Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:14]2[C:19](=[O:20])[CH:18]=[C:17]([CH3:21])[N:16]=[C:15]2[CH3:22])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1.C([O-])([O-])=O.[K+].[K+].Br[CH2:30][C:31]#[CH:32]>CC#N>[F:1][C:2]1[CH:3]=[C:4]([N:14]2[C:19](=[O:20])[CH:18]=[C:17]([CH3:21])[N:16]=[C:15]2[CH3:22])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:9][CH2:10][N:11]([CH2:32][C:31]#[CH:30])[CH2:12][CH2:13]1
Reactant: C#CCBr
Reactant: Cc1cc(=O)n(-c2ccc(N3CCNCC3)c(F)c2)c(C)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C#CCN1CCN(c2ccc(-n3c(C)nc(C)cc3=O)cc2F)CC1
Temperature: 25 °C
Reaction time: 36 h
Yield: 44.1 %

Procedure:
To a suspension of 3-(3-fluoro-4-(piperazin-1-yl)phenyl)-2,6-dimethylpyrimidin-4(3H)-one (0.30 g, 1.00 mmol) and K2CO3 (0.69 g, 5.00 mmol) in CH3CN (15 mL) was added 3-bromoprop-1-yne (0.12 g, 1.01 mmol) and the mixture was stirred at rt for 36 h. The mixture was then filtered, and the filtrate was concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (V/V)=1:1) to give the title compound as a white solid (0.15 g, 44%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [CH2:1]([CH:4]([CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[CH2:5][OH:6])[CH2:2][CH3:3].[C:12](O)(=[O:18])[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]>O>[C:12]([O:6][CH2:5][CH:4]([CH2:1][CH2:2][CH3:3])[CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])(=[O:18])[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: CCCCCC(CO)CCC
Reactant: CCCCCC(=O)O
Solvent: O
Product: CCCCCC(=O)OCC(CCC)CCCCC
Yield: 98 %

Procedure:
158.3 g 2-propylheptanol (1 mol) and 116.2 g caproic acid (1 mol) were heated for 4 h to 220° C. on a water separator together with 0.27 g Fascat® 2001 (Sn oxalate: 0.1% by weight, based on the composition as a whole). After the separation of water had stopped, the crude product was distilled in an oil pump vacuum through a 250 mm Vigreux column (T=111-126° C.). 251.4 g of a colorless oil were obtained: OHV=<1, AV=<0.1.
Reaction SMILES: [Na+].[O:2]=[C:3]([CH2:7][CH:8]([CH3:10])[CH3:9])[C:4]([O-:6])=[O:5].[CH2:11](Cl)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>CN(C=O)C.C(Cl)(Cl)Cl>[CH3:9][CH:8]([CH3:10])[CH2:7][C:3](=[O:2])[C:4]([O:6][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:5]
Reactant: ClCc1ccccc1
Reactant: CC(C)CC(=O)C(=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: CC(C)CC(=O)C(=O)OCc1ccccc1
Reaction time: 5 h
Yield: 93.7 %

