Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N1C2C(=CC=CC=2)C(C2CCC(=O)CC2)=C1.O1[C:21]2([CH2:26][CH2:25][CH:24]([C:27]3[C:35]4[C:30](=[CH:31][C:32]([F:36])=[CH:33][CH:34]=4)[NH:29][CH:28]=3)[CH2:23][CH2:22]2)[O:20]CC1>>[F:36][C:32]1[CH:31]=[C:30]2[C:35]([C:27]([CH:24]3[CH2:23][CH2:22][C:21](=[O:20])[CH2:26][CH2:25]3)=[CH:28][NH:29]2)=[CH:34][CH:33]=1
Reactant: Fc1ccc2c(C3CCC4(CC3)OCCO4)c[nH]c2c1
Agent: O=C1CCC(c2c[nH]c3ccccc23)CC1
Product: O=C1CCC(c2c[nH]c3cc(F)ccc23)CC1
Yield: 425.3 %

Procedure:
This compound was prepared in the manner described above for intermediate 3a by replacing 3-(1,4-dioxa-spiro[4,5]dec-8-yl)-1H-indole with 3-(1,4-dioxa-spiro[4,5]dec-8-yl)-6-fluoro-1H-indole (5.4 g) to afford 19.29 g (99%) of the title compound as a white solid: mp 102-105° C.
Reaction SMILES: [Br:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][C:7]2[S:8][C:9]([CH3:27])=[C:10]([CH3:26])[C:11]=2[C:12]([C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[C:16]([CH:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)[CH:15]=2)=[O:13])=[CH:4][CH:3]=1.[H-].[Na+].[CH3:32][N:33]1[CH:37]=[C:36]([S:38](Cl)(=[O:40])=[O:39])[CH:35]=[N:34]1>>[Br:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][C:7]2[S:8][C:9]([CH3:27])=[C:10]([CH3:26])[C:11]=2[C:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][S:38]([C:36]3[CH:35]=[N:34][N:33]([CH3:32])[CH:37]=3)(=[O:40])=[O:39])=[C:16]([CH:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)[CH:15]=2)=[O:13])=[CH:4][CH:3]=1
Reactant: Cn1cc(S(=O)(=O)Cl)cn1
Reactant: Cc1sc(Cc2ccc(Br)cc2)c(C(=O)c2ccc(O)c(C3CCCC3)c2)c1C
Agent: [H-]
Agent: [Na+]
Product: Cc1sc(Cc2ccc(Br)cc2)c(C(=O)c2ccc(OS(=O)(=O)c3cnn(C)c3)c(C3CCCC3)c2)c1C
Reaction time: 0.5 h
Yield: 54.6 %

Procedure:
At ambient temperature, to a stirred solution of [2-(4-bromobenzyl)-4,5-dimethyl-thiophen-3-yl]-(3-cyclopentyl-4-hydroxy-phenyl)-methanone (0.283 g, 0.603 mmol) in N,N-DMF (3.0 mL) was added 60% sodium hydride/mineral oil (24.1 mg, 0.603 mmol). After 0.5 h, to the reaction was added a solution of 1-methyl-1H-pyrazole-4-sulfonyl chloride (0.120 g, 0.664 mmol) in N,N-DMF (1.3 mL). After 3 h, the reaction was quenched with 1N NaOH (40 mL), extracted with CH2Cl2, dried (Na2SO4) and concentrated. Purification on Biotage KP-Sil eluting with 20% acetone/hexane gave 0.202 g (55%) of the title compound as a yellow solid, mp 55-60° C. (DMSO-d6) δ1.29-1.34 (m, 2H), 1.59-1.79 (m, 6H), 1.81 (s, 3H), 2.28 (s, 3H), 3.08 (quintet, 1H), 3.87 (s, 2H), 3.89 (s, 3H), 6.98 (d, 2H), 7.32 (d, 1H), 7.39 (d, 2H), 7.53-7.57 (m, 2H), 7.97 (s, 1H), 8.62 (s, 1H). IR (KBr) 3450, 2950, 1650, 1490, 1400, 1370 and 1170 cm−1. mass spectrum (+ESI) m/z 613/615 (M+H).
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([N:12]2[CH2:16][CH:15]([NH:17][CH3:18])[C:14]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=3)=[N:13]2)=[O:11])=[CH:5][CH:4]=1.[C:28](Cl)(=[O:32])[CH:29]([CH3:31])[CH3:30].N1C=CC=CC=1>C(OCC)(=O)C>[F:27][C:2]([F:1])([F:26])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([N:12]2[CH2:16][CH:15]([N:17]([CH3:18])[C:28](=[O:32])[CH:29]([CH3:31])[CH3:30])[C:14]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=3)=[N:13]2)=[O:11])=[CH:5][CH:4]=1
Reactant: CC(C)C(=O)Cl
Reactant: CNC1CN(C(=O)Nc2ccc(C(F)(F)F)cc2)N=C1c1ccc(Cl)cc1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CC(C)C(=O)N(C)C1CN(C(=O)Nc2ccc(C(F)(F)F)cc2)N=C1c1ccc(Cl)cc1
Reaction time: 8 h
Yield: 80.9 %

