Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]([CH:6]([NH:14][C:15](=[O:33])[C:16]1[CH:21]=[CH:20][CH:19]=[N:18][C:17]=1[N:22]1[CH:26]=[CH:25][C:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[N:23]1)[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:3]([OH:5])=O.[N:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[CH2:40][NH2:41]>>[OH:1][CH:2]([C:3](=[O:5])[NH:41][CH2:40][C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][N:34]=1)[CH:6]([NH:14][C:15](=[O:33])[C:16]1[CH:21]=[CH:20][CH:19]=[N:18][C:17]=1[N:22]1[CH:26]=[CH:25][C:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[N:23]1)[CH2:7][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: O=C(NC(Cc1ccccc1)C(O)C(=O)O)c1cccnc1-n1ccc(-c2ccccc2)n1
Reactant: NCc1ccccn1
Product: O=C(NC(Cc1ccccc1)C(O)C(=O)NCc1ccccn1)c1cccnc1-n1ccc(-c2ccccc2)n1

Procedure:
The reaction was carried out in analogy to reaction step 1.3 by reacting 2-hydroxy-4-phenyl-3-(2-(3-phenyl-1H-pyrazol-1-yl)nicotinamido)butanoic acid with pyridin-2-ylmethylamine; ESI-MS [M+H]+: 533.2
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[N:3]=1.[S:9]1[CH:13]=[CH:12][C:11](B(O)O)=[CH:10]1>O1CCCC1.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>[Br:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([C:11]2[CH:12]=[CH:13][S:9][CH:10]=2)[N:3]=1
Reactant: Brc1cccc(Br)n1
Reactant: OB(O)c1ccsc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Brc1cccc(-c2ccsc2)n1
Yield: 58.7 %

Procedure:
Tetrakis(triphenylphosphine)palladium(0) (5 mol %) was added to a degassed and stirred mixture of 2,6-dibromopyridine (3.78 g, 15.6 mmol) and thiophene-3-boronic acid (2.20 g, 16.8 mmol) in tetrahydrofuran (40 ml) under an atmosphere of nitrogen then heated to reflux for 24 h. Solvent was removed in vacuo and purification by chromatography on silica gel eluting with a gradient of diethyl ether-isohexane (5-10%) gave 2-bromo-6-(thien-3-yl)pyridine (2.20 g) as a white solid: δH (400 MHz, CDCl3) 7.32-7.41 (2H, m), 7.53-7.55 (2H, m), 7.61-7.64 (1H, m), 7.94-7.96 (1H, m); m/z (ES+) 240/242 (M++H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[OH:11])[C:5]([OH:7])=[O:6].[CH2:12](Br)[CH2:13][CH2:14][CH2:15][CH3:16]>>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[C:5]([OH:7])=[O:6]
Reactant: O=C(O)c1ccc(O)c(Br)c1
Reactant: CCCCCBr
Product: CCCCCOc1ccc(C(=O)O)cc1Br
Yield: 87.2 %

Procedure:
25.8 g (0.119 mol) of the 3-bromo-4-hydroxybenzoic acid was reacted with 36.0 g (0.238 mol) pentyl bromide to yield 29.8 g of purified 3-bromo-4-n-pentyloxybenzoic acid. The yield was calculated to be 87.2%.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[Li]CCCC.[CH2:13]([N:20]1[CH2:24][CH2:23][C:22]2([CH2:29][CH2:28][C:27](=[O:30])[CH2:26][CH2:25]2)[CH2:21]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C1COCC1>[CH2:13]([N:20]1[CH2:24][CH2:23][C:22]2([CH2:29][CH2:28][C:27]([C:2]3[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=3)([OH:30])[CH2:26][CH2:25]2)[CH2:21]1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: O=C1CCC2(CC1)CCN(Cc1ccccc1)C2
Reactant: Brc1cccnc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OC1(c2cccnc2)CCC2(CCN(Cc3ccccc3)C2)CC1
Reaction time: 1 h
Yield: 44 %

