Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][C:21]=2[F:22])[N:18]([CH3:23])[C:17](=[O:24])[CH2:16][CH2:15]3)[CH:9]=[N:10][CH:11]=1.[CH3:25][C:26]1[C:30]([C:31](O)=[O:32])=[C:29]([CH3:34])[O:28][N:27]=1>>[F:22][C:21]1[CH:20]=[C:19]2[C:14]([CH2:15][CH2:16][C:17](=[O:24])[N:18]2[CH3:23])=[CH:13][C:12]=1[C:8]1[CH:7]=[C:6]([O:5][CH2:4][CH2:3][NH:2][C:31]([C:30]2[C:26]([CH3:25])=[N:27][O:28][C:29]=2[CH3:34])=[O:32])[CH:11]=[N:10][CH:9]=1
Reactant: CN1C(=O)CCc2cc(-c3cncc(OCCN)c3)c(F)cc21
Reactant: Cc1noc(C)c1C(=O)O
Agent: Cl
Product: Cc1noc(C)c1C(=O)NCCOc1cncc(-c2cc3c(cc2F)N(C)C(=O)CC3)c1

Procedure:
In analogy to the procedure described for the preparation of example 219, 6-[5-(2-amino-ethoxy)-pyridin-3-yl]-7-fluoro-1-methyl-3,4-dihydro-1H-quinolin-2-one hydrochloride (example 238) has been coupled with 3,5-dimethyl-isoxazole-4-carboxylic acid to give the title compound as a colorless solid. MS: 439.4 (M+H+).
Reaction SMILES: [Cl:1]C(OCC)=O.[F:7][C:8]1[C:13]([F:14])=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:15][CH2:16][O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]([OH:26])=O.C(N(CC)CC)C>ClCCl>[F:7][C:8]1[C:13]([F:14])=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:15][CH2:16][O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]([Cl:1])=[O:26]
Reactant: CCOC(=O)Cl
Reactant: O=C(O)CCCCCCOCCc1cccc(F)c1F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Cl)CCCCCCOCCc1cccc(F)c1F
Yield: 95.4 %

Procedure:
Ethyl chloroformate (414 mg, 3.82 mmol) was added at 0° C. to a solution of 7-[2-(2,3-difluoro-phenyl)-ethoxy]-heptanoic acid (800 mg, 2.94 mmol) and triethylamine (387 mg, 3.82 mmol) in dichloromethane (15 mL), then after 2 h volatile material was removed by distillation, producing 7-[2-(2,3-difluoro-phenyl)-ethoxy]-heptanoyl chloride (855 mg). This was redissolved in acetone (2 mL) and treated at 0° C. with a solution of sodium azide (268 mg, 4.12 mmol) in water (4 mL) under vigorous stirring. The reaction mixture was stirred for 1 h at 10° C., then partitioned between toluene and brine. The organic layer was separated and heated at 65° C. for 90 min, then concentrated in vacuo, affording [6-(2,3-difluoro-benzyloxy)-hexyl]-isocyanate (486 mg, 61%) as a yellow oil.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C@:12]1([CH3:18])[CH2:16][O:15][C:14](=[O:17])[NH:13]1)[CH:6]=[CH:5]2.[CH:19]1([CH:24]2[CH2:29][CH2:28][CH:27](O)[CH2:26][CH2:25]2)[CH2:23][CH2:22][CH2:21][CH2:20]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O1CCCC1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>>[CH:19]1([CH:24]2[CH2:25][CH2:26][CH:27]([O:1][C:2]3[CH:3]=[C:4]4[C:9](=[CH:10][CH:11]=3)[CH:8]=[C:7]([C@:12]3([CH3:18])[CH2:16][O:15][C:14](=[O:17])[NH:13]3)[CH:6]=[CH:5]4)[CH2:28][CH2:29]2)[CH2:20][CH2:21][CH2:22][CH2:23]1
Reactant: OC1CCC(C2CCCC2)CC1
Reactant: C[C@@]1(c2ccc3cc(O)ccc3c2)COC(=O)N1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C[C@@]1(c2ccc3cc(OC4CCC(C5CCCC5)CC4)ccc3c2)COC(=O)N1
Yield: 27 %

