Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11](=[C:18](Cl)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:10]1=[O:26])(=O)C1C=CC=CC=1.[NH2:27][C:28]1[CH:29]=[C:30]([CH:34]=[CH:35][CH:36]=1)[C:31]([NH2:33])=[O:32].[OH-].[Na+]>C1COCC1.CO>[NH2:33][C:31]([C:30]1[CH:29]=[C:28]([NH:27]/[C:18](=[C:11]2\[C:10](=[O:26])[NH:9][C:17]3[C:12]\2=[CH:13][CH:14]=[CH:15][CH:16]=3)/[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:36]=[CH:35][CH:34]=1)=[O:32]
Reactant: NC(=O)c1cccc(N)c1
Reactant: O=C1C(=C(Cl)c2ccccc2)c2ccccc2N1C(=O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: NC(=O)c1cccc(N/C(=C2\C(=O)Nc3ccccc32)c2ccccc2)c1

Procedure:
Prepared analogously to Example 9 from 1-benzoyl-3-(1-chloro-1-phenyl-methylidene)-2-indolinone and 3-aminobenzoic acid amide in THF and subsequent treatment with sodium hydroxide solution in methanol.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([NH:9][CH2:10][C:11]1[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=1)=[O:8].[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[N:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)=[CH:21][CH:20]=1>>[CH3:17][O:18][C:19]1[CH:20]=[CH:21][C:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[N:31]2[CH2:36][CH2:35][N:34]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([NH:9][CH2:10][C:11]3[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=3)=[O:8])[CH2:33][CH2:32]2)=[CH:23][CH:24]=1
Reactant: O=C(CCCCCBr)NCc1ccncc1
Reactant: COc1ccc(-c2ccccc2N2CCNCC2)cc1
Product: COc1ccc(-c2ccccc2N2CCN(CCCCCC(=O)NCc3ccncc3)CC2)cc1

Procedure:
The title compound was prepared starting from 6-bromo-N-(4-pyridylmethyl)hexa namide and 1-[2-(4-methoxyphenyl)phenyl]piperazine following the procedure outlined for Example 21. 1H NMR (CDCl3): δ 1.34-1.43 (m, 2H), 1.53-1.63 (m, 2H), 1.67-1.77 (m, 2H), 2.28 (t, 2H, J=7.4 Hz), 2.42 (app. t, 2H), 2.66 (br s, 4H), 3.10 (br s, 4H),3.81 (s, 3H), 4.45 (d, 2H, J=6.1 Hz), 6.10 (br t, 1H, D2O exchanged), 6.94 (d, 2H, J=8.8 Hz), 7.00 (d, 1H, J=8.0 Hz), 7.09-7.16 (m, 3H), 7.22-7.30 (m, 2H), 7.46 (d, 2H, J=8.8 Hz), 8.55 (dd, 2H, J=1.4, 4.4 Hz). GC-MS m/z 473 (M+1, 1), 472 (M+, 5), 379 (15), 282 (82), 226 (100), 210 (43).
Reaction SMILES: [H-].[Na+].[N+:3]([C:6]1[CH:22]=[CH:21][C:9]([C:10]([CH2:12]P(=O)(OCC)OCC)=[O:11])=[CH:8][CH:7]=1)([O-:5])=[O:4].[CH:23]([CH:25]1[CH2:30][CH2:29][N:28]([CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH2:27][CH2:26]1)=O.O>O1CCCC1>[CH2:31]([N:28]1[CH2:29][CH2:30][CH:25]([CH:23]=[CH:12][C:10]([C:9]2[CH:8]=[CH:7][C:6]([N+:3]([O-:5])=[O:4])=[CH:22][CH:21]=2)=[O:11])[CH2:26][CH2:27]1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: CCOP(=O)(CC(=O)c1ccc([N+](=O)[O-])cc1)OCC
Reactant: O=CC1CCN(Cc2ccccc2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=C(C=CC1CCN(Cc2ccccc2)CC1)c1ccc([N+](=O)[O-])cc1
Reaction time: 0.17 h
Yield: 56.5 %

