Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][N:3]1[C:8]1[C:9](OS(C(F)(F)F)(=O)=O)=[N:10][C:11]2[C:16]([N:17]=1)=[CH:15][C:14]([C:18]([O:20][CH3:21])=[O:19])=[CH:13][CH:12]=2.[F:30][C:31]1[CH:32]=[CH:33][C:34]2[O:38][C:37](B(O)O)=[CH:36][C:35]=2[CH:42]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.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>[F:30][C:31]1[CH:32]=[CH:33][C:34]2[O:38][C:37]([C:9]3[C:8]([N:3]4[CH2:4][CH2:5][CH2:6][CH2:7][C@@H:2]4[CH3:1])=[N:17][C:16]4[C:11](=[CH:12][CH:13]=[C:14]([C:18]([O:20][CH3:21])=[O:19])[CH:15]=4)[N:10]=3)=[CH:36][C:35]=2[CH:42]=1
Reactant: COC(=O)c1ccc2nc(OS(=O)(=O)C(F)(F)F)c(N3CCCC[C@@H]3C)nc2c1
Reactant: OB(O)c1cc2cc(F)ccc2o1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)c1ccc2nc(-c3cc4cc(F)ccc4o3)c(N3CCCC[C@@H]3C)nc2c1
Temperature: 90 °C
Reaction time: 1 h

Procedure:
To a solution of (S)-methyl 3-(2-methylpiperidin-1-yl)-2-(trifluoromethylsulfonyloxy)quinoxaline-6-carboxylate (240 mg, crude) in dioxane (5 mL) was added 5-fluorobenzofuran-2-ylboronic acid (337 mg, 1.87 mmol), K3PO4 (397 mg, 1.87 mmol), Pd(PPh3)4 (36 mg, 0.03 mmol) and water (5 drops). The resulting solution was stirred for 1 hour at 90° C. and then concentrated under vacuum to give a residue, which was purified via silica gel column chromatography (2% ethyl acetate in petroleum ether) to afford (S)-methyl 2-(5-fluorobenzofuran-2-yl)-3-(2-methylpiperidin-1-yl)quinoxaline-6-carboxylate as a yellow solid (135.0 mg, 59% 2 steps).
Reaction SMILES: [C:1]([C:4]12[CH2:11][CH2:10][C:7]([NH:12][CH2:13][C:14]([N:16]3[CH2:20][C@@H:19]([F:21])[CH2:18][C@H:17]3[C:22]#[N:23])=[O:15])([CH2:8][CH2:9]1)[CH2:6][CH2:5]2)(O)=[O:2].[Cl:24][C:25]1[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:26]=1[NH2:27]>>[Cl:24][C:25]1[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:26]=1[NH:27][C:1]([C:4]12[CH2:5][CH2:6][C:7]([NH:12][CH2:13][C:14]([N:16]3[CH2:20][C@@H:19]([F:21])[CH2:18][C@H:17]3[C:22]#[N:23])=[O:15])([CH2:8][CH2:9]1)[CH2:10][CH2:11]2)=[O:2]
Reactant: Nc1ccc(Cl)cc1Cl
Reactant: N#C[C@@H]1C[C@H](F)CN1C(=O)CNC12CCC(C(=O)O)(CC1)CC2
Product: N#C[C@@H]1C[C@H](F)CN1C(=O)CNC12CCC(C(=O)Nc3ccc(Cl)cc3Cl)(CC1)CC2
Yield: 35.3 %

