Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][C:5](Cl)=[O:6].Cl.[NH2:9][CH:10]1[CH2:22][C:21]2[C:13](=[CH:14][C:15]3[CH2:19][CH2:18][O:17][C:16]=3[CH:20]=2)[CH2:12][CH2:11]1.C(N(CC)CC)C>C1C=CC=CC=1.O>[Cl:1][CH2:2][CH2:3][CH2:4][C:5]([NH:9][CH:10]1[CH2:22][C:21]2[C:13](=[CH:14][C:15]3[CH2:19][CH2:18][O:17][C:16]=3[CH:20]=2)[CH2:12][CH2:11]1)=[O:6]
Reactant: NC1CCc2cc3c(cc2C1)OCC3
Reactant: O=C(Cl)CCCCl
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: O=C(CCCCl)NC1CCc2cc3c(cc2C1)OCC3
Reaction time: 1 h

Procedure:
4.2 g of 4-chlorobutyryl chloride are added at room temperature to a mixture of 5 g of the compound of Example 2 and 4.2 g of triethylamine in 60 ml of benzene. After 1 hour at room temperature, the medium is diluted with water and filtered and the aqueous phase is extracted with benzene. The filtrate and the precipitate are combined and the benzene is evaporated off under vacuum. The dry residue is solidified in ether.
Reaction SMILES: [C:1](/[CH:3]=[C:4](\[O-])/[C:5]([O:7][CH2:8][CH3:9])=[O:6])#[N:2].[K+].Cl.[CH2:13]([O:20][C:21]1[CH:22]=[C:23]([NH:27][NH2:28])[CH:24]=[CH:25][CH:26]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(O)C>[NH2:2][C:1]1[N:27]([C:23]2[CH:24]=[CH:25][CH:26]=[C:21]([O:20][CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:22]=2)[N:28]=[C:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH:3]=1
Reactant: CCOC(=O)/C([O-])=C/C#N
Reactant: NNc1cccc(OCc2ccccc2)c1
Agent: Cl
Agent: [K+]
Solvent: CCO
Product: CCOC(=O)c1cc(N)n(-c2cccc(OCc3ccccc3)c2)n1
Temperature: 25 °C
Yield: 67.8 %

Procedure:
To a suspension of potassium (Z)-1-cyano-3-ethoxy-3-oxoprop-1-en-2-olate (3.73 g, 20.82 mmol) in ethanol (100 mL) was added (3-(benzyloxy)phenyl)hydrazine hydrochloride (Preparation 61, 5.22 g, 20.82 mmol) and the reaction was heated at reflux for 24 hours. The reaction was cooled to room temperature, the solid was filtered and the filtrate was concentrated in vacuo. The residue was purified using silica gel column chromatography eluting with 20-40% EtOAc in heptanes to afford the title compound (4.76 g, 68%).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([OH:19])=O)=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[CH3:20][C@@H:21]1[CH2:25][CH2:24][CH2:23][N:22]1[CH2:26][C@@H:27]1[CH2:31][CH2:30][CH2:29][NH:28]1>>[CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([C:11]2[CH:12]=[CH:13][C:14]([C:17]([N:28]3[CH2:29][CH2:30][CH2:31][C@H:27]3[CH2:26][N:22]3[CH2:23][CH2:24][CH2:25][C@H:21]3[CH3:20])=[O:19])=[CH:15][CH:16]=2)=[CH:9][CH:10]=1)(=[O:3])=[O:4]
Reactant: C[C@@H]1CCCN1C[C@@H]1CCCN1
Reactant: CS(=O)(=O)c1ccc(-c2ccc(C(=O)O)cc2)cc1
Product: C[C@@H]1CCCN1C[C@@H]1CCCN1C(=O)c1ccc(-c2ccc(S(C)(=O)=O)cc2)cc1

