Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH3:12])[C:5]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][C:21]([OH:23])=[O:22])=[CH:16][C:15]=2[O:24][CH3:25])=[C:4]([CH3:26])[N:3]=1.[CH2:27](O)[CH2:28][OH:29].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[NH2:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH3:12])[C:5]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][C:21]([O:23][CH2:27][CH2:28][OH:29])=[O:22])=[CH:16][C:15]=2[O:24][CH3:25])=[C:4]([CH3:26])[N:3]=1
Reactant: OCCO
Reactant: CCCCNc1nc(N)nc(C)c1Cc1ccc(CC(=O)O)cc1OC
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCCCNc1nc(N)nc(C)c1Cc1ccc(CC(=O)OCCO)cc1OC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The product from step (vi) (100 mg), ethane-1,2-diol (0.031 ml) and Hunig's Base (0.146 ml) were combined in DMF (5 mL) and HATU (106 mg) was added and stirred at rt for 1 h. The reaction mixture was purified by RPHPLC to give the title compound as a solid, 6 mg.
Reaction SMILES: C([O:3][C:4]([C:6]1([S:16]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][CH:28]([CH3:30])[CH3:29])=[CH:21][CH:20]=2)(=[O:18])=[O:17])[CH2:11][CH2:10][N:9]([CH2:12][CH2:13][CH2:14][CH3:15])[CH2:8][CH2:7]1)=[O:5])C>C1COCC1.CO.[OH-].[Na+]>[CH2:12]([N:9]1[CH2:8][CH2:7][C:6]([S:16]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][CH:28]([CH3:29])[CH3:30])=[CH:21][CH:20]=2)(=[O:18])=[O:17])([C:4]([OH:5])=[O:3])[CH2:11][CH2:10]1)[CH2:13][CH2:14][CH3:15]
Reactant: CCCCN1CCC(C(=O)OCC)(S(=O)(=O)c2ccc(OCCC(C)C)cc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCCCN1CCC(C(=O)O)(S(=O)(=O)c2ccc(OCCC(C)C)cc2)CC1

Procedure:
1-Butyl-4-[4-(3-methyl-butoxy)-benzenesulfonyl]-piperidine-4-carboxylic acid was prepared starting from 1-Butyl-4-[4-(3-methyl-butoxy)-benzenesulfonyl]-piperidine-4-carboxylic ethyl ester (4.4 g, 10 mmol) dissolved in THF:methanol (3:1 150 ml) and 10 N NaOH (20 ml). The resulting reaction mixture was worked up as outlined in example 83. Yield 3.2 g (77%); white solid; mp 188° C.; MS: 412 (M+H)+
Reaction SMILES: [CH2:1]([C@:3]1([OH:29])[C:26]2[CH:25]=[C:24]3[N:10]([CH2:11][C:12]4[C:13]3=[N:14][C:15]3[CH:16]=[C:17]([F:23])[CH:18]=[C:19]([F:22])[C:20]=3[CH:21]=4)[C:9](=[O:27])[C:8]=2[CH2:7][O:6][C:5](=[O:28])[CH2:4]1)[CH3:2].[CH:30](=O)[CH2:31][CH2:32][CH2:33][CH2:34]C>>[CH2:1]([C@:3]1([OH:29])[C:26]2[CH:25]=[C:24]3[N:10]([CH2:11][C:12]4[C:13]3=[N:14][C:15]3[CH:16]=[C:17]([F:23])[CH:18]=[C:19]([F:22])[C:20]=3[C:21]=4[CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[C:9](=[O:27])[C:8]=2[CH2:7][O:6][C:5](=[O:28])[CH2:4]1)[CH3:2]
Reactant: CC[C@@]1(O)CC(=O)OCc2c1cc1n(c2=O)Cc2cc3c(F)cc(F)cc3nc2-1
Reactant: CCCCCC=O
Product: CCCCCc1c2c(nc3cc(F)cc(F)c13)-c1cc3c(c(=O)n1C2)COC(=O)C[C@]3(O)CC

