Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:37])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]([N:12]2[CH2:17][CH:16]=[C:15]([C:18]3[NH:36][C:21]4[N:22]=[CH:23][N:24]=[C:25]([NH:26][C:27]5[CH:35]=[CH:34][C:30]6[N:31]=[CH:32][S:33][C:29]=6[CH:28]=5)[C:20]=4[CH:19]=3)[CH2:14][CH2:13]2)=[O:11])[CH:5]=1.[OH-].[Na+]>CO.O.CCOC(C)=O>[S:33]1[C:29]2[CH:28]=[C:27]([NH:26][C:25]3[C:20]4[CH:19]=[C:18]([C:15]5[CH2:16][CH2:17][N:12]([C:10]([C:6]6[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=6)[C:3]([OH:37])=[O:2])=[O:11])[CH2:13][CH:14]=5)[NH:36][C:21]=4[N:22]=[CH:23][N:24]=3)[CH:35]=[CH:34][C:30]=2[N:31]=[CH:32]1
Reactant: COC(=O)c1cccc(C(=O)N2CC=C(c3cc4c(Nc5ccc6ncsc6c5)ncnc4[nH]3)CC2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(O)c1cccc(C(=O)N2CC=C(c3cc4c(Nc5ccc6ncsc6c5)ncnc4[nH]3)CC2)c1
Temperature: 65 °C
Reaction time: 16 h

Procedure:
3-{4-[4-(Benzothiazol-6-ylamino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-3,6-dihydro-2H-pyridine-1-carbonyl}-benzoic acid methyl ester (0.624 mmol) was suspended in a mixture of MeOH (6.0 mL) and water (2.0 mL). 2 M NaOH solution (1.0 mmol) was then added to the above suspension and the reaction temperature increased to 65° C. The resulting suspension was stirred for a further period of 16 h. The mixture was allowed to reach r.t and diluted with EtOAc (30 mL) and washed with 2M NaOH (2×20 mL). The aqueous phase was then acidified by careful addition of conc. HCl solution until pH≈1. The resulting brown precipitate was then filtered and dried under vacuum affording the title compound. 1H NMR (DMSO, 400 MHz): δ=9.45(1H,s), 8.7(1H,s), 8.15(1H,d), 8.1(1H,d), 8.0(1H,s), 7.8(1H,d), 7.7 (1H, d), 7.6(1H, t), 6.9(1H, s), 6.6(1H, m), 6.35(1H, m), 4.35(1H, m), 4.1(1H, m), 3.9(1H, m), 2.6(1H, m). [MH+—CO2]=498.25.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][C:23]=1[CH3:24])[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.[Cl:25][C:26]1[CH:34]=[CH:33][C:29]([C:30](O)=[O:31])=[CH:28][C:27]=1[C:35]([F:38])([F:37])[F:36].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>CN(C)C=O>[Cl:25][C:26]1[CH:34]=[CH:33][C:29]([C:30]([NH:1][C:2]2[CH:3]=[C:4]([O:5][C:6]3[CH:7]=[CH:8][C:9]4[N:10]([CH:12]=[C:13]([NH:15][C:16]([CH:18]5[CH2:20][CH2:19]5)=[O:17])[N:14]=4)[N:11]=3)[CH:21]=[CH:22][C:23]=2[CH3:24])=[O:31])=[CH:28][C:27]=1[C:35]([F:36])([F:37])[F:38]
Reactant: O=C(O)c1ccc(Cl)c(C(F)(F)F)c1
Reactant: Cc1ccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)cc1N
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: Cc1ccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)cc1NC(=O)c1ccc(Cl)c(C(F)(F)F)c1
Yield: 62.7 %

