Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:3]=1[O:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:15]=[C:14]([C:16]#[N:17])[O:13][N:12]=2)[CH2:7][CH2:6]1.Cl.[NH+]1C=CC=CC=1.[N-:30]=[N+:31]=[N-:32].[Na+].Cl>CN1C(=O)CCC1.O>[Br:1][C:2]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:3]=1[O:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:15]=[C:14]([C:16]3[NH:32][N:31]=[N:30][N:17]=3)[O:13][N:12]=2)[CH2:7][CH2:6]1
Reactant: N#Cc1cc(N2CCC(Oc3cc(F)ccc3Br)CC2)no1
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [Na+]
Agent: c1cc[nH+]cc1
Solvent: CN1CCCC1=O
Solvent: O
Product: Fc1ccc(Br)c(OC2CCN(c3cc(-c4nnn[nH]4)on3)CC2)c1
Temperature: 130 °C

Procedure:
A mixture of 3-[4-(2-bromo-5-fluorophenoxy)piperidin-1-yl]isoxazole-5-carbonitrile (1.4 g, 3.82 mmol), pyridinium hydrochloride (0.9 g, 7.79 mmol) and sodium azide (1.3 g, 20.00 mmol) in NMP (12 mL) was stirred and heated at 130° C. bath for 2 h. After cooling, the mixture was diluted with water and acidified with 1N HCl (some precipitate appeared). The whole mixture was then extracted with EtOAc. The EtOAc extract was washed with water (3×), dried (Na2SO4) and concentrated. The residue was triturated with diethyl ether to give the title compound as a light brown powder.
Reaction SMILES: [CH2:1]([NH:3][C:4](=[O:43])[NH:5][C:6]1[N:11]=[CH:10][C:9]([C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[N:18]([CH2:22][C@H:23]2[CH2:27][CH2:26][NH:25][CH2:24]2)[CH:17]=[C:16]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[C:15]3=[O:33])=[C:8]([C:34]2[S:35][CH:36]=[C:37]([C:39]([F:42])([F:41])[F:40])[N:38]=2)[CH:7]=1)[CH3:2].Cl.O.[N:46]1([CH2:52][CH:53]=O)[CH2:51][CH2:50][O:49][CH2:48][CH2:47]1.C([BH3-])#N>CO>[CH2:1]([NH:3][C:4](=[O:43])[NH:5][C:6]1[N:11]=[CH:10][C:9]([C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[N:18]([CH2:22][C@H:23]2[CH2:27][CH2:26][N:25]([CH2:53][CH2:52][N:46]4[CH2:51][CH2:50][O:49][CH2:48][CH2:47]4)[CH2:24]2)[CH:17]=[C:16]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[C:15]3=[O:33])=[C:8]([C:34]2[S:35][CH:36]=[C:37]([C:39]([F:42])([F:41])[F:40])[N:38]=2)[CH:7]=1)[CH3:2]
Reactant: O=CCN1CCOCC1
Reactant: CCNC(=O)Nc1cc(-c2nc(C(F)(F)F)cs2)c(-c2ccc3c(c2)c(=O)c(C(=O)OCC)cn3C[C@H]2CCNC2)cn1
Agent: Cl
Agent: [BH3-]C#N
Solvent: O
Solvent: CO
Product: CCNC(=O)Nc1cc(-c2nc(C(F)(F)F)cs2)c(-c2ccc3c(c2)c(=O)c(C(=O)OCC)cn3C[C@H]2CCN(CCN3CCOCC3)C2)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 40.2 %

