Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[N:10]=[C:9]2[C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][C:19]=2[CH3:25])=[CH:4][CH:3]=1.[Br:26]N1C(=O)CCC1=O.O>CCO>[Br:26][C:12]1[N:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[C:9]([C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][C:19]=2[CH3:25])=[N:10][C:11]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: CCOC(=O)c1cn(-c2ccc(Cl)cc2)c(-c2ccc(C)cc2C)n1
Reactant: O=C1CCC(=O)N1Br
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1nc(-c2ccc(C)cc2C)n(-c2ccc(Cl)cc2)c1Br
Temperature: 25 °C
Reaction time: 3 h
Yield: 128.9 %

Procedure:
Ethyl 1-(4-chlorophenyl)-2-(2,4-dimethylphenyl)-1H-imidazole-4-carboxylate (1.23 g, 3.47 mmol) was dissolved in EtOH (15 mL) and treated with N-bromosuccinimide (1.25 g, 7.02 mmol). The solution was stirred at rt for 3 h. Water was added. Extraction with dichloromethane, which was then washed with NaCl solution, gave an orange solid (1.94 g). Purification by chromatography over silica gel (20% EtOAc in hexane) afforded a light tan solid (1.028 g, 68%): 1H NMR (300 MHz, CDCl3) δ 7.35 (d, 2H), 7.03 (d, 2H), 7.00 (m, 1H), 6.86 (m, 2H), 4.44 (q, 2H), 2.26 (s, 3H), 2.10 (s, 3H), 1.43 (t, 3H); LC-MS m/z 433.1 (MH+), retention time 3.84 min (method 1).
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:15]=[C:16]([CH:22]=[CH:23][CH:24]=2)[C:17]([N:19]([CH3:21])[CH3:20])=[O:18])[N:8]=1)=O.[Cl:26][C:27]1[CH:28]=[C:29]([NH:33]N)[CH:30]=[CH:31][CH:32]=1>>[Cl:26][C:27]1[CH:28]=[C:29]([N:33]2[C:5]([C:7]3[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]4[CH:15]=[C:16]([CH:22]=[CH:23][CH:24]=4)[C:17]([N:19]([CH3:21])[CH3:20])=[O:18])[N:8]=3)=[CH:4][CH:3]=[N:2]2)[CH:30]=[CH:31][CH:32]=1
Reactant: CN(C)/C=C/C(=O)c1nn(-c2cccc(C(=O)N(C)C)c2)ccc1=O
Reactant: NNc1cccc(Cl)c1
Product: CN(C)C(=O)c1cccc(-n2ccc(=O)c(-c3ccnn3-c3cccc(Cl)c3)n2)c1

Procedure:
The product was obtained starting from 3-[3-((E)-3-Dimethylamino-acryloyl)-4-oxo-4H-pyridazin-1-yl]-N,N-dimethyl-benzamide (A-20) and 3-chloro-phenylhydrazine according to the method described for example 91. MS: M=420.2 (M+H)+
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:4][C:3]=1[C:17]1[N:18]=[CH:19][C:20]([NH2:23])=[N:21][CH:22]=1.Br[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[S:31]([CH:34]([CH3:36])[CH3:35])(=[O:33])=[O:32]>>[F:1][C:2]1[CH:7]=[C:6]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[S:31]([CH:34]([CH3:36])[CH3:35])(=[O:32])=[O:33])[CH:5]=[CH:4][C:3]=1[C:17]1[N:18]=[CH:19][C:20]([NH2:23])=[N:21][CH:22]=1
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)cn3)c(F)c2)OC1(C)C
Reactant: CC(C)S(=O)(=O)c1ccccc1Br
Product: CC(C)S(=O)(=O)c1ccccc1-c1ccc(-c2cnc(N)cn2)c(F)c1

