Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]12[CH2:11][CH2:10][C:7]([NH:12][CH2:13][C:14]([N:16]3[CH2:20][C@@H:19]([F:21])[CH2:18][C@H:17]3[C:22]#[N:23])=[O:15])([CH2:8][CH2:9]1)[CH2:6][CH2:5]2)(O)=[O:2].[CH3:24][O:25][C:26]1[CH:31]=[CH:30][C:29]([NH:32]C2C=CC=CC=2)=[CH:28][CH:27]=1>>[F:21][C@@H:19]1[CH2:20][N:16]([C:14](=[O:15])[CH2:13][NH:12][C:7]23[CH2:8][CH2:9][C:4]([C:1]([NH:32][C:29]4[CH:30]=[CH:31][C:26]([O:25][CH3:24])=[CH:27][CH:28]=4)=[O:2])([CH2:5][CH2:6]2)[CH2:11][CH2:10]3)[C@H:17]([C:22]#[N:23])[CH2:18]1
Reactant: N#C[C@@H]1C[C@H](F)CN1C(=O)CNC12CCC(C(=O)O)(CC1)CC2
Reactant: COc1ccc(Nc2ccccc2)cc1
Product: COc1ccc(NC(=O)C23CCC(NCC(=O)N4C[C@@H](F)C[C@H]4C#N)(CC2)CC3)cc1
Yield: 49.6 %

Procedure:
In a similar manner to Example 51, (2S,4S)-1-[[N-(4-carboxybicyclo[2.2.2]oct-1-yl)amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (30.0 mg) and 4-methoxyphenylaniline (22.9 mg) were used to obtain (2S,4S)-4-fluoro-1-[[N-[4-[N-(4-methoxyphenyl)amino]carbonylbicyclo[2.2.2]oct-1-yl]amino]acetyl]pyrrolidine-2-carbonitrile (19.7 mg).
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][N:4]=1.[CH3:13][NH:14][CH3:15].O>O1CCCC1>[CH3:13][N:14]([CH2:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][N:4]=1)[CH3:15]
Reactant: CNC
Reactant: COC(=O)c1ccc(CBr)nc1
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1ccc(CN(C)C)nc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of methyl 6-bromomethylnicotinate (350 mg) in tetrahydrofuran (5 ml) was added a 50% aqueous dimethylamine solution (3 ml), and the mixture was vigorously stirred at room temperature for 10 minutes. To the reaction mixture was added water and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The resulting residue was purified by silica gel column chromatography (solvent: chloroform:methanol=100:1) to obtain methyl 6-(dimethylamino)methylnicotinate (276 mg) as brownish powder.
Reaction SMILES: Br[C:2]1[C:3]([N:9]([CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:4][C:5]([NH2:8])=[N:6][CH:7]=1.C([O-])([O-])=O.[K+].[K+]>CC(N(C)C)=O.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH:10]1([N:9]2[C:16]3[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:2]3[CH:7]=[N:6][C:5]([NH2:8])=[N:4][C:3]2=3)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: Nc1ncc(Br)c(N(c2ccccc2)C2CCCCC2)n1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CC(=O)N(C)C
Product: Nc1ncc2c3ccccc3n(C3CCCCC3)c2n1
Temperature: 160 °C
Yield: 41.7 %

Procedure:
A mixture of compound 41 (0.35 g, 0.99 mmol), Pd(OAc)2 (33 mg, 0.15 mmol), (cyclohexyl)3PBF4 (110 mg, 0.30 mmol), and K2CO3 (138 mg, 0.10 mmol) in DMA (3 mL) was purged with N2 for 20 minutes and then heated at 160° C. for 3 hours. The reaction was cooled to room temperature and diluted with ethyl acetate. The organic layer was washed with water and brine, dried over sodium sulfate and concentrated. Purification by flash chromatography (ethyl acetate/hexane) gave compound 42 as a yellow solid (110 mg, 41%). LCMS-ESI (POS), M/Z, M+1: Found 267.1, Calculated 267.2.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3=[N:19][CH:20]=[N:21][C:22](Cl)=[C:17]3[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:24][C:25]1[CH:26]=[C:27]([OH:31])[CH:28]=[CH:29][CH:30]=1>CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3=[N:19][CH:20]=[N:21][C:22]([O:31][C:27]4[CH:28]=[CH:29][CH:30]=[C:25]([F:24])[CH:26]=4)=[C:17]3[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(n2ncc3c(Cl)ncnc32)CC1
