Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:9]([NH2:10])=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[NH2:11].[CH3:12][O:13][CH2:14][C:15](Cl)=[O:16]>N1C=CC=CC=1>[CH3:12][O:13][CH2:14][C:15]([NH:11][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([NH:10][C:15](=[O:16])[CH2:14][O:13][CH3:12])[C:2]=1[Cl:1])[C:6]#[N:7])=[O:16]
Reactant: COCC(=O)Cl
Reactant: N#Cc1cc(N)c(Cl)c(N)c1
Solvent: c1ccncc1
Product: COCC(=O)Nc1cc(C#N)cc(NC(=O)COC)c1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 4-chloro-3,5-diaminobenzonitrile (3.34 g) in pyridine (60 ml) is added dropwise methoxyacetyl chloride (4.0 ml) at room temperature. The mixture is stirred at room temperature for 2 hours, and thereafter, pyridine is distilled off under reduced pressure. To the residue is added water, and the resulting solid substance is separated by filtration and washed with water. The resulting crude crystals are recrystallized from ethanol to give the title compound (5.1 g) having the following physical properties.
Reaction SMILES: C([O:3][C:4]([CH2:6][O:7][C:8]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:9]=1[CH2:10][CH2:11][CH:12]([CH2:18][N:19]1[C:24](=[O:25])[CH:23]=[CH:22][C:21]([CH:26]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[N:20]1)[CH2:13]2)=[O:5])C.[OH-].[Na+]>COCCOC>[C:4]([CH2:6][O:7][C:8]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:9]=1[CH2:10][CH2:11][CH:12]([CH2:18][N:19]1[C:24](=[O:25])[CH:23]=[CH:22][C:21]([CH:26]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)=[N:20]1)[CH2:13]2)([OH:5])=[O:3]
Reactant: CCOC(=O)COc1cccc2c1CCC(Cn1nc(C(c3ccccc3)c3ccccc3)ccc1=O)C2
Agent: [Na+]
Agent: [OH-]
Solvent: COCCOC
Product: O=C(O)COc1cccc2c1CCC(Cn1nc(C(c3ccccc3)c3ccccc3)ccc1=O)C2
Yield: 81.2 %

Procedure:
A solution of 2-[(1,2,3,4-tetrahydro-5-ethoxycarbonylmethoxy-2-naphthyl)methyl]-6-diphenylmethyl-3(2H)-pyridazinone (0.43 g) in 1,2-dimethoxyethane (9.0 ml) and 1.0N aqueous solution of sodium hydroxide (0.85 ml) was stirred at room temperature For 5 hours. The solution was evaporated in vacuo and extracted with ethyl acetate and 1N hydrochloric acid. The organic layer was separated and washed with water and brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was crystallized from n-hexane, ethyl acetate and ether to give 2-[(1,2,3,4-tetrahydro-5-carboxymethoxy-2-naphthyl)methyl]-6-diphenylmethyl-3(2H)-pyridazinone (330 mg) as a white powder.
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[C:10]2[C:5](=[CH:6][CH:7]=[C:8](OS(C(F)(F)F)(=O)=O)[CH:9]=2)[C:4](=[O:19])[CH2:3]1.[CH3:21][C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1>>[CH3:1][C:2]1([CH3:20])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:25]3[CH:26]=[CH:27][C:22]([CH3:21])=[CH:23][CH:24]=3)[CH:9]=2)[C:4](=[O:19])[CH2:3]1
Reactant: Cc1ccc(B(O)O)cc1
Reactant: CC1(C)CC(=O)c2ccc(OS(=O)(=O)C(F)(F)F)cc21
Product: Cc1ccc(-c2ccc3c(c2)C(C)(C)CC3=O)cc1