Procedure:
In a similar manner to Example 63, (2S,4S)-1-[[N-(4-carboxybicyclo[2.2.2]oct-1-yl)amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (50.0 mg) and 2,4-dichloroaniline (55.1 mg) were used to obtain (2S,4S)-1-[[N-[4-[N-(2,4-dichlorophenyl)amino]carbonylbicyclo[2.2.2]oct-1-yl]amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (25.5 mg).
Reaction SMILES: [CH3:1][C:2]([Si:5]([CH3:28])([CH3:27])[O:6][CH2:7][C@@H:8]([O:10][C:11]1[CH:12]=[C:13]([CH:23]=[C:24]([OH:26])[CH:25]=1)[C:14]([NH:16][C:17]1[CH:21]=[CH:20][N:19]([CH3:22])[N:18]=1)=[O:15])[CH3:9])([CH3:4])[CH3:3].Cl[C:30]1[CH:39]=[CH:38][C:33]([C:34]([O:36][CH3:37])=[O:35])=[CH:32][N:31]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C>[CH3:1][C:2]([Si:5]([CH3:28])([CH3:27])[O:6][CH2:7][C@@H:8]([O:10][C:11]1[CH:25]=[C:24]([O:26][C:30]2[N:31]=[CH:32][C:33]([C:34]([O:36][CH3:37])=[O:35])=[CH:38][CH:39]=2)[CH:23]=[C:13]([C:14]([NH:16][C:17]2[CH:21]=[CH:20][N:19]([CH3:22])[N:18]=2)=[O:15])[CH:12]=1)[CH3:9])([CH3:3])[CH3:4]
Reactant: COC(=O)c1ccc(Cl)nc1
Reactant: C[C@@H](CO[Si](C)(C)C(C)(C)C)Oc1cc(O)cc(C(=O)Nc2ccn(C)n2)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: COC(=O)c1ccc(Oc2cc(O[C@@H](C)CO[Si](C)(C)C(C)(C)C)cc(C(=O)Nc3ccn(C)n3)c2)nc1
Yield: 73.2 %

Procedure:
A solution of 3-[((1S)-2-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-1-methylethyl)oxy]-5-hydroxy-N-(1-methyl-1H-pyrazol-3-yl)benzamide (1.00 g, 2.47 mmol), methyl 6-chloronicotinate (0.450 g, 2.60 mmol), and cesium carbonate (1.204 g, 3.71 mmol) in acetonitrile (15 mL) was heated at 160° C. using microwave heating for 90 minutes. The acetonitrile was removed in vaccuo and the residual oil partitioned between water (50 mL) and ethyl acetate (75 mL). The ethyl acetate layer was separated, washed with brine, dried (MgSO4), and evaporated to a residue which was chromatographed on silica, eluting with 50% ethyl acetate in isohexane, to give the desired compound (0.977 g).
Reaction SMILES: [CH2:1]=[CH:2][CH2:3][CH:4]1[C:8](=[O:9])[CH:7]=[CH:6][CH2:5]1.[N+:10]([CH3:13])([O-:12])=[O:11]>>[CH2:3]([CH:4]1[CH2:5][CH:6]([CH2:13][N+:10]([O-:12])=[O:11])[CH2:7][C:8]1=[O:9])[CH:2]=[CH2:1]
Reactant: C=CCC1CC=CC1=O
Reactant: C[N+](=O)[O-]
Product: C=CCC1CC(C[N+](=O)[O-])CC1=O
Temperature: 60 °C
Yield: 57 %

Procedure:
A stirred solution of 5-(propene-3-yl)cyclopent-2-enone (0.428, 3.5 mmol) in nitromethane (2 mL) under nitrogen was treated with DOWEX® 550A-OH resin (0.80 g, rinsed with methanol and partially air dried), and heated to 60° C. for 2 h. The mixture was cooled to room temperature, diluted with dichloromethane (20 mL), and filtered. The filtrate was concentrated in vacuo, redissolved in minimum dichloromethane, and added to a silica gel column (˜100 cc) and eluted with dichloromethane to afford the subject compound (0.368 g, 57%) as a colorless oil. NMR (CDCl3): δ 5.65-5.80 (m, 1 H), 5.00-5.15 (m, 2 H), 4.40-4.50 (m, 2 H), 2.85-3.15 (m, 1 H), 2.30-2.70 (m, 4 H), 1.90-2.20 (m, 3 H). MS (M+1): 183.9.
Reaction SMILES: [CH3:1][C:2]1([CH3:28])[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:12]([OH:14])=O)[CH:9]=2)[NH:4][CH:3]1[C:15]1[CH:20]=[C:19]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[CH:18]=[C:17]([CH3:27])[CH:16]=1.[CH:29]1([S:32]([NH2:35])(=[O:34])=[O:33])[CH2:31][CH2:30]1>CN(C)C1C=CN=CC=1.ClCCl>[CH3:1][C:2]1([CH3:28])[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:12]([NH:35][S:32]([CH:29]3[CH2:31][CH2:30]3)(=[O:34])=[O:33])=[O:14])[CH:9]=2)[NH:4][CH:3]1[C:15]1[CH:20]=[C:19]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[CH:18]=[C:17]([CH3:27])[CH:16]=1
Reactant: Cc1cc(C2Nc3ccc(C(=O)O)cc3CC2(C)C)cc(N2CCOCC2)c1
Reactant: NS(=O)(=O)C1CC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: Cc1cc(C2Nc3ccc(C(=O)NS(=O)(=O)C4CC4)cc3CC2(C)C)cc(N2CCOCC2)c1
Temperature: 65 °C
Yield: 23.9 %

