Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2/[C:10](=[CH:18]/[C:19]2[NH:23][C:22]([CH3:24])=[C:21]([C:25]([OH:27])=O)[C:20]=2[CH3:28])/[C:11](=[O:17])[NH:12]3)=[CH:4][CH:3]=1.[N:29]1([CH2:34][C@@H:35]2[CH2:40][CH2:39][CH2:38][NH:37][CH2:36]2)[CH2:33][CH2:32][CH2:31][CH2:30]1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>C1COCC1.C(#N)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2/[C:10](=[CH:18]/[C:19]2[NH:23][C:22]([CH3:24])=[C:21]([C:25]([N:37]4[CH2:38][CH2:39][CH2:40][C@@H:35]([CH2:34][N:29]5[CH2:30][CH2:31][CH2:32][CH2:33]5)[CH2:36]4)=[O:27])[C:20]=2[CH3:28])/[C:11](=[O:17])[NH:12]3)=[CH:6][CH:7]=1
Reactant: C1CNC[C@H](CN2CCCC2)C1
Reactant: Cc1[nH]c(/C=C2\C(=O)Nc3cccc(-c4ccc(Cl)cc4)c32)c(C)c1C(=O)O
Agent: On1nnc2ccccc21
Solvent: CC#N
Solvent: ClCCCl
Solvent: C1CCOC1
Product: Cc1[nH]c(/C=C2\C(=O)Nc3cccc(-c4ccc(Cl)cc4)c32)c(C)c1C(=O)N1CCC[C@@H](CN2CCCC2)C1
Yield: 54.9 %

Procedure:
5-[4-(4-Chloro-phenyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (112 mg, 0.3 mmol) was coupled with (R)-3-pyrrolidin-1-ylmethyl-piperidine (99 mg, 2 eq.), HOBt (1 eq.), EDC (1.5 eq.) and TEA (3 drops) in THF (1 mL) and acetonitrile (1 mL) at rt for overnight to give 89.5 mg (55%) of the titled compound as a yellow solid.
Reaction SMILES: Cl.[CH3:2][C:3]1[O:7][C:6]([C:8]2[CH:16]=[CH:15][C:11]([C:12](O)=[O:13])=[CH:10][CH:9]=2)=[N:5][C:4]=1[CH2:17][S:18]([C:21]1[CH:26]=[CH:25][C:24]([CH2:27][CH2:28][CH2:29][N:30]2[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)=[CH:23][CH:22]=1)(=[O:20])=[O:19].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C.[N:64]1[CH:69]=[CH:68][CH:67]=[C:66]([CH2:70][NH2:71])[CH:65]=1>CN(C)C=O.O>[CH3:2][C:3]1[O:7][C:6]([C:8]2[CH:9]=[CH:10][C:11]([C:12]([NH:71][CH2:70][C:66]3[CH:65]=[N:64][CH:69]=[CH:68][CH:67]=3)=[O:13])=[CH:15][CH:16]=2)=[N:5][C:4]=1[CH2:17][S:18]([C:21]1[CH:22]=[CH:23][C:24]([CH2:27][CH2:28][CH2:29][N:30]2[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)=[CH:25][CH:26]=1)(=[O:20])=[O:19]
Reactant: NCc1cccnc1
Reactant: Cc1oc(-c2ccc(C(=O)O)cc2)nc1CS(=O)(=O)c1ccc(CCCN2CCOCC2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1oc(-c2ccc(C(=O)NCc3cccnc3)cc2)nc1CS(=O)(=O)c1ccc(CCCN2CCOCC2)cc1
Reaction time: 0.2 h
Yield: 24.2 %

