Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:9]([O:11][CH3:12])=[O:10])[CH:5]=[N:6][C:7]=1Cl.[Na+].[I-:14]>I>[Br:1][C:2]1[CH:3]=[C:4]([C:9]([O:11][CH3:12])=[O:10])[CH:5]=[N:6][C:7]=1[I:14]
Reactant: COC(=O)c1cnc(Cl)c(Br)c1
Reactant: [I-]
Agent: I
Agent: [Na+]
Product: COC(=O)c1cnc(I)c(Br)c1
Temperature: 50 °C
Reaction time: 8 h
Yield: 40.8 %

Procedure:
To a solution of methyl 5-bromo-6-chloro-3-pyridinecarboxylate (4500 mg, 17.97 mmol) in HI (30 ml) was added NaI (3501 mg, 23.36 mmol). The mixture was stirred at 50° C. overnight. Reaction was cooled at 0° C. and the precipitated solid was isolated by filtration and washed with 15 ml of MeOH. The obtained solid was suspended in 25 ml of water and pH was adjusted to 9 with NaOH 6N (1.5 ml). The aqueous phase was extracted twice with DCM and once with DCM/MeOH (5%). Organic layers were dried over Na2SO4. Volatiles were removed under vacuum to afford 2.505 g (40%) of the desired compound as a white solid. The solution of HI and MeOH was dissolved in water and pH was adjusted to 9 with NaOH 6N. The organic phase was extracted twice with DCM and once with DCM/MeOH (5%). Organic layers were dried over Na2SO4. Volatiles were removed under vacuum to afford an additional quantity of the desired compound (649 mg, 10%) as beige solid.
Reaction SMILES: [CH2:1]([CH:3]([CH2:6][CH2:7][CH2:8][CH3:9])[CH2:4][OH:5])[CH3:2].[OH-].[Na+]>O>[CH2:1]([C:3](=[CH:6][CH2:7][CH2:8][CH3:9])[CH:4]=[O:5])[CH3:2]
Reactant: CCCCC(CC)CO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCCC=C(C=O)CC

Procedure:
The aldol reaction of n-butyraldehyde with simultaneous elimination of water to form 2-ethylhexenal is carried out worldwide on a large scale since the hydrogenation product, viz. 2-ethylhexanol, is used in large quantities as plasticizer alcohol. As catalyst, use is usually made of a base dissolved in water. The use of aqueous sodium hydroxide having an NaOH content in the percentage range is typical. The reaction is frequently carried out in a temperature range of 80-150° C., a pressure of less than 5 bar and a phase ratio of organic phase to aqueous catalyst phase of from 1 to 20 (Hydrocarbon Processing, October 1980, Section 2, pages 93-102). This reaction can, for example, be carried out in a stirred vessel (DE 19 06 850, DE 927 626), in a packed column which is operated in countercurrent (G. Dümbgen, D. Neubauer, Chemie-Ing.-Techn., 41, 974 (1969)), or in a flow tube (GB 761 203). All these processes give 2-ethylhexenal in a selectivity of up to 98% at conversions of 98.5%. A disadvantage is that at relatively high temperatures, part of the n-butyraldehyde used is irreversibly lost as a result of the Cannizzaro reaction. The butyric acid formed in the Cannizzaro reaction neutralizes the basic catalyst. Part of the catalyst solution containing a high burden of organic material therefore has to be continually discharged and replaced by fresh catalyst.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([OH:12])[CH:8]=2)[N:3]=1.B([C:16]1[CH:24]=[CH:23][C:19]([C:20]([OH:22])=[O:21])=[C:18]([F:25])[CH:17]=1)(O)O>>[F:25][C:18]1[CH:17]=[C:16]([C:2]2[CH:11]=[CH:10][C:9]3[C:4](=[CH:5][CH:6]=[C:7]([OH:12])[CH:8]=3)[N:3]=2)[CH:24]=[CH:23][C:19]=1[C:20]([OH:22])=[O:21]
Reactant: Oc1ccc2nc(Cl)ccc2c1
Reactant: O=C(O)c1ccc(B(O)O)cc1F
Product: O=C(O)c1ccc(-c2ccc3cc(O)ccc3n2)cc1F

