Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [SH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8].O.[CH3:11][S:12](=O)(SC)=O>C(O)C.[Cl-].[Na+]>[CH3:11][S:12][S:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8]
Reactant: O=C(O)CCCCCS
Reactant: CSS(C)(=O)=O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CSSCCCCCC(=O)O
Yield: 73.6 %

Procedure:
To an ice/water bath cooled flask containing a solution of 6-mercaptohexanoic acid (500.0 mg, 3.37 mmol) de ionized water (2 mL) was added a solution of S-Methyl methanethiosulfonate (468 mg, 3.71 mmol) in ethanol (1 mL). After 16 hr the reaction was diluted with saturated sodium chloride (400 mL) and extracted with ethyl ether (3×150 mL). The combined extracts were washed with saturated NaCl (100 mL), dried over anhydrous Na2SO4 and concentrated in vacuo. The product was purified by silica chromatography eluting with ethyl acetate/hexanes/acetic acid (40:58:2). Product containing fractions were combined and concentrated in vacuo to give 482 mg (73% yield) of the desired product. MS calcd (M+Na)+, 217.3; found, 217.3
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([O:13]C)=[O:12])=[CH:7][NH:8]2)=[CH:4][C:3]=1[C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23][CH2:24][N:25]2[CH2:30][CH2:29][O:28][CH2:27][C:26]2=[O:31])=[CH:17][CH:16]=1.[OH-].[Na+]>CO>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([OH:13])=[O:12])=[CH:7][NH:8]2)=[CH:4][C:3]=1[C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23][CH2:24][N:25]2[CH2:30][CH2:29][O:28][CH2:27][C:26]2=[O:31])=[CH:17][CH:16]=1
Reactant: COC(=O)c1c[nH]c2cc(Cl)c(-c3ccc(OCCCN4CCOCC4=O)cc3)cc12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1c[nH]c2cc(Cl)c(-c3ccc(OCCCN4CCOCC4=O)cc3)cc12
Temperature: 70 °C
Reaction time: 24 h
Yield: 5.3 %

Procedure:
To a solution of methyl 6-chloro-5-{4-[3-(3-oxomorpholin-4-yl)propoxy]phenyl}-1H-indole-3-carboxylate (55 mg, 0.22 mmol) in methanol (8 mL) was added 1.0 M aq. NaOH (2.0 mL, 2.0 mmol). The mixture was stirred at 70° C. for 24 hours. The mixture was adjusted to pH 7 and purified by reverse phase HPLC to give the title compound as a white solid (5 mg, 9% yield). MS (ES+) 429.1 (M+H)+. 1H NMR (400 MHz, CD3OD): δ 7.90 (m, 2 H), 7.5 (s, 1 H), 7.29 (d, 2 H), 6.92 (d, 2 H), 4.05 (m, 4 H), 3.83 (t, 2 H), 3.58 (t, 2 H), 3.42 (t, 2 H), 2.05 (m, 2 H).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:4][CH2:3]1.Br[CH2:17][CH2:18][O:19][CH2:20][CH2:21]Br.C(N(CC)CC)C>CN(C)C=O>[N:1]1([C@H:2]2[CH2:7][CH2:6][C@H:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:12])([CH3:14])[CH3:13])[CH2:4][CH2:3]2)[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](N)CC1
Reactant: BrCCOCCBr
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@H](N2CCOCC2)CC1
Temperature: 70 °C
Reaction time: 6 h

Procedure:
To a solution of 21.43 g (0.1 mol) of tert-butyl N-(trans-4-aminocyclohexyl)carbamate in 250 mL of N,N-dimethylformamide were added 16.76 mL (0.12 mol) of bis(2-bromoethyl)ether and 34.85 mL (0.25 mol) of triethylamine, and the mixture was stirred for 6 hours at 70° C. Then solvent was removed under reduced pressure and the residue was treated with ethyl acetate. The organic layer was washed with sodium carbonate aqueous solution and saturated saline solution, then, dried over with anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography (eluent: chloroform alone to chloroform/methanol=30/1) to give 19.92 g (70%) of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9]C(C)C)=[CH:4][C:3]=1[N:13]1[C:18](=[O:19])[C:17]([CH3:20])=[C:16]([C:21]([F:24])([F:23])[F:22])[CH:15]=[N:14]1.O>S(=O)(=O)(O)O>[F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([OH:9])=[CH:4][C:3]=1[N:13]1[C:18](=[O:19])[C:17]([CH3:20])=[C:16]([C:21]([F:23])([F:24])[F:22])[CH:15]=[N:14]1
Reactant: Cc1c(C(F)(F)F)cnn(-c2cc(OC(C)C)c(Cl)cc2F)c1=O
Agent: O=S(=O)(O)O
Solvent: O
Product: Cc1c(C(F)(F)F)cnn(-c2cc(O)c(Cl)cc2F)c1=O
Temperature: 25 °C
Yield: 102.1 %

