Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[NH:4][C:5](=[O:10])[CH:6]=[C:7]([CH3:9])[N:8]=1)[CH3:2].Br[CH2:12][CH2:13][O:14][C:15]1[CH:22]=[CH:21][C:18]([CH:19]=[O:20])=[CH:17][CH:16]=1.[Li+].[Br-].[H-].[Na+]>>[CH2:1]([C:3]1[N:4]([CH2:12][CH2:13][O:14][C:15]2[CH:22]=[CH:21][C:18]([CH:19]=[O:20])=[CH:17][CH:16]=2)[C:5](=[O:10])[CH:6]=[C:7]([CH3:9])[N:8]=1)[CH3:2]
Reactant: CCc1nc(C)cc(=O)[nH]1
Reactant: O=Cc1ccc(OCCBr)cc1
Agent: [Br-]
Agent: [H-]
Agent: [Li+]
Product: CCc1nc(C)cc(=O)n1CCOc1ccc(C=O)cc1
Yield: 41 %

Procedure:
The title compound (1.7 g, 42%) was prepared from 2-ethyl-4-methyl-1,6-dihydro-6-pyrimidone (2.0 g, 14.49 mmol), 4-[2-bromoethoxy]benzaldehyde (3.32 g, 14.49 mmol), LiBr (2.9 g 33.33 mmol) and NaH (0.45 g, 18.84 mmol) as base, by a similar procedure to that described in preparation 1.
Reaction SMILES: [Li]CCCC.Br[C:7]1[CH:8]=[C:9]2[C:17](=[CH:18][CH:19]=1)[N:16]([CH3:20])[C:15]1[C:14]3[CH:21]=[CH:22][CH:23]=[CH:24][C:13]=3[O:12][CH2:11][C:10]2=1.[C:25](=[O:27])=[O:26]>C1COCC1>[CH3:20][N:16]1[C:15]2[C:14]3[CH:21]=[CH:22][CH:23]=[CH:24][C:13]=3[O:12][CH2:11][C:10]=2[C:9]2[C:17]1=[CH:18][CH:19]=[C:7]([C:25]([OH:27])=[O:26])[CH:8]=2
Reactant: Cn1c2c(c3cc(Br)ccc31)COc1ccccc1-2
Reactant: O=C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cn1c2c(c3cc(C(=O)O)ccc31)COc1ccccc1-2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
n-BuLi was added dropwise into 8-bromo-11-methyl-6,11-dihydro-5-oxa-11-aza-benzo[a]fluorene (420 mg, 1.338 mmoL) in THF (5 mL) at −78° C. After an additional 30 minutes, the reaction mixture was transferred into dry ice (˜10 g). The reaction mixture was then slowly warmed to room temperature. The solvent was removed and the residue was partitioned between EtOAc and 1 N NaOH solution. The aqueous layer was then acidified to a pH of about 2 using 1N HCl and extracted three times with EtOAc. The organic phase of each extraction was combined, washed with water, brine, dried over anhydrous Na2SO4, filtered and concentrated to yield a clear oil. The oil was then purified by column chromatography (silica gel, hexanes:EtOAc 1:1 as eluent) to yield the title compound as a white solid.
Reaction SMILES: [CH:1]1([CH2:7][N:8]2[C:16](=[O:17])[C:15]3[N:14]=C(C4C=CC(/C=C/C(O)=O)=CC=4)[NH:12][C:11]=3[N:10]([CH2:29][CH:30]3[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]3)[C:9]2=[O:36])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.NC1N(CC2CCCCC2)C(=O)N(CC2CCCCC2)C(=O)C=1N=O.C(C1C=CC=CC=1C(O)=O)=O>>[CH:30]1([CH2:29][N:10]2[C:11]([NH2:12])=[C:15]([NH2:14])[C:16](=[O:17])[N:8]([CH2:7][CH:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)[C:9]2=[O:36])[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]1
Reactant: O=C(O)/C=C/c1ccc(-c2nc3c(=O)n(CC4CCCCC4)c(=O)n(CC4CCCCC4)c3[nH]2)cc1
Agent: Nc1c(N=O)c(=O)n(CC2CCCCC2)c(=O)n1CC1CCCCC1
Agent: O=Cc1ccccc1C(=O)O
Product: Nc1c(N)n(CC2CCCCC2)c(=O)n(CC2CCCCC2)c1=O

