Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:13][CH2:12][N:11]([S:14]([C:17]2[C:18]3[C:19](Br)=[CH:20][N:21]=[CH:22][C:23]=3[CH:24]=[CH:25][CH:26]=2)(=[O:16])=[O:15])[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:28](C1C=C(C)C=C(C(C)(C)C)C=1O)(C)(C)[CH3:29].C(C([Sn])=C(CCCC)CCCC)CCC>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>[C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:13][CH2:12][N:11]([S:14]([C:17]2[C:18]3[C:19]([CH:28]=[CH2:29])=[CH:20][N:21]=[CH:22][C:23]=3[CH:24]=[CH:25][CH:26]=2)(=[O:16])=[O:15])[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NC1CCN(S(=O)(=O)c2cccc3cncc(Br)c23)C1
Reactant: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CCCCC([Sn])=C(CCCC)CCCC
Solvent: Cc1ccccc1
Product: C=Cc1cncc2cccc(S(=O)(=O)N3CCC(NC(=O)OC(C)(C)C)C3)c12
Temperature: 25 °C
Yield: 21298.1 %

Procedure:
A solution of Intermediate 1 (250 mg) obtained in Example 1, Step A, 2,6-di(tert-butyl)-4-methylphenol (0.5 mg, Tokyo Kasei Kogyo), and tri(n-butyl)vinyltin (0.25 ml, Tokyo Kasei Kogyo) in toluene (8 ml) is added with tetrakis(triphenylphosphine)palladium(0) (13 mg, Kanto Chemicals) under a nitrogen gas atmosphere, and the mixture is refluxed by heating for 12 hours. The reaction mixture is cooled to room temperature, and then the solvent is evaporated under reduced pressure. The residue is purified by silica gel chromatography (n-hexane:ethyl acetate=2:1) to obtain the title compound (195 mg (predictive yield)).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](I)[C:5]2[O:10][CH:9]([C:11]([F:14])([F:13])[F:12])[C:8]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:7][C:6]=2[CH:20]=1.C(=O)([O-])[O-].[K+].[K+].[Cl:28][C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1.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.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:32]2[CH:33]=[CH:34][C:29]([Cl:28])=[CH:30][CH:31]=2)[C:5]2[O:10][CH:9]([C:11]([F:14])([F:13])[F:12])[C:8]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:7][C:6]=2[CH:20]=1
Reactant: CCOC(=O)C1=Cc2cc(Cl)cc(I)c2OC1C(F)(F)F
Reactant: OB(O)c1ccc(Cl)cc1
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: [K+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CCOC(=O)C1=Cc2cc(Cl)cc(-c3ccc(Cl)cc3)c2OC1C(F)(F)F
Temperature: 25 °C
Yield: 62.7 %

