Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][N:12]([C:14]([N:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[O:15])[CH2:11][CH:10]([C:22]([OH:24])=O)[CH2:9]2)=[CH:4][C:3]=1[C:25]([F:28])([F:27])[F:26].O[N:30]=[C:31]([NH2:37])[CH2:32][S:33]([CH3:36])(=[O:35])=[O:34]>>[CH3:36][S:33]([CH2:32][C:31]1[N:37]=[C:22]([CH:10]2[CH2:9][CH:8]([C:5]3[CH:6]=[CH:7][C:2]([CH3:1])=[C:3]([C:25]([F:28])([F:27])[F:26])[CH:4]=3)[CH2:13][N:12]([C:14]([N:16]3[CH2:17][CH2:18][O:19][CH2:20][CH2:21]3)=[O:15])[CH2:11]2)[O:24][N:30]=1)(=[O:35])=[O:34]
Reactant: Cc1ccc(C2CC(C(=O)O)CN(C(=O)N3CCOCC3)C2)cc1C(F)(F)F
Reactant: CS(=O)(=O)CC(N)=NO
Product: Cc1ccc(C2CC(c3nc(CS(C)(=O)=O)no3)CN(C(=O)N3CCOCC3)C2)cc1C(F)(F)F

Procedure:
100 mg (0.23 mmol) of the compound from Example 160A and 53 mg (0.35 mmol) of N′-hydroxy-2-(methylsulphonyl)ethanimidamide were reacted according to the General Method 2. Yield: 65 mg (54% of theory)
Reaction SMILES: C(OC(C)C)(=O)C.[C:8]([O:12][C:13]([NH:15][CH:16]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH:17]([OH:20])[CH2:18][Cl:19])=[O:14])([CH3:11])([CH3:10])[CH3:9]>>[C:8]([O:12][C:13]([NH:15][C@@H:16]([CH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[C@H:17]([OH:20])[CH2:18][Cl:19])=[O:14])([CH3:11])([CH3:9])[CH3:10]
Reactant: CC(C)(C)OC(=O)NC(Cc1ccccc1)C(O)CCl
Solvent: CC(=O)OC(C)C
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@H](O)CCl

Procedure:
The thus-obtained isopropyl acetate solution was analyzed by HPLC, and it was identified that 3-tert-butoxycarbonylamino-1-chloro-2-hydroxy-4-phenylbutane (0.57 g) was obtained in a yield of 83%. A ratio of the desired product (2S,3S) and its isomer (2R,3S) formed was (2S,3S):(2R,3S)=83.2:16.8.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[CH2:11][O:10][CH2:9][CH:8]([C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=3)[C:6]=2[N:7]=1.[CH3:20][NH:21][CH3:22]>>[Cl:1][C:2]1[N:3]=[C:4]([N:21]([CH3:22])[CH3:20])[C:5]2[CH2:11][O:10][CH2:9][CH:8]([C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=3)[C:6]=2[N:7]=1
Reactant: Clc1ccc(C2COCc3c(Cl)nc(Cl)nc32)cc1
Reactant: CNC
Product: CN(C)c1nc(Cl)nc2c1COCC2c1ccc(Cl)cc1
Yield: 77.9 %

Procedure:
2,4-dichloro-8-(4-chlorophenyl)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidine (Preparation K) (500 mg, 1.584 mmol) and Dimethylamine (2.0 M in THF) (1.188 mL, 2.377 mmol) were combined an purified as per Preparation Ha to give 2-chloro-8-(4-chlorophenyl)-N,N-dimethyl-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-4-amine (400 mg, 1.234 mmol, 78% yield) as a white solid. LC-MS (M+H)+=324.0. 1H NMR (500 MHz, CDCl3) δ ppm 7.20-7.31 (2 H, m), 7.04-7.15 (2 H, m), 4.70-4.89 (2 H, m), 4.17 (1 H, dd, J=11.60, 5.49 Hz), 4.05 (1 H, t, J=5.49 Hz), 3.87 (1 H, dd, J=11.60, 5.49 Hz), 3.05-3.19 (6 H, m).
Reaction SMILES: [CH:1]1([C:7](=[NH:17])[NH:8][CH2:9][C:10](OC(C)(C)C)=[O:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:18][CH2:19]CCl>FC(F)(F)C(O)=O>[Cl:18][C:19]1[N:17]=[C:7]([CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[NH:8][C:9]=1[CH:10]=[O:11]
Reactant: CC(C)(C)OC(=O)CNC(=N)C1CCCCC1
Reactant: ClCCCl
Solvent: O=C(O)C(F)(F)F
Product: O=Cc1[nH]c(C2CCCCC2)nc1Cl
Temperature: 25 °C
Reaction time: 24 h