Procedure:
The title compound was prepared from trifluoro-methanesulfonic acid 3,3-dimethyl-1-oxo-indan-5-yl ester and 4-methylphenyl boronic acid according to the procedure described in example 21. MS (ES) m/z 251.1; HRMS: calcd for C18H18O+H+, 251.14304; found (ESI, [M+H]+), 251.1431.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4]([C:9]([O:11][CH3:12])=[O:10])[N:3]=1.[CH:13]1([NH2:18])[CH2:17][CH2:16][CH2:15][CH2:14]1.C(N(CC)CC)C>C1COCC1.C(Cl)Cl>[Cl:1][C:2]1[N:3]=[C:4]([C:9]([O:11][CH3:12])=[O:10])[CH:5]=[C:6]([NH:18][CH:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)[N:7]=1
Reactant: NC1CCCC1
Reactant: COC(=O)c1cc(Cl)nc(Cl)n1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: ClCCl
Product: COC(=O)c1cc(NC2CCCC2)nc(Cl)n1

Procedure:
A cooled (0° C.) solution of methyl 2,4-dichloropyrimidine-6-carboxylate (Apollo, OR2558, 4.50 g; 21.7 mmol) in anhydrous THF (200 mL) was treated with a solution of cyclopentylamine (Aldrich, 2.36 mL; 23.9 mmol) and triethylamine (3.03 mL; 21.7 mmol) in DCM (60 mL). The reaction mixture was stirred for 1 h30. The organic solvent was removed in vacuo and the crude was redissolved in EtOAc then washed with water and brine. The organic extracts were dried over magnesium sulfate, filtered and concentrated to obtain the crude product, which was purified by column chromatography (silica) eluting with cyclohexane containing increasing amounts of EtOAc. The title product was obtained as a white solid.
Reaction SMILES: [CH2:1]([O:4][N:5]([C@H:18]1[CH2:23][NH:22][C@H:21]([C:24]([NH2:26])=[O:25])[C:20]([CH2:27][CH3:28])=[CH:19]1)S(C1C=CC=CC=1[N+]([O-])=O)(=O)=O)[CH:2]=[CH2:3].C(ON[C@@H]1C(C)=C[C@@H](CO[Si](C(C)(C)C)(C)C)NC1)C=C>CO.ClCCl>[CH2:1]([O:4][NH:5][CH:18]1[CH2:23][NH:22][C@@H:21]([C:24]([NH2:26])=[O:25])[C:20]([CH2:27][CH3:28])=[CH:19]1)[CH:2]=[CH2:3]
Reactant: C=CCON([C@@H]1C=C(CC)[C@@H](C(N)=O)NC1)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Agent: C=CCON[C@H]1CN[C@H](CO[Si](C)(C)C(C)(C)C)C=C1C
Solvent: ClCCl
Solvent: CO
Product: C=CCONC1C=C(CC)[C@H](C(N)=O)NC1
Yield: 74.3 %

Procedure:
The title compound was prepared from (2S,5R)-5-(N-(allyloxy)-2-nitrophenylsulfonamido)-3-ethyl-1,2,5,6-tetrahydropyridine-2-carboxamide (Intermediate 213, 0.87 g, 2.12 mmol) following the procedure described for Intermediate 12. Silica gel chromatography (0%-8% methanol/dichloromethane) afforded the title compound (0.355 g, 74.3%) as an off-white solid upon drying on high-vacuum.
Reaction SMILES: [NH2:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl.Br[C:18]1[C:19]2[N:20]([CH:25]=[CH:26][N:27]=2)[N:21]=[C:22]([Cl:24])[CH:23]=1>CCO>[Cl:24][C:22]1[CH:23]=[C:18]([NH:1][C:2]2[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=2)[C:19]2[N:20]([CH:25]=[CH:26][N:27]=2)[N:21]=1
Reactant: Clc1cc(Br)c2nccn2n1
Reactant: Nc1ccc(N)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: Nc1ccc(Nc2cc(Cl)nn3ccnc23)cc1
Temperature: 90 °C
Reaction time: 1 h

