Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][NH:13][C:12](=[O:16])[CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].Br[CH2:18][CH2:19][CH:20]=[CH2:21]>CN(C)C=O.O1CCCC1>[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][N:13]([CH2:21][CH2:20][CH:19]=[CH2:18])[C:12](=[O:16])[CH2:11]1)=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: CC(C)(C)OC(=O)N1CCNC(=O)C1
Reactant: C=CCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: C=CCCN1CCN(C(=O)OC(C)(C)C)CC1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 85.3 %

Procedure:
Sodium hydride (60% dispersion in mineral oil, 42 mg, 1.05 mmol) was added at room temperature to a solution of 3-oxo-piperazine-1-carboxylic acid tert-butyl ester (200 mg, 1.00 mmol) in N,N-dimethylformamide (4 ml), then after 10 min a solution of 4-bromo-1-butene (148 mg, 1.10 mmol) in tetrahydrofuran (1 ml) was added dropwise. The reaction mixture was stirred for 3 h at room temperature, then another portion of 4-bromo-1-butene (40 mg, 0.30 mmol) was added dropwise, and the reaction mixture was heated at 50° C. for 18 h. After cooling, the reaction mixture was partitioned between water and heptane/ethyl acetate 1:1. The organic layer was washed with brine, dried (MgSO4), and evaporated. Chromatography (SiO2; heptane/ethyl acetate 1:1) afforded the title compound (217 mg, 81%). Colorless oil, MS (ISP)=255.2 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:8](=[O:23])[CH2:9][CH:10]2[CH2:15][CH2:14][N:13](CC3C=CC=CC=3)[CH2:12][CH2:11]2)[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[Na+].[Na+].ClC(Cl)Cl.Cl[C:35]([O:37][CH2:38][CH3:39])=[O:36]>O>[CH3:1][C:2]1[CH:3]=[C:4]([C:8](=[O:23])[CH2:9][CH:10]2[CH2:11][CH2:12][N:13]([C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH2:14][CH2:15]2)[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cccc(C(=O)CC2CCN(Cc3ccccc3)CC2)c1
Reactant: CCOC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O
Product: CCOC(=O)N1CCC(CC(=O)c2cccc(C)c2)CC1
Reaction time: 8 h
Yield: 91 %

Procedure:
To a stirred mixture of 20.9 parts of 1-(3-methylphenyl)-2-[1-(phenylmethyl)-4-piperidinyl]ethanone, 0.75 parts of sodium carbonate and 150 parts of trichloromethane are added dropwise 8.1 parts of ethyl chloroformate. Upon completion, stirring is continued overnight at room temperature. Water is added to the reaction mixture and the layers are separated. The aqueous phase is extracted with trichloromethane. The combined organic phases are washed with water, dried, filtered and evaporated. The residue is purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (95:5 by volume) as eluent. The pure fractions are collected and the eluent is evaporated, yielding 18 parts (91%) of ethyl 4-[2-(3-methylphenyl)-2-oxoethyl]-1-piperidinecarboxylate as an oily residue.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([C:15]#[N:16])=[CH:11][CH:12]=[CH:13][CH:14]=2)=[CH:5][CH:4]=1)=[O:2].[CH3:17][Mg]Br.Cl>O1CCCC1>[OH:2][CH:1]([C:3]1[CH:4]=[CH:5][C:6]([C:9]2[C:10]([C:15]#[N:16])=[CH:11][CH:12]=[CH:13][CH:14]=2)=[CH:7][CH:8]=1)[CH3:17]
Reactant: C[Mg]Br
Reactant: N#Cc1ccccc1-c1ccc(C=O)cc1
Agent: Cl
Solvent: C1CCOC1
Product: CC(O)c1ccc(-c2ccccc2C#N)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 93 %

