Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[C:9]1[C:17]1[C:18](=[O:34])[N:19]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31])[CH:20]=[C:21]([C:23]([OH:25])=O)[CH:22]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:35]1[CH:39]=[C:38]([NH2:40])[CH:37]=[N:36]1.O.ON1C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.Cl.CN(C)CCCN=C=NCC>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[C:9]1[C:17]1[C:18](=[O:34])[N:19]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:31])([CH3:33])[CH3:32])[CH:20]=[C:21]([C:23](=[O:25])[NH:40][C:38]2[CH:39]=[N:35][NH:36][CH:37]=2)[CH:22]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: Nc1cn[nH]c1
Reactant: CC(C)(C)OC(=O)n1c(-c2cc(C(=O)O)cn(COCC[Si](C)(C)C)c2=O)cc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)n1c(-c2cc(C(=O)Nc3cn[nH]c3)cn(COCC[Si](C)(C)C)c2=O)cc2ccccc21
Temperature: 40 °C

Procedure:
To a solution of intermediate (1c), 2-[5-carboxy-2-oxo-1-(2-trimethylsilanyl-ethoxymethyl)-1,2-dihydro-pyridin-3-yl]indole-1-carboxylic acid tert-butyl ester, (3 g, 6.2 mmol) in tetrahydrofuran (100 mL) was added intermediate (2H), 1H-pyrazol-4-ylamine (0.62 g, 7.46 mmol), 1-hydroxybenzotriazole hydrate (1.09 g, 8.07 mmol), N,N-diisopropylethylamine (2.4 g, 3.24 mL, 18.6 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (1.55 g, 8.07 mmol). The reaction mixture was heated at 40° C. for 2 hours. The reaction mixture was cooled and partitioned between ethyl acetate and aqueous saturated sodium hydrogen bicarbonate solution. The ethyl acetate layer was separated and washed with brine, dried (Na2SO4) and concentrated in vacuo. The resultant crude product was purified by flash chromatography on SiO2 eluting with hexane—66% ethyl acetate/hexane (gradient) to afford the desired title compound as a yellow solid, 1.36 g, 40%.
Reaction SMILES: [C:1]([O:4][C:5](=[O:7])[CH3:6])(=O)[CH3:2].[CH3:8][CH2:9][CH2:10]CCC.O.N1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[C:5]([O:4][CH2:1][CH2:2][CH:17]([CH2:18][CH2:19][CH:20]=[C:9]([CH3:10])[CH3:8])[CH3:16])(=[O:7])[CH3:6]
Reactant: c1ccncc1
Reactant: CC(=O)OC(C)=O
Reactant: CCCCCC
Solvent: O
Product: CC(=O)OCCC(C)CCC=C(C)C
Reaction time: 48 h

Procedure:
To 15.6 g (0.1 mol) d1-citronellol in 20 ml of dry pyridine under nitrogen is added 11.3 ml (0.12 mol) of acetic anhydride. The reaction is stirred about 48 hours and then ice is added. After one hour, the reaction is poured into hexane and water. The organic phase is washed with 5% HCl, 2M sodium carbonate, and saturated NaCl solutions, dried over calcium sulfate and solvent removed to yield dl-citronellyl acetate.
Reaction SMILES: [CH:1](=[C:8]1[CH2:12][N:11]([C:13]([O:15]C(C)(C)C)=O)[C@H:10]([C:20]([OH:22])=O)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:23]=[C:24]1[C:29](C(Cl)=O)=[CH:28][CH:27]=[C:26]([CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[O:25]1.[CH2:38]([N:40]1[C:52]2[CH:51]=[CH:50][C:49]([NH2:53])=[CH:48][C:47]=2[C:46]2[C:41]1=[CH:42][CH:43]=[CH:44][CH:45]=2)[CH3:39]>>[CH:1](=[C:8]1[CH2:12][N:11]([C:13]([C:29]2[C:24](=[O:23])[O:25][C:26]([CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])=[CH:27][CH:28]=2)=[O:15])[C@H:10]([C:20]([NH:53][C:49]2[CH:50]=[CH:51][C:52]3[N:40]([CH2:38][CH3:39])[C:41]4[C:46]([C:47]=3[CH:48]=2)=[CH:45][CH:44]=[CH:43][CH:42]=4)=[O:22])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CC(=Cc2ccccc2)C[C@H]1C(=O)O
Reactant: CCn1c2ccccc2c2cc(N)ccc21
Reactant: CCCCCc1ccc(C(=O)Cl)c(=O)o1
Product: CCCCCc1ccc(C(=O)N2CC(=Cc3ccccc3)C[C@H]2C(=O)Nc2ccc3c(c2)c2ccccc2n3CC)c(=O)o1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-4-benzylidene-1-(tert-butoxycarbonyl)-2-pyrrolidinecarboxylic acid, 2-oxo-6-pentyl-2H-pyran-3-carbonyl chloride, and 9-ethyl-9H-carbazol-3-amine the title compound was obtained in 47% purity by LC/MS. MS(ESI+): m/z=588.4.
Reaction SMILES: [I:1][C:2]1[CH:3]=[N:4][NH:5][CH:6]=1.[H-].[Na+].Br[CH2:10][CH2:11][OH:12]>CN(C=O)C>[I:1][C:2]1[CH:3]=[N:4][N:5]([CH2:10][CH2:11][OH:12])[CH:6]=1
Reactant: Ic1cn[nH]c1
Reactant: OCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: OCCn1cc(I)cn1
Temperature: 25 °C
Yield: 64.3 %

