Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:12]([O:22][C:23]3[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH2:31][N:32]4[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]4)=[CH:25][CH:24]=3)=[C:13]3[C:18](=[CH:19][CH:20]=2)[CH:17]=[C:16]([OH:21])[CH:15]=[CH:14]3)=[CH:7][CH:6]=1)(=[O:4])=[O:3].C(N(CC)CC)C.[CH3:45][N:46]=[C:47]=[O:48].C(=O)(O)[O-].[Na+]>ClCCl>[CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([C:11]2[C:12]([O:22][C:23]3[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH2:31][N:32]4[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]4)=[CH:25][CH:24]=3)=[C:13]3[C:18](=[CH:19][CH:20]=2)[CH:17]=[C:16]([O:21][C:47](=[O:48])[NH:46][CH3:45])[CH:15]=[CH:14]3)=[CH:9][CH:10]=1)(=[O:4])=[O:3]
Reactant: CN=C=O
Reactant: CS(=O)(=O)c1ccc(-c2ccc3cc(O)ccc3c2Oc2ccc(OCCN3CCCCC3)cc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CNC(=O)Oc1ccc2c(Oc3ccc(OCCN4CCCCC4)cc3)c(-c3ccc(S(C)(=O)=O)cc3)ccc2c1
Reaction time: 0.5 h
Yield: 59.5 %

Procedure:
Dissolve the compound of Example 3 (201 mg, 0.38 mmol) in dichloromethane (4 L) and add triethylamine (0.50 mL, 3.5 mmol) followed by methylisocyanate (500 mg, 8.7 mmol). After stirring for 30 minutes, pour the reaction mixture into saturated aqueous sodium bicarbonate and extract with dichloromethane. Dry the organic layer with sodium sulfate, filter and concentrate in vacuo. Chromatograph the residue on a SiO2 column eluting with methanol in dichloromethane (0 to 4%) to give 130 mg of the title compound (60%): mass spectrum (ion spray): m/z=575.3 (M+H) and 518.3 (M-MeNCO).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:10]2[CH:18]([CH:19]3[CH2:23][CH2:22][CH2:21][CH2:20]3)[CH:17]3[C:12]([C:13]4[CH:27]=[CH:26][C:25]([C:28]([OH:30])=[O:29])=[CH:24][C:14]=4[CH2:15][CH2:16]3)=[N:11]2)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].[CH:31]1([CH2:37]O)[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1>>[Cl:1][C:2]1[CH:3]=[C:4]([N:10]2[CH:18]([CH:19]3[CH2:20][CH2:21][CH2:22][CH2:23]3)[CH:17]3[C:12]([C:13]4[CH:27]=[CH:26][C:25]([C:28]([O:30][CH2:37][CH:31]5[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]5)=[O:29])=[CH:24][C:14]=4[CH2:15][CH2:16]3)=[N:11]2)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: OCC1CCCCC1
Reactant: N#Cc1ccc(N2N=C3c4ccc(C(=O)O)cc4CCC3C2C2CCCC2)cc1Cl
Product: N#Cc1ccc(N2N=C3c4ccc(C(=O)OCC5CCCCC5)cc4CCC3C2C2CCCC2)cc1Cl
Yield: 67 %

Procedure:
The title compound was prepared from (±)-(3SR,3aRS)-2-(3-chloro-4-cyanophenyl)-3-cyclopentyl-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylic acid, Example 15 and cyclohexylmethanol according to Method E (yellow solid, 165 mg, 0.320 mmol, 67% yield). ES-HRMS m/z calc. for C31H35ClN3O2 (M+H) 516.2412, found 516.2403.
Reaction SMILES: [Cl:1][C:2]1[C:11]([S:12](Cl)(=[O:14])=[O:13])=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].C([O-])([O-])=O.[K+].[K+].[CH2:22]([NH2:24])[CH3:23]>C1C=CC=CC=1>[Cl:1][C:2]1[C:11]([S:12]([NH:24][CH2:22][CH3:23])(=[O:14])=[O:13])=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1cccc(S(=O)(=O)Cl)c1Cl
Reactant: CCN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccccc1
Product: CCNS(=O)(=O)c1cccc(C(=O)OC)c1Cl
Yield: 53.4 %

