Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12]C)[CH:10]=2)[N:5]=[C:4]([C:14]2[CH:19]=[CH:18][C:17]([O:20]C)=[C:16]([F:22])[CH:15]=2)[C:3]=1[Cl:23].[NH:24]1C(=O)CC[C@H:25]1C(O)=O.Cl>>[Cl:23][C:3]1[C:4]([C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[C:16]([F:22])[CH:15]=2)=[N:5][C:6]2[C:11]([C:2]=1[C:25]#[N:24])=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=2
Reactant: O=C1CC[C@@H](C(=O)O)N1
Reactant: COc1ccc2nc(-c3ccc(OC)c(F)c3)c(Cl)c(Br)c2c1
Agent: Cl
Product: N#Cc1c(Cl)c(-c2ccc(O)c(F)c2)nc2ccc(O)cc12
Yield: 41 %

Procedure:
This compound was prepared from 34b according to method F and method G (using Pyr./HCl). Yellow solid; Yield: 41% (for two steps); mp 325–328° C. (dec.); 1H-NMR (300 MHz, DMSO-d6) δ 7.10 (dd, J=8.8, 8.7 Hz, 1H), 7.27 (d, J=2.5 Hz, 1H), 7.43 (dd, J=8.4, 1.4 Hz, 1H), 7.49 (dd, J=9.2, 2.5 Hz, 1H), 7.55 (dd, J=12.2, 2.0 Hz, 1H), 8.04 (d, J=9.1 Hz, 1H), 10.37 (s, 1H), 10.97 (s, 1H); MS (ESI) m/z 313 ([M−H]−), 315 ([M+H]+); Anal. Calcd for C16H8ClFN2O2: C: 61.07, H: 2.56, N: 8.90. Found: C: 60.80, H: 2.57, N: 8.55.
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[NH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1>C1(C)C(C)=CC=CC=1>[Br-:1].[NH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N+:11]=1[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: BrCc1ccccc1
Reactant: Nc1ccccn1
Solvent: Cc1ccccc1C
Product: Nc1cccc[n+]1Cc1ccccc1
Product: [Br-]
Yield: 63.9 %

Procedure:
A solution of α-bromotoluene (100.0 g), 2-aminopyridine (82.0 g) and 1000 ml of xylene are heated under reflux for 7 hours to give 99.1 g of the title compound, melting point 187°-190°C.
Reaction SMILES: C(O[C:4](=[O:17])[CH2:5][O:6][C:7]1[C:8]([N+:14]([O-])=O)=[N:9][C:10](Br)=[CH:11][CH:12]=1)C.BrC1N=C([N+]([O-])=O)[C:22]([OH:28])=CC=1.C([O-])([O-])=O.[K+].[K+].BrCC(OCC)=O>CC(C)=O.CCOCC>[O:17]=[C:4]1[CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([CH:22]=[O:28])=[N:9][C:8]=2[NH:14]1
Reactant: CCOC(=O)COc1ccc(Br)nc1[N+](=O)[O-]
Reactant: O=[N+]([O-])c1nc(Br)ccc1O
Agent: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CC(C)=O
Product: O=Cc1ccc2c(n1)NC(=O)CO2
Temperature: 25 °C
Reaction time: 20 h
Yield: 74 %

