Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClC1C=C(C=C(C=O)N=1)C(OC)=O.[Cl:14][C:15]1[CH:16]=[C:17]([C:21]2[N:26]=[C:25]([C:27](O)=[O:28])[CH:24]=[C:23]([C:30]([O:32][CH3:33])=[O:31])[CH:22]=2)[CH:18]=[CH:19][CH:20]=1>>[Cl:14][C:15]1[CH:16]=[C:17]([C:21]2[CH:22]=[C:23]([CH:24]=[C:25]([CH:27]=[O:28])[N:26]=2)[C:30]([O:32][CH3:33])=[O:31])[CH:18]=[CH:19][CH:20]=1
Reactant: COC(=O)c1cc(C(=O)O)nc(-c2cccc(Cl)c2)c1
Agent: COC(=O)c1cc(Cl)nc(C=O)c1
Product: COC(=O)c1cc(C=O)nc(-c2cccc(Cl)c2)c1

Procedure:
methyl 2-(3-chlorophenyl)-6-formylisonicotinate was synthesized from methyl 2-chloro-6-formylisonicotinate and converted to 6-(3-chlorophenyl)-4-(methoxycarbonyl)picolinic acid following the general procedure as described herein.
Reaction SMILES: Cl[C:2]1[C:3]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)=[CH:11][CH:10]=2)=[N:4][CH:5]=[CH:6][N:7]=1.[CH3:22][C:23]1[CH:28]=[C:27](B(O)O)[CH:26]=[CH:25][N:24]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>COCCOC.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:22][C:23]1[CH:28]=[C:27]([C:2]2[C:3]([O:8][C:9]3[CH:14]=[CH:13][C:12]([NH:15][C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=4)=[CH:11][CH:10]=3)=[N:4][CH:5]=[CH:6][N:7]=2)[CH:26]=[CH:25][N:24]=1
Reactant: Clc1nccnc1Oc1ccc(Nc2ccccn2)cc1
Reactant: Cc1cc(B(O)O)ccn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: COCCOC
Product: Cc1cc(-c2nccnc2Oc2ccc(Nc3ccccn3)cc2)ccn1
Reaction time: 8 h

Procedure:
To a 50 mL round-bottomed flask was added N-(4-(3-chloropyrazin-2-yloxy)phenyl)pyridin-2-amine (0.2890 g, 0.967 mmol), 2-methylpyridin-4-ylboronic acid (0.1684 g, 1.20 mmol), and trans-dichlorobis(triphenylphosphine)palladium (II) (0.0355 g, 0.0484 mmol) in DME. An aqueous solution of cesium carbonate (0.213 ml, 2.61 mmol) was added and the temperature was brought to 80° C. to stir overnight. The crude product was adsorbed onto a plug of silica gel and chromatographed to provide N-(4-(3-(2-methylpyridin-4-yl)pyrazin-2-yloxy)phenyl)pyridin-2-amine. MS (ESI, pos. ion) m/z: 356.1. IC50 (uM)=0.033.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[N:5]=[C:4]2[S:12][CH:13]=[C:14]([CH3:15])[C:3]=12.[Cl:16][CH2:17][C:18](Cl)=[O:19]>>[Cl:16][CH2:17][C:18]([NH:1][C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[N:5]=[C:4]2[S:12][CH:13]=[C:14]([CH3:15])[C:3]=12)=[O:19]
Reactant: Cc1csc2nc3c(c(N)c12)CCCC3
Reactant: O=C(Cl)CCl
Product: Cc1csc2nc3c(c(NC(=O)CCl)c12)CCCC3
Temperature: 25 °C

