Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([CH3:25])[CH:3]([NH:8][C:9]([C:11]1[S:12][C:13]([C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-])=O)=[CH:18][CH:17]=2)=[CH:14][N:15]=1)=[O:10])[C:4]([O:6][CH3:7])=[O:5].C(=O)([O-])[O-].[K+].[K+].Br[CH2:33][C:34]1[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=1.O>CC(C)=O>[F:40][C:37]1[CH:38]=[CH:39][C:34]([CH2:33][NH:22][C:19]2[CH:20]=[CH:21][C:16]([C:13]3[S:12][C:11]([C:9]([NH:8][CH:3]([CH:2]([CH3:25])[CH3:1])[C:4]([O:6][CH3:7])=[O:5])=[O:10])=[N:15][CH:14]=3)=[CH:17][CH:18]=2)=[CH:35][CH:36]=1
Reactant: COC(=O)C(NC(=O)c1ncc(-c2ccc([N+](=O)[O-])cc2)s1)C(C)C
Reactant: Fc1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: COC(=O)C(NC(=O)c1ncc(-c2ccc(NCc3ccc(F)cc3)cc2)s1)C(C)C
Temperature: 62.5 °C
Reaction time: 8 h

Procedure:
To a solution of the methyl 2-(5-(4-aminophenyl)thiazole-2-carboxamido)-3-methylbutanoate (Intermediate 2, 250 mg) in acetone (8 ml) was added potassium carbonate (155 mg, 1.5 eq) and 1-(bromomethyl)-4-fluorobenzene (0.112 ml, 1.2 eq). The reaction mixture was stirred for 8 hours at 60-65° C. Water was added after the completion of the reaction, and the reaction mixture was extracted with ethyl acetate. Organic layer was washed with water and concentrated. The compound was purified by column chromatography using 10-15% ethylacetate in petroleum ether to give the title compound. Yield: 130 mg (39%). 1H NMR (CDCl3; 300 MHz): δ 7.87 (s, 1H), 7.66 (d, 1H), 7.44 (d, 2H), 7.37 (m, 2H), 7.08 (t, 2H), 6.68 (d, 2H), 4.74 (m, 1H), 4.37 (s, 2H), 3.79 (s, 3H), 2.37 (m, 1H), 1.05 (t, 6H); MS (ESI) m/z 442.1 [M+H]+, 464.1 [M+Na]+.
Reaction SMILES: [CH3:1][C:2]1[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[C:3]=1[CH2:4][O:5][C:6]1[C:7]([CH3:18])=[C:8]([CH:15]=[CH:16][CH:17]=1)[CH2:9][C:10]1NN=N[N:11]=1.[C-]#N.[Na+]>CN(C=O)C.CCOC(C)=O>[CH3:1][C:2]1[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[C:3]=1[CH2:4][O:5][C:6]1[C:7]([CH3:18])=[C:8]([CH2:9][C:10]#[N:11])[CH:15]=[CH:16][CH:17]=1
Reactant: Cc1cccc(C)c1COc1cccc(Cc2nnn[nH]2)c1C
Agent: [C-]#N
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1cccc(C)c1COc1cccc(CC#N)c1C

Procedure:
The solution of 1-(bromomethyl)-3-(2,6-dimethylbenzyloxy)-2-methylbenzene (Step D, 4.28 g, 13.41 mmol) and NaCN (0.789 g, 16.10 mmol) in dry DMF (20 ml) was heated at 120° C. for 3 hours then cooled and diluted with EtOAc (50 ml). The organic layer was washed with water (30 ml), brine, dried over Na2SO4, filtered, concentrated, and purified by flash chromatography on a silica gel column (hex:ethyl acetate 4:1) to give the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][CH2:13][C:14]([CH3:19])([CH3:18])[C:15](O)=[O:16])[N:5]=[C:4]([CH3:20])[C:3]=1[C:21]([O:23][CH2:24][CH3:25])=[O:22].[CH:26]1([NH2:29])[CH2:28][CH2:27]1>>[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][CH2:13][C:14]([CH3:18])([CH3:19])[C:15]([NH:29][CH:26]2[CH2:28][CH2:27]2)=[O:16])[N:5]=[C:4]([CH3:20])[C:3]=1[C:21]([O:23][CH2:24][CH3:25])=[O:22]
Reactant: NC1CC1
Reactant: CCOC(=O)c1c(C)nc2cccc(OCC(C)(C)C(=O)O)c2c1N
Product: CCOC(=O)c1c(C)nc2cccc(OCC(C)(C)C(=O)NC3CC3)c2c1N