Procedure:
p-Aminoaniline (0.48 g, 4.4 mmol) and triethylamine (1.3 ml, 9.2 mmol) were added to 8-bromo-6-chloroimidazo[1,2-b]pyridazine HCl (1.0 g, 4.2 mmol) from Example I(1), step 1b in EtOH (20 mL). The mixture was heated to 90° C. and stirred for 1 hr. The solution was then concentrated in vacuo to give crude N1-(6-chloroimidazo[1,2-b]pyridazin-8-yl)benzene-1,4-diamine. Cold ethanol was then added and the crude solid rinsed 3×. Following filtration, collected 0.45 g of the desired material.
Reaction SMILES: [CH3:1][C:2]1[C:18]([CH2:19][C:20]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH:23]=[CH:22][CH:21]=2)=[C:5]2[N:6]=[C:7]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)[CH:8]=[C:9]([C:10]#[N:11])[N:4]2[N:3]=1.[N-:30]=[N+:31]=[N-:32].[Na+].[Cl-].[NH4+]>CN(C)C=O>[CH3:1][C:2]1[C:18]([CH2:19][C:20]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH:23]=[CH:22][CH:21]=2)=[C:5]2[N:6]=[C:7]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)[CH:8]=[C:9]([C:10]3[NH:32][N:31]=[N:30][N:11]=3)[N:4]2[N:3]=1
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1nn2c(C#N)cc(N3CCOCC3)nc2c1Cc1cccc2ccccc12
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1nn2c(-c3nnn[nH]3)cc(N3CCOCC3)nc2c1Cc1cccc2ccccc12
Yield: 33.1 %

Procedure:
In a 5 mL microwave vial was added in 2-methyl-5-(4-morpholinyl)-3-(1-naphthalenylmethyl)pyrazolo[1,5-a]pyrimidine-7-carbonitrile (60 mg, 0.156 mmol), sodium azide (81 mg, 1.252 mmol) and ammonium chloride (67.0 mg, 1.252 mmol) in N,N-Dimethylformamide (DMF) (2 mL). The reaction was subjected to MW irradiation at 180° C. for 15 min. The reaction mixture was added to a saturated NH4Cl solution and extracted with DCM (30 mL×2). The combined organic phases were dried and concentrated. The residue was purified on silica column (20˜60% EtOAc/Hexane) and then (0˜10% MeOH/DCM) to give the titled product (22 mg, 31%). 1H NMR (400 MHz, DMSO-d6) δ ppm 2.25 (s, 3H) 3.70 (m, 8H) 4.38 (s, 2H) 7.12 (br. s., 1H) 7.29-7.45 (m, 2H) 7.47-7.57 (m, 2H) 7.77 (d, J=8.08 Hz, 1H) 7.85-7.96 (m, 1H) 8.49 (m, 1H); LC/MS: MS (ES+) m/e 427.0 [M+H]+.
Reaction SMILES: C[O:2][C:3](=[O:32])[C:4]1[CH:9]=[CH:8][C:7]([O:10][C@H:11]2[CH2:15][CH2:14][N:13]([C:16]3[CH:21]=[CH:20][C:19]([C:22](=[O:31])[NH:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[NH2:30])=[CH:18][CH:17]=3)[CH2:12]2)=[CH:6][CH:5]=1.[OH-].[K+]>C1COCC1.O.CO>[NH2:30][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=1[NH:23][C:22]([C:19]1[CH:18]=[CH:17][C:16]([N:13]2[CH2:14][CH2:15][C@H:11]([O:10][C:7]3[CH:6]=[CH:5][C:4]([C:3]([OH:32])=[O:2])=[CH:9][CH:8]=3)[CH2:12]2)=[CH:21][CH:20]=1)=[O:31]
Reactant: COC(=O)c1ccc(O[C@H]2CCN(c3ccc(C(=O)Nc4ccccc4N)cc3)C2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: Nc1ccccc1NC(=O)c1ccc(N2CC[C@H](Oc3ccc(C(=O)O)cc3)C2)cc1
Temperature: 25 °C
Reaction time: 120 h
Yield: 20.8 %

