Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[CH:15]=[CH:14][C:7]([O:8][CH:9]2[NH:12][C:11](=[O:13])[CH2:10]2)=[CH:6][CH:5]=1)(O)=[O:2].B.CSC.B.CO>O1CCCC1>[OH:2][CH2:1][C:4]1[CH:15]=[CH:14][C:7]([O:8][CH:9]2[NH:12][C:11](=[O:13])[CH2:10]2)=[CH:6][CH:5]=1
Reactant: O=C1CC(Oc2ccc(C(=O)O)cc2)N1
Agent: B
Solvent: C1CCOC1
Solvent: CSC
Solvent: CO
Product: O=C1CC(Oc2ccc(CO)cc2)N1
Reaction time: 8 h

Procedure:
To a solution of (4S)-3,3-diethyl-1-[(R)-α-n-propyl-(4-methyl)-benzylaminocarbonyl)]-4-(4-carboxyphenoxy)-azetidin-2-one (1.04 g, 2.30 mmol) in tetrahydrofuran (20 mL) cooled to 0° C. was added dropwise with stirring under a nitrogen atmosphere a 2.0M solution of borane-methyl sulfide in tetrahydrofuran (3.0 mL, 6 mmol). The solution was allowed to attain room temperature and stirred overnight. Excess borane was decomposed by slow addition of methanol. The solution was evaporated, and the crude product was subjected to flash chromatography on silica gel using 30% ethyl acetate in hexane as the mobile phase. (4S)-3,3-Diethyl-1-[(R)-α-n-propyl-(4-methyl)-benzylaminocarbonyl)]-4-[4-(hydroxymethyl)-phenoxy]-azetidin-2-one was obtained as a colorless oil. Triphenylphosphine (637 mg, 2.43 mmol) was dissolved in acetonitrile (11 mL) and bromine (0.12 mL) was added with stirring to give rise to a yellow-orange solution. Additional triphenylphosphine was added until a faintly yellow solution was obtained. A solution of (4S)-3,3-diethyl-1-[(R)-α-n-propyl-(4-methyl)-benzylaminocarbonyl]-4-[4-(hydroxymethyl)-phenoxy]-azetidin-2-one (1.0 g, 2.28 mmol) in acetonitrile (10 mL) was added dropwise with stirring. The reaction mixture was stirred ovenight at room temperature, evaporated, and the crude mixture subjected to flash chromatography on silica gel using 5% ethyl acetate in hexane as the mobile phase.
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]([O:25]C(C)(C)C)=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[CH:30]=[C:31]([N:34]([CH:44]3[CH2:49][CH2:48][CH2:47][CH2:46][CH2:45]3)[C:35]([NH:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])=[O:36])[CH:32]=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].FC(F)(F)C(O)=O>>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]([OH:25])=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[CH:30]=[C:31]([N:34]([CH:44]3[CH2:45][CH2:46][CH2:47][CH2:48][CH2:49]3)[C:35]([NH:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])=[O:36])[CH:32]=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCCCNC(=O)N(c1ccc2nc(CCCC)n(Cc3ccc(-c4ccccc4C(=O)OC(C)(C)C)cc3)c2c1)C1CCCCC1
Solvent: O=C(O)C(F)(F)F
Product: CCCCCCNC(=O)N(c1ccc2nc(CCCC)n(Cc3ccc(-c4ccccc4C(=O)O)cc3)c2c1)C1CCCCC1

Procedure:
Prepared in analogous manner to Example 9 from tert.butyl 4'-[(2-n-butyl-6-(N-(n-hexylaminocarbonyl)-cyclohexylamino)-benzimidazol-1-yl)-methyl]biphenyl-2-carboxylate and trifluoroacetic acid..
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([NH:7][C:8]([NH:10][S:11]([C:14]2[CH:15]=[N:16][C:17](Cl)=[C:18]([Cl:20])[CH:19]=2)(=[O:13])=[O:12])=[O:9])=[N:4][CH:3]=1.[CH3:22][CH:23]1[CH2:27][CH2:26][CH2:25][NH:24]1>CN(C=O)C.C(OCC)(=O)C>[Br:1][C:2]1[S:6][C:5]([NH:7][C:8]([NH:10][S:11]([C:14]2[CH:15]=[N:16][C:17]([N:24]3[CH2:25][CH2:26][CH2:27][CH:23]3[CH3:22])=[C:18]([Cl:20])[CH:19]=2)(=[O:13])=[O:12])=[O:9])=[N:4][CH:3]=1
Reactant: O=C(Nc1ncc(Br)s1)NS(=O)(=O)c1cnc(Cl)c(Cl)c1
Reactant: CC1CCCN1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC1CCCN1c1ncc(S(=O)(=O)NC(=O)Nc2ncc(Br)s2)cc1Cl

