Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[C:11]([CH3:18])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(S([O-])=O)([O-])=O.[Na+].[Na+].N>CO.O>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([NH2:15])=[C:11]([CH3:18])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cc(OCc2ccccc2)ccc1[N+](=O)[O-]
Agent: N
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: Cc1cc(OCc2ccccc2)ccc1N
Yield: 34.4 %

Procedure:
A solution of 4-benzyloxy-2-methyl nitrobenzene (6.4 mmol, 1.5 g) and sodium hydrosulfite (16 mmol, 2.2 g) in 140 mL of MeOH/water (2:1) was refluxed for two hours. Upon cooling, the solution was poured into 500 mL of aqueous ammonia and the product extracted into CH2Cl2 (4×). The organic layer was washed with water, brine and dried over Na2SO4, filtered and concentrated to provide 4-benzyloxy-2-methylaniline (0.47 g, 51%) as a light brown oil. 1H NMR (300 MHz, CDCl3) δ:7.4 (m, 5 H), 6.76 (d, J=2.1 Hz, 1 H), 6.70 (dd, J=7.2, 2.1 Hz, 1 H), 6.61 (d, J=7.2 Hz, 1 H), 4.98 (s, 2 H), 2.15 (s, 3 H).
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:14]=[CH:15][C:16]=2[O:17][CH:18]([F:20])[F:19])[C:10]([O:12]C)=[O:11])[CH2:5][CH2:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].O>CO>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:14]=[CH:15][C:16]=2[O:17][CH:18]([F:19])[F:20])[C:10]([OH:12])=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COC(=O)c1ccc(OC(F)F)c(OC2CCCC2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: O=C(O)c1ccc(OC(F)F)c(OC2CCCC2)c1

Procedure:
A solution of methyl 3-cyclopentyloxy-4-difluoromethoxybenzoate (0.6 g; that is prepared as described in Reference Example 41) in methanol (10 mL) is treated with potassium carbonate (0.35 g) and water (4 mL), and then it is heated at reflux for 3 hours. Methanol is evaporated off under reduced pressure, and the residue is dissolved in water (40 mL). The solution is washed with diethyl ether (40 mL), acidified with concentrated hydrochloric acid, and extracted with ethyl acetate (3×40 mL). The combined ethyl acetate extracts are dried over magnesium sulfate and evaporated under reduced pressure, to give 3-cyclopentyloxy-4-difluoromethoxybenzoic acid (0.47 g), in the form of a white solid, m.p. 126°-128° C.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH:9]1[CH2:14][CH2:13][N:12]([C:15]2[C:20]([C:21]#[C:22][C:23]3[CH:24]=[N:25][C:26]([NH2:29])=[CH:27][CH:28]=3)=[C:19]([CH3:30])[N:18]=[CH:17][N:16]=2)[CH2:11][CH2:10]1)(C)(C)C.Cl>C(Cl)Cl.CO.O1CCOCC1>[NH2:7][CH2:8][CH:9]1[CH2:14][CH2:13][N:12]([C:15]2[C:20]([C:21]#[C:22][C:23]3[CH:28]=[CH:27][C:26]([NH2:29])=[N:25][CH:24]=3)=[C:19]([CH3:30])[N:18]=[CH:17][N:16]=2)[CH2:11][CH2:10]1
Reactant: Cc1ncnc(N2CCC(CNC(=O)OC(C)(C)C)CC2)c1C#Cc1ccc(N)nc1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: CO
Product: Cc1ncnc(N2CCC(CN)CC2)c1C#Cc1ccc(N)nc1
Temperature: 50 °C

