Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH:2]([O:5][CH:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)([CH3:4])[CH3:3].C(N(CC)CC)C.[F:19][C:20]1[CH:28]=[CH:27][C:26]([CH2:29][C:30]2[C:39]3[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=3)[C:33](=[O:40])[NH:32][N:31]=2)=[CH:25][C:21]=1[C:22](O)=[O:23].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1>CN(C)C=O>[F:19][C:20]1[CH:28]=[CH:27][C:26]([CH2:29][C:30]2[C:39]3[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=3)[C:33](=[O:40])[NH:32][N:31]=2)=[CH:25][C:21]=1[C:22]([N:9]1[CH2:10][CH2:11][CH:6]([O:5][CH:2]([CH3:4])[CH3:3])[CH2:7][CH2:8]1)=[O:23]
Reactant: O=C(O)c1cc(Cc2n[nH]c(=O)c3ccccc23)ccc1F
Reactant: CC(C)OC1CCNCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)OC1CCN(C(=O)c2cc(Cc3n[nH]c(=O)c4ccccc34)ccc2F)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 60.6 %

Procedure:
A solution of 4-isopropoxypiperidine hydrochloride (120 mg, 0.67 mmol) and triethylamine (0.206 mL, 1.48 mmol), in N,N dimethylformamide (2 mL) was added in one portion to a stirred solution of 2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoic acid (1) (200 mg, 0.67 mmol), triethylamine (0.206 mL, 1.48 mmol) and O-Benzotriazol-1-yl-N,N,N′,N′-tetra-methyluronium hexafluorophosphate (381 mg, 1.01 mmol) in N,N dimethylformamide (2 mL) at 25° C. The resulting solution was stirred at 25° C. for 4 hours. The crude product was purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5μ silica, 30 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford the desired compound (172 mg, 60.6% yield); 1H NMR (399.902 MHz, DMSO) δ 1.06-1.11 (6H, m), 1.21-1.46 (2H, m), 1.61-1.87 (2H, m), 3.04 (1H, t), 3.62 (2H, td), 3.70 (1H, quintet), 3.92-4.01 (1H, m), 4.07 (1H, q), 4.33 (2H, s), 7.19-7.25 (1H, m), 7.32-7.37 (1H, m), 7.38-7.44 (1H, m), 7.81-7.92 (2H, m), 7.96-8.00 (1H, m), 8.26-8.29 (1H, m), 12.58 (1H, s); m/z (LC-MS, ESI+), RT=1.98 (M+H 424.6).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][NH:9][C:10]([C:12]2[CH:21]=[CH:20][C:15]([C:16]([O:18]C)=[O:17])=[CH:14][CH:13]=2)=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CO.[OH-].[Na+]>O>[C:1]1([CH2:7][CH2:8][NH:9][C:10]([C:12]2[CH:13]=[CH:14][C:15]([C:16]([OH:18])=[O:17])=[CH:20][CH:21]=2)=[O:11])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)c1ccc(C(=O)NCCc2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1ccc(C(=O)NCCc2ccccc2)cc1
Yield: 94.4 %

Procedure:
The product from step (a) (23.5 g 83 mmoles) was dissolved in refluxing methanol (250 ml) and a solution of sodium hydroxide (6.64 g, 166 mmoles) in water (10 ml) was added. The solid, which separated almost immediately, was filtered off, dissolved in water and acidified. The precipitate was separated, washed with water, dried and triturated with ether to give the sub-title acid (21.1 g) as a white solid mp 237°-238.5°.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:4]=1[NH2:5].C(N(CC)CC)C.[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][C:27](Cl)=[O:28])=[CH:22][CH:21]=1.O>C(Cl)Cl>[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][C:27]([NH:5][C:4]2[CH:6]=[C:7]([O:10][CH3:11])[CH:8]=[CH:9][C:3]=2[Cl:2])=[O:28])=[CH:22][CH:21]=1
Reactant: O=C(Cl)Cc1ccc(Cl)cc1
Reactant: COc1ccc(Cl)c(N)c1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: COc1ccc(Cl)c(NC(=O)Cc2ccc(Cl)cc2)c1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
5.8 g (30 mmol) of 2-chloro-5-methoxyaniline-hydrochloride are dissolved with 7.08 g (70 mmol) of triethylamine in 100 ml methylene chloride and whilst cooling with ice 5.86 g (31 mmol) of 4-chlorophenylacetyl chloride are added dropwise. After 2 hours' stirring the mixture is added to water and extracted with methylene chloride. The extracts are dried and evaporated down. The evaporation residue is recrystallised from ether/petroleum ether. Melting point: 149-151° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1.[B:14](OC)([O:17]C)[O:15]C>>[F:1][C:2]1[C:3]([C:8]2[CH:9]=[CH:10][N:11]=[CH:12][CH:13]=2)=[CH:4][CH:5]=[CH:6][C:7]=1[B:14]([OH:17])[OH:15]
Reactant: Fc1ccccc1-c1ccncc1
Reactant: COB(OC)OC
Product: OB(O)c1cccc(-c2ccncc2)c1F

