Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C@@H:2]([CH2:33][OH:34])[C:3]([N:5]1[CH2:10][CH2:9][C:8]([C:11]2[C:16]([F:17])=[CH:15][C:14]([N:18]3[CH2:22][C@H:21]([CH2:23][NH:24]C4ON=C(C)C=4)[O:20][C:19]3=[O:31])=[CH:13][C:12]=2[F:32])=[CH:7][CH2:6]1)=[O:4].C(OC(N[C:43]1[N:47]=[CH:46][O:45][N:44]=1)=O)(C)(C)C.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1COCC1>[O:45]1[CH:46]=[N:47][C:43]([CH:23]([NH2:24])[C@H:21]2[O:20][C:19](=[O:31])[N:18]([C:14]3[CH:13]=[C:12]([F:32])[C:11]([C:8]4[CH2:9][CH2:10][N:5]([C:3](=[O:4])[C@@H:2]([OH:1])[CH2:33][OH:34])[CH2:6][CH:7]=4)=[C:16]([F:17])[CH:15]=3)[CH2:22]2)=[N:44]1
Reactant: CC(C)(C)OC(=O)Nc1ncon1
Reactant: Cc1cc(NC[C@H]2CN(c3cc(F)c(C4=CCN(C(=O)[C@@H](O)CO)CC4)c(F)c3)C(=O)O2)on1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: NC(c1ncon1)[C@@H]1CN(c2cc(F)c(C3=CCN(C(=O)[C@@H](O)CO)CC3)c(F)c2)C(=O)O1
Temperature: 0 °C
Reaction time: 18 h
Yield: 45.6 %

Procedure:
To a stirred solution of the appropriate intermediate of Example 20 (600 mg, 1.37 mmol) in anhydrous THF (30 ml) under an atmosphere of nitrogen was added 3-t-butyloxycarbonylamino-1,2,4-oxadiazole (304 mg, 1.64 mmol) and tri-n-butylphosphine (510 μL, 2.05 mmol). The mixture was cooled to 0° C. and 1,1′-(azodicarbonyl)-di-piperidine (518 mg, 2.05 mmol) was added portionwise. The reaction was allowed to warm to room temperature and stir for 18 hours. The THF was removed under reduced pressure and the resulting residue taken into dichloromethane (15 ml) and cooled to 0° C. A white solid precipitated and the solution was filtered and purified by MPLC (Merck 9385 silica, 40-60% ethyl acetate in iso-hexane). The solvent was removed under reduced pressure to give a clear, colourless oil which was triturated with ether to yield the title compound as a fine white powder (291 mg, 35%). 1H-NMR (300 MHz, DMSO-d6): δ=1.31 (d, 6H), 1.47 (s, 9H), 2.27-2.48 (m, 2H), 3.61-4.28 (m, 10H), 4.87-5.02 (m, 2H), 5.89 (broad s, 1H), 7.33 (d, 2H), 9.54 (s, 1H). MS: ESP+ (M+H)+606.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]([NH:6][C:7]1[C:12]([C:13]([F:16])([F:15])[F:14])=[CH:11][CH:10]=[CH:9][C:8]=1[C:17](=[O:27])[CH2:18][C:19]([NH:21][C:22]1[S:23][CH:24]=[CH:25][N:26]=1)=[O:20])=O>CN(C)C1C=CN=CC=1.O1CCCC1>[OH:27][C:17]1[C:8]2[C:7](=[C:12]([C:13]([F:16])([F:15])[F:14])[CH:11]=[CH:10][CH:9]=2)[N:6]=[C:4]([CH2:3][O:2][CH3:1])[C:18]=1[C:19]([NH:21][C:22]1[S:23][CH:24]=[CH:25][N:26]=1)=[O:20]
Reactant: COCC(=O)Nc1c(C(=O)CC(=O)Nc2nccs2)cccc1C(F)(F)F
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: COCc1nc2c(C(F)(F)F)cccc2c(O)c1C(=O)Nc1nccs1
Temperature: 20 °C
Reaction time: 2 h
Yield: 84.4 %