Procedure:
A solution of 3-bromopyridine (290 μl, 2.96 mmol, 1.20 eq.) in dry THF (9 ml) was added dropwise to a solution of n-BuLi (2.47 ml, 4.94 mmol, 2.0 eq., 2M solution in hexane) in THF (9 ml) at −78° C. and the reaction mixture was stirred at same temperature for 1 h. A solution of 2-benzyl-2-azaspiro[4.5]decan-8-one (600 mg, 2.47 mmol, 1.0 eq.) (see step-6 product AMN-39) in THF (10 ml) was added dropwise at −78° C. and the reaction mixture was stirred at the same temperature for 1 h. After completion of the reaction (monitored by TLC), the reaction mixture was quenched with water (15 ml) while cooling and extracted with ethyl acetate (2×30 ml). The combined organic layers were washed with water (20 ml) and brine (20 ml), and dried over sodium sulfate. The solvent was evaporated under reduced pressure to give the crude product which was purified by column chromatography (silica gel; 10% MeOH/MC) to yield the desired compound as a light brown semi-solid. Yield: 44% (350 mg, 1.08 mmol).
Reaction SMILES: C1(C)C=CC(S([CH2:10][N+:11]#[C-])(=O)=O)=CC=1.CC(C)([O-])C.[K+].[C:20]1([N:26]([C:33]2[CH:40]=[CH:39][C:36]([CH:37]=O)=[CH:35][CH:34]=2)[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.CO>C(COC)OC>[C:20]1([N:26]([C:33]2[CH:40]=[CH:39][C:36]([CH2:37][C:10]#[N:11])=[CH:35][CH:34]=2)[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Reactant: O=Cc1ccc(N(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: CO
Product: N#CCc1ccc(N(c2ccccc2)c2ccccc2)cc1
Temperature: -55 °C
Reaction time: 1 h
Yield: 77.6 %

Procedure:
A solution of 68.3 g (0.35 mol) of (p-toluenesulfonyl)methyl isocyanide (TOSMIC) in 300 ml of dimethoxyethane was added dropwise to a stirred suspension of 78 g (0.70 mol) of potassium tert-butoxide in 300 ml of dimethoxyethane at −30° C. under nitrogen. After the solution had been cooled to −55° C., a solution of 92 g (0.34 mol) of 4-(N,N-diphenylamino)benzaldehyde in 100 ml of dimethoxyethane was added dropwise. After stirring at −55° C. for 1 hour, methanol was added. The reaction solution was heated to boiling under reflux for 30 min. After the solution had been concentrated to dryness, the residue was taken up with 600 ml of water and 30 ml of acetic acid. The aqueous solution was extracted with methylene chloride. The combined organic phases were washed with a saturated sodium carbonate solution, dried over magnesium sulfate and concentrated to dryness. 75 g (79% of theory) of the desired nitrile were obtained.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([NH:9][C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:18]3[CH:23]=[C:22]([O:24][CH3:25])[CH:21]=[C:20]([O:26][CH3:27])[CH:19]=3)[CH2:14][CH2:13]2)=[O:11])=[C:4]([O:28][CH3:29])[CH:3]=1.[H-].[Na+].I[CH2:33][CH3:34]>CN(C)C=O>[CH2:33]([N:9]([C:5]1[CH:6]=[C:7]([CH3:8])[C:2]([CH3:1])=[CH:3][C:4]=1[O:28][CH3:29])[C:10]([N:12]1[CH2:17][CH2:16][N:15]([C:18]2[CH:23]=[C:22]([O:24][CH3:25])[CH:21]=[C:20]([O:26][CH3:27])[CH:19]=2)[CH2:14][CH2:13]1)=[O:11])[CH3:34]
Reactant: CCI
Reactant: COc1cc(OC)cc(N2CCN(C(=O)Nc3cc(C)c(C)cc3OC)CC2)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCN(C(=O)N1CCN(c2cc(OC)cc(OC)c2)CC1)c1cc(C)c(C)cc1OC
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 89 %

