Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:36]([O:40][C:41](=[O:47])[NH:42][CH:43]([CH3:46])[CH2:44]O)([CH3:39])([CH3:38])[CH3:37].[CH2:48]([O:50][C:51]([C:53]1[NH:54][N:55]=[C:56]([CH2:58][O:59][C:60]2[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=2)[CH:57]=1)=[O:52])[CH3:49]>C1COCC1>[CH2:48]([O:50][C:51]([C:53]1[N:54]([CH2:44][CH:43]([NH:42][C:41]([O:40][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:47])[CH3:46])[N:55]=[C:56]([CH2:58][O:59][C:60]2[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=2)[CH:57]=1)=[O:52])[CH3:49]
Reactant: CC(CO)NC(=O)OC(C)(C)C
Reactant: CCOC(=O)c1cc(COc2ccccc2)n[nH]1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)c1cc(COc2ccccc2)nn1CC(C)NC(=O)OC(C)(C)C
Temperature: 120 °C
Reaction time: 0.33 h
Yield: 227.1 %

Procedure:
Di-tert-butyl azodicarboxylate (2.52 g, 10.96 mmol) was added to a stirred solution of triphenylphosphine (2.87 g, 10.96 mmol), rac-2-hydroxy-1-methyl-ethyl-carbamic acid tert-butyl ester (2.13 g, 12.18 mmol) and 5-phenoxymethyl-2H-pyrazole-3-carboxylic acid ethyl ester (1.5 g, 6.09 mmol) in THF (45 mL). The mixture was stirred at 120° C. for 20 minutes under microwave irradiation and the solvents evaporated in vacuo. The crude product was purified by open column chromatography (silica; AcOEt in DCM 0/100 to 10/90). The desired fractions were collected and the solvents evaporated in vacuo to yield 2-(2-tert-butoxycarbonylamino-propyl)-5-phenoxymethyl-2H-pyrazole-3-carboxylic acid ethyl ester (5.58 g, 91% yield, 40% pure) as a colorless oil that crystallized upon standing in white crystals.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([S:10]([NH2:13])(=[O:12])=[O:11])[CH:7]=[N:8][CH:9]=1)([O-:3])=[O:2].[C:14](OC(=O)C)(=[O:16])[CH3:15]>S(=O)(=O)(O)O>[C:14]([NH:13][S:10]([C:6]1[CH:7]=[N:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1)(=[O:11])=[O:12])(=[O:16])[CH3:15]
Reactant: NS(=O)(=O)c1cncc([N+](=O)[O-])c1
Reactant: CC(=O)OC(C)=O
Agent: O=S(=O)(O)O
Product: CC(=O)NS(=O)(=O)c1cncc([N+](=O)[O-])c1

Procedure:
A mixture of 0.5g. of 5-nitro- 3-pyridinesulfonamide, 2 ml. of acetic anhydride and 2 drops of conc. sulfuric acid was stirred at 90° C. for 1 hour. The solvent was then distilled off from the reaction mixture and the crystalline residue was recrystallized from ethanol to give 0.36g. of the desired product. m.p. 176° - 178° C.
Reaction SMILES: CO[C:3](=[O:14])[C:4]1[C:9]([Cl:10])=[CH:8][C:7]([Cl:11])=[CH:6][C:5]=1[CH2:12]Br.[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([C@@H:22]([NH2:24])[CH3:23])=[CH:18][CH:17]=1.C([O-])([O-])=O.[K+].[K+].C(OCC)(=O)C>C1(C)C=CC=CC=1.CCCCCC>[Cl:11][C:7]1[CH:6]=[C:5]2[C:4](=[C:9]([Cl:10])[CH:8]=1)[C:3](=[O:14])[N:24]([C@H:22]([C:19]1[CH:20]=[CH:21][C:16]([Cl:15])=[CH:17][CH:18]=1)[CH3:23])[CH2:12]2
Reactant: COC(=O)c1c(Cl)cc(Cl)cc1CBr
Reactant: C[C@H](N)c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: C[C@@H](c1ccc(Cl)cc1)N1Cc2cc(Cl)cc(Cl)c2C1=O
Temperature: 100 °C
Reaction time: 2 h
Yield: 34.5 %