Procedure:
5.03 g of 4-dimethylamino-pyridine were added to a solution of 16.5 g of the product of Step B in 205 ml of tetrahydrofuran and the mixture was stirred at 20° C. for 41/2 hours. The tetrahydrofuran was distilled off under reduced pressure at 40° C. and the dry residue was taken up in 500 ml of water. 42 ml of N hydrochloric acid were added to the mixture and the suspension was stirred at 20° C. for 30 minutes and was vacuum filtered. The product was washed with water, dried under reduced pressure at 70° C. and was crystallized from 310 ml of dioxane. The mixture was vacumm filtered at 15° C. and the product was washed with 30 ml of dioxane and dried under reduced pressure at 70° C. to obtain 13.3 g of 4-hydroxy-2-methoxymethyl-N-(2-thiazolyl)-8-trifluoromethyl-3-quinoline-carboxamide melting at 260° C.
Reaction SMILES: Cl.[CH2:2]([O:9][C:10](=[O:14])[CH2:11][NH:12][CH3:13])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[N:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][C@@H:22]([C:24]([OH:26])=[O:25])[NH2:23])[CH:16]=1.[C:27]1([CH2:33][S:34](Cl)(=[O:36])=[O:35])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(N(CC)CC)C>CN(C)C=O.C(#N)C>[CH2:2]([O:9][C:10](=[O:14])[CH2:11][NH:12][CH3:13])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:33]([S:34]([NH:23][C@H:22]([C:24]([OH:26])=[O:25])[CH2:21][C:17]1[CH:16]=[N:15][CH:20]=[CH:19][CH:18]=1)(=[O:36])=[O:35])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: O=S(=O)(Cl)Cc1ccccc1
Reactant: N[C@@H](Cc1cccnc1)C(=O)O
Agent: CNCC(=O)OCc1ccccc1
Agent: Cl
Solvent: CC#N
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(O)[C@H](Cc1cccnc1)NS(=O)(=O)Cc1ccccc1
Yield: 25.7 %

Procedure:
The title compound was prepared under the same manner as described in Example 58, using 2.44 g (6.7 mmole) of the compound of Example 57 in 10 mL of dry dimethylformamide and 25 mL acetonitrile, alpha-toluenesulfonyl chloride (1.9 g, 10.1 mmole), and triethylamine (5 mL, 34 mmole). This afforded 0.86 g (27% yield) of the title compound as a brownish-yellow foam. Rf=0.45 (1:9 methanol:dichloromethane).
Reaction SMILES: Cl[C:2]1[C:11]2[CH2:10][N:9]([C@H:12]([C:23]([CH3:26])([CH3:25])[CH3:24])[C:13]([O:15]CC3C=CC=CC=3)=[O:14])[C:8](=[O:27])[C:7]3=[CH:28][N:29]([S:30]([C:33]4[CH:39]=[CH:38][C:36]([CH3:37])=[CH:35][CH:34]=4)(=[O:32])=[O:31])[C:5]([C:6]=23)=[N:4][CH:3]=1.[CH3:40][Al](C)C>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.O1CCOCC1>[CH3:25][C:23]([CH3:24])([CH3:26])[C@@H:12]([N:9]1[C:8](=[O:27])[C:7]2=[CH:28][N:29]([S:30]([C:33]3[CH:39]=[CH:38][C:36]([CH3:37])=[CH:35][CH:34]=3)(=[O:31])=[O:32])[C:5]3[C:6]2=[C:11]([C:2]([CH3:40])=[CH:3][N:4]=3)[CH2:10]1)[C:13]([OH:15])=[O:14]
Reactant: Cc1ccc(S(=O)(=O)n2cc3c4c(c(Cl)cnc42)CN([C@@H](C(=O)OCc2ccccc2)C(C)(C)C)C3=O)cc1
Reactant: C[Al](C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: Cc1ccc(S(=O)(=O)n2cc3c4c(c(C)cnc42)CN([C@@H](C(=O)O)C(C)(C)C)C3=O)cc1
Temperature: 120 °C
Yield: 439.1 %

