Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.[F:55][C:56]1[CH:62]=[CH:61][C:59]([NH2:60])=[CH:58][CH:57]=1>CN(C=O)C>[F:55][C:56]1[CH:62]=[CH:61][C:59]([NH:60][C:19](=[O:21])[C:18]2[CH:22]=[CH:23][C:15]([O:14][CH2:13][C:3]3[C:4]([C:7]4[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=4)=[N:5][O:6][C:2]=3[CH3:1])=[N:16][CH:17]=2)=[CH:58][CH:57]=1
Reactant: Nc1ccc(F)cc1
Reactant: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)O)cn1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)Nc2ccc(F)cc2)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.4 %

Procedure:
To a solution of 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid (100 mg, 0.32 mmol) in DMF (2 mL) were added 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (114 mg, 0.35 mmol), N,N-diisopropyl ethyl amine (275 μL, 1.6 mmol) and 4-fluoroaniline (1 M in DMF, 0.35 mmol). The resulting reaction mixture was stirred overnight at room temperature. Concentration and purification by chromatography (SiO2, heptane:ethyl acetate=100:0 to 1:1) afforded the title compound (109 mg, 84%) which was obtained as a white solid. MS: m/e=404.4 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:39]#[N:40])=[C:6]([C:8]2[C:13]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:12][N:11]([CH:20]([CH3:37])[C:21]([NH:23][C:24]3[CH:36]=[CH:35][C:27]([C:28]([O:30]C(C)(C)C)=[O:29])=[CH:26][CH:25]=3)=[O:22])[C:10](=[O:38])[CH:9]=2)[CH:7]=1.C(O)(C(F)(F)F)=O>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:39]#[N:40])=[C:6]([C:8]2[C:13]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:12][N:11]([CH:20]([CH3:37])[C:21]([NH:23][C:24]3[CH:25]=[CH:26][C:27]([C:28]([OH:30])=[O:29])=[CH:35][CH:36]=3)=[O:22])[C:10](=[O:38])[CH:9]=2)[CH:7]=1
Reactant: CC(C(=O)Nc1ccc(C(=O)OC(C)(C)C)cc1)n1cc(OCC(F)(F)F)c(-c2cc(Cl)ccc2C#N)cc1=O
Solvent: O=C(O)C(F)(F)F
Product: CC(C(=O)Nc1ccc(C(=O)O)cc1)n1cc(OCC(F)(F)F)c(-c2cc(Cl)ccc2C#N)cc1=O

Procedure:
113 mg (0.14 mmol) of tert-butyl 4-({2-[4-(5-chloro-2-cyanophenyl)-2-oxo-5-(2,2,2-trifluoroethoxy)pyridin-1(2H)-yl]propanoyl}amino)benzoate (racemate) were hydrolysed with TFA according to General Method 2. Yield: 39 mg (purity 90%, 49% of theory)
Reaction SMILES: [S:1]1(=[O:7])(=[O:6])[CH:5]=[CH:4][CH2:3][NH:2]1.[CH3:8][O-:9].[Na+]>CO>[CH3:8][O:9][CH:4]1[CH2:5][S:1](=[O:7])(=[O:6])[NH:2][CH2:3]1
Reactant: O=S1(=O)C=CCN1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC1CNS(=O)(=O)C1
Temperature: 70 °C
Reaction time: 3 h
Yield: 13 %

