Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N+:8]([O-:10])=[O:9])=[N:6][CH:7]=1.[CH2:11]([N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)[CH3:12].C([O-])([O-])=O.[K+].[K+].CS(C)=O>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.O>[CH2:11]([N:13]1[CH2:18][CH2:17][N:16]([C:2]2[CH:7]=[N:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=2)[CH2:15][CH2:14]1)[CH3:12]
Reactant: CCN1CCNCC1
Reactant: O=[N+]([O-])c1ccc(Br)cn1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: O
Solvent: CS(C)=O
Product: CCN1CCN(c2ccc([N+](=O)[O-])nc2)CC1
Temperature: 90 °C

Procedure:
To a sealed tube equipped with a stirring bar, 5-bromo-2-nitropyridine (3.00 g, 14.78 mmol), 1-ethylpiperazine (5.06 g, 44.34 mmol), tetrabutylammonium iodide (273 mmol, 0.739 mmol), K2CO3 (6.128 g, 44.34 mmol), and DMSO (30 mL) were added. The tube was sealed and heated at 90° C. overnight. Water (200 mL) was added and the precipitation was filtered to afford 138a as a yellow solid, 1.24 g.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][C:8]1[CH:13]=[C:12]([C:14]([OH:16])=O)[CH:11]=[CH:10][C:9]=1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH3:23].[NH2:24][S:25]([C:28]1[CH:33]=[CH:32][C:31]([C:34](=[N:36]O)[NH2:35])=[CH:30][CH:29]=1)(=[O:27])=[O:26].C(C1C=CC(S(N)(=O)=O)=CC=1)#N.CCN(C(C)C)C(C)C>>[CH3:7][C:8]1[CH:13]=[C:12]([C:14]2[O:16][N:36]=[C:34]([C:31]3[CH:30]=[CH:29][C:28]([S:25]([NH2:24])(=[O:26])=[O:27])=[CH:33][CH:32]=3)[N:35]=2)[CH:11]=[CH:10][C:9]=1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH3:23]
Reactant: NC(=NO)c1ccc(S(N)(=O)=O)cc1
Reactant: Cc1ccccc1-c1ccc(C(=O)O)cc1C
Agent: N#Cc1ccc(S(N)(=O)=O)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccccc1-c1ccc(-c2nc(-c3ccc(S(N)(=O)=O)cc3)no2)cc1C

Procedure:
Oxalyl chloride (134 mL; 1.59 mmol), Intermediate 3 (120 mg; 0.53 mmol), 4-(aminosulfonyl)-N′-hydroxybenzenecarboximidamide, prepared as described in WO 2006/013104 A1 from 4-cyanobenzene-1-sulfonamide (ABCR; CD10716), (114 mg; 0.53 mmol, 1 eq.) and DIEA (274 mL; 1.59 mmol) were reacted according to the procedure described for Example 38. Purification by recrystallisation from DCM/n-pentane afforded the title compound as a white solid. LC/MS (Method A): 404.3 (M−H)−. HPLC (Method A) Rt 5.17 min (purity 95.4%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[C:9]1[CH:10]=[N:11][C:12]([N:15]2[C:23]3[C:18](=[CH:19][CH:20]=[C:21]([C:24]([N:26]([CH2:28][C:29]([O:31]C)=[O:30])[CH3:27])=[O:25])[CH:22]=3)[C:17]([S:33][CH3:34])=[CH:16]2)=[N:13][CH:14]=1.O.[OH-].[Li+]>C1COCC1.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[C:9]1[CH:10]=[N:11][C:12]([N:15]2[C:23]3[C:18](=[CH:19][CH:20]=[C:21]([C:24]([N:26]([CH2:28][C:29]([OH:31])=[O:30])[CH3:27])=[O:25])[CH:22]=3)[C:17]([S:33][CH3:34])=[CH:16]2)=[N:13][CH:14]=1
Reactant: COC(=O)CN(C)C(=O)c1ccc2c(SC)cn(-c3ncc(-c4cc(C)ccc4F)cn3)c2c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CSc1cn(-c2ncc(-c3cc(C)ccc3F)cn2)c2cc(C(=O)N(C)CC(=O)O)ccc12

