Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N1CCCCC1.[C:7]([O:15][CH2:16][CH3:17])(=[O:14])[CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10].CO[CH2:20][O:21][C:22]1[CH:29]=[CH:28][C:25]([CH:26]=O)=[CH:24][CH:23]=1.C(OCC)(=O)C>C(O)C>[CH3:20][O:21][C:22]1[CH:29]=[CH:28][C:25]([CH:26]=[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:7]([O:15][CH2:16][CH3:17])=[O:14])=[CH:24][CH:23]=1
Reactant: COCOc1ccc(C=O)cc1
Reactant: CCOC(=O)CC(=O)OCC
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: C1CCNCC1
Product: CCOC(=O)C(=Cc1ccc(OC)cc1)C(=O)OCC

Procedure:
Piperidine (1.5 ml) and diethyl malonate (14.9 ml) were added to a solution of 4-methoxymethoxybenzaldehyde (16.2 g) in ethanol (160 ml). The mixture was heated at reflux for 7 hours. At the end of this time ethyl acetate was added to the reaction mixture and the ethyl acetate was washed with aqueous hydrogen chloride solution (0.8N) and saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate and then concentrated. The residue was purified via chromatography on a silica gel column using hexane/ethyl acetate=9/1-3/1 as the eluant to afford the desired compound (5.00 g) as a syrup.
Reaction SMILES: [OH-].[K+].[CH:3]([N:6]([CH:44]([CH3:46])[CH3:45])[C:7](=[O:43])[CH:8]=[C:9]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[N:22]=[N:23][C:24]1[CH:29]=[C:28]([CH3:30])[C:27]([O:31]S(C2C=CC(C)=CC=2)(=O)=O)=[C:26]([CH3:42])[CH:25]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([CH3:5])[CH3:4].Cl>C(O)C>[CH:44]([N:6]([CH:3]([CH3:5])[CH3:4])[C:7](=[O:43])[CH:8]=[C:9]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[N:22]=[N:23][C:24]1[CH:25]=[C:26]([CH3:42])[C:27]([OH:31])=[C:28]([CH3:30])[CH:29]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([CH3:46])[CH3:45]
Reactant: Cc1ccc(S(=O)(=O)Oc2c(C)cc(N=Nc3ccccc3C(=CC(=O)N(C(C)C)C(C)C)c3ccccc3)cc2C)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cc(N=Nc2ccccc2C(=CC(=O)N(C(C)C)C(C)C)c2ccccc2)cc(C)c1O

Procedure:
A solution of potassium hydroxide (10.3 mL, 6 M) and N,N-diisopropyl-3-[2-(3,5-dimethyl-4-tosyloxyphenylazo)phenyl]-3-phenylpropenamide (3.5 g, 5.74 mmol) in ethanol (110 mL) was refluxed for 1 h. The mixture was acidified with hydrochloric acid (conc.) and the solvent evaporated. The residue was partioned between toluene and water. The organic layer was dried (MgSO4) and the solvent evaporated. The crude residue was chromatographed on silica (toluene-ethyl acetate 9:2). Yield 1.3 g (50%). 1H NNR (CDCl3) δ0.71 (d, 3H), 0.80 (br, 3H), 1.27 (d, 3H), 1.40 (d, 3H), 2.20 (s, 3H), 2.23 (s, 3H), 3.25 (m, 1H), 4.35 (m, 1H), 5.52 (brd, 1H), 6.05 and 6.60 (s, 1H), 7.00-7.80 (m, 11H).
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[F:9].[S-:10][C:11]#[N:12].[NH4+].BrBr>CC(O)=O>[Br:1][C:2]1[C:3]([F:9])=[CH:4][C:5]2[N:6]=[C:11]([NH2:12])[S:10][C:7]=2[CH:8]=1
Reactant: Nc1ccc(Br)c(F)c1
Reactant: N#C[S-]
Agent: BrBr
Agent: [NH4+]
Solvent: CC(=O)O
Product: Nc1nc2cc(F)c(Br)cc2s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 57 %

