Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][CH:9]1[CH2:18][CH2:17][C:12]2(OCC[O:13]2)[CH2:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.O.[Cl-].[Na+]>C(OC(C)C)(C)C>[CH2:1]([O:8][CH:9]1[CH2:18][CH2:17][C:12](=[O:13])[CH2:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc(COC2CCC3(CC2)OCCO3)cc1
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CC(C)OC(C)C
Solvent: O
Product: O=C1CCC(OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 95.5 %

Procedure:
294 g of 8-benzyloxy-1,4-dioxaspiro[4.5]decane were dissolved in 1400 ml of diisopropyl ether, and 580 ml of four molar hydrochloric acid were added. After 20 hours' stirring at room temperature, 300 ml of water and 180 ml of saturated sodium chloride solution were added, and stirring was carried out for a further four hours. The phases were separated, and the aqueous phase was neutralized with solid sodium hydrogen carbonate and extracted repeatedly with diisopropyl ether. The combined organic phases were dried over sodium sulfate, filtered and concentrated. Distillation under a high vacuum yielded 231 g of 4-benzyloxycyclohexanone.
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]1[C:9]2[CH:10]=[CH:11][C:12]([N+:14]([O-:16])=[O:15])=[CH:13][C:8]=2[O:7][CH2:6][C:5]1=[O:17].C(=O)([O-])[O-].[K+].[K+].[CH3:24][N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1.C(=O)([O-])O.[Na+]>C(#N)C>[CH3:24][N:25]1[CH2:30][CH2:29][N:28]([CH2:2][CH2:3][N:4]2[C:9]3[CH:10]=[CH:11][C:12]([N+:14]([O-:16])=[O:15])=[CH:13][C:8]=3[O:7][CH2:6][C:5]2=[O:17])[CH2:27][CH2:26]1
Reactant: CN1CCNCC1
Reactant: O=C1COc2cc([N+](=O)[O-])ccc2N1CCCl
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CN1CCN(CCN2C(=O)COc3cc([N+](=O)[O-])ccc32)CC1
Temperature: 80 °C
Reaction time: 48 h

Procedure:
To a mixture of 4-(2-chloroethyl)-7-nitro-2H-1,4-benzoxazine-3(4H)-one (Preparation Example 430) (1.08 g), potassium carbonate (0.87 g) and acetonitrile (10.8 mL), 1-methylpiperazine (1.39 mL) was added and stirred at 80° C. for 48 hours. After the reaction liquid was cooled, saturated aqueous sodium hydrogen carbonate was added, and the reaction liquid was extracted with ethyl acetate and the extract was washed with saturated aqueous sodium chloride. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (eluent; chloroform:methanol=100:0 to 20:1) to give 4-[2-(4-methylpiperazin-1-yl)ethyl]-7-nitro-2H-1,4-benzoxazine-3(4H)-one (690 mg) as a yellow liquid.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([NH:13][C:14](=[O:39])[C:15]3[CH:20]=[CH:19][CH:18]=[N:17][C:16]=3[NH:21][CH2:22][C:23]3[CH:28]=[CH:27][N:26]=[C:25]([O:29][CH2:30][CH2:31][CH:32]4[CH2:37][CH2:36][N:35]([CH3:38])[CH2:34][CH2:33]4)[CH:24]=3)[CH:11]=2)[C:6]([CH3:41])([CH3:40])[CH2:5]1)(=O)C.CCO>Cl>[CH3:40][C:6]1([CH3:41])[C:7]2[C:12](=[CH:11][C:10]([NH:13][C:14](=[O:39])[C:15]3[CH:20]=[CH:19][CH:18]=[N:17][C:16]=3[NH:21][CH2:22][C:23]3[CH:28]=[CH:27][N:26]=[C:25]([O:29][CH2:30][CH2:31][CH:32]4[CH2:33][CH2:34][N:35]([CH3:38])[CH2:36][CH2:37]4)[CH:24]=3)=[CH:9][CH:8]=2)[NH:4][CH2:5]1
Reactant: CC(=O)N1CC(C)(C)c2ccc(NC(=O)c3cccnc3NCc3ccnc(OCCC4CCN(C)CC4)c3)cc21
Agent: Cl
Solvent: CCO
Product: CN1CCC(CCOc2cc(CNc3ncccc3C(=O)Nc3ccc4c(c3)NCC4(C)C)ccn2)CC1