Procedure:
To a solution of 2,3-dihydroisothiazole-1,1-dioxide (0.100 g, 0.8 mmol) in methanol (1 mL) was added 25% sodium methoxide in methanol (0.181 g, 0.8 mmol) and the solution stirred at 60° C. for 2 hrs and at 70° C. for 3 hrs. The mixture was concentrated and suspended in 1 N aqueous hydrochloric acid. The aqueous mixture was extracted with ethyl acetate (3×), and the organic layers dried (anhydrous sodium sulfate), filtered, and concentrated in vacuo. The crude material was purified by silica gel chromatography (0-6% methanol/methylene chloride) to give the product (0.011 g, 13%). 1H NMR (300 MHz, CDCl3) δ 4.53 (br s, 1H), 4.33-4.29 (m, 1H), 3.48-3.30 (m, 3H), 3.37 (s, 3H), 3.19-3.13 (m, 1H). 13C NMR (100 MHz, CDCl3) δ 80.8, 57.1, 53.3, 48.7.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:8])[CH2:6][NH2:7])[CH3:3].C(=O)([O-])[O-].[K+].[K+].CCOCC.[C:20]1([C:25](Cl)=[O:26])[S:24][CH:23]=[CH:22][CH:21]=1>O.C1C=CC=CC=1>[CH2:2]([O:4][C:5](=[O:8])[CH2:6][NH:7][C:25](=[O:26])[C:20]1[S:24][CH:23]=[CH:22][CH:21]=1)[CH3:3]
Reactant: CCOC(=O)CN
Reactant: O=C(Cl)c1cccs1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOCC
Solvent: c1ccccc1
Product: CCOC(=O)CNC(=O)c1cccs1
Temperature: 25 °C
Yield: 68.4 %

Procedure:
To a solution of glycine ethyl ester hydrochloride (22 g) and potassium carbonate (86 g) in water (600 ml) was added a mixture of benzene (600 ml) and ether (400 ml) and stirred at room temperature. 2-Thenoyl chloride (25 g) in benzene (100 ml) was added during a period of about 30 minutes under stirring and then the mixture was stirred for 2 hours at room temperature. The organic layer was separated and after dried over anhydrous sodium sulfate, concentrated under reduced pressure to give colorless crystals, which were recrystallized from ethanol to obtain the objective compound (23 g), mp 82°-83° C.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[C:7]([N:9]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[N:10]2)[CH:6]=[CH:5][C:4]=1[CH2:18][CH2:19][NH2:20].ON1C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.[F:40][C:41]([F:52])([F:51])[C:42]1[C:43]([C:48](O)=[O:49])=[N:44][CH:45]=[CH:46][CH:47]=1>ClCCl>[Cl:2][C:3]1[CH:8]=[C:7]([N:9]2[CH:13]=[CH:12][C:11]([C:14]([F:15])([F:16])[F:17])=[N:10]2)[CH:6]=[CH:5][C:4]=1[CH2:18][CH2:19][NH:20][C:48]([C:43]1[C:42]([C:41]([F:52])([F:40])[F:51])=[CH:47][CH:46]=[CH:45][N:44]=1)=[O:49]
Reactant: NCCc1ccc(-n2ccc(C(F)(F)F)n2)cc1Cl
Reactant: O=C(O)c1ncccc1C(F)(F)F
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCCc1ccc(-n2ccc(C(F)(F)F)n2)cc1Cl)c1ncccc1C(F)(F)F
Reaction time: 12 h

Procedure:
To a solution of 2-chloro-4-[3-(trifluoromethyl)-1H-pyrazol-1-yl]benzeneethanamine hydrochloride (1:1) (i.e. the product of Step C; 300 mg, 1.11 mmol), N-(3-dimethyl-aminopropyl)-N′-ethylcarbodiimide (297 mg, 1.66 mmol), 1-hydroxybenzotriazole (212 mg, 1.66 mmol) and N,N-diisopropylethylamine (0.9 mL, 5.55 mmol) in dichloromethane (15 mL) was added 3-(trifluoromethyl)pyridine-2-carboxylic acid (198 mg, 1.21 mmol), and the resulting mixture was stirred for 12 h. The reaction mixture was washed with water and brine, dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel eluted with 50% ethyl acetate in hexanes to afford the title compound (210 mg) as a brown solid.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([CH2:16][CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:13]([OH:15])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CI.[H-].[Na+].[CH3:29]COC(C)=O>C1COCC1.O>[CH2:1]([O:8][C:9]([N:11]([CH3:29])[C@H:12]([CH2:16][CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:13]([OH:15])=[O:14])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)CC[C@@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: CCOC(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: O
Solvent: C1CCOC1
Product: CN(C(=O)OCc1ccccc1)[C@H](CCC(=O)OC(C)(C)C)C(=O)O
Temperature: 25 °C

