Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[Cl:13][C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1.[C:20]([O:24][C:25]([N:27]1[CH:32]2[CH2:33][CH2:34][CH:28]1[CH2:29][C:30](=[O:35])[CH2:31]2)=[O:26])([CH3:23])([CH3:22])[CH3:21].[Cl-].[NH4+]>C1COCC1.C(OCC)(=O)C>[C:20]([O:24][C:25]([N:27]1[CH:32]2[CH2:33][CH2:34][CH:28]1[CH2:29][C:30]([C:19]1[CH:18]=[CH:17][N:16]=[CH:15][C:14]=1[Cl:13])([OH:35])[CH2:31]2)=[O:26])([CH3:23])([CH3:21])[CH3:22]
Reactant: Clc1cccnc1
Reactant: CC(C)(C)OC(=O)N1C2CCC1CC(=O)C2
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1C2CCC1CC(O)(c1ccncc1Cl)C2
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 11.4 %

Procedure:
n-Butyl lithium (2.5M, 3.88 mL, 9.7 mmol) was added dropwise to a solution of diisopropylamine (1.43 mL, 10.13 mmol) in THF (20 mL) at −78° C. under nitrogen, warmed to 0° C., stirred for 30 minutes then re-cooled to −78° C. This was then added to a solution of 3-chloropyridine (0.83 mL, 8.81 mmol) in THF (12 mL) and stirred for 1.5 hours. 3-Oxo-8-aza-bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (1.98 g, 8.81 mmol) in THF (12 mL) was added, the reaction mixture warmed to room temperature for 1.5 hours. Saturated aqueous ammonium chloride and ethyl acetate were added, the organics separated, washed with more saturated aqueous ammonium chloride and brine, dried over magnesium sulphate, filtered and the solvent removed by evaporation under vacuum. The residue was purified by flash chromatography on silica eluting with 0-100% ethyl acetate/pentane. The fractions containing the desired product were concentrated under vacuum to give the title compound (0.34 g). 1H NMR (400 MHz, CDCl3): δ 8.48 (s, 1H), 8.47 (d, 1H), 7.69 (d, 1H), 4.38 (m, broad, 2H), 3.05-2.80 (m, broad, 2H), 2.28-2.0 (broad, 5H), 1.6-1.5 (m, broad, 2H), 1.49 (s, 9H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH2:7])[C:2]=1[NH2:8].[CH2:9]([O:16][C:17]1[CH:18]=[CH:19][C:20]([O:26][CH:27]([CH3:29])[CH3:28])=[C:21]([CH:25]=1)[C:22](O)=O)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O.O.C(O)C.C(O)(=O)C>[CH2:9]([O:16][C:17]1[CH:18]=[CH:19][C:20]([O:26][CH:27]([CH3:29])[CH3:28])=[C:21]([C:22]2[NH:8][C:2]3=[N:1][CH:6]=[CH:5][CH:4]=[C:3]3[N:7]=2)[CH:25]=1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: CC(C)Oc1ccc(OCc2ccccc2)cc1C(=O)O
Reactant: Nc1cccnc1N
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCO
Solvent: O
Product: CC(C)Oc1ccc(OCc2ccccc2)cc1-c1nc2cccnc2[nH]1
Yield: 32.2 %