Procedure:
Ethyl 6-chloro-8-iodo-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylate (Example 73, Step 2) (1.3 g, 3.02 mmol), potassium carbonate (1.25 g, 9.06 mmol), 4-chorophenylboronic acid (0.52 g, 3.33 mmol), and tetrakis(triphenylphosphine)palladium(0) (0.174 g, 0.151 mmol) were added to toluene (30 mL) and the resulting solution was heated to reflux for 18 hours. After cooling to room temperature the reaction mixture was poured into ethyl acetate (50 mL). It was washed with 1 N HCl (2×25 mL), saturated aqueous sodium bicarbonate (2×25 mL), and water (2×25 mL). The organic phase was dried over MgSO4, filtered, and concentrated in vacuo to yield a brown oil. The crude material was purified by flash chromatography using 1% ethyl acetate in hexane yielding a white solid. Recrystallization from hexane afforded the ester as a white solid (0.79 g, 64%): mp 114.2–115.9° C. 1H NMR (CDCl3/300 MHz) 7.69 (s, 1H), 7.41 (s, 4H), 7.30 (d, 1H, J=2.4 Hz), 7.22 (d, 1H, J=2.6 Hz), 5.70 (q, 1H, J=6.9 Hz), 4.37–4.29 (m, 2H), 1.35 (t, 3H, J=7.1 Hz). ESLRMS m/z 434 (M+NH4+). FABHRMS m/z 434.0574 (M+NH4+, Calc'd. 434.0538). Anal. Calc'd. for C19H13Cl2F3O3: C, 54.70; H, 3.14; Cl, 17.00. Found: C, 54.79; H, 3.18; Cl, 16.65.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[NH:8][C:7]3[N:15]=[CH:16][CH:17]=[CH:18][C:6]=3[N:5]2[C:19]=1[C:20]1[CH:25]=[CH:24][C:23]([C:26]2([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])[CH2:29][CH2:28][CH2:27]2)=[CH:22][CH:21]=1.[CH:38]1[C:47]2[C:42](=[CH:43][C:44](B(O)O)=[CH:45][CH:46]=2)[CH:41]=[CH:40][N:39]=1.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.CCOC(C)=O.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.Cl[Pd]Cl>[CH:38]1[C:47]2[C:42](=[CH:43][C:44]([C:2]3[N:3]=[C:4]4[C:10]5[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=5[NH:8][C:7]5[N:15]=[CH:16][CH:17]=[CH:18][C:6]=5[N:5]4[C:19]=3[C:20]3[CH:25]=[CH:24][C:23]([C:26]4([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:34])[CH3:35])[CH2:29][CH2:28][CH2:27]4)=[CH:22][CH:21]=3)=[CH:45][CH:46]=2)[CH:41]=[CH:40][N:39]=1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(Br)nc4n3-c3cccnc3Nc3ccccc3-4)cc2)CCC1
Reactant: OB(O)c1ccc2cnccc2c1
Agent: Cl[Pd]Cl
Agent: CN(C)c1ccc(P(C(C)(C)C)C(C)(C)C)cc1
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccc5cnccc5c4)nc4n3-c3cccnc3Nc3ccccc3-4)cc2)CCC1
Yield: 73.3 %

Procedure:
A mixture of tert-butyl {1-[4-(2-bromo-9H-imidazo[1,2-d]pyrido[2,3-b][1,4]benzodiazepin-3-yl)phenyl]cyclobutyl}carbamate (50 mg, 0.090 mmol), isoquinolin-6-ylboronic acid (31 mg, 0.18 mmol), bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (6 mg, 0.09 mmol), and 2M Na2CO3 aq. (0.090 mL, 0.18 mmol) in DMF (2.5 mL) was treated with microwave (160° C. for 1 hour). The mixture was diluted with AcOEt, washed with water(×3), brine, dried over Na2SO4, then filtrated through Celite pad. The filtrate was concentrated and the residue was purified by preparative thin-layer chromatography (n-hexane/AcOEt=1:4) to afford the desired product (40 mg, 74%) as a white solid. 1HNMR (CDCl3) 400 MHz δ: 9.17 (s, 1H), 8.45 (d, J=6.3 Hz, 1H), 8.22 (dd, J=8.0 Hz and 1.7 Hz, 1H), 8.13-8.11 (m, 1H), 8.04 (dd, J=4.0 Hz and 1.1 Hz, 1H), 7.82-7.73 (m, 2H), 7.54 (d, J=5.7 Hz, 1H), 7.41 (dd, J=8.6 Hz and 1.7 Hz, 2H), 7.33 (td, J=8.0 Hz and 1.7 Hz, 1H), 7.21-7.17 (m, 2H), 6.97 (d, J=6.9 Hz, 1H), 6.84 (d, J=7.4 Hz, 1H), 6.62 (dd, J=8.0 Hz and 5.2 Hz, 1H), 6.27 (s, 1H), 5.16 (br s, 1H), 2.60-2.52 (m, 2H), 2.52-2.30 (m, 2H), 2.23-2.13 (m, 1H), 1.96-1.88 (m, 1H), 1.39 (br s, 9H). LCMS: 607 [M+H].
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C@@H:12]3[CH2:17][CH2:16][CH2:15][N:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13]3)[N:9]=[C:10](I)[C:3]=12.[F:25][C:26]1[CH:47]=[CH:46][CH:45]=[C:44]([F:48])[C:27]=1[O:28][C:29]1[CH:34]=[CH:33][C:32](B2OC(C)(C)C(C)(C)O2)=[CH:31][CH:30]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C@@H:12]3[CH2:17][CH2:16][CH2:15][N:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13]3)[N:9]=[C:10]([C:32]3[CH:31]=[CH:30][C:29]([O:28][C:27]4[C:44]([F:48])=[CH:45][CH:46]=[CH:47][C:26]=4[F:25])=[CH:34][CH:33]=3)[C:3]=12
Reactant: CC1(C)OB(c2ccc(Oc3c(F)cccc3F)cc2)OC1(C)C
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](n2nc(I)c3c(N)ncnc32)C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCC[C@@H](n2nc(-c3ccc(Oc4c(F)cccc4F)cc3)c3c(N)ncnc32)C1
Temperature: 90 °C
Reaction time: 15 h
Yield: 84.7 %

