Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.[Br:10][CH2:11][C:12](Br)=[O:13].C(N(CC)CC)C>C(OCC)(=O)C>[Br:10][CH2:11][C:12]([NH:7][CH2:6][C:5]1[CH:8]=[CH:9][C:2]([F:1])=[CH:3][CH:4]=1)=[O:13]
Reactant: O=C(Br)CBr
Reactant: NCc1ccc(F)cc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: O=C(CBr)NCc1ccc(F)cc1

Procedure:
Commercially available 4-fluorobenzylamine (500 mg, 3.99 mmol) was reacted with bromoacetyl bromide (380 μl, 4.39 mmol) in presence of triethylamine (600 μl, 4.39 mmol) at room temperature for 20 min. The progress of the reaction was monitored by a faster moving spot in silica TLC (60% ethyl acetate in hexanes). At the end of the reaction, the mixture was filtered, and the solvent was dried to obtain 2-bromo-N-[4-fluorobenzyl]acetamide. Potassium iodide (166 mg, 1 mmol) and Cs2CO3 (325 mg, 1 mmol) and 2-bromo-N-(4-fluorobenzyl)acetamide (270 mg, 1.20 mmol) were added to the compound 1 (311 mg, 1 mmol) in DMF (2 ml). The reaction mixture was heated at 95° C. for 60 min. The solvent was evaporated to dryness, and the residue was dissolved in chloroform. After brine and water wash, the organic phase was dried over anhydrous sodium sulfate, and concentrated to obtain a crude yellow solid. The crude compound was recrystallized from chloroform and hexanes to get the title compound 23 as a yellow crystalline solid (252 mg, 53% yield). 1H NMR (300 MHz, CDCl3): 7.93 (s, 1H), 7.83 (s, 2H, C═CH), 7.75-7.02 (m, 8H, Ar—H), 6.97 (dd, 2H, Ar—H, J=7.2, 2.1), 6.68 (t, 2H, Ar—H, J=7.2), 4.19 (s, 2H, benzylic), 4.17 (s, 2H, benzylic), 3.76 (s, 4H). ESI Mass calculated for C28H23F3N2NaO2(M+Na)+499.16. found 499.91.
Reaction SMILES: [CH:1]1([N:4]2[CH2:13][C:12]([CH3:15])([CH3:14])[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([C:16]#[CH:17])[CH:10]=3)[CH2:5]2)[CH2:3][CH2:2]1.[CH2:18]([O:20][C:21](=[O:31])[CH2:22][C:23]1[CH:28]=[CH:27][C:26](I)=[CH:25][C:24]=1[F:30])[CH3:19].C(N(CC)CC)C.C(OCC)(=O)C>CCCCCC.[Cu]I.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>[CH2:18]([O:20][C:21](=[O:31])[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([C:17]#[C:16][C:9]2[CH:10]=[C:11]3[C:6](=[CH:7][CH:8]=2)[CH2:5][N:4]([CH:1]2[CH2:3][CH2:2]2)[CH2:13][C:12]3([CH3:14])[CH3:15])=[CH:25][C:24]=1[F:30])[CH3:19]
Reactant: CCOC(=O)Cc1ccc(I)cc1F
Reactant: C#Cc1ccc2c(c1)C(C)(C)CN(C1CC1)C2
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CCOC(=O)Cc1ccc(C#Cc2ccc3c(c2)C(C)(C)CN(C2CC2)C3)cc1F
Yield: 47.4 %