Procedure:
The product of Example 100 is treated with hexanal according to a procedure similar to Stage 95e in order to produce the expected solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[CH:11][C:10]([OH:13])=[N:9]2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[Na+].Cl[CH2:23][C:24](=[O:26])[CH3:25].[Cl-].[Li+]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH:12]=[CH:11][C:10]([O:13][CH2:23][C:24](=[O:26])[CH3:25])=[N:9]2)=[CH:6][CH:7]=1
Reactant: CC(=O)CCl
Reactant: Oc1ccn(-c2ccc(Cl)cc2)n1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [I-]
Solvent: CN(C)C=O
Product: CC(=O)COc1ccn(-c2ccc(Cl)cc2)n1
Reaction time: 5 h

Procedure:
5.50 g (28.3 mmol) 1-(4-chlorophenyl)pyrazol-3-ol, 3.91 g (28.3 mmol) potassium carbonate and 50 mg sodium iodide in 30 ml DMF have been stirred for 5 min at ambient temperature. Then 2.62 g (28.3 mmol) chloroacetone have been added dropwise while stirring which was continued at 60° C. for 5 h. The mixture was poured into excess 10% aqueous lithium chloride solution and extracted with ethyl acetate three times. The combined extracts have been washed with 10% lithium chloride solution twice and dried with sodium sulfate. After removal of the solvent in vacuo the crude product has been purified by chromatography on silica. Yield 6.5 g. The product was used for the next step.
Reaction SMILES: [Cl:1][C:2]1[C:10]([C:11]([F:14])([F:13])[F:12])=[CH:9][C:5]([C:6]([NH2:8])=O)=[C:4]([O:15][CH2:16][CH2:17][O:18][CH:19]([CH3:21])[CH3:20])[N:3]=1.O=P(Cl)(Cl)Cl.N1C=CC=CC=1.[OH-].[Na+]>C(#N)C>[Cl:1][C:2]1[C:10]([C:11]([F:14])([F:13])[F:12])=[CH:9][C:5]([C:6]#[N:8])=[C:4]([O:15][CH2:16][CH2:17][O:18][CH:19]([CH3:21])[CH3:20])[N:3]=1
Reactant: CC(C)OCCOc1nc(Cl)c(C(F)(F)F)cc1C(N)=O
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: CC#N
Solvent: O=P(Cl)(Cl)Cl
Product: CC(C)OCCOc1nc(Cl)c(C(F)(F)F)cc1C#N
Reaction time: 1 h

