Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS(Cl)(=O)=O.[CH2:6]([O:13][CH2:14][C@H:15]1[CH2:17][C@@H:16]1[CH2:18]O)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.O.[C-:21]#[N:22].[K+]>C1COCC1>[CH2:6]([O:13][CH2:14][C@H:15]1[CH2:17][C@@H:16]1[CH2:18][C:21]#[N:22])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: [C-]#N
Reactant: OC[C@H]1C[C@@H]1COCc1ccccc1
Agent: CS(=O)(=O)Cl
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: N#CC[C@H]1C[C@@H]1COCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 74.8 %

Procedure:
Methanesulfonyl chloride (443 μL, 5.72 mmol) was added to a solution of ((1S,2S)-2-((benzyloxy)methyl)cyclopropyl)methanol (1.00 g, 5.20 mmol) and TEA (797 μL, 5.72 mmol) in THF (15 mL) at 0° C., and the mixture was stirred at room temperature for 3 hr. The reaction mixture was poured into water (80 mL), and the mixture was extracted with ethyl acetate (×3). The organic layer was washed with water and brine, and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was dissolved in DMF (15 mL), and potassium cyanide (0.677 g, 10.40 mmol) was added thereto at room temperature. The reaction mixture was stirred at 60° C. for 2 hr, and poured into water (100 mL), and the mixture was extracted with ethyl acetate (×3). The organic layer was washed with water and brine, and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent gradient; 17→38% ethyl acetate/hexane) to give 2-((1R,2S)-2-((benzyloxy)methyl)cyclopropyl)acetonitrile (782 mg, 3.89 mmol, 75%) as a colorless oil.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][P:5]([OH:7])[OH:6].[I-].[O:9]1[CH2:23][CH:10]1[CH2:11][N:12]1[C:16](=[O:17])[C:15]2=[CH:18][CH:19]=[CH:20][CH:21]=[C:14]2[C:13]1=[O:22]>C[Si](C)(C)N[Si](C)(C)C.Cl>[NH2:1][CH2:2][CH2:3][CH2:4][P:5]([CH2:23][CH:10]([OH:9])[CH2:11][N:12]1[C:16](=[O:17])[C:15]2=[CH:18][CH:19]=[CH:20][CH:21]=[C:14]2[C:13]1=[O:22])(=[O:7])[OH:6]
Reactant: O=C1c2ccccc2C(=O)N1CC1CO1
Reactant: NCCCP(O)O
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: Cl
Agent: [I-]
Product: NCCCP(=O)(O)CC(O)CN1C(=O)c2ccccc2C1=O
Reaction time: 1 h

Procedure:
A suspension of 2.46 g of 3-aminopropylphosphonous acid in 20 ml of hexamethyldisilazane is heated to reflux under an inert atmosphere for 24 hours after which a clear solution results. The excess hexamethyldisilazane is removed by distillation at atmospheric pressure under a slight positive pressure of inert gas to afford a colourless oil. The oil is cooled to circa 66° and treated with 0.64 g of anhydrouszinc iodide and 4.62 g of N-(2,3-epoxypropyl)phthalimide. An exothermic reaction occurs. The reaction mixture is refluxed for 6 hours after which time thin layer chromatography indicates the reaction to be complete. The reaction mixture is filtered and the filtrate evaporated to dryness in vacuo at 40°. The residue is dissolved in water and stirred at roomtemperature for 1 hour and the water removed in vacuo to give an oily solid. This is dissolved in 25 ml of 2.0M aqueous hydrochloric acid and washed with dichloromethane and ether. Removal of the water at 40° in vacuo affords a brown solid which is purified by ion-exchange chromatography on DOWEX® 50 W ×8 (14-40 mesl) to give 3-aminopropyl(2-hydroxy-3-phthalimido-propyl) phosphinic acid, m.p. 268°-71°, as a white solid.
Reaction SMILES: C(O)(=O)/C=C/C(O)=O.[CH3:9][CH:10]1[CH2:15][C:14]([C:16]2[C:24]3[O:23][CH:22]=[CH:21][C:20]=3[CH:19]=[C:18]([F:25])[CH:17]=2)=[CH:13][CH2:12][NH:11]1.C(O)(=O)/C=C/C(O)=O.CC1C=C(C2C3OC=CC=3C=C(F)C=2)CCN1>[Pd].C(O)C>[CH3:9][CH:10]1[CH2:15][CH:14]([C:16]2[C:24]3[O:23][CH:22]=[CH:21][C:20]=3[CH:19]=[C:18]([F:25])[CH:17]=2)[CH2:13][CH2:12][NH:11]1
Reactant: CC1CC(c2cc(F)cc3ccoc23)=CCN1
Agent: [Pd]
Agent: CC1C=C(c2cc(F)cc3ccoc23)CCN1
Agent: O=C(O)/C=C/C(=O)O
Solvent: CCO
Product: CC1CC(c2cc(F)cc3ccoc23)CCN1
Reaction time: 5 h
Yield: 79.1 %

