Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][N:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][C:5]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)=[CH:4][C:3]1=S.[CH2:23]([O:25][C:26](=[O:31])[CH:27](Cl)[CH:28]=O)[CH3:24].C([O-])(O)=O.[Na+]>CCO>[CH2:23]([O:25][C:26]([C:27]1[CH:28]=[N:1][N:2]2[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][C:5]([C:12]3[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=3)=[CH:4][C:3]=12)=[O:31])[CH3:24]
Reactant: Nn1c(C(F)(F)F)cc(-c2ccc(C(F)(F)F)cc2)cc1=S
Reactant: CCOC(=O)C(Cl)C=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)cc12
Reaction time: 18 h
Yield: 61.6 %

Procedure:
A solution of 1-amino-6-trifluoromethyl-4-(4-trifluoromethyl-phenyl)-1H-pyridine-2-thione (example C.22 step 6) (3.14 g, 9.28 mmol) and 2-chloro-3-oxo-propionic acid ethyl ester (example C.22 reagent 1) (4.19 g, 27.85 mmol) in EtOH (45 mL) was refluxed for 20 h, the added again 2-chloro-3-oxo-propionic acid ethyl ester (example C.22 reagent 1) (2.20 g, 14.61 mmol) and refluxing was continued for another 18 h. Poured into sat. NaHCO3-sol., extracted with EtOAc, washed the organic layer with brine, dried over Na2SO4 and evaporated to leave a residue, which was purified by flash chromatography (600 g SiO2) with heptane/EtOAc 9:1, followed by trituration with heptane (ca. 50 mL) at −70° C. to give the title compound as a light yellow solid (2.30 g, 62%). MS (ISP) 403 [(M+H)+]; mp 130° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([NH:17][C:18]([C@:20]4([S:25][CH3:26])[CH2:24][CH2:23][NH:22][CH2:21]4)=[O:19])[CH:15]=3)[NH:10][N:9]=2)[CH:5]=[CH:4][N:3]=1.Cl[CH2:28][C:29]([CH:31]1[CH2:36][CH2:35][N:34]([C:37]2[S:38][CH:39]=[CH:40][N:41]=2)[CH2:33][CH2:32]1)=[O:30].C(N(CC)CC)C>CN(C=O)C>[CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([NH:17][C:18]([C@:20]4([S:25][CH3:26])[CH2:24][CH2:23][N:22]([CH2:28][C:29](=[O:30])[CH:31]5[CH2:32][CH2:33][N:34]([C:37]6[S:38][CH:39]=[CH:40][N:41]=6)[CH2:35][CH2:36]5)[CH2:21]4)=[O:19])[CH:15]=3)[NH:10][N:9]=2)[CH:5]=[CH:4][N:3]=1
Reactant: O=C(CCl)C1CCN(c2nccs2)CC1
Reactant: CS[C@@]1(C(=O)Nc2ccc3[nH]nc(-c4ccnc(C)c4)c3c2)CCNC1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CS[C@@]1(C(=O)Nc2ccc3[nH]nc(-c4ccnc(C)c4)c3c2)CCN(CC(=O)C2CCN(c3nccs3)CC2)C1
Temperature: 45 °C
Yield: 77.3 %

Procedure:
(S)—N-(3-(2-methylpyridin-4-yl)-1H-indazol-5-yl)-3-(methylthio)pyrrolidine-3-carboxamide 6 (176 mg, 0.2 mmol) and 2-chloro-1-(1-(thiazol-2-yl)piperidin-4-yl)ethanone 5 (52 mg, 0.2 mmol) was mixed in DMF (2 mL) together with triethylamine (0.1 mL). The reaction mixture was heated at 45° C. for 3 hrs before concentrated to dryness in vacuo. The resulting crude was purified on silica gel column (eluting with 2% to 4% NH3/MeOH (2 N) in CH2Cl2) to yield 7 as a light yellow solid (89 mg, 77%). LCMS M+1=576.3 retention time=1.73 min.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH3:12])=[N:7]2.[NH2:13][C:14]1[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][C:15]=1[S:21][C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=1>>[CH3:20][C:18]1[CH:17]=[CH:16][C:15]([S:21][C:22]2[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=2)=[C:14]([NH:13][C:2]2[C:3]3[C:8](=[N:7][C:6]([CH3:12])=[CH:5][CH:4]=3)[N:9]=[CH:10][CH:11]=2)[CH:19]=1
Reactant: Cc1ccc2c(Cl)ccnc2n1
Reactant: Cc1ccc(Sc2ccc(O)cc2)c(N)c1
Product: Cc1ccc(Sc2ccc(O)cc2)c(Nc2ccnc3nc(C)ccc23)c1