Procedure:
N-(1-Acetyl-3,3-dimethyl-2,3-dihydro-1H-indol-6-yl)-2-({2-[2-(1-methyl-piperidin-4-yl)-ethoxy]-pyridin-4-ylmethyl}-amino)-nicotinamide (300 mg, Example 871) was dissolved in conc. HCl (20 ml) and EtOH (20 ML) and heated at 70° C. for 4 H. The mixture was concentrated and the residue was diluted with sat'd NaHCO3 and CH2Cl2. The organic layer was dried over Na2SO4 and concentrated to obtain the desired compound. M+H 515. Calc'd for C30H38N6O2: 514.
Reaction SMILES: [Si]([O:18][CH2:19][C@:20]12[C@H:26]([OH:27])[C@H:23]([O:24][CH2:25]1)[C@H:22]([N:28]1[CH:35]=[CH:34][C:32](=[O:33])[NH:31][C:29]1=[O:30])[O:21]2)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[OH:27][C@@H:26]1[C@@H:23]2[O:24][CH2:25][C@:20]1([CH2:19][OH:18])[O:21][C@H:22]2[N:28]1[CH:35]=[CH:34][C:32](=[O:33])[NH:31][C:29]1=[O:30]
Reactant: CC(C)(C)[Si](OC[C@]12CO[C@H]([C@H](n3ccc(=O)[nH]c3=O)O1)[C@H]2O)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: O=c1ccn([C@@H]2O[C@@]3(CO)CO[C@H]2[C@H]3O)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 3 h
Yield: 90 %

Procedure:
Compound 110 (8.7 g) was dissolved in anhydrous THF (80 mL) and TBAF (5.05 g, 20 mL of 1 M solution in THF) was added and the reaction mixture stirred at room temperature for 3 hours at which time the reaction was complete. The solvent was carefully removed and the residue purified on silica gel column to give Compound 111 in 90% yield.
Reaction SMILES: NC[C@@H]1[C@H](C)CCCN1C(C1C=C(C)C=CC=1C1C=NN(C)C=1)=O.[F:25][C:26]1[CH:52]=[CH:51][C:29]([C:30]([N:32]2[CH2:37][CH2:36][CH2:35][C@@H:34]([CH3:38])[C@H:33]2[CH2:39][N:40]2C(=O)C3C(=CC=CC=3)C2=O)=[O:31])=[C:28]([C:53]2[N:58]=[CH:57][CH:56]=[CH:55][N:54]=2)[CH:27]=1>>[NH2:40][CH2:39][C@@H:33]1[C@H:34]([CH3:38])[CH2:35][CH2:36][CH2:37][N:32]1[C:30]([C:29]1[CH:51]=[CH:52][C:26]([F:25])=[CH:27][C:28]=1[C:53]1[N:54]=[CH:55][CH:56]=[CH:57][N:58]=1)=[O:31]
Reactant: C[C@@H]1CCCN(C(=O)c2ccc(F)cc2-c2ncccn2)[C@@H]1CN1C(=O)c2ccccc2C1=O
Agent: Cc1ccc(-c2cnn(C)c2)c(C(=O)N2CCC[C@@H](C)[C@H]2CN)c1
Product: C[C@@H]1CCCN(C(=O)c2ccc(F)cc2-c2ncccn2)[C@@H]1CN

