Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[CH:10][C:9]=2[C:13]([OH:15])=O)=[CH:4][CH:3]=1.[CH3:16][NH:17][C:18]([CH:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1)=[O:19]>>[CH3:16][NH:17][C:18]([CH:20]1[CH2:25][CH2:24][N:23]([C:13]([C:9]2[CH:10]=[N:11][O:12][C:8]=2[C:5]2[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=2)=[O:15])[CH2:22][CH2:21]1)=[O:19]
Reactant: CNC(=O)C1CCNCC1
Reactant: Cc1ccc(-c2oncc2C(=O)O)cc1
Product: CNC(=O)C1CCN(C(=O)c2cnoc2-c2ccc(C)cc2)CC1

Procedure:
The title compound was prepared from 5-(4-methylphenyl)isoxazole-4-carboxylic acid (10.2 mg, 0.050 mmol) and piperidine-4-carboxylic acid methylamide (8.5 mg, 0.060 mmol) as described in synthetic method B and thereafter purified by preparative HPLC method B to give a solid (5.1 mg). HRMS calcd for C18H21N3O3: 327.1583, found 327.1580.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([I:12])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[NH:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16][CH2:15][CH2:14]1.N1C2C(=CC=CC=2)C=NC=1>O1CCOCC1.CC(=O)OCC>[N:13]1([C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([I:12])[CH:10]=3)[N:5]=[CH:4][N:3]=2)[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16][CH2:15][CH2:14]1
Reactant: Clc1ncnc2ccc(I)cc12
Reactant: c1ccc2c(c1)CCCN2
Agent: c1ccc2ncncc2c1
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Ic1ccc2ncnc(N3CCCc4ccccc43)c2c1
Yield: 81 %

Procedure:
1.30 g of 4-chloro-6-iodoquinazoline, 1.50 ml of 1,2,3,4-tetrahydroquinoline in 10 ml of dioxane are heated at 110° C. in a flask until the quinazoline has reacted completely (HPLC check, about 3 hours). The cooled reaction solution is diluted with EA and washed 3 times with 5% citric acid. The organic phase is dried over sodium sulfate and purified by means of column chromatography (gradient heptane: EA 0-100% in 18 min.), giving 1.27 g of 4-(3,4-dihydro-2H-quinolin-1-yl)-6-iodoquinazoline as yellowish solid (yield 81%, content 99%); MS-FAB (M+H+)=388.0; Rf (polar method): 2.89 min.
Reaction SMILES: [CH2:1]=O.[NH:3]1[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1.[NH:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[C:10]1[C:18]1[C:19](=[O:30])[NH:20][N:21]=[C:22]([C:24]2[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=2)[CH:23]=1.[OH-].[Na+]>C(O)(=O)C.O1CCOCC1>[N:3]1([CH2:1][C:11]2[C:12]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=3)[NH:9][C:10]=2[C:18]2[C:19](=[O:30])[NH:20][N:21]=[C:22]([C:24]3[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=3)[CH:23]=2)[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1
Reactant: C=O
Reactant: C1COCCN1
Reactant: O=c1[nH]nc(-c2ccncc2)cc1-c1cc2ccccc2[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: C1COCCO1
Product: O=c1[nH]nc(-c2ccncc2)cc1-c1[nH]c2ccccc2c1CN1CCOCC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 14 μl formaldehyde (37% solution in water) and 17 μl morpholine in 0.5 ml glacial acetic acid is added dropwise at 0° C. to 50 mg 4-(1H-indol-2-yl)-6-pyridin-4-yl-2H-pyridazin-3-one suspended in 2.24 ml glacial acetic acid and 2.6 ml 1,4-dioxan. The resulting mixture is stirred for 3 h at room temperature, subsequently poured into ice/water and the pH is adjusted to 13.3 with 2N sodium hydroxide. The product is isolated by filtration.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.[Cl:10][S:11](O)(=[O:13])=[O:12]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]([S:11]([Cl:10])(=[O:13])=[O:12])[CH:3]=1
Reactant: O=S(=O)(O)Cl
Reactant: COc1ccc(F)cc1
Product: COc1ccc(F)cc1S(=O)(=O)Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4-Fluoroanisole (10.0 g) was carefully added to chlorosulphonic acid (45.81 g) at 0° C. The mixture was stirred at RT for 2 h, then quenched with ice-water (500 ml) and the solid filtered and dried, yield 16.50 g.
Reaction SMILES: C1(C=CC2C=CC=CC=2)C=CC=CC=1.[C:15]1([CH:21]=[C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH3:23])[CH:20]=[CH:19][CH:18]=[CH:17]C=1.C(=O)C1C=CC=CC=1.C([Mg]Br)C1C=CC=CC=1>>[C:24]1([C:22]([C:21]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:15]=2)=[CH2:23])[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: CC(=Cc1ccccc1)c1ccccc1
Agent: Br[Mg]Cc1ccccc1
Agent: C(=Cc1ccccc1)c1ccccc1
Solvent: O=Cc1ccccc1
Product: C=C(c1ccccc1)c1ccccc1

