Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH2:7].[Cl:9][C:10]1[CH:21]=[CH:20][C:13]([O:14][C:15]([N:17]=[C:18]=[S:19])=[O:16])=[CH:12][CH:11]=1>>[Cl:9][C:10]1[CH:21]=[CH:20][C:13]([O:14][C:15]([NH:17][C:18](=[S:19])[NH:7][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=2[NH:8][C:18]([NH:17][C:15]([O:14][C:13]2[CH:20]=[CH:21][C:10]([Cl:9])=[CH:11][CH:12]=2)=[O:16])=[S:19])=[O:16])=[CH:12][CH:11]=1
Reactant: Nc1ccccc1N
Reactant: O=C(N=C=S)Oc1ccc(Cl)cc1
Product: O=C(NC(=S)Nc1ccccc1NC(=S)NC(=O)Oc1ccc(Cl)cc1)Oc1ccc(Cl)cc1

Procedure:
3.3 g. of o-phenylenediamine were dropped into the mixture containing the resulting 4-chlorophenoxycarbonylisothiocyanate at a temperature of 0°-20° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[C:5]1[CH:15]=[C:14]([F:16])[CH:13]=[C:7]([C:8]([O:10]CC)=[O:9])[C:6]=1[O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH3:2].[OH-].[Na+]>C(O)C>[CH2:1]([O:3][C:4](=[O:25])[C:5]1[CH:15]=[C:14]([F:16])[CH:13]=[C:7]([C:8]([OH:10])=[O:9])[C:6]=1[O:17][CH2:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[CH3:2]
Reactant: CCOC(=O)c1cc(F)cc(C(=O)OCC)c1OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)c1cc(F)cc(C(=O)O)c1OCc1ccccc1
Reaction time: 1 h

Procedure:
25.63 g (74 mmol) of 2-benzyloxy-5-fluoroisophthalic acid diethyl ester is dissolved in 200 ml of dry ethanol with exclusion of moisture and a solution of 1.48 g of sodium hydroxide in 50 ml of ethanol is instilled into this solution in the course of 2 hours at room temperature. The monosodium salt gradually precipitates. When the instillation is completed, it is stirred for 1 hour more, the precipitate is suctioned off and the filtrate is concentrated by evaporation to about half. In this process additional monosodium salt precipitates which is also suctioned off. The two filter residues are combined, suspended in water and the suspension is acidified with concentrated hydrochloric acid. The monoacid is shaken out with ethyl acetate, the ethyl acetate solution is dried on sodium sulfate, filtered and concentrated by evaporation. The solid residue is dried in a vacuum at 50° C. 14.93 g (46.92 mmol)=63.4% of the theoretical yield is obtained as a partially crystalline, partially amorphous solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C(#N)C.CS(O[CH:17]1[CH2:20][N:19]([CH:21]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:18]1)(=O)=O>>[CH:21]([N:19]1[CH2:20][CH:17]([O:8][C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[CH2:18]1)([C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: CS(=O)(=O)OC1CN(C(c2ccccc2)c2ccccc2)C1
Reactant: Oc1ccc(F)cc1
Solvent: CC#N
Product: Fc1ccc(OC2CN(C(c3ccccc3)c3ccccc3)C2)cc1
Temperature: 100 °C
Reaction time: 0.08 h

Procedure:
To a stirred solution of 4-fluorophenol (0.80 g, 7.16 mmol) in acetonitrile (15 ml) potassium carbonate (1.3 g, 9.30 mmol) was added followed by the addition of 1-benzhydrylazetidin-3-yl methanesulfonate (D19) (2.5 g, 7.87 mmol) and the mixture was stirred under microwave irradiation at 100° C. for 5 mins. The reaction mixture was evaporated in vacuo and the residue was taken up in a mixture diethylether/water (10 ml/10 ml). The aqueous layer was extracted with diethylether (2×10 ml). The organics after solvent evaporation were loaded on SPE-Si (25 g) cartridge eluting with a mixture cyclohexane/ethylacetate (from 100/0 to 85/15. Collected fractions gave, after evaporation, the title compound (D21) (1.8 g).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]([O:12][CH3:13])=[O:11])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.Br[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=1[F:23].[H-].[Na+].CO>CN(C=O)C>[F:23][C:17]1[CH:18]=[C:19]([F:22])[CH:20]=[CH:21][C:16]=1[CH2:15][N:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]([O:12][CH3:13])=[O:11])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: Fc1ccc(CBr)c(F)c1
Reactant: COC(=O)c1ccc2[nH]ccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: COC(=O)c1ccc2c(ccn2Cc2ccc(F)cc2F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.2 %

