Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].[C:2]([C:5]1[CH:9]=[C:8]([C:10]2[CH:26]=[CH:25][C:13]([O:14][CH2:15][CH2:16][NH:17]C(=O)OC(C)(C)C)=[CH:12][CH:11]=2)[N:7]([C:27]2[CH:28]=[N:29][C:30]([O:33][CH3:34])=[CH:31][CH:32]=2)[N:6]=1)([CH3:4])=[CH2:3]>O1CCOCC1.C(Cl)Cl>[ClH:1].[ClH:1].[C:2]([C:5]1[CH:9]=[C:8]([C:10]2[CH:11]=[CH:12][C:13]([O:14][CH2:15][CH2:16][NH2:17])=[CH:25][CH:26]=2)[N:7]([C:27]2[CH:28]=[N:29][C:30]([O:33][CH3:34])=[CH:31][CH:32]=2)[N:6]=1)([CH3:4])=[CH2:3]
Reactant: C=C(C)c1cc(-c2ccc(OCCNC(=O)OC(C)(C)C)cc2)n(-c2ccc(OC)nc2)n1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: C=C(C)c1cc(-c2ccc(OCCN)cc2)n(-c2ccc(OC)nc2)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A 4M solution of HCl in dioxane (2 ml) was added to a solution of ter-butyl (2-{4-[3-isopropenyl-1-(6-methoxy-3-pyridinyl)-1H-pyrazol-5-yl]phenoxy}ethyl)carbamate (269.7 mg) in CH2Cl2 (2 ml) . The reaction mixture was stirred at ambient temperature for 2 hours, then, was concentrated in vacuo to give (2-{4-[3-isopropenyl-1-(6-methoxy-3-pyridinyl)-1H-pyrazol-5-yl]phenoxy}ethyl)amine dihydrochloride (259 mg) as an amorphous powder.
Reaction SMILES: C[O:2][C:3]1[N:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][C:12]([CH3:16])([CH3:15])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.Cl.N1C=CC=CC=1.[OH-].[Na+]>O>[CH3:15][C:12]1([CH3:16])[CH2:11][CH2:10][N:9]([C:6]2[CH:7]=[N:8][C:3]([OH:2])=[CH:4][CH:5]=2)[CH2:14][CH2:13]1
Reactant: COc1ccc(N2CCC(C)(C)CC2)cn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: O
Product: CC1(C)CCN(c2ccc(O)nc2)CC1
Temperature: 200 °C
Yield: 71.8 %

Procedure:
A mixture of 6′-methoxy-4,4-dimethyl-3,4,5,6-tetrahydro-2H-[1,3′]bipyridinyl (1.28 g, 5.81 mmol) and pyridine hydrochloride (5.00 g, 43.3 mmol) was heated in a kugelrohr oven at 200° C. for 15 minutes. After cooling to room temperature water was added and the solution was made slightly basic with aqueous 1N sodium hydroxide. The solution was extracted three times with dichloromethane and the combined organic layers were dried over sodium sulphate, filtered and evaporated in vacuo, yielding the title compound (0.86 g, 72% yield).
Reaction SMILES: [H-].[Na+].Cl.Cl[CH2:5][CH2:6][N:7]1[CH2:12][CH2:11][O:10][CH2:9][CH2:8]1.[CH3:13][N:14]1[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[NH:18][C:17](=[O:25])[C:16]2=[CH:26][S:27][CH:28]=[C:15]12>CN(C)C=O>[CH3:13][N:14]1[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[N:18]([CH2:5][CH2:6][N:7]2[CH2:12][CH2:11][O:10][CH2:9][CH2:8]2)[C:17](=[O:25])[C:16]2=[CH:26][S:27][CH:28]=[C:15]12
Reactant: CN1c2ccccc2NC(=O)c2cscc21
Reactant: ClCCN1CCOCC1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1c2cscc2C(=O)N(CCN2CCOCC2)c2ccccc21
Reaction time: 18 h