Procedure:
To 1.8 g (4.5 mmole) of N-(4-trifluoromethylphenyl)-3-(4-chlorophenyl)-4-(N-methylamino)-4,5-dihydro-1H-pyrazole-1-carboxamide (Example 116) in 10 ml of ethyl acetate cooled to 0° C. was added 0.5 g (4.7 mmole) of isobutyryl chloride and 0.4 g of pyridine. After stirring overnight the mixture was diluted with ethyl acetate, washed with water and brine and dried over anhydrous magnesium sulfate. Concentration in vacuo and trituration with diethyl ether gave 1.7 g of the title compound, a white solid, mp 180°-182° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][N:8]2[C:11](Br)=[CH:12][N:13]=[C:7]2[N:6]=1)=[O:4].CC1(C)C(C)(C)OB([C:23]2[CH:24]=[C:25]([C:29]3[C:30]([C:35]#[N:36])=[CH:31][CH:32]=[CH:33][CH:34]=3)[CH:26]=[CH:27][CH:28]=2)O1>>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][N:8]2[C:11]([C:27]3[CH:26]=[C:25]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=4[C:35]#[N:36])[CH:24]=[CH:23][CH:28]=3)=[CH:12][N:13]=[C:7]2[N:6]=1)=[O:4]
Reactant: COC(=O)c1ccn2c(Br)cnc2n1
Reactant: CC1(C)OB(c2cccc(-c3ccccc3C#N)c2)OC1(C)C
Product: COC(=O)c1ccn2c(-c3cccc(-c4ccccc4C#N)c3)cnc2n1

Procedure:
3-Bromoimidazo[1,2-a]pyrimidine-7-carboxylic acid methyl ester was coupled with 3′-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)biphenyl-2-carbonitrile as described in Example 1 to give 3-(2′-cyanobiphenyl-3-yl)-imidazo[1,2-a]pyrimidine-7-carboxylic acid methyl ester as a pale yellow powder: δH (400 MHz, CDCl3) 4.07 (3H, s), 7.50-7.54 (1H, m), 7.58-7.76 (6H, m), 7.81-7.84 (2H, m), 8.18 (1H, s), 9.10 (1H, d, J 7); m/z (ES+) 355 (M++H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:19]=[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:12]([OH:20])=[C:11]([I:21])[CH:10]=1.[C:22](OC(=O)C)(=[O:24])[CH3:23]>N1C=CC=CC=1>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:10]=[C:11]([I:21])[C:12]([O:20][C:22](=[O:24])[CH3:23])=[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:19]=1
Reactant: CCOC(=O)c1cc(-c2ccc(F)cc2F)cc(I)c1O
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CCOC(=O)c1cc(-c2ccc(F)cc2F)cc(I)c1OC(C)=O