Procedure:
To 12.7 g of 4-amino-3-methyl-5,6,7,8-tetrahydrothieno[2,3-b]quinoline, was added 40 ml of chloroacetyl chloride, and the mixture was refluxed for 40 minutes. The oil bath was removed and the reaction mixture was added with 50 ml of 1,2-dichloroethane and cooled to 25° C. The precipitated crystals were collected by filtration and washed with 1,2-dichloroethane. The crystals were suspended in a mixed solvent of 250 ml of chloroform, 55 ml of water and 60 ml of ethanol, and 4.3 ml of concentrated ammonia water was added thereto. The suspension was heated to 40° C. to dissolve substantially all the crystals.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([C:12]2[C:16]3[S:17][CH:18]=[CH:19][C:15]=3[O:14][N:13]=2)[CH:9]=[CH:10][CH:11]=1.ClCCCOC1C=C(C2C3SC=CC=3ON=2)C=CC=1.O.Cl.[NH2:41][CH2:42][C:43]1[CH:48]=[CH:47][C:46]([S:49]([NH2:52])(=[O:51])=[O:50])=[CH:45][CH:44]=1.C(=O)([O-])[O-].[K+].[K+]>>[O:14]1[C:15]2[CH:19]=[CH:18][S:17][C:16]=2[C:12]([C:8]2[CH:7]=[C:6]([CH:11]=[CH:10][CH:9]=2)[O:5][CH2:4][CH2:3][CH2:2][NH:41][CH2:42][C:43]2[CH:44]=[CH:45][C:46]([S:49]([NH2:52])(=[O:50])=[O:51])=[CH:47][CH:48]=2)=[N:13]1
Reactant: BrCCCOc1cccc(-c2noc3ccsc23)c1
Reactant: NCc1ccc(S(N)(=O)=O)cc1
Agent: Cl
Agent: ClCCCOc1cccc(-c2noc3ccsc23)c1
Agent: O=C([O-])[O-]
Solvent: O
Product: NS(=O)(=O)c1ccc(CNCCCOc2cccc(-c3noc4ccsc34)c2)cc1
Yield: 27 %

Procedure:
The title compound is prepared from a mixture of 3-[3-(3-bromo-propoxy)-phenyl]-thieno[2,3-d]isoxazole, 3-[3-(3-chloro-propoxy)-phenyl]-thieno[2,3-d]isoxazole, 4-(aminomethyl) benzenesulfonamide hydrochloride monohydrate and potassium carbonate essentially as described above in example 4 except that the column is eluted using a graded solvent mixture of dichloromethane:methanol (95:5). Combine the appropriate fractions and concentrate to give the title compound (0.12 g, 27% Yield) as a solid. Purity by LC/MS (APCI)=100% area, [M+H]+=444 m/e.
Reaction SMILES: [C:1]1(=[CH:6][C:7]#[N:8])[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH3:9]>CO>[NH2:9][C:1]1([CH2:6][C:7]#[N:8])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: N#CC=C1CCCC1
Reactant: N
Solvent: CO
Product: N#CCC1(N)CCCC1

Procedure:
A solution of 15.91 g (0.15 mol) of cyclopentylideneacetonitrile in 170 ml of an aqueous ammonia solution (29%) and 57 ml of methanol was heated at 100° C. in a sealed tube for 24 h. The reaction mixture was concentrated, and the residue was chromatographed on silica gel eluting with a mixture of dichloromethane/methanol in the proportions 90/10 to afford 12.15 g of the product as a colorless oil.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:14]=[C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([N:22](S(C)(=O)=O)[S:23]([CH3:26])(=[O:25])=[O:24])=[CH:18][CH:17]=2)[N:12]=[CH:11][C:10]=1[CH2:31][C:32]([NH2:34])=[O:33])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl>CO.[OH-].[Na+].O>[CH2:1]([NH:8][C:9]1[CH:14]=[C:13]([NH:15][C:16]2[CH:17]=[CH:18][C:19]([NH:22][S:23]([CH3:26])(=[O:25])=[O:24])=[CH:20][CH:21]=2)[N:12]=[CH:11][C:10]=1[CH2:31][C:32]([NH2:34])=[O:33])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)N(c1ccc(Nc2cc(NCc3ccccc3)c(CC(N)=O)cn2)cc1)S(C)(=O)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CS(=O)(=O)Nc1ccc(Nc2cc(NCc3ccccc3)c(CC(N)=O)cn2)cc1
Temperature: 50 °C
Reaction time: 0.17 h
Yield: 98.6 %