Procedure:
A solution of 4-iodo-1H-pyrazole (4.50 g, 23.20 mmol) in DMF (45 mL) was treated with sodium hydride (60% w/w, 1.42 g, 35.5 mmol) at 0° C. and stirred at room temperature. After 1 hour the resulting mixture was treated with 2-bromoethanol (2.5 mL, 35.2 mmol) at 0° C. The resulting mixture was heated to 65° C. for 3 days. The reaction quenched with brine/EtOAc and the aqueous layer extracted with EtOAc. The combined organic layers were washed with water, brine, dried and concentrated. The residue was purified by silica gel column chromatography eluting with 0 to 50% EtOAc in cyclohexane to give the title compound (3.55 g, 64%).
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[O:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][N:8]=[C:7]2[C:13]([OH:15])=O.Cl.Cl.[N:20]12[CH2:27][CH2:26][CH:23]([CH2:24][CH2:25]1)[CH:22]([CH2:28][NH2:29])[CH2:21]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>O1CCCC1.CN(C)C=O>[N:20]12[CH2:27][CH2:26][CH:23]([CH2:24][CH2:25]1)[CH:22]([CH2:28][NH:29][C:13]([C:7]1[C:6]3[C:10](=[CH:11][CH:12]=[C:4]([O:3][C:2]([F:1])([F:17])[F:16])[CH:5]=3)[NH:9][N:8]=1)=[O:15])[CH2:21]2
Reactant: O=C(O)c1n[nH]c2ccc(OC(F)(F)F)cc12
Reactant: NCC1CN2CCC1CC2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: O=C(NCC1CN2CCC1CC2)c1n[nH]c2ccc(OC(F)(F)F)cc12
Temperature: 60 °C
Yield: 20 %

