Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:13][CH:12]([CH2:14][O:15][C:16]3[CH:20]=[CH:19][O:18][N:17]=3)[O:11][C:10]2=[O:21])[CH:5]=[CH:6][C:7]=1I.[OH:22][CH2:23][C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1>C1(C)C=CC=CC=1.CCO.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>[F:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:13][CH:12]([CH2:14][O:15][C:16]3[CH:20]=[CH:19][O:18][N:17]=3)[O:11][C:10]2=[O:21])[CH:5]=[CH:6][C:7]=1[C:27]1[CH:28]=[CH:29][C:24]([CH2:23][OH:22])=[CH:25][CH:26]=1
Reactant: OCc1ccc(B(O)O)cc1
Reactant: O=C1OC(COc2ccon2)CN1c1ccc(I)c(F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: O
Product: O=C1OC(COc2ccon2)CN1c1ccc(-c2ccc(CO)cc2)c(F)c1

Procedure:
A degassed mixture containing 3-(3-fluoro-4-iodo-phenyl)-5-(isoxazol-3-yloxymethyl)-oxazolidin-2-one (1.0 g, 2.48 mmol), 4-(hydroxymethyl)phenylboronic acid (0.46 g, 3.00 mmol) and Pd(PPh3)4 in toluene (24 mL), EtOH (8 mL) and H2O (8 mL) was heated to reflux for 15 h. The reaction was concentrated, the crude residue was suspended in H2O, filtered and dried in vacuo to give 3-(2-fluoro-4′-hydroxymethyl-biphenyl-4-yl)-5-(isoxazol-3-yloxymethyl)-oxazolidin-2-one. This crude material was dissolved in CH2Cl2 (10 mL) and Hunig's base (0.88 mL, 5.3 mmol), then MsCl (0.32 mL, 2.65 mmol) was added and the mixture was stirred at room temperature for 15 h. The reaction was partitioned between dilute sodium bicarbonate (NaHCO3, 20 mL) and CH2Cl2 (30 mL). The two layers were separated and the organic phase was washed with saturated ammonium chloride (NH4Cl, 1×20 mL) and H2O (1×20 mL) and dried over Na2SO4. The solvent was evaporated and the crude was purified on silica gel eluting with 0–3% MeOH in CH2Cl2 to give benzyl chloride 107 as white crystalline solid (0.46 g; 43% yield over the last two steps). LCMS (ESI) m/z 403 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:11])[C:5]([O:7][CH2:8][CH:9]=[CH2:10])=[CH2:6])[CH3:2].CO[CH2:14][N:15]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:16][Si](C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH2:1]([O:3][C:4]([C:5]1([O:7][CH2:8][CH:9]=[CH2:10])[CH2:6][CH2:14][N:15]([CH2:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:16]1)=[O:11])[CH3:2]
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Reactant: C=CCOC(=C)C(=O)OCC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C=CCOC1(C(=O)OCC)CCN(Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of the 2-allyloxy-acrylic acid ethyl ester (431 mg) and N-(methoxymethyl)-N-(trimethylsilylmethyl)benzylamine (847 μl) in dichloromethane (10 ml) was added at 0° C. trifluoroacetic acid (21 μl). The resulting solution was warmed to room temperature and stirred overnight. The crude product was purified by column chromatography on silica gel, eluted with a solution of ethyl acetate in hexanes (25-100%) to give the title compound (341 mg).
Reaction SMILES: Cl.Cl.[Br:3][C:4]1[C:5]([O:22][C:23]2[CH:24]=[C:25]([CH:34]=[CH:35][C:36]=2[Cl:37])[C:26]([NH:28][CH2:29][CH2:30][N:31]([CH3:33])[CH3:32])=[O:27])=[CH:6][C:7]([NH:10][C:11]2[S:15][N:14]=[C:13]([CH:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)[N:12]=2)=[N:8][CH:9]=1.CCN(C(C)C)C(C)C.[C:47](Cl)(=[O:49])[CH3:48]>CN(C=O)C>[C:47]([N:19]1[CH2:20][CH2:21][CH:16]([C:13]2[N:12]=[C:11]([NH:10][C:7]3[CH:6]=[C:5]([O:22][C:23]4[CH:24]=[C:25]([CH:34]=[CH:35][C:36]=4[Cl:37])[C:26]([NH:28][CH2:29][CH2:30][N:31]([CH3:33])[CH3:32])=[O:27])[C:4]([Br:3])=[CH:9][N:8]=3)[S:15][N:14]=2)[CH2:17][CH2:18]1)(=[O:49])[CH3:48]
Reactant: CC(=O)Cl
Reactant: CN(C)CCNC(=O)c1ccc(Cl)c(Oc2cc(Nc3nc(C4CCNCC4)ns3)ncc2Br)c1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N1CCC(c2nsc(Nc3cc(Oc4cc(C(=O)NCCN(C)C)ccc4Cl)c(Br)cn3)n2)CC1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 5.9 %

