Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[C:11]([C:13]3[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=3)[N:10]=[N:9][C:8]=2[C:19]2[CH:26]=[CH:25][C:22]([CH:23]=O)=[CH:21][CH:20]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN(C)C1N=NC(C2C=CC(C=O)=CC=2)=C(C2C=CC=CC=2)C=1.[NH:50]1[CH2:55][CH2:54][CH:53]([C:56]2[N:60]=[C:59]([C:61]3[CH:66]=[CH:65][CH:64]=[CH:63][N:62]=3)[NH:58][N:57]=2)[CH2:52][CH2:51]1.N1CCC(C2C=C(C3C=CC=CN=3)NN=2)CC1>>[C:1]1([C:7]2[CH:12]=[C:11]([C:13]3[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=3)[N:10]=[N:9][C:8]=2[C:19]2[CH:26]=[CH:25][C:22]([CH2:23][N:50]3[CH2:55][CH2:54][CH:53]([C:56]4[N:60]=[C:59]([C:61]5[CH:66]=[CH:65][CH:64]=[CH:63][N:62]=5)[NH:58][N:57]=4)[CH2:52][CH2:51]3)=[CH:21][CH:20]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=Cc1ccc(-c2nnc(-c3cccnc3)cc2-c2ccccc2)cc1
Reactant: c1ccc(-c2nc(C3CCNCC3)n[nH]2)nc1
Agent: CN(C)c1cc(-c2ccccc2)c(-c2ccc(C=O)cc2)nn1
Agent: c1ccc(-c2cc(C3CCNCC3)n[nH]2)nc1
Product: c1ccc(-c2cc(-c3cccnc3)nnc2-c2ccc(CN3CCC(c4n[nH]c(-c5ccccn5)n4)CC3)cc2)cc1

Procedure:
4-Phenyl-6-pyridin-3-yl-3-(4-{[4-(5-pyridin-2-yl-1H-1,2,4-triazol-3-yl)piperidin-1-yl]methyl}phenyl)pyridazine (3-4) was prepared according to the procedure described in Scheme 1, except 4-(4-phenyl-6-pyridin-3-ylpyridazin-3-yl)benzaldehyde (3-2) is substituted for 4-[6-(dimethylamino)-4-phenylpyridazin-3-yl]benzaldehyde (1-3) and 2-(3-piperidin-4-yl-1H-1,2,4-triazol-5-yl)pyridine (3-3; see synthesis below) for 2-(3-piperidin-4-yl-1H-pyazol-5-yl)pyridine (1-4). NMR (CDCl3): δ9.34 (1H, s), 8.76 (1H, d, J=4 Hz), 8.64 (1H, d, J=4.3 Hz), 8.58 (1H, d, J=8 Hz), 8.14 (1H, d, J=7.8 Hz), 7.88 (1H, s), 7.83 (1H, t, J=7.8 Hz), 7.44-7.53 (3H, m), 7.30-7.42 (5H, m), 3.57 (2H, s), 2.98 (2H, br s), 2.87 (1H, m), 2.06-2.22 (4H, m), 2.00 (2H, m); m/e (m+1): 551.5
Reaction SMILES: C([O:3][C:4]([C@@H:6]([NH:15][C@H:16]1[CH2:22][S:21][CH:20]([C:23]2[S:24][CH:25]=[CH:26][CH:27]=2)[CH2:19][N:18]([CH2:28][C:29]([OH:31])=[O:30])[C:17]1=[O:32])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:5])C.[OH-].[Na+]>>[C:4]([C@@H:6]([NH:15][C@H:16]1[CH2:22][S:21][CH:20]([C:23]2[S:24][CH:25]=[CH:26][CH:27]=2)[CH2:19][N:18]([CH2:28][C:29]([OH:31])=[O:30])[C:17]1=[O:32])[CH2:7][CH2:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)([OH:5])=[O:3]
Reactant: CCOC(=O)[C@H](CCc1ccccc1)N[C@H]1CSC(c2cccs2)CN(CC(=O)O)C1=O
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)CN1CC(c2cccs2)SC[C@H](N[C@@H](CCc2ccccc2)C(=O)O)C1=O
Yield: 86.3 %

