Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[CH2:2]([O:4][C:5]([C:7]1[CH:8]=[N:9][N:10]([CH3:24])[C:11]=1[S:12]([NH:15][C:16]([N+:18]1[CH:23]=CC=CC=1)=[O:17])(=[O:14])=[O:13])=[O:6])[CH3:3].NC1[N:31]=[C:30]([O:32][CH3:33])[CH:29]=[C:28]([O:34][CH3:35])[N:27]=1.O>C(#N)C>[CH3:33][O:32][C:30]1[CH:29]=[C:28]([O:34][CH3:35])[N:27]=[C:23]([NH:18][C:16]([NH:15][S:12]([C:11]2[N:10]([CH3:24])[N:9]=[CH:8][C:7]=2[C:5]([O:4][CH2:2][CH3:3])=[O:6])(=[O:13])=[O:14])=[O:17])[N:31]=1
Reactant: COc1cc(OC)nc(N)n1
Reactant: CCOC(=O)c1cnn(C)c1S(=O)(=O)NC(=O)[n+]1ccccc1
Agent: [OH-]
Solvent: O
Solvent: CC#N
Product: CCOC(=O)c1cnn(C)c1S(=O)(=O)NC(=O)Nc1nc(OC)cc(OC)n1
Temperature: 25 °C
Yield: 98.9 %

Procedure:
3.42 g (10.1 mmole) of 1-[[(4-ethoxycarbonyl-1-methylpyrazole-5-sulfonyl)amino]carbonyl]pyridinium hydroxide was dissolved in 10.00 g of dry acetonitrile. To the resulting solution was added 1.55 g (10.0 mmole) of 2-amino-4,6-dimethoxypyrimidine with stirring. The reaction mixture was stirred for one hour while maintaining the temperature of 40° to 45° C. to complete the reaction. After the reaction was completed, 25.00 g of water was added to the reaction solution. The mixture was then adjusted to pH 5 to 6, cooled to 25° C. and filtered. The resulting product was washed with water and acetonitrile and then dried to obtain 4.10 g (Yield 99%) of the title compound as the white powder.
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[C:23]([O:24][CH2:25][CH3:26])=[N:22][CH:21]=[CH:20][C:10]=1[C:11]([N:13](C(C)C)C(C)C)=[O:12].C[Si](C)(C)N[Si](C)(C)C.[Na].CO>C1COCC1>[CH2:25]([O:24][C:23]1[N:22]=[CH:21][CH:20]=[C:10]2[C:9]=1[C:3]1[CH:4]=[C:5]([F:8])[CH:6]=[CH:7][C:2]=1[NH:13][C:11]2=[O:12])[CH3:26]
Reactant: CCOc1nccc(C(=O)N(C(C)C)C(C)C)c1-c1cc(F)ccc1N
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: [Na]
Solvent: C1CCOC1
Solvent: CO
Product: CCOc1nccc2c(=O)[nH]c3ccc(F)cc3c12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 3-(2-amino-5-fluorophenyl)-2-ethoxy-N,N-diisopropylisonicotinamide (170 mg, 0.473 mmol) in THF (3153 μl), was added sodium hexamethyldisilazane (946 μl, 0.946 mmol, 1.0 M in THF). The reaction mixture was stirred at room temperature for 30 min. Methanol was added and the mixture was concentrated under reduced pressure. The residue was then triturated with diethyl ether (25 mL) and stirred for 1 h. The mixture was filtered through a frit, and the filter cake was collected and dried to afford the title compound as a beige solid.
Reaction SMILES: ClC(OC(Cl)=O)C.C1(C[N:15]2[CH2:20][CH2:19][N:18]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[N:22]=3)[C:17](=[O:28])[CH2:16]2)C=CC=CC=1>ClCCl>[Cl:27][C:23]1[N:22]=[C:21]([N:18]2[CH2:19][CH2:20][NH:15][CH2:16][C:17]2=[O:28])[CH:26]=[CH:25][CH:24]=1
Reactant: O=C1CN(Cc2ccccc2)CCN1c1cccc(Cl)n1
Agent: CC(Cl)OC(=O)Cl
Solvent: ClCCl
Product: O=C1CNCCN1c1cccc(Cl)n1
Temperature: -14 °C
Reaction time: 3 h
Yield: 41.9 %