Procedure:
A vial was charged with (S)-ethyl 6-(6-(3-ethylureido)-4-(4-(trifluoromethyl)thiazol-2-yl)pyridin-3-yl)-4-oxo-1-(pyrrolidin-3-ylmethyl)-1,4-dihydroquinoline-3-carboxylate (Example 234, 800 mg, 1.3 mmol) and morpholin-4-yl-acetaldehyde monohydrate hydrochloride (270 mg, 1.47 mmol) in methanol (10 mL). MP-cyanoborohydride (850 mg, 2.0 mmol) beads were added and the resulting mixture was allowed to stir at room temperature overnight. The mixture was filtered and the beads were washed with more methanol. The filtrate was concentrated and purified by Analogix SF15-24 g in DCM/methanol system to give a light yellow solid (380 mg, 45.8%).
Reaction SMILES: [Na][Na].[C:3]([NH:5][C:6](=[O:16])[CH2:7][CH2:8][CH2:9][CH2:10][C:11]([NH:13][C:14]#[N:15])=[O:12])#[N:4].[CH2:17](I)[CH2:18][CH2:19][CH3:20]>CN1CCCC1=O>[C:14]([N:13]([CH2:6][CH2:7][CH2:8][CH3:9])[C:11](=[O:12])[CH2:10][CH2:9][CH2:8][CH2:7][C:6]([N:5]([CH2:17][CH2:18][CH2:19][CH3:20])[C:3]#[N:4])=[O:16])#[N:15]
Reactant: CCCCI
Reactant: N#CNC(=O)CCCCC(=O)NC#N
Agent: [Na][Na]
Solvent: CN1CCCC1=O
Product: CCCCN(C#N)C(=O)CCCCC(=O)N(C#N)CCCC

Procedure:
Analogously to Example 3, 23.8 g (0.1 mol) of the disodium salt of adipic acid bis-(N-cyanamide) and 55.2 g (0.2 mol+50% excess) of n-butyl iodide are reacted in 50 ml of N-methylpyrrolidone at 92°-100° C. for 5 hours and 15 minutes and the mixture is worked up.
Reaction SMILES: [Si:1]([O:8][CH:9]([C:19]([F:22])([F:21])[F:20])[CH:10]([NH:14][C:15](=[O:18])[CH2:16]Cl)[CH:11]([CH3:13])[CH3:12])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Na+].[I-:24].S([O-])([O-])(=O)=S.[Na+].[Na+]>CC(C)=O.O>[Si:1]([O:8][CH:9]([C:19]([F:22])([F:21])[F:20])[CH:10]([NH:14][C:15](=[O:18])[CH2:16][I:24])[CH:11]([CH3:13])[CH3:12])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: [I-]
Reactant: CC(C)C(NC(=O)CCl)C(O[Si](C)(C)C(C)(C)C)C(F)(F)F
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: CC(C)C(NC(=O)CI)C(O[Si](C)(C)C(C)(C)C)C(F)(F)F
Reaction time: 8 h
Yield: 91.9 %

Procedure:
N-(2-tert-Butyldimethylsilyloxy-3,3,3-trifluoro-1-isopropylpropyl)-2-chloroacetamide (15.56 g) was added to a solution of NaI (19.3 g) in acetone (130 mL). The mixture was stirred overnight and the yellow reaction mixture was diluted with water (180 mL). The resulting precipitate was filtered; washed with water and saturated aqueous sodium thiosulfate; and dried under vacuum at 40° C. overnight. After spectral data indicated the presence of starting material, the product was subjected to another iteration of the above reaction conditions. The subsequent work-up was identical except that no sodium thiosulfate wash was performed. Purification by chromatography, eluting with hexane:ethyl acetate (gradient, 80:20 and 50:50), and drying under vacuum afforded N-(2-tert-butyldimethylsilyloxy-3,3,3-trifluoro-1-isopropylpropyl)-2-iodoacetamide (17.91 g); TLC: Rf =0.30, hexane:ethyl acetate (9:1); MS: m/z=454(M+1).
Reaction SMILES: [C:1]([CH:4]([C:7]1[CH:12]=[CH:11][C:10]([S:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:9][CH:8]=1)[C:5]#[N:6])(=O)[CH3:2].Cl.[NH2:21][NH:22]C(N)=O.CO>O>[NH2:6][C:5]1[C:4]([C:7]2[CH:12]=[CH:11][C:10]([S:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:9][CH:8]=2)=[C:1]([CH3:2])[NH:22][N:21]=1
Reactant: NNC(N)=O
Reactant: CC(=O)C(C#N)c1ccc(Sc2ccccc2)cc1
Agent: Cl
Solvent: O
Solvent: CO
Product: Cc1[nH]nc(N)c1-c1ccc(Sc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 91.4 %

