Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[OH:2][NH3+:3].[F:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]([OH:34])[CH2:12][CH2:13][CH:14]2[C:17](=[O:18])[N:16]([C:19]3[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][CH:20]=3)[CH:15]2[C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)=[CH:7][CH:6]=1.C(N(CC)CC)C>C(O)(C)C>[F:33][C:30]1[CH:29]=[CH:28][C:27]([CH:15]2[CH:14]([CH2:13][CH2:12][CH:11]([C:8]3[CH:7]=[CH:6][C:5]([F:4])=[CH:10][CH:9]=3)[OH:34])[C:17](=[O:18])[N:16]2[C:19]2[CH:26]=[CH:25][C:22]([C:23]([NH:3][OH:2])=[NH:24])=[CH:21][CH:20]=2)=[CH:32][CH:31]=1
Reactant: N#Cc1ccc(N2C(=O)C(CCC(O)c3ccc(F)cc3)C2c2ccc(F)cc2)cc1
Reactant: [NH3+]O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: N=C(NO)c1ccc(N2C(=O)C(CCC(O)c3ccc(F)cc3)C2c2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
279 mg of hydroxylammonium hydrochloride were added to a solution of 280 mg of 4-[3-[3-(4-fluorophenyl)-3-hydroxypropyl]-2-(4-fluorophenyl)-4-oxoazetidin-1-yl]benzonitrile (11) and 0.65 ml of triethylamine in 15 ml of isopropanol. The mixture was stirred at room temperature for 12 h. The reaction solution was extracted twice with ethyl acetate/water. The organic phases were dried over magnesium sulfate and concentrated. This gave the product of molecular weight 451.48 (C25H23F2N3O3); MS (ESI): 452.10 (M+H+).
Reaction SMILES: CS(O)(=O)=O.O[CH2:7][CH2:8][CH2:9][N:10]1[C:14]2[CH:15]=[CH:16][C:17]([CH3:19])=[CH:18][C:13]=2[NH:12][C:11]1=[O:20].[C:21]1([N:27]2[C:31]3([CH2:36][CH2:35][NH:34][CH2:33][CH2:32]3)[C:30](=[O:37])[NH:29][CH2:28]2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O>[CH3:19][C:17]1[CH:16]=[CH:15][C:14]2[N:10]([CH2:9][CH2:8][CH2:7][N:34]3[CH2:33][CH2:32][C:31]4([N:27]([C:21]5[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=5)[CH2:28][NH:29][C:30]4=[O:37])[CH2:36][CH2:35]3)[C:11](=[O:20])[NH:12][C:13]=2[CH:18]=1
Reactant: Cc1ccc2c(c1)[nH]c(=O)n2CCCO
Reactant: O=C1NCN(c2ccccc2)C12CCNCC2
Agent: CS(=O)(=O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc2c(c1)[nH]c(=O)n2CCCN1CCC2(CC1)C(=O)NCN2c1ccccc1
Temperature: 60 °C
Reaction time: 1 h
Yield: 24 %