Procedure:
A mixture of 2-Bromomethyl-4,6-dichloro-benzoic acid methyl ester (0.119 g, 0.4 mmol), (S)-1-(4-chloro-phenyl)-ethyl amine (0.067 mL, 0.48 mmol), and K2CO3 (0.104 g, 0.8 mmol) in toluene (5 mL) was heated with stirring at 100° C. for 2 h. Workup and silica gel column chromatography of the product using 30% ethyl acetate in hexane afforded (S)-5,7-dichloro-2-[1-(4-chloro-phenyl)-ethyl]-2,3-dihydro-isoindol-1-one (0.047 g, 35%). 1H NMR (300 MHz, CDCl3): δ (ppm) 1.64 (d, 3H), 3.94 (d, 1H), 4.26 (d, 1H), 5.74 (q, 1H) 7.22-7.42 (m, 6H). GC-MS: m/z 340 (M)+.
Reaction SMILES: COC1C=CC(N2CCN(CCC3C=CC=CC=3)CC2)=CC=1.[F:23][C:24]1[CH:29]=[C:28]([O:30]C)[C:27]([F:32])=[CH:26][C:25]=1[N:33]1[CH2:38][CH2:37][N:36]([S:39]([C:42]2[CH:47]=[CH:46][C:45]([F:48])=[CH:44][CH:43]=2)(=[O:41])=[O:40])[CH2:35][CH2:34]1>>[F:23][C:24]1[CH:29]=[C:28]([OH:30])[C:27]([F:32])=[CH:26][C:25]=1[N:33]1[CH2:34][CH2:35][N:36]([S:39]([C:42]2[CH:43]=[CH:44][C:45]([F:48])=[CH:46][CH:47]=2)(=[O:41])=[O:40])[CH2:37][CH2:38]1
Reactant: COc1cc(F)c(N2CCN(S(=O)(=O)c3ccc(F)cc3)CC2)cc1F
Agent: COc1ccc(N2CCN(CCc3ccccc3)CC2)cc1
Product: O=S(=O)(c1ccc(F)cc1)N1CCN(c2cc(F)c(O)cc2F)CC1
Yield: 73 %

Procedure:
Production Example 2 was repeated except that 1-(4-methoxyphenyl)-4-phenethylpiperazine was replaced with 4-(2,5-difluoro-4-methoxyphenyl)-1-(4-fluorophenylsulfonyl)-piperazine (300 mg). The resulting crude product was purified on TLC (developer, hexane: ethyl acetate=2:1) to provide 4-(2,5-difluoro-4-hydroxyphenyl)-1-(4-fluorophenylsulfonyl)-piperazine (211 mg).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([S:8]([C:11]2[CH:20]=[C:19]3[C:14]([CH2:15][CH2:16][C@H:17]([CH2:21][NH2:22])[O:18]3)=[CH:13][CH:12]=2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.Cl[CH2:24][C:25]([NH:27][CH3:28])=[O:26].C(N(CC)CC)C.[Na+].[I-]>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([S:8]([C:11]2[CH:20]=[C:19]3[C:14]([CH2:15][CH2:16][C@H:17]([CH2:21][NH:22][CH2:24][C:25]([NH:27][CH3:28])=[O:26])[O:18]3)=[CH:13][CH:12]=2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1
Reactant: CNC(=O)CCl
Reactant: NC[C@H]1CCc2ccc(S(=O)(=O)c3cccc(F)c3)cc2O1
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CNC(=O)CNC[C@H]1CCc2ccc(S(=O)(=O)c3cccc(F)c3)cc2O1
Temperature: 80 °C
Yield: 51 %

