Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)=[O:16])[CH2:10][CH2:9]1)C1C=CC=CC=1.[H][H]>CO.O1CCCC1.[Pd]>[NH:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]([NH:17][C:18]2[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=2)=[O:16])[CH2:10][CH2:9]1
Reactant: [H][H]
Reactant: O=C(Nc1ccc(F)cc1)NC1CCN(Cc2ccccc2)CC1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(Nc1ccc(F)cc1)NC1CCNCC1
Yield: 90.6 %

Procedure:
To a solution of N-(1-benzylpiperidin-4-yl)-N′-(4-fluorophenyl)urea (3.0 g) in a mixture of methanol (15 ml) and tetrahydrofuran (15 ml) was added palladium on carbon (10% w/w, 50% wet, 0.6 g), and the mixture was hydrogenated under atmospheric pressure of hydrogen for 8 hours. The catalyst was filtered off, and the solvents were evaporated under reduced pressure to give a residue, which was triturated with diisopropyl ether to give N-(piperidin-4-yl)-N′-(4-fluorophenyl)urea (1.97 g).
Reaction SMILES: [NH2:1][CH:2]1[CH2:46][N:5]2[C:6]3[CH:7]=[CH:8][C:9]([C:13]4[C:28]([CH3:29])=[C:27]([O:30]CC5C=CC=CC=5)[C:16]([C:17]([O:19]CC5C=CC=CC=5)=[O:18])=[C:15]([O:38]CC5C=CC=CC=5)[N:14]=4)=[CH:10][C:11]=3[CH:12]=[C:4]2[CH2:3]1.[ClH:47]>CO.[Pd]>[ClH:47].[NH2:1][CH:2]1[CH2:46][N:5]2[C:6]3[CH:7]=[CH:8][C:9]([C:13]4[NH:14][C:15](=[O:38])[C:16]([C:17]([OH:19])=[O:18])=[C:27]([OH:30])[C:28]=4[CH3:29])=[CH:10][C:11]=3[CH:12]=[C:4]2[CH2:3]1
Reactant: Cc1c(-c2ccc3c(c2)cc2n3CC(N)C2)nc(OCc2ccccc2)c(C(=O)OCc2ccccc2)c1OCc1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: Cc1c(-c2ccc3c(c2)cc2n3CC(N)C2)[nH]c(=O)c(C(=O)O)c1O
Temperature: 25 °C
Reaction time: 16 h
Yield: 49 %

Procedure:
The intermediate from Step 4 (36 mg, 0.06 mmol) was dissolved in MeOH (2 mL). To the solution was added 10% Pd/C (20 mg) and 3 N HCl in MeOH (0.1 mL). The mixture stirred under H2 (1 atm) at room temperature for 16 h. The mixture was filtered through a 5 μm cartridge. The filtrate was concentrated, leaving the product (21 mg, 49%) as an off white powder.
Reaction SMILES: [CH:1]1([N:7]=[C:8]=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[N:18]=[CH:19][N:20](COCC[Si](C)(C)C)[C:21]=2[C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)=[CH:13][CH:12]=1>>[CH:1]1([NH:7][C:8]([C:19]2[NH:20][C:21]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=3)=[C:17]([C:14]3[CH:13]=[CH:12][C:11]([Cl:10])=[CH:16][CH:15]=3)[N:18]=2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C=NC1CCCCC1
Reactant: C[Si](C)(C)CCOCn1cnc(-c2ccc(Cl)cc2)c1-c1ccc(Cl)cc1
Product: O=C(NC1CCCCC1)c1nc(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2)[nH]1