Procedure:
N-[(5-Bromo-1,3-thiazol-2-yl)carbamoyl]-5,6-dichloropyridine-3-sulfonamide (20 mg, 0.05 mmol) was dissolved in DMF (1 ml) and reacted with 2-methylpyrrolidine (0.10 ml, 1 mmol) at 50° C. for 2.5 hours. The reaction mixture was diluted with ethyl acetate (30 ml) and washed with water, NaHCO3 (half sat. 3×), 5% KHSO4/10% K2SO4, NaCl sat., dried (MgSO4.2H2O), filtered and concentrated under reduced pressure. The crude was purified by preparative RP-HPLC: 6 mg, MS: m/e 477.9 (MH−).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[C:9]([CH:13]=1)[C:10]([OH:12])=O)(=[O:4])=[O:3].Cl.[CH2:21]([S:25]([C:28]1[S:32][C:31]([N:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)=[N:30][CH:29]=1)(=[O:27])=[O:26])[CH2:22][CH2:23][CH3:24]>>[CH2:21]([S:25]([C:28]1[S:32][C:31]([N:33]2[CH2:38][CH2:37][N:36]([C:10]([C:9]3[CH:13]=[C:5]([S:2]([CH3:1])(=[O:3])=[O:4])[CH:6]=[CH:7][C:8]=3[O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[O:12])[CH2:35][CH2:34]2)=[N:30][CH:29]=1)(=[O:27])=[O:26])[CH2:22][CH2:23][CH3:24]
Reactant: CS(=O)(=O)c1ccc(OCC(F)(F)F)c(C(=O)O)c1
Reactant: CCCCS(=O)(=O)c1cnc(N2CCNCC2)s1
Agent: Cl
Product: CCCCS(=O)(=O)c1cnc(N2CCN(C(=O)c3cc(S(C)(=O)=O)ccc3OCC(F)(F)F)CC2)s1
Yield: 63 %

Procedure:
Prepared in analogy to example 1 (b) from 5-methanesulfonyl-2-(2,2,2-trifluoro-ethoxy)-benzoic acid (Example A3) and 1-[5-(butane-1-sulfonyl)-thiazol-2-yl]-piperazine hydrochloride (Example 38(c)). The crude material was purified by chromatography (SiO2, ethyl acetate/heptane) followed by trituration in ether to yield the title compound as a white crystalline solid (yield 63%). MS (m/e): 570.4 (M+H+, 15%), 587.3 (M+NH4+, 100%).
Reaction SMILES: [Cl:1][C:2]1[C:7]2[CH:8]=[C:9]([CH3:12])[N:10]([CH3:11])[C:6]=2[C:5]([C:13]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)=[O:14])=[CH:4][N:3]=1.[Cl:21][C:22]1[CH:23]=[C:24]([CH:26]=[CH:27][CH:28]=1)[NH2:25].CS(O)(=O)=O.Cl>O1CCOCC1.C(OCC)(=O)C.C(OCC)C>[ClH:1].[Cl:21][C:22]1[CH:23]=[C:24]([NH:25][C:2]2[C:7]3[CH:8]=[C:9]([CH3:12])[N:10]([CH3:11])[C:6]=3[C:5]([C:13]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[O:14])=[CH:4][N:3]=2)[CH:26]=[CH:27][CH:28]=1
Reactant: Nc1cccc(Cl)c1
Reactant: Cc1cc2c(Cl)ncc(C(=O)N3CCOCC3)c2n1C
Agent: CS(=O)(=O)O
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCOCC
Solvent: C1COCCO1
Product: Cc1cc2c(Nc3cccc(Cl)c3)ncc(C(=O)N3CCOCC3)c2n1C
Temperature: 180 °C

