Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:5][C:6](=[O:43])[CH2:7][CH2:8][C@H:9]([NH:13][C:14]([C:16]1[CH:20]=[C:19]([O:21][CH2:22][C:23]([N:25]2[CH2:29][CH2:28][CH2:27][C@H:26]2[C:30](=[O:36])[NH:31][CH:32]2[CH2:35][CH2:34][CH2:33]2)=[O:24])[N:18]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[N:17]=1)=[O:15])[C:10](O)=[O:11])(C)(C)C.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.[CH2:77]([O:84][C:85]([N:87]1[CH2:92][CH2:91][NH:90][CH2:89][CH2:88]1)=[O:86])[C:78]1[CH:83]=[CH:82][CH:81]=[CH:80][CH:79]=1>CN(C=O)C>[CH2:77]([O:84][C:85]([N:87]1[CH2:92][CH2:91][N:90]([C:10](=[O:11])[C@@H:9]([NH:13][C:14]([C:16]2[CH:20]=[C:19]([O:21][CH2:22][C:23]([N:25]3[CH2:29][CH2:28][CH2:27][C@H:26]3[C:30](=[O:36])[NH:31][CH:32]3[CH2:33][CH2:34][CH2:35]3)=[O:24])[N:18]([C:37]3[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=3)[N:17]=2)=[O:15])[CH2:8][CH2:7][C:6]([OH:5])=[O:43])[CH2:89][CH2:88]1)=[O:86])[C:78]1[CH:83]=[CH:82][CH:81]=[CH:80][CH:79]=1
Reactant: CC(C)(C)OC(=O)CC[C@H](NC(=O)c1cc(OCC(=O)N2CCC[C@H]2C(=O)NC2CCC2)n(-c2ccccc2)n1)C(=O)O
Reactant: O=C(OCc1ccccc1)N1CCNCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(O)CC[C@H](NC(=O)c1cc(OCC(=O)N2CCC[C@H]2C(=O)NC2CCC2)n(-c2ccccc2)n1)C(=O)N1CCN(C(=O)OCc2ccccc2)CC1
Reaction time: 24 h

Procedure:
To a solution of 100 mg (S)-2-({5-[2-((S)-2-cyclobutylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-1-phenyl-1H-pyrazole-3-carbonyl}-amino)-pentanedioic acid 5-tert-butyl ester in 5 ml DMF were added 55 μl DIPEA, 64 mg HATU and 56 mg piperazine-1-carboxylic acid benzyl ester. After stirring for 24 h the solution was concentrated, the residue dissolved in 1.5 ml dichloromethane and treated with 360 μl TFA. After stirring for 4 h the solvents were removed under reduced pressure and the residue purified by preparative HPLC (C18 reverse phase column, elution with a water/MeCN gradient with 0.1% TFA). The fractions containing the product were lyophilized to yield the pure product.
Reaction SMILES: [C:1]([CH2:4][S:5][C:6]1([CH3:11])[CH2:10][CH2:9][CH2:8][O:7]1)(O)=[O:2].O>O1CCCC1>[OH:2][CH2:1][CH2:4][S:5][C:6]1([CH3:11])[CH2:10][CH2:9][CH2:8][O:7]1
Reactant: CC1(SCC(=O)O)CCCO1
Solvent: C1CCOC1
Solvent: O
Product: CC1(SCCO)CCCO1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a solution of 2 mmol of 26 in 10 mL of anhydrous tetrahydrofuran (kept at 0° C.) 3 mL of BH3. THF complex (1M) is added slowly. The mixture is stirred for 3 hours in a nitrogen atmosphere at 0° C. Approximately 10 mL of water added slowly and the reaction is stirred for 15 min. The mixture is concentrated in vacuo at 40°-45° C. and the aqueous residue is extracted with ethyl acetate. The organic layer is washed with 10% bicarbonate. The ethyl acetate layer is dried and evaporated to give the product, 27 as an oil.
Reaction SMILES: [OH:1][C@H:2]([CH2:15][CH2:16][C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1)[C@H:3]([CH3:14])[O:4][C:5]1[CH:10]=[CH:9][C:8](B(O)O)=[CH:7][CH:6]=1.Br[C:24]1[CH:29]=[CH:28][C:27]([NH:30][C:31]([NH2:33])=[O:32])=[CH:26][CH:25]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[OH:1][C@H:2]([CH2:15][CH2:16][C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1)[C@H:3]([CH3:14])[O:4][C:5]1[CH:10]=[CH:9][C:8]([C:24]2[CH:29]=[CH:28][C:27]([NH:30][C:31]([NH2:33])=[O:32])=[CH:26][CH:25]=2)=[CH:7][CH:6]=1
Reactant: C[C@H](Oc1ccc(B(O)O)cc1)[C@H](O)CCc1cccnc1
Reactant: NC(=O)Nc1ccc(Br)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: C[C@H](Oc1ccc(-c2ccc(NC(N)=O)cc2)cc1)[C@H](O)CCc1cccnc1
Temperature: 100 °C
Yield: 23.6 %