Procedure:
To a solution of 4-bromo-3-fluoro-aniline (3.68 g, 19.37 mmol) in glacial AcOH (40 mL) was added ammonium thiocyanate (2.95 g, 38.74 mmol). When the reaction mixture was almost clear, it was placed in a cold water bath and a solution of bromine (3.1 g, 19.37 mmol) in glacial AcOH (10 mL) was added dropwise over a 10 min period. The reaction mixture was stirred at room temperature for 1 h, then it was concentrated in vacuo. The residue was partitioned between 1 N aqueous KOH and ethyl acetate. The aqueous layer was further extracted with ethyl acetate, and the combined organic layers were adsorbed on silica gel. Purification by flash chromatography on silica gel using a gradient of 0-70% ethyl acetate/hexane afforded 2.73 g of 6-bromo-5-fluoro-benzothiazol-2-ylamine as a light yellow solid (57% yield): 1H NMR (DMSO-d6) δ 7.29 (d, 1H), 7.78 (broad s, 2H), 7.99 (d, 1H); MS (m/z) 247, 249 [M+H+]+.
Reaction SMILES: BrC1C(C)(C)OC2C(C=1)=CC=C(OC)C=2.BrC1C=CC=CC=1[N+]([O-])=O.[CH3:26][O:27][C:28]1[CH:37]=[C:36]2[C:31]([CH:32]=[C:33]([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=3[N+:46]([O-])=O)[C:34]([CH3:39])([CH3:38])[O:35]2)=[CH:30][CH:29]=1>>[CH3:26][O:27][C:28]1[CH:37]=[C:36]2[C:31]([CH2:32][CH:33]([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=3[NH2:46])[C:34]([CH3:39])([CH3:38])[O:35]2)=[CH:30][CH:29]=1
Reactant: COc1ccc2c(c1)OC(C)(C)C(c1ccccc1[N+](=O)[O-])=C2
Agent: COc1ccc2c(c1)OC(C)(C)C(Br)=C2
Agent: O=[N+]([O-])c1ccccc1Br
Product: COc1ccc2c(c1)OC(C)(C)C(c1ccccc1N)C2
Yield: 80.7 %

Procedure:
Synthesized from 3-bromo-7-methoxy-2,2-dimethyl-2H-chromene and 1-bromo-2-nitrobenzene according to an analogous synthetic method to Preparation Example 107 described below, 7-methoxy-2,2-dimethyl-3-(2-nitrophenyl)-2H-chromene (790 mg) was used according to an analogous synthetic method to Example 30 to provide the title compound (580 mg).
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[C:6]([CH3:13])[C:5]=1[OH:14].[CH2:15]([N:22]1[C:30]2[C:29](Cl)=[N:28][C:27]([Cl:32])=[N:26][C:25]=2[CH:24]=[CH:23]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CN1C(=O)CCC1.O>[CH2:15]([N:22]1[C:30]2[C:29]([O:14][C:5]3[C:4]([CH3:3])=[CH:9][C:8]([N+:10]([O-:12])=[O:11])=[CH:7][C:6]=3[CH3:13])=[N:28][C:27]([Cl:32])=[N:26][C:25]=2[CH:24]=[CH:23]1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: Clc1nc(Cl)c2c(ccn2Cc2ccccc2)n1
Reactant: Cc1cc([N+](=O)[O-])cc(C)c1O
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: O
Product: Cc1cc([N+](=O)[O-])cc(C)c1Oc1nc(Cl)nc2ccn(Cc3ccccc3)c12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 94.4 %

