Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[C:14]2[C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[NH:7][C:6]=2[CH:5]2[CH2:15][CH2:16][N:2]1[CH2:3][CH2:4]2.Br[C:18]1[CH:27]=[CH:26][C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[N:19]=1>>[N:19]1[C:20]2[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:26]=[CH:27][C:18]=1[N:7]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=2[C:14]2[CH2:1][N:2]3[CH2:3][CH2:4][CH:5]([C:6]1=2)[CH2:15][CH2:16]3
Reactant: Brc1ccc2ccccc2n1
Reactant: c1ccc2c3c([nH]c2c1)C1CCN(CC1)C3
Product: c1ccc2nc(-n3c4c(c5ccccc53)CN3CCC4CC3)ccc2c1

Procedure:
The reaction of 3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole (212 mg, 1.0 mmol; Example 187A) and 2-bromoquinoline (312 mg, 1.5 mmol; Alfa Aesar) was performed as described in Example 68 to afford the title compound: 1H NMR (300 MHz, methanol-d4) δ ppm 1.97-2.12 (m, 2H) 2.19-2.32 (m, 2H) 3.11-3.29 (m, 5H) 4.36 (s, 2H) 7.11-7.19 (m, 2H) 7.40-7.48 (m, 2H) 7.60 (d, J=9 Hz, 1H) 7.66 (t, J=8 Hz, 1H) 7.79-7.87 (m, 1H) 8.03 (t, J=7 Hz, 2H) 8.55 (d, J=8 Hz, 1H); MS (DCI/NH3) m/z 340 (M+H)+.
Reaction SMILES: [CH3:1][CH:2]([CH3:14])[C:3]([C:5]1[CH:13]=[CH:12][CH:11]=[CH:10][C:6]=1[C:7]([OH:9])=[O:8])=[O:4].C(O)(C)(C)C.CC(C)([O-])C.[K+].Br[CH:27]([C:33]([O:35][CH2:36][CH3:37])=[O:34])[C:28]([O:30][CH2:31][CH3:32])=[O:29]>C(O)C>[CH2:31]([O:30][C:28]([C:27]1([C:33]([O:35][CH2:36][CH3:37])=[O:34])[C:3]([OH:4])([CH:2]([CH3:1])[CH3:14])[C:5]2[C:6](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:7](=[O:8])[O:9]1)=[O:29])[CH3:32]
Reactant: CC(C)C(=O)c1ccccc1C(=O)O
Reactant: CCOC(=O)C(Br)C(=O)OCC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: CCO
Product: CCOC(=O)C1(C(=O)OCC)OC(=O)c2ccccc2C1(O)C(C)C
Reaction time: 0.17 h
Yield: 94.2 %

Procedure:
A stirred mixture of 2-(2-methylpropanoyl)benzoic acid (44.27 g) and tert-butanol (300 ml) was treated portionwise with potassium tert-butoxide (28.14 g) over 5 minutes at room temperature and the reaction mixture stirred for a further 10 minutes and then treated dropwise over 10 minutes with a solution of diethyl bromomalonate (55.1 g) in ethanol (200 ml). The stirred mixture was refluxed for 18 hours and then evaporated to dryness. The residue was treated with diethyl ether (400 ml) and washed with water (400 ml). The aqueous phase was re-extracted with diethyl ether (200 ml) and the combined ethereal extracts washed with water (200 ml), saturated aqueous sodium hydrogen carbonate solution (200 ml) and water (200 ml), dried over magnesium sulphate and evaporated to give crude 3,3-bis(ethoxycarbonyl)-4-hydroxy-4-isopropyl-3,4-dihydroisocoumarin (76 g) as an amber oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12](=[O:21])[NH:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)=[CH:8][N:7]=1.[CH2:23](O)C>S(=O)(=O)(O)O.C(OCC)(=O)C>[CH2:1]([O:2][C:3](=[O:22])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12](=[O:21])[NH:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)=[CH:8][N:7]=1)[CH3:23]
Reactant: COC(=O)COc1ccc(C(=O)Nc2ccc(F)cc2)cn1
Reactant: CCO
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Product: CCOC(=O)COc1ccc(C(=O)Nc2ccc(F)cc2)cn1
Yield: 20 %

