Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[N:8][C:9]([NH2:10])=[C:4]2[CH:3]=[N:2]1.[H-].[Na+].CS(O[CH:18]1[CH2:23][CH2:22][CH2:21][N:20]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:19]1)(=O)=O>CN(C=O)C>[NH2:10][C:9]1[N:8]=[CH:7][N:6]=[C:5]2[N:1]([CH:22]3[CH2:23][CH2:18][CH2:19][N:20]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:21]3)[N:2]=[CH:3][C:4]=12
Reactant: Nc1ncnc2[nH]ncc12
Reactant: CC(C)(C)OC(=O)N1CCCC(OS(C)(=O)=O)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCCC(n2ncc3c(N)ncnc32)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 44 %

Procedure:
To a solution of 1H-pyrazolo[3,4-d]pyrimidin-4-amine (675 mg, 5 mmol) in DMF (12 mL) was added NaH (60% wt in mineral oil, 240 mg, 6.0 mmol, 1.2 eq) and the mixture was stirred at rt for 0.5 h. The tert-butyl 3-((methylsulfonyl)oxy)piperidine-1-carboxylate (1.67 g, 6 mmol, 1.2 eq) was added and the mixture was heated to 100° C. for 16 h. The solution was cooled to rt and the reaction was quenched with brine (50 mL) and extracted with EtOAc (80 mL×4). The organic layers were dried over Na2SO4, concentrated in vacuo to afford a residue which was purified by column chromatography (silica gel, pure EtOAc) to give the title product (700 mg, yield: 50%) as a light yellow solid. 1H NMR (400 MHz, DMSO-d6) δ: 9.24 (br s, 1H), 8.72 (br s, 1H), 8.41 (s, 1H), 8.33 (s, 1H), 4.67-4.62 (m, 1H), 4.05-3.58 (m, 3H), 3.40-3.33 (m, 1H), 2.98-2.95 (m 1H), 2.16-2.04 (m, 1H), 1.61-1.24 (m, 11H). ESI-MS (M+H+): 319.0.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([CH3:33])=[C:5]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=2)[C:6]=1[C:7]([NH:9][C@H:10]([C:12]1[CH:21]=[CH:20][C:15]([C:16]([O:18]C)=[O:17])=[CH:14][CH:13]=1)[CH3:11])=[O:8].[Li+].[OH-].Cl>C1COCC1.CO>[CH3:1][C:2]1[S:3][C:4]([CH3:33])=[C:5]([CH2:22][C:23]2[CH:24]=[CH:25][C:26]([C:29]([F:31])([F:32])[F:30])=[CH:27][CH:28]=2)[C:6]=1[C:7]([NH:9][C@H:10]([C:12]1[CH:21]=[CH:20][C:15]([C:16]([OH:18])=[O:17])=[CH:14][CH:13]=1)[CH3:11])=[O:8]
Reactant: COC(=O)c1ccc([C@H](C)NC(=O)c2c(C)sc(C)c2Cc2ccc(C(F)(F)F)cc2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1sc(C)c(C(=O)N[C@@H](C)c2ccc(C(=O)O)cc2)c1Cc1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 19 h

Procedure:
A solution of methyl 4-{(1S)-1-[({2,5-dimethyl-4-[4-(trifluoromethyl)benzyl]-3-thienyl}carbonyl)amino]ethyl}benzoate from Example 11, Step 5 (5.68 g, 11.9 mmol) in THF (305 mL) and MeOH (152 mL) was treated with LiOH (1N in water, 35.8 mL, 35.8 mmol) at r.t. for 44 h and at 50° C. for 3.5 h. The solution was allowed to cool to r.t., and 1N HCl was added (38.2 mL, 3.2 eq). 350 mL of volatiles were removed in vacuo, 800 mL of water was added to the residue and the resulting suspension was stirred for 19 h. The solid was collected by filtration, rinsed with water and dried. The desired product was obtained as a white solid. MS (−APCI): m/z 460 (M−1)−.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][C:4]([C:7]([O:9][CH3:10])=[O:8])=[CH:3]1.C1C(=O)N([Br:18])C(=O)C1>O1CCCC1>[Br:18][C:6]1[N:2]([CH3:1])[CH:3]=[C:4]([C:7]([O:9][CH3:10])=[O:8])[CH:5]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1ccn(C)c1
Solvent: C1CCOC1
Product: COC(=O)c1cc(Br)n(C)c1
Yield: 79 %