Procedure:
A mixture of 520 mg of α-acetyl-4-phenylthiophenylacetonitrile, 217 mg of semicarbazide hydrochloride, 15 ml of methanol and 3 ml of water was stirred at 0° C. for 10 minutes. Removing the ice bath, 40 hours later, the mixture was stirred at room temperature for 1 hour while keeping the pH at 9 to 10 by using aqueous solution of 2N sodium hydroxide. Adding 50 ml of water, the mixture was stirred for 30 minutes in ice-cooling, and the precipitate was filtered. It was directly added to the mixed solution of 5 ml of aqueous solution of 2N sodium hydroxide and 50 ml of methanol, and the mixture was stirred for 4 hours at room temperature, and then 80 ml of water was added, and the mixture was stirred for 30 minutes in ice-cooling, then the precipitate was filtered, Washed in water and dried, thereby obtaining 500 mg of the title compound.
Reaction SMILES: NCC(N)C.[NH2:6][CH2:7][CH:8]([NH2:12])[CH2:9][CH2:10][CH3:11].[C:13]([NH:21][C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][N:30]=1)[C:25](O)=O)(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[CH2:9]([CH:8]1[CH2:7][NH:6][C:25]([C:24]2[CH:28]=[CH:29][N:30]=[C:22]([NH:21][C:13](=[O:20])[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:23]=2)=[N:12]1)[CH2:10][CH3:11]
Reactant: O=C(O)c1ccnc(NC(=O)c2ccccc2)c1
Reactant: CCCC(N)CN
Agent: CC(N)CN
Product: CCCC1CNC(c2ccnc(NC(=O)c3ccccc3)c2)=N1
Yield: 20 %

Procedure:
Following the procedure as described in EXAMPLE 9, making variations as required to replace 1,2-diaminopropane with 1,2-diaminopentane to react with 2-benzamidoisonicotinic acid, N-(4-(4-propyl-4,5-dihydro-1H-imidazol-2-yl)pyridin-2-yl)benzamide was obtained in 20% yield: MS (ES+) m/z 309.4 (M+1).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[C:10]([F:12])[C:9]([O:13][CH3:14])=[CH:8][C:7]=2[C:15]2[C:16]3[N:23]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:22]([CH3:32])=[C:21]([C:33](O)=[O:34])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:3][CH2:2]1.[NH2:36][C@@H:37]1[CH2:42][CH2:41][C@H:40]([NH:43][C:44](=[O:50])[O:45][C:46]([CH3:49])([CH3:48])[CH3:47])[CH2:39][CH2:38]1>>[CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[C:10]([F:12])[C:9]([O:13][CH3:14])=[CH:8][C:7]=2[C:15]2[C:16]3[N:23]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:30])([CH3:29])[CH3:31])[C:22]([CH3:32])=[C:21]([C:33]([NH:36][C@@H:37]4[CH2:42][CH2:41][C@H:40]([NH:43][C:44](=[O:50])[O:45][C:46]([CH3:47])([CH3:49])[CH3:48])[CH2:39][CH2:38]4)=[O:34])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:3][CH2:2]1
Reactant: COc1cc(-c2ncnc3c(C(=O)O)c(C)n(COCC[Si](C)(C)C)c23)c(OCC2CC2)cc1F
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](N)CC1
Product: COc1cc(-c2ncnc3c(C(=O)N[C@H]4CC[C@@H](NC(=O)OC(C)(C)C)CC4)c(C)n(COCC[Si](C)(C)C)c23)c(OCC2CC2)cc1F

