Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]([CH2:16][CH3:17])[CH:4]1[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[C:9]([N+:13]([O-])=O)[CH:10]=2)[CH2:5]1)[CH3:2]>CO.[Pd]>[CH2:16]([N:3]([CH2:1][CH3:2])[CH:4]1[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[C:9]([NH2:13])[CH:10]=2)[CH2:5]1)[CH3:17]
Reactant: CCN(CC)C1Cc2ccc([N+](=O)[O-])cc2C1
Agent: [Pd]
Solvent: CO
Product: CCN(CC)C1Cc2ccc(N)cc2C1
Reaction time: 8 h

Procedure:
To a solution of Example 226B (2.0 g, 8.54 mmol) in methanol (50 ml) was added Pd/C (10%, 2 g). The mixture was bubbled with hydrogen and stirred overnight. The reaction mixture was filtered through a pad of diatomaceous earth and concentrated. The crude product was purified by HPLC (C18 column, mobile phase A: 10 mM NH4HCO3 in water, mobile phase B: acetonitrile, 50-75% B) to provide the title compound. MS m/z: 205 (M+H)+. 1H NMR (400 MHz, CDCl3): δ 6.95 (d, J=8.0 Hz, 1H), 6.54 (s, 1H), 6.46 (dd, J=7.6, 2.0 Hz, 1H), 3.61-3.54 (m, 1H), 2.97-2.91 (m, 2H), 2.83-2.73 (m, 2H), 2.64 (q, J=7.2 Hz, 4H), 1.05 (t, J=6.8 Hz, 6H).
Reaction SMILES: I[C:2]1[C:3](=O)[NH:4][CH:5]=[N:6][C:7]=1[CH3:8].[Br-].[F:11][C:12]([F:23])([F:22])[C:13]1[CH:18]=[CH:17][C:16]([C:19]#[C:20][Zn+])=[CH:15][CH:14]=1.O1CCCC1.O=P(Cl)(Cl)[Cl:31]>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.CN(C)C=O>[Cl:31][C:3]1[C:2]([C:20]#[C:19][C:16]2[CH:17]=[CH:18][C:13]([C:12]([F:23])([F:22])[F:11])=[CH:14][CH:15]=2)=[C:7]([CH3:8])[N:6]=[CH:5][N:4]=1
Reactant: Cc1nc[nH]c(=O)c1I
Reactant: FC(F)(F)c1ccc(C#C[Zn+])cc1
Reactant: O=P(Cl)(Cl)Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: Cc1ncnc(Cl)c1C#Cc1ccc(C(F)(F)F)cc1
Temperature: 25 °C

Procedure:
5-Iodo-6-methyl-4(3H)-pyrimidinone and [4-(trifluoromethyl)phenyl]ethynylzinc bromide were reacted in a solvent mixture of tetrahydrofuran and N,N-dimethylformamide (1:1) in the presence of tetrakis(triphenylphosphine)palladium while stirring under room temperature to heating to obtain a compound. The compound was mixed with POCl3 and reacted while heating under reflux to obtain a target substance. The target substance was subjected to e.g., proton nuclear magnetic resonance spectrometry (1H-NMR) and mass spectrometry (MS) and confirmed as the titled compound. Furthermore, MS measurement result is shown.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH:7]=O)([O-:3])=[O:2].C(O)(=O)[CH2:13][C:14]([OH:16])=[O:15].N1CCCCC1.Cl>O.N1C=CC=CC=1>[N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH:7]=[CH:13][C:14]([OH:16])=[O:15])([O-:3])=[O:2]
Reactant: O=C(O)CC(=O)O
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Solvent: C1CCNCC1
Product: O=C(O)C=Cc1cccc([N+](=O)[O-])c1
Temperature: 80 °C