Procedure:
A solution of methyl 1-methyl-1H-pyrrole-3-carboxylate (690 mg, 4.96 mmol) and NBS (883 mg, 4.96 mmol) in tetrahydrofuran (24.800 ml) was stirred at 25° C. for 1 h. The solution was then partitioned between H2O-DCM and the aqueous phase was washed several times with DCM. The combined organic fractions were dried over Na2SO4, concentrated and purified via column chromatography (10-50% EtOAc in hexanes) affording methyl 5-bromo-1-methyl-1H-pyrrole-3-carboxylate (950 mg, 3.92 mmol, 79% yield) as an orange solid: LCMS (ES) m/e 218, 220 (M, M+2)+.
Reaction SMILES: [CH2:1]([N:3]1[C:15]2[C:14](=[O:16])[NH:13][CH2:12][CH2:11][C:10]=2[C:9]2[C:4]1=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH3:2].I[C:18]1[CH:19]=[N:20][CH:21]=[CH:22][C:23]=1[CH3:24].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[Cu](I)I.O1CCOCC1>[CH2:1]([N:3]1[C:15]2[C:14](=[O:16])[N:13]([C:18]3[CH:19]=[N:20][CH:21]=[CH:22][C:23]=3[CH3:24])[CH2:12][CH2:11][C:10]=2[C:9]2[C:4]1=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH3:2]
Reactant: CCn1c2c(c3ccccc31)CCNC2=O
Reactant: Cc1ccncc1I
Agent: I[Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: CCn1c2c(c3ccccc31)CCN(c1cnccc1C)C2=O
Yield: 13.3 %

Procedure:
9-Ethyl-2,3,4,9-tetrahydro-b-carbolin-1-one (I-38f: 0.1 g, 0.4672 mmol) was reacted with 3-iodo-4-methyl-pyridine (0.102 g, 0.4672 mmol), 1,4-dioxane (15 mL), copper iodide (0.0089 g, 0.0467 mmol), trans-N,N′-dimethyl-cyclohexyl-1,2-diamine (0.019 g, 0.01401 mmol) and potassium phosphate (0.247 g, 1.168 mmol) to afford the crude product. Purification by column chromatography on silica gel (70% ethylacetate in hexane), followed by preparative HPLC afforded 0.019 g of the product (13.3% yield).
Reaction SMILES: [I:1][C:2]1[C:3]([OH:11])=[C:4]([CH:7]=[C:8]([I:10])[CH:9]=1)[CH:5]=O.[C:12]([NH:16][OH:17])([CH3:15])([CH3:14])[CH3:13]>>[I:1][C:2]1[C:3]([OH:11])=[C:4]([CH:5]=[N+:16]([C:12]([CH3:15])([CH3:14])[CH3:13])[O-:17])[CH:7]=[C:8]([I:10])[CH:9]=1
Reactant: O=Cc1cc(I)cc(I)c1O
Reactant: CC(C)(C)NO
Product: CC(C)(C)[N+]([O-])=Cc1cc(I)cc(I)c1O