Procedure:
tert-Butyl N-[cyclohexyl(imino)methyl]glycinate (830 mg) was dissolved in a solution (10%, 15 ml) of trifluoroacetic acid in 1,2-dichloroethane and the mixture was stirred at room temperature for 1 day. The reaction mixture was concentrated under reduced pressure. The residue was suspended in toluene, phosphorus oxychloride (3.21 ml) was added and the mixture was stirred at 80° C. for 30 min. DMF (2.67 ml) was added and the mixture was stirred at 100° C. for 5 hr. The reaction mixture was ice-cooled, basified by pouring into an aqueous sodium hydroxide solution, and extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and a fraction eluted with ethyl acetate-hexane (10:90-100:0) was concentrated under reduced pressure to give the object product (495 mg).
Reaction SMILES: [ClH:1].[CH2:2]([O:4][C:5]1[C:6]([CH3:24])=[N:7][C:8]2[C:13]([CH:14]=1)=[C:12]([NH:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)[CH:11]=[CH:10][N:9]=2)[CH3:3].O.[C:26]([OH:30])(=[O:29])[CH:27]=[O:28].FC(F)(F)C(O)=O.Cl>C(=O)(O)[O-].[Na+].O.C(O)(=O)C>[OH2:4].[OH2:28].[ClH:1].[CH2:2]([O:4][C:5]1[C:6]([CH:24]=[CH:27][C:26]([OH:30])=[O:29])=[N:7][C:8]2[C:13]([CH:14]=1)=[C:12]([NH:15][C:16]1[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=1)[CH:11]=[CH:10][N:9]=2)[CH3:3]
Reactant: CCOc1cc2c(Nc3ccc(OC)cc3)ccnc2nc1C
Reactant: O=CC(=O)O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CC(=O)O
Solvent: O
Product: CCOc1cc2c(Nc3ccc(OC)cc3)ccnc2nc1C=CC(=O)O
Temperature: 95 °C

Procedure:
A mixture of 3-ethoxy-5-(4-methoxyanilino)-2-methyl-1,8-naphthyridine hydrochloride (5.0 g), glyoxylic acid monohydrate (2.2 g) and glacial acetic acid (50 ml) were stirred and treated dropwise with trifluoroacetic acid (12.5 ml). The mixture was stirred and heated at 95° C. for 22 hours and cooled to ambient temperature. The mixture was filtered and the solid obtained was stirred in sodium bicarbonate solution (100 ml) for 15 minutes. The mixture was filtered. The solid obtained was stirred in water (100 ml) and acidified with concentrated hydrochloric acid to pH 1. After stirring for an hour the mixture was filtered to give a solid. The filtrate was evaporated to dryness and the residue triturated with water and filtered. The crops of solid were combined, dissolved in dichloromethane/methanol, dried, filtered and evaporated. The residue was triturated with hot ethyl acetate and hot filtered. The solid obtained was combined with the solid obtained from the acidic mixture above, triturated with hot ethyl acetate and hot filtered. The solid obtained was purified by flash column chromatography on silica using a mixture of ethyl acetate:dichloromethane:methanol, 5:5:1 and then 1:1:1 to give a solid. The solid was triturated with hot ethyl acetate and hot filtered to give 3-[3-ethoxy-5-(4-methoxyanilino)-1,8-naphthyridin-2-yl]acrylic acid hydrochloride dihydrate, m.p. 230°-235° C. (with decomposition).
Reaction SMILES: COC(=O)C1C=CC(C2C=NC(N)=C(C3SC4C=CC=CC=4N=3)C=2)=CC=1.[S:27]1[C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=2[N:29]=[C:28]1[C:36]1[C:37]([NH2:51])=[N:38][CH:39]=[C:40](B2OC(C)(C)C(C)(C)O2)[CH:41]=1.[CH3:52][O:53][C:54]([C:56]1[CH:61]=[C:60](I)[CH:59]=[CH:58][N:57]=1)=[O:55].C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.O.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>[CH3:52][O:53][C:54]([C:56]1[CH:61]=[C:60]([C:40]2[CH:39]=[N:38][C:37]([NH2:51])=[C:36]([C:28]3[S:27][C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=4[N:29]=3)[CH:41]=2)[CH:59]=[CH:58][N:57]=1)=[O:55]
Reactant: COC(=O)c1cc(I)ccn1
Reactant: CC1(C)OB(c2cnc(N)c(-c3nc4ccccc4s3)c2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: COC(=O)c1ccc(-c2cnc(N)c(-c3nc4ccccc4s3)c2)cc1
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)c1cc(-c2cnc(N)c(-c3nc4ccccc4s3)c2)ccn1