Procedure:
To a solution of methyl 2-chloro-3-(chlorosulfonyl)benzoate (608 mg, 2.26 mmol) and K2CO3 (770 mg, 5.6 mmol) in 10 mL benzene was added ethylamine (5.6 mL, 11.2 mmol). Purification of the product provided methyl 2-chloro-3-[(ethylamino)sulfonyl]benzoate (335 mg, 53%) as a solid. 1H NMR (400 MHz, CDCl3), δ 8.24 (dd, 1H, J=8.0, 1.7 Hz), 7.90 (dd, 1H, J=7.8, 1.7 Hz), 7.47 (t, 1H, J=7.8 Hz), 5.14 (t, 1H, J=5.9 Hz), 3.94 (s, 3H), 2.98 (qd, 2H, J=7.3, 6.0 Hz), 1.09 (t, 3H, J=7.2 Hz); ESI-MS 278 (M+H), 300 (M+Na). Methyl 2-chloro-3-[(ethylamino)sulfonyl]benzoate was hydrolyzed using aqueous NaOH to provide 2-chloro-3-[(ethylamino)sulfonyl]benzoic acid as a solid, which was used without further purification. ESI-MS 264 (M+H), 286 (M+Na).
Reaction SMILES: [O:1]=[S:2]1(=[O:13])[CH2:6][CH2:5][C:4]2[CH:7]=[C:8]([CH2:11][OH:12])[CH:9]=[CH:10][C:3]1=2.C(Cl)Cl>>[O:1]=[S:2]1(=[O:13])[CH2:6][CH2:5][C:4]2[CH:7]=[C:8]([CH2:11][O:12][S:2]([CH3:3])(=[O:13])=[O:1])[CH:9]=[CH:10][C:3]1=2
Reactant: O=S1(=O)CCc2cc(CO)ccc21
Solvent: ClCCl
Product: CS(=O)(=O)OCc1ccc2c(c1)CCS2(=O)=O
Reaction time: 3 h

Procedure:
To a solution of (1,1-Dioxo-2,3-dihydro-1H-1lambda*6*-benzo[b]thiophen-5-yl)-methanol (crude, 160 mg, 0.64 mmol) and triethylamne (180 ul, 1.29 mmol) in DCM (7 ml) Methanesulfonylchloride (60 ul, 0.77 mmol) was added at rt. The reaction mixture was stirred at it for 3 hours.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[N:9]([CH2:17][C:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:19])[CH2:10][CH2:11][N:12]([CH2:15][CH3:16])[CH2:13][CH3:14].[CH3:26][Mg]I>C(OCC)C>[CH2:15]([N:12]([CH2:13][CH3:14])[CH2:11][CH2:10][N:9]([CH2:17][C:18]([OH:19])([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[CH3:26])[C:3]1[CH:4]=[C:5]([Cl:8])[CH:6]=[CH:7][C:2]=1[Cl:1])[CH3:16]
Reactant: CCN(CC)CCN(CC(=O)c1ccccc1)c1cc(Cl)ccc1Cl
Reactant: C[Mg]I
Solvent: CCOCC
Product: CCN(CC)CCN(CC(C)(O)c1ccccc1)c1cc(Cl)ccc1Cl

