Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][S:9][C:10]2[NH:14][C:13]3=[CH:15][S:16][CH:17]=[C:12]3[N:11]=2)=[N:6][CH:7]=1.Cl[C:19]([O:21][C:22]1[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=1)=[O:20]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[N+:28]([C:25]1[CH:24]=[CH:23][C:22]([O:21][C:19]([N:11]2[C:12]3=[CH:17][S:16][CH:15]=[C:13]3[N:14]=[C:10]2[S:9][CH2:8][C:5]2[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][N:6]=2)=[O:20])=[CH:27][CH:26]=1)([O-:30])=[O:29]
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: Cc1ccc(CSc2nc3cscc3[nH]2)nc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: Cc1ccc(CSc2nc3cscc3n2C(=O)Oc2ccc([N+](=O)[O-])cc2)nc1

Procedure:
The title compound was prepared in analogy to Example 17 from 2-(5-methyl-2-picolylmercapto)-1H-thieno[3,4-d]imidazole and p-nitrophenyl chloroformate. After working up and chromatography on silica gel using toluene/ethyl acetate (1:1), the appropriate fractions were crystallized from ethyl acetate, and the title compound was obtained. Melting point 165°-168° C.
Reaction SMILES: C1([C:7]2[C:16]3[C:11](=CC=CC=3)[CH:10]=[C:9]3[C:17](O[C:20](=[O:21])[C:8]=23)=[O:18])C=CC=CC=1.[NH2:22][NH2:23]>>[C:17]1(=[O:18])[C:9]2[C:8](=[CH:7][CH:16]=[CH:11][CH:10]=2)[C:20](=[O:21])[N:23]=[N:22]1
Reactant: O=C1OC(=O)c2c1cc1ccccc1c2-c1ccccc1
Reactant: NN
Product: O=C1N=NC(=O)c2ccccc21

Procedure:
Later it was found (F. G. Baddar, M. F. El-Newaihy and M. R. Salem, J. Chem. Soc. 838, 1969) that in the reaction of 1-phenylnaphthalene-2,3-dicarboxylic anhydride (R=H in formula (XXX)) ##STR5## with hydrazine that a mixture of the N-amino compound and the phthalazine-1,4-dione were obtained. The 4'-7-dimethoxy anhydride (R=OMe) however gave the N-amino compound.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][N:8]([C:11]3[CH:16]=[CH:15][C:14]([N:17]4[CH2:21][C@H:20]([CH2:22][N:23]=[N+:24]=[N-:25])[O:19][C:18]4=[O:26])=[CH:13][C:12]=3[F:27])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[C:28]12CC(CC1)=C[CH:29]=2>O1CCOCC1>[O:1]1[C:5]2([CH2:10][CH2:9][N:8]([C:11]3[CH:16]=[CH:15][C:14]([N:17]4[CH2:21][C@H:20]([CH2:22][N:23]5[CH:29]=[CH:28][N:25]=[N:24]5)[O:19][C:18]4=[O:26])=[CH:13][C:12]=3[F:27])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1
Reactant: [N-]=[N+]=NC[C@H]1CN(c2ccc(N3CCC4(CC3)OCCO4)c(F)c2)C(=O)O1
Reactant: C1=C2CCC(=C1)C2
Solvent: C1COCCO1
Product: O=C1O[C@@H](Cn2ccnn2)CN1c1ccc(N2CCC3(CC2)OCCO3)c(F)c1
Yield: 57.5 %