Procedure:
Following the procedure for 4-(6-Amino-5-benzothiazol-2-ylpyridin-3-yl)-benzoic acid methyl ester, the title compound was prepared from 3-benzothiazol-2-yl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-2-ylamine (BB8) (1.41 g, 4.0 mmol), 4-iodopyridine-2-carboxylic acid methyl ester (0.85 g, 3.2 mmol), Pd(PPh3)4 (2 mol %) and Cs2CO3 (2.5 g, 7.7 mmol) in dioxane/water (5:1; 18 mL). 1H NMR (CD3OD, 300 MHz): δ=4.01 (s, 3H), 7.38-7.45 (m, 2H), 7.70 (dd, J=7.2, 2.4 Hz, 1H), 7.85 (d, J=6.8 Hz, 1H), 7.95 (d, J=6.8 Hz, 1H), 8.21 (d, J=2.4 Hz, 1H), 8.31 (d, J=2.4 Hz, 1H), 8.44 (d, J=2.4 Hz, 1H), 8.70 (d, J=7.2 Hz, 1H).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][S:5][C:6]=1[C:7]([O:9][CH3:10])=[O:8].N1C=CC=CC=1.[Br:17][C:18]1[C:19]([Cl:29])=[C:20]([CH2:25][C:26](Cl)=[O:27])[C:21]([Cl:24])=[CH:22][CH:23]=1>C(#N)C>[Br:17][C:18]1[C:19]([Cl:29])=[C:20]([CH2:25][C:26]([NH:1][C:2]2[N:3]=[CH:4][S:5][C:6]=2[C:7]([O:9][CH3:10])=[O:8])=[O:27])[C:21]([Cl:24])=[CH:22][CH:23]=1
Reactant: COC(=O)c1scnc1N
Reactant: O=C(Cl)Cc1c(Cl)ccc(Br)c1Cl
Solvent: CC#N
Solvent: c1ccncc1
Product: COC(=O)c1scnc1NC(=O)Cc1c(Cl)ccc(Br)c1Cl
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 74.8 %

Procedure:
2.0 g (12.64 mmol) of methyl 4-amino-1,3-thiazole-5-carboxylate were dissolved in 20 acetonitrile, and 2.05 ml (25.29 mmol) of pyridine were added. After 5 min of stirring at room temperature, a solution of 4.21 g (13.91 mmol) of (3-bromo-2,6-dichlorophenyl)acetyl chloride (obtained from (3-bromo-2,6-dichlorophenyl)acetic acid, see WO9736868) in 10 ml of acetonitrile was added dropwise. The reaction mixture was stirred at RT for 12 h. The precipitate formed was filtered off, washed with water and dried under reduced pressure. The resulting mother liquor was concentrated by evaporation, dissolved in chloroform and chromatographed (ethyl acetate/n-heptane: 20/80 to 80/20). This gives a total of 4.01 g of methyl 4-{[(3-bromo-2,6-dichlorophenyl)acetyl]amino}-1,3-thiazole-5-carboxylate.
Reaction SMILES: O[C@H:2]([CH3:35])[CH2:3][NH:4][C:5]([C:7]1[NH:8][C:9]([C:12]2[CH:17]=[C:16]([O:18][C:19]3[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:21][CH:20]=3)[CH:15]=[C:14]([O:29][C@@H:30]([CH3:34])[CH2:31][O:32][CH3:33])[CH:13]=2)=[CH:10][CH:11]=1)=[O:6].CS(O)(=O)=O.C(N(CC)CC)C.C(=O)([O-])O.[Na+]>O1CCCC1>[CH3:33][O:32][CH2:31][C@H:30]([CH3:34])[O:29][C:14]1[CH:13]=[C:12]([C:9]2[NH:8][C:7]([C:5]3[O:6][C@@H:2]([CH3:35])[CH2:3][N:4]=3)=[CH:11][CH:10]=2)[CH:17]=[C:16]([O:18][C:19]2[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:26])=[O:27])=[CH:21][CH:20]=2)[CH:15]=1
Reactant: COC[C@H](C)Oc1cc(Oc2ccc(S(C)(=O)=O)cc2)cc(-c2ccc(C(=O)NC[C@@H](C)O)[nH]2)c1
Agent: CS(=O)(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC[C@H](C)Oc1cc(Oc2ccc(S(C)(=O)=O)cc2)cc(-c2ccc(C3=NC[C@H](C)O3)[nH]2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 73.9 %