Procedure:
3-(5-Bromo-2-(3-(piperidin-4-yl)-1,2,4-thiadiazol-5-ylamino)pyridin-4-yloxy)-4-chloro-N-(2-(dimethylamino)ethyl)benzamide dihydrochloride (0.12 g, 0.18 mmol) was dissolved in DMF (2 mL) and the solution was cooled to 0° C. DIEA (0.13 mL, 0.73 mmol) was added followed by acetyl chloride (0.017 mL, 0.24 mmol). The solution was warmed to ambient temperature. After 15 minutes, the solution was quenched with water, extracted with EtOAc, dried, and concentrated. HPLC purification gave the title compound (0.0066 g, 6%) as a white solid. 1H NMR (400 MHz, CDCl3) δ 1.69-1.76 (m, 1H), 1.81-1.88 (m, 1H), 1.86-2.12 (m, 2H), 2.04 (s, 3H), 2.26 (s, 6H) 2.60 (t, 2H), 2.78-2.85 (m, 1H), 2.95-3.04 (m, 1H), 3.13-3.21 (m, 1H), 3.54-3.60 (m, 2H), 3.78-3.84 (m, 1H), 4.41-4.46 (m, 1H), 6.15 (s, 1H), 7.40 (s, 1H), 7.53 (d, 1H), 7.59-7.64 (m, 3H), 8.49 (s, 1H).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][S:5][CH2:4][CH2:3]1.[CH3:8][S:9](Cl)(=[O:11])=[O:10].C(N(CC)CC)C>C(Cl)Cl>[CH3:8][S:9]([O:1][CH:2]1[CH2:7][CH2:6][S:5][CH2:4][CH2:3]1)(=[O:11])=[O:10]
Reactant: CS(=O)(=O)Cl
Reactant: OC1CCSCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OC1CCSCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a 300 ml methylene chloride solution of 14.6 g (0.12 mol) of 4-hydroxytetrahydrothiopyran, 11.5 ml (0.15 mol) of methanesulfonyl chloride and 25.8 ml (0.19 mol) of triethylamine were added at 0° C. and stirred at room temperature for 1 hour. The reaction mixture was diluted with methylene chloride (100 ml) and successively washing with water (100 ml) and saturated saline (100 ml), followed by drying over anhydrous sodium sulfate. The solvent was then distilled off under vacuum to obtain 24.5 g (quant.) of the above-identified compound as a slightly brown crystal.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:12]=[C:11]([NH2:13])[NH:10][N:9]=2)[CH:5]=[CH:4][N:3]=1.[CH3:14]NN>>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:12]=[C:11]([NH2:13])[N:10]([CH3:14])[N:9]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Nc1cc(-c2ccnc(Cl)c2)n[nH]1
Reactant: CNN
Product: Cn1nc(-c2ccnc(Cl)c2)cc1N
Yield: 89 %

Procedure:
This title intermediate was prepared starting from 18.B (3.10 g, 17.3 mmol) according the procedure described above for conversion of 18.B to 18.C, except that methylhydrazine (3.5 equiv.) was used. The crude product was purified by flash chromatography on silica gel using 0-8% MeOH/CH2Cl2 for elution to provide 23.A (3.44 g mg, 89%) as a brown solid.
Reaction SMILES: [NH2:1][C:2]1[N:6]=[C:5]([CH3:7])[NH:4][N:3]=1.CN(C)[CH:10]=[CH:11][C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=1)=O>C(O)(=O)C>[CH3:7][C:5]1[N:6]=[C:2]2[N:1]=[CH:10][CH:11]=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:21])([F:22])[F:23])[CH:15]=3)[N:3]2[N:4]=1
Reactant: Cc1nc(N)n[nH]1
Reactant: CN(C)C=CC(=O)c1cccc(C(F)(F)F)c1
Solvent: CC(=O)O
Product: Cc1nc2nccc(-c3cccc(C(F)(F)F)c3)n2n1