Procedure:
A mixture of 4-chloro-1,2-dimethyl-7-(4-morpholinylcarbonyl)-1H-pyrrolo[3,2-c]pyridine (68 mg), 3-chloroaniline (0.05 ml) and methanesulfonic acid (0.03 ml) in dry 1,4-dioxan was heated under microwave conditions at 180° C. for fifteen minutes. The reaction mixture was transferred to a round bottom flask and evaporated. The residue was partitioned between ethyl acetate (10 ml) and saturated sodium bicarbonate solution and washed with saturated sodium bicarbonate solution and water. The organic layer was dried (MgSO4) and evaporated to afford a brown oil. The oil was purified by Biotage chromatography on silica gel loading the column using dichloromethane and eluting with 5% ethyl acetate/hexane (200 ml) increasing the percentage of ethyl acetate to 20%, 50% and 100% to afford a white foam. The foam was dissolved in warm ethyl acetate and treated with 1M hydrochloric acid in diethyl ether. The mixture was evaporated, the residue triturated with diethyl ether to afford a white solid which was filtered off, washed with diethyl ether and dried to afford the title compound (59 mg).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]([NH:10][C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]=[C:13]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:12]=2)[NH:8][N:9]=1)=[O:4].[OH-].[Na+].Cl>>[C:3]([C:5]1[CH:6]=[C:7]([NH:10][C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]=[C:13]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:12]=2)[NH:8][N:9]=1)([OH:4])=[O:2]
Reactant: COC(=O)c1cc(Nc2nc(-c3ccccc3)nc3ccccc23)[nH]n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)c1cc(Nc2nc(-c3ccccc3)nc3ccccc23)[nH]n1
Temperature: 50 °C
Reaction time: 5 h
Yield: 94.2 %

Procedure:
(5-Methoxycarbonyl-2H-pyrazol-3-yl)-(2-phenyl-quinazolin-4-yl)-amine (III-73) (345 mg, 1 mmole in THF, 6 mL) was treated with NaOH (1M, 4.0 mL), stirred at 50° C. for 5 hours, cooled to room temperature, and neutralised with 1M HCl. The mixture was concentrated in vacuo to remove THF then diluted with water and the resulting precipitate filtered. The residual solid was dried at 80° C. under vacuum to afford III-72 as an off-white solid (312 mg, 94%): mp 289–291° C. (dec.); 1H NMR (DMSO) δ 7.45 (1H, br s), 7.50–7.60 (5H, m), 7.80–7.88 (2H, m), 7.40–7.50 (2H, m), 8.60–8.70 (1H, d), 10.70 (1H, s), 13.00–13.80 (2H, br s); IR (solid) 1699, 1624, 1607, 1570, 1539, 1506, 1486, 1398, 1333, 1256, 1177, 1004, 827, 764, 705; MS 332.3(M+H)+.
Reaction SMILES: [CH2:1](N1CCCC(CCN2C(OC)=NC3C2=NC(O[C@@H](C)CCC)=NC=3N)C1)[CH3:2].[CH3:29][C@H:30]([O:34][C:35]1[N:43]=[C:42]2[C:38]([N:39]=[C:40]([O:52][CH3:53])[N:41]2[CH2:44][CH2:45][CH:46]2[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]2)=[C:37]([NH2:54])[N:36]=1)[CH2:31][CH2:32][CH3:33].ICC>>[CH2:1]([N:49]1[CH2:48][CH2:47][CH:46]([CH2:45][CH2:44][N:41]2[C:40]([O:52][CH3:53])=[N:39][C:38]3[C:42]2=[N:43][C:35]([O:34][C@@H:30]([CH3:29])[CH2:31][CH2:32][CH3:33])=[N:36][C:37]=3[NH2:54])[CH2:51][CH2:50]1)[CH3:2]
Reactant: CCC[C@H](C)Oc1nc(N)c2nc(OC)n(CCC3CCNCC3)c2n1
Reactant: CCC[C@H](C)Oc1nc(N)c2nc(OC)n(CCC3CCCN(CC)C3)c2n1
Solvent: CCI
Product: CCC[C@H](C)Oc1nc(N)c2nc(OC)n(CCC3CCN(CC)CC3)c2n1

