Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[S:6][C:5]([C:7]2[S:8][C:9](Br)=[C:10]([C:12]([O:14][CH2:15][CH:16]([CH2:23][CH2:24][CH2:25][CH3:26])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[O:13])[CH:11]=2)=[CH:4][C:3]=1[C:28]([O:30][CH2:31][CH:32]([CH2:39][CH2:40][CH2:41][CH3:42])[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])=[O:29].C([Sn](CCCC)(CCCC)[C:48]1[S:49][CH:50]=[CH:51][CH:52]=1)CCC>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.CN(C=O)C>[S:6]1[CH:2]=[CH:3][CH:4]=[C:5]1[C:2]1[S:6][C:5]([C:7]2[S:8][C:9]([C:50]3[S:49][CH:48]=[CH:52][CH:51]=3)=[C:10]([C:12]([O:14][CH2:15][CH:16]([CH2:23][CH2:24][CH2:25][CH3:26])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[O:13])[CH:11]=2)=[CH:4][C:3]=1[C:28]([O:30][CH2:31][CH:32]([CH2:39][CH2:40][CH2:41][CH3:42])[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])=[O:29]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccs1
Reactant: CCCCCCC(CCCC)COC(=O)c1cc(-c2cc(C(=O)OCC(CCCC)CCCCCC)c(Br)s2)sc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: CCCCCCC(CCCC)COC(=O)c1cc(-c2cc(C(=O)OCC(CCCC)CCCCCC)c(-c3cccs3)s2)sc1-c1cccs1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To the mixture of bis(2-butyl-1-octyl) 5,5′-dibromo-2,2′-bithiophene-4,4′-dicarboxylate (1.00 g, 1.34 mmol) and 2-tributylstannylthiophene (1.50 g, 4 mmol) was added Pd(PPh3)4 (46 mg, 0.04 mmol), and anhydrous DMF (15 ml). The mixture was placed under vacuum and flushed with argon several times and was put on a microwave reactor with a setting of 160° C. for 60 min. The reaction mixture was cooled to room temperature and the solvent was removed. The residue was washed with methanol to remove traces of DMF. After drying, the liquid was dissolved in hexane and purified twice by column chromatography on silica gel using a mixture of hexane/ethyl acetate (9/1) (Rf=0.5). A light yellow liquid was obtained. Yield: 1.01 g (100%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[OH:11])[C:5]([OH:7])=[O:6].[F:12][C:13]([F:23])([F:22])[C:14]1[CH:21]=[CH:20][C:17]([CH2:18]Br)=[CH:16][CH:15]=1>>[F:12][C:13]([F:23])([F:22])[C:14]1[CH:21]=[CH:20][C:17]([CH2:18][O:6][C:5](=[O:7])[C:4]2[CH:8]=[CH:9][C:10]([O:11][CH2:18][C:17]3[CH:16]=[CH:15][C:14]([C:13]([F:12])([F:22])[F:23])=[CH:21][CH:20]=3)=[C:2]([F:1])[CH:3]=2)=[CH:16][CH:15]=1
Reactant: O=C(O)c1ccc(O)c(F)c1
Reactant: FC(F)(F)c1ccc(CBr)cc1
Product: O=C(OCc1ccc(C(F)(F)F)cc1)c1ccc(OCc2ccc(C(F)(F)F)cc2)c(F)c1
Yield: 69 %