Procedure:
A mixture of 500 mg (1.24 mmol) of ethyl 5-(2,4-difluorophenyl)-3-iodo-salicylate (Example 10) in 12 ml of pyridine and 3 ml of acetic anhydride was heated in a water bath for 20 min. The mixture was allowed to cool and poured over ice and the product was extracted with dichloromethane. After drying the organic phase and after evaporating the solvent at low pressure, the crude was recrystalized.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:27]2[CH:28]=[N:29][N:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=23)=[N:4][C:5]([NH:8][C:9]2[CH:14]=[C:13]([N+:15]([O-])=O)[C:12]([N:18]3[CH2:21][CH:20]([N:22]([CH3:24])[CH3:23])[CH2:19]3)=[CH:11][C:10]=2[O:25][CH3:26])=[N:6][CH:7]=1.[NH4+].[Cl-].O>C(O)C.[Fe]>[Cl:1][C:2]1[C:3]([C:27]2[CH:28]=[N:29][N:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=23)=[N:4][C:5]([NH:8][C:9]2[C:10]([O:25][CH3:26])=[CH:11][C:12]([N:18]3[CH2:21][CH:20]([N:22]([CH3:24])[CH3:23])[CH2:19]3)=[C:13]([NH2:15])[CH:14]=2)=[N:6][CH:7]=1
Reactant: COc1cc(N2CC(N(C)C)C2)c([N+](=O)[O-])cc1Nc1ncc(Cl)c(-c2cnn3ccccc23)n1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: COc1cc(N2CC(N(C)C)C2)c(N)cc1Nc1ncc(Cl)c(-c2cnn3ccccc23)n1
Yield: 93.6 %

Procedure:
A mixture of 5-chloro-N-[4-(3-dimethylaminoazetidin-1-yl)-2-methoxy-5-nitrophenyl]-4-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-2-amine (Intermediate 25, 265 mg, 0.54 mmol), iron (179 mg, 3.21 mmol) and NH4Cl (20.05 mg, 0.37 mmol) was heated at reflux in ethanol (6 mL) and water (2 mL) for 1 h. The crude product was purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 7M methanolic ammonia and appropriate fractions were concentrated in vacuo to give the title compound (235 mg, 94%) as a yellow solid which was used without further purification; 1H NMR: 2.13 (6H, s), 3.07 (1H, s), 3.50 (2H, t), 3.66 (3H, s), 4.00 (3H, t), 4.05 (2H, s), 6.28 (1H, s), 6.79 (1H, s), 7.10 (1H, t), 7.3-7.39 (1H, m), 8.33 (1H, s), 8.37 (1H, s), 8.80 (1H, d), 8.93 (1H, s); m/z: ES+ MH+ 465.25.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:33]=[CH:32][CH:31]=[CH:30][C:5]=1[CH2:6][NH:7][C@H:8]1[CH2:13][CH2:12][CH2:11][N:10]([CH2:14][CH2:15][CH2:16][CH2:17][NH:18]C2SC=CN=2)[C@H:9]1[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.BrC1SC=CN=1.[Cl:40][C:41]1[O:42][C:43]2[CH:49]=[CH:48][CH:47]=[CH:46][C:44]=2[N:45]=1>>[ClH:40].[O:42]1[C:43]2[CH:49]=[CH:48][CH:47]=[CH:46][C:44]=2[N:45]=[C:41]1[NH:18][CH2:17][CH2:16][CH2:15][CH2:14][N:10]1[CH2:11][CH2:12][CH2:13][C@H:8]([NH:7][CH2:6][C:5]2[CH:30]=[CH:31][CH:32]=[CH:33][C:4]=2[O:3][CH3:2])[C@@H:9]1[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: COc1ccccc1CN[C@H]1CCCN(CCCCNc2nccs2)[C@H]1c1ccccc1
Reactant: Clc1nc2ccccc2o1
Agent: Brc1nccs1
Agent: Cl
Product: COc1ccccc1CN[C@H]1CCCN(CCCCNc2nc3ccccc3o2)[C@H]1c1ccccc1