Procedure:
A solution of 372 (100 mg, 0.23 mmol) and KOH (100 mg, 1.78 mmol) in 1:1:1 mixture of THF/water/MeOH (6 mL) was stirred at room temperature for 5 days. The reaction mixture was concentrated and partitioned between water (5 mL) and ether (5 mL). Organic phase was discarded and the aqueous phase was acidified to pH=6 using 1M HCl solution and extracted with EtOAc. The extract was dried over Na2SO4, filtered and concentrated. The residue was purified by flash chromatography, eluent MeOH-DCM (gradient of MeOH from 5 till 20% MeOH) to afford the title compound (20 mg, 21% yield). 1H NMR (DMSO) δ 9.34 (σ, 1H), 7.85 (m, 4H), 7.11 (d, 1H, J=7.8 Hz), 7.00 (d, J=8.4 Hz, 2H), 6.92 (d, 2H, J=7.7 Hz), 6.75 (d, J=8.0 Hz, 2H), 6.6 (m, 3H), 5.26 (br.s., 1H), 3.75 (m, 1H), [3.34 DMSO, 4H], 2.44 (m, 1H), 2.31 (m, 1H) m/z: 418.4 (MH+).
Reaction SMILES: Br[C:2]1[S:10][C:9]2[C:8](=[O:11])[NH:7][C:6]3([CH2:15][CH2:14][CH2:13][CH2:12]3)[N:5]([CH2:16][CH3:17])[C:4]=2[CH:3]=1.[CH3:18][C:19]1[C:23](B2OC(C)(C)C(C)(C)O2)=[CH:22][N:21](C(OC(C)(C)C)=O)[N:20]=1.C(=O)([O-])[O-].[Na+].[Na+].COCCOC>O>[CH2:16]([N:5]1[C:4]2[CH:3]=[C:2]([C:23]3[CH:22]=[N:21][NH:20][C:19]=3[CH3:18])[S:10][C:9]=2[C:8](=[O:11])[NH:7][C:6]21[CH2:15][CH2:14][CH2:13][CH2:12]2)[CH3:17]
Reactant: CCN1c2cc(Br)sc2C(=O)NC12CCCC2
Reactant: Cc1nn(C(=O)OC(C)(C)C)cc1B1OC(C)(C)C(C)(C)O1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CCN1c2cc(-c3cn[nH]c3C)sc2C(=O)NC12CCCC2
Temperature: 100 °C
Reaction time: 1 h
Yield: 54.4 %

Procedure:
A flask was charged with 6′-bromo-1′-ethyl-1′H-spiro [cyclopentane-1,2′-thieno[3,2-d]pyrimidin]-4′(3′H)-one (158 mg, 0.50 mmol), tert-butyl 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate (463 mg, 1.5 mmol), sodium carbonate (150 mg, 2.5 mmol), 1,2-dimethoxyethane (3.0 mL) and water (1.5 mL). The flask was purged with argon. Then, 1,1′-bis(diphenylphosphino)ferrocenepalladium (II) dichloride dichloromethane adduct (41 mg, 0.050 mmol) was added to the mixture. The flask was purged with argon again. After stirring at 100° C. for 1 h, 8 M aqueous NaOH (0.5 mL) was added. After stirring at 100° C. for 1 h, organic materials were extracted with EtOAc. The combined extracts were washed with brine, dried over Na2SO4 and filtered. After removal of the solvent at reduced pressure, the residue was purified by column chromatography (Purif, silica gel, 50:50 hexane/EtOAc to EtOAc), then crystallized from MeOH/EtOAc/hexane to give the title compound (86 mg, 54%) as a yellow solid:
Reaction SMILES: OC1C=C2C(C[C@@H](C(=O)[NH:20][C@H:21]3[C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[CH2:24][CH2:23][CH2:22]3)N(C(OC(C)(C)C)=O)C2)=CC=1.[CH2:32]([O:39][C:40]([N:42]1[CH2:46][C:45](=[O:47])[CH2:44][C@H:43]1[C:48]([OH:50])=O)=[O:41])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.[C@H]1(N)C2C(=CC=CC=2)CCC1>>[O:47]=[C:45]1[CH2:46][N:42]([C:40]([O:39][CH2:32][C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)=[O:41])[C@H:43]([C:48](=[O:50])[NH:20][C@H:21]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH2:24][CH2:23][CH2:22]2)[CH2:44]1
Reactant: O=C1C[C@@H](C(=O)O)N(C(=O)OCc2ccccc2)C1
Reactant: CC(C)(C)OC(=O)N1Cc2cc(O)ccc2C[C@H]1C(=O)N[C@@H]1CCCc2ccccc21
Agent: N[C@@H]1CCCc2ccccc21
Product: O=C1C[C@@H](C(=O)N[C@@H]2CCCc3ccccc32)N(C(=O)OCc2ccccc2)C1
Yield: 100 %

