Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][C@H:3]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH2:2]1.[CH:15](=O)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].O>C(Cl)Cl>[CH2:15]([N:1]1[CH2:6][CH2:5][CH2:4][C@H:3]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:11])([CH3:13])[CH3:12])[CH2:2]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=Cc1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)N[C@H]1CCCN(Cc2ccccc2)C1
Reaction time: 8 h
Yield: 34.4 %

Procedure:
To a solution of (S)-tert-butyl piperidin-3-ylcarbamate (2.0 g, 10.0 mmol) and benzaldehyde (1.3 g, 12.0 mmol) in CH2Cl2 under nitrogen was added NaBH(OAc)3 (4.2 g, 20.0 mmol) and the reaction was stirred for overnight. The mixture was diluted with CH2Cl2 (50 mL) and ice cooled water (20 mL). The CH2Cl2 layer was separated and the aqueous layer was extracted with CH2Cl2 (3×20 mL). The combined CH2Cl2 layer was dried over Na2SO4 and evaporated in vacuo to give the crude product which was purified by column chromatography (silica gel, gradient EtOAc in hexanes) to afford (1.0 g, 34%) of the titled intermediate. LC-MS: m/z [M+1]=291.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[C:5]1[C:10]([NH:11][CH2:12][CH2:13][CH2:14][CH3:15])=[C:9]([NH2:16])[C:8]([NH:17][CH2:18][CH:19]([CH3:21])[CH3:20])=[N:7][C:6]=1[CH3:22])[CH3:2].C(O)(=O)C.[N:28]([O-])=O.[Na+]>O>[CH2:1]([O:3][C:4]([C:5]1[C:10]([NH:11][CH2:12][CH2:13][CH2:14][CH3:15])=[C:9]2[N:16]=[N:28][N:17]([CH2:18][CH:19]([CH3:21])[CH3:20])[C:8]2=[N:7][C:6]=1[CH3:22])=[O:23])[CH3:2]
Reactant: O=N[O-]
Reactant: CCCCNc1c(N)c(NCC(C)C)nc(C)c1C(=O)OCC
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CCCCNc1c(C(=O)OCC)c(C)nc2c1nnn2CC(C)C
Reaction time: 10 h

Procedure:
33 g. of the oil obtained in part d, 5-amino-4-butylamino-6-(2-methylpropyl)amino-2-methylnicotinic acid ethyl ester (about 0.1 mol.), are dissolved in 100 ml. of acetic acid 20 ml. of water. A solution of 0.75 g. of sodium nitrite in 20 ml. of water is added dropwise at about 10° with stirring. Stirring is continued for 10 hours. After this time, the mixture is evaporated. The resulting oil is mixed with 100 ml. of water and extracted three times with 50 ml. portions of ether. The ether phase is dried over sodium sulfate, filtered and evaporated. The residue, 7-butylamino-5-methyl-3-(2-methylpropyl) [1,2,3]triazolo[4,5-b]pyridine-6-carboxylic acid ethyl ester, is recrystallized from benzene, yield 27 g. (81%), m.p. 34°-36°.
Reaction SMILES: [CH3:1][C:2]1([CH3:38])[C:26](=[O:27])[CH2:25][CH2:24][C@@:23]2([CH3:28])[C:3]1=[CH:4][CH2:5][C@@H:6]1[C@@H:22]2[CH2:21][CH2:20][C@@:19]2([CH3:29])[C@H:7]1[CH2:8][C@H:9]([O:30][Si](C(C)(C)C)(C)C)[C@@H:10]2[C@H:11]([CH3:18])[CH2:12][CH2:13][CH2:14][CH:15]([CH3:17])[CH3:16].Cl>C(O)C>[CH3:38][C:2]1([CH3:1])[C:26](=[O:27])[CH2:25][CH2:24][C@@:23]2([CH3:28])[C:3]1=[CH:4][CH2:5][C@@H:6]1[C@@H:22]2[CH2:21][CH2:20][C@@:19]2([CH3:29])[C@H:7]1[CH2:8][CH:9]([OH:30])[C@@H:10]2[C@H:11]([CH3:18])[CH2:12][CH2:13][CH2:14][CH:15]([CH3:17])[CH3:16]
Reactant: CC(C)CCC[C@@H](C)[C@H]1[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H]2[C@@H]3CC=C4C(C)(C)C(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: Cl
Solvent: CCO
Product: CC(C)CCC[C@@H](C)[C@H]1C(O)C[C@H]2[C@@H]3CC=C4C(C)(C)C(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Yield: 66.6 %

