Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6](Cl)=[C:7]3[N:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:8]3=[N:9][C:10]=2[CH:11]=1.[CH3:19][N:20]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][NH2:28])[CH3:21].C1(O)C=CC=CC=1.[ClH:36]>CC(C)=O.C(O)C>[ClH:1].[ClH:36].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]([NH:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][N:20]([CH3:21])[CH3:19])=[C:7]3[N:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:8]3=[N:9][C:10]=2[CH:11]=1
Reactant: COc1ccc2nc3cc(Cl)ccc3c(Cl)c2n1
Reactant: CN(C)CCCCCCN
Agent: Cl
Solvent: CCO
Solvent: Oc1ccccc1
Solvent: CC(C)=O
Product: COc1ccc2nc3cc(Cl)ccc3c(NCCCCCCN(C)C)c2n1

Procedure:
A mixture of 2.8 g. of 7,10-dichloro-2-methoxypyrido [3,2-b]quinoline, 1.5 g. of dimethylaminohexylamine and 6.5 g. of phenol is stirred and heated on a steam bath for 3 hours. The mixture is cooled, 20 ml. of ethanol are added and the dark solution is poured into a mixture of 200 ml. of acetone and 2.5 ml. of concentrated hydrochloric acid. The mixture is cooled in ice. The solid is collected, air-dried and recrystallized from 3A alcohol:acetone (50:50), giving the desired product as yellow crystals, mp. 243°-244° C. (dec.).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11](O)([C:14]2[C:22]3[O:21][CH:20]=[CH:19][C:18]=3[C:17]([F:23])=[CH:16][C:15]=2[F:24])[CH:10]([CH3:26])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N1CCC(OC(=O)C(C)=O)(C2C3OC=CC=3C(F)=CC=2F)C(C)C1)C1C=CC=CC=1.C([SnH](CCCC)CCCC)CCC>>[CH2:1]([N:8]1[CH2:13][CH2:12][C@H:11]([C:14]2[C:22]3[O:21][CH:20]=[CH:19][C:18]=3[C:17]([F:23])=[CH:16][C:15]=2[F:24])[C@H:10]([CH3:26])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1CN(Cc2ccccc2)CCC1(O)c1c(F)cc(F)c2ccoc12
Agent: CC(=O)C(=O)OC1(c2c(F)cc(F)c3ccoc23)CCN(Cc2ccccc2)CC1C
Agent: CCCC[SnH](CCCC)CCCC
Product: C[C@@H]1CN(Cc2ccccc2)CC[C@@H]1c1c(F)cc(F)c2ccoc12
Yield: 76.6 %

Procedure:
Beginning with 1.24 gm (3.48 mMol) 1-benzyl-3-methyl-4-hydroxy-4-(4,6-difluorobenzofur-7-yl)piperidine, 1-benzyl-3-methyl-4-(methyl oxoacetoxy)-4-(4,6-difluorobenzofur-7-yl)piperidine were prepared essentially as described in EXAMPLE 16. This material was treated with tri(n-butyl)tin hydride essentially as described in EXAMPLE 16 to prepare 0.91 gm (77%) of the desired compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([O:18][CH3:19])[C:11]=1[O:12][CH2:13][CH:14]=[C:15]([CH3:17])[CH3:16])[C:6]([OH:8])=O.[NH2:20][CH2:21][CH:22]1[CH2:26][CH2:25][CH2:24][N:23]1[CH2:27][CH3:28]>>[CH2:27]([N:23]1[CH2:24][CH2:25][CH2:26][CH:22]1[CH2:21][NH:20][C:6](=[O:8])[C:5]1[CH:9]=[C:10]([O:18][CH3:19])[C:11]([O:12][CH2:13][CH:14]=[C:15]([CH3:17])[CH3:16])=[C:3]([O:2][CH3:1])[CH:4]=1)[CH3:28]
Reactant: CCN1CCCC1CN
Reactant: COc1cc(C(=O)O)cc(OC)c1OCC=C(C)C
Product: CCN1CCCC1CNC(=O)c1cc(OC)c(OCC=C(C)C)c(OC)c1
Yield: 530.5 %

