Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1](Cl)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[OH:9][CH:10]1[CH2:15][CH2:14][N:13]([C:16]([N:18]2[CH:22]=[CH:21][N:20]=[CH:19]2)=[O:17])[CH2:12][CH2:11]1>CN(C)C=O>[C:4]([Si:1]([CH3:3])([CH3:2])[O:9][CH:10]1[CH2:15][CH2:14][N:13]([C:16]([N:18]2[CH:22]=[CH:21][N:20]=[CH:19]2)=[O:17])[CH2:12][CH2:11]1)([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=C(N1CCC(O)CC1)n1ccnc1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OC1CCN(C(=O)n2ccnc2)CC1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
tert-Butyldimethylsilyl chloride (30.14 g, 0.20 mol) was added to a stirred solution of (4-hydroxy-piperidin-1-yl)-imidazol-1-yl-methanone (39.05 g, 0.20 mol) in dimethylformamide (200 mL). After stirring for 3 days at room temperature, the solvent was removed by evaporation in vacuo. The residue was redissolved in dichloromethane, extracted twice with water, dried over sodium sulphate, filtered and evaporated in vacuo, yielding the title compound, which was used without further purification.
Reaction SMILES: CC(OC(=O)[NH:7][C@H:8]([CH2:16][OH:17])[CH2:9][C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1)(C)C.[ClH:19]>O1CCOCC1>[ClH:19].[ClH:19].[NH2:7][C@@H:8]([CH2:9][C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1)[CH2:16][OH:17]
Reactant: CC(C)(C)OC(=O)N[C@H](CO)Cc1cccnc1
Agent: Cl
Solvent: C1COCCO1
Product: N[C@H](CO)Cc1cccnc1

Procedure:
To a solution of (S)-[1-(hydroxymethyl)-2-(3-pyridinyl)ethyl]carbamic acid 1,1-dimethylethyl ester (1.27 g, 5.03 mmol) in 1,4-dioxan (3 ml) was added 1,4-dioxan saturated with HCl gas (10 ml) followed by a further portion of 1,4-dioxan (10 ml). After 2 h at room temperature the precipitated solid was collected by filtration, washed with 1,4-dioxan (5 ml) and ether then dried in vacuo to give the title compound (0.928 g) as a solid, nmr(δ,DMSO-d6) includes 3.11(bd,2H), 3.4-3.7(m,3H), 7.86(dd,1H), 8.1-8.3(bs,3H), 8.45(d,1H), 8.81(d,1H), 8.9(s,1H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]2[O:23][C:17]3=[CH:18][N:19]=[C:20](Cl)[CH:21]=[C:16]3[CH2:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:24]([S:26]([N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1)(=[O:28])=[O:27])[CH3:25]>>[C:1]([O:5][C:6]([N:8]1[CH:13]=[CH:12][C:11]([CH:14]2[O:23][C:17]3=[CH:18][N:19]=[C:20]([N:32]4[CH2:31][CH2:30][N:29]([S:26]([CH2:24][CH3:25])(=[O:27])=[O:28])[CH2:34][CH2:33]4)[CH:21]=[C:16]3[CH2:15]2)=[CH:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(C2Cc3cc(Cl)ncc3O2)CC1
Reactant: CCS(=O)(=O)N1CCNCC1
Product: CCS(=O)(=O)N1CCN(c2cc3c(cn2)OC(C2=CCN(C(=O)OC(C)(C)C)C=C2)C3)CC1

Procedure:
The title compound is prepared from 4-(5-chloro-2,3-dihydro-furo[2,3-c]pyridin-2-yl)-piperidine-1-carboxylic acid tert-butyl ester and 1-(ethylsulfonyl)piperazine following a procedure analogous to that described in Example 79. LC (method 10): tR=1.45 min;
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1([OH:21])[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[CH2:10][CH2:9][C:8]2[CH:17]=[CH:18][CH:19]=[CH:20][C:7]1=2.C[O:23][C:24](=[O:46])[C@H:25]([CH2:44]O)[NH:26]C(OCC1C2C=CC=CC=2C2C1=CC=CC=2)=O>>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1([O:21][CH2:44][C@@H:25]([C:24]([OH:46])=[O:23])[NH2:26])[C:7]2[CH:20]=[CH:19][CH:18]=[CH:17][C:8]=2[CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]1=2
Reactant: COC(=O)[C@H](CO)NC(=O)OCC1c2ccccc2-c2ccccc21
Reactant: OC1(c2cccs2)c2ccccc2CCc2ccccc21
Product: N[C@@H](COC1(c2cccs2)c2ccccc2CCc2ccccc21)C(=O)O

