Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][CH:3]=1.[NH2:9][C:10]1[CH:11]=[C:12](B(O)O)[CH:13]=[CH:14][CH:15]=1.C(=O)([O-])[O-].[Na+].[Na+].C(OCC)(=O)C>CN(C)C=O.O>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([C:14]2[CH:13]=[CH:12][CH:11]=[C:10]([NH2:9])[CH:15]=2)=[CH:3][CH:4]=1
Reactant: Brc1ccc(Br)cc1
Reactant: Nc1cccc(B(O)O)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Nc1cccc(-c2ccc(Br)cc2)c1
Temperature: 80 °C
Reaction time: 3 h
Yield: 56.4 %

Procedure:
1,4-Dibromobenzene (311 mg, 1.3 mmol) and 201 mg (1.3 mmol) of 3-aminophenylboronic acid were dissolved in 17 ml of N,N-dimethylformamide and 4.2 ml of water. Tetrakistriphenylphosphine palladium (154 mg, 0.13 mmol) and 211 mg (2.0 mmol) of sodium carbonate were added to the solution, and the mixture was stirred at 80° C. for 3 hr. Ethyl acetate (60 ml) and 8.5 ml of water were added to the reaction solution, and the mixture was filtered through Celite. The organic layer as the filtrate was washed five times with 30 ml of water. The organic layer was dried over anhydrous sodium sulfate and was filtered. The solvent was then removed by distillation. The residue was purified by column chromatography on silica gel (n-hexane:ethyl acetate=5:1) to give 182 mg (yield 57%) of the title compound.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[S:24](=[O:26])(=[O:25])[CH2:23][CH2:22][C:21]([C:27]([NH:29][C:30]4[CH:35]=[CH:34][C:33]([CH:36]([OH:43])[C:37]5[CH:42]=[CH:41][CH:40]=[CH:39][N:38]=5)=[CH:32][CH:31]=4)=[O:28])=[CH:20][C:19]=3[CH:44]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].ClC1C=CC=C(C(OO)=[O:53])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[S:24](=[O:26])(=[O:25])[CH2:23][CH2:22][C:21]([C:27]([NH:29][C:30]4[CH:31]=[CH:32][C:33]([CH:36]([OH:43])[C:37]5[CH:42]=[CH:41][CH:40]=[CH:39][N+:38]=5[O-:53])=[CH:34][CH:35]=4)=[O:28])=[CH:20][C:19]=3[CH:44]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(C(O)c4ccccn4)cc2)CCS3(=O)=O)cc1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(C(O)c4cccc[n+]4[O-])cc2)CCS3(=O)=O)cc1
Yield: 79.2 %

Procedure:
To a solution of 7-[4-(2-butoxyethoxy)phenyl]-N-[4-[hydroxy(2-pyridyl)methyl]phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (Compound 150) (230 mg) in dichloromethane (10 ml) was added at 0° C. 3-chloroperbenzoic acid (70%, 0.12 g), and the mixture was stirred at room temperature for 24 hours. To the reaction mixture was added sodium thiosulfate solution, and the mixture was stirred for a few minutes and extracted with ethyl acetate. The organic layer was washed with sodium bicarbonate solution and saturated brine, dried with magnesium sulfate and concentrated under reduced pressure, and the residue was purified with column chromatography (ethanol/ethyl acetate=1:9→1:4) to give colorless crystals of 7-[4-(2-butoxyethoxy)phenyl]-N-[4-[hydroxy(1-oxidopyridin-2-yl)methyl]phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (Compound 151) (187 mg).
Reaction SMILES: CC1(C)[O:9][C:8](=[O:10])[C:5]2([CH2:7][CH2:6]2)[C:4](=[O:11])O1.[F:13][C:14]1[CH:15]=[C:16]([CH:18]=[CH:19][C:20]=1[C:21]([F:24])([F:23])[F:22])[NH2:17]>C(O)C>[F:13][C:14]1[CH:15]=[C:16]([N:17]2[CH2:6][CH2:7][CH:5]([C:8]([OH:9])=[O:10])[C:4]2=[O:11])[CH:18]=[CH:19][C:20]=1[C:21]([F:23])([F:24])[F:22]
Reactant: CC1(C)OC(=O)C2(CC2)C(=O)O1
Reactant: Nc1ccc(C(F)(F)F)c(F)c1
Solvent: CCO
Product: O=C(O)C1CCN(c2ccc(C(F)(F)F)c(F)c2)C1=O
Yield: 34.8 %

