Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1]CCCC.[H-].[Na+].[CH3:8][N:9]([CH3:37])[S:10]([N:13]1[CH:17]=[C:16]([CH:18]([OH:29])[C:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[N:22]=[CH:21][CH:20]=2)[N:15]=[C:14]1[Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31])(=[O:12])=[O:11].CI>C1COCC1>[CH3:8][N:9]([CH3:37])[S:10]([N:13]1[CH:17]=[C:16]([CH:18]([O:29][CH3:1])[C:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[N:22]=[CH:21][CH:20]=2)[N:15]=[C:14]1[Si:30]([C:33]([CH3:34])([CH3:36])[CH3:35])([CH3:32])[CH3:31])(=[O:11])=[O:12]
Reactant: CN(C)S(=O)(=O)n1cc(C(O)c2ccnc3ccccc23)nc1[Si](C)(C)C(C)(C)C
Reactant: CCCCC
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: C1CCOC1
Product: COC(c1cn(S(=O)(=O)N(C)C)c([Si](C)(C)C(C)(C)C)n1)c1ccnc2ccccc12
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 83 %

Procedure:
To pentane washed sodium hydride (0.048 g, 1.2 mmol) in 5 ml of THF at 0° C., 2-(tert-Butyldimethylsilyl)-4-(hydroxyquinolin-4-yl-methyl)-imidazole-1-sulfonic acid dimethylamide (example 8, step A) (0.375 g, 0.811 mmol) was added slowly over a period of 5 minutes. After stirring at room temperature for 15 minutes, it was, again cooled to 0° C. and methyl iodide (0.1 ml, 1.62 mmol) was added neat. The reaction mixture was stirred at room temperature for 1 hour, concentrated under reduced pressure and partitioned between EtOAc (10 ml) and water (10 ml). The organic layer was dried over sodium sulfate, filtered and concentrated to yield 0.32 g (83%) of the product as a syrup.
Reaction SMILES: [F:1][C:2]1[C:11]([N+:12]([O-])=O)=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].O.NN>C1COCC1.CO.[Ni]>[NH2:12][C:11]1[C:2]([F:1])=[C:3]([CH:8]=[CH:9][CH:10]=1)[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1cccc([N+](=O)[O-])c1F
Agent: [Ni]
Agent: NN
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: COC(=O)c1cccc(N)c1F
Temperature: 70 °C

Procedure:
To a solution of methyl 2-fluoro-3-nitrobenzoate (78 g) in THF (400 ml) and methanol (100 ml) was added Raney Ni (40 g), the mixture was heated to 70° C., and then 25 ml of hydrazine hydrate (N2H4.H2O, 85%) was added dropwise. The reaction was monitored by TLC, when the starting material was totally consumed the addition of hydrazine was stop. The mixture was cooled to rt and filtered, the filtrate was concentrated under vacuum to leave a brown oil, which was purified by chromatography (SiO2, 300-400 mesh, PE: EtOAc=11:2) to afford the title compound was obtained as a yellow oil (45 g, 68%). 1H NMR (300 MHz, DMSO) δ ppm 6.96 (m, 3H), 5.36 (s, 2H), 3.81 (s, 3H).
Reaction SMILES: [CH:1]1[CH:2]=[C:3]2[C:8]3=[C:9]([C:11]([O:13][C:14](=[O:15])[C:7]3=[CH:6][CH:5]=[CH:4]2)=[O:12])[CH:10]=1.[Br:16]Br>>[CH:1]1[CH:10]=[C:9]2[C:11]([O:13][C:14](=[O:15])[C:7]3=[C:8]2[C:3](=[CH:4][C:5]([Br:16])=[CH:6]3)[CH:2]=1)=[O:12]
Reactant: BrBr
Reactant: O=C1OC(=O)c2cccc3cccc1c23
Product: O=C1OC(=O)c2cc(Br)cc3cccc1c23
Temperature: 50 °C
Reaction time: 4 h
Yield: 22.7 %