Procedure:
To a stirred solution of NaH (61.9 mg, 2.6 mmol) in dry NMP (4.7 mL) was added 2,6-dimethyl-4-nitrophenol (258.9 mg, 1.55 mmol) and stirred at room temperature for 30 min under argon. The reaction mixture was added to a solution of 5-benzyl-2,4-dichloro-5H-pyrrolo[3,2-d]pyrimidine (431 mg, 1.55 mmol) in dry NMP (4 mL) and heated at 90° C. for 16 h. After completion of the reaction, the resulting mixture was diluted with water and washed with EtOAc. The combined organic layers were washed twice with water, washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel column chromatography, eluting with hexanes:ethyl acetate (3:1-1:1), to give the product as a white solid (598 mg, 94%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:39])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2([NH:16][C:17]3[N:22]=[C:21]([O:23][CH2:24][C:25]([F:28])([F:27])[F:26])[N:20]=[C:19]([NH:29][C:30]4[CH:38]=[CH:37][C:33]([C:34](O)=[O:35])=[CH:32][CH:31]=4)[N:18]=3)[CH2:15][CH2:14]2)=[CH:9][CH:8]=1)[CH3:2].[N:40]1([CH2:45][C:46]2([CH2:49][NH2:50])[CH2:48][CH2:47]2)[CH2:44][CH2:43][CH2:42][CH2:41]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[N:40]1([CH2:45][C:46]2([CH2:49][NH:50][C:34]([C:33]3[CH:32]=[CH:31][C:30]([NH:29][C:19]4[N:20]=[C:21]([O:23][CH2:24][C:25]([F:27])([F:28])[F:26])[N:22]=[C:17]([NH:16][C:13]5([C:10]6[CH:9]=[CH:8][C:7]([O:6][CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:39])=[CH:12][CH:11]=6)[CH2:15][CH2:14]5)[N:18]=4)=[CH:38][CH:37]=3)=[O:35])[CH2:48][CH2:47]2)[CH2:44][CH2:43][CH2:42][CH2:41]1
Reactant: NCC1(CN2CCCC2)CC1
Reactant: CCOC(=O)COc1ccc(C2(Nc3nc(Nc4ccc(C(=O)O)cc4)nc(OCC(F)(F)F)n3)CC2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)COc1ccc(C2(Nc3nc(Nc4ccc(C(=O)NCC5(CN6CCCC6)CC5)cc4)nc(OCC(F)(F)F)n3)CC2)cc1
Yield: 65 %

Procedure:
4-(4-(1-(4-(2-ethoxy-2-oxoethoxy)phenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzoic acid (330 mg, 0.603 mmol), (1-(pyrrolidin-1-ylmethyl)cyclopropyl)methanamine (112 mg, 0.723 mmol), HATU (344 mg, 0.904 mmol), and Hunig's Base (0.526 mL, 3.01 mmol) were stirred in DCM (Volume: 5 mL) for 16 h. The solvent was removed and the crude material was purified by silica gel chromatography using EtOAc then 5% DCM/MeOH to give ethyl 2-(4-(1-(4-(4-((1-(pyrrolidin-1-ylmethyl)cyclopropyl)methylcarbamoyl)phenylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)cyclopropyl)phenoxy)acetate (268 mg). LC-MS (Condition A), MS m/z (M++H) 684.1.
Reaction SMILES: [CH2:1]=[C:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[CH2:8][O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[CH2:17]1C2(CCC(C(OCC)=O)CC2)C1>>[CH2:10]([O:9][CH2:8][CH:3]1[CH2:4][CH2:5][CH2:6][CH2:7][C:2]21[CH2:17][CH2:1]2)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: CCOC(=O)C1CCC2(CC1)CC2
Reactant: C=C1CCCCC1COCc1ccccc1
Product: c1ccc(COCC2CCCCC23CC3)cc1