Procedure:
A mixture of 5.68 parts of 1,3-dihydro-1-(3-hydroxypropyl)-5-methyl-2H-benzimidazol-2-one methanesulfonate, 4.62 parts of 1-phenyl-1,3,8-triazaspiro[4,5]decan-4-one, 3.7 parts of sodium carbonate and 45 parts of N,N-dimethylformamide is stirred for 1 hour at 60° C. The reaction mixture is cooled and poured onto water. The precipitated product is filtered off and purified by column-chromatography over silica gel using a mixture of trichloromethane and 10% of methanol as eluent. The pure fractions are collected and the eluent is evaporated. The residue is crystallized from a mixture of N,N-dimethylformamide and water, yielding 2 parts (24%) of 8-[3-(1,3-dihydro-5-methyl-2-oxo-2H-benzimidazol-1-yl)propyl]-1-phenyl-1,3,8-triazaspiro[4,5]decan-4-one; mp. 255.5° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH2:8][O:9][C:10]1[N:15]=[C:14]([NH:16][NH2:17])[CH:13]=[C:12]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[N:11]=1.[C:24]1([CH3:32])[CH:29]=[CH:28][CH:27]=[C:26]([CH:30]=O)[CH:25]=1.C(O)(=O)C>CCOC(C)=O>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH2:8][O:9][C:10]1[N:15]=[C:14]([NH:16][N:17]=[CH:32][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([CH3:30])[CH:25]=2)[CH:13]=[C:12]([N:18]2[CH2:19][CH2:20][O:21][CH2:22][CH2:23]2)[N:11]=1
Reactant: Cc1cccc(C=O)c1
Reactant: NNc1cc(N2CCOCC2)nc(OCCc2ccccn2)n1
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: Cc1cccc(C=NNc2cc(N3CCOCC3)nc(OCCc3ccccn3)n2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A stirred suspension of 2-[2-(pyridin-2-yl)-ethoxy]-4-hydrazino-6-(morpholin-4-yl)-pyrimidine (Product 3) (5 g, 15.8 mmol, 95% purity), m-tolualdehyde (1.99 g, 16.6 mmol), ethyl acetate (25 mL) and acetic acid (45 μL) was heated to reflux for 15 minutes to give a clear solution. When TLC indicated that the reaction was completion, the reaction was allowed to cool to room temperature causing a solid precipitate to formed. The creamy solid was filtered out, washed with ethyl acetate (EtOAc) (3×5 mL) and dried to obtain crude Compound 6. The crude product (5 g, 75.6%) was dissolved in EtOAc (34 mL) under reflux. The resulting clear solution was concentrated to about 20 mL and cooled to room temperature causing Compound 6 to precipitate out forming a suspension. The suspension was stirred for 2 hours, then the precipitate was filtered out, washed with EtOAc (2×10 mL) and vacuum-dried to give Compound 6 as an off-white solid, 4.1 g (82%).
Reaction SMILES: Cl[Si](C)(C)C=C[Si](Cl)(C)C.[Cl:11][Si:12]([CH2:23][CH3:24])([CH2:21][CH3:22])[CH:13]=[CH:14][Si:15]([Cl:20])([CH2:18][CH3:19])[CH2:16][CH3:17]>>[Cl:20][Si:15]([CH2:16][CH3:17])([CH2:18][CH3:19])[CH2:14][CH2:13][Si:12]([Cl:11])([CH2:21][CH3:22])[CH2:23][CH3:24]
Reactant: CC[Si](Cl)(C=C[Si](Cl)(CC)CC)CC
Agent: C[Si](C)(Cl)C=C[Si](C)(C)Cl
Product: CC[Si](Cl)(CC)CC[Si](Cl)(CC)CC

Procedure:
Example 1 was repeated with the modification that, instead of 300.0 g (1.41 mol) of 1,2-bis(chlorodimethylsilyl)ethene, 300.0 g (1.11 mol) of 1,2-bis(chlorodiethylsilyl)ethene were used. The results are summarized in Table 1.
Reaction SMILES: Cl.Cl.[CH2:3]([O:5][C:6](=[O:14])[CH2:7][N:8]1[CH2:12][CH2:11][C@@H:10]([NH2:13])[CH2:9]1)[CH3:4].[Cl:15][C:16]1[S:20][C:19]([C:21](O)=[O:22])=[CH:18][CH:17]=1>>[CH2:3]([O:5][C:6](=[O:14])[CH2:7][N:8]1[CH2:12][CH2:11][C@@H:10]([NH:13][C:21]([C:19]2[S:20][C:16]([Cl:15])=[CH:17][CH:18]=2)=[O:22])[CH2:9]1)[CH3:4]
Reactant: O=C(O)c1ccc(Cl)s1
Reactant: CCOC(=O)CN1CC[C@@H](N)C1
Agent: Cl
Product: CCOC(=O)CN1CC[C@@H](NC(=O)c2ccc(Cl)s2)C1

