Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[CH:6][C:7]([C:15]([OH:17])=O)=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:14][CH2:13]2)[CH2:3][CH2:2]1.[NH2:18][CH:19]([CH2:22][CH:23]1[CH2:26][CH2:25][CH2:24]1)[CH2:20][OH:21]>>[CH:23]1([CH2:22][CH:19]([NH:18][C:15]([C:7]2[CH:6]=[N:5][C:4]([CH:1]3[CH2:2][CH2:3]3)=[C:9]([O:10][CH2:11][CH:12]3[CH2:13][CH2:14]3)[N:8]=2)=[O:17])[CH2:20][OH:21])[CH2:26][CH2:25][CH2:24]1
Reactant: NC(CO)CC1CCC1
Reactant: O=C(O)c1cnc(C2CC2)c(OCC2CC2)n1
Product: O=C(NC(CO)CC1CCC1)c1cnc(C2CC2)c(OCC2CC2)n1

Procedure:
The title compound was synthesized in analogy to Example 69, using 5-cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid (Example 10 g, 50 mg, 0.21 mmol) and 2-amino-3-cyclobutyl-propan-1-ol (38.7 mg, 0.3 mmol) as starting materials and isolated (30 mg, 41%) as white solid; LC-MS (UV peak area, ESI) 99.69%, 346.2 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:12]2[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][CH:13]=2)=[CH:4][C:5]2[O:9][C:8]([CH3:10])=[N:7][C:6]=2[CH:11]=1.[F:19][C:20]1[CH:28]=[CH:27][CH:26]=[CH:25][C:21]=1[C:22](Cl)=[O:23].CCN(C(C)C)C(C)C.C([O-])(O)=O.[Na+].C(Cl)Cl>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Cl:1][C:2]1[C:3]([C:12]2[CH:17]=[CH:16][C:15]([NH:18][C:22]([C:21]3[CH:25]=[CH:26][CH:27]=[CH:28][C:20]=3[F:19])=[O:23])=[CH:14][CH:13]=2)=[CH:4][C:5]2[O:9][C:8]([CH3:10])=[N:7][C:6]=2[CH:11]=1
Reactant: Cc1nc2cc(Cl)c(-c3ccc(N)cc3)cc2o1
Reactant: O=C(Cl)c1ccccc1F
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc2cc(Cl)c(-c3ccc(NC(=O)c4ccccc4F)cc3)cc2o1
Temperature: 25 °C
Reaction time: 3 h
Yield: 57.5 %