Procedure:
Following general procedure F and using 2-cyclopropyl-6-ethynyl-4,4-dimethyl-1,2,3,4-tetrahydro-isoquinoline (Intermediate 27, 0.13 g, 0.571 mmol), 2-fluoro-4-iodo phenyl acetic acid ethyl ester (Reagent C, 0.16 g, 0.52 mmol), triethyl amine (0.8 mL), anhydrous tetrahydrofuiran (2 mL), copper(I)iodide (0.051 g, 0.27 mmol) and dichlorobis(triphenylphosphine)palladium(II) (0.1 g, 0.14 mmol) followed by flash column chromatography over silica gel (230-400 mesh) using 10% ethyl acetate in hexane as the eluent, 0.1 g of the title compound was obtained as an oil. It was further purified by preparative normal phase HPLC on a partisil-10 silica column using 10% ethyl acetate in hexane as the mobile phase (0.055 g, 24%).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].C[Si]([C:11]#[C:12][C:13]1[N:18]=[C:17]([NH:19][C:20](=[O:22])[CH3:21])[CH:16]=[CH:15][CH:14]=1)(C)C>CO>[C:12]([C:13]1[N:18]=[C:17]([NH:19][C:20](=[O:22])[CH3:21])[CH:16]=[CH:15][CH:14]=1)#[CH:11]
Reactant: CC(=O)Nc1cccc(C#C[Si](C)(C)C)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C#Cc1cccc(NC(C)=O)n1
Temperature: 25 °C
Yield: 60 %

Procedure:
Anhydrous potassium carbonate (110 mg, 0.8 mmoles) was added to a solution of N-(6-((trimethylsilyl)ethynyl)pyridine-2-yl)acetamide (1.86 g, 8 mmol) in 20 ml anhydrous methanol. The reaction mixture was stirred at room temperature for fifteen minutes then filtered. The filtrate was concentrated in vacuo. The crude product mixture was chromatographed on Silica Gel (230-400 Mesh) eluting with 2.5% MeOH/98% CH2Cl2 to yield A436.1 as an off-white solid. (770 mg, 60% yield). M+H+=218.20 1H NMR (400 MHz) MEOD δ 8.13 (m, 1H), 7.75 (m, 1H), 7.27 (m, 1H), 3.65 (s, 1H), 2.18 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:6][N:5]=[C:4]2[N:14]([CH2:23][C:24](O)=[O:25])[N:15]=[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:3]=12.ClC1C(C2C=CC=CC=2)=NN=C2N(CC(N3CCN(C)CC3)=O)N=C(C3C=CC=CC=3)C=12.[CH:59]([N:62]1[CH2:67][CH2:66][NH:65][CH2:64][CH2:63]1)([CH3:61])[CH3:60]>>[Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:6][N:5]=[C:4]2[N:14]([CH2:23][C:24]([N:65]3[CH2:66][CH2:67][N:62]([CH:59]([CH3:61])[CH3:60])[CH2:63][CH2:64]3)=[O:25])[N:15]=[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:3]=12
Reactant: CC(C)N1CCNCC1
Reactant: O=C(O)Cn1nc(-c2ccccc2)c2c(Cl)c(-c3ccccc3)nnc21
Agent: CN1CCN(C(=O)Cn2nc(-c3ccccc3)c3c(Cl)c(-c4ccccc4)nnc32)CC1
Product: CC(C)N1CCN(C(=O)Cn2nc(-c3ccccc3)c3c(Cl)c(-c4ccccc4)nnc32)CC1

Procedure:
Compound 38 was synthesised from 2-(4-chloro-3,5-diphenyl-1H-pyrazolo[3,4-c]pyridazin-1-yl)acetic acid following a similar procedure outlined in Example 17 (Compound 1), using N-isopropylpiperazine instead of N-methylpiperazine in the final step.
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[CH2:28]([O:30][CH:31]([C:45]([O:47]CC)=O)[NH:32][C:33](=[O:44])[C:34]1[C:35](=[C:39]([F:43])[CH:40]=[CH:41][CH:42]=1)[C:36]([OH:38])=O)[CH3:29].C(OC(C(OCC)=O)NC(=O)C1C(=CC=CC=1F)C(O)=O)C.[NH2:72][CH2:73][C:74]1[CH:81]=[CH:80][C:77]([C:78]#[N:79])=[CH:76][C:75]=1[N+:82]([O-:84])=[O:83]>>[C:78]([C:77]1[CH:80]=[CH:81][C:74]([CH2:73][NH:72][C:45](=[O:47])[CH:31]([O:30][CH2:28][CH3:29])[N:32]2[C:36](=[O:38])[C:35]3[C:34](=[CH:42][CH:41]=[CH:40][C:39]=3[F:43])[C:33]2=[O:44])=[C:75]([N+:82]([O-:84])=[O:83])[CH:76]=1)#[N:79]
Reactant: N#Cc1ccc(CN)c([N+](=O)[O-])c1
Reactant: CCOC(=O)C(NC(=O)c1cccc(F)c1C(=O)O)OCC
Agent: CCOC(=O)C(NC(=O)c1c(F)cccc1C(=O)O)OCC
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Product: CCOC(C(=O)NCc1ccc(C#N)cc1[N+](=O)[O-])N1C(=O)c2cccc(F)c2C1=O

