Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@@H:14]([OH:15])[C:13](=[O:16])[N:12]([CH2:17][CH2:18][N:19]([C:21]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[O:22])[CH3:20])[C:11]3[CH:31]=[CH:32][C:33]([CH3:35])=[CH:34][C:10]=3[S:9]2)=[CH:4][CH:3]=1.[C:36](Cl)(=[O:43])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.N1C=CC=CC=1>C1C=CC=CC=1>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@@H:14]([O:15][C:36](=[O:43])[C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[C:13](=[O:16])[N:12]([CH2:17][CH2:18][N:19]([C:21]([O:23][CH2:24][C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)=[O:22])[CH3:20])[C:11]3[CH:31]=[CH:32][C:33]([CH3:35])=[CH:34][C:10]=3[S:9]2)=[CH:4][CH:3]=1
Reactant: Cc1ccc([C@@H]2Sc3cc(C)ccc3N(CCN(C)C(=O)OCc3ccccc3)C(=O)[C@@H]2O)cc1
Reactant: O=C(Cl)c1ccccc1
Solvent: c1ccccc1
Solvent: c1ccncc1
Product: Cc1ccc([C@@H]2Sc3cc(C)ccc3N(CCN(C)C(=O)OCc3ccccc3)C(=O)[C@@H]2OC(=O)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 110.3 %

Procedure:
A mixture of 1.6 g of (±)-cis-2-(4-methylphenyl)-3-hydroxy-5-[2-(N-benzyloxycarbonyl-N-methylamino)ethyl]-8-methyl-2,3-dihydro-1,5-benzothiazepin-4(5H)-one, 0.69 g of benzoyl chloride, 5 ml of pyridine and 2 ml of benzene is stirred at room temperature for 2 hours. The mixture is poured into ice-water, and the aqueous mixture is extracted with ethyl acetate. The extract is washed with water, dried and then evaporated under reduced pressure to remove solvent. 2.14 g of (±)-cis-2-(4-methylphenyl)-3-benzoyloxy-5-[2-(N-benzyloxycarbonyl-N-methylamino)ethyl]-8-methyl-2,3-dihydro-1,5-benzothiazepin-4(5H)-one are obtained as an oil.
Reaction SMILES: Cl.C(O[C:5]([C:7]1[C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:10][S:9][C:8]=1[NH2:18])=[O:6])C.[Cl:19][CH2:20][C:21]#[N:22].C(=O)([O-])O.[Na+]>O1CCOCC1.O>[Cl:19][CH2:20][C:21]1[NH:22][C:5](=[O:6])[C:7]2[C:11]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)=[CH:10][S:9][C:8]=2[N:18]=1
Reactant: N#CCCl
Reactant: CCOC(=O)c1c(-c2ccccc2)csc1N
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: O=c1[nH]c(CCl)nc2scc(-c3ccccc3)c12
Temperature: 25 °C
Reaction time: 18 h
Yield: 66.8 %

Procedure:
Hydrogen chloride gas was bubbled through a stirred solution of 2-amino-4-phenylthiophene-3-carboxylic acid ethyl ester (4.94 g, 0.02 mol) and chloroacetonitrile (1.4 ml, 0.022 mol) in anhydrous 1,4-dioxane (60 ml) for about 4 hours. A thick suspension formed initially which slowly dissolved. The mixture was stirred at ambient temperature for 18 hours before being poured into water (250 ml) and basified (pH 8) by the addition of sodium hydrogen carbonate. The supernatant was then decanted to leave a gummy solid which was triturated with aqueous ethanol to give 2-chloromethyl-5-phenyl-3H-thieno[2,3-d]pyrimidin-4-one as a yellow solid (3.70 g), which was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:11])[N:4]([CH3:10])[C:5](=[O:9])[NH:6][C:7]=1[NH2:8].[Cl:12][C:13]1[CH:20]=[CH:19][C:16]([CH:17]=O)=[CH:15][CH:14]=1.C([BH3-])#N.[Na+]>O.C(O)(=O)C>[NH2:8][C:7]1[NH:6][C:5](=[O:9])[N:4]([CH3:10])[C:3](=[O:11])[C:2]=1[NH:1][CH2:17][C:16]1[CH:19]=[CH:20][C:13]([Cl:12])=[CH:14][CH:15]=1
Reactant: O=Cc1ccc(Cl)cc1
Reactant: Cn1c(=O)[nH]c(N)c(N)c1=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: Cn1c(=O)[nH]c(N)c(NCc2ccc(Cl)cc2)c1=O
Temperature: 25 °C
Reaction time: 5 h
Yield: 41.7 %