Procedure:
A solution of [5-(4-fluorophenylcarbamoyl)pyridin-2-yloxy]acetic acid methyl ester (0.030 g, 0.99 mmole), ethanol (2 mL), and sulfuric acid (1 drop) was heated in a sealed tube at 80° C. After 6 h the reaction mixture was poured into ethyl acetate and washed with saturated sodium bicarbonate and dried over sodium sulfate. Removal of the solvents provided 6 mg (20%) of the titled product as a white solid: 1H NMR (300 MHz, DMSO-d6) δ 10.30 (s 1H), 8.66 (m, 1H), 8.22 (m, 1H), 7.73 (m, 2H), 7.16 (m, 2H), 7.04 (m, 1H), 4.96 (s, 2H); 4.11 (m, 2H); 1.16 (m, 3H); MS (EI) m/z 317.17 (M−H)−.
Reaction SMILES: [NH2:1][CH:2]([CH2:15][O:16][CH3:17])[CH2:3][O:4][C:5]1[C:9]2[CH:10]=[C:11]([Cl:14])[CH:12]=[CH:13][C:8]=2[O:7][N:6]=1.[C:18]([C:22]1[CH:23]=[C:24]([CH:27]=[C:28]([C:31]([CH3:34])([CH3:33])[CH3:32])[C:29]=1[OH:30])[CH:25]=O)([CH3:21])([CH3:20])[CH3:19].C1(C)C=CC(S(O)(=O)=O)=CC=1.C([BH3-])#N.[Na+].[OH-].[Na+].Cl>CO.C(OCC)C.O1CCOCC1.O.C(OCC)(=O)C>[ClH:14].[C:31]([C:28]1[CH:27]=[C:24]([CH:23]=[C:22]([C:18]([CH3:21])([CH3:20])[CH3:19])[C:29]=1[OH:30])[CH2:25][NH:1][CH:2]([CH2:15][O:16][CH3:17])[CH2:3][O:4][C:5]1[C:9]2[CH:10]=[C:11]([Cl:14])[CH:12]=[CH:13][C:8]=2[O:7][N:6]=1)([CH3:33])([CH3:34])[CH3:32]
Reactant: COCC(N)COc1noc2ccc(Cl)cc12
Reactant: CC(C)(C)c1cc(C=O)cc(C(C)(C)C)c1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Agent: [BH3-]C#N
Solvent: CCOC(C)=O
Solvent: CO
Solvent: C1COCCO1
Product: COCC(COc1noc2ccc(Cl)cc12)NCc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1

Procedure:
To a suspension of 0.50 g of 3-(2-amino-3-methoxypropoxy)-5-chloro-1,2-benzoisoxazole and 0.5 g of 3,5-di-tert-butyl-4-hydroxybenzaldehyde in 5 ml of methanol is added 0.41 g of p-toluenesulfonic acid at 20°-25° C., and they are subjected to reaction at the same temperature for one hour. Subsequently, 0.13 g of sodium cyanoborohydride is added at 20°-25° C., and they are subjected to reaction at the same temperature overnight. Water and ethyl acetate are added to the reaction mixture and the pH is adjusted to 10 with a 10% (w/w) aqueous sodium hydroxide solution, after which the organic layer is separated. The separated organic layer is washed with a saturated saline solution and dried over anhydrous magnesium sulfate, after which the solvent is removed by distillation under reduced pressure. The residue obtained is purified by a column chromatography [eluant:n-hexane:ethyl acetate=5:1], to obtain an oily product. The oily product obtained is dissolved in 10 ml of diethyl ether and 1 ml of water and to this solution is added 0.58 ml of a dioxane solution (2.2N) of hydrogen chloride, after which the crystals precipitated are collected by filtration and recrystallized from 50% ethanol, to obtain 0.27 g of colorless, crystalline 3-[2-(3,5-di-tert-butyl-4-hydroxybenzyl)amino-3-methoxypropoxy]-5-chloro-1,2-benzoisoxazole hydrochloride having a melting point of 191°-192° C.
Reaction SMILES: C[CH:2]1[C:7]2[CH:8]=[C:9]3C(C)(C)C(C)C(C)(C)[C:10]3=[CH:11][C:6]=2[CH2:5][O:4][CH2:3]1>CCCCCC>[O:4]1[C:3]2[CH:2]=[CH:7][CH:8]=[CH:9][C:10]=2[CH:11]=[CH:6][CH2:5]1
Reactant: CC1COCc2cc3c(cc21)C(C)(C)C(C)C3(C)C
Solvent: CCCCCC
Product: C1=Cc2ccccc2OC1
Temperature: -30 °C
Reaction time: 1 h