Procedure:
4-(2-Fluorophenyl)pyridine was lithiated and reacted with trimethyl borate as described in Example 31 to afford 2-fluoro-3-(pyridin-4-yl)benzeneboronic acid as a white solid: m/z (ES+) 218 (M++H).
Reaction SMILES: S(OC(C)C#C)([C:4]1[CH:10]=CC(C)=[CH:6][CH:5]=1)(=O)=O.[CH3:16][C:17]1[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[C:18]=1[NH2:19]>>[CH3:6][CH:5]([NH:19][C:18]1[C:20]([CH3:24])=[CH:21][CH:22]=[CH:23][C:17]=1[CH3:16])[C:4]#[CH:10]
Reactant: C#CC(C)OS(=O)(=O)c1ccc(C)cc1
Reactant: Cc1cccc(C)c1N
Product: C#CC(C)Nc1c(C)cccc1C
Temperature: 0 °C

Procedure:
22.4 g of 1-butyn-3-ol tosylate in 26 g of 2,6-dimethylaniline are stirred at 110° C. for 3 hours. The mixture is then poured into ice-water, extracted with ethyl acetate, dried over sodium sulfate and filtered. The solvent is distilled off to yield N-(1-methyl-2-propynyl)-2,6-xylidine; b.p. 68°-72° C./0.05 Torr; m.p. 32°-33° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([O:11][CH3:12])=[O:10].N1C=CC=CC=1.[CH2:19]([O:21][C:22]([CH2:24][S:25](Cl)(=[O:27])=[O:26])=[O:23])[CH3:20]>C1(C)C=CC=CC=1>[CH2:19]([O:21][C:22]([CH2:24][S:25]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([O:11][CH3:12])=[O:10])(=[O:27])=[O:26])=[O:23])[CH3:20]
Reactant: CCOC(=O)CS(=O)(=O)Cl
Reactant: COC(=O)Cc1ccccc1N
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CCOC(=O)CS(=O)(=O)Nc1ccccc1CC(=O)OC
Temperature: 25 °C

Procedure:
To a solution of 82.7 g of methyl 2-aminophenylacetate (see Example l) in 1.2 l of toluene is added 42 ml of pyridine and the mixture is stirred at room temperature. To this mixture is added a solution of 93.2 g of ethoxycarbonylmethylsulfonyl chloride in 150 ml of toluene in a dropwise manner over a period of 30 minutes, maintaining the temperature of the reaction below 10° by means of an ice-water bath. After stirring at 0° for an additional 1 hour, the mixture is poured into 50 ml of ice-water, the organic layer is separated and washed with 150 ml of cold dilute hydrochloric acid followed by 150 ml of brine. The toluene extract is dried over anhydrous magnesium sulfate, filtered and the solvent evaporated under reduced pressure to yield methyl 2-(ethoxycarbonylmethylsulfonylamino)-phenylacetate as an oil which is used in the next step without further purification.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3]1.[CH:11](=[O:15])/[CH:12]=[CH:13]/[CH3:14].FC(F)(F)C(O)=O.C([C@@H]1N[C@H](C(C)(C)C)N(C)C1=O)C1C=CC=CC=1>>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C@H:13]([CH3:14])[CH2:12][CH:11]=[O:15])=[CH:3]1
Reactant: Cn1ccc2ccccc21
Reactant: C/C=C/C=O
Agent: CN1C(=O)[C@H](Cc2ccccc2)N[C@@H]1C(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: C[C@H](CC=O)c1cn(C)c2ccccc12

