Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=2)=[C:10]([Cl:23])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:24]([C:36]3[N:40]([CH3:41])[CH:39]=[N:38][CH:37]=3)([C:26]3[CH:27]=[N:28][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:30][CH:31]=3)[OH:25])[CH:8]=2)[N:3]=1.[NH:42]1[CH2:45][CH2:44][CH2:43]1.CN(C)C=O>C(OCC)(=O)C>[N:42]1([C:2]2[C:11]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([C:19]([F:20])([F:21])[F:22])=[CH:15][CH:14]=3)=[C:10]([Cl:23])[C:9]3[C:4](=[CH:5][CH:6]=[C:7]([C:24]([C:36]4[N:40]([CH3:41])[CH:39]=[N:38][CH:37]=4)([C:26]4[CH:27]=[N:28][C:29]([C:32]([F:33])([F:34])[F:35])=[CH:30][CH:31]=4)[OH:25])[CH:8]=3)[N:3]=2)[CH2:45][CH2:44][CH2:43]1
Reactant: Cn1cncc1C(O)(c1ccc(C(F)(F)F)nc1)c1ccc2nc(Cl)c(Cc3ccc(C(F)(F)F)cc3)c(Cl)c2c1
Reactant: C1CNC1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cn1cncc1C(O)(c1ccc(C(F)(F)F)nc1)c1ccc2nc(N3CCC3)c(Cc3ccc(C(F)(F)F)cc3)c(Cl)c2c1
Temperature: 100 °C

Procedure:
To a 75 mL sealed tube was added (2,4-dichloro-3-(4-(trifluoromethyl)benzyl)quinolin-6-yl)(1-methyl-1H-imidazol-5-yl)(6-(trifluoromethyl)pyridin-3-yl)methanol (2.50 g, 4.09 mmol, intermediate 60), azetidine (0.83 mL, 12.3 mmol) and dimethylformamide (30 mL). The reaction vessel was sealed and heated in a 100° C. oil bath. After overnight heating, the vessel was cooled and contents transferred to a separatory funnel with ethyl acetate dilution. The organic phase was extracted with a saturated, aqueous ammonium chloride solution and deionized water. The organic phase was separated, dried over magnesium sulfate, filtered and evaporated to dryness under reduced pressure. Chromatography on silica gel (dichloromethane increasing to 10% ((2M ammonia in methanol) in dichloromethane)) provided the title compound. MS (ESI): mass calcd. for C31H24ClF6N5O, 631.16; m/z found, 632.5 [M+H]+. 1H NMR (600 MHz, Chloroform-d) δ 8.81 (d, J=2.2 Hz, 1H), 8.05 (d, J=2.1 Hz, 1H), 7.87 (dd, J=8.3, 2.2 Hz, 1H), 7.70 (d, J=8.8 Hz, 1H), 7.60 (d, J=8.3 Hz, 1H), 7.52 (d, J=8.0 Hz, 2H), 7.46 (dd, J=8.8, 2.2 Hz, 1H), 7.21 (d, J=8.0 Hz, 2H), 7.09 (d, J=1.1 Hz, 1H), 6.19 (d, J=1.1 Hz, 1H), 4.32 (s, 2H), 4.13 (t, J=7.7 Hz, 4H), 3.31 (s, 3H), 2.29-2.20 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([C:6]([C:22]#[CH:23])([OH:21])[C:7]2[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][N:16]([CH2:19][CH3:20])[CH2:17][CH3:18])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[H][H]>[Pd].C1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([CH2:22][CH3:23])([OH:21])[C:7]2[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][N:16]([CH2:17][CH3:18])[CH2:19][CH3:20])=[CH:9][CH:8]=2)=[CH:24][CH:25]=1
Reactant: [H][H]
Reactant: C#CC(O)(c1ccc(Cl)cc1)c1ccc(OCCN(CC)CC)cc1
Agent: [Pd]
Solvent: c1ccccc1
Product: CCN(CC)CCOc1ccc(C(O)(CC)c2ccc(Cl)cc2)cc1

