Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:10]([CH:19]=O)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:21]1([CH:27]2[CH2:33][CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[CH2:1]([N:8]1[CH2:12][CH:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:10]([CH2:19][N:30]2[CH2:31][CH2:32][CH2:33][CH:27]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:28][CH2:29]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc(C2CCCNCC2)cc1
Reactant: O=CC1CN(Cc2ccccc2)CC1c1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: c1ccc(CN2CC(CN3CCCC(c4ccccc4)CC3)C(c3ccccc3)C2)cc1
Yield: 58.7 %

Procedure:
The title compound was prepared from 20 mg of 1-Benzyl-3-(SR)-formyl-4-(SR)-phenylpyrrolidine, 13 mg of 4-phenyl-perhydro-azepine and 25 mg of sodium triacetoxyborohydride using a procedure analogous to that described in Example 9, Step B to provide 18.5 mg of the title compound. RF : 0.37 (50% EtOAc in hexanes). 1H NMR (300 MHz, CDCl3): δ1.48-1.83 (m, 6H), 2.37-2.69 (m, 10H), 2.88-3.01 (m, 3H), 3.67 (ABq, J=13 Hz, 2H), 7.09-7.39 (m, 15H). Mass Spectrum (CI): 425.3 (M+H).
Reaction SMILES: [C:1]([OH:4])(=[O:3])C.[CH:5]([C:8]1[S:9][CH:10]=[C:11]([C:13]([N:15]2[CH2:20][C:19]3([CH2:25][CH2:24][N:23]([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][C:31]([CH3:35])([CH3:34])[CH:32]=O)[CH2:22][CH2:21]3)[O:18][CH2:17][CH2:16]2)=[O:14])[N:12]=1)([CH3:7])[CH3:6].C(O)(=O)C.[NH2:40][CH2:41][C@@H:42]([C:44]1[C:52]2[S:51][C:50](=[O:53])[NH:49][C:48]=2[C:47]([OH:54])=[CH:46][CH:45]=1)[OH:43].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO>[CH:1]([OH:4])=[O:3].[OH:54][C:47]1[C:48]2[NH:49][C:50](=[O:53])[S:51][C:52]=2[C:44]([C@@H:42]([OH:43])[CH2:41][NH:40][CH2:35][C:31]([CH3:32])([CH3:34])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][N:23]2[CH2:22][CH2:21][C:19]3([O:18][CH2:17][CH2:16][N:15]([C:13]([C:11]4[N:12]=[C:8]([CH:5]([CH3:7])[CH3:6])[S:9][CH:10]=4)=[O:14])[CH2:20]3)[CH2:25][CH2:24]2)=[CH:45][CH:46]=1
Reactant: NC[C@H](O)c1ccc(O)c2[nH]c(=O)sc12
Reactant: CC(C)c1nc(C(=O)N2CCOC3(CCN(CCCCCC(C)(C)C=O)CC3)C2)cs1
Reactant: CC(=O)O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Product: CC(C)c1nc(C(=O)N2CCOC3(CCN(CCCCCC(C)(C)CNC[C@H](O)c4ccc(O)c5[nH]c(=O)sc45)CC3)C2)cs1
Product: O=CO
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
Acetic acid (0.053 mL) was added to a mixture of 7-(4-(2-isopropylthiazole-4-carbonyl)-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)-2,2-dimethylheptanal (example 102, step d) (0.33 g) and (R)-7-(2-amino-1-hydroxyethyl)-4-hydroxybenzo[d]thiazol-2(3H)-one hydrochloride (WO2007027134, example 1, step d) (0.25 g) with 3 Å molecular sieves in anhydrous methanol (10 mL). The mixture was stirred for 5 min then cooled to 0° C. Sodium triacetoxyborohydride (0.13 g) was added and the resulting mixture stirred at RT for 16.5 h. The solution was filtered then concentrated in vacuo. The residue was dissolved in a mixture of acetonitrile and water and purified by preparative HPLC (Phenomenex Gemini®, Gradient: 10-40% acetonitrile in 0.1% aqueous formic acid). The fractions containing product were combined and freeze-dried to give the titled compound as a white solid. Yield 0.1 g.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([OH:10])=[O:9])[CH:5]=[CH:4][N:3]=1.[CH2:11](CN)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[CH2:20]([N:22](CC)CC)C>C(Cl)Cl>[CH2:11]([N:22]([CH3:20])[C:2]1[CH:7]=[C:6]([CH:5]=[CH:4][N:3]=1)[C:8]([OH:10])=[O:9])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=C(O)c1ccnc(Cl)c1
Reactant: NCCc1ccccc1
Reactant: CCN(CC)CC
Solvent: ClCCl
Product: CN(Cc1ccccc1)c1cc(C(=O)O)ccn1
Temperature: 120 °C