Procedure:
A mixture of 0.31 g. of 55% sodium hydride-mineral oil dispersion and 0.65 g. of N-(2-chloroethyl)morpholine hydrochloride in 25 ml. of dry dimethylformamide is stirred at room temperature for 0.5 hours. To the mixture is added 0.40 g. of 4,9-dihydro-4-methyl-10H-thieno[3,4-b] [1,5]benzodiazepin-10-one and stirring is continued for 18 hours. The reaction mixture is cooled, quenched with water and extracted with chloroform. The dried chloroform extracts are concentrated to dryness and the solid residue is recrystallized from ethyl acetate-hexane to give white crystals, m.p. 109°-111°C.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([S:9]([CH2:12][CH2:13][CH2:14][N:15]2C(=O)C3C(=CC=CC=3)C2=O)(=[O:11])=[O:10])[CH:6]=[CH:7][CH:8]=1.[BrH:26]>C(O)(=O)C>[BrH:26].[NH2:15][CH2:14][CH2:13][CH2:12][S:9]([C:5]1[CH:4]=[C:3]([OH:2])[CH:8]=[CH:7][CH:6]=1)(=[O:10])=[O:11]
Reactant: COc1cccc(S(=O)(=O)CCCN2C(=O)c3ccccc3C2=O)c1
Agent: Br
Solvent: CC(=O)O
Product: NCCCS(=O)(=O)c1cccc(O)c1

Procedure:
The sulfone from Step B (1.32 g, 3.67 mmol) in acetic acid (2 mL) and 48% HBr (2 mL) was heated at 100° C. for 72 hours. The reaction mixture was concentrated and the solid residue triturated with ether (200 mL) to produce the title compound as a grey solid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[CH:3]=1.[Br:10][C:11]1[CH:16]=[C:15](F)[CH:14]=[C:13]([Cl:18])[CH:12]=1.C(=O)([O-])[O-].[K+].[K+].Cl>CN1C(=O)CCC1.O>[Br:10][C:11]1[CH:16]=[C:15]([CH:14]=[C:13]([Cl:18])[CH:12]=1)[O:1][C:2]1[CH:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[CH:3]=1
Reactant: Fc1cc(Cl)cc(Br)c1
Reactant: Cc1cc(O)cc(=O)[nH]1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN1CCCC1=O
Product: Cc1cc(Oc2cc(Cl)cc(Br)c2)cc(=O)[nH]1
Temperature: 140 °C

Procedure:
4-Hydroxy-6-methylpyridin-2(1H)-one (3-2; 10.0 g; 80 mmol) and 1-bromo-3-chloro-5-fluorobenzene (16.74 g; 80 mmol) and potassium carbonate (33.1 g; 240 mmol) were suspended in NMP (200 mL) and then heated at 140° C. for 5 days. The reaction mixture was cooled to room temperature, diluted with water (900 mL) and the pH of the solution was adjusted to 5 with concentrated HCl. The solid was filtered off, washed with water and suctioned dry. The crude material was adsorbed onto silica and purified in 2 runs on a silica column eluted with DCM:MeOH to give the title product (9-1) as a yellow solid. Rf=0.6(DCM:MeOH, 95:5). LCMS: M+=315. 1H NMR (DMSO-d6): δ 11.48 (s, 1H), 7.65 (s, 1H), 7.43 (s, 1H), 7.36 (s,1H), 5.86 (s, 1H), 5.36 (s, 1H), 2.16 (s, 3H).
Reaction SMILES: [H-].[Na+].[O:3]1[CH2:8][C:7](=[O:9])[NH:6][C:5]2[N:10]=[CH:11][CH:12]=[CH:13][C:4]1=2.[CH3:14][Si:15]([CH3:22])([CH3:21])[CH2:16][CH2:17][O:18][CH2:19]Cl>CN(C=O)C>[CH3:14][Si:15]([CH3:22])([CH3:21])[CH2:16][CH2:17][O:18][CH2:19][N:6]1[C:7](=[O:9])[CH2:8][O:3][C:4]2[CH:13]=[CH:12][CH:11]=[N:10][C:5]1=2
Reactant: C[Si](C)(C)CCOCCl
Reactant: O=C1COc2cccnc2N1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCN1C(=O)COc2cccnc21
Reaction time: 1 h