Procedure:
To a solution of 5,6-diamino-3-methylpyrimidine-2,4(1H,3H)-dione (0.8 g, 5.13 mmol) in water (10 mL) and acetic acid (0.5 mL) was added 4-chlorobenzaldehyde (0.72 g, 5.14 mmol), the mixture was stirred at room temperature for 5 h. The mixture was cooled to 0° C., sodium cyanoborohydride (0.3 g, 4.76 mmol) was added and the resulting mixture was stirred at room temperature overnight. The mixture was concentrated and filtered, and the filter cake was washed with methanol, dried in vacuo to give 6-amino-5-(4-chlorobenzylamino)-3-methylpyrimidine-2,4(1H,3H)-dione (0.6 g, 42.9% yield) as yellow solid. LCMS MH+ 281.
Reaction SMILES: CON(C)[C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[N:10][C:11]([C:17]([F:20])([F:19])[F:18])=[CH:12][CH:13]=2)[N:8]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([Br:28])[N:23]=2)[CH:7]=1)=[O:5].[F:30][C:31]1[CH:32]=[C:33]([Mg]Cl)[CH:34]=[CH:35][C:36]=1[O:37][CH3:38]>C1COCC1>[Br:28][C:24]1[N:23]=[C:22]([CH2:21][N:8]2[C:9]3[C:14](=[CH:13][CH:12]=[C:11]([C:17]([F:20])([F:19])[F:18])[N:10]=3)[C:15](=[O:16])[C:6]([C:4](=[O:5])[C:33]3[CH:34]=[CH:35][C:36]([O:37][CH3:38])=[C:31]([F:30])[CH:32]=3)=[CH:7]2)[CH:27]=[CH:26][CH:25]=1
Reactant: COc1ccc([Mg]Cl)cc1F
Reactant: CON(C)C(=O)c1cn(Cc2cccc(Br)n2)c2nc(C(F)(F)F)ccc2c1=O
Solvent: C1CCOC1
Product: COc1ccc(C(=O)c2cn(Cc3cccc(Br)n3)c3nc(C(F)(F)F)ccc3c2=O)cc1F

Procedure:
Experimental conditions analogous to those described for Step 6 of Example 60, from 80 mg of 1-(6-bromo-pyridin-2-ylmethyl)-4-oxo-7-trifluoromethyl-1,4-dihydro-[1,8]naphthyridine-3-carboxylic acid methoxy-methyl-amide, 2 mL of THF was treated with 3-fluoro-4-methoxyphenyl magnesium chloride (0.5 M in THF, 1.3 mL, 2 equiv) at rt for 2 h. The reaction was quenched by slow addition of saturated aqueous ammonium chloride. The mixture was subjected to HPLC and then preparative TLC purification to give 1-(6-Bromo-pyridin-2-ylmethyl)-3-(3-fluoro-4-methoxy-benzoyl)-7-trifluoromethyl-1H-[1,8]naphthyridin-4-one. LCMS (ES) M+H 536.0.
Reaction SMILES: [CH:1]1([NH:4][C:5]2[N:10]3[N:11]=[CH:12][C:13](/[CH:14]=[C:15]4/[C:16](=[O:21])[NH:17][C:18](=[O:20])[NH:19]/4)=[C:9]3[N:8]=[C:7](S(C)=O)[N:6]=2)[CH2:3][CH2:2]1.C1(NC2N3N=CC(/C=C4/C(=O)NC(=O)N/4)=C3N=C(S(C)(=O)=O)N=2)CC1.[NH:50]1[C:54]2[CH:55]=[CH:56][C:57]([C:59]([OH:61])=[O:60])=[CH:58][C:53]=2[N:52]=[CH:51]1>C(O)(C)C>[CH:1]1([NH:4][C:5]2[N:10]3[N:11]=[CH:12][C:13](/[CH:14]=[C:15]4\[NH:19][C:18](=[O:20])[NH:17][C:16]\4=[O:21])=[C:9]3[N:8]=[C:7]([N:50]3[C:54]4[CH:55]=[CH:56][C:57]([C:59]([OH:61])=[O:60])=[CH:58][C:53]=4[N:52]=[CH:51]3)[N:6]=2)[CH2:3][CH2:2]1
Reactant: O=C(O)c1ccc2[nH]cnc2c1
Reactant: CS(=O)c1nc(NC2CC2)n2ncc(/C=C3\NC(=O)NC3=O)c2n1
Agent: CS(=O)(=O)c1nc(NC2CC2)n2ncc(/C=C3\NC(=O)NC3=O)c2n1
Solvent: CC(C)O
Product: O=C1NC(=O)/C(=C/c2cnn3c(NC4CC4)nc(-n4cnc5cc(C(=O)O)ccc54)nc23)N1
Temperature: 150 °C