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-4-fluoro-5-methoxyphenyl]-6-methyl-5-{[2-(trimethylsilyl)ethoxy]methyl}-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (example D.c10) and commercially available tert-butyl cis-(4-amino-cyclohexyl)-carbamate the title compound is obtained as colorless foam.
Reaction SMILES: [C:1]1([C:15]([O-])=[C:11]([N+:12]([O-:14])=[O:13])[CH:10]=[C:6]([N+:7]([O-:9])=[O:8])[CH:5]=1)[N+:2]([O-:4])=[O:3].[NH4+:17].P([O-])([O-])(O)=O.[NH4+].[NH4+].O>S1(CCCC1)(=O)=O>[CH:5]1[C:1]([N+:2]([O-:4])=[O:3])=[C:15]([NH2:17])[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][C:6]=1[N+:7]([O-:9])=[O:8]
Reactant: [NH4+]
Reactant: O=[N+]([O-])c1cc([N+](=O)[O-])c([O-])c([N+](=O)[O-])c1
Agent: O=P([O-])([O-])O
Solvent: O
Solvent: O=S1(=O)CCCC1
Product: Nc1c([N+](=O)[O-])cc([N+](=O)[O-])cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 5 h
Yield: 87.7 %

Procedure:
Ammonium picrate (0.92 g, 3.7 mmol) and diammonium hydrogen phosphate (0.99 g, 7.5 mmol) are suspended in dry sulfolane (3 ml) and stirred in a Teflon® capped glass pressure tube (8 ml) for 2 hr with the application of heat, which raises the temperature of the reaction from 25° C. to 177° C. The reaction is continued an additional 5 hr at 177° C. and cooled to ambient temperature. Water (30 ml) is added to the slurry and the product is collected and washed with water. Vacuum drying yields 0.74 g picramide (87%) (Table 1, entry 2).
Reaction SMILES: [CH2:1]([NH2:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].C([O:21][C:22]1[C:31]2[C:26](=[C:27]([NH:32]C(C)=O)[CH:28]=[CH:29][CH:30]=2)[CH:25]=[CH:24][C:23]=1[S:36](Cl)(=[O:38])=[O:37])(=O)C>CC(C)=O>[NH2:32][C:27]1[CH:28]=[CH:29][CH:30]=[C:31]2[C:26]=1[CH:25]=[CH:24][C:23]([S:36](=[O:38])(=[O:37])[NH:17][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[C:22]2[OH:21]
Reactant: CCCCCCCCCCCCCCCCN
Reactant: CC(=O)Nc1cccc2c(OC(C)=O)c(S(=O)(=O)Cl)ccc12
Solvent: CC(C)=O
Product: CCCCCCCCCCCCCCCCNS(=O)(=O)c1ccc2c(N)cccc2c1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 40.6 %