Procedure:
Sodium hydride (60% dispersion in mineral oil; 0.48 g, 12 mmol) is added in portions to a solution of 2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one (1.50 g, 10 mmol) in DMF (20 mL) at 0° C. and the mixture is stirred for 1 h. 2-(Trimethylsilyl)ethoxymethylchloride (2.1 mL, 12 mmol) is added slowly dropwise and the mixture is then stirred at rt for 1 h. The reaction is quenched by pouring into ice-water and the mixture is then extracted with CH2Cl2 (×3). The combined organic extracts are washed with brine, dried (MgSO4), filtered and concentrated in vacuo. The crude product is purified by silica gel chromatography (gradient elution with hexanes-EtOAc) to afford the title compound.
Reaction SMILES: [CH3:1][O:2][CH2:3][C@H:4]([CH3:24])[O:5][C:6]1[CH:7]=[C:8]([OH:23])[CH:9]=[C:10]([C:12]2[NH:13][C:14]([C:17]3[O:18][C@@H:19]([CH3:22])[CH2:20][N:21]=3)=[CH:15][CH:16]=2)[CH:11]=1.F[C:26]1[CH:31]=[CH:30][C:29]([S:32]([N:35]2[CH2:40][CH2:39][N:38]([CH3:41])[CH2:37][CH2:36]2)(=[O:34])=[O:33])=[CH:28][CH:27]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:1][O:2][CH2:3][C@H:4]([CH3:24])[O:5][C:6]1[CH:7]=[C:8]([CH:9]=[C:10]([C:12]2[NH:13][C:14]([C:17]3[O:18][C@@H:19]([CH3:22])[CH2:20][N:21]=3)=[CH:15][CH:16]=2)[CH:11]=1)[O:23][C:26]1[CH:31]=[CH:30][C:29]([S:32]([N:35]2[CH2:40][CH2:39][N:38]([CH3:41])[CH2:37][CH2:36]2)(=[O:33])=[O:34])=[CH:28][CH:27]=1
Reactant: CN1CCN(S(=O)(=O)c2ccc(F)cc2)CC1
Reactant: COC[C@H](C)Oc1cc(O)cc(-c2ccc(C3=NC[C@H](C)O3)[nH]2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC[C@H](C)Oc1cc(Oc2ccc(S(=O)(=O)N3CCN(C)CC3)cc2)cc(-c2ccc(C3=NC[C@H](C)O3)[nH]2)c1
Temperature: 100 °C
Reaction time: 1 h
Yield: 36.6 %