Procedure:
Following a procedure analogous to that for the synthesis of Compound D of Example 1, (S)-1-((benzyloxy)carbonyl)-4-oxopyrrolidine-2-carboxylic acid (Aldrich, 4.00 g, 15.2 mmol) and (R)-1,2,3,4-tetrahydronaphthalen-1-amine (Alfa Aesar, 2.23 mL, 15.2 mmol) were converted to the title compound (5.96 g, 100%). MS (ESI+) m/z 393.1 (M+H)+.
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:23]=[CH:22][C:17]([C:18]([O:20]C)=[O:19])=[CH:16][C:15]=3[CH3:24])=[CH:11][CH:12]=2)[C@H:7]([NH:25][C:26]([O:28][CH:29]([CH3:31])[CH3:30])=[O:27])[CH2:6][C@@H:5]1[CH3:32])(=[O:3])[CH3:2].[OH-].[Na+].CS(C)=O.CC#N>C(O)C>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:23]=[CH:22][C:17]([C:18]([OH:20])=[O:19])=[CH:16][C:15]=3[CH3:24])=[CH:11][CH:12]=2)[C@H:7]([NH:25][C:26]([O:28][CH:29]([CH3:31])[CH3:30])=[O:27])[CH2:6][C@@H:5]1[CH3:32])(=[O:3])[CH3:2]
Reactant: COC(=O)c1ccc(-c2ccc3c(c2)[C@H](NC(=O)OC(C)C)C[C@H](C)N3C(C)=O)c(C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: CC#N
Solvent: CCO
Product: CC(=O)N1c2ccc(-c3ccc(C(=O)O)cc3C)cc2[C@H](NC(=O)OC(C)C)C[C@@H]1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 83 %

Procedure:
A solution of methyl 4-[(2S,4R)-1-acetyl-2-methyl-4-({[(1-methylethyl)oxy]carbonyl}amino)-1,2,3,4-tetrahydro-6-quinolinyl]-3-methylbenzoate (for a preparation see Intermediate 108) (20 mg, 0.046 mmol) in ethanol (0.5 mL) was treated with NaOH (1M in water, 0.182 mL, 0.182 mmol) and the resulting mixture was stirred at room temperature for 30 min. It was then made up to 0.9 mL by addition of 1:1 solvent mixture of DMSO/CH3CN and purified by MDAP to give 4-[(2S,4R)-1-acetyl-2-methyl-4-({[(1-methylethyl)oxy]carbonyl}amino)-1,2,3,4-tetrahydro-6-quinolinyl]-3-methylbenzoic acid (16 mg, 0.038 mmol, 83%) as a white solid. LCMS (method A): Retention time 0.91 min, [M+H]+=425.18
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[N:10]=2)[CH:5]=[CH:4][CH:3]=1.[OH-].[K+].I[CH2:19][CH2:20][CH3:21]>CN(C)C=O>[CH3:1][C:2]1[N:7]=[C:6]([N:8]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[N:10]=2)[CH2:19][CH2:20][CH3:21])[CH:5]=[CH:4][CH:3]=1
Reactant: CCCI
Reactant: Cc1cccc(Nc2cccc(C)n2)n1
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CCCN(c1cccc(C)n1)c1cccc(C)n1
Reaction time: 1 h
Yield: 82.9 %