Procedure:
A solution of 4-(5-methyl-4-((4-(3-morpholinopropyl)phenylsulfonyl)methyl)oxazol-2-yl)benzoic acid hydrochloride (1.5 g, 2.88 mmol, 1.00 equiv), EDCI (660 mg, 3.46 mmol, 1.20 equiv), HOBt (460 mg, 3.41 mmol, 1.18 equiv), triethylamine (1.16 g, 11.49 mmol, 3.98 equiv) and pyridin-3-ylmethanamine (380 mg, 3.52 mmol, 1.22 equiv) in N,N-dimethylformamide (40 mL) was stirred overnight at 25-30° C. The resulting solution was diluted with 100 mL of water and extracted with 1×100 mL of ethyl acetate. The organic layer was washed with 3×50 mL of brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product (550 mg) was purified by Prep-HPLC with the following conditions (1#-Pre-HPLC-005(Waters)): Column, Xbridge Prep C18, 5 um, 19*150 mm; mobile phase, WATER WITH 0.05% TFA and CH3CN (10% CH3CN up to 30% in 12 min, up to 100% in 1 min); Detector, uv 220/254 nm, to give 400 mg (20%) of 4-(5-methyl-4-((4-(3-morpholinopropyl)phenylsulfonyl)methyl)oxazol-2-yl)-N-(pyridin-3-ylmethyl)benzamide acid trifluoroacetic acid salt as a white solid. LC-MS: (ES, m/z): 575 [M+H]+, 288, 126. 1HNMR (400 MHz, DMSO-d6, ppm): δ 8.79 (m, 1H), 8.70 (d, J=4.8 Hz, 1H), 8.31 (d, J=8.0 Hz, 1H), 7.98 (d, J=8.8 Hz, 2H), 7.92 (d, J=8.4 Hz, 2H), 7.87-7.84 (m, 1H), 7.72 (d, J=8.0 Hz, 2H), 7.48 (d, J=8.4 Hz, 2H), 4.62 (s, 4H), 3.98-3.94 (m, 2H), 3.64 (s, 2H), 3.42-3.39 (m, 2H), 3.12-3.00 (m, 4H), 2.78-2.73 (m, 2H), 2.09 (s, 3H), 2.00-1.92 (m, 2H).
Reaction SMILES: [CH2:1]([OH:5])[CH2:2][CH2:3][CH3:4].ClCl.Cl[CH:9](Cl)[CH:10](Cl)Cl.Cl[C:15](Cl)([CH2:18]C)[CH:16]=O>CN(C=O)C.Cl.C(O)C(C)C>[C:4]1([CH2:3][CH2:2][CH2:1][OH:5])[CH:10]=[CH:9][CH:18]=[CH:15][CH:16]=1
Reactant: CCCCO
Reactant: CCC(Cl)(Cl)C=O
Reactant: ClC(Cl)C(Cl)Cl
Agent: Cl
Agent: ClCl
Solvent: CC(C)CO
Solvent: CN(C)C=O
Product: OCCCc1ccccc1

Procedure:
n-Butanol and Cl2 were added concurrently to a 100 ml, four necked, round bottomed flask containing ~10 g of DMF/HCl catalyst and 25 ml of 1,1,2,2-tetrachloroethane. The temperature was maintained between 50° and 55° C. by controlling the rates of the addition. Upon completion of the addition, the reaction mixture was shown to contain mainly the product 2,2-dichlorobutyraldehyde by GC and NMR analysis. Similar results were obtained with isobutanol and 3-phenylpropanol. Analysis was in agreement with authentic products by GC, IR and NMR.
Reaction SMILES: [CH3:1][C:2]1[C:19]([O:20]C(=O)C)=[CH:18][C:5]2[CH:6]=[C:7]([C:9](=[O:17])[CH2:10][N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)[O:8][C:4]=2[C:3]=1[CH3:24].[BH4-].[Na+].O>CO>[OH:17][CH:9]([C:7]1[O:8][C:4]2[C:3]([CH3:24])=[C:2]([CH3:1])[C:19]([OH:20])=[CH:18][C:5]=2[CH:6]=1)[CH2:10][N:11]1[CH2:12][CH2:13][O:14][CH2:15][CH2:16]1
Reactant: CC(=O)Oc1cc2cc(C(=O)CN3CCOCC3)oc2c(C)c1C
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: Cc1c(O)cc2cc(C(O)CN3CCOCC3)oc2c1C
Temperature: 25 °C
Reaction time: 4 h
Yield: 68.2 %