Procedure:
17.9 g. of 4-chloro-4'-[2-(diethylamino)ethoxy]-α-ethinyl-benzhydrol are dissolved in 180 ml. of benzene, and the reaction mixture is hydrogenated in the presence of 0.9 g. of a 10% palladium-on-charcoal catalyst. As soon as the uptake of the calculated amount of hydrogen is complete, the catalyst is filtered off, and benzene is distilled off under reduced pressure. The solid residue is crystallized from n-hexane to yield 14.2 g. of the title compound, melting at 50° to 51° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([Cl:8])[CH:5]=[C:4]([NH2:9])[N:3]=1.CO[CH:12](OC)[CH2:13][CH:14](OC)OC>>[NH2:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]2[CH:14]=[CH:13][CH:12]=[N:9][C:4]=2[N:3]=1
Reactant: COC(CC(OC)OC)OC
Reactant: Nc1cc(Cl)nc(N)n1
Product: Nc1nc(Cl)c2cccnc2n1

Procedure:
Starting from 2,6-diamino-4-chloropyrimidine and 1,1,3,3-tetramethoxypropane and using a procedure analogous to that of Example 71, the above compound is isolated after chromatographic purification on silica gel with methanol/diisopropylether (1:1) as a yellow oil which can be used in the following reactions without any further purification.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[C:8]([N:11]([C:22](=[O:30])[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[Cl:29])[C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH3:21])[CH:13]=2)[S:9][CH:10]=1)=[O:5])C.C(O)(=O)C.Cl>O1CCOCC1>[Cl:29][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1[C:22]([N:11]([C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH3:21])[CH:13]=1)[C:8]1[S:9][CH:10]=[C:6]([C:4]([OH:5])=[O:3])[N:7]=1)=[O:30]
Reactant: CCOC(=O)c1csc(N(C(=O)c2ccccc2Cl)c2ccc(OC)c(OC)c2)n1
Agent: Cl
Solvent: CC(=O)O
Solvent: C1COCCO1
Product: COc1ccc(N(C(=O)c2ccccc2Cl)c2nc(C(=O)O)cs2)cc1OC
Temperature: 60 °C

Procedure:
A mixture of 2.09 g (4.68 mmol) 2-[(2-Chloro-benzoyl)-(3,4-dimethoxy-phenyl)-amino]-thiazole-4-carboxylic acid ethyl ester, 2.5 ml acetic acid and 7.5 ml HCl conc. in 10 ml dioxane was heated to 60° C. for 2 h. The mixture was subjected to reversed phase HPLC purification eluting with an acetonitrile/water gradient to yield after evaporation of the product fractions 1.1 g (56%) of the title compound. MS (m/e): 419.2 (MH+, 100%)
Reaction SMILES: [CH2:1]([N:4]([CH2:16][CH2:17][CH3:18])[C:5]1[C:10]2[N:11]([CH3:15])[C:12](=[O:14])[NH:13][C:9]=2[CH:8]=[CH:7][CH:6]=1)[CH2:2][CH3:3].[Br:19]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl.O>[Br:19][C:8]1[C:9]2[NH:13][C:12](=[O:14])[N:11]([CH3:15])[C:10]=2[C:5]([N:4]([CH2:1][CH2:2][CH3:3])[CH2:16][CH2:17][CH3:18])=[CH:6][CH:7]=1
Reactant: CCCN(CCC)c1cccc2[nH]c(=O)n(C)c12
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: O
Product: CCCN(CCC)c1ccc(Br)c2[nH]c(=O)n(C)c12
Yield: 27.7 %

Procedure:
A mixture of 7-dipropylamino-1-methyl-1,3-dihydro-2H-benzimidazol-2-one (200 mg, 0.809 mmol), N-bromosuccinimide (216 mg, 1.21 mmol) and catalytic amount of benzoylperoxide in carbon tetrachloride (20 ml) was refluxed for 60 h and diluted with water. The aqueous solution was extracted with dichloromethane. The extract was washed with brine, dried over magnesium sulfate and concentrated under vacuum. The residue was purified by column chromatography eluting 30% ethyl acetate/n-hexane to afford 73 mg (28%) of the title compound.
Reaction SMILES: Br[C:2]1[N:3]([CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][O:19]2)[C:4]2[C:9]([N:10]=1)=[C:8]([NH2:11])[N:7]=[C:6]([O:12][CH2:13][CH2:14][CH:15]([CH3:17])[CH3:16])[N:5]=2.[CH3:24][O-:25].[Na+]>CCOC(C)=O>[CH3:16][CH:15]([CH3:17])[CH2:14][CH2:13][O:12][C:6]1[N:5]=[C:4]2[C:9]([N:10]=[C:2]([O:25][CH3:24])[N:3]2[CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][O:19]2)=[C:8]([NH2:11])[N:7]=1
Reactant: CC(C)CCOc1nc(N)c2nc(Br)n(C3CCCCO3)c2n1
Reactant: C[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: COc1nc2c(N)nc(OCCC(C)C)nc2n1C1CCCCO1