Procedure:
To a solution of methyl 1H-indole-5-carboxylate (2 g, 11.4 mmol, 1 equiv) and 1-(bromomethyl)-2,4-difluorobenzene (1.61 mL, 12.6 mmol, 1.1 equiv) in anhydrous DMF (50 mL) under argon atmosphere was added sodium hydride (913 mg, 22.8 mmol, 2 equiv) in small portions. The mixture was stirred 2 h at room temperature. The reaction mixture was then neutralized by addition of methanol and concentrated in vacuo. The residue was dissolved in AcOEt, washed with brine and dried over MgSO4. The crude was purified by flash chromatography (Hexane/AcOEt 7/3) to afford the title compound as a colorless oil (3.14 g, 10.4 mmol, 91%). ESI-MS (m/z): 302 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:30][C@H:31]2[CH2:36][CH2:35][CH2:34][CH2:33][C@@H:32]2[C:37]2[C:38]([N+:48]([O-])=O)=[N:39][N:40](C3CCCCO3)[CH:41]=2)=[CH:4][C:5]([F:29])=[C:6]([S:8]([N:11](CC2C=CC(OC)=CC=2OC)[C:12]2[CH:17]=[CH:16][N:15]=[CH:14][N:13]=2)(=[O:10])=[O:9])[CH:7]=1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O.ClCCl>CO>[NH2:48][C:38]1[C:37]([C@H:32]2[CH2:33][CH2:34][CH2:35][CH2:36][C@@H:31]2[O:30][C:3]2[C:2]([Cl:1])=[CH:7][C:6]([S:8]([NH:11][C:12]3[CH:17]=[CH:16][N:15]=[CH:14][N:13]=3)(=[O:9])=[O:10])=[C:5]([F:29])[CH:4]=2)=[CH:41][NH:40][N:39]=1
Reactant: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2cc(Cl)c(O[C@H]3CCCC[C@@H]3c3cn(C4CCCCO4)nc3[N+](=O)[O-])cc2F)c(OC)c1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CO
Product: Nc1n[nH]cc1[C@H]1CCCC[C@@H]1Oc1cc(F)c(S(=O)(=O)Nc2ccncn2)cc1Cl
Yield: 95.8 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 22c by using the 5-chloro-N-(2,4-dimethoxybenzyl)-2-fluoro-4-({(1S*,2R*)-2-[3-nitro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl]cyclohexyl}oxy)-N-(pyrimidin-4-yl)benzenesulfonamide (264 mg, 0.362 mmol) prepared in Example 71a, triethylsilane (0.10 mL), trifluoroacetic acid (0.5 mL), dichloromethane (2.0 mL) and methanol (1.0 mL), to yield the title compound (162 mg, 90%) as a white solid.
Reaction SMILES: B.C([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)C1C=CC=CC=1.[NH2:17][C:18]1C=CC=C[CH:19]=1.C(OC=C(C(OCC)=O)C(OCC)=O)C.C1(OC2C=CC=CC=2)C=CC=CC=1>>[OH:9][C:10]1[C:11]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:17]=[CH:18][CH:19]=1
Reactant: Nc1ccccc1
Reactant: c1ccc(COCc2ccccc2)cc1
Agent: B
Agent: CCOC=C(C(=O)OCC)C(=O)OCC
Solvent: c1ccc(Oc2ccccc2)cc1
Product: Oc1ccnc2ccccc12