Procedure:
As described for example 18a, 3-fluoro-4-hydroxybenzoic acid (2.5 g, 16 mmol) [using 4-(trifluoromethyl)-benzyl bromide instead of 4-fluorobenzyl bromide] was converted to the title compound (5.3 g, 69%) which was obtained as a white solid. MS: m/e=472.1 (M+).
Reaction SMILES: [CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([O:13][N:14]=[C:15]2[CH2:20][CH2:19][N:18]([C:21]3[CH:26]=[C:25]([F:27])[C:24]([NH2:28])=[CH:23][C:22]=3[F:29])[CH2:17][CH2:16]2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2].[O-:30][C:31]#[N:32].[K+].C(O)(=O)C>C1COCC1.O>[CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([O:13][N:14]=[C:15]2[CH2:20][CH2:19][N:18]([C:21]3[CH:26]=[C:25]([F:27])[C:24]([NH:28][C:31]([NH2:32])=[O:30])=[CH:23][C:22]=3[F:29])[CH2:17][CH2:16]2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2]
Reactant: CC(C)OC(=O)N1CCC(ON=C2CCN(c3cc(F)c(N)cc3F)CC2)CC1
Reactant: N#C[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CC(C)OC(=O)N1CCC(ON=C2CCN(c3cc(F)c(NC(N)=O)cc3F)CC2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 34-1 (72.5 mg, 0.18 mmol) in THF (1 mL) and water (1 mL), was added potassium cyanate (30 mg, 0.37 mmol), acetic acid (0.2 mL) and water (1.8 mL). The biphasic solution was stirred at room temperature for 2 h then concentrated, dissolved in DCM and purified on preparative HPLC to give 37-1: LC-MS 454.1 (MH), tR=6.42 (Method 2). EC50: 71 nM.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[N:15]([CH2:16][CH:17]([CH3:19])[CH3:18])[C:14]([CH2:20][CH2:21][CH2:22][CH3:23])=[N:13][C:7]=3[C:8]([NH2:12])=[N:9][C:10]=2[CH:11]=1.[CH2:24]([O:27][C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1)[CH2:25][CH3:26]>>[CH2:20]([C:14]1[N:15]([CH2:16][CH:17]([CH3:19])[CH3:18])[C:6]2[C:5]3[CH:4]=[CH:3][C:2]([C:31]4[CH:32]=[CH:33][C:28]([O:27][CH2:24][CH2:25][CH3:26])=[CH:29][CH:30]=4)=[CH:11][C:10]=3[N:9]=[C:8]([NH2:12])[C:7]=2[N:13]=1)[CH2:21][CH2:22][CH3:23]
Reactant: CCCCc1nc2c(N)nc3cc(Br)ccc3c2n1CC(C)C
Reactant: CCCOc1ccc(B(O)O)cc1
Product: CCCCc1nc2c(N)nc3cc(-c4ccc(OCCC)cc4)ccc3c2n1CC(C)C

Procedure:
7-Bromo-2-butyl-1-isobutyl-1H-imidazo[4,5-c]quinolin-4-amine and 4-propoxybenzeneboronic acid were coupled according to the general procedure described in Part J of Example 1. The product was recrystallized from isopropanol, collected by filtration, dissolved in CH2Cl2, and then precipitated with hexanes to afford 2-butyl-1-isobutyl-7-(4-propoxyphenyl)-1H-imidazo[4,5-c]quinolin-4-amine as a pale yellow solid, m.p. 194–197° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:4]=1[CH:5]=O.[CH:13]([C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1)([CH3:15])[CH3:14]>>[CH3:1][O:2][C:3]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:4]=1[CH2:5][NH:20][C:19]1[CH:21]=[CH:22][C:16]([CH:13]([CH3:15])[CH3:14])=[CH:17][CH:18]=1
Reactant: COc1ccc(C=O)c(OC)c1
Reactant: CC(C)c1ccc(N)cc1
Product: COc1ccc(CNc2ccc(C(C)C)cc2)c(OC)c1
Yield: 372.3 %

Procedure:
By the reaction and treatment in the same manner as in Preparation Example 1 using 2,4-dimethoxybenzaldehyde (8.0 g) and 4-isopropylaniline (1.4 g) as starting materials, [(2,4-dimethoxyphenyl)methyl](4-isopropylphenyl)amine (11 g) was obtained.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][C:8]([N+:14]([O-])=O)=[CH:9][CH:10]=2)[CH:5]=1)([O-:3])=[O:2].[SH-].[Na+]>CO.O>[N+:1]([C:4]1[CH:5]=[C:6]2[C:11]([CH:10]=[CH:9][C:8]([NH2:14])=[CH:7]2)=[CH:12][CH:13]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc2ccc([N+](=O)[O-])cc2c1
Agent: [Na+]
Agent: [SH-]
Solvent: CO
Solvent: O
Product: Nc1ccc2ccc([N+](=O)[O-])cc2c1
Temperature: 0 °C

