Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH2:8][C@@H:9]1[CH2:13][CH2:12][N:11]([C:14]2[N:22]=[C:21]3[C:17]([N:18]=[CH:19][N:20]3[C@@H:23]3[CH2:27][C@H:26]([N:28]4[CH:32]=[C:31]([CH2:33][OH:34])[CH:30]=[N:29]4)[C@@H:25]([OH:35])[C@H:24]3[OH:36])=[C:16]([NH:37][CH2:38][CH:39]([C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)[C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[N:15]=2)[CH2:10]1.FC(F)(F)C(O)=O.O[C@@H]1[C@H](O)[C@@H](N2C=C(C)C=N2)C[C@H]1N1C=NC2C1=NC(NC1CCC(N[C:104]([NH:106][CH:107]3[CH2:112][CH2:111][N:110]([C:113]4[CH:118]=[CH:117][CH:116]=[CH:115][N:114]=4)[CH2:109][CH2:108]3)=[O:105])CC1)=NC=2NCC(C1C=CC=CC=1)C1C=CC=CC=1>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[OH:36][C@@H:24]1[C@H:25]([OH:35])[C@@H:26]([N:28]2[CH:32]=[C:31]([CH2:33][OH:34])[CH:30]=[N:29]2)[CH2:27][C@H:23]1[N:20]1[CH:19]=[N:18][C:17]2[C:21]1=[N:22][C:14]([N:11]1[CH2:12][CH2:13][C@@H:9]([NH:8][C:104]([NH:106][CH:107]3[CH2:108][CH2:109][N:110]([C:113]4[CH:118]=[CH:117][CH:116]=[CH:115][N:114]=4)[CH2:111][CH2:112]3)=[O:105])[CH2:10]1)=[N:15][C:16]=2[NH:37][CH2:38][CH:39]([C:46]1[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=1)[C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1
Reactant: N[C@@H]1CCN(c2nc(NCC(c3ccccc3)c3ccccc3)c3ncn([C@@H]4C[C@H](n5cc(CO)cn5)[C@@H](O)[C@H]4O)c3n2)C1
Reactant: Cc1cnn([C@H]2C[C@@H](n3cnc4c(NCC(c5ccccc5)c5ccccc5)nc(NC5CCC(NC(=O)NC6CCN(c7ccccn7)CC6)CC5)nc43)[C@H](O)[C@@H]2O)c1
Solvent: O=C(O)C(F)(F)F
Product: O=C(NC1CCN(c2ccccn2)CC1)N[C@@H]1CCN(c2nc(NCC(c3ccccc3)c3ccccc3)c3ncn([C@@H]4C[C@H](n5cc(CO)cn5)[C@@H](O)[C@H]4O)c3n2)C1

Procedure:
This compound is prepared from (1R,2S,3R,5S)-3-[2-((R)-3-amino-pyrrolidin-1-yl)-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-5-(4-hydroxymethyl-pyrazol-1-yl)-cyclopentane-1,2-diol trifluoroacetate (Example 76) using a procedure analogous to that of 1-{4-[9-[(1R,2S,3R,4S)-2,3-dihydroxy-4-(4-methyl-pyrazol-1-yl)-cyclopentyl]-6-(2,2-diphenyl-ethylamino)-9H-purin-2-ylamino]-cyclohexyl}-3-(3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-urea trifluoroacetate (Example 42). MS (ES+) m/e 400 (MH+/2)
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]=O)=[CH:6][N:5]=[C:4]2[NH:10][CH:11]=[CH:12][C:3]=12.Cl.[CH2:14]([N:21]1[CH2:26][CH2:25][CH2:24][CH:23]([NH:27][NH2:28])[CH2:22]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CCCCO>[CH2:14]([N:21]1[CH2:26][CH2:25][CH2:24][CH:23]([N:27]2[C:2]3=[C:3]4[CH:12]=[CH:11][NH:10][C:4]4=[N:5][CH:6]=[C:7]3[CH:8]=[N:28]2)[CH2:22]1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: NNC1CCCN(Cc2ccccc2)C1
Reactant: O=Cc1cnc2[nH]ccc2c1Cl
Agent: Cl
Solvent: CCCCO
Product: c1ccc(CN2CCCC(n3ncc4cnc5[nH]ccc5c43)C2)cc1
Temperature: 90 °C
Yield: 14.3 %