Procedure:
A mixture of 0.045 gm (0.13 mMol) 2-methyl-4-(5-fluorobenzofur-7-yl)-1,2,3,6-tetrahydropyridine fumarate and 2-methyl-4-(5-fluorobenzofur-7-yl)-1,2,5,6-tetrahydropyridine fumarate and 0.010 gm 10% palladium on carbon in 5 mL ethanol was hydrogenated at 1 atmosphere at room temperature for 5 hours. The reaction mixture was filtered through a pad of celite. The pad was rinsed with ethanol and the filtrate was concentrated under reduced pressure. The residue was subjected to ion exchange chromatography on an SCX column, eluting with methanol followed by 0.5N ammonia in methanol. Fractions containing product were combined and concentrated under reduced pressure to provide 0.024 gm (79%) 2-methyl-4-(5-fluorobenzofur-7-yl)piperidine. This was dissolved in 5 mL ethanol and the solution was heated to reflux. To this solution were added 0.007 gm (0.06 mMol) fumaric acid. After mixing for about 5 minutes, the reaction mixture was diluted with diethyl ether. The mixture was concentrated under reduced pressure and the residue dried at 60° C. under vacuum for about 15 hours to provide 0.013 gm of the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH:11]2[CH2:12][CH2:13][CH:7]1[CH2:8][CH:9]([N:14]1[CH2:19][CH2:18][CH:17]([NH2:20])[CH2:16][CH2:15]1)[CH2:10]2)=[O:5])[CH3:2].Cl[C:22]1[N:27]=[C:26](Cl)[CH:25]=[C:24]([CH3:29])[N:23]=1.[C:30]([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[CH2:1]([O:3][C:4]([N:6]1[CH:7]2[CH2:13][CH2:12][CH:11]1[CH2:10][CH:9]([N:14]1[CH2:19][CH2:18][CH:17]([NH:20][C:26]3[CH:25]=[C:24]([CH3:29])[N:23]=[C:22]([CH3:30])[N:27]=3)[CH2:16][CH2:15]1)[CH2:8]2)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1C2CCC1CC(N1CCC(N)CC1)C2
Reactant: O=C([O-])[O-]
Reactant: Cc1cc(Cl)nc(Cl)n1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)N1C2CCC1CC(N1CCC(Nc3cc(C)nc(C)n3)CC1)C2
Temperature: 80 °C
Reaction time: 8 h

Procedure:
The 3-(4-Amino-piperidin-1-yl)-8-aza-bicyclo[3.2.1]octane-8-carboxylic acid ethyl ester (30 mg; 0.11 mmol; 1 eq.) was dissolved in DMF (3 mL) and 2,4-dichloro-6-methyl-pyrimidine (17 mg; 1 eq.) and K2CO3 (22 mg; 1.5 eq.) was added and the reaction was heated to 80° C. and stirred under N2 overnight. The solution was diluted with H2O (10 mL) and extracted with AcOEt (2×25 mL). The organic layer was washed with brine and dried over Na2SO4, filtered, and concentrated under high vacuum to provide the product as an oil. The crude product was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([O:9][CH3:10])=[CH:4][N:3]=1.[C:11]([CH2:13][CH:14]([N:29]1[CH:33]=[C:32](B2OC(C)(C)C(C)(C)O2)[CH:31]=[N:30]1)[CH2:15][CH:16]1[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]1)#[N:12].O1CCOCC1.C(=O)([O-])[O-].[Na+].[Na+].O>CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:1][C:2]1[N:7]=[C:6]([C:32]2[CH:31]=[N:30][N:29]([CH:14]([CH2:13][C:11]#[N:12])[CH2:15][CH:16]3[CH2:17][CH2:18][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:26])[CH3:27])=[O:23])[CH2:20][CH2:21]3)[CH:33]=2)[C:5]([O:9][CH3:10])=[CH:4][N:3]=1
Reactant: COc1cnc(Cl)nc1Cl
Reactant: CC(C)(C)OC(=O)N1CCC(CC(CC#N)n2cc(B3OC(C)(C)C(C)(C)O3)cn2)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COc1cnc(Cl)nc1-c1cnn(C(CC#N)CC2CCN(C(=O)OC(C)(C)C)CC2)c1
Temperature: 100 °C
Yield: 76.7 %

