Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:8]([N:9]=[C:10]3[C:15]=1[CH:14](O)[CH2:13][CH2:12][CH2:11]3)=[CH:7][CH:6]=[CH:5][CH:4]=2.[NH:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1.C(=O)C1C=CC=CC=1>C1(C)C=CC=CC=1>[N:17]1([CH:14]2[C:15]3[C:10](=[N:9][C:8]4[C:3]([C:2]=3[NH2:1])=[CH:4][CH:5]=[CH:6][CH:7]=4)[CH2:11][CH2:12][CH2:13]2)[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1
Reactant: Nc1c2c(nc3ccccc13)CCCC2O
Reactant: C1COCCN1
Solvent: Cc1ccccc1
Solvent: O=Cc1ccccc1
Product: Nc1c2c(nc3ccccc13)CCCC2N1CCOCC1
Reaction time: 8 h

Procedure:
9-Amino-1,2,3,4-tetrahydroacridin-1-ol (15.0 g) was refluxed in 1000 ml of toluene that contained 12.18 g of morpholine and 9.285 g of benzaldehyde that had been freshly washed in K2CO3. The reaction mixture wasrefluxed overnight and allowed to cool. It was then filtered off and the crude product was purified by flash chromatography (20% PrOH/EtOAc) to give 2.20 g of analytically pure product after recrystallization from benzene/pentane, m.p. 215°-217°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:13]([O-])=O)=[C:6]([NH:8][CH2:9][C:10]([OH:12])=[O:11])[CH:7]=1>C(O)C.[Ni]>[NH2:13][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][C:6]=1[NH:8][CH2:9][C:10]([OH:12])=[O:11]
Reactant: O=C(O)CNc1cc(Cl)ccc1[N+](=O)[O-]
Agent: [Ni]
Solvent: CCO
Product: Nc1ccc(Cl)cc1NCC(=O)O
Yield: 91.9 %

Procedure:
19.5 g (84.6 mmol) of N-(5-chloro-2-nitrophenyl)glycine were dissolved in 250 ml of ethanol and, after addition of 5 g of Raney nickel, hydrogenated under 1 bar at 45°-50° C. The mixture was then filtered, and the filtrate was evaporated under reduced pressure to yield 15.6 g (93%) of the product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([O:12][C:13]1[CH:24]=[CH:23][C:16]([O:17][CH:18]([CH3:22])[C:19](Cl)=[O:20])=[CH:15][CH:14]=1)[CH:6]=[N:5]2.Cl.[F:26][C:27]([F:38])([O:30][C:31]1[CH:36]=[CH:35][C:34]([NH2:37])=[CH:33][CH:32]=1)[CH2:28][F:29].C(N(CC)CC)C.[OH-].[Na+]>C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([O:12][C:13]1[CH:24]=[CH:23][C:16]([O:17][CH:18]([CH3:22])[C:19]([NH:37][C:34]3[CH:35]=[CH:36][C:31]([O:30][C:27]([F:26])([F:38])[CH2:28][F:29])=[CH:32][CH:33]=3)=[O:20])=[CH:15][CH:14]=1)[CH:6]=[N:5]2
Reactant: Nc1ccc(OC(F)(F)CF)cc1
Reactant: CC(Oc1ccc(Oc2cnc3cc(Cl)ccc3n2)cc1)C(=O)Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(Oc1ccc(Oc2cnc3cc(Cl)ccc3n2)cc1)C(=O)Nc1ccc(OC(F)(F)CF)cc1
Yield: 20 %