Procedure:
A mixture of 3,3-dimethyl-2-(3-methyl-5-morpholin-4-yl-phenyl)-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (150 mg, 0.39 mmol), 1-3-dimethylaminopropyl-3-ethylcarbodiimide hydrochloride (110 mg, 0.59 mmol), 4-dimethylaminopyridine (72 mg, 0.59 mmol), cyclopropane sulfonamide (140 mg, 1.17 mmol) in dichloromethane (5 mL) was heated for at 65° C. for 12 hours. Removal of the solvent afforded 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 cyclopropanesulfonic acid [3,3-dimethyl-2-(3-methyl-5-morpholin-4-yl-phenyl)-1,2,3,4-tetrahydro-quinoline-6-carbonyl]-amide (45 mg, 25%) as a light yellow solid: LC/MS m/e calcd for C26H33N3O4S (M+H)+: 484.6, observed: 484.2.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH:12]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)[CH:11]([CH2:21][CH2:22][CH:23]([C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)[OH:24])[C:10]2=[O:32])=[CH:5][CH:4]=1.[C:33](O)(=[O:47])[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][C:44]([OH:46])=[O:45].C(N=C=NC(C)C)(C)C.OC1C2N=NNC=2C=CC=1>CN(C)C=O.C(N(CC)CC)C>[F:31][C:28]1[CH:27]=[CH:26][C:25]([CH:23]([OH:24])[CH2:22][CH2:21][CH:11]2[C:10](=[O:32])[N:9]([C:6]3[CH:7]=[CH:8][C:3]([CH2:2][NH:1][C:33]([CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][C:44]([OH:46])=[O:45])=[O:47])=[CH:4][CH:5]=3)[CH:12]2[C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)=[CH:30][CH:29]=1
Reactant: COc1ccc(C2C(CCC(O)c3ccc(F)cc3)C(=O)N2c2ccc(CN)cc2)cc1
Reactant: O=C(O)CCCCCCCCCCC(=O)O
Agent: CC(C)N=C=NC(C)C
Agent: Oc1cccc2[nH]nnc12
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1ccc(C2C(CCC(O)c3ccc(F)cc3)C(=O)N2c2ccc(CNC(=O)CCCCCCCCCCC(=O)O)cc2)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A solution of 70 mg of 1-(4-aminomethylphenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-4-(4-methoxyphenyl)azetidin-2-one (5), and 23 μl of triethylamine in 1 ml of dimethylformamide was added to a solution of 371 mg of dodecanedioic acid, 63 μl of diisopropylcarbodiimide, 55 mg of hydroxybenzotriazole in 2 ml of dimethylformamide, and the mixture was stirred at room temperature for 12 h. The reaction solution was concentrated and separated by HPLC(Knauer Eurospher-100-10-C18, water (0.1% trifluoroacetic acid)/acetonitrile (0.1% trifluoroacetic acid)=80/20→10/90). This gave the product of molecular weight 646.81 (C38H47F1N2O6); MS (ESI) 647.35 (M+H+)
Reaction SMILES: [NH2:1][C:2]1[C:11]([F:12])=[C:10](F)[C:9]([O:14][CH3:15])=[C:8]2[C:3]=1[C:4](=[O:22])[C:5]([C:19]([OH:21])=[O:20])=[CH:6][N:7]2[CH:16]1[CH2:18][CH2:17]1.[CH3:23][NH:24][CH2:25][CH2:26][NH:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=1.C(N(CC)CC)C>CS(C)=O>[NH2:1][C:2]1[C:11]([F:12])=[C:10]([N:24]([CH3:23])[CH2:25][CH2:26][NH:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=2)[C:9]([O:14][CH3:15])=[C:8]2[C:3]=1[C:4](=[O:22])[C:5]([C:19]([OH:21])=[O:20])=[CH:6][N:7]2[CH:16]1[CH2:18][CH2:17]1
Reactant: COc1c(F)c(F)c(N)c2c(=O)c(C(=O)O)cn(C3CC3)c12
Reactant: CNCCNc1ccccn1
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: COc1c(N(C)CCNc2ccccn2)c(F)c(N)c2c(=O)c(C(=O)O)cn(C3CC3)c12
Temperature: 100 °C
Reaction time: 3 h
Yield: 61.7 %