Procedure:
30 g of hexadecylamine was dissolved in 250 liters of acetone. To this solution was added gradually a solution of 40 g of 1-acetoxy-5-acetamino-naphthalene-2-sulfonyl chloride synthesized above in 150 ml of acetone while stirring, and, after completion of the addition, stirring was continued for about one hour at about 40° C. Then, the reaction solution was ice-cooled, and the precipitated crystals were collected by filtration and well washed with 1 liter of methanol. The crystals were refluxed for 8 hours together with 200 ml of ethanol, 30 g of NaOH, and 100 ml of water. After being allowed to cool to room temperature, the solution was neutralized with acetic acid, and the crystals thus precipitated were collected by filtration and recrystallized from an ethanol-water mixture solvent to obtain 22 g (54% yield) of product.
Reaction SMILES: [C:1]1(=[O:44])[N:5]([CH:6]2[C:37](=[O:38])[N:8]3[C:9]([C:21]([O:23][CH:24]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[O:22])=[C:10]([CH2:13][S:14][C:15]4[S:16][C:17]([CH3:20])=[N:18][N:19]=4)[CH2:11][S:12][C@H:7]23)[C:4](=[O:39])[C:3]2=[CH:40][CH:41]=[CH:42][CH:43]=[C:2]12.C1C[O:48]CC1.O.S(=O)(=O)(O)O>C(OCC)(=O)C>[C:1]([C:2]1[CH:43]=[CH:42][CH:41]=[CH:40][C:3]=1[C:4]([NH:5][CH:6]1[C:37](=[O:38])[N:8]2[C:9]([C:21]([O:23][CH:24]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)=[O:22])=[C:10]([CH2:13][S:14][C:15]3[S:16][C:17]([CH3:20])=[N:18][N:19]=3)[CH2:11][S:12][C@H:7]12)=[O:39])([OH:48])=[O:44]
Reactant: C1CCOC1
Reactant: Cc1nnc(SCC2=C(C(=O)OC(c3ccccc3)c3ccccc3)N3C(=O)C(N4C(=O)c5ccccc5C4=O)[C@H]3SC2)s1
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1nnc(SCC2=C(C(=O)OC(c3ccccc3)c3ccccc3)N3C(=O)C(NC(=O)c4ccccc4C(=O)O)[C@H]3SC2)s1
Reaction time: 0.25 h

Procedure:
A solution of benzhydryl 7-phthalimido-3-(5-methyl-1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylate (2 mmol.) in 25 ml. of THF and 8 ml. of water is cooled in an ice-water bath, and 660 mg. of Na2S. 9H2O are then added. The mixture is stirred for 15 minutes, and 10 ml. of water and 40 ml. of ethyl acetate are added. The layers are separated, and a neutral material is obtained from the ethyl acetate layer. The aqueous layer is acidified to pH 4.3 with 1N sulfuric acid and is extracted twice with ethyl acetate. The ethyl acetate extract is washed, dried, and evaporated to give the title compound.
Reaction SMILES: C(OC([NH:11][C@H:12]([C:17]([NH:19][C@@H:20]([CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[C@H:21]([OH:35])[CH2:22][N:23]1[C@H:27]([C:28]([NH:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:26][S:25][CH2:24]1)=[O:18])[CH2:13][C:14](=[O:16])[NH2:15])=O)C1C=CC=CC=1.Br>C(O)(=O)C.C(OCC)C>[NH2:11][C@H:12]([C:17]([NH:19][C@@H:20]([CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[C@H:21]([OH:35])[CH2:22][N:23]1[C@H:27]([C:28]([NH:30][C:31]([CH3:33])([CH3:34])[CH3:32])=[O:29])[CH2:26][S:25][CH2:24]1)=[O:18])[CH2:13][C:14](=[O:16])[NH2:15]
Reactant: CC(C)(C)NC(=O)[C@@H]1CSCN1C[C@@H](O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(N)=O)NC(=O)OCc1ccccc1
Agent: Br
Solvent: CCOCC
Solvent: CC(=O)O
Product: CC(C)(C)NC(=O)[C@@H]1CSCN1C[C@@H](O)[C@H](Cc1ccccc1)NC(=O)[C@@H](N)CC(N)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.3 %

Procedure:
A mixture of 170 mg of 3-[3(S)-[[N-(benzyloxycarbonyl)-L-asparaginyl]amino]-2(R)-hydroxy-4-phenylbutyl]-N-tert.butyl-4(R)-thiazolidinecarboxamide and 0.3 ml of 32% (w/w) hydrogen bromide in glacial acetic acid was stirred at room temperature for 1 hour. The solution was diluted with diethyl ether and the precipitated solid was rapidly filtered off, washed with diethyl ether and dissolved in water. The solution was made alkaline by the addition of potassium carbonate and extracted with three portions of chloroform. The combined chloroform extracts were dried over anhydrous sodium sulphate, filtered and evaporated to give 110 mg of 3-[3(S)-[[L-asparaginyl]amino]-2(R)-hydroxy-4-phenylbutyl]-N-tert.butyl-4(R)-thiazolidinecarboxamide; MS: m/e 466 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[C:10](=[O:11])[CH2:9][CH2:8][N:7]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:6]1)=[O:4].[H-].[Na+].[CH2:21](Cl)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:10](=[O:11])[CH2:9][CH2:8][N:7]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:6]1)=[O:4]
Reactant: COC(=O)C1CN(Cc2ccccc2)CCC1=O
Reactant: ClCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C1(Cc2ccccc2)CN(Cc2ccccc2)CCC1=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 83.9 %

