Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[C:12]1[N:17]=[CH:16][N:15]=[C:14]([NH:18][C:19]2[CH:27]=[CH:26][C:22]3[N:23]=[CH:24][S:25][C:21]=3[CH:20]=2)[CH:13]=1.C(O)(=O)C.[CH:32]1([CH:38]=O)[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CCOC(C)=O.ClCCCl>[S:25]1[C:21]2[CH:20]=[C:19]([NH:18][C:14]3[CH:13]=[C:12]([C:3]4[CH:4]=[CH:5][C:6]([C:8]([F:10])([F:11])[F:9])=[CH:7][C:2]=4[NH:1][CH2:38][CH:32]4[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]4)[N:17]=[CH:16][N:15]=3)[CH:27]=[CH:26][C:22]=2[N:23]=[CH:24]1
Reactant: O=CC1CCCCC1
Reactant: Nc1cc(C(F)(F)F)ccc1-c1cc(Nc2ccc3ncsc3c2)ncn1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: FC(F)(F)c1ccc(-c2cc(Nc3ccc4ncsc4c3)ncn2)c(NCC2CCCCC2)c1
Temperature: 0 °C

Procedure:
To a 5-mL, round-bottomed flask was added [6-(2-amino-4-trifluoromethylphenyl)pyrimidin-4-yl]benzothiazol-6-ylamine (0.060 g, 0.15 mmol), 1,2-dichloroethane (1 mL), acetic acid (0.018 mL, 0.31 mmol) and cyclohexanecarboxaldehyde (0.055 mL, 0.45 mmol, Aldrich). Sodium triacetoxy-borohydride (0.083 g, 0.39 mmol, Aldrich) was added to the mixture with stirring at 0° C. and the mixture was stirring for 17 h at room temperature. The reaction mixture was diluted with EtOAc (3 mL) and quenched with H2O (3 mL) and satd NaHCO3 (7 mL). The phases were separated and the aqueous phase was extracted with EtOAc (3×3 mL). The combined organic extracts were washed with brine, dried over Na2SO4 and concentrated in vacuo onto silica gel. Purification by silica gel chromatography with gradient from 20% to 50% solution of EtOAc in hexane afforded the title compound as a yellow solid. MS (ESI, pos. ion.) m/z: 484 (M+1).
Reaction SMILES: C(O[CH:5]1[O:19][C@H:18]([CH2:20][O:21]C(=O)C2C=CC(Cl)=CC=2)[C@@H:7]([O:8]C(=O)C2C=CC(Cl)=CC=2)[CH2:6]1)(=O)C.C[Si]([NH:35][C:36]1[N:41]=[C:40]([O:42][Si](C)(C)C)[N:39]=[CH:38][N:37]=1)(C)C.S(O)(C(F)(F)F)(=O)=O.CO[Na]>CO.CS(C)=O.CC#N>[CH2:6]1[C@H:5]([N:39]2[C:40](=[O:42])[N:41]=[C:36]([NH2:35])[N:37]=[CH:38]2)[O:19][C@H:18]([CH2:20][OH:21])[C@H:7]1[OH:8]
Reactant: CC(=O)OC1C[C@H](OC(=O)c2ccc(Cl)cc2)[C@@H](COC(=O)c2ccc(Cl)cc2)O1
Reactant: C[Si](C)(C)Nc1ncnc(O[Si](C)(C)C)n1
Agent: CO[Na]
Agent: O=S(=O)(O)C(F)(F)F
Solvent: CS(C)=O
Solvent: CO
Solvent: CC#N
Product: Nc1ncn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)n1
Temperature: 0 °C
Reaction time: 24 h

Procedure:
A mixture of MeCN (45 mL), 1-O-acetyl-3,5-di-O-(4-chlorobenzoyl)-2-deoxy-D-ribofuranose (3.0 g), 2-[(trimethylsilyl)amino]4-[(trimethylsilyl)oxy]-s-triazine (1.78 g) and TfOH (0.5 g) were stirred at about 0° C. for 24 hours. DMSO (6 mL) was added and the mixture was evaporated at 30˜50° C. under reduced pressure to remove the MeCN. A 29% solution of MeONa in MeOH (1.8 g, 9.9 mmol, 1.5 eq.) was added with stirring at about 20˜25° C. After the reaction was complete, MeOH was added to effect precipitation and the solid was filtered, washed and dried to give crude decitabine. API grade decitabine (>99.0 HPLC purity) is prepared by the recrystallization of crude decitabine from MeOH, followed by three washes with MeOH and drying at 40° C. under vacuum.
