Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:10]([OH:11])=[C:9]2[C:5]([CH2:6][CH2:7][CH:8]2[CH2:12][CH2:13][NH:14][C:15](=[O:19])[CH2:16][CH2:17][CH3:18])=[CH:4][CH:3]=1.Br[CH2:21]Br.C(=O)([O-])[O-].[K+].[K+].Cl>CN(C)C=O.[Cu]=O.O>[O:11]1[C:10]2[C:9]3[CH:8]([CH2:12][CH2:13][NH:14][C:15](=[O:19])[CH2:16][CH2:17][CH3:18])[CH2:7][CH2:6][C:5]=3[CH:4]=[CH:3][C:2]=2[O:1][CH2:21]1
Reactant: BrCBr
Reactant: CCCC(=O)NCCC1CCc2ccc(O)c(O)c21
Agent: O=[Cu]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: O
Product: CCCC(=O)NCCC1CCc2ccc3c(c21)OCO3
Yield: 66.5 %

Procedure:
A solution of N-[2-(6,7-dihydroxyindan-1-yl)ethyl]butyramide (1.13 g, 4.29 mmol.), dibromomethane (2.98 g, 17.2 mmol.), potassium carbonate (1.78 g, 12.9 mmol.) and copper-(II) oxide (34 mg, 0.43 mmol.) in N,N-dimethylformamide (15 mL) was stirred for 3 hours at 110° C. The reaction mixture was cooled, which was poured into water, followed by neutralizing with dilute hydrochloric acid. The organic matter was extracted with ethyl acetate. The extract solution was washed with a saturated aqueous saline solution and water, which was then dried over anhydrous magnesium sulfate, followed by distilling off the solvent under reduced pressure. The residue was purified by means of silica gel column chromatography (ethyl acetate) to afford the title compound (yield 785 mg, 67%).
Reaction SMILES: [CH2:1]=[C:2]1[CH2:7][CH2:6][C:5]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([CH2:8][NH:9][C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[O:18][CH3:19])=[O:11])[CH2:4][CH2:3]1.B1C2CCCC1CCC2.[OH-:35].[Na+].OO>C1COCC1.C(Cl)Cl>[OH:35][CH2:1][CH:2]1[CH2:7][CH2:6][C:5]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)([CH2:8][NH:9][C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[O:18][CH3:19])=[O:11])[CH2:4][CH2:3]1
Reactant: C=C1CCC(CNC(=O)c2ccccc2OC)(c2ccccc2)CC1
Reactant: [OH-]
Agent: B1C2CCCC1CCC2
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: COc1ccccc1C(=O)NCC1(c2ccccc2)CCC(CO)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 1-methylidene-4-phenyl-4-(3-(2-methoxyphenyl)-3-oxo-2-azaprop-1-yl)cyclohexane (Example 165, 117 mg, 0.35 mmol) was added 9-BBN (7 mL, 0.5 N, 3.5 mmol) in THF. The reaction mixture was stirred at rt for 1 h, and then heated to 45° C. for 3 h. To the solution was then added NaOH (3 mL, 10%) and H2O2 (4 mL, 30%) and the mixture was heated at 45° C. for 14 h. The reaction mixture was poured into CH2Cl2 and washed with 2N HCl and dried over Na2SO4, filtered and concentrated. The residue was purified by flash chromatography (silica, EtOAc/hexane, 2:1) to give the title compound as a 2:1 mixture of two diastereomers.
Reaction SMILES: [CH2:1]([O:4][C:5]([C:7]1[N:11]2[C:12](=[O:24])[C@H:13]([C@H:14]([O:16][Si](C(C)(C)C)(C)C)[CH3:15])[C@H:10]2[C@@H:9]([CH3:25])[C:8]=1[S:26][C@H:27]1[CH2:31][NH:30][C:29](=[S:32])[CH2:28]1)=[O:6])[CH:2]=[CH2:3].F.[NH4+].P([O-])([O-])([O-])=O>CN(C)C=O>[CH2:1]([O:4][C:5]([C:7]1[N:11]2[C:12](=[O:24])[C@H:13]([C@H:14]([OH:16])[CH3:15])[C@H:10]2[C@@H:9]([CH3:25])[C:8]=1[S:26][C@H:27]1[CH2:31][NH:30][C:29](=[S:32])[CH2:28]1)=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)C1=C(S[C@H]2CNC(=S)C2)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O[Si](C)(C)C(C)(C)C)C(=O)N12
Agent: F
Agent: O=P([O-])([O-])[O-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: C=CCOC(=O)C1=C(S[C@H]2CNC(=S)C2)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Temperature: 25 °C
Reaction time: 72 h
Yield: 85.3 %