Procedure:
30 mg of 4-(benzylamino)-6-({4-[bis(methylsulfonyl)amino]phenyl}amino)pyridine-3-carboxyamide (the compound of Example 300) was dissolved in 3 mL of methanol, to which 1 mL of 4 mol/L sodium hydroxide in water was added at room temperature, and stirred at 50° C. for 10 minutes. Under ice cooling, 2 mol/L hydrochloric acid in water was added to acidify the solution, extracted with chloroform, the extract was washed with water, and dried on anhydrous sodium sulfate. The solvent was evaporated to obtain 25 mg (99%) of the title compound as a slight yellow crystalline powder.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:9]=[C:8]([N+:10]([O-])=O)[CH:7]=[CH:6][C:5]=1[O:13][C:14]([F:17])([F:16])[F:15]>C(O)C>[CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:9]=[C:8]([NH2:10])[CH:7]=[CH:6][C:5]=1[O:13][C:14]([F:15])([F:17])[F:16]
Reactant: COC(=O)c1cc([N+](=O)[O-])ccc1OC(F)(F)F
Solvent: CCO
Product: COC(=O)c1cc(N)ccc1OC(F)(F)F
Temperature: 75 °C
Reaction time: 2 h
Yield: 75.2 %

Procedure:
5-Nitro-2-trifluoromethoxybenzoic acid methyl ester (5.69 g, 21.5 mmol) was dissolved in ethanol 99.9% (80 mL) and stannous (II) chloride dihydrate (24.2 g, 107 mmol) was added. The suspension was stirred on an oil-bath at 75° C. for 2 hours and concentrated in vacuo. Ethyl acetate (100 mL) and water (50 mL) was added and pH was adjusted to pH 8 with 4N sodium hydroxide (50 mL). The liquid was decanted from the precipitation. The precipitate was washed twice with ethyl acetate. The aqueous phase was extracted twice with ethyl acetate (60 mL). The combined organic phases were washed with a saturated sodium chloride solution (2×100 mL), dried (MgSO4) and concentrated in vacuo. Purification by column chromatography (120 g silica) using ethyl acetate and heptane (1:1) as eluent afforded 3.8 g of 5-amino-2-trifluoromethoxybenzoic acid methyl ester.
Reaction SMILES: [C:1]([C:3]1([NH:6][C:7](=[O:34])[C@H:8]([CH2:31][CH2:32][CH3:33])[NH:9][C@@H:10]([C:15]2[CH:20]=[CH:19][C:18](C3C=CC(S(C)(=O)=O)=CC=3)=[CH:17][CH:16]=2)[C:11]([F:14])([F:13])[F:12])[CH2:5][CH2:4]1)#[N:2].[F:35][C:36]1[CH:37]=[C:38](B(O)O)[CH:39]=[CH:40][C:41]=1[F:42].BrC1C=CC([C@H](N[C@H](C(NC2(C#N)CC2)=O)CCC)C(F)(F)F)=CC=1>C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].Cl[Pd]Cl>[C:1]([C:3]1([NH:6][C:7](=[O:34])[C@@H:8]([NH:9][C@@H:10]([C:15]2[CH:20]=[CH:19][C:18]([C:38]3[CH:39]=[CH:40][C:41]([F:42])=[C:36]([F:35])[CH:37]=3)=[CH:17][CH:16]=2)[C:11]([F:12])([F:14])[F:13])[CH2:31][CH2:32][CH3:33])[CH2:5][CH2:4]1)#[N:2]
Reactant: OB(O)c1ccc(F)c(F)c1
Reactant: CCC[C@H](N[C@@H](c1ccc(-c2ccc(S(C)(=O)=O)cc2)cc1)C(F)(F)F)C(=O)NC1(C#N)CC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CCC[C@H](N[C@@H](c1ccc(Br)cc1)C(F)(F)F)C(=O)NC1(C#N)CC1
Product: CCC[C@H](N[C@@H](c1ccc(-c2ccc(F)c(F)c2)cc1)C(F)(F)F)C(=O)NC1(C#N)CC1