Procedure:
A mixture of 2-Oxo-4-methyl pentanoic acid sodium salt (10 g, 65.7 mmol) and benzyl chloride (8 g, 63 mmol) in 300 ml DMF was stirred at 40°-50° C. for 5 h. It was filtered, and the filtrate was evaporated under reduced pressure to provide an oil. The oil was dissolved in chloroform, washed with water, dried, filtered, and evaporated to provide the desired product (13 g, 94%). 1H NMR (CDCl3, TMS) δ0.95 (d,6H), 2.15 (m,1H), 2.7 (d,2H), 5.28 (s,2H), 7.4 (m,5H). Mass spectrum: (M+H)+ =221.
Reaction SMILES: C1([C:4]2([N:7]([CH2:40][C:41]3[CH:46]=[C:45]([CH2:47][CH2:48][CH2:49][O:50][CH3:51])[CH:44]=[C:43]([OH:52])[CH:42]=3)[C:8](=[O:39])[CH:9]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][O:29][C:30]4[C:35]([Cl:36])=[CH:34][C:33]([CH3:37])=[CH:32][C:31]=4[Cl:38])=[CH:22][CH:21]=3)[CH2:10][NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH2:6][CH2:5]2)CC1.CS(O[CH2:58][CH2:59][CH2:60][S:61][CH3:62])(=O)=O.C(=O)([O-])[O-].[Cs+].[Cs+].CCOC(C)=O>CN(C=O)C>[CH:4]1([N:7]([CH2:40][C:41]2[CH:42]=[C:43]([O:52][CH2:58][CH2:59][CH2:60][S:61][CH3:62])[CH:44]=[C:45]([CH2:47][CH2:48][CH2:49][O:50][CH3:51])[CH:46]=2)[C:8](=[O:39])[CH:9]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][O:29][C:30]3[C:31]([Cl:38])=[CH:32][C:33]([CH3:37])=[CH:34][C:35]=3[Cl:36])=[CH:22][CH:21]=2)[CH2:10][NH:11][C:12](=[O:18])[O:13][C:14]([CH3:16])([CH3:17])[CH3:15])[CH2:6][CH2:5]1
Reactant: CSCCCOS(C)(=O)=O
Reactant: COCCCc1cc(O)cc(CN(C(=O)C(CNC(=O)OC(C)(C)C)Cc2ccc(OCCOc3c(Cl)cc(C)cc3Cl)cc2)C2(C3CC3)CC2)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COCCCc1cc(CN(C(=O)C(CNC(=O)OC(C)(C)C)Cc2ccc(OCCOc3c(Cl)cc(C)cc3Cl)cc2)C2CC2)cc(OCCCSC)c1
Temperature: 60 °C

Procedure:
To a solution of tert-butyl (3-{cyclopropyl[3-hydroxy-5-(3-methoxypropyl)benzyl](cyclopropyl)amino}-2-{4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]benzyl}-3-oxopropyl)carbamate from Example 70, Step 2 (1 eq.) in DMF (0.05 M) was added 3-(methylthio)propyl methanesulfonate from the previous step (1.4 eq.) and cesium carbonate (1.4 eq.). The resulting suspension was heated at 60° C. for 12 h. The reaction mixture was quenched sat. aq. NaHCO3 and then extracted with ether. The combined organic extracts were washed with water and brine, dried over MgSO4, filtered and the filtrate concentrated in vacuo. Purification of the crude product thus obtained by way of flash chromatography (SiO2, 3:2 (v/v) Hex:EtOAc→2:3 (v/v) Hex:EtOAc) afforded the title compound as a colorless oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14](Cl)[CH:15]=2)[C:10]([CH3:19])([CH3:18])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl-].[CH3:21][Zn+]>>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([CH3:21])[CH:15]=2)[C:10]([CH3:19])([CH3:18])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CC(C)(C)c2ccc(Cl)cc21
Reactant: C[Zn+]
Agent: [Cl-]
Product: Cc1ccc2c(c1)N(C(=O)OC(C)(C)C)CC2(C)C

Procedure:
The title compound was prepared from 6-chloro-3,3-dimethyl-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester and methylzinc chloride following similar methods to those described in Preparation 117, MS: [M+H]+=206 (-tBu).
Reaction SMILES: [CH3:1][N:2]([CH3:27])[CH2:3][CH2:4][NH:5][C:6]([C:8]1[C:21]2[C:12](=[N:13][C:14]3[C:19]([N:20]=2)=[C:18]2[CH:22]=[CH:23][C:24]([NH2:26])=[CH:25][C:17]2=[CH:16][CH:15]=3)[CH:11]=[CH:10][CH:9]=1)=[O:7].[C:28](Cl)(=[O:30])[CH3:29]>>[CH3:1][N:2]([CH3:27])[CH2:3][CH2:4][NH:5][C:6]([C:8]1[C:21]2[C:12](=[N:13][C:14]3[C:19]([N:20]=2)=[C:18]2[CH:22]=[CH:23][C:24]([NH:26][C:28](=[O:30])[CH3:29])=[CH:25][C:17]2=[CH:16][CH:15]=3)[CH:11]=[CH:10][CH:9]=1)=[O:7]
Reactant: CN(C)CCNC(=O)c1cccc2nc3ccc4cc(N)ccc4c3nc12
Reactant: CC(=O)Cl
Product: CC(=O)Nc1ccc2c(ccc3nc4cccc(C(=O)NCCN(C)C)c4nc32)c1

