Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=1[NH:4][CH2:5][C:6]1[CH:7]=[C:8]([CH:13]=[CH:14][CH:15]=1)[C:9]([O:11][CH3:12])=[O:10].Cl.[C:21](Cl)(=[O:31])[O:22][C@@H:23]1[CH:28]2[CH2:29][CH2:30][N:25]([CH2:26][CH2:27]2)[CH2:24]1.C(Cl)(=O)O[C@@H]1C2CCN(CC2)C1>N1C=CC=CC=1.CN(C)C1C=CN=CC=1>[NH3:4].[F:1][C:2]1[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=1[N:4]([CH2:5][C:6]1[CH:7]=[C:8]([CH:13]=[CH:14][CH:15]=1)[C:9]([O:11][CH3:12])=[O:10])[C:21]([O:22][C@@H:23]1[CH:28]2[CH2:29][CH2:30][N:25]([CH2:26][CH2:27]2)[CH2:24]1)=[O:31]
Reactant: COC(=O)c1cccc(CNc2ccccc2F)c1
Reactant: O=C(Cl)O[C@H]1CN2CCC1CC2
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: c1ccncc1
Product: COC(=O)c1cccc(CN(C(=O)O[C@H]2CN3CCC2CC3)c2ccccc2F)c1
Product: N
Temperature: 0 °C
Reaction time: 1 h
Yield: 146.3 %
Yield: 10 %

Procedure:
To a stirred solution of methyl 3-[(2-fluoroanilino)methyl]benzoate (0.3 g, 1.157 mmol) in anhydrous pyridine (6 mL) at 0° C. under N2 (g) was added 4-(dimethylamino)pyridine (0.014 g, 0.116 mmol) followed by (R)-quinuclidin-3-yl carbonochloridate hydrochloride (0.314 g, 1.39 mmol) in one portion. After stirring at 0° C. for 1 hour, the reaction was allowed to warm to room temperature. After 2.5 hours, further (R)-quinuclidin-3-yl carbonochloridate (0.628 g, 2.777 mmol) was added, and the reaction was stirred at room temperature for 65 hours. The reaction was quenched by addition of 10% aqueous potassium carbonate solution and extracted with ethyl acetate (×3). The combined organic extracts were washed with brine and dried (sodium sulfate), filtered, and the solvent was removed in vacuo to afford a brown oil. The crude material was purified by silica gel column chromatography eluting sequentially with ethyl acetate, 5% methanol in ethyl acetate, 5% 7N methanolic ammonia in ethyl acetate and 10% 7N methanolic ammonia in ethyl acetate to afford the title compound as a yellow oil (0.349 g, 73%).
Reaction SMILES: [CH:1]1([N:6]2[C:15]3[N:14]=[C:13]([NH:16][C:17]4[CH:18]=[CH:19][C:20]([C:30](O)=[O:31])=[C:21]5[C:25]=4[O:24][CH:23]([CH2:26][N:27]([CH3:29])[CH3:28])[CH2:22]5)[N:12]=[CH:11][C:10]=3[N:9]([CH3:33])[C:8](=[O:34])[C@H:7]2[CH2:35][CH3:36])[CH2:5][CH2:4][CH2:3][CH2:2]1.F[B-](F)(F)F.[N:42]1(OC(N(C)C)=[N+](C)C)[C:46]2[CH:47]=[CH:48]C=[CH:50][C:45]=2N=N1.[CH:59]([N:62](C(C)C)CC)(C)C.[Cl-].[Na+]>ClCCl>[CH:1]1([N:6]2[C:15]3[N:14]=[C:13]([NH:16][C:17]4[CH:18]=[CH:19][C:20]([C:30]([NH:42][CH:46]5[CH2:45][CH2:50][N:62]([CH3:59])[CH2:48][CH2:47]5)=[O:31])=[C:21]5[C:25]=4[O:24][CH:23]([CH2:26][N:27]([CH3:29])[CH3:28])[CH2:22]5)[N:12]=[CH:11][C:10]=3[N:9]([CH3:33])[C:8](=[O:34])[C@H:7]2[CH2:35][CH3:36])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: CC[C@@H]1C(=O)N(C)c2cnc(Nc3ccc(C(=O)O)c4c3OC(CN(C)C)C4)nc2N1C1CCCC1
Reactant: CCN(C(C)C)C(C)C
Agent: F[B-](F)(F)F
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Product: CC[C@@H]1C(=O)N(C)c2cnc(Nc3ccc(C(=O)NC4CCN(C)CC4)c4c3OC(CN(C)C)C4)nc2N1C1CCCC1
Reaction time: 2 h
Yield: 76.2 %

