Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7](Br)[CH:8]=[CH:9][C:10]=1[O:11][CH3:12])([CH3:4])([CH3:3])[CH3:2].[Mg].Br[C:16]1[S:20][C:19]([C:21]([O:23][CH3:24])=[O:22])=[CH:18][CH:17]=1>C1COCC1.[Cl-].[Zn+2].[Cl-]>[C:1]([C:5]1[CH:6]=[C:7]([C:16]2[S:20][C:19]([C:21]([O:23][CH3:24])=[O:22])=[CH:18][CH:17]=2)[CH:8]=[CH:9][C:10]=1[O:11][CH3:12])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc(Br)cc1C(C)(C)C
Reactant: COC(=O)c1ccc(Br)s1
Agent: [Cl-]
Agent: [Mg]
Agent: [Zn+2]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(-c2ccc(OC)c(C(C)(C)C)c2)s1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of 2 g (8.2 mmol) of 3-tert-butyl-4-methoxybromobenzene is added dropwise to a suspension of 300 mg (12 mmol) of magnesium in 10 ml of THF. Once the addition is complete, the mixture is refluxed for one hour. At room temperature, 1.35 g (9.9 mmol) of anhydrous zinc chloride are added and the mixture is stirred for one hour. 1.2 g (5.5 mmol) of methyl 5-bromo-2-thiophenecarboxylate and 60 mg (0.12 mmol) of the NiCl2 /DPPE complex are then added successively and the mixture is left stirring at room temperature for 12 hours. The reaction medium is poured into ice-water and extracted with ethyl ether and the organic phase is separated out after settling has taken place, dried over magnesium sulphate and evaporated. The residue obtained is chromatographed on a column of silica eluted with a mixture of hexane and dichloromethane (50/50% by volume). After evaporation of the solvents, 1.56 g (93%) of the expected methyl ester are collected, with a melting point of 94-5° C.
Reaction SMILES: O[CH:2]1[CH2:7][C:6]([CH3:9])([CH3:8])[O:5][C:4]2[CH:10]=[CH:11][S:12][C:3]1=2.C1(C)C=CC(S(O)(=O)=O)=CC=1>>[CH3:8][C:6]1([CH3:9])[O:5][C:4]2[CH:10]=[CH:11][S:12][C:3]=2[CH:2]=[CH:7]1
Reactant: CC1(C)CC(O)c2sccc2O1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CC1(C)C=Cc2sccc2O1
Temperature: -5 °C
Reaction time: 1.5 h

Procedure:
A mixture of 5,6-dihydro-7-hydroxy-5,5-dimethyl-7H-thieno [3,2-b]pyran (1.3g, 7.06 mmol), p-toluenesulfonic acid (0.11 g, 0.58 mmol) and ground molecular sieves (1.3 g) was stirred at -5° C. for 1.5 h. The mixture was washed with 1.0 N aqueous sodium hydroxide and dried over magnesium sulfate. The solvent was evaporated in vacuo to give the product, 1.17 g (99%), as a red oil: IR (neat): 2976, 1504 and 1531 cm-1 ; MS: m/z 167 (MH+); 1H NMR (CDCl3): δ1.45 (s, 6H), 5.27 (d, J=9.8 Hz, 1H), 6.30 (d, J=9.8 Hz, 1H), 6.60 (d, J=5.3 Hz, 1H) and 6.99 (d, J=5.3 Hz, 1H). This oil was used without further purification in the next step.