Procedure:
Prepared according to the method described in Example 12b) from (1S,2R)-4-(2-hydroxy-1-methyl-4-pyridin-3-ylbutoxy)benzeneboronic acid (0.15 g, Example 33), 4-bromophenylurea (0.16 g), 2M aqueous sodium carbonate (0.25 ml) and tetrakis(triphenylphosphine)palladium (0) (0.1 g) in ethanol (3 ml). The reaction mixture was heated at 100° C. for 3 hours. After cooling, the solution was concentrated under reduced pressure. The residue was triturated with acetone and then filtered through silica gel. The filtrate was concentrated under reduced pressure and purified by flash column chromatography eluting with 10% methanol in dichloromethane give the title compound as a solid (0.046 g).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[NH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.Cl>O.COCCO>[C:12]1([NH:11][C:2]2[CH:7]=[CH:6][N:5]=[CH:4][C:3]=2[N+:8]([O-:10])=[O:9])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=[N+]([O-])c1cnccc1Cl
Reactant: Nc1ccccc1
Agent: Cl
Solvent: O
Solvent: COCCO
Product: O=[N+]([O-])c1cnccc1Nc1ccccc1

Procedure:
A solution of 4-chloro-3-nitropyridine (II: R′=4-aza, halogen=Cl) (3.22 g, 0.020 mol), aniline (III: R1′=H) (1.85 mL, 0.020 mol) and conc. HCl (0.17 mL, 0.02 mol) in 1:1 water/2-methoxyethanol (40 mL) was refluxed for 18 hours, then concentrated to dryness. The residue was partitioned between saturated aqueous NaHCO3 and EtOAc, and the organic portion was worked up to give an oil which was chromatographed on silica gel. Petroleum ether eluted foreruns, while EtOAc/petroleum ether (1:1) gave 4-(N-phenylamino)-3-nitropyridine (VI: R′=4-aza, R1′=H) (2.02 g, 41%); mp (EtOAc/petroleum ether) 119° C.
Reaction SMILES: [C:1]([O:9][O:10]C(=O)C1C=CC=CC=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Na].Cl>C(Cl)(Cl)Cl.CO>[C:2]1([C:1]([O:9][OH:10])=[O:8])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(OOC(=O)c1ccccc1)c1ccccc1
Agent: Cl
Agent: [Na]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: O=C(OO)c1ccccc1
Temperature: -5 °C
Reaction time: 0.5 h
Yield: 83.5 %