Procedure:
1,8-Naphthalic anhydride (compound 73, 100 g, 505 mmol) was slurried in c-nitric acid (70%, 2.0 L) and heated to 50° C. Bromine (19.4 mL, 379 mmol) was added evenly over 10 min, and the resulting solution was held at 50° C. for 4 h before cooling to 0° C. The resulting solid was isolated by filtration and dried in vacuo to yield the title compound (23.8 g, 17%) as a white solid.
Reaction SMILES: [F:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH2:11][C:12]3[C:20]([I:21])=[CH:19][C:15]4[O:16][CH2:17][O:18][C:14]=4[CH:13]=3)[NH:8]2)=[C:4]([NH2:22])[N:3]=1.Br[CH2:24][CH2:25][CH2:26][NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[NH2:22][C:4]1[N:3]=[C:2]([F:1])[N:10]=[C:9]2[C:5]=1[N:6]=[C:7]([CH2:11][C:12]1[C:20]([I:21])=[CH:19][C:15]3[O:16][CH2:17][O:18][C:14]=3[CH:13]=1)[N:8]2[CH2:24][CH2:25][CH2:26][NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31]
Reactant: CC(C)(C)OC(=O)NCCCBr
Reactant: Nc1nc(F)nc2[nH]c(Cc3cc4c(cc3I)OCO4)nc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCCn1c(Cc2cc3c(cc2I)OCO3)nc2c(N)nc(F)nc21
Temperature: 25 °C
Reaction time: 24 h
Yield: 67.9 %

Procedure:
To a solution of 2-fluoro-8-((6-iodobenzo[d][1,3]dioxol-5-yl)methyl)-9H-purin-6-amine (3.3 g, 8 mmol) in DMF (50 mL) was added t-butyl (3-bromopropyl)carbamate (9.6 g, 40 mmol) and Cs2CO3 (5.26 g, 16 mmol). The resulting mixture was stirred at room temperature for 1 day. The reaction mixture was condensed and purified by flash chromatography to yield t-butyl (3-(6-amino-2-fluoro-8-((6-iodobenzo[d][1,3]dioxol-5-yl)methyl)-9H-purin-9-yl)propyl)carbamate as white solid (3.1 g, 66%). The solution of t-butyl (3-(6-amino-2-fluoro-8-((6-iodobenzo[d][1,3]dioxol-5-yl)methyl)-9H-purin-9-yl)propyl)carbamate (1.9 g, 3.3 mmol) in the mixture of TFA/CH2Cl2 (10 mL/2 mL) was stirred at room temperature for 2 hrs. The reaction mixture was condensed, purified by flash chromatography to yield 9-(3-aminopropyl)-2-fluoro-8-((6-iodobenzo[d][1,3]dioxol-5-yl)methyl)-9H-purin-6-amine as yellow solid (1.4 g, 89%). 1H NMR (600 MHz, CDCl3/MeOH-d4): δ 7.28 (s, 1H), 6.70 (s, 1H), 5.98 (s, 2H), 4.21 (s, 2H), 4.13 (t, J=7.1 Hz, 2H), 2.67 (t, J=6.8 Hz, 2H), 1.89 (m, 2H); 13C NMR (150 MHz, CDCl3/MeOH-d4): δ 160.8, 159.4, 157.8, 153.7, 152.1, 150.4, 149.4, 132.4, 120.1, 117.2, 111.3, 103.4, 89.8, 41.7, 40.4, 39.3, 33.6; HRMS (ESI) m/z [M+H]+ calcd. for C16H17IFN6O2, 471.0436. found 471.0442.
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][N:3]=1.Cl.[NH2:13][C:14]1([CH3:33])[CH2:18][CH2:17][CH2:16][CH:15]1[NH:19][C:20](=[O:32])[O:21][C@@H:22]1[CH2:27][C@H:26]([CH3:28])[CH2:25][CH2:24][C@H:23]1[CH:29]([CH3:31])[CH3:30].CCN(C(C)C)C(C)C.C(=O)(O)[O-].[Na+]>CS(C)=O.C(OCC)(=O)C>[CH3:33][C@:14]1([NH:13][C:2]2[CH:7]=[N:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][N:3]=2)[CH2:18][CH2:17][CH2:16][C@@H:15]1[NH:19][C:20](=[O:32])[O:21][C@@H:22]1[CH2:27][C@H:26]([CH3:28])[CH2:25][CH2:24][C@H:23]1[CH:29]([CH3:30])[CH3:31]
Reactant: FC(F)(F)c1cnc(Cl)cn1
Reactant: CC(C)[C@@H]1CC[C@@H](C)C[C@H]1OC(=O)NC1CCCC1(C)N
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CC(C)[C@@H]1CC[C@@H](C)C[C@H]1OC(=O)N[C@H]1CCC[C@]1(C)Nc1cnc(C(F)(F)F)cn1