Procedure:
To a mixture of 2,4-dichloro-5-methoxypyrimidine (0.967 g, 0.00540 mol), and tert-butyl 4-{3-cyano-2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]propyl}piperidine-1-carboxylate (from example 1 step 3, 2.00 g, 0.00450 mol) in 1,4-dioxane (40 mL, 0.5 mol) was added a 1 M solution of sodium carbonate (0.954 g, 0.00900 mol) in water (8.99 mL, 0.499 mol) and tetrakis(triphenylphosphine)palladium(0) (0.4 g, 0.0003 mol). The reaction mixture was heated at 100° C. overnight. After cooling to room temperature, the mixture was diluted with EtOAc, washed with water, brine, dried over MgSO4, and concentrated. The residue was purified on silica gel, eluting with 0 to 80% EtOAc in hexanes, to provide the desired product (1.59 g, 76.64%). LCMS (M+Na) 483.4.
Reaction SMILES: [C:1]1([CH:11]=[C:12]([CH2:18][CH2:19][CH2:20][O:21][CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][O:23]2)[C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1>C(O)C.[C].[Pd]>[C:1]1([CH2:11][CH:12]([CH2:18][CH2:19][CH2:20][O:21][CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][O:23]2)[C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)C(=Cc1cccc2ccccc12)CCCOC1CCCCO1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)C(CCCOC1CCCCO1)Cc1cccc2ccccc12
Yield: 99.2 %

Procedure:
3.37 g of ethyl 3-(1-naphthyl)-2-[3-(2-tetrahydropyranyloxy)propyl]-2-propenoate was dissolved in 5 ml of ethanol and hydrogenated under atmospheric pressure by means of 10% palladium carbon. The reaction mixture was subjected to filtration, the solvent of the filtrate was distilled off under reduced pressure to obtain 3.36 g of ethyl (2RS)-2-(1-naphthylmethyl)-5-(2-tetrahydropyranyloxy)pentanoate as oily substance.
Reaction SMILES: [CH2:1]([C:8]1[S:12][C:11]([NH2:13])=[N:10][C:9]=1[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N([CH2:27][CH3:28])CC)C.[C:29]1([CH3:39])[CH:34]=[CH:33][C:32]([S:35](Cl)(=[O:37])=[O:36])=[CH:31][CH:30]=1>C1COCC1>[CH2:1]([C:8]1[S:12][C:11]([N:13]([S:35]([C:32]2[CH:33]=[CH:34][C:27]([CH3:28])=[CH:30][CH:31]=2)(=[O:37])=[O:36])[S:35]([C:32]2[CH:33]=[CH:34][C:29]([CH3:39])=[CH:30][CH:31]=2)(=[O:37])=[O:36])=[N:10][C:9]=1[C:14]1[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(-c2nc(N)sc2Cc2ccccc2)cc1
Reactant: CCN(CC)CC
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: C1CCOC1
Product: COc1ccc(-c2nc(N(S(=O)(=O)c3ccc(C)cc3)S(=O)(=O)c3ccc(C)cc3)sc2Cc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 51 %