Procedure:
This compound was prepared according to general method 1 starting from 6,6-dimethyl-5,7-dioxaspiro[2.5]octane-4,8-dione (0.250 g; 1.45 mmol) and 3-fluoro-4-(trifluoromethyl)aniline (0.806 g; 4.36 mmol) in ethanol (3 mL). 1-(3-fluoro-4-(trifluoromethyl)phenyl)-2-oxopyrrolidine-3-carboxylic acid 0.147 g (35%) was obtained as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][C:5]([C:6]([CH:8]([CH3:12])C(O)=O)=O)=[CH:4][CH:3]=1.[C:15]([O-:18])(=O)C.[Na+].Cl.[C:21]([NH:25][NH2:26])([CH3:24])([CH3:23])[CH3:22]>C(O)CCC>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]2[CH2:8][CH2:12][C:15](=[O:18])[N:25]([C:21]([CH3:24])([CH3:23])[CH3:22])[N:26]=2)=[CH:13][CH:14]=1
Reactant: CC(C(=O)O)C(=O)c1ccc(Cl)cc1
Reactant: CC(=O)[O-]
Reactant: CC(C)(C)NN
Agent: Cl
Agent: [Na+]
Solvent: CCCCO
Product: CC(C)(C)N1N=C(c2ccc(Cl)cc2)CCC1=O
Yield: 34.4 %

Procedure:
To a solution of 4-chlorobenzoylpropionic acid (4.24 g) in n-butanol (150 ml) was added anhydrous sodium acetate (1.54 g) and t-butylhydrazine hydrochloride (2.75 g) portionwise at room temperature. The resulting mixture was refluxed for 9 hours distilling off 65 ml of n-butanol during that time. The resulting mixture was cooled and poured into water (500 ml) and extracted with methylene chloride (3×150 ml). The combined organic layers were washed with 2% aqueous sodium hydroxide (3×100 ml), water (2×100 ml), 2% aqueous hydrochloric acid (3×100 ml), and water (1×100 ml), dried and evaporated under vacuum yielding 1.71 g of the expected product.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[C:21]3[C:22]4=[C:23]5[C:18](=[CH:19][CH:20]=3)[CH:17]=[CH:16][CH:15]=[C:14]5[CH:13]=[CH:12][C:11]4=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:24][C:25]1([CH3:59])[C:49]2[C:29]([CH:30]=[C:31]3[CH:48]=[C:47]4[C:34]([C:35]5[C:40]([C:41]6[C:46]4=[CH:45][CH:44]=[CH:43][CH:42]=6)=[CH:39][CH:38]=[CH:37][CH:36]=5)=[CH:33][C:32]3=2)=[CH:28][C:27](B2OC(C)(C)C(C)(C)O2)=[CH:26]1.C([O-])([O-])=O.[Na+].[Na+].CCO>CO.C1(C)C=CC=CC=1>[CH3:59][C:25]1([CH3:24])[C:49]2[C:29]([CH:30]=[C:31]3[C:32]=2[CH:33]=[C:34]2[C:47]([C:46]4[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=4[C:40]4[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=42)=[CH:48]3)=[CH:28][C:27]([C:6]2[CH:7]=[CH:2][CH:3]=[C:4]([C:8]3[C:21]4[C:22]5=[C:23]6[C:18](=[CH:19][CH:20]=4)[CH:17]=[CH:16][CH:15]=[C:14]6[CH:13]=[CH:12][C:11]5=[CH:10][CH:9]=3)[CH:5]=2)=[CH:26]1
Reactant: CC1(C)C=C(B2OC(C)(C)C(C)(C)O2)C=C2C=c3cc4c5ccccc5c5ccccc5c4cc3=C21
Reactant: Brc1cccc(-c2ccc3ccc4cccc5ccc2c3c45)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: Cc1ccccc1
Solvent: CCO
Product: CC1(C)C=C(c2cccc(-c3ccc4ccc5cccc6ccc3c4c56)c2)C=C2C=c3cc4c5ccccc5c5ccccc5c4cc3=C21
Temperature: 90 °C
Yield: 57 %