Procedure:
1-[(4,5-Dimethyl-2-methoxyphenyl)aminocarbonyl]-4-(3,5-dimethoxyphenyl)piperazine(0.2 g, 0.5 mmole) was dissolved in dimethylformamide(15 ml), and thereto sodium hydride(12 mg, 0.5 mmole) was added slowly. The resulting mixture was stirred at room temperature for 15 min. After iodoethane(78 mg, 0.5 mmol) was added, the resulting mixture was stirred at room temperature for 16 hours. The resulting mixture was concentrated under the reduced pressure to remove the used solvent, extracted with methylene chloride, dryed, filtered and purified by column chromatography to obtain the titled compound.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:24]([OH:26])=O)[CH2:13][CH2:14][CH2:15][NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:27]([O:31][C:32](=[O:39])[NH:33][CH2:34][C@H:35]([NH2:38])[CH2:36][OH:37])([CH3:30])([CH3:29])[CH3:28].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>CN(C)C=O>[CH2:1]([O:8][C:9](=[O:10])[NH:11][C@H:12]([C:24]([NH:38][C@H:35]([CH2:36][OH:37])[CH2:34][NH:33][C:32]([O:31][C:27]([CH3:28])([CH3:29])[CH3:30])=[O:39])=[O:26])[CH2:13][CH2:14][CH2:15][NH:16][C:17]([O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[O:18])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)NC[C@H](N)CO
Reactant: CC(C)(C)OC(=O)NCCC[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)NCCC[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@H](CO)CNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Under argon, 0.18 g (0.49 mmol) of N2-[(benzyloxy)carbonyl]-N5-(tert-butoxycarbonyl)-L-ornithine and 0.122 g (0.64 mmol) of tert-butyl[(2S)-2-amino-3-hydroxypropyl]carbamate (Example 251A) are dissolved in 6 ml of dimethylformamide. Then, at 0° C. (ice bath), 0.123 g (0.64 mmol) of EDC and 0.02 g (0.15 mmol) of HOBt are added. The mixture is slowly warmed to RT and stirred at RT for 12 h. The solution is concentrated in vacuo and the residue is taken up with ethyl acetate. The organic phase is washed successively with saturated sodium bicarbonate and sodium chloride solutions, dried over magnesium sulfate and evaporated in vacuo. The remaining solid is purified by preparative HPLC (Kromasil, mobile phase acetonitrile/0.25% aqueous trifluoroacetic acid 5:95→95:5).
Reaction SMILES: [C:1](Cl)(=[O:5])[CH2:2][CH2:3][CH3:4].[CH:7]1[CH:8]=[C:9]2[CH2:23][C:17]3[CH:18]=[CH:19][CH:20]=[C:21]([OH:22])[C:16]=3[C:14](=[O:15])[C:10]2=[C:11]([OH:13])[CH:12]=1>C1C=CC=CC=1.N1C=CC=CC=1>[OH:22][C:21]1[C:16]2[C:14](=[O:15])[C:10]3[C:9](=[CH:8][CH:7]=[CH:12][C:11]=3[OH:13])[CH:23]([C:1](=[O:5])[CH2:2][CH2:3][CH3:4])[C:17]=2[CH:18]=[CH:19][CH:20]=1
Reactant: O=C1c2c(O)cccc2Cc2cccc(O)c21
Reactant: CCCC(=O)Cl
Solvent: c1ccccc1
Solvent: c1ccncc1
Product: CCCC(=O)C1c2cccc(O)c2C(=O)c2c(O)cccc21

Procedure:
28.6 g (0.27 moles) butyryl chloride is added, while stirring, to a mixture containing 50.9 g (0.225 moles) anthraline in 1575 ml benzene and 27.5 ml pyridine. The reaction mixture is cooked using a return condenser for 10 hours while stirring. The solution is filtered and the filrate is evaporated dry under a lowered pressure. The residue is crystallized out from acetic acid. Yield 17.0 g (25.5% of the theoretical).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:15]=[C:16]([C:19]([CH3:22])([CH3:21])[CH3:20])[C:17]=1[OH:18])[CH:8]=[C:9]1[CH2:13][CH2:12][NH:11][C:10]1=[O:14])([CH3:4])([CH3:3])[CH3:2].[CH2:23]1[CH2:27][O:26][CH2:25][CH2:24]1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>C(OCC)(=O)C>[CH2:25]([O:26][N:11]([CH3:12])[C:10]([N:11]1[CH2:12][CH2:13][C:9](=[CH:8][C:7]2[CH:6]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:17]([OH:18])=[C:16]([C:19]([CH3:22])([CH3:21])[CH3:20])[CH:15]=2)[C:10]1=[O:14])=[O:14])[C:24]1[CH:23]=[CH:27][CH:3]=[CH:1][CH:2]=1
Reactant: CC(C)(C)c1cc(C=C2CCNC2=O)cc(C(C)(C)C)c1O
Reactant: C1CCOC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CCOC(C)=O
Product: CN(OCc1ccccc1)C(=O)N1CCC(=Cc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)C1=O
Temperature: -70 °C
Reaction time: 1 h
Yield: 32 %