Procedure:
The title compound was prepared according to the procedure described in Example 1 using 3,5-diiodo-2-hydroxybenzaldehyde and N-tert-butylhydroxylamine. The title compound was isolated in 73.8% yield as a yellow crystalline solid, m.p. 164.1° C. (Rf=0.38 on a silica gel plate using 7:3 hexanes/EtOAc as an eluant)
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)/[C:7](=[CH:11]\[C:12]1[CH:17]=[CH:16][C:15]([S:18][CH3:19])=[CH:14][CH:13]=1)/[C:6]([CH3:20])=[C:5]2[CH2:21][CH2:22]I.[C-:24]#[N:25].[K+].O>CN(C=O)C.[Cl-].[Na+].O>[C:24]([CH2:22][CH2:21][C:5]1[C:4]2[C:8](=[CH:9][CH:10]=[C:2]([F:1])[CH:3]=2)/[C:7](=[CH:11]\[C:12]2[CH:17]=[CH:16][C:15]([S:18][CH3:19])=[CH:14][CH:13]=2)/[C:6]=1[CH3:20])#[N:25]
Reactant: CSc1ccc(/C=C2/C(C)=C(CCI)c3cc(F)ccc32)cc1
Reactant: [C-]#N
Agent: [Cl-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CSc1ccc(/C=C2/C(C)=C(CCC#N)c3cc(F)ccc32)cc1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A mixture of the iodide from Step 1 (3.7g, 8.5 mmol) and potassium cyanide (5.5 g, 85 mmol) in DMF (40 mL) was stirred at room temperature for 45 minutes. There was added water (50 mL) and brine (100 mL) and the mixture was extracted with 1:1 ethyl acetate-hexane (4×100 mL); the combined extracts were washed with water (2×50 mL) and brine (1×50 mL), dried and evaporated. The crude residue was chromatographed on silica gel eluting with a 1:2 mixture of ether-ethyl acetate to afford the title compound as a yellow oil.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([C:21]([F:24])([F:23])[F:22])[N:10]([C:12]3[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][OH:20])=[CH:14][CH:13]=3)[CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[CH3:32][S:33](Cl)(=[O:35])=[O:34]>ClCCl>[CH3:32][S:33]([O:20][CH2:19][CH2:18][C:15]1[CH:16]=[CH:17][C:12]([N:10]2[CH:11]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[N:8]=[C:9]2[C:21]([F:23])([F:24])[F:22])=[CH:13][CH:14]=1)(=[O:35])=[O:34]
Reactant: OCCc1ccc(-n2cc(-c3ccccc3)nc2C(F)(F)F)cc1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCc1ccc(-n2cc(-c3ccccc3)nc2C(F)(F)F)cc1
Reaction time: 1 h

Procedure:
To a stirred solution of 2-{4-[4-phenyl-2-(trifluoromethyl)-1H-imidazol-1-yl]phenyl}ethanol (450 mg, 1.35 mmol) and triethylamine (377 μL, 2.70 mmol) in dichloromethane (13 mL) was added methanesulfonyl chloride (126 μL, 1.62 mmol) at ambient temperature. After 1 h, the reaction mixture was partitioned between dichloromethane and water. The aqueous phase was extracted with dichloromethane (3×10 mL) and the combined organic phase was dried (MgSO4) and concentrated under reduced pressure to give the title compound as a brown oil (quant.). MS (EI) m/z 410 [M]+.
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:40])[CH2:6][C:7]1[CH:8]=[N:9][CH:10]=[C:11]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([CH2:37][CH3:38])([C:22]3[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][C:30]([CH2:34][CH3:35])([OH:33])[CH2:31][CH3:32])=[C:24]([CH3:36])[CH:23]=3)[CH2:20][CH3:21])=[CH:15][C:14]=2[CH3:39])[CH:12]=1.Cl>CO>[CH2:20]([C:19]([C:16]1[CH:17]=[CH:18][C:13]([C:11]2[CH:12]=[C:7]([CH2:6][C:5]([OH:40])=[O:4])[CH:8]=[N:9][CH:10]=2)=[C:14]([CH3:39])[CH:15]=1)([C:22]1[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][C:30]([CH2:31][CH3:32])([OH:33])[CH2:34][CH3:35])=[C:24]([CH3:36])[CH:23]=1)[CH2:37][CH3:38])[CH3:21]
Reactant: CCC(O)(CC)CCc1ccc(C(CC)(CC)c2ccc(-c3cncc(CC(=O)OC)c3)c(C)c2)cc1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCC(O)(CC)CCc1ccc(C(CC)(CC)c2ccc(-c3cncc(CC(=O)O)c3)c(C)c2)cc1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 101.1 %