Procedure:
30 g. 3-Nitrobenzaldehyde and 30 g. malonic acid were heated in 60 ml. pyridine at a maximum temperature of 50° C. until a clear solution was obtained. Subsequently, 3 ml. piperidine were added thereto and the solution was heated for 1 hour at 80° C. Thereafter, it was heated under reflux for 3 hours. The solution was then poured into 400 ml. water which contained 50 ml. concentrated hydrochloric acid. The precipitated solid material was filtered off and washed with water. It was subsequently dissolved in 400 ml. water in which 8 g. sodium hydroxide had been dissolved. Insoluble materials were then filtered off and the 3-nitrocinnamic acid obtained was again precipitated out by acidification with hydrochloric acid. The compound was recrystallised from ethanol, the yield being 17 g.; m.p. 204° C.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:3]=1[C:4]([OH:6])=O.[NH2:12][CH2:13][CH2:14][CH2:15][C@H:16]1[O:20][C:19](=[O:21])[N:18]([C:22]2[CH:23]=[CH:24][C:25]3[S:30][CH2:29][C:28](=[O:31])[NH:27][C:26]=3[CH:32]=2)[CH2:17]1>>[NH2:1][C:2]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:3]=1[C:4]([NH:12][CH2:13][CH2:14][CH2:15][C@H:16]1[O:20][C:19](=[O:21])[N:18]([C:22]2[CH:23]=[CH:24][C:25]3[S:30][CH2:29][C:28](=[O:31])[NH:27][C:26]=3[CH:32]=2)[CH2:17]1)=[O:6]
Reactant: Nc1ccc(F)cc1C(=O)O
Reactant: NCCC[C@@H]1CN(c2ccc3c(c2)NC(=O)CS3)C(=O)O1
Product: Nc1ccc(F)cc1C(=O)NCCC[C@@H]1CN(c2ccc3c(c2)NC(=O)CS3)C(=O)O1
Yield: 70 %

Procedure:
Starting from 2-amino-5-fluorobenzoic acid and 6-[(R)-5-(3-amino-propyl)-2-oxo-oxazolidin-3-yl]-4H-benzo[1,4]thiazin-3-one (described in WO 2010/041219) and using Procedure D, the title compound was obtained as a beige solid (160 mg; 70% yield).
Reaction SMILES: [CH2:1]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[Cl-].[Al+3].[Cl-].[Cl-].C1(CC(Cl)=[O:27])C=CC=CC=1>C(=S)=S>[C:9]1([C:1]([CH2:2][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)=[O:27])[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: CCCCCCCCc1ccccc1
Reactant: O=C(Cl)Cc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: O=C(Cc1ccccc1)c1ccccc1
Temperature: 0 °C
Yield: 156.3 %

Procedure:
57.0 g (0.30 mole) of n-octylbenzene are dissolved in 500 ml of carbon disulfide, 45.0 g (0.34 mole) of aluminum chloride are added at 0° C., and a solution of 46.4 g (0.30 mole) of phenylacetyl chloride and 50 ml of carbon disulfide are added dropwise at from 0° to 5° C., while stirring. The reaction mixture is stirred for a further 2 hours at from 0° to 5° C. and then for 15 hours without being cooled, after which it is poured carefully onto 1 l of semiconcentrated ice-cold hydrochloric acid. The phases are separated, the organic phase is extracted by shaking with 300 ml of water, the aqueous phase is extracted with three times 300 ml of methylene chloride, and the combined organic phases are dried over sodium sulfate. The solution is filtered and the solvent is distilled off to give 92 g (=100% of theory) of deoxybenzoin as a colorless crystalline mass, which is shown by thin layer chromatography (silica gel/CH2Cl2 : R≈0.95; toluene: R≈0.61) to be sufficiently pure for the subsequent bromination.
Reaction SMILES: [ClH:1].Cl.[NH2:3][CH2:4][C:5]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)([OH:8])[CH2:6][NH2:7].[CH:15](OCC)=O.O.Cl>C(O)C.CO>[ClH:1].[OH:8][C:5]1([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:4][NH:3][CH:15]=[N:7][CH2:6]1
Reactant: NCC(O)(CN)c1ccccc1
Reactant: CCOC=O
Agent: Cl
Solvent: CCO
Solvent: O
Solvent: CO
Product: OC1(c2ccccc2)CN=CNC1
Temperature: 100 °C
Yield: 84 %