Procedure:
Prepared as in Example 24a from 3-((4-amino-3-(ethoxycarbonyl)-2-methylquinolin-5-yl)oxy)-2,2-dimethylpropanoic acid (Example 47b) and cyclopropanamine as a pale yellow solid (64%). 1H NMR (400 MHz, DMSO-d6) δ 0.14-0.45 (m, 2H), 0.57-0.62 (m, 2H), 1.25 (s, 6H), 1.35 (t, J=8.0 Hz, 3H), 2.58 (s, 3H), 2.62-2.65 (m, 1H), 4.13 (s, 2H), 4.35 (q, J=8.0 Hz, 2H), 6.90 (d, 1H), 7.27 (d, 1H), 7.53 (t, J=8.0 Hz, 1H), 7.79 (d, J=4.0 Hz, 1H), 8.09 (s, 2H). MS 386 (MH+).
Reaction SMILES: [CH2:1]([OH:6])[CH2:2][C@H:3]([OH:5])[CH3:4].C(N(CC)CC)C.[C:14]([Si:18]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)Cl)([CH3:17])([CH3:16])[CH3:15].[NH4+].[Cl-]>C(Cl)Cl>[O:6]([CH2:1][CH2:2][C@H:3]([OH:5])[CH3:4])[Si:18]([C:14]([CH3:17])([CH3:16])[CH3:15])([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: C[C@@H](O)CCO
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@@H](O)CCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 15 h

Procedure:
A mixture of (R)-1,3-butanediol (2 g), triethylamine (4 mL) and t-butyldiphenylchlorosilane (6.7 g) in CH2Cl2 (80 mL) was stirred at r.t. for 15 h. Saturated NH4Cl was added and the mixture was extracted with ethyl acetate. The combined organics were dried (MgSO4) and concentrated. Flash chromatography of the residue (9:1 hexane/ethyl acetate) provided the title compound as an oil.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([NH2:12])=[O:11])=[CH:8][CH:7]=1.[C@@H:15]12[CH2:21][CH2:20][C@@H:19]1[CH2:18][NH:17][CH2:16]2.[I-].[Na+]>>[C@@H:15]12[CH2:21][CH2:20][C@@H:19]1[CH2:18][N:17]([CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([NH2:12])=[O:11])=[CH:8][CH:7]=1)[CH2:16]2
Reactant: C1C[C@H]2CNC[C@@H]12
Reactant: NC(=O)c1ccc(OCCCCl)cc1
Agent: [I-]
Agent: [Na+]
Product: NC(=O)c1ccc(OCCCN2C[C@H]3CC[C@H]3C2)cc1
Reaction time: 16 h

Procedure:
To the reaction mixture of Step 1, at ambient temperature, there are added 0.004 mol of (1R,5S)-3-azabicyclo[3.2.0]heptane, the synthesis of which is described in the publication J. Med. Chem. 1967, 10, 621-623, and 0.002 mol of sodium iodide. Heating at reflux is then resumed for 16 hours. The precipitate is filtered off and rinsed with acetonitrile. The filtrate is concentrated to dryness. The residue is taken up in dichloromethane. The resulting solution is extracted with sodium hydroxide solution and then with water, before being dried over magnesium sulphate and concentrated to dryness. The residue is purified by a preparative chromatography technique on a Lichroprep RP-18 phase.
Reaction SMILES: [Br:1][C:2]1[C:3](N)=[N:4][C:5]([CH3:9])=[C:6]([Br:8])[CH:7]=1.C(ON=O)(C)(C)C>C1COCC1>[Br:8][C:6]1[C:5]([CH3:9])=[N:4][CH:3]=[C:2]([Br:1])[CH:7]=1
Reactant: Cc1nc(N)c(Br)cc1Br
Agent: CC(C)(C)ON=O
Solvent: C1CCOC1
Product: Cc1ncc(Br)cc1Br
Yield: 42.5 %