Procedure:
A mixture of (1R,5S,6S)-2-[(4R)-pyrrolidine-2-thion-4-ylthio]-6-[(1R)-1-t-butyldimethylsilyloxyethyl]-1-methylcarbapen-2-em-3-carboxylic acid allyl ester (1.00 g), dimethylformamide (10 ml) and ammonium hydrogenfluoride (459 mg) is stirred at room temperature for three days. To the reaction solution is added a phosphate buffer (pH 7.0), and the mixture is extracted with ethyl acetate. The organic layer is washed with a phosphate buffer, and the washing and the phosphate buffer layer are combined, and extracted with ethyl acetate. The organic layers are combined, washed, dried and concentrated under reduced pressure. The resulting residue is crystallized from a mixture of ethyl acetate and n-hexane (2:1) to give (1R,5S,6S)-2-[(4R)-pyrrolidine-2-thion-4-ylthio]-6-[(1R)-1-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylic acid allyl ester (657 mg). The filtrate of the above crystallization is concentrated under reduced pressure, and the residue is purified by silica gel flash column chromatography (solvent; chloroform:ethanol= 30:1), and further crystallized from a mixture of ethyl acetate and n-hexane (2:1) to give (1R,5S,6S)-2-[(4R)-pyrrolidine-2-thion-4-ylthio]-6-[(1R)-1-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylic acid ally ester (24 mg).
Reaction SMILES: [CH3:1][C@@:2]12[C:10](=[O:11])[CH2:9][CH2:8][C@H:7]1[C@@H:6]1[CH2:12][CH:13]=[C:14]3[CH2:19][C@@H:18]([OH:20])[CH2:17][CH2:16][C@:15]3([CH3:21])[C@H:5]1[CH2:4][CH2:3]2.O.[CH:23](O)=[O:24]>>[CH:23]([O:20][C@H:18]1[CH2:17][CH2:16][C@@:15]2([CH3:21])[CH:14]([CH2:13][CH2:12][C@@H:6]3[C@@H:5]2[CH2:4][CH2:3][C@@:2]2([CH3:1])[C@H:7]3[CH:8]=[CH:9][C:10]2=[O:11])[CH2:19]1)=[O:24]
Reactant: O=CO
Reactant: C[C@]12CC[C@H](O)CC1=CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Solvent: O
Product: C[C@]12CC[C@H](OC=O)CC1CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)C=C[C@@H]12
Temperature: 60 °C

Procedure:
Following the procedure described by Ringold (H. J. Ringold, et al., J. Am. Chem. Soc. 78, 816, 1956), dehydroepiandrosterone (2.88 g, 10 mmol) dissolved in 85% formic acid (100 mL) is heated at 60° C. for 1 h. After cooling, the mixture is poured into iced water and after 16 h, crystals are filtered and dried in vacuo.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[CH2:15]([NH:22][CH2:23][CH2:24][C:25]1[CH:40]=[CH:39][C:28]([O:29][C:30]2[CH:38]=[CH:37][C:33]([C:34]([NH2:36])=[O:35])=[CH:32][N:31]=2)=[CH:27][CH:26]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[CH:41](=O)[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1.C(O)(=O)C.[OH-].[Na+]>ClCCCl>[CH2:15]([N:22]([CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[CH2:23][CH2:24][C:25]1[CH:40]=[CH:39][C:28]([O:29][C:30]2[CH:38]=[CH:37][C:33]([C:34]([NH2:36])=[O:35])=[CH:32][N:31]=2)=[CH:27][CH:26]=1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: NC(=O)c1ccc(Oc2ccc(CCNCc3ccccc3)cc2)nc1
Reactant: O=Cc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: NC(=O)c1ccc(Oc2ccc(CCN(Cc3ccccc3)Cc3ccccc3)cc2)nc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 64.9 %