Procedure:
In a manner identical to Example 15, 3,5-dimethoxy-4-prenyloxybenzoic acid (0.80 g) was subjected to a condensation reaction with 2-aminomethyl-1-ethylpyrrolidine (0.39 g), thereby yielding 1. 6 g (89%) of the aimed compound.
Reaction SMILES: Br[CH2:2][CH2:3][C:4]#[C:5][Si:6]([CH3:9])([CH3:8])[CH3:7].[NH:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[N:11]1.C([O-])([O-])=O.[K+].[K+].C[Si](C)(C)C#CCCN1C2C(=CC=CC=2)C=N1>CC(C)=O.O>[CH3:7][Si:6]([CH3:9])([CH3:8])[C:5]#[C:4][CH2:3][CH2:2][N:11]1[CH:12]=[C:13]2[C:18]([CH:17]=[CH:16][CH:15]=[CH:14]2)=[N:10]1
Reactant: C[Si](C)(C)C#CCCBr
Reactant: c1ccc2[nH]ncc2c1
Agent: C[Si](C)(C)C#CCCn1ncc2ccccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: C[Si](C)(C)C#CCCn1cc2ccccc2n1
Temperature: 150 °C
Yield: 60.9 %

Procedure:
A suspension of (4-bromo-but-1-ynyl)-trimethyl-silane (374 mg, 1.83 mmol), indazole (200 mg, 1.69 mmol) and K2CO3 (459 mg, 3.32 mmol) in acetone (2 mL) was heated at 150° C. for 900 s in a microwave. After the addition of water, acetone was evaporated. The aqueous phase was extracted with DCM. The organic phase was washed with brine, dried over MgSO4, filtered and evaporated to yield 250 mg (1.03 mmol, 62%) of 2-(4-trimethylsilanyl-but-3-ynyl)-2H-indazole and 1-(4-trimethylsilanyl-but-3-ynyl)-1H-indazole.
Reaction SMILES: COC1CC2[C:6]3([C:18]4[C:13](=CC(OC)=C(OC)C=4O)CN2CC3)CC1.N[C@H:25]([C:30]([OH:32])=O)[CH2:26][C:27](=O)O.COC1CC2C3(C4C(=CC(OC)=C(OC)C=4O)CN2CC3)CC1.[NH2:56][C@H:57]([C:63]([OH:65])=[O:64])CCC(=O)O>>[C:63]([OH:65])(=[O:64])[CH2:57][NH:56][C:30]([C:25]1[CH:26]=[CH:27][CH:6]=[CH:18][CH:13]=1)=[O:32]
Reactant: COc1cc2c(c(O)c1OC)C13CCC(OC)CC1N(CC3)C2
Reactant: N[C@@H](CCC(=O)O)C(=O)O
Reactant: N[C@@H](CC(=O)O)C(=O)O
Product: O=C(O)CNC(=O)c1ccccc1
Reaction time: 5 h

