Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][C:23]=1[Cl:24])[O:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]([CH:12]=[C:13]([NH:15][C:16]([CH:18]3[CH2:20][CH2:19]3)=[O:17])[N:14]=2)[N:11]=1.[F:25][C:26]([F:37])([F:36])[C:27]1[CH:28]=[C:29]([CH:33]=[CH:34][CH:35]=1)[C:30](Cl)=[O:31].C(=O)([O-])O.[Na+]>CN1CCCC1=O>[Cl:24][C:23]1[CH:22]=[CH:21][C:4]([O:5][C:6]2[CH:7]=[CH:8][C:9]3[N:10]([CH:12]=[C:13]([NH:15][C:16]([CH:18]4[CH2:20][CH2:19]4)=[O:17])[N:14]=3)[N:11]=2)=[CH:3][C:2]=1[NH:1][C:30](=[O:31])[C:29]1[CH:33]=[CH:34][CH:35]=[C:27]([C:26]([F:25])([F:36])[F:37])[CH:28]=1
Reactant: Nc1cc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)ccc1Cl
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: O=C(Nc1cc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)ccc1Cl)c1cccc(C(F)(F)F)c1
Temperature: 50 °C
Reaction time: 0.17 h
Yield: 84.6 %

Procedure:
A mixture of N-[6-(3-amino-4-chlorophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (103 mg, 0.30 mmol), 3-(trifluoromethyl)benzoyl chloride (75 mg, 0.36 mmol) and N-methylpyrrolidone (3.0 mL) was heated to 50° C., and the mixture was stirred for 10 min. The reaction mixture was poured into saturated aqueous sodium hydrogencarbonate solution, and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=1/19→ethyl acetate) to give the title compound (131 mg, 85%) as a white powder.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:5]=[C:4]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[N:3]=1.[CH3:22][NH:23][NH2:24].C(O)CO>O>[NH2:9][C:8]1[C:7]2[C:2](=[N:3][C:4]([N:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[CH:5][C:6]=2[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:23]([CH3:22])[N:24]=1
Reactant: CNN
Reactant: N#Cc1c(-c2ccccc2)cc(N2CCOCC2)nc1Cl
Solvent: OCCO
Solvent: O
Product: Cn1nc(N)c2c(-c3ccccc3)cc(N3CCOCC3)nc21
Temperature: 170 °C

Procedure:
A mixture consisting of 3.0 gm (0.01 mol) of 2-chloro-6-morpholino-4-phenyl-3-cyano-pyridine, 1.4 gm (0.03 mol) of methyl-hydrazine and 4 ml of ethylene glycol was refluxed for 3 hours at 170° C. (bath temperature). The resulting solution was then taken up in 50 ml of water, whereupon the reaction product initially separated out as a pasty precipitate. The pasty product was collected and digested with water, and after it has solidified it was suction-filtered off, washed and dried, yielding 2.8 gm (91% of theory) of the compound of the formula ##STR7## After recrystallizing the product over from methanol it had a melting point of 149°-152° C.
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][N:7]2[C:11]3=[N:12][CH:13]=[C:14]([O:16][CH3:17])[CH:15]=[C:10]3[CH:9]=[C:8]2/[CH:18]=[CH:19]/[C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:4][CH:3]=1>CCO.CCOC(C)=O.[Pd]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:11]3=[N:12][CH:13]=[C:14]([O:16][CH3:17])[CH:15]=[C:10]3[CH:9]=[C:8]2[CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:25][CH:26]=1
Reactant: CCOC(=O)/C=C/c1cc2cc(OC)cnc2n1Cc1ccc(Cl)cc1
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCOC(=O)CCc1cc2cc(OC)cnc2n1Cc1ccc(Cl)cc1