Procedure:
A mixture consisting of 5.56 g (0.0335 mol) of 1,3-diamino-2-phenylpropan-2-ol dihydrochloride (m.p. (inst.)=242° C.) and 2.479 g (0.0335 mol; 2.7 ml) of ethyl formate is heated at 100° C. for 3 h. It is then heated at 100° C. under reduced pressure (vacuum obtained by means of a water-jet pump) for 1 h. The reaction medium is cooled, taken up with CH3OH, acidified with ethanol containing HCl and evaporated to dryness, and the evaporation residue is triturated with ether, acetone and chloroform. The precipitate formed is collected by filtration and then recrystallized from an ethanol/diethyl ether mixture (1:1 v/v) to give 6 g (yield: 84%) of CRL 41 382. M.p. (inst.)=206° C.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][C:6]2[C:11]([C:12]=1Cl)=[CH:10][C:9]([O:14][CH3:15])=[C:8]([O:16][CH3:17])[CH:7]=2)#[N:2].[NH2:18][C:19]1[CH:20]=[N:21][CH:22]=[C:23]([Br:25])[CH:24]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>COCCO>[Br:25][C:23]1[CH:24]=[C:19]([NH:18][C:12]2[C:11]3[C:6](=[CH:7][C:8]([O:16][CH3:17])=[C:9]([O:14][CH3:15])[CH:10]=3)[N:5]=[CH:4][C:3]=2[C:1]#[N:2])[CH:20]=[N:21][CH:22]=1
Reactant: Nc1cncc(Br)c1
Reactant: COc1cc2ncc(C#N)c(Cl)c2cc1OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: COCCO
Product: COc1cc2ncc(C#N)c(Nc3cncc(Br)c3)c2cc1OC
Temperature: 153 °C

