Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:8][CH3:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.ClCCCl.[Br:20]Br.N1C=CC=CC=1>C1(C)C=CC=CC=1>[Br:20][C:8]([CH3:9])=[C:7]([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC=C(c1ccccc1)c1ccccc1
Reactant: BrBr
Solvent: c1ccncc1
Solvent: ClCCCl
Solvent: Cc1ccccc1
Product: CC(Br)=C(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 53.1 %

Procedure:
Into a reactor were introduced 19.4 g (100 mmol) of the 1,1-diphenylpropene and 78 mL of 1,2-dichloroethane under a nitrogen atmosphere. The contents were cooled to 0° C., and 15.9 g (100 mmol) of bromine was gradually added dropwise thereto. The resultant mixture was stirred at room temperature for 1 hour. Thereafter, 32.4 mL (400 mmol) of pyridine and 156 mL of toluene were added thereto and this mixture was stirred at 80° C. for 3 hours. After being cooled, the reaction mixture was washed with saturated aqueous sodium hydrogen carbonate solution and saturated aqueous sodium chloride solution and then dried with anhydrous magnesium sulfate. Thereafter, the solvent was removed under reduced pressure. The concentrate was purified by column chromatography and then recrystallized from methanol to obtain 14.5 g (53%) of the target compound as white crystals.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:6]=[C:7]([CH:41]=[CH:42][C:43]=1[OH:44])[C:8]([NH:10][C@H:11]([B:28]1[O:36][CH:35]2[C:30]([CH3:40])([CH:31]3[CH2:37][CH:33]([CH2:34]2)[C:32]3([CH3:39])[CH3:38])[O:29]1)[CH2:12][C:13]1[C:14]([O:26][CH3:27])=[C:15]([CH:23]=[CH:24][CH:25]=1)[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[O:9])(=[O:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].Br[CH2:52][CH2:53][NH:54]C(=O)OC(C)(C)C.O>CN(C=O)C>[C:1]([O:4][C:5]1[CH:6]=[C:7]([CH:41]=[CH:42][C:43]=1[O:44][CH2:52][CH2:53][NH2:54])[C:8]([NH:10][C@H:11]([B:28]1[O:36][CH:35]2[C:30]([CH3:40])([CH:31]3[CH2:37][CH:33]([CH2:34]2)[C:32]3([CH3:39])[CH3:38])[O:29]1)[CH2:12][C:13]1[C:14]([O:26][CH3:27])=[C:15]([CH:23]=[CH:24][CH:25]=1)[C:16]([O:18][C:19]([CH3:21])([CH3:20])[CH3:22])=[O:17])=[O:9])(=[O:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NCCBr
Reactant: COc1c(C[C@H](NC(=O)c2ccc(O)c(OC(C)=O)c2)B2OC3CC4CC(C4(C)C)C3(C)O2)cccc1C(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1c(C[C@H](NC(=O)c2ccc(OCCN)c(OC(C)=O)c2)B2OC3CC4CC(C4(C)C)C3(C)O2)cccc1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To tert-butyl 3-((2R)-2-(3-acetoxy-4-hydroxybenzamido)-2-(2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.02,6]dec-4-yl)ethyl)-2-methoxybenzoate (100 mg from step 1) in DMF (3 mL) was added K2CO3 (100 mg) followed by tert-butyl 2-bromoethylcarbamate (100 mg). The resulting reaction mixture was stirred at room temperature overnight. Water was added to the reaction mixture and extracted with EtOAc three times. The combined organic phases were dried and concentrated to afford the product which was carried on to the next step without further purification.
Reaction SMILES: [CH:1]1([O:4][N:5]=[C:6]([C:45]2[N:46]=[C:47]([NH:50]C=O)[S:48][CH:49]=2)[C:7]([NH:9][C@@H:10]2[C:43](=[O:44])[N:12]3[C:13]([C:27]([O:29][CH:30]([C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)[C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)=[O:28])=[C:14]([CH2:17][S:18]/[CH:19]=[CH:20]\[C:21]4[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=4)[CH2:15][S:16][C@H:11]23)=[O:8])[CH2:3][CH2:2]1.Cl.C(OCC)(=O)C.C(=O)(O)[O-].[Na+]>CO>[NH2:50][C:47]1[S:48][CH:49]=[C:45]([C:6](=[N:5][O:4][CH:1]2[CH2:3][CH2:2]2)[C:7]([NH:9][C@@H:10]2[C:43](=[O:44])[N:12]3[C:13]([C:27]([O:29][CH:30]([C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)[C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=4)=[O:28])=[C:14]([CH2:17][S:18]/[CH:19]=[CH:20]\[C:21]4[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=4)[CH2:15][S:16][C@H:11]23)=[O:8])[N:46]=1
Reactant: O=CNc1nc(C(=NOC2CC2)C(=O)N[C@@H]2C(=O)N3C(C(=O)OC(c4ccccc4)c4ccccc4)=C(CS/C=C\c4cccnc4)CS[C@H]23)cs1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Product: Nc1nc(C(=NOC2CC2)C(=O)N[C@@H]2C(=O)N3C(C(=O)OC(c4ccccc4)c4ccccc4)=C(CS/C=C\c4cccnc4)CS[C@H]23)cs1
Temperature: 35 °C
Yield: 63.4 %