Procedure:
3-Acetylamino-benzo[a]phenazine-11-carboxylic acid (2-dimethylamino-ethyl)-amide was prepared in an analogous manner from 3-amino-benzo[a]phenazine-11-carboxylic acid (2-dimethylamino-ethyl)-amide and acetyl chloride;
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[C:9]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][N:21]3[C:25]([CH:26]=O)=[C:24]([Cl:28])[N:23]=[C:22]3[CH2:29][CH2:30][CH2:31][CH3:32])=[CH:16][CH:15]=2)=[CH:10][CH:11]=[CH:12][CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:33][OH:34].Cl.N1C=CC=CC=1>O>[C:1]([O:5][C:6]([C:8]1[C:9]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][N:21]3[C:25]([CH:26]=[N:33][OH:34])=[C:24]([Cl:28])[N:23]=[C:22]3[CH2:29][CH2:30][CH2:31][CH3:32])=[CH:16][CH:15]=2)=[CH:10][CH:11]=[CH:12][CH:13]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCCCc1nc(Cl)c(C=O)n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Reactant: NO
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: CCCCc1nc(Cl)c(C=NO)n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Reaction time: 1 h
Yield: 93.6 %

Procedure:
Intermediate (4a) (12.1 g, 26.7 mmol) and NH2OH.HCl (2.4 g, 34.7 mmol) were combined in 80 mL water and 160 mL pyridine and stirred at room temperature overnight. Water (80 mL) was added and the mixture was stirred for 1 hour. The precipitate was filtered and dried to yield 11.7 g of intermediate (4b), which was used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N:18]3[C:22]([CH3:23])=[CH:21][CH:20]=[C:19]3[CH3:24])[N:13]=2)[CH:3]=1.[CH3:25][O:26][NH:27][CH3:28]>CN(C=O)C>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:27]([O:26][CH3:25])[CH3:28])=[O:8])=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N:18]3[C:19]([CH3:24])=[CH:20][CH:21]=[C:22]3[CH3:23])[N:13]=2)[CH:3]=1
Reactant: CNOC
Reactant: Cc1ccc(C)n1-c1cccc(Nc2cc(Cl)ccc2C(=O)O)n1
Solvent: CN(C)C=O
Product: CON(C)C(=O)c1ccc(Cl)cc1Nc1cccc(-n2c(C)ccc2C)n1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 33.8 %

Procedure:
A mixture of 4-chloro-2-[6-(2,5-dimethyl-pyrrol-1-yl)-pyridin-2-ylamino]-benzoic acid (4.2 g) in DMF (25 mL) and carbonyldiimide (2.4 g) was stirred at 60° C. for 30 min, and N-methoxy-N-methylamine (1.41 g) was added. The mixture was stirred at 80° C. for 16 h, then the volatiles evaporated, and the residue partitioned between EtOAc and H2O, then between EtOAc and HCl (0.1 N aq). The organic phase was adsorbed on silica gel and chromatographed. Chromatography on silica (80 g) against hexane/EtOAc (100:0 to 50:50) provided 4-chloro-2-[6-(2,5-dimethyl-pyrrol-1-yl)-pyridin-2-ylamino]-N-methoxy-N-methyl-benzamide (˜1.6 g).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[C:5](=O)[CH2:6][C:7]([C:9]1[O:10][CH:11]=[CH:12][CH:13]=1)=[O:8])[CH3:2].Cl.[NH2:17]O>>[CH2:1]([O:3][C:4]([C:5]1[CH:6]=[C:7]([C:9]2[O:10][CH:11]=[CH:12][CH:13]=2)[O:8][N:17]=1)=[O:15])[CH3:2]
Reactant: CCOC(=O)C(=O)CC(=O)c1ccco1
Reactant: NO
Agent: Cl
Product: CCOC(=O)c1cc(-c2ccco2)on1
Temperature: 85 °C
Reaction time: 2 h
Yield: 77 %