Procedure:
To a solution of 1-benzyl-4-oxo-piperidine-3-carboxylic acid methyl ester (5.14 g, 20.8 mmol) in DMF (130 mL) at 0° C. was added sodium hydride (60% by weight in mineral oil, 0.874 g, 21.8 mmol) in four portions over 0.5 h. After stirring at 0° C. for an additional 0.5 h, benzyl chloride (2.87 mL, 25.0 mmol) was added and the reaction mixture was allowed to stir for 14 h while warming to room temperature. The reaction mixture was partitioned between EtOAc and saturated aqueous sodium bicarbonate solution, the organic layer was removed and the aqueous layer was washed four times with EtOAc. The combined organic layers were dried over sodium sulfate, filtered and concentrated under vacuum. Purification by silica gel chromatography employing 0.5% MeOH/0.2% NH4OH/CH2Cl2 as the eluant afforded the compound of Example 200, Step A as a pale yellow oil (5.89 g): +APcl MS (M+1)+ 338; 1H NMR (400 MHz, CDCl3) δ: 7.09-7.39 (arom, series of m, 10 H), 3.60 (s, 3H), 3.56 (d, 2H), 3.38 (m, 1H), 3.20 (d, 1H), 2.93 (m, 2H), 2.78 (m, 1H), 2.42 (m, 2H), 2.31 (m, 1H).
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])C.[NH2:8][CH2:9][CH2:10][C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([O:21][CH3:22])[C:18]=2[Cl:20])[NH:13][CH:12]=1>C(O)=O>[CH:1]([NH:8][CH2:9][CH2:10][C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([O:21][CH3:22])[C:18]=2[Cl:20])[NH:13][CH:12]=1)=[O:3]
Reactant: COc1ccc2[nH]cc(CCN)c2c1Cl
Reactant: CC(=O)OC(C)=O
Solvent: O=CO
Product: COc1ccc2[nH]cc(CCNC=O)c2c1Cl
Reaction time: 0.17 h

Procedure:
To a mixture of formic acid (90%, 1.25 ml) and acetic anhydride (2.75 ml) was added 3-(2-aminoethyl)-4-chloro-5-methoxyindole (220 mg, 0.98 mmol), and the solution was stirred for 10 minutes. Removal of volatile components in vacuo at 30° C. left a residue which was partitioned between aqueous sodium bicarbonate and chloroform. The organic phase was separated, dried (Na2SO4) and evaporated to dryness. Purification by chromatography (SiO2 ; C6H14 /CHCl3) gave 3-(2-formylaminoethyl)-4-chloro-5-methoxyindole (176 mg) m.p. 120-121° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:13][CH2:12][N:11]([C:14]3[N:19]=[CH:18][NH:17][C:16](=[O:20])[N:15]=3)[CH2:10][CH:9]=2)=[CH:4][CH:3]=1.Cl[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:13][CH2:12][N:11]([C:14]3[N:19]=[CH:18][N:17]([CH2:22][C:23]4[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=4)[C:16](=[O:20])[N:15]=3)[CH2:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: COc1ccc(CCl)cc1
Reactant: O=c1nc(N2CC=C(c3ccc(F)cc3)CC2)nc[nH]1
Product: COc1ccc(Cn2cnc(N3CC=C(c4ccc(F)cc4)CC3)nc2=O)cc1
Yield: 81.6 %