Procedure:
Prepared similarly to Intermediate 46 from 2-{[(1S)-1-methylbutyl]oxy}-8-(methyloxy)-9-[2-(4-piperidinyl)ethyl]-9H-purin-6-amine and 2-iodoethane.
Reaction SMILES: [CH2:1]1[O:11][C:10]2[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][C:3]=2[O:2]1.[Cl:12][C:13]1[N:14]=[C:15](Cl)[C:16]2[CH:21]=[C:20]([Cl:22])[S:19][C:17]=2[N:18]=1>>[Cl:12][C:13]1[N:14]=[C:15]([NH:7][CH2:6][C:5]2[CH:8]=[CH:9][C:10]3[O:11][CH2:1][O:2][C:3]=3[CH:4]=2)[C:16]2[CH:21]=[C:20]([Cl:22])[S:19][C:17]=2[N:18]=1
Reactant: Clc1nc(Cl)c2cc(Cl)sc2n1
Reactant: NCc1ccc2c(c1)OCO2
Product: Clc1nc(NCc2ccc3c(c2)OCO3)c2cc(Cl)sc2n1

Procedure:
Following the procedure of Example 1, the reaction of 3,4-methylenedioxybenzylamine with 2,4,6-trichloro-thieno-[2,3-d]-pyrimidine gives 2,6-dichloro-4-(3,4-methylenedioxybenzylamino)-thieno-[2,3-d]-pyrimidine
Reaction SMILES: C[O:2][C:3](=[O:31])[CH2:4][CH2:5][NH:6][C:7](=[O:30])[C:8]1[CH:13]=[CH:12][C:11]([CH:14]([O:22][C:23]2[CH:28]=[CH:27][C:26](Br)=[CH:25][CH:24]=2)[CH2:15][CH2:16][CH2:17][C:18]([F:21])([F:20])[F:19])=[CH:10][CH:9]=1.[CH2:32]([C:34]1[CH:39]=[CH:38][C:37](B(O)O)=[CH:36][CH:35]=1)[CH3:33]>>[CH2:32]([C:34]1[CH:39]=[CH:38][C:37]([C:26]2[CH:25]=[CH:24][C:23]([O:22][CH:14]([C:11]3[CH:12]=[CH:13][C:8]([C:7]([NH:6][CH2:5][CH2:4][C:3]([OH:2])=[O:31])=[O:30])=[CH:9][CH:10]=3)[CH2:15][CH2:16][CH2:17][C:18]([F:21])([F:19])[F:20])=[CH:28][CH:27]=2)=[CH:36][CH:35]=1)[CH3:33]
Reactant: CCc1ccc(B(O)O)cc1
Reactant: COC(=O)CCNC(=O)c1ccc(C(CCCC(F)(F)F)Oc2ccc(Br)cc2)cc1
Product: CCc1ccc(-c2ccc(OC(CCCC(F)(F)F)c3ccc(C(=O)NCCC(=O)O)cc3)cc2)cc1

Procedure:
The title compound is prepared in a manner substantially similar to Example 128 starting from 3-{4-[1-(4-bromo-phenoxy)-5,5,5-trifluoro-pentyl]-benzoylamino}-propionic acid methyl ester and 4-ethyl phenyl boronic acid. MS: 572.3 [M−H]−.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([CH2:18][N:19]([C:32]([O:34][CH3:35])=[O:33])[C:20]3[CH:21]=[C:22]([CH:29]=[CH:30][CH:31]=3)[O:23][CH2:24][C:25]([O:27]C)=[O:26])[O:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O[Li].O.CO>O>[C:1]1([C:7]2[N:8]=[C:9]([CH2:18][N:19]([C:32]([O:34][CH3:35])=[O:33])[C:20]3[CH:21]=[C:22]([CH:29]=[CH:30][CH:31]=3)[O:23][CH2:24][C:25]([OH:27])=[O:26])[O:10][C:11]=2[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)COc1cccc(N(Cc2nc(-c3ccccc3)c(-c3ccccc3)o2)C(=O)OC)c1
Agent: [Li]O
Solvent: CO
Solvent: O
Product: COC(=O)N(Cc1nc(-c2ccccc2)c(-c2ccccc2)o1)c1cccc(OCC(=O)O)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 54.5 %