Procedure:
750 grams of the liquid phase benzopyran mixture was prepared according to Example 15 of U.S. Pat. No. 3,360,530, the specification of which is herein incorporated by reference, containing 78% by weight of 1,3,4,6,7,8-hexahydro-4,6,6,7,8,8-hexamethyl-cyclopenta[G]-2-benzopyran and 500 grams of hexane were admixed and cooled to a temperature of −30° C. with stirring. Stirring continued for a period of 1 hour at which point in time solid particles began to precipitate. The mixture was stirred for an additional 3 hours while slowly increasing the temperature of the benzopyran-solvent mixture to 0° C. The white solids were filtered at 0° C., resulting in the isolation of 240 grams of a mixture containing the following substances in the weight percentage stated:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][N:12]=[C:11]([C@H:15]2[CH2:19][CH2:18][C@@:17]3([CH2:23][CH2:22][N:21]([CH3:24])[C:20]3=[O:25])[NH:16]2)[CH:10]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O.[F:61][CH2:62][CH2:63]O>C1COCC1.C1(C)C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:63][CH2:62][F:61])=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][N:12]=[C:11]([CH:15]2[CH2:19][CH2:18][C:17]3([CH2:23][CH2:22][N:21]([CH3:24])[C:20]3=[O:25])[NH:16]2)[CH:10]=1
Reactant: OCCF
Reactant: CN1CC[C@@]2(CC[C@H](c3cc(-c4cc(O)ccc4F)ccn3)N2)C1=O
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CN1CCC2(CCC(c3cc(-c4cc(OCCF)ccc4F)ccn3)N2)C1=O
Temperature: 120 °C

Procedure:
To a Smith microwave vial was added (2R,5S)-2-[4-(2-fluoro-5-hydroxy-phenyl)-2-pyridyl]-7-methyl-1,7-diazaspiro[4.4]nonan-6-one (which may be prepared as described in Description 134) (66.5 mg, 0.1900 mmol), triphenyl phosphine (102.19 mg, 0.3900 mmol), Di-tert-butyl azodicarboxylate ((89.71 mg, 0.3900 mmol) and 2-fluoroethanol (0.02 mL, 0.2900 mmol) in THF (0.5000 mL). Toluene (1 mL) was added. The reaction mixture was heated by microwave at 120° C. for 45 min. The reaction mixture was eluted on an SCX-2 cartrige (0.5 g) and washed with DCM followed MeOH. The desired product was eluted off the cartridge with ammonia in MeOH (0.2M). Evaporation of solvents gave colourless oil. The crude residue was purified by silica gel chromatography (KPNH silica 11 g) eluting with ethyl acetate in iso-hexane (10-100%) followed by methanol in ethyl acetate (0-18%). Evaporation of desired fractions gave colourless oil. It was further purified by a ChiralPak IA column eluting with ethanol/n-heptane (20%:80%) to give 2R,5S)-2-[4-[2-fluoro-5-(2-fluoroethoxyl)phenyl]-2-pyridyl]-7-methyl-1,7-diazaspiro[4.4]nonan-6-one;
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[C:24]([O:26][CH3:27])[CH:23]=[CH:22][C:21]=4[O:28][CH2:29][CH:30]4[CH2:32][CH2:31]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1.Cl[C:34]([C:36]1([O:39]C(=O)C)[CH2:38][CH2:37]1)=[O:35]>>[OH:39][C:36]1([C:34]([NH:1][C@H:2]2[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]3[C:15]4[N:16]=[CH:17][N:18]=[C:19]([C:20]5[CH:25]=[C:24]([O:26][CH3:27])[CH:23]=[CH:22][C:21]=5[O:28][CH2:29][CH:30]5[CH2:31][CH2:32]5)[C:14]=4[NH:13][CH:12]=3)=[O:10])[CH2:4][CH2:3]2)=[O:35])[CH2:38][CH2:37]1
Reactant: CC(=O)OC1(C(=O)Cl)CC1
Reactant: COc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@H]4CC[C@H](N)CC4)c[nH]c23)c1
Product: COc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@H]4CC[C@H](NC(=O)C5(O)CC5)CC4)c[nH]c23)c1