Procedure:
1-Chloroethylchloroformate (143 μL, 1.33 mmol) was added slowly to a stirred, cooled (−18° C.) solution of 4-phenylmethyl-1-(6-chloro-2-pyridinyl)piperazin-2-one (Description 152, 400 mg, 1.33 mmol) in dichloromethane (10 mL) and the mixture was stirred at −14° C. for 3 hours. The solvent was evaporated under reduced pressure, methanol (10 mL) was added and the mixture was heated under reflux for 30 minutes. The mixture was cooled, the solvent was evaporated under reduced pressure and methanolic ammonia (2M, 10 mL) was added. The solvent was evaporated under reduced pressure and the residue was purified by flash column chromatography on silica gel, eluting with CH2Cl2/MeOH/NH3(Aq.) (120:8:1), to give the title compound as a tan gum (118 mg, 42%). m/z (ES+) 212, 214 (M+1)+.
Reaction SMILES: [F:1][C:2]1[C:3](=[O:9])[NH:4][C:5](=[O:8])[NH:6][CH:7]=1.N12CCCN=C1CCCCC2.Br[CH2:22][CH:23]([CH3:25])[CH3:24]>CC#N>[F:1][C:2]1[C:3](=[O:9])[NH:4][C:5](=[O:8])[N:6]([CH2:22][CH:23]([CH3:25])[CH3:24])[CH:7]=1
Reactant: CC(C)CBr
Reactant: O=c1[nH]cc(F)c(=O)[nH]1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: CC(C)Cn1cc(F)c(=O)[nH]c1=O
Temperature: 25 °C
Yield: 35.3 %

Procedure:
To a solution of 5-fluoropyrimidine-2,4(1H,3H)-dione (5.0 g, 38 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU; 6.4 g, 42 mmol) in dry CH3CN (150 mL) at room temperature and under nitrogen was added 1-bromo-2-methylpropane (5.3 g, 38 mmol) dropwise. The reaction was then heated to reflux for 18 h. After cooling to room temperature, the solvent was removed in vacuo. The crude residue was purified by normal phase chromatography (gradient, 0 to 20% EtOAc/Petroleum ether), providing 5-fluoro-1-isobutylpyrimidine-2,4(1H,3H)-dione (2.5 g, 35%) as a white solid: mp 173-174° C.; 1H NMR (400 MHz, CDCl3) δ 8.61 (s, 1H), 7.21 (d, J=5.5 Hz, 1H), 3.53 (d, J=7.5 Hz, 2H), 2.13-2.01 (m, 1H), 0.98 (d, J=6.7 Hz, 6H); ESIMS m/z 185 ([M−H]−).
Reaction SMILES: [N:1]([CH2:4][CH2:5][CH:6]([CH2:12][CH2:13][N:14]=[N+]=[N-])[CH2:7][CH2:8][N:9]=[N+]=[N-])=[N+]=[N-].[H][H]>C(O)C.[Pd]>[NH2:1][CH2:4][CH2:5][CH:6]([CH2:12][CH2:13][NH2:14])[CH2:7][CH2:8][NH2:9]
Reactant: [H][H]
Reactant: [N-]=[N+]=NCCC(CCN=[N+]=[N-])CCN=[N+]=[N-]
Agent: [Pd]
Solvent: CCO
Product: NCCC(CCN)CCN
Yield: 100 %

