Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]([OH:12])=O.[NH2:13][CH2:14][CH2:15][CH2:16][CH2:17][OH:18].ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(N(C(C)C)CC)(C)C>CN(C=O)C>[OH:18][CH2:17][CH2:16][CH2:15][CH2:14][NH:13][C:10]([C:2]1[O:1][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=1)=[O:12]
Reactant: NCCCCO
Reactant: O=C(O)c1cc2ccccc2o1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCCCCO)c1cc2ccccc2o1
Temperature: 25 °C
Reaction time: 8 h
Yield: 48.7 %

Procedure:
2-Benzofurancarboxylic acid (5.0 g, 30.8 mmol) and 4-amino-1-butanol (3.4 ml, 37 mmol) were dissolved in DMF (45 ml). 1-hydroxybenzotriazole (5.0 g, 37 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (7.7 g, 40 mmol), and diisopropylethylamine (10.7 ml, 61.7 mmol) were added sequentially to the solution and allowed to stir at room temperature overnight. After removing excess solvent in vacuo, the residue was taken up in water and the product was extracted into dichloromethane. The organics were combined, washed with brine, dried over Na2SO4, and solvent removed in vacuo to give a solid which was purified by column chromatography (100% ethyl acetate) to give 3.5 g (50% yield) of a white solid. 1H NMR (DMSO-d6): δ1.35-1.62 (m, CH2, CH2), 3.29 (q, CH2), 3.41 (q, CH2), 4.3 (t, NH), 7.78 (d, 1 Ar H), 7.63 (d, 1 Ar H), 7.51 (s, 1 Ar H), 7.46 (t, 1 Ar H), 7.35 (t, 1 Ar H), 8.71 (t, NH) Electrospray Mass Spec: m/z 234.2 (M+H)+.
Reaction SMILES: [Si]([O:18][CH2:19][C:20]1[C:21]([N:38]2[CH2:43][C@H:42]([CH3:44])[O:41][C@H:40]([CH3:45])[CH2:39]2)=[C:22]([F:37])[C:23](F)=[C:24]([C:26]([C:29]2[CH:34]=[N:33][C:32](Cl)=[CH:31][N:30]=2)=[N:27][OH:28])[CH:25]=1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.[CH3:46][S-:47].[Na+].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.C(OC(=O)C)C>[CH3:44][C@@H:42]1[CH2:43][N:38]([C:21]2[C:20]([CH2:19][OH:18])=[CH:25][C:24]3[C:26]([C:29]4[CH:34]=[N:33][C:32]([S:47][CH3:46])=[CH:31][N:30]=4)=[N:27][O:28][C:23]=3[C:22]=2[F:37])[CH2:39][C@H:40]([CH3:45])[O:41]1
Reactant: C[C@@H]1CN(c2c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)cc(C(=NO)c3cnc(Cl)cn3)c(F)c2F)C[C@H](C)O1
Reactant: C[S-]
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CSc1cnc(-c2noc3c(F)c(N4C[C@@H](C)O[C@@H](C)C4)c(CO)cc23)cn1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 39.3 %

Procedure:
1-{5-({[tert-Butyl(diphenyl)silyl]oxy}methyl)-4-[(2R,6S)-2,6-dimethylmorpholin-4-yl]-2,3-difluorophenyl}-1-(5-chloropyrazin-2-yl)-N-hydroxymethanimine (Intermediate 200, 400 mg, 0.61 mmol) in DMF (5 mL) was treated with sodium thiomethoxide (45.3 mg, 0.61 mmol) at room temperature, the mixture was stirred at room temperature for 10 min. K2CO3 (5 eq) was added and the mixture was heated to 100° C. for 1 hour. The reaction mixture was diluted with ethylacetate (20 ml). Organic layer washed with water and brine, then dried over sodium sulfate, filtered, and the filtrate was concentrated, purified by silica gel column chromatography (Hexanses/EtOAc, gradient) to give the desired product (97 mg, 39.0%).
Reaction SMILES: [CH2:1]([NH:8][C@@H:9]1[CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][C:16]=2[OH:19])[CH2:11][C@H:10]1[OH:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[O-].[Na+].Br[CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27]>CS(C)=O>[CH2:1]([NH:8][C@@H:9]1[CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][C:16]=2[O:19][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:11][C@H:10]1[OH:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)CBr
Reactant: Oc1cccc2c1C[C@@H](NCc1ccccc1)[C@H](O)C2
Agent: C[O-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CCOC(=O)COc1cccc2c1C[C@@H](NCc1ccccc1)[C@H](O)C2
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 70.4 %