Procedure:
To a suspension of benzhydryl 7β-[2-cyclopropyloxyimino-2-(2-formamidothiazol-4-yl)acetamido]-3-[(Z)-2-(3-pyridyl)vinylthiomethyl]-3-cephem-4-carboxylate (syn isomer) (1.32 g) in methanol (30 ml) was added concentrated hydrochloric acid (0.44 ml) and the mixture was stirred at 35° C. for an hour. The mixture was poured into a mixture of ethyl acetate and ice-water and adjusted to pH 7 with saturated aqueous solution of sodium bicarbonate. The organic layer was separated, washed with saturated aqueous solution of sodium chloride and water successively and concentrated in vacuo to give benzhydryl 7β-[2-(2-aminothiazol-4-yl)-2-(cyclopropyloxyimino)acetamido]-3-[(Z)-2-(3-pyridyl)vinylthiomethyl]-3-cephem-4-carboxylate (syn isomer) (806 mg).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH2:10][CH2:11][CH:12]2[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]2)[N:5]=[CH:4][C:3]=1[C:19]1[NH:23]C2C=CC(F)=C(C)C=2N=1.[CH3:30][O-:31].[Na+]>CO>[CH3:30][O:31][C:2]1[C:3]([C:19]#[N:23])=[CH:4][N:5]=[C:6]([O:8][CH2:9][CH2:10][CH2:11][CH:12]2[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]2)[CH:7]=1
Reactant: Cc1c(F)ccc2[nH]c(-c3cnc(OCCCC4CCN(C)CC4)cc3Cl)nc12
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1cc(OCCCC2CCN(C)CC2)ncc1C#N
Temperature: 25 °C
Yield: 100 %

Procedure:
A solution of 4-chloro-6-[3-(1-methyl-piperidin-4-yl)-propoxy]-nicotinonitrile (Example 115) in methanol (0.2 M) was treated with sodium methoxide (4 equiv) at reflux temperature for 4 h. The mixture was cooled to rt, diluted with satd. aq. NaHCO3, and extracted with chloroform. The organic extract was dried (Na2SO4), filtered, and concentrated to yield 4-methoxy-6-[3-(1-methyl-piperidin-4-yl)-propoxy]-nicotinonitrile (100%). This intermediate was converted to the title compound according to Example 115. MS (electrospray): mass calculated for C23H30ClN4O2, 394.24. m/z found, 395.4 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:7]=[C:6]([C:8]2[NH:16][C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[CH:9]=2)[NH:5][C:4]=1[CH:17]=O.[CH3:19][C:20]1[NH:21][CH:22]=[C:23]([CH3:25])[CH:24]=1.Cl>CO.CCOCC>[CH3:25][C:23]1[CH:24]=[C:20]([CH3:19])[NH:21][C:22]=1/[CH:17]=[C:4]1\[N:5]=[C:6]([C:8]2[NH:16][C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[CH:9]=2)[CH:7]=[C:3]\1[O:2][CH3:1]
Reactant: COc1cc(-c2cc3cccnc3[nH]2)[nH]c1C=O
Reactant: Cc1c[nH]c(C)c1
Agent: Cl
Solvent: CCOCC
Solvent: CO
Product: COC1=CC(c2cc3cccnc3[nH]2)=N/C1=C\c1[nH]c(C)cc1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 75.8 %