Procedure:
To a 100 ml eggplant-shaped flask were added 1.00 g (3.37 mmol) 5-benzyl-4-(4-methoxy-phenyl)-thiazol-2-ylamine prepared in Example 1, 0.68 g (6.75 mmol) triethylamine and 25 ml THF, added dropwise 1.28 g (6.74 mmol) p-tolylsulfonyl chloride which was dissolved in 5 ml THF. The resulting mixture was stirred at room temperature for 24 hours, filtered, washed with THF, the mother liquid was concentrated under a reduced pressure to a give crude product, which was recrystallized with acetone to obtain a 1.04 g product as a off-white solid in a yield of 51.0%, mp: 182-183 └. 1H-NMR (DMSO-d6, 400 MHz) δ: 2.45 (6H, s, 2×PhCH3), 3.84 (3H, s, OCH3), 4.26 (2H, s, CH2), 6.92 (2H, d, J=8.68 Hz, ArH), 7.18˜7.36 (9H, m, ArH), 7.46 (2H, d, J=8.68 Hz, ArH), 7.92 (4H, d, J=8.68 Hz, ArH); EI-MS m/e (%): 604.2 (M+, 19), 450.2 (44), 294.2 (78), 91.1 (100); HREI-MS Calcd. for C31H28N2O5S3: 604.1160. found: 604.1165. Anal. Calcd. for C31H28N2O5S3: C, 61.57; H, 4.67; N, 4.63. found: C, 61.71; H, 4.49; N, 4.82.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([Cl:12])=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[CH3:13][CH:14]1[CH2:19][NH:18][CH2:17][CH2:16][NH:15]1>>[Cl:12][C:8]1[CH:7]=[C:6]2[C:11]([C:2]([N:18]3[CH2:17][CH2:16][NH:15][CH:14]([CH3:13])[CH2:19]3)=[CH:3][CH:4]=[N:5]2)=[CH:10][CH:9]=1
Reactant: Clc1ccc2c(Cl)ccnc2c1
Reactant: CC1CNCCN1
Product: CC1CN(c2ccnc3cc(Cl)ccc23)CCN1

Procedure:
4,7-Dichloroquinoline (0.5 g, 2.5 mmol) and 2-methylpiperazine (1.25 g, 12.5 mmol) are reacted according to method A yielding the product as a brown oil.
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[K].[Cl:13][C:14]1[S:15][C:16]([CH2:19]Cl)=[CH:17][N:18]=1>CN(C=O)C>[Cl:13][C:14]1[S:15][C:16]([CH2:19][N:5]2[C:1](=[O:11])[C:2]3=[CH:10][CH:9]=[CH:8][CH:7]=[C:3]3[C:4]2=[O:6])=[CH:17][N:18]=1
Reactant: ClCc1cnc(Cl)s1
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1Cc1cnc(Cl)s1
Reaction time: 0.75 h
Yield: 80.4 %

Procedure:
To a mixture of potassium phthalimide (10.4 g) and dry DMF (100 ml) was dropwise added a solution of 2-chloro-5-(chloromethyl)thiazole (9.0 g) obtained in the same manner as in Example 2, in 10 ml of DMF in an oil bath at 20° C. over 15 min. After completion of the addition stirring was continued at 60° C. for 45 min. followed by separation of insoluble materials by filtration on celite. The filtrate was concentrated under reduced pressure. To the residue was added 100 ml of dichloromethane again followed by separation of insoluble materials by filtration and concentration of the filtrate. The residue was purified by column chromatography (eluted with dichloromethane-ethyl acetate 20:1) to give 12.0 g of N-(2-chloro-5-thiazolylmethyl)phthalimide, mp 108°-109° C.
Reaction SMILES: [C:1]1([As:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:20]1([CH3:31])[CH:25]=[CH:24][C:23]([S:26]([O:29]C)(=[O:28])=[O:27])=[CH:22][CH:21]=1>>[C:20]1([CH3:31])[CH:21]=[CH:22][C:23]([S:26]([O-:29])(=[O:27])=[O:28])=[CH:24][CH:25]=1.[CH3:20][As+:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: c1ccc([As](c2ccccc2)c2ccccc2)cc1
Reactant: COS(=O)(=O)c1ccc(C)cc1
Product: C[As+](c1ccccc1)(c1ccccc1)c1ccccc1
Product: Cc1ccc(S(=O)(=O)[O-])cc1
Reaction time: 1 h

