Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[C:10]([OH:12])=O)[CH:3]=[CH:2]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)C(C)C)(C)C.[C:44]([C:48]1[CH:68]=[CH:67][C:51]([CH2:52][NH:53][CH2:54][CH2:55][C:56]2[CH:61]=[C:60]([C:62]([F:65])([F:64])[F:63])[CH:59]=[CH:58][C:57]=2[F:66])=[CH:50][CH:49]=1)([CH3:47])([CH3:46])[CH3:45]>CN(C=O)C.O>[C:44]([C:48]1[CH:49]=[CH:50][C:51]([CH2:52][N:53]([CH2:54][CH2:55][C:56]2[CH:61]=[C:60]([C:62]([F:65])([F:63])[F:64])[CH:59]=[CH:58][C:57]=2[F:66])[C:10]([C:8]2[CH:7]=[CH:6][CH:5]=[C:4]3[C:9]=2[NH:1][CH:2]=[CH:3]3)=[O:12])=[CH:67][CH:68]=1)([CH3:47])([CH3:45])[CH3:46]
Reactant: O=C(O)c1cccc2cc[nH]c12
Reactant: CC(C)(C)c1ccc(CNCCc2cc(C(F)(F)F)ccc2F)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)c1ccc(CN(CCc2cc(C(F)(F)F)ccc2F)C(=O)c2cccc3cc[nH]c23)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 77 %

Procedure:
To a solution of 48 mg (0.3 mmol) of 1H-indole-7-carboxylic acid and 96 mg of TBTU (0.3 mmol) in 3 ml DMF, were added 0.26 ml (1.5 mmol) of N,N-diisopropylethyl amine. After stirring for 5 min at rt, 118 mg (0.3 mmol) (4-tert-butyl-benzyl)-[2-(2-fluoro-5-trifluoromethyl-phenyl)-ethyl]-amine in 2 ml DMF was added. After 3¾ h stirring at rt, the reaction mixture was diluted with 50 ml water and extracted with 2×50 ml EtOAc. The combined organic phases were washed with water and brine, dried with magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (8 g silica gel; EtOAc/heptane 1:9) to give 120 mg light yellow viscous oil (77%). MS (EI) 496.3 (M)+.
Reaction SMILES: [C:1](=[O:4])([O-:3])[O-].[K+].[K+].[OH-].[K+].Cl[C:10]1[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:11]=1[C:12]([OH:14])=[O:13].[CH2:20]([CH2:26][CH2:27][NH2:28])[CH2:21][CH2:22]C(O)=O>O>[C:1]([CH:26]([CH2:20][CH2:21][CH3:22])[CH2:27][NH:28][C:10]1[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:11]=1[C:12]([OH:14])=[O:13])([OH:3])=[O:4]
Reactant: NCCCCCC(=O)O
Reactant: O=C([O-])[O-]
Reactant: O=C(O)c1ccc(Cl)cc1Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: CCCC(CNc1cc(Cl)ccc1C(=O)O)C(=O)O
Temperature: 25 °C
Yield: 64.2 %

