Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2][CH2:3][C:4](OCC)=[O:5].S(Cl)(Cl)(=O)=O.[NH2:14][C:15]1[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][CH:16]=1.CN(C1C2C(N(C)C)=CC=CC=2C=CC=1)C>ClCCl>[CH3:22][O:21][C:19]([C:18]1[CH:23]=[C:24]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:4](=[O:5])[CH:3]2[S:2][CH3:1])=[O:20]
Reactant: CCOC(=O)CSC
Reactant: COC(=O)c1ccc(N)cc1
Agent: CN(C)c1cccc2cccc(N(C)C)c12
Solvent: O=S(=O)(Cl)Cl
Solvent: ClCCl
Product: COC(=O)c1ccc2c(c1)C(SC)C(=O)N2
Temperature: -70 °C
Yield: 42.1 %

Procedure:
A solution of 2.66 g (20.0 mmol) of ethyl (methylthio)acetate dissolved in 200 mL of dichioromethane was cooled with stirring to −70° C. and 2.7 g (20.0 mmol) of sulfuryl chloride was added. The reaction was stirred for 30 min. at −70° C., and a solution of 3.0 g (20 mol) of methyl 4-aminobenzoate and 4.3 g (20 mmol) of Proton Sponge® in 250 mL of dichloromethane was added dropwise over 1 h. The resulting pink slurry was treated with 2.3 9 (23 mmol) of TEA in one portion, and the solution was allowed to warm to rt. The solution was washed with three 250-mL portions of water, dried over MgSO4, and concentrated to give an oil. This was chromatographed on silica gel eluting with hexane:EtOAc (1:1) to yield 2.0 g (42% yield) of 3-methylthio-2-oxo-2,3-dihydro-1H-indole-5-carboxylic acid methyl ester: 1H NMR (DMSO-d6): δ 1.97 (s, 3H), 3.35 (s, 3H), 4.67 (s, 1H), 6.97 (d, J=8.2 Hz, 1H), 7.84 (s, 1H), 7.91 (d, J=8.2 Hz, 1H), 10.97 (s, 1H), solution of 2.0 g (8.4 mmol) of 3-methylthio-2-oxo-2,3-dihydro-1H-indole-5-carboxylic acid methyl ester in 20 mL of acetic acid was treated with 10 g of zinc powder. The reaction mixture was stirred for 2 h at rt, filtered through celite and concentrated to dryness. The residue was chromatographed on silica gel eluting with hexane:EtOAc (1:1) to yield 1.6 g (99% yield) of 2-oxo-2,3-dihydro-1H-indole-5-carboxylic acid methyl ester as a pink solid: 1H NMR (DMSO-d6): δ 3.52 (s, 2H), 3.77 (s, 3H), 6.87 (d, J=8.2 Hz, 1H), 7.74 (s, J=1H), 7.80 (d, J=8.2 Hz, 1H), 10.72 (br s, 1H). Conversion to the 3-dimethylaminomethylene-2-oxo-2,3-dihydro-1H-indole-5-carboxylic acid methyl ester (mixture of E and Z isomers) was carried out via Procedure G in 49% yield: 1H NMR (DMSO-d6): δ 3.29 Z (s, 6H), 3.31 E (s, 6H), 3.76 Z (s, 3H), 3.76 E (s, 3H), 6.74 Z (d, J=8.1 Hz, 1H), 6.81 E (d, J=8.2 Hz, 1H), 7.47-7.50 Z (m, 1H), 7.50-7.52 E (m, 1H), 7.57 E (dd, J=1.3, 8.2 Hz, 1H), 7.74 Z (s, 1H), 7.89 Z (s, 1H), 7.94 E (s, 1H), 10.33 Z (bs, 1H), 10.43 E (bs, 1H). The title compound was prepared in 41% yield from 3-[(dimethylamino)methylene]oxindole-5-carboxylic acid methyl ester and 4-aminobenzenesulfonamide according to Procedure J: 1H NMR (DMSO-d6): δ 3.81 (s, 3H), 6.92 (d, J=8.2 Hz, 1H), 7.26 (s, 2H), 7.60 (d, J=8.4 Hz, 2H), 7.69 (d, J=8.2 Hz, 1H), 7.75 (d, J=8.4 Hz, 2H), 8.29 (s, 1H), 8.86 (d, J=12.4 Hz, 1H), 10.80 (d, J=12.4 Hz, 1H), 10.94 (s, 1H); APCI−MS m/z 372 (M−1)−. Anal. Calcd for C17H15N3O5S: C, 54.68, H, 4.05; N, 11.25; S, 8.59. Found C, 54.65, H, 4.12; N, 11.17; S. 8.49.