Reaction SMILES: C(OC([NH:8]/[C:9](/[NH:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]2[CH2:35][CH2:34][CH2:33][C@@H:26]2[C:27]([NH:29][CH:30]2[CH2:32][CH2:31]2)=[O:28])=[CH:21][CH:20]=1)=[N:10]/C(OC(C)(C)C)=O)=O)(C)(C)C.C(Cl)Cl.C(O)(C(F)(F)F)=O>CO>[CH:30]1([NH:29][C:27]([C@H:26]2[CH2:33][CH2:34][CH2:35][N:25]2[C:22]2[CH:21]=[CH:20][C:19]([NH:18][C:9]([NH2:10])=[NH:8])=[CH:24][CH:23]=2)=[O:28])[CH2:32][CH2:31]1
Reactant: CC(C)(C)OC(=O)/N=C(/NC(=O)OC(C)(C)C)Nc1ccc(N2CCC[C@@H]2C(=O)NC2CC2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: N=C(N)Nc1ccc(N2CCC[C@@H]2C(=O)NC2CC2)cc1
Reaction time: 4 h
Yield: 76.4 %

Procedure:
To 1-[4-({(E)-[(tert-butoxycarbonyl)amino][(tert-butoxycarbonyl)imino]methyl}amino)phenyl]-N-cyclopropyl-D-prolinamide (Method 62; 2.0 g) was added DCM (60 ml) and TFA (20 ml). The reaction stirred for 4 hours before removal of the solvent in vacuo. To the gum was added DCM (75 ml) and macroporous polystyrene carbonate resin (0.49 g of capacity 3.0 m.equ per g) solid supported reagent (20 g), the reaction was slowly stirred overnight. The reaction was filtered and the solvent removed in vacuo to yield very little product. A white solid was present in the filter cup, this was dissolved in MeOH, the resin was also added to the MeOH, the system was stirred for 10 minutes before being filtered, the solvent was removed in vacuo to yield the title compound as a white solid (0.90 g, 75%). NMR (299.954 MHz, CDCl3) δ 7.26 (s, 3H), 6.85 (d, 2H), 6.49 (d, 2H), 3.93 (d, 1H), 3.62-3.60 (m, 1H), 3.17 (q, 1H), 2.70-2.62 (m, 1H), 2.32-2.14 (m, 2H), 2.00-1.92 (m, 2H), 0.76-0.63 (m, 2H), 0.42 (q, 2H); m/z 287.