Procedure:
The title compound was prepared in a similar manner to the compound of Example 1 by replacing (2S, 3S)-3-(2-methoxybenzyl)amino-2-phenylpiperidine with the corresponding racemate and 2-bromothiazole with 2-chlorobenzoxazole; mp 158°-160° C. (dec.) 1H NMR (CDCl3) 67 1.58 (m, 5H), 1.90 (m, 1H), 2.04 (m, 4H), 2.20 (m, 1H), 2.56 (m, 1H), 2.71 (d, 1H, J=2), 3.25 (m, 1H), 3.38 (m, 5H), 3.57 (d, 1H, J=15), 3.96 (d, 1H, J=15), 6.60 (d, 1H, J=6), 6.76 (t, 1H, J=6), 6.96 (m, 2H), 7.12 (m, 3H), 7.28 (m, 6H). HRMS calc'd for C30H36N4O2 : 484.2838. Found: 484.2844.
Reaction SMILES: C1(S([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][C:17]3[S:25][C:24]4[C:23]([N:26]5[CH2:31][CH2:30][O:29][CH2:28][CH2:27]5)=[N:22][C:21](Cl)=[N:20][C:19]=4[CH:18]=3)[CH2:12][CH2:11]2)(=O)=O)C=CC=CC=1.[NH2:33][C:34]1[CH:39]=[CH:38][C:37](B2OC(C)(C)C(C)(C)O2)=[CH:36][N:35]=1>>[O:29]1[CH2:30][CH2:31][N:26]([C:23]2[C:24]3[S:25][C:17]([CH2:16][N:13]4[CH2:12][CH2:11][NH:10][CH2:15][CH2:14]4)=[CH:18][C:19]=3[N:20]=[C:21]([C:37]3[CH:38]=[CH:39][C:34]([NH2:33])=[N:35][CH:36]=3)[N:22]=2)[CH2:27][CH2:28]1
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Reactant: O=S(=O)(c1ccccc1)N1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Product: Nc1ccc(-c2nc(N3CCOCC3)c3sc(CN4CCNCC4)cc3n2)cn1

Procedure:
6-(4-Benzenesulfonyl-piperazin-1-ylmethyl)-2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine following General Procedure B-3 was reacted with 2-aminopyridine-5-boronic acid pinacol ester using General Procedure A. Purification on silica yielded 121. (400 MHz, CDCl3): 2.65-2.67 (4H, m, CH2), 3.13 (4H, m, CH2), 3.82 (2H, s, CH2), 3.85-3.88 (4H, m, CH2), 3.99-4.02 (4H, m, CH2), 4.63 (211, b, NH2), 6.57 (1H, dd (J=8.62, 0.62), ar), 7.27 (1H, s, ar), 7.58-7.60 (2H, m, ar), 7.63-7.67 (1H, m, ar), 7.80 (2H, d (J=7.07), ar), 8.46 (1H, dd (J=8.59-2.26), ar), 9.16 (1H, d (J=1.66), ar). (M+H)+ 552.34
Reaction SMILES: [CH3:1][CH:2]([CH3:17])[C:3]([C:5](=[CH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1)C(OC)=O)=[O:4].C(N(CC)CC)C.[F:25][C:26]1[CH:33]=[CH:32][C:29]([CH:30]=[O:31])=[CH:28][CH:27]=1.[OH-].[Na+]>[Cl-].C([N+]1C(C)=C(CCO)SC=1)C1C=CC=CC=1.C(OCC)(=O)C.O1CCCC1.O>[F:25][C:26]1[CH:33]=[CH:32][C:29]([C:30](=[O:31])[CH:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)[CH2:5][C:3](=[O:4])[CH:2]([CH3:1])[CH3:17])=[CH:28][CH:27]=1
Reactant: COC(=O)C(=Cc1ccccn1)C(=O)C(C)C
Reactant: O=Cc1ccc(F)cc1
Agent: Cc1c(CCO)sc[n+]1Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)C(=O)CC(C(=O)c1ccc(F)cc1)c1ccccn1
Temperature: 70 °C
Reaction time: 8 h
Yield: 36.4 %