Procedure:
Using essentially the same procedure as Example 25, Step B-C, but using cyclohexyl isocyanate (0.027 mL, 0.21 mmol) in Step B, 4,5-di-(4-chlorophenyl)-1-(2-(trimethylsilyl)ethoxymethyl)imidazole (36 mg, 0.086 mmol) from Example 25, Step A was converted to the SEM intermediate and then to the title compound with TBAF.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@:8]([C:17]2[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[C:19]([F:27])[CH:18]=2)([NH2:16])[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:6][CH:7]=1.[F:28][C:29]([F:34])([F:33])[C@@H:30]1[CH2:32][O:31]1>C(#N)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@@:8]([NH:16][CH2:32][C@@H:30]([OH:31])[C:29]([F:34])([F:33])[F:28])([C:17]2[CH:22]=[C:21]([C:23]([F:26])([F:24])[F:25])[CH:20]=[C:19]([F:27])[CH:18]=2)[CH2:9][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[N:6][CH:7]=1
Reactant: N[C@@](Cc1ccccc1)(c1cc(F)cc(C(F)(F)F)c1)c1ccc(Cl)cn1
Reactant: FC(F)(F)[C@@H]1CO1
Solvent: CC#N
Product: O[C@H](CN[C@@](Cc1ccccc1)(c1cc(F)cc(C(F)(F)F)c1)c1ccc(Cl)cn1)C(F)(F)F
Temperature: 140 °C
Yield: 64 %

Procedure:
(S)-1-(5-chloropyridin-2-yl)-1-(3-fluoro-5-(trifluoromethyl)phenyl)-2-phenyl ethanamine (0.148 g, 0.376 mmol, prepared as described in Procedures 5, 6 and 7) was dissolved in anhydrous acetonitrile (1 mL). (S)-2-(trifluoromethyl)oxirane (approximate 85:15 ratio of R to S) (0.20 mL, excess) was added to the solution in a microwave vial followed by Yb(OSO2CF3)3 (0.020 g, mmol). The sealed vial was heated to 140° C. for 20 mins in the microwave. The reaction mixture was taken from the reaction vial via syringe and injected directly onto a silica gel ISCO cartridge column (40 g). The product eluted at 8 minutes with a gradient of 0-50% EtOAc in hexanes over 18 minutes and flow rate of 40 mL/min, (0.122 mg, 64% yield). The crude NMR of this material showed an 85:15 ratio of R to S at the hydroxy centre. The material was further purified on a Chiral cell AD column with 5% IPA in hexane as the mobile phase yielding 0.068 g of (R)-3-((S)-1-(5-chloropyridin-2-yl)-1-(3fluoro-5-(trifluoromethyl)phenyl)-2-phenylethylamino)-1,1,1-trifluoropropan-2-ol as a colorless oil and a further 0.044 g of mixed fractions. LCMS: 2.06 min [M+1] 507.2 (2 min gradient, MeOH/H2O 0.1% TFA); HPLC: 7.88 min (8 min gradient, MeOH/H2O 0.2% PPA Purity 100%; NMR: 400 MHz 1H (CDCl3) 8.42 ppm, 1H, d, J=2.2 Hz; 7.55 ppm, 1H, dd, J=8.36 and J=2.64 Hz; 7.30 ppm, 1H, s; 7.13 ppm, 3H, m; 7.08 ppm, 2H, m; 6.57 ppm, 2H, d, J=7.04 Hz; 3.85 ppm, IH, m; 3.76 ppm, 1H, d, J=12.2 Hz; 3.50 ppm, 1H, d, J=12.2 Hz; 2.78 ppm, 1H, dd, J=6.12 and 12.0 Hz; 2.64 ppm, 1H, dd, J=3.96 and J=12.2 Hz.
Reaction SMILES: [OH-].[Na+].[Cl:3][S:4]([OH:7])(=O)=[O:5].[Cl:8][C:9]1[N:17]=[C:16]2[C:12]([N:13]=[CH:14][N:15]2[CH2:18][CH3:19])=[C:11]([NH:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[N:10]=1>>[Cl:8][C:9]1[N:17]=[C:16]2[C:12]([N:13]=[CH:14][N:15]2[CH2:18][CH3:19])=[C:11]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([S:4]([Cl:3])(=[O:7])=[O:5])=[CH:23][CH:22]=2)[N:10]=1
Reactant: O=S(=O)(O)Cl
Reactant: CCn1cnc2c(Nc3ccccc3)nc(Cl)nc21
Agent: [Na+]
Agent: [OH-]
Product: CCn1cnc2c(Nc3ccc(S(=O)(=O)Cl)cc3)nc(Cl)nc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 89.6 %