Procedure:
To a solution of (R)-2-(((benzyloxy)carbonyl)amino)-5-(tert-butoxy)-5-oxopentanoic acid (1.41 g, 4.18 mmol) and MeI (2.091 mL, 33.4 mmol) in THF (12.66 ml) at 0° C. was slowly added NaH (0.501 g, 12.54 mmol) and the suspension was allowed to stir while warming up to room temperature for 24 hours. The reaction mixture was cooled to 0° C. before 10 mL of EtOAc were added along with 5 mL of water to quench the excess of NaH. The crude product was partitioned between a saturated NaHCO3 aqueous solution and Et2O. The two phases were separated and the organic phase was washed with a saturated NaHCO3 solution and both aqueous extracts were combined. The aqueous solution was brought to pH 3 using a 6N HCl aqueous solution. The aqueous phase was extracted with EtOAc, the organic extracts were combined and dried over anhydrous sodium sulfate. After filtration and concentration, (R)-2-(((benzyloxy)carbonyl)(methyl)amino)-5-(tert-butoxy)-5-oxopentanoic acid was obtained as a yellow oil, 1.4 g (78%). LCMS showed the m/z of desired product, (M+Na)+ 374.
Reaction SMILES: ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C.[CH3:18][N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1.[CH:25]([C:27]1[NH:28][C:29]2[CH2:30][CH2:31][CH2:32][CH2:33][C:34]=2[C:35]=1[CH2:36][CH2:37][C:38](O)=[O:39])=[O:26]>CN(C)C=O.CO.ClCCl>[CH3:18][N:19]1[CH2:24][CH2:23][N:22]([C:38](=[O:39])[CH2:37][CH2:36][C:35]2[C:34]3[CH2:33][CH2:32][CH2:31][CH2:30][C:29]=3[NH:28][C:27]=2[CH:25]=[O:26])[CH2:21][CH2:20]1
Reactant: CN1CCNCC1
Reactant: O=Cc1[nH]c2c(c1CCC(=O)O)CCCC2
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CO
Product: CN1CCN(C(=O)CCc2c(C=O)[nH]c3c2CCCC3)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 78 %

Procedure:
1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide-hydrochloide (1.34 g, 7 mmol), anhydrous 1-hydroxybenzotriazole (0.95 g, 7 mmol), triethylamine(1.0 ml, 7.5 mmol) and N-methylpiperazine (664 μl, 6 mmol) were added to a mixture of [3-(2-formyl-4,5,6,7-tetrahydro-1H-indol-3-yl)-propionic acid] (1.1 g, 5 mmol) in 20 ml of N,N-dimethylformamide. The reaction was stirred at room temperature overnight. Thin layer chromatography (methanol: dichloromethane 5:1) showed one major spot. The reaction solution was concentrated under high vacuum over night then the residue was purified by flash chromatography and eluting with (dichloromethane: methanol 15/1, 10/1, 5/1) to give 3-[3-(4-methyl-piperazin-1-yl)-3-oxo-propyl]-4,5,6,7-tetrahydro-1H-indole-2-carbaldehyde (1.18 g, 78% yield).
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[C:11]3[CH2:19][CH2:18][NH:17][CH2:16][C:12]=3[N:13]=[CH:14][N:15]=2)=[CH:5][CH:4]=1.[C:22]1([CH3:31])[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1B(O)O.C(N(CC)CC)C>C1COCC1.CC([O-])=O.CC([O-])=O.[Cu+2]>[F:21][C:2]([F:1])([F:20])[C:3]1[CH:4]=[CH:5][C:6]([NH:9][C:10]2[C:11]3[CH2:19][CH2:18][N:17]([C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=4[CH3:31])[CH2:16][C:12]=3[N:13]=[CH:14][N:15]=2)=[CH:7][CH:8]=1
Reactant: FC(F)(F)c1ccc(Nc2ncnc3c2CCNC3)cc1
Reactant: Cc1ccccc1B(O)O
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1ccccc1N1CCc2c(ncnc2Nc2ccc(C(F)(F)F)cc2)C1
Reaction time: 6 h
Yield: 4.6 %