Reaction SMILES: [CH3:1][C:2]([NH:5][CH2:6][CH:7]([OH:29])[CH2:8][O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16](=[O:28])[CH2:17][CH2:18][C:19]1[CH:27]=[CH:26][CH:25]=[C:24]2[C:20]=1[CH:21]=[CH:22][NH:23]2)([CH3:4])[CH3:3].[Cl:30]N1C(=O)CCC1=O.C(O)(=O)C.[OH-].[Na+]>O>[Cl:30][C:21]1[C:20]2[C:24](=[CH:25][CH:26]=[CH:27][C:19]=2[CH2:18][CH2:17][C:16]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[O:9][CH2:8][CH:7]([OH:29])[CH2:6][NH:5][C:2]([CH3:1])([CH3:3])[CH3:4])=[O:28])[NH:23][CH:22]=1
Reactant: CC(C)(C)NCC(O)COc1ccccc1C(=O)CCc1cccc2[nH]ccc12
Reactant: O=C1CCC(=O)N1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: CC(C)(C)NCC(O)COc1ccccc1C(=O)CCc1cccc2[nH]cc(Cl)c12
Temperature: 25 °C
Reaction time: 2 h
Yield: 68.1 %

Procedure:
A mixture of 8.6 g of 1-[2-[3-(1,1-dimethylethylamino)-2-hydroxypropoxy]-phenyl]-3-(1H-indol-4-yl)-1-propanone, 3 g of N-chlorosuccinimide and 170 ml of acetic acid was stirred at room temperature for 2 hours and was then diluted with water. The mixture was made alkaline by addition of sodium hydroxide and was extracted with ethyl acetate. The organic phase was washed with water, dried and evaporated to dryness under reduced pressure. The residue was chromatographed over silica and eluted with a 6-3-1 chloroform-acetone-triethylamine mixture to obtain 6.37 g of 3-(3-chloro-1H-indol-4-yl)-1-[2-[3-(1,1-dimethylethylamino)-2-hydroxypropoxy]-phenyl]-1-propanone.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:35]=[CH:36][CH:37]=1)[O:7][C@@H:8]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH2:9][CH2:10][N:11]1[CH2:16][CH2:15][CH:14]([C:17]2[CH:18]=[C:19]([NH:23][C:24](=[O:28])[CH:25]([CH3:27])[CH3:26])[CH:20]=[CH:21][CH:22]=2)[CH2:13][CH2:12]1)(=[O:3])[CH3:2].[CH3:38]I>>[C:1]([C:4]1[CH:5]=[C:6]([CH:35]=[CH:36][CH:37]=1)[O:7][C@@H:8]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH2:9][CH2:10][N:11]1[CH2:16][CH2:15][CH:14]([C:17]2[CH:18]=[C:19]([N:23]([CH3:38])[C:24](=[O:28])[CH:25]([CH3:27])[CH3:26])[CH:20]=[CH:21][CH:22]=2)[CH2:13][CH2:12]1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1cccc(O[C@H](CCN2CCC(c3cccc(NC(=O)C(C)C)c3)CC2)c2ccccc2)c1
Reactant: CI
Product: CC(=O)c1cccc(O[C@H](CCN2CCC(c3cccc(N(C)C(=O)C(C)C)c3)CC2)c2ccccc2)c1

Procedure:
Prepared by Procedure T and Scheme AD using N-(3-{1-[(3R)-3-(3-acetylphenoxy)-3-phenylpropyl]-4-piperidinyl}phenyl)-2-methylpropanamide and methyl iodide: ESMS m/e: 513.2 (M+H)+.