Procedure:
(6-Bromo-2-nitro-pyridin-3-yloxy)-acetic acid ethyl ester. To a suspension of 6-bromo-2-nitro-pyridin-3-ol (3.07 g, 14.0 mmol) in acetone (20 mL) was added K2CO3 (3.93 g, 28.0 mmol) and ethyl bromoacetate (1.55 mL, 14.0 mmol). The mixture was heated to reflux and stirred for 20 h. The resulting suspension was cooled to RT, diluted with Et2O (100 mL) and filtered. The filtrate was concentrated to afford 3.14 g (74%) of the title compound, which was used without further purification. MS (ESI): exact mass calculated for C9H9BrN2O5, 303.97; m/z found, 305.2 [M+H]+. 1H NMR (400 MHz, CDCl3): 7.67 (d, J=8.6, 1H), 7.35 (d, J=8.7, 1H), 4.78 (s, 2H), 4.27 (q, J=7.1, 2H), 1.30 (t, J=8.5, 3H).
Reaction SMILES: O=[C:2]1[CH2:6][CH2:5][S:4][CH:3]1[C:7]([O:9][CH3:10])=[O:8].[CH:11]1([CH:17]([C:19]2[CH:20]=C(O)[CH:22]=[C:23]([CH:25]=2)[OH:24])[CH3:18])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1>>[CH:11]1([CH:17]([C:19]2[CH:25]=[C:23]([OH:24])[C:22]3[C:2]4[CH2:6][CH2:5][S:4][C:3]=4[C:7](=[O:8])[O:9][C:10]=3[CH:20]=2)[CH3:18])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: COC(=O)C1SCCC1=O
Reactant: CC(c1cc(O)cc(O)c1)C1CCCCC1
Product: CC(c1cc(O)c2c3c(c(=O)oc2c1)SCC3)C1CCCCC1

Procedure:
Following a procedure similar to that described in Example 1B hereinabove, methyl 3-oxo-2,3,4,5-tetrahydrothiophene-2-carboxylate is reacted with 5-(1-cyclohexylethyl) resorcinol to give 7-(1-cyclohexylethyl)-1,2-dihydro-9-hydroxy-4-oxo-4H-thieno[2,3-c] [1]benzopyran.
Reaction SMILES: CN([CH:4]=[O:5])C.[Br:6][C:7]1[C:8]([Cl:16])=[C:9]([CH:13]=[CH:14][CH:15]=1)[C:10](O)=[O:11].CI.C(=O)([O-])[O-].[K+].[K+]>C(OCC)(=O)C.O>[Br:6][C:7]1[C:8]([Cl:16])=[C:9]([CH:13]=[CH:14][CH:15]=1)[C:10]([O:5][CH3:4])=[O:11]
Reactant: O=C(O)c1cccc(Br)c1Cl
Reactant: CN(C)C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CI
Solvent: O
Product: COC(=O)c1cccc(Br)c1Cl
Reaction time: 1 h
Yield: 79 %