Procedure:
1.3 Using general method D, ((R)-3-amino-pyrrolidin-1-yl)-acetic acid ethyl ester dihydrochloride was coupled with 5-chlorothiophene-2-carboxylic acid to give {(R)-3-[(5-chloro-thiophene-2-carbonyl)-amino]-pyrrolidin-1-yl}-acetic acid ethyl ester. Off-white amorphous solid. MS 317.0 ([M+H]+)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[NH:8][C:7](=[O:14])[C:6]2=[O:15].[CH3:16][O:17][C:18]1[CH:23]=[C:22]([O:24][CH3:25])[CH:21]=[CH:20][C:19]=1Br>>[CH3:16][O:17][C:18]1[CH:23]=[C:22]([O:24][CH3:25])[CH:21]=[CH:20][C:19]=1[C:6]1([OH:15])[C:5]2[C:9](=[CH:10][C:11]([O:12][CH3:13])=[C:3]([O:2][CH3:1])[CH:4]=2)[NH:8][C:7]1=[O:14]
Reactant: COc1cc2c(cc1OC)C(=O)C(=O)N2
Reactant: COc1ccc(Br)c(OC)c1
Product: COc1ccc(C2(O)C(=O)Nc3cc(OC)c(OC)cc32)c(OC)c1
Yield: 59.6 %

Procedure:
With 1.38 g of 5,6-dimethoxyisatin and 3.61 g of 2,4-dimethoxy bromobenzene as starting material, 1.37 g of the title compound (brown solid) was obtained by a similar method to Step 21-1.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([N:13]([CH:23]2[CH2:25][CH2:24]2)[CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[C:5]2[N:6]([C:8]([C:11]#[N:12])=[CH:9][N:10]=2)[N:7]=1.[N:26]1[C:31]([NH2:32])=[CH:30][CH:29]=[CH:28][C:27]=1[NH2:33].C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>[Cu]I.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].COCCOC>[NH2:33][C:27]1[N:26]=[C:31]([NH:32][C:2]2[CH:3]=[C:4]([N:13]([CH:23]3[CH2:25][CH2:24]3)[CH2:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)[C:5]3[N:6]([C:8]([C:11]#[N:12])=[CH:9][N:10]=3)[N:7]=2)[CH:30]=[CH:29][CH:28]=1
Reactant: COc1ccc(CN(c2cc(Cl)nn3c(C#N)cnc23)C2CC2)cc1
Reactant: Nc1cccc(N)n1
Agent: [Cu]I
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: COCCOC
Product: COc1ccc(CN(c2cc(Nc3cccc(N)n3)nn3c(C#N)cnc23)C2CC2)cc1
Temperature: 125 °C
Yield: 23.4 %

Procedure:
A sealed tube was charged with DME (1.5 mL) and purged with argon. The vessel was then charged with 1G (0.050 g, 0.14 mmol), pyridine-2,6-diamine (0.039 g, 0.35 mmol), cesium carbonate (0.184 g, 0.57 mmol), copper(I) iodide (0.013 g, 0.071 mmol), Xantphos (0.016 g, 0.028 mmol), and Pd2(dba)3 (0.013 g, 0.014 mmol), in one portion. The resulting suspension was pump/purged with argon three times. The cap was placed on the vessel, and the suspension heated to 125° C. overnight. The solids were filtered off, and the filtrate was concentrated in vacuo. The crude product was dissolved in a small amount of DCM and charged to a 24 g silica gel cartridge which was eluted at 30 mL/min with a 20 min gradient from 100% DCM to 60% EtOAc/DCM, monitoring at 254 nm, affording 2A (0.014 g, 23% yield) as a tan solid. HPLC: Rt=3.62 min (YMC S5 ODS 4.6×50 mm, 10-90% aqueous methanol containing 0.2% H3PO4, 4 min gradient, monitored at 220 nm). MS (ES): m/z=427.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.19-8.28 (1 H, m), 7.41 (1H, s), 7.03-7.12 (3H, m), 6.96-7.03 (1H, m), 6.79-6.86 (2H, m), 6.13 (1H, s), 5.49 (2H, s), 3.68 (3H, s), 3.49-3.65 (3H, m), 2.45 (1H, d, J=3.78 Hz), 0.91-0.98 (2H, m), 0.74 (2H, m).
Reaction SMILES: [CH2:1]([CH:3]1[C:8]2[NH:9][C:10]3[C:15]([C:7]=2[CH2:6][CH2:5][N:4]1[CH3:17])=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=3)[CH3:2].N1CCC[C@H]1C(O)=O.[O-]P([O-])([O-])=O.[K+].[K+].[K+].Br[CH:35]=[C:36]([C:38]1[CH:43]=[CH:42][C:41]([Cl:44])=[C:40]([Cl:45])[CH:39]=1)[CH3:37]>CN(C=O)C.[Cu]I>[Cl:45][C:40]1[CH:39]=[C:38]([C:36]([CH3:37])=[CH:35][N:9]2[C:10]3[C:15](=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=3)[C:7]3[CH2:6][CH2:5][N:4]([CH3:17])[CH:3]([CH2:1][CH3:2])[C:8]2=3)[CH:43]=[CH:42][C:41]=1[Cl:44]
Reactant: CCC1c2[nH]c3ccc(C)cc3c2CCN1C
Reactant: CC(=CBr)c1ccc(Cl)c(Cl)c1
Agent: [Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=P([O-])([O-])[O-]
Solvent: CN(C)C=O
Product: CCC1c2c(c3cc(C)ccc3n2C=C(C)c2ccc(Cl)c(Cl)c2)CCN1C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 54.6 %