Procedure:
Under ice cooling, 0.40 g of 64% sodium hydride was added to 3.03 g of diethyl (4-nitrobenzoylmethyl)phosphonate dissolved in 30 ml of tetrahydrofuran. After about 10 minutes, 4.07 g of 4-formyl-1-benzylpiperidine was added to the mixture. The mixture was stirred under ice cooling for 30 minutes and then stirred at room temperature for about 16 hours. After completion of the reaction, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The obtained residue was applied to silica gel column chromatography to obtain 1.99 g of the title compound as pale yellow crystal.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.CC(C)([O-])C.[K+].[CH:23](Cl)([Cl:25])[Cl:24]>CN(C=O)C.C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[C:10]([CH:23]([Cl:25])[Cl:24])[CH:9]=2)=[CH:6][CH:7]=1
Reactant: ClC(Cl)Cl
Reactant: O=[N+]([O-])c1ccc(-c2ccc(Cl)cc2)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(-c2ccc(Cl)cc2)cc1C(Cl)Cl
Temperature: -73 °C
Reaction time: 0.02 h
Yield: 63 %

Procedure:
4′-Chloro-4-nitro-biphenyl [J. Amer. Chem. Soc; 68; 1946; 404] (2.74 g, 11.7 mmol) was dissolved in DMF (20 ml) and THF (6 ml), then potassium t-butoxide 5.26 g (47 mmol) was added. The stirred mixture was cooled to −73° C. then a solution of chloroform in THF (6 ml) was slowly introduced, maintaining this temperature. After a further 1 minute, the reaction was quenched with acetic acid (5 ml). The mixture was poured into water (200 ml) and extracted with dichloromethane. The crude product was purified by flash chromatography on silica (using dichloromethane-hexane as eluents) to give 4′-chloro-3-(1,1-dichloro-methyl)-4-nitro-biphenyl in 63% yield;
Reaction SMILES: [CH:1]1([C:4]2[C:5]([O:18][CH2:19][C:20]3([CH3:27])[CH2:25][CH2:24][C:23](=[O:26])[CH2:22][CH2:21]3)=[CH:6][C:7]([F:17])=[C:8]([CH:16]=2)[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:3][CH2:2]1.[BH4-].[Na+]>CO>[CH:1]1([C:4]2[C:5]([O:18][CH2:19][C:20]3([CH3:27])[CH2:25][CH2:24][CH:23]([OH:26])[CH2:22][CH2:21]3)=[CH:6][C:7]([F:17])=[C:8]([CH:16]=2)[C:9]([O:11][C:12]([CH3:13])([CH3:14])[CH3:15])=[O:10])[CH2:3][CH2:2]1
Reactant: CC1(COc2cc(F)c(C(=O)OC(C)(C)C)cc2C2CC2)CCC(=O)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC1(COc2cc(F)c(C(=O)OC(C)(C)C)cc2C2CC2)CCC(O)CC1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 98.7 %

Procedure:
To a solution of tert-butyl 5-cyclopropyl-2-fluoro-4-((1-methyl-4-oxocyclohexyl)-methoxy)benzoate (0.071 g, 0.190 mmol) in (3 mL) and methanol (1 mL) was added sodium borohydride (0.014 g, 0.38 mmol) and the reaction mixture was stirred 20 minutes at ambient temperature. The mixture was then quenched by addition of 1N hydrochloric acid until reaching pH=1. The mixture was extracted with dichloromethane (3×10 mL), the organic layers were combined and washed with brine (15 mL), dried over anhydrous magnesium sulfate, filtered and concentrated to afford tert-butyl 5-cyclopropyl-2-fluoro-4-((4-hydroxy-1-methylcyclohexyl)methoxy)benzoate (0.071 g, 99%) which was used directly for next step. To a solution of the previous compound in dichloromethane (3 mL) at −78° C. was added dropwise diethylaminosulfur trifluoride (0.15 g, 0.94 mmol) dissolved in dichloromethane (1 mL) and the reaction mixture was stirred 1 hour at −78° C., then slowly warmed up to ambient temperature during 2 hours. The mixture was then stirred at ambient temperature for a further 1 hour and then cooled down to −78° C. and quenched by addition of methanol (1 mL), followed by a saturated aqueous solution of sodium bicarbonate (2 mL). The mixture was warmed up to ambient temperature and extracted with dichloromethane (3×10 mL). The organic layers were combined and washed with brine (15 mL), dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by chromatography (0 to 30% ethyl acetate in hexanes) to give the title compound (0.048 g, 70%). 1H NMR (300 MHz, CDCl3) δ 7.38 (d, J=8.43 Hz, 1H), 6.49 (d, J=12.75 Hz, 1H), 5.73-5.56 (m, 2H), 3.76-3.61 (m, 2H), 2.14-1.43 (m, 16H), 1.08 (s, 3H), 0.92-0.78 (m, 2H), 0.66-0.57 (m, 2H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[CH:8]=[N:9][CH:10]=[CH:11][C:5]2=[N:4][C:3]=1[N:12]1[CH2:17][CH2:16][N:15]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=2[F:26])[CH2:14][CH2:13]1.[CH:27]1([NH2:31])[CH2:30][CH2:29][CH2:28]1.[F-].[K+].CCN(C(C)C)C(C)C>CS(C)=O.O>[CH:27]1([NH:31][C:2]2[N:7]=[C:6]3[CH:8]=[N:9][CH:10]=[CH:11][C:5]3=[N:4][C:3]=2[N:12]2[CH2:17][CH2:16][N:15]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[F:26])[CH2:14][CH2:13]2)[CH2:30][CH2:29][CH2:28]1
Reactant: NC1CCC1
Reactant: Fc1ccc(CN2CCN(c3nc4ccncc4nc3Cl)CC2)c(F)c1
Agent: [F-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: Fc1ccc(CN2CCN(c3nc4ccncc4nc3NC3CCC3)CC2)c(F)c1
Temperature: 23 °C
Reaction time: 16 h
Yield: 78.5 %