Procedure:
A mixture of 6-chloro-2-(2-isopropoxyethoxy)-5-(trifluoromethyl)nicotinamide (0.2 g, 0.61 mmol) in acetonitrile (20 mL) was added POCl3 (0.28 g, 1.84 mmol) and pyridine (0.29 g, 3.68 mmol). After stirred at r.t for 1 hr, the mixture was diluted by 0.2 M NaOH solution, extracted by EtOAc and the organic layer was concentrated in vacuo to afford 6-chloro-2-(2-isopropoxyethoxy)-5-(trifluoromethyl)nicotinonitrile. (180 mg, 95.7%). 1H-NMR (400 MHz, CDCl3) δ (ppm) 8.14 (s, 1H), 4.64-4.61 (t, 2H), 3.83-3.81 (t, 2H), 3.72-3.66 (m, 1H), 1.19-1.17 (d, 6H).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.[Li]C(C)(C)C.[CH3:11][C:12]1([CH3:43])[CH2:21][CH:20]=[C:19](OS(C(F)(F)F)(=O)=O)[C:18]2[CH:17]=[C:16]([N:30]=[N:31][C:32]3[CH:42]=[CH:41][C:35]([C:36]([O:38][CH2:39][CH3:40])=[O:37])=[CH:34][CH:33]=3)[CH:15]=[CH:14][C:13]1=2>C1COCC1.[NH4+].[Cl-].[Cl-].[Cl-].[Zn+2].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Pd]>[CH3:43][C:12]1([CH3:11])[CH2:21][CH:20]=[C:19]([C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)[C:18]2[CH:17]=[C:16]([N:30]=[N:31][C:32]3[CH:33]=[CH:34][C:35]([C:36]([O:38][CH2:39][CH3:40])=[O:37])=[CH:41][CH:42]=3)[CH:15]=[CH:14][C:13]1=2
Reactant: c1ccsc1
Reactant: CCOC(=O)c1ccc(N=Nc2ccc3c(c2)C(OS(=O)(=O)C(F)(F)F)=CCC3(C)C)cc1
Agent: [Pd]
Agent: [Cl-]
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(N=Nc2ccc3c(c2)C(c2cccs2)=CCC3(C)C)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a cold solution (-78° C.) of thiophene (0.07 ml, 0.75 mmol) in 1.5 ml of TBF was added t-BuLi (0.457 ml, 0.75 mmol, 1.7 M in pentane) and stirred for 2 h. To this solution, ZnCl2 (168 mg, 1.2 mmol) in 1.5 ml of THF was added. The resulting solution was warmed to room temperature, stirred for 1 h and was added (via cannula) to a solution of ethyl 4-[(5,6-dihydro-5,5-dimethyl-8-trifluoromethylsulfonyloxy-naphthalen-2-yl)azo]benzoate (Compound D11, 150 mg, 0.30 mmol) and tetrakis(triphenylphosphine)palladium(O) (10.6 mg) in 2.5 ml of THF. The resulting mixture was heated at 50° C. for 2.5 h. The reaction was diluted with sat. aqueous NH4Cl and extracted with ethyl acetate. The combined organic layer was dried over Na2SO4 and concentrated to an oil. The crude product was purified by flash chromatography (silica, ethyl acetate: hexane 5:95) to afford the title compound as a red foam.
Reaction SMILES: [SH:1][C:2]1[S:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([Cl:13])[CH:8]=2)[N:3]=1.[O-]Cl.[Na+].[OH-].[NH4+:18]>[OH-].[Na+].O>[Cl:13][C:9]1[CH:8]=[C:7]([C:4]2[N:3]=[C:2]([S:1][NH2:18])[S:6][N:5]=2)[CH:12]=[CH:11][CH:10]=1
Reactant: Sc1nc(-c2cccc(Cl)c2)ns1
Reactant: [NH4+]
Agent: [Na+]
Agent: [O-]Cl
Agent: [OH-]
Solvent: O
Product: NSc1nc(-c2cccc(Cl)c2)ns1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of 41 g of 5-mercapto-3-(3-chlorophenyl)-1,2,4-thiadiazole in 602 ml of 5% sodium hydroxide and a solution prepared by diluting 378 ml of 5.25% NaOCl to 602 ml with water were added dropwise simultaneously to 1634 ml of ammonium hydroxide solution while maintaining the mixture at 0° C. with a salt/ice bath. The resulting mixture was stirred for 30 minutes and the solids were collected, washed with water and dried under vacuum (with P2O5) to give 5.4 g of solid, m.p.>150° dec.
Reaction SMILES: [F:1][CH:2]([F:25])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]([OH:14])=O)=[C:7]2[N:6]=[C:5]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[CH:4]=1.[NH2:26][C:27]1[CH:28]=[C:29]([S:33]([NH:36][CH2:37][C:38]2[CH:43]=[CH:42][N:41]=[CH:40][CH:39]=2)(=[O:35])=[O:34])[CH:30]=[CH:31][CH:32]=1>>[N:41]1[CH:42]=[CH:43][C:38]([CH2:37][NH:36][S:33]([C:29]2[CH:28]=[C:27]([NH:26][C:12]([C:11]3[CH:10]=[N:9][N:8]4[C:3]([CH:2]([F:1])[F:25])=[CH:4][C:5]([C:15]5[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=5)=[N:6][C:7]=34)=[O:14])[CH:32]=[CH:31][CH:30]=2)(=[O:35])=[O:34])=[CH:39][CH:40]=1
Reactant: O=C(O)c1cnn2c(C(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Reactant: Nc1cccc(S(=O)(=O)NCc2ccncc2)c1
Product: O=C(Nc1cccc(S(=O)(=O)NCc2ccncc2)c1)c1cnn2c(C(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12