Procedure:
To a solution of 3.10 g (7.34 mmol) {1-[5-(6-amino-pyridin-3-ylethynyl)-6-methyl-pyrimidin-4-yl]-piperidin-4-ylmethyl}-carbamic acid tert-butyl ester in 20 mL DCM and 20 mL MeOH at RT is added 2.75 mL (11.0 mmol) 4 M HCl in dioxane. The reaction is to stirred over night at 50° C. The solvent is removed under reduced pressure and the residue is taken up in a small amount of MeOH. The precipitated product is filtered off and washed with few MeOH. After drying 3.06 g (95%) of the desired product is obtained.
Reaction SMILES: [CH:1]([P:3](=[O:9])([CH:7]=[CH2:8])[CH:4]([CH3:6])[CH3:5])=[CH2:2].[CH2:10]([NH2:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>O>[CH2:10]([N:17]1[CH2:8][CH2:7][P:3](=[O:9])([CH:4]([CH3:6])[CH3:5])[CH2:1][CH2:2]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: NCc1ccccc1
Reactant: C=CP(=O)(C=C)C(C)C
Solvent: O
Product: CC(C)P1(=O)CCN(Cc2ccccc2)CC1
Temperature: 85 °C
Yield: 62.6 %

Procedure:
A 20 L four-necked round bottom flask fitted with an overhead stirrer and reflux condenser, flame dried and cooled in a stream of nitrogen, was charged with the product of Step 1 (250 g, 1734 mmol), THE (2500 mL), water (2500 mL) and benzyl amine (297.3 g, 2774 mmol). The reaction mixture was heated at 85° C. for 16 h. After completion, THF was removed under reduced pressure. The aqueous layer was extracted with ether to remove the excess of benzyl amine and later with dichloromethane (2×2500 mL). The combined dichloromethane layers were washed with brine (2×1000 mL), dried over sodium sulfate and concentrated to give 1-benzyl-4-(propan-2-yl)-1,4-azaphosphinane 4-oxide (273 g, 63%) as brown oil.
Reaction SMILES: ClC1C=CN=C2C=C(C(N(CCO)C)=O)SC=12.[Si](Cl)(C(C)(C)C)(C)C.CCN(CC)CC.[Cl:33][C:34]1[CH:39]=[CH:38][N:37]=[C:36]2[CH:40]=[C:41]([C:43]([N:45]3[CH2:49]CC[C@H:46]3[CH2:50][O:51][Si:52]([C:55]([CH3:58])([CH3:57])[CH3:56])([CH3:54])[CH3:53])=[O:44])[S:42][C:35]=12>>[Si:52]([O:51][CH2:50][CH2:46][N:45]([CH3:49])[C:43]([C:41]1[S:42][C:35]2[C:36](=[N:37][CH:38]=[CH:39][C:34]=2[Cl:33])[CH:40]=1)=[O:44])([C:55]([CH3:58])([CH3:57])[CH3:56])([CH3:54])[CH3:53]
Reactant: CC(C)(C)[Si](C)(C)OC[C@@H]1CCCN1C(=O)c1cc2nccc(Cl)c2s1
Agent: CC(C)(C)[Si](C)(C)Cl
Agent: CN(CCO)C(=O)c1cc2nccc(Cl)c2s1
Solvent: CCN(CC)CC
Product: CN(CCO[Si](C)(C)C(C)(C)C)C(=O)c1cc2nccc(Cl)c2s1
Yield: 78 %

Procedure:
This material was prepared from 7-chloro-N-(2-hydroxyethyl)-N-methylthieno[3,2-b]pyridine-2-carboxamide 31a (1.27 g, 4.68 mmole), t-butyldimethylsilyl chloride (0.705 g, 4.68 mmole) and Et3N (0.718 ml, 4.68 mmole) in a manner as previously described for 3b to give an orange oil (1.40 g, 78%). 1H NMR (300 MHz, CDCl3) ε 8.61 (1H, d, J=5.1 Hz), 7.74 (1H, s), 7.32 (1H, d, J=5.1 Hz), 3.89 (2H, m), 3.71 (2H, m), 3.37 (3H, s), 0.89 (9H, m), 0.07 (6H, m); ESIMS (MH+): 385.10.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1/[C:8](=[N:19]/[OH:20])/[C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([CH3:17])[C:10]=1[OH:18].[C:21](OC(=O)C)(=[O:23])[CH3:22]>>[C:21]([O:20]/[N:19]=[C:8](/[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[F:1])\[C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([CH3:17])[C:10]=1[OH:18])(=[O:23])[CH3:22]
Reactant: COc1ccc(/C(=N\O)c2ccccc2F)c(O)c1C
Reactant: CC(=O)OC(C)=O
Product: COc1ccc(/C(=N\OC(C)=O)c2ccccc2F)c(O)c1C