Reactant: Oc1cccc(F)c1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(n2ncc3c(Oc4cccc(F)c4)ncnc32)CC1

Procedure:
4-[4-(3-Fluoro-phenoxy)-pyrazolo[3,4-d]pyrimidin-1-yl]-piperidine-1-carboxylic acid tert-butyl ester was prepared according to General Procedure B by the reaction of 4-(4-chloro-pyrazolo[3,4-d]pyrimidin-1-yl)-piperidine-1-carboxylic acid tert-butyl ester (Intermediate 19) with 3-fluorophenol (available from Aldrich Chemical Company, Inc., Milwaukee, Wis., USA) in dimethylformamide. 1H NMR (400 MHz, DMSO-d6) δ 1.43 (s, 9H), 1.93-2.08 (m, 4H), 2.97-3.07 (m, 2H), 4.05-4.15 (m, 2H), 4.98-5.03 (m, 1H), 7.20-7.24 (m, 2H), 7.33-7.38 (m, 1H), 7.52-7.56 (m, 1H), 8.28 (s, 1H), 8.58 (s, 1H). Mass spectrum MH+=414.
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:11][C:12]3[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][N:13]=3)[CH:9]=2)[C:4](=[O:20])[CH2:3]1.C([O-])([O-])=[O:23].[K+].[K+].CS(C)=O>O>[CH3:1][C:2]1([CH3:21])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:11][C:12]3[CH:19]=[CH:18][C:15]([C:16]([NH2:17])=[O:23])=[CH:14][N:13]=3)[CH:9]=2)[C:4](=[O:20])[CH2:3]1
Reactant: CC1(C)CC(=O)c2ccc(Oc3ccc(C#N)cn3)cc21
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CC1(C)CC(=O)c2ccc(Oc3ccc(C(N)=O)cn3)cc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 188.3 %

Procedure:
Add 30% aqueous H2O3 (3.15 ml) to a suspension of 6-(3,3-Dimethyl-1-oxo-indan-5-yloxy)nicotinonitrile (877 mg, 3.15 mmol), K2CO3 (218 mg, 1.57 mmol) and DMSO (10 ml) stirring under nitrogen at ambient temperature. After four hours, dilute the reaction mixture with water (100 ml) and extract with EtOAc (2×). Wash the extract with water and brine, dry (MgSO4) and concentrate on rotary evaporator to yield 876 mg of the title compound as an off-white solid. Mass spectrum (ion spray): m/z=297 (M+1); 1HNMR (CDCl3): 8.62 (s, 1H), 8.24 (d, 1H), 7.75 (d, 1H), 7.24 (s, 1H), 7.14 (d, 1H), 7.07 (d, 1H), 5.91 (broad, 2H), 2.63 (s, 2H), 1.43 (s, 6H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][CH:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([CH:18]=O)[CH:14]=2)[CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[NH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>CN(C)C(=O)C>[C:1]([O:5][C:6](=[O:20])[NH:7][CH:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([CH2:18][N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)[CH:14]=2)[CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: C1CCNCC1
Reactant: CC(C)(C)OC(=O)NC1CCc2cc(C=O)ccc2C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CC(C)(C)OC(=O)NC1CCc2cc(CN3CCCCC3)ccc2C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
(6-Formyl-1,2,3,4-tetrahydro-naphthalen-2-yl)-carbamic acid tert-butyl ester (Step D) (0.090 g, 0.33 mmol) was dissolved in N,N-dimethylacetamide (10 mL). Piperdine (0.162 mL, 1.63 mmol) was added and the mixture was stirred at RT for 30 min. NaBH(OAc)3 (0.173 g, 0.817 mmol) was added in one portion and the reaction was stirred at RT until complete consumption of starting material was observed by HPLC analysis. The reaction was in concentrated in vacuo and the residue was diluted with CH2Cl2 and H2O and the aqueous layer was made basic with NaOH. The layers were separated and the organics were dried over MgSO4 and concentrated in vacuo to afford the crude title compound, which was used without further purification. MS (APCI pos) 345 (M+H).