Reaction SMILES: [O:1]=[C:2]1[C:7]([C:8]2[NH:9][C:10]3[CH:16]=[C:15]([C:17]([OH:19])=O)[CH:14]=[CH:13][C:11]=3[N:12]=2)=[CH:6][C:5]([C:20]2[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=2)=[N:4][NH:3]1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[CH2:57]([N:59]([CH2:62][CH2:63][NH2:64])[CH2:60][CH3:61])[CH3:58]>O.CN(C)C=O>[CH2:57]([N:59]([CH2:60][CH3:61])[CH2:62][CH2:63][NH:64][C:17]([C:15]1[CH:14]=[CH:13][C:11]2[NH:12][C:8]([C:7]3[C:2](=[O:1])[NH:3][N:4]=[C:5]([C:20]4[CH:21]=[CH:22][N:23]=[CH:24][CH:25]=4)[CH:6]=3)=[N:9][C:10]=2[CH:16]=1)=[O:19])[CH3:58]
Reactant: O=C(O)c1ccc2nc(-c3cc(-c4ccncc4)n[nH]c3=O)[nH]c2c1
Reactant: CCN(CC)CCN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCN(CC)CCNC(=O)c1ccc2[nH]c(-c3cc(-c4ccncc4)n[nH]c3=O)nc2c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A mixture consisting of 50 mg of 2-(3-oxo-6-pyridin-4-yl-2,3-dihydropyridazin-4-yl)-3H-benzoimidazole-5-carboxylic acid, 0.065 ml of triethylamine and 1.5 ml of dimethylformamide (DMF) is stirred at room temperature for 10 minutes, mixed with 68.4 mg of O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (Hatu) and stirred at room temperature for a further 30 minutes. Then 21 mg of diethylaminoethylamine are added, and the mixture is stirred at 50° C. for 3 hours. After cooling, it is diluted with 5 ml of water, and the precipitate is filtered off with suction and stirred with isopropanol at 60° C., filtered off with suction and dried in vacuo.
Reaction SMILES: [NH2:1][CH2:2][C:3]([NH:5][CH2:6][C:7]1[N:8]=[C:9]([NH:12][C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][C:17]=2[C:23]([CH:25]2[CH2:29][CH2:28][CH2:27][CH2:26]2)=[O:24])=[O:14])[S:10][CH:11]=1)=[O:4].[CH3:30][S:31](Cl)(=[O:33])=[O:32]>>[CH:25]1([C:23]([C:17]2[CH:18]=[C:19]([CH3:22])[CH:20]=[CH:21][C:16]=2[NH:15][C:13](=[O:14])[NH:12][C:9]2[S:10][CH:11]=[C:7]([CH2:6][NH:5][C:3](=[O:4])[CH2:2][NH:1][S:31]([CH3:30])(=[O:33])=[O:32])[N:8]=2)=[O:24])[CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: CS(=O)(=O)Cl
Reactant: Cc1ccc(NC(=O)Nc2nc(CNC(=O)CN)cs2)c(C(=O)C2CCCC2)c1
Product: Cc1ccc(NC(=O)Nc2nc(CNC(=O)CNS(C)(=O)=O)cs2)c(C(=O)C2CCCC2)c1
Yield: 83.5 %

Procedure:
N-{2-[3-(2-Cyclopentanecarbonyl-4-methyl-phenyl)-ureido]-thiazol-4-ylmethyl}-2-methanesulfonylamino-acetamide (103 mg, 84%) was prepared from 2-amino-N-{2-[3-(2-cyclopentanecarbonyl-4-methyl-phenyl)-ureido]-thiazol-4-ylmethyl}-acetamide (104 mg, 0.25 mmol) and methanesulfonyl chloride (0.04 mL, 0.5 mmol) following the general procedure L.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([S:11][C:12]3[CH:17]=[CH:16][C:15]([C:18]4[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=4)=[CH:14][C:13]=3[C:24]([F:27])([F:26])[F:25])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.OC1CCNC1.[NH:34]1[CH2:39][CH2:38][CH:37]([CH2:40][OH:41])[CH2:36][CH2:35]1>>[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([S:11][C:12]3[CH:17]=[CH:16][C:15]([C:18]4[CH:19]=[CH:20][N:21]=[C:22]([N:34]5[CH2:39][CH2:38][CH:37]([CH2:40][OH:41])[CH2:36][CH2:35]5)[CH:23]=4)=[CH:14][C:13]=3[C:24]([F:25])([F:26])[F:27])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: FC(F)(F)c1cc(-c2ccncc2)ccc1Sc1ccc2c(c1)OCCO2
Reactant: OCC1CCNCC1
Agent: OC1CCNC1
Product: OCC1CCN(c2cc(-c3ccc(Sc4ccc5c(c4)OCCO5)c(C(F)(F)F)c3)ccn2)CC1

Procedure:
The title compound was prepared according to the procedures of Example 38E, substituting compound 76 with compound 118 (0.033 g, 0.0779 mmol) and 3-hydroxypyrrolidine with 4-piperidinemethanol. A yellow solid 122 was obtained (0.0284 g, 57%). 1H-NMR (CDCl3, 400 MHz) δ 1.41–1.51 (m, 2H), 1.86–1.95 (m, 1H), 1.97–2.04 (m, 2H), 3.23–3.31 (m, 2H), 3.57 (d, J=5.8 Hz, 2H), 4.28–4.34 (m, 4H), 4.36–4.41 (m, 2H), 6.92 (d, J=6.6 Hz, 1H), 6.93–6.97 (m, 2H), 7.05 (dd, J=1.8 Hz, 8.4 Hz, 1H), 7.09 (d, J=1.8 Hz, 1H), 7.12 (d, J=8.4 Hz, 1H), 7.52 (d, J=8.4 Hz, 1H), 7.82 (s, 1H), 8.25 (d, J=6.6 Hz, 1H); MS (APCI) m/z 503 (M+H)+.