Reaction SMILES: [BH4-].[Na+].[F:3][C@H:4]1[CH2:21][C@@:19]2([CH3:20])[C@@H:15]([CH2:16][CH2:17][C:18]2=[O:22])[C@H:14]2[C@H:5]1[C:6]1[CH:7]=[CH:8][C:9]([O:44][CH:45]3[CH2:50][CH2:49][CH2:48][CH2:47][O:46]3)=[CH:10][C:11]=1[CH2:12][C@H:13]2[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][N:28]([CH3:43])[CH2:29][CH2:30][CH2:31][S:32][CH2:33][CH2:34][CH2:35][C:36]([F:42])([F:41])[C:37]([F:40])([F:39])[F:38]>C1COCC1.C(O)C.O>[F:3][C@H:4]1[CH2:21][C@@:19]2([CH3:20])[C@@H:15]([CH2:16][CH2:17][C@@H:18]2[OH:22])[C@H:14]2[C@H:5]1[C:6]1[CH:7]=[CH:8][C:9]([O:44][CH:45]3[CH2:50][CH2:49][CH2:48][CH2:47][O:46]3)=[CH:10][C:11]=1[CH2:12][C@H:13]2[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][N:28]([CH3:43])[CH2:29][CH2:30][CH2:31][S:32][CH2:33][CH2:34][CH2:35][C:36]([F:42])([F:41])[C:37]([F:38])([F:39])[F:40]
Reactant: CN(CCCCC[C@@H]1Cc2cc(OC3CCCCO3)ccc2[C@@H]2[C@@H]1[C@@H]1CCC(=O)[C@@]1(C)C[C@@H]2F)CCCSCCCC(F)(F)C(F)(F)F
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: C1CCOC1
Product: CN(CCCCC[C@@H]1Cc2cc(OC3CCCCO3)ccc2[C@@H]2[C@@H]1[C@@H]1CC[C@H](O)[C@@]1(C)C[C@@H]2F)CCCSCCCC(F)(F)C(F)(F)F
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
350 mg of sodium borohydride are added in portions at 0° C. to 2.0 g of 11β-fluoro-7α-{5-[N-methyl-N-3-(4,4,5,5,5-pentafluoropentylthio)propylamino]pentyl}-3-(tetrahydropyran-2-yloxy)oestra-1,3,5(10)-trien-17-one in 17 ml of THF, 10 ml of ethanol and 4.2 ml of water. After 30 min, the reaction mixture is stirred into ice-water, extracted with ethyl acetate, washed with saturated sodium chloride solution and concentrated in vacuo. 1.7 g of crude 11β-fluoro-7α-{5-[N-methyl-N-3-(4,4,5,5,5-pentafluoropentylthio)propylamino]pentyl}-3-(tetrahydropyran-2-yloxy)oestra-1,3,5(10)-trien-17β-ol are obtained as a foam.
Reaction SMILES: [C:1]([C:3]1[N:8]=[C:7]([C:9]([OH:11])=[O:10])[CH:6]=[CH:5][CH:4]=1)#[N:2].[ClH:12].[H][H]>C(O)C.[Pd]>[ClH:12].[NH2:2][CH2:1][C:3]1[N:8]=[C:7]([C:9]([OH:11])=[O:10])[CH:6]=[CH:5][CH:4]=1
Reactant: N#Cc1cccc(C(=O)O)n1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: NCc1cccc(C(=O)O)n1

Procedure:
6-Cyano-pyridine-2-carboxylic acid (compound F2) (250 mg, 1.6 mmol) is dissolved in ethanol (100 mL), concentrated hydrochloric acid (1 mL) and Pd/C (150 mg) are added and the mixture is hydrogenated at 3 bar hydrogen pressure for 6 h. The catalyst is filtered of and the crude product is transferred to the next step without any purification.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][NH:5][C:4](=[O:8])[CH:3]=1.[C:9](Cl)(=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>N1C=CC=CC=1>[C:9]([O:1][C:2]1[CH:7]=[CH:6][NH:5][C:4](=[O:8])[CH:3]=1)(=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: O=c1cc(O)cc[nH]1
Solvent: c1ccncc1
Product: O=C(Oc1cc[nH]c(=O)c1)c1ccccc1
Yield: 44 %

Procedure:
50 ml of a solution of 1.00 g of 4-hydroxy-2-pyridone and 1.35 ml of benzoyl chloride in pyridine was refluxed for 6 hours. After the pyridine was distilled off, the residue was mixed with water. The precipitate was recovered by filtration and was washed with a small amount of ethanol to obtain 0.86 g of the title compound in a yield of 44%.