Procedure:
To a solution of 4′-formylbiphenyl-2-carbonitrile (10.00 g) in tetrahydrofuran (100 mL) was slowly added dropwise a 1 M solution (50 mL) of methylmagnesium bromide in tetrahydrofuran at 0° C., and the mixture was stirred at room temperature for 2 hr. The reaction mixture was poured into 1 M hydrochloric acid (60 mL), and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a pale-yellow oil (10.03 g, 93%).
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([CH:23]=[CH:24][CH:25]=1)[CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][C:21]#[N:22])=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N-:26]=[N+:27]=[N-:28].[Na+].[Cl-].[NH4+]>CN(C)C=O.C(OCC)(=O)C>[O:1]([C:8]1[CH:9]=[C:10]([CH:23]=[CH:24][CH:25]=1)[CH2:11][O:12][C:13]1[CH:14]=[CH:15][C:16]([CH2:19][CH2:20][C:21]2[NH:28][N:27]=[N:26][N:22]=2)=[CH:17][CH:18]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [N-]=[N+]=[N-]
Reactant: N#CCCc1ccc(OCc2cccc(Oc3ccccc3)c2)cc1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: c1ccc(Oc2cccc(COc3ccc(CCc4nnn[nH]4)cc3)c2)cc1
Yield: 42.4 %

Procedure:
A solution of 3-(4-((3-phenoxybenzyl)oxy)phenyl)propanenitrile (0.5 g, 1.52 mmol), sodium azide (0.49 g, 7.54 mmol) and ammonium chloride (0.41 g, 7.66 mmol) in N,N-dimethylformamide (20 ml) was stirred at 110° C. for 28 hrs. The reaction solution was diluted with ethyl acetate, washed successively with aqueous citric acid solution, water and aqueous sodium chloride solution, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained residue was subjected to silica gel chromatography (ethyl acetate:hexane=2:3-2:1) to give an oil, which was crystallized from ethyl acetate-tetrahydrofuran to give the title compound (0.24 g, 43%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:31]=[CH:30][C:6]([CH2:7][NH:8][C:9]([C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[C:21]([C:23]4[O:24][C:25]([CH3:28])=[N:26][N:27]=4)[CH:20]=[CH:19][C:18]=3[CH3:29])=[CH:13][CH:12]=2)=[O:10])=[CH:5][CH:4]=1.I[CH3:33]>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]([CH3:33])[C:9]([C:11]2[CH:12]=[CH:13][C:14]([C:17]3[CH:22]=[C:21]([C:23]4[O:24][C:25]([CH3:28])=[N:26][N:27]=4)[CH:20]=[CH:19][C:18]=3[CH3:29])=[CH:15][CH:16]=2)=[O:10])=[CH:30][CH:31]=1
Reactant: CI
Reactant: COc1ccc(CNC(=O)c2ccc(-c3cc(-c4nnc(C)o4)ccc3C)cc2)cc1
Product: COc1ccc(CN(C)C(=O)c2ccc(-c3cc(-c4nnc(C)o4)ccc3C)cc2)cc1

Procedure:
N-(4-Methoxybenzyl)-N-methyl-2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxamide was prepared from N-(4-methoxybenzyl)-2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxamide and iodomethane using method L. NMR; δH [2H6]—DMSO 7.89,(1H. d), 7.75,(1H, s), 7.55-7.47,(5H, m), 7.30,(1H, m), 7.13,(1H, m), 6.94,(2H, d), 4.62-4.46,(2H, m), 3.74,(3H, s), 2.85,(3H, b), 2.55,(3H, s), 2.31,(3H, s). LCMS; retention time 3.46 min, MH+ 428.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-])=[O:20])=[CH:15][CH:14]=2)=[CH:11][CH:10]=[N:9]1.[C:22]1([CH3:31])[CH:27]=[CH:26][C:25]([CH2:28]C#N)=[CH:24][CH:23]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]2[CH:18]=[CH:17][C:16]3=[N:19][O:20][C:31]([C:22]4[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=4)=[C:15]3[CH:14]=2)=[CH:11][CH:10]=[N:9]1
Reactant: O=[N+]([O-])c1ccc(-c2ccnn2-c2ccccc2Cl)cc1
Reactant: Cc1ccc(CC#N)cc1
Product: Cc1ccc(-c2onc3ccc(-c4ccnn4-c4ccccc4Cl)cc23)cc1

