Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:9][CH:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:17][CH2:18][OH:19].C(=O)([O-])[O-].[K+].[K+]>C(C(C)=O)C>[OH:19][CH2:18][CH2:17][N:13]1[CH2:14][CH2:15][CH:10]([NH:9][C:1](=[O:8])[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:11][CH2:12]1
Reactant: OCCBr
Reactant: O=C(NC1CCNCC1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: O=C(NC1CCN(CCO)CC1)c1ccccc1
Yield: 62.4 %

Procedure:
A mixture of 2.04 grams (0.01 mole) of 4-benzamidopiperidine, 1.25 grams (1 equivalent) of 2-bromoethanol and 2.76 grams (4 equivalents) of potassium carbonate were stirred at 100° C in 2 milliliters of methyl etyl ketone for 2 hours. The mixture was filtered hot and the inorganic residue was washed well with hot methyl ethyl ketone. The filtrate was evaporated to dryness and the resulting white solid recrystallised from ethyl acetate to give 1.55 grams (62%) of 1-(2-hydroxyethyl)-4-benzamidopiperidine.
Reaction SMILES: Br[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([N:11]2[C:16](=[O:17])[C:15]([CH3:18])=[C:14]([C:19]([F:22])([F:21])[F:20])[N:13]([CH3:23])[C:12]2=[O:24])=[C:4]([F:25])[CH:3]=1.[CH3:26][Si:27]([C:30]#[CH:31])([CH3:29])[CH3:28]>C(N(CC)CC)C.[Cu]I>[F:25][C:4]1[CH:3]=[C:2]([C:31]#[C:30][Si:27]([CH3:29])([CH3:28])[CH3:26])[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]=1[N:11]1[C:16](=[O:17])[C:15]([CH3:18])=[C:14]([C:19]([F:22])([F:21])[F:20])[N:13]([CH3:23])[C:12]1=[O:24]
Reactant: Cc1c(C(F)(F)F)n(C)c(=O)n(-c2cc([N+](=O)[O-])c(Br)cc2F)c1=O
Reactant: C#C[Si](C)(C)C
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: Cc1c(C(F)(F)F)n(C)c(=O)n(-c2cc([N+](=O)[O-])c(C#C[Si](C)(C)C)cc2F)c1=O
Temperature: 25 °C
Reaction time: 5 h
Yield: 87 %

