenyl-1,3-oxazol-4-ylmethoxy)benzyl]oxy}-1-methyl-1H-pyrazole-4-carboxylic acid (350 mg, yield 93%). The crystals were recrystallized from acetone-hexane. melting point: 169-170° C.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([NH2:12])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[O:13]([NH2:15])[CH3:14]>>[CH3:14][O:13][NH:15][C:2]1[N:11]=[C:10]([NH2:12])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: Nc1nc(Cl)nc2ccccc12
Reactant: CON
Product: CONc1nc(N)c2ccccc2n1

Procedure:
Prepared as in Example 42 from 2-chloroquinazolin-4-amine (Example 38) and methoxylamine. 1H NMR (400 MHz, DMSO-d6) δ 3.79 (s, 3H), 7.48-7.44 (m, 1H), 7.86-7.80 (m, 2H), 8.27 (d, J=8.0 Hz, 1H), 8.99 (s, 1H), 9.16 (s, 1H), 12.39-12.08 (m, 1H). MS 191 (MH+).
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][C:10]=1[CH2:16][O:17][C:18](=[O:26])[NH:19][CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1)([CH3:4])([CH3:3])[CH3:2].[CH3:28][C:29]1[O:33][C:32]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[N:31][C:30]=1[CH2:40][CH2:41]OS(C1C=CC(C)=CC=1)(=O)=O.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[C:1]([O:5][C:6](=[O:27])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:41][CH2:40][C:30]2[N:31]=[C:32]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[O:33][C:29]=2[CH3:28])=[CH:11][C:10]=1[CH2:16][O:17][C:18](=[O:26])[NH:19][CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1ccc(S(=O)(=O)OCCc2nc(-c3ccccc3)oc2C)cc1
Reactant: CC(C)(C)OC(=O)CCc1ccc(O)cc1COC(=O)NC1CCCCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Cc1oc(-c2ccccc2)nc1CCOc1ccc(CCC(=O)OC(C)(C)C)c(COC(=O)NC2CCCCC2)c1
Temperature: 55 °C
Yield: 58.1 %

Procedure:
A 40 mL Carousel tube was charged with 3-(2-cyclohexylcarbamoyloxymethyl-4-hydroxyphenyl)propionic acid tert-butyl ester (0.10 g, 0.26 mmol) in anhydrous DMF (1.0 mL). Toluene-4-sulfonic acid 2-(5-methyl-2-phenyloxazol-4-yl)ethyl ester (0.104 g, 0.292 mmol) and cesium carbonate (0.13 g, 0.40 mmol) were added. The mixture was stirred and heated at 55° C. under a nitrogen atmosphere for 30 h and was concentrated. The residue was diluted with EtOAc (50 mL) and washed twice with brine (2×), dried (Na2SO4), and concentrated. The crude residue was purified using radial chromatography (EtOAc: CH2Cl2 2:98 to 5:95) to give a white solid (0.085 g, 57%). 1H NMR (400 MHz, CDCl3) 1.07-1.19 (m, 3H), 1.24-1.38 (m, 2H), 1.42 (s, 9H), 1.56-1.60 (m, 1H), 1.67-1.70 (m, 2H), 1.91-1.93 (m, 2H), 2.37 (s, 3H), 2.46 (t, J=7.8 Hz, 2H), 2.88 (t, J=7.8 Hz, 2H), 2.96 (t, J=7.8 Hz, 2H), 3.48-3.50 (m, 1H), 4.22 (t, J=6.8 Hz, 2H), 4.69-4.71 (m, 1H), 5.07 (s, 2H), 6.80 (dd, J=8.3, 2.4 Hz, 1H), 6.90 (d, J=2.4 Hz, 1H), 7.10 (d, J=8.3 Hz, 1H), 7.39-7.45 (m, 3H), 7.98 (dd, J=4.2, 2.2 Hz, 2H). MS (ES) m/e 563 (M+1).
Reaction SMILES: [OH-].[Li+].C[O:4][C:5]([C:7]1[N:8]=[C:9]([CH2:15][CH:16]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[NH:10][C:11](=[O:14])[C:12]=1[OH:13])=[O:6]>O.C1COCC1>[C:23]1([CH:16]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:15][C:9]2[NH:10][C:11](=[O:14])[C:12]([OH:13])=[C:7]([C:5]([OH:6])=[O:4])[N:8]=2)[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: COC(=O)c1nc(CC(c2ccccc2)c2ccccc2)[nH]c(=O)c1O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1nc(CC(c2ccccc2)c2ccccc2)[nH]c(=O)c1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 15.6 %

Procedure:
A solution of lithium hydroxide (21.9 mg, 913 μmol) in water (2 ml) was added to a flask containing a stirred solution of 2-(2,2-diphenyl-ethyl)-5-hydroxy-6-oxo-1,6-dihydro-pyrimidine-4-carboxylic acid methyl ester (0.160 g, 457 μmol) in THF (8 ml). The mixture was stirred at room temperature for 8 h, quenched with 1M HCl, extracted into EtOAc, washed with brine, dried (MgSO4) and evaporated to dryness. Purification by preparative HPLC provided the desired product as a white solid (0.024 g; 15%). LCMS: m/z=337 (MH+).
Reaction SMILES: [N:1]([C@H:4]1[C@H:8]([F:9])[CH2:7][N:6](C(OC(C)(C)C)=O)[CH2:5]1)=[N+:2]=[N-:3].Cl.CCOC(C)=O>CCOC(C)=O>[N:1]([C@H:4]1[C@H:8]([F:9])[CH2:7][NH:6][CH2:5]1)=[N+:2]=[N-:3]
Reactant: CC(C)(C)OC(=O)N1C[C@@H](F)[C@H](N=[N+]=[N-])C1
Agent: Cl
Solvent: CCOC(C)=O
Product: [N-]=[N+]=N[C@@H]1CNC[C@H]1F
Temperature: 25 °C
Reaction time: 4 h
Yield: 126.9 %

Procedure:
To a solution of (trans)-tert-butyl 3-azido-4-fluoropyrrolidine-1-carboxylate (25 g, 109 mmol), as prepared in step 3 of Preparation 3, in EtOAc (100 mL) was added HCl/EtOAc (50 mL) at 0-5° C. Then the mixture was stirred at rt for 4 hr. The solid was filtered and washed with petroleum ether/EtOAc (2:1, 40 mL) to give the title compound (18 g) as a gray solid, which was used directly in the next step.