Procedure:
D253K HCPB (4 μg/ml for Hipp-Asp and 0.5 μg/ml for Hipp-Glu) was added to these substrates (500 μl reaction volume) to start the reaction. Samples were incubated for 5 h at 37° C. Reactions were terminated by the addition of 500 μl methanol/distilled water (80/20) containing 0.2% TFA. The amount of hippuric acid produced was quantified by HPLC as described in Example 20.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[CH:35]=[CH:34][C:13]2=[C:14]3[C:19](=[C:20]([NH2:22])[N:21]=[C:12]2[CH:11]=1)[N:18]=[CH:17][C:16]([C:23]#[C:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][C:26]=1[CH3:33])=[CH:15]3)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(O)C.[H][H]>[Pd].C(Cl)Cl>[Si:1]([O:8][CH2:9][C:10]1[CH:35]=[CH:34][C:13]2=[C:14]3[C:19](=[C:20]([NH2:22])[N:21]=[C:12]2[CH:11]=1)[N:18]=[CH:17][C:16]([CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][C:26]=1[CH3:33])=[CH:15]3)([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:2])[CH3:3]
Reactant: COc1ccc(C#Cc2cnc3c(N)nc4cc(CO[Si](C)(C)C(C)(C)C)ccc4c3c2)c(C)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: ClCCl
Solvent: CCO
Product: COc1ccc(CCc2cnc3c(N)nc4cc(CO[Si](C)(C)C(C)(C)C)ccc4c3c2)c(C)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a round bottom flask was added 8-((tert-butyldimethylsilyloxy)methyl)-2-(4-methoxy-2-methylphenyl)ethynyl)benzo[f][1,7]naphthyridin-5-amine (from step 4) (1 equiv.) with a stirring bar. Ethanol and methylene chloride (1:2, 0.2 M) were added, followed by palladium in carbon (activated powder, wet, 10% on carbon, 0.1 equiv.). The contents were vacuumed followed by hydrogen flush for three times. The reaction mixture was stirred vigorously under hydrogen balloon at room temperature overnight. Afterwards the reaction mixture was filtered through a celite pad, and the celite pad was washed subsequently with methylene chloride and EtOAc until filtrate has no UV absorption. Combined organic washes were concentrated. Flash chromatography (silica gel, 0-50% EtOAc in CH2Cl2) afforded 8-((tert-butyldimethylsilyloxy)methyl)-2-(4-methoxy-2-methylphenethyl)benzo[f][1,7]naphthyridin-5-amine as a yellow solid.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([P:11]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([O:26][CH3:27])=[O:25])=[CH:20][CH:19]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:7][CH:6]=1)([O:3][CH3:4])=[O:2].[C:28]1([CH3:39])[CH:33]=[CH:32][C:31]([S:34]([O:37]C)(=[O:36])=[O:35])=[CH:30][CH:29]=1>>[C:28]1([CH3:39])[CH:29]=[CH:30][C:31]([S:34]([O-:37])(=[O:35])=[O:36])=[CH:32][CH:33]=1.[C:24]([C:21]1[CH:22]=[CH:23][C:18]([PH+:11]([C:8]2[CH:7]=[CH:6][C:5]([C:1]([O:3][CH3:4])=[O:2])=[CH:10][CH:9]=2)[CH2:12][C:13]2[CH:28]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:19][CH:20]=1)([O:26][CH3:27])=[O:25]
Reactant: COS(=O)(=O)c1ccc(C)cc1
Reactant: COC(=O)c1ccc(P(c2ccccc2)c2ccc(C(=O)OC)cc2)cc1
Product: COC(=O)c1ccc([PH+](Cc2ccccc2)c2ccc(C(=O)OC)cc2)cc1
Product: Cc1ccc(S(=O)(=O)[O-])cc1
Reaction time: 1 h

Procedure:
This compound was prepared by quaternization of bis(p-carbomethoxyphenyl)phenylphosphine (I) with methyl p-toluenesulfonate (II) in the melt phase. A mixture of 18.92 g (0.05 mol) of I and 9.31 g (0.05 mol) of II was heated in a 130°-C. bath for 1 hr with stirring. The viscous material was cooled to an amorphous glass which was hygroscopic.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[CH:11][CH:10]=[C:9]2[C:13]#[N:14])=[CH:4][CH:3]=1.[Br:15]N1C(=O)CCC1=O>O1CCCC1>[Br:15][C:11]1[CH:10]=[C:9]([C:13]#[N:14])[N:8]([C:5]2[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=2)[CH:12]=1
Reactant: Cc1ccc(-n2cccc2C#N)cc1
Reactant: O=C1CCC(=O)N1Br
Solvent: C1CCOC1
Product: Cc1ccc(-n2cc(Br)cc2C#N)cc1
Reaction time: 3 h
Yield: 97.5 %