Procedure:
A solution (20 ml) of pyridine-2,3-diamine (0.6 g), 5-(benzyloxy)-2-isopropoxybenzoic acid (1.31 g), 1-hydroxybenztriazole hydrate (0.93 g) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.32 g) in N,N-dimethylformamide was stirred at room temperature for 18 hr. The reaction mixture was diluted with water and extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate and concentrated to give as pale-brown crystals. The obtained crystals were added to acetic acid (2.5 ml)-ethanol (2.5 ml), and the mixture was subjected to microwave irradiation in a sealed reaction container at 180° C. for 40 min. The reaction mixture was concentrated, and the precipitated crystals were collected by filtration and washed with ethanol to give the title compound (0.53 g, yield 32%) as colorless crystals. melting point 160-162° C. purity 95%. M+H: 360. 1H NMR (CDCl3) δ: 1.50 (6H, d, J=6.2 Hz), 4.64-4.85 (1H, m), 5.16 (2H, s), 6.95-7.56 (8H, m), 8.08 (1H, d, J=7.9 Hz), 8.21 (1H, d, J=2.8 Hz), 8.36 (1H, t, J=5.6 Hz), 11.06 (1H, s).
Reaction SMILES: [H-].[Na+].[NH2:3]/[C:4](/[C:11]([F:14])([F:13])[F:12])=[CH:5]\[C:6]([O:8]CC)=O.[CH3:15][O:16][C:17]1[C:22]([CH3:23])=[CH:21][C:20]([C:24]2[C:28]3[CH:29]=[C:30]([N:33]=[C:34]=[O:35])[CH:31]=[CH:32][C:27]=3[S:26][N:25]=2)=[CH:19][CH:18]=1>CCOCC.CN(C)C=O>[CH3:15][O:16][C:17]1[C:22]([CH3:23])=[CH:21][C:20]([C:24]2[C:28]3[CH:29]=[C:30]([N:33]4[C:6](=[O:8])[CH:5]=[C:4]([C:11]([F:12])([F:13])[F:14])[NH:3][C:34]4=[O:35])[CH:31]=[CH:32][C:27]=3[S:26][N:25]=2)=[CH:19][CH:18]=1
Reactant: COc1ccc(-c2nsc3ccc(N=C=O)cc23)cc1C
Reactant: CCOC(=O)/C=C(\N)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: COc1ccc(-c2nsc3ccc(-n4c(=O)cc(C(F)(F)F)[nH]c4=O)cc23)cc1C
Temperature: -10 °C
Reaction time: 1.5 h
Yield: 70.3 %

Procedure:
A mixture of 60% sodium hydride in mineral oil (15.9 g, 0.397 mol) and N,N-dimethylformamide is cooled to -10° C., treated over one hour with a solution of ethyl 3-amino-4,4,4-trifluorocrotonate (72.7 g, 0.397 mol) in ether, warmed to and stirred at room temperature for 90 minutes, cooled to -70° C., treated over 80 minutes with a solution of 3-(6-methoxy-m-tolyl)-1,2-benzisothiazol-5-yl isocyanate (107 g, 0.361 mol) in N,N-dimethylformamide while maintaining the temperature below about -65° C., slowly warmed to and stirred at room temperature overnight, and poured onto ice. The resultant aqueous mixture is washed with ethyl acetate, acidified to pH 2 with concentrated hydrochloric acid, and extracted with diethyl ether. The organic extract is dried over anhydrous magnesium sulfate and concentrated in vacuo to give the title product as an orange oil (110 g, 70.5%) which is identified by NMR spectral analyses.
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5]([O:7][C@:8]1([C@:29]2([CH3:30])[C@H:15]([C@H:16]3[C@H:26]([C@@H:27]([OH:31])[CH2:28]2)[C@:24]2([CH3:25])[C:19](=[CH:20][C:21](=[O:32])[CH:22]=[CH:23]2)[C@@H:18]([CH3:33])[CH2:17]3)[CH2:14][CH2:13]1)[C:9](=[O:12])[CH2:10][OH:11])=[O:6])[CH3:2]>C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cl-].[Rh]>[CH2:1]([O:3][CH2:4][C:5]([O:7][C@:8]1([C@:29]2([CH3:30])[C@H:15]([C@H:16]3[C@H:26]([C@@H:27]([OH:31])[CH2:28]2)[C@:24]2([CH3:25])[C:19](=[CH:20][C:21](=[O:32])[CH2:22][CH2:23]2)[C@@H:18]([CH3:33])[CH2:17]3)[CH2:14][CH2:13]1)[C:9](=[O:12])[CH2:10][OH:11])=[O:6])[CH3:2]
Reactant: CCOCC(=O)O[C@]1(C(=O)CO)CC[C@H]2[C@@H]3C[C@H](C)C4=CC(=O)C=C[C@]4(C)[C@H]3[C@@H](O)C[C@@]21C
Agent: [Rh]
Agent: [Cl-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CCOCC(=O)O[C@]1(C(=O)CO)CC[C@H]2[C@@H]3C[C@H](C)C4=CC(=O)CC[C@]4(C)[C@H]3[C@@H](O)C[C@@]21C
Yield: 78.7 %

