Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([C:15]([NH:17][C:18]3[CH:27]=[C:26]4[C:21]([CH:22]=[C:23]([C:28]([OH:30])=O)[CH:24]=[N:25]4)=[CH:20][CH:19]=3)=[O:16])=[CH:11][CH:12]=[CH:13][CH:14]=2)=[CH:5][CH:4]=1.[NH2:33][CH:34]([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>ClCCl>[CH:34]([NH:33][C:28]([C:23]1[CH:24]=[N:25][C:26]2[C:21]([CH:22]=1)=[CH:20][CH:19]=[C:18]([NH:17][C:15]([C:10]1[C:9]([C:6]3[CH:7]=[CH:8][C:3]([C:2]([F:31])([F:1])[F:32])=[CH:4][CH:5]=3)=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:16])[CH:27]=2)=[O:30])([C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: NC(c1ccccc1)c1ccccc1
Reactant: O=C(O)c1cnc2cc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cc3)ccc2c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NC(c1ccccc1)c1ccccc1)c1cnc2cc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cc3)ccc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 47.7 %

Procedure:
7-[(4′-Trifluoromethyl-biphenyl-2-carbonyl)-amino]-quinoline-3-carboxylic acid (100 mg, 0.23 mmol) was combined with aminodiphenylmethane (42 mg, 0.23 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (53 mg, 0.27 mmol), 1-hydroxybenzotriazole (34 mg, 0.25 mmol), and triethylamine (0.13 ml, 0.92 mmol) in 1.5 ml of dichloromethane. After stirring overnight at ambient temperature, the reaction mixture was diluted with 50 ml of dichloromethane, and the organic phase washed sequentially with water, and brine, and then dried over anhydrous magnesium sulfate, filtered and concentrated under vacuum to provide a residue. This material was purified by preparative thin-layer-chromatography on silica eluting with ethyl acetate. The product containing band was collected and eluted with 5% methanol in ethyl acetate to afford 66 mg of the title compound as a colorless solid.
Reaction SMILES: Cl.[CH2:2]([NH:4][C:5]([N:7]1[CH2:11][C:10]([CH3:13])([CH3:12])[CH:9]=[N:8]1)=[NH:6])[CH3:3].CCN(C(C)C)C(C)C.[Cl:23][C:24]1[CH:25]=[C:26]([S:30](Cl)(=[O:32])=[O:31])[CH:27]=[CH:28][CH:29]=1>C(Cl)Cl>[Cl:23][C:24]1[CH:25]=[C:26]([S:30]([N:6]=[C:5]([N:7]2[CH2:11][C:10]([CH3:12])([CH3:13])[CH:9]=[N:8]2)[NH:4][CH2:2][CH3:3])(=[O:32])=[O:31])[CH:27]=[CH:28][CH:29]=1
Reactant: CCNC(=N)N1CC(C)(C)C=N1
Reactant: O=S(=O)(Cl)c1cccc(Cl)c1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCNC(=NS(=O)(=O)c1cccc(Cl)c1)N1CC(C)(C)C=N1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
6.39 g N-Ethyl-4,4-dimethyl-4,5-dihydro-pyrazole-1-carboxamidine hydrochloride was suspended in 65 mL DCM. 12.0 mL DIPEA and 3.96 mL 3-chloro-benzenesulfonyl chloride were added and the suspension was stirred for 20 h. at room temperature, resulting in a dark brown turbid solution. The mixture was extracted with 2M NaOH (2×125 mL) and 1M HCl (2×125 mL)7 washed with water (100 mL), and the organic layer was dried over Na2SO4 followed by evaporation under reduced pressure to yield 7.70 g of a brown oil. The oil (1.0 g) was dissolved in MTBE (3 mL) under reflux, and the solution was slowly cooled to room temperature, initializing crystallization The suspension was stirred for 10 min at room temperature, hexane (6 mL) was added over a period of 1 minute. The resulting suspension was stirred for 20 min. at room temperature and 50 min. at 0° C., and product was collected by filtration and washed with hexane (1 mL). Drying under reduced pressure at 40° C. yielded 0.85 g of a light-brown solid, m.p. 62-67° C.