Procedure:
3-(4-Bromo-2-fluoro-5-nitrophenyl)-1,5-dimethyl-6-trifluoromethyl-2,4(1H,3H)-pyrimidinedione (12.85 g), trimethylsilylacetylene (5.93 g), a palladium chloride-ditriphenylphosphine complex (1.06 g) and copper(I) iodide (0.302 g) were suspended in triethylamine (210 ml), and the mixture was stirred at room temperature for 5 hours. After the reaction, triethylamine was distilled off under reduced pressure. Ethyl acetate was added thereto, and insolubles were filtered. Then, ethyl acetate was distilled off, and the resulting residue was purified by chromatography on silica gel (ethyl acetate:n-hexane=1:3) to obtain the objective 3-{2-fluoro-5-nitro-4-[2-(trimethylsilyl)-1-ethynyl]phenyl}-1,5-dimethyl-6-trifluoromethyl-2,4(1H,3H)-pyrimidinedione (11.63 g).
Reaction SMILES: [CH:1]1([CH2:7][OH:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].Br[C:12]1[O:16][C:15]([C:17]([O:19][CH2:20][CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[O:18])=[CH:14][CH:13]=1>CN1C(=O)CCC1>[CH:1]1([CH2:7][O:8][C:12]2[O:16][C:15]([C:17]([O:19][CH2:20][CH:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)=[O:18])=[CH:14][CH:13]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: OCC1CCCCC1
Reactant: O=C(OCC1CCCCC1)c1ccc(Br)o1
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: O=C(OCC1CCCCC1)c1ccc(OCC2CCCCC2)o1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Cyclohexylmethanol (1.60 g, 14.0 mmol) was slowly added to a cooled (0° C.) suspension of sodium hydride (0.30 g, 12.5 mmol) in anhydrous NMP (5 mL) under Ar. A solution of cyclohexylmethyl 5-bromofuran-2-carboxylate (1.79 g, 6.23 mmol) in anhydrous NMP (6 mL) was added to the reaction mixture and stirred overnight at room temperature. The reaction mixture was partitioned between aqueous NH4Cl (25%) and hexanes. Aqueous layer was extracted with hexanes and combined organic layers were washed with brine and concentrated under reduced pressure. Purification by flash chromatography (2%-10% EtOAc—hexanes gradient) gave cyclohexylmethyl 5-(cyclohexylmethoxy)furan-2-carboxylate as a colorless oil. Yield (1.05 g, 53%); 1H NMR (400 MHz, CDCl3) δ 7.10 (d, J=3.4 Hz, 1H), 5.27 (d, J=3.9 Hz, 1H), 4.05 (d, J=6.4 Hz, 2H), 3.91 (d, J=5.9 Hz, 2H), 1.62-1.85 (m, 12H), 1.10-1.33 (m, 6H), 0.94-1.10 (m, 4H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][CH:15]=1)[C:12]1[N:8]([CH:9]=[C:10]([C:16]3[N:20]([CH2:21][CH2:22][OH:23])[N:19]=[C:18]([CH3:24])[N:17]=3)[N:11]=1)[CH2:7][CH2:6][O:5]2.[CH3:25][N:26]1[CH2:31][CH2:30][CH:29]([CH:32]2[CH2:36][CH2:35][CH2:34][NH:33]2)[CH2:28][CH2:27]1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.C(O[Na])(C)(C)C>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:24][C:18]1[N:17]=[C:16]([C:10]2[N:11]=[C:12]3[C:13]4[CH:14]=[CH:15][C:2]([N:33]5[CH2:34][CH2:35][CH2:36][CH:32]5[CH:29]5[CH2:28][CH2:27][N:26]([CH3:25])[CH2:31][CH2:30]5)=[CH:3][C:4]=4[O:5][CH2:6][CH2:7][N:8]3[CH:9]=2)[N:20]([CH2:21][CH2:22][OH:23])[N:19]=1
Reactant: CN1CCC(C2CCCN2)CC1
Reactant: Cc1nc(-c2cn3c(n2)-c2ccc(Br)cc2OCC3)n(CCO)n1
Agent: [Pd]
Agent: CC(C)(C)O[Na]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: C1COCCO1
Product: Cc1nc(-c2cn3c(n2)-c2ccc(N4CCCC4C4CCN(C)CC4)cc2OCC3)n(CCO)n1
Temperature: 100 °C
Reaction time: 8 h
Yield: 3.6 %