Procedure:
A mixture of 249 mg (1 mmole) of 3-cyano-4-chloro-6,7-dimethoxy quinoline, 346 mg (2 mmoles) of 3-amino-5-bromo pyridine and 20 mg (about 0.1 mmole) of p-toluenesulfonic acid monohydrate in 5 ml of 2-methoxy ethanol was stirred and refluxed in an oil bath at 153° C. for 7 hours. On cooling overnight to room temperature, the solid was filtered and washed with ethanol, then with ether to give 287 mg (74.5%) of N-[4-[(5-bromo-3-pyridinyl)amino]-6,7-dimethoxy-3-quinolinecarbonitrile, which melted at 272-275° C. mass spectrum (electrospray, m/e) M+H=384.9, 386.8.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:39])[NH:4][C@H:5]([C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[C:16]1[NH:17][CH:18]=[C:19]([C:21]2[CH:26]=[CH:25][C:24]([C:27]3[CH:32]=[C:31]([Cl:33])[C:30]([NH2:34])=[CH:29][C:28]=3[C:35]([F:38])([F:37])[F:36])=[CH:23][CH:22]=2)[N:20]=1)=[O:10])[CH:6]([CH3:8])[CH3:7].[F:40][C:41]1[CH:46]=[CH:45][C:44]([C:47](Cl)=[O:48])=[CH:43][N:42]=1>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:39])[NH:4][C@H:5]([C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[C:16]1[NH:17][CH:18]=[C:19]([C:21]2[CH:22]=[CH:23][C:24]([C:27]3[CH:32]=[C:31]([Cl:33])[C:30]([NH:34][C:47]([C:44]4[CH:43]=[N:42][C:41]([F:40])=[CH:46][CH:45]=4)=[O:48])=[CH:29][C:28]=3[C:35]([F:37])([F:38])[F:36])=[CH:25][CH:26]=2)[N:20]=1)=[O:10])[CH:6]([CH3:8])[CH3:7]
Reactant: O=C(Cl)c1ccc(F)nc1
Reactant: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1nc(-c2ccc(-c3cc(Cl)c(N)cc3C(F)(F)F)cc2)c[nH]1)C(C)C
Solvent: ClCCl
Product: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1nc(-c2ccc(-c3cc(Cl)c(NC(=O)c4ccc(F)nc4)cc3C(F)(F)F)cc2)c[nH]1)C(C)C
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of ((S)-1-{(S)-2-[4-(4′-amino-5′-chloro-2′-trifluoromethyl-biphenyl-4-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (50 mg, 0.09 mmol; Preparation 52) dissolved in DCM (0.3 mL) was slowly added a solution of 2-fluoropyridine-5-carbonyl chloride (14 mg, 0.091 mmol) dissolved in DCM (0.3 mL). The reaction mixture was stirred at RT for 5 min and concentrated to produce {(S)-1-[(S)-2-(4-{5′-chloro-4′-[(6-fluoro-pyridine-3-carbonyl)-amino]-2′-trifluoromethyl-biphenyl-4-yl}-1H-imidazol-2-yl)-pyrrolidine-1-carbonyl]-2-methyl-propyl}-carbamic acid methyl ester as a yellow solid.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[C:4]([C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)[N:3]=1.[F:20][C:21]1[CH:22]=[C:23]2[C:27](=[CH:28][CH:29]=1)[NH:26][C:25](=[O:30])[C:24]12[O:34][CH2:33][CH2:32][O:31]1.[OH-:35].[K+].O>CS(C)=O>[F:20][C:21]1[CH:29]=[CH:28][C:27]([NH:26][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=3)[N:5]=[C:4]([C:14]3[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=3)[N:3]=2)=[C:23]([C:24]2([C:25]([OH:35])=[O:30])[O:34][CH2:33][CH2:32][O:31]2)[CH:22]=1
Reactant: [OH-]
Reactant: O=C1Nc2ccc(F)cc2C12OCCO2
Reactant: COc1ccc2nc(-c3cccnc3)nc(Cl)c2c1
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: COc1ccc2nc(-c3cccnc3)nc(Nc3ccc(F)cc3C3(C(=O)O)OCCO3)c2c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 31.5 %

Procedure:
To a mixture of 4-chloro-6-methoxy-2-(pyridin-3-yl)quinazoline (0.50 g, 1.84 mmol) and 5′-fluorospiro[[1,3]-dioxolane-2,3′-indolin]-2′-one (0.42 g, 2.02 mmol) in dry DMSO (4 mL) was added KOH powder (0.11 g, 2.02 mmol). The reaction mixture was stirred for 15 h at room temperature and then the reaction mixture was poured into water. The aqueous layer was washed with ethyl acetate 20 mL) and the resulting aqueous layer was acidified with 5N HCl to give a precipitate. The solid was filtered to give 2-(5-fluoro-2-(6-methoxy-2-(pyridin-3-yl)quinazolin-4-ylamino)phenyl)-1,3-dioxolane-2-carboxylic acid as a light yellow powder (0.27 g, 0.58 mmol, 32%). LCMS m/z=432 (M+1) (Method C) 1H NMR (300 MHz, DMSO) δ 9.50-9.38 (m, 2H), 8.69-8.59 (m, 2H), 8.42 (dd, J=9.7, 5.3 Hz, 1H), 7.86 (d, J=9.1 Hz, 1H), 7.64 (d, J=2.6 Hz, 1H), 7.61-7.41 (m, 4H), 4.25-4.11 (m, 4H), 3.98 (s, 3H).
Reaction SMILES: Cl[S:2]([N:5]=[C:6]=[O:7])(=[O:4])=[O:3].[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:19]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:18][NH:17][N:16]=2)=[CH:11][CH:10]=1.[CH3:26][NH:27][CH3:28]>ClCCl>[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:19]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:18][N:17]([C:6]([NH:5][S:2]([N:27]([CH3:28])[CH3:26])(=[O:4])=[O:3])=[O:7])[N:16]=2)=[CH:13][CH:14]=1
Reactant: Clc1ccc(C2=NNCC2c2ccccc2)cc1
Reactant: O=C=NS(=O)(=O)Cl
Reactant: CNC
Solvent: ClCCl
Product: CN(C)S(=O)(=O)NC(=O)N1CC(c2ccccc2)C(c2ccc(Cl)cc2)=N1
Reaction time: 0.5 h
Yield: 58 %