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:9]=[C:8]([C:10]([OH:13])([CH3:12])[CH3:11])[CH:7]=[CH:6][C:5]=1[C:14]1[S:18][C:17]([NH:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([CH2:26][OH:27])[N:21]=2)=[C:16]([C:28]([NH2:30])=[O:29])[CH:15]=1.Br[CH2:32][CH2:33][O:34][CH3:35]>CN(C=O)C>[F:3][C:4]1[CH:9]=[C:8]([C:10]([OH:13])([CH3:11])[CH3:12])[CH:7]=[CH:6][C:5]=1[C:14]1[S:18][C:17]([NH:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([CH2:26][O:27][CH2:32][CH2:33][O:34][CH3:35])[N:21]=2)=[C:16]([C:28]([NH2:30])=[O:29])[CH:15]=1
Reactant: COCCBr
Reactant: CC(C)(O)c1ccc(-c2cc(C(N)=O)c(Nc3cccc(CO)n3)s2)c(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCCOCc1cccc(Nc2sc(-c3ccc(C(C)(C)O)cc3F)cc2C(N)=O)n1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a suspension of NaH (7.5 mg, 0.19 mmol) in DMF (1.25 mL) at 0° C. under argon was added 5-[2-fluoro-4-(1-hydroxy-1-methylethyl)phenyl]-2-{[6-(hydroxymethyl)pyridin-2-yl]amino}thiophene-3-carboxamide (Example 43) (50 mg, 0.13 mmol) and the mixture was allowed to stir for 10 minutes. 1-Bromo-2-methoxyethane (26 mg, 0.187 mmol) was then added and the reaction was allowed to warm to room temperature overnight. The reaction was then quenched by the addition of water, extracted with ethyl acetate and concentrated in vacuo. The crude residue was reverse phase HPLC (acteonitrile/water with formic acid as a modifier) to afford the title compound.
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][CH2:7][C:8]([OH:10])=O)(=[O:3])[CH3:2].[CH:11]1([NH:14][C:15]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[N:25]=[C:26]([N:33]4[CH2:38][CH2:37][O:36][CH2:35][C@@H:34]4[CH3:39])[C:27]4[CH2:32][NH:31][CH2:30][C:28]=4[N:29]=3)=[CH:20][CH:19]=2)=[O:16])[CH2:13][CH2:12]1>>[CH:11]1([NH:14][C:15](=[O:16])[NH:17][C:18]2[CH:19]=[CH:20][C:21]([C:24]3[N:25]=[C:26]([N:33]4[CH2:38][CH2:37][O:36][CH2:35][C@@H:34]4[CH3:39])[C:27]4[CH2:32][N:31]([C:8](=[O:10])[CH2:7][CH2:6][CH2:5][NH:4][C:1](=[O:3])[CH3:2])[CH2:30][C:28]=4[N:29]=3)=[CH:22][CH:23]=2)[CH2:13][CH2:12]1
Reactant: C[C@H]1COCCN1c1nc(-c2ccc(NC(=O)NC3CC3)cc2)nc2c1CNC2
Reactant: CC(=O)NCCCC(=O)O
Product: CC(=O)NCCCC(=O)N1Cc2nc(-c3ccc(NC(=O)NC4CC4)cc3)nc(N3CCOC[C@@H]3C)c2C1
Yield: 39 %

Procedure:
Method as example 127 using 4-acetamidobutanoic acid and (S)-1-cyclopropyl-3-(4-(4-(3-methylmorpholino)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)phenyl)urea (example 3) as starting materials. Purified by Prep HPLC at low pH to afford a white solid (46.5 mg, 0.089 mmol, 39%).