Procedure:
E-2'-fluoro-2-hydroxy-4-methoxy-3-methylbenzophenone oxime (20.0 g) is warmed on a steam bath for one hour with 12 ml of acetic anhydride. The acetic anhydride is evaporated in vacuo and the product is distributed between ether and H2O, then the ether is washed with 10% NaHCO3. Evaporation and trituration of the crystalline product with hexane gives E-2'-fluoro-2-hydroxy-4-methoxy-3-methylbenzophenone O-acetyl oxime, mp 83°-86° C.
Reaction SMILES: [NH:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C@H:2]([C:4]([OH:6])=O)[CH3:3].CN1CCOCC1.Cl.[NH2:22][C@H:23]([C:25]([O:27][CH3:28])=[O:26])[CH3:24].CN(C=O)C>C1COCC1>[NH:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C@H:2]([C:4]([NH:22][C@H:23]([C:25]([O:27][CH3:28])=[O:26])[CH3:24])=[O:6])[CH3:3]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: COC(=O)[C@H](C)N
Agent: Cl
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)OC(C)(C)C
Temperature: 25 °C

Procedure:
To a cold (−15° C.) solution of Boc-Ala-OH (1.034 g, 5.47 mmol) and NMM (901 μl, 8.20 mmol) in THF (15 mL) was added ECF (538 μl, 5.63 mmol) under N2 atmosphere and vigorously stirred. After 2 min of stirring, a solution of methyl alaninate hydrochloride (840 mg, 6.01 mmol) in a mixture of solvents THF:DMF (4 mL:3 mL) was added to the reaction mixture followed by NMM (1.5 mL, 13.67 mmol) and stirred. After 10 min the mixture was warmed to 25° C. and stirred for further 8 h. THF was removed under reduced pressure and the resulting viscous solution was diluted with water (10 mL) and thoroughly extracted with ethyl acetate. The combined organic extracts were washed with saturated citric acid (10 mL), saturated NaHCO3 (10 mL) and dried over by Na2SO4 and concentrated under reduced pressure to give a residue, which was purified by silica gel flash column chromatograph (EtOAc:Hexane—3:17) to give the desired product as a solid (m.p. 107-108° C.) in good yields (1.48 g, 98.6%). (TLC:EtOAc:Hexanes 7:3—Rf—0.55).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:27])[C:15]2[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=2)[CH2:10][CH:9]1[C:28]([OH:30])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].O[N:32]1[C:36](=O)CC[C:33]1=O.C1(N=C=NC2CCCCC2)CCCCC1.Cl.CNC>O1CCOCC1.C(N(CC)CC)C>[CH3:33][N:32]([CH3:36])[C:28]([CH:9]1[CH2:10][N:11]([C:14](=[O:27])[C:15]2[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=2)[CH2:12][CH2:13][N:8]1[C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:7])=[O:30]
Reactant: COc1cc(C(=O)N2CCN(C(=O)OC(C)(C)C)C(C(=O)O)C2)cc(OC)c1OC
Reactant: O=C1CCC(=O)N1O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CNC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: COc1cc(C(=O)N2CCN(C(=O)OC(C)(C)C)C(C(=O)N(C)C)C2)cc(OC)c1OC
Reaction time: 5 h
Yield: 65.8 %