Procedure:
To a solution of Ethyl (E)-3-[1-(4-chloro-benzyl)-5-methoxy-1H-pyrrolo[2,3-b]pyridin-2-yl]-acrylate (100 mg, 0.270 mmol) in a mixture of EtOH (2 mL) and EtOAc (2 mL) was added Pd/C (˜15 mg) and maintained under an atmosphere of H2 for 36 hrs. The resulting slurry was filtered through celite eluting with EtOAc, and the solvent evaporated to afford the title acid as a green oil used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:42])[C@@H:4]([NH:32][C@H:33]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[CH2:34][CH3:35])[CH2:5][C:6]1[CH:31]=[CH:30][C:9]2[O:10][C@@H:11]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH2:21][C:22]4[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([Cl:29])[CH:23]=4)[CH:15]=3)[CH2:12][O:13][C:8]=2[CH:7]=1.C=O.F[C:46](F)(F)C(O)=O.C([O-])(O)=O.[Na+]>O1CCOCC1>[CH3:1][O:2][C:3]([C@@H:4]1[CH2:5][C:6]2[CH:7]=[C:8]3[O:13][CH2:12][C@H:11]([C:14]4[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH2:21][C:22]5[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([Cl:29])[CH:23]=5)[CH:15]=4)[O:10][C:9]3=[CH:30][C:31]=2[CH2:46][N:32]1[C@H:33]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[CH2:34][CH3:35])=[O:42]
Reactant: CC[C@H](N[C@@H](Cc1ccc2c(c1)OC[C@H](c1cccc(OCc3ccc(Cl)c(Cl)c3)c1)O2)C(=O)OC)c1ccccc1
Reactant: O=C(O)C(F)(F)F
Agent: C=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: CC[C@@H](c1ccccc1)N1Cc2cc3c(cc2C[C@H]1C(=O)OC)OC[C@H](c1cccc(OCc2ccc(Cl)c(Cl)c2)c1)O3
Temperature: 0 °C

Procedure:
(S)-3-{(S)-2-[3-(3,4-Dichloro-benzyloxy)-phenyl]-2,3-dihydro-benzo[1,4]dioxin-6-yl}-2-((S)-1-phenyl-propylamino)-propionic acid methyl ester (0.2 g) was dissolved in 8 mL dry dioxane and cooled to 0° C.; paraformaldehyde (50 mg) and 2 mL trifluoroacetic acid were added. The reaction was stirred for 12 hours at room temperature and neutralized to pH 7 with aqueous NaHCO3, then the mixture was extracted with EtOAc. The organic extract was washed with water and brine, and then dried over Na2SO4, filtered and evaporated. The residue was purified by silica gel flash chromatography (9:1 to 7:3 hexanes/EtOAc) to get (3S,8S)-3-[3-(3,4-dichloro-benzyloxy)-phenyl]-7-((S)-1-phenyl-propyl)-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carboxylic acid methyl ester (0.14 g). LCMS (m/z): 619.
Reaction SMILES: [CH:1]1[C:5]2=[C:6]([OH:15])[C:7]3[CH:14]=[CH:13][C:11](=[O:12])[O:10][C:8]=3[CH:9]=[C:4]2[O:3][CH:2]=1.Cl[CH2:17][CH2:18][CH2:19][C:20]#[CH:21].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>C(#N)C>[CH2:21]([O:15][C:6]1[C:7]2[CH:14]=[CH:13][C:11](=[O:12])[O:10][C:8]=2[CH:9]=[C:4]2[O:3][CH:2]=[CH:1][C:5]=12)[CH2:20][CH2:19][C:18]#[CH:17]
Reactant: C#CCCCCl
Reactant: O=c1ccc2c(O)c3ccoc3cc2o1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: C#CCCCOc1c2ccoc2cc2oc(=O)ccc12