Procedure:
To a solution of potassium carbonate (3.62 g), potassium hydroxide (3.38 g), 2,4-dichlorobenzoic acid (VI) (5.0 g) and 6-amino-n-caproic acid (13.8 g) in water (50 ml) was added cupric chloride (0.05 g) and the resulting solution was refluxed for 18 hours. After this reaction solution was cooled to room temperature, the copper salt was removed by filtration and concentrated hydrochloric acid (25 ml) was added to the resulting filtrate. Then; the resulting precipitate was collected by filtration, washed with water and dried under vacuum to give 4.8 g of the desired compound (yield, 64%).
Reaction SMILES: C([O:3][CH:4]1[CH:8]([NH:9][C:10]([C@H:12]2[N:23]3[C@@H:16]([CH2:17][CH2:18][CH2:19][CH2:20][C@H:21]([NH:25][C:26](=[O:33])[C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[C:22]3=[O:24])[CH2:15][N:14]([C:34](=[O:36])[CH3:35])[CH2:13]2)=[O:11])[CH2:7][C:6](=[O:37])[O:5]1)C.FC(F)(F)C(O)=O>C(#N)C.O>[OH:3][CH:4]1[CH:8]([NH:9][C:10]([C@H:12]2[N:23]3[C@@H:16]([CH2:17][CH:18]=[CH:19][CH2:20][C@H:21]([NH:25][C:26](=[O:33])[C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[C:22]3=[O:24])[CH2:15][N:14]([C:34](=[O:36])[CH3:35])[CH2:13]2)=[O:11])[CH2:7][C:6](=[O:37])[O:5]1
Reactant: CCOC1OC(=O)CC1NC(=O)[C@@H]1CN(C(C)=O)C[C@@H]2CCCC[C@H](NC(=O)c3ccccc3)C(=O)N21
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CC(=O)N1C[C@@H]2CC=CC[C@H](NC(=O)c3ccccc3)C(=O)N2[C@H](C(=O)NC2CC(=O)OC2O)C1
Reaction time: 0.5 h

Procedure:
A solution of (4S,6S,10aS)-2-acetyl-6-benzoylamino-5-oxo-decahydro-2,4a-diaza-benzocyclooctene-4-carboxylic acid (2-ethoxy-5-oxo-tetrahydrofuran-3-yl)amide, 19, (70 mg, 0.14 mmol) in acetonitrile/water is treated with trifluoroacetic acid. After stirring for 30 minutes the solution is concentrated in vacuo and the crude product purified by preparative reverse phase HPLC to afford the desired product as a white solid.
Reaction SMILES: [OH-].[Na+].[C:3]([C:7]1[CH:8]=[C:9]([OH:13])[CH:10]=[CH:11][CH:12]=1)([CH3:6])([CH3:5])[CH3:4].Br[CH2:15][CH2:16][CH:17]1[O:22][CH2:21][CH2:20][CH2:19][O:18]1>O.C(OCC)(=O)C.C(O)(=O)C>[C:3]([C:7]1[CH:8]=[C:9]([CH:10]=[CH:11][CH:12]=1)[O:13][CH2:15][CH2:16][CH:17]1[O:22][CH2:21][CH2:20][CH2:19][O:18]1)([CH3:6])([CH3:4])[CH3:5]
Reactant: BrCCC1OCCCO1
Reactant: CC(C)(C)c1cccc(O)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CC(C)(C)c1cccc(OCCC2OCCCO2)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Sodium hydroxide (3.46 g, 1.3 eq) was taken up in water (20 mL) and stirred for about 30 minutes. Then 3-tert-butyl phenol (10.0 g, 66.6 mmol) was added and the resulting mixture was stirred at room temperature for 30 minutes. Next, 2-(2-bromoethyl)-[1,3]dioxane (9.9 mL, 1.1 eq) was added ant the resulting mixture was heated at reflux for 40 hours. The reaction mixture was cooled to room temperature and then added ethyl acetate (150 mL) and with stirring acetic acid was added to pH=4, followed by dilution with water (100 mL) and ethyl acetate (150 mL). After partitioning, the layers were separated and then washed the organic layer with water (3×100 mL) and the ethyl acetate layers were dried over magnesium sulfate, filtered and concentrated to give the title compound as a colorless oil (16.91 g).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:21])[CH:10]([C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[C:15]([OH:20])[CH:14]=1)[CH2:11]Br.[C:22]([O-:25])(=O)[CH3:23].[Na+]>CO>[OH:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:21])[C:10]([C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[C:15]([OH:20])[CH:14]=1)=[CH2:11].[OH:8][C:6]1[CH:7]=[C:2]2[C:3]([C:9](=[O:21])[CH:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:11]([C:4]3[CH:5]=[CH:23][C:22]([OH:25])=[C:2]([OH:1])[CH:3]=3)[O:1]2)=[CH:4][CH:5]=1
Reactant: O=C(c1ccc(O)cc1O)C(CBr)c1ccc(O)c(O)c1
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: CO
Product: C=C(C(=O)c1ccc(O)cc1O)c1ccc(O)c(O)c1
Product: O=C1c2ccc(O)cc2OC(c2ccc(O)c(O)c2)C1c1ccccc1
Temperature: 60 °C