Procedure:
To a solution of 5-(trifluoromethoxy)-1H-indazole-3-carboxylic acid (0.40 mmol) in tetrahydrofuran (5.0 mL) and N,N-dimethylformamide (5.0 mL) was added 1-(1-azabicyclo[2.2.2]oct-3-yl)methanamine dihydrochloride (0.40 mmol) and HATU (0.40 mmol). N,N-Diisopropylethylamine (10.0 mmol) was added and the reaction mixture was maintained for 16 h. The reaction mixture was heated at 60° C. for 1 h, and was filtered and concentrated. The residue was redissolved in methanol and loaded on a 5 g SCX column. The column was washed with methanol and the product was eluted with methanoudimethylethylamine (9/1) and concentrated. The residue was purified by preparative HPLC to produce the desired product in 20% yield. 1H NMR (CDCl3) δ 8.47 (s, 1 H), 8.10 (s, 1 H), 7.67 (d, J=9.1, 1H), 7.36 (d, J=9.1, 1H), 3.63-3.52 (m, 3 H), 3.48-3.23 (m, 4 H), 3.08-3.01 (m, 1 H), 2.66-2.44 (m, 1 H), 2.32-2.22 (m, 1 H), 2.14-2.08 (m, 1 H), 2.06-1.85 (m, 3 H); LC/MS (EI) tR 4.8 min, m/z 369 (M++1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][O:9][C:10]2[CH:15]=[CH:14][N:13]([CH2:16][CH2:17][C:18]3[CH:28]=[CH:27][C:21]4[CH2:22][CH2:23][NH:24][CH2:25][CH2:26][C:20]=4[CH:19]=3)[C:12](=[O:29])[CH:11]=2)=[N:6][CH:7]=1.C=O.[C:32](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][O:9][C:10]2[CH:15]=[CH:14][N:13]([CH2:16][CH2:17][C:18]3[CH:28]=[CH:27][C:21]4[CH2:22][CH2:23][N:24]([CH3:32])[CH2:25][CH2:26][C:20]=4[CH:19]=3)[C:12](=[O:29])[CH:11]=2)=[N:6][CH:7]=1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: O=c1cc(OCc2ccc(Br)cn2)ccn1CCc1ccc2c(c1)CCNCC2
Agent: C=O
Agent: [Na+]
Solvent: C1CCOC1
Product: CN1CCc2ccc(CCn3ccc(OCc4ccc(Br)cn4)cc3=O)cc2CC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To 60 mg (0.13 mmol) 4-(5-bromo-pyridin-2-ylmethoxy)-1-[2-(2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)-ethyl]-1H-pyridin-2-one (example 23.15) in 5.0 mL THF is added 43 μL (0.53 mmol) aqueous 37% formaldehyde solution and 56 mg (0.26 mmol) sodium triacetoxy-borohydride. The mixture is acidified with pH 5 buffer solution and is stirred 48 h at RT. After filtration is the residue purified via reverse HPLC chromatography (Waters Xbridge; water (0.30% NH4OH)/acetonitrile (0.30% NH4OH) 95:5 to 5:95).
Reaction SMILES: Br[C:2]1[N:6]([CH:7]([CH3:9])[CH3:8])[C:5]2[CH:10]([C:23]3[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[CH:25][CH:24]=3)[N:11]([C:14]3[CH:19]=[C:18]([Cl:20])[C:17](=[O:21])[N:16]([CH3:22])[CH:15]=3)[C:12](=[O:13])[C:4]=2[CH:3]=1.[CH3:31][O:32][C:33]1[N:38]=[C:37]([O:39][CH3:40])[C:36](B(O)O)=[CH:35][N:34]=1.BrC1N(C(C)C)C2C(C3C=CC(Cl)=CC=3)N(C3C=C(Cl)C=CC=3C)C(=O)C=2C=1.COC1C(B2OC(C)(C)C(C)(C)O2)=CN=C(N)N=1>>[Cl:20][C:18]1[C:17](=[O:21])[N:16]([CH3:22])[CH:15]=[C:14]([N:11]2[C:12](=[O:13])[C:4]3[CH:3]=[C:2]([C:36]4[C:37]([O:39][CH3:40])=[N:38][C:33]([O:32][CH3:31])=[N:34][CH:35]=4)[N:6]([CH:7]([CH3:9])[CH3:8])[C:5]=3[CH:10]2[C:23]2[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[CH:25][CH:24]=2)[CH:19]=1
Reactant: CC(C)n1c(Br)cc2c1C(c1ccc(C#N)cc1)N(c1cc(Cl)c(=O)n(C)c1)C2=O
Reactant: COc1ncc(B(O)O)c(OC)n1
Agent: COc1nc(N)ncc1B1OC(C)(C)C(C)(C)O1
Agent: Cc1ccc(Cl)cc1N1C(=O)c2cc(Br)n(C(C)C)c2C1c1ccc(Cl)cc1
Product: COc1ncc(-c2cc3c(n2C(C)C)C(c2ccc(C#N)cc2)N(c2cc(Cl)c(=O)n(C)c2)C3=O)c(OC)n1