Procedure:
Ester hydrolysis of 304b) (0.5 g, 1.05 mmol) with lithium hydroxide monohydrate in THF/water. White solid. Yield: 0.48 g (98% of theory)
Reaction SMILES: [N:1]1([C:7]2[C:12]([Br:13])=[CH:11][N:10]=[C:9]([CH2:14][S:15][C:16]3[NH:20][C:19]4[CH:21]=[CH:22][C:23]([O:25][CH3:26])=[CH:24][C:18]=4[N:17]=3)[CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[O:27]1CCN(C2C3N(Cl)CN(SCC4C=CC=CN=4)C=3C=CC=2OC)CC1>>[N:1]1([C:7]2[C:12]([Br:13])=[CH:11][N:10]=[C:9]([CH2:14][S:15]([C:16]3[NH:20][C:19]4[CH:21]=[CH:22][C:23]([O:25][CH3:26])=[CH:24][C:18]=4[N:17]=3)=[O:27])[CH:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COc1ccc2c(c1N1CCOCC1)N(Cl)CN2SCc1ccccn1
Reactant: COc1ccc2[nH]c(SCc3cc(N4CCCCC4)c(Br)cn3)nc2c1
Product: COc1ccc2[nH]c(S(=O)Cc3cc(N4CCCCC4)c(Br)cn3)nc2c1

Procedure:
Substituting 2-(4-piperidino-5-bromo-2-pyridylmethylthio)-5-methoxy-(1H)-benzimidazole (3.83 g) for 2-(4-morpholino-3-chloro-2-pyridylmethylthio-5-methoxy-(1H)-benzimidazole and using corresponding molar proportions of the other reagents in the method of Example 4 gave after chromatography (silica gel, chloroform:methanol-ammonia) 2-(4-piperidino-5-bromo-2-pyridylmethylsulphinyl)-5-methoxy-(1H)-benzimidazole, 3.15 g, m.p. 114°-8° C., from ether.
Reaction SMILES: [CH:1]([NH:4][CH3:5])([CH3:3])[CH3:2].[OH-].[K+].[N+:8]([C:11]1[CH:12]=[C:13]([S:17](Cl)(=[O:19])=[O:18])[CH:14]=[CH:15][CH:16]=1)([O-:10])=[O:9]>O.C1COCC1>[CH:1]([N:4]([CH3:5])[S:17]([C:13]1[CH:14]=[CH:15][CH:16]=[C:11]([N+:8]([O-:10])=[O:9])[CH:12]=1)(=[O:18])=[O:19])([CH3:3])[CH3:2]
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)Cl)c1
Reactant: CNC(C)C
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)N(C)S(=O)(=O)c1cccc([N+](=O)[O-])c1
Temperature: 0 °C