Procedure:
A mixture of 2-(5-{12-bromo-9-oxa-3,6-diazatricyclo[8.4.0.02,6]tetradeca-1(14),2,4,10,12-pentaen-4-yl}-3-methyl-1H-1,2,4-triazol-1-yl)ethan-1-ol (80.0 mg, 0.206 mmol), 1-methyl-4-(pyrrolidin-2-yl)piperidine (41.5 mg, 0.247 mmol), Pd2(dba)3 (9.4 mg, 0.010 mmol), Xphos (9.8 mg, 0.021 mmol), and t-BuONa (59.3 mg, 0.618 mmol) in dioxane (10 ml) was degassed with N2 3 times. The resulting mixture was sealed in a microwave vial and stirred at 100° C. overnight. The solid was filtered off. The filtrate was concentrated to give the crude product, which was purified by prep-HPLC (Gilson GX 281, Shim-pack PRC-ODS 250 mm×20 mm×2, gradient: CH3CN/10 mm/L NH4HCO3, 17 min) to afford 237 (3.5 mg, 4% yield) as an off white solid. LCMS (ESI): RT=4.03 min, m/z: 478.4 [M+H+]. 1H NMR (500 MHz, MeOD-d4) δ 8.40 (m, 1H), 8.10-8.09 (d, J=8.5 Hz, 1H), 7.56 (s, 1H), 6.44-6.42 (dd, J=9.0, 2.0 Hz, 1H), 6.17 (d, J=2.5 Hz, 1H), 4.68-4.66 (m, 2H), 4.37-4.32 (m, 4H), 3.93-3.91 (t, J=5.5 Hz, 2H), 3.79-3.76 (m, 1H), 3.46-3.37 (m, 3H), 3.17-3.12 (m, 1H), 2.82 (m, 1H), 2.69 (s, 3H), 2.26 (s, 3H), 1.99-1.82 (m, 6H), 1.73-1.70 (m, 1H), 1.56-1.51 (m, 2H), 1.23-1.19 (m, 2H)
Reaction SMILES: Cl[C:2]([N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[C:8](=[O:15])[NH:7][C:6]2[CH:16]=[CH:17][CH:18]=[N:19][C:5]1=2)=[O:3].[CH2:20]([N:22]([CH2:35][CH3:36])[CH2:23][CH2:24][CH2:25][CH:26]1[CH2:31][CH2:30][N:29]([CH2:32][CH2:33][NH2:34])[CH2:28][CH2:27]1)[CH3:21]>C(OCC)(=O)C>[CH2:35]([N:22]([CH2:20][CH3:21])[CH2:23][CH2:24][CH2:25][CH:26]1[CH2:31][CH2:30][N:29]([CH2:32][CH2:33][NH:34][C:2]([N:4]2[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[C:8](=[O:15])[NH:7][C:6]3[CH:16]=[CH:17][CH:18]=[N:19][C:5]2=3)=[O:3])[CH2:28][CH2:27]1)[CH3:36]
Reactant: CCN(CC)CCCC1CCN(CCN)CC1
Reactant: O=C1Nc2cccnc2N(C(=O)Cl)c2ccccc21
Solvent: CCOC(C)=O
Product: CCN(CC)CCCC1CCN(CCNC(=O)N2c3ccccc3C(=O)Nc3cccnc32)CC1
Yield: 92 %

Procedure:
Prepared analogously to Example 2 from 11-(chlorocarbonyl)-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one and 2[4-[3-(diethylamino)propyl]-piperidin-1-yl]ethanamine in yield of 92% of theory. Colourless crystals, m.p. 165°-166° C. (ethyl acetate).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:22])=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:20][CH3:21])=[C:16]([OH:19])[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:42][O:43][C:44]([C@H:46]1[CH2:51][C@@H:50](O)[CH2:49][CH2:48][N:47]1[C:53]([O:55][C:56]([CH3:59])([CH3:58])[CH3:57])=[O:54])=[O:45]>C(Cl)Cl>[Cl:1][C:2]1[C:3]([F:22])=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:20][CH3:21])=[C:16]([O:19][C@@H:50]4[CH2:49][CH2:48][N:47]([C:53]([O:55][C:56]([CH3:57])([CH3:58])[CH3:59])=[O:54])[C@@H:46]([C:44]([O:43][CH3:42])=[O:45])[CH2:51]4)[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1O
Reactant: COC(=O)[C@H]1C[C@@H](O)CCN1C(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)[C@H]1C[C@H](Oc2cc3c(Nc4cccc(Cl)c4F)ncnc3cc2OC)CCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 62.4 %