Procedure:
A mixture of 4,4-dimethyl-16β-(tert-butyldimethylsilyloxy)cholest-5-en-3-one (40 mg, 0.07 mmol), concentrated HCl (0.2 mL) and ethanol (5 mL) were heated to reflux for 20 hours. Removal of solvent under reduced pressure and recrystallization twice from methanol gave 4,4-dimethylcholest-5-en-16-ol-3-one (20 mg).
Reaction SMILES: B#B.[C:3]([NH:6][C:7]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:8]=1[CH:9]=[CH:10][CH:11]=[C:12]2[S:17]([NH:20][C:21]1[C:26]([O:27][CH3:28])=[N:25][C:24]([Br:29])=[CH:23][N:22]=1)(=[O:19])=[O:18])(=O)[CH3:4]>C1COCC1>[CH2:3]([NH:6][C:7]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:8]=1[CH:9]=[CH:10][CH:11]=[C:12]2[S:17]([NH:20][C:21]1[C:26]([O:27][CH3:28])=[N:25][C:24]([Br:29])=[CH:23][N:22]=1)(=[O:19])=[O:18])[CH3:4]
Reactant: COc1nc(Br)cnc1NS(=O)(=O)c1cccc2c(NC(C)=O)cccc12
Agent: B#B
Solvent: C1CCOC1
Product: CCNc1cccc2c(S(=O)(=O)Nc3ncc(Br)nc3OC)cccc12
Yield: 32.7 %

Procedure:
A 1.0M solution of diborane in THF (6.65 ml) was added to a solution of 5-acetamido-N-(5-bromo-3-methoxy-2-pyrazinyl)-1-naphthalenesulphonamide (0.725 g) in dry THF (60 ml) at 0° C. under argon. The solution was heated under reflux for 24 hours and then volatile material was removed by evaporation. The residue was purified by flash chromatography, eluting with ethyl acetate/hexane (7:13 v/v), to give 5-ethylamino-N-(5-bromo-3-methoxy-2-pyrazinyl)-1-naphthalenesulphonamide (0.23 g), m.p. 216°-218° C. (after trituration with ether); 1H NMR (d6 -DMSO): 1.3 (t,3H), 3.25 (q,2H), 3.9 (s,3H), 6.6 (d,1H), 7.4-7.6 (m,2H), 7.75 (s,1H), 7.95 (d,1H), 8.25 (d,1H), 8.5 (d,1H), 11.3-11.5 (br, 1H); mass spectrum (+ve FAB, methanol/NBA): 438 (M+H)+.
Reaction SMILES: CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.Cl[C:36]1[C:45]2[C:40](=[CH:41][C:42]([F:46])=[CH:43][CH:44]=2)[N:39]=[C:38]([C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][N:48]=2)[C:37]=1[CH3:53].[NH2:54][C:55]1[CH:56]=[C:57]([CH:62]=[C:63]([N:65]2[CH2:70][CH2:69][O:68][CH2:67][CH2:66]2)[CH:64]=1)[C:58]([NH:60][CH3:61])=[O:59].C(=O)([O-])[O-].[K+].[K+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(O)(C)(C)C>[F:46][C:42]1[CH:41]=[C:40]2[C:45]([C:36]([NH:54][C:55]3[CH:56]=[C:57]([CH:62]=[C:63]([N:65]4[CH2:66][CH2:67][O:68][CH2:69][CH2:70]4)[CH:64]=3)[C:58]([NH:60][CH3:61])=[O:59])=[C:37]([CH3:53])[C:38]([C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][N:48]=3)=[N:39]2)=[CH:44][CH:43]=1
Reactant: Cc1c(-c2ccccn2)nc2cc(F)ccc2c1Cl
Reactant: CNC(=O)c1cc(N)cc(N2CCOCC2)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: CC(C)(C)O
Product: CNC(=O)c1cc(Nc2c(C)c(-c3ccccn3)nc3cc(F)ccc23)cc(N2CCOCC2)c1