Procedure:
4-Chloro-1H-pyrrolo[2,3-b]pyridine-5-carbaldehyde (0.40 g, 2.21 mmol, Adesis) and 1-benzyl-3-hydrazinylpiperidine hydrochloride (1.39 g, 4.43 mmol) were suspended in n-BuOH (11.1 mL). The mixture was heated at about 90° C. for about 3 h and then heated at about 120° C. for about 5 h. The reaction mixture was cooled to ambient temperature and the solvent was removed under reduced pressure. The residue was purified by silica gel chromatography eluting with a gradient of 0-5% MeOH in DCM to yield 1-(1-benzylpiperidin-3-yl)-1,6-dihydropyrazolo[3,4-d]pyrrolo[2,3-b]pyridine (0.105 g, 14%) as a brown oil: LC/MS (Table 1, Method b) Rt=1.53 min; MS m/z: 332 (M+H)+.
Reaction SMILES: C(OC([NH:8][C:9]1[CH2:10][C:11]([C:36](=[O:52])[N:37]([CH2:41][CH2:42][CH2:43][O:44][Si](C(C)(C)C)(C)C)[CH2:38][CH2:39][CH3:40])=[CH:12][C:13]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][C:23]([CH2:26][C:27]([O:29][CH2:30][CH2:31][CH2:32][N:33]([CH3:35])[CH3:34])=[O:28])=[CH:22][CH:21]=3)=[CH:16][C:14]=2[N:15]=1)=O)(C)(C)C>ClCCl.C(O)(C(F)(F)F)=O>[NH2:8][C:9]1[CH2:10][C:11]([C:36](=[O:52])[N:37]([CH2:41][CH2:42][CH2:43][OH:44])[CH2:38][CH2:39][CH3:40])=[CH:12][C:13]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][C:23]([CH2:26][C:27]([O:29][CH2:30][CH2:31][CH2:32][N:33]([CH3:34])[CH3:35])=[O:28])=[CH:22][CH:21]=3)=[CH:16][C:14]=2[N:15]=1
Reactant: CCCN(CCCO[Si](C)(C)C(C)(C)C)C(=O)C1=Cc2ccc(-c3ccc(CC(=O)OCCCN(C)C)cc3)cc2N=C(NC(=O)OC(C)(C)C)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCN(CCCO)C(=O)C1=Cc2ccc(-c3ccc(CC(=O)OCCCN(C)C)cc3)cc2N=C(N)C1
Reaction time: 1 h

Procedure:
3-(dimethylamino)propyl 2-(4-((1E,4E)-2-(tert-butoxycarbonylamino)-4-((3-(tert-butyldimethylsilyloxy)propyl)(propyl)carbamoyl)-3H-benzo[b]azepin-8-yl)phenyl)acetate was dissolved in 2 mls of dichloromethane and 0.5 ml of TFA. After about one hour, the mixture was concentrated under reduced pressure and the resulting residue was then re-dissolved in dichloromethane and 1 ml of concentrated ammonium hydroxide added and the mixture vigorously stirred for 15 minutes. This mixture was then diluted with water, extracted with dichloromethane (2×), extracts dried over sodium sulfate and concentrated under reduced pressure. Preparative thin layer chromatography (2×0.5 mm plates, 10% MeOH/DCM/0.5% NH4OH) afforded 3-(dimethylamino)propyl 2-(4-((1E,4E)-2-amino-4-((3-hydroxypropyl)(propyl)carbamoyl)-3H-benzo[b]azepin-8-yl)phenyl)acetate. 1H NMR (400 MHz, CDCl3) δ 7.57-7.65 (m, 2H), 7.46-7.51 (m, 1H), 7.28-7.40 (m, 4H), 6.87 (s, 2H), 4.07-4.21 (m, 2H), 3.56-3.71 (m, 6H), 3.40-3.54 (m, 2H), 2.82 (s, 2H), 2.26-2.36 (m, 2H), 2.20 (s, 6H), 1.59-1.87 (m, 6H), 0.86-0.99 (m, 3H); m/z (APCI-pos) M+1=521.3.
Reaction SMILES: [S-:1][C:2]#[N:3].[K+].[NH2:5][C:6]1[CH:34]=[CH:33][C:9]([O:10][C:11]2[CH:12]=[CH:13][C:14]([F:32])=[C:15]([NH:17][C:18](=[O:31])[C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([C:28]#[N:29])([CH3:27])[CH3:26])[C:20]=3[Cl:30])[CH:16]=2)=[C:8]([N+:35]([O-:37])=[O:36])[CH:7]=1.BrBr>C(O)(=O)C>[NH2:3][C:2]1[S:1][C:7]2[C:8]([N+:35]([O-:37])=[O:36])=[C:9]([O:10][C:11]3[CH:12]=[CH:13][C:14]([F:32])=[C:15]([NH:17][C:18](=[O:31])[C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([C:28]#[N:29])([CH3:27])[CH3:26])[C:20]=4[Cl:30])[CH:16]=3)[CH:33]=[CH:34][C:6]=2[N:5]=1
Reactant: CC(C)(C#N)c1cccc(C(=O)Nc2cc(Oc3ccc(N)cc3[N+](=O)[O-])ccc2F)c1Cl
Reactant: N#C[S-]
Agent: BrBr
Agent: [K+]
Solvent: CC(=O)O
Product: CC(C)(C#N)c1cccc(C(=O)Nc2cc(Oc3ccc4nc(N)sc4c3[N+](=O)[O-])ccc2F)c1Cl
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 25.9 %