Procedure:
Add sodium triacetoxyborohydride (0.2600 g, 1.227 mmol) to a stirred solution of 6-[4-(2-benzylamino-ethyl)-phenoxy]-nicotinamide (0.3058 g, 0.8802 mmol), benzaldehyde (0.092 mL, 0.905 mmol), glacial acetic acid (0.052 mL, 0.908 mmol) and 1,2-dichloroethane (8 mL). Stir for 18 h at room temperature under nitrogen. Pour the reaction into 1N sodium hydroxide (50 mL) and extract with diethyl ether (3×50 mL). Wash the diethyl ether extracts with brine, dry over magnesium sulfate, filter, and concentrate on a rotary evaporator to give the crude product. The crude product is purified by flash chromatography on silica gel eluting with 75% ethyl acetate/hexanes to yield 0.2501 g (65%) of 6-[4-(2-dibenzylamino-ethyl)-phenoxy]-nicotinamide: HPLC (30/70 to 90/10 ACN/(0.1% TFA in water) Zorbax SB-Phenyl Column 4.6 mm×5 cm×5 micron: Retention time: 8.14 minutes, Purity: 99.7%; mass spectrum (ion spray): m/z=438.0 (M+1).
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[CH:19][CH:18]=3)=[CH:13][C:11]=2[CH:12]=1)(=O)=O.[C:25]([NH:29][CH3:30])([CH3:28])([CH3:27])[CH3:26]>>[C:25]([N:29]([CH3:30])[CH2:6][CH2:7][C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[CH:19][CH:18]=3)=[CH:13][C:11]=2[CH:12]=1)([CH3:28])([CH3:27])[CH3:26]
Reactant: CS(=O)(=O)OCCc1cc2cc(-c3ccc(C#N)cc3)ccc2o1
Reactant: CNC(C)(C)C
Product: CN(CCc1cc2cc(-c3ccc(C#N)cc3)ccc2o1)C(C)(C)C

Procedure:
The product from Example 1C and tert-butyl(methyl)amine were processed as described in Example 1D to provide the titled compound. MS (DCI) m/z 333 (+H)+;
Reaction SMILES: [CH2:1]([NH:8][CH2:9][CH:10]([O:14][CH2:15][CH3:16])[O:11][CH2:12][CH3:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:17]1[C:29]2[CH:28]([CH2:30][O:31][C:32]([NH:34][C@@H:35]([CH2:39][C:40]3[CH:45]=[CH:44][C:43]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[CH:42][CH:41]=3)[C:36](O)=[O:37])=[O:33])[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:21]=2[CH:20]=[CH:19][CH:18]=1>>[CH2:1]([N:8]([CH2:9][CH:10]([O:11][CH2:12][CH3:13])[O:14][CH2:15][CH3:16])[C:36](=[O:37])[C@@H:35]([NH:34][C:32](=[O:33])[O:31][CH2:30][CH:28]1[C:29]2[CH:17]=[CH:18][CH:19]=[CH:20][C:21]=2[C:22]2[C:27]1=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:39][C:40]1[CH:45]=[CH:44][C:43]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[CH:42][CH:41]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)Oc1ccc(C[C@H](NC(=O)OCC2c3ccccc3-c3ccccc32)C(=O)O)cc1
Reactant: CCOC(CNCc1ccccc1)OCC
Product: CCOC(CN(Cc1ccccc1)C(=O)[C@H](Cc1ccc(OC(C)(C)C)cc1)NC(=O)OCC1c2ccccc2-c2ccccc21)OCC
Yield: 43.5 %