Procedure:
According to general procedure C, but using 2.2 eq. of BOP coupling reagent and adding the amine component after a delay time of 1 h, (RS)-N-(ethoxy-ethoxycarbonyl-methyl)-6-fluoro-phthalamic acid and its regioisomer (RS)-N-(ethoxy-ethoxycarbonyl-methyl)-3-fluoro-phthalamic acid (example 35.2) was reacted with 4-aminomethyl-3-nitrobenzonitrile (CAS 701269-65-0) to give (RS)-N-(4-cyano-2-nitro-benzyl)-2-ethoxy-2-(4-fluoro-1,3-dioxo-1,3-dihydro-isoindol-2-yl)-acetamide as yellow viscous oil which was further processed as follows, MS 427.3 ([M+H]+).
Reaction SMILES: C[Li].Br[C:4]1[C:9]([CH3:10])=[CH:8][C:7]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:6][C:5]=1[CH3:19].[Li]C(C)(C)C.[F:25][C:26]1[CH:42]=[CH:41][C:29]([CH2:30][C:31]2[CH:32]=[C:33]([CH:36]=[CH:37][C:38]=2[O:39][CH3:40])[CH:34]=[O:35])=[CH:28][CH:27]=1.[NH4+].[Cl-]>C(OCC)C.C1COCC1>[F:25][C:26]1[CH:42]=[CH:41][C:29]([CH2:30][C:31]2[CH:32]=[C:33]([CH:34]([OH:35])[C:4]3[C:9]([CH3:10])=[CH:8][C:7]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:6][C:5]=3[CH3:19])[CH:36]=[CH:37][C:38]=2[O:39][CH3:40])=[CH:28][CH:27]=1
Reactant: Cc1cc(NC(=O)OC(C)(C)C)cc(C)c1Br
Reactant: COc1ccc(C=O)cc1Cc1ccc(F)cc1
Agent: [Cl-]
Agent: [Li]C
Agent: [Li]C(C)(C)C
Solvent: CCOCC
Solvent: C1CCOC1
Product: COc1ccc(C(O)c2c(C)cc(NC(=O)OC(C)(C)C)cc2C)cc1Cc1ccc(F)cc1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 46 %

Procedure:
1.3 ml of methyllithium (2.1 mmol, 1.6 M in diethyl ether) are introduced into 1 ml of diethyl ether and, at −78° C., 600 mg (1.99 mmol) of tert-butyl 4-bromo-3,5-dimethylphenylcarbamate (Example IV) in 2 ml of diethyl ether/1 ml of THF are added. After 20 min, 1.53 ml of t-BuLi (2.6 mmol, 1.7 M in pentane) are added dropwise and the mixture is stirred at −78° C. for 30 min. 3-(4-Fluorobenzyl)-4-methoxybenzaldehyde dissolved in 3 ml of THF is added dropwise. After stirring at −78° C. for 1 h, aqueous NH4Cl solution is added. The mixture is diluted with diethyl ether and extracted with water, and the organic phase is dried and concentrated in a rotary evaporator. Chromatography (cyclohexane/ethyl acetate=6:1) affords 493 mg (46%) of tert-butyl 4-[[3-(4-fluorobenzyl)-4-methoxyphenyl](hydroxy)methyl]-3,5-dimethylphenylcarbamate.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:14]2[CH2:18][C@H:17]([C:19]([NH:21][O:22]CC3C=CC=CC=3)=[O:20])[O:16][C:15]2=[O:30])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1>CO.[Pd]>[F:1][C:2]1[CH:3]=[C:4]([N:14]2[CH2:18][C@H:17]([C:19]([NH:21][OH:22])=[O:20])[O:16][C:15]2=[O:30])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1
Reactant: O=C(NOCc1ccccc1)[C@H]1CN(c2ccc(N3CCOCC3)c(F)c2)C(=O)O1
Agent: [Pd]
Solvent: CO
Product: O=C(NO)[C@H]1CN(c2ccc(N3CCOCC3)c(F)c2)C(=O)O1
Reaction time: 1 h