Procedure:
A mixture of methyl [3-[[(4,5-diphenyl-2-oxazolyl)methyl](methoxycarbonyl) amino]phenoxy]acetate (4.16 g, 9 mmol), LiOH.H2O (0.56 g, 13 mmol), MeOH (45 mL) and H2O (15 mL) was stirred at room temperature for about 3 hours. The solvent was removed in vacuo, the residue diluted with H2O and 2N HCl until pH=2 and a yellow solid filtered off. Recrystallization from a mixture of CH2Cl2 and hexanes gave [3-[[(4,5-diphenyl-2-oxazolyl)methyl](methoxycarbonyl)amino]phenoxy]acetic acid (2.25 g, 55%), mp 153-155° C. IR (KBr) 2700-2500 (CO2H), 1750 (NCO2CH3), 1710 (CO2H) cm-1 ; 1H NMR (CDCl3) δ3.68 (3H, s, NCO2CH3), 4.51 (2H, s, OCH2CO2H), 4.60 (1H, bs, CO2H), 4.95 (2H, s, CH2 -oxazole), 6.77 (1H, dd, J=9 Hz, J'=2 Hz, aromatic H), 6.94 (2H, m, aromatic H), 7.15 to 7.40 (7H, m, aromatic H), 7.45 to 7.65 (4H, m, aromatic H); MS m/z 459 (MH+).
Reaction SMILES: O.[NH2:2]N.[Cl:4][C:5]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:12][N:13]1[C:17]2[CH:18]=[C:19]([N:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)[CH:20]=[C:21]([C:22](/[N:24]=[CH:25]/[N:26](C)C)=O)[C:16]=2[N:15]=[C:14]1[CH3:35].C([O-])(O)=O.[Na+]>C(O)(=O)C>[Cl:4][C:5]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:12][N:13]1[C:17]2[CH:18]=[C:19]([N:29]3[CH2:30][CH2:31][O:32][CH2:33][CH2:34]3)[CH:20]=[C:21]([C:22]3[N:24]=[CH:25][NH:26][N:2]=3)[C:16]=2[N:15]=[C:14]1[CH3:35]
Reactant: Cc1nc2c(C(=O)/N=C/N(C)C)cc(N3CCOCC3)cc2n1Cc1cccc(Cl)c1Cl
Reactant: NN
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: Cc1nc2c(-c3nc[nH]n3)cc(N3CCOCC3)cc2n1Cc1cccc(Cl)c1Cl
Temperature: 130 °C
Reaction time: 0.33 h
Yield: 53 %

Procedure:
Hydrazine monohydrate (2 mL) was added to a solution of 1-[(2,3-dichlorophenyl)methyl]-N-[(1E)-(dimethylamino)methylidene]-2-methyl-6-(4-morpholinyl)-1H-benzimidazole-4-carboxamide (220 mg, 0.46 mmol) in acetic acid (5 mL) and stirred at 130° C. for 20 min. The reaction mixture was cooled to rt and poured into saturated NaHCO3 solution (15 mL). The mixture was extracted with DCM (30 mL×3). The combined organic layers were dried over MgSO4, filtered and concentrated. The resulting residue was purified by silica gel chromatography eluted with DCM:MeOH=30:1 to give the desired product (110 mg, 53%), as a white solid. 1H NMR (300 MHz, DMSO-d6) δ ppm 2.50 (s, 3H), 3.12 (t, 4H, J=4.8 Hz), 3.75 (t, 4H, J=4.8 Hz), 5.62 (s, 2H), 6.36 (d, 1H, J=8.1 Hz), 7.21 (s, 1H), 7.27 (t, 1H, J=8.1 Hz), 7.54 (s, 1H), 7.61 (d, 1H, J=8.1 Hz), 8.08 (s, 1H), 13.80 (s, 1H); LC-MS: m/e=443 [M+1]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][NH:11][C:12]1[N:17]=[C:16]([O:18][CH3:19])[N:15]=[C:14]([C:20]2[CH:21]=[C:22]([CH:26]=[CH:27][CH:28]=2)[C:23](O)=[O:24])[CH:13]=1.C(N(C(C)C)CC)(C)C.Cl.[CH2:39]([O:41][C:42](=[O:45])[CH2:43][NH2:44])[CH3:40].O>CN(C)C=O>[CH2:39]([O:41][C:42](=[O:45])[CH2:43][NH:44][C:23](=[O:24])[C:22]1[CH:26]=[CH:27][CH:28]=[C:20]([C:14]2[CH:13]=[C:12]([NH:11][CH2:10][CH2:9][C:3]3[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=3[Cl:1])[N:17]=[C:16]([O:18][CH3:19])[N:15]=2)[CH:21]=1)[CH3:40]
Reactant: CCOC(=O)CN
Reactant: COc1nc(NCCc2ccc(Cl)cc2Cl)cc(-c2cccc(C(=O)O)c2)n1
Agent: Cl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)CNC(=O)c1cccc(-c2cc(NCCc3ccc(Cl)cc3Cl)nc(OC)n2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 79.5 %