Procedure:
After a suspension of 10.0 g of 4-furan-2-yl-2,4-dioxo-butyric ethyl ester prepared above and hydroxylamine hydrochloride was stirred at 85° C. for 2 hrs, the solvent was removed under reduced pressure. The concentrate was dissolved in a mixture of methylene chloride and distilled water, followed by separating the organic layer. The organic layer was dried over anhydrous sodium sulfate, filtered through a silica gel layer, and concentrated in vacuo to produce a yield of 8.01 g of 5-furan-2-yl-isoxazole-3-carboxylic acid ethyl ester (Yield 77%). The concentrate was used in the next step without further purification.
Reaction SMILES: [C:1]([N:9]1[CH:14]=[CH:13][CH:12]([CH2:15][C:16]2[N:20]([CH3:21])[C:19]3[CH:22]=[CH:23][CH:24]=[CH:25][C:18]=3[N:17]=2)[CH:11]=[CH:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>[Pd].CO>[C:1]([N:9]1[CH:10]=[CH:11][C:12]([CH2:15][C:16]2[N:20]([CH3:21])[C:19]3[CH:22]=[CH:23][CH:24]=[CH:25][C:18]=3[N:17]=2)=[CH:13][CH2:14]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [H][H]
Reactant: Cn1c(CC2C=CN(C(=O)c3ccccc3)C=C2)nc2ccccc21
Agent: [Pd]
Solvent: CO
Product: Cn1c(CC2=CCN(C(=O)c3ccccc3)C=C2)nc2ccccc21
Yield: 58.5 %

Procedure:
A mixture of 16 parts of 1-benzoyl-1,4-dihydro-4-[(1-methyl-1H-benzimidazol-2-yl)methyl]pyridine and 160 parts of methanol was hydrogenated at normal pressure and at 50° C. with 5 parts of palladium-on-charcoal catalyst 10%. After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (97.5:2.5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The oily residue was crystallized from 14 parts of 1,1'-oxybisethane. The product was filtered off and dried, yielding 7.8 parts (58.5%) of 1-benzoyl-4-[(1-methyl-1H-benzimidazol-2-yl)methyl]pyridine; mp. 159.3° C. (32).
Reaction SMILES: [I:1]I.C1(C)C=CC=CC=1.[C:10]1([P:16]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C(OCC)C>[I-:1].[I-:1].[C:23]1([P:16]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: II
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: [I-]
Temperature: 25 °C

Procedure:
A suspension of iodine (13.0 g, 51 mmol) and toluol (100 mL) was heated with reflux for 20 min. The solution formed was cooled to room temperature and added in drops to a solution of triphenylphosphine (14.0 g, 53 mmol) in anhydrous diethyl ether (100 mL). The separated yellow precipitate was filtered off and washed with diethyl ether.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][C:17]=1[N+:18]([O-])=O)[O:5][CH2:6][CH2:7][CH2:8][N:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1>[Pd]>[CH3:1][C:2]1[CH:3]=[C:4]([O:5][CH2:6][CH2:7][CH2:8][N:9]2[CH2:10][CH2:11][O:12][CH2:13][CH2:14]2)[CH:15]=[CH:16][C:17]=1[NH2:18]
Reactant: Cc1cc(OCCCN2CCOCC2)ccc1[N+](=O)[O-]
Agent: [Pd]
Product: Cc1cc(OCCCN2CCOCC2)ccc1N
Yield: 32 %