Procedure:
Combined 3-chloro-2-(4-(2,4-difluorobenzyl)piperazin-1-yl)pyrido[3,4-b]pyrazine (0.7226 g, 1.923 mmol), cyclobutanamine (0.493 mL, 5.77 mmol), and potassium fluoride (0.145 g, 2.500 mmol) in DMSO (7.2 mL) and DIPEA (0.670 mL, 3.85 mmol) at 23° C. The reaction was stirred at 23° C. for 16 hr and diluted with water (30 mL) to furnish a yellow-orange suspension. The resulting solid was filtered, rinsed with water, and dried in vacuo to give the title compound (0.62 g, 79%) as a yellow solid. 1H NMR (500 MHz, DMSO-d6) δ ppm 1.68-1.77 (m, 2H), 2.12 (quind, J=9.3, 2.7 Hz, 2H), 2.27-2.35 (m, 2H), 2.56-2.68 (m, 4H), 3.35-3.42 (m, 4H), 3.60 (s, 2H), 4.57 (sextet, J=8.0 Hz, 1H), 6.98 (d, J=7.3 Hz, 1H), 7.06-7.12 (m, 1H), 7.22 (td, J=9.9, 2.7 Hz, 1H), 7.43 (d, J=5.4 Hz, 1H), 7.46-7.53 (m, 1H), 8.27 (d, J=5.4 Hz, 1H), 8.76 (s, 1H); ESI-MS m/z [M+H]+ 411.0.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][CH:14]=1)[O:5][CH2:6][CH2:7][CH2:8][C:9]([OH:11])=O.C(Cl)(=O)C(Cl)=O.[CH2:21]([O:28][NH2:29])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C([O-])([O-])=O.[Na+].[Na+]>ClCCl.CN(C=O)C>[CH2:21]([O:28][NH:29][C:9](=[O:11])[CH2:8][CH2:7][CH2:6][O:5][C:4]1[CH:12]=[CH:13][CH:14]=[C:2]([I:1])[CH:3]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C(O)CCCOc1cccc(I)c1
Reactant: NOCc1ccccc1
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(CCCOc1cccc(I)c1)NOCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution in dichloromethane (20 mL) containing a few drops of DMF of 4-(3-iodophenoxy)butanoic acid (2.26 g, 7.38 mmol) was added oxalyl chloride (0.60 mL, 6.9 mmol) slowly via syringe. The reaction mixture was stirred for 30 minutes at ambient temperature, and then was decanted into a dichloromethane solution of O-benzylhydroxylamine (3.5 g, 22 mmol; prepared by shaking O-benzylhydroxylamine in a mixture of dichloromethane and saturated aqueous Na2CO3, separating the layers, and drying the organic phase over MgSO4). The reaction mixture was stirred for 3.5 hours at ambient temperature and then was extracted with water and saturated aqueous Na2CO3. The organic phase was dried over MgSO4, filtered, and concentrated in vacuo to give a white solid. The solid was dissolved in dichloromethane and the organic solution was washed with aqueous 1M HCl, dried over MgSO4, filtered, and concentrated in vacuo to give O-benzyl-4-(3-iodophenoxy)butanohydroxamic acid (3.12 g) as a fluffy white solid.
Reaction SMILES: Cl[CH2:2][N:3]1[C:13](=[O:14])[C:12]2[C:7](=[CH:8][C:9]([O:18][CH3:19])=[CH:10][C:11]=2[CH:15]([CH3:17])[CH3:16])[S:4]1(=[O:6])=[O:5].[Na].[C:21]1([N:27]2[C:31]([SH:32])=[N:30][N:29]=[N:28]2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CN(C)C=O>[C:21]1([N:27]2[C:31]([S:32][CH2:2][N:3]3[C:13](=[O:14])[C:12]4[C:7](=[CH:8][C:9]([O:18][CH3:19])=[CH:10][C:11]=4[CH:15]([CH3:17])[CH3:16])[S:4]3(=[O:6])=[O:5])=[N:30][N:29]=[N:28]2)[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: COc1cc(C(C)C)c2c(c1)S(=O)(=O)N(CCl)C2=O
Reactant: Sc1nnnn1-c1ccccc1
Agent: [Na]
Solvent: CN(C)C=O
Product: COc1cc(C(C)C)c2c(c1)S(=O)(=O)N(CSc1nnnn1-c1ccccc1)C2=O
Temperature: 0 °C
Yield: 81.8 %