Procedure:
To a solution of 2,7-dinitronaphthalene (500 mg, 2.29 mmol) in methanol (5 mL) heated to reflux, is added over 15 minutes, a solution of sodium hydrosulfide (196 mg, 3.44 mmol) in methanol (5 mL) and water (10 mL). The reaction mixture is heated at reflux for 30 minutes and then poured into ice-water and filtered to give an orange solid. After washing the solid with boiling 10% aqueous HCl, the filtrate is basified with solid NaOH and extracted with EtOAc. The organic layer is dried (Na2SO4) and the solvents are evaporated to give 7-nitro-2-aminonaphthalene as a bright orange solid.
Reaction SMILES: [CH2:1]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[C:9]=1[NH:15][C:16](=[O:21])[CH2:17][CH2:18][CH2:19]Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:22]([C:29]1[CH:34]=[CH:33][C:32]([CH:35]2[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]2)=[CH:31][CH:30]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[CH2:1]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[C:9]=1[NH:15][C:16](=[O:21])[CH2:17][CH2:18][CH2:19][N:38]1[CH2:39][CH2:40][CH:35]([C:32]2[CH:33]=[CH:34][C:29]([O:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:30][CH:31]=2)[CH2:36][CH2:37]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cccc(Cc2ccccc2)c1NC(=O)CCCCl
Reactant: c1ccc(Oc2ccc(C3CCNCC3)cc2)cc1
Product: Cc1cccc(Cc2ccccc2)c1NC(=O)CCCN1CCC(c2ccc(Oc3ccccc3)cc2)CC1

Procedure:
The compound (14) synthesized in Reference Example 14 and the compound (4) synthesized in Reference Example 4 were used to produce the above compound in the same way as Example 1.
Reaction SMILES: [O:1]=[CH:2][C@@H:3]([C@H:5]([C@@H:7]([CH2:9][OH:10])[OH:8])[OH:6])[OH:4].[O:11]=[CH:12][C@@H:13]([C@H:15]([C@@H:17]([C@@H:19]([CH2:21][OH:22])[OH:20])[OH:18])[OH:16])[OH:14]>>[O:11]=[CH:12][C@@H:13]([C@H:15]([C@@H:17]([C@@H:19]([CH2:21][OH:22])[OH:20])[OH:18])[OH:16])[OH:14].[OH:1][CH2:2][C:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:12][OH:11])[OH:10])[OH:8])[OH:6])=[O:4]
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)CO
Agent: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Product: O=C(CO)[C@@H](O)[C@H](O)[C@H](O)CO
Temperature: 70 °C
Reaction time: 24 h