Procedure:
To a solution of 15.4 g (66 mmol) of 2-(2-methyl-1-oxopropyl)-3-(2-pyridinyl)propenoic acid, methyl ester, 6.5 ml (46.2 mmol) of triethylamine and 8.2 g (66 mmol) of 4-fluorobenzaldehyde was added 15 mole percent of 3-benzyl-5-(2-hydroxyethyl)-4-methyl-1,3-thiazolium chloride (Aldrich Chemical Co., Milwaukee, WI, USA). The resulting mixture was heated at 70° C. for 3 hours, cooled, dissolved in ethyl acetate and washed successively with brine and water. The organic layer was separated, dried to yield the crude products an oil. The material was redissolved in 300 ml of tetrahydrofuran, and 150 ml of water and 6.6 g (165 mmol) of sodium hydroxide were added. This mixture was vigorously stirred overnight, concentrated, and the residue dissolved in a mixture of diethyl ether and ethyl acetate. The extract was washed with water and then extracted with 2M hydrochloric acid. The acid extract was made alkaline and extracted with diethyl ether. The ether extract was evaporated to yield 7.2 g (36%) of 1-(4-fluorophenyl)-5-methyl-2-(2-pyridinyl)hexane-1,4-dione.
Reaction SMILES: [NH2:1][C:2](=[N:21][N+:22]([O-:24])=[O:23])[NH:3][CH2:4][CH2:5][CH2:6][C@H:7]([C:9]([N:11]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1)[CH3:12])=[O:10])[NH2:8].[C:25]1([CH:31]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:32](Cl)=[O:33])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[NH2:1][C:2](=[N:21][N+:22]([O-:24])=[O:23])[NH:3][CH2:4][CH2:5][CH2:6][C@H:7]([C:9]([N:11]([CH2:13][C:14]1[CH:15]=[CH:16][C:17]([OH:20])=[CH:18][CH:19]=1)[CH3:12])=[O:10])[NH:8][C:32](=[O:33])[CH:31]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: CN(Cc1ccc(O)cc1)C(=O)[C@H](N)CCCNC(N)=N[N+](=O)[O-]
Reactant: O=C(Cl)C(c1ccccc1)c1ccccc1
Product: CN(Cc1ccc(O)cc1)C(=O)[C@@H](CCCNC(N)=N[N+](=O)[O-])NC(=O)C(c1ccccc1)c1ccccc1
Yield: 85 %

Procedure:
Prepared analogously to Example 69c) from (R)-N5 -[amino(nitroimino)methyl]-N-[(4-hydroxyphenyl)methyl]-N-methyl-ornithinamide and diphenylacetylchloride in a yield of 85% of theory.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([N:8]2[CH:12]=[CH:11][N:10]=[CH:9]2)=[CH:6][CH:7]=1.[NH:13]1[CH2:18][CH2:17][C:16]2([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[O:20][CH2:19]2)[CH2:15][CH2:14]1.C(N(CC)CC)C.O>CN(C)C=O>[N:8]1([C:5]2[N:4]=[N:3][C:2]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=5[O:20][CH2:19]4)[CH2:15][CH2:14]3)=[CH:7][CH:6]=2)[CH:12]=[CH:11][N:10]=[CH:9]1
Reactant: c1ccc2c(c1)OCC21CCNCC1
Reactant: Clc1ccc(-n2ccnc2)nn1
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: c1ccc2c(c1)OCC21CCN(c2ccc(-n3ccnc3)nn2)CC1
Temperature: 160 °C
Reaction time: 0.33 h
Yield: 73.7 %