Procedure:
Into a 250 mL 3-necked round-bottom flask purged and maintained under an inert atmosphere of nitrogen, was placed a solution of tert-butyl (3R)-3-[4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate (500 mg, 1.13 mmol, 1.00 equiv) in 1,4-dioxane/H2O (100/30 mL), 2-[4-(2,6-difluorophenoxy)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (420 mg, 1.26 mmol, 1.1 equiv), sodium carbonate (240 mg, 2.26 mmol, 2.0 equiv), and Pd(PPh3)4 (65 mg, 0.06 mmol, 0.05 equiv). The resulting solution was stirred for 15 h at 90° C. in an oil bath and then concentrated under vacuum. The residue was diluted with water and extracted with dichloromethane and the organic layers combined. The organics were washed with brine, dried over anhydrous sodium sulfate and concentrated. The residue was loaded onto a silica gel column and eluted with dichloromethane/methanol (10/1) to give 500 mg (85%) of tert-butyl (3R)-3-[4-amino-3-[4-(2,6-difluorophenoxy)-phenyl]-1H-pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate as a white solid.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:20][C@@H:19]2[N:11]([C:12]3[N:13]=[C:14]4[CH2:23][O:22][CH2:21][C:15]4=[CH:16][C:17]=3[CH2:18]2)[C@H:10]([CH3:24])[CH2:9]1)=O)(C)(C)C.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[CH3:24][C@@H:10]1[CH2:9][N:8]([CH3:6])[CH2:20][C@@H:19]2[N:11]1[C:12]1[N:13]=[C:14]3[CH2:23][O:22][CH2:21][C:15]3=[CH:16][C:17]=1[CH2:18]2
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]2Cc3cc4c(nc3N21)COC4
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: C[C@@H]1CN(C)C[C@H]2Cc3cc4c(nc3N21)COC4
Temperature: 25 °C
Yield: 71.6 %

Procedure:
A mixture of 0.100 g (5R,8aR)-5-methyl-3,5,6,8,8a,9-hexahydro-1H-2-oxa-4,4b,7-triaza-cyclopenta[b]fluorene-7-carboxylic acid tert-butyl ester and 0.040 g lithium aluminum hydride in 3 ml tetrahydrofuran was heated to reflux for 2 h. The reaction mixture was cooled to room temperature and partitioned between water and ethyl acetate. The organic phase was washed with brine evaporated and purified by chromatography on silica gel with dichloromethane:methanol:ammonia=90:10:1. to yield 0.053 g of the title compound as slightly yellow gum (MS: 246.4 (M+H+))
Reaction SMILES: C([O:3][C:4]1[CH:16]=[CH:15][C:7]2[N:8]=[C:9]([S:11]([NH2:14])(=[O:13])=[O:12])[S:10][C:6]=2[CH:5]=1)C.[Al+3].[Cl-].[Cl-].[Cl-]>C(Cl)Cl>[OH:3][C:4]1[CH:16]=[CH:15][C:7]2[N:8]=[C:9]([S:11]([NH2:14])(=[O:13])=[O:12])[S:10][C:6]=2[CH:5]=1
Reactant: CCOc1ccc2nc(S(N)(=O)=O)sc2c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: NS(=O)(=O)c1nc2ccc(O)cc2s1
Temperature: 25 °C
Reaction time: 24 h
Yield: 95.9 %