Procedure:
A solution of 0.10 mole of 2-[N-(2,5-dichlorophenyl)-N-(β-diethylaminoethyl)amino]acetophenone in 200 ml of dry diethylether is added to a solution of 0.10 mole of methylmagnesium iodide in 500 ml of dry diethylether maintained at a temperature of from 0° to -5° C under nitrogen atmosphere. Thirty minutes after the addition the reaction mixture is washed with ice cold aqueous 2M ammonium chloride, dried over sodium sulfate, filtered and evaporated to give N-(β-diethylaminoethyl)-N-(β-hydroxy-β-phenylpropyl)-2,5-dichloroaniline.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:17]=[CH:18][C:19]=1[O:20][CH3:21])[CH2:6][NH:7][CH2:8][CH:9](O)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.CS(O)(=O)=O>ClCCl>[CH3:21][O:20][C:19]1[CH:18]=[C:17]2[C:5](=[CH:4][C:3]=1[O:2][CH3:1])[CH2:6][NH:7][CH2:8][CH:9]2[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: COc1ccc(CNCC(O)c2ccccc2)cc1OC
Agent: CS(=O)(=O)O
Solvent: ClCCl
Product: COc1cc2c(cc1OC)C(c1ccccc1)CNC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 421.9 %

Procedure:
Add the amino-alcohol from step A (2.2 g) to a mixture of methanesulfonic acid (100 mL) and dichloromethane (150 mL) and stir overnight at room temperature. Pour the mixture into ice-water, separate and concentrate the organic layer to a residue. Triturate with benzene then recrystallize from ethanol to give 8.7 g of the title amine as the methanesulfonate salt, mp=198°-199° C.
Reaction SMILES: [CH3:1][C:2]([CH3:6])=[CH:3][CH2:4][NH2:5].C[N:8](N=O)[C:9]([NH:11][N+:12]([O-:14])=[O:13])=N>CCO.O>[CH3:1][C:2]([CH3:6])=[CH:3][CH2:4][NH:5][C:9]([NH:11][N+:12]([O-:14])=[O:13])=[NH:8]
Reactant: CC(C)=CCN
Reactant: CN(N=O)C(=N)N[N+](=O)[O-]
Solvent: O
Solvent: CCO
Product: CC(C)=CCNC(=N)N[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 18 h

Procedure:
3-methyl-2-butenylamine (3.0 g) is added dropwise at room temperature to a slurry of 1-methyl-3-nitro-1 -nitrosoguanidine (4.3 g) in 50 ml of EtOH/H2O (1/1). After stirring the mixture at room temperature for 18 hours, the precipitate which forms is removed by filtration. The solid is then slurred with dilute hydrochloric acid, collected by filtration and washed with ethanol/water (30/70). Recrystallization from ethanol gives a white solid with mp 134°-136° C.
Reaction SMILES: I[C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][C:6]=2[N+:12]([O-:14])=[O:13].[C:15]1([S:21]([O-:23])=[O:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[Na+]>CN(C)C=O>[N+:12]([C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:5]=1[N:4]=[CH:3][C:2]([S:21]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)(=[O:23])=[O:22])=[CH:11]2)([O-:14])=[O:13]
Reactant: O=[N+]([O-])c1cccc2cc(I)cnc12
Reactant: O=S([O-])c1ccccc1
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cccc2cc(S(=O)(=O)c3ccccc3)cnc12
Temperature: 65 °C
Yield: 57.6 %

