Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([CH2:13][N:14]([CH:31]([CH3:33])[CH3:32])[C:15](=[O:30])[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH2:25][CH2:26][CH2:27][O:28][CH3:29])[CH:17]=2)[C@H:10]([C:34](C)(C)[O:35][SiH2]C(C)(C)C)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O.O.O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O.CCOC(C)=O>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([CH2:13][N:14]([CH:31]([CH3:32])[CH3:33])[C:15](=[O:30])[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH2:25][CH2:26][CH2:27][O:28][CH3:29])[CH:17]=2)[C@H:10]([CH2:34][OH:35])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COCCCOc1cc(C(=O)N(C[C@@H]2CN(C(=O)OC(C)(C)C)C[C@H]2C(C)(C)O[SiH2]C(C)(C)C)C(C)C)ccc1OC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COCCCOc1cc(C(=O)N(C[C@@H]2CN(C(=O)OC(C)(C)C)C[C@H]2CO)C(C)C)ccc1OC
Reaction time: 8 h

Procedure:
To a solution of (3S,4R)-3-(tert-butyl-dimethyl-silanyloxymethyl)-4-({isopropyl-[4-methoxy-3-(3-methoxy-propoxy)-benzoyl]-amino}-methyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (8.75 g, 14.37 mmol) in THF (50 mL) is added tetrabutylammonium fluoride trihydrate (6.8 g, 24.55 mmol) under a nitrogen atmosphere. The reaction mixture is stirred overnight. Water and AcOEt are added, the layers are separated and the aqueous one extracted twice with AcOEt. The combined organic extracts are dried (Na2SO4), and the solvent is removed in vacuo. The crude product is purified by flash chromatography on silica gel (eluent: CH2Cl2/MeOH 97:3 to 95:5) to give the title product. TLC, Rf (CH2Cl2/MeOH 95:5)=0.3. MS (LC-MS): 395.1 [M+H-Boc]+; tR (HPLC, Macherey-Nagel Nucleosil C18 column, 10-100% CH3CN/H2O/5 min, 100% CH3CN/3 min, CH3CN and H2O containing 0.1% TFA, flow: 1.5 mL/min): 5.01 min.
Reaction SMILES: [CH3:1][C:2]([CH3:4])=[O:3].[CH3:5][O:6][P:7]([O-:10])[O:8][CH3:9].C[O-].[Na+]>>[OH:3][C:2]([P:7](=[O:10])([O:8][CH3:9])[O:6][CH3:5])([CH3:4])[CH3:1]
Reactant: COP([O-])OC
Reactant: CC(C)=O
Agent: C[O-]
Agent: [Na+]
Product: COP(=O)(OC)C(C)(C)O
Temperature: 25 °C
Reaction time: 16 h
Yield: 59.5 %

Procedure:
Into a flask fitted with a reflux condenser was placed a mixture of 37 ml (29 g, 0.50 mol) of acetone and 46 ml (55 g, 0.50 ml) of dimethylphosphite followed by 3 ml of saturated methanolic sodium methoxide solution. A vigorous exotherm ensued and the mixture was allowed to stir at RT for about 16 h. A large deposit of crystals formed and were filtered and washed well with ether-hexane (1:1) to give 50 g of dimethyl 1-hydroxy-1-methylethylphosphonate, mp 75°-77° C.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH2:13])(=[O:12])=[O:11])=[CH:6][CH:5]=1)([OH:3])=[O:2].Cl.[CH2:15](O)[CH3:16]>>[CH2:15]([O:2][C:1](=[O:3])[C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH2:13])(=[O:12])=[O:11])=[CH:6][CH:5]=1)[CH3:16]
Reactant: NS(=O)(=O)c1ccc(C(=O)O)cc1
Reactant: CCO
Agent: Cl
Product: CCOC(=O)c1ccc(S(N)(=O)=O)cc1