Procedure:
The product from Example 7d (277 mg, 0.156 mmol) was reacted with the product from Example 9c (361 mg, 0.156 mmol) for 5 h by the procedure in Example 7g giving the title compound after purification of the crude product by HPLC with TFA as the trifluoroacetic acid salt (231 mg, 30%). 1H NMR (300 MHz, DMSO-d6) δ ppm: 2.33 (s, 3 H) 2.77 (s, 3 H) 6.29 (d, J=6.99 Hz, 1 H) 6.73 (d, J=8.82 Hz, 2 H) 7.01 (d, J=7.72 Hz, 1 H) 7.19 (d, J=8.46 Hz, 2 H) 7.24 (s, 1 H) 7.27 (s, 1 H) 7.81 (d, J=8.82 Hz, 1 H) 8.44 (d, J=6.99 Hz, 1 H) 9.01 (d, J=8.82 Hz, 1 H) 9.91 (s, 1 H) 11.03 (s, 1 H) 14.38 (br. s, 1 H); MS (ESI+) m/z 374 (M+H)+.
Reaction SMILES: [CH:1]([NH:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([CH2:13][CH2:14][O:15][C:16]2[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=2)[C:19]([OH:21])=O)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2].[NH2:25][CH:26]1[CH:33]2[CH2:34][C:29]3([CH2:36][OH:37])[CH2:30][CH:31]([CH2:35][CH:27]1[CH2:28]3)[CH2:32]2>>[CH:1]([NH:4][C:5]([N:7]1[CH2:8][CH2:9][CH:10]([CH2:13][CH2:14][O:15][C:16]2[CH:24]=[CH:23][CH:22]=[C:18]([C:19](=[O:21])[NH:25][CH:26]3[CH:27]4[CH2:35][CH:31]5[CH2:30][C:29]([CH2:36][OH:37])([CH2:34][CH:33]3[CH2:32]5)[CH2:28]4)[CH:17]=2)[CH2:11][CH2:12]1)=[O:6])([CH3:2])[CH3:3]
Reactant: CC(C)NC(=O)N1CCC(CCOc2cccc(C(=O)O)c2)CC1
Reactant: NC1C2CC3CC1CC(CO)(C3)C2
Product: CC(C)NC(=O)N1CCC(CCOc2cccc(C(=O)NC3C4CC5CC3CC(CO)(C5)C4)c2)CC1

Procedure:
Prepared from 3-[2-(1-isopropylcarbamoyl-piperidin-4-yl)-ethoxy]-benzoic acid and 4-amino-1-hydroxymethyladamantane to give the title compound as a mixture of two isomers. 1H NMR (400 MHz, CDCl3) δ: 7.30-7.37 (m, 2H), 7.23-7.29 (m, 1H), 7.02 (d, 1H), 6.32-6.43 (m, 1H), 4.16-4.24 (m, 1H), 4.06 (t, 2H), 3.94-4.02 (m, 1H), 3.91 (d, 2H), 3.26 (d, 2H), 2.77 (t, 2H), 2.11-2.19 (m, 2H), 1.99-2.05 (m, 1H), 1.41-1.94 (m, 15H), 1.18-1.29 (m, 2H), 1.15 (d, 6H).
Reaction SMILES: [F:1][CH:2]([F:23])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:18]=[CH:17][CH:16]=[C:15]3[C:11]=2[CH2:12][CH2:13][C:14]3=[O:19])=[C:6]([OH:20])[C:5]=1[O:21][CH3:22].C(=O)([O-])[O-].[K+].[K+].Br[CH2:31][C:32]1[CH:37]=[CH:36][C:35]([S:38]([NH2:41])(=[O:40])=[O:39])=[CH:34][CH:33]=1>C(#N)C>[F:1][CH:2]([F:23])[O:3][C:4]1[C:5]([O:21][CH3:22])=[C:6]([C:7]([C:10]2[CH:18]=[CH:17][CH:16]=[C:15]3[C:11]=2[CH2:12][CH2:13][C:14]3=[O:19])=[CH:8][CH:9]=1)[O:20][CH2:31][C:32]1[CH:33]=[CH:34][C:35]([S:38]([NH2:41])(=[O:40])=[O:39])=[CH:36][CH:37]=1
Reactant: NS(=O)(=O)c1ccc(CBr)cc1
Reactant: COc1c(OC(F)F)ccc(-c2cccc3c2CCC3=O)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1c(OC(F)F)ccc(-c2cccc3c2CCC3=O)c1OCc1ccc(S(N)(=O)=O)cc1
Temperature: 80 °C
Yield: 32.7 %