Procedure:
A mixture of 50.0 g (0.1632 mol) of triphenylarsine and 30.4 g (0.1632 mol) of methyl p-toluenesulfonate was heated in a 125°-145° C. bath under nitrogen with stirring for 1 hr and cooled. The glassy solid was crystallized by treatment with ether, collected and dried.
Reaction SMILES: [F:1][C:2]1[CH:40]=[C:39]([F:41])[CH:38]=[C:37]([F:42])[C:3]=1[CH2:4][N:5]1[C:13]([C:14]2[CH:15]=[C:16]([C:20]#[C:21][C:22]3[CH:23]=[C:24]([CH:30]=[CH:31][CH:32]=3)[C:25]([O:27]CC)=[O:26])[CH:17]=[CH:18][CH:19]=2)=[C:12]2[C:7]([C:8]([C:33]([F:36])([F:35])[F:34])=[CH:9][CH:10]=[CH:11]2)=[N:6]1.[OH-].[Na+]>CO.C1COCC1>[F:1][C:2]1[CH:40]=[C:39]([F:41])[CH:38]=[C:37]([F:42])[C:3]=1[CH2:4][N:5]1[C:13]([C:14]2[CH:15]=[C:16]([C:20]#[C:21][C:22]3[CH:23]=[C:24]([CH:30]=[CH:31][CH:32]=3)[C:25]([OH:27])=[O:26])[CH:17]=[CH:18][CH:19]=2)=[C:12]2[C:7]([C:8]([C:33]([F:34])([F:35])[F:36])=[CH:9][CH:10]=[CH:11]2)=[N:6]1
Reactant: CCOC(=O)c1cccc(C#Cc2cccc(-c3c4cccc(C(F)(F)F)c4nn3Cc3c(F)cc(F)cc3F)c2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1cccc(C#Cc2cccc(-c3c4cccc(C(F)(F)F)c4nn3Cc3c(F)cc(F)cc3F)c2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.6 %

Procedure:
A solution of ethyl 3-({3-[2-(2,4,6-trifluorobenzyl)-7-(trifluoromethyl)-2H-indazol-3-yl]phenyl}ethynyl)benzoate (0.19 g, 0.33 mmol) in CH3OH-THF (1:1, v/v) containing 1.0 mL of 1 N NaOH was stirred overnight at ambient temperature, then neutralized with dilute acid and partitioned with ethyl acetate and brine. The organic phase was dried (Na2SO4) and concentrated in vacuo to give 0.15 g of the title compound as a white solid.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([C:11]([C:13]3[CH:18]=[CH:17][N:16]=[C:15]([C:19]4[C:28]5[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=5)[CH:22]=[N:21][CH:20]=4)[CH:14]=3)=[O:12])[NH:8]2)=[CH:4][N:3]=1.[CH3:29][N:30]([CH3:37])[CH:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1.CCN(C(C)C)C(C)C>CC(N(C)C)=O>[CH3:29][N:30]([CH3:37])[CH:31]1[CH2:36][CH2:35][N:34]([C:2]2[N:10]=[C:9]3[C:5]([N:6]=[C:7]([C:11]([C:13]4[CH:18]=[CH:17][N:16]=[C:15]([C:19]5[C:28]6[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=6)[CH:22]=[N:21][CH:20]=5)[CH:14]=4)=[O:12])[NH:8]3)=[CH:4][N:3]=2)[CH2:33][CH2:32]1
Reactant: CN(C)C1CCNCC1
Reactant: O=C(c1ccnc(-c2cncc3ccccc23)c1)c1nc2cnc(Cl)nc2[nH]1
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)C1CCN(c2ncc3nc(C(=O)c4ccnc(-c5cncc6ccccc56)c4)[nH]c3n2)CC1
Temperature: 120 °C

Procedure:
To a 0.5 mL DMA solution of crude (2-chloro-9H-purin-8-yl)-(2-isoquinolin-4-yl-pyridin-4-yl)-methanone (60 mg, 0.155 mmol) was added dimethyl-piperidin-4-yl-amine (199 mg, 1.55 mmol) and DIEA (270 μl, 1.55 mmol). The mixture was heated to 120° C. for 1 hour. The mixture was then cooled and evaporated to dryness. Purification by preparative LCMS gave the title compound. HRMS m/z 479.2329 (M+H)+.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:15])/[CH:10]=[CH:11]/N(C)C)=[C:5]([OH:16])[CH:4]=1>ClCCl>[Br:2][C:3]1[CH:4]=[C:5]2[C:6]([C:9](=[O:15])[CH:10]=[CH:11][O:16]2)=[CH:7][CH:8]=1
Reactant: CN(C)/C=C/C(=O)c1ccc(Br)cc1O
Agent: Cl
Solvent: ClCCl
Product: O=c1ccoc2cc(Br)ccc12
Temperature: 25 °C
Yield: 100000 %