Procedure:
from 10,11-dihydro-5-(2-thienyl)-5H-dibenzo[a,d]cyclohepten-5-ol (Example 2d) and Nα -(9-fluorenylmethoxycarbonyl)-L-serine methyl ester;
Reaction SMILES: [F:1][C:2]1([F:29])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[NH:11][C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([O:19][CH:20]2[CH2:25][CH2:24][N:23]([CH:26]([CH3:28])[CH3:27])[CH2:22][CH2:21]2)=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1.[C:30]([C:32]1[CH:33]=[C:34](B(O)O)[CH:35]=[CH:36][C:37]=1[F:38])#[N:31]>>[F:29][C:2]1([F:1])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[N:11]([C:34]3[CH:35]=[CH:36][C:37]([F:38])=[C:32]([CH:33]=3)[C:30]#[N:31])[C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([O:19][CH:20]2[CH2:25][CH2:24][N:23]([CH:26]([CH3:27])[CH3:28])[CH2:22][CH2:21]2)=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1
Reactant: CC(C)N1CCC(Oc2ccc3[nH]c(C(=O)N4CCC(F)(F)CC4)cc3c2)CC1
Reactant: N#Cc1cc(B(O)O)ccc1F
Product: CC(C)N1CCC(Oc2ccc3c(c2)cc(C(=O)N2CCC(F)(F)CC2)n3-c2ccc(F)c(C#N)c2)CC1

Procedure:
In analogy to the procedure described for the synthesis of example 6, the title compound was synthesized from (4,4-difluoro-piperidin-1-yl)-[5-(1-isopropyl-piperidin-4-yloxy)-1H-indol-2-yl]-methanone (intermediate 1) and 3-cyano-4-fluorophenylboronic acid. The title compound was obtained in 22% yield as orange oil. MS (m/e): 525.2 (MH+, 100%).
Reaction SMILES: I([O-])(=O)(=O)=[O:2].[Na+].[C:7]([C:9]1[CH:27]=[CH:26][C:12]([NH:13][C:14](=[O:25])[C:15]([OH:24])([C:20]([F:23])([F:22])[F:21])[CH2:16][S:17][CH2:18][CH3:19])=[CH:11][C:10]=1[C:28]([F:31])([F:30])[F:29])#[N:8]>O.CO>[C:7]([C:9]1[CH:27]=[CH:26][C:12]([NH:13][C:14](=[O:25])[C:15]([OH:24])([C:20]([F:21])([F:22])[F:23])[CH2:16][S:17]([CH2:18][CH3:19])=[O:2])=[CH:11][C:10]=1[C:28]([F:30])([F:31])[F:29])#[N:8]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: CCSCC(O)(C(=O)Nc1ccc(C#N)c(C(F)(F)F)c1)C(F)(F)F
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CCS(=O)CC(O)(C(=O)Nc1ccc(C#N)c(C(F)(F)F)c1)C(F)(F)F
Reaction time: 48 h