Procedure:
Part A: To a stirred solution of chlorosulfonyl isocyanate (1.73 mL, 20 mmol) in dry dichloromethane (20 mL) is very slowly added a solution of 3-(4-chlorophenyl)-4-phenyl-4,5-dihydro-1H-pyrazole (5.13 gram, 20 mmol) in dry dichloromethane (125 mL) at −5° C. After stirring for 30 minutes the reaction mixture is allowed to attain room temperature and stirred for another 2 hours. After cooling to 0° C. liquid dimethylamine (5 mL) is added and the resulting solution is stirred for another hour at 0° C. and for 2 hours at room temperature. The solution is washed with water, filtered over hyflo and concentrated in vacuo. Flash chromatography (MTBE, Rf ˜0.3) gives 3-(4-chlorophenyl)-N-((dimethylamino)sulfonyl)-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboxamide (4.75 g, 58%). MP: 210-212° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:35][CH3:36])=[C:6]([CH:34]=1)[CH2:7][CH:8]1[C:14](=[O:15])[N:13]([C:16]([NH:18][CH:19]([CH2:31][CH3:32])[C:20]([NH:22][CH2:23][C:24]([O:26]C(C)(C)C)=[O:25])=[O:21])=[O:17])[CH2:12][C:11](=[O:33])[NH:10][CH2:9]1.Cl.[C:38](OC(=O)CN)([CH3:41])([CH3:40])[CH3:39].C(OC(=O)[C@H](CC(C)C)N)(C)(C)C>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:35][CH3:36])=[C:6]([CH:34]=1)[CH2:7][CH:8]1[C:14](=[O:15])[N:13]([C:16]([NH:18][C@H:19]([CH2:31][CH3:32])[C:20]([NH:22][C@@H:23]([CH2:39][CH:38]([CH3:41])[CH3:40])[C:24]([OH:26])=[O:25])=[O:21])=[O:17])[CH2:12][C:11](=[O:33])[NH:10][CH2:9]1
Reactant: CCC(NC(=O)N1CC(=O)NCC(Cc2cc(Cl)ccc2OC)C1=O)C(=O)NCC(=O)OC(C)(C)C
Reactant: CC(C)(C)OC(=O)CN
Agent: CC(C)C[C@H](N)C(=O)OC(C)(C)C
Agent: Cl
Product: CC[C@@H](NC(=O)N1CC(=O)NCC(Cc2cc(Cl)ccc2OC)C1=O)C(=O)N[C@@H](CC(C)C)C(=O)O

Procedure:
Instead of the starting material compound of Example 220, that is, the glycine tert-butyl ester hydrochloride, L-leucine tert-butyl ester was used for the similar procedure as in Example 220 and Example 245 to obtain the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:22](=[CH:23][CH:24]=1)[NH:21][C:20]1[C:9]3([C:17]4[C:12](=[CH:13][CH:14]=[C:15]([Cl:18])[CH:16]=4)[NH:11][C:10]3=[O:19])[NH:8][CH:7]([CH3:25])[CH2:6][C:5]2=1.[C:26]([Cu])#[N:27].CCOC(C)=O>CN1CCCC1=O.CCCCCC>[Cl:18][C:15]1[CH:16]=[C:17]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10](=[O:19])[C:9]12[C:20]2[NH:21][C:22]3[C:4](=[CH:3][C:2]([C:26]#[N:27])=[CH:24][CH:23]=3)[C:5]=2[CH2:6][CH:7]([CH3:25])[NH:8]1
Reactant: CC1Cc2c([nH]c3ccc(Br)cc23)C2(N1)C(=O)Nc1ccc(Cl)cc12
Reactant: N#C[Cu]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: CC1Cc2c([nH]c3ccc(C#N)cc23)C2(N1)C(=O)Nc1ccc(Cl)cc12
Reaction time: 0.5 h