Procedure:
To a solution of 1-(4-methylphenyl)pyrrole-2-carbonitrile (1.274 g) in tetrahydrofuran (25 ml) was added N-bromosuccinimide (1.776 g) in several portions at ambient temperature. After being stirred for 3 hours at the same temperature, the mixture was concentrated in vacuo. The residue was treated with diethyl ether. The precipitates were removed by filtration and washed with a small amounts of diethyl ether. The filtrates were concentrated in vacuo to give an oily residue, which was purified by silica gel column chromatography (elution by 40% dichloromethane in n-hexane) to yield 4-bromo-1-(4-methylphenyl)pyrrole-2-carbonitrile (1.78 g) as a solid.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]([OH:13])[CH:10]([CH2:14]O)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>ClCCl>[CH2:1]([N:8]1[CH2:12][CH:11]([OH:13])[CH:10]([CH2:14][S:24]([CH3:23])(=[O:26])=[O:25])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCC1CN(Cc2ccccc2)CC1O
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)CC1CN(Cc2ccccc2)CC1O
Yield: 93.9 %

Procedure:
1-Benzyl-3-hydroxymethyl-4-hydroxypyrrolidine (66.2 g) and triethylamine (38.8 g) are added to dry dichloromethane (700 ml) and the mixture is cooled till a temperature of from -5° to -10° C. At this temperature, methanesulfonyl chloride (36.6 g) is added dropwise to the mixture with stirring. After the addition, the mixture is stirred for 30 minutes, and then washed with an aqueous sodium hydrogen carbonate and subsequently with water. Thereafter, the dichloromethane layer is separated, dried and concentrated to give 1-benzyl-4-hydroxy-3-methanesulfonylmethylpyrrolidine (80.8 g) as an oil.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1([CH2:18][CH2:19][OH:20])[CH2:10][CH2:9][CH2:8][N:7]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:6][CH2:5]1.[S:21](Cl)([CH3:24])(=[O:23])=[O:22]>C(Cl)Cl.O>[CH3:24][S:21]([O:1][CH2:2][CH2:3][C:4]1([CH2:18][CH2:19][O:20][S:21]([CH3:24])(=[O:23])=[O:22])[CH2:10][CH2:9][CH2:8][N:7]([C:11]([O:13][C:14]([CH3:16])([CH3:15])[CH3:17])=[O:12])[CH2:6][CH2:5]1)(=[O:23])=[O:22]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCCC(CCO)(CCO)CC1
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)N1CCCC(CCOS(C)(=O)=O)(CCOS(C)(=O)=O)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
TEA (1.1 ml, 8.36 mmol, 3.0 eq.) was added to a cooled solution of tert-butyl 4,4-bis(2-hydroxyethyl)azepane-1-carboxylate (800 mg, 2.78 mmol, 1.0 eq.) in methylene chloride (10 ml) at 0° C. and then mesylchloride (0.47 ml, 6.13 mmol, 2.2 eq.) was added to the reaction mixture and it was stirred at RT for 2 h. After completion (monitored by TLC), the reaction mixture was diluted with water (20 ml) and methylene chloride (100 ml). The organic part was separated and the water layer was extracted with methylene chloride (2×20 ml). The combined organic layers were washed with brine (20 ml), dried over Na2SO4 and concentrated under reduced pressure to give the crude product which was used in the next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[C:8](OC1C=CC(N)=CC=1)[CH:7]=[CH:6]2.[F:23][C:24]1[CH:30]=[CH:29][C:27]([NH2:28])=[CH:26][CH:25]=1.CC[N:33]([CH:37]([CH3:39])[CH3:38])C(C)C.[CH2:40]([N:47]1[CH2:50][C:49]([C:54]([OH:56])=[O:55])([C:51]([OH:53])=[O:52])[CH2:48]1)[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>CN(C=O)C.C(OCC)(=O)C>[CH2:40]([N:47]1[CH2:48][C:49]([C:51]([OH:53])=[O:52])([C:54]([OH:56])=[O:55])[CH2:50]1)[C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1.[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:2][C:3]1[CH:4]=[CH:38][C:37]([NH:33][C:54]([C:49]2([C:51]([NH:28][C:27]3[CH:29]=[CH:30][C:24]([F:23])=[CH:25][CH:26]=3)=[O:53])[CH2:48][N:47]([CH2:40][C:41]3[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=3)[CH2:50]2)=[O:56])=[CH:39][CH:12]=1
Reactant: Nc1ccc(F)cc1
Reactant: CCN(C(C)C)C(C)C
Reactant: COc1cc2ccc(Oc3ccc(N)cc3)nc2cc1OC
Agent: O=C(O)C1(C(=O)O)CN(Cc2ccccc2)C1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1cc2nccc(Oc3ccc(NC(=O)C4(C(=O)Nc5ccc(F)cc5)CN(Cc5ccccc5)C4)cc3)c2cc1OC
Temperature: 25 °C
Reaction time: 6 h
Yield: 23.5 %