Procedure:
Followed Scheme 3: Starting Materials: 2-chloroquinolin-6-ol (Intermediate 2) and 4-borono-2-fluorobenzoic acid. 1H NMR (CD3OD, 400 MHz): δ 8.54 (d, J=8.4 Hz, 1H), 8.20-8.06 (m, 3H), 8.06-7.96 (m, 2H), 7.55 (dd, J=9.2, 2.4 Hz, 1H), 7.32 (d, J=2.8 Hz, 1H). MS (ESI): m/z 283.6 [M+1]+.
Reaction SMILES: [CH3:1][CH:2]([CH3:18])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[CH:7]=1)=[O:4].[C:19]1([CH2:25][CH2:26][CH2:27][CH2:28]Cl)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(N(C(C)C)CC)(C)C>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.O1CCOCC1>[CH3:1][CH:2]([CH3:18])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH:12]2[CH2:17][CH2:16][N:15]([CH2:28][CH2:27][CH2:26][CH2:25][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:14][CH2:13]2)[CH:7]=1)=[O:4]
Reactant: ClCCCCc1ccccc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCCc3ccccc3)CC2)c1
Yield: 25.1 %

Procedure:
A mixture of 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide (28.3 mg, 0.100 mmol), 4-phenyl-1-chlorobutane (21.1 mg, 0.125 mmol), diisopropylethylamine (0.50 mL), catalytic amount of tetrabutylammonium iodide and dioxane (2.0 mL) was heated at reflux temperature for 3 days. The reaction mixture was concentrated and chromatographed using preparative TLC plates [2.5% of NH3 (2.0 M in methanol) in CHCl3] afforded the product, 2-methyl-N-{3-[1-(4-phenylbutyl)-4-piperidinyl]phenyl}propanamide (9.50 mg, 25.1% yield) as a thick oil: 1H NMR δ 7.37 (s, 1H), 7.29 (apparent d, 1H, J=7.9 Hz), 7.18 (m, 3H), 7.11 (m, 3H), 6.90 (apparent d, 1H, J=7.9 Hz), 3.02 (d, 2H, J=6.8 Hz), 2.41 (m, 4H, partially hidden), 2.01 (m, 2H), 1.78 (m, 4H), 1.57 (m, 4H), 1.18 (d, 6H, J=7.7 Hz); ESMS m/e: 379.4 (M+H)+.
Reaction SMILES: Br[C:2]1[C:3]2[N:4]([N:21]=[CH:22][N:23]=2)[C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)=[N:6][CH:7]=1.[S:24]1[CH:28]=[CH:27][CH:26]=[C:25]1B(O)O.C([O-])([O-])=O.[Cs+].[Cs+].O1CCOCC1>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.O>[S:24]1[CH:28]=[CH:27][CH:26]=[C:25]1[C:2]1[C:3]2[N:4]([N:21]=[CH:22][N:23]=2)[C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)=[N:6][CH:7]=1
Reactant: OB(O)c1cccs1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncc(Br)c3ncnn23)CC1
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: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(c2ncc(-c3cccs3)c3ncnn23)CC1
Temperature: 100 °C
Reaction time: 8 h
Yield: 82.4 %