Procedure:
0.157 g of 1-(2,4-dihydroxyphenyl)-2-(3′,4′-dihydroxyphenyl)-1-oxo-3-bromo-propane, the major product of step 3 in Example 3, and about 2 molar equivalents of sodium acetate ware mixed with 88 mL of methanol and heated at about 60° C. for 4 hours. After cooling, the mixture was acidified to pH 5 and the methanol was removed under reduced pressure. Tile residue was dissolved in ethyl acetate (50 mL) and the solution was washed with water and concentrated. The crude product was separated by column chromatography to yield approximately equal amounts of 1-(2,4-dihydroxyphenyl)-2-(3′,4′-dihydroxyphenyl)-1-oxo-2-propene and 7-hydroxy-(3′,4′,-dihydroxyphenyl)-2,3-dihydroisoflavone.
Reaction SMILES: [CH:1]1([P:7]([CH:29]2[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:14]2[C:19]([CH:20]([CH3:22])[CH3:21])=[CH:18][C:17](C(C)C)=[CH:16][C:15]=2[CH:26]([CH3:28])[CH3:27])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)Cl.[OH:38][S:39](O)(=[O:41])=[O:40].[OH-].[Na+:44]>CO>[CH:1]1([P:7]([CH:29]2[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:14]2[C:19]([CH:20]([CH3:22])[CH3:21])=[CH:18][C:17]([S:39]([O-:41])(=[O:40])=[O:38])=[CH:16][C:15]=2[CH:26]([CH3:28])[CH3:27])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Na+:44]
Reactant: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Reactant: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Product: CC(C)c1cc(S(=O)(=O)[O-])cc(C(C)C)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Temperature: 0 °C
Reaction time: 24 h
Yield: 94 %

Procedure:
To an oven-dried 25 mL round bottom flask equipped with a Teflon-coated magnetic stir bar and rubber septum was added dicyclohexyl-(2′,4′,6′-triisopropyl-biphenyl-2-yl)-phosphane (476 mg, 1.00 mmol) and CH2Cl2 (1.0 mL). The solution was cooled to 0° C. using an ice/water bath and then concentrated H2SO4 (1.00 mL) and fuming sulfuric acid (3.0 mL, 20% SO3) were added dropwise. The solution was allowed to warm to room temperature and stir for 24 h. At this time it was cooled to 0° C. using an ice/water bath and crushed ice (˜10 g) was added. The solution turned cloudy and white in color. An aqueous solution of NaOH (6.0 M, ˜20.0 mL) was then added dropwise to the cooled solution until it became neutral (pH ˜7.0 as judged by pH paper). The aqueous solution was extracted with CH2Cl2 (3×50 mL) and concentrated under reduced pressure to give a beige solid. The crude material was then dissolved in a minimum amount of cold methanol (˜20 mL), filtered and concentrated (this cycle was repeated) to give sodium 2′-(dicyclohexyl-phosphanyl)-2,6-diisopropyl-biphenyl-4-sulfonate (4) as a beige solid (503 mg, 94%). Mp=>250° C. 1H NMR (400 MHz, CD3OD) δ: 7.52 (s, 2H), 7.46 (m, 1H), 7.22 (m, 2H), 6.90 (m, 1H), 2.24 (m, 1H), 0.71-1.83 (34H). 13C NMR (125 MHz, CD3OD) δ: 148.4, 147.9, 147.8, 147.5, 145.6, 142.8, 137.4, 137.2, 133.92, 133.91, 132.43, 132.42, 129.3, 128.1, 121.3, 121.0, 40.1, 39.9, 39.7, 39.5, 39.3, 38.8, 35.8, 35.7, 32.5, 32.3, 31.9, 30.8, 30.6, 28.7, 28.6, 28.4, 28.3, 27.7, 26.0, 25.9, 23.3, 23.1. 31P NMR (162 MHz, CD3OD) δ: −10.7. IR (neat, cm−1): 3459, 2927, 2851, 1634, 1463, 1447, 1184, 1078, 1040. Anal. Calcd for C30H42NaO3PS: C, 67.14; H, 7.89. Found: C, 66.93; H, 7.77.
Reaction SMILES: [NH2:1][C@@H:2]([CH3:5])[CH2:3][OH:4].C(=O)(O)[O-].[Na+].[N+:11]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[S:20](Cl)(=[O:22])=[O:21])([O-:13])=[O:12]>O.O1CCCC1>[OH:4][CH2:3][C@@H:2]([NH:1][S:20]([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[N+:11]([O-:13])=[O:12])(=[O:21])=[O:22])[CH3:5]
Reactant: C[C@H](N)CO
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: C[C@@H](CO)NS(=O)(=O)c1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 39 h
Yield: 87.3 %