Procedure:
To a solution of 4-(5-chloro-2-methylbenzoxazol-6-yl)phenylamine (56) (23 mg, 0.089 mmol) and 2 mg DMAP in 2 ml DCM was added 2-fluorobenzoyl chloride (21 μl, 0.18 mmol) followed by addition of DIEA (78 μl). The resulting brown solution was stirred at r.t. for 3 h. The reaction mixture was worked up with aq. NaHCO3/DCM. DCM phase was washed with brine, concentrated to dryness. The residue was dissolved in 2 ml THF/MeOH/H2O (5:4:1) and stirred with 1N NaOH (200 μl) at r.t. for 2 h before worked up with EA/aq. NaHCO3. Silica gel flash chromatography furnished 19.5 mg 57 as off-white solid. (yield: 57.5%).
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([O:6][CH2:7][C:8]2[N:9]([CH3:23])[C:10]3[C:15]([C:16]=2[CH2:17][CH2:18][C:19]([O:21]C)=[O:20])=[CH:14][CH:13]=[CH:12][CH:11]=3)=[CH:4][CH:3]=1.[OH-].[Li+]>O1CCCC1>[Cl:1][C:2]1[CH:25]=[CH:24][C:5]([O:6][CH2:7][C:8]2[N:9]([CH3:23])[C:10]3[C:15]([C:16]=2[CH2:17][CH2:18][C:19]([OH:21])=[O:20])=[CH:14][CH:13]=[CH:12][CH:11]=3)=[CH:4][CH:3]=1
Reactant: COC(=O)CCc1c(COc2ccc(Cl)cc2)n(C)c2ccccc12
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cn1c(COc2ccc(Cl)cc2)c(CCC(=O)O)c2ccccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Under a nitrogen atmosphere in a round bottom flask 2-[(4-chlorophenoxy)methyl]-1-methyl-3-[2-(methoxycarbonyl)ethyl]-1H-indole (0.275 g, 0.771 mmol) was dissolved in 8 ml of dry tetrahydrofuran. To this solution was added 4.0 ml of a 2.0 N lithium hydroxide solution. The reaction mixture was stirred at room temperature overnight. The progress of the reaction was monitored by thin layer chromatography.
Reaction SMILES: Br[C:2]1[C:3]([NH:9][CH2:10][CH:11]([NH:14][C:15](=[O:24])[O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:12][CH3:13])=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.[CH2:25]([O:27][CH:28]([O:31][CH2:32][CH3:33])[C:29]#[CH:30])[CH3:26].ClC1N=C(NCCNC(=O)OC(C)(C)C)C(C#CC(OCC)OCC)=CN=1>>[Cl:8][C:5]1[N:4]=[C:3]([NH:9][CH2:10][CH:11]([NH:14][C:15](=[O:24])[O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:12][CH3:13])[C:2]([C:30]#[C:29][CH:28]([O:31][CH2:32][CH3:33])[O:27][CH2:25][CH3:26])=[CH:7][N:6]=1
Reactant: CCC(CNc1nc(Cl)ncc1Br)NC(=O)OCc1ccccc1
Reactant: C#CC(OCC)OCC
Agent: CCOC(C#Cc1cnc(Cl)nc1NCCNC(=O)OC(C)(C)C)OCC
Product: CCOC(C#Cc1cnc(Cl)nc1NCC(CC)NC(=O)OCc1ccccc1)OCC

Procedure:
benzyl N-[1-[[[2-chloro-5-(3,3-diethoxyprop-1-ynyl)pyrimidin-4-yl]amino]methyl]propyl]carbamate is prepared by treating benzyl N-[1-[[(5-bromo-2-chloro-pyrimidin-4-yl)amino]methyl]propyl]-carbamate with 3,3-diethoxyprop-1-yne in the presence of a catalyst such as Pddba using similar experimental conditions as described for the synthesis of tert-butyl N-[2-[[2-chloro-5-(3,3-diethoxyprop-1-ynyl)pyrimidin-4 yl]amino]ethyl]carbamate LCMS (ESI) (M+H) 461.
Reaction SMILES: Cl.[CH3:2][NH:3][C:4](=[NH:11])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.Cl[CH2:13][C:14](=O)[CH2:15][C:16]([OH:18])=[O:17].C[Si](C)(C)N[Si](C)(C)C.C[Si](C)(C)Cl.[C:34](#N)[CH3:35]>>[CH3:2][N:3]1[CH:13]=[C:14]([CH2:15][C:16]([O:18][CH2:34][CH3:35])=[O:17])[N:11]=[C:4]1[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: O=C(O)CC(=O)CCl
Reactant: CC#N
Reactant: CNC(=N)c1ccccc1
Agent: C[Si](C)(C)Cl
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: Cl
Product: CCOC(=O)Cc1cn(C)c(-c2ccccc2)n1

Procedure:
A mixture of 6.12 g of N-methylbenzamidine hydrochloride, 4.95 g of the ethyl ester of 4-chloroacetoacetic acid, 18.5 ml of hexamethyldisilazane, 1.27 ml of trimethylchlorosilane, and 350 ml of acetonitrile was heated under reflux until the analytical TLC control no longer indicated any starting compound (about 72 hours). Then the mixture was allowed to cool, the volume of the reaction solution was reduced, by concentration under vacuum, to about one-half, thereafter combined with 200 ml of water, and repeatedly extracted with an ether/hexane (1/1) mixture. The combined organic phases were dried over magnesium sulfate, the solvent was removed under vacuum, and the residue was purified by column chromatography on silica gel with pentane/0-100% ethyl acetate as the eluent. Yield: 3.53 g (48%) of the title compound.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:20]=[CH:19][C:6]([NH:7][C:8]2[S:9][C:10]3[N:18]=[CH:17][CH:16]=[CH:15][C:11]=3[C:12](=[O:14])[N:13]=2)=[CH:5][CH:4]=1.[H-].[Li+].[CH3:25]I>>[CH3:25][N:13]1[C:12](=[O:14])[C:11]2[CH:15]=[CH:16][CH:17]=[N:18][C:10]=2[S:9][C:8]1=[N:7][C:6]1[CH:19]=[CH:20][C:3]([C:2]([F:1])([F:21])[F:22])=[CH:4][CH:5]=1
Reactant: CI
Reactant: O=c1nc(Nc2ccc(C(F)(F)F)cc2)sc2ncccc12
Agent: [H-]
Agent: [Li+]
Product: Cn1c(=Nc2ccc(C(F)(F)F)cc2)sc2ncccc2c1=O