Procedure:
A solution of acetic acid 6,7-dimethyl-2-(2-morpholin4-yl-acetyl)-benzofuran-5-yl ester (35 mg), prepared as in Example 17, in MeOH (10 mL) was stirred while NaBH4 (40 mg) was added, and the mixture was stirred at room temperature for an additional 4 h. The mixture was poured into water, and extracted with ethylacetate. The organic layer was dried over MgSO4 and evaporated. The residue was purified by silica gel column eluting with 5% MeOH in DCM to give 21 mg of 2-(1-hydroxy-2-morpholin-4-yl-ethyl)-6,7-dimethyl-benzofuran-5-ol as an oil. Conversion into HCl salt gave a yellow solid. 1H NMR (CD3OD, 300 MHz) δ: 6.77 (s, 1H), 6.67 (s, 1H), 5.29 (dd, J=10.4, 3.3 Hz, 1H), 4.04 (m, 2H), 3.85 (q, 2H), 3.70-3.50 (m, 4H), 3.30 (m, 2H), 2.40 (s, 3H), 2.20 (s, 3H) ppm. 13C NMR (CD3OD, 75 MHz) (as HCl salt) δ: 154.72, 151.88, 149.40, 125.02, 121.67, 120.21, 104.51, 102.50, 63.77, 63.69, 61.70, 60.19, 53.82, 51.28, 11.24, 11.10 ppm. M/S 292 (M+H+).
Reaction SMILES: [CH3:1][CH:2]([C:5]1[N:6]([CH2:17][C:18]2[N:23]=[C:22]([C:24]([NH2:26])=O)[CH:21]=[CH:20][CH:19]=2)[C:7]2[C:12]([CH:13]=1)=[CH:11][C:10]([O:14][CH3:15])=[C:9]([Cl:16])[CH:8]=2)[CH2:3][CH3:4].C(N(CC)CC)C.FC(F)(F)C(OC(=O)C(F)(F)F)=O.C(=O)([O-])O.[Na+]>ClCCl>[CH3:1][CH:2]([C:5]1[N:6]([CH2:17][C:18]2[N:23]=[C:22]([C:24]#[N:26])[CH:21]=[CH:20][CH:19]=2)[C:7]2[C:12]([CH:13]=1)=[CH:11][C:10]([O:14][CH3:15])=[C:9]([Cl:16])[CH:8]=2)[CH2:3][CH3:4]
Reactant: CCC(C)c1cc2cc(OC)c(Cl)cc2n1Cc1cccc(C(N)=O)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: CCN(CC)CC
Product: CCC(C)c1cc2cc(OC)c(Cl)cc2n1Cc1cccc(C#N)n1
Temperature: 25 °C
Reaction time: 22 h
Yield: 87.3 %

Procedure:
To a solution of 6-[2-(butan-2-yl)-6-chloro-5-methoxyindol-1-ylmethyl]pyridine-2-carboxamide (118 mg) in dichloromethane (1.6 mL) were successively added triethylamine (0.225 mL) and trifluoroacetic anhydride (0.112 mL) under ice-cooling. This mixture was stirred at room temperature for 22 hours. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate solution, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate-hexane) to obtain the title compound (98 mg). 1H-NMR (CDCl3) δ ppm: 0.86 (3H, t, J=7.4 Hz), 1.24 (3H, d, J=6.8 Hz), 1.45-1.80 (2H, m), 2.60-2.75 (1H, m), 3.93 (3H, s), 5.40 (2H, s), 6.31 (1H, s), 6.50-6.65 (1H, m), 7.11 (1H, s), 7.14 (1H, s), 7.50-7.70 (2H, m).
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([S:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][NH:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[NH:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:32]([N:35]=[C:36]=[O:37])[CH2:33][CH3:34]>CCCCCC>[C:1]1([C:7]2[N:8]=[C:9]([S:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][N:24]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[C:36]([NH:35][CH2:32][CH2:33][CH3:34])=[O:37])[NH:10][C:11]=2[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCCCCCCNCCCCCSc1nc(-c2ccccc2)c(-c2ccccc2)[nH]1
Reactant: CCCN=C=O
Solvent: CCCCCC
Product: CCCCCCCN(CCCCCSc1nc(-c2ccccc2)c(-c2ccccc2)[nH]1)C(=O)NCCC
Temperature: 25 °C
Reaction time: 4 h
Yield: 18.7 %