Procedure:
According to the procedure described in the synthesis method of Compound III-1, N-benzyl-2,2-diethoxyethanamine (Compound IX-13) (43.3 g, 190 mmol) was coupled with (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(4-tert-butoxyphenyl)propanoic acid (128.6 g, 280 mmol) and the obtained residue was purified by silica gel column chromatography (eluent: n-hexane:ethyl acetate=4:1) to obtain the title compound (55.0 g, 43%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:10](N2C=CN=C2)=[O:11])=[N:4][C:5]([Cl:9])=[C:6]([NH2:8])[N:7]=1.[NH2:17][CH2:18][CH2:19][N:20]([CH2:24][CH2:25][CH3:26])[CH2:21][CH2:22][NH2:23]>O1CCCC1>[NH2:1][C:2]1[C:3]([C:10]([NH:17][CH2:18][CH2:19][N:20]([CH2:21][CH2:22][NH2:23])[CH2:24][CH2:25][CH3:26])=[O:11])=[N:4][C:5]([Cl:9])=[C:6]([NH2:8])[N:7]=1
Reactant: Nc1nc(N)c(C(=O)n2ccnc2)nc1Cl
Reactant: CCCN(CCN)CCN
Solvent: C1CCOC1
Product: CCCN(CCN)CCNC(=O)c1nc(Cl)c(N)nc1N
Temperature: 25 °C
Reaction time: 8 h
Yield: 78 %

Procedure:
A mixture of 23.87 g (100.0 mmol) of 1-(3,5-diamino-6-chloropyrazinoyl)imidazole and 58.51 g (300.0 mmol) of N-(2-aminoethyl)-N-propyl-1,2-ethanediamine in 250 ml of tetrahydrofuran was stirred at ambient temperature overnight. The solvent and excess triamine were evaporated and the residue chromatographed on silica gel (150 g) using 1.5:98.5 (v/v) methanol:tetrahydrofuran saturated with ammonia gas as eluent. There was obtained 24.64 g (78.0 mmol, 78%) of 3,5-diamino-N-[2-[(2-aminoethyl)propylamino]ethyl]-6-chloropyrazinecarboxamide as a yellow solid; mp 91°-94° C.
Reaction SMILES: [C:1]([C:5]1[CH:11]=[CH:10][C:8]([NH2:9])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[C:12]([C:16]1[CH:31]=[CH:30][CH:29]=[CH:28][C:17]=1[O:18][C:19]1[C:24]([N:25]=[C:26]=[S:27])=[CH:23][CH:22]=[CH:21][N:20]=1)([CH3:15])([CH3:14])[CH3:13]>ClCCCl>[C:12]([C:16]1[CH:31]=[CH:30][CH:29]=[CH:28][C:17]=1[O:18][C:19]1[C:24]([NH:25][C:26]([NH:9][C:8]2[CH:7]=[CH:6][C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])=[CH:11][CH:10]=2)=[S:27])=[CH:23][CH:22]=[CH:21][N:20]=1)([CH3:15])([CH3:13])[CH3:14]
Reactant: CC(C)(C)c1ccc(N)cc1
Reactant: CC(C)(C)c1ccccc1Oc1ncccc1N=C=S
Solvent: ClCCCl
Product: CC(C)(C)c1ccc(NC(=S)Nc2cccnc2Oc2ccccc2C(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 54.3 %

Procedure:
To a solution of 4-tert-butyl aniline (30 mg, 0.20 mmol) in DCE (2 mL) was slowly added 1c (50 mg, 0.17 mmol). The reaction was stirred 48 h at rt and concentrated. 96a was crystallized from methanol to afford 40 mg (52% yield) of white crystals. [M+H]+=434.04.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:17]=[CH:16][C:7]([CH:8]=[C:9]2[S:13][C:12](=[O:14])[NH:11][C:10]2=[O:15])=[CH:6][CH:5]=1.Br[CH2:19][C:20]([C:22]1[N:23]=[C:24]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:25][C:26]=1[CH3:27])=[O:21].C(O)(=O)C>CN(C)C=O>[CH3:27][C:26]1[O:25][C:24]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[N:23][C:22]=1[C:20](=[O:21])[CH2:19][O:3][C:4]1[CH:17]=[CH:16][C:7]([CH:8]=[C:9]2[S:13][C:12](=[O:14])[NH:11][C:10]2=[O:15])=[CH:6][CH:5]=1
Reactant: Cc1oc(-c2ccccc2)nc1C(=O)CBr
Reactant: O=C1NC(=O)C(=Cc2ccc(O)cc2)S1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: Cc1oc(-c2ccccc2)nc1C(=O)COc1ccc(C=C2SC(=O)NC2=O)cc1
Reaction time: 0.5 h
Yield: 33.3 %

