Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([O:18][CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][N:24]([C:27](=O)[CH2:28][C@@H:29]([NH:38][C:39]2[CH:44]=[CH:43][C:42]([S:45]([NH2:48])(=[O:47])=[O:46])=[CH:41][C:40]=2[S:49]([C:52]([F:55])([F:54])[F:53])(=[O:51])=[O:50])[CH2:30][S:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH2:23][CH2:22]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B.C1COCC1>C1COCC1.N.CO>[Si:1]([O:18][CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][N:24]([CH2:27][CH2:28][C@@H:29]([NH:38][C:39]2[CH:44]=[CH:43][C:42]([S:45]([NH2:48])(=[O:46])=[O:47])=[CH:41][C:40]=2[S:49]([C:52]([F:54])([F:53])[F:55])(=[O:50])=[O:51])[CH2:30][S:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH2:23][CH2:22]1)([C:14]([CH3:15])([CH3:16])[CH3:17])([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)[Si](OCCN1CCN(C(=O)C[C@H](CSc2ccccc2)Nc2ccc(S(N)(=O)=O)cc2S(=O)(=O)C(F)(F)F)CC1)(c1ccccc1)c1ccccc1
Agent: B
Agent: N
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)[Si](OCCN1CCN(CC[C@H](CSc2ccccc2)Nc2ccc(S(N)(=O)=O)cc2S(=O)(=O)C(F)(F)F)CC1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 25.5 %

Procedure:
(R)-4-(4-(4-(2-(tert-Butyldiphenylsilyloxy)ethyl)piperazin-1-yl)-4-oxo-1-(phenylthio)butan-2-ylamino)-3-(trifluoromethyl sulfonyl)benzenesulfonamide (INTERMEDIATE 21, 0.98 g, 1.15 mmol) was dissolved in THF (4.6 ml), under a nitrogen atmosphere, and a solution of borane-THF complex (1M in THF; 6.93 ml, 6.93 mmol) was added. The mixture was diluted with NH3 in MeOH (7N, 20 ml) and stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, diluted with EtOAc (75 ml), washed with water (40 ml), and dried (Na2SO4). Evaporation of the volatiles under reduced pressure afforded a concentrate, which was purified by column chromatography (ISCO, 40 g silica gel column, eluting with 0→100% EtOAc/hexanes) to provide the title compound (245 mg, yield: 25%).
Reaction SMILES: [C:1]([C:5]1[CH:13]=[C:12]2[C:8]([C:9]([Sn](CCCC)(CCCC)CCCC)=[N:10][N:11]2[CH3:14])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[C:28]([CH:30]1[CH2:33][N:32]([C:34](=[O:58])[C@H:35]([NH:37][C:38]([C:40]2[C:48]3[C:43](=[N:44][CH:45]=[C:46](Br)[N:47]=3)[N:42]([CH2:50][O:51][CH2:52][CH2:53][Si:54]([CH3:57])([CH3:56])[CH3:55])[CH:41]=2)=[O:39])[CH3:36])[CH2:31]1)#[N:29]>CN(C=O)C.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.[Cu]I>[C:28]([CH:30]1[CH2:31][N:32]([C:34](=[O:58])[C@H:35]([NH:37][C:38]([C:40]2[C:48]3[C:43](=[N:44][CH:45]=[C:46]([C:9]4[C:8]5[C:12](=[CH:13][C:5]([C:1]([CH3:2])([CH3:3])[CH3:4])=[CH:6][CH:7]=5)[N:11]([CH3:14])[N:10]=4)[N:47]=3)[N:42]([CH2:50][O:51][CH2:52][CH2:53][Si:54]([CH3:57])([CH3:56])[CH3:55])[CH:41]=2)=[O:39])[CH3:36])[CH2:33]1)#[N:29]
Reactant: CCCC[Sn](CCCC)(CCCC)c1nn(C)c2cc(C(C)(C)C)ccc12
Reactant: C[C@@H](NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Br)nc12)C(=O)N1CC(C#N)C1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: C[C@@H](NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4cc(C(C)(C)C)ccc34)nc12)C(=O)N1CC(C#N)C1
Temperature: 80 °C
Yield: 83.9 %