Procedure:
Starting from trans-4-(2-cyclopropylmethoxy-5-methoxy-phenyl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (4-amino-cyclohexyl)-amide (example A153) and acetic acid 1-chlorocarbonyl-cyclopropyl ester the title compound is obtained as colorless solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13](I)[CH:12]=[CH:11][C:10]=1[N:16]1[S:20](=[O:22])(=[O:21])[NH:19][C:18](=[O:23])[CH2:17]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:24]([Si:27]([CH:39]([CH3:41])[CH3:40])([CH:36]([CH3:38])[CH3:37])[N:28]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29]1)([CH3:26])[CH3:25].C([O-])([O-])=O.[Na+].[Na+]>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([C:30]2[CH:31]=[CH:32][N:28]([Si:27]([CH:36]([CH3:38])[CH3:37])([CH:39]([CH3:41])[CH3:40])[CH:24]([CH3:25])[CH3:26])[CH:29]=2)[CH:12]=[CH:11][C:10]=1[N:16]1[S:20](=[O:22])(=[O:21])[NH:19][C:18](=[O:23])[CH2:17]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc(B(O)O)c1
Reactant: O=C1CN(c2ccc(I)cc2OCc2ccccc2)S(=O)(=O)N1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CC(C)[Si](C(C)C)(C(C)C)n1ccc(-c2ccc(N3CC(=O)NS3(=O)=O)c(OCc3ccccc3)c2)c1
Temperature: 120 °C

Procedure:
To a solution of 5-(2-benzyloxy-4-iodophenyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one (100 mg, 0.225 mmol) in DME (5 mL) is added 1-triisopropylsilylpyrrole-3-boronic acid (120 mg, 0.450 mmol), Pd(PPh3)4 (27 mg, 0.023 mmol) and 0.5 mL of Na2CO3 (2M aqueous solution) and the mixture is heated in a microwave apparatus at 120° C. for 5 min. The mixture is concentrated under reduced pressure and the residue purified by reverse phase MPLC using a gradient of 10-50% MeCN/water as eluent to afford the title compound: (M−1)−=538.
Reaction SMILES: Cl.[F:2][C:3]([F:29])([F:28])[C:4]1[CH:12]=[CH:11][C:7]([C:8](Cl)=[O:9])=[C:6]([NH:13][C:14]2[C:23]3[C:18](=[C:19]([C:24]([F:27])([F:26])[F:25])[CH:20]=[CH:21][CH:22]=3)[N:17]=[CH:16][CH:15]=2)[CH:5]=1.ClC1C2C(=C(C(F)(F)F)C=CC=2)N=CC=1.NC1C=C(C(F)(F)F)C=CC=1C(O)=O.S(Cl)(Cl)=O.[NH2:63][CH:64]1[CH2:69][CH2:68][CH2:67][N:66]([CH2:70][CH3:71])[CH2:65]1>>[CH2:70]([N:66]1[CH2:67][CH2:68][CH2:69][CH:64]([NH:63][C:8](=[O:9])[C:7]2[CH:11]=[CH:12][C:4]([C:3]([F:29])([F:28])[F:2])=[CH:5][C:6]=2[NH:13][C:14]2[C:23]3[C:18](=[C:19]([C:24]([F:27])([F:26])[F:25])[CH:20]=[CH:21][CH:22]=3)[N:17]=[CH:16][CH:15]=2)[CH2:65]1)[CH3:71]
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1Nc1ccnc2c(C(F)(F)F)cccc12
Reactant: CCN1CCCC(N)C1
Agent: Cl
Agent: FC(F)(F)c1cccc2c(Cl)ccnc12
Agent: Nc1cc(C(F)(F)F)ccc1C(=O)O
Solvent: O=S(Cl)Cl
Product: CCN1CCCC(NC(=O)c2ccc(C(F)(F)F)cc2Nc2ccnc3c(C(F)(F)F)cccc23)C1