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17]([C@@H:19]3[CH:24]4[CH2:25][CH2:26][N:21]([CH2:22][CH2:23]4)[CH2:20]3)=[O:18])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1.[C:27]1([S:33]([Cl:36])(=[O:35])=[O:34])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>N1C=CC=CC=1>[ClH:36].[C:27]1([S:33]([NH:3][C:4]2[CH:9]=[CH:8][C:7]([C:10]3[CH:11]=[CH:12][C:13]([NH:16][C:17]([C@@H:19]4[CH:24]5[CH2:23][CH2:22][N:21]([CH2:26][CH2:25]5)[CH2:20]4)=[O:18])=[CH:14][CH:15]=3)=[CH:6][CH:5]=2)(=[O:35])=[O:34])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: Nc1ccc(-c2ccc(NC(=O)[C@H]3CN4CCC3CC4)cc2)cc1
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: Cl
Solvent: c1ccncc1
Product: O=C(Nc1ccc(-c2ccc(NS(=O)(=O)c3ccccc3)cc2)cc1)[C@H]1CN2CCC1CC2

Procedure:
A solution of 80 mg (0.20 mmol) of ((3R)—N-(4′-aminobiphenyl-4-yl)quinuclidine-3-carboxamide dihydrochloride (Example 7A) and 71.7 mg (0.41 mmol) of phenylsulfonyl chloride in 1.0 ml of pyridine is stirred at room temperature for 18 h. The reaction mixture is concentrated in vacuo and the residue is purified by preparative HPLC. The product fractions are concentrated, mixed with 3 ml of 1 N hydrochloric acid, again concentrated and dried under high vacuum. 52 mg (51.5% of theory) of the title compound are obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1.[Cl:15][C:16]1[CH:24]=[C:23]([C:25](=[O:29])[N:26]([CH3:28])[CH3:27])[CH:22]=[CH:21][C:17]=1[C:18](O)=[O:19]>>[Cl:15][C:16]1[CH:24]=[C:23]([C:25]([N:26]([CH3:28])[CH3:27])=[O:29])[CH:22]=[CH:21][C:17]=1[C:18]([NH:6][C:5]1[CH:7]=[CH:8][C:2]([Cl:1])=[C:3]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[CH:4]=1)=[O:19]
Reactant: CN(C)C(=O)c1ccc(C(=O)O)c(Cl)c1
Reactant: Nc1ccc(Cl)c(-c2ccccn2)c1
Product: CN(C)C(=O)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)c(Cl)c1

Procedure:
290 mg of dimethylamine hydrochloride was coupled to 1 g of 4-(tert-butoxycarbonyl)-3-chlorobenzoic acid via Procedure G. The reaction mixture was diluted with ethyl acetate, washed with 0.1 N HCl, 0.1 N NaOH and brine, dried (MgSO4) and evaporated to afford tert-butyl 2-chloro-4-(dimethylcarbamoyl)benzoate. 1.1 g of tert-butyl 2-chloro-4-(dimethylcarbamoyl)benzoate was treated with TFA (4 mL) containing trace amounts of H2O for 2 h. The reaction mixture was evaporated, and then added 0.1 N HCl. The resulting solid was filtered and washed with H2O to yield 2-chloro-4-(dimethylcarbamoyl)benzoic acid. 100 mg of 4-chloro-3-(pyridine-2-yl)aniline was coupled to 2-chloro-4-(dimethylcarbamoyl)benzoic acid via Procedure G. The product was purified on reverse phase HPLC to yield 2-chloro-N1-(4-chloro-3-(pyridin-2-yl)phenyl)-N4,N4-dimethylterephthalamide.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:12]=[CH:11][C:10]2[NH:9][C:8]3[CH2:13][CH2:14][NH:15][C:16](=[O:17])[C:7]=3[C:6]=2[CH:5]=1.[C:18]1([S:24](Cl)(=[O:26])=[O:25])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.CO>CN(C=O)C.C(Cl)Cl>[F:3][C:4]1[CH:12]=[CH:11][C:10]2[N:9]([S:24]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)(=[O:26])=[O:25])[C:8]3[CH2:13][CH2:14][NH:15][C:16](=[O:17])[C:7]=3[C:6]=2[CH:5]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: O=C1NCCc2[nH]c3ccc(F)cc3c21
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CO
Product: O=C1NCCc2c1c1cc(F)ccc1n2S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 53.6 %

Procedure:
60% NaH (196 mg, 8.16 mmol) was added to a stirred solution of 8-fluoro-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-1-one (500 mg, 2.44 mmol) in DMF (20 mL) at −10° C. and stirred for 10 minutes at room temperature. This was followed by the addition of benzene sulfonyl chloride (517 mg, 2.92 mmol) at 0° C. and the resulting reaction mass was stirred at room temperature for 5 minutes. The reaction was monitored by TLC (5% methanol in DCM). The reaction mass was quenched with ice and extracted using ethyl acetate. The organic layer was washed with water, brine solution, dried over Na2SO4 and concentrated to afford the crude product. Purification by column chromatography on silica gel (0.5% methanol in DCM) afforded 450 mg of the product (53.6% yield).