Procedure:
19 g (78 mmol) of dibenzoyl peroxide are dissolved in 125 ml of chloroform at −5° C. 2.2 g (94 mmol) of sodium dissolved in 50 ml of methanol under a stream of nitrogen are added dropwise. After stirring at −5° C. for 30 minutes, ice-cold water is added and the medium is acidified with a 2N aqueous hydrochloric acid solution. Extraction with dichloromethane is carried out and then the organic phase is dried over magnesium sulphate, filtered and concentrated. 9 g of benzenecarboperoxoic acid are obtained in the form of a white solid with a yield of 83%.
Reaction SMILES: [CH3:1][N:2]([CH2:28][CH:29]1[CH2:33][CH2:32][NH:31][CH2:30]1)[C:3]1[S:4][C:5]2[CH:11]=[C:10]([NH:12][C:13]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=4)=[CH:17][CH:16]=3)=[O:14])[CH:9]=[CH:8][C:6]=2[N:7]=1.[CH:34](=O)[CH3:35].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C1COCC1.C(Cl)Cl>[CH2:34]([N:31]1[CH2:32][CH2:33][CH:29]([CH2:28][N:2]([CH3:1])[C:3]2[S:4][C:5]3[CH:11]=[C:10]([NH:12][C:13]([C:15]4[CH:16]=[CH:17][C:18]([C:21]5[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=5)=[CH:19][CH:20]=4)=[O:14])[CH:9]=[CH:8][C:6]=3[N:7]=2)[CH2:30]1)[CH3:35]
Reactant: CN(CC1CCNC1)c1nc2ccc(NC(=O)c3ccc(-c4ccc(F)cc4)cc3)cc2s1
Reactant: CC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCN1CCC(CN(C)c2nc3ccc(NC(=O)c4ccc(-c5ccc(F)cc5)cc4)cc3s2)C1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 78.2 %

Procedure:
Place 4′-fluoro-biphenyl-4-carboxylic acid [2-(methyl-pyrrolidin-3-ylmethyl-amino)-benzothiazol-6-yl]-amide (123 mg, 0.267 mmol) in THF (3 mL) and cool to 0° C. Add acetaldehyde (0.040 mL, 0.716 mmol) and sodium triacetoxyborohydride (88 mg, 0.415 mmol). Stir at 0° C. for 10 min. Dilute with DCM and wash with 1N NaOH. Collect the organic layer and chromatograph (silica gel, eluting with 10% 2M NH3 in MeOH:DCM) to yield 102 mg (78%) of the title compound: mass spectrum (ion-spray): (m/z)=489.0 (M+1).
Reaction SMILES: Br[CH:2]([C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1)[C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[C:6]#[N:7].[NH:18]1[CH2:21][CH:20]([C:22]([C:28]2[CH:33]=[C:32]([F:34])[CH:31]=[C:30]([F:35])[CH:29]=2)([OH:27])[C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:19]1.C(N(CC)C(C)C)(C)C>C(#N)C>[Cl:17][C:14]1[CH:15]=[CH:16][C:11]([CH:2]([N:18]2[CH2:21][CH:20]([C:22]([C:28]3[CH:29]=[C:30]([F:35])[CH:31]=[C:32]([F:34])[CH:33]=3)([OH:27])[C:23]([CH3:24])([CH3:25])[CH3:26])[CH2:19]2)[C:3]2[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=2)[C:6]#[N:7])=[CH:12][CH:13]=1
Reactant: N#Cc1cccc(C(Br)c2ccc(Cl)cc2)c1
Reactant: CC(C)(C)C(O)(c1cc(F)cc(F)c1)C1CNC1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)C(O)(c1cc(F)cc(F)c1)C1CN(C(c2ccc(Cl)cc2)c2cccc(C#N)c2)C1