Procedure:
To a solution of C—[(R)-7-(3-Fluoro-benzenesulfonyl)-chroman-2-yl]-methylamine (0.07 g, 0.22 mmol) and 2-chloro-N-methylacetamide (0.023 g, 0.22 mmol) in dry DMF (3 mL) in a sealable tube was added triethylamine (0.1 mL, 0.72 mmol) and NaI (0.01 g). The tube was sealed and heated for four hours at 80° C., then cooled and quenched by addition of water. The reaction mixture was extracted EtOAc, and the combined organic layers were washed with water and brine, dried (Na2SO4), filtered and contrated under reduced pressure. Purification of the residue by flash chromatography (EtOAc:MeOH 99:1 to 97:3) gave 0.044 g of 2-{[(R)-7-(3-fluoro-benzenesulfonyl)-chroman-2-ylmethyl]-amino}-N-methyl-acetamide as a foam. MS (M+H)=393.
Reaction SMILES: FC(F)(F)C([N:5]1[CH2:11][CH2:10][C:9]2[CH:12]=[CH:13][C:14]([NH:16][C:17]3[N:22]=[C:21]([NH:23][CH3:24])[C:20]([N+:25]([O-:27])=[O:26])=[CH:19][N:18]=3)=[CH:15][C:8]=2[CH2:7][CH2:6]1)=O.O1CCCC1.[OH-].[Na+]>O>[CH2:10]1[C:9]2[CH:12]=[CH:13][C:14]([NH:16][C:17]3[N:22]=[C:21]([NH:23][CH3:24])[C:20]([N+:25]([O-:27])=[O:26])=[CH:19][N:18]=3)=[CH:15][C:8]=2[CH2:7][CH2:6][NH:5][CH2:11]1
Reactant: CNc1nc(Nc2ccc3c(c2)CCN(C(=O)C(F)(F)F)CC3)ncc1[N+](=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CNc1nc(Nc2ccc3c(c2)CCNCC3)ncc1[N+](=O)[O-]

Procedure:
650 mg of 2-(3-trifluoroacetyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl-amino)-4-methylamino-5-nitro-pyrimidine, 20 ml tetrahydrofuran, 10 ml water and 3.2 ml of 1N sodium hydroxide solution are stirred for 2 hours at ambient temperature and then the reaction mixture is combined with 100 ml of water. The solid precipitated is suction filtered and dried.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][C:15]=1[CH2:16][CH2:17][N+:18]([O-:20])=O)[O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1.C[O-].[Li+].[C:24]([C:26]1[C:27]([NH2:33])=[N:28][C:29]([NH2:32])=[CH:30][CH:31]=1)#[CH:25].C(N(CC)CC)C>[Ti](Cl)(Cl)(Cl)Cl.O.O1CCCC1.C(OCC)(=O)C.CO>[F:1][C:2]1[CH:3]=[C:4]([O:5][CH2:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=2)[CH:13]=[CH:14][C:15]=1[CH2:16][C:17]1[CH:25]=[C:24]([C:26]2[C:27]([NH2:33])=[N:28][C:29]([NH2:32])=[CH:30][CH:31]=2)[O:20][N:18]=1
Reactant: O=[N+]([O-])CCc1ccc(OCc2ccccn2)cc1F
Reactant: C#Cc1ccc(N)nc1N
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: C[O-]
Agent: [Li+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CO
Product: Nc1ccc(-c2cc(Cc3ccc(OCc4ccccn4)cc3F)no2)c(N)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 2.7 %

