Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(O)=O.C[N:9]([CH:11]=[C:12]([N:18]1[CH:22]=[C:21]([C:23]#[N:24])[N:20]=[CH:19]1)[C:13]([O:15]CC)=O)C.[NH:25]([C:27]1[N:32]=[CH:31][N:30]=[C:29]([N:33]2[CH2:36][CH:35]([OH:37])[CH2:34]2)[CH:28]=1)N>C(OCC)(=O)C>[OH:37][CH:35]1[CH2:36][N:33]([C:29]2[N:30]=[CH:31][N:32]=[C:27]([N:25]3[C:13](=[O:15])[C:12]([N:18]4[CH:22]=[C:21]([C:23]#[N:24])[N:20]=[CH:19]4)=[CH:11][NH:9]3)[CH:28]=2)[CH2:34]1
Reactant: NNc1cc(N2CC(O)C2)ncn1
Reactant: CCOC(=O)C(=CN(C)C)n1cnc(C#N)c1
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1cn(-c2c[nH]n(-c3cc(N4CC(O)C4)ncn3)c2=O)cn1
Temperature: 100 °C
Reaction time: 10 h

Procedure:
46 μl (68 mg, 0.6 mmol) of trifluoroacetic acid are added to a mixture of 700 mg (3.0 mmol) of the compound from Example 6A and 541 mg (3.0 mmol) of the compound from Example 10A in 10 ml of ethyl acetate, and the mixture is stirred at 100° C. for 10 h. The reaction mixture is concentrated under reduced pressure and taken up in 5 ml of ethanol, and the precipitate is filtered off. The solid is suspended in 10 ml of water, and 1 N aqueous sodium hydroxide solution (pH=9) is added until the solid is dissolved. The pH is then adjusted to 7 using 1 N hydrochloric acid, the mixture is concentrated to a volume of about 5 ml and the precipitate formed is filtered off. The residue is washed with water and diisopropyl ether and chromatographed by preparative HPLC (Method 8). The solid is then suspended in 10 ml of water, and 1 N aqueous sodium hydroxide solution (pH=9) is added until the solid is dissolved. The pH is then adjusted to 7 using 1 N hydrochloric acid, the mixture is concentrated to a volume of about 2.5 ml and the precipitate formed is filtered off. The filtrate is concentrated to about 2 ml and filtered again. Both residues are combined, washed with water and ethyl acetate and dried under reduced pressure. Yield: 78 mg (8% of theory)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH2:10][O:11][CH3:12])=[CH:5][N:4]=1.C[Li].CN([CH:18]=[O:19])C>C1COCC1.C(NC(C)C)(C)C>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:6]([O:9][CH2:10][O:11][CH3:12])=[CH:5][N:4]=1)[CH:18]=[O:19]
Reactant: COCOc1ccc(OC)nc1
Reactant: CN(C)C=O
Agent: [Li]C
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: COCOc1cnc(OC)cc1C=O
Temperature: 0 °C
Reaction time: 3 h
Yield: 95.4 %

Procedure:
To a mixture of 2-methoxy-5-(methoxymethoxy)pyridine (30 g, 0.178 mol) and diisopropylamine (507 uL, 3.6 mmol) in THF (500 mL) was added methyl lithium (1.6 M/THF, 200 mL, 0.32 mol) at −40° C. Upon the completion of addition, the mixture was warmed to 0° C. and continued to stir at 0° C. for 3 h. The reaction mixture was then cooled back down to −40° C. followed by addition of DMF (24.7 mL, 0.32 mol) slowly. The mixture was then stirred at −40° C. for 1 h and quenched with a mixture of HCl (12 N, 120 mL) and THF (280 mL). Water (200 mL) was added and the pH of the mixture was adjusted to pH 8-9 with solid K2CO3. The mixture was extracted with EtOAc (300 mL) twice. The organic layer was combined, dried over Na2SO4, and concentrated to give 2-methoxy-5-(methoxymethoxy)isonicotinaldehyde (33.5 g, 95.7%) as a brown solid, which was used for next step without further purification. 1H NMR (400 MHz; CD3OD) 7.90 (s, 1H), 6.92 (s, 1H), 5.64 (s, 1H), 5.20 (s, 2H), 3.84 (s, 3H), 3.48 (s, 3H); MS (ESI) m/z 198.1 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][C:13]([F:19])([CH:16]([OH:18])[CH3:17])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:27][S:28](Cl)(=[O:30])=[O:29]>ClCCl>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][C:13]([F:19])([CH:16]([O:18][S:28]([CH3:27])(=[O:30])=[O:29])[CH3:17])[CH2:12]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(O)C1(F)CCN(C(=O)OCc2ccccc2)C1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(OS(C)(=O)=O)C1(F)CCN(C(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.5 %