Procedure:
Stilbene and 1,2-diphenylpropene may be prepared by reacting benzaldehyde with benzylmagnesium bromide and then carrying out dehydration. Further, 1,1-diphenylethylene may be obtained by reacting diphenyl ketone with a Grignard reagent such as methylmagnesium iodide, followed by dehydration.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][C@@H:8]1[C@@:40]2([CH3:41])[C:12](=[CH:13][CH2:14][C@@H:15]3[C@@H:39]2[CH2:38][CH2:37][C@@:36]2([CH3:42])[C@H:16]3[CH2:17][CH2:18][C@@H:19]2[C@H:20]([CH2:34]I)[CH2:21][CH2:22][C@@H:23]([F:33])[C:24]([O:27][CH:28]([O:30][CH2:31][CH3:32])[CH3:29])([CH3:26])[CH3:25])[CH2:11][C@@H:10]([O:43][CH:44]2[CH2:49][CH2:48][CH2:47][CH2:46][O:45]2)[CH2:9]1.C([SnH](CCCC)CCCC)CCC>O1CCCC1>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][C@@H:8]1[C@@:40]2([CH3:41])[C:12](=[CH:13][CH2:14][C@@H:15]3[C@@H:39]2[CH2:38][CH2:37][C@@:36]2([CH3:42])[C@H:16]3[CH2:17][CH2:18][C@@H:19]2[C@H:20]([CH3:34])[CH2:21][CH2:22][C@@H:23]([F:33])[C:24]([O:27][CH:28]([O:30][CH2:31][CH3:32])[CH3:29])([CH3:26])[CH3:25])[CH2:11][C@@H:10]([O:43][CH:44]2[CH2:49][CH2:48][CH2:47][CH2:46][O:45]2)[CH2:9]1
Reactant: CCOC(C)OC(C)(C)[C@H](F)CC[C@@H](CI)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](OC5CCCCO5)C[C@H](OC5CCCCO5)[C@]4(C)[C@H]3CC[C@]12C
Agent: CCCC[SnH](CCCC)CCCC
Solvent: C1CCOC1
Product: CCOC(C)OC(C)(C)[C@H](F)CC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](OC5CCCCO5)C[C@H](OC5CCCCO5)[C@]4(C)[C@H]3CC[C@]12C

Procedure:
By an alternative procedure, a mixture of 0.206 g. (0.00025 mole) of [1α,3β,24R]-1,3-bis[(tetrahydro-2H-pyran-2yl)oxy]-25-(1-ethoxyethoxy)-24-fluoro-21iodocholest-5-ene, 0.087 g. (0.00030 mole) of tri-n-butyltin hydride and 3 ml of tetrahydrofuran were stirred at 25° C. for 18 hr under an argon atmosphere. The mixture was evaporated to dryness and the residue was purified by chromatography on 0.06-0.20 mm silica gel to yield [1α,3β,24R]-1,3-bis-[(tetrahydro-2H-pyran-2-yl)oxy]-25-(1-ethoxyethoxy)-24-fluorocholest-5-ene, [α]D21 +7° (c 1, CHCl3).
Reaction SMILES: C[C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[N+:11]([O-])([OH:13])=[O:12]>S(=O)(=O)(O)O>[N+:11]([C:9]1[CH:8]=[CH:7][C:5]2[N:6]=[CH:2][S:3][C:4]=2[CH:10]=1)([O-:13])=[O:12]
Reactant: O=[N+]([O-])O
Reactant: Cc1nc2ccccc2s1
Agent: O=S(=O)(O)O
Product: O=[N+]([O-])c1ccc2ncsc2c1
Temperature: 25 °C