Procedure:
To a solution of 3-methoxy-5-(1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-pyrrole-2-carbaldehyde (8 mg) and 2,4-dimethyl-1H-pyrrole (3.2 mg) in 1 mL of MeOH was added 2 small drops of a solution of 2 N HCl in ether. The dark-red reaction solution was stirred at r.t. for 1 h and then quenched with 3 mL of pH 7 sodium phosphate buffer solution. The product was extracted with 2×5 mL of EtOAc. The combined extracts were dried over Na2SO4, filtered, and concentrated. The residue was purified by Combiflash on a silica gel column eluted with a gradient up to 80% EtOAc/hexanes to give 8 mg of the title compound as a dark solid.
Reaction SMILES: C([O:3][C:4](=[O:48])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:27]=[C:26]([S:28]([CH3:31])(=[O:30])=[O:29])[CH:25]=[C:24]([C:32]3[CH:33]=[CH:34][C:35]4[S:39][CH:38]=[N:37][C:36]=4[CH:40]=3)[CH:23]=2)[C:10]=1[CH2:41][CH2:42][C:43]([O:45]CC)=[O:44])C.[OH-].[Na+]>>[S:39]1[C:35]2[CH:34]=[CH:33][C:32]([C:24]3[CH:23]=[C:22]([CH:27]=[C:26]([S:28]([CH3:31])(=[O:29])=[O:30])[CH:25]=3)[O:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][C:11]3[C:10]([CH2:41][CH2:42][C:43]([OH:45])=[O:44])=[C:9]([CH:14]=[CH:13][CH:12]=3)[O:8][CH2:7][CH2:6][CH2:5][C:4]([OH:48])=[O:3])=[CH:40][C:36]=2[N:37]=[CH:38]1
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(-c3ccc4scnc4c3)cc(S(C)(=O)=O)c2)c1CCC(=O)OCC
Agent: [Na+]
Agent: [OH-]
Product: CS(=O)(=O)c1cc(OCCCCCCc2cccc(OCCCC(=O)O)c2CCC(=O)O)cc(-c2ccc3scnc3c2)c1
Yield: 55.8 %

Procedure:
A similar procedure as described in Example 40, step 8 was used, starting from 4-[3-[6-(3-benzothiazol-5-yl-5-methanesulfonyl-phenoxy)-hexyl]-2-(2-ethoxycarbonyl-ethyl)-phenoxy]-butyric acid ethyl ester (100 mg, 0.14 mmol) and 1.0 N aqueous sodium hydroxide (1.44 mL) to afford 4-[3-[6-(3-benzothiazol-5-yl-5-methanesulfonyl-phenoxy)-hexyl]-2-(2-carboxy-ethyl)-phenoxy]-butyric acid (50 mg, 54.4%) as an amorphous white solid: ES(+)-HRMS m/e calcd for C33H37NO8S2 (M+H)+ 640.2034, found 640.2030.
Reaction SMILES: [BH4-].[Li+].Cl[Si](C)(C)C.[CH:8]1([C:11]2[N:16]=[C:15]([O:17][CH3:18])[C:14](/[CH:19]=[CH:20]/[N+:21]([O-])=O)=[CH:13][CH:12]=2)[CH2:10][CH2:9]1>C1COCC1>[CH:8]1([C:11]2[N:16]=[C:15]([O:17][CH3:18])[C:14]([CH2:19][CH2:20][NH2:21])=[CH:13][CH:12]=2)[CH2:10][CH2:9]1
Reactant: COc1nc(C2CC2)ccc1/C=C/[N+](=O)[O-]
Agent: C[Si](C)(C)Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1nc(C2CC2)ccc1CCN
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 100.2 %