Procedure:
An ethanolic (20 mL) solution of 4-(3-(3-methyl-4-nitrophenoxy)propyl) morpholine (0.75 g, 2.7 mmol) was subjected to hydrogenation using the H-cube (Pd/C catalyst cartridge and H2, 1-5 bar) for 1 hour. 2-Methyl-4-(3-morpholinopropoxy)aniline was isolated by concentration under reduced pressure (0.22 g, 32% yield). 1H-NMR (400 MHz DMSO-d6): δ 6.57-6.51 (m, 3H), 3.85 (t, 6.4 Hz, 2H), 3.69-3.62 (m, 4H), 3.46-3.43 (m, 2H), 2.56 (m, 4H), 2.02 (s, 3H), 1.88-1.85 (m, 2H). MS (EI): 251 (MH+).
Reaction SMILES: C([O:3][C:4](=O)[C@@H:5]([N:7]([CH:21]([CH3:23])[CH3:22])[C:8]1[C:17]([N+:18]([O-])=O)=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][N:9]=1)[CH3:6])C.P(OC1C=CC=CC=1)(OC1C=CC=CC=1)OC1C=CC=CC=1>ClCCl.[NH4+].[O-][V](=O)=O.[Pt]>[CH:21]([N:7]1[C@@H:5]([CH3:6])[C:4](=[O:3])[NH:18][C:17]2[CH:16]=[C:11]([C:12]([O:14][CH3:15])=[O:13])[CH:10]=[N:9][C:8]1=2)([CH3:23])[CH3:22]
Reactant: CCOC(=O)[C@H](C)N(c1ncc(C(=O)OC)cc1[N+](=O)[O-])C(C)C
Agent: O=[V](=O)[O-]
Agent: [Pt]
Agent: [NH4+]
Solvent: ClCCl
Product: COC(=O)c1cnc2c(c1)NC(=O)[C@H](C)N2C(C)C
Reaction time: 6 h
Yield: 94.3 %

Procedure:
(S)-methyl 6-((1-ethoxy-1-oxopropan-2-yl)(isopropyl)amino)-5-nitronicotinate (0.900 g, 2.65 mmol) was dissolved in dichloromethane (10 mL). To this solution was added triphenyl phosphite (3.0 mg, 9.7 umol), ammonium metavanadate (30 mg, 0.265 mmol) and Pt/C (5% wt., 0.120 g). The reaction mixture was hydrogenated at 80 psi at 25° C. for 6 h. The mixture was filtered through a small pad of celite and the pad was washed with dichloromethane (20 mL). The combined filtrates were concentrated in vacuo and crystallized with ethyl ether to afford the title compounds as a white solid (0.658 g, 94%). 1H NMR (400 MHz, CHLOROFORM-d) δ (ppm): 1.33 (d, J=6.82 Hz, 3 H) 1.36-1.41 (m, 6 H) 3.90 (s, 3 H) 4.34 (q, J=6.65 Hz, 1 H) 4.86 (m, 1 H) 7.52 (d, J=1.77 Hz, 1 H) 8.59 (d, J=1.77 Hz, 1 H) 8.73 (br. s., 1 H); [M+H] calc'd for C13H17N3O3, 264; found, 264.
Reaction SMILES: [CH3:1][C:2]1([CH3:7])[CH2:6][CH2:5][NH:4][CH2:3]1.[CH:8]1([C:11]2[N:16]=[C:15]([C:17]([NH:19][C:20]3[CH:28]=[N:27][CH:26]=[CH:25][C:21]=3[C:22](O)=[O:23])=[O:18])[C:14]([NH:29][C:30]3[CH:31]=[N:32][CH:33]=[N:34][CH:35]=3)=[CH:13][CH:12]=2)[CH2:10][CH2:9]1>>[CH3:1][C:2]1([CH3:7])[CH2:6][CH2:5][N:4]([C:22]([C:21]2[CH:25]=[CH:26][N:27]=[CH:28][C:20]=2[NH:19][C:17]([C:15]2[C:14]([NH:29][C:30]3[CH:31]=[N:32][CH:33]=[N:34][CH:35]=3)=[CH:13][CH:12]=[C:11]([CH:8]3[CH2:10][CH2:9]3)[N:16]=2)=[O:18])=[O:23])[CH2:3]1
Reactant: O=C(O)c1ccncc1NC(=O)c1nc(C2CC2)ccc1Nc1cncnc1
Reactant: CC1(C)CCNC1
Product: CC1(C)CCN(C(=O)c2ccncc2NC(=O)c2nc(C3CC3)ccc2Nc2cncnc2)C1
Yield: 34 %