Procedure:
The procedure described in Example 44 was repeated, except that 80 mg of α-{6(R)-[1(S)-ethoxycarbonyl-3-phenylpropylamino]-5-oxo-2-(2-thienyl)perhydro-1,4-thiazepin-4-yl}acetic acid (prepared as described in Example 64) were used as the starting material. After hydrolysis of the starting material with sodium hydroxide, 65 mg of the title compound were obtained as a powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13]2[S:14][C:15]([C:19](=O)[CH3:20])=[C:16]([CH3:18])[N:17]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[OH-].[Na+].[NH2:24][NH:25][C:26]([NH2:28])=[S:27].O>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13]2[S:14][C:15]([C:19](=[N:24][NH:25][C:26]([NH2:28])=[S:27])[CH3:20])=[C:16]([CH3:18])[N:17]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10]
Reactant: COc1cc(-c2nc(C)c(C(C)=O)s2)cc(OC)c1OC
Reactant: NNC(N)=S
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COc1cc(-c2nc(C)c(C(C)=NNC(N)=S)s2)cc(OC)c1OC
Yield: 65 %

Procedure:
2-(3,4,5-trimethoxyphenyl)-4-methyl-5-acetylthiazole prepared in Example 1 (1.0 g corresponding to its 0.0033 mol) was dissolved in 30 ml of ethanol, and to the solution, 8.6 ml of an aqueous 2% solution of sodium hydroxide (0.0045 mol) and 0.4 g (0.0044 mol) of thiosemicarbazide were added, and the mixture was heated for 3 hours under a reflux condenser. After cooling the reaction mixture, it was introduced into 300 ml of iced water, and the precipitate which separated was collected by filtration. After washing the precipitate with water, it was recrystallized from ethanol to obtain the object consisting of yellow needle-like crystals amounting to 0.82 g at a yield of 65%, which decomposed at 209° to 212° C.
Reaction SMILES: [C:1]1([C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4])[OH:2].[Br-:9].[Br-].O1CCOCC1>CCOCC>[Br:9][C:6]1[CH:5]=[C:3]([OH:4])[C:1](=[CH:8][CH:7]=1)[OH:2]
Reactant: Oc1ccccc1O
Reactant: [Br-]
Solvent: CCOCC
Solvent: C1COCCO1
Product: Oc1ccc(Br)cc1O

Procedure:
Catechol (11.0 g; 0.100 mol) is dissolved in 50 ml of ether and 29 g of freshly-prepared dioxane dibromide (Yanovskaya, Terent'ev and Belsn'kii), J. Gen. Chem. Vol. 22:1594 (1952)) is added slowly as a solution in 50 ml of ether. The organic solution is washed with water (3 times) and dried over MgSO4. The solvent is removed under reduced pressure to yield 4-bromocatechol as a red-brown oil. 1H NMR δ 5.52 (s, 1), 5.70 (s, 1), 6.74 (d, 1, J=8.74 Hz), 6.92 (dd, 1, J=8.3, 2.3 Hz), and 7.01 ppm (d, 1, J=2.6 Hz).
Reaction SMILES: ClC1C=CC2C3N=C(NC4C=CC(I)=CC=4)N=CC=3CC(=O)NC=2C=1.C(NC(=O)OC(C)(C)C)C#C.C(OC(=O)[NH:43][CH2:44][C:45]#[C:46][C:47]1[CH:52]=[CH:51][C:50]([NH:53][C:54]2[N:55]=[CH:56][C:57]3[CH2:63][C:62](=[O:64])[NH:61][C:60]4[CH:65]=[C:66]([Cl:69])[CH:67]=[CH:68][C:59]=4[C:58]=3[N:70]=2)=[CH:49][CH:48]=1)(C)(C)C>>[NH2:43][CH2:44][C:45]#[C:46][C:47]1[CH:52]=[CH:51][C:50]([NH:53][C:54]2[N:55]=[CH:56][C:57]3[CH2:63][C:62](=[O:64])[NH:61][C:60]4[CH:65]=[C:66]([Cl:69])[CH:67]=[CH:68][C:59]=4[C:58]=3[N:70]=2)=[CH:49][CH:48]=1
Reactant: CC(C)(C)OC(=O)NCC#Cc1ccc(Nc2ncc3c(n2)-c2ccc(Cl)cc2NC(=O)C3)cc1
Agent: C#CCNC(=O)OC(C)(C)C
Agent: O=C1Cc2cnc(Nc3ccc(I)cc3)nc2-c2ccc(Cl)cc2N1
Product: NCC#Cc1ccc(Nc2ncc3c(n2)-c2ccc(Cl)cc2NC(=O)C3)cc1