Procedure:
To a solution of (S)-(+)-2-amino-1-propanol (2.6 kg, 35 mol) in purified water (10.5 L) was added sodium bicarbonate (4.4 kg, 52 mol). To the resulting mixture was added a solution of 2-nitrobenzenesulfonyl chloride (7.3 kg, 33 mol) in tetrahydrofuran (10.2 L) at an internal temperature of −8° C. to −6° C. Subsequently, the resulting reaction mixture was stirred at room temperature for 39 hours. After confirming the disappearance of 2-nitrobenzenesulfonyl chloride by TLC, the mixture was filtered. The filtrate was then extracted with ethyl acetate, and the resulting organic layer was washed with saturated brine, dried over magnesium sulfate, and filtered. The filtrate was then concentrated under reduced pressure. The residue thus obtained was crystallized from petroleum ether/ethyl acetate to give the target product as a white solid (7.5 kg, yield 82.4%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([Cl:11])[N:10]=1)[C:5]([OH:7])=[O:6].S(Cl)(Cl)=O.[CH2:16](O)[CH3:17]>>[NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([Cl:11])[N:10]=1)[C:5]([O:7][CH2:16][CH3:17])=[O:6]
Reactant: CCO
Reactant: Nc1cc(C(=O)O)cc(Cl)n1
Solvent: O=S(Cl)Cl
Product: CCOC(=O)c1cc(N)nc(Cl)c1
Yield: 88 %