Procedure:
3-[(1S)-2-Methoxy-1-methylethoxy]-5-{5-[(5S)-5-methyl-4,5-dihydro-1,3-oxazol-2-yl]-1H-pyrrol-2-yl}phenol (40 mg, 0.12 mmol) synthesized in Example (116d) and 1-[(4-fluorophenyl)sulfonyl]-4-methylpiperazine (25 mg, 0.15 mmol) synthesized in Example (116a) were dissolved in N,N-dimethylformamide (2 mL), and potassium carbonate (51 mg, 0.37 mmol) was added, followed by stirring at 100° C. for 1 hour under nitrogen atmosphere. 1-[(4-Fluorophenyl)sulfonyl]-4-methylpiperazine (30 mg) was added again, and the mixture was stirred at 90° C. overnight. The reaction solution was cooled to room temperature, water (10 mL) was added, and extraction was carried out twice with ethyl acetate (10 mL). The organic layer was washed with saturated brine, and subsequently dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: methanol/methylene chloride=0%-5%) to afford the desired compound (25 mg, yield 35%) as a white solid.
Reaction SMILES: [CH:1]1([NH:7][C:8]2[CH:13]=[CH:12][C:11]([S:14]([NH:17][C:18](=[O:34])[C:19]3[CH:24]=[CH:23][C:22](B4OC(C)(C)C(C)(C)O4)=[CH:21][CH:20]=3)(=[O:16])=[O:15])=[CH:10][C:9]=2[N+:35]([O-:37])=[O:36])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Br:38][C:39]1[CH:44]=[CH:43][C:42](I)=[CH:41][CH:40]=1.C1([As](C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.C(OCC)(=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Br:38][C:39]1[CH:44]=[CH:43][C:42]([C:22]2[CH:21]=[CH:20][C:19]([C:18]([NH:17][S:14]([C:11]3[CH:12]=[CH:13][C:8]([NH:7][CH:1]4[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]4)=[C:9]([N+:35]([O-:37])=[O:36])[CH:10]=3)(=[O:16])=[O:15])=[O:34])=[CH:24][CH:23]=2)=[CH:41][CH:40]=1
Reactant: CC1(C)OB(c2ccc(C(=O)NS(=O)(=O)c3ccc(NC4CCCCC4)c([N+](=O)[O-])c3)cc2)OC1(C)C
Reactant: Brc1ccc(I)cc1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: O=C(NS(=O)(=O)c1ccc(NC2CCCCC2)c([N+](=O)[O-])c1)c1ccc(-c2ccc(Br)cc2)cc1
Reaction time: 5 h

Procedure:
A mixture of Example 3C (105 mg, 0.2 mmol), 4-bromo-1-iodobenzene (140 mg, 0.5 mmol), Pd2(dba)3 (18 mg, 0.04 mmol), triphenylarsine (36 mg, 0.12 mmol) and 1M Na2CO3 (0.5 mL) in dioxane (4 mL) was heated to 95° C. and stirred for 5 hours. The mixture was diluted with ethyl acetate (50 mL), washed sequentially with 1M HCl (5 mL), water (5 mL), and brine (5 mL), dried (MgSO4), filtered, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 50% ethyl acetate/hexanes to provide the desired product. MS (ESI(−)) m/e 556 (M−H)−; 1H NMR (400 MHz, DMSO-d6) δ 8.53 (d, 1H), 8.16 (d, 1H), 7.95 (d, 2H), 7.91 (dd, 1H), 7.68-7.60 (m, 5H), 4.12 (d, 1H), 3.76 (m, 1H), 2.00-1.31 (m, 10H).
Reaction SMILES: [CH3:1][C:2]1[C:6](B2OC(C)(C)C(C)(C)O2)=[C:5]([CH3:16])[O:4][N:3]=1.I[C:18]1[CH:19]=[C:20]([NH:24][C:25](=[O:27])[OH:26])[CH:21]=[CH:22][CH:23]=1>>[CH3:1][C:2]1[C:6]([C:18]2[CH:19]=[C:20]([NH:24][C:25](=[O:26])[OH:27])[CH:21]=[CH:22][CH:23]=2)=[C:5]([CH3:16])[O:4][N:3]=1
Reactant: O=C(O)Nc1cccc(I)c1
Reactant: Cc1noc(C)c1B1OC(C)(C)C(C)(C)O1
Product: Cc1noc(C)c1-c1cccc(NC(=O)O)c1

Procedure:
Using the same method as in Example 5-(i), 3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole was reacted with the (3-iodophenyl)carbamic acid.tert-butyl to give [3-(3,5-dimethylisoxazol-4-yl)phenyl]carbamic acid.tert-butyl (yield: 85%).
Reaction SMILES: [O:1]1[CH2:7][CH2:6][C:5](=[O:8])[NH:4][CH2:3][CH2:2]1.[C:9]([O:13][C:14](=O)[O:15]C(C)(C)C)([CH3:12])([CH3:11])[CH3:10].CN(C1C=CC=CN=1)C.C(N(CC)CC)C>ClCCl.O>[O:8]=[C:5]1[CH2:6][CH2:7][O:1][CH2:2][CH2:3][N:4]1[C:14]([O:13][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:15]
Reactant: O=C1CCOCCN1
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Agent: CN(C)c1ccccn1
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCOCCC1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 465 %