Procedure:
This intermediate was prepared from (((2-methylenecyclohexyl)methoxy)methyl)benzene by using the same protocol as described for ethyl spiro[2.5]octane-6-carboxylate (I-7A). 1H NMR (400 MHz, CDCl3) δ 7.35-7.31 (m, 4H), 7.29 (m, 1H) 4.49 (q, J=12.4 Hz, 2H), 3.52 (t, J=9.2 Hz, 1H), 3.41 (dd, J=9.2, 5.2 Hz, 1H), 1.72-1.67 (m, 1H), 1.49-1.43 (m, 4H), 1.33-1.26 (m, 1H), 0.88-0.85 (m, 1H), 0.37-0.31 (m, 2H), 0.19-0.14 (m, 2H). MS m/z 231.1 (M+1).
Reaction SMILES: Cl[CH2:2][C:3]([C:5]1[CH2:10][N:9]([C:11]([O:13][CH2:14][CH:15]=[CH2:16])=[O:12])[CH:8]([CH3:17])[CH2:7][CH:6]=1)=O.[C:18](=[S:21])([S-:20])[NH2:19].[NH4+]>CO.C(N)(=S)C1C=CN=CC=1>[CH3:17][CH:8]1[CH2:7][CH:6]=[C:5]([C:3]2[N:19]=[C:18]([SH:21])[S:20][CH:2]=2)[CH2:10][N:9]1[C:11]([O:13][CH2:14][CH:15]=[CH2:16])=[O:12]
Reactant: C=CCOC(=O)N1CC(C(=O)CCl)=CCC1C
Reactant: NC(=S)[S-]
Agent: NC(=S)c1ccncc1
Agent: [NH4+]
Solvent: CO
Product: C=CCOC(=O)N1CC(c2csc(S)n2)=CCC1C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 64 %

Procedure:
To a solution of allyl 5-(chloroacetyl)-2-methyl-3,6-dihydro-1(2 H)-pyridinecarboxylate (0.50 g, 1.94 mmol) in methanol (10 ml) were added at 0–5° C. thioisonicotinamide (5 mg) and ammonium dithiocarbamate (0.32 g, 2.9 mmol). The reaction mixture was raised to room temperature, stirred for 10 minutes and then stirred at 60–70° C. for 50 minutes. The solvent was removed in vacuo. To the residue was added an aqueous 1N NaOH solution to made alkaline. To the solution were added ethyl acetate and hexane and the solution was separated with a separating funnel. After 6N hydrochloric acid was added to the aqueous layer and ethyl acetate was added thereto, the mixture was again separated with a separating funnel. The aqueous layer was extracted with ethyl acetate. The organic layer was washed twice with a saturated aqueous sodium chloride solution, dried over magnesium sulfate and the solvent was removed in vacuo to give allyl 2-methyl-5-(2-mercapto-1,3-thiazol-4-yl)-3,6-dihydro-1(2 H)-pyridinecarboxylate (368 mg, 64%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][C:7]=1[C@H:13]1[CH2:17][CH2:16][CH2:15][N:14]1[C:18]1[CH:23]=[CH:22][N:21]2[N:24]=[CH:25][C:26]([CH2:27]O)=[C:20]2[N:19]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.ClC(Cl)(Cl)Cl>C(Cl)Cl>[F:12][C:9]1[CH:8]=[C:7]2[C:6](=[CH:11][CH:10]=1)[O:5][CH2:4][CH2:3][CH2:2][NH:1][CH2:27][C:26]1=[C:20]3[N:19]=[C:18]([CH:23]=[CH:22][N:21]3[N:24]=[CH:25]1)[N:14]1[C@@H:13]2[CH2:17][CH2:16][CH2:15]1
Reactant: NCCCOc1ccc(F)cc1[C@H]1CCCN1c1ccn2ncc(CO)c2n1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: ClC(Cl)(Cl)Cl
Product: Fc1ccc2c(c1)[C@H]1CCCN1c1ccn3ncc(c3n1)CNCCCO2
Temperature: 25 °C
Reaction time: 8 h
Yield: 57.4 %

Procedure:
A mixture of (R)-(5-(2-(2-(3-aminoprop oxy)-5-fluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl)methanol (50 mg, 0.130 mmol), PS—PPh3 (0.259 mmol) and perchloromethane (200 mg, 1.30 mmol) in DCM (5 mL) was shaken at ambient temperature overnight. The reaction was filtered, concentrated and purified by reverse-phase column chromatography eluting with 0-60% acetonitrile/H2O to yield the title product (27.4 mg, 57.5% yield). MS (apci) m/z=368.1 (M+H).
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:14]([OH:16])=[O:15])[CH2:10][CH:11]([CH3:13])[CH3:12])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[NH2:17][C@H:18]([C:23]([OH:25])=O)[CH2:19][CH:20]([CH3:22])[CH3:21].Cl.[CH3:27][NH:28][O:29][CH3:30].O.ON1C2C=CC=CC=2N=N1.CN1CCOCC1.Cl.C(N=C=NCCCN(C)C)C>CN(C=O)C>[C:1]([NH:8][C@H:9]([C:14]([OH:16])=[O:15])[CH2:10][CH:11]([CH3:12])[CH3:13])([O:3][C:4]([CH3:6])([CH3:5])[CH3:7])=[O:2].[CH3:27][N:28]([O:29][CH3:30])[C:23](=[O:25])[C@H:18]([CH2:19][CH:20]([CH3:22])[CH3:21])[NH2:17]
Reactant: CC(C)C[C@H](N)C(=O)O
Reactant: CNOC
Agent: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Solvent: CN1CCOCC1
Product: CON(C)C(=O)[C@@H](N)CC(C)C
Reaction time: 40 h