Reaction SMILES: C(=O)(O)[O-].[K+].Cl.[C:7](=[NH:10])([NH2:9])[CH3:8].Br[CH2:12][C:13]([C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[C:17]([Br:22])[CH:16]=1)=O>O1CCCC1.O>[Br:22][C:17]1[CH:16]=[C:15]([C:13]2[NH:9][C:7]([CH3:8])=[N:10][CH:12]=2)[CH:20]=[CH:19][C:18]=1[CH3:21]
Reactant: Cc1ccc(C(=O)CBr)cc1Br
Reactant: CC(=N)N
Agent: Cl
Agent: O=C([O-])O
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ncc(-c2ccc(C)c(Br)c2)[nH]1
Temperature: 70 °C
Reaction time: 3 h
Yield: 4.2 %

Procedure:
Potassium bicarbonate (2.10 g, 20.7 mmol) was added portionwise to a solution of acetimidamide hydrochloride (1.06 g, 11.2 mmol) in tetrahydrofuran (20 mL) and water (5 mL). The resulting mixture was heated to reflux and 2-bromo-1-(3-bromo-4-methylphenyl)ethanone (preparation 58a, 2.74 g, 9.4 mmol) was added dropwise over a period of 20 minutes. After 3 hours, further acetamidamide hydrochloride (1.06 g, 11.2 mmol) and potassium bicarbonate (1.03 g, 10.1 mmol) were added and the was mixture refluxed overnight. The mixture was evaporated to dryness and partitioned between 2M aqueous hydrochloric acid and ethyl acetate. The acidic aqueous layer was bascified with solid sodium hydroxide and extracted with ethyl acetate. The organic layer was dried (MgSO4) and the solvent was evaporated under reduced pressure to give a semi solid. This semi solid was heated in vacuo at 70° C. for one hour in order to remove excess acetamidamide to give the pure title compound (0.10 g, 5%) as a white solid.
Reaction SMILES: [C:1]([C:4]1([NH:10][S:11]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)(=[O:13])=[O:12])[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1)(=O)[CH3:2].ClC1C=CC(CS(Cl)(=O)=O)=CC=1.C(NC1CCCCC1)#C.C(N(CC)CC)C>O1CCCC1.C(OCC)(=O)C>[Cl:21][C:18]1[CH:17]=[CH:16][C:15]([CH2:14][S:11]([NH:10][C:4]2([C:1]#[CH:2])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9]2)(=[O:13])=[O:12])=[CH:20][CH:19]=1
Reactant: CC(=O)C1(NS(=O)(=O)Cc2ccc(Cl)cc2)CCCCC1
Agent: C#CNC1CCCCC1
Agent: O=S(=O)(Cl)Cc1ccc(Cl)cc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C#CC1(NS(=O)(=O)Cc2ccc(Cl)cc2)CCCCC1
Yield: 80 %

Procedure:
The preparation of N-(1-acetylcyclohexyl)-4-chlorophenyl-methanesulfonamide, shown below, was performed as described in Pestic. Sci. 1993, 39, 185–192. 4-chloro-phenylmethanesulfonyl chloride (1.37 g, 6 mmol) and ethynylcyclohexylamine (0.73 g, 6 mmol) were stirred in tetrahydrofuran (10 mL) with triethylamine (0.9 mL, 6.6 mmol) for several hours at room temperature. The mixture was diluted with ethyl acetate, washed with water, dried (Na2SO4) and evaporated. Recrystallisation from ethanol yielded 4-chlorophenyl-N-(1-ethynylcyclohexyl)methane-sulfonamide (1.5 g, 80%) as a solid.