Procedure:
A three necked round bottomed flask of 250 ml equipped with a bubbler (NaOH) and a magnetic stirrer is charged with 32.2 ml of 98% chlorosulfonic acid (483 mmoles) and cooled to 0° C. 22 g of 2-chloro-9-ethyl-6-(phenyl-amino)-9H-purine (80 mmoles) are added slowly. The mixture is stirred at RT for 2 hours and at 60° C. for 1 hour. The crude mixture is then poured drop by drop into a water bath cooled to 0° C., filtered and dried at 50° C. under HV. 26.67 g (89% yield) of 2-chloro-6-(4-chlorosulfonyl-phenyl-amino)-9-ethyl-9H-purine are obtained as a white crystalline powder. Rf=0.52 (CH2Cl2/MeOH (95/5); m.p. decomp. 220° C.; ESI-MS: 372 (M+H)+; 1H-NMR (d6-DMSO, 200 MHz, TMS): 1.4 ppm (t, 3H, J1=7 Hz, H1), 4.2 ppm (q, 2H, J1=7 Hz, H2), 7.55 ppm (d, 2H, J2=9 Hz, H5), 7.75 ppm (d, 2H, J2=9 Hz, H6), 8.55 ppm (s, 1H, H3), 10.5 ppm (s, 1H, H4).
Reaction SMILES: [C:1]([C:5]1[CH:31]=[CH:30][C:8]([C:9]([NH:11][C:12]2[CH:28]=[C:27]([NH2:29])[CH:26]=[CH:25][C:13]=2[C:14]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)=[O:15])=[O:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:32]([S:36](Cl)(=[O:38])=[O:37])[CH2:33][CH2:34][CH3:35]>C(N(CC)CC)C>[C:1]([C:5]1[CH:31]=[CH:30][C:8]([C:9]([NH:11][C:12]2[CH:28]=[C:27]([NH:29][S:36]([CH2:32][CH2:33][CH2:34][CH3:35])(=[O:38])=[O:37])[CH:26]=[CH:25][C:13]=2[C:14]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)=[O:15])=[O:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccc(NC(=O)c2ccc(N)cc2NC(=O)c2ccc(C(C)(C)C)cc2)cc1
Reactant: CCCCS(=O)(=O)Cl
Solvent: CCN(CC)CC
Product: CCCCS(=O)(=O)Nc1ccc(C(=O)Nc2ccc(OC)cc2)c(NC(=O)c2ccc(C(C)(C)C)cc2)c1
Yield: 20 %

Procedure:
Using the procedure described in Example 59, Part E, 2-(4-tert-butylbenzoylamino)-4-amino-N-(4-methoxyphenyl)benzamide (500 mg, 1.20 mmol) was reacted with butylsulfonyl chloride in the presence of triethylamine to yield 130 mg (20%) of the title compound as an off-white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([C:14]#[N:15])[C:11]=1[O:12][CH3:13])[C:5]([O:7]C)=[O:6].O.[OH-].[Li+]>O1CCCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([C:14]#[N:15])[C:11]=1[O:12][CH3:13])[C:5]([OH:7])=[O:6]
Reactant: COC(=O)c1cc(Cl)c(OC)c(C#N)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COc1c(Cl)cc(C(=O)O)cc1C#N
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 98.9 %