Procedure:
To a solution of 8-bromo-2-[(3-methylbutyl)oxy]-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-amine (314 mg) was added sodium methoxide solution (0.460 mL, 30% wt. MeOH) and the mixture was stirred at reflux for 4 h. The reaction was allowed to cool and was concentrated in vacuo to give an orange residue. The residue was taken up in EtOAc (20 mL) and was extracted with saturated ammonium chloride solution (20 mL), followed by water (20 mL). The organics were separated, dried over MgSO4, filtered and concentrated in vacuo to give the title compound as a light orange solid (210 mg).
Reaction SMILES: [N:1]1([CH2:7][CH2:8][CH2:9][NH:10][C:11]2[N:12]=[N+:13]([O-:24])[C:14]3[CH:23]=[C:22]4[C:18]([CH2:19][CH2:20][CH2:21]4)=[CH:17][C:15]=3[N:16]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C[OH:26]>>[N:1]1([CH2:7][CH2:8][CH2:9][NH:10][C:11]2[N:12]=[N+:13]([O-:24])[C:14]3[CH:23]=[C:22]4[C:18]([CH2:19][CH2:20][CH2:21]4)=[CH:17][C:15]=3[N+:16]=2[O-:26])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: CO
Reactant: [O-][n+]1nc(NCCCN2CCOCC2)nc2cc3c(cc21)CCC3
Product: [O-][n+]1nc(NCCCN2CCOCC2)[n+]([O-])c2cc3c(cc21)CCC3

Procedure:
H2O2 (70%, 0.60 mL, ca. 11.9 mmol) was added dropwise to a stirred solution of TFAA (1.7 mL, 11.9 mmol) in DCM (15 mL) at 0° C. The solution was stirred at 0° C. for 5 min, warmed to 20° C. for 10 min, then cooled to 0° C. and added to a stirred solution of 1-oxide 60 (412 mg, 1.2 mmol) and TFA (0.46 mL, 6.0 mmol) in DCM (20 mL) at 0° C. The solution was stirred at 20° C. for 4 h, diluted with dilute aqueous NH3 solution (10 mL) and extracted with CHCl3 (4×50 mL). The combined organic fraction was dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (0-10%) of MeOH/DCM, to give (i) starting material 60 (208 mg, 50%) and (ii) 1,4-dioxide 61 (122 mg, 30%) as a red solid: mp (MeOH) 158-160° C.; 1H NMR δ 8.37 (br s, 1H, NH), 8.11 (s, 1H, H-5), 8.09 (s, 1H, H-9), 3.80-3.84 (m, 4H, 2×CH2O), 3.64-3.69 (m, 2H, CH2N), 3.02-3.10 (m, 4H, H-6, H-8), 2.56 (dd, J=6.2, 6.1 Hz, 2H, CH2N), 2.48-2.52 (m, 4H, 2×CH2N), 2.15-2.22 (m, 2H, H-7), 1.85-1.91 (m, 2H, CH2); 13C NMR δ 155.5, 149.5, 145.6, 138.0, 129.6, 115.8, 111.6, 66.9 (2), 57.7, 53.8 (2), 41.6, 33.3, 32.3, 25.5, 24.5. Anal. calcd for C17H23N5O3.¼CH3OH: C, 58.6; H, 6.9; N, 19.8. Found: C, 58.4; H, 6.7; N, 19.9%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][C:10](OCC)=[O:11])=[C:4]([F:16])[CH:3]=1.O.[NH2:18][NH2:19]>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([OH:11])[NH:19][N:18]=2)=[C:4]([F:16])[CH:3]=1
Reactant: CCOC(=O)CC(=O)c1ccc(Cl)cc1F
Reactant: NN
Solvent: CCO
Solvent: O
Product: Oc1cc(-c2ccc(Cl)cc2F)n[nH]1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 77.7 %