Procedure:
A solution of sodium metaperiodate (0.407 g.) in water (15 ml.) was added dropwise to a stirred solution of 4-cyano-3-trifluoromethyl-N-(3-ethylthio-2-hydroxy-2-trifluoromethylpropionyl)aniline (0.6 g.) in methanol (25 ml.) and the mixture was stirred at laboratory temperature for 48 hours and then filtered. The solid was washed with methanol (25 ml.) and the mixture was filtered, and the combined filtrates were evaporated to dryness under reduced pressure. The residue was dissolved in ethyl acetate (150 ml.) and the solution was washed successively with water (15 ml.), saturated aqueous sodium sulphite solution (25 ml.) and saturated aqueous sodium chloride solution (25 ml.), dried over magnesium sulphate and evaporated to dryness under reduced pressure. The residue was chromatographed on silica gel (Merck 7734) using a 1:1 v/v mixture of ethyl acetate and petroleum ether (b.p. 60°-80° C.) as eluant, and the two diastereoisomers of 4-cyano-3-trifluoromethyl-N-(3-ethylsulphinyl-2-hydroxy-2-trifluoromethylpropionyl)aniline were obtained by evaporation of the appropriate fractions of the eluate. These had m.p. 141°-143° C. (more polar isomer) and 160°-162° C. (less polar isomer).
Reaction SMILES: [OH:1][C@@H:2]1[C@H:6]([CH2:7][CH:8]([CH3:10])[CH3:9])[N:5]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C:4](=[O:18])[CH2:3]1.[OH-:19].[Na+].Cl>CC(C)=O>[CH3:9][CH:8]([CH3:10])[CH2:7][C@H:6]([NH:5][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C@@H:2]([OH:1])[CH2:3][C:4]([OH:18])=[O:19]
Reactant: CC(C)C[C@H]1[C@@H](O)CC(=O)N1C(=O)OC(C)(C)C
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: CC(C)=O
Product: CC(C)C[C@H](NC(=O)OC(C)(C)C)[C@@H](O)CC(=O)O
Reaction time: 2 h

Procedure:
1 g of this 4-hydroxy-2-pyrrolidinone is dissolved in 5 ml of acetone. 2 ml of 1M sodium hydroxide are added dropwise. After 2 hours, the reaction mixture is acidified carefully with dilute hydrochloric acid to pH 3-4. The Boc-statine obtained is precipitated by adding water, drained, washed with water and then with hexane and dried under vacuum in the presence of potassium hydroxide pellets. 810 mg of this statine are thus obtained, in the form of a white solid having the following characteristics: mp=120°-120° C.; Rf=0.52 (eluent CHCl3 /MeOH/AcOH: 180/10/5); [α]D20 =+41.9°(c=1,MEOH); 1HNMR(DMSO-d6) δ ppm: 0.85(6H,dd,CH3); 1.26(2H,m,CH2); 1.37(9H,s,Boc); 1.55(1H,m,CH); 2.21(2H,m,H-2); 3.51(1H,m,H-4); 3.80(1H,m,H-3); 6.31(1H,d,NH); MS-FAB+: 276.
Reaction SMILES: [CH2:1]([NH2:6])[CH2:2][CH:3]([CH3:5])[CH3:4].C([CH:9]([C:23]([O-:25])=O)[C:10]([C:20]([O-:22])=O)([OH:19])[C:11](CC)(CC)[C:12]([O-:14])=O)C>CO>[CH2:1]([NH:6][C:12](=[O:14])[CH2:11][C:10]([CH2:9][C:23]([NH:6][CH2:1][CH2:2][CH:3]([CH3:5])[CH3:4])=[O:25])([C:20]([NH:6][CH2:1][CH2:2][CH:3]([CH3:5])[CH3:4])=[O:22])[OH:19])[CH2:2][CH:3]([CH3:5])[CH3:4]
Reactant: CCC(C(=O)[O-])C(O)(C(=O)[O-])C(CC)(CC)C(=O)[O-]
Reactant: CC(C)CCN
Solvent: CO
Product: CC(C)CCNC(=O)CC(O)(CC(=O)NCCC(C)C)C(=O)NCCC(C)C
Temperature: 25 °C
Reaction time: 48 h
Yield: 52.1 %