Procedure:
The title compound was prepared in similar manner to that described for N1-(1-cyanocyclopropyl)-N2-{(1S)-2,2,2-trifluoro-1-[4′-(methylsulfonyl)-1,1′-biphenyl-4-yl]ethyl}-L-norvalinamide via Suzuki cross-coupling between 3,4-difluorophenylboronic acid and N2-[(1S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl]-N1-(1-cyanocyclopropyl)-L-norvalinamide in the presence of 1,1′-bis(diphenylphosphino)ferrocene]-dichloropalladium(II), dichloromethane complex.
Reaction SMILES: [C:1]([N:20]1[CH:24]=[C:23](I)[N:22]=[CH:21]1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH: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.CC[Mg+].[Br-].[CH2:30]([C:32]1[S:33][C:34]([CH2:39][CH3:40])=[CH:35][C:36]=1[CH:37]=[O:38])[CH3:31]>C(Cl)Cl.ClCl>[CH2:30]([C:32]1[S:33][C:34]([CH2:39][CH3:40])=[CH:35][C:36]=1[CH:37]([C:23]1[N:22]=[CH:21][N:20]([C:1]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:24]=1)[OH:38])[CH3:31]
Reactant: CCc1cc(C=O)c(CC)s1
Reactant: Ic1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: CC[Mg+]
Agent: ClCl
Agent: [Br-]
Solvent: ClCCl
Product: CCc1cc(C(O)c2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)c(CC)s1
Reaction time: 3 h

Procedure:
To a solution of N-trityl-4-iodo-imidazole (13.5 g, 31 mmol) in dry CH2Cl2 (75 mL) was added EtMgBr (10.0 mL, 3.0M in Et2O) and the solution was stirred for 3 hrs. Then a solution of 2,5-diethylthiophene-3-carboxaldehyde, D6, (5.0 g, 30 mmol) in CH2 Cl2 (20 mL) was added, and the reaction mixture was stirred at room temperature overnight. The reaction was quenched with NH4Cl (aq) and the mixture was transferred to a separatory funnel. The aqueous layer was extracted with a second portion of CH2Cl2. The extracts were combined and washed with a small portion of water, dried (Na2 SO4), and filtered. The solvent was evaporated in vacuo to give a thick syrup which was triturated with Et2O to give a solid which was recrystallized from EtOAc to give (2,5-diethylthien-3-yl)-1-trityl-imidazol-4-yl-methanol, E6. 1H NMR (CDCl3) supported the assigned structure. ##STR52##
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH:8]=[C:7]([CH3:10])[C:6]=2[CH:11]=1.[C:12](Cl)(=[O:16])[CH:13]([CH3:15])[CH3:14].[Cl-].[Al+3].[Cl-].[Cl-].O>[N+](C)([O-])=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:12](=[O:16])[CH:13]([CH3:15])[CH3:14])=[C:7]([CH3:10])[C:6]=2[CH:11]=1
Reactant: CC(C)C(=O)Cl
Reactant: Cc1coc2ccc(F)cc12
Agent: [Al+3]
Agent: [Cl-]
Solvent: C[N+](=O)[O-]
Solvent: O
Product: Cc1c(C(=O)C(C)C)oc2ccc(F)cc12
Temperature: 0 °C
Reaction time: 1 h
Yield: 65.9 %

