Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]([N+:11]([O-])=O)[CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5]>CCO.[Pd]>[NH2:11][C:9]1[CH:8]=[CH:7][C:3]([C:4]([NH2:6])=[O:5])=[C:2]([CH3:1])[CH:10]=1
Reactant: Cc1cc([N+](=O)[O-])ccc1C(N)=O
Agent: [Pd]
Solvent: CCO
Product: Cc1cc(N)ccc1C(N)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-methyl-4-nitrobenzamide (E111) was dissolved in EtOH under Ar and 10% Pd/C added. The reaction was pump-purged with H2 and left stirring at room temperature overnight. The catalyst was removed by filtration and the reaction concentrated to give pure 4-amino-2-methylbenzamide (E112).
Reaction SMILES: [NH:1]1[CH2:7][C:5](=[O:6])[NH:4][C:2]1=[O:3].[H-].[Na+].Br[CH2:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]=[O:17])=[CH:14][CH:13]=1.[NH4+].[Cl-]>CN(C=O)C>[O:3]=[C:2]1[NH:1][CH2:7][C:5](=[O:6])[N:4]1[CH2:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]=[O:17])=[CH:14][CH:13]=1
Reactant: O=C1CNC(=O)N1
Reactant: O=Cc1ccc(CBr)cc1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: O=Cc1ccc(CN2C(=O)CNC2=O)cc1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
Hydantoin (0.80 g, 8.00 mmol) was dissolved in DMF (10 mL) and cooled to 0° C. Sodium hydride (60% in mineral oil, 88 mg, 2.20 mmol) was added. The mixture was stirred at room temperature for 3 hours. 4-(Bromomethyl)benzaldehyde (0.40 g, 2.00 mmol) was added. The mixture was stirred at room temperature for 2.5 days. Saturated aqueous NH4Cl (1 mL) was added. The mixture was concentrated to dryness. Water (10 mL) was added, extracted with dichloromethane, and the organic phase was dried over anhydrous Na2SO4. Solvent was removed and the crude compound was purified by column chromatography (silica gel 230-400 mesh; 5% methanol in CH2Cl2 as eluent) to give 4-(2,5-dioxo-imidazolidin-1-ylmethyl)-benzaldehyde as a white solid. Yield: 0.28 g (64%).
Reaction SMILES: C([O:3][C:4](=O)[NH:5][CH:6]([CH3:19])[CH2:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]([CH2:17][CH3:18])[CH:9]=1)C.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>O=P(Cl)(Cl)Cl>[CH2:17]([N:10]1[C:9]2[C:4](=[O:3])[NH:5][CH:6]([CH3:19])[CH2:7][C:8]=2[C:16]2[C:11]1=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH3:18]
Reactant: CCOC(=O)NC(C)Cc1cn(CC)c2ccccc12
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: O=P(Cl)(Cl)Cl
Product: CCn1c2c(c3ccccc31)CC(C)NC2=O
Yield: 16.1 %

Procedure:
Using an analogous reaction procedure and workup as described in Example 1, [2-(1-ethyl-1H-indol-3-yl)-1-methyl-ethyl]carbamic acid ethyl ester (I-42c: 3 g, 10.8695 mmol) in POCl3 (30 mL) was reacted with P2O5 (3.080 g, 21.739 mmol) at 120° C. for 1 hour to afford the crude product. Purification by column chromatography on silica gel (25% ethylacetate in hexane) afforded 0.400 g of the product (16.1% yield).
Reaction SMILES: [F:1][C:2]1[C:7]2[N:8]=[N:9][S:10][C:6]=2[CH:5]=[C:4]2[NH:11][C:12](=[O:22])[N:13]([C:14]3[CH:19]=[CH:18][C:17]([I:20])=[CH:16][C:15]=3[F:21])[C:3]=12.C(N(CC)CC)C.[CH2:30]([C:33]1([S:36](Cl)(=[O:38])=[O:37])[CH2:35][CH2:34]1)[CH:31]=[CH2:32]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH2:30]([C:33]1([S:36]([N:11]2[C:4]3=[CH:5][C:6]4[S:10][N:9]=[N:8][C:7]=4[C:2]([F:1])=[C:3]3[N:13]([C:14]3[CH:19]=[CH:18][C:17]([I:20])=[CH:16][C:15]=3[F:21])[C:12]2=[O:22])(=[O:38])=[O:37])[CH2:35][CH2:34]1)[CH:31]=[CH2:32]
Reactant: C=CCC1(S(=O)(=O)Cl)CC1
Reactant: O=c1[nH]c2cc3snnc3c(F)c2n1-c1ccc(I)cc1F
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CCC1(S(=O)(=O)n2c(=O)n(-c3ccc(I)cc3F)c3c(F)c4nnsc4cc32)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.1 %