Procedure:
4-Trifluoromethyl-2-(8-trifluoromethyl-4-quinolylamino)benzoyl chloride hydrochloride prepared by reaction of 4-chloro-8-trifluoromethyl quinoline with 2-amino-4-trifluoromethylbenzoic acid and treatment of the reaction product with thionyl chloride, is reacted with 3-amino-1-ethylpiperidine to form the title compound.
Reaction SMILES: O=[C:2]([CH3:14])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH2:13])(=[O:12])=[O:11])=[CH:6][CH:5]=1.N.[N:16]1([CH2:22][CH2:23][C:24]2[S:28][C:27]([NH:29][C:30]([NH2:32])=[S:31])=[N:26][N:25]=2)[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1>>[CH3:14][C:2]1[N:32]=[C:30]([NH:29][C:27]2[S:28][C:24]([CH2:23][CH2:22][N:16]3[CH2:17][CH2:18][O:19][CH2:20][CH2:21]3)=[N:25][N:26]=2)[S:31][C:3]=1[C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH2:13])(=[O:12])=[O:11])=[CH:6][CH:5]=1
Reactant: CC(=O)Cc1ccc(S(N)(=O)=O)cc1
Reactant: NC(=S)Nc1nnc(CCN2CCOCC2)s1
Agent: N
Product: Cc1nc(Nc2nnc(CCN3CCOCC3)s2)sc1-c1ccc(S(N)(=O)=O)cc1

Procedure:
The titled compound is prepared from 4-(2-oxo-propyl)-benzenesulfonyl chloride (prepared as described in European patent specification EP 91749 A2) following the procedures described in Example 1, using ammonia and [5-(2-morpholin-4-yl-ethyl)-[1,3,4]thiadiazol-2-yl}-thiourea (54c).
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([NH:15][CH2:16][C:17]2[C:22]([F:23])=[CH:21][CH:20]=[C:19]([F:24])[C:18]=2[Cl:25])[C:5]([NH:8][CH2:9][CH2:10][C:11](OC)=[O:12])=[N:6][CH:7]=1>CC(O)=O>[Br:1][C:2]1[CH:7]=[N:6][C:5]2[NH:8][CH2:9][CH2:10][C:11](=[O:12])[N:15]([CH2:16][C:17]3[C:22]([F:23])=[CH:21][CH:20]=[C:19]([F:24])[C:18]=3[Cl:25])[C:4]=2[N:3]=1
Reactant: COC(=O)CCNc1ncc(Br)nc1NCc1c(F)ccc(F)c1Cl
Solvent: CC(=O)O
Product: O=C1CCNc2ncc(Br)nc2N1Cc1c(F)ccc(F)c1Cl

Procedure:
A solution of methyl N-{5-bromo-3-[(2-chloro-3,6-difluorobenzyl)amino]pyrazin-2-yl}-β-alaninate in HOAc was heated at reflux for 4 hrs. After volatile components were removed on rotavap, the residue was taken in to a mixture of EtOAc and aq. NaHCO3. The combined organic layers from extraction was dried, concentrated, and then purified by silica gel column chromatography (EtOAc/Hexanes 4:1) to furnish 3-bromo-5-(2-chloro-3,6-difluorobenzyl)-5,7,8,9-tetrahydro-6H-pyrazino[2,3-b][1,4]diazepin-6-one.
Reaction SMILES: C(Br)CCC.[Li].Br[C:8]1[C:9]2[C:14]([N:15]=[C:16]3[C:21]=1[CH:20]=[CH:19][CH:18]=[CH:17]3)=[CH:13][CH:12]=[CH:11][CH:10]=2.I[C:23]1[CH:30]=[CH:29][C:26]([CH:27]=[CH2:28])=[CH:25][CH:24]=1>CCOCC.[Co](Cl)Cl>[CH:27]([C:26]1[CH:29]=[CH:30][C:23]([C:8]2[C:9]3[C:14]([N:15]=[C:16]4[C:21]=2[CH:20]=[CH:19][CH:18]=[CH:17]4)=[CH:13][CH:12]=[CH:11][CH:10]=3)=[CH:24][CH:25]=1)=[CH2:28]
Reactant: C=Cc1ccc(I)cc1
Reactant: Brc1c2ccccc2nc2ccccc12
Agent: Cl[Co]Cl
Agent: [Li]
Solvent: CCOCC
Solvent: CCCCBr
Product: C=Cc1ccc(-c2c3ccccc3nc3ccccc23)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 38.5 %