Procedure:
A slurry of 10.0 g (0.05 mole) of p-carboxybenzenesulfonamide in 200 ml of absolute ethanol was treated with 10 g of anhydrous hydrogen chloride and heated at reflux for 5 h to give, after crystallization from ethyl acetate/petroleum ether, 10.6 g (93%) of white powder, mp 102°-104° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.S(=O)(=O)(O)O.C([O-])(O)=O.[Na+].[C:19](OC(=O)C)(=[O:21])[CH3:20]>O>[C:19]([O:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=1)(=[O:21])[CH3:20]
Reactant: CC(=O)OC(C)=O
Reactant: Oc1cccc(Br)c1
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: CC(=O)Oc1cccc(Br)c1
Reaction time: 2 h
Yield: 99 %

Procedure:
To a stirred solution of 3-bromophenol (25 g, 145 mmol) in acetic anhydride (14 ml) was added a few drop of sulfuric acid, and the mixture was stirred for 2 hours. The mixture was poured into a solution of NaHCO3 (1.3 g, 15.5 mmol) in water (160 ml). The whole was extracted with diethylether. The organic layer was washed with saturated NaHCO3 aqueous solution, brine, dried over MgSO4, and concentrated in vacuo. The residue was used for next reaction without purification. (31 g, 99% yield). 1H-NMR (CDCl3) δ: 7.39-7.35 (m, 1H), ?0.29-7.22 (m, 2H), 7.07-7.02 (m, 1H), 2.30 (s, 3H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][N:3]=1.[Br:9][C:10]1[CH:15]=[CH:14][C:13](B(O)O)=[C:12]([F:19])[CH:11]=1>COCCOC.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>[Br:9][C:10]1[CH:15]=[CH:14][C:13]([C:2]2[N:3]=[CH:4][C:5]([OH:8])=[CH:6][CH:7]=2)=[C:12]([F:19])[CH:11]=1
Reactant: OB(O)c1ccc(Br)cc1F
Reactant: Oc1ccc(Br)nc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: COCCOC
Product: Oc1ccc(-c2ccc(Br)cc2F)nc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 10.9 %

Procedure:
A mixture of Pd(PPh3)2Cl2 (0.42 g, 0.57 mmol) and 2-bromo-5-hydroxypyridine (1.0 g, 5.75 mmol) in DME (20 mL) was degassed with N2. 2M Na2CO3 (10 mL) was added, and the mixture was stirred at ambient temperature for 10 minutes. 4-Bromo-2-fluorobenzeneboronic acid (1.48 g, 6.61 mmol) was added. The reaction mixture was degassed again, purged with N2 and heated at 80° C. overnight, then cooled to ambient temperature, and partitioned between water and EtOAc. Concentrated HCl was added carefully to adjust aqueous pH to about 8, the mixture was filtered thought Celite®, and the EtOAc layer was separated and washed with brine, dried over Na2SO4, filtered, and the filtrate was concentrated to give the crude product as a dark brown oil. The crude product was purified by chromatography on a silica gel column eluted with 20% EtOAc/hexane to give 0.168 g of 6-(4-bromo-2-fluorophenyl)-3-pyridinol as an off-white solid. The impure fractions were combined, concentrated and further purified with 1:5 acetone/hexane to give additional 78 mg of 6-(4-bromo-2-fluorophenyl)-3-pyridinol (0.246 g overall, 16% yield). 1H NMR (400 MHz, CD3OD): δ 8.20 (d, 1H, J=2.7 Hz), 7.75-7.65 (m, 1H), 7.62 (dd, 1H, Ja=8.7 Hz, Jb=2.1 Hz), 7.50-7.40 (m, 2H), 7.28 (dd, 1H, Ja=8.5 Hz, Jb=2.9 Hz); LRMS (ESI), m/z 268/270 (M+H).
Reaction SMILES: [O:1]=[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]1[C:8]1[CH:18]=[CH:17][C:11]([C:12]([O:14]CC)=[O:13])=[CH:10][CH:9]=1.[OH-].[Li+]>O1CCCC1.O>[O:1]=[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]1[C:8]1[CH:18]=[CH:17][C:11]([C:12]([OH:14])=[O:13])=[CH:10][CH:9]=1
Reactant: CCOC(=O)c1ccc(-n2ccccc2=O)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1ccc(-n2ccccc2=O)cc1
Temperature: 70 °C
Reaction time: 1 h
Yield: 85 %