Procedure:
The title compound, light green solid (39 mg, 30%), MS (ISP) m/z=386.2 [(M+H)+], mp 176° C., was prepared in accordance with the general method of example 1 from 1-(2-chloro-phenyl)-5-(4-nitro-phenyl)-1H-pyrazole (intermediate L) (100 mg, 353 μmol) and commercially available 2-(p-tolyl)-acetonitrile.
Reaction SMILES: FC(F)(F)C(O)=O.[F:8][C:9]1[C:21]([CH:22]=[CH2:23])=[C:20]([F:24])[CH:19]=[CH:18][C:10]=1[C:11]([O:13]C(C)(C)C)=[O:12]>ClCCl>[F:8][C:9]1[C:21]([CH:22]=[CH2:23])=[C:20]([F:24])[CH:19]=[CH:18][C:10]=1[C:11]([OH:13])=[O:12]
Reactant: C=Cc1c(F)ccc(C(=O)OC(C)(C)C)c1F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C=Cc1c(F)ccc(C(=O)O)c1F
Reaction time: 5 h
Yield: 94.6 %

Procedure:
A 4.27 ml portion of trifluoroacetic acid was added to 30 ml of dichloromethane solution containing 1.33 g of tert-butyl 2,4-difluoro-3-vinylbenzoate and stirred for 5 hours. After evaporation of the solvent, appropriate amounts of purified water and saturated sodium bicarbonate aqueous solution were added thereto and the water layer was washed with diethyl ether. The water layer was adjusted to pH 1 with 1 M hydrochloric acid aqueous solution, extracted with diethyl ether and then dried with anhydrous magnesium sulfate. After concentration, 964 mg (95%) of 2,4-difluoro-3-vinylbenzoic acid (Reference Example 6-1) was obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:17]3[C:12](=[N:13][CH:14]=[C:15]([CH2:18][C:19]4[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=4)[CH:16]=3)[C:11]([OH:26])=[C:10]([C:27](OCC)=[O:28])[C:9]2=[O:32])=[CH:4][CH:3]=1.[NH2:33][CH2:34][CH2:35][OH:36]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:17]3[C:12](=[N:13][CH:14]=[C:15]([CH2:18][C:19]4[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=4)[CH:16]=3)[C:11]([OH:26])=[C:10]([C:27]([NH:33][CH2:34][CH2:35][OH:36])=[O:28])[C:9]2=[O:32])=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(-c2ccc(F)cc2)c1=O
Reactant: NCCO
Product: O=C(NCCO)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(-c2ccc(F)cc2)c1=O
Yield: 87 %

Procedure:
In a similar manner to that described in example 196, from ethyl 1-(4-fluorophenyl)-7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate (26 mg, 0.0596 mmol) and 2-aminoethanol (0.05 mL), was prepared 1-(4-fluorophenyl)-7-[(4-fluorophenyl)methyl]-4-hydroxy-N-(2-hydroxyethyl)-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxamide (24 mg, 87% yield) as a white solid. 1H NMR (CDCl3) δ 10.14 (s, 1 H), 8.50 (s, 1 H), 7.29-7.24 (m, 2 H), 7.20-7.16 (m, 2 H), 7.01-6.90 (m, 5 H), 6.71 (s, 1 H), 3.93 (s, 2 H), 3.76-3.73 (m, 2 H), 3.59-3.73 (m, 2 H); HRMS m/z calcd for C24H20F2N3O4: 452.1422. Found: 452.1424.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6](=[O:22])[N:7]3[CH2:14][CH2:13][C:12](=[CH:15][C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[C:8]3=[N:9][C:10]=2[CH:11]=1.[C:23]1(=[O:33])[O:28][C:26](=[O:27])[C:25]2=[CH:29][CH:30]=[CH:31][CH:32]=[C:24]12>O1CCCC1>[CH:15](=[C:12]1[C:8]2=[N:9][C:10]3[CH:11]=[C:2]([NH:1][C:23]([C:24]4[CH:32]=[CH:31][CH:30]=[CH:29][C:25]=4[C:26]([OH:28])=[O:27])=[O:33])[CH:3]=[CH:4][C:5]=3[C:6](=[O:22])[N:7]2[CH2:14][CH2:13]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Nc1ccc2c(=O)n3c(nc2c1)C(=Cc1ccccc1)CC3
Reactant: O=C1OC(=O)c2ccccc21
Solvent: C1CCOC1
Product: O=C(O)c1ccccc1C(=O)Nc1ccc2c(=O)n3c(nc2c1)C(=Cc1ccccc1)CC3
Reaction time: 14 h
Yield: 52.9 %