Procedure:
1-Benzyl-azetidine-3,3-dicarboxylic acid was prepared by following the literature procedure (Miller, R. A.; et al. Syn. Comm. 2003, 33, 3347). To a solution of 4-(6,7-dimethoxy-quinolinyloxy)-phenylamine (4.2 mmol, 1 equiv.) and 4-fluoroaniline (4.2 mmol, 1 equiv.) in DMF (20 mL) was charged with DIEA (12.6 mmol, 3 equiv.) and a solution of 1-benzyl-azetidine-3,3-dicarboxylic acid (4.2 mmol, 1 equiv.) in DMF (10 mL). The reaction mixture was allowed to stir at RT and monitored by LCMS. The reaction was complete in 6 h. The reaction mixture was diluted with ethyl acetate and washed with 10% LiCl (3×), brine (3×), dried with sodium sulfate, filtered and the solvent was reduced in vacuo. The crude product was purified by silica gel chromatography eluting with 2% of MeOH in EtOAc. The fractions containing the desired product were further purified using preparative HPLC to give ′N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)-1-(phenylmethyl)azetidine-3,3-dicarboxamide (300 mg, 12% yield) as a white solid. 1HNMR (DMSO-d6): 10.0 (s, 1H), 9.90 (s, 1H), 8.45 (d, 1H), 7.80 (d, 2H), 7.70 (m, 2H), 7.50 (s, 1H), 7.40 (s, 1H), 7.48-7.15 (m, 9H), 3.95 (s, 6H), 3.70 (s, 4H), 3.60 (s, 2H). LCMS (POS): 607.2 (M+H).
Reaction SMILES: C(N1C2C(=CC=CC=2)C(O)(CC(=O)C2C=CC=CN=2)C1=O)CCC.[Cl:25][C:26]1[CH:27]=[C:28]2[C:32](=[CH:33][CH:34]=1)[N:31]([CH2:35][CH2:36][CH3:37])[C:30](=[O:38])[C:29]2=[O:39].[CH3:40][O:41][C:42]1[C:47]([C:48](=[O:50])[CH3:49])=[CH:46][CH:45]=[C:44]([O:51][CH3:52])[N:43]=1>>[Cl:25][C:26]1[CH:27]=[C:28]2[C:32](=[CH:33][CH:34]=1)[N:31]([CH2:35][CH2:36][CH3:37])[C:30](=[O:38])[C:29]2([CH2:49][C:48]([C:47]1[C:42]([O:41][CH3:40])=[N:43][C:44]([O:51][CH3:52])=[CH:45][CH:46]=1)=[O:50])[OH:39]
Reactant: CCCN1C(=O)C(=O)c2cc(Cl)ccc21
Reactant: COc1ccc(C(C)=O)c(OC)n1
Agent: CCCCN1C(=O)C(O)(CC(=O)c2ccccn2)c2ccccc21
Product: CCCN1C(=O)C(O)(CC(=O)c2ccc(OC)nc2OC)c2cc(Cl)ccc21