Procedure:
Compound 63 (30 mg, 0.072 mmol), CuCN (9.67 mg, 0.108 mmol) in N-methylpyrrolidone (0.12 mL) was refluxed for 16 hr. The solvent was removed under reduced pressure overnight and the black residue was stirred for 30 minutes with 30% aq. ammonia (0.2 mL), followed by addition of chloroform. An insoluble material was filtered off and washed 5 times with boiling chloroform. The organic phases were combined, washed with water and dried with sodium sulfate. The product was isolated using flash column chromatography with 10%-35% EtOAc in hexane (3.0 mg, 11.5%). 1H NMR (300 MHz, DMSO-d6): δ 11.11 (s, 1H), 10.54 (s, 1H), 7.99 (s, 1H), 7.92-7.83 (m, 3H), 7.05 (d, J=2.1 Hz, 1H), 6.94 (d, J=8.4 Hz, 1H), 3.98-3.85 (m, 1H), 2.85 (dd, J=15.5, 3.6 Hz, 1H), 2.42 (dd, J=15.3, 10.5 Hz, 1H), 1.18 (d, J=6.9 Hz, 3H); MS (ESI) m/z 363.0 (M+H)+.
Reaction SMILES: [CH3:1][C:2]([CH3:21])([O:4][C:5](=[O:20])[CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH:15]([CH3:19])[C:16]([OH:18])=[O:17])=[CH:10][CH:9]=1)[CH3:3].[N+](=[CH2:24])=[N-]>C(OCC)C>[CH3:3][C:2]([CH3:1])([O:4][C:5](=[O:20])[CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH:15]([CH3:19])[C:16]([O:18][CH3:24])=[O:17])=[CH:10][CH:9]=1)[CH3:21]
Reactant: C=[N+]=[N-]
Reactant: CC(Cc1ccc(OCC(=O)OC(C)(C)C)cc1)C(=O)O
Solvent: CCOCC
Product: COC(=O)C(C)Cc1ccc(OCC(=O)OC(C)(C)C)cc1

Procedure:
Dissolve (+)-4-[[2-(1,1-dimethylethoxy)-2-oxoethyl]oxy]-alpha-methyl-benzenepropanoic acid (90% ee) (6.04 g, 20.5 mmol) in ethyl ether (400 mL) and treat with excess diazomethane. Wash with saturated sodium hydrogen carbonate (2×300 mL) and brine (300 mL). Dry (MgSO4) and evaporate the solvent in vacuo to give (+)-4-[[2-(1,1-dimethylethoxy)-2-oxoethyl]oxy]-alpha-methyl-benzenepropanoic acid, methyl ester (5.85 g).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@:13]([CH2:22][CH2:23][CH2:24][OH:25])([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[O:12][C:11]2=[O:26])[CH3:9])=[CH:4][CH:3]=1.[NH2:27][C:28]1[N:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1>>[NH2:27][C:28]1[N:33]=[CH:32][C:31]([C:2]2[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]3[CH2:15][CH2:14][C@:13]([CH2:22][CH2:23][CH2:24][OH:25])([C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=4)[O:12][C:11]3=[O:26])[CH3:9])=[CH:4][CH:3]=2)=[CH:30][CH:29]=1
Reactant: Nc1ccc(B(O)O)cn1
Reactant: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CCCO)(c2ccccc2)OC1=O
Product: C[C@@H](c1ccc(-c2ccc(N)nc2)cc1)N1CC[C@](CCCO)(c2ccccc2)OC1=O