Procedure:
To a solution of 5-fluoro-3-methyl-1-benzofuran (2.0 g) synthesized in Example A67(2) and isobutyryl chloride (1.56 g) in nitromethane (40 mL) was added aluminum chloride (anhydrous) (2.66 g) at 0° C., and the mixture was stirred at 0° C. for 1 hr, and at room temperature for 12 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated. The residue was subjected to silica gel column chromatography (hexane-ethyl acetate 100:0-90:10, v/v) to give the title compound (1.933 g, 66%) as a colorless oil.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH2:7]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:19]=[C:18]([F:20])[S:17][C:16]=2[CH2:21][O:22][C:23]2[C:28]([F:29])=[CH:27][C:26]([CH2:30][CH2:31][C:32](OCC)=[O:33])=[CH:25][C:24]=2[F:37])=[CH:11][CH:10]=1)[CH3:8]>>[CH2:7]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:19]=[C:18]([F:20])[S:17][C:16]=2[CH2:21][O:22][C:23]2[C:24]([F:37])=[CH:25][C:26]([CH2:30][CH2:31][CH2:32][OH:33])=[CH:27][C:28]=2[F:29])=[CH:11][CH:10]=1)[CH3:8]
Reactant: CCOC(=O)CCc1cc(F)c(OCc2sc(F)cc2-c2ccc(CC)cc2)c(F)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: CCc1ccc(-c2cc(F)sc2COc2c(F)cc(CCCO)cc2F)cc1

Procedure:
The title compound was prepared according to the procedure described in Example 223 by LAH reduction of ethyl 3-(4-((3-(4-ethylphenyl)-5-fluorothiophen-2-yl)methoxy)-3,5-difluoro phenyl)propanoate to give the desired product as off-white oil. 1HNMR (300 MHz, CD3OD) δ 7.37 (d, J=8.1 Hz, 2H), 7.26 (d, J=8.1 Hz, 2H), 6.81 (t, J=9.3 Hz, 1H), 6.63 (s, 2H), 5.01 (s, 2H), 3.58 (t, J=6.0 Hz, 2H), 2.63-2.74 (m, 4H), 1.77-1.87 (m, 2H), 1.28 (t, J=7.8 Hz, 3H). Mass spectrum (ESI, m/z): Calcd. for C22H21F3O2S, 219.1[M-C9H9F2O2]. found 219.1.
Reaction SMILES: [O-2].[Zn+2:2].[CH3:3][O:4][C:5]1[CH:13]=[CH:12][CH:11]=[CH:10][C:6]=1[C:7]([OH:9])=[O:8]>O>[CH3:3][O:4][C:5]1[CH:13]=[CH:12][CH:11]=[CH:10][C:6]=1[C:7]([O-:9])=[O:8].[Zn+2:2].[CH3:3][O:4][C:5]1[CH:13]=[CH:12][CH:11]=[CH:10][C:6]=1[C:7]([O-:9])=[O:8]
Reactant: COc1ccccc1C(=O)O
Agent: [O-2]
Agent: [Zn+2]
Solvent: O
Product: COc1ccccc1C(=O)[O-]
Yield: 70 %

Procedure:
Zinc o-methoxybenzoate was prepared by mixing 32.6 g of zinc oxide with 138 g of o-methoxybenzoic acid and 600 g of water and refluxing for 4 hours. After cooling in an ice bath, the solid was filtered off and dried in a vacuum oven at 25 mm Hg and 50° C. to yield 103 g of zinc o-methoxybenzoate. An elemental analysis gave 52.8% C, 3.95% H and 16.0% Zn (calculated: 52.26% C, 3.81% H and 17.8% Zn).
Reaction SMILES: [CH3:1][C:2](=[CH2:6])[CH2:3][Mg]Cl.O1CCCC1.[F:12][C:13]1[CH:14]=[C:15]([NH:25][C:26]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=2)=[O:27])[CH:16]=[CH:17][C:18]=1[C:19](N(OC)C)=[O:20].N1C=CC=CC=1C(O)=O>O>[F:12][C:13]1[CH:14]=[C:15]([NH:25][C:26]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=2)=[O:27])[CH:16]=[CH:17][C:18]=1[C:19](=[O:20])[CH2:3][C:2]([CH3:6])=[CH2:1]
Reactant: CON(C)C(=O)c1ccc(NC(=O)c2ccccn2)cc1F
Reactant: C=C(C)C[Mg]Cl
Agent: O=C(O)c1ccccn1
Solvent: O
Solvent: C1CCOC1
Product: C=C(C)CC(=O)c1ccc(NC(=O)c2ccccn2)cc1F
Reaction time: 3 h