Procedure:
The title compound was prepared following the same general protocol as described for ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(5-methyl-2-(1-methyl-1H-pyrazol-4-yl)phenyl)methanone in Example A1 using 2-(((2S,3R)-1-(4-fluoro-2-(pyrimidin-2-yl)benzoyl)-3-methylpiperidin-2-yl)methyl)isoindoline-1,3-dione. MS (ESI) 329 (M+H).
Reaction SMILES: [C:1]([C:6](=[CH:12][NH:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][C:21](=[O:28])[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:16][C:15]=1[O:29][CH3:30])[C:7](OCC)=[O:8])(=[O:5])[CH2:2][CH2:3][CH3:4].C1(OC2C=CC=CC=2)C=CC=CC=1>>[C:1]([C:6]1[C:7](=[O:8])[C:19]2[C:14](=[C:15]([O:29][CH3:30])[CH:16]=[C:17]([O:20][C:21](=[O:28])[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:18]=2)[NH:13][CH:12]=1)(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC(=O)C(=CNc1ccc(OC(=O)c2ccccc2)cc1OC)C(=O)OCC
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CCCC(=O)c1c[nH]c2c(OC)cc(OC(=O)c3ccccc3)cc2c1=O
Yield: 92.6 %

Procedure:
Ethyl 2-butyryl-3-(4-benzoyloxy-2-methoxyphenylamino)acrylate (22 g) was added portionwise to boiling diphenyl ether and heated under reflux for 45 minutes. When cool, the mixture was chromatographed (silica gel, 2% methanol in dichloromethane) to give 3-butyryl-6-benzoyloxy-8-methoxy-4(1H)-quinolone as a light brown solid (18.1 g, 92%), m.p. 102°-4°.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([NH:10][C:11]([C:13]2[C:14]([CH3:23])=[N:15][C:16]3[C:21]([CH:22]=2)=[CH:20][CH:19]=[CH:18][N:17]=3)=[O:12])[CH3:9])=[CH:4][CH:3]=1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.[O-]P([O-])([O-])=O.[K+].[K+].[K+].[NH:66]1[CH2:71][CH2:70][CH2:69][CH2:68][CH2:67]1>COCCOC.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]>[CH3:23][C:14]1[C:13]([C:11]([NH:10][C@H:8]([C:5]2[CH:6]=[CH:7][C:2]([N:66]3[CH2:71][CH2:70][CH2:69][CH2:68][CH2:67]3)=[CH:3][CH:4]=2)[CH3:9])=[O:12])=[CH:22][C:21]2[C:16](=[N:17][CH:18]=[CH:19][CH:20]=2)[N:15]=1
Reactant: C1CCNCC1
Reactant: Cc1nc2ncccc2cc1C(=O)N[C@@H](C)c1ccc(Br)cc1
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: COCCOC
Product: Cc1nc2ncccc2cc1C(=O)N[C@@H](C)c1ccc(N2CCCCC2)cc1
Temperature: 80 °C
Yield: 30.7 %

Procedure:
A mixture of 174 mg (0.47 mmol) (S)—N-(1-(4-bromophenyl)ethyl)-2-methyl-1,8-naphthyridine-3-carboxamide, 11 mg (0.012 mmol) Pd2dba3 and 23 mg (0.048 mmol) XPhos in 3.5 ml DME was stirred an degassed at room temperature for 5 min in a thick walled sealable tube. 250 mg (1.18 mmol) K3PO4 and 52 μl (0.52 mmol) piperidine were added. The tube was sealed and heated at 80° C. over night. The reaction mixture was cooled to room temperature and filtered through a pad of silica with CH2Cl2/MeOH 9:1. The filtrate was concentrated and purified with flash chromatography (SiO2, CH2Cl2/MeOH 30:1) to give 54 mg (31%) of the title compound.
Reaction SMILES: [OH:1][CH:2]([CH2:9][OH:10])[CH2:3][NH:4][C:5](=[O:8])[CH2:6][Cl:7].[CH2:11]([O:14][CH:15](OCC=C)OCC=C)[CH:12]=[CH2:13].[Cl-].[NH4+]>ClC(Cl)C>[CH2:11]([O:14][CH:15]1[O:1][CH:2]([CH2:3][NH:4][C:5](=[O:8])[CH2:6][Cl:7])[CH2:9][O:10]1)[CH:12]=[CH2:13]
Reactant: O=C(CCl)NCC(O)CO
Reactant: C=CCOC(OCC=C)OCC=C
Agent: [Cl-]
Agent: [NH4+]
Solvent: CC(Cl)Cl
Product: C=CCOC1OCC(CNC(=O)CCl)O1
Temperature: 25 °C
Yield: 33.9 %