Procedure:
1-ethyl-2,6-dimethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (72 mg, 0.31 mmol) was dissolved in DMF (5 mL). To this solution was added CuI (6 mg, 0.032 mmol), L-proline (7 mg, 0.063 mmol), K3PO4 (134 mg, 0.63 mmol). The reaction mixture was stirred for 10 min at room temperature followed by addition of 4-(1-bromoprop-1-en-2-yl)-1,2-dichlorobenzene (100 mg, 0.378 mmol). The reaction mixture was heated at 80° C. for 18 h. Solvent was evaporated under reduced pressure, the residue was diluted with brine and extracted with ethyl acetate. Organic layer was dried over Na2SO4, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography to obtain 70 mg of 9-(2-(3,4-dichlorophenyl)prop-1-enyl)-1-ethyl-2,6-dimethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole. 1H NMR FREE BASE (CDCl3): 7.63 (s, 1H), 7.49 (d, 1H), 7.39 (d, 1H), 7.34 (s, 1H), 7.05-7.0 (m, 2H), 6.94 (s, 1H), 3.44-3.38 (m, 1H), 3.24-3.15 (m, 1H), 2.95-2.84 (m, 2H), 2.68-2.6 (m, 1H), 2.53 (s, 2H), 2.46 (s, 3H), 1.97 (s, 3H), 1.75-1.65 (m, 2H), 0.98 (t, 3H).
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[O:3][C:4]([F:27])([F:26])[C:5]([F:25])([F:24])[O:6][C:7]([F:23])([F:22])[C:8]([F:21])([F:20])[O:9][C:10]([F:19])([F:18])[CH2:11][O:12][CH2:13][CH2:14][CH2:15][CH2:16]Br.[CH2:30]([C:38]1[CH:39]=[N:40][C:41]([C:44]2[CH:49]=[CH:48][C:47]([OH:50])=[CH:46][CH:45]=2)=[N:42][CH:43]=1)[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]>>[CH2:30]([C:38]1[CH:43]=[N:42][C:41]([C:44]2[CH:49]=[CH:48][C:47]([O:50][CH2:16][CH2:15][CH2:14][CH2:13][O:12][CH2:11][C:10]([O:9][C:8]([F:20])([F:21])[C:7]([F:22])([F:23])[O:6][C:5]([F:24])([F:25])[C:4]([F:26])([F:27])[O:3][C:2]([F:28])([F:29])[F:1])([F:19])[F:18])=[CH:46][CH:45]=2)=[N:40][CH:39]=1)[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]
Reactant: CCCCCCCCc1cnc(-c2ccc(O)cc2)nc1
Reactant: FC(F)(F)OC(F)(F)C(F)(F)OC(F)(F)C(F)(F)OC(F)(F)COCCCCBr
Product: CCCCCCCCc1cnc(-c2ccc(OCCCCOCC(F)(F)OC(F)(F)C(F)(F)OC(F)(F)C(F)(F)OC(F)(F)F)cc2)nc1