Procedure:
To a solution of 4-fluoro-5-(2-fluoro-4-iodophenyl)-5H-imidazo[4′,5′:4,5]benzo[1,2-d][1,2,3]thiadiazol-6(7H)-one (50 mg, 0.12 mmol) in DCM (5 mL) was added triethylamine (24 mg, 0.23 mmol) at 0° C. followed by 1-allylcyclopropane-1-sulfonyl chloride (32 mg, 0.17 mmol) and DMAP (10 mg). After stirring at room temperature for 1 h, the mixture was washed with saturated NaHCO3 (aq.). The aqueous layer was extracted with DCM (20 mL×2). The combined organic phase was washed by water (20 mL) and brine (20 mL) sequentially, dried over Na2SO4, filtered and concentrated to give a residue, which was purified by flash chromatography on silica gel (petroleum ether/ethyl acetate, 5:1, v/v) to give the corresponding product (60 mg, 89.9% yield). 1H NMR (400 MHz, CDCl3): δ 8.36 (s, 1H), 7.76-7.74 (m, 2H), 7.35 (m, 1H), 5.75-5.58 (m, 1H), 5.05 (m, 2H), 2.90-2.80 (m, 1H), 2.10-2.0 (m, 1H), 1.95-1.86 (m, 2H), 1.25-1.11 (m, 2H).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([S:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[C:12]=2[F:18])[N:3]=1.[C@@H:19]1(O)[CH2:23][CH2:22][CH2:21][C@H:20]1[OH:24].[H-].[Na+]>C1COCC1>[Cl:8][C:6]1[N:5]=[C:4]([S:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[C:12]=2[F:18])[N:3]=[C:2]([C@@H:19]2[CH2:23][CH2:22][CH2:21][C@H:20]2[OH:24])[CH:7]=1
Reactant: Fc1cccc(CSc2nc(Cl)cc(Cl)n2)c1F
Reactant: O[C@@H]1CCC[C@H]1O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O[C@@H]1CCC[C@H]1c1cc(Cl)nc(SCc2cccc(F)c2F)n1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 4,6-dichloro-2-[(2,3-difluorobenzyl)thio]pyrimidine (the product of example 1 step ii), 2.3 g) and (trans)-cyclopentane-1,2-diol (1 g) in THF (50 ml) was added NaH (0.30 g) slowly and the reaction was then allowed to stir for 18 h at RT. The reaction mixture was then partitioned between DCM (150 ml) and H2O (100 ml). The organics were separated and the aqueous layer was re-extracted with DCM (2×150 ml). Organics were combined, dried (MgSO4) and reduced in vacuo and the resulting clear oil was purified by column chromatography on silica gel EtOAc/iso-Hexane (2:8) to give the subtitle compound as a clear colourless oil. Yield 0.94 g
Reaction SMILES: Cl[C:2]1[S:6][N:5]=[C:4]([S:7][CH2:8][CH:9]=[CH2:10])[N:3]=1.[CH2:11]([OH:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[H-].[Na+].[Cl-].[Na+]>CN(C)C=O>[CH2:11]([O:18][C:2]1[S:6][N:5]=[C:4]([S:7][CH2:8][CH:9]=[CH2:10])[N:3]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: OCc1ccccc1
Reactant: C=CCSc1nsc(Cl)n1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCSc1nsc(OCc2ccccc2)n1
Reaction time: 1 h
Yield: 90.9 %