Procedure:
The compound was prepared in a manner similar as to that described above using (R)-4-(6-hydroxynaphthalen-2-yl)-4-methyloxazolidin-2-one, 4-cyclopentyl-cyclohexanol (1.5 g, 0.0090 mol), triphenylphosphine (2.6 g, 0.0099 mol), tetrahydrofuran (45 mL, 0.55 mol) and diisopropyl azodicarboxylate (2.0 g, 0.0099 mol) to give 895 mg of a 1.6 to 1 diasteromeric ratio of the desired compound as a yellow solid (27%). ESI-MS: 368 (M+H)+. 1H NMR (400 MHz, CDCl3) δ=7.80-7.63 (m, 3H), 7.39 (dd, J=1.9, 8.7 Hz, 1H), 7.22-7.08 (m, 2H), 4.70-4.58 (br. s., 0.63H), 4.43-4.36 (s, 2H), 4.34-4.21 (tt, J=4.2, 6.5 Hz, 0.39H), 2.04 (s, 2H), 1.87-1.70 (m, 2H), 1.65-0.77 (m, 17H)
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9]/[C:10](=[C:17]2\[C:18](=[O:26])[NH:19][C:20]3[C:25]\2=[CH:24][CH:23]=[CH:22][CH:21]=3)/[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:5][CH:4]=1.[C:27]([O:31][C:32]([NH:34][CH2:35][C:36](O)=[O:37])=[O:33])([CH3:30])([CH3:29])[CH3:28].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.C(N(C(C)C)C(C)C)C>CN(C=O)C>[C:27]([O:31][C:32]([NH:34][CH2:35][C:36]([NH:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([NH:9]/[C:10](=[C:17]2\[C:18](=[O:26])[NH:19][C:20]3[C:25]\2=[CH:24][CH:23]=[CH:22][CH:21]=3)/[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:7][CH:8]=1)=[O:37])=[O:33])([CH3:30])([CH3:29])[CH3:28]
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: NCc1ccc(N/C(=C2\C(=O)Nc3ccccc32)c2ccccc2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCC(=O)NCc1ccc(N/C(=C2\C(=O)Nc3ccccc32)c2ccccc2)cc1

Procedure:
Prepared analogously to Example 18 from (Z)-3-{1-[4-(aminomethyl)phenylamino]-1-phenyl-methylidene}-2-indolinone, N-tert.butoxycarbonyl-glycine, TBTU, HOBt and N-ethyl-N,N-diisopropylamine in DMF.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]([CH:10]=O)=[O:9])[CH:5]=[CH:6][CH:7]=1.[CH3:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][NH2:21])=[CH:15][CH:14]=1>>[CH3:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][NH:21][CH2:10][CH:8]([OH:9])[C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)=[CH:15][CH:14]=1
Reactant: Cc1ccc(CCN)cc1
Reactant: O=CC(=O)c1cccc(Cl)c1
Product: Cc1ccc(CCNCC(O)c2cccc(Cl)c2)cc1

Procedure:
The title compound was prepared in the manner described in Example 9 using 3-chlorophenylglyoxal and 2-(4-methylphenyl)ethanamine. Recrystallization of the chromatographed material from cyclohexane gave the title compound m.p. 85-88 (analysed as the hemi-hydrate). τ(CDCl3) 7.7 (3H, s), 7.0-7.5 (6H, m, +2H disappears with D2O), 5.4 (1H, dd), 2.9 (4H, s), 2.6-2.8 (4H, m).
Reaction SMILES: [N:1]1([C:7]2[CH:19]=[C:18]([C:20]([O:22][CH3:23])=[O:21])[C:10]3[NH:11][C:12]([C:14]([F:17])([F:16])[F:15])=[N:13][C:9]=3[CH:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([Cl:38])[C:33]=1[Cl:39]>CN(C)C=O>[Cl:39][C:33]1[C:34]([Cl:38])=[CH:35][CH:36]=[CH:37][C:32]=1[CH2:31][N:13]1[C:9]2[CH:8]=[C:7]([N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)[CH:19]=[C:18]([C:20]([O:22][CH3:23])=[O:21])[C:10]=2[N:11]=[C:12]1[C:14]([F:17])([F:15])[F:16]
Reactant: COC(=O)c1cc(N2CCOCC2)cc2nc(C(F)(F)F)[nH]c12
Reactant: Clc1cccc(CBr)c1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc(N2CCOCC2)cc2c1nc(C(F)(F)F)n2Cc1cccc(Cl)c1Cl
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 6.05 %