Procedure:
2-Amino-6-chloroisonicotinic acid (500 mg, 2.90 mmol) was dissolved in ethanol (29.0 mL), and the solution was stirred under heat and reflux for 3 hours after adding thionyl chloride (1.06 mL, 14.5 mmol). The solvent was then evaporated under reduced pressure. The residue was extracted with chloroform after adding a sodium hydrogen carbonate aqueous solution. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give ethyl 2-amino-6-chloroisonicotinate (510 mg, yield 88%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[CH2:13][CH2:12][S:11][C:10]2=[NH:14])=[CH:4][N:3]=1.Cl.C(N=C=NCCCN(C)C)C.[C:27]1([CH2:33][C:34](O)=[O:35])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>CN(C)C1C=CN=CC=1.ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[CH2:13][CH2:12][S:11][CH:10]2[NH:14][C:34](=[O:35])[CH2:33][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:4][N:3]=1
Reactant: O=C(O)Cc1ccccc1
Reactant: N=C1SCCN1Cc1ccc(Cl)nc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: O=C(Cc1ccccc1)NC1SCCN1Cc1ccc(Cl)nc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3-(2-Chloro-5-pyridinylmethyl)-2-iminothiazolidine (132 mg, 0.5 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (96 mg, 0.5 mmol) and 4-dimethylaminopyridine (65 mg, 0.54 mmol) in 3 ml of dichloromethane, phenylacetic acid (68 mg, 0.5 mmol) was added in portions, and stirred at room temperature overnight. After distilling the solvent off, the resultant crude crystal was washed with 1% hydrochloric acid, recrystallized from ethyl acetate thereby obtaining the intended substance. Yield: 100 mg (58%). Melting point: 157-158° C.
Reaction SMILES: O1CCC[CH2:2]1.[CH3:6][O:7][C:8]1[C:13]([O:14][CH3:15])=[C:12]([O:16][CH3:17])[CH:11]=[C:10]([CH3:18])[C:9]=1[CH:19]([C:21]1[C:26]([Br:27])=[CH:25][N:24]=[CH:23][C:22]=1Br)[OH:20].C([Li])CCC.CI>O>[CH3:6][O:7][C:8]1[C:13]([O:14][CH3:15])=[C:12]([O:16][CH3:17])[CH:11]=[C:10]([CH3:18])[C:9]=1[CH:19]([C:21]1[C:22]([CH3:2])=[CH:23][N:24]=[CH:25][C:26]=1[Br:27])[OH:20]
Reactant: COc1cc(C)c(C(O)c2c(Br)cncc2Br)c(OC)c1OC
Reactant: C1CCOC1
Agent: [Li]CCCC
Solvent: CI
Solvent: O
Product: COc1cc(C)c(C(O)c2c(C)cncc2Br)c(OC)c1OC
Reaction time: 0.08 h
Yield: 25 %

Procedure:
A tetrahydrofuran (15 ml) solution of 2.0 g (4.6 mmol) of (2,3,4-trimethoxy-6-methylphenyl)(3,5-dibromo-4-pyridyl)methanol obtained in step (a) was cooled to −78° C., 6.0 ml (9.4 mmol) of n-butyllithium (1.56 M hexane solution) was dropwise added thereto, followed by stirring for 5 minutes, and 0.5 ml (8.0 mmol) of methyl iodide was added thereto, followed by stirring for 2.5 hours. 20 ml of water was added, and tetrahydrofuran was distilled off under reduced pressure. The aqueous layer was extracted with ethyl acetate, the organic layer was dried over anhydrous sodium sulfate and subjected to filtration, and the solvent was distilled off under reduced pressure. The crude product thus obtained was purified by silica gel column chromatography to obtain 0.44 g (yield 25%) of (2,3,4-trimethoxy-6-methylphenyl)(3-bromo-5-methyl-4-pyridyl)methanol.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[NH2:6].Br[CH2:8][C:9](=O)[CH2:10][CH2:11][N:12]1[CH2:17][CH2:16][CH:15]([NH:18][C:19]2[N:23]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)[C:22]3[CH:32]=[CH:33][CH:34]=[CH:35][C:21]=3[N:20]=2)[CH2:14][CH2:13]1.C(=O)([O-])[O-].[Na+].[Na+].CC1C=CC=CC=1>O>[F:31][C:28]1[CH:29]=[CH:30][C:25]([CH2:24][N:23]2[C:22]3[CH:32]=[CH:33][CH:34]=[CH:35][C:21]=3[N:20]=[C:19]2[NH:18][CH:15]2[CH2:14][CH2:13][N:12]([CH2:11][CH2:10][C:9]3[N:6]=[C:2]4[N:3]([CH:8]=3)[CH:4]=[CH:5][S:1]4)[CH2:17][CH2:16]2)=[CH:26][CH:27]=1
Reactant: O=C(CBr)CCN1CCC(Nc2nc3ccccc3n2Cc2ccc(F)cc2)CC1
Reactant: Nc1nccs1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: Fc1ccc(Cn2c(NC3CCN(CCc4cn5ccsc5n4)CC3)nc3ccccc32)cc1
Yield: 5.3 %