Procedure:
A mixture of (Z)-5((4-(cyclopropylamino)-2-(methylsulfinyl)pyrazolo[1,5-a][1,3,5]triazin-8-yl)methylene)imidazolidine-2,4-dione and (Z)-5-((4-(cyclopropylamino)-2-(methylsulfonyl)pyrazolo[1,5-a][1,3,5]triazin-8-yl)methylene)imidazolidine-2,4-dione (10 mg, 0.028 mmol) was mixed with 1H-benzo[d]imidazole-5-carboxylic acid (20 mg, 0.140 mmol) in isopropanol (1 mL). The mixture was stirred under microwave heating at 150° C. for 20 minutes. The solvent was removed to provide (Z)-1-(4-(cyclopropylamino)-8-((2,5-dioxoimidazolidin-4-ylidene)methyl)pyrazolo[1,5-a][1,3,5]triazin-2-yl)-1H-benzo[d]imidazole-5-carboxylic acid as a crude mixture which was taken on to the next step without further purification. LCMS (ES):>95% pure, m/z 446 [M+H]+
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Cl[C:15]([O:17][C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=1)=[O:16]>ClCCl.C(N(CC)CC)C>[N+:24]([C:21]1[CH:20]=[CH:19][C:18]([O:17][C:15]([N:11]2[CH2:10][CH2:9][N:8]([C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH2:13][CH2:12]2)=[O:16])=[CH:23][CH:22]=1)([O-:26])=[O:25]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCN(C(=O)Oc2ccc([N+](=O)[O-])cc2)CC1
Yield: 99.7 %

Procedure:
To N—BOC-piperazine (500 mg) in dichloromethane (5 mL) and triethylamine (0.41 ml) was added 4-nitrophenyl chloroformate (541 mg). After 1 hour the reaction mixture was diluted with dichloromethane, washed with brine, dried (MgSO4) and the solvent removed in vacuo to yield piperazine-1,4-dicarboxylic acid tert-butyl ester 4-nitro-phenyl ester (940 mg).
Reaction SMILES: [CH3:1][Mg]Br.[O:4]=[C:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH:7]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:6]1>O1CCCC1>[CH3:1][C@:5]1([OH:4])[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C@@H:7]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:6]1
Reactant: C[Mg]Br
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1c1ccccc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC[C@](C)(O)C[C@@H]1c1ccccc1
Reaction time: 1 h
Yield: 28.6 %

Procedure:
Methylmagnesium bromide (3 M solution in ether, 1.2 mL, 3.6 mmol) was added to a solution of tert-butyl 4-oxo-2-phenylpiperidine-1-carboxylate (328 mg, 1.2 mmol), in tetrahydrofuran (20 mL) at 0° C. and the resulting mixture was stirred at this temperature one hour. The reaction mixture was then quenched with saturated aqueous ammonium chloride solution (20 mL) and diluted with ethyl acetate (80 mL). The organic portion was separated, washed with water, then brine solution, dried over sodium sulfate, filtered and concentrated. The residue purified by silica gel chromatography (25% to 70% ethyl acetate in hexane gradient) to give the first eluting isomer assigned as (±)-tert-butyl (2R,4S)-4-methyl-2-phenylpiperidin-4-ol-1-carboxylate (100 mg, 29% yield), LC-MS for C17H25NO3: 292 (MH+); and the second eluting isomer assigned as (±)-tert-butyl (2R,4R)-4-methyl-2-phenylpiperidin-4-ol-1-carboxylate (120 mg, 35% yield), MS (EI) for C17H25NO3: 292 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH:13]=[CH:14][C:15]([OH:17])=[CH:16][C:11]=3[S:10][N:9]=2)=[CH:4][CH:3]=1.[Br:18][CH2:19][CH2:20][CH2:21][CH2:22]Br>>[Br:18][CH2:19][CH2:20][CH2:21][CH2:22][O:17][C:15]1[CH:14]=[CH:13][C:12]2[C:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)=[N:9][S:10][C:11]=2[CH:16]=1
Reactant: Oc1ccc2c(-c3ccc(F)cc3)nsc2c1
Reactant: BrCCCCBr
Product: Fc1ccc(-c2nsc3cc(OCCCCBr)ccc23)cc1