Procedure:
To a solution of 6-tert-butyl-1-methyl-3-tributylstannyl-1H-indazole (crude from Step 5, 217 mg, 0.45 mmol) and 2-bromo-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(3-cyano-azetidin-1-yl)-1-methyl-2-oxo-ethyl]-amide (125 mg, 0.25 mmol) in DMF (1.5 mL) were added Pd(PPh3)4 (14 mg, 0.012 mmol) and copper(I) iodide (9 mg, 0.05 mmol). The yellow reaction mixture was purged with argon then heated at 80° C. for 1.5 h then cooled to room temperature, quenched with sat NH4Cl and extracted with EtOAc (2×). The combined organics were washed with sat LiCl and brine then dried over MgSO4 and concentrated. The crude residue was purified by silica gel chromatography with 50% to 100% EtOAc/heptane to isolate 129 mg (85%) of 2-(6-tert-butyl-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(3-cyano-azetidin-1-yl)-1-methyl-2-oxo-ethyl]-amide as a white solid.
Reaction SMILES: C([S:4][CH:5]([CH2:9][C:10](=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:6]([OH:8])=[O:7])(=O)C.S(=O)(=O)(O)O>C(O)(=O)C>[C:10]([CH2:9][CH:5]([SH:4])[C:6]([OH:8])=[O:7])(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CC(=O)SC(CC(=O)c1ccccc1)C(=O)O
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: O=C(CC(S)C(=O)O)c1ccccc1
Reaction time: 2 h
Yield: 83.8 %

Procedure:
To a solution of 2.52 g of 2-acetylthio-3-benzoylpropionic acid in 20 ml of glacial acetic acid was added 4 ml of 10N sulfuric acid, and the mixture was refluxed at heating with stirring for 2 hours. The acetic acid was removed from the mixture by evaporation under reduced pressure, and ethyl acetate was added to the residue. The mixture was washed with water and dried over magnesium sulfate, and the ethyl acetate was removed from the mixture by evaporation. The residue was purified by silica gel column chromatograpy using a mixture of hexane and chloroform as an eluent, and then recrystallized from a mixture of hexane and diethyl ether to give 1.76 g of 3-benzoyl-2-mercaptopropionic acid.
Reaction SMILES: [OH-].[Li+].[Br:3][C:4]1[CH:5]=[CH:6][C:7]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=2)=[C:8]([CH:21]=1)[C:9]([O:11]CC1C=CC(OC)=CC=1)=[O:10]>O.C1COCC1>[Br:3][C:4]1[CH:5]=[CH:6][C:7]([O:22][CH2:23][C:24]2[CH:25]=[CH:26][C:27]([O:30][CH3:31])=[CH:28][CH:29]=2)=[C:8]([CH:21]=1)[C:9]([OH:11])=[O:10]
Reactant: COc1ccc(COC(=O)c2cc(Br)ccc2OCc2ccc(OC)cc2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(COc2ccc(Br)cc2C(=O)O)cc1
Temperature: 20 °C
Reaction time: 16 h

Procedure:
A solution of lithium hydroxide (367 mg, 8.75 mmol) in water (20 ml) was added dropwise to a stirred solution of [4-(methyloxy)phenyl]methyl 5-bromo-2-({[4-(methyloxy)phenyl]methyl}oxy)benzoate (may be prepared as described in Description 17; 400 mg, 0.875 mmol) in THF over 1 min. The reaction mixture was stirred at 20° C. for 16 h. The organic phase was evaporated and the aqueous phase (20 ml) was extracted with ethyl acetate (20 ml). The aqueous phase (20 ml) was adjusted to pH 2 with 2M hydrochloric acid (1 ml) and was extracted with ethyl acetate (3×20 ml). The organic phase was evaporated in vacuo to yield the title compound as a light yellow solid. 200 mg.
Reaction SMILES: [C:1]([OH:6])(=O)[CH:2]([CH3:4])[CH3:3].[N+:7]([C:10]1[CH:11]=[C:12]([S:16]([NH2:19])(=[O:18])=[O:17])[CH:13]=[CH:14][CH:15]=1)([O-:9])=[O:8].Cl.CN(C)CCCN=C=NCC>CN(C)C1C=CN=CC=1.ClCCl>[CH:2]([C:1]([NH:19][S:16]([C:12]1[CH:13]=[CH:14][CH:15]=[C:10]([N+:7]([O-:9])=[O:8])[CH:11]=1)(=[O:18])=[O:17])=[O:6])([CH3:4])[CH3:3]
Reactant: NS(=O)(=O)c1cccc([N+](=O)[O-])c1
Reactant: CC(C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CC(C)C(=O)NS(=O)(=O)c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 59.9 %