Procedure:
To a stirring solution of 4-(4-(difluoromethoxy)-2-hydroxy-3-methoxyphenyl)-2,3-dihydro-1H-inden-1-one (80 mg, 0.25 mmol) in acetonitrile (10 mL), was added potassium carbonate (104 mg, 0.75 mmol) and 4-bromomethyl-benzenesulfonamide (125 mg, 0.5 mmol) and the resultant reaction mixture was heated to 80° C. for 16 h. The reaction mixture was cooled to RT and filtered through celite and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 0-70° A) ethyl acetate in pet ether) to afford title compound as a solid (40 mg, 33%).
Reaction SMILES: [CH:1]([C@@H:4]1[NH:9][CH2:8][CH2:7][N:6]([C:10]2[C:11]3[C:18]([CH3:19])=[CH:17][NH:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH2:5]1)([CH3:3])[CH3:2].[Br:20][C:21]1[CH:22]=[C:23]([NH:27][C:28](=[N:36][C:37]#[N:38])OC2C=CC=CC=2)[CH:24]=[CH:25][CH:26]=1>C(O)(C)C>[Br:20][C:21]1[CH:22]=[C:23]([NH:27][C:28]([N:9]2[CH2:8][CH2:7][N:6]([C:10]3[C:11]4[C:18]([CH3:19])=[CH:17][NH:16][C:12]=4[N:13]=[CH:14][N:15]=3)[CH2:5][C@@H:4]2[CH:1]([CH3:3])[CH3:2])=[N:36][C:37]#[N:38])[CH:24]=[CH:25][CH:26]=1
Reactant: Cc1c[nH]c2ncnc(N3CCN[C@@H](C(C)C)C3)c12
Reactant: N#CN=C(Nc1cccc(Br)c1)Oc1ccccc1
Solvent: CC(C)O
Product: Cc1c[nH]c2ncnc(N3CCN(C(=NC#N)Nc4cccc(Br)c4)[C@@H](C(C)C)C3)c12
Temperature: 120 °C
Yield: 7 %

Procedure:
The piperazine from step A was combined with phenyl N-3-bromophenyl-N′-cyanocarbamimidate, from example 5, step A, (40 mg, 1.2 mmol) in isopropanol in a sealed tube. The reaction was heated to 120° C., monitored by LC/MS until no starting material remained, and then concentrated under vacuum. The residue was purified by prep HPLC (Sunfire C18 5u 30×100 mm, 10% to 100% B, gradient time=13 min, flow rate=45 ml/min, wavelength=220 nm, solvent A=10 mM aq. Ammonium acetate, solvent B=acetonitrile) to give (S)—N-(3-bromophenyl)-N′-cyano-2-isopropyl-4-(5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazine-1-carboximidamide (2.2 mg, 7%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([NH:15][C@H:16]1[CH2:20][CH2:19][N:18]([C@H:21]([CH3:25])[C:22]([OH:24])=O)[C:17]1=[O:26])(=[O:14])=[O:13])[CH:6]=[CH:5]2.Cl.CN(C)CCCN=C=NCC.C1C=CC2N(O)N=NC=2C=1.[NH:49]1[CH2:54][CH2:53][O:52][CH2:51][CH2:50]1>C(Cl)Cl.C(N(CC)CC)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([NH:15][C@H:16]1[CH2:20][CH2:19][N:18]([C@H:21]([CH3:25])[C:22]([N:49]3[CH2:54][CH2:53][O:52][CH2:51][CH2:50]3)=[O:24])[C:17]1=[O:26])(=[O:13])=[O:14])[CH:6]=[CH:5]2
Reactant: C1COCCN1
Reactant: C[C@H](C(=O)O)N1CC[C@H](NS(=O)(=O)c2ccc3cc(Cl)ccc3c2)C1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@H](C(=O)N1CCOCC1)N1CC[C@H](NS(=O)(=O)c2ccc3cc(Cl)ccc3c2)C1=O
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of (2R)-2-((3S)-3-{[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoic acid [Intermediate 28] (0.037 g) in DCM (1.0 ml) were added 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (0.036 g), HOBT (0.025 g) and triethylamine (0.026 ml) and the mixture was stirred at room temperature for 5 min. Morpholine (0.012 ml) was added and the resultant mixture stirred at room temperature for 15.5 h. The mixture was partitioned between DCM and saturated sodium bicarbonate solution and then passed through a hydrophobic frit. The organic extract was concentrated under reduced pressure and the residue was partially purified using preparative thin layer chromatography (20 cm×20 cm 1 mm thick Whatman PKF256 SiO2 plate, eluting with hexane:ethyl acetate 1:5) to give an impure sample of the title compound. This sample was repurified using preparative thin layer chromatography (20 cm×20 cm 1 mm thick Whatman PKF256 SiO2 plate, eluting with hexane:ethyl acetate 1:8) to give the title compound (0.036 g) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[NH:13][C:12](=[O:14])[N:11]([C:15]2[CH:24]=[CH:23][C:18]([C:19]([O:21]C)=[O:20])=[CH:17][CH:16]=2)[N:10]=1.[OH-].[Na+]>C1COCC1.O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[NH:13][C:12](=[O:14])[N:11]([C:15]2[CH:24]=[CH:23][C:18]([C:19]([OH:21])=[O:20])=[CH:17][CH:16]=2)[N:10]=1
Reactant: COC(=O)c1ccc(-n2nc(-c3c(F)cccc3Cl)[nH]c2=O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1ccc(-n2nc(-c3c(F)cccc3Cl)[nH]c2=O)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 52 %