Procedure:
To a solution of N-[5-(4,5-diphenyl-1H-imidazol-2-ylthio)pentyl]-1-heptanamine (0.36 g, 0.0008 mol) in hexane (15 mL) was added propylisocyanate (0.094 mL, 0.085 g, 0.001 mol), and the reaction mixture was stirred at ambient temperature for 4 hours. The reaction mixture was then treated with additional propylisocyanate (0.094 mL, 0.085 g, 0.001 mol) and stirred at ambient temperature overnight and then at reflux for 72 hours. The reaction mixture was concentrated under vacuum and the residue was chromatographed using 2:8 hexane-ethyl acetate. The resulting oil was triturated with hexane to give the title compound (0.8 g, 0.00015 mol) as a white solid, mp 78°-80°. 1H NMR (CDCl3) δ 7.6-7.2(m, 10H), 4.4(t,1H,J=7 Hz), 3.4-2.9 (m, 8H), I.9-1.1 (m, 19H), 1.0-0.75 (m, 6H).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[C:20]([S:21](=[O:24])(=[O:23])[NH2:22])=[CH:19][C:15]([C:16]([OH:18])=[O:17])=[CH:14][C:13]=2[NH2:25])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[OH-].[Na+].[CH2:28](Cl)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>O>[C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[C:20]([S:21](=[O:23])(=[O:24])[NH2:22])=[CH:19][C:15]([C:16]([OH:18])=[O:17])=[CH:14][C:13]=2[NH:25][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: ClCc1ccccc1
Reactant: CC(=O)Nc1ccc(Nc2c(N)cc(C(=O)O)cc2S(N)(=O)=O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(=O)Nc1ccc(Nc2c(NCc3ccccc3)cc(C(=O)O)cc2S(N)(=O)=O)cc1

Procedure:
The starting material is prepared as follows: To the mixture of 3.6 g of 4-(4-acetamidophenylamino)-3-amino-5-sulfamoylbenzoic acid, 20 ml of water and the sufficient amount of N aqueous sodium hydroxide to reach a pH = 7.4, 1.3 g of benzyl chloride are added while stirring at 30°. The mixture is stirred for 16 hours at room temperature, during which time 4N aqueous sodium hydroxide is added dropwise to keep said pH value. It is filtered, the filtrate acidified with 2 ml of glacial acetic acid and the precipitate formed filtered off, to yield the 4-(4-acetamidophenylamino)-3-benzylamino-5-sulfamoylbenzoic acid which is used as such without further purification.
Reaction SMILES: FC1C=C(NC(=O)[CH2:20][C:21]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)=[O:22])C=CC=1OC1C2SC=CC=2N=CN=1.[F:32][C:33]1[CH:34]=[C:35]([NH:52][C:53](NC(=O)CC2C=CC(F)=CC=2)=S)[CH:36]=[CH:37][C:38]=1[O:39][C:40]1[C:45]2=[C:46]([CH3:51])[C:47](OC)=[CH:48][N:44]2[N:43]=[CH:42][N:41]=1.C(N(C(C)C)CC)(C)C.[B-](F)(F)(F)F.CN(C([O:87]N1N=NC2C1=CC=CC=2)=[N+](C)C)C>CN(C=O)C>[F:32][C:33]1[CH:34]=[C:35]([NH:52][C:53](=[O:87])[CH2:20][C:21]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)=[O:22])[CH:36]=[CH:37][C:38]=1[O:39][C:40]1[C:45]2=[C:46]([CH3:51])[CH:47]=[CH:48][N:44]2[N:43]=[CH:42][N:41]=1
Reactant: O=C(CC(=O)Nc1ccc(Oc2ncnc3ccsc23)c(F)c1)Nc1ccc(F)cc1
Reactant: COc1cn2ncnc(Oc3ccc(NC(=S)NC(=O)Cc4ccc(F)cc4)cc3F)c2c1C
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccn2ncnc(Oc3ccc(NC(=O)CC(=O)Nc4ccc(F)cc4)cc3F)c12
Reaction time: 17.5 h
Yield: 75.4 %