Procedure:
This compound was made in a similar manner to 1-butyl-3-hydroxy-3-(2-oxo-2-(pyridin-2-yl)ethyl)indolin-2-one using 5-chloro-1-propylindoline-2,3-dione and 1-(2,6-dimethoxypyridin-3-yl)ethanone (purchased from Fisher Scientific). 1H-NMR δ 8.12 (d, 1H), 7.39 (s, 1H), 7.27 (d, 1H), 6.80 (d, 1H), 6.35 (d, 1H) 4.63 (bs, OH), 4.00 (s, 3H), 3.83 (s, 3H), 3.71 (d, 1H), 3.68 (m, 2H), 3.47 (d, 1H), 1.73 (m, 2H), 0.99 (t, 3H). Calculated mass for C20H21ClN2O5, 404.11. Observed 427.1 (M+Na)
Reaction SMILES: [F:1][C:2]1[CH:21]=[C:20]([S:22]([CH3:25])(=[O:24])=[O:23])[CH:19]=[CH:18][C:3]=1[O:4][CH2:5][CH2:6][C@@H:7]1[CH2:9][C@@H:8]1[CH:10]1[CH2:15][CH2:14][N:13]([C:16]#[N:17])[CH2:12][CH2:11]1.[OH:26][NH:27][C:28](=N)[CH2:29][O:30][CH3:31]>O1CCCC1.[Cl-].[Zn+2].[Cl-]>[F:1][C:2]1[CH:21]=[C:20]([S:22]([CH3:25])(=[O:23])=[O:24])[CH:19]=[CH:18][C:3]=1[O:4][CH2:5][CH2:6][C@H:7]1[CH2:9][C@H:8]1[CH:10]1[CH2:11][CH2:12][N:13]([C:16]2[O:26][N:27]=[C:28]([CH2:29][O:30][CH3:31])[N:17]=2)[CH2:14][CH2:15]1
Reactant: COCC(=N)NO
Reactant: CS(=O)(=O)c1ccc(OCC[C@@H]2C[C@@H]2C2CCN(C#N)CC2)c(F)c1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: C1CCOC1
Product: COCc1noc(N2CCC([C@@H]3C[C@@H]3CCOc3ccc(S(C)(=O)=O)cc3F)CC2)n1
Temperature: 25 °C

Procedure:
To a solution of 4-((1R,2S)-2-{2-{2-fluoro-4-(methylsulfonyl)phenoxy]ethyl}cyclopropyl)piperidine-1-carbonitrile (Step D, Example 111; 100 mg, 0.27 mmol) and N-hydroxy-2-methoxyacetimidamide (38 mg, 0.37 mmol) in tetrahydrofuran (5 mL) was added zinc chloride (0.8 mL, 0.5 M in tetrahydrofuran, 0.4 mmol). The mixture was refluxed for 2 h, cooled to RT, and concentrated to dryness under reduced pressure. The residue was dissolved in 2 mL of 4N HCl ethanol and water (1:1). The solution was refluxed for 30 min, cooled to RT, and concentrated to dryness under reduced pressure. The residue was dissolved in methanol (5 mL), neutralized by the addition of excess potassium carbonate, mixed silica gel (2 g), and concentrated to dryness under reduced pressure. The residue was loaded on a silica gel column (10 g of silica gel) and eluted with a gradient of dichloromethane/CMA, 19:1, 500 mL; 4:1, 500 mL to provide the title compound. MS (ESI) m/z 454 [M+H]+.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6]1[N:7]=[C:8]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([N:18]3[CH:22]=[C:21]([CH3:23])[N:20]=[CH:19]3)=[C:14]([O:24][CH3:25])[CH:13]=2)[S:9][CH:10]=1)C.[CH2:27]([NH2:31])[CH2:28][CH2:29][CH3:30]>>[CH2:27]([NH:31][C:4](=[O:3])[CH2:5][C:6]1[N:7]=[C:8]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([N:18]3[CH:22]=[C:21]([CH3:23])[N:20]=[CH:19]3)=[C:14]([O:24][CH3:25])[CH:13]=2)[S:9][CH:10]=1)[CH2:28][CH2:29][CH3:30]
Reactant: CCOC(=O)Cc1csc(Nc2ccc(-n3cnc(C)c3)c(OC)c2)n1
Reactant: CCCCN
Product: CCCCNC(=O)Cc1csc(Nc2ccc(-n3cnc(C)c3)c(OC)c2)n1

