Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](=O)[CH2:7][C:8](=O)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].O.[NH2:18][NH2:19]>C(O)C>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:7]=[C:8]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[NH:19][N:18]=1
Reactant: NN
Reactant: CCCCCCC(=O)CC(=O)c1cccs1
Solvent: O
Solvent: CCO
Product: CCCCCCc1cc(-c2cccs2)n[nH]1
Yield: 59.5 %

Procedure:
In ethanol (20 ml), 1-(2-thienyl)-1,3-nonanedione (1.30 g) and hydrazine hydrate (1.26 g) are refluxed for 3 hours by heating. After the reaction is completed, the solvent is distilled off. The obtained residue is added to petroleum ether and crystallized to obtain the objective 3-(2-thienyl)-5-n-hexylpyrazole (0.76 g) as colorless crystals. mp. 53-55° C.
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([Cl:15])=[CH:10][CH:9]=2)=[O:5])C.Br[CH2:17][C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][CH:19]=1>>[Cl:15][C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:17][C:18]1[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH:21]=[CH:20][CH:19]=1)[C:6]([C:4]([OH:3])=[O:5])=[CH:14]2
Reactant: BrCc1cccc2ccccc12
Reactant: CCOC(=O)c1cc2cc(Cl)ccc2[nH]1
Product: O=C(O)c1cc2cc(Cl)ccc2n1Cc1cccc2ccccc12

Procedure:
Using general procedure B, 5-chloro-1H-indole-2-carboxylic acid ethyl ester was coupled with 1-bromomethyl-naphthalene and the product obtained was hydrolyzed to give the title compound as a white solid. MS: 334.0 ([M−H]−).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4]Br.[Cl:6][C:7]1[CH:8]=[C:9]([OH:28])[CH:10]=[CH:11][C:12]=1[CH:13]([CH3:27])[C:14]([OH:26])([C:19]1[CH:24]=[N:23][C:22]([CH3:25])=[CH:21][N:20]=1)[C:15]([F:18])([F:17])[F:16]>>[Cl:6][C:7]1[CH:8]=[C:9]([O:28][CH2:4][CH2:3][O:2][CH3:1])[CH:10]=[CH:11][C:12]=1[CH:13]([CH3:27])[C:14]([C:19]1[CH:24]=[N:23][C:22]([CH3:25])=[CH:21][N:20]=1)([OH:26])[C:15]([F:18])([F:16])[F:17]
Reactant: COCCBr
Reactant: Cc1cnc(C(O)(C(C)c2ccc(O)cc2Cl)C(F)(F)F)cn1
Product: COCCOc1ccc(C(C)C(O)(c2cnc(C)cn2)C(F)(F)F)c(Cl)c1

Procedure:
The title compound was prepared in analogy to Example 74 from 2-bromoethyl methyl ether and 3-chloro-4-[3,3,3-trifluoro-2-hydroxy-1-methyl-2-(5-methyl-pyrazin-2-yl)-propyl]-phenol (Example 72). MS (m/e)=405.3 (MH+).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[CH:6]=[C:7]([C@@H:10]([OH:13])[CH2:11]Br)[CH:8]=[CH:9][C:2]1=2.[OH-].[K+].C(OCC)C>CO.O1CCCC1.O>[S:1]1[CH:5]=[CH:4][C:3]2[CH:6]=[C:7]([C@@H:10]3[CH2:11][O:13]3)[CH:8]=[CH:9][C:2]1=2
Reactant: O[C@@H](CBr)c1ccc2sccc2c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCOCC
Solvent: C1CCOC1
Product: c1cc2cc([C@@H]3CO3)ccc2s1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 79.2 %