Procedure:
The title compound was prepared essentially as in Example 1 by combining 4-(2-(2-(2-(trifluoromethoxy)tetrafluoroethoxy)tetrafluoroethoxy)-2,2-difluoroethoxy)-1-bromobutane (20.9 g, 38.5 mol; prepared from 1,4-dibromobutane and 2-(2-(2-(trifluoromethoxy)tetrafluoroethoxy)tetrafluoroethoxy)-2,2-difluoroethanol) with 5-octyl-2-(4-hydroxyphenyl)pyrimidine (10.0 g, 0.35 mol). The resulting product was further purified by recrystallization from ethanol and subsequent Kugelrohr distillation to provide a yield of 17.5 g (b.p. 195-220° C. at 0.1 torr).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[CH:6][C:7]2[CH2:16][C@H:15]3[C@H:10]([CH2:11][CH2:12][CH2:13][NH:14]3)[C:9]([CH3:18])([CH3:17])[C:8]=2[CH:19]=1.O.O.O.[C:23]([O-])(=[O:25])[CH3:24].[Na+].C(OC(=O)C)(=O)C>>[C:23]([N:14]1[C@@H:15]2[C@@H:10]([C:9]([CH3:17])([CH3:18])[C:8]3[CH:19]=[C:4]([O:3][CH3:2])[CH:5]=[CH:6][C:7]=3[CH2:16]2)[CH2:11][CH2:12][CH2:13]1)(=[O:25])[CH3:24]
Reactant: COc1ccc2c(c1)C(C)(C)[C@H]1CCCN[C@H]1C2
Reactant: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: COc1ccc2c(c1)C(C)(C)[C@H]1CCCN(C(C)=O)[C@H]1C2

Procedure:
A mixture of 0.56 g. of cis-1,2,3,4,4a,5,10,10a-octahydro-7-methoxy-5,5-dimethylbenzo[g]quinoline hydrochloride, 0.27 g. of sodium acetate trihydrate, and 7 ml. of acetic anhydride was stirred and heated on a steam bath for three hours. The reaction mixture was evaporated to dryness under reduced pressure, and the resulting residue was partitioned between water and diethyl ether. The ether layer was washed with 1N-hydrochloric acid and with saturated aqueous sodium bicarbonate solution. After drying the ethereal solution, filtering, and removing the solvent by evaporation under reduced pressure, there was obtained 0.52 g. of a syrup which crystallized from hexane to yield cis-1-acetyl-1,2,3,4,4a,5,10,10a-octahydro-7-methoxy-5,5-dimethylbenzo[g]quinoline, m.p. 81°-85° C.; ir (CHCl3), 1630 cm.-1 (C=O); nmr (CDCl3), 80 (s,3), 78 (s,3).
Reaction SMILES: [CH:1]([N:14]1[CH2:17][C:16](=[O:18])[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:19]([Mg]I)[CH2:20][CH3:21].ICCC.[Mg].[Cl-].[NH4+]>C(OCC)C.O>[CH:1]([N:14]1[CH2:17][C:16]([OH:18])([CH2:19][CH2:20][CH3:21])[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCC[Mg]I
Reactant: O=C1CN(C(c2ccccc2)c2ccccc2)C1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: CCCI
Solvent: CCOCC
Solvent: O
Product: CCCC1(O)CN(C(c2ccccc2)c2ccccc2)C1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A solution of 7.5 g of 1-benzhydryl-3-oxoazetidine dissolved in 50 cm3 of ethyl ether is added in the course of 20 minutes at between 0 and 5° C. to a solution of propylmagnesium iodide in ethyl ether, prepared under the usual conditions from 10.75 g of iodopropane and 1.55 g of magnesium in 75 cm3 of ethyl ether. The temperature is allowed to rise to approximately 20° C. and the mixture is stirred at the same temperature for 2 hours. After cooling to approximately 0° C., 50 cm3 of water and 50 cm3 of 10% aqueous ammonium chloride solution are added successively while the latter temperature is maintained. The aqueous phase is extracted with 3 times 50 cm3 of ethyl ether. The combined organic extracts are dried over magnesium sulphate and concentrated to dryness under reduced pressure (20 kPa) at approximately 30° C. The dry extract is chromatographed on 100 g of silica gel (0.04-0.063 mm) suspended in a cyclohexane mixture containing 20% of ethyl acetate. The desired product is eluted with 130 cm3 of the same solvent mixture. 8 g of 1-benzhydryl-3-hydroxy-3-propyl-azetidine are obtained in the form of a pale yellow oil, which is used without further purification for the subsequent steps.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]=[N:7][N:8]2[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([O-])=O.[Cl-].[NH4+]>[Fe].CCO.O>[C:13]1([N:8]2[C:9]3[CH:10]=[CH:11][CH:12]=[C:4]([NH2:1])[C:5]=3[CH:6]=[N:7]2)[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=[N+]([O-])c1cccc2c1cnn2-c1ccccc1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: Nc1cccc2c1cnn2-c1ccccc1
Yield: 58 %