Procedure:
Nitration of 2-methylbenzothiazole was performed following the method of Mizuno (1952) J. Pharm. Soc. Japan 72:745. A mixture of fuming nitric acid (1.6 mL) and concentrated sulfuric acid (1.2 mL) was added to an ice-cooled solution of 2-methylbenzothiazole (2 g) in sulfuric acid (8 mL). The resulting solution was allowed to warm to room temperature for one hour, then poured onto 100 mL of ice. The resulting solid was filtered, washed with water, and recrystallized from ethanol (80 mL) to provide 2.5 g of 6-nitrobenzothiazole (1) in the form of yellowish needles.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10].[N:11]1([CH2:16][CH2:17][O:18][C:19]2[CH:20]=[C:21]3[C:25](=[CH:26][CH:27]=2)[NH:24][C:23]([CH:28]=O)=[CH:22]3)[CH2:15][CH2:14][CH2:13][CH2:12]1.N1CCCCC1>C(O)C>[N:11]1([CH2:16][CH2:17][O:18][C:19]2[CH:20]=[C:21]3[C:25](=[CH:26][CH:27]=2)[NH:24][C:23]([CH:28]=[C:3]2[C:4]4[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=4)[NH:1][C:2]2=[O:10])=[CH:22]3)[CH2:12][CH2:13][CH2:14][CH2:15]1
Reactant: O=C1Cc2ccccc2N1
Reactant: O=Cc1cc2cc(OCCN3CCCC3)ccc2[nH]1
Solvent: CCO
Solvent: C1CCNCC1
Product: O=C1Nc2ccccc2C1=Cc1cc2cc(OCCN3CCCC3)ccc2[nH]1
Temperature: 100 °C
Yield: 81.7 %

Procedure:
A mixture of oxindole (26.6 mg, 0.2 mmol), 5-(2-pyrrolidin-1-yl-ethoxy)-1H-indole-2-carbaldehyde (52 mg, 0.2 mmol) and piperidine (0.1 mL) in ethanol (1 mL) was heated at 100° C. for 2 hours. The precipitate was collected by vacuum filtration, washed with ethanol and dried to give 61 mg (81%) of the title compound.
Reaction SMILES: CCCC[N+](CCCC)(CCCC)CCCC.[F-].[C:19]([O:23][C:24](=[O:47])[N:25]([CH2:30][C:31]1[CH:36]=[CH:35][C:34]([Cl:37])=[C:33]([C:38](C)(C)[O:39][SiH2]C(C)(C)C)[CH:32]=1)[CH2:26][CH:27]1[CH2:29][CH2:28]1)([CH3:22])([CH3:21])[CH3:20].CCOC(C)=O>C1COCC1>[C:19]([O:23][C:24](=[O:47])[N:25]([CH2:30][C:31]1[CH:36]=[CH:35][C:34]([Cl:37])=[C:33]([CH2:38][OH:39])[CH:32]=1)[CH2:26][CH:27]1[CH2:29][CH2:28]1)([CH3:22])([CH3:20])[CH3:21]
Reactant: CC(C)(C)OC(=O)N(Cc1ccc(Cl)c(C(C)(C)O[SiH2]C(C)(C)C)c1)CC1CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N(Cc1ccc(Cl)c(CO)c1)CC1CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 43.8 %