Procedure:
DTAD (7.26 g, 31.5 mmol) dissolved in 50 ml of DCM was added over a period of 10 minutes to a stirred suspension of 4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-ol (5.00 g, 15.7 mmol), triphenylphosphine (8.57 g, 62.6 mmol) and (2R,4S)—N-(tert-butoxycarbonyl)-4-hydroxypiperidine-2-carboxylic acid methyl ester (ex ACROS, 5.42 g, 20.9 mmol) in DCM (150 ml) at −15° C. (acetone/ice). The reaction mixture was allowed to warm to room temperature and stirred for 2 hours, concentrated to approximately 50 ml and purified directly by flash chromatography (silica gel, eluting with a gradient from 100% DCM to DCM/EtOAc (80/20) to DCM/EtOAc (50/50) to give 1-tert-butyl 2-methyl (2R,4R)-4-({4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}oxy)piperidine-1,2-dicarboxylate (6) (5.5 g, 81%) as a white foam; 1H NMR Spectrum: (DMSO d6) 1.47-1.53 (m, 11H), 1.86-1.91 (m, 1H), 2.25-2.36 (m, 1H), 2.95-3.13 (m, 1H), 3.70 (s, 3H), 3.95 (s, 3H), 3.98-4.04 (m, 1H), 4.45 (m, 1H), 4.86-4.94 (m, 1H), 7.31 (t, 1H), 7.51-7.64 (m, 3H), 7.80 (s, 1H), 8.39 (s, 1H), 9.54 (s, 1H); Mass Spectrum: (M+H)+ 561.1.
Reaction SMILES: [C:1]([OH:18])(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].CN(C1C=CC=CN=1)C.C1(N=C=NC2CCCCC2)CCCCC1.[C:43]([O:47][C:48](=[O:70])[C@H:49]([CH2:68][SH:69])[NH:50][C:51](=[O:67])[CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH3:66])([CH3:46])([CH3:45])[CH3:44]>C(Cl)(Cl)Cl>[C:43]([O:47][C:48](=[O:70])[C@H:49]([CH2:68][S:69][C:1](=[O:18])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[NH:50][C:51](=[O:67])[CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH3:66])([CH3:44])([CH3:45])[CH3:46]
Reactant: CCCCCCCCCCCCCCCC(=O)N[C@@H](CS)C(=O)OC(C)(C)C
Reactant: CCCCCCCCCCCCCCCC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccccn1
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCCCCCCC(=O)N[C@@H](CSC(=O)CCCCCCCCCCCCCCC)C(=O)OC(C)(C)C

Procedure:
Palmitic acid (2.5 g, 9.6 mmol), dimethylaminopyridine (130 mg, 0.9 mmol) and dicyclohexylcarbodiimide (9.6 mmol) are dissolved in 100 ml of chloroform. The solution is stirred for half an hour and N-palmitoylcysteine tert.-butyl ester (2 g, 4.8 mmol), which has previously been dissolved in 50 ml of chloroform, is added dropwise to the other solution. After 11/2 h, the solvent is removed in a rotary evaporator, and the residue is taken up in 100 ml of chloroform/methanol 1:5. The product forms a voluminous precipitate at -20 degrees C. It is filtered off with suction and dried under high vacuum.
Reaction SMILES: [CH3:1][C:2]1[N:3]([NH:15]C(=O)OC(C)(C)C)[C:4]2[C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[N:7]=[CH:6][C:5]=2[N:14]=1.[ClH:23]>CCO>[ClH:23].[CH3:1][C:2]1[N:3]([NH2:15])[C:4]2[C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[N:7]=[CH:6][C:5]=2[N:14]=1
Reactant: Cc1nc2cnc3ccccc3c2n1NC(=O)OC(C)(C)C
Agent: Cl
Solvent: CCO
Product: Cc1nc2cnc3ccccc3c2n1N

Procedure:
tert-Butyl N-(2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)carbamate (5.00 g, 16.8 mmol) was dissolved in 40 mL of 1.65 M HCl in EtOH, and the reaction mixture was heated to reflux for 2 h. The reaction mixture was cooled and concentrated under reduced pressure to give a brown solid. The brown solid was crystallized from ethanol/H2O to give 3.13 g of 2-methyl-1H-imidazo[4,5-c]quinolin-1-amine hydrochloride.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[NH:16][C:15](=[O:17])[N:14]([CH3:18])[C:13](=[N:19][C:20]3[C:25]([CH3:26])=[CH:24][C:23]([CH3:27])=[CH:22][C:21]=3[CH3:28])[CH:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[CH3:29][C:30](C)([O-])C.[K+].C(I)C.O>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[N:16]([CH2:29][CH3:30])[C:15](=[O:17])[N:14]([CH3:18])[C:13](=[N:19][C:20]3[C:25]([CH3:26])=[CH:24][C:23]([CH3:27])=[CH:22][C:21]=3[CH3:28])[CH:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: CC(C)(C)[O-]
Reactant: COc1ccc(-c2cc(=Nc3c(C)cc(C)cc3C)n(C)c(=O)[nH]2)cc1OC
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCI
Product: CCn1c(-c2ccc(OC)c(OC)c2)cc(=Nc2c(C)cc(C)cc2C)n(C)c1=O
Reaction time: 3 h
Yield: 54.6 %