Procedure:
(R)-Benzyl 2-(6-chloro-3-oxo-1-tosylpyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)-3,3-dimethylbutanoate (10 mg, 0.018 mmol), Pd(Ph3P)4 (10 mg, 0.009 mmol), and dioxane (1 mL) were combined in a 2 mL microwave vial. The mixture was purged with nitrogen, and trimethylaluminum (2.0M/toluene, 0.053 mL, 0.11 mmol) was added. The vial was sealed and the reaction mixture was heated in a Biotage Initiator™ microwave for 1 h at 120° C. The reaction was repeated three times with an increased amount of (R)-benzyl 2-(6-chloro-3-oxo-1-tosylpyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)-3,3-dimethylbutanoate (30 mg) in each reaction. The reaction mixtures were combined and the resulting mixture was concentrated and purified by preparative HPLC (30-70% AcCN/H2O with 0.035% TFA) to afford the title compound as a yellow oil (36 mg, 44%). 1H NMR (500 MHz, CD3OD) δ 1.21 (s, 9H), 2.30 (s, 3H), 2.36 (s, 3H), 4.94 (s, 1H), 5.07 (d, J=18.6 Hz, 1 H), 5.21 (d, J=19.0 Hz, 1 H), 7.36 (d, J=8.3 Hz, 2 H), 8.04 (d, J=4.9 Hz, 2 H), 8.10 (s, 1 H), 8.22 (s, 1 H). [M+H] calc'd for C23H25N3O5S, 456; found, 456
Reaction SMILES: [C:1]([C:3]1[O:4][C:5]2[CH:13]=[C:12]([OH:14])[CH:11]=[CH:10][C:6]=2[C:7](=[O:9])[CH:8]=1)#[N:2].Cl[CH2:16][C:17]1[CH:18]=[C:19]([CH:32]=[CH:33][CH:34]=1)[O:20][CH2:21][C:22]1[CH:31]=[CH:30][C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[N:23]=1.[OH-].[Na+]>CS(C)=O>[C:1]([C:3]1[O:4][C:5]2[CH:13]=[C:12]([O:14][CH2:16][C:17]3[CH:34]=[CH:33][CH:32]=[C:19]([O:20][CH2:21][C:22]4[CH:31]=[CH:30][C:29]5[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=5)[N:23]=4)[CH:18]=3)[CH:11]=[CH:10][C:6]=2[C:7](=[O:9])[CH:8]=1)#[N:2]
Reactant: ClCc1cccc(OCc2ccc3ccccc3n2)c1
Reactant: N#Cc1cc(=O)c2ccc(O)cc2o1
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: N#Cc1cc(=O)c2ccc(OCc3cccc(OCc4ccc5ccccc5n4)c3)cc2o1
Temperature: 0 °C

Procedure:
To 2-cyano-7-hydroxy-4-oxo-4H-1-benzopyran (11.87 mmoles) and 2-((3-chloromethylphenoxy)methyl)quinoline (11.87 mmoles) in dimethylsulfoxide (20 ml) is added powdered sodium hydroxide (0.475 g). After one week the reaction mixture is poured into ice water and the resulting precipitate collected and purified by HPLC to give 2-cyano-7-(3-(quinolin-2-ylmethoxy)benzyloxy)-4-oxo-4H-1-benzopyran which is used directly in the next step
Reaction SMILES: [Si]([O:8][C@H:9]1[CH2:13][N:12]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C@H:11]([CH2:21][C:22]#N)[CH2:10]1)(C(C)(C)C)(C)C.C(N(CC)CC)C.[C:31](OC(OC(C)(C)C)=O)(OC(C)(C)C)=[O:32].[OH2:46]>Cl.C(O)(=O)C>[OH:8][C@H:9]1[CH2:13][N:12]([C:14]([O:16][C:17]([CH3:18])([CH3:19])[CH3:20])=[O:15])[C@H:11]([CH2:21][C:22]([O:32][CH3:31])=[O:46])[CH2:10]1
Reactant: CC(C)(C)OC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1CC#N
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC(=O)O
Product: COC(=O)C[C@@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 14 h
Yield: 71 %