Procedure:
To a 1 L round bottomed flask equipped with a magnetic stir bar, rubber septum, and argon inlet containing DCM (500 mL) was placed 6-ethoxybenzo[d]thiazole-2-sulfonamide (25 g, 108.7 mmol). To this solution at 0° C. (ice bath) was added AlCl3 (50 g, 376 mmol) portion-wise and the reaction was allowed to stir at rt for 24 h. Solvent was removed in vacuo and the residue was cautiously quenched into 3 M HCl (600 mL). The mixture was filtered and the solid was washed with cooled 3 M HCl (2×50 mL). The product was dried under high vacuum for 48 h to afford compound 1 as a yellow solid (24 g).
Reaction SMILES: C1(C(C2C=CC=CC=2)[N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]3([CH2:20][O:19][C:18]4=[CH:21][C:22]5[CH2:26][CH2:25][O:24][C:23]=5[CH:27]=[C:17]34)[C:9]2=[O:28])C=CC=CC=1.[H][H]>C(O)(=O)C.[OH-].[Pd+2].[OH-]>[NH:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]2([CH2:20][O:19][C:18]3=[CH:21][C:22]4[CH2:26][CH2:25][O:24][C:23]=4[CH:27]=[C:17]23)[C:9]1=[O:28]
Reactant: [H][H]
Reactant: O=C1N(C(c2ccccc2)c2ccccc2)c2ccccc2C12COc1cc3c(cc12)OCC3
Agent: [Pd+2]
Agent: [OH-]
Solvent: CC(=O)O
Product: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCC3
Yield: 71.6 %

Procedure:
A mixture of 1′-(diphenylmethyl)-6,7-dihydrospiro[benzo[1,2-b:4,5-b′]difuran-3,3′-indol]-2′(1′H)-one (0.29 g, 0.65 mmol) and palladium hydroxide (0.10 g, 20% on activated carbon) in acetic acid (20.0 mL) was hydrogenated at 60° C. under normal pressure of hydrogen for 20 hours. The reaction mixture was filtered through celite and washed with acetone (50.0 mL). The filtrate was concentrated in vacuo to dryness to give the title compound (0.13 g, 69%): MS (ES+) m/z 280.2 (M+1).
Reaction SMILES: C(N(C(C)C)CC)(C)C.C(Cl)CCl.C1C=NC2N(O)N=NC=2C=1.[Cl:24][C:25]1[C:29]([Cl:30])=[C:28]([CH3:31])[NH:27][C:26]=1[C:32](NC1CCN(C2C=CN=C(S(C)=O)N=2)CC1)=[O:33].Cl.[NH2:51][CH:52]1[CH2:57][CH2:56][N:55]([C:58]2[CH:59]=[C:60]([CH:64]=[C:65]([Cl:67])[N:66]=2)[C:61]([NH2:63])=[O:62])[CH2:54][CH2:53]1>CN(C=O)C>[Cl:67][C:65]1[CH:64]=[C:60]([CH:59]=[C:58]([N:55]2[CH2:54][CH2:53][CH:52]([NH:51][C:32]([C:26]3[NH:27][C:28]([CH3:31])=[C:29]([Cl:30])[C:25]=3[Cl:24])=[O:33])[CH2:57][CH2:56]2)[N:66]=1)[C:61]([NH2:63])=[O:62]
Reactant: NC(=O)c1cc(Cl)nc(N2CCC(N)CC2)c1
Reactant: Cc1[nH]c(C(=O)NC2CCN(c3ccnc(S(C)=O)n3)CC2)c(Cl)c1Cl
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1[nH]c(C(=O)NC2CCN(c3cc(C(N)=O)cc(Cl)n3)CC2)c(Cl)c1Cl
Reaction time: 8 h
Yield: 30 %