Procedure:
A mixture of 5 g (14 mmol) of 1-(3-bromophenyl)pyrene, 7.53 g (16 mmol) of 2-(10,10-dimethyl-10H-indeno[1,2-b]triphenylen-12-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane, 0.16 g (0.14 mmol) of tetrakis(triphenyl phosphine)palladium, 11 ml of 2M Na2CO3, 30 ml of EtOH and 65 ml toluene was degassed and placed under nitrogen, and then heated at 90° C. for 4 h. After finishing the reaction, the mixture was allowed to cool to room temperature. Than 500 ml MeOH was added, while stirring and the precipitated product was filtered off with suction to give 4.95 g (yield 57%) of yellow product which was recrystallized from toluene. MS(m/z, FAB+): 620.1; 1H NMR (CDCl3, 400 MHz): chemical shift (ppm) 9.05 (s, 1H), 8.46˜8.41 (m, 2H), 8.40 (s, 1H), 8.06˜7.84 (m, 9H), 7.74 (d, J=8.00 Hz, 1H), 7.69˜7.59 (m, 4H), 7.54˜7.39 (m, 5H), 7.31˜7.16 (m, 3H), 1.82 (s, 6H).
Reaction SMILES: [NH:1]1C=CN=[C:2]1[C:6]1[C:7]([O:24][CH3:25])=[CH:8][C:9]([CH:21]([CH3:23])[CH3:22])=[C:10]([CH:20]=1)[O:11][C:12]1[C:13]([NH2:19])=[N:14][C:15]([NH2:18])=[N:16][CH:17]=1.[OH-:26].[Na+]>C(O)C>[NH2:18][C:15]1[N:14]=[C:13]([NH2:19])[C:12]([O:11][C:10]2[C:9]([CH:21]([CH3:23])[CH3:22])=[CH:8][C:7]([O:24][CH3:25])=[C:6]([CH:20]=2)[C:2]([NH2:1])=[O:26])=[CH:17][N:16]=1
Reactant: COc1cc(C(C)C)c(Oc2cnc(N)nc2N)cc1-c1ncc[nH]1
Reactant: [OH-]
Agent: [Na+]
Solvent: CCO
Product: COc1cc(C(C)C)c(Oc2cnc(N)nc2N)cc1C(N)=O
Temperature: 110 °C

Procedure:
To 5-(2,4-diamino-pyrimidin-5-yloxy)-4-isopropyl-2-methoxy-benzonitrile (49 mg, 0.16 mmol, from Example 15) suspended in ethanol (1 mL) was added sodium hydroxide (64 mg, 1.60 mmol, dissolved in 1 mL water). The reaction was heated at 110° C. for 5 hours, cooled, and washed with dichloromethane (25 mL). The dichloromethane layer was concentrated and purified by preparatory TLC plates (92/8/0.5 dichloromethane/methanol/ammonium hydroxide) to yield 5-(2,4-diamino-pyrimidin-5-yloxy)-4-isopropyl-2-methoxy-benzamide as white solid (9 mg, 17%, MS (M+H)=318), which was converted to the hydrochloride salt.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([O:11][C:12]2[CH:13]=[C:14]3[C:18](=[C:19]([O:21][CH:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[CH:20]=2)[NH:17][C:16]([C:28]([O:30]CC)=[O:29])=[CH:15]3)=NC=1)(=[O:4])=[O:3].[OH-].[Na+].O1CC[CH2:37][CH2:36]1>C(O)C>[CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([O:11][C:12]2[CH:13]=[C:14]3[C:18](=[C:19]([O:21][CH:22]4[CH2:23][CH2:24][O:25][CH2:26][CH2:27]4)[CH:20]=2)[NH:17][C:16]([C:28]([OH:30])=[O:29])=[CH:15]3)=[CH:37][CH:36]=1)(=[O:3])=[O:4]
Reactant: CCOC(=O)c1cc2cc(Oc3ccc(S(C)(=O)=O)cn3)cc(OC3CCOCC3)c2[nH]1
Reactant: C1CCOC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CS(=O)(=O)c1ccc(Oc2cc(OC3CCOCC3)c3[nH]c(C(=O)O)cc3c2)cc1
Temperature: 60 °C
Reaction time: 0.67 h
Yield: 74 %