Procedure:
A mixture of ethyl 4-(2-oxopyridin-1(2H)-yl)benzoate (0.40 g, 1.64 mmol) and lithium hydroxide (0.28 g, 6.60 mmol) in tetrahydrofuran/water mixture was stirred at 70° C. for 1 h. The organic solvent was removed in vacuo. The water layer was washed with ethyl acetate (25 mL) and then acidified by addition of 15% hydrochloric acid solution. The solid obtained was collected by filtration, washed with water and dried in air to afford the title compound in 85% yield (0.30 g); 1H NMR (300 MHz, DMSO-d6) δ 13.14 (s, 1H), 8.02 (d, J=8.4 Hz, 2H), 7.65 (dd, J=1.9, 6.9 Hz, 1H), 7.51 (d, J=8.5 Hz, 2H), 7.48 (dd, J=1.9, 6.9 Hz, 1H), 6.47 (d, J=9.2 Hz, 1H), 6.31 (dt, J=1.0, 6.9 Hz, 1H).
Reaction SMILES: C([O:3][C:4]([CH:6]1[O:10][C:9]2[CH:11]=[C:12]([CH3:24])[C:13]([S:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)(=[O:17])=[O:16])=[CH:14][C:8]=2[O:7]1)=O)C.[NH3:25]>O1CCOCC1>[C:18]1([S:15]([C:13]2[C:12]([CH3:24])=[CH:11][C:9]3[O:10][CH:6]([C:4]([NH2:25])=[O:3])[O:7][C:8]=3[CH:14]=2)(=[O:17])=[O:16])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: N
Reactant: CCOC(=O)C1Oc2cc(C)c(S(=O)(=O)c3ccccc3)cc2O1
Solvent: C1COCCO1
Product: Cc1cc2c(cc1S(=O)(=O)c1ccccc1)OC(C(N)=O)O2

Procedure:
34.8 g (0.1 mol) of 5-phenylsulphonyl-6-methyl-1,3-benzodioxole-2-carboxylic acid ethyl ester (from Example 2) are dissolved in 350 ml of dioxan (absolute) and treated in a pressure autoclave with approximately 20 g of ammonia gas. The reaction mixture is heated for 10 hours at 80° in the autoclave, the pressure is released, and the solution is concentrated to dryness by evaporation under reduced pressure. The residue is recrystallised from 120 ml of ethanol, yielding colourless crystals of 5-phenylsulphonyl-6-methyl-1,3-benzodioxole-2-carboxylic acid amide having a melting point of 138°-141°.
Reaction SMILES: F[C:2]1[C:3]([N+:14]([O-:16])=[O:15])=[C:4]([N:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.CN(C=O)C.[N-:22]=[N+:23]=[N-:24].[Na+]>CCOC(C)=O>[N:22]([C:6]1[CH:7]=[CH:2][C:3]([N+:14]([O-:16])=[O:15])=[C:4]([N:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)[CH:5]=1)=[N+:23]=[N-:24]
Reactant: [N-]=[N+]=[N-]
Reactant: O=[N+]([O-])c1c(F)cccc1N1CCCCC1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: [N-]=[N+]=Nc1ccc([N+](=O)[O-])c(N2CCCCC2)c1
Reaction time: 6 h
Yield: 74 %