Procedure:
3.5 g of (R)-1-(benzo[b]thiophen-5-yl)-2-bromoethanol was dissolved in a mixed solvent of 20 ml of methanol and 10 ml of tetrahydrofuran. Thereto was added a solution of 1.5 g of potassium hydroxide dissolved in 5 ml of water, with ice cooling. The resulting mixture was stirred for 5 minutes at the same temperature and further for 10 minutes at room temperature. The reaction mixture was added to a mixture of 60 ml of diethyl ether and 60 ml of ice water. The organic layer was separated. The aqueous layer was extracted with 30 ml of diethyl ether. The extract was combined with the previously separated organic layer. The combined organic layer was washed with water and a saturated aqueous sodium chloride solution in this order, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure to obtain 1.9 g of (R)-2-(benzo[b]thiophen-5-yl)oxirane.
Reaction SMILES: C[O:2][C:3](=[O:36])[CH2:4][O:5][C:6]1[CH:14]=[CH:13][C:12]([S:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][C:28]([O:31][C:32]([F:35])([F:34])[F:33])=[CH:27][CH:26]=3)=[CH:19][CH:18]=2)=[C:11]2[C:7]=1[CH2:8][CH2:9][CH2:10]2.[K+].[Br-]>>[F:34][C:32]([F:33])([F:35])[O:31][C:28]1[CH:29]=[CH:30][C:25]([CH2:24][O:23][C:20]2[CH:19]=[CH:18][C:17]([CH2:16][S:15][C:12]3[CH:13]=[CH:14][C:6]([O:5][CH2:4][C:3]([OH:36])=[O:2])=[C:7]4[C:11]=3[CH2:10][CH2:9][CH2:8]4)=[CH:22][CH:21]=2)=[CH:26][CH:27]=1
Reactant: COC(=O)COc1ccc(SCc2ccc(OCc3ccc(OC(F)(F)F)cc3)cc2)c2c1CCC2
Agent: [Br-]
Agent: [K+]
Product: O=C(O)COc1ccc(SCc2ccc(OCc3ccc(OC(F)(F)F)cc3)cc2)c2c1CCC2

Procedure:
The title compound was prepared in the manner analogous to Example 1 using 75D. mp 140-142° C.; IR (KBr) cm−1: 3072, 3043, 1724, 1511, 1226, 1156; 400 MHz 1H NMR (DMSO-d6): δ 12.95 (br(s), 1H), 7.47-7.57 (m, 2H), 7.29-7.39 (m, 2H), 7.00-7.16 (m, 3H), 6.81-6.91 (m, 2H), 6.56 (d, 1H, J=8.5 Hz), 5.05 (s, 2H), 4.61 (s, 2H), 3.94 (s, 2H), 2.75 (t, 2H, J=7.4 Hz), 2.67 (t, 2H, J=7.4 Hz), 1.88 (pentet, 2H) MS m/z 503 (M−1). Anal. Calc'd for C26H23F3O5S: C, 61.90; H, 4.60. found: C, 61.53; H, 4.36.
Reaction SMILES: C([O:8][C:9]([CH:11]1[CH2:16][O:15][C:14]([CH3:18])([CH3:17])[CH2:13][N:12]1CC1C=CC=CC=1)=[O:10])C1C=CC=CC=1>CC(O)=O.CO.[OH-].[OH-].[Pd+2]>[CH3:17][C:14]1([CH3:18])[CH2:13][NH:12][CH:11]([C:9]([OH:10])=[O:8])[CH2:16][O:15]1
Reactant: CC1(C)CN(Cc2ccccc2)C(C(=O)OCc2ccccc2)CO1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Solvent: CC(=O)O
Product: CC1(C)CNC(C(=O)O)CO1
Temperature: 25 °C
Reaction time: 72 h
Yield: 95.4 %