Procedure:
To a solution of 1,4-oxazepan-5-one (6.9 g, 60.0 mmol) in dichloromethane (120.0 mL) were added di-tert-butylcarbonate (1.75 g, 8.00 mmol) and dimethylaminopyridine (7.90 g, 65.0 mmol), and triethylamine (12.5 mL, 90.0 mmol) was added dropwise. After stirring for 16 hours at room temperature, to the mixture was added water, and the aqueous layer was extracted with chloroform. The organic layer was washed with saturated aqueous solution of ammonium chloride and brine, and then dried over sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified with silica gel column (hexane/ethyl acetate=90/10 to 0/100) to give the title compound (7.30 g, 37.2 mmol, 62%).
Reaction SMILES: [CH3:1][Si:2]([CH3:19])([CH3:18])[C:3]#[C:4][Sn](CCCC)(CCCC)CCCC.[NH2:20][C:21]1[C:26]([F:27])=[C:25]([C:28]2[CH:33]=[CH:32][C:31](I)=[CH:30][CH:29]=2)[N:24]=[C:23]([C:35]([O:37][CH3:38])=[O:36])[C:22]=1[Cl:39]>CN(C)C=O.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>[NH2:20][C:21]1[C:26]([F:27])=[C:25]([C:28]2[CH:33]=[CH:32][C:31]([C:4]#[C:3][Si:2]([CH3:1])([CH3:18])[CH3:19])=[CH:30][CH:29]=2)[N:24]=[C:23]([C:35]([O:37][CH3:38])=[O:36])[C:22]=1[Cl:39]
Reactant: CCCC[Sn](C#C[Si](C)(C)C)(CCCC)CCCC
Reactant: COC(=O)c1nc(-c2ccc(I)cc2)c(F)c(N)c1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1nc(-c2ccc(C#C[Si](C)(C)C)cc2)c(F)c(N)c1Cl
Temperature: 90 °C
Reaction time: 20 h
Yield: 73 %

Procedure:
Trimethyl((tributylstannyl)ethynyl)silane (510 mg, 1.3 mmol, 1.1 equiv) was added to a stirred mixture of methyl 4-amino-3-chloro-5-fluoro-6-(4-iodophenyl)picolinate (490 mg, 1.2 mmol, 1.0 equiv) and tetrakis(triphenylphosphine)palladium(0) (140 mg, 0.12 mmol, 0.10 equiv) in N,N-dimethylformamide (2.4 mL) at 23° C. The reaction mixture was heated to 90° C., resulting in a homogeneous yellow solution, and stirred for 20 h. The cooled reaction mixture was diluted with water (200 mL) and extracted with diethyl ether (4×100 mL). Hexanes (100 mL) was added to the combined organic layers and the turbid solution was washed with water (200 mL). The organic layer was dried (magnesium sulfate), gravity filtered, and concentrated by rotary evaporation. The residue was purified by silica gel column chromatography (25% ethyl acetate in hexanes) to afford the title compound as a tan powder (330 mg, 73%): mp 83-86° C.; IR (thin film) 3487 (m), 3375 (s), 2958 (s), 2159 (m), 1739 (s), 1618 (s) cm−1; 1H NMR (300 MHz, CDCl3) δ 7.89 (m, 2H), 7.55 (m, 2H), 4.89 (br s, 2H), 3.99 (s, 3H), 0.26 (s, 9H); ESIMS m/z 377 ([M+H]+).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5]([C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)#[N:6].[C:14]1(=[O:20])[O:19][C:17](=[O:18])[CH2:16][CH2:15]1.Cl>C(Cl)(Cl)C(Cl)Cl>[C:5]([C:7]1[CH:8]=[CH:9][C:10]([OH:13])=[C:11]([CH:12]=1)[C:14]([CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[O:20])#[N:6]
Reactant: N#Cc1ccc(O)cc1
Reactant: O=C1CCC(=O)O1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClC(Cl)C(Cl)Cl
Product: N#Cc1ccc(O)c(C(=O)CCC(=O)O)c1