Procedure:
A solution of 2-chloro-5-(trifluoromethyl)pyrazine (CAS number 799557-87-2; 0.816 ml, 6.61 mmol), (1R,2S,5R)-5-methyl-2-(propan-2-yl)cyclohexyl N-(2-amino-2-methylcyclopentyl)carbamate hydrochloride (Intermediate 27; 2.00 g, 6.01 mmol) and DIPEA (3.15 ml, 18.02 mmol) in DMSO (10 mL) was subjected to microwave irradiation at 140° C. for 5 hours. The reaction was diluted with ethyl acetate (100 ml) and a saturated solution of sodium bicarbonate (50 m). The organics were washed with water (40 ml), brine (40 ml), dried over magnesium sulfate, filtered through a hydrophobic frit and concentrated in vacuo. The crude product was purified by column chromatography (silica, 0-20% ethyl acetate/petrol) to afford the title compound
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]([C:6]([C:8]2[C:9]([CH3:19])=[C:10]([CH2:14][CH2:15][C:16](O)=[O:17])[CH:11]=[CH:12][CH:13]=2)=[O:7])=[CH:4][CH:3]=1.S(Cl)([Cl:24])=O>>[Cl:1][C:2]1[CH:21]=[CH:20][C:5]([C:6]([C:8]2[C:9]([CH3:19])=[C:10]([CH2:14][CH2:15][C:16]([Cl:24])=[O:17])[CH:11]=[CH:12][CH:13]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: Cc1c(CCC(=O)O)cccc1C(=O)c1ccc(Cl)cc1
Product: Cc1c(CCC(=O)Cl)cccc1C(=O)c1ccc(Cl)cc1

Procedure:
830 mg of 3-(3'-p-chlorobenzoyl-2'-methyl-phenyl)-propionic acid and 4.2 ml of thionyl chloride were refluxed for 3 hours and then excess thionyl chloride was distilled off and the last traces were removed by entrainment with benzene to obtain 876 mg of 3-(3'-p-chlorobenzoyl-2'-methyl-phenyl)-propionyl chloride which was used as is for the next step.
Reaction SMILES: [CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[OH-].[K+].C(=O)([O-])[O-].[K+].[K+].I[CH:23]([CH2:25][CH3:26])[CH3:24]>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.CN(C=O)C>[CH:23]([N:12]1[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]2[C:13]1=[CH:1][CH:2]=[CH:3][CH:4]=2)([CH2:25][CH3:26])[CH3:24]
Reactant: CCC(C)I
Reactant: c1ccc2c(c1)[nH]c1ccccc12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: O=S(=O)([O-])O
Solvent: CN(C)C=O
Product: CCC(C)n1c2ccccc2c2ccccc21
Yield: 24.1 %