Procedure:
The title compound was prepared in analogy to the procedure described for Example 25 but 4-[2-bromo-5-(5-chloro-1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl)-1-isopropyl-4-oxo-1,4,5,6-tetrahydro-pyrrolo[3,4-b]pyrrol-6-yl]-benzonitrile (Intermediate AS) and 2,4-dimethoxypyrimidine-5-boronic acid were used instead of 2-bromo-5-(5-chloro-2-methyl-phenyl)-6-(4-chloro-phenyl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-b]pyrrol-4-one and 4-methoxy-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrimidin-2-ylamine respectively. The title compound was obtained as a beige solid. tR: 2.69 min (HPLC 5); ESI-MS: tR=0.90 min, [M+H]+ 545/547 (LC-MS 1).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][N:7]1[C:15]2[C:10](=[CH:11][C:12]([NH:16][C:17]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][C:25]=4[O:27][C@@H:28]([CH3:32])[C:29](O)=[O:30])[N:20]=[CH:19][N:18]=3)=[CH:13][CH:14]=2)[CH:9]=[N:8]1.[NH:33]1[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1>>[CH3:32][C@H:28]([O:27][C:25]1[CH:24]=[CH:23][CH:22]=[C:21]2[C:26]=1[C:17]([NH:16][C:12]1[CH:11]=[C:10]3[C:15](=[CH:14][CH:13]=1)[N:7]([CH2:6][C:2]1[S:1][CH:5]=[CH:4][N:3]=1)[N:8]=[CH:9]3)=[N:18][CH:19]=[N:20]2)[C:29]([N:33]1[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1)=[O:30]
Reactant: C[C@H](Oc1cccc2ncnc(Nc3ccc4c(cnn4Cc4nccs4)c3)c12)C(=O)O
Reactant: C1COCCN1
Product: C[C@H](Oc1cccc2ncnc(Nc3ccc4c(cnn4Cc4nccs4)c3)c12)C(=O)N1CCOCC1
Yield: 37 %

Procedure:
Using the same procedure as in Example 44, (2S)-2-[(4-{[1-(1,3-thiazol-2-ylmethyl)-1H-indazol-5-yl]amino}quinazolin-5-yl)oxy]propanoic acid (380 mg, 0.84 mmol) was reacted with morpholine to give the title compound as a white solid (158 mg, 37%); NMR Spectrum 1.58 (d, 3H), 3.40-3.75 (m, 8H), 5.88 (q, 1H), 6.04 (s, 2H), 7.29 (d, 1H), 7.36 (d, 1H), 7.66 (s, 1H), 7.73-7.78 (m, 3H), 7.88-7.90 (m, 1H), 8.20 (s, 1H), 8.52 (s, 1H), 8.55 (s, 1H), 11.15 (br s, 1H); Mass spectrum MH+ 516.
Reaction SMILES: [CH:1]#[C:2][CH2:3][CH2:4][CH2:5][CH3:6].C(N(CC)CC)C.[O:14]=[C:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17](=[O:24])[N:16]1[CH2:25][C:26](Cl)=[N:27][OH:28]>C(Cl)(Cl)Cl>[CH2:3]([C:2]1[O:28][N:27]=[C:26]([CH2:25][N:16]2[C:15](=[O:14])[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]2=[O:24])[CH:1]=1)[CH2:4][CH2:5][CH3:6]
Reactant: O=C1c2ccccc2C(=O)N1CC(Cl)=NO
Reactant: C#CCCCC
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCCCc1cc(CN2C(=O)c3ccccc3C2=O)no1
Temperature: 25 °C
Reaction time: 8 h
Yield: 35.8 %

