Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13]3[N:14]([CH3:21])[C:15](=[O:20])[C:16]([CH3:19])=[C:17]([OH:18])[C:12]=3[C:11](=[O:22])[N:10]([CH:23]3[CH2:25][CH2:24]3)[C:9]2=[O:26])=[CH:4][CH:3]=1.C(#N)C.[S:30](Cl)([C:33]1[CH:39]=[CH:38][C:36]([CH3:37])=[CH:35][CH:34]=1)(=[O:32])=[O:31]>C(N(CC)CC)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13]3[N:14]([CH3:21])[C:15](=[O:20])[C:16]([CH3:19])=[C:17]([O:18][S:30]([C:33]4[CH:39]=[CH:38][C:36]([CH3:37])=[CH:35][CH:34]=4)(=[O:32])=[O:31])[C:12]=3[C:11](=[O:22])[N:10]([CH:23]3[CH2:24][CH2:25]3)[C:9]2=[O:26])=[CH:4][CH:3]=1
Reactant: Cc1c(O)c2c(=O)n(C3CC3)c(=O)n(-c3ccc(Br)cc3)c2n(C)c1=O
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)Oc2c(C)c(=O)n(C)c3c2c(=O)n(C2CC2)c(=O)n3-c2ccc(Br)cc2)cc1
Temperature: 25 °C
Yield: 74.3 %

Procedure:
To 1-(4-bromo-phenyl)-3-cyclopropyl-5-hydroxy-6,8-dimethyl-1H,8H-pyrido[2,3-d]pyrimidine-2,4,7-trione 38 (400 mg) obtained in Step 5 was added acetonitrile (8.0 ml), tosyl chloride 11 (458 mg) and triethylamine (0.34 ml) were added under a nitrogen atmosphere, and the mixture was stirred under reflux for 30 hrs. After allowing to cool to room temperature, the mixture was concentrated under reduced pressure. The residue was purified by column chromatography (chloroform:acetone=25:1→20:1) to give toluene-4-sulfonic acid 1-(4-bromo-phenyl)-3-cyclopropyl-6,8-dimethyl-2,4,7-trioxo-1,2,3,4,7,8-hexahydro-pyrido[2,3-d]pyrimidin-5-yl ester 39 (407 mg, yield 74%) as ocher crystals.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([O:12][CH3:13])=[C:7]([O:14][CH3:15])[CH:6]=2.[CH3:16][OH:17]>>[CH3:13][O:12][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][C:7]=1[O:14][CH3:15])[N:4]=[CH:3][C:2]([NH:1][CH2:9][C:10]([CH3:11])([CH3:5])[CH2:16][OH:17])=[CH:11]2
Reactant: COc1cc2cc(N)cnc2cc1OC
Reactant: CO
Product: COc1cc2cc(NCC(C)(C)CO)cnc2cc1OC

Procedure:
The reaction is run similar to the preparation in Example 11. To a MeOH solution of 4 Å powdered molecular sieves (0.35 g) under argon is added 3-amino-6,7-dimethoxyquinoline (0.32 g, 1.6 mmol) and 2,2-dimethyl-3-hydroxypropionaldelhyde (0.19 g, 1.9 mmol). The product mixture is chromatographed (3% MeOH/CHCl3) to afford 0.10 g of material which is partitioned between CH2Cl2/10% NaOH. The organic layer is washed with 10% NaOH, H2O. and brine, then dried (NvgSO4), and recrystallized from EtOAc/hexanes to provide a light-orange solid (m.p. 170-173.5° C.). Anal. Calcd. for C16H22N2O3; C, 66.18; H, 7.64; N. 9.65; Found: C, 66.11; H, 7.49; N, 9.33.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1([CH3:22])[N:8]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[C@H:7]([CH:16]([OH:21])[C:17]([F:20])([F:19])[F:18])[CH2:6][O:5]1.[CH2:23](Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CN(C=O)C>[CH2:23]([O:21][C@H:16]([C@@H:7]1[CH2:6][O:5][C:4]([CH3:22])([CH3:3])[N:8]1[C:9]([O:11][C:12]([CH3:13])([CH3:14])[CH3:15])=[O:10])[C:17]([F:18])([F:20])[F:19])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CC(C)(C)OC(=O)N1[C@H](C(O)C(F)(F)F)COC1(C)C
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1[C@H]([C@@H](OCc2ccccc2)C(F)(F)F)COC1(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.4 %