Procedure:
To a mixture of 1-tert-butoxycarbonyl-4-(3,4,5-trimethoxybenzoyl)piperazine-2-carboxylic acid (3.0 g), N-hydroxysuccinimide (1.2 g) and dioxane (30 ml) is added, at room temperature, dicyclohexyl carbodiimide (2.6 g). The mixture is stirred for 5 hours. To a mixture of dimethylamine hydrochloride (8.0 g), triethylamine (10.0g) and dioxane (30 ml) is added dropwise at 0° C the solution of active ester prepared above. The reaction mixture is concentrated, and the concentrate is dissolved in dichloromethane. The solution is washed with a 5% aqueous solution of citric acid and a saturated aqueous solution of sodium hydrogencarbonate, which is then dried and further concentrated. The crude product is subjected to a silica gel column chromatography (ethyl acetate-methanol=9:1) to afford N,N-dimethyl 1-tert-butoxycarbonyl-4-(3,4,5-trimethoxybenzoyl)piperazine-2carboxamide (2.1 g) as colorless crystals, m.p. 146-147° C.
Reaction SMILES: COC(=O)[CH:4]([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][C:7]=1[C:14](OC)=[O:15])Br.COC(=O)C(C1C=CC(Cl)=CC=1C(OC)=O)Br.[Cl:36][C:37]1[CH:38]=[CH:39][C:40]([OH:45])=[C:41]([CH:44]=1)[C:42]#[N:43].OC1C=CC=CC=1C#N>>[OH:15][C:14]1[C:7]2[C:6](=[CH:11][CH:10]=[C:9]([O:12][CH3:13])[CH:8]=2)[C:4]2[O:45][C:40]3[CH:39]=[CH:38][C:37]([Cl:36])=[CH:44][C:41]=3[C:42]=2[N:43]=1
Reactant: COC(=O)c1cc(OC)ccc1C(Br)C(=O)OC
Reactant: N#Cc1cc(Cl)ccc1O
Agent: COC(=O)c1cc(Cl)ccc1C(Br)C(=O)OC
Agent: N#Cc1ccccc1O
Product: COc1ccc2c(c1)c(O)nc1c3cc(Cl)ccc3oc21

Procedure:
The procedure was similar to step S19B, while the starting material was 28A in stead of 19A, and used 5-chloro-2-hydroxy-benzonitrile in stead of 2-hydroxy-benzonitrile.
Reaction SMILES: [C:1]([N@:4]1[CH2:6][CH:5]1[C:7]([O:9][CH3:10])=[O:8])(=[O:3])[CH3:2].[CH2:11]([OH:14])[C:12]#[CH:13].B(F)(F)F.CCOCC>>[C:1]([NH:4][C@@H:5]([CH2:6][O:14][CH2:11][C:12]#[CH:13])[C:7]([O:9][CH3:10])=[O:8])(=[O:3])[CH3:2]
Reactant: COC(=O)C1CN1C(C)=O
Reactant: C#CCO
Agent: FB(F)F
Solvent: CCOCC
Product: C#CCOC[C@H](NC(C)=O)C(=O)OC
Yield: 63.2 %

Procedure:
Using (S)-methyl 1-acetylaziridine-2-carboxylate (1.50 g, 10.49 mmol), propargyl alcohol (0.92 mL, 15.74 mmol) and BF3.Et2O (1.39 mL, 11.01 mmol), and the preceding procedure gave 1.32 g (63%) of desired product as a white solid: mp 59-59.5° C.; [α]25D +65.3° (c 1, CHCl3); Rf=0.35 (3/1 EtOAc/hexanes); IR (nujol mull) 3296, 2924, 2116, 1740, 1641, 1543, 1457 cm−1; 1H NMR (CDCl3) δ 2.06 (s, CH3C(O)), 2.46 (t, J=2.4 Hz, CH2CCH), 3.78 (s, OCH3), 3.79 (dd, J=3.2, 9.4 Hz, CHH′OCH2), 3.98 (dd, J=3.0, 9.4 Hz, CHH′OCH2), 4.12 (½HH′q, J=2.4, 16.2 Hz, OCHH′C), 4.18 (½HH′q, J=2.4, 16.2 Hz, OCHH′C), 4.77-4.82 (m, CH), 6.32-6.34 (br d, J=7.2, NHCH); 13C NMR (CDCl3) δ 23.3 (CH3C(O)), 52.6 (CH), 52.8 (OCH3), 58.7 (CH2CCH), 69.6 (CH2OCH2), 75.3 (CH2CCH), 79.0 (CH2CCH), 170.1, 170.7 (2 C(O)); HRMS (ESI) 200.0917 [M+H+] (calcd. for C9H14NO4 200.0923); Anal. (C9H13NO4) Calcd.: C, 54.26%; H, 6.58%; N, 7.03%. Found: C, 54.05%; H, 6.55%; N, 6.95%.
Reaction SMILES: [Cl:1][C:2]1[C:9]([OH:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[NH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1.[BH4-].[Na+]>C(O)C>[Cl:1][C:2]1[C:9]([OH:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][N:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: O=Cc1cccc(O)c1Cl
Reactant: C1CCNCC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: Oc1cccc(CN2CCCCC2)c1Cl