Procedure:
A solution of 5.8 mmol of 2-(4-((6-chloro-2-quinoxalinyl)oxy)phenoxy)propanoyl chloride (previously prepared from 2.0 g, 5.8 mmol, of the corresponding acid) in 15 ml of acetonitrile was added to a mixture of 1.32 g (5.8 mmol) of 4-(1,1,2-trifluoroethoxy)benzeneamine hydrochloride (contaminated with approximately 20 percent of 4-(1,2-difluoroethenyloxy)benzeneamine), 1.47 g (14.5 mmol) of triethylamine and 15 ml of acetonitrile. The mixture was stirred at reflux for 2.5 hours, poured over ice and made basic with dilute aqueous sodium hydroxide. The resulting precipitate was filtered and dried (2.9 g, 97 percent of theoretical) and then recrystallized from methylcyclohexane. This gave the desired product (contaminated with approximately 20 percent of 2-(4-((6-chloro-2-quinoxalinyl)oxy)phenoxy)-N-(4-(1,2-difluoroethenyloxy)phenyl)propanamide) as a solid, m.p. 137°-140° C. (Compound 40)
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][C@H:6]1[CH2:11][CH2:10][C@H:9]([N:12]([CH3:26])[S:13]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=2)(=[O:15])=[O:14])[CH2:8][CH2:7]1.CC(O)[C:29]#[N:30].N12CCCN=C1CCCCC2>C(#N)C>[C:29]([CH2:2][CH2:3][CH2:4][O:5][C@H:6]1[CH2:11][CH2:10][C@H:9]([N:12]([CH3:26])[S:13]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=2)(=[O:15])=[O:14])[CH2:8][CH2:7]1)#[N:30]
Reactant: CC(O)C#N
Reactant: CN([C@H]1CC[C@H](OCCCBr)CC1)S(=O)(=O)c1ccc(C(F)(F)F)cc1
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: CN([C@H]1CC[C@H](OCCCC#N)CC1)S(=O)(=O)c1ccc(C(F)(F)F)cc1
Temperature: 25 °C

Procedure:
To 1.0 g (2.18 mmol) trans-N-[4-(3-Bromo-propoxy)-cyclohexyl]-N-methyl-4-trifluoromethyl-benzenesulfonamide in 10 ml acetonitrile was added 0.29 ml (3.1 mmol) acetocyanhydrine in 5 ml acetonitrile and 0.37 ml (2.5 mmol) 1,8-Diazabicyclo-(5,4,0)-undec-7-ene in 5 ml acetonitrile. The solution was stirred at RT over night. An additonal amount of acetocyanhydrine and 1,8-Diazabicyclo-(5,4,0)-undec-7-ene were added and the solution stirred at 50° C. for 6 h. The mixture was concentrated and dissolved in water/ether. The organic phase was washed with brine, dried over Na2SO4 and was evaporated to give 366 mg (41%) trans-N-[4-(3-Cyano-propoxy)-cyclohexyl]-N-methyl-4-trifluoromethyl-benzenesulfonamide as light yellow oil, MS: 404 (M).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@:12](C(C)(C)C)([CH2:13][NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=2)[CH2:11][O:10][C:9]1([CH3:27])[CH3:26])=[O:7])([CH3:4])([CH3:3])[CH3:2].CO[CH:30](OC)[C:31]1[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=1>>[C:1]([O:5][C:6]([N:8]1[C@@H:12]([CH2:13][N:14]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=2)[CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=2)[CH2:11][O:10][C:9]1([CH3:27])[CH3:26])=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1C(C)(C)OC[C@@]1(CNc1cccc(Cl)c1)C(C)(C)C
Reactant: COc1ccc(C(OC)OC)cc1
Product: COc1ccc(CN(C[C@H]2COC(C)(C)N2C(=O)OC(C)(C)C)c2cccc(Cl)c2)cc1