Procedure:
3-Chloro-6-(1H-imidazol-1-yl)pyridazine (180 mg), spiro[1-benzofuran-3,4′-piperidine] (200 mg) and triethylamine (0.42 mL) were dissolved in N,N-dimethylformamide (1 mL), and the solution was stirred at 160° C. under irradiation of microwave for 20 min. Water (10 mL) was added, and the resulting precipitate was collected by filtration, and recrystallized from ethyl acetate-hexane to give the object product (245 mg, 74%).
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([CH:6]=[C:7]2[CH2:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:8]2=[O:16])=[CH:4][CH:3]=1.[Br:19]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:19][CH:15]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8](=[O:16])[C:7]1=[CH:6][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:18][CH:17]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: O=C1C(=Cc2ccc(Cl)cc2)Cc2ccccc21
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: O=C1C(=Cc2ccc(Cl)cc2)C(Br)c2ccccc21
Temperature: 25 °C

Procedure:
2-(4-chlorobenzylidene)indan-1-one (2.44 g, 9.58 mmol) was dissolved in 35 mL of CCl4. N-bromosuccinimide (1.685 g, 9.58 mmol) and benzoyl peroxide (122 mg, 0.52 mmol) were added in one portion. The solution was then stirred under reflux for one hour and then filtered once cooled to room temperature. The precipitate was separated using flash column chromatography (15:1 Hexanes/EtOAc) provided 14a as white crystals.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][O:8][C:9]2[CH:18]=[CH:17][CH:16]=[C:15]3[C:10]=2[C:11]([NH2:20])=[N:12][C:13]([NH2:19])=[N:14]3)[CH2:3][CH2:2]1.CN1CCOCC1.[F:28][C:29]1[CH:30]=[C:31]([CH:34]=[CH:35][C:36]=1[F:37])[CH2:32]Br.C(O)C(N)(CO)CO>CN(C)C=O>[F:28][C:29]1[CH:30]=[C:31]([CH:34]=[CH:35][C:36]=1[F:37])[CH2:32][N:1]1[CH2:6][CH2:5][CH:4]([CH2:7][O:8][C:9]2[CH:18]=[CH:17][CH:16]=[C:15]3[C:10]=2[C:11]([NH2:20])=[N:12][C:13]([NH2:19])=[N:14]3)[CH2:3][CH2:2]1
Reactant: Fc1ccc(CBr)cc1F
Reactant: Nc1nc(N)c2c(OCC3CCNCC3)cccc2n1
Agent: NC(CO)(CO)CO
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: Nc1nc(N)c2c(OCC3CCN(Cc4ccc(F)c(F)c4)CC3)cccc2n1
Reaction time: 2 h
Yield: 41.7 %

Procedure:
5-(Piperidin-4-ylmethoxy)quinazoline-2,4-diamine (50 mg; 0.18 mmol) was shaken for 60 hours at 60° C. in the presence of 3-(morpholino)propyl polystyrene sulfonamide (PS-NMM) (160 mg; 0.4 mmol) and 3,4-difluorobenzyl bromide (77 mg; 0.37 mmol) in 4 mL N,N-dimethylformamide. Tris-(2-aminoethyl)aminomethyl polystyrene (PS-Trisamine) (112 mg; 0.4 mmol) was then added to the mixture and continued to shake for an additional 2 hours. Resins were filtered off and rinsed with methanol. Filtrate was concentrated at reduced pressure, and residue was triturated with 2 mL 1 N NaOH and ethanol (1:1). Solids were collected by filtration to yield 5-[1-(3,4-difluorobenzyl)piperidin-4-ylmethoxy]quinazoline-2,4-diamine (30 mg; 42% yield). 1HNMR (400 MHz, DMSO-d6) δ 7.61 (m, 2H), 7.34 (m, 2H), 7.14 (m, 2H), 6.76 (m, 1H), 6.52 (m, 1H), 5.94 (br s, 2H), 3.99 (d, J=6.0 Hz, 2H), 3.46 (s, 3H), 3.12 (m, 1H), 2.82 (br d, J=10.8 Hz, 1H), 2.11 (m, 2H), 1.95 (m, 2H), 1.73 (br d, J=11.2 Hz, 1H), 1.34 (m, 1H). MS m/z (ESI) 400 (M+H)+.
Reaction SMILES: [C:1]([NH:4][C:5]1[C:6]([I:25])=[C:7]([C:16]([I:24])=[C:17]([NH:20][C:21](=[O:23])[CH3:22])[C:18]=1[I:19])[C:8]([NH:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14])=[O:9])(=[O:3])[CH3:2].[N+:26]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1O)([O-:28])=[O:27].C1(N=C=NC2CCCCC2)CCCCC1>>[N+:26]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[O:14][C:13](=[O:15])[CH2:12][CH2:11][NH:10][C:8](=[O:9])[C:7]1[C:6]([I:25])=[C:5]([NH:4][C:1](=[O:3])[CH3:2])[C:18]([I:19])=[C:17]([NH:20][C:21](=[O:23])[CH3:22])[C:16]=1[I:24])([O-:28])=[O:27]
Reactant: CC(=O)Nc1c(I)c(NC(C)=O)c(I)c(C(=O)NCCC(=O)O)c1I
Reactant: O=[N+]([O-])c1ccccc1O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Product: CC(=O)Nc1c(I)c(NC(C)=O)c(I)c(C(=O)NCCC(=O)Oc2ccccc2[N+](=O)[O-])c1I