Procedure:
Tris(2-azidoethyl)methane (15.06 g, 0.0676 mol), (assuming 100% yield from previous reaction) in ethanol (200 ml) was treated with 10% palladium on charcoal (2 g, 50% water) and hydrogenated for 12 h. The reaction vessel was evacuated every 2 hours to remove nitrogen evolved from the reaction and refilled with hydrogen. A sample was taken for NMR analysis to confirm complete conversion of the triazide to the triamine. Caution: unreduced azide could explode on distillation. The reaction was filtered through a celite pad to remove the catalyst and concentrated in vacuo to give tris(2-aminoethyl)methane as an oil. This was further purified by Kugelrohr distillation bp. 180-200° C. at 0.4 mm/Hg to give a colourless oil (8.1 g, 82.7% overall yield from the triol).
Reaction SMILES: COC1C=CC(C[O:8][C:9]2[C:14]([C:15]3[O:19][N:18]=[C:17]([C:20]4[CH:25]=[CH:24][C:23]([P:26]([CH3:31])(=[O:30])[O:27][CH2:28][CH3:29])=[CH:22][CH:21]=4)[CH:16]=3)=[CH:13][N:12]=[C:11]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=3)[N:10]=2)=CC=1.FC(F)(F)C(O)=O>C(Cl)Cl>[OH:8][C:9]1[C:14]([C:15]2[O:19][N:18]=[C:17]([C:20]3[CH:21]=[CH:22][C:23]([P:26]([CH3:31])(=[O:30])[O:27][CH2:28][CH3:29])=[CH:24][CH:25]=3)[CH:16]=2)=[CH:13][N:12]=[C:11]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=2)[N:10]=1
Reactant: CCOP(C)(=O)c1ccc(-c2cc(-c3cnc(-c4ccccn4)nc3OCc3ccc(OC)cc3)on2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOP(C)(=O)c1ccc(-c2cc(-c3cnc(-c4ccccn4)nc3O)on2)cc1
Temperature: 25 °C
Reaction time: 10 h
Yield: 94.7 %

Procedure:
To a solution of compound 38-f (440 mg, 0.80 mmol) in DCM (5 mL) was added 2,2,2-trifluoroacetic acid (2 mL). After being stir for 10 h at room temperature, the reaction mixture was concentrated under reduce pressure and the residue was purified by pre-TLC (DCM:methanol=15:1) to afford compound 38-g (320 mg, 94%). 1H NMR (300 MHz, CD3OD) δ 8.79-8.80 (m, 1H), 8.71 (s, 1H), 8.38-8.41 (m, 1H), 8.10-8.12 (m, 3H), 7.89-7.93 (m, 2H), 7.67-7.72 (m, 2H), 3.91-3.96 (m, 2H), 1.67-1.72 (d, J=14.4 Hz, 3H), 1.18-1.22 (m, 3H). LC-MS 423 [M+H]+
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][S:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[NH:12]1[CH2:17][CH2:16][CH:15]([C:18]2[CH:19]=[C:20]([NH:24][C:25]([CH:27]3[CH2:29][CH2:28]3)=[O:26])[CH:21]=[CH:22][CH:23]=2)[CH2:14][CH2:13]1>>[C:6]1([S:5][CH2:4][CH2:3][CH2:2][N:12]2[CH2:17][CH2:16][CH:15]([C:18]3[CH:19]=[C:20]([NH:24][C:25]([CH:27]4[CH2:28][CH2:29]4)=[O:26])[CH:21]=[CH:22][CH:23]=3)[CH2:14][CH2:13]2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=C(Nc1cccc(C2CCNCC2)c1)C1CC1
Reactant: ClCCCSc1ccccc1
Product: O=C(Nc1cccc(C2CCN(CCCSc3ccccc3)CC2)c1)C1CC1

Procedure:
Prepared by Procedure G and Scheme B1 using [(3-chloropropyl)sulfanyl]benzene and N-[3-(4-piperidinyl)phenyl]cyclopropanecarboxamide: ESMS m/e: 395.1 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:14](=[O:19])C(F)(F)F)=[CH:7][N:8]2[CH:11]([CH3:13])[CH3:12])=[CH:4][CH:3]=1.[OH-:20].[Na+].Cl>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:14]([OH:19])=[O:20])=[CH:7][N:8]2[CH:11]([CH3:12])[CH3:13])=[CH:4][CH:3]=1
Reactant: CC(C)n1cc(C(=O)C(F)(F)F)c2ccc(Cl)cc21
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Product: CC(C)n1cc(C(=O)O)c2ccc(Cl)cc21
Temperature: 110 °C
Yield: 99 %