Procedure:
To a methanol (20.0 mL) solution of 2-(3-fluoro-4-(2-nitro-ethyl)-phenoxymethyl)-pyridine (400 mg, 1.45 mmol) described in Manufacturing Example 95-1-3 was added lithium methoxide (110 mg, 2.90 mmol), which was stirred for 30 minutes at room temperature. The reaction mixture was concentrated under a reduced pressure, and anhydrous dichloromethane (20.0 mL) and anhydrous tetrahydrofuran (10.0 mL) were added to the residue. Titanium (IV) chloride (510 μL, 4.64 mmol) was added dropwise to the reaction mixture on a dry ice-ethanol bath (−78° C.), which was stirred for 60 minutes at room temperature. Water, ethyl acetate, and tetrahydrofuran were added to the reaction mixture on an ice bath (0° C.), and the organic layer was extracted with ethyl acetate. This organic layer was washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and then filtered. The filtrate was concentrated under a reduced pressure to obtain a crude product (360 mg). To a tetrahydrofuran (5.00 mL) solution of 3-ethynyl-pyridin-2,6-diamine (40.0 mg, 0.300 mmol) described in Manufacturing Example 13-1-3 and this crude product (180 mg) was added triethylamine (125 μL, 0.900 mmol) at room temperature, which was stirred for 2 hours at room temperature. Water was added to the reaction solution at room temperature, which was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, and the solvent was evaporated under a reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate:heptane=2:1→3:1), and then further purified by reverse-phase high performance liquid chromatography (using an acetonitrile-water mobile phase containing 0.1% trifluoroacetic acid) to obtain the title compound (3.20 mg, 1.72%) as a ditrifluoroacetic acid salt.
Reaction SMILES: [CH2:1]([C:8]1[C:17]([CH3:18])=[C:16](Cl)[C:15]2[C:10](=[CH:11][C:12]([F:21])=[CH:13][C:14]=2[F:20])[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:22][C:23]1([CH3:38])[C:27]2=[N:28][CH:29]=[C:30]([N:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)[CH:31]=[C:26]2[NH:25][CH2:24]1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.CC(C)([O-])C.[Na+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(C)C=CC=CC=1>[CH2:1]([C:8]1[C:17]([CH3:18])=[C:16]([N:25]2[C:26]3[C:27](=[N:28][CH:29]=[C:30]([N:32]4[CH2:33][CH2:34][O:35][CH2:36][CH2:37]4)[CH:31]=3)[C:23]([CH3:38])([CH3:22])[CH2:24]2)[C:15]2[C:10](=[CH:11][C:12]([F:21])=[CH:13][C:14]=2[F:20])[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1(C)CNc2cc(N3CCOCC3)cnc21
Reactant: Cc1c(Cc2ccccc2)nc2cc(F)cc(F)c2c1Cl
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: Cc1ccccc1
Product: Cc1c(Cc2ccccc2)nc2cc(F)cc(F)c2c1N1CC(C)(C)c2ncc(N3CCOCC3)cc21
Temperature: 95 °C

Procedure:
A screw cap vial was charged with 2-benzyl-4-chloro-5,7-difluoro-3-methylquinoline (37 mg, 0.122 mmol), 4-(3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)morpholine (36.9 mg, 0.158 mmol), Pd2dba3 (16.7 mg, 0.018 mmol), 2-(dicyclohexylphosphino)-2′,4′,6′-tri-i-propyl-1,1′-biphenyl (17.4 mg, 0.037 mmol), sodium tert-butoxide (35.1 mg, 0.365 mmol), and toluene (1.22 mL). The mixture was heated to 95° C. under N2 for 18 h. The reaction was concentrated and diluted with EtOAc, then washed with saturated aqueous sodium bicarbonate solution, water, brine, and 1M NaOH. The organic layer was dried (MgSO4) and concentrated. The crude product was purified by preparative HPLC (10-70% acetonitrile in water) to give 2-benzyl-4-(3,3-dimethyl-6-(4-morpholinyl)-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-5,7-difluoro-3-methylquinoline as a yellow solid. 1H NMR (400 MHz, chloroform-d) δ ppm 7.60-7.68 (1H, m), 7.50 (1H, d, J=2.3 Hz), 7.27-7.31 (2H, m), 7.22-7.25 (3H, m), 6.96 (1H, ddd, J=11.9, 9.0, 2.5 Hz), 5.52 (1H, d, J=2.3 Hz), 4.42 (2H, s), 3.79-3.85 (1H, m), 3.68-3.77 (4H, m), 3.56 (1H, d, J=9.0 Hz), 2.89-2.96 (4H, m), 2.19 (3H, s), 1.51 (3H, s), 1.45 (3H, s). Mass Spectrum (ESI) m/e=512.0 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:28])[CH2:5][CH2:6][NH:7][C:8](=[O:27])[CH2:9][N:10]1[C:16](=[O:17])[C:15]2[CH:18]=[C:19]([N+:22]([O-])=O)[CH:20]=[CH:21][C:14]=2[N:13]([CH3:25])[C:12](=[O:26])[CH2:11]1)[CH3:2].[CH2:29]([N:36]=[C:37]=[O:38])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>CCO.[Pd]>[CH2:1]([O:3][C:4](=[O:28])[CH2:5][CH2:6][NH:7][C:8](=[O:27])[CH2:9][N:10]1[C:16](=[O:17])[C:15]2[CH:18]=[C:19]([NH:22][C:37]([NH:36][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[O:38])[CH:20]=[CH:21][C:14]=2[N:13]([CH3:25])[C:12](=[O:26])[CH2:11]1)[CH3:2]
Reactant: O=C=NCc1ccccc1
Reactant: CCOC(=O)CCNC(=O)CN1CC(=O)N(C)c2ccc([N+](=O)[O-])cc2C1=O
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CCNC(=O)CN1CC(=O)N(C)c2ccc(NC(=O)NCc3ccccc3)cc2C1=O