Procedure:
To a stirred solution of lithium borohydride (1226 μL, 2.45 mmol) in THF was added chlorotrimethylsilane (622 μl, 4.90 mmol) dropwise. After stirring for 15 minutes, argon was bubbled through the reaction mixture for 2 minutes to eliminate any trimethylsilane in the reaction mixture. (E)-6-cyclopropyl-2-methoxy-3-(2-nitrovinyl)pyridine (135 mg, 0.613 mmol) was added (in 1 mL of THF). The reaction was heated to reflux for 2 hours, cooled to 0° C. and carefully quenched with methanol (1 mL). The reaction mixture was concentrated, diluted with dichloromethane and 20% aqueous KOH. The layers were separated and the organic layer was dried over sodium sulfate, filtered and concentrated to yield 2-(6-cyclopropyl-2-methoxypyridin-3-yl)ethanamine (118 mg, 0.614 mmol, 100% yield).
Reaction SMILES: [CH3:1][N:2]([CH3:20])[CH2:3][CH2:4][NH:5][C:6](=[O:19])[C:7]1[CH:12]=[CH:11][C:10]([NH:13][CH2:14][CH3:15])=[C:9]([N+:16]([O-])=O)[CH:8]=1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[CH2:32]([N:39]1[C:43](=[O:44])[C:42](=[C:45]2[N:49]([CH3:50])[C:48]3[CH:51]=[CH:52][CH:53]=[CH:54][C:47]=3[S:46]2)[S:41][CH2+:40]1SC)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>>[CH2:32]([N:39]1[C:43](=[O:44])[C:42](=[C:45]2[N:49]([CH3:50])[C:48]3[CH:51]=[CH:52][CH:53]=[CH:54][C:47]=3[S:46]2)[S:41][C:40]1=[N:16][C:9]1[CH:8]=[C:7]([CH:12]=[CH:11][C:10]=1[NH:13][CH2:14][CH3:15])[C:6]([NH:5][CH2:4][CH2:3][N:2]([CH3:20])[CH3:1])=[O:19])[C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: CCNc1ccc(C(=O)NCCN(C)C)cc1[N+](=O)[O-]
Reactant: CS[CH2+]1SC(=C2Sc3ccccc3N2C)C(=O)N1Cc1ccccc1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Product: CCNc1ccc(C(=O)NCCN(C)C)cc1N=C1SC(=C2Sc3ccccc3N2C)C(=O)N1Cc1ccccc1

Procedure:
In a manner similar to Example 30, intermediate N-(2-dimethylaminoethyl)-4-ethylamino-3-nitrobenzamide was hydrogenated and then condensed with 3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-2-methylthio-4-oxo-2-thiazolium p-toluenesulfonate to afford the title compound.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[CH3:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10](=[O:15])[C:9]2=[O:16]>OS(O)(=O)=O>[CH3:5][C:6]1[CH:7]=[C:8]2[C:12](=[C:13]([N+:1]([O-:4])=[O:2])[CH:14]=1)[NH:11][C:10](=[O:15])[C:9]2=[O:16]
Reactant: Cc1ccc2c(c1)C(=O)C(=O)N2
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: Cc1cc2c(c([N+](=O)[O-])c1)NC(=O)C2=O
Reaction time: 0.12 h