Procedure:
To a DMF solution (30 ml) containing 2.70 g of 3-bromo-2-chlorobenzoic acid were added 1.10 ml of methyl iodide and 2.38 g of potassium carbonate in order at room temperature, followed by 1 hour of stirring. The reaction liquid was mixed with water and then diluted with ethyl acetate. After a layer separation operation, the organic layer was washed with water and saturated brine in that order, dried with anhydrous magnesium sulfate and then concentrated under a reduced pressure. The thus obtained residue was purified by a silica gel column chromatography using ethyl acetate-n-hexane (100:3) as the elution solvent to obtain 2.26 g (79%) of methyl 3-bromo-2-chlorobenzoate. FA: 250
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C:14]([OH:16])=O)[CH2:10][CH:11]([CH3:13])[CH3:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:17]1([CH:23]([CH:35]2[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]2)[C:24]([NH:26][C@H:27]2[C@H:34]3[C@H:30]([CH2:31][NH:32][CH2:33]3)[CH2:29][CH2:28]2)=[O:25])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1.OC1C2N=NNC=2C=CC=1.CN(C)CCCN=C=NCC>ClCCl>[CH:35]1([CH:23]([CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[C:24]([NH:26][C@H:27]2[C@H:34]3[C@H:30]([CH2:31][N:32]([C:14](=[O:16])[C@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH2:10][CH:11]([CH3:12])[CH3:13])[CH2:33]3)[CH2:29][CH2:28]2)=[O:25])[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40]1
Reactant: O=C(N[C@@H]1CC[C@H]2CNC[C@H]21)C(C1CCCCC1)C1CCCCC1
Reactant: CC(C)C[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Oc1cccc2[nH]nnc12
Solvent: ClCCl
Product: CC(C)C[C@@H](NC(=O)OC(C)(C)C)C(=O)N1C[C@@H]2CC[C@@H](NC(=O)C(C3CCCCC3)C3CCCCC3)[C@@H]2C1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
N-(tert-Butoxycarbonyl)-D-leucine (72.7 mg, 0.314 mmol), 2,2-dicyclohexyl-N-[(3aS,4R,6aR)-octahydrocyclopenta[c]pyrrol-4-yl]acetamide (95 mg, 0.286 mmol) from Example 74, and hydroxybenzotriazole (48.1 mg, 0.314 mmol) were combined in dichloromethane (10 mL). After 20 minutes, N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide (0.056 mL, 0.314 mmol) was added, and the reaction mixture was stirred at room temperature for 18 hours. The reaction was quenched with water. The separated organic layer was reduced in volume, and the crude material was applied to a silica gel cartridge (Analogix®, Burlington, Wis., RS-12) and eluted first with 10% to 100% ethyl acetate/hexanes and then with 1-10% methanol (2 N ammonia)/dichloromethane to give tert-butyl(R)-1-((3aS,4R,6aR)-4-(2,2-dicyclohexylacetamido)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)-4-methyl-1-oxopentan-2-ylcarbamate: 1H NMR (500 MHz, pyridine-d5) δ ppm 8.26 (dd, J=7.2, 24.0, 1H), 7.91 (d, J=8.6, 1H), 4.48-4.36 (m, 1H), 4.12-3.96 (m, 1H), 3.87 (dd, J=7.4, 10.3, 1H), 3.70 (ddd, J=8.0, 14.4, 23.7, 1H), 3.40 (dd, J=5.7, 12.3, 1H), 2.77 (s, 1H), 2.58 (d, J=6.1, 1H), 2.08 (s, 1H), 2.01 (dd, J=5.6, 10.4, 2H), 1.96-1.55 (m, 17H), 1.54-1.50 (m, 9H), 1.49-1.37 (m, 2H), 1.19 (qdd, J=12.3, 22.3, 24.7, 11H), 1.00 (t, J=6.6, 3H), 0.88 (d, J=6.6, 1H).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=O)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].C(Cl)Cl.S(Cl)(Cl)=O.[CH2:21]([O:28][C:29](=[O:44])[NH:30][C:31]1[C:32]([NH2:43])=[N:33][C:34]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[CH:35][CH:36]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CN(C=O)C>[CH2:21]([O:28][C:29](=[O:44])[NH:30][C:31]1[C:32]([NH:43][C:9](=[O:11])[C:8]2[CH:7]=[CH:6][C:5]([NH:4][C:1](=[O:3])[CH3:2])=[CH:13][CH:12]=2)=[N:33][C:34]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[CH:35][CH:36]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: Nc1nc(-c2ccccc2)ccc1NC(=O)OCc1ccccc1
Reactant: CC(=O)Nc1ccc(C(=O)O)cc1
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: CC(=O)Nc1ccc(C(=O)Nc2nc(-c3ccccc3)ccc2NC(=O)OCc2ccccc2)cc1