Procedure:
3-Iodo-8-nitroquinoline (D3) (135 g, 0.45 mol), was suspended in dimethylformamide (2.4 L) in a 5 L 3-necked flask fitted with an overhead stirrer, under an argon atmosphere. This mixture was treated successively with anhydrous sodium phenylsulfinate (99.6 g 0.608 mol), and bis-(copper (I) triflate) benzene complex (170 g, 0.338 mol). The resulting slurry was heated to 65° C. for 18 h. The mixture was cooled, filtered and the solvent evaporated in vacuo. Acetone (2.5 L) was added to the residue and the solution filtered. The filtrate was evaporated in vacuo, a further 2.5 L of acetone added and the mixture filtered again. The solvent was evaporated in vacuo and the residue dissolved in chloroform (3 L) and washed with 10% aqueous ammonia (2×2 L), and the organic phase was dried over magnesium sulphate and the solvent evaporated in vacuo. The dark brown residue was purified using a Biotage flash-150 chromatography apparatus (5 kg silica gel) eluting with hexane and increasing proportions of ethyl acetate to give the title compound (D4) (81.5 g, 58%) as a yellow solid;
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([OH:12])=[O:11])=[CH:5][C:4]=1[CH3:13].[Br:14]Br>C(O)(=O)C.[Cl-].[Na+].O>[Br:14][C:8]1[CH:7]=[C:6]([CH2:9][C:10]([OH:12])=[O:11])[CH:5]=[C:4]([CH3:13])[C:3]=1[O:2][CH3:1]
Reactant: COc1ccc(CC(=O)O)cc1C
Reactant: BrBr
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: COc1c(C)cc(CC(=O)O)cc1Br

Procedure:
To a solution of 4-methoxy-3-methylphenylacetic acid (0.43 g) in glacial acetic acid (7 mL) was added 0.2 mL of neat bromine carefully while stirring. The mixture was stirred in dark at ambient temperature for 27 h. The resulting mixture was diluted with brine, extracted with ethyl acetate, dried and concentrated in vacuo to afford 3-bromo-5-methyl-4-methoxyphenylacetic acid. This crude product was dissolved in methanol (30 mL), treated with concentrated sulfuric acid (1 mL) carefully, stirred at reflux for 16 h. Cooled reaction mixture was concentrated under reduced pressure, diluted with brine, extracted with ethyl acetate. The combined organic layers were dried and concentrated in vacuo. The residue was dissolved in dichloromethane (10 mL), treated-with boron tribromide (1 M, 2 mL) under nitrogen and stirred at ambient temperature for 1 h. The reaction mixture was poured to stirring water and extracted with ethyl acetate from 1 N HCl. The combined organic layers were dried and concentrated. Flash column chromatography on silica gel with ethyl acetate/hexane (0-50% gradient elution) afforded 3-bromo-5-methyl-4-hydroxyphenylacetic acid methyl ester (0.21 g, 34%).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][S:16]([CH3:19])(=[O:18])=[O:17])[CH:10]=2)[N:3]=1.[F:20][C:21]1([F:33])[O:25][C:24]2[CH:26]=[CH:27][CH:28]=[C:29](B(O)O)[C:23]=2[O:22]1>>[F:33][C:21]1([F:20])[O:22][C:23]2[CH:29]=[CH:28][CH:27]=[C:26]([C:2]3[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]4[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][S:16]([CH3:19])(=[O:18])=[O:17])[CH:10]=4)[N:3]=3)[C:24]=2[O:25]1
Reactant: CS(=O)(=O)Cc1cccc(Nc2ncnc(Cl)n2)c1
Reactant: OB(O)c1cccc2c1OC(F)(F)O2
Product: CS(=O)(=O)Cc1cccc(Nc2ncnc(-c3cccc4c3OC(F)(F)O4)n2)c1

Procedure:
Example 6 was prepared under similar conditions as described in the preparation of Example 1 using crude 4-chloro-N-{3-[(methylsulfonyl)methyl]phenyl}-1,3,5-triazin-2-amine and (2,2-difluoro-1,3-benzodioxol-4-yl)boronic acid (Aalen Chemical Co., Ltd.). The batch was purified by preparative HPLC:
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([S:12]([NH:15][C:16]3[S:17][CH:18]=[CH:19][N:20]=3)(=[O:14])=[O:13])=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[C:27]1([CH:33]2[CH2:37][CH2:36][NH:35][CH2:34]2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>CN(C=O)C>[C:27]1([CH:33]2[CH2:37][CH2:36][N:35]([C:2]3[C:11]4[C:6](=[CH:7][C:8]([S:12]([NH:15][C:16]5[S:17][CH:18]=[CH:19][N:20]=5)(=[O:14])=[O:13])=[CH:9][CH:10]=4)[CH:5]=[CH:4][N:3]=3)[CH2:34]2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: O=S(=O)(Nc1nccs1)c1ccc2c(Cl)nccc2c1
Reactant: c1ccc(C2CCNC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=S(=O)(Nc1nccs1)c1ccc2c(N3CCC(c4ccccc4)C3)nccc2c1
Temperature: 110 °C
Reaction time: 8 h