Procedure:
TBAF (1M in THF, 14.0 mL, 14.0 mmol) was added to a sol. of [3-(tert-butyl-dimethyl-silanyloxymethyl)-4-chloro-benzyl]-cyclopropylmethyl-carbamic acid tert-butyl ester (3.08 g, 7.00 mmol) in THF (68 mL) at 0° C. The mixture was stirred for 1 h while warming up to rt. EtOAc was added, and the mixture was washed with aq. sat. NH4Cl and brine. The org. layer was dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the crude by FC (CH2Cl2→CH2Cl2/MeOH 9:1) yielded the title compound (1.00 g, 44%). LC-MS: tR=0.99 min; ES+: 326.10.
Reaction SMILES: [Br-].[Br-].[Br-].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[NH:22]1[C:30]2[C:25](=[C:26]([C:31]3[CH:32]=[N:33][C:34]([NH2:37])=[N:35][CH:36]=3)[CH:27]=[CH:28][CH:29]=2)[CH:24]=[CH:23]1.[OH2:38]>CC(O)(C)C.C(O)C.C(O)(=O)C.[Zn]>[NH2:37][C:34]1[N:35]=[CH:36][C:31]([C:26]2[CH:27]=[CH:28][CH:29]=[C:30]3[C:25]=2[CH2:24][C:23](=[O:38])[NH:22]3)=[CH:32][N:33]=1
Reactant: Nc1ncc(-c2cccc3[nH]ccc23)cn1
Reactant: O
Agent: [Br-]
Agent: [Zn]
Agent: c1cc[nH+]cc1
Solvent: CCO
Solvent: CC(C)(C)O
Solvent: CC(=O)O
Product: Nc1ncc(-c2cccc3c2CC(=O)N3)cn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Pyridinium tribromide (90% purity from Aldrich, 7.1 g, 19.98 mmol) was added in portions over 10 minutes to a suspension of 5-(1H-indol-4-yl)-pyrimidin-2-ylamine (1.4 g, 6.66 mmol) in 2-methyl-2-propanol (50 mL), ethanol (30 mL) and acetic acid (18 mL). The mixture was stirred at room temperature for 2 hours, and then acetic acid (72 mL), water (1 mL) and zinc (6.5 g, 100 mmol) were added. Stirring was continued for 1.5 hours. The unreacted zinc dust was filtered off and washed with methanol. The filtrate was concentrated and the syrupy residue was suspended in water (100 mL) overnight. The solid which formed was filtered off. The filtrate was basified with aqueous sodium bicarbonate and extracted with ethanol:dichloromethane (5:95) to give 4-(2-amino-pyrimidin-5-yl)-1,3-dihydro-indol-2-one. 1H NMR (360 MHz, DMSO-d6) δ 10.46 (s, 1H, NH), 8.47 (s, 2H), 7.24 (t, J=7.6 Hz, 1H), 6.99 (d, J=7.6 Hz, 1H), 6.79 (d, J=7.6 Hz, 1H), 6.78 (s, 2H, NH2), 3.64 (s, 2H)
Reaction SMILES: [C:1](Cl)(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH:9]=[CH:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[CH3:21][C:22]1([CH3:30])[O:27][C:26](=[O:28])[CH2:25][C:24](=[O:29])[O:23]1>>[OH:19][C:1](=[C:25]1[C:26](=[O:28])[O:27][C:22]([CH3:30])([CH3:21])[O:23][C:24]1=[O:29])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH:9]=[CH:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: CCCCCCCCC=CCCCCCCCC(=O)Cl
Product: CCCCCCCCC=CCCCCCCCC(O)=C1C(=O)OC(C)(C)OC1=O
Yield: 88.4 %

Procedure:
Starting from 9-octadecenoyl chloride (15 g) and 2,2-dimethyl-1,3-dioxane-4,6-dione (8 g), 5-(1-hydroxy-9-octadecenylidene)-2,2-dimethyl-1,3-dioxane-4,6-dione (18 g) was obtained as oil according to a similar manner to that of Preparation A-2(1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:14]3[CH:15]=[CH:16][N:17]([CH3:18])[C:13]=3[C:12]([C:19](O)=[O:20])=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.ON1C2C=CC=CC=2N=N1.C([N:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1)C.Cl.C(N=C=NCCCN(C)C)C.N1CCOCC1>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:14]3[CH:15]=[CH:16][N:17]([CH3:18])[C:13]=3[C:12]([C:19]([N:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)=[O:20])=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCN1CCOCC1
Reactant: Cn1ccc2c(Nc3cccc(Cl)c3)ncc(C(=O)O)c21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1COCCN1
Solvent: CN(C)C=O
Product: Cn1ccc2c(Nc3cccc(Cl)c3)ncc(C(=O)N3CCOCC3)c21
Reaction time: 24 h