Procedure:
A mixture of 1-(6-chloro-1-isopropyl-1H-indol-3-yl)-2,2,2-trifluoro-ethanone (475 mg, 1.64 mmol) in a 20% aqueous sodium hydroxide solution was heated at 110° C. for 18 h. At this time, the reaction was cooled to 25° C. and treated with a 1N aqueous hydrochloric acid solution. This solution was extracted with ethyl acetate (1×50 mL). The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo to afford 6-chloro-1-isopropyl-1H-indole-3-carboxylic acid (385 mg, 99%) as a yellow solid: mp 206-208° C.; EI-HRMS m/e calcd for C12H12ClNO2 (M+) 237.0056, found 237.0554.
Reaction SMILES: [OH:1][CH:2]1[CH2:6][CH2:5][N:4]([C:7]([C:9]2[CH:14]=[C:13]([S:15]([CH3:18])(=[O:17])=[O:16])[CH:12]=[CH:11][C:10]=2[O:19][CH:20]([CH3:22])[CH3:21])=[O:8])[CH2:3]1.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>>[CH:20]([O:19][C:10]1[CH:11]=[CH:12][C:13]([S:15]([CH3:18])(=[O:17])=[O:16])=[CH:14][C:9]=1[C:7]([N:4]1[CH2:5][CH2:6][CH:2]([O:1][S:24]([CH3:23])(=[O:26])=[O:25])[CH2:3]1)=[O:8])([CH3:22])[CH3:21]
Reactant: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)N1CCC(O)C1
Reactant: CS(=O)(=O)Cl
Product: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)N1CCC(OS(C)(=O)=O)C1
Yield: 99 %

Procedure:
Prepared in analogy to Example 3(b) from rac-(3-hydroxy-pyrrolidin-1-yl)-(2-isopropoxy-5-methanesulfonyl-phenyl)-methanone (Example 9(a)) and methanesulfonyl chloride. The crude material was purified by partitioning between dichoromethane and water to yield the title compound as a yellow oil (yield 99%). MS (m/e): 406.4 (M+H+, 100%).
Reaction SMILES: [CH3:1][N:2]([CH3:10])[C@@H:3]1[CH2:8][CH2:7][CH2:6][CH2:5][C@H:4]1[NH2:9].[CH:11](OCC)=[O:12]>>[CH3:1][N:2]([CH3:10])[C@@H:3]1[CH2:8][CH2:7][CH2:6][CH2:5][C@H:4]1[NH:9][CH:11]=[O:12]
Reactant: CCOC=O
Reactant: CN(C)[C@@H]1CCCC[C@H]1N
Product: CN(C)[C@@H]1CCCC[C@H]1NC=O
Yield: 85 %

Procedure:
A solution of the trans 2-(dimethylamino)cyclohexylamine prepared as in Procedure VIII (5.12 g.; 0.036 mole) and 100 ml. of ethyl formate (distilled over K2CO3) was refluxed for 17 hours and evaporated. The titled product (A) was distilled at 0.1 mm, b.p. 104°, 5.2 g. (85% yield). ir NH 3280, 3040; CH 2930, 2860; N-alkyl 2770; C=O 1670; amide II 1540; other 1450, 1385. nmr in CDCl3 (100 MHz) was in accord. Mass spectrum M+ 170.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=2)[N:5]=[CH:4][C:3]=1C(OCC)=O.Cl.C(O)(=O)C>[OH-].[Na+]>[N:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[N:6]1[C:2]([NH2:1])=[CH:3][CH:4]=[N:5]1
Reactant: CCOC(=O)c1cnn(-c2ccccn2)c1N
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: Nc1ccnn1-c1ccccn1
Temperature: 25 °C
Yield: 31.3 %