Procedure:
A mixture of 5-amino-1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylic acid (400 mg, 1.44 mmol), N-methyl-N′-(2-pyridyl)-1,2-ethanediamine (326 mg, 2.16 mmol) and triethylamine (0.300 mL, 2.15 mmol) in anhydrous DMSO (6 mL) was stirred at 100° C. for 3 h. Triethylamine (0.300 mL, 2.15 mmol) was added and the mixture was stirred at 100° C. for 3 h. After cooling, the reaction mixture was poured into ice-water (50 mL), the resulting precipitate was collected by filtration, washed with water and dried to give 5-amino-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-[methyl[2-(2-pyridylamino)ethyl]amino]-4-oxoquinoline-3-carboxylic acid (392 mg, 62%) as a yellow solid.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]([OH:9])=O)=[CH:5][CH:4]=[N:3]1.[NH2:10][C:11]1[N:16]=[CH:15][C:14]2[C:17]([CH3:25])([CH3:24])[C:18](=[O:23])[N:19]([CH:20]3[CH2:22][CH2:21]3)[C:13]=2[CH:12]=1>>[CH:20]1([N:19]2[C:13]3[CH:12]=[C:11]([NH:10][C:7]([C:6]4[N:2]([CH3:1])[N:3]=[CH:4][CH:5]=4)=[O:9])[N:16]=[CH:15][C:14]=3[C:17]([CH3:24])([CH3:25])[C:18]2=[O:23])[CH2:22][CH2:21]1
Reactant: Cn1nccc1C(=O)O
Reactant: CC1(C)C(=O)N(C2CC2)c2cc(N)ncc21
Product: Cn1nccc1C(=O)Nc1cc2c(cn1)C(C)(C)C(=O)N2C1CC1

Procedure:
Prepared in analogy to example 26 from 1-methyl-1H-pyrazole-5-carboxylic acid and 6-amino-1-cyclopropyl-3,3-dimethyl-1H-pyrrolo[3,2-c]pyridin-2(3H)-one (example 79c). The title compound was obtained as white foam.
Reaction SMILES: [O:1]=[C:2]1[C:10]2([CH2:14][O:13][C:12]3[CH:15]=[C:16]4[C:20](=[CH:21][C:11]2=3)[CH2:19][CH2:18][O:17]4)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[CH2:22][C:23]1[CH:24]=[C:25]([CH:30]=[CH:31][CH:32]=1)[C:26]([O:28]C)=[O:27].O.[OH-].[Li+]>O1CCCC1.O>[O:1]=[C:2]1[C:10]2([CH2:14][O:13][C:12]3[CH:15]=[C:16]4[C:20](=[CH:21][C:11]2=3)[CH2:19][CH2:18][O:17]4)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[CH2:22][C:23]1[CH:24]=[C:25]([CH:30]=[CH:31][CH:32]=1)[C:26]([OH:28])=[O:27]
Reactant: COC(=O)c1cccc(CN2C(=O)C3(COc4cc5c(cc43)CCO5)c3ccccc32)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cccc(CN2C(=O)C3(COc4cc5c(cc43)CCO5)c3ccccc32)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 81.9 %