Procedure:
7-[[(7R)-8-Cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pteridin-2-yl]amino]-2-(dimethylaminomethyl)-2,3-dihydrobenzofuran-4-carboxylic acid 29j (30 mg, 0.06 mmol) was dissolved in 10 mL of dichloromethane followed by the addition of 1-methyl-piperidyl-4-yl-amine (7 mg, 0.06 mmol), O-(benzotriazol-1-yl)-N,N,N′,N′-tetra methyluronium tetrafluoroborate (20 mg, 0.06 mmol) and diisopropylethylamine (24 mg, 0.18 mmol). The reaction solution was stirred for 2 hours. The resulting solution was added with 10 mL of saturated sodium chloride solution and extracted with dichloromethane (10 mL×3). The combined organic phase was washed with water (10 mL) and saturated sodium chloride solution (10 mL) successively, then dried over anhydrous magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound 7-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pteridin-2-yl]amino]-2-(dimethylaminomethyl)-N-(1-methyl-4-piperidyl)-2,3-dihydrobenzofuran-4-carboxamide 29 (27 mg, yield: 77.1%) as a white solid.
Reaction SMILES: [C:1](=O)([O-])[O-].[K+].[K+].[CH3:7][O:8][C:9]1[CH:10]=[C:11]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17]1[CH2:16][CH2:15][CH2:14][C:13](=[O:22])[C:12]2=1.S(OC)(OC)(=O)=O.O>CC(C)=O>[CH3:7][O:8][C:9]1[CH:10]=[C:11]2[C:19](=[CH:20][CH:21]=1)[N:18]([CH3:1])[C:17]1[CH2:16][CH2:15][CH2:14][C:13](=[O:22])[C:12]2=1
Reactant: COc1ccc2[nH]c3c(c2c1)C(=O)CCC3
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Solvent: COS(=O)(=O)OC
Product: COc1ccc2c(c1)c1c(n2C)CCCC1=O
Reaction time: 0.5 h
Yield: 78.2 %

Procedure:
Anhydrous potassium carbonate (2.24 g) was added to a solution of the product of Stage (i) (3 g) in acetone (30 ml) at room temperature and stirred for 30 min. Dimethyl sulphate (1.6 ml) was added and the mixture was heated to reflux for 4 h. The resulting solution was poured into water (150 ml) and the resulting precipitate filtered off to give the title compound as a solid (2.5 g), m.p. 150°-151°.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH:12]=[C:11]([C:14]#[C:15][C:16]2[S:17][CH:18]=[CH:19][CH:20]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl>C(OCC)C.O>[S:17]1[CH:18]=[CH:19][CH:20]=[C:16]1[C:15]#[C:14][C:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH:10]=1
Reactant: CC(C)(C)OC(=O)N1CC=C(C#Cc2cccs2)CC1
Agent: Cl
Solvent: CCOCC
Solvent: O
Product: C(#Cc1cccs1)C1=CCNCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 78.4 %