Procedure:
6-amino-3-benzylidene-1,2,3,9-tetrahydro-pyrrolo[2,1-b]quinazoline-9-one (2 g) was reacted with phthalic anhydride (4.6 g) in tetrahydrofuran (150 ml) under stirring at the reflux temperature for 14 hours. After cooling the precipitate was filtered and washed with tetrahydrofuran and then with water to give 1.6 g of 2-[N-(3-benzylidene-9-oxo-1,2,3,9-tetrahydro-pyrrolo[2,1-b]quinazolin-6-yl)-aminocarbonyl]-benzoic acid, m.p. 302°-308° C.,
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[CH:5][N:4]([CH3:7])[N:3]=1.C[O:9][C:10]([C:12]1[CH:22]=[C:21]([OH:23])[C:15]2[CH2:16][C:17]([CH3:20])([CH3:19])[O:18][C:14]=2[CH:13]=1)=O>>[CH3:7][N:4]1[CH:5]=[CH:6][C:2]([NH:1][C:10]([C:12]2[CH:22]=[C:21]([OH:23])[C:15]3[CH2:16][C:17]([CH3:20])([CH3:19])[O:18][C:14]=3[CH:13]=2)=[O:9])=[N:3]1
Reactant: Cn1ccc(N)n1
Reactant: COC(=O)c1cc(O)c2c(c1)OC(C)(C)C2
Product: Cn1ccc(NC(=O)c2cc(O)c3c(c2)OC(C)(C)C3)n1

Procedure:
The title compound was prepared in a similar manner as described for Example 1, from 3-amino-1-methylpyrazole (201 mg, 2.07 mmol) and 4-hydroxy-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid methyl ester (3e) (45 mg, 0.22 mmol) to give a white solid (28 mg, 48% yield). 1H NMR (400 MHz, CDCl3) δ 8.53 (s, 1 H) 7.30 (d, J=1.77 Hz, 1 H) 7.05-7.12 (m, 1 H) 7.00 (s, 1 H) 6.80 (d, J=2.02 Hz, 1 H) 3.81 (s, 3 H) 3.00 (s, 2 H) 1.50 (s, 6 H); LCMS for C15H17N3O3 m/z 288.10 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([CH2:9][CH2:10][CH2:11][CH3:12])[NH:5][C:6](=[O:8])[CH:7]=1.[OH-].[Na+].[Cl-].[C:16]1([N+:22]#[N:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.NC1C=CC=CC=1>O>[NH2:1][C:2]1[N:3]=[C:4]([CH2:9][CH2:10][CH2:11][CH3:12])[NH:5][C:6](=[O:8])[C:7]=1[N:23]=[N:22][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CCCCc1nc(N)cc(=O)[nH]1
Reactant: N#[N+]c1ccccc1
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: Nc1ccccc1
Solvent: O
Product: CCCCc1nc(N)c(N=Nc2ccccc2)c(=O)[nH]1