Procedure:
N-[(2R)-2-Hydroxypropyl]-5-{3-[(1S)-2-methoxy-1-methylethoxy]-5-[4-(methylsulfonyl)phenoxy]phenyl}-1H-pyrrole-2-carboxamide (191 mg, 0.380 mmol) synthesized in Example (31a) was dissolved in tetrahydrofuran (10 mL), and anhydrous methanesulfonic acid (100 mg, 0.574 mmol) and triethylamine (0.16 mL, 1.15 mmol) were added, followed by stirring at room temperature for 18 hours under nitrogen atmosphere. A saturated aqueous sodium hydrogencarbonate solution (10 mL) was added, and the solution was separated with ethyl acetate (20 mL). The organic layer was washed with saturated brine, and subsequently dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate/hexane=30%-70%) to afford the desired product (136 mg, yield 74%) as a white solid.
Reaction SMILES: Cl.[C:2]1([CH:9]=[CH:8][CH:7]=[C:5]([OH:6])[CH:4]=1)[OH:3].ClCC#N.[C:14]([O-])(=[O:16])[CH3:15].[K+]>[Cl-].[Zn+2].[Cl-].O.C(O)C.CCOCC>[OH:3][C:2]1[CH:4]=[C:5]2[C:7]([C:14](=[O:16])[CH2:15][O:6]2)=[CH:8][CH:9]=1
Reactant: Oc1cccc(O)c1
Reactant: CC(=O)[O-]
Agent: Cl
Agent: N#CCCl
Agent: [Cl-]
Solvent: O
Solvent: CCOCC
Solvent: CCO
Product: O=C1COc2cc(O)ccc21
Yield: 53.6 %

Procedure:
Hydrogen chloride gas was blown into a mixture of 150 g (1.36 moles) of resorcinol, 800 ml of dry ether, 100 g (1.32 moles) of chloroacetonitrile and 100 g (0.73 mole) of zinc chloride for about 2 hours. Crystals which precipitated were obtained by decantation. The crystals were washed with ether and 1500 ml of water was added. The mixture was refluxed for 1 hour and then cooled. The crystals were collected by filtration. Potassium acetate (130 g; 1.33 moles) and 850 ml of ethanol were added to the crystals, and the mixture was refluxed for 30 minutes. After cooling, 1500 ml of water was added, and the crystals were collected by filtration to give 107 g of the desired product (yield 54%).
Reaction SMILES: Cl[C:2]1[O:3][C:4]2[C:5](=[C:7]([C:19]#[N:20])[C:8]([CH3:18])=[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:10]=2[F:11])[N:6]=1.[CH:21]([N:24](C(C)C)[CH2:25]C)(C)C.CNC>ClCCl>[F:11][C:10]1[C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:8]([CH3:18])[C:7]([C:19]#[N:20])=[C:5]2[C:4]=1[O:3][C:2]([N:24]([CH3:25])[CH3:21])=[N:6]2
Reactant: Cc1c(-c2ccccc2)c(F)c2oc(Cl)nc2c1C#N
Reactant: CCN(C(C)C)C(C)C
Agent: CNC
Solvent: ClCCl
Product: Cc1c(-c2ccccc2)c(F)c2oc(N(C)C)nc2c1C#N
Temperature: 60 °C
Reaction time: 3 h
Yield: 87.1 %