Procedure:
Aluminum chloride (148 g, 1.11 mole) was added to a stirred mixture of 4-cyanophenol (44 g, 0.37 mole), succinic anhydride (33.3 g, 0.33 mole), and sym-tetrachloroethane (260 ml), and the mixture was then heated at 135° for 2 hours. The resultant complex was decomposed with ice and hydrochloric acid, and 3-(5-cyano-2-hydroxybenzoyl)propionic acid was isolated by standard procedures.
Reaction SMILES: [CH:1]1([CH:7]([C:9]2[C:10]([O:25][CH3:26])=[N:11][N:12]([C:14]3[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=3)[CH:13]=2)O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]([N:36]([CH3:44])[CH2:37][CH2:38][C:39]([O:41]CC)=[O:40])=[O:35])=[CH:30][CH:29]=1>>[CH:1]1([CH:7]([NH:27][C:28]2[CH:29]=[CH:30][C:31]([C:34]([N:36]([CH3:44])[CH2:37][CH2:38][C:39]([OH:41])=[O:40])=[O:35])=[CH:32][CH:33]=2)[C:9]2[C:10]([O:25][CH3:26])=[N:11][N:12]([C:14]3[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=3)[CH:13]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)CCN(C)C(=O)c1ccc(N)cc1
Reactant: COc1nn(-c2ccc(OC(F)(F)F)cc2)cc1C(O)C1CCCCC1
Product: COc1nn(-c2ccc(OC(F)(F)F)cc2)cc1C(Nc1ccc(C(=O)N(C)CCC(=O)O)cc1)C1CCCCC1
Yield: 11.3 %

Procedure:
Using cyclohexyl{3-methoxy-1-[4-(trifluoromethoxy)phenyl]-1H-pyrazol-4-yl}methanol (0.75 g) synthesized in Example 62(2) and ethyl 3-{[(4-aminophenyl)carbonyl](methyl)amino}propanoate (0.50 g) synthesized in Example 2(2) and in the same manner as in Example 1(7), the title object compound (0.13 g, 12%) was obtained as a white solid.
Reaction SMILES: [C:1]([CH2:3][C:4]1[CH:9]=[C:8]([CH3:10])[CH:7]=[C:6]([CH2:11][C:12]#[N:13])[CH:5]=1)#[N:2].Cl.N[C:16]1[C:21]([F:22])=[C:20]([F:23])[CH:19]=[CH:18][C:17]=1[SH:24]>>[F:22][C:21]1[C:16]2[N:13]=[C:12]([CH2:11][C:6]3[CH:5]=[C:4]([CH2:3][C:1]#[N:2])[CH:9]=[C:8]([CH3:10])[CH:7]=3)[S:24][C:17]=2[CH:18]=[CH:19][C:20]=1[F:23]
Reactant: Cc1cc(CC#N)cc(CC#N)c1
Reactant: Nc1c(S)ccc(F)c1F
Agent: Cl
Product: Cc1cc(CC#N)cc(Cc2nc3c(F)c(F)ccc3s2)c1
Yield: 16.7 %

Procedure:
The procedure of Example 22-i) was repeated using 1,3-biscyanomethyl-5-methylbenzene (680 mg, 4 mmol) and 2-amino-3,4-difluorothiophenol hydrochloride (888 mg, 4.5 mmol) and the resultant product was recrystallized from ethyl acetate-hexane to give 3-[(4,5-difluorobenzothiazol-2-yl)methyl]-5-methylphenylacetonitrile (210 mg, 17%) as a colorless powder.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[C:13]([O-])(=O)[CH3:14].[K+].O>C1COCC1.O>[Cl:1][C:2]1[N:11]=[C:10]([NH:3][C:4]2[CH:9]=[CH:8][C:13]([CH3:14])=[CH:6][CH:5]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: CC(=O)[O-]
Reactant: Clc1nc(Cl)c2ccccc2n1
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(Nc2nc(Cl)nc3ccccc23)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 144.8 %