Procedure:
In a manner similar to that described for Method O, 9-chloro-2-(4-iodo-phenylamino)-5H,7H-benzo[b]pyrimido[4,5-d]azepin-6-one (I-36) and tert-butyl prop-2-ynylcarbamate were converted to {3-[4-(9-chloro-6-oxo-6,7-dihydro-5H-benzo[b]pyrimido[4,5-d]azepin-2-ylamino)-phenyl]-prop-2-ynyl}-carbamic acid tert-butyl ester, which was deprotected according to Method K to give I-46 (29%): HRMS Calcd. for C21H16ClN5O: 390.1121, Found 390.1120.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([O:16][CH3:17])=[O:15])=[CH:7][C:6]=2[CH:18]=1.B([O-])([O-])O[C:21]1[CH:26]=[CH:25][C:24]([O:27][CH2:28][CH2:29][CH3:30])=[CH:23][CH:22]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.C(O)C.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:28]([O:27][C:24]1[CH:25]=[CH:26][C:21]([C:2]2[CH:3]=[CH:4][C:5]3[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([O:16][CH3:17])=[O:15])=[CH:7][C:6]=3[CH:18]=2)=[CH:22][CH:23]=1)[CH2:29][CH3:30]
Reactant: CCCOc1ccc(OB([O-])[O-])cc1
Reactant: COC(=O)C1=Cc2cc(Br)ccc2S(=O)(=O)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCS3(=O)=O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 81.4 %

Procedure:
Under argon atmosphere, a mixture of methyl 7-bromo-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (0.70 g), 4-propoxyphenyl borate (0.38 g) and potassium carbonate (0.58 g) in toluene/ethanol/water (20/2/2 ml) was stirred at room temperature for 1 hour. To the mixture was added tetrakistriphenylphosphinepalladium (0.12 g), and the mixture was refluxed for 18 hours, cooled, extracted with ethyl acetate, washed with saturated brine, dried with magnesium sulfate and concentrated under reduced pressure. The residue was purified with column chromatography (ethyl acetate/hexane=1:2→1:1) to give pale yellow crystals of methyl 7-(4-propoxyphenyl)-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (616.4 mg).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([OH:10])=O)=[C:6]([CH3:11])[CH:5]=[C:4]([Cl:12])[N:3]=1.[F:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=1)[CH2:17][NH2:18].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC>C1COCC1>[Cl:1][C:2]1[C:7]([C:8]([NH:18][CH2:17][C:16]2[CH:19]=[CH:20][CH:21]=[C:14]([F:13])[CH:15]=2)=[O:10])=[C:6]([CH3:11])[CH:5]=[C:4]([Cl:12])[N:3]=1
Reactant: NCc1cccc(F)c1
Reactant: Cc1cc(Cl)nc(Cl)c1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1cc(Cl)nc(Cl)c1C(=O)NCc1cccc(F)c1
Temperature: 70 °C
Yield: 73.8 %

Procedure:
To a solution of 17.4 g (84.4 mmol) of 2,6-dichloro-4-methyl-pyridine-3-carboxylic acid in THF (340 ml) were added 10.6 ml (92.9 mmol) 3-fluorobenzylamine, 32.0 g (84.4 mmol) HATU and 35.0 ml (253.3 mmol) NEt3. The RM was then heated at 70° C. for 16. After dilution with EtOAc (350 ml) the mixture was washed with a 4M aq. NH4Cl sol., a 1M aq. NaHCO3 sol. and brine. The organic layer was dried over MgSO4 and concentrated in vacuo. Purification of the residue by CC (hexane/EtOAc 3:2) provided 19.5 g (62.3 mmol, 74%) 2,6-dichloro-N-(3-fluorobenzyl)-4-methyl-pyridine-3-carboxylic acid amide.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][N:12]([C:15]3[C:16]([CH3:38])=[C:17]([CH3:37])[C:18]4[O:22][C:21]([CH2:24][N:25]5[CH2:34][CH2:33][C:28]6(OCC[O:29]6)[CH2:27][CH2:26]5)([CH3:23])[CH2:20][C:19]=4[C:35]=3[CH3:36])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.Cl.C(OCC)(=O)C.Cl.O.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N:9]2[CH2:10][CH2:11][N:12]([C:15]3[C:16]([CH3:38])=[C:17]([CH3:37])[C:18]4[O:22][C:21]([CH2:24][N:25]5[CH2:34][CH2:33][C:28](=[O:29])[CH2:27][CH2:26]5)([CH3:23])[CH2:20][C:19]=4[C:35]=3[CH3:36])[CH2:13][CH2:14]2)=[CH:7][CH:8]=1
Reactant: COc1ccc(N2CCN(c3c(C)c(C)c4c(c3C)CC(C)(CN3CCC5(CC3)OCCO5)O4)CC2)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: COc1ccc(N2CCN(c3c(C)c(C)c4c(c3C)CC(C)(CN3CCC(=O)CC3)O4)CC2)cc1
Temperature: 50 °C
Reaction time: 2 h
Yield: 49.8 %