Procedure:
The reaction mixture of 135 mg (0.44 mmol) of 3-[bromo(4-chlorophenyl)methyl]benzonitrile, 105 mg (0.367 mmol) of 1-azetidin-3-yl-1-(3,5-difluorophenyl)-2,2-dimethylpropan-1-ol (3) and 230 uL (1.32 mmol) of N,N-diisopropylethylamine in 6 mL of acetonitrile was refluxed for 3 h. Then it was concentrated and the residue was dissolved in 5 mL of hexane/ether. 1 mL of 1N HCl in ether was added to above solution to make salt. It was filtered and washed with hexane/ether. The residue was neutralized with base and was purified by silica gel chromatography with hexanes/ethyl acetate to afford one racemic diastereomer of the title compound; Mass Spectrum: m/e=481 (M+1 35Cl) and 483 (M+1 37Cl). Further elution of the column afforded the other racemic diastereomer of the title compound; Mass Spectrum: m/e=481 (M+1 35Cl) and 483 (M+1 37Cl).
Reaction SMILES: [CH:1]([C:4]1[C:8]([C:9]2[CH:14]=[CH:13][N:12]=[C:11](S(C)(=O)=O)[N:10]=2)=[CH:7][NH:6][N:5]=1)([CH3:3])[CH3:2].[C@H:19]1([NH2:28])[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:21][CH2:20]1>CS(C)=O.ClCCl>[C@H:19]1([NH:28][C:11]2[N:10]=[C:9]([C:8]3[C:4]([CH:1]([CH3:3])[CH3:2])=[N:5][NH:6][CH:7]=3)[CH:14]=[CH:13][N:12]=2)[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:21][CH2:20]1
Reactant: N[C@@H]1CCc2ccccc21
Reactant: CC(C)c1n[nH]cc1-c1ccnc(S(C)(=O)=O)n1
Solvent: CS(C)=O
Solvent: ClCCl
Product: CC(C)c1n[nH]cc1-c1ccnc(N[C@@H]2CCc3ccccc32)n1
Temperature: 150 °C
Reaction time: 8 h
Yield: 41.7 %

Procedure:
To a solution of 4-(3-isopropyl-1H-pyrazol-4-yl)-2-methanesulfonyl-pyrimidine (40 mg, 0.15 mmol) in anhydrous DMSO (0.25 mL) is added (R)-indan-1-ylamine (58 uL, 0.45 mmol). The reaction mixture is stirred at 150° C. overnight, diluted with dichloromethane, and washed with water. The organic layer is dried over sodium sulfate and concentrated in vacuo. The crude product is purified by preparative HPLC to provide 20 mg of (R)-indan-1-yl-[4-(3-isopropyl-1H-pyrazol-4-yl)-pyrimidin-2-yl]-amine. (Example 83).
Reaction SMILES: Br[C:2]1[C:10]2[C:6](=[CH:7][N:8]([CH3:11])[N:9]=2)[CH:5]=[CH:4][C:3]=1[CH3:12].[C:13]([Cu])#[N:14].O>CN1C(=O)CCC1>[CH3:11][N:8]1[CH:7]=[C:6]2[C:10]([C:2]([C:13]#[N:14])=[C:3]([CH3:12])[CH:4]=[CH:5]2)=[N:9]1
Reactant: Cc1ccc2cn(C)nc2c1Br
Reactant: N#C[Cu]
Solvent: O
Solvent: CN1CCCC1=O
Product: Cc1ccc2cn(C)nc2c1C#N
Yield: 40 %

Procedure:
To a solution of 7-bromo-2,6-dimethyl-2H-indazole (1 equiv.) in NMP, was added CuCN (2 equiv.) and heated at 130 oC for 16 h. On completion, water was added to quench the reaction, solid precipitated was filtered and purified by column chromatography to afford the title compound (40-60% yield)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=2[F:27])=[C:6]([CH2:8][C:9]2[N:14]=[C:13]([C:15]#[N:16])[CH:12]=[CH:11][C:10]=2[CH3:17])[CH:7]=1.[OH-:28].[Na+]>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=2[F:27])=[C:6]([CH2:8][C:9]2[N:14]=[C:13]([C:15]([NH2:16])=[O:28])[CH:12]=[CH:11][C:10]=2[CH3:17])[CH:7]=1
Reactant: Cc1ccc(C#N)nc1Cc1cc(Cl)ccc1OCc1ccc(Cl)cc1F
Reactant: [OH-]
Agent: [Na+]
Solvent: CCO
Product: Cc1ccc(C(N)=O)nc1Cc1cc(Cl)ccc1OCc1ccc(Cl)cc1F
Yield: 81 %