Procedure:
500 mg (2.473 mmol) of 5-hydroxypsoralen and 405.85 mg (3.957 mmol) of 5-chloro-1-pentyne were refluxed in 30 ml of acetonitrile in the presence of an excess of anhydrous potassium carbonate (2.0 gm) and catalytic amounts of potassium iodide for 24 hours. The progress of the reaction was monitored by thin layer chromatography. After 24 hours the reaction mixture was concentrated under reduced pressure. The oily residue was cooled, diluted with water and acidified with concentrated hydrochloric acid to pH 1. The aqueous phase was extracted with dichloromethane. The dichloromethane phase was extracted with 25 ml of 1% sodium hydroxide to separate the un-reacted 5-hydroxypsoralen. The dichloromethane phase was washed with acidic water and then with water to pH˜6-7. The organic phase was then dried over anhydrous sodium sulphate and concentrated to dryness. The residue was dissolved in methanol, decolorized with charcoal and re-crystallized from methanol.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH:13]1([C:20]#[N:21])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.[CH2:22](Cl)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>O1CCCC1>[C:23]1([CH2:22][C:13]2([C:20]#[N:21])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: N#CC1CCCCCC1
Reactant: ClCc1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: N#CC1(Cc2ccccc2)CCCCCC1
Yield: 55.8 %

Procedure:
Obtained by operating as in example 27b, from 195 mmoles of lithiated diisopropylamine (25.6 g (252.9 mmoles) of diisopropylamine treated with 122 ml (195 mmoles) of n-butyllithium 1.6M in hexane) in 300 ml of dry tetrahydrofuran, 24 g (195 mmoles) of commercial cycloheptanecarbonitrile and 24.6 g (195 mmoles) of benzyl chloride. After distillation, there is obtained 23.2 g (yield=55.8%) of a yellow viscous liquid. b.p.16 =190°-7° C.
Reaction SMILES: [C:1]([NH:4][C:5]1[C:14]([F:15])=[C:13](F)[C:12]([CH3:17])=[C:11]2[C:6]=1[C:7](=[O:25])[C:8]([C:22]([OH:24])=[O:23])=[CH:9][N:10]2[C@@H:18]1[CH2:20][C@@H:19]1[F:21])(=[O:3])[CH3:2].[C:26]([O:30][C:31]([NH:33][C:34]1([C@H:37]2[CH2:41][NH:40][CH2:39][C@H:38]2[F:42])[CH2:36][CH2:35]1)=[O:32])([CH3:29])([CH3:28])[CH3:27]>CS(C)=O>[C:1]([NH:4][C:5]1[C:14]([F:15])=[C:13]([N:40]2[CH2:41][C@H:37]([C:34]3([NH:33][C:31]([O:30][C:26]([CH3:28])([CH3:27])[CH3:29])=[O:32])[CH2:35][CH2:36]3)[C@H:38]([F:42])[CH2:39]2)[C:12]([CH3:17])=[C:11]2[C:6]=1[C:7](=[O:25])[C:8]([C:22]([OH:24])=[O:23])=[CH:9][N:10]2[C@@H:18]1[CH2:20][C@@H:19]1[F:21])(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1c(F)c(F)c(C)c2c1c(=O)c(C(=O)O)cn2[C@@H]1C[C@@H]1F
Reactant: CC(C)(C)OC(=O)NC1([C@H]2CNC[C@H]2F)CC1
Solvent: CS(C)=O
Product: CC(=O)Nc1c(F)c(N2C[C@@H](F)[C@@H](C3(NC(=O)OC(C)(C)C)CC3)C2)c(C)c2c1c(=O)c(C(=O)O)cn2[C@@H]1C[C@@H]1F
Temperature: 80 °C
Reaction time: 38 h