Procedure:
Prepared according to Procedure X using palladium (II) acetate (2.1 mg, 9.17 μmol), XPhos (0.013 g, 0.028 mmol), 4-chloro-7-fluoro-3-methyl-2-(pyridin-2-yl)quinoline (0.050 g, 0.183 mmol), 3-amino-N-methyl-5-morpholinobenzamide (0.043 g, 0.183 mmol), potassium carbonate (0.063 g, 0.458 mmol), and tert-butanol (1 mL). Purification using column chromatography (silica; 0-5% methanol in DCM) afforded 3-((7-fluoro-3-methyl-2-(2-pyridinyl)-4-quinolinyl)amino)-N-methyl-5-(4-morpholinyl)benzamide as a yellow amorphous solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.70-8.76 (1H, m), 7.80-7.95 (3H, m), 7.72-7.79 (1H, m), 7.35-7.44 (1H, m), 7.14-7.23 (1H, m), 6.88-6.96 (1H, m), 6.53-6.59 (1H, m), 6.36-6.43 (1H, m), 6.21-6.32 (1H, m), 6.15 (1H, br. s.), 3.76-3.84 (4H, m), 3.07-3.14 (4H, m), 2.93 (3H, d, J=4.7 Hz), 2.33 (3H, s). Mass Spectrum (ESI) m/e=472.1 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2([C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][C:24]4[N:29]=[CH:28][N:27]=[C:26]5[N:30](C6CCCCO6)[N:31]=[CH:32][C:25]=45)=[CH:19][CH:18]=3)=[O:15])[CH2:13][CH2:12]2)=[O:10])=[CH:4][CH:3]=1.Cl.O1CCOCC1>CCOCC>[F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([C:11]2([C:14]([NH:16][C:17]3[CH:18]=[CH:19][C:20]([O:23][C:24]4[N:29]=[CH:28][N:27]=[C:26]5[NH:30][N:31]=[CH:32][C:25]=45)=[CH:21][CH:22]=3)=[O:15])[CH2:13][CH2:12]2)=[O:10])=[CH:6][CH:7]=1
Reactant: O=C(Nc1ccc(F)cc1)C1(C(=O)Nc2ccc(Oc3ncnc4c3cnn4C3CCCCO3)cc2)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: O=C(Nc1ccc(F)cc1)C1(C(=O)Nc2ccc(Oc3ncnc4[nH]ncc34)cc2)CC1
Yield: 62.4 %

Procedure:
To a round bottom flask equipped with a magnetic stir bar was added N-(4-fluorophenyl)-N′-(4-{[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl]oxy}phenyl)cyclopropane-1,1-dicarboxamide (0.050 mg, 0.10 mmol, 1.0 eq.) and 4M HCl/Dioxane (5 ml). After 5 minutes ether was added. The resulting solid was filtered and washed twice with ether. The solid was further dried under vacuum to give N-(4-fluorophenyl)-N′-[4-(1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)phenyl]cyclopropane-1,1-dicarboxamide (0.027 g, 67% yield). 1H NMR (400 MHz, DMSO): 10.20 (s, 1H), 10.10 (s, 1H), 8.50 (s, 1H), 8.06 (s, 1H), 7.75 (m, 2H), 7.67 (m, 2H), 7.27 (m, 2H), 7.13 (m, 2H), 4.47 (bs, 1H), 1.47 (s, 4H); MS (ESI) for C22H17FN6O3: 433 (MH+).
Reaction SMILES: [OH-].[Na+].[CH:3]1([CH2:7][O:8][C:9]2[C:17]3[N:16]([CH2:18][CH2:19][CH:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)[C:15](=[O:26])[N:14]([CH3:27])[C:13]=3[CH:12]=[CH:11][C:10]=2[C:28]2[C:29]3[CH:38]=[CH:37][N:36](S(C4C=CC(C)=CC=4)(=O)=O)[C:30]=3[C:31](=[O:35])[N:32]([CH3:34])[CH:33]=2)[CH2:6][CH2:5][CH2:4]1>O.CO>[CH:3]1([CH2:7][O:8][C:9]2[C:17]3[N:16]([CH2:18][CH2:19][CH:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)[C:15](=[O:26])[N:14]([CH3:27])[C:13]=3[CH:12]=[CH:11][C:10]=2[C:28]2[C:29]3[CH:38]=[CH:37][NH:36][C:30]=3[C:31](=[O:35])[N:32]([CH3:34])[CH:33]=2)[CH2:6][CH2:5][CH2:4]1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(-c4ccc5c(c4OCC4CCC4)n(CCC4CCNCC4)c(=O)n5C)cn(C)c(=O)c32)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cn1cc(-c2ccc3c(c2OCC2CCC2)n(CCC2CCNCC2)c(=O)n3C)c2cc[nH]c2c1=O
Temperature: 60 °C
Reaction time: 1 h
Yield: 7.2 %