Reaction SMILES: Cl[CH2:2][C:3]1[S:4][CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:7]=1.[C:14]1([N:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[C:8]1([C:6]2[N:7]=[C:3]([CH2:2][N:23]3[CH2:24][CH2:25][N:20]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[CH2:21][CH2:22]3)[S:4][CH:5]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: ClCc1nc(-c2ccccc2)cs1
Reactant: c1ccc(N2CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: c1ccc(-c2csc(CN3CCN(c4ccccc4)CC3)n2)cc1
Yield: 75 %

Procedure:
A mixture of crude 2-chloromethyl-4-phenylthiazole (4.19g; 0.02 mole), N-phenylpiperazine (3.24 g; 0.02 mole) and finely-powdered, anhydrous sodium carbonate in absolute ethanol (60 ml) was stirred and boiled under reflux for 8 hours. The solvent was evaporated to dryness, solid residue suspended in water (100 ml) and then extracted with 2 × 100 ml CH2Cl2. The extracts were washed with water and dried over anhydrous MgSO4. On evaporation of the solvent, and recrystallisation of the residue from benzene/60°-80° C. petroleum ether mixture (with charcoal treatment) there was obtained the required product (5.03 g; 75%) having m.p. 142°-3° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH:18]=[C:17]([C:19]3[CH:20]=[N:21][CH:22]=[C:23](Br)[CH:24]=3)[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:26][C:27]1[CH:28]=[CH:29][C:30]([F:46])=[C:31]([C:33]2[CH:42]=[C:41](B(O)O)[C:40]3[C:35](=[N:36][CH:37]=[CH:38][CH:39]=3)[N:34]=2)[CH:32]=1.C(=O)(O)[O-].[Na+]>CN(C=O)C.O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH:18]=[C:17]([C:19]3[CH:20]=[N:21][CH:22]=[C:23]([C:41]4[C:40]5[C:35](=[N:36][CH:37]=[CH:38][CH:39]=5)[N:34]=[C:33]([C:31]5[CH:32]=[C:27]([Cl:26])[CH:28]=[CH:29][C:30]=5[F:46])[CH:42]=4)[CH:24]=3)[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(-c3cncc(Br)c3)cn2)CC1
Reactant: OB(O)c1cc(-c2cc(Cl)ccc2F)nc2ncccc12
Agent: Cl[Pd]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(n2cc(-c3cncc(-c4cc(-c5cc(Cl)ccc5F)nc5ncccc45)c3)cn2)CC1
Temperature: 80 °C
Reaction time: 40 h

Procedure:
A slurry of 204 mg (0.50 mmol) 4-[4-(5-bromo-pyridin-3-yl)-pyrazol-1-yl]-piperidine-1-carboxylic acid tert-butyl-ester, 167 mg (0.55 mmol) 2-(5-chloro-2-fluoro-phenyl)-[1,8]naphthyridine-4-boronic acid and 50.4 mg (0.6 mmol) sodium bicarbonate in 2 ml DMF and 0.5 ml water were heated to 80° C. under nitrogen. Then 7.0 mg (0.01 mmol) bis-(triphenylphosphine)-palladium(II)-chloride were added. The reaction mixture was stirred for 40 hours at 80° C. The reaction mixture was partitioned between water and dichloromethane. The organic phase was dried over sodium sulfate and evaporated. The residue was chromatographed on a silica gel column with petrolether/ethylacetate as eluent yielding 4-(4-{5-[2-(5-chloro-2-fluoro-phenyl)-[1,8]naphthyridin-4-yl]-pyridin-3-yl}-pyrazol-1-yl)-piperidine-1-carboxylic acid tert-butyl ester as colourless crystals; HPLC-MS: 2.55 min, [M+H] 585.