Procedure:
Diisopropylethylamine (0.063 ml, 0.37 mmol), EDC (0.095 g, 0.31 mmol) and HOAT (0.042 g, 0.31 mmol) were added to a stirred solution of 3,4-dichloro-5-methyl-1H-pyrrole-2-carboxylic acid (Intermediate 3, 0.060 g, 0.31 mmol) in DMF (1.0 ml) at room temperature. The resultant solution was stirred for 30 mins and a solution of 2-(4-aminopiperidin-1-yl)-6-chloroisonicotinamide hydrochloride (Intermediate 70, 0.096 g, 0.37 mmol) in 1 ml of DMF was added. The reaction was stirred overnight, then concentrated under vacuum and the residue was partitioned between water and EtOAc. The aqueous layer was extracted with EtOAc (×2) and the combined organic extracts were washed with 1 N HCl, water and brine, dried over MgSO4 and concentrated under vacuum. The residue was purified by reverse phase chromatography to give the desired product as a white solid (40 mg).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([I:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[C:12](Cl)(=O)[C:13](Cl)=O.CCO>C(Cl)Cl>[CH2:12]([O:8][C:7](=[O:9])[C:6]1[CH:10]=[C:2]([Br:1])[CH:3]=[CH:4][C:5]=1[I:11])[CH3:13]
Reactant: O=C(O)c1cc(Br)ccc1I
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCO
Product: CCOC(=O)c1cc(Br)ccc1I
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 50.1 %

Procedure:
5-Bromo-2-iodo-benzoic acid (25.0 g, 76.47 mol) was dissolved in CH2Cl2 (75 ml) at room temperature. Oxalyl chloride (14.5 ml, 152.94 mmol) was added and the mixture was stirred at 40° C. for 30 minutes. The mixture was allowed to cool to room temperature and EtOH (6.69 ml, 114.71 mmol) was added. The mixture was concentrated under reduced pressure to give 27.2 g (quantitative) of 5-bromo-2-iodo-benzoic acid ethyl ester as a yellow crystalline solid.
Reaction SMILES: C([O:4][CH2:5][CH:6]1[O:11][CH2:10][CH2:9][NH:8][CH2:7]1)=CC.Cl.[C:13]1([C:19]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)Cl)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])O.[Na+]>CC(C)=O.O.C(Cl)Cl.C(N(CC)CC)C>[OH:4][CH2:5][CH:6]1[O:11][CH2:10][CH2:9][N:8]([C:19]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:7]1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC=COCC1CNCCO1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: OCC1CN(C(c2ccccc2)(c2ccccc2)c2ccccc2)CCO1
Reaction time: 2 h
Yield: 64.2 %

Procedure:
The crude 2-(1-propenyloxymethyl)morpholine (32.7 g) was dissolved in an acetone-water (9:1) mixed solvent containing 2.0N hydrochloric acid, followed by heating under reflux for 4 hours. After completion of the reaction, the solvent was evaporated to obtain a crude alcohol compound (41.8 g) as a pale yellow oily substance. Triethylamine (145 ml) was added dropwise to a methylene chloride solution (300 ml) of the crude alcohol compound (41.8 g) under ice-cooling, and triphenylchloromethane (41.5 g, 0.208 mol) was added thereto at the same temperature, followed by stirring for 2 hours. After completion of the reaction, a saturated aqueous solution of sodium hydrogencarbonate (150 ml) was added to the reaction mixture, and the mixture was extracted with chloroform. The extract was dried over magnesium sulfate, the solvent evaporated, and the residue recrystallized from methylene chloride-hexane to give 2-hydroxymethyl-4-tritylmorpholine (48.0 g).
Reaction SMILES: [CH2:1]([C:3]1[NH:7][CH:6]=[N:5][C:4]=1[C:8]1[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=1)[CH3:2].C([O-])(=O)C.[K+].[I:19]I.O>CO.C(OCC)(=O)C>[CH2:1]([C:3]1[NH:7][C:6]([I:19])=[N:5][C:4]=1[C:8]1[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=1)[CH3:2]
Reactant: II
Reactant: CCc1[nH]cnc1-c1cccnc1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CO
Product: CCc1[nH]c(I)nc1-c1cccnc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.6 %