Procedure:
Potassium thiocyanate (1.63 g, 16.8 mmol) was suspended in acetic acid (40 mL), and the suspension was stirred at room temperature for 10 min. N-[5-(4-Amino-2-nitrophenoxy)-2-fluorophenyl]-2-chloro-3-(1-cyano-1-methylethyl)benzamide (1.57 g, 3.36 mmol) was added to the obtained solution, and the mixture was further stirred at room temperature for 10 min. A solution of bromine (966 mg, 6.05 mmol) in acetic acid (10 mL) was slowly added dropwise to the obtained solution, and the mixture was stirred at room temperature for 2 hr. A solution of bromine (400 mg, 2.50 mmol) in acetic acid (5 mL) was added, and the mixture was further stirred at room temperature for 6 hr. The resulting yellow insoluble material was filtered off and washed with acetic acid. The filtrate and washings were combined and the mixture was concentrated under reduced pressure. The obtained residue was suspended in ethyl acetate (400 mL)/tetrahydrofuran (200 mL), washed successively with saturated aqueous sodium hydrogen carbonate solution (500 mL) and saturated brine (500 mL), and dried over anhydrous sodium sulfate. Insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (eluate: ethyl acetate), and the obtained solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/n-hexane=50/50→100/0), and the obtained solution was concentrated under reduced pressure to give the title compound (458 mg, 26%) as a yellow powder.
Reaction SMILES: O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.[Br:15][C:16]1[CH:30]=[CH:29][C:19]([C:20]([NH:22][CH2:23][CH:24]([O:27]C)OC)=O)=[CH:18][CH:17]=1>CS(O)(=O)=O>[Br:15][C:16]1[CH:17]=[CH:18][C:19]([C:20]2[O:27][CH:24]=[CH:23][N:22]=2)=[CH:29][CH:30]=1
Reactant: COC(CNC(=O)c1ccc(Br)cc1)OC
Agent: CS(=O)(=O)O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Product: Brc1ccc(-c2ncco2)cc1
Temperature: 25 °C

Procedure:
A solution of 21 mmol of phosphorous pentoxide in 20 ml of methylsulfonic acid was treated with 7 mmol of 4-Bromo-N-(2,2-dimethoxy-ethyl)-benzamide. The reaction mixture was heated for 5 hours at 130°, cooled to room temperature and poured into ice-water. The resulting solid was filtered off and dried to yield the crude title compound as a brownish solid. MS (m/e): 224.0 (MH+, 24%)
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([CH2:16][N:17]3[CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[C@@H:19]([CH3:30])[CH2:18]3)[CH:11]=2)[CH:6]=[CH:7][C:8]=1[F:9].[NH:31]1[CH2:36][CH2:35][CH:34]([C:37]2[CH:38]=[C:39]([CH:43]=[CH:44][CH:45]=2)[C:40](O)=[O:41])[CH2:33][CH2:32]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>CN(C=O)C>[F:9][C:8]1[CH:7]=[CH:6][C:5]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([CH2:16][N:17]3[CH2:22][CH2:21][NH:20][C@@H:19]([CH3:30])[CH2:18]3)[CH:11]=2)=[CH:4][C:3]=1[CH2:2][NH:1][C:40](=[O:41])[C:39]1[CH:43]=[CH:44][CH:45]=[C:37]([CH:34]2[CH2:33][CH2:32][NH:31][CH2:36][CH2:35]2)[CH:38]=1
Reactant: C[C@H]1CN(Cc2cccc(-c3ccc(F)c(CN)c3)c2)CCN1C(=O)OC(C)(C)C
Reactant: O=C(O)c1cccc(C2CCNCC2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H]1CN(Cc2cccc(-c3ccc(F)c(CNC(=O)c4cccc(C5CCNCC5)c4)c3)c2)CCN1
Yield: 19.8 %