Procedure:
A mixture of ethyl 5-{[5-(methylsulfonyl)pyridin-2-yl]oxy}-7-(tetrahydro-2H-pyran-4-yloxy)-1H-indole-2-carboxylate (5.33 g), 1M aqueous sodium hydroxide solution (20 mL), tetrahydrofuran (20 mL), and ethanol (20 mL) was stirred at 60° C. for 40 min. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in water, and washed with ethyl acetate. To the aqueous layer was added 1M hydrochloric acid (30 mL), and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure to give the title compound (1.95 g, yield 74%) as an orange amorphous solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@:8]2([O:31][CH3:32])[O:13][C@H:12]([CH:14]=[O:15])[C@@H:11]([O:16][Si](C)(C)C)[C@H:10]([O:21][Si](C)(C)C)[C@H:9]2[O:26][Si](C)(C)C)=[CH:4][C:3]=1[CH2:33][O:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.C=O.C[CH2:44][O-:45].[Na+].S(=O)(=O)(O)[O-].[Na+]>CCO.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@:8]2([O:31][CH3:32])[C@H:9]([OH:26])[C@@H:10]([OH:21])[C@H:11]([OH:16])[C:12]([CH2:44][OH:45])([CH2:14][OH:15])[O:13]2)=[CH:4][C:3]=1[CH2:33][O:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: CC[O-]
Reactant: CO[C@@]1(c2ccc(Cl)c(COc3ccccc3)c2)O[C@H](C=O)[C@@H](O[Si](C)(C)C)[C@H](O[Si](C)(C)C)[C@H]1O[Si](C)(C)C
Agent: C=O
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CO[C@@]1(c2ccc(Cl)c(COc3ccccc3)c2)OC(CO)(CO)[C@@H](O)[C@H](O)[C@H]1O
Temperature: 55 °C

Procedure:
To a solution of (2S,3R,4S,5R,6S)-6-(4-chloro-3-(phenoxymethyl)phenyl)-6-methoxy-3,4,5-tris((trimethylsilyl)oxy)tetrahydro-2H-pyran-2-carbaldehyde (22.9 g, 36.7 mmol) in EtOH (92 mL) under nitrogen atmosphere, was added para-formaldehyde (33.0 g, 1.1 mol) at 55° C. followed by addition of 21% NaOEt in ethanol (23.12 g NaOEt/110 mL EtOH). The reaction mixture was heated at 55° C. overnight. After the completion of the reaction as confirmed by TLC, ethanol was evaporated. The crude compound was extracted with ethyl acetate (700 mL) followed by washing with sodium bisulphate solution (68.67 g, 660.6 mmol) in water (458.7 mL). The organic layer was separated, dried over Na2SO4 and concentrated in vacuo to afford crude compound, which was purified by column chromatography (silica gel, 6:4 MeOH:DCM) to obtain the compound as a white solid (12 g).
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[NH:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1.CC1C=CC(S(O)(=O)=O)=CC=1>C1CCCCC1>[N:15]1([C:11]2[CH2:10][CH2:9][N:8]([C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH2:13][CH:12]=2)[CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: C1CCNC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCCCC1
Product: CC(C)(C)OC(=O)N1CC=C(N2CCCC2)CC1
Temperature: 25 °C

Procedure:
A mixture of Boc-4-piperidone (5.5 g, 27.6 mmol), pyrrolidine (2.42 ml, 29 mmol) and PTSA (30 mg) in cyclohexane (30 mL) is refluxed overnight with a Dean-Stark trap to remove water. The mixture is cooled to rt and the solvent is removed in vacuo and the thick oil obtained is used in the next step without further purification.
Reaction SMILES: [CH3:1][O:2][CH:3]1[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.Cl[C:10]1[N:15]=[C:14]([O:16][CH3:17])[C:13]([N+:18]([O-:20])=[O:19])=[C:12]([O:21][CH3:22])[N:11]=1.C(N(C(C)C)CC)(C)C>C1COCC1.O>[CH3:17][O:16][C:14]1[C:13]([N+:18]([O-:20])=[O:19])=[C:12]([O:21][CH3:22])[N:11]=[C:10]([N:6]2[CH2:7][CH2:8][CH:3]([O:2][CH3:1])[CH2:4][CH2:5]2)[N:15]=1
Reactant: COc1nc(Cl)nc(OC)c1[N+](=O)[O-]
Reactant: COC1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: C1CCOC1
Product: COc1nc(N2CCC(OC)CC2)nc(OC)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.1 %