Procedure:
1,3-Bis(cyclohexylmethyl)-5,6-diaminouracil was prepared as in part (d) of Example 1 by reduction of 1, 6-amino 1,3-bis(cyclohexylmethyl)-5-nitrosouracil (2.00 g) and immediately condensed with 2-formylbenzoic acid (Aldrich, 1.424 g) by the method of J. Perumattam (Synthetic Commun. 1989, 19: 3367-3370) to give title compound as an off-white solid off-white solid (1.22 g, 46%), m.p. 271-274° C.; 1H-NMR (DMSO-d6) consistent with structure.
Reaction SMILES: [C:1]([C:3]1[C:4]([CH:19]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([Cl:30])[CH:24]=2)[CH2:20][CH:21]=O)=[C:5]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[S:6][C:7]=1[N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)#[N:2].Cl.[CH3:32][NH:33][CH3:34].C([O-])(=O)C.[Na+].C([BH3-])#N.[Na+].C([O-])(O)=O.[Na+]>CO.CCOC(C)=O>[C:1]([C:3]1[C:4]([CH:19]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([Cl:30])[CH:24]=2)[CH2:20][CH2:21][N:33]([CH3:34])[CH3:32])=[C:5]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[S:6][C:7]=1[N:8]1[CH2:9][CH2:10][O:11][CH2:12][CH2:13]1)#[N:2]
Reactant: CCOC(=O)c1sc(N2CCOCC2)c(C#N)c1C(CC=O)c1ccc(Cl)c(Cl)c1
Reactant: CNC
Agent: CC(=O)[O-]
Agent: Cl
Agent: O=C([O-])O
Solvent: CCOC(C)=O
Solvent: CO
Product: CCOC(=O)c1sc(N2CCOCC2)c(C#N)c1C(CCN(C)C)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 71.9 %

Procedure:
To a solution of ethyl 4-cyano-3-[1-(3,4-dichlorophenyl)-3-oxopropyl]-5-(morpholin-4-yl)thiophene-2-carboxylate (38.0 mg, 0.0813 mmol) (from example 56, step 1) in methanol (1.00 mL) was added dimethylamine hydrochloride (9.94 mg, 0.122 mmol), sodium acetate (8.00 mg, 0.0976 mmol), and sodium cyanoborohydride (6.13 mg, 0.0976 mmol). The reaction was stirred at rt for 2 h. The mixture was distributed between NaHCO3(aq) saturated solution and EtOAc. The aqueous layer was extracted with EtOAc (×2). The combined organic layer was dried and concentrated. Purification on a silica gel column (gradient elution, 0-15% MeOH/CH2Cl2) provided ethyl 4-cyano-3-[1-(3,4-dichlorophenyl)-3-(dimethylamino)propyl]-5-(morpholin-4-yl)thiophene-2-carboxylate as a yellow syrup (29.0 mg, 71.8% yield). LCMS: (AA) ES+ 496, 498, 500; 1H NMR (400 MHz, CDCl3) δ 7.52-7.44 (d, J=1.9 Hz, 1H), 7.41-7.34 (m, 1H), 7.33-7.27 (m, 1H), 5.54-5.40 (t, J=7.7 Hz, 1H), 4.38-4.27 (q, J=7.1 Hz, 2H), 3.88-3.76 (t, J=4.9 Hz, 4H), 3.58-3.49 (dd, J=5.7, 4.0 Hz, 4H), 2.57-2.31 (m, 3H), 2.29-2.24 (s, 6H), 2.24-2.16 (m, 1H), 1.41-1.30 (t, J=7.1 Hz, 3H).
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8]([OH:10])=O)=[CH:6][N:5]=[C:4]([C:11]2[N:16]=[CH:15][CH:14]=[CH:13][N:12]=2)[N:3]=1.[Cl-].[F:18][C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][CH:27]=1)[N:24]([NH3+:28])[CH:23]=[C:22]2[CH3:29].CN1CCOCC1.[Cl-].COC1N=C(OC)N=C([N+]2(C)CCOCC2)N=1>O.CN(C=O)C>[F:18][C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][CH:27]=1)[N:24]([NH:28][C:8]([C:7]1[C:2]([CH3:1])=[N:3][C:4]([C:11]3[N:16]=[CH:15][CH:14]=[CH:13][N:12]=3)=[N:5][CH:6]=1)=[O:10])[CH:23]=[C:22]2[CH3:29]
Reactant: Cc1nc(-c2ncccn2)ncc1C(=O)O
Reactant: Cc1cn([NH3+])c2ccc(F)cc12
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: [Cl-]
Solvent: CN1CCOCC1
Solvent: O
Solvent: CN(C)C=O
Product: Cc1nc(-c2ncccn2)ncc1C(=O)Nn1cc(C)c2cc(F)ccc21
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 60 %