Procedure:
A solution of 6-[(5-chloro-2-{[(4-chloro-2-fluorophenyl)methyl]oxy}phenyl)-methyl]-5-methyl-2-pyridinecarbonitrile (127 mg) in 2M sodium hydroxide solution (0.8 ml) and ethanol (4 ml) was stirred under reflux for 2 hours. Solvent was removed in vacuo and water (5 ml) added. The mixture was extracted with ethyl acetate (3×5 ml) and the combined extracts washed with brine (5 ml), dried (MgSO4) and concentrated in vacuo to afford the title compound (107 mg, 81%) as a white solid. LC/MS [MH+]=419/421, RT=3.57 min.
Reaction SMILES: Br[C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[N:4]([CH3:11])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[Li][CH2:17][CH2:18][CH2:19][CH3:20].C(C(C)=O)C.OS(O)(=O)=O>C1COCC1>[CH2:18]([C:19]1([CH3:20])[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]([CH3:11])[C:3]2[C:2]1=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH3:17]
Reactant: CN(c1ccccc1)c1ccccc1Br
Reactant: [Li]CCCC
Agent: O=S(=O)(O)O
Solvent: C1CCOC1
Solvent: CCC(C)=O
Product: CCC1(C)c2ccccc2N(C)c2ccccc21
Temperature: -78 °C
Reaction time: 1 h
Yield: 57 %

Procedure:
A flame-dried two-necked flask was charged with 2-bromo-N-methyl-N-phenylaniline (1.0 g, 3.8 mmol) and 100 mL dry THF under argon and cooled to −78° C. in a dry ice-acetone bath. 2.6 mL of a 1.6 M solution of n-BuLi in hexanes (4.16 mmol) was added dropwise over 5 minutes and the reaction stirred at −78° C. under argon for 1 h. Methyl ethyl ketone (0.302 g, 4.2 mmol) was added in one portion to the reaction mixture at −78° C., the reaction allowed to warm to room temperature and stirred overnight under argon. After quenching with saturated ammonium chloride, the reaction was extracted with Et2O, the organic layers combined, washed with brine and water and dried over anhydrous MgSO4 and the solvent evaporated under reduced pressure. To the neat residue thus obtained was added 2 mL of concentrated H2SO4 under argon and the mixture stirred at room temperature for 1 h under argon. After dilution with 30 mL DI H2O, the reaction was extracted with Et2O (5×50 mL), the organic layers were combined, washed with brine and water and dried over anhydrous MgSO4, and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography using hexanes as the eluent to yield 0.57 g (57%) of the desired compound as a clear oil. 1H NMR (400 MHz, CHCl3) δ 1.66 (dd, J=6.8 Hz, J=0.8 Hz, 3H), 1.78 (t, J=1.2 Hz, 3H), 3.10 (s, 3H), 5.49 (m, 1H), 6.66 (m, 3H), 7.18 (m, 6H). 13C NMR (100 MHz, CHCl3) δ 14.2, 15.2, 16.5, 24.2, 39.2, 39.6, 113.8, 114.1, 117.1, 117.4, 122.4, 124.4, 125.7025.9, 128.0, 128.2, 128.5, 128.8, 128.9, 130.6, 131.5, 136.4, 140.4, 144.3, 145.8, 146.9, 149.2, 149.4. HRMS (ESI) calc for C17H19N [M+H]+ 238.1590, found 238.1587. IR (KBr plate) 692 (m), 747 (m), 1345 (m), 1444 (m), 1499 (s), 1592 (s), 1602 (s), 2918 (m), 3024 (m) cm−1.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([C:11](=[O:13])[CH3:12])=[CH:10][C:5]=2[CH2:4][CH2:3][CH2:2]1.[H-].[Na+].[F:16][C:17]([F:24])([F:23])[C:18](OCC)=[O:19].O>O1CCCC1>[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([C:11](=[O:13])[CH2:12][C:18](=[O:19])[C:17]([F:24])([F:23])[F:16])=[CH:10][C:5]=2[CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)C(F)(F)F
Reactant: CC(=O)c1ccc2c(c1)CCCO2
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=C(CC(=O)C(F)(F)F)c1ccc2c(c1)CCCO2
Temperature: 25 °C
Reaction time: 3 h
Yield: 100 %