Procedure:
In analogy to example 2.1, 3-(4-fluoro-phenyl)-benzo[d]isothiazol-6-ol and 1,4-dibromobutane were converted to yield 6-(4-Bromo-butoxy)-3-(4-fluoro-phenyl)-benzo[d]isothiazole, MS: 379 (M,1Br).
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[N:11][NH:12][CH:13]=2)[O:3]1.Br[CH2:16][CH2:17][CH2:18][O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C([O-])([O-])=O.[Cs+].[Cs+].O>CN(C=O)C>[CH2:20]([O:19][CH2:18][CH2:17][CH2:16][N:12]1[CH:13]=[C:9]([B:4]2[O:5][C:6]([CH3:7])([CH3:8])[C:2]([CH3:14])([CH3:1])[O:3]2)[CH:10]=[N:11]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: BrCCCOCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CC1(C)OB(c2cnn(CCCOCc3ccccc3)c2)OC1(C)C
Temperature: 90 °C
Reaction time: 8 h

Procedure:
A solution of 4-(4,4,5,5-Tetramethyl[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (8.47 g, 43.6 mmol) in DMF (85 mL) was treated with 1-bromo-3-benzyloxypropane (10.0 g, 43.6 mmol) and Cs2CO3 (14.2 g, 43.6 mmol). This mixture was heated to 90° C. and allowed to stir under N2 overnight. The reaction mixture was poured into water and extracted twice with EtOAc. The combined organic layers were washed with water 3 times, once with brine, dried over Na2SO4, filtered and concentrated to an orange oil which was purified on a Teledyne ISCO Combiflash® Rf system (0-30% EtOAc/DCM) to afford the title compound as 8.5 g of a clear oil (57%). 1H NMR (400 MHz, CDCl3) δ 7.79 (s, 1H), 7.66 (s, 1H), 7.29-7.40 (m, 5H), 4.48 (s, 2H), 4.26 (t, J=6.8 Hz, 2H), 3.43 (t, J=5.9 Hz, 2H), 2.16 (quin, J=6.3 Hz, 2H), 1.60 (dd, J=6.6, 8.6 Hz, 2H), 1.33 (s, 12H).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:16]([O:18][C:19]1[CH:20]=[C:21]([CH:25]=[CH:26][CH:27]=1)[C:22]([OH:24])=[O:23])=[O:17])[CH:13]([CH3:15])[CH3:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].C([N+](CCCC)(CCCC)CCCC)CCC.[Cl:46][CH2:47]I>O1CCOCC1>[CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:16]([O:18][C:19]1[CH:20]=[C:21]([CH:25]=[CH:26][CH:27]=1)[C:22]([O:24][CH2:47][Cl:46])=[O:23])=[O:17])[CH:13]([CH3:15])[CH3:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClCI
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)Oc1cccc(C(=O)O)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [OH-]
Solvent: C1COCCO1
Product: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)Oc1cccc(C(=O)OCCl)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 3-(N-benzyloxycarbonyl-valyloxy)benzoic acid (7.42 g, 20 mmole) in 1,4-dioxane (100 ml) was added a 40% solution of tetrabutylammonium hydroxide (12.97 g, 20 mmole) and the mixture was stirred 2 hours at room temperature. The mixture was evaporated under reduced pressure and co-evaporated two times with 1,4-dioxane and two times with toluene. The dried product was dissolved in dichloromethane (50 ml) and chloroiodomethane (35.3 g, 200 mmole) was added. The solution was stirred for two days at room temperature and evaporated under reduced pressure. Ethyl acetate (100 ml) was added and the organic phase washed twice with water, dried with sodium sulfate and evaporated under reduced pressure: The product was isolated by silica gel column chromatography. Yield: 3.8 g=45%.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)(OC(C)(C)C)=O.ClC1[N:16]=[C:17]([NH:25][CH2:26][C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:28]=2[Cl:34])[C:18]2[CH:24]=[CH:23][CH:22]=[N:21][C:19]=2[N:20]=1.C(N(CC)C(C)C)(C)C>C(O)CCC>[Cl:34][C:28]1[CH:29]=[C:30]([Cl:33])[CH:31]=[CH:32][C:27]=1[CH2:26][NH:25][C:17]1[C:18]2[CH:24]=[CH:23][CH:22]=[N:21][C:19]=2[N:20]=[C:1]([N:8]2[CH2:9][CH2:10][NH:11][CH2:12][CH2:13]2)[N:16]=1
Reactant: Clc1ccc(CNc2nc(Cl)nc3ncccc23)c(Cl)c1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: Clc1ccc(CNc2nc(N3CCNCC3)nc3ncccc23)c(Cl)c1
Reaction time: 10 h
Yield: 99.9 %