Procedure:
A 250 mL round bottom flask was equipped with a magnetic stirrer. The flask was charged with isopropylmethylamine (0.85 g, 11.6 mmol) followed by THF (50 mL). The mixture was cooled to 0° C. by placing the flask in an ice bath. Potassium hydroxide (23.2 mmol) was dissolved in water (20 mL) and added to the flask. An addition funnel was installed and charged with 3-nitrobenzenesulfonyl chloride (11.6 mmol) in THF (40 mL). The solution was added dropwise over 20 minutes, then the ice bath was removed. TLC (dichloromethane) indicated that the reaction was complete after addition of the 2-nitrobenzenesulfonyl chloride. The reaction was concentrated under diminished pressure, water (100 mL) was added, the mixture extracted with ethyl acetate (150 mL), dried (Na2SO4), and filtered. The solvent was removed under reduced pressure. The residue was dissolved in dichloromethane (20 mL) and loaded onto a plug of silica gel (400 g in a 600 mL sintered glass funnel), and eluted with dichloromethane. Fractions were taken (100 mL) until the product eluted, as determined by TLC. Fractions containing the product were collected, and the solvent was removed in vacuo to yield N-(isopropyl)-N-(methyl)-3-nitrobenzenesulfonamide as a pale yellow, crystalline solid. 2.38 g, (79%). 1H-NMR (CDCl3): δ 1.03-1.05 (d, 6H, J=6.7 Hz); 2.78 (s, 3H); 4.23-4.32 (m, 1H, J=6.7 Hz); 7.70-7.76 (t, 1H, J=8.0 Hz); 8.13-8.15 (d, 1H, J=6.8 Hz); 8.40-8.43 (d, 1H, J=8.2 Hz); 8.64 (s, 1H).
Reaction SMILES: [F:1][C:2]1[C:3]([C:24]([F:27])([F:26])[F:25])=[N:4][N:5]([C:14]2[CH:15]=[CH:16][C:17]([S:20]([NH2:23])(=[O:22])=[O:21])=[N:18][CH:19]=2)[C:6]=1[C:7]1[CH:12]=[CH:11][C:10](Br)=[CH:9][CH:8]=1.BrC1C=CC(C2(CC)N([C:40]3C=C[C:43]([S:46](N)(=O)=O)=[N:44][CH:45]=3)NC(C(F)(F)F)=C2)=CC=1>>[F:1][C:2]1[C:3]([C:24]([F:27])([F:26])[F:25])=[N:4][N:5]([C:14]2[CH:15]=[CH:16][C:17]([S:20]([NH2:23])(=[O:22])=[O:21])=[N:18][CH:19]=2)[C:6]=1[C:7]1[CH:12]=[CH:11][C:10]([C:40]2[S:46][CH:43]=[N:44][CH:45]=2)=[CH:9][CH:8]=1
Reactant: NS(=O)(=O)c1ccc(-n2nc(C(F)(F)F)c(F)c2-c2ccc(Br)cc2)cn1
Reactant: CCC1(c2ccc(Br)cc2)C=C(C(F)(F)F)NN1c1ccc(S(N)(=O)=O)nc1
Product: NS(=O)(=O)c1ccc(-n2nc(C(F)(F)F)c(F)c2-c2ccc(-c3cncs3)cc2)cn1

Procedure:
The title compound was prepared according to the procedure of step 1 in the Example 10 using 5-[4-fluoro-5-(4-bromophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]-2-pyridinesulfonamide (Example 8, step 1), instead of 5-[5-(4-bromophenyl)-5-ethyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]-2-pyridinesulfonamide.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:6]=[CH:7][C:8]2[NH:13][C:12](=[O:14])[O:11][C:10]([CH3:16])([CH3:15])[C:9]=2[CH:17]=1.[Cl:18][C:19]1[CH:20]=[C:21]([SH:26])[CH:22]=[CH:23][C:24]=1[Cl:25]>>[Cl:18][C:19]1[CH:20]=[C:21]([S:26][CH2:2][CH2:3][O:4][C:5]2[CH:6]=[CH:7][C:8]3[NH:13][C:12](=[O:14])[O:11][C:10]([CH3:16])([CH3:15])[C:9]=3[CH:17]=2)[CH:22]=[CH:23][C:24]=1[Cl:25]
Reactant: CC1(C)OC(=O)Nc2ccc(OCCCl)cc21
Reactant: Sc1ccc(Cl)c(Cl)c1
Product: CC1(C)OC(=O)Nc2ccc(OCCSc3ccc(Cl)c(Cl)c3)cc21

Procedure:
Prepared analogously to Example 1 from 6-(2-chloroethoxy)-4,4-dimethyl-4H-3,1-benzoxazin-2-one and 3,4-dichloro-thiophenol.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:10])=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5]Br.NC(N)=[S:13]>C(O)C>[Cl:1][C:2]1[C:3]([F:10])=[C:4]([CH2:5][SH:13])[CH:7]=[CH:8][CH:9]=1
Reactant: Fc1c(Cl)cccc1CBr
Reactant: NC(N)=S
Solvent: CCO
Product: Fc1c(Cl)cccc1CS
Yield: 89.8 %