Procedure:
In CHART C, carboxylic acid C-1, 3-methyl-3-(4-nitrophenyl)butanoic acid prepared by carbonylation of the corresponding Grignard, is reduced to the corresponding alcohol with borane. The resulting alcohol C-2 is protected as the benzyl ether and the corresponding nitro functionality is reduced to aniline C-3. Heating C-3 with diethyl ethoxymethylenemalonate followed by thermolysis in refluxing diphenylether affords the 4-hydroxyquinoline C-4. Aminolysis of compound C-4 with 4-chlorobenzylamine at about 190 ° C. provides amide C-5 which is then alkylated at the pyridone nitrogen with an alkylhalide and potassium carbonate to afford compound C-6. Deprotection of the benzyl ether under hydrogenolysis conditions affords the desired hydroxyalkyl 4-quinolone carboxamide of formula I of the present invention.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([S:6]([OH:9])(=O)=[O:7])[CH:3]=[N:2]1.P(Cl)(Cl)(Cl)(Cl)[Cl:11]>C1(C)C=CC=CC=1>[NH:1]1[CH:5]=[C:4]([S:6]([Cl:11])(=[O:9])=[O:7])[CH:3]=[N:2]1
Reactant: O=S(=O)(O)c1cn[nH]c1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: O=S(=O)(Cl)c1cn[nH]c1
Temperature: 180 °C

Procedure:
A mixture of 1H-pyrazole-4-sulfonic acid (J. Am. Chem. Soc.; 1955, 77, 6532) (1.0 g, 4.0 mmol) and phosphorous pentachloride (1.6 g, 7.7 mmol) were heated up to 180° C. over the period of an hour. The mixture began to reflux but not fully molten. The reaction mixture was cooled to 130° C. and toluene (5 ml) was added and allowed to cool to room temperature with stirring. The white solid was filtered off. The filtrate solvent was removed under reduced pressure and azeotroped with toluene and DCM to afford the title compound as a colourless oil and impure.
Reaction SMILES: BrC1C(N2CCN(C(C3C=CC=CN=3)C)CC2)=C([N+]([O-])=O)C(N)=NC=1.[N:26]1[CH:31]=[C:30]([CH2:32][N:33]2[CH2:38][CH2:37][N:36]([C:39](OC(C)(C)C)=O)[CH2:35][CH2:34]2)[CH:29]=[N:28][CH:27]=1.C(O)(C(F)(F)F)=O.ClC1[C:59]([Cl:60])=[CH:58][N:57]=[C:56]([NH2:61])[C:55]=1[N+:62]([O-:64])=[O:63]>CC(O)C.CCN(C(C)C)C(C)C.C(Cl)Cl>[Cl:60][C:59]1[C:39]([N:36]2[CH2:35][CH2:34][N:33]([CH2:32][C:30]3[CH:29]=[N:28][CH:27]=[N:26][CH:31]=3)[CH2:38][CH2:37]2)=[C:55]([N+:62]([O-:64])=[O:63])[C:56]([NH2:61])=[N:57][CH:58]=1
Reactant: Nc1ncc(Cl)c(Cl)c1[N+](=O)[O-]
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2cncnc2)CC1
Agent: CC(c1ccccn1)N1CCN(c2c(Br)cnc(N)c2[N+](=O)[O-])CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: CC(C)O
Product: Nc1ncc(Cl)c(N2CCN(Cc3cncnc3)CC2)c1[N+](=O)[O-]