Procedure:
To a solution of 3,5-dibromo-6-methyl-pyridin-2-ylamine (2.0 g, 7.5 mmol) in THF (75 mL) was added t-butylnitrite (1.5 mL, 12.6 mmol) and the reaction was heated to reflux for 2 hours. The reaction was concentrated in vacuo and purified by flash chromatography (SiO2, CH2Cl2) to give 52A (0.8 g 42%). HPLC Rt=2.77 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([F:12])([F:11])[F:10])=[CH:5][C:4]=1[N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1.[CH:19]12[N:26]([C:27](=[O:38])[CH:28]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH2:29][CH2:30]Cl)[CH:23]([CH2:24][CH2:25]1)[CH2:22][CH2:21][CH2:20]2.C(N(C(C)C)CC)(C)C.[I-].[K+].O.Cl.Cl>CN(C)C=O>[CH:23]12[N:26]([C:27](=[O:38])[CH:28]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH2:29][CH2:30][N:16]3[CH2:15][CH2:14][N:13]([C:4]4[CH:5]=[C:6]([C:9]([F:10])([F:12])[F:11])[CH:7]=[CH:8][C:3]=4[O:2][CH3:1])[CH2:18][CH2:17]3)[CH:19]([CH2:25][CH2:24]1)[CH2:20][CH2:21][CH2:22]2
Reactant: O=C(C(CCCl)c1ccccc1)N1C2CCCC1CC2
Reactant: COc1ccc(C(F)(F)F)cc1N1CCNCC1
Agent: Cl
Agent: [I-]
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(C(F)(F)F)cc1N1CCN(CCC(C(=O)N2C3CCCC2CC3)c2ccccc2)CC1
Yield: 67.5 %

Procedure:
The title compound was prepared from 4-(2-methoxy-5-trifluoromethyl-phenyl)-piperazine 0.7 g, 2.3 mmole, prepared according to the method reported in example 2), 1-(8-aza-bicyclo[3.2.1]oct-8-yl)-4-chloro-2-phenyl-butan-1-one (0.7 g, 2.3 mmole), diisopropylethylamine (0.4 g, 3.0 mmole) and potassium iodide (0.5 g, 3.0 mmole) in dimethylformamide (25 mL) in the manner described in example 2 to yield 0.8 g of title product as the hydrochloride hemihydrate, m.p. 198°-199° C.
Reaction SMILES: CC1N=C(C#CC(C2CCNCC2)O)C=CC=1.[NH:18]1[CH2:23][CH2:22][CH:21]([C:24]([OH:28])([C:26]#[CH:27])[CH3:25])[CH2:20][CH2:19]1.Cl[C:30]1[C:35]([N+:36]([O-:38])=[O:37])=[CH:34][CH:33]=[C:32]([CH3:39])[N:31]=1>>[CH3:39][C:32]1[N:31]=[C:30]([N:18]2[CH2:23][CH2:22][CH:21]([C:24]([OH:28])([C:26]#[CH:27])[CH3:25])[CH2:20][CH2:19]2)[C:35]([N+:36]([O-:38])=[O:37])=[CH:34][CH:33]=1
Reactant: C#CC(C)(O)C1CCNCC1
Reactant: Cc1ccc([N+](=O)[O-])c(Cl)n1
Agent: Cc1cccc(C#CC(O)C2CCNCC2)n1
Product: C#CC(C)(O)C1CCN(c2nc(C)ccc2[N+](=O)[O-])CC1
Yield: 93 %

Procedure:
The title compound was prepared as described for the compound of Example 237 but starting from Compound 312b instead of Compound 237a and 2-chloro-6-methyl-3-nitropyridine instead of 2-bromo-3-nitropyridine. After the work-up, the residue was purified by automated flash liquid chromatography (Horizon™-Biotage) eluting with PE-EtOAc from PE:EtOAc 9:1 affording the title products as yellow oil. Yield: 93%.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[C:5]([C:10]([C:12]1[C:17](Cl)=[N:16][CH:15]=[CH:14][N:13]=1)=[O:11])=[CH:6][N:7]([CH3:9])C)[CH3:2].C(OC(C1C(=O)C2C(=CC=CN=2)N(C[C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=2[C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)C=1)=O)C>>[CH2:1]([O:3][C:4]([C:5]1[C:10](=[O:11])[C:12]2[C:17]([N:7]([CH2:9][C:48]3[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=3[C:38]3[CH:37]=[CH:42][CH:41]=[CH:40][CH:39]=3)[CH:6]=1)=[N:16][CH:15]=[CH:14][N:13]=2)=[O:19])[CH3:2]
Reactant: CCOC(=O)c1cn(Cc2ccccc2-c2ccccc2)c2cccnc2c1=O
Reactant: CCOC(=O)C(=CN(C)C)C(=O)c1nccnc1Cl
Product: CCOC(=O)c1cn(Cc2ccccc2-c2ccccc2)c2nccnc2c1=O
Yield: 36.71 %