Procedure:
To a solution of 1-(fluoro-2-nitro-phenyl)-piperidine (389 mg, 1.73 mmol, as prepared in the previous step) in 5, mL of DMF was added sodium azide (169 mg, 2.60 mmol) and the resultant mixture heated to 50° C. for 14 h, and then 80° C. for 6 h. The reaction was diluted with EtOAc (100 mL), washed with water (2×50 mL), dried (Na2SO4) and concentrated in vacuo. Purification by preparative TLC (50% EtOAc-hexane) afforded 316 mg (74%) of the title compound as a tan solid. Mass spectrum (ESI, m/z): Calcd. for C11H13N5O2, 248.1 (M+H), found 247.9.
Reaction SMILES: Cl[C:2]1[C:3]([C:8]2[CH:13]=[C:12]([S:14][CH3:15])[N:11]=[CH:10][N:9]=2)=[N:4][CH:5]=[CH:6][N:7]=1.[NH2:16][C:17]1[C:22]([F:23])=[CH:21][N:20]=[C:19]([NH:24][S:25]([CH2:28][CH2:29][CH3:30])(=[O:27])=[O:26])[C:18]=1[F:31].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C([O-])([O-])=O.[Cs+].[Cs+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[F:31][C:18]1[C:19]([NH:24][S:25]([CH2:28][CH2:29][CH3:30])(=[O:27])=[O:26])=[N:20][CH:21]=[C:22]([F:23])[C:17]=1[NH:16][C:2]1[C:3]([C:8]2[CH:13]=[C:12]([S:14][CH3:15])[N:11]=[CH:10][N:9]=2)=[N:4][CH:5]=[CH:6][N:7]=1
Reactant: CCCS(=O)(=O)Nc1ncc(F)c(N)c1F
Reactant: CSc1cc(-c2nccnc2Cl)ncn1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CCCS(=O)(=O)Nc1ncc(F)c(Nc2nccnc2-c2cc(SC)ncn2)c1F
Temperature: 150 °C
Reaction time: 5 h

Procedure:
A stirred mixture of 4-(3-chloropyrazin-2-yl)-6-(methylthio)pyrimidine (143 mg, 0.6 mmol), N-(4-amino-3,5-difluoropyridin-2-yl)propane-1-sulfonamide (100 mg, 0.4 mmol), Pd2(dba)3 (109 mg, 0.12 mmol), Xantphos (138 mg, 0.24 mmol), Cs2CO3 (389 mg, 1.19 mmol), 4 Å molecular sieves (500 mg) and dioxane (15 ml) was heated with stirring in a sealed vessel at 150° C. for 5 h. The reaction mixture was cooled to rt and filtered. The filtrate was concentrated, then the residue was chromatographed on silica gel (10-30% ethyl acetate in hexanes eluant) to provide the title compound. MS m/z 454.1 (M+1).
Reaction SMILES: [OH:1][NH2:2].C([O:5][C:6](=O)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]([C:20]1[CH:25]=[C:24]([O:26][CH2:27][CH2:28][CH3:29])[CH:23]=[CH:22][N:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1)C>CN(C=O)C.CO>[OH:1][NH:2][C:6](=[O:5])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]([C:20]1[CH:25]=[C:24]([O:26][CH2:27][CH2:28][CH3:29])[CH:23]=[CH:22][N:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1
Reactant: CCCOc1ccnc(N(CCCCCCC(=O)OCC)c2ccccn2)c1
Reactant: NO
Solvent: CO
Solvent: CN(C)C=O
Product: CCCOc1ccnc(N(CCCCCCC(=O)NO)c2ccccn2)c1
Reaction time: 22.5 h
Yield: 50 %

Procedure:
HONH2 (50% aqueous, 2 mL) was added to III (16 mg, 0.045 mmol) in DMF (0.5 mL) and MeOH (2 mL) at rt. The reaction mixture was stirred for 22.5 h, after which the solvents were evaporated under reduced pressure. The resulting residue was dissolved and co-evaporated with toluene (2×2 mL) then was purified by silica gel column chromatography eluting with CH2Cl2/MeOH (100:5 to 100:8) to furnish IV as a colourless oil (14 mg, 50%).
Reaction SMILES: [Si]([O:18][CH:19]1[CH2:22][N:21]([C:23]2[S:24][CH:25]=[C:26]([C:28](=[O:46])[NH:29][CH2:30][CH2:31][NH:32][C:33]([O:35][CH2:36][C:37]3[CH:42]=[CH:41][C:40]([N+:43]([O-:45])=[O:44])=[CH:39][CH:38]=3)=[O:34])[N:27]=2)[CH2:20]1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.C(O)(=O)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[OH:18][CH:19]1[CH2:22][N:21]([C:23]2[S:24][CH:25]=[C:26]([C:28](=[O:46])[NH:29][CH2:30][CH2:31][NH:32][C:33]([O:35][CH2:36][C:37]3[CH:42]=[CH:41][C:40]([N+:43]([O-:45])=[O:44])=[CH:39][CH:38]=3)=[O:34])[N:27]=2)[CH2:20]1
Reactant: CC(C)(C)[Si](OC1CN(c2nc(C(=O)NCCNC(=O)OCc3ccc([N+](=O)[O-])cc3)cs2)C1)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: O=C(NCCNC(=O)c1csc(N2CC(O)C2)n1)OCc1ccc([N+](=O)[O-])cc1
Reaction time: 2.5 h
Yield: 86 %