Procedure:
To a suspension of NaH (60% in mineral oil, 300.0 mg, 7.50 mmol) in DMF (20 mL) was added (S)-tert-butyl 2,2-dimethyl-4-(2,2,2-trifluoro-1-hydroxyethyl)oxazolidine-3-carboxylate (1.09 g, 3.64 mmol) in DMF (20 mL) and the mixture was stirred at room temperature for 1 h. Then, benzyl bromide (0.86 mL, 7.23 mmol) was added and the mixture was stirred at room temperature overnight then quenched with ice-water, extracted with EtOAc. The organic extracts were washed with water, brine and dried over Na2SO4. Removal of the solvent gave a residue, which was purified by silica gel chromatography to give (S)-tert-butyl 4-((R)-1-(benzyloxy)-2,2,2-trifluoroethyl)-2,2-dimethyloxazolidine-3-carboxylate (1.21 g, 85%), which showed a complicated NMR spectrum because of the different rotamers. 1H NMR (400 MHz, CDCl3, δ in ppm) 7.28˜7.33 (m, 5H), 4.60˜4.85 (m, 3H), 3.93˜4.23 (m, 3H), 1.42˜1.65 (m, 15H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][N:5]([C:8]2[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][CH:9]=2)[C:4](=[O:18])[CH:3]=1.IC.[C:21]([O-])([O-])=O.[K+].[K+]>CC(C)=O>[CH3:21][O:1][C:2]1[CH:7]=[CH:6][N:5]([C:8]2[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][CH:9]=2)[C:4](=[O:18])[CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1ccc(-n2ccc(O)cc2=O)cc1
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: COC(=O)c1ccc(-n2ccc(OC)cc2=O)cc1

Procedure:
A solution of Example 296A (2.3 g, 10 mmol) in acetone (300 mL) was treated with iodomethane (5 mL) and K2CO3 (15 g), heated to reflux for 18 hours, and filtered. The filtrate was concentrated and the concentrate purified by flash column chromatography on silica gel with 4:1 hexanes/ethyl acetate to provide the desired product. MS (ESI) m/e 260 (M+H)+.
Reaction SMILES: [CH:1]1[C:14]2[C:5](=[CH:6][C:7]3[C:12]([C:13]=2[C:15]2[CH:32]=[CH:31][C:30]4[C:29]5[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=5)[C:23]5[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=5)[C:17]=4[CH:16]=2)=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH:4]=[CH:3][CH:2]=1.[Br:33]N1C(=O)CCC1=O.S([O-])([O-])(=O)=S.[Na+].[Na+]>II.C1COCC1>[Br:33][C:6]1[C:5]2[C:14](=[CH:1][CH:2]=[CH:3][CH:4]=2)[C:13]([C:15]2[CH:32]=[CH:31][C:30]3[C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[C:17]=3[CH:16]=2)=[C:12]2[C:7]=1[CH:8]=[CH:9][CH:10]=[CH:11]2
Reactant: O=C1CCC(=O)N1Br
Reactant: c1ccc2c(-c3ccc4c5ccccc5c5ccccc5c4c3)c3ccccc3cc2c1
Agent: II
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: C1CCOC1
Product: Brc1c2ccccc2c(-c2ccc3c4ccccc4c4ccccc4c3c2)c2ccccc12
Temperature: 25 °C
Reaction time: 5 h
Yield: 88.8 %