Procedure:
A mixture consisting of 5-acetylamino-6,7-difluoro-1-[(1R,2S)-2-fluoro-1-cyclopropyl]-1,4-dihydro-8-methyl-4-oxoquinoline-3-carboxylic acid (50.2 mg), (3S,4R)-4-(1-tert-butoxycarbonylaminocyclopropyl)-3-fluoropyrrolidine (53.1 mg) and dimethyl sulfoxide (0.25 ml) was stirred at an outer temperature of 80° C. for 38 hours. When quantitative analysis was carried out by a high performance liquid chromatography after completion of the reaction, formed amount of the compound of interest 5-acetylamino-7-[(3S,4R)-4-(1-tert-butoxycarbonylaminocyclopropyl)-3-fluoropyrrolidinyl]-6-fluoro-1-[(1R,2S)-2-fluoro-1-cyclopropyl]-1,4-dihydro-8-methyl-4-oxoquinoline-3-carboxylic acid corresponded to 63.0 mg. The formation ratio was 76.8%.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[N:14][C:15]=3[NH2:17])[N:10]([C@H:18]3[CH2:23][CH2:22][C@@H:21]([N:24]4[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]4)[CH2:20][CH2:19]3)[N:9]=2)=[CH:4][C:3]=1[O:31][CH3:32].[CH2:33]1[O:41][CH:34]1[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>C(O)(C)C>[NH2:17][C:15]1[N:14]=[CH:13][N:12]=[C:11]2[N:10]([C@H:18]3[CH2:23][CH2:22][C@@H:21]([N:24]4[CH2:25][CH2:26][N:27]([CH3:30])[CH2:28][CH2:29]4)[CH2:20][CH2:19]3)[N:9]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([NH:1][CH:34]([C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)[CH2:33][OH:41])=[C:3]([O:31][CH3:32])[CH:4]=3)[C:16]=12
Reactant: c1ccc(C2CO2)cc1
Reactant: COc1cc(-c2nn([C@H]3CC[C@@H](N4CCN(C)CC4)CC3)c3ncnc(N)c23)ccc1N
Solvent: CC(C)O
Product: COc1cc(-c2nn([C@H]3CC[C@@H](N4CCN(C)CC4)CC3)c3ncnc(N)c23)ccc1NC(CO)c1ccccc1

Procedure:
Cis-3-(4-amino-3-methoxyphenyl)-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.075 g, 0.000172 mol) and styrene oxide (0.029 g, 0.000172 mol) were dissolved in isopropanol (3 mL) and the resulting mixture was heated at reflux for 24 hours. The solvent was removed and the residue purified by preparative HPLC (Hypersil C18, 8 μm, 25 cm; 10-60% acetonitrile-0.1M ammonium acetate over 25 min, 21 mL/min) to yield cis-2-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-methoxyanilino)-2-phenyl-1-ethanol (0.005 g, 0.0000089 mol) as an off-white solid.
Reaction SMILES: [CH2:1]([NH2:4])[C:2]#[CH:3].[F:5][C:6]([F:17])([F:16])[C:7]1[CH:8]=[C:9]([N:13]=[C:14]=[O:15])[CH:10]=[CH:11][CH:12]=1>CC#N>[CH2:1]([NH:4][C:14]([NH:13][C:9]1[CH:10]=[CH:11][CH:12]=[C:7]([C:6]([F:5])([F:16])[F:17])[CH:8]=1)=[O:15])[C:2]#[CH:3]
Reactant: C#CCN
Reactant: O=C=Nc1cccc(C(F)(F)F)c1
Solvent: CC#N
Product: C#CCNC(=O)Nc1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 85.9 %