Procedure:
A mixture of 2-chloromethyl-4-isopropyl-6-methoxysaccharin (0.25 g) and 1-phenyltetrazole-5-thiol sodium salt (0.173 g) in dimethylformamide (10 mL) was heated at 60°-80° C. for 8 hours, then poured into ice-water containing saturated aqueous sodium bicarbonate. The resulting mixture was extracted with ether. The ether extract was washed with water and saturated aqueous sodium chloride, passed through silica gel and stripped of ether affording 2-(1-phenyltetrazol-5-yl)thiomethyl-4-isopropyl-6-methoxysaccharin as a foam (0.3 g, 83% yield).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:9])=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[CH2:10]([O:12][C:13](=[O:17])[C:14]#[C:15][CH3:16])[CH3:11].N12CCCN=C1CCCCC2>O1CCCC1>[CH2:10]([O:12][C:13](=[O:17])[CH:14]=[C:15]([O:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[F:9])[CH3:16])[CH3:11]
Reactant: Oc1cccc(Cl)c1F
Reactant: CC#CC(=O)OCC
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: CCOC(=O)C=C(C)Oc1cccc(Cl)c1F
Temperature: 130 °C
Reaction time: 8 h
Yield: 61 %

Procedure:
A mixture of 3-chloro-2-fluoro-phenol (1.31 g, 8.93 mmol) and ethyl-2-butynoate (2.0 g, 17.83 mmol) in tetrahydrofuran (14 mL) was treated with 1,8-diazabicyclo[5.4.0]undec-7-ene (1.4 mL, 9.37 mmol). The reaction was then heated at 130° C. for 2 h. At this time, the reaction was cooled to 25° C. and was stirred at 25° C. overnight. At this time, the reaction was concentrated in vacuo. The residue was dissolved in dichloromethane (100 mL) and was washed with a 2N aqueous hydrochloric acid solution (1×100 mL), a 1N aqueous sodium hydroxide solution (1×100 mL) and a saturated aqueous sodium chloride solution (1×100 mL). The organics were then dried over magnesium sulfate, filtered, rinsed with dichloromethane, and concentrated in vacuo. Purification by Analogix flash chromatography (40 g, 1-10% ethyl acetate/hexanes) afforded 3-(3-chloro-2-fluoro-phenoxy)-but-2-enoic acid ethyl ester (1.41 g, 61%) as a white solid: HR-ES-MS m/z calculated for C12H12O3FCl [M+H]+ 259.0532, observed 259.0531; 1H NMR (400 MHz, DMSO-d6) δ ppm 1.14 (t, J=7.1 Hz, 3H), 2.45 (s, 3H), 4.03 (q, J=7.1 Hz, 2H), 4.76 (s, 1H), 7.27-7.39 (m, 2H), 7.50-7.61 (m, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=2)[CH2:11][CH2:10]1.C([Li])CCC.[F:28][C:29]1[CH:36]=[CH:35][C:32]([CH2:33]Br)=[CH:31][CH:30]=1.Cl>C1COCC1.O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:10][CH2:11][N:12]([CH2:15][CH:16]([CH2:33][C:32]2[CH:35]=[CH:36][C:29]([F:28])=[CH:30][CH:31]=2)[C:17]2[CH:18]=[CH:19][N:20]=[CH:21][CH:22]=2)[CH2:13][CH2:14]1
Reactant: COc1ccccc1N1CCN(CCc2ccncc2)CC1