Procedure:
A 3.0 M solution of sodium hydroxide in water (0.40 L) was added to the solution of 4-(cyclobutylmethoxy)-1-methyl-5-{6-methyl-1-[(4-methylphenyl)sulfonyl]-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl}-3-(2-piperidin-4-ylethyl)-1,3-dihydro-2H-benzimidazol-2-one (20.0 mg, 0.031 mmol) in methanol (1.0 mL), and the resultant reaction mixture was stirred at 60° C. for 1 h. The reaction mixture was purified via preparative LCMS (XBridge C18 column, eluting with a gradient of acetonitrile/water 0.1% ammonium hydroxide, at flow rate of 60 mL/min) to give the desired product (1.1 mg, 7%). LCMS calculated for C28H36N5O3 (M+H)+: m/z=490.3. found: 490.3.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[C:4](Cl)[N:3]=1.[F:13][C:14]1[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:15]=1[CH2:16][NH2:17].C(N(CC)CC)C>CO>[CH3:11][O:10][C:8]([C:6]1[CH:5]=[C:4]([NH:17][CH2:16][C:15]2[CH:18]=[CH:19][C:20]([F:22])=[CH:21][C:14]=2[F:13])[N:3]=[C:2]([Cl:1])[N:7]=1)=[O:9]
Reactant: COC(=O)c1cc(Cl)nc(Cl)n1
Reactant: NCc1ccc(F)cc1F
Solvent: CCN(CC)CC
Solvent: CO
Product: COC(=O)c1cc(NCc2ccc(F)cc2F)nc(Cl)n1
Reaction time: 1 h
Yield: 45.93 %

Procedure:
A suspension of methyl 2,6-dichloropyrimidine-4-carboxylate (1 g, 4.87 mmol) in methanol (20 ml) was cooled to −20° C., to this 2,4-difluoro benzylamine (0.627 mg, 4.39 mmol) and triethylamine (0.98 mg, 9.74 mmol) were added. The reaction mixture was stirred at same temperature for 1 hr then at room temperature for 4 hrs. Methanol was removed under vacuum. The residue was purified by column chromatography to get the title compound.
Reaction SMILES: CN.[N:3]1[CH:8]=[CH:7][C:6]([C:9]2([C:14]([S:16]C)=S)[CH2:13][CH2:12][CH2:11][S:10]2)=[CH:5][CH:4]=1.C.[C:19](#[N:21])C>C(O)C>[CH3:19][NH:21][C:14]([C:9]1([C:6]2[CH:7]=[CH:8][N:3]=[CH:4][CH:5]=2)[CH2:13][CH2:12][CH2:11][S:10]1)=[S:16]
Reactant: CSC(=S)C1(c2ccncc2)CCCS1
Reactant: CC#N
Agent: CN
Solvent: CCO
Product: CNC(=S)C1(c2ccncc2)CCCS1
Temperature: 20 °C
Reaction time: 1 h