Procedure:
A suspension of ethyl 5-amino-1-(2-pyridinyl)-1H-pyrazole-4-carboxylate (27.9 g, 120 mmol) in 4N sodium hydroxide (300 mL) was heated under reflux for 1 hour. The suspension was allowed to cool to room temperature, neutralized by the addition of conc. hydrochloric acid, and further made acidic by the addition of acetic acid. The resulting crystals were collected by filtration, washed with ethanol, and air dried. The crystals thus obtained were subjected to heat at 200° C., and washed with diethylether to give the title compound (6.02 g, 31% yield). NMR (CDCl3) δ: 5.51 (1H, d, J=1.8 Hz), 5.95 (2H, br s), 7.07-7.13 (1H, m), 7.42 (1H, d, J=1.8 Hz), 7.75-7.84 (1H, m), 7.98 (1H, d, J=8.4 Hz), 8.33 (1H, dd, J=1.6 Hz, 4.6 Hz).
Reaction SMILES: [C:1]([NH:4][C@H:5]([C:8]([OH:10])=[O:9])[CH2:6][SH:7])(=[O:3])[CH3:2].[C:11]([NH:17][C@H:18]([C:21]([OH:23])=[O:22])[CH2:19][SH:20])(=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13]>>[C:1]([NH:4][C@@H:5]([CH2:6][S:7][S:20][CH2:19][C@H:18]([NH:17][C:11](=[O:16])[C:12]([CH3:14])([CH3:13])[CH3:15])[C:21]([OH:23])=[O:22])[C:8]([OH:10])=[O:9])(=[O:3])[CH3:2]
Reactant: CC(C)(C)C(=O)N[C@@H](CS)C(=O)O
Reactant: CC(=O)N[C@@H](CS)C(=O)O
Product: CC(=O)N[C@@H](CSSC[C@H](NC(=O)C(C)(C)C)C(=O)O)C(=O)O

Procedure:
The compound was obtained following the procedure given in Example 18, starting from N-acetyl-L-cysteine and N-pivaloyl-L-cysteine.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:26]=[CH:27][CH:28]=1)[C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][Si:16]([CH3:22])([CH3:21])[C:17]([CH3:20])([CH3:19])[CH3:18])=[CH:11][C:10]=1[N+:23]([O-])=O)=[O:7])#[N:2].CCO>[Pd].C1COCC1>[C:1]([C:3]1[CH:4]=[C:5]([CH:26]=[CH:27][CH:28]=1)[C:6]([NH:8][C:9]1[C:10]([NH2:23])=[CH:11][C:12]([O:15][Si:16]([CH3:21])([CH3:22])[C:17]([CH3:20])([CH3:19])[CH3:18])=[CH:13][CH:14]=1)=[O:7])#[N:2]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(NC(=O)c2cccc(C#N)c2)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)Oc1ccc(NC(=O)c2cccc(C#N)c2)c(N)c1
Reaction time: 12 h
Yield: 58.7 %

Procedure:
A mixture of N-(3-cyanobenzoyl)-2-nitro-4-(dimethyl-t-butylsiloxy)aniline (5.00 g, 12.6 mmol), 10% Pd/C (2.5 g), EtOH (160 mL), and THF (160 mL) was hydrogenated at 1 atm for 12 h. The reaction was filtered through diatomaceous earth with hot methanolic washes. The filtrate was concentrated and chromatographed (20% EtOAc/hexanes to 30% EtOAc/hexanes) to give the title compound as a solid (2.72 g, 59%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([OH:9])=[N:6][C:7]=1[CH3:8].S(=O)(=O)(O)O.[N+:15]([O-])([OH:17])=[O:16]>>[CH3:1][C:2]1[CH:3]=[C:4]([N+:15]([O-:17])=[O:16])[C:5]([OH:9])=[N:6][C:7]=1[CH3:8]
Reactant: O=[N+]([O-])O
Reactant: Cc1ccc(O)nc1C
Agent: O=S(=O)(O)O
Product: Cc1cc([N+](=O)[O-])c(O)nc1C
Temperature: 0 °C
Reaction time: 1 h
Yield: 54 %