Procedure:
In analogy to example 20.a tert-butyl (S)-4-[(3-chloro-phenylamino)-methyl]-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester was reacted with p-anisaldehyde dimethyl acetal to give (S)-4-{[(3-chloro-phenyl)-(4-methoxy-benzyl)-amino]-methyl}-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester. White solid. MS (ISP): 463.1 ([{37Cl}M+H]+), 461.1 ([{35Cl}M+H]+)
Reaction SMILES: [NH2:1][C@H:2]([CH2:7][C:8]1[CH:9]=[C:10]2[C:14](=[C:15]([CH3:17])[CH:16]=1)[NH:13][N:12]=[CH:11]2)[C:3]([O:5][CH3:6])=[O:4].C(N(C(C)C)CC)(C)C.C1C(=O)N(OC(ON2C(=O)CCC2=O)=O)[C:29](=[O:30])C1.[NH:45]1[CH2:50][CH2:49][CH:48]([N:51]2[CH2:60][C:59]3[C:54](=[CH:55][CH:56]=[CH:57][CH:58]=3)[NH:53][C:52]2=[O:61])[CH2:47][CH2:46]1>CN(C)C=O>[CH3:6][O:5][C:3](=[O:4])[C@H:2]([NH:1][C:29]([N:45]1[CH2:46][CH2:47][CH:48]([N:51]2[CH2:60][C:59]3[C:54](=[CH:55][CH:56]=[CH:57][CH:58]=3)[NH:53][C:52]2=[O:61])[CH2:49][CH2:50]1)=[O:30])[CH2:7][C:8]1[CH:9]=[C:10]2[C:14](=[C:15]([CH3:17])[CH:16]=1)[NH:13][N:12]=[CH:11]2
Reactant: COC(=O)[C@H](N)Cc1cc(C)c2[nH]ncc2c1
Reactant: O=C1Nc2ccccc2CN1C1CCNCC1
Reactant: O=C(ON1C(=O)CCC1=O)ON1C(=O)CCC1=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@@H](Cc1cc(C)c2[nH]ncc2c1)NC(=O)N1CCC(N2Cc3ccccc3NC2=O)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of (R)-methyl 2-amino-3-(7-methyl-1H-indazol-5-yl)propanoate (1.07 g, 4 mmol) and diisopropylethylamine (2.09 mL, 12 mmol) in dimethylformamide (15 mL) at room temperature was added N,N-disuccinimidyl carbonate (0.52 g, 4 mmol). The resulting mixture was stirred at room temperature for 30 min and treated with 3-(piperidin-4-yl)-3,4-dihydroquinazolin-2(1H)-one (0.92 g, 4 mmol) in portions. The reaction was stirred for 24 h. The mixture was concentrated, and the residue was purified by flash chromatography (silica gel, 30:1 dichloromethane/methanol 60:1, 30:1) to give 2 g (100%). Mass spec.: 491.38 (MH)+, HPLC tR=2.25.
Reaction SMILES: [CH3:1][N:2]([CH3:39])[C:3](=[O:38])[NH:4][C:5]1[CH:6]=[C:7]([C:11]2[N:20]=[C:19]([NH:21][C:22]3[CH:23]=[C:24]4[C:28](=[CH:29][CH:30]=3)[N:27](C(OC(C)(C)C)=O)[N:26]=[CH:25]4)[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:12]=2)[CH:8]=[CH:9][CH:10]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:27]1[C:28]2[C:24](=[CH:23][C:22]([NH:21][C:19]3[C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[N:12]=[C:11]([C:7]4[CH:6]=[C:5]([NH:4][C:3](=[O:38])[N:2]([CH3:1])[CH3:39])[CH:10]=[CH:9][CH:8]=4)[N:20]=3)=[CH:30][CH:29]=2)[CH:25]=[N:26]1
Reactant: CN(C)C(=O)Nc1cccc(-c2nc(Nc3ccc4c(cnn4C(=O)OC(C)(C)C)c3)c3ccccc3n2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN(C)C(=O)Nc1cccc(-c2nc(Nc3ccc4[nH]ncc4c3)c3ccccc3n2)c1