Procedure:
A 33% (weight/volume) solution of methylamine in ethanol (12 cc) is added dropwise, in the course of 15 minutes, to a solution of methyl 2-(pyrid-4-yl)-tetrahydrothiophen-2-carbodithioate (16 g) in ethanol (35 cc), kept at 20° C. The solution is subsequently stirred for 1 hour at a temperature of about 20° C. and is then cooled to 0° C. The resulting crystals are filtered off, washed twice with ethanol (30 cc in total) and dried under reduced pressure (20 mm Hg; 2.7 kPa) at a temperature of about 20° C. A crystalline crude product (11 g) is thus obtained, which is redissolved in boiling ethanol (100 cc); decolourising charcoal (0.3 g) is added to the solution obtained, which is filtered hot, and the filtrate is then cooled for one hour at 0° C. The resulting crystals are filtered off, washed twice with ethanol (20 cc in total) and dried under reduced pressure (20 mm Hg; 2.7 kPa) at a temperature of about 20° C. The product thus obtained (9 g) is chromatographed on neutral silica gel (20 g) contained in a column of diameter 1.7 cm. Elution is carried out with methylene chloride (1000 cc) and then with a methylene chloride/ethanol mixture (90/10 by volume; 250 cc), 250 cc fractions being collected. Fractions 1 to 5 are combined and concentrated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at 50° C. The product thus obtained (8 g) is dissolved in boiling ethanol (94 cc); decolourising charcoal (0.4 g) is added to the solution, which is filtered hot, and the filtrate is then cooled for 15 hours at a temperature of about 5° C. The resulting crystals are filtered off, washed twice with ethanol (14 cc in total) and dried under reduced pressure (20 mm Hg; 2.7 kPa) at a temperature of about 20° C. The product thus obtained (6.9 g) is dissolved in boiling acetonitrile (75 cc) and the solution, to which decolourising charcoal (0.2 g) is added, is filtered hot and the filtrate is then cooled for 1 hour at 0° C. The resulting crystals are filtered off, washed with acetonitrile (7 cc) and dried under reduced pressure (1 mm Hg; 0.13 kPa) at 60° C. N-Methyl-2-(pyrid-4-yl)-tetrahydrothiophen-2-carbothioamide (5.9 g), melting at 178° C., is thus obtained.
Reaction SMILES: [N:1]1([CH:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)[CH2:6][CH2:5][CH:4]([N:7]2[CH:11]3[CH2:12][CH2:13][CH2:14][CH2:15][CH:10]3[NH:9][C:8]2=[O:16])[CH2:3][CH2:2]1.C(N(C(C)C)CC)(C)C.[S:32]1[CH:36]=[CH:35][CH:34]=[C:33]1[C:37](Cl)=[O:38]>ClCCl.C(Cl)(Cl)Cl>[S:32]1[CH:36]=[CH:35][CH:34]=[C:33]1[C:37]([N:20]1[CH2:21][CH2:22][CH:17]([N:1]2[CH2:2][CH2:3][CH:4]([N:7]3[CH:11]4[CH2:12][CH2:13][CH2:14][CH2:15][CH:10]4[NH:9][C:8]3=[O:16])[CH2:5][CH2:6]2)[CH2:18][CH2:19]1)=[O:38]
Reactant: O=C(Cl)c1cccs1
Reactant: O=C1NC2CCCCC2N1C1CCN(C2CCNCC2)CC1
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1cccs1)N1CCC(N2CCC(N3C(=O)NC4CCCCC43)CC2)CC1
Reaction time: 48 h