Procedure:
A mixture of 2,4-dichloroquinazoline (5.8 g, 0.029 mol), p-tolyamine (3.5 g, 0.032 mol), and potassium acetate (3.72 g, 0.038 mol) in THF/water (66 ml/30 ml) was stirred at room temperature for 16 h. Water (66 ml) was added to the mixture, and a precipitate was formed. The precipitate was washed with water, filtered, and dried under high vacuum to afford (2-chloro-quinazolin-4-yl)-p-tolyl-amine (5.65 g, 0.021 mol, 70%). m.p.: 198-199° C.; 1H NMR (300 MHz, DMSO-d6) δ 2.27 (s, 3H), 7.21 (d, J=7.8 Hz, 2H), 7.50 (d, J=7.2 Hz, 3H), 7.83 (t, J=8.5 Hz, 2H), 8.50 (t, J=8.0 Hz, 1H).
Reaction SMILES: [N:1]([CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[CH:15][CH:14]=1)=[N+:2]=[N-:3].[I:27][C:28]1[CH:33]=[CH:32][C:31]([O:34][CH2:35][C:36]#[CH:37])=[CH:30][CH:29]=1.O>C1COCC1.[O-]S([O-])(=O)=O.[Cu+2]>[I:27][C:28]1[CH:33]=[CH:32][C:31]([O:34][CH2:35][C:36]2[N:3]=[N:2][N:1]([CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][O:12][C:13]3[CH:14]=[CH:15][C:16]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:23])([CH3:25])[CH3:24])=[CH:17][CH:18]=3)[CH:37]=2)=[CH:30][CH:29]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(OCCOCCOCCN=[N+]=[N-])cc1
Reactant: C#CCOc1ccc(I)cc1
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)Nc1ccc(OCCOCCOCCn2cc(COc3ccc(I)cc3)nn2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.2 %

Procedure:
To a solution of tert-butyl 4-(2-(2-(2-azidoethoxy)ethoxy)ethoxy)phenylcarbamate (1.78 g, 4.86 mmol) and 1-iodo-4-(prop-2-ynyloxy)benzene (1.25 g, 4.86 mmol) in THF (30 mL) was added H2O (8.0 mL), Cu powder (0.31 g, 4.86 mmol) and CuSO4 (0.12 g, 0.486 mmol). The reaction mixture was stirred at room temperature for at least 12 hours (overnight). The reaction mixture was filtered through celite and washed with EtOAc. The organic layer was separated, washed with EDTA solution, dried and concentrated in vacuo to give a crude product which was purified by flash chromatography with hexane/EtOAc (1:1) as eluent to give tert-butyl 4-(2-(2-(2-(4-((4-iodophenoxy)methyl)-1H-1,2,3-triazol-1-yl)ethoxy)ethoxy)ethoxy)phenylcarbamate (2.069 g, 68%). 1H NMR (400 MHz, CDCl3) δ 7.74 (s, 1H), 7.46 (d, J=9.2 Hz, 2H), 7.15 (d, J=8.8 Hz, 2H), 6.74 (d, J=9.2 Hz, 2H), 6.66 (d, J=8.8 Hz, 2H), 6.25 (brs, 1H), 5.04 (s, 2H), 4.47 (t, J=5.0 Hz, 2H), 3.99 (t, J=4.8 Hz, 2H), 3.79 (t, J=5.0 Hz, 2H), 3.80 (t, J=5.0 Hz, 2H), 3.71 (t, J=5.0 Hz, 2H), 3.60-3.53 (m, 4H), 1.44 (s, 9H); MS (ESI), 625 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[N:10][N:11]([CH3:13])[CH:12]=2)=[CH:4][CH:3]=1.[Li]CCCC.CN([CH:22]=[O:23])C.[Cl-].[NH4+]>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[N:10][N:11]([CH3:13])[C:12]=2[CH:22]=[O:23])=[CH:6][CH:7]=1
Reactant: Cn1cc(-c2ccc(F)cc2)nn1
Reactant: CN(C)C=O
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cn1nnc(-c2ccc(F)cc2)c1C=O
Temperature: -75 °C
Reaction time: 1 h
Yield: 94.2 %