Procedure:
To a mixture of (5R)-(−)-3-[3-fluoro-4-(4-morpholinyl)phenyl]-N-benzyloxy-2-oxo-5-oxazolidinecarboxamide (Step 1, 300 mg, 0.722 mmol) in methanol (28.8 mL) is added 5% palladium-on-carbon (77 mg) under nitrogen. The resulting mixture is degassed and stirred under a hydrogen atmosphere (balloon) for 1 h. The catalyst is then removed by filtration through Celite, rinsing with methanol (60 mL), and the filtrate is concentrated under reduced pressure. Trituration of this residue with (5% methanol/methylene chloride)/diethyl ether gives the title compound, mp 141-143° C.; MS (ESI+) for C14H16FN3O5 m/z 326 (M+H)+; [α]25D=−70° (c 0.99, DMSO).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][C@@H:3]([NH:6][C:7]2[C:12]([C:13]3[N:14]=[C:15]4[CH:21]=[CH:20][N:19]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:16]4=[N:17][CH:18]=3)=[CH:11][CH:10]=[CH:9][N:8]=2)[CH2:2]1.[CH3:30][O:31][C:32](Cl)=[O:33].CCN(C(C)C)C(C)C>>[CH3:30][O:31][C:32]([N:1]1[CH2:5][CH2:4][C@@H:3]([NH:6][C:7]2[C:12]([C:13]3[N:14]=[C:15]4[CH:21]=[CH:20][N:19]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:16]4=[N:17][CH:18]=3)=[CH:11][CH:10]=[CH:9][N:8]=2)[CH2:2]1)=[O:33]
Reactant: COC(=O)Cl
Reactant: C[Si](C)(C)CCOCn1ccc2nc(-c3cccnc3N[C@@H]3CCNC3)cnc21
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)N1CC[C@@H](Nc2ncccc2-c2cnc3c(ccn3COCC[Si](C)(C)C)n2)C1

Procedure:
(R)-3-{3-[5-(2-Trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-pyridin-2-ylamino}-pyrrolidine-1-carboxylic acid methyl ester was prepared from (R)-pyrrolidin-3-yl-{3-[5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-pyridin-2-yl}-amine and methylchloroformate using DIPEA as base and following the general synthetic procedures described in the above Examples.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([S:6][CH2:7][CH2:8][C:9]([O:11]CC)=[O:10])=[CH:2]1.[OH-].[K+]>C(O)C.O>[O:1]1[CH:5]=[CH:4][C:3]([S:6][CH2:7][CH2:8][C:9]([OH:11])=[O:10])=[CH:2]1
Reactant: CCOC(=O)CCSc1ccoc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)CCSc1ccoc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 33.5 %

Procedure:
A mixture of ethyl 3-(3-furylthio)propionate (0.52 g, 0.0026 mole) and potassium hydroxide (0.29 g, 0.0052 m) in ethanol (25 ml) and water (1.0 ml) was stirred at ambient temperature for 4 hours. The mixture was concentrated in vacuo below 40° C., water (20 ml) was added to the residue and the solution extracted with methylene chloride (20 ml). The aqueous layer was acidified with 3NHCl, extracted with methylene chloride (3×25 ml) and the combined extracts washed twice with water. After drying over sodium sulfate, the solvent was evaporated in vacuo to give 0.15 g (33%) of oily product.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:8]([OH:10])=[O:9])=[N:4][CH:5]=[CH:6][N:7]=1.[CH3:11]O>S(=O)(=O)(O)O>[CH3:1][C:2]1[C:3]([C:8]([O:10][CH3:11])=[O:9])=[N:4][CH:5]=[CH:6][N:7]=1
Reactant: Cc1nccnc1C(=O)O
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1nccnc1C
Yield: 83 %