Procedure:
5-Biphenyl-2-ylmethyl-8-oxo-5,8-dihydro-pyrido[2,3-b]pyrazine-7-carboxylic acid ethyl ester (14) (0.600 g, 36.71%) was synthesized as a brown sticky solid from 1.2 g of 2-(3-chloro-pyrazine-2-carbonyl)-3-dimethylamino-acrylic acid ethyl ester (13) following the procedure described for 1-biphenyl-2-ylmethyl-4-oxo-1,4-dihydro-[1,5]naphthyridine-3-carboxylic acid ethyl ester (6).
Reaction SMILES: [Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([CH3:8])[NH:4][C:3]=1[C:9]([NH:11][CH:12]1[CH2:17][CH2:16][N:15]([C:18]2[CH:23]=[CH:22][N:21]=[C:20](Cl)[N:19]=2)[CH2:14][CH2:13]1)=[O:10].[CH3:25][S-:26].[Na+]>CN(C=O)C.CCOC(C)=O.O>[Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([CH3:8])[NH:4][C:3]=1[C:9]([NH:11][CH:12]1[CH2:17][CH2:16][N:15]([C:18]2[CH:23]=[CH:22][N:21]=[C:20]([S:26][CH3:25])[N:19]=2)[CH2:14][CH2:13]1)=[O:10]
Reactant: C[S-]
Reactant: Cc1[nH]c(C(=O)NC2CCN(c3ccnc(Cl)n3)CC2)c(Cl)c1Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CSc1nccc(N2CCC(NC(=O)c3[nH]c(C)c(Cl)c3Cl)CC2)n1
Temperature: 90 °C
Yield: 96.9 %

Procedure:
3,4-Dichloro-N-[1-(2-chloropyrimidin-4-yl)piperidin-4-yl]-5-methyl-1H-pyrrole-2-carboxamide (Example 307, 200 mg, 0.515 mmol) and sodium thiomethoxide (108.2 mg, 1.545 mmol) were combined in DMF (12 ml) and heated at 90° C. for 1 h. The reaction mixture was cooled to room temperature, diluted with EtOAc and water. The phases were separated, and the aqueous phase was extracted three times with EtOAc. The combined organic portions were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give a peach coloured solid (200 mg, 0.499 mmol, 97% yield) that was used without further purification.
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=1)=[O:3].CC1C=C(C)[N:18]=C(C)C=1>ClCCl>[C:2](=[O:3])([O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=1)[NH2:18]
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: Cc1cc(C)nc(C)c1
Solvent: ClCCl
Product: NC(=O)Oc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
Para-nitrophenyl chloroformate (483 mg, 2.40 mmol) was dissolved in 10 mL dichloromethane (dry, mol. sieve). A solution of amine 18d (1.00 g, 2.31 mmol) in 5 mL dichloromethane (dry, mol. sieve) and 1.8 mL of sym-collidine were added and mixture was stirred at room temperature for 40 min. Dichloromethane was removed under reduced pressure, residue was acidified with acetic acid and purified by RP-HPLC to yield para-nitrophenyl carbamate 18e.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:19](O)=[O:20])[CH:11]=[N:12][C:13]=2[O:14][CH:15]2[CH2:18][CH2:17][CH2:16]2)=[CH:4][CH:3]=1.[NH2:22][N:23]1[CH2:28][CH2:27][CH:26]([OH:29])[CH2:25][CH2:24]1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:19]([NH:22][N:23]3[CH2:28][CH2:27][CH:26]([OH:29])[CH2:25][CH2:24]3)=[O:20])[CH:11]=[N:12][C:13]=2[O:14][CH:15]2[CH2:16][CH2:17][CH2:18]2)=[CH:4][CH:3]=1
Reactant: NN1CCC(O)CC1
Reactant: O=C(O)c1cnc(OC2CCC2)c(-c2ccc(Cl)cc2)c1
Product: O=C(NN1CCC(O)CC1)c1cnc(OC2CCC2)c(-c2ccc(Cl)cc2)c1