Procedure:
To a mixture of 3,4-dihydro-6-(3,4-dimethoxyphenyl)-3-methyl-4-(2,4,6-trimethylphenylimino)-2(1H)-pyrimidinone (2.73 g) and potassium tert-butoxide (1.0 g) in dimethylformamide (27 ml) was added ethyl iodide (1.2 ml) and mixture was stirred for 3 hours. Then another potassium tert-butoxide (1.1 g) and ethyl iodide (0.57 ml) were added. The mixture was stirred for more 2 hours and poured into water. The precipitate was collected by filtration and added to 1N hydrochloric acid (15 ml). The mixture was refluxed for 5 hours. After being cooled, the reaction mixture was adjusted to pH 8.5 with aqueous sodium hydroxide. The precipitate was collected by filtration and added to diisopropyl ether (50 ml). The resultant mixture was filtered and the filtrate was evaporated in vacuo. The residue was recrystallized from a mixture of ethanol and water (3:1) to give 3,4-dihydro-6-(3,4-dimethoxyphenyl)-1-ethyl-3-methyl-4-(2,4,6-tri-methylphenylimino)-2(1H)-pyrimidinone (1.6 g). mp 116° -118° C.
Reaction SMILES: FC(F)(F)C(O)=O.[OH:8][C:9]1[C:10]([C:19]([NH:21][C:22]2[CH:34]=[C:33]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[CH:32]=[CH:31][C:23]=2[C:24]([O:26]C(C)(C)C)=[O:25])=[O:20])=[CH:11][C:12]2[O:17][CH2:16][CH2:15][O:14][C:13]=2[CH:18]=1>C(Cl)Cl>[OH:8][C:9]1[C:10]([C:19]([NH:21][C:22]2[CH:34]=[C:33]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[CH:32]=[CH:31][C:23]=2[C:24]([OH:26])=[O:25])=[O:20])=[CH:11][C:12]2[O:17][CH2:16][CH2:15][O:14][C:13]=2[CH:18]=1
Reactant: CC(C)(C)OC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1cc2c(cc1O)OCCO2
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(Nc1cc(-c2ccccc2)ccc1C(=O)O)c1cc2c(cc1O)OCCO2
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 92.7 %

Procedure:
A trifluoroacetic acid (4 mL) solution of the obtained tert-butyl 2-(7-hydroxy-2,3-dihydrobenzo[1,4]dioxine-6-carboxamido)-4-phenylbenzoate (0.37 g) was stirred at room temperature for 15 minutes. Methylene chloride (10 mL) was added to the reaction mixture, followed by stirring at room temperature for 1 hour and 15 minutes. The solvent was evaporated under reduced pressure, and ethyl acetate was added to the obtained residue. The solid substance was collected by filtration to obtain 0.30 g of 2-(7-hydroxy-2,3-dihydrobenzo[1,4]dioxine-6-carboxamido)-4-phenylbenzoic acid as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[S:10][CH:11]=[C:12]([C:14]([O:16]CC)=[O:15])[N:13]=1.[OH-].[Na+].Cl>CCO>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[S:10][CH:11]=[C:12]([C:14]([OH:16])=[O:15])[N:13]=1
Reactant: CCOC(=O)c1csc(-c2ccccc2OC)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccccc1-c1nc(C(=O)O)cs1
Temperature: 25 °C

