Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[N:2]([C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])[CH2:3][CH2:4][C:5]1[CH:12]=[CH:11][C:9]([OH:10])=[C:7]([OH:8])[CH:6]=1.[C:23]([NH:33][CH2:34][CH2:35][C:36]1C=CC(O)=[C:38]([OH:39])[CH:37]=1)(OCC1C=CC=CC=1)=O>C1C=CC=CC=1>[C:38]([C:7]1([OH:8])[C:9]([C:38](=[O:39])[C:37]2[CH:36]=[CH:35][CH:34]=[N:33][CH:23]=2)([OH:10])[CH:11]=[CH:12][C:5]([CH2:4][CH2:3][NH:2][C:13]([O:15][CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[O:14])=[CH:6]1)(=[O:39])[C:37]1[CH:36]=[CH:35][CH:34]=[N:33][CH:23]=1
Reactant: O=C(NCCc1ccc(O)c(O)c1)OCc1ccccc1
Reactant: CN(CCc1ccc(O)c(O)c1)C(=O)OCc1ccccc1
Solvent: c1ccccc1
Product: O=C(NCCC1=CC(O)(C(=O)c2cccnc2)C(O)(C(=O)c2cccnc2)C=C1)OCc1ccccc1

Procedure:
By working as described in Example 1, but replacing the N-methyl-N-carbobenzoxy-dopamine with an equivalent amount of N-carbobenzoxy-dopamine, 3,4-dinicotinoyl-N-carbobenzoxy-dopamine is obtained (m.p. 86°-90° C., from benzene).
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].I[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(#N)C>[C:13]1([CH:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:1]([O:9][CH2:10][CH3:11])=[O:8])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Ic1ccccc1
Reactant: CCOC(=O)CC(=O)OCC
Solvent: CC#N
Product: CCOC(=O)C(C(=O)OCC)c1ccccc1

Procedure:
607 μl of diethyl malonate (3 mmoles), 224 μl of iodobenzene (2 mmoles), 1.2 ml of acetonitrile and 600 mg of ground and activated 3 Å molecular sieve were then added.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][C:19]=1[Cl:20])[O:5][C:6]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:7]=1[C:8]([NH:10][CH3:11])=O>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][C:19]=1[Cl:20])[O:5][C:6]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:7]=1[CH2:8][NH:10][CH3:11]
Reactant: CNC(=O)c1cc(F)ccc1Oc1ccc(Cl)c(Cl)c1
Solvent: C1CCOC1
Product: CNCc1cc(F)ccc1Oc1ccc(Cl)c(Cl)c1

Procedure:
Under N2, a mixture of 0.313 g (1.0 mmol) of 2-(3,4-dichlorophenoxy)-5-fluoro-N-methyl-benzamide in 5.0 mL of anhydrous tetrahydrofuran (THF) was treated via syringe with 4.0 mL (4.0 mmol) of 1.0 M BH3 in THF (Aldrich Chem. Co.). and the mixture was heated to reflux for a total of 48 hr. The reaction was quenched by the addition of 25 mL of 6N HCl and heating to reflux until the free amine could be detected by tlc (CHCl3:CH3OH:TEA, (95:5:1)). The cooled mixture was then diluted with water, basified with K2CO3and extracted with EtOAc. The combined organic layers were washed with water and saturated NaCl, then dried with MgSO4, filtered and concentrated in vacuo to the free base as a light brown oil, 0.164 g, 54%). This compound was converted to the hydrochloride salt as described previously, m.p. 200-202°.
Reaction SMILES: CO[C:3]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[CH2:7][CH2:6][CH2:5][C:4]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15].[CH3:19][Mg]I.C(OCC)C.[Cl-].[NH4+]>O1CCCC1>[CH3:19][C:3]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[CH2:7][CH2:6][CH2:5][C:4]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: CCOC(=O)C1=C(OC)c2ccccc2CCC1
Reactant: C[Mg]I
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCOC(=O)C1=C(C)c2ccccc2CCC1
Temperature: -5 °C
Reaction time: 2 h