Procedure:
According to the general method described in step 3 of example 53, reaction of 3,3-dimethyl-pyrrolidine with 3-{[6-cyclopropyl-3-(pyrimidin-5-ylamino)-pyridine-2-carbonyl]-amino}-isonicotinic acid provided the title compound (34%) as amorphous yellow solid.
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[F:24])[CH:15]=2)[C:10]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[Cl:31])=[N:9]1)=O)(C)(C)C.C[O-].[Na+]>CO>[Cl:31][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=1[C:10]1[C:11]2[C:16](=[CH:15][C:14]([O:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[F:24])=[CH:13][CH:12]=2)[NH:8][N:9]=1
Reactant: CC(C)(C)OC(=O)n1nc(-c2ccccc2Cl)c2ccc(Oc3ccccc3F)cc21
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: Fc1ccccc1Oc1ccc2c(-c3ccccc3Cl)n[nH]c2c1
Yield: 62 %

Procedure:
A solution of 3-(2-Chloro-phenyl)-6-(2-fluoro-phenoxy)-indazole-1-carboxylic acid tert-butyl ester (90 mg, 0.2 mmol) and sodium methoxide (22 mg, 0.41 mmol) in methanol (2 mL) was stirred at room temperature for 1 h, and then concentrated under vacuum. The residue was diluted with EtOAc, washed with water, dried over Na2SO4 filtered, concentrated and the residue was purified by flash chromatography eluting with Hex:EtOAc 4:1 to yield 42 mg of 3-(2-Chloro-phenyl)-6-(2-fluoro-phenoxy)-1H-indazole: MS (M+H)+=339
Reaction SMILES: [O:1]1[CH:5]([CH2:6][NH2:7])[CH2:4][C:3]2[CH:8]=[CH:9][C:10]3[C:15]([C:2]1=2)=[CH:14][CH:13]=[CH:12][CH:11]=3.C(N(C(C)C)CC)(C)C.Cl[C:26]([O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:27].CC1C=CC(S(OC)(=O)=O)=CC=1>>[O:1]1[CH:5]([CH2:6][NH:7][C:26](=[O:27])[O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:4][C:3]2[CH:8]=[CH:9][C:10]3[C:15]([C:2]1=2)=[CH:14][CH:13]=[CH:12][CH:11]=3
Reactant: NCC1Cc2ccc3ccccc3c2O1
Reactant: O=C(Cl)OCc1ccccc1
Agent: COS(=O)(=O)c1ccc(C)cc1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCC1Cc2ccc3ccccc3c2O1)OCc1ccccc1
Yield: 90.4 %

Procedure:
Treatment of (±)-1-(2,3-dihydronaphtho[1,2-b]furan-2-yl)methanamine (1.19 g, 5.97 mmol) with diisopropylethylamine (0.849 g, 6.57 mmol) followed by benzyl chloroformate (1.07 g, 6.27 mmol) generally according to the procedure described for Intermediate 7 afforded 1.80 g (90%) of (±)-benzyl 2,3-dihydronaphtho[1,2-b]furan-2-ylmethylcarbamate as a white solid. Rf=0.47 (silica, ethyl acetate:hexanes 1:4); mp 110-112° C.; Anal. calcd. for C21H19NO3: C, 75.66; H, 5.74; N, 4.2. Found: C, 75.4; H, 5.57; N, 4.12. Chiral HPLC separation of (±)-benzyl 2,3-dihydronaphtho[1,2-b]furan-2-ylmethylcarbamate (Chiralcel OJ, ethanol) provided two fractions. Fraction 1 (Rt=19.572 min, Chiralcel OJ, ethanol); Fraction 2 (Rt=30.782 min, Chiralcel OJ, ethanol).
Reaction SMILES: Cl[C:2]1[C:7]([F:8])=[CH:6][N:5]=[C:4]2[N:9]([Si:12]([CH:19]([CH3:21])[CH3:20])([CH:16]([CH3:18])[CH3:17])[CH:13]([CH3:15])[CH3:14])[CH:10]=[CH:11][C:3]=12.[CH3:22][NH:23][CH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1.CC(C)([O-])C.[Na+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(CCC)=CC(CCC)=CC=2CCC)CCCCC1>CC([O-])=O.CC([O-])=O.[Pd+2].O1CCOCC1>[CH:24]1([N:23]([CH3:22])[C:2]2[C:3]3[CH:11]=[CH:10][N:9]([Si:12]([CH:19]([CH3:21])[CH3:20])([CH:16]([CH3:18])[CH3:17])[CH:13]([CH3:15])[CH3:14])[C:4]=3[N:5]=[CH:6][C:7]=2[F:8])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc2c(Cl)c(F)cnc21
Reactant: CNC1CCCCC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: C1COCCO1
Product: CC(C)[Si](C(C)C)(C(C)C)n1ccc2c(N(C)C3CCCCC3)c(F)cnc21
Temperature: 100 °C