Procedure:
To a solution of 3-t-butyldiphenylsilyloxy-1-{4-[2-(p-nitrobenzyloxycarbonylamino)-ethylcarbamoyl]-1,3-thiazol-2-yl}azetidine (1.21 g, 1.84 mmol) (obtained as described in Reference Example 56(4)) in anhydrous tetrahydrofuran (60.6 ml) were added successively acetic acid (0.13 ml, 2.27 mmol) and a solution of 1.0M tetra-n-butylammonium fluoride in tetrahydrofuran (2.2 ml, 2.2 mmol) in an ice bath. The mixture was stirred for 2.5 hours under the same conditions. After checking the completion of the reaction, the reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate solution. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. To the residue was added isopropyl ether, and the mixture was stirred, washed and filtered off to give 3-hydroxy-1-{4-[2-(p-nitrobenzyloxycarbonylamino)-ethylcarbamoyl]-1,3-thiazol-2-yl}azetidine (667 mg, yield 86%) as a yellow solid.
Reaction SMILES: [C:1]1([CH2:7][NH:8][C:9]([N:11]2[CH2:15][CH2:14][CH2:13][C@H:12]2[C:16]([N:18]2[CH2:22][CH2:21][CH2:20][C@H:19]2[C:23](=[O:33])[CH2:24][O:25]CC2C=CC=CC=2)=[O:17])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>CO.O.C(O)(=O)C.[Pd]>[OH:25][CH2:24][C:23]([C@@H:19]1[CH2:20][CH2:21][CH2:22][N:18]1[C:16]([C@@H:12]1[CH2:13][CH2:14][CH2:15][N:11]1[C:9]([NH:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[O:10])=[O:17])=[O:33]
Reactant: O=C(COCc1ccccc1)[C@@H]1CCCN1C(=O)[C@@H]1CCCN1C(=O)NCc1ccccc1
Agent: [Pd]
Solvent: O
Solvent: CO
Solvent: CC(=O)O
Product: O=C(CO)[C@@H]1CCCN1C(=O)[C@@H]1CCCN1C(=O)NCc1ccccc1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 80.7 %

Procedure:
(S)-N-(Phenylmethyl)-2-[[(S)-2-[(phenylmethyloxy)acetyl]-1-pyrrolidinyl]carbonyl]-1-pyrrolidinecarboxamide (40.0 g) was dissolved in a mixed solvent of methanol (200 ml), water (40 ml) and acetic acid (20 ml). Palladium-black (4.0 g) was added and the mixture was stirred at room temperature under a hydrogen atmosphere for 3.5 hours. The catalyst in the reaction mixture was filtered off and the filtrate was concentrated to give the title compound (25.8 g).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C:9]1[N:14]=[C:13]([C:15]2[CH:16]=[N:17][N:18]([CH3:20])[CH:19]=2)[C:12]2[C:21](=[O:36])[N:22](CC3C=CC(OC)=CC=3OC)[CH:23]([CH3:24])[C:11]=2[C:10]=1[F:37].[C:38]([OH:44])([C:40]([F:43])([F:42])[F:41])=[O:39]>>[NH2:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C:9]1[N:14]=[C:13]([C:15]2[CH:16]=[N:17][N:18]([CH3:20])[CH:19]=2)[C:12]2[C:21](=[O:36])[NH:22][CH:23]([CH3:24])[C:11]=2[C:10]=1[F:37].[C:38]([OH:44])([C:40]([F:43])([F:42])[F:41])=[O:39]
Reactant: COc1ccc(CN2C(=O)c3c(-c4cnn(C)c4)nc(N[C@@H]4CCCC[C@@H]4N)c(F)c3C2C)c(OC)c1
Solvent: O=C(O)C(F)(F)F
Product: CC1NC(=O)c2c(-c3cnn(C)c3)nc(N[C@@H]3CCCC[C@@H]3N)c(F)c21
Temperature: 60 °C