Procedure:
Into 4 ml of N,N-dimethylformamide were dissolved 193 mg of 5-chloro-3-allylthio-1,2,4-thiadiazole and 108 mg of benzyl alcohol, 48 mg of sodium hydride (60% in oil) was added thereto under ice-cooling, and the reaction mixture was stirred for 1 hour under ice-cooling. The reaction mixture was added to saturated sodium chloride aqueous solution, and extracted with t-butyl methyl ether. The organic layer was concentrated, and the residue obtained was subjected to silica gel column chromatography to give 240 mg of 5-benzyloxy-3-allylthio-1,2,4-thiadiazole (hereinafter, referred to as the present compound (30)).
Reaction SMILES: [NH:1]([C:5]1[NH:6][CH2:7][CH2:8][CH2:9][N:10]=1)[N+]([O-])=O.N[CH2:12][CH:13]([OH:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C1(C)C(C)=CC=CC=1>O>[NH:6]1[CH2:7][CH2:8][CH2:9][N:10]=[C:5]1[NH:1][CH2:12][CH:13]([OH:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: NCC(O)c1ccccc1
Reactant: O=[N+]([O-])NC1=NCCCN1
Solvent: O
Solvent: Cc1ccccc1C
Product: OC(CNC1=NCCCN1)c1ccccc1

Procedure:
A mixture of 7.2 parts of 1,4,5,6-tetrahydro-2-nitraminopyrimidine, 7.55 parts of α-(aminomethyl)benzyl alcohol and 12 parts of xylene is stirred and refluxed for 4 hours on a water-tap. The xylene is evaporated and the residue is dissolved in 20 parts of acetone. The product is crystallized at room temperature. It is filtered off and dried, yielding α-(1,4,5,6-tetrahydro-2-pyrimidinylaminomethyl)benzyl alcohol.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:8]([CH3:46])([CH3:45])[C@H:9]2[C@:22]([CH3:25])([CH2:23][CH:24]=1)[C@@H:21]1[C@:12]([CH3:44])([C@@:13]3([CH3:43])[C@H:18]([CH2:19][CH2:20]1)[C@H:17]1[C@H:26]([C:29]([CH3:31])=[CH2:30])[CH2:27][CH2:28][C@:16]1([NH:32][CH2:33][CH2:34][N:35]1[CH2:40][CH2:39][S:38](=[O:42])(=[O:41])[CH2:37][CH2:36]1)[CH2:15][CH2:14]3)[CH2:11][CH2:10]2)(=O)=O.[C:49]([NH:52][C:53]1([C:68]([O:70][CH3:71])=[O:69])[CH2:58][CH2:57][C:56](B2OC(C)(C)C(C)(C)O2)=[CH:55][CH2:54]1)(=[O:51])[CH3:50]>>[C:49]([NH:52][C:53]1([C:68]([O:70][CH3:71])=[O:69])[CH2:58][CH2:57][C:56]([C:7]2[C:8]([CH3:46])([CH3:45])[C@H:9]3[C@:22]([CH3:25])([CH2:23][CH:24]=2)[C@@H:21]2[C@:12]([CH3:44])([C@@:13]4([CH3:43])[C@H:18]([CH2:19][CH2:20]2)[C@H:17]2[C@H:26]([C:29]([CH3:31])=[CH2:30])[CH2:27][CH2:28][C@:16]2([NH:32][CH2:33][CH2:34][N:35]2[CH2:36][CH2:37][S:38](=[O:41])(=[O:42])[CH2:39][CH2:40]2)[CH2:15][CH2:14]4)[CH2:11][CH2:10]3)=[CH:55][CH2:54]1)(=[O:51])[CH3:50]
Reactant: COC(=O)C1(NC(C)=O)CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: C=C(C)[C@@H]1CC[C@]2(NCCN3CCS(=O)(=O)CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(OS(=O)(=O)C(F)(F)F)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Product: C=C(C)[C@@H]1CC[C@]2(NCCN3CCS(=O)(=O)CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(C6=CCC(NC(C)=O)(C(=O)OC)CC6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Yield: 65.7 %