Procedure:
(5R)-3-(4-(1,4-Dioxa-8-azaspiro[4,5]decan-8-yl)-3-fluorophenyl)-5-azidomethyloxazolidin-2-one (2.44 g, 6.5 mM) was dissolved in dioxane (50 ml), treated with norbornadiene (2.98 g, 32.3 mM) and heated under reflux for 20 hours. After removal of the solvent, the residue was dissolved in dichloromethane (350 ml) washed with water (3×200 ml), and dried over magnesium sulfate. After filtration and evaporation the residue was purified by chromatography on a 20 g silica Mega Bond Elut® column, eluting with a gradient increasing in polarity from 0 to 2.5% methanol in dichloromethane. Relevant fractions were combined and evaporated to give the desired product (1.5 g).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH:11][C:12]2[CH:16]=[C:15]([CH:17]3[CH2:19][CH2:18]3)[NH:14][N:13]=2)=[O:10])=[CH:4][CH:3]=1.[F-].[Cs+].[C:22]1(B(O)O)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>COCCOC.CO.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>[C:2]1([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH:11][C:12]2[NH:13][N:14]=[C:15]([CH:17]3[CH2:19][CH2:18]3)[CH:16]=2)=[O:10])=[CH:4][CH:3]=1
Reactant: O=C(Cc1ccc(Br)cc1)Nc1cc(C2CC2)[nH]n1
Reactant: OB(O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: CO
Solvent: COCCOC
Product: O=C(Cc1ccc(-c2ccccc2)cc1)Nc1cc(C2CC2)n[nH]1
Temperature: 80 °C
Reaction time: 18 h

Procedure:
To 40 mg of 2-(4-bromophenyl)-N-(5-cyclopropyl-1H-pyrazol-3-yl)acetamide resin linked 1 ml of a 10.4M solution of CsF in DME:MeOH (3:1), phenylboronic acid (0, 12 mmol) in DME (0.5 ml) and tetrakis triphenylphosphine palladium, (Pd(PPh3)4, 0.008 mmol) in DME (1 ml) were added. The mixture was shaken 18 hrs at 80° C. and then washed with DMF (3×5 ml), MeOH (3×5 ml) and DCM (3×5 ml). To the resin 5 ml of TFA 10% in DCM were added and the mixture was shaken 1 hr at room temperature, the organic phase was filtered off and the resin was washed with DCM (3×5 ml) and DMSO (2×5 ml). The organic fractions were collected and evaporated under reduced pressure and the residue was analyzed by HPLC-MS (area count 90%, 254 nm; M+1=318, 2M+1=365) without further purification.
Reaction SMILES: [Si]([O:8][CH2:9][C:10]([NH:13][C:14]([C:16]1[C:20]2=[N:21][C:22]([C:25]3[C:33]4[C:28](=[CH:29][CH:30]=[C:31]([O:34][CH:35]([F:37])[F:36])[CH:32]=4)[N:27]([CH2:38][CH2:39][CH2:40][N:41]([CH3:43])[CH3:42])[N:26]=3)=[CH:23][N:24]=[C:19]2[N:18](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:17]=1)=[O:15])([CH3:12])[CH3:11])(C(C)(C)C)(C)C.FC(F)(F)C(O)=O>ClCCl>[F:37][CH:35]([F:36])[O:34][C:31]1[CH:32]=[C:33]2[C:28](=[CH:29][CH:30]=1)[N:27]([CH2:38][CH2:39][CH2:40][N:41]([CH3:42])[CH3:43])[N:26]=[C:25]2[C:22]1[N:21]=[C:20]2[C:16]([C:14]([NH:13][C:10]([CH3:11])([CH3:12])[CH2:9][OH:8])=[O:15])=[CH:17][NH:18][C:19]2=[N:24][CH:23]=1
Reactant: CN(C)CCCn1nc(-c2cnc3c(n2)c(C(=O)NC(C)(C)CO[Si](C)(C)C(C)(C)C)cn3C(c2ccccc2)(c2ccccc2)c2ccccc2)c2cc(OC(F)F)ccc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN(C)CCCn1nc(-c2cnc3[nH]cc(C(=O)NC(C)(C)CO)c3n2)c2cc(OC(F)F)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 36.6 %