Procedure:
Methyl 3-chloro-5-cyano-4-methoxybenzoate (1.02 g) was dissolved in tetrahydrofuran (15 mL) and water (6 mL), and lithium hydroxide monohydrate (759 mg) was added to the solution, and then the mixture was stirred at room temperature for 90 minutes. The organic solvent was distilled off and the aqueous layer was washed with n-hexane. The aqueous layer was acidified with 1N hydrochloric acid and then extracted with ethyl acetate. The organic layer was washed with saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound (946 mg) as a colorless crystal.
Reaction SMILES: CCCCCC.C([Li])CCC.Br[C:13]1[CH:14]=[C:15]([F:19])[CH:16]=[CH:17][CH:18]=1.[N:20]1[C:29]2[C:24](=[C:25]3[CH:37]=[CH:36][CH:35]=[CH:34][C:26]3=[C:27]3[CH:33]=[CH:32][CH:31]=[CH:30][C:28]3=2)[N:23]=[CH:22][CH:21]=1>ClCCl.O.O1CCCC1>[F:19][C:15]1[CH:14]=[C:13]([C:22]2[CH:21]=[N:20][C:29]3[C:24](=[C:25]4[CH:37]=[CH:36][CH:35]=[CH:34][C:26]4=[C:27]4[CH:33]=[CH:32][CH:31]=[CH:30][C:28]4=3)[N:23]=2)[CH:18]=[CH:17][CH:16]=1
Reactant: c1ccc2c(c1)c1ccccc1c1nccnc21
Reactant: Fc1cccc(Br)c1
Agent: [Li]CCCC
Solvent: O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Fc1cccc(-c2cnc3c4ccccc4c4ccccc4c3n2)c1
Temperature: -78 °C
Reaction time: 2 h
Yield: 23 %

Procedure:
First, under a nitrogen atmosphere, 27.5 mL (1.58 mol/L) of a hexane solution of n-butyllithium was dripped into a mixed solution of 6.87 g of 3-bromofluorobenzene and 40 mL of tetrahydrofuran at −78° C. Then, with the temperature maintained at −78° C., the mixture was stirred for 2 hours. To the obtained solution was added 7.54 g of dibenzo[f,h]quinoxaline in five additions at −78° C. The mixture was heated to room temperature, and stirred for 12 hours with the temperature maintained at room temperature. Water was added to this mixture and dichloromethane was used as an extraction solvent, so that an organic layer was extracted. The obtained organic layer was dried with anhydrous magnesium sulfate. The solution obtained by the drying was filtrated. The solvent of this solution was distilled off, and then, by recrystallization with ethanol, the organometallic complex of the present invention, Hdbq-3FP, which was the target substance, was obtained (a light-orange powder, yield: 23%). Synthesis scheme of Step 1 is shown in (a-2) below.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[CH:12][N:11]=2)[CH2:6][CH2:5]1.N1C=CN=C1.[Si:23](Cl)([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24]>CN(C=O)C.CCOC(C)=O>[C:26]([Si:23]([CH3:25])([CH3:24])[O:1][CH2:2][CH2:3][N:4]1[CH2:5][CH2:6][N:7]([C:10]2[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[CH:12][N:11]=2)[CH2:8][CH2:9]1)([CH3:29])([CH3:28])[CH3:27]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: N#Cc1ccc(N2CCN(CCO)CC2)nc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)OCCN1CCN(c2ccc(C#N)cn2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 75.3 %

Procedure:
To a solution of 6-[4-(2-hydroxy-ethyl)-piperazin-1-yl]-nicotinonitrile (350 mg, 1.51 mmol) and imidazole (236 mg, 3.47 mmol) in anhydrous DMF (3 mL) was added TBDMS chloride (295 mg, 1.96 mmol) in anhydrous DMF (2 mL) and the reaction mixture stirred for 16 h at RT. The reaction mixture was diluted with EtOAc (5 mL) and washed with water (10 mL) and brine (10 mL). The organic phase was separated, passed through a phase separation cartridge and concentrated in vacuo. The crude residue was purified on silica gel column chromatography eluting with 30% EtOAc/isohexane, and increasing the polarity to 50% EtOAc/isohexane to afford 6-{4-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-piperazin-1-yl}-nicotinonitrile as a pale yellow solid (394 mg, 75%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([NH:9][CH2:10][C:11](OCC)=[O:12])=[CH:7][C:6]([CH2:16][S:17](/[CH:20]=[CH:21]/[C:22]2[C:27]([O:28][CH3:29])=[CH:26][C:25]([O:30][CH3:31])=[CH:24][C:23]=2[O:32][CH3:33])(=[O:19])=[O:18])=[CH:5][N:4]=1.[NH3:34]>O>[CH3:1][O:2][C:3]1[C:8]([NH:9][CH2:10][C:11]([NH2:34])=[O:12])=[CH:7][C:6]([CH2:16][S:17](/[CH:20]=[CH:21]/[C:22]2[C:23]([O:32][CH3:33])=[CH:24][C:25]([O:30][CH3:31])=[CH:26][C:27]=2[O:28][CH3:29])(=[O:18])=[O:19])=[CH:5][N:4]=1
Reactant: N
Reactant: CCOC(=O)CNc1cc(CS(=O)(=O)/C=C/c2c(OC)cc(OC)cc2OC)cnc1OC
Solvent: O
Product: COc1cc(OC)c(/C=C/S(=O)(=O)Cc2cnc(OC)c(NCC(N)=O)c2)c(OC)c1
Temperature: 60 °C
Reaction time: 4 h
Yield: 26 %