Procedure:
2-Chloro-7-fluoro-5-methyl-6-phenyl-1,3-benzoxazole-4-cabonitrile (I-130) (0.20 g, 0.70 mmol) was dissolved in dichloromethane (7 ml), then diisopropylethylamine (0.15 ml, 0.88 mmol), dimethylamine (2.0 M tetrahydrofuran solution, 0.50 ml, 1.00 mmol) were added. After stirring in a sealed tube at an external temperature of about 60° C. for 3 hours, this was diluted with dichloromethane. After washing with water and drying over anhydrous sodium sulfate, the solvent was evaporated away under reduced pressure, and the resulting residue was purified by silica gel column chromatography (dichloromethane) to obtain a colorless solid (0.18 g, 87%).
Reaction SMILES: [CH3:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH2:5][C:4]=2[CH:3]=1.Cl.[N:16]1[CH:21]=[CH:20][C:19]([CH2:22]Cl)=[CH:18][CH:17]=1.[OH-].[Na+]>C1(C)C=CC=CC=1>[N:16]1[CH:21]=[CH:20][C:19]([CH2:22][C:5]2([CH2:22][C:19]3[CH:20]=[CH:21][N:16]=[CH:17][CH:18]=3)[C:4]3[CH:3]=[C:2]([CH3:1])[CH:14]=[CH:13][C:12]=3[C:11]3[C:6]2=[CH:7][CH:8]=[CH:9][CH:10]=3)=[CH:18][CH:17]=1
Reactant: ClCc1ccncc1
Reactant: Cc1ccc2c(c1)Cc1ccccc1-2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: Cc1ccc2c(c1)C(Cc1ccncc1)(Cc1ccncc1)c1ccccc1-2

Procedure:
The title compound was prepared following the procedure of Example 5 from 0.95 g of 2-methylfluorene, 2.17 g of 4-picolylchloride hydrochloride, 50 mg of cetyl(Bu)3PBr, 30 ml toluene, and 5 ml 50% NaOH by reaction at 50° for 6 hrs. The material was chromatographed to yield 0.2 g product. NMR (CDCl3,200 MHz) δ: 2.47(s,3H), 3.37(s,4H), 6.49(d,J=5.3Hz,4H), 7.03-7.45(arom.H), 8.09(d,4H). HRMS calculated for C26H22N2 : 362.1783 Found: 362.1778
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[CH2:3][O:4][C:5]1([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([OH:24])[CH:19]=2)[C:8]2([CH:15]3[CH2:16][CH:11]4[CH2:12][CH:13]([CH2:17][CH:9]2[CH2:10]4)[CH2:14]3)[O:7][O:6]1.N1C=CC=CC=1.[C:33](Cl)(=[O:35])[CH3:34]>C(Cl)Cl>[F:26][C:2]([F:1])([F:25])[CH2:3][O:4][C:5]1([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([O:24][C:33](=[O:35])[CH3:34])[CH:19]=2)[C:8]2([CH:15]3[CH2:14][CH:13]4[CH2:12][CH:11]([CH2:10][CH:9]2[CH2:17]4)[CH2:16]3)[O:7][O:6]1
Reactant: CC(=O)Cl
Reactant: Oc1cccc(C2(OCC(F)(F)F)OOC23C2CC4CC(C2)CC3C4)c1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)Oc1cccc(C2(OCC(F)(F)F)OOC23C2CC4CC(C2)CC3C4)c1
Reaction time: 2 h

Procedure:
A solution of dioxetane 3 (78.2 mg) in 15 mL of CH2Cl2 was placed under argon. Dry pyridine (40 μL, 2.3 eq.) was added followed after 5 min by 16.6 μL (1.1 eq.) of acetyl chloride. The reaction was judged complete by TLC after 2 hours, showing a new material which emitted blue-green light when the plate was heated. The volatiles were removed in vacuo leaving a yellow oil which was purified by preparative TLC using CH2Cl2 as eluent. A colorless oil (44 mg) was obtained: 1H NMR (CDCl3) δ 0.98 (m, 1H), 1.29 (m, 1H), 1.46-2.00 (m, 10H), 2.20 (br s, 1H), 2.325 (s, 3H), 3.06 (br s, 1H), 3.624 (dq, 1H), 3.938 (dq, 1H), 7.20 (dd, 1H), 7.28-7.64 (m, 3H).
Reaction SMILES: C(O)(=O)C.[NH:5]1[CH2:8][CH:7]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:6]1.[CH:16]([C:18]1[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][CH:19]=1)=O.C([BH3-])#N.[Na+]>CO>[C:22]([C:21]1[CH:24]=[CH:25][C:18]([CH2:16][N:5]2[CH2:6][CH:7]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:8]2)=[CH:19][CH:20]=1)#[N:23]
Reactant: N#Cc1ccc(C=O)cc1
Reactant: CC(C)(C)OC(=O)C1CNC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)(C)OC(=O)C1CN(Cc2ccc(C#N)cc2)C1
Temperature: 0 °C
Reaction time: 8 h
Yield: 89 %