Procedure:
A 50 mL round bottom flask was charged with tert-butyl 4-(8-bromo-[1,2,4]triazolo[1,5-c]pyrimidin-5-yl)piperazine-1-carboxylate (0.6 g, 1.57 mmol), thiophene-2-boronic acid (0.35 g, 2.74 mmol), tetrakis(triphenylphosphine)palladium(0) (0.25 g, 0.21 mmol), Cs2CO3 (2 g, 6.36 mmol), 1,4-dioxane (20 mL) and water (5 mL). After the air was purged by bubbling N2 into the solution, the resulting mixture was stirred at 100° C. under N2 overnight. Work-up: the reaction mixture was diluted with water and extracted with CH2Cl2 (50 mL×3). The combined organic layers were dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel to afford 0.5 g (82%) of the product as a white solid.
Reaction SMILES: ClC1C=C[C:5]2[N:6]([C:8](CNC3N=C(N4CCC(C)(O)CC4)C=CN=3)=[C:9](C3C=CC=CC=3)[N:10]=2)[CH:7]=1.[Cl:33][C:34]1[CH:39]=[CH:38][C:37]([C:40]2[N:41]=[C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][N:43]3[C:48]=2[CH2:49][C:50]2[CH:55]=[N:54][CH:53]=[C:52](Cl)[N:51]=2)=[CH:36][CH:35]=1.CN(C)CCN>>[Cl:33][C:34]1[CH:39]=[CH:38][C:37]([C:40]2[N:41]=[C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][N:43]3[C:48]=2[CH2:49][C:50]2[N:51]=[C:52]([NH:10][CH2:9][CH2:8][N:6]([CH3:7])[CH3:5])[CH:53]=[N:54][CH:55]=2)=[CH:36][CH:35]=1
Reactant: Clc1ccc(-c2nc3ccccn3c2Cc2cncc(Cl)n2)cc1
Reactant: CC1(O)CCN(c2ccnc(NCc3c(-c4ccccc4)nc4ccc(Cl)cn34)n2)CC1
Agent: CN(C)CCN
Product: CN(C)CCNc1cncc(Cc2c(-c3ccc(Cl)cc3)nc3ccccn23)n1

Procedure:
The title compound was prepared in the same fashion as that described for compound 187 from 2-(4-chlorophenyl)-3-((6-chloropyrazin-2-yl)methyl)imidazo[1,2-a]pyridine and N1,N1-dimethylethane-1,2-diamine. M/e+ 407 for C22H24ClN6 (M+H)+; 1H-NMR (400 MHz, CDCl3) δ 8.12 (d, J=6.9 Hz, 1H), 7.85 (d, J=8.8 Hz, 2H), 7.78 (s, 1H), 7.63 (d, J=8.4 Hz, 2H), 7.42 (d, J=8.4 Hz, 2H), 7.20 (m, 1H), 6.78 (m, 1H), 5.30 (s, 1H), 4.34 (s, 2H), 3.29 (q, J=5.5 Hz, 2H), 2.46 (t, J=5.5 Hz, 2H), 2.21 (s, 6H) ppm.
Reaction SMILES: C([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27][C:28]([O:30][C@@H:31]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=4[CH3:39])[CH3:32])=[O:29])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])C.CO.[OH-].[Li+].Cl>O>[CH3:26][C:23]1[C:22]([NH:27][C:28]([O:30][C@@H:31]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=2[CH3:39])[CH3:32])=[O:29])=[C:21]([C:18]2[CH:19]=[CH:20][C:15]([C:12]3[CH:11]=[CH:10][C:9]([C:6]4([C:4]([OH:5])=[O:3])[CH2:8][CH2:7]4)=[CH:14][CH:13]=3)=[CH:16][CH:17]=2)[O:25][N:24]=1
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4NC(=O)O[C@H](C)c4ccccc4C)cc3)cc2)CC1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1ccccc1[C@@H](C)OC(=O)Nc1c(C)noc1-c1ccc(-c2ccc(C3(C(=O)O)CC3)cc2)cc1
Temperature: 25 °C