Procedure:
A mixture of 0.49 g. of 3-amino-5-methyl-1,2,4-triazole and 1.26 g. of 3-dimethylamino-3'-trifluoromethylacrylophenone in 25 ml. of glacial acetic acid refluxed for 16 hours. The resulting mixture is worked up as described in Example 54 to give the product of the Example, m.p. 153°-154° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([S:12](Cl)(=[O:14])=[O:13])[CH:7]=1.[CH3:17][C:18]1[CH:24]=[CH:23][C:21]([NH2:22])=[CH:20][CH:19]=1.C([O-])(O)=O.[Na+]>O1CCOCC1.O>[CH3:1][O:2][C:3](=[O:16])[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([S:12](=[O:14])(=[O:13])[NH:22][C:21]2[CH:23]=[CH:24][C:18]([CH3:17])=[CH:19][CH:20]=2)[CH:7]=1
Reactant: COC(=O)C=Cc1cccc(S(=O)(=O)Cl)c1
Reactant: Cc1ccc(N)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)C=Cc1cccc(S(=O)(=O)Nc2ccc(C)cc2)c1
Yield: 79.3 %

Procedure:
A solution of 3-(3-chlorosulfonylphenyl)-acrylic acid methyl ester (3) (2.0 g, 7.23 mmol) in dioxane (10 ml) was added to a mixture of 4-methylaniline (0.77 g, 7.23 mmol) in dioxane (20 ml) and NaHCO3 (1.2 g, 14.5 mmol) in water (20 ml), and the resultant solution was stirred at room temperature for one hour. The reaction mixture was evaporated and the residue was partitioned between ethyl acetate and 2N HCl. The organic layer was washed successively with water, saturated NaCl, and dried (Na2SO4). The solvent was removed and the residue was chromatographed on silica gel with dichloromethane-ethyl acetate (20:1, v/v) as eluent. The obtained product was washed with diethyl ether to give the title compound (1.9 g, 79%). 1H NMR (DMSO-d6, HMDSO), δ: 2.16 (3H, s); 3.69 (3H, s); 6.65 (1H, d, J=16.0 Hz); 7.00 (4H, s); 7.49-8.11 (5H, m); 10.14 (1H, br s).
Reaction SMILES: [N:1]1([C:8]2[CH:9]=[CH:10][C:11]3[N:12]([C:14]([C:17]([F:20])([F:19])[F:18])=[N:15][N:16]=3)[N:13]=2)[CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH3:21][O:22][C:23]1[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=1[CH:25]=O>>[CH3:21][O:22][C:23]1[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=1[CH2:25][N:4]1[CH2:5][CH2:6][CH2:7][N:1]([C:8]2[CH:9]=[CH:10][C:11]3[N:12]([C:14]([C:17]([F:18])([F:19])[F:20])=[N:15][N:16]=3)[N:13]=2)[CH2:2][CH2:3]1
Reactant: FC(F)(F)c1nnc2ccc(N3CCCNCC3)nn12
Reactant: COc1ccccc1C=O
Product: COc1ccccc1CN1CCCN(c2ccc3nnc(C(F)(F)F)n3n2)CC1

Procedure:
Reductive amination of 6-(1,4-diazepan-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine with 2-methoxybenzaldehyde was carried out according to General Synthetic Method 8. The crude product was purified by hplc using a Waters XBridge Prep C18 OBD column (5μ silica, 19 mm diameter, 100 mm length) eluted with decreasingly polar mixtures of water (containing 0.05% aqueous ammonia) and acetonitrile as eluents to give 6-[4-[(2-methoxyphenyl)methyl]-1,4-diazepan-1-yl]-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=2)[CH:16]=O)[CH2:4][CH2:3]1.[F:21][C:22]1[C:23]([CH3:30])=[C:24]([NH2:29])[C:25]([NH2:28])=[CH:26][CH:27]=1>CN(C=O)C>[F:21][C:22]1[CH:27]=[CH:26][C:25]2[N:28]=[C:16]([C:15]3[CH:18]=[CH:19][CH:20]=[C:13]([O:12][CH2:11][CH2:10][CH2:9][O:8][CH:5]4[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]4)[CH:14]=3)[NH:29][C:24]=2[C:23]=1[CH3:30]
Reactant: Cc1c(F)ccc(N)c1N
Reactant: CN1CCC(OCCCOc2cccc(C=O)c2)CC1
Solvent: CN(C)C=O
Product: Cc1c(F)ccc2nc(-c3cccc(OCCCOC4CCN(C)CC4)c3)[nH]c12
Yield: 37.8 %