Procedure:
Fuming nitric acid (10 mL) was added drop wise over a period of 30 min to a solution of 5-methyl-1H-indole-2,3-dione (20 g, 0.124 mol) in conc. H2SO4 (80 mL) at −5° C., utes. The reaction mass was stirred for another 5-10 min at the same temperature and was poured into crushed ice. The precipitate was filtered and washed with chilled water several times. Finally it was dried in a vacuum oven to get 6.5 g of the required product as a yellow coloured solid.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC(=O)[NH:14][C:15]([CH3:46])([CH2:43][CH2:44][CH3:45])[CH2:16][NH:17][C:18]([C:20]1[C:21]([CH3:42])=[N:22][N:23]2[C:28]([O:29][CH2:30][C:31]3[C:36]([F:37])=[CH:35][CH:34]=[CH:33][C:32]=3[F:38])=[CH:27][C:26]([CH:39]3[CH2:41][CH2:40]3)=[CH:25][C:24]=12)=[O:19])(C)(C)C>ClCCl>[NH2:14][C:15]([CH3:46])([CH2:43][CH2:44][CH3:45])[CH2:16][NH:17][C:18]([C:20]1[C:21]([CH3:42])=[N:22][N:23]2[C:28]([O:29][CH2:30][C:31]3[C:36]([F:37])=[CH:35][CH:34]=[CH:33][C:32]=3[F:38])=[CH:27][C:26]([CH:39]3[CH2:41][CH2:40]3)=[CH:25][C:24]=12)=[O:19]
Reactant: CCCC(C)(CNC(=O)c1c(C)nn2c(OCc3c(F)cccc3F)cc(C3CC3)cc12)NC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCC(C)(N)CNC(=O)c1c(C)nn2c(OCc3c(F)cccc3F)cc(C3CC3)cc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1 ml of trifluoroacetic acid were added to a solution of 125 mg (0.2 mmol) of rac-{1-[({5-cyclopropyl-7-[(2,6-difluorobenzyl)oxy]-2-methylpyrazolo[1,5-a]pyridin-3-yl}carbonyl)amino]-2-methylpentan-2-yl}carbamic acid tert-butyl ester (Example 150A) in 4 ml of dichloromethane. The reaction mixture was stirred at room temperature for 1 h and concentrated under reduced pressure. The residue was purified by chromatography on SCX-2 silica gel (mobile phase: methanol then 20% (2 M ammonia in methanol) in dichloromethane). This gave 40 mg of the target compound (39% of theory).
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH:11]=[O:12])[CH:9]=2)[NH:4][N:3]=1.Br[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][C:16]=1[C:25]([F:28])([F:27])[F:26]>>[F:26][C:25]([F:27])([F:28])[C:16]1[CH:17]=[C:18]([C:21]([F:24])([F:22])[F:23])[CH:19]=[CH:20][C:15]=1[CH2:14][N:4]1[C:5]2[C:10](=[CH:9][C:8]([CH:11]=[O:12])=[CH:7][CH:6]=2)[C:2]([CH3:1])=[N:3]1
Reactant: Cc1n[nH]c2ccc(C=O)cc12
Reactant: FC(F)(F)c1ccc(CBr)c(C(F)(F)F)c1
Product: Cc1nn(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)c2ccc(C=O)cc12

Procedure:
1-(2,4-Bis-trifluoromethyl-benzyl)-3-methyl-1H-indazole-5-carbaldehyde was prepared from 3-Methyl-1H-indazole-5-carbaldehyde and 1-Bromomethyl-2,4-bis-trifluoromethyl-benzene following general procedure A.
Reaction SMILES: C([NH:6][C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][C:8]=1[C:16]#[C:17][C:18]([CH3:24])([CH3:23])[C:19]([O:21][CH3:22])=[O:20])(=O)CCC>C(#N)C>[CH3:23][C:18]([C:17]1[NH:6][C:7]2[C:8]([CH:16]=1)=[CH:9][C:10]([N+:13]([O-:15])=[O:14])=[CH:11][CH:12]=2)([CH3:24])[C:19]([O:21][CH3:22])=[O:20]
Reactant: CCCC(=O)Nc1ccc([N+](=O)[O-])cc1C#CC(C)(C)C(=O)OC
Solvent: CC#N
Product: COC(=O)C(C)(C)c1cc2cc([N+](=O)[O-])ccc2[nH]1
Temperature: 25 °C
Yield: 22.6 %

Procedure:
To a deoxygenated solution of methyl 4-(2-butyramido-5-nitrophenyl)-2,2-dimethylbut-3-ynoate (1.8 g, 5.4 mmol) in acetonitrile (30 mL) was added Pd(CH3CN)2Cl2(0.42 g, 1.6=mmol) under N2. The mixture was heated at reflux for 24 h. After cooling the mixture to ambient temperature, the solid was filtered off and washed with EtOAc (50 mL×3). The filtrate was evaporated under reduced pressure to give a residue, which was purified by column chromatography on silica gel (petroleum ether/ethyl acetate=30/1) to give methyl 2-methyl-2-(5-nitro-1H-indol-2-yl)propanoate (320 mg, 23%). 1 H NMR (400 MHz, CDCl3) δ 9.05(brs, 1H), 8.52(d, J=2.0 Hz, 1 H), 8.09(dd, J=2.0, 8.8 Hz, 1 H), 7.37(d, J=8.8 Hz, 1 H), 6.54(d, J=1.6 Hz, 1 H), 3.78(d, J=9.6 Hz, 3 H), 1.70(s, 6 H).
Reaction SMILES: [OH:1][C:2]1[CH:21]=[CH:20][CH:19]=[CH:18][C:3]=1[C:4]([NH:6][CH:7]([CH3:17])[CH2:8][NH:9]C(=O)OC(C)(C)C)=[O:5]>Cl.CO>[NH2:9][CH2:8][CH:7]([NH:6][C:4](=[O:5])[C:3]1[CH:18]=[CH:19][CH:20]=[CH:21][C:2]=1[OH:1])[CH3:17]
Reactant: CC(CNC(=O)OC(C)(C)C)NC(=O)c1ccccc1O
Agent: Cl
Solvent: CO
Product: CC(CN)NC(=O)c1ccccc1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 113.6 %