Procedure:
Under a nitrogen atmosphere, 1-(3,4-dihydro-2H-1-benzopyran-6-yl)ethan-1-one (49a) (1.55 g, 8.8 mmol) was dissolved in anhydrous tetrahydrofuran (48 mL) and sodium hydride (60% in mineral oil, 0.42 g, 10.6 mmol) was added portionwise, maintaining the temperature between −5 and 0° C. After 30 minutes stirring at the same temperature, ethyl trifluoroacetate (1.5 mL, 10.6 mmol) was added and the reaction mixture was stirred at room temperature for 3 hours. Water (10 mL) was added and tetrahydrofuran was removed in vacuo. The resulting aqueous layer was extracted with ethyl acetate (2×20 mL). The organic layer was washed with brine (10 mL), dried over sodium sulfate and concentrated in vacuo to provide 1-(3,4-dihydro-2H-1-benzopyran-6-yl)-4,4,4-trifluorobutane-1,3-dione (49b) (2.39 g, 8.8 mmol, 100%) which was used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[NH:12][S:13]([CH3:16])(=[O:15])=[O:14])[C:8](=[O:17])[N:7]([CH2:18][C:19]([OH:21])=[O:20])[C:6]2=[O:22].[Cl:23][C:24]1[CH:25]=[N+:26]([O-:49])[CH:27]=[C:28]([Cl:48])[C:29]=1[CH2:30][C@@H:31]([C:33]1[CH:38]=[CH:37][C:36]([O:39][CH:40]([F:42])[F:41])=[C:35]([O:43][CH2:44][CH:45]2[CH2:47][CH2:46]2)[CH:34]=1)O.C(Cl)CCl>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Cl:23][C:24]1[CH:25]=[N+:26]([O-:49])[CH:27]=[C:28]([Cl:48])[C:29]=1[CH2:30][C@@H:31]([C:33]1[CH:38]=[CH:37][C:36]([O:39][CH:40]([F:42])[F:41])=[C:35]([O:43][CH2:44][CH:45]2[CH2:47][CH2:46]2)[CH:34]=1)[O:20][C:19](=[O:21])[CH2:18][N:7]1[C:6](=[O:22])[C:5]2[C:9](=[CH:10][C:11]([NH:12][S:13]([CH3:16])(=[O:15])=[O:14])=[C:3]([O:2][CH3:1])[CH:4]=2)[C:8]1=[O:17]
Reactant: COc1cc2c(cc1NS(C)(=O)=O)C(=O)N(CC(=O)O)C2=O
Reactant: [O-][n+]1cc(Cl)c(C[C@H](O)c2ccc(OC(F)F)c(OCC3CC3)c2)c(Cl)c1
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: ClCCl
Product: COc1cc2c(cc1NS(C)(=O)=O)C(=O)N(CC(=O)O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC3CC3)c1)C2=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 23.9 %