Procedure:
A mixture of methyl 5-(4-morpholinyl)-2-(trifluoromethyl)-1H-benzimidazole-7-carboxylate, prepared as described in Example 45 (1.5 g, 4.56 mmol) and potassium carbonate (1.889 g, 13.67 mmol) in N,N-Dimethylformamide (DMF) (10 mL) was stirred at rt for 10 min. After addition of 1-(bromomethyl)-2,3-dichlorobenzene (1.639 g, 6.83 mmol), the mixture was warmed to 80° C. and stirred for 3 h at this temperature. The resulting mixture was cooled to rt and poured over ice. The precipitate formed was collected by filtration and air dried to give crude product (2.2 g, 4.51 mmol, 99% yield) (91% pure). A portion of this material (230 mg) was purified by reverse phase-HPLC (25 to 95% AcCN in water, plus 0.1% TFA) to give the desired product (137.4 mg, 0.276 mmol, 6.05% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 7.65 (d, J=2.27 Hz, 1H), 7.61 (dd, J=8.08, 1.26 Hz, 1H), 7.48 (d, J=2.27 Hz, 1H), 7.24 (t, J=7.96 Hz, 1H), 6.25 (dd, J=7.83, 1.26 Hz, 1H), 5.77 (s, 2H), 3.93 (s, 3H), 3.68-3.81 (m, 4H), 3.13-3.24 (m, 4H). MS(ES+) m/e 488 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1([CH3:29])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([C:14]([C:16]3[CH:17]=[C:18]([CH:22]=[CH:23][C:24]([O:26]CC)=[O:25])[CH:19]=[CH:20][CH:21]=3)=[CH2:15])[CH:5]=[CH:4][C:3]1=2.[OH-].[Na+].Cl>C1COCC1>[CH3:1][C:2]1([CH3:29])[CH2:11][CH2:10][C:9]([CH3:12])([CH3:13])[C:8]2[CH:7]=[C:6]([C:14]([C:16]3[CH:17]=[C:18]([CH:22]=[CH:23][C:24]([OH:26])=[O:25])[CH:19]=[CH:20][CH:21]=3)=[CH2:15])[CH:5]=[CH:4][C:3]1=2
Reactant: C=C(c1cccc(C=CC(=O)OCC)c1)c1ccc2c(c1)C(C)(C)CCC2(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: C=C(c1cccc(C=CC(=O)O)c1)c1ccc2c(c1)C(C)(C)CCC2(C)C

Procedure:
A solution of the product of Example 11 (690 mg, 1.8 mmol) and sodium hydroxide (285 mg) in THF (20 ml) is refluxed for 8 h, acidified to pH 1 (concentrated HCl), extracted with ethyl acetate and washed with water. After drying, the organic phase is concentrated on a rotary evaporator under vacuum at 40° C. and the product is washed with heptane.
Reaction SMILES: [F:1][C:2]1[CH:20]=[CH:19][CH:18]=[CH:17][C:3]=1[CH2:4][CH:5]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[F:16])[C:6]([OH:8])=O.Cl.Cl.[CH3:23][O:24][C:25](=[O:34])[C@H:26]([CH2:28][C:29]1[N:33]=[CH:32][NH:31][CH:30]=1)[NH2:27].C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.C(N(CC)CC)C>CN(C)C=O>[CH3:23][O:24][C:25](=[O:34])[C@H:26]([CH2:28][C:29]1[N:33]=[CH:32][NH:31][CH:30]=1)[NH:27][C:6](=[O:8])[CH:5]([CH2:4][C:3]1[CH:17]=[CH:18][CH:19]=[CH:20][C:2]=1[F:1])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[F:16]
Reactant: COC(=O)[C@@H](N)Cc1c[nH]cn1
Reactant: O=C(O)C(Cc1ccccc1F)Cc1ccccc1F
Agent: Cl
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)[C@H](Cc1c[nH]cn1)NC(=O)C(Cc1ccccc1F)Cc1ccccc1F
Yield: 71.8 %