Procedure:
To a homogeneous solution of 3-fluoro-4-(5-methylpyrrolo[2,1-f][1,2,4]triazin-4-yloxy)benzenamine (52 mg, 0.20 mmol, Compound B of Example 28) and 3-(4-fluorophenylamino)-3-oxopropanoic acid (39 mg, 0.20 mmol, Compound A of Example 25) in anhydrous DMF (2 mL), at room temperature under nitrogen atmosphere, was added diisopropylethylamine (52 μL, 0.30 mmol). The mixture was stirred for 5 minutes before o-benzotriazol-l-yl-N,N,N′,N′-tetramethyluronium tetrafluoroborate (96 mg, 0.30 mmol) was added in one portion. The mixture was stirred for 17.5 h before the reaction was concentrated in vacuo to remove volatiles. The resultant residue was diluted with ethyl acetate and washed twice with 10% aqueous lithium chloride before being concentrated in vacuo. Purification by silica gel (Merck KGaA, 230-400 mesh particle size) flash chromatography, eluting with 1% methanol in chloroform, afforded an off-white solid that was triturated and sonicated in the presence of anhydrous ethyl ether (3 mL). The title compound (66 mg, 75%) was isolated by filtration as a white solid. 1H NMR (CDCl3) δ 9.28 (s, 1H), 8.67 (s, 1H), 7.83 (s, 1H), 7.80-7.73 (m, 1H), 7.67 (d, 1H, J=2.5 Hz), 7.54-7.49 (m, 2H), 7.28-7.26 (m, 2H), 7.10-7.02 (m, 2H), 6.64 (d, 1H, J=2.3 Hz), 3.56 (s, 2H), 2.60 (s, 3H); HRMS(ESI), 436.1221 (M+H)+ calc, 436.1230 (M+H)+ found.
Reaction SMILES: [Br:1][C:2]1[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:3]=1[C:4](Cl)=[N:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]([Cl:12])[C:7]=1F.NC(N)=[S:22].N1C=CC=CC=1.CCN(CC)CC>C(O)(C)C>[Br:1][C:2]1[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:3]=1[C:4]1[S:22][C:7]2[C:8]([Cl:12])=[N:9][CH:10]=[CH:11][C:6]=2[N:5]=1
Reactant: Fc1c(N=C(Cl)c2c(Cl)cccc2Br)ccnc1Cl
Reactant: NC(N)=S
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Solvent: CC(C)O
Product: Clc1cccc(Br)c1-c1nc2ccnc(Cl)c2s1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 53 %

Procedure:
A stirred solution of 2-bromo-6-chloro-N-(2-chloro-3-fluoropyridin-4-yl)-benzimidoyl chloride (4.2 g, 11.0 mmol), thiourea (2.5 g, 33.0 mmol) and pyridine (3.1 mL, 38.4 mmol) in isopropanol (50 mL) under a nitrogen atmosphere was heated under reflux for 3 hours. Et3N (7.6 mL, 54.6 mmol) was added and the reaction mixture was heated under reflux for 1.5 hours. After cooling to room temperature, the volatiles were removed under reduced pressure. The resultant residue was triturated with water (100 mL) and then boiled in isopropanol (15 mL) for 10 minutes. After cooling to room temperature, the resultant solid was collected by filtration and then purified by column chromatography on silica gel eluting with 25% diethyl ether in pentane to afford the title compound as a colourless solid (2.1 g, 53%). LCMS (Method E): RT=4.16 min, m/z: 361 [M+H+].
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[OH-].[Na+].Br[CH2:12][CH2:13][OH:14].CCCCCC>CO.CC(OC)(C)C>[OH:14][CH2:13][CH2:12][S:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1
Reactant: OCCBr
Reactant: Oc1ccc(S)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: COC(C)(C)C
Solvent: CCCCCC
Product: OCCSc1ccc(O)cc1
Temperature: -5 °C
Reaction time: 1 h
Yield: 79 %