Procedure:
To a solution of 5-ethyl-4-(3-pyridyl)imidazole (1.50 g) and potassium acetate (2.55 g) in methanol (40 ml) was added iodine (2.86 g), and the mixture was stirred at room temperature overnight. To the reaction mixture were added water and ethyl acetate, and the organic layer was collected, washed with a saturated aqueous sodium thiosulfate solution and brine and dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The resulting residue was purified by NH silica gel flush column chromatography (solvent: ethyl acetate) to obtain 5-ethyl-2-iodo-4-(3-pyridyl)imidazole (1.75 g).
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[Cl:7][C:8]1[N:13]=[CH:12][C:11]([CH2:14][OH:15])=[CH:10][CH:9]=1.IC>C1COCC1>[Cl:7][C:8]1[CH:9]=[CH:10][C:11]([CH2:14][O:15][CH3:1])=[CH:12][N:13]=1
Reactant: CC(C)(C)[O-]
Reactant: OCc1ccc(Cl)nc1
Agent: [K+]
Solvent: C1CCOC1
Solvent: CI
Product: COCc1ccc(Cl)nc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
2.6 g (23.0 mmol) of potassium tert-butoxide are dissolved in 50 ml of THF. 3.0 g (20.9 mmol) of (6-chloropyridin-3-yl)methanol are added, and the mixture is stirred at RT for 15 min. 4.4 g (31.3 mmol) of iodomethane are then added slowly, and the mixture is stirred for about 30 min until the slightly exothermic reaction has subsided. The solvent is removed, and the residue is taken up in dichloromethane and washed twice with water. The organic phase is dried over magnesium sulfate and concentrated, and the residue is purified by column chromatography on silica gel (Biotage chromatography, mobile phase: cyclohexane/ethyl acetate 85:15).
Reaction SMILES: [CH3:1][C:2]1[C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[NH:7][C:6]=2[C:5]([S:15][CH3:16])=[C:4]([CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH:3]=1.[C:25]1([CH2:31][CH2:32][CH2:33]Br)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[CH3:1][C:2]1[C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[N:7]([CH2:33][CH2:32][CH2:31][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:6]=2[C:5]([S:15][CH3:16])=[C:4]([CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH:3]=1
Reactant: BrCCCc1ccccc1
Reactant: CSc1c(CC(=O)OC(C)(C)C)cc(C)c2c1[nH]c1ccccc12
Product: CSc1c(CC(=O)OC(C)(C)C)cc(C)c2c3ccccc3n(CCCc3ccccc3)c12
Yield: 74 %

Procedure:
Following a procedure and using relative proportions of starting materials similar to those described in Example 4, but using tert-butyl (4-methyl-1-methylthiocarbazol-2-yl)acetate and 3-phenylpropyl bromide as starting materials, the title compound was obtained in a yield of 74% as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:18]([C:26]4[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=4)([C:20]4[N:24]([CH3:25])[CH:23]=[N:22][CH:21]=4)[OH:19])[CH:16]=3)[N:11]3[N:34]=[N:35][N:36]=[C:10]3[NH:9]2)[CH:5]=[CH:6][CH:7]=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:17]3[CH:16]=[C:15]([C:18]([C:26]4[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=4)([C:20]4[N:24]([CH3:25])[CH:23]=[N:22][CH:21]=4)[OH:19])[CH:14]=[CH:13][C:12]=3[NH:11][C:10]3=[N:36][N:35]=[N:34][N:9]23)[CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(C(O)(c2ccc3c(c2)C(c2cccc(Cl)c2)Nc2nnnn2-3)c2cncn2C)cc1
Solvent: Cc1ccccc1
Product: COc1ccc(C(O)(c2ccc3c(c2)C(c2cccc(Cl)c2)n2nnnc2N3)c2cncn2C)cc1
Yield: 26.7 %