Procedure:
A 2 N sodium hydroxide aqueous solution (0.12 mL) was added to a solution of [5-(4-{1-ethyl-1-[4-(3-ethyl-3-hydroxy-pentyl)-3-methyl-phenyl]-propyl}-2-methyl-phenyl)-pyridin-3-yl]-acetic acid methyl ester (Example 111-(1); 29.5 mg, 0.0572 mmol) in methanol (0.77 mL) at room temperature, and the mixture was stirred at room temperature for three hours. The mixture was acidified with dilute hydrochloric acid aqueous solution, followed by extraction with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure to give the title compound (29 mg, 100%).
Reaction SMILES: Cl[C:2]1[CH:17]=[C:6]2[C:7]3[C:12]([CH2:13][CH2:14][N:5]2[C:4](=[O:18])[N:3]=1)=[CH:11][C:10]([O:15][CH3:16])=[CH:9][CH:8]=3.[Br:19][C:20]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[C:21]=1[NH2:22]>>[Br:19][C:20]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[C:21]=1[NH:22][C:2]1[CH:17]=[C:6]2[C:7]3[C:12]([CH2:13][CH2:14][N:5]2[C:4](=[O:18])[N:3]=1)=[CH:11][C:10]([O:15][CH3:16])=[CH:9][CH:8]=3
Reactant: Nc1c(F)cccc1Br
Reactant: COc1ccc2c(c1)CCn1c-2cc(Cl)nc1=O
Product: COc1ccc2c(c1)CCn1c-2cc(Nc2c(F)cccc2Br)nc1=O

Procedure:
The title compound was prepared from 2-chloro-9-methoxy-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one (4) and 2-bromo-6-fluoro-aniline as in Example 1 d. 1H-NMR (400 MHz, d6-DMSO) δ 9.26 (br, 1H), 7.72 (br, 1H), 7.57 (brd, 1H), 7.34 (br, 2H), 7.05-6.95 (2H), 6.37 (br, 1H), 3.94 (t, 2H), 3.84 (s, 3H) and 2.96 (t, 2H); MS (ESI) (M+H)+ 416, 418.
Reaction SMILES: [CH3:1][O:2][CH2:3][C@@H:4]1[CH2:8][CH2:7][CH2:6][N:5]1[S:9]([C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[NH:17][C:16](=O)[C:15]12[O:26]CCCO1)(=[O:11])=[O:10].Cl[CH2:28][C:29]1([C:33]#[N:34])[CH2:32][CH2:31][CH2:30]1>>[CH3:1][O:2][CH2:3][C@@H:4]1[CH2:8][CH2:7][CH2:6][N:5]1[S:9]([C:12]1[CH:20]=[CH:19][C:18]2[N:17]3[CH2:28][C:29]4([CH2:32][CH2:31][CH2:30]4)[CH2:33][N:34]=[C:16]3[C:15](=[O:26])[C:14]=2[CH:13]=1)(=[O:10])=[O:11]
Reactant: N#CC1(CCl)CCC1
Reactant: COC[C@@H]1CCCN1S(=O)(=O)c1ccc2c(c1)C1(OCCCO1)C(=O)N2
Product: COC[C@@H]1CCCN1S(=O)(=O)c1ccc2c(c1)C(=O)C1=NCC3(CCC3)CN12

Procedure:
The title compound was prepared as a yellow solid from 5′-{[(2S)-2-(methoxymethyl)pyrrolidin-1-yl]sulfonyl}spiro[1,3-dioxane-2,3′-indol]-2′(1′H)-one and 1-chloromethyl-cyclobutanecarbonitrile (Syn. Comm. 20(12) 1757, 1990) using a procedure similar to that of steps 3-5 of Example 12. NMR (400 Mz, DMSO-d6): consistent. MS: (ES−) m/z 402 [M−H]. m.p.: 146.8.8-147.4° C.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:12]([O:14][CH3:15])=[O:13])[C:5]2[N:6]([C:8]([CH3:11])=[N:9][N:10]=2)[N:7]=1.[CH3:16][NH:17][C@H:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH3:19]>CS(C)=O.CC(=O)OCC>[CH3:11][C:8]1[N:6]2[N:7]=[C:2]([N:17]([CH3:16])[C@H:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH3:19])[CH:3]=[C:4]([C:12]([O:14][CH3:15])=[O:13])[C:5]2=[N:10][N:9]=1
Reactant: CN[C@@H](C)c1ccccc1
Reactant: COC(=O)c1cc(Cl)nn2c(C)nnc12
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: COC(=O)c1cc(N(C)[C@@H](C)c2ccccc2)nn2c(C)nnc12
Temperature: 130 °C
Reaction time: 0.5 h
Yield: 13.9 %