Procedure:
30 g (179.46 mmol) of carbazole, 71 g of 85% KOH, 40 g of potassium carbonate, 6.0 g of tetra-n-butylammonium hydrogensulfate, 50.0 g (271.7 mmol) of 2-iodobutane and 300 ml of DMF were allowed to react and after treated in the same manner as with Example 7 (1) to obtain 9.66 g of 9-s-butylcarbazole.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([OH:12])=O)=[CH:5][CH:4]=1.C(N(CC)CC)C.O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[C:43]([O:47][C:48]([N:50]1[CH2:54][C@@H:53]([CH2:55][N:56]([CH:73]([CH3:75])[CH3:74])[C:57](=[O:72])[C:58]2[CH:63]=[CH:62][C:61]([O:64][CH3:65])=[C:60]([O:66][CH2:67][CH2:68][CH2:69][O:70][CH3:71])[CH:59]=2)[C@H:52]([CH2:76][NH:77][CH:78]2[CH2:80][CH2:79]2)[CH2:51]1)=[O:49])([CH3:46])([CH3:45])[CH3:44].C([O-])(O)=O.[Na+]>C(Cl)Cl>[C:43]([O:47][C:48]([N:50]1[CH2:54][C@@H:53]([CH2:55][N:56]([CH:73]([CH3:74])[CH3:75])[C:57](=[O:72])[C:58]2[CH:63]=[CH:62][C:61]([O:64][CH3:65])=[C:60]([O:66][CH2:67][CH2:68][CH2:69][O:70][CH3:71])[CH:59]=2)[C@H:52]([CH2:76][N:77]([CH:78]2[CH2:79][CH2:80]2)[C:10](=[O:12])[CH2:9][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)[CH2:51]1)=[O:49])([CH3:45])([CH3:46])[CH3:44]
Reactant: COCCCOc1cc(C(=O)N(C[C@@H]2CN(C(=O)OC(C)(C)C)C[C@H]2CNC2CC2)C(C)C)ccc1OC
Reactant: COc1ccc(CC(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: COCCCOc1cc(C(=O)N(C[C@@H]2CN(C(=O)OC(C)(C)C)C[C@H]2CN(C(=O)Cc2ccc(OC)cc2)C2CC2)C(C)C)ccc1OC
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of 4-methoxyphenylacetic acid (0.075 g, 0.45 mmol) in CH2Cl2 (3 mL), are added triethylamine (0.063 mL, 0.45 mmol), 1-hydroxy-benzotriazol hydrate (0.061 g, 0.45 mmol) and N-(3-dimethylaminopropyl)-N′-ethyl-carbodiimide hydrochloride (EDC) (0.086 g, 0.45 mmol) followed by (3R*,4R*)-3-cyclopropylaminomethyl-4-({isopropyl-[4-methoxy-3-(3-methoxy-propoxy)-benzoyl]-amino}-methyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (0.2 g, 0.375 mmol). The resulting mixture is stirred for 2 days at RT, then diluted with CH2Cl2 and poured into an aqueous saturated solution of NaHCO3. The organic layer is separated, and the aqueous one is extracted twice with CH2Cl2. The combined organic extracts are dried over Na2SO4, filtered and concentrated. The crude product is purified by flash chromatography on silica gel (eluent: c-hexane/AcOEt 50:50 to 0:100) to give the title compound. TLC, Rf (CH2Cl2/MeOH 95:5)=0.35. MS (LC-MS): 682.4 [M+H]+; tR (HPLC, Macherey-Nagel Nucleosil C18 column, 5-100% CH3CN/H2O/6 min, 100% CH3CN/2 min, CH3CN and H2O containing 0.1% TFA, flow: 1 mL/min): 5.77 min.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8](B(O)O)=[CH:7][CH:6]=1)=[O:4].Br[C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][N:16]=1>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>[N+:21]([C:18]1[CH:17]=[N:16][C:15]([C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[C:3]([O:2][CH3:1])=[O:4])=[CH:20][CH:19]=1)([O-:23])=[O:22]
Reactant: COC(=O)c1ccc(B(O)O)cc1
Reactant: O=[N+]([O-])c1ccc(Br)nc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: COC(=O)c1ccccc1-c1ccc([N+](=O)[O-])cn1
Yield: 78.9 %