Procedure:
60% sodium hydride in oil (0.24 g) was added to a solution of 5-(4-hydroxybenzylidene)-2,4-thiazolidinedione (0.663 g) in N,N-dimethylformamide (20 ml) and the mixture was stirred for 30 minutes. Then, a solution of 4-bromoacetyl-5-methyl-2-phenyloxazole (0.841 g) in N,N-dimethylformamide (10 ml) was added dropwise to the mixture under ice-cooling. After stirring under ice-cooling for 30 minutes, the reaction solution was poured into ice-cold water. The aqueous mixture was made acid with acetic acid. The solid which precipitated was collected by filtration, washed with water, and crystallized from acetone to give 5-{4-[2-(5-methyl-2-phenyl-4-oxazolyl)-2-oxoethoxy]benzylidene}-2,4-thiazolidinedione (0.42 g, 32.3%). Recrystallization from chloroform-ethanol yielded colorless needles, m.p. 244°-245° C. Elemental analysis for C22H16N2O5S, Calcd.: C, 62.85; H, 3.84; N, 6.66. Found: C, 62.80; H, 3.69; N, 6.93.
Reaction SMILES: [CH3:1][C:2]1[C:6]2[CH:7]=[C:8]([C:11]3[CH:16]=[CH:15][C:14]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:13][CH:12]=3)[CH:9]=[CH:10][C:5]=2[O:4][CH:3]=1.[I:23]I>C1C=CC=CC=1>[I:23][C:3]1[O:4][C:5]2[CH:10]=[CH:9][C:8]([C:11]3[CH:16]=[CH:15][C:14]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:13][CH:12]=3)=[CH:7][C:6]=2[C:2]=1[CH3:1]
Reactant: II
Reactant: CCOC(=O)Cc1ccc(-c2ccc3occ(C)c3c2)cc1
Solvent: c1ccccc1
Product: CCOC(=O)Cc1ccc(-c2ccc3oc(I)c(C)c3c2)cc1

Procedure:
To a solution of 2.8 g. of the product of step B in 50 ml. of benzene is added 2.7 g. of iodine and 2.4 g. of mercuric oxide followed by stirring and heating at 60°-65° C. for about three days. The mixture is cooled and evaporated, and the residue is chromatographed on silica gel, eluting with a carbon tetrachloride-dichloromethane mixture, to provide ethyl 4-(2-iodo-3-methylbenzofuran-5-yl)phenylacetate. To this intermediate is added dichloromethane, then dinitrogen tetraoxide. After one hour the mixture is washed with water, then with sodium bisulfite solution and dried. Evaporation provides a residue which is recrystallized from a dichloromethane-hexane mixture to yield ethyl 4-(3-methyl-2-nitrobenzofuran-5-yl)phenylacetate.
Reaction SMILES: [C:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]([O:11][C:12]2[C:13]([C:29]3[CH:34]=[CH:33][C:32](OC(F)(F)F)=[CH:31][CH:30]=3)=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH:18]=[C:17]([C@:22]2([CH3:28])[CH2:26][O:25][C:24](=[O:27])[NH:23]2)[CH:16]=[CH:15]3)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[Cl:40]C1C=C(B(O)O)C=CC=1>>[C:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]([O:11][C:12]2[C:13]([C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([Cl:40])[CH:30]=3)=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH:18]=[C:17]([C@:22]2([CH3:28])[CH2:26][O:25][C:24](=[O:27])[NH:23]2)[CH:16]=[CH:15]3)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: OB(O)c1cccc(Cl)c1
Reactant: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3cc([C@]4(C)COC(=O)N4)ccc3c2-c2ccc(OC(F)(F)F)cc2)CC1
Product: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3cc([C@]4(C)COC(=O)N4)ccc3c2-c2cccc(Cl)c2)CC1