Procedure:
6-Fluoro-7-methyl-2-{3-[3-(1-methyl-piperidin-4-yloxy)-propoxy]-phenyl}-1H-benzoimidazole. To a stirred solution of 3-[3-(1-methyl-piperidin-4-yloxy)-propoxy]-benzonitrile (0187 g, 0.68 mmol, 1.0 equiv) in toluene (5.0 mL) at 0° C. was added 1.5 M diisobutylaluminum hydride in toluene (1.02 mL, 1.02 mmol, 1.5 equiv). After 3 h, methanol (9 mL) and 1 M H2SO4 (10 mL) were added. The mixture was stirred for 30 min, then 1.0 M NaOH (10 mL) was added, followed by satd. aq. sodium potassium tartrate (40 mL) and dichloromethane (100 mL). After stirring for 30 min, the mixture was extracted three times with chloroform (50 mL) and the combined extracts were washed with brine, dried (Na2SO4), filtered, and concentrated. The residue was partially purified by Method 2 to afford 106 mg of a mixture of 3-[3-(1-methyl-piperidin-4-yloxy)-propoxy]-benzaldehyde and several other unidentified products. A solution of the crude 3-[3-(1-methyl-piperidin-4-yloxy)-propoxy]-benzaldehyde (53 mg), 4-fluoro-3-methyl-benzene-1,2-diamine (27 mg), and Na2S2O5 in DMF was stirred at 90° C. for 18 h. The reaction mixture was loaded directly on silica gel and purified according to Method 2, which afforded 28.7 mg of the title compound.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]2[CH:10]=[CH:9][N:8](C(OC(C)(C)C)=O)[C:5]2=[CH:6][N:7]=1.[NH2:18][C:19]1[N:20]=[CH:21][C:22]([C:25]#[N:26])=[N:23][CH:24]=1.C(=O)([O-])[O-].[Cs+].[Cs+].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>O1CCOCC1>[NH:8]1[C:5]2=[CH:6][N:7]=[C:2]([NH:18][C:19]3[N:20]=[CH:21][C:22]([C:25]#[N:26])=[N:23][CH:24]=3)[CH:3]=[C:4]2[CH:10]=[CH:9]1
Reactant: CC(C)(C)OC(=O)n1ccc2cc(Cl)ncc21
Reactant: N#Cc1cnc(N)cn1
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: N#Cc1cnc(Nc2cc3cc[nH]c3cn2)cn1
Temperature: 150 °C
Yield: 45.4 %

Procedure:
A mixture of tert-butyl 5-chloro-1H-pyrrolo[2,3-c]pyridine-1-carboxylate (0.030 g, 0.119 mmol), 5-aminopyrazine-2-carbonitrile (0.017 g, 0.142 mmol), cesium carbonate (0.077 g, 0.237 mmol), Xantphos (0.011 g, 0.019 mmol) and tris(benzylideneacetone)dipalladium (0) (0.009 g, 0.010 mmol) in dioxane (0.8 mL) was degassed by bubbling argon through the mixture for 10 minutes. The sealed reaction vessel was heated to 150° C. for 1 hour in a microwave reactor. The crude mixture was filtered through an SCX-2 acidic resin cartridge, eluting with 2 M ammonia in methanol. The basic filtrate was concentrated and purified by column chromatography to give the title compound (0.018 g, 0.054 mmol, 45%). LC-MS (3) Rt=1.30 min; m/z (ESI+) 237 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([NH:14][NH2:15])=[N:12][N:11]([CH2:16][C:17]3[C:18]([CH3:27])=[N:19][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:21][CH:22]=3)[C:10](=[O:28])[C:9]=2[C:29]2[CH:36]=[CH:35][C:32]([C:33]#[N:34])=[CH:31][CH:30]=2)=[CH:4][CH:3]=1.[CH2:37]1C[O:40][CH2:39][CH2:38]1.CCN(CC)CC.C(Cl)(=O)CC>CCOC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([NH:14][NH:15][C:39](=[O:40])[CH2:38][CH3:37])=[N:12][N:11]([CH2:16][C:17]3[C:18]([CH3:27])=[N:19][C:20]([C:23]([F:25])([F:26])[F:24])=[CH:21][CH:22]=3)[C:10](=[O:28])[C:9]=2[C:29]2[CH:30]=[CH:31][C:32]([C:33]#[N:34])=[CH:35][CH:36]=2)=[CH:4][CH:3]=1
Reactant: Cc1nc(C(F)(F)F)ccc1Cn1nc(NN)c(-c2ccc(Cl)cc2)c(-c2ccc(C#N)cc2)c1=O
Reactant: C1CCOC1
Agent: CCC(=O)Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCC(=O)NNc1nn(Cc2ccc(C(F)(F)F)nc2C)c(=O)c(-c2ccc(C#N)cc2)c1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 47 %