Procedure:
A solution of 5.0 g (35.7 mmol) 4-mercaptophenol in 50 ml methyl alcohol was treated at −5° C. dropwise over a period of 30 min with 39.2 ml (39.2 mmol) aqueous NaOH 1N and stirred 1 h at −5° C. Afterwards a solution of 5.2 ml (39.2 mmol) 2-bromo ethanol in 16.5 ml methyl alcohol was added at −5° C. dropwise over a period of 15 min. The reaction mixture was stirred for 21 h at room temperature, concentrated and the residue treated with 10 ml water and 30 ml tBME. After extraction and phase separation, the organic phase was washed with 20 ml saturated NaHCO3 and 20 ml brine. The combined organic phases were dried over Na2SO4 and the solvent was removed under reduced pressure to yield 6.03 g crude product. The crude product was dissolved in 18 ml tBME at 40° C. and subsequently treated dropwise with 25 ml hexane. The so formed suspension was stirred 16 h at room temperature and 1 h at 4° C. The crystals were separated on a filter funnel and washed with 5 ml hexane (4° C.) to yield 4.8 g (77.7%) product as white crystals.
Reaction SMILES: [C:1]([C:3]1[N:4]=[C:5]([O:14][C@H:15]2[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16]2)[C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[C:8]([F:13])[CH:7]=2)#[N:2].[NH2:27][NH2:28].O>CO>[F:13][C:8]1[CH:7]=[C:6]2[C:11]([CH:12]=[C:3]([C:1]([NH:27][NH2:28])=[NH:2])[N:4]=[C:5]2[O:14][C@H:15]2[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16]2)=[CH:10][CH:9]=1
Reactant: NN
Reactant: CC(C)(C)OC(=O)N1CC[C@H](Oc2nc(C#N)cc3ccc(F)cc23)C1
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)N1CC[C@H](Oc2nc(C(=N)NN)cc3ccc(F)cc23)C1

Procedure:
To a mixture of (S)-tert-butyl 3-((3-cyano-7-fluoroisoquinolin-1-yl)oxy)pyrrolidine-1-carboxylate (400 mg, 1.12 mmol) in MeOH (5 mL) was added NH2NH2—H2O (5 mL). The reaction mixture was heated to reflux for 2 hours. The solvent was subsequently removed to give the title compound as a white solid, which was used in next step without purification (450 mg, 100%). ESI-MS m/z [M+H]+ 390.
Reaction SMILES: [NH2:1][C@:2]12[CH2:37][CH2:36][C@@H:35]([C:38]([CH3:40])=[CH2:39])[C@@H:3]1[C@@H:4]1[C@@:17]([CH3:20])([CH2:18][CH2:19]2)[C@@:16]2([CH3:21])[C@@H:7]([C@:8]3([CH3:34])[C@@H:13]([CH2:14][CH2:15]2)[C:12]([CH3:23])([CH3:22])[C:11]([C:24]2[CH:33]=[CH:32][C:27]([C:28]([O:30]C)=[O:29])=[CH:26][CH:25]=2)=[CH:10][CH2:9]3)[CH2:6][CH2:5]1.CN(C)CCC(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(O)=O)=CC=2)=CC3)CC1)=O.[C:87]([O:91][C:92]([N:94]1[CH2:98][C:97]([F:100])([F:99])[CH2:96][C@H:95]1[C:101]([OH:103])=O)=[O:93])([CH3:90])([CH3:89])[CH3:88]>>[C:87]([O:91][C:92]([N:94]1[CH2:98][C:97]([F:99])([F:100])[CH2:96][C@H:95]1[C:101]([NH:1][C@:2]12[CH2:37][CH2:36][C@@H:35]([C:38]([CH3:40])=[CH2:39])[C@@H:3]1[C@@H:4]1[C@@:17]([CH3:20])([CH2:18][CH2:19]2)[C@@:16]2([CH3:21])[C@@H:7]([C@:8]3([CH3:34])[C@@H:13]([CH2:14][CH2:15]2)[C:12]([CH3:23])([CH3:22])[C:11]([C:24]2[CH:25]=[CH:26][C:27]([C:28]([OH:30])=[O:29])=[CH:32][CH:33]=2)=[CH:10][CH2:9]3)[CH2:6][CH2:5]1)=[O:103])=[O:93])([CH3:88])([CH3:89])[CH3:90]
Reactant: CC(C)(C)OC(=O)N1CC(F)(F)C[C@H]1C(=O)O
Reactant: 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
Agent: C=C(C)[C@@H]1CC[C@]2(NC(=O)CCN(C)C)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
Product: C=C(C)[C@@H]1CC[C@]2(NC(=O)[C@@H]3CC(F)(F)CN3C(=O)OC(C)(C)C)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: 29 %