Procedure:
To a solution of methyl 3-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzoate (2.80 g, 6.5 mmol) in tetrahydrofuran (30 mL) and water (10 mL) was added lithium hydroxide monohydrate (0.82 g, 19 mmol). The reaction mixture was stirred at ambient temperature for 16 h. Most of the tetrahydrofuran was removed in vacuo and the resultant solution was washed with diethyl ether (2×50 mL). The aqueous phase was rendered acidic to litmus by the addition of 1 M hydrochloric acid and extracted with ethyl acetate (3×50 mL). The combined organic solution was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was triturated with diethyl ether (50 mL) and the solid was collected by vacuum filtration, washed with diethyl ether (20 mL), air-dried and dried under high vacuum to afford 3-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzoic acid (2.20 g, 81%) as a colorless solid: mp>250° C. (water); 1H NMR (300 MHz, DMSO-d6) δ13.06 (br s, 1H), 7.89-7.82 (m, 2H), 7.66 (d, J=7.6 Hz, 1H), 7.55-7.47 (m, 1H), 7.29-7.16 (m, 2H), 7.07-6.96 (m, 2H), 6.49 (s, 1H), 6.42 (s, 1H), 5.17-4.72 (m, 4H), 4.55-4.45 (m, 2H), 3.06-2.88 (m, 2H); 13C NMR (75 MHz, DMSO-d6) δ177.2, 167.1, 161.2, 160.7, 142.0, 136.9, 132.2, 131.8, 131.2, 129.1, 128.8, 128.4, 127.3, 123.8, 123.2, 120.5, 120.0, 118.9, 109.3, 92.5, 79.7, 72.1, 57.0, 42.5; MS (ES+) m/z 414.0 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][NH:10][CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+].[C:28]1([NH:34][C:35]([NH:37][CH2:38][CH2:39][CH2:40]Br)=[O:36])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>CC#N.CN(C=O)C>[C:28]1([NH:34][C:35](=[O:36])[NH:37][CH2:38][CH2:39][CH2:40][N:10]([CH2:11][CH2:12][C:13]2[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=2)[CH2:9][CH2:8][C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: O=C(NCCCBr)Nc1ccccc1
Reactant: Clc1ccc(CCNCCc2ccc(Cl)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Solvent: CN(C)C=O
Product: O=C(NCCCN(CCc1ccc(Cl)cc1)CCc1ccc(Cl)cc1)Nc1ccccc1
Temperature: 80 °C
Reaction time: 18 h
Yield: 13.3 %

Procedure:
To a mixture of bis[2-(4-chlorophenyl)ethyl]amine (48 mg, 0.16 mmol), potassium carbonate (44 mg, 0.32 mmol) and potassium iodide (26 mg, 0.16 mmol) in CH3CN (2 ml) was added N-phenylcarbamoyl-3-bromopropylamine (215 mg, 0.64 mmol) in DMF (2 ml). The mixture was stirred at 80° C. for 18 h, and then concentrated under vacuum to dryness. The residue was adsorbed on a plate of silica gel and then developed with 10% methanol/chloroform to afford [3-(phenylureido)propyl]bis[2-(4-chlorophenyl)ethyl]amine (10 mg, 13%): MS(ES+) m/e 470 [M+H]+; 1H NMR (400 MHz, CDCl3) δ 7.24 (m, 9H), 7.03 (m, 5H), 6.59 (br, 1H), 3.24 (t, J=6.3 Hz, 2H), 2.87 (m, 1H), 2.76 (m, 1H), 2.73-2.61 (m, 8H), 1.64 (m, 2H).
Reaction SMILES: C1(C)C=CC=CC=1.[F:8][C:9]1[CH:18]=[CH:17][C:12]([NH:13][CH:14]([CH3:16])[CH3:15])=[CH:11][CH:10]=1.[Cl:19][CH2:20][C:21](Cl)=[O:22]>N1C=CC=CC=1>[Cl:19][CH2:20][C:21]([N:13]([CH:14]([CH3:16])[CH3:15])[C:12]1[CH:17]=[CH:18][C:9]([F:8])=[CH:10][CH:11]=1)=[O:22]
Reactant: O=C(Cl)CCl
Reactant: CC(C)Nc1ccc(F)cc1
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: CC(C)N(C(=O)CCl)c1ccc(F)cc1
Yield: 97 %