Procedure:
4-[4-(4-Fluorophenyl)-5,6-dihydropyridin-1(2H)-yl]-1,3,5-triazin-2(1H)-one (294 mg, 1.08 mmol) synthesized in Reference Synthesis Example 342 and 1-(chloromethyl)-4-methoxybenzene (162 μL, 1.19 mmol) were used to obtain the title compound (346 mg, yield 82%) by synthesis in a similar manner to Reference Synthesis Example 16.
Reaction SMILES: C1(C2C=CC=CC=2)C=CC(C2C=COC=2)=CC=1.Br[C:19]1[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][CH:20]=1.[Br:27][C:28]1[CH:33]=[CH:32][C:31](OB(O)O)=[CH:30][CH:29]=1>CCO>[Br:27][C:28]1[CH:33]=[CH:32][C:31]([C:19]2[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][CH:20]=2)=[CH:30][CH:29]=1
Reactant: OB(O)Oc1ccc(Br)cc1
Reactant: N#Cc1ccc(Br)cc1
Agent: c1ccc(-c2ccc(-c3ccoc3)cc2)cc1
Solvent: CCO
Product: N#Cc1ccc(-c2ccc(Br)cc2)cc1
Yield: 67.3 %

Procedure:
As described in Example 1(a) for the preparation of 3-biphenyl-4-yl-furan, 4-bromobenzonitrile (9.42 g, 51.8 mmol) and 4-bromophenylboric acid (5.20 g, 25.9 mmol) were coupled in EtOH to afford 4.50 g (67%) of 4′-bromo-biphenyl-4-carbonitrile as a grey powder, mp 147-8° C. (lit 153-5° C.; McNamara, J.; Gleason, W. B. J. Org Chem. 1976, 41, 1071). The material had an NMR spectrum that matched literature (see Amatore, C.; Juland, A.; Negri, S. J. Organomet. Chem. 1990, 390, 389-398) and was typically used without further purification.
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.CN(C)C1C=CC=CC=1.[CH3:15][O:16][C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[N:23]=[N:22][CH:21]=[C:20]2O>>[CH3:15][O:16][C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[N:23]=[N:22][CH:21]=[C:20]2[Cl:3]
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1ccc2nncc(O)c2c1
Solvent: CN(C)c1ccccc1
Product: COc1ccc2nncc(Cl)c2c1
Yield: 59 %

Procedure:
Phosphorous oxychloride (5 ml) was added to a mix of dimethylaniline (157 mg, 1.3 mmol) and 6-methoxy-4-hydroxycinnoline (208 mg, 1.2 mmol). The reaction was heated at reflux for 15 min, then cooled and concentrated under vacuum. The residue was partitioned between chloroform (100 ml) and water (30 ml), then the organic layer was washed with brine and dried (Na2SO4). Chromatography of the residue adsorbed onto silica gel (3 g) on silica gel (15 g) eluent CH2Cl2 to 10% Ethylacetate/CH2Cl2 gave 6-methoxy-4-chlorocinnoline (135 mg, 0.7 mmol) in 59% yield as white yellow solid. δH (CDCl3)=4.03 (s, 3H); 7.28 (d, 1H); 7.51 (dd, 1H); 8.41 (d, 1H) and 9.22 (br s, 1H). MS (ESI) (M+H)+195.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:13]=[C:12]([Br:14])[CH:11]=[C:10]2[C:5]=1[N:6]=[C:7]([O:17][CH3:18])[C:8]([O:15][CH3:16])=[N:9]2.C(N(CC)CC)C.[Cl-].[CH2:27]([O:29][C:30](=[O:34])[C:31](O)=[O:32])[CH3:28]>C1COCC1>[CH2:27]([O:29][C:30](=[O:34])[C:31]([NH:2][CH2:3][C:4]1[CH:13]=[C:12]([Br:14])[CH:11]=[C:10]2[C:5]=1[N:6]=[C:7]([O:17][CH3:18])[C:8]([O:15][CH3:16])=[N:9]2)=[O:32])[CH3:28]
Reactant: COc1nc2cc(Br)cc(CN)c2nc1OC
Reactant: CCOC(=O)C(=O)O
Agent: Cl
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)C(=O)NCc1cc(Br)cc2nc(OC)c(OC)nc12
Temperature: 0 °C
Reaction time: 2 h