Procedure:
A mixture of tert-butyl 2-(2-hydroxybenzamido)propylcarbamate (2.4 g, 8.16 mmol) in saturated HCl-MeOH (50 mL) was stirred (RT, 2 h) and concentrated under reduced pressure to afford N-(1-aminopropan-2-yl)-2-hydroxybenzamide (1.8 g, 96%) as a white solid. Mass calculated for C10H14N2O2=194.23; found: [M+H]+=195.2.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[NH:13][C:14]1[C:15]2[S:23][CH2:22][CH2:21][C:16]=2[N:17]=[C:18]([Cl:20])[N:19]=1)(C)(C)C.Cl.CO>O1CCOCC1>[ClH:20].[Cl:20][C:18]1[N:19]=[C:14]([NH:13][CH:9]2[CH2:10][CH2:11][CH2:12][NH:7][CH2:8]2)[C:15]2[S:23][CH2:22][CH2:21][C:16]=2[N:17]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCC[C@@H]1Nc1nc(Cl)nc2c1SCC2
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: Clc1nc2c(c(NC3CCCNC3)n1)SCC2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 180.4 %

Procedure:
1.77 g (4.8 mmol) of tert-butyl 3-(2-chloro-6,7-dihydrothieno[3,2-d]pyrimidin-4-ylamino)piperidin-1-carboxylate (V) is placed in 21.5 mL of a 4% hydrochloric acid solution in dioxane, and methanol is added. The solution is stirred for 0.5 hours at ambient temperature, whereupon a precipitate is formed. This is suction filtered, washed with diethyl ether, and dried. 1.33 g of product (VI) (91%) is obtained.
Reaction SMILES: Br[C:2]1[N:10]([CH2:11][C:12]2[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=2[C:14]#[N:15])[C:9]2[C:8](=[O:20])[NH:7][C:6](=[O:21])[N:5]([CH3:22])[C:4]=2[N:3]=1.[NH:23]1[CH2:29][CH2:28][CH2:27][CH2:26][CH:25]([NH2:30])[CH2:24]1.C(N(CC)CC)C.O>CS(C)=O.ClCCl>[NH2:30][CH:25]1[CH2:26][CH2:27][CH2:28][CH2:29][N:23]([C:2]2[N:10]([CH2:11][C:12]3[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=3[C:14]#[N:15])[C:9]3[C:8](=[O:20])[NH:7][C:6](=[O:21])[N:5]([CH3:22])[C:4]=3[N:3]=2)[CH2:24]1
Reactant: Cn1c(=O)[nH]c(=O)c2c1nc(Br)n2Cc1ccccc1C#N
Reactant: NC1CCCCNC1
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: O
Product: Cn1c(=O)[nH]c(=O)c2c1nc(N1CCCCC(N)C1)n2Cc1ccccc1C#N
Reaction time: 4 h