Procedure:
(R)-4-(6-(trans-4-tert-butylcyclohexyloxy)-5-(3-chlorophenyl)naphthalen-2-yl)-4-methyloxazolidin-2-one was synthesized as per (R)-4-(6-(trans-4-tert-butylcyclohexyloxy)-5-(4-(trifluoromethoxy)phenyl)naphthalen-2-yl)-4-methyloxazolidin-2-one (Example 220) in 69% yield using 3-chlorophenylboronic acid as the reagent.
Reaction SMILES: [Br:1][CH2:2][C:3]1[C:11]2[C:10](=[O:12])[C:9]([C:13](=[O:17])[CH:14]([CH3:16])[CH3:15])=[CH:8][N:7]([CH2:18][C:19]3[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=3[F:26])[C:6]=2[S:5][C:4]=1[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.[N+:33]([O-])([O-:35])=[O:34].[Na+].O>CS(O)(=O)=O.C(OCC)(=O)C>[Br:1][CH2:2][C:3]1[C:11]2[C:10](=[O:12])[C:9]([C:13](=[O:17])[CH:14]([CH3:16])[CH3:15])=[CH:8][N:7]([CH2:18][C:19]3[C:20]([F:26])=[CH:21][CH:22]=[CH:23][C:24]=3[F:25])[C:6]=2[S:5][C:4]=1[C:27]1[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][CH:28]=1
Reactant: CC(C)C(=O)c1cn(Cc2c(F)cccc2F)c2sc(-c3ccccc3)c(CBr)c2c1=O
Reactant: O=[N+]([O-])[O-]
Agent: CS(=O)(=O)O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)C(=O)c1cn(Cc2c(F)cccc2F)c2sc(-c3ccc([N+](=O)[O-])cc3)c(CBr)c2c1=O
Temperature: 11 °C
Reaction time: 2 h
Yield: 59.5 %

Procedure:
The compound obtained in Example 16 (1 g) was dissolved in methanesulfonic acid (5 ml) with cooling at 10 to 12° C. and then treated dropwise with a solution of sodium nitrate (0.165 g) in methanesulfonic acid (2.5 ml). The mixture was stirred as it was for 2 hours, and then poured into a cool water, and the crystal precipitated was recovered by a filtration, washed with water and diisopropylether, dried in vacuo to obtain a crude crystal (1.04 g). This was suspended in ethyl acetate (15 ml) with stirring and then cooled on ice, and the crystal precipitated was recovered by a filtration, washed with a cool ethyl acetate to obtain the title compound (0.647 g, 59.5%).
Reaction SMILES: COC(=O)CC1CC2C(=CC(OCCNC(OC(C)(C)C)=O)=CC=2)NC1=O.[CH3:28][O:29][C:30](=[O:62])[CH2:31][C:32]1[C:33](=[O:61])[N:34]([CH2:54][C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)[C:35]2[C:40]([CH:41]=1)=[CH:39][CH:38]=[C:37]([O:42][CH2:43][CH2:44][CH2:45][NH:46]C(OC(C)(C)C)=O)[CH:36]=2>>[CH3:28][O:29][C:30](=[O:62])[CH2:31][C:32]1[C:33](=[O:61])[N:34]([CH2:54][C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)[C:35]2[C:40]([CH:41]=1)=[CH:39][CH:38]=[C:37]([O:42][CH2:43][CH2:44][CH2:45][NH2:46])[CH:36]=2
Reactant: COC(=O)Cc1cc2ccc(OCCCNC(=O)OC(C)(C)C)cc2n(Cc2ccccc2)c1=O
Agent: COC(=O)CC1Cc2ccc(OCCNC(=O)OC(C)(C)C)cc2NC1=O
Product: COC(=O)Cc1cc2ccc(OCCCN)cc2n(Cc2ccccc2)c1=O