Reaction SMILES: [NH:1]1[C:5]2=[C:6]([NH:10][C:11](=[O:13])[CH3:12])[N:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[CH:2]1.[C:14]([C:16]1[CH:24]=[C:23]([Cl:25])[C:19]([C:20](Cl)=[O:21])=[C:18]([Cl:26])[CH:17]=1)#[N:15]>>[Cl:25][C:23]1[CH:24]=[C:16]([C:14]#[N:15])[CH:17]=[C:18]([Cl:26])[C:19]=1[C:20]([C:3]1[C:4]2[C:5](=[C:6]([NH:10][C:11](=[O:13])[CH3:12])[N:7]=[CH:8][CH:9]=2)[NH:1][CH:2]=1)=[O:21]
Reactant: N#Cc1cc(Cl)c(C(=O)Cl)c(Cl)c1
Reactant: CC(=O)Nc1nccc2cc[nH]c12
Product: CC(=O)Nc1nccc2c(C(=O)c3c(Cl)cc(C#N)cc3Cl)c[nH]c12

Procedure:
N-[3-(2,6-Dichloro-4-cyanobenzoyl)-1H-pyrrolo[2,3-c]pyridin-7-yl]acetamide (Compound No. 21) was prepared from N-(1H-pyrrolo[2,3-c]pyridin-7-yl)acetamide and 4-cyano-2,6-dichloro benzoyl chloride.
Reaction SMILES: C([O:3][C:4](=O)[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([N+:11]([O-:13])=[O:12])[C:6]=1[O:14][CH2:15][CH3:16])C.O1CCCC1.CO.[BH4-].[Li+]>O>[CH2:15]([O:14][C:6]1[C:7]([N+:11]([O-:13])=[O:12])=[CH:8][CH:9]=[CH:10][C:5]=1[CH2:4][OH:3])[CH3:16]
Reactant: CCOC(=O)c1cccc([N+](=O)[O-])c1OCC
Agent: [BH4-]
Agent: [Li+]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CCOc1c(CO)cccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a mixture of the compound (117 mg) obtained in Example 417a, tetrahydrofuran (5 ml) and methanol (2 ml), lithium borohydride (10.7 mg) was added. The reaction mixture was stirred at room temperature for 15 h, and, after addition of water, concentrated under reduced pressure. To the resulting residue, 2 N HCl was added and the mixture was subjected to extraction with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried with anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent, ethyl acetate:n-hexane=1:2) to give the titled compound quantitatively.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:25]([F:28])([F:27])[F:26])[O:13][N:12]=[C:11]([C:14]3[CH:19]=[CH:18][C:17]([C:20]4([F:24])[CH2:23][NH:22][CH2:21]4)=[CH:16][CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.C(N(CC)CC)C.[C:36](OC(=O)C)(=[O:38])[CH3:37]>ClCCl.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:25]([F:27])([F:26])[F:28])[O:13][N:12]=[C:11]([C:14]3[CH:19]=[CH:18][C:17]([C:20]4([F:24])[CH2:23][N:22]([C:36](=[O:38])[CH3:37])[CH2:21]4)=[CH:16][CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: FC1(c2ccc(C3=NOC(c4cc(Cl)cc(Cl)c4)(C(F)(F)F)C3)cc2)CNC1
Reactant: CC(=O)OC(C)=O
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N1CC(F)(c2ccc(C3=NOC(c4cc(Cl)cc(Cl)c4)(C(F)(F)F)C3)cc2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91 %

Procedure:
To a solution of 5-(3,5-dichlorophenyl)-3-(4-(3-fluoroazetidin-3-yl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole (Preparation 15, 200 mg, 0.462 mMol) in dichloromethane (3 mL) was added triethylamine (0.192 mL) followed by acetic anhydride (50.2 μL). The reaction was allowed to stir at room temperature overnight. The solution was diluted with water and allowed to stir for 10 minutes. The mixture was passed through an ISCO Phase Separator. A stream of nitrogen was blown onto the organics then placed under high vacuum to form a white foam 200 mg (91% yield) 1H NMR (400 MHz, CDCl3-d) δ ppm 2.01 (s, 3H) 3.73 (d, 1H) 3.92 (qd, 1H) 4.12 (d, 1H) 4.32-4.56 (m, 3H) 4.59-4.70 (m, 1H) 7.46 (t, 1H) 7.52-7.59 (m, 4H) 7.76 (d, 2H), LC/MS retention time=3.510 min; MS calculated for (C21H16Cl2F4N2O2), 474.052; found 475.0 M+H.