Procedure:
A solution of 4-(acetylamino)benzoic acid (33.6 mg, 0.188 mmol) and methylene chloride (0.190 mL) was cooled to 0° C. and treated with thionyl chloride (41 uL, 0.563 mmol) and a drop of DMF. The cold bath was removed, and the reaction progress was checked via piperidine quench and LCMS. The reaction was thoroughly concentrated and dissolved in methylene chloride:THF (1:1, 0.240 mL) and benzyl(2-amino-6-phenylpyridin-3-yl)carbamate (20 mg, 0.0626 mmol) added. After 2 days the reaction was concentrated, taken into DMF and purified via reversed phase HPLC, 20-80% MeCN in water with 0.05% TFA to afford the requisite compound which was taken to the next reaction. MS cal'd 481 (M+H)+, exp 481 (M+H)+.
Reaction SMILES: [N:1]([CH2:4][C:5]1[N:6]=[C:7]([N:10]2[CH2:13][CH:12]([O:14][Si:15]([C:28]([CH3:31])([CH3:30])[CH3:29])([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:11]2)[S:8][CH:9]=1)=[N+]=[N-].Cl[C:33]([O:35][CH3:36])=[O:34].C(N(CC)CC)C>CO.[OH-].[Pd+2].[OH-]>[Si:15]([O:14][CH:12]1[CH2:13][N:10]([C:7]2[S:8][CH:9]=[C:5]([CH2:4][NH:1][C:33]([O:35][CH3:36])=[O:34])[N:6]=2)[CH2:11]1)([C:28]([CH3:31])([CH3:30])[CH3:29])([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CC(C)(C)[Si](OC1CN(c2nc(CN=[N+]=[N-])cs2)C1)(c1ccccc1)c1ccccc1
Reactant: COC(=O)Cl
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: CO
Product: COC(=O)NCc1csc(N2CC(O[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)C2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.9 %

Procedure:
1-(4-Azidomethyl-1,3-thiazol-2-yl)-3-t-butyldiphenylsilyloxyazetidine (2.12 g, 4.71 mmol) (obtained as described in Reference Example 62(1)) in methanol (106 ml) was subjected to catalytic reduction in the presence of 20% palladium hydroxide (2.12 g) at room temperature. After checking the completion of the reaction, the reaction mixture was filtered in order to remove the catalyst and the filtrate concentrated under reduced pressure. The residue was dissolved in methylene chloride (100 ml). To the mixture were added methyl chloroformate (0.43 ml, 5.65 mmol) and triethylamine (0.79 ml, 5.65 mmol), and the mixture was stirred at room temperature for 2 hours. After checking the completion of the reaction, the mixture was distilled under reduced pressure. The residue was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate solution. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using ethyl acetate as the eluant to afford 3-t-butyldiphenylsilyloxy-1-[4-(methoxycarbonylamino-methyl)-1,3-thiazol-2-yl]azetidine (1.88 g, yield 45%) as pale yellow oil.
Reaction SMILES: O.[N+:2]([C:5]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=[CH:8][C:6]=1[NH2:7])([O-:4])=[O:3].[Br:15]Br.N>C(O)(=O)C>[Br:15][C:8]1[CH:9]=[C:10]([N+:12]([O-:14])=[O:13])[CH:11]=[C:5]([N+:2]([O-:4])=[O:3])[C:6]=1[NH2:7]
Reactant: BrBr
Reactant: Nc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Agent: N
Solvent: CC(=O)O
Solvent: O
Product: Nc1c(Br)cc([N+](=O)[O-])cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 83.9 %

Procedure:
To a stirred mixture of water (3.75 L) and acetic acid (375 mL) at rt was added 2,4-dinitroaniline (500 g, 2.73 mol) followed by dropwise addition of bromine (210 mL, 4.09 mol) over 30 min. The reaction mixture was stirred at rt for 15 min then heated to 100° C. for 2 h. The reaction mixture was then cooled to rt poured onto ice-cold water (5-6 L) and basified (pH 8-10) with aqueous ammonia. The solid thus obtained was filtered, washed with cold water and dried under vacuum. The resulting solid was washed with n-pentane to give the desired product (600 g, 84%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:14]([O:16]C)=O)[CH:7]=[C:8]([CH:13]=1)[C:9]([O:11]C)=O)([O-:3])=[O:2].[NH2:18][CH:19]([CH2:22][OH:23])[CH2:20][OH:21]>CO>[OH:21][CH2:20][CH:19]([NH:18][C:9](=[O:11])[C:8]1[CH:13]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=[C:6]([C:14]([NH:18][CH:19]([CH2:22][OH:23])[CH2:20][OH:21])=[O:16])[CH:7]=1)[CH2:22][OH:23]
Reactant: NC(CO)CO
Reactant: COC(=O)c1cc(C(=O)OC)cc([N+](=O)[O-])c1
Solvent: CO
Product: O=C(NC(CO)CO)c1cc(C(=O)NC(CO)CO)cc([N+](=O)[O-])c1
Temperature: 20 °C
Yield: 99.7 %