Procedure:
1-Chloro-N-(thiazol-2-yl)isoquinoline-6-sulfonamide (from Example 73, step 2; 0.050 g, 0.153 mmol) and potassium carbonate (0.106 g, 0.767 mmol) were dissolved in DMF (1.023 ml). 3-Phenyl-pyrrolidine (0.032 ml, 0.230 mmol) was added and the reaction was stirred overnight at 110° C. The reaction was filtered through a syringe filter and purified via HPLC (25 to 70% MeCN:H2O with 0.1% TFA modifier). The product fractions were combined and concentrated. The material was dissolved in methanol and passed through an SCX ion exchange column (pre-wetted with methanol). The column was flushed with methanol, then the product was liberated by flushing the column with 2 M ammonia in methanol. The filtrate was combined to afford 1-(3-phenylpyrrolidin-1-yl)-N-(thiazol-2-yl)isoquinoline-6-sulfonamide as a light yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm=8.34 (d, J=8.9 Hz, 1H), 8.16 (d, J=1.9 Hz, 1H), 8.00 (d, J=5.6 Hz, 1H), 7.71 (dd, J=1.9, 8.9 Hz, 1H), 7.40-7.31 (m, 4H), 7.28-7.22 (m, 1H), 7.19 (d, J=5.6 Hz, 1H), 7.11 (d, J=4.2 Hz, 1H), 6.67 (d, J=4.3 Hz, 1H), 4.12-3.97 (m, 2H), 3.94-3.77 (m, 2H), 3.55-3.42 (m, 1H), 2.42-2.27 (m, 1H), 2.19-2.04 (m, 1H). m/z (ESI) 437.2 (M+H)+.
Reaction SMILES: [C:1]([C:4]1[C:5]([O:16][CH3:17])=[CH:6][C:7]([O:14][CH3:15])=[C:8]([CH:13]=1)[C:9]([O:11][CH3:12])=[O:10])(=[O:3])[CH3:2].[BH4-].[Na+].Cl>CO>[CH3:15][O:14][C:7]1[CH:6]=[C:5]([O:16][CH3:17])[C:4]([CH:1]([OH:3])[CH3:2])=[CH:13][C:8]=1[C:9]([O:11][CH3:12])=[O:10]
Reactant: COC(=O)c1cc(C(C)=O)c(OC)cc1OC
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1cc(C(C)O)c(OC)cc1OC
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A 1.00 g portion of methyl 5-acetyl-2,4-dimethoxybenzoate was dissolved in 10 ml of methanol, and 0.24 g of sodium borohydride was added in small portions. After 10 minutes of stirring at room temperature, 1N hydrochloric acid aqueous solution was added thereto, and the thus precipitated product of interest was collected by filtration, washed with water and then dried under a reduced pressure to give 0.90 g of methyl 2,4-dimethoxy-5-(1-hydroxy)ethylbenzoate.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][O:9][CH:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1.[N+:16]([C:19]1[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[C:21]([C:29]([F:32])([F:31])[F:30])[CH:20]=1)([O-:18])=[O:17]>C(Cl)Cl>[CH3:8][O:9][CH:10]1[CH2:15][CH2:14][N:13]([S:25]([C:22]2[CH:23]=[CH:24][C:19]([N+:16]([O-:18])=[O:17])=[CH:20][C:21]=2[C:29]([F:30])([F:31])[F:32])(=[O:27])=[O:26])[CH2:12][CH2:11]1
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)c(C(F)(F)F)c1
Reactant: COC1CCNCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC1CCN(S(=O)(=O)c2ccc([N+](=O)[O-])cc2C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Triethylamine (1.0 g) and 4-methoxypiperidine (1.15 g) were added to a solution of 4-nitro-2-trifluoromethyl-benzene sulphonyl chloride (2.89 g) in methylene chloride (40 ml). The mixture was stirred at 25°C. for 2 hours and then evaporated to dryness in vacuo. The residual oil was triturated with 1:1 aqueous isopropanol and the resulting solid was recrystallized from isopropanol to give 1-(4-methoxypiperidinosulphonyl)-4-nitro-2-trifluoromethyl-benzene, m.p. 141°-143°C.
Reaction SMILES: C[Si](C)(C)[O:3][C:4]1[N:13]=[C:12]([O:14][Si](C)(C)C)[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1.[Br:21][CH2:22][CH2:23][CH2:24]Br.C(=O)(O)[O-].[Na+]>>[Br:21][CH2:22][CH2:23][CH2:24][N:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:12](=[O:14])[NH:13][C:4]1=[O:3]
Reactant: BrCCCBr
Reactant: C[Si](C)(C)Oc1nc(O[Si](C)(C)C)c2ccccc2n1
Agent: O=C([O-])O
Agent: [Na+]
Product: O=c1[nH]c(=O)n(CCCBr)c2ccccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 25.1 %