Reactant: Fc1ccc(CBr)cc1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: COc1ccccc1N1CCN(CC(Cc2ccc(F)cc2)c2ccncc2)CC1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
1-(2-Methoxyphenyl)-4-[2-(4-pyridyl)ethyl]piperazine (5.94 g, 20 mmol) was dissolved in anhydrous THF (70 ml) and the solution cooled to about -78° C., n-Butyllithium (1.6M solution in hexane, 18 ml) was added in portions, then the mixture was stirred for 1 hour, at below -70° C. The anion was quenched with p-fluorobenzylbromide (3.18 g, 16.8 mmol) in THF (3 ml and the mixture was warmed to room temperature when water (50 ml) was added. The organic component was extracted by dichloromethane, then washed with brine, dried using sodium sulphate and concentrated in vacuo. The resulting oil was purified by column chromatography using methanol:chloroform (0:100-5:95 gradient), affording the pure product. Addition of ethanolic HCl to the oil gave the title compound as the trihydrochloride 1.5 hydrate (1.25 g), m.p. 173°-175° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:19]([NH2:20])=[N:18][C:12]2[N:13]=[C:14]([CH3:17])[N:15]=[CH:16][C:11]=2[CH:10]=1.[Cl:21][CH2:22][C:23](O)=[O:24].C(N1C=CN=C1)(N1C=CN=C1)=O>ClCCCl>[Cl:21][CH2:22][C:23]([NH:20][C:19]1[C:9]([C:3]2[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=2[Cl:8])=[CH:10][C:11]2[CH:16]=[N:15][C:14]([CH3:17])=[N:13][C:12]=2[N:18]=1)=[O:24]
Reactant: Cc1ncc2cc(-c3c(Cl)cccc3Cl)c(N)nc2n1
Reactant: O=C(O)CCl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCCl
Product: Cc1ncc2cc(-c3c(Cl)cccc3Cl)c(NC(=O)CCl)nc2n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A suspension of 3.0 g of 6-(2,6-dichlorophenyl)-2-methylpyrido[2,3-d]pyrimidin-7-amine and 50 ml of 1,2-dichloroethane is boiled on a steam bath until the distilling vapors reach a temperature of 83° C. The suspension is cooled to room temperature and 1.6 g of chloroacetic acid and 2.6 g of carbonyldiimidazole are added sequentially. The mixture is stirred at room temperature for 3 hours and the resulting solution is immediately chromatographed over 150 g of silica gel. The crude product is eluted with a 99/1 chloroform/methanol mixture. Trituration of this with ether gives pure 2-chloro-N-[6-(2,6-dichlorophenyl)-2-methylpyrido[2,3-d]-pyrimidin-7-yl]acetamide, decomposing above ca 170° C.
Reaction SMILES: Cl[CH2:2][C:3]#[N:4].[Na+].[N:6]1[CH:11]=[CH:10][CH:9]=[C:8]([S:12]([O-:14])=[O:13])[CH:7]=1>CN(C=O)C>[N:6]1[CH:11]=[CH:10][CH:9]=[C:8]([S:12]([CH2:2][C:3]#[N:4])(=[O:14])=[O:13])[CH:7]=1
Reactant: N#CCCl
Reactant: O=S([O-])c1cccnc1
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#CCS(=O)(=O)c1cccnc1
Reaction time: 1 h
Yield: 67.4 %