Procedure:
Six and seven-tenths g (0.04 mole) of N-(2,3-dihydroxypropyl) chloroacetamide, 7.3 g (0.04 mole) of triallylorthoformate, 0.2 g of ammonium chloride, and 50 ml of dichloroethane were combined in a reaction flask and distilled to a head temperature of 82° C. The distillate was cooled to room temperature, stirred with potassium carbonate and filtered over Florisil. The filtrate was evaporated to yield 3.2 g of 2-allyloxy-4-(chloroacetylamino) methyl-1,3-dioxolane, a yellow oil. Structure was confirmed by NMR. nD30 =1.4888.
Reaction SMILES: Cl[C:2]1[C:7]([S:8][CH3:9])=[C:6]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[N:5]=[C:4]([C:16]2[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=2)[N:3]=1.[NH:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1.C(N(CC)CC)C>O1CCOCC1>[CH3:9][S:8][C:7]1[C:2]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)=[N:3][C:4]([C:16]2[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=2)=[N:5][C:6]=1[N:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1
Reactant: CSc1c(Cl)nc(-c2ccc(N)cc2)nc1N1CCOCC1
Reactant: C1COCCN1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CSc1c(N2CCOCC2)nc(-c2ccc(N)cc2)nc1N1CCOCC1

Procedure:
A mixture of 4-(4-chloro-5-methylsulfanyl-6-morpholin-4-yl-pyrimidin-2-yl)-phenylamine (200 mg, 0.594 mmol.), morpholin (103 mg, 1.118 mmol, 2.0 eq), triethylamine (120 mg, 1.118 mmol, 2.0 eq) in dioxane (8 ml) and the mixture was reacted for 16 hrs at 90° C. The reaction mixture was dried and the solvent was removed by evaporation in vacuo. The reaction mixture was partitioned between EA and water. The organic layer was washed with brine, dried over MgSO4, filtered and evaporated in vacuo. The resulting residue was purified using flash chromatography on silica gel (EA), and recrystallized by (Hexane/EtOAc) to give a gray white 106 mg (46.1%).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[C:6]([CH:7]=O)[C:5]([O:10][CH3:11])=[CH:4][CH:3]=1.Cl.[NH2:13]O.C([O-])(=O)C.[Na+].C(OC(=O)C)(=O)C.[OH-].[Na+]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH3:11])=[C:6]([CH:9]=1)[C:7]#[N:13]
Reactant: COc1ccc(Br)cc1C=O
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Product: COc1ccc(Br)cc1C#N
Temperature: 100 °C
Reaction time: 1 h