Procedure:
To 1-{4′-[3-methyl-4-((R)-1-o-tolyl-ethoxycarbonylamino)-isoxazol-5-yl]-biphenyl-4-yl}-cyclopropanecarboxylic acid ethyl ester (0.36 mmol) in 2:1 MeOH:H2O was added lithium hydroxide (1.1 mmol), and the reaction was stirred at room temperature until no starting material was seen by analytical LCMS. The mixture was acidified with 1N aqueous HCl and extracted with EtOAc. The combined organic layers were dried, filtered, and concentrated to give the title compound.
Reaction SMILES: [H-].[Na+].[CH2:3]([C:5]1[C:13]2[C:8](=[CH:9][C:10]([C:14]([N:16]([O:18][CH3:19])[CH3:17])=[O:15])=[CH:11][CH:12]=2)[NH:7][N:6]=1)[CH3:4].[CH3:20][Si:21]([CH3:28])([CH3:27])[CH2:22][CH2:23][O:24][CH2:25]Cl>O1CCCC1>[CH2:3]([C:5]1[N:6]([CH2:25][O:24][CH2:23][CH2:22][Si:21]([CH3:28])([CH3:27])[CH3:20])[N:7]=[C:8]2[C:13]=1[CH:12]=[CH:11][C:10]([C:14]([N:16]([O:18][CH3:19])[CH3:17])=[O:15])=[CH:9]2)[CH3:4]
Reactant: CCc1n[nH]c2cc(C(=O)N(C)OC)ccc12
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCc1c2ccc(C(=O)N(C)OC)cc2nn1COCC[Si](C)(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
NaH (1.3 g, 60% dispersion in mineral oil, 0.033 mol) and tetrahydrofuran (223 mL) were mixed in a 1-necked flask and cooled to 0° C. To this was added dropwise a mixture of 3-ethyl-N-methoxy-N-methyl-1H-indazole-6-carboxamide (2.6 g, 0.011 mol) in tetrahydrofuran (60 mL), and the mixture was stirred at 0° C. for 1 hour. [β-(Trimethylsilyl)ethoxy]methyl chloride (2.4 mL, 0.013 mol) was then added and the reaction mixture was allowed to warm to room temperature. The resulting mixture was partitioned between water (50 mL) and ethyl acetate (50 mL). The layers were separated and the organics were washed with brine (25 mL), dried (sodium sulfate) and concentrated in vacuo to afford 4.0 g (quantitative yield) of 3-ethyl-N-methoxy-N-methyl-2-{[2-(trimethylsilyl)ethoxy]methyl}-2H-indazole-6-carboxamide, which was used without further purification.
Reaction SMILES: [C:1]1([CH2:7][C:8]([OH:10])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:11]1([CH:18]=[CH:17][CH:16]=[C:14]([OH:15])[CH:13]=1)[OH:12].B(F)(F)F.CCOCC>CC([O-])=O.[Na+]>[OH:12][C:11]1[CH:13]=[C:14]([OH:15])[CH:16]=[CH:17][C:18]=1[C:8](=[O:10])[CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Oc1cccc(O)c1
Reactant: O=C(O)Cc1ccccc1
Agent: CC(=O)[O-]
Agent: FB(F)F
Agent: [Na+]
Solvent: CCOCC
Product: O=C(Cc1ccccc1)c1ccc(O)cc1O
Temperature: 80 °C
Reaction time: 2 h
Yield: 86.9 %

Procedure:
Phenylacetic acid (0.82 g, 6 mmol), resorcinol (0.66 g, 6 mmol), and boron trifloride etherate (4 ml, 33 mmol) were mixed together and heated to 80° C. under argon. The mixture was then poured into 10% NaOAc (100 ml) and after standing for two hours a brown solid precipitate formed. This was purified by flash chromatography to give the required compound as a white solid (1.19 g, 87%); Rf 0.5 hexane/ethyl acetate (70/30).
Reaction SMILES: C([O-])(=O)C.[Na+].[CH2:6]([O:8][C:9](=[O:23])[CH2:10][C:11](=O)[CH2:12][CH2:13][NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH3:7].Cl.[NH2:25][CH2:26][C:27]([C:29]1[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=1)=O>O.C(O)C>[CH2:6]([O:8][C:9]([C:10]1[C:27]([C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=2)=[CH:26][NH:25][C:11]=1[CH2:12][CH2:13][NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[O:23])[CH3:7]
Reactant: CCOC(=O)CC(=O)CCNC(=O)OC(C)(C)C
Reactant: NCC(=O)c1ccc(F)cc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1c(-c2ccc(F)cc2)c[nH]c1CCNC(=O)OC(C)(C)C
Yield: 91.4 %