Procedure:
A mixture of 5,6-dimethylpyridin-2-ol (9.57 g, 0.078 mol) and concentrated sulfuric acid (116 mL) cooled in an ice bath was treated with 70% nitric acid (6.5 mL) in a dropwise manner so that the reaction temperature remains below 15° C., after which the reaction was stirred for a further 1 hour. The mixture was poured into ice-water (300 ml), stirred for 5 minutes then filtered, washed with water (60 mL) and dried under vacuum at 60° C. to yield 5,6-dimethyl-3-nitropyridin-2-ol (7.09 g, 54%). 400 M Hz 1H NMR (DMSO-d6) δ: 12.74 (s, 1H), 8.32 (s, 1H), 2.26 (s, 3H), 2.03 (s, 3H).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=O)=[CH:8][CH:7]=1.Cl.Cl.[NH2:17][C@@H:18]([CH2:32][C:33]1[CH:38]=[C:37]([F:39])[CH:36]=[C:35]([F:40])[CH:34]=1)[C@H:19]([OH:31])[CH2:20][NH:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH2:29][CH3:30])[CH:24]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[F:39][C:37]1[CH:38]=[C:33]([CH:34]=[C:35]([F:40])[CH:36]=1)[CH2:32][C@H:18]([NH:17][C:10](=[O:12])[C:9]1[CH:8]=[CH:7][C:6]([C:2]2[O:1][CH:5]=[CH:4][N:3]=2)=[CH:14][CH:13]=1)[C@H:19]([OH:31])[CH2:20][NH:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH2:29][CH3:30])[CH:24]=1
Reactant: O=C(O)c1ccc(-c2ncco2)cc1
Reactant: CCc1cccc(CNC[C@@H](O)[C@@H](N)Cc2cc(F)cc(F)c2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCc1cccc(CNC[C@@H](O)[C@H](Cc2cc(F)cc(F)c2)NC(=O)c2ccc(-c3ncco3)cc2)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 4-(1,3-oxazol-2-yl)benzoic acid (105 mg, 0.6 mmol), (2R,3S)-3-amino-4-(3,5-difluorophenyl)-1-[(3-ethylbenzyl)amino]butan-2-ol dihydrochloride (220 mg, 0.6 mmol), and HATU (210 mg, 0.6 mmol) stirring in methylene chloride (5 mL) is added N,N-diisopropylethylamine (340 μL, 1.9 mmol). The reaction mixture is stirred at room temperature for 18 h. The reaction mixture is partitioned between methylene chloride and water. The organic layer is washed with water, dried (sodium sulfate), filtered, and concentrated under reduced pressure to afford a crude solid. Purification by flash column chromatography (silica, gradient 96:4 to 93:7 methylene chloride/methanol) provided the title compound. ESI MS m/z 506.2 [M+H]+.
Reaction SMILES: [CH:1]1([N:9]2[C:12](=[O:13])[C:11]([CH3:15])([CH3:14])[NH:10]2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:16]1([C:26](Cl)=[O:27])[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][CH:17]=1>>[CH:1]1([N:9]2[C:12](=[O:13])[C:11]([CH3:15])([CH3:14])[N:10]2[C:26]([C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:19]=[CH:18][CH:17]=2)=[O:27])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(Cl)c1cccc2ccccc12
Reactant: CC1(C)NN(C2CCCCCCC2)C1=O
Product: CC1(C)C(=O)N(C2CCCCCCC2)N1C(=O)c1cccc2ccccc12

Procedure:
2-Cyclooctyl-4,4-dimethyl-1,2-diazetidin-3-one and 1-naphtoyl chloride were used for a similar reaction and treatment as Example 96, and the title compound was obtained as a colorless oil.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][C@H:3]1[O:15][CH2:16][CH3:17].[Cl:18][C:19]1[N:20]=[C:21]([C:25](O)=[O:26])[NH:22][C:23]=1[CH3:24].CCN=C=NCCCN(C)C.Cl>CN(C1C=CN=CC=1)C>[Cl:18][C:19]1[N:20]=[C:21]([C:25]([NH:1][C@H:2]2[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[O:9])[CH2:4][C@H:3]2[O:15][CH2:16][CH3:17])=[O:26])[NH:22][C:23]=1[CH3:24]
Reactant: Cc1[nH]c(C(=O)O)nc1Cl
Reactant: CCO[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@@H]1N
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Product: CCO[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@@H]1NC(=O)c1nc(Cl)c(C)[nH]1
Yield: 43 %