Reaction SMILES: C(O[BH-](O[C:11](=[O:13])[CH3:12])OC(=O)C)(=O)C.[Na+].ClC1C2[C:20](=[CH:21][C:22]([O:26][CH:27]3[CH2:32][CH2:31][CH2:30][NH:29][CH2:28]3)=[CH:23][CH:24]=2)[CH:19]=[CH:18][N:17]=1.[CH:33](=O)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.Cl>C(O)(=O)C.CN(C)C=O>[CH2:33]([N:29]1[CH2:30][CH2:31][CH2:32][CH:27]([O:26][C:22]2[CH:21]=[C:20]3[C:12](=[CH:24][CH:23]=2)[C:11](=[O:13])[NH:17][CH:18]=[CH:19]3)[CH2:28]1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: O=Cc1ccccc1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: Clc1nccc2cc(OC3CCCNC3)ccc12
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: O=c1[nH]ccc2cc(OC3CCCN(Cc4ccccc4)C3)ccc12
Temperature: 180 °C
Reaction time: 17 h

Procedure:
Sodium triacetoxyborohydride (100 mg, 3.9 mol eq) was added to a solution of 1-chloro-6-(piperidin-3-yloxy)isoquinoline (40mg), acetic acid (1 drops) and benzaldehyde (40 μl) in N, N-dimethylformamide (0.5 ml) and shaken for 17 hours. The reactions were quenched with water (0.5 ml) and shaken for 1 h then loaded onto a pre-acidified SCX column using methanol and eluted with 2M ammonia in methanol. The product was concentrated in vacuo to give a residue which was treated with 5M aqueous hydrochloric acid and heated in the microwave at 180° C. for 60 minutes. The mixture was concentrated in vacuo to give a residue which was purified by prep-HPLC to give 6-(1-benzylpiperidin-3-yloxy)-2H-isoquinolin-1-one, El-MS: m/z=335.7 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][C:10]=2[F:17])=[C:6]([F:18])[C:5]([CH3:19])=[CH:4][CH:3]=1.C1C(=O)N([Br:27])C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)(Cl)Cl>[Br:27][CH2:19][C:5]1[C:6]([F:18])=[C:7]([O:8][C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][C:10]=2[F:17])[C:2]([Cl:1])=[CH:3][CH:4]=1
Reactant: Cc1ccc(Cl)c(Oc2ccc(C#N)cc2F)c1F
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: N#Cc1ccc(Oc2c(Cl)ccc(CBr)c2F)c(F)c1
Temperature: 80 °C
Reaction time: 8 h
Yield: 51.7 %

Procedure:
To a solution of 4-[(6-chloro-2-fluoro-3-methylphenyl)oxy]-3-fluorobenzonitrile (2.41 g, 8.62 mmol) and NBS (1.534 g, 8.62 mmol) in carbon tetrachloride (150 ml) was added AIBN (1.415 g, 8.62 mmol) and the reaction mixture was stirred at 80° C. overnight. The solvent was removed and the crude material was purified via silica gel chromatography to give 4-{[3-(bromomethyl)-6-chloro-2-fluorophenyl]oxy}-3-fluorobenzonitrile (1.60 g, 4.46 mmol, 52% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.08 (dd, 1H), 7.62 (d, 1H), 7.48-7.59 (m, 2H), 6.92 (t, 1H), 4.70 (s, 2H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][CH:10]2[CH:15]([C:16]([OH:18])=O)[CH2:14][CH:13]=[CH:12][CH2:11]2)=[CH:4][CH:3]=1.Cl.[NH2:20][CH2:21][C:22]#[N:23].F[P-](F)(F)(F)(F)F.N1([PH+](N2CCCC2)N2CCCC2)CCCC1.C(N(CC)CC)C>CN(C)C=O>[C:21]([CH2:22][NH:23][C:16]([CH:15]1[CH:10]([CH2:9][S:8][C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[CH2:11][CH:12]=[CH:13][CH2:14]1)=[O:18])#[N:20]
Reactant: O=C(O)C1CC=CCC1CSc1ccc(F)cc1
Reactant: N#CCN
Agent: C1CCN([PH+](N2CCCC2)N2CCCC2)C1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: N#CCNC(=O)C1CC=CCC1CSc1ccc(F)cc1
Temperature: 0 °C
Reaction time: 28 h

Procedure:
(1R/S,6R/S)-6-{[(4-Fluorophenyl)sulfanyl]methyl}cyclohex-3-ene-1-carboxylic acid (620 mg, 2.34 mmol) was weighed into a 25 mL round bottom flask and aminoacetonitrile hydrochloride (480 mg, 5.20 mmol) and benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (1.34 g, 2.60 mmol) were added. Dimethylformamide (8.0 mL) was added and the reaction mixture was cooled to 0° C. After adding triethylamine (1.2 mL, 8.6 mmol) the reaction mixture was stirred at ambient temperature for 28 h, and then partitioned between water and ethyl acetate. The organic layer was washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, and concentrated. Chromatography of the residue on silica gel with 45:55 ethyl acetate:hexanes eluent provided the title compound as a colorless solid. 1H NMR (500 MHz, acetone-d6): δ=7.92 (1H, br s), 7.41 (2H, dd), 7.08 (2H, dd), 5.64 (2H, m), 4.24 (2H, m), 3.22 (1H, dd), 2.72 (1H, dd), 2.50-2.40 (2H, m), 2.26-2.20 (2H, m), 2.12 (1H, m), 1.86 (1H, m). MS [ESI, (M−H)−] m/z=303.1 amu.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:12]3[N:13]=[C:14]([NH:17][C@H:18]4[CH2:23][CH2:22][C@H:21]([NH2:24])[CH2:20][CH2:19]4)[CH:15]=[CH:16][C:11]3=[N:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.N1C=CC=CC=1.[Cl:31][CH2:32][C:33](Cl)=[O:34].C([O-])(O)=O.[Na+]>C(Cl)Cl.CO>[Cl:31][CH2:32][C:33]([NH:24][C@H:21]1[CH2:22][CH2:23][C@H:18]([NH:17][C:14]2[CH:15]=[CH:16][C:11]3[N:12]([C:8]([C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=4)=[CH:9][N:10]=3)[N:13]=2)[CH2:19][CH2:20]1)=[O:34]
Reactant: O=C(Cl)CCl
Reactant: N[C@H]1CC[C@H](Nc2ccc3ncc(-c4cccc(Cl)c4)n3n2)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CO
Product: O=C(CCl)N[C@H]1CC[C@H](Nc2ccc3ncc(-c4cccc(Cl)c4)n3n2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of trans-N1-(3-(3-chlorophenyl)imidazo[1,2-b]pyridazin-6-yl)cyclohexane-1,4-diamine (90 mg, 0.26 mmol) and pyridine (0.08 mL, 1.04 mmol) in CH2Cl2 (2.6 mL) was added dropwise chloroacetyl chloride (0.03 mL, 0.39 mmol). The resulting mixture was stirred at room temperature overnight. TLC (CH2Cl2:MeOH=10:1) showed the reaction was complete. The mixture was poured into sat. aq. NaHCO3 (100 mL) and extracted with EtOAc (50 mL*3). The extracts were dried over Na2SO4, filtered and concentrated in vacuo to give crude 2-chloro-N-(trans-4-((3-(3-chlorophenyl)imidazo[1,2-b]pyridazin-6-yl)amino)cyclohexyl)acetamide (110 mg, 101%) as a yellow solid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]([CH3:18])=[C:5]2[CH2:19][C:20]([NH2:22])=[O:21].[H-].[Na+].[CH2:25](Br)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>CS(C)=O.O>[CH2:25]([O:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]([CH3:18])=[C:5]2[CH2:19][C:20]([NH2:22])=[O:21])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: BrCc1ccccc1
Reactant: Cc1c(CC(N)=O)c2cc(O)ccc2n1Cc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: Cc1c(CC(N)=O)c2cc(OCc3ccccc3)ccc2n1Cc1ccccc1
Reaction time: 0.5 h
Yield: 82 %

Procedure:
5-Hydroxy-2-methyl-1-(phenylmethyl)-1H-indole-3-acetamide (400 mg, 1.4 mmol) was dissolved in 50 mL of DMSO, 40 mg (1.0 mmol) of 60% NaH/mineral oil added, stirred approximately 0.5 hour, 0.2 mL of benzyl bromide added and stirring maintained 2.5 hours. The mixture was diluted with water, extracted with EtOAc, the EtOAc solution washed with water, saturated NaCl solution, dried (Na2SO4), and concentrated at reduced pressure. The residue was chromatographed on silica(eluted with a gradient, CH2Cl2→2% MeOH/CH2Cl2) and crystallized from CH2Cl2/MeOH to give 440 mg (82% yield) of 5-benzyloxy-2-methyl-1-(phenylmethyl)-1H-indole-3-acetamide, mp, 118-120° C.