Procedure:
To a solution of 4-amino-2-butylpyrimid-6-one (7.65 g.) and sodium hydroxide (3.7 g.) in water (115 ml.) was added, at below 5° C, benzene diazonium chloride solution prepared (by the method well known in the art) from aniline (4.64 ml.), and the mixture was then heated to reflux for 1 hour. The pH was adjusted to 6 by the addition of aqueous sodium hydroxide solution, the product was filtered off, washed with water, dried and recrystallised from ethanol to give 4-amino-2-n-butyl-5-phenylazopyrimid-6-one (2.52 g.), m.p. 266°-270° C, pure enough for use in the next stage of the preparation.
Reaction SMILES: [NH2:1][C:2]1[C:11]([F:12])=[CH:10][C:9]([Br:13])=[CH:8][C:3]=1[C:4]([NH:6][CH3:7])=[O:5].Br.CN1CCCC1=O.C(N(CC)C(C)C)(C)C.[Cl:31][C:32]1[N:37]=[C:36](Cl)[C:35]([Cl:39])=[CH:34][N:33]=1>>[Br:13][C:9]1[CH:10]=[C:11]([F:12])[C:2]([NH:1][C:34]2[C:35]([Cl:39])=[CH:36][N:37]=[C:32]([Cl:31])[N:33]=2)=[C:3]([CH:8]=1)[C:4]([NH:6][CH3:7])=[O:5]
Reactant: CNC(=O)c1cc(Br)cc(F)c1N
Reactant: Clc1ncc(Cl)c(Cl)n1
Agent: Br
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)c1cc(Br)cc(F)c1Nc1nc(Cl)ncc1Cl
Temperature: 100 °C
Reaction time: 0.08 h
Yield: 50 %

Procedure:
2-Amino-5-bromo-3-fluoro-N-methyl-benzamide; hydrobromide (2.00 g, 6.10 mmol) was placed in N-methylpyrrolidinone (20.0 mL, 207 mmol) and N,N-diisopropylethylamine (3.19 mL, 18.3 mmol) was added. The reaction was stirred for 5 minutes and then 2,4,5-trichloro-pyrimidine (3.50 mL, 30.5 mmol) was added. The reaction was heated at 100° C. for 24 hours and then concentrated under reduced pressure. The residue was taken up in DCM (100 mL) and washed twice with water (100 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. Purification by silica gel chromatography using a gradient of 0-40% EtOAc/hex as the eluting solvent to obtain 5-bromo-2-(2,5-dichloro-pyrimidin-4-ylamino)-3-fluoro-N-methyl-benzamide as a tan solid (1.19 g, 50%). m.p.=246-249° C.; LCMS (m/e) 393 (M+H); 1H-NMR (d6-DMSO, 400 MHz) δ 9.73 (s, 1H), 8.68-8.57 (m, 1H), 8.43 (s, 1H), 7.87 (d, 1H, J=9.6 Hz), 7.66 (s, 1H), 2.69 (d, 3H, J=3.9 Hz); 19F-NMR (d6-DMSO, 400 MHz) δ −113.
Reaction SMILES: [C:1]([C:3]1[N:7]2[N:8]=[CH:9][CH:10]=[CH:11][C:6]2=[N:5][CH:4]=1)#[CH:2].[CH3:12][N:13]([CH3:41])[C@@H:14]1[CH2:18][CH2:17][N:16]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([NH:26][C:27](=[O:36])[C:28]3[CH:33]=[CH:32][C:31]([CH3:34])=[C:30](I)[CH:29]=3)=[CH:22][C:21]=2[C:37]([F:40])([F:39])[F:38])[CH2:15]1.C(N(CC)C(C)C)(C)C>CN(C=O)C.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.[Cu]I>[CH3:41][N:13]([CH3:12])[C@@H:14]1[CH2:18][CH2:17][N:16]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([NH:26][C:27](=[O:36])[C:28]3[CH:33]=[CH:32][C:31]([CH3:34])=[C:30]([C:2]#[C:1][C:3]4[N:7]5[N:8]=[CH:9][CH:10]=[CH:11][C:6]5=[N:5][CH:4]=4)[CH:29]=3)=[CH:22][C:21]=2[C:37]([F:40])([F:39])[F:38])[CH2:15]1
Reactant: Cc1ccc(C(=O)Nc2ccc(CN3CC[C@@H](N(C)C)C3)c(C(F)(F)F)c2)cc1I
Reactant: C#Cc1cnc2cccnn12
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(C(=O)Nc2ccc(CN3CC[C@@H](N(C)C)C3)c(C(F)(F)F)c2)cc1C#Cc1cnc2cccnn12
Temperature: 25 °C
Reaction time: 72 h
Yield: 13.1 %