Procedure:
The title compound was prepared following the method described in step 1 for the preparation of Example 1, using (1R,3aS,5aR,5bR,7aR,11aR,11bR,13aR,13bR)-3a-((2-(1,1-dioxidothiomorpholino)ethyl)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 trifluoromethanesulfonate and methyl 1-acetamido-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-3-enecarboxylate as the reactants. The product was obtained as a mixture of diastereomers in 65.7% yield. MS: m/e 766.8 (M+H)+, 2.72 min (method 3). 1H NMR (400 MHz, CHLOROFORM-d) δ 5.82 (d, J=3.0 Hz, 1H), 5.26 (br. s., 1H), 5.21-5.12 (m, 1H), 4.70 (d, J=2.0 Hz, 1H), 4.58 (d, J=1.3 Hz, 1H), 3.78-3.68 (m, 3H), 3.14-2.90 (m, 7H), 2.75-2.42 (m, 6H), 2.40-2.19 (m, 3H), 2.13-2.05 (m, 1H), 1.98 (d, J=2.0 Hz, 3H), 1.95-1.69 (m, 6H), 1.68 (s, 3H), 1.65-1.30 (m, 7H), 1.25 (m, 11H), 1.10-1.01 (m, 6H), 0.98-0.87 (m, 6H), 0.87-0.83 (m, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:32]=[CH:33][CH:34]=1)[C:5]([N:7]([CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][CH:20]([C:23](=[O:31])[C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)[CH2:19][CH2:18]1)[C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=1)=[O:6].[C:35](OC(=O)C)(=[O:37])[CH3:36]>>[C:35]([NH:1][C:2]1[CH:3]=[C:4]([CH:32]=[CH:33][CH:34]=1)[C:5]([N:7]([CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][CH:20]([C:23](=[O:31])[C:24]2[CH:25]=[CH:26][C:27]([F:30])=[CH:28][CH:29]=2)[CH2:19][CH2:18]1)[C:8]1[CH:9]=[CH:10][C:11]([CH3:14])=[CH:12][CH:13]=1)=[O:6])(=[O:37])[CH3:36]
Reactant: Cc1ccc(N(CCN2CCC(C(=O)c3ccc(F)cc3)CC2)C(=O)c2cccc(N)c2)cc1
Reactant: CC(=O)OC(C)=O
Product: CC(=O)Nc1cccc(C(=O)N(CCN2CCC(C(=O)c3ccc(F)cc3)CC2)c2ccc(C)cc2)c1
Yield: 97.8 %

Procedure:
Using 3-amino-N-{2-[4-(4-fluorobenzoyl)piperidino]ethyl}-N-(4-methylphenyl)benzamide (230.1 mg, 0.50 mmol) and acetic anhydride (0.057 ml, 0.60 mmol), the procedure of Inventive Example 94 was repeated to obtain 245.2 mg (97.8%) of the title compound in a light yellow amorphous form.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[C:14]([O:16]CC)=[O:15].Cl>[OH-].[Na+].O>[OH:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[C:14]([OH:16])=[O:15]
Reactant: CCOC(=O)c1cnc2cc(OC)ccc2c1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1ccc2c(O)c(C(=O)O)cnc2c1
Temperature: 25 °C
Yield: 98.8 %

Procedure:
A suspension of ethyl 4-hydroxy-7-methoxyquinoline-3-carboxylate (12.0 g, 48 mmol) in 10% sodium hydroxide/water (200 mL) was heated at reflux for 1.5 hr. The reaction mixture was allowed to cool to ambient temperature and then made acidic (pH=3) by the dropwise addition of concentrated hydrochloric acid. The resulting precipitate was isolated by filtration, washed twice with water and then dried overnight in a vacuum oven at 80° C. to provide 10.4 g of 4-hydroxy-7-methoxyquinoline-3-carboxylic acid.
Reaction SMILES: Cl[C:2]1[C:10](=[O:11])[C:9]2[N:8]([CH3:12])[N:7]=[CH:6][C:5]=2[C:4](=[O:13])[C:3]=1[N:14]([C:18](=[O:20])[CH3:19])[CH:15]([CH3:17])[CH3:16].[CH:21]([NH2:24])([CH3:23])[CH3:22]>C(Cl)Cl>[CH:21]([NH:24][C:2]1[C:10](=[O:11])[C:9]2[N:8]([CH3:12])[N:7]=[CH:6][C:5]=2[C:4](=[O:13])[C:3]=1[N:14]([C:18](=[O:20])[CH3:19])[CH:15]([CH3:17])[CH3:16])([CH3:23])[CH3:22]
Reactant: CC(C)N
Reactant: CC(=O)N(C1=C(Cl)C(=O)c2c(cnn2C)C1=O)C(C)C
Solvent: ClCCl
Product: CC(=O)N(C1=C(NC(C)C)C(=O)c2c(cnn2C)C1=O)C(C)C