Procedure:
A mixture of 2 parts of 2-thiazolamine, 12.7 parts of 1-bromo-4-[4-[[1-[(4-fluorophenyl)methyl]-1H-benzimidazol-2-yl]amino]-1-piperidinyl]-2-butanone, 6.4 parts of sodium carbonate and 135 parts of methylbenzene was stirred and refluxed for 3 hours using a water separator. The whole was filtered and the filtrate was evaporated. The residue was purified twice by column chromatography over silica gel using a mixture of trichloromethane and methanol, saturated with ammonia, (96:4 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from acetonitrile, yielding 0.5 parts (5.3%) of 1-[(4-fluorophenyl)methyl]-N-[1-[2-(imidazo[2,1-b]thiazol-6-yl)ethyl]-4-piperidinyl]-1H-benzimidazol-2-amine; mp. 222.7° C. (compound 149).
Reaction SMILES: [CH3:1][NH:2][C:3](=[S:6])[NH:4][NH2:5].[CH2:7]([Cl:16])[C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=O>CO>[ClH:16].[CH3:1][NH:2][C:3]1[S:6][CH2:7][C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:5][N:4]=1
Reactant: CNC(=S)NN
Reactant: O=C(CCl)c1ccccc1
Solvent: CO
Product: CNC1=NN=C(c2ccccc2)CS1
Product: Cl
Reaction time: 48 h

Procedure:
5.255 g (0.05 mole) of 4-methyl-thiosemicarbazide and 7.73 g (0.05 mole) of phenacyl chloride are heated and stirred at reflux (65° C.) in 200 ml of methanol for 30 minutes. At this time, the solvent is removed in vacuo. The residue is dissolved in methanol, warmed and then diluted with acetone. Thereafter, it is concentrated to approximately 200 ml. After standing for 2 days, 8.33 g of N-methyl-5-phenyl-6H-1,3,4-thiadiazin-2-amine hydrochloride are deposited. m.p. 176°-178° C.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([N+:11]([O-])=O)[C:6](=[O:10])[NH:7][C:8]=1[CH3:9])[CH3:2]>CO.O1CCCC1.[Pd]>[NH2:11][C:5]1[C:6](=[O:10])[NH:7][C:8]([CH3:9])=[C:3]([CH2:1][CH3:2])[CH:4]=1
Reactant: CCc1cc([N+](=O)[O-])c(=O)[nH]c1C
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: CCc1cc(N)c(=O)[nH]c1C
Yield: 68.1 %

Procedure:
A yellow solution of the 5-ethyl-6-methyl-3-nitro-2-(1H)-pyridinone (10 g, 55 mmol) in a mixture of methanol and tetrahydrofuran (100 mL, 1:1 v/v) was reduced catalytically in the presence of 7% palladium on charcoal (0.7 g) under an atmosphere of hydrogen (50 psi) at room temperature over a period of 3.5 hours. The resultant mixture was filtered through a small pad of Celite. The filtrate was concentrated under reduced pressure (15 torr) to provide 5.7 g (68%) of the corresponding aminopyridone.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([NH:12][N:13]=[C:14]([C:23]([OH:25])=[O:24])[CH2:15][CH2:16][CH2:17][N:18]([CH2:21][CH3:22])[CH2:19][CH3:20])[CH2:9][N:8]=[C:7]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[Cl:32])[C:6]=2[CH:33]=1.[N+](=[CH2:36])=[N-]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([NH:12][N:13]=[C:14]([C:23]([O:25][CH3:36])=[O:24])[CH2:15][CH2:16][CH2:17][N:18]([CH2:21][CH3:22])[CH2:19][CH3:20])[CH2:9][N:8]=[C:7]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[Cl:32])[C:6]=2[CH:33]=1
Reactant: C=[N+]=[N-]
Reactant: CCN(CC)CCCC(=NNC1=Nc2ccc(Cl)cc2C(c2ccccc2Cl)=NC1)C(=O)O
Product: CCN(CC)CCCC(=NNC1=Nc2ccc(Cl)cc2C(c2ccccc2Cl)=NC1)C(=O)OC