Procedure:
(E)-ethyl 2-(2-methoxy-5-((2,4,6-trimethoxystyrylsulfonyl)methyl)pyridin-3-ylamino)acetate (20 mg, 0.04 mmol) was added to a solution of ammonia (5 mL 7N in methanol) and H2O (5 mL). The mixture was stirred at 60° C. for 4 h. After evaporated to dryness, the residue was purified by silica gel chromatography, eluting with PE/EtOAc (1:1, v/v) to afford pure product as a brown powder (9.2 mg, 26%). 1H-NMR (CDCl3): δ 3.80 (d, 2H, J=1.6 Hz, CH2), 3.87 (s, 6H, 2×OCH3), 3.87 (s, 3H, OCH3), 4.01 (s, 3H, OCH3), 4.16 (s, 2H, CH2), 5.43 (s, 1H, NH), 6.12 (s, 2H, Ph-H), 6.75 (d, 1H, J=2.0 Hz, Py-H), 7.09 (d, 1H, J=15.6 Hz, CH), 7.56 (d, 1H, J=2.0 Hz, Py-H), 7.81 (d, 1H, J=15.6 Hz, CH); HR-MS (ESI+) m/z 452.1560 [M+H]+ C20H25N3O7S requires 451.1413.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][CH:19]3[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]3)[CH:13]=2)=[O:11])=[CH:4][C:3]=1[C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([CH2:32][N:33]2[CH2:38][CH2:37][N:36](C(OCC3C=CC=CC=3)=O)[C@@H:35]([CH3:49])[CH2:34]2)[CH:27]=1.[H][H]>CO.[Pd]>[F:1][C:2]1[C:3]([C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([CH2:32][N:33]3[CH2:38][CH2:37][NH:36][C@@H:35]([CH3:49])[CH2:34]3)[CH:27]=2)=[CH:4][C:5]([CH2:8][NH:9][C:10](=[O:11])[C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][CH:19]3[CH2:20][CH2:21][N:22]([CH3:25])[CH2:23][CH2:24]3)[CH:13]=2)=[CH:6][CH:7]=1
Reactant: C[C@H]1CN(Cc2cccc(-c3cc(CNC(=O)c4cccc(CC5CCN(C)CC5)c4)ccc3F)c2)CCN1C(=O)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: C[C@H]1CN(Cc2cccc(-c3cc(CNC(=O)c4cccc(CC5CCN(C)CC5)c4)ccc3F)c2)CCN1
Yield: 68.3 %