Procedure:
To the solution of N-(1-(tert-butyldimethylsilyloxy)-2-methylpropan-2-yl)-2-(5-(difluoromethoxy)-1-(3-(dimethylamino)propyl)-1H-indazol-3-yl)-5-trityl-5H-pyrrolo[3,2-b]pyrazine-7-carboxamide (88 mg, 0.12 mmol) in 3 mL of dichloromethane was added 3 mL of trifluoroacetic acid. The reaction mixture was stirred overnight at room temperature. After solvent evaporation, the residue was purified by preparative-HPLC (Gemini 5u C18 150×21.2 mm; inject volume: 3 mL/inj, flow rate: 20 mL/min; wavelength: 214 nm and 254 nm; the gradient conditions are: 40% acetonitrile/60% water (0.1% trifluoroacetic acid V/V) initially, and then proceed to 50% acetonitrile/50% water (0.1% trifluoroacetic acid V/V) in a linear fashion after just 9 min) to afford 2-(5-(difluoromethoxy)-1-(3-(dimethylamino)propyl)-1H-indazol-3-yl)-N-(1-hydroxy-2-methylpropan-2-yl)-5H-pyrrolo[3,2-b]pyrazine-7-carboxamide as yellow solid (22 mg, 34.5%). LCMS: (M+H)+=502; 1H NMR (300 MHz, CD3OD): δ 9.04 (s, 1H), 8.17 (s, 1H), 8.11 (s, 1H), 7.66 (d, 1H, J=8.7 Hz), 7.35 (d, 1H, J=8.1 Hz), 6.85 (t, 1H, J=74.1 Hz), 4.59 (s, 2H), 3.84 (s, 2H), 3.34-3.32 (m, 2H), 2.89 (s, 6H), 2.44 (s, 2H), 1.64 (s, 6H).
Reaction SMILES: [NH:1]1[CH2:4][CH2:3][CH2:2]1.[Cl:5][C:6]1[N:7]=[N:8][C:9](Cl)=[CH:10][CH:11]=1.C(N(CC)C(C)C)(C)C>C(O)CC>[N:1]1([C:9]2[N:8]=[N:7][C:6]([Cl:5])=[CH:11][CH:10]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: C1CNC1
Reactant: Clc1ccc(Cl)nn1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCO
Product: Clc1ccc(N2CCC2)nn1
Temperature: 25 °C
Reaction time: 216 h
Yield: 84.7 %

Procedure:
Azetidine (250 mg) was added to a stirred solution of 3,6-dichloropyridazine (650 mg) and N,N-diisopropyl-ethylamine (0.9 mL) in n-propanol (10 mL). The mixture was stirred at room temperature for 9 days and then concentrated. The solid residue was partitioned between ethyl acetate (100 mL) and water (10 mL). The organic layer was separated and washed with brine (10 mL), dried (Na2SO4), and concentrated to leave a white solid (627 mg). Chromatography on a 12-g silica gel cartridge (eluted with a 0-100% ethyl acetate in hexanes gradient) afforded the title compound as a white solid. Yield: 441 mg (59% of theory); 1H NMR (CDCl3) δ 2.47 (m, 2H), 4.13 (m, 4H), 6.48 (d, 1H), 7.16 (d, 1H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[C:4]1[C:9]([CH:10]=O)=[C:8]([O:12][Si:13]([CH3:21])([CH3:20])[C:14]([CH3:19])([CH3:18])[CH:15]([CH3:17])[CH3:16])[CH:7]=[C:6]([O:22][CH3:23])[C:5]=1[F:24].C([SiH](CC)CC)C>FC(F)(F)C(O)=O.ClCCl>[CH3:1][O:2][C:3](=[O:25])[C:4]1[C:9]([CH3:10])=[C:8]([O:12][Si:13]([CH3:20])([CH3:21])[C:14]([CH3:19])([CH3:18])[CH:15]([CH3:16])[CH3:17])[CH:7]=[C:6]([O:22][CH3:23])[C:5]=1[F:24]
Reactant: COC(=O)c1c(F)c(OC)cc(O[Si](C)(C)C(C)(C)C(C)C)c1C=O
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1c(C)c(O[Si](C)(C)C(C)(C)C(C)C)cc(OC)c1F
Reaction time: 18 h
Yield: 87.9 %