Procedure:
The reaction procedure of Example 11 was followed except that 646 mg of 2-(4-trifluoromethylanilino)-4H-pyrido[3,2-e]-1,3-thiazin-4-one, 18 mg of lithium hydride and 0.13 ml of methyl iodide were used. As a result, 565 mg of 3-methyl-2-[(4-trifluoromethylphenyl)imino]-2,3-dihydro-4H-pyrido[3,2-e]-1,3-thiazin-4-one was obtained as a low polarity substance, and 25 mg of 2-[N-methyl-N-(4-trifluoromethylphenyl)amino]-4H-pyrido[3,2-e]-1,3-thiazin-4-one was obtained as a high polarity substance.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:10]3[CH2:11][CH2:12][N:13](C(OC(C)(C)C)=O)[CH2:14][C:9]=3[S:8][C:4]=2[N:5]=[CH:6][N:7]=1.[NH2:22][C:23]1[C:24]([F:31])=[CH:25][C:26]([F:30])=[C:27]([OH:29])[CH:28]=1>>[ClH:1].[F:30][C:26]1[CH:25]=[C:24]([F:31])[C:23]([NH:22][C:2]2[C:3]3[C:10]4[CH2:11][CH2:12][NH:13][CH2:14][C:9]=4[S:8][C:4]=3[N:5]=[CH:6][N:7]=2)=[CH:28][C:27]=1[OH:29]
Reactant: Nc1cc(O)c(F)cc1F
Reactant: CC(C)(C)OC(=O)N1CCc2c(sc3ncnc(Cl)c23)C1
Product: Cl
Product: Oc1cc(Nc2ncnc3sc4c(c23)CCNC4)c(F)cc1F

Procedure:
The title compound was prepared in analogy to Example 65A from tert-butyl 4-chloro-5,8-dihydropyrido[4′,3′:4,5]thieno[2,3-d]pyrimidine-7(6H)-carboxylate from Example 11A (4.00 g, 12.3 mmol) and 5-amino-2,4-difluorophenol (1.87 g, 12.9 mmol) to yield 740 mg (16%).
Reaction SMILES: C([O:8][C:9]1[C:10]([C:16]([NH:18][CH2:19][CH2:20][NH:21]C(=O)OC(C)(C)C)=[O:17])=[N:11][CH:12]=[C:13]([Cl:15])[CH:14]=1)C1C=CC=CC=1>FC(F)(F)C(O)=O>[ClH:15].[NH2:21][CH2:20][CH2:19][NH:18][C:16]([C:10]1[C:9]([OH:8])=[CH:14][C:13]([Cl:15])=[CH:12][N:11]=1)=[O:17]
Reactant: CC(C)(C)OC(=O)NCCNC(=O)c1ncc(Cl)cc1OCc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: Cl
Product: NCCNC(=O)c1ncc(Cl)cc1O