Procedure:
To a solution of 4-benzyl-6,6-dimethyl-morpholine-3-carboxylic acid benzyl ester (Intermediate 18, 1.25 g) in 40 ml of 10% AcOH/MeOH (under nitrogen) was added 250 mg of 20% Pd(OH)2 on charcoal. The reaction mixture was purged with hydrogen (balloon) and was stirred at ambient temperature for 72 hrs. To the resulting gray mixture was added 4 ml of water to help dissolution. The catalyst was removed by filtration and the filtrate was concentrated to dryness. The residue was co-evaporated with ethanol (2×) and then triturated with EtOAc. The generated white solid was filtered off and dried under high vacuum to give 559 mg of 6,6-dimethyl-morpholine-3-carboxylic acid (95% yield). 1H-NMR (300 MHz, D2O): δ 1.35 (s, 3H), 1.38(s, 3H), 3.11 (d, 1H), 3.32 (d, 1H), 3.81-3.87 (m, 1H), 4.05 (bt, 1H), 4.17 (bd, 1H). MS (M+H+): 160.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[CH:12]([CH3:17])[C:13](OC)=[O:14].O.[NH2:19][NH2:20]>CO>[F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[CH:12]([CH3:17])[C:13]([NH:19][NH2:20])=[O:14]
Reactant: COC(=O)C(C)c1cc2cccnc2cc1F
Reactant: NN
Solvent: CO
Solvent: O
Product: CC(C(=O)NN)c1cc2cccnc2cc1F
Yield: 100 %

Procedure:
A solution of methyl 2-(7-fluoroquinolin-6-yl)propanoate (756 mg, 3.24 mmol) and hydrazine monohydrate (1.5 mL) in methanol (5 mL) was heated at 50° C. overnight. After cooling, the solvent was removed in vacuo to afford the title compound (756 mg, 100%) which was used without further purification. LCMS (method A): [MH]+=234, tR=3.14 min.
Reaction SMILES: [F:1][C:2]1[C:3]([O:24][CH3:25])=[C:4]([C:18]2[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=2)[CH:5]=[C:6]([NH:8][C:9](=[O:17])OC2C=CC=CC=2)[CH:7]=1.[CH3:26][O:27][C:28]1[CH:29]=[C:30]2[C:34](=[CH:35][C:36]=1[C:37]([F:40])([F:39])[F:38])[NH:33][CH2:32][CH2:31]2>>[F:1][C:2]1[C:3]([O:24][CH3:25])=[C:4]([C:18]2[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=2)[CH:5]=[C:6]([NH:8][C:9]([N:33]2[C:34]3[C:30](=[CH:29][C:28]([O:27][CH3:26])=[C:36]([C:37]([F:39])([F:40])[F:38])[CH:35]=3)[CH2:31][CH2:32]2)=[O:17])[CH:7]=1
Reactant: COc1cc2c(cc1C(F)(F)F)NCC2
Reactant: COc1c(F)cc(NC(=O)Oc2ccccc2)cc1-c1cccnc1
Product: COc1cc2c(cc1C(F)(F)F)N(C(=O)Nc1cc(F)c(OC)c(-c3cccnc3)c1)CC2
Yield: 53 %

Procedure:
The title compound (0.34 g, 53%) was prepared from phenyl N-[5-fluoro-4-methoxy-3-(pyrid-3-yl)phenyl)carbamate (D24) (0.48 g, 0.0014 mole) and 5-methoxy-6-trifluoromethylindoline (D11) using the method of Example 28.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:34]=[CH:33][C:11]([NH:12]/[C:13](=[C:20]3\[C:21](=[O:32])[NH:22][C:23]4[C:28]\3=[CH:27][CH:26]=[C:25]([C:29]([OH:31])=O)[CH:24]=4)/[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:10][CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:35]([NH:37][CH3:38])[CH3:36]>>[N:1]1([CH2:7][C:8]2[CH:9]=[CH:10][C:11]([NH:12]/[C:13](=[C:20]3\[C:21](=[O:32])[NH:22][C:23]4[C:28]\3=[CH:27][CH:26]=[C:25]([C:29](=[O:31])[N:37]([CH2:35][CH3:36])[CH3:38])[CH:24]=4)/[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)=[CH:33][CH:34]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCNC
Reactant: O=C1Nc2cc(C(=O)O)ccc2/C1=C(/Nc1ccc(CN2CCCCC2)cc1)c1ccccc1
Product: CCN(C)C(=O)c1ccc2c(c1)NC(=O)/C2=C(\Nc1ccc(CN2CCCCC2)cc1)c1ccccc1