Procedure:
Under the nitrogen atmosphere, 2-(anthracen-9-yl)triphenylene (3.3 g) as the eleventh intermediate compound, N-bromosuccinimide (NBS) (1.7 g), iodine (0.1 g) and THF (25 ml) were added to a flask, and stirred at room temperature for 5 hours. An aqueous solution of sodium thiosulfate was added and the reaction was terminated. The precipitates were collected by suction filtration. The obtained solid was washed with methanol and subsequently with heptane and purified by silica gel column chromatography (solvent: toluene) to give 2-(10-bromoanthracen-9-yl)triphenylene (3.5 g) as a twelfth intermediate compound. The scheme is shown in the following “Reaction 22”.
Reaction SMILES: C([Li])CCC.[F:6][C:7]1[N:12]=[CH:11][C:10]([C@H:13]([N:15]2[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]2)[CH3:14])=[CH:9][CH:8]=1.[B:28](OC(C)C)([O:33]C(C)C)[O:29]C(C)C>C1COCC1>[C:24]([O:23][C:21]([N:18]1[CH2:17][CH2:16][N:15]([C@@H:13]([C:10]2[CH:9]=[C:8]([B:28]([OH:33])[OH:29])[C:7]([F:6])=[N:12][CH:11]=2)[CH3:14])[CH2:20][CH2:19]1)=[O:22])([CH3:26])([CH3:25])[CH3:27]
Reactant: C[C@H](c1ccc(F)nc1)N1CCN(C(=O)OC(C)(C)C)CC1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C[C@H](c1cnc(F)c(B(O)O)c1)N1CCN(C(=O)OC(C)(C)C)CC1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 81.3 %

Procedure:
n-Butyllithium (2.5 M in hexanes, Aldrich; 20.0 mL, 50.0 mmol) was added (dropwise over 20 min) to a solution of (R)-tert-butyl 4-(1-(6-fluoropyridin-3-yl)ethyl)piperazine-1-carboxylate (10.0 g, 32.3 mmol) in THF (150 mL) at −78° C., and the resulting mixture was stirred at −78° C. for 20 min. Triisopropyl borate (15.0 mL, 65.2 mmol) was then added (dropwise over 10 min), followed by additional THF (20 mL) to rinse solidified triisopropyl borate from the side of the flask. The resulting mixture was stirred at −78° C. for 15 min, and the cooling bath was then removed. The reaction mixture was stirred for 1 h, and 1 N aq. NaOH (100 mL) and water (40 mL) were then sequentially added. The resulting mixture was stirred for 10 min, and the organic layer was separated. The organic layer was extracted with 1 N aq. NaOH (40 mL), and the aqueous layers were then combined and pH-adjusted with 5 N aqueous HCl to a final pH of about 5. The resulting mixture was extracted with EtOAc (3×200 mL), and the combined organic extracts were dried over sodium sulfate, filtered, and concentrated in vacuo to provide (R)-5-(1-(4-(tert-butoxycarbonyl)piperazin-1-yl)ethyl)-2-fluoropyridin-3-ylboronic acid (9.27 g, 81% yield) as a white solid. 1H NMR (400 MHz, d4-MeOH) δ 8.39 (br. s., 1H), 8.26 (d, J=6.5 Hz, 1H), 4.54-4.63 (m, 1H), 3.31 (br. s., 4H; masked by MeOH), 3.13 (br. s., 4H), 1.80 (d, J=6.8 Hz, 3H), 1.45 (s, 9H). 19F NMR (377 MHz, d4-MeOH) δ −60.93 (br. s., 1 F). m/z (ESI, +ve) 354.2 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13](I)[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].FC(F)(F)C(O)=O.[C@H:25]12[CH2:31][C@H:28]([NH:29][CH2:30]1)[CH2:27][O:26]2>>[C:1]([O:5][C:6]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([N:29]3[CH2:30][C@@H:25]4[CH2:31][C@H:28]3[CH2:27][O:26]4)[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C1O[C@@H]2CN[C@H]1C2
Reactant: CC(C)(C)OC(=O)N1Cc2ccc(I)cc2C1
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)OC(=O)N1Cc2ccc(N3C[C@@H]4C[C@H]3CO4)cc2C1