Procedure:
428.4 g of ethyl 3-(4-chloro-2-fluorophenyl)-3-oxopropionate were initially charged in 1400 ml of ethanol. Over a period of 15 min, 92 g of hydrazine hydrate were added dropwise, the mixture was stirred at room temperature overnight, the precipitated solid was filtered off and the filtrate was concentrated to ⅓ of its original volume. The mixture was stirred for another two nights, the resulting solid was filtered off with suction and the filtrate was again concentrated to ⅓ of its original volume. This gave a total of 289.1 g (77.7%) of 3-(4-chloro-2-fluorophenyl)-5-hydroxy-1H-pyrazole as a colorless solid. M.p.: 194° C.
Reaction SMILES: Br.[Br-].[N:3]1([CH2:8][CH2:9][CH2:10][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH2:7][CH2:6][CH2:5][CH2:4]1.C([Li])CCC.[Br:35][C:36]1[CH:52]=[CH:51][C:39]2[O:40][CH2:41][C:42]3[CH:49]=[CH:48][C:47]([Br:50])=[CH:46][C:43]=3[C:44](=O)[C:38]=2[CH:37]=1.CS(C)=O>CCCCCC.O1CCCC1>[Br:35][C:36]1[CH:52]=[CH:51][C:39]2[O:40][CH2:41][C:42]3[CH:49]=[CH:48][C:47]([Br:50])=[CH:46][C:43]=3/[C:44](=[CH:10]/[CH2:9][CH2:8][N:3]3[CH2:4][CH2:5][CH2:6][CH2:7]3)/[C:38]=2[CH:37]=1
Reactant: O=C1c2cc(Br)ccc2COc2ccc(Br)cc21
Reactant: c1ccc([P+](CCCN2CCCC2)(c2ccccc2)c2ccccc2)cc1
Agent: Br
Agent: [Br-]
Agent: [Li]CCCC
Solvent: CS(C)=O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Brc1ccc2c(c1)/C(=C/CCN1CCCC1)c1cc(Br)ccc1OC2

Procedure:
Anhydrous 3-(N-pyrrolidinyl)propyltriphenylphosphonium bromide hydrobromide (47 g, 0.08 mole), 0.20 mole of n-butyl lithium in hexane (1.6 M), and 2,9-dibromo-6,11-dihydrodibenz[b,e]oxepin-11-one (25 g, 0.07 mole) in one liter of dry tetrahydrofuran by the procedure of Example 1, Step a. The crude product was chromatographed on a silica gel column (Waters Associates - Prep 500) with ethyl acetate/methanol (95:5) to give the product as 98% pure Z-isomer (0.30 g), mp 102°-103° C. pmr (DMSO-d6) δ: 7.31-7.54 (m, 5H, aromatic H), 6.79 (d, J=7.8 Hz, H4 of 98% Z), 6.67 (d, J=7.8 Hz, H of 2% E), 6.11 (t, CH= of 2% E), 5.78 (t, CH= of 98% Z), 2.34-2.56 (m, 8H, CH2 and 3NHCH2), 1.63 (m, 4H, 2CH2). And it gave another batch of the product as 90% pure E-isomer (0.18 g), mp 115°-116° C., pmr (DMSO) δ: 7.71-7.68 (m, 5H, aromatic H), 6.80 (d, J=7.8 Hz, H4 of 10% Z), 6.70 (d, J=7.8 Hz, H4 of 90% E), 6.10 (t, CH= of 90% E), 5.81 (t, CH= of 10% Z), 2.26-2.40 (m, 8H, CH2 and 3NCH2), 1.60 (m, 4H, 2CH2).
Reaction SMILES: B.[NH2:2][C:3]1[CH:4]=[CH:5][C:6]([S:13][CH:14]([CH3:16])[CH3:15])=[C:7]([CH:12]=1)[C:8]([NH:10][CH3:11])=O.Cl>C1COCC1>[CH:14]([S:13][C:6]1[CH:5]=[CH:4][C:3]([NH2:2])=[CH:12][C:7]=1[CH2:8][NH:10][CH3:11])([CH3:16])[CH3:15]
Reactant: CNC(=O)c1cc(N)ccc1SC(C)C
Agent: B
Agent: Cl
Solvent: C1CCOC1
Product: CNCc1cc(N)ccc1SC(C)C
Temperature: 70 °C
Yield: 112.1 %