Procedure:
Prepared from 3-Z-[1-(4-(piperidin-1-yl-methyl)-anilino)-1-phenyl-methylene]-6-carboxy-2-indolinone and N-ethyl-N-methyl-amine Rf value: 0.5 (aluminium oxide, methylene chloride/ethanol=20:1) C31H34N4O2
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17]Cl)=[CH:10][CH:9]=2)[S:6][CH:7]=1.[NH:19]1[CH2:23][CH2:22][CH2:21][CH2:20]1.C(=O)([O-])[O-].[K+].[K+].[I-].[Na+]>C(#N)C.ClCCl>[N:19]1([CH2:2][C:3]2[N:4]=[C:5]([C:8]3[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][N:19]4[CH2:23][CH2:22][CH2:21][CH2:20]4)=[CH:10][CH:9]=3)[S:6][CH:7]=2)[CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: ClCCCOc1ccc(-c2nc(CCl)cs2)cc1
Reactant: C1CCNC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: ClCCl
Solvent: CC#N
Product: c1cc(-c2nc(CN3CCCC3)cs2)ccc1OCCCN1CCCC1
Temperature: 90 °C
Yield: 13 %

Procedure:
A mixture of 4-(chloromethyl)-2-[4-(3-chloropropoxy)phenyl]-1,3-thiazole ax72 (250 mg, 0.83 mmole, 1 eq) and pyrrolidine (0.3 ml, 3.6 mmol, 4.4 eq) is dissolved in acetonitrile (10 ml). Potassium carbonate (0.5 g, 3.6 mmole, 4.4 eq) and sodium iodide (25 mg, 0.17 mmole, 0.2 eq) are added. The solution is heated at 90° C. in a sealed tube for 48 h. After cooling, the solution is taken up in dichloromethane, washed with water and dried over magnesium sulfate. The crude material is purified by chromatography on silicagel (gradient: dichloromethane/methanol/ammonia 95:4.5:0.5 to 90:9:1) to provide 0.31 g of 4-(1-pyrrolidinylmethyl)-2-{4-[3-(1-pyrrolidinyl)propoxy]phenyl}-1,3-thiazole 73 as a brown oil.
Reaction SMILES: [O:1]=[C:2]1[N:6]([C@@H:7]2[CH2:12][CH2:11][CH2:10][CH2:9][C@H:8]2[OH:13])[CH2:5][CH2:4][O:3]1.F[C:15]1[CH:20]=[CH:19][C:18]([C:21]([C:23]2[C:24]3[CH:45]=[CH:44][C:43]([O:46]CC4C=CC=CC=4)=[CH:42][C:25]=3[S:26][C:27]=2[C:28]2[CH:33]=[CH:32][C:31]([O:34][CH2:35][CH2:36][N:37]3[CH2:41][CH2:40][CH2:39][CH2:38]3)=[CH:30][CH:29]=2)=[O:22])=[CH:17][CH:16]=1>>[O:1]=[C:2]1[N:6]([C@@H:7]2[CH2:12][CH2:11][CH2:10][CH2:9][C@H:8]2[O:13][C:15]2[CH:20]=[CH:19][C:18]([C:21]([C:23]3[C:24]4[CH:45]=[CH:44][C:43]([OH:46])=[CH:42][C:25]=4[S:26][C:27]=3[C:28]3[CH:29]=[CH:30][C:31]([O:34][CH2:35][CH2:36][N:37]4[CH2:41][CH2:40][CH2:39][CH2:38]4)=[CH:32][CH:33]=3)=[O:22])=[CH:17][CH:16]=2)[CH2:5][CH2:4][O:3]1
Reactant: O=C1OCCN1[C@@H]1CCCC[C@H]1O
Reactant: O=C(c1ccc(F)cc1)c1c(-c2ccc(OCCN3CCCC3)cc2)sc2cc(OCc3ccccc3)ccc12
Product: O=C(c1ccc(O[C@@H]2CCCC[C@H]2N2CCOC2=O)cc1)c1c(-c2ccc(OCCN3CCCC3)cc2)sc2cc(O)ccc12
Yield: 49 %