Procedure:
A solution of 1-tert-butoxycarbonyl-4-(2-thienyl)ethynyl-1,2,3,6-tetrahydropyridine (530 mg, 1.8 mmol) (prepared in a manner analogous to Example 1) in diethyl ether (10 ml) at room temperature under a nitrogen atmosphere was treated with excess ethereal hydrogen chloride. Following a 3 hour stir at room temperature the dark mixture was diluted with water and extracted with diethyl ether (2×30 ml). The aqueous phase was made basic with potassium carbonate solution (sat.) and extracted with diethyl ether (3×50 ml). The extracts were dried (K2CO3) and evaporated in vacuo to give the title compound as a brown oil (267 mg, 77%); δH (CDCl3) 2.24-2.29 (2H, m, tetrahydropyridinyl CH2), 3.00 (2H, J 5.7 Hz, tetrahydropyridinyl CH2), 3.45-3.47 (2H, m, tetrahydropyridinyl CH2), 6.17-6.19 (1H, m, tetrahydropyridinyl CH), 6.94-6.97 (1H, m, ArH), 7.16-7.17 (1H, m, ArH) and 7.22-7.26 (1H, m, ArH).
Reaction SMILES: [Sn](Cl)(Cl)(Cl)Cl.[CH2:6]([C:13]1[S:14][C:15]([CH3:19])=[C:16]([CH3:18])[CH:17]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[C:20](Cl)(=[O:29])[C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=1.ClCCl>O>[CH2:6]([C:13]1[S:14][C:15]([CH3:19])=[C:16]([CH3:18])[C:17]=1[C:20]([C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=1)=[O:29])[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: Cc1cc(Cc2ccccc2)sc1C
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: ClCCl
Solvent: O
Product: COc1ccc(C(=O)c2c(Cc3ccccc3)sc(C)c2C)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 87.7 %

Procedure:
Tin tetrachloride (4.6 mL, 71.76 mmol) was added dropwise over a 10 minute period to a stirred, −78° C. solution of 2-benzyl-4,5-dimethylthiophene (6.6 g, 32.62 mmol), anisoyl chloride (5.90 g, 34.6 mmol) and dichloromethane (120 mL) under a dry nitrogen atmosphere. After 5 hours at −78° C., the reaction mixture was slowly warmed to room temperature over a 2 h period. The reaction mixture was added to water and extracted with ether. The ether extract was washed with sat. aq. sodium bicarbonate and brine. The solvent was removed and the resultant solid was triturated with ether to give the title compound as a off-white solid (9.62 g, 88%): mp 85-86° C.: NMR (CDCl3); δ7.80 (ddd, J=8, 8, 1 Hz, 2H), 7.24-7.10 (m, 5H), 7.92 (ddd, J=8, 8, 1 Hz, 2H), 3.93 (s, 2H), 3.88 (s, 3H), 2.28 (s, 3H), 1.90 (s, 3H); MS (EI): 336 (100%, MI); Anal. Calc. for C21H20O2S: C, 74.97; H, 5.99; N, 0.00. Found: C, 75.11; H, 6.02; N, 0.05.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([N:11]2[CH:15]=[CH:14][N:13]=[CH:12]2)[CH:6]=1)(=[O:3])[CH3:2].[H-].[Na+].[H][H].F[C:21]1[CH:26]=[CH:25][C:24]([I:27])=[CH:23][C:22]=1[N+:28]([O-:30])=[O:29]>CN(C=O)C.O>[C:1]([N:4]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([N:11]2[CH:15]=[CH:14][N:13]=[CH:12]2)[CH:6]=1)[C:21]1[CH:26]=[CH:25][C:24]([I:27])=[CH:23][C:22]=1[N+:28]([O-:30])=[O:29])(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1cccc(-n2ccnc2)c1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1cc(I)ccc1F
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)N(c1cccc(-n2ccnc2)c1)c1ccc(I)cc1[N+](=O)[O-]
Temperature: 120 °C
Reaction time: 5 h
Yield: 25.3 %