Procedure:
To a mixture of isobutyric acid (4.6 ml, 0.05 mol), 3-nitrophenyl sulphonamide (10.1 g, 0.05 mol) and 4-dimethylaminopyridine (6.1 g, 0.05 mol) in anhydrous dichloromethane (400 ml) under an atmosphere of nitrogen was added 1-[3-(dimethylamino)propyl]-3-ethyl carbodiimide hydrochloride (9.6 g 0.05 mol). The mixture was stirred at ambient temperature for 20 h. The mixture was extracted with 1M NaOH and tile separated aqueous phase was acidified using 5M HCl. The solid which precipitated was collected by filtration, washed with water and dried under vacuum to afford the title compound (8.16 g, 60%) as a colourless powder. mp 136°-138° C. 1H NMR (360 MHz, D6 -DMSO) δ 0.95 (6H, d, J=6.8 Hz), 2.48 (1H, septet, J=6.8 Hz), 7.95 (1H, dd, J=8.1 and 8.1 Hz), 8.33 (1H, dd, J=8.0 and 1.4 Hz), 8.54 (1H, dd, J=8.0, 1.4 Hz), 8.60 (1H, dd, J=1.4 and 1.4 Hz), 12.38 (1H, brs).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]3[NH:14][C:13]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=4)=[C:12]([CH3:23])[C:10]3=2)[NH:5][C:4](=[O:24])[CH:3]=1.[F:25][C:26]([F:31])([F:30])[C:27](O)=O>>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]3[N:14]([CH2:27][C:26]([F:31])([F:30])[F:25])[CH:13]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=4)[CH:12]([CH3:23])[C:10]3=2)[NH:5][C:4](=[O:24])[CH:3]=1
Reactant: Cc1c(-c2ccc(Cl)c(Cl)c2)[nH]c2ccc3[nH]c(=O)cc(Cl)c3c12
Reactant: O=C(O)C(F)(F)F
Product: CC1c2c(ccc3[nH]c(=O)cc(Cl)c23)N(CC(F)(F)F)C1c1ccc(Cl)c(Cl)c1

Procedure:
This compound was prepared using the method described in Example 23 from 9-chloro-2-(3,4-dichlorophenyl)-1-methyl-3,6-dihydro-pyrrolo[3,2-f]quinolin-7-one, and trifluoroacetic acid. Spectral data for compound 157: 1H NMR (500 MHz, DMSO-d6) δ 11.91 (s, 1H), 7.75 (d, J=1.9 Hz, 1H), 7.73 (d, J=8.3 Hz, 1H), 7.49 (dd, J=8.3, 1.9 Hz, 1H), 7.34 (d, J=8.8 Hz, 1H), 7.30 (d, J=8.8 Hz, 1H), 6.78 (d, J=1.7 Hz, 1H), 5.02 (d, J=7.0 Hz, 1H), 4.30 (qn, J=7.0 Hz, 1H), 4.25 (dq, J=16.5, 10.2 Hz, 1H), 3.71 (dq, J=16.5, 9.2 Hz, 1H), 0.76 (d, J=7.0 Hz, 3H).
Reaction SMILES: Cl.[C:2]1([S:8]([NH:11][C:12]2[CH:21]=[CH:20][CH:19]=[C:18]3[C:13]=2[CH2:14][CH2:15][NH:16][CH2:17]3)(=[O:10])=[O:9])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:23][CH2:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27]>>[C:2]1([S:8]([NH:11][C:12]2[CH:21]=[CH:20][CH:19]=[C:18]3[C:13]=2[CH2:14][CH2:15][N:16]([CH2:23][CH2:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:17]3)(=[O:10])=[O:9])[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)CCCBr
Reactant: O=S(=O)(Nc1cccc2c1CCNC2)c1ccccc1
Agent: Cl
Product: CCOC(=O)CCCN1CCc2c(cccc2NS(=O)(=O)c2ccccc2)C1