Procedure:
Using a procedure similar to that described below in Example 19, the title compound was prepared in 49% yield from (±)-trans-2-(2-oxooxazolidin-3-yl)cylohexanol (Part A) and 6-benzyloxy-2-[4-[2-(1-pyrrolidinyl)ethoxy]phenyl]-benzo[b]thiophen-3-yl 4-fluorophenyl ketone (Part B).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][C:2]1=[O:6].I[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>>[C:8]1([N:1]2[CH2:5][CH2:4][CH2:3][C:2]2=[O:6])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: Ic1ccccc1
Reactant: O=C1CCCN1
Product: O=C1CCCN1c1ccccc1

Procedure:
Following General Procedure A (90° C., 30 hours), pyrrolidin-2-one (116 μL, 1.5 mmol) is coupled with iodo-benzene (112 μL, 1.0 mmol). The crude brown oil is purified by flash chromatography on silica gel (eluent: dichloromethane/ethylacetate=80/20) to provide 130 mg (81% isolated yield) of the desired product as a yellow solid.
Reaction SMILES: [N+:1]([N:4]=[N:5][CH2:6][NH:7][CH2:8][CH2:9][CH2:10][C@H:11]([NH:20][C:21](=[O:41])[C@H:22]([CH2:37][CH:38]([CH3:40])[CH3:39])[C@@H:23]([N:27]([CH:35]=[O:36])[O:28]C1CCCCO1)[CH2:24][CH2:25][CH3:26])[C:12](=[O:19])[NH:13][C:14]1[S:15][CH:16]=[CH:17][N:18]=1)([O-:3])=[O:2]>C(O)(=O)C>[N+:1]([N:4]=[N:5][CH2:6][NH:7][CH2:8][CH2:9][CH2:10][C@H:11]([NH:20][C:21](=[O:41])[C@H:22]([CH2:37][CH:38]([CH3:40])[CH3:39])[C@@H:23]([N:27]([CH:35]=[O:36])[OH:28])[CH2:24][CH2:25][CH3:26])[C:12](=[O:19])[NH:13][C:14]1[S:15][CH:16]=[CH:17][N:18]=1)([O-:3])=[O:2]
Reactant: CCC[C@@H]([C@@H](CC(C)C)C(=O)N[C@@H](CCCNCN=N[N+](=O)[O-])C(=O)Nc1nccs1)N(C=O)OC1CCCCO1
Solvent: CC(=O)O
Product: CCC[C@@H]([C@@H](CC(C)C)C(=O)N[C@@H](CCCNCN=N[N+](=O)[O-])C(=O)Nc1nccs1)N(O)C=O
Temperature: 40 °C
Yield: 74.3 %

Procedure:
(2R,3S)-3-(Formyl-2-tetrahydropyranyloxyamino)-2-(2-methyl-1-propyl)hexanoic acid [(1S)-4-(nitroimino-amino)methylamino-1-(1,3-thiazol-2-ylcarbamoyl)-1-butyl]amide (166 mg) is dissolved in 2 mL 80% acetic acid and heated at 40° C. for 20 h. Concentration in vacuo and trituration in dichloromethane—ether provides (2R,3S)-3-(formyl-hydroxyamino)-2-(2-methyl-1-propyl)hexanoic acid [(1S)-4-(nitroimino-amino)methylamino-1-(1,3-thiazol-2-ylcarbamoyl)-1-butyl]amide as a solid (106 mg, 74%).
Reaction SMILES: [Br:1][C:2]1[C:11]([OH:12])=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH3:13])=[N:9]2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].I[CH:21]([CH3:23])[CH3:22].C(OCC)(=O)C>CC(C)=O.O>[Br:1][C:2]1[C:11]([O:12][CH:21]([CH3:23])[CH3:22])=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH3:13])=[N:9]2)=[CH:4][CH:3]=1
Reactant: CC(C)I
Reactant: Cc1ccc2ccc(Br)c(O)c2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: Cc1ccc2ccc(Br)c(OC(C)C)c2n1
Temperature: 25 °C
Yield: 96 %