Procedure:
The solution of tert-butyl (2R,4R)-4-{[tert-butyl(dimethyl)silyl]oxy}-2-(cyanomethyl)pyrrolidine-1-carboxylate (7.81 g, 22.9 mmol, step 1 of Example 9) in concentrated hydrochloric acid-acetic acid (50 mL-50 mL) was refluxed for 15 h and concentrated under reduced pressure. The resulting residue was dissolved in 10% hydrochloric acid in methanol (50 mL). The mixture was refluxed for 18 h and concentrated under reduced pressure. To the suspension of resulting residue in dichloromethane (100 mL) were added triethylamine (9.58 mL, 68.7 mmol) and di-tert-butyl dicarbonate (7.50 g, 34.4 mmol) at 0° C. The mixture was allowed to warm to room temperature and stirred for 14 h. To the mixture was added water (100 mL). The organic layer was separated, dried over sodium sulfate, and concentrated under reduced pressure. The resulting residue was chromatographed on a column of silica gel eluting with n-hexane/ethyl acetate (1:1) to give 4.23 g (71%) of the title compound as a colorless oil.
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([C:11]2[CH:12]=[N:13][N:14]([CH3:16])[CH:15]=2)[CH:8]=[CH:7][N:6]=1)(=O)=O.CS(C1N=C(C2C=NN(C)C=2)C=CN=1)=[O:19].[NH2:32][C:33]1[CH:38]=[CH:37][C:36](O)=[CH:35][C:34]=1[F:40].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[F:40][C:34]1[CH:35]=[CH:36][C:37]([O:19][C:5]2[N:10]=[C:9]([C:11]3[CH:12]=[N:13][N:14]([CH3:16])[CH:15]=3)[CH:8]=[CH:7][N:6]=2)=[CH:38][C:33]=1[NH2:32]
Reactant: Cn1cc(-c2ccnc(S(C)=O)n2)cn1
Reactant: Cn1cc(-c2ccnc(S(C)(=O)=O)n2)cn1
Reactant: Nc1ccc(O)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cn1cc(-c2ccnc(Oc3ccc(F)c(N)c3)n2)cn1
Temperature: 100 °C

Procedure:
The above mixture of 2-methanesulfonyl-4-(1-methyl-1H-pyrazol-4-yl)-pyrimidine and 2-methanesulfinyl-4-(1-methyl-1H-pyrazol-4-yl)-pyrimidine (1 g, 4.2 mmol), 4-amino-3-fluoro-phenol (1.1 g, 8.6 mmol) and K2CO3 (1.2 g, 8.6 mmol) in DMF (10 mL) was heated at 100° C. for 12 h. The reaction was partitioned between H2O and EtOAc (3×50 mL). The combined organics were dried (Na2SO4), concentrated in vacuo and chromatographed to provide 2-fluoro-5-(4-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yloxy)benzenamine (402 mg). 1H NMR (400 MHz, DMSO-d6): δ 8.44 (d, J=5.2 Hz, 1H), 8.39 (s, 1H), 8.07 (s, 1H), 7.41 (d, J=5.2 Hz, 1H), 6.98 (t, J=9.6 Hz, 1H), 6.53 (dd, J=5.6, 2.0 Hz, 1H), 6.28 (d, J=8.4 Hz, 1H), 5.25 (br s, 2H), 3.88 (s, 3H). MS (ESI) m/z: 286.2 (M+H+).
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:17])=[C:11](F)[C:12]=3[O:14][CH3:15])[C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5]2)[CH2:3][CH2:2]1.[NH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1.COB(OC)OC.C(#N)C>O>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:17])=[C:11]([N:25]4[CH:24]=[CH:23][N:22]=[CH:27][CH2:26]4)[C:12]=3[O:14][CH3:15])[C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5]2)[CH2:3][CH2:2]1
Reactant: COc1c(F)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12
Reactant: C1CNCCN1
Agent: COB(OC)OC
Solvent: CC#N
Solvent: O
Product: COc1c(N2C=CN=CC2)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12
Temperature: 25 °C
Yield: 81.7 %