Reaction SMILES: F[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]([CH3:13])[CH3:12])=[C:4]([NH:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)[N:3]=1.CCN(C(C)C)C(C)C.[NH2:31][C@H:32]([CH2:36][CH3:37])[C@@H:33]([OH:35])[CH3:34]>CCCCO.CS(C)=O>[CH:11]([N:8]1[CH:7]=[N:6][C:5]2[C:9]1=[N:10][C:2]([NH:31][C@H:32]([CH2:36][CH3:37])[C@@H:33]([OH:35])[CH3:34])=[N:3][C:4]=2[NH:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1)([CH3:13])[CH3:12]
Reactant: CC[C@@H](N)[C@H](C)O
Reactant: CC(C)n1cnc2c(NCc3ccccn3)nc(F)nc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Solvent: CS(C)=O
Product: CC[C@@H](Nc1nc(NCc2ccccn2)c2ncn(C(C)C)c2n1)[C@H](C)O
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a stirred solution of (2-fluoro-9-isopropyl-9H-purin-6-yl)-pyridin-2-ylmethyl-amine (30 mg, 1 eq, 0.10 mmol) in n-BuOH/DMSO (2.5 mL, 4:1) at room temperature under an argon atmosphere was added DIEA (0.2 mL, 10.96 eq, 1.14 mmol) followed by (2S,3R)-3-amino-pentan-2-ol (60 mg, 5.5 eq, 0.58 mmol). The reaction mixture was placed in a preheated oil bath at 160° C. and stirred at this temperature for 72 h. The reaction mixture was allowed to cool to room temperature and the solvent was evaporated in vacuo. The residue was partitioned between EtOAc (50 mL) and water (50 mL), the aqueous phase was extracted with more EtOAc (2×25 mL), and the combined organic phase was washed with brine (50 mL), dried (MgSo4) and evaporated in vacuo. The residue was purified by gradient column chromatography on silica gel eluted with CHCl3:MeOH (100:0→98:2), to afford the title compound as a white solid. Yield: 36.1 mg (93%). (80% de 3R,2S: 20% de 3R,2R). 1H-NMR (d-CDCl3, 250 MHz): δ 0.91 & 1.06 (2×t, 3H, J=7.11 & 7.42 Hz, —NHCH(CH2CH3)CH(CH3)OH), 1.16 & 1.29 (2×d, 3H, J=6.48 & 3.48 Hz, —NHCH (CH2CH3)CH3)OH) 1.57 (d, 6H, J=6.79 Hz, —CH(CH3)2), 1.71-2.01 (m, 2H, —NHCH(CH2CH3)CH(CH3)OH), 3.98 (m, 2H, —NHCH(CH2CH3)CH(CH3)OH), 4.58-4.69 (m, 1H, —CH(CH3)2), 4.83-5.00 (m, 2H, —HNCH2-Pyr), 6.75-6.91 (m, 1H, —HNCH2-Pyr), 7.19-7.25 (m, 1H, Pyr-H), 7.37 (d, 1H, J=8.05 Hz, Pyr-H), 7.57 (s, 1H, —N═CH—N), 7.64-7.71 (m, 1H, Pyr-H), 8.61 (d, 1H, J=4.58 Hz, Pyr-H). FABMS m/z (relative intensity): 370 ([M+H]+, 100), 324 (40). Accurate Mass (M+H): Actual: 370.2355, Measured: 370.2347.