Procedure:
N,N′,N″-tri-iso-amylcitramide was prepared by the reaction of iso-amylamine with triethylcitrate. To a round-bottomed flask were added triethylcitrate (30.001 g, 1 eq), iso-amylamine (28.399 g, 3.0 eq) and methanol (40 mL). The clear light yellow solution stirred for 2 days at room temperature and then additional amine (1.1 eq) was added. After stirring 1 week, a clear yellow solution was observed. Methanol was removed in vacuo and the resulting white solid was triturated using diethylether, collected via filtration and dried in vacuo to give a white powder with a very slight odor (22.52 g, 52.1% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[S:4][C:3]=1[C:13]([O:15][CH3:16])=[O:14].[Br-:17].[Br-].[Br-].C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.C(=O)([O-])[O-].[Ca+2]>ClCCl.CO>[NH2:1][C:2]1[C:6]([Br:17])=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[S:4][C:3]=1[C:13]([O:15][CH3:16])=[O:14]
Reactant: COC(=O)c1sc(-c2ccccc2)cc1N
Reactant: [Br-]
Agent: C[N+](C)(C)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: CO
Solvent: ClCCl
Product: COC(=O)c1sc(-c2ccccc2)c(Br)c1N
Reaction time: 8 h
Yield: 88.1 %

Procedure:
To a mixture of methyl 3-amino-5-phenylthiophene-2-carboxylate (2.33 g, 10 mmol) and phenyltrimethylammonium tribromide (9.4 g, 25 mmol) in dichloromethane (25 mL) and methanol (25 mL) was added calcium carbonate (4.03 g, 40 mmol) and the mixture stirred overnight. The solid was filtered off and the filtrate concentrated. The residue was purified by flash chromatography on silica gel using 1:10 ethyl acetate/hexanes to give 2.75 g of the title compound. 1H NMR (DMSO-d6) δ 7.62-7.65 (m, 2H), 7.47-7.51 (m, 3H), 3.80 (s, 3H).
Reaction SMILES: C[CH2:2][CH:3]([C:5]1[C:10]([O:11]C(NC)=O)=[CH:9][CH:8]=[CH:7][CH:6]=1)C.C=CC1C=CC=CC=1.C([O:32][O:33][C:34](=[O:41])C1C=CC=CC=1)(=O)C1C=CC=CC=1.O=O>CO>[CH2:2]=[CH:3][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[C:34]([O:33][O-:32])(=[O:41])[O-:11]
Reactant: CCC(C)c1ccccc1OC(=O)NC
Reactant: O=C(OOC(=O)c1ccccc1)c1ccccc1
Agent: O=O
Solvent: C=Cc1ccccc1
Solvent: CO
Product: O=C([O-])O[O-]
Reaction time: 1 h

Procedure:
A glass ampoule having an inner volume of 20 ml was filled with 2.08 g of BPMC (purity 96.0% by weight), 8.0 g of refined styrene, and 0.1 g of benzoyl peroxide (purity 99.8% by weight), displaced with nitrogen gas, and then sealed by fusion. This ampoule was kept immersed in a constant oil bath at 100° C. for one hour. Then, the ampoule was taken out of the bath, cooled, and opened. The reaction product was dropped into 500 ml of methanol and allowed to precipitate therein. The white solid consequently formed was separated by filtration and dried under a vacuum. The product consequently obtained weighed 5.8 g. The active oxygen content of the product was found to be 1.20%. In the infrared absorption spectrum of this product, absorptions by carbonyl group were observed at 1725 and 1795 cm-1 and a characteristic absorption by benzene ring was observed below 1600 cm-1. The data indicate that the white solid was a copolymer formed of styrene structural units and peroxycarbonate structural units. The conditions of copolymerization and the analyses of the produced copolymer are shown in Table 4A and the data on the copolymer's stability of storage are shown in Table 7.
Reaction SMILES: BrC1C(CSCCN)=NC=CC=1.C([NH:21][C:22]([NH:35][CH2:36][CH2:37][S:38][CH2:39][C:40]1[C:45]([Br:46])=[CH:44][CH:43]=[CH:42][N:41]=1)=[N:23][CH2:24][CH2:25][S:26][CH2:27][C:28]1[C:33]([Br:34])=[CH:32][CH:31]=[CH:30][N:29]=1)(=O)C1C=CC=CC=1>N1C=CC=CC=1>[Br:46][C:45]1[C:40]([CH2:39][S:38][CH2:37][CH2:36][NH:35][C:22]([NH:23][CH2:24][CH2:25][S:26][CH2:27][C:28]2[C:33]([Br:34])=[CH:32][CH:31]=[CH:30][N:29]=2)=[NH:21])=[N:41][CH:42]=[CH:43][CH:44]=1
Reactant: O=C(NC(=NCCSCc1ncccc1Br)NCCSCc1ncccc1Br)c1ccccc1
Agent: NCCSCc1ncccc1Br
Solvent: c1ccncc1
Product: N=C(NCCSCc1ncccc1Br)NCCSCc1ncccc1Br