Reaction SMILES: C([O:3][C:4](=[O:20])[CH2:5][N:6]([C:12](=[O:19])[CH:13]([CH3:18])[CH2:14][S:15][CH2:16][CH3:17])[CH:7]1[CH2:11][CH2:10][CH2:9][CH2:8]1)C.Cl>[OH-].[Na+]>[CH2:16]([S:15][CH2:14][CH:13]([CH3:18])[C:12]([N:6]([CH:7]1[CH2:11][CH2:10][CH2:9][CH2:8]1)[CH2:5][C:4]([OH:20])=[O:3])=[O:19])[CH3:17]
Reactant: CCOC(=O)CN(C(=O)C(C)CSCC)C1CCCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CCSCC(C)C(=O)N(CC(=O)O)C1CCCC1
Reaction time: 7 h

Procedure:
A mixture of 3.8 g (0.012) of N-(3-ethylthio-2-methyl propanoyl)-N-cyclopentyl glycine ethyl ester in 80 ml of 10% NaOH was stirred for 7 hours. It was then cooled, acidified with 10% HCl, extracted with ether, dried over MgSO4, and evaporated to dryness giving oily residue which was purified by HPLC using HOAc-EtOAc-Hexane (5:45:50).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@:9]([CH3:20])([C:17]([OH:19])=O)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.Cl.[NH2:45][CH2:46][C:47]([O:49][CH2:50][CH3:51])=[O:48].C(N(CC)CC)C>C(Cl)Cl>[C:1]([O:5][C:6]([NH:8][C@@:9]([CH3:20])([C:17]([NH:45][CH2:46][C:47]([O:49][CH2:50][CH3:51])=[O:48])=[O:19])[CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N[C@](C)(Cc1ccccc1)C(=O)O
Reactant: CCOC(=O)CN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)CNC(=O)[C@@](C)(Cc1ccccc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 91.8 %

Procedure:
To a stirring solution of (R)-N-(tert-butyloxycarbonyl)-α-methylphenylalanine (0.72 g, 2.6 mmol) in dry CH2Cl2 (16 mL) was added N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.69 g, 4.4 mmol) and 1-hydroxybenzotriazole hydrate (0.39 g, 2.9 mmol). The reaction was stirred at ambient temperature for 30 min and then glycine, ethyl ester hydrochloride (0.62 g, 5.2 mmol) and triethylamine (0.85 ml, 5.7 mmol) were added. After stirring at ambient temperature for 3 h, the reaction was transferred to a separatory funnel with CH2Cl2. Extraction with CH2Cl2 and washing of the organic layer with water, saturated NaHCO3, and brine and drying with MgSO4 afforded 0.94 g of crude product after evaporation of the solvent. Purification by flash chromatography (SiO2, 0.2 to 10% MeOH in CH2Cl2) afforded pure product (0.87 g, 93% yield). MS (ESI) 365 (M+H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[OH:10])[CH:3]=[CH:2]1.CCCCCCC=CCCC.[CH3:22][N:23]=[C:24]=[O:25].CCCCCC.C(OCC)(=O)C>C(Cl)Cl>[CH3:22][NH:23][C:24](=[O:25])[O:10][C:8]1[CH:7]=[CH:6][CH:5]=[C:4]2[C:9]=1[NH:1][CH:2]=[CH:3]2
Reactant: Oc1cccc2cc[nH]c12
Reactant: CN=C=O
Agent: CCCC=CCCCCCC
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: ClCCl
Product: CNC(=O)Oc1cccc2cc[nH]c12
Temperature: 25 °C

Procedure:
3-(N-Cyclopropyl)amino-4-methyl-1,2,3,4-tetrahydrocyclopent b!indol-7-ol (2.2 g) was dissolved in CH2Cl2 (200 ml) with 1,8-diazabicyclo 5.4.0!undec-7-ene (DBU; 0.21 g) and the solution was cooled to 0° C. A solution of methyl isocyanate (0.52 g in 30 ml CH2Cl2) was added slowly to the cooled solution and the reaction was monitored by thin layer chromatography (silica gel, 1:1 hexane/ethyl acetate). After warming to room temperature, the mixture was washed successively with water (2×100 ml), brine (1×100 ml) and again with water (1×100 ml). The organic layer was dried over Na2SO4 and the solvent removed in vacuo. The crude material was recrystallized from acetonitrile. 3-(N-Cyclo-propyl)amino-4-methyl-1,2,3,4-tetrahydrocyclopent b!indol-7-yl methylcarbamate was isolated as light yellow/white plates (1.0 g).