Procedure:
The title compound is prepared according to the procedure of Example 78 except that [7-(2-tert-butoxycarbonylamino-ethoxy)-2-oxo-1,2,3,4-tetrahydro-quinolin-3-yl]-acetic acid methyl ester is replaced with [7-(3-tert-butoxycarbonylaminopropoxy)-1-benzyl-2-oxo-1,2-dihydro-quinolin-3-yl]acetic acid methyl ester.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6](Cl)[CH:5]=[C:4]([NH2:9])[C:3]=1[N+:10]([O-:12])=[O:11].CN1CCC[C:15]1=[O:19]>C[O-].[Na+].CO>[NH2:1][C:2]1[CH:7]=[C:6]([O:19][CH3:15])[CH:5]=[C:4]([NH2:9])[C:3]=1[N+:10]([O-:12])=[O:11]
Reactant: Nc1cc(Cl)cc(N)c1[N+](=O)[O-]
Reactant: CN1CCCC1=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1cc(N)c([N+](=O)[O-])c(N)c1

Procedure:
0.024 mole (4.5 g) of 2,6-diamino-4-chloronitrobenzene in 9 ml of N-methylpyrrolidone and 22.5 ml of 30% sodium methylate in methanol were refluxed for 4 hours 30 minutes. Upon dilution of the reaction medium with water, the desired product precipitated out. After filtering, water washing and vacuum drying in the presence of P2O5, the product obtained was recrystallized from toluene; a black insoluble product was eliminated by hot filtration. The desired product melted at 140° C.
Reaction SMILES: O[CH:2]([C:4](=[CH2:7])[C:5]#[N:6])[CH3:3].CCCCC(C([O-])=O)CC.CCCCC(C([O-])=O)CC.[Sn+2].[CH3:29][N:30]=[C:31]=[O:32].[N-]=C=O>>[C:5]([C:4]([CH:2]([C:31](=[O:32])[NH:30][CH3:29])[CH3:3])=[CH2:7])#[N:6]
Reactant: C=C(C#N)C(C)O
Reactant: CN=C=O
Agent: CCCCC(CC)C(=O)[O-]
Agent: [N-]=C=O
Agent: [Sn+2]
Product: C=C(C#N)C(C)C(=O)NC
Reaction time: 6 h

Procedure:
2-Cyano-3-(N-methyl carbamyl)-1-butene was prepared through the following reaction. A three-necked 250 ml round bottom flask equipped with an overhead stirrer, N2 inlet, water condenser and dropping funnel was charged with 47.5 parts 2-(1-hydroxyethyl) acrylonitrile and 0.71 parts stannous octoate. To this stirred mixture, 28.5 parts methyl isocyanate was added through the dropping funnel. The mixture was maintained below 35° C. during addition by cooling and adjustment of the addition rate of the isocyanate. After the addition was complete, the mixture was stirred for an additional six hours. The product was then subjected to reduced pressure to remove any unreacted methyl isocyanate. The product was obtained as a viscous oil.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][SH:4].[C:5]1(=O)[CH:10]=[CH:9][C:8](=[O:11])[CH:7]=[CH:6]1>>[OH:11][C:8]1[CH:7]=[CH:6][C:5]2[S:4][CH2:3][CH2:2][NH:1][C:10]=2[CH:9]=1
Reactant: NCCS
Reactant: O=C1C=CC(=O)C=C1
Product: Oc1ccc2c(c1)NCCS2