Procedure:
A solution of 1.95 g of t-butyl [2-(3-benzyloxy-5-chloropyridine-2-carboxamido)ethyl]carbamate, m.p. 130°-133°, in 30 ml of trifluoroacetic acid was stirred at 50° for 7 hours. The mixture was thereafter evaporated to dryness on a rotary evaporator, the residue was dissolved in methanol and the solution was treated with hydrogen chloride in methanol (6N). After recrystallization from methanol there was obtained N-(2-aminoethyl)-3-hydroxy-5-chloropyridine-2-carboxamide hydrochloride, m.p. 220°-223°.
Reaction SMILES: OS(O)(=O)=O.[CH2:6]([C:8]1[CH:9]=[C:10]([CH:14]=[CH:15][CH:16]=1)[C:11]([OH:13])=[O:12])[CH3:7].[CH3:17]O>O>[CH2:6]([C:8]1[CH:9]=[C:10]([CH:14]=[CH:15][CH:16]=1)[C:11]([O:13][CH3:17])=[O:12])[CH3:7]
Reactant: CCc1cccc(C(=O)O)c1
Reactant: CO
Agent: O=S(=O)(O)O
Solvent: O
Product: CCc1cccc(C(=O)OC)c1
Temperature: 25 °C
Yield: 91 %

Procedure:
Concentrated H2SO4 (1.0 mL) was added to a solution of 3-ethylbenzoic acid (500 mg, 3.33 mmol) in MeOH (10 mL). The mixture was heated at reflux for 18 h then cooled to room temperature. The mixture was diluted with water (50 mL) and extracted with Et2O (3×100 mL). The combined organic phase was dried (Na2SO4), filtered and concentrated in vacuo. Purification of the crude residue by chromatography on silica gel (hexanes→20% EtOAc/hexanes, gradient) afforded 500 mg (91%) of methyl 3-ethylbenzoate.
Reaction SMILES: Cl[CH2:2][N:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:4](Cl)=[O:5].[Cl:13][C:14]1[CH:15]=[C:16]([CH:27]=[CH:28][C:29]=1[Cl:30])[CH2:17][NH:18][C:19]([NH:21][CH2:22][C:23]([F:26])([F:25])[F:24])=[S:20]>C1C=CC=CC=1>[F:26][C:23]([F:24])([F:25])[CH2:22][N:21]=[C:19]1[N:18]([CH2:17][C:16]2[CH:27]=[CH:28][C:29]([Cl:30])=[C:14]([Cl:13])[CH:15]=2)[C:4](=[O:5])[N:3]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH2:2][S:20]1
Reactant: FC(F)(F)CNC(=S)NCc1ccc(Cl)c(Cl)c1
Reactant: O=C(Cl)N(CCl)c1ccccc1
Solvent: c1ccccc1
Product: O=C1N(Cc2ccc(Cl)c(Cl)c2)C(=NCC(F)(F)F)SCN1c1ccccc1
Yield: 40.2 %

Procedure:
1.00 g of N-chloromethyl-N-phenylcarbamoyl chloride and 1.55 g of 1-(3,4-dichlorobenzyl)-3-(2,2,2-trifluoroethyl)thiourea were dissolved in 30 m1 of benzene, and the solution was heated under reflux. After the reaction, benzene was evaporated under reduced pressure. The resulting oily product was purified by column chromatography silica gel; eluent: hexane/ethyl acetate (10/1)] to give 0.88 g of the captioned compound.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[C:9]([C:10]3[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=3)=[CH:8][CH:7]=[CH:6][N:5]2[CH:17]=1.[H-].[Na+].Cl[C:21]1[N:25]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31])[C:24]2[CH:34]=[CH:35][CH:36]=[CH:37][C:23]=2[N:22]=1.O>CN(C=O)C>[CH3:1][C:2]1[N:3]=[C:4]2[C:9]([C:10]3[CH:15]=[CH:14][C:13]([O:16][C:21]4[N:25]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:32])([CH3:33])[CH3:31])[C:24]5[CH:34]=[CH:35][CH:36]=[CH:37][C:23]=5[N:22]=4)=[CH:12][CH:11]=3)=[CH:8][CH:7]=[CH:6][N:5]2[CH:17]=1
Reactant: C[Si](C)(C)CCOCn1c(Cl)nc2ccccc21
Reactant: Cc1cn2cccc(-c3ccc(O)cc3)c2n1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cn2cccc(-c3ccc(Oc4nc5ccccc5n4COCC[Si](C)(C)C)cc3)c2n1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 68.5 %