Procedure:
A solution of 4-[(3-chlorophenyl)amino]-1-methyl-1H-pyrrolo[3,2-c]pyridine-7-carboxylic acid (25.0 g) in dry dimethylformamide (300 ml), was treated with 1-hydroxybenzotriazole (14.00 g), N-ethylmorpholine (42 ml), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (19.03 g) and morpholine (14.4 ml) at 23° C. under argon with stirring. After 24 h, the solution was evaporated in vacuo and treated with aqueous saturated sodium carbonate (200 ml) and water (300 ml). The mixture was extracted with ethyl acetate (5×200 ml), and the combined, dried (Na2SO4) organic extracts were evaporated in vacuo. The residue was purified by column chromatography on a Biotage silica column (800 g) eluting with ethyl acetate-hexane (1:1 to 7:3) to give the free base of the title compound (26.9 g). A portion of the free base (21.9 g) in methanol (250 ml) was treated with 1.0M hydrochloric acid in diethyl ether to pH1 and then evaporated in vacuo. Trituration of the residue with ether followed by filtration yielded the title compound (22.75 g).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]2[CH:11]=[C:10]([C:12]3[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][C:13]=3[Cl:19])[C:9]([NH2:20])=[N:8][C:6]=2[N:7]=1.[CH3:21][N:22]([CH3:27])[CH2:23][CH2:24][CH2:25]N>>[NH2:20][C:9]1[C:10]([C:12]2[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:19])=[CH:11][C:5]2[CH:4]=[N:3][C:2]([NH:1][CH2:25][CH2:24][CH2:23][N:22]([CH3:27])[CH3:21])=[N:7][C:6]=2[N:8]=1
Reactant: Nc1ncc2cc(-c3c(Cl)cccc3Cl)c(N)nc2n1
Reactant: CN(C)CCCN
Product: CN(C)CCCNc1ncc2cc(-c3c(Cl)cccc3Cl)c(N)nc2n1

Procedure:
The title compound was prepared as in Example 20 by reacting 3.0 g of 2,7-diamino-6-(2,6-dichlorophenyl)-pyrido[2,3-d]pyrimidine from Example 1 and 60 mL of 3-(dimethylamino)propylamine to give the title compound.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([N:8]=[C:9]=[S:10])=[O:7].[NH2:11][CH2:12][CH2:13][CH2:14][N:15]1[C:23]2[C:22]([CH3:24])=[C:21]([CH3:25])[N:20]=[C:19]([NH2:26])[C:18]=2[N:17]=[C:16]1[CH3:27]>>[NH2:26][C:19]1[C:18]2[N:17]=[C:16]([CH3:27])[N:15]([CH2:14][CH2:13][CH2:12][NH:11][C:9]([NH:8][C:6]([C:2]3[O:1][CH:5]=[CH:4][CH:3]=3)=[O:7])=[S:10])[C:23]=2[C:22]([CH3:24])=[C:21]([CH3:25])[N:20]=1
Reactant: Cc1nc(N)c2nc(C)n(CCCN)c2c1C
Reactant: O=C(N=C=S)c1ccco1
Product: Cc1nc(N)c2nc(C)n(CCCNC(=S)NC(=O)c3ccco3)c2c1C