Procedure:
Following the procedure outlined in Example 40, 1,1-dimethylethyl (2S)-4-{[3′-(aminomethyl)-4′-fluoro-3-biphenylyl]methyl}-2-methyl-1-piperazinecarboxylate (0.100 g, 0.242 mmol), 3-(4-piperidinyl)benzoic acid (0.074 g, 0.243 mmol), HATU (0.103 g, 0.271 mmol), and diisopropylethylamine (0.10 mL, 0.574 mmol) in DMF (2.5 mL) were reacted to give the desired product (0.024 g, 21.0%). EI-MS m/z 501 (M−H)+.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][Cl:5].[CH3:6][O:7][C:8]1[CH:9]=[C:10]([N:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)[CH:11]=[CH:12][C:13]=1[O:14][CH3:15].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:5][CH2:4][CH2:3][CH2:2][N:19]1[CH2:18][CH2:17][N:16]([C:10]2[CH:11]=[CH:12][C:13]([O:14][CH3:15])=[C:8]([O:7][CH3:6])[CH:9]=2)[CH2:21][CH2:20]1
Reactant: ClCCCBr
Reactant: COc1ccc(N2CCNCC2)cc1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(N2CCN(CCCCl)CC2)cc1OC
Reaction time: 0.5 h

Procedure:
The 1-(3-chloropropyl-4-(3,4-dimethoxyphenyl)piperazine is prepared in the following manner: 11.5 g (70.2 m. moles) of 1-bromo-3-chloropropane are added quickly with stirring to a mixture of 13 g (58.5 m. moles) of 1-(3,4-dimethoxyphenyl)piperazine [prepared according to P. C. Jain et coll. J. Med. Chem. 10, 812 (1967)] and 9.7 g (70.2 m. moles) of potassium carbonate in 60 cc of N,N-dimethylformamide. The stirring is continued for 4 hours 30 min at ambient temperature. The inorganic products are then filtered and the filtrate concentrated to dryness under reduced pressure. The residue is dissolved in ether and the solution obtained washed with water, then dried on sodium sulfate. After evaporation of the ether, there is obtained 14 g (yield) 80%) of 1-(3-chloropropyl)-4-(3,4-dimethoxyphenyl)piperazine that is used without any other purification.
Reaction SMILES: [CH2:1]([C:3]1[S:7][C:6]([C:8]([C:10]2[CH:15]=[C:14]([Br:16])[CH:13]=[CH:12][C:11]=2[Cl:17])=O)=[CH:5][CH:4]=1)[CH3:2].C([SiH](CC)CC)C.C(=O)([O-])O.[Na+]>ClCCl>[Br:16][C:14]1[CH:13]=[CH:12][C:11]([Cl:17])=[C:10]([CH2:8][C:6]2[S:7][C:3]([CH2:1][CH3:2])=[CH:4][CH:5]=2)[CH:15]=1
Reactant: CCc1ccc(C(=O)c2cc(Br)ccc2Cl)s1
Agent: CC[SiH](CC)CC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCc1ccc(Cc2cc(Br)ccc2Cl)s1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 89.2 %