Procedure:
A mixture of 3-ethynylimidazo[1,2-b]pyridazine (0.051 g, 0.34 mmol), 0.150 g (0.28 mmol) of (R)—N-(4-((3-(dimethylamino)pyrrolidin-1-yl)methyl)-3-(trifluoromethyl)phenyl)-3-iodo-4-methylbenzamide, 0.016 g (0.014 mmol) of Pd(PPh3)4, 0.004 g (0.021 mmol) of CuI, and 0.09 mL (0.51 mmol) of N,N-diisopropylethylamine in 3.5 mL of DMF was stirred at ambient temperature, under an atmosphere of N2, for 3 days (reaction pushed to completion with additional equivalents of reagents and heating to 80° C.). The reaction mixture was concentrated and the crude product was purified by silica gel chromatography (eluted with 0-10% MeOH/DCM; MeOH was pre-saturated with ammonia gas) to provide 0.020 g of product as a solid: 547 m/z (M+H).
Reaction SMILES: N[C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([N:12]([CH3:17])[S:13]([CH3:16])(=[O:15])=[O:14])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].N([O-])=[O:19].[Na+].O>Cl.CO>[OH:19][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([N:12]([CH3:17])[S:13]([CH3:16])(=[O:15])=[O:14])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: O=N[O-]
Reactant: COC(=O)c1cc(N)cc(N(C)S(C)(=O)=O)c1
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COC(=O)c1cc(O)cc(N(C)S(C)(=O)=O)c1
Temperature: 70 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
To a mixture of methyl 3-amino-5-[methyl(methylsulfonyl)amino]benzoate 1.29 g (5.0 mmol) in 2N hydrochloric acid (10 mL) and methanol (15 mL) was added sodium nitrite 0.759 g (11 mmol) under ice-cooling. Thereto was further added water (20 mL) and the mixture was stirred at 70° C. for 2 hours. The mixture was extracted twice with ethyl acetate (30 mL) and dried on magnesium sulfate and the solvent was evaporated to give 1.33 g (5.0 mmol) of the title compound (yield: 100%).
Reaction SMILES: C[O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7](=[O:17])[C:8]([C:14]([OH:16])=[O:15])=[CH:9][N:10]2[CH3:13])=[CH:5][CH:4]=1.Br>O>[OH:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7](=[O:17])[C:8]([C:14]([OH:16])=[O:15])=[CH:9][N:10]2[CH3:13])=[CH:5][CH:4]=1
Reactant: COc1ccc2c(=O)c(C(=O)O)cn(C)c2c1
Agent: Br
Solvent: O
Product: Cn1cc(C(=O)O)c(=O)c2ccc(O)cc21