Procedure:
9.89 ml of (2-methyl-2-propen-1-yl)magnesium chloride (0.50 M tetrahydrofuran solution) was added to a tetrahydrofuran (10 ml) solution of 500 mg of N-(3-fluoro-4-((methoxy(methyl)amino)carbonyl)phenyl)pyridine-2-carboxamide obtained in the same method as in Example 145 (step 3) or in accordance with the method or by combining it with an ordinary method but using pyridine-2-carboxylic acid, with cooling with ice. The reaction liquid was stirred for 3 hours with cooling with ice, and then water was poured into the reaction solution, extracted with ethyl acetate and dried with anhydrous sodium sulfate. The solvent was evaporated away under reduced pressure, and the resulting residue was purified through silica gel column chromatography (developing solvent: hexane/ethyl acetate=3/1) to obtain the entitled compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH2:6][C:5]2([CH3:14])[CH3:13].C(=O)([O-])[O-].[Cs+].[Cs+].[C:21]([O:27][CH2:28]I)(=[O:26])[C:22]([CH3:25])([CH3:24])[CH3:23].O>CN(C=O)C>[CH3:23][C:22]([CH3:25])([CH3:24])[C:21]([O:27][CH2:28][N:8]1[C:9]2[C:4](=[CH:3][C:2]([Br:1])=[CH:11][CH:10]=2)[C:5]([CH3:14])([CH3:13])[CH2:6][C:7]1=[O:12])=[O:26]
Reactant: CC1(C)CC(=O)Nc2ccc(Br)cc21
Reactant: CC(C)(C)C(=O)OCI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)C(=O)OCN1C(=O)CC(C)(C)c2cc(Br)ccc21
Temperature: 25 °C
Reaction time: 4 h

Procedure:
1.0 g of 6-bromo-3,4-dihydro-4,4-dimethylquinolin-2(1H)-one was dissolved in 10 ml of dry DMF, 3.85 g of cesium carbonate were added and 953 mg of iodomethyl pivalate were added dropwise while cooling with water, and the mixture was stirred at room temperature for 4 hours. The experiment was left to stand at room temperature overnight. Then a further 0.4 ml of iodomethyl pivalate was added at room temperature and the mixture was stirred at room temperature for a further 2 hours. (According to TLC and LC-MS, there is still reactant in the reaction solution). 50 ml of water were added, the mixture was extracted three times with 50 ml each time of ethyl acetate. The combined organic phases were dried over MgSO4, then concentrated under reduced pressure and purified on silica gel with the n-heptane/ethyl acetate solvent mixture as a linear gradient of 100% n-heptane=>100% ethyl acetate. This gave 700 mg of 6-bromo-4,4-dimethyl-2-oxo-3,4-dihydro-2H-quinolin-1-ylmethyl 2,2-dimethylpropionate.
Reaction SMILES: [CH2:1]([N:3]([CH2:16][CH:17]([OH:19])[CH3:18])[C:4]1[CH:15]=[CH:14][C:7]2=[N:8][N:9]=C(C)C(=O)[N:6]2[N:5]=1)[CH3:2]>Cl>[CH2:1]([N:3]([CH2:16][CH:17]([OH:19])[CH3:18])[C:4]1[N:5]=[N:6][C:7]([NH:8][NH2:9])=[CH:14][CH:15]=1)[CH3:2]
Reactant: CCN(CC(C)O)c1ccc2nnc(C)c(=O)n2n1
Agent: Cl
Product: CCN(CC(C)O)c1ccc(NN)nn1