Procedure:
A solution of propargyl amine (4.41 g, 5.13 mL, 80 mmol) in MeCN (30 mL) was added to a stirred solution of 3-(trifluoromethyl)phenyl isocyanate (15.0 g, 12.12 mL, 80 mmol) in MeCN (60 mL) under a nitrogen atmosphere. The reaction mixture was cooled with a RT cooling bath and the rate of addition was such that the internal temperature did not exceed 35° C. After 1.5 h the mixture was concentrated in vacuo. EtOAc (10 ml) was added to the residue and the mixture was sonicated for 2 minutes. The resultant slurry was diluted with cyclohexane (40 ml). The mixture was stirred for 10 minutes and the solid was then recovered by filtration. The mother liquors were concentrated in vacuo and the residue dissolved in EtOAc (10 mL). Dilution with cyclohexane (90 ml) precipitated a second batch of product which was recovered by filtration. The two batches were combined as an ethyl acetate solution and concentrated in vacuo to afford the title compound as a fawn solid (16.65 g).
Reaction SMILES: [C:1]([C:4]1[CH:27]=[CH:26][C:7]([O:8][CH2:9][C:10]2[CH:25]=[CH:24][C:13]([C:14]([C:16]3[CH:17]=[N:18][CH:19]=[C:20]([CH:23]=3)[C:21]#[N:22])=[O:15])=[CH:12][CH:11]=2)=[C:6]([CH2:28][CH2:29][CH3:30])[C:5]=1[OH:31])(=[O:3])[CH3:2].Cl>C(O)(=O)C.[Zn]>[C:1]([C:4]1[CH:27]=[CH:26][C:7]([O:8][CH2:9][C:10]2[CH:11]=[CH:12][C:13]([CH:14]([OH:15])[C:16]3[CH:17]=[N:18][CH:19]=[C:20]([CH:23]=3)[C:21]#[N:22])=[CH:24][CH:25]=2)=[C:6]([CH2:28][CH2:29][CH3:30])[C:5]=1[OH:31])(=[O:3])[CH3:2]
Reactant: CCCc1c(OCc2ccc(C(=O)c3cncc(C#N)c3)cc2)ccc(C(C)=O)c1O
Agent: Cl
Agent: [Zn]
Solvent: CC(=O)O
Product: CCCc1c(OCc2ccc(C(O)c3cncc(C#N)c3)cc2)ccc(C(C)=O)c1O
Reaction time: 1 h
Yield: 61.7 %

Procedure:
Add zinc dust (5.00 g, 76.5 mmol) to a solution of 5-[4-(4-acetyl-3-hydroxy-2-propyl-phenoxymethyl)-benzoyl]-nicotinonitrile (4.50 g, 10.9 mmol) in acetic acid (70 ml) and stir vigorously. After 1 hour, cool reaction in an ice bath and add 1N hydrochloric acid (200 ml). Extract with ethyl acetate. Combine the organic layers, dry with sodium sulfate, filter, and concentrate under reduced pressure to give a residue. Purify the residue by flash chromatography eluting with acetone:hexanes to yield the title product as a white solid (2.80 g, 62%): 1H NMR (DMSO-d6) δ 0.86 (t, 3H), 1.47 (sextet, 2H), 2.56 (m, 5H), 5.22 (s, 2H), 5.88 (m, 1H), 6.32 (d, 1H), 6.71 (d, 1H), 7.44 (q, 4H), 7.79 (d, 1H), 8.27 (t, 1H), 8.88 (dd, 1H), 12.84 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:14](=[O:15])[CH:13]=[C:12]([O:16][CH:17]3[CH2:22][CH2:21][N:20]([C:23]4[N:28]=[CH:27][C:26]([CH2:29][CH2:30][CH3:31])=[CH:25][N:24]=4)[CH2:19][CH2:18]3)[C:11](C(O)=O)=[N:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].C([O-])([O-])=O.[K+].[K+]>CN1C(=O)CCC1>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:14](=[O:15])[CH:13]=[C:12]([O:16][CH:17]3[CH2:22][CH2:21][N:20]([C:23]4[N:24]=[CH:25][C:26]([CH2:29][CH2:30][CH3:31])=[CH:27][N:28]=4)[CH2:19][CH2:18]3)[CH:11]=[N:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CCCc1cnc(N2CCC(Oc3cc(=O)n(-c4ccc(Cl)c(Cl)c4)nc3C(=O)O)CC2)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: CCCc1cnc(N2CCC(Oc3cnn(-c4ccc(Cl)c(Cl)c4)c(=O)c3)CC2)nc1
Temperature: 150 °C
Yield: 68.8 %