Procedure:
To a flask were added 1.0 g 6-methyl-N-(6-methylpyridin-2-yl)pyridin-2-amine, 0.84 g of pulverized potassium hydroxide and 15 ml of N,N-dimethylformamide. After stirring for 1 hour under nitrogen, the mixture was cooled to 5 C and 0.85 g of 1-iodopropane were added. The mixture was allowed to warm to 22 C and stirred for 16 hours. After quenching with 15 ml water, the product was extracted twice with diethyl ether and washed with water. Following removal of solvent, the product was purified by silica gel chromatography using 10% ethyl acetate in hexane to give 1.0 g of a colorless oil.
Reaction SMILES: [C:1]([OH:11])(=O)[C:2]1[C:3](=[CH:6][CH:7]=[CH:8][CH:9]=1)[CH:4]=O.C(O)C.[CH2:15]([NH2:18])[CH2:16][NH2:17].[ClH:19]>CO>[ClH:19].[NH:17]1[CH:4]2[C:3]3[C:2]([C:1](=[O:11])[N:18]2[CH2:15][CH2:16]1)=[CH:9][CH:8]=[CH:7][CH:6]=3
Reactant: NCCN
Reactant: O=Cc1ccccc1C(=O)O
Agent: Cl
Solvent: CO
Solvent: CCO
Product: O=C1c2ccccc2C2NCCN12

Procedure:
A solution of 7.5 g. of phthalaldehydic acid in 30 ml. of ethanol and 34 ml. of ethylenediamine was refluxed for 16 hours. The solution was concentrated in vacuo and the residue was dissolved in methylene chloride. The solution was washed with water, dried and concentrated. The residue was distilled in a bulb tube at 0.3 mm at a bath temperature of 150°-180°. A colorless oil was obtained which was dissolved in methanol and on addition of ethereal hydrogen chloride gave white prisms of 1,2,3,9b-tetrahydro-5H-imidazo[2,1-a]isoindol-5-one hydrochloride, m.p. 222°-224° dec.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[Cl-].[Al+3].[Cl-].[Cl-].[F:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[O:16][CH3:17]>C(Cl)Cl>[CH3:2][C:1]([C:14]1[CH:13]=[CH:12][C:11]([O:16][CH3:17])=[C:10]([F:9])[CH:15]=1)=[O:3]
Reactant: CC(=O)Cl
Reactant: COc1ccccc1F
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COc1ccc(C(C)=O)cc1F
Temperature: 0 °C
Yield: 88.1 %

Procedure:
To a solution of 700 ml of dried methylene chloride and 157 g of acetyl chloride was added dropwise 267 g of anhydrous aluminum chloride over 30 minutes with stirring while holding temperature at 15°-25° C., which were further stirred at room temperature for about 2 hours. Separately, a solution of 206 g of o-fluoroanisole and 170 ml of dried methylene chloride was cooled on an ice water bath, to which was added dropwise the previously prepared solution of acetyl chloride and aluminum chloride in methylene chloride over about 2.5 hours. The resulting mixture was further stirred on the ice water bath for 1 hour and at room temperature for 1 hour. The resulting reaction mixture was poured into 1.4 l of ice water and separated into two layers. The extraction with 400 ml of methylene chloride on aqueous layer was repeated two times, and thereafter the organic layers were gathered, washed with water and dried on magnesium sulfate. After magnesium sulfate was filtered off, the filtrate was concentrated and dried to obtain a light brown crystal. This crystal was recrystallized with ethanol to obtain 242 g (yield: 88%) of a white crystal having a melting point of 89.5°-90.0° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[N:14]([CH:15]=2)[C:13]2[CH:16]=[CH:17][CH:18]=[CH:19][C:12]=2[S:11]3)=[CH:4][C:3]=1[OH:20].[CH3:21][O:22][C:23]1[CH:36]=[CH:35][C:26]([CH2:27][O:28][C:29](=[O:34])[CH2:30][C:31](O)=[O:32])=[CH:25][CH:24]=1>>[CH3:21][O:22][C:23]1[CH:24]=[CH:25][C:26]([CH2:27][O:28][C:29]([CH2:30][C:31]([O:20][C:3]2[CH:4]=[C:5]([C:8]3[N:9]=[C:10]4[N:14]([CH:15]=3)[C:13]3[CH:16]=[CH:17][CH:18]=[CH:19][C:12]=3[S:11]4)[CH:6]=[CH:7][C:2]=2[Cl:1])=[O:32])=[O:34])=[CH:35][CH:36]=1
Reactant: COc1ccc(COC(=O)CC(=O)O)cc1
Reactant: Oc1cc(-c2cn3c(n2)sc2ccccc23)ccc1Cl
Product: COc1ccc(COC(=O)CC(=O)Oc2cc(-c3cn4c(n3)sc3ccccc34)ccc2Cl)cc1
Yield: 45.3 %