Procedure:
In a similar manner to that described in Reference example 14(a), a reaction was carried out using 4-methoxycarbonylphenyl boronic acid (3.24 g), 2-bromo-5-nitropyridine (4.75 g) and tetrakis(triphenylphosphine)palladium (1.04 g) and treated to afford the desired compound (3.67 g) as colorless crystals.
Reaction SMILES: FC(F)(F)C(O)=O.[CH:8]1([C:13]([N:15]2[CH2:20][CH:19]([C:21]3[CH:26]=[CH:25][C:24]([CH2:27][CH3:28])=[CH:23][CH:22]=3)[CH2:18][CH:17]([NH2:29])[CH2:16]2)=[O:14])[CH2:12][CH2:11][CH2:10][CH2:9]1.[C:30]1([CH2:36][C:37](O)=[O:38])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[CH:8]1([C:13]([N:15]2[CH2:20][CH:19]([C:21]3[CH:22]=[CH:23][C:24]([CH2:27][CH3:28])=[CH:25][CH:26]=3)[CH2:18][CH:17]([NH:29][C:37](=[O:38])[CH2:36][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH2:16]2)=[O:14])[CH2:9][CH2:10][CH2:11][CH2:12]1
Reactant: CCc1ccc(C2CC(N)CN(C(=O)C3CCCC3)C2)cc1
Reactant: O=C(O)Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CCc1ccc(C2CC(NC(=O)Cc3ccccc3)CN(C(=O)C3CCCC3)C2)cc1

Procedure:
57 mg (0.12 mmol) of 1-(cyclopentylcarbonyl)-5-(4-ethylphenyl)piperidine-3-amine trifluoroacetate (Example 8A) and 16 mg (0.12 mmol, 1.0 eq.) of phenylacetic acid were reacted according to General Method 1. Yield: 28 mg (58% of theory)
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:11]=[CH:10][C:8]([NH2:9])=[C:7]([N+:12]([O-:14])=[O:13])[CH:6]=1.[C:15]([N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16].O>C1COCC1>[NH2:9][C:8]1[CH:10]=[CH:11][C:5]([O:4][CH2:3][CH2:2][N:25]2[CH2:24][CH2:23][N:22]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:27][CH2:26]2)=[CH:6][C:7]=1[N+:12]([O-:14])=[O:13]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Nc1ccc(OCCBr)cc1[N+](=O)[O-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(CCOc2ccc(N)c([N+](=O)[O-])c2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 56.9 %