Procedure:
Borane (1M solution in THF, 10 mL, 10 mmol) was added slowly dropwise to a solution of 16C (0.98 g, 4.37 mmol) in THF (60 mL) at 0° C. The reaction mixture was then heated to 70° C. overnight. The reaction mixture was cooled in an ice bath and quenched by cautious addition of hydrochloric acid (2N, 12 mL, 24 mmol). The reaction mixture was refluxed for 2 h and then concentrated almost to dryness in vacuo. The residue was coevaporated with methanol (3×), diluted with ethyl acetate and sodium hydroxide solution (2N). The aqueous layer was extracted with ethyl acetate (3×), dried (MgSO4), and concentrated in vacuo to give 16D (1.03 g, 100%) as a clear oil. MS (ESI) m/z 211.1 (M+H)+.
Reaction SMILES: [P:1]([O:6][CH3:7])([O:4][CH3:5])[O:2]C.[Br:8][C:9]1[C:10]([OH:19])=[C:11]([CH:14]=[C:15]([O:17][CH3:18])[CH:16]=1)[CH2:12]Br>>[CH3:5][O:4][P:1]([CH2:12][C:11]1[CH:14]=[C:15]([O:17][CH3:18])[CH:16]=[C:9]([Br:8])[C:10]=1[OH:19])(=[O:2])[O:6][CH3:7]
Reactant: COc1cc(Br)c(O)c(CBr)c1
Reactant: COP(OC)OC
Product: COc1cc(Br)c(O)c(CP(=O)(OC)OC)c1

Procedure:
8.8 g of trimethyl phosphite are added to 20.0 g of 3-bromo-2-hydroxy-5-methoxy-benzyl bromide and, with stirring, the mixture is heated for 3 hours at 140° (complete conversion according to TLC). The resulting oil is filtered with toluene/ethyl acetate (4:1) as eluant over a small amount of silica gel. [(3-Bromo-2-hydroxy-5-methoxy-phenyl)methyl]phosphonic acid dimethyl ester is thus obtained [1H-NMR (360 MHz, CDCl3): 3.20 (d, 2H, CH2P, 2JP-H =21 Hz), 3.70 (s, 3H, OCH3), 3.74 (d, 6H, 2×OCH33JP-H =1 Hz), 6.70 (m, 1H), 7.07 (m, 1H) ppm].
Reaction SMILES: [Li].[C:2]([C:4]1[CH:5]=[C:6]([C:15]([O-])=[CH:16][C:17](=O)[C:18]([O:20]CC)=[O:19])[CH:7]=[C:8]([O:10][C:11]([F:14])([F:13])[F:12])[CH:9]=1)#[N:3].ClC1C=C(C2N(C3C=CC=CN=3)N=C(C(O)=O)C=2)C=C(F)C=1.Cl.[N:48]1[CH:53]=[CH:52][CH:51]=[C:50]([NH:54][NH2:55])[CH:49]=1>>[C:2]([C:4]1[CH:5]=[C:6]([C:15]2[N:54]([C:50]3[CH:49]=[N:48][CH:53]=[CH:52][CH:51]=3)[N:55]=[C:17]([C:18]([OH:20])=[O:19])[CH:16]=2)[CH:7]=[C:8]([O:10][C:11]([F:12])([F:13])[F:14])[CH:9]=1)#[N:3]
Reactant: NNc1cccnc1
Reactant: CCOC(=O)C(=O)C=C([O-])c1cc(C#N)cc(OC(F)(F)F)c1
Agent: Cl
Agent: O=C(O)c1cc(-c2cc(F)cc(Cl)c2)n(-c2ccccn2)n1
Agent: [Li]
Product: N#Cc1cc(OC(F)(F)F)cc(-c2cc(C(=O)O)nn2-c2cccnc2)c1