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[N:11][NH:12][CH:13]=2)[O:3]1.C(OCN1C2N=CN=C(C3C=NN([CH:37]([O:39][CH2:40][CH3:41])[CH3:38])C=3)C=2C=C1)(=O)C(C)(C)C.Cl.C([O-])(O)=O.[Na+]>O1CCOCC1.C1(C)C=CC=CC=1>[CH2:37]([O:39][CH2:40][CH2:41][N:12]1[CH:13]=[C:9]([B:4]2[O:5][C:6]([CH3:7])([CH3:8])[C:2]([CH3:14])([CH3:1])[O:3]2)[CH:10]=[N:11]1)[CH3:38]
Reactant: CCOC(C)n1cc(-c2ncnc3c2ccn3COC(=O)C(C)(C)C)cn1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: C1COCCO1
Product: CCOCCn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Temperature: 37.5 °C
Reaction time: 1 h
Yield: 97.3 %

Procedure:
A 22 L 4-neck flask equipped with a mechanical stirrer, thermowell, addition funnel, condenser and N2 inlet was charged with 4-(4,4,5,5-tetra-methyl[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (17, 1.42 kg, 7.32 mol), toluene (9.5 L) and ethyl vinyl ether (18, 790.5 g, 1050 mL, 10.98 mol, 1.50 equiv). A 4 M HCl in dioxane (50 mL) was added via an addition funnel over 10 minutes and the resulting reaction mixture was heated at 35-40° C. for 7 hr to give a clear homogeneous solution. When the reaction was shown to be complete by GC, solid NaHCO3 (130 g) was added and the mixture was stirred for 1 hr before being filtered. The filtrate was concentrated under reduced pressure. Heptane (200 mL) was added to the residue to affect crystallization. The solid was collected by filtration and dried in a vacuum oven to afford 1-(ethoxyethyl)-4-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (19, 1.896 Kg, 1.948 Kg theoretical, 97.3%) as a white to off-white solid. For 19: 1H NMR (DMSO-d6, 400 MHz) δ ppm 8.09 (s, 1H), 8.58 (s,1H), 7.62 (s,1H), 5.55 (q, 1H, J=6.1 Hz), 3.37 (dq, 1H, J=7.1, 9.6 Hz), 3.12 (dq, 1H, J=7.0, 9.7 Hz), 1.56 (d, 3H, J=6.0 Hz), 1.24 (s, 12H), 1.00 (t, 3H, J=7.0 Hz); C13H23BN2O3 (MW, 266.14), LCMS (EI) m/e 267 (M++H).