Procedure:
1-Hexyne (5.16 g, 62.9 mmol) and triethylamine (6.36 g, 62.9 mmol) were sequentially added to a suspension of 2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-N-hydroxyethanimidoyl chloride (5.0 g, 21 mmol) in chloroform (80 mL). The solution was stirred overnight at room temperature, washed sequentially with 0.5 M hydrochloric acid and brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by flash column chromatography on silica gel (eluting with 3:1 to 1:1 hexane:ethyl acetate) to provide 2.14 g of 2-[(5-butylisoxazol-3-yl)methyl]-1H-isoindole-1,3(2H)-dione as a white, crystalline solid.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][C:4]([C:9]([C:16]3[CH:20]=[CH:19][S:18][CH:17]=3)([C:11]3[CH:15]=[CH:14][S:13][CH:12]=3)[OH:10])([CH2:5][CH2:6]1)[CH2:3][CH2:2]2.[C:21]1([O:27][CH2:28][CH2:29][CH2:30][Br:31])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CO>[Br-:31].[OH:10][C:9]([C:11]1[CH:15]=[CH:14][S:13][CH:12]=1)([C:16]1[CH:20]=[CH:19][S:18][CH:17]=1)[C:4]12[CH2:7][CH2:8][N+:1]([CH2:30][CH2:29][CH2:28][O:27][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)([CH2:6][CH2:5]1)[CH2:2][CH2:3]2
Reactant: BrCCCOc1ccccc1
Reactant: OC(c1ccsc1)(c1ccsc1)C12CCN(CC1)CC2
Solvent: CO
Product: OC(c1ccsc1)(c1ccsc1)C12CC[N+](CCCOc3ccccc3)(CC1)CC2
Product: [Br-]
Yield: 44.6 %

Procedure:
Following the general procedure outlined in Example 4, 1-azabicyclo[2.2.2]oct-4-yl(di-3-thienyl)methanol (0.0808 g, 0.264 mmol) and 3-bromopropyl phenyl ether (0.070 mL, 0.444 mmol) in 2 MeOH/3 CHCl3/2 CH3CN (5.0 mL) were reacted to give the desired product (0.0613 g, 44.7%). EI-MS m/z 440 (M+) Rt (2.05 min).
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][O:9][C:10](=[O:60])[C@H:11]([NH:52]C(OC(C)(C)C)=O)[C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([C:29]3[CH:34]=[CH:33][C:32]([CH2:35][CH2:36][CH:37]([O:42][Si](C(C)(C)C)(C)C)[C:38]([CH3:41])([CH3:40])[CH3:39])=[C:31]([CH3:50])[CH:30]=3)([CH2:27][CH3:28])[CH2:25][CH3:26])=[CH:20][C:19]=2[CH3:51])=[CH:14][CH:13]=1>ClCCl>[CH3:8][O:9][C:10](=[O:60])[C@H:11]([NH2:52])[C:12]1[CH:13]=[CH:14][C:15]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([CH2:25][CH3:26])([C:29]3[CH:34]=[CH:33][C:32]([CH2:35][CH2:36][CH:37]([OH:42])[C:38]([CH3:39])([CH3:40])[CH3:41])=[C:31]([CH3:50])[CH:30]=3)[CH2:27][CH3:28])=[CH:20][C:19]=2[CH3:51])=[CH:16][CH:17]=1
Reactant: CCC(CC)(c1ccc(CCC(O[Si](C)(C)C(C)(C)C)C(C)(C)C)c(C)c1)c1ccc(-c2ccc([C@@H](NC(=O)OC(C)(C)C)C(=O)OC)cc2)c(C)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCC(CC)(c1ccc(CCC(O)C(C)(C)C)c(C)c1)c1ccc(-c2ccc([C@@H](N)C(=O)OC)cc2)c(C)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 65.1 %

Procedure:
Trifluoroacetic acid (0.1 mL) was added to a solution of (R)-t-butoxycarbonylamino-[4′-(1-{4-[3-(t-butyldimethyl-silanyloxy)-4,4-dimethyl-pentyl]-3-methyl-phenyl}-1-ethyl-propyl)-2′-methyl-biphenyl-4-yl]-acetic acid methyl ester (Example 168-(1); 43.1 mg, 0.058 mmol) in dichloromethane (3 mL) at 0° C., and the mixture was stirred at room temperature for one hour. Then, the reaction mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (chloroform:methanol=10:1) to give the target compound as a colorless oil (20.0 mg, 65%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:12])=[C:6]([CH2:8][C:9](O)=[O:10])[CH:7]=1.S(Cl)([Cl:15])=O.CN(C)C=O.CO>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:12])=[C:6]([CH2:8][C:9]([Cl:15])=[O:10])[CH:7]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)Cc1cc(Br)ccc1F
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Solvent: CO
Product: O=C(Cl)Cc1cc(Br)ccc1F
Temperature: 80 °C
Reaction time: 4 h
Yield: 105 %