Procedure:
The reaction of 2-amino-ethyl thiol with benzoquinone followed by air oxidation affords 6-hydroxy-dihydro-1,4-benzothiazine.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([NH:8][C@@H:9]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([CH3:19])[CH:13]=2)[CH2:10][CH3:11])=[CH:4][C:3]=1[CH:20]([O:23][CH3:24])[O:21][CH3:22].[CH2:25](Cl)Cl.[Zn](C)C>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([C@H:9]([NH:8][C:5]2[CH:6]=[N:7][C:2]([CH3:25])=[C:3]([CH:20]([O:23][CH3:24])[O:21][CH3:22])[CH:4]=2)[CH2:10][CH3:11])=[CH:13][C:14]=1[CH3:19]
Reactant: CC[C@@H](Nc1cnc(Cl)c(C(OC)OC)c1)c1ccc(Cl)c(C)c1
Reactant: ClCCl
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: C[Zn]C
Solvent: C1COCCO1
Product: CC[C@@H](Nc1cnc(C)c(C(OC)OC)c1)c1ccc(Cl)c(C)c1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
A mixture of INT 48 (250 mg, 0.677 mmol) and Pd(dppf)Cl2.CH2Cl2 (16.6 mg, 0.020 mmol) was dissolved in degassed dioxane (7 mL) and ZnMe2 (2 M in toluene, 1.02 mL, 2.04 mmol) was added. The mixture was stirred in a sealed vessel at 100° C. overnight. After cooling down, the mixture was quenched with a few drops of MeOH and the mixture was diluted with EtOAc, washed with saturated aqueous sodium bicarbonate and brine, dried over sodium sulfate and concentrated. The crude product was purified by flash chromatography (cyclohexane/EtOAc) to give INT 49.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([Cl:10])[CH:9]=1)[CH:5]=O.[NH2:11][C:12]1[CH:13]=[C:14]([CH:24]=[CH:25][C:26]=1[O:27][CH3:28])[C:15]([NH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:16].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([Cl:10])[CH:9]=1)[CH2:5][NH:11][C:12]1[CH:13]=[C:14]([CH:24]=[CH:25][C:26]=1[O:27][CH3:28])[C:15]([NH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:16]
Reactant: COc1ccc(C(=O)Nc2ccccc2)cc1N
Reactant: O=Cc1cc(Cl)cc(Cl)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Product: COc1ccc(C(=O)Nc2ccccc2)cc1NCc1cc(Cl)cc(Cl)c1
Yield: 32.4 %

Procedure:
Prepared according to the procedure of Example 50 using 3,5-dichloro-benzaldehyde (0.88 g, 5.0 mmol), 3-amino-4-methoxy-N-phenyl-benzamide (1.22 g, 5.0 mmol), acetic acid (0.24 g, 5.3 mmol), and sodium triacetoxyborohydride (1.12 mmol) to afford the product (0.65 g); m.p. 164-165° C. after recrystallization from ethanol.
Reaction SMILES: N[C:2]1[CH:3]=[CH:4][C:5]([C:8]#[N:9])=[N:6][CH:7]=1.C1C=CN=CC=1.[FH:16].N([O-])=O.[Na+]>>[F:16][C:2]1[CH:3]=[CH:4][C:5]([C:8]#[N:9])=[N:6][CH:7]=1
Reactant: N#Cc1ccc(N)cn1
Reactant: F
Agent: O=N[O-]
Agent: [Na+]
Solvent: c1ccncc1
Product: N#Cc1ccc(F)cn1
Temperature: 65 °C
Reaction time: 0.33 h
Yield: 52 %

Procedure:
To a 100 mL round bottom flask charged with 5-aminopicolinonitrile (285 mg, 2.44 mmol) at 0° C. was added HF-pyridine (5 mL) under N2. A pale brown solution was formed. In 4 aliquots, NaNO2 (250 mg, 3.62 mmol) was added with stirring. The solution turned green and a brown gas was liberated. After 20 min at 0° C., the solution was allowed to reach rt and stirred for an additional 20 min. A reflux condenser was attached and the reaction mixture was heated at 65° C. for 20 min then allowed to cool to rt. The orange slurry was quenched by the addition of crushed ice and the aqueous layer was extracted with DCM (3×10 mL). The combined organic portions were dried over Na2SO4, decanted and concentrated under reduced pressure to yield 5-fluoropicolinonitrile (152 mg, 52% yield) as a pale orange powder. LCMS: RT=0.63 min [M+H] 122.9 (2 min Phenomenex Luna C18 column, 4.6×30 mm eluting with 10-90% MeOH/H2O over 2 minutes containing 0.1% TFA; 5 mL/min, monitoring at 220 nm); HPLC: RT=0.99 min (Phenomenex Luna C18 column, 4.6×50 mm eluting with 10-90% MeOH/H2O over 4 minutes containing 0.2% PPA; 4 mL/min, monitoring at 220 nm, Purity 96%); NMR: 400 MHz 1H (CDCl3) ppm 8.52 (d, J=2.64 Hz, 1H), 7.70 (dd, J=4.4 and J=8.36 Hz, 1H), 7.50 (m, 1 H).