Reaction SMILES: C([O:5][C:6](=[O:37])[NH:7][CH:8]([CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[CH:9]([OH:29])[CH2:10][N:11]([CH2:25][CH:26]([CH3:28])[CH3:27])[S:12]([C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[NH:20][N:19]=[C:18]2[CH3:24])(=[O:14])=[O:13])(C)(C)C.Cl.C(N(C(C)C)CC)(C)C.[O:48]1[CH:52]2[O:53][CH2:54][CH2:55][CH:51]2[CH:50](OC(=O)ON2C(=O)CCC2=O)[CH2:49]1>O1CCOCC1>[O:48]1[CH:52]2[O:53][CH2:54][CH2:55][CH:51]2[CH:50]([O:5][C:6](=[O:37])[NH:7][CH:8]([CH2:30][C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:9]([OH:29])[CH2:10][N:11]([CH2:25][CH:26]([CH3:28])[CH3:27])[S:12]([C:15]2[CH:16]=[C:17]3[C:21](=[CH:22][CH:23]=2)[NH:20][N:19]=[C:18]3[CH3:24])(=[O:13])=[O:14])[CH2:49]1
Reactant: Cc1n[nH]c2ccc(S(=O)(=O)N(CC(C)C)CC(O)C(Cc3ccccc3)NC(=O)OC(C)(C)C)cc12
Reactant: O=C(OC1COC2OCCC12)ON1C(=O)CCC1=O
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: Cc1n[nH]c2ccc(S(=O)(=O)N(CC(C)C)CC(O)C(Cc3ccccc3)NC(=O)OC3COC4OCCC34)cc12
Reaction time: 8 h

Procedure:
{1-Benzyl-2-hydroxy-3-[isobutyl-(3-methyl-1H-indazole-5-sulfonyl)-amino]-propyl}-carbamic acid tert-butyl ester (25 mg, 0.047 mmol) was added to a solution of 4N HCl in dioxane (0.25 mL). Material precipitated out so 800 uL conc. HCl was added and the reaction heated at reflux for 2 h. The resulting solution was concentrated under vacuum and concentrated 2 additional times from 1 mL methylene chloride. This crude amine was dissolved in 0.5 mL methylene chloride and diisopropylethylamine (80 uL, 0.46 mmol) was then added. To this solution was added carbonic acid 2,5-dioxo-pyrrolidin-1-yl ester hexahydro-furo[2,3-b]furan-3-yl ester (16 mg, 0.055 mmol) and the reaction stirred overnight. The reaction was concentrated under vacuum and purified by preparative HPLC. MS 587 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6](Br)[N:5]=[C:4]([C:9]([O:11][CH3:12])=[O:10])[C:3]=1[O:13][CH3:14].C([Sn](CCCC)(CCCC)[C:20]([O:22][CH2:23][CH3:24])=[CH2:21])CCC.[Sn]>ClCCCl.[Pd].Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:1][C:2]1[CH:7]=[C:6]([C:20]([O:22][CH2:23][CH3:24])=[CH2:21])[N:5]=[C:4]([C:9]([O:11][CH3:12])=[O:10])[C:3]=1[O:13][CH3:14]
Reactant: COC(=O)c1nc(Br)cc(N)c1OC
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Pd]
Agent: [Sn]
Solvent: ClCCCl
Product: C=C(OCC)c1cc(N)c(OC)c(C(=O)OC)n1
Temperature: 120 °C
Reaction time: 0.5 h
Yield: 86.9 %

Procedure:
Methyl 4-amino-6-bromo-3-methoxypicolinate (2 g, 7.66 mmol), tributyl(1-ethoxyvinyl)stannane (4.15 g, 11.49 mmol) and bis(triphenylphosphine)palladium(ii) chloride (0.807 g, 1.149 mmol) in DCE (19.15 ml) were stirred under microwave irradiation (120° C., 30 min). The reaction was not completed (LC). Additional tin reagent (1 equiv) and palladium catalyst (0.15 equiv) were added and the reaction mixture was stirred under microwave irradiation (120° C., 30 min). The mixture was adsorbed onto celite and purified by flash column chromatography (ISCO, SiO2 80 g, hexane/EtOAc 100:0 to 0:100 gradient) to afford methyl 4-amino-6-(1-ethoxyvinyl)-3-methoxypicolinate (1.68 g, 6.66 mmol, 87% yield) as a yellow solid. Mp 72-73° C.; EIMS m/z 253 ([M+H]+); 1H NMR (400 MHz, CDCl3) δ 7.15 (s, 1H), 5.34 (d, J=2.0 Hz, 1H), 4.45 (s, 2H), 4.31 (d, J=1.9 Hz, 1H), 3.96 (s, 3H), 3.92 (q, J=7 Hz, 2H), 3.86 (s, 3H), 1.41 (t, J=7.0 Hz, 3H).