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH:22]4[CH2:24][CH2:23]4)=[CH:20][C:19]([CH:25]4[CH2:27][CH2:26]4)=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[O:28]1[CH2:32][CH2:31][NH:30][C:29]1=[O:33]>>[CH:22]1([C:21]2[C:16]([N:13]3[CH2:14][CH2:15][N:10]([C:8]([C:5]4[CH:4]=[CH:3][C:2]([N:30]5[CH2:31][CH2:32][O:28][C:29]5=[O:33])=[N:7][CH:6]=4)=[O:9])[CH2:11][CH2:12]3)=[N:17][CH:18]=[C:19]([CH:25]3[CH2:27][CH2:26]3)[CH:20]=2)[CH2:24][CH2:23]1
Reactant: O=C1NCCO1
Reactant: O=C(c1ccc(Br)nc1)N1CCN(c2ncc(C3CC3)cc2C2CC2)CC1
Product: O=C(c1ccc(N2CCOC2=O)nc1)N1CCN(c2ncc(C3CC3)cc2C2CC2)CC1
Yield: 26.5 %

Procedure:
By reaction and treatment in the same manner as in Example 1 and using (6-bromopyridin-3-yl)[4-(3,5-dicyclopropylpyridin-2-yl)piperazin-1-yl]methanone (641 mg) described in Preparation Example 112 and oxazolidin-2-one (200 mg), the title compound (172 mg) was obtained.
Reaction SMILES: C[Si](C)(C)CCOC[N:7](COCC[Si](C)(C)C)[C:8]1[N:13]2[N:14]=[CH:15][C:16]([C:17]3[CH:18]=[N:19][C:20]4[C:25]([CH:26]=3)=[CH:24][C:23]([F:27])=[CH:22][CH:21]=4)=[C:12]2[N:11]=[C:10]2[N:28]([CH:32]3[CH2:37][CH2:36][N:35](C(OC(C)(C)C)=O)[CH2:34][CH2:33]3)[CH:29]=[C:30]([CH3:31])[C:9]=12.C(O)(C(F)(F)F)=O.O>>[F:27][C:23]1[CH:24]=[C:25]2[C:20](=[CH:21][CH:22]=1)[N:19]=[CH:18][C:17]([C:16]1[CH:15]=[N:14][N:13]3[C:8]([NH2:7])=[C:9]4[C:30]([CH3:31])=[CH:29][N:28]([CH:32]5[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]5)[C:10]4=[N:11][C:12]=13)=[CH:26]2
Reactant: Cc1cn(C2CCN(C(=O)OC(C)(C)C)CC2)c2nc3c(-c4cnc5ccc(F)cc5c4)cnn3c(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)c12
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: Cc1cn(C2CCNCC2)c2nc3c(-c4cnc5ccc(F)cc5c4)cnn3c(N)c12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
At 0° C., tert-butyl 4-(8-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-3-(6-fluoroquinolin-3-yl)-7-methyl-5H-pyrazolo[1,5-a]pyrrolo[2,3-d]pyrimidin-5-yl)piperidine-1-carboxylate (95 mg, 0.12 mmol) was treated with 80% TFA/H2O (5 mL). After stirring at room temperature for 30 min, concentration afforded crude 3-(6-fluoroquinolin-3-yl)-7-methyl-5-(piperidin-4-yl)-5H-pyrazolo[1,5-a]pyrrolo[2,3-d]pyrimidin-8-amine which was used for next step without further purification. LCMS is =0.69 Min (5 min run, UV254nm), Mass calculated for M+415.2, observed m/z 416.2 (M+H).