Procedure:
To a stirring solution of 1-(3,4-dichlorophenyl)-6-oxo-4-(1-(5-propylpyrimidin-2-yl)piperidin-4-yloxy)-1,6-dihydropyridazine-3-carboxylic acid (15 mg, 0.03 mmol) in NMP (2 mL) at room temperature under argon was added K2CO3 (8.22 mg, 0.06 mmol). The reaction mixture was heated at 150° C. overnight. The crude product was directly purified by preparative HPLC (C18 column; 10-100% methanol in water without TFA) to give 2-(3,4-dichlorophenyl)-5-(1-(5-propylpyrimidin-2-yl)piperidin-4-yloxy)pyridazin-3(2H)-one (9.5 mg, tan solid, 66%). 1H NMR (400 MHz, CDCl3) δ ppm 0.93 (t, J=7.47 Hz, 2H) 1.38-1.72 (m, 2H) 1.81-2.02 (m, 2H) 2.00-2.21 (m, 2H) 2.40 (t, J=7.69 Hz, 2H) 3.50-3.80 (m, 2H) 4.06-4.37 (m, 2H) 4.47-4.68 (m, 1H) 5.56 (s, 1H) 7.28 (dd, J=8.57, 2.42 Hz, 2H) 7.44-7.72 (m, 2H) 8.16 (s, 2H). MS (ESI) 461 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:25][CH:26]([F:28])[F:27])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:20][CH2:21][O:22][CH3:23])[C:17](O)=[O:18])[C:10](=[O:24])[CH:9]=2)[CH:7]=1.[NH2:29][C:30]1[CH:38]=[C:37]2[C:33]([C:34](=[O:47])[N:35]([CH3:46])[N:36]2[C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])=[CH:32][CH:31]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:25][CH:26]([F:28])[F:27])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:20][CH2:21][O:22][CH3:23])[C:17]([NH:29][C:30]3[CH:38]=[C:37]4[C:33]([C:34](=[O:47])[N:35]([CH3:46])[N:36]4[C:39]([O:41][C:42]([CH3:43])([CH3:44])[CH3:45])=[O:40])=[CH:32][CH:31]=3)=[O:18])[C:10](=[O:24])[CH:9]=2)[CH:7]=1
Reactant: COCCC(C(=O)O)n1cc(OC)c(-c2cc(Cl)ccc2OC(F)F)cc1=O
Reactant: Cn1c(=O)c2ccc(N)cc2n1C(=O)OC(C)(C)C
Product: COCCC(C(=O)Nc1ccc2c(=O)n(C)n(C(=O)OC(C)(C)C)c2c1)n1cc(OC)c(-c2cc(Cl)ccc2OC(F)F)cc1=O

Procedure:
113 mg (purity 82%, 0.26 mmol) of 2-{4-[5-chloro-2-(difluoromethoxy)phenyl]-5-methoxy-2-oxopyridin-1(2H)-yl}-4-methoxybutanoic acid (racemate) and 79 mg (0.29 mmol, 1.1 eq.) of tert-butyl 6-amino-2-methyl-3-oxo-2,3-dihydro-1H-indazole-1-carboxylate were reacted according to General Method 5A. Yield: 132 mg (73% of theory)
Reaction SMILES: [C:1]([NH:4][C:5]1[C:14]([O:15][CH2:16][CH:17]2[CH2:19][CH2:18]2)=[C:13]([O:20][CH3:21])[CH:12]=[CH:11][C:6]=1[C:7](OC)=[O:8])(=[O:3])[CH3:2].C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>O1CCCC1>[CH:17]1([CH2:16][O:15][C:14]2[C:13]([O:20][CH3:21])=[CH:12][CH:11]=[C:6]3[C:5]=2[NH:4][C:1](=[O:3])[CH:2]=[C:7]3[OH:8])[CH2:19][CH2:18]1
Reactant: COC(=O)c1ccc(OC)c(OCC2CC2)c1NC(C)=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc2c(O)cc(=O)[nH]c2c1OCC1CC1
Reaction time: 8 h
Yield: 84.9 %