Procedure:
To a solution of phenylmethyl (2S)-4-[(2′-fluoro-5′-{[({3-[(1-methyl-4-piperidinyl)methyl]phenyl}carbonyl)amino]methyl)-3-biphenylyl)methyl]-2-methyl-1-piperazinecarboxylate (120 mg, 0.18 mmol) in 5 mL of MeOH, was added 10% Pd/C (60 mg). The mixture was hydrogenated using a hydrogen balloon for 12 hours. After flittering off the catalyst, the mixture was concentrated and the residue was purified by Gilson reverse phase HPLC, eluting with acetonitrile/water/0.1% TFA (10/90 to 70/30, v/v, over 12 min), to give the title compound (65 mg, 41%). LC/MS: m/z, 529 (M+H), 1.29 min.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([Cl:12])[N:3]=1.[OH:13][CH:14]([C:16]1[CH:25]=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][CH:17]=1)[CH3:15]>>[Cl:12][C:4]1[N:3]=[C:2]([O:13][CH:14]([C:16]2[CH:25]=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][CH:17]=2)[CH3:15])[C:11]2[C:6]([CH:5]=1)=[CH:7][CH:8]=[CH:9][CH:10]=2
Reactant: Clc1cc2ccccc2c(Cl)n1
Reactant: COC(=O)c1ccc(C(C)O)cc1
Product: COC(=O)c1ccc(C(C)Oc2nc(Cl)cc3ccccc23)cc1

Procedure:
The title compound was prepared from 1,3-dichloroisoquinoline and racemic methyl 4-(1-hydroxyethyl)benzoate as described in the preparation of INTERMEDIATE 3. 1H NMR (500 MHz, CDCl3): δ 8.35 (d, J=8.4 Hz, 1H); 8.08 (d, J=8.3 Hz, 2H); 7.72-7.68 (m, 2H); 7.64 (d, J=8.3 Hz, 2H); 7.60-7.56 (m, 1H); 7.31 (s, 1H); 6.56 (q, J=6.6 Hz, 1H); 3.95 (s, 3H); 1.81 (d, J=6.5 Hz, 3H). LCMS1 4.26 min. (M-(CH3CHPhCO2Me)+H)=180
Reaction SMILES: [NH2:1][C:2]([CH2:21][CH2:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])([CH2:12][CH2:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:3][CH2:4][C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6].[Br:30][CH2:31][C:32](Br)=[O:33].CCN(CC)CC>C(Cl)Cl>[Br:30][CH2:31][C:32]([NH:1][C:2]([CH2:12][CH2:13][C:14]([O:16][C:17]([CH3:18])([CH3:19])[CH3:20])=[O:15])([CH2:3][CH2:4][C:5]([O:7][C:8]([CH3:11])([CH3:9])[CH3:10])=[O:6])[CH2:21][CH2:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[O:33]
Reactant: O=C(Br)CBr
Reactant: CC(C)(C)OC(=O)CCC(N)(CCC(=O)OC(C)(C)C)CCC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)CCC(CCC(=O)OC(C)(C)C)(CCC(=O)OC(C)(C)C)NC(=O)CBr
Temperature: 25 °C
Reaction time: 8 h
Yield: 40.1 %

Procedure:
To a solution of di-tert-butyl 4-amino-4-(3-(tert-butoxy)-3-oxopropyl)heptanedioate (5.00 g, 12.0 mmol) and 2-bromoacetyl bromide (1.46 mL, 3.40 g, 16.80 mmol) in DCM (60 mL) was added Et3N (2.5 mL) at room temperature. The reaction mixtures were stirred at room temperature for overnight. The reaction mixtures were diluted with DCM (300 mL), washed with 1N HCl solution, and dried over Na2SO4. Solvent was evaporated under reduce pressure to afford a residue, which was purified by biotage eluting with 10% EtOC in hexanes to 100% EtOAc to afford di-tert-butyl 4-(2-bromoacetamido)-4-(3-(tert-butoxy)-3-oxopropyl)heptanedioate (2.58 g, 40%). 1H NMR (400 MHz, CDCl3) 6.43 (s, 1H), 3.76 (s, 2H), 2.20 (t, J=8.0 Hz, 2H), 1.98 (t, J=8.0 Hz, 6H), 1.43 (s, 27H); MS (ESI), 558, 560 (M+Na)+.
Reaction SMILES: [C:1]([O:4][C@H:5]1[CH2:10][CH2:9][C@H:8]2[C@H:11]3[C@H:20]([CH2:21][CH2:22][C@:6]12[CH3:7])[C:19]1[CH:18]=[CH:17][C:16]([O:23][CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][O:25]2)=[CH:15][C:14]=1[CH2:13][C@H:12]3[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][O:35]C(=O)C)(=[O:3])[CH3:2].[OH-].[Na+]>CO.C(OCC)C>[C:1]([O:4][C@H:5]1[CH2:10][CH2:9][C@H:8]2[C@H:11]3[C@H:20]([CH2:21][CH2:22][C@:6]12[CH3:7])[C:19]1[CH:18]=[CH:17][C:16]([O:23][CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][O:25]2)=[CH:15][C:14]=1[CH2:13][C@H:12]3[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][OH:35])(=[O:3])[CH3:2]
Reactant: CC(=O)OCCCCC[C@@H]1Cc2cc(OC3CCCCO3)ccc2[C@H]2CC[C@]3(C)[C@@H](OC(C)=O)CC[C@H]3[C@H]12
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CO
Product: CC(=O)O[C@H]1CC[C@H]2[C@@H]3[C@H](CCCCCO)Cc4cc(OC5CCCCO5)ccc4[C@H]3CC[C@]12C
Yield: 59.7 %