Procedure:
To a solution of 4-(2-methylimidazo[1,2-a]pyridin-8-yl)phenol (0.40 g) in DMF (5 ml) was added sodium hydride (60% in oil, 0.086 g), and the mixture was stirred at room temperature for 5 min. To the reaction mixture was added 2-chloro-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-benzimidazole (0.50 g), and the mixture was stirred under microwave irradiation at 150° C. for 1 hr. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by basic silica gel column chromatography (hexane/ethyl acetate) to give the title compound (0.57 g).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]([C:17]3[CH:22]=[CH:21][N:20]=[C:19]([NH:23][C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([O:30][CH2:31][CH2:32][CH2:33][N:34]5[CH2:39][CH2:38][O:37][CH2:36][CH2:35]5)[CH:25]=4)[N:18]=3)=[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][N:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[S:40]1[CH:44]=[CH:43][CH:42]=[C:41]1[CH2:45][C:46](Cl)=[O:47]>>[N:34]1([CH2:33][CH2:32][CH2:31][O:30][C:26]2[CH:25]=[C:24]([NH:23][C:19]3[N:18]=[C:17]([C:16]4[C:8]([C:4]5[CH:3]=[C:2]([NH:1][C:46](=[O:47])[CH2:45][C:41]6[S:40][CH:44]=[CH:43][CH:42]=6)[CH:7]=[CH:6][CH:5]=5)=[N:9][N:10]5[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=45)[CH:22]=[CH:21][N:20]=3)[CH:29]=[CH:28][CH:27]=2)[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1
Reactant: Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Nc3cccc(OCCCN4CCOCC4)c3)n2)c1
Reactant: O=C(Cl)Cc1cccs1
Product: O=C(Cc1cccs1)Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Nc3cccc(OCCCN4CCOCC4)c3)n2)c1
Yield: 37 %

Procedure:
The title compound was synthesized from 4-[2-(3-aminophenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-(3-{[3-(4-morpholinyl)propyl]oxy}phenyl)-2-pyrimidinamine using acylation with 2-thienylacetyl chloride as described in Example 10, Step E to yield a light brown solid in 37% yield. 1H NMR (400 MHz, DMSO-D6) δ ppm 1.8 (d, J=1.1 Hz, 2H) 2.3 (s, 6H) 3.5 (d, J=4.6 Hz, 4H) 3.9 (s, 2H) 3.9 (m, 2H) 6.5 (m, 2H) 7.0 (m, 2H) 7.1 (m, 2H) 7.3 (dt, J=7.6, 1.4 Hz, 2H) 7.4 (m, 3H) 7.5 (t, J=2.1 Hz, 1H) 7.7 (d, J=1.8 Hz, 1H) 7.9 (t, J=1.8 Hz, 1H) 8.2 (d, J=5.3 Hz, 1H) 8.5 (d, J=8.6 Hz, 1H) 8.8 (m, 1H) 9.5 (s, 1H) 10.3 (s, 1H). ES-LC/MS m/z 646 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16](S(C)(=O)=O)[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([NH:26][C:27]([C:29]4[S:30][CH:31]=[CH:32][CH:33]=4)=[O:28])[CH:22]=[CH:23][C:24]=3[CH3:25])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:38].[CH3:39][C:40]1([CH3:49])[CH2:45][CH:44]([NH2:46])[CH2:43][C:42]([CH3:48])([CH3:47])[NH:41]1>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([NH:46][CH:44]3[CH2:45][C:40]([CH3:49])([CH3:39])[NH:41][C:42]([CH3:48])([CH3:47])[CH2:43]3)[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([NH:26][C:27]([C:29]4[S:30][CH:31]=[CH:32][CH:33]=4)=[O:28])[CH:22]=[CH:23][C:24]=3[CH3:25])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:38]
Reactant: Cc1ccc(NC(=O)c2cccs2)cc1-c1nc(S(C)(=O)=O)nc2c1ccc(=O)n2-c1c(F)cccc1F
Reactant: CC1(C)CC(N)CC(C)(C)N1
Product: Cc1ccc(NC(=O)c2cccs2)cc1-c1nc(NC2CC(C)(C)NC(C)(C)C2)nc2c1ccc(=O)n2-c1c(F)cccc1F