Procedure:
A mixture of compound methyl 6-chloro-3-methyl-[1,2,4]triazolo[4,3-b]pyridazine-8-carboxylate (2.0 g, 8.85 mmol) and (S)-N-methyl-1-phenylethanamine (2.39 g, 17.7 mmol) in anhydrous DMSO (20 mL) was stirred for 30 min at 130° C. under microwave condition. After cooled to room temperature, the mixture was diluted with EA (100 mL) and washed with H2O (100 mL*3). The organic layer was dried over Na2SO4, concentrated in vacuum and purified by flash column chromatography (silica-gel, DCM: MeOH=10:1) to give product (S)-methyl 3-methyl-6-(methyl (1-phenylethyl)amino)-[1,2,4]triazolo[4,3-b]pyridazine-8-carboxylate as a yellow oil (400 mg, 14.5%). LRMS (M+H+) m/z: calcd 326; found 326.
Reaction SMILES: Br[CH2:2]/[C:3](=[CH:7]\[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)/[C:4]([OH:6])=[O:5].[C:14]([OH:20])(=[S:19])[C:15]([CH3:18])([CH3:17])[CH3:16]>>[C:14]([S:19][CH2:2]/[C:3](=[CH:7]\[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)/[C:4]([OH:6])=[O:5])(=[O:20])[C:15]([CH3:18])([CH3:17])[CH3:16]
Reactant: O=C(O)/C(=C/c1ccccc1)CBr
Reactant: CC(C)(C)C(O)=S
Product: CC(C)(C)C(=O)SC/C(=C\c1ccccc1)C(=O)O
Yield: 93 %

Procedure:
The (Z)-2-bromomethyl-3-phenylpropenoic acid described in Example 1 (step A) is reacted with thiopivaloic acid according to the experimental procedure described in Example 1 (step B). Yield: 93% 1H NMR (CDCl3): 9.10 (broad s, 1H); 7.90 (s, 1H); 7.35 (s, 5H); 4.00 (s, 2H); 1.20 (s, 9H)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8](O)[C:9]2[C:10]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[N:11][N:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=3)[C:13]=2[CH3:14])=[CH:4][CH:3]=1.[NH2:30][C:31]1[CH:32]=[C:33]([CH3:39])[C:34](=[O:38])[N:35]([CH3:37])[CH:36]=1>C(Cl)Cl.CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:30][C:31]2[CH:32]=[C:33]([CH3:39])[C:34](=[O:38])[N:35]([CH3:37])[CH:36]=2)[C:9]2[C:10]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[N:11][N:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=3)[C:13]=2[CH3:14])=[CH:4][CH:3]=1
Reactant: Cc1cc(N)cn(C)c1=O
Reactant: CCOC(=O)c1nn(Cc2ccc(OC)cc2)c(C)c1C(O)c1ccc(Cl)cc1
Solvent: CO
Solvent: ClCCl
Product: CCOC(=O)c1nn(Cc2ccc(OC)cc2)c(C)c1C(Nc1cc(C)c(=O)n(C)c1)c1ccc(Cl)cc1

Procedure:
The title compound was prepared in analogy to the procedure described in Step 10.3 using ethyl 4-((4-chlorophenyl)(hydroxy)methyl)-1-(4-methoxybenzyl)-5-methyl-1H-pyrazole-3-carboxylate (Step 1.3) and 5-amino-1,3-dimethylpyridin-2(1H)-one (Step 20.2). tR: 4.94 min (HPLC 1); tR: 1.13 min (LC-MS 2); ESI-MS: 535 [M+H]+ (LC-MS 2); Rf=0.45 (CH2Cl2/MeOH 9:1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[CH:9]([O:11][C:12](=[O:27])[NH:13][C:14]1[C:15]([CH3:26])=[N:16][O:17][C:18]=1[C:19]1[CH:24]=[CH:23][C:22](Br)=[CH:21][CH:20]=1)[CH3:10].[CH2:28]([O:30][C:31](=[O:48])[CH2:32][C:33]1[CH:38]=[CH:37][C:36](B2OC(C)(C)C(C)(C)O2)=[CH:35][CH:34]=1)[CH3:29]>>[CH2:28]([O:30][C:31](=[O:48])[CH2:32][C:33]1[CH:38]=[CH:37][C:36]([C:22]2[CH:23]=[CH:24][C:19]([C:18]3[O:17][N:16]=[C:15]([CH3:26])[C:14]=3[NH:13][C:12]([O:11][CH:9]([C:3]3[C:2]([F:1])=[CH:7][CH:6]=[CH:5][C:4]=3[F:8])[CH3:10])=[O:27])=[CH:20][CH:21]=2)=[CH:35][CH:34]=1)[CH3:29]
Reactant: Cc1noc(-c2ccc(Br)cc2)c1NC(=O)OC(C)c1c(F)cccc1F
Reactant: CCOC(=O)Cc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Product: CCOC(=O)Cc1ccc(-c2ccc(-c3onc(C)c3NC(=O)OC(C)c3c(F)cccc3F)cc2)cc1