Procedure:
To a −10° C. solution of 3-fluoro-3-(1-hydroxyethyl)pyrrolidine-1-carboxylic acid benzyl ester (Example A14, 0.267 g, 1.00 mmol), triethylamine (0.4 g, 4 mmol) and dichloromethane (10 mL) is added methanesulfonyl chloride (0.229 g, 2.00 mmol). The mixture is stirred at room temperature for 2 hours and concentrated in vacuo. The residue is partitioned between ethyl acetate and water. The organic layer is dried over Na2SO4 and concentrated to afford the title compound (0.330 g). 1H NMR (200 MHz, CDCl3): δ 7.36 (s, 5H), 5.14 (s, 2H), 4.99-4.81 (m, 1H), 3.76-3.37 (m, 4H), 3.06 (s, 3H), 2.25-1.96 (m, 2H), 1.52-1.47 (m, 3H).
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]([Si:18]([CH3:21])([CH3:20])[CH3:19])[C:10]=1[C:11](Cl)=[O:12].Cl.[CH2:23]([NH:26][CH:27]([CH3:29])[CH3:28])[CH2:24][CH3:25]>C1(C)C=CC=CC=1>[Cl:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]([Si:18]([CH3:21])([CH3:20])[CH3:19])[C:10]=1[C:11]([N:26]([CH:27]([CH3:29])[CH3:28])[CH2:23][CH2:24][CH3:25])=[O:12]
Reactant: CCCNC(C)C
Reactant: C[Si](C)(C)c1cccc(Cl)c1C(=O)Cl
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCCN(C(=O)c1c(Cl)cccc1[Si](C)(C)C)C(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.1 %

Procedure:
Triethylamine (27.89 mL, 200 mmol) was added to a mixture of the compound of Example b (2.47 g, 10 mmol) and N-propyl-N-iso-propylamine hydrochloride (- 92 mmol) in toluene (100 mL). The reaction was stirred overnight at ambient temperature, then was partitioned between ethyl acetate and dilute citric acid. The organic phase was washed with brine, dried (MgSO4), and concentrated to afford 2.50 g of the title compound as a waxy amber solid, an 80% yield.
Reaction SMILES: C([N:3]1[C:9]2[CH:10]=[CH:11][C:12](C3C=CC(C)=CC=3)=[CH:13][C:8]=2[CH:7]=[C:6]([C:21]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([CH2:30][N:31]([CH3:38])[CH:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)=[CH:26][CH:25]=2)=[O:22])[CH2:5][CH2:4]1)=O.Cl.C(=O)([O-])O.[Na+].O>C(OCC)(=O)C>[CH3:38][N:31]([CH2:30][C:27]1[CH:26]=[CH:25][C:24]([NH:23][C:21]([C:6]2[CH2:5][CH2:4][NH:3][C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=3[CH:7]=2)=[O:22])=[CH:29][CH:28]=1)[CH:32]1[CH2:33][CH2:34][O:35][CH2:36][CH2:37]1
Reactant: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CN(C)C4CCOCC4)cc2)CCN3C=O)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: CN(Cc1ccc(NC(=O)C2=Cc3ccccc3NCC2)cc1)C1CCOCC1
Temperature: 100 °C
Reaction time: 1 h
Yield: 88.9 %