Procedure:
To a mixture of commercially available 5-bromo-2-fluorophenylacetic acid (compound B1A, [CAS No. 883514-21-4], 6.42 g, 26 mmol) in toluene (52 ml) and thionyl chloride (SOCl2) (4.721 ml, 40 mmol) at 23° C. was added a drop of N,N-dimethylformamide (DMF) and the mixture was stirred at 80° C. for 4 hours (reaction checked by HPLC with product+MeOH). All volatiles were removed by rotary evaporation and the residue was dried in high vacuum to give the title compound as a colorless liquid (7.01 g, 105%), which was used without further purification.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:4]=[CH:5][C:6]([N:9]2[CH2:16][CH:15]3[CH:11]([CH2:12][NH:13][CH2:14]3)[CH2:10]2)=[N:7][CH:8]=1.[CH3:19][C:20]1[CH:24]=[CH:23][O:22][C:21]=1[C:25](O)=[O:26]>>[CH3:19][C:20]1[CH:24]=[CH:23][O:22][C:21]=1[C:25]([N:13]1[CH2:14][CH:15]2[CH:11]([CH2:10][N:9]([C:6]3[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:17])[F:18])=[CH:8][N:7]=3)[CH2:16]2)[CH2:12]1)=[O:26]
Reactant: Cc1ccoc1C(=O)O
Reactant: FC(F)(F)c1ccc(N2CC3CNCC3C2)nc1
Product: Cc1ccoc1C(=O)N1CC2CN(c3ccc(C(F)(F)F)cn3)CC2C1

Procedure:
The title compound was prepared in a manner analogous to Example 15, utilizing 2-(5-(trifluoromethyl)pyridin-2-yl)octahydropyrrolo[3,4-c]pyrrole and 3-methylfuran-2-carboxylic acid. MS (ESI) mass calcd. C18H18F3N3O2, 365.36; m/z found 366.0 [M+H]+. 1H NMR (CDCl3): 8.39 (s, 1H), 7.62 (d, J=9.1 Hz, 1H), 7.32 (d, J=1.4 Hz, 1H), 6.39 (d, J=8.8 Hz, 1H), 6.32 (d, J=1.4 Hz, 1H), 4.17 (brs, 1H), 3.94 (brs, 1H), 3.81 (brs, 3H), 3.71-3.67 (m, 1H), 3.50 (br s, 2H), 3.11 (brs, 2H), 2.37 (s, 3H).
Reaction SMILES: [H-].[Na+].[NH:3]1[C:7]([CH2:8][CH2:9][CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=2)=[N:6][N:5]=[N:4]1.Cl[CH2:20][C:21]1[N:22]=[C:23]([CH:26]=[CH:27][C:28]2[CH:33]=[CH:32][C:31]([S:34]([F:39])([F:38])([F:37])([F:36])[F:35])=[CH:30][CH:29]=2)[O:24][CH:25]=1.Cl>CN(C)C=O.O>[F:37][S:34]([F:35])([F:36])([F:38])([F:39])[C:31]1[CH:32]=[CH:33][C:28](/[CH:27]=[CH:26]/[C:23]2[O:24][CH:25]=[C:21]([CH2:20][O:18][C:15]3[CH:14]=[CH:13][C:12]([CH2:11][CH2:10][CH2:9][CH2:8][C:7]4[N:6]=[N:5][NH:4][N:3]=4)=[CH:17][CH:16]=3)[N:22]=2)=[CH:29][CH:30]=1
Reactant: FS(F)(F)(F)(F)c1ccc(C=Cc2nc(CCl)co2)cc1
Reactant: Oc1ccc(CCCCc2nnn[nH]2)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: FS(F)(F)(F)(F)c1ccc(/C=C/c2nc(COc3ccc(CCCCc4nn[nH]n4)cc3)co2)cc1
Reaction time: 0.25 h
Yield: 21.9 %