Procedure:
1.0 g of 17-ethoxyacetoxy-11β,21-dihydroxy-6α-methyl-1,4-pregnadiene-3,20-dione is hydrogenated as described in Example 19 with 700 mg of tris(triphenylphosphine)rhodium(I) chloride. After the reaction mixture has been worked up and purified, 790 mg of 17-ethoxyacetoxy-11β,21-dihydroxy-6α-methyl-4-pregnene-3,20-dione is isolated.
Reaction SMILES: [CH3:1]I.[C:3]([O:7][C:8]([NH:10][CH:11]([C:14]1[CH:15]=[C:16]([CH:30]=[CH:31][CH:32]=1)[CH2:17][CH2:18][NH:19][C:20](=[O:29])[O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:12][OH:13])=[O:9])([CH3:6])([CH3:5])[CH3:4].[OH-].[Na+]>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.ClCCl>[C:3]([O:7][C:8]([NH:10][CH:11]([C:14]1[CH:15]=[C:16]([CH:30]=[CH:31][CH:32]=1)[CH2:17][CH2:18][NH:19][C:20](=[O:29])[O:21][CH2:22][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[CH2:12][O:13][CH3:1])=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: CI
Reactant: CC(C)(C)OC(=O)NC(CO)c1cccc(CCNC(=O)OCc2ccccc2)c1
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Product: COCC(NC(=O)OC(C)(C)C)c1cccc(CCNC(=O)OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 48.2 %

Procedure:
A mixture of methyl iodide (98 ml, 1.57 mmol), benzyl 3-{(1R/S)-1-[(tert-butoxycarbonyl)amino]-2-hydroxyethyl}phenethylcarbamate (preparation 119) (590 mg, 1.4 mmol), benzyltriethylammonium chloride (325 mg, 1.4 mmol) and NaOH solution (185 ml, 10M, 1.85 mmol) in dichloromethane (10 ml), was stirred at room temperature for 3 days. The reaction mixture was partitioned between dichloromethane and water, the phases separated, and the organic layer dried over MgSO4 and evaporated under reduced pressure. The residual oil was purified by column chromatography on silica gel using an elution gradient of ethyl acetate:pentane (0:100 to 50:50) to provide the title compound as a colourless oil, (289 mg, 47%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](=[C:8]2C(=O)OC(C)(C)[O:10][C:9]2=[O:17])[NH:6][CH:7]=1.[ClH:18]>>[ClH:18].[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([OH:17])=[O:10])=[N:6][CH:7]=1
Reactant: CC1(C)OC(=O)C(=C2C=CC(Br)=CN2)C(=O)O1
Agent: Cl
Product: O=C(O)Cc1ccc(Br)cn1

Procedure:
5-(5-Bromopyridin-2(1H)-ylidene)-2,2-dimethyl-1,3-dioxane-4,6-dione (example 42f) (3.55 g, 11.87 mmol) was suspended in conc. HCl (55 mL) and refluxed for 3 h. The solution was concentrated under reduced pressure and a residue was triturated with EtOH to provide white crystals that were filtered off and washed with EtOH (2.34 g, 78%). 1H NMR (400 MHz, dMSO): δ 3.81 (s, 2H), 7.44-7.46 (d, 1H), 8.12-8.15 (dd, 1H), 8.70-8.71 (d, 1H), 11.30 (bs, 1H); MS+H (218).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][O:11][CH:10]([CH:14]([CH3:16])[CH3:15])[CH2:9]1)=O)(C)(C)C.Cl>O1CCOCC1>[CH:14]([CH:10]1[O:11][CH2:12][CH2:13][NH:8][CH2:9]1)([CH3:16])[CH3:15]
Reactant: CC(C)C1CN(C(=O)OC(C)(C)C)CCO1
Agent: Cl
Solvent: C1COCCO1
Product: CC(C)C1CNCCO1