Procedure:
To a stirring solution of trans 3-benzylamino-2,5-dihydroxy-1,2,3,4-tetrahydronaphthalene (14 g) in dry dimethylsulfoxide (150 mL) was added sodium methoxide (3.05 g). This was stirred for 10 min at room temperature, then cooled in a 10° C. bath while ethyl bromoacetate (9.1 g) was added over 3 min, during which the temperature of the mixture remained below 25° C. The cooling bath was removed, and the reaction mixture was stirred for 4.5 h at room temperature under nitrogen. Dilution with a half-saturated aqueous sodium bicarbonate solution (800 mL) was followed by extraction with diethyl ether (250 mL four times). The combined extracts were washed sequentially with cold 5% aqueous sodium hydroxide solution, water (300 mL twice), and brine and dried over anhydrous sodium sulfate. The solvent was evaporated under vacuum to provide crude product. The crude product was recrystallized from 50% ethyl acetate in hexane (100 mL) to yield the title product (13 g) as a white solid (mp 93-97° C.).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([F:9])[CH:3]=1.CC(C)([O-])C.[K+].C(=O)([O-])[O-].[K+].[K+].[Cl:22][C:23]1[N:28]=[C:27]2[NH:29][CH:30]=[CH:31][C:26]2=[C:25]([N+]([O-])=O)[CH:24]=1>CN(C=O)C.C(OCC)(=O)C>[Cl:22][C:23]1[N:28]=[C:27]2[NH:29][CH:30]=[CH:31][C:26]2=[C:25]([O:8][C:5]2[CH:6]=[CH:7][C:2]([NH2:1])=[CH:3][C:4]=2[F:9])[CH:24]=1
Reactant: O=[N+]([O-])c1cc(Cl)nc2[nH]ccc12
Reactant: Nc1ccc(O)c(F)c1
Agent: CC(C)(C)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Nc1ccc(Oc2cc(Cl)nc3[nH]ccc23)c(F)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
4-Amino-2-fluorophenol (0.77 g, 6.07 mmol) is dissolved in DMF. Potassium tert-butoxide (0.68 g, 6.07 mmol) is added, and the mixture is stirred at room temperature for 30 minutes. Powdered potassium carbonate (0.35 g, 2.53 mmol) and 1 g (5.06 mmol) of 6-chloro-4-nitro-1H-pyrrolo[2,3-b]pyridine (from example XXX) are then added successively. The mixture is stirred at 120° C. for 12 hours. After cooling, the mixture is diluted with ethyl acetate (200 ml). The suspension is filtered off with suction through Celite®, and the filtercake is washed with ethyl acetate. The solution is extracted successively with aqueous sodium bicarbonate solution and sodium chloride solution. The organic phase is dried over anhydrous magnesium sulfate and concentrated. The residue is purified by column chromatography (silica gel 60, mobile phase: DCM:acetone=5:1). This gives 0.95 g (67% of theory) of product.
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[NH:7][CH:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[CH3:15][C:16]([CH3:18])=O.C(O)(=O)C.[BH3-]C#N.[Na+]>CO>[C:1]([O:5][C:6](=[O:14])[NH:7][CH:8]1[CH2:13][CH2:12][N:11]([CH:16]([CH3:18])[CH3:15])[CH2:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: CC(C)=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)N1CCC(NC(=O)OC(C)(C)C)CC1
Temperature: 0 °C
Yield: 72.7 %