Procedure:
6-Chloro-5-(N-acetyl-N-isopropylamino)-1-methyl-1H-indazole-4,-7-dione (3 grams) and isopropylamine (3 grams) in methylene chloride (25 milliliters) were heated under reflux for 15 minutes. The solvent was then removed under reduced pressure and the residue recrystallized from ethanol to give 6-isopropylamino-5-(N-acetyl-N-isopropylamino)-1-methyl-1H-indazole-4,7-dione as a red solid having a melting point of 123°-126° C.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23](=[O:31])OC2C=CC=CC=2)=[CH:18][CH:17]=1)#[N:2].[NH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=1.O>CS(C)=O>[C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23]([NH:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=2)=[O:31])=[CH:18][CH:17]=1)#[N:2]
Reactant: Nc1ccccn1
Reactant: COc1cc2nccc(Oc3ccc(NC(=O)Oc4ccccc4)cc3)c2cc1C#N
Solvent: O
Solvent: CS(C)=O
Product: COc1cc2nccc(Oc3ccc(NC(=O)Nc4ccccn4)cc3)c2cc1C#N
Temperature: 80 °C
Reaction time: 1.5 h
Yield: 54.7 %

Procedure:
Phenyl N-(4-(6-cyano-7-methoxy-4-quinolyl)oxyphenyl)carbamate (150 mg) and 2-aminopyridine (69 mg) were dissolved in 1 ml of dimethylsulfoxide, and the solution was heated and stirred at 80° C. for 1.5 hours. After cooling, water was added, and the precipitated solid was filtered out and washed with ethyl acetate to obtain 82 mg of the title compound as light brown crystals (54% yield).
Reaction SMILES: C([O:8][C:9]1[CH:35]=[CH:34][C:33]([CH:36]2[CH2:41][CH2:40][N:39]([CH3:42])[CH2:38][CH2:37]2)=[CH:32][C:10]=1[C:11]([NH:13][C:14]1[CH:23]=[C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([O:30][CH3:31])[CH:25]=2)[CH:21]=[CH:20][C:15]=1[C:16]([O:18][CH3:19])=[O:17])=[O:12])C1C=CC=CC=1.C(Cl)(Cl)Cl>CO.C(OCC)(=O)C.[C].[Pd]>[OH:8][C:9]1[CH:35]=[CH:34][C:33]([CH:36]2[CH2:41][CH2:40][N:39]([CH3:42])[CH2:38][CH2:37]2)=[CH:32][C:10]=1[C:11]([NH:13][C:14]1[CH:23]=[C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([O:30][CH3:31])[CH:25]=2)[CH:21]=[CH:20][C:15]=1[C:16]([O:18][CH3:19])=[O:17])=[O:12]
Reactant: COC(=O)c1ccc(-c2cccc(OC)c2)cc1NC(=O)c1cc(C2CCN(C)CC2)ccc1OCc1ccccc1
Agent: [Pd]
Solvent: ClC(Cl)Cl
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(-c2cccc(OC)c2)cc1NC(=O)c1cc(C2CCN(C)CC2)ccc1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 33.3 %