Procedure:
This example describes the alkylation of 1-methyl-1H-indole with (E)-crotonaldehyde, catalyzed by the trifluoroacetic acid salt of (1), to provide (R)-3-(1-methyl-1H-indol-3-yl)-butanal.
Reaction SMILES: [OH:1][CH:2]([C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=1)[C:3]([O:5][CH3:6])=[O:4].[H-].[Na+].CI.[C:21](OCC)(=O)C>CN(C=O)C>[CH3:21][O:1][CH:2]([C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=1)[C:3]([O:5][CH3:6])=[O:4]
Reactant: CCOC(C)=O
Reactant: COC(=O)C(O)c1ccc2ccccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)C(OC)c1ccc2ccccc2c1
Reaction time: 24 h
Yield: 53 %

Procedure:
To a stirred solution of methyl 2-hydroxy-2-(naphthalen-2-yl)acetate (0.63 g, 1 eq) in dry DMF was added NaH (0.45 g, 4 eq) and methyl iodide (0.74 mL, 4.1 eq). Stirring was then continued for 24 hours. The reaction mixture was then poured into ethyl acetate and washed with H2O. The combined organic fractions were dried over Na2SO4, filtered, and concentrated under reduced pressure to yield an oil that was purified by column chromatography using ethyl acetate and hexanes to yield an oil (0.358 g, 53%).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:22]=[CH:21][C:10]2[C:11]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)=[N:12][S:13][C:9]=2[CH:8]=1.[OH:23][C@@H:24]1[CH2:28][CH2:27][NH:26][CH2:25]1>>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([C:11]2[C:10]3[CH:21]=[CH:22][C:7]([O:6][CH2:5][CH2:4][CH2:3][CH2:2][N:26]4[CH2:27][CH2:28][C@@H:24]([OH:23])[CH2:25]4)=[CH:8][C:9]=3[S:13][N:12]=2)=[CH:15][CH:16]=1
Reactant: Clc1ccc(-c2nsc3cc(OCCCCBr)ccc23)cc1
Reactant: O[C@@H]1CCNC1
Product: O[C@@H]1CCN(CCCCOc2ccc3c(-c4ccc(Cl)cc4)nsc3c2)C1

Procedure:
According to the method in example 7, 6-(4-Bromo-butoxy)-3-(4-chloro-phenyl)-benzo[d]isothiazole and (R)-3-Hydroxypyrrolidine were converted to yield (3R)-1-{4-[3-(4-Chloro-phenyl)-benzo[d]isothiazol-6-yloxy]-butyl}-pyrrolidin-3-ol, MS: 403 (MH+, 1Cl).
Reaction SMILES: [NH2:1][CH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3]1.[C:11](Cl)(=[O:20])[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=1>CCCCCC>[C:11]([NH:1][CH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3]1)(=[O:20])[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=1
Reactant: COc1cccc(C(=O)Cl)c1
Reactant: NC1CCc2ccccc21
Solvent: CCCCCC
Product: COc1cccc(C(=O)NC2CCc3ccccc32)c1

Procedure:
The title compound was prepared from (rac)-1-aminoindan (1.6 g, 12.3 mmole) and m-anisoyl chloride (1.9 g, 13.54 mmole) as in Ex. 46; crystallization from EtOAc: hexane gave 2.0 g (7.2 mmole, 59%) white solid, mp: 140° C.
Reaction SMILES: [Br:1][C:2]1[C:3]([C:10]([OH:12])=[O:11])=[N:4][C:5]([S:8][CH3:9])=[N:6][CH:7]=1.[CH3:13][Si](C=[N+]=[N-])(C)C>CO>[Br:1][C:2]1[C:3]([C:10]([O:12][CH3:13])=[O:11])=[N:4][C:5]([S:8][CH3:9])=[N:6][CH:7]=1
Reactant: CSc1ncc(Br)c(C(=O)O)n1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Product: COC(=O)c1nc(SC)ncc1Br