Procedure:
A mixture of 2,4-bis(trimethylsiloxy)-quinazoline (9.14 g) and 1,3-dibromopropane (30 g) was stirred for 2 hours at 130°-140° C. The reaction mixture was cooled at ambient temperature and a mixture of ice-water and saturated sodium bicarbonate aqueous solution was added to the reaction mixture and then the mixture was stirred vigorously to give precipitates. After the mixture was suspended with chloroform, the precipitates were collected by filtration. The precipitates were washed with water and with chloroform respectively and then dried to give 1-(3-bromopropyl)-2,4(1H, 3H)-quinazolinedione (2.12 g) as a crystal, which was used in the next step without purification. m.p. 159°-170° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:13]([C:14]2[NH:15][C:16]([C:19]3[CH:24]=[CH:23][C:22]([Br:25])=[CH:21][CH:20]=3)=[CH:17][N:18]=2)[CH:12]2[CH2:26][CH:9]1CC2)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(O[C:32]([N:34]1C(C(=O)NCC(C2C=CC(Br)=CC=2)=O)C2CC1CC2)=O)(C)(C)C>>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH:26]([C:32]#[N:34])[CH2:12][CH:13]1[C:14]1[NH:15][C:16]([C:19]2[CH:24]=[CH:23][C:22]([Br:25])=[CH:21][CH:20]=2)=[CH:17][N:18]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1C2CCC(C2)C1C(=O)NCC(=O)c1ccc(Br)cc1
Reactant: CC(C)(C)OC(=O)N1C2CCC(C2)C1c1ncc(-c2ccc(Br)cc2)[nH]1
Product: CC(C)(C)OC(=O)N1CC(C#N)CC1c1ncc(-c2ccc(Br)cc2)[nH]1