Procedure:
This was prepared using the same procedure as for 5-bromo-3-nitro-4-(4-(1-(pyridin-2-yl)ethyl)piperazin-1-yl)pyridin-2-amine, but here using tert-butyl 4-(pyrimidin-5-ylmethyl)piperazine-1-carboxylate (1.1 eq, 0.13 mmol, 35 mg), TFA (0.25 mL) and CH2Cl2 (1 mL), then 4,5-dichloro-3-nitropyridin-2-amine (37 mg, 0.11 mmol) in iPrOH (1 mL) and DIPEA (0.25 mL). Filtration and washing as previously described gave the product (22 mg, 50% for two steps) as a yellow solid; δH (500 MHz, DMSO-d6) 2.52 (s, br, 4H, piperazine N(CH2)2), 3.07 (t, J=4.5 Hz, 4H, piperazine N(CH2)2), 3.60 (s, 2H, CH2), 6.95 (s, br, 2H, NH2), 8.06 (s, 1H, pyridine H-6), 8.75 (s, 2H, pyrimidine H-4 & H-6), 9.10 (s, 1H, pyrimidine H-2);
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]([C:26]2[CH:31]=[CH:30][C:29]([O:32][CH:33]([CH3:35])[CH3:34])=[CH:28][CH:27]=2)[C:8]2[C:13]([CH:14]=1)=[C:12]([NH2:15])[C:11]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH:23]([CH3:25])[CH3:24])=[CH:18][CH:17]=1)=[CH:10][CH:9]=2)=[O:5])[CH3:2].[C:36](Cl)(=[O:38])[CH3:37].CCN(CC)CC.Cl>CC#N>[CH2:1]([O:3][C:4]([C:6]1[N:7]([C:26]2[CH:31]=[CH:30][C:29]([O:32][CH:33]([CH3:34])[CH3:35])=[CH:28][CH:27]=2)[C:8]2[C:13]([CH:14]=1)=[C:12]([NH:15][C:36](=[O:38])[CH3:37])[C:11]([C:16]1[CH:17]=[CH:18][C:19]([O:22][CH:23]([CH3:25])[CH3:24])=[CH:20][CH:21]=1)=[CH:10][CH:9]=2)=[O:5])[CH3:2]
Reactant: CC(=O)Cl
Reactant: CCOC(=O)c1cc2c(N)c(-c3ccc(OC(C)C)cc3)ccc2n1-c1ccc(OC(C)C)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCOC(=O)c1cc2c(NC(C)=O)c(-c3ccc(OC(C)C)cc3)ccc2n1-c1ccc(OC(C)C)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 104 %

Procedure:
A mixture of 4-amino-1,5-bis(4-isopropoxyphenyl)indole-2-carboxylic acid ethyl ester (160 mg, 0.34 mmol; see Example 5(a)), acetyl chloride (50 mg, 0.63 mmol), Et3N (63 mg, 0.63 mmol) and MeCN (10 mL) was stirred at room temperature for 30 minutes, then poured into HCl (1M) and extracted with EtOAc. The combined extracts were washed with water and brine, and dried over Na2SO4. Concentration and purification by chromatography gave the sub-title compound (182 mg, 84%).
Reaction SMILES: Cl[C:2]1[C:10]2[NH:9][C:8]3[CH2:11][CH2:12][N:13]([CH3:15])[CH2:14][C:7]=3[C:6]=2[CH:5]=[CH:4][CH:3]=1.CC(C)([O-])C.[Na+].[N:22]1[CH:27]=[CH:26][C:25]([CH2:28][NH2:29])=[CH:24][CH:23]=1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:15][N:13]1[CH2:12][CH2:11][C:8]2[NH:9][C:10]3[C:6]([C:7]=2[CH2:14]1)=[CH:5][CH:4]=[CH:3][C:2]=3[NH:29][CH2:28][C:25]1[CH:26]=[CH:27][N:22]=[CH:23][CH:24]=1
Reactant: NCc1ccncc1
Reactant: CN1CCc2[nH]c3c(Cl)cccc3c2C1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Product: CN1CCc2[nH]c3c(NCc4ccncc4)cccc3c2C1
Temperature: 85 °C