Procedure:
3-(3,5-Di-tert-butyl-4-hydroxybenzylidene)pyrrolidin-2-one (3.01 g, 10 mmole) was dissolved into THF (60 ml), which was cooled to -70° C. To this mixture, a solution of 1.0M lithium bis(trimethylsilyl)amide dissolved into THF (24 ml) was added. Furthermore, N-benzyloxy-N-methylphenylcarbamate (2.9 g, 12 mmole) was added thereto and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into ethyl acetate, which was washed with an aqueous solution of 0.1N hydrochloric acid, water, and saturated brine, dried over magnesium sulfate, and evaporated. The obtained residue was separated by using silica gel chromatography (toluene:ethyl acetate=10:1), whereby 1.5 g of the objective compound (Ia-11) was obtained as white amorphous in 32% yield.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([CH2:13][NH:14][CH:15]([CH3:17])[CH3:16])[C@H:10]([C:18]([CH3:26])([CH3:25])[O:19][SiH2:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:27][C:28]1[CH:36]=[CH:35][C:31]([C:32](O)=[O:33])=[CH:30][C:29]=1[O:37][CH2:38][CH2:39][CH2:40][O:41][CH3:42].C(N(CC)CC)C.C(OC(C)(C)C)=O>CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([CH2:13][N:14]([C:32](=[O:33])[C:31]2[CH:35]=[CH:36][C:28]([CH3:27])=[C:29]([O:37][CH2:38][CH2:39][CH2:40][O:41][CH3:42])[CH:30]=2)[CH:15]([CH3:16])[CH3:17])[C@H:10]([C:18]([CH3:26])([CH3:25])[O:19][SiH2:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)NC[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]1C(C)(C)O[SiH2]C(C)(C)C
Reactant: COCCCOc1cc(C(=O)O)ccc1C
Agent: CC(C)(C)OC=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COCCCOc1cc(C(=O)N(C[C@@H]2CN(C(=O)OC(C)(C)C)C[C@H]2C(C)(C)O[SiH2]C(C)(C)C)C(C)C)ccc1C

Procedure:
From (3S,4R)-3-(tert-butyl-dimethyl-silanyloxymethyl)-4-(isopropylamino-methyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (5 g, 12.9 mmol), 4-methyl-3-(3-methoxy-propoxy)-benzoic acid (4.06 g, 18.1 mmol), BOPCI (4.6 g, 18.1 mmol) and triethylamine (7.2 mL, 51.7 mmol). TLC, Rf (AcOEt)=0.7. MS (LC-MS): 493 [M+H-Boc]+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH:14]=[O:15])=[CH:4][NH:5][C:6]=1[C:7]1[C:8]([F:13])=[N:9][CH:10]=[CH:11][CH:12]=1.[H-].[Na+].C1OCCOCCOCCOCCOC1.[CH3:33][N:34]1[CH:38]=[C:37]([S:39](Cl)(=[O:41])=[O:40])[CH:36]=[N:35]1>O1CCCC1.O>[Cl:1][C:2]1[C:3]([CH:14]=[O:15])=[CH:4][N:5]([S:39]([C:37]2[CH:36]=[N:35][N:34]([CH3:33])[CH:38]=2)(=[O:41])=[O:40])[C:6]=1[C:7]1[C:8]([F:13])=[N:9][CH:10]=[CH:11][CH:12]=1
Reactant: Cn1cc(S(=O)(=O)Cl)cn1
Reactant: O=Cc1c[nH]c(-c2cccnc2F)c1Cl
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Cn1cc(S(=O)(=O)n2cc(C=O)c(Cl)c2-c2cccnc2F)cn1
Reaction time: 0.25 h
Yield: 65 %