Procedure:
5-Phenylsulphonamido-1,2,3,4-tetrahydroisoquinoline hydrochloride (2.7 g) was reacted with ethyl 4-bromobutyrate in the manner described in Example 2(a). After elution from a silica column with ethyl acetate:methanol mixtures, the product was recrystallised from ethanol to give ethyl 4-[5-phenylsulphonamido-1,2,3,4-tetrahydroisoquinolin-2-yl]butyrate as a white solid (2.0 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:27]=[CH:28][C:29]=1[Cl:30])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]2([CH:18](C(OCC)=O)[C:17](=[O:24])[NH:16][C:15]2=[O:25])[C:7]1=[O:26].C(O)(=O)C>O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:27]=[CH:28][C:29]=1[Cl:30])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]2([CH2:18][C:17](=[O:24])[NH:16][C:15]2=[O:25])[C:7]1=[O:26]
Reactant: CCOC(=O)C1C(=O)NC(=O)C12C(=O)N(Cc1ccc(Cl)c(Cl)c1)c1ccccc12
Solvent: CC(=O)O
Solvent: O
Product: O=C1CC2(C(=O)N1)C(=O)N(Cc1ccc(Cl)c(Cl)c1)c1ccccc12
Yield: 33.4 %

Procedure:
A mixture of 1'-(3,4-dichlorobenzyl)-4-ethoxycarbonyl-spiro[pyrrolidine-3,3'-indoline]-2,2',5-trione(8.2 g.) and acetic acid (50 ml.) was heated under reflux for 22 hours. The solution obtained was cooled and poured into water (300 ml.). The solid which formed was collected by filtration and recrystallised from methanol to give 1'-(3,4-dichlorobenzyl)-spiro[pyrrolidine-3,3'-indoline]-2,2',5-trione (2.3 g.), m.p. 203°-204° C.
Reaction SMILES: [OH-].[Na+].[C:3]1([OH:10])[CH:8]=[CH:7][CH:6]=[C:5]([OH:9])[CH:4]=1.[Cl:11][C:12]1[N:17]=[C:16](Cl)[CH:15]=[CH:14][N:13]=1>O.CC(C)=O>[Cl:11][C:12]1[N:17]=[C:16]([O:9][C:5]2[CH:4]=[C:3]([OH:10])[CH:8]=[CH:7][CH:6]=2)[CH:15]=[CH:14][N:13]=1
Reactant: Oc1cccc(O)c1
Reactant: Clc1ccnc(Cl)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Product: Oc1cccc(Oc2ccnc(Cl)n2)c1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
Sodium hydroxide (1.68 g; powder 98% pure; 40 mmol) is dissolved in water (30 mL), cooled to 0° C. and treated with benzene-1,3-diol (4.4 g; 40 mmol). Within 15 min, 2,4-dichloropyrimidine (5.95 g; 40 mmol) dissolved in acetone (50 mL) is added dropwise, keeping the reaction temperature below 5° C. After 15 min at 0° C., the ice bath is removed and the reaction kept stirring for additional 17.5 h. After filtering off the precipitate, the solvent is removed under reduced pressure. The residual oil is taken up into EtOAc, washed with sodium bicarbonate solution (10%), water and brine and dried over Na2SO4. After filtering, the crude product is isolated as an oil and purified by flash chromatography over silica gel (eluting with CH2Cl2/MeOH; 0-5%) to give the title compound of Stage 5.1 as a beige solid; ES-MS: [M+H]+; m/z=223; Rf (CH2Cl2/MeOH 9:1)=0.57; HPLC: AtRet=3.50 min.
Reaction SMILES: [NH2:1][CH:2]([C:6]([OH:8])=[O:7])[CH:3]([CH3:5])[OH:4].[CH2:9](O)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].CC1C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[NH2:1][CH:2]([CH:3]([OH:4])[CH3:5])[C:6]([O:8][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH3:9])=[O:7]
Reactant: CC(O)C(N)C(=O)O
Reactant: CCCCCCCCCCCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCOC(=O)C(N)C(C)O
Yield: 101.5 %