Procedure:
A solution of 2e from Example 3 (30 g, 0.15 mol) in dry DMF (200 ml) is cooled to 0° C. under nitrogen. Sodium hydride (7.2 g of a 60% dispersion in mineral oil) is added portionwise. When the evolution of hydrogen has ceased a solution of 1c from Example 1 (52 g, 0.19 mol) in 50 ml DMF is added. The mixture is stirred at 120° C. for 5 hours and left at ambient temperature over night. The reaction mixture is poured into four volumes of water and the crude product is filtered off. Purification on silica gel using a mixture of ethyl acetate and petroleum ether (3:17) as the eluent affords pure 6c as an oil (17 g, 25%).
Reaction SMILES: BrC[CH2:3][Cl:4].[Cl:5][C:6]1[C:7](=[O:19])[N:8]([CH:16]([CH3:18])[CH3:17])[N:9]=[CH:10][C:11]=1[O:12][CH2:13][CH2:14]Cl.Cl[C:21]1C(=O)N(C(C)C)N=CC=1O>>[Cl:5][C:6]1[C:7](=[O:19])[N:8]([C:16]([CH3:21])([CH3:18])[CH3:17])[N:9]=[CH:10][C:11]=1[O:12][CH2:13][CH2:14][CH2:3][Cl:4]
Reactant: CC(C)n1ncc(O)c(Cl)c1=O
Reactant: ClCCBr
Reactant: CC(C)n1ncc(OCCCl)c(Cl)c1=O
Product: CC(C)(C)n1ncc(OCCCCl)c(Cl)c1=O

Procedure:
Further, by using 1-bromo-2-chloroethane instead of 1-bromo-3-chloropropane, 4-chloro-5-(2-chloroethyloxy)-2-i-propyl-3(2H)pyridazinone (crystals, melting point: 100°-103° C.) was prepared from 4-chloro-5-hydroxy-2-i-propyl-3(2H)pyridazinone.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][N:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.[C:15]([C:19]1[O:20][C:21]2[C:27]([S:28](Cl)(=[O:30])=[O:29])=[C:26]([Cl:32])[CH:25]=[CH:24][C:22]=2[N:23]=1)([CH3:18])([CH3:17])[CH3:16].O>O1CCCC1>[C:15]([C:19]1[O:20][C:21]2[C:27]([S:28]([N:12]3[CH2:13][CH2:14][N:9]([CH3:8])[CH2:10][CH2:11]3)(=[O:30])=[O:29])=[C:26]([Cl:32])[CH:25]=[CH:24][C:22]=2[N:23]=1)([CH3:18])([CH3:16])[CH3:17]
Reactant: CN1CCNCC1
Reactant: CC(C)(C)c1nc2ccc(Cl)c(S(=O)(=O)Cl)c2o1
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: CN1CCN(S(=O)(=O)c2c(Cl)ccc3nc(C(C)(C)C)oc23)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.7 %

Procedure:
1.62 ml (11.68 mmol; 1.2 eq) of triethylamine followed by 1.20 ml (10.71 mmol; 1.1 eq) of 1-methylpiperazine were added to a solution of 3.0 g (9.73 mmol; 1.0 eq) of 2-tert-butyl-6-chlorobenzoxazole-7-sulfonyl chloride (commercial ?) in 45 ml of tetrahydrofuran. The reaction medium was stirred at ambient temperature for 2 hours. Water was added and the reaction medium was extracted with ethyl acetate. The organic phases were combined, dried over magnesium sulfate, filtered and evaporated. 3.57 g of 2-tert-butyl-6-chloro-7-(4-methylpiperazine-1-sulfonyl)benzooxazole were obtained in the form of a tacky brown foam. Yield=98%.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.Cl.[Cl:12][C:13]1[CH:14]=[CH:15][C:16]2[S:20][C:19](=[O:21])[N:18]([CH2:22][C:23]([N:25]3[CH2:30][CH2:29][N:28]([NH2:31])[CH2:27][CH2:26]3)=[O:24])[C:17]=2[CH:32]=1.[OH-].[Na+].O>O1CCOCC1>[Cl:12][C:13]1[CH:14]=[CH:15][C:16]2[S:20][C:19](=[O:21])[N:18]([CH2:22][C:23]([N:25]3[CH2:26][CH2:27][N:28]([NH:31][C:6](=[O:7])[C:5]4[CH:9]=[CH:10][C:2]([F:1])=[CH:3][CH:4]=4)[CH2:29][CH2:30]3)=[O:24])[C:17]=2[CH:32]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: NN1CCN(C(=O)Cn2c(=O)sc3ccc(Cl)cc32)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: O=C(NN1CCN(C(=O)Cn2c(=O)sc3ccc(Cl)cc32)CC1)c1ccc(F)cc1
Reaction time: 0.5 h
Yield: 56.6 %