Procedure:
To a solution of 4-chloro-5-(2-fluoropyridin-3-yl)-1H-pyrrole-3-carbaldehyde (150 mg) in tetrahydrofuran (20 mL) was added sodium hydride (60% in oil, 81 mg) at room temperature and the mixture was stirred for 15 min. 15-Crown-5 (442 mg) was added dropwise and the mixture was stirred for 5 min. 1-methyl-1H-pyrazole-4-sulfonyl chloride (242 mg) was added and the mixture was further stirred for 30 min. The reaction mixture was diluted with water, and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=1:1→1:4) to give the title compound as a colorless oil (yield 160 mg, 65%).
Reaction SMILES: [Na+].[NH:2]1[CH:6]=[N:5][C:4]([C:7]([NH-:9])=[O:8])=[N:3]1.[C:10](Cl)(=[O:18])[C:11]1[C:12](=[CH:14][CH:15]=[CH:16][CH:17]=1)[OH:13]>C(#N)C>[C:10]([C:6]1[NH:2][N:3]=[C:4]([C:7]([NH2:9])=[O:8])[N:5]=1)(=[O:18])[C:11]1[C:12](=[CH:14][CH:15]=[CH:16][CH:17]=1)[OH:13]
Reactant: O=C(Cl)c1ccccc1O
Reactant: [NH-]C(=O)c1nc[nH]n1
Agent: [Na+]
Solvent: CC#N
Product: NC(=O)c1n[nH]c(C(=O)c2ccccc2O)n1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A 25 ml. portion of dry acetonitrile is added to a mixture of 1.3 g. of the s-triazole carboxamide sodium salt and 2 g. of salicyloyl chloride followed by a few pellets of 4A molecular sieves. The mixture is stirred at room temperature for 16 hours and then filtered through Celite. The colorless solid is obtained on evaporating the filtrate is washed with diethyl ether; yield, 1 g., m.p. 147°-150° C. (dec.). Its infrared spectrum is essentially the same as that obtained from the product in Example 7.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][N:6]2[C:11]([C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=1)([CH2:16][CH3:17])/[CH:12]=[CH:13]/[C:14]#[N:15].CN1CCOCC1.[CH3:32][S:33](Cl)(=[O:35])=[O:34]>C(Cl)Cl>[Cl:24][C:21]1[CH:20]=[CH:19][C:18]([C:11]([N:6]2[C:7]3[C:3](=[C:2]([NH:1][S:33]([CH3:32])(=[O:35])=[O:34])[CH:10]=[CH:9][CH:8]=3)[CH:4]=[CH:5]2)([CH2:16][CH3:17])/[CH:12]=[CH:13]/[C:14]#[N:15])=[CH:23][CH:22]=1
Reactant: CS(=O)(=O)Cl
Reactant: CCC(/C=C/C#N)(c1ccc(Cl)cc1)n1ccc2c(N)cccc21
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CCC(/C=C/C#N)(c1ccc(Cl)cc1)n1ccc2c(NS(C)(=O)=O)cccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of compound from step B (123 mg, 0.367 mmol) and NMM (74 mg, 0.734 mmol) in DCM (15 mL) was added methanesulfonyl chloride (62 mg, 0.550 mmol) dropwise. Then the mixture was stirred at room temperature overnight. The reaction was quenched with saturated ammonium chloride solution, and extracted with ethyl acetate (20 mL). The organic layer was washed with brine, dried over sodium sulfate, filtered and evaporated. The residue was purified by silica gel chromatography eluting with PE/EA (10/1 to 3/1, v/v) to afford the title compound as a white solid. LC/MS m/z=436.1 [M+Na]+.
Reaction SMILES: C([O:4][CH2:5][CH3:6])(=O)C.[CH3:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]>>[C:9]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:6][CH2:5][OH:4])[CH:8]=[CH:7][CH:12]=[CH:11][CH:10]=1
Reactant: CCOC(C)=O
Reactant: CCCCCC
Product: OCCCCCCCCCCCCCc1ccccc1

Procedure:
Rf value : 0.24 (ethyl acetate:hexane=1:5)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[CH2:9][CH2:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][NH:16][CH:15]([C:19]([NH2:21])=[O:20])[CH2:14]2)=[CH:4][CH:3]=1.[Cl:29][C:30]1[CH:31]=[C:32]([CH2:42][NH:43][C:44](=[O:50])[O:45][C:46]([CH3:49])([CH3:48])[CH3:47])[CH:33]=[C:34]([Cl:41])[C:35]=1[NH:36][C:37](=[O:40])[CH2:38]Cl.C(N(CC)CC)C>CN(C)C=O>[NH2:21][C:19]([CH:15]1[CH2:14][N:13]([CH2:12][CH2:11][CH2:10][CH2:9][CH:8]([C:22]2[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=2)[C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[CH2:18][CH2:17][N:16]1[CH2:38][C:37]([NH:36][C:35]1[C:34]([Cl:41])=[CH:33][C:32]([CH2:42][NH:43][C:44](=[O:50])[O:45][C:46]([CH3:48])([CH3:47])[CH3:49])=[CH:31][C:30]=1[Cl:29])=[O:40])=[O:20]
Reactant: CC(C)(C)OC(=O)NCc1cc(Cl)c(NC(=O)CCl)c(Cl)c1
Reactant: NC(=O)C1CN(CCCCC(c2ccc(F)cc2)c2ccc(F)cc2)CCN1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCc1cc(Cl)c(NC(=O)CN2CCN(CCCCC(c3ccc(F)cc3)c3ccc(F)cc3)CC2C(N)=O)c(Cl)c1
Temperature: 70 °C
Yield: 80.7 %