Procedure:
The title compound was prepared from 7-difluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.1) and 3-amino-N-pyridin-4-ylmethyl-benzenesulfonamide (example B.3) according to general procedure II. Yellow solid. MS (ISP) 601.2 [(M−H)−]; mp 221° C.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH3:11][N:12]1[CH2:17][CH:16]=[C:15]([C:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[NH:20][CH:19]=2)[CH2:14][CH2:13]1.[C:27]1([S:33](Cl)(=[O:35])=[O:34])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C1COCC1>[CH3:11][N:12]1[CH2:13][CH:14]=[C:15]([C:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[N:20]([S:33]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)(=[O:35])=[O:34])[CH:19]=2)[CH2:16][CH2:17]1
Reactant: CN1CC=C(c2c[nH]c3ccccc23)CC1
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: CN1CC=C(c2cn(S(=O)(=O)c3ccccc3)c3ccccc23)CC1
Reaction time: 1 h
Yield: 21.3 %

Procedure:
Sodium bis(trimethylsilyl)amide (0.23 mL, 1M inTHF, 0.23 mmol) was added to a solution of 3-(1-methyl-1,2,3,6-tetrahydro-4-pyridinyl)indole (Example 4e, 25.0 mg, 0.12 mmol) in THF (1.5 mL) at -78° C. and the mixture was stirred for 1 h. Phenylsulfonyl chloride (30 uL, 0.24 mmol) was added and the mixture stirred at room temperature for 2 h. prior to quenching with water (4 drops) and silica gel (~1g). Purification using solid phase extraction tubes (1000 mg silica, eluting with 0-10% 2M methanolic ammonia in dichloromethane) yielded 3-(1-methyl-1,2,3,6-tetrahydro-4-pyridinyl)-1-phenylsulfonylindole (9.0 mg, 22%, HRMS-FAB+ for C20H20N2O2S: calculated MH+ : 353.13239; found: 353.13235).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:27]=[C:26]([CH2:28][CH3:29])[CH:25]=[CH:24][C:10]=1[O:11][C:12]1[CH:17]=[CH:16][C:15]([NH:18][CH2:19][CH2:20][CH2:21][NH2:22])=[CH:14][C:13]=1[F:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:30](OC(=O)C)(=[O:32])[CH3:31]>ClCCl>[C:30]([N:18]([C:15]1[CH:16]=[CH:17][C:12]([O:11][C:10]2[CH:24]=[CH:25][C:26]([CH2:28][CH3:29])=[CH:27][C:9]=2[O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[C:13]([F:23])[CH:14]=1)[CH2:19][CH2:20][CH2:21][NH2:22])(=[O:32])[CH3:31]
Reactant: CCc1ccc(Oc2ccc(NCCCN)cc2F)c(OCc2ccccc2)c1
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Product: CCc1ccc(Oc2ccc(N(CCCN)C(C)=O)cc2F)c(OCc2ccccc2)c1