Procedure:
Using N-[6-(3-amino-4-methylphenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (80 mg, 0.25 mmol), 4-chloro-3-(trifluoromethyl)benzoic acid (57 mg, 0.25 mmol), N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (50 mg, 0.26 mmol), 1-hydroxybenzotriazole (35 mg, 0.26 mmol) and N,N-dimethylformamide (4.0 mL) as starting materials and in the same manner as in Example 318, the title compound (83 mg, 63%) was obtained as a white powder.
Reaction SMILES: [F:1][C:2]1([F:8])[CH2:4][CH:3]1[C:5](O)=[O:6].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.C(=O)(O)[O-].[Na+].[NH:28]1[C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=2[N:30]=[C:29]1[C:37]1[C:45]2[C:40](=[CH:41][CH:42]=[C:43]([NH2:46])[CH:44]=2)[N:39]([CH:47]2[CH2:52][CH2:51][CH2:50][CH2:49][O:48]2)[N:38]=1>CN(C=O)C>[NH:30]1[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[N:28]=[C:29]1[C:37]1[C:45]2[C:40](=[CH:41][CH:42]=[C:43]([NH:46][C:5]([CH:3]3[CH2:4][C:2]3([F:8])[F:1])=[O:6])[CH:44]=2)[N:39]([CH:47]2[CH2:52][CH2:51][CH2:50][CH2:49][O:48]2)[N:38]=1
Reactant: Nc1ccc2c(c1)c(-c1nc3ccccc3[nH]1)nn2C1CCCCO1
Reactant: O=C(O)C1CC1(F)F
Agent: O=C([O-])O
Agent: On1nnc2ccccc21
Agent: [Na+]
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: O=C(Nc1ccc2c(c1)c(-c1nc3ccccc3[nH]1)nn2C1CCCCO1)C1CC1(F)F
Temperature: 25 °C
Reaction time: 24 h
Yield: 50 %

Procedure:
2,2-Difluorocyclopropanecarboxylic acid (8 mg, 0.065 mmol), HOBt (12 mg, 0.089 mmol), EDC (17 mg, 0.089 mmol) and sodium bicarbonate (56 mg, 0.059 mmol) were added to a solution of 3-(1H-benzo[d]imidazol-2-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-amine (20 mg, 0.059 mmol) in DMF (6 mL). The reaction mixture was stirred at room temperature for 24 h, and then the solvent was removed in vacuo. Purification by flash chromatography (6% CH3OH/CH2Cl2) afforded the title compound as a solid in a 50% yield. 1H NMR (400 MHz, CD3OD): δ 8.51 (s, 1H), 7.77 (m, 1H), 7.67 (m, 3H), 7.27 (m, 2H), 5.86 (d, 1H, J=7.6 Hz), 4.00 (m, 1H), 3.81 (m, 1H), 2.74-2.61 (m, 2H), 2.13 (m, 3H), 1.84 (m, 2H), 1.69 (m, 2H).
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][N:6]1[C:10]([CH3:11])=[CH:9][CH:8]=[N:7]1)C.O.[NH2:14][NH2:15]>C(O)C>[CH3:11][C:10]1[N:6]([CH2:5][C:4]([NH:14][NH2:15])=[O:3])[N:7]=[CH:8][CH:9]=1
Reactant: NN
Reactant: CCOC(=O)Cn1nccc1C
Solvent: CCO
Solvent: O
Product: Cc1ccnn1CC(=O)NN
Temperature: 25 °C
Yield: 95 %

Procedure:
As described for example 112a, (5-methyl-pyrazol-1-yl)-acetic acid ethyl ester in ethanol was reacted with hydrazine hydrate (2 equivalents) and the resulting mixture was heated under reflux for 8 h. The mixture was cooled to rt and the precipitated product was filtered off, dried and crystallized from toluene. The title compound (95% purity, based on NMR) was obtained as a white solid (yield: 45%). 1H-NMR (300 MHz, DMSO): δ=2.24 (s, 3H), 4.29 (s, 2H), 4.65 (s, 2H), 6.00 (d, J=1 Hz, 1H), 7.55 (d, J=1 Hz, 1H), 9.27 (s, 1H).
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH2:6]Cl)([O-:3])=[O:2].[N-:12]=[N+:13]=[N-:14].[Na+]>C(O)C>[N+:1]([C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH2:6][N:12]=[N+:13]=[N-:14])([O-:3])=[O:2]
Reactant: [N-]=[N+]=[N-]
Reactant: O=[N+]([O-])c1ccccc1CCl
Agent: [Na+]
Solvent: CCO
Product: [N-]=[N+]=NCc1ccccc1[N+](=O)[O-]