Procedure:
A solution of 10.2 g of 17β-acetoxy-7α-(5-acetoxypentyl)-3-(tetrahydropyran-2-yloxy)-estra-1,3,5(10)-triene in 205 ml of methanol is stirred with 33.7 ml of sodium hydroxide solution for 45 minutes at 15° C. Then, it is diluted with diethyl ether, washed with water, dried on sodium sulfate and concentrated by evaporation in a vacuum. 5.6 g of 17β-acetoxy-7α-(5-hydroxypentyl)-3-(tetrahydropyran-2-yloxy)-estra-1,3,5(10)-triene is obtained. [α]D22 =+32.2° (c=0.505% in chloroform)
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:9]([CH:12]=O)=[C:8]2[C:3]=1[C:4](=[O:15])[CH:5]=[C:6]([CH3:14])[O:7]2.[CH3:16][C:17](=[O:22])[CH2:18][C:19](=[O:21])[CH3:20].C(O)(=O)C.N1CCCCC1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>ClCCl>[F:1][C:2]1[CH:11]=[CH:10][C:9]([CH:12]=[C:18]([C:17](=[O:22])[CH3:16])[C:19](=[O:21])[CH3:20])=[C:8]2[C:3]=1[C:4](=[O:15])[CH:5]=[C:6]([CH3:14])[O:7]2
Reactant: Cc1cc(=O)c2c(F)ccc(C=O)c2o1
Reactant: CC(=O)CC(C)=O
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: C1CCNCC1
Product: CC(=O)C(=Cc1ccc(F)c2c(=O)cc(C)oc12)C(C)=O

Procedure:
239 mg (1.16 mmol) of 5-fluoro-2-methyl-4-oxo-4H-chromene-8-carbaldehyde, 0.14 ml (1.28 mmol) of 2,4-pentanedione, 0.085 ml (1.45 mmol) of acetic acid and 0.01 ml (0.12 mmol) of piperidine are heated under reflux in 25 ml of anhydrous dichloromethane for 3 h. After addition of 80 mg of pyridinium para-toluenesulfonate and heating under reflux for a further 12 h, the reaction solution is washed with water and with brine and concentrated. 308.4 mg (91% of theory) of a red oil are obtained and are directly reacted further.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][C:9]=2[F:15])=[C:6](Cl)[N:5]2[N:17]=[C:18]([CH3:20])[N:19]=[C:4]2[N:3]=1.O.C1COCC1.[NH4+].[Cl-]>C(O)C.[Zn]>[Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][C:9]=2[F:15])=[CH:6][N:5]2[N:17]=[C:18]([CH3:20])[N:19]=[C:4]2[N:3]=1
Reactant: Cc1nc2nc(Cl)c(-c3ccc(F)cc3F)c(Cl)n2n1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: Cc1nc2nc(Cl)c(-c3ccc(F)cc3F)cn2n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 57 %