Procedure:
Prepared in analogy to Example A3(d) from 5-iodo-1,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester (Example A38(b)) and (1S,4S)-2-oxa-5-aza-bicyclo[2.2.1]heptane trifluoroacetate. Orange oil. MS (m/e): 317.3 ([M+H]+, 100%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.C(=O)([O-])[O-].[K+].[K+].Br[CH2:19][C:20](=[N:26]O)[C:21]([O:23]CC)=[O:22]>C(Cl)Cl>[Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[C:7]2[C:3]=1[C:4]([CH2:19][C@@H:20]([C:21]([OH:23])=[O:22])[NH2:26])=[CH:5][NH:6]2
Reactant: Clc1cc(Cl)c2cc[nH]c2c1
Reactant: CCOC(=O)C(CBr)=NO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: N[C@@H](Cc1c[nH]c2cc(Cl)cc(Cl)c12)C(=O)O
Yield: 80.8 %

Procedure:
Mix 4,6-dichloroindole (5.90g, 31.72mmol), potassium carbonate (1.81g, 47.6mmol) and anhydrous methylene chloride (200mL). Stir and add a solution of ethyl 3-bromo-2-hydroxyiminopropanoate (7.00g, 33.31mmol) in methylene chloride (75mL). Stir under a nitrogen atmosphere for 48 hours. Take the solution up in methylene chloride (100mL) and wash with water (300mL), saturated sodium hydrogen carbonate (200mL) and brine (100mL). Dry (MgSO4) and evaporate the solvent in vacuo to give a tan solid. Purify by silica gel chromatography (1 to 3% acetone in chloroform) to give the title compound as a yellow solid (7.00g, 99% based on consumed starting material ). Recrystallize (diethyl ether/hexane) to give the tit le compound as white crystals (4.0g, 56%); mp 175°-176° C.
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][C:5]2[N:6]([CH3:13])[C:7](=[O:12])[NH:8][S:9](=[O:11])(=[O:10])[C:4]=2[CH:3]=1.[H-].[Na+].[CH3:18][O:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24]Cl)=[CH:22][CH:21]=1>CN(C=O)C>[Br:1][C:2]1[CH:15]=[CH:14][C:5]2[N:6]([CH3:13])[C:7](=[O:12])[N:8]([CH2:24][C:23]3[CH:26]=[CH:27][C:20]([O:19][CH3:18])=[CH:21][CH:22]=3)[S:9](=[O:10])(=[O:11])[C:4]=2[CH:3]=1
Reactant: CN1C(=O)NS(=O)(=O)c2cc(Br)ccc21
Reactant: COc1ccc(CCl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(CN2C(=O)N(C)c3ccc(Br)cc3S2(=O)=O)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 7-bromo-4-methyl-2H-benzo[e][1,2,4]thiadiazin-3(4H)-one 1,1-dioxide (510 mg, 1.7 mmol) in DMF (10 mL), 60% NaH (69 mg, 1.7 mmol) was added in portions at 0° C. The resulting mixture was stirred at rt for 10 min and p-methoxybenzyl chloride (0.25 mL, 1.7 mmol) was added. The resulting mixture was stirred at 70° C. for 5 h, cooled to rt and poured over ice. The resulting compound was extracted with EtOAc (3×20 mL). The combined EtOAc layers were dried over Na2SO4, filtered, and concentrated. The residue obtained was purified by flash column chromatography on silica gel (0-100% EtOAc/heptanes) to obtain compound 40a. 1H-NMR (400 MHz, CDCl3) δ (ppm): 8.01 (d, J=2.0 Hz, 1H), 7.74 (dd, J=8.8, 2.3 Hz, 1H), 7.40 (d, J=8.6 Hz, 2H), 7.10 (d, J=8.6 Hz, 1H), 6.83 (d, J=8.6 Hz, 2H), 4.99 (s, 2H), 3.77 (s, 3H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([NH2:27])=[CH:11][C:12]2[C:17]([CH:18]=1)=[CH:16][C:15]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[CH:14][CH:13]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31].C(=O)([O-])[O-].[K+].[K+].Cl>CN(C=O)C>[CH2:33]([O:32][C:30](=[O:31])[CH2:29][NH:27][C:10]1[C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[C:15]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:16]=2)[CH:11]=1)[CH3:34]
Reactant: CCOC(=O)CBr
Reactant: Nc1cc2ccc(OCc3ccccc3)cc2cc1OCc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)CNc1cc2ccc(OCc3ccccc3)cc2cc1OCc1ccccc1
Temperature: 60 °C