Procedure:
To 100 ml dry toluene 15.3 g (0.1 m) 4-fluoro-N-isopropylaniline and 8.7 ml (0.11 m) pyridine were added and stirred. To this solution 12.4 g (0.11 m) chloroacetyl chloride was added dropwise below 25° C. It was allowed to stir overnight at room temperature and the mixture was washed with 2×100 ml water. The organic layer was dried on anhydrous magnesium sulfate and evaporated to give 22.2 g pale yellow liquid, yield 97%.
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:3]=1[C:4]1[CH:5]=[CH:6][C:7]([CH2:22][CH3:23])=[C:8]([CH:10]2[C:15](=[O:16])[C:14]([CH3:18])([CH3:17])[O:13][C:12]([CH3:20])([CH3:19])[C:11]2=[O:21])[CH:9]=1.[N:29]([O-:31])=[O:30].[Na+].[N+]([O-])(O)=O>C(O)(=O)C>[Cl:1][C:2]1[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:3]=1[C:4]1[CH:5]=[CH:6][C:7]([CH2:22][CH3:23])=[C:8]([C:10]2([N+:29]([O-:31])=[O:30])[C:15](=[O:16])[C:14]([CH3:17])([CH3:18])[O:13][C:12]([CH3:19])([CH3:20])[C:11]2=[O:21])[CH:9]=1
Reactant: O=N[O-]
Reactant: CCc1ccc(-c2ccc(Cl)cc2Cl)cc1C1C(=O)C(C)(C)OC(C)(C)C1=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O=[N+]([O-])O
Product: CCc1ccc(-c2ccc(Cl)cc2Cl)cc1C1([N+](=O)[O-])C(=O)C(C)(C)OC(C)(C)C1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 1202.4 %

Procedure:
To a solution of 4-(2′,4′-dichloro-4-ethylbiphen-3-yl)-2,2,6,6-tetramethylpyran-3,5-dione (0.200 g, 0.478 mmol) in glacial acetic acid (5 ml) is added sodium nitrite (0.0025 g, 0.036 mmol) then fuming nitric acid (0.12 ml). The mixture is stirred at room temperature for 2 hours, then the resulting slurry is poured into ice-water (50 ml). After swirling for 5 minutes the precipitate is filtered, dried, then washed with hexanes to afford 4-(2′,4′-dichloro-4-ethyl-biphen-3-yl)-2,2,6,6-tetramethyl-4-nitropyran-3,5-dione (0.201 g, 91%) as a yellow solid, m.p.=138-140° C.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([Cl:9])[C:4]=1[CH2:10][C:11](=[NH:13])[NH2:12].[Na].[C:15](OCC)(=[O:22])[CH2:16][C:17](OCC)=[O:18]>C(O)C>[Cl:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([Cl:9])[C:4]=1[CH2:10][C:11]1[N:12]=[C:17]([OH:18])[CH:16]=[C:15]([OH:22])[N:13]=1
Reactant: N=C(N)Cc1c(Cl)cccc1Cl
Reactant: CCOC(=O)CC(=O)OCC
Agent: Cl
Agent: [Na]
Solvent: CCO
Product: Oc1cc(O)nc(Cc2c(Cl)cccc2Cl)n1
Yield: 76.4 %