Procedure:
Dimethyl 5-nitroisophthalate (120 g, 0.5 mol) and serinol (113.6 g, 1.25 mol) are dissolved in methanol (960 mL), and then heated to reflux for 48 h. Cooled to 20° C., the solid is collected filtration using vacuum and the filter cake washed with methanol (50 mL×3). The filter cake is then dried to constant weight to obtain 178.2 g product as a white powder in 99% yield.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH:16]=O)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(=O)C.[H-].C([Na])#N.[NH2:26][C:27]1[CH:49]=[CH:48][C:47]([Cl:50])=[CH:46][C:28]=1[CH:29]([OH:45])[C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([CH2:36][NH:37][C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH:31]=1>CO.C(OCC)(=O)C>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][CH2:16][NH:26][C:27]2[CH:49]=[CH:48][C:47]([Cl:50])=[CH:46][C:28]=2[CH:29]([OH:45])[C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([CH2:36][NH:37][C:38]([O:40][C:41]([CH3:43])([CH3:44])[CH3:42])=[O:39])[CH:31]=2)=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=CCc1ccc(OCc2ccccc2)cc1
Reactant: CC(C)(C)OC(=O)NCc1cccc(C(O)c2cc(Cl)ccc2N)c1
Agent: N#C[Na]
Agent: [H-]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)(C)OC(=O)NCc1cccc(C(O)c2cc(Cl)ccc2NCCc2ccc(OCc3ccccc3)cc2)c1
Temperature: 60 °C
Reaction time: 0.67 h

Procedure:
In methanol (15 ml) were dissolved 2-amino-5-chloro-α-(3-tert-butoxycarbonylaminomethylphenyl)benzyl alcohol produced in Example 1-(2) (0.5 g) and 4-benzyloxyphenylacetaldehyde (0.4 g). To the solution were added acetic acid (0.1 g) and, subsequently, cyano sodium hydride (0.11 g). The mixture was stirred for 40 minutes at 60° C. The reaction mixture was diluted with ethyl acetate (60 ml), which was washed with water and dried over anhydrous sodium sulfate. The solvent was distilled off to leave 2-[2-(4-benzyloxyphenyl)ethyl]amino-α-(3-tert-butoxycarbonylaminomethylphenyl)-5-chloro-benzyl alcohol (0.45 g) as a colorless oily product.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][S:5][C:6]=1[CH:7]=O.[Br-].[CH3:10][CH:11]([CH3:34])[C:12](=[O:33])[CH2:13][As+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+].C(#N)C>O>[CH3:10][CH:11]([CH3:34])[C:12](=[O:33])[CH:13]=[CH:7][C:6]1[S:5][CH:4]=[N:3][C:2]=1[CH3:1]
Reactant: Cc1ncsc1C=O
Reactant: CC(C)C(=O)C[As+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Br-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: Cc1ncsc1C=CC(=O)C(C)C

Procedure:
The title compound was prepared as described in General Method 1 using 1.4 g (11.0 mmol) of 4-methyl-5-thiazolecarbaldehyde (Example A-12), 6.2 g (13.1 mmol) of (3-methyl-2-oxobutyl)triphenylarsonium bromide, 1.8 g (13.1 mmol) of potassium carbonate, 75 mL of acetonitrile, and 0.75 mL of H2O. Chromatography of the residue, eluting with 3:1 hexane:EtOAc gave the title compound.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[C:11]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:10]([Br:20])=[CH:9][N:8]=1)(=O)=O.[CH2:23]1[O:31][C:30]2[CH:29]=[CH:28][C:27]([Sn](CCCC)(CCCC)CCCC)=[CH:26][C:25]=2[O:24]1.C1(C)C(C)=CC=CC=1>[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC.C(OCC)(=O)C.CCCCCC>[CH2:13]([C:11]1[C:10]([Br:20])=[CH:9][N:8]=[C:7]([C:28]2[CH:27]=[CH:26][C:25]3[O:24][CH2:23][O:31][C:30]=3[CH:29]=2)[CH:12]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc2c(c1)OCO2
Reactant: O=S(=O)(Oc1cc(Cc2ccccc2)c(Br)cn1)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Solvent: Cc1ccccc1C
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: Brc1cnc(-c2ccc3c(c2)OCO3)cc1Cc1ccccc1
Yield: 38.1 %