Procedure:
3,6-Bis-benzyloxynaphthalen-2-ylamine (0.332 g, 0.934 mmol) is dissolved in DMF (5 mL). Ethyl bromoacetate (0.114 mL, 1.03 mmol) and potassium carbonate (0.194 g, 1.40 mmol) are added. The reaction is heated to 60° C. for 3 h and then poured into 1 N HCl and extracted with EtOAc. The combined organic layers are washed with brine, dried and evaporated to a red foam, which is purified over silica, eluting with 8:1 hexanes/MTBE, to afford (3,6-bis-benzyloxynaphthalen-2-ylamino)-acetic acid ethyl ester as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:25])[C:5]([CH3:24])=[C:6]([CH2:12][C:13]2[CH:14]=[C:15]([CH2:19][CH2:20][C:21](O)=[O:22])[CH:16]=[CH:17][CH:18]=2)[C:7](=[O:11])[C:8]=1[O:9][CH3:10].[NH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1>>[CH3:1][O:2][C:3]1[C:4](=[O:25])[C:5]([CH3:24])=[C:6]([CH2:12][C:13]2[CH:14]=[C:15]([CH2:19][CH2:20][C:21]([N:26]3[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]3)=[O:22])[CH:16]=[CH:17][CH:18]=2)[C:7](=[O:11])[C:8]=1[O:9][CH3:10]
Reactant: COC1=C(OC)C(=O)C(Cc2cccc(CCC(=O)O)c2)=C(C)C1=O
Reactant: C1CCNCC1
Product: COC1=C(OC)C(=O)C(Cc2cccc(CCC(=O)N3CCCCC3)c2)=C(C)C1=O
Yield: 34.7 %

Procedure:
3-[3-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-ylmethyl)phenyl]propionic acid (65 mg, 0.19 mmol) obtained in Example 31 and piperidine (0.022 ml, 0.21 mmol) were used, and a method similar to that described in Example 24 was employed to obtain the title compound (27 mg, 0.066 mmol, yield 35%).
Reaction SMILES: Br[C:2]1[C:10]2[O:9][C:8]([C:11]3[CH:16]4[CH2:17][CH2:18][N:13]([CH2:14][CH2:15]4)[CH:12]=3)=[CH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[NH3:19]>CO.CO.N>[N:13]12[CH2:18][CH2:17][CH:16]([CH2:15][CH2:14]1)[C:11]([C:8]1[O:9][C:10]3[C:2]([NH2:19])=[CH:3][CH:4]=[CH:5][C:6]=3[CH:7]=1)=[CH:12]2
Reactant: Brc1cccc2cc(C3=CN4CCC3CC4)oc12
Reactant: N
Solvent: CO
Product: Nc1cccc2cc(C3=CN4CCC3CC4)oc12
Temperature: 120 °C