Procedure:
To a solution of (trans (+/−))-1-(1,4′-bipiperidin-4-yl)octahydro-2H-benzimidazol-2-one. 2TFA (180 mg, 0.31 mmol) in a mixture of dichloromethane and chloroform (1:4) was added diisopropylethylamine (0.2 mL, 1.1 mmol) followed by thiophene-2-carbonyl chloride (0.1 mL, 0.6 mmol) at room temperature. The mixture stirred 48 hours and then quenched with water. Diluted in dichloromethane (60 mL) and washed with 1N NaOH (5 mL) and brine (5 mL) and concentrated in vacuo. The crude was purified by high pH prep LCMS (acetonitrile/water) to provide 26 mg of the title compound as a white solid. 1H NMR (400 MHz, CHLOROFORM-D): δ ppm 1.26-1.58 (m, 6H), 1.59-2.03 (m, 9H), 2.12-2.34 (m, 3H), 2.44-2.64 (m, 1H), 2.82-3.06 (m, 6H), 3.62-3.84 (m, 1H), 4.29-4.57 (m, 2H), 4.63 (s, 1H), 7.01 (d, J=5.08 Hz, 1H), 7.18-7.27 (m, 1H), 7.35-7.46 (m, 1H). MS (M+1): 417.3
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:15]=[N:16][C:17]([O:20][CH2:21][CH3:22])=[CH:18][CH:19]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:23]>CCOC(C)=O>[ClH:23].[CH2:21]([O:20][C:17]1[N:16]=[CH:15][C:14]([CH:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)=[CH:19][CH:18]=1)[CH3:22]
Reactant: CCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2)cn1
Agent: Cl
Solvent: CCOC(C)=O
Product: CCOc1ccc(C2CCNCC2)cn1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To 4.30 g (13.9 mmol) 6-Ethoxy-3′,4′,5′,6′-tetrahydro-2′H-[3,4]bipyridinyl-1′-carboxylic acid tert-butyl ester (VII.1) in 10 mL EtOAc are added 120 mL 4N HCl in EtOAc. The mixture is stirred for 12 h at rt. After that time, the solvent is evaporated to yield the desired product.
Reaction SMILES: [CH2:1]([C:3]1[S:7][C:6]([C:8](=[O:10])[CH3:9])=[CH:5][C:4]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH3:17])[CH3:2].[CH3:18][C:19]1[CH:20]=[C:21]([CH:24]=[C:25]([CH3:28])[C:26]=1[OH:27])[CH:22]=O>C(O)C.Cl.C(O)(C)C.O>[CH2:1]([C:3]1[S:7][C:6]([C:8](=[O:10])[CH2:9][CH2:22][C:21]2[CH:24]=[C:25]([CH3:28])[C:26]([OH:27])=[C:19]([CH3:18])[CH:20]=2)=[CH:5][C:4]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH3:17])[CH3:2]
Reactant: CCc1sc(C(C)=O)cc1-c1ccccc1C
Reactant: Cc1cc(C=O)cc(C)c1O
Agent: Cl
Solvent: CC(C)O
Solvent: CCO
Solvent: O
Product: CCc1sc(C(=O)CCc2cc(C)c(O)c(C)c2)cc1-c1ccccc1C
Reaction time: 18 h
Yield: 27.6 %

Procedure:
A solution of 1-(5-ethyl-4-o-tolyl-thiophen-2-yl)-ethanone (51 mg, 0.209 mmol) and 3,5-dimethyl-4-hydroxybenzaldehyde (47 mg, 0.172 mmol) in ethanol (1.5 mL) and 5 N HCl in isopropanol (0.7 mL) is stirred at it for 18 h. The solution is diluted with water and extracted with EA. The organic extract is evaporated, dissolved in methanol (3 mL) and THF (3 mL) and treated with Pd/C (10 mg, 10% Pd). The slurry is stirred under 1.5 bar of H2 for 18 h. The mixture is filtered, the solvent of the filtrate is removed in vacuo and the crude product is purified on prep. TLC plates with heptane:EA 3:1 to give 1-(5-ethyl-4-o-tolyl-thiophen-2-yl)-3-(4-hydroxy-3,5-dimethyl-phenyl)-propan-1-one (18 mg) as a colourless oil; LC-MS: tR=1.12 min, [M+1]+=379.24.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[S:7][C:6]([Cl:8])=[N:5][CH:4]=1.Br.[CH3:10][O:11][C:12](=N)[NH:13][N+:14]([O-:16])=[O:15].[Cl-].[Na+].[OH-].[Na+]>O>[CH3:10][O:11][C:12](=[N:13][N+:14]([O-:16])=[O:15])[NH:1][CH2:2][C:3]1[S:7][C:6]([Cl:8])=[N:5][CH:4]=1
Reactant: NCc1cnc(Cl)s1
Reactant: COC(=N)N[N+](=O)[O-]
Agent: Br
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: COC(=N[N+](=O)[O-])NCc1cnc(Cl)s1
Temperature: 25 °C
Reaction time: 24 h
Yield: 69.4 %