Procedure:
To a solution mixture of the obtained methyl 2-(2-(benzyloxy)-5-(1-methylpiperidin-4-yl)benzamido)-4-(3-methoxyphenyl)benzoate (0.093 g) in methanol (2.0 mL) and ethyl acetate (2.0 mL), 10% palladium-carbon (0.050 g) was added, followed by stirring under a hydrogen atmosphere at room temperature for 2 hours. Chloroform was added to the reaction mixture. The insoluble substance was removed by filtration, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent: 100-92% chloroform/methanol] to obtain 0.026 g of methyl 2-(2-hydroxy-5-(1-methylpiperidin-4-yl)benzamido)-4-(3-methoxyphenyl)benzoate as a white solid.
Reaction SMILES: O.S(S([O-])=O)([O-])=O.[Na+].[Na+].[C:10]([C:14]1[C:15](=[O:25])[C:16]([C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:17][C:18](=[O:20])[CH:19]=1)([CH3:13])([CH3:12])[CH3:11]>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.C(OCC)(=O)C>[C:10]([C:14]1[CH:19]=[C:18]([OH:20])[CH:17]=[C:16]([C:21]([CH3:24])([CH3:23])[CH3:22])[C:15]=1[OH:25])([CH3:13])([CH3:12])[CH3:11]
Reactant: CC(C)(C)C1=CC(=O)C=C(C(C)(C)C)C1=O
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: O=S([O-])S(=O)[O-]
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)c1cc(O)cc(C(C)(C)C)c1O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 60 mL of water, 15.8 g (90.8 mmol) of sodium hydrosulfite, 50 mL of ethyl acetate, 10.0 g (45.5 mmol) of 2,6-di-tert-butyl-1,4-benzoquinone and 1.04 g (4.57 mmol) of benzyltriethylammonium chloride were added and the mixture was stirred for 1 hour at 25° C. The reaction mixture was subjected to liquid-liquid separation and the aqueous layer was discarded. The organic layer was washed with 20 mL of 10% aqueous sodium chloride and the solvent was distilled off under reduced pressure to give 2,6-di-tert-butylhydroquinone.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@@:9]2([CH3:27])[NH:18][C:17](=[O:19])[C:12]3([CH2:16][CH2:15][CH2:14][CH2:13]3)[N:11]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1.[H-].[Na+].[CH2:30](Br)[CH:31]=[CH2:32]>CN(C=O)C>[CH2:32]([N:18]1[C:17](=[O:19])[C:12]2([CH2:16][CH2:15][CH2:14][CH2:13]2)[N:11]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:10][C@:9]1([C:4]1[CH:5]=[C:6]([F:8])[CH:7]=[C:2]([F:1])[CH:3]=1)[CH3:27])[CH:31]=[CH2:30]
Reactant: CC(C)(C)OC(=O)N1C[C@@](C)(c2cc(F)cc(F)c2)NC(=O)C12CCCC2
Reactant: C=CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCN1C(=O)C2(CCCC2)N(C(=O)OC(C)(C)C)C[C@@]1(C)c1cc(F)cc(F)c1
Temperature: 0 °C
Reaction time: 18 h

Procedure:
A solution of tert-butyl (8R)-8-(3,5-difluorophenyl)-8-methyl-10-oxo-6,9-diazaspiro[4.5]decane-6-carboxylate (500 mg, 1.314 mmol) in 2 ml of DMF was added to a suspension of sodium hydride (49.8 mg, 1.971 mmol). When the gas evolution had ceased, allyl bromide (0.171 mL, 1.971 mmol) was added to the ice cooled solution. After 18 hours, the reaction was quenched with brine and extracted with ethyl acetate (3×30 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The oily residue was purified on silica gel, eluting with a gradient of ethyl acetate:hexanes—0:100 to 50:50. The clean fractions were concentrated in vacuo to yield the title compound. MS: m/z=421 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]=[N:11][N:10]([CH3:13])[C:9]=2[CH2:14][O:15][C:16]2[N:21]=[N:20][C:19]([C:22]([OH:24])=O)=[CH:18][CH:17]=2)=[N:6][CH:7]=1.[NH2:25][N:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1>>[N:26]1([NH:25][C:22]([C:19]2[N:20]=[N:21][C:16]([O:15][CH2:14][C:9]3[N:10]([CH3:13])[N:11]=[N:12][C:8]=3[C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][N:6]=3)=[CH:17][CH:18]=2)=[O:24])[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1
Reactant: Cn1nnc(-c2ccc(F)cn2)c1COc1ccc(C(=O)O)nn1
Reactant: NN1CCOCC1
Product: Cn1nnc(-c2ccc(F)cn2)c1COc1ccc(C(=O)NN2CCOCC2)nn1
Yield: 56 %