Procedure:
Streptomyces olivaceus, strain NRRL B-3583, is cultivated in a nutrient medium containing 0.7 percent xylose, 0.3 percent dextrose, 0.5 percent beef extract, 0.25 percent yeast extract, 1.0 percent peptone, 0.5 percent NaCl, 0.05% MgSO4.7H2O and 0.024 percent CoCl2.6H2O. The fermentation is allowed to proceed at 28° C. for 24 hours. A 2 percent (weight per volume) solution of a cationic polyelectrolyte is added to the fermentation broth in amounts equivalent to 0.05 percent (weight per volume) of the dry flocculant. The broth is briefly agitated to promote aggregation of the cells. Agitation is then stopped and sedimentation of the flocculated cells is allowed to proceed. The cell aggregates are harvested in a manner analogous to that described in Example 1. The flocculated cells are dried at 60° C. for 24 hours before subjecting the dried cell mass to gentle mechanical crushing action to reduce to particle sizes suitable for column operation. The crushed cell material is poured into a jacketed column partially filled with a 1.0 M glucose solution. The packed column is heated to 70° C. and a 1.0 M glucose solution containing 0.04 M MgCl2.6H2O adjusted to pH 8 is passed through the column to give conversion of glucose to fructose.
Reaction SMILES: [CH3:1][C:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:13])[C:3]=1[N:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]=[C:28]=[O:29])=[CH:23][CH:22]=1>O1CCCC1>[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([NH:27][C:28]([N:17]2[CH2:18][CH2:19][N:14]([C:3]3[C:4](=[O:13])[C:5]4[C:10]([C:11](=[O:12])[C:2]=3[CH3:1])=[CH:9][CH:8]=[CH:7][CH:6]=4)[CH2:15][CH2:16]2)=[O:29])=[CH:23][CH:22]=1
Reactant: CC1=C(N2CCNCC2)C(=O)c2ccccc2C1=O
Reactant: O=C=Nc1ccc(Cl)cc1
Solvent: C1CCOC1
Product: CC1=C(N2CCN(C(=O)Nc3ccc(Cl)cc3)CC2)C(=O)c2ccccc2C1=O
Reaction time: 0.5 h
Yield: 83.4 %

Procedure:
A solution of 150 mg of 3-methyl-2-piperazinyl-1,4-naphthoquinone in 50 ml of tetrahydrofuran was treated with a solution of 100 mg of 4-chlorophenylisocyanate in 10.ml of tetrahydrofuran. This mixture was stirred 1/2 hour, then evaporated in vacuo and the residue taken up in dichloromethane and filtered. The filtrate was evaporated and the residue recrystallized from dichloromethane/hexane, giving 200 mg of the desired product, mp 190-192°C.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([OH:8])=[O:7].[N+](=[CH2:11])=[N-].C(O)(=O)C>C(OCC)C>[CH3:11][O:7][C:6]([C:2]1[NH:1][CH:5]=[CH:4][CH:3]=1)=[O:8]
Reactant: O=C(O)c1ccc[nH]1
Reactant: C=[N+]=[N-]
Solvent: CCOCC
Solvent: CC(=O)O
Product: COC(=O)c1ccc[nH]1
Yield: 88.8 %

Procedure:
Method 4 General Experimental: Pyrrole-2-carboxylic acid (90.0 mmol, 10.0 g) in diethyl ether (200 ml) was treated with diazomethane (270 mmol, generated from N-nitroso-N-methyl urea), then back titrated with acetic acid until the yellow color dissipated. The solution was washed with saturated aqueous sodium bicarbonate (3×20 ml) and brine (3×20 ml), then concentrated under reduced pressure to provide 10 g (88%) of pyrrole-2-carboxylic acid methyl ester. 1H NMR (CDCl3) δ9.14 (1H, s), 6.98-6.65 (1H, m), 6.94-6.91 (1H, m), 6.29-6.26 (1H, m), 3.86 (3H, s).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:7]2[N:11]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[C:14]([Br:19])[CH:13]=3)[C:10](=[O:20])[O:9][N:8]=2)=[N:4][O:5][N:6]=1.CO[CH:23](OC)[CH2:24][NH:25][S:26]([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])(=[O:28])=[O:27].FC(F)(F)C(O)=O.C([SiH](CC)CC)C>ClCCl>[Br:19][C:14]1[CH:13]=[C:12]([N:11]2[C:10](=[O:20])[O:9][N:8]=[C:7]2[C:3]2[C:2]([NH:1][CH2:23][CH2:24][NH:25][S:26]([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])(=[O:27])=[O:28])=[N:6][O:5][N:4]=2)[CH:17]=[CH:16][C:15]=1[F:18]
Reactant: COC(CNS(=O)(=O)NC(=O)OC(C)(C)C)OC
Reactant: Nc1nonc1-c1noc(=O)n1-c1ccc(F)c(Br)c1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NS(=O)(=O)NCCNc1nonc1-c1noc(=O)n1-c1ccc(F)c(Br)c1
Temperature: 25 °C
Yield: 24.2 %