Procedure:
The reaction of 3-bromo-2-[(2-aminoethyl)thiomethyl]pyridine with N-benzoyl-bis-dimethylthioimidocarbonate in pyridine by the method described in Example 12 yielded N-benzoyl-N',N"-bis-[2-((3-bromo-2-pyridyl)methylthio)ethyl]guanidine which, on acid hydrolysis, yielded the title compound.
Reaction SMILES: [I:1][C:2]1[N:3]=[C:4]([CH3:7])[NH:5][CH:6]=1.C1(C)C=CC(S(O[CH2:18][C:19]([F:22])([F:21])[F:20])(=O)=O)=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.C(OCC)(=O)C.O>[I:1][C:2]1[N:3]=[C:4]([CH3:7])[N:5]([CH2:18][C:19]([F:22])([F:21])[F:20])[CH:6]=1
Reactant: Cc1nc(I)c[nH]1
Reactant: Cc1ccc(S(=O)(=O)OCC(F)(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: Cc1nc(I)cn1CC(F)(F)F
Temperature: 50 °C
Reaction time: 18 h
Yield: 43.1 %

Procedure:
4-Iodo-2-methyl-1H-imidazole (1.0 g, 4.8 mmol) was dissolved in 10 mL of DMF. Trifluoroethyl p-toluenesulfonate (4.89 g, 19.2 mmol) and cesium carbonate (1.57 g, 4.8 mmol) were added and the mixture was stirred for 18 h in a 50° C. oil bath. The reaction was cooled and taken up in ethyl acetate and water. The layers were separated, and the aqueous layer was extracted twice more with ethyl acetate. The combined organic layers were washed with water and brine, and dried over sodium sulfate. After evaporation, the residue was purified by silica gel chromatography (ethyl acetate/hexanes) to give 0.6 g (43%) of 4-iodo-2-methyl-1-(2,2,2-trifluoro-ethyl)-1H-imidazole. (M+H)+=291.
Reaction SMILES: [H-].[Na+].[C:3]([CH2:5]P(=O)(OCC)OCC)#[N:4].[CH:14]([C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:27]=[CH:26][C:25]([CH:28]([CH3:37])[CH2:29][NH:30][S:31]([CH:34]([CH3:36])[CH3:35])(=[O:33])=[O:32])=[CH:24][CH:23]=2)=[CH:18][CH:17]=1)=O>O1CCCC1.O>[C:3]([CH:5]=[CH:14][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:27]=[CH:26][C:25]([CH:28]([CH3:37])[CH2:29][NH:30][S:31]([CH:34]([CH3:36])[CH3:35])(=[O:33])=[O:32])=[CH:24][CH:23]=2)=[CH:18][CH:17]=1)#[N:4]
Reactant: CCOP(=O)(CC#N)OCC
Reactant: CC(CNS(=O)(=O)C(C)C)c1ccc(-c2ccc(C=O)cc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(CNS(=O)(=O)C(C)C)c1ccc(-c2ccc(C=CC#N)cc2)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a suspension of 0.4 g (10.4 mmol) of sodium hydride (washed three times with hexane) in 2 mL of tetrahydrofuran was added 1.6 mL (10.4 mmol) of diethyl cyanomethylphosphonate. The mixture was stirred at ambient temperature for 15 minutes. To the mixture was added a solution of 3.0 g (8.7 mmol) of material from Example 45 in 15 mL of tetrahydrofuran. After stirring for two hours, the mixture was diluted with 25 mL of water and extracted three times with 20 mL each of ethyl ether. The combined organics were dried (MgSO4), filtered and concentrated in vacuo.
Reaction SMILES: C1(S([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([Br:20])[C:18]([Cl:19])=[C:13]3[CH:12]=[C:11]2[I:21])(=O)=O)C=CC=CC=1.BrC1C(Cl)=C2C=C(I)N(S(C3C=CC=CC=3I)(=O)=O)C2=NC=1.[OH-].[Na+]>C1COCC1.CO>[Br:20][C:17]1[C:18]([Cl:19])=[C:13]2[CH:12]=[C:11]([I:21])[NH:10][C:14]2=[N:15][CH:16]=1
Reactant: O=S(=O)(c1ccccc1)n1c(I)cc2c(Cl)c(Br)cnc21
Agent: O=S(=O)(c1ccccc1I)n1c(I)cc2c(Cl)c(Br)cnc21