Procedure:
Using the methods of Examples 75-85, 2-furoylisothiocyanate was reacted with 1-(3-aminopropyl)-2,6,7-trimethyl-1H-imidazo[4,5-c]pyridin-4-amine to provide the desired compound. The observed accurate mass was 387.1608.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:12][CH3:13])[CH:8]=2)[N:3]=1.[C:14]([C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[C:19]([Cl:26])[CH:18]=1)([OH:16])=[O:15].C([O-])([O-])=O.[K+].[K+]>COCCOCCO.O.CCOC(C)=O.Cl[Pd]Cl>[Cl:26][C:19]1[CH:18]=[C:17]([CH:22]=[CH:21][C:20]=1[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:12][CH3:13])[CH:8]=2)[N:3]=1)[C:14]([OH:16])=[O:15]
Reactant: O=C(O)c1ccc(B(O)O)c(Cl)c1
Reactant: COc1ccc2nc(Cl)ccc2c1
Agent: Cl[Pd]Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: COCCOCCO
Solvent: O
Product: COc1ccc2nc(-c3ccc(C(=O)O)cc3Cl)ccc2c1
Temperature: 110 °C
Yield: 46 %

Procedure:
A mixture of 2-chloro-6-methoxyquinoline (Intermediate 1) (200 mg, 1.04 mmol), 4-carboxy-2-chlorophenylboronic acid (247 mg, 1.24 mmol) and K2CO3 (369 mg, 2.70 mmol) in DEGME/H2O (7.0 mL/2.0 mL) was degassed three times under N2 atmosphere. Then PdCl2 (dppf) (75 mg, 0.104 mmol) was added and the mixture was heated to 110° C. for 3 hours under N2 atmosphere. The reaction mixture was diluted with EtOAc (100 mL) and filtered. The filtrate was washed with brine (20 mL), dried over Na2SO4, filtered and concentrated to give 3-chloro-4-(6-methoxyquinolin-2-yl)benzoic acid (150 mg, yield 46%) as a yellow solid, which was used for the next step without further purification.
Reaction SMILES: C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.[Cl:18][C:19]1[CH:20]=[C:21]([C:25]([C:35]2[CH:40]=[CH:39][CH:38]=[C:37]([Cl:41])[CH:36]=2)=[CH:26][C:27]([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)=[O:28])[CH:22]=[CH:23][CH:24]=1.C(Cl)Cl.[CH3:45][O:46][C:47]1[CH:48]=[C:49]([CH:53]=[CH:54][C:55]=1[O:56][CH3:57])[C:50](O)=[O:51]>C(N(CC)CC)C>[Cl:41][C:37]1[CH:36]=[C:35]([C:25]([C:21]2[CH:22]=[CH:23][CH:24]=[C:19]([Cl:18])[CH:20]=2)=[CH:26][C:27]([N:29]2[CH2:34][CH2:33][N:32]([C:50](=[O:51])[C:49]3[CH:53]=[CH:54][C:55]([O:56][CH3:57])=[C:47]([O:46][CH3:45])[CH:48]=3)[CH2:31][CH2:30]2)=[O:28])[CH:40]=[CH:39][CH:38]=1
Reactant: COc1ccc(C(=O)O)cc1OC
Reactant: O=C(C=C(c1cccc(Cl)c1)c1cccc(Cl)c1)N1CCNCC1
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(C(=O)N2CCN(C(=O)C=C(c3cccc(Cl)c3)c3cccc(Cl)c3)CC2)cc1OC
Temperature: 25 °C
Reaction time: 16 h
Yield: 94.6 %

Procedure:
0.44 ml of diphenylphosphoryl azide and 0.545 g of 1-[3,3-bis(3-chlorophenyl)acryloyl]piperazine (prepared as described in Preparation 111) were added to 10 ml of a methylene chloride solution containing 0.25 g of 3,4-dimethoxybenzoic acid and 0.38 ml of triethylamine, and the reaction mixture was stirred for 16 hours at room temperature. At the end of this time, the mixture was washed with 10% w/v aqueous hydrochloric acid, with a saturated aqueous solution of sodium bicarbonate and with water, in that order, after which it was dried over anhydrous sodium sulfate. The solvent was then removed by distillation under reduced pressure, and the resulting residue was purified by medium pressure chromatography using two Lobar B columns eluted with mixtures of hexane and ethyl acetate ranging from 1:2 to 1:4 by volume, to give 0.682 g of the title compound as a white powder.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[CH2:10][N:11]2[CH2:16][CH2:15][N:14]([C:17]3[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=3[NH2:24])[CH2:13][CH2:12]2)=[CH:4][CH:3]=1.Cl[CH2:26][CH2:27][N:28]=[C:29]=[O:30].[H-].[Na+]>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[CH2:10][N:11]2[CH2:12][CH2:13][N:14]([C:17]3[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=3[N:24]3[CH2:26][CH2:27][NH:28][C:29]3=[O:30])[CH2:15][CH2:16]2)=[CH:4][CH:3]=1
Reactant: Nc1ccc(F)cc1N1CCN(C/C=C/c2ccc(Cl)cc2)CC1
Reactant: O=C=NCCCl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C1NCCN1c1ccc(F)cc1N1CCN(C/C=C/c2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 56.4 %