Procedure:
Then, 3.5 g (9.7 mmol) of 2-[2-fluoro-4-chloro-5-isopropoxyphenyl]-4-methyl-5-trifluoromethylpyridazin-3-one was dissolved in about 10 ml of concentrated sulfuric acid under ice cooling, and the solution was warmed to room temperature. After ten minutes, about 100 ml of water was added to the reaction mixture. The deposited crystals were collected by filtration, and then washed twice with 20 ml of water and once with 10 ml of hexane in this order. The crystals thus obtained were recrystallized from isopropanol, which afforded 3.2 g (9.9 mmol) of 2-[2-fluoro-4-chloro-5-hydroxy-phenyl]-4-methyl-5-trifluoromethylpyridazin-3-one.
Reaction SMILES: [CH:1]1[C:13]2[N:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]4[O:21][C:22]([C:25]5[CH:30]=[CH:29][CH:28]=[C:27]([O:31]C)[CH:26]=5)=[N:23][N:24]=4)=[CH:16][CH:15]=3)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.B(Br)(Br)Br.C(=O)=O.CC(C)=O>ClCCl>[CH:10]1[C:11]2[N:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]4[O:21][C:22]([C:25]5[CH:26]=[C:27]([OH:31])[CH:28]=[CH:29][CH:30]=5)=[N:23][N:24]=4)=[CH:16][CH:15]=3)[C:13]3[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=3)[C:6]=2[CH:7]=[CH:8][CH:9]=1
Reactant: COc1cccc(-c2nnc(-c3ccc(-n4c5ccccc5c5ccccc54)cc3)o2)c1
Agent: BrB(Br)Br
Agent: O=C=O
Solvent: ClCCl
Solvent: CC(C)=O
Product: Oc1cccc(-c2nnc(-c3ccc(-n4c5ccccc5c5ccccc54)cc3)o2)c1
Temperature: 0 °C
Reaction time: 5 h

Procedure:
To a solution of 2-(4-carbazol-9-ylphenyl)-5-(3-methoxyphenyl)-1,3,4-oxadiazole (1.0 g, 2.40 mmol) in dichloromethane (10.0 ml) was dropwise added BBr3 (10.0 ml, 1M in dichloromethane) at −78° C. (dry-ice/acetone) under nitrogen. After addition of BBr3 solution, the reaction was taken to room temperature and kept at room temperature for 5 h. The reaction mixture was poured into ice-water (50.0 ml). Dichloromethane was evaporated under reduced pressure. The white solid was collected by filtration. After drying under vacuum, product as white solid was obtained in 0.97 g (100%) yield. 1H NMR (400 MHz, acetone-d6, δ): 8.91 (s, 1H, OH), 8.48 (m, 2H), 8.24 (dt, J1=8.0 Hz, J2=1.2 Hz, 2H), 7.91 (m, 2H), 7.71 (t, J=1.2 Hz, 1H), 7.69 (t, J=1.6 Hz, 1H), 7.56 (d, J=0.8 Hz, 1H), 7.54 (t, J=0.8 Hz, 1H), 7.46 (m, 3H), 7.32 (m, 2H), 7.12 (m, 111), 3.93 (s, 3H, OCH3). 13C NMR (100 MHz, acetone-d6, δ): 165.43, 164.72, 158.87, 141.48, 141.12, 131.44, 129.41, 128.23, 127.17, 126.04, 124.56, 123.65, 121.43, 121.26, 119.88, 118.89, 114.18, 110.62. MS-EI (m/z): [M]+ calcd for C26H17N3O2, 403.1. found 403.1.
Reaction SMILES: [N+](=[CH:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])=[N-].[CH2:9]([C:13]1[S:17][C:16]([CH:18]=[CH2:19])=[CH:15][CH:14]=1)[CH2:10][CH2:11][CH3:12]>ClCCl.S([O-])([O-])(=O)=O.[Cu+2]>[CH2:9]([C:13]1[S:17][C:16]([CH:18]2[CH2:19][CH:3]2[C:4]([O:6][CH2:7][CH3:8])=[O:5])=[CH:15][CH:14]=1)[CH2:10][CH2:11][CH3:12]
Reactant: CCOC(=O)C=[N+]=[N-]
Reactant: C=Cc1ccc(CCCC)s1
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Solvent: ClCCl
Product: CCCCc1ccc(C2CC2C(=O)OCC)s1
Yield: 64.8 %