Procedure:
To a solution of methyl 4-[3-(2-chloro-6-fluorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]benzoate (2.0 g, 5.76 mmol) in THF:water (5 mL:10 mL) was added sodium hydroxide (0.691 g, 17.27 mmol). The reaction mass was stirred at RT for 3 h. The reaction mass was diluted with water and washed the aqueous layer with diethyl ether and toluene. The aqueous layer was cooled to 15° C. and acidified with dilute HCl. The reaction mass was filtered off to afford 1.0 g of desired product. 1H NMR (300 MHz, DMSO d6): δ 7.50 (t, J=9.0 Hz, 1H), 7.58 (d, J=7.8 Hz, 1H), 7.67-7.74 (m, 1H), 8.06 (s, 4H), 12.77 (br s, 1H).
Reaction SMILES: [C:1]1(=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[CH:3]=[CH:2]1.[CH2:13]([N:18]1[CH:22]=[CH:21][CH:20]=[CH:19]1)[CH2:14][CH2:15][CH2:16][CH3:17]>C(O)(=O)C>[CH2:13]([N:18]1[C:22]([C:3]2[C:4](=[O:11])[C:5]3[C:10]([C:1](=[O:12])[CH:2]=2)=[CH:9][CH:8]=[CH:7][CH:6]=3)=[CH:21][CH:20]=[C:19]1[C:3]1[C:4](=[O:11])[C:5]2[C:10]([C:1](=[O:12])[CH:2]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: CCCCCn1cccc1
Reactant: O=C1C=CC(=O)c2ccccc21
Solvent: CC(=O)O
Product: CCCCCn1c(C2=CC(=O)c3ccccc3C2=O)ccc1C1=CC(=O)c2ccccc2C1=O
Yield: 87 %

Procedure:
The same procedure as in Example 7 was followed by stirring 10 millimol of 1,4-naphthoquinone with 2.5 millimol of N-pentylpyrrole in 40 ml of acetic acid at 50° C. for 5 hours. The 1-pentyl-2,5-bis(1,4-naphthoquinon-2-yl)pyrrole was thus obtained in a yield of 87% after chromatography on a column of silica.
Reaction SMILES: [CH:1]1([C:6]([N:8]2[CH2:13][CH:12]([C:14]3[CH:19]=[CH:18][C:17]([CH2:20][CH3:21])=[CH:16][CH:15]=3)[CH2:11][CH:10]([C:22](O)=[O:23])[CH2:9]2)=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.O[N:26]=[C:27]([C:29]1[N:30]=[C:31]([CH3:34])[S:32][CH:33]=1)[NH2:28]>>[CH:1]1([C:6]([N:8]2[CH2:9][CH:10]([C:22]3[O:23][N:28]=[C:27]([C:29]4[N:30]=[C:31]([CH3:34])[S:32][CH:33]=4)[N:26]=3)[CH2:11][CH:12]([C:14]3[CH:15]=[CH:16][C:17]([CH2:20][CH3:21])=[CH:18][CH:19]=3)[CH2:13]2)=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1nc(C(N)=NO)cs1
Reactant: CCc1ccc(C2CC(C(=O)O)CN(C(=O)C3CCCC3)C2)cc1
Product: CCc1ccc(C2CC(c3nc(-c4csc(C)n4)no3)CN(C(=O)C3CCCC3)C2)cc1