Procedure:
The title compound was prepared as described in Example 1d from N-{3-[8-(2,6-difluorophenyl)-2-(methylsulfonyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl]-4-methylphenyl}-2-thiophenecarboxamide and 2,2,6,6-tetramethyl-4-piperidinamine: LC-MS m/z 629 (M+H)+, 2.0 min (ret time).
Reaction SMILES: [OH:1][CH:2]1[C:8]2=[N:9][C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=3[CH:16]=[C:7]2[CH2:6][NH:5][CH2:4][CH2:3]1.Cl[C:18]([O:20][CH2:21][CH3:22])=[O:19]>>[CH2:21]([O:20][C:18]([N:5]1[CH2:4][CH2:3][CH:2]([O:1][C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:8]2=[N:9][C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=3[CH:16]=[C:7]2[CH2:6]1)=[O:19])[CH3:22]
Reactant: OC1CCNCc2cc3ccccc3nc21
Reactant: CCOC(=O)Cl
Product: CCOC(=O)OC1CCN(C(=O)OCC)Cc2cc3ccccc3nc21
Yield: 80 %

Procedure:
5-(Ethoxy-carbonyloxy)-2,3,4,5-tetrahydro-1H-2-azepino [4,3-b]quinoline-carboxylic acid ethyl ester was prepared from 5-hydroxy-2,3,4,5-tetrahydro-1H-azepino[4,3-b]quinoline and ethyl chloroformate analogous to Example 63.
Reaction SMILES: [C:1]1([S:7]([CH:10]2[CH:16]=[C:15](SC3C=CC=CC=3)[CH2:14][CH2:13][C@@H:12]([O:24][Si](C)(C)C)[C@H:11]2[CH3:29])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:30][C:31]([Si:34](Cl)([CH3:36])[CH3:35])([CH3:33])[CH3:32].N1C=CN=C1.C1C[O:46]CC1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>CN(C=O)C>[C:1]1([S:7]([C:10]2[C@H:11]([CH3:29])[C@@H:12]([O:24][Si:34]([C:31]([CH3:33])([CH3:32])[CH3:30])([CH3:36])[CH3:35])[C@@H:14]([CH3:13])[C@H:15]([OH:46])[CH:16]=2)(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C[C@H]1C(S(=O)(=O)c2ccccc2)C=C(Sc2ccccc2)CC[C@H]1O[Si](C)(C)C
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: C1CCOC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: C[C@@H]1[C@H](O[Si](C)(C)C(C)(C)C)[C@@H](C)C(S(=O)(=O)c2ccccc2)=C[C@H]1O
Temperature: 70 °C
Reaction time: 20 h
Yield: 84 %