Procedure:
A mixture of N-Boc-L-leucine-L-leucine (1 g), N,O-dimethylhydroxylamine hydrochloride (423 mg), 1-hydroxybenzotriazole monohydrate (509 mg), and N-methylmorpholine (0.42 mL) was dissolved in DMF (20 mL). 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (610 mg) was added at 0° C. for 2 h, then at room temperature for 40 h. The reaction was quenched with water (80 mL) and the mixture was extracted with EtOAc (3×100 mL). The combined organic layers were washed with aqueous 10% HCl, saturated NaHCO3, and brine then dried over anhydrous MgSO4, filtered, and evaporated to afford the product (923 mg) as a white solid.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[N:13]=[CH:12][CH:11]=[CH:10]2)(=O)=O.C(N(C(C)C)CC)(C)C.[CH3:28][Si:29]([CH3:50])([CH3:49])[CH2:30][CH2:31][O:32][CH2:33][N:34]1[CH:38]=[C:37]([C:39]2[CH:40]=[CH:41][C:42]3[N:43]([C:45]([SH:48])=[N:46][N:47]=3)[N:44]=2)[CH:36]=[N:35]1.C>CN(C=O)C>[CH3:28][Si:29]([CH3:50])([CH3:49])[CH2:30][CH2:31][O:32][CH2:33][N:34]1[CH:38]=[C:37]([C:39]2[CH:40]=[CH:41][C:42]3[N:43]([C:45]([S:48][C:7]4[CH:8]=[C:9]5[C:14](=[CH:15][CH:16]=4)[N:13]=[CH:12][CH:11]=[CH:10]5)=[N:46][N:47]=3)[N:44]=2)[CH:36]=[N:35]1
Reactant: O=S(=O)(Oc1ccc2ncccc2c1)C(F)(F)F
Reactant: C[Si](C)(C)CCOCn1cc(-c2ccc3nnc(S)n3n2)cn1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C[Si](C)(C)CCOCn1cc(-c2ccc3nnc(Sc4ccc5ncccc5c4)n3n2)cn1
Temperature: 70 °C
Yield: 37.1 %

Procedure:
A solution of 6-quinolinyl trifluoromethanesulfonate (436 mg, 1.57 mmol), diisopropylethylamine (0.746 mL, 4.29 mmol) in DMF (3.8 mL) under nitrogen was degassed by bubbling in nitrogen for 30 min. Tris(dibenzylideneacetone)dipalladium (33 mg, 2.5 mol %, Strem catalyst) and Xantphos (41 mg, 5 mol %) were added together in one portion, followed by 6-[1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazol-4-yl]-[1,2,4]triazolo[4,3-b]pyridazine-3-thiol (498 mg, 1.43 mmol) under a stream of nitrogen. The reaction mixture was stirred at 100° C. for 3 h before 500 mg of activated decolorizing charcoal were added. The suspension was stirred at 70° C. for 20, then the warm mixture was directly filtered through a plug of celite, using DMF as eluent. The solvent was evaporated in vacuo and the residue taken up in dichloromethane and washed with 1N aqueous NaOH and concentrated onto silica gel and purified by flash column chromatography eluting with dichloromethane:methanol 100:0 to 92:8 to return title compound as a light yellow foam (250 mg, 0.53 mmol, 37% yield): 1H NMR (DMSO-d6) δ 0.00 (9H, s), 0.90 (2H, t), 3.62 (2H, t), 5.54 (2H, s), 7.62 (1H, dd), 7.83 (1H, dd), 7.91 (1H, d), 8.07 (1H, d), 8.18 (1H, s), 8.23 (1H, d), 8.43 (1H, dd), 8.57 (1H, d), 8.75 (1H, d), 8.96 (1H, dd); MS (m/z) 476 [M+H]+.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.C[N+](C)=CCl.[Cl-].C(Cl)(=O)[C:17](Cl)=[O:18]>CN(C)C=O>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[CH:17]=[O:18]
Reactant: c1ccc2[nH]ccc2c1
Reactant: O=C(Cl)C(=O)Cl
Agent: C[N+](C)=CCl
Agent: [Cl-]
Solvent: CN(C)C=O
Product: O=Cc1cc2ccccc2[nH]1