Procedure:
A mixture of 1.48 g of 1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylic acid (5 mmol), 0.86 g of anhydrous piperazine (10 mmol), 1.04 g of trimethoxyborane (10 mmol) and 7.5 ml of acetonitrile was refluxed with heating for 4 hours. The reaction solution was cooled to room temperature, 20 ml of water was added therein, a pH was adjusted to 8 with 6N--HCl, and separated crystals were filtered and dried to obtain 1.46 g of the objective compound.
Reaction SMILES: [CH:1]([CH:4]1[NH:8][C:7](=[O:9])[NH:6][C:5]1=[O:10])([CH3:3])[CH3:2].[CH3:11]I>>[CH:1]([CH:4]1[NH:8][C:7](=[O:9])[N:6]([CH3:11])[C:5]1=[O:10])([CH3:3])[CH3:2]
Reactant: CC(C)C1NC(=O)NC1=O
Reactant: CI
Product: CC(C)C1NC(=O)N(C)C1=O

Procedure:
Using 5-isopropylimidazolidine-2,4-dione (1.00 g) and methyl iodide (0.46 mL) and by the reaction and treatment in the same manner as in Preparation Example 214, the title compound (0.88 g) was obtained.
Reaction SMILES: FC(F)(F)C1C=C([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH2:11][C:12](=[O:18])[NH:13]3)C=CC=1.C[C@H]1N[C@@H](C)CN(C(C2C=C(C)NC=2C=O)=O)C1>C(O)C.N1CCCCC1>[NH:13]1[C:14]2[C:10](=[CH:9][CH:17]=[CH:16][CH:15]=2)[CH2:11][C:12]1=[O:18]
Reactant: O=C1Cc2c(cccc2-c2cccc(C(F)(F)F)c2)N1
Agent: Cc1cc(C(=O)N2C[C@@H](C)N[C@@H](C)C2)c(C=O)[nH]1
Solvent: CCO
Solvent: C1CCNCC1
Product: O=C1Cc2ccccc2N1
Temperature: 25 °C
Reaction time: 72 h
Yield: 278.5 %

Procedure:
To a solution of 4-(3-trifluoromethyl-phenyl)-1,3-dihydro-indol-2-one (56.8 mg, 0.25 mmol) and 3-[(cis)3,5-dimethyl-piperazine-1-carbonyl]-5-methyl-1H-pyrrole-2-carbaldehyde (62.3 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide pure product 3-[3-((cis)-3,5-dimethyl-piperazine-1-carbonyl]-5-methyl-1H-pyrrol-2-ylmethylene]-4-2-trifluoromethyl-phenyl)-1,3-dihydro-indol-2-one as a yellow solid (92.7 mg, 73%).
Reaction SMILES: [CH3:1][CH:2]([N:4]1[C:12]2[C:7](=[N:8][CH:9]=[CH:10][CH:11]=2)[N:6]([C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[N:18](C(OC(C)(C)C)=O)[CH2:17][CH2:16]3)[C:5]1=[O:29])[CH3:3].Cl>CCOC(C)=O.C1COCC1.CCOC(C)=O>[NH:18]1[C:19]2[C:15](=[CH:14][C:13]([N:6]3[C:7]4=[N:8][CH:9]=[CH:10][CH:11]=[C:12]4[N:4]([CH:2]([CH3:1])[CH3:3])[C:5]3=[O:29])=[CH:21][CH:20]=2)[CH2:16][CH2:17]1
Reactant: CC(C)n1c(=O)n(-c2ccc3c(c2)CCN3C(=O)OC(C)(C)C)c2ncccc21
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)n1c(=O)n(-c2ccc3c(c2)CCN3)c2ncccc21
Temperature: 80 °C
Reaction time: 2 h