Procedure:
A solution of ethyl 9-methoxy-6,7-dihydro-5H-benzocycloheptene-8-carboxylate (4.00 g, 16.2 mmol) in tetrahydrofuran (60 ml) was cooled to −10° C., and methylmagnesium iodide (a 2M diethyl ether solution 16.2 ml, 32.5 mmol) was added dropwise thereto. The reaction mixture was stirred at −5° C. for 2 hours, poured into a cold aqueous ammonium chloride solution and then extracted twice with ethyl acetate. The extract solution was washed with an aqueous sodium hydrogen-carbonate solution and a 5% aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the resulting residue was purified by a silica gel column chromatography (eluent: ethyl acetate/n-hexane=2/98) to obtain 0.81 g of ethyl 9-methyl-6,7-dihydro-5H-benzocycloheptene-8-carboxylate.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[C:8](B3OC(C)(C)C(C)(C)O3)[CH:9]=[CH:10][C:5]=2[O:4][C:3]1=[O:20].Br[C:22]1[CH:23]=[N:24][CH:25]=[CH:26][C:27]=1[CH:28]1[CH2:31][CH2:30][O:29]1.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:1][N:2]1[C:6]2[CH:7]=[C:8]([C:22]3[CH:23]=[N:24][CH:25]=[CH:26][C:27]=3[CH:28]3[CH2:31][CH2:30][O:29]3)[CH:9]=[CH:10][C:5]=2[O:4][C:3]1=[O:20]
Reactant: Cn1c(=O)oc2ccc(B3OC(C)(C)C(C)(C)O3)cc21
Reactant: Brc1cnccc1C1CCO1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1c(=O)oc2ccc(-c3cnccc3C3CCO3)cc21
Temperature: 100 °C
Yield: 4.8 %

Procedure:
A mixture of 3-Methyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3H-benzooxazol-2-one (123 mg, 0.44 mmol), 3-Bromo-4-oxetan-2-yl-pyridine (96 mg, 0.44 mmol), Na2CO3 (2 M in water, 067 mL, 1.35 mmol) and PdCl2(PPh3)2 (16 mg, 0.02 mmol) in DMF (4 mL) was heated at 100° C. for 3 h. After concentration, the resulting residue was diluted with DCM and saturated NH4Cl solution. After filteration, the filtrates were concentrated and the residue was purified by flash column (MeOH/CH2Cl2, v/v, 0-3.5%) and afforded the title compound (6 mg, 5%); ESI-MS m/z: 283 [M+1]+, Retention time 1.03 min; 1HNMR (MeOD, 400.342 MHz) δ ppm 2.60-2.65 (m, 1H), 2.83-2.87 (m, 1H), 3.47 (s, 3H), 4.62-4.68 (m, 1H), 4.75-4.82 (m, 1H), 5.91 (t, J=7.6 Hz, 1H), 7.06 (dd, J=8, 1.6 Hz, 1H), 7.15 (d, J=1.6 Hz, 1H), 7.39 (d, J=8 Hz, 1H), 7.94 (d, J=5.2 Hz, 1H), 8.46 (s, 1H), 8.67 (d, J=5.2 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:29]=[CH:28][C:5]2[N:6]([C@@H:23]3[CH2:27][CH2:26][NH:25][CH2:24]3)[C:7]([CH2:9][N:10]3[C:14]4=[CH:15][N:16]=[CH:17][CH:18]=[C:13]4[C:12]([S:19]([CH3:22])(=[O:21])=[O:20])=[N:11]3)=[N:8][C:4]=2[CH:3]=1.CCN(CC)CC.[CH3:37][S:38](Cl)(=[O:40])=[O:39]>C(Cl)Cl>[Cl:1][C:2]1[CH:29]=[CH:28][C:5]2[N:6]([C@@H:23]3[CH2:27][CH2:26][N:25]([S:38]([CH3:37])(=[O:40])=[O:39])[CH2:24]3)[C:7]([CH2:9][N:10]3[C:14]4=[CH:15][N:16]=[CH:17][CH:18]=[C:13]4[C:12]([S:19]([CH3:22])(=[O:20])=[O:21])=[N:11]3)=[N:8][C:4]=2[CH:3]=1
Reactant: CS(=O)(=O)c1nn(Cc2nc3cc(Cl)ccc3n2[C@@H]2CCNC2)c2cnccc12
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)c1nn(Cc2nc3cc(Cl)ccc3n2[C@@H]2CCN(S(C)(=O)=O)C2)c2cnccc12
Reaction time: 2 h