Procedure:
3-(7-Bromo-1-benzofuran-2-yl)-1-azabicyclo[2.2.2]oct-2-ene (300 mg, 0.986 mmol; Intermediate 25) was dissolved in methanol (2 mL). A solution of concentrated aqueous ammonia (25%; 10 mL) and CuCl2 (15 mg) were added and the resulting mixture was heated at 120° C. for 48 h. The mixture was run through a silica plug using methanol/ammonia solution (9:1) as eluent. Concentration in vacuo furnished 236 mg of the crude title product. This material was used directly in subsequent experiments.
Reaction SMILES: [C:1](=[O:16])([O:4][C:5]1[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][C:6]=1[C:12]([CH3:15])([CH3:14])[CH3:13])[O:2][CH3:3].[N+:17]([O-])([O-:19])=[O:18].[K+]>OS(O)(=O)=O>[C:1](=[O:16])([O:4][C:5]1[CH:10]=[C:9]([N+:17]([O-:19])=[O:18])[C:8]([Br:11])=[CH:7][C:6]=1[C:12]([CH3:13])([CH3:15])[CH3:14])[O:2][CH3:3]
Reactant: O=[N+]([O-])[O-]
Reactant: COC(=O)Oc1ccc(Br)cc1C(C)(C)C
Agent: O=S(=O)(O)O
Agent: [K+]
Product: COC(=O)Oc1cc([N+](=O)[O-])c(Br)cc1C(C)(C)C
Temperature: 0 °C
Reaction time: 2 h
Yield: 59.9 %

Procedure:
Methyl (2-tert-butyl-4-bromophenyl) carbonate (470 g, 1.67 mol) was dissolved in conc. H2SO4 (1000 ml) at 0° C. KNO3 (253 g, 2.5 mol) was added in portions over 90 min. The reaction mixture was stirred at 0° C. for 2 h and poured into ice-water (20 L). The resulting precipitate was collected via filtration and washed with water thoroughly, dried and recrystallized from ether to give methyl (2-tert-butyl-4-bromo-5-nitrophenyl) carbonate (332 g, 60% over 3 steps).
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=2)[N:8]=1)=O.[F:25][C:26]([F:36])([F:35])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[NH:33]N>>[F:21][C:20]([F:23])([F:22])[C:16]1[CH:15]=[C:14]([N:9]2[CH:10]=[CH:11][C:12](=[O:13])[C:7]([C:5]3[N:33]([C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=4[C:26]([F:25])([F:35])[F:36])[N:2]=[CH:3][CH:4]=3)=[N:8]2)[CH:19]=[CH:18][CH:17]=1
Reactant: NNc1ccccc1C(F)(F)F
Reactant: CN(C)/C=C/C(=O)c1nn(-c2cccc(C(F)(F)F)c2)ccc1=O
Product: O=c1ccn(-c2cccc(C(F)(F)F)c2)nc1-c1ccnn1-c1ccccc1C(F)(F)F
Yield: 46 %

Procedure:
The product was obtained starting from 3-((E)-3-Dimethylamino-acryloyl)-1-(3-trifluoromethyl-phenyl)-1H-pyridazin-4-one (A-3) and o-trifluoromethyl-phenylhydrazine according to the method described for Example 1 in 46% yield. MS: M=451.1 (M+H)+
Reaction SMILES: [C:1]1([CH:7]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@H:8]2[C:13](=O)[C@@H:12]3[CH2:15][CH2:16][N:9]2[C@H:10]([CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:11]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:31][O:32][C:33]1[CH:40]=[CH:39][CH:38]=[CH:37][C:34]=1[CH2:35][NH2:36].C1COCC1.B1C2CCCC1CCC2>C1(C)C=CC=CC=1.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>[C:25]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C@@H:8]2[C@H:13]([NH:36][CH2:35][C:34]3[CH:37]=[CH:38][CH:39]=[CH:40][C:33]=3[O:32][CH3:31])[C@@H:12]3[CH2:15][CH2:16][N:9]2[C@H:10]([CH2:17][CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:11]3)[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: COc1ccccc1CN
Reactant: O=C1[C@@H]2CCN([C@H](CCc3ccccc3)C2)[C@@H]1C(c1ccccc1)c1ccccc1
Agent: B1C2CCCC1CCC2
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: COc1ccccc1CN[C@@H]1[C@@H]2CCN([C@H](CCc3ccccc3)C2)[C@@H]1C(c1ccccc1)c1ccccc1
Yield: 23.3 %