Procedure:
A solution of 4-fluorobenzoyl chloride (761 mg) in dioxane (3 ml) was added dropwise to a mixture of 5-chloro-3-[(4-amino-1-piperazinyl)carbonylmethyl]-2-benzothiazolinone hydrochloride (872 mg), 1N-NaOH (5.3 ml), dioxane (30 ml) and water (5 ml) at 5° C. The resulting mixture was stirred for 30 minutes and concentrated under reduced pressure. The residue obtained was filtered, washed with water and ethyl acetate, and recrystallized from methanol to give 5-chloro-3-{[4-(4-fluorobenzamido)-1-piperazinyl]carbonylmethyl}-2-benzothiazolinone (0.61 g).
Reaction SMILES: [F:1][C:2]([F:38])([F:37])[C:3]1[CH:4]=[C:5]([CH:30]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:32]=1)[CH2:6][NH:7][CH2:8][C:9]1[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:11][C:10]=1[C:19]1[CH:24]=[C:23]([CH:25]([CH3:27])[CH3:26])[CH:22]=[CH:21][C:20]=1[O:28][CH3:29].[CH3:39][S:40](Cl)(=[O:42])=[O:41].C(N(CC)C(C)C)(C)C.O>C(Cl)Cl>[F:1][C:2]([F:37])([F:38])[C:3]1[CH:4]=[C:5]([CH:30]=[C:31]([C:33]([F:36])([F:34])[F:35])[CH:32]=1)[CH2:6][N:7]([CH2:8][C:9]1[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:11][C:10]=1[C:19]1[CH:24]=[C:23]([CH:25]([CH3:26])[CH3:27])[CH:22]=[CH:21][C:20]=1[O:28][CH3:29])[S:40]([CH3:39])(=[O:42])=[O:41]
Reactant: CS(=O)(=O)Cl
Reactant: COc1ccc(C(C)C)cc1-c1ccc(C(F)(F)F)cc1CNCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: ClCCl
Product: COc1ccc(C(C)C)cc1-c1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)S(C)(=O)=O
Temperature: 25 °C

Procedure:
To a solution of [3,5-bis(trifluoromethyl)benzyl]{[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}amine (8.3 mg, 0.015 mmol) (Example 20) and methanesulfonyl chloride (10.5 μL, 0.135 mmol) in CH2Cl2 (500 μL) was added N,N-diisopropylethylamine (47.4 μL, 0.273 mmol). The reaction was stirred at room temperature for twenty minutes and then was poured into H2O (10 mL). The mixture was extracted with EtOAc (50 mL), and the organic extracts were washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated. Purification by flash chromatography with 50% CH2Cl2/hexanes afforded N-[3,5-bis(trifluoromethyl)benzyl]-N-{[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}methanesulfonamide. Rf=0.20 (50% CH2Cl2/hexanes). LCMS=628.3 (M+1)+. 1H NMR (CDCl3, 600 MHz) δ 7.69 (s, 1H), 7.55 (s, 1H), 7.50 (d, J=8.4 Hz, 1H), 7.47 (s, 2H), 7.28-7.30 (m, 2H), 6.94 (d, J=9.0 Hz, 1H), 6.92 (d, J=1.8 Hz, 1H), 4.44 (d, J=15.0, 1H), 4.32 (d, J=15.0 Hz, 1H), 4.19 (d, J=15.6 Hz, 1H), 4.14 (d, J=15.6 Hz, 1H), 3.72 (s, 3H), 2.89 (m, 1H), 2.69 (s, 3H), 1.21-1.25 (m, 6H).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5].[CH3:12][N:13]1[C:18]([N:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)=[CH:17][C:16](=[O:25])[N:15]([CH3:26])[C:14]1=[O:27].C(N(CC)CC)C>O1CCOCC1>[ClH:1].[CH3:12][N:13]1[C:18]([N:19]2[CH2:24][CH2:23][N:22]([CH2:2][CH2:3][C:4](=[O:5])[C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=3)[CH2:21][CH2:20]2)=[CH:17][C:16](=[O:25])[N:15]([CH3:26])[C:14]1=[O:27]
Reactant: Cn1c(N2CCNCC2)cc(=O)n(C)c1=O
Reactant: O=C(CCCl)c1ccccc1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: Cl
Product: Cn1c(N2CCN(CCC(=O)c3ccccc3)CC2)cc(=O)n(C)c1=O
Temperature: 80 °C
Reaction time: 1 h
Yield: 65.9 %