Procedure:
The title compound is prepared in a manner substantially analogous to Procedure B′ starting from 4′-methanesulfonyl-biphenyl-4-carboxylic acid (CAS 16734-98-8) and 2-(R)-Methyl-1-(2-(S)-pyrrolidinylmethyl)pyrrolidine. MS (M+H) 427.2
Reaction SMILES: [CH2:1]1[N:6](C(OCC2C=CC=CC=2)=O)[CH2:5][CH2:4][N:3]2[CH2:17][CH2:18][CH2:19][CH2:20][C@H:2]12>CO>[CH2:1]1[NH:6][CH2:5][CH2:4][N:3]2[CH2:17][CH2:18][CH2:19][CH2:20][C@H:2]12
Reactant: O=C(OCc1ccccc1)N1CCN2CCCC[C@@H]2C1
Solvent: CO
Product: C1CCN2CCNC[C@H]2C1
Yield: 103.8 %

Procedure:
Phenylmethyl (9aR)-octahydro-2H-pyrido[1,2-a]pyrazine-2-carboxylate (688 mg, 2.50 mmol) was dissolved in MeOH (15 mL), degassed and placed under argon. 10% Pd/C (206 mg) was added, and the contents were thoroughly degassed and placed under a hydrogen balloon for 2 h. The contents were then degassed, and the Pd/C was removed by filtration through Celite, washing with MeOH. The filtrate was concentrated in vacuo to provide pure (9aR)-octahydro-2H-pyrido[1,2-a]pyrazine (364 mg, 99%). LCMS: (M+H)+: 141.1.
Reaction SMILES: [CH2:1]([CH:4]1[CH:30]=[C:29]([CH3:31])[CH2:28][CH:27]([CH3:32])[CH2:26][CH:25]([O:33][CH3:34])[CH:24]2[O:35][C:20]([OH:39])([CH:21]([CH3:38])[CH2:22][CH:23]2[O:36][CH3:37])[C:19](=[O:40])[C:18](=[O:41])[N:17]2[CH:12]([CH2:13][CH2:14][CH2:15][CH2:16]2)[C:11](=[O:42])[O:10][CH:9]([C:43]([CH3:61])=[CH:44][CH:45]2[CH2:50][CH2:49][CH:48]([O:51][Si:52]([C:55]([CH3:58])([CH3:57])[CH3:56])([CH3:54])[CH3:53])[CH:47]([O:59][CH3:60])[CH2:46]2)[CH:8]([CH3:62])[CH:7]([OH:63])[CH2:6][C:5]1=[O:64])[CH:2]=[CH2:3].[C:65](OC(=O)C)(=[O:67])[CH3:66]>N1C=CC=CC=1>[C:65]([O:63][CH:7]1[CH2:6][C:5](=[O:64])[CH:4]([CH2:1][CH:2]=[CH2:3])[CH:30]=[C:29]([CH3:31])[CH2:28][CH:27]([CH3:32])[CH2:26][CH:25]([O:33][CH3:34])[CH:24]2[O:35][C:20]([OH:39])([CH:21]([CH3:38])[CH2:22][CH:23]2[O:36][CH3:37])[C:19](=[O:40])[C:18](=[O:41])[N:17]2[CH:12]([CH2:13][CH2:14][CH2:15][CH2:16]2)[C:11](=[O:42])[O:10][CH:9]([C:43]([CH3:61])=[CH:44][CH:45]2[CH2:50][CH2:49][CH:48]([O:51][Si:52]([C:55]([CH3:58])([CH3:57])[CH3:56])([CH3:53])[CH3:54])[CH:47]([O:59][CH3:60])[CH2:46]2)[CH:8]1[CH3:62])(=[O:67])[CH3:66]
Reactant: C=CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O[Si](C)(C)C(C)(C)C)C(OC)C3)C(C)C(O)CC1=O)C(C)CC2OC
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: C=CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O[Si](C)(C)C(C)(C)C)C(OC)C3)C(C)C(OC(C)=O)CC1=O)C(C)CC2OC
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of 17-allyl-12-[2-(4-tert-butyl-dimethylsilyloxy-3-methoxycyclohexyl)-1-methylvinyl]-1,14-dihydroxy-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (39.9 mg) in pyridine (1.5 ml) was added acetic anhydride (0.5 ml), and the mixture was stirred at room temperature for 6 hours. The solvent was removed from the reaction mixture under reduced pressure to give a crude oil, which was purified on silica gel thin layer chromatography (developing solvent: diethyl ether and hexane, 1:1 v/v) to afford 14-acetoxy-17-allyl-12-[2-(4-tert-butyl-dimethylsilyloxy-3-methoxycyclohexyl)-1-methylvinyl]-1-hydroxy-23,25-dimethoxy-13,19,21,27tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (26.5 mg).
Reaction SMILES: C(C(C(=O)C)[C:5]([C:7]1[CH:12]=[CH:11]C=CC=1)=[O:6])(C)C.C[O:17][C:18](C)(C(C)C)[C:19]1C=CC=C[CH:20]=1>C(C1C=CC=CC=1C(C)C)(C)C>[C:18]([O:6][CH2:5][CH2:7][CH2:12][CH3:11])(=[O:17])[CH:19]=[CH2:20]
Reactant: COC(C)(c1ccccc1)C(C)C
Reactant: CC(=O)C(C(=O)c1ccccc1)C(C)C
Agent: CC(C)c1ccccc1C(C)C
Product: C=CC(=O)OCCCC