Procedure:
This Example illustrates the preparation of 4-[2-(5-n-butylthiophen-2-yl)-trans-cyclopropylmethyl]-2,6-cis-dimethylmorpholine (Compound No. 8 in Table I). Phosphorus oxychloride (12.02 g, 0.078 mol) was added dropwise to N-methylformanilide (10.62 g, 0.079 mol) and a yellow solid was produced. This was cooled to 0° C. for 1/2 hour, then 2-n-butylthiophene (10 g, 0.071 mol) was added dropwise and the mixture stirred at room temperature for 3 hours. The mixture was poured into ice/water, neutralised with sodium carbonate and extracted into diethyl ether. The ethereal extracts were washed with water, dried over anhydrous sodium sulphate and the solvent removed to give a brown oil. Purification by column chromatography (silica eluted with petroleum ether/ethyl acetate 9:1) gave 5-n-butyl-2-thiophenecarboxaldehyde (11.8 g, 99%). Sodium hydride (6.63 g-50% suspension in oil, 0.138 mol) was washed with petroleum ether, suspended in dry DMSO (100 ml) and heated with stirring at 60°-70° C. for 2 hours. The reaction mixture was then cooled to 15° C. and methyltriphenylphosphonium bromide (48.72 g, 0.136 mol) was added portionwise with rapid stirring over a 1/2 hour period. The reaction mixture was stirred at room temperature for a further 1 hour after the addition and 5-n-butyl-2-thiophenecarboxaldehyde (23 g, 0.137 mol) was added dropwise over a period of 1 hour. The resultant reaction mixture was stirred at room temperature for 12 hours, poured into water (300 ml) and extracted with ether (4×150 ml). The ethereal extracts were washed with water (4×100 ml) and dried over anhydrous sodium sulphate. Removal of the solvent gave a yellow oil which was purified by column chromatography (silica eluted with petroleum ether/ethyl acetate 9:1) to give (5-n-butylthiophen-2-yl)-ethylene (18.5 g, 82%). Ethyl diazoacetate (13.0 g, 0.11 mol) in dry dichloromethane (150 ml) was added dropwise to a solution of (5-n-butylthiophen-2-yl)-ethylene (18.3 g, 0.11 mol) and anhydrous copper (II) sulphate (0.3 g) in dry dichloromethane (50 ml) at 90° C. by means of a syringe pump over a period of 5 hours. The dichloromethane was distilled over during the addition. After complete addition the remaining dichloromethane was removed in vacuo and the resulting brown oil purified by column chromatography (silica eluted with petroleum ether/ethyl acetate 1:1) to give ethyl 2-(5-n-butylthiophen-2-yl)-cyclopropanecarboxylate (18 g, 71%).
Reaction SMILES: [C:1]([O:4][CH2:5][C@H:6]1[CH2:11][CH2:10][C@H:9]([O:12][C@@H:13]([C:15]2[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[C:17]([C:25]([F:28])([F:27])[F:26])[CH:16]=2)[CH3:14])[C@@H:8]([C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=2)[C@@H:7]1[CH:36]=O)(=[O:3])[CH3:2].[CH2:38]([NH2:45])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[C:1]([O:4][CH2:5][C@H:6]1[CH2:11][CH2:10][C@H:9]([O:12][C@@H:13]([C:15]2[CH:16]=[C:17]([C:25]([F:26])([F:28])[F:27])[CH:18]=[C:19]([C:21]([F:24])([F:22])[F:23])[CH:20]=2)[CH3:14])[C@@H:8]([C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=2)[C@@H:7]1[CH2:36][NH:45][CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@H]1CC[C@H](O[C@H](C)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H](c2ccc(F)cc2)[C@@H]1C=O
Reactant: NCc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: CC(=O)OC[C@H]1CC[C@H](O[C@H](C)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H](c2ccc(F)cc2)[C@@H]1CNCc1ccccc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 97.5 %