Procedure:
As described for example 51c, 6-[5-(5-fluoro-pyridin-2-yl)-3-methyl-3H-[1,2,3]triazol-4-ylmethoxy]-pyridazine-3-carboxylic acid (50 mg, 0.15 mmol) was converted, using N-aminomorpholine instead of 2-amino-2-methyl-1-propanol, to the title compound (35 mg, 56%) which was obtained as a light yellow solid. MS: m/e=415.3 [M+H]+.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22]([NH:24][C:25]3[N:26]([C:34]4[CH:39]=[CH:38][C:37]([CH3:40])=[CH:36][CH:35]=4)[N:27]=[C:28]([C:30]([CH3:33])([CH3:32])[CH3:31])[CH:29]=3)=[O:23])=[CH:17][N:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl>CCOCC>[C:30]([C:28]1[CH:29]=[C:25]([NH:24][C:22]([NH:21][C:18]2[CH:17]=[N:16][C:15]([NH:14][CH:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)=[CH:20][CH:19]=2)=[O:23])[N:26]([C:34]2[CH:39]=[CH:38][C:37]([CH3:40])=[CH:36][CH:35]=2)[N:27]=1)([CH3:33])([CH3:31])[CH3:32]
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Nc2ccc(NC3CCN(C(=O)OC(C)(C)C)CC3)nc2)cc1
Agent: Cl
Solvent: CCOCC
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Nc2ccc(NC3CCNCC3)nc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Treat a 22° C. solution of 4-{5-[3-(5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl)-ureido]-pyridin-2-ylamino}-piperidine-1-carboxylic acid tert-butyl ester (1.1 mmol, 0.6 g) in Et2O (5 mL) with HCl (2.0 M solution in diethyl ether, 5 mL, 10 mmol). Stir the solution overnight at room temperature. Concentrate under reduced pressure to give a residue, then subject residue to SCX cartridge eluting with ammonia 2.0 N in methanol. Obtain the title compound as the free base. MS(ES): m/z=488 [M+H].
Reaction SMILES: [CH2:1]1[CH2:7][S:4](=[O:6])(=[O:5])[O:3][CH2:2]1.[CH3:8][C:9]([NH2:14])([CH2:12][CH3:13])[CH2:10][CH3:11]>CC(=O)CC.C1(C)C=CC=CC=1>[CH2:10]([C:9]([NH:14][CH2:2][CH2:1][CH2:7][S:4]([OH:3])(=[O:6])=[O:5])([CH3:8])[CH2:12][CH3:13])[CH3:11]
Reactant: CCC(C)(N)CC
Reactant: O=S1(=O)CCCO1
Solvent: Cc1ccccc1
Solvent: CCC(C)=O
Product: CCC(C)(CC)NCCCS(=O)(=O)O
Temperature: 25 °C

Procedure:
A solution of 1,3-propanesultone (2.5 g, 20 mmol) in 2-butanone (10 mL) was added to a solution of 3-methyl-3-ethyl-3-propylamine in toluene (total volume: 30 mL). The mixture was heated to reflux for 5 hours then was cooled to room temperature. The solid was collected by suction-filtration and rinsed with acetone (2×5 mL). The solid was dried overnight at 45° C. in the vacuum oven. The title compound was obtained as a fine white solid (3.63 g, 16.3 mmol, 33% overall yield). 1H NMR (500 MHz, DMSO-d6) δ 0.79 (t, J=7.3 Hz, 6H), 1.15 (s, 3H), 1.53-1.59 (m, 4H), 1.97-2.00 (m, 2H), 2.89 (t, J=7.1 Hz, 2H), 3.03 (t, J=7.6 Hz, 2H); 13C NMR (125 MHz, DMSO-d6) δ 6.8, 20.2, 21.9, 27.7, 39.7, 48.2, 63.3 ES-MS 224; (M+H)
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1.C(O)(=O)C.O.[BrH:16]>C(Cl)Cl>[Br:16][CH2:7][C:6]1[CH:9]=[CH:10][C:3]([CH:2]=[O:1])=[CH:4][CH:5]=1
Reactant: O=Cc1ccc(CO)cc1
Reactant: Br
Solvent: CC(=O)O
Solvent: O
Solvent: ClCCl
Product: O=Cc1ccc(CBr)cc1
Reaction time: 8 h
Yield: 95 %