Procedure:
N-(4-(Trifluoromethyl)phenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-amine (100 mg, 0.34 mmol) was dissolved in anhydrous THF (2 mL). To the mixture was added o-tolylboronic acid (92 mg, 0.68 mmol), Cu(OAc)2 (124 mg, 0.68 mmol) and triethylamine (0.68 g, 0.095 mL). The mixture was agitated for 6 h and the solvent was removed under a vacuum. The residue was purified using a gradient of ethyl acetate:hexane (0-100%) to give the desired compound as reddish powder (6.0 mg, 5%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH:8][CH2:9][C:10]#[N:11])=[C:6]([S:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[C:15]=2[F:21])[N:5]=[C:4]([S:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[C:25]=2[F:31])[N:3]=1.[OH-].[K+]>CO.ClCCl>[Cl:30][C:26]1[C:25]([F:31])=[C:24]([CH2:23][S:22][C:4]2[N:5]=[C:6]([S:12][CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[C:15]=3[F:21])[C:7]3[C:2](=[N:1][C:10]([NH2:11])=[CH:9][N:8]=3)[N:3]=2)[CH:29]=[CH:28][CH:27]=1
Reactant: N#CCNc1c(N)nc(SCc2cccc(Cl)c2F)nc1SCc1cccc(Cl)c1F
Agent: [K+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Product: Nc1cnc2c(SCc3cccc(Cl)c3F)nc(SCc3cccc(Cl)c3F)nc2n1

Procedure:
A solution of the product from example 13, step (b) (1.4 g) and potassium hydroxide (110 mg) in methanol (80 ml) and dichloromethane (120 ml) was stirred at room temperature for 24 hours. After evaporation in vacuo, the residue rendered the subtitled compound as a pale yellow solid (1.4 g).
Reaction SMILES: C(N(CC)CC)C.[C:8]1([S:14](Cl)(=[O:16])=[O:15])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[NH2:18][C:19]1[CH:45]=[CH:44][C:22]([CH2:23][N:24]2[C:28]3[CH:29]=[C:30]([C:33](=[O:42])[NH:34][CH2:35][C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][N:37]=4)[CH:31]=[CH:32][C:27]=3[N:26]=[C:25]2[CH3:43])=[CH:21][CH:20]=1.O>C(Cl)(Cl)Cl>[C:8]1([S:14]([NH:18][C:19]2[CH:20]=[CH:21][C:22]([CH2:23][N:24]3[C:28]4[CH:29]=[C:30]([C:33](=[O:42])[NH:34][CH2:35][C:36]5[CH:41]=[CH:40][CH:39]=[CH:38][N:37]=5)[CH:31]=[CH:32][C:27]=4[N:26]=[C:25]3[CH3:43])=[CH:44][CH:45]=2)(=[O:16])=[O:15])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Cc1nc2ccc(C(=O)NCc3ccccn3)cc2n1Cc1ccc(N)cc1
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: Cc1nc2ccc(C(=O)NCc3ccccn3)cc2n1Cc1ccc(NS(=O)(=O)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.1 %

Procedure:
Triethylamine (0.185 g) and benzenesulfonyl chloride (0.210 g) were added to a solution of 0.340 g of 1-(4-aminobenzyl)-2-methyl-6-[(2-pyridylmethyl)carbamoyl]-benzimidazole in 10 ml of chloroform, and the mixture was stirred at room temperature for 8 hours. Water was added thereto to stop the reaction, and the reaction mixture was extracted with chloroform. The organic layer was washed three times with water, dried, and concentrated. The residue was then purified through silica-gel column chromatography (eluent: a mixture of ethyl acetate and methanol at a ratio of 100:1 to 4:1) to give 0.300 g of 1-[4-(benzenesulfonylamino)benzyl]-2-methyl-6-[(2-pyridylmethyl)carbamoyl]benzimidazole (263).
Reaction SMILES: [CH:1]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8][N:7]([C:16](=[NH:25])[O:17][CH2:18][CH2:19][O:20][N:21]=[C:22]([CH3:24])[CH3:23])[CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[C:26](Cl)(=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[C:26]([N:25]=[C:16]([N:7]1[CH2:8][C:9]2[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=2[C:11]2[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=2[CH2:6]1)[O:17][CH2:18][CH2:19][O:20][N:21]=[C:22]([CH3:23])[CH3:24])(=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CC(C)=NOCCOC(=N)N1Cc2ccccc2-c2ccccc2C1
Product: CC(C)=NOCCOC(=NC(=O)c1ccccc1)N1Cc2ccccc2-c2ccccc2C1