Procedure:
To a solution of N1-[4-(2-Benzyloxy-4-ethylphenoxy)-3-fluorophenyl]propan-1,3-diamine (60 mg, 0.15 mmol) in 10 ml of dry dichloromethane, cooled to 0° C., was added acetic anhydride (20 mg, 0.19 mmol) taken in 0.5 ml of dichloromethane dropwise.
Reaction SMILES: Cl.[OH:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][N:9]([CH3:23])[CH:10]2[C:13]2([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:16][CH2:15][CH2:14]2)=[CH:5][CH:4]=1.N.C(OC(=O)C)(=O)C.[N+:32]([O-])([OH:34])=[O:33].C(=O)(O)[O-].[Na+].[C:41]([OH:46])(=[O:45])[C:42]([OH:44])=[O:43]>O.C(O)(=O)C.C(OCC)(=O)C>[C:41]([OH:46])(=[O:45])[C:42]([OH:44])=[O:43].[OH:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][N:9]([CH3:23])[CH:10]2[C:13]2([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:14][CH2:15][CH2:16]2)=[CH:5][C:4]=1[N+:32]([O-:34])=[O:33]
Reactant: O=[N+]([O-])O
Reactant: CN1CCc2ccc(O)cc2C1C1(c2ccccc2)CCC1
Agent: Cl
Agent: N
Agent: O=C(O)C(=O)O
Solvent: CC(=O)O
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: CN1CCc2cc([N+](=O)[O-])c(O)cc2C1C1(c2ccccc2)CCC1
Temperature: 0 °C
Reaction time: 0.67 h

Procedure:
The product of Example 41 (4 g) was dissolved in water at 80° C. The solution was basified with aqueous ammonia solution and extracted with ethyl acetate. The extract gave a residue which was dissolved in acetic acid (40 ml). The solution was cooled to 0° C. and acetic anhydride (20 ml) and then a mixture of 70% nitric acid (1.4 ml), acetic acid (30 ml) and acetic anhydride (20 ml) were added. The mixture was kept at 5° C. for 40 minutes and was then added to aqueous sodium bicarbonate and left for 16 hours before being extracted with ethyl acetate. The extract gave a residue which was purified by flash chromatography to give a solid which was dissolved in ethyl acetate. Addition of ethereal oxalic acid solution gave a solid which was triturated with hot ethyl acetate to give 7-hydroxy-2-methyl-6-nitro-1-(1-phenylcyclobutyl)-1,2,3,4-tetrahydroisoquinoline oxalate, m.p. 172°-173° C. (dec).
Reaction SMILES: C([N:8]([C:16]1[C:21]([F:22])=[CH:20][C:19](Br)=[CH:18][C:17]=1[F:24])[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])(OC(C)(C)C)=O.COC1C=CC=C(OC)C=1C1C=CC=CC=1P(C1CCCCC1)C1CCCCC1.C(O[K])(C)(C)C.[CH2:60]([N:62]1[CH2:67][CH2:66][NH:65][CH2:64][CH2:63]1)[CH3:61]>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[C:9]([NH:8][C:16]1[C:17]([F:24])=[CH:18][C:19]([N:65]2[CH2:66][CH2:67][N:62]([CH2:60][CH3:61])[CH2:63][CH2:64]2)=[CH:20][C:21]=1[F:22])([O:11][C:12]([CH3:13])([CH3:14])[CH3:15])=[O:10]
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1c(F)cc(Br)cc1F
Reactant: CCN1CCNCC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)O[K]
Solvent: O
Solvent: Cc1ccccc1
Product: CCN1CCN(c2cc(F)c(NC(=O)OC(C)(C)C)c(F)c2)CC1
Temperature: 60 °C
Reaction time: 14 h