Reaction SMILES: O.[C:2]1([CH3:12])[CH:7]=[CH:6][C:5]([S:8]([OH:11])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[C:13]1(C)C=CC(S(O)(=O)=O)=CC=1.[C:24]([C:27]1([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1)([OH:26])=[O:25]>CO>[C:2]1([CH3:12])[CH:3]=[CH:4][C:5]([S:8]([OH:11])(=[O:9])=[O:10])=[CH:6][CH:7]=1.[CH3:13][O:25][C:24]([C:27]1([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH2:28][CH2:29][NH:30][CH2:31][CH2:32]1)=[O:26]
Reactant: O=C(O)C1(c2ccccc2)CCNCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CO
Product: COC(=O)C1(c2ccccc2)CCNCC1
Yield: 453.8 %

Procedure:
1 g of p-toluenesulfonic acid monohydrate is added to a solution of 10 g of 4-carboxy-4-phenylpiperidine p-toluenesulfonate in 300 ml of MeOH and the reaction mixture is refluxed for 3 days. It is concentrated under vacuum, the residue is taken up with acetone, and ether is added until precipitation occurs. 9.34 g of the expected product are obtained after wringing of the precipitate formed.
Reaction SMILES: Br[C:2]1[C:3]([NH2:9])=[N:4][CH:5]=[C:6]([Br:8])[CH:7]=1.[C:10]([S-:15])(=S)OCC.[K+].S(Cl)([Cl:20])(=O)=O.O>CN(C=O)C.Cl>[ClH:20].[Br:8][C:6]1[CH:7]=[C:2]2[S:15][C:10]([Cl:20])=[N:9][C:3]2=[N:4][CH:5]=1
Reactant: Nc1ncc(Br)cc1Br
Reactant: CCOC(=S)[S-]
Reactant: O=S(=O)(Cl)Cl
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Clc1nc2ncc(Br)cc2s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.7 %

Procedure:
A solution of 3,5-dibromopyridine-2-amine (5 g, 19.85 mmol) and potassium O-ethyl carbonodithioate (7.64 g, 47.6 mmol) in DMF (25.6 mL) was heated to 130° C. where it stirred overnight. After this time, the reaction mixture was allowed to cool to rt. Once at the prescribed temperature, the reaction mixture was diluted with HCl (1 N, 150 mL), and then stirred at rt for an additional hour. At the conclusion of this period, the resulting solid was collected by filtration, washed with water (2×15 mL), and then air-dried. The resulting material was suspended in CH2Cl2 (26 mL) and sulfuryl chloride (17.1 mL, 210 mmol) was slowly added. After 2 hr, water (50 mL) was slowly added to decompose the excess sulfuryl chloride (cooled to 0° C.). The resulting precipitate was collected by filtration and dried to afford Compound 21A as a light yellow solid (5.6 g, 99% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.88 (d, J=2.2 Hz, 1H), 8.79 (d, J=2.2 Hz, 1H). LC/MS (m/z)=250 (M+H)+.