Procedure:
The title compound was prepared in 29% 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-(3-(dimethylamino)propanamido)-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 (S)-1-(tert-butoxycarbonyl)-4,4-difluoropyrrolidine-2-carboxylic acid was used instead of 3-(dimethylamino)propionic acid hydrochloride in Step 1. LCMS: m/e 763.5 (M+H)+, 2.55 min (method 6). 1H NMR (500 MHz, 1:1 CDCl3:MeOD) δ=7.92 (d, J=8.5 Hz, 2H), 7.20 (d, J=8.5 Hz, 2H), 6.46 (br. s., 1H), 5.29 (dd, J=1.7, 6.3 Hz, 1H), 4.72 (s, 1H), 4.63 (br. s., 1H), 4.50 (d, J=9.2 Hz, 1H), 3.84 (br. s., 1H), 3.72 (td, J=6.7, 13.4 Hz, 1H), 2.84 (br. s., 1H), 2.55 (d, J=13.4 Hz, 1H), 2.51-2.37 (m, 2H), 2.12 (dd, J=6.4, 17.1 Hz, 1H), 1.96 (br. s., 1H), 1.73 (br. s., 1H), 1.70 (s, 4H), 1.61 (br. s., 2H), 1.56 (br. s., 9H), 1.53-1.45 (m, 5H), 1.45-1.37 (m, 3H), 1.36-1.29 (m, 2H), 1.28-1.23 (m, 1H), 1.17-1.09 (m, 2H), 1.08 (s, 3H), 1.02 (s, 6H), 0.94 (s, 3H), 0.93 (s, 3H).
Reaction SMILES: [C:1]([C:4]1([CH2:17][CH2:18][C:19](=O)[CH3:20])[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:10]2[C:5]1=[CH:6][CH:7]=[CH:8][CH:9]=2)(=[O:3])[NH2:2].[CH2:22]([NH2:24])[CH3:23].[H][H]>C(O)C>[C:1]([C:4]1([CH2:17][CH2:18][CH:19]([NH:24][CH2:22][CH3:23])[CH3:20])[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:10]=2[C:11]2[C:16]1=[CH:15][CH:14]=[CH:13][CH:12]=2)(=[O:3])[NH2:2]
Reactant: [H][H]
Reactant: CCN
Reactant: CC(=O)CCC1(C(N)=O)c2ccccc2-c2ccccc21
Solvent: CCO
Product: CCNC(C)CCC1(C(N)=O)c2ccccc2-c2ccccc21