Procedure:
4-Methoxypiperidine (1.31 g, 11 mmol, 1 equiv) was added via syringe to a mixture of 2-chloro-4,6-dimethoxy-5-nitropyrimidine (2.5 g, 11 mmol) and diisopropylethylamine (5.97 mL, 34 mmol, 3 equiv) in THF (60 mL). The reaction mixture was stirred at RT for 1 h, and then additional 4-methoxypiperidine (0.6 g, 5 mmol, 0.47 equiv) was added via syringe. The mixture was stirred for another 1 h and then diluted with water and extracted with ethyl acetate (2×). The organic extracts were dried over sodium sulfate, filtered and concentrated. The crude material was purified using a Biotage Isolera One (SiO2, 80 g, 0-80% EtOAc in heptane gradient) to afford 2.99 g (88%) of 4,6-dimethoxy-2-(4-methoxypiperidin-1-yl)-5-nitropyrimidine as a yellow solid. 1H NMR (400 MHz, CDCl3) δ 4.14 (ddd, J=13.2, 7.5, 3.9 Hz, 2H) 3.99 (s, 6H) 3.63 (ddd, J=13.2, 8.5, 3.8 Hz, 2H) 3.51 (tt, J=7.4, 3.6 Hz, 1H) 3.40 (s, 3H) 1.86-1.96 (m, 2H) 1.61-1.70 (m, 2H). LCMS m/z=299.1 (M+1).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[OH:13])[C:6]([O:8][CH3:9])=[O:7])#[N:2].CI.[C:16]([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[C:1]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[O:13][CH3:16])[C:6]([O:8][CH3:9])=[O:7])#[N:2]
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1ccc(O)c(C#N)c1
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc(OC)c(C#N)c1
Temperature: 80 °C
Reaction time: 2 h
Yield: 51.4 %

Procedure:
To a stirred solution of methyl 3-cyano-4-hydroxybenzoate (2.0 g, 11.20 mmol) in DMF (20 mL) were added CH3I (2.40 g, 16.01 mmol) and K2CO3 (2.30 g, 16.01 mmol) at 0° C. under a N2 atmosphere. The reaction mixture was stirred at 80° C. for 2 h. After completion of starting material (monitored by TLC), reaction mixture was diluted with water and extracted with EtOAc (2×100 mL). The combined organic layers were washed with water (2×50 mL), brine and dried over anhydrous Na2SO4. After filtration and evaporation in vacuo, the crude material was purified by silica gel column chromatography to afford methyl 3-cyano-4-methoxybenzoate (1.1 g, 52%), as a pale yellow solid.
Reaction SMILES: [CH3:1][O:2][C@@H:3]([C@@H:33]([N:38]([CH3:46])[C:39](=[O:45])[C@H:40]([CH:42]([CH3:44])[CH3:43])[NH2:41])[C@@H:34]([CH3:37])[CH2:35][CH3:36])[CH2:4][C:5]([N:7]1[CH2:11][CH2:10][CH2:9][C@H:8]1[C@H:12]([O:31][CH3:32])[C@@H:13]([CH3:30])[C:14](=[O:29])[NH:15][C@H:16]([C:24]1[S:25][CH:26]=[CH:27][N:28]=1)[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:6].[C:47]([O:51][C:52]([N:54]1[CH2:58][CH2:57][C@:56]([F:62])([C:59](O)=[O:60])[CH2:55]1)=[O:53])([CH3:50])([CH3:49])[CH3:48].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>ClCCl>[F:62][C@:56]1([C:59](=[O:60])[NH:41][C@@H:40]([CH:42]([CH3:44])[CH3:43])[C:39]([N:38]([C@@H:33]([C@@H:34]([CH3:37])[CH2:35][CH3:36])[C@H:3]([O:2][CH3:1])[CH2:4][C:5]([N:7]2[CH2:11][CH2:10][CH2:9][C@H:8]2[C@H:12]([O:31][CH3:32])[C@@H:13]([CH3:30])[C:14](=[O:29])[NH:15][C@H:16]([C:24]2[S:25][CH:26]=[CH:27][N:28]=2)[CH2:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)=[O:6])[CH3:46])=[O:45])[CH2:57][CH2:58][N:54]([C:52]([O:51][C:47]([CH3:48])([CH3:49])[CH3:50])=[O:53])[CH2:55]1
Reactant: CC(C)(C)OC(=O)N1CC[C@](F)(C(=O)O)C1
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@@H](Cc1ccccc1)c1nccs1)OC)N(C)C(=O)[C@@H](N)C(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@@H](Cc1ccccc1)c1nccs1)OC)N(C)C(=O)[C@@H](NC(=O)[C@@]1(F)CCN(C(=O)OC(C)(C)C)C1)C(C)C
Yield: 40.5 %