Reaction SMILES: O.[OH-].[Li+].C[O:5][C:6](=[O:34])[CH2:7][C:8]1[C:17]([CH3:18])=[C:16]([C:19]2[CH:24]=[CH:23][C:22]([S:25](=[O:32])(=[O:31])[N:26]([CH2:29][CH3:30])[CH2:27][CH3:28])=[CH:21][CH:20]=2)[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([F:33])[CH:14]=2)[CH:9]=1.C1COCC1.O>CCCCCC>[CH2:29]([N:26]([CH2:27][CH3:28])[S:25]([C:22]1[CH:23]=[CH:24][C:19]([C:16]2[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([F:33])[CH:14]=3)[CH:9]=[C:8]([CH2:7][C:6]([OH:34])=[O:5])[C:17]=2[CH3:18])=[CH:20][CH:21]=1)(=[O:31])=[O:32])[CH3:30]
Reactant: CCN(CC)S(=O)(=O)c1ccc(-c2c(C)c(CC(=O)OC)cc3ccc(F)cc23)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCN(CC)S(=O)(=O)c1ccc(-c2c(C)c(CC(=O)O)cc3ccc(F)cc23)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 88.9 %

Procedure:
Lithium hydroxide monohydrate (0.020 g, 0.45 mmol) was added to a stirred solution of [4-(4-diethylsulfamoyl-phenyl)-6-fluoro-3-methyl-naphthalen-2-yl]-acetic acid methyl ester (0.05 g, 0.11 mmol) in a 3:1 mixture of THF—H2O mixture (6 mL). The reaction mixture was stirred for 16 hours at room temperature. The reaction mixture was concentrated to remove THF, and the crude material was diluted with water, acidified [pH˜2] with a 6 N aqueous solution of hydrochloric acid. The mixture was extracted twice with ethyl acetate. The collected organic layers were washed with water and brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to give the crude product. Trituration with hexane gave [4-(4-diethylsulfamoyl-phenyl)-6-fluoro-3-methyl-naphthalen-2-yl]-acetic acid (0.042 g, 87%) as a solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.48 (br. s, 1 H), 8.01 (dd, J=9.20, 6.20 Hz, 1 H), 7.97 (d, J=8.31 Hz, 2 H), 7.91 (s, 1 H), 7.48 (d, J=8.31 Hz, 2 H), 7.39 (td, J=8.80, 2.40 Hz, 1 H), 6.68 (dd, J=11.00, 2.40 Hz, 1 H), 3.85 (s, 2 H), 3.28 (q, J=7.10 Hz, 4 H), 2.07 (s, 3 H), 1.09 (t, J=7.09 Hz, 6 H). MS calcd. for C23H23FNO4S [(M−H)−] 428, obsd. 428.0.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([C:11](Cl)=[O:12])=[C:5]([C:7]([F:10])([F:9])[F:8])[N:6]=1.[Br:14][C:15]1[CH:21]=[C:20]([O:22][C:23]([F:26])([F:25])[F:24])[CH:19]=[C:18]([Br:27])[C:16]=1[NH2:17]>C(#N)C>[CH3:1][C:2]1[S:3][C:4]([C:11]([NH:17][C:16]2[C:18]([Br:27])=[CH:19][C:20]([O:22][C:23]([F:26])([F:24])[F:25])=[CH:21][C:15]=2[Br:14])=[O:12])=[C:5]([C:7]([F:10])([F:9])[F:8])[N:6]=1
Reactant: Cc1nc(C(F)(F)F)c(C(=O)Cl)s1
Reactant: Nc1c(Br)cc(OC(F)(F)F)cc1Br
Solvent: CC#N
Product: Cc1nc(C(F)(F)F)c(C(=O)Nc2c(Br)cc(OC(F)(F)F)cc2Br)s1
Reaction time: 6.5 h
Yield: 98.9 %

Procedure:
2-Methyl-4-trifluoromethyl-5-chlorocarbonyl thiazole 6.47 g and 2,6-dibromo-4-trifluoromethoxy aniline 8.91 g were added in acetonitrile 16.8 ml, and they were heated to reflex for 6.5 hours. Solvent was removed from the reaction mixture by distillation under a reduced pressure, and then ethyl acetate 420 g and water 300 ml were added and they were agitated. After standing calmly, the ethyl acetate layer was collected, and washed with 300 ml each of water, saturated sodium bicarbonate solution, and water in succession. Then, after drying over anhydrous sodium sulfate, solvent was removed by distillation under a reduced pressure, to obtain thifluzamide 13.9 g.