Procedure:
To a solution of N,N-di-Boc-4-bromo-2,6-difluoro-phenylamine (9.0 g, 22.0 mmol) obtained in Step A, palladium acetate (49 mg, 0.218 mmol), S-Phos (181 mg, 0.441 mmol), and tert-butoxy potassium (4.45 g, 39.7 mmol) in toluene (100 ml), 1-ethyl-piperazine (4.20 ml, 33.1 mmol) was added, followed by stirring at 60° C. for 14 hours. After cooling to room temperature, 100 ml of water was added, followed by extraction with ethyl acetate (100 ml×2). The organic layer was dried over sodium sulfate, and the solvent was distilled off under reduced pressure. This was purified by silica gel column chromatography (dichloromethane/methanol=100/1 to 10/1), whereby the desired compound was obtained (2.4 g, 32%).
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:7][N:6]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=3)=[CH:10][CH:9]=2)[C:5](=[O:23])[CH2:4]1.C(N(CC)CC)C.[C:31](Cl)(=[O:33])[CH3:32]>ClCCl>[F:22][C:18]1[CH:17]=[C:16]([CH:21]=[CH:20][CH:19]=1)[CH2:15][O:14][C:11]1[CH:10]=[CH:9][C:8]([N:6]2[C:5](=[O:23])[CH2:4][C@H:3]([NH:2][C:31](=[O:33])[CH3:32])[CH2:7]2)=[CH:13][CH:12]=1
Reactant: N[C@H]1CC(=O)N(c2ccc(OCc3cccc(F)c3)cc2)C1
Reactant: CC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N[C@H]1CC(=O)N(c2ccc(OCc3cccc(F)c3)cc2)C1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A suspension of 11.3 mmol of (S)-4-amino-1-[4-(3-fluoro-benzyloxy)-phenyl]-pyrrolidin-2-one hydrochloride in 86 ml of dichloromethane was treated with 23.8 mmol of triethylamine and cooled to 0° C. To this solution, 12.5 mmol of acetylchloride were added and stirring at 0° C. was continued for 15 min. For the working-up, the reaction mixture was extracted twice with 100 ml of water. The organic layer was separated, dried over sodium sulfate and evaporated under reduced pressure. The crude product was triturated in 100 ml of toluene, then the solid collected on a filter funnel. In a second step, the product was triturated in 200 ml of tert-butylmethylether at RT. Again, the solid product was collected on a filter funnel and dried under high vacuum. There was obtained (S)-N-{1-[4-(3-fluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidin-3-yl}-acetamide as a white solid. MS: m/e=343 (M+H)+; enantiomeric excess: >99.5%.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]=[C:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)[CH:5]=[CH:6][CH:7]=1.C([O-])([O-])=O.[K+].[K+].O1[CH2:33][CH2:32]OCC1>O.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>[C:11]([C:10]1[CH:9]=[C:8]([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([CH:8]=[C:9]3[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]3)[CH:3]=2)[CH:4]=[CH:32][CH:33]=1)#[N:12]
Reactant: C1COCCO1
Reactant: CC(C)(C)OC(=O)N1CCC(=Cc2cccc(Br)c2)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(=Cc2cccc(-c3cccc(C#N)c3)c2)CC1
Temperature: 130 °C
Yield: 86 %

Procedure:
To 1,1-dimethylethyl 4-[(3-bromophenyl)methylidene]-1-piperidinecarboxylate (2.11 g, 5.99 mmol) in 1,4-dioxane (30 mL) and water (10.00 mL) was added m-NC(C6H4)B(OH)2 (1.056 g, 7.19 mmol), Pd(Ph3P)4 0.277 g, 0.240 mmol), and K2CO3 (2.483 g, 17.97 mmol). The resultant mixture was split into two equal portions and each portion was heated in a microwave at 130° C. for 15 min. The reaction mixture was concentrated by Glas-Col evaporator and purified with CombiFlash chromatograph to afford the title compound (1.93 g, 86%). LC-MS m/z 749 (2M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[N:16]=[C:15]([C:17]([N:19]3[CH2:24][CH2:23][N:22]([C:25]4[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=4)[CH2:21][CH2:20]3)=[O:18])[CH:14]=[CH:13][CH:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[O:32]1[CH2:36][CH2:35]OC1=O.C(=O)([O-])[O-].[K+].[K+].Cl.C(=O)([O-])O.[Na+]>O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[N:16]=[C:15]([C:17]([N:19]3[CH2:20][CH2:21][N:22]([C:25]4[CH:26]=[CH:27][C:28]([O:31][CH2:35][CH2:36][OH:32])=[CH:29][CH:30]=4)[CH2:23][CH2:24]3)=[O:18])[CH:14]=[CH:13][CH:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: O=C1OCCO1
Reactant: COc1ccc(-c2cccc(C(=O)N3CCN(c4ccc(O)cc4)CC3)n2)cc1OC
Agent: Cl
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Solvent: O
Product: COc1ccc(-c2cccc(C(=O)N3CCN(c4ccc(OCCO)cc4)CC3)n2)cc1OC
Temperature: 100 °C
Reaction time: 1.5 h
Yield: 12.5 %