Procedure:
A mixture of 400 mg of 4-benzyl-5-bromo-2-pyridyl trifluoromethanesulfonate, 410 mg of (3,4-methylenedioxyphenyl)tributyltin, 300 mg of tetrabutylammonium chloride, 20 mg of tetrakis(triphenylphsphine)palladium(0) and 2 ml of xylene was stirred under heating for 3 hours in an oil bath kept at 140° C. in a nitrogen atmosphere. The reaction solution was subjected to silica gel column chromatography using 5-10% ethyl acetate/hexane, to give 140 mg of the title compound.
Reaction SMILES: O[N:2]([CH3:21])[C:3](=[O:20])[CH:4]([NH:6][C:7]1[C:12]([N+:13]([O-:15])=[O:14])=[CH:11][C:10]([CH3:16])=[CH:9][C:8]=1[N+:17]([O-:19])=[O:18])[CH3:5].[CH3:22][S:23](Cl)(=[O:25])=[O:24].CN1C=CN=C1.[OH2:33]>C(Cl)Cl>[CH3:22][S:23]([O:25][C:4]([NH:6][C:7]1[C:12]([N+:13]([O-:15])=[O:14])=[CH:11][C:10]([CH3:16])=[CH:9][C:8]=1[N+:17]([O-:19])=[O:18])([CH3:5])[C:3]([NH:2][CH3:21])=[O:20])(=[O:33])=[O:24]
Reactant: CS(=O)(=O)Cl
Reactant: O
Reactant: Cc1cc([N+](=O)[O-])c(NC(C)C(=O)N(C)O)c([N+](=O)[O-])c1
Agent: Cn1ccnc1
Solvent: ClCCl
Product: CNC(=O)C(C)(Nc1c([N+](=O)[O-])cc(C)cc1[N+](=O)[O-])OS(C)(=O)=O
Yield: 22 %

Procedure:
2.8 g of N-hydroxy-N-methyl-2-(4-methyl-2,6-dinitrophenylamino)propanamide in 50 ml methylene chloride was added at room temperature to a stirred suspension of the product prepared from 1.4 g methane sulfonyl chloride and 0.8 g N-methylimidazole. After 3 hours the resulting mixture was poured into water. The methylene chloride layer was evaporated to dryness and the residue was crystallized from ethanol to give a 0.8 g (22% yield) of product as a yellow solid; m.p. 145° C. with decomposition, (d,1) isomer form.
Reaction SMILES: [CH:1]1[C:11]2[CH2:10][CH2:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[O:6][C:5]=2[CH:4]=[CH:3][C:2]=1[CH2:16][C:17]([OH:19])=O.[NH3:20].O>O1CCCC1.C(Cl)(=O)C(Cl)=O.CN(C)C=O>[CH:1]1[C:11]2[CH2:10][CH2:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[O:6][C:5]=2[CH:4]=[CH:3][C:2]=1[CH2:16][C:17]([NH2:20])=[O:19]
Reactant: N
Reactant: O=C(O)Cc1ccc2c(c1)CCc1ccccc1O2
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: O
Product: NC(=O)Cc1ccc2c(c1)CCc1ccccc1O2
Yield: 48 %