Procedure:
5-bromo-2-(methylthio)pyrimidine-4-carboxylic acid (2 g, 8.03 mmol) was stirred in MeOH (40 mL) at room temperature. To this stirred mixture was added (trimethylsilyl)diazomethane (12.04 mL, 2M, 24-09 mmol). LCMS of aliquot taken immediately after addition indicated there was still unreacted starting acid. Added more (trimethylsilyl)diazomethane (6 mL, 2 M, 12 mmol). LCMS indicated completion of reaction. The reaction was quenched adding about 0.5 mL of TFA into the crude mixture. Volatiles were removed under reduced pressure. The resulting crude mixture was purified by flash chromatography (SiO2, Biotage 40M cartridge). The column was eluted with a EtOAc/hexanes gradient mixture (0% to 30%). Related fraction were pooled and evaporated to afford a colorless crystalline solid as the titled compound. LCMS calc.=263.94; found=264.79.
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([O:15][C:16]1[C:25]3[C:20](=[CH:21][C:22]([O:28][CH3:29])=[C:23]([O:26][CH3:27])[CH:24]=3)[N:19]=[CH:18][CH:17]=1)=[CH:10][CH:9]=2)=[O:5])C.[OH-].[Na+]>C1COCC1.CO>[CH3:27][O:26][C:23]1[CH:24]=[C:25]2[C:20](=[CH:21][C:22]=1[O:28][CH3:29])[N:19]=[CH:18][CH:17]=[C:16]2[O:15][C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:4]([OH:5])=[O:3])=[CH:14]2
Reactant: CCOC(=O)c1cc2cc(Oc3ccnc4cc(OC)c(OC)cc34)ccc2[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COc1cc2nccc(Oc3ccc4[nH]c(C(=O)O)cc4c3)c2cc1OC
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 5-(6,7-dimethoxy-quinolin-4-yloxy)-1H-indole-2-carboxylic acid ethyl ester (0.2 g, 0.51 mmol, from step a) in 1:1 THF/MeOH (4 mL) was added 1.53 mL of 1N NaOH. The reaction was stirred at RT for 16 h then concentrated in vacuo. The remaining solution was acidified with 10% HCl to pH ˜5. The white precipitate was collected, dried in vacuo to afford white solid as desired acid. MS (ESI pos. ion) m/z: 365 (M+H). Calc'd Exact Mass for C20H16N2O5: 364.35.
Reaction SMILES: [Si]([O:8][CH:9]([CH:16]([CH3:25])[CH:17]=[CH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:10][CH:11]=[CH:12][C:13]([O-:15])=[O:14])(C(C)(C)C)(C)C>C(Cl)Cl.FC(F)(F)C(O)=O>[OH:8][CH:9]([CH:16]([CH3:25])[CH:17]=[CH:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[CH2:10][CH:11]=[CH:12][C:13]([OH:15])=[O:14]
Reactant: CC(C=Cc1ccccc1)C(CC=CC(=O)[O-])O[Si](C)(C)C(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C=Cc1ccccc1)C(O)CC=CC(=O)O
Temperature: 23 °C
Reaction time: 4 h
Yield: 49 %

Procedure:
tert-Butyl (2E, 5S, 6R, 7E)-5-[(tert-butyl-dimethylsilyl)-oxy]-6-methyl-8-phenyl-octa-2,7-dienoate (725 mg, 1.74 mmol) was dissolved in CH2Cl2 (8 mL) and trifluoroacetic acid (2 mL). The solution was stirred at 23° C. for 4 h then concentrated in-vacuo. Residual trifluoroacetic acid was removed by coevaporation with toluene. Flash chromatography (2% MeOH/CH2Cl2+1% AcOH) afforded the title compound 9 (210 mg, 49%) as pale yellow oil. TLC Rf=0.24 (2% MeOH/CH2Cl2+1% AcOH, KMnO4 stain); 1H NMR (CDCl3, 400 MHz) δ 7.23-7.39 (m, 5H), 7.16 (dt, J=15.6, 7.4, 1H), 6.49 (d, J=15.8, 1H), 6.13 (dd, J=15.8, 8.7, 1H), 5.94 (dt, J=15.6, 1.4, 1H), 3.68 (ddd, J=7.9, 6.0, 3.9, 1H), 2.50-2.56 (m, 1H), 2.36-2.44 (m, 2H), 1.16 (d, J=6.8, 3H); 13C NMR (CDCl3, 101 MHz) δ 171.0, 148.5, 137.0, 132.4, 130.9, 128.8, 127.7, 126.4, 122.9, 73.9, 43.6, 37.5, 17.0; MS (ESI+) m/z 269.1 [M+Na]+ (C15H18NaO3 requires 269.1).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[C:5](Cl)=[O:6].[CH2:14]([NH:16][CH2:17][CH3:18])[CH3:15]>>[CH2:14]([N:16]([CH2:17][CH3:18])[C:5](=[O:6])[C:4]1[CH:8]=[CH:9][CH:10]=[CH:11][C:3]=1[C:2]([F:13])([F:12])[F:1])[CH3:15]
Reactant: CCNCC
Reactant: O=C(Cl)c1ccccc1C(F)(F)F
Product: CCN(CC)C(=O)c1ccccc1C(F)(F)F
Yield: 97 %