Procedure:
The same operation as in Example (1g) was performed using tert-butyl cis(±)-4-amino-3-ethoxypiperidine-1-carboxylate obtained in Example (18a) (0.34 g, 1.37 mmol), 4-chloro-5-methyl-1H-imidazole-2-carboxylic acid obtained by the method described in Example (5c) (0.16 g, 0.91 mmol), WSC hydrochloride (1.18 g, 6.15 mmol) and DMAP (0.12 g, 0.94 mmol), to obtain 0.23 g of the title compound as a pale yellow solid (43%).
Reaction SMILES: [C:1]([NH:9][N:10]=[C:11]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:12](OC)=[O:13])(=O)[CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.O.[NH2:23][NH2:24]>N1C=CC=CC=1>[CH:2]1([C:1]2[N:23]([NH2:24])[C:12](=[O:13])[C:11]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[N:10][N:9]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: COC(=O)C(=NNC(=O)C1CCCCC1)c1ccccc1
Reactant: NN
Solvent: O
Solvent: c1ccncc1
Product: Nn1c(C2CCCCC2)nnc(-c2ccccc2)c1=O
Yield: 19.6 %

Procedure:
28.8 g (0.1 mol) of phenylglyoxylic acid methyl ester-2-hexahydrobenzoylhydrazone and 10 g of hydrazine hydrate (0.2 mol) were stirred in 100 ml of pyridine, which had been dried over potassium hydroxide, for 45 minutes at 100°C and the mixture was subsequently cooled. Thereupon, the mixture solidifed to a paste. 100 ml of water were added and the whole was stirred for some hours and the product filtered off. After washing with water and drying, 5.3 g (19.7% of theory) of 3-cyclohexyl-4-amino-6-phenyl-5-H-1,2,4-triazin-5-one were obtained in colorless flakes of melting point 178°-180°C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][CH:15]=1)[O:5][CH2:6][CH:7]1[CH2:12][CH2:11][O:10][CH2:9][CH2:8]1.[CH2:16]([NH:19][C:20](=[O:25])[C:21]([F:24])([F:23])[F:22])[CH:17]=[CH2:18].CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.CCN(CC)CC>CC([O-])=O.CC([O-])=O.[Pd+2].CN(C=O)C>[F:22][C:21]([F:24])([F:23])[C:20]([NH:19][CH2:16]/[CH:17]=[CH:18]/[C:2]1[CH:15]=[CH:14][CH:13]=[C:4]([O:5][CH2:6][CH:7]2[CH2:12][CH2:11][O:10][CH2:9][CH2:8]2)[CH:3]=1)=[O:25]
Reactant: C=CCNC(=O)C(F)(F)F
Reactant: Brc1cccc(OCC2CCOCC2)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(NC/C=C/c1cccc(OCC2CCOCC2)c1)C(F)(F)F