Procedure:
To a solution of ethyl acetate (2.0 mL) containing 8-({5-[4-(4-Methoxyphenyl)piperazin-1-yl]-2,4,6,7-tetramethyl-2,3-dihydro-1-benzofuran-2-yl}methyl)-1,4-dioxa-8-azaspiro[4.5]decane (55 mg, 0.105 mmol) synthesized in Example 115, a solution of 4N hydrochloric acid-ethyl acetate (2.0 mL) was added, and the mixture was stirred at room temperature for 5 hours and at 50° C. for 2 hours. After that, 6N hydrochloric acid was (1.0 mL) was added thereto, and the mixture was further stirred at 70° C. for 2 hours. After cooled to room temperature, the reaction solution was poured into saturated sodium bicarbonate water, and extraction was performed using ethyl acetate. The extract was washed saturated saline, and then dried using anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel chromatography (hexane-ethyl acetate 95:5-72:28) and crystallized from ethyl acetate-hexane to give 25 mg of the title compound (yield 50%). Melting point was 123 to 127° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:12][C:11]2[C:10]([C:13]3[NH:14][C:15]4[C:20]([CH:21]=3)=[CH:19][C:18]([C:22](C)(C)[O:23][SiH2]C(C)(C)C)=[CH:17][CH:16]=4)=[N:9][NH:8][C:7]=2[CH:6]=1)=[O:4].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1.C(OCC)(=O)C>[CH3:1][O:2][C:3]([C:5]1[S:12][C:11]2[C:10]([C:13]3[NH:14][C:15]4[C:20]([CH:21]=3)=[CH:19][C:18]([CH2:22][OH:23])=[CH:17][CH:16]=4)=[N:9][NH:8][C:7]=2[CH:6]=1)=[O:4]
Reactant: COC(=O)c1cc2[nH]nc(-c3cc4cc(C(C)(C)O[SiH2]C(C)(C)C)ccc4[nH]3)c2s1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)c1cc2[nH]nc(-c3cc4cc(CO)ccc4[nH]3)c2s1
Reaction time: 8 h
Yield: 63.2 %

Procedure:
A solution of 3-[5-(tert-butyl-dimethyl-silanyloxymethyl)-1H-indol-2-yl]-1H-thieno[3,2-c]pyrazole-5-carboxylic acid methyl ester [192 mg, 0.435 mmol, Intermediate (28)] is dissolved in tetrahydrofuran (10 mL) and treated with tetrabutylammonium fluoride (1.0 M in tetrahydrofuran, 0.52 mL) and stirred overnight. The reaction mixture is diluted in ethyl acetate and washed with water, brine and dried over sodium sulfate. The residue is chromatographed on 10 g silica gel cartridge (50% ethyl acetate in heptane then ethyl acetate) to obtain solid. Recrystallization from ethyl acetate and heptane afforded 3-(5-hydroxymethyl-1H-indol-2-yl)-1H-thieno[3,2-c]pyrazole-5-carboxylic acid methyl ester [90 mg, 73%, Example 40] as beige solid; 1H NMR [(CD3)2SO)]: δ 13.66 (1H, s), 11.60 (1H, s), 7.92 (1H, s), 7.51 (1H, s), 7.38 (1H, d, J=8.2 Hz), 7.10 (1H, d, J=8.2 Hz), 6.68 (1H, s), 5.75 (1H, br s, OH), 4.54 (2H, s, —CH2OH), 3.90 (3H, s, —CO2CH3); LC/MS 328 (M++H).
Reaction SMILES: FC(F)(F)C(O)=O.[N:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][CH2:15][CH2:16][CH2:17][CH2:18][O:19][C:20]1[CH:21]=[C:22]([S:26](N[C@H](C#C)CC(O)=O)(=[O:28])=[O:27])[CH:23]=[CH:24][CH:25]=1.[NH:37]1[CH2:46][CH2:45][CH:40]([C:41]([O:43]C)=[O:42])[CH2:39][CH2:38]1>>[N:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][CH2:15][CH2:16][CH2:17][CH2:18][O:19][C:20]1[CH:21]=[C:22]([S:26]([N:37]2[CH2:46][CH2:45][CH:40]([C:41]([OH:43])=[O:42])[CH2:39][CH2:38]2)(=[O:28])=[O:27])[CH:23]=[CH:24][CH:25]=1
Reactant: C#C[C@H](CC(=O)O)NS(=O)(=O)c1cccc(OCCCCNc2ccccn2)c1
Reactant: COC(=O)C1CCNCC1
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)C1CCN(S(=O)(=O)c2cccc(OCCCCNc3ccccn3)c2)CC1