Procedure:
To a solution of 1-({5-chloro-1-[(3R)-(pyrrolidin-3-yl)]-1H-benzo[d]imidazol-2-yl}methyl)-3-(methylsulfonyl)-1H-pyrazolo[3,4-c]pyridine (200 mg, 0.46 mmol) and Et3N (0.2 mL) in 8 mL of DCM was added 80 mg of methanesulfonyl chloride. The mixture was stirred for 2 hours. The mixture was then purified by preparative-HPLC to give the title compound.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[CH:17]=[C:16]([NH2:18])[CH:15]=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[C:19]([O:23][C:24]([NH:26][CH2:27][C:28]1[O:29][C:30]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[C:31]([C:33](O)=[O:34])[N:32]=1)=[O:25])([CH3:22])([CH3:21])[CH3:20]>>[C:19]([O:23][C:24](=[O:25])[NH:26][CH2:27][C:28]1[O:29][C:30]([C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)=[C:31]([C:33](=[O:34])[NH:18][C:16]2[CH:15]=[N:14][N:13]([CH2:12][C:10]3[O:11][C:7]([C:2](=[O:6])[CH3:1])=[CH:8][CH:9]=3)[CH:17]=2)[N:32]=1)([CH3:22])([CH3:20])[CH3:21]
Reactant: CC(C)(C)OC(=O)NCc1nc(C(=O)O)c(-c2ccccc2)o1
Reactant: CC1(c2ccc(Cn3cc(N)cn3)o2)OCCO1
Product: CC(=O)c1ccc(Cn2cc(NC(=O)c3nc(CNC(=O)OC(C)(C)C)oc3-c3ccccc3)cn2)o1

Procedure:
Following general procedure B, starting from 1-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-1H-pyrazol-4-ylamine and 2-(tert-butoxycarbonylamino-methyl)-5-phenyl-oxazole-4-carboxylic acid. LC-MS-conditions 02: tR=1.01 min; [M+H]+=506.44.
Reaction SMILES: CC(C)(C)C[C:4](=[O:20])[CH2:5][C@H:6]([C:10]1[O:11][CH:12]=[C:13]([C:15]([O:17]CC)=[O:16])[N:14]=1)[CH2:7][CH:8]=[CH2:9].O.[OH-].[Li+].[OH-].[Li+].C(O)(=O)[CH2:29][C:30]([CH2:35]C(O)=O)([C:32](O)=O)[OH:31]>O1CCOCC1.O>[C:30]([O:31][C:4](=[O:20])[CH2:5][C@H:6]([C:10]1[O:11][CH:12]=[C:13]([C:15]([OH:17])=[O:16])[N:14]=1)[CH2:7][CH:8]=[CH2:9])([CH3:35])([CH3:32])[CH3:29]
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Reactant: C=CC[C@H](CC(=O)CC(C)(C)C)c1nc(C(=O)OCC)co1
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: C=CC[C@H](CC(=O)OC(C)(C)C)c1nc(C(=O)O)co1
Temperature: 0 °C
Reaction time: 4 h
Yield: 228.7 %