Reaction SMILES: [CH3:1][C:2]([OH:41])([C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:9]=1[CH2:10][CH2:11][C@@H:12]([S:32][CH2:33][C:34]1([CH2:37][C:38]([OH:40])=[O:39])[CH2:36][CH2:35]1)[C:13]1[CH:14]=[CH:15][CH:16]=[C:17](/[CH:19]=[CH:20]/[C:21]2[CH:22]=[CH:23][C:24]3[CH:25]=[CH:26][C:27]([Cl:31])=[CH:28][C:29]=3[N:30]=2)[CH:18]=1)[CH3:3].[OH-].[Na+:43]>C1COCC1>[CH3:3][C:2]([OH:41])([C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:9]=1[CH2:10][CH2:11][C@@H:12]([S:32][CH2:33][C:34]1([CH2:37][C:38]([O-:40])=[O:39])[CH2:35][CH2:36]1)[C:13]1[CH:14]=[CH:15][CH:16]=[C:17](/[CH:19]=[CH:20]/[C:21]2[CH:22]=[CH:23][C:24]3[CH:25]=[CH:26][C:27]([Cl:31])=[CH:28][C:29]=3[N:30]=2)[CH:18]=1)[CH3:1].[Na+:43]
Reactant: CC(C)(O)c1ccccc1CC[C@@H](SCC1(CC(=O)O)CC1)c1cccc(/C=C/c2ccc3ccc(Cl)cc3n2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)(O)c1ccccc1CC[C@@H](SCC1(CC(=O)[O-])CC1)c1cccc(/C=C/c2ccc3ccc(Cl)cc3n2)c1

Procedure:
Montelukast cyclohexylamine salt suspended in toluene (5 parts) was treated with aqueous acetic acid (5 parts) until a pH of 5.0˜5.5 was reached. The organic phase was separated and washed with water (5 parts) twice, and the resulting organic layer was concentrated to provide a crude oil of montelukast acid. The montelukast acid (100.0 g, 170.2 mmol) thus obtained was dissolved in 500 mL THF, and then 78 mL of ca. 2N NaOH aqueous solution was added under nitrogen. After stirring for several minutes, the solvent was removed under reduced pressure at 30° C. to afford montelukast sodium as a crude oil. The crude oil was taken up in 2.5 L water and concentrated to remove the remaining THF until the total volume was about 2.7 L (THF remained as analyzed by GC was 1.7%). The aqueous solution of montelukast sodium was filtered, and its purity was determined by HPLC (99.7%). The filtered solution was subjected to spray drying at various conditions, and the results were listed in Table 5.
