Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]([C:8]([F:11])([F:10])[F:9])=[CH:5][C:4](=[O:12])[N:3]1[C:13]1[CH:14]=[CH:15][C:16]2[S:20][N:19]=[C:18]([O:21][CH2:22][C:23]#[N:24])[C:17]=2[CH:25]=1.[C:26](=O)([O-])[O-].[K+].[K+].IC.C(Cl)Cl>CN(C)C=O.C(OCC)(=O)C>[CH3:26][N:7]1[C:6]([C:8]([F:9])([F:11])[F:10])=[CH:5][C:4](=[O:12])[N:3]([C:13]2[CH:14]=[CH:15][C:16]3[S:20][N:19]=[C:18]([O:21][CH2:22][C:23]#[N:24])[C:17]=3[CH:25]=2)[C:2]1=[O:1]
Reactant: O=C([O-])[O-]
Reactant: N#CCOc1nsc2ccc(-n3c(=O)cc(C(F)(F)F)[nH]c3=O)cc12
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CI
Solvent: CN(C)C=O
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2ccc3snc(OCC#N)c3c2)c1=O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A mixture of {{5-[3,6-dihydro-2,6-dioxo-4-(trifluoromethyl)-1(2H)-pyrimidinyl]-1,2-benzisothiazol-3-yl}oxy}acetonitrile (2.63 g, 7.15 mmol) and potassium carbonate (1.97 g, 14.3 mmol) in N,N-dimethylformamide is stirred for 30 minutes, treated with iodomethane (2.03 g, 14.3 mmol), stirred overnight at room temperature, and poured into an ice-water mixture. The resultant aqueous mixture is filtered to obtain a solid. The solid is dissolved in ethyl acetate and the resultant solution is washed sequentially with water and brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo to obtain a brown solid. Column chromatography of the solid using silica gel and methylene chloride affords a yellow solid. The yellow solid is recrystallized from a methylene chloride/hexanes solution to give the title product as an off-white solid, mp 265-266° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:14]=[CH:13][N:12]([CH2:15][C@@H:16]([NH:18][C:19]([C:21]3[N:22]=[C:23]([CH:26]4[CH2:31][CH2:30][N:29](C(OC(C)(C)C)=O)[CH2:28][CH2:27]4)[S:24][CH:25]=3)=[O:20])[CH3:17])[N:11]=2)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].C(O)(C(F)(F)F)=O>C(Cl)Cl.C(O)(C(F)(F)F)=O.O.C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:14]=[CH:13][N:12]([CH2:15][C@@H:16]([NH:18][C:19]([C:21]3[N:22]=[C:23]([CH:26]4[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]4)[S:24][CH:25]=3)=[O:20])[CH3:17])[N:11]=2)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: C[C@@H](Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1)NC(=O)c1csc(C2CCN(C(=O)OC(C)(C)C)CC2)n1
Solvent: ClCCl
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H](Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1)NC(=O)c1csc(C2CCNCC2)n1
Reaction time: 8 h
Yield: 82 %

Procedure:
(S)-tert-butyl 4-(4-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-ylcarbamoyl)thiazol-2-yl)piperidine-1-carboxylate (0.3 g, 0.540 mmol) and TFA (0.768 g, 6.73 mmol) was dissolved in a mixture of DCM/TFA/H2O and stirred overnight. The reaction mixture was diluted with DCM, washed with saturated Na2CO3 and with water. The organic layer was evaporated. Yield 82%. 1H-NMR (400 MHz; DMSO-d6): δ 1.24 (d, 3H), 1.52 (dd, 1H), 1.58 (dd, 1H), 1.91-1.97 (m, 2H), 2.54-2.62 (m, 2H), 2.97-3.03 (d, 2H), 3.04-3.11 (m, 1H), 4.33 (dd, 1H), 4.41 (dd, 1H), 4.44-4.51 (m, 1H), 6.96 (d, 1H), 7.85 (d, 1H), 7.94 (dd, 1H), 7.99 (d, 1H), 8.07 (d, 1H), 8.08 (s, 1H), 8.28 (d, 1H).
Reaction SMILES: [CH3:1][C:2]([CH3:14])([O:5][C:6]1[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[CH:8][CH:7]=1)[C:3]#[CH:4].I[C:16]1[N:21]=[CH:20][CH:19]=[CH:18][N:17]=1>C(N(CC)CC)C.[Pd](Cl)Cl.[Cu]I.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:1][C:2]([CH3:14])([O:5][C:6]1[CH:7]=[CH:8][C:9]([C:10]#[N:11])=[CH:12][CH:13]=1)[C:3]#[C:4][C:16]1[N:21]=[CH:20][CH:19]=[CH:18][N:17]=1
Reactant: Ic1ncccn1
Reactant: C#CC(C)(C)Oc1ccc(C#N)cc1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: CC(C)(C#Cc1ncccn1)Oc1ccc(C#N)cc1
Yield: 64.8 %