Reaction SMILES: [CH2:1]([C:4]1([OH:17])[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1)[CH:2]=[CH2:3].C[N+]1([O-])CC[O:22]CC1.O1CCCC1.[OH2:31]>C(O)(C)(C)C.[Os](=O)(=O)(=O)=O>[OH:31][CH:2]([CH2:3][OH:22])[CH2:1][C:4]1([OH:17])[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1
Reactant: C[N+]1([O-])CCOCC1
Reactant: O
Reactant: C=CCC1(O)CCN(C(=O)OC(C)(C)C)CC1
Agent: O=[Os](=O)(=O)=O
Solvent: C1CCOC1
Solvent: CC(C)(C)O
Product: CC(C)(C)OC(=O)N1CCC(O)(CC(O)CO)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
9.83 g of tert-butyl 4-allyl-4-hydroxy-1-piperidinecarboxylate was dissolved in 60 ml tetrahydrofuran/water (9:1), a solution (2.5 wt %, 2 ml) of osmium tetraoxide in tert-butyl alcohol and 6.68 g of N-methylmorpholine-N-oxide were added thereto, and the mixture was stirred at room temperature overnight. The reaction solution was evaporated, and the resulting residue was partitioned into ethyl acetate and water, washed with brine and dried over magnesium sulfate. After filtration, the solvent was evaporated, and the resulting residue was purified by silica gel column chromatography (ethyl acetate/methanol) to give 9.11 g of tert-butyl 4-(2,3-dihydroxypropyl)-4-hydroxy-1-piperidinecarboxylate.
Reaction SMILES: Br[C:2]1[C:10]2[C:9]([Cl:11])=[N:8][CH:7]=[N:6][C:5]=2[NH:4][CH:3]=1.[Li]CCCC.[C:17]1([C:23](Cl)=[O:24])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.O>C1COCC1.CCOC(C)=O>[Cl:11][C:9]1[C:10]2[C:2]([C:23]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[O:24])=[CH:3][NH:4][C:5]=2[N:6]=[CH:7][N:8]=1
Reactant: Clc1ncnc2[nH]cc(Br)c12
Reactant: O=C(Cl)c1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(c1ccccc1)c1c[nH]c2ncnc(Cl)c12
Temperature: -78 °C
Reaction time: 0.67 h

Procedure:
To a solution of 5-bromo-4-chloro-7H-pyrrolo[2,3-d]pyrimidine (1.47 g, 6.38 mmol) in THF (60 mL) at −78° C. under N2 was added n-BuLi (2.5 M in hexane, 5.74 mL, 14.36 mmol) dropwise. After completion of addition, the mixture was stirred at −78° C. for additional 40 min. PhCOCl (0.88 mL) was added and the reaction was stirred for an additional 1 hour. Water (1 mL) was added to quench the reaction. The reaction mixture was then poured into water (100 mL). EtOAc (200 mL) was added for extraction. The organic layer was separated, dried (Na2SO4), filtered and concentrated to a residue. The residue was dissolved into small amount of DCM and a little MeOH. It was loaded to silica gel column. The purification was down by eluent with 1/1 DCM/EtOAc. The (4-chloro-7H-pyrrolo[2,3-d]pyrimidin-5-yl)(phenyl)methanone was obtained as a white solid (0.49 g, 29%). 1H NMR (DMSO-d6, 400 MHz) 8.74 (s, 1H), 8.17 (s, 1H), 7.87 (m, 2H), 7.68 (m, 1H), 7.56 (m, 2H). LCMS [M+1]: 258.