Procedure:
To tert-butyl 5-(2-(3-(3,3-dimethylureido)phenyl)quinazolin-4-ylamino)-1H-indazole-1-carboxylate (50 mg, 0.10 mmol) was added a solution of 1:1 TFA:CH2Cl2 (3 mL) and stirred at RT for 2 h. The reaction mixture was concentrated in vacuo and left under high vacuum for several hours. The crude product was triturated with ethyl ether and the yellow solid was purified by prep HPLC (method 25-50—70 mins) to afford 3-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenyl)-1,1-dimethylurea. (36 mg, 86%)
Reaction SMILES: [S:1](Cl)([CH3:4])(=[O:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].[CH:12]([NH:14][CH:15]1[C:39](=[O:40])[N:17]2[C:18]([C:23]([O:25][CH:26]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[O:24])=[C:19]([OH:22])[CH2:20][S:21][C@H:16]12)=[O:13]>CN(C)C=O>[CH:12]([NH:14][CH:15]1[C:39](=[O:40])[N:17]2[C:18]([C:23]([O:25][CH:26]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[O:24])=[C:19]([O:22][S:1]([CH3:4])(=[O:3])=[O:2])[CH2:20][S:21][C@H:16]12)=[O:13]
Reactant: O=CNC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(O)CS[C@H]12
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CS(=O)(=O)OC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC=O)[C@H]2SC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Mesyl chloride (0.66 ml) and potassium carbonate (1.38 g) were added to a solution of benzhydryl 7-formamido-3-hydroxy-3-cephem-4-carboxylate (2.05 g) in N,N-dimethylformamide (6 ml) at -30° C. The mixture was stirred at -30°°C. for 30 minutes. Mesyl chloride (0.4 ml) was added to the mixture. The reaction mixture was stirred at -30°C for 20 minutes, poured into ice-water and extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate and filtered, and the filtrate was evaporated in vacuo. The residue was dissolved in a small amount of ethyl acetate and the mixture was subjected to column chromatography on silica gel and eluted with a mixture of benzene and ethyl acetate (1:1). The eluent was evaporated in vacuo. The residue was triturated with diisopropyl ether to give benzhydryl 7-formamido-3-mesyloxy-3-cephem-4-carboxylate (0.85 g).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][O:15][CH2:16][CH:17]([NH2:23])[CH:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:24][C:25]1[C:33]2[C:28](=[CH:29][C:30]([C:34](O)=[O:35])=[CH:31][CH:32]=2)[NH:27][CH:26]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([CH2:14][O:15][CH2:16][CH:17]([NH:23][C:34]([C:30]2[CH:29]=[C:28]3[C:33]([C:25]([Cl:24])=[CH:26][NH:27]3)=[CH:32][CH:31]=2)=[O:35])[CH:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(O)c1ccc2c(Cl)c[nH]c2c1
Reactant: CC(C)(C)OC(=O)N1CCC(COCC(N)C2CCCC2)CC1
Product: CC(C)(C)OC(=O)N1CCC(COCC(NC(=O)c2ccc3c(Cl)c[nH]c3c2)C2CCCC2)CC1

Procedure:
Using coupling method A, 4-(2-amino-2-cyclopentyl-ethoxymethyl)piperidine-1-carboxylic acid tert-butyl ester (460 mg, 1.4 mmol) and 3-chloroindole-6-carboxylic acid (275 mg, 1.4 mmol) afforded, after purification (SiO2: 40% EtOAc in hexane), 211 mg (30%) of the title compound.
Reaction SMILES: [C:1]1([NH:7][C:8]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:16]1[C:20]2[CH:21]=[CH:22][C:23]([CH:25]=O)=[CH:24][C:19]=2[O:18][CH2:17]1>>[C:1]1([NH:7][C:8]([N:10]2[CH2:15][CH2:14][N:13]([CH2:25][C:23]3[CH:22]=[CH:21][C:20]4[O:16][CH2:17][O:18][C:19]=4[CH:24]=3)[CH2:12][CH2:11]2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Nc1ccccc1)N1CCNCC1
Reactant: O=Cc1ccc2c(c1)OCO2
Product: O=C(Nc1ccccc1)N1CCN(Cc2ccc3c(c2)OCO3)CC1

Procedure:
The title compound was prepared from piperazine-1-carboxylic acid phenylamide and benzo[1,3]dioxole-5-carbaldehyde. 1H NMR (400 MHz, CDCl3): 7.36-7.24 (m, 4H), 7.05-6.99 (m, 1H), 6.86 (br s, 1H), 6.77-6.72 (m, 2H), 6.43 (br s, 1H), 5.95 (s, 2H), 3.50-3.46 (m, 4H), 3.43 (s, 2H), 2.46-2.42 (m, 4H).
Reaction SMILES: [N+]([C:4]1[CH:5]=[C:6]([C:12]#[N:13])[C:7](=[CH:10][CH:11]=1)[C:8]#[N:9])([O-])=O.[CH3:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[C:16]=1[OH:22].C([O-])([O-])=O.[K+].[K+].CN(C=O)C>O>[CH3:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[C:16]=1[O:22][C:4]1[CH:5]=[C:6]([C:12]#[N:13])[C:7](=[CH:10][CH:11]=1)[C:8]#[N:9]
Reactant: Cc1cccc(C)c1O
Reactant: N#Cc1ccc([N+](=O)[O-])cc1C#N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cccc(C)c1Oc1ccc(C#N)c(C#N)c1
Temperature: 60 °C
Yield: 87 %