Procedure:
0.63 g of 4-(1,1-dimethyl-2-propynyloxy)benzonitrile, 0.75 g of 2-iodopyrimidine, 18 mg of triphenylphosphine, 12 mg of palladium(II) chloride and 3.5 mg of copper(I) iodide were stirred overnight in 20 ml of triethylamine under nitrogen. The mixture was evaporated to dryness and then ethyl acetate and water were added. The organic phase was dried over sodium sulphate and evaporated. The residue was chromatographed on silica gel using ethyl acetate/petroleum ether (1:3) and subsequently ethyl acetate/petroleum ether (1:1) for the elution. There were obtained 580 mg of 4-[1,1-dimethyl-3-(2-pyrimidinyl)-2-propynyloxy]benzonitrile as an oil.
Reaction SMILES: C1([C@@H:4](C2C=CC(B3OC(C)(C)C(C)(C)O3)=CC=2)[N:5]2[CH2:10][CH2:9][C@:8]([CH2:17][C:18]([OH:21])(C)C)(C3C=CC=CC=3)OC2=O)CC1.Br[C:39]1[CH:44]=[CH:43][C:42]([C@H:45]([CH:64]2[CH2:66][CH2:65]2)[N:46]2[CH2:51][CH2:50][C@:49]([CH2:58][C:59]([OH:62])([CH3:61])[CH3:60])([C:52]3[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=3)[O:48][C:47]2=[O:63])=[CH:41][CH:40]=1.BrC1C=CC(=O)N(C)C=1>>[CH:64]1([C@@H:45]([C:42]2[CH:43]=[CH:44][C:39]([C:9]3[CH:8]=[CH:17][C:18](=[O:21])[N:5]([CH3:4])[CH:10]=3)=[CH:40][CH:41]=2)[N:46]2[CH2:51][CH2:50][C@:49]([CH2:58][C:59]([OH:62])([CH3:61])[CH3:60])([C:52]3[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=3)[O:48][C:47]2=[O:63])[CH2:66][CH2:65]1
Reactant: CC(C)(O)C[C@]1(c2ccccc2)CCN([C@H](c2ccc(Br)cc2)C2CC2)C(=O)O1
Reactant: CC(C)(O)C[C@]1(c2ccccc2)CCN([C@H](c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)C2CC2)C(=O)O1
Agent: Cn1cc(Br)ccc1=O
Product: Cn1cc(-c2ccc([C@H](C3CC3)N3CC[C@](CC(C)(C)O)(c4ccccc4)OC3=O)cc2)ccc1=O

Procedure:
The title compound was prepared from 3-{(S)-cyclopropyl-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]methyl}-(S)-6-(2-hydroxy-2-methyl-propyl)-6-phenyl-[1,3]oxazinan-2-one {prepared in analogy to the intermediate in Example 3 from 3-[(S)-(4-bromo-phenyl)-cyclopropyl-methyl]-(S)-6-(2-hydroxy-2-methyl-propyl)-6-phenyl-[1,3]oxazinan-2-one} and 5-bromo-1-methyl-1H-pyridin-2-one following a procedure analogous to that described in Example 3. LC-MS (Method 1): tR=3.35 min; Mass spectrum (ESI+): m/z=487 [M+H]+.
Reaction SMILES: [OH:1][CH2:2][C:3]([CH2:8][OH:9])([CH2:6][OH:7])[CH2:4][OH:5].[Si:10](Cl)([C:23]([CH3:26])([CH3:25])[CH3:24])([C:17]1C=CC=CC=1)[C:11]1C=CC=CC=1>N1C=CC=CC=1.CCOC(C)=O>[OH:1][CH2:2][C:3]([CH2:8][O:9][Si:10]([CH3:17])([CH3:11])[C:23]([CH3:26])([CH3:25])[CH3:24])([CH2:6][OH:7])[CH2:4][OH:5]
Reactant: OCC(CO)(CO)CO
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)OCC(CO)(CO)CO
Yield: 133.4 %