Procedure:
N,N-Diethyl-2-(trifluoromethyl)benzamide was prepared from 2-trifluoromethylbenzoyl chloride and diethylamine according to General Method E1. No purification was needed to obtain 17.2 g of this compound, a 97% yield.
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH:23]4[CH2:25][CH2:24]4)=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[N:6][CH:7]=1.[CH3:26][N:27]1[CH2:31][CH2:30][NH:29][C:28]1=[O:32]>>[CH:23]1([C:19]2[CH:20]=[C:21]([CH3:22])[C:16]([N:13]3[CH2:14][CH2:15][N:10]([C:8]([C:5]4[N:6]=[CH:7][C:2]([N:29]5[CH2:30][CH2:31][N:27]([CH3:26])[C:28]5=[O:32])=[N:3][CH:4]=4)=[O:9])[CH2:11][CH2:12]3)=[N:17][CH:18]=2)[CH2:25][CH2:24]1
Reactant: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2cnc(Br)cn2)CC1
Reactant: CN1CCNC1=O
Product: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2cnc(N3CCN(C)C3=O)cn2)CC1
Yield: 54.7 %

Procedure:
Using (5-bromopyrazin-2-yl)[4-(5-cyclopropyl-3-methylpyridin-2-yl)piperazin-1-yl]methanone (150 mg) described in Preparation Example 243 and 1-methylimidazolidin-2-one (56 mg) and by the reaction and treatment in the same manner as in Example 536, the title compound (86 mg) was obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:11]([F:14])([F:13])[F:12])[C:5]([C:8](=[O:10])[CH3:9])=[N:6][CH:7]=1.[Br-:15].[Br-].[Br-].C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1>C1COCC1>[Br:15][CH2:9][C:8]([C:5]1[C:4]([C:11]([F:14])([F:12])[F:13])=[CH:3][C:2]([Br:1])=[CH:7][N:6]=1)=[O:10]
Reactant: CC(=O)c1ncc(Br)cc1C(F)(F)F
Reactant: [Br-]
Agent: C[N+](C)(C)c1ccccc1
Solvent: C1CCOC1
Product: O=C(CBr)c1ncc(Br)cc1C(F)(F)F
Temperature: 25 °C

Procedure:
Dissolve 1-(5-bromo-3-(trifluoromethyl)pyridin-2-yl)ethanone (0.7 g, 0.0026 mol) in anhydrous THF at room temperature under N2 atmosphere. Add phenyltrimethyl-ammonium tribromide (1.47 g, 0.0039 moles, 1.5 eq.) to the reaction mixture and reflux overnight. Cool the reaction mixture to room temperature, filter the insoluble solid and concentrate the filtrate under vacuum. Purify by column chromatography to afford the title compound as a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:24]3[CH2:29][CH2:28][CH2:27][N:26]([C:30](=[O:34])[CH2:31][C:32]#[N:33])[CH2:25]3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:13][CH:12]=3)[C:3]=12.CO.N1CCCCC1.[CH:43](=O)[C:44]([CH3:47])([CH3:46])[CH3:45]>ClCCl>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C@@H:24]3[CH2:29][CH2:28][CH2:27][N:26]([C:30]([C:31](=[CH:43][C:44]([CH3:47])([CH3:46])[CH3:45])[C:32]#[N:33])=[O:34])[CH2:25]3)[N:9]=[C:10]([C:11]3[CH:12]=[CH:13][C:14]([O:17][C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)=[CH:15][CH:16]=3)[C:3]=12
Reactant: N#CCC(=O)N1CCCC(n2nc(-c3ccc(Oc4ccccc4)cc3)c3c(N)ncnc32)C1
Reactant: CC(C)(C)C=O
Solvent: C1CCNCC1
Solvent: ClCCl
Solvent: CO
Product: CC(C)(C)C=C(C#N)C(=O)N1CCC[C@@H](n2nc(-c3ccc(Oc4ccccc4)cc3)c3c(N)ncnc32)C1
Temperature: 30 °C
Reaction time: 48 h
Yield: 26.1 %