Procedure:
300 mg (0.81 mmol) of the compound of Example 11A is reacted analogously to the synthesis of the compound of Example 20A with 175 mg (1.21 mmol) of 3-pyridylhydrazine hydrochloride. After hydrolysis, 148 mg (49% of theory) of the title compound is obtained.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:12]=[C:11]([O:13][C:14]([F:17])([F:16])[F:15])[CH:10]=[CH:9][C:8]=2[OH:18])=[CH:5][CH:4]=[N:3]1.[C:19]([C:21]1[CH:22]=[C:23]([S:28]([NH:31][C:32]2[S:33][CH:34]=[CH:35][N:36]=2)(=[O:30])=[O:29])[CH:24]=[CH:25][C:26]=1F)#[N:20]>>[C:19]([C:21]1[CH:22]=[C:23]([S:28]([NH:31][C:32]2[S:33][CH:34]=[CH:35][N:36]=2)(=[O:30])=[O:29])[CH:24]=[CH:25][C:26]=1[O:18][C:8]1[CH:9]=[CH:10][C:11]([O:13][C:14]([F:15])([F:16])[F:17])=[CH:12][C:7]=1[C:6]1[N:2]([CH3:1])[N:3]=[CH:4][CH:5]=1)#[N:20]
Reactant: N#Cc1cc(S(=O)(=O)Nc2nccs2)ccc1F
Reactant: Cn1nccc1-c1cc(OC(F)(F)F)ccc1O
Product: Cn1nccc1-c1cc(OC(F)(F)F)ccc1Oc1ccc(S(=O)(=O)Nc2nccs2)cc1C#N
Yield: 97 %

Procedure:
2-(1-methyl-1H-pyrazol-5-yl)-4-(trifluoromethoxy)phenol (Preparation 533, 50.0 mg, 0.20 mmol) and 3-cyano-4-fluoro-N-(1,3-thiazol-2-yl)benzenesulfonamide (Preparation 46, 57 mg, 0.20 mmol) were used to prepare the title compound using Method F above. The product was purified by flash column chromatography (SiO2) eluting with dichloromethane:ethyl acetate (gradient 8:2 to 2:8, by volume) to afford the title compound, 98 mg, 97% yield.
Reaction SMILES: O[CH2:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[C:5]([C:13]2[NH:14][C:15](=[O:22])[C:16]([CH:19]([CH3:21])[CH3:20])([CH3:18])[N:17]=2)[N:4]=1.S(Cl)([Cl:25])=O>C(Cl)(Cl)Cl>[Cl:25][CH2:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[C:5]([C:13]2[NH:14][C:15](=[O:22])[C:16]([CH:19]([CH3:21])[CH3:20])([CH3:18])[N:17]=2)[N:4]=1
Reactant: O=S(Cl)Cl
Reactant: COC(=O)c1ccc(CO)nc1C1=NC(C)(C(C)C)C(=O)N1
Solvent: ClC(Cl)Cl
Product: COC(=O)c1ccc(CCl)nc1C1=NC(C)(C(C)C)C(=O)N1

Procedure:
To a solution of 8.7 g of methyl 6-hydroxymethyl-2-(4-isopropyl-4-methyl-5-oxo-2-imidazolin-2-yl)nicotinate in 90 mL chloroform, stirred at room temperature, is added dropwise 4.2 mL of thionyl chloride. When the addition is complete, the solution is heated at reflux for 1 hour. The reaction is concentrated in vacuo, and the residue is dissolved in methylene chloride and washed with saturated sodium bicarbonate solution. The organic phase is dried and concentrated in vacuo to an oil. Trituration of this oil affords the desired product as a solid. Recrystallization from methylene chloride-hexane gives analytically pure material, mp 127°-129° C.
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[C:12](Cl)=[C:11]([Cl:16])[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:17][C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1.C([O-])([O-])=O.[Na+].[Na+].O>C1(C)C=CC=CC=1.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>[CH2:1]([N:8]1[C:13](=[O:14])[C:12]([C:21]2[CH:22]=[CH:23][C:18]([Cl:17])=[CH:19][CH:20]=2)=[C:11]([Cl:16])[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: O=c1c(Cl)c(Cl)cnn1Cc1ccccc1
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: O
Solvent: Cc1ccccc1
Product: O=c1c(-c2ccc(Cl)cc2)c(Cl)cnn1Cc1ccccc1
Temperature: 100 °C
Reaction time: 16 h
Yield: 30.2 %