Procedure:
Pentaerythritol [2,2-bis(hydroxymethyl)propane-1,3-diol] (10.55 g, 77 mmol) was taken up in 100 mL of dry pyridine. Tert-butyldiphenylsilyl chloride (4.26 g, 15 mmol, 0.2 eq) was then added dropwise over 10 minutes to the pyridine solution at ambient temperature. The reaction mixture was stirred at ambient temperature for 24 hours at which point TLC (EtOAc) indicated that the reaction was complete. The reaction was worked-up by diluting the reaction mixture with 250 mL of EtOAc and washing the organic layer with 10% HCl (3×200 mL). The organic layer was dried over sodium sulfate and then concentrated in vacuo to afford a thick pale yellow oil. Column chromatography on 200 g of silica gel eluting with EtOAc followed by concentration of the appropriate fractions afforded 5.01 g of the product as a clear colorless oil which solidified very slowly upon standing (86%). 1H NMR (CDCl3, 300 MHz): δ1.08 (s, 9H), 3.66 (s, 2H), 3.74 (s, 6H), 7.42 (m, 6H), 7.65 (m, 4H); MS (70 eV, EI) 392 (M+NH4)+.
Reaction SMILES: [CH2:1]([O:3][C:4]1[N:8]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([NH:17][CH2:18][CH3:19])=[O:16])=[CH:11][CH:10]=2)[N:7]=[N:6][C:5]=1[C:20]([O:22]C)=O)[CH3:2].[OH-].[Na+].[CH:26]1([NH2:29])[CH2:28][CH2:27]1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>CO>[CH:26]1([NH:29][C:20]([C:5]2[N:6]=[N:7][N:8]([C:9]3[CH:10]=[CH:11][C:12]([C:15]([NH:17][CH2:18][CH3:19])=[O:16])=[CH:13][CH:14]=3)[C:4]=2[O:3][CH2:1][CH3:2])=[O:22])[CH2:28][CH2:27]1
Reactant: NC1CC1
Reactant: CCNC(=O)c1ccc(-n2nnc(C(=O)OC)c2OCC)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Agent: [Na+]
Solvent: CO
Product: CCNC(=O)c1ccc(-n2nnc(C(=O)NC3CC3)c2OCC)cc1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 81.5 %

Procedure:
To a solution of methyl 5-ethoxy-1-{4-[(ethylamino)carbonyl]phenyl}-1H-1,2,3-triazole-4-carboxylate (159 mg, 0.5 mmol) obtained in Example 1212a) in methanol (5 ml) was added 1N sodium hydroxide (2 ml) and the mixture was stirred at 60° C. for 30 min. The solvent was evaporated, and the residue was adjusted to pH 2-3 with 1N hydrochloric acid. The precipitated crystals were collected by filtration, dried and dissolved in DMF (5 ml). Cyclopropylamine (29 mg, 0.5 mmol), HOBt (84 mg, 0.55 mmol) and WSC (105 mg, 0.55 mmol) were successively added, and the reaction mixture was stirred at room temperature overnight. The solvent was evaporated under reduced pressure, water (5 ml) was added to the residue, and the precipitated crystals were collected by filtration and dried to give the title compound as a white powder (140 mg, 82%).
Reaction SMILES: [CH3:1][N:2]([CH3:24])[CH:3]=[N:4][S:5]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]([CH3:23])([CH3:22])[CH2:15][CH:16]([OH:21])[C:17]([F:20])([F:19])[F:18])(=[O:7])=[O:6].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>ClCCl>[CH3:24][N:2]([CH3:1])[CH:3]=[N:4][S:5]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]([CH3:22])([CH3:23])[CH2:15][C:16](=[O:21])[C:17]([F:18])([F:19])[F:20])(=[O:7])=[O:6]
Reactant: CN(C)C=NS(=O)(=O)c1ccccc1C(C)(C)CC(O)C(F)(F)F
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: CN(C)C=NS(=O)(=O)c1ccccc1C(C)(C)CC(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.7 %