Procedure:
A mixture of 4-nitro-phthalonitrile (1 eq), 2,6-dimethylphenol (1.2 eq), K2CO3 (2 eq), and DMF (1 mL/mmol 4-nitro-phthalonitrile) was heated under nitrogen at 60° C. for 3 h with stirring. After cooling to ambient temperature the mixture was poured into water (6 mL/mL DMF) with stirring. The mixture was extracted twice with EtOAc. The combined organic phases were dried over MgSO4 and concentrated in vacuo. The residue was recrystallized from EtOH to give the title compound as a tan solid (yield: 87%); 1H NMR (CDCl3, 200 MHz): δ=7.70 (d, 1H), 7.05 to 7.16 (m, 5H), 2.08 (s, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[NH:12][C:11]([CH3:14])([CH3:13])[CH2:10][O:9]2)=[CH:4][CH:3]=1.[Li]CCCC.CN([CH:23]=[O:24])C.O>C(OCC)C.CCCCCC>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][CH2:10][C:11]([CH3:14])([CH3:13])[N:12]=2)=[C:4]([CH:3]=1)[CH:23]=[O:24]
Reactant: CN(C)C=O
Reactant: CC1(C)COC(c2ccc(Cl)cc2)N1
Agent: [Li]CCCC
Solvent: O
Solvent: CCOCC
Solvent: CCCCCC
Product: CC1(C)COC(c2ccc(Cl)cc2C=O)=N1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a cold solution of 2-(4-chloro-phenyl)-4,4-dimethyl-oxazolidine (17.2 g, 82 mmol) in ethyl ether (100 mL) and hexane (100 mL) at −30° C. was added n-BuLi (1.6 M in hexane, 67 mL, 107 mmol). The mixture was allowed to warm to room temperature and stirred for 3 h, then cooled to −20° C. To the mixture was added DMF (12.6 mL), and the reaction mixture was allowed to warm to room temperature and stirred overnight. The mixture was poured into water (200 mL), extracted with ethyl ether for 3 times. The organic layers were combined, washed with water, dried over anhydrous Na2SO4, concentrated in vacuo to give the title product (13 g).
Reaction SMILES: C(Cl)(=O)C.[CH3:5][O:6][CH2:7][C@@H:8]1[CH2:13][C:12]([C:14]([O:16][C:17](C)(C)C)=[O:15])=[CH:11][CH2:10][N:9]1[C:21]([O:23][CH2:24][CH:25]=[CH2:26])=[O:22]>CO>[CH3:5][O:6][CH2:7][C@@H:8]1[CH2:13][C:12]([C:14]([O:16][CH3:17])=[O:15])=[CH:11][CH2:10][N:9]1[C:21]([O:23][CH2:24][CH:25]=[CH2:26])=[O:22]
Reactant: C=CCOC(=O)N1CC=C(C(=O)OC(C)(C)C)C[C@H]1COC
Solvent: CO
Solvent: CC(=O)Cl
Product: C=CCOC(=O)N1CC=C(C(=O)OC)C[C@H]1COC
Reaction time: 0.5 h
Yield: 92.8 %