Procedure:
4-Methyl-[2,2]bipyrimidinyl-5-carboxylic acid (0.5 g, 2.31 mmol) is combined with 5-fluoro-3-methyl-indol-1-yl-ammonium chloride (464 mg, 2.31 mmol), N-methylmorpholine (233 mg, 2.31 mmol) and DMF (10 mL). The suspension is stirred for 5 minutes at rt, then 4-(4,6-dimethoxy-[1,3,5]triazin-2-yl)-4-methyl-morpholin-4-ium chloride is added (640 mg, 2.31 mmol). The reaction is heated to 50° C. for 4 h. The reaction is then poured into water (50 mL), the suspension is chilled for 2 h in the refrigerator, and then filtered. The solids are then suspended in acetonitrile at 50° C. for 4 h, cooled, then filtered to afford 4-methyl-[2,2′]bipyrimidinyl-5-carboxylic acid (5-fluoro-3-methyl-indol-1-yl)-amide (60%). MS: 363 (M+H); 1H NMR (300 MHz, CDCl3): δ=2.27 (s, 3H), 2.77 (s, 3H), 7.07 (dt, 1H), 7.36 (dd, 1H), 7.38 (s, 1H), 7.44-7.48 (m, 1H), 7.70 (t, 1H), 9.05 (d, 2H), 9.29 (s, 1H), 11.9 (s, 1H). IC50=4.5 nM.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:24]=[CH:23][C:12]3[C@:13]4([CH3:22])[C@@H:18]([CH2:19][CH2:20][C:11]=3[CH:10]=2)[NH:17][C:16](=[O:21])[CH2:15][CH2:14]4)=[CH:5][CH:4]=1)#[N:2].[C:25](O)(C)(C)C.CC(C)([O-])C.[K+].CI>C(OCC)(=O)C>[CH3:25][N:17]1[C@H:18]2[C@@:13]([CH3:22])([C:12]3[CH:23]=[CH:24][C:9]([C:6]4[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][CH:7]=4)=[CH:10][C:11]=3[CH2:20][CH2:19]2)[CH2:14][CH2:15][C:16]1=[O:21]
Reactant: CC(C)(C)O
Reactant: C[C@]12CCC(=O)N[C@@H]1CCc1cc(-c3ccc(C#N)cc3)ccc12
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CI
Product: CN1C(=O)CC[C@]2(C)c3ccc(-c4ccc(C#N)cc4)cc3CC[C@@H]12
Temperature: 25 °C
Reaction time: 4 h
Yield: 80 %