Procedure:
The procedure for the preparation of the product of EXAMPLE 17 was repeated using methyl isonipecotate (Aldrich) in the place of ethyl (3S)-3-aminopent-4-ynoate hydrochloride to provide the title product. 1H (CD3OD): δ 7.86 (1H, d); 7.61 (1H, t); 7.49 (1H, t); 7.32 (1H, d); 7.24 (1H, s); 7.20 (1H, d); 6.74 (1H, d); 6.66 (1H, t); 4.12 (2H, t); 3.57 (2H, br. d); 3.37 (2H, t); 2.52 (2H, t); 2.27 (1H, tt); 1.94 (4H, m); 1.84 (2H, p); 1.71 (2H, br. q).
Reaction SMILES: [CH3:1][N:2]([CH3:29])[CH2:3][CH2:4][N:5]([C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[C:15](=[O:19])[N:14]([CH2:20][C:21]([O:23]C(C)(C)C)=[O:22])[C:13]2=[O:28])[S:6]([CH3:9])(=[O:8])=[O:7].[ClH:30]>O1CCOCC1>[ClH:30].[CH3:1][N:2]([CH3:29])[CH2:3][CH2:4][N:5]([C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[C:15](=[O:19])[N:14]([CH2:20][C:21]([OH:23])=[O:22])[C:13]2=[O:28])[S:6]([CH3:9])(=[O:8])=[O:7]
Reactant: CN(C)CCN(c1ccc2c(c1)C(=O)N(CC(=O)OC(C)(C)C)C2=O)S(C)(=O)=O
Agent: Cl
Solvent: C1COCCO1
Product: CN(C)CCN(c1ccc2c(c1)C(=O)N(CC(=O)O)C2=O)S(C)(=O)=O
Temperature: 100 °C
Yield: 87 %

Procedure:
To a solution of tert-butyl 2-(5-(N-(2-(dimethylamino)ethyl)-methylsulfonamido)-1,3-dioxoisoindolin-2-yl)acetate (300 mg, 0.705 mmol) in dioxane (8 ml), 4M HCl in dioxane (1.763 ml, 7.05 mmol) was added, and the mixture was heated under microwave irradiation at 100° C. for 2 hours. The volatiles were removed under vacuum and the crude was purified by trituration with Et2O affording after filtration 2-(5-(N-(2-(dimethylamino)ethyl)methylsulfonamido)-1,3-dioxoisoindolin-2-yl)acetic acid hydrochloride (250 mg, 0.616 mmol, 87% yield), MS/ESI+ 370.0 [MH]+).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]([Cl:30])[CH:8]=[C:9]2[C:14]=1[NH:13][CH:12]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([NH:21][C:22]([C:25]([OH:27])=[O:26])([CH3:24])[CH3:23])[CH:16]=1)[C:11]([CH3:29])([CH3:28])[CH2:10]2)=[O:4].O.[OH-].[Li+].O.Cl>CO.O1CCCC1>[C:25]([C:22]([NH:21][C:17]1[CH:16]=[C:15]([CH:12]2[C:11]([CH3:28])([CH3:29])[CH2:10][C:9]3[C:14](=[C:5]([C:3]([OH:4])=[O:2])[CH:6]=[C:7]([Cl:30])[CH:8]=3)[NH:13]2)[CH:20]=[CH:19][CH:18]=1)([CH3:23])[CH3:24])([OH:27])=[O:26]
Reactant: COC(=O)c1cc(Cl)cc2c1NC(c1cccc(NC(C)(C)C(=O)O)c1)C(C)(C)C2
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(Nc1cccc(C2Nc3c(cc(Cl)cc3C(=O)O)CC2(C)C)c1)C(=O)O
Temperature: 60 °C
Reaction time: 12 h
Yield: 25 %