Procedure:
t-Butyl-piperidin-4-ylcarbamate (3 g, 15 mmol) obtained in Preparation Example 2-ii was dissolved in methanol (30 ml) in a 100 ml vessel, and acetone (7.70 ml, 105 mmol) and acetic acid (0.45 ml, 7.5 mmol) were added thereto while stirring. To the resulting mixture, NaCNBH3 (1.88 mg, 30 mmol) was added dropwise in 4-divided portions and reacted for 18 hrs. After the completion of reaction, ice water was poured to the reaction product while stirring, and the resulting mixture was extracted with ethyl acetate. The organic layer was separated, washed with an aqueous sodium bicarbonate solution and brine in order, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue thus obtained was subjected to a silica gel column chromatography to obtain 2.644 g of the title compound as a white solid (yield 73.3%).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1C=CC(COC(/N=N/C(OCC2C=CC=CC=2)=O)=O)=CC=1.[F:42][C:43]([F:52])([F:51])[C:44]1[CH:49]=[CH:48][C:47]([OH:50])=[CH:46][CH:45]=1.[CH3:53][C:54]1[O:58][C:57]([CH2:59][CH2:60]O)=[CH:56][CH:55]=1>C1COCC1>[CH3:53][C:54]1[O:58][C:57]([CH2:59][CH2:60][O:50][C:47]2[CH:46]=[CH:45][C:44]([C:43]([F:51])([F:52])[F:42])=[CH:49][CH:48]=2)=[CH:56][CH:55]=1
Reactant: Oc1ccc(C(F)(F)F)cc1
Reactant: Cc1ccc(CCO)o1
Agent: O=C(/N=N/C(=O)OCc1ccccc1)OCc1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1ccc(CCOc2ccc(C(F)(F)F)cc2)o1
Reaction time: 0.17 h
Yield: 66.5 %

Procedure:
To a solution of triphenylphosphine (1.56 g, 5.95 mmol) in THF (40 mL) was added DBAD (1.37 g, 5.95 mmol). After 10 min, 4-trifluoromethylphenol (0.964 g, 5.95 mmol) was added. After 10 additional minutes, compound 21A (0.500 g, 3.97 mmol) was added. After 14 h at 25° C., the reaction was concentrated in vacuo and purified by flash chromatography on silica eluting with chloroform to give 0.713 g (44%) of compound 232A as a clear oil.
Reaction SMILES: [SH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.[Br:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]Br.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Br:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][S:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:10][CH:11]=1
Reactant: BrCCCCCBr
Reactant: COC(=O)c1ccc(S)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc(SCCCCCBr)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 73.4 %