Procedure:
3-Chloro-2-fluorobenzyl bromide (1.00 g) and thiourea (0.35 g) were heated together at reflux in ethanol (10 ml) for 1 hour. The solvent was removed in-vacuo and the residue was suspended in 10% aqueous sodium hydroxide (10 ml) and heated at reflux for 3 hours. The solution was then acidified with conc. HCl and extracted into ether. Concentration of the organic phase in-vacuo gave the subtitle compound as a pale yellow oil (0.71 g).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][O:7][C:8]2=[C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[NH:13][C:12]2=[O:20])=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.[Cl:30][CH2:31][CH2:32][CH2:33][C:34](Cl)=[O:35]>C1COCC1>[Cl:30][CH2:31][CH2:32][CH2:33][C:34]([NH:1][C:2]1[CH:10]=[C:9]2[C:5](=[CH:4][CH:3]=1)[CH2:6][O:7][C:8]2=[C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[NH:13][C:12]1=[O:20])=[O:35]
Reactant: O=C(Cl)CCCCl
Reactant: Nc1ccc2c(c1)C(=C1C(=O)Nc3ccccc31)OC2
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CCCCl)Nc1ccc2c(c1)C(=C1C(=O)Nc3ccccc31)OC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.4 %

Procedure:
To a solution of 3-(6-Amino-3H-isobenzofuran-1-ylidene)-1,3-dihydro-indol-2-one (50.0 mg, 0.189 mmol) and N,N-diisopropylethylamine (98.8 μL, 0.567 mmol) in 2.0 mL THF was added 4-chlorobutyryl chloride (21.2 μL, 0.189 mmol). After stirring at room temperature for 1 h, the slurry was filtered and rinsed with MeOH and EtOAc/hexanes (1:1) to afford the title compound (58.8 mg, 84%) as a yellow solid.
Reaction SMILES: [Si]([O:8][C@H:9]1[CH2:13][CH2:12][C@H:11]([NH:14][C:15]2[S:16][C:17]([CH:22]([CH3:24])[CH3:23])([CH3:21])[C:18](=[O:20])[N:19]=2)[CH2:10]1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C1COCC1>>[OH:8][C@H:9]1[CH2:13][CH2:12][C@H:11]([NH:14][C:15]2[S:16][C:17]([CH:22]([CH3:24])[CH3:23])([CH3:21])[C:18](=[O:20])[N:19]=2)[CH2:10]1
Reactant: CC(C)C1(C)SC(N[C@H]2CC[C@H](O[Si](C)(C)C(C)(C)C)C2)=NC1=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC(C)C1(C)SC(N[C@H]2CC[C@H](O)C2)=NC1=O
Reaction time: 8 h

Procedure:
A 5 mL flask was charged flask with 2-((1S,3S)-3-(tert-butyldimethylsilyloxy)cyclopentylamino)-5-isopropyl-5-methylthiazol-4(5H)-one (0.470 g, 1.3 mmol) and tetrabutylammonium fluoride, (1.0M in THF (5.1 ml, 5.1 mmol) and allowed to stir at ambient temp. overnight. The crude reaction mixture was concentrated onto silica gel and the mixture was purified by column chromatography (2-6% MeOH/DCM) to give 2-((1S,3S)-3-hydroxycyclopentylamino)-5-isopropyl-5-methylthiazol-4(5H)-one as a white solid.
Reaction SMILES: [C:1]([O:4][C:5]([CH3:11])([CH:8]1[CH2:10][CH2:9]1)[C:6]#[N:7])(=[O:3])[CH3:2].[OH-].[Na+]>[Cl-].[Na+]>[C:1]([O:4][C@@:5]([CH3:11])([CH:8]1[CH2:10][CH2:9]1)[C:6]#[N:7])(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)(C#N)C1CC1
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Product: CC(=O)O[C@](C)(C#N)C1CC1
Temperature: 10 °C
Yield: 12.3 %