Procedure:
According to the general procedure D, from #86 (300 mg, 0.45 mmol, 1 eq.), #168 (106 mg, 0.45 mmol, 1 eq.), dichloromethane (10 mL), HATU (194 mg, 0.54 mmol, 1.2 eq.) and diisopropylethylamine (117 mg, 0.9 mmol, 2 eq.) was synthesized the crude desired material, which was purified by reverse phase chromatography (Method P) to afford #191 (159 mg, 40%) as a white solid. HPLC (Protocol X): m/z 873.4 [M+H+], retention time=3.32 minutes (purity=99%).
Reaction SMILES: O.[NH2:2][NH2:3].Cl[C:5]1[C:10]([C:11]#[N:12])=[CH:9][C:8]([C:13]#[N:14])=[CH:7][N:6]=1.C(N(CC)CC)C>C(O)C>[C:13]([C:8]1[CH:9]=[C:10]2[C:5](=[N:6][CH:7]=1)[NH:3][N:2]=[C:11]2[NH2:12])#[N:14]
Reactant: NN
Reactant: N#Cc1cnc(Cl)c(C#N)c1
Solvent: CCN(CC)CC
Solvent: CCO
Solvent: O
Product: N#Cc1cnc2[nH]nc(N)c2c1
Temperature: 60 °C

Procedure:
Hydrazine hydrate (55%, 125 μL, 2.20 mmol) was added to a stirred suspension of 2-chloro-3,5-dicyanopyridine (240 mg, 1.47 mmol) and triethylamine (205 μL, 1.47 mmol) in ethanol (3 mL) and the resulting red mixture was heated to 60° C. After 16 h the mixture was cooled and filtered to give the title compound:
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:15]([NH2:20])=[N:16][CH:17]=[CH:18][CH:19]=2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:22][CH2:23][S:24](Cl)(=[O:26])=[O:25].O>CN(C)C(=O)C>[O:1]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:15]3=[N:20][S:24](=[O:26])(=[O:25])[CH2:23][CH2:22][N:16]3[CH:17]=[CH:18][CH:19]=2)=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=S(=O)(Cl)CCCl
Reactant: Nc1ncccc1-c1ccc(Oc2ccccc2)cc1
Solvent: O
Solvent: CC(=O)N(C)C
Product: O=S1(=O)CCN2C=CC=C(c3ccc(Oc4ccccc4)cc3)C2=N1
Temperature: 60 °C
Reaction time: 4 h
Yield: 85.7 %