Procedure:
46.3 mg (1.84 mmol) 95% sodium hydride were given at 0° C. to a solution of 200 mg (0.916 mmol) 4-(4-tetrazol-5-yl-butyl)-phenol in 5.0 ml N,N-dimethylformamide and stirred for 15 min. 317 mg (0.916 mmol) 4-chloromethyl-2-[2-(4-pentafluorosulfanyl-phenyl)-vinyl]-oxazole were added and stirring continued at 25° C. for 2 h. The reaction mixture was neutralized with HCl, poured into water and the resulting precipitate was purified by HPLC-MS, treated with diethyl ether, filtered and dried to yield 106 mg (22%) of the title compound.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[C:9]([NH:12][C:13]1[CH:18]=[C:17]([C:19]([O:21]CC)=[CH2:20])[N:16]=[C:15]([C:24]([O:26][CH3:27])=[O:25])[C:14]=1[Cl:28])(=[O:11])[CH3:10]>C1COCC1.O>[C:9]([NH:12][C:13]1[CH:18]=[C:17]([C:19](=[O:20])[CH2:21][Br:1])[N:16]=[C:15]([C:24]([O:26][CH3:27])=[O:25])[C:14]=1[Cl:28])(=[O:11])[CH3:10]
Reactant: C=C(OCC)c1cc(NC(C)=O)c(Cl)c(C(=O)OC)n1
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1nc(C(=O)CBr)cc(NC(C)=O)c1Cl
Reaction time: 0.25 h
Yield: 95.8 %

Procedure:
N-Bromosuccinimide (0.377 g, 2.13 mmol) was added all at once to a solution of methyl 4-acetamido-3-chloro-6-(1-ethoxyvinyl)pyridine-2-carboxylate (0.636 g, 2.13 mmol) in THF (40 mL) and water (2 mL) at room temperature. After 15 minutes, the reaction mixture was concentrated and the residue partitioned between dichloromethane and water. The organic layer was separated, dried (MgSO4), and concentrated to provide methyl 4-acetamido-3-chloro-6-(bromoacetyl)pyridine-2-carboxylate (0.714 g, 2.04 mmol). 1H NMR (CDCl3): δ 9.12 (s, 1H), 7.99 (br.s, 1H), 4.82 (s, 2H), 4.06 (s, 3H), 2.36 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:25]2[C:30]([CH3:31])=[CH:29][C:28]([O:32][CH2:33][C:34](OC)=[O:35])=[CH:27][C:26]=2[CH3:38])=[C:6]2[C:10]=1[C@H:9]([O:11][C:12]1[CH:24]=[CH:23][C:15]3[C@H:16]([CH2:19][C:20]([OH:22])=[O:21])[CH2:17][O:18][C:14]=3[CH:13]=1)[CH2:8][CH2:7]2.[NH3:39]>O1CCOCC1>[NH2:39][C:34](=[O:35])[CH2:33][O:32][C:28]1[CH:29]=[C:30]([CH3:31])[C:25]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[C:10]3[C:6]=2[CH2:7][CH2:8][C@H:9]3[O:11][C:12]2[CH:24]=[CH:23][C:15]3[C@H:16]([CH2:19][C:20]([OH:22])=[O:21])[CH2:17][O:18][C:14]=3[CH:13]=2)=[C:26]([CH3:38])[CH:27]=1
Reactant: N
Reactant: COC(=O)COc1cc(C)c(-c2ccc(F)c3c2CC[C@H]3Oc2ccc3c(c2)OC[C@H]3CC(=O)O)c(C)c1
Solvent: C1COCCO1
Product: Cc1cc(OCC(N)=O)cc(C)c1-c1ccc(F)c2c1CC[C@H]2Oc1ccc2c(c1)OC[C@H]2CC(=O)O

Procedure:
The title compound is prepared from 2-((S)-6-((R)-7-fluoro-4-(4-(2-methoxy-2-oxoethoxy)-2,6-dimethylphenyl)-2,3-dihydro-1H-inden-1-yloxy)-2,3-dihydrobenzofuran-3-yl)acetic acid and 0.5 M solution of ammonia in 1,4-dioxane following a procedure analogous to that described in example 12. LC (method 9): tR=1.01 min; Mass spectrum (ESI+): m/z=506 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([N+:10]([O-])=O)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].O.Cl>C(O)C.[Fe]>[CH3:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[O:8][CH3:9])[NH2:10]
Reactant: COc1ccc([N+](=O)[O-])cc1C
Agent: [Fe]
Agent: Cl
Solvent: O
Solvent: CCO
Product: COc1ccc(N)cc1C
Yield: 123 %