Procedure:
Catalytic hydrogenation of 3-[2-(1-methyl-7-nitro-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl)-acetylamino]-propionic acid ethyl ester in EtOH in the presence of 10% Pd/C at RT and atmospheric pressure followed by acylation with benzylisocyanate as described in Example 1d) gave 3-[2-[7-(3-benzyl-ureido)-1-methyl-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl]-acetylamino]-propionic acid ethyl ester: mp. 100-102° C.; MS (ISP): 496 (M+1)+.
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[C:7](=[O:8])[CH2:6][C:5](=[O:9])[C:4]([CH3:11])([CH3:10])[C:3]1=[O:12].C(Cl)(Cl)Cl.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.[Br:30][C:31]1[CH:36]=[CH:35][C:34]([Pb+3])=[C:33]([CH2:38][CH3:39])[CH:32]=1.Cl>CN(C)C1C=CN=CC=1.C1(C)C=CC=CC=1>[Br:30][C:31]1[CH:36]=[CH:35][C:34]([CH:6]2[C:5](=[O:9])[C:4]([CH3:11])([CH3:10])[C:3](=[O:12])[C:2]([CH3:13])([CH3:1])[C:7]2=[O:8])=[C:33]([CH2:38][CH3:39])[CH:32]=1
Reactant: CC1(C)C(=O)CC(=O)C(C)(C)C1=O
Reactant: CCc1cc(Br)ccc1[Pb+3]
Agent: CC(=O)[O-]
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: ClC(Cl)Cl
Product: CCc1cc(Br)ccc1C1C(=O)C(C)(C)C(=O)C(C)(C)C1=O
Temperature: 80 °C
Yield: 35.5 %

Procedure:
2,2,6,6-Tetramethylcyclohexane-1,3,5-trione (5 g, 0.027 mol) and 4-dimethylamino-pyridine (16.47 g, 0.135 mol) are added to a mixture of chloroform (100 ml) and toluene (25 ml). The reaction mixture is flushed with nitrogen for 15 minutes at ambient temperature. 4-Bromo-2-ethylphenyllead triacetate (17.16 g, 0.03 mol) is added in one portion and the reaction mixture is stirred and heated to 80° C. (pre-heated oil bath) under an atmosphere of nitrogen for 1 hour. The reaction mixture is cooled to room temperature, acidified to pH 1 with 2N aqueous hydrochloric acid, filtered through a plug of diatomaceous earth and the two phases are separated. The organic phase is collected, and the aqueous phase is extracted with dichloromethane (2×75 ml). the organic phases are combined, washed with water, and dried over anhydrous sodium sulfate. The mixture is filtered, and the filtrate is evaporated under reduced pressure. The residue is purified by column chromatography on silica gel to give 4-(4-bromo-2-ethylphenyl)-2,2,6,6-tetramethyl-cyclohexane-1,3,5-trione as a white solid (3.5 g).
Reaction SMILES: C([O:5][C:6](=[O:39])[C:7]([CH3:38])([O:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][C:17](=[O:37])[NH:18][CH2:19][C:20]2[C:21]([CH3:36])=[N:22][C:23]([C:26]3[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=3)=[CH:24][CH:25]=2)=[CH:12][CH:11]=1)[CH3:8])(C)(C)C.C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:38][C:7]([O:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][C:17](=[O:37])[NH:18][CH2:19][C:20]2[C:21]([CH3:36])=[N:22][C:23]([C:26]3[CH:27]=[CH:28][C:29]([C:32]([F:35])([F:33])[F:34])=[CH:30][CH:31]=3)=[CH:24][CH:25]=2)=[CH:12][CH:11]=1)([CH3:8])[C:6]([OH:39])=[O:5]
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)ccc1CNC(=O)Cc1ccc(OC(C)(C)C(=O)OC(C)(C)C)cc1
Solvent: ClCCl
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: Cc1nc(-c2ccc(C(F)(F)F)cc2)ccc1CNC(=O)Cc1ccc(OC(C)(C)C(=O)O)cc1
Temperature: 50 °C
Yield: 83.2 %