Procedure:
To 1-formyl-7-(4-methylphenyl)-N-[4-[[N-methyl-N-(tetrahydro-2H-pyran-4-yl)amino]methyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (1177 mg) was added 1N hydrochloric acid (20 ml), and the mixture was stirred at 100° C. for 1 hour. The mixture was dilute with ethyl acetate(50 ml) and made weakly basic with saturated sodium hydrogen carbonate solution (45 ml). To the mixture were added ethyl acetate (250 ml) and water (100 ml), and separated. The organic layer was dried with anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified with silica gel column chromatography (75 g, ethyl acetate/ethanol=9:1) to give 7-(4-methyl-phenyl)phenyl)-N-[4-[[N-methyl-N-(tetrahydro-2H-pyran-4-yl)amino]methyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (Compound 318) (804 mg, 72%) as amorphous.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C@H:9]([NH:11][C:12]1[CH:19]=[C:18]([N:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)[CH:17]=[CH:16][C:13]=1[C:14]#[N:15])[CH3:10].C(OC([N:33]1[CH2:38][CH2:37][CH2:36][CH2:35][C@@H:34]1[C:39](O)=[O:40])=O)(C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN1C(=O)CCC1>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C@H:9]([NH:11][C:12]1[CH:19]=[C:18]([N:20]2[CH2:25][CH2:24][N:23]([C:39]([C@H:34]3[CH2:35][CH2:36][CH2:37][CH2:38][NH:33]3)=[O:40])[CH2:22][CH2:21]2)[CH:17]=[CH:16][C:13]=1[C:14]#[N:15])[CH3:10]
Reactant: CC(C)(C)OC(=O)N1CCCC[C@@H]1C(=O)O
Reactant: C[C@@H](Nc1cc(N2CCNCC2)ccc1C#N)c1ccc(Cl)cc1Cl
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](Nc1cc(N2CCN(C(=O)[C@H]3CCCCN3)CC2)ccc1C#N)c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 76.2 %

Procedure:
To a stirred solution of the (R)-2-(1-(2,4-dichlorophenyl)ethylamino)-4-(piperazin-1-yl)benzonitrile (0.080 g, 0.21 mmol) and (R)-1-(t-butoxycarbonyl)piperidine-2-carboxylic acid (0.049 g, 0.21 mmol) in 1-methyl pyyrolidinone (NMP) (1.0 mL) was added HATU (0.085 g, 0.22 mmol) and iPr2NEt (0.055 g, 0.43 mmol). The reaction mixture was stirred at room temperature for 2 h, and quenched with deionzied water. The aqueous layer was extracted with diethyl ether (2×10 mL). The organic layer was dried (Na2SO4), filtered, and concentrated in vacuo. The crude product was purified by flash chromatography (SiO2, 0-25% ethyl acetate in hexanes) to afford the desired product (0.095 g, 0.16 mmol, 77%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:11])[C:5](=[CH:9][CH:10]=1)[C:6]([OH:8])=O.[F:12][C:13]([F:26])([F:25])[C:14]1[CH:15]=[C:16]([CH:18]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:20]=1)[NH2:17]>>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:17][C:16]2[CH:18]=[C:19]([C:21]([F:22])([F:23])[F:24])[CH:20]=[C:14]([C:13]([F:12])([F:25])[F:26])[CH:15]=2)=[O:8])=[C:4]([OH:11])[CH:3]=1
Reactant: O=C(O)c1ccc(Cl)cc1O
Reactant: Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Product: O=C(Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ccc(Cl)cc1O
Yield: 55.8 %