Procedure:
A mixture of 4-chloro-5-fluoro-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine (250 mg), N-methylcyclohexanamine (306 μl), Pd(OAc)2(17 mg), sodium tert-butoxide (176 mg), 2-dicyclohexylphosphino-2′,4′,6′-tri-1-propyl-1,1′-biphenyl (73 mg) and 1,4-dioxane (2.5 mL) was evacuated and backfield with N2 three times, then degassed with N2 for 10 minutes. The mixture was heated at 100° C. for 2.5 hours. After cooling to ambient temperature, the reaction mixture was concentrated. Purification of the crude product by column chromatography (silica gel, n-hexane:EtOAc=1:50) afforded N-cyclohexyl-5-fluoro-N-methyl-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridin-4-amine (53 mg) as a colorless solid.
Reaction SMILES: [NH:1]([C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][N:4]=1)[NH2:2].[CH:12](=O)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(O)C>[N+:9]([C:6]1[CH:7]=[CH:8][C:3]([NH:1][N:2]=[CH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:4][CH:5]=1)([O-:11])=[O:10]
Reactant: NNc1ccc([N+](=O)[O-])cn1
Reactant: O=Cc1ccccc1
Solvent: CCO
Product: O=[N+]([O-])c1ccc(NN=Cc2ccccc2)nc1
Temperature: 100 °C
Yield: 62 %

Procedure:
In 20 ml of ethanol were dispersed 1.59 g of 2-hydrazino-5-nitropyridine and 1.13 g of benzaldehyde. The dispersion was refluxed at 100° C. for 16.5 hours. The reaction solution was allowed to cool at room temperature. The resulting precipitate was collected by suction filtration, washed with ethanol and air dried, obtaining 1.55 g (yield 62%) of orange yellow fine acicular crystals.
Reaction SMILES: Cl.Cl.Cl.[NH2:4][CH2:5][C@H:6]([N:11]1[CH2:16][CH2:15][N:14]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=2)[CH2:13][CH2:12]1)[C:7]([O:9][CH3:10])=[O:8].Cl.[CH3:26][C:27]1[CH:36]=[C:35]([CH2:37][O:38][C:39]2[CH:44]=[CH:43][C:42]([S:45](Cl)(=[O:47])=[O:46])=[CH:41][CH:40]=2)[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[N:28]=1>>[CH3:26][C:27]1[CH:36]=[C:35]([CH2:37][O:38][C:39]2[CH:44]=[CH:43][C:42]([S:45]([NH:4][CH2:5][C@H:6]([N:11]3[CH2:12][CH2:13][N:14]([CH2:17][C:18]4[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=4)[CH2:15][CH2:16]3)[C:7]([O:9][CH3:10])=[O:8])(=[O:47])=[O:46])=[CH:41][CH:40]=2)[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[N:28]=1
Reactant: Cc1cc(COc2ccc(S(=O)(=O)Cl)cc2)c2ccccc2n1
Reactant: COC(=O)[C@H](CN)N1CCN(Cc2ccc(C)cc2)CC1
Agent: Cl
Product: COC(=O)[C@H](CNS(=O)(=O)c1ccc(OCc2cc(C)nc3ccccc23)cc1)N1CCN(Cc2ccc(C)cc2)CC1