Procedure:
To a solution of methyl 4-mercaptobenzoate (3.39 g) and 1,5-dibromopentane (9.31 g) in dimethyl formamide (100 mL), potassium carbonate (3.07 g) was added. The reaction mixture was stirred at room temperature for 3 hours. To the reaction mixture, water (300 mL) was added and the aqueous layer was extracted twice with an n-hexane-ethyl acetate solution (n-hexane:ethyl acetate=1:1) (150 mL). The combined organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and then concentrated. The residue was purified by silica gel chromatography (n-hexane:ethyl acetate=1:0→8:2) to obtain the title compound (4.69 g) having the following physical properties.
Reaction SMILES: [OH:1][C:2]([C:11]1[CH:12]=[CH:13][C:14]2[NH:20][C:19]3[N:21]=[C:22]([C:25]([F:28])([F:27])[F:26])[CH:23]=[CH:24][C:18]=3[CH2:17][N:16]([S:29]([C:32]3[CH:37]=[CH:36][C:35]([O:38][C:39]([F:42])([F:41])[F:40])=[CH:34][CH:33]=3)(=[O:31])=[O:30])[C:15]=2[CH:43]=1)([CH:8]([CH3:10])[CH3:9])[C:3]([O:5]CC)=[O:4].[Li+].[OH-].Cl>CCO.O>[OH:1][C:2]([C:11]1[CH:12]=[CH:13][C:14]2[NH:20][C:19]3[N:21]=[C:22]([C:25]([F:27])([F:28])[F:26])[CH:23]=[CH:24][C:18]=3[CH2:17][N:16]([S:29]([C:32]3[CH:33]=[CH:34][C:35]([O:38][C:39]([F:40])([F:42])[F:41])=[CH:36][CH:37]=3)(=[O:31])=[O:30])[C:15]=2[CH:43]=1)([CH:8]([CH3:10])[CH3:9])[C:3]([OH:5])=[O:4]
Reactant: CCOC(=O)C(O)(c1ccc2c(c1)N(S(=O)(=O)c1ccc(OC(F)(F)F)cc1)Cc1ccc(C(F)(F)F)nc1N2)C(C)C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)C(O)(C(=O)O)c1ccc2c(c1)N(S(=O)(=O)c1ccc(OC(F)(F)F)cc1)Cc1ccc(C(F)(F)F)nc1N2
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of ethyl 2-hydroxy-3-methyl-2-[6-{[4-(trifluoromethoxy)phenyl]sulfonyl}-2-(trifluoromethyl)-6,11-dihydro-5H-pyrido[2,3-b][1,5]benzodiazepin-8-yl]butanoate (153 mg, 0.242 mmol, Example 509) in 4 mL of EtOH was added a solution of 1N LiOH (2.5 ml) in water, and the solution was stirred for 48 h at rt. LC-MS showed the reaction complete. The reaction pH was adjusted to 6-7 with 1N HCl, and the mixture was concentrated. The resulting residue was dissolved in CH2Cl2 and filtered to remove the salt. The filtrate was concentrated and the residue was purified by chromatography to give the title compound as a white solid; Mass Spectrum: m/e=606 (M+1).
Reaction SMILES: [CH3:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][CH3:10])[C:4]=1[NH:11]C(C)=O.C(O)(=O)C.S(=O)(=O)(O)O.[N+:24]([O-])([OH:26])=[O:25]>O>[CH2:2]([C:3]1[CH:8]=[C:7]([N+:24]([O-:26])=[O:25])[CH:6]=[C:5]([CH2:9][CH3:10])[C:4]=1[NH2:11])[CH3:1]
Reactant: O=[N+]([O-])O
Reactant: CCc1cccc(CC)c1NC(C)=O
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(=O)O
Product: CCc1cc([N+](=O)[O-])cc(CC)c1N
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 58 parts of 2,6-diethylacetanilide in 100 parts of glacial acetic acid and 184 parts of concentrated sulfuric acid is treated at 10° with a mixture of 19.5 parts by volume of concentrated nitric acid and 13 parts by volume of concentrated sulfuric acid. After addition is completed, the mixture is stirred at 25°C for 1 hour. It is then poured into water and ice, and the solid filtered, washed with water and dried. The 2,6-diethyl-4-nitroacetanilide (30 parts) is treated with 150 parts by volume of refluxing 70% sulfuric acid solution for one hour, and the mixture poured onto ice and made basic with 5N sodium hydroxide solution. The solid 2,6-diethyl-4-nitroaniline is filtered, washed with water and recrystallized from methyl alcohol-water.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][N:8]([C:12](=[O:17])[C:13]([F:16])([F:15])[F:14])[CH2:9]2)=[C:4]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[Cl:24])[CH:3]=1.C(N(CC)CC)C.[Cl:32][C:33]1[CH:38]=[CH:37][C:36]([S:39](Cl)(=[O:41])=[O:40])=[CH:35][CH:34]=1>ClCCl>[Cl:32][C:33]1[CH:38]=[CH:37][C:36]([S:39]([NH:1][C:2]2[CH:11]=[C:10]3[C:5]([CH2:6][CH2:7][N:8]([C:12](=[O:17])[C:13]([F:16])([F:14])[F:15])[CH2:9]3)=[C:4]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:24])[CH:3]=2)(=[O:41])=[O:40])=[CH:35][CH:34]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: Nc1cc2c(c(-c3ccccc3Cl)c1)CCN(C(=O)C(F)(F)F)C2
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(N1CCc2c(cc(NS(=O)(=O)c3ccc(Cl)cc3)cc2-c2ccccc2Cl)C1)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 44 %

Procedure:
1-[7-amino-5-(2-chloro-phenyl)-3,4-dihydro-1H-isoquinolin-2-yl]-2,2,2-trifluoro-ethanone (80 mgs, 0.2 mmoles) was stirred in dichloromethane (12 mls) and triethylamine (80 ul, 0.58 mmoles) was added, followed by 4-chlorobenzenesulphonyl chloride (75 mgs, 0.36 mmoles). The reaction was flushed with nitrogen and left stirring at room temperature overnight. The reaction was purified by semi-preparative C18 HPLC (47 mgs, 44% yield, 100% pure, CO-AAW00034).
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=1[N:19]1[N:23]=[CH:22][CH:21]=[N:20]1)=[O:11].F[C:25]1[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][N:26]=1>>[F:18][C:15]1[CH:16]=[CH:17][C:12]([C:10]([N:4]2[CH2:5][CH2:6][CH2:7][C@@H:8]([CH3:9])[C@H:3]2[CH2:2][NH:1][C:25]2[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][N:26]=2)=[O:11])=[C:13]([N:19]2[N:23]=[CH:22][CH:21]=[N:20]2)[CH:14]=1
Reactant: Fc1ccc(C(F)(F)F)cn1
Reactant: C[C@@H]1CCCN(C(=O)c2ccc(F)cc2-n2nccn2)[C@@H]1CN
Product: C[C@@H]1CCCN(C(=O)c2ccc(F)cc2-n2nccn2)[C@@H]1CNc1ccc(C(F)(F)F)cn1