Procedure:
A mixture of 6-((1R,2S)-2-aminocyclohexylamino)-2-(2,4-dimethoxybenzyl)-7-fluoro-1-methyl-4-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[3,4-c]pyridin-3(2H)-one (20 mg, 0.039 mmol) and TFA (1 mL) was heated at 60° C. for 2 h. Following reaction, the mixture was purified by preparative HPLC eluting with water (0.05% TFA) and ACN (15-25% gradient, 0.035% TFA) to give the title compound as a TFA salt (10 mg, 71%). 1H NMR (500 MHz, DMSO-d6) δ ppm 1.41 (d, J=6.59 Hz, 3H), 1.46 (d, J=7.02 Hz, 2H), 1.60-1.84 (m, 5H), 3.68 (br s, 1H), 3.89 (s, 2H), 4.44 (br s, 1H), 4.71 (q, J=6.65 Hz, 1H), 6.52 (br s, 1H), 6.73 (d, J=6.53 Hz, 1H), 7.72 (br s, 2H), 8.24-8.32 (m, 1H), 8.46 (s, 1H), 8.82 (s, 1H). [M+H] calc'd for C18H23FN6O, 359. found, 359.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][C:7](=[O:12])[CH:6]=[C:5]2[OH:13].N1C=CC=CC=1.[C:20]1([CH3:30])[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1>C(Cl)Cl>[Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[O:8][C:7](=[O:12])[CH:6]=[C:5]([O:13][S:26]([C:23]3[CH:24]=[CH:25][C:20]([CH3:30])=[CH:21][CH:22]=3)(=[O:28])=[O:27])[C:4]=2[CH:3]=1
Reactant: O=c1cc(O)c2cc(Cl)ccc2o1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)Oc2cc(=O)oc3ccc(Cl)cc23)cc1
Reaction time: 1 h
Yield: 89.8 %

Procedure:
6-Chloro-4-hydroxycoumarin (25.4 mmol, 5.0 g) is suspended in DCM (50 mL) and pyridine (63.3 mmol, 5.1 mL) is added. The mixture is cooled in an ice bath and p-toluenesulfonyl chloride (26.8 mmol, 5.1 g) is added. The ice bath is removed and the compound slowly dissolves and a solid is deposited (pyridine HCl). After 1 hr the mixture is transferred to a separatory funnel, HCl (2 M) is added, and a solid is formed. The organic layer is removed and the solid-containing aqueous layer is filtered to remove the precipitate. The filtrate is washed with DCM and the combined organic layers are washed with H2O, NaHCO3 (sat.), H2O, and brine. The extract is then dried over MgSO4 and is evaporated. The residue is triturated with Et2O to give the title compound (8.0 g, 90%) as a cream solid. 1H NMR (CDCl3, 400 MHz) δ 7.91 (2H, d, J=8 Hz), 7.54 (1H, d, J=2 Hz), 7.51 (1H, dd, J=2, 9 Hz), 7.42 (2H, d, J=8 Hz), 7.26 (1H, d, J=9 Hz), 6.38 (1H, s), 2.49 (3H, s); LCMS (MeCN—H2O, Luna 3μC18(2) 30×4.6 mm; MS (ESI, Pos.) calcd for C16H11ClO5S m/z [M+H]=351 found [no mass ion detected].
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([C@H:10]([OH:24])[C@@H:11]2[CH2:16][CH2:15][CH2:14][N:13]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:12]2)[CH:7]=[CH:8][CH:9]=1.Br[CH2:26][CH2:27][CH2:28][C:29]#[N:30].[NH4+].[Cl-]>CC#N.C(OCC)(=O)C>[Cl:3][C:4]1[CH:5]=[C:6]([C@H:10]([O:24][CH2:26][CH2:27][CH2:28][C:29]#[N:30])[C@@H:11]2[CH2:16][CH2:15][CH2:14][N:13]([C:17]([O:19][C:20]([CH3:21])([CH3:23])[CH3:22])=[O:18])[CH2:12]2)[CH:7]=[CH:8][CH:9]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]([C@@H](O)c2cccc(Cl)c2)C1
Reactant: N#CCCCBr
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC[C@@H]([C@@H](OCCCC#N)c2cccc(Cl)c2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 23.5 %