Procedure:
Following the procedure described in Example 36, Step 6, [5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-carbamic acid 1-(2,6-difluoro-phenyl)-ethyl ester and [4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-acetic acid ethyl ester were reacted to provide (4′-{4-[1-(2,6-difluoro-phenyl)-ethoxycarbonylamino]-3-methyl-isoxazol-5-yl}-biphenyl-4-yl)-acetic acid ethyl ester, which was hydrolyzed to the acid as described in Example 34, Step 2.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH2:6][CH2:5]1.C(N(CC)CC)C.[S:22](Cl)([CH3:25])(=[O:24])=[O:23]>O1CCCC1>[CH3:25][S:22]([O:1][CH2:2][CH2:3][C:4]1([NH:7][C:8]([O:9][C:10]([CH3:11])([CH3:13])[CH3:12])=[O:14])[CH2:5][CH2:6]1)(=[O:24])=[O:23]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)NC1(CCO)CC1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NC1(CCOS(C)(=O)=O)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 85 %

Procedure:
To a cooled solution of tert-butyl [1-(2-hydroxyethyl)cyclopropyl]carbamate (8.0 g, 0.04 mol) and triethylamine (12.14 g) in anhydrous tetrahydrofuran (120 mL) at −20° C. was added a solution of mesyl chloride (17.8 g) in anhydrous tetrahydrofuran (30 mL). The resulting mixture was allowed to warm to room temperature and stirred at this temperature for 2 hours. The resulting mixture was poured into ice-water (50 mL) and the separated organic layer was washed with brine (100 mL), dried over sodium sulfate and concentrated in vacuo. The residue was triturated with petroleum ether and filtered to give 9.5 g of the pure product as an orange solid (yield was 95%).
Reaction SMILES: C(N(CC)CC)C.[OH:8][N:9]=[C:10](Cl)[C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1.[C:18]([O:22][CH3:23])(=[O:21])[CH:19]=[CH2:20]>C(O)C>[N:13]1[CH:14]=[CH:15][CH:16]=[C:11]([C:10]2[CH2:20][CH:19]([C:18]([O:22][CH3:23])=[O:21])[O:8][N:9]=2)[CH:12]=1
Reactant: ON=C(Cl)c1cccnc1
Reactant: C=CC(=O)OC
Solvent: CCN(CC)CC
Solvent: CCO
Product: COC(=O)C1CC(c2cccnc2)=NO1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.5 %

Procedure:
) A solution of N,N-diethylethanamine (0.544 mol) in ethanol (600 ml) was added dropwise to a stirred suspension of N-hydroxy-3-pyridinecarboximidoyl chloride (0.259 mol) and methyl 2-propenoate (1.295 mol) in ethanol (1500 ml) over a period of 1 hour. The reaction mixture was stirred for 1 hour at RT. The reaction mixture was evaporated. The residue was mixed with diethyl ether and filtered. The organic layer was separated, washed three times with water, separated again, dried (MgSO4), filtered and left overnight. Partial crystallization occurred on overnight standing. The crystals were filtered and dried and the filtrate was evaporated, yielding 52.6 g (98%) of (±)-methyl 4,5-dihydro-3-(3-pyridinyl)-5-isoxazolecarboxylate (interm. 1).
Reaction SMILES: [CH3:1][C:2]1[N:3]([NH:8][C:9](=[O:12])[CH2:10][Cl:11])[C:4]([CH3:7])=[CH:5][CH:6]=1.[CH3:13][C:14]1[S:15][CH:16]=[C:17]([CH2:19]Cl)[N:18]=1.[H-].[Na+]>CN(C=O)C>[CH3:13][C:14]1[S:15][CH:16]=[C:17]([CH2:19][N:8]([N:3]2[C:2]([CH3:1])=[CH:6][CH:5]=[C:4]2[CH3:7])[C:9](=[O:12])[CH2:10][Cl:11])[N:18]=1
Reactant: Cc1nc(CCl)cs1
Reactant: Cc1ccc(C)n1NC(=O)CCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1nc(CN(C(=O)CCl)n2c(C)ccc2C)cs1
Yield: 20.8 %