Procedure:
A solution of 8.5 g. of 9-carbamoyl 9-(3-oxobutyl)fluorene from Example 2 in 400 ml of ethanol containing 5.0 g. of 5% polladium on carbon and 35 ml. of ethylamine was stirred at 150° C. for eight hours under 1000 psi of hydrogen. The reaction mixture was cooled, filtered and concentrated to dryness. The product was dissolved in 100 ml. of ethyl acetate and 100 ml. of diethyl ether and the solution was extracted several times with 6N hydrochloric acid. The acidic extracts were combined, cooled in an ice bath and made alkaline by addition of 10% sodium hydroxide. The alkaline solution was extracted with fresh ethyl acetate and diethyl ether. The organic layer was washed with water, dried and concentrated to dryness to provide 8.2 g. of the title product. The product was chromatographed over silica gel (eluting with 1% diethylamine in methanol v/v). The chromatographed product was dissolved in diethyl ether and the solution was stirred during addition of hydrogen chloride. The precipitated crystals were collected by filtration and recrystallized from ethanol and ethyl acetate to afford 5.1 g. of 9-carbamoyl-9-(3-ethylaminobutyl)fluorene hydrochloride. m.p. 180°-182° C.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:12]=[C:11]([N+:13]([O-])=O)[CH:10]=[CH:9][C:8]=2[O:16][CH3:17])=[C:5]([CH3:18])[O:4][N:3]=1.O.CC1C=C2N=C3C(=NC(NC3=O)=O)N(C[C@H](O)[C@H](O)[C@H](O)CO)C2=CC=1C>CCOC(C)=O.C(O)C.[Pd]>[CH3:1][C:2]1[C:6]([C:7]2[CH:12]=[C:11]([CH:10]=[CH:9][C:8]=2[O:16][CH3:17])[NH2:13])=[C:5]([CH3:18])[O:4][N:3]=1.[CH3:1][C:2]1[C:6]([C:7]2[CH:12]=[C:11]([NH2:13])[CH:10]=[CH:9][C:8]=2[O:16][CH3:17])=[C:5]([CH3:18])[O:4][N:3]=1
Reactant: COc1ccc([N+](=O)[O-])cc1-c1c(C)noc1C
Agent: [Pd]
Agent: Cc1cc2nc3c(=O)[nH]c(=O)nc-3n(C[C@H](O)[C@H](O)[C@H](O)CO)c2cc1C
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCO
Product: COc1ccc(N)cc1-c1c(C)noc1C
Reaction time: 24 h
Yield: 100 %

Procedure:
3,5-Dimethyl-4-[2-(methyloxy)-5-nitrophenyl]isoxazole (for a preparation see Intermediate 1) (43.9 g, 177 mmol) was dissolved in EtOAc (1 liter) diluted with ethanol (1 liter) and added to Pd/C (8 g, 5% w/w, 50% water, Type E101 NO/W) in a 5 liter hydrogenation flask under vacuum, having first purged the vessel twice with vacuum/nitrogen cycles. The mixture was stirred for 24 h. No hydrogen uptake for the first 8-10 h, then steady uptake till approximately 20 liters had been consumed. The mixture purged with vacuum/nitrogen cycle×3 then was filtered through Celite™ under nitrogen and the filtrate evaporated in vacuo to give [3-(3,5-dimethyl-4-isoxazolyl)-4-(methyloxy)phenyl]amine 3-(3,5-dimethyl-4-isoxazolyl)-4-(methyloxy)aniline (38.6 g, 177 mmol, 100% yield) as a brown crystalline solid. LCMS (formate) Rt 0.50 min, MH+ 219
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[NH2:11][CH2:12][CH2:13][NH:14][CH2:15][CH2:16][OH:17].CN1CCCC1=O>O>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([NH:11][CH2:12][CH2:13][NH:14][CH2:15][CH2:16][OH:17])=[CH:3][CH:4]=1)([O-:10])=[O:9]
Reactant: NCCNCCO
Reactant: O=[N+]([O-])c1ccc(F)cc1
Solvent: O
Solvent: CN1CCCC1=O
Product: O=[N+]([O-])c1ccc(NCCNCCO)cc1
Temperature: 60 °C
Yield: 92.7 %

Procedure:
6 g of 4-fluoronitrobenzene and 10 g of 2-(2-aminoethylamino)ethanol were added to a solution of 100 ml of N-methylpyrrolidinone. The reaction medium was heated at 60° C. for 4 hours and, after cooling to room temperature, was then poured into a water and ice mixture. The yellow precipitate formed was filtered off, reslurried in water and then dried over P2O5. 8.88 g of 2-[2-(4-nitrophenylamino)ethylamino]ethanol (1) were obtained.