Procedure:
Using 4-chlorosalicylic acid and 3,5-bis(trifluoromethyl)aniline as the raw materials, the same operation as the Example 1(1) gave the title compound.
Reaction SMILES: [C:1](Cl)(=[O:5])[C:2](Cl)=[O:3].[C:7]([C:15]1[CH:31]=[CH:30][C:18]([C:19]([N:21]2[CH2:26][CH2:25][C:24]3[CH:27]=CO[C:23]=3[CH2:22]2)=[O:20])=[CH:17][CH:16]=1)(=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.O>CN(C)C=O>[C:7]([C:15]1[CH:31]=[CH:30][C:18]([C:19]([N:21]2[CH2:26][CH2:25][C:24]3[CH:27]=[C:2]([CH:1]=[O:5])[O:3][C:23]=3[CH2:22]2)=[O:20])=[CH:17][CH:16]=1)(=[O:14])[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: O=C(c1ccccc1)c1ccc(C(=O)N2CCc3ccoc3C2)cc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1cc2c(o1)CN(C(=O)c1ccc(C(=O)c3ccccc3)cc1)CC2
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To 30 ml of N,N-dimethylformamide, 0.20 ml (2.3 mmol) of oxalyl chloride was added at -78° C., followed by stirring at room temperature for 15 minutes. To this mixture, a solution of 0.684 g (2.064 mmol) of 6-(4-benzoylbenzoyl)-4,5,6,7-tetrahydrofuro[2,3-c]pyridine in 10 ml of N,N-dimethylformamide was added, followed by overnight stirring at room temperature. After water was added, the reaction mixture was extracted with ethyl acetate 3 times. The combined organic layer was dried over anhydrous magnesium sulfate; the solvent was distilled off under reduced pressure. The resulting crude product was purified by silica gel flush column chromatography (hexane/ethyl acetate=1/1 to 1/3) to yield the desired product.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]2[S:6][CH:7]=[C:8]([CH2:9][CH:10]3[N:14]4[CH:15]=[CH:16][CH:17]=[CH:18][C:13]4=[N:12][C:11]3=[S:19])[C:4]=2[CH:3]=1.Br[CH2:23][CH2:24][CH2:25][C:26]([O:28][CH3:29])=[O:27].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[CH3:29][O:28][C:26](=[O:27])[CH2:25][CH2:24][CH2:23][S:19][C:11]1[N:12]=[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]2[C:10]=1[CH2:9][C:8]1[C:4]2[CH:3]=[C:2]([Cl:1])[CH:21]=[CH:20][C:5]=2[S:6][CH:7]=1
Reactant: S=C1N=C2C=CC=CN2C1Cc1csc2ccc(Cl)cc12
Reactant: COC(=O)CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)CCCSc1nc2ccccn2c1Cc1csc2ccc(Cl)cc12
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 60 mg (0.18 mmol) of 3-(5-chloro-benzo[b]thiophen-3-ylmethyl)-imidazo[1,2-a]pyridine-2-thione and 38 mg (0.21 mmol) of methyl 4-bromobutyrate and 58 mg (0.42 mmol) of potassium carbonate in 2 mL of DMF is stirred at room temperature for 18 h. The mixture is diluted with water and the product is extracted with ethyl acetate. The organic layer is washed with water and brine, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue is purified by flash chromatography on silica gel eluted with 1˜5% methanol in dichloromethane to give the desired compound.
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:4]=[C:5]([CH:25]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:27]=1)[CH2:6][N:7]([CH3:24])[C@@H:8]1[CH2:12][N:11]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=2)[C@H:10]([C:21]([OH:23])=O)[CH2:9]1.[F:34][C:35]([F:49])([F:48])[C:36]1[CH:37]=[C:38]([N:42]2[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]2)[CH:39]=[CH:40][CH:41]=1>>[F:33][C:2]([F:32])([F:1])[C:3]1[CH:4]=[C:5]([CH:25]=[C:26]([C:28]([F:31])([F:29])[F:30])[CH:27]=1)[CH2:6][N:7]([CH3:24])[C@@H:8]1[CH2:12][N:11]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=2)[C@H:10]([C:21]([N:45]2[CH2:44][CH2:43][N:42]([C:38]3[CH:39]=[CH:40][CH:41]=[C:36]([C:35]([F:48])([F:49])[F:34])[CH:37]=3)[CH2:47][CH2:46]2)=[O:23])[CH2:9]1
Reactant: FC(F)(F)c1cccc(N2CCNCC2)c1
Reactant: CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)[C@H]1C[C@@H](C(=O)O)N(Cc2cccc(Cl)c2)C1
Product: CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)[C@H]1C[C@@H](C(=O)N2CCN(c3cccc(C(F)(F)F)c3)CC2)N(Cc2cccc(Cl)c2)C1
Yield: 10 %

Procedure:
As described for Example 64e, [(2S,4S)-4-[(3,5-bis-trifluoromethyl-benzyl)-methyl-amino]-1-(3-chloro-benzyl)-pyrrolidine-2-carboxylic acid (1 mmol) was converted, using 4-(3-trifluoromethyl-phenyl)-piperazine instead of 2-cyclohexyl-1,3,8-triaza-spiro[4.5]dec-1-en-4-one, to the title product (71 mg) in 10% yield as colorless oil.
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[C:13]([N+:21]([O-:23])=[O:22])[CH:12]=2)[C:8](O)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[NH2:58][C:59]1[CH:64]=[CH:63][N:62]=[CH:61][N:60]=1>C(Cl)Cl>[CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[C:13]([N+:21]([O-:23])=[O:22])[CH:12]=2)[C:8]([NH:58][C:59]2[CH:64]=[CH:63][N:62]=[CH:61][N:60]=2)=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: Nc1ccncn1
Reactant: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)O)cc1[N+](=O)[O-]
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)Nc2ccncn2)cc1[N+](=O)[O-]
Yield: 30.5 %