Procedure:
A mixture of 3-[3-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]piperidin-1-yl]-3-oxopropanenitrile (150 mg, 0.33 mmol, 1.00 equiv), methanol (15 mL), dichloromethane (5 mL), piperidine (56 mg, 0.66 mmol, 2 equiv) and pivalaldehyde (142 mg, 1.66 mmol, 5 equiv) was stirred for 48 h at 30° C. in a 25-mL sealed tube. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with dichloromethane/methanol (100/1) to give 45 mg (26%) of (R)-2-(3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-4,4-dimethylpent-2-enenitrile as a white solid. MS (ESI, pos. ion) m/z: 522 (M+1) 1HNMR (300 MHz, CDCl3, ppm) 8.396 (1H, s), 7.684˜7.656 (2H, d, J=8.4), 7.440˜7.388 (2H, t), 7.222˜7.092 (5H, m), 6.956 (1H, s), 5.613 (2H, s), 5.006˜4.909 (1H, m), 4.626˜3.290 (4H, m), 2.419˜1.732 (4H, m), 1.275 (9H, s).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[CH:5]=[CH:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([NH2:13])[CH:8]=1)[CH3:2].[Br:15][C:16]1[N:21]=[C:20]([C:22](O)=[O:23])[CH:19]=[CH:18][CH:17]=1>>[CH2:1]([O:3][C:4](=[O:14])[CH:5]=[CH:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([NH:13][C:22]([C:20]2[CH:19]=[CH:18][CH:17]=[C:16]([Br:15])[N:21]=2)=[O:23])[CH:8]=1)[CH3:2]
Reactant: CCOC(=O)C=Cc1cccc(N)c1
Reactant: O=C(O)c1cccc(Br)n1
Product: CCOC(=O)C=Cc1cccc(NC(=O)c2cccc(Br)n2)c1

Procedure:
Aniline (60) (124 mg, 0.6 mmol) was coupled to 6-bromo-pyridine-2-carboxylic acid (131 mg, 0.6 mmol) using Method C. The residue was purified by column chromatography eluting in 10% EtOAc in heptane to give the title compound.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]([N:11]1[CH2:18][CH2:17][C@@H:16]2[C@@H:13]([N:14]([C:19]3[N:24]=[C:23]([CH3:25])[CH:22]=[C:21]([CH3:26])[N:20]=3)[CH2:15]2)[CH2:12]1)=[O:10].[N:27]1[CH:32]=[C:31](B(O)O)[CH:30]=[N:29][CH:28]=1.C([O-])([O-])=O.[K+].[K+].O1CCOCC1>O>[CH3:26][C:21]1[CH:22]=[C:23]([CH3:25])[N:24]=[C:19]([N:14]2[C@@H:13]3[C@@H:16]([CH2:17][CH2:18][N:11]([C:9]([C:3]4[CH:4]=[C:5]([F:8])[CH:6]=[CH:7][C:2]=4[C:31]4[CH:32]=[N:27][CH:28]=[N:29][CH:30]=4)=[O:10])[CH2:12]3)[CH2:15]2)[N:20]=1
Reactant: Cc1cc(C)nc(N2C[C@@H]3CCN(C(=O)c4cc(F)ccc4Br)C[C@@H]32)n1
Reactant: OB(O)c1cncnc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1cc(C)nc(N2C[C@@H]3CCN(C(=O)c4cc(F)ccc4-c4cncnc4)C[C@@H]32)n1
Temperature: 150 °C
Yield: 24 %