Procedure:
5.83 g. (25 mmol) of 1,4-dihydro-7-methoxy-1-methyl-4-quinolone-3-carboxylic acid is refluxed for 4 hours with 65 ml. of hydrobromic acid. The mixture is poured into water; the solid product is filtered off and recrystallized from acetic acid.
Reaction SMILES: [CH3:1][N:2]([CH3:19])[CH2:3][CH2:4][N:5]1[CH2:11][CH2:10][CH2:9][C:8]2[NH:12][C:13]([CH:16]=O)=[C:14]([CH3:15])[C:7]=2[C:6]1=[O:18].[F:20][C:21]1[CH:22]=[C:23]2[C:27](=[CH:28][C:29]=1[NH:30][C:31](=[O:35])[CH2:32][O:33][CH3:34])[NH:26][C:25](=[O:36])[CH2:24]2>>[CH3:1][N:2]([CH3:19])[CH2:3][CH2:4][N:5]1[CH2:11][CH2:10][CH2:9][C:8]2[NH:12][C:13](/[CH:16]=[C:24]3\[C:25](=[O:36])[NH:26][C:27]4[C:23]\3=[CH:22][C:21]([F:20])=[C:29]([NH:30][C:31](=[O:35])[CH2:32][O:33][CH3:34])[CH:28]=4)=[C:14]([CH3:15])[C:7]=2[C:6]1=[O:18]
Reactant: COCC(=O)Nc1cc2c(cc1F)CC(=O)N2
Reactant: Cc1c(C=O)[nH]c2c1C(=O)N(CCN(C)C)CCC2
Product: COCC(=O)Nc1cc2c(cc1F)/C(=C/c1[nH]c3c(c1C)C(=O)N(CCN(C)C)CCC3)C(=O)N2
Yield: 76.5 %

Procedure:
The title compound was prepared under the same conditions as described in step 4 of Example 23 with 5-(2-dimethylamino-ethyl)-3-methyl-4-oxo-1,4,5,6,7,8-hexahydro-pyrrolo[3,2-c]azepine-2-carbaldehyde 23c obtained from step 3 of Example 23 and N-(5-fluoro-2-oxo-2,3-dihydro-1H-indol-6-yl)-2-methoxy-acetamide 7a obtained from step 1 of Example 7 as starting materials to obtain (Z)—N-{3-[5-(2-dimethylamino-ethyl)-3-methyl-4-oxo-1,4,5,6,7,8-hexahydro-pyrrolo[3,2-c]azepin-2-ylmethylene]-5-fluoro-2-oxo-2,3-dihydro-1H-indol-6-yl}-2-methoxy-acetamide 39 (75 mg, yield 76.5%) as a brown solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:14])=[C:6]([CH2:8][C@@H:9]([N:11]=[N+]=[N-])[CH3:10])[CH:7]=1>CCOC(C)=O.[Pd]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:14])=[C:6]([CH2:8][C@@H:9]([NH2:11])[CH3:10])[CH:7]=1
Reactant: Cc1ccc(Cl)cc1C[C@H](C)N=[N+]=[N-]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Cc1ccc(Cl)cc1C[C@H](C)N
Yield: 48 %

Procedure:
To a solution of (1S)-2-(5-chloro-2-methylphenyl)-1-methylethyl azide (500 mg, 2.38 mmol) in 50 mL of EtOAc was added Pd/C (150 mg of 10% Pd) and the mixture was hydrogenated under hydrogen balloon for 20 min. The catalyst was removed by filtration through celite, then passed through silicagel plug eluting first with EtOAc (40 mL), then MeOH/EtOAc/NH4OH 20:75:5 (120 mL). The fraction with product was evaporated to give (1S)-2-(5-chloro-2-methylphenyl)-1-methylethylamine (210 mg, 48%) as pale oil. ESI-MS: m/z (MH+) 184.4. 1H NMR (300 MHz, CDCl3): δ 7.12 (s, 1H), 7.08 (s, 2H), 3.16 (m, 1H), 2.48-2.70 (m, 2H), 2.28 (s, 3H), 1.23 (s, 2H), 1.13 (d, J=6.21 Hz, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:20][CH:21]=[CH2:22])[CH2:9][C:10]([C:12]2[CH:13]=[CH:14][C:15](=[O:19])[N:16]([CH3:18])[CH:17]=2)=O)=[CH:4][CH:3]=1.Cl.[NH2:24][OH:25].C([O-])(O)=O.[Na+]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:20][CH:21]=[CH2:22])[CH2:9]/[C:10](/[C:12]2[CH:13]=[CH:14][C:15](=[O:19])[N:16]([CH3:18])[CH:17]=2)=[N:24]\[OH:25])=[CH:4][CH:3]=1
Reactant: NO
Reactant: C=CCC(CC(=O)c1ccc(=O)n(C)c1)c1ccc(Br)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: C=CCC(C/C(=N\O)c1ccc(=O)n(C)c1)c1ccc(Br)cc1