Procedure:
A mixture of 2-[3-(1-carboxy-1-methyl-ethylamino)-phenyl]-6-chloro-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-8-carboxylic acid methyl ester (100 mg, 0.23 mmol), lithium hydroxide hydrate (98 mg, 2.3 mmol), water (0.5 mL) in methanol (1 mL) and tetrahydrofuran (5 mL) was stirred at 60° C. for 12 h. The mixture was neutralized with a 3 N aqueous hydrochloric acid solution and extracted with ethyl acetate (2×50 mL), washed with water, dried over anhydrous sodium sulfate and then concentrated in vacuo to afford an oil residue. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% formic acid in water) afforded 2-[3-(1-carboxy-1-methyl-ethylamino)-phenyl]-6-chloro-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-8-carboxylic acid (24 mg, 25%) as a white solid: LC/MS m/e calcd for C22H25ClN2O4 (M+H)+: 417.91, observed: 417.0.
Reaction SMILES: Br[CH2:2][C:3](=[O:17])[CH:4]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.C(N(CC)C(C)C)(C)C.[CH2:27]([O:34][C:35]([N:37]1[CH2:41][CH2:40][CH2:39][C@H:38]1[CH2:42][NH:43][CH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][C:46]=1[O:51][CH3:52])=[O:36])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>O1CCCC1>[CH2:27]([O:34][C:35]([N:37]1[CH2:41][CH2:40][CH2:39][C@H:38]1[CH2:42][N:43]([CH2:2][C:3](=[O:17])[CH:4]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][C:46]=1[O:51][CH3:52])=[O:36])[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: O=C(CBr)C(c1ccccc1)c1ccccc1
Reactant: COc1ccccc1CNC[C@@H]1CCCN1C(=O)OCc1ccccc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccccc1CN(CC(=O)C(c1ccccc1)c1ccccc1)C[C@@H]1CCCN1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 6.1 %

Procedure:
3-Bromo-1,1-diphenyl-2-propanone (12.7 g) and N,N-diisopropylethylamine (15.7 ml) were added successively to a solution of (2S)-2-[(2-methoxybenzylamino)methyl]pyrrolidine-1-carboxylic acid benzyl ester (15.6 g) in tetrahydrofuran (156 ml) at 0° C. After being stirred at room temperature for 2 hours, the mixture was poured into ice-water (100 ml) and extracted with ethyl acetate (100 ml×2). The extract was washed with brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel using a mixed solvent of hexane and ethyl acetate (3:1). The fractions containing the objective compound were collected and evaporated under reduced pressure to give a colorless syrup of (2S)-2-[[N-(2-oxo-3,3-diphenylpropyl)-N-(2-methoxybenzyl)amino]methyl]pyrrolidine-1-carboxylic acid benzyl ester (1.51 g).
Reaction SMILES: [H-].[Na+].CI.[CH2:5]([S:7][C:8]1[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[CH:23][C:9]=1[C:10]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][N:14]=1)=[O:11])[CH3:6].[CH2:31]1COCC1>O>[CH2:5]([S:7][C:8]1[CH:26]=[C:25]([C:27]([F:30])([F:28])[F:29])[CH:24]=[CH:23][C:9]=1[C:10]([N:12]([CH3:31])[C:13]1[CH:18]=[CH:17][C:16]([C:19]([F:20])([F:21])[F:22])=[CH:15][N:14]=1)=[O:11])[CH3:6]
Reactant: CCSc1cc(C(F)(F)F)ccc1C(=O)Nc1ccc(C(F)(F)F)cn1
Reactant: C1CCOC1
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: O
Product: CCSc1cc(C(F)(F)F)ccc1C(=O)N(C)c1ccc(C(F)(F)F)cn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
0.12 g of 60% sodium hydride (oil-based) and 0.56 g of methyl iodide were added to a mixture of 0.78 g of 2-ethylsulfanyl-4-trifluoromethyl-N-(5-trifluoromethyl-pyri din-2-yl)-benzamide and 5 mL of THF, and the mixture was stirred at room temperature for 2 hours. 1 g of methyl iodide was added to the reaction mixture, and the mixture was stirred at room temperature for 2 hours. 1 g of methyl iodide was further added to the reaction mixture, and the mixture was stirred at room temperature for 1 hour. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure, and the resulting residue was applied to a silica gel column chromatography to obtain 0.59 g of 2-ethylsulfanyl-N-methyl-4-trifluoromethyl-N-(5-trifluoromethyl-pyridin-2-yl)-benzamide (hereinafter, referred to as Compound of Present Invention 2).
Reaction SMILES: [CH2:1]([O:3][C:4]([C@H:6]1[CH2:11][CH2:10][C@@H:9]([OH:12])[CH2:8][CH2:7]1)=[O:5])[CH3:2].N1C=CN=C1.[Si:18](Cl)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19].CN(C=O)C>O>[CH2:1]([O:3][C:4]([C@H:6]1[CH2:11][CH2:10][C@@H:9]([O:12][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19])[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)[C@H]1CC[C@@H](O)CC1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)[C@H]1CC[C@@H](O[Si](C)(C)C(C)(C)C)CC1
Reaction time: 8 h