Procedure:
Two identical reactions were put on each containing the following: A solution of ethyl 2-[(1R)-1-(4,4-dimethyl-2-oxopentyl)-3-butenyl]-1,3-oxazole-4-carboxylate (Preparation 115) (4.0 g, 12.9 mmol) in 1,4-dioxan (40 ml) and water (20 ml) was cooled to 0° C. and treated with lithium hydroxide monohydrate (0.8 g, 19.0 mmol). The mixture was stirred at 0° C. for 4 hours. Further lithium hydroxide monhydrate (0.8 g, 19.0 mmol) was added and stirred at 0° C. for 10 minutes. The two reactions were combined and partitioned between ethyl acetate and water. The aqueous layer was neutralised with citric acid (16.3 g, 38.0 mmol) and extracted with ethyl acetate (×3). The combined organic extracts were washed with water and brine, dried over anhydrous sodium sulphate, filtered and the solvent removed under reduced pressure to afford the title compound as a colourless oil (8.3 g).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][C:10]([C:25]([F:28])([F:27])[F:26])([CH2:13]OS(C2C(C)=CC=CC=2)(=O)=O)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N-:29]=[N+:30]=[N-:31].C([N+](CCCC)(CCCC)CCCC)CCC>C(#N)C.C(Cl)Cl>[CH2:1]([N:8]1[CH2:12][CH2:11][C:10]([C:25]([F:28])([F:27])[F:26])([CH2:13][N:29]=[N+:30]=[N-:31])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1ccccc1S(=O)(=O)OCC1(C(F)(F)F)CCN(Cc2ccccc2)C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CC#N
Solvent: ClCCl
Product: [N-]=[N+]=NCC1(C(F)(F)F)CCN(Cc2ccccc2)C1

Procedure:
The compound (2.43 g) from step 456c was dissolved in acetonitrile, then reacted with tetrabutylammonium azide at 80° C. for 16 hours. The mixture was diluted with methylene chloride, then washed with water and brine and dried. Removal of the solvent gave 0.751 g of the title compound.
Reaction SMILES: Br[C:2]1[C:10]2[O:11][CH2:12][CH2:13][C:9]=2[C:8]2[C:7](=[O:14])[CH2:6][CH2:5][C:4]=2[C:3]=1Br.C([O-])(=O)C.[Na+].O>CO.[Pd]>[CH2:13]1[CH2:12][O:11][C:10]2[CH:2]=[CH:3][C:4]3[CH2:5][CH2:6][C:7](=[O:14])[C:8]=3[C:9]1=2
Reactant: O=C1CCc2c(Br)c(Br)c3c(c21)CCO3
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: O=C1CCc2ccc3c(c21)CCO3
Temperature: 40 °C
Reaction time: 1.5 h
Yield: 82.9 %

Procedure:
To a suspension of 4,5-dibromo-1,2,6,7-tetrahydro-8H-indeno[5,4-b]furan-8-one (18.4 g, 55.4 mmols) in methanol (400 mL) was added 10% Palladium on activated carbon (2.0 g, 50% hydrous) followed by sodium acetate (12.6 g, 154 mmols). The mixture was stirred at 40° C. for 1.5 hours under hydrogen atmosphere (4 kgf/cm2). The catalyst was filtered off and the filtrate was concentrated under reduced pressure. Crystals were collected by filtration, washed with water and recrystallized successively with methanol:water=5:1 to obtain 8.0 g (yield: 83%) of the title compound.
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[O:18][CH:15]([CH:16]=[CH2:17])[CH:4]([CH:5]([O:9][CH:10]([O:12][CH2:13][CH3:14])[CH3:11])[CH2:6][C:7]#N)[O:3]1.[H-].C([Al+]CC(C)C)C(C)C.S(=O)(=O)(O)[OH:31]>C1(C)C=CC=CC=1.CCOCC>[CH3:1][C:2]1([CH3:19])[O:18][CH:15]([CH:16]=[CH2:17])[CH:4]([CH:5]([O:9][CH:10]([O:12][CH2:13][CH3:14])[CH3:11])[CH2:6][CH:7]=[O:31])[O:3]1
Reactant: O=S(=O)(O)O
Reactant: C=CC1OC(C)(C)OC1C(CC#N)OC(C)OCC
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: C=CC1OC(C)(C)OC1C(CC=O)OC(C)OCC
Temperature: -78 °C
Reaction time: 1.67 h