Procedure:
The mixture of diol 23 (585 mg, 2.07 mmol), TBSCl (1.0 g, 6.63 mmol), and imidazole (564 mg, 8.28 mmol) in DMF (5.0 mL) was stirred at 70° C. for 20 h under nitrogen. After being quenched by aqueous NH4Cl, the reaction mixture was extracted with diethyl ether (3×20 mL). The organic layers were washed with brine, dried over Na2SO4, concentrated via rotary evaporation, and further dried in vacuo. The crude residue was dissolved in THF (20 mL), and a THF solution (2.3 mL, 2.3 mmol, 1M) of TBAF was added at room temperature. After being stirred at room temperature for 30 min, the solution was quenched with aqueous NH4Cl solution, and the product was extracted with ethyl acetate (3×10 mL). The organic layers were dried over Na2SO4 and concentrated via rotary evaporation. The crude product was purified by flash column chromatography (ethyl acetate/hexanes; 1:4) to afford 690 mg (84%) of 38 as a white solid. Mp 106.6-108.5° C.; 1H NMR (CDCl3, 300 MHz): δ 7.86 (d, J=7.5 Hz, 2H), 7.48-7.62 (m, 3H), 7.00 (d, J=2.1 Hz, 1H), 4.13 (d, J=9.3 Hz, 1H), 3.54 (s, 1H), 2.27 (q, J=6.9 Hz, 1H), 2.01 (s, 1H), 1.78 (m, 1H), 1.24 (d, J=7.2 Hz, 3H), 1.09 (d, J=6.3 Hz, 3H), 0.64 (s, 9H), −0.06 (s, 3H), −0.35 (s, 3H); 13C NMR (CDCl3, 75 MHz): δ 142.8, 140.4, 139.4, 133.3, 129.2, 128.2, 77.9, 70.7, 37.7, 36.3, 25.6, 18.5, 17.7, 14.9, −4.7, −5.3. Anal. Calcd for C20H32O4SSi: C, 60.57; H, 8.13. Found: C, 60.82; H, 8.07.
Reaction SMILES: [CH:1]1([O:5][CH2:6][C:7]2[CH:29]=[CH:28][C:10]([C:11]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([N:20]4[CH2:24][CH2:23][CH:22]5[CH2:25][NH:26][CH2:27][CH:21]45)=[CH:16][CH:15]=3)=[O:12])=[CH:9][CH:8]=2)[CH2:4][CH2:3][CH2:2]1.[CH3:30][N:31]([CH3:36])[CH2:32][C:33](O)=[O:34]>>[CH:1]1([O:5][CH2:6][C:7]2[CH:8]=[CH:9][C:10]([C:11]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([N:20]4[CH2:24][CH2:23][CH:22]5[CH2:25][N:26]([C:33](=[O:34])[CH2:32][N:31]([CH3:36])[CH3:30])[CH2:27][CH:21]45)=[CH:16][CH:15]=3)=[O:12])=[CH:28][CH:29]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: CN(C)CC(=O)O
Reactant: O=C(Nc1ccc(N2CCC3CNCC32)cc1)c1ccc(COC2CCC2)cc1
Product: CN(C)CC(=O)N1CC2CCN(c3ccc(NC(=O)c4ccc(COC5CCC5)cc4)cc3)C2C1

Procedure:
4-Cyclobutoxymethyl-N-[4-(hexahydropyrrolo[3,4-b]pyrrol-1-yl)phenyl]-benzamide was reacted with N,N-dimethylglycine by method E. The product with the molecular weight of 476.62 (C28H36N4O3); MS (ESI): 477 (M+H+) was obtained in this way.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([S:8]([N:11]2[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:14][C:13]([CH2:22][N:23]([CH3:31])C(=O)OC(C)(C)C)=[CH:12]2)(=[O:10])=[O:9])[CH:5]=[N:6][CH:7]=1.C(N(CC)CC)C.CO.[C:41]([O:44][CH2:45]C)(=[O:43])C.[ClH:47]>C(O)C>[ClH:47].[CH3:31][NH:23][CH2:22][C:13]1[CH:14]=[C:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:11]([S:8]([C:4]2[CH:5]=[N:6][CH:7]=[C:2]([CH:3]=2)[C:41]([O:44][CH3:45])=[O:43])(=[O:10])=[O:9])[CH:12]=1
Reactant: CN(Cc1cc(-c2ccccc2)n(S(=O)(=O)c2cncc(Br)c2)c1)C(=O)OC(C)(C)C
Reactant: CCOC(C)=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CO
Solvent: CCO
Product: CNCc1cc(-c2ccccc2)n(S(=O)(=O)c2cncc(C(=O)OC)c2)c1
Temperature: 100 °C
Reaction time: 12 h
Yield: 56 %