Procedure:
(Warning: Highly toxic hydrogen cyanide is formed in the experiment; use adequate protection). 111.1 g (725 mmol) racemic α-(acetyloxy)-α-methyl-cyclopropaneacetonitrile was emulsified in 6.0 L of 0.1 M sodium chloride/3.8 mM sodium phosphate buffer pH 7.0 by stirring. The emulsion was cooled to 10° C. and the hydrolytic reaction started by adding 6.0 g of cholesterase from Candida cylindraceae (Roche Applied Sciences; Cat. No. 10129046) and the pH maintained at 7.0 by the controlled addition of 1.0 N sodium hydroxide solution under vigorous stirring. After a consumption of 618.3 mL solution (corresponding to 85% conversion) the reaction was stopped by adding 5 L dichloromethane under vigorous stirring. The emulsion was allowed to stand for phase separation. The organic phase was removed (the turbid part was filtered through silicon-treated Phase Separator (1PS; Whatman) and the filtrate stirred with ca. 1 L of Speedex filter aid). The aqueous phase was extracted again with 2×5 L dichloromethane. The combined organic phases were concentrated in vacuo down to a volume of ca. 40 mL and distilled (finally ca. 69–70° C./4 mbar) to give 13.70 g (89 mmol; 12%) of (S)-α-(acetyloxy)-α-methyl-cyclopropaneacetonitrile as a colorless oil. Analysis: >99% GC; 96.8% ee (column: BGB-176; 30 m×0.25 mm; 100–140° C. with 2° C./min; H2; 90 kPa; Inj. 200° C.; Det. 210° C.); αD20: −31.61° (c=1.00; EtOH); EI-MS: 154.1 (M+H+).
Reaction SMILES: C([NH2+]CC[NH2+]C(C)C)(C)C.[CH2:11]1[C:14](=[O:15])[N:13]2[C@@H:16]([C:22]([OH:24])=[O:23])/[C:17](/[O:21][C@H:12]12)=[CH:18]/[CH2:19][OH:20].C(C(CCCC)C([O-])=O)C.[K+:35]>O.C(O)(C)C>[CH2:11]1[C:14](=[O:15])[N:13]2[C@@H:16]([C:22]([O-:24])=[O:23])/[C:17](/[O:21][C@H:12]12)=[CH:18]/[CH2:19][OH:20].[K+:35]
Reactant: O=C(O)[C@H]1/C(=C/CO)O[C@@H]2CC(=O)N21
Agent: CC(C)[NH2+]CC[NH2+]C(C)C
Agent: CCCCC(CC)C(=O)[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)O
Product: O=C([O-])[C@H]1/C(=C/CO)O[C@@H]2CC(=O)N21
Yield: 70 %

Procedure:
N,N'-diisopropylethylenediammonium diclavulanate (10 g, clavulanic acid content 69%) was dissolved in water (10 ml), the solution was diluted with isopropanol (190 ml) and a solution (15 ml, 2M) of potassium 2-ethylhexanoate in isopropanol was added within 15 min. with stirring. The obtained suspension was stirred for another 30 min. whereat a precipitate separated, which was filtered off, washed with isopropanol and then dried. Thus there was obtained potassium clavulanate (4.8 g; 70%), (USP Grade, clavulanic acid content 81% as determined by the HPLC method).
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:10](=[O:11])[C:9]([CH2:12][O:13][S:14]([CH3:17])(=[O:16])=[O:15])=[CH:8][C:7]([C:18]3[CH:19]=[CH:20][C:21]4[O:25][CH2:24][CH2:23][C:22]=4[CH:26]=3)=[N:6]2)[CH2:3][CH2:2]1.[Cl:27][C:28]1[CH:54]=[CH:53]C(C=CCN2C(=O)C(CO)=CC(C3C=CC4OCCC=4C=3)=N2)=[CH:30][CH:29]=1>>[Cl:27][C:28]1[CH:54]=[CH:53][C:3]([CH:2]=[CH:1][CH2:4][N:5]2[C:10](=[O:11])[C:9]([CH2:12][O:13][S:14]([CH3:17])(=[O:15])=[O:16])=[CH:8][C:7]([C:18]3[CH:19]=[CH:20][C:21]4[O:25][CH2:24][CH2:23][C:22]=4[CH:26]=3)=[N:6]2)=[CH:30][CH:29]=1
Reactant: O=c1c(CO)cc(-c2ccc3c(c2)CCO3)nn1CC=Cc1ccc(Cl)cc1
Reactant: CS(=O)(=O)OCc1cc(-c2ccc3c(c2)CCO3)nn(CC2CC2)c1=O
Product: CS(=O)(=O)OCc1cc(-c2ccc3c(c2)CCO3)nn(CC=Cc2ccc(Cl)cc2)c1=O
Yield: 83.3 %