Procedure:
A solution of concentrated hydrochloric acid (30 mL) was added to a solution of (E)-1-(4-bromo-2-hydroxyphenyl)-3-(dimethylamino)prop-2-en-1-one (10.4 g, 38.5 mmol) in dichloromethane (250 mL). The mixture was heated at reflux for 30 minutes and cooled to room temperature. The aqueous phase was extracted with dichloromethane (20 mL). The combined organic phases were washed with saturated sodium bicarbonate (50 mL), dried over sodium sulfate and filtered. The solvent was removed under reduced pressure to yield 7-bromo-4H-chromen-4-one (8.7 g, 38.5 mol, 100%).
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]([C:5]1[CH:6]=[CH:7][C:8]([OH:16])=[C:9]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH:10]=1)[OH:4].[CH2:17]([O:24][C:25]([C@H:27]1[CH2:31][CH2:30][CH2:29][N:28]1[S:32]([C:35]1[CH:40]=[CH:39][C:38]([N:41]2[CH2:46][CH2:45][C:44](=O)[CH2:43][CH2:42]2)=[CH:37][CH:36]=1)(=[O:34])=[O:33])=[O:26])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[CH2:17]([O:24][C:25]([C@H:27]1[CH2:31][CH2:30][CH2:29][N:28]1[S:32]([C:35]1[CH:36]=[CH:37][C:38]([N:41]2[CH2:46][CH2:45][CH:44]([NH:1][CH2:2][C@H:3]([OH:4])[C:5]3[CH:6]=[CH:7][C:8]([OH:16])=[C:9]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH:10]=3)[CH2:43][CH2:42]2)=[CH:39][CH:40]=1)(=[O:33])=[O:34])=[O:26])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: O=C1CCN(c2ccc(S(=O)(=O)N3CCC[C@@H]3C(=O)OCc3ccccc3)cc2)CC1
Reactant: CS(=O)(=O)Nc1cc([C@@H](O)CN)ccc1O
Product: CS(=O)(=O)Nc1cc([C@@H](O)CNC2CCN(c3ccc(S(=O)(=O)N4CCC[C@@H]4C(=O)OCc4ccccc4)cc3)CC2)ccc1O

Procedure:
The title compound was prepared from N-[5-((1R)-2-Amino-1-hydroxy-ethyl)-2-hydroxy-phenyl]-methanesulfonamide and Reference Example 23, (2R)-1-[4-(4-oxo-piperidin-1-yl)-benzenesulfonyl]-pyrrolidine-2-carboxylic acid benzyl ester, according to the procedure of Example 1 as a white solid; mp 62-69° C.; 1H NMR (300 MHz, DMSO-d6) δ 1.20-1.40 (m, 2H), 1.40-1.90 (m, 6H), 2.50-3.20 (m, 5H), 3.75-3.85 (m, 2H), 4.15 (dd, 1H), 4.40-4.50 (m, 1H), 5.19 (s, 2H), 6.80 (d, 1H), 6.92 (d, 3H), 7.15 (d, 1H), 7.40-7.50(m, 5H), 7.52 (d, 2H); MS (ES) m/z: 673.1.1 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH:22]3[CH2:24][CH2:23]3)[C:10](=[O:21])[N:11]([S:13]([C:16]3[NH:20][N:19]=[CH:18][N:17]=3)(=[O:15])=[O:14])[N:12]=2)=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.[F:34][C:35]([F:45])([F:44])[C:36]1[CH:43]=[CH:42][CH:41]=[CH:40][C:37]=1[CH2:38]Br>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]([CH:22]3[CH2:24][CH2:23]3)[C:10](=[O:21])[N:11]([S:13]([C:16]3[N:20]([CH2:38][C:37]4[CH:40]=[CH:41][CH:42]=[CH:43][C:36]=4[C:35]([F:34])([F:44])[F:45])[N:19]=[CH:18][N:17]=3)(=[O:15])=[O:14])[N:12]=2)=[CH:6][CH:7]=1
Reactant: FC(F)(F)c1ccccc1CBr
Reactant: O=c1n(S(=O)(=O)c2ncn[nH]2)nc(-c2ccc(Cl)cc2)n1C1CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=c1n(S(=O)(=O)c2ncnn2Cc2ccccc2C(F)(F)F)nc(-c2ccc(Cl)cc2)n1C1CC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
37 mg (0.10 mmol) of the compound from Example 93A were dissolved in 3 ml of dichloromethane, and 21 μl (0.13 mmol) of N,N-diisopropylethylamine were added. 30 mg (0.13 mmol) of 2-(trifluoromethyl)benzyl bromide dissolved in 1 ml of dichloromethane were then added, and the mixture was stirred at RT for 48 h. For work-up, the mixture was concentrated under reduced pressure and the crude product was purified chromatographically [Method 19]. This gave 33 mg (63% of theory) of the target compound.
Reaction SMILES: [C:1]1([N:7]2[C:11]3([CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)[C:10](=[O:17])[NH:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:18]1([CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][C:25]2=O)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C[Si]([C:35]#[N:36])(C)C.[OH-].[Na+]>CC(O)=O>[O:17]=[C:10]1[C:11]2([CH2:12][CH2:13][N:14]([C:25]3([C:35]#[N:36])[CH2:26][CH2:27][CH2:28][CH2:29][CH:24]3[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH2:15][CH2:16]2)[N:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:8][NH:9]1
Reactant: O=C1CCCCC1c1ccccc1
Reactant: O=C1NCN(c2ccccc2)C12CCNCC2
Reactant: C[Si](C)(C)C#N
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: N#CC1(N2CCC3(CC2)C(=O)NCN3c2ccccc2)CCCCC1c1ccccc1
Temperature: 80 °C