Procedure:
Following the procedure of example 33 the product is synthesized from 13.7 g (20 mMol) N-(3,5-diacetamido-2,4,6-triiodobenzoyl)-β-alanine, 3.5 g (25 mMol)-o-nitrophenol and 5 g (24 mMol) N,N'-dicyclohexylcarbodiimide. Yield 11 g (68%).
Reaction SMILES: [Si:1]([O:8][C:9]1[C:10]([F:18])=[C:11]([CH:14]=[C:15]([F:17])[CH:16]=1)[CH:12]=[O:13])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH2:19]([Mg]Br)[CH3:20]>C1COCC1>[Si:1]([O:8][C:9]1[C:10]([F:18])=[C:11]([CH:12]([OH:13])[CH2:19][CH3:20])[CH:14]=[C:15]([F:17])[CH:16]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC[Mg]Br
Reactant: CC(C)(C)[Si](C)(C)Oc1cc(F)cc(C=O)c1F
Solvent: C1CCOC1
Product: CCC(O)c1cc(F)cc(O[Si](C)(C)C(C)(C)C)c1F
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 31 %

Procedure:
A 200 mL round bottom flask was charged with 90.B (1.38 g, 5.1 mmol) and THF (10 mL) and cooled to −78° C. under N2. To the cold solution was added ethylmagnesium bromide (3.0 M in ether) (commercially available from Aldrich) (5.1 mL, 15 mmol) dropwise. The mixture was stirred for 30 minutes at −78° C. The cooling bath was removed, and the mixture was stirred for 30 minutes at ambient temperature. The reaction was quenched with saturated aqueous ammonium chloride and diluted with EtOAc. The organic layers were washed with water and brine, dried (MgSO4), and concentrated. The crude product was purified by silica gel flash chromatography (0-15% EtOAc/hexane) to afford 90.C (0.48 g, 31% yield) as a colorless oil.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[C:5]([CH3:12])[CH:4]=1)#[N:2].N[C@H]1CC[CH2:17][CH2:16][C@@H:15]1[OH:20].C[Si]([N-][Si](C)(C)C)(C)C.[Na+].IC1COC1>C(O)(C)C.C(O)C.[Ni](I)I>[CH3:12][C:5]1[CH:4]=[C:3]([CH:8]=[CH:7][C:6]=1[CH:16]1[CH2:15][O:20][CH2:17]1)[C:1]#[N:2]
Reactant: Cc1cc(C#N)ccc1B(O)O
Reactant: N[C@H]1CCCC[C@@H]1O
Agent: I[Ni]I
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: IC1COC1
Solvent: CCO
Solvent: CC(C)O
Product: Cc1cc(C#N)ccc1C1COC1
Temperature: 90 °C
Yield: 1084.7 %