Procedure:
A mixture of intermediate 17 (0.0006 mol) in toluene (10 ml) was stirred and refluxed for 5 hours, then brought to room temperature and the solvent, was evaporated till dryness. The residue was taken up in DCM. The solvent was evaporated till dryness. The residue was purified by column chromatography over kromasil® (10 μm) (eluent: DCM/MeOH/Et3N 95/5/0.5). The pure fractions were collected and the solvent was evaporated. The residue (0.12 g, 40%) was taken up in DCM. The solvent was evaporated till dryness, yielding 0.08 g (27%) of 9-(3-chlorophenyl)-4,9-dihydro-α-(4-methoxyphenyl)-α-(1-methyl-1H-imidazol-5-yl)-tetrazolo[5,1-b]quinazoline-7-methanol (compound 3).
Reaction SMILES: [CH:1]1([C:4](=[O:8])[CH2:5][C:6]#[N:7])[CH2:3][CH2:2]1.[H-].[Na+].Br[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[N+:25]([O-:27])=[O:26])=[CH:15][CH:14]=1>CS(C)=O.[Cl-].[Na+].O>[CH:1]1([C:4](=[O:8])[CH:5]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[N+:25]([O-:27])=[O:26])=[CH:17][CH:18]=2)[C:6]#[N:7])[CH2:3][CH2:2]1
Reactant: O=[N+]([O-])c1ccccc1-c1ccc(CBr)cc1
Reactant: N#CCC(=O)C1CC1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: N#CC(Cc1ccc(-c2ccccc2[N+](=O)[O-])cc1)C(=O)C1CC1
Reaction time: 1 h
Yield: 33.6 %

Procedure:
To a solution of 2.61 g (24.0 mmol) 3-cyclopropyl-3-oxopropanenitrile in 150 mL DMSO was added 1.01 g (25.2 mmol) 60% NaH in oil. After 1 hour, 3.50 g (12.0 mmol) 4'-bromomethyl-2-nitrobiphenyl was added all at once to the solution. After 3 hours, the solution was poured into brine and extracted 3 times with ether. The combined organic material was dried over MgSO4, stripped of solvent in vacuo, and was chromatographed on silica gel under medium pressure using 3/40/57 EtOAc/CH2Cl2/hexanes to give 1.29 g (34% yield) of the title compound as a yellow glass. Rf 0.13 in 3/40/57 EtOAc/CH2Cl2/hexanes, visualized by UV and ammonium molybdate/ceric sulfate stain; Rf of the dialkylated material is 0.19 in the same solvent mixture.
Reaction SMILES: [CH:1]([NH2:4])([CH3:3])[CH3:2].C[Al](C)C.[Br:9][C:10]1[CH:14]=[C:13]([C:15]([NH:17][C:18]2[CH:19]([C:25](OCC)=[O:26])[CH2:20][CH2:21][CH2:22][C:23]=2[CH3:24])=[O:16])[N:12]([C:30]2[C:35]([Cl:36])=[CH:34][CH:33]=[CH:32][N:31]=2)[N:11]=1>ClCCl>[Br:9][C:10]1[CH:14]=[C:13]([C:15]([NH:17][C:18]2[CH:23]([CH3:24])[CH2:22][CH2:21][CH2:20][C:19]=2[C:25]([NH:4][CH:1]([CH3:3])[CH3:2])=[O:26])=[O:16])[N:12]([C:30]2[C:35]([Cl:36])=[CH:34][CH:33]=[CH:32][N:31]=2)[N:11]=1
Reactant: CCOC(=O)C1CCCC(C)=C1NC(=O)c1cc(Br)nn1-c1ncccc1Cl
Reactant: CC(C)N
Agent: C[Al](C)C
Solvent: ClCCl
Product: CC(C)NC(=O)C1=C(NC(=O)c2cc(Br)nn2-c2ncccc2Cl)C(C)CCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Isopropyl amine (77 μL, 0.9 mmol) was added to a solution of trimethylaluminum (0.45 mL, 2M solution in hexanes, 0.9 mmol) in dichloromethane (10 mL). After stirring at ambient temperature for 1 h, ethyl 2-[[[3-bromo-1-(3-chloro-2-pyridinyl)-1H-pyrazol-5-yl]carbonyl]amino]-3-methyl-2-cyclohexene-1-carboxylate (i.e. the product of Step G) was added (425 mg, 0.9 mmol) in dichloromethane (5 mL) and the solution was heated at reflux for 24 hours and then overnight at ambient temperature. The reaction was quenched with water and the mixture was filtered through a column of celite and washed with dichloromethane. The eluent was concentrated and purified by silica gel column chromatography (eluted with 60% then 80% ethyl ether in petroleum ether then ethyl ether then ethyl acetate) to give the title compound, a compound of present invention, as a colorless oil (100 mg).