Procedure:
In 30 ml of N,N-dimethylformamide were suspended 1.8 g of bis(2-fluorobenzyl)acetic acid and 1.9 g of L-histidine methyl ester dihydrochloride, and to the suspension were successively added 1.68 ml of diphenylphosphoryl azide and 2.9 ml of triethylamine with stirring under ice-cooling. The mixture was still stirred for 16 hours. The reaction mixture was evaporated under reduced pressure, and to the residue was added a 5% aqueous sodium bicarbonate solution. The mixture was extracted with ethyl acetate, and the ethyl acetate layer was washed with water, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: chloroform/methanol=1) to obtain 2.0 g of N- bis(2-fluorobenzyl)acetyl-L-histidine methyl ester having an Rf1 value of 0.76 as a white powder.
Reaction SMILES: [NH2:1][C:2]1[C:3]([O:8][CH3:9])=[N:4][CH:5]=[CH:6][CH:7]=1.[N-:10]([C:13]#[N:14])[C:11]#[N:12].[Na+]>>[C:11]([N:10]=[C:13]([NH2:14])[NH:1][C:2]1[C:3]([O:8][CH3:9])=[N:4][CH:5]=[CH:6][CH:7]=1)#[N:12]
Reactant: COc1ncccc1N
Reactant: N#C[N-]C#N
Agent: [Na+]
Product: COc1ncccc1NC(N)=NC#N

Procedure:
A solution of 3-amino-2-methoxypyridine and sodium dicyanamide was processed as described in Example 71 A to provide the desired product.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]=[N:11][O:12][CH2:13][CH2:14][OH:15])=[CH:6][N:5]=1)[CH3:2].O[C:17]1[CH:49]=[CH:48][C:20]([CH2:21][CH:22]2[S:26][C:25](=[O:27])[N:24]([C:28]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:23]2=[O:47])=[CH:19][CH:18]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]=[N:11][O:12][CH2:13][CH2:14][O:15][C:17]2[CH:49]=[CH:48][C:20]([CH2:21][CH:22]3[S:26][C:25](=[O:27])[N:24]([C:28]([C:41]4[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=4)([C:35]4[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=4)[C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[C:23]3=[O:47])=[CH:19][CH:18]=2)=[CH:6][N:5]=1)[CH3:2]
Reactant: CCOc1ccc(C=NOCCO)cn1
Reactant: O=C1SC(Cc2ccc(O)cc2)C(=O)N1C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CCOc1ccc(C=NOCCOc2ccc(CC3SC(=O)N(C(c4ccccc4)(c4ccccc4)c4ccccc4)C3=O)cc2)cn1
Yield: 74.9 %

Procedure:
Following a procedure similar to that described in Example 1(a), but using 570 mg of 2-(2-ethoxy-5-pyridylmethyleneaminooxy)ethanol (prepared as described in Preparation 12), 1.20 g of 5-(4-hydroxybenzyl)-3-tritylthiazolidine-2,4-dione, 695 mg of triphenylphosphine and 462 mg of diethyl azodicarboxylate, 1.27 g of the title compound were obtained as a foam-like solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[S:4](=[O:12])(=[O:11])[NH:3]1.[N+:14]([O-])([O-:16])=[O:15].[K+]>OS(O)(=O)=O>[CH3:1][C:2]1([CH3:13])[C:6]2[CH:7]=[CH:8][C:9]([N+:14]([O-:16])=[O:15])=[CH:10][C:5]=2[S:4](=[O:12])(=[O:11])[NH:3]1
Reactant: O=[N+]([O-])[O-]
Reactant: CC1(C)NS(=O)(=O)c2ccccc21
Agent: O=S(=O)(O)O
Agent: [K+]
Product: CC1(C)NS(=O)(=O)c2cc([N+](=O)[O-])ccc21
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
3,3-Dimethyl-2,3-dihydro-benzo[d]isothiazole 1,1-dioxide was added to KNO3 in H2SO4 cooled to 0° C. and stirred for 15 min. The reaction was warmed to RT and stirred overnight. The mix was poured into ice and extracted with EtOAc (3×), washed with H2O and brine, dried and evaporated to give the compound which was used without further purification.
Reaction SMILES: [Li:1][CH2:2][CH2:3][CH2:4][CH3:5].Br[C:7]1[CH:14]=CC=C[C:8]=1[CH:9]=C.C1COCC1>C(OCC)C>[Li:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:14][C:3]=1[CH:4]=[CH2:5]
Reactant: C=Cc1ccccc1Br
Reactant: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: [Li]c1ccccc1C=C