Procedure:
To 100 mg of (10,11-dihydro dibenzo[b,f]oxepin-2-yl)-acetic acid in 5 ml of dry tetrahydrofuran were added 4 drops of oxalyl chloride, and the mixture was stirred with ice-cooling. To the mixture were added 1 drop of dimethylformamide 1.75 hours later, 4 drops of oxalyl chloride 4 hours later and 1% ammonia in 5 ml tetrahydrofuran 6 hours later, and the resulting mixture was stirred for 17 hours at room temperature. To this was added water, and the mixture was extracted with ethyl acetate. The extract was washed with a 1% sodium hydroxide solution and then with a saturated sodium chloride solution and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain a residue, which was recrystallized from ethyl acetate to yield 48 mg (yield: 48%) of (10,11-dihydro dibenzo[b,f]oxepin-2-yl)-acetamide as colorless crystals having a melting point of 205°-206° C.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:10]([NH:11][NH2:12])=[CH:9][C:8](=[O:13])[N:7]([CH3:14])[C:6]2=[O:15])[CH2:3][CH2:2]1.[Cl:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][CH:21]=[C:20]2[CH:26]=O.[C:28]([C:31]1[CH:32]=[C:33]([CH:37]=O)[N:34]([CH3:36])[CH:35]=1)(=[O:30])[CH3:29]>>[C:28]([C:31]1[CH:32]=[C:33]([C:37]2[N:12]([CH2:26][C:20]3[C:19]4[C:23](=[CH:24][CH:25]=[C:17]([Cl:16])[CH:18]=4)[NH:22][CH:21]=3)[N:11]=[C:10]3[C:9]=2[C:8](=[O:13])[N:7]([CH3:14])[C:6](=[O:15])[N:5]3[CH2:4][CH:1]2[CH2:2][CH2:3]2)[N:34]([CH3:36])[CH:35]=1)(=[O:30])[CH3:29]
Reactant: CC(=O)c1cc(C=O)n(C)c1
Reactant: O=Cc1c[nH]c2ccc(Cl)cc12
Reactant: Cn1c(=O)cc(NN)n(CC2CC2)c1=O
Product: CC(=O)c1cc(-c2c3c(=O)n(C)c(=O)n(CC4CC4)c3nn2Cc2c[nH]c3ccc(Cl)cc23)n(C)c1

Procedure:
This compound was made following the procedure described above, starting with 1-(cyclopropylmethyl)-6-hydrazino-3-methylpyrimidine-2,4(1H,3H)-dione, and condensing first with 5-chloro-1H-indole-3-carbaldehyde, followed by 4-acetyl-1-methyl-1H-pyrrole-2-carbaldehyde. Mass: 505.12 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7](=O)[NH:8][CH:9]=[N:10]2)=[CH:5][C:4]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[Cl:20][C:21]1[CH:29]=[C:28]2[C:24]([CH2:25][CH2:26][NH:27]2)=[CH:23][CH:22]=1>>[Cl:20][C:21]1[CH:29]=[C:28]2[C:24]([CH2:25][CH2:26][N:27]2[C:7]2[C:6]3[C:11](=[CH:12][C:3]([O:2][CH3:1])=[C:4]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[CH:5]=3)[N:10]=[CH:9][N:8]=2)=[CH:23][CH:22]=1
Reactant: Clc1ccc2c(c1)NCC2
Reactant: COc1cc2nc[nH]c(=O)c2cc1-c1ccccc1
Product: COc1cc2ncnc(N3CCc4ccc(Cl)cc43)c2cc1-c1ccccc1

Procedure:
The title compound was prepared from 7-Methoxy-6-phenyl-3H-quinazolin-4-one (250 mg, 0.99 mmol) and 6-chloroindoline (152 mg, 0.99 mmol) utilizing the method of Example 45 (163 mg, 39%). One hundred sixty-three milligrams (39%) of product was obtained after column chromatography and precipitation as the HCl salt.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]#[N:12])[CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[CH2:13]([I:16])[CH:14]=[CH2:15]>C1(C)C=CC=CC=1>[I-:16].[C:11]([C:8]1[CH:9]=[C:10]2[C:5]([CH:4]=[CH:3][CH:2]=[N+:1]2[CH2:15][CH:14]=[CH2:13])=[CH:6][CH:7]=1)#[N:12]
Reactant: N#Cc1ccc2cccnc2c1
Reactant: C=CCI
Solvent: Cc1ccccc1
Product: C=CC[n+]1cccc2ccc(C#N)cc21
Product: [I-]
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.3 %