Procedure:
A solution of butyl lithium in ether was obtained by reacting a solution consisting of 137 g of butyl bromide and 200 ml of ether with a suspension consisting of 17 g of lithium and 400 ml of ether by the use of the same apparatus as that used in Referential Example 1. This solution was added dropwise to 300 ml of an ether solution containing 180 g of 9-bromoacridine at 0°-5° C., and the mixture was then warmed gradually to room temperature and stirred for further 3 hours. To the mixture was added dropwise 322 g of p-iodostyrene diluted with 300 ml of ether in the presence of cobalt chloride with stirring in a nitrogen gas stream, and the mixture was then refluxed for 5 hours. The reaction mixture was poured onto hydrochloric acid-ice and stirred. The organic layer was extracted with ether, and the extract was dried over anhydrous sodium sulfate. The solvent was then distilled off to obtain yellowish white crystals. The crystals were purified by alumina column chromatography to obtain 75.6 g of 9-(p-vinylphenyl)acridine, yield 38.4%.
Reaction SMILES: [CH2:1]([NH2:3])[CH3:2].Cl[CH2:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]1([NH:17][C:18]2[C:19](=[O:38])[N:20]([C:24]3[C:25]([CH3:37])=[CH:26][C:27]([F:36])=[C:28]([CH:35]=3)[C:29]([NH:31][CH:32]3[CH2:34][CH2:33]3)=[O:30])[CH:21]=[CH:22][N:23]=2)[CH2:16][CH2:15]1>O1CCOCC1.C1COCC1>[CH:32]1([NH:31][C:29](=[O:30])[C:28]2[CH:35]=[C:24]([N:20]3[CH:21]=[CH:22][N:23]=[C:18]([NH:17][C:14]4([C:9]5[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=5[O:7][CH2:6][CH2:5][NH:3][CH2:1][CH3:2])[CH2:16][CH2:15]4)[C:19]3=[O:38])[C:25]([CH3:37])=[CH:26][C:27]=2[F:36])[CH2:34][CH2:33]1
Reactant: Cc1cc(F)c(C(=O)NC2CC2)cc1-n1ccnc(NC2(c3ccccc3OCCCl)CC2)c1=O
Reactant: CCN
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: CCNCCOc1ccccc1C1(Nc2nccn(-c3cc(C(=O)NC4CC4)c(F)cc3C)c2=O)CC1

Procedure:
A solution of ethylamine (2.012 mL of 2M in THF) and 5-[3-({1-[2-(2-chloroethoxy)phenyl]cyclopropyl}amino)-2-oxopyrazin-1(2H)-yl]-N-cyclopropyl-2-fluoro-4-methylbenzamide (Example 318h, 100 mg) in dioxane (3 mL) was heated for 24 h at 100° C. in a sealed tube. Further ethylamine (2.012 mL of a 2M solution in THF) was added and the reaction was heated for a further 24 h. Purification by preparative HPLC (Xbridge column eluting with a gradient of acetonitrile in 0.2% (v/v) aqueous ammonia) gave the title compound as a solid (10 mg).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[C:5]([C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[OH:18])=[CH2:11])[CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.C(=O)([O-])[O-].[K+].[K+].[Cl:25][CH2:26][CH2:27][CH2:28]Br>CC(C)=O>[Cl:25][CH2:26][CH2:27][CH2:28][O:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[C:10]([C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:4]=1[CH:3]=[CH:2][NH:1]2)=[CH2:11]
Reactant: ClCCCBr
Reactant: C=C(c1ccccc1O)c1cccc2[nH]ccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=C(c1ccccc1OCCCCl)c1cccc2[nH]ccc12