Procedure:
The product of Example 2 (5.04 g), 2-methyl-4-chloromethyl-1,3-thiazole (4 g) and sodium hydride (1.56 g) in 120 ml dry DMF were treated at 0° C. according to the procedure of Example 3. Work-up yielded 1.67 g of title product (chromatographed on silica gel and by h.p.l.c.).
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]1[C:11](=[O:12])[C:10]2[CH:13]=[C:14]([CH2:16][CH2:17][CH3:18])[S:15][C:9]=2[NH:8][C:7]1=[O:19].Br[CH2:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]2[C:35]([C:40]#[N:41])=[CH:36][CH:37]=[CH:38][CH:39]=2)=[CH:30][C:29]=1[F:42].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[O:19]=[C:7]1[N:8]([CH2:27][C:28]2[CH:33]=[CH:32][C:31]([C:34]3[C:35]([C:40]#[N:41])=[CH:36][CH:37]=[CH:38][CH:39]=3)=[CH:30][C:29]=2[F:42])[C:9]2[S:15][C:14]([CH2:16][CH2:17][CH3:18])=[CH:13][C:10]=2[C:11](=[O:12])[NH:6]1
Reactant: CCCc1cc2c(=O)n(Cc3ccc(OC)cc3OC)c(=O)[nH]c2s1
Reactant: N#Cc1ccccc1-c1ccc(CBr)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCc1cc2c(=O)[nH]c(=O)n(Cc3ccc(-c4ccccc4C#N)cc3F)c2s1
Temperature: 50 °C
Reaction time: 2 h
Yield: 63.6 %

Procedure:
A mixture of 3-(2,4-dimethoxybenzyl)-6-propylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (2.7 g), 4′-(bromomethyl)-3′-fluorobiphenyl-2-carbonitrile (2.6 g), potassium carbonate (2.1 g) and acetonitrile (100 mL) was stirred at 50° C. for 2 hr. Insoluble material was filtered off, and the solvent was evaporated under reduced pressure. The obtained residue was dissolved in trifluoroacetic acid (50 mL), and the mixture was stirred at 50° C. for 2 hr. To the reaction mixture was added toluene (50 mL), and the mixture was concentrated under reduced pressure. To the obtained residue was added ethyl acetate (50 mL), and the mixture was concentrated under reduced pressure. The precipitated solid was collected by filtration to give the title compound as a colorless solid (2 g, 64%).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:11]=[CH:10][C:9]([C:12]([CH3:17])([CH3:16])[C:13]([OH:15])=O)=[CH:8][CH:7]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)CC)(C)C.[CH3:49][O:50][CH2:51][CH2:52][NH2:53]>C(Cl)Cl>[CH3:49][O:50][CH2:51][CH2:52][NH:53][C:13](=[O:15])[C:12]([C:9]1[CH:8]=[CH:7][C:6]([C:2]2[O:1][CH:5]=[CH:4][CH:3]=2)=[CH:11][CH:10]=1)([CH3:17])[CH3:16]
Reactant: CC(C)(C(=O)O)c1ccc(-c2ccco2)cc1
Reactant: COCCN
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COCCNC(=O)C(C)(C)c1ccc(-c2ccco2)cc1
Reaction time: 2 h
Yield: 88.2 %