Procedure:
To a round bottom flask was added 4-(5-(4-chlorophenyl)-6-hydrazinyl-2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)methyl)-3-oxo-2,3-dihydropyridazin-4-yl)benzonitrile (96 mg, 0.187 mmol), THF (31 ml), Et3N (37.8 mg, 0.374 mmol) and propionyl chloride (17.3 mg, 0.187 mmol). The resulting reaction mixture was stirred at rt for 20 min. After this time, the reaction mixture was diluted with EtOAc (30 ml). The resulting solution was poured into a separatory funnel and the layers were separated. The organic layer was washed with water (2×10 ml) and saturated aqueous NaCl (10 mL). The organic layer was then slurried with MgSO4 to remove excess water, filtered and concentrated to give the crude product. The crude product was purified using an automated column chromatography system (ISCO, 4 gm silica gel) eluting with a gradient of 20-80% EtOAc/Hex to give product N′-(4-(4-chlorophenyl)-5-(4-cyanophenyl)-1-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)methyl)-6-oxo-1,6-dihydropyridazin-3-yl)propionohydrazide as light yellow solid 50 mg (47% yield, for 2 steps). HPLC retention time (method A) 2.941 min; LCMS (M+H)=567.3.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[C:9]([C:10]2[NH:14][CH:13]=[C:12]([CH2:15][N:16]([CH3:24])[C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[C:11]=2[F:25])=[CH:8][CH:7]=[CH:6][N:5]=1.C1OCCOCCOCCOCCOC1.[Cl:41][C:42]1[S:46][C:45]([S:47](Cl)(=[O:49])=[O:48])=[CH:44][CH:43]=1>O1CCCC1.O>[Cl:41][C:42]1[S:46][C:45]([S:47]([N:14]2[C:10]([C:9]3[C:4]([F:3])=[N:5][CH:6]=[CH:7][CH:8]=3)=[C:11]([F:25])[C:12]([CH2:15][N:16]([CH3:24])[C:17](=[O:23])[O:18][C:19]([CH3:21])([CH3:22])[CH3:20])=[CH:13]2)(=[O:49])=[O:48])=[CH:44][CH:43]=1
Reactant: CN(Cc1c[nH]c(-c2cccnc2F)c1F)C(=O)OC(C)(C)C
Reactant: O=S(=O)(Cl)c1ccc(Cl)s1
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CN(Cc1cn(S(=O)(=O)c2ccc(Cl)s2)c(-c2cccnc2F)c1F)C(=O)OC(C)(C)C
Reaction time: 0.25 h
Yield: 98 %