Procedure:
5-Bromo-2-chlorobenzoic acid (5.00 g) was suspended in dichloromethane (10 ml), and thereto were added oxalyl chloride (2.2 ml) and N,N-dimethylformamide (2 drops). The mixture was stirred at room temperature for 6 hours. The solvent was evaporated under reduced pressure to give 5-bromo-2-chlorobenzoyl chloride. This compound and 2-ethylthiophene (2.38 g) were dissolved in dichloromethane (20 ml), and thereto was added aluminum chloride (3.11 g) at 0° C. The mixture was stirred at the same temperature for one hour. The reaction mixture was poured into a cold 10% aqueous hydrochloric acid solution, and the mixture was extracted with ethyl acetate. The extract was washed successively with 10% aqueous hydrochloric acid solution, water, a saturated aqueous sodium hydrogen carbonate solution, and brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, the residue was purified by silica gel column chromatography (hexane:ethyl acetate=100:1) to give 5-bromo-2-chlorophenyl 5-ethyl-2-thienyl ketone (5.29 g) as an oil. APCI-Mass m/Z 329/331 (M+H). (2) A solution of the above 5-bromo-2-chlorophenyl 5-ethyl-2-thienyl ketone (5.29 g) in dichloromethane (50 ml)acetonitrile (50 ml) was cooled under ice-cooling, and thereto were added dropwise triethylsilane (7.69 ml) and boron trifluoride•diethyl ether complex (6.1 ml). Subsequently, the mixture was stirred at room temperature for 3.5 hours, and was cooled again under ice-cooling. To the mixture was added a saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with chloroform, washed with brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane) to give 5-bromo-2-chloro-1-(5-ethyl-2-thienylmethyl)benzene (4.52 g) as a colorless liquid.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[C:17]3[C:31](/[CH:32]=[CH:33]/[C:34]4[CH:39]=[CH:38][CH:37]=[C:36]([N:40]5[CH2:44][CH2:43][CH2:42][C:41]5=[O:45])[CH:35]=4)=[N:30][N:29](C4CCCCO4)[C:18]=3[N:19]=[C:20]([C:22]3[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=3)[CH:21]=2)=[O:15])[CH2:10][CH2:9]1)=O)(C)(C)C.Cl.C(OCC)C>CO.O1CCOCC1>[OH:28][C:25]1[CH:24]=[CH:23][C:22]([C:20]2[N:19]=[C:18]3[NH:29][N:30]=[C:31](/[CH:32]=[CH:33]/[C:34]4[CH:35]=[C:36]([N:40]5[CH2:44][CH2:43][CH2:42][C:41]5=[O:45])[CH:37]=[CH:38][CH:39]=4)[C:17]3=[C:16]([C:14]([N:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)=[O:15])[CH:21]=2)=[CH:27][CH:26]=1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)c2cc(-c3ccc(O)cc3)nc3c2c(/C=C/c2cccc(N4CCCC4=O)c2)nn3C2CCCCO2)CC1
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Solvent: CO
Product: O=C(c1cc(-c2ccc(O)cc2)nc2[nH]nc(/C=C/c3cccc(N4CCCC4=O)c3)c12)N1CCNCC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 103.8 %

Procedure:
To a solution of 4-[6-(4-Hydroxy-phenyl)-3-{(E)-2-[3-(2-oxo-pyrrolidin-1-yl)-phenyl]-vinyl}-1-(tetrahydro-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridine-4-carbonyl]-piperazine-1-carboxylic acid tert-butyl ester (0.246 g, 0.36 mmol) in methanol (5 ml) was added 4N HCl in dioxane (0.9 ml). The reaction mixture was stirred at room temperature for 18 hours, diethyl ether was then added, the resulting precipitated was filtered and washed once with diethyl ether to afford the hydrochloride salt of the title compound (0.19 g, 93%) as an orange solid.
Reaction SMILES: Cl.C(OC([NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[NH:16][C:17](=[O:37])[C:18]1[CH:23]=[CH:22][C:21]([CH:24]2[CH2:29][CH2:28][N:27](C(OC(C)(C)C)=O)[CH2:26][CH2:25]2)=[CH:20][CH:19]=1)=O)(C)(C)C>O1CCOCC1>[NH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[NH:16][C:17](=[O:37])[C:18]1[CH:23]=[CH:22][C:21]([CH:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)=[CH:20][CH:19]=1
Reactant: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)c1ccc(C2CCN(C(=O)OC(C)(C)C)CC2)cc1
Agent: Cl
Solvent: C1COCCO1
Product: Nc1ccccc1NC(=O)c1ccc(C2CCNCC2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 81.7 %