Procedure:
To a stirred solution of DL-threonine 26 (5 g, 41.9 mmol) in toluene (100 mL) was added 1-dodecanol 2 (7 g, 37.7 mmol) in one lot, followed by pTSA (8.77 g, 46.16 mmol). After addition, the temperature of the reaction mixture was slowly raised to reflux temperature and the water was separated azeotropically. The reaction mixture was monitored by TLC. The reaction mixture was concentrated under vacuum. The obtained residue was taken in ethyl acetate (200 mL) and washed with aqueous 5% Na2CO3 (3×50 mL) followed by brine solution. The organic layer was dried over Na2SO4 and concentrated under vacuum to afford crude 27 (11 g, yield: 91%) as a liquid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1Cl)=[CH:13][CH:12]=[C:11]([Cl:17])[C:10]=2[O:18][CH3:19])=[O:5])[CH3:2].[F:20][CH2:21][CH2:22][CH2:23][CH2:24][NH2:25]>>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:25][CH2:24][CH2:23][CH2:22][CH2:21][F:20])=[CH:13][CH:12]=[C:11]([Cl:17])[C:10]=2[O:18][CH3:19])=[O:5])[CH3:2]
Reactant: NCCCCF
Reactant: CCOC(=O)c1cnc2c(OC)c(Cl)ccc2c1Cl
Product: CCOC(=O)c1cnc2c(OC)c(Cl)ccc2c1NCCCCF

Procedure:
4,7-Dichloro-8-methoxy-quinoline-3-carboxylic acid ethyl ester (250 mg, 84 mmol) was treated with 4-fluoro-butylamine following general procedure B to afford 7-chloro-4-(4-fluoro-butylamino)-8-methoxy-quinoline-3-carboxylic acid ethyl ester (240 mg). Thus obtained amino-ester was hydrolyzed to the corresponding acid using general procedure D and then transformed into the corresponding ethylamide (175 mg) following general procedure E. The above ethylamide (0.52 mmol) was subjected to reaction with methyl chloroformate according to general procedure F to furnish 8-chloro-3-ethyl-1-(4-fluoro-butyl)-7-methoxy-1H-pyrimido[5,4-c]quinoline-2,4-dione (117 mg). LCMS: m/z 380 [M+1]+.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH:5]([C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=1)[C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][CH:7]=1.[Cl:20][C:21]1[CH:36]=[CH:35][C:24]2[N:25]([CH:29]3[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]3)[C:26](=[O:28])[NH:27][C:23]=2[CH:22]=1.C(=O)([O-])[O-].[Na+].[Na+].CC(C)CC(=O)C>O>[Cl:20][C:21]1[CH:36]=[CH:35][C:24]2[N:25]([CH:29]3[CH2:30][CH2:31][N:32]([CH2:2][CH2:3][CH2:4][CH:5]([C:13]4[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=4)[C:6]4[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][CH:7]=4)[CH2:33][CH2:34]3)[C:26](=[O:28])[NH:27][C:23]=2[CH:22]=1
Reactant: ClCCCC(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Reactant: O=c1[nH]c2cc(Cl)ccc2n1C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)CC(C)C
Solvent: O
Product: O=c1[nH]c2cc(Cl)ccc2n1C1CCN(CCCC(c2ccc(Cl)cc2)c2ccc(Cl)cc2)CC1