Procedure:
The title compound was prepared using analogous conditions to those described in Example 1 utilizing 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrazin-2-amine and 1-bromo-2-(isopropylsulfonyl)benzene. MS (ESI): mass calcd. for C19H18FN3O2S, 371.11; m/z found, 372.1 [M+H]+. 1H NMR (400 MHz, CD3OD) δ 8.42 (s, 1H), 8.15 (dd, J=8.0, 1.1, 1H), 8.09 (d, J=1.4, 1H), 7.93 (m, 1H), 7.78 (m, 1H), 7.68 (m, 1H), 7.51-7.44 (m, 1H), 7.37-7.28 (m, 2H), 2.90-2.77 (m, 1H), 1.09 (d, J=6.8, 6H).
Reaction SMILES: [N:1]1[C:5]2[C:6]3[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=3[O:8][CH2:9][CH2:10][C:4]=2[S:3][C:2]=1[NH:15][CH:16]1[CH2:21][CH2:20][CH:19]([CH2:22][NH:23][C:24](=O)[CH2:25][CH3:26])[CH2:18][CH2:17]1.CCOC(C)=O.Cl>C1COCC1>[CH2:24]([NH:23][CH2:22][CH:19]1[CH2:20][CH2:21][CH:16]([NH:15][C:2]2[S:3][C:4]3[CH2:10][CH2:9][O:8][C:7]4[CH:11]=[CH:12][CH:13]=[CH:14][C:6]=4[C:5]=3[N:1]=2)[CH2:17][CH2:18]1)[CH2:25][CH3:26]
Reactant: CCC(=O)NCC1CCC(Nc2nc3c(s2)CCOc2ccccc2-3)CC1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCNCC1CCC(Nc2nc3c(s2)CCOc2ccccc2-3)CC1
Temperature: 25 °C
Yield: 72.4 %

Procedure:
To a solution of N1-{[4-(4,5-dihydrobenzo[2,3]oxepino[4,5-d][1,3]thiazol-2-ylamino)cyclohexyl]methyl}propanamide (0.380 g, 0.944 mmol) in anhydrous THF (7 ml) was added 1M BH3 in THF (2.0 ml, 2.0 mmol). The solution was stirred for several hours at room temperature. TLC (EtOAc) indicated reaction to be incomplete and an additional 2.5 ml 1M BH3 in THF was added to the solution which was then stirred overnight. 4N HCl (25 ml) was slowly added to the stirred solution and the solution was washed with EtOAc. The aqueous layer was made basic by addition of 20% NaOH. The resulting solution was extracted with EtOAc and the extract washed with water. Upon removal of the solvent, 72% (254 mg) of the product was obtained as a white solid: 1H-NMR (CDCl3) δ 0.88 (3H, t, J=7.3 Hz), 1.12 (4H, m), 1.43 (3H, m), 1.75 (2H, m), 2.14 (2H, m), 2.41 (2H, d, J=6.6 Hz), 2.51 (2H, t, J=7.4 Hz), 2.60 (1H, m), 3.10 (2H, t, J=5.0 Hz), 3.22 (1H, m), 4.27 (2H, t, J=5.0 Hz), 5.35 (1H, m), 6.95 (1H, d, J=7.6 Hz), 7.06 (2H, m), 8.20 (1H, d, J=7.3 Hz); 372 (ESMS, MH+).
Reaction SMILES: [NH2:1][C:2]([O:4][CH2:5][CH3:6])=[O:3].[N-]=[C:8]=[O:9].[N-]=C=[O:12].C1(CC2C=CC=CC=2)C=CC=CC=1>>[C:8]([OH:9])(=[O:12])[CH:5]=[CH2:6].[NH2:1][C:2]([O:4][CH2:5][CH3:6])=[O:3]
Reactant: [N-]=C=O
Agent: CCOC(N)=O
Solvent: c1ccc(Cc2ccccc2)cc1
Product: C=CC(=O)O