Procedure:
A 15 mL round bottom flask was charged with (+)-(4aR)-(10bR)-8-(4-cyanophenyl)-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one (24 mg, 0.08 mmol), 0.20 mL of t-butanol, and potassium t-butoxide (26 mg, 0.24 mmol). Methyl iodide (0.014 mL, 0.24 mmol) was added and the mixture was stirred at room temperature for 4 h. The mixture was diluted with ethyl acetate, and purified by silica gel chromatography (ethyl acetate eluent) to give 20 mg (80%) of the title compound as a white solid. mp 148°-150°. FDMS: m/e=330.
Reaction SMILES: O.NN.O=C1C2C(=CC=CC=2)C(=O)[N:6]1[CH2:15][C:16]([NH:18][C:19]1[CH:20]=[N:21][N:22]([CH3:44])[C:23]=1[NH:24][C:25]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:17]>C(O)C.O1CCCC1>[NH2:6][CH2:15][C:16]([NH:18][C:19]1[CH:20]=[N:21][N:22]([CH3:44])[C:23]=1[NH:24][C:25]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)=[O:17]
Reactant: Cn1ncc(NC(=O)CN2C(=O)c3ccccc3C2=O)c1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: NN
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: Cn1ncc(NC(=O)CN)c1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 70 °C
Reaction time: 2 h
Yield: 81.8 %

Procedure:
Hydrazine monohydrate (1.46 ml) was added to a solution of 2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-N-[1-methyl-5-(tritylamino)-1H-pyrazol-4-yl]acetamide (5.42 g) in ethanol (108 ml) and tetrahydrofuran (54 ml) at room temperature, and the mixture was stirred at 70° C. for 2 hours. The reaction mixture was cooled to 0° C., and the insoluble materials were removed by filtration. The filtrate was concentrated in vacuo. The residue was triturated with diisopropyl ether, collected by filtration and dried in vacuo to give 2-amino-N-[1-methyl-5-(tritylamino)-1H-pyrazol-4-yl]acetamide (3.37 g) as a solid. This product was used in the next step without further purification.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:8]2[CH2:16][CH:15]3[CH2:17][N:11]4[CH2:12][CH:13]([CH2:18][CH:9]2[CH2:10]4)[CH2:14]3)[CH:5]=[N:6][CH:7]=1.[F:19][C:20]([F:31])([F:30])[C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1>>[F:19][C:20]([F:31])([F:30])[C:21]1[CH:26]=[CH:25][C:24]([C:2]2[CH:3]=[C:4]([N:8]3[CH2:16][CH:15]4[CH2:17][N:11]5[CH2:12][CH:13]([CH2:18][CH:9]3[CH2:10]5)[CH2:14]4)[CH:5]=[N:6][CH:7]=2)=[CH:23][CH:22]=1
Reactant: Brc1cncc(N2CC3CC4CC2CN(C4)C3)c1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Product: FC(F)(F)c1ccc(-c2cncc(N3CC4CC5CC3CN(C5)C4)c2)cc1

Procedure:
The title compound was prepared from the product of Example 65A and 4-trifluoromethylphenylboronic acid according to General Method B: LC-MS Method D (ESI+) m/z 374.0 (M+H)+, retention time 1.47 minutes.
Reaction SMILES: P(=O)(O)(O)O.CC(C)CC(=O)C.[NH2:13][C:14]1[CH:18]=[CH:17][S:16][C:15]=1/[C:19](=[CH:21]/[CH:22]([CH3:24])[CH3:23])/[CH3:20].NC1C=CSC=1/C(=C\C(C)C)/C>O>[NH2:13][C:14]1[CH:18]=[CH:17][S:16][C:15]=1[C:19]([CH2:21][CH:22]([CH3:24])[CH3:23])=[CH2:20]
Reactant: C/C(=C\C(C)C)c1sccc1N
Agent: C/C(=C/C(C)C)c1sccc1N
Agent: O=P(O)(O)O
Solvent: O
Solvent: CC(=O)CC(C)C
Product: C=C(CC(C)C)c1sccc1N
Temperature: 25 °C
Yield: 34 %