Procedure:
A mixture of 4.7 parts of 4-chloro-1,1'-butylidene bis[4-chlorobenzene], 3 parts of 5-chloro-1-(4-piperidyl)- 2-benzimidazolinone, 3.7 parts of sodium carbonate and 100 parts of 4-methyl-2-pentanone is stirred and refluxed overnight with water-separator. The reaction mixture is cooled, water is added and the layers are separated. The organic layer is dried, filtered and evaporated. The residue is purified by column-chromatography over silicagel, using a mixture of trichloromethane and 5% of methanol as eluent. The pure fractions are collected and the eluent is evaporated. The residue is crystallized from a mixture of 2-propanol and 2,2'-oxybispropane, yielding 5-chloro-1-{1-[4,4-bis(4-chlorophenyl)butyl]-4-piperidinyl}-1,3-dihydro-2H-benzimidazol-2-one; mp. 165.4° C.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([C:12]2[C:13]([CH3:42])([CH3:41])[C@H:14]3[C@:27]([CH3:30])([CH2:28][CH:29]=2)[C@@H:26]2[C@:17]([CH3:40])([C@@:18]4([CH3:39])[C@H:23]([CH2:24][CH2:25]2)[C@H:22]2[C@H:31]([C:34]([CH3:36])=[CH2:35])[CH2:32][CH2:33][C@:21]2([CH:37]=O)[CH2:20][CH2:19]4)[CH2:16][CH2:15]3)[CH:9]=[CH:8][C:3]=1[C:4]([O:6]C)=[O:5].C(O)(=O)C(O)=O.[NH2:49][CH2:50][CH2:51][N:52]1[CH2:56][CH2:55][CH2:54][C:53]1=[O:57]>>[F:1][C:2]1[CH:11]=[C:10]([C:12]2[C:13]([CH3:42])([CH3:41])[C@H:14]3[C@:27]([CH3:30])([CH2:28][CH:29]=2)[C@@H:26]2[C@:17]([CH3:40])([C@@:18]4([CH3:39])[C@H:23]([CH2:24][CH2:25]2)[C@H:22]2[C@H:31]([C:34]([CH3:36])=[CH2:35])[CH2:32][CH2:33][C@:21]2([CH2:37][NH:49][CH2:50][CH2:51][N:52]2[CH2:56][CH2:55][CH2:54][C:53]2=[O:57])[CH2:20][CH2:19]4)[CH2:16][CH2:15]3)[CH:9]=[CH:8][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: NCCN1CCCC1=O
Reactant: C=C(C)[C@@H]1CC[C@]2(C=O)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)c(F)c6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: O=C(O)C(=O)O
Product: C=C(C)[C@@H]1CC[C@]2(CNCCN3CCCC3=O)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)c(F)c6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Yield: 60 %

Procedure:
The title compound was prepared in 60% yield following steps 5 and 6, using methyl 2-fluoro-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-formyl-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 and 1-(2-aminoethyl)pyrrolidin-2-one oxalate as the reactant amine MS: m/e 673.6 (MH+), 1.72 min (method 2). 1H NMR (400 MHz, MeOD) δ ppm 0.96 (s, 3H) 0.98 (s, 3H) 1.02 (s, 3H) 1.08 (s, 3H) 1.17 (s, 3H) 1.73 (s, 3H) 2.01-2.21 (m, 4H) 2.44 (t, J=8.16 Hz, 2H) 2.51 (td, J=10.79, 5.52 Hz, 1H) 2.94 (d, J=13.05 Hz, 1H) 3.30 (dt, J=3.26, 1.63 Hz, 3H) 3.55 (t, J=7.15 Hz, 2H) 3.58-3.70 (m, 2H) 4.62-4.67 (m, 1H) 4.76 (d, J=1.76 Hz, 1H) 5.35 (dd, J=6.27, 1.76 Hz, 1H) 6.94 (dd, J=11.92, 1.38 Hz, 1H) 7.02 (dd, J=8.03, 1.51 Hz, 1H) 7.83 (t, J=7.91 Hz, 1H). 19F NMR (376 MHz, MeOD) δ ppm −112.75 (s, 1 F).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[CH:13]=[N:12][CH:11]=[N:10]1.C([Li])CCC.[Cl:19]C(Cl)(Cl)C(Cl)(Cl)Cl>C1COCC1>[Cl:19][C:13]1[N:9]([C:3]2[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=2[F:1])[N:10]=[CH:11][N:12]=1
Reactant: Fc1ccc(-n2cncn2)c(F)c1
Reactant: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Fc1ccc(-n2ncnc2Cl)c(F)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 66.3 %