Procedure:
A 0.35M solution of 2-lithiostyrene was prepared dropwise addition of nBuLi to a -78° C. solution of 2-bromostyrene in 5:1 THF:diethyl ether.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]([CH3:17])([C:14]([OH:16])=O)[CH2:10][CH2:9]1)=O)(C)(C)C.[CH:18]1([NH2:24])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1.C(OC(N1CCC(C(=O)NC2CCCCC2)CC1)=O)(C)(C)C>>[CH:18]1([NH:24][C:14]([C:11]2([CH3:17])[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)=[O:16])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: NC1CCCCC1
Reactant: CC(C)(C)OC(=O)N1CCC(C)(C(=O)O)CC1
Agent: CC(C)(C)OC(=O)N1CCC(C(=O)NC2CCCCC2)CC1
Product: CC1(C(=O)NC2CCCCC2)CCNCC1

Procedure:
The title compound is prepared according to the reaction sequence 3.01a-2.01b described above using 1-(tert-butoxycarbonyl)-4-methylpiperidine-4-carboxylic acid instead of 1-(tert-butoxycarbonyl)-piperidine-4-carboxylic acid and cyclohexylamine instead of cyclohexylamine as in 3.01a: LC-MS A: tR=0.50 min; [M+H]+=225.17.
Reaction SMILES: [F:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:13][CH:14]=3)[CH:9]=[C:8]2[CH:20]([C:22]2[S:23][CH:24]=[CH:25][N:26]=2)[OH:21])=[CH:4][CH:3]=1>ClCCl.[O-2].[O-2].[Mn+4]>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([S:16]([CH3:19])(=[O:17])=[O:18])=[CH:13][CH:14]=3)[CH:9]=[C:8]2[C:20]([C:22]2[S:23][CH:24]=[CH:25][N:26]=2)=[O:21])=[CH:27][CH:28]=1
Reactant: CS(=O)(=O)c1ccc2c(c1)cc(C(O)c1nccs1)n2Cc1ccc(F)cc1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc2c(c1)cc(C(=O)c1nccs1)n2Cc1ccc(F)cc1
Reaction time: 0.5 h
Yield: 45.7 %

Procedure:
To absolution of the compound obtained in Example 27 (5) (110 mg) in dichloromethane (20 ml), manganese dioxide (900 mg) was added at 15 to 30° C. and the mixture was stirred for 30 minutes. The reaction solution was then filtered through Celite and concentrated under reduced pressure. The resulting residue was subjected to silica gel preparative thin-layer chromatography (hexane:ethyl acetate=1:1) to obtain 50 mg of the desired products as a yellow powder.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C@H:4]([CH2:13][OH:14])[NH:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7].N1C=CC=CC=1.[C:22](Cl)([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23]>C(Cl)Cl>[CH2:25]([O:24][C:22]([O:14][CH2:13][C@H:4]([NH:5][C:6]([O:8][C:9]([CH3:12])([CH3:10])[CH3:11])=[O:7])[C:3]([O:2][CH3:1])=[O:15])=[O:23])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: COC(=O)[C@H](CO)NC(=O)OC(C)(C)C
Reactant: O=C(Cl)OCc1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)[C@H](COC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.4 %

Procedure:
A solution of N-(tert-butoxycarbonyl)-L-serine methyl ester (25.0 g, 114 mmol) in DCM (570 mL) was cooled to −50° C. Pyridine (23.0 mL, 285 mmol) was added. CBZ-Cl (18.9 mL, 125 mmol) was added dropwise over 1 hour. The reaction mixture was warmed to ambient temperature and stirred overnight. The reaction mixture was then diluted with DCM, washed with 10% citric acid and brine, dried and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (5:1 hexanes/EtOAc) to give (S)-methyl 3-(benzyloxycarbonyloxy)-2-(tert-butoxycarbonylamino)propanoate (36.0 g, 89%).
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH3:12][C:13]1[C:21]([C:22]2[S:23]C(C3NC=NN=3)=C(C3C=CC=CC=3)[N:26]=2)=[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][N:15]2[N:14]=1.Cl[CH:39]([C:45]([C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][C:48]=1[F:53])=O)[C:40]([O:42][CH2:43][CH3:44])=[O:41]>CC(O)C>[F:53][C:48]1[CH:49]=[CH:50][CH:51]=[CH:52][C:47]=1[C:45]1[N:26]=[C:22]([C:21]2[C:13]([CH3:12])=[N:14][N:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=23)[S:23][C:39]=1[C:40]([O:42][CH2:43][CH3:44])=[O:41]
Reactant: Cc1nn2ccccc2c1-c1nc(-c2ccccc2)c(-c2nnc[nH]2)s1
Reactant: CCOC(=O)C(Cl)C(=O)c1ccccc1F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)O
Product: CCOC(=O)c1sc(-c2c(C)nn3ccccc23)nc1-c1ccccc1F
Yield: 68.8 %