Procedure:
A urethane acrylate oligomer was prepared in the same manner as in Synthesis Example 1, with the exception that a urethane prepolymer obtained by adjusting the proportions of polyol, chain extender and diphenylmethane diisocyanate so that the ratio of HS/SS was about 1/1.51 was used.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:9]([C:11]2[C:20](=[O:21])[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[NH:13][CH:12]=2)=[O:10])=[N:6][C:7]=1[CH3:8].[H-].[Na+].[Br:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([CH:31](Br)[CH3:32])[N:26]=1>CN(C)C=O>[Br:24][C:25]1[N:26]=[C:27]([CH:31]([N:13]2[C:14]3[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:20](=[O:21])[C:11]([C:9]([C:5]3[CH:4]=[CH:3][C:2]([CH3:1])=[C:7]([CH3:8])[N:6]=3)=[O:10])=[CH:12]2)[CH3:32])[CH:28]=[CH:29][CH:30]=1
Reactant: Cc1ccc(C(=O)c2c[nH]c3ccccc3c2=O)nc1C
Reactant: CC(Br)c1cccc(Br)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)c2cn(C(C)c3cccc(Br)n3)c3ccccc3c2=O)nc1C

Procedure:
Experimental conditions analogous to those described for Step 3 of Example 1, from 50 mg (0.18 mmol) of 3-(5,6-dimethyl-pyridine-2-carbonyl)-1H-quinolin-4-one, 9 mg (0.22 mmol) of 60% sodium hydride, 57 mg (0.22 mmol) of 2-bromo-6-(1-bromo-ethyl)-pyridine and 0.7 mL of N,N-dimethylformamide. Yield: 4.4 mg of a white solid: LC-MSD, m/z for C24H20BrN3O2 [M+H]+=462.0, 464.0; HPLC retention time: 2.0 min.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:25][CH3:26])=[C:6]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=3[F:24])=[CH:12][CH:11]=2)=[O:9])[CH:7]=1.[CH2:27]([N:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1)[C:28]#[CH:29].C([O-])([O-])=O.[Cs+].[Cs+].C(N(CC)C(C)C)(C)C>COCCOCCOC.CC(OC)(C)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[F:24][C:18]1[CH:19]=[C:20]([F:23])[CH:21]=[CH:22][C:17]=1[NH:16][C:13]1[CH:14]=[CH:15][C:10]([C:8]([C:6]2[CH:7]=[C:2]([C:29]#[C:28][CH2:27][N:30]3[CH2:35][CH2:34][O:33][CH2:32][CH2:31]3)[CH:3]=[CH:4][C:5]=2[O:25][CH3:26])=[O:9])=[CH:11][CH:12]=1
Reactant: C#CCN1CCOCC1
Reactant: COc1ccc(Br)cc1C(=O)c1ccc(Nc2ccc(F)cc2F)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Solvent: CCN(C(C)C)C(C)C
Solvent: COC(C)(C)C
Solvent: COCCOCCOC
Product: COc1ccc(C#CCN2CCOCC2)cc1C(=O)c1ccc(Nc2ccc(F)cc2F)cc1
Yield: 40.6 %

Procedure:
(5-Bromo-2-methoxy-phenyl)-[4-(2,4-difluoro-phenylamino)-phenyl]-methanone (1.00 g; 2.37 mmol), 4-prop-2-ynyl-morpholine (1.2 g; 9.5 mmol) PdCl2(PPh3)2 (320 mg; 0.4 mmol), Cs2CO3 (2.0 g; 6.2 mmol) and CuI (100 mg; 0.52 mmol) are dissolved in diethylene glycol dimethyl ether (10 ml) and N,N-diisopropylethylamine (5 ml) and heated to 140° C. for 1 hour. The reaction mixture is diluted with TBME, filtered, evaporated and purified by chromatography (SiO2, acetone/hexanes 3/7>6/4) to yield the title compound as yellow foam (445 mg; 40%).
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]([OH:31])=[C:7]2[C:12](=[CH:13][N:14]=1)[N:11]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10](=[O:22])[C:9]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=1)=[CH:8]2)=O.[OH-].[Na+].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.Cl.[CH2:49]([O:51][C:52](=[O:57])[CH2:53][CH2:54][CH2:55][NH2:56])[CH3:50].CCN(C(C)C)C(C)C>CCOC(C)=O.C(Cl)Cl.C1COCC1.CO>[CH2:49]([O:51][C:52](=[O:57])[CH2:53][CH2:54][CH2:55][NH:56][C:3]([C:5]1[C:6]([OH:31])=[C:7]2[C:12](=[CH:13][N:14]=1)[N:11]([CH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[C:10](=[O:22])[C:9]([C:23]1[CH:24]=[CH:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=1)=[CH:8]2)=[O:2])[CH3:50]
Reactant: COC(=O)c1ncc2c(cc(-c3ccc(OC)cc3)c(=O)n2Cc2ccccc2)c1O
Reactant: CCOC(=O)CCCN
Agent: Cl
Agent: On1nnc2ccccc21
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCOC(=O)CCCNC(=O)c1ncc2c(cc(-c3ccc(OC)cc3)c(=O)n2Cc2ccccc2)c1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 31.5 %