Procedure:
To a solution of 4-(4-fluoro-phenyl)-1-methyl-1H-[1,2,3]triazole (709 mg, 4.0 mmol) in THF (20 mL) was added n-BuLi (1.6 M in hexane, 3.0 mL, 4.8 mmol) dropwise at −75° C. under Argon. The resulting solution was stirred at −75° C. for 1 h, then DMF (401 μL, 5.2 mmol) was added dropwise at −75° C. and the reaction mixture was allowed to warm up to room temperature over 1 h. The mixture was then poured into saturated ammonium chloride solution and extracted with ethyl acetate and the combined organic extracts washed with brine, dried over sodium sulphate, filtered and evaporated. Purification by chromatography (silica, 0 to 100% ethyl acetate in heptane) afforded the title compound (773 mg, 94%) as a white solid. MS: m/e=206.2 [M]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([NH:11][C:12]2[C:13]3[N:14]([CH:26]=[CH:27][N:28]=3)[N:15]=[C:16]([N:18]3[CH2:22][CH2:21][CH:20]([C:23](O)=[O:24])[CH2:19]3)[CH:17]=2)=[N:7][C:8]=1[O:9][CH3:10].[NH2:29][C:30]1[CH:42]=[CH:41][C:33]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])=[CH:32][CH:31]=1.CCN=C=NCCCN(C)C.CN1C=CN=C1>ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([NH:11][C:12]2[C:13]3[N:14]([CH:26]=[CH:27][N:28]=3)[N:15]=[C:16]([N:18]3[CH2:22][CH2:21][CH:20]([C:23]([NH:29][C:30]4[CH:42]=[CH:41][C:33]([C:34]([O:36][C:37]([CH3:38])([CH3:39])[CH3:40])=[O:35])=[CH:32][CH:31]=4)=[O:24])[CH2:19]3)[CH:17]=2)=[N:7][C:8]=1[O:9][CH3:10]
Reactant: CC(C)(C)OC(=O)c1ccc(N)cc1
Reactant: COc1ccc(Nc2cc(N3CCC(C(=O)O)C3)nn3ccnc23)nc1OC
Agent: CCN=C=NCCCN(C)C
Agent: Cn1ccnc1
Solvent: ClCCl
Product: COc1ccc(Nc2cc(N3CCC(C(=O)Nc4ccc(C(=O)OC(C)(C)C)cc4)C3)nn3ccnc23)nc1OC
Temperature: 25 °C
Reaction time: 16 h
Yield: 170.2 %

Procedure:
A mixture of 1-(8-(5,6-dimethoxypyridin-2-ylamino)imidazo[1,2-b]pyridazin-6-yl)pyrrolidine-3-carboxylic acid (80 mg, 0.21 mmol), tert-butyl 4-aminobenzoate (40 mg, 0.21 mmol), EDCI (159 mg, 0.08 mmol) and 1-methyl-1H-imidazole (68 mg, 0.8 mmol) in dichloromethane (5 mL) was stirred at room temperature for 16 h. The residue was concentrated to give crude tert-butyl 4-(1-(8-(5,6-dimethoxypyridin-2-ylamino)imidazo[1,2-b]pyridazin-6-yl)pyrrolidine-3-carboxamido)benzoate (200 mg, crude) as brown liquid that was used directly without purification. LC-MS: 560 [M+1]+, tR=1.510 min.