Procedure:
In a mixture of diisopropyl benzene, isopropyl acetyl acetophenone, and dimethyl isopropyl phenyl carbinol
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[C:7]([O:24][CH3:25])=[CH:8][C:9]([CH:21]([CH3:23])[CH3:22])=[C:10]([CH:20]=1)[O:11][C:12]1[CH:13]([NH2:19])[NH:14][C:15]([NH2:18])=[N:16][CH:17]=1.I[CH3:27].[OH-].[K+]>CC(C)=O>[CH:21]([C:9]1[CH:8]=[C:7]([O:24][CH3:25])[C:6]([C:2]2[N:1]([CH3:27])[CH:5]=[CH:4][N:3]=2)=[CH:20][C:10]=1[O:11][C:12]1[CH:13]([NH2:19])[NH:14][C:15]([NH2:18])=[N:16][CH:17]=1)([CH3:23])[CH3:22]
Reactant: CI
Reactant: COc1cc(C(C)C)c(OC2=CN=C(N)NC2N)cc1-c1ncc[nH]1
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)=O
Product: COc1cc(C(C)C)c(OC2=CN=C(N)NC2N)cc1-c1nccn1C
Temperature: 30 °C
Yield: 52.2 %

Procedure:
To a solution of 5-[5-(1H-Imidazol-2-yl)-2-isopropyl-4-methoxy-phenoxy]-3,4-dihydro-pyrimidine-2,4-diamine (0.044g, 0.129 mmols) and iodomethane (9 ul, 0.145 mmols) in acetone (5 ml) was added KOH (0.055g, 0.98 mmols), the mixture was heated at 30° C. for 20 minutes, the mixture was filtered through celite, washed with CH2Cl2, the combined organic solution was concentrated in vacuo. The residue was purified via preparative TLC silica plates, eluted with 5% MeOH/CH2Cl2/NH4OH four times to give 5-[2-Isopropyl4-methoxy-5-(1-methyl-1H-imidazol-2-yl)-phenoxy]-3,4-dihydro-pyrimidine-2,4-diamine (0.024g, 52%). Mass Spec: M+H: 355.
Reaction SMILES: [C:1]([O:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([OH:16])[CH:11]=1)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4]C=1.C1(O)CCCCC1>>[CH:1]1([O:9][C:10]2[CH:11]=[C:12]([OH:16])[CH:13]=[CH:14][CH:15]=2)[CH2:2][CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: O=C(Oc1cccc(O)c1)c1ccccc1
Solvent: OC1CCCCC1
Product: Oc1cccc(OC2CCCCC2)c1
Yield: 32.3 %