Procedure:
A mixture of 2-(5-methoxy-6-(methylsulfonamido)-1,3-dioxoisoindolin-2-yl)acetic acid (0.183 g, 0.557 mmol), (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-hydroxyethyl)pyridine 1-oxide (0.234 g, 0.557 mmol), EDC (0.321 g, 1.672 mmol) and DMAP (0.034 g, 0.279 mmol) in DCM (20 ml) was stirred at room temperature for 2 hours. The mixture was diluted with DCM and washed with 1N HCl, 5% NaHCO3 and brine. The organic phase was dried over sodium sulfate, the solvent was removed, and the crude was purified by flash chromatography on silica gel cartridge (DCM:ethyl acetate from 1:1 to 4:1) affording (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(2-(5-methoxy-6-(methylsulfonamido)-1,3-dioxoisoindolin-2-yl)acetoxy)ethyl)pyridine 1-oxide as a pale orange solid (0.097 g, 0.133 mmol, 24% yield). MS/ESI+ 730.13 [MH]+; [αD]=−33.40, c=0.43, DCM; 1H NMR (300 MHz, DMSO-d6) δ ppm 9.54 (br. s., 1H), 8.44 (s, 2H), 7.77 (s, 1H), 7.55 (s, 1H), 7.19 (d, 1H), 7.08 (d, 1H), 6.96 (dd, 1H), 7.08 (t, 1H), 6.01 (dd, 1H), 4.39 (s, 2H), 4.04 (s, 3H), 3.93 (d, 2H), 3.39 (dd, 1H), 3.23 (dd, 1H), 3.15 (s, 3H), 1.01-1.37 (m, 1H), 0.50-0.72 (m, 2H), 0.25-0.45 (m, 2H)
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([NH2:12])=[CH:7][CH:6]=2.[CH3:13][O-:14].[Na+]>CO.[Cu]>[CH3:13][O:14][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([NH2:12])=[CH:7][CH:6]=2
Reactant: C[O-]
Reactant: Nc1ccc2ncc(Br)cc2c1
Agent: [Cu]
Agent: [Na+]
Solvent: CO
Product: COc1cnc2ccc(N)cc2c1
Temperature: 135 °C
Yield: 59.8 %

Procedure:
A suspension of 3-bromo-quinolin-6-ylamine (9.0 g, 40.3 mmol, 1.0 eq), sodium methoxide (10.9 g, 201.7 mmol, 5.0 eq) and copper powder (7.7 g, 121.0 mmol, 3.0 eq) in methanol (240 mL) is heated at 135° C. for 15 hours. The reaction mixture is then filtered and the filtrate is concentrated to give a yellow residue that is purified by column chromatography (silica gel, eluent: petroleum ether:ethyl acetate:triethylamine, 2:1:0.05, v/v/v) to afford 3-methoxy-quinolin-6-ylamine as a yellow solid (4.2 g, 59% yield).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4](Br)[N:3]=1.[CH3:9][O-:10].[Na+].CO>CO>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:10][CH3:9])[N:3]=1
Reactant: Brc1cccc(Br)n1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1cccc(Br)n1
Reaction time: 2 h

Procedure:
While heating under stirring a mixture of 200 g of 2,6-dibromopyridine and 150 ml of methanol on an oil bath at 80° C., 250 ml of a 28% sodium methoxide/methanol solution was added dropwise slowly. The mixture was heated under stirring as it was for 2 hours, and after standing to cool, it was extracted with diethyl ether-water. The organic layer was washed with water and brine, and then dried over anhydrous magnesium sulfate. The solvent was removed, to give 150 g of the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH:5]([CH2:11][CH:12]1[CH2:14][CH2:13]1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2].[H-].[Na+].C1C(=O)N([Br:25])C(=O)C1>C1COCC1>[CH2:9]([O:8][C:6](=[O:7])[C:5]([Br:25])([CH2:11][CH:12]1[CH2:13][CH2:14]1)[C:4]([O:3][CH2:1][CH3:2])=[O:15])[CH3:10]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)C(CC1CC1)C(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C(Br)(CC1CC1)C(=O)OCC
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 87.1 %