Procedure:
1H-NMR (250 MHz, CDCl3): δ 0.18 (s, 6H); 0.80 (d, 6H); 0.85 (s, 6H); 1.60 (m, 1H); 3.78 (s, 3H); 3.83 (s, 3H); 6.29 (d, 1H); 10.07 (d, 1H) ppm. (b) To a solution of 1.3 g of 2-fluoro-6-formyl-3-methoxy-5-[dimethyl-(1,1,2-trimethyl-propyl)-silanyloxy]-benzoic acid methyl ester in 4 ml of trifluoroacetic acid, cooled to 0° C., was added over 10 min a solution of 0.6 g of triethylsilane in 4 ml of dichloromethane. The solution was kept at 0° C. for 18 h and then evaporated in vacuo. The residue was taken up in ethyl acetate and the solution was successively washed with water, saturated sodium carbonate solution and brine, and dried over sodium sulfate. The solvent was evaporated in vacuo and the residue was chromatographed on silica gel using ethyl acetate/hexane (1:3, v/v) as eluent to yield 1.1 g of 2-fluoro-3-methoxy-6-methyl-5-[dimethyl-(1,1,2-trimethyl-propyl)-silanyloxy]-benzoic acid methyl ester as colorless oil.
Reaction SMILES: [CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([C:21]3[NH:25][C:24]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=4)=[CH:23][CH:22]=3)[CH2:14][CH:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.[Cl:32]N1C(=O)CCC1=O>O1CCCC1.C(OCC)(=O)C>[Cl:32][C:22]1[CH:23]=[C:24]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=2)[NH:25][C:21]=1[CH:13]([C:10]1[CH:9]=[CH:8][C:7]([S:4]([CH:1]2[CH2:2][CH2:3]2)(=[O:6])=[O:5])=[CH:12][CH:11]=1)[CH2:14][CH:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1
Reactant: O=C1CCC(=O)N1Cl
Reactant: O=S(=O)(c1ccc(C(CC2CCOCC2)c2ccc(-c3ccccn3)[nH]2)cc1)C1CC1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=S(=O)(c1ccc(C(CC2CCOCC2)c2[nH]c(-c3ccccn3)cc2Cl)cc1)C1CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 22.7 %

Procedure:
To a solution of 2-(5-{1-[4-(cyclopropylsulfonyl)phenyl]-2-(tetrahydro-2H-pyran-4-yl)ethyl}-1H-pyrrol-2-yl)pyridine (200 mg) in tetrahydrofuran (5 mL) was added N-chlorosuccinimide (61.2 mg) at 0° C., and the mixture was stirred overnight at room temperature, and further at 50° C. for 1 day. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate, and washed with saturated aqueous sodium hydrogen carbonate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and the title compound (49.0 mg, yield 23%) was obtained as a pale-yellow amorphous solid from a fraction eluted with ethyl acetate-hexane (2:1, volume ratio). MS: 471 (MH+).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][NH:11][C:12]3[CH:17]=[C:16](Cl)[N:15]=[C:14]([O:19][CH3:20])[N:13]=3)=[CH:9][C:4]=2[CH:3]=[CH:2]1.[C:21]([C:24]([C:27]1[CH:28]=[C:29](B(O)O)[CH:30]=[CH:31][CH:32]=1)([CH3:26])[CH3:25])([OH:23])=[O:22].C([O-])([O-])=O.[Cs+].[Cs+]>COCCOC.O.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>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][NH:11][C:12]3[N:13]=[C:14]([O:19][CH3:20])[N:15]=[C:16]([C:29]4[CH:28]=[C:27]([C:24]([CH3:26])([CH3:25])[C:21]([OH:23])=[O:22])[CH:32]=[CH:31][CH:30]=4)[CH:17]=3)=[CH:9][C:4]=2[CH:3]=[CH:2]1
Reactant: CC(C)(C(=O)O)c1cccc(B(O)O)c1
Reactant: COc1nc(Cl)cc(NCc2ccc3occc3c2)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: [Cs+]
Solvent: O
Solvent: COCCOC
Product: COc1nc(NCc2ccc3occc3c2)cc(-c2cccc(C(C)(C)C(=O)O)c2)n1
Temperature: 90 °C
Reaction time: 6 h
Yield: 34.2 %