Reaction SMILES: Br[C:2]1[NH:3][C:4]2[CH:5]=[CH:6][CH:7]=[C:8]3[C:14](=[O:15])[NH:13][CH2:12][CH2:11][C:10]=1[C:9]=23.C([O-])([O-])=O.[K+].[K+].[N+:22]([C:25]1[CH:26]=[C:27](B(O)O)[CH:28]=[CH:29][CH:30]=1)([O-:24])=[O:23].O>O1CCOCC1>[N+:22]([C:25]1[CH:30]=[C:29]([C:2]2[NH:3][C:4]3[CH:5]=[CH:6][CH:7]=[C:8]4[C:14](=[O:15])[NH:13][CH2:12][CH2:11][C:10]=2[C:9]=34)[CH:28]=[CH:27][CH:26]=1)([O-:24])=[O:23]
Reactant: O=C1NCCc2c(Br)[nH]c3cccc1c23
Reactant: O=[N+]([O-])c1cccc(B(O)O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: O=C1NCCc2c(-c3cccc([N+](=O)[O-])c3)[nH]c3cccc1c23
Temperature: 100 °C

Procedure:
Tricyclic bromide 11 (27 mg, 0.10 mmol) in 1,4-dioxane (1.0 mL) was treated with solid K2CO3 (41 mg, 0.30 mmol), m-nitrophenylboronic acid (34 mg, 0.20 mmol), and water (0.25 mL). The solution was degassed and tetrakis(triphenylphosphine)palladium(0) (12 mg, 10 mol %) was added. The solution was heated at 100° C. for 1 h, then cooled to ambient temperature and diluted with water (2 mL). The aqueous layer was adjusted to pH=7-8 with saturated aqueous K2CO3 and extracted with EtOAc (5 mL×3). The organic solution was washed with water and brine, dried (Na2SO4), filtered, and concentrated. The crude product was purified by flash chromatography (3-5% MeOH in CHCl3) to yield 14 as a yellow solid, 26.3 mg (87%). mp 268-270° C. (dec.); 1H NMR (DMSO-d6) δ3.16 (m, 2H), 3.45 (m, 2H), 7.33 (m, 1H), 7.65 (m, 1H), 7.76 (m, 1H), 7.78 (m, 1H), 8.30 (m, 1H), 8.53 (bs, 1H), 8.16 (m, 2H), 11.93 (bs, 1H); HRMS (M+Na) Calcd for C17H13N3O3+Na: 330.0855, Found: 330.0847; Anal. (C17H13N3O3.H2O) C, H, N.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:11]2[CH:19]=[CH:18][C:14]([C:15](Cl)=[O:16])=[CH:13][CH:12]=2)=[O:10])=[CH:5][CH:4]=1.[CH3:22][C@H:23]1[CH2:28][N:27]([CH2:29][C:30]2[CH:35]=[CH:34][C:33]([NH:36][CH3:37])=[CH:32][CH:31]=2)[CH2:26][CH2:25][N:24]1[C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39].C(N(CC)CC)C>C(Cl)Cl.O>[CH3:22][C@H:23]1[CH2:28][N:27]([CH2:29][C:30]2[CH:35]=[CH:34][C:33]([N:36]([CH3:37])[C:15]([C:14]3[CH:18]=[CH:19][C:11]([C:9]([C:6]4[CH:7]=[CH:8][C:3]([C:2]([F:21])([F:20])[F:1])=[CH:4][CH:5]=4)=[O:10])=[CH:12][CH:13]=3)=[O:16])=[CH:32][CH:31]=2)[CH2:26][CH2:25][N:24]1[C:38]([O:40][C:41]([CH3:42])([CH3:44])[CH3:43])=[O:39]
Reactant: O=C(Cl)c1ccc(C(=O)c2ccc(C(F)(F)F)cc2)cc1
Reactant: CNc1ccc(CN2CCN(C(=O)OC(C)(C)C)[C@@H](C)C2)cc1
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@H]1CN(Cc2ccc(N(C)C(=O)c3ccc(C(=O)c4ccc(C(F)(F)F)cc4)cc3)cc2)CCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The acid chloride from step 1 was taken up in DCM (2 mL) and added drop-wise to a mixture of 1,1-dimethylethyl (2S)-2-methyl-4-{[4-(methylamino)phenyl]methyl}-1-piperazinecarboxylate (D3) (0.170 g, 0.53 mmol) and triethylamine (0.11 mL) in DCM (2 mL). The reaction mixture was stirred at room temperature under argon overnight then diluted with water (20 mL) and DCM (20 mL). The aqueous layer was extracted with DCM (20 mL) and the combined organic layers were dried, concentrated and purified by column chromatography. Elution with 0-30% EtOAc/pentane gave the title compound as a colourless oil (0.244 g). MS (ES): MH+ 596.2.