Procedure:
A mixture of 3-{6-[2-(2,4-dichloro-phenyl)-ethylamino]-2-methoxy-pyrimidin-4-yl}-benzoic acid [127 mg, 0.3 mmol, Example 35(w)], O-(benzotriazol-1-yl)-N,N,N′N′-tetramethyluronium tetrafluoroborate (116 mg, 0.36 mmol), diisopropylethylamine (131 μL, 0.75 mmol) and glycine ethyl ester hydrochloride (63 mg, 0.45 mmol) in dimethylformamide (3 mL) is stirred at ambient temperature for 18 hours. The mixture is poured into water and extracted three times with EtOAc (20 mL). The organic extracts are combined and washed twice with water (20 mL), dried over magnesium sulfate, filtered and concentrated by rotary evaporator to provide a solid. The solid is absorbed onto silica and subjected to flash column chromatography on silica (40 g) eluting with 0% to 50% ethyl acetate/heptane gradient, to afford (3-{6-[2-(2,4-dichloro-phenyl)-ethylamino]-2-methoxy-pyrimidin-4-yl}-benzoylamino)-acetic acid ethyl ester [120 mg, 79%, Example 58]. MS: 503 (M+H).
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:28])[CH2:6][C:7]1[C:15]2[C:10](=[N:11][CH:12]=[CH:13][CH:14]=2)[N:9]([S:16]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([Cl:26])[CH:20]=2)(=[O:18])=[O:17])[C:8]=1[CH3:27]>C1COCC1.CO>[Cl:26][C:21]1[CH:20]=[C:19]([S:16]([N:9]2[C:10]3=[N:11][CH:12]=[CH:13][CH:14]=[C:15]3[C:7]([CH2:6][C:5]([OH:28])=[O:4])=[C:8]2[CH3:27])(=[O:17])=[O:18])[CH:24]=[CH:23][C:22]=1[Cl:25]
Reactant: COC(=O)Cc1c(C)n(S(=O)(=O)c2ccc(Cl)c(Cl)c2)c2ncccc12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1c(CC(=O)O)c2cccnc2n1S(=O)(=O)c1ccc(Cl)c(Cl)c1
Reaction time: 18 h

Procedure:
1M Aqueous NaOH (1.5 mL) is added to a solution of [1-(3,4-dichloro-benzenesulfonyl)-2-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl]-acetic acid methyl ester (218 mg, 0.53 mmol) in 1:1 THF/MeOH (6 mL). After 18 hours, the reaction is evaporated and the residue dissolved in water. The aqueous solution is acidified to pH 1, and the resulting precipitate is collected by filtration to afford [1-(3,4-dichloro-benzenesulfonyl)-2-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl]-acetic acid; MH+=399.
Reaction SMILES: O.[OH-].[Li+].C[O:5][C:6]([C:8]1[C:13]([NH2:14])=[N:12][C:11]([NH2:15])=[CH:10][N:9]=1)=[O:7].O1CCCC1.[OH-].[Na+]>O.CO>[NH2:14][C:13]1[C:8]([C:6]([OH:7])=[O:5])=[N:9][CH:10]=[C:11]([NH2:15])[N:12]=1
Reactant: COC(=O)c1ncc(N)nc1N
Agent: [Li+]
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: Nc1cnc(C(=O)O)c(N)n1
Temperature: 25 °C
Reaction time: 17 h
Yield: 36.4 %