Procedure:
Argon is bubbled through a mixture of benzofuran-5-ylmethyl-(6-chloro-2-methyoxy-pyrimidin-4-yl)-amine (100 mg, 0.35 mmol), 3-(1-carboxy-1-methyl-ethyl)-phenyl boronic acid [131 mg, 0.63 mmol, see Example 49(b) step 2], Cs2CO3 (342 mg, 1.05 mmol), and tetrakis(triphenylphosphine)palladium (0) (46 mg, 0.04 mmol) in ethylene glycol dimethyl ether (1.7 mL) and water (0.3 mL), for a period of 10 minutes. The reaction vessel is sealed and heated to 90° C. After stirring for 6 hours the heating is turned off and the mixture is allowed to cool to ambient temperature upon standing for 24 hours. The mixture is diluted with water (20 mL) and extracted twice with EtOAc (30 μL). The organic extracts are combined and dried over magnesium sulfate, filtered and concentrated to afford 2-(3-{6-[(benzofuran-5-ylmethyl)-amino]-2-methyoxy-pyrimidin-4-yl}-phenyl)-2-methyl-propionic acid [50 mg, 34%, Example 93] as a solid. LCMS RT=2.05 minutes, MS: 418 (M+H).
Reaction SMILES: [NH2:1][CH2:2][C:3]([NH2:5])=[O:4].CC[O-].[Na+].[CH2:10](Br)[CH:11]=[CH:12][CH3:13].[Br-].[Na+]>C(O)C>[CH2:10]([NH:5][C:3](=[O:4])[CH2:2][NH2:1])[CH:11]=[CH:12][CH3:13]
Reactant: NCC(N)=O
Reactant: CC=CCBr
Agent: CC[O-]
Agent: [Br-]
Agent: [Na+]
Solvent: CCO
Product: CC=CCNC(=O)CN
Temperature: 50 °C
Yield: 80.4 %

Procedure:
7.4 g of glycine amide and 6.8 g of sodium ethylate were charged into a 100 ml four-necked flask, and 30 ml of ethyl alcohol was added to the mixture. To the resulting solution was then added dropwise 13.5 g of crotyl bromide over a period of one hour at room temperature. After completion of the addition, the mixture was heated at a temperature of 50° C. for 2 hours. After completion of the reaction, sodium bromide which precipitated upon cooling the reaction mixture was removed by filtration and the solvent was removed by distillation under reduced pressure to obtain 10.3 g of the desired N-crotylglycine amide as a pale yellow oily substance having nD23.5 1.4991.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.[NH2:25][CH2:26][C:27]1[CH:36]=[CH:35][CH:34]=[C:33]2[C:28]=1[C:29](=[O:46])[N:30]([CH:38]1[CH2:43][CH2:42][C:41](=[O:44])[NH:40][C:39]1=[O:45])[C:31]([CH3:37])=[N:32]2>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([NH:25][CH2:26][C:27]2[CH:36]=[CH:35][CH:34]=[C:33]3[C:28]=2[C:29](=[O:46])[N:30]([CH:38]2[CH2:43][CH2:42][C:41](=[O:44])[NH:40][C:39]2=[O:45])[C:31]([CH3:37])=[N:32]3)=[O:11])=[CH:6][CH:7]=1
Reactant: O=C(O)Cc1ccc(Cl)cc1
Reactant: Cc1nc2cccc(CN)c2c(=O)n1C1CCC(=O)NC1=O
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: Cc1nc2cccc(CNC(=O)Cc3ccc(Cl)cc3)c2c(=O)n1C1CCC(=O)NC1=O
Reaction time: 1 h
Yield: 71.1 %