Procedure:
A mixture of 5-Bromo-o-anisaldehyde (6.45 g), hydroxylamine hydrochloride (2.2 g), sodium acetate (4.1 g) and acedc acid (20 mL) was heated at 100° C. with stirring for 1 h. Acetic anhydride was added (20 mL) and the mixture was refluxed for 8 h. The reaction mixture was poured onto ice water and the mixture was made basic by the careful addition of 50% sodium hydroxide. The product was extracted with ether, the ether extracts were dried over magnesium sulfate and the solvent was removed in vacuo. The residue was crystallized from ether/hexane to afford 5-Bromo-2-methoxy-benzonitrile.
Reaction SMILES: FC(F)(F)C(O)=O.ClC1C2C(=CC(S(NC3(C(O)=O)CCCC3)(=O)=O)=CC=2)C(NC(N)=N)=NC=1.Cl.NC(N)=N.[CH2:40]([O:42][C:43](=[O:69])[C:44]1([CH2:68][CH2:67][CH2:66][CH2:65]1)[NH:45][S:46]([C:49]1[CH:58]=[C:57]2[C:52]([C:53]([Cl:64])=[CH:54][NH:55][C:56]2(Cl)[NH:59][C:60]([NH2:62])=[NH:61])=[CH:51][CH:50]=1)(=[O:48])=[O:47])[CH3:41]>CS(C)=O>[CH2:40]([O:42][C:43](=[O:69])[C:44]1([CH2:65][CH2:66][CH2:67][CH2:68]1)[NH:45][S:46]([C:49]1[CH:58]=[C:57]2[C:52]([C:53]([Cl:64])=[CH:54][N:55]=[C:56]2[NH:59][C:60]([NH2:62])=[NH:61])=[CH:51][CH:50]=1)(=[O:47])=[O:48])[CH3:41]
Reactant: CCOC(=O)C1(NS(=O)(=O)c2ccc3c(c2)C(Cl)(NC(=N)N)NC=C3Cl)CCCC1
Agent: Cl
Agent: N=C(N)N
Agent: N=C(N)Nc1ncc(Cl)c2ccc(S(=O)(=O)NC3(C(=O)O)CCCC3)cc12
Solvent: O=C(O)C(F)(F)F
Solvent: CS(C)=O
Product: CCOC(=O)C1(NS(=O)(=O)c2ccc3c(Cl)cnc(NC(=N)N)c3c2)CCCC1
Temperature: 40 °C
Yield: 21.8 %

Procedure:
N-[(4-chloro-1-guanidino-7-isoquinolinyl)sulphonyl]cycloleucine trifluoroacetate ##STR48## NaH (1.12 g, 80% dispersion by wt in mineral oil, 37.3 mmol) was added portionwise to a stirred suspension of guanidine hydrochloride (5.85 g, 59.4 mmol) in DMSO (320 mL) and the mixture was heated at 30-50° C. under N2 for 30 min. N-[(1,4-Dichloro-1-guanidino-7-isoquinolinyl)sulphonyl]-cycloleucine ethyl ester (6.2 g, 14.9 mmol) was added in one portion and the mixture heated at 80° C. for 8 h. The cooled mixture concentrated in vacuo to ca. 160 mL and poured into water (800 mL). The aqueous mixture was extracted with EtOAc (4×150 mL) and the combined organic extracts were then washed with water, brine, dried (MgSO4) and evaporated in vacuo. The residue was purified by column chromatography upon silica gel using CH2Cl2 -MeOH-0.880NH3 (95:5:0.5 to 90:10:1) as eluant and then recrystallised from EtOAc to give N-[(4-chloro-1-guanidino-7-isoquinolinyl)sulphonyl]cyclo-leucine ethyl ester (1.43 g, 3.25 mmol) as a yellow solid.
Reaction SMILES: [CH2:1]([O:3][P:4](C(OCC)OCC)([CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:5])[CH3:2].C(OC(Cl)=O)C>Cl.ClCCl>[CH2:1]([O:3][PH:4]([CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:5])[CH3:2]
Reactant: CCOC(OCC)P(=O)(Cc1ccccc1)OCC
Agent: CCOC(=O)Cl
Agent: Cl
Solvent: ClCCl
Product: CCO[PH](=O)Cc1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A suspension of 128 g of diethoxymethyl(benzyl)phosphinic acid ethyl ester in 400 ml of hydrochloric acid is heated under reflux for 20 hours, cooled to room temperature, washed with diethyl ether/hexane (1:1) and concentrated to dryness by evaporation. The residue is taken up in dichloromethane, dried over sodium sulfate and again concentrated by evaporation. The viscous benzylphosphinic acid that remains is then dried under a high vacuum. 13.34 g of benzylphosphinic acid are dissolved in 150 ml of dichloromethane, the solution is cooled to 5°, and 8.64 g of triethylamine are added dropwise. An exothermic reaction takes place. The mixture is cooled to 5° again, and 9.3 g of chloroformic acid ethyl ester are added dropwise within a period of 30 minutes. A precipitate forms in an exothermic reaction with the evolution of gas. The mixture is allowed to warm to room temperature and is then stirred at room temperature for 3 hours, taken up in dichloromethane and washed with water, and the organic solvent is removed. The crude product is distilled under a high vacuum, yielding benzylphosphinic acid ethyl ester having a boiling point of 96°100° (5×10-6 bar).
Reaction SMILES: Br[CH:2]1[C:6](=O)[CH2:5][CH2:4][CH:3]1[C:8]#[N:9].[NH2:10][C:11]([NH2:13])=[S:12]>O1CCOCC1>[NH2:13][C:11]1[S:12][C:2]2[CH:3]([C:8]#[N:9])[CH2:4][CH2:5][C:6]=2[N:10]=1
Reactant: NC(N)=S
Reactant: N#CC1CCC(=O)C1Br
Solvent: C1COCCO1
Product: N#CC1CCc2nc(N)sc21
Temperature: 80 °C
Reaction time: 1 h