Procedure:
A 4M solution of hydrogen chloride in dioxane (5 ml, 20 mmol) was added to a stirred solution of N-(2-t-butoxycarbonylaminophenyl)-4-(1-t-butoxycarbonylpiperidin-4-yl)benzamide (Method 15, 693 mg, 1.40 mmol) in 1,4-dioxane (5 ml) and the mixture stirred at ambient temperature for 18 hours. The resultant precipitate was filtered and washed with diethyl ether. The resultant solid was dissolved in water and basified to pH 12 with 2M solution of aqueous sodium hydroxide. The resultant precipitate was filtered, washed with water and dried in vacuo to give the title compound (338 mg, 82%); NMR Spectrum: (DMSO-d6) 1.52 (m, 2H), 1.69 (m, 2H), 2.60 (m, 3H), 3.02 (m, 2H), 4.84 (br, 2H), 6.58 (m, 1H), 6.76 (d, 1H), 6.95 (m, 1H), 7.16 (d, 1H), 7.34 (d, 2H), 7.89 (d, 2H), 9.53 (br, 1H); Mass Spectrum: M+H+ 296.
Reaction SMILES: [C:1]([N:5]1[C:13]2[C:8](=[CH:9][C:10]([C:14]([NH2:16])=[O:15])=[CH:11][CH:12]=2)[CH:7]=[C:6]1[N:17]1[CH2:22][CH2:21][CH:20]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:19][CH2:18]1)(=[O:4])[CH:2]=[CH2:3].[CH2:30]([NH2:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>>[CH2:30]([NH:37][CH2:3][CH2:2][C:1]([N:5]1[C:13]2[C:8](=[CH:9][C:10]([C:14]([NH2:16])=[O:15])=[CH:11][CH:12]=2)[CH:7]=[C:6]1[N:17]1[CH2:22][CH2:21][CH:20]([CH2:23][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH2:19][CH2:18]1)=[O:4])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: C=CC(=O)n1c(N2CCC(Cc3ccccc3)CC2)cc2cc(C(N)=O)ccc21
Reactant: NCc1ccccc1
Product: NC(=O)c1ccc2c(c1)cc(N1CCC(Cc3ccccc3)CC1)n2C(=O)CCNCc1ccccc1

Procedure:
was prepared by reacting 1-acryloyl-(4-benzylpiperidinyl)-indole-5-carboxamide with benzylamine. M+ 479.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=[C:4]([Cl:17])[CH:3]=1.[F:18][C:19]([F:31])([F:30])[O:20][C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1>>[Cl:17][C:4]1[CH:3]=[C:2]([C:24]2[CH:23]=[CH:22][C:21]([O:20][C:19]([F:18])([F:30])[F:31])=[CH:26][CH:25]=2)[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=1
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Reactant: Cc1c2n(c3c(Br)cc(Cl)cc13)CCNC2=O
Product: Cc1c2n(c3c(-c4ccc(OC(F)(F)F)cc4)cc(Cl)cc13)CCNC2=O

Procedure:
The title compound, white solid (70 mg, 71%), MS (ISP) m/z=395.5 [(M+H)+], mp 212° C., was prepared in accordance with the general method of example 1 from 6-bromo-8-chloro-10-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (intermediate 12) (78.4 mg, 0.25 mmol) and commercially available 4-trifluoromethoxy-phenylboronic acid (66.9 mg, 0.325 mmol).
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][C:5]=2[N:6]=1.[CH2:12]([C@H:14]1[O:16][CH2:15]1)Cl.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[O:16]1[CH2:15][C@H:14]1[CH2:12][O:11][C:8]1[CH:9]=[CH:10][C:4]2[S:3][C:2]([CH3:1])=[N:6][C:5]=2[CH:7]=1
Reactant: Cc1nc2cc(O)ccc2s1
Reactant: ClC[C@@H]1CO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Cc1nc2cc(OC[C@@H]3CO3)ccc2s1
Reaction time: 8 h

Procedure:
A mixture of 2-methylbenzothiazol-5-ol, a compound of formula (1) (6.0 g, 36 mmol), (S)-(+)-epichlorohydrin, a compound of formula (2) (20 ml, 182 mmol), and potassium carbonate (20 g, 144 mmol) in acetone (100 ml), was heated to reflux and allowed to stir overnight. The solution was allowed to cool and filtered through Celite 512. The filtrate was evaporated (in vacuo), to yield an oil. The oil was chromatographed on silica gel, eluting with 20% ethyl acetate/hexanes, to yield 5-[((2S)oxiran-2-yl)methoxy]-2-methylbenzothiazole as a white solid (6.2 g, 28 mmol).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:11])[CH2:5][C:6]1[N:7]=[N:8][NH:9][N:10]=1)[CH3:2].S(=O)(=O)(O)O.C(OCC)(=O)C.[OH-].[Na+].[CH3:25][C:26](O)([CH3:28])[CH3:27]>FC(F)(F)C(O)=O>[CH2:1]([O:3][C:4](=[O:11])[CH2:5][C:6]1[N:7]=[N:8][N:9]([C:26]([CH3:28])([CH3:27])[CH3:25])[N:10]=1)[CH3:2]
Reactant: CC(C)(C)O
Reactant: CCOC(=O)Cc1nn[nH]n1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)Cc1nnn(C(C)(C)C)n1
Temperature: 25 °C
Reaction time: 12 h
Yield: 52 %