Reaction SMILES: CC(C1C=[C:6]([O:10]C2N=CC(NC(=O)[C@@H](C)N)=CC=2)C=CC=1)C.[CH3:23][C:24]1[C:29]([O:30][CH3:31])=[CH:28][CH:27]=[CH:26][C:25]=1[O:32][C:33]1[N:38]=[CH:37][C:36]([NH:39][C:40](=[O:44])[C@@H:41]([CH3:43])[NH2:42])=[CH:35][CH:34]=1>>[CH3:43][C@H:41]1[NH:42][C:6](=[O:10])[N:39]([C:36]2[CH:37]=[N:38][C:33]([O:32][C:25]3[CH:26]=[CH:27][CH:28]=[C:29]([O:30][CH3:31])[C:24]=3[CH3:23])=[CH:34][CH:35]=2)[C:40]1=[O:44]
Reactant: COc1cccc(Oc2ccc(NC(=O)[C@@H](C)N)cn2)c1C
Reactant: CC(C)c1cccc(Oc2ccc(NC(=O)[C@@H](C)N)cn2)c1
Product: COc1cccc(Oc2ccc(N3C(=O)N[C@H](C)C3=O)cn2)c1C

Procedure:
The title compound was made in a similar fashion to the preparation of Example 9 replacing N1-(6-{[3-(1-methylethyl)phenyl]oxy}-3-pyridinyl)-D-alaninamide with N1-(6-{[2-methyl-3-(methyloxy)phenyl]oxy}-3-pyridinyl)-D-alaninamide (Intermediate 63, 200 mg) to afford the title compound (184 mg).
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH2:3][CH3:4].BrC1[CH:12]=[C:11]2[O:13][CH2:14][O:15][C:10]2=CC=1C.CN(C)[CH:19]=[O:20].O>O1CCCC1>[CH3:4][C:3]1[CH:12]=[C:11]2[O:13][CH2:14][O:15][C:10]2=[CH:1][C:2]=1[CH:19]=[O:20]
Reactant: [Li]CCCC
Reactant: CN(C)C=O
Reactant: Cc1cc2c(cc1Br)OCO2
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc2c(cc1C=O)OCO2
Reaction time: 0.5 h
Yield: 99.4 %

Procedure:
13 ml (20 mmol) of n-butyllithium (1.5 M hexane solution) was dropwise added at −78° C. to a solution having 4.0 g (19 mmol) of 2-bromo-4,5-(methylenedioxy)toluene dissolved in 50 ml of tetrahydrofuran, followed by stirring for 30 minutes, and 1.5 ml (19 mmol) of dimethylformamide was added thereto, followed by stirring for 70 minutes. 30 ml of water was added to the mixture to terminate the reaction, and tetrahydrofuran was distilled off under reduced pressure. Extraction with chloroform was carried out, the organic layer was dried over anhydrous sodium sulfate and subjected to filtration by using a silica gel cake, and the solvent was distilled off under reduced pressure to obtain 3.1 g (yield 99%) of 2-methyl-4,5-(methylenedioxy)benzaldehyde (m.p. 84-86° C.).
Reaction SMILES: [CH2:1](N(CC)CC)C.B.Cl.[CH3:10][O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[N:18]1[CH2:23][CH2:22][N:21]([CH2:24][CH2:25][NH2:26])[CH2:20][CH2:19]1>O1CCCC1.C(OCC)(=O)C>[CH3:10][O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[N:18]1[CH2:19][CH2:20][N:21]([CH2:24][C@H:25]([NH2:26])[CH3:1])[CH2:22][CH2:23]1
Reactant: COc1ccccc1N1CCN(CCN)CC1
Reactant: CCN(CC)CC
Agent: B
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1ccccc1N1CCN(C[C@@H](C)N)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The above mentioned (R)-{1-methyl-2-[4-(2-methoxyphenyl)-piperazin-1-yl]-2-amino-propan-2-1-one hydrochloride (5.90 g, 19.7 mmol) was dissolved in anhydrous tetrahydrofuran (60 mL) at room temperature. Triethylamine (6.3 mL, 45 mmol) was added, followed by dropwise addition of a 1M solution of borane in tetrahydrofuran (77.5 mL, 45 mmol). The resulting mixture was refluxed for 18 hours. After cooling the reaction mixture to room temperature, ethyl acetate (60 mL) and 2N aqueous HCl were added and the resulting mixture was stirred at room temperature for one hour. The layers were separated and the aqueous layer was made basic by careful addition of 50% aqueous NaOH. The resulting basic mixture was extracted with three 50 mL portions of ethyl acetate. The combined organic layers were washed with brine (50 mL) and dried over anhydrous sodium sulfate. Filtration and concentration on a rotary evaporator yielded 4.62 g (94%) of the desired of 2-[4-(2-methoxyphenyl)-piperazin-1-yl]-ethylamine as a colorless oil which was used without further purification.