Procedure:
To an ice-cooled solution of 2-cyclopropylmethylmalonic acid diethyl ester (1.3 g, 6.067 mmol) in THF (45 mL) was added, portionwise, sodium hydride (0.485 g, 60% in oil, 12.13 mmol). The mixture was stirred in the ice bath for 15 min, and then at RT for 15 min. The suspension was re-cooled in the ice bath and NBS (1.19 g, 6.67 mmol) was added over 5 min. The mixture was stirred in the ice bath for 10 min, and then at RT for 30 min. The reaction mixture was filtered through Celite® and the filtrate concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC, gradient 2-8% EtOAc in cyclohexane) affording the title compound as a colourless oil (1.55 g, 87%). 1H NMR (CDCl3, 300 MHz): δ 4.33-4.22 (4H, m), 2.24 (2H, d, J=6.6 Hz) 1.30 (6H, d, J=7.1 Hz) 1.01-0.88 (1H, m), 0.54-0.48 (2H, m), 0.17-0.12 (2H, m).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]([C:17]3[CH:22]=[CH:21][N:20]=[C:19]([NH:23][C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([CH2:30][N:31]([CH3:33])[CH3:32])[CH:25]=4)[N:18]=3)=[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][N:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1.C1COCC1.C1C=CC2N(O)N=NC=2C=1.[S:49]1[CH:53]=[CH:52][C:51]([CH2:54][C:55](O)=[O:56])=[CH:50]1>CC(N(C)C)=O>[CH3:32][N:31]([CH2:30][C:26]1[CH:25]=[C:24]([NH:23][C:19]2[N:18]=[C:17]([C:16]3[C:8]([C:4]4[CH:3]=[C:2]([NH:1][C:55](=[O:56])[CH2:54][C:51]5[CH:52]=[CH:53][S:49][CH:50]=5)[CH:7]=[CH:6][CH:5]=4)=[N:9][N:10]4[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=34)[CH:22]=[CH:21][N:20]=2)[CH:29]=[CH:28][CH:27]=1)[CH3:33]
Reactant: O=C(O)Cc1ccsc1
Reactant: CN(C)Cc1cccc(Nc2nccc(-c3c(-c4cccc(N)c4)nn4ccccc34)n2)c1
Agent: On1nnc2ccccc21
Solvent: CC(=O)N(C)C
Solvent: C1CCOC1
Product: CN(C)Cc1cccc(Nc2nccc(-c3c(-c4cccc(NC(=O)Cc5ccsc5)c4)nn4ccccc34)n2)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 49.7 %

Procedure:
To a solution of 4-[2-(3-aminophenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-{3-[(dimethylamino)methyl]phenyl}-2-pyrimidinamine (50 mg, 0.115 mmol) in 5:1 THF:DMA (2 mL) was added HOBT (46 mg, 0.34 mmol), 0.28 g polystyrene-bound carbodiimide resin (280 mg, 0.34 mmol), and 3-thienylacetic acid (48 mg, 0.34 mmol). After stirring at rt for 48 h, excess Dowex 550A OH anion-exchange resin was added and the resulting mixture was allowed to stir overnight. The solids were then removed by vacuum filtration and rinsed with THF (25 mL) and MeOH (25 mL). The filtrate was concentrated under reduced pressure and purified by column chromatography (0-100% 9:1:0.1 DCM:MeOH:NH4OH) to afford the title compound (32 mg, 50%). 1H NMR (400 MHz, CDCl3) δ 2.27 (s, 6H), 3.46 (s, 2H), 3.78 (s, 2H), 6.54 (d, 1H, J=5.31 Hz), 6.90 (dd, 1H, J=1.47, 6.96 Hz), 6.99-7.00 (m, 1H), 7.06 (dd, 1H, J=1.28, 4.94 Hz), 7.22-7.38 (m, 8H), 7.53-7.56 (m, 2H), 7.61-7.63 (m, 1H), 7.77-7.80 (m, 1H), 8.16 (d, 1H, J=5.31 Hz), 8.32-8.35 (m, 1H), 8.46-8.48 (m, 1H). ES-LC/MS m/z=560 [M+H]+.