Procedure:
2.1 ml (33.4 mmol) of chloroacetonitrile were added to a solution of 4.6 g (42 mmol) of pyridine-3-sulphinic acid sodium salt in 50 ml of DMF and stirred at 90° for 1 hr. The reaction solution was evaporated, the residue was partitioned between H2O and CH2Cl2. The aqueous phase was washed three times with CH2Cl2. The combined organic phases were washed once with H2O, dried (MgSO4) filtered and evaporated. Chromatography (SiO2, AcOEt/hexane 2:1) yielded 4.1 g (80%) of (pyridine-3-sulphonyl)-acetonitrile as a beige solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][NH:12][C:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[N:10][CH2:9]2)=[CH:4][CH:3]=1.[C:20](=O)([O:22]C(C)(C)C)[NH2:21]>CN(C=O)C.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:13][N:12]3[C:20](=[O:22])[NH:21][C:19]4[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=4[C:11]3=[N:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(N)=O
Reactant: Clc1ccc(C2CN=C(c3ccccc3)NC2)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Product: O=C1Nc2ccccc2C2=NCC(c3ccc(Cl)cc3)CN12
Temperature: 100 °C
Yield: 12 %

Procedure:
A mixture of 5-(4-chlorophenyl)-2-phenyl-1,4,5,6-tetrahydropyrimidine (12.9 mg, 0.048 mmol), tert-butyl carbamate (16.7 mg, 0.143 mmol) and copper(II) acetate (8.7 mg, 0.048 mmol) in 0.6 mL DMF was heated at 100° C. in a sealed reaction vessel under an oxygen gas atmosphere. After 1 hour the DMF solvent was evaporated and the residue chromatographed eluting with 5% MeOH/CHCl3 to give the title compound as a pale yellow solid (1.8 mg, 12%). 1H NMR (Acetone-d6) δ: 9.54 (br. s, 1H), 8.10 (d, J=7.9 Hz, 1H), 7.36-7.49 (m, 5H), 7.05-7.13 (m, 2H), 4.32-4.41 (m, 1H), 3.79-3.89 (m, 1H), 3.54-3.71 (m, 2H), 3.05-3.20 (m, 1H).
Reaction SMILES: S(=O)(=O)=O.[BrH:5].[NH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]1[C:16]([CH3:17])=[CH:15][CH:14]=[CH:13][N:12]=1.BrBr>FC(Cl)(F)C(Cl)(Cl)F>[Br:5][C:14]1[CH:15]=[C:16]([CH3:17])[C:11]([CH2:10][CH2:9][CH2:8][CH2:7][NH2:6])=[N:12][CH:13]=1
Reactant: Cc1cccnc1CCCCN
Reactant: Br
Agent: BrBr
Agent: O=S(=O)=O
Solvent: FC(F)(Cl)C(F)(Cl)Cl
Product: Cc1cc(Br)cnc1CCCCN
Yield: 46.1 %

Procedure:
A solution of sulphur trioxide (150 ml) in 1,1,2-tri-fluorotrichloroethane (550 ml) was added over 30 min to a suspension of 2-(4-aminobutyl)-3-methyl-pyridine hydrobromide (14.2 g) [prepared by reacting 2-(4-aminobutyl)-3-methyl-pyridine with hydrobromic acid (0.89M)] in 1,1,2-trifluoro-trichloroethane and to this mixture was added liquid bromine (5.56 g). The mixture was heated under reflux for ca 16 hr. The solvent was removed by distillation and unbrominated starting material was removed by acetylation as described in Example 1(h) to yield 5-bromo-2-(4-amino-butyl)-3-methylpyridine (6.49 g) as an oil.
Reaction SMILES: Cl.[NH2:2][C:3]1[C:9]([OH:10])=[CH:8][CH:7]=[CH:6][C:4]=1[OH:5].O.[CH2:12](O)C>>[OH:10][C:9]1[C:3]2[N:2]=[CH:12][O:5][C:4]=2[CH:6]=[CH:7][CH:8]=1
Reactant: Nc1c(O)cccc1O
Reactant: CCO
Agent: Cl
Solvent: O
Product: Oc1cccc2ocnc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2-Aminoresorcinol hydrochloride (2 g) and triethylchloroformate (4.5 ml) were heated to reflux under nitrogen for 3 h. After cooling to room temperature, the reaction mixture was poured into a mixture of water (70 ml) and ethanol (20 ml). The mixture was stirred vigorously for 30 minutes, then left to stand at room temperature overnight. The beige precipitate which formed was collected by filtration, and dried by azeotroping with toluene to give the title compound as a beige solid (1.2 g).
Reaction SMILES: [NH2:1][C:2]1[CH:40]=[CH:39][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]3[N:13](CC4C=CC(OC)=CC=4)[N:14]=[C:15]([NH:16][CH:17]4[CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19][CH2:18]4)[C:8]=23)=[C:4]([F:41])[CH:3]=1.[F:42][C:43]1[CH:48]=[CH:47][C:46]([N:49]2[C:54](=[O:55])[C:53]([C:56]([OH:58])=O)=[CH:52][CH:51]=[N:50]2)=[CH:45][CH:44]=1>>[F:41][C:4]1[CH:3]=[C:2]([NH:1][C:56]([C:53]2[C:54](=[O:55])[N:49]([C:46]3[CH:45]=[CH:44][C:43]([F:42])=[CH:48][CH:47]=3)[N:50]=[CH:51][CH:52]=2)=[O:58])[CH:40]=[CH:39][C:5]=1[O:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]2[NH:13][N:14]=[C:15]([NH:16][CH:17]3[CH2:18][CH2:19][NH:20][CH2:21][CH2:22]3)[C:8]=12
Reactant: O=C(O)c1ccnn(-c2ccc(F)cc2)c1=O
Reactant: COc1ccc(Cn2nc(NC3CCN(C(=O)OC(C)(C)C)CC3)c3c(Oc4ccc(N)cc4F)ccnc32)cc1
Product: O=C(Nc1ccc(Oc2ccnc3[nH]nc(NC4CCNCC4)c23)c(F)c1)c1ccnn(-c2ccc(F)cc2)c1=O
Yield: 34 %