Procedure:
2-(8-Bromo-3-methyl-2,6-dioxo-1,2,3,6-tetrahydropurin-7-ylmethyl)benzonitrile (79A) (181 mg, 0,5 mmol) and azepan-3-ylamine (342 mg, 3 mmol), and triethylamine (0.35 ml, 2.5 mmol) were dissolved in 20 ml of DMSO and the mixture was subjected to microwaves (method F, 100° C., 300 W) for four hours. To the reaction mixture was added 100 ml of water and 100 ml of dichloromethane, and the organic layer was separated and dried over sodium sulfate. The solvents were evaporated and the crude product was purified by preparative HPLC (method A1, Rt=6.22 min.). Evaporation of the solvent afforded the title compound as an yellow oil.
Reaction SMILES: [CH3:1][N:2]([CH3:21])[C:3]([C:6]1[CH:11]=[CH:10][C:9](B2OC(C)(C)C(C)(C)O2)=[CH:8][CH:7]=1)([CH3:5])[CH3:4].Br.[NH2:23][C:24]1[C:29]([C:30]2[CH:31]=[C:32]3[C:37](=[CH:38][CH:39]=2)[C:36](=[O:40])[NH:35][CH2:34][CH2:33]3)=[CH:28][C:27](Br)=[CH:26][N:25]=1>>[NH2:23][C:24]1[C:29]([C:30]2[CH:31]=[C:32]3[C:37](=[CH:38][CH:39]=2)[C:36](=[O:40])[NH:35][CH2:34][CH2:33]3)=[CH:28][C:27]([C:9]2[CH:8]=[CH:7][C:6]([C:3]([N:2]([CH3:1])[CH3:21])([CH3:4])[CH3:5])=[CH:11][CH:10]=2)=[CH:26][N:25]=1
Reactant: Nc1ncc(Br)cc1-c1ccc2c(c1)CCNC2=O
Reactant: CN(C)C(C)(C)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Agent: Br
Product: CN(C)C(C)(C)c1ccc(-c2cnc(N)c(-c3ccc4c(c3)CCNC4=O)c2)cc1
Yield: 11.3 %

Procedure:
General Method C was applied to N,N-dimethyl-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propan-2-amine (109 mg, 0.38 mmol) and 6-(2-amino-5-bromopyridin-3-yl)-3,4-dihydroisoquinolin-1(2H)-one hydrobromide (125 mg, 0.31 mmol) to afford 6-(2-amino-5-(4-(2-(dimethylamino)propan-2-yl)phenyl)pyridin-3-yl)-3,4-dihydroisoquinolin-1(2H)-one (14 mg, 11% yield) as a white solid after purification by flash chromatography. 1H NMR (300 MHz, DMSO-d6) δ ppm 8.32 (s, 1H), 7.81-8.11 (m, 2H), 7.37-7.79 (m, 7H), 5.87 (s, 2H), 3.41 (m, 2H), 2.85-3.10 (m, 2H), 2.11 (s, 6H), 1.30 (s, 6 H); MS (EI) m/z=401.5 [M+1]+.
Reaction SMILES: [OH:1][CH2:2][CH:3]([O:6][CH2:7][N:8]1[CH:16]=[N:15][C:14]2[C:13](=[O:17])[NH:12][C:11]([NH2:18])=[N:10][C:9]1=2)[CH2:4][OH:5]>CN(C)C1C=CN=CC=1.C(OC(=O)C)(=O)C>[C:2]([O:1][CH2:2][CH:3]([O:6][CH2:7][N:8]1[CH:16]=[N:15][C:14]2[C:13](=[O:17])[NH:12][C:11]([NH2:18])=[N:10][C:9]1=2)[CH2:4][O:5][C:13](=[O:17])[CH3:14])(=[O:1])[CH3:3]
Reactant: Nc1nc2c(ncn2COC(CO)CO)c(=O)[nH]1
Agent: CN(C)c1ccncc1
Solvent: CC(=O)OC(C)=O
Product: CC(=O)OCC(COC(C)=O)OCn1cnc2c(=O)[nH]c(N)nc21
Temperature: 25 °C
Reaction time: 72 h
Yield: 181.5 %