Procedure:
A solution of 4-nitro-1-phenyl-1H-indazole (0.140 g, 0.585 mmol), ammonium chloride (0.016 g, 0.293 mmol) in 4:1 v/v EtOH/water (5 mL) was treated with iron (0.327 g, 5.85 mmol) and refluxed for 2 hours. The mixture was concentrated and the residue taken in EtOAc/water, filtered through glass fiber filter paper and concentrated again to provide 1-phenyl-1H-indazol-4-amine (0.071 g, 58% yield) as a beige solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[CH:6]=O.[CH3:13][O:14][CH:15]([O:18][CH3:19])[CH2:16][NH2:17]>C1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[CH:6]=[N:17][CH2:16][CH:15]([O:18][CH3:19])[O:14][CH3:13]
Reactant: COc1ccc(C=O)cc1OC
Reactant: COC(CN)OC
Solvent: c1ccccc1
Product: COc1ccc(C=NCC(OC)OC)cc1OC
Yield: 99 %

Procedure:
3,4-Dimethoxybenzaldehyde (12.20 g, 73.42 mmol) was dissolved in benzene (200 mL) and aminoacetaldehyde dimethyl acetal (12.0 mL, 11.7 g, 111 mmol) was added. The mixture was stirred at reflux for 4 h using a Dean-Stark trap. The reaction mixture was then concentrated and dissolved in CHCl3 (250 mL). The solution was washed with water (4×150 mL) and brine (150 mL), dried (Na2SO4) and concentrated, and the last traces of solvent were removed under vacuum to provide the imine (18.41 g, 99.1%) as a light yellow solid: mp 50-52° C. 1H NMR (300 MHz, CDCl3) δ 8.18 (s, 1H), 7.42 (s, 1H), 7.15 (d, J=8.4 Hz, 1H), 6.86 (d, J=8.4 Hz, 1H), 4.65 (t, J=5.1 Hz, 1H), 3.92 (s, 3H), 3.90 (s, 3H), 3.74 (d, J=5.1 Hz, 2H), 3.40 (s, 6H).
Reaction SMILES: Cl.[NH:2]1[CH2:5][CH:4]([C:6]2[CH:15]=[CH:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[N:7]=2)[CH2:3]1.C([O-])([O-])=O.[Cs+].[Cs+].[Br:22][C:23]1[C:24](F)=[N:25][CH:26]=[CH:27][CH:28]=1>CN(C=O)C.O>[Br:22][C:23]1[C:24]([N:2]2[CH2:3][CH:4]([C:6]3[CH:15]=[CH:14][C:13]4[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=4)[N:7]=3)[CH2:5]2)=[N:25][CH:26]=[CH:27][CH:28]=1
Reactant: Fc1ncccc1Br
Reactant: c1ccc2nc(C3CNC3)ccc2c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: Brc1cccnc1N1CC(c2ccc3ccccc3n2)C1
Temperature: 90 °C
Yield: 56.8 %