Reaction SMILES: [C:1]([C:3]1[O:7][C:6]([S:8]([NH:11][C:12]2[CH:17]=[C:16]([O:18][C@H:19]([CH3:41])[CH2:20][O:21]C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[N:15]=[C:14]([S:42][CH2:43][C:44]3[CH:49]=[CH:48][CH:47]=[C:46]([F:50])[C:45]=3[F:51])[N:13]=2)(=[O:10])=[O:9])=[CH:5][CH:4]=1)#[N:2].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(OC)C=CC=CC=1.O>CO>[C:1]([C:3]1[O:7][C:6]([S:8]([NH:11][C:12]2[CH:17]=[C:16]([O:18][C@H:19]([CH3:41])[CH2:20][OH:21])[N:15]=[C:14]([S:42][CH2:43][C:44]3[CH:49]=[CH:48][CH:47]=[C:46]([F:50])[C:45]=3[F:51])[N:13]=2)(=[O:10])=[O:9])=[CH:5][CH:4]=1)#[N:2]
Reactant: C[C@H](COC(c1ccccc1)(c1ccccc1)c1ccccc1)Oc1cc(NS(=O)(=O)c2ccc(C#N)o2)nc(SCc2cccc(F)c2F)n1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: O
Solvent: COc1ccccc1
Product: C[C@H](CO)Oc1cc(NS(=O)(=O)c2ccc(C#N)o2)nc(SCc2cccc(F)c2F)n1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of 5-cyano-N-{2-[(2,3-difluorobenzyl)thio]-6-[(1R)-1-methyl-2-(triphenylmethyloxy)ethoxy]pyrimidin-4-yl}furan-2-sulfonamide (the product of step ii) (0.15 g) in methanol (5 mL) was added para-toluenesulfonic acid hydrate (39 mg) and anisole (0.23 mL). After stirring at room temperature for 5 h, H2O (5 mL) was added and the mixture extracted with EtOAc (3×10 mL). The combined organic layers were washed with brine (10 mL), dried (MgSO4), filtered and evaporated to dryness in vacuo. The resulting crude solid was purified by reverse phase HPLC (75% to 5% gradient of 0.1% aqueous ammonium acetate in acetonitrile as eluent) to give the title compound as a white solid. Yield: 20 mg.
Reaction SMILES: [Cl:1][C:2]1[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][C:3]=1[C:4]([O:6][CH2:7][C:8](=[O:26])[C@@H:9]([NH:18]C(OC(C)(C)C)=O)[CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:5].C1(C)C=CC([S:38]([OH:41])(=[O:40])=[O:39])=CC=1>CCOCC>[C:3]1([CH3:4])[C:2]([S:38]([OH:41])(=[O:40])=[O:39])=[CH:30][CH:29]=[CH:28][CH:27]=1.[Cl:1][C:2]1[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][C:3]=1[C:4]([O:6][CH2:7][C:8](=[O:26])[C@@H:9]([NH2:18])[CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:5]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCc1ccccc1)C(=O)COC(=O)c1cc(Cl)ccc1Cl
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOCC
Product: Cc1ccccc1S(=O)(=O)O
Product: N[C@@H](CCc1ccccc1)C(=O)COC(=O)c1cc(Cl)ccc1Cl
Temperature: 25 °C
Reaction time: 12 h

Procedure:
The crude (S)-3-tert-butoxycarbonylamino-2-oxo-5-phenylpentyl 2,5-dichlorobenzoate was dissolved in ether (5 mL) and a solution of azeotropically dried p-toluenesulfonic acid (1.31 g, 7.7 mmol) in ether (5 mL) was added. The mixture was stirred at room temperature for approximately 12 hours and then ether (200 mL) was added to provide a solid material. The solid material was broken up, filtered, washed with ether (2×50 mL) and dried in vacuo to provide (S)-3-amino-2-oxo-5-phenylpentyl 2,5-dichlorobenzoate toluenesulfonic acid salt (1.24 g, 2.3 mmol).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[PH:9](=O)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH2:16][CH3:17])[CH3:2].C(N(CC)CC)C.Cl[SiH](Cl)Cl>C(#N)C>[CH2:16]([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[PH:9][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[CH2:1][CH3:2])[CH3:17]
Reactant: CCc1ccccc1[PH](=O)c1ccccc1CC
Agent: Cl[SiH](Cl)Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCc1ccccc1Pc1ccccc1CC

Procedure:
Into a 1 L Schlenk flask was added the phosphine oxide (3a) (17.21 g, 66.7 mmol). To this was added acetonitrile (400 ml) and triethylamine (27.9 ml, 200.1 mmol). Then trichlorosilane (20.2 ml, 200.1 mmol) was added slowly. The addition of the trichlorosilane gave the formation of some white precipitate. The resultant mixture was then refluxed overnight. The resultant suspension was then cooled to 0° in an ice bath and a solution of potassium hydroxide (40 g) in water (200 ml) which had been degassed with nitrogen gas was added slowly. This gave a bi-phasic mixture. Additional acetonitrile (100 ml) was then added. The upper organic phase was then removed by cannula into a clean Schlenk flask and the solvent removed under vacuum. This gave an off-white solid (3b). Yield=13.60 g, 84%.