Procedure:
4,5-(Dimethylmethylenedioxy)-3-(1-ethoxyethoxy)-6-heptenenitrile (1.40 g) was dissolved in 13 ml of dry toluene, and 2.0 ml of 2N diisobutyl aluminum hydride was added dropwise at -78° C. After stirring at -78° C. for 100 minutes, the temperature was then elevated to 0° C., and 10% dilute sulfuric acid was then gradually added. The reaction mixture was diluted with ether, and the organic layer was washed with a sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain 2.61 g of 4,5-(dimethylmethylenedioxy)-3-(1-ethoxyethoxy)-6-heptenal.
Reaction SMILES: [F:1][CH:2]1[C:7]([Si:8]([CH3:11])([CH3:10])[CH3:9])=[C:6]([F:12])[CH:5]=[CH:4][C:3]1([CH2:14][O:15][CH3:16])[OH:13].[Li]CCCC.[CH3:22][S:23]SC>C1COCC1>[F:1][CH:2]1[C:7]([Si:8]([CH3:9])([CH3:10])[CH3:11])=[C:6]([F:12])[CH:5]=[C:4]([S:23][CH3:22])[C:3]1([CH2:14][O:15][CH3:16])[OH:13]
Reactant: COCC1(O)C=CC(F)=C([Si](C)(C)C)C1F
Reactant: CSSC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COCC1(O)C(SC)=CC(F)=C([Si](C)(C)C)C1F
Temperature: -78 °C
Reaction time: 2.5 h
Yield: 67.7 %

Procedure:
A flame-dried 3-necked flask was charged with 2,4-difluoro-3-trimethylsilyl-1-methoxymethylphenol (27, 0.63 g, 2.56 mmol) in 15 mL of freshly distilled THF under argon and this mixture was cooled to −78° C. (FIG. 2E). nBuLi (2.5 M solution in hexane, 1.16 mL, 2.9 mmol) was added to this reaction mixture which was allowed to stir at −78° C. for 2.5 h under argon. Methyldisulfide (0.27 g, 2.9 mmol) was then added to the mixture at −78° C. and then the acetone/dry ice bath was removed and the reaction was allowed to proceed at room temperature for 14 hours. Sat. NH4Cl (˜10 mL) was added to the mixture which was then stirred for an additional 10 min and then extracted with ethyl ether (3×10 mL). The combined organic solution was washed with brine, water and then dried (MgSO4) and filtered. The solvent was removed under vacuo to afford the product purified by flash chromatography on silica gel (EtOAc:hexanes; 5:95) to yield a yellow oil (0.51 g, 68%). 1H NMR (CDCl3) δ6.55-6.58 (dd, 1 H, ArH), 5.09 (s, 2 H, CH2), 3.63 (s, 3 H, CH3), 2.41 (s, 3 H, CH3), 0.34-0.35 (t, 9 H, Si(CH3)3); FAB-MS 293 (MH+, 24), 292 (M+, 70), 262 (66), 261 (100).
Reaction SMILES: [Li][CH2:2]CCC.[Br:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[C:14]([CH:22]=O)=[CH:15][C:16]([N:19]([CH3:21])[CH3:20])=[CH:17][CH:18]=2)=[CH:9][CH:8]=1>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[Br:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][C:16]([N:19]([CH3:21])[CH3:20])=[CH:15][C:14]=2[CH:22]=[CH2:2])=[CH:9][CH:8]=1
Reactant: [Li]CCCC
Reactant: CN(C)c1ccc(-c2ccc(Br)cc2)c(C=O)c1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Product: C=Cc1cc(N(C)C)ccc1-c1ccc(Br)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 58.4 %