Procedure:
A solution of 3-methylpyrazine-2-carboxylic acid (10 g, 72.4 mmol) in 80 mL methanol and sulfuric acid, 95% (5 ml, 90 mmol) was heated to 60° C. for 4 h. The solution was concentrated to remove MeOH, the residue was dissolved in 50 mL of water and neutralized with 10% aq Na2CO3 solution to pH 12. The resulting solution was extracted with ethyl acetate. The combined organics were dried and concentrated to give crude methyl 3-methylpyrazine-2-carboxylate (9.1 g, 83% yield) which was used for next step without further purification.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:8]=1[CH3:9])[CH3:2].[Cl:10][C:11]1[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=1[CH2:13][CH2:14]Br>>[Cl:10][C:11]1[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=1[CH2:13][CH2:14][CH2:9][C:8]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[CH2:1][CH3:2]
Reactant: CCc1cnccc1C
Reactant: Clc1ccccc1CCBr
Product: CCc1cnccc1CCCc1ccccc1Cl
Yield: 42.8 %

Procedure:
1.13 g (9.35 mmol) of 3-ethyl-4-methylpyridine and 2.05 g (9.35 mmol) of 2-chlorophenethyl bromide were reacted in the same manner as in Example 1. The reaction product was purified to obtain 1.04 g of the desired compound (yield: 42.8%).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[CH:8]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:7][CH2:6]2.Br>O>[OH:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[CH:8]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:7][CH2:6]2
Reactant: COc1ccc2c(c1)CCC(c1ccccc1)C2=O
Agent: Br
Solvent: O
Product: O=C1c2ccc(O)cc2CCC1c1ccccc1

Procedure:
6-Methoxy-2-phenyl-3,4-dihydro-2H-naphthalen-1-one (1.0 g) was refluxed with 47% HBr (20 ml) until disappearance of the starting material. The mixture was poured into water and extracted with ethyl acetate. Ethyl acetate was dried and evaporated. The product was recrystallised from toluene. 1H NMR (400 MHz, d6-DMSO) δ: 10.35 (s, 1H), 7.79 (d, 1H, J 8.6 Hz), 7.15-7.33 (m, 5H), 6.75 (dd, 1H, J 8.6, 2.4 Hz), 6.68 (d, 1H, J 2.3 Hz), 3.79-3.85 (m, 1H), 2.99-3.06 (m, 1H), 2.83-2.90 (m, 1H), 2.19-2.33 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:14]=[C:13]([N+:15]([O-])=O)[CH:12]=[CH:11][C:4]=1[O:5][CH2:6][C:7]([CH3:10])([OH:9])[CH3:8]>[Pd].CCO>[NH2:15][C:13]1[CH:12]=[CH:11][C:4]([O:5][CH2:6][C:7]([CH3:10])([OH:9])[CH3:8])=[C:3]([O:2][CH3:1])[CH:14]=1
Reactant: COc1cc([N+](=O)[O-])ccc1OCC(C)(C)O
Agent: [Pd]
Solvent: CCO
Product: COc1cc(N)ccc1OCC(C)(C)O
Reaction time: 6 h