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Clc1c(Br)cnc2[nH]c(I)cc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of a 4:6 mixture of 1-benzenesulfonyl-5-bromo-4-chloro-2-iodo-1H-pyrrolo[2,3-b]pyridine and 5-bromo-4-chloro-2-iodo-1-(2-iodobenzenesulfonyl)-1H-pyrrolo[2,3-b]pyridine (100 mg, 0.178 mmol) in THF (4 mL) was added 3N NaOH in methanol (1 mL), and the mixture was stirred at RT for 30 min. The reaction was quenched with saturated ammonium chloride solution (2 mL), water (5 mL) was added, and the mixture was filtered. The precipitate obtained was washed with water (3×10 mL) followed by hexane (3×10 mL) and dried under vacuum to yield the title compound as white solid. 1H NMR (400 MHz, CD3OD): δ=8.21 (s, 1H), 6.74 (s, 1H); MS (ES+): m/z 358.75 (100) [MH+]; HPLC: tR=5.68 min (ZQ2000, nonpolar—15 min).
Reaction SMILES: O=[C:2]1[C:10]2[C:5](=[CH:6][C:7]([O:11][C:12]3[CH:20]=[CH:19][C:15]([C:16]([NH2:18])=[O:17])=[CH:14][N:13]=3)=[CH:8][CH:9]=2)[CH2:4][CH2:3]1.[CH3:21][C:22]1[CH:23]=[C:24]([CH2:28][CH2:29][NH2:30])[CH:25]=[CH:26][CH:27]=1.C1COCC1.[BH3-]C#N.[Na+]>CO.Cl[Ti](Cl)(Cl)Cl>[C:22]1([CH3:21])[CH:27]=[CH:26][CH:25]=[C:24]([CH2:28][CH2:29][NH:30][CH:2]2[C:10]3[C:5](=[CH:6][C:7]([O:11][C:12]4[CH:20]=[CH:19][C:15]([C:16]([NH2:18])=[O:17])=[CH:14][N:13]=4)=[CH:8][CH:9]=3)[CH2:4][CH2:3]2)[CH:23]=1
Reactant: NC(=O)c1ccc(Oc2ccc3c(c2)CCC3=O)nc1
Reactant: Cc1cccc(CCN)c1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cccc(CCNC2CCc3cc(Oc4ccc(C(N)=O)cn4)ccc32)c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 73 %

Procedure:
Add Ti(iPro)4 (1.70 g, 6.00 mmol) to a suspension of 6-(1-oxo-indan-5-yloxy)-nicotinamide (Intermediate 4,805 mg, 3.00 mmol), 2-(3-methylphenyl)ethylamine (446 mg, 3.30 mmol) and THF (20 ml) and stir for six hours under a nitrogen atmosphere at ambient temperature. After cooling in an ice/water bath, treat the reaction mixture with a solution of TiCl4 (1.0M/DCM, 6.00 ml, 6.00 mmol) and stir at 0-5° C. for two hours before adding NaBH3CN (377 mg, 6.00 mmol) dissolved in MeOH (5 ml). Allow the reaction mixture to warm to ambient temperature as the cold bath warms and stir overnight. Quench the reaction with 2N aq. NaOH, making the suspension basic. Stir the suspension for one hour and filter through a filter aid to remove solids, washing them with EtOAc. Separate layers in the filtrate/wash and wash the organic layer with brine before drying (MgSO4) and concentrating. Purify on silica gel (5% (1N NH3/MeOH)/45% EtOAc/DCM) to obtain 849 mg of the title compound as a light yellow solid. Mass spectrum (ion spray): m/z=388 (M+1); 1HNMR (CDCl3): 8.59 (s, 1H), 8.15 (d, 1H), 7.30 (d, 1H), 7.19 (t, 1H), 7.05-7.01 (m, 3H), 6.98 (s, 1H), 6.93 (d, 2H), 5.96 (br. s, 2H), 4.26 (t, 1H), 3.02-2.94 (m, 3H), 2.86-2.76 (m, 3H), 2.44 (m, 1H), 2.33 (s, 3H), 1.84 (m, 1H).
Reaction SMILES: [Cl-].[NH4+].[C-]#N.[K+].[C:6]1(=[O:12])[CH2:11][CH2:10][CH2:9][CH:8]=[CH:7]1.[CH3:13][N:14](C)C=O>O>[C:13]([CH:8]1[CH2:9][CH2:10][CH2:11][C:6](=[O:12])[CH2:7]1)#[N:14]
Reactant: O=C1C=CCCC1
Reactant: CN(C)C=O
Agent: [C-]#N
Agent: [Cl-]
Agent: [K+]
Solvent: O
Product: N#CC1CCCC(=O)C1
Temperature: 100 °C
Reaction time: 3 h
Yield: 5.4 %