Procedure:
A mixture of 3.00 g of 9-(1,3-dihydroxy-2-propoxymethyl)guanine, 300 mg of 4-dimethylaminopyridine, and 100 ml of acetic anhydride was vigorously stirred for 3 days at room temperature. The acetic anhydride was removed by evaporation at reduced pressure and the residue recrystallized from methanol to give 3.62 g of 9-(1,3-diacetyloxy-2-propoxymethyl)guanine, m.p. 237°-239°.
Reaction SMILES: [C:1]12([CH2:11][C:12](Cl)=[O:13])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[NH2:15][N:16]1[C:21](=[O:22])[C:20]2[CH:23]=[C:24]([CH3:26])[S:25][C:19]=2[N:18]=[C:17]1[CH3:27]>>[C:1]12([CH2:11][C:12]([NH:15][N:16]3[C:21](=[O:22])[C:20]4[CH:23]=[C:24]([CH3:26])[S:25][C:19]=4[N:18]=[C:17]3[CH3:27])=[O:13])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: O=C(Cl)CC12CC3CC(CC(C3)C1)C2
Reactant: Cc1cc2c(=O)n(N)c(C)nc2s1
Product: Cc1cc2c(=O)n(NC(=O)CC34CC5CC(CC(C5)C3)C4)c(C)nc2s1

Procedure:
1-Adamantaneacetyl chloride and 3-amino-2,6-dimethylthieno[2,3-d]pyrimidin-4(3H)-one (Matrix) were processed using the method described in Example 42C to afford the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.54-1.76 (m, 12 H) 1.89-1.99 (m, 3 H) 2.04-2.18 (m, 2 H) 2.37 (s, 3 H) 2.5 (s, 3 H) 7.09 (s, 1 H) 10.83 (s, 1 H); MS (ESI+) m/z 372 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](=O)[NH:8][N:9]=[CH:10][CH:11]=1)=[O:5])[CH3:2].O=P(Cl)(Cl)[Cl:15]>>[CH2:1]([O:3][C:4]([C:6]1[CH:11]=[CH:10][N:9]=[N:8][C:7]=1[Cl:15])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ccn[nH]c1=O
Reactant: O=P(Cl)(Cl)Cl
Product: CCOC(=O)c1ccnnc1Cl
Temperature: 100 °C

Procedure:
A mixture of 3-oxo-2,3-dihydro-pyridazine-4-carboxylic acid ethyl ester (355 mg, 2.11 mmol) and POCl3 (6 ml) was heated to 100° C. for 1 h. The volatiles were then removed and the remaining residue was neutralized with sat. NaHCO3-solution. This mixture was extracted three times with Et2O and the combined extracts were dried (Na2SO4) and evaporated to obtain the crude title compound. The remaining brown solid (364 mg, 1.95 mmol, 92%) was used in the next reaction step without further purification. MS: m/e=187.1 [M+H+].
Reaction SMILES: [CH2:1]([N:3]1[C:7](B2OC(C)(C)C(C)(C)O2)=[CH:6][CH:5]=[N:4]1)[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[C:24]1[CH:25]=[C:26]([C:30]([O:32][CH3:33])=[O:31])[O:27][C:28]=1[CH3:29]>COCCOC.O.C(Cl)Cl.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[CH2:1]([N:3]1[C:7]([C:24]2[CH:25]=[C:26]([C:30]([O:32][CH3:33])=[O:31])[O:27][C:28]=2[CH3:29])=[CH:6][CH:5]=[N:4]1)[CH3:2]
Reactant: COC(=O)c1cc(Br)c(C)o1
Reactant: CCn1nccc1B1OC(C)(C)C(C)(C)O1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Solvent: COCCOC
Product: CCn1nccc1-c1cc(C(=O)OC)oc1C
Temperature: 72 °C
Reaction time: 2 h

Procedure:
To a 100 mL sealed flask was added 1-ethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (2.2 g, 9.91 mmol), potassium carbonate (2.84 g, 20.54 mmol), methyl 4-bromo-5-methyl-2-furancarboxylate (1.5 g, 6.85 mmol) and BIS(TRI-T-BUTYLPHOSPHINE)PALLADIUM(0) (0.175 g, 0.34 mmol) in 1,2-dimethoxyethane (6 mL) and H2O (1 mL). After stirring for 2 h at 72° C., the reaction solution was diluted with DCM (50 mL) and washed with H2O. The organic layer was dried Na2SO4, filtered and concentrated. The residue was purified on silica gel [EtOAC/hexanes, 10-30%] to give the product [1.1 g, 68.6%] as an off white solid: LC-MS (ES) m/z 235 (M+H)+.