Procedure:
The title compound was prepared in analogy to example 27 from 100 mg (0.27 mmol) ({2-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenylamino]-thiazol-4-yl}-acetic acid ethyl ester and 70 mg (0.94 mmol) n-butylamine yielding 95 mg (89%) N-butyl-2-{2-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenylamino]-thiazol-4-yl}-acetamide as a brown foam. MS ISP (m/e): 400.3 (100) (M+H)+. 1H NMR (DMSO-D6, 250 MHz): δ (ppm)=10.45 (s, 1H), 7.93 (t, 1H), 7.68 (s, 1H), 7.64 (s, 1H), 7.23 (d, 1H), 7.19 (d, 1H), 7.02 (s, 1H), 6.62 (s, 1H), 3.79 (s, 3H), 3.57 (s, 2H), 3.05 (br q, 2H), 2.14 (s, 3H), 1.39-1.26 (m, 6H), 0.85 (t, 3H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([O:10][CH3:11])[N:3]=1.[N:12]([S:15]([O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:25]1[N:26]=[N:27][S:28][CH:29]=1)(=[O:17])=[O:16])=[C:13]=[O:14]>O1CCCC1>[CH3:9][O:8][C:6]1[CH:5]=[C:4]([O:10][CH3:11])[N:3]=[C:2]([NH:1][C:13]([NH:12][S:15](=[O:17])(=[O:16])[O:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[C:25]2[N:26]=[N:27][S:28][CH:29]=2)=[O:14])[N:7]=1
Reactant: COc1cc(OC)nc(N)n1
Reactant: O=C=NS(=O)(=O)Oc1ccccc1-c1csnn1
Solvent: C1CCOC1
Product: COc1cc(OC)nc(NC(=O)NS(=O)(=O)Oc2ccccc2-c2csnn2)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 26.7 %

Procedure:
By the procedure of Example 4, 5.3 g of 2-amino-4,6-dimethoxypyrimidine in 20 ml of tetrahydrofuran was reacted with 14 g of the isocyanate prepared in Example 5 above in 30 ml of tetrahydrofuran. After stirring the mixture at 25° C. for 3 hours, the mixture was filtered and the solid isolated was recrystallized from acetonitrile to yield 4 g of the title compound; m.p. 173°-175° C.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11](=O)[C:12]([OH:14])=[O:13].[C:16]([O:20][C:21]([CH2:23][O:24][NH2:25])=[O:22])([CH3:19])([CH3:18])[CH3:17].[OH-].[Na+]>O.N1C=CC=CC=1.O1CCCC1>[C:16]([O:20][C:21]([CH2:23][O:24][N:25]=[C:11]([C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:1]=1)[C:12]([OH:14])=[O:13])=[O:22])([CH3:19])([CH3:18])[CH3:17]
Reactant: O=C(O)C(=O)c1ccc2ccccc2c1
Reactant: CC(C)(C)OC(=O)CON
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CON=C(C(=O)O)c1ccc2ccccc2c1
Reaction time: 3 h
Yield: 81 %

Procedure:
To a solution of 2-naphthylglyoxylic acid (6 g) in water (60 ml) and pyridine (6 ml) was added tert-butoxycarbonylmethoxyamine (9 g) in tetrahydrofuran (40 l) at room temperature and the mixture was stirred at the same temperature for 3 hours. The resultant mixture was adjusted to pH 7.5 with 10% aqueous sodium hydroxide and washed with ethyl acetate. The aqueous layer was acidified to pH 2.0 with 10% hydrochloric acid and the acidified solution was extracted with ethyl acetate. The organic layer was washed with brine and dried over magnesium sulfate. The solution was evaporated in vacuo to give 2-(tert-butoxycarbonylmethoxyimino)-2-(2-naphthyl)acetic acid (syn isomer) (8 g).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:16](=[O:24])[CH2:17][C:18](O)([CH2:21][CH3:22])[CH2:19][CH3:20])[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])([CH3:3])[CH3:2].[ClH:25]>C(OCC)C>[C:1]([C:5]1[CH:6]=[C:7]([C:16](=[O:24])[CH2:17][C:18]([Cl:25])([CH2:21][CH3:22])[CH2:19][CH3:20])[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCC(O)(CC)CC(=O)c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Reactant: Cl
Solvent: CCOCC
Product: CCC(Cl)(CC)CC(=O)c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 10 h