Procedure:
A mixture of 1-benzyl-5-hydroxy-3-(4-methoxy-phenyl)-2-oxo-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (51 mg, 0.123 mmol), 2 M NaOH (3 mL), MeOH (3 mL) and THF (3 mL) was stirred at r.t. overnight, then concentrated to approximately one-third of its original volume. 1 M HCl was added to acidify the mixture, and the resulting suspension was extracted with EtOAc. The organic layer was dried over MgSO4 and concentrated. To the residue were then added HOBt (27 mg, 0.20 mmol), CH2Cl2 (3 mL), and EDC (42 mg, 0.22 mmol), and the resulting mixture was stirred for 10 min. 4-Amino-butyric acid ethyl ester HCl salt (33 mg, 0.20 mmol) and Hunig's base (0.080 mL, 0.44 mmol) were added, and the mixture was stirred overnight. The mixture was diluted with EtOAc and washed with 0.1 M HCl. The organic layer was dried over MgSO4 and concentrated. The crude product was purified by silica gel chromatography (5-45% EtOAc/hexanes+1% AcOH) to give 20 mg of the title compound. MS: (+) m/z 516.37 (M+1).
Reaction SMILES: [Cl-].[CH3:2][O:3][CH2:4][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CC(C)([O-])C.[K+].[F:30][C:31]1[C:36]([F:37])=[CH:35][CH:34]=[CH:33][C:32]=1[CH:38]1[CH2:43][CH2:42][C:41](=O)[CH2:40][CH2:39]1>CCOCC>[F:30][C:31]1[C:36]([F:37])=[CH:35][CH:34]=[CH:33][C:32]=1[CH:38]1[CH2:43][CH2:42][C:41](=[CH:2][O:3][CH3:4])[CH2:40][CH2:39]1
Reactant: O=C1CCC(c2cccc(F)c2F)CC1
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CCOCC
Product: COC=C1CCC(c2cccc(F)c2F)CC1
Reaction time: 0.5 h
Yield: 89.8 %

Procedure:
First, 27.4 g of (methoxymethyl)triphenylphosphonium chloride, 9 g of potassium t-butoxide, and 225 ml of dry ether were placed in a 500 ml flask whose content was replaced with argon. The mixture was stirred for 30 minutes under ice water cooling. Then, 50 ml of an ether solution containing 16.8 g of 4-(2,3-difluorophenyl)cyclohexanone was added dropwise to the reaction mixture. The reaction mixture was stirred under ice water cooling for 30 minutes and at room temperature for 8 hours. Thereafter, a precipitate was filtered out. A filtrate was washed with water and dried over anhydrous sodium sulfate. The solvent was distilled away. Thereafter, the residue was purified by silica gel column chromatography (eluent: toluene/hexane=1/4) to obtain 17.1 g of 1-(2,3-difluorophenyl)-4-methoxymethylene cyclohexane (Y: 89.7%). The compound thus obtained had a purity of 99.2% by GC.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:18])=[C:6]([CH:17]=1)[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][OH:16])=[CH:10][CH:9]=1.C(=O)([O-])[O-].[Na+].[Na+].[C:25](OC=C)(=O)[CH3:26]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:18])=[C:6]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][O:16][CH:25]=[CH2:26])=[CH:10][CH:9]=2)[CH:17]=1
Reactant: OCCc1ccc(Cc2cc(Br)ccc2Cl)cc1
Reactant: C=COC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: C=COCCc1ccc(Cc2cc(Br)ccc2Cl)cc1
Temperature: 100 °C
Reaction time: 2 h
Yield: 86.7 %