Procedure:
A mixture of 7 parts of 4-[5,5-bis(4-fluorophenyl)pentyl]-2-piperazinecarboxamide, 6.6 parts of (1,1-dimethylethyl) [[3,5-dichloro-4-[(2-chloroacetyl)amino]phenyl)methyl)carbamate, 2.8 parts of N,N-diethylethanamine and 94 parts of N,N-dimethylformamide was stirred over weekend at 70° C. The reaction mixture was evaporated and the residue was taken up in water. The product was extracted twice with dichloromethane. The combined extracts were washed with water, dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol, saturated with ammonia, (96:4 by volume) as eluent. The desired fractions were collected and the eluent was evaporated, yielding 8.7 parts (80.7%) of (1,1-dimethylethyl) [[4-[[2-[2-(aminocarbonyl)-4-[5,5-bis(4-fluorophenyl)pentyl]-1-piperazinyl]acetyl]amino]-3,5-dichlorophenyl]methyl]carbamate as a residue (int. 102).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([F:13])[C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9].[CH2:14]([Zn]CC)[CH3:15]>O1CCOCC1>[CH2:14]([C:2]1[CH:3]=[N:4][CH:5]=[C:6]([F:13])[C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH3:15]
Reactant: CC[Zn]CC
Reactant: CCOC(=O)c1c(F)cncc1Br
Solvent: C1COCCO1
Product: CCOC(=O)c1c(F)cncc1CC
Temperature: 70 °C
Reaction time: 0.75 h
Yield: 50.7 %

Procedure:
To a solution of ethyl 3-bromo-5-fluoropyridine-4-carboxylate (4.8 g, 20 mmol) in anhydrous 1,4-dioxane (30 mL) at room temperature was added (1,1′-bis(diphenylphosphino)ferrocene)dichloropalladium (II) (325 mg, 0.43 mmol), followed by a diethylzinc solution (22 mL, 20 mmol, 1.1 M solution in toluene). The mixture was stirred at 70° C. for 45 minutes. After cooling to room temperature, the reaction was quenched with MeOH. Ethyl acetate (100 mL) was added. The mixture was extracted with 0.1 N HCl (200 mL). The organic layer was recovered. The pH of the aqueous phase was brought to 6 with 2 N NaOH. The mixture was extracted with EtOAc (1×100 mL). The combined organic extracts were dried over MgSO4, filtered, evaporated, and dried in vacuo. The crude product was purified by flash chromatography (0-20% ethyl acetate/hexane), affording ethyl 3-ethyl-5-fluoropyridine-4-carboxylate (2.0 g, 51% yield)
Reaction SMILES: P(Cl)(Cl)(Cl)=O.CN(C)[CH:8]=[O:9].[CH3:11][C:12]1[S:13][C:14]([CH3:17])=[CH:15][CH:16]=1>O>[CH3:11][C:12]1[S:13][C:14]([CH3:17])=[CH:15][C:16]=1[CH:8]=[O:9]
Reactant: Cc1ccc(C)s1
Reactant: CN(C)C=O
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1cc(C=O)c(C)s1
Temperature: 100 °C
Reaction time: 15 h
Yield: 10.1 %