Procedure:
Boc-piperazine (122 mg, 0.65 mmol) was added to the solution of (2-Chloro-pyrido[2,3-d]pyrimidin-4-yl)-(2,4-dichloro-benzyl)-amine(185 mg, 0.54 mmol) and N,N-diisopropylethylamine (145 μL, 0.82 mmol) in n-butanol (2 mL). The reaction mixture was stirred at 85° for 10 h. All starting material was consumed as seen on HPLC. The reaction mixture was concentrated at room temperature under vacuo. The resulting residue was suspended in 2 mL of TFA-CH2Cl2 (1:1) mixture and stirred at room temperature for 45 minutes. The reaction mixture was concentrated in vacuo, diluted with saturated aqueous sodium bicarbonate solution. The aqueous layer was extracted with CH2Cl2 (2×10 mL), dried (Na2SO4) and concentratd to furnish (2,4-Dichloro-benzyl)-(2-piperazin-1-yl-pyrido[2,3-d]pyrimidin-4-yl)-amine(210 mg) as pale brown oil. The crude was carried forward as such in the next reaction.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([OH:8])=O.C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:21][C@H:22]([C:33]1[NH:34][CH:35]=[C:36]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[N:37]=1)[CH2:23][C:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[NH:26][CH:25]=1>>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([NH:21][C@H:22]([C:33]1[NH:34][CH:35]=[C:36]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[N:37]=1)[CH2:23][C:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[NH:26][CH:25]=1)=[O:8]
Reactant: N[C@@H](Cc1c[nH]c2ccccc12)c1nc(-c2ccccc2)c[nH]1
Reactant: O=C(O)c1ccco1
Agent: O=C(n1ccnc1)n1ccnc1
Product: O=C(N[C@@H](Cc1c[nH]c2ccccc12)c1nc(-c2ccccc2)c[nH]1)c1ccco1
Temperature: 22 °C
Reaction time: 12 h
Yield: 93.8 %

Procedure:
2-Furancarboxylic acid (12.6 mg, 0.11 mmol) was activated overnight at about 22° C. with carbonyldiimidazole (0.11 mmol, 0.2M in chloroform). 2-{(1S)-1-Amino-2-[indol-3-yl]ethyl}-4-phenyl-1H-imidazole (0.1 mmol, 0.5M in chloroform) was added to the media and the mixture was stirred for about 12 hours at about 22° C. Aminomethylated resin was then added (50-60 mg, 1.2 mmol/g, Novabiochem) in order to quench the excess of acylating agent for about 12 hours. Purification on silica gel pad (200 mg, Alltech) with ethyl acetate as eluent gave the expected product (37.2 mg, 94%). 1H-NMR (CDCl3, 100 MHz) δ: 8.36 (br s, 1H); 7.67-6.4 (m, 16H); 5.48 (qd, J=7.1 Hz, 1H); 3.6 (ABX system, 2H). LC/MS: m/z=397 (M+H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[C:9]1([S:15]([N:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:20](B(O)O)=[CH:19]2)(=[O:17])=[O:16])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(#N)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>[C:9]1([S:15]([N:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:20]([C:6]3[CH:5]=[CH:4][N:3]=[C:2]([Cl:1])[N:7]=3)=[CH:19]2)(=[O:17])=[O:16])[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: O=S(=O)(c1ccccc1)n1cc(B(O)O)c2ccccc21
Reactant: Clc1ccnc(Cl)n1
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: CC#N
Product: O=S(=O)(c1ccccc1)n1cc(-c2ccnc(Cl)n2)c2ccccc21