Procedure:
To a round bottom flask was added N-[1-dimethylaminomethylidene]-2-(4,4,4-trifluoro-3-hydroxy-1,1-dimethylbutyl)benzenesulfonamide (367 mg, 1.00 mmol) in 25 mL of dry dichloromethane, followed by the addition of Dess-Martin periodinane (600 mg, 1.42 mmol). The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was quenched with 50 mL of saturated aqueous sodium bicarbonate solution and extracted with 250 mL of ethyl acetate. The organic layer was separated, washed with 50 mL of brine, dried over sodium sulfate, filtered, and concentrated in vacuo. Dichloromethane was added to the residue and the solid which did not dissolve in dichloromethane was filtered. The mother liquor was then concentrated in vacuo and the crude mixture was purified by flash chromatography. The column was eluted with 0-40% EtOAc/hexanes to afford 345 mg (95%) of N-[1-dimethylaminomethylidene]-2-(4,4,4-trifluoro-1,1-dimethyl-3-oxobutyl)benzenesulfonamide. MS (ES+) m/z 365 [M+H]+.
Reaction SMILES: C(C1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1)#N.S(=O)(=O)(O)O.O.[C:32]([OH:35])(=[O:34])[CH3:33]>>[CH2:16]([O:15][C:12]1[CH:13]=[CH:14][C:9]([C:6]2[CH:5]=[CH:4][C:33]([C:32]([OH:35])=[O:34])=[CH:8][CH:7]=2)=[CH:10][CH:11]=1)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: CC(=O)O
Reactant: CCCCCCCCCCOc1ccc(-c2ccc(C#N)cc2)cc1
Agent: O=S(=O)(O)O
Solvent: O
Product: CCCCCCCCCCOc1ccc(-c2ccc(C(=O)O)cc2)cc1

Procedure:
Quantities: compound 57 (17.00 g, 0.051 mol), concentrated sulphuric acid (40 ml), water (40 ml), glacial acetic acid (200 ml).
Reaction SMILES: [ClH:1].Cl.[CH3:3][S:4]([NH:7][C:8]1[CH:38]=[CH:37][C:11]([C:12]([NH:14][CH2:15][CH:16]2[CH2:21][N:20]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=3)[CH2:19][CH2:18][N:17]2CC2C=CC=CC=2)=[O:13])=[CH:10][CH:9]=1)(=[O:6])=[O:5]>[OH-].[OH-].[Pd+2]>[ClH:1].[ClH:1].[CH3:29][O:28][C:24]1[CH:23]=[C:22]([N:20]2[CH2:19][CH2:18][NH:17][CH:16]([CH2:15][NH:14][C:12](=[O:13])[C:11]3[CH:37]=[CH:38][C:8]([NH:7][S:4]([CH3:3])(=[O:6])=[O:5])=[CH:9][CH:10]=3)[CH2:21]2)[CH:27]=[CH:26][CH:25]=1
Reactant: COc1cccc(N2CCN(Cc3ccccc3)C(CNC(=O)c3ccc(NS(C)(=O)=O)cc3)C2)c1
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Product: COc1cccc(N2CCNC(CNC(=O)c3ccc(NS(C)(=O)=O)cc3)C2)c1

Procedure:
In a manner similar to Example 1, react 4-[(methylsulfonyl)amino]-N-[[4-(3-methoxyphenyl)-1-(phenylmethyl)piperazin-2-yl]methyl]benzamide dihydrochloride (2.3 g, 4 mmol) with H2 over Pd(OH)2 (0.3 g) catalyst to give the title compound.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([NH:46][S:47]([CH2:50][CH:51]2[CH2:56][CH2:55][O:54][CH2:53][CH2:52]2)(=[O:49])=[O:48])[CH:6]=[CH:7][C:8]=1[C:9]1[C:17]2[C:16]([NH:18][C@H:19]([C:21]3[N:26]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[C:25](=[O:33])[C:24]4=[C:34]([CH3:37])[CH:35]=[CH:36][N:23]4[N:22]=3)[CH3:20])=[N:15][CH:14]=[N:13][C:12]=2[N:11](COCC[Si](C)(C)C)[CH:10]=1.B(Br)(Br)Br.N>ClCCl>[OH:2][C:3]1[CH:4]=[C:5]([NH:46][S:47]([CH2:50][CH:51]2[CH2:52][CH2:53][O:54][CH2:55][CH2:56]2)(=[O:49])=[O:48])[CH:6]=[CH:7][C:8]=1[C:9]1[C:17]2[C:16]([NH:18][C@H:19]([C:21]3[N:26]([C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=4)[C:25](=[O:33])[C:24]4=[C:34]([CH3:37])[CH:35]=[CH:36][N:23]4[N:22]=3)[CH3:20])=[N:15][CH:14]=[N:13][C:12]=2[NH:11][CH:10]=1
Reactant: COc1cc(NS(=O)(=O)CC2CCOCC2)ccc1-c1cn(COCC[Si](C)(C)C)c2ncnc(N[C@@H](C)c3nn4ccc(C)c4c(=O)n3-c3ccccc3)c12
Agent: BrB(Br)Br
Agent: N
Solvent: ClCCl
Product: Cc1ccn2nc([C@H](C)Nc3ncnc4[nH]cc(-c5ccc(NS(=O)(=O)CC6CCOCC6)cc5O)c34)n(-c3ccccc3)c(=O)c12
Yield: 18.3 %