Procedure:
In the manner given in Example 14, 7-chloro-2-[[1-carboxy-4-(diethylamino)butylidene]hydrazino]-5-(o-chlorophenyl)-3H-1,4-benzodiazepine can be treated with ethereal diazomethane to give 7-chloro-2-[[1-(methoxycarbonyl)-4-(diethylamino)butylidene]hydrazino]-5-(o-chlorophenyl)-3H-1,4-benzodiazepine.
Reaction SMILES: COC1C=C(C(C2C=CC(OC)=C(OC)C=2)=CC(OC)=O)C=CC=1OC.[CH2:27]([C:29]1[CH:30]=[C:31]([C:37](=O)[C:38]2[CH:43]=[CH:42][C:41]([O:44][CH3:45])=[C:40]([O:46][CH3:47])[CH:39]=2)[CH:32]=[CH:33][C:34]=1[CH2:35][CH3:36])[CH3:28].C(OP([CH2:57][C:58]#[N:59])(=O)OCC)C.C[Si](C)(C)[N-][Si](C)(C)C.[Li+]>CCCCCC>[CH2:27]([C:29]1[CH:30]=[C:31]([C:37]([C:38]2[CH:43]=[CH:42][C:41]([O:44][CH3:45])=[C:40]([O:46][CH3:47])[CH:39]=2)=[CH:57][C:58]#[N:59])[CH:32]=[CH:33][C:34]=1[CH2:35][CH3:36])[CH3:28]
Reactant: CCOP(=O)(CC#N)OCC
Reactant: CCc1ccc(C(=O)c2ccc(OC)c(OC)c2)cc1CC
Agent: COC(=O)C=C(c1ccc(OC)c(OC)c1)c1ccc(OC)c(OC)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CCCCCC
Product: CCc1ccc(C(=CC#N)c2ccc(OC)c(OC)c2)cc1CC

Procedure:
3-(3,4-Diethylphenyl)-3-(3,4-dimethoxyphenyl)acrylonitrile was prepared analogously to methyl 3,3-bis-(3,4-dimethoxyphenyl)acrylate using 3′,4′-diethyl-3,4-dimethoxybenzophenone (0.51 g, 1.7 mmol), diethylcyanomethylphosphonate (0.31 mL, 1.9 mmol) and lithium hexamethyldisilazide (1.4 mL, 1.9 mmol, 1.3 M) with a reaction time of 60 hours at room temperature. The crude product was purified by chromatography (silica gel, 1% ethyl acetate/methylene chloride) to afford an oil which was stirred in hexane until it solidified. The resulting slurry was filtered, the solid washed with hexane, air dried, and dried in vacuo to afford 0.31 g (57%) of a mixture of the E and Z isomers as an off white solid: mp 78-82° C.; 1H NMR (CDCl3) δ 7.30-6.75 (m, 12 H), 5.61 (s, 1 H), 5.60 (s, 1 H), 3.94 (s, 3 H), 3.92 (s, 3 H), 3.87 (s, 3 H), 3.83 (s, 3 H), 2.80-2.59 (m, 8 H), 1.35-1.14 (m, 12 H); 13C NMR (CDCl3) δ 163.0, 163.0, 151.0, 150.5, 148.8, 148.6, 144.6, 143.9, 142.1, 141.8, 136.8, 134.5, 131.9, 129.7, 128.6, 128.5, 128.2, 127.3, 126.3, 123.2, 122.2, 118.7, 118.6, 112.8, 111.3, 110.7, 92.5, 92.2, 56.1, 56.0, 25.5, 25.4, 25 4, 25.3, 15.3, 15.2, 15.0, 14.9; Anal. Calcd for C21H23NO2. Theoretical: C, 78.47; H, 7.21; N, 4.36. Found: C, 77.80; H, 7.25; N, 4.68.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[CH:10]([CH3:24])[C:11]([C:17]1[CH:22]=[CH:21][N:20]=[C:19](Cl)[CH:18]=1)([OH:16])[C:12]([F:15])([F:14])[F:13].[I-:25].[Na+].I>C(C(C)=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[CH:10]([CH3:24])[C:11]([C:17]1[CH:22]=[CH:21][N:20]=[C:19]([I:25])[CH:18]=1)([OH:16])[C:12]([F:15])([F:14])[F:13]
Reactant: COc1ccc(C(C)C(O)(c2ccnc(Cl)c2)C(F)(F)F)c(Cl)c1
Reactant: [I-]
Agent: I
Agent: [Na+]
Solvent: CCC(C)=O
Product: COc1ccc(C(C)C(O)(c2ccnc(I)c2)C(F)(F)F)c(Cl)c1
Yield: 79.5 %