Procedure:
In a similar manner to that described in Example 17 2-chloro-3-hydroxybenzaldehyde (9 g) in absolute ethanol (60 ml) was treated with piperidine (11.7 ml) and sodium borohydride (2.2 g) to yield N-(2-chloro-3-hydroxybenzyl)piperidine. The piperidine thus prepared was reacted with 4-bromobutyronitrile to give 4-(2-chloro-3-piperidinomethylphenoxy)butyronitrile.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]([CH2:25][C:26]2[CH:27]=[N:28][NH:29][CH:30]=2)[C:11]([CH:13]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([O:23][CH3:24])[CH:21]=3)[CH2:16][CH2:15][CH2:14]2)=[O:12])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[CH2:31](I)[CH2:32][CH3:33]>>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]([N:10]([CH2:25][C:26]2[CH:27]=[N:28][N:29]([CH2:31][CH2:32][CH3:33])[CH:30]=2)[C:11]([CH:13]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([O:23][CH3:24])[CH:21]=3)[CH2:16][CH2:15][CH2:14]2)=[O:12])=[CH:8][CH:9]=1)([CH3:3])[CH3:2]
Reactant: CCCI
Reactant: COc1ccc2c(c1)C(C(=O)N(Cc1cn[nH]c1)c1ccc(C(C)C)cc1)CCC2
Product: CCCn1cc(CN(C(=O)C2CCCc3ccc(OC)cc32)c2ccc(C(C)C)cc2)cn1

Procedure:
By the reaction and treatment in the same manner as in Example 83 using N-(4-isopropylphenyl)-7-methoxy-N-[(pyrazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.44 g) and propyl iodide (0.01 mL) as starting materials, N-(4-isopropylphenyl)-N-[(1-propylpyrazol-4-yl)methyl]-7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.31 g) was obtained.
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][CH:8]([C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[C:17]([F:22])[CH:16]=1)[C:9](=[O:14])N(OC)C)([CH3:4])([CH3:3])[CH3:2].[I:24][C:25]1[CH:30]=[CH:29][C:28](I)=[CH:27][CH:26]=1>>[C:1]([O:5][C:6](=[O:23])[NH:7][CH:8]([C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[C:17]([F:22])[CH:16]=1)[C:9]([C:28]1[CH:29]=[CH:30][C:25]([I:24])=[CH:26][CH:27]=1)=[O:14])([CH3:2])([CH3:3])[CH3:4]
Reactant: Ic1ccc(I)cc1
Reactant: CON(C)C(=O)C(NC(=O)OC(C)(C)C)c1ccc(C)c(F)c1
Product: Cc1ccc(C(NC(=O)OC(C)(C)C)C(=O)c2ccc(I)cc2)cc1F

Procedure:
The title compound was prepared from rac-[(3-fluoro-4-methyl-phenyl)-(methoxy-methyl-carbamoyl)-methyl]-carbamic acid tert-butyl ester (Intermediate 7) and 1,4-di-iodobenzene in analogy to Example 1a): MS (ISP): 470.0 (M+H)+.
Reaction SMILES: Cl[C:2]1[NH:17][C:5]2=[N:6][CH:7]=[C:8]([C:10]3[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=3)[CH:9]=[C:4]2[CH:3]=1.CCN(CC)CC.CO>C1COCC1.[Pd]>[F:16][C:12]1[CH:11]=[C:10]([C:8]2[CH:9]=[C:4]3[CH:3]=[CH:2][NH:17][C:5]3=[N:6][CH:7]=2)[CH:15]=[CH:14][CH:13]=1
Reactant: Fc1cccc(-c2cnc3[nH]c(Cl)cc3c2)c1
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CO
Product: Fc1cccc(-c2cnc3[nH]ccc3c2)c1
Reaction time: 3 h
Yield: 115.7 %