Procedure:
The above compound could be made in the following manner: 2-Isopropyl-morpholine-4-carboxylic acid tert-butyl ester in 4N solution of hydrogen chloride in dioxane could be stirred at 60° C. for 3 h. The solvent could be removed in vacuo and 1N aqueous hydrogen chloride solution could be added to the resulting residue, and the mixture could be washed with diethyl ether. The aqueous layer could be adjusted to pH 14 by addition of 2N NaOH solution and extracted with methylene chloride. The organic layer could be washed with brine and dried over sodium sulfate. After filtering, the material could be purified by column chromatography.
Reaction SMILES: C([O:5][C:6](=[O:63])[CH2:7][O:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH2:21][CH2:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][CH2:31][CH2:32][O:33][CH2:34][CH2:35][O:36][CH2:37][CH2:38][O:39][CH2:40][CH2:41][O:42][CH2:43][CH2:44][N:45]([CH:50]2[C:62]3[CH:61]=[CH:60][CH:59]=[CH:58][C:57]=3[C:56]3[C:51]2=[CH:52][CH:53]=[CH:54][CH:55]=3)[C:46]([O:48][CH3:49])=[O:47])=[CH:26][CH:25]=1)(C)(C)C>C1(C)C=CC=CC=1>[CH:52]1[C:51]2[CH:50]([N:45]([C:46]([O:48][CH3:49])=[O:47])[CH2:44][CH2:43][O:42][CH2:41][CH2:40][O:39][CH2:38][CH2:37][O:36][CH2:35][CH2:34][O:33][CH2:32][CH2:31][O:30][C:27]3[CH:26]=[CH:25][C:24]([O:23][CH2:22][CH2:21][O:20][CH2:19][CH2:18][O:17][CH2:16][CH2:15][O:14][CH2:13][CH2:12][O:11][CH2:10][CH2:9][O:8][CH2:7][C:6]([OH:63])=[O:5])=[CH:29][CH:28]=3)[C:62]3[C:57](=[CH:58][CH:59]=[CH:60][CH:61]=3)[C:56]=2[CH:55]=[CH:54][CH:53]=1
Reactant: COC(=O)N(CCOCCOCCOCCOCCOc1ccc(OCCOCCOCCOCCOCCOCC(=O)OC(C)(C)C)cc1)C1c2ccccc2-c2ccccc21
Solvent: Cc1ccccc1
Product: COC(=O)N(CCOCCOCCOCCOCCOc1ccc(OCCOCCOCCOCCOCCOCC(=O)O)cc1)C1c2ccccc2-c2ccccc21
Reaction time: 0.08 h
Yield: 84.3 %

Procedure:
To Compound 29 (196 mg, 0.25 mmol), 5% hydrated trifluoroacetic acid (1.5 ml) was added at room temperature; this was followed by stirring for 5 minutes. Toluene (about 1 ml) was added; after concentration under reduced pressure, the concentrate was purified by silica gel column chromatography (Yamazen YFLC Gel, eluent; chloroform containing 3% methanol-ethyl acetate solution containing 10% methanol) to yield Compound 30 (colorless oil 175 mg, 96%).
Reaction SMILES: [CH3:1][C:2]1[C:11](OS(C(F)(F)F)(=O)=O)=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:7]2.[CH3:27][N:28](C=O)C>[C-]#N.[Zn+2].[C-]#N.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>[C:27]([C:11]1[C:2]([CH3:1])=[C:3]2[C:8](=[CH:9][CH:10]=1)[CH2:7][N:6]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:5][CH2:4]2)#[N:28]
Reactant: Cc1c(OS(=O)(=O)C(F)(F)F)ccc2c1CCN(C(=O)OC(C)(C)C)C2
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: Cc1c(C#N)ccc2c1CCN(C(=O)OC(C)(C)C)C2
Reaction time: 0.25 h

Procedure:
A solution of 1,1-dimethylethyl 5-methyl-6-{[(trifluoromethyl)sulfonyl]oxy}-3,4-dihydro-2(1H)-isoquinolinecarboxylate (Preparation 15; 395 mg; 1.00 mmol) in DMF (4 ml) was de-gassed under high vacuum with stirring for 15 min, followed by addition of zinc cyanide (153 mg; 1.30 mmol) and tetrakis(triphenylphosphine)palladium (0) (116 mg; 0.10 mmol) under nitrogen. The resulting deep yellow mixture was stirred at 100° C. for 6 h. The solvent was removed, the residue dissolved in ethyl acetate, and the solution washed with saturated sodium bicarbonate. The aqueous layer was further extracted with ethyl acetate, and the combined organic layers washed with brine, dried (MgSO4), and evaporated to give the crude product. Purification by flash chromatography on silica gel, eluting with a gradient of 5-25% ethyl acetate in cyclohexane, gave the title compound (214 mg) as a white solid.
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[C:3]([OH:8])([CH3:7])[C:4](O)=[O:5].S(Cl)(Cl)=O.[NH2:15][C:16]1[CH:30]=[CH:29][C:19]([C:20]([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)=[O:21])=[CH:18][CH:17]=1.O>CN(C)C(=O)C.C(Cl)Cl.CCCCCC>[F:28][C:25]1[CH:26]=[CH:27][C:22]([C:20]([C:19]2[CH:29]=[CH:30][C:16]([NH:15][C:4](=[O:5])[C:3]([OH:8])([CH3:7])[C:2]([F:10])([F:9])[F:1])=[CH:17][CH:18]=2)=[O:21])=[CH:23][CH:24]=1
Reactant: CC(O)(C(=O)O)C(F)(F)F
Reactant: Nc1ccc(C(=O)c2ccc(F)cc2)cc1
Solvent: O=S(Cl)Cl
Solvent: CC(=O)N(C)C
Solvent: CCCCCC
Product: CC(O)(C(=O)Nc1ccc(C(=O)c2ccc(F)cc2)cc1)C(F)(F)F
Reaction time: 1 h
Yield: 9.2 %