Procedure:
In a manner analogous to example 3.6, using 1.0 g (2.5 mmol) of methyl (S)-3-amino-2-[4-(4-methylbenzyl)piperazin-1-yl]propanoate trihydrochloride and 1.3 g (3.5 mmol) of 4-(2-methylquinolin-4-ylmethoxy)benzenesulfonyl chloride hydrochloride (prepared as described in example 17.2), 950 mg (63%) of methyl (S)-3-[4-(2-methylquinolin-4-ylmethoxy)benzenesulfonylamino]-2-[4-(4-methylbenzyl)piperazin-1-yl]propenoate are obtained in the form of a white solid.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[Na+].[I-].Cl[CH2:10][CH2:11][C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:13].[CH3:20][CH:21]([CH3:37])[C:22]([NH:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([CH:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)[CH:26]=1)=[O:23]>>[CH3:20][CH:21]([CH3:37])[C:22]([NH:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([CH:31]2[CH2:36][CH2:35][N:34]([CH2:10][CH2:11][C:12](=[O:13])[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:33][CH2:32]2)[CH:26]=1)=[O:23]
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Reactant: O=C(CCCl)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCC(=O)c3ccccc3)CC2)c1

Procedure:
Prepared by Procedure K and Scheme E using K2CO3 instead of Na2CO3 and NaI instead S of KI and 3-chloro-1-phenyl-1-propanone and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 379.3 (M+H)+.
Reaction SMILES: [CH3:1][CH:2]([N:4]1[CH2:7][CH2:6][CH:5]1[CH2:8][OH:9])[CH3:3].[O:10]([C:17]1[CH:22]=[CH:21][C:20](O)=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[CH3:1][CH:2]([N:4]1[CH2:7][CH2:6][CH:5]1[CH2:8][O:9][C:20]1[CH:21]=[CH:22][C:17]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:18][CH:19]=1)[CH3:3]
Reactant: CC(C)N1CCC1CO
Reactant: Oc1ccc(Oc2ccccc2)cc1
Product: CC(C)N1CCC1COc1ccc(Oc2ccccc2)cc1

Procedure:
The title compound is prepared from 1-(1-methylethyl)-2-azetidinemethanol and 4-phenoxyphenol according to the procedures of Example 8.
Reaction SMILES: [CH3:1][Si:2]([CH3:7])([CH3:6])[CH2:3][CH2:4][OH:5].[C:8]([CH2:10][C:11](O)=[O:12])#[N:9].C1(N=C=NC2CCCCC2)CCCCC1.N1(C2C=CN=CC=2)CCCC1>C(OCC)C>[CH3:1][Si:2]([CH3:7])([CH3:6])[CH2:3][CH2:4][O:5][C:11](=[O:12])[CH2:10][C:8]#[N:9]
Reactant: N#CCC(=O)O
Reactant: C[Si](C)(C)CCO
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: c1cc(N2CCCC2)ccn1
Solvent: CCOCC
Product: C[Si](C)(C)CCOC(=O)CC#N
Temperature: 25 °C
Reaction time: 3 h

Procedure:
2000 mg (16.91 mmol) 2-(Trimethylsilyl)ethanol are dissolved in 160 ml diethylether. 1307 mg (15.38 mmol) cyanoacetic acid, 3489 mg (16.91 mmol) N,N′-dicyclohexylcarbodiimide and 227 mg (1.54 mmol) 4-(1-pyrrolidinyl)pyridine are added. The mixture is stirred at room temperature for 3 hours under an argon atmosphere and kept at room temperature overnight. The suspension is filtered and the filtrate is washed twice with 5% aqueous acetic acid and twice with water. The organic phase is dried over sodium sulfate, filtered and the solvent is evaporated in vacuo. The residue is re-dissolved in 10 ml hexane and the suspension is filtered over 1 g silica. After evaporation of the solvent, distillation at 0.51 mbar yields the desired product.