Procedure:
The title compound was prepared from (R)-3-((S)-1-(4-bromophenyl)ethyl)-6-(3-hydroxypropyl)-6-phenyl-1,3-oxazinan-2-one and 6-aminopyridine-3-boronic acid following procedures analogous to those described in Example 75 Step 1. LC-MS Method 2 tR=0.963 min, m/z=431.8; 1H NMR (CDCl3) 1.36 (d, 3H), 1.75 (m, 1H), 1.98 (m, 3H), 2.21 (m, 1H), 2.38 (m, 2H), 2.89 (m, 1H), 3.56 (m, 2H), 5.05 (s, 1H), 5.65 (m, 1H), 6.62 (d, 1H), 6.97 (d, 2H), 7.17 (d, 2H), 7.20-7.39 (m, 5H), 7.63 (d, 1H), 8.12 (s, 1H).
Reaction SMILES: [O:1]=[C:2]1[CH2:10][C:9]2[C:4](=[C:5]([S:11]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)=[O:12])[CH:6]=[CH:7][CH:8]=2)[NH:3]1.[O:20]1CCOCC1.[OH-].[Na+:27]>O>[NH2:3][C:4]1[C:5]([S:11]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)=[O:12])=[CH:6][CH:7]=[CH:8][C:9]=1[CH2:10][C:2]([O-:20])=[O:1].[Na+:27]
Reactant: O=C1Cc2cccc(S(=O)c3ccc(Cl)cc3)c2N1
Reactant: C1COCCO1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Nc1c(CC(=O)[O-])cccc1S(=O)c1ccc(Cl)cc1
Reaction time: 15 h

Procedure:
A mixture of 2-oxo-7-(4-chlorophenylsulfinyl)indoline (4.7 g) and dioxane (30 ml) was added to a solution of sodium hydroxide (2.5 g) in water (30 ml), and the mixture was refluxed with stirring for 15 hrs. Dioxane was distilled off from the reaction mixture in vacuo, and the residue was dissolved in water and washed with diethyl ether. The aqueous solution was adjusted to pH 7 with 5% sulfuric acid and extracted with ethyl acetate (200 ml×2). The extract was washed with saline, dried over magnesium sulfate and then evaporated in vacuo. The residue was dissolved in 1N-sodium hydroxide (12.2 ml) under heating and the solution was concentrated in vacuo. The residue was recrystallized from ethanol twice to give powdery sodium 2-[2-amino-3-(4-chlorophenylsulfinyl)phenyl]acetate (1.5 g). mp 242°-245° C. (dec.).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12](/[CH:15]=[CH:16]/[C@H:17]3[O:26][C@H:20]4[O:21][C:22]([CH3:25])([CH3:24])[O:23][C@H:19]4[C@H:18]3[CH2:27][CH2:28][N:29]3[C:34](=[O:35])[C:33]4[CH:36]=[CH:37][CH:38]=[CH:39][C:32]=4[N:31]=[N:30]3)=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.O1CCCC1.[H][H]>[Pd].CO>[CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([C:9]2[CH:10]=[CH:11][C:12]([CH2:15][CH2:16][C@H:17]3[O:26][C@H:20]4[O:21][C:22]([CH3:24])([CH3:25])[O:23][C@H:19]4[C@H:18]3[CH2:27][CH2:28][N:29]3[C:34](=[O:35])[C:33]4[CH:36]=[CH:37][CH:38]=[CH:39][C:32]=4[N:31]=[N:30]3)=[CH:13][CH:14]=2)=[CH:5][CH:4]=1
Reactant: [H][H]
Reactant: COc1ccc(-c2ccc(/C=C/[C@H]3O[C@H]4OC(C)(C)O[C@H]4[C@H]3CCn3nnc4ccccc4c3=O)cc2)cn1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(-c2ccc(CC[C@H]3O[C@H]4OC(C)(C)O[C@H]4[C@H]3CCn3nnc4ccccc4c3=O)cc2)cn1