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[CH:7]([CH2:8][C:9]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)=[O:10])[O:6][C:4](=[O:5])[CH2:3]1.[ClH:20].[CH2:21](O)[CH3:22]>>[CH2:21]([O:6][C:4](=[O:5])[CH2:3][C:2]([CH3:19])([CH3:1])[CH:7]([Cl:20])[CH2:8][C:9]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1)=[O:10])[CH3:22]
Reactant: CCO
Reactant: COc1ccc(C(=O)CC2OC(=O)CC2(C)C)cc1
Reactant: Cl
Product: CCOC(=O)CC(C)(C)C(Cl)CC(=O)c1ccc(OC)cc1

Procedure:
78.6 g of 3,3-dimethyl-4-(4'-methoxy-phenacyl)-γ-butyrolactone were dissolved in 500 ml of ethanol, and dry hydrogen chloride was passed in until the temperature had reached 50° C. A slow stream of hydrogen chloride was then passed through the solution at 50° C., initially while cooling, for 3 hours, and then continued to be passed in until the mixture reached room temperature again. Distilling off the ethanol in vacuo gave 98 g of 6-(4'-methoxy-phenyl)-6-oxo-4-chloro-3,3-dimethyl-hexanoic acid ethyl ester.
Reaction SMILES: Cl[C:2]1[O:3][C:4]2[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:5]=2[N:6]=1.[K].O[C:14]1[CH:22]=[CH:21][CH:20]=[CH:19][C:15]=1[C:16]([OH:18])=[O:17].CS(C)=[O:25]>C(O)(=O)C>[Cl:11][C:8]1[CH:9]=[CH:10][C:4]2[O:3][C:2]([O:25][C:20]3[CH:21]=[CH:22][CH:14]=[C:15]([CH:19]=3)[C:16]([OH:18])=[O:17])=[N:6][C:5]=2[CH:7]=1
Reactant: O=C(O)c1ccccc1O
Reactant: Clc1ccc2oc(Cl)nc2c1
Reactant: CS(C)=O
Agent: [K]
Solvent: CC(=O)O
Product: O=C(O)c1cccc(Oc2nc3cc(Cl)ccc3o2)c1

Procedure:
Substantially equimolar amounts of 2,5-dichlorobenzoxazole and the potassium salt of 2-hydroxy benzoic acid are reacted, in an inert organic solvent, e.g., dimethylsulfoxide, in the presence of acetic acid giving 5-(5-chloro-2-benzoxazolyloxy) benzoic acid. The benzoate is then nitrated by, for example, reaction with a mixture of nitric acid, sulfuric acid and acetic anhydride to give the corresponding 2-nitrobenzoic acid prepared as previously described. The 2-nitrobenzoic acid is then reacted with ethyl 2-chloropropionate, as previously described, giving the desired 1-(ethoxycarbonyl)ethyl 5-(5-chloro-2-benzoxazolyloxy)-2-nitrobenzoate.