Procedure:
To 297 mg of 4-[6-(3,4-dimethoxyphenyl)pyridine-2-carbonyl]-1-(4-hydroxyphenyl)piperazine were added 623 mg of [1,3]dioxolan-2-one and 147 mg of potassium carbonate, followed by 1.5 hours of stirring at 100° C. After the mixture was cooled to room temperature, water and then 1M hydrochloric acid were added to the reaction solution, which was then neutralized with a saturated aqueous sodium hydrogen carbonate solution, followed by extraction with chloroform. The organic layer was washed with brine and then dried over anhydrous magnesium sulfate, and thereafter, the solvent was evaporated. The residue was purified by silica gel column chromatography (chloroform-methanol) and then recrystallization was carried out from ethyl acetate to obtain 41 mg of 2-(4-{4-[6-(3,4-dimethoxyphenyl)pyridine-2-carbonyl]piperazin-1-yl}phenoxy)ethanol as pale yellow crystals.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[CH:4](P(OC)(OC)=O)[NH:5][C:6]([O:8][CH3:9])=[O:7].CC(C)=O.C(=O)=O.[O:24]1[CH2:29][CH2:28][CH:27]([CH:30]=O)[CH2:26][CH2:25]1>C1COCC1.CCOC(C)=O>[CH3:1][O:2][C:3](=[O:16])[C:4]([NH:5][C:6]([O:8][CH3:9])=[O:7])=[CH:30][CH:27]1[CH2:28][CH2:29][O:24][CH2:25][CH2:26]1
Reactant: O=CC1CCOCC1
Reactant: COC(=O)NC(C(=O)OC)P(=O)(OC)OC
Agent: O=C=O
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)NC(=CC1CCOCC1)C(=O)OC
Temperature: -78 °C
Reaction time: 2 h
Yield: 45.7 %

Procedure:
To a solution of (Dimethoxy-phosphoryl)-methoxycarbonylamino-acetic acid methyl ester (0.34 g, 1.35 mmol) in THF (5.4 mL) at −78° C. (external, Acetone/CO2 bath) was added 1,1,3,3-tetramethguanidine (0.17 mL, 1.35 mmol). The solution was stirred for 15 min before Tetrahydro-pyran-4-carbaldehyde (0.15 g, 1.35 mmol) was added. The reaction was stirred at −78° C. for 2 h and then allowed to warm to room temperature. The reaction was diluted with EtOAc and washed with HCl (1N) and brine. The aqueous layers were back extracted with EtOAc. The combined organic layers were dried over Na2SO4 and concentrated. The crude oil was purified by column chromatography (SiO2, 20→100% EtOAc in Hexanes) to provide 2-Methoxycarbonylamino-3-(tetrahydro-pyran-4-yl)-acrylic acid methyl ester (0.15 g, 45%). LCMS-ESI+: calc'd for C11H17NO5: 243.11 (M+); Found: 243.96 (M+H+).
Reaction SMILES: [C:1]([C:9]1[NH:10][C:11]2[C:16]([C:17]=1[CH2:18][C:19](O)=[O:20])=[CH:15][CH:14]=[C:13]([Cl:22])[CH:12]=2)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:24][NH:25][CH3:26].C(N(CC)CC)C.P(C#N)(=O)(OCC)OCC>CN(C=O)C.O>[C:1]([C:9]1[NH:10][C:11]2[C:16]([C:17]=1[CH2:18][C:19]([N:25]([CH3:26])[CH3:24])=[O:20])=[CH:15][CH:14]=[C:13]([Cl:22])[CH:12]=2)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)Cc1c(C(=O)c2ccccc2)[nH]c2cc(Cl)ccc12
Reactant: CNC
Agent: CCOP(=O)(C#N)OCC
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CN(C)C(=O)Cc1c(C(=O)c2ccccc2)[nH]c2cc(Cl)ccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 32.6 %