Procedure:
A mixture of 3-(4-amino-1,2,5-oxadiazol-3-yl)-4-(3-bromo-4-fluorophenyl)-1,2,4-oxadiazol-5(4H)-one (103 mg, 0.302 mmol, 1.5 equiv.; Step D) and tert-butyl N-(2,2-dimethoxyethyl)sulfamoylcarbamate (57.2 mg, 0.201 mmol) in dichloromethane (1.0 mL) was stirred under N2 at room temperature. To this mixture was added trifluoroacetic acid (0.50 mL, 6.5 mmol) and triethylsilane (80.2 μL, 0.502 mmol, 2.5 equiv.) drop-wise. This reaction mixture was stirred at room temperature for 2 h. HPLC indicated approximately 30% conversion. The reaction mixture was cooled to 0° C. and quenched with saturated sodium bicarbonate to pH ˜8. The mixture was extracted in ethyl acetate (3×10 mL). The combined organic extracts were washed with brine, dried over sodium sulfate and concentrated. The residue was purified by preparative TLC (50% ethyl acetate/hexane) to give the desired product (27.5 mg, 29.5%) as an off-white solid. 1H NMR (DMSO-d6, 400 MHz): δ 10.90 (s, 1H), 8.08 (dd, J=6.2, 2.5 Hz, 1H), 7.72 (m, 1H), 7.59 (t, J=8.6 Hz, 1H), 6.58 (t, J=5.7 Hz, 1H), 3.38 (dd, J=12.7, 6.2 Hz, 2H), 3.10 (dd, J=12.1, 5.9 Hz, 2H), 1.41 (s, 9H). C17H19BrFN7O7S (MW 564.34), LCMS (EI) m/e 485.8/487.8 (M+-C5H8O2+Na).
Reaction SMILES: [CH3:1][CH:2]1[S:8][CH:7]([C:9]([OH:11])=[O:10])[CH2:6][C:5]2[CH:12]=[C:13]3[O:18][CH2:17][O:16][C:14]3=[CH:15][C:4]=2[C:3]1=[O:19]>CO>[CH3:1][C@H:2]1[S:8][C@H:7]([C:9]([OH:11])=[O:10])[CH2:6][C:5]2[CH:12]=[C:13]3[O:18][CH2:17][O:16][C:14]3=[CH:15][C:4]=2[C:3]1=[O:19]
Reactant: CC1SC(C(=O)O)Cc2cc3c(cc2C1=O)OCO3
Solvent: CO
Product: C[C@H]1S[C@H](C(=O)O)Cc2cc3c(cc2C1=O)OCO3
Reaction time: 1 h

Procedure:
In 340 mL of methanol was suspended 20.00 g of a racemic mixture, 1,2,4,5-tetrahydro-4-methyl-7,8-methylenedioxy-5-oxo-3-benzothiepin-2-carboxylic acid (content 100%; trans compound 87.1%, cis compound 12.9%). To the suspension was added 11.01 g (1 equivalent) of (1S,2R)-norephedrine at room temperature (25° C.), followed by stirring for 1 hour. The resulting crystals were collected by filtration, washed with 80 mL of cold methanol, and dried over one night at room temperature under reduced pressure to afford 10.39 g of substantially pure (2S,4R)-1,2,4,5-tetrahydro-4-methyl-7,8-methylenedioxy-5-oxo-3-benzothiepin-2-carboxylic acid.(1S,2R)-norephedrine salt as colorless crystals [HPLC area percentage: (2R,4R):(2S,4S):(2S,4R):(2R,4S)=0%:0.7%:94.2%:4.0%].
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][C@H:12]1[CH2:16][CH2:15][CH2:14][N:13]1[CH3:17].[CH3:18][C:19]([OH:23])([CH:21]=[CH2:22])[CH3:20].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(#N)C>[OH:23][C:19]([CH3:20])([CH3:18])[CH:21]=[CH:22][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][C@H:12]1[CH2:16][CH2:15][CH2:14][N:13]1[CH3:17]
Reactant: CN1CCC[C@@H]1Cc1c[nH]c2ccc(Br)cc12
Reactant: C=CC(C)(C)O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CN1CCC[C@@H]1Cc1c[nH]c2ccc(C=CC(C)(C)O)cc12
Yield: 25.2 %