Procedure:
starting from 2-[(isopropylideneamino)oxy]-ethyl 5,7-dihydro-6H-dibenz[c,e]azepine-6-carboximidate and benzoyl chloride, there is obtained 2-[(isopropylideneamino)oxy]-ethyl N-benzoyl-5,7-dihydro-6H-dibenz[c,e]-azepine-6-carboximidate as a resin, mass spectrum m/e: M+ 441 (11), 341 (39), 194 (100), 105 (60), 100 (60);
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][C:10](Cl)=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:13][O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>ClCCl.[Al+3].[Cl-].[Cl-].[Cl-]>[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([C:10](=[O:11])[CH2:9][CH2:8][CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:17][CH:16]=1
Reactant: COc1ccccc1
Reactant: O=C(Cl)CCCc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COc1ccc(C(=O)CCCc2ccccc2)cc1
Reaction time: 0.5 h
Yield: 57.5 %

Procedure:
A procedure similar to step 2 of 5.3.1 was used. 4-Phenylbutyryl chloride prepared in the step 1 and methylphenyl ether were used as starting materials, allowed to react in dichloromethane with AlCl3 as catalyst, stirred at −10° C. to −15° C. for 30 minutes and then at room temperature for 3 hours, a crude product was obtained, purified under a reduced pressure by silica gel column chromatography eluted with a gradient of petroleum ether and ethyl acetate at a ratio of 20:1-10:1 (V:V) to obtain a product as a white crystal in a yield of 57.5%, mp: 60-61 └. 1H-NMR (CDCl3, 400 MHz) δ: 2.07 (2H, quintuple, J=7.56 Hz), 2.72 (2H, t, J=7.56 Hz), 2.93 (2H, t, J=7.56 Hz), 3.86 (3H, s, OCH3), 6.91 (2H, d, J=7.00 Hz, ArH), 7.16˜7.21 (5H, m, ArH), 7.91 (2H, d, J=7.00 Hz, ArH); FAB-MS: 255.2 (M+1, 100), 150.1 (27), 135.1 (22), 91.1 (7).
Reaction SMILES: [NH:1]([C:5]1[S:6][CH:7]=[C:8]([C:10](NN)=[O:11])[N:9]=1)[C:2]([NH2:4])=[NH:3].C(=N)([O:18]CC)CCC.Cl.C(OC(=N)CCC)C>C(O)C>[NH:1]([C:5]1[S:6][CH:7]=[C:8]([C:10]([OH:11])=[O:18])[N:9]=1)[C:2]([NH2:4])=[NH:3]
Reactant: N=C(N)Nc1nc(C(=O)NN)cs1
Reactant: CCCC(=N)OCC
Agent: Cl
Solvent: CCO
Product: N=C(N)Nc1nc(C(=O)O)cs1
Yield: 56.7 %

Procedure:
2.90 g (14.48 mol) of 2-guanidino-4-thiazole carboxylic acid hydrazide in 50 ml dry ethanol was slurried with 29.1 mmol of ethyl butyrimidate (prepared from 4.41 g (29.1 mmol) of ethylbutyrimidate hydrochloride) for 5 days at 25°. The slurry was filtered and washed with ethanol and ether and dried to give 3.071 g (78%) of 2-guanidino-4-thiazole carboxylic acid 2-butyriminohydrazide.
Reaction SMILES: [F:1][C:2]([C:5]1[O:9][C:8]([CH2:10][N:11]2[N:15]=[C:14]([NH2:16])[CH:13]=[N:12]2)=[CH:7][CH:6]=1)([F:4])[CH3:3].[CH3:17][C:18]1[O:19][C:20]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[C:21]([C:23](O)=[O:24])[N:22]=1>>[F:4][C:2]([C:5]1[O:9][C:8]([CH2:10][N:11]2[N:15]=[C:14]([NH:16][C:23]([C:21]3[N:22]=[C:18]([CH3:17])[O:19][C:20]=3[C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)=[O:24])[CH:13]=[N:12]2)=[CH:7][CH:6]=1)([F:1])[CH3:3]
Reactant: Cc1nc(C(=O)O)c(-c2ccccc2)o1
Reactant: CC(F)(F)c1ccc(Cn2ncc(N)n2)o1
Product: Cc1nc(C(=O)Nc2cnn(Cc3ccc(C(C)(F)F)o3)n2)c(-c2ccccc2)o1