Reaction SMILES: [CH2:1]([OH:4])[C:2]#[CH:3].Br[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=1.C(N(CC)CC)C.Cl>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.O.C(#N)C>[N:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=1[C:3]#[C:2][CH2:1][OH:4]
Reactant: C#CCO
Reactant: Brc1ccccn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: CC#N
Product: OCC#Cc1ccccn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 70 %

Procedure:
2-Propynyl alcohol (35 ml) was added dropwise to a stirred mixture of 2-bromopyridine (13.7 g), bis(triphenylphosphine)palladium chloride (1.54 g), triethylamine (21 ml), cuprous iodide (1.5 g) and acetonitrile (150 ml) and the mixture was stirred at ambient temperature for 30 minutes and then heated to 60° C. for 2 hours. The mixture was cooled to ambient temperature, poured into water (200 ml) and neutralised by adding dilute aqueous hydrochloric acid. The mixture was extracted with methylene chloride (2×500 ml) and the combined extracts were washed with water (500 ml), dried (MgSO4) and evaporated. The residue was purified by column chromatography eluting with a 1:1 v/v mixture of methylene chloride and ethyl acetate to give 3-(2-pyridyl)prop-2-yn-1-yl alcohol (14 g, 70%), m.p. 78°-80° C. (recrystallised from a mixture of hexane and ethyl acetate).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:12]=[CH:11][C:10]([C:13](Cl)=[O:14])=[CH:9][N:8]=1.[NH2:16][N:17]1[C:25]2[C:20](=[C:21]([F:26])[CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18]1.C([O-])([O-])=O.[K+].[K+].O>CCOC(C)=O>[F:26][C:21]1[CH:22]=[CH:23][CH:24]=[C:25]2[C:20]=1[CH:19]=[CH:18][N:17]2[NH:16][C:13]([C:10]1[CH:9]=[N:8][C:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)=[N:12][CH:11]=1)=[O:14]
Reactant: Nn1ccc2c(F)cccc21
Reactant: O=C(Cl)c1cnc(-c2ccccn2)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(Nn1ccc2c(F)cccc21)c1cnc(-c2ccccn2)nc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 17.3 %

Procedure:
A suspension of 2-(pyridine-2-yl)-pyrimidine-5-carbonyl chloride (0.44 g) in EtOAc (20 mL) is added portion wise to a mixture of 1-amino-4-fluoroindole (0.30 g) and K2CO3 (0.276 g) in EtOAc (10 mL)/water (20 mL) and the resulting mixture is stirred at rt for 24 h. The aqueous phase is separated and extracted twice with EtOAc. The combined organic layer is washed with water and brine, dried (MgSO4), filtered and concentration in vacuo. The residue is purified by silica gel chromatography eluting with EtOAc to afford 2-(pyridin-2-yl)pyrimidine-5-carboxylic acid-(4-fluoroindol-1-yl)amide (0.115 g, 17%) as a solid. MS: 334 (M+H); 1H NMR (300 MHz, DMSO-d6): δ 6.65 (d, 1H), 6.89-6.95 (q, 1H), 7.16-7.23 (m, 1H), 7.32-7.35 (d, 1H), 7.57 (d, 1H), 7.57-7.64 (m, 1H), 8.02-8.08 (t, 1H), 8.50-8.52 (d, 1H), 8.82-8.83 (d, 1H), 9.49 (s, 2H), 12.30 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:3]=1N.N(OCCC(C)C)=O.[ClH:23]>C(#N)C.[Cu](Cl)Cl>[Cl:23][C:3]1[C:2]([CH3:1])=[CH:7][CH:6]=[CH:5][C:4]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: Cc1cccc(-c2ccccc2)c1N
Reactant: Cl
Agent: Cl[Cu]Cl
Agent: CC(C)CCON=O
Solvent: CC#N
Product: Cc1cccc(-c2ccccc2)c1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