Procedure:
A stirred solution of anhydrous sodium acetate (2.05 g, 25 mmol) in water (12.5 ml) was added with the solution of 5-tert-butoxycarbonylamino-3-oxo-pentanoic acid ethyl ester (3.23 g, 12.5 mmol) in anhydrous ethanol (2 ml), then the mixture was added with 2-amino-1-(4-fluoro-phenyl)-ethanone hydrochloride (2.37 g, 12.5 mmol), heated to reflux for 3 hours. The resulting mixture was extracted with ethyl acetate (50 ml×3) and the combined extracts were washed with brine (50 ml×3), dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 2-(2-tert-butoxycarbonylamino-ethyl)-4-(4-fluoro-phenyl)-1H-pyrrole-3-carboxylic acid ethyl ester (4.3 g, 91.7%) as a yellow solid.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[O:14][CH2:13][CH2:12][C:11]3[CH:10]=[C:9]([C:15]4[N:16]([C:20]5[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=5[F:27])[N:17]=[CH:18][N:19]=4)[S:8][C:7]=3[C:6]=2[N:28]=1.[CH3:29][C@H:30]1[CH2:35][NH:34][CH2:33][C@@H:32]([CH3:36])[NH:31]1.CC([O-])(C)C.[Na+].C(N1CCN2CCN(CCCC)P1N(CCCC)CC2)CCC>CC([O-])=O.CC([O-])=O.[Pd+2]>[F:27][C:21]1[CH:22]=[C:23]([F:26])[CH:24]=[CH:25][C:20]=1[N:16]1[C:15]([C:9]2[S:8][C:7]3[C:6]4[N:28]=[C:2]([N:34]5[CH2:33][C@H:32]([CH3:36])[NH:31][C@H:30]([CH3:29])[CH2:35]5)[CH:3]=[CH:4][C:5]=4[O:14][CH2:13][CH2:12][C:11]=3[CH:10]=2)=[N:19][CH:18]=[N:17]1
Reactant: C[C@@H]1CNC[C@H](C)N1
Reactant: Fc1ccc(-n2ncnc2-c2cc3c(s2)-c2nc(Cl)ccc2OCC3)c(F)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Product: C[C@@H]1CN(c2ccc3c(n2)-c2sc(-c4ncnn4-c4ccc(F)cc4F)cc2CCO3)C[C@H](C)N1
Temperature: 120 °C
Reaction time: 1 h
Yield: 61.8 %

Procedure:
A mixture of 9-Chloro-2-[2-(2,4-difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulene (300 mg, 0.72 mmol), (2S,6R)-2,6-dimethylpiperazine (164 mg, 1.44 mmol), tBuONa (47 mg, 0.48 mmol), Pd(OAc)2 (49 mg, 0.3 mmol) and 2,8,9-tributyl-2,5,8,9-tetraaza-1-phosphabicyclo[3.3.3]undecane (99 mg, 0.29 mmol), in dioxane (2 mL) was bubbled N2 for 10 min and then stirred at 120° C. for 1 h under the irradition of microwave. The mixture was filtered by celite. The filtrate was concentrated to dryness and purified by pre-TLC(EtOAc) to afford 220 mg of 2-[2-(2,4-Difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-9-((3R,5S)-3,5-dimethyl-piperazin-1-yl)-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulene. (Yield: 62%) 1H NMR (DMSO, 400 MHz): δ8.28 (s, 1H), 8.22 (s, 1H), 7.94-7.88 (m, 1H), 7.72-7.67 (m, 1H), 7.40 (d, J=2.4 Hz, 1H), 7.24 (t, J=2.4 Hz, 1H), 6.79 (d, J=8.8 Hz, 1H), 4.20 (t, J=4.4 Hz, 2H), 3.99 (q, J=2.4, 12.8 Hz, 2H), 3.12 (t, J=4.8 Hz, 2H), 2.87-2.82 (m, 2H), 1.10 (d, J=6.0 Hz, 6H). LC-MS (ESI): m/z=495 [M+H]+
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[CH:4][N:3]=1.CO[CH:11]1[CH2:15][CH2:14][CH:13](OC)O1>C(O)(=O)C>[Cl:1][C:2]1[C:7]([N:8]2[CH:11]=[CH:15][CH:14]=[CH:13]2)=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: Nc1cccnc1Cl
Reactant: COC1CCC(OC)O1
Solvent: CC(=O)O
Product: Clc1ncccc1-n1cccc1
Reaction time: 2 h
Yield: 75 %