Procedure:
To a stirred, cooled (-20° C.) solution of 3,3,3-trifluoro-2-hydroxy-2-methylpropanoic acid (1.58 g, 10 mmol) in N,N-dimethylacetamide (15 mL) was added thionyl chloride (1.25 g, 10.5 mmol) and the mixture stirred at -20° to -5° C. for 1 hour. 4-Amino-4'-fluorobenzophenone (1.44 g, 6.7 mmol) was added in one portion and the reaction mixture stirred at room temperature overnight. The reaction mixture was poured into water, the cloudy solution decanted from a gum and filtered through a thin pad of Celite. The Celite was washed with methylene chloride and the solution added to a solution of the gum in methylene chloride. The combined methylene chloride solution was dried (MgSO4), filtered and the solvent removed to yield an oil. The oil was treated with 50 mL of hexane and enough methylene chloride to dissolve the oil. The solution volume was reduced slightly on a steam bath and the solution cooled and scratched until crystals formed. The volume was reduced further on the steam bath, the mixture refrigerated for several hours and the resulting solid filtered off. The 1.60 g of impure product was further purified by chromatography on 80 g of flash column silica gel using ethyl ether as eluent. The solvent was stripped from the first 150 mL of eluent, the residual oil dissolved in 15 mL of methylene chloride and added to 250 mL of rapidly stirred hexane. The resulting solid was collected and dried to yield the title propanamide (0.22 g, 58%) as a pale yellow solid; mp 131°-133° C. 1H-NMR (250 MHz, CDCl3): 1.77 (s, 3H, CH3), 4.09 (s, 1H, OH), 7.14-7.28 (m, 2H,aromatic), 7.69-7.85 (m, 6H, aromatic), 8.68 (s, 1H, NH). MS (CI, CH4): 356M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5](B2OC(C)(C)C(C)(C)O2)=[CH:4][C:3]=1[NH:17][C:18](=[O:27])[C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=1.Br[C:29]1[CH:34]=[CH:33][C:32]([C:35](=[O:37])[CH3:36])=[CH:31][CH:30]=1.COCCOC.C([O-])([O-])=O.[Na+].[Na+]>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.O>[C:35]([C:32]1[CH:33]=[CH:34][C:29]([C:5]2[CH:6]=[CH:7][C:2]([NH2:1])=[C:3]([NH:17][C:18](=[O:27])[C:19]3[CH:20]=[CH:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=3)[CH:4]=2)=[CH:30][CH:31]=1)(=[O:37])[CH3:36]
Reactant: COc1ccc(C(=O)Nc2cc(B3OC(C)(C)C(C)(C)O3)ccc2N)cc1
Reactant: CC(=O)c1ccc(Br)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: COc1ccc(C(=O)Nc2cc(-c3ccc(C(C)=O)cc3)ccc2N)cc1
Temperature: 75 °C
Reaction time: 8 h
Yield: 25.2 %