Procedure:
BuLi (2.5M in hexanes, 2.96 mL, 7.40 mmol) was added to a solution of methyltriphenylphosphonium bromide (2.94 g, 8.22 mmol) in THF (20 mL). The mixture was stirred at 0° C. for 1 hr. A solution of 4′-bromo-4-(dimethylamino)biphenyl-2-carbaldehyde (1.25 g, 4.11 mmol) in THF (20 mL) was added dropwise at 0° C. The mixture was stirred overnight from 0° C. to r.t. The reaction was filtered and evaporated. The residue was diluted with diethyl ether and washed with water and brine. The ether layer was dried (MgSO4), filtered and evaporated to give the crude material. The crude material was purified on the Biotage (5-15% EtOAc:Hex) to give 4′-bromo-N,N-dimethyl-2-vinylbiphenyl-4-amine (725 mg, 2.399 mmol, 58% yield) as a yellow solid. 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 2.97-3.07 (m, 6H) 5.20 (d, J=10.99 Hz, 1H) 5.69 (d, J=17.40 Hz, 1H) 6.70 (dd, J=17.40, 10.99 Hz, 1H) 6.76 (dd, J=8.55, 2.75 Hz, 1H) 6.95 (d, J=2.44 Hz, 1H) 7.16 (d, J=8.55 Hz, 1H) 7.21 (m, J=8.24 Hz, 2H) 7.50 (m, J=8.55 Hz, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[N:14]([CH2:15][CH2:16][CH2:17][OH:18])[C:13]([CH2:19][CH2:20][CH3:21])=[N:12][C:7]=3[CH:8]=[N:9][C:10]=2[CH:11]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.O[N:56]1[C:60](=[O:61])[C:59]2=[CH:62][CH:63]=[CH:64][CH:65]=[C:58]2[C:57]1=[O:66]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[N:14]([CH2:15][CH2:16][CH2:17][O:18][N:56]4[C:60](=[O:61])[C:59]5[C:58](=[CH:65][CH:64]=[CH:63][CH:62]=5)[C:57]4=[O:66])[C:13]([CH2:19][CH2:20][CH3:21])=[N:12][C:7]=3[CH:8]=[N:9][C:10]=2[CH:11]=1
Reactant: CCCc1nc2cnc3cc(Br)ccc3c2n1CCCO
Reactant: O=C1c2ccccc2C(=O)N1O
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CCCc1nc2cnc3cc(Br)ccc3c2n1CCCON1C(=O)c2ccccc2C1=O
Yield: 71.9 %

Procedure:
A modification of the method described in Part A of Example 1 was followed using 3-(7-bromo-2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)propan-1-ol (4.60 g, 13.2 mmol), triphenylphosphine (4.17 g, 15.9 mmol), diisopropyl azodicarboxylate (3.13 mL, 15.9 mmol), and N-hydroxyphthalimide (2.59 g, 15.9 mmol). After the solvent was removed under reduced pressure, the residue was dissolved in chloroform (200 mL), washed sequentially with saturated aqueous sodium bicarbonate (2×30 mL) and brine (20 mL), dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The crude product was triturated twice with ethyl acetate to provide 4.68 g of 2-[3-(7-bromo-2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)propoxy]-1H-isoindole-1,3(2H)-dione.
Reaction SMILES: [CH2:1]1[C@H:3]2[C:4](=[O:28])[CH2:5][C@H:6]3[C@:19]([CH3:20])([C@@H:2]12)[C@@H:18]1[C@H:9]([C@H:10]2[C@@:14]([CH2:16][CH2:17]1)([CH3:15])[C@@H:13]([O:21][CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][O:23]1)[CH2:12][CH2:11]2)[CH2:8][CH2:7]3.[Li]>O1CCCC1.C(OCC)C>[CH2:1]1[C@H:3]2[CH:4]([OH:28])[CH2:5][C@H:6]3[C@:19]([CH3:20])([C@@H:2]12)[C@@H:18]1[C@H:9]([C@H:10]2[C@@:14]([CH2:16][CH2:17]1)([CH3:15])[C@@H:13]([O:21][CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][O:23]1)[CH2:12][CH2:11]2)[CH2:8][CH2:7]3
Reactant: C[C@]12CC[C@H]3[C@@H](CC[C@H]4CC(=O)[C@@H]5C[C@@H]5[C@@]43C)[C@@H]1CC[C@@H]2OC1CCCCO1
Agent: [Li]
Solvent: CCOCC
Solvent: C1CCOC1
Product: C[C@]12CC[C@H]3[C@@H](CC[C@H]4CC(O)[C@@H]5C[C@@H]5[C@@]43C)[C@@H]1CC[C@@H]2OC1CCCCO1
Yield: 99.5 %