Procedure:
To a stirred solution of (4-chloro-phenyl)-acetic acid (0.31 g, 1.8 mmol) in DMF in a 40° C. oil bath (8 mL), was added 1.1′-carbonyldiimidazole (0.33 g, 2.0 mmol) and stirred for one hour. To the mixture, 3-(5-aminomethyl-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione hydrogen chloride (0.62 g, 1.8 mmol) was added, and the mixture was stirred for 15 minutes. The solvent was evaporated, and the residue was purified by flash column chromatography (Silica gel, methanol/methylene chloride 4%/96%) to give 2-(4-chloro-phenyl)-N-[3-(2,6-dioxo-piperidin-3-yl)-2-methyl-4-oxo-3,4-dihydro-quinazolin-5-ylmethyl]-acetamide as an off-white solid (580 mg, 70% yield); HPLC, Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 10/90 CH3CN/0.1% H3PO4, grad. to 95/5 in 5 min, kept 5 min, 6.10 min (98.5%); mp, 285° C. (decomposed); 1HNMR (DMSO-d6) 2.14-2.19 (m, 1H, CHH), 2.57-2.86 (m, 6H, CHCH2, CH3), 3.54 (s, 2H, ArCH2), 4.74-4.78 (m, 2H, CH2NH), 5.23 (dd, J=6, 11 Hz, 1H, CH), 7.26-7.72 (m, 7H, Ar), 8.39 (t, J=6 Hz, 1H, CH2NH), 11.02 (s, 1H, NH); 13C NMR (DMSO-d6) δ 20.74, 23.28, 30.59, 41.49, 41.72, 56.48, 117.68, 124.72, 125.59, 128.13, 130.92, 131.08, 133.82, 135.32, 140.64, 148.44, 154.80, 160.90, 169.50, 169.88, 172.59. LCMS MH=453, 455; Anal Calcd For C23H21N4O4Cl+0.15H2O+0.06 CH2Cl2: C, 60.12; H, 4.69; N, 12.16; Cl, 8.62. Found: C, 59.78; H, 4.60; N, 12.22; Cl, 9.00.
Reaction SMILES: C(O/[CH:4]=[C:5]1\[C:6](=O)[C:7]2[C:12]([O:13][C:14]3\1[CH2:19][CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16][CH2:15]3)=[CH:11][C:10]([F:27])=[CH:9][CH:8]=2)C.[ClH:29].[NH2:30][N:31](C)[C:32](=O)OC(C)(C)C.O1CCOCC1>>[ClH:29].[ClH:29].[F:27][C:10]1[CH:9]=[CH:8][C:7]2[C:6]3[N:31]([CH3:32])[N:30]=[CH:4][C:5]=3[C:14]3([CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[O:13][C:12]=2[CH:11]=1
Reactant: CCO/C=C1\C(=O)c2ccc(F)cc2OC12CCN(C(=O)OC(C)(C)C)CC2
Reactant: CN(N)C(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: Cn1ncc2c1-c1ccc(F)cc1OC21CCNCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 68.5 %