Procedure:
3-aminothiophene phosphate (5.0 g, 16.1 mmol) was added into water (100 g) in an ice water bath for dissolving. Toluene (50.0 g) was added in an ice water bath, and then a 10% aqueous sodium hydroxide solution was added under stirring in an ice water bath for adjusting the reaction solution to the alkaline side. The organic layer was separated, and then the aqueous layer was further extracted with toluene. To the toluene solution of 3-aminothiophene obtained as described above were added 85% phosphoric acid (0.9 g, 8.1 mmol) and 4-methyl-2-pentanone (50.0 g, 499.2 mmol) at room temperature, and the resulting solution was stirred under reflux under nitrogen atmosphere for 5 hours with removing water. The reaction solution was cooled to room temperature, and then washed with a 10% aqueous sodium hydroxide solution two times, and the obtained organic layer was concentrated under reduced pressure to give an oily substance. The resulting concentrate was purified by silica gel column chromatography to give 1.0 g of an oily substance as a mixture of three compounds including 3-amino-2-{(E)-(4-methyl-2-penten-2-yl)}thiophene, 3-amino-2-{(Z)-(4-methyl-2-penten-2-yl)}thiophene and 3-amino-2-(4-methyl-1-penten-2-yl)thiophene (yield: 34%).
Reaction SMILES: C([O:3][C:4]([C@H:6]1[C@H:10]([NH:11][C@@H:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH3:13])[CH2:9][N:8]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:7]1)=[O:5])C.[OH-].[Na+].Cl>O1CCCC1>[C:23]([O:22][C:20]([N:8]1[CH2:9][C@@H:10]([NH:11][C@@H:12]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH3:13])[C@H:6]([C:4]([OH:5])=[O:3])[CH2:7]1)=[O:21])([CH3:24])([CH3:25])[CH3:26]
Reactant: CCOC(=O)[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]1N[C@H](C)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: C[C@@H](N[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]1C(=O)O)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of (3R,4S)-4-[(R)-1-phenyl-ethylamino]-pyrrolidine-1,3-dicarboxylic acid 1-tert-butyl ester 3-ethyl ester (prepared according to the procedure of X. Wang, J. F. Espinosa and S. H. Gellman, J. Am. Chem. Soc. 2000, 122, 4821; 107 mg, 295 μmol) in tetrahydrofuran (2 mL) was treated with 1.0 M sodium hydroxide solution (600 μL, 600 μmol) and the heterogenous mixture was stirred at room temperature. After 18 h , the now homogenous solution was treated with 1.0 M hydrochloric acid (600 μL, 600 μmol) and concentrated in vacuo. The residue was dissolved in water and lyophilized to provide the product, along with sodium chloride, as a white solid (115 mg, quantitative), used without further purification. 1H NMR (300 mHz, CD3OD) δ7.48 (m, 5H), 4.44 (m, 1H), 3.89 (m, 1H), 3.78 (m, 1H), 3.44-3.14 (3H), 1.67 (d, 3H), 1.4 (bs, 9H); mass spec. (ES+) m/z 335.3.
Reaction SMILES: [C:1]1([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[NH:9][C:8]=2[C:16](O)=[S:17])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N.F[P-](F)(F)(F)(F)F.[N:27]1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C)C=O>[C:1]1([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[NH:9][C:8]=2[C:16]([NH2:27])=[S:17])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OC(=S)c1[nH]c2ccccc2c1-c1ccccc1
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: N
Solvent: CN(C)C=O
Product: NC(=S)c1[nH]c2ccccc2c1-c1ccccc1