Procedure:
By following the same procedure as in Example 2 using 1.9 g of 2-(4-chloro-3-hydroxyphenyl)imidazo[2,1-b]benzothiazole and 2.7 g of malonic acid mono-p-methoxybenzyl ester, 1.05 g of 2-(3-carboxyacetoxy-4-chloro)phenylimidazo[2,1-b]benzothiazole.hydrochloride was obtained through 2-[3-(p-methoxybenzyloxycarbonylacetoxy)-4-chlorophenyl]imidazo[2,1-b]benzothiazole (yield of 1.45 g, melting point of 113°-115° C.).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:5]2[S:10][C:9]([CH2:11]N3CC4(CCN(C)CC4)C3)=[CH:8][C:6]=2[N:7]=1.[NH:28]1[CH2:33][CH2:32][CH:31]([N:34]2[CH2:37][CH2:36][C:35]2=[O:38])[CH2:30][CH2:29]1>>[Cl:1][C:2]1[N:3]=[C:4]([N:22]2[CH2:23][CH2:24][O:25][CH2:26][CH2:27]2)[C:5]2[S:10][C:9]([CH2:11][N:28]3[CH2:33][CH2:32][CH:31]([N:34]4[CH2:37][CH2:36][C:35]4=[O:38])[CH2:30][CH2:29]3)=[CH:8][C:6]=2[N:7]=1
Reactant: CN1CCC2(CC1)CN(Cc1cc3nc(Cl)nc(N4CCOCC4)c3s1)C2
Reactant: O=C1CCN1C1CCNCC1
Product: O=C1CCN1C1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1

Procedure:
Prepared according to the method used in the preparation of 2-chloro-6-(7-methyl-2,7-diaza-spiro[3.5]non-2-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine using 1-piperidin-4-yl-azetidin-2-one in place of 7-methyl-2,7-diaza-spiro[3.5]nonane. The title compound was obtained as a pale yellow solid (205 mg, 81%).
Reaction SMILES: [CH:1]1([NH:4][C:5]([C:7]2[N:8]=[N:9][N:10]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([NH:22][CH2:23][CH3:24])=[O:21])=[CH:16][CH:15]=3)[C:11]=2[CH2:12][OH:13])=[O:6])[CH2:3][CH2:2]1.[F:25][C:26]1[CH:31]=[CH:30][C:29]([N:32]=[C:33]=[O:34])=[CH:28][CH:27]=1>N1C=CC=CC=1>[F:25][C:26]1[CH:31]=[CH:30][C:29]([NH:32][C:33](=[O:34])[O:13][CH2:12][C:11]2[N:10]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([NH:22][CH2:23][CH3:24])=[O:21])=[CH:16][CH:15]=3)[N:9]=[N:8][C:7]=2[C:5]([NH:4][CH:1]2[CH2:2][CH2:3]2)=[O:6])=[CH:28][CH:27]=1
Reactant: O=C=Nc1ccc(F)cc1
Reactant: CCNC(=O)c1ccc(-n2nnc(C(=O)NC3CC3)c2CO)cc1
Solvent: c1ccncc1
Product: CCNC(=O)c1ccc(-n2nnc(C(=O)NC3CC3)c2COC(=O)Nc2ccc(F)cc2)cc1
Temperature: 60 °C
Yield: 35.7 %