Procedure:
A mixture of chloride 6 (5.23 g, 21.3 mmol), 10% Pd/C (2.7 g), Et3N (3.6 mL, 25.8 mmol) in THF:MeOH=5:1 (180 mL) was stirred under H2 overnight. More 10% Pd/C (1.3 g) was added and stirring was continued for 3 h. Catalyst was removed by filtration and the solution was concentrated to dryness in vacuum. The residue was purified by SGC with CH2Cl2:AcOEt as eluent in gradient (up to 20% AcOEt) to afford 7 (5.23 g, 88%), greenish powder. 1H NMR (400 MHz, CDCl3) δ 6.59 (dd, J=3.5, 2.0 Hz, 1H), 7.04-7.10 (m, 1H), 7.33-7.37 (m, 1H), 7.40-7.48 (m, 3H), 8.14 (d, J=2.1 Hz, 1H), 8.57 (d, J=2.1 Hz, 1H), 9.91 (bs, 1H).
Reaction SMILES: COC1C=C(C=C(OC)C=1OC)C=O.[CH3:15][O:16][C:17]1[CH:18]=[C:19]([CH:21]=[C:22]([O:26][CH3:27])[C:23]=1[O:24][CH3:25])[NH2:20].[CH:28]([C:30]1[CH:31]=[CH:32][C:33]2[O:37][C:36]([C:38]([O:40][CH2:41][CH3:42])=[O:39])=[CH:35][C:34]=2[CH:43]=1)=O>>[CH2:41]([O:40][C:38]([C:36]1[O:37][C:33]2[CH:32]=[CH:31][C:30]([CH2:28][NH:20][C:19]3[CH:21]=[C:22]([O:26][CH3:27])[C:23]([O:24][CH3:25])=[C:17]([O:16][CH3:15])[CH:18]=3)=[CH:43][C:34]=2[CH:35]=1)=[O:39])[CH3:42]
Reactant: COc1cc(N)cc(OC)c1OC
Reactant: CCOC(=O)c1cc2cc(C=O)ccc2o1
Agent: COc1cc(C=O)cc(OC)c1OC
Product: CCOC(=O)c1cc2cc(CNc3cc(OC)c(OC)c(OC)c3)ccc2o1
Yield: 99 %

Procedure:
Following the same procedure as described in Example 4, Step 2, but substituting compound 20 and 3,4,5-trimethoxybenzaldehyde for 3,4,5-trimethoxyaniline and compound 27, the title compound was obtained in 99% yield. 1H NMR: (DMSO) δ (ppm): 7.75 (d, J=1.0 Hz, 1H), 7.73 (d, J=1.0 Hz, 1H), 7.66 (d, J=8.6 Hz, 1H), 7.51 (dd, J=8.6, 1.8 Hz, 1H), 6.11 (t, J=6.1 Hz, 1H), 5.89 (s, 2H), 4.37-4.32 (m, 4H), 3.63 (s, 6H), 3.49 (s, 3H), 1.33 (t, J=7.0, 3H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:12][C:13]2[CH:17]=[CH:16][NH:15][N:14]=2)[N:3]=1.[CH:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][C:19]=1B(O)O>>[CH:26]1[C:27]2[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:23]=[CH:24][C:25]=1[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:12][C:13]2[CH:17]=[CH:16][NH:15][N:14]=2)[N:3]=1
Reactant: Clc1nc(Nc2cc[nH]n2)cc2ccccc12
Reactant: OB(O)c1ccc2ccccc2c1
Product: c1ccc2cc(-c3nc(Nc4cc[nH]n4)cc4ccccc34)ccc2c1