Procedure:
To tert-butyl (3Z)-3-(ethoxymethylene)-7-fluoro-4-oxo-spiro[chromane-2,4′-piperidine]-1′-carboxylate (2.6 g, 5.9 mmol) was added hydrochloric acid (22.3 mL, 89.1 mmol) (4 M in dioxane). The reaction mixture was allowed to stir at 25° C. for 2 hours. Solvent was removed under vacuum, and the obtained solid was dissolved in EtOH (3×25 mL) and the solvent was evaporated to dryness. The resulting beige-white solid was fully dissolved in ethanol (21 mL) at 25° C. prior to the addition of tert-butyl N-amino-N-methyl-carbamate (1.0 g, 7.1 mmol). The solution was allowed to stir at 25° C. overnight. To the thick beige-white slurry that formed was added hydrochloric acid, 4 M in dioxane (7.4 mL, 29.7 mmol). The mixture was heated at 60° C. to yield a clear yellow solution. After 1″hour at 60° C., a thick beige-white slurry developed. The slurry was allowed to slowly cool to 25° C. over 1 hour, and solids were collected by vacuum filtration. The cake was rinsed with a 10% solution of ethanol in hexanes (2×). Residual solvent was further removed under reduced pressure providing 7-fluoro-1-methyl-spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]dihydrochloride (1.4 g, 67%) as a light tan solid. ESI-MS m/z calc. 273.1. found 274.3 (M+1)+; Retention time: 1.59 minutes (3 min run). 1H NMR (400 MHz, MeOD) δ 7.80 (dd, J=8.7, 6.1 Hz, 1H), 7.45 (d, J=1.7 Hz, 1H), 7.00 (dd, J=9.8, 2.6 Hz, 1H), 6.91 (td, J=8.6, 2.6 Hz, 1H), 4.14 (s, 3H), 3.53-3.42 (m, 2H), 3.41-3.33 (m, 2H), 2.29 (d, J=13.9 Hz, 2H), 2.23-2.11 (m, 2H).
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:14]=[CH:13][C:12]([S:15]([CH3:18])(=[O:17])=[O:16])=[CH:11][C:7]=1[C:8]([OH:10])=O)[CH:2]([CH3:4])[CH3:3].FC(F)(F)C(O)=O.[F:26][C:27]([F:40])([F:39])[C:28]1[S:32][C:31]([N:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)=[N:30][N:29]=1>>[CH2:1]([O:5][C:6]1[CH:14]=[CH:13][C:12]([S:15]([CH3:18])(=[O:17])=[O:16])=[CH:11][C:7]=1[C:8]([N:36]1[CH2:35][CH2:34][N:33]([C:31]2[S:32][C:28]([C:27]([F:39])([F:26])[F:40])=[N:29][N:30]=2)[CH2:38][CH2:37]1)=[O:10])[CH:2]([CH3:3])[CH3:4]
Reactant: CC(C)COc1ccc(S(C)(=O)=O)cc1C(=O)O
Reactant: FC(F)(F)c1nnc(N2CCNCC2)s1
Solvent: O=C(O)C(F)(F)F
Product: CC(C)COc1ccc(S(C)(=O)=O)cc1C(=O)N1CCN(c2nnc(C(F)(F)F)s2)CC1

Procedure:
Prepared in analogy to example 1 (b) from 2-isobutoxy-5-methanesulfonyl-benzoic acid (Example A8) and 1-(5-trifluoromethyl-[1,3,4]thiadiazol-2-yl)-piperazine trifluoroacetate (Example 62(b)). The crude material was purified by chromatography (SiO2, dichloromethane/methanol 98:2) to yield the title compound as a colorless solid. MS (m/e): 493.4 (M+H+, 100%).
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([C:10]3[C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[C:12](=[O:19])[C:11]=3[C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:4][C:3]=2[O:2]1.[CH3:25][O:26][C:27]1[CH:28]=[C:29]([Mg]Br)[CH:30]=[CH:31][CH:32]=1>C1COCC1>[OH:19][C:12]1([C:31]2[CH:30]=[CH:29][CH:28]=[C:27]([O:26][CH3:25])[CH:32]=2)[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:10]([C:5]2[CH:6]=[CH:7][C:8]3[O:9][CH2:1][O:2][C:3]=3[CH:4]=2)=[C:11]1[C:20]([O:22][CH2:23][CH3:24])=[O:21]
Reactant: COc1cccc([Mg]Br)c1
Reactant: CCOC(=O)C1=C(c2ccc3c(c2)OCO3)c2ccccc2C1=O
Solvent: C1CCOC1
Product: CCOC(=O)C1=C(c2ccc3c(c2)OCO3)c2ccccc2C1(O)c1cccc(OC)c1
Reaction time: 0.25 h
Yield: 112.4 %