Procedure:
A stirred solution of 5-bromo-3-(N-methyl-2(R)-pyrrolidinylmethyl)-1H-indole (WO-A-92/06973; 879 mg, 3.0 mmol), 2-methylbut-3-en-2-ol (0.408 ml, 3.9 mmol), tri-o-tolylphosphine (273 mg, 0.90 mmol), palladium(II) acetate (45 mg, 0.20 mmol), triethylamine (0.84 ml, 6.0 mmol) and acetonitrile (50 ml), under nitrogen, was heated under reflux for 24 hours, allowed to cool, then partitioned between ethyl acetate and 2M aqueous sodium carbonate solution. The organic phase was separated, washed sequentially with 2M aqueous sodium carbonate solution (×2) and brine (×1), dried (Na2SO4) and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel, eluting with a solvent gradient of 0.880 aqueous ammonia:methanol: dichloromethane (0:5:95 to 0.5:5:95), to afford the title compound as a solid (226 mg), m.p. 155°-158° C. Rf 0.10 (SS 1). [α]D25 +81° (c=0.1, CH3OH). Found: C,75.27; H,8.96; N,8.99. C19H26N2O; 0.25 H2O requires C,75.33; H,8.82; N,9.25%.
Reaction SMILES: I[C:2]1[N:3]=[C:4]([CH3:16])[N:5]([C:8]2[CH:13]=[N:12][N:11]([CH3:14])[C:10](=[O:15])[CH:9]=2)[C:6]=1[CH3:7].[Cl:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([C:24]#[CH:25])[CH:19]=1>>[Cl:17][C:18]1[CH:19]=[C:20]([C:24]#[C:25][C:2]2[N:3]=[C:4]([CH3:16])[N:5]([C:8]3[CH:13]=[N:12][N:11]([CH3:14])[C:10](=[O:15])[CH:9]=3)[C:6]=2[CH3:7])[CH:21]=[CH:22][CH:23]=1
Reactant: Cc1nc(I)c(C)n1-c1cnn(C)c(=O)c1
Reactant: C#Cc1cccc(Cl)c1
Product: Cc1nc(C#Cc2cccc(Cl)c2)c(C)n1-c1cnn(C)c(=O)c1

Procedure:
The title compound, light brown cristalline solid, MS: m/e=339.2, 341.1 (M+H+), was prepared in accordance with the general method of example 1c from 5-(4-iodo-2,5-dimethyl-imidazol-1-yl)-2-methyl-2H-pyridazin-3-one and 1-chloro-3-ethynyl-benzene.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]2[C:16]([CH2:17][OH:18])=[C:15]([CH3:19])[N:14]([CH2:20][CH2:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:13]([CH3:29])=[C:12]2[C:30]#[N:31])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]>ClC(Cl)C.[O-2].[O-2].[Mn+4]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]2[C:16]([CH:17]=[O:18])=[C:15]([CH3:19])[N:14]([CH2:20][CH2:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:13]([CH3:29])=[C:12]2[C:30]#[N:31])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(C2C(C#N)=C(C)N(CCCc3ccccc3)C(C)=C2CO)cc1OC
Agent: [Mn+4]
Agent: [O-2]
Solvent: CC(Cl)Cl
Product: COc1ccc(C2C(C#N)=C(C)N(CCCc3ccccc3)C(C)=C2C=O)cc1OC
Temperature: 80 °C
Yield: 57.7 %