Procedure:
The title compound was prepared following the same general protocol as described for Example A1 using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(4-fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone and 2-fluoro-5-(trifluoromethyl)pyridine. ESI-MS (m/z): 463.4 [M+1]+. 1H NMR (300 MHz, DMSO-d6) δ 8.40-6.55 (m, 9H), 4.85-2.70 (m, 5H), 1.85-0.65 (m, 8H).
Reaction SMILES: I[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.[Cl-].[Li+].C([Mg]Cl)(C)C.[CH3:19][C:20]([CH3:25])([CH3:24])[CH2:21][CH:22]=[O:23].O>O1CCCC1>[OH:23][CH:22]([C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1)[CH2:21][C:20]([CH3:25])([CH3:24])[CH3:19]
Reactant: CC(C)(C)CC=O
Reactant: COC(=O)c1ccc(I)cc1
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1ccc(C(O)CC(C)(C)C)cc1
Temperature: -40 °C
Reaction time: 0.5 h
Yield: 94.7 %

Procedure:
To a −40° C. solution of methyl 4-iodobenzoate (1 g, 4 mmol) in tetrahydrofuran (10 mL) was added isopropylmagnesium chloride lithium chloride (3.82 mL, 1.3 M in THF, 4.98 mmol). The mixture was stirred at −40° C. for 30 minutes. 3,3-Dimethylbutanal (573 mg, 2.86 mmol) was added. The reaction was stirred at room temperature for 4 hours. Water (10 mL) was added and the mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered and concentrated. Purification by column chromatography gave (+/−)-methyl 4-(1-hydroxy-3,3-dimethylbutyl)benzoate (640 mg, 95%). 1H NMR (400 MHz, CDCl3, δ): 7.93 (d, 2H), 7.34 (d, 2H), 4.81-4.84 (m, 1H), 3.84 (s, 3H), 1.70-1.61 (m, 1H), 1.53-1.49 (m, 1H), 0.94 (s, 9H).
Reaction SMILES: [N+:1]([C:4]1[CH:19]=[CH:18][C:7]2[N:8]=[C:9]([CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[NH:10][C:6]=2[CH:5]=1)([O-])=O.NC1C=C2C(=CC=1)N(CC1C=CC=CC=1)C=C2>>[NH2:1][C:4]1[CH:19]=[CH:18][C:7]2[NH:8][C:9]([CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[N:10][C:6]=2[CH:5]=1
Reactant: O=[N+]([O-])c1ccc2nc(Cc3ccccc3)[nH]c2c1
Agent: Nc1ccc2c(ccn2Cc2ccccc2)c1
Product: Nc1ccc2[nH]c(Cc3ccccc3)nc2c1

Procedure:
The title compound was prepared from 5-nitro-2-benzylbenzimidazole by an analogous reduction method to that described above for 5-amino-1-benzyl-1H-indole; m/z (M+1)+224. Also note the published method (J. Het. Chem., 23, 1109-13, (1986)).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]2[N:9]=[CH:10][C:11]([C:12]([OH:14])=O)=[C:4]2[N:3]=1.[C:15]([C:17]1[CH:23]=[CH:22][C:20]([NH2:21])=[CH:19][CH:18]=1)#[CH:16].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>[C:15]([C:17]1[CH:23]=[CH:22][C:20]([NH:21][C:12]([C:11]2[CH:10]=[N:9][N:5]3[C:6]([CH3:8])=[CH:7][C:2]([CH3:1])=[N:3][C:4]=23)=[O:14])=[CH:19][CH:18]=1)#[CH:16]
Reactant: C#Cc1ccc(N)cc1
Reactant: Cc1cc(C)n2ncc(C(=O)O)c2n1
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#Cc1ccc(NC(=O)c2cnn3c(C)cc(C)nc23)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 45.5 %