Procedure:
0.23 g (0.42 mmol) of 2-methyl-2-[4-({[2-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-ylmethyl]-carbamoyl}-methyl)-phenoxy]-propionic acid tert-butyl ester was dissolved in 10 ml of MeCl2. Then, 0.14 ml=0.139 g (1.28 mmol) of anisole was added followed by 0.32 ml=0.48 g (4.2 mmol) of trifluoroacetic acid. The reaction mixture was stirred at reflux (oil bath 50° C.) for 16 hours. It was then poured into crashed ice and extracted twice with MeCl2. The combined organic phases were washed with water, dried over anhydrous magnesium sulfate and evaporated. The crude product was purified by flash chromatography (SiO2, MeCl2/MeOH) to give 0.17 g of the title compound as colorless solid.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10].[CH3:11][C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[NH:14][C:13]=1[CH:21]=O.N1CCCCC1>C(O)C>[CH3:11][C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[NH:14][C:13]=1[CH:21]=[C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[NH:1][C:2]1=[O:10]
Reactant: O=C1Cc2ccccc2N1
Reactant: Cc1c(C=O)[nH]c2ccccc12
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1c(C=C2C(=O)Nc3ccccc32)[nH]c2ccccc12
Temperature: 95 °C

Procedure:
A mixture of 2-oxindole (133 mg), 3-methyl-indole-2-carbaldehyde (190 mg) (prepared according to Synthetic Communications, 1986, 16, 1799) and piperidine (10 mg) in ethanol was heated in a sealed tube at 95° C. for 4 hours. The mixture was cooled to room temperature. The solid was collected by vacuum filtration, washed with cold ethanol and dried in vacuum oven for overnight to give 3-(3-methyl-1H-indol-2-ylmethylene)-1,3-dihydro-indol-2-one.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:5]2[N:6]=[CH:7][NH:8][C:4]=2[CH:3]=1.[C:11]1([CH2:17][CH2:18][NH2:19])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2N(C)C)CCCCC1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].C1COCC1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:18]([NH:19][C:2]1[CH:10]=[CH:9][C:5]2[NH:6][CH:7]=[N:8][C:4]=2[CH:3]=1)[CH2:17][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Brc1ccc2nc[nH]c2c1
Reactant: NCCc1ccccc1
Agent: [Pd]
Agent: CN(C)c1ccccc1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Solvent: C1CCOC1
Product: c1ccc(CCNc2ccc3[nH]cnc3c2)cc1