Procedure:
A 100 mL flask was charged with 4-(2-bromoethoxy)-2-nitroaniline (2.2 g, 8.4 mmol) in THF (20 mL) and 4-N-boc-piperazine (1.56 g, 8.4 mmol) was added and stirred at room temperature. The reaction was monitored by LCMS. After 30 minutes, the reaction mixture was treated with deionized water (100 mL) and sonicated. The resulting solid was collected by filtration and dried at reduced pressure to give 1.75 g of tert-butyl 4-(2-(4-amino-3-nitrophenoxy)ethyl)piperazine-1-carboxylate (59% yield). MS (EI): 367 (MH+).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:9]([O:11][C:12](=[O:27])[NH:13][C:14]2[C:15]([CH3:26])=[N:16][O:17][C:18]=2[C:19]2[CH:24]=[CH:23][C:22](Br)=[CH:21][CH:20]=2)[CH3:10])[CH:6]=[CH:7][CH:8]=1)#[N:2].[CH2:28]([O:30][C:31]([C:33]1([C:36]2[CH:41]=[CH:40][C:39](B3OC(C)(C)C(C)(C)O3)=[CH:38][CH:37]=2)[CH2:35][CH2:34]1)=[O:32])[CH3:29]>>[CH2:28]([O:30][C:31]([C:33]1([C:36]2[CH:41]=[CH:40][C:39]([C:22]3[CH:23]=[CH:24][C:19]([C:18]4[O:17][N:16]=[C:15]([CH3:26])[C:14]=4[NH:13][C:12]([O:11][CH:9]([C:5]4[CH:6]=[CH:7][CH:8]=[C:3]([C:1]#[N:2])[CH:4]=4)[CH3:10])=[O:27])=[CH:20][CH:21]=3)=[CH:38][CH:37]=2)[CH2:34][CH2:35]1)=[O:32])[CH3:29]
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1NC(=O)OC(C)c1cccc(C#N)c1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4NC(=O)OC(C)c4cccc(C#N)c4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 6, Step 3 using [5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-carbamic acid 1-(3-cyano-phenyl)-ethyl ester and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: Cl[C:2]1[C:12]2[C:11](=[O:13])[NH:10][CH2:9][CH2:8][CH2:7][C:6]=2[CH:5]=CC=1OC.[Cl:16][C:17]1[C:18]([O:29][CH3:30])=[CH:19][C:20]2[C:26](=[O:27])[NH:25][CH2:24][CH2:23][CH2:22][C:21]=2[CH:28]=1.C(OC1C(CCl)=C(C)C=C(C)N=1)C1C=CC=CC=1.CC([O-])=O.[Na+].CC(O)=O>CN(C=O)C>[Cl:16][C:17]1[C:18]([O:29][CH3:30])=[CH:19][C:20]2[C:26](=[O:27])[N:25]([CH2:2][C:12]3[C:11](=[O:13])[NH:10][C:9]([CH3:8])=[CH:7][C:6]=3[CH3:5])[CH2:24][CH2:23][CH2:22][C:21]=2[CH:28]=1
Reactant: COc1ccc2c(c1Cl)C(=O)NCCC2
Reactant: COc1cc2c(cc1Cl)CCCNC2=O
Agent: CC(=O)[O-]
Agent: Cc1cc(C)c(CCl)c(OCc2ccccc2)n1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: COc1cc2c(cc1Cl)CCCN(Cc1c(C)cc(C)[nH]c1=O)C2=O
Temperature: 80 °C
Yield: 36 %

Procedure:
To a mixture of 9-chloro-8-methoxy-2,3,4,5-tetrahydro-1H-2-benzazepin-1-one (132a) and 7-chloro-8-methoxy-2,3,4,5-tetrahydro-1H-2-benzazepin-1-one (132b) (35.0 mg, 0.150 mmol) in DMF (5 mL) was added 2-(benzyloxy)-3-(chloromethyl)-4,6-dimethylpyridine (Cpd Z, 47.1 mg, 0.180 mmol). The reaction mixture was heated at 80° C. for 24 hours. The reaction mixture was poured into a NaOAc-HOAc buffer (5 mL) and extracted with EtOAc (2×10 mL). The combined organic layers were dried over sodium sulfate and concentrated under vacuum. The resulting brown oil was dissolved in MeOH (1 mL) and HCl (3 M in n-butanol, 0.05 mL) was added. The reaction mixture was heated at 70° C. for 24 hours. The solvent was removed in vacuum and the residue was purified by preparative HPLC to give the title compounds (Example 132-A, first eluting product, 20 mg, 36%); 1H NMR (400 MHz, methanol-d4) δ 7.09-7.14 (m, 1H), 7.05-7.10 (m, 1H), 6.13 (s, 1H), 4.89 (s, 1H), 4.71-4.79 (m, 1H), 3.88 (s, 3H), 3.38 (dd, J=5.93, 14.86 Hz, 1H), 2.92-3.01 (m, 1H), 2.57-2.73 (m, 2H), 2.35 (s, 3H), 2.25 (s, 3H), 2.06-2.14 (m, 1H), 1.53-1.64 (m, 1H); MS 361.1 [M+1]; and (Example 132-B, second eluting product, 4 mg, 7%); 1H NMR (400 MHz, methanol-d4) δ 7.26 (s, 1H), 7.22 (s, 1H), 6.13 (s, 1H), 4.78 (s, 2H), 3.91 (s, 3H), 3.26-3.29 (m, 2H), 2.63 (t, J=7.09 Hz, 2H), 2.34 (s, 3H), 2.26 (s, 3H), 1.78 (t, J=6.66 Hz, 2H); MS 361.1 [M+1]; as a white solids.
Reaction SMILES: [CH3:1][NH:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([CH:13]=O)[CH:11]=2)[N:6]=[CH:5][N:4]=1.[S:15]1[CH2:19][C:18](=[O:20])[NH:17][C:16]1=[O:21]>>[CH3:1][NH:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([CH:13]=[C:19]3[S:15][C:16](=[O:21])[NH:17][C:18]3=[O:20])[CH:11]=2)[N:6]=[CH:5][N:4]=1
Reactant: O=C1CSC(=O)N1
Reactant: CNc1ncnc2ccc(C=O)cc12
Product: CNc1ncnc2ccc(C=C3SC(=O)NC3=O)cc12