Procedure:
A mixture of 2-bromo-3-oxocyclopentanecarbonitrile (crude from A.1.2.1.; ca. 13 g) and thiourea (13.77 g, 181 mmol) in dioxane (600 mL) was stirred at 80° C. for 1 h. The mixture was allowed to cool to RT, quenched with aq. sat. NaHCO3 and extracted with EtOAc. The comb. org. layers were washed with brine, dried over MgSO4, and conc. in vacuo. Purification by means of CC (2-20% MeOH (0.5% Et3N)/DCM) provided a brown solid.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:32])[C@@H:10]1[CH2:14][CH2:13][CH2:12][N:11]1[C:15](=[O:31])[C@H:16]([CH2:25][C:26]1[N:27]=[CH:28][S:29][CH:30]=1)[NH:17]C(OC(C)(C)C)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:33].C(OCC)C>C(OCC)(=O)C>[ClH:33].[CH2:1]([O:8][C:9](=[O:32])[C@@H:10]1[CH2:14][CH2:13][CH2:12][N:11]1[C:15](=[O:31])[C@H:16]([CH2:25][C:26]1[N:27]=[CH:28][S:29][CH:30]=1)[NH2:17])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1cscn1)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Agent: Cl
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: N[C@@H](Cc1cscn1)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Reaction time: 3 h

Procedure:
To a solution of the compound (30) (3 g, 6.528 mmol) in ethyl acetate (10 ml) was added a solution of 4N hydrogen chloride in ethyl acetate (33 ml) under ice-cooling and the resulting mixture was stirred for 3 h. To the reaction mixture was added diethyl ether and the precipitation which apl)eare(d was filtered off to give 2.77 g of compound (32). This compound was used in the next reaction without purification.
Reaction SMILES: [ClH:1].Cl.[NH2:3][CH:4]([CH2:8][C:9]1[CH:18]=[C:17]2[C:12]([CH:13]=[CH:14][N:15]=[C:16]2[NH2:19])=[CH:11][CH:10]=1)[C:5]([OH:7])=[O:6].Cl.Cl.[CH3:22]OC(=O)C(N)CC1C=C2C(=CC=1)C(N)=NC=C2>>[ClH:1].[ClH:1].[CH3:22][O:6][C:5](=[O:7])[CH:4]([NH2:3])[CH2:8][C:9]1[CH:18]=[C:17]2[C:12]([CH:13]=[CH:14][N:15]=[C:16]2[NH2:19])=[CH:11][CH:10]=1
Reactant: Nc1nccc2ccc(CC(N)C(=O)O)cc12
Reactant: COC(=O)C(N)Cc1ccc2c(N)nccc2c1
Agent: Cl
Product: COC(=O)C(N)Cc1ccc2ccnc(N)c2c1