Procedure:
(S)—N-(3-Methoxy-4-(4-((1-(5-methyl-4-oxo-3-phenyl-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-2-yl)ethyl)amino)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)-1-(tetrahydro-2H-pyran-4-yl)methanesulfonamide (50 mg, 0.05 mmol, 80% purity) was treated with boron tribromide (1M in dichloromethane, 2.0 ml, 2.0 mmol) with dichloromethane (1.0 ml) as a solvent according to the method described in Example 23. and then with a solution of ammonia (7N in methanol, 5.0 ml, 35.0 mmol) according to the method described in Example 27. The residue was purified using SP1® Purification System (reverse phase, 0% to 100% water-acetonitrile/methanol 1:1) to obtain 6 mg (16% yield) of the title compound.
Reaction SMILES: C[N:2](C)[CH:3]=[CH:4][C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=2)[N:8]=1)=O.Cl.[CH3:26][O:27][C:28]1[CH:36]=[CH:35][C:31]([CH2:32][NH:33]N)=[CH:30][CH:29]=1.CCN(CC)CC.Cl>CO>[CH3:26][O:27][C:28]1[CH:36]=[CH:35][C:31]([CH2:32][N:33]2[C:5]([C:7]3[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]4[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=4)[N:8]=3)=[CH:4][CH:3]=[N:2]2)=[CH:30][CH:29]=1
Reactant: CN(C)C=CC(=O)c1nn(-c2cccc(C(F)(F)F)c2)ccc1=O
Reactant: COc1ccc(CNN)cc1
Agent: Cl
Solvent: CO
Solvent: CCN(CC)CC
Product: COc1ccc(Cn2nccc2-c2nn(-c3cccc(C(F)(F)F)c3)ccc2=O)cc1
Temperature: 25 °C
Yield: 43 %