Procedure:
A solution of 3-cyclopentyl-2-(4-methanesulfonyl-3-nitrophenyl)-propionic acid (prepared as in Example 14, 150 mg, 0.439 mmol), triethylamine (0.184 mL, 1.32 mmol), benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate (291 mg, 0.659 mmol), and 4-aminopyrimidine (63 mg, 0.659 mmol) in methylene chloride (4 mL) was stirred at 25° C. overnight. The crude reaction mixture was directly purified by Biotage chromatography (FLASH 40M, Silica, 1/2 hexanes/ethyl acetate) to afford 3-cyclopentyl-2-(4-methanesulfonyl-3-nitro-phenyl)-N-pyrimidin-4-yl-propionamide (56 mg, 30%) as a pale yellow foam: mp 91–95° C. (foam to gel); EI-HRMS m/e calcd for C19H22N4O5S (M+) 418.1311, found 418.1310.
Reaction SMILES: [C:1]1(=[O:11])[C:10]2[C:5](=[CH:6][CH:7]=[N:8][CH:9]=2)[CH2:4][CH2:3][NH:2]1.I[C:13]1[CH:14]=[N:15][CH:16]=[CH:17][C:18]=1[CH3:19].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.[Cu](I)I>[CH3:19][C:18]1[CH:17]=[CH:16][N:15]=[CH:14][C:13]=1[N:2]1[CH2:3][CH2:4][C:5]2[C:10](=[CH:9][N:8]=[CH:7][CH:6]=2)[C:1]1=[O:11]
Reactant: Cc1ccncc1I
Reactant: O=C1NCCc2ccncc21
Agent: I[Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: Cc1ccncc1N1CCc2ccncc2C1=O
Yield: 12.4 %

Procedure:
3,4-Dihydro-2,7-naphthyridin-1(2H)-one (I-65f: 80 mg, 0.5399 mmol) was reacted with 3-iodo-4-methylpyridine (177 mg, 0.8099 mmol), copper iodide (8 mg, 10% w/w), trans-N,N′-dimethyl-cyclohexyl-1,2-diamine (16 mg, 20% w/w) and potassium phosphate (287 mg, 1.3498 mmol) in 1,4-dioxane (5 mL) to afford the crude product. Purification by column chromatography on silica gel (3% methanol in CHCl3), followed by preparative HPLC afforded 16 mg of the product (12.4% yield).
Reaction SMILES: C=O.[CH3:3][CH:4]1[CH2:9][C@H:8]([OH:10])[C@@H:7]([CH:11]([CH3:13])[CH3:12])[CH2:6][CH2:5]1.[Cl:14][CH:15](Cl)CCl>Cl>[Cl:14][CH2:15][O:10][CH:8]1[CH:7]([CH:11]([CH3:13])[CH3:12])[CH2:6][CH2:5][CH:4]([CH3:3])[CH2:9]1
Reactant: CC1CC[C@H](C(C)C)[C@@H](O)C1
Reactant: ClCC(Cl)Cl
Agent: C=O
Agent: Cl
Product: CC1CCC(C(C)C)C(OCCl)C1
Reaction time: 2 h

Procedure:
3.0 g (0.1 mole) of paraformaldehyde were stirred at 0°-5° C. with 15.6 g (0.1 mole) of (+) Menthol in 1,1,2-trichloroethane and HCl gas was passed for 2 hours. The product was further diluted to 1M concentration.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C@H:16]([CH2:22][CH2:23][CH3:24])[CH2:17][C:18]([O:20][CH3:21])=[O:19])[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[C:25](=O)([O-])[O-].[K+].[K+].CB1OB(C)OB(C)O1>CN(C=O)C.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>[CH3:25][C:2]1[CH:3]=[C:4]([C@H:16]([CH2:22][CH2:23][CH3:24])[CH2:17][C:18]([O:20][CH3:21])=[O:19])[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CCC[C@H](CC(=O)OC)c1ccc(OCc2ccccc2)c(Br)c1
Reactant: O=C([O-])[O-]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CB1OB(C)OB(C)O1
Agent: [K+]
Solvent: CN(C)C=O
Product: CCC[C@H](CC(=O)OC)c1ccc(OCc2ccccc2)c(C)c1
Temperature: 100 °C
Yield: 61.3 %