Procedure:
To a solution of N-cyclopropyl-1-{4-[(ethylamino)carbonyl]phenyl}-5-(hydroxymethyl)-1H-1,2,3-triazole-4-carboxamide (200 mg) obtained in Example 112 in pyridine (5 ml) was added 1-fluoro-4-isocyanatobenzene (125 mg) and the mixture was heated at 60° C. for 18 hr. The solvent was evaporated under reduced pressure and the obtained residue was recrystallized from ethyl acetate/hexane to give the title compound as a colorless powder (101 mg).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH2:21][CH2:22]O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Br)(Br)(Br)[Br:25].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[Br:25][CH2:22][CH2:21][O:20][CH2:19][CH2:18][O:17][CH2:16][CH2:15][O:14][CH2:13][CH2:12][O:11][CH2:10][CH2:9][O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrC(Br)(Br)Br
Reactant: OCCOCCOCCOCCOCCOCc1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: BrCCOCCOCCOCCOCCOCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.1 %

Procedure:
To a solution of Compound 19 (2.04 g, 6.21 mmol) in methylene chloride (20 ml), a solution of carbon tetrabromide (4.12 g, 12.4 mmol) in methylene chloride (10 ml) was added at room temperature; after cooling with ice, triphenylphosphine (2.51 g, 12.4 mmol) was added. The water bath was removed, and this was followed by stirring at room temperature for 1 hour. After concentration under reduced pressure, the residue obtained was purified by silica gel column chromatography (Yamazen YFLC Gel, eluent (n-hexane:ethyl acetate 2:1-1:1)) to yield Compound 20 (light-yellow oil 2.14 g, 88%).
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:11]=1[CH2:12][CH2:13][CH2:14][CH:15]2[C:20]([N:22]([C:29]1[CH:30]=[N:31][C:32]([CH:35]([CH3:37])[CH3:36])=[CH:33][CH:34]=1)[CH2:23][C:24]1[CH:25]=[N:26][NH:27][CH:28]=1)=[O:21])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Cl:38][C:39]1[CH:46]=[CH:45][C:42]([CH2:43]Cl)=[CH:41][CH:40]=1>>[CH2:2]([O:9][C:10]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:11]=1[CH2:12][CH2:13][CH2:14][CH:15]2[C:20]([N:22]([CH2:23][C:24]1[CH:25]=[N:26][N:27]([CH2:43][C:42]2[CH:45]=[CH:46][C:39]([Cl:38])=[CH:40][CH:41]=2)[CH:28]=1)[C:29]1[CH:30]=[N:31][C:32]([CH:35]([CH3:37])[CH3:36])=[CH:33][CH:34]=1)=[O:21])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CC(C)c1ccc(N(Cc2cn[nH]c2)C(=O)C2CCCc3c(OCc4ccccc4)cccc32)cn1
Reactant: ClCc1ccc(Cl)cc1
Agent: Cl
Product: CC(C)c1ccc(N(Cc2cnn(Cc3ccc(Cl)cc3)c2)C(=O)C2CCCc3c(OCc4ccccc4)cccc32)cn1
Yield: 83.3 %

Procedure:
By the reaction and treatment in the same manner as in Example 271 using 5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-[(pyrazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide hydrochloride (0.78 g) and 4-chlorobenzyl chloride (0.48 g) as starting materials, 5-benzyloxy-N-({1-[(4-chlorophenyl)methyl]pyrazol-4-yl}methyl)-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.76 g) was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]#[C:10][Si](C)(C)C.C(=O)([O-])[O-].[K+].[K+]>CO.C(OCC)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]#[CH:10]
Reactant: C[Si](C)(C)C#Cc1cc(F)ccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CCOCC
Product: C#Cc1cc(F)ccc1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of ((2-chloro-5-fluorophenyl)ethynyl)trimethylsilane (4.2 g, 18 mmol) in methanol (40 mL) was added potassium carbonate (7.7 g, 56 mmol), and the reaction mixture was stirred for 2 hours at room temperature. The reaction mixture was then diluted with diethyl ether (100 mL) and washed with water (300 mL). The organic layer was separated, dried over sodium sulfate, filtered, and evaporated in vacuo to afford a residue that was purified by flash chromatography (silica, 220 g, ISCO, heptane) to afford the title compound as a pale yellow, waxy solid (2.0 g, 70%), which was used in the next step without further purification.