Procedure:
A mixture of aldehyde (0.56 g, 1.0 mmol) from Step L, benzylamine (0.15 mL, 1.4 mmol) and sodium triacetoxy borohydride (1.0 g, 4.7 mmol) in 50 mL dimethyl chloride was stirred at room temperature for 12 hr. The mixture was washed with sat. aq. NaHCO3, then brine, dried over MgSO4 and filtered. The solvent was evaporated under vacuum to give an oil (0.61 g), which was used in the next step without purification. MS: (MH)+ 624.5.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[CH:11][CH:10]=2)O1.Br[C:25]1[C:30]([F:31])=[C:29]([F:32])[C:28]([NH2:33])=[C:27]([F:34])[C:26]=1[F:35]>>[F:31][C:30]1[C:29]([F:32])=[C:28]([NH2:33])[C:27]([F:34])=[C:26]([F:35])[C:25]=1[C:9]1[CH:10]=[CH:11][C:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[CH:13][CH:14]=1
Reactant: CCCCCCCCc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Reactant: Nc1c(F)c(F)c(Br)c(F)c1F
Product: CCCCCCCCc1ccc(-c2c(F)c(F)c(N)c(F)c2F)cc1
Reaction time: 2 h
Yield: 91.1 %

Procedure:
A mixture of 4,4,5,5-tetramethyl-2-(4-octylphenyl)-1,3,2-dioxaborolane (415.0 mg, 1.31 mmol), 4-bromo-2,3,5,6-tetrafluorobenzenamine (213.0 mg, 0.87 mmol), and a quaternary ammonium salt (Aliquat 336, 0.090 g) was degassed three times with nitrogen before dry toluene (7.0 mL) was added. This step was followed by addition of tetrakis(triphenylphosphine) palladium (100.0 mg) and sodium carbonate (aq. 1 M, 4.0 mL), which had been deaerated for 2 hour, under nitrogen. The mixture was stirred vigorously, and heated at reflux for 20 hours. The organic phase of the resulting reaction mixture was filtered through a thin layer of Celite® and evaporated to dryness to give 0.6 g of a crude product. The crude material was purified by chromatography on silica gel (by using ethyl acetate:hexanes (1:9) as the eluent) to yield 2,3,5,6-tetrafluoro-4′-octylbiphenyl-4-amine as an off-white solid (0.280 g, 91% yield).
Reaction SMILES: BrC1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11](=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH:6]=[C:5]2[CH2:19][CH2:20][N:21]1[CH2:25]C[CH2:23][CH2:22]1.C([Sn](CCCC)(CCCC)[C:31]1[O:32][C@H:33]([CH2:43]OOC)[C@@H:34](OOC)[C@H:35](OOC)[CH:36]=1)CCC>>[O:32]1[CH:31]=[CH:36][CH2:35][CH2:34][CH:33]1[C:43]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11](=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH:6]=[C:5]2[CH:19]1[CH2:23][CH2:22][N:21]([CH3:25])[CH2:20]1
Reactant: O=C(c1ccccc1)n1cc(CCN2CCCC2)c2cc(Br)ccc21
Reactant: CCCC[Sn](CCCC)(CCCC)C1=C[C@@H](OOC)[C@H](OOC)[C@@H](COOC)O1
Product: CN1CCC(c2cn(C(=O)c3ccccc3)c3ccc(C4CCC=CO4)cc23)C1

Procedure:
3-(2-Pyrrolidinylethyl)-5-(3,4,6-trimethoxyglucal-1-yl)-1-benzoylindole: (80%), from 5-bromo-3-(2-pyrrolidinylethyl)-1-benzoylindole (Example 5c) and 2-tributylstannyl-tri-O-methoxy-D-glucal (Example 8).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([N:9]2[C:13]([CH3:14])=[CH:12][C:11]([CH3:15])=[N:10]2)[N:3]=1.[Cl:16][C:17]1[CH:23]=[CH:22][C:20]([NH2:21])=[CH:19][CH:18]=1.Cl>O.C(O)C>[Cl:8][C:6]1[N:5]=[C:4]([N:9]2[C:13]([CH3:14])=[CH:12][C:11]([CH3:15])=[N:10]2)[N:3]=[C:2]([NH:21][C:20]2[CH:22]=[CH:23][C:17]([Cl:16])=[CH:18][CH:19]=2)[CH:7]=1
Reactant: Cc1cc(C)n(-c2nc(Cl)cc(Cl)n2)n1
Reactant: Nc1ccc(Cl)cc1
Agent: Cl
Solvent: CCO
Solvent: O
Product: Cc1cc(C)n(-c2nc(Cl)cc(Nc3ccc(Cl)cc3)n2)n1
Temperature: 88 °C
Reaction time: 6 h
Yield: 99.7 %