Procedure:
To a flask charged with 27.2 (0.8986 g, 2.30 mmol), tetrakis(triphenylphosphine)palladium (0) (0.265 g, 0.230 mmol), and potassium carbonate (0.635 g, 4.59 mmol) in DMF (10 mL) was added trimethylboroxine (0.959 mL, 6.89 mmol). The resulting mixture was then heated at 100° C. overnight. The reaction was allowed to cool and was then filtered and concentrated. The product was purified by silica gel chromatography (0 to 20% EtOAc/Hexanes) yielding 27.3 (0.46 g, 61% yield).
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[O:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[CH2:15][NH:14][CH2:13][CH:12]([NH:16][C:17](=[O:24])[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:11]2)=[CH:6][CH:5]=1.[N:27]([CH2:30][CH2:31][O:32][CH3:33])=[C:28]=[O:29].C(N(CC)CC)C>C1COCC1>[CH3:33][O:32][CH2:31][CH2:30][NH:27][C:28]([N:14]1[CH2:15][CH:10]([C:7]2[CH:6]=[CH:5][C:4]([O:3][C:2]([F:1])([F:25])[F:26])=[CH:9][CH:8]=2)[CH2:11][CH:12]([NH:16][C:17]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)=[O:24])[CH2:13]1)=[O:29]
Reactant: O=C(NC1CNCC(c2ccc(OC(F)(F)F)cc2)C1)c1ccccc1
Reactant: COCCN=C=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COCCNC(=O)N1CC(NC(=O)c2ccccc2)CC(c2ccc(OC(F)(F)F)cc2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
70 mg (0.19 mmol) of N-{5-[4-(trifluoromethoxy)phenyl]piperidin-3-yl}benzamide were initially charged in 2.5 ml of THF, and 19 mg (0.19 mmol) of 1-isocyanato-2-methoxyethane and 29 μl (0.21 mmol) of triethylamine were added. The mixture was stirred at RT overnight. The reaction mixture was then purified by preparative HPLC (Reprosil C18, water/acetonitrile gradient). Yield: 32 mg (35% of theory)
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:12][CH2:11][N:10]2[C:19](OC2C=CC([N+]([O-])=O)=CC=2)=[O:20])=[CH:5][CH:4]=1.[NH2:33][C:34]1[CH:35]=[N:36][C:37]([C:40]([F:43])([F:42])[F:41])=[CH:38][CH:39]=1.[H-].[Na+].O>CC#N>[F:31][C:2]([F:1])([F:32])[C:3]1[CH:4]=[CH:5][C:6]([C@@H:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:12][CH2:11][N:10]2[C:19]([NH:33][C:34]2[CH:35]=[N:36][C:37]([C:40]([F:43])([F:41])[F:42])=[CH:38][CH:39]=2)=[O:20])=[CH:7][CH:8]=1
Reactant: Nc1ccc(C(F)(F)F)nc1
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)N1CCc2ccccc2[C@H]1c1ccc(C(F)(F)F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: O=C(Nc1ccc(C(F)(F)F)nc1)N1CCc2ccccc2[C@H]1c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (R)-4-nitrophenyl 1-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (70 mg, 158 example 88) in MeCN (0.5 mL) was added 3-amino-6-(trifluoromethyl)pyridine (77 mg, 475 μmol). The resulting mixture was then subjected to a microwave irradiation at 150° C. for 15 min and at 180° C. for 15 min. Then, sodium hydride, 60% dispersion in mineral oil (18 mg, 475 μmol) was added and the mixture was stirred at RT for overnight. Then, H2O (0.5 mL) was added and the solvents were removed. The residue was then dissolved in a solution of MeOH and DMSO (1:1. 1.0 mL). The solution mixture was purified by preparative HPLC (0%-100% MeCN 0.1% TFA/H2O 0.1% TFA) to give the desired product, which was then dissolved in MeOH (1.0 mL). The solution was then washed through PL-HCO3 MP resin (polymerlabs, 200 mg/6 mL tube) and the resin was washed with MeOH (2×0.5 mL). The combined washings were then concentrated and dried under vacuum to give the title compound as a yellow solid. MS (ESI, positive ion) m/z: 466 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:9][CH:8]=[N:7][C:6]=1[NH:10][NH2:11])=[O:4].C(N(CC)CC)C.C[O:20][C:21](=O)[N:22]=[C:23](SC)[C:24]([C:38]1[CH:39]=[C:40]([CH2:48][CH3:49])[C:41]2[O:46][CH2:45][O:44][CH2:43][C:42]=2[CH:47]=1)=[N:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]2[N:36]=[C:35]([CH3:37])[O:34][N:33]=2)=[CH:28][CH:27]=1>C1COCC1>[CH3:1][O:2][C:3]([C:5]1[S:9][CH:8]=[N:7][C:6]=1[N:10]1[C:21](=[O:20])[NH:22][C:23]([CH:24]([C:38]2[CH:39]=[C:40]([CH2:48][CH3:49])[C:41]3[O:46][CH2:45][O:44][CH2:43][C:42]=3[CH:47]=2)[NH:25][C:26]2[CH:27]=[CH:28][C:29]([C:32]3[N:36]=[C:35]([CH3:37])[O:34][N:33]=3)=[CH:30][CH:31]=2)=[N:11]1)=[O:4]
Reactant: CCc1cc(C(=Nc2ccc(-c3noc(C)n3)cc2)C(=NC(=O)OC)SC)cc2c1OCOC2
Reactant: COC(=O)c1scnc1NN
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCc1cc(C(Nc2ccc(-c3noc(C)n3)cc2)c2nn(-c3ncsc3C(=O)OC)c(=O)[nH]2)cc2c1OCOC2
Temperature: 60 °C
Reaction time: 8 h