Procedure:
Lithium hydroxide monohydrate (2.50 g, 59.5 mmol) was added to 3,5-diamino-pyrazine-2-carboxylic acid methyl ester (10.0 g, 59.5 mmol) described in Preparation Example AA-1 in a mixture solvent of tetrahydrofuran (100 mL), methanol (10 mL) and water (10 mL) at room temperature. The solution was stirred at room temperature for 17 hours, then, an aqueous solution of 5N sodium hydroxide (15 mL) was added thereto, followed by further stirring for 4.5 hours under reflux. The reaction solution was cooled to room temperature, and partitioned in 5N hydrochloric acid solution and ethyl acetate. The organic layer was separated, washed with brine, and then, dried over anhydrous magnesium sulfate. The organic layer was filtered, then, the solvent was evaporated in vacuo, and the title compound (3.34 g, 36%) was obtained as a crude product of a white solid.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:27]=[C:28]([CH3:30])[N:29]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)=[CH:10][CH:9]=1)=[O:6].[CH3:31][CH:32]1[CH2:36][CH2:35][CH2:34][NH:33]1>>[CH3:30][C:28]1[CH:27]=[C:4]([CH:3]=[C:2]([N:33]2[CH2:34][CH2:35][CH2:36][CH:32]2[CH3:31])[N:29]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)=[CH:10][CH:9]=1)=[O:6]
Reactant: CC1CCCN1
Reactant: Cc1cc(C(=O)Nc2ccc(OCCN3CCOCC3)c3ccccc23)cc(Cl)n1
Product: Cc1cc(C(=O)Nc2ccc(OCCN3CCOCC3)c3ccccc23)cc(N2CCCC2C)n1

Procedure:
Compound is formed by reacting 2-chloro-6-methyl-N-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-1-yl]-isonicotinamide with 2-methylpyrrolidine under conditions described in general procedure A. 1H NMR (300 MHz, DMSO-d6) δ 10.34 (s, 1H), 8.26 (d, 1H), 8.22 (m, 1H), 7.84 (m, 1H), 7.57 (m, 2H), 7.45 (d, 1H), 7.39 (s, 1H), 7.13 (d, 1H), 7.05 (d, 1H), 4.41 (d, 2H), 4.31 (t, 2H), 3.60 (m, 4H), 2.88 (m, 4H), 2.58 (m, 4H), 1.7 (m, 4H), 1.11 (m 1H), 0.95 (d, 3H). MS: 475.2 (M+1).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH2:17][CH2:16][CH2:15][C:4]=2[N:5]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=2)[N:7]=1.[CH3:18][N:19]([CH3:29])[CH2:20][CH2:21][C:22]1[CH:28]=[CH:27][C:25]([NH2:26])=[CH:24][CH:23]=1>>[ClH:1].[Cl:14][C:10]1[CH:9]=[C:8]([C:6]2[N:7]=[C:2]([NH:26][C:25]3[CH:24]=[CH:23][C:22]([CH2:21][CH2:20][N:19]([CH3:18])[CH3:29])=[CH:28][CH:27]=3)[C:3]3[CH2:17][CH2:16][CH2:15][C:4]=3[N:5]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: Clc1cccc(-c2nc(Cl)c3c(n2)CCC3)c1
Reactant: CN(C)CCc1ccc(N)cc1
Product: CN(C)CCc1ccc(Nc2nc(-c3cccc(Cl)c3)nc3c2CCC3)cc1
Product: Cl
Yield: 75.2 %

Procedure:
Following general procedure B1, 4-chloro-2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine (0.093 g, 0.35 mmol) was reacted with 4-(2-(dimethylamino)ethyl)aniline (0.069 g, 0.42 mmol), followed by formation of the hydrochloride salt to afford the title compound (0.113 g, 75%) as a light yellow solid. MW=429.39. 1H NMR (DMSO-d6, 500 MHz) δ 8.80 (s, 1H), 8.30-8.22 (m, 2H), 7.72 (d, J=8.5 Hz, 2H), 7.55-7.49 (m, 2H), 7.24 (d, J=8.5 Hz, 2H), 2.93-2.85 (m, 4H), 2.80-2.66 (m, 4H), 2.37 (s, 6H), 2.10 (quin, J=8.5 Hz, 2H); APCI MS m/z 393 [M+H]+.
Reaction SMILES: [CH3:1][N:2]([C:4]1[CH:9]=[CH:8][C:7]([C:10]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[C:11]2[CH:19]=[CH:18][C:14](=[N+:15]([CH3:17])[CH3:16])[CH:13]=[CH:12]2)=[CH:6][CH:5]=1)[CH3:3].[Cl-].[C-:27]#[N:28].[Na+].O.C(OCC)C>C(OCC)(=O)C>[CH3:1][N:2]([CH3:3])[C:4]1[CH:5]=[CH:6][C:7]([C:10]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([C:11]2[CH:12]=[CH:13][C:14]([N:15]([CH3:17])[CH3:16])=[CH:18][CH:19]=2)[C:27]#[N:28])=[CH:8][CH:9]=1
Reactant: CN(C)c1ccc(C(=C2C=CC(=[N+](C)C)C=C2)c2ccccc2)cc1
Reactant: [C-]#N
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CCOC(C)=O
Solvent: O
Product: CN(C)c1ccc(C(C#N)(c2ccccc2)c2ccc(N(C)C)cc2)cc1
Reaction time: 3 h