Procedure:
4,6-Dichloro-2-(3,5-dimethyl-pyrazol-1-yl)-pyrimidine (3.5 g, 14.4 mmol) and 4-chloroaniline (3.7 g, 28.8 mmol) were suspended in water (120 mL) and ethanol (17 mL). Concentrated hydrochloric acid (0.6 mL, 7.2 mmol) was added and the mixture was heated to 88° C. over-night. Additional 4-chloroaniline (918 mg) was added and stirring was continued for six hours. The mixture was cooled to room temperature and diluted with water. The resulting solid was collected by filtration to give [6-chloro-2-(3,5-dimethylpyrazol-1-yl)-pyrimidin-4-yl]-(4-chloro-phenyl)-amine (4.8 g, 99%) as a white solid.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([NH:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=2)[N:9]=1)[C:5]#[N:6].[Cl:19][C:20]1[C:21](B(O)O)=[CH:22][C:23]([F:26])=[N:24][CH:25]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.CCOC(C)=O.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>[Cl:19][C:20]1[C:21]([C:2]2[CH:3]=[C:4]([C:5]#[N:6])[CH:7]=[C:8]([NH:10][CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=3)[N:9]=2)=[CH:22][C:23]([F:26])=[N:24][CH:25]=1
Reactant: OB(O)c1cc(F)ncc1Cl
Reactant: N#Cc1cc(Cl)nc(NCc2cccc(F)c2)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: N#Cc1cc(NCc2cccc(F)c2)nc(-c2cc(F)ncc2Cl)c1
Temperature: 110 °C
Yield: 46.5 %

Procedure:
To a degassed suspension of 2-chloro-6-(3-fluorobenzylamino) isonicotinonitrile (150 mg, 0.573 mmol) and 5-chloro-2-fluoropyridin-4-ylboronic acid (151 mg, 0.860 mmol) in DME (5 ml) was added Na2CO3 (1.433 ml, 2M, 2.87 mmol) and Pd(Ph3P)4 (66.2 mg, 0.057 mmol). The reaction mixture was capped and heated to 110° C. in an oil bath for 2 hr. The reaction mixture was diluted with EtOAc and washed with sat NaHCO3, and then sat NaCl. The organic layer was dried over Na2SO4, filtered and concentrated. The resulting residue was purified by column chromatography on silica gel (0-20% EtOAc/Hexane) to give 5′-chloro-2′-fluoro-6-(3-fluorobenzylamino)-2,4′-bipyridine-4-carbonitrile (95 mg, 47%). LCMS (m/z): 357.0 (MH+), retention time=1.09 min
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[N:15]1[CH2:20][CH2:19][CH:18]([N:21]2[C:30](=[O:31])[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][C:28]=3[CH3:32])[NH:23][C:22]2=[O:33])[CH2:17][CH2:16]1.[CH2:34](I)[CH2:35][CH3:36]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[N:15]1[CH2:16][CH2:17][CH:18]([N:21]2[C:30](=[O:31])[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][C:28]=3[CH3:32])[N:23]([CH2:34][CH2:35][CH3:36])[C:22]2=[O:33])[CH2:19][CH2:20]1
Reactant: COc1cc2ncnc(N3CCC(n4c(=O)[nH]c5cccc(C)c5c4=O)CC3)c2cc1OC
Reactant: CCCI
Product: CCCn1c(=O)n(C2CCN(c3ncnc4cc(OC)c(OC)cc34)CC2)c(=O)c2c(C)cccc21
Yield: 73 %