Procedure:
To methanol (19 ml, 470 mmol) was added at 0° C. acetyl chloride (12 ml, 169 mmol) and the mixture was stirred at the same temperature for 30 minutes. This solution was added to a solution of 1-allyl 4-tert-butyl (2S)-2-(methoxymethyl)-3,6-dihydro-1,4(2 H)-pyridinedicarboxylate (744 mg, 2.4 mmol) in methanol (3 ml) and the mixture was stirred at room temperature for 2 hours. The solvent was removed and the residue was dissolved in ethyl acetate. The solution was washed with a saturated sodium hydrogen carbonate solution and a saturated aqueous sodium chloride solution and dried over magnesium sulfate. The solvent was removed in vacuo to give 1-allyl 4-methyl (2S)-2-(methoxymethyl)-3,6-dihydro-1,4(2 H)-pyridinedicarboxylate (600 mg, 93%).
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@H:9]1[C:16]([OH:18])=O)=[O:7])(C)(C)C.[CH3:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[C:26]1[CH:31]=[CH:30][C:29](C(O)=O)=[C:28]([CH3:35])[CH:27]=1.[NH2:36][CH2:37][CH:38]([OH:49])[CH2:39][O:40][C:41]1[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[CH:43][CH:42]=1>>[CH3:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[C:26]1[CH:31]=[CH:30][C:29]([C:6]([N:8]2[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@H:9]2[C:16]([NH:36][CH2:37][CH:38]([OH:49])[CH2:39][O:40][C:41]2[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[CH:43][CH:42]=2)=[O:18])=[O:7])=[C:28]([CH3:35])[CH:27]=1
Reactant: Cc1cc(-c2ccccc2C)ccc1C(=O)O
Reactant: CON=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Reactant: COc1ccc(OCC(O)CN)cc1
Product: CON=C1C[C@@H](C(=O)NCC(O)COc2ccc(OC)cc2)N(C(=O)c2ccc(-c3ccccc3C)cc2C)C1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylic acid, 2′,3-dimethyl[1,1′-biphenyl]-4-carboxylic acid, and (2RS)-1-amino-3-(4methoxyphenoxy)-2-propanol, the title compound was obtained in 77% purity by HPLC. MS(ESI+): m/z=546.
Reaction SMILES: [C:1]([O:9][CH2:10]C)(=[O:8])[CH2:2][C:3]([O:5][CH2:6]C)=[O:4].[CH2:12]([C:17]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)([CH2:21][CH2:22][CH:23]([CH3:25])[CH3:24])[C:18](Cl)=[O:19])[CH2:13][CH:14]([CH3:16])[CH3:15].C1(C(CCC)(CCC)C(Cl)=O)C=CC=CC=1>>[CH2:12]([C:17]([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)([CH2:21][CH2:22][CH:23]([CH3:24])[CH3:25])[C:18]([CH:2]([C:1]([O:9][CH3:10])=[O:8])[C:3]([O:5][CH3:6])=[O:4])=[O:19])[CH2:13][CH:14]([CH3:16])[CH3:15]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: CC(C)CCC(CCC(C)C)(C(=O)Cl)c1ccccc1
Agent: CCCC(CCC)(C(=O)Cl)c1ccccc1
Product: COC(=O)C(C(=O)OC)C(=O)C(CCC(C)C)(CCC(C)C)c1ccccc1

Procedure:
The title compound was prepared following the procedure of Example 1E, substituting dimethyl malonate for diethyl malonate, and substituting the product of Example 6D for the product of Example 1D. 1H NMR (300 MHz, CDCl3): δ 7.32 (m, 5 H), 4.54 (s, 1 H), 3.56 (s, 6 H), 2.00 (m, 4 H), 1.49 (m, 2 H), 0.87 (m, 16 H).
Reaction SMILES: [CH2:1]([CH:3]1[CH2:8][CH2:7][CH2:6][C:5](=[CH:9]O)[C:4]1=[O:11])[CH3:2].[CH2:12]([SH:16])[CH2:13][CH2:14][CH3:15].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1C=CC=CC=1>[CH2:12]([S:16][CH:9]=[C:5]1[CH2:6][CH2:7][CH2:8][CH:3]([CH2:1][CH3:2])[C:4]1=[O:11])[CH2:13][CH2:14][CH3:15]
Reactant: CCC1CCCC(=CO)C1=O
Reactant: CCCCS
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: CCCCSC=C1CCCC(CC)C1=O