Procedure:
6-Chloro-2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole (0.5 g, 2.27 mmol), sodium tert-butoxide (1.30 g, 1.36 mmol), palladium acetate (0.101 g, 0.453 mmol) and 2-di-tert-butyl-phosphino-2′-4′-6′-triisopropyl-biphenyl (0.192 g, 0.45 mmol) were mixed in a reaction bottle which was evacuated and back filled with nitrogen for 5 min. Dry toluene (3 mL) was added under a nitrogen atmosphere. (Pyridin-4-yl)methanamine (291 mg, 2.72 mmol) was added and the mixture was heated at 85° C. overnight. The reaction mass was filtered and washed with EtOAc (2×25 mL). The filtrate was concentrated under vacuum and the residue purified on neutral alumina using 0-10% MeOH:EtOAc as eluent. Yield: 180 mg (freebase).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[O:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[N:16]([CH2:20][CH3:21])[C:15]([CH:22]=O)=[CH:14]2.[NH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl>[CH2:20]([N:16]1[C:17]2[C:13](=[CH:12][C:11]([O:10][C:2]3[S:1][C:5]4[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=4[N:3]=3)=[CH:19][CH:18]=2)[CH:14]=[C:15]1[CH2:22][N:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1)[CH3:21]
Reactant: CCn1c(C=O)cc2cc(Oc3nc4ccccc4s3)ccc21
Reactant: C1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CCn1c(CN2CCCCC2)cc2cc(Oc3nc4ccccc4s3)ccc21
Temperature: 25 °C
Reaction time: 60 h
Yield: 69.8 %

Procedure:
To a suspension of 5-(benzothiazol-2-yloxy)-1-ethyl-1H-indole-2-carbaldehyde (100 mg, 0.3 mmol) in DCE (3 mL) was added piperidine (0.06 mL, 51 mg, 0.62 mmol), Na(OAc)3BH (131 mg, 0.62 mmol) and the reaction mixture was stirred (rt, 60 h). The reaction mixture was partitioned between saturated NaHCO3 (10 ml) and DCM (20 mL). The organic layer was separated and the aqueous layer was extracted with DCM (2×25 mL). The organic layer was dried, filtered and concentrated in vacuo. The resulting residue was purified by silica gel flash chromatography using MeOH (0.2 M NH3):DCM (0-8%) to provide the title compound as a yellow solid (82 mg, 68%). MS (ESI): mass calcd. for C23H25N3OS, 391.2; m/z found, 392.1 [M+H]+. 1H NMR (400 MHz, CDCl3): 7.73 (d, J=8.1, 1H), 7.59 (d, J=7.9, 1H), 7.49 (d, J=2.3, 1H), 7.39-7.29 (m, 2H), 7.23 (d, J=13.2, 1H), 7.12 (dd, J=8.8, 2.4, 1H), 6.35 (s, 1H), 4.36-4.21 (m, 2H), 3.56 (s, 2H), 2.49-2.25 (m, 4H), 1.54 (d, J=5.3, 4H), 1.51-1.32 (m, 5H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5](/[C:9](/[CH3:14])=[CH:10]/[C:11](O)=[O:12])[CH:6]=[CH:7][CH:8]=1)#[N:2].C(N(CC)CC)C.ClC(OCC)=O.[BH4-].[Na+].Cl>O1CCCC1.O1CCCC1.O>[OH:12][CH2:11]/[CH:10]=[C:9](/[C:5]1[CH:4]=[C:3]([CH:8]=[CH:7][CH:6]=1)[C:1]#[N:2])\[CH3:14]
Reactant: C/C(=C\C(=O)O)c1cccc(C#N)c1
Agent: CCOC(=O)Cl
Agent: Cl
Agent: [BH4-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: C/C(=C\CO)c1cccc(C#N)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 81.2 %