Procedure:
To a solution of 2-(4-(5-bromo-2-chlorobenzyl)phenyl)ethanol (intermediate BH) (500 mg, 1.46 mmol), [IrCl(cod)]2 (9.8 mg, 0.015 mmol) and sodium carbonate (93 mg, 0.87 mmol) in toluene (2 mL) was added vinyl acetate (0.27 mL, 2.91 mmol) under argon. The reaction mixture was heated to 100° C. and stirred for 2 h. The solution was allowed to cool to room temperature, and then diluted with 50 mL of ethyl acetate. The mixture was washed with water (20 mL) and then with brine (20 mL), and dried over sodium sulfate. The residue was concentrated and purified by column chromatography (eluent EA:PE:Et3N=1:20:0.01) to provide 445 mg of yellow solid. 1H-NMR (CDCl3, 400 MHz): δ 7.22˜7.14 (m, 3H), 7.10 (d, 2H), 7.04 (d, 2H), 6.40 (dd, J=14.4 and 6.8 Hz, 1H), 4.11 (dd, J=14.4 and 2.0 Hz, 1H), 3.96 (s, 2H), 3.93 (dd, J=6.8 and 2.0 Hz, 1H), 3.82 (t, J=7.2 Hz, 2H), 2.88 (t, J=7.2 Hz, 2H).
Reaction SMILES: [CH2:1]([C:3]1[S:7][C:6]([S:8][CH:9]([C:11]2[N:16]=[C:15]([NH:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([NH:25][C:26]([O:28][CH2:29][CH:30]=[CH2:31])=[O:27])C=3)[CH:14]=[C:13]([N:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)[CH:12]=2)C)=[N:5][N:4]=1)[CH3:2].C(Br)C1C=CC=CC=1.ClCC1[N:53]=C(C(OCC)=O)C=CC=1>>[CH2:1]([C:3]1[S:7][C:6]([S:8][CH2:9][C:11]2[N:16]=[C:15]([NH:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([NH:25][C:26]([O:28][CH2:29][CH:30]=[CH2:31])=[O:27])[N:53]=3)[CH:14]=[C:13]([N:32]3[CH2:33][CH2:34][O:35][CH2:36][CH2:37]3)[CH:12]=2)=[N:5][N:4]=1)[CH3:2]
Reactant: C=CCOC(=O)Nc1cccc(CNc2cc(N3CCOCC3)cc(C(C)Sc3nnc(CC)s3)n2)c1
Reactant: CCOC(=O)c1cccc(CCl)n1
Agent: BrCc1ccccc1
Product: C=CCOC(=O)Nc1cccc(CNc2cc(N3CCOCC3)cc(CSc3nnc(CC)s3)n2)n1

Procedure:
The above identified compound was obtained as a pale yellow solid in the same manner as in Example 1-(6), Example 4-(2) and (3) and Example 1-(7) except that benzyl bromide was changed to ethyl 6-chloromethylpyridine-2-carboxylate.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH:5][C:6]([NH2:8])=[S:7].C([O:11][CH:12](OCC)[CH2:13][C:14](OCC)=O)C.C[O-].[Na+]>CO>[CH3:1][O:2][CH2:3][CH2:4][N:5]1[CH:14]=[CH:13][C:12](=[O:11])[NH:8][C:6]1=[S:7]
Reactant: COCCNC(N)=S
Reactant: CCOC(=O)CC(OCC)OCC
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COCCn1ccc(=O)[nH]c1=S
Temperature: 60 °C
Yield: 44.8 %