Procedure:
In 15 ml of dioxane were dissolved 1.68 g of 3-chloropropiophenone, 2.24 g of 1,3-dimethyl-6-(1-piperazinyl)-2,4(1H,3H)-pyrimidinedione and 1.6 ml of triethylamine, and the solution was then stirred at 80° C. for 1 hour. Next, the solvent was distilled off, and the resultant residue was dissolved in chloroform, washed with water, and then concentrated to dryness. The residue was further recrystallized from methanol, thereby obtaining 2.58 g of the crystals of 1,3-dimethyl-6-[4-(3-oxo-3-phenylpropyl)piperazin-1-yl]-2,4(1H,3H)-pyrimidinedione.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1.[CH3:12][C:13]1[CH:20]=[CH:19][C:16]([NH:17][CH3:18])=[CH:15][CH:14]=1>>[CH3:12][C:13]1[CH:20]=[CH:19][C:16]([N:17]([CH3:18])[C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=[CH:4][N:3]=2)=[CH:15][CH:14]=1
Reactant: Clc1ncnc2ccccc12
Reactant: CNc1ccc(C)cc1
Product: Cc1ccc(N(C)c2ncnc3ccccc23)cc1

Procedure:
The title compound was prepared from 4-chloroquinazoline and 4-methyl-N-methylaniline by a procedure similar to example 28 (80% yield). 1H NMR (CDCl3): 8.23 (s, 1H), 7.82 (d, J=8.4 Hz, 1H), 7.57 (ddd, J=8.4, 6.3 and 1.8 Hz, 1H), 7.17-7.20 (m, 2H), 7.00-7.10 (m, 4H), 3.61 (s, 3H), 2.39 (s, 3H).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH:14]([F:16])[C@:13]([CH3:24])([C:17]([O:19]C(C)(C)C)=[O:18])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>ClCCl>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH:14]([F:16])[C@:13]([CH3:24])([C:17]([OH:19])=[O:18])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)[C@]1(C)CN(C(=O)OCc2ccccc2)CC1F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@@]1(C(=O)O)CN(C(=O)OCc2ccccc2)CC1F
Reaction time: 2 h