Procedure:
In a pressure vessel, N-[2-Amino-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-4-methoxybenzamide (116) (170 mg, 0.462 mmol), 1-(4-bromophenyl)ethanone (184 mg, 0.923 mmol), (or any aryl bromide from the tables below), DME (4.6 mL per mmol of 116) and H2O (2.15 mL per mmol of 116) were added. Air was then removed by vacuum and then the vessel was purged with nitrogen. Pd(PPh3)4 (27 mg, 0.023 mmol, 0.05 eq.) and Na2CO3 (147 mg, 1.38 mmol, 3.0 eq.) were then added and oxygen was removed after each addition. The pressure vessel was sealed and the mixture was stirred at 75° C. overnight. The mixture was cooled at room temp., water was added and the mixture was extracted with EtOAc. The combined organic layers were rinsed with brine, dried over MgSO4 and concentrated to give 42 mg (25%) of the title compound 117. 1H NMR (DMSO-d6) (ppm): 9.61 (s, 1H), 7.96 (dd, J=12.8, 8.8 Hz, 4H), 7.70 (d, J=8.8 Hz, 2H), 7.60 (d, J=2.1 Hz, 1H), 7.42 (dd, J=8.4, 2.3 Hz, 1H), 7.04 (d, J=8.8 Hz, 2H), 6.86 (d, J=8.2 Hz, 1H), 5.26 (s, 2H), 3.84 (s, 3H), 2.58 (s, 3H). MS (m/z): 360.41 (calc) 361.1 (MH+) (found).
Reaction SMILES: [N:1]1[C:6]2[NH:7][CH:8]=[CH:9][C:5]=2[C:4]([N:10]2[CH2:14][CH2:13][C@@H:12]([NH:15]C(=O)OC(C)(C)C)[CH2:11]2)=[N:3][CH:2]=1.[ClH:23]>>[ClH:23].[N:1]1[C:6]2[NH:7][CH:8]=[CH:9][C:5]=2[C:4]([N:10]2[CH2:14][CH2:13][C@@H:12]([NH2:15])[CH2:11]2)=[N:3][CH:2]=1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCN(c2ncnc3[nH]ccc23)C1
Agent: Cl
Product: N[C@@H]1CCN(c2ncnc3[nH]ccc23)C1

Procedure:
(R)-tert-butyl 1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrrolidin-3-ylcarbamate (600 mg, 1.97 mmol) was treated with HCl (in MeOH, 6 N, 5 mL) at the ambient temperature for 2 h. The volatiles were removed under reduced pressure to give (R)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrrolidin-3-amine hydrochloride salt. MS (m/z): 204 (M+H)+.
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[Cl:6][C:7]1[C:16]2[C:11](=[CH:12][C:13]([S:17]([Cl:20])(=[O:19])=[O:18])=[CH:14][CH:15]=2)[C:10](=O)[NH:9][CH:8]=1.CCOCC>CC#N>[Cl:20][S:17]([C:13]1[CH:12]=[C:11]2[C:16]([C:7]([Cl:6])=[CH:8][N:9]=[C:10]2[Cl:3])=[CH:15][CH:14]=1)(=[O:19])=[O:18]
Reactant: O=c1[nH]cc(Cl)c2ccc(S(=O)(=O)Cl)cc12
Reactant: O=P(Cl)(Cl)Cl
Solvent: CC#N
Solvent: CCOCC
Product: O=S(=O)(Cl)c1ccc2c(Cl)cnc(Cl)c2c1
Yield: 84.2 %

Procedure:
Phosphorus oxychloride (POCl3) (9.65 mL, 103.5 mmol) was added to a stirred suspension of 4-chloro-7-chlorosulphonyl-1-(2H)-isoquinolone (22.1 g, 79.6 mmol) in MeCN (500 mL) at room temperature and the mixture was then heated at reflux for 15 h. On cooling, the MeCN solution was decanted from the insoluble sludge and evaporated in vacuo. The residue was extracted with hot EtOAc and evaporated to leave a solid which was stirred with Et2O (1.2 L) at room temperature overnight. The ethereal solution was decanted from the insoluble material and evaporated in vacuo to give 7-chlorosulphonyl-1,4-dichloroisoquinoline (20 g, 67 mmol) as a pale yellow solid.
Reaction SMILES: [CH:1]12[N:8]([C:9]3[CH:15]=[CH:14][C:12]([NH2:13])=[CH:11][CH:10]=3)[CH:5]([CH2:6][CH2:7]1)[CH2:4][CH2:3][CH2:2]2.[F:16]C1C=CC([N+]([O-])=O)=CC=1>>[CH:5]12[N:8]([C:9]3[CH:10]=[CH:11][C:12]([NH2:13])=[CH:14][C:15]=3[F:16])[CH:1]([CH2:7][CH2:6]1)[CH2:2][CH2:3][CH2:4]2
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: Nc1ccc(N2C3CCCC2CC3)cc1
Product: Nc1ccc(N2C3CCCC2CC3)c(F)c1