Procedure:
The general procedure of Example 1 (5) was repeated by use of 2-(4-chlorocinnamyl)-6-(2,3-dihydro-1-benzofuran-5-yl)-4-hydroxymethyl-2H-pyridazin-3-one, to thereby yield the title compound as a pale yellow powder (yield: 83.3%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Al](C)C.[Br:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[C:16]#[N:17].CO>C1(C)C=CC=CC=1>[Br:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)/[C:16](=[N:1]\[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)/[NH2:17]
Reactant: Nc1ccccc1
Reactant: N#Cc1cccc(Br)c1
Agent: C[Al](C)C
Solvent: CO
Solvent: Cc1ccccc1
Product: N/C(=N/c1ccccc1)c1cccc(Br)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 46 %

Procedure:
Aniline (5.12 g, 55.0 mmol) was charged into the reaction flask with 100 mL of toluene. This solution was chilled using a wet ice bath. A 2.0 M toluene solution of trimethylaluminum (41.2 mL, 82 mmol) was added dropwise to the chilled reaction mixture over a 15 min period. The cooling bath was removed and the reaction mixture was stirred at room temperature for 2 h. 3-bromobenzonitrile (10.01 g, 55 mmol) was dissolved in 80 mL of toluene and was added dropwise to the reaction mixture. The reaction mixture was then stirred at 75° C. for 18 h. The reaction mixture was cooled to room temperature then was slowing poured into a beaker containing 75 g of silica gel and 150 mL methanol/300 mL DCM. This mixture was stirred at room temperature for 30 min then was filtered through a pad of Celite®. The pad was rinsed with DCM/methanol. The filtrate was stripped under vacuum and the crude residue was triturated with hexanes yielding (E)-3-bromo-N′-phenylbenzimidamide (6.95 g, 25.3 mmol, 45.9%)
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13]([OH:14])=[C:12]([C:15](=O)[CH3:16])[C:11]([CH3:18])=[N:10]2)[CH:5]=[CH:6][C:7]=1[CH3:8].[CH3:19][O:20][C:21]([C:23]1[CH:32]=[CH:31][C:26]([C:27]([NH:29][NH2:30])=[O:28])=[CH:25][CH:24]=1)=[O:22]>>[CH3:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13](=[O:14])[C:12](=[C:15]([NH:30][NH:29][C:27](=[O:28])[C:26]3[CH:25]=[CH:24][C:23]([C:21]([O:20][CH3:19])=[O:22])=[CH:32][CH:31]=3)[CH3:16])[C:11]([CH3:18])=[N:10]2)[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: CC(=O)c1c(C)nn(-c2ccc(C)c(C)c2)c1O
Reactant: COC(=O)c1ccc(C(=O)NN)cc1
Product: COC(=O)c1ccc(C(=O)NNC(C)=C2C(=O)N(c3ccc(C)c(C)c3)N=C2C)cc1

Procedure:
From 1-(1-(3,4-dimethylphenyl)-5-hydroxy-3-methyl-1H-pyrazol-4-yl)-ethanone and 4-methoxycarbonylbenzhydrazide, 53.0 mg of the desired product was obtained in the same manner as in Synthetic Example 4 as a pale yellow solid (yield 64%).
Reaction SMILES: [Cl:1][C:2]1[C:19]([F:20])=[C:18]([F:21])[C:17]([Cl:22])=[C:16]([F:23])[C:3]=1[C:4]([C:6](=[CH:12]OCC)[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5].[CH:24]1([NH2:27])[CH2:26][CH2:25]1>C(O)C>[Cl:1][C:2]1[C:19]([F:20])=[C:18]([F:21])[C:17]([Cl:22])=[C:16]([F:23])[C:3]=1[C:4]([C:6](=[CH:12][NH:27][CH:24]1[CH2:26][CH2:25]1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5]
Reactant: NC1CC1
Reactant: CCOC=C(C(=O)OCC)C(=O)c1c(F)c(Cl)c(F)c(F)c1Cl
Solvent: CCO
Product: CCOC(=O)C(=CNC1CC1)C(=O)c1c(F)c(Cl)c(F)c(F)c1Cl
Temperature: 25 °C
Reaction time: 4 h