Procedure:
To a mixture of 0.26 g (1.15 mmol) 1-phenyl-1,3,8-triaza-spiro[4.5]decan-4-one in 2 ml AcOH were added 0.2 g (1.15 mmol) rac-2-phenylcyclohexanone followed by the dropwise addition of 0.86 ml (5.75 mmol) trimethylsilyl cyanide. The resulting mixture was heated to 80° C. overnight. The reaction mixture was poured onto 200 ml iced sodium hydroxide (25%,) and the resulting colorless solid filtered off. The solid was dissolved in 50 ml dichloromethane and washed with 40 ml water, dried over Na2SO4, filtered and evaporated: 52 mg 1-(4-oxo-1-phenyl-1,3,8-triaza-spiro[4.5]dec-8-yl)-2-phenyl-cyclohexane-carbonitrile as colorless solid; MS (ISP): 415.4 MH+.
Reaction SMILES: CS(C1C=CC(N2CCCC2)=C(C=1)C(O)=O)(=O)=O.Cl[C:20]1[CH:28]=[CH:27][C:26]([S:29]([CH2:32][CH3:33])(=[O:31])=[O:30])=[CH:25][C:21]=1[C:22]([OH:24])=[O:23].[NH:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1>>[CH2:32]([S:29]([C:26]1[CH:27]=[CH:28][C:20]([N:34]2[CH2:39][CH2:38][O:37][CH2:36][CH2:35]2)=[C:21]([CH:25]=1)[C:22]([OH:24])=[O:23])(=[O:31])=[O:30])[CH3:33]
Reactant: C1COCCN1
Reactant: CCS(=O)(=O)c1ccc(Cl)c(C(=O)O)c1
Agent: CS(=O)(=O)c1ccc(N2CCCC2)c(C(=O)O)c1
Product: CCS(=O)(=O)c1ccc(N2CCOCC2)c(C(=O)O)c1
Yield: 77 %

Procedure:
The title compound was synthesised according to the procedure described for the synthesis of 5-Methanesulfonyl-2-pyrrolidin-1-yl-benzoic acid from 2-Chloro-5-(ethane-2-sulfonyl)-benzoic acid and morpholine and obtained in 77% yield. MS (m/e): 298.2 (MH−, 100%).
Reaction SMILES: [H-].[Li+].[O:3]=[C:4]1[C:9]([C:10]([O:12][CH3:13])=[O:11])=[CH:8][CH:7]=[CH:6][NH:5]1.I[CH3:15]>CN(C=O)C.CCOC(C)=O>[CH3:15][N:5]1[CH:6]=[CH:7][CH:8]=[C:9]([C:10]([O:12][CH3:13])=[O:11])[C:4]1=[O:3]
Reactant: CI
Reactant: COC(=O)c1ccc[nH]c1=O
Agent: [H-]
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1cccn(C)c1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
LiH (10 mg, 1.3 mmol) was added to the solution of methyl 2-oxo-1,2-dihydropyridine-3-carboxylate (0.10 g, 0.65 mmol) in DMF (3 mL) at 0° C. After stirring for 30 minutes, iodomethane (0.08 mL, 1.30 mmol) was added to the reaction mixture at the temperature, and the reaction was warmed to room temperature. After stirring for 3 days, the reaction mixture was diluted with EtOAc, quenched with ice water, extracted with EtOAc, dried over MgSO4, and concentrated to give the desired product.