Procedure:
In Step 1 of Scheme F, indole compound a is treated with the Vilsmeier reagent formed by mixing oxalyl chloride with dimethyl formamide to form indole aldehyde w, which in turn is reacted with Meldrum's acid in Step 2 to yield indole compound x. Indole x is then treated with Grignard reagent y in Step 3 to afford indole compound z. In Step 4 compound z is reacted with amine d in the presence of pyridine to give indole amide r, which is then reduced in Step 5 to provide aminopropyl indole compound s. Compound s is a compound of formula I in accordance with the invention.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:6][C@H:7]1[CH2:26][CH2:25][C@@:24]2([CH3:27])[C@@H:9]([CH2:10][CH2:11][C:12]3[C:13]4[C@:20]([CH3:28])([CH2:21][CH2:22][C:23]=32)[C@@H:16]([C@H:17]([OH:19])[CH3:18])[CH2:15][CH:14]=4)[C:8]1([CH3:30])[CH3:29])[CH3:5])[CH3:2].CC(C)([O-])C.[K+].C1OCCOCCOCCOCCOCCOC1.[CH2:55](Br)[C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1>O.C1(C)C=CC=CC=1>[CH2:1]([O:3][CH:4]([O:6][C@H:7]1[CH2:26][CH2:25][C@@:24]2([CH3:27])[C@@H:9]([CH2:10][CH2:11][C:12]3[C:13]4[C@:20]([CH3:28])([CH2:21][CH2:22][C:23]=32)[C@@H:16]([C@H:17]([O:19][CH2:55][C:56]2[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=2)[CH3:18])[CH2:15][CH:14]=4)[C:8]1([CH3:30])[CH3:29])[CH3:5])[CH3:2]
Reactant: CCOC(C)O[C@H]1CC[C@]2(C)C3=C(CC[C@H]2C1(C)C)C1=CC[C@H]([C@@H](C)O)[C@@]1(C)CC3
Reactant: BrCc1ccccc1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(C)O[C@H]1CC[C@]2(C)C3=C(CC[C@H]2C1(C)C)C1=CC[C@H]([C@@H](C)OCc2ccccc2)[C@@]1(C)CC3
Temperature: 70 °C

Procedure:
v)—A mixture of (3β,5α,20R)-3-[(1-ethoxyethyl)oxy]-4,4-dimethylpregna-8,14-dien-20-ol (19b; 0.80 g), dry toluene (56 ml), potassium t-butoxide (2.76 g), 18-crown-6 (0.48 g) and benzyl bromide (1.13 ml) was heated at 70° C. for 1 h. After cooling, the reaction mixture was poured into water and the product extracted into ethyl acetate. The combined organic phases were washed with water and with brine, dried over sodium sulfate, and concentrated under reduced pressure to give (3β,5α,20R)-3-[(1-ethoxyethyl)oxy]-4,4-dimethyl-20-(phenylmethoxy)pregna-8,14-diene (compound 20b; 1.92 g), which was used in the following step without further purification.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][O:12][C:13]=2[NH2:14])=[CH:5][CH:4]=1.[CH3:17][O:18][C:19]1[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[C:20]=1[C:21](Cl)=[O:22]>C1(C)C=CC=CC=1>[CH3:29][O:28][C:24]1[CH:25]=[CH:26][CH:27]=[C:19]([O:18][CH3:17])[C:20]=1[C:21]([NH:14][C:13]1[O:12][N:11]=[CH:10][C:9]=1[C:6]1[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:15])[F:16])=[CH:8][CH:7]=1)=[O:22]
Reactant: Nc1oncc1-c1ccc(C(F)(F)F)cc1
Reactant: COc1cccc(OC)c1C(=O)Cl
Solvent: Cc1ccccc1
Product: COc1cccc(OC)c1C(=O)Nc1oncc1-c1ccc(C(F)(F)F)cc1