Procedure:
A solution of 3-(4-phenoxyphenyl)pyridin-2-amine (301 mg) in N,N-dimethylacetoamide (3 mL) was added dropwise to 2-chloroethanesulfonyl chloride (382 mg) and additional N,N-dimethylacetoamide (2 mL) was used to complete the addition of above solution. After being stirred at 60° C. for 4 hr, the mixture was cooled to room temperature. Water (10 mL) was added dropwise to the reaction mixture and the whole was stirred at room temperature for 0.5 hr. The precipitate was collected by filtration, washed with water (10 mL) and THF (3 mL), and dried in vacuo at 60° C. to give the title compound (346.7 mg) as an off-white powder.
Reaction SMILES: C(O[C:4]([C:6]1[N:7]=[C:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[O:21][CH3:22])[N:9]([CH3:14])[C:10](=[O:13])[C:11]=1[OH:12])=[O:5])C.[Cl:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][C:31]=1[CH3:32])[CH2:27][NH2:28]>>[Cl:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][C:31]=1[CH3:32])[CH2:27][NH:28][C:4]([C:6]1[N:7]=[C:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[O:21][CH3:22])[N:9]([CH3:14])[C:10](=[O:13])[C:11]=1[OH:12])=[O:5]
Reactant: Cc1ccc(CN)cc1Cl
Reactant: CCOC(=O)c1nc(-c2ccccc2OC)n(C)c(=O)c1O
Product: COc1ccccc1-c1nc(C(=O)NCc2ccc(C)c(Cl)c2)c(O)c(=O)n1C

Procedure:
Prepared according to the procedure described for example 2 from 5-hydroxy-2-(2-methoxy-phenyl)-1-methyl-6-oxo-1,6-dihydro-pyrimidine-4-carboxylic acid ethyl ester (45.6 mg, 0.15 mmol) and 3-chloro-4-methylbenzylamine (107 mg, 0.75 mmol). The title product was obtained as a brown solid (57.5 mg, 93% yield). 1HNMR (500 MHz, CDCl3) δ: 12.04 (1H, br s), 7.90 (1H, t, J=5.49 Hz), 7.48 (1H, td, J=8.24, 1.83 Hz), 7.30–7.25 (2H, m), 7.17 (1H, d, J=7.94 Hz), 7.10–7.05 (2H, m), 6.98 (1H, d, J=8.55 Hz), 4.50 (2H, d, J 6.41 Hz), 3.82 (3H, s), 3.34 (3H, s), 2.34 (3H, s). HRMS (ESI) calcd for C21H21ClN3O4 (M+H): 414.1221; found: 414.1234.
Reaction SMILES: [CH3:1][C:2]1[C:11]([CH2:12]O)=[CH:10][C:9]2[C:4](=[CH:5][C:6]([CH3:15])=[CH:7][C:8]=2[CH3:14])[N:3]=1.P(Br)(Br)[Br:17]>C(Cl)Cl.C(OCC)(=O)C.C([O-])(O)=O.[Na+]>[Br:17][CH2:12][C:11]1[C:2]([CH3:1])=[N:3][C:4]2[C:9]([CH:10]=1)=[C:8]([CH3:14])[CH:7]=[C:6]([CH3:15])[CH:5]=2
Reactant: Cc1cc(C)c2cc(CO)c(C)nc2c1
Reactant: BrP(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Cc1cc(C)c2cc(CBr)c(C)nc2c1
Temperature: 23 °C
Reaction time: 8 h

Procedure:
To a solution of (2,5,7-trimethylquinolin-3-yl)methanol (42.1 mg, 0.205 mmol) in DCM (1.5 ml) was added PBr3 (0.039 ml, 0.410 mmol). Reaction mixture was stirred overnight at 23° C. Reaction mixture was diluted with ethyl acetate/NaHCO3 sat. aq solution. Layers were separated and aqueous layer was extracted once more with ethyl acetate. Organic layer was dried over sodium sulfate, filtered and evaporated to afford the title compound. HPLC (Method G) Rt=1.409 min, MS (Method V) [M+H]+=264.2, 266.2.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([C:7]([O:9][CH3:10])=[O:8])[NH:5][CH:6]=1.I[CH2:12][CH2:13][CH3:14]>>[CH2:12]([N:5]1[CH:6]=[C:2]([I:1])[CH:3]=[C:4]1[C:7]([O:9][CH3:10])=[O:8])[CH2:13][CH3:14]
Reactant: COC(=O)c1cc(I)c[nH]1
Reactant: CCCI
Product: CCCn1cc(I)cc1C(=O)OC
Yield: 64.7 %