Procedure:
To a suspension of sodium hydride (60% in oil, 24.0 mg) in tetrahydrofuran (2 mL) was added tert-butyl {[5-(2-fluoropyridin-3-yl)-4-fluoro-1H-pyrrol-3-yl]methyl}methylcarbamate (150 mg) under ice-cooling, and the mixture was stirred for 15 min. 15-Crown-5 (133 mg) and a solution of 5-chlorothiophene-2-sulfonyl chloride in tetrahydrofuran (1 mL) were added dropwise and the mixture was further stirred at room temperature for 1 hr. The reaction mixture was diluted with water, and extracted with ethyl acetate. The separated aqueous layer was extracted again with ethyl acetate. The combined organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=9:1→2:1) to give the title compound as a colorless oil (yield 229 mg, 98%).
Reaction SMILES: Cl.Cl.[NH:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[C:20]4[C:19]([NH2:21])=[N:18][CH:17]=[N:16][C:15]=4[N:14]([CH3:22])[CH:13]=3)=[CH:9][CH:10]=2)[CH2:5][CH2:4]1.[CH3:23][C:24]1[CH:25]=[C:26]([CH2:30][C:31](O)=[O:32])[CH:27]=[CH:28][CH:29]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.O>[CH3:22][N:14]1[C:15]2[N:16]=[CH:17][N:18]=[C:19]([NH2:21])[C:20]=2[C:12]([C:8]2[CH:7]=[C:6]3[C:11](=[CH:10][CH:9]=2)[N:3]([C:31](=[O:32])[CH2:30][C:26]2[CH:27]=[CH:28][CH:29]=[C:24]([CH3:23])[CH:25]=2)[CH2:4][CH2:5]3)=[CH:13]1
Reactant: Cc1cccc(CC(=O)O)c1
Reactant: Cn1cc(-c2ccc3c(c2)CCN3)c2c(N)ncnc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cccc(CC(=O)N2CCc3cc(-c4cn(C)c5ncnc(N)c45)ccc32)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.6 %

Procedure:
In a 20 mL vial with cap, to the solution of 5-(2,3-dihydro-1H-indol-5-yl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine-2HCl (70.6 mg, 0.209 mmol), (3-methylphenyl)acetic acid (31.4 mg, 0.209 mmol), HATU (79 mg, 0.209 mmol) in DMF (2 mL) was added Hunig's base (0.146 mL, 0.836 mmol). The mixture was stirred at room temperature for overnight. LCMS showed reaction was completed. The reaction was poured into water, light brown colored solid formed. The solid was filtered and dried to afford 7-methyl-5-{1-[(3-methylphenyl)acetyl]-2,3-dihydro-1H-indol-5-yl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine (57 mg). 1H NMR (400 MHz, DMSO-d6) δ ppm 2.30 (s, 3H), 3.16-3.23 (m, 2H), 3.72 (s, 3H), 3.82 (s, 2H), 4.17-4.24 (m, 2H), 7.06-7.14 (m, 3H), 7.20-7.27 (m, 3H), 7.30 (s, 1H), 8.11-8.18 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:22]=[CH:21][C:11]([C:12]([NH:14][CH:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)=[O:13])=[CH:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.Cl[C:24]1[N:32]=[CH:31][N:30]=[C:29]2[C:25]=1[N:26]=[CH:27][N:28]2[CH:33]([CH2:36][CH3:37])[CH2:34][OH:35].C(O)CCC.O>C(N(CC)CC)C>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:22]=[CH:21][C:11]([C:12]([NH:14][CH:15]3[CH2:16][CH2:17][N:18]([C:24]4[N:32]=[CH:31][N:30]=[C:29]5[C:25]=4[N:26]=[CH:27][N:28]5[CH:33]([CH2:34][OH:35])[CH2:36][CH3:37])[CH2:19][CH2:20]3)=[O:13])=[CH:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(NC1CCNCC1)c1ccc(-c2cccc(F)c2)nc1
Reactant: CCC(CO)n1cnc2c(Cl)ncnc21
Solvent: CCCCO
Solvent: O
Solvent: CCN(CC)CC
Product: CCC(CO)n1cnc2c(N3CCC(NC(=O)c4ccc(-c5cccc(F)c5)nc4)CC3)ncnc21
Temperature: 85 °C