Procedure:
By using 3-hydroxyphenyl benzoate (100 mg) and cyclohexanol (54.3 μl) as starting materials, the title compound (29 mg) was obtained in the same manner as that of Reference Example 15.
Reaction SMILES: [C:1]([NH:8][C@H:9]([C@H:17]1[O:21][C:20](=[O:22])[CH2:19][CH2:18]1)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Br[CH2:34][C:35]1[CH:36]=[C:37]([CH:40]=[CH:41][CH:42]=1)[C:38]#[N:39].CCCCCC.C(OCC)(=O)C>C1COCC1.CCCCCC>[C:1]([NH:8][C@H:9]([C@H:17]1[O:21][C:20](=[O:22])[C@H:19]([CH2:34][C:35]2[CH:42]=[CH:41][CH:40]=[C:37]([C:38]#[N:39])[CH:36]=2)[CH2:18]1)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([O:3][C:4]([CH3:6])([CH3:7])[CH3:5])=[O:2]
Reactant: N#Cc1cccc(CBr)c1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@@H]1CCC(=O)O1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@@H]1C[C@@H](Cc2cccc(C#N)c2)C(=O)O1

Procedure:
Analogously to Example 21 D) 1)c), 2.0 g (6.55 mmol) of 5(S)-[1(S)-(Boc-amino)-2-phenylethyl]-dihydrofuran-2-(3H)-one [Example 21 D) 1)b)] dissolved in 40 ml of THF are deprotonated at -75° C. with 13.1 ml of lithium bis(trimethylsilyl)amide 1M in THF and alkylated (60 min -60° C.) with 1.4 g (7.2 mmol) of 3-bromomethylbenzonitrile (Fluka; Buchs/Switzerland). Column chromatography (SiO2, hexane/ethyl acetate 2:1) and stirring in hexane yields the pure title compound: TLC Rf (D)=0.41; tRet (I)=16.1 min.
Reaction SMILES: [C:1]([NH:4][CH2:5][C@@H:6]1[O:10][C:9](=[O:11])[N:8]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([O:20][C:21]3C(F)=C(F)C(F)=C(F)C=3F)=[O:19])=[C:14]([F:32])[CH:13]=2)[CH2:7]1)(=[S:3])[CH3:2].C[O-].[Na+]>CO>[C:1]([NH:4][CH2:5][C@@H:6]1[O:10][C:9](=[O:11])[N:8]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([O:20][CH3:21])=[O:19])=[C:14]([F:32])[CH:13]=2)[CH2:7]1)(=[S:3])[CH3:2]
Reactant: CC(=S)NC[C@H]1CN(c2ccc(C(=O)Oc3c(F)c(F)c(F)c(F)c3F)c(F)c2)C(=O)O1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1ccc(N2C[C@H](CNC(C)=S)OC2=O)cc1F
Yield: 83.6 %

Procedure:
A solution of 5-(S)-thioacetamidomethyl-3-[4′-(pentafluorophenoxy)carbonyl-3′-fluorophenyl]oxazolidine-2-one (0.100 g, 0.209 mmol) and 25% sodium methoxide in methanol (0.0573 ml, 0.251 mmol) in methanol (2 mL) was stirred at r.t. for 1 h. solvent was removed under vacuum and the residue purified by PTLC (10% MeOH in DCM) to give the pure product as a white solid (0.057 g, 84%). M.p. 152-4° C. MS (m/z): [M+H]+=327.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([NH:12][C:13]([CH3:16])([CH3:15])[CH3:14])[C:8]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[N:7]2.CC1(C)C(C)(C)OB([C:31]2[NH:39][C:38]3[CH2:37][CH2:36][NH:35][C:34](=[O:40])[C:33]=3[CH:32]=2)O1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1>O1CCOCC1.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CO.C(Cl)Cl>[C:13]([NH:12][C:9]1[C:8]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[N:7][C:6]2[C:11]([N:10]=1)=[C:2]([C:31]1[NH:39][C:38]3[CH2:37][CH2:36][NH:35][C:34](=[O:40])[C:33]=3[CH:32]=1)[CH:3]=[CH:4][CH:5]=2)([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)Nc1nc2c(Br)cccc2nc1-c1ccccc1
Reactant: CC1(C)OB(c2cc3c([nH]2)CCNC3=O)OC1(C)C
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: CO
Product: CC(C)(C)Nc1nc2c(-c3cc4c([nH]3)CCNC4=O)cccc2nc1-c1ccccc1
Temperature: 100 °C
Reaction time: 1 h
Yield: 52.4 %