Procedure:
Following the general method as outlined in Example 1, starting from 4-methylamino-quinazoline-6-carbaldehyde (intermediate 11) and 1,3-thiazolidine-2,4-dione, the title compound was obtained.
Reaction SMILES: [CH2:1]([NH:11][C:12]([C:14]1[CH:19]=[C:18]([N+:20]([O-])=O)[CH:17]=[C:16]([C:23]([NH:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])=[O:24])[CH:15]=1)=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]>[Pd].O1CCCC1>[NH2:20][C:18]1[CH:19]=[C:14]([C:12]([NH:11][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])=[O:13])[CH:15]=[C:16]([C:23]([NH:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])=[O:24])[CH:17]=1
Reactant: CCCCCCCCCCNC(=O)c1cc(C(=O)NCCCCCCCCCC)cc([N+](=O)[O-])c1
Agent: [Pd]
Solvent: C1CCOC1
Product: CCCCCCCCCCNC(=O)c1cc(N)cc(C(=O)NCCCCCCCCCC)c1
Reaction time: 17 h
Yield: 77.4 %

Procedure:
A mixture of 21 g (0.043 mol) of N,N'-didecyl-5-nitro-1,3-benzenedicarboxamide and 7.0 g of 10% palladium on carbon in 250 ml of tetrahydrofuran was shaken under hydrogen pressure (52 psi initially) on a Parr Hydrogenator for 17 hours. The catalyst was removed by filtration and the solvent was removed from the filtrate at reduced pressure to give a solid which was recrystallized from methanol-water to give 15.3 g (77% yield, mp 188°-189°) of 5-amino-N,N'-didecyl-1,3-benzenedicarboxamide.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])O[C:6]([C:13]([OH:15])=[O:14])=[C:5]2[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.Cl.[CH3:23][O:24][NH2:25].C[O-].[Na+]>CO>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:25]([O:24][CH3:23])[C:6]([C:13]([OH:15])=[O:14])=[C:5]2[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: O=C(O)c1oc(=O)c2ccc(Cl)cc2c1-c1ccccc1
Reactant: CON
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COn1c(C(=O)O)c(-c2ccccc2)c2cc(Cl)ccc2c1=O
Temperature: 25 °C
Reaction time: 12 h