Procedure:
Following the basic procedure of Example 7(d), by reacting 1.96 g (7.8 mmol) of methyl 4-iodo-2-pyrrolecarboxylate with 940 μl (9.6 mmol) of 3-iodopropane, 1.48 g (64%) of methyl N-propyl-4-iodo-2-pyrrolecarboxylate was obtained in the form of a slightly yellow oil.
Reaction SMILES: Br[CH2:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([Cl:12])[CH:7]=1)=[O:4].[CH3:13][O:14][C:15]1[CH:16]=[C:17]([CH2:23][NH2:24])[CH:18]=[CH:19][C:20]=1[O:21][CH3:22]>>[Cl:12][C:8]1[CH:7]=[C:6]([NH:5][C:3](=[O:4])[CH2:2][NH:24][CH2:23][C:17]2[CH:18]=[CH:19][C:20]([O:21][CH3:22])=[C:15]([O:14][CH3:13])[CH:16]=2)[CH:11]=[CH:10][CH:9]=1
Reactant: COc1ccc(CN)cc1OC
Reactant: O=C(CBr)Nc1cccc(Cl)c1
Product: COc1ccc(CNCC(=O)Nc2cccc(Cl)c2)cc1OC

Procedure:
In a manner similar to Preparation 11, react 2-bromo-N-(3-chlorophenyl)acetamide (4.4 g, 18 mmol) with 3,4-dimethoxybenzenemethanamine (8.7 g, 53 mmol) to obtain the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9](=[O:11])[CH3:10])[CH:5]=[CH:6][C:7]=1[OH:8].[N+:12]([O-])([O-:14])=[O:13].[K+]>S(=O)(=O)(O)O>[Cl:1][C:2]1[CH:3]=[C:4]([C:9](=[O:11])[CH3:10])[CH:5]=[C:6]([N+:12]([O-:14])=[O:13])[C:7]=1[OH:8]
Reactant: O=[N+]([O-])[O-]
Reactant: CC(=O)c1ccc(O)c(Cl)c1
Agent: O=S(=O)(O)O
Agent: [K+]
Product: CC(=O)c1cc(Cl)c(O)c([N+](=O)[O-])c1
Temperature: 0 °C
Reaction time: 0.88 h

Procedure:
A 500-milliliter flask was charged with 300 milliliters of concentrated sulfuric acid, chilled to 5° to 10° C. and at this temperature 17.1 grams of 3'-chloro-4'-hydroxyacetophenone was slowly added. To the stirred clear solution 20 grams of potassium nitrate was slowly added during a period of about 30-40 minutes while the temperature was maintained between 5° and 10° C. After stirring for an additional 45-60 minutes, the solution was stirred into 1,000 grams of ice. The resulting pale yellow solid was filtered and washed with water.
Reaction SMILES: [CH3:1][CH2:2][Mg+].[Br-].[CH3:5][C:6]1[CH:13]=[C:12]([S:14][CH3:15])[CH:11]=[CH:10][C:7]=1[C:8]#N.[OH:16]S(O)(=O)=O>C1(C)C=CC=CC=1>[CH3:5][C:6]1[CH:13]=[C:12]([S:14][CH3:15])[CH:11]=[CH:10][C:7]=1[C:8](=[O:16])[CH2:2][CH3:1]
Reactant: O=S(=O)(O)O
Reactant: CC[Mg+]
Reactant: CSc1ccc(C#N)c(C)c1
Agent: [Br-]
Solvent: Cc1ccccc1
Product: CCC(=O)c1ccc(SC)cc1C
Reaction time: 8 h

Procedure:
To a solution of EtMgBr (11.90 ml, 35.72 mmol) in toluene (40 ml) at 0° C. is added 2-Methyl-4-methylsulfanyl-benzonitrile (2.43 g, 14.89 mmol) in toluene dropwise over 30 mins. The reaction is then left to reach RT overnight with stirring. After this time, the contents are poured into ice, conc. H2SO4 (3 ml) is added and the contents are vigorously stirred for 4 hrs at RT. The misture is extracted into EtOAc, washed with H2O, brine, dried (MgSO4) and concentrated in vacuo to give a yellow solid; MS m/z=195.1 [M+H]+; H NMR 400.13 MHz (CDCl3) −7.09 (2H, m), 2.41 (2H, q), 2.52 (6H, s), 1.20 (3H, t).