Procedure:
7-Quinolinecarbonitrile (1.01 g, 6.6 mmol) and allyl iodide (1.2 mL, 13.2 mmol) in toluene (10 ml) was heated at 90° C. then at 120° C. for 2 h. More allyl iodide was then added (1.2 ml, 13.2 mmol). After other 2 h more allyl iodide was added (1.2 ml, 13.2 mmol). After 2 h more the reaction was cooled to rt. The solid was filtered off, washed with toluene and dried in vacuo at 45° C. overnight to afford the desired compound (1.75 g, 82%).
Reaction SMILES: [C:1]([O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][C:21]([C:24](Cl)=[O:25])=[CH:20][CH:19]=2)=[CH:14][CH:13]=1)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].C1COCC1.[Cl:32][C@H:33]([CH3:36])[CH2:34][OH:35].C(N(CC)CC)C>CCOCC>[Cl:32][CH:33]([CH3:36])[CH2:34][O:35][C:24]([C:21]1[CH:20]=[CH:19][C:18]([C:15]2[CH:16]=[CH:17][C:12]([O:11][C:1]([O:3][CH2:4][C:5]3[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=3)=[O:2])=[CH:13][CH:14]=2)=[CH:23][CH:22]=1)=[O:25]
Reactant: O=C(OCc1ccccc1)Oc1ccc(-c2ccc(C(=O)Cl)cc2)cc1
Reactant: C[C@@H](Cl)CO
Solvent: CCN(CC)CC
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(Cl)COC(=O)c1ccc(-c2ccc(OC(=O)OCc3ccccc3)cc2)cc1
Reaction time: 6 h
Yield: 68 %

Procedure:
61.5 m moles(22.6 g) of 4'-carbobenzoxyoxybiphenyl-4-carboxylic acid chloride was added dropwise into a THF solution of 61.5 m moles(5.2 g) of (R)-(-)-2-chloro-1-propanol and 10 ml of triethylamine, and stirred for 6 hours. After the reaction, the reaction solution was ether extracted. The extrate was purified by column chromatography to obtain 15.9 g of the ester compound [[α]D23 =+22.5°(CHCl3)]. (yield: 61%)
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([S:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[C:12]=2[F:18])[N:3]=1.[OH:19][C@@H:20]1[CH2:24][O:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21]1.[H-].[Na+].O>C1COCC1>[Cl:8][C:6]1[N:5]=[C:4]([S:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[C:12]=2[F:18])[N:3]=[C:2]([O:19][C@@H:20]2[CH2:24][O:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21]2)[CH:7]=1
Reactant: Fc1cccc(CSc2nc(Cl)cc(Cl)n2)c1F
Reactant: CC(C)(C)OC(=O)N1C[C@H](O)CO1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1C[C@H](Oc2cc(Cl)nc(SCc3cccc(F)c3F)n2)CO1
Temperature: 60 °C

Procedure:
To a stirred solution of 4,6-Dichloro-2-[(2,3-difluorobenzyl)thio]pyrimidine (the product of Example 1, step ii) (0.25 g) and 1,1-dimethylethyl (S)-4-hydroxyisoxazolidine-2-carboxylate (0.16 g) in dry THF (5 mL) was added 60% Sodium hydride (0.034 g) over 5 min. The reaction mixture was stirred and heated at 60° C. for 7 days, H2O was added and the solvents were partially evaporated. The residue was extracted with EtOAc which was washed with H2O, dried (MgSO4) and the solvent evaporated under reduced pressure. The residue was purified by flash chromatography on silica gel, eluting with Et2O/iso-hexane (1:9) to give the subtitle compound as a gum. Yield: 0.15 g.