Procedure:
A solution of 3-[3-(dimethylamino)prop-2-enoyl]-1-[3-(trifluoromethyl)phenyl]pyridazin-4(1H)-one (675 mg, 2 mmol), (4-methoxybenzyl)hydrazine hydrochloride (755 mg, 4 mmol), and Et3N (0.558 mL, 4 mmol) in MeOH (20 mL) was refluxed for 3 h. After cooling to room temperature, the reaction mixture was poured into 1 M HCl aqueous solution and extracted with AcOEt. The extract was washed with brine, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography eluting with AcOEt and recrystallized from hexane/AcOEt to give the title compound (367 mg, 43% yield) as an off-white solid: mp 159-161° C.; 1H NMR (300 MHz, CDCl3): δ ppm 3.73 (3H, s), 5.67 (2H, s), 6.69-6.75 (3H, m), 6.81-6.86 (2H, m), 7.41 (1H, d, J=1.9 Hz), 7.45-7.51 (1H, m), 7.54-7.59 (1H, m), 7.65-7.71 (3H, m), 8.17 (1H, d, J=7.9 Hz). LC-MS (ESI) m/z 427 [M+H]+. Anal. Calcd for C22H17F3N4O2: C, 61.97; H, 4.02; N, 13.14. Found: C, 61.95; H, 4.14; N, 13.08.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([N:8]2[C:20](=[O:21])[C:19]3[S:18][C:17]4[CH2:16][CH2:15][CH2:14][CH2:13][C:12]=4[C:11]=3[CH:10]=[N:9]2)[C:3]=1[CH:22]=[O:23].[CH3:24][N:25]1[CH:30]=[C:29](B2OC(C)(C)C(C)(C)O2)[CH:28]=[C:27]([NH:40][C:41]2[CH:46]=[CH:45][N:44]=[CH:43][N:42]=2)[C:26]1=[O:47].C([O-])(=O)C.[Na+].[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(#N)C.O>[CH3:24][N:25]1[C:26](=[O:47])[C:27]([NH:40][C:41]2[CH:46]=[CH:45][N:44]=[CH:43][N:42]=2)=[CH:28][C:29]([C:2]2[CH:7]=[CH:6][N:5]=[C:4]([N:8]3[C:20](=[O:21])[C:19]4[S:18][C:17]5[CH2:16][CH2:15][CH2:14][CH2:13][C:12]=5[C:11]=4[CH:10]=[N:9]3)[C:3]=2[CH:22]=[O:23])=[CH:30]1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cc(Nc2ccncn2)c1=O
Reactant: O=Cc1c(Cl)ccnc1-n1ncc2c3c(sc2c1=O)CCCC3
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: CC#N
Solvent: O
Product: Cn1cc(-c2ccnc(-n3ncc4c5c(sc4c3=O)CCCC5)c2C=O)cc(Nc2ccncn2)c1=O
Temperature: 100 °C
Yield: 30.5 %

Procedure:
A 50-mL single-neck round-bottomed flask equipped with a magnetic stirrer and a reflux condenser was charged with 4-chloro-2-{6-oxo-8-thia-4,5-diazatricyclo[7.4.0.02,7]trideca-1(9),2(7),3-trien-5-yl}pyridine-3-carbaldehyde 124a (345 mg, 1.0 mmol), 1-methyl-3-(pyrimidin-4-ylamino)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one 143a (328 mg, 1.0 mmol), Pd(dppf)Cl2 (82 mg, 0.10 mmol), sodium acetate (162 mg, 2.0 mmol), K3PO4 (424 mg, 2.0 mmol), and acetonitrile/water (20/1 mL). After three cycles of vacuum/argon flush, the mixture was heated at 100° C. for 3 h. It was then cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by silica-gel column chromatography eluting with 40:1 dichloromethane/methanol to afford 182a as a yellow solid (156 mg, 30%). MS-ESI: [M+H]+ 512.1.
Reaction SMILES: [CH3:1][N:2]([CH3:4])[CH3:3].C[N+](CC(O)=O)(C)C.Cl.C[NH+](C)C.[Cl:18][CH2:19][C:20]([OH:22])=[O:21]>>[Cl:18][CH2:19][C:20]([O-:22])=[O:21].[CH3:1][NH+:2]([CH3:4])[CH3:3]
Reactant: O=C(O)CCl
Reactant: CN(C)C
Agent: C[N+](C)(C)CC(=O)O
Agent: C[NH+](C)C
Agent: Cl
Product: O=C([O-])CCl

Procedure:
maintaining the reaction solution from step (1) at pH 7.5-10, as necessary, by addition of a molar excess of liquid trimethylamine, to effect the formation of betaine and trimethyl ammonium hydrochloride until substantially all of the monochloroacetic acid has been reacted, leaving a residual amount of trimethylammoniumchloroacetate in the reaction solution;
Reaction SMILES: [C:1]([NH:8][CH2:9][CH2:10][C:11]1[CH:18]=[C:17](F)[C:14]([C:15]#[N:16])=[C:13]([F:20])[CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH:21]1([CH2:26][OH:27])[CH2:25][CH2:24][CH2:23][CH2:22]1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>C1COCC1.O>[C:1]([NH:8][CH2:9][CH2:10][C:11]1[CH:12]=[C:13]([F:20])[C:14]([C:15]#[N:16])=[C:17]([O:27][CH2:26][CH:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)[CH:18]=1)([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2]
Reactant: OCC1CCCC1
Reactant: CC(C)(C)OC(=O)NCCc1cc(F)c(C#N)c(F)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)NCCc1cc(F)c(C#N)c(OCC2CCCC2)c1
Reaction time: 8 h
Yield: 44.9 %