Procedure:
To a stirring solution of 1-(2-methoxyethyl)thiourea (21.38 g, 159.3 mmol) and ethyl 3,3-diethoxypropanoate (46.5 mL, 239.0 mmol) in MeOH (300 mL) was added a freshly prepared solution of 0.96N sodium methoxide in MeOH (250 mL, 239.0 mmol) dropwise over 30 minutes at room temperature under argon. The reaction mixture was heated to 60° C. for 45 minutes and cooled to room temperature. Solvent was removed under reduced pressure and toluene (250 mL) was added to the residue. The mixture was stirred at reflux for an additional 3 hours and then cooled to room temperature. Water (200 mL) was added and the layers were separated. The aqueous layer was washed with CH2Cl2 (50 mL), neutralized with 2N aqueous HCl and extracted with CH2Cl2 (3×200 mL). The combined organic layers were dried over Na2SO4 and concentrated in vacuo. The residue was recrystallized from i-PrOH (200 mL) to give the title compound (13.3 g, 45%) as a light yellow crystalline solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:24])=[C:6]([C:8]2[CH:17]=[C:16]3[C:11]([CH:12]=[C:13]([NH:18][C:19]([CH:21]4[CH2:23][CH2:22]4)=[O:20])[N:14]=[CH:15]3)=[CH:10][CH:9]=2)[CH:7]=1.N1C=CC=CC=1.[Br:31][CH:32]([C:34]1[CH:42]=[CH:41][C:37]([C:38](Cl)=[O:39])=[CH:36][CH:35]=1)[CH3:33]>ClCCl>[Br:31][CH:32]([C:34]1[CH:42]=[CH:41][C:37]([C:38]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([CH3:24])=[C:6]([C:8]3[CH:17]=[C:16]4[C:11]([CH:12]=[C:13]([NH:18][C:19]([CH:21]5[CH2:22][CH2:23]5)=[O:20])[N:14]=[CH:15]4)=[CH:10][CH:9]=3)[CH:7]=2)=[O:39])=[CH:36][CH:35]=1)[CH3:33]
Reactant: Cc1ccc(N)cc1-c1ccc2cc(NC(=O)C3CC3)ncc2c1
Reactant: CC(Br)c1ccc(C(=O)Cl)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1ccc(NC(=O)c2ccc(C(C)Br)cc2)cc1-c1ccc2cc(NC(=O)C3CC3)ncc2c1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of N-(7-(5-amino-2-methylphenyl)isoquinolin-3-yl)cyclopropanecarboxamide (51.8 mg, 0.163 mmol) and pyridine (0.05 mL, 0.6 mmol) in 2 mL dichloromethane was added a solution of the residue from Step 1 in 2 mL dichloromethane. The resulting mixture was stirred at room temperature for 1.5 hours, and then carried forward without purification.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]#[C:15][C:16]2[CH:17]=[C:18]3[C:23](=[CH:24][CH:25]=2)[N:22]=[CH:21][N:20]=[C:19]3Cl)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl.[CH3:28][O:29][C:30]1[CH:31]=[C:32]([CH:34]=[CH:35][C:36]=1[O:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[NH2:33].CCOC(C)=O>CC(O)(C)C.C(Cl)CCl.CO.Cl>[CH3:28][O:29][C:30]1[CH:31]=[C:32]([NH:33][C:19]2[C:18]3[C:23](=[CH:24][CH:25]=[C:16]([C:15]#[C:14][CH:11]4[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]4)[CH:17]=3)[N:22]=[CH:21][N:20]=2)[CH:34]=[CH:35][C:36]=1[O:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: CC(C)(C)OC(=O)N1CCC(C#Cc2ccc3ncnc(Cl)c3c2)CC1
Reactant: COc1cc(N)ccc1Oc1ccccc1
Agent: Cl
Solvent: ClCCCl
Solvent: CC(C)(C)O
Solvent: CO
Product: COc1cc(Nc2ncnc3ccc(C#CC4CCNCC4)cc23)ccc1Oc1ccccc1
Reaction time: 0.17 h
Yield: 76.7 %