Procedure:
To a stirred mixture of tert-butyl 5-[1-(1-methylethyl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl]-2,3-dihydro-1H-indole-1-carboxylate in AcOEt/EtOH (1/1, 10 mL) was added 4N HCl in AcOEt (4 mL). The mixture was stirred at 80° C. for 2 h, evaporated, treated with saturated NaHCO3, and extracted with AcOEt. The organic layer was dried over MgSO4 and concentrated in vacuo. The residue was suspended in IPE and the suspension was collected by filtration to give the title compound as white crystals (313 mg).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1)[NH2:7])([O-:3])=[O:2].[CH3:15][O:16][CH2:17][C:18](O)=[O:19].ON1C2C=CC=CC=2N=N1.CN1CCOCC1>CN(C=O)C.O>[CH3:15][O:16][CH2:17][C:18]([NH:7][C:6]1[CH:8]=[C:9]([C:11]([F:12])([F:13])[F:14])[CH:10]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1)=[O:19]
Reactant: Nc1cc([N+](=O)[O-])cc(C(F)(F)F)c1
Reactant: COCC(=O)O
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Solvent: O
Product: COCC(=O)Nc1cc([N+](=O)[O-])cc(C(F)(F)F)c1
Temperature: 25 °C
Yield: 38.9 %

Procedure:
Stir the mixture of 3-nitro-5-(trifluoromethyl)aniline (500 mg, 2.4 mmol), 2-methoxyacetic acid (220 mg, 2.4 mmol), 1-hydroxybenzotriazole (HOBt, 324 mg, 2.4 mmol), N-methyl morpholine (NMM, 480 mg, 4.8 mmol), 1-ethyl-3-(3-dimethyllaminopropyl)carbodiimide hydrochloride (EDCI.HCl, 920 mg, 4.8 mmol) in DMF (8 mL) at 80° C. for 16 hrs. Cool the reaction mixture to room temperature, add water (100 mL), extract with ethyl acetate (30 mL×2), combine the organic layers, wash with brine, dry over anhydrous sodium sulfate, and concentrate under reduced pressure to give the crude product. Purify by flash chromatography (silica gel, EtOAc:PE=15:85) to yield the target compound (260 mg, 39%).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][C@H:3]([O:6][C:7]([O:9]N2C(=O)CCC2=O)=O)[CH2:2]1.Cl.Cl.[CH3:19][C:20]1[N:24]([CH:25]2[CH2:31][CH:30]3[N:32]([CH2:33][CH2:34][C:35]4([C:41]5[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=5)[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]4)[CH:27]([CH2:28][CH2:29]3)[CH2:26]2)[C:23]2[CH:47]=[CH:48][CH:49]=[CH:50][C:22]=2[N:21]=1.C(N(CC)C(C)C)(C)C>C(#N)C>[CH3:19][C:20]1[N:24]([CH:25]2[CH2:31][C@H:30]3[N:32]([CH2:33][CH2:34][C:35]4([C:41]5[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=5)[CH2:36][CH2:37][N:38]([C:7]([O:6][C@H:3]5[CH2:4][CH2:5][O:1][CH2:2]5)=[O:9])[CH2:39][CH2:40]4)[C@H:27]([CH2:28][CH2:29]3)[CH2:26]2)[C:23]2[CH:47]=[CH:48][CH:49]=[CH:50][C:22]=2[N:21]=1
Reactant: Cc1nc2ccccc2n1C1CC2CCC(C1)N2CCC1(c2ccccc2)CCNCC1
Reactant: O=C(O[C@H]1CCOC1)ON1C(=O)CCC1=O
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: Cc1nc2ccccc2n1C1C[C@H]2CC[C@@H](C1)N2CCC1(c2ccccc2)CCN(C(=O)O[C@H]2CCOC2)CC1