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:10][O:9][CH2:8][C@H:7]([O:11][CH2:12][CH2:13][CH:14]([CH3:16])[CH3:15])[C@@H:6]([O:17][CH2:18][CH2:19][CH:20]([CH3:22])[CH3:21])[C@H:5]([CH3:23])[O:4][C:3]1=[O:24].[OH:25][C:26]1[C:27]([C:34](O)=[O:35])=[N:28][CH:29]=[CH:30][C:31]=1[O:32][CH3:33].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(C(C)C)C(C)C)C>C(Cl)Cl>[CH2:12]([O:11][C@@H:7]1[C@@H:6]([O:17][CH2:18][CH2:19][CH:20]([CH3:22])[CH3:21])[C@H:5]([CH3:23])[O:4][C:3](=[O:24])[C@@H:2]([NH:1][C:34](=[O:35])[C:27]2[C:26]([OH:25])=[C:31]([O:32][CH3:33])[CH:30]=[CH:29][N:28]=2)[CH2:10][O:9][CH2:8]1)[CH2:13][CH:14]([CH3:16])[CH3:15]
Reactant: CC(C)CCO[C@H]1[C@H](C)OC(=O)[C@@H](N)COC[C@@H]1OCCC(C)C
Reactant: COc1ccnc(C(=O)O)c1O
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccnc(C(=O)N[C@H]2COC[C@H](OCCC(C)C)[C@@H](OCCC(C)C)[C@H](C)OC2=O)c1O
Temperature: 25 °C
Yield: 42.3 %

Procedure:
(3S,7S,8S,9S)-3-amino-7,8-bis(isopentyloxy)-9-methyl-1,5-dioxonan-2-one (130 mg, 0.376 mmol) and 3-hydroxy-4-methoxypicolinic acid (70.0 mg, 0.414 mmol) were diluted with DCM (3763 μl). PyBOP (215 mg, 0.414 mmol) was added, followed by N-ethyl-N-isopropylpropan-2-amine (216 μl, 1.242 mmol), and the mixture was stirred at room temperature until thin layer chromatography (TLC) indicated complete consumption of starting material. The reaction mixture was purified by column chromatography (SiO2; hexanes/EtOAc) to furnish the title compound (79.1 mg, 0.159 mmol, 42.3% yield) as a white solid: mp 61-70° C.; IR (thin film) 3530, 3371, 2955, 2873, 1750, 1649, 1529, 1262 cm−1; 1H NMR (400 MHz, CDCl3) δ 11.94 (s, 1H), 8.67 (d, J=8.1 Hz, 1H), 8.01-7.98 (m, 1H), 6.87 (d, J=5.2 Hz, 1H), 5.04 (ddd, J=8.2, 6.8, 5.0 Hz, 1H), 5.01-4.89 (m, 1H), 4.05 (dd, J=11.9, 6.8 Hz, 1H), 3.94 (s, 3H), 3.92-3.85 (m, 1H), 3.85-3.78 (m, 2H), 3.66-3.58 (m, 2H), 3.57-3.48 (m, 2H), 3.26-3.14 (m, 2H), 1.69 (dp, J=13.4, 6.7 Hz, 2H), 1.51-1.38 (m, 7H), 0.90 (dt, J=6.2, 2.7 Hz, 12H); 13C NMR (101 MHz, CDCl3) δ 170.30, 168.94, 155.32, 148.72, 140.66, 130.22, 109.56, 85.02, 83.63, 75.28, 73.94, 73.17, 72.48, 69.35, 56.09, 52.12, 39.23, 38.95, 24.96, 22.91, 22.67, 22.62, 22.50, 18.59; HRMS-ESI (m/z) [M+Na]+ calcd for C25H40N2NaO8, 519.2677, found 519.2687.