Procedure:
To a solution of (E)-3-(3-cyanophenyl)-2-butenoic acid (Preparation 32, 15.83 g, 84.6 mmol) and triethylamine (8.99 g, 88.8 mmol) in tetrahydrofuran (150 ml) at 0° C. was added over 10 minutes ethyl chloroformate (9.65 g, 88.8 mmol). The mixture was then stirred at 0° C. for 30 minutes and at room temperature for a further 30 minutes. The resulting precipitate was collected by filtration and the solid was washed with cold tetrahydrofuran (2×30 ml). The preformed mixed anhydride in tetrahydrofuran was then added over 30 minutes via cannula to sodium borohydride (11.2 g, 0.30 mol) in a mixture of tetrahydrofuran/water (4:1, lOoml) at 0° C. The resultant mixture was stirred at 0° C. for 1 h, at room temperature for 3 h and then cooled to 0° C. 2N Hydrochloric acid was added cautiously until effervescence had ceased. The mixture was concentrated in vacuo and 1N hydrochloric acid (100 ml) was added. The aqueous solution was extracted with ethyl acetate (3×150 ml) and the combined extracts were dried (MgSO4), filtered and concentrated in vacuo. The crude oil was purified by silica column chromatography eluting with a gradient of ethyl acetate:hexane (1:1 to 100:0). An impurity, unreacted starting carboxylic acid, was removed by a basic wash with 2N sodium hydroxide solution (150 ml) and the pure product was extracted with dichloromethane (3×100 ml). The combined extracts were dried (MgSO4), filtered and concentrated in vacuo to give the title compound as a colourless oil (11.9 g, 82%).
Reaction SMILES: [CH2:1]([O:4][C:5]1[C:14]2[C:15](=[O:27])[N:16]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[C:17](=[O:18])[C:13]=2[C:12]([O:28]COC)=[C:11]2[C:6]=1[CH:7]=[CH:8][CH:9]=[N:10]2)[CH:2]=[CH2:3].FC(F)(F)C(O)=O>ClCCl>[CH2:1]([O:4][C:5]1[C:14]2[C:15](=[O:27])[N:16]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[C:17](=[O:18])[C:13]=2[C:12]([OH:28])=[C:11]2[C:6]=1[CH:7]=[CH:8][CH:9]=[N:10]2)[CH:2]=[CH2:3]
Reactant: C=CCOc1c2c(c(OCOC)c3ncccc13)C(=O)N(Cc1ccc(F)cc1)C2=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C=CCOc1c2c(c(O)c3ncccc13)C(=O)N(Cc1ccc(F)cc1)C2=O
Temperature: 25 °C
Yield: 44 %

Procedure:
5-Allyloxy-7-(4-fluoro-benzyl)-9-methoxymethoxy-pyrrolo[3,4-g]quinoline-6,8-dione 10 was dissolved in 1 mL dichloromethane. Ten equivalents of trifluoroacetic acid was added and the mixture was stirred at room temperature. After one hour another 10 equivalents of trifluoroacetic acid was added. The mixture was then stirred overnight, concentrated in vacuo, and azeotroped with toluene (2×), to give crude 11 which was triturated with 2 mL of 1:1 diethylether/hexane two times to give allyl ether 11 (0.0025 g, 0.0066 mmol, 44%). 1H NMR (CDCl3) δ 9.0 (s, 1H), 8.7 (d, 1H), 7.7 (m, 1H), 7.5 (m, 2H), 7.0 (t, 2H), 6.1 (m, 1H), 5.4 (d, 1H), 5.3 (d, 1H), 5.1 (d, 2H), 4.8 (s, 2H). MS: 379 (M+1).
Reaction SMILES: N[C@]12CC[C@@H](C(C)=C)[C@@H]1[C@@H]1[C@@](C)(CC2)[C@@]2(C)[C@@H]([C@]3(C)[C@@H](CC2)C(C)(C)C(C2C=CC(C(OC)=O)=CC=2)=CC3)CC1.[F:41][C:42]1([F:90])[CH2:47][CH2:46][N:45]([CH2:48][C:49]([NH:51][C@:52]23[CH2:86][CH2:85][C@@H:84]([C:87]([CH3:89])=[CH2:88])[C@@H:53]2[C@@H:54]2[C@@:67]([CH3:70])([CH2:68][CH2:69]3)[C@@:66]3([CH3:71])[C@@H:57]([C@:58]4([CH3:83])[C@@H:63]([CH2:64][CH2:65]3)[C:62]([CH3:73])([CH3:72])[C:61]([C:74]3[CH:82]=[CH:81][C:77]([C:78]([OH:80])=[O:79])=[CH:76][CH:75]=3)=[CH:60][CH2:59]4)[CH2:56][CH2:55]2)=[O:50])C[CH2:43]1>>[F:41][C:42]1([F:90])[CH2:47][CH2:46][N:45]([CH2:48][C:49]([NH:51][C@:52]23[CH2:86][CH2:85][C@@H:84]([C:87]([CH3:89])=[CH2:88])[C@@H:53]2[C@@H:54]2[C@@:67]([CH3:70])([CH2:68][CH2:69]3)[C@@:66]3([CH3:71])[C@@H:57]([C@:58]4([CH3:83])[C@@H:63]([CH2:64][CH2:65]3)[C:62]([CH3:73])([CH3:72])[C:61]([C:74]3[CH:82]=[CH:81][C:77]([C:78]([OH:80])=[O:79])=[CH:76][CH:75]=3)=[CH:60][CH2:59]4)[CH2:56][CH2:55]2)=[O:50])[CH2:43]1
Reactant: C=C(C)[C@@H]1CC[C@]2(NC(=O)CN3CCC(F)(F)CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: C=C(C)[C@@H]1CC[C@]2(N)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Product: C=C(C)[C@@H]1CC[C@]2(NC(=O)CN3CCC(F)(F)C3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Yield: 38 %