Procedure:
A solution of 4-(4-chloro-quinazolin-6-ylethynyl)-piperidine-1-carboxylic acid tert-butyl ester (131 mg, 0.304 mmol) and 3-methoxy-4-phenoxyaniline hydrochloride (77 mg, 0.306 mmol) in tBuOH/ClCH2CH2Cl (1.0 /1.0 mL) was heated in a tightly capped reaction vial at 90° C. for 30 minutes. After cooling, the yellow mixture was diluted with MeOH and HCl gas was passed through the mixture for 10 minutes. After stirring for 2 hours, EtOAc was added to precipitate more solid which was collected by suction filtration, rinsed with EtOAc, and further dried to give 105 mg (66%) of yellow solid: 1H NMR (CD3OD) δ 1.93 -2.02 (m, 2H), 2.18 -2.24 (m, 2H), 3.12 -3.21 (m, 2H), 3.41 -3.47 (m, 2H), 3.81 (s, 3H), 6.87 (d, 2H), 7.02 (t, 1H), 7.06 (d, 1H), 7.27 (t, 2H), 7.33 (dd, 1H), 7.56 (d, 1H), 7.80 (d, 1H), 8.06 (d, 1H), 8.79 (s, 1H), 8.83 (s, 1H); MS m/z (MH+) 451.3.
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][N:10]3[CH:13]=[CH:14][N:15]=[C:9]3[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[I:16]I.C(=O)(O)[O-].[Na+]>C(O)(=O)C>[I:16][C:13]1[N:10]2[CH:11]=[CH:12][C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[CH:8][C:9]2=[N:15][CH:14]=1
Reactant: c1ccc(-c2ccn3ccnc3c2)cc1
Reactant: II
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: Ic1cnc2cc(-c3ccccc3)ccn12
Temperature: 70 °C
Reaction time: 24 h

Procedure:
A solution of 7-phenylimidazo[1,2-a]pyridine (1-4, 110 mg, 0.56 mmol, 1 equiv) and iodine (140 mg, 0.56 mmol, 1.0 equiv) in acetic acid (4 mL) was stirred at 23° C. for 18 h. More iodine (130 mg) was added and the mixture was stirred for 24 h at 70° C. A third portion of iodine (130 mg) was added and heating (70° C.) was continued for 2 h. The reaction mixture was basified with aqueous saturated sodium bicarbonate solution (100 mL), and the remaining iodine was quenched with addition of aqueous saturated sodium thiosulfate solution (10 mL). The mixture was extracted with EtOAc (100 mL), and the organic layer was washed with brine, dried over sodium sulfate, and then concentrated to give 3-iodo-7-phenylimidazo[1,2-a]pyridine (1-5) as a light-brown solid. 1H NMR (300 MHz, CDCl3) δ 8.18 (d, 1H, J=7.3 Hz), 7.82 (s, 1H), 7.73 (s, 1H), 7.67 (m, 2H), 7.50 (t, 2H, J=7.3 Hz), 7.42 (t, 1H, J=7.3 Hz), 7.23 (d, 1H, J=7.0 Hz).
Reaction SMILES: [O:1]=[C:2]1[CH2:10][C:9]2[C:4](=[CH:5][C:6]([C:11]([OH:13])=[O:12])=[CH:7][CH:8]=2)[NH:3]1.[O:14]=[C:15]1[C:20]2=[CH:21][NH:22][C:23]([CH:24]=O)=[C:19]2[CH2:18][CH2:17][O:16]1>>[O:1]=[C:2]1[C:10](=[CH:24][C:23]2[NH:22][CH:21]=[C:20]3[C:15](=[O:14])[O:16][CH2:17][CH2:18][C:19]=23)[C:9]2[C:4](=[CH:5][C:6]([C:11]([OH:13])=[O:12])=[CH:7][CH:8]=2)[NH:3]1
Reactant: O=C1Cc2ccc(C(=O)O)cc2N1
Reactant: O=Cc1[nH]cc2c1CCOC2=O
Product: O=C1Nc2cc(C(=O)O)ccc2C1=Cc1[nH]cc2c1CCOC2=O

Procedure:
2-Oxo-2,3-dihydro-1H-indole-6-carboxylic acid was condensed with 4-oxo-2,4,6,7-tetrahydro-pyrano[3,4-c]pyrrole-1-carbaldehyde to give the title compound.
Reaction SMILES: [C:1]1([CH:7]2[C:16]3[C:11]4=[C:12]([CH:22]([C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=5)[CH2:23][CH2:24][N:10]4[CH2:9][CH2:8]2)[CH:13]=[C:14]([C:17]([O:19]CC)=[O:18])[CH:15]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+]>CCO>[C:25]1([CH:22]2[C:12]3[C:11]4=[C:16]([CH:7]([C:1]5[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=5)[CH2:8][CH2:9][N:10]4[CH2:24][CH2:23]2)[CH:15]=[C:14]([C:17]([OH:19])=[O:18])[CH:13]=3)[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: CCOC(=O)c1cc2c3c(c1)C(c1ccccc1)CCN3CCC2c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1cc2c3c(c1)C(c1ccccc1)CCN3CCC2c1ccccc1