Procedure:
To a suspension of NaH (763 mg, 19.1 mmol) and (R)-tert-butyl 3-((R)-(3-chlorophenyl)(hydroxy)methyl)piperidine-1-carboxylate (1.55 g, 4.77 mmol) in CH3CN (20 mL) at 0-5° C. was added dropwise a solution of 4-bromobutyronitrile (3.17 g, 21.5 mmol) in CH3CN (5 mL), the reaction mixture was stirred for overnight at rt. The reaction mixture was poured into saturated aqueous NH4Cl, ethyl acetate (50 mL) was added. The organic layer was washed with water (3×20 mL) and brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by preparative HPLC to afford (R)-tert-butyl 3-((R)-(3-chlorophenyl)(3-cyanopropoxy)methyl)piperidine-1-carboxylate (0.44 g, 21% yield). 1H NMR (CD3OD, 400 MHz) δ 7.38-7.28 (m, 3H), 7.22 (m, 1H), 4.22 (m, 1H), 4.02 (d, 1H), 3.86 (d, 1H), 3.34 (m, 2H), 2.77 (q, 2H), 2.56 (t, 2H), 1.62 (m, 1H), 1.59 (m, 1H), 1.43 (s, 9H), 1.35-1.25 (m, 3H), 1.12 (d, 1H).
Reaction SMILES: [F:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[OH:8].[H-].[Na+].[C:11]([O:15][C:16](=[O:44])[CH2:17][O:18][C:19]1[C:24]([CH3:25])=[CH:23][C:22]([C:26]2[O:27][C:28]3[N:29]=[C:30](S(C)(=O)=O)[N:31]=[C:32]([O:35][CH2:36][CH2:37][CH3:38])[C:33]=3[N:34]=2)=[CH:21][C:20]=1[CH3:43])([CH3:14])([CH3:13])[CH3:12]>CN(C)C=O>[C:11]([O:15][C:16](=[O:44])[CH2:17][O:18][C:19]1[C:24]([CH3:25])=[CH:23][C:22]([C:26]2[O:27][C:28]3[N:29]=[C:30]([O:8][C@@H:3]4[CH2:4][CH2:5][CH2:6][CH2:7][C@H:2]4[F:1])[N:31]=[C:32]([O:35][CH2:36][CH2:37][CH3:38])[C:33]=3[N:34]=2)=[CH:21][C:20]=1[CH3:43])([CH3:12])([CH3:13])[CH3:14]
Reactant: CCCOc1nc(S(C)(=O)=O)nc2oc(-c3cc(C)c(OCC(=O)OC(C)(C)C)c(C)c3)nc12
Reactant: O[C@@H]1CCCC[C@H]1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCOc1nc(O[C@@H]2CCCC[C@H]2F)nc2oc(-c3cc(C)c(OCC(=O)OC(C)(C)C)c(C)c3)nc12
Yield: 93.7 %