Procedure:
To a solution of ethyl 3-(3,4-methylenedioxyphenyl)-1-oxoindene-2-carboxylate (100 mg, 0.31 mmol) in THF (2 ml) under an argon atmosphere at 0° C. was added a solution of freshly prepared 3-methoxyphenyl magnesium bromide (0.31 mmol). After stirring for 15 min, additional 3-methoxyphenyl magnesium bromide (0.06 mmol) was added. Stirring was continued for 45 min, at which time thin layer chromatographic analysis indicated that the reaction was incomplete. Additional 3-methoxyphenyl magnesium bromide (0.12 mmol) was added. After stirring for 2 h more, the mixture was partitioned between 3M HCl and EtOAc. The organic extract was washed successively with H2O, 5% aqueous NaHCO3, H2O and saturated aqueous NaCl. The solvent was removed in vacuo, and the residue was purified by flash chromatography, eluting with 15% EtOAc/hexanes to afford the title compound (150 mg, 100%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH2:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[NH:8][C:7]=1[C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH3:2].[CH3:21][O:22][C:23](=[O:31])[C:24]1[CH:29]=[CH:28][CH:27]=[C:26](Br)[CH:25]=1.C([O-])([O-])=O.[K+].[K+]>CN1CCCC1=O.[Cu]Br>[CH2:18]([O:17][C:15]([C:7]1[N:8]([C:26]2[CH:27]=[CH:28][CH:29]=[C:24]([C:23]([O:22][CH3:21])=[O:31])[CH:25]=2)[C:9]2[C:14]([C:6]=1[CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:20])=[CH:13][CH:12]=[CH:11][CH:10]=2)=[O:16])[CH3:19]
Reactant: CCOC(=O)Cc1c(C(=O)OCC)[nH]c2ccccc12
Reactant: COC(=O)c1cccc(Br)c1
Agent: [Cu]Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: CCOC(=O)Cc1c(C(=O)OCC)n(-c2cccc(C(=O)OC)c2)c2ccccc12
Yield: 73.3 %

Procedure:
A solution of (2-ethoxycarbonyl-indol-3-yl)-acetic acid ethyl ester (J. Med. Chem. 1991, 34, 1283–1292, 2.2 g, 8.0 mmol), methyl-3-bromobenzoate (5.16 g, 24 mmol), anhydrous powdered K2CO3 (2.2 g, 16 mmol), and copper (I) bromide (2.3 g, 16 mmol) in N-methylpyrrolidone (NMP, 10 mL) was stirred at 170° C. overnight under inert atmosphere. The solvent was then removed by stream of nitrogen, and the residue was suspended in EtOAc (20 mL). The suspension was passed through a pad of silica gel using EtOAc-hexanes (1:2) as an eluent. The filtrate was concentrated in vacuo and purified by HPLC on LUNA 10μ silica column 25×250 mm with RI detector to afford 2.4 g of 3-ethoxycarbonylmethyl-1-(3-methoxycarbonyl-phenyl)-1H-indole-2-carboxylic acid ethyl ester as a white solid (73% yield): 1H NMR (CDCl3) δ 1.11 (t, J=7.3 Hz, 3H), 1.27 (t, J=7.1 Hz, 3H), 3.91 (s, 3H), 4.12–4.24 (m, 6H), 7.01–7.06 (m, 1H), 7.17–7.32 (m, 2H), 7.51–7.62 (m, 2H), 7.69–7.75 (m, 1H), 8.01–8.04 (m, 1H), 8.11–8.14 (m, 1H).
Reaction SMILES: [CH:1]1([C:7]([C:9]2[N:13]([CH3:14])[C:12]([S:15]([NH2:18])(=[O:17])=[O:16])=[CH:11][CH:10]=2)=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.NN.O.[OH-].[K+]>C(O)COCCO.O>[CH:1]1([CH2:7][C:9]2[N:13]([CH3:14])[C:12]([S:15]([NH2:18])(=[O:17])=[O:16])=[CH:11][CH:10]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: Cn1c(C(=O)C2CCCCC2)ccc1S(N)(=O)=O
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: OCCOCCO
Solvent: O
Product: Cn1c(CC2CCCCC2)ccc1S(N)(=O)=O
Yield: 44 %

Procedure:
To a solution of compound 25d (1.1 g, 4.1 mmol) in diethylene glycol (50 mL) was added NH2NH2.H2O (0.28 g, 4.5 mmol). The mixture was refluxed for 2 h and then the water and excess NH2NH2.H2O was removed under vacuum. Then KOH (0.46 g, 8.2 mmol) was added and the mixture was refluxed for 4 h, cooled, diluted with water and extracted with EA. The combined organic layers were washed with brine, dried over Na2SO4, evaporated and purified by prep-TLC to give compound 25e (462 mg, 46%).