Procedure:
A solution of 7-bromo-2-methylquinolin-8-ol (1.00 g, 4.20 mmol), K2CO3 (1.74 g, 12.6 mmol), and 2-iodopropane (0.84 ml, 8.40 mmol) in acetone (20 mL) was stirred at 88° C. in a seal tube for 24 hours. After cooling to ambient temperature, ethyl acetate (50 mL) and water (30 mL) was added. The organic layer was separated, washed with brine, dried (sodium sulfate), filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (5:1 hexane/ethyl acetate) to give 7-bromo-8-isopropoxy-2-methylquinoline (1.13 g, 96.0%) as an oil.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11]3([C:14]4[N:18]5[N:19]=[C:20]([C:23]6[CH:31]=[CH:30][C:26]([C:27]([OH:29])=O)=[CH:25][CH:24]=6)[CH:21]=[N:22][C:17]5=[N:16][N:15]=4)[CH2:13][CH2:12]3)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[NH2:32][C@@H:33]([CH3:37])[C:34]([NH2:36])=[O:35].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[NH2:36][C:34](=[O:35])[C@@H:33]([NH:32][C:27](=[O:29])[C:26]1[CH:30]=[CH:31][C:23]([C:20]2[CH:21]=[N:22][C:17]3[N:18]([C:14]([C:11]4([C:7]5[CH:6]=[C:5]6[C:10](=[CH:9][CH:8]=5)[N:1]=[CH:2][CH:3]=[CH:4]6)[CH2:12][CH2:13]4)=[N:15][N:16]=3)[N:19]=2)=[CH:24][CH:25]=1)[CH3:37]
Reactant: C[C@H](N)C(N)=O
Reactant: O=C(O)c1ccc(-c2cnc3nnc(C4(c5ccc6ncccc6c5)CC4)n3n2)cc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](NC(=O)c1ccc(-c2cnc3nnc(C4(c5ccc6ncccc6c5)CC4)n3n2)cc1)C(N)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 4-[3-(1-quinolin-6-ylcyclopropyl)[1,2,4]triazolo[4,3-b][1,2,4]triazin-6-yl]benzoic acid (10 mg, 0.02 mmol), (2S)-2-aminopropanamide (3.2 mg, 0.037 mmol), benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (13 mg, 0.029 mmol), and N,N-diisopropylethylamine (13 μL, 0.073 mmol) in methylene chloride (0.5 mL) was stirred at RT overnight. The solvent was evaporated. The residue was dissolved in methanol, and purified by RP-HPLC (pH=10) to afford the desired product. Analytical LCMS: (M+H)+=479.0.
Reaction SMILES: [NH2:1][CH2:2][C:3]([OH:5])=[O:4].[OH-].[Na+].[Cl:8][C:9]1[C:10]([O:17][CH2:18][C:19](Cl)=[O:20])=[N:11][C:12]([F:16])=[C:13]([Cl:15])[CH:14]=1>O.C1C=CC=CC=1>[Cl:8][C:9]1[C:10]([O:17][CH2:18][C:19]([NH:1][CH2:2][C:3]([OH:5])=[O:4])=[O:20])=[N:11][C:12]([F:16])=[C:13]([Cl:15])[CH:14]=1
Reactant: NCC(=O)O
Reactant: O=C(Cl)COc1nc(F)c(Cl)cc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: c1ccccc1
Product: O=C(O)CNC(=O)COc1nc(F)c(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A solution was prepared by admixing 2.93 grams (0.039 mole) of glycine with 4.67 grams (0.117 mole) of sodium hydroxide in 117 milliliters of water. To this solution was added 10.0 grams of (3,5-dichloro-6-fluoro-2-pyridyloxy)acetyl chloride in 30 milliliters of benzene. The mixture was allowed to stand at a temperature of ~2°-5° C. for about 10 minutes and the mixture was warmed to room temperature and stirred for about 30 minutes. The reaction mixture was diluted with additional benzene and the aqueous layer which formed was removed and acidified. The solid which precipated was removed by filtration, dried and recrystallized from 50 percent ethanol. The N-[(3,5-dichloro-6-fluoro-2-pyridyloxy)acetyl]glycine product was recovered in a yield of 5.0 grams and melted at 155°-157° C. and upon analysis was found to have carbon, hydrogen, chlorine and nitrogen contents of 35.7, 2.1, 24.2 and 8.7 percent, respectively as compared with the theoretical contents of 36.5, 2.4, 23.9 and 9.4 percent, respectively, calculated for the above named compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][CH:18]=[CH:17][C:4]=1[C:5]([S:7][C:8]1[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=1[C:10](O)=[O:11])=O.C([N:23](CC)CC)C.ClC(OCC)=O.[N-]=[N+]=[N-].[Na+].C(P(CCCC)CCCC)CCC>CC(C)=O.O>[CH3:1][O:2][C:3]1[CH:20]=[CH:19][CH:18]=[CH:17][C:4]=1[C:5]1[S:7][C:8]2[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=2[C:10](=[O:11])[N:23]=1
Reactant: CCN(CC)CC
Reactant: COc1ccccc1C(=O)Sc1ccccc1C(=O)O
Agent: CCCCP(CCCC)CCCC
Agent: CCOC(=O)Cl
Agent: [N-]=[N+]=[N-]
Solvent: O
Solvent: CC(C)=O
Product: COc1ccccc1-c1nc(=O)c2ccccc2s1
Temperature: -10 °C
Yield: 105 %