Procedure:
To a solution of 13 mg (0.026 mmol) of 1,4-dihydro-4-(3,4-dimethoxyphenyl)-2,6-dimethyl-1-(3-phenylpropyl) -3-cyano-5-hydroxymethylpyridine in 0.45 ml of dichloroethane was added 5 mg of activated manganese dioxide. The mixture was heated at 80° C. for one hour. Then the mixture was filtered and concentrated. The resulting residue was purified by thin layer chromatography (AcOEt:Hexane 1:1) to give 7.4 mg (0.015 mmol) of 1,4-dihydro-4-(3,4-dimethoxyphenyl)-2,6-dimethyl -1-(3-phenylpropyl)-3-cyano-5-formylpyridine (yield: 58%).
Reaction SMILES: C[N:2](/[CH:4]=[N:5]/[C:6]([C:8]1[N:9]([CH2:29][O:30][CH3:31])[C:10]2[C:15]([CH:16]=1)=[CH:14][CH:13]=[CH:12][C:11]=2[N:17]([CH2:26][O:27][CH3:28])[S:18]([C:21]1[S:22][CH:23]=[CH:24][CH:25]=1)(=[O:20])=[O:19])=O)C.O.[NH2:33]N.C(O)(=O)C>O>[CH3:28][O:27][CH2:26][N:17]([C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:10]=1[N:9]([CH2:29][O:30][CH3:31])[C:8]([C:6]1[N:5]=[CH:4][NH:2][N:33]=1)=[CH:16]2)[S:18]([C:21]1[S:22][CH:23]=[CH:24][CH:25]=1)(=[O:20])=[O:19]
Reactant: NN
Reactant: COCN(c1cccc2cc(C(=O)/N=C/N(C)C)n(COC)c12)S(=O)(=O)c1cccs1
Solvent: CC(=O)O
Solvent: O
Product: COCN(c1cccc2cc(-c3nc[nH]n3)n(COC)c12)S(=O)(=O)c1cccs1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
A mixture of N-[(1E)-(dimethylamino)methylene]-1-(methoxymethyl)-7-[(methoxymethyl)(2-thienylsulfonyl)amino]-1H-indole-2-carboxamide (1.06 g), hydrazine monohydrate (0.22 mL) and acetic acid (10 mL) was stirred at 80° C. for 1 hr. Water was added to the reaction mixture, and the obtained crystals were filtrated, washed with water and dried to give the title compound (0.99 g, quantitative) as colorless crystals. melting point 97-99° C.
Reaction SMILES: [CH3:1][C:2]([C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-])=O)=[CH:9][CH:8]=1)([CH2:5][OH:6])[CH2:3][OH:4]>C(O)C.[Pd]>[NH2:13][C:10]1[CH:9]=[CH:8][C:7]([C:2]([CH3:1])([CH2:5][OH:6])[CH2:3][OH:4])=[CH:12][CH:11]=1
Reactant: CC(CO)(CO)c1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CCO
Product: CC(CO)(CO)c1ccc(N)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 97.1 %