Procedure:
The title compound was prepared from 3-phenylthioindole-2-carboxylic acid (prepared according to the procedure described by Atkinson, J. G. et al., Synthesis, p. 480-481 (1988), (4.01 g, 0.015 mol), ammonia (large excess), and benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorphosphate (7.2 g, 0.016 mol) in dimethylformamide according to the general procedure described in Example 1 for the preparation of N-(3-pyridylmethyl)-5-chloro-3-phenylthio-2-carboxamide. The title compound was obtained as a pale yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH2:15]Cl)=[N:13][N:14]=[C:10]3[CH2:9][N:8]=[C:7]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[Cl:23])[C:6]=2[CH:24]=1.[NH2:25][OH:26].[H-].[Na+]>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH2:15][NH:25][OH:26])=[N:13][N:14]=[C:10]3[CH2:9][N:8]=[C:7]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[Cl:23])[C:6]=2[CH:24]=1
Reactant: ClCc1nnc2n1-c1ccc(Cl)cc1C(c1ccccc1Cl)=NC2
Reactant: NO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: ONCc1nnc2n1-c1ccc(Cl)cc1C(c1ccccc1Cl)=NC2

Procedure:
In the manner given in Example 15, 8-chloro-1-(chloromethyl)-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine is treated with a cold mixture of hydroxylamine and sodium hydride in dimethylformamide to give 8-chloro-1-[(hydroxyamino)methyl]-6-(o-chlorophenyl)-4H-s-triazolo [4,3-a][1,4]benzodiazepine.
Reaction SMILES: Br[C:2]([F:9])([F:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[C:10]([O:14][CH2:15][CH3:16])(=[O:13])[CH:11]=[CH2:12].CN(CCN(C)C)C.[Cl-].[NH4+]>O1CCCC1.[Cu].C(OC)(C)(C)C>[F:8][C:2]([F:9])([CH2:12][CH2:11][C:10]([O:14][CH2:15][CH3:16])=[O:13])[C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: C=CC(=O)OCC
Reactant: CCOC(=O)C(F)(F)Br
Agent: [Cu]
Agent: CN(C)CCN(C)C
Agent: [Cl-]
Solvent: COC(C)(C)C
Solvent: C1CCOC1
Product: CCOC(=O)CCC(F)(F)C(=O)OCC
Temperature: 50 °C
Reaction time: 3 h
Yield: 299.5 %

Procedure:
To a solution of ethyl bromodifluoroacetate (33.2 g) in tetrahydrofuran (94.0 g) was added ethyl acrylate (8.2 g) and copper powder (10.9 g). After heating to 50° C., TMEDA (9.5 g) was added dropwise and the reaction mixture was then stirred for 3 hours at the same temperature. Upon disappearance of ethyl acrylate as the starting material, to the reaction solution was added methyl t-butyl ether (MTBE, 73.7 g) followed by addition of 10% aqueous ammonium chloride solution (49.8 g) dropwise, and the mixture was then stirred for 30 minutes. The remaining copper residue was removed by filtration through a celite, and methyl t-butyl ether (MTBE, 66.3 g) was added to separate the layers. The separated organic layer was washed successively with 10% aqueous NH4Cl solution (66.3 g) and 3 N aqueous hydrochloric acid solution (99.6 g) in order and then distilled under reduced pressure to obtain 55.0 g of the desired title compound.
Reaction SMILES: [I-:1].[OH:2][C:3]1[CH:4]=[C:5]([C@@H:9]([N+:11]([CH3:21])([CH3:20])[C@H:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH3:13])[CH3:10])[CH:6]=[CH:7][CH:8]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:28]([N:30]([CH3:34])[C:31](Cl)=[O:32])[CH3:29]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C(#N)C>[I-:1].[CH2:28]([N:30]([CH3:34])[C:31]([O:2][C:3]1[CH:4]=[C:5]([C@@H:9]([N+:11]([CH3:21])([CH3:20])[C@H:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH3:13])[CH3:10])[CH:6]=[CH:7][CH:8]=1)=[O:32])[CH3:29]
Reactant: C[C@@H](c1ccccc1)[N+](C)(C)[C@@H](C)c1cccc(O)c1
Reactant: CCN(C)C(=O)Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Br-]
Solvent: CC#N
Product: CCN(C)C(=O)Oc1cccc([C@H](C)[N+](C)(C)[C@@H](C)c2ccccc2)c1
Temperature: 60 °C