Procedure:
9.0 g of 1α,2α-methylene-17β-(tetrahydropyran-2-yloxy)-5α-androstan-3-one is stirred in 90 ml of tetrahydrofuran with 10 g of lithium tri-tert-butoxyalanate for 2.5 hours at room temperature. The reaction solution is diluted with diethyl ether, washed with 2N sulfuric acid and water, dried, and evaporated, yielding as a residue 9.0 g of 1α,2α-methylene-17β-(tetrahydropyran-2-yloxy)-5α-androstan-3-ol.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1/[CH:10]=[CH:11]/[CH:12]=[C:13](\[O:18][CH3:19])/[C:14]([O:16]C)=[O:15].CCO.O>>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1/[CH:10]=[CH:11]/[CH:12]=[C:13](\[O:18][CH3:19])/[C:14]([OH:16])=[O:15]
Reactant: COC(=O)/C(=C/C=C/c1cc2ccccc2s1)OC
Solvent: O
Solvent: CCO
Product: CO/C(=C\C=C\c1cc2ccccc2s1)C(=O)O
Yield: 53.1 %

Procedure:
To a stirred solution of methyl (2Z,4E)-5-(benzothiophen-2-yl)-2-methoxy-2,4-pentadienoate (107 mg, 0.39 mmol) in EtOH/water 1/1 (10 ml) potassium hydroxide (47 mg, 0.78 mmol) was added. The solution was refluxed for 1 hour, then it was treated as seen in example 2. Pure title compound (54 mg, 0.207 mmol, yield 53.2%) was obtained as yellow crystals.
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[NH:7][C:6](=[O:8])[CH2:5][CH2:4]1.Br[C:10]1[CH:15]=[CH:14][C:13]([C:16]([N:18]2[CH2:23][CH2:22][N:21]([C:24]3[C:29]([CH3:30])=[CH:28][C:27]([CH3:31])=[C:26]([CH3:32])[N:25]=3)[CH2:20][CH2:19]2)=[O:17])=[C:12]([F:33])[CH:11]=1>>[F:33][C:12]1[CH:11]=[C:10]([N:7]2[C@H:3]([CH2:2][OH:1])[CH2:4][CH2:5][C:6]2=[O:8])[CH:15]=[CH:14][C:13]=1[C:16]([N:18]1[CH2:19][CH2:20][N:21]([C:24]2[C:29]([CH3:30])=[CH:28][C:27]([CH3:31])=[C:26]([CH3:32])[N:25]=2)[CH2:22][CH2:23]1)=[O:17]
Reactant: Cc1cc(C)c(N2CCN(C(=O)c3ccc(Br)cc3F)CC2)nc1C
Reactant: O=C1CC[C@@H](CO)N1
Product: Cc1cc(C)c(N2CCN(C(=O)c3ccc(N4C(=O)CC[C@H]4CO)cc3F)CC2)nc1C

Procedure:
Using (S)-5-hydroxymethylpyrrolidin-2-one and (4-bromo-2-fluorophenyl)[4-(3,5,6-trimethylpyridin-2-yl)piperazin-1-yl]methanone (406 mg) described in Preparation Example 128 and by the reaction and treatment in the same manner as in Example 1, the title compound (171 mg) was obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([N+:11]([O-:13])=[O:12])[CH:10]=1)[NH:7]C(=O)[C:5]2=[O:15].[OH:16]O.Cl>[OH-].[Na+].O>[NH2:7][C:8]1[C:9]([N+:11]([O-:13])=[O:12])=[CH:10][C:2]([CH3:1])=[CH:3][C:4]=1[C:5]([OH:15])=[O:16]
Reactant: OO
Reactant: Cc1cc2c(c([N+](=O)[O-])c1)NC(=O)C2=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1cc(C(=O)O)c(N)c([N+](=O)[O-])c1
Reaction time: 12 h
Yield: 85 %