Procedure:
Using 2-methylpyrazolo[1,5-a]pyridine-3-carbothioamide hydrochloride (300 mg, 1.3 mmol) produced in Example 11-B (v), ethyl 2-chloro-3-(2-fluorophenyl)-3-oxopropanoate (1.0 g, 4.09 mmol) produced above and 2-propanol (25 mL) as starting materials and in the same manner as in Example 11(vi), the title compound (341 mg, 68%) was obtained as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[N:11]=[CH:10][C:9](=[O:12])[N:8]([CH2:13][C@@H:14]3[CH2:16][O:15]3)[C:7]=2[N:17]=1.[NH2:18][CH2:19][C@@H:20]1[CH2:24][N:23]([C:25]2[CH:26]=[CH:27][C:28]3[O:29][CH2:30][C:31](=[O:35])[NH:32][C:33]=3[N:34]=2)[C:22](=[O:36])[CH2:21]1>C(O)C.O>[OH:15][C@H:14]([CH2:13][N:8]1[C:9](=[O:12])[CH:10]=[N:11][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[N:17][C:7]1=2)[CH2:16][NH:18][CH2:19][C@@H:20]1[CH2:24][N:23]([C:25]2[CH:26]=[CH:27][C:28]3[O:29][CH2:30][C:31](=[O:35])[NH:32][C:33]=3[N:34]=2)[C:22](=[O:36])[CH2:21]1
Reactant: COc1ccc2ncc(=O)n(C[C@@H]3CO3)c2n1
Reactant: NC[C@H]1CC(=O)N(c2ccc3c(n2)NC(=O)CO3)C1
Solvent: O
Solvent: CCO
Product: COc1ccc2ncc(=O)n(C[C@@H](O)CNC[C@H]3CC(=O)N(c4ccc5c(n4)NC(=O)CO5)C3)c2n1
Temperature: 60 °C
Reaction time: 15 h
Yield: 27.7 %

Procedure:
In a mixed solvent (60 ml) of ethanol and water (9:1) were dissolved 6-methoxy-4-[(2R)-oxiran-2-ylmethyl]pyrido[2,3-b]pyrazin-3(4H)-one (2.94 g, 12.60 mmol) and 6-[(4R)-4-(aminomethyl)-2-oxopyrrolidin-1-yl]-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one (Reference Example 54; 3.30 g, 12.60 mmol), and the obtained mixture was then stirred in a sealed tube at 60° C. for 15 hours. Thereafter, the reaction solution was cooled in the air, and the solvent was then removed under reduced pressure. The residue was purified by silica gel column chromatography (chloroform/methanol) to yield 1.73 g (28%) of the above-captioned compound in the form of a light yellow solid.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([NH2:31])[C:5]([NH:8][CH:9]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]3[CH:20]=[N:21][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:23][CH:24]=3)=[C:13]([O:29][CH3:30])[CH:12]=2)[CH3:10])=[N:6][CH:7]=1.Cl[CH2:33]C1C=CC(C(F)(F)F)=NC=1.C(OCC)(OCC)OCC.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)C>[I:1][C:2]1[CH:3]=[C:4]2[N:31]=[CH:33][N:8]([CH:9]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]4[CH:20]=[N:21][C:22]([C:25]([F:27])([F:26])[F:28])=[CH:23][CH:24]=4)=[C:13]([O:29][CH3:30])[CH:12]=3)[CH3:10])[C:5]2=[N:6][CH:7]=1
Reactant: COc1cc(C(C)Nc2ncc(I)cc2N)ccc1OCc1ccc(C(F)(F)F)nc1
Reactant: FC(F)(F)c1ccc(CCl)cn1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CCOC(OCC)OCC
Solvent: CCO
Product: COc1cc(C(C)n2cnc3cc(I)cnc32)ccc1OCc1ccc(C(F)(F)F)nc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100 %