Procedure:
Under a nitrogen atmosphere, ammonium chloride (4.17 g, 0.078 mol) and potassium cyanide (6.77 g, 0.104 mol) were added to a solution of 2-cyclohexen-1-one (5.0 g, 0.052 mol) in a 15%-aqueous N,N-dimethylformamide solution (60 ml) at room temperature, and the resulting mixture was heated to 100° C. After 3 hours, the reaction solution was poured into water and extracted with chloroform, and the organic layer was dried over anhydrous magnesium sulfate. The organic layer dried was concentrated under reduced pressure and the resulting residue was purified by a silica gel column chromatography (eluent: hexane/ethyl acetate) to obtain 1-cyanocyclohexan-3-one (345.4 mg, 5.4%).
Reaction SMILES: CC1C=CC(S(O[C:12]2[C:13]3[CH2:23][CH2:22][CH2:21][C:20]4[N:24]([CH3:27])[N:25]=[CH:26][C:19]=4[C:14]=3[N:15]=[C:16]([NH2:18])[N:17]=2)(=O)=O)=CC=1.[NH:28]1[CH2:32][CH2:31][C@@H:30]([NH:33]C(=O)OC(C)(C)C)[CH2:29]1>>[NH2:33][C@@H:30]1[CH2:31][CH2:32][N:28]([C:12]2[C:13]3[CH2:23][CH2:22][CH2:21][C:20]4[N:24]([CH3:27])[N:25]=[CH:26][C:19]=4[C:14]=3[N:15]=[C:16]([NH2:18])[N:17]=2)[CH2:29]1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCNC1
Reactant: Cc1ccc(S(=O)(=O)Oc2nc(N)nc3c2CCCc2c-3cnn2C)cc1
Product: Cn1ncc2c1CCCc1c-2nc(N)nc1N1CC[C@@H](N)C1

Procedure:
The compound from Example 8C (65 mg, 0.168 mmol) was treated with (R)-tert-butyl pyrrolidin-3-ylcarbamate (36 mg, 0.2 mmol) as described in Example 2 to yield the title compound: 1H NMR (300 MHz, DMSO-d6) δ 7.80 (s, 1 H), 5.5 (br s, 2 H), 3.73 (m, 3 H), 3.55 (m, 2 H), 3.42 (m, 2 H), 3.11 (m, 1 H), 2.89 (m, 2 H), 2.59 (m, 2 H), 1.95 (m, 3 H), 1.57 (m, 1 H); MS (ESI+) m/z 300 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH3:9].C([Li])CCC.[Cl:15][C:16]1[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][C:17]=1[C:18](Cl)=[O:19].Cl>C(OCC)C.O1CCCC1.[Cl-].[Zn+2].[Cl-].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Pd]>[Cl:15][C:16]1[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][C:17]=1[C:18]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH3:9])=[O:19]
Reactant: COc1ccccc1Br
Reactant: O=C(Cl)c1cc([N+](=O)[O-])ccc1Cl
Agent: [Pd]
Agent: Cl
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CCOCC
Product: COc1ccccc1C(=O)c1cc([N+](=O)[O-])ccc1Cl
Temperature: -70 °C
Reaction time: 1 h