Procedure:
300 mg (1 mmol) of 5-aminomethyl-7-bromo-2,3-dimethoxyquinoxaline hydrochloride are suspended in 10 ml of THF and the suspension is cooled to 0° C. 0.183 ml (1.3 equiv.) of triethylamine is added and then 0.123 ml (1.1 equiv.) of oxalic acid monoethyl ester chloride is added dropwise in the course of 30 minutes. The mixture is stirred at 0° C. for 2 hours, then at 20° C. for 16 hours and is concentrated by evaporation. The residue is stirred in diethyl ether, and the solid is filtered off, washed with water and diethyl ether and dried.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][C@H:14]([OH:16])[CH2:13][C@H:12]1[C:17]([OH:19])=[O:18])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:27][S:28](Cl)(=[O:30])=[O:29].Cl>O1CCCC1>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][C@H:14]([O:16][S:28]([CH3:27])(=[O:30])=[O:29])[CH2:13][C@H:12]1[C:17]([OH:19])=[O:18])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)Cl
Reactant: O=C(O)[C@@H]1C[C@@H](O)CN1C(=O)OCc1ccccc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CS(=O)(=O)O[C@@H]1C[C@@H](C(=O)O)N(C(=O)OCc2ccccc2)C1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of (2S,4R)-1-benzyloxycarbonyl-2-carboxy-4-hydroxypyrrolidine (50 g) and triethylamine (63.1 ml) in tetrahydrofuran (250 ml) was dropwise added methanesulfonyl chloride (35.0 ml) with stirring at -5°-0° C. for 2 hours. After stirring for 1 hour, the mixture was poured into ice-water (500 ml) and the solution was adjusted to pH 2 with concentrated hydrochloric acid. The mixture was extracted with ethyl acetate (250 ml). The organic layer was washed in turn with 1N hydrochloric acid (250 ml×2) and brine (250 ml), dried over magnesium sulfate, and evaporated under reduced pressure to give (2S,4R)-1-benzyloxycarbonyl-2-carboxy-4-methanesulfonyloxypyrrolidine (66.21 g).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]([NH:12][C:13](NC2C3C(=CC=CC=3)N=C(C)C=2)=[O:14])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.Cl.C[O:29][C:30](=[O:36])[C@H:31]([CH:33]([CH3:35])[CH3:34])[NH2:32].CCN(C(C)C)C(C)C>CO>[CH3:34][CH:33]([CH3:35])[C@H:31]([NH:32][C:13]([NH:12][C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=[C:2]([CH3:1])[CH:11]=1)=[O:14])[C:30]([OH:29])=[O:36]
Reactant: Cc1cc(NC(=O)Nc2cc(C)nc3ccccc23)c2ccccc2n1
Reactant: COC(=O)[C@@H](N)C(C)C
Agent: Cl
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(NC(=O)N[C@H](C(=O)O)C(C)C)c2ccccc2n1
Temperature: 80 °C

Procedure:
A suspension of 1,3-bis-(2-methyl-quinolin-4-yl)-urea (342.4 mg, 1 mmol), valin methyl ester hydrochloride (167.6 mg, 1 mmol) and DIPEA (0.34 mL, 2 mmol) in MeOH (10 mL) is heated at 80° C. for 15 h. The solvent is evaporated and the residue is dissolved in 6N aqueous HCl (6 mL). The reaction mixture is heated at 90° C. for 12 h. Evaporation and purification by preparative HPLC provides the title compound.