Procedure:
A solution of 1-({[(3S)-tetrahydrofuran-3-yloxy]carbonyl}oxy)pyrrolidine-2,5-dione (U.S. Pat. No. 6,344,465) (55 mg, 0.24 mmol), amine dihydrochloride II (100 mg, 0.199 mmol) and N,N-diisopropylethylamine (0.14 mL, 0.80 mmol) in acetonitrile (3 mL) was stirred overnight at rt. The solvent was removed at reduced pressure and the remaining material was dissolved in dichloromethane, washed with saturated sodium bicarbonate solution and dried over magnesium sulfate. Filtration and evaporation of the dichloromethane solution provided the crude product which was purified by chromatography on silica gel eluting with 5% methanol/dichloromethane. Title compound in example 692 was obtained as a white hygroscopic powder (70 mg, 65%). 1H NMR (400 MHz, CDCl3) δ 7.66 (d, 1H, J=8 Hz), 7.37 (m, 2H), 7.30-7.20 (m, 4H), 7.16 (m, 2H), 5.25 (m, 1H), 4.61 (m, 1H), 3.85 (m, 4H), 3.73 (m, 2H), 3.22 (m, 4H), 2.58 (br s, 3H), 2.36 (m, 2H), 2.17 (m, 3H), 2.05-1.70 (m, 13H). HRMS C33H42N4O3 m/z 543.3335 (M+H)Cal., 543.3331 (M+H)Obs..
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7]C=[CH:5][CH:4]=1.[C:9]([C@H:12]1[CH2:17][CH2:16][CH2:15][N:14]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C@H:13]1[CH2:25][C:26]1[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=1)(=[O:11])[CH3:10].[Cl-].[NH4+].[CH2:36](OCC)C>>[CH2:18]([N:14]1[CH2:15][CH2:16][CH2:17][C@H:12]([C:9]([CH3:36])([C:10]2[CH:7]=[CH:8][CH:3]=[CH:4][CH:5]=2)[OH:11])[C@@H:13]1[CH2:25][C:26]1[CH:27]=[CH:28][C:29]([O:32][CH3:33])=[CH:30][CH:31]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: Brc1ccccc1
Reactant: CCOCC
Reactant: COc1ccc(C[C@H]2[C@@H](C(C)=O)CCCN2Cc2ccccc2)cc1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Product: COc1ccc(C[C@H]2[C@@H](C(C)(O)c3ccccc3)CCCN2Cc2ccccc2)cc1

Procedure:
To the Grignard reagent prepared from 2.4 g. of magnesium turnings and 15.7 g. of bromobenzene in diethyl ether there is added dropwise an ethereal solution of 33.7 g. of cis-3-acetyl-1-benzyl-2-(p-methoxybenzyl)piperidine. After this addition is completed, the reaction mixture is stirred and refluxed for four hours and poured into aqueous ammonium chloride solution. The ether layer is separated, dried, and filtered. The filtrate is evaporated to dryness under reduced pressure to yield cis-1-benzyl-2-(p-methoxy-benzyl)-α-methyl-α-phenyl-3-piperidinemethanol.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:17][CH3:18])=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]([O:14]C)=[O:13])[CH:8]=[C:7]2[OH:16].CO.C1COCC1.[Li+].[OH-]>O>[Cl:1][C:2]1[C:3]([O:17][CH3:18])=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]([OH:14])=[O:13])[CH:8]=[C:7]2[OH:16]
Reactant: COC(=O)c1cc(O)c2ccc(OC)c(Cl)c2n1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc2c(O)cc(C(=O)O)nc2c1Cl
Temperature: 25 °C
Yield: 93.5 %

Procedure:
To a solution of methyl 8-chloro-4-hydroxy-7-methoxyquinoline-2-carboxylate (36.5 g, 0.145 mol) in a mixture of 1:1 of MeOH: THF (160 mL total) was added a solution of LiOH (30.5 g, 0.725 mol) in H2O (80 mL). The mixture was stirred at room temperature for an hour when LCMS analysis showed complete conversion to the carboxylic acid. The reaction was worked up by removal of the volatiles and adjusting the pH of the solution to 6 using aqueous 6N HCl. The resulted gummy residue was filtered and dried on the lypholizer for 2 days to provide 34.4 g (99.6%) of the product as a white solid. EI MS (m/z) 253.9 [M+H].
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]2[N:15]([C:16]=1[C:17]1[CH:18]=[CH:19][C:20]3[N:21]([C:23]([C:26](OCC)=[O:27])=[N:24][N:25]=3)[N:22]=1)[CH:14]=[CH:13][O:12]2.[CH3:31][Mg]Cl.[Cl-].[NH4+].C(Cl)Cl>C1COCC1.O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]2[N:15]([C:16]=1[C:17]1[CH:18]=[CH:19][C:20]3[N:21]([C:23]([C:26](=[O:27])[CH3:31])=[N:24][N:25]=3)[N:22]=1)[CH:14]=[CH:13][O:12]2
Reactant: CCOC(=O)c1nnc2ccc(-c3c(-c4ccc(F)cc4F)nc4occn34)nn12
Reactant: C[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(=O)c1nnc2ccc(-c3c(-c4ccc(F)cc4F)nc4occn34)nn12
Temperature: -30 °C
Reaction time: 0.42 h