Procedure:
In analogy to example 151, step 3, 5-[3-(4-bromo-phenyl)-hex-5-enoyl]-1-methyl-1H-pyridin-2-one was reacted with hydroxylamine hydrochloride in the presence of NaHCO3 to give the title compound as a colorless solid, MS (ESI−): m/z=373.1 [M−H]−.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[CH2:5]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH2:13][CH3:14])[C:8]=1[C:15]1[CH:20]=[C:19]([S:21]([NH2:24])(=[O:23])=[O:22])[CH:18]=[CH:17][C:16]=1[CH3:25])[CH3:6].C(O)(=O)C.N([O-])=O.[Na+]>O>[CH2:13]([C:9]1[CH:10]=[C:11]([N+:1]([O-:4])=[O:2])[CH:12]=[C:7]([CH2:5][CH3:6])[C:8]=1[C:15]1[CH:20]=[C:19]([S:21]([NH2:24])(=[O:22])=[O:23])[CH:18]=[CH:17][C:16]=1[CH3:25])[CH3:14]
Reactant: CCc1cccc(CC)c1-c1cc(S(N)(=O)=O)ccc1C
Reactant: O=[N+]([O-])O
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CCc1cc([N+](=O)[O-])cc(CC)c1-c1cc(S(N)(=O)=O)ccc1C
Temperature: 0 °C
Yield: 36.2 %

Procedure:
To 13 ml of 70% nitric acid in 100 ml of water was added 15.17 g (50.0 mmol) of the -toluenesulfonate obtained in step A, followed by the addition of 100 ml of glacial acetic acid and 0.37 g (5.0 mmol) of sodium nitrite. The mixture was heated on a steam bath for 1.5 hrs, cooled, diluted with 250 g of ice, and the precipitate was collected to yield 8.82 g of crude product. The crude product was chromatographed on 300 g of silica gel with 5:1 and 3:1 hexane:ethyl acetate to yield 6.30 g (36.2%) of 2,6-diethyl-4-nitrophenyl-p-toluenesulfonamide. NMR (CDCl3):δ 1.10 (t, 6H), 2.5 (m, 7H), 6.5 (s, 1H), 7.2-7.7 (dd, 4H), 7.97 (s, 2H).
Reaction SMILES: C[O:2][C:3](=O)[CH:4]([F:12])[C:5]1([CH2:10][CH3:11])[O:9][CH2:8][CH2:7][O:6]1.Cl.[NH2:15][OH:16].CO[Na]>N1C=CC=CC=1>[CH2:10]([C:5]1([CH:4]([F:12])[C:3]([NH:15][OH:16])=[O:2])[O:9][CH2:8][CH2:7][O:6]1)[CH3:11]
Reactant: NO
Reactant: CCC1(C(F)C(=O)OC)OCCO1
Agent: CO[Na]
Agent: Cl
Solvent: c1ccncc1
Product: CCC1(C(F)C(=O)NO)OCCO1
Reaction time: 0.5 h
Yield: 33.3 %

Procedure:
A mixture of 2-(2-ethyl-[1,3]dioxolan-2-yl)fluoroacetic acid methyl ester (1.50 g, 7.80 mmol) and hydroxylamine hydrochloride (1.07 g, 15.6 mmol) were dissolved in pyridine (8 mL). MeONa (30% in MeOH, 3.94 mL, 15.6 mmol) was dropped slowly over 15 min. More pyridine (8 mL) was added. The mixture was stirred for 30 min, then filtered. AcOH (1 mL) was added to the filtrate. The mixture was stirred for 5 min, then the solvents were removed under reduced pressure. Purification by FC (MeOH/CH2Cl2 1:10) yielded the title compound (502 mg, 40%).