Procedure:
The title compound was prepared in 38% yield from methyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-amino-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate following the same procedure as described for the preparation of 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(2-(4,4-difluoropiperidin-1-yl)acetamido)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoic acid, except and 3,3-difluoropyrrolidine, HCl was used instead of 4,4-difluoropiperidine, HCl in Step 2. LCMS: m/e 677.5 (M+H)+, 2.26 min (method 6). 1H NMR (500 MHz, 1:1 CDCl3:MeOD) δ=7.92 (d, J=8.2 Hz, 2H), 7.40 (s, 1H), 7.20 (d, J=8.2 Hz, 2H), 5.29 (dd, J=1.7, 6.3 Hz, 1H), 4.75 (d, J=1.2 Hz, 1H), 4.65 (s, 1H), 3.59-3.44 (m, 2H), 3.43-3.36 (m, 1H), 3.31-3.20 (m, 2H), 2.63-2.55 (m, 1H), 2.55-2.47 (m, 3H), 2.47-2.39 (m, 1H), 2.13 (dd, J=6.4, 17.1 Hz, 1H), 1.94-1.83 (m, 1H), 1.81-1.76 (m, 2H), 1.76-1.73 (m, 1H), 1.72 (s, 3H), 1.70-1.65 (m, 1H), 1.57-1.46 (m, 6H), 1.46-1.40 (m, 2H), 1.39-1.31 (m, 2H), 1.26 (dd, J=2.7, 10.7 Hz, 1H), 1.19-1.10 (m, 2H), 1.09 (s, 3H), 1.03 (s, 3H), 1.02 (s, 3H), 0.95 (s, 3H), 0.94 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:20]2[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=2)[C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=[CH:12][CH:11]=2)=[CH:5][CH:4]=1.Cl.COC1C=CC(C(C2C=CC(OCCN3CCCC3)=CC=2)C2C3C(=CC=CC=3)C=CC=2)=CC=1.C([O-])([O-])=O.[K+].[K+].Cl.Cl[CH2:69][CH2:70][N:71]1[CH2:76][CH2:75][CH2:74][CH2:73][CH2:72]1>CC(C)=O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:20]2[CH:21]=[CH:22][C:23]([O:26][CH2:69][CH2:70][N:71]3[CH2:76][CH2:75][CH2:74][CH2:73][CH2:72]3)=[CH:24][CH:25]=2)[C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=[CH:12][CH:11]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(C(c2ccc(O)cc2)c2cccc3ccccc23)cc1
Reactant: ClCCN1CCCCC1
Agent: COc1ccc(C(c2ccc(OCCN3CCCC3)cc2)c2cccc3ccccc23)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CC(C)=O
Product: COc1ccc(C(c2ccc(OCCN3CCCCC3)cc2)c2cccc3ccccc23)cc1