Procedure:
To a solution of 2-azetidin-3-yl-quinoline hydrochloride (1.70 g, 7.75 mmol) in DMF (30 mL) at room temperature was added Cs2CO3 (5.2 g, 16 mmol) and 3-bromo-2-fluoro-pyridine (1.5 g, 9.0 mmol). The reaction mixture was heated to 90° C. overnight and then diluted with water (60 mL) and extracted with EtOAc (2×50 mL). The combined organic extracts were washed with water (60 mL) and brine (60 mL), dried over Na2SO4, and filtered. The filtrate was evaporated in vacuo and the residue was purified by flash column chromatography on silica gel (5% to 30% EtOAc in hexanes) to give the title product (1.50 g, 4.4 mmol, 58% yield) as a white solid.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH3:23])[C:13](=[O:22])[N:14]([C:15]4[C:16]([CH3:21])=[N:17][N:18]([CH3:20])[CH:19]=4)[C:5]=3[C:4]=2[CH:3]=1.[F:24][C:25]1[C:26]([O:34][CH3:35])=[N:27][CH:28]=[C:29](B(O)O)[CH:30]=1>>[CH3:20][N:18]1[CH:19]=[C:15]([N:14]2[C:5]3[C:4]4[CH:3]=[C:2]([C:29]5[CH:28]=[N:27][C:26]([O:34][CH3:35])=[C:25]([F:24])[CH:30]=5)[CH:11]=[CH:10][C:9]=4[N:8]=[CH:7][C:6]=3[N:12]([CH3:23])[C:13]2=[O:22])[C:16]([CH3:21])=[N:17]1
Reactant: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(Br)cc3c21
Reactant: COc1ncc(B(O)O)cc1F
Product: COc1ncc(-c2ccc3ncc4c(c3c2)n(-c2cn(C)nc2C)c(=O)n4C)cc1F

Procedure:
The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A, 40 mg, 0.105 mmol) and 3-fluoro-2-methoxypyridine-5-boronic acid (Apollo Scientific, Cheshire, United Kingdom, 21 mg, 0.123 mmol) to give the title compound as a pink solid. (HPLC: tR 2.70 min (Method A); M+H=419 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 8.97 (s, 1H), 8.18-8.05 (m, 3H), 7.96-7.89 (m, 1H), 7.81-7.74 (m, 1H), 7.49 (s, 1H), 3.99 (s, 3H), 3.92 (s, 3H), 3.59 (s, 3H), 1.98 (s, 3H))
Reaction SMILES: N([O-])=O.[Na+].N[C:6]1[C:14]([Cl:15])=[CH:13][CH:12]=[CH:11][C:7]=1[C:8]([OH:10])=[O:9].[I-:16].[K+]>O.CS(C)=O.OS(O)(=O)=O>[Cl:15][C:14]1[C:6]([I:16])=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]([OH:10])=[O:9]
Reactant: [I-]
Reactant: Nc1c(Cl)cccc1C(=O)O
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: O=C(O)c1cccc(Cl)c1I
Temperature: 0 °C
Reaction time: 2 h
Yield: 67.1 %

Procedure:
A solution of sodium nitrite (4.82 g, 69.9 mmol) in water (25 mL) was added dropwise via addition funnel to a solution of 2-amino-3-chlorobenzoic acid (8.0 g, 46.6 mmol) in DMSO (25 mL) and 30% H2SO4 (75 mL) that had previously been cooled to 0° C. The mixture was stirred at 0° C. for 1 hour, at which time a solution of potassium iodide (19.3 g, 117 mmol) in water (25 mL) was added via addition funnel. The ice bath was removed, and the mixture was stirred for 2 hours. EtOAc (200 mL) was added, and the mixture was washed with 2N sodium sulfite (3×). The organic layer was then washed once with water and once with brine, dried over anhydrous MgSO4, and concentrated in vacuo to give 8.83 g of 3-chloro-2-iodobenzoic acid as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[CH:8][C:7]([C:10](=O)[CH2:11][C:12]#[N:13])=[CH:6][CH:5]=1.[C:16]1([NH:22][NH2:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(O)C>[CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[C:12]([NH2:13])[N:22]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[N:23]=2)=[CH:6][CH:5]=1
Reactant: COC(=O)c1ccc(C(=O)CC#N)cc1
Reactant: NNc1ccccc1
Solvent: CCO
Product: COC(=O)c1ccc(-c2cc(N)n(-c3ccccc3)n2)cc1