Procedure:
37.1 g (0.1 mol) of ethyl 2-(2,5-dichloro-3,4,6-trifluorobenzoyl)-3-ethoxyacrylate are initially introduced into the reaction vessel in 100 ml of ethanol. 6.8 g (0.12 mol) of cyclopropylamine, dissolved in 10 ml of ethanol, are added dropwise. The mixture is then stirred at room temperature for 4 hours. The precipitate is filtered off with suction, washed with petroleum ether and dried in air.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([Cl:12])=[CH:8][C:9]=2[Cl:11])[NH:4][C:3]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14].[C:18]1([S:24](Cl)(=[O:26])=[O:25])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>N1C=CC=CC=1>[C:18]1([S:24]([NH:1][C:2]2[C:10]3[C:5](=[CH:6][C:7]([Cl:12])=[CH:8][C:9]=3[Cl:11])[NH:4][C:3]=2[C:13]([O:15][CH2:16][CH3:17])=[O:14])(=[O:26])=[O:25])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CCOC(=O)c1[nH]c2cc(Cl)cc(Cl)c2c1N
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: c1ccncc1
Product: CCOC(=O)c1[nH]c2cc(Cl)cc(Cl)c2c1NS(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 63 %

Procedure:
Mix 3-amino-2-carbethoxy-4,6-dichloroindole (3.31 g, 12.1 mmol) and anhydrous pyridine (50 mL). Add, by dropwise addition, phenylsulfonyl chloride (2.35 g, 13.33 mmol). Stir for 48 hours at room temperature. Pourinto 1N hydrochloric acid (500 mL), extract with ethyl acetate and dry (MgSO4). Evaporate the solvent in vacuo and recrystallize (ethyl acetate/hexane) to give the title compound (3.15 g, 63%); mp 245°-7° C.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][CH:6]([C:13]1[CH:21]=[C:20]2[C:16]([C:17]([C:22]#[N:23])=[CH:18][NH:19]2)=[CH:15][CH:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1)C.OCCC(C1C=CC=C2C=1C(C#N)=CN2)C1C=CC=CC=1>>[OH:3][CH2:4][CH2:5][CH:6]([C:13]1[CH:21]=[C:20]2[C:16]([C:17]([C:22]#[N:23])=[CH:18][NH:19]2)=[CH:15][CH:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1
Reactant: CCOC(=O)CC(c1ccc2c(C#N)c[nH]c2c1)c1ccccn1
Agent: N#Cc1c[nH]c2cccc(C(CCO)c3ccccc3)c12
Product: N#Cc1c[nH]c2cc(C(CCO)c3ccccn3)ccc12

Procedure:
6-(3-Hydroxy-1-pyridin-2-yl-propyl)-1H-indole-3-carbonitrile CLXXII was prepared from 3-(3-cyano-1H-indol-6-yl)-3-pyridin-2-yl-propionic acid ethyl ester using the procedure described for preparation of 4-(3-Hydroxy-1-phenyl-propyl)-1H-indole-3-carbonitrile LX (Example 14).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[NH:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9]1.C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.CCOCC>[N:3]1[CH:4]=[CH:5][CH:6]=[C:7]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]=[CH:9]2)[CH:2]=1
Reactant: c1ccc2[nH]ccc2c1
Reactant: Brc1ccccn1
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: c1cncc(-n2ccc3ccccc32)c1
Temperature: 100 °C
Yield: 14.6 %