Procedure:
A stirred EtOH suspension (320 mL) containing 1-(2-methoxy-4-nitrophenoxy)-2-methylpropan-2-ol Part A (13.6 g, 56.4 mmol) and 10% Pd/C (0.25 g) was hydrogenated under 60 psi H2 for 6 hr. HPLC analysis revealed no starting nitro catechol ether remained. The resultant black suspension was filtered through a fiberglass filter paper under a blanket of N2 gas. The resultant clear wine colored solution was immediately concentrated using a rotary evaporator under vacuum to yield 12.4 of desired product as a dark orange oil which was used without further purification. 1H NMR (CDCl3) δ 1.29 (s, 6H), 3.40, (br s, 2H), 3.74 (s, 2H), 3.78 (s, 3H), 6.20 (dd, J=8.35 Hz, 2.64 Hz, 1H), 6.28 (d, J=2.64 Hz, 1H), 6.76 (d, J=8.35 Hz, 1H); 13C NMR (CDCl3) δ 25.90, 55.67, 70.02, 80.30, 100.76, 106.81, 118.27, 141.55, 141.93, 150.99; HPLC (Method #1): 0.88 min retention time; LCMS (ES): m/z 212.1 [M+H].
Reaction SMILES: [OH:1][CH2:2][C@@H:3]([NH:10][C:11]([C:13]1[NH:14][CH:15]=[C:16]([C:18]2[C:23]([CH3:24])=[CH:22][N:21]=[C:20](S(CCC)(=O)=O)[N:19]=2)[CH:17]=1)=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH2:31]([NH2:33])[CH3:32]>CS(C)=O>[OH:1][CH2:2][C@@H:3]([NH:10][C:11]([C:13]1[NH:14][CH:15]=[C:16]([C:18]2[C:23]([CH3:24])=[CH:22][N:21]=[C:20]([NH:33][CH2:31][CH3:32])[N:19]=2)[CH:17]=1)=[O:12])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CCN
Reactant: CCCS(=O)(=O)c1ncc(C)c(-c2c[nH]c(C(=O)N[C@H](CO)c3ccccc3)c2)n1
Solvent: CS(C)=O
Product: CCNc1ncc(C)c(-c2c[nH]c(C(=O)N[C@H](CO)c3ccccc3)c2)n1
Temperature: 130 °C

Procedure:
To a solution of 4-[5-methyl-2-(propane-1-sulfonyl)-pyrimidin-4-yl]-1H-pyrrole-2-carboxylic acid (2-hydroxy-1-(S)-phenyl-ethyl)-amide (47 μmol, 20 mg) in DMSO (1 mL) was added ethylamine (0.5 mmol, 150 μL). The mixture was heated at 130° C. for 24 hours to afford the title compound. LC/MS(m/z) 366.2 (M+1); HPLC Method B, Rt=4.2 minutes; 1H NMR consistent with the structure.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([NH:9][CH3:10])[N:3]=1.[CH:11]1([NH:17][C:18]([C@H:20]2[O:25][CH2:24][C@@H:23]([CH2:26][CH3:27])[NH:22][CH2:21]2)=[O:19])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1.CCN(C(C)C)C(C)C>CC#N.O>[Cl:8][C:6]1[N:5]=[C:4]([NH:9][CH3:10])[N:3]=[C:2]([N:22]2[C@H:23]([CH2:26][CH3:27])[CH2:24][O:25][C@H:20]([C:18]([NH:17][CH:11]3[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]3)=[O:19])[CH2:21]2)[CH:7]=1
Reactant: CC[C@@H]1CO[C@H](C(=O)NC2CCCCC2)CN1
Reactant: CNc1nc(Cl)cc(Cl)n1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CC[C@@H]1CO[C@H](C(=O)NC2CCCCC2)CN1c1cc(Cl)nc(NC)n1
Temperature: 100 °C
Yield: 100 %

Procedure:
4,6-Dichloro-N-methyl-2-pyrimidinamine (0.141 g, 0.791 mmol) was added to a 20 mL microwave vial followed by the addition of (2S,5R)—N-cyclohexyl-5-ethyl-2-morpholinecarboxamide (0.190 g, 0.791 mmol) in CH3CN (5 mL) and Hunig's base (0.690 mL, 3.95 mmol). The reaction was irradiated at 150° C. for 10 minutes. The reaction was left in the 20 mL sealed microwave vessel and heated to 100° C. over the weekend. The reaction mixture was diluted with water and extracted with EtOAc (2×). The organic layers were combined and dried to afford the title compound (0.302 g). LC-MS (ES) m/z=382 [M+H]+.
Reaction SMILES: [CH3:1][S:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]1[CH:15]=[CH:14][C:13](=[O:16])[C:12]([C:17]2[N:21]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[N:20]=[CH:19][CH:18]=2)=[N:11]1)=[O:3].[OH:28]O>C(O)(=O)C>[CH3:1][S:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]1[CH:15]=[CH:14][C:13](=[O:16])[C:12]([C:17]2[N:21]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[N:20]=[CH:19][CH:18]=2)=[N:11]1)(=[O:28])=[O:3]
Reactant: OO
Reactant: CS(=O)c1ccccc1-n1ccc(=O)c(-c2ccnn2-c2ccccc2)n1
Solvent: CC(=O)O
Product: CS(=O)(=O)c1ccccc1-n1ccc(=O)c(-c2ccnn2-c2ccccc2)n1
Temperature: 40 °C
Reaction time: 18 h
Yield: 6.4 %