Procedure:
A mixture of methyl-4-(cyanoacetyl)benzoate (5.0 g, 24.6 mmol) and phenylhydrazine (2.42 ml, 24.6 mmol) in ethanol (100 ml) was heated to reflux for 20 hours. The mixture was cooled and the product was collected by filtration. The product was purified by trituration in hot acetonitrile, cooled and collected by filtration to give the product 4-(5-amino-1-phenyl-1H-pyrazole-3-yl)-benzoic acid methyl ester as a colorless solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[CH2:11][CH2:12][CH:13]2[C:18]([OH:20])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:21][N:22]([CH3:40])[C:23]1[CH:28]=[CH:27][C:26]([CH2:29][NH:30][C:31]2[CH:36]=[CH:35][C:34]([CH:37]([CH3:39])[CH3:38])=[CH:33][CH:32]=2)=[CH:25][CH:24]=1>>[CH2:1]([O:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[CH2:11][CH2:12][CH:13]2[C:18]([N:30]([CH2:29][C:26]1[CH:25]=[CH:24][C:23]([N:22]([CH3:40])[CH3:21])=[CH:28][CH:27]=1)[C:31]1[CH:32]=[CH:33][C:34]([CH:37]([CH3:39])[CH3:38])=[CH:35][CH:36]=1)=[O:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)c1ccc(NCc2ccc(N(C)C)cc2)cc1
Reactant: O=C(O)C1CCc2c(OCc3ccccc3)cccc21
Product: CC(C)c1ccc(N(Cc2ccc(N(C)C)cc2)C(=O)C2CCc3c(OCc4ccccc4)cccc32)cc1
Yield: 110.9 %

Procedure:
By the reaction and treatment in the same manner as in Example 12 using 4-benzyloxyindan-1-carboxylic acid (0.7 g) and [(4-dimethylaminophenyl)methyl](4-isopropylphenyl)amine (0.7 g) as starting materials, 4-benzyloxy-N-[(4-dimethylaminophenyl)methyl]-N-(4-isopropylphenyl)indan-1-carboxamide (1.5 g) was obtained.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3](/[CH:7]=[CH:8]/[C:9]([OH:11])=O)[CH:2]=1.Br.[OH:13][C:14]1[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=1)[CH2:17][CH2:18][NH2:19]>ClCCl.C(N(CC)CC)C.C(Cl)(=O)C(C)(C)C>[OH:13][C:14]1[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=1)[CH2:17][CH2:18][NH:19][C:9](=[O:11])/[CH:8]=[CH:7]/[C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1
Reactant: NCCc1cccc(O)c1
Reactant: O=C(O)/C=C/c1cccnc1
Agent: Br
Agent: CC(C)(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(/C=C/c1cccnc1)NCCc1cccc(O)c1
Yield: 78.1 %

Procedure:
To a solution of trans-3-(3-pyridyl)acrylic acid (179 g) in dichloromethane (4.8 L), triethylamine (584 ml) and pivaloyl chloride (148 ml) were sequentially added under ice-cooling and stirring and stirred for 15 minutes. Subsequently, 3-hydroxyphenethylamine hydrobromide (263 g) was added at the same temperature and stirred for 2 hours. After the solvent was distilled out under reduced pressure, water was added to the residue and the precipitated crystal was filtered, washed with water and recrystallized in ethanol to yield the titled compound (251.4 g, 78%).