Procedure:
A process according to claim 1 in which 7-[ethyl(2-hydroxypropyl)amino]-3-methyl-4-oxo-4H-pyridazino-[6,1-c] [1,2,4]triazine is hydrolyzed in dilute hydrochloric acid and the 3-[ethyl(2-hydroxypropyl)amino]-6-hydrazinopyridazine obtained is acylated with ethyl chlorocarbonate to give ethyl (6-[ethyl(2-hydroxypropyl)amino]-3-pyridazinyl)-hydrazinocarboxylate.
Reaction SMILES: Cl.FC1C=C(C=CC=1)CN1C=C(C2C3C(=NC=C(C4C=CC(C5CCNCC5)=CC=4)C=3)N(S(C3C=CC(C)=CC=3)(=O)=O)C=2)C=N1.[F:46][C:47]1[CH:48]=[C:49]([CH:92]=[CH:93][CH:94]=1)[CH2:50][N:51]1[C:55]([CH3:56])=[C:54]([C:57]2[C:65]3[C:60](=[N:61][CH:62]=[C:63]([C:66]4[CH:67]=[CH:68][C:69]([N:72]5[CH2:77][CH2:76][N:75]([CH2:78][C@@H:79]([OH:81])[CH3:80])[CH2:74][CH2:73]5)=[N:70][CH:71]=4)[CH:64]=3)[N:59](S(C3C=CC(C)=CC=3)(=O)=O)[CH:58]=2)[CH:53]=[N:52]1.[OH-].[Li+]>C1COCC1.CO.O>[F:46][C:47]1[CH:48]=[C:49]([CH:92]=[CH:93][CH:94]=1)[CH2:50][N:51]1[C:55]([CH3:56])=[C:54]([C:57]2[C:65]3[C:60](=[N:61][CH:62]=[C:63]([C:66]4[CH:67]=[CH:68][C:69]([N:72]5[CH2:77][CH2:76][N:75]([CH2:78][C@@H:79]([OH:81])[CH3:80])[CH2:74][CH2:73]5)=[N:70][CH:71]=4)[CH:64]=3)[NH:59][CH:58]=2)[CH:53]=[N:52]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3C)c3cc(-c4ccc(N5CCN(C[C@H](C)O)CC5)nc4)cnc32)cc1
Agent: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(C5CCNCC5)cc4)cnc32)cc1
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: Cc1c(-c2c[nH]c3ncc(-c4ccc(N5CCN(C[C@H](C)O)CC5)nc4)cc23)cnn1Cc1cccc(F)c1
Yield: 11 %

Procedure:
Using similar reaction conditions as described in step-iii of example-1, (S)-1-(4-(5-(3-(1-(3-fluorobenzyl)-5-methyl-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)pyridin-2-yl) piperazin-1-yl)propan-2-ol (350 mg, 0.51 mmol) was hydrolyzed with lithium hydroxide (65 mg, 1.54 mmol) in THF/methanol/water (6/4/2 mL) to yield 40 mg (11% yield) after purification by preparative HPLC as a mixture of two isomers. MS: m/z=526.5 (M+1). HPLC: 89.1% in method B.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[NH:13][C:12](=[O:14])[CH2:11][N:10]=[C:9]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:8]=2[CH:21]=1)([O-:3])=[O:2].Cl.[NH2:23][OH:24]>N1C=CC=CC=1.C(Cl)Cl>[NH2:10][CH2:11][C:12]([NH:13][C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:21][C:8]=1[C:9](=[N:23][OH:24])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:14]
Reactant: O=C1CN=C(c2ccccc2)c2cc([N+](=O)[O-])ccc2N1
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: NCC(=O)Nc1ccc([N+](=O)[O-])cc1C(=NO)c1ccccc1

Procedure:
A solution of 10 g (35.55 mmol) of 1,3-dihydro-7-nitro-5-phenyl-2H-1,4-benzodiazepin-2-one and 3.7 g (53.3 mmol) of hydroxylamine hydrochloride in 80 ml of pyridine is heated under reflux for 1 hour. After cooling, the mixture is taken up in methylene chloride, washed with water, dried and evaporated. The residual pyridine is removed in vacuo azeotropically with toluene. The solid crude product is suspended in hot tert.-butyl methyl ether and filtered off. There is obtained 2-amino-2'-[α-(hydroxyimino)-benzyl]-4'-nitro-acetanilide of melting point 167° (decomposition).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]([CH3:23])[C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]=[C:12]([CH2:20][C:21]#[N:22])[N:11]=2)=[CH:5][CH:4]=1.Cl>C(Cl)Cl.CO.[Pd]>[NH2:22][CH2:21][CH2:20][C:12]1[N:11]=[C:10]([N:9]([C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)[CH3:23])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]=1
Reactant: COc1ccc(N(C)c2nc(CC#N)nc3ccccc23)cc1
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: COc1ccc(N(C)c2nc(CCN)nc3ccccc23)cc1
Reaction time: 72 h
Yield: 8.3 %