Procedure:
Compound 7 (357 mg, 0.904 mmol), 2-methoxybenzylamine (189 mg, 1.38 mmol) and camphorsulfonic acid (2.0 mg) were dissolved in toluene (30 ml), and the resultant mixture was heated at reflux for 3 days under a dehydrating condition with MS 4A. After replacement of the solvent with THF a solution of 9-BBN (0.5M in THF, 5.4 ml) was added, and the resultant mixture was stirred for 4 days at room temperature. After evaporation of the solvent the residue was basified at pH=13, extracted with CH2Cl2, dried over Na2SO4, and concentrated down. The crude material was purified by combination of column chromatography (silica-gel, MeOH/CH2Cl2), preparative TLC (silica-gel, 10% MeOH/CH2 Cl2) and crystallization from MeOH to provide pure compound 8 (109 mg, 23%).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.[CH3:12][C:13]1[CH:18]=[C:17]([C:19](O)=[O:20])[CH:16]=[CH:15][C:14]=1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[CH3:12][C:13]1[CH:18]=[C:17]([C:19]([NH:1][C:2]2[CH:11]=[C:10]3[C:5]([CH:6]=[CH:7][CH:8]=[N:9]3)=[CH:4][CH:3]=2)=[O:20])[CH:16]=[CH:15][C:14]=1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: Cc1cc(C(=O)O)ccc1-c1ccccc1
Reactant: Nc1ccc2cccnc2c1
Product: Cc1cc(C(=O)Nc2ccc3cccnc3c2)ccc1-c1ccccc1

Procedure:
Using the procedure outlined in Example 56, the title compound was prepared from 7-aminoquinoline (D55) (30 mg, 0.21 mmol) and 2-methyl-1,1′-biphenyl-4-carboxylic acid (D60) (53 mg, 0.25 mmol) as a white solid. MS(ES): MH+ 339
Reaction SMILES: [C:1]([NH:4][NH:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-])=O)=[CH:8][CH:7]=1)(=[O:3])[CH3:2].[H][H]>C(O)C.[Pd]>[C:1]([NH:4][NH:5][C:6]1[CH:11]=[CH:10][C:9]([NH2:12])=[CH:8][CH:7]=1)(=[O:3])[CH3:2]
Reactant: [H][H]
Reactant: CC(=O)NNc1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CCO
Product: CC(=O)NNc1ccc(N)cc1

Procedure:
1-Acetyl-2-(4-nitrophenyl)hydrazine (12.7 g, 0.065 mole) and 10% palladium/charcoal (catalytic amount) was suspended in absolute ethanol (300 ml) in a Parr shaker bottle. The reaction mixture was hydrogenated at room temperature until hydrogen uptake ceased (theoretical uptake 15.6 psi-actual uptake was 17 psi).
Reaction SMILES: [F:1][CH:2]([F:12])[O:3][C:4]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:5]=1[NH2:6].C(=O)([O-])[O-].[K+].[K+].[Cl:19][CH2:20][C:21](Cl)=[O:22]>CC(C)=O>[Cl:19][CH2:20][C:21]([NH:6][C:5]1[C:7]([CH3:11])=[CH:8][CH:9]=[CH:10][C:4]=1[O:3][CH:2]([F:12])[F:1])=[O:22]
Reactant: O=C(Cl)CCl
Reactant: Cc1cccc(OC(F)F)c1N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Cc1cccc(OC(F)F)c1NC(=O)CCl
Yield: 94.3 %