Procedure:
To a stirred solution of 2-methyl-2-(4-nitrophenyl)propane-1,3-diol (1.2 g, 5.68 mmol, 1.0 eq) in ethanol (30 mL) was added 10% Pd/C (300 mg) and the mixture was stirred under hydrogen gas balloon atmosphere for 5 h at RT. The reaction mixture was filtered through celite pad and filtrate concentrated under vacuum to get 2-(4-aminophenyl)-2-methylpropane-1,3-diol (1 g, 97%; TLC system: chloroform/MeOH (9:1); Rf: 0.3).
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH2:17][CH:18]2[C:24](=[O:25])[N:23]([C:26](C(C)(C)C)(C3C=CC=CC=3)[C:27](=[O:29])[NH2:28])[C:22]3[CH:40]=[CH:41][CH:42]=[CH:43][C:21]=3[N:20]([C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)[C:19]2=[O:50])=[N:9]1)=O)(C)(C)C>Cl.O1CCOCC1>[C:18]([N:28]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:27](=[O:29])[CH2:26][N:23]1[C:24](=[O:25])[CH:18]([CH2:17][C:10]2[C:11]3[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=3)[NH:8][N:9]=2)[C:19](=[O:50])[N:20]([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[C:40]2[CH:41]=[CH:42][CH:43]=[CH:21][C:22]1=2)([CH3:24])([CH3:19])[CH3:17]
Reactant: CC(C)(C)OC(=O)n1nc(CC2C(=O)N(c3ccccc3)c3ccccc3N(C(C(N)=O)(c3ccccc3)C(C)(C)C)C2=O)c2ccccc21
Agent: Cl
Solvent: C1COCCO1
Product: CC(C)(C)N(C(=O)CN1C(=O)C(Cc2n[nH]c3ccccc23)C(=O)N(c2ccccc2)c2ccccc21)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 57.7 %

Procedure:
263 mg (0.392 mmol) 3-[1-(tert-Butyl-phenyl-carbamoylmethyl)-2,4-dioxo-5-phenyl-2,3,4,5,-tetrahydro-1H-benzo[b][1,4]diazepin-3-ylmethyl]-indazole-1-carboxylic acid tert-butyl ester, prepared as in Intermediate 65, is dissolved in 3 mL 4N HCl in Dioxane and stirred 1 h at ambient temperature. The solvent is removed in vacuo and the residue taken into EtOAc (50 mL), washed with satd. NaHCO3 (30 mL) and brine (30 mL), dried (MgSO4), filtered and concentrated in vacuo. The crude product is purified by flash chromatography on 5 g silica gel eluted successively with EtOAc/Hexanes (1:2, 50 mL), (2:3, 80 mL), (1:1, 50 mL). Appropriate fractions were combined and concentrated in vacuo to give 65 mg (0.113 mmol) of the title compound as a white foam: 1H NMR (CDCl3, 300 MHz) δ7.82 (d, 1H, J=7.5), 7.43-7.06 (m, 16H), 4.19 (m, 2H), 4.08 (m, 1H), 3.79 (m, 1H), 3.63 (m, 1H), 1.37 (s, 9H); low resolution MS (FAB) m/e 572.2 (MH+); TLC Rf =0.41 (EtOAc/Hexanes, 3:2).
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][N:7]2[C:16](=[O:17])[C:15]3[C:10](=[CH:11][C:12]([C:18](O)=[O:19])=[CH:13][CH:14]=3)[NH:9][C:8]2=[O:21])=[CH:4][CH:3]=1.[CH2:24]([CH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][N:27]1[CH2:32][CH2:33][CH2:34][NH2:35])[CH3:25]>>[CH2:24]([CH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][N:27]1[CH2:32][CH2:33][CH2:34][NH:35][C:18]([C:12]1[CH:11]=[C:10]2[C:15]([C:16](=[O:17])[N:7]([CH2:6][C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:23][CH:22]=3)[C:8](=[O:21])[NH:9]2)=[CH:14][CH:13]=1)=[O:19])[CH3:25]
Reactant: O=C(O)c1ccc2c(=O)n(Cc3ccc(Cl)cc3)c(=O)[nH]c2c1
Reactant: CCC1CCCCN1CCCN
Product: CCC1CCCCN1CCCNC(=O)c1ccc2c(=O)n(Cc3ccc(Cl)cc3)c(=O)[nH]c2c1

Procedure:
55 mg (42%) of the target compound was obtained in the same manner of Example 1, using 3-(4-chloro-benzyl)-2,4-dioxoquinazoline-7-carboxylic acid (90 mg, 0.272 mmol) obtained in Example 1 and 3-(2-ethyl-piperidine-1-yl)-propylamine (101 mL, 0.598 mmol).