Procedure:
Under an argon atmosphere, a solution of bromopyridine (1.7 mL, 17.6 mmol) in toluene (15 mL) is added to indole (2.0 g, 17.1 mmol), tris(dibenzylideneacetone)palladium (480 mg, 0.52 mmol), 2-(di-tert-butylphosphino)biphenyl (5.52 mg, 0.76 mmol), sodium tert-butoxide and toluene (25 mL) and the stirred mixture is heated at 100° C. for 48 hr. After cooling to room temperature, ether is added and the reaction mixture is filtered through Hi-Flo and concentrated. The residue is purified by chromatography eluting with pentane-25% ethyl acetate. Product containing fractions are combined and concentrated to afford 1-(pyridin-3-yl)-1H-indole (485 mg, 15%) as a yellow-brown oil.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[N:8]([CH3:11])[N:9]=[CH:10][C:5]2=[C:4]([N:12]2[CH2:18][CH:17]3[O:19][CH:14]([CH2:15][CH2:16]3)[CH2:13]2)[N:3]=1.[NH2:20][C:21]1[CH:26]=[CH:25][C:24](B2OC(C)(C)C(C)(C)O2)=[CH:23][CH:22]=1>C1(C)C=CC=CC=1.C(O)C.C(=O)([O-])[O-].[Na+].[Na+].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>[CH:14]12[O:19][CH:17]([CH2:16][CH2:15]1)[CH2:18][N:12]([C:4]1[N:3]=[C:2]([C:24]3[CH:25]=[CH:26][C:21]([NH2:20])=[CH:22][CH:23]=3)[N:7]=[C:6]3[N:8]([CH3:11])[N:9]=[CH:10][C:5]=13)[CH2:13]2
Reactant: Cn1ncc2c(N3CC4CCC(C3)O4)nc(Cl)nc21
Reactant: CC1(C)OB(c2ccc(N)cc2)OC1(C)C
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: Cc1ccccc1
Solvent: CCO
Product: Cn1ncc2c(N3CC4CCC(C3)O4)nc(-c3ccc(N)cc3)nc21
Temperature: 120 °C

Procedure:
A mixture of 3-(6-chloro-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-8-oxa-3-azabicyclo[3.2.1]octane (0.40 g, 1.4 mmol), 4-aminophenylboronic acid pinacol ester (0.47 g, 2.1 mmol), and tetrakis(triphenylphosphine)palladium(0) (0.16 g, 10 mol %) in toluene/ethanol (1:1, 7 mL) and 2 M aqueous sodium carbonate solution (2 mL) was heated in a 10-20 mL Smith process vial in the microwave reactor for one hour at 120° C. The cooled mixture was partitioned between ethyl acetate and water. The aqueous phase was extracted three times with ethyl acetate. The combined extracts were washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated to dryness under reduced pressure. The crude residue was triturated with dichloromethane and the light brown solid was collected by Buchner filtration to furnish 4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)aniline. MS (ES+): 337.0 (M+H)+
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[C:6]([NH2:10])=[CH:7][CH:8]=[CH:9][C:2]1=2.N1C=CC=CC=1.[CH3:17][S:18](Cl)(=[O:20])=[O:19]>C(Cl)Cl>[S:1]1[CH:5]=[CH:4][C:3]2[C:6]([NH:10][S:18]([CH3:17])(=[O:20])=[O:19])=[CH:7][CH:8]=[CH:9][C:2]1=2
Reactant: CS(=O)(=O)Cl
Reactant: Nc1cccc2sccc12
Solvent: c1ccncc1
Solvent: ClCCl
Product: CS(=O)(=O)Nc1cccc2sccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.8 %

Procedure:
To a stirred solution of benzo[b]thiophen-4-amine (1 g, 6.70 mmol) and pyridine (1.355 mL, 16.75 mmol) in CH2Cl2 (15 mL) was added dropwise methanesulfonyl chloride (0.574 mL, 7.37 mmol) at 0° C. under nitrogen atmosphere. The reaction mixture was then allowed to warm to room temperature while stirring overnight. The reaction mixture was washed with saturated sodium bicarbonate solution, water, brine and dried over sodium sulfate. Evaporation of the solvent furnished a crude residue, which was subjected to BIOTAGE® (100% methylene chloride) to give the title compound as a white solid (1.2 g, 79%). LC/MS: Example 105A @ 2.88 min (RT) (Condition H). MS (ES): m/z=226.0, [M+H]+. 1H NMR (400 MHz, MeOD) δ ppm 7.77 (1 hr, d, J=7.81 Hz), 7.59 (2 hr, d, J=1.26 Hz), 7.25-7.42 (2 hr, m), 2.94 (3 hr, s).