Procedure:
A solution of 5-methyl-7-nitro-1H-indole-2,3-dione (6.5 g, 0.0315 mol) in 2N NaOH (35 mL) was cooled to 20° C. and a 30% aq. solution of H2O2 (6.5 mL) was added slowly over a period of 15 min. The reaction mixture was brought to room temperature and stirred for 12 h, then diluted with water (75 mL). The pH was adjusted to 2 with conc. HCl. The formed precipitate was filtered and dried in a vacuum oven to get 5.3 g of the required product as a yellow coloured solid (85%).
Reaction SMILES: [C:1]1(=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:8][C:9]1[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=1[CH2:11][C:12]#[N:13].[OH-].[K+]>>[C:1]1(=[C:11]([C:10]2[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=2[CH3:8])[C:12]#[N:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1ccccc1CC#N
Reactant: O=C1CCCCC1
Agent: [K+]
Agent: [OH-]
Product: Cc1ccccc1C(C#N)=C1CCCCC1
Temperature: 140 °C
Yield: 63 %

Procedure:
The mixture of cyclohexanone (44.7 g, 0.46 mol) and 2-methyl benzylcyanide (41.9 g, 0.32 mol) is treated with KOH (3.58 g, 0064 mol) and the resulting mixture is heated to 120° C. (oilbath temperature 140° C.) for 2 h with concomitant distillation of H2O as an azeotrope with cyclohexanone. The temperature is raised to 130° C. (oilbath temperature 150° C.) for 30 min, before cooling to 60° C. and dilution of the viscous mixture with toluene (50 ml). Standard aqueous workup is effected with toluene, H2O, sat. aq. Na2CO3-solution and brine. The organic layer is dried over MgSO4 and the volatiles removed in vacuo. The crude product (67 g), which crystallizes upon standing, is subjected to a short path distillation at 0.05 mbar/120-127° C. to yield 42.6 g of crystalline product which is recrystallized three times from hexane. From this, 33.6 g of white crystalline product is obtained (50% yield), m.p. 65.2-66.0° C.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[C:10]([O:11][CH3:12])=[CH:9][C:8]([F:13])=[CH:7][C:6]=1[Cl:14])=O.[NH2:15][C:16]([NH2:18])=[S:17]>CCO>[Cl:14][C:6]1[CH:7]=[C:8]([F:13])[CH:9]=[C:10]([O:11][CH3:12])[C:5]=1[C:3]1[N:15]=[C:16]([NH2:18])[S:17][CH:2]=1
Reactant: NC(N)=S
Reactant: COc1cc(F)cc(Cl)c1C(=O)CBr
Solvent: CCO
Product: COc1cc(F)cc(Cl)c1-c1csc(N)n1
Yield: 28.5 %

Procedure:
A solution of 2-bromo-1-(2-chloro-4-fluoro-6-methoxyphenyl)ethanone (14-1, 0.84 g) and thiourea (0.27 g, 3.6 mmol) in 95% EtOH (8.0 mL) was heated at reflux for 60 min. The solution was concentrated under reduced pressure, and the residue was re-dissolved in ethyl acetate. The solution was washed with saturated aqueous NaHCO3, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel to give 4-(2-chloro-4-fluoro-6-methoxyphenyl)thiazol-2-ylamine (14-2, 0.22 g, 0.85 mmol) as yellow solids in 28% yield: 1H NMR (500 MHz, CDCl3) δ 6.81 (m, 1 H), 6.60 (m, 1 H), 6.49 (s, 1 H), 3.79 (s, 3 H).