Procedure:
3-(2-Chloro-4-methoxy-phenyl)-2-(2-chloro-pyridin-4-yl)-1,1,1-trifluoro-butan-2-ol (Example 132, 0.38 g) in ethyl-methyl ketone (5 mL) was treated with sodium iodide (600 mg) and HI-57% (0.132 mL) and heated for 2.5 h under reflux. The reaction mixture was then concentrated in vacuo, diluted with water, and pH adjusted to 7 with a saturated aqueous NaHCO3 solution. The mixture was extracted twice with ethyl acetate. The combined organic phases were washed with 0.5M sodium-thiosulfate and brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by flash chromatography (20 g silica gel, ethyl acetate/heptane 20:80) to give the title compound as white solid (375 mg). MS (m/e)=471.9 (MH+).
Reaction SMILES: [C:1]([C:5]1[CH:21]=[CH:20][C:8]([C:9]([NH:11][C:12]2[C:17]([Br:18])=[CH:16][CH:15]=[CH:14][C:13]=2[Br:19])=O)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:31])=CC=1>C1(C)C=CC=CC=1>[C:1]([C:5]1[CH:21]=[CH:20][C:8]([C:9](=[S:31])[NH:11][C:12]2[C:17]([Br:18])=[CH:16][CH:15]=[CH:14][C:13]=2[Br:19])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CC(C)(C)c1ccc(C(=O)Nc2c(Br)cccc2Br)cc1
Solvent: Cc1ccccc1
Product: CC(C)(C)c1ccc(C(=S)Nc2c(Br)cccc2Br)cc1
Yield: 41 %

Procedure:
4-tert-butyl-N-(2,6-dibromophenyl)benzamide prepared as in Example 18 (1.20 g, 2.92 mmol) was dissolved in toluene (45 mL) and treated with Lawesson's reagent (1.18 g, 2.92 mmol.) The solution was heated to reflux for 2 h and then cooled. The solvent was removed under reduced pressure, and the residue was adsorbed onto silica gel. Elution with 10% to 20% acetone/hexane gave 0.509 g (41%) of product. MS (ESI) m/z 425.952; HPLC Method B, purity 85.7% at 210-370 nm, 11.1 min.; 91.1% at 262 nm, 11.1 min.; HRMS: calcd for C17H17Br2NS+H+, 425.95212; found (ESI, [M+H]+), 425.952.
Reaction SMILES: S(Cl)([Cl:3])=O.[O:5]1[CH2:10][CH2:9][N:8]([CH2:11][C:12]#[C:13][CH2:14]O)[CH2:7][CH2:6]1>ClCCl>[ClH:3].[O:5]1[CH2:10][CH2:9][N:8]([CH2:11][C:12]#[C:13][CH2:14][Cl:3])[CH2:7][CH2:6]1
Reactant: OCC#CCN1CCOCC1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: Cl
Product: ClCC#CCN1CCOCC1
Reaction time: 0.5 h

Procedure:
Thionyl chloride (2.1 ml) was added to a solution of 4-morpholino-2-butyn-1-ol (1.47 g) in dichloromethane (10 ml) with ice bath cooling. After stirring for 0.5 hour, the solution was evaporate din vacuo. The residue was triturated with ethyl acetate to give 4-morpholino-2-butynyl chloride hydrochloride (1.91 g).