Procedure:
A mixture of (4-methoxyphenyl)-(4-hydroxyphenyl)-naphth-1-yl-methane of formula 1 (0.3 gm, 0.001 mol), anhydrous K2CO3 (1.5 gm), 1-(2-chloroethyl)piperidine hydrochloride (0.276 gm, 0.002 mol) and dry acetone (100 ml) was refluxed for 810 hrs K2CO3 was filtered off, acetone was distilled off, and the residue was diluted with water. The reaction mixture was extracted with ethyl acetate washed with water dried over Na2SO4 and concentrated to give an oil. This oil was purified by column chromatography over basic alumina using benzene as the eluent. Solvent was distilled off to give the title compound of general formula I as an oil. Yield 0.3 gm(67%).
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([Cl:11])=[CH:8][CH:9]=2)[NH:4][C:3]=1[C:12]([C:14]1[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][N:15]=1)=[O:13].[C:21](Cl)(=[O:26])[CH2:22][CH:23]([CH3:25])[CH3:24]>>[Cl:11][C:7]1[CH:6]=[C:5]2[C:10]([C:2]([NH:1][C:21](=[O:26])[CH2:22][CH:23]([CH3:25])[CH3:24])=[C:3]([C:12]([C:14]3[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][N:15]=3)=[O:13])[NH:4]2)=[CH:9][CH:8]=1
Reactant: Cc1cccnc1C(=O)c1[nH]c2cc(Cl)ccc2c1N
Reactant: CC(C)CC(=O)Cl
Product: Cc1cccnc1C(=O)c1[nH]c2cc(Cl)ccc2c1NC(=O)CC(C)C

Procedure:
The title compound was prepared according to the procedure described in Example 19 from 3-amino-6-chloro-2-(3-methylpyridine-2-carbonyl)indole (Example 367) and isovaleryl chloride. m.p.: 142-144° C. (recrystallized from ethyl acetate)
Reaction SMILES: [O:1]=[C:2]([CH2:9][CH2:10][CH3:11])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[C:12]([O:16][CH3:17])(=[O:15])[CH:13]=[CH2:14]>C1CCN2C(=NCCC2)CC1.C1CCCCC1>[CH3:17][O:16][C:12](=[O:15])[CH2:13][CH2:14][C:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])([C:2](=[O:1])[CH2:9][CH2:10][CH3:11])[CH2:2][CH2:3][C:4]([O:6][CH3:7])=[O:5]
Reactant: CCCC(=O)CC(=O)OCC
Reactant: C=CC(=O)OC
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCCCC1
Product: CCCC(=O)C(CCC(=O)OC)(CCC(=O)OC)C(=O)OCC
Temperature: 60 °C
Reaction time: 2 h
Yield: 115.4 %

Procedure:
41.2 g (0.26 mol) of ethyl 3-oxo-hexanoate and 1.9 g (0.012 mol) of DBU were placed in a three necked round bottom flask, equipped with dropping funnel and reflux condenser. At room temperature, 56.3 g (0.65 mol) of methyl acrylate was slowly added drop by drop. After the exothermal behavior of the reaction leveled off, the reaction mixture was stirred at 60° C. for an additional two hours. The mixture was poured into cyclohexane and was washed with diluted hydrochloric acid and was subsequently washed with distilled water until the aqueous layer showed a neutral reaction. The organic layer was dried with sodium sulfate, the solvent was removed, and the residual addition product was isolated by fractional distillation in a vacuum. 50.0 g (0.15 mol) of 4-(ethoxycarbonyl)-4-(1-oxobutyl)-heptanedioic acid 1,7-dimethyl ester was obtained (yield: 58%; boiling point: 149° C. at 0.007 mbar; colorless).