Procedure:
1-(3,5-Di-tert-butyl-4-hydroxyphenyl)-3-hydroxy-3-ethyl-pentan-1-one (prepared by method analogous to that of Example 1) (1.6 g) is dissolved in dry 1N hydrogen chloride solution in ethyl ether (50 mL) and the mixture is stirred at ambient temperature for 10 hours. The solution is washed three times with water, dried over anhydrous sodium sulfate and the solvent is removed under reduced pressure. The crude product is crystallized twice from petroleum ether to give 1-(3,5-di-tert-butyl-4-hydroxyphenyl)-3-chloro-3-ethyl-pentan-1-one as white solid, mp 72° C.
Reaction SMILES: [C:1]([CH:4]([CH2:10][CH2:11][CH2:12][CH3:13])[C:5](OCC)=[O:6])(=O)[CH3:2].C(=O)(O)O.[NH2:18][C:19]([NH2:21])=[NH:20]>C(O)C>[NH2:21][C:19]1[N:20]=[C:5]([OH:6])[C:4]([CH2:10][CH2:11][CH2:12][CH3:13])=[C:1]([CH3:2])[N:18]=1
Reactant: CCCCC(C(C)=O)C(=O)OCC
Reactant: N=C(N)N
Agent: O=C(O)O
Solvent: CCO
Product: CCCCc1c(C)nc(N)nc1O
Yield: 47.6 %

Procedure:
A mixture of ethyl 2-acetylhexanoate (5.59 g, 30 mmol), guanidine carbonate (6.49 g, 30 mmol) and ethanol (20 ml) was refluxed for 11 hours and then ice-cooled. The precipitated crystals were filtered, washed with ethanol and dried in vacuo to give 2-amino-5-butyl-6-methylpyrimidine-4-ol (2.59 g, 47%).
Reaction SMILES: CO[C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10]Br)=[CH:6][CH:5]=1.[CH:13]1([S:16]([NH2:19])(=[O:18])=[O:17])[CH2:15][CH2:14]1.[F:20][C:21]1[CH:26]=[CH:25][C:24]([C@@H:27]2[C@:29]3([C:37]4[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=4)[NH:31][C:30]3=[O:38])[CH2:28]2)=[CH:23][CH:22]=1>>[CH:13]1([S:16]([NH:19][C:3](=[O:12])[C:4]2[CH:5]=[CH:6][C:7]([CH2:10][N:31]3[C:32]4[C:37](=[CH:36][CH:35]=[CH:34][CH:33]=4)[C@:29]4([CH2:28][C@H:27]4[C:24]4[CH:23]=[CH:22][C:21]([F:20])=[CH:26][CH:25]=4)[C:30]3=[O:38])=[CH:8][CH:9]=2)(=[O:18])=[O:17])[CH2:15][CH2:14]1
Reactant: NS(=O)(=O)C1CC1
Reactant: O=C1Nc2ccccc2[C@@]12C[C@@H]2c1ccc(F)cc1
Reactant: COC(=O)c1ccc(CBr)cc1
Product: O=C(NS(=O)(=O)C1CC1)c1ccc(CN2C(=O)[C@@]3(C[C@H]3c3ccc(F)cc3)c3ccccc32)cc1

Procedure:
The title compound was prepared in analogy to Example 60 starting from 4-bromomethyl-benzoic acid methyl ester, cyclopropanesulfonamide (commercially available), (1R,2S) and (1S,2R)-2-(4-fluorophenyl)spiro[cyclopropane-1,3′-indolin]-2′-one prepared as in Scheme 1. LC/MS m/e calcd. for C27H23FN2O4S: 490, observed (M+H)+: 491.2 1H NMR (400 MHz, DMSO-d6) δppm 0.70-0.81 (m, 2 H) 0.84-0.91 (m, 2 H) 2.06-2.17 (m, 1 H) 2.31-2.40 (m, 1 H) 2.91-3.02 (m, 1 H) 3.14-3.24 (m, 2 H) 5.04 (s, 2 H) 6.09 (d, 1 H) 6.68 (t, 1 H) 6.89 (d, 1 H) 7.05 (t, 2 H) 7.11-7.19 (m, 3 H) 7.89 (d, 2 H).