Procedure:
2-Nitrobenzylchloride dissolved in ethanol is heated at reflux with a 10% molar excess of sodium azide for from six to eight hours. Insoluble salts are removed by filtration, the ethanol removed, and the resultant oil is dissolved in diethyl ether. Additional insoluble material is removed by filtration and 2-nitrobenzylazide is obtained as a pale yellow oil by removal of the diethyl ether.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[C:8](Cl)[N:7]=[C:6]([Cl:11])[CH:5]=1.[S-][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[Na+].[S:21]([O-:26])(O[O-])(=O)=[O:22].[K+].[K+]>CN(C=O)C>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:5]=[C:6]([Cl:11])[N:7]=[C:8]([S:21]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:26])=[O:22])[CH:9]=1
Reactant: [S-]c1ccccc1
Reactant: COC(=O)c1cc(Cl)nc(Cl)c1
Reactant: O=S(=O)([O-])O[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc(Cl)nc(S(=O)(=O)c2ccccc2)c1
Yield: 92.6 %

Procedure:
Mix 2,6-dichloro-isonicotinic acid methyl ester (1 g, 4.85 mmol) and sodium thiophenoxide (0.64 g, 4.85 mmol) in DMF (10 mL) at room temperature for 4 h. Quench with water and extract with dichloromethane. Dry the dichloromethane layer over magnesium sulfate and concentrate. Dissolve the residue in chloroform (30 mL) and add neutral alumina (6 g) and potassium peroxymonosulfate (11.92 g, 19.39 mmol). Reflux for 16 h, concentrate and purify (silica gel chromatography, eluting with 0:100 to 20:80 ethyl acetate:hexanes) to give the title compound as a white solid (1.4 g, 93%).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N+:11]([O-])=[CH:10][CH:9]=[CH:8]2)([CH3:4])([CH3:3])[CH3:2].C[Si]([C:20]#[N:21])(C)C.CN(C)C>C(#N)C>[C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]=[C:10]([C:20]#[N:21])[CH:9]=[CH:8]2)([CH3:4])([CH3:3])[CH3:2]
Reactant: C[Si](C)(C)C#N
Reactant: CC(C)(C)c1ccc2c(ccc[n+]2[O-])c1
Agent: CN(C)C
Solvent: CC#N
Product: CC(C)(C)c1ccc2nc(C#N)ccc2c1
Temperature: 120 °C
Reaction time: 0.25 h
Yield: 91.1 %

Procedure:
A mixture of 6-tert-butylquinoline 1-oxide (310 mg, 1.54 mmol), trimethylsilylcyanide (458 mg, 4.62 mmol), and trimethylamine (312 mg, 3.08 mmol) in acetonitrile (3 ml) was stirred for 15 minutes at 120° C. under microwave irradiation. The mixture was applied to a silica gel column and eluted with hexane/EtOAc (20:1) to furnish the title compound (295 mg, 91% yield) as a white solid. 1H NMR (300 MHz, CDCl3) δ 1.44 (9H, s), 7.68 (1H, d, J=8.8 Hz), 7.79 (1H, d, J=2.2 Hz), 7.94 (1H, d, J=2.2, 8.8 Hz), 8.11 (1H, d, J=8.8 Hz), 8.26 (1H, d, J=8.8 Hz). MS (ESI): m/z 211 (M+H)+.
Reaction SMILES: [CH:1]1[C:6]([OH:7])=[CH:5][CH:4]=[C:3]([CH3:8])[CH:2]=1.[C:9](Cl)(=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.Cl>N1C=CC=CC=1>[C:9]([O:7][C:6]1[CH:5]=[CH:4][C:3]([CH3:8])=[CH:2][CH:1]=1)(=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: Cc1ccc(O)cc1
Reactant: O=C(Cl)c1ccccc1
Agent: Cl
Solvent: c1ccncc1
Product: Cc1ccc(OC(=O)c2ccccc2)cc1
Yield: 91.9 %

Procedure:
A mixture of 65.0 g (0.60 mol) of p-cresol, 92.7 g (0.66 mol) of benzoyl chloride and 6 mL of anhydrous pyridine was refluxed for 1.5 hr and then added to 600 mL of 2% hydrochloric acid. The product was extracted with 2×100 mL of diethyl ether, the combined extract was washed by 2% NaOH, then dried over Na2SO4, and evaporated to dryness. Drying of the residue in vacuum gave 117 g (92%) of p-tolyl benzoate (bp 127-135° C./25 mm Hg). A mixture of 117 g (0.552 mol) of p-tolyl benzoate and 92.0 (0.689 mol) of AlCl3 was slowly heated to 120-125° C. This mixture was stirred for 1 hr, and then 1000 mL of 2M HCl was added at 0° C. The product was extracted with 3×200 mL of diethyl ether, the combined extracts dried over Na2SO4 and then evaporated to dryness. This procedure gave 116 g (99%) of the 31 which was further used without an additional purification.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][C:23]=1[Cl:24])[CH:6]=[CH:7][C:8]1=[N:9][CH2:10][CH2:11][N:12]([CH3:20])[C:13]2[CH:18]=[CH:17][C:16](N)=[CH:15][C:14]1=2.[N:25]1C=CC=[CH:27][CH:26]=1.C(OC(=O)C)(=[O:33])C>ClCCl>[ClH:2].[Cl:2][C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][C:23]=1[Cl:24])[CH:6]=[CH:7][C:8]1=[N:9][CH2:10][CH2:11][N:12]([CH3:20])[C:13]2[CH:18]=[CH:17][C:16]([CH2:27][C:26]([NH2:25])=[O:33])=[CH:15][C:14]1=2
Reactant: CC(=O)OC(C)=O
Reactant: CN1CCN=C(C=Cc2ccc(Cl)c(Cl)c2)c2cc(N)ccc21
Reactant: c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CN1CCN=C(C=Cc2ccc(Cl)c(Cl)c2)c2cc(CC(N)=O)ccc21
Reaction time: 4 h

Procedure:
To a solution of 43 mg, 0.125 mmol) of (E)-5-(3,4-dichlorostyryl)-2,3-dihydro-1-methyl-1H-1,4-benzodiazepin-7-amine hydrochloride in 3 ml of dichloromethane was added 0.05 ml, 0.626 mmol) of pyridine, and 0.02 ml of acetic anhydride (0.15 mmol). The solution was stirred for 4 hours, concentrated under reduced pressure and the residue partitioned between brine and dichloromethane. The organic phase was dried over magnesium sulphate, filtered and evaporated, The residue was chromatographed on silica gel using first dichloromethane/methanol (98:2) and then dichloromethane/methanol (97:3) for the elution. The product was redissolved in a solution of hydrogen chloride in ethyl acetate and the solvent removed to afford (E)-5-(3,4-dichlorostyryl)-2,3-dihydro-1-methyl-1H-1,4-benzodiazepin-7-acetamide hydrochloride as a dark red solid MS: m/e 388.2 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[C:10]2[S:9][C:8]([NH:11][C:12]([NH:14][CH2:15][CH3:16])=[O:13])=[N:7][C:6]=2[CH:5]=[C:4]([C:17]2[CH:18]=[N:19][C:20]([N:23]3[CH2:28][CH2:27][C:26]([CH3:34])([C:29]([O:31]CC)=[O:30])[CH2:25][CH2:24]3)=[N:21][CH:22]=2)[CH:3]=1.CC(C)([O-])C.[K+].O>CS(C)=O>[Br:1][C:2]1[C:10]2[S:9][C:8]([NH:11][C:12](=[O:13])[NH:14][CH2:15][CH3:16])=[N:7][C:6]=2[CH:5]=[C:4]([C:17]2[CH:18]=[N:19][C:20]([N:23]3[CH2:28][CH2:27][C:26]([CH3:34])([C:29]([OH:31])=[O:30])[CH2:25][CH2:24]3)=[N:21][CH:22]=2)[CH:3]=1
Reactant: CCNC(=O)Nc1nc2cc(-c3cnc(N4CCC(C)(C(=O)OCC)CC4)nc3)cc(Br)c2s1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CCNC(=O)Nc1nc2cc(-c3cnc(N4CCC(C)(C(=O)O)CC4)nc3)cc(Br)c2s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.5 %

Procedure:
To an ice-cold solution of ethyl 1-(5-(7-bromo-2-(3-ethylureido)benzothiazol-5-yl)pyrimidin-2-yl)-4-methylpiperidine-4-carboxylate (25 g, 45.7 mmol) in DMSO (50 mL) was added potassium tert-butoxide (25.5 g, 228 mmol). The resulting mixture was stirred at rt for 1 h. After completion of reaction (by TLC), water (250 mL) was added followed by extraction with EtOAc (2×250 mL). The organic layer was discarded; the pH of the aqueous layer was adjusted up to 4-5 and then extracted with hot EtOAc (3×250 mL). The combined organic layer was dried over Na2SO4, filtered and evaporated under reduced pressure. The residue thus obtained was triturated with ether to obtain the desired product as off-white solid (21 g, 88%). 1H NMR (DMSO-d6): δ 1.09 (t, J=7.20 Hz, 3H), 1.18 (s, 3H), 1.41 (m, 2H), 2.02 (m, 2H), 3.20 (m, 2H), 3.33 (m, 2H), 4.29 (m, 2H), 6.80 (br s, 1H), 7.70 (s, 1H), 7.87 (s, 1H), 8.76 (s, 2H), 10.95 (br s, 1H) and 12.46 (br, s, 1H). MS: 519.19 [M+H]+.
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[CH:5]=[C:6]([N:10]2[C:25](=[O:26])[C:14]3[CH:15]=[N:16][C:17]4[C:18]([O:23][CH3:24])=[CH:19][CH:20]=[CH:21][C:22]=4[C:13]=3[N:12]([CH:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)[C:11]2=[O:33])[CH:7]=[CH:8][CH:9]=1.[C:34](Cl)(=[O:41])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>>[C:34]([N:30]1[CH2:31][CH2:32][CH:27]([N:12]2[C:13]3[C:22]4[CH:21]=[CH:20][CH:19]=[C:18]([O:23][CH3:24])[C:17]=4[N:16]=[CH:15][C:14]=3[C:25](=[O:26])[N:10]([C:6]3[CH:7]=[CH:8][CH:9]=[C:4]([Cl:3])[CH:5]=3)[C:11]2=[O:33])[CH2:28][CH2:29]1)(=[O:41])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: COc1cccc2c1ncc1c(=O)n(-c3cccc(Cl)c3)c(=O)n(C3CCNCC3)c12
Agent: Cl
Product: COc1cccc2c1ncc1c(=O)n(-c3cccc(Cl)c3)c(=O)n(C3CCN(C(=O)c4ccccc4)CC3)c12

Procedure:
1-(1-Benzoyl-piperidin-4-yl)-3-(3-chloro-phenyl)-7-methoxy-1H-pyrimido[5,4-c]quinoline-2,4-dione (51 mg) was prepared according to general procedure H from 3-(3-chloro-phenyl)-7-methoxy-1-piperidin-4-yl-1H-pyrimido[5,4-c]quinoline-2,4-dione.dihydrochloride (50 mg, 0.1 mmol) and benzoyl chloride. LCMS: m/z 541 [M+1]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2([C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][C:24]4[C:33]5[C:28](=[CH:29][C:30]([OH:36])=[C:31]([O:34][CH3:35])[CH:32]=5)[N:27]=[CH:26][CH:25]=4)=[C:19]([F:37])[CH:18]=3)=[O:15])[CH2:13][CH2:12]2)=[O:10])=[CH:4][CH:3]=1.[CH2:38]([N:40]([CH2:44][CH3:45])[CH2:41][CH2:42]O)[CH3:39].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C(Cl)Cl>[CH2:38]([N:40]([CH2:44][CH3:45])[CH2:41][CH2:42][O:36][C:30]1[CH:29]=[C:28]2[C:33]([C:24]([O:23][C:20]3[CH:21]=[CH:22][C:17]([NH:16][C:14]([C:11]4([C:9]([NH:8][C:5]5[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=5)=[O:10])[CH2:12][CH2:13]4)=[O:15])=[CH:18][C:19]=3[F:37])=[CH:25][CH:26]=[N:27]2)=[CH:32][C:31]=1[O:34][CH3:35])[CH3:39]
Reactant: CCN(CC)CCO
Reactant: COc1cc2c(Oc3ccc(NC(=O)C4(C(=O)Nc5ccc(F)cc5)CC4)cc3F)ccnc2cc1O
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCN(CC)CCOc1cc2nccc(Oc3ccc(NC(=O)C4(C(=O)Nc5ccc(F)cc5)CC4)cc3F)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 34 %

Procedure:
To a mixture of cyclopropane-1,1-dicarboxylic acid [3-fluoro-4-(7-hydroxy-6-methoxy-quinolin-4-yloxy)-phenyl]-amide(4-fluoro-phenyl)-amide (186 mg, 0.36 mmol) in CH2Cl2 (10 mL) was added 2-(diethylamino)ethanol (63 mg, 0.54 mmol), and PPh3 (141 mg, 0.54 mmol). DIAD (109 mg, 0.54 mmol) was then added as a CH2Cl2 (1 mL) solution. The resulted solution was stirred at room temperature for 2 h and the solvent was removed under reduced pressure. To the residue was added 1 N HCl (50 mL), and it was washed with EtOAc (50 mL×2). The aqueous phase was basified by adding 15% NaOH aqueous solution until pH=11-13, and then extracted with ether (50 mL×2). The combined organic layer was dried (MgSO4), and concentrated in vacuo. The residue was purified on preparative HPLC to give N-(4-{[7-{[2-(diethylamino)ethyl]oxy}-6-(methyloxy)quinolin-4-yl]oxy}-3-fluorophenyl)-N′-(4-fluoro-phenyl)cyclopropane-1,1-dicarboxamide (74 mg, 34%) as a pale yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 10.40 (br s, 1 H), 10.02 (br s, 1 H), 8.47 (d, J=5.2 Hz, 1 H), 7.91 (br d, J=13.9 Hz, 1 H), 7.54-7.52 (m, 2 H), 7.55-7.50 (m, 1 H), 7.52 (s, 1 H), 7.50-7.40 (m, 1 H), 7.41 (s, 1 H), 7.16 (br t, J=8.7 Hz, 2 H), 6.41 (br d, J=4.7 Hz, 1 H), 4.18 (t, J=6.0 Hz, 2 H), 3.94 (s, 3 H), 2.87 (br t, J=6.3 Hz, 2 H), 2.59 (q, J=7.1 Hz, 4 H), 1.47 (br s, 4 H), 1.00 (t, J=7.0 Hz, 6H).
Reaction SMILES: [C:1]([CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][C:14](=O)[CH3:15])=[CH:9][CH:8]=1)([O:3][CH3:4])=[O:2].[OH:17][CH2:18][CH2:19][O:20][CH:21]([C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[CH:25]=1)[CH2:22][NH2:23].[H][H].CC(C)=O.C(OCC)C>CO.[Pt]>[ClH:30].[ClH:30].[C:1]([CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH:14]([NH:23][CH2:22][CH:21]([O:20][CH2:19][CH2:18][OH:17])[C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[CH:25]=2)[CH3:15])=[CH:9][CH:8]=1)([O:3][CH3:4])=[O:2]
Reactant: [H][H]
Reactant: COC(=O)COc1ccc(CC(C)=O)cc1
Reactant: NCC(OCCO)c1cccc(Cl)c1
Agent: [Pt]
Solvent: CC(C)=O
Solvent: CO
Solvent: CCOCC
Product: COC(=O)COc1ccc(CC(C)NCC(OCCO)c2cccc(Cl)c2)cc1
Product: Cl

Procedure:
1-(4-Carbomethoxymethoxyphenyl)propan-2-one (4.4 g) and 2-(2-hydroxyethoxy)-2-(3-chlorophenyl)ethanamine (4.3 g) in methanol (100 ml) was hydrogenated in the presence of platinum (from platinum oxide, 50 mg) until hydrogen uptake ceased. The solution was filtered through diatomaceous earth, and the solvent removed under vacuum. Chromatography over silica gel in 2.5% methanol in dichloromethane gave an oil. Treatment of this oil with an ethereal solution of hydrogen chloride gave the title compound, mp 72°-75° C. (acetone-diethyl ether) as a 56:44 mixture of diastereoisomers.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]2[CH2:8][CH2:9][CH2:10][C:5]2=[C:4]([Cl:11])[CH:3]=1.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=1B(O)O>>[ClH:1].[Cl:11][C:4]1[CH:3]=[C:2]([C:17]2[CH:18]=[C:13]([Cl:12])[CH:14]=[CH:15][C:16]=2[Cl:19])[N:7]=[C:6]2[CH2:8][CH2:9][CH2:10][C:5]=12
Reactant: OB(O)c1cc(Cl)ccc1Cl
Reactant: Clc1cc(Cl)c2c(n1)CCC2
Product: Cl
Product: Clc1ccc(Cl)c(-c2cc(Cl)c3c(n2)CCC3)c1
Yield: 53.2 %

Procedure:
Following General Procedure F, 2,4-dichloro-6,7-dihydro-5H-cyclopenta[b]pyridine (0.300 g, 1.60 mmol) was reacted with (2,5-dichlorophenyl)boronic acid (0.396 g, 2.07 mmol), followed by the formation of the hydrochloride salt to afford the title compound (0.285 g, 95% yield) as a white solid. MW=335.06. 1H NMR (CDCl3, 300 MHz) δ 13.09 (s, 1H), 7.56 (d, J=2.4 Hz, 1H), 7.45-7.37 (m, 2H), 7.33-7.29 (m, 1H), 3.16 (t, J=7.6 Hz, 2H), 3.06 (t, J=7.6 Hz, 2H), 2.21 (quin, J=7.6 Hz, 2H); APCI MS m/z 297 [M+H]+.
Reaction SMILES: Br[C:2]1[S:3][C:4]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)=[C:5]([CH3:7])[N:6]=1.CC1(C)C(C)(C)OB([C:23]2[CH:24]=[CH:25][C:26]3[CH2:33][C@H:32]4[C@:34]5([CH2:38][N:37]([CH2:39][C:40]([F:43])([F:42])[F:41])[S:36](=[O:45])(=[O:44])[NH:35]5)[C@H:29]([CH2:30][CH2:31]4)[CH2:28][C:27]=3[CH:46]=2)O1>>[CH3:7][C:5]1[N:6]=[C:2]([C:23]2[CH:24]=[CH:25][C:26]3[CH2:33][C@H:32]4[C@:34]5([CH2:38][N:37]([CH2:39][C:40]([F:43])([F:42])[F:41])[S:36](=[O:44])(=[O:45])[NH:35]5)[C@H:29]([CH2:30][CH2:31]4)[CH2:28][C:27]=3[CH:46]=2)[S:3][C:4]=1[C:8]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=1
Reactant: Cc1nc(Br)sc1-c1ccc(F)cc1
Reactant: CC1(C)OB(c2ccc3c(c2)C[C@H]2CC[C@@H](C3)[C@]23CN(CC(F)(F)F)S(=O)(=O)N3)OC1(C)C
Product: Cc1nc(-c2ccc3c(c2)C[C@H]2CC[C@@H](C3)[C@]23CN(CC(F)(F)F)S(=O)(=O)N3)sc1-c1ccc(F)cc1

Procedure:
Prepared from the bromothiazole from Step 3 and the homochiral boronate from Example 24 Step 1 by the method described for Example 36 Step 3. MS (ES+) 552 ([MH]+).
Reaction SMILES: [CH:1]([C:4]1[N:5]=[C:6]2[CH:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][N:7]2[C:15]=1[S:16]([OH:19])(=[O:18])=O)([CH3:3])[CH3:2].C(N(CC)CC)C.P(Cl)(Cl)([Cl:29])=O.[NH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.C(=O)([O-])O.[Na+]>ClC(Cl)C>[CH:1]([C:4]1[N:5]=[C:6]2[CH:11]=[C:10]([C:12](=[O:14])[NH:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[CH:9]=[CH:8][N:7]2[C:15]=1[S:16]([Cl:29])(=[O:18])=[O:19])([CH3:2])[CH3:3]
Reactant: Nc1ccccc1
Reactant: CC(C)c1nc2cc(C(=O)O)ccn2c1S(=O)(=O)O
Reactant: O=P(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CC(Cl)Cl
Product: CC(C)c1nc2cc(C(=O)Nc3ccccc3)ccn2c1S(=O)(=O)Cl
Temperature: 100 °C
Reaction time: 4 h
Yield: 101 %

Procedure:
2-Isopropyl-3-sulfoimidazo[1,2-a]pyridine-7-carboxylic acid (0.93 g, 3.25 mmol) obtained in step 2 was dissolved in dichloroethane (30 mL), and the solution was stirred at 100° C. for 4 hours after adding triethylamine (1.13 mL, 8.13 mmol) and phosphorus oxychloride (0.760 mL, 8.13 mmol). The reaction mixture was allowed to cool to room temperature, and stirred at room temperature for 2.5 hours after adding aniline (0.300 mL, 3.25 mmol). Then, a saturated sodium hydrogen carbonate aqueous solution was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was then evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=80/20→50/50) to give 2-isopropyl-7-phenylcarbamoylimidazo[1,2-a]pyridine-3-sulfonylchloride (1.24 g, yield 97%).
Reaction SMILES: [CH2:1]([O:4][C:5]1([CH3:34])[CH2:10][CH2:9][N:8]([C:11]2[N:16]3[N:17]=[C:18]([CH2:20]I)[CH:19]=[C:15]3[N:14]=[C:13]([CH3:22])[C:12]=2[C@H:23]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:7][CH2:6]1)[CH:2]=[CH2:3].CCN(C(C)C)C(C)C.[CH2:44]([C:48]1[CH:58]=[C:57]([F:59])[CH:56]=[CH:55][C:49]=1[CH2:50][NH:51][CH:52]1[CH2:54][CH2:53]1)[CH2:45][CH:46]=[CH2:47]>C(#N)C>[CH2:1]([O:4][C:5]1([CH3:34])[CH2:10][CH2:9][N:8]([C:11]2[N:16]3[N:17]=[C:18]([CH2:20][N:51]([CH2:50][C:49]4[CH:55]=[CH:56][C:57]([F:59])=[CH:58][C:48]=4[CH2:44][CH2:45][CH:46]=[CH2:47])[CH:52]4[CH2:54][CH2:53]4)[CH:19]=[C:15]3[N:14]=[C:13]([CH3:22])[C:12]=2[C@H:23]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:7][CH2:6]1)[CH:2]=[CH2:3]
Reactant: C=CCOC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OCC)c(C)nc3cc(CI)nn23)CC1
Reactant: C=CCCc1cc(F)ccc1CNC1CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: C=CCCc1cc(F)ccc1CN(Cc1cc2nc(C)c([C@H](OC(C)(C)C)C(=O)OCC)c(N3CCC(C)(OCC=C)CC3)n2n1)C1CC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 73.6 %

Procedure:
To a mixture of (S)-ethyl 2-(7-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-(iodomethyl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate (53.3 mg, 0.091 mmol) in acetonitrile (2 mL) at 0° C. was added Hunig's Base (0.016 mL, 0.091 mmol) and N-(2-(but-3-en-1-yl)-4-fluorobenzyl)cyclopropanamine (20 mg, 0.091 mmol). It was stirred at 0° C. for 2 h and then quenched with water, extracted with EtOAc. The organic layer was dried over MgSO4, filtered and concentrated. The residue was purified by biotage, eluting with 20% EtOAc/hexane to obtain (S)-ethyl 2-(7-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-(((2-(but-3-en-1-yl)-4-fluorobenzyl)(cyclopropyl)amino)methyl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate (45 mg, 0.067 mmol, 73.0% yield) as an oil. 1H NMR (400 MHz, CDCl3) δ 7.36 (dd, J=8.3, 6.1 Hz, 1H), 6.89-6.78 (m, 2H), 6.41 (s, 1H), 6.06-5.95 (m, 2H), 5.80 (ddt, J=17.1, 10.3, 6.6 Hz, 1H), 5.41 (d, J=17.1 Hz, 1H), 5.17 (d, J=11.0 Hz, 1H), 5.03-4.92 (m, 2H), 4.30-4.13 (m, 2H), 4.01 (d, J=4.9 Hz, 2H), 3.88 (s, 2H), 3.80 (s, 2H), 2.76-2.69 (m, 2H), 2.63 (s, 3H), 2.33-2.22 (m, 2H), 2.10-1.87 (m, 4H), 1.72 (br. s., 1H), 1.36 (br. s., 3H), 1.27-1.21 (m, 12H), 0.48-0.31 (m, 4H), 4 protons from piperidine were missing. LCMS (M+1)=676.5.