Procedure:
A solution of methyl 2-acetamido-3-(cyclopropylmethoxy)-4-methoxybenzoate (93%, 55 g, 175 mmol) and tetrahydrofuran (500 mL) was added dropwise (internal temperature kept below −65° C.) to a solution of sodium bis(trimethylsilyl)amide (NaHMDS) (691 mL, 1M toluene, 691 mmol) at −78° C. under N2. The cooling bath was removed, and the reaction was stirred overnight. The reaction was quenched with water/ice (1 L) and washed with diethyl ether (300 mL×2). The aqueous phase was adjusted to pH=3, with 6 N HCl. The resulting solids were collected by filtration, washed with water (500 mL×2), and dried in an oven to give 38.8 g of 8-(cyclopropylmethoxy)-4-hydroxy-7-methoxyquinolin-2(1H)-one as a yellow solid. MS (ESI): 262.0.
Reaction SMILES: Cl.[CH3:2][C:3]1[C:8]([CH3:9])=[CH:7][C:6]([CH3:10])=[C:5]([CH2:11][CH:12]=[CH2:13])[C:4]=1[OH:14].C(=O)([O-])O.[Na+]>C(O)C>[CH3:13][CH:12]1[CH2:11][C:5]2[C:6]([CH3:10])=[CH:7][C:8]([CH3:9])=[C:3]([CH3:2])[C:4]=2[O:14]1
Reactant: C=CCc1c(C)cc(C)c(C)c1O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: Cc1cc(C)c2c(c1C)OC(C)C2
Yield: 68.7 %

Procedure:
Concentrated hydrochloric acid (130 mL) was added to a solution of ethanol (520 mL) containing 2,3,5-trimethyl-6-prop-2-en-1-ylphenol (52.0 g, 295 mmol) synthesized in Reference Example 51, and the mixture was heated to reflux for 16 hours. The reaction solution was neutralized with a sodium hydrogencarbonate aqueous solution, and then the mixture was extracted using ethyl acetate. The organic layer was washed with saturated saline, and then dried using anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate 95:5) to give 35.7 g of the title compound as an oily product (yield: 69%).
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([NH2:8])=[CH:4][CH:3]=1.Cl.[F:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]([CH:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)=[O:18])=[CH:13][CH:12]=1>CN1CCCC1=O>[NH2:8][C:5]1[N:6]=[N:7][C:2]([N:22]2[CH2:23][CH2:24][CH:19]([C:17]([C:14]3[CH:15]=[CH:16][C:11]([F:10])=[CH:12][CH:13]=3)=[O:18])[CH2:20][CH2:21]2)=[CH:3][CH:4]=1
Reactant: O=C(c1ccc(F)cc1)C1CCNCC1
Reactant: Nc1ccc(Cl)nn1
Agent: Cl
Solvent: CN1CCCC1=O
Product: Nc1ccc(N2CCC(C(=O)c3ccc(F)cc3)CC2)nn1
Yield: 46 %

Procedure:
A stirred mixture of 6-chloropyridazin-3-ylamine (0.95 g, 7.28 mmol) and (4-fluorophenyl)piperidin-4-ylmethanone hydrochloride (3.22 g, 10.92 mmol) was heated at 150° C. in N-methylpyrrolidinone (125 mL) for 24 hours. The solvent was evaporated in vacuo and the residue was treated with 1 N NaOH solution and extracted with ethyl acetate. The organic layer was separated, dried over Na2SO4 and concentrated. The residue was purified by column chromatography to afford [1-(6-aminopyridazin-3-yl)piperidin-4-yl]-(4-fluorophenyl)methanone in 46% yield (1.00 g, 3.33 mmol).
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)=[N:7][S:8][C:9]=1[C:10]([O:12]C)=[O:11])=[O:4].[OH-].[Na+].Cl>O>[Cl:20][C:17]1[CH:16]=[CH:15][C:14]([C:6]2[C:5]([C:3]([OH:4])=[O:2])=[C:9]([C:10]([OH:12])=[O:11])[S:8][N:7]=2)=[CH:19][CH:18]=1
Reactant: COC(=O)c1snc(-c2ccc(Cl)cc2)c1C(=O)OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)c1snc(-c2ccc(Cl)cc2)c1C(=O)O
Yield: 97.4 %