Procedure:
A solution of 2-bromoanisole (27.9 g, 145 mmol) in diethyl ether is cooled to −70° C., treated with butyllithium (64.0 mL, 160 mmol), stirred at −70° C. for one hour, treated with 0.5 M zinc chloride in tetrahydrofuran solution (320 mL, 160 mmol), stirred for one hour at −70° C., warmed to about 0° C., and concentrated in vacuo to obtain a yellow-green oil. A solution of the oil in tetrahydrofuran is treated sequentially with tetrakis(triphenylphosphine)palladium(O) (5.00 g, 4.35 mmol) and a solution of 2-chloro-5-nitrobenzoyl chloride (35.0 g, 159 mmol) in tetrahydrofuran, stirred for three days, and poured into 10% hydrochloric acid. The resultant aqueous mixture is extracted with methylene chloride. The organic extracts are combined, washed sequentially with water and brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo to obtain a semi-solid. The solid is triturated with diethyl ether to give the title product as a yellow solid which is identified by NMR spectral analyses.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]([C:9]([OH:11])=[O:10])[NH2:8])[CH:2]=1.N1C=CC=C(C=O)C=1.[CH3:20][O:21][C:22]1[CH:34]=[CH:33][C:25]([CH2:26][O:27][C:28](N=[N+]=[N-])=[O:29])=[CH:24][CH:23]=1>>[CH3:20][O:21][C:22]1[CH:23]=[CH:24][C:25]([CH2:26][O:27][C:28]([NH:8][CH:7]([C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)[C:9]([OH:11])=[O:10])=[O:29])=[CH:33][CH:34]=1
Reactant: NC(C(=O)O)c1cccnc1
Reactant: COc1ccc(COC(=O)N=[N+]=[N-])cc1
Agent: O=Cc1cccnc1
Product: COc1ccc(COC(=O)NC(C(=O)O)c2cccnc2)cc1

Procedure:
DL-2-(3-Pyridyl)glycine (prepared from pyridine-3-aldehyde by the Strecker synthesis) is reacted with (p-methoxybenzyloxycarbonyl)azide according to the procedure set forth in Example 2(a) to yield DL-α-[[[(4-methoxyphenyl)methoxy]carbonyl]amino]-3-pyridineacetic acid; m.p. 155°-156° (dec.).
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:17]=[C:16]2[C:7]([NH:8][C:9]3[C:14]([S:15]2)=[CH:13][CH:12]=[CH:11][CH:10]=3)=[C:6]2[CH:18]=[CH:19][CH:20]=[CH:21][C:5]=12.[CH3:22][O:23][CH2:24]Cl.C(OCC)C>C1COCC1.O>[CH3:22][O:23][CH2:24][O:3][C:4]1[CH:17]=[C:16]2[C:7]([NH:8][C:9]3[C:14]([S:15]2)=[CH:13][CH:12]=[CH:11][CH:10]=3)=[C:6]2[CH:18]=[CH:19][CH:20]=[CH:21][C:5]=12
Reactant: COCCl
Reactant: Oc1cc2c(c3ccccc13)Nc1ccccc1S2
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOCC
Product: COCOc1cc2c(c3ccccc13)Nc1ccccc1S2
Reaction time: 0.25 h

Procedure:
Sodium hydride (75 mg) was added to a solution of 5-hydroxy-12H-benzo[a]phenothiazine (1) (500 mg) and chloromethyl methyl ether (154 mg) in THF (10 ml) and the reaction mixture was stirred for 15 minutes. Diethyl ether (60 ml) was added to the reaction mixture followed by water (60 ml). The ether layer was decanted, dried and evaporated to dryness. The resulting residue was chromatographed on silica gel (CH2Cl2 /hexane (7:3)) to afford the title compound, m.p. 103° C. Anal. C18H15NO2S; Calcd.: C, 69.87; H, 4.89; N, 4.53; S, 10.36. Found: C, 69.75; H, 5.01; N, 4.41; S, 10.53.