Procedure:
Compound 37i was prepared from 37h using the procedure described for 1j. 1H-NMR 200 MHz (CD3OD) δ: 3.38-3.60 (2H, m), 3.80 (3H, s), 4.52 (1H, t, J=7 Hz), 7.25 (1H, dd, J=7 Hz and J=1 Hz), 7.59 (1H, d, J=7 Hz), 7.87-7.99 (2H, m), 8.48 (1H, br.s).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([NH:10][C:11]2[CH:19]=[C:18]([C:20]3[CH:28]=[CH:27][CH:26]=[C:25]4[C:21]=3[CH:22]=[CH:23][NH:24]4)[CH:17]=[C:16]3[C:12]=2[CH:13]=[N:14][NH:15]3)=[O:9])[C:5](F)=[CH:4][CH:3]=1>N1CCCCC1.CS(C)=O.CO>[CH3:8][N:10]([CH3:11])[C:5]1[C:6]([C:8]([NH:10][C:11]2[CH:19]=[C:18]([C:20]3[CH:28]=[CH:27][CH:26]=[C:25]4[C:21]=3[CH:22]=[CH:23][NH:24]4)[CH:17]=[C:16]3[C:12]=2[CH:13]=[N:14][NH:15]3)=[O:9])=[N:7][C:2]([N:7]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)=[CH:3][CH:4]=1
Reactant: O=C(Nc1cc(-c2cccc3[nH]ccc23)cc2[nH]ncc12)c1nc(Cl)ccc1F
Solvent: CO
Solvent: C1CCNCC1
Solvent: CS(C)=O
Product: CN(C)c1ccc(N2CCCCC2)nc1C(=O)Nc1cc(-c2cccc3[nH]ccc23)cc2[nH]ncc12
Temperature: 160 °C
Yield: 24.3 %

Procedure:
6-Chloro-3-fluoro-N-[6-(1H-indol-4-yl)-1H-indazol-4-yl]-2-pyridinecarboxamide (50 mg, 0.12 mmol) was placed in a microwave vial and dissolved in piperidine (0.5 ml). The mixture was heated at 160° C. for 1 h under microwave irradiation. The solvent was removed under a stream of nitrogen to give a crude residue that was dissolved in DMSO/MeOH (1:1) and purified by Mass Directed Automated Preparative HPLC (Method C). The product was loaded onto a 1 g aminopropyl column, eluted with MeOH and the solvent removed under a stream of nitrogen to give the title compound (7 mg) as a yellow solid.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:10](=[O:21])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCC(C)[BH-](C(C)CC)C(C)CC.[K+]>C1COCC1>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:10]([OH:21])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CN(Cc2ccccc2)CCC1Cc1ccccc1
Agent: CCC(C)[BH-](C(C)CC)C(C)CC
Agent: [K+]
Solvent: C1CCOC1
Product: OC1CN(Cc2ccccc2)CCC1Cc1ccccc1
Temperature: -70 °C
Reaction time: 1 h
Yield: 71.9 %

Procedure:
To a solution of 9.0 g (SR)-1,4-dibenzyl-piperidin-3-one (32 mmol) in 200 ml dry THF were added at −78° C. dropwise 48 ml K-selectride® (1 N in THF, 48 mmol). The reaction mixture was stirred for 1 h at −70° C. and then warmed to r.t. The reaction was quenched by the addition of 100 ml NaHCO3-solution and the aqueous phase was extracted twice with ethyl acetate (200 ml). The combined organic phases were washed with water (100 ml) and brine (100 ml). The organic phase was dried over MgSO4, filtrated and the solvent was removed under reduced pressure to give the crude product. Purification by chromatography (ethyl acetate/hexane 1/2 to 2/1) yielded 6.5 g of the product (23 mmol, 72%) as a yellow oil.
Reaction SMILES: [CH3:1][CH:2]([NH:13][C:14](=[O:22])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1I)[CH:3]=[CH:4][C:5]1[CH:6]=[N:7][C:8]([O:11][CH3:12])=[CH:9][CH:10]=1.C(N(CCCC)CCCC)CCC>[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C=O)C.C([O-])(=O)C.C([O-])(=O)C.[Pd+2]>[CH3:12][O:11][C:8]1[N:7]=[CH:6][C:5]([CH:4]=[C:3]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14](=[O:22])[NH:13][CH:2]2[CH3:1])=[CH:10][CH:9]=1
Reactant: COc1ccc(C=CC(C)NC(=O)c2ccccc2I)cn1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CN(C)C=O
Solvent: CCCCN(CCCC)CCCC
Product: COc1ccc(C=C2c3ccccc3C(=O)NC2C)cn1
Temperature: 150 °C
Reaction time: 20 h