Procedure:
The procedure similar to that described in Example 1 was repeated, except that 300 mg (0.67 mmol) of Compound 100 was used in place of Compound 24 and propyl iodide was used in place of methyl iodide. As a result, 238.8 mg (yield: 73%) of Compound 58 was obtained as white crystals.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([Cl:12])=[CH:9][CH:10]=2)[C:5]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:4][N:3]=1.[C:19]([NH:22][NH2:23])(=O)[CH3:20]>C(O)CCC>[Cl:12][C:8]1[CH:7]=[C:6]2[C:11](=[CH:10][CH:9]=1)[C:2]1=[N:23][N:22]=[C:19]([CH3:20])[N:3]1[N:4]=[C:5]2[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CC(=O)NN
Reactant: Clc1ccc2c(Cl)nnc(-c3ccccc3)c2c1
Solvent: CCCCO
Product: Cc1nnc2c3ccc(Cl)cc3c(-c3ccccc3)nn12

Procedure:
A mixture of 1,6-dichloro-4-phenyl-phthalazine (8 g), acetyl hydrazine (4.4 g) and butanol (100 ml) is refluxed for 25 hours. Then the solvent is evaporated off and the residue is washed carefully with a small amount of water and crystallized from ethanol yielding 6 g of the compound of the title. M.p. 236°-38° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([C:15]([C:17]2[CH:22]=[CH:21][C:20]([N:23]3[C:27](=[O:28])[CH2:26][CH:25]([C:29]([OH:31])=O)[CH2:24]3)=[CH:19][CH:18]=2)=[O:16])[CH2:11][CH2:10]1.[CH3:32][N:33]([CH3:39])[C@H:34]1[CH2:38][CH2:37][NH:36][CH2:35]1>>[CH3:32][N:33]([CH3:39])[C@H:34]1[CH2:38][CH2:37][N:36]([C:29]([CH:25]2[CH2:24][N:23]([C:20]3[CH:19]=[CH:18][C:17]([C:15]([N:12]4[CH2:13][CH2:14][N:9]([C:3]5[CH:4]=[CH:5][C:6]([CH3:8])=[CH:7][C:2]=5[CH3:1])[CH2:10][CH2:11]4)=[O:16])=[CH:22][CH:21]=3)[C:27](=[O:28])[CH2:26]2)=[O:31])[CH2:35]1
Reactant: CN(C)[C@H]1CCNC1
Reactant: Cc1ccc(N2CCN(C(=O)c3ccc(N4CC(C(=O)O)CC4=O)cc3)CC2)c(C)c1
Product: Cc1ccc(N2CCN(C(=O)c3ccc(N4CC(C(=O)N5CC[C@H](N(C)C)C5)CC4=O)cc3)CC2)c(C)c1
Yield: 39.2 %

Procedure:
Using 1-{4-[4-(2,4-dimethylphenyl)piperazine-1-carbonyl]phenyl}-5-oxopyrrolidine-3-carboxylic acid (100 mg) described in Example 333 and (S)-3-(dimethylamino)pyrrolidine (27 mg) and by the reaction and treatment in the same manner as in Example 87, the title compound (48 mg) was obtained.
Reaction SMILES: C(O[CH:4](OCC)[CH2:5][O:6][C:7]1[C:14]([F:15])=[CH:13][C:12]([F:16])=[CH:11][C:8]=1[CH:9]=O)C.[BH4-].[Na+].P(Br)(Br)[Br:23]>C(O)(=O)C>[Br:23][CH2:4][C:5]1[O:6][C:7]2[C:14]([F:15])=[CH:13][C:12]([F:16])=[CH:11][C:8]=2[CH:9]=1
Reactant: BrP(Br)Br
Reactant: CCOC(COc1c(F)cc(F)cc1C=O)OCC
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Product: Fc1cc(F)c2oc(CBr)cc2c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 61.2 %