Procedure:
5-(Aminomethyl)-2-chlorothiazole (7.43 g, 50.0 mmol) was dissolved in water (96 ml), and 47% hydrobromic acid (5.78 ml 50.0 mmol) was added. The pH was 3.4 at this time. To this reaction mixture was added O-methyl-N-nitroisourea (7.19 g, 60.0 mmol) and sodium chloride (17.5 g, 0.30 mol), and adjusted to pH 6.2 with aqueous sodium hydroxide solution (0.5 N) using pH meter. After 24 hours of stirring at room temperature, the resulting white crystals were collected by filtration under reduced pressure, and washed with water. The washed crystals were dried under reduced pressure (80° C., 2 hours) to provide 8.7 g (69.4% yield) of O-methyl-N-(2-chloro-5-thiazolylmethyl)-N'-nitroisourea.
Reaction SMILES: [Li+].[OH-].[O:3]=[C:4]1[N:10]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C@@H:20]([C:30]([O:32]C)=[O:31])[CH2:21][C:22]3[CH:23]=[N:24][C:25]([NH2:29])=[C:26]([CH3:28])[CH:27]=3)=[O:18])[CH2:13][CH2:12]2)[CH2:9][CH2:8][C:7]2[CH:34]=[CH:35][CH:36]=[CH:37][C:6]=2[NH:5]1>O.C1COCC1>[O:3]=[C:4]1[N:10]([CH:11]2[CH2:12][CH2:13][N:14]([C:17]([O:19][C@@H:20]([C:30]([OH:32])=[O:31])[CH2:21][C:22]3[CH:23]=[N:24][C:25]([NH2:29])=[C:26]([CH3:28])[CH:27]=3)=[O:18])[CH2:15][CH2:16]2)[CH2:9][CH2:8][C:7]2[CH:34]=[CH:35][CH:36]=[CH:37][C:6]=2[NH:5]1
Reactant: COC(=O)[C@@H](Cc1cnc(N)c(C)c1)OC(=O)N1CCC(N2CCc3ccccc3NC2=O)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)O)cnc1N
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 100 mg (4.18 mmol) LiOH in 25 mL water was added to a solution of 1.27 g (2.64 mmol) of (R)-2-(6-amino-5-methyl-pyridin-3-yl)-1-methoxycarbonyl-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate in 30 mL THF and the reaction solution was stirred for 1 h at RT. The mixture was evaporated down i.vac., the residue was taken up in water, 2 M KHSO4 solution were added with stirring, the supernatant solution was decanted off, the residue was dried, stirred with THF and the product was filtered.
Reaction SMILES: C([C:5]1([CH2:18][CH2:19][C:20](=[O:23])[CH2:21][CH3:22])[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:15][CH3:16])[C:11]=2[CH3:14])[C:6]1=O)CCC>C(O)(=O)C.Cl.CCOC(C)=O>[CH2:13]([CH:18]1[CH:5]2[C:6]([C:7]3[C:12]([CH2:13]2)=[C:11]([CH3:14])[C:10]([O:15][CH3:16])=[CH:9][CH:8]=3)=[C:21]([CH3:22])[C:20](=[O:23])[CH2:19]1)[CH2:5][CH2:6][CH3:7]
Reactant: CCCCC1(CCC(=O)CC)Cc2c(ccc(OC)c2C)C1=O
Agent: Cl
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CCCCC1CC(=O)C(C)=C2c3ccc(OC)c(C)c3CC21
Temperature: 100 °C