Procedure:
To a solution of 3-methyl-4-methoxynitrobenzene(7.59 g, 45 mmol) in ethanol was added iron powder (35 g), water(5 mL) and concentrated hydrochloric acid (0.4 mL). The mixture was refluxed for 1 hour and then filtered while hot. The filtrate was concentrated to dryness. The residue was dissolved in chloroform. The chloroform solution was dried with sodium sulfated and evaporated to give 3-methyl-4-methoxyaniline (7.59 g). To a solution of this compound (6.17 g, 45 mmol) in acetic acid (55 mL) were added dropwise acetic anhydride (4,4 mL, 46 mmol) at room temperature with stirring and then bromine(2,4 mL, 46 mmol) at 50° C. with stirring. The reaction mixture was stirred at the same temperature for 2 hours and poured into ice-water. The resulting precipitate was filtered off, washed with water and dissolved in ethyl acetate. This solution was washed with saturated sodium chloride solution, dried with sodium sulfate and evaporated to dryness to give 2-bromo-4-methoxy-5-methylacetanilide as a crude product. Crystallization from diethyl ether gave pure product (8.27 g).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=2)[C:13]([C:24]([OH:26])=O)=[CH:12][N:11]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:27][NH:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[C:1]([O:5][C:6](=[O:7])[NH:8][CH2:9][C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=2)[C:13]([C:24](=[O:26])[N:28]([CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH3:27])=[CH:12][N:11]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CNCc1ccccc1
Reactant: COc1cc2c(C(=O)O)cnc(CNC(=O)OC(C)(C)C)c2cc1OC
Product: COc1cc2c(C(=O)N(C)Cc3ccccc3)cnc(CNC(=O)OC(C)(C)C)c2cc1OC
Yield: 8 %

Procedure:
As described in example 1E, 80 mgs of 1-(tert-butoxycarbonylamino-methyl)-6,7-dimethoxy-isoquinoline-4-carboxylic acid was coupled with N-methylbenzylamine to give 82 mgs (8%) of [4-(benzyl-methyl-carbamoyl)-6,7-dimethoxy-isoquinolin-1-ylmethyl]-carbamic acid tert-butyl ester: 1H NMR (CDCl3) δ 1.50 (s, 9H), 3.77 (s, 3H), 4.02 and 4.03 (2s, 6H), 4.87-4.90 (m, 4H), 6.10-6.22 (m, 1H), 6.93 (s, 0.6H), 7.06-7.12 (m, 1H), 7.16 (s, 0.4H), 7.27-7.42 (m, 4H), 7.50 (d, 1H, J=7.60 Hz), 8.32 (s, 1H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[N:8]3[CH2:14][CH2:13][CH2:12][C:9]3=[N:10][N:11]=2)=[CH:3][CH:2]=1.O=C1[CH:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])CCCN1.C(NN)(=O)C1C=CN=CC=1>C(Cl)Cl.CCO>[N:1]1[CH:2]=[CH:3][C:4]([C:7]2[N:8]3[CH2:14][CH2:13][CH2:12][CH:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:9]3=[N:10][N:11]=2)=[CH:5][CH:6]=1
Reactant: CCOC(=O)C1CCCNC1=O
Reactant: c1cc(-c2nnc3n2CCC3)ccn1
Agent: NNC(=O)c1ccncc1
Solvent: ClCCl
Solvent: CCO
Product: CCOC(=O)C1CCCn2c(-c3ccncc3)nnc21

Procedure:
The title compound was prepared analogous to 3-pyridin-4-yl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole from ethyl 2-oxopiperidine-3-carboxylate (2.57 g, 15 mmol), Me3OBF4 (2.66 g, 18 mmol) and isonicotinic hydrazide (2.06 g, 15 mmol) in DCM (150 ml) and EtOH (16 ml). Recrystallization from EA afforded 1.67 g (41%). 1H NMR: 1.29 (t, 3 H), 2.03 (m, 1 H), 2.14-2.25 (m, 2 H), 2.32 (m, 1 H), 4.01-4.12 (m, 1 H), 4.16-4.27 (m, 4 H), 7.64 (d, 2 H), 8.74 (d, 2 H)