Procedure:
To a mixture of 2-benzyl-4,5-dichloropyridazin-3(2H)-one (30.6 g, 120 mmol), prepared as described in Example 244A, 4-chlorophenyl boronic acid (20.6 g, 132 mmol) and tetrakis(triphenylphosphine)palladium (5 g, 4.3 mmol) in toluene (300 mL) under an atmosphere of argon, and was added an aqueous Na2CO3 solution (2M, 66 mL, 132 mmol). The reaction mixture was stirred at 100° C. under argon for 16 h. The reaction was then allowed to cool to RT and was subsequently poured into water (200 mL). The resulting mixture was extracted with EtOAc (3×150 mL). The combined organic layers were washed with saturated aqueous NaCl. The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The obtained thick syrup was dissolved in MeOH (100 mL) and the resulting solution kept at 0° C. until white solid precipitated. The solid was collected by filtration, washed with hexanes, and then triturated with EtOAc-hexanes to give the title compound, 2-benzyl-5-chloro-4-(4-chlorophenyl)pyridazin-3(2H)-one (12 g, 30%) as a white powder. LC/MS (method A, general procedure): RT=3.81 min, (M+H)+=331.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][C:7]([CH3:13])([CH3:12])[CH:6]([OH:14])[CH:5]2[CH2:15][S:16]([NH:19][CH2:20][C:21](O)=[O:22])(=[O:18])=[O:17].C1N=CN(C(N2C=NC=C2)=O)C=1.[CH2:36]([NH2:44])[CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>C1COCC1.CC(=O)OCC>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][C:7]([CH3:12])([CH3:13])[CH:6]([OH:14])[CH:5]2[CH2:15][S:16]([NH:19][CH2:20][C:21]([NH:44][CH2:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)=[O:22])(=[O:18])=[O:17]
Reactant: CC1(C)Oc2ccc(Cl)cc2C(CS(=O)(=O)NCC(=O)O)C1O
Reactant: NCCc1ccccc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC1(C)Oc2ccc(Cl)cc2C(CS(=O)(=O)NCC(=O)NCCc2ccccc2)C1O
Reaction time: 8 h
Yield: 87.5 %

Procedure:
A solution of 0.5 g (1.37 mmol) of [(6-chloro-3-hydroxy-2,2-dimethylchroman-4-yl)methanesulfonylamino]acetic acid and 0.27 g (1.65 mmol) of CDI in 7 ml of THF was stirred at RT for 3 h. 0.33 g (2.75 mmol) of phenethylamine was then added and the reaction mixture was stirred overnight. After stripping off the solvent, the residue was taken up in EA and washed with dil. hydrochloric acid and water. After purification through a short chromatography column, 0.56 g of 2-[(6-chloro-3-hydroxy-2,2-dimethylchroman-4-yl)methanesulfonylamino]-N-phenethylacetamide was obtained; m.p. 168-170° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]([N:13]([C:24]2[CH:29]=[CH:28][C:27]([C:30](OC)=[O:31])=[CH:26][CH:25]=2)[C:14]2[CH:19]=[CH:18][C:17]([C:20](OC)=[O:21])=[CH:16][CH:15]=2)[CH:10]=[CH:9][C:4]=1[C:5](OC)=[O:6].[H-].[Al+3].[Li+].[H-].[H-].[H-].O>O1CCCC1.ClCCl>[OH:21][CH2:20][C:17]1[CH:16]=[CH:15][C:14]([N:13]([C:24]2[CH:25]=[CH:26][C:27]([CH2:30][OH:31])=[CH:28][CH:29]=2)[C:11]2[CH:10]=[CH:9][C:4]([CH2:5][OH:6])=[C:3]([O:2][CH3:1])[CH:12]=2)=[CH:19][CH:18]=1
Reactant: COC(=O)c1ccc(N(c2ccc(C(=O)OC)cc2)c2ccc(C(=O)OC)c(OC)c2)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(N(c2ccc(CO)cc2)c2ccc(CO)cc2)ccc1CO
Temperature: -78 °C
Reaction time: 1 h
Yield: 96 %