Procedure:
A mixture of tert-butyl ({1-[(5-bromopyridin-3-yl)sulfonyl]-5-phenyl-1H-pyrrol -3-yl}methyl)methylcarbamate (112 mg), dichloro[bis(triphenylphosphine)]palladium (28 mg), triethylamine (0.25 mL) and methanol (15 mL) was stirred under a carbon monoxide atmosphere (3 atm) at 100° C. for 12 hr. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. A saturated aqueous sodium hydrogencarbonate solution was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=19:1→3:2) to give a colorless oil. The obtained-oil was dissolved in ethanol (2 mL), and a 4 mol/L hydrogen chloride-ethyl acetate solution (2 mL) was added. After stirring at room temperature for 1 hr, the mixture was concentrated under reduced pressure, and recrystallized from ethanol to give the title compound as a solid (yield 47.0 mg, 56%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:29][C:30]2[C:35]([C:36]3[CH:41]=[CH:40][N:39]=[N:38][CH:37]=3)=[CH:34][C:33]([C:42]3[CH:47]=[CH:46][C:45]([F:48])=[CH:44][CH:43]=3)=[C:32]([Cl:49])[CH:31]=2)=[CH:4][C:5]([F:28])=[C:6]([S:8]([N:11](CC2C=CC(OC)=CC=2OC)[C:12]2[S:13][CH:14]=[N:15][N:16]=2)(=[O:10])=[O:9])[CH:7]=1.FC(F)(F)C(O)=O.CO>ClCCl>[Cl:1][C:2]1[C:3]([O:29][C:30]2[C:35]([C:36]3[CH:41]=[CH:40][N:39]=[N:38][CH:37]=3)=[CH:34][C:33]([C:42]3[CH:43]=[CH:44][C:45]([F:48])=[CH:46][CH:47]=3)=[C:32]([Cl:49])[CH:31]=2)=[CH:4][C:5]([F:28])=[C:6]([S:8]([NH:11][C:12]2[S:13][CH:14]=[N:15][N:16]=2)(=[O:10])=[O:9])[CH:7]=1
Reactant: COc1ccc(CN(c2nncs2)S(=O)(=O)c2cc(Cl)c(Oc3cc(Cl)c(-c4ccc(F)cc4)cc3-c3ccnnc3)cc2F)c(OC)c1
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Solvent: ClCCl
Product: O=S(=O)(Nc1nncs1)c1cc(Cl)c(Oc2cc(Cl)c(-c3ccc(F)cc3)cc2-c2ccnnc2)cc1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 43.3 %

Procedure:
5-Chloro-4-(2-chloro-4′-fluoro-5-(pyridazin-4-yl)biphenyl-4-yloxy)-N-(2,4-dimethoxybenzyl)-2-fluoro-N-(1,3,4-thiadiazol-2-yl)benzenesulfonamide (Preparation 70, 220 mg, 0.30 mmol) was dissolved in dichloromethane (2 mL) and trifluoroacetic acid (1 mL) was added. The reaction was stirred at room temperature for 3 hours. Methanol (5 mL) was added to quench the reaction and the suspension was stirred vigorously for 1 hour. The resulting precipitate was filtered through Celite™ and washed with methanol and the filtrate concentrated in vacuo. The residue was suspended in hot methanol (5 mL) and the remaining solids filtered off. The filtrate was concentrated in vacuo and the residue triturated with ethyl acetate and filtered to give the title compound (77 mg, 43%) as a white solid.
Reaction SMILES: C([O:3][C:4](=[O:14])[C@@H:5]([N:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]1=[O:13])[CH3:6])C.C1COCC1.[OH-].[Na+]>O>[O:13]=[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][N:7]1[C@@H:5]([CH3:6])[C:4]([OH:14])=[O:3]
Reactant: CCOC(=O)[C@H](C)n1ccccc1=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: C[C@@H](C(=O)O)n1ccccc1=O
Reaction time: 1 h
Yield: 26.9 %

Procedure:
A stirred mixture of (S)-2-(2-Oxo-2H-pyrid-1-yl)-propionic acid ethyl ester (364 mg, 1.87 mmol), THF (2 ml), water (1 ml) and sodium hydroxide (90 mg, 2.24 mmol) was kept at room temperature for 1 h, then concentrated under reduced pressure. The residue was dissolved in ether and the resulting solution washed with water. The organic layer was discarded and the aqueous layer was acidified with concentrated HCl then extracted several times with ethyl acetate. The combined organic extracts were dried (MgSO4), filtered and concentrated. The residue was triturated with ether to afford the title compound as a colorless solid (84 mg, 27%): [α]31D=−50° (c=0.2, CH3OH); 1H NMR (400 MHz, DMSO) δ 1.5 (3H, d), 5.1 (1H, q), 6.2 (1H, t), 6.4 (1H, d), 7.4 (1H, m), 7.6 (1H, d).