Procedure:
Using the procedure of Step E of Example 1, 6.7 g of 2-[1-(1H-indol-4-yl)-ethenyl]-phenol of Step A of Example 22, 70 ml of acetone, 4 g of potassium carbonate and 11.5 ml of 1-chloro-3-bromo-propane were heated for 20 hours at reflux and after chromatography and crystallization from petroleum ether (Eb=40°-70° C.), 7.05 g of the desired product melting at 70° to 72° C. were obtained.
Reaction SMILES: [K].[C:2]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)#[N:3].[Br:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]Br>>[C:2]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][Br:11])=[CH:6][CH:5]=1)#[N:3]
Reactant: N#Cc1ccc(O)cc1
Reactant: BrCCCCCCCBr
Agent: [K]
Product: N#Cc1ccc(OCCCCCCCBr)cc1

Procedure:
The intermediate 7-(4-cyanophenoxy)heptyl bromide was prepared from the potassium salt of 4-cyanophenol and 1,7-dibromoheptane.
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:8]2[CH:13]=[CH:12][C:11](/[CH:14]=[CH:15]/[C:16]([OH:18])=O)=[CH:10][CH:9]=2)[C:4]([CH3:7])=[CH:5][CH:6]=1.ClC(OCC)=O.Cl.[CH3:26][NH:27][OH:28]>ClCCl.C(N(CC)CC)C>[CH3:1][C:2]1[N:3]([C:8]2[CH:13]=[CH:12][C:11](/[CH:14]=[CH:15]/[C:16]([N:27]([OH:28])[CH3:26])=[O:18])=[CH:10][CH:9]=2)[C:4]([CH3:7])=[CH:5][CH:6]=1
Reactant: Cc1ccc(C)n1-c1ccc(/C=C/C(=O)O)cc1
Reactant: CNO
Agent: CCOC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(C)n1-c1ccc(/C=C/C(=O)N(C)O)cc1
Reaction time: 16 h

Procedure:
A solution of 12.05 g of (E)-3-[4-(2,5-dimethyl-1H-pyrrol-1-yl)-phenyl]-2-propenoic acid in 350 ml of dichloromethane and 9.7 ml triethylamine, is cooled in an ice bath. To this stirred solution is added 7.0 ml of ethyl chloroformate dropwise. After four hours at ice-bath temperature, 20.7 ml of triethylamine is added, followed by 12.6 g of N-methylhydroxylamine hydrochloride and the mixture is kept at room temperature for 16 hours. This mixture is washed with cold 0.3 N aqueous hydrochloric acid, ice cold sodium bicarbonate and brine. The organic phase is dried over MgSO4, treated with charcoal and filtered. The solvent is evaporated at 50° under reduced pressure and the product is crystallized from ether to give (E)-3-[4-(2,5-dimethyl-1H-pyrrol-1-yl)-phenyl]-N-hydroxy-N-methyl-2-propenamide, m.p. 143°-145°, the compound of formula IV wherein R1 and R2 represent methyl at the 2 and 5 positions, R4 represents methyl, and R3, R8 and R9 represent hydrogen; the compound may also be named (E)-3-[4-(2,5-dimethyl-1H-pyrrol-1-yl)-phenyl]-N-methyl-2-propenohydroxamic acid. The product can also be recrystallized from ethyl acetate (with charcoal and silica gel).
Reaction SMILES: [NH2:1][C:2]1[C:11]([OH:12])=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[Cl:13][CH2:14][C:15](OC)(OC)OC>C(O)C>[Cl:13][CH2:14][C:15]1[O:12][C:11]2[C:2](=[C:3]([C:4]([O:6][CH3:7])=[O:5])[CH:8]=[CH:9][CH:10]=2)[N:1]=1
Reactant: COC(=O)c1cccc(O)c1N
Reactant: COC(CCl)(OC)OC
Solvent: CCO
Product: COC(=O)c1cccc2oc(CCl)nc12
Temperature: 25 °C
Yield: 66.4 %