Procedure:
To a stirred solution of ethyl 2-(2-methoxy-phenyl)thiazole-4-carboxylate (0.27 g, 1.03 mmol) in EtOH (10 mL) was added 1N NaOH (aq) (5 mL). The resulting mixture was heated to reflux for 2 h. The mixture was cooled to RT, acidified with 1N HCl (aq) and concentrated by rotary evaporation. The residue was extracted with CH2Cl2 (3×15 mL). The extracts were combined, dried over MgSO4, filtered and concentrated by rotary evaporation to afford the title compound as an off-white solid. EI-MS m/z 236 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:22]=[CH:21][C:6]([CH2:7][O:8][C@H:9]([C@H:11]([OH:20])[C@H:12]([CH:18]=[CH2:19])[CH2:13][CH2:14][CH:15]([CH3:17])[CH3:16])[CH3:10])=[CH:5][CH:4]=1.[H-].[Na+].Br[CH2:26][CH:27]1[CH2:29][CH2:28]1>CN(C=O)C>[CH:27]1([CH2:26][O:20][C@H:11]([C@H:12]([CH:18]=[CH2:19])[CH2:13][CH2:14][CH:15]([CH3:16])[CH3:17])[C@@H:9]([O:8][CH2:7][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:22][CH:21]=2)[CH3:10])[CH2:29][CH2:28]1
Reactant: C=C[C@H](CCC(C)C)[C@@H](O)[C@H](C)OCc1ccc(OC)cc1
Reactant: BrCC1CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=C[C@H](CCC(C)C)[C@@H](OCC1CC1)[C@H](C)OCc1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 82.4 %

Procedure:
A solution of (2S,3R,4S)-2-((4-methoxybenzyl)oxy)-7-methyl-4-vinyloctan-3-ol (2.0 g, 6.53 mmol) in anhydrous DMF (12 mL) was added at room temperature to a solution of NaH (NaH; 0.326 g, 8.16 mmol, 60% dispersion in mineral oil) in anhydrous DMF (12 ml). The reaction was stirred for 15 minutes (min) at room temperature, treated with (bromomethyl)cyclopropane (0.823 ml, 8.48 mmol) at room temperature, and then was heated to 40° C. for and stirred for 6 h. The reaction was cooled to room temperature and additional NaH (0.131 g, 3.27 mmol) and (bromomethyl)cyclopropane (0.317 mL, 3.27 mmol) were added, and the reaction was heated at 45° C. for 4 h. The reaction was again cooled to room temperature and a third batch of NaH (0.131 g, 3.27 mmol) followed by (bromomethyl)cyclopropane (0.317 mL, 3.27 mmol) was added and the reaction was heated at 45° C. for 2 h. The reaction mixture was quenched with saturated aqueous ammonium chloride (NH4Cl) and the phases were separated. The aqueous phase was extracted with diethyl ether (Et2O), and the combined organic phases were washed with brine, dried over magnesium sulfate (MgSO4), concentrated, and purified by column chromatography on SiO2 (gradient, hexanes/ethyl acetate) to furnish the title product as a colorless oil (1.94 g, 82%): IR (neat) 2953, 2868, 1613, 1513, 1247, 1084 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.25-7.20 (m, 2H), 6.89-6.81 (m, 2H), 5.52 (dt, J=17.0, 10.0 Hz, 1H), 5.03-4.92 (m, 2H), 4.52-4.32 (m, 2H), 3.78 (s, 3H), 3.65-3.56 (m, 2H), 3.34 (dd, J=10.0, 6.9 Hz, 1H), 3.28-3.22 (m, 1H), 2.09 (tdd, J=10.1, 7.7, 3.1 Hz, 1H), 1.81-1.67 (m, 1H), 1.55-1.42 (m, 1H), 1.28-1.13 (m, 2H), 1.19 (d, J=6.3 Hz, 3H), 1.13-0.95 (m, 2H), 0.87 (d, J=6.4 Hz, 3H), 0.86 (d, J=6.8 Hz, 3H), 0.56-0.45 (m, 2H), 0.25-0.14 (m, 2H); ESIMS m/z 383.4 ([M+Na]+).
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]1([CH2:22][O:21][C:20]3[CH:23]=[C:24]4[C:28](=[CH:29][C:19]1=3)[CH2:27][CH2:26][O:25]4)[C:5](=[O:18])[N:6]2[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1.BrC1C=CC=C2C=1C1(C3=CC4OCOC=4C=C3OC1)C(=O)N2CCCCC.[N:57]1[CH:62]=[C:61](B(O)O)[CH:60]=[N:59][CH:58]=1.CN(C)C1N=CC(B(O)O)=CC=1>>[N:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[CH2:11][N:6]1[C:7]2[C:3](=[C:2]([C:61]3[CH:62]=[N:57][CH:58]=[N:59][CH:60]=3)[CH:10]=[CH:9][CH:8]=2)[C:4]2([CH2:22][O:21][C:20]3[CH:23]=[C:24]4[C:28](=[CH:29][C:19]2=3)[CH2:27][CH2:26][O:25]4)[C:5]1=[O:18]
Reactant: OB(O)c1cncnc1
Reactant: O=C1N(Cc2ccccn2)c2cccc(Br)c2C12COc1cc3c(cc12)CCO3
Agent: CCCCCN1C(=O)C2(COc3cc4c(cc32)OCO4)c2c(Br)cccc21
Agent: CN(C)c1ccc(B(O)O)cn1
Product: O=C1N(Cc2ccccn2)c2cccc(-c3cncnc3)c2C12COc1cc3c(cc12)CCO3