Procedure:
Mix 7.9 g (0.02 mol) of(S)-1-(3-hydroxyphenyl)-N,N-dimethyl-N—((S)-1-phenylethyl)ethanaminium iodide (formula VIII) with 180 ml of acetonitrile, 4.1 g (0.03 mol) of potassium carbonate, 3.6 (0.03 mol) ethyl(methyl)carbamic chloride and 0.1 g of tetrabutylammonium bromide at room temperature, heat it to 60° C. and react it for 12 hours. After it is cooled to room temperature, filter it and reduce the pressure to recover the solvent and receive 9.5 g of red-brown liquid to be directly used in the next reaction.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)[CH:3]=1.C([Li])CCC.N#N.Cl.C1C[O:27][CH2:26]C1>CN(C=O)C>[F:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][C:4]2[CH:3]=[C:2]([CH:7]=[CH:6][CH:5]=2)[CH:26]=[O:27])=[CH:10][CH:11]=1
Reactant: C1CCOC1
Reactant: Fc1ccc(Oc2cccc(Br)c2)cc1
Agent: Cl
Agent: N#N
Agent: [Li]CCCC
Solvent: CN(C)C=O
Product: O=Cc1cccc(Oc2ccc(F)cc2)c1
Temperature: -75 °C
Reaction time: 0.5 h

Procedure:
To a cooled (-75° C.), stirred solution of 1-bromo-3-(4-fluorophenoxy)benzene (38.5 g; 0.1442M) in dry THF (80 ml) was added n-butyllithium (1.63M in n-hexane, 68 ml; 0.11M) dropwise at under N2. After stirring for 30 min at -73° C., DMF (11.38 g; 0.1557M) was added dropwise to the mixture at -73° C. The mixture was stirred for further 30 min, and then allowed to warm to room temperature. 2M aqueous HCl (200 ml) was added to the mixture and the whole was extracted with Et2O (100 ml×3). The combined organic layers were washed with water (150 ml), brine (150 ml), dried over MgSO4, and concentrated in vacuo. The residual oil was purified by flash column (SiO2) eluting with ethyl acetate-n-hexane (1: 10) to give 21.6 g of the subtitle compound [B] as a colorless oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[CH:11]([OH:12])[CH:10]([C:13]2[C:14](=[O:20])[N:15]([CH3:19])[CH:16]=[CH:17][CH:18]=2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([NH2:21])[CH:8]=2)[O:3]1.[CH:23](O)=[O:24]>N1C=CC=CC=1>[CH3:1][C:2]1([CH3:22])[CH:11]([OH:12])[CH:10]([C:13]2[C:14](=[O:20])[N:15]([CH3:19])[CH:16]=[CH:17][CH:18]=2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([NH:21][CH:23]=[O:24])[CH:8]=2)[O:3]1
Reactant: Cn1cccc(C2c3cc(N)ccc3OC(C)(C)C2O)c1=O
Reactant: O=CO
Solvent: c1ccncc1
Product: Cn1cccc(C2c3cc(NC=O)ccc3OC(C)(C)C2O)c1=O

Procedure:
A solution of 1 g of 2,2-dimethyl-4-(1-methyl-1,2-dihydro-2-oxo-3-pyridyl)-6-amino-3-chromanol in15 ml of formic acid and 1 ml of pyridine is boiled for 24 hours and evaporated. Customary working up gives 2,2-dimethyl-4-(1-methyl-1,2-dihydro-2-oxo-3-pyridyl)-6-formamido-3-chromanol.
Reaction SMILES: [ClH:1].[Cl:2][C:3]1[CH:4]=[C:5]([CH:14]=[CH:15][C:16]=1[Cl:17])[C:6](=O)[CH2:7][CH:8]([C:11]#[N:12])[C:9]#[N:10].CCOCC>C(Cl)(Cl)Cl>[Cl:1][C:9]1[NH:10][C:6]([C:5]2[CH:14]=[CH:15][C:16]([Cl:17])=[C:3]([Cl:2])[CH:4]=2)=[CH:7][C:8]=1[C:11]#[N:12]
Reactant: N#CC(C#N)CC(=O)c1ccc(Cl)c(Cl)c1
Reactant: Cl
Solvent: ClC(Cl)Cl
Solvent: CCOCC
Product: N#Cc1cc(-c2ccc(Cl)c(Cl)c2)[nH]c1Cl
Temperature: 0 °C
Reaction time: 0.42 h
Yield: 76 %