Procedure:
A solution of the crude diketone from step 1 in acetic acid (1 mL) and 6N HCl (1 mL) was stirred and heated in an oil bath at 100° C. for 5 hours. After cooling, the reaction mixture was diluted with EtOAc (20 mL), washed with water (10 mL) and brine (10 mL), dried over MgSO4, filtered, and the solvent evaporated under vacuum. The residue was purified by preparative layer chromatography on two 0.1×20×20 cm silica gel GF plates, using 5% EtOAc in CH2Cl2 as developing solvent, to afford 9a butyl-4,8-dimethyl-7-methoxy-1,2,9,9a-tetrahydro-3H-fluoren-3-one (84 mg) as a gum.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4](/[CH:9]=[CH:10]/[C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:5]([Cl:8])=[N:6][CH:7]=1.[C:16]1([CH2:22][SH:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.CCN(C(C)C)C(C)C>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].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.O1CCOCC1>[CH2:22]([S:23][C:2]1[CH:3]=[C:4](/[CH:9]=[CH:10]/[C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:5]([Cl:8])=[N:6][CH:7]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CCOC(=O)/C=C/c1cc(Br)cnc1Cl
Reactant: SCc1ccccc1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)/C=C/c1cc(SCc2ccccc2)cnc1Cl
Temperature: 80 °C
Yield: 104.1 %

Procedure:
A vial was charged with (E)-ethyl 3-(5-bromo-2-chloropyridin-3-yl)acrylate (660 mg, 2.272 mmol), phenylmethanethiol (296 mg, 2.385 mmol), Xantphos (131 mg, 0.227 mmol), Pd2(dba)3 (104 mg, 0.114 mmol), 1,4-dioxane (9086 μl), and Hunig's base (793 μl, 4.54 mmol). The vial was purged with argon and the mixture was heated at 80° C. for 1 h. Water and EtOAc were added, and the layers were separated. The organic portion was dried, filtered and concentrated. The crude material was purified by silica gel chromatography, 0-50% EtOAc/heptane to provide (E)-ethyl 3-(5-(benzylthio)-2-chloropyridin-3-yl)acrylate (790 mg, 2.366 mmol, 104% yield) as a yellow oil. m/z (ESI) 334.0 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5]([NH:7][C:8]([CH3:28])([CH3:27])[CH2:9][N:10]1[C:22]2[C:21]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[N:15]=[CH:14][C:13]=2[N:12]=[C:11]1[CH2:23][O:24][CH2:25][CH3:26])=[O:6])[CH3:2].ClC1C=C(C=CC=1)C(OO)=[O:34]>C(Cl)Cl>[CH2:1]([O:3][CH2:4][C:5]([NH:7][C:8]([CH3:27])([CH3:28])[CH2:9][N:10]1[C:22]2[C:21]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[N+:15]([O-:34])=[CH:14][C:13]=2[N:12]=[C:11]1[CH2:23][O:24][CH2:25][CH3:26])=[O:6])[CH3:2]
Reactant: CCOCC(=O)NC(C)(C)Cn1c(COCC)nc2cnc3ccccc3c21
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CCOCC(=O)NC(C)(C)Cn1c(COCC)nc2c[n+]([O-])c3ccccc3c21
Reaction time: 3 h
Yield: 87.4 %

Procedure:
A solution of 2-ethoxy-N-{2-[2-(ethoxymethy)-1H-imidazo[4,5-c]quinolin-1-yl]-1,1-dimethylethyl}acetamide (998 mg, 2.60 mmol) in 20 mL of CH2Cl2 was treated with 3-chloroperoxybenzoic acid (77%, 668 mg, 2.99 mmol). After stirring for 3 h, the reaction mixture was treated with 30 mL of additional CH2Cl2 and was washed with 1% Na2CO3 solution (2×50 mL), H2O and brine. The organic portion was then dried over Na2SO4 and concentrated to give 2-ethoxy-N-{2-[2-(ethoxymethy)-5-oxido-1H-imidazo[4,5-c]quinolin-1-yl]-1,1-dimethylethyl}acetamide (910 mg) as a light brown oil.