Procedure:
To a solution of 1-[(E)-3-(4-chloro-phenyl)-allyl]-4-(5-fluoro-2-amino-phenyl)-piperazine (1.0 g, Example 3, Step B) in tetrahydrofuran (10 ml) at 0° C. was added 2-chloroethylisocyanate (327 mg) and the resulting solution was stirred under nitrogen at room temperature for 18 hours. The residue was dissolved in a minimum volume of tetrahydrofuran, then added to a suspension of sodium hydride (146 mg, 50% in oil) in tetrahydrofuran (10 ml). The reaction mixture was stirred at room temperature for 3 hours, concentrated under reduced pressure, then triturated with diethyl ether to afford 1-(2-{4-[(E)-3-(4-chloro-phenyl)-allyl]-piperazin-1-yl}-4-fluoro-phenyl)-imidazolidin-2-one (677 mg) as white crystals. M.p. 170-172° C.; 1H NMR (400 MHz, CDCl3) 2.7 (m, 4H), 3.11 (m, 4H), 3.26 (d, J=6.8 Hz, 2H), 3.63 (t, J=5.7 Hz, 2H), 3.99 (t, J=5.7 Hz, 2H), 5.12 (br s, 1H), 6.32 (dt, J=15.6, 6.8 Hz, 1H), 6.57 (d, J=15.6 Hz, 1H), 6.82 (m, 2H), 7.3-7.4 (m, 4H); MS (ES+) 415/417 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([NH2:8])[N:3]=1.[Cl:9][C:10]1[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:11]=1[C:12](Cl)=[O:13]>O1CCOCC1>[NH2:8][C:4]1[N:3]=[C:2]([NH:1][C:12](=[O:13])[C:11]2[C:10]([Cl:9])=[CH:18][CH:17]=[CH:16][C:15]=2[Cl:19])[CH:7]=[CH:6][CH:5]=1
Reactant: Nc1cccc(N)n1
Reactant: O=C(Cl)c1c(Cl)cccc1Cl
Solvent: C1COCCO1
Product: Nc1cccc(NC(=O)c2c(Cl)cccc2Cl)n1
Yield: 66.5 %

Procedure:
Using a method similar to Preparation 48, using 2,6-diaminopyridine (2.6 g, 24 mmol), dioxane (75 mL), and 2,6-dichlorobenzoyl chloride (1.68 g, 8 mmol) (stir at 25° C. for 16 hr.) gives the title intermediate (1.5 g, 66% yield): mass spectrum (ion spray): m/z=282.0 (M+1)
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:22]=[C:21]([C:23]([OH:25])=[O:24])[CH:20]=[C:19]2[C:6]=1[C@@:7]1([CH3:31])[C@H:16]([CH2:17][S:18]2(=[O:27])=[O:26])[C@:15]2([CH3:28])[C@H:10]([C:11]([CH3:30])([CH3:29])[CH2:12][CH2:13][CH2:14]2)[CH2:9][CH2:8]1)=[O:4].O[Li].O>CO.O>[CH3:31][C@@:7]12[CH2:8][CH2:9][C@@H:10]3[C@:15]([CH3:28])([CH2:14][CH2:13][CH2:12][C:11]3([CH3:29])[CH3:30])[C@H:16]1[CH2:17][S:18](=[O:26])(=[O:27])[C:19]1[C:6]2=[C:5]([C:3]([OH:4])=[O:2])[CH:22]=[C:21]([C:23]([OH:25])=[O:24])[CH:20]=1
Reactant: COC(=O)c1cc(C(=O)O)cc2c1[C@]1(C)CC[C@H]3C(C)(C)CCC[C@]3(C)[C@H]1CS2(=O)=O
Agent: [Li]O
Solvent: O
Solvent: CO
Product: CC1(C)CCC[C@]2(C)[C@H]3CS(=O)(=O)c4cc(C(=O)O)cc(C(=O)O)c4[C@]3(C)CC[C@@H]12
Temperature: 90 °C
Yield: 103.6 %