Procedure:
Following the procedure as described in EXAMPLE 4, and making non-critical variations using 4′-bromo-1′-(pyridin-2-ylmethyl)-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one to replace 4′-bromo-1′-pentylspiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one, and pyrimidin-5-ylboronic acid to replace [6-(dimethylamino)pyridin-3-yl]boronic acid, the title compound was obtained (16%) as a colorless solid: mp >200° C.; 1H NMR (300 MHz, CDCl3) δ 9.09 (s, 1H), 8.59 (d, 1H), 8.14 (s, 2H), 7.74 (t, 1H), 7.67 (d, 1H), 7.63 (d, 1H), 7.52 (d, 1H), 7.47-7.42 (m, 1H), 7.37 (d, 1H), 7.30 (d, 1H), 7.09 (d, 1H), 6.82 (d, 1H), 6.62 (s, 1H), 6.07 (s, 1H), 5.18 (ABq, 2H), 4.62 (ABq, 2H), 4.62-4.48 (m, 2H), 3.02 (t, 2H); MS (ES+) m/z 449.5 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[CH2:23][C:24]1[CH:25]=[C:26]([C:30]2[CH:35]=[C:34]([O:36][CH3:37])[C:33]([O:38][CH3:39])=[C:32]([O:40][CH3:41])[CH:31]=2)[CH:27]=[N:28][CH:29]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)[CH2:23][C:24]2[CH:25]=[C:26]([C:30]3[CH:35]=[C:34]([O:36][CH3:37])[C:33]([O:38][CH3:39])=[C:32]([O:40][CH3:41])[CH:31]=3)[CH:27]=[N:28][CH:29]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(NC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Reactant: COc1cc(-c2cncc(CCl)c2)cc(OC)c1OC
Product: COc1cc(-c2cncc(CN(c3ccc(C)cc3)C3CCN(C(=O)OC(C)(C)C)CC3)c2)cc(OC)c1OC