Procedure:
A solution of 8-bromo-N-(tert-butyl)-3-phenylquinoxalin-2-amine (83.0 mg, 0.233 mmol), 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (Example 609; 172 mg, 0.466 mmol), K3PO4 (148 mg, 0.699 mmol), dicyclohexyl(2′,4′,6′-triisopropyl-[1,1′-biphenyl]-2-yl)phosphine (XPhos; Strem Chemicals, Inc.; 11.11 mg, 0.023 mmol), and Pd2dba3 (Aldrich; 10.67 mg, 0.012 mmol) in a mixture of 1,4-dioxane (2.0 mL) and water (0.400 mL) was stirred under argon at 100° C. for 1 h. The reaction mixture was then concentrated onto silica gel and chromatographically purified (silica gel, 50-100% EtOAc/hexanes, then 0-10% MeOH/DCM) to provide 2-(3-(tert-butylamino)-2-phenylquinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (50.0 mg, 0.122 mmol, 52% yield) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ ppm 12.72 (1H, br. s.), 7.99 (1H, dd, J=7.6, 1.4 Hz), 7.77 (1H, dd, J=8.1, 1.3 Hz), 7.71 (2H, dd, J=7.8, 1.6 Hz), 7.53-7.62 (3H, m), 7.41 (1H, t, J=7.8 Hz), 7.13 (1H, d, J=2.2 Hz), 5.98-6.21 (1H, m), 5.36 (1H, s), 3.71 (2H, t, J=6.9 Hz), 3.03 (2H, t, J=7.0 Hz), 1.59 (9H, s). m/z (ESI, +ve) 412.0 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][C:12]([C:18]3[CH2:19][CH2:20][O:21][CH2:22][CH:23]=3)=[C:13](Cl)[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:24]([Sn](CCCC)(CCCC)CCCC)=[CH2:25]>>[C:1]([O:5][C:6]([N:8]1[CH2:9][C:10]2[C:15](=[CH:14][C:13]([CH:24]=[CH2:25])=[C:12]([C:18]3[CH2:19][CH2:20][O:21][CH2:22][CH:23]=3)[CH:11]=2)[CH2:16]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: CC(C)(C)OC(=O)N1Cc2cc(Cl)c(C3=CCOCC3)cc2C1
Product: C=Cc1cc2c(cc1C1=CCOCC1)CN(C(=O)OC(C)(C)C)C2