Procedure:
To the solution of the compound obtained from step b above (8.5 g) in a solvent mixture of tetrahydrofuran:methanol (60 mL:40 mL), 10% palladium on charcoal (4 g) was added at room temperature, and the reaction mixture was hydrogenated with hydrogen at 35 psi for 4 hours in a Paar apparatus. The reaction mixture was filtered through a celite pad and the residue was washed with methanol. The filtrate was concentrated to afford the title compound (8.1 g).
Reaction SMILES: [Cl:1][C:2]([Cl:6])([Cl:5])[S:3]Cl.C(N(CC)CC)C.[NH:14]1[CH2:20][C:18](=[O:19])[NH:17][C:15]1=[O:16]>C(OCC)(=O)C>[Cl:1][C:2]([Cl:6])([Cl:5])[S:3][N:14]1[CH2:20][C:18](=[O:19])[N:17]([S:3][C:2]([Cl:6])([Cl:5])[Cl:1])[C:15]1=[O:16]
Reactant: ClSC(Cl)(Cl)Cl
Reactant: O=C1CNC(=O)N1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: O=C1CN(SC(Cl)(Cl)Cl)C(=O)N1SC(Cl)(Cl)Cl
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 90.5 %

Procedure:
At about 0° C., 37.2 g (0.2 mole) of trichloromethylsulfenyl chloride and subsequently 20.2 g (0.2 mole) of triethylamine are dripped, while stirring thoroughly, into a suspension of 10 g (0.1 mole) of hydantoin in 150 ml of anhydrous ethyl acetate. After stirring for 90 minutes at room temperature, the precipitated triethylamine hydrochloride is filtered off and washed with 100 ml of ethyl acetate. The filtrate is concentrated and the residue is crystallized by trituration with n-pentane. There is obtained 36.1 g (90.5% of theory) of 1,3-bis-(trichloromethylthio)-hydantoin; m.p.: 142° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:14]=[C:13]2[C:9]([C:10]([CH:24]=[O:25])=[C:11]([CH:21]([CH3:23])[CH3:22])[N:12]2[CH2:15][C:16]2[O:17][CH:18]=[CH:19][N:20]=2)=[CH:8][CH:7]=1)=[O:5])[CH3:2].[O-:26]Cl=O.[Na+]>CC(O)(C)C.CC(=CC)C.O>[CH2:1]([O:3][C:4]([C:6]1[CH:14]=[C:13]2[C:9]([C:10]([C:24]([OH:26])=[O:25])=[C:11]([CH:21]([CH3:22])[CH3:23])[N:12]2[CH2:15][C:16]2[O:17][CH:18]=[CH:19][N:20]=2)=[CH:8][CH:7]=1)=[O:5])[CH3:2]
Reactant: [O-][Cl+][O-]
Reactant: CCOC(=O)c1ccc2c(C=O)c(C(C)C)n(Cc3ncco3)c2c1
Agent: CC=C(C)C
Agent: [Na+]
Solvent: O
Solvent: CC(C)(C)O
Product: CCOC(=O)c1ccc2c(C(=O)O)c(C(C)C)n(Cc3ncco3)c2c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Following General Procedure D, ethyl3-formyl-2-isopropyl-1-(oxazol-2-ylmethyl)-1H-indole-6-carboxylate (Compound 38, 240 mg, 0.70 mmol) in t-BuOH (20 ml), 2-methyl-2-butene (2.0 ml) was added a solution of NaH2PO4 (1.69 g, 14.0 mmol) and NaClO2 (80%, 1.27 g, 14.0 mmol) in H2O (4 ml). The mixture was stirred at room temperature for 12 h. The reaction mixture was extracted with EtOAc (×3) and the combined organic layer was washed with brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by chromatography on silica gel (0→55% EtOAc-hexanes) to yield the title compound as a light tan solid.