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][NH:11][C:12]([C:14]1[CH:18]=[CH:17][N:16]([C:19]2[C:20]([NH:34][CH2:35][CH:36]3[CH2:41][CH2:40][CH2:39][N:38](C(OC(C)(C)C)=O)[CH2:37]3)=[CH:21][C:22]([NH:25][C:26]3[CH:31]=[N:30][C:29]([C:32]#[N:33])=[CH:28][N:27]=3)=[N:23][CH:24]=2)[CH:15]=1)=[O:13])(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[C:32]([C:29]1[N:30]=[CH:31][C:26]([NH:25][C:22]2[N:23]=[CH:24][C:19]([N:16]3[CH:17]=[CH:18][C:14]([C:12]([NH:11][CH2:10][CH2:9][OH:8])=[O:13])=[CH:15]3)=[C:20]([NH:34][CH2:35][CH:36]3[CH2:41][CH2:40][CH2:39][NH:38][CH2:37]3)[CH:21]=2)=[N:27][CH:28]=1)#[N:33]
Reactant: CC(C)(C)OC(=O)N1CCCC(CNc2cc(Nc3cnc(C#N)cn3)ncc2-n2ccc(C(=O)NCCO[Si](C)(C)C(C)(C)C)c2)C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: N#Cc1cnc(Nc2cc(NCC3CCCNC3)c(-n3ccc(C(=O)NCCO)c3)cn2)cn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
tert-Butyl 3-((5-(3-(2-(tert-butyldimethylsilyloxy)ethylcarbamoyl)-1H-pyrrol-1-yl)-2-(5-cyanopyrazin-2-ylamino)pyridin-4-ylamino)methyl)piperidine-1-carboxylate (80 mg, 0.118 mmol) was dissolved in THF (2 mL) and tetrabutylammonium fluoride on silica (1.5 mmol/g; 237 mg, 0.355 mmol) was added. The reaction mixture was stirred for 1 h at room temperature. The mixture was filtered and the solvent was evaporated. The residue was dissolved in methanol (1 mL) and absorbed on to a TsOH solid phase extraction cartridge. After 1.5 h the cartridge was eluted with 7M ammonia in methanol. The eluent was evaporated to dryness and the residue was purified by HPLC to give 1-(6-(5-cyanopyrazin-2-ylamino)-4-(piperidin-3-ylmethylamino)pyridin-3-yl)-N-(2-hydroxyethyl)-1H-pyrrole-3-carboxamide.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:39])[N:10]([C@H:12]([C:14](=[O:38])[NH:15][C:16]1[C:17](=[O:37])[N:18]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([O:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH:25]=2)[C:19](Cl)=[CH:20][CH:21]=1)[CH3:13])[CH3:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:40]1(B(O)O)[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1.[F-].[K+]>[Pd].[Pd].C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C1COCC1>[CH2:1]([O:8][C:9](=[O:39])[N:10]([C@H:12]([C:14](=[O:38])[NH:15][C:16]1[C:17](=[O:37])[N:18]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([O:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH:25]=2)[C:19]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)=[CH:20][CH:21]=1)[CH3:13])[CH3:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@@H](C(=O)Nc1ccc(Cl)n(Cc2cccc(Oc3ccccc3)c2)c1=O)N(C)C(=O)OCc1ccccc1
Reactant: OB(O)c1ccccc1
Agent: [Pd]
Agent: O=C(C=Cc1ccccc1)C=Cc1ccccc1
Agent: [F-]
Solvent: C1CCOC1
Product: C[C@@H](C(=O)Nc1ccc(-c2ccccc2)n(Cc2cccc(Oc3ccccc3)c2)c1=O)N(C)C(=O)OCc1ccccc1
Yield: 80.1 %

Procedure:
To a mixture of compound 20C (37 mg, 0.068 mmol), phenyl boronic acid (12 mg, 0.10 mmol) tri-tert-butylphosphonium tetra fluoroborate (16 mg, 0.054 mmol), tris(dibenzylideneacetone) dipalladium (12 mg, 0.027 mmol) and potassium fluoride (61 mg, 1.0 mmol) is added under nitrogen atmosphere anhydrous THF (1.0 mL). The mixture is heated at reflux for 20 hours and is concentrated. The residue is purified by silica gel preparative TLC (40% ethyl acetate in hexane) to provide the title compound 20D (32 mg, 80%):