Procedure:
Prepared by a 2-step process from tert-butyl 4-(4-(4-amino-2-fluorophenoxy)-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridin-3-ylamino)piperidine-1-carboxylate (prepared as described in Example 101, Step A, using tert-butyl 4-aminopiperidine-1-carboxylate) and 2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxylic acid according to the procedure of Example 101, Step B. The crude material was purified by silica gel flash column chromatography (60% MeOH in CH2Cl2) to afford 19 mg (34%) of the desired product. LRMS (ESI pos) m/e 559.1 (M+1). 1H-NMR (400 MHz, CD3OD/CDCl3) δ 8.41 (d, 1H), 8.33 (d, 1H), 8.14 (d, 1H), 8.02 (dd, 1H), 7.65 (m, 2H), 7.47 (d, 1H), 7.37 (t, 1H), 7.28 (t, 2H), 6.12 (d, 1H), 3.80 (m, 1H), 3.16 (d, 2H), 2.79 (t, 2H), 2.24 (d, 2H), 1.53 (m, 2H); 19F NMR (376 MHz, CD3OD/CDCl3) δ −113.1, −127.7.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[O:25]=[C:26]1[C:38]2[C:37]3[C:36]([C:39]([O:41][CH3:42])=[O:40])=[CH:35][CH:34]=[CH:33][C:32]=3[NH:31][C:30]=2[CH2:29][NH:28][CH2:27]1.[CH2:43]([O:50][C:51]([NH:53][C:54]([CH3:59])([CH3:58])[C:55](O)=[O:56])=[O:52])[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1.C(N(C(C)C)CC)(C)C>CN(C=O)C>[CH2:43]([O:50][C:51]([NH:53][C:54]([CH3:59])([CH3:58])[C:55]([N:28]1[CH2:27][C:26](=[O:25])[C:38]2[C:37]3[C:36]([C:39]([O:41][CH3:42])=[O:40])=[CH:35][CH:34]=[CH:33][C:32]=3[NH:31][C:30]=2[CH2:29]1)=[O:56])=[O:52])[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1
Reactant: COC(=O)c1cccc2[nH]c3c(c12)C(=O)CNC3
Reactant: CC(C)(NC(=O)OCc1ccccc1)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1cccc2[nH]c3c(c12)C(=O)CN(C(=O)C(C)(C)NC(=O)OCc1ccccc1)C3

Procedure:
A solution of HATU (86 mg) in DMF (2 ml) was added to a mixture of methyl 4-oxo-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-5-carboxylate (36 mg), 2-(((benzyloxy)carbonyl)amino)-2-methylpropanoic acid (21 mg), diisopropylethylamine (58) and DMF (8 ml) and the resultant mixture was stirred at ambient temperature for 16 hours. The DMF was evaporated to give methyl 2-(2-(((benzyloxy)carbonyl)amino)-2-methylpropanoyl)-4-oxo-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-5-carboxylate which was used in the next step without further purification.