Procedure:
4-(4-(Trifluoromethyl)phenyl)-5-aminoisoxazole (1.0 g) and 2,6-dimethoxybenzoylchloride (2 g) were refluxed in 100 ml. toluene for 3 hours. The reaction mixture was cooled and the final product was then collected and recrystallized from ethanol, m.p. 199°-201° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([C:11]([S:20]C#N)([CH:17]([CH3:19])[CH3:18])[C:12]([O:14][CH2:15][CH3:16])=[O:13])[N:4]=1.FC(F)(F)C(O)=O>ClCCl>[CH3:10][O:9][C:7]1[CH:8]=[C:3]([O:2][CH3:1])[N:4]=[C:5]([C:11]([SH:20])([CH:17]([CH3:19])[CH3:18])[C:12]([O:14][CH2:15][CH3:16])=[O:13])[N:6]=1
Reactant: CCOC(=O)C(SC#N)(c1nc(OC)cc(OC)n1)C(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)C(S)(c1nc(OC)cc(OC)n1)C(C)C
Temperature: 25 °C
Reaction time: 24 h
Yield: 33.9 %

Procedure:
A mixture of the product of Example 16 (0.8 g), trifluoroacetic acid (1 ml) and dichloromethane (10 ml) was stirred at room temperature for 24 hours, and was then washed with water and aqueous sodium bicarbonate. The organic layer was dried, evaporated to dryness under vacuum, and flash chromatographed on silica gel, eluting with ethyl acetate/60°-80° petroleum ether, to give 0.25 g of the desired product which partly solidified.
Reaction SMILES: C([O:3][C:4](=[O:33])[CH:5]([O:30][CH2:31][CH3:32])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]2[S:19][C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH3:27])[CH:21]=3)=[N:17][C:16]=2[CH3:28])=[CH:9][C:8]=1[CH3:29])C.[Li+].[OH-]>>[CH2:31]([O:30][CH:5]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]2[S:19][C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH3:27])[CH:21]=3)=[N:17][C:16]=2[CH3:28])=[CH:9][C:8]=1[CH3:29])[C:4]([OH:33])=[O:3])[CH3:32]
Reactant: CCOC(=O)C(Cc1ccc(OCc2sc(-c3cccc(OC)c3)nc2C)cc1C)OCC
Agent: [Li+]
Agent: [OH-]
Product: CCOC(Cc1ccc(OCc2sc(-c3cccc(OC)c3)nc2C)cc1C)C(=O)O