Procedure:
Similar procedure as described in example 131 was used, starting from (1-chloro-isoquinolin-3-yl)-(1H-pyrazol-3-yl)-amine and 2-naphthaleneboronic acid to give (1-naphthalen-2-yl-isoquinolin-3-yl)-(1H-pyrazol-3-yl)-amine. LC-MS m/e 337(MH+).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:12])=[CH:4][C:5]([OH:11])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1.S(=O)(=O)(O)O.[Br:18]N1C(=O)CCC1=O>O.ClCCl.CC(O)=O>[Br:18][C:4]1[C:5]([OH:11])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=[C:2]([Cl:1])[C:3]=1[F:12]
Reactant: CC(=O)c1cc(Cl)c(F)cc1O
Reactant: O=C1CCC(=O)N1Br
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: O
Solvent: ClCCl
Product: CC(=O)c1cc(Cl)c(F)c(Br)c1O
Temperature: 60 °C
Yield: 80.7 %

Procedure:
1-(5-Chloro-4-fluoro-2-hydroxyphenyl)ethanone (e.g., from Example 13, step 1) (20.0 g, 101 mmol, 1.00 eq) and a 50% aqueous sulfuric acid (120 mL) were added to the flask. The resulting mixture was heated to 60° C. in a water bath with stirring. N-Bromosuccinimide (21.52 g, 120.9 mmol, 1.20 eq) was added in three portions [7.0 g+7.0 g+7.52 g] in 8 minute intervals. After the reaction mixture was heated at 60° C. for 3 hours, the reaction was complete. The reaction mixture was diluted with water (160 ml) and dichloromethane (DCM) (300 ml), and the mixture was stirred for 0.5 hour. The organic layer was separated and the aqueous layer was extracted with dichloromethane (100 ml). The combined organic layers were washed with 1 N HCl (100 ml×2), water (100 ml), brine (60 ml), and concentrated under reduced pressure to afford the crude product (29.1 g) as a yellowish solid. The crude product was dissolved in HOAc (100 ml) and then diluted with water (200 ml) under stirring. The resulting mixture was stirred for 20 min at room temperature and the product was collected by filtration and dried to give 1-(3-bromo-5-chloro-4-fluoro-2-hydroxyphenyl)ethanone (21.8 g, 80.9%) as a yellowish solid. 1H-NMR (300 MHz, CDCl3) δ 13.18 (s, 1H, —OH), 7.78 (d, J=7.78 Hz, 1 H), 2.63 (s, 3 H).
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH:4]1[O:24][C@:23]2([C:25]([CH2:27][OH:28])=[O:26])[C@@H:6]([CH2:7][C@@H:8]3[C@:22]2([CH3:29])[CH2:21][C@H:20]([OH:30])[C@H:19]2[C@H:9]3[CH2:10][CH2:11][C:12]3[C@:18]2([CH3:31])[CH:17]=[CH:16][C:14](=[O:15])[CH:13]=3)[O:5]1.Cl[C:33]([O:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45])=[O:34].CCN(CC)CC.O>C(Cl)Cl>[CH3:1][CH2:2][CH2:3][CH:4]1[O:24][C@:23]2([C:25]([CH2:27][OH:28])=[O:26])[C@@H:6]([CH2:7][C@@H:8]3[C@:22]2([CH3:29])[CH2:21][C@H:20]([OH:30])[C@H:19]2[C@H:9]3[CH2:10][CH2:11][C:12]3[C@:18]2([CH3:31])[CH:17]=[CH:16][C:14](=[O:15])[CH:13]=3)[O:5]1.[CH2:36]([O:35][C:33](=[O:5])[O-:34])[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45]
Reactant: CCCCCCCCCCOC(=O)Cl
Agent: CCCC1O[C@@H]2C[C@H]3[C@@H]4CCC5=CC(=O)C=C[C@]5(C)[C@H]4[C@@H](O)C[C@]3(C)[C@]2(C(=O)CO)O1
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CCCCCCCCCCOC(=O)[O-]
Temperature: 25 °C