Procedure:
The title compound was synthesized in analogy to Example 1 using 5-(4-chlorophenyl)-6-(cyclobutoxy)-3-pyridinecarboxylic acid and 1-amino-4-piperidinol (CAN 79414-82-7) as starting materials; MS (EI) 402.4 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH:11]2[CH2:16][CH2:15][CH:14]([OH:17])[CH2:13][CH2:12]2)=[CH:6][C:5]=1[C:18]([F:21])([F:20])[F:19])([O-:3])=[O:2].[H-].[Na+].C([O:28][C:29](=[O:31])[CH3:30])(C)(C)C.FC(F)(F)C(O)=O>O1CCCC1.C(OCC)(=O)C.ClCCl.O>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH:11]2[CH2:16][CH2:15][CH:14]([O:17][CH2:30][C:29]([OH:31])=[O:28])[CH2:13][CH2:12]2)=[CH:6][C:5]=1[C:18]([F:19])([F:20])[F:21])([O-:3])=[O:2]
Reactant: CC(=O)OC(C)(C)C
Reactant: O=[N+]([O-])c1ccc(NC2CCC(O)CC2)cc1C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: O=C(O)COC1CCC(Nc2ccc([N+](=O)[O-])c(C(F)(F)F)c2)CC1
Temperature: 5 °C
Reaction time: 0.25 h
Yield: 59 %

Procedure:
4-(4-Nitro-3-trifluoromethyl-phenylamino)-cyclohexanol (2.79 mmol) is dissolved in dry tetrahydrofuran (7 mL) and sodium hydride (60% suspension in oil, 7.0 mmol) is added. The resulting mixture is stirred for 15 min and is cooled down to 5° C. prior to the addition of acetic acid tert-butyl ester (2.79 mmol). After 1.5 hours reaction time, water (5 mL) is slowly added under vigorous stirring and the mixture is then diluted with ethyl acetate (20 mL). The organic phase is collected and is concentrated under reduced pressure. The residue obtained is then treated with a 1 to 1 mixture of dichloromethane and trifluoroacetic acid (7 mL). After complete conversion of the intermediate ester into the desired acid, the reaction mixture is again concentrated under reduced pressure. The residue obtained is taken up in dichloromethane (20 mL) and the organic phase is extracted with aqueous 3N sodium hydroxide solution (10 mL). The organic phase is then washed with water (2×7 mL), and these aqueous phases are in turn extracted with dichloromethane (2×7 mL). The pH of all combined aqueous phases is then brought to 5-6 by the addition of aqueous 5N hydrochloric acid. The acidic aqueous phase is extracted with dichloromethane (2×15 mL) and the combined organic layers are dried over magnesium sulphate, filtered and concentrated under reduced pressure to afford the desired acid (59% yield).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:11][CH:12]2[CH2:14][CH2:13]2)[C:5]2[O:10][CH:9]=[CH:8][C:6]=2[N:7]=1.[NH2:15][C:16]1[CH:25]=[C:24]2[C:19]([CH2:20][CH2:21][C:22](=[O:26])[NH:23]2)=[CH:18][CH:17]=1.C([O-])([O-])=O.[K+].[K+].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>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].CC(O)(CC)C>[CH:12]1([NH:11][C:4]2[C:5]3[O:10][CH:9]=[CH:8][C:6]=3[N:7]=[C:2]([NH:15][C:16]3[CH:25]=[C:24]4[C:19]([CH2:20][CH2:21][C:22](=[O:26])[NH:23]4)=[CH:18][CH:17]=3)[N:3]=2)[CH2:14][CH2:13]1
Reactant: Clc1nc(NC2CC2)c2occc2n1
Reactant: Nc1ccc2c(c1)NC(=O)CC2
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCC(C)(C)O
Product: O=C1CCc2ccc(Nc3nc(NC4CC4)c4occc4n3)cc2N1
Temperature: 78 °C
Reaction time: 0.25 h
Yield: 30.8 %