Procedure:
In a 100 mL round-bottomed flask, ethyl 6-(6-(2,4-difluorophenyl)imidazo[2,1-b]oxazol-5-yl)-[1,2,4]triazolo[4,3-b]pyridazine-3-carboxylate (2.00 g, 4.87 mmol, Example #37, Step D) was suspended in THF (30 mL) and cooled to about −30° C. Methylmagnesium chloride (3.0 M in THF, 6.50 mL, 19.5 mmol) was added over about 10 min to the suspension. The mixture was stirred for about 25 min at about −30° C., followed by slow addition of a saturated solution of ammonium chloride (15 mL). The suspension was diluted with the addition of water (20 mL) and then DCM (20 mL). The layers were separated and the aqueous layer was extracted DCM (2×50 mL). The combined organic extracts were washed with water and brine, dried over MgSO4, filtered, and the solvents were removed under reduced pressure to give a solid that was triturated with Et2O (15 mL) and collected by vacuum filtration as a powder (1.50 g, 81%): LC/MS (Table 1, Method g) Rt=2.06 min; MS m/z: 380.9 (M+H)+.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][C:10](=[O:18])[NH:11][C:12]1[CH:16]=[C:15]([CH3:17])[O:14][N:13]=1)(C)(C)C.[Si]([I:24])(C)(C)C.CO>CC#N>[IH:24].[NH2:7][CH2:8][CH2:9][C:10]([NH:11][C:12]1[CH:16]=[C:15]([CH3:17])[O:14][N:13]=1)=[O:18]
Reactant: C[Si](C)(C)I
Reactant: Cc1cc(NC(=O)CCNC(=O)OC(C)(C)C)no1
Solvent: CC#N
Solvent: CO
Product: Cc1cc(NC(=O)CCN)no1
Product: I
Reaction time: 0.5 h

Procedure:
To a stirred solution of [2-(5-methyl-isoxazol-3-ylcarbamoyl)-ethyl]-carbamic acid tert-butyl ester (0.1 g, 0.37 mmol) in MeCN (3 ml) is added dropwise TMSI (0.11 ml, 0.74 mmol). After 30 minutes, MeOH (1 ml) is added to afford a yellow suspension which is collected by filtration and washed with EtOAc to afford the title compound. Further product is obtained by concentration of the filtrate.
Reaction SMILES: [C:1]1([C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)([CH2:9][CH3:10])O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O:19]C(=O)C)C.[N-]=C=O.N1C=CC=CC=1>CCOCC>[C:1]1([CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:9][CH2:10][OH:19])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(C)=O
Reactant: CCC(O)(c1ccccc1)c1ccccc1
Agent: [N-]=C=O
Solvent: c1ccncc1
Solvent: CCOCC
Product: OCCC(c1ccccc1)c1ccccc1

Procedure:
3.2 G of diphenyl-ethyl-carbinol, 1.9 g of isocyanate acetic acid ethyl ester and 1.6 ml of pyridine are heated at 50° C for 72 hours. The solution is diluted with 50 ml of ether, washed several times at 0° C with 0.1-molar citric acid solution and water, dried over sodium sulfate, and completely evaporated under reduced pressure. After elimination of 2.3 g of diphenylethylcarbinol by means of petroleum ether, 1,1-diphenyl-propyloxycarbonyl-glycine-ethyl ester is obtained in the form of an oil; Rf = 0.2 in the thin-layer chromatogram in chloroform.