Procedure:
Title compound was prepared according to the method employed to prepare 3-[5-(4-Bromo-phenyl)-1H-imidazol-2-yl]-2-aza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (Example AS), and substituting 2-[2-(4-Bromo-phenyl)-2-oxo-ethylcarbamoyl]-4-cyano-pyrrolidine-1-carboxylic acid tert-butyl ester for 3-[2-(4-bromo-phenyl)-2-oxo-ethylcarbamoyl]-2-aza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester.
Reaction SMILES: [F:1][C:2]1[CH:31]=[C:30]([N+:32]([O-])=O)[CH:29]=[CH:28][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([C:14]3[N:19]=[CH:18][C:17]([CH2:20][N:21]4[C:25](=[O:26])[CH2:24][CH2:23][C:22]4=[O:27])=[CH:16][CH:15]=3)[S:13][C:6]=12.[NH4+].[Cl-]>CO.O.[Zn]>[NH2:32][C:30]1[CH:29]=[CH:28][C:3]([O:4][C:5]2[CH:10]=[CH:9][N:8]=[C:7]3[CH:11]=[C:12]([C:14]4[N:19]=[CH:18][C:17]([CH2:20][N:21]5[C:22](=[O:27])[CH2:23][CH2:24][C:25]5=[O:26])=[CH:16][CH:15]=4)[S:13][C:6]=23)=[C:2]([F:1])[CH:31]=1
Reactant: O=C1CCC(=O)N1Cc1ccc(-c2cc3nccc(Oc4ccc([N+](=O)[O-])cc4F)c3s2)nc1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CO
Solvent: O
Product: Nc1ccc(Oc2ccnc3cc(-c4ccc(CN5C(=O)CCC5=O)cn4)sc23)c(F)c1
Temperature: 25 °C
Yield: 85.4 %

Procedure:
To a suspension of 138 (100 mg, 0.209 mmol) in MeOH (10 mL) was added zinc (109 mg, 1.672 mmol) and NH4Cl (44.7 mg, 0.836 mmol) in water (1 mL) and the reaction mixture was heated to reflux for 48 hrs, cooled to RT and concentrated. The crude product was dissolved in MeOH/DCM and washed with water. The organic phase was collected, dried over anhydrous Na2SO4, filtered and concentrated to afford title compound 139 (80 mg, 85% yield) that was used without additional purification. MS (m/z)=448.47 (M+H).
Reaction SMILES: [K].[OH:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.I[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][OH:25].C1OCCOCCOCCOCCOCCOC1>C1(C)C=CC=CC=1>[OH:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=2)=[CH:7][CH:8]=1
Reactant: O=[N+]([O-])c1ccc(-c2ccc(O)cc2)cc1
Reactant: OCCCCCCI
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K]
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1ccc(-c2ccc(OCCCCCCO)cc2)cc1
Temperature: 25 °C

Procedure:
To 500 ml of toluene in a one liter round bottom flask, fitted with a condenser and magnetic stirrer, are added 7.6 g (0.03M) of the potassium salt of 4-hydroxy-4'-nitrobiphenyl, 4.9 g (0.035M) of 6-iodo-1-hexanol, and 0.5 g of 18-crown-6 ether. The mixture is refluxed for about 20 hours until all of the potassium salt has dissolved and reacted as evidenced by the absence of the blue crystalline solid. The solution is filtered hot, and then cooled to room temperature. After solvent removal, the solid residue is recrystallized from ethanol to yield a purified product, m.p. 117°-119° C.
Reaction SMILES: C[O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])(=[O:12])=[O:11])[CH2:7][N:6]1[C:20]1[S:21][C:22]([C:25]([F:28])([F:27])[F:26])=[N:23][N:24]=1)=[O:4].[OH-].[Li+]>>[Cl:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[S:10]([C@H:8]1[CH2:7][N:6]([C:20]2[S:21][C:22]([C:25]([F:27])([F:26])[F:28])=[N:23][N:24]=2)[C@H:5]([C:3]([OH:4])=[O:2])[CH2:9]1)(=[O:11])=[O:12]
Reactant: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2Cl)CN1c1nnc(C(F)(F)F)s1
Agent: [Li+]
Agent: [OH-]
Product: O=C(O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2Cl)CN1c1nnc(C(F)(F)F)s1