Procedure:
To the stirred solution of 2,6-dichlorobenzeneethanimidamide HCl (1:1), (0.0042 mol) in ethanol (20 ml), a solution of sodium (0.013 mol) in ethanol (10 ml) was added dropwise first and then propanedioic acid, diethyl ester (0.0109 mol) was added. The reaction mixture was stirred and refluxed for 4 hours and then stirred at room temperature overnight. After adding another equivalent of propanedioic acid, diethyl ester (stirring and refluxing it overnight), the solvent was evaporated and the residue was dissolved in water and acidified with 1 N HCl. The solid was filtered off, washed with water and dried, yielding 0.87 g (76.4%) of 2-[(2,6-dichloro-phenyl)methyl]-4,6-pyrimidinediol (interm. 8).
Reaction SMILES: [CH:1]1([N:6]2[C:10]3[N:11]=[C:12]([NH:15][C:16]4[CH:24]=[CH:23][C:19]([C:20]([OH:22])=O)=[CH:18][N:17]=4)[N:13]=[CH:14][C:9]=3[CH:8]=[C:7]2[C:25](=[O:29])[N:26]([CH3:28])[CH3:27])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:30]([N:37]1[CH2:44][CH:43]2[O:45][CH:39]([CH2:40][NH:41][CH2:42]2)[CH2:38]1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>>[CH3:27][N:26]([CH3:28])[C:25]([C:7]1[N:6]([CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)[C:10]2[N:11]=[C:12]([NH:15][C:16]3[CH:24]=[CH:23][C:19]([C:20]([N:41]4[CH2:40][CH:39]5[O:45][CH:43]([CH2:44][N:37]([CH2:30][C:31]6[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=6)[CH2:38]5)[CH2:42]4)=[O:22])=[CH:18][N:17]=3)[N:13]=[CH:14][C:9]=2[CH:8]=1)=[O:29]
Reactant: c1ccc(CN2CC3CNCC(C2)O3)cc1
Reactant: CN(C)C(=O)c1cc2cnc(Nc3ccc(C(=O)O)cn3)nc2n1C1CCCC1
Product: CN(C)C(=O)c1cc2cnc(Nc3ccc(C(=O)N4CC5CN(Cc6ccccc6)CC(C4)O5)cn3)nc2n1C1CCCC1
Yield: 43.4 %

Procedure:
Following general amide formation method 1, 6-(7-cyclopentyl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-nicotinic acid (200 mg, 0.507 mmol, 1.0 eq) was combined with 3-benzyl-9-oxa-3,7-diaza-bicyclo[3.3.1]nonane (162 mg, 0.558 mmol, 1.1 eq) (Reference: PCT Int. Appl. 2006137769, 2 Dec. 2006) which gave 2-[5-(7-Benzyl-9-oxa-3,7-diaza-bicyclo[3.3.1]nonane-3-carbonyl)-pyridin-2-ylamino]-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide as solid (131 mg) in 39% yield.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][CH2:11][CH2:12][N:13]([CH3:15])[CH3:14])([O-])=O.[ClH:16]>CO.[Pd]>[ClH:16].[NH2:1][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][CH2:11][CH2:12][N:13]([CH3:15])[CH3:14]
Reactant: CN(C)CCNc1ccccc1[N+](=O)[O-]
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CN(C)CCNc1ccccc1N
Reaction time: 5.5 h

Procedure:
To a solution of N-(2-nitrophenyl)-N',N'-dimethylethylenediamine (149.2 g) in methanol (1500 ml) were added concentrated hydrochloric acid (60 ml) and 10% palladium-on-carbon (15 g). The reaction mixture was stirred under a hydrogen atmosphere at atmospheric pressure for 5.5 hours. The reaction mixture was then filtered and concentrated under reduced pressure to give 149.2 g of N-(2-aminophenyl)-N',N'-dimethylethylenediamine hydrochloride.
Reaction SMILES: [O:1]1[CH2:5]CCC1.C([N-]C(C)C)(C)C.[Li+].[Cl:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][C:24]=1[Cl:25])[N:21]=[C:20]([O:26][CH3:27])[C:19]([O:28][CH3:29])=[N:18]2.[O:30]1CCCC1>>[Cl:25][C:24]1[C:15]([Cl:14])=[CH:16][C:17]2[N:18]=[C:19]([O:28][CH3:29])[C:20]([O:26][CH3:27])=[N:21][C:22]=2[C:23]=1[C:5]([OH:1])=[O:30]
Reactant: COc1nc2cc(Cl)c(Cl)cc2nc1OC
Reactant: C1CCOC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Product: COc1nc2cc(Cl)c(Cl)c(C(=O)O)c2nc1OC
Reaction time: 1 h
Yield: 68 %