Procedure:
To a solution of tert-butyl azetidine-3-carboxylate acetic acid salt (92.0 g, 0.423 mol) in methanol (1.0 L) at room temperature was added 4-formylbenzonitrile (50.8 g, 0.381 mol). The reaction mixture was cooled to 0° C., and sodium cyanoborohydride (28.8 g, 0.458 mol) was added portion-wise. The reaction mixture was allowed to warm to room temperature and stirring continued overnight. After the reaction mixture was concentrated under reduced pressure the residue was diluted with 10% aqueous sodium bicarbonate solution and extracted with ethyl acetate. The organic layer was collected, washed with brine, and dried over anhydrous sodium sulfate. Concentration under reduced pressure followed by purification by silica gel chromatography using 20% ethyl acetate in petroleum ether afforded tert-butyl 1-(4-cyanobenzyl)azetidine-3-carboxylate (89%) (After chromatography, Int.1-D contained a small amount of 4-hydroxymethylbenzonitrile. This material was taken forward to the next step without further purification). LC/MS M+1=273.18. 1H NMR (400 MHz, CDCl3) δ ppm 1.46 (s, 9H), 3.22-3.31 (m, 3H), 3.48-3.56 (m, 2H), 3.66 (s, 2H), 7.39 (d, J=8.28 Hz, 2H), and 7.60 (d, J=8.28 Hz, 2H).
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:26])[O:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[C:13]([O:27][CH3:28])[CH:12]=3)=[CH:9][N:8]([CH:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)[C:4]=2[N:5]=[CH:6][N:7]=1.[N:35]1C=CC=CC=1CO>N1C=CC=CC=1>[NH2:1][C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:26])[O:19][CH2:20][C:25]4[CH:24]=[CH:23][CH:22]=[CH:21][N:35]=4)=[C:13]([O:27][CH3:28])[CH:12]=3)=[CH:9][N:8]([CH:29]3[CH2:30][CH2:31][O:32][CH2:33][CH2:34]3)[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: COc1cc(-c2cn(C3CCOCC3)c3ncnc(N)c23)ccc1NC(=O)Oc1ccccc1
Reactant: OCc1ccccn1
Solvent: c1ccncc1
Product: COc1cc(-c2cn(C3CCOCC3)c3ncnc(N)c23)ccc1NC(=O)OCc1ccccn1
Temperature: 100 °C

Procedure:
Phenyl N-[4-(4-amino-7-tetrahydro-2H-4-pyranyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-methoxyphenyl]carbamate (30 mg, 0.065 mmol) was mixed 2-pyridylmethanol (0.05 mL) in pyridine (0.5 mL). The reaction mixture was heated at 100° C. overnight. The solvent was removed and the residue was purified by preparative reverse phase LC/MS to give 2-pyridylmethyl N-[4-(4-amino-7-tetrahydro-2H-4-pyranyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-methoxyphenyl]carbamate (11 mg, 0.023 mmol). The solid was dissolved in ethyl acetate (2 mL) and 1.0N HCl in ether (0.1 mL) was added slowly. The precipitate was collected through filtration under nitrogen to give 2-pyridylmethyl N-[4-(4-amino-7-tetrahydro-2H-4-pyranyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-methoxyphenyl]carbamate hydrochloride (12 mg, 0.023 mmol). 1H NMR (DMSO-d6) δ 1.92(m, 2H), 2.16(m, 2H), 3.55(m, 2H), 3.89(s, 3H), 4.02(m, 2H), 4.91 (m, 1H), 5.23(s, 2H), 7.05(d, J=8.2 Hz, 1H), 7.14 (s, 1H), 7.37(m, 1H), 7.53(d, J=7.8 Hz, 1H), 7.87(m, 3H), 8.42(s, 1H), 8.57(d, J=4.2 Hz, 1H), 8.85(s, 1H). LC/MS MH30 =475.
Reaction SMILES: ClC(Cl)C.C(OC([NH:12][C@@H:13]([CH2:20][CH2:21][CH2:22][CH3:23])[CH:14]([C:16]1[C:17](=[O:19])[CH:18]=1)[OH:15])=O)(C)(C)C.O.[C:25]1([CH3:35])[CH:30]=[CH:29][C:28]([S:31]([OH:34])(=[O:33])=[O:32])=[CH:27][CH:26]=1>>[C:25]1([CH3:35])[CH:26]=[CH:27][C:28]([S:31]([OH:34])(=[O:32])=[O:33])=[CH:29][CH:30]=1.[NH2:12][C@@H:13]([CH2:20][CH2:21][CH2:22][CH3:23])[CH:14]([C:16]1[C:17](=[O:19])[CH:18]=1)[OH:15]
Reactant: CCCC[C@H](NC(=O)OC(C)(C)C)C(O)c1cc1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CC(Cl)Cl
Product: CCCC[C@H](N)C(O)c1cc1=O
Temperature: 25 °C
Reaction time: 5 h
Yield: 131.5 %