Procedure:
Following general procedure Z2, starting from 2-[5-(1,1-difluoro-ethyl)-furan-2-ylmethyl]-2H-[1,2,3]triazol-4-ylamine and 2-methyl-5-phenyl-oxazole-4-carboxylic acid.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]=[O:11])=[CH:2]1.[Cl:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[S:19](Cl)(=[O:21])=[O:20].C(N(C(C)C)CC)(C)C.C(=O)([O-])O.[Na+]>C(Cl)Cl>[Cl:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[S:19]([N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]=[O:11])=[CH:2]1)(=[O:21])=[O:20]
Reactant: O=S(=O)(Cl)c1ccccc1Cl
Reactant: O=Cc1c[nH]c2ccccc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=Cc1cn(S(=O)(=O)c2ccccc2Cl)c2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.7 %

Procedure:
A solution of 1H-indole-3-carboxaldehyde (0.290 g, 2.00 mmol) in methylene chloride (4 mL) was added with 2-chlorophenylsulfonyl chloride (0.507 g, 2.40 mmol) and diisopropylethylamine (0.310 g, 2.40 mmol), and the mixture was stirred overnight at room temperature. The reaction mixture was added with saturated aqueous sodium hydrogencarbonate to terminate the reaction, and then extracted three times with methylene chloride. The organic layer was dried over anhydrous magnesium sulfate, then the solvent was evaporated, and the resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain 1-(2-chlorophenylsulfonyl)-1H-indole-3-carboxaldehyde (0.580 g, 90%).
Reaction SMILES: [CH2:1]([N:3]1[CH2:12][CH2:11][CH:10]2[C:5](=[C:6]([NH2:14])[CH:7]=[CH:8][CH:9]2[Br:13])[CH2:4]1)[CH3:2].[C:15](OC(=O)C)(=[O:17])[CH3:16]>>[Br:13][C:9]1[CH:8]=[CH:7][C:6]([NH:14][C:15](=[O:17])[CH3:16])=[C:5]2[C:10]=1[CH2:11][CH2:12][N:3]([CH2:1][CH3:2])[CH2:4]2
Reactant: CC(=O)OC(C)=O
Reactant: CCN1CCC2C(=C(N)C=CC2Br)C1
Product: CCN1CCc2c(Br)ccc(NC(C)=O)c2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 67 %

Procedure:
The product from Example 27 (0.35 mmol) was cooled in an ice bath, treated with acetic anhydride (10 mL), and stirred at room temperature under nitrogen overnight. Excess acetic anhydride was evaporated, the residue washed with ether, and evaporated. The white solid was triturated with ether and collected by filtration. The solid was washed with a mixture of ethyl acetate and saturated sodium bicarbonate. The organic layer was washed with sodium bicarbonate and sodium chloride solutions, dried over MgSO4, filtered, and evaporated. The acetamide was obtained as a white solid (crystallized from ethyl acetate, 0.07 g, 67% yield).
Reaction SMILES: [H-].[Na+].NC1C=CC=CC=1.[CH3:10][C:11]1[CH2:15][C:14]([CH3:16])=[C:13]([CH3:17])[C:12]=1[CH3:18].Cl[Si:20]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(=O)([O-])O.[Na+].C(=O)([O-])[O-].[Na+].[Na+]>O1CCCC1.C1(C)C=CC=CC=1>[C:33]1([Si:20]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:15]2[CH:14]([CH3:16])[C:13]([CH3:17])=[C:12]([CH3:18])[C:11]=2[CH3:10])[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: Cl[Si](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC1=C(C)C(C)=C(C)C1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Solvent: Nc1ccccc1
Product: CC1=C(C)C(C)C([Si](c2ccccc2)(c2ccccc2)c2ccccc2)=C1C
Temperature: 50 °C
Reaction time: 1 h
Yield: 66.4 %