Procedure:
A mixture of 3 g of cis-4-hydroxy-cyclohexanecarboxylic acid ethyl ester, 3 g of imidazole, 33 g of tert-butyldimethylsilyl-chloride, and 6 mL of DMF was stirred under inert atmosphere overnight. The mixture was diluted with 250 mL of water and extracted into 3×50 mL portions of ether. The combined ether extracts were washed with 2×50 mL of water, dried over magnesium sulfate and concentrated under reduced pressure. Drying under vacuum overnight gave 4.5 g of product as a colorless oil: 1H NMR (400 MHz, CDCl3) 4.1 (dd, 2H), 3.58 (m, cis isomer, 0.85H), 2.2 (m, 1H), 1.95 (m, 4H), 1.6 (m, 1H), 1.5 (m, 1H), 1.22 (m, 6H), 0.9 (s, 9H), 0.04 (s, 6H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]2[O:13][CH2:12][CH2:11][N:10]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:9]2)=[CH:4][C:3]=1[CH3:21].Br[C:23]1[CH:28]=[CH:27][C:26]([Br:29])=[CH:25][N:24]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1>[Br:29][C:26]1[CH:27]=[CH:28][C:23]([NH:1][C:2]2[N:7]=[CH:6][C:5]([CH:8]3[O:13][CH2:12][CH2:11][N:10]([C:14]([O:16][C:17]([CH3:18])([CH3:20])[CH3:19])=[O:15])[CH2:9]3)=[CH:4][C:3]=2[CH3:21])=[N:24][CH:25]=1
Reactant: Cc1cc(C2CN(C(=O)OC(C)(C)C)CCO2)cnc1N
Reactant: Brc1ccc(Br)nc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: Cc1cc(C2CN(C(=O)OC(C)(C)C)CCO2)cnc1Nc1ccc(Br)cn1
Temperature: 100 °C
Reaction time: 8 h
Yield: 28.3 %

Procedure:
tert-Butyl (RS)-2-(6-amino-5-methylpyridin-3-yl)morpholine-4-carboxylate (60 mg), 2,5-dibromopyridine (72.7 mg, CAS 624-28-2) and cesium carbonate (100 mg) were combined with dioxane (2 ml) to give a yellow suspension. The mixture was degassed by bubbling argon into the mixture for several minutes. Xantphos (14.1 mg) and tris(dibenzylideneacetone)dipalladium chloroform complex (12.6 mg) were then added. The reaction mixture was then capped and stirred at 100° C. overnight and then at 120° C. for 2 hours. The crude reaction mixture was cooled to room temperature and filtered. The filtrate was concentrated in vacuo and the residue was purified by flash column chromatography (silica gel; gradient: 0% to 100% EtOAc in hexanes) to afford tert-butyl (RS)-2-(6-(5-bromopyridin-2-ylamino)-5-methylpyridin-3-yl)morpholine-4-carboxylate (26 mg, 28%) as a yellow amorphous solid. MS (ISP): 451.1 ([{81Br}M+H]+), 449.1 ([{79Br}M+H]+).