Procedure:
2-{[2-(Methoxy)benzoyl]thio}benzoic acid (1.90 g, 3.5 mmol) was suspended in acetone (10 ml). While stirring under ice cooling, triethylamine (0.93 g, 9.2 mmol) and then ethyl chloroformate (0.99 g, 7.3 mmol) were dropwise added to the suspension. After stirring at the same temperature for an hour, an aqueous solution (10 ml) of sodium azide (0.64 g, 9.9 mmol) was dropwise added to the reaction mixture, followed by further stirring for an hour. The reaction mixture was diluted with water and the dilution was extracted with toluene (100 ml×2). The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and then filtered. The toluene solution was cooled to about −10° C. and tributylphosphine (1.60 g, 7.9 mmol) was dropwise added to the solution. After completion of the dropwise addition, the reaction temperature was reverted to room temperature and the mixture was heated under reflux for 15 minutes. The reaction solution was concentrated under reduced pressure and recrystallized from ethanol to give the title compound (0.99 g, 56%) as crystals.
Reaction SMILES: [OH:1][CH:2]([CH2:15][N:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)[CH2:3][NH:4][S:5]([C:8]1[CH:14]=[CH:13][C:11]([NH2:12])=[CH:10][CH:9]=1)(=[O:7])=[O:6].Cl.CC(O)CC.Cl[C:29]1[N:34]=[C:33]([NH:35][CH2:36][CH3:37])[C:32]([C:38]#[N:39])=[CH:31][N:30]=1>CO>[C:38]([C:32]1[C:33]([NH:35][CH2:36][CH3:37])=[N:34][C:29]([NH:12][C:11]2[CH:10]=[CH:9][C:8]([S:5](=[O:6])(=[O:7])[NH:4][CH2:3][CH:2]([OH:1])[CH2:15][N:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)=[CH:14][CH:13]=2)=[N:30][CH:31]=1)#[N:39]
Reactant: CCNc1nc(Cl)ncc1C#N
Reactant: Nc1ccc(S(=O)(=O)NCC(O)CN2CCCCC2)cc1
Agent: Cl
Solvent: CCC(C)O
Solvent: CO
Product: CCNc1nc(Nc2ccc(S(=O)(=O)NCC(O)CN3CCCCC3)cc2)ncc1C#N
Temperature: 50 °C
Yield: 10.2 %