Procedure:
A solution of 2-ethyl-6-(hydroxymethylene)cyclohexanone (43.0 g, 0.277 mole), described in Example 2, butylmercaptan (28.6 g, 0.318 mole) and p-toluenesulfonic acid (50 mg) in dry benzene (200 ml) is heated at reflux under nitrogen for 4 hr using a Dean-Stark water separator. The reaction mixture is cooled and washed with saturated aqueous sodium bicarbonate (50 ml), water and brine, then dried (MgSO4). After removal of the solvent at reduced pressure the residue is distilled to give the title compound, bp 110° - 115° C/1.5 mm, nmr (CDCl3) δ 0.92 (6H), 7.5 (m,1H).
Reaction SMILES: [OH-].[Na+].[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4]1.[OH-].C([N+](CCCC)(CCCC)CCCC)CCC.[C:30]([N:33]1[CH2:42][CH2:41][C:40]2[C:35](=[CH:36][C:37]([S:43](Cl)(=[O:45])=[O:44])=[CH:38][CH:39]=2)[CH2:34]1)(=[O:32])[CH3:31]>O1CCCC1>[N:3]1([S:43]([C:37]2[CH:36]=[C:35]3[C:40]([CH2:41][CH2:42][N:33]([C:30](=[O:32])[CH3:31])[CH2:34]3)=[CH:39][CH:38]=2)(=[O:44])=[O:45])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4]1
Reactant: c1ccc2[nH]ccc2c1
Reactant: CC(=O)N1CCc2ccc(S(=O)(=O)Cl)cc2C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(=O)N1CCc2ccc(S(=O)(=O)n3ccc4ccccc43)cc2C1
Reaction time: 0.08 h
Yield: 72 %

Procedure:
A 50% solution of sodium hydroxide (100 ml) was added to a vigorously stirred solution of indole (5.8 g, 50 mmol) and tetrabutylammonium hydroxide (40% by weight solution, 2 ml, 3.1 mmol) in tetrahydrofuran (100 ml). After 5 minutes, a solution of 2-acetyl-1,2,3,4-tetrahydroisoquinoline-7-sulfonyl chloride (R. G. Pendleton et al., J. Pharmacol. Exp. Ther., 1979, 208, 24; U.S. Pat. No. 3,725,388 (1973)) (13.7 g, 50 mmol) in tetrahydrofuran (50 ml) was added over 10 minutes and the resulting mixture was vigorously stirred for a further 3 h. The mixture was then extracted with ethyl acetate (250 ml) and the extract dried (MgSO4), concentrated in vacuo and the residue purified by column chromatography over silica gel eluting with a dichloromethane/methanol gradient to give the title compound (D1) (12.8 g, 72%), NMR (CDCl3; rotamers observed)/ppm 2.12, 2.14 (3H, 2×s), 2.77-2.88 (2H, m), 3.60, 3.74 (3H, 2×t J=7 Hz), 4.59, 4.68 (2H, 2×s), 6.65-6.67 (1H, m), 7.16-7.34 (3H, m), 7.50-7.69 (4H, m), 7.94-7.99 (1H, m); MS: m/z (MH+) 355.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([C:12]([F:15])([F:14])[F:13])=[N:7]2.CC1(C)COB([C:23]2[CH:24]=[CH:25][C:26]([F:38])=[C:27]([C:29]3[C:30]([C:36]#[N:37])=[CH:31][C:32]([F:35])=[CH:33][CH:34]=3)[CH:28]=2)OC1>>[F:35][C:32]1[CH:31]=[C:30]([C:36]#[N:37])[C:29]([C:27]2[CH:28]=[C:23]([C:2]3[C:3]4[C:8](=[N:7][C:6]([C:12]([F:15])([F:14])[F:13])=[CH:5][CH:4]=4)[N:9]=[CH:10][CH:11]=3)[CH:24]=[CH:25][C:26]=2[F:38])=[CH:34][CH:33]=1
Reactant: CC1(C)COB(c2ccc(F)c(-c3ccc(F)cc3C#N)c2)OC1
Reactant: FC(F)(F)c1ccc2c(Cl)ccnc2n1
Product: N#Cc1cc(F)ccc1-c1cc(-c2ccnc3nc(C(F)(F)F)ccc23)ccc1F
Yield: 14.4 %