Procedure:
To a solution of (2H-tetrazol-5-yl)-acetic acid ethyl ester (2.0 g, 13 mmol) in 2-methyl-propan-2-ol (2.6 mL) and trifluoroacetic acid (6 mL) was added concentrated sulfuric acid (0.35 mL, 6.4 mmol) and the reaction was stirred at room temperature for 12 h. Ethyl acetate was added and the solution was neutralized by addition of an aqueous sodium hydroxide solution (2 N). The solution was extracted several times with ethyl acetate, and the organic layers were combined, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified via silica gel column chromatography to provide (2-tert-butyl-2H-tetrazol-5-yl)-acetic acid ethyl ester (2.0 g, 52% yield).
Reaction SMILES: [CH3:1][C:2]([CH3:15])=[CH:3][C:4](/[N:6]=[C:7](/[N:10]1[CH2:14][CH2:13][CH2:12][CH2:11]1)\SC)=O.C(O)(=O)C(O)=O.[CH2:22]([NH:24][NH2:25])[CH3:23].C(N(CC)C(C)C)(C)C>O1CCOCC1.C(OCC)(=O)C>[CH2:22]([N:24]1[C:4]([CH:3]=[C:2]([CH3:15])[CH3:1])=[N:6][C:7]([N:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[N:25]1)[CH3:23]
Reactant: CCNN
Reactant: CS/C(=N\C(=O)C=C(C)C)N1CCCC1
Agent: O=C(O)C(=O)O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CCn1nc(N2CCCC2)nc1C=C(C)C
Temperature: 100 °C
Reaction time: 3 h
Yield: 38.1 %

Procedure:
A mixture of (Z)-methyl N-3-methylbut-2-enoylpyrrolidine-1-carbimidothioate (1.19 g, 5.26 mmol, Eq: 1.00), ethylhydrazine oxalate (2.37 g, 15.8 mmol, Eq: 3) and N,N-diisopropyl ethyl amine (5.44 g, 7.15 ml, 42.1 mmol, Eq: 8) in dioxane (20 ml) was heated to 100° C., the resulting suspension was stirred for 3 hours at 100° C. The mixture was diluted with ethyl acetate and washed with water for 3 times. The organic layer was separated, dried over magnesium sulfate, filtrated and evaporated. The crude material was applied on silicagel and purified by flash chromatography over a 20 g silicagel column using heptane/ethyl acetate 30-70% as eluent affording 1-ethyl-5-(2-methyl-propenyl)-3-pyrrolidin-1-yl-1H-[1,2,4]triazole (441 mg/38.1%) as a light yellow oil. MS: m/e=221.0 (M+H+)
Reaction SMILES: [CH3:1][O:2][C:3]1[S:4][CH:5]=[CH:6][CH:7]=1.[Li]CCCC.[C:13](=[O:15])=[O:14]>O1CCCC1>[CH3:1][O:2][C:3]1[S:4][C:5]([C:13]([OH:15])=[O:14])=[CH:6][CH:7]=1
Reactant: COc1cccs1
Reactant: O=C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1ccc(C(=O)O)s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 91 %

Procedure:
2-(methyloxy)thiophene (1.01 g, 8.85 mmol) was added slowly over 15 min to a 100 mL round-bottomed flask containing 2.5M nBuLi in hexanes (3.8 mL, 9.50 mmol) in Tetrahydrofuran (THF) (40 mL) at −78° C. After warming to room temperature and stirring for 2 h, the mixture was cooled to −35° C. and crushed solid CO2 was added. The mixture warmed to room temperature over 3 hours and was cooled in an ice bath and quenched with NH4Cl(sat.). The cold reaction mixture was partitioned between CHCl3/H2O, the aqueous layer was made acidic with 6N HCl. The separated organic layer was dried with Na2SO4 and concentrated affording the title compound (1.3 g, 8.05 mmol, 91%) which was used without further purification: LC-MS (ES) m/z=159 (M+H)+.