Procedure:
4-[N-(2-Hydroxy-3-piperidinopropyl)sulphamoyl]aniline (Method 118; 200 mg, 0.64 mmol) was dissolved in methanol (4 ml). 1M Ethereal hydrogen chloride (1.28 ml, 1.28 mmol) was added and the mixture gently warmed to give a solution. The volatiles were partially evaporated to give a volume of approx. 1.5 ml. 2-Butanol (5 ml) was added and the cloudy solution warmed to 50° C. 2-Chloro-5-cyano-4-ethylaminopyrimidine (Method 56; 233 mg, 1.28 mmol) was added in portions and the reaction was then heated at 95° C. for 20 hours. The hot supernatant was decanted from the solid residue and the solution allowed to cool. The resulting precipitate was collected by filtration, washed with diethyl ether and suspended in water (approx. 35 ml). The suspension was adjusted to pH>10 with 2M aqueous sodium hydroxide solution and extracted with ethyl acetate (3×15 ml). The extracts were dried, the volatiles evaporated and the residue purified by chromatography on silica eluting with DCM/methanolic ammonia (100:0) increasing in polarity to (85:15). The product was triturated with diethyl ether and collected by filtration to give the title compound (30 mg, 10%). NMR: 1.15 (t, 3H), 1.35 (m, 2H), 1.43 (m, 4H), 2.10-2.35 (m, 6H), 2.68 (m, 1H), 2.83 (m, 1H), 3.48 (quin, 2H), 3.56 (m, 1H), 4.59 (s, 1H) 7.36 (brt, 1H), 7.70 (d, 2H), 7.88 (t, 1H), 7.95 (d, 2H), 8.40 (s, 1H) 10.16 (s, 1H); m/z: 460.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@@H:10]([O:13][CH2:14][P:15]([O:21][CH:22]([CH3:24])[CH3:23])([O:17][CH:18]([CH3:20])[CH3:19])=[O:16])[CH2:11]I)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[H][H]>CO.[Pd]>[CH2:1]([O:8][CH2:9][C@@H:10]([O:13][CH2:14][P:15]([O:21][CH:22]([CH3:24])[CH3:23])([O:17][CH:18]([CH3:19])[CH3:20])=[O:16])[CH3:11])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [H][H]
Reactant: CC(C)OP(=O)(CO[C@@H](CI)COCc1ccccc1)OC(C)C
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CO
Product: CC(C)OP(=O)(CO[C@@H](C)COCc1ccccc1)OC(C)C
Reaction time: 2 h
Yield: 93.8 %

Procedure:
A solution of (R)-1-(benzyloxy)-2-[(diisopropylphosphono)methoxy]-3-iodopropane (12.0 g, 25.5 mmol) in 15 mL of methanol was treated with triethylamine (3.10 g, 30.6 mmol) and 10% palladium on carbon (2.0 g), and the mixture was placed under 40 psi hydrogen atmosphere in a Parr shaker apparatus. After 2 hours, the reaction mixture was filtered through a 1" pad of Celite, and the collected solid was washed with methanol. The filtrate was concentrated and treated with ethyl acetate (200 mL). The precipitate was removed by filtration, the filtrate was concentrated in vacuo, and the residue was purified by column chromatography on silica gel (10:1, 75% ethyl acetate/hexane) to afford 8.24 g (94%) of the title compound as a clear, colorless oil.
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([CH2:27][CH3:28])[NH:8][C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4].[CH3:29][O:30][C:31]1[CH:36]=[CH:35][C:34](B(O)O)=[CH:33][CH:32]=1.N1C=CC=CC=1.C(N(CC)CC)C>C(OCC)(=O)C.C([O-])(=O)C.[Cu+2].C([O-])(=O)C.ClCCl>[CH2:1]([C:5]1[N:6]=[C:7]([CH2:27][CH3:28])[N:8]([C:34]2[CH:35]=[CH:36][C:31]([O:30][CH3:29])=[CH:32][CH:33]=2)[C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4]
Reactant: COc1ccc(B(O)O)cc1
Reactant: CCCCc1nc(CC)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCCCc1nc(CC)n(-c2ccc(OC)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reaction time: 144 h
Yield: 101.1 %

Procedure:
A mixture of 4′-[(4-butyl-2-ethyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile (2.0 g), 4-methoxyphenylboronic acid (1.6 g), copper(II) acetate (2.0 g), pyridine (2.2 mL), triethylamine (3.8 mL), molecular sieves 4 A (4.0 g) and dichloromethane (40 mL) was stirred for 6 days. The reaction mixture was diluted with ethyl acetate, and the insoluble material was filtered off. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound (2.6 g, 100%) as a colorless liquid.