Procedure:
The compound was synthesized starting from 5-bromobenzimidazole (200 mg; 1 mmol; 1 eq.), phenylethylamine (146 mg; 0.152 ml; 1.2 mmol; 1.2 eq.), 2-dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl (9 mg; 0.024 mmol; 0.024 eq.; 2.4 mol %), Pd2 dba3 (9 mg; 0.01 mmol; 0.01 eq.; 1 mol %) and lithiumbis(trimethylsilyl)amide 1 M in THF (2.2 ml; 2.2 mmol; 2.2 eq.) according to method 1; Yield: 0.051 g (21.5%); MS m/z: 238.3 [M+H]+; 1H-NMR (500 MHz, DMSO d6): δ 2.86 (t, 2H, 3J=7.6 Hz); 3.25 (t, 2H, 3J=7.6 Hz); 6.59 (dd, 1H, 4J=2.1 Hz, 3J=8.5 Hz); 6.62 (br s, 1H); 7.18-7.22 (m, 1H); 7.27-7.31 (m, 5H); 7.92 (s, 1H); HPLC (METHOD [A]): rt 11.20 min (84.4%)
Reaction SMILES: CNC1N=C(C(O)=O)[CH:6]=[C:5]([CH2:12]CC)[N:4]=1.[CH2:15]([C:19]1[N:24]=[C:23](S(C)(=O)=O)[N:22]=[C:21]([C:29]([OH:31])=[O:30])[CH:20]=1)[CH:16]([CH3:18])[CH3:17].C(N)(C)C>>[CH2:15]([C:19]1[N:24]=[C:23]([NH:4][CH:5]([CH3:12])[CH3:6])[N:22]=[C:21]([C:29]([OH:31])=[O:30])[CH:20]=1)[CH:16]([CH3:18])[CH3:17]
Reactant: CCCc1cc(C(=O)O)nc(NC)n1
Reactant: CC(C)Cc1cc(C(=O)O)nc(S(C)(=O)=O)n1
Solvent: CC(C)N
Product: CC(C)Cc1cc(C(=O)O)nc(NC(C)C)n1

Procedure:
The title compound is obtained as a beige solid (103 mg) in analogy to 2-methylamino-6-propyl-pyrimidine-4-carboxylic acid starting from 6-isobutyl-2-methanesulfonyl-pyrimidine-4-carboxylic acid and isopropylamine; LC-MS: tR=0.77 min, [M+H]+=238.04.
Reaction SMILES: [CH2:1]([C:8]1[CH:45]=[CH:44][C:11]([CH2:12][N:13]2[C:21]3[C:16](=[CH:17][C:18]([O:22][CH2:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[CH:19][CH:20]=3)[C:15]([C:30](=[O:43])[C:31]([NH:33][C:34]3[CH:35]=[C:36]([CH:40]=[CH:41][CH:42]=3)[C:37](O)=[O:38])=[O:32])=[CH:14]2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1COCC1.CCN=C=NCCCN(C)C.[CH3:62][C:63]1[CH:64]=[CH:65][C:66]([S:69]([NH2:72])(=[O:71])=[O:70])=[CH:67][CH:68]=1>CN(C1C=CN=CC=1)C.C(OCC)(=O)C>[CH2:1]([C:8]1[CH:9]=[CH:10][C:11]([CH2:12][N:13]2[C:21]3[C:16](=[CH:17][C:18]([O:22][CH2:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[CH:19][CH:20]=3)[C:15]([C:30](=[O:43])[C:31]([NH:33][C:34]3[CH:42]=[CH:41][CH:40]=[C:36]([C:37]([NH:72][S:69]([C:66]4[CH:65]=[CH:64][C:63]([CH3:62])=[CH:68][CH:67]=4)(=[O:71])=[O:70])=[O:38])[CH:35]=3)=[O:32])=[CH:14]2)=[CH:44][CH:45]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Nc1cccc(C(=O)O)c1)C(=O)c1cn(Cc2ccc(Cc3ccccc3)cc2)c2ccc(OCc3ccccc3)cc12
Reactant: Cc1ccc(S(N)(=O)=O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1ccc(S(=O)(=O)NC(=O)c2cccc(NC(=O)C(=O)c3cn(Cc4ccc(Cc5ccccc5)cc4)c4ccc(OCc5ccccc5)cc34)c2)cc1
Reaction time: 8 h
Yield: 35.8 %