Procedure:
2.35 g (7.5 mmol) 5,7-Dichloro-6-(2,4-difluorophenyl)-2-methyl-[1,2,4]triazolo[1,5-a]pyrimidine are given in 189 mL ethanol, 135 mL water and 73 mL THF. 1.89 g (35.3 mmol) NH4Cl and 3.1 g (47.7 mmol) zinc powder are added and the mixture is stirred at room temperature for 3 h. The reaction mixture is filtered and the organic solvents are removed. The residue is diluted with water and extracted three times with ethyl acetate. The combined organic layers are washed with brine and dried over Na2SO4. After evaporation of the solvent, the residue is purified by chromatography. 1.2 g (51.6%) of the desired product are obtained.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]([O:5][C:6](=[O:11])[C:7](F)(F)F)=[O:4].C=C=O.FC(F)(F)C(O)=O>>[F:1][C:2]([F:13])([F:12])[C:3]([O:5][C:6](=[O:11])[CH3:7])=[O:4]
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Agent: C=C=O
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)OC(=O)C(F)(F)F

Procedure:
Process for the production of trifluoroacetic anhydride (TFAA) which comprises contacting ketene and trifluoroacetic acid (TFA) to produce a mixed anhydride, acetyl trifluoroacetate (Ac-TFA) and subjecting the mixed anhydride to reactive distillation to produce a lower boiling product comprising TFAA and a higher boiling product comprising acetic anhydride (AC2O).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]3[N:12]=[C:13]4[C:19]([C:20]([OH:22])=O)=[CH:18][NH:17][C:14]4=[N:15][CH:16]=3)=[N:7][NH:8]2)=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C.Cl.[NH2:44][C:45]1([C:48]#[N:49])[CH2:47][CH2:46]1>CN(C1C=CN=CC=1)C.CN(C=O)C.O>[C:48]([C:45]1([NH:44][C:20]([C:19]2[C:13]3[C:14](=[N:15][CH:16]=[C:11]([C:6]4[C:5]5[C:9](=[CH:10][C:2]([CH3:1])=[CH:3][CH:4]=5)[NH:8][N:7]=4)[N:12]=3)[NH:17][CH:18]=2)=[O:22])[CH2:47][CH2:46]1)#[N:49]
Reactant: N#CC1(N)CC1
Reactant: Cc1ccc2c(-c3cnc4[nH]cc(C(=O)O)c4n3)n[nH]c2c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc2c(-c3cnc4[nH]cc(C(=O)NC5(C#N)CC5)c4n3)n[nH]c2c1
Reaction time: 16 h
Yield: 4.1 %

Procedure:
To a stirred solution of 2-(6-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (100 mg, 0.34 mmol), DIEA (200 mg, 1.55 mmol), EDCI (123 mg, 0.64 mmol) and DMAP (110 mg, 0.90 mmol) in 6 mL of DMF was added 1-aminocyclopropanecarbonitrile hydrochloride (100 mg, 0.84 mmol) in one portion at room temperature, then the mixture was stirred for 16 hours. The reaction mixture was poured into 40 mL of water, filtered and the filter cake was purified by preparative-HPLC (Gemini 5u C18 150×21.2 mm; inject volume: 3 mL/inj, flow rate: 20 mL/min; wavelength: 214 nm and 254 nm; the gradient conditions were: 35% acetonitrile/65% water (0.1% trifluoroacetic acid, v/v) initially, proceeding to 70% acetonitrile/30% water (0.1% trifluoroacetic acid, v/v) in a linear fashion over 9 min.) to give N-(1-cyanocyclopropyl)-2-(6-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (5 mg, 4.1%) as a yellow solid. MS: (M+H)+=358; 1H NMR (300 MHz, DMSO): δ 13.40 (s, 1H), 13.00 (s, 1H), 9.19 (s, 1H), 8.98 (s, 1H), 8.56 (d, 1H, J=3.0 Hz), 8.38 (d, 1H, J=8.1 Hz), 7.46 (s, 1H), 7.21 (d, 1H, J=8.4 Hz), 2.53 (s, 3H), 1.78-1.74 (m, 2H), 1.48-1.44 (m, 2H).