Procedure:
To (4-cyano-2-methyl-phenyl)boronic acid (1.75 g, 10.90 mmol), nickel iodide (0.10 g, 0.33 mmol), (1S,2S)-2-aminocyclohexan-1-ol (0.05 g, 0.33 mmol) and NaHMDS (2.01 g, 10.90 mmol) in isopropanol (10 mL) under an atmosphere of nitrogen was added 3-iodooxetane (1.00 g, 5.40 mmol) in isopropanol (1 mL) via cannula. The reaction mixture was heated at 90° C. for 2 hours, then cooled, diluted with ethanol (20 mL) and filtered over Celite®. The filtrate was concentrated in vacuo, then the residue was purified by silica gel column chromatography using 0-60% EtOAc/hexane as eluant to give 3-methyl-4-(oxetan-3-yl)benzonitrile (0.62 g, 65%) as a white solid. ESI-MS m/z calc. 173.1. Found 174.3 (M+1)+; Retention time: 1.09 minutes (3 min run).
Reaction SMILES: [CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13](Br)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18].[CH3:19][C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[C:24]([CH3:26])[CH:25]=1.C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1>ClCCl.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CO>[CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([C:22]4[CH:23]=[C:24]([CH3:26])[CH:25]=[C:20]([CH3:19])[CH:21]=4)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18]
Reactant: Cc1cc(C)cc(B(O)O)c1
Reactant: CN1C(=O)CC[C@]2(C)c3ccc(Br)cc3CC[C@@H]12
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Solvent: Cc1ccccc1
Product: Cc1cc(C)cc(-c2ccc3c(c2)CC[C@H]2N(C)C(=O)CC[C@]32C)c1
Yield: 85.8 %

Procedure:
A 15 mL round bottom flask was charged with (+)-(4aR)-(10bR)-4-methyl-8-bromo-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one (200 mg, 0.65 mmol), tetrakis(triphenylphosphine) palladium (0) (23 mg, 0.02 mmol), 3,5-dimethylphenylboronic acid (117 mg, 0.78 mmol), 0.65 mL of 2M sodium carbonate solution, 1.5 mL of toluene, and 1 mL of methanol, fitted with a reflux condenser, and the stirred mixture was heated at 80°, under nitrogen, for 24 h. The mixture was cooled, diluted with dichloromethane (75 mL) and washed with brine (2×25 mL). The combined organic extracts were dried over sodium sulfate, concentrated, and purified by silica gel chromatography (ethyl acetate eluent), to give 186 mg (86%) of the title compound as a white solid mp 129°-130°. FDMS: m/e=333. α[D]589 =+73.31 (c=1.00, chloroform).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.[F:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[C:21]([CH2:28][O:29][CH3:30])[N:20]=2)=[CH:15][CH:14]=1>>[F:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:27]=[CH:26][C:22]([C:23]([NH:1][C:2]3[CH:11]=[C:10]4[C:5]([CH:6]=[CH:7][CH:8]=[N:9]4)=[CH:4][CH:3]=3)=[O:24])=[C:21]([CH2:28][O:29][CH3:30])[N:20]=2)=[CH:15][CH:14]=1
Reactant: Nc1ccc2cccnc2c1
Reactant: COCc1nc(-c2ccc(F)cc2)ccc1C(=O)O
Product: COCc1nc(-c2ccc(F)cc2)ccc1C(=O)Nc1ccc2cccnc2c1

Procedure:
Using the procedure outlined in Example 56, the title compound was prepared from 7-aminoquinoline (D55) (11 mg, 0.076 mmol) and 6-(4-fluorophenyl)-2-(methoxymethyl)-nicotinic acid (D86) (19 mg, 0.073 mmol) as an orange solid. 1H NMR (250 MHz, CDCl3) δ (ppm): 10.40 (br.s, 1H), 8.92 (dd, 1H), 8.41 (d, 1H), 8.29 (d, 1H), 8.05-8.20 (m, 4H), 7.85 (m, 2H), 7.36 (dd, 1H), 7.20 (t, 2H), 4.91 (s, 2H), 3.68 (s, 3H).