Reaction SMILES: [H-].[Na+].[C:3]([CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])#[N:4].I[C:12]1[CH:20]=[CH:19][CH:18]=[C:17]2[C:13]=1[CH2:14][CH2:15][CH:16]2[O:21][Si](C)(C)C.Cl>CN1CCN(C)C1=O>[C:3]([CH:5]([C:12]1[C:13]2[CH2:14][CH2:15][CH:16]([OH:21])[C:17]=2[CH:18]=[CH:19][CH:20]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])#[N:4]
Reactant: CCOC(=O)CC#N
Reactant: C[Si](C)(C)OC1CCc2c(I)cccc21
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCN(C)C1=O
Product: CCOC(=O)C(C#N)c1cccc2c1CCC2O
Reaction time: 4 h

Procedure:
6 ml of 1,3-dimethyl-2-imidazolidone and 0.99 g of sodium hydride at 50% are cooled to +15° C., 2.2 ml of ethyl cyanacetate in 10 ml of 1,3-dimethyl-2-imidazolidone is added over 5 minutes, with agitation for 40 minutes. 4.39 g of cuprous iodide, 3.62 g of 4-iodo-1-trimethylsilyloxy indane and 4 ml of 1,3-dimethyl-2-imidazolidone are added. The mixture is taken to 100° C. for 4 hours. After cooling, it is poured into 100 ml of 2N hydrochloric acid, filtered on celite, and rinsed with water; the filtrate is extracted with isopropyl ether, washed with a saturated solution of sodium bicarbonate and with water, dried and brought to dryness. The residue is chromatographed on silica in a hexane-ethyl acetate mixture (1-1) and 1.22 g of expected product is obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([N+:9]([O-:11])=[O:10])[C:4]=1[NH2:12].[I:13]I>C(O)(=O)C.S([O-])([O-])(=O)=O.[Ag+2]>[I:13][C:7]1[CH:6]=[C:5]([N+:9]([O-:11])=[O:10])[C:4]([NH2:12])=[C:3]([O:2][CH3:1])[CH:8]=1
Reactant: COc1cccc([N+](=O)[O-])c1N
Reactant: II
Agent: [Ag+2]
Agent: O=S(=O)([O-])[O-]
Solvent: CC(=O)O
Product: COc1cc(I)cc([N+](=O)[O-])c1N
Temperature: 60 °C
Reaction time: 12 h
Yield: 79 %

Procedure:
A mixture of 6.2 g (36.9 mmol) 2-methoxy-6-nitro-phenylamine, 9.4 g (37 mmol) iodine and 5.8 g (18.5 mmol) silver sulfate in 90 ml glacial acetic acid is stirred at 60° C. for 12 h. The reaction mixture is cooled to room temperature, poured on water and extracted (3×) with ethyl acetate. The combined organic layers are washed with water (2×) and brine, dried over MgSO4, filtered and concentrated in vacuo. The residue is purified by flash-chromatography on silica gel (hexane:EtOAc=2:1) to afford 8.57 g of the title compound as bright red crystals.