Procedure:
A solution of acetic acid (25 ml), 2-chloro-3-aminopyridine (5.1 g, 0.04 m) and 2,5-dimethoxytetrahydrofuran (0.05 m) was heated to reflux. After two hours, the mixture was concentrated to dryness, treated with ice and neutralized with saturate Na2CO3 solution. The aqueous layer was extracted with CHCl3 (3×100 ml). The organic extract was dried over Na2SO4, filtered and concentrated to dryness. The residue was distilled to yield 5.3 g (75% yield) of 2-chloro-3-(1-pyrrolyl) pyridine; b.p=95°-100° at 0.5 mm.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:9][C:10](=[O:27])[C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[C:13](B3OC(C)(C)C(C)(C)O3)[CH:12]=2)[CH:6]=[CH:7][CH:8]=1.C(=O)([O-])[O-].[Na+].[Na+].Br[C:35]1[CH:49]=[CH:48][C:38]2[C:39]([CH:42]3[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]3)=[N:40][O:41][C:37]=2[CH:36]=1>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.COCCOC>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:9][C:10](=[O:27])[C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[C:13]([C:35]3[CH:49]=[CH:48][C:38]4[C:39]([CH:42]5[CH2:43][CH2:44][NH:45][CH2:46][CH2:47]5)=[N:40][O:41][C:37]=4[CH:36]=3)[CH:12]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: Brc1ccc2c(C3CCNCC3)noc2c1
Reactant: COc1cccc(NC(=O)c2ccc(C)c(B3OC(C)(C)C(C)(C)O3)c2)c1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: COc1cccc(NC(=O)c2ccc(C)c(-c3ccc4c(C5CCNCC5)noc4c3)c2)c1
Yield: 57 %

Procedure:
N-(3-Methoxyphenyl)-4-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzamide (Intermediate 19, 54 mg), DME (3 ml), aqueous sodium carbonate (1M, 2 ml), tetrakis (triphenylphosphine) palladium (20 mg) and 6-bromo-3-piperidin-4-yl-1,2-benzisoxazole (44 mg) were heated together at 80° C. under nitrogen for 18 h. The solvent was evaporated and the residue was purified by column chromatography on silica (10 g) eluting with dichloromethane:ethanol:ammonia (40:8:1) to give the title compound (37 mg).
Reaction SMILES: [NH2:1][C:2]([C:19]1[NH:23][C:22]2[CH:24]=[CH:25][C:26]([C:28]#[N:29])=[CH:27][C:21]=2[N:20]=1)([C:7]1[C:15]([O:16]C)=[CH:14][C:13]([CH3:18])=[C:12]2[C:8]=1[CH:9]=[CH:10][NH:11]2)[C:3]([F:6])([F:5])[F:4].B(Br)(Br)Br.C(=O)(O)[O-].[Na+]>C(Cl)Cl.CCOC(C)=O>[NH2:1][C:2]([C:19]1[NH:23][C:22]2[CH:24]=[CH:25][C:26]([C:28]#[N:29])=[CH:27][C:21]=2[N:20]=1)([C:7]1[C:15]([OH:16])=[CH:14][C:13]([CH3:18])=[C:12]2[C:8]=1[CH:9]=[CH:10][NH:11]2)[C:3]([F:6])([F:5])[F:4]
Reactant: COc1cc(C)c2[nH]ccc2c1C(N)(c1nc2cc(C#N)ccc2[nH]1)C(F)(F)F
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Cc1cc(O)c(C(N)(c2nc3cc(C#N)ccc3[nH]2)C(F)(F)F)c2cc[nH]c12
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
To a suspension of (−)-2-(1-amino-2,2,2-trifluoro-1-(5-methoxy-7-methyl-1H-indol-4-yl)ethyl)-1H-benzo[d]imidazole-5-carbonitrile (Example 36-E-b) (63 mg, 0.158 mmol) in methylene chloride (Volume: 1.6 mL) at 0° C. was added 1 M BBr3 in DCM (315 μl, 0.315 mmol). The reaction was stirred in ice bath for 5 minutes and then the suspension was allowed to stir at room temperature for 2 hours. The reaction was poured into ice water, treated with saturated a solution of sodium bicarbonate, and then diluted with EtOAc and the EtOAc layer was removed, dried, concentrated and absorbed onto silica to purify via FCC (0-5% MeOH containing 10% ammonium hydroxide:dcm) to obtain the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.55-12.76 (m, 1H) 11.01-11.28 (m, 1H) 10.82 (br. s., 1H) 8.35 (s, 1H) 7.83-8.06 (m, 1H) 7.46-7.65 (m, 2H) 6.88 (t, J=2.91 Hz, 1H) 6.50 (s, 1H) 4.84 (br. s., 1H) 2.27-2.43 (m, 3H). MS (ESI+) m/z 386.3 (M+H).
Reaction SMILES: [CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([NH:19][C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=3[F:27])[C:14]([O:16]CC)=[O:15])=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.[OH-].[Li+].C1COCC1.CO>O>[CH:1]1([S:4]([C:7]2[CH:8]=[CH:9][C:10]([CH:13]([NH:19][C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=3[F:27])[C:14]([OH:16])=[O:15])=[CH:11][CH:12]=2)(=[O:5])=[O:6])[CH2:2][CH2:3]1
Reactant: CCOC(=O)C(Nc1ccc(F)cc1F)c1ccc(S(=O)(=O)C2CC2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)C(Nc1ccc(F)cc1F)c1ccc(S(=O)(=O)C2CC2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 90.1 %