Procedure:
Under an atmosphere of nitrogen a solution of 1-(2,4-difluoro-phenyl)-1H-[1,2,4]triazole (15.7 g, 86.7 mmol) in THF (300 mL) at −78° C. was treated with n-butyllithium (38 mL, 2.5 M, 95.3 mmol) dropwise. After stirring for 1.5 h a solution of hexachloroethane (22.6 g, 95.3 mmol) in THF (30 mL) was added dropwise. The resultant reaction mixture was stirred for 1.5 h before allowing to warm to RT and quenching with water. The resultant mixture was diluted with water and extracted with ethyl acetate, the combined organic extracts were dried (Na2SO4), filtered and concentrated in vacuo to give an oil which crystallised on standing. The solid was recrystallised from cyclohexane to give 5-Chloro-1-(2,4-difluoro-phenyl)-1H-[1,2,4]triazole (12.4 g, 66%). 1H NMR δ (ppm) (CDCl3): 8.04 (1 H, s), 7.51-7.43 (1 H, m), 7.10-7.04 (2 H, m).
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:10]([NH2:13])[CH2:11][CH3:12]>C(Cl)Cl>[CH2:10]([NH:13][C:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:11][CH3:12]
Reactant: O=C(Cl)c1ccccc1
Reactant: CCCN
Solvent: ClCCl
Product: CCCNC(=O)c1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 89.8 %

Procedure:
Dry DCM (30 mL) was added to benzoyl chloride (2.06 mL, 17.7 mmol) followed by the dropwise addition of propylamine (3.19 mL, 38.9 mmol) over 5 min at 0° C. The system was stirred at 0° C. under nitrogen for 1 h and monitored by TLC. After 1 h the system was washed with 1M HCl (20 mL), brine (10 mL) and dried with MgSO4. The solvent was removed to give N-Propylbenzamide as a white solid (2.6 g, 15.9 mmol, 90%); Rf 0.38 (40:60 EtOAc:petrol). mp 87.6-88.9° C. Lit. 83-84° C.7 1H NMR: (300 MHz, CDCl3) δ 0.90 (t, 3H, J=7.4 Hz, CH2—CH2—CH3), 1.56 (sex, 2H, J=7.2 Hz, N—CH2—CH2), 3.33 (m, 2H, N—CH2), 6.21 (bs, 1H, NH), 7.31-7.43 (m, 3H, Ar—H), 7.69 (m, 2H, Ar—H). 13C NMR: (75 MHz, CDCl3) δ 11.8, 23.3, 42.1, 127.2, 128.8, 131.6, 135.2, 167.9. LC/MS-ES+ m/z 164.2 [MH+], 327.1, 328.1.
Reaction SMILES: [CH2:1]([O:5][C:6](=N)[C:7](Cl)(Cl)Cl)[CH2:2][CH2:3][CH3:4].[CH3:12][C:13](=CCC/C(=C/CO)/C)C.B(F)(F)F.C([O-])(O)=O.[Na+]>C1CCCCC1>[CH2:1]([O:5][CH2:6][CH2:7][CH2:12][CH3:13])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOC(=N)C(Cl)(Cl)Cl
Reactant: CC(C)=CCC/C(C)=C/CO
Agent: FB(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCCCC1
Product: CCCCOCCCC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Compound (13) is prepared as follows: To a solution of 18.9 g t.butyltrichloroacetimidate in 50 ml cyclohexane is added a solution of 12.1 g geraniol (10) in 50 ml cyclohexane. After external cooling in ice is added dropwise in 15 min 0.8 ml BF3 -etherate. The reaction mixture is stirred at room temperature for 2 hours. Then 1.0 g NaHCO3 is added and the mixture is stirred for 10 min. The precipitate is filtered off and washed with hexane. After separation, washing with 5% aqueous NaHCO3 -solution and water successively, drying and evaporation to dryness, the organic phase yields 17.3 g of a product. This product is purified by flash chromatography; the desired t.butylether (13) is obtained in a yield of 11.43 g (69%). Identification by NMR: 1H-NMR(CDCl3); δ: 5.33 (t.1H); 5.09 (t.1H); 3.92 (d.2H); 2.15-1.95 (4H); 1.67 (s. 3H); 1.66(s.-3H); 1.59 (s.3H); 1.23 (s.9H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:10](=[O:12])[N:9]([CH3:13])[CH:8]=[N:7][C:6]=2[CH:5]=[C:4]([Cl:14])[N:3]=1.[CH:15]([NH2:18])([CH3:17])[CH3:16]>O1CCOCC1>[Cl:14][C:4]1[N:3]=[C:2]([NH:18][CH:15]([CH3:17])[CH3:16])[C:11]2[C:10](=[O:12])[N:9]([CH3:13])[CH:8]=[N:7][C:6]=2[CH:5]=1
Reactant: CC(C)N
Reactant: Cn1cnc2cc(Cl)nc(Cl)c2c1=O
Solvent: C1COCCO1
Product: CC(C)Nc1nc(Cl)cc2ncn(C)c(=O)c12
Temperature: 80 °C