Procedure:
Lithium diisopropylamide mono(tetrahydrofuran) (1.5M in cyclohexane, 15.5 mL, 23.3 mmol) was added to a stirred suspension of 6,7-dichloro-2,3-dimethoxyquinoxaline (Preparation 1, 5.0 g, 19.3 mmol) in dry tetrahydrofuran (150 mL) at −78° C. under nitrogen. The reaction mixture was stirred at this temperature for 1 hour, then anhydrous carbon dioxide was bubbled through the solution at −78° C. for 1 hour. Saturated aqueous ammonium chloride solution (80 mL) was added and the resulting mixture was allowed to reach room temperature, acidified to pH 1 using 2M aqueous hydrochloric acid solution and extracted with ethyl acetate (3×50 mL). The combined organic extracts were then extracted with 1M aqueous sodium hydroxide solution. The aqueous solution was acidified to pH 1 using 2M aqueous hydrochloric acid solution and extracted with dichloromethane (3×50 mL). The combined dichloromethane extracts were dried (MgSO4) and concentrated under reduced pressure to give the title compound (4.0 g, 68%) as a pale brown solid, mp 230-232° C.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([CH2:8][N:9]2[C:14]3[CH:15]=[CH:16][S:17][C:13]=3[C:12](=[O:18])[N:11]([OH:19])[C:10]2=[O:20])=[CH:4][CH:3]=1.[C:21]([CH:25]=[CH:26]B(O)O)([CH3:24])([CH3:23])[CH3:22]>>[CH3:22][C:21]([CH3:24])([CH3:23])[CH:25]=[CH:26][C:2]1[N:7]=[CH:6][C:5]([CH2:8][N:9]2[C:14]3[CH:15]=[CH:16][S:17][C:13]=3[C:12](=[O:18])[N:11]([OH:19])[C:10]2=[O:20])=[CH:4][CH:3]=1
Reactant: O=c1c2sccc2n(Cc2ccc(Cl)nc2)c(=O)n1O
Reactant: CC(C)(C)C=CB(O)O
Product: CC(C)(C)C=Cc1ccc(Cn2c(=O)n(O)c(=O)c3sccc32)cn1

Procedure:
The title compound was prepared from 1-(6-chloro-pyridin-3-ylmethyl)-3-hydroxy-1H-thieno[3,2-d]pyrimidine-2,4-dione and 2-tert-butyl vinyl boronic acid via general procedure C. The crude product was purified by mass-triggered preparative HPLC. 1H NMR (DMSO-d6) δ 10.8 (bs, 1H), 8.53 (d, 1H, J=2.1 Hz), 8.14 (d, 1H, J=5.4 Hz), 7.62 (dd, 1H, J=2.1, 7.8 Hz), 7.38 (d, 1H, J=5.1 Hz), 7.36 (d, 1H, J=7.8 Hz), 6.78 (d, 1H, J=16.2 Hz), 6.35 (d, 1H, J=16.2 Hz), 5.29 (s, 2H), 1.09 (s, 9H); Electrospray MS: 358 (M+H); retention time: 2.62 min.
Reaction SMILES: Br[CH2:2][CH:3]1[O:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[O:5][CH2:4]1.[CH3:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH:20]1[CH2:25][CH2:24][CH2:23][NH:22][CH2:21]1.Cl.C(N(CC)CC)C>C(#N)C>[O:8]1[C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[O:5][CH2:4][CH:3]1[CH2:2][N:22]1[CH2:23][CH2:24][CH2:25][CH:20]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[CH3:13])[CH2:21]1
Reactant: Cc1ccccc1C1CCCNC1
Reactant: BrCC1COc2ccccc2O1
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1ccccc1C1CCCN(CC2COc3ccccc3O2)C1

Procedure:
A mixture of 2-bromomethyl-2,3-dihydrobenzo[1,4]dioxine (35 mg, 0.15 mmol), 3-(2-methylphenyl)piperidine.HCl (35 mg, 0.16 mmol) and triethylamine (38 mg, 0.38 mmol) in acetonitrile (2 mL) was heated in a microwave reactor at 140-150° C. for 12.5 h. The mixture was absorbed on silica and purified by flash chromatography using a gradient of heptane and EtOAc as eluent to give 29 mg of the title compound.