Procedure:
A solution of compound 7 (1.35 g, 3 mmol) in 20 mL of THF is added dropwise to a suspension of lithium aluminium hydride (LiAlH4, 1.7 g, 45 mmol, 15 eq.) in dry tetrahydrofuran (THF) (30 mL) at −78° C. The temperature of the medium is allowed to return to room temperature and then the reaction is heated under reflux with stirring. After 1 hour, the solution is cooled to −78° C. and diluted with dichloromethane, and then water (10 mL) is slowly poured in. The solid obtained is filtered and washed with dichloromethane. The mother liquors are washed with water and with brine and then dried and concentrated to give 1.05 g (2.88 mmol) of a pasty compound (yield: 97%).
Reaction SMILES: [NH2:1][CH:2]1[CH2:6][CH2:5][N:4]([C:7]2[C:16]([F:17])=[C:15]3[C:10]([C:11](=[O:27])[C:12]([C:22]([O:24]CC)=[O:23])=[CH:13][N:14]3[CH:18]([CH3:21])[CH2:19]Cl)=[CH:9][C:8]=2[F:28])[CH2:3]1.C(O)C.[OH-].[K+]>O>[NH2:1][CH:2]1[CH2:6][CH2:5][N:4]([C:7]2[C:16]([F:17])=[C:15]3[C:10]([C:11](=[O:27])[C:12]([C:22]([OH:24])=[O:23])=[CH:13][N:14]3[C:18]([CH3:21])=[CH2:19])=[CH:9][C:8]=2[F:28])[CH2:3]1
Reactant: CCOC(=O)c1cn(C(C)CCl)c2c(F)c(N3CCC(N)C3)c(F)cc2c1=O
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: C=C(C)n1cc(C(=O)O)c(=O)c2cc(F)c(N3CCC(N)C3)c(F)c21
Yield: 39.2 %

Procedure:
159 mg (0.38 mmol) of ethyl 7-(3-amino-1-pyrrolidinyl)-1-(1-chloroprop-2-yl)-6,8-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate (Compound No.1) prepared in Example 1 was dissolved into 20 ml of ethanol. To this was added 65 mg (1.15 mmol) of pulverized potassium hydroxide and the mixture was heated under refluxing for 14 hours. 3 ml of water was added and the mixture was heated under refluxing for a further 3 hours. After cooling, the reaction mixture was concentrated under reduced pressure, the residue was washed with water, and dried to obtain a crude product. The crude product was purified by silica gel column chromatography (chloroform:methanol=5:1) to obtain 52 mg of light yellow crystals of 7-(3-amino-1-pyrrolidinyl)-6,8-difluoro-1,4-dihydro-4-oxo-1-(prop-1-en-2-yl)-quinoline-3-carboxylic acid (Compound No. 19).
Reaction SMILES: [Cl:1][C:2]1[C:11]([NH:12][C:13](=O)[CH2:14][O:15][CH2:16][CH3:17])=[C:10]([NH:19][CH2:20][CH2:21][CH2:22][C:23]#[CH:24])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.C(=O)([O-])[O-].[K+].[K+]>C(O)C.O>[Cl:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:14][O:15][CH2:16][CH3:17])[N:19]([CH2:20][CH2:21][CH2:22][C:23]#[CH:24])[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1
Reactant: C#CCCCNc1c(NC(=O)COCC)c(Cl)nc2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: C#CCCCn1c(COCC)nc2c(Cl)nc3ccccc3c21

Procedure:
A solution of N-[2-chloro-4-(pent-4-ynylamino)quinolin-3-yl]-2-ethoxyacetamide (10.23 g, 29.58 mmol) and 6 M aqueous potassium carbonate (7.40 mL, 44.4 mmol) in 9:1 ethanol/water (100 mL) was heated at 50° C. for 16 hours. The volatiles were removed under reduced pressure and the resulting slurry was partitioned between ethyl acetate and water. The organic phase was washed with water (2×) and brine (2×), dried over magnesium sulfate, filtered, and concentrated to afford 4-chloro-2-(ethoxymethyl)-1-pent-4-ynyl-1H-imidazo[4,5-c]quinoline as a slightly impure tan solid (9.5 g).