Procedure:
A mixture of {4-[(4-methoxy-phenyl)-methyl-amino]-quinazolin-2-yl}-acetonitrile (250 mg, 0.82 mmol), 10% Pd/C (100 mg) and HCl (12 M, 1 mL, 12 mmol) in CH2Cl2/MeOH (1:1, 10 mL) was treated with H2 (50 psi) and shaken for three days. The Pd/C was filtered off and the filtrate concentrated and purified to give 21 mg of the title compound as a solid. 1H NMR (CDCl3) δ 7.64 (d, 1H), 7.55 (ddd, 1H), 7.13 (d, 2H), 6.95 (m, 2H), 6.93 (d, 2H), 3.85 (s, 3H), 3.62 (t, 2H), 3.56 (s, 3H), 3.4 (t, 2H); LC-MS (ESI+; 309 ([M+H]+)).
Reaction SMILES: [C:1]([O:5][C:6](=[O:11])[NH:7][CH2:8][CH2:9][OH:10])([CH3:4])([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:31][O:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1O.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[C:1]([O:5][C:6](=[O:11])[NH:7][CH2:8][CH2:9][O:10][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=1[O:32][CH3:31])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCCO
Reactant: COc1ccccc1O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1ccccc1OCCNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 33.1 %

Procedure:
Under an atmosphere of nitrogen, (2-hydroxy-ethyl)-carbamic acid tert-butyl ester (584 mg, 3.62 mmol) and triphenylphosphine (951 mg, 3.63 mmol) were added to a solution of ortho-methoxyphenol (500 mg, 4.03 mmol) in THF (8 ml). Subsequently, diethyl azodicarboxylate (772 mg, 4.44 mmol) was added at 0° C. and the reaction mixture was then stirred for 3 h at r.t. The solvent was evaporated under reduced pressure, the residue was taken up in ethyl acetate, washed (H2O), and dried (Na2SO4). Chromatographic purification gave the title compound (320 mg, 30%).
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([NH:5][C:6](=[O:20])[C:7]2[CH:12]=[CH:11][C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=3)=[N:9][CH:8]=2)[CH2:2]1.CCN(C(C)C)C(C)C.[C:30](Cl)(=[O:35])[C:31]([CH3:34])([CH3:33])[CH3:32]>CN(C=O)C.C(OCC)(=O)C.O>[CH3:32][C:31]([CH3:34])([CH3:33])[C:30]([N:1]1[CH2:4][CH:3]([NH:5][C:6](=[O:20])[C:7]2[CH:12]=[CH:11][C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=3)=[N:9][CH:8]=2)[CH2:2]1)=[O:35]
Reactant: O=C(NC1CNC1)c1ccc(-c2cccc(F)c2)nc1
Reactant: CC(C)(C)C(=O)Cl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)C(=O)N1CC(NC(=O)c2ccc(-c3cccc(F)c3)nc2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 117.2 %

Procedure:
To a solution of N-azetidin-3-yl-6-(3-fluorophenyl)nicotinamide (50 mg, 0.12 mmol) in DMF (1 mL) was added DIPEA (0.06 mL, 0.32 mmol) and pivaloyl chloride (29.4 mg, 0.24 mmol). The reaction mixture was stirred at room temperature overnight and then diluted with ethyl acetate and water. The layers were separated and the organic layer washed with brine, dried (MgSO4) and the solvent removed to give a solid, which was purified by chromatography (silica, 80% etoac:hex) to give the desired product, N-[1-(2,2-dimethylpropanoyl)azetidin-3-yl]-6-(3-fluorophenyl)nicotinamide (50 mg, 86%). HRMS (M+H)=356.1856 observed, 356.1774 expected.