Procedure:
5,7-Dimethylpyrazolo[1,5-a]pyrimidine-3-carboxylic acid (722 mg, 3.78 mmol), 4-ethynylaniline (442 mg, 3.78 mmol), and HATU (1436 mg, 3.78 mmol) were taken up in DMF (10 ml) and then treated with diisopropylethylamine (1.979 ml, 11.33 mmol). The contents stirred at room temperature overnight. The product had precipitated from reaction mixture. The reaction was diluted with water, filtered through a Büchner funnel under house vacuum. The residue was washed with water (×2), then CH2Cl2, diethyl ether, and air dried to obtain N-(4-ethynylphenyl)-5,7-dimethylpyrazolo[1,5-a]pyrimidine-3-carboxamide (500 mg, 1.72 mmol, 46% yield). LC-MS: rt (min)=3.65. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.71 (s, 3H), 2.77 (s, 3H), 4.11 (s, 1H), 7.21 (s, 1H), 7.49 (d, J=8.6 Hz, 2H), 7.77 (d, J=8.6 Hz, 2H), 8.65 (s, 1H), 10.31 (s, 1H).
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=2)[CH2:5][CH2:4]1)[CH3:2].Cl[C:17]1([C:41]2[C:42]([O:47][CH2:48][CH3:49])=[N:43][CH:44]=[CH:45][CH:46]=2)[C:25]2[C:20](=[CH:21][CH:22]=[C:23]([I:26])[CH:24]=2)[N:19]([S:27]([C:30]2[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][C:31]=2[O:38][CH3:39])(=[O:29])=[O:28])[C:18]1=[O:40]>ClCCl>[CH3:39][O:38][C:31]1[CH:32]=[C:33]([O:36][CH3:37])[CH:34]=[CH:35][C:30]=1[S:27]([N:19]1[C:20]2[C:25](=[CH:24][C:23]([I:26])=[CH:22][CH:21]=2)[C:17]([C:41]2[C:42]([O:47][CH2:48][CH3:49])=[N:43][CH:44]=[CH:45][CH:46]=2)([NH:15][C:12]2[CH:13]=[CH:14][C:9]([N:6]3[CH2:5][CH2:4][N:3]([CH2:1][CH3:2])[CH2:8][CH2:7]3)=[CH:10][CH:11]=2)[C:18]1=[O:40])(=[O:29])=[O:28]
Reactant: CCOc1ncccc1C1(Cl)C(=O)N(S(=O)(=O)c2ccc(OC)cc2OC)c2ccc(I)cc21
Reactant: CCN1CCN(c2ccc(N)cc2)CC1
Solvent: ClCCl
Product: CCOc1ncccc1C1(Nc2ccc(N3CCN(CC)CC3)cc2)C(=O)N(S(=O)(=O)c2ccc(OC)cc2OC)c2ccc(I)cc21
Temperature: 120 °C
Reaction time: 4 h
Yield: 11.3 %

Procedure:
4-(4-Ethylpiperazin-1-yl)phenylamine (44 mg, 0.21 mmol) was added to a solution of 3-chloro-1-(2,4-dimethoxyphenylsulfonyl)-3-(2-ethoxypyridin-3-yl)-5-iodo-1,3-dihydro-indol-2-one (110 mg, 0.18 mmol) in dichloromethane (15 ml). The reaction mixture was agitated in a Biotage microwave vial at 120° C. for 4 hours. The reaction mixture was concentrated under reduced pressure. Purification by chromatography (silica gel, 0-8% methanol in dichloromethane) resulted in 16 mg of the title compound (11% yield).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:35][CH2:36][CH2:37][CH3:38])[N:14]([CH2:15][CH2:16][CH2:17][N:18]([CH2:23][C:24]3[CH:25]=[C:26]([CH2:30][C:31]([O:33][CH3:34])=[O:32])[CH:27]=[CH:28][CH:29]=3)[CH2:19][CH2:20][CH2:21]Cl)[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1.[NH:39]1[CH2:44][CH2:43][O:42][CH2:41][CH2:40]1>>[NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:35][CH2:36][CH2:37][CH3:38])[N:14]([CH2:15][CH2:16][CH2:17][N:18]([CH2:23][C:24]3[CH:25]=[C:26]([CH2:30][C:31]([O:33][CH3:34])=[O:32])[CH:27]=[CH:28][CH:29]=3)[CH2:19][CH2:20][CH2:21][N:39]3[CH2:44][CH2:43][O:42][CH2:41][CH2:40]3)[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1
Reactant: C1COCCN1
Reactant: CCCCc1nc2c(N)nc3ccccc3c2n1CCCN(CCCCl)Cc1cccc(CC(=O)OC)c1
Product: CCCCc1nc2c(N)nc3ccccc3c2n1CCCN(CCCN1CCOCC1)Cc1cccc(CC(=O)OC)c1