Procedure:
Commercially obtained Malachite Green, oxalate salt (4.644 g) and sodium cyanide (2.456 g) were combined, followed by addition of water (150 mL) and diethyl ether (150 mL). The mixture was rapidly stirred for three hours, at which point the green color had faded, and the mixture was a muddy brown. The mixture was transferred to a separatory funnel with the aid of ethyl acetate, partitioned, and the aqueous phase extracted with three portions of ethyl acetate (100 mL each). The combined organics were washed once with brine (50 mL), dried over sodium sulfate, filtered and concentrated by rotary evaporation to provide crude nitrile 3A contaminated by some of the triarylcarbinol.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:9]=[CH:8][S:7][C:6]=2[CH:10]=1.[Li]CCCC.CN([CH:19]=[O:20])C.[NH4+].[Cl-]>C1COCC1.CCOCC>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:9]=[C:8]([CH:19]=[O:20])[S:7][C:6]=2[CH:10]=1
Reactant: Clc1ccc2ccsc2c1
Reactant: CN(C)C=O
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: O=Cc1cc2ccc(Cl)cc2s1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 6-chlorobenzo[b]thiophene (1.0 g, 5.93 mmol) in THF (60 mL) at −78° C. is added a 1.6 M solution of n-BuLi in THF (3.9 mL, 6.23 mmol). After 10 minutes, 0.5 mL of DMF is added. The solution is stirred for 0.5 hours, then allowed to warm to ambient temperature. The solution is poured into a solution of saturated NH4Cl. The solution is diluted with ether and the layers are separated. The organic layer is washed with H2O and saturated NaCl. The organic layer is dried over MgSO4, filtered and concentrated. The title compound is obtained as a white solid. MS (EI): m/z 196 (M+).
Reaction SMILES: [Cl:1][C:2]([Cl:14])=[C:3]([C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=1)[C:4](Cl)=[O:5].[CH2:15]([NH2:27])[CH2:16][C:17]1[CH:26]=[CH:25][C:22]([O:23][CH3:24])=[C:19]([O:20][CH3:21])[CH:18]=1.C(N(CC)CC)C>C(Cl)Cl>[Cl:1][C:2]([Cl:14])=[C:3]([C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=1)[C:4]([NH:27][CH2:15][CH2:16][C:17]1[CH:26]=[CH:25][C:22]([O:23][CH3:24])=[C:19]([O:20][CH3:21])[CH:18]=1)=[O:5]
Reactant: COc1ccc(CCN)cc1OC
Reactant: O=C(Cl)C(=C(Cl)Cl)c1ccc(Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(CCNC(=O)C(=C(Cl)Cl)c2ccc(Cl)cc2)cc1OC
Temperature: 22.5 °C
Reaction time: 3 h
Yield: 83.5 %

Procedure:
A solution of 10.8 g (0.04 mol) of the acyl chloride prepared in Example 5 in 20 ml of methylene chloride was added dropwise to a solution of 7.24 g (0.04 mol) of homoveratrylamine and 4.04 g 25 (0.04 mol) of triethylamine in 80 ml of methylene chloride. The solution was stirred for 3 hours at 20 to 25° C., and washed with 3 N sodium hydroxide solution and then with 10% by weight strength hydrochloric acid. The organic phase was freed from solvent, and 13.85 g of the title compound were obtained from the residue following chromatography on silica gel with cyclohehane [sic]/MtBE (3:1).