Procedure:
A solution of 4.4 g of 5 and 2.8 g of NaOH in 20 ml of water is kept at reflux for 2.5 h. The reaction mixture is cooled, diluted with water (150 ml) and acidified with conc. HCl (aq). A precipitate forms. The water layer is extracted with EtOAc (2×200 ml; the precipitate slowly dissolves). The combined organic layers are washed with brine and dried (Na2SO4). Concentration afforded 3.9 grams of 6 as a white solid.
Reaction SMILES: [N:1]1([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[Br:14][CH2:15][CH2:16]Br.CCN(C(C)C)C(C)C>>[Br:14][CH2:15][CH2:16][N:4]1[CH2:5][CH2:6][N:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:2][CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: BrCCBr
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCN(CCBr)CC1
Temperature: 30 °C
Reaction time: 72 h
Yield: 36 %

Procedure:
A mixture of tert-butyl piperazine-1-carboxylate (5.0 g, 26.9 mmol), 1,2-dibromoethane (25 mL), DIPEA (3.5 g, 26.9 mmol) was stirred at 30° C. under argon for 72 h. The solvent was removed under reduced pressure and the residue was purified by column chromatography on silica gel (1-2% methanol/dichloroethane) to afford the desired product (2.8 g, 36% yield) as a solid. ESI-MS m/z: 293.1[M+1]+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][C@H:10]([N:13]3[CH2:17][CH2:16][CH2:15][C@@H:14]3[CH3:18])[CH2:9]2)[CH:5]=[CH:4][C:3]=1[NH2:19].[F:20][C:21]1[CH:22]=[CH:23][C:24]([C:30](F)(F)F)=[C:25]([CH:29]=1)[C:26](Cl)=[O:27]>>[F:20][C:21]1[CH:22]=[CH:23][C:24]([CH3:30])=[C:25]([CH:29]=1)[C:26]([NH:19][C:3]1[CH:4]=[CH:5][C:6]([N:8]2[CH2:12][CH2:11][CH:10]([N:13]3[CH2:17][CH2:16][CH2:15][CH:14]3[CH3:18])[CH2:9]2)=[CH:7][C:2]=1[CH3:1])=[O:27]
Reactant: O=C(Cl)c1cc(F)ccc1C(F)(F)F
Reactant: Cc1cc(N2CC[C@H](N3CCC[C@@H]3C)C2)ccc1N
Product: Cc1cc(N2CCC(N3CCCC3C)C2)ccc1NC(=O)c1cc(F)ccc1C

Procedure:
The title compound was prepared in a manner substantially the same as Example 1 by coupling 2-methyl-4-(2-(S)-methyl-[1,3′(S)]bipyrrolidinyl-1′-yl)-phenylamine with 5-fluoro-2-trifluoromethyl-benzoyl chloride. LCMS: RT=2.53 minutes, MS: 450 (M+H).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[N:18][CH:17]=[C:16]([N:20]([CH3:29])[CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([CH3:28])[N:23]=3)[N:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>>[CH3:29][N:20]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH3:28])[N:23]=1)[C:16]1[N:15]=[C:14]([N:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)[CH:19]=[N:18][CH:17]=1
Reactant: Cc1cccc(CN(C)c2cncc(N3CCN(C(=O)OC(C)(C)C)CC3)n2)n1
Solvent: O=C(O)C(F)(F)F
Product: Cc1cccc(CN(C)c2cncc(N3CCNCC3)n2)n1

Procedure:
6′-[Methyl-(6-methyl-pyridin-2-ylmethyl)-amino]-2,3,5,6-tetrahydro-[1,2′]-bipyrazinyl-4-carboxylic acid tert-butyl ester I-4g was deprotected with TFA as the procedure described in Example 4-A to afford the title compound 4-Q.