Procedure:
To a stirred solution of the above benzonitrile intermediate (8.66 mmol) and cyclopentanemethanol (781 mg, 7.8 mmol) in THF (45 mL) at 0° C. was added N-sodium hexamethyldisilazane (1 M in THF, 7.8 mL, 7.8 mmol) and the reaction was stirred overnight. It was diluted with water, extracted with dichloromethane, washed with brine, dried with sodium sulfate, concentrated and dried in vacuo to give 4-(N-boc-2-aminoethyl)-2-cyclopentylmethoxy-6-fluorobenzonitrile (1.27 g, 3.5 mmol, 45%).
Reaction SMILES: [Cl:1][C:2]1[C:6]([N:7]([CH2:13][C:14]#[CH:15])[C:8](=[O:12])[CH2:9][NH:10][CH3:11])=[CH:5][N:4]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)[N:3]=1.[CH3:22][S:23](Cl)(=[O:25])=[O:24].C(N(C(C)C)CC)(C)C.C([O-])(O)=O.[Na+]>C(Cl)Cl>[Cl:1][C:2]1[C:6]([N:7]([CH2:13][C:14]#[CH:15])[C:8](=[O:12])[CH2:9][N:10]([CH3:11])[S:23]([CH3:22])(=[O:25])=[O:24])=[CH:5][N:4]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)[N:3]=1
Reactant: C#CCN(C(=O)CNC)c1cn(-c2cccnc2)nc1Cl
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C#CCN(C(=O)CN(C)S(C)(=O)=O)c1cn(-c2cccnc2)nc1Cl
Temperature: 25 °C
Reaction time: 24 h
Yield: 72.3 %

Procedure:
To a solution of N-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-2-(methylamino)-N-(prop-2-yn-1-yl)acetamide (0.100 g, 0.329 mmol) in DCM (0.65 ml) was added methanesulfonyl chloride (0.057 g, 0.494 mmol) followed by diisopropylethylamine (0.11 ml, 0.658 mmol) and the reaction was stirred at room temperature for 24 h. The reaction mixture was poured into a solution of saturated NaHCO3 and subsequently extracted with DCM. The organic layers were combined and concentrated, and the residue was purified using silica gel chromatography (50-100% EtOAc/hexanes) to afford the title compound as a yellow solid (0.091 g, 0.238 mmol, 72%): (IR thin film) 1678 cm−1; 1H NMR (400 MHz, CDCl3) δ 8.97 (d, J=2.6 Hz, 1H), 8.65 (dd, J=4.8, 1.3 Hz, 1H), 8.15 (s, 1H), 8.04 (ddd, J=8.3, 2.7, 1.4 Hz, 1H), 7.48 (dd, J=8.4, 4.7 Hz, 1H), 3.77 (hept, J=6.9 Hz, 2H), 3.05 (s, 2H), 3.01 (s, 3H), 2.87 (s, 3H), 2.31 (t, J=2.5 Hz, 1H); ESIMS m/z 382 ([M+H]+).
Reaction SMILES: [C:1]([O:5][C:6](=[O:42])[NH:7][C@@H:8]1[C@H:13]([OH:14])[CH2:12][CH2:11][N:10]([C:15]([C:17]2[CH:39]=[C:38](OC)[C:20]3[N:21]([CH3:37])[C:22]([C:24]4[N:32]([CH2:33][CH:34]5[CH2:36][CH2:35]5)[C:27]5=[N:28][CH:29]=[CH:30][CH:31]=[C:26]5[CH:25]=4)=[N:23][C:19]=3[CH:18]=2)=[O:16])[CH2:9]1)([CH3:4])([CH3:3])[CH3:2].C(OC(=O)N[C@@H]1[C@H](O)CCNC1)(C)(C)C>>[C:1]([O:5][C:6](=[O:42])[NH:7][C@@H:8]1[C@H:13]([OH:14])[CH2:12][CH2:11][N:10]([C:15]([C:17]2[CH:39]=[CH:38][C:20]3[N:21]([CH3:37])[C:22]([C:24]4[N:32]([CH2:33][CH:34]5[CH2:36][CH2:35]5)[C:27]5=[N:28][CH:29]=[CH:30][CH:31]=[C:26]5[CH:25]=4)=[N:23][C:19]=3[CH:18]=2)=[O:16])[CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1cc(C(=O)N2CC[C@@H](O)[C@@H](NC(=O)OC(C)(C)C)C2)cc2nc(-c3cc4cccnc4n3CC3CC3)n(C)c12
Agent: CC(C)(C)OC(=O)N[C@H]1CNCC[C@H]1O
Product: Cn1c(-c2cc3cccnc3n2CC2CC2)nc2cc(C(=O)N3CC[C@@H](O)[C@@H](NC(=O)OC(C)(C)C)C3)ccc21