Procedure:
Prepared in analogy to Example A54(a) from 5-chloro-6-(3,6-dihydro-2H-pyran-4-yl)-1,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester (Example A61(a)) and vinyltributylstannane. White solid. MS (m/e): 272.4 ([M+H−Me2C═CH2]+, 100%).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]([OH:9])=O)[CH:3]=1.ClC(N(C)C)=C(C)C.CCN(C(C)C)C(C)C.[NH:27]1[C:35]2[C:30](=[C:31]([C:36]3[CH:37]=[C:38]([NH2:51])[C:39]4[C:43]([CH:44]=3)=[N:42][N:41](C3CCCCO3)[CH:40]=4)[CH:32]=[CH:33][CH:34]=2)[CH:29]=[CH:28]1.CC1C=CC(S(O)(=O)=O)=CC=1.N>C1COCC1.CO>[NH:27]1[C:35]2[C:30](=[C:31]([C:36]3[CH:44]=[C:43]4[C:39]([CH:40]=[N:41][NH:42]4)=[C:38]([NH:51][C:7]([C:4]4[CH:3]=[C:2]([CH3:1])[O:6][N:5]=4)=[O:9])[CH:37]=3)[CH:32]=[CH:33][CH:34]=2)[CH:29]=[CH:28]1
Reactant: Nc1cc(-c2cccc3[nH]ccc23)cc2nn(C3CCCCO3)cc12
Reactant: Cc1cc(C(=O)O)no1
Agent: CC(C)=C(Cl)N(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: N
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Cc1cc(C(=O)Nc2cc(-c3cccc4[nH]ccc34)cc3[nH]ncc23)no1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
5-Methyl-3-isoxazolecarboxylic acid (21 mg) was treated with anhydrous THF (2 ml) and then 1-chloro-N,N,2-trimethylpropenylamine (0.026 ml). The reaction was stirred at RT under nitrogen for 2 h. The reaction was then treated with anhydrous DIPEA (0.131 ml) and 2 ml of solution of 6-(1H-indol-4-yl)-2-(tetrahydro-2H-pyran-2-yl)-2H-indazol-4-amine (750 mg) in THF (30 ml). The reaction was then stirred at RT under nitrogen for 69 h. The solvent was blown off under a stream of nitrogen, dissolved in methanol (3 ml) and then the solvent removed under reduced pressure. The crude reaction mixture was dissolved in methanol (5 ml), treated with macroporous tosic acid resin (102 mg; 4.45 mmol/g) stirred at RT for 17 h and then treated with 0.88 ammonia (0.5 ml), stirred for 30 min and then filtered. The solvent was removed under reduced pressure and then purified by mass directed preparative HPLC (Method A) to give the title compound.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][C:6]=1[Br:7].[CH2:8]([C:10]1[CH:17]=[CH:16][C:13]([CH:14]=[O:15])=[CH:12][CH:11]=1)[CH3:9]>>[Br:7][C:6]1[CH:5]=[CH:4][S:3][C:2]=1[CH:14]([C:13]1[CH:16]=[CH:17][C:10]([CH2:8][CH3:9])=[CH:11][CH:12]=1)[OH:15]
Reactant: Brc1ccsc1Br
Reactant: CCc1ccc(C=O)cc1
Product: CCc1ccc(C(O)c2sccc2Br)cc1

Procedure:
2,3-Dibromothiophene and 4-ethylbenzaldehyde were treated in a manner similar to Reference Example 1-(1) to give 3-bromo-2-thienyl-4-ethylphenylmethanol as yellow oil. APCI-Mass m/Z 279/281 (M+H−H2O).
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[O:11][C:10]2[C:5](=[CH:6][C:7]([C:12]#[N:13])=[CH:8][CH:9]=2)[C@@H:4]2[O:14][C@H:3]12.[CH3:16][O:17][C:18]1[CH:19]=[CH:20][C:21]2[O:25][NH:24][C:23](=[O:26])[C:22]=2[CH:27]=1>>[OH:14][C@H:3]1[C@H:4]([O:26][C:23]2[C:22]3[CH:27]=[C:18]([O:17][CH3:16])[CH:19]=[CH:20][C:21]=3[O:25][N:24]=2)[C:5]2[C:10](=[CH:9][CH:8]=[C:7]([C:12]#[N:13])[CH:6]=2)[O:11][C:2]1([CH3:15])[CH3:1]
Reactant: CC1(C)Oc2ccc(C#N)cc2[C@@H]2O[C@@H]21
Reactant: COc1ccc2o[nH]c(=O)c2c1
Product: COc1ccc2onc(O[C@@H]3c4cc(C#N)ccc4OC(C)(C)[C@H]3O)c2c1

Procedure:
Following the procedure in Example 1, using (S,S)-2,2-dimethyl-1a,7b-dihydro-2H-1,3-dioxa-cyclopropa[a]naphthalene-6-carbonitrile and 5-methoxy-benzo[d]isoxazol-3-one as starting materials, the title compound was prepared as a white solid.
Reaction SMILES: Br[C:2]1[N:6]([Cl:7])[C:5]([Cl:8])=[C:4]([CH:9]([O:11][CH3:12])[CH3:10])[N:3]=1.[CH2:13]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][CH3:22])[C:16]=1B(O)O)[CH3:14]>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:13]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][CH3:22])[C:16]=1[C:2]1[N:6]([Cl:7])[C:5]([Cl:8])=[C:4]([CH:9]([O:11][CH3:12])[CH3:10])[N:3]=1)[CH3:14]
Reactant: CCc1cccc(CC)c1B(O)O
Reactant: COC(C)c1nc(Br)n(Cl)c1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CCc1cccc(CC)c1-c1nc(C(C)OC)c(Cl)n1Cl
Temperature: 110 °C