Procedure:
In analogy to the procedure described in example 10 d], [rac]-2-ethoxy-3-{4-[2-(3-methoxy-phenyl)-4-methyl-thiazol-5-ylmethoxy]-2-methyl-phenyl}-propionic acid ethyl ester was treated with LiOH to obtain [rac]-2-ethoxy-3-{4-[2-(3-methoxy-phenyl)-4-methyl-thiazol-5-ylmethoxy]-2-methyl-phenyl}-propionic acid as colorless foam.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:6]([CH3:21])[C:7](=[O:20])[C:8]3([CH2:19][CH2:18]3)[CH2:9][N:10]([CH:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)[C:11]=2[N:12]=1.[NH2:22][C:23]1[CH:36]=[CH:35][C:26]([C:27]([NH:29][CH2:30][CH2:31][N:32]([CH3:34])[CH3:33])=[O:28])=[CH:25][C:24]=1[Cl:37].C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>O1CCOCC1.C(Cl)Cl>[Cl:37][C:24]1[CH:25]=[C:26]([CH:35]=[CH:36][C:23]=1[NH:22][C:2]1[N:3]=[CH:4][C:5]2[N:6]([CH3:21])[C:7](=[O:20])[C:8]3([CH2:19][CH2:18]3)[CH2:9][N:10]([CH:13]3[CH2:14][CH2:15][CH2:16][CH2:17]3)[C:11]=2[N:12]=1)[C:27]([NH:29][CH2:30][CH2:31][N:32]([CH3:34])[CH3:33])=[O:28]
Reactant: CN(C)CCNC(=O)c1ccc(N)c(Cl)c1
Reactant: CN1C(=O)C2(CC2)CN(C2CCCC2)c2nc(Cl)ncc21
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Solvent: C1COCCO1
Product: CN(C)CCNC(=O)c1ccc(Nc2ncc3c(n2)N(C2CCCC2)CC2(CC2)C(=O)N3C)c(Cl)c1
Temperature: 100 °C
Yield: 4.1 %

Procedure:
2′-chloro-9′-cyclopentyl-5′-methyl-8′,9′-dihydrospiro[cyclopropane-1,7′-pyrimido[5,4-b][1,4]diazepin]-6′(5′H)-one (Intermediate 130; 100 mg, 0.33 mmol) and 4-amino-3-chloro-N-(2-dimethylaminoethyl)benzamide (Intermediate 213; 89 mg, 0.37 mmol) were dissolved in 1,4 dioxane (4 mL) and caesium carbonate (234 mg, 0.72 mmol) was added. The reaction mixture was sparged with nitrogen for 15 minutes prior to addition of tris-dibenzylideneacetone dipalladium (II) (19 mg, 0.02 mmol) followed by XANTPHOS (19 mg, 0.03 mmol). The reaction mixture was heated at 100° C. overnight, cooled to room temperature and diluted with DCM (20 mL). The resultant mixture was filtered and the filtrate loaded onto an SCX-3 (5 g) cartridge. The cartridge was washed through with methanol (50 mL) and then eluted with 2M ammonia in methanol (50 mL). Evaporation of the ammoniacal fraction afforded an amber gum which was purified by acid modified reverse phase preparative HPLC. The resultant material was dissolved in MeOH/Water and poured onto an SCX-3 cartridge (2 g) and cartridge which was then washed with methanol and eluted with 2M ammonia in methanol, and the ammoniacal solution evaporated to yield the title compound as a solid (7 mg, 3%).
Reaction SMILES: [CH3:1][N:2]([CH3:22])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]2[CH:13]=[CH:14][C:15]3[N:16]([C:18]([CH3:21])=[N:19][N:20]=3)[N:17]=2)[CH:7]=1)=[O:4].[H-].[Na+].CI.[C:27](=O)(O)[O-].[Na+]>CN(C)C=O>[CH3:1][N:2]([CH3:22])[C:3]([N:5]([CH3:27])[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]2[CH:13]=[CH:14][C:15]3[N:16]([C:18]([CH3:21])=[N:19][N:20]=3)[N:17]=2)[CH:7]=1)=[O:4]
Reactant: Cc1nnc2ccc(-c3cccc(NC(=O)N(C)C)c3)nn12
Reactant: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Product: Cc1nnc2ccc(-c3cccc(N(C)C(=O)N(C)C)c3)nn12
Reaction time: 0.5 h

Procedure:
A suspension of 1.0 g of N,N-dimethyl-N'-[3-(3-methyl-1,2,4-triazolo[4,3-b]pyridazin-6-yl)phenyl]urea and 0.09 g of sodium hydride in 100 ml of dry dimethylformamide was stirred for 30 minutes, then 0.23 ml of methyl iodide was added. This solution was stirred overnight, then poured into saturated aqueous sodium bicarbonate and extracted with four 100 ml portions of dichloromethane. The extracts were combined and treated as described in Example 19, giving 0.8 g of the desired product as off-white crystals mp 159°-6° C.