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([C:10]1[C:11](F)=[N:12][CH:13]=[CH:14][CH:15]=1)[OH:9].[Br-].[K+].Cl[O-].[Na+].C(=O)(O)[O-].[Na+].[C:27]([C:30]1[CH:35]=[CH:34][N:33]=[CH:32][CH:31]=1)(=[O:29])[CH3:28].[OH-].[Li+].[Cl-].[Na+].P(=O)(O)(O)O.C(=O)([O-])[O-].[K+].[K+]>ClCCl.O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([C:10]1[C:11]([CH:28]=[C:27]([OH:29])[C:30]2[CH:35]=[CH:34][N:33]=[CH:32][CH:31]=2)=[N:12][CH:13]=[CH:14][CH:15]=1)=[O:9]
Reactant: OC(c1ccccc1Cl)c1cccnc1F
Reactant: CC(=O)c1ccncc1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: O=P(O)(O)O
Solvent: O
Solvent: ClCCl
Product: O=C(c1ccccc1Cl)c1cccnc1C=C(O)c1ccncc1
Temperature: 25 °C

Procedure:
To a solution of (2-chloro-phenyl)-(2-fluoropyridin-3-yl)methanol (140 g, 0.59 mol) in dichloromethane (1.1 L) under an argon atmosphere, add 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO) (1.43 g, 9.15 mmol) and potassium bromide (10% w/w in water, 57.1 mL, 0.048 mol). To the resulting mixture add a solution of sodium hypochlorite (13% w/w active chlorine in water, 403 mL, 0.85 mol) and sodium bicarbonate (20.3 g, 0.24 mol) in water (403 mL) while stirring vigorously and while maintaining the temperature below 20° C. Continue stirring the reaction mixture for 30 min or until the reaction is complete. Separate the layers, and concentrate the organic layer to approximately 200 mL total volume. Add dimethylsulfoxide and concentrate until no dichloromethane remains in the solution. Add 4-acetylpyridine (107 g, 0.88 mol) and powdered lithium hydroxide (28.2 g, 1.17 mol) and stir at 60° C. for 2.5 h or until the reaction is complete. Cool to ambient temperature and add dichloromethane (1.4 L) and an aqueous solution of 10% sodium chloride (1.3 L) while maintaining the temperature between 20° C. and 24° C. Separate the layers and extract the aqueous layer with dichloromethane (1.4 L). Separate the layers and combine the organic layers. Wash the combined organic layers with an aqueous solution of 10% sodium chloride (3×2.6 L). Concentrate the organic layer to approximately 500 mL total volume, then add methanol (1.0 L). Concentrate under vacuum until the weight of the resulting residue is approximately 500 g, then add more methanol (207 mL). Heat the solution to 60° C. When the temperature reaches 45° C., add phosphoric acid (85% w/w in water, 67.4 g, 0.58 mol). Stir the resulting slurry at 22° C. for 16 h. Collect the resulting solid by filtration and wash with methanol (3×65 mL) and water (3×65 mL). Add the resulting solid to a solution of potassium carbonate (49.3 g, 0.356 mol) in water (714 mL) and stir for 4 h. Collect the resulting solid by filtration, wash with water (50 mL) and dry under vacuum at 50° C. to afford the title compound as an orange solid. 1H NMR (400 MHz, DMSO-D6) δ ppm 4.89 (s, 2H) 6.93 (d, J=7.33 Hz, 1H) 7.09 (s, 1H) 7.11-7.17 (m, 2H) 7.24 (dd, J=7.58, 5.31 Hz, 1H) 7.40-7.67 (m, 15H) 7.71-7.77 (m, 3H) 7.85 (d, J=7.83 Hz , 1H) 7.89 (d, J=6.06 Hz, 2H) 8.15 (d, J=7.58 Hz, 1H) 8.50 (d, J=3.79 Hz, 1H) 8.62 (d, J=3.79 Hz, 3H) 8.67 (d, J=5.81 Hz, 2H) 8.73 (dd, J=4.80, 1.52 Hz, 1H) 8.83 (d, J=5.81 Hz, 1H).