Procedure:
To a solution of tert-butyl (3S)-1-benzyloxycarbonyl-4-fluoro-3-methylpyrrolidine-3-carboxylate (isomer A) (1.80 g, 5.33 mmol) in dichloromethane (10 mL), trifluoroacetic acid (10 mL) was added dropwise and, and the mixture was stirred for 2 hours. The reaction mixture was concentrated under reduced pressure, and saturated aqueous solution of sodium hydrogencarbonate (30 mL) was added to the concentrate under reduced pressure. The aqueous solution was washed with diethylether (50 mL), and to the aqueous layer was added 1 mol/l hydrochloric acid to pH 2 to 3, and the mixture was extracted with chloroform (200 mL×2). The organic layer was dried with anhydrous sodium sulfate, and after filtration, the filtrate was concentrated under reduced pressure. The concentrate was azeotropically distilled by adding toluene (20 mL), and dried under reduced pressure to obtain 1.86 g (quantitative) of the title compound (isomer A) as a colorless oily substance.
Reaction SMILES: [OH:1][C:2]1([CH:13]2[CH2:18][NH:17][CH2:16][CH2:15][NH:14]2)[CH2:5][N:4]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:3]1.C(N(CC)C(C)C)(C)C.[N+:28]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[S:37](Cl)(=[O:39])=[O:38])([O-:30])=[O:29]>C1COCC1>[OH:1][C:2]1([CH:13]2[CH2:18][N:17]([S:37]([C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=3[N+:28]([O-:30])=[O:29])(=[O:38])=[O:39])[CH2:16][CH2:15][NH:14]2)[CH2:3][N:4]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:5]1
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CC(O)(C2CNCCN2)C1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CC(O)(C2CN(S(=O)(=O)c3ccccc3[N+](=O)[O-])CCN2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 79.5 %

Procedure:
To a solution of 1,1-dimethylethyl 3-hydroxy-3-piperazin-2-ylazetidine-1-carboxylate (227 mg, 0.88 mmol) and N,N-diisopropylethylamine (436 μL, 2.64 mmol) in THF (5 mL) was added 2-nitrobenzenesulfonyl chloride (195 mg, 0.88 mmol). The mixture was stirred at room temperature for 2 hours. The solution was concentrated and the residue was purified by column chromatography (95% dichloromethane: 5% methanol) to provide 1,1-dimethylethyl 3-hydroxy-3-{4-[(2-nitrophenyl)sulfonyl]piperazin-2-yl}azetidine-1-carboxylate as a white foam (308 mg, 0.70 mmol, 79% yield). 1H NMR. (400 MHz, CDCl3): 7.98 (m, 1H), 7.72 (m, 2H), 7.64 (m, 1H), 3.96 (d, 1H), 3.94 (d, 1H), 3.85 (d, 1H), 3.79 (d, 1H), 3.79-3.73 (m, 2H), 3.11 (m, 1H), 3.05 (dd, 1H), 3.00 (br s, 1H), 2.94 (dt, 1H), 2.78 (dt, 1H), 2.68 (dd, 1H), 1.45 (s, 9H).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:34].C(N(CC)CC)C.[Cl:42][C:43]1[CH:48]=[CH:47][C:46]([S:49](Cl)(=[O:51])=[O:50])=[CH:45][CH:44]=1>C(#N)C>[Cl:42][C:43]1[CH:48]=[CH:47][C:46]([S:49]([O:1][C:2]2[CH:10]=[CH:9][C:8]([C:11]3[N:12]([C:27]([O:29][C:30]([CH3:31])([CH3:33])[CH3:32])=[O:28])[C:13]4[C:18]([CH:19]=3)=[CH:17][C:16]([CH2:20][N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)=[CH:15][CH:14]=4)=[C:7]3[C:3]=2[CH2:4][NH:5][C:6]3=[O:34])(=[O:51])=[O:50])=[CH:45][CH:44]=1
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(O)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)n1c(-c2ccc(OS(=O)(=O)c3ccc(Cl)cc3)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Yield: 41.1 %