Procedure:
66 mg (0.20 mmol) of 1-(cyclopentylcarbonyl)-5-(4-ethylphenyl)piperidine-3-carboxylic acid (Example 7A) and 35 mg (0.22 mmol, 1.1 eq.) of N′-hydroxy-2-methyl-1,3-thiazole-4-carboximidamide were reacted according to the General Method 1. Yield: 36 mg (40% of theory)
Reaction SMILES: [C:1]1([C@H:7]([CH3:13])[CH2:8][NH:9][C:10]([NH2:12])=[S:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH:15]([CH2:19][CH3:20])[C:16](O)=[O:17]>>[CH2:19]([C@@H:15]1[S:11][C:10]([NH:9][CH2:8][C@H:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH3:13])=[N:12][C:16]1=[O:17])[CH3:20]
Reactant: CCC(Br)C(=O)O
Reactant: C[C@H](CNC(N)=S)c1ccccc1
Product: CC[C@@H]1SC(NC[C@@H](C)c2ccccc2)=NC1=O

Procedure:
Synthesis was performed from N-[(2S)-2-phenylpropyl]thiourea and 2-bromo-butyric acid according to Method D3.
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[NH:7][C:8]1[C:13]([N+:14]([O-])=O)=[CH:12][C:11]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[F:23])=[C:10]([N:24]([CH3:26])[CH3:25])[CH:9]=1)([CH3:4])([CH3:3])[CH3:2]>[Pd]>[C:1]([O:5][C:6](=[O:27])[NH:7][C:8]1[C:13]([NH2:14])=[CH:12][C:11]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[F:23])=[C:10]([N:24]([CH3:25])[CH3:26])[CH:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(C)c1cc(NC(=O)OC(C)(C)C)c([N+](=O)[O-])cc1-c1ccccc1F
Agent: [Pd]
Product: CN(C)c1cc(NC(=O)OC(C)(C)C)c(N)cc1-c1ccccc1F

Procedure:
The title compound was prepared from (2-dimethylamino-2′-fluoro-5-nitro-biphenyl-4-yl)-carbamic acid tert.-butyl ester (Example C18) (4.54 g, 12.1 mmol) by hydrogenation with 10% Pd/C according to the general procedure J (method a). Obtained as a light brown solid (3.324 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][C:5]([C@@H:8]([NH2:10])[CH3:9])=[N:6][CH:7]=1.Cl[C:12]1[N:17]=[C:16]([NH:18][C:19]2[CH:23]=[C:22]([CH3:24])[NH:21][N:20]=2)[C:15]([CH3:25])=[CH:14][N:13]=1.CCN(C(C)C)C(C)C>CCCCO>[F:1][C:2]1[CH:3]=[N:4][C:5]([C@@H:8]([NH:10][C:12]2[N:17]=[C:16]([NH:18][C:19]3[CH:23]=[C:22]([CH3:24])[NH:21][N:20]=3)[C:15]([CH3:25])=[CH:14][N:13]=2)[CH3:9])=[N:6][CH:7]=1
Reactant: C[C@H](N)c1ncc(F)cn1
Reactant: Cc1cc(Nc2nc(Cl)ncc2C)n[nH]1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: Cc1cc(Nc2nc(N[C@@H](C)c3ncc(F)cn3)ncc2C)n[nH]1
Temperature: 180 °C
Yield: 36.3 %