Procedure:
In analogy to the procedure described in example 253e, (2S,4R)-4-(2-chloro-benzenesulfonyl)-1-(5-trifluoromethyl-[1,3,4]thiadiazol-2-yl)-pyrrolidine-2-carboxylic acid methyl ester was saponified in the presence of lithium hydroxide to give the title compound as yellow oil. MS (ESI): m/z=442.0 [M+H]+.
Reaction SMILES: N1(O[C:11]2[N:16]=[C:15]([NH:17][C:18]3[CH:26]=[CH:25][CH:24]=[C:23]4[C:19]=3[CH:20]=[CH:21][N:22]4[CH3:27])[C:14]([C:28]([NH2:30])=[O:29])=[CH:13][N:12]=2)C2C=CC=CC=2N=N1.[NH2:31][C@@H:32]1[CH2:37][CH2:36][CH2:35][CH2:34][C@@H:33]1[NH:38]C(=O)OCCCC.CCN(C(C)C)C(C)C>>[NH2:31][C@H:32]1[CH2:37][CH2:36][CH2:35][CH2:34][C@H:33]1[NH:38][C:11]1[N:16]=[C:15]([NH:17][C:18]2[CH:26]=[CH:25][CH:24]=[C:23]3[C:19]=2[CH:20]=[CH:21][N:22]3[CH3:27])[C:14]([C:28]([NH2:30])=[O:29])=[CH:13][N:12]=1
Reactant: CCCCOC(=O)N[C@H]1CCCC[C@H]1N
Reactant: Cn1ccc2c(Nc3nc(On4nnc5ccccc54)ncc3C(N)=O)cccc21
Solvent: CCN(C(C)C)C(C)C
Product: Cn1ccc2c(Nc3nc(N[C@@H]4CCCC[C@@H]4N)ncc3C(N)=O)cccc21
Temperature: 80 °C
Yield: 22.1 %

Procedure:
To a solid of 2-(1H-benzo[d][1,2,3]triazol-1-yloxy)-4-(1-methyl-1H-indol-4-ylamino)pyrimidine-5-carboxamide (100 mg, 0.25 mmol) in vial was added ten butyl (1S,2R)-2-aminocyclohexylcarbamate (0.3 M solution in NMP, 1.25 mL, 0.375 mmol) and DIPEA (0.09 mL, 0.5 mmol). It was heated at 80° C. for 2 h, cooled and purified by preparative HPLC to give 2-((1R,2S)-2-aminocyclohexylamino)-4-(1-methyl-1H-indol-4-ylamino)pyrimidine-5-carboxamide (21 mg). MS found for C20H25N2O as (M+H)+ 380.4. UV: λ=219.2, 241.6, 336.7.
Reaction SMILES: Cl[C:2]1[C:7](=[O:8])[C:6]([Cl:9])=[N:5][S:4][N:3]=1.[OH:10][C:11]1[CH:12]=[N:13][C:14]([CH3:17])=[CH:15][CH:16]=1.C(N(CC)CC)C>O1CCCC1>[Cl:9][C:6]1[C:7](=[O:8])[C:2]([O:10][C:11]2[CH:12]=[N:13][C:14]([CH3:17])=[CH:15][CH:16]=2)=[N:3][S:4][N:5]=1
Reactant: O=c1c(Cl)nsnc1Cl
Reactant: Cc1ccc(O)cn1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1ccc(Oc2nsnc(Cl)c2=O)cn1
Yield: 77.2 %

Procedure:
This compound was prepared in the manner of Example 3, using 14.6 grams (0.08 mole) of 3,5-dichloro-4H-1,2,6-thiadiazin-4-one, 8.7 grams (0.08 mole) of 3-hydroxy-6-methylpyridine and 8.9 grams (0.088 mole) of triethylamine in 300 ml of tetrahydrofuran. The crude product was recrystallized from ethanol to give 15.8 grams (77%) of 3-chloro-5-(6-methyl-3-pyridyloxy)-4H-1,2,6-thiadiazin-4-one; m.p. 155°-156° C.