Procedure:
The procedures of Example 3 were repeated except that the starting material was 50 ml of an acetone solution containing 8.9 g (51 mmol) of 2-difluoromethoxy-6-methyl aniline, to which 10.5 g (77 mmol) of potassium carbonate and 7.0 g (62 mmol) of chloroacetyl chloride were added. As a result, 12.0 g of 2-chloro-2'-difluoromethoxy-6'-methylacetanilide was obtained. It had a melting point of 85° to 86° C.
Reaction SMILES: [H-].[Na+:2].[CH:3]1[C:16]2[NH:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[S:8][C:7]=2[CH:6]=[CH:5][CH:4]=1.[CH2:17]1[CH2:23][S:20](=[O:22])(=[O:21])[O:19][CH2:18]1>O1CCCC1>[CH:13]1[C:14]2[N:15]([CH2:18][CH2:17][CH2:23][S:20]([O-:22])(=[O:21])=[O:19])[C:16]3[C:7](=[CH:6][CH:5]=[CH:4][CH:3]=3)[S:8][C:9]=2[CH:10]=[CH:11][CH:12]=1.[Na+:2]
Reactant: O=S1(=O)CCCO1
Reactant: c1ccc2c(c1)Nc1ccccc1S2
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=S(=O)([O-])CCCN1c2ccccc2Sc2ccccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A portion of sodium hydride (17.7 g, 0.44 moles) dispersed in mineral oil is first washed with petroleum ether (b.p. 40-60° C.) and then suspended in 200 mL dry tetrahydrofuran, in a 2 L three-neck flask. A solution of phenothiazine (80.0 g, 0.4 moles) dissolved in tetrahydrofuran (400 mL) is added under argon through a cannula. The mixture is shaken, always under argon, for one hour at room temperature and then for 30 minutes at 50° C. The mixture acquires an orange colour, following the formation of the phenothiazine anion. After the suspension has cooled to 0° C., a solution of 1,3-propanesultone (35 mL, 0.4 moles) in tetrahydrofuran is added also through a cannula. The colour of the mixture changes almost immediately to clear yellow. The mixture is stirred at 0° C. for thirty minutes after the addition of the sultone and then at room temperature for another thirty minutes.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Cl:7][C:8]1[C:9]2[C:21]([CH:22]=[O:23])=[C:20]([OH:24])[CH:19]=[CH:18][C:10]=2[S:11][C:12]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14].S(C1C=CC(C)=CC=1)(O[CH2:29][C@@H:30]1[O:32][CH2:31]1)(=O)=O.O>CN(C)C=O>[Cl:7][C:8]1[C:9]2[C:21]([CH:22]=[O:23])=[C:20]([O:24][CH2:29][C@@H:30]3[O:32][CH2:31]3)[CH:19]=[CH:18][C:10]=2[S:11][C:12]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: CCOC(=O)c1sc2ccc(O)c(C=O)c2c1Cl
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2CO2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1sc2ccc(OC[C@H]3CO3)c(C=O)c2c1Cl
Temperature: 60 °C
Reaction time: 3 h
Yield: 87.8 %

Procedure:
Potassium carbonate (2.62 g) was added to a stirred solution of ethyl 3-chloro-4-formyl-5-hydroxybenzo[b]thiophene-2-carboxylate (4.90 g, prepared as described above) in dry dimethylformamide (50 ml) and then a solution of (R)-glycidyl tosylate (4.12 g) in dry dimethyl formamide (50 ml) was added slowly. The mixture was then stirred at 60° C. for 3 hours, cooled and poured into water (1200 ml). The resulting pale-green solid was collected by filtration, washed with water (200 ml) and dried to give ethyl (R)-3-chloro-5-(2,3-epoxypropoxy)-4-formylbenzo[b]thiophene-2-carboxylate (5.15 g).