Procedure:
In a similar manner to Step 1 of Example 233, 4-hydroxy-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.0295 g, 0.0639 mmol) was dissolved in acetonitrile (0.650 mL), and the solution was treated with triethylamine (0.0530 mL, 0.383 mmol) and 4-chlorobenzenesulfonyl chloride (0.0400 g, 0.192 mmol) to obtain 4-(4-chlorobenzenesulfonyloxy)-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.0167 g, yield 41%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([C@@H:10]([NH2:12])[CH3:11])[N:7]([C:13]3[CH:14]=[N:15][CH:16]=[C:17]([F:19])[CH:18]=3)[C:6]=2[CH:20]=1.[NH2:21][C:22]1[N:27]=[C:26](Cl)[C:25]([C:29]#[N:30])=[CH:24][N:23]=1.CCN(C(C)C)C(C)C>CC(O)C.CO>[NH2:21][C:22]1[N:27]=[C:26]([NH:12][C@H:10]([C:8]2[N:7]([C:13]3[CH:14]=[N:15][CH:16]=[C:17]([F:19])[CH:18]=3)[C:6]3[CH:20]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=3[N:9]=2)[CH3:11])[C:25]([C:29]#[N:30])=[CH:24][N:23]=1
Reactant: N#Cc1cnc(N)nc1Cl
Reactant: C[C@H](N)c1nc2ccc(F)cc2n1-c1cncc(F)c1
Solvent: CO
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](Nc1nc(N)ncc1C#N)c1nc2ccc(F)cc2n1-c1cncc(F)c1
Temperature: 25 °C
Yield: 57 %

Procedure:
A mixture of (S)-1-[6-fluoro-1-(5-fluoropyridin-3-yl)-1H-benzoimidazol-2-yl]-ethylamine.2HCl (118 mg, 0.34 mmol), 2-amino-4-chloropyrimidine-5-carbonitrile (40 mg, 0.26 mmol) and DIPEA (222 μL, 1.29 mmol) in IPA (0.75 mL) was heated at 90° C. in a sealed vial for 18 h. After cooling to RT, the reaction mixture was diluted with MeOH and loaded into an Isolute® SCX-2 cartridge. The cartridge was washed with MeOH followed by 2M NH3/MeOH. The basic fractions were combined, concentrated in vacuo and the resulting residue purified by column chromatography (Si—PCC, gradient 0-100% EtOAc in DCM) followed by reverse phase HPLC (Phenomenex Gemini 5 μm C18 on a gradient 5-75%, 0.1% NH4OH in acetonitrile/water) to afford 363 as a white solid (58 mg, 57%). LCMS (Method K): RT 3.10 min [M+H]+ 392.97. 1H NMR (DMSO-d6, 400 MHz): δ 8.66 (1H, d, J=2.64 Hz), 8.62 (1H, s), 8.06 (1H, s), 8.03 (1H, d, J=9.27 Hz), 7.76-7.75 (2H, m), 7.15 (1H, ddd, J=9.85, 8.79, 2.51 Hz), 7.08 (1H, dd, J=8.96, 2.50 Hz), 7.05-6.60 (2H, m), 5.56 (1H, m), 1.55 (3H, d, J=6.75 Hz)
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].C(=O)([O-])[O-].[K+].[K+].Br[C:19]([CH3:28])([CH3:27])[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21]>CN(C)C=O>[CH3:8][O:7][C:5]([C:4]1[CH:3]=[C:2]([CH:11]=[CH:10][CH:9]=1)[O:1][C:19]([CH3:28])([CH3:27])[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[O:6]
Reactant: COC(=O)c1cccc(O)c1
Reactant: CC(C)(C)OC(=O)C(C)(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(OC(C)(C)C(=O)OC(C)(C)C)c1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
Methyl 3-hydroxybenzoate (17.05 g, 0.112 mol) was dissolved in dimethylformamide (100 mL). Subsequently, potassium carbonate (20.12 g, 0.145 mol) and then tert-butyl 2-bromoisobutyrate (50.00 g, 0.224 mol) were added thereto, and the mixture was stirred overnight at 80° C. The reaction mixture was concentrated under reduced pressure, and ethyl acetate was added to the concentrate. Washing was performed sequentially with water and saturated brine, followed by drying over sodium sulfate. The reaction mixture was subjected to filtration, concentration under reduced pressure, and purification by silica gel column chromatography (n-hexane/ethyl acetate=10/1), whereby a colorless oil was obtained (17.03 g, 57.80 mmol, 51.6%).