Procedure:
A solution of ethyl 1,7-diphenyl-1,2,3,5,6,7-hexahydropyrido[3,2,1-ij]quinoline-9-carboxylate (13), (4 g, 10 mmol), in EtOH (40 mL) was subjected to saponification reaction using 2N NaOH (40 mL). The residue was isolated in a typical aqueous workup and purified by MPLC (medium pressure liquid chromatography) using silica gel column with 30 to 40% EtOAc:Hexane to give 1,7-diphenyl-1,2,3,5,6,7-hexahydropyrido[3,2,1-ij]quinoline-9-carboxylic acid (14), (2 g 54%).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[C:5]([N+:10]([O-:12])=[O:11])[CH:4]=1.[NH:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[N:14]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[N:13]1[N:14]([CH2:2][C:3]2[CH:8]=[CH:7][C:6]([OH:9])=[C:5]([N+:10]([O-:12])=[O:11])[CH:4]=2)[CH:15]=[C:16]2[C:21]=1[CH:20]=[CH:19][CH:18]=[CH:17]2
Reactant: c1ccc2[nH]ncc2c1
Reactant: O=[N+]([O-])c1cc(CCl)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1cc(Cn2cc3ccccc3n2)ccc1O
Temperature: 23 °C
Reaction time: 18 h
Yield: 23.8 %

Procedure:
In a 100 mL round-bottomed flask was added 4-(chloromethyl)-2-nitrophenol (1.0 g, 5.33 mmol), 1H-indazole (0.630 g, 5.33 mmol), and potassium carbonate (0.884 g, 6.40 mmol) in DMF (26.7 mL). The mixture was stirred at 23° C. for 18 h. The reaction was diluted with water (100 mL) and the resulting solid was isolated by filtration, washed with water, and dried in vacuo. The crude solid was purified via ISCO flash chromatography (0-75% EtOAc in hexanes; 40 g column) to give the title compound as a yellow solid (341 mg, 24% yield): 1H NMR (DMSO-d6, 400 MHz): δ=8.50 (d, J=1.0 Hz, 1H), 7.82 (d, J=2.0 Hz, 1H), 7.68-7.72 (m, 1H), 7.56-7.61 (m, 1H), 7.48 (dd, J=8.6, 2.3 Hz, 1H), 7.10 (dd, J=8.5, 7.2 Hz, 2H), 7.00-7.06 (m, 1H), 5.62 ppm (s, 2H). ESI-MS: m/z 270.2 (M+H)+.
Reaction SMILES: [Si](OCC1SC(C(CN2[C:29](=[O:30])[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)C2=O)C(OC)=O)=CC=1)(C(C)(C)C)(C)C.[Li+].[OH-:33].O>C1COCC1.O>[C:29]([OH:30])(=[O:33])[C:28]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: [OH-]
Reactant: COC(=O)C(CN1C(=O)c2ccccc2C1=O)c1ccc(CO[Si](C)(C)C(C)(C)C)s1
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1ccccc1
Reaction time: 1.5 h

Procedure:
To methyl 2-(5-((tert-butyldimethylsilyloxy)methyl)thiophen-2-yl)-3-(1,3-dioxoisoindolin-2-yl)propanoate (E233) in THF/H2O was added LiOH*H2O, and the solution was stirred for 1.5 h or until complete conversion to product was visible by LC-MS. The solution was then poured into EtOAc/NH4Cl(sat)/1 N HCl (3:1) and the aqueous layer was further extracted with EtOAc. The organics were dried (Na2SO4), filtered, evaporated, and dried to give crude 2-(2-(5-(tert-butyldimethylsilyloxy)methyl)thiophen-2-yl)-2-carboxyethylcarbamoyl)benzoic acid (E234).