Procedure:
A mixture of 5,7-dichloro-3-methylpyrido[4,3-d]pyrimidin-4(3H)-one (920.2 mg, 4.0 mmol) and isopropylamine (1.7 mL, 1.182 g, 20.0 mmol) in dioxane (10 mL) was heated at 80° C. for 26 hours and evaporated to result in a residue which was partitioned between saturated NH4Cl solution (200 mL) and EtOAc (100 mL). The aqueous phase was extracted with EtOAc (2×50 mL) and the combined organic phases were washed with brine (20 mL), dried over Na2SO4, and evaporated to afford crude title product. 1H NMR (DMSO-d6) 1.22 (d, J=6.4 Hz, 6H, 2CH3), 3.42 (s, 3H, NCH3), 4.19 (m, 1H), 6.59 (s, 1H), 8.45 (s, 1H), 8.90 (d, J=7.6 Hz, 1H, NH); ESI-MS m/z 253.1 (MH+).
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:18][C:17]([CH3:20])([CH3:19])[CH2:16][C:15]2[N:14]=[C:13]([CH:21]([CH3:23])[CH3:22])[C:12]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[C:11](I)[C:10]1=2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[O:30]1[CH2:35][CH:34]=[C:33](B2OC(C)(C)C(C)(C)O2)[CH2:32][CH2:31]1>>[Si:1]([O:8][C@H:9]1[CH2:18][C:17]([CH3:20])([CH3:19])[CH2:16][C:15]2[N:14]=[C:13]([CH:21]([CH3:23])[CH3:22])[C:12]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[C:11]([C:33]3[CH2:34][CH2:35][O:30][CH2:31][CH:32]=3)[C:10]1=2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC1(C)OB(C2=CCOCC2)OC1(C)C
Reactant: CCOC(=O)c1c(C(C)C)nc2c(c1I)[C@@H](O[Si](C)(C)C(C)(C)C)CC(C)(C)C2
Product: CCOC(=O)c1c(C(C)C)nc2c(c1C1=CCOCC1)[C@@H](O[Si](C)(C)C(C)(C)C)CC(C)(C)C2

Procedure:
Obtained by starting from (S)-ethyl 5-(tert-butyldimethylsilyloxy)-4-iodo-2-isopropyl-7,7-dimethyl-5,6,7,8-tetrahydroquinoline-3-carboxylate and 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane.