Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[C:7]([O:11][C:12]([N:14]1[CH2:19][C@H:18]([CH2:20]Cl)[N:17]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:16][C@H:15]1[CH3:29])=[O:13])([CH3:10])([CH3:9])[CH3:8].Cl.[CH3:31][C@@H:32]1[CH2:37][O:36][CH2:35][CH2:34][NH:33]1>C(#N)C>[C:7]([O:11][C:12]([N:14]1[CH2:19][C@H:18]([CH2:20][N:33]2[CH2:34][CH2:35][O:36][CH2:37][C@H:32]2[CH3:31])[N:17]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:16][C@H:15]1[CH3:29])=[O:13])([CH3:10])([CH3:9])[CH3:8]
Reactant: C[C@@H]1CN(Cc2ccccc2)[C@@H](CCl)CN1C(=O)OC(C)(C)C
Reactant: C[C@@H]1COCCN1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C[C@@H]1COCCN1C[C@H]1CN(C(=O)OC(C)(C)C)[C@H](C)CN1Cc1ccccc1
Temperature: 70 °C
Reaction time: 18 h
Yield: 69.2 %

Procedure:
K2CO3 (81.6 g, 591 mmol) and KI (73.6 g, 443 mmol) were added to a solution of (2R,5R)-4-benzyl-5-chloromethyl-2-methyl-piperazine-1-carboxylic acid tert-butyl ester (50 g, 147.9 mmol) in acetonitrile (400 mL) followed by (R)-3-methyl-morpholine hydrochloride (26.4 g, 192 mmol). The reaction was stirred at 70° C. for 18 h. The solid was then removed by filtration and the solvent removed in vacuo. The crude material was purified by chromatography using a pad of silica (20% EtOAc in Petrol) to give the title compound (41.3 g) as a white solid. MS: [M+H]+=404.
Reaction SMILES: C([O:4][C@H:5]1[C@H:9]([N:10]2[C:14]3[CH:15]=[C:16]([Cl:20])[C:17]([Cl:19])=[CH:18][C:13]=3[N:12]=[CH:11]2)[CH2:8][C@H:7]([CH2:21][O:22]C(=O)C)[C@H:6]1[O:26]C(=O)C)(=O)C.C(=O)([O-])[O-].[Na+].[Na+].C(O)C.CO>O.C(O)(=O)C>[Cl:19][C:17]1[C:16]([Cl:20])=[CH:15][C:14]2[N:10]([C@H:9]3[C@H:5]([OH:4])[C@H:6]([OH:26])[C@@H:7]([CH2:21][OH:22])[CH2:8]3)[CH:11]=[N:12][C:13]=2[CH:18]=1
Reactant: CC(=O)OC[C@H]1C[C@@H](n2cnc3cc(Cl)c(Cl)cc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Solvent: O
Product: OC[C@H]1C[C@@H](n2cnc3cc(Cl)c(Cl)cc32)[C@H](O)[C@@H]1O
Yield: 59.3 %

Procedure:
(1S, 2R, 3R, 5R)-3-(Acetoxymethyl)-5-(5,6-dichloro-1H-benzimidazol-1-yl)-1,2-cyclopentanediyl diacetate (0.96 g, 2.17 mmol) and sodium carbonate (0.230 g, 2.17 mmol) were stirred in water (3 mL)-ethanol(15 mL)-methanol(15 mL) at ambient temperature for 24 hours. The pH was adjusted to 7 with acetic acid and the volatiles removed in vacuo. The residual solid was slurried in water (25 mL) and filtered. Resolidification from 2:1 ethanol-methanol gave (1S, 2R, 3R, 5R)-5-(5,6-dichloro-1H-benzimidazol-1-yl)-3-(hydroxymethyl)-1,2-cyclopentanediol as white powder (408 mg, 60%), m.p. 222-225° C.; 1H-NMR(DMSO-d6) δ: 8.49, 8.09, and 7.96 (all s, 1 each, 3 benzimidazole CH), 5.04 (d, J=7.0 Hz, 1, OH), 4.87 (t, J=5.1 Hz, 1, CH2OH), 4.8-4.6 (m overlapping d at 4.76, J=4.3 Hz, 2, NCH and OH), 4.25-4.10 (m, 1, OCH), 3.9-3.8 (m, 1, OCH), 3.6-3.45 (m, 2, CH2O), 2.45-2.25 (m, 1, CH), 2.2-2.0 (m, 1, CH), 1.85-1.65 (m, 1, CH); mass spectrum(CI): 317 (M+1); [α]20 589-12.2°, [α]20 578 -12.9°, [α]20 546-14.1° (c=0.255, methanol).
Reaction SMILES: FC(F)(F)C(O)=O.[CH:8]([N:11]1[C:15]([C:16]2[N:25]=[C:24]3[N:18]([CH2:19][CH2:20][O:21][C:22]4[CH:29]=[C:28]([CH:30]5[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]5)[CH:27]=[CH:26][C:23]=43)[CH:17]=2)=[N:14][CH:13]=[N:12]1)([CH3:10])[CH3:9].C(=O)([O-])[O-].[K+].[K+].[CH:42]([NH:45][C:46](=[O:49])[CH2:47]Cl)([CH3:44])[CH3:43]>C1COCC1>[CH:42]([NH:45][C:46](=[O:49])[CH2:47][N:33]1[CH2:34][CH2:35][CH:30]([C:28]2[CH:27]=[CH:26][C:23]3[C:24]4[N:18]([CH:17]=[C:16]([C:15]5[N:11]([CH:8]([CH3:10])[CH3:9])[N:12]=[CH:13][N:14]=5)[N:25]=4)[CH2:19][CH2:20][O:21][C:22]=3[CH:29]=2)[CH2:31][CH2:32]1)([CH3:44])[CH3:43]
Reactant: CC(C)NC(=O)CCl
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(C3CCNCC3)cc1OCC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: CC(C)NC(=O)CN1CCC(c2ccc3c(c2)OCCn2cc(-c4ncnn4C(C)C)nc2-3)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 53.1 %

Procedure:
To a suspension of 2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-8-piperidin-4-yl-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene trifluoroacetic acid salt (350 mg, 0.71 mmol) in THF was added potassium carbonate (245 mg, 1.78 mmol) followed by N-isopropyl-2-chloroacetamide (106 mg, 0.78 mmol) and the reaction mixture stirred for 18 h at RT then heated at 50° C. for 2 h. The resultant mixture was concentrated in vacuo and the residue subjected to flash chromatography (SiO2, gradient 0 to 5% MeOH in DCM to give 247 as a white solid (180 mg, 53%). 1H NMR δ (ppm) (DMSO-d6): 8.28 (1H, d, J=8.28 Hz), 7.86 (1H, d, J=0.63 Hz), 7.85 (1H, s), 7.40 (1H, d, J=8.18 Hz), 7.03 (1H, dd, J=8.36, 1.77 Hz), 6.89 (1H, d, J=1.72 Hz), 5.88-5.79 (1H, m), 4.48-4.41 (4H, m), 3.89-3.83 (1H, m), 2.89-2.79 (4H, m), 2.13 (2H, td, J=10.70, 4.11 Hz), 1.74-1.64 (4H, m), 1.43 (6H, d, J=6.60 Hz), 1.04 (6H, d, J=6.59 Hz). 1 Proton obscured by solvent peak. LCMS: RT=2.94 min, M+H+=478
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Si]([O:26][C:27]1[CH:28]=[C:29]([CH:36]=[CH:37][CH:38]=1)[O:30][CH2:31][C:32]([O:34][CH3:35])=[O:33])(C(C)(C)C)(C)C>C1COCC1>[OH:26][C:27]1[CH:28]=[C:29]([CH:36]=[CH:37][CH:38]=1)[O:30][CH2:31][C:32]([O:34][CH3:35])=[O:33]
Reactant: COC(=O)COc1cccc(O[Si](C)(C)C(C)(C)C)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: COC(=O)COc1cccc(O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 61.4 %

Procedure:
Tetrabutylammonium fluoride in THF (1 M, 3.4 mL, 3.4 mmol) was added to a solution of methyl 2-(3-((t-butyldimethylsilyl)oxy)phenoxy)acetate (0.50 g, 1.7 mmol) in THF (5 mL) in a 100 mL round bottom flask. The reaction was allowed to stir overnight at room temperature. The reaction was quenched with saturated aqueous ammonium chloride (100 mL) and extracted with ethyl acetate (200 mL). The organic extract was dried (Na2SO4), filtered and concentrated. The resulting crude residue was purified by combiflash (40 g column, hexanes→100% ethyl acetate/hexanes, gradient) to afford 0.19 g (60%) of methyl 2-(3-hydroxyphenoxy)acetate.
Reaction SMILES: [CH3:1][C:2]1([CH3:32])[C@@H:4]([CH:5]=[C:6]=[CH:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[C@H:3]1[C:13]([O:15][C@H:16]([C:30]#N)[C:17]1[CH:22]=CC=[C:19]([O:23]C2C=CC=CC=2)[CH:18]=1)=[O:14].[CH2:33]([C:36]1C(=O)CC(O)C=1C)[CH:34]=C>>[CH3:1][C:2]1([CH3:32])[C@H:4]([CH:5]=[C:6]=[CH:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[C@H:3]1[C:13]([O:15][CH:16]1[CH2:30][C:19](=[O:23])[C:18]([CH2:36][CH:33]=[CH2:34])=[C:17]1[CH3:22])=[O:14]
Reactant: C=CCC1=C(C)C(O)CC1=O
Reactant: CCOC(=O)C=C=C[C@H]1[C@@H](C(=O)O[C@H](C#N)c2cccc(Oc3ccccc3)c2)C1(C)C
Product: C=CCC1=C(C)C(OC(=O)[C@@H]2[C@@H](C=C=CC(=O)OCC)C2(C)C)CC1=O

Procedure:
Using the procedure of Example 22, 1.5 g of (S) 3-allyl-2-metyl-1-hydroxy-2-cyclopenten-4-one were reacted to obtain 0.794 g of 3-allyl-2-methyl-4-oxo-2-cyclopenten-1-yl (1R,trans) 2,2-dimethyl-3-(4-ethoxy-4-oxo-1,2-butadienyl)-cyclopropanecarboxylate.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11](C2C=CC=CC=2S([O-])(=O)=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:24]([O:32][CH2:33][CH3:34])(=[O:31])[CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27].[O-]CC.[Na+].CCO>CCO>[CH2:33]([O:32][C:24](=[O:31])[CH:25]([CH:11]1[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9][CH2:10]1)[C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH3:34]
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccccc2S(=O)(=O)[O-])CC1
Reactant: CCOC(=O)CC(=O)OCC
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C(C(=O)OCC)C1CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 22 h

Procedure:
A mixture of 1-tert-butoxycarbonylpiperidine-4-ol, triethylamine, benzenesulfonyl chloride and methylene chloride was stirred for two days at room temperature to give 1-tert-butoxycarbonylpiperidine-4-ylbenzenesulfonate. A mixture of the obtained 1-tert-butoxycarbonylpiperidine-4-ylbenzenesulfonate, diethyl malonate, 20% sodium ethoxide-EtOH solution and EtOH was stirred for 22 hours heated to reflux to give diethyl[1-(tert-butoxycarbonyl)piperidine-4-yl]malonate. A mixture of the obtained diethyl[1-(tert-butoxycarbonyl)piperidine-4-yl]malonate, lithium borohydride, toluene and THF was stirred for 18 hours at 60° C. to give 2-(1-tert-butoxycarbonylpiperidine-4-yl)propane-1,3-diol. A mixture of the obtained 2-(1-tert-butoxycarbonylpiperidine-4-yl)propane-1,3-diol, 4M HCl-dioxane solution and MeOH was stirred for one hour at room temperature to give 2-piperidine-4-ylpropane-1,3-diol hydrochloride.
Reaction SMILES: C(OC(=O)C)(=O)C.O[C:9]1[C:14]([O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:22])=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:23][CH2:24][C:25]([OH:27])=[O:26]>C1C=CC=CC=1>[Cl:22][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[O:15][C:14]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:9]=1[O:27][C:25](=[O:26])[CH2:24][CH2:23]2
Reactant: O=C(O)CCc1cccc(Oc2ccccc2Cl)c1O
Solvent: c1ccccc1
Solvent: CC(=O)OC(C)=O
Product: O=C1CCc2cccc(Oc3ccccc3Cl)c2O1
Yield: 83.1 %

Procedure:
Acetic anhydride (10 ml) was added to a solution of 3-[2-hydroxy-3-(2-chlorophenoxy)phenyl]propionic acid (5.0 g) in benzene (30 ml), and refluxed under heating for 1.5 hours. The reaction mixture was evaporated, and toluene was added to the residue and then evaporated again. The crystalline residue (4.30 g) was recrystallized from a mixture of ethyl acetate and n-hexane to give 8-(2-chlorophenoxy)chroman-2-one (3.9 g). mp 123°-125° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[NH:10][CH:9]=2)[C:5]([Cl:17])=[CH:4][N:3]=1.[NH2:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]2[CH2:30][CH2:29][CH:28]([NH:31][CH2:32][CH2:33][OH:34])[CH2:27][CH2:26]2)=[CH:21][C:20]=1[O:35][CH3:36]>>[Cl:17][C:5]1[C:6]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[NH:10][CH:9]=2)=[N:7][C:2]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([N:25]3[CH2:30][CH2:29][CH:28]([NH:31][CH2:32][CH2:33][OH:34])[CH2:27][CH2:26]3)=[CH:21][C:20]=2[O:35][CH3:36])=[N:3][CH:4]=1
Reactant: Clc1ncc(Cl)c(-c2c[nH]c3ccccc23)n1
Reactant: COc1cc(N2CCC(NCCO)CC2)ccc1N
Product: COc1cc(N2CCC(NCCO)CC2)ccc1Nc1ncc(Cl)c(-c2c[nH]c3ccccc23)n1

Procedure:
Starting materials: 3-(2,5-dichloropyrimidin-4-yl)-1H-indole (INTERMEDIATE 2) 2-(1-(4-amino-3-methoxyphenyl)piperidin-4-ylamino)ethanol (INTERMEDIATE 31).
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:18][CH:19]2[CH2:26][CH:22]3[CH2:23][NH:24][CH2:25][CH:21]3[CH2:20]2)=[N:4][C:5]([NH:8][C:9]2[N:13]([CH3:14])[N:12]=[C:11]([CH:15]3[CH2:17][CH2:16]3)[CH:10]=2)=[N:6][CH:7]=1.[C:27]([CH2:29][C:30](O)=[O:31])#[N:28].CCN=C=NCCCN(C)C.C1C=NC2N(O)N=NC=2C=1>C(Cl)Cl.CN(C=O)C>[Cl:1][C:2]1[C:3]([NH:18][CH:19]2[CH2:26][CH:22]3[CH2:23][N:24]([C:30](=[O:31])[CH2:29][C:27]#[N:28])[CH2:25][CH:21]3[CH2:20]2)=[N:4][C:5]([NH:8][C:9]2[N:13]([CH3:14])[N:12]=[C:11]([CH:15]3[CH2:17][CH2:16]3)[CH:10]=2)=[N:6][CH:7]=1
Reactant: N#CCC(=O)O
Reactant: Cn1nc(C2CC2)cc1Nc1ncc(Cl)c(NC2CC3CNCC3C2)n1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cn1nc(C2CC2)cc1Nc1ncc(Cl)c(NC2CC3CN(C(=O)CC#N)CC3C2)n1
Temperature: 45 °C
Reaction time: 1 h
Yield: 57.3 %

Procedure:
To a solution of 5-chloro-N2-(3-cyclopropyl-1-methyl-1H-pyrazol-5-yl)-N4-(octahydrocyclopenta[c]pyrrol-5-yl)pyrimidine-2,4-diamine (251.7 mg, 0.67 mmol) and 2-cyanoacetic acid (107.2 mg, 1.26 mmol) in a mixture of DCM (20 mL) and DMF (5 mL) were added EDCI (292.5 mg, 1.51 mmol) and HOAT (205.3 mg, 1.51 mmol). After addition, the reaction mixture was stirred at 45° C. for 1 h, then quenched with H2O (30 mL) and extracted with DCM (100 mL×3). The combined organic phases were washed with brine (100 mL), and dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (MeOH/DCM (v/v)=1/40) to give the title compound as a beige solid (169.4 mg, 57.1%).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([I:11])=[CH:7][C:3]=1[C:4](O)=[O:5].C(O)(=O)C.[CH:16](N)=[NH:17]>C(O)C>[I:11][C:8]1[CH:7]=[C:3]2[C:2](=[CH:10][CH:9]=1)[N:1]=[CH:16][NH:17][C:4]2=[O:5]
Reactant: N=CN
Reactant: Nc1ccc(I)cc1C(=O)O
Solvent: CCO
Solvent: CC(=O)O
Product: O=c1[nH]cnc2ccc(I)cc12
Temperature: 0 °C
Yield: 80.9 %

Procedure:
A solution of 2-amino-5-iodobenzoic acid (26.3 g, 100 mmol) and formamidine acetate (13.5 g, 130 mmol) in ethanol (400 mL) was refluxed for 20 hours. After cooling to 0° C., the solid product was collected by filtration. Further drylng in vacuo provided 6-iodo-4-quinazolinone (22.0 g, 81%) as a grey crystalline solid. 1H NMR (400 MHz; DMSO-d6) δ: 12.38 (br. s, 1H), 8.35 (d, 1H), 8.05-8.10 (m, 2H), 7.43 (dd, 1H). LRMS: 272.9 (MH+).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5](O)=[C:6]([C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:18]4[N:22]([CH:23]5[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]5)[C:21]5[CH:29]=[CH:30][C:31]([C:33]([OH:35])=[O:34])=[CH:32][C:20]=5[N:19]=4)[CH:14]=3)[N:9]=2)[CH:7]=1.C(C1C=CC([NH:46][C:47](=[O:49])[CH3:48])=CC=1)(=O)C.[OH-].[K+]>C(O)C>[C:47]([NH:46][C:3]1[CH:4]=[CH:5][C:6]([C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:18]4[N:22]([CH:23]5[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]5)[C:21]5[CH:29]=[CH:30][C:31]([C:33]([OH:35])=[O:34])=[CH:32][C:20]=5[N:19]=4)[CH:14]=3)[N:9]=2)=[CH:7][CH:2]=1)(=[O:49])[CH3:48]
Reactant: O=C(O)c1ccc2c(c1)nc(-c1ccc3nc(-c4cc(Br)ccc4O)ccc3c1)n2C1CCCCC1
Reactant: CC(=O)Nc1ccc(C(C)=O)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CC(=O)Nc1ccc(-c2ccc3cc(-c4nc5cc(C(=O)O)ccc5n4C4CCCCC4)ccc3n2)cc1
Yield: 15 %

Procedure:
Following the procedure and workup for Compound 354, Compound 354e (100 mg, 0.256 mmol) was reacted with N-(4-acetyl-phenyl)-acetamide (0.256 mmol) in ethanol (2 mL) using 10% w/v KOH in ethanol (506 μL, 0.64 mmol) to produce the title compound (19 mg, 15% yield). MS: 505.26 (M+H+); HPLC Procedure A, retention time=9.94 min.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH2:17][OH:18])=[CH:11][CH:10]=2)O1.I[C:21]1[CH:33]=[CH:32][CH:31]=[CH:30][C:22]=1[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24].C(=O)([O-])[O-].[Na+].[Na+].CN(C=O)C>O>[OH:18][CH2:17][CH2:16][CH2:15][C:12]1[CH:13]=[CH:14][C:9]([C:21]2[C:22]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[CH:30][CH:31]=[CH:32][CH:33]=2)=[CH:10][CH:11]=1
Reactant: CC(C)(C)OC(=O)c1ccccc1I
Reactant: CC1(C)OB(c2ccc(CCCO)cc2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)c1ccccc1-c1ccc(CCCO)cc1
Temperature: 80 °C

Procedure:
A mixture of 3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]propanol (37.9 mmol), tert-butyl 2-iodobenzoate (11.5 g, 37.9 mmol), sodium carbonate (10 g, 94.8 mmol), 1,1′-bis(diphenylphosphino)ferroncene-palladium dichloride dichloromethane complex (1:1), DMF (170 mL) and water (22 mL) was heated at 80° C. under nitrogen overnight. The reaction mixture was cooled to RT, poured into water, and the product was extracted with EtOAc-Hexanes (1:1). The combined organic extracts were washed with water and brine, dried (Na2SO4) and concentrated, and the residue was purified on silica gel (Hexane/EtOAc, from 2/1 to 1/1) to afford tert-butyl 4′-(3-hydroxypropyl)biphenyl-2-carboxylate.
Reaction SMILES: [C:1](=O)([O-])[O-:2].[K+].[K+].Cl[C:8]1[CH:9]=[CH:10][C:11]2[N:12]([C:14]([CH2:17][C:18]3[CH:19]=[C:20]4[C:25](=[CH:26][CH:27]=3)[N:24]=[CH:23][C:22]([C:28]3[CH:29]=[N:30][N:31]([CH3:33])[CH:32]=3)=[CH:21]4)=[N:15][N:16]=2)[N:13]=1>CO>[CH3:1][O:2][C:8]1[CH:9]=[CH:10][C:11]2[N:12]([C:14]([CH2:17][C:18]3[CH:19]=[C:20]4[C:25](=[CH:26][CH:27]=3)[N:24]=[CH:23][C:22]([C:28]3[CH:29]=[N:30][N:31]([CH3:33])[CH:32]=3)=[CH:21]4)=[N:15][N:16]=2)[N:13]=1
Reactant: Cn1cc(-c2cnc3ccc(Cc4nnc5ccc(Cl)nn45)cc3c2)cn1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: COc1ccc2nnc(Cc3ccc4ncc(-c5cnn(C)c5)cc4c3)n2n1
Temperature: 130 °C

Procedure:
To a 5 ml microwave vial 1 ml of methanol was added followed by 15 mg of potassium carbonate, and 25 mg (0.067 mmol) of 6-(6-chloro-[1,2,4]triazolo[4,3-b]pyridazin-3-ylmethyl)-3-(1-methyl-1H-pyrazol-4-yl)quinoline. The reaction mixture was heated for 3800 seconds at 130° C. in a microwave. The reaction mixture was then filtered and purified by preparatory HPLC to return the title compound (11.6 mg, 47%). Analytical data is presented in Table 2.
Reaction SMILES: [N:1]1[C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[NH:3][C:2]=1[SH:10].[H-].[Na+].[N+]([C:16]1[O:20][C:19]([CH:21]=[O:22])=[CH:18][CH:17]=1)([O-])=O>O1CCCC1>[N:1]1[C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[NH:3][C:2]=1[S:10][C:16]1[O:20][C:19]([CH:21]=[O:22])=[CH:18][CH:17]=1
Reactant: O=Cc1ccc([N+](=O)[O-])o1
Reactant: Sc1nc2ccncc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=Cc1ccc(Sc2nc3ccncc3[nH]2)o1
Temperature: 25 °C
Yield: 11 %

Procedure:
3H-Imidazo[4,5-c]pyridine-2-thiol (1.51 g, 10.0 mmol) is suspended into 80 mL of tetrahydrofuran under argon. Then, 0.72 g (15.0 mmol) of sodium hydride is added. The reaction mixture is stirred at room temperature until gas evolution has ceased. 5-Nitro-2-furaldehyde (1.41 g, 10.0 mmol) is then added and the reaction mixture is stirred at room temperature for 16 h, upon which it is poured on ice and extracted 3 times with ethyl acetate. The organic extracts are combined and filtered. The filtrate is washed with brine, dried on magnesium sulfate, filtered and concentrated under reduced pressure. The residue is purified by chromatography on a prepacked 70 g 15-40 μm silica gel cartridge (eluting solvent: dichloromethane/acetonitrile/methanol from 75/20/5 to 90/0/10 v/v/v; rate: 40 mL/min). The fractions containing the desired product are combined and concentrated to dryness under reduced pressure. The residue is triturated in diethyl ether, filtered and dried under reduced pressure. 270 mg of 5-(3H-imidazo[4,5-c]pyridin-2-ylsulfanyl)-furan-2-carbaldehyde are obtained as a crystalline yellow powder. LCMS: m/z 246: [M+H]+ (base peak); m/z 244: [M−H]− (base peak).
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]([C:11]2[C:15]3[S:16][CH:17]=[CH:18][C:14]=3[O:13][N:12]=2)[CH:8]=[CH:9][CH:10]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:25][CH2:26][CH2:27][CH:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>C(#N)C>[CH2:27]([CH:28]1[CH2:33][CH2:32][N:31]([CH2:2][CH2:3][O:4][C:5]2[CH:6]=[C:7]([C:11]3[C:15]4[S:16][CH:17]=[CH:18][C:14]=4[O:13][N:12]=3)[CH:8]=[CH:9][CH:10]=2)[CH2:30][CH2:29]1)[CH2:26][CH3:25]
Reactant: BrCCOc1cccc(-c2noc3ccsc23)c1
Reactant: CCCC1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCC1CCN(CCOc2cccc(-c3noc4ccsc34)c2)CC1

Procedure:
The title compound is prepared from 3-[3-(2-bromo-ethoxy)-phenyl]-thieno[2,3-d]isoxazole, potassium carbonate, 4-N-propylpiperidine and acetonitrile essentially as described above in example 40. Purity by LC/MS (APCI)=96%, [M+H]+=371.
Reaction SMILES: [Cl:1][C:2]([F:9])([F:8])[CH2:3][CH2:4][C:5](O)=[O:6].S(Cl)([Cl:12])=O>CN(C)C=O>[Cl:1][C:2]([F:9])([F:8])[CH2:3][CH2:4][C:5]([Cl:12])=[O:6]
Reactant: O=C(O)CCC(F)(F)Cl
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: O=C(Cl)CCC(F)(F)Cl

Procedure:
15.8 g of 4-chloro-4,4-difluorobutyric acid are mixed with 50 ml of thionyl chloride and 0.2 ml of dimethylformamide and heated to +70° C. over the course of 2 hours and then maintained at +70° C. for a further 30 minutes. The reaction mixture is distilled in vacuo, and the liquid boiling at 35°-37° C./21 mbar is collected. 10.5 g of 4-chloro-4,4-difluorobutyryl chloride are obtained in the form of a clear colourless liquid.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][NH:8][C:9]2[S:10][C:11]([C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[CH3:22])=[O:15])=[CH:12][N:13]=2)[CH2:3][CH2:2]1.Cl.[S:24]1[CH:28]=[CH:27][CH:26]=[C:25]1[S:29](Cl)(=[O:31])=[O:30].CCN(CC)CC>C(Cl)Cl.CO>[S:24]1[CH:28]=[CH:27][CH:26]=[C:25]1[S:29]([N:1]1[CH2:6][CH2:5][CH:4]([CH2:7][NH:8][C:9]2[S:10][C:11]([C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[CH3:22])=[O:15])=[CH:12][N:13]=2)[CH2:3][CH2:2]1)(=[O:31])=[O:30]
Reactant: O=S(=O)(Cl)c1cccs1
Reactant: Cc1ccccc1C(=O)c1cnc(NCC2CCNCC2)s1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CO
Product: Cc1ccccc1C(=O)c1cnc(NCC2CCN(S(=O)(=O)c3cccs3)CC2)s1
Temperature: 60 °C
Reaction time: 16 h

Procedure:
A mixture of 35.2 mg (0.1 mmol) {2-[(piperidin-4-ylmethyl)-amino]-thiazol-5-yl}-o-tolyl-methanone; hydrochloride, 21.9 mg (0.12 mmol) thiophene-2-sulfonyl chloride (commercially available) and 44.6 ul (0.32 mmol) NEt3 in a mixture of DCM/MeOH 3/1 was stirred at 60° C. for 16 h. After cooling to room temperature the mixture was concentrated and MeOH (1 ml) and formic acid (0.5 ml) was added and the mixture was subjected to reversed phase HPLC purification eluting with a gradient of acetonitrile/water. After evaporation of the product fractions 22 mg (48%) of the title compound was obtained.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][C:12]=1[O:13][CH3:14])[CH:8]=O)([CH3:3])[CH3:2].[N:15]1([C:20]2[CH:25]=[CH:24][C:23]([NH2:26])=[C:22]([NH2:27])[CH:21]=2)[CH:19]=[N:18][CH:17]=[N:16]1>[N+](C1C=CC=CC=1)([O-])=O>[CH:1]([O:4][C:5]1[CH:6]=[C:7]([C:8]2[NH:27][C:22]3[CH:21]=[C:20]([N:15]4[CH:19]=[N:18][CH:17]=[N:16]4)[CH:25]=[CH:24][C:23]=3[N:26]=2)[CH:10]=[CH:11][C:12]=1[O:13][CH3:14])([CH3:3])[CH3:2]
Reactant: Nc1ccc(-n2cncn2)cc1N
Reactant: COc1ccc(C=O)cc1OC(C)C
Solvent: O=[N+]([O-])c1ccccc1
Product: COc1ccc(-c2nc3ccc(-n4cncn4)cc3[nH]2)cc1OC(C)C
Temperature: 150 °C
Yield: 55 %

Procedure:
A 5.98 g portion of a known compound 3-isopropoxy-4-methoxybenzaldehyde was added to 4.49 g of 4-(1,2,4-triazol-1-yl)-o-phenylenediamine obtained in Reference Example 2, and the mixture was stirred for 18 hours in 37 ml of nitrobenzene while heating at 150° C. After cooling, nitrobenzene was evaporated under a reduced pressure. By crystallizing the resulting residue with ethyl acetate/hexane, 4.90 g (55%) of the title compound was obtained. Its physical property values are shown as the Compound No. 1 in Table 1.
Reaction SMILES: Cl.[NH2:2][OH:3].C([O-])(=O)C.[Na+].[F:9][C:10]([F:28])([F:27])[C:11]1[CH:12]=[C:13]([CH:24]=[CH:25][CH:26]=1)[CH2:14][N:15]1[CH2:19][CH:18]2[C:20](=O)[CH2:21][CH2:22][CH:17]2[CH2:16]1>O.C(O)C>[F:9][C:10]([F:28])([F:27])[C:11]1[CH:12]=[C:13]([CH:24]=[CH:25][CH:26]=1)[CH2:14][N:15]1[CH2:19][CH:18]2[C:20](=[N:2][OH:3])[CH2:21][CH2:22][CH:17]2[CH2:16]1
Reactant: O=C1CCC2CN(Cc3cccc(C(F)(F)F)c3)CC12
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: ON=C1CCC2CN(Cc3cccc(C(F)(F)F)c3)CC12
Temperature: 70 °C
Reaction time: 1 h

Procedure:
Hydroxylamine hydrochloride (3.47 g, 50.0 mmol) and sodium acetate (4.27 g, 52.0 mmol) were dissolved in water (15 mL) and added to a solution of 2-(3-(trifluoromethyl)benzyl)hexahydrocyclopenta[c]pyrrol-4(5H)-one (Example 56C, 11.33 g, 40 mmol) in ethanol (80 mL). The reaction was brought to reflux and then allowed to cool to 70° C. After 1 hour, the solvent was removed in vacuo to give the title compound.
Reaction SMILES: [N:1]1[NH:2][N:3]=[C:4]([CH2:6][O:7][C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH:18]=[N:17][N:16]=[N:15]3)=[CH:10][C:9]=2[F:19])[CH:5]=1.[CH2:20]([C:22]1[CH:23]=[N:24][C:25]([N:28]2[CH2:33][CH2:32][C@H:31](O)[C@H:30]([F:35])[CH2:29]2)=[N:26][CH:27]=1)[CH3:21]>>[CH2:20]([C:22]1[CH:23]=[N:24][C:25]([N:28]2[CH2:33][CH2:32][C@@H:31]([N:2]3[N:3]=[C:4]([CH2:6][O:7][C:8]4[CH:13]=[CH:12][C:11]([N:14]5[CH:18]=[N:17][N:16]=[N:15]5)=[CH:10][C:9]=4[F:19])[CH:5]=[N:1]3)[C@H:30]([F:35])[CH2:29]2)=[N:26][CH:27]=1)[CH3:21]
Reactant: Fc1cc(-n2cnnn2)ccc1OCc1cn[nH]n1
Reactant: CCc1cnc(N2CC[C@H](O)[C@H](F)C2)nc1
Product: CCc1cnc(N2CC[C@@H](n3ncc(COc4ccc(-n5cnnn5)cc4F)n3)[C@H](F)C2)nc1

Procedure:
The title compound was synthesized using 1-(4-((2H-1,2,3-triazol-4-yl)methoxy)-3-fluorophenyl)-1H-tetrazole (Intermediate 16) and cis-1-(5-ethylpyrimidin-2-yl)-3-fluoropiperidin-4-ol (Intermediate 17) in a manner similar to that described in Example 29.