Procedure:
To 5 ml of a dichloroethane solution of 150 mg of 2-((2S)-2-tert-butoxycarbonylamino-1-hydroxyhexyl) cyclopropenone obtained in Example 22 was added 106 mg of p-toluene sulfonate monohydrate. After stirring at room temperature for 5 hours, the solvent was distilled off under reduced pressure to give 250 mg of the titled product.
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.[CH2:32]([N:36]=[C:37]=[O:38])[CH2:33][CH2:34][CH3:35].[OH2:39]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[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.[CH2:32]([NH:36][C:37](=[O:38])[O-:39])[CH2:33][CH2:34][CH3:35]
Reactant: CCCCN=C=O
Reactant: O
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
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCCCNC(=O)[O-]
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To the solution of budesonide (500 mg, 1.16 mmol) in DCM (5.0 mL) was added butyl isocyanate (144 μL, 1.28 mmol) and DMAP (312 mg, 2.55 mmol) at room temperature. The reaction mixture was stirred at room temperature for 24 hours. During this 24 hours more butyl isocyanate (72 μL, 0.64 mmol) and DMAP (156 mg, 1.27 mmol). The reaction was followed by HPLC. The reaction mixture 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 butylcarbamate. The product was purified by chromatography, eluted with Hexane: AcOEt=9:1 to 3:1 to provide 560 mg of 1:1 mixture of epimers (originated from budesonide) (99.22 area % purity on HPLC). 1H NMR (CDCl3) δ 0.82-2.7 (m, 30H), 3.06-3.20 (m, 3H), 4.45 (m, 1H), 4.58 (t, 1H, 4.5 Hz), 4.75-5.36 (m, 5H), 5.99 (s, 1H), 6.24 (d, 1H, 10.1 Hz), 7.29 (d, 1H, 10.1 Hz). 13C NMR (CDCl3) δ 13.98, 14.08,14.22, 17.09, 17.30, 17.37, 17.73, 20.09, 20.28, 21.26, 30.56, 31.22, 32.11, 32.59, 33.13, 33.65, 34.27, 35.23, 37.34, 40.30, 40.73, 40.99, 41.17, 44.37, 46,09, 47.49, 50.01, 53.15, 55.43, 55.52, 67.82, 69.82, 69.93, 82.11, 83.37, 97.84, 98.75, 104.66, 108.43, 122.61, 127.97, 155.94, 156.03, 156.79, 170.45, 170.56, 186.95, 203.89 and 205.21.
Reaction SMILES: [F:1][CH2:2][C:3]([CH2:15][F:16])([CH3:14])[C:4]([O:6]CC1C=CC=CC=1)=[O:5]>CCOC(C)=O.[Pd]>[F:1][CH2:2][C:3]([CH2:15][F:16])([CH3:14])[C:4]([OH:6])=[O:5]
Reactant: CC(CF)(CF)C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(CF)(CF)C(=O)O
Reaction time: 12 h
Yield: 88.2 %

Procedure:
To a stirred solution of Intermediate 209A (0.300 g, 1.314 mmol) in EtOAc (5 mL) was added 10% Pd/C (0.140 g, 0.131 mmol). The reaction mixture was stirred for 12 h under an atmosphere of hydrogen (15 psi). The reaction mixture was then filtered through a pad of CELITE® and the cake was washed with EtOAc. The filtrate was concentrated under reduced pressure to afford Intermediate 209B as a yellow liquid (160 mg, 88%). The crude product was used without further purification. 1H NMR (400 MHz, DMSO-d6) δ ppm 13.02 (bs, 1H), 4.40-4.66 (m, 4H), 1.06-1.20 (m, 3H).