Procedure:
To the solution of budesonide (431 mg, 1.0 mmol) in DCM (4.5 mL) was added decyl chloroformate (460 μL, 2.0 mmol) and Et3N (512 μL, 3.7 mmol) at room temperature. After the reaction mixture was stirred at room temperature over night, it was poured into water (20 mL) and DCM (10 mL); the aqueous phase was extracted with DCM (10 mL). The combined organic phases were washed with water (10 mL) and brine (10 mL), dried over Na2SO4, filtered, and concentrated in vacuo to provide crude budesonide decylcarbonate. The product was purified by chromatography, eluted with Hexane: AcOEt=9:1 to 3:1 to provide 348 mg of 1:1 mixture of epimers (originated from budesonide) (99.22 area % purity on HPLC). 1H NMR (CDCl3) δ 0.85-2.24 (m, 42H), 2.36 (dd, 1H, 13.4 and 2.9 Hz), 2.59 (dt, 1H, 13.5 and 4.5 Hz), 4.18 (t, 1H, 6.7 Hz), 4.51 (s, 1H), 4.6-5.2 (m, 5H), 6.03 (s, 1H), 6.30 (d, 1H, 10.1 Hz), 7.49 (d, 1H, 10.1 Hz). 13C NMR (CDCl3) δ 14.14, 14.17, 14.31, 17.06, 17.24, 17.36, 17.68, 21.19, 22.83, 25.78, 28.76, 29.37, 29.40, 29.66, 30.52, 31.16, 32.04, 33.05, 33.56, 34.22, 35.16, 37.25, 40.58, 40.89, 44.38, 46.06, 47.49, 49.98, 53.05, 55.38, 55.48, 68.90, 68.94, 69.65, 69.75, 69.92, 70.01, 82.05, 83.34, 97.69, 98.56, 104.65, 108.47, 122.51, 127.84, 155.04, 156.96, 170.61, 170.71, 186.84, 186.89, 202.08 and 203.37. Mass spectrum (m/e) 615 (M+).
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1Br)([CH3:4])([CH3:3])[CH3:2].[C:17]([O:21][CH3:22])(=[O:20])[CH:18]=[CH2:19]>CN(C=O)C.CCOC(C)=O>[CH3:22][O:21][C:17](=[O:20])[CH:18]=[CH:19][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[CH2:8][NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:16]
Reactant: C=CC(=O)OC
Reactant: CC(C)(C)OC(=O)NCc1ccccc1Br
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)C=Cc1ccccc1CNC(=O)OC(C)(C)C
Temperature: 80 °C

Procedure:
To compound of Step A (161.0 g, 561.8 mmol) in DMF (800 mL) was added methyl acrylate (58.0 g, 674.2 mmol), TEA (170.5 g, 1685.4 mmol) and dichlorobis(triphenylphosphine) palladium(II) (7.9 g, 11.2 mmol). The mixture was heated at 80° C. for about 32 hours. The mixture was cooled, diluted with 1000 mL of EtOAc and washed with 10% aqueous sodium bisulfate. The aqueous portion was extracted three times with EtOAc and the combined organics were dried (Na2SO4) and concentrated to dryness. The residue was dissolved in a small amount of DCM and filtered through 7 inches of silica gel in a 2 L sintered glass funnel eluting with 25% EtOAc/hexanes. The eluent was concentrated to dryness and recrystallized from EtOAc/hexanes to afford about 116.9 g (71%) of Step B compound.
Reaction SMILES: [Br:1]Br.[CH2:3]([O:5][C:6](=[O:12])[CH2:7][CH2:8][C:9]([CH3:11])=[O:10])[CH3:4].N#N>CCO>[CH2:3]([O:5][C:6](=[O:12])[CH2:7][CH2:8][C:9](=[O:10])[CH2:11][Br:1])[CH3:4]
Reactant: CCOC(=O)CCC(C)=O
Reactant: BrBr
Agent: N#N
Solvent: CCO
Product: CCOC(=O)CCC(=O)CBr
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Bromine (22 g, 7.2 mL, 138.8 mmol) was added to a solution of ethyllevulinate (20 g, 138.8 mmol) in 250 mL EtOH at room temperature under a flow of N2 for a period of 0.5 h. After the addition was complete, the reaction mixture was stirred at room temperature for another 0.5 h, and then refluxed for 1.5 h. The reaction mixture was cooled to room temperature and concentrated in vacuo. The residue was taken into ether, washed with saturated aqueous NaHCO3 (3×50 mL), water, brine, dried (MgSO4) and concentrated to give 20.3 g of K-13 as a dark brown oil. This was used without purification for next step. 1H NMR.