Procedure:
A flask was charged with 2-methyl-2-butanol (140 mL) and the solvent was sparged with N2 for about 15 min. To the solvent were added 2-chloro-N-cyclopropylfuro[3,2-d]pyrimidin-4-amine (6.5 g, 31 mmol, Example #3, Step C), 7-amino-3,4-dihydroquinolin-2(1H)-one (5.03 g, 31.0 mmol, Astatech), and K2CO3 (8.57 g, 62.0 mmol). The flask was purged with N2 (3×) followed by the addition of X-Phos (2.07 g, 4.34 mmol) and Pd2dba3 (1.99 g, 2.17 mmol). The flask was again purged with N2 (2×) and the mixture was heated to about 78° C. for about 24 h. The mixture was cooled to rt and filtered through a pad of Celite®. The filter pad was washed with DCM (˜900 mL) and the combined filtrates were concentrated under reduced pressure to about ½ the initial volume. The mixture was dissolved in DCM (200 mL) and washed with water (100 mL). The layers were separated and the organic solution was dried over anhydrous MgSO4, filtered and concentrated under reduced pressure to about ⅕ volume. Additional DCM/MeOH (3:1, 100 mL) was added along with silica gel (˜25 g, 200-400 Mesh, 60 Å) and the solvents were removed under reduced pressure. The crude material was purified by silica gel chromatography (220 g) eluting with 0.5 to 2.5% MeOH in DCM over about 20 min, 2.5 to 3.5% MeOH in DCM over 15 min, and isocratic at 3.5% MeOH in DCM for about 25 min. The product containing fractions were combined and concentrated under reduced pressure to give a solid that was triturated with MeOH (˜30 mL). The solid was collected by vacuum filtration to give 7-(4-(cyclopropylamino)furo[3,2-d]pyrimidin-2-ylamino)-3,4-dihydroquinolin-2(1H)-one (3.2 g, 31%): LC/MS (Table 2, Method c) Rt=1.71 min; MS m/z: 336 (M+H)+. Syk IC50=A
Reaction SMILES: [H-].[Na+].[N:3]1([CH2:8][CH2:9][OH:10])[CH2:7][CH2:6][CH2:5][CH2:4]1.F[C:12]1[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][C:13]=1[N+:22]([O-])=O>C1COCC1>[N:3]1([CH2:8][CH2:9][O:10][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][C:13]=2[NH2:22])[CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: OCCN1CCCC1
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Nc1cc(C(F)(F)F)ccc1OCCN1CCCC1

Procedure:
To a suspension of NaH (60%, 248 mg, 6.21 mmol) in dry THF was added 2-Pyrrolidin-1-yl-ethanol (0.68 mL, 5.74 mmol). Bubbling was observed. The reaction was stirred for 5 minutes, at which time 1-Fluoro-2-nitro-4-trifluoromethyl-benzene (0.67 mL, 4.79 mmol) was added. The solution turned red, and LCMS indicated completion of the reaction. The reaction was quenched by addition of H2O, and the mixture was extracted with EtOAc, dried with MgSO4, filtered, and concentrated to afford the title compound as an orange oil.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH2:11][NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[N+:19]([O-])=O)=[CH:3]1.[H][H]>C(O)C.[Pd]>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH2:11][NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[NH2:19])=[CH:3]1
Reactant: Cn1cc(CNc2ccccc2[N+](=O)[O-])c2ccccc21
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: Cn1cc(CNc2ccccc2N)c2ccccc21
Yield: 89.8 %

Procedure:
829 mg (6 mmol) of 2-nitroaniline and 1242 mg (7.8 mmol) of 1-methylindole carboxyaldehyde were dissolved in 20 ml of tetrahydrofuran followed by the sequential addition of 200 μl of acetic acid and 5087 mg (24 mmol) of NaBH(OAc)3 and stirring overnight at room temperature. After adding saturated aqueous sodium bicarbonate solution, extracting with ethyl acetate and drying with anhydrous magnesium sulfate, the solvent was distilled off and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=95:5) to obtain 264 mg of ((1-methylindole-3-yl)methyl)(2-nitrophenyl)amine (yield: 18%). 264 mg (0.939 mmol) of ((1-methylindole-3-yl)methyl)(2-nitrophenyl)amine were then dissolved in 10 ml of ethanol followed by the addition of 50 mg (0.047 mmol) of 10% Pd—C and stirring for 6 hours at room temperature in a hydrogen atmosphere. After completion of the reaction, the Pd—C was filtered out and the solvent was distilled off under reduced pressure to obtain 212 mg of ((1-methylindole-3-yl)methyl)(2-aminophenyl)amine (yield: 90%).
Reaction SMILES: C[C:2]1(C)[CH2:7][C:6]([CH3:9])([CH3:8])[CH2:5][CH2:4][C:3]1=[O:10].Cl.[CH3:13]C(C)=O>[Cl-].[Na+].O>[CH3:9][C:6]1([CH:8]=[CH2:13])[CH2:7][CH2:2][C:3](=[O:10])[CH2:4][CH2:5]1
Reactant: CC(C)=O
Reactant: CC1(C)CCC(=O)C(C)(C)C1
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: C=CC1(C)CCC(=O)CC1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 94 %