Procedure:
Prepared in a similar manner to Intermediate 48 from (2-(1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1-methyl-1H-benzo[d]imidazole-5-4-carboxylic acid and tert-butyl((3S,4R)-4-hydroxypiperidin-3-yl)carbamate.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4](/[C:8](/[CH2:38][CH3:39])=[C:9](\[C:25]2[CH:30]=[CH:29][C:28](/[CH:31]=[CH:32]/[C:33]([O:35][CH2:36][CH3:37])=[O:34])=[CH:27][CH:26]=2)/[C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[N:15]([CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][O:20]2)[N:14]=[CH:13]3)[CH:5]=[CH:6][CH:7]=1.C([O-])([O-])=O.[Cs+].[Cs+].I[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][N:48]=1.N1C=CC=CC=1CC(=O)C>CS(C)=O>[N:48]1[CH:49]=[CH:50][CH:51]=[CH:52][C:47]=1[O:1][C:2]1[CH:3]=[C:4](/[C:8](/[CH2:38][CH3:39])=[C:9](\[C:25]2[CH:26]=[CH:27][C:28](/[CH:31]=[CH:32]/[C:33]([O:35][CH2:36][CH3:37])=[O:34])=[CH:29][CH:30]=2)/[C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[N:15]([CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][O:20]2)[N:14]=[CH:13]3)[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)/C=C/c1ccc(/C(=C(/CC)c2cccc(O)c2)c2ccc3c(cnn3C3CCCCO3)c2)cc1
Reactant: Ic1ccccn1
Agent: CC(=O)Cc1ccccn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: CCOC(=O)/C=C/c1ccc(/C(=C(/CC)c2cccc(Oc3ccccn3)c2)c2ccc3c(cnn3C3CCCCO3)c2)cc1
Temperature: 80 °C
Reaction time: 14 h
Yield: 64.4 %

Procedure:
A mixture of (E)-ethyl 3-(4-((E)-2-(3-hydroxyphenyl)-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)but-1-en-1-yl)phenyl)acrylate (300 mg, 0.57 mmol; Compound 346, Step 1), CuBr (3.6 mg, 0.025 mmol), Cs2CO3 (320 mg, 0.98 mmol), 2-iodopyridine (103 mg, 0.50 mmol), 1-(pyridin-2-yl)propan-2-one (15 mg, 0.11 mmol), and DMSO (1 mL) was degassed with three vacuum/N2 cycles, heated at 80° C. for 5 h, heated at 90° C. for 2 h, and then stirred at rt for 14 h. The reaction was diluted with EtOAc and filtered through Celite. The organic filtrate was washed with H2O (50 mL), washed with brine (40 mL), dried (MgSO4), filtered, concentrated, and purified by silica gel chromatography (10%-30% EtOAc in hexanes) to give 193 mg of (E)-ethyl 3-(4-((E)-2-(3-(pyridin-2-yloxy)phenyl)-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)but-1-en-1-yl)phenyl)acrylate as a white foam. 1H NMR (400 MHz, DMSO-d6): δ 8.13 (dd, 1H), 8.11 (s, 1H), 7.69-7.75 (m, 2H), 7.64 (s, 1H), 7.52 (d, 1H), 7.44 (d, 2H), 7.30 (t, 1H), 7.23 (dd, 1H), 7.06-7.10 (m, 2H), 6.90-6.95 (m, 3H), 6.85-6.88 (m, 1H), 6.65 (d, 1H), 6.52 (d, 1H), 5.85 (d, 1H), 4.16 (q, 2H), 3.87-3.92 (m, 1H), 3.70-3.78 (m, 1H), 2.38-2.48 (m, 3H), 1.95-2.08 (m, 2H), 1.70-1.81 (m, 1H), 1.56-1.62 (m, 2H), 1.25 (t, 3H), 0.94 (t, 3H); LCMS: 600 (M+H)+.