Procedure:
Hydrogen chloride gas is bubbled through a mixture of (3,4-dichlorophenacyl)malononitrile (8.3 g, 0.333 mol), ether (150 mL) and chloroform (100 mL) at a moderate rate, keeping the reaction mixture temperature below 35°-40° C. After 25 minutes, TLC shows the reaction is complete by UV analysis. The brown reaction mixture is poured into an ice-water mixture and extracted with ether. The combined organic extracts are washed with brine, dried over anhydrous magnesium sulfate and concentrated in vacuo to obtain a brown solid. The brown solid is washed with methylene chloride and filtered to give the title product as an off-white solid (6.7 g, 76%, mp >200° C.). Identified by IR and NMR spectral analyses.
Reaction SMILES: [OH-].[K+].[O:3]([CH3:15])[CH:4]1[O:12][C@@H:11]([CH2:13][OH:14])[C@H:9]([OH:10])[C@@H:7]([OH:8])[C@@H:5]1[OH:6].[CH2:16](Cl)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>O1CCOCC1>[CH2:16]([O:6][C@H:5]1[C@H:7]([O:8][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@@H:9]([O:10][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@H:11]([CH2:13][O:14][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[O:12][C@H:4]1[O:3][CH3:15])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: ClCc1ccccc1
Reactant: COC1O[C@@H](CO)[C@H](O)[C@@H](O)[C@@H]1O
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CO[C@@H]1O[C@@H](COCc2ccccc2)[C@H](OCc2ccccc2)[C@@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Reaction time: 4 h

Procedure:
Powdered potassium hydroxide (25 g.) was added to a magnetically stirred solution of syrupy methyl L-glucopyranoside (4.8 g.) in dry 1,4-dioxane (30 ml.). This stirred solution was gently heated on an oil bath (reflux), and freshly distilled benzyl chloride (32 ml.) was added dropwise over a 1 hour period. Heating and stirring were continued for an additional 4 hour period, at which time the dioxane was distilled and the resultant mixture cooled, diluted with water (200 ml.) and extracted with chloroform (3×75 ml.). The chloroform extracts were then washed with dilute hydrochloric acid and then with water. The chloroform layer was dried over sodium sulfate and then concentrated at reduced pressure to a syrup (17 g.) which was seen to contain three components (t.l.c., benzene/ethyl acetate 10:1 v/v) having Rf values of approximately 0.4, 0.48, and 0.73. T.L.C. comparison (benzene/ethyl acetate 10:1 v/v) of this mixture with the previously prepared methyl 2,3,4,6-tetra-O-benzyl-D-glucopyranosides and also with benzyl ether showed that the component with the greatest mobility was benzyl ether whereas the one having the least mobility was likely the α-anomer and the middle component the β-anomer. A small portion of this reaction mixture was purified by column chromatography on silica gel by eluting first with benzene to remove benzyl ether and then with a 10:1 mixture of benzene-ethyl acetate to give methyl 2,3,4,6-tetra-O-benzyl-α-L-glucopyranoside as a syrup having [α]D -25.4° (c 3.8, chloroform) as compared with [α]D +23.8° (c 3.42, chloroform), or [α]D +18.7° (c 1.5, chloroform) for methyl 2,3,4,6-tetra-O-benzyl-α-D-glucopyranoside, and crystalline methyl 2,3,4,6-tetra-O-benzyl-β-L-glucopyranoside having m.p. 69.5°-70°, [α]D -12.1° (c 4.2, dioxane) as compared to m.p. 68°-69°, [α]D +11° (c 5.3, dioxane) for methyl 2,3,4,6-tetra-O-benzyl-β-D-glucopyranoside.