Procedure:
5-Chloro-2-trifluoromethyl[1,8]naphthyridine (50 mg, 0.22 mmol) was coupled to 5′-(5,5-dimethyl-[1,3,2]dioxaborinan-2-yl)-4,2′-difluorobiphenyl-2-carbonitrile (77 mg, 0.24 mmol) as described in Example 7 part g), affording 4,2′-difluoro-5′-(7-trifluoromethyl-[1,8]naphthyridin-4-yl)biphenyl-2-carbonitrile (13 mg, 14%). δH (400 MHz, CDCl3) 7.41-7.49 (2H, m), 7.54-7.63 (5H, m), 7.88 (1H, d, J 9.0), 8.68 (1H, d, J 8.2), 9.29 (1H, d, J 4.3). m/z (ES+) 412 [MH]+.
Reaction SMILES: [O:1]=[C:2]1[NH:6][C@@H:5]([C:7]([OH:9])=O)[CH2:4][O:3]1.[N+]([O-])(O)=O.[N+:14]([O:17][CH2:18][CH2:19][NH2:20])([O-:16])=[O:15]>>[N+:14]([O:17][CH2:18][CH2:19][NH:20][C:7]([C@H:5]1[CH2:4][O:3][C:2](=[O:1])[NH:6]1)=[O:9])([O-:16])=[O:15]
Reactant: O=C1N[C@@H](C(=O)O)CO1
Reactant: NCCO[N+](=O)[O-]
Solvent: O=[N+]([O-])O
Product: O=C1N[C@@H](C(=O)NCCO[N+](=O)[O-])CO1
Yield: 41.6 %

Procedure:
Following a procedure similar to that described in Example 1, but using 0.23 g of (4R)-2-oxooxazolidine-4-carboxylic acid and 0.36 g of N-(2-nitrooxyethyl)amine nitrate, 0.16 g of the title compound was obtained as colorless needles, melting at 110°-112° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][OH:8])=[CH:3][CH:2]=1.[F:9][C:10]([F:16])([F:15])[S:11]([OH:14])(=[O:13])=[O:12].[CH2:17]1[S:19][CH2:18]1>C(Cl)Cl.O>[F:9][C:10]([F:16])([F:15])[S:11]([O-:14])(=[O:13])=[O:12].[OH:8][CH2:7][C:4]1[CH:5]=[CH:6][N+:1]([CH2:17][CH2:18][SH:19])=[CH:2][CH:3]=1
Reactant: C1CS1
Reactant: O=S(=O)(O)C(F)(F)F
Reactant: OCc1ccncc1
Solvent: ClCCl
Solvent: O
Product: O=S(=O)([O-])C(F)(F)F
Product: OCc1cc[n+](CCS)cc1
Temperature: 60 °C

Procedure:
To a solution of 4-pyridinemethanol (1.635 g, 0.015 mol) in 10 mL of CH2Cl2, at 0° C. under N2, was added dropwise trifluoromethanesulfonic acid (1.327 mL, 0.015 mol). A yellow-brown oil rapidly separated out. An additional equivalent of 4-pyridine-methanol (1.635 g, 0.015 mol) was added to this mixture and the solvent was removed under reduced pressure to give an oil. To this oil was added ethylene sulfide (0.891 mL, 0.015 mol) and the resulting homogeneous mixture was heated (oil bath) at about 60° C. for 3 h. The reaction mixture was then taken up in 15 mL of H2O and the aqueous solution was washed with CH2Cl2 (5×5 mL). After removing residual organic solvent in vacuo the aqueous solution was applied to a C18 reverse-phase column. Elution with H2O and subsequent evaporation of the relevant fractions afforded an oilwhich was further dried in vacuo over P2O5 to give the product (4.64 g, 97% as a colourless oil. ir (film) νmax : 3455 (s, OH), 2565, (w, SH) cm-1 ; 1Hnmr (d6 -acetone) δ: 9.07, 8.18 (ABq, J=6.8 Hz, 4H, aromatic), 5.03 (s, 2H, CH2OH), 4.96 (t, J=6.5 Hz, 2H, N--CH2), 4.09 (br s, 1H, --OH), 3.5-3.1 (m, 2H, S--CH2), 2.25 (brs, 1H, --SH).