Procedure:
Example 198 was prepared by the following procedure: (1R,6S)-3-[(2-bromo-5-fluorophenyl)carbonyl]-8-(4,6-dimethylpyrimidin-2-yl)-3,8-diazabicyclo[4.2.0]octane (100 mg, 0.24 mmol), pyrimidine-5-boronic acid (44 mg, 0.36 mmol), Pd(ddpf)Cl2 (19 mg, 0.02 mmol) and K2CO3 (98 mg, 0.72 mmol) were suspended a 1.2 ml of a mixture of 1,4-dioxane and water (5:1) in a sealed tube and heated to 150° C. for 2 h. The reaction was cooled to 23° C., and purified directly on 16 g SiO2 with 0-50% ethyl acetate/hexanes to give 24 mg (24% yield). MS (ESI) mass calcd. for C23H23FN6O, 418.5; m/z found, 419.2 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:8][NH:9][C:10]([CH:12]2[CH2:15][C:14](=[CH2:16])[CH2:13]2)=O)=[N:4][CH:5]=[CH:6][N:7]=1.CN(C=O)C.O=P(Cl)(Cl)Cl.N#N>CC#N>[Cl:1][C:2]1[C:3]2[N:4]([C:10]([CH:12]3[CH2:15][C:14](=[CH2:16])[CH2:13]3)=[N:9][CH:8]=2)[CH:5]=[CH:6][N:7]=1
Reactant: C=C1CC(C(=O)NCc2nccnc2Cl)C1
Agent: N#N
Solvent: O=P(Cl)(Cl)Cl
Solvent: CC#N
Solvent: CN(C)C=O
Product: C=C1CC(c2ncc3c(Cl)nccn23)C1

Procedure:
3-Methylene-cyclobutanecarboxylic acid (3-chloro-pyrazin-2-ylmethyl)-amide (52.1 g, 219.2 mmol) was dissolved in 1.0 L of anhydrous MeCN. Followed by the addition of DMF (1.0 mL) and POCl3 (100 mL, 1.09 mol). The reaction was heated to 55° C. for 30 min. with a slow N2 bubbling the reaction. The reaction was then concentrated in vacuo, basified with cold 2.0M NH3 in IPA with CH2Cl2. The IPA/CH2Cl2 was concentrated in vacuo and the salts were dissolved with minimal water and extracted with CH2Cl2 (4×). The organic layers where combined and washed with sat. NaHCO3 (1×), dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified via silica gel column chromatography [eluting with 2:1 Hex:EtOAc] to yield the title compound as a light yellow solid; 1H NMR (400 MHz, CDCl3) δ 3.24-3.30 (4H, m), 3.78-3.85 (1H, m), 4.89-4.94 (2H, m), 7.33 (1H, d, J=4.99 Hz), 7.53 (1H, d, J=5.09 Hz), 7.82 (1H, s); MS (ES+): m/z 220.28/222.30 (100/80) [MH+]; HPLC: tR=2.87 min (OpenLynx, polar—5 min).
Reaction SMILES: [N:1]([CH2:4][CH2:5][C:6]1[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)[N:9]=[C:8]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:7]=1)=[N+]=[N-].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C1COCC1.O>[CH2:19]([C:8]1[N:7]=[C:6]([CH2:5][CH2:4][NH2:1])[CH:11]=[C:10]([C:12]2[CH:13]=[CH:14][C:15]([CH3:18])=[CH:16][CH:17]=2)[N:9]=1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: Cc1ccc(-c2cc(CCN=[N+]=[N-])nc(Cc3ccccc3)n2)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(-c2cc(CCN)nc(Cc3ccccc3)n2)cc1
Reaction time: 18 h
Yield: 98.9 %

Procedure:
To a solution of the product of Step C (0.066 g, 0.2 mmol) in THF (2 mL) was added PPh3 (0.059 g, 2.2 mmol). After 18 h, water was added (0.10 mL) and the mixture was stirred for 48 h. The mixture was diluted with water and extracted with CH2Cl2 (2×). The combined organic layers were dried and concentrated. The resulting residue was purified via SiO2 chromatography (5-15% EtOAc/hexanes) to give 0.060 g (99%) of the title compound. MS (ESI): exact mass calcd. for C20H21N3, 303.17; m/z found, 304.4 [M+H]+. 1H NMR (CDCl3): 7.98-7.96 (m, 2H), 7.45-7.44 (m, 2H), 7.36 (s, 1H), 7.32-7.28 (m, 4H), 7.23-7.19 (m, 1H), 4.31 (s, 2H), 3.13 (t, J=6.5, 2H), 2.91 (t, J=6.5, 2H), 2.42 (s, 3H).