Procedure:
6-Chloro-1-oxo-4-phenyl-1H-isochromen-3-carboxylic acid (150 mg) was dissolved in methanol (3.0 ml) and O-methylhydroxylamine hydrochloride (420 mg) and sodium methoxide (270 mg) were added. The mixture was stirred at room temperature for 12 hrs. and concentrated under reduced pressure. The residue was partitioned between ethyl acetate and 1N hydrochloric acid, and the organic layer was dried over magnesium sulfate and concentrated under reduced pressure to dryness. Then, 4N hydrochloric acid ethyl acetate solution (3 ml) was added to the residue and the mixture was stirred at room temperature for 12 hrs. Water was added to wash the reaction mixture, and the organic layer was dried over magnesium sulfate and concentrated under reduced pressure to give 6-chloro-2-methoxy-1-oxo-4-phenyl-1,2-dihydroisoquinoline-3-carboxylic acid.
Reaction SMILES: Cl.[F:2][C:3]([F:17])([F:16])[C:4]1[CH:5]=[C:6]([CH:10]2[O:15][CH2:14][CH2:13][NH:12][CH2:11]2)[CH:7]=[CH:8][CH:9]=1.CCN(C(C)C)C(C)C.[F:27][C:28]([F:33])([F:32])[C@@H:29]1[CH2:31][O:30]1>C(#N)C>[F:27][C:28]([F:33])([F:32])[C@@H:29]([OH:30])[CH2:31][N:12]1[CH2:13][CH2:14][O:15][CH:10]([C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([C:3]([F:2])([F:16])[F:17])[CH:5]=2)[CH2:11]1
Reactant: FC(F)(F)c1cccc(C2CNCCO2)c1
Reactant: FC(F)(F)[C@@H]1CO1
Agent: Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: O[C@@H](CN1CCOC(c2cccc(C(F)(F)F)c2)C1)C(F)(F)F
Temperature: 25 °C
Reaction time: 72 h
Yield: 80.1 %

Procedure:
In a 50 mL round-bottomed flask, 2-(3-(trifluoromethyl)phenyl)morpholine hydrochloride (515 mg, 1.92 mmol) and DIPEA (249 mg, 336 μl, 1.92 mmol) were combined with acetonitrile (10 ml) to give a white suspension. (S)-2-(trifluoromethyl)oxirane (323 mg, 2.89 mmol) was added. The reaction mixture was stirred at room temperature for 3 days and then was concentrated in vacuo. The reaction mixture was taken up in 100 mL dilute aqueous NaHCO3 and extracted with dichloromethane (3×50 mL). The organic layers were dried over Na2SO4 and concentrated in vacuo to afford 528 mg (80%) of (2S)-1,1,1-trifluoro-3-(2-(3-(trifluoromethyl)phenyl)morpholino)propan-2-ol, which was used as is in the next step. (M+H)+=344 m/e.
Reaction SMILES: Cl.[NH:2]([C:4]1[CH:5]=[C:6]([C:9]#[N:10])[S:7][CH:8]=1)[NH2:3].[F:11][C:12]([F:24])([F:23])[C:13](=O)[CH2:14][C:15]([C:17]1[O:18][CH:19]=[CH:20][CH:21]=1)=O.C1(C)C=CC=CC=1>CC(O)=O>[O:18]1[CH:19]=[CH:20][CH:21]=[C:17]1[C:15]1[N:2]([C:4]2[CH:5]=[C:6]([C:9]#[N:10])[S:7][CH:8]=2)[N:3]=[C:13]([C:12]([F:11])([F:23])[F:24])[CH:14]=1
Reactant: O=C(CC(=O)C(F)(F)F)c1ccco1
Reactant: N#Cc1cc(NN)cs1
Agent: Cl
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: N#Cc1cc(-n2nc(C(F)(F)F)cc2-c2ccco2)cs1
Reaction time: 0.37 h
Yield: 73.7 %

Procedure:
To a solution of compound 13 (0.701 g, 3.99 mmol) in AcOH (10 mL) was added 4,4,4-trifluoro-1-(2-furyl)-1,3-butanedione (0.591 mL, 3.99 mmol). The solution was stirred at 80 degrees for a total of 22 minutes. After the addition of toluene to the brown solution it was concentrated under reduced pressure to a brown-green sludge. The sludge was dry loaded onto a 40M Biotage column and then eluted with a gradient of 5 to 20% ethyl acetate in hexanes to furnish compound 14 (0.909 g, 74%) as a light brown oil which solidified upon standing. LRMS (ESI): calc. 309.2; found 310.1 (MH)+.