Procedure:
To a solution of 1-[2-(methylsulfinyl)phenyl]-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-4(1H)-one (60% purity, 300 mg, 0.80 mmol) in 20 mL of acetic acid was added 30% H2O2 aqueous solution (362 mg, 3.19 mmol), and the mixture was stirred at 40° C. for 18 h. The solvents were removed under reduced pressure, water was added, extracted with AcOEt, washed with water, Na2CO3 aqueous solution and brine, dried over Na2SO4, and then concentrated. The residue was purified by prep.—HPLC to give the title compound (20 mg, 6% yield) as a red solid: 1H NMR (400 MHz, CDCl3): δ 2.89 (3H, s), 6.60 (1H, d, J=8.0 Hz), 6.96 (1H, d, J=2.0 Hz), 7.24-7.35 (4H, m), 7.41-7.43 (2H, m), 7.70-7.77 (3H, m), 7.92 (1H, d, J=8.0 Hz), 8.16-8.18 (1H, m); LCMS (mobile phase: from 90% water and 10% CH3CN to 5% water and 95% CH3CN in 6 min, finally under these conditions for 0.5 min.) purity is >90%, Rt=3.073 min; MS Calcd.: 392; MS Found: 393 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[CH:6][CH:7]=1.Cl[C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[C:17]([F:22])[CH:18]=2)[N:13]=1.C(=O)([O-])[O-].[K+].[K+].C1(C)C=CC=CC=1>O1CCCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][C:2]1[CH:3]=[C:4]([C:12]2[CH:21]=[CH:20][C:19]3[C:14](=[CH:15][CH:16]=[C:17]([F:22])[CH:18]=3)[N:13]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Fc1ccc2nc(Cl)ccc2c1
Reactant: Cc1cccc(B(O)O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Solvent: O
Product: Cc1cccc(-c2ccc3cc(F)ccc3n2)c1
Temperature: 100 °C
Reaction time: 24 h
Yield: 80.1 %