Procedure:
A microwave reaction vessel was charged with (S)-1-(5-fluoropyrimidin-2-yl)ethanamine (Method 7, 111 mg, 0.63 mmol), 2-chloro-5-methyl-N-(5-methyl-1H-pyrazol-3-yl)pyrimidin-4-amine (Method 22, 0.50 g, 1.77 mmol), and DIPEA (0.225 mL, 1.26 mmol). Anhydrous n-BuOH (2.1 ml) was added, and the tube was sealed and heated in a microwave reactor at 180° C. for 4 hours. The solvent was removed under reduced pressure and the residue was purified by Gilson (5-95% MeCN/H2O, 15 minutes) to give the titled compound as solid (75 mg) 1H NMR (300 MHz, DMSO-d6) δ 10.08 (s, 1H) 8.93 (s, 2H) 8.70 (s, 1H) 7.74 (s, 1H) 5.98 (s, 1H) 4.79-5.44 (m, 1H) 2.23 (s, 3H) 2.10 (s, 3H) 1.57 (d, 3H); m/z 330.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:16])[C:8]3=[CH:7][C:6]=2[C:5]([F:17])=[C:4]([F:18])[CH:3]=1.[F:19][C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1>>[F:18][C:4]1[CH:3]=[C:2]([C:23]2[CH:24]=[CH:25][C:20]([F:19])=[CH:21][CH:22]=2)[C:10]2[N:9]3[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:16])[C:8]3=[CH:7][C:6]=2[C:5]=1[F:17]
Reactant: OB(O)c1ccc(F)cc1
Reactant: O=C1NCCCn2c1cc1c(F)c(F)cc(Br)c12
Product: O=C1NCCCn2c1cc1c(F)c(F)cc(-c3ccc(F)cc3)c12

Procedure:
The title compound, light grey solid (79 mg, 96%), MS (ISP) m/z=331.2 [(M+H)+], mp 287° C., was prepared in accordance with the general method of example 1 from 7-bromo-9,10-difluoro-2,3,4,5-tetrahydro-[1,4]diazepino[1,2-a]indol-1-one (intermediate 5) (78.8 mg, 0.25 mmol) and commercially available 4-fluoro-phenylboronic acid (45.5 mg, 0.325 mmol).
Reaction SMILES: C[O:2][C:3](=[O:34])[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([F:14])=[CH:11][CH:12]=2)[C:7]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]#[N:23])=[CH:18][C:17]=2[S:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)(=[O:26])=[O:25])=[C:6]1[CH3:33].[OH-].[Li+].Cl>O1CCCC1>[C:27]1([S:24]([C:17]2[CH:18]=[C:19]([C:22]#[N:23])[CH:20]=[CH:21][C:16]=2[CH2:15][C:7]2[C:8]3[C:13](=[CH:12][CH:11]=[C:10]([F:14])[CH:9]=3)[N:5]([CH2:4][C:3]([OH:34])=[O:2])[C:6]=2[CH3:33])(=[O:26])=[O:25])[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: COC(=O)Cn1c(C)c(Cc2ccc(C#N)cc2S(=O)(=O)c2ccccc2)c2cc(F)ccc21
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1c(Cc2ccc(C#N)cc2S(=O)(=O)c2ccccc2)c2cc(F)ccc2n1CC(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 54.3 %

Procedure:
A solution of [3-(2-benzenesulfonyl-4-cyanobenzyl)-5-fluoro-2-methylindol-1-yl]acetic acid methyl ester (0.11 g) in tetrahydrofuran (0.30 mL) was treated with 1.0 M aqueous lithium hydroxide solution (2.0 mL), and the resulting mixture was stirred at room temperature for 2 hours. The mixture was acidified by the addition of 1.0 M aqueous hydrochloric acid solution and concentrated under reduced pressure. The residue was purified by preparative reverse-phase HPLC, eluting with a mixture of acetonitrile and water (2:3 to 19:1 by volume) to afford the title compound as a white solid (0.058 g).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:17][C:18]1[CH:19]=[N:20][N:21]([CH:23]2[CH2:28][CH2:27][N:26]([CH3:29])[CH2:25][CH2:24]2)[CH:22]=1.[Cl:30][C:31]1[CH:36]=[C:35](B2OC(C)(C)C(C)(C)O2)[CH:34]=[C:33]([Cl:46])[C:32]=1[OH:47]>>[CH:14]1([C:12]([C:6]2[CH:7]=[N:8][C:9]3[C:4]([C:5]=2[NH:17][C:18]2[CH:19]=[N:20][N:21]([CH:23]4[CH2:24][CH2:25][N:26]([CH3:29])[CH2:27][CH2:28]4)[CH:22]=2)=[CH:3][C:2]([C:35]2[CH:36]=[C:31]([Cl:30])[C:32]([OH:47])=[C:33]([Cl:46])[CH:34]=2)=[CH:11][CH:10]=3)=[O:13])[CH2:15][CH2:16]1
Reactant: CC1(C)OB(c2cc(Cl)c(O)c(Cl)c2)OC1(C)C
Reactant: CN1CCC(n2cc(Nc3c(C(=O)C4CC4)cnc4ccc(Br)cc34)cn2)CC1
Product: CN1CCC(n2cc(Nc3c(C(=O)C4CC4)cnc4ccc(-c5cc(Cl)c(O)c(Cl)c5)cc34)cn2)CC1
Yield: 61 %