Procedure:
The title compound was prepared by the method of example 11 step (x) using the product from example 11 step (ix) (627 mg) and morpholine (1 ml) to give product as a white solid 165 mg.
Reaction SMILES: [S:1]1[CH2:6][CH2:5][CH2:4][S:3][CH2:2]1.[Li]CCCC.[C:12]1([C:18]([CH2:20][CH2:21][C:22]#[CH:23])=[O:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>O1CCCC1.CCCCCC>[OH:19][C:18]([CH:2]1[S:3][CH2:4][CH2:5][CH2:6][S:1]1)([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[CH2:20][CH2:21][C:22]#[CH:23]
Reactant: C#CCCC(=O)c1ccccc1
Reactant: C1CSCSC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: C#CCCC(O)(c1ccccc1)C1SCCCS1
Reaction time: 1.25 h
Yield: 75 %

Procedure:
1,3-Dithiane (3.8 g, 31.6 mmol) was stirred in 120 mL of tetrahydrofuran at -40° C. under argon and 13.2 g (33 mmol) of 2.5M n-BuLi in hexane was added. After 10 minutes the temperature was adjusted to -20° C. and 1.25 hours later 2.27 g (14.36 mmol) of but-3-ynyl phenyl ketone was added as a solid. Stirring was continued for 20 minutes before placing in a freezer at -20° C. for 20 hours. The mixture was then poured onto water, the layers were separated, and the aqueous portion extracted with methylene chloride (3×30 mL). The combined organics were washed with brine, dried (MgSO4) and solvents evaporated at reduced pressure. The residue was chromatographed on 75 g silica (98:2, hexane:EtAc, then 4%, 10%, and 20% EtAc) to give 3.0 g (75%) of product.
Reaction SMILES: [C:1]([C:4]([CH:17]1[CH2:21][CH2:20][NH:19][CH2:18]1)([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)(=[O:3])[NH2:2].[CH2:22]1[O:33][C:32]2[CH:31]=[CH:30][C:26]([CH2:27][CH2:28]Br)=[CH:25][C:24]=2[O:23]1.C(=O)([O-])[O-].[K+].[K+].C(#N)C>O>[C:1]([C:4]([CH:17]1[CH2:21][CH2:20][N:19]([CH2:28][CH2:27][C:26]2[CH:30]=[CH:31][C:32]3[O:33][CH2:22][O:23][C:24]=3[CH:25]=2)[CH2:18]1)([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)(=[O:3])[NH2:2]
Reactant: NC(=O)C(c1ccccc1)(c1ccccc1)C1CCNC1
Reactant: BrCCc1ccc2c(c1)OCO2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: NC(=O)C(c1ccccc1)(c1ccccc1)C1CCN(CCc2ccc3c(c2)OCO3)C1
Temperature: 25 °C

Procedure:
A mixture containing 3-(R,S)-(1-carbamoyl-1,1-diphenylmethyl)pyrrolidine (0.3 g -see Preparation 8), 3,4-methylenedioxyphenethyl bromide (0.247 g -see Preparation 16), anhydrous potassium carbonate (0.4 g) and acetonitrile (10 ml) was heated under reflux for 3 hours. The mixture was allowed to cool to room temperature, water (6 ml) was added and the mixture was extracted with dichloromethane (3×50 ml). The combined dichloromethane extracts were dried (MgSO4) and concentrated in vacuo to give a colourless foam which was purified by column chromatography on silica eluting with dichloromethane containing methanol (0% up to 6%). The product-containing fractions were combined and concentrated in vacuo to give the title compound as a colourless foam, yield 0.27 g.