Procedure:
Alcohol 2 (6.46 g, 47.5) was dissolved in DCM (100 ml) before HBr in acetic acid (33 wt %, 42 ml, 243, 5 eq) was added and stirred overnight. Water (100 ml) was added to the reaction mixture and the phases were separated and the organic phase obtained was washed with a NaOH solution (2 M, 2×100 ml), dried over Na2SO4, and evaporated. The residue was washed through a silica plug to yield 3 as a white solid (9.04 g, 45.4 mmol, 95%). Rf=0.77 (DCM); m.p.=100° C. (recrystallised from hexane); νmax=1682, 1604, 1209, 1200, 830, 770, 726 cm−1; 1H NMR (300 MHz, CDCl3) δ=10.02 (s, 1H, CHO), 7.87 (d, 3J(H,H)=8.2 Hz, 2H, ArCH α to CHO), 7.56 (d, 3J(H,H)=8.2 Hz, 2H, ArCH α to CH2Br), 4.52 (s, 21-1, CH2Br); 13C NMR (75 MHz, CDCl3) δ=191.5 (CHO), 144.2 (ArCCBr), 136.2 (ArCCHO), 130.2 (ArCH α to ArCCHO), 129.7 (ArCH α to ArCCH2Br), 31.9 (CH2Br); HRMS (ESI−): m/z calculated for C8H6BrO [M−H]−: 196.9602, found 196.9602; elemental analysis calcd (%) for C8H7BrO (199.04): C, 48.27; H, 3.54. found: C, 47.40; H, 3.53.
Reaction SMILES: [CH2:1]([O:4][C:5]1[C:14]2[C:9](=[CH:10][C:11]([O:15][CH3:16])=[CH:12][CH:13]=2)[C:8]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:7]([C:23]#[N:24])[N:6]=1)[CH:2]=[CH2:3].[CH3:25][C:26]1([CH3:33])[O:30]C(CO)C[O:27]1>>[CH3:25][C:26]1([CH3:33])[O:30][CH:2]([CH2:1][O:4][C:5]2[C:14]3[C:9](=[CH:10][C:11]([O:15][CH3:16])=[CH:12][CH:13]=3)[C:8]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[C:7]([C:23]#[N:24])[N:6]=2)[CH2:3][O:27]1
Reactant: C=CCOc1nc(C#N)c(-c2ccccc2)c2cc(OC)ccc12
Reactant: CC1(C)OCC(CO)O1
Product: COc1ccc2c(OCC3COC(C)(C)O3)nc(C#N)c(-c3ccccc3)c2c1

Procedure:
Following the procedure for 1-(allyloxy)-6-methoxy-4-phenylisoquinoline-3-carbonitrile, using solketal in place of allyl alcohol, the title compound was synthesized.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11](/[CH:14]=[CH:15]/[C:16]([OH:18])=O)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[CH3:19][N:20]([CH3:30])[CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([NH2:29])=[CH:25][CH:24]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[CH:10][C:11](/[CH:14]=[CH:15]/[C:16]([NH:29][C:26]3[CH:25]=[CH:24][C:23]([CH2:22][CH2:21][N:20]([CH3:19])[CH3:30])=[CH:28][CH:27]=3)=[O:18])=[CH:12][CH:13]=2)=[CH:6][CH:7]=1
Reactant: CN(C)CCc1ccc(N)cc1
Reactant: O=C(O)/C=C/c1ccc(-c2ccc(Cl)cc2)cc1
Product: CN(C)CCc1ccc(NC(=O)/C=C/c2ccc(-c3ccc(Cl)cc3)cc2)cc1

Procedure:
Prepared analogously to Example 172 starting from (E)-3-(4′-chloro-biphenyl-4-yl)-acrylic acid and 4-(2-dimethylamino-ethyl)-phenylamine.