Procedure:
1-(tert-Butoxycarbonyl)-4-[(4-methylphenyl)amino]piperidine (581 mg) and 5-chloromethyl-3-(3,4,5-trimethoxyphenyl)pyridine (588 mg) was treated in the same manner as described in Example 9 to give light yellow amorphous of the title compound.
Reaction SMILES: [CH2:1]([N:3]([CH2:21][CH3:22])[CH:4]=[CH:5][C:6]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:11][CH:10]=1)=[O:7])[CH3:2].N1CC[CH:26]([CH2:29][OH:30])CC1.C(OC1C=CC(C2C=CC=CC=2)=CC=1)(=O)C#C>>[OH:30][CH2:29][CH:26]1[CH2:2][CH2:1][N:3](/[CH:4]=[CH:5]/[C:6]([O:8][C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:13][CH:14]=2)=[O:7])[CH2:21][CH2:22]1
Reactant: OCC1CCNCC1
Reactant: CCN(C=CC(=O)Oc1ccc(-c2ccccc2)cc1)CC
Agent: C#CC(=O)Oc1ccc(-c2ccccc2)cc1
Product: O=C(/C=C/N1CCC(CO)CC1)Oc1ccc(-c2ccccc2)cc1
Yield: 84 %

Procedure:
The compound 39 was prepared according to the method described for compound 2 employing piperidin-4-ylmethanol (900 mg, 4.05 mmol) and compound 1 (466 mg, 4.05 mmol) to give white solid compound 39 (1.15 g, 84%). 1H NMR (300 MHz, CD2Cl2) δ 1.29 (m, 1H), 1.80 (m, 2H), 3.08 (br s, 1H), 3.51 (s, 2H), 3.62 (d, J=9.9 Hz, 2H), 4.82 (d, J=13.0 Hz, 1H), 7.15 (d, J=8.2 Hz, 2H), 7.35 (m, 1H), 7.45 (t, J=7.0 Hz, 2H), 7.60 (br s, 5H). HRMS ESI (m/z): Calculated for C21H23NO3 ([M+Na]+): 338.1678. found: 338.1751.
Reaction SMILES: [O:1]=[C:2]1[CH2:19][CH2:18][C@@:17]2([CH3:20])[C:4](=[CH:5][CH2:6][C@@H:7]3[C@@H:16]2[CH2:15][CH2:14][C@@:12]2([CH3:13])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C:21]([OH:23])=[O:22])[NH:3]1.C([O-])(=O)C.[NH4+]>C(O)(=O)C>[CH3:13][C@@:12]12[C@@H:11]([C:21]([OH:23])=[O:22])[CH2:10][CH2:9][C@H:8]1[C@@H:7]1[CH2:6][CH2:5][C@H:4]3[NH:3][C:2](=[O:1])[CH2:19][CH2:18][C@:17]3([CH3:20])[C@H:16]1[CH2:15][CH2:14]2
Reactant: C[C@]12CC[C@H]3[C@@H](CC=C4NC(=O)CC[C@@]43C)[C@@H]1CC[C@@H]2C(=O)O
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Product: C[C@]12CCC(=O)N[C@@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](C(=O)O)CC[C@@H]12
Reaction time: 0.5 h

Procedure:
The hydrogenation vessel was charged with acetic acid (530 l), 3-oxo-4-aza-5-androstene-17β-carboxylic acid 2 (33.5 kg.), and ammonium acetate (1.0 kg, 0.1 eq.). After purging at 20-25° C. with nitrogen, the platinum oxide catalyst (3.0 kg.) was charged, the stirrer started and the temperature adjusted to 20-25° C. After purging with hydrogen, the stirring batch was allowed to take up hydrogen. After 30 minutes at ≦30° C., the temperature was adjusted to 60-65° C., and stirring continued until hydrogen uptake ceased. After purging with nitrogen, Solka Floc (1.7 kg.) was charged, and the hot reaction mixture recirculated through a filter until the solution was clear. The hot reaction filtrate was transferred to a clean vessel. The reactor was rinsed with hot acetic acid (100 l.), and the rinse was recirculated as a wash through the filter. The combined filtrates/wash were distilled under vacuum at ≦70° C. to about 3.6 volumes. The resulting slurry was cooled to ≦25° C. Methanol (130 l.) was added and the mixture stirred for at least 2 hours at ≦25° C. The product was collected by filtration; the cake washed with methanol and dried in vacuo at ≦60° C. Weight range: 25-28.5 kg (75-85% theory, 75-85% w/w).