Procedure:
A stirred solution of 17 (380 mg, 1.39 mmol) in acetic acid (10 mL) was refluxed for 24 h. After cooling, the solution was evaporated to dryness. The crude product (300 mg) was dissolved in EtOH (5 mL). NaBH4 (73 mg, 1.98 mmol) was added portionwise at 0° C., with vigorous stirring. The suspension was stirred at 0° C. for 15 min and then at room temperature for 1.5 h. Solvents were evaporated off in-vacuo. The crude residue (280 mg) was dissolved in toluene (20 mL) and the solution was cooled to 0° C. PBr3 (142 μL, 1.52 mmol) was added dropwise over 15 min. The reaction mixture was then brought up to room temperature and stirred for 1 h. The solvent was evaporated off in-vacuo. The residue was adsorbed on silica gel and purified by flash chromatography, eluting with hexane/EtOAc (4:1) to give 18 (210 mg, 61%). 1H NMR (500 MHz, CDCl3): δ: 7.03 (1H, d, J=7.50 Hz, H-4), 6.87 (1H, t, J=9.80, H-5), 6.79 (1H, s, H-3), 4.59 (2H, s, 2-CH2).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]2[C:8]([CH3:12])([CH3:11])[CH2:9][NH:10][C:4]=2[CH:3]=1.[C:13](OC([O-])=O)([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14].O>C1COCC1.CN(C)C1C=CN=CC=1>[C:16]([O:15][C:13]([N:10]1[C:4]2[CH:3]=[C:2]([Cl:1])[N:7]=[CH:6][C:5]=2[C:8]([CH3:12])([CH3:11])[CH2:9]1)=[O:14])([CH3:19])([CH3:18])[CH3:17]
Reactant: CC1(C)CNc2cc(Cl)ncc21
Reactant: CC(C)(C)OC(=O)OC(=O)[O-]
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CC(C)(C)c2cnc(Cl)cc21
Reaction time: 2 h
Yield: 49.7 %

Procedure:
To a solution of 6-chloro-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-c]pyridine (1.3 g, 7.4 mmol) in THF (20 mL) were added tert-butyl dicarbonate (4.1 g, 18.6 mmol) and dimethyl-pyridin-4-yl-amine (2.22 g, 18.6 mmol) and the solution was stirred for 2 h. Water (60 mL) was added and the product was extracted with EtOAc. The organic phase was washed with brine, dried (MgSO4), filtered and evaporated. Chromatography (SiO2, eluted with petrol-EtOAc 0-40%) gave the title compound (1.04 g). 1H NMR (Me-d3-OD): 8.04 (1H, s), 7.60 (1H, s), 3.81 (2H, s), 1.59 (9H, s), 1.40 (6H, s). MS: [M+H]+=283.
Reaction SMILES: [F:1][C:2]1[C:3]([C:8]([OH:10])=O)=[N:4][CH:5]=[CH:6][CH:7]=1.Cl.CN(C)CCCN=C=NCC.[NH2:23][C:24]1[N:29]=[C:28]([NH:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[N:27]=[C:26]([C:37](=[N:39]O)[NH2:38])[N:25]=1>N1C=CC=CC=1>[F:1][C:2]1[C:3]([C:8]2[O:10][N:39]=[C:37]([C:26]3[N:27]=[C:28]([NH:30][C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[N:29]=[C:24]([NH2:23])[N:25]=3)[N:38]=2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1ncccc1F
Reactant: NC(=NO)c1nc(N)nc(Nc2ccccc2)n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: c1ccncc1
Product: Nc1nc(Nc2ccccc2)nc(-c2noc(-c3ncccc3F)n2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 13 %

Procedure:
3-Fluoropyridine-2-carboxylic acid (1.75 g, 12.38 mmol) was dissolved in pyridine (15 mL) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (2.74 g, 14.28 mmol) was added. The mixture was stirred at room temperature for 2 h. 4-Amino-N′-hydroxy-6-(phenylamino)-1,3,5-triazine-2-carboximidamide (prepared in an analogous manner to Intermediate 4, 2.33 g, 9.52 mmol) was added and the mixture stirred at room temperature for 16 h. LCMS showed incomplete conversion, so further N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (1.30 g, 6.8 mmol) was added and the mixture stirred at room temperature for 3 h, before being heated to 60 C under nitrogen for 16 h. Pyridine was removed under vacuum and water (100 mL) was added to the residue. The mixture was extracted with EtOAc (100 mL), with the addition of brine (100 mL) to aid separation of an emulsion. The aqueous phase was then extracted with DCM (100 mL), which also formed an emulsion. After separation the aqueous phase was filtered to remove an insoluble gum. The aqueous phase was then further extracted with DCM (2×100 mL). The combined DCM and EtOAc layers were dried over sodium sulfate and concentrated under vacuum to yield a pale orange solid. This was purified by FCC using a gradient of 0-8% MeOH in DCM. The crude product was further purified by trituration with DCM to afford the title compound as a white solid (0.425 g, 13%).