Procedure:
A solution of 2,4-dichloropyrimidine (2.42 g, 16 mmol), 1-(phenylsulfonyl)-1H-indol-3-ylboronic acid (3.89 g, 13 mmol) and sodium carbonate (5.03 g, 47 mmol) in acetonitrile/water (2:1, 60 mL) was degassed with argon, then tetrakis(triphenylphosphine)palladium (300 mg, 1.6 mol) was added. The resulting mixture was heated to reflux for 2 h while a white suspension formed. The precipitate was cooled and filtered through a CELITE™/Silica gel plug. The filter cake was washed with EtOAc, the organic layer separated, washed with brine, dried over Na2SO4, filtered, and evaporated under reduced pressure. The residue was recrystallized from EtOAc/hexanes to give 1-benzenesulfonyl-3-(2-chloro-pyrimidin-4-yl)-1H-indole as a light-pink solid. The solid filtrate from the reaction mixture was dissolved in DCM, dried over Na2SO4, filtered, and combined with the previous batch of product. The collected solids were dissolved in DCM, the solvent was evaporated under reduced pressure and EtOAc was added to form a suspension, the product was filtered and washed with hexanes, to give 1-benzenesulfonyl-3-(2-chloro-pyrimidin-4-yl)-1H-indole (2.0 g, 33% yield) as a light-pink solid. An additional 0.45 g of product was obtained from the mother liquors.
Reaction SMILES: [CH3:1][Si:2]([CH3:33])([CH3:32])[CH2:3][CH2:4][O:5][CH2:6][N:7]1[C:11]2[N:12]=[CH:13][N:14]=[C:15]([C:16]3[CH:17]=[N:18][N:19]([CH:21]([CH2:27][C:28]([O:30]C)=[O:29])[CH2:22][C:23]([O:25]C)=[O:24])[CH:20]=3)[C:10]=2[CH:9]=[CH:8]1.CO.O.[OH-].[Li+]>O>[CH3:33][Si:2]([CH3:1])([CH3:32])[CH2:3][CH2:4][O:5][CH2:6][N:7]1[C:11]2[N:12]=[CH:13][N:14]=[C:15]([C:16]3[CH:17]=[N:18][N:19]([CH:21]([CH2:27][C:28]([OH:30])=[O:29])[CH2:22][C:23]([OH:25])=[O:24])[CH:20]=3)[C:10]=2[CH:9]=[CH:8]1
Reactant: COC(=O)CC(CC(=O)OC)n1cc(-c2ncnc3c2ccn3COCC[Si](C)(C)C)cn1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C(CC(=O)O)CC(=O)O)c3)ncnc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 78.6 %

Procedure:
Dimethyl 3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]pentanedioate (43.0 g, 0.0908 mol) was dissolved in methanol (271.2 mL, 6.695 mol) and lithium hydroxide monohydrate (15 g, 0.36 mol) dissolved in water (125 mL) was added. The reaction was stirred at rt for 2 h. The methanol was removed in vacuo and a resulting aqueous layer was cooled in an ice bath. The solution was made acidic pH-4 with 1N HCl to give a white precipitate. The solid precipitate was collected, washed with water, dried to give 3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]pentanedioic acid as a white crystalline powder (31.8 gm, 80%), LC/MS (M+H)+: 446, 1H NMR (DMSO-d6) δ 8.85s 1H), 8.75 (s, 1H), 8.42 (s, 1H), 7.85 (d, 1H), 7.17 (d, 1H), 5.71 (s, 2H), 5.18 (m, 1H), 3.65 (t, 2H), 3.05 (m, 4H), 0.92 (t, 2H), 0.1 (s, 9H).
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([CH3:11])[N:10]=[C:6]2[N:5]=[C:4]([C:12]([O:14][CH3:15])=[O:13])[CH:3]=1.O.[SH2:17].[Na]>CO>[SH:17][C:2]1[N:7]2[N:8]=[C:9]([CH3:11])[N:10]=[C:6]2[N:5]=[C:4]([C:12]([O:14][CH3:15])=[O:13])[CH:3]=1
Reactant: S
Reactant: COC(=O)c1cc(Cl)n2nc(C)nc2n1
Agent: [Na]
Solvent: CO
Solvent: O
Product: COC(=O)c1cc(S)n2nc(C)nc2n1
Temperature: 60 °C
Reaction time: 5 h
Yield: 83.4 %