Procedure:
The title compound was prepared using the procedure as described for the preparation of the product of Example 6B, substituting 3,4-difluoronitrobenzene for 4-fluoronitrobenzene 1H NMR (300 MHz, CDCl3) δ 6.69 (m, 1H), 6.40 (m, 2H), 4.00 (brs, 2H), 3.42 (brs, 2H), 1.86-2.03 (m, 4H), 1.65-1.77 (m, 3H), 1.32-1.57 (m, 3H).
Reaction SMILES: [CH2:1]([OH:7])[CH2:2][C:3]#[C:4][CH2:5][CH3:6].[H-].[Na+].Cl[C:11]1[C:15]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)=[N:14][S:13][N:12]=1.O>O1CCCC1>[CH2:1]([O:7][C:11]1[C:15]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)=[N:14][S:13][N:12]=1)[CH2:2][C:3]#[C:4][CH2:5][CH3:6]
Reactant: Clc1nsnc1-c1cccnc1
Reactant: CCC#CCCO
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCC#CCCOc1nsnc1-c1cccnc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 3-hexyn-1-ol (880 mg, 9 mmol) and sodium hydride (310 mg, 9 mmol) in dry tetrahydrofuran was added a solution of 3-(3-chloro-1,2,5-thiadiazol-4-yl)pyridine (590 mg, 3 mmol) in dry tetrahydrofuran. The reaction mixture was stirred at room temperature for 1 h. Water was added and the mixture was extracted with ether. The ether phase was dried and evaporated to give the title compound.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:4]=[N:5][CH:6]=[C:7]([CH:10]=1)[C:8]#[N:9].[BH4-].[Na+].Cl.[NH4+].[OH-]>CCO>[F:11][C:2]([F:1])([F:12])[C:3]1[CH:10]=[C:7]([CH2:8][NH2:9])[CH:6]=[N:5][CH:4]=1
Reactant: N#Cc1cncc(C(F)(F)F)c1
Agent: Cl
Agent: [BH4-]
Agent: [NH4+]
Solvent: CCO
Product: NCc1cncc(C(F)(F)F)c1
Temperature: 50 °C
Reaction time: 2 h
Yield: 31.3 %

Procedure:
5-(trifluoromethyl)nicotinonitrile (0.31 g, 1.95 mmol, 1 eq) and CoCl2.6H2O (0.23 g, 0.97 mmol, 0.5 eq) were dissolved in 10 mL EtOH. The flask was fitted with a reflux condenser and heated to 50° C. under Ar. NaBH4 (0.22 g, 5.85 mmol, 3 eq) was added in 2 batches and the mixture was stirred at 50° C. for 2 h. The mixture was then cooled to room temperature and 5 N HCl was added to pH=1-2. The reaction was stirred until the bubbling stopped and NH4OH (28%) was added to pH=9. The mixture was then concentrated in vacuo and the residue was extracted with CHCl3/MeOH/water (8:1:1) (×2). The combined extracts were dried over Na2SO4. The inorganics were filtered off, and the solvent was removed in vacuo yielding 0.1 g (0.61 mmol, 31% yield) of (5-(trifluoromethyl)pyridin-3-yl)methanamine.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:15]([O:17]C)=[O:16])[C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][C:3]=1[CH3:19].[Cl:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25]Cl)=[CH:23][CH:22]=1>>[C:15]([C:10]1[C:11](=[O:14])[N:12]([CH2:25][C:24]2[CH:27]=[CH:28][C:21]([Cl:20])=[CH:22][CH:23]=2)[N:13]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[C:3]([CH3:19])[CH:4]=2)[CH:9]=1)([OH:17])=[O:16]
Reactant: ClCc1ccc(Cl)cc1
Reactant: COC(=O)c1cc(-c2ccc(F)c(C)c2)n[nH]c1=O
Product: Cc1cc(-c2cc(C(=O)O)c(=O)n(Cc3ccc(Cl)cc3)n2)ccc1F
Yield: 46.5 %

Procedure:
Following the procedure of Example 1(6), 6-(4-fluoro-3-methylphenyl)-4-methoxycarbonyl-2H-pyridazin-3-one and 4-chlorobenzyl chloride were reacted. Without purification, the reaction product was reacted further following the procedure of Example 1(7) to yield the title compound as a pale yellow crystalline powder (yield: 46.5%).