During a five minute period a solution of 3-methyl-[1,1'-biphenyl]-2-amine (5.8 g, 0.0316 mole) in 15 ml of dry acetonitrile was added to a stirred mixture of anhydrous copper (II) chloride (7.5 g, 0.038 mole) and isoamyl nitrite (5.55 g, 0.0474 mole) in 100 ml of anhydrous acetonitrile. The reaction mixture was stirred at room temperature for two hours, 65° for two hours, then room temperature for two days. The mixture was diluted with 600 ml of 2N aqueous hydrochloric acid and extracted with two 150 ml portions of diethyl ether. The extracts were combined, washed with 200 ml of 2N aqueous hydrochloric acid, and dried over anhydrous magnesium sulfate. The mixture was filtered and the filtrate evaporated under reduced pressure to give an oil. The oil was purified by column chromatography on silica gel to give 2-chloro-3-methyl-[1,1'-biphenyl] (0.4 g).
Reaction SMILES: [Si:1]([O:8][CH2:9][CH:10]([OH:24])[CH:11]([C:16](=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[N:19][CH:18]=1)[CH2:12][CH2:13][CH2:14][OH:15])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].N1C=CN=C1.[C:30]([Si:34]([C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)Cl)([CH3:33])([CH3:32])[CH3:31]>CN(C)C=O.C(OCC)(=O)C>[Si:1]([O:8][CH2:9][CH:10]([OH:24])[CH:11]([C:16](=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[N:19][CH:18]=1)[CH2:12][CH2:13][CH2:14][O:15][Si:34]([C:30]([CH3:33])([CH3:32])[CH3:31])([C:42]1[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=1)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OCC(O)C(CCCO)C(=O)c1cccnc1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCC(O)C(CCCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)C(=O)c1cccnc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4.69 g (0.0133 mole) of 1-(t-butyldimethylsilyloxy)-3-nicotinoylhexan-2,6-diol, 2.18 g (0.032 mole) of imidazole in 12 ml of dimethylformamide is added at once 4.38 g (0.0159 mole) of t-butyldiphenylchlorosilane, the mixture is stirred at room temperature overnight, diluted with 30 ml of ethyl acetate and washed with water (2×10 ml) and brine, dried (MgSO4) and evaporated. The residue is purified by flash chromatography using ethyl acetate-methylene chloride (2:3) as eluent to give 1-(t-butyldimethylsilyloxy)-6-(t-butyldiphenylsilyloxy)-3-nicotinoylhexan-2-ol as an oil.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:6][N:5]=[C:4]2[N:14]([CH3:18])[N:15]=[C:16]([I:17])[C:3]=12.[OH-:19].[Na+]>CS(C)=O.O1CCOCC1>[I:17][C:16]1[C:3]2[C:2]([OH:19])=[C:7]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[N:6]=[N:5][C:4]=2[N:14]([CH3:18])[N:15]=1
Reactant: [OH-]
Reactant: Cn1nc(I)c2c(Cl)c(-c3ccccc3)nnc21
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CS(C)=O
Product: Cn1nc(I)c2c(O)c(-c3ccccc3)nnc21
Temperature: 50 °C

Procedure:
A mixture of 4-chloro-3-iodo-1-methyl-5-phenyl-1H-pyrazolo[3,4-c]pyridazine (1.5 g, 4.05 mmol) and NaOH aqueous solution (4 M, 2 mL) in DMSO (6 mL) and dioxane (6 mL) was heated to 50° C. for 2.5 h. The mixture was left to cool to rt, then neutralised to pH 2-3, when a precipitate formed. The solid was filtered, washed with water and dried, to give 1.33 g of the intermediate.