Procedure:
Following general procedure D, (6-bromo-4-(1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-ylamino) quinoline-3-yl)(cyclopropyl)methanone (50 mg, 0.11 mmol) was reacted with 2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (49 mg, 0.17 mmol) to afford the desired product (36 mg, 63%) as a yellow solid: 1H NMR (500 MHz, CD3OD+TFA-d) δ 9.45 (s, 1H), 8.23 (d, J=9.0 Hz, 1H), 8.01 (d, J=9.2 Hz, 2H), 7.68 (s, 1H), 7.40 (s, 1H), 4.62 (m, 1H), 3.68 (d, J=12.8 Hz, 2H), 3.41 (m, 1H), 3.25 (m, 2H), 2.94 (s, 3H), 2.37 (m, 3H), 1.22 (m, 3H); ESI MS m/z 536 [C28H27Cl2N5O2+H]+; HPLC 98.4% (AUC), tR=10.57 min.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:14]3[C:9](=[CH:10][N:11]=[CH:12][CH:13]=3)[C:8](=[O:15])[NH:7][C:6]=2[CH:16]=1.[CH3:17][O:18][CH2:19][CH2:20]Br>CN(C=O)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:14]3[C:9](=[CH:10][N:11]=[CH:12][CH:13]=3)[C:8](=[O:15])[N:7]([CH2:20][CH2:19][O:18][CH3:17])[C:6]=2[CH:16]=1
Reactant: O=c1[nH]c2cc(Cl)ccc2c2ccncc12
Reactant: COCCBr
Solvent: CN(C)C=O
Solvent: O
Product: COCCn1c(=O)c2cnccc2c2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 12 h
Yield: 80 %

Procedure:
To a stirred solution of 8-chlorobenzo[c][2,7]naphthyridin-5(6H)-one (0.150 g, 0.650 mmol) in anhydrous DMF (2 mL) at 0° C. was added 2-bromoethyl methyl ether (0.090 g, 0.650 mmol) under nitrogen. The reaction mixture was allowed to warm to RT and stirred for 12 h. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (2×20 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to afford 8-chloro-6-(2-methoxyethyl)benzo[c][2,7]naphthyridin-5(6H)-one (150 mg, 0.520 mmol, 80% yield). LC/MS (ESI) m/e 289.1 [(M+H)+, calcd for C15H13ClN2O2 289.1]; LC/MS retention time (method A): tR=1.65 min.
Reaction SMILES: C([O:8][C:9](=[O:40])[C:10]([CH3:39])([O:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH:19]2[CH2:24][CH2:23][CH2:22][N:21]([C:25](=[O:38])[NH:26][CH2:27][C:28]3[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][CH:29]=3)[CH2:20]2)[CH:14]=1)[CH3:11])C1C=CC=CC=1>[Pd].CO>[CH3:39][C:10]([O:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH:19]2[CH2:24][CH2:23][CH2:22][N:21]([C:25](=[O:38])[NH:26][CH2:27][C:28]3[CH:29]=[CH:30][C:31]([C:34]([F:36])([F:37])[F:35])=[CH:32][CH:33]=3)[CH2:20]2)[CH:14]=1)([CH3:11])[C:9]([OH:40])=[O:8]
Reactant: CC(C)(Oc1cccc(C2CCCN(C(=O)NCc3ccc(C(F)(F)F)cc3)C2)c1)C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CC(C)(Oc1cccc(C2CCCN(C(=O)NCc3ccc(C(F)(F)F)cc3)C2)c1)C(=O)O
Reaction time: 4 h
Yield: 44.4 %