Procedure:
A solution containing 2-bromo-1-methoxyethyl-3,4-dichloroimidazole (2.74 g, 10 mmol), 2,6-diethylphenylboronic acid (2.14 g, 12 mmol.) and Pd(PPh3)4 (0.23 mg, 0.2 mmol) in toluene/2M Na2CO3 (30 ml/15 mL) in a sealed tube is degassed, then allowed to heat to 110° C. overnight. The organic layer is separated and concentrated in vacuo to dryness. The residue is purified by column chromatography on silica gel (hexane/ethyl acetate 100/5) to obtain the 2-(2,6-diethylphenyl)-1-methoxyethyl-3,4-dichloroimidazole. Synthesis of 2-(2,6-diethylphenyl)-1-methoxyethyl-4-chloro-imidazole-3-carboxaldehyde
Reaction SMILES: CS(O[CH2:6][C@@H:7]1[C@H:10]([NH:11][C:12]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:13])[C:9](=[O:22])[N:8]1[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][C:25]=1[O:32][CH3:33])(=O)=O.[CH2:34]([CH2:36][NH2:37])[OH:35].CCN(C(C)C)C(C)C>C(#N)C.CCOC(C)=O>[CH3:33][O:32][C:25]1[CH:26]=[C:27]([O:30][CH3:31])[CH:28]=[CH:29][C:24]=1[CH2:23][N:8]1[C:9](=[O:22])[C@@H:10]([NH:11][C:12](=[O:13])[O:14][CH2:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[C@H:7]1[CH2:6][NH:37][CH2:36][CH2:34][OH:35]
Reactant: COc1ccc(CN2C(=O)[C@@H](NC(=O)OCc3ccccc3)[C@H]2COS(C)(=O)=O)c(OC)c1
Reactant: NCCO
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(CN2C(=O)[C@@H](NC(=O)OCc3ccccc3)[C@H]2CNCCO)c(OC)c1
Temperature: 80 °C
Yield: 75.2 %

Procedure:
To a solution of ((2S,3S)-3-(((benzyloxy)carbonyl)amino)-1-(2,4-dimethoxybenzyl)-4-oxoazetidin-2-yl)methyl methanesulfonate (6.43 g, 13.4 mmol) in Acetonitrile (44.8 ml) was added ethanolamine (8.13 ml, 134 mmol) followed by DIPEA (7.0 ml, 40 mmol). The solution was heated to 80° C. for 20 h, whereupon it was cooled to rt, diluted with EtOAc, washed with water, dried over Na2SO4 and concentrated in vacuo, afford the title compound (4.47 g, 75%) as a white solid. LCMS: Rf=0.60 min, m/z=444.2 (M+1).
Reaction SMILES: [CH2:1]([N:8]1[C:13](=O)[CH2:12][O:11][CH:10]([CH2:15][O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[CH2:23][C:24]2[S:28][CH:27]=[CH:26][CH:25]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].C(OCC)(=O)C.[C@H](O)(C([O-])=O)[C@@H](O)C([O-])=O.[Na+].[K+]>C1C=CC=CC=1.CCOCC.O>[CH2:1]([N:8]1[CH2:13][CH2:12][O:11][CH:10]([CH2:15][O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[CH2:23][C:24]2[S:28][CH:27]=[CH:26][CH:25]=2)[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1COC(COc2ccccc2Cc2cccs2)CN1Cc1ccccc1
Agent: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: CCOC(C)=O
Solvent: c1ccccc1
Solvent: O
Product: c1ccc(CN2CCOC(COc3ccccc3Cc3cccs3)C2)cc1
Yield: 90.2 %