Procedure:
Phosphorus oxychloride (10 ml) was slowly added dropwise to dimethylformamide (30 g) under ice-cooling, and 2,5-dimethylthiophene (11.2 g) was added. The mixture was stirred at 100° C. for 15 hours, poured into water and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 2,5-dimethyl-3-thiophenecarbaldehyde (1.41 g). 2,5-Dimethyl-3-thiophenecarbaldehyde (3.89 g) synthesized in this manner was dissolved in acetonitrile (30 ml), and sodium dihydrogen phosphate (1.2 g) in water (15 ml) and 30% aqueous hydrogen peroxide (3.5 ml) were added dropwise. The mixture was stirred at room temperature for 2 hours, alkalified with 1N aqueous sodium hydroxide and washed with diethyl ether. The aqueous layer was acidified with 1N hydrochloric acid and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 2,5-dimethyl-3-thiophenecarboxylic acid (4.09 g) as crystals.
Reaction SMILES: [Br:1][C:2]1[CH:6]=[CH:5][NH:4][N:3]=1.Cl[C:8]1[C:13]([Cl:14])=[CH:12][CH:11]=[CH:10][N:9]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CN(C)C=O>O>[Br:1][C:2]1[CH:6]=[CH:5][N:4]([C:8]2[C:13]([Cl:14])=[CH:12][CH:11]=[CH:10][N:9]=2)[N:3]=1
Reactant: Brc1cc[nH]n1
Reactant: Clc1cccnc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: Clc1cccnc1-n1ccc(Br)n1
Temperature: 100 °C
Reaction time: 8 h
Yield: 68.5 %

Procedure:
A mixture of 10.7 g of 3-bromo-1H-pyrazole, 11.8 g of 2,3-dichloropyridine, 57.3 g of cesium carbonate and 80 mL of N,N-dimethylformamide was stirred at 100° C. for 8 hours. After cooling to room temperature and adding water, the reaction mixture was extracted twice with methyl tert-butyl ether. The organic layers were combined, washed sequentially with water and a saturated sodium chloride solution, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography to obtain 12.9 g of 2-(3-bromo-1H-pyrazol-1-yl)-3-chloropyridine. 2-(3-bromo-1H-pyrazol-1-yl)-3-chloropyridine
Reaction SMILES: [F:1][C:2]1[C:31]([F:32])=[CH:30][CH:29]=[CH:28][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[N:17][C:18]=3[NH2:20])[N:13]([C@@H:21]3[CH2:26][CH2:25][CH2:24][NH:23][CH2:22]3)[N:12]=2)=[C:7]([F:27])[CH:6]=1.[C:33]([C:35](=[CH:39][CH:40]([CH3:42])[CH3:41])[C:36](O)=[O:37])#[N:34].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[NH2:20][C:18]1[N:17]=[CH:16][N:15]=[C:14]2[N:13]([C@@H:21]3[CH2:26][CH2:25][CH2:24][N:23]([C:36]([C:35](=[CH:39][CH:40]([CH3:42])[CH3:41])[C:33]#[N:34])=[O:37])[CH2:22]3)[N:12]=[C:11]([C:8]3[CH:9]=[CH:10][C:5]([O:4][C:3]4[CH:28]=[CH:29][CH:30]=[C:31]([F:32])[C:2]=4[F:1])=[CH:6][C:7]=3[F:27])[C:19]=12
Reactant: Nc1ncnc2c1c(-c1ccc(Oc3cccc(F)c3F)cc1F)nn2[C@@H]1CCCNC1
Reactant: CC(C)C=C(C#N)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)C=C(C#N)C(=O)N1CCC[C@@H](n2nc(-c3ccc(Oc4cccc(F)c4F)cc3F)c3c(N)ncnc32)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 19.4 %

Procedure:
To a mixture of (R)-3-(4-(2,3-difluorophenoxy)-2-fluorophenyl)-1-(piperidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (100 mg, 0.23 mmol, 1.0 eq), 2-cyano-4-methyl-pent-2-enoic acid (38 mg, 0.27 mmol, 1.2 eq) and DIEA (88 mg, 0.68 mmol, 3.0 eq) in 10 ml DCM was added HATU (130 mg, 0.34 mmol, 1.5 eq). The reaction mixture was stirred for 4 h at RT under N2. The mixture was purified by Pre-HPLC to give the title compound (25 mg 40% yield). LCMS: m/Z+ (562.2) (M+H)+1HNMR (400 MHz, CDCl3): δ 0.784˜1.186 (m, 7H), 1.765˜2.254 (m, 5H), 2.861˜4.937 (m, 4H), 6.218 (m, 0.4H), 6.857˜7.600 (m, 6H), 8.255 (s, 1H) and 9.888 (m, 1H).