Procedure:
To the acid obtained in Example 71 (0.1 g) in CH2C2 (10 mL) is added THF (5 mL) to help dissolve the compound. EDCI (0.045 g) and DMAP (0.02 g) was added and the mixture was stirred a room temperature of 1 h. p-Toluenesulfonamide (0.04 g) was added and the reaction was stirred overnight. The reaction mixture was take up in ethyl acetate and washed with water, dried (MgSO4), filtered and concentrated. Chromatography (7% MeOH/CH2Cl2) afforded the title compound (0.045 g, 40%) as a yellow solid. MS: m/z (M-1) 746
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.Cl[C:7]1[N:8]=[C:9]([NH:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH3:28])[CH:20]=2)[C:10]2[CH:15]=[C:14]([Cl:16])[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH3:28])[CH:20]=3)[C:10]3[CH:15]=[C:14]([Cl:16])[S:13][C:11]=3[N:12]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: COc1ccc(CNc2nc(Cl)nc3sc(Cl)cc23)cc1OC
Reactant: c1c[nH]cn1
Product: COc1ccc(CNc2nc(-n3ccnc3)nc3sc(Cl)cc23)cc1OC

Procedure:
Following the procedure of Example 97, the reaction of imidazole with 2,6-dichloro-4-(3,4-dimethoxybenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(imidazol-1-yl)-6-chloro-4-(3,4-dimethoxybenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [CH2:1]([O:3][C:4]1([C:7]2[CH:12]=[CH:11][C:10]([C:13]#[C:14][C:15]3[CH:25]=[CH:24][C:18]([C:19]([O:21]CC)=[O:20])=[CH:17][CH:16]=3)=[CH:9][C:8]=2[CH:26]([CH3:28])[CH3:27])[CH2:6][CH2:5]1)[CH3:2].[OH-].[Na+]>C(O)C.O1CCCC1>[CH2:1]([O:3][C:4]1([C:7]2[CH:12]=[CH:11][C:10]([C:13]#[C:14][C:15]3[CH:16]=[CH:17][C:18]([C:19]([OH:21])=[O:20])=[CH:24][CH:25]=3)=[CH:9][C:8]=2[CH:26]([CH3:27])[CH3:28])[CH2:6][CH2:5]1)[CH3:2]
Reactant: CCOC(=O)c1ccc(C#Cc2ccc(C3(OCC)CC3)c(C(C)C)c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CCOC1(c2ccc(C#Cc3ccc(C(=O)O)cc3)cc2C(C)C)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.4 %

Procedure:
Using General Procedure I; A solution of ethyl 4-[4-(1-ethoxycyclopropyl)-3-isopropyl-phenylethynyl]-benzoate (Compound 99, 28.0 mg, 0.07 mmol) in ethanol (2 mL) and tetrahydrofuran (2 mL) was treated with NaOH (80.0 mg, 2.0 mmols, 2.0 mL of a 1N aqueous solution) and stirred overnight at room temperature. Work-up afforded 24 mg (92%) the title compound as a pale-yellow solid.
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[N:8]2[CH:9]=[C:10]([CH3:13])[CH:11]=[CH:12][C:7]2=[N:6][C:5]=1[C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1.[F:21][C:22]1[CH:27]=[C:26]([F:28])[N:25]=[C:24]([NH2:29])[N:23]=1>>[F:21][C:22]1[CH:27]=[C:26]([F:28])[N:25]=[C:24]([NH:29][CH2:3][C:4]2[N:8]3[CH:9]=[C:10]([CH3:13])[CH:11]=[CH:12][C:7]3=[N:6][C:5]=2[C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[N:23]=1
Reactant: Cc1ccc2nc(-c3ccc(F)cc3)c(CCl)n2c1
Reactant: Nc1nc(F)cc(F)n1
Agent: Cl
Product: Cc1ccc2nc(-c3ccc(F)cc3)c(CNc3nc(F)cc(F)n3)n2c1
Yield: 39 %

Procedure:
The title compound was prepared according to Method A and the experimentals described for compound 139 from 3-(chloromethyl)-2-(4-fluorophenyl)-6-methylimidazo[1,2-a]pyridine hydrochloride and 4,6-difluoropyrimidin-2-amine. (0.23 g, 39% yield), M/e+ 370.1 for C19H14F3N5 (M+H)+.