Procedure:
To ethyl 2-(4-cyclopropylsulfonylphenyl)-2-(2,4-difluoroanilino)acetate (0.6 g, 1.51 mmol) was added a solution of lithium hydroxide (0.317 g, 7.22 mmol) in water (4 mL) followed by THF (4 mL) and methanol (0.5 mL) and stirred for 12 hours at 25° C. Organic solvents were evaporated from the reaction mixture and aqueous layer was acidified 1N HCl, extracted with ethyl acetate (3×15 mL), organic layer was washed with brine solution, dried over anhydrous sodium sulfate, and washed concentrated under reduced pressure to provide 2-(4-cyclopropylsulfonylphenyl)-2-(2,4-difluoroanilino)acetic acid (0.5 g).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([Cl:22])[C:5]2[C:10](I)=[CH:9][N:8]([S:12]([C:15]3[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:6]=2[N:7]=1.[Cl-].[CH3:24][Zn+]>C1COCC1.C(OCC)(=O)C.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>[Cl:1][C:2]1[N:3]=[C:4]([Cl:22])[C:5]2[C:10]([CH3:24])=[CH:9][N:8]([S:12]([C:15]3[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:6]=2[N:7]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(I)c3c(Cl)nc(Cl)nc32)cc1
Reactant: C[Zn+]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1ccc(S(=O)(=O)n2cc(C)c3c(Cl)nc(Cl)nc32)cc1
Temperature: 60 °C
Reaction time: 18 h

Procedure:
2,4-dichloro-5-iodo-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidine (800 mg, 1.71 mmol) and Pd(PPh3)4 (40 mg, 0.034 mmol) were combined in dry THF (20 ml) and a 2M solution of methylzinc chloride in THF (1.28 ml, 2.56 mmol) was added under N2. The reaction mixture was let stir at 60° C. for 18 h at which time the reaction was diluted with ethyl acetate and the organic layer was washed with a saturated solution of sodium bicarbonate, water and a saturated brine solution, then dried over sodium sulfate. Solvents were removed under reduced pressure and the residue purified by chromatography on SiO2 to afford 2,4-dichloro-5-methyl-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidine (487 mg, 1.37 mmol) as a tan solid. This reaction was repeated to synthesize sufficient material as needed for subsequent reactions. ESIMS(M+H)+=357.