Procedure:
To a solution of (2-benzoyl-6-chloro-1H-indol-3-yl)acetic acid (Example 2, 140 mg, 0.45 mmol), dimethylamine hydrochloride (45 mg, 0.54 mmol) and triethylamine (0.1 ml, 0.54 mmol) in DMF (2 ml) at 0° C. was added diethyl phosphorocyanidate (DEPC, 0.1 ml, 0.54 mmol). The mixture was then stirred at room temperature for 1 h. The mixture was poured into water (20 ml) and extracted with diethyl ether (50 ml×2). The organic extracts were washed with water (30 ml×2), dried (MgSO4) and concentraied. The residual solids were recrystallized from ethyl acetate/hexane to afford 50 mg (33%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[N:12]1([CH:18]([C:21]2[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=2)[CH2:19][NH2:20])[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1>>[Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:20][CH2:19][CH:18]([N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)[C:21]1[CH:22]=[CH:23][N:24]=[CH:25][CH:26]=1)=[O:6]
Reactant: O=C(O)c1cccc(Cl)c1Cl
Reactant: NCC(c1ccncc1)N1CCOCC1
Product: O=C(NCC(c1ccncc1)N1CCOCC1)c1cccc(Cl)c1Cl

Procedure:
From 2,3-dichlorobenzoic acid and (2-morpholin-4-yl-2-pyridin-4-ylethyl)amine.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]([N:5]1[CH:9]=[CH:8][C:7]([C:10]2[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[C:12]([Cl:18])[C:11]=2[CH3:19])=[N:6]1)[CH3:4].[C:20]([C:23]1[CH:27]=[C:26]([C:28](O)=[O:29])[NH:25][N:24]=1)(=[O:22])[CH3:21]>>[C:20]([C:23]1[CH:27]=[C:26]([C:28]([NH:1][CH2:2][C@H:3]([N:5]2[CH:9]=[CH:8][C:7]([C:10]3[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[C:12]([Cl:18])[C:11]=3[CH3:19])=[N:6]2)[CH3:4])=[O:29])[NH:25][N:24]=1)(=[O:22])[CH3:21]
Reactant: CC(=O)c1cc(C(=O)O)[nH]n1
Reactant: Cc1c(-c2ccn([C@H](C)CN)n2)ccc(C#N)c1Cl
Product: CC(=O)c1cc(C(=O)NC[C@@H](C)n2ccc(-c3ccc(C#N)c(Cl)c3C)n2)[nH]n1
Yield: 18.5 %

Procedure:
(R)-4-(1-(1-aminopropan-2-yl)-1H-pyrazol-3-yl)-2-chloro-3-methylbenzonitrile (300 mg, 1.09 mmol) was coupled with 3-acetyl-1H-pyrazole-5-carboxylic acid (202 mg, 1.31 mmol) using the method of Example 34(d). Crude product was purified by CombiFlash (column: C-18, eluent: 0-100% MeCN in water) to yield 83 mg (19%) of the title compound. 1H-NMR (400 MHz; CDCl3): δ 1.62 (d, 3H), 2.52-2.58 (m, 6H), 3.79 (dd, 1H), 3.91 (dd, 1H), 4.60-4.71 (m, 1H), 6.92 (d, 1H), 7.25 (s, 1H), 7.27-7.29 (m, 1H), 7.52 (d, 1H), 7.54-7.60 (m, 2H).