Procedure:
After adding 71 mg of 4-hydrazinothiazole-5-carboxylic acid methyl ester (Example (162c)) and 300 μl of triethylamine to a solution of 198 mg of [2-(8-ethyl-4H-benzo[1,3]dioxin-6-yl)-2-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylimino]-1-methylsulfanylethylidene]carbamic acid methyl ester (Example (27b)) in 6 ml of THF, the mixture was stirred overnight at 60° C. under a nitrogen atmosphere. The reaction mixture was then concentrated. The residue was dissolved in 6 ml of DMF, and then 0.3 ml of triethylamine was added and the mixture was stirred at 80° C. for 6 hours.
Reaction SMILES: [CH2:1]([CH2:3][NH2:4])[OH:2].C(N(CC)CC)C.Cl.[CH:13]1([CH2:16][N:17]2[C:21]3[CH:22]=[CH:23][C:24]([S:26]([C:29]([CH3:34])([CH3:33])[C:30](Cl)=[O:31])(=[O:28])=[O:27])=[CH:25][C:20]=3[N:19]=[C:18]2[CH2:35][C:36]([CH3:39])([CH3:38])[CH3:37])[CH2:15][CH2:14]1>ClCCl>[CH:13]1([CH2:16][N:17]2[C:21]3[CH:22]=[CH:23][C:24]([S:26]([C:29]([CH3:33])([CH3:34])[C:30]([NH:4][CH2:3][CH2:1][OH:2])=[O:31])(=[O:28])=[O:27])=[CH:25][C:20]=3[N:19]=[C:18]2[CH2:35][C:36]([CH3:39])([CH3:38])[CH3:37])[CH2:14][CH2:15]1
Reactant: NCCO
Reactant: CC(C)(C)Cc1nc2cc(S(=O)(=O)C(C)(C)C(=O)Cl)ccc2n1CC1CC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)Cc1nc2cc(S(=O)(=O)C(C)(C)C(=O)NCCO)ccc2n1CC1CC1
Reaction time: 1 h
Yield: 54.4 %

Procedure:
To a mixture of ethanolamine (54 mg, 0.886 mmol), triethylamine (0.184 mL, 1.32 mmol) and dichloromethane (3 mL) was added a solution of 2-{[1-(cyclopropylmethyl)-2-(2,2-dimethylpropyl)-1H-benzimidazol-5-yl]sulfonyl}-2-methylpropanoyl chloride hydrochloride (Step A of Example 7, 198 mg, 0.443 mmol) in dichloromethane (2 mL) at room temperature. After stirring at the same temperature for 1 h, the mixture was concentrated under reduced pressure. The residue was purified by HPLC (ODS, gradient elution with acetonitrile/0.01% aq. NH3=4:96 to 96:4, by volume; flow rate 40 mL/min) to afford the title compound (105 mg, 55%) as an amorphous.