Procedure:
Methyl 7-chloro-2-methyl-s-triazolo[1,5-a]pyrimidine-5-carboxylate (0.80 g) (3.53 mmol) are suspended in 35 ml of methanol and treated with 0.78 g (10.6 mmol) of sodium hydrogen sulphide hydrate. After stirring at 60° C. for 5 hours the mixture is concentrated and the residue is dissolved in 20 ml of water. The solution is acidified to pH 3 with 3N aqueous hydrochloric acid. The separated product is filtered off under suction and washed with water and methanol. After recrystallization from methanol/dichloromethane there is obtained 0.66 g of methyl 7-mercapto-2-methyl-s-triazolo[1,5-a]pyrimidine-5-carboxylate as yellow crystals of melting point 237° C. (dec.).
Reaction SMILES: Cl.C(O)(=O)C.C([NH:10][C:11]1[N:16]=[C:15]([N:17]2[C:26]3[C:21](=[CH:22][C:23]([F:29])=[C:24]([F:28])[C:25]=3[F:27])[C:20](=[O:30])[C:19]([C:31]([O:33]CC)=[O:32])=[CH:18]2)[C:14]([F:36])=[CH:13][C:12]=1[F:37])(C)(C)C>O>[NH2:10][C:11]1[N:16]=[C:15]([N:17]2[C:26]3[C:21](=[CH:22][C:23]([F:29])=[C:24]([F:28])[C:25]=3[F:27])[C:20](=[O:30])[C:19]([C:31]([OH:33])=[O:32])=[CH:18]2)[C:14]([F:36])=[CH:13][C:12]=1[F:37]
Reactant: CCOC(=O)c1cn(-c2nc(NC(C)(C)C)c(F)cc2F)c2c(F)c(F)c(F)cc2c1=O
Agent: Cl
Solvent: CC(=O)O
Solvent: O
Product: Nc1nc(-n2cc(C(=O)O)c(=O)c3cc(F)c(F)c(F)c32)c(F)cc1F
Reaction time: 7 h
Yield: 95 %

Procedure:
To a mixed solution of 0.5 ml of 4N hydrochloric acid and 0.5 ml of acetic acid was added 235 mg of ethyl 1-[6-(t-butylamino)-3,5-difluoropyridin-2-yl]-6,7,8-trifluoro-4-oxo-1,4-dihydroquinoline-3-carboxylate, and the mixture was heated under reflux with stirring for 7 hours. After adding 1 ml of distilled water, the mixture was allowed to cool, and the precipitate was collected by filtration and washed with ethanol and diisopropylether successively to obtain 182 mg of the title compound as a colorless powder.
Reaction SMILES: [CH:1]1([C:4](Cl)=[O:5])[CH2:3][CH2:2]1.[CH3:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][NH:15][C:16]2[O:20][N:19]=[C:18]([CH3:21])[N:17]=2)=[CH:10][CH:9]=1.C(N(CC)CC)C>C1C=CC=CC=1>[CH3:21][C:18]1[N:17]=[C:16]([N:15]([CH2:14][C:11]2[CH:12]=[CH:13][C:8]([CH3:7])=[CH:9][CH:10]=2)[C:4]([CH:1]2[CH2:3][CH2:2]2)=[O:5])[O:20][N:19]=1
Reactant: O=C(Cl)C1CC1
Reactant: Cc1ccc(CNc2nc(C)no2)cc1
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: Cc1ccc(CN(C(=O)C2CC2)c2nc(C)no2)cc1

Procedure:
Cyclopropane carboxylic acid chloride (3.45 g, 0.033 mole) was added dropwise to a solution of 5-(4-methylphenyl)methylamino-3-methyl-1,2,4-oxadiazole (6.1 g, 0.03 mole) and triethylamine (3.45 g, 0.035 mole) in dry benzene keeping the temperature below 10° C. After the addition the temperature was allowed to reach room temperature and then refluxed overnight. On cooling the reaction mixture was washed twice with 2 N HCl and twice with a saturated solution of NaHCO3 and dried over MgSO4 and charcoaled. The product was purified by column chromatography--silica gel (110 g) eluting with petroleum ether 40°-60° C. increasing polarity to 10% ether in petroleum ether. The title compound was recrystallised from petroleum ether 60°-80° C. as white needles. m.p. 49.5°-50.5° C.