Procedure:
A mixture of 4-((3-bromophenoxy)methyl)tetrahydro-2H-pyran (1.86 g, 6.86 mmol), N-allyl-2,2,2-trifluoroacetamide (1.14 g, 7.45 mmol), P(o-Tol)3 (0.31 g, 1.02 mmol), Pd(OAc)2 (0.12 g, 0.534 mmol), Et3N (2.0 mL, 14.35 mmol) and anhydrous DMF (10 mL) was degassed by bubbling Ar for at least 5 mins, then applying vacuum/Ar once. The reaction mixture was heated under Ar at +90° C. for 20 hrs then concentrated under reduced pressure. Aqueous NH4Cl was added to the residue and extracted twice with EtOAc. Combined organic layers were washed with brine, treated with activated charcoal and dried over anhydrous MgSO4 and concentrated under reduced pressure. Purification by flash chromatography (20%-50% EtOAc-hexanes gradient) gave (E)-2,2,2-trifluoro-N-(3-(3-((tetrahydro-2H-pyran-4-yl)methoxy)phenyl)allyl)acetamide as a light yellow oil. Yield (2.01 g, 85%); 1H NMR (400 MHz, DMSO-d6) δ 9.70 (m, 1H), 7.21 (t, J=7.63 Hz, 1H), 6.94-7.00 (m, 2H), 6.78-6.83 (m, 1H), 6.48 (d, J=15.85 Hz, 1H), 6.25 (dt, J=15.85, 5.87 Hz, 1H), 3.90-4.00 (m, 2H), 3.75-3.90 (m, 4H), 3.31 (t, J=11.74 Hz, 2H), 1.90-2.04 (m, 1H), 1.60-1.70 (m, 2H), 1.24-1.37 (m, 2H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH3:12])[CH:7]=[C:6]2[C@@H:13]1[CH2:18][CH2:17][C@H:16]([N:19]2[CH2:24][CH2:23][N:22]([C:25]3[CH:26]=[C:27]([C:35]([OH:37])=[O:36])[CH:28]=[C:29]4[C:34]=3[N:33]=[CH:32][CH:31]=[CH:30]4)[CH2:21][CH2:20]2)[CH2:15][CH2:14]1)#[N:2].[CH3:38]O>C1(C)C=CC=CC=1.CCO>[C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH3:12])[CH:7]=[C:6]2[C@@H:13]1[CH2:18][CH2:17][C@H:16]([N:19]2[CH2:20][CH2:21][N:22]([C:25]3[CH:26]=[C:27]([C:35]([O:37][CH3:38])=[O:36])[CH:28]=[C:29]4[C:34]=3[N:33]=[CH:32][CH:31]=[CH:30]4)[CH2:23][CH2:24]2)[CH2:15][CH2:14]1)#[N:2]
Reactant: Cn1cc([C@H]2CC[C@@H](N3CCN(c4cc(C(=O)O)cc5cccnc45)CC3)CC2)c2cc(C#N)ccc21
Reactant: CO
Solvent: Cc1ccccc1
Solvent: CCO
Product: COC(=O)c1cc(N2CCN([C@H]3CC[C@@H](c4cn(C)c5ccc(C#N)cc54)CC3)CC2)c2ncccc2c1
Temperature: 23 °C
Reaction time: 12 h

Procedure:
To 50 mg (0.1 mmol) of 8-[4-[(cis)-4-(5-cyano-1-methyl-1H-indole-3-yl)cyclohexyl]-1-piperazinyl]-6-quinolinecarboxylic acid in 1 mL of MeOH and 3 mL of C6H5CH3 at 23° C. was added 0.9 mL (0.39 mmol) of a 10% solution of (CH2)3SiCHN2 in hexanes. After stirring at 23° C. for 12 hours, the volatiles were removed by rotary evaporation. The crude product was chromatographed on silica gel eluting with 20:1 CH2Cl2:MeOH. The product fractions were pooled, stripped, and treated with 5 mg (0.05 mmol) of (CO2H)2 in absolute EtOH to give 20 mg (0.04 mmol, a 40% yield) of the oxalate salt of the title compound as a tan crystalline solid. mp: 153-155° C.; MS (ES) m/z: 599 (MH)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH3:21])=[C:11](Br)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:24][O:25][CH2:26][CH2:27][O:28][CH2:29][O:30][C:31]1[C:38](B2OC(C)(C)C(C)(C)O2)=[CH:37][CH:36]=[CH:35][C:32]=1[CH:33]=[O:34]>>[C:1]([O:5][C:6](=[O:23])[NH:7][CH2:8][C:9]1[CH:10]=[C:11]([C:38]2[CH:37]=[CH:36][CH:35]=[C:32]([CH:33]=[O:34])[C:31]=2[O:30][CH2:29][O:28][CH2:27][CH2:26][O:25][CH3:24])[C:12]([O:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH3:21])=[CH:13][CH:14]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COCCOCOc1c(C=O)cccc1B1OC(C)(C)C(C)(C)O1
Reactant: COCCOCOc1ccc(CNC(=O)OC(C)(C)C)cc1Br
Product: COCCOCOc1ccc(CNC(=O)OC(C)(C)C)cc1-c1cccc(C=O)c1OCOCCOC

Procedure:
Proceeding as in Reference 19, but substituting tert-butyl[3-bromo-4-(2-methoxyethoxymethoxy)-benzyl]carbamate (2.3 g, 5.9 mmol) and 2-(2-methoxyethoxymethoxy)-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzaldehyde (60 mL, 0.1 M in toluene), gave tert-butyl[3′-formyl-6,2′-bis(2-methoxyethoxymethoxy)biphenyl-3-ylmethyl]carbamate (2.96 g).