Procedure:
6-(3-fluorophenyl)-N-(piperidin-4-yl)nicotinamide (2.0 g, 5.37 mmol) and 2-(6-chloro-9H-purin-9-yl)butan-1-ol (1.58 g, 6.98 mmol) were placed in a flask along with 10 mL of butanol, 10 mL of water and 10 mL of triethylamine. The mixture was heated to 85° C. for 2 hours. The reaction mixture was partitioned between ethyl acetate and brine. The ethyl acetate was washed 3× with brine and then dried over MgSO4, filtered and concentrated. The residue was purified by chromatography (silica, 1.5% EtOH/EtOAc) to give the desired racemic product (Example 88, 1.34 g, 57%). The material was purified by chiral chromatography-SFC (50% iPrOH in CO2, AD-H 30×250 mm col) to give the two peaks (enantiomeric pair)
Reaction SMILES: [Cl:1][C:2]([Cl:17])=[C:3]([C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=1)[C:4]([OH:6])=O.O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1.C(N(CC)CC)C.[Cl:40][C:41]1[CH:51]=[C:50]([O:52][CH2:53][CH:54]=[C:55]([Cl:57])[Cl:56])[CH:49]=[C:48]([Cl:58])[C:42]=1[O:43][CH2:44][CH2:45][CH2:46][NH2:47]>ClCCl.C(OCC)(=O)C>[Cl:17][C:2]([Cl:1])=[C:3]([C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=1)[C:4]([NH:47][CH2:46][CH2:45][CH2:44][O:43][C:42]1[C:48]([Cl:58])=[CH:49][C:50]([O:52][CH2:53][CH:54]=[C:55]([Cl:57])[Cl:56])=[CH:51][C:41]=1[Cl:40])=[O:6]
Reactant: O=C(O)C(=C(Cl)Cl)c1ccc(C(F)(F)F)cc1
Reactant: NCCCOc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=C(NCCCOc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl)C(=C(Cl)Cl)c1ccc(C(F)(F)F)cc1

Procedure:
74 mg of 3,3-dichloro-2-(4-trifluoromethyl-phenyl)-acrylic acid, 67 mg of bis(2-oxo-3-oxazolidinyl)-phosphinic acid chloride, 53 mg of triethylamine and 100 mg of 3-[2,6-dichloro-4-(3,3-dichloro-allyloxy)-phenoxy]-propylamine are stirred in 2 ml of dichloromethane for 48 hours at 40° C. The reaction mixture is diluted with 16 ml of ethyl acetate and washed twice with aqueous potassium carbonate solution. After concentration of the organic phase and purification over silica gel, the title compound is obtained.
Reaction SMILES: [Mg].C[O-].[Mg+2].C[O-].[CH2:7]([C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=1)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[C:26](O)(=[O:28])C>CO.C1(C)C=CC=CC=1>[CH2:7]([C:19]1[CH:20]=[C:21]([CH:26]=[O:28])[C:22]([OH:25])=[CH:23][CH:24]=1)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CC(=O)O
Reactant: CCCCCCCCCCCCc1ccc(O)cc1
Agent: C[O-]
Agent: [Mg+2]
Agent: [Mg]
Solvent: CO
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCc1ccc(O)c(C=O)c1
Temperature: 45 °C
Reaction time: 0.75 h
Yield: 65 %

Procedure:
A 2 liter round-bottomed flask was charged with magnesium turnings (12.2 g, 0.50 mole), methanol (13 3 ml), toluene (60 ml), and magnesium methoxide solution (10 ml of an 8 weight % solution of magnesium methoxide in methanol). The reaction mixture was heated to 45° C. at which point the magnesium dissolution became vigorous. The temperature of the reaction mixture was maintained between 45 and 55° C. Para-dodecyl phenol (128.0 g, 0.50 mole) dissolved in toluene (125 ml) was added in one portion to the reaction mixture which was then maintained at 65° C. for one hour. Glacial acetic acid (30.1 g, 0.50 mole) was added over a 1 hour period, while maintaining the reaction mixture at reflux (65-66°). The reaction flask was then rigged for fractional distillation and the methanol/toluene azeotrope was distilled off until an internal temperature of 85° C. A total of 117 g of distillate, assaying 65% methanol and 35% toluene, was collected. Toluene (130 g) was added to the reaction mixture in one portion. Paraformaldehyde (45.0 g) slurried in toluene (90 g) was then added over a 90 minute period. During the addition, the reaction mixture was maintained at a temperature of 85-90° C. allowing a continuous distillation of the volatile reaction by-products. When the paraformaldehyde addition was complete, the reaction mixture was maintained at 90° C. for an additional 90 minutes. The reaction mass was then cooled to 35° C. and 500 ml of 20 vol % sulfuric acid was added. The hydrolysis mass was then stirred for an additional 45 minutes. After phase separation, the organic phase was washed twice with 200 ml portions of water. The washed organic phase was then separated, dried and rendered free of the solvent to yield crude 5-dodecyl salicylaldehyde. A 65% yield was obtained.