Procedure:
3-methylphenyl boronic acid (13 mmol), 2-chloro-6-fluoroquinoline (10 mmol), tetrakis(triphenylphosphine)palladium(0) (0.5 mmol) and potassium carbonate (15 g) are put in a two-neck round-bottom flask and dissolved in tetrahydrofuran (THF) (30 mL) and H2O (10 mL). Subsequently, the resulting solution is stirred in a bath under a temperature of about 100° C. for 24 hours. After completion of the reaction, THF and toluene are removed. The reaction mixture is extracted with dichloromethane and water, and then being distilled under reduced pressure. The resulting residence is filtered by silica gel column and distilled under reduced pressure again. Next, by re-crystallizing and filtering, 2-(3-methylphenyl)-6-fluoroquinoline (1.9 g) is yielded.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])C.C(O)=O.[N:11]1([C:17]2[CH:26]=[CH:25][CH:24]=[C:23]3[C:18]=2[CH2:19][CH2:20][C:21](=[O:27])[NH:22]3)[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1.ClCCl>O>[CH:1]([N:14]1[CH2:15][CH2:16][N:11]([C:17]2[CH:26]=[CH:25][CH:24]=[C:23]3[C:18]=2[CH2:19][CH2:20][C:21](=[O:27])[NH:22]3)[CH2:12][CH2:13]1)=[O:3]
Reactant: O=C1CCc2c(cccc2N2CCNCC2)N1
Reactant: CC(=O)OC(C)=O
Solvent: O=CO
Solvent: ClCCl
Solvent: O
Product: O=CN1CCN(c2cccc3c2CCC(=O)N3)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 1.22 ml of acetic anhydride and 0.5 ml of formic acid was stirred at 50°-60° C. for 2 hours. After cooling to room temperature, 1.0 g of 5-piperazinyl-3,4-dihydrocarbostyril was added portionwise to the reaction mixture, during which operation the product was solidified. To the solids was added 5 ml of dichloromethane and the mixture was stirred at room temperature for 2 hours. Then, a large amount of water was added thereto and the mixture was extracted with chloroform. After washing with water, the extract was dried over anhydrous sodium sulfate followed by removal of chloroform by distillation. Recrystallization of the residue from methanol gave 420 mg of 5-(4-formyl-1-piperazinyl)-3,4-dihydrocarbostyril, m.p. 263°-265° C., colorless granules.
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH3:12])[C:7](=[O:13])[C@@H:6]([CH2:14][CH3:15])[N:5]([CH:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)[C:4]=2[N:3]=1.[Cl:21][C:22]1[NH:23][CH:24]=[CH:25][N:26]=1>>[Cl:21][C:22]1[N:23]([C:2]2[N:11]=[CH:10][C:9]3[N:8]([CH3:12])[C:7](=[O:13])[C@@H:6]([CH2:14][CH3:15])[N:5]([CH:16]4[CH2:20][CH2:19][CH2:18][CH2:17]4)[C:4]=3[N:3]=2)[CH:24]=[CH:25][N:26]=1
Reactant: CC[C@@H]1C(=O)N(C)c2cnc(Cl)nc2N1C1CCCC1
Reactant: Clc1ncc[nH]1
Product: CC[C@@H]1C(=O)N(C)c2cnc(-n3ccnc3Cl)nc2N1C1CCCC1

Procedure:
The title compound was prepared similarly to the methods described in Example 185, with Intermediate B instead of Intermediate C and 2-chloro-1H-imidazole instead of 2-(3,5-dichlorophenyl)-1H-imidazole. LCMS: 361.2 m/z (M+H)+; ret. Time 10.06 min (Analytical Method C).
Reaction SMILES: Cl.[CH3:2][C:3]1[N:7]([CH:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[C:6]2[CH:14]=[CH:15][C:16]([C:18](O)=O)=[CH:17][C:5]=2[N:4]=1.[NH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[SH:28].N>>[S:28]1[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[N:21]=[C:18]1[C:16]1[CH:15]=[CH:14][C:6]2[N:7]([CH:8]3[CH2:13][CH2:12][O:11][CH2:10][CH2:9]3)[C:3]([CH3:2])=[N:4][C:5]=2[CH:17]=1
Reactant: Cc1nc2cc(C(=O)O)ccc2n1C1CCOCC1
Reactant: Nc1ccccc1S
Agent: Cl
Agent: N
Product: Cc1nc2cc(-c3nc4ccccc4s3)ccc2n1C1CCOCC1
Temperature: 150 °C
Reaction time: 17 h
Yield: 1.9 %

Procedure:
A 4-neck flask (50 mL) equipped with reflux condenser was charged with 2-methyl-1-(tetrahydropyran-4-yl)benzimidazole-5-carboxylic acid HCl salt (see Working Example 4-3) (0.28 g, 1.08 mmol), 2-aminobenzenethiol (0.14 g, 1.08 mmol) and polyphosphoric acid (approx. 11 g), and this was heated to 150° C. and stirred for 17 hours. After being allowed to cool to room temperature, this was cooled in ice (0 to 5° C.), and concentrated aqueous ammonia (28%) was added to the liquid to give approx. pH 9. After distilling off the solvent under reduced pressure, the brown viscous residue was extracted with ethyl acetate, this was dried over anhydrous magnesium sulfate. The residue obtained after again distilling off the solvent under reduced pressure was purified by PTLC to yield the title compound (0.007 g, 1.8% yield) as greenish-pale yellow crystals.