Procedure:
To a stirred solution of 2 (1.98 mmol, 360 mg) in acetone (7.76 mL) was added 10% aqueous hydrochloric acid solution (3.02 mL), and the resulting mixture was stirred at room temperature for 2.5 hours. The reaction mixture was then diluted with brine (40 mL) and extracted with methylene chloride/ethyl ether (1:2, 3×30 mL). The organic layers were combined and washed with saturated aqueous sodium bicarbonate solution (2×30 mL) and brine (1×30 mL), then dried over magnesium sulfate, filtered, and concentrated in vacuo to give 19 (251.6 mg, 1.92 mmol, 94%) as a yellow oil that was used in the next reaction without further purification: 1H NMR (CDCl3) δ 5.89 (1H, dd, J=0.5, 17.3 Hz), 5.15 (1H, dd, J=1, 3.5 Hz), 5.12 (1H, dd, J=0.5, 10 Hz), 2.42-2.28 (4H, m), 1.97-1.91 (2H, m), 1.74-1.68 (2H, m), 1.12 (3H, s); 13C NMR (CDCl3) δ 212.4, 145.5, 112.9, 38.2, 37.1, 27.4; MS (EI) m/z 138.1 [M+], 123.1, 110.1, 105.1, 97.1, 86.0 (100%), 68.1, 63.0, 54.9; HRMS (EI) calcd for C9H14O 138.1045 found 138.1048.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]([CH2:14][O:15][CH2:16][CH:17]3[CH2:22][CH2:21][CH2:20][NH:19][CH2:18]3)=[C:11]([CH3:13])[N:12]=2)=[CH:4][CH:3]=1.F[C:24]1[CH:31]=[CH:30][CH:29]=[CH:28][C:25]=1[CH:26]=[O:27]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]([CH2:14][O:15][CH2:16][CH:17]3[CH2:22][CH2:21][CH2:20][N:19]([C:24]4[CH:31]=[CH:30][CH:29]=[CH:28][C:25]=4[CH:26]=[O:27])[CH2:18]3)=[C:11]([CH3:13])[N:12]=2)=[CH:4][CH:3]=1
Reactant: O=Cc1ccccc1F
Reactant: Cc1nc(-c2ccc(Cl)cc2)sc1COCC1CCCNC1
Product: Cc1nc(-c2ccc(Cl)cc2)sc1COCC1CCCN(c2ccccc2C=O)C1
Yield: 32.5 %

Procedure:
Using 3-[[2-(4-chlorophenyl)-4-methylthiazol-5-yl]methoxymethyl]piperidine (106 mg, 0.315 mmol) and 2-fluorobenzaldehyde (0.0329 mL, 0.315 mmol), the same procedure was followed as in Step 1c of Example 1 to give 45.2 mg (32%) of the desired compound as a colorless oil.
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[C:5]([C:9]([C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=2)=O)=O)[CH:6]=[CH:7][CH:8]=1.[S:20]([NH2:24])([NH2:23])(=[O:22])=[O:21]>CO>[F:2][C:3]1[CH:4]=[C:5]([C:9]2[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=3)=[N:24][S:20](=[O:22])(=[O:21])[N:23]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: O=C(C(=O)c1cccc(F)c1)c1cccc(F)c1
Reactant: NS(N)(=O)=O
Agent: Cl
Solvent: CO
Product: O=S1(=O)N=C(c2cccc(F)c2)C(c2cccc(F)c2)=N1
Temperature: 66 °C
Yield: 72.8 %

Procedure:
Hydrogen chloride is bubbled through a solution of 3,3′-difluorobenzil (20) (3.81 g, 15.7 mmol) and sulfamide (1.53 g, 15.9 mmol) in methanol (15 mL) for 0.5 min followed by heating at 66° C. for 2 h. The reaction mixture is cooled to RT, the solvent rotary evaporated, and the residue triturated from heptane to give 3.50 g of the product 21.