Procedure:
Under a N2 atmosphere, 8 g (19 mmol) of an (E/Z) mixture of rac. 2-iodo-benzoic acid-[1-methyl-3-(6-methoxy-pyridin-3-yl)-allylamide], 5.9 g (19 mmol) of tetrabutylammonium chloride and 0.12 g of palladium diacetate are dissolved in 170 ml of DMF, then 8.9 g (48 mmol) of tributylamine are added and stirred for 20 h at 150° C. The mixture is filtered and the DMF is partially evaporated on a RE. The residue is dissolved with EtOAc and water, the water phase separated, extracted twice with EtOAc and discarded. The organic phases are washed with water, extracted with 200 ml of 1N HCl and 2 portions of 200 ml 0.5 N HCl, washed with saturated Na2CO3 solution and brine, dried (Na2SO4) and concentrated by evaporation. Column chromatography (SiO2, hexane/EtOAc 1:1→1:2) and recrystallisation from acetonitrile yield rac. 4-[1-(6-methoxy-pyridin-3-yl)-methylidene]-3-methyl-3,4-dihydro-2H-isoquinolin-1-one (m.p. 194-195° C.; FAB-MS: (M+H)+=281; TLC(hexane/EtOAc 1:1): Rf=0.26). The acidic aqueous extracts are collected in a solution of 60 g of K2CO3 in 0.5 l of water. Upon standing, 4-[(6-methoxy-pyridin-3-yl)-methyl]-3-methyl-2H-isoquinolin-1-one crystallises, and can be filtered off by suction, washed with water and recrystallised from boiling EtOAc/methanol (m.p. 234-236° C.; FAB-MS: (M+H)+=281; TLC(hexane/EtOAc 1:1): Rf=0.18).
Reaction SMILES: [Li+].[OH-].C[O:4][C:5]([C:7]1[CH2:8][N:9]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:10][CH2:11][C:12]=1[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]2[O:25][N:24]=[C:23]([C:26]3[C:31]([F:32])=[CH:30][CH:29]=[C:28]([F:33])[C:27]=3[Cl:34])[CH:22]=2)=[CH:15][CH:14]=1)=[O:6].Cl>C1COCC1>[C:38]([O:37][C:35]([N:9]1[CH2:10][CH2:11][C:12]([C:13]2[CH:14]=[CH:15][C:16]([O:19][CH2:20][C:21]3[O:25][N:24]=[C:23]([C:26]4[C:31]([F:32])=[CH:30][CH:29]=[C:28]([F:33])[C:27]=4[Cl:34])[CH:22]=3)=[CH:17][CH:18]=2)=[C:7]([C:5]([OH:6])=[O:4])[CH2:8]1)=[O:36])([CH3:41])([CH3:39])[CH3:40]
Reactant: COC(=O)C1=C(c2ccc(OCc3cc(-c4c(F)ccc(F)c4Cl)no3)cc2)CCN(C(=O)OC(C)(C)C)C1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(OCc3cc(-c4c(F)ccc(F)c4Cl)no3)cc2)=C(C(=O)O)C1
Temperature: 60 °C
Reaction time: 72 h

Procedure:
Aq. 1M LiOH (15.0 mL, 15.0 mmol) was added to a sol. of compound C7 (2.04 g, 3.64 mmol) in THF (15 mL). The mixture was stirred at 60° C. for 3 days, and aq. 1M HCl was added. The mixture was extracted with EtOAc (2×). The combined org. extracts were washed with aq. 1M HCl and brine, dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the crude by FC (EtOAc) yielded the crude title compound mixed with 4-{4-[3-(2-chloro-3,6-difluoro-phenyl)-isoxazol-5-ylmethoxy]-phenyl}-3,6-dihydro-2H-pyridine-1,3-dicarboxylic acid 1-tert-butyl ester (600 mg, 30%). LC-MS: tR=1.08 min; ES+: 547.20.