Procedure:
To a stirred solution of 5-iodo-N2-(1-(3-methoxy-4-((6-(trifluoromethyl)pyridin-3-yl)methoxy)phenyl)ethyl)pyridine-2,3-diamine [prepared from 5-(chloromethyl)-2-(trifluoromethyl)pyridine using the procedures described in Example 3-45-1 through Example 3-45-5] (0.710 g, 1.30 mmol) in ethanol (30 mL) was added triethyl orthoformate (1.0 mL, 5.89 mmol). The yellow solution was treated with p-toluenesulfonic acid monohydrate (0.025 g, 0.13 mmol) and heated to reflux. After 30 min, the mixture was allowed to cool to room temperature and was concentrated. The residue was partitioned between ethyl acetate (50 mL) and saturated potassium carbonate solution (50 mL). The phases were separated, and the organic phase was dried over magnesium sulfate, filtered, and concentrated to provide 0.739 g (>100%) of 6-iodo-3-(1-(3-methoxy-4-((6-(trifluoromethyl)pyridin-3-yl)methoxy)phenyl)ethyl)-3H-imidazo[4,5-b]pyridine as an orange solid.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[C:12]([F:15])([F:14])[F:13])[NH:8][CH2:7][CH2:6]2.I[Si](C)(C)C.CO>C(Cl)(Cl)Cl>[OH:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[C:12]([F:15])([F:13])[F:14])[NH:8][CH2:7][CH2:6]2
Reactant: COc1cc2c(cc1C(F)(F)F)NCC2
Agent: C[Si](C)(C)I
Solvent: CO
Solvent: ClC(Cl)Cl
Product: Oc1cc2c(cc1C(F)(F)F)NCC2

Procedure:
A mixture of 5-methoxy-6-trifluoromethylindoline (D3, 7.5 g, 34.3 mmol) and iodotrimethylsilane (12.5 ml, 89.3 mmol) in dry chloroform (70 ml) was heated under reflux for 65 h. Methanol was then added cautiously with stirring to the cooled mixture, and solvent was then removed in vacuo. The residue was treated with saturated sodium bicarbonate solution and water until basic, and then extracted with dichloromethane/methanol. The organic extract was washed with brine, dried and evaporated. The residue was extracted with ether in a Soxhlet apparatus, and concentration of the resultant solution gave the title compound in three crops (total 2.85 g, 41%), m.p.>180° (decomp.).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:18])([CH2:12][N:13]1[CH:17]=[N:16][CH:15]=[N:14]1)[CH2:10][SH:11].[H-].[Na+].Cl[CH2:22][S:23]([N:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1)(=[O:25])=[O:24]>O1CCCC1>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:18])([CH2:10][S:11][CH2:22][S:23]([N:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1)(=[O:25])=[O:24])[CH2:12][N:13]1[CH:17]=[N:16][CH:15]=[N:14]1
Reactant: O=S(=O)(CCl)N1CCCCC1
Reactant: OC(CS)(Cn1cncn1)c1ccc(Cl)cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=S(=O)(CSCC(O)(Cn1cncn1)c1ccc(Cl)cc1Cl)N1CCCCC1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
2-(2,4-Dichlorophenyl)-1-mercapto-3-(1H-1,2,4-triazol-1-yl)-propan-2-ol (0.304 g) was stirred in tetrahydrofuran (5 ml) whilst sodium hydride (58 mg of a 50% dispersion in oil, 1.2 equiv.) was added in one portion. After stirring a further five minutes, N-(chloro-methylsulphonyl)piperidine (0.296 g, 1.1 equiv.) was added and heated under reflux for 3 hours. The reaction mixture was allowed to cool to room temperature then poured into an ice/water mixture (20 ml), and extracted with ethyl acetate (3×15 ml). The organic extracts were combined, dried (Na2SO4) and evaporated to a gum, 0.71 g.