Procedure:
A mixture of (1R,10R,11S,16S)-3-(methoxycarbonyl)-1,11,15,15-tetramethyl-8,8-dioxo-8λ6-thiatetracyclo[8.8.0.02,7.011,16]octadeca-2,4,6-triene-5-carboxylic acid (84) (0.1 g, 0.2 mmol) and LiOH.H2O (0.1 g, 4 mmol) in MeOH (5.0 mL) and water (5.0 mL) was heated at 90° C. for 72 h. The reaction mixture was cooled to room temperature, concentrated under reduced pressure and acidified with 1 M HCl. The resulting solid was collected by filtration to give (1R,10R,11S,16S)-1,11,15,15-tetramethyl-8,8-dioxo-8λ6-thiatetracyclo-[8.8.0.02,7.011,16]octadeca-2,4,6-triene-3,5-dicarboxylic acid (85) (0.09 g, 94%) as a white solid. 1H NMR (CD3OD): δ 8.43 (d, 1H), 8.07 (d, 1H), 3.56 (m, 2H), 2.92 (d, 1H), 2.18 (d, 1H), 1.90-1.38 (m, 11H), 1.30-1.17 (m, 2H), 1.08-0.96 (m, 5H), 0.90 (s, 3H), 0.87 (s, 3H). MS m/z 433 (O23H30O6S−H+).
Reaction SMILES: [C:1]1([Sb:7](=O)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:21]([OH:25])(=[O:24])[CH:22]=[CH2:23]>>[C:21]([O-:25])(=[O:24])[CH:22]=[CH2:23].[C:21]([O-:25])(=[O:24])[CH:22]=[CH2:23].[C:14]1([Sb+2:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: O=[Sb](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: C=CC(=O)O
Product: C=CC(=O)[O-]
Product: c1ccc([Sb+2](c2ccccc2)c2ccccc2)cc1

Procedure:
Triphenyl antimony oxide was reacted with acrylic acid to yield triphenyl antimony diacrylate. ##STR13##
Reaction SMILES: O[C:2]1[C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[NH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[Br:15][CH2:16][CH2:17]Br.[OH-:19].[Na+]>O>[Br:15][CH2:16][CH2:17][O:19][C:3]1[CH:4]=[CH:5][C:6]2[NH:7][C:8]3[C:13]([C:14]=2[CH:2]=1)=[CH:12][CH:11]=[CH:10][CH:9]=3
Reactant: Oc1cccc2[nH]c3ccccc3c12
Reactant: [OH-]
Reactant: BrCCBr
Agent: [Na+]
Solvent: O
Product: BrCCOc1ccc2[nH]c3ccccc3c2c1
Yield: 32 %

Procedure:
A mixture of 1.83 g (10 mmol) of 4-hydroxycarbazole (J. Chem. Soc. (1955), 3475-3477; J. Med. Chem. (1964) 7, 158-161), 1.08 ml (12,5 mmol) of 1,2-dibromoethane and 2.6 ml (10.5 mmol) of a 4 M aqueous solution of NaOH in 2 ml of water is heated under reflux for 5 hours. After the temperature returns to 20° C., the product is extracted using 2 times 30 ml of CH2Cl2. The organic solutions collected are then successively washed with 20 ml of water and 20 ml of salt water. After drying over MgSO4, filtration and concentration under vacuum, the residue is purified on a silica column (eluent: heptane/AcOEt: 80/20). A beige powder is obtained with a yield of 32%. Melting point: 135-136° C.