Reaction SMILES: [C:1]([Cl:4])(Cl)=[O:2].C(=O)([O-])[O-].[K+].[K+].C1(C(C2C=CC=CC=2)[N:18]2[CH2:21][CH:20]([O:22][C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([Cl:30])[CH:24]=3)[CH2:19]2)C=CC=CC=1>C(Cl)Cl>[Cl:30][C:25]1[CH:24]=[C:23]([CH:28]=[CH:27][C:26]=1[Cl:29])[O:22][CH:20]1[CH2:19][N:18]([C:1]([Cl:4])=[O:2])[CH2:21]1
Reactant: Clc1ccc(OC2CN(C(c3ccccc3)c3ccccc3)C2)cc1Cl
Reactant: O=C(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: O=C(Cl)N1CC(Oc2ccc(Cl)c(Cl)c2)C1
Reaction time: 1 h
Yield: 39.5 %

Procedure:
A solution of 14 g (0.144 mole) of phosgene in 200 ml of methylene chloride was treated with 19.9 g (0.144 mole) of anhydrous potassium carbonate and stirred for 1 hr, then 45.9 g (0.12 mole) of 1-diphenylmethyl-3-(3,4-dichlorophenoxy)azetidine in 100 ml of methylene chloride was added dropwise and stirring was continued for 72 hr. The reaction mixture was filtered to remove the inorganic salts and then concentrated in vacuo to a pale yellow oil (67 g). Trituration of the residue with cyclohexane yielded a crude pale yellow solid (23.6 g). The filtrate was treated with ligroin and upon standing, an additional 13.3 g of tacky material was obtained. After several recrystallizations from cyclohexane to remove traces of diphenylmethyl chloride a portion was obtained as fine white crystals, in 70.1% yield, m.p. 96°-99° C.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[N:11]=[C:12]([C:21]4[CH:29]=[CH:28][C:24]([C:25](O)=[O:26])=[CH:23][CH:22]=4)[NH:13][C:14]=3[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=3)=[CH:9][C:4]=2[O:3][CH2:2]1.C(Cl)(=O)C([Cl:33])=O>ClCCl.CN(C)C=O>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[N:11]=[C:12]([C:21]4[CH:29]=[CH:28][C:24]([C:25]([Cl:33])=[O:26])=[CH:23][CH:22]=4)[NH:13][C:14]=3[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1ccc(-c2nc(-c3ccc4c(c3)OCO4)c(-c3ccccn3)[nH]2)cc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)c1ccc(-c2nc(-c3ccc4c(c3)OCO4)c(-c3ccccn3)[nH]2)cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
4-(4-Benzo[1,3]dioxol-5-yl-5-pyridin-2-yl-1H-imidazol-2-yl)benzoic acid (prepared according to the method of Example 1) (379 mg; 0.98 mmol ) was suspended in dry dichloromethane (20 ml) and treated with oxalyl chloride (2 ml) and N,N-dimethylformamide (1 drop). This mixture was stirred at ambient temperature for 5 h then evaporated to dryness under reduced pressure to give the title compound as a yellow powder.
Reaction SMILES: [OH:1][C:2]1[CH:38]=[CH:37][C:5]([C:6]([N:8]([CH:34]([CH3:36])[CH3:35])[C:9]2[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:10]=2[CH:17]2[CH2:26][CH2:25][C:24]3[CH:23]=[C:22]([O:27]C(=O)C(C)(C)C)[CH:21]=[CH:20][C:19]=3[CH2:18]2)=O)=[CH:4][CH:3]=1.Cl[CH2:40][CH2:41][N:42]1[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]1>>[N:42]1([CH2:41][CH2:40][O:1][C:2]2[CH:3]=[CH:4][C:5]([CH2:6][N:8]([CH:34]([CH3:36])[CH3:35])[C:9]3[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:10]=3[CH:17]3[CH2:26][CH2:25][C:24]4[CH:23]=[C:22]([OH:27])[CH:21]=[CH:20][C:19]=4[CH2:18]3)=[CH:37][CH:38]=2)[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]1
Reactant: ClCCN1CCCCCC1
Reactant: COc1ccc(C2CCc3cc(OC(=O)C(C)(C)C)ccc3C2)c(N(C(=O)c2ccc(O)cc2)C(C)C)c1
Product: COc1ccc(C2CCc3cc(O)ccc3C2)c(N(Cc2ccc(OCCN3CCCCCC3)cc2)C(C)C)c1
Yield: 19 %

Procedure:
Synthesized from pivalic acid 6-{2-[(4-hydroxybenzoyl)isopropylamino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (30 mg) and 1-(2-chloroethyl)azepane (23 mg) according to an analogous synthetic method to Example 404 and purified by NH silica gel column chromatography (hexane-ethyl acetate system), the title compound (6.0 mg) was obtained.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=2)=[C:4]2[C:18]3[CH2:19][CH2:20][CH:21]([C:23](O)=[O:24])[CH2:22][C:17]=3[S:16][C:5]2=[N:6][C:7]=1[CH2:8][N:9]1[C:13](=[O:14])[CH2:12][CH2:11][C:10]1=[O:15].[NH:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1.Cl.CN(C)CCCN=C=NCC.CN(C=O)C>O>[Cl:1][C:2]1[C:3]([C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=2)=[C:4]2[C:18]3[CH2:19][CH2:20][CH:21]([C:23]([N:34]4[CH2:39][CH2:38][O:37][CH2:36][CH2:35]4)=[O:24])[CH2:22][C:17]=3[S:16][C:5]2=[N:6][C:7]=1[CH2:8][N:9]1[C:13](=[O:14])[CH2:12][CH2:11][C:10]1=[O:15]
Reactant: C1COCCN1
Reactant: COc1ccc(-c2c(Cl)c(CN3C(=O)CCC3=O)nc3sc4c(c23)CCC(C(=O)O)C4)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(-c2c(Cl)c(CN3C(=O)CCC3=O)nc3sc4c(c23)CCC(C(=O)N2CCOCC2)C4)cc1
Temperature: 25 °C
Reaction time: 10 h
Yield: 455.1 %

Procedure:
A mixture of the compound obtained in Example 37 (500 mg), morpholine (99 mg), N,N-dimethylaminopyridine (13 mg), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (197 mg), and DMF (10 ml) was stirred at room temperature for 10 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO4), and then evaporated under reduced pressure to remove the solvent. The residue was subjected to column chromatography on silica gel to obtain 1-{[3-chloro-4-(4-methoxyphenyl)-7-[(4-morpholinyl)carbonyl]-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-2-yl]methyl}-2,5-pyrrolidinedione (2.6 g, 92%) from the eluates with ethyl acetate. It was recrystallized from chloroform-hexane. Colorless prisms. Melting point 170-171° C.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:14]=[N:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][CH2:23][NH2:24])=[CH:17][CH:16]=3)=[N:11]2)=[CH:6][CH:5]=1.[F:27][C:28]1[CH:33]=[CH:32][C:31]([NH:34][C:35]([NH2:37])=[S:36])=[C:30]([CH:38]([CH3:40])[CH3:39])[CH:29]=1.[C:41]([O-])(=[O:43])C.[Na+]>>[F:27][C:28]1[CH:33]=[CH:32][C:31]([NH:34][C:35]([NH:37][C:41]([NH:24][CH2:23][CH2:22][CH2:21][C:18]2[CH:19]=[CH:20][C:15]([C:12]3[N:13]=[CH:14][N:10]([C:7]4[CH:6]=[CH:5][C:4]([O:3][C:2]([F:1])([F:25])[F:26])=[CH:9][CH:8]=4)[N:11]=3)=[CH:16][CH:17]=2)=[O:43])=[S:36])=[C:30]([CH:38]([CH3:40])[CH3:39])[CH:29]=1
Reactant: CC(=O)[O-]
Reactant: CC(C)c1cc(F)ccc1NC(N)=S
Reactant: NCCCc1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Agent: [Na+]
Product: CC(C)c1cc(F)ccc1NC(=S)NC(=O)NCCCc1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1

Procedure:
The title compound was prepared as described in Example 63 using 3-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)propan-1-amine (C60) and 1-(4-fluoro-2-isopropylphenyl)thiourea. Sodium acetate was used in place of sodium bicarbonate. The title compound was isolated as a white solid (0.116 g, 36%): 1H NMR (400 MHz, DMSO-d6) δ 11.85 (s, 1H), 10.11 (s, 1H), 9.39 (s, 1H), 8.15-7.97 (m, 4H), 7.63 (dd, J=8.7, 1.5 Hz, 2H), 7.39 (dd, J=8.5, 5.7 Hz, 3H), 7.16 (dd, J=10.4, 3.0 Hz, 1H), 7.12-6.97 (m, 2H), 3.26-3.11 (m, 2H), 3.05-2.89 (m, 1H), 2.70 (dd, J=8.6, 6.7 Hz, 2H), 1.92-1.71 (m, 2H), 1.16 (d, J=6.8 Hz, 6H); 19F NMR (376 MHz, DMSO-d6) δ −56.97, −114.39; ESIMS m/z 601 ([M+H]+), 599 ([M−H]−).