Procedure:
To a solution of 2-(4-(furan-2-yl)-phenyl)-2-methyl-propionic Acid (reference example 28) (344 mg, 1.5 mmol) in CH2Cl2 (4 mL) is added TBTU (528 mg, 1.65 mmol) followed by diisopropylethylamine (280 mL, 1.6 mmol). The resulting mixture is stirred for 2 h then a further portion of DIEA added (280 mL) along with 2-methoxy-ethylamine (225 mL, 2.6 mmol). The resulting solution is stirred for 90 minutes then concentrated. The residue is purified by flash chromatography (eluting with 10% CH2Cl2/50% ethyl acetate in hexanes) to give 380 mg of product as a white solid. 1H NMR (CD3OD) d 1.58 (s, 6H), 3.24 (s, 3H), 3.36 (m, 4H), 5.58 (bs, 1H), 6.47 (dd, J=3, 2 Hz, 1H), 6.65 (d, J=3 Hz, 1H), 7.41 (m, 2H), 7.49 (d, J=2 Hz, 1H), 7.65 (m, 2H). MS (EI) m/z 287 (M+).
Reaction SMILES: [CH:1]1[S:2][CH:3]=[C:4]2[C:10]=1[CH2:9][NH:8][C:7]1[CH:11]=[CH:12][CH:13]=[CH:14][C:6]=1[NH:5]2.[C:15]1([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:16]([C:21]([NH:23][C:24]2[CH:32]=[CH:31][C:27](C(Cl)=O)=[C:26]([Cl:33])[CH:25]=2)=[O:22])=[CH:17][CH:18]=[CH:19][CH:20]=1>>[CH:1]1[S:2][CH:3]=[C:4]2[C:10]=1[CH2:9][N:8]([C:27]1[CH:31]=[CH:32][C:24]([NH:23][C:21]([C:16]3[C:15]([C:34]4[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=4)=[CH:20][CH:19]=[CH:18][CH:17]=3)=[O:22])=[CH:25][C:26]=1[Cl:33])[C:7]1[CH:11]=[CH:12][CH:13]=[CH:14][C:6]=1[NH:5]2
Reactant: O=C(Cl)c1ccc(NC(=O)c2ccccc2-c2ccccc2)cc1Cl
Reactant: c1ccc2c(c1)NCc1cscc1N2
Product: O=C(Nc1ccc(N2Cc3cscc3Nc3ccccc32)c(Cl)c1)c1ccccc1-c1ccccc1

Procedure:
As described for Example 400, 9,10-dihydro-4H-thieno[3,4-b][1,5]benzodiazepine is reacted with 4-[([1,1'-biphenyl]-2-carbonyl)amino]-2-chlorobenzoyl chloride to give the product as a solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[CH:11]1[NH:16][C:15](=[O:17])[CH2:14][CH2:13][CH2:12]1.Br[CH:19]([C:21]1[CH:26]=[CH:25][C:24]([O:27][C:28]([F:31])([F:30])[F:29])=[CH:23][CH:22]=1)[CH3:20]>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[CH:11]1[N:16]([CH:19]([C:21]2[CH:22]=[CH:23][C:24]([O:27][C:28]([F:29])([F:30])[F:31])=[CH:25][CH:26]=2)[CH3:20])[C:15](=[O:17])[CH2:14][CH2:13][CH2:12]1
Reactant: COc1cccc(OC)c1C1CCCC(=O)N1
Reactant: CC(Br)c1ccc(OC(F)(F)F)cc1
Product: COc1cccc(OC)c1C1CCCC(=O)N1C(C)c1ccc(OC(F)(F)F)cc1

Procedure:
Prepared according to the described general procedure 4 (GP4) by reaction of 6-(2,6-dimethoxyphenyl)piperidin-2-one with 1-(1-bromoethyl)-4-(trifluoromethoxy)benzene. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.94 min.; [M+H]+: 424.23 g/mol.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([C:12]([OH:14])=O)=[CH:7][CH:6]=2.Cl.[CH3:16][NH:17][CH3:18]>>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([C:12]([N:17]([CH3:18])[CH3:16])=[O:14])=[CH:7][CH:6]=2
Reactant: CNC
Reactant: O=C(O)c1ccc2cnc(Cl)cc2c1
Agent: Cl
Product: CN(C)C(=O)c1ccc2cnc(Cl)cc2c1

Procedure:
The title compound was prepared according to the method described for Preparation 52 using 3-chloroisoquinoline-6-carboxylic acid (Preparation 54) and dimethylamine hydrochloride.