Procedure:
Under nitrogen atmosphere, sodium hydride dispersed in mineral oil (0.54 g, 22.32 mmol as sodium hydride) was washed with hexane to remove mineral oil, and thereafter tetrahydrofuran (35 ml) was added. The temperature of the mixture was elevated to 50° C. and aniline (0.14 g, 1.49 mmol) was added. The mixture was stirred at 50° C. for 1 hour. A solution obtained by dissolving 1,2,3,4-tetramethylcyclopenta-1,3-diene (2.00 g, 16.37 mmol) in tetrahydrofuran (9 ml) was added dropwise to this, and the mixture was stirred at 50° C. for 2 hours and cooled to 20° C. To the solution, a solution obtained by dissolving chlorotriphenylsilane (4.39 g, 14.88 mmol) in toluene (9 ml) was added dropwise, and the mixture was stirred at 35° C. overnight. The resultant mixture was added dropwise at 0° C. to a mixture of a 10% sodium hydrogen carbonate solution (22 ml) and a 10% sodium carbonate solution (22 ml). Toluene (22 ml) was added to separate an organic phase. The organic phase was dried over sodium sulfate and filtrated, and the solvent was concentrated under reduced pressure to obtain 1-triphenylsilyl-2,3,4,5-tetramethylcyclopentadiene (3.76 g, yield 66.3%).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[C:7]1[N:12]=[C:11]([CH3:13])[C:10]([CH:14]([CH2:19][CH2:20][CH3:21])[C:15]([O:17][CH3:18])=[O:16])=[C:9]([C:22]2[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=2)[N:8]=1>O1CCCC1>[CH3:13][C:11]1[C:10]([CH:14]([CH2:19][CH2:20][CH3:21])[C:15]([O:17][CH3:18])=[O:16])=[C:9]([C:22]2[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=2)[N:8]=[C:7]([N:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)[N:12]=1
Reactant: C1CCNC1
Reactant: CCCC(C(=O)OC)c1c(C)nc(Cl)nc1-c1ccc(C)cc1
Solvent: C1CCOC1
Product: CCCC(C(=O)OC)c1c(C)nc(N2CCCC2)nc1-c1ccc(C)cc1
Yield: 92.8 %

Procedure:
Methyl 2-(4-methyl-2-(pyrrolidin-1-yl)-6-p-tolylpyrimidin-5-yl)pentanoate was prepared according to the general method A starting from pyrrolidine (0.111 mL; 1.32 mmol) and methyl 2-(2-chloro-4-methyl-6-p-tolylpyrimidin-5-yl)pentanoate (0.110 g; 0.264 mmol) in tetrahydrofuran (2 mL). Purification by flash-chromatography on silica gel using a gradient of ethyl acetate (5-20%) in heptane furnished 90 mg (93%) of the title compound as an oil. ESI/APCI(+): 368 (M+H), 390 (M+Na). ESI/APCI(−): 366 (M−H).
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH2:13][OH:14])[N:8]2[CH2:11][CH3:12])=[C:4]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[N:3]=1.[CH3:21][C:22]1[NH:23][C:24]2[CH:30]=[CH:29][CH:28]=[CH:27][C:25]=2[N:26]=1>>[CH2:11]([N:8]1[C:7]([CH2:13][OH:14])=[N:6][C:5]2[C:9]1=[N:10][C:2]([N:23]1[C:24]3[CH:30]=[CH:29][CH:28]=[CH:27][C:25]=3[N:26]=[C:22]1[CH3:21])=[N:3][C:4]=2[N:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1)[CH3:12]
Reactant: Cc1nc2ccccc2[nH]1
Reactant: CCn1c(CO)nc2c(N3CCOCC3)nc(Cl)nc21
Product: CCn1c(CO)nc2c(N3CCOCC3)nc(-n3c(C)nc4ccccc43)nc21

Procedure:
(2-chloro-9-ethyl-6-morpholino-9H-purin-8-yl)methanol (2.3 g) was reacted with 2-methylbenzimidazole via General Procedure I for Buchwald coupling. The crude product (9-ethyl-2-(2-methyl-1H-benzo[d]imidazol-1-yl)-6-morpholino-9H-purin-8-yl)methanol (3g) was obtained after concentration of the reaction mixture and filtration after addition of water.