Procedure:
26 mg of trans-2-fluoro-cyclohexanol were added under argon atmosphere at 0° C. to a suspension of 10 mg of sodium hydride (60% in mineral oil) in 2 ml of N,N-dimethylformamide. After 15 min a solution of 100 mg of [4-(5-methanesulfonyl-7-propoxy-oxazolo[5,4-d]pyrimidin-2-yl)-2,6-dimethyl-phenoxy]-acetic acid tert-butyl ester in 1 ml of N,N-dimethylformamide was slowly added. After 12 h at room temperature the mixture was quenched by the addition of water and extracted twice with ethyl acetate. The combined organic layers were dried and concentrated in vacuo. 101 mg of the title compound were obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([CH2:11][C@@H:12]2[CH2:23][CH2:22][C:21]3[S:20][C:19]4[N:18]=[CH:17][N:16]=[C:15]([O:24][CH:25]5[CH2:30][CH2:29][CH:28]([N:31]([CH3:39])[C:32](=O)OC(C)(C)C)[CH2:27][CH2:26]5)[C:14]=4[C:13]2=3)=[O:10])=[N:6][CH:7]=1.Cl.C=O.[BH3-]C#N.[Na+]>ClCCl.CO>[CH3:39][N:31]([CH3:32])[CH:28]1[CH2:29][CH2:30][CH:25]([O:24][C:15]2[C:14]3[C:13]4[C@H:12]([CH2:11][C:9]([NH:8][C:5]5[CH:4]=[CH:3][C:2]([F:1])=[CH:7][N:6]=5)=[O:10])[CH2:23][CH2:22][C:21]=4[S:20][C:19]=3[N:18]=[CH:17][N:16]=2)[CH2:26][CH2:27]1
Reactant: CN(C(=O)OC(C)(C)C)C1CCC(Oc2ncnc3sc4c(c23)[C@H](CC(=O)Nc2ccc(F)cn2)CC4)CC1
Agent: C=O
Agent: Cl
Agent: [BH3-]C#N
Solvent: ClCCl
Solvent: CO
Product: CN(C)C1CCC(Oc2ncnc3sc4c(c23)[C@H](CC(=O)Nc2ccc(F)cn2)CC4)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 13 %

Procedure:
To a 25-mL round-bottom flask containing a solution of 23.1 (195 mg, 0.35 mmol, 1.00 equiv) in dichloromethane (15 mL) was added hydrochloric acid (12 M, 2 mL) at 0° C. under nitrogen. The resulting solution was stirred for 2 h at room temperature and concentrated under vacuum. The resulting N-(5-fluoropyridin-2-yl)-2-[(3S)-12-[[4-(methylamino)cyclohexyl]oxy]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-3-yl]acetamide hydrochloride (130 mg, crude) was used in the next step directly without further purification. A solution of this material (130 mg, crude) and HCHO (37%, 1 mL) in methanol (10 mL) was stirred at room temperature for 30 min, whereupon NaBH3CN (55 mg, 0.78 mmol, 3.06 equiv) was added and the mixture stirred for an additional 2 h at room temperature. The reaction was then quenched by the addition of 20 mL of water and extracted with 3×30 mL of ethyl acetate. The combined organic layers were concentrated under vacuum. The crude product (70 mg) was purified by preparative HPLC(SHIMADZU) under the following conditions: column: Xbridge Prep C18 5 um, 19*150 mm; mobile phase: water (0.05% NH4HCO3) and CH3CN (6.0% CH3CN up to 50.0% in 25 min); UV detection at 254 and 220 nm. The fractions were collected and evaporated under reduced pressure to give the 2-[(3S)-12-[[4-(dimethylamino)cyclohexyl]oxy]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-3-yl]-N-(5-fluoropyridin-2-yl)acetamide (I-38, 21.4 mg) as a white solid. 1H NMR (300 MHz, CDCl3) δ 8.49 (s, 1H), 8.20 (m, 2H), 7.63 (m, 1H), 5.28 (m, 1H), 3.93 (t, 1H), 3.33 (m, 2H), 3.03 (m, 1H), 2.82 (m, 1H), 2.77 (m, 1H), 2.55 (m, 10H), 2.03 (m, 2H), 1.55 (m, 4H). MS: m/z 470 (M+H)+.