Reaction SMILES: [CH3:1][C:2]1[CH:26]=[CH:25][C:5]([C:6]([NH:8][C:9]2[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[C:11]([N:19]3[CH:23]=[C:22]([CH3:24])[N:21]=[CH:20]3)[CH:10]=2)=[O:7])=[CH:4][C:3]=1[NH:27][C:28]1[N:33]=[C:32]([C:34]2[CH:35]=[N:36][CH:37]=[CH:38][CH:39]=2)[CH:31]=[CH:30][N:29]=1.[P:40]([OH:43])([OH:42])[OH:41]>CO>[P:40]([OH:7])([OH:43])([OH:42])=[O:41].[CH3:1][C:2]1[CH:26]=[CH:25][C:5]([C:6]([NH:8][C:9]2[CH:14]=[C:13]([C:15]([F:16])([F:17])[F:18])[CH:12]=[C:11]([N:19]3[CH:23]=[C:22]([CH3:24])[N:21]=[CH:20]3)[CH:10]=2)=[O:7])=[CH:4][C:3]=1[NH:27][C:28]1[N:33]=[C:32]([C:34]2[CH:35]=[N:36][CH:37]=[CH:38][CH:39]=2)[CH:31]=[CH:30][N:29]=1
Reactant: OP(O)O
Agent: Cc1cn(-c2cc(NC(=O)c3ccc(C)c(Nc4nccc(-c5cccnc5)n4)c3)cc(C(F)(F)F)c2)cn1
Solvent: CO
Product: O=P(O)(O)O
Temperature: 64 °C
Reaction time: 0.5 h

Procedure:
To a 1 L round-bottom flask equipped with a mechanical stirrer, a thermometer, and a condenser, 4 g of 4-methyl-N-[3-(4-methyl-imidazol-1-yl)-5-trifluoromethyl-phenyl]-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-benzamide free base and 500 mL of methanol were charged. The slurry was stirred and heated to 64° C. and held at that temperature for ˜30 minutes. To the resulting clear solution, 7.5 mL of 1 M phosphorous acid solution (in methanol) was added. The mixture was stirred at 64° C. for one hour, cooled down to room temperature by natural cooling (cooling rate ˜0.5° C./min) and held at room temperature for 3-4 hours. The solid was collected by filtration and was dried at 50-55° C./10-20 ton for 8-16 hours to obtain 4-methyl-N-[3-(4-methyl-imidazol-1-yl)-5-trifluoromethyl-phenyl]-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-benzamide monophosphate salt (3.25 g) as a white solid. Melting point=˜208° C. (dec.); x-ray diffraction pattern showing maxima at 2θ=6.1°, 7.5°, 9.1°, 15.8°, 17.5°, 18.3°, 21.8°, 23.1°, 24.9°, 26.6°.
Reaction SMILES: Br[CH2:2][C:3]([N:5]([CH2:8][CH3:9])[CH2:6][CH3:7])=[O:4].[NH2:10][C:11]1[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=1.[Br:18][C:19]1[N:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][C:20]=1[Cl:29]>>[Br:18][C:19]1[N:24]=[CH:23][C:22]([S:25]([N:10]([C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=2)[CH2:2][C:3]([N:5]([CH2:8][CH3:9])[CH2:6][CH3:7])=[O:4])(=[O:26])=[O:27])=[CH:21][C:20]=1[Cl:29]
Reactant: Cc1ccc(N)cc1
Reactant: O=S(=O)(Cl)c1cnc(Br)c(Cl)c1
Reactant: CCN(CC)C(=O)CBr
Product: CCN(CC)C(=O)CN(c1ccc(C)cc1)S(=O)(=O)c1cnc(Br)c(Cl)c1

Procedure:
prepared by reaction of 2-bromo-N,N-diethylacetamide with p-toluidine and 6-bromo-5-chloro-pyridine-3-sulfonyl chloride