Procedure:
10% Palladium on carbon (53 mg, 50 wt %) was added to a solution of 2-methyl-2-{3-[1-(4-trifluoromethyl-benzylcarbamoyl)-piperidin-3-yl]-phenoxy}-propionic acid benzyl ester (111 mg, 0.226 mmol) in methanol (5 mL) and the resulting mixture hydrogenated at 50 psi for 4 h. The reaction mixture was filtered through a plug of celite and the celite plug washed thoroughly with ethyl acetate. The combined filtrates were concentrated under reduced pressure. The resultant oil was flash chromatographed with 2% methanol/chloroform to provide 46.6 mg (51%) of 2-methyl-2-{3-[1-(4-trifluoromethyl-benzylcarbamoyl)-piperidin-3-yl]-phenoxy}-propionic acid as a clear oil.
Reaction SMILES: [C:1]1([C:7]2[O:8][C:9]([C:15]([F:18])([F:17])[F:16])=[C:10]([C:12]([OH:14])=O)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:19][C:20]1[CH:21]=[CH:22][C:23]([N:26]2[CH2:30][CH2:29][CH2:28][C@H:27]2[CH2:31][OH:32])=[N:24][CH:25]=1>>[OH:32][CH2:31][C@@H:27]1[CH2:28][CH2:29][CH2:30][N:26]1[C:23]1[N:24]=[CH:25][C:20]([NH:19][C:12]([C:10]2[N:11]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[O:8][C:9]=2[C:15]([F:18])([F:17])[F:16])=[O:14])=[CH:21][CH:22]=1
Reactant: O=C(O)c1nc(-c2ccccc2)oc1C(F)(F)F
Reactant: Nc1ccc(N2CCC[C@H]2CO)nc1
Product: O=C(Nc1ccc(N2CCC[C@H]2CO)nc1)c1nc(-c2ccccc2)oc1C(F)(F)F

Procedure:
With a procedure similar to example 43 above, 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [6-((S)-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-amide was prepared from 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid and [(S)-1-(5-amino-pyridin-2-yl)-pyrrolidin-2-yl]-methanol. LCMS calcd for C21H19F3N4O3 (m/e) 432, obsd 433 (M+H).
Reaction SMILES: [CH3:1][C:2]1[NH:6][C:5]2[CH:7]=[C:8]([C:11]3[CH:12]=[CH:13][C:14]4[O:20][CH2:19][CH2:18][N:17]([C:21]5[C:30]6[C:25](=[C:26]([O:39][CH3:40])[C:27]([O:31][CH2:32][C:33]7C=CC=CC=7)=[CH:28][CH:29]=6)[N:24]=[CH:23][N:22]=5)[CH2:16][C:15]=4[CH:41]=3)[CH:9]=[CH:10][C:4]=2[N:3]=1.[CH3:42][N:43](CCCl)[CH3:44]>>[CH3:42][N:43]([CH3:44])[CH2:33][CH2:32][O:31][C:27]1[C:26]([O:39][CH3:40])=[C:25]2[C:30]([C:21]([N:17]3[CH2:16][C:15]4[CH:41]=[C:11]([C:8]5[CH:9]=[CH:10][C:4]6[N:3]=[C:2]([CH3:1])[NH:6][C:5]=6[CH:7]=5)[CH:12]=[CH:13][C:14]=4[O:20][CH2:19][CH2:18]3)=[N:22][CH:23]=[N:24]2)=[CH:29][CH:28]=1
Reactant: COc1c(OCc2ccccc2)ccc2c(N3CCOc4ccc(-c5ccc6nc(C)[nH]c6c5)cc4C3)ncnc12
Reactant: CN(C)CCCl
Product: COc1c(OCCN(C)C)ccc2c(N3CCOc4ccc(-c5ccc6nc(C)[nH]c6c5)cc4C3)ncnc12

Procedure:
Synthesized according to the method of example 10 using 7-(2-methyl-1H-benzimidazol-6-yl)-4-{8-(methyloxy)-7-[(phenylmethyl)oxy]quinazolin-4-yl}-2,3,4,5-tetrahydro-1,4-benzoxazepine (example 1) in step 1 and 2-(N,N-dimethylamino)-1-chloroethane in step 2. 1H NMR (400 MHz, d6-DMSO): 8.57 (s, 1H), 7.93 (s, 1H), 7.82 (m, 3H), 7.59 (d, 1H), 7.51 (d, 1H), 7.01 (d, 1H), 7.01 (d, 1H), 5.38 (br s, 2H), 4.61 (m, 4H), 4.45 (br s, 2H), 3.95 (br s, 2H), 3.72 (t, 2H), 2.90 (s, 6H), 2.77 (s, 3H); MS (EI) for C30H32N6O3: 525 (MH+).