Procedure:
A mixture of methyl 2-amino-3-hydroxybenzoate (3.5 g, 20.70 mmol) and 2-chloro-1,1,1-trimethoxyethane (3.0 mL, 22.06 mmol) in ethanol (30 mL) was stirred under reflux for 6 h. The reaction mixture was cooled to ambient temperature and the solvent volume was reduced under reduced pressure approximately to ⅔ of initial volume. The precipitate formed was filtered, washed with ether (3×10 mL), and dried under vacuum to afford methyl 2-(chloromethyl)benzoxazole-4-carboxylate (3.1 g, 66%) as a yellow solid: 1H NMR (500 MHz, CDCl3) δ 8.05 (dd, J=8.0, 1.0 Hz, 1H), 7.78 (dd, J=9.0, 1.0 Hz 1H), 7.47 (t, J=5.0 Hz, 1H), 4.84 (s, 2H), 4.04 (s, 3H); (APCI+) m/z 226 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N:16]2[CH:20]=[N:19][N:18]=[C:17]2[CH2:21][N:22]2[C:26](=[O:27])[C:25]3=[CH:28][CH:29]=[CH:30][CH:31]=[C:24]3[C:23]2=[O:32])=[C:6]([CH:15]=1)[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:8].[Cl:33]N1C(=O)CCC1=O>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:16]2[C:17]([CH2:21][N:22]3[C:26](=[O:27])[C:25]4=[CH:28][CH:29]=[CH:30][CH:31]=[C:24]4[C:23]3=[O:32])=[N:18][N:19]=[C:20]2[Cl:33])=[C:6]([CH:15]=1)[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:8]
Reactant: O=C(c1ccccc1)c1cc(F)ccc1-n1cnnc1CN1C(=O)c2ccccc2C1=O
Reactant: O=C1CCC(=O)N1Cl
Product: O=C(c1ccccc1)c1cc(F)ccc1-n1c(Cl)nnc1CN1C(=O)c2ccccc2C1=O

Procedure:
Following the procedure of Example 2, 5-fluoro-2-[3-phthalimidomethyl-4H-1,2,4-triazol-4-yl]benzophenone is reacted with N-chlorosuccinimide to form-5-fluoro-2-[3-chloro-5-phthalimidomethyl-4H-1,2,4-triazol-4-yl]benzophenone.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH:12]=[CH2:13])[CH:10]=2)[N:5]=[C:4]([N:14]2[CH2:20][C:19]3[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=3[S:17](=[O:26])(=[O:25])[CH2:16][CH2:15]2)[CH:3]=1.[CH2:27]([NH2:31])[CH2:28][CH2:29][NH2:30]>>[O:25]=[S:17]1(=[O:26])[C:18]2[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=2[CH2:20][N:14]([C:4]2[CH:3]=[C:2]([NH:30][CH2:29][CH2:28][CH2:27][NH2:31])[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([CH:12]=[CH2:13])[CH:10]=3)[N:5]=2)[CH2:15][CH2:16]1
Reactant: C=Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(Cl)c2c1
Reactant: NCCCN
Product: C=Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(NCCCN)c2c1

Procedure:
The title compound was prepared in analogy to Example 52 in Scheme 22 by using 4-(4-chloro-6-ethenylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide and propane-1,3-diamine. MS obsd. (ESI+) [(M+H)+] 423, 1H NMR (400 MHz, CD3OD) δ ppm 8.12 (s, 1 H), 8.05-8.02 (q, J=8 Hz, 1 H), 7.89-7.81 (m, 2 H), 7.77-7.70 (m, 2 H), 7.56-7.54 (t, J=4.4 Hz, 1 H), 6.80-6.74 (m, 1 H), 5.95-5.90 (m, 2 H), 5.36-5.30 (m, 3 H), 4.51 (s, 2 H), 3.71 (s, 2 H), 3.61-3.60 (t, J=3.2 Hz, 2 H), 3.11-3.10 (t, J=5.2 Hz, 2 H), 2.13-2.11 (t, J=5.6 Hz, 2 H).