Procedure:
A solution of 23 g of 4-benzyl-2-[2-(2-thenyl)phenoxymethyl]-morpholin-5-one in 200 ml of benzene was added dropwise to a suspension of 7 g of lithium aluminum hydride in 200 ml of ether with stirring and cooling. The resulting mixture was heated under reflux with stirring for 5 hours. To the mixture was added 10 ml of ethyl acetate, and the whole mixture was stirred for 30 minutes. To the mixture were added water under cooling and then 300 ml of a saturated aqueous Rochelle salt solution, and the resulting mixture was stirred for 30 minutes. The organic layer was collected and dried over anhydrous magnesium sulfate. The solvent was distilled off to give 20 g of 4-benzyl-2-[2-(2-thenyl)phenoxymethyl]morpholine as an oil. The oil was dissolved in ether, and a mixture of 4.8 g of oxalic acid in ether and ethanol was added to the solution to give 23 g of the corresponding oxalate salt as colorless crystals, melting at 179°-181.5° C. The thus-obtained oxalate was converted into the free base, which was used as the starting compound of Example 1.
Reaction SMILES: C(N([C:15]1[N:16]([C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=2)[N:17]=[C:18]2[C:23]=1[CH:22]=[CH:21][CH:20]=[CH:19]2)C(NC1CCCCC1)=O)CCC.[Cl:31][C:32]1[CH:33]=[C:34]([NH2:39])[CH:35]=[CH:36][C:37]=1[F:38]>CN1CCCC1=O>[Cl:31][C:32]1[CH:33]=[C:34]([NH:39][C:15]2[N:16]([C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=3)[N:17]=[C:18]3[C:23]=2[CH:22]=[CH:21][CH:20]=[CH:19]3)[CH:35]=[CH:36][C:37]=1[F:38]
Reactant: Nc1ccc(F)c(Cl)c1
Reactant: CCCCN(C(=O)NC1CCCCC1)c1c2ccccc2nn1-c1ccc(Cl)cc1
Solvent: CN1CCCC1=O
Product: Fc1ccc(Nc2c3ccccc3nn2-c2ccc(Cl)cc2)cc1Cl

Procedure:
In analogy to the procedure described in example 4.1, 3-chloro-2-(4-chloro-phenyl)-2H-indazole (Ardakani, Manouchehr; Smalley, Robert K.; Smith, Richard H., Synthesis (1979), (4), 308-9) was reacted with 3-chloro-4-fluoro-phenylamine ([857091-30-6]) in N-methyl 2-pyrrolidone for 3 d at 175° C. in a sealed tube to give the title compound as grey crystals. MS: m/e=372.1 [M+H+].
Reaction SMILES: [CH:1]1[CH:5]=[C:4]([CH:6]=[O:7])[O:3][CH:2]=1.[Cl:8][C:9]1[CH:18]=[CH:17][C:12]([C:13](=[N:15]O)[NH2:14])=[CH:11][CH:10]=1>N1CCCCC1.C1(C)C=CC=CC=1>[Cl:8][C:9]1[CH:18]=[CH:17][C:12]([C:13]2[NH:15][CH:6]([C:4]3[O:3][CH:2]=[CH:1][CH:5]=3)[O:7][N:14]=2)=[CH:11][CH:10]=1
Reactant: O=Cc1ccco1
Reactant: NC(=NO)c1ccc(Cl)cc1
Solvent: C1CCNCC1
Solvent: Cc1ccccc1
Product: Clc1ccc(C2=NOC(c3ccco3)N2)cc1
Temperature: 25 °C
Yield: 6 %

Procedure:
A mixture of 2-furfural (0.69 mL, 804 mg, 8.4 mmol), 4-chloro-N′-hydroxybenzimidamide (1.02 g, 6.0 mmol) and one drop of piperidine in toluene (100 mL) was heated to reflux for 18 h in a Soxhlett apparatus, that was charged with 3 Angstrom molecular sieves (8 g). The mixture was cooled to room temperature and the solvent was removed in vacuo. After purification by automated column chromatography on the ISCO COMPANION (SiO2, gradient heptane/ethyl acetate) the 3-(4-chlorophenyl)-5-(furan-2-yl)-4,5-dihydro-1,2,4-oxadiazole product was obtained as an orange oil that solidified to a tan solid upon standing (85 mg) with a yield of 6%. LC-MS [M+H] 249 (C12H9ClN2O2+H, expected 249.04)