Procedure:
A mixture of 2-chloro-pyridine-4-carboxylic acid (300 mg, 1.9 mmol), benzylmethylamine (230 mg, 1.9 mmol) and triethylamine (192 mg, 1.9 mmol) is heated at 120° C. for 12 h. The residue is dissolved in CH2Cl2 (30 mL) and extracted with 1M aqueous NaOH (3×5 mL). The aqueous layer is adjusted to pH 1-2 with 12N aqueous HCl and extracted with EtOAc (6×5 mL). The organic extracts are combined, dried (MgSO4), and evaporated to provide the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][C:7](=O)[CH:8]2[CH2:13][C:14]([O:16]CC)=O.[C:20]1([CH2:26][CH2:27][CH2:28][NH2:29])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.O>C1(C)C=CC=CC=1>[CH:20]1([CH2:26][CH2:27][CH2:28][N:29]2[C@@H:7]3[C@@H:8]([C:9]4[CH:10]=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[C:4]=4[CH2:5][CH2:6]3)[CH2:13][C:14]2=[O:16])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: NCCCc1ccccc1
Reactant: CCOC(=O)CC1C(=O)CCc2c(OC)cccc21
Solvent: O
Solvent: Cc1ccccc1
Product: COc1cccc2c1CC[C@H]1[C@@H]2CC(=O)N1CCCC1CCCCC1
Reaction time: 10 h
Yield: 60.1 %

Procedure:
4.0 g (0.01525 mol) of ethyl 1,2,3,4-tetrahydro-5-methoxy-2-oxo-1-naphthylacetate were dissolved in 80 ml of toluene, 2.29 ml (0.016 mol) of 3-phenylpropylamine were added thereto and the mixture was boiled for 20 hours on a water separator. After concentration the residue was hydrogenated with 1.5 g of Raney-nickel in 150 ml of ethanol at 120° and 140 bar for 10 hours. The product was chromatographed over silica gel with cyclohexane/ethyl acetate 2:1. There were obtained 3.13 g (61%) of oily rac-cis-3-(3-cyclohexyl-propyl)-1,3,3a,4,5,9b-hexahydro-6-methoxy-2H-benzo[e]indol-2-one.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:21]=[C:20]2[C:16]([CH:17]=[C:18]([C:23](OCC)=[O:24])[N:19]2C)=[C:15]([C:28]([F:31])([F:30])[F:29])[CH:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[NH2:33][C:34]([NH2:36])=[NH:35].[CH3:37][O-].[Na+]>CO>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:21]=[C:20]2[C:16]([CH:17]=[C:18]([C:23]([N:35]=[C:34]([NH2:36])[NH:33][CH3:37])=[O:24])[NH:19]2)=[C:15]([C:28]([F:31])([F:30])[F:29])[CH:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)c1cc2c(C(F)(F)F)cc(OCCCNC(=O)OC(C)(C)C)cc2n1C
Reactant: C[O-]
Reactant: N=C(N)N
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CNC(N)=NC(=O)c1cc2c(C(F)(F)F)cc(OCCCNC(=O)OC(C)(C)C)cc2[nH]1

Procedure:
The reaction was carried out in a manner similar to Example 1 except for using 1.28 g (2.88 mmol) of ethyl 6-(3-tert-butoxycarbonylaminopropoxy)-1-methyl-4-trifluoromethyl-2-indolecarboxylate, 5.50 g (57.6 mmol) of guanidine hydrochloride and 60 ml of methanol solution of 3.11 g (57.6 mmol) of sodium methoxide. 6-(3-tert-Butoxycarbonylaminopropoxy)-1-methyl-4-trifluoromethyl-2-indoloylguanidine was thus obtained in an amount of 0.41 g. This compound, 0.41 g, was treated in a manner similar to Example 114 to give 0.27 g (21.8%) of 6-(3-aminopropoxy)-1-methyl-4-trifluoromethyl-2-indoloylguanidine dihydrochloride.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][CH:5]=[C:6]2[CH:10]=[C:9]([C:11]3[CH:12]=[C:13]([CH:20]=[CH:21][C:22]=3[CH3:23])[C:14]([NH:16][CH:17]3[CH2:19][CH2:18]3)=[O:15])[S:8][C:7]=12.[NH:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1>C(#N)C>[CH:17]1([NH:16][C:14](=[O:15])[C:13]2[CH:20]=[CH:21][C:22]([CH3:23])=[C:11]([C:9]3[S:8][C:7]4=[C:2]([N:24]5[CH2:29][CH2:28][O:27][CH2:26][CH2:25]5)[N:3]=[N:4][CH:5]=[C:6]4[CH:10]=3)[CH:12]=2)[CH2:19][CH2:18]1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-c1cc2cnnc(Cl)c2s1
Reactant: C1COCCN1
Solvent: CC#N
Product: Cc1ccc(C(=O)NC2CC2)cc1-c1cc2cnnc(N3CCOCC3)c2s1
Temperature: 150 °C

Procedure:
A 2.5 ml glass microwave reaction vessel was charged with 3-(7-chlorothieno[2,3-d]pyridazin-2-yl)-N-cyclopropyl-4-methylbenzamide: (0.020 g, 0.058 mmol), acetonitrile (1 ml), morpholine (0.015 g, 0.17 mmol). The reaction mixture was heated in a Smith Synthesizer microwave reactor (Personal Chemistry, Inc., Upssala, Sweden) at 150° C. for 50 min. The solvent was evaporated under reduced pressure and the crude product was adsorbed onto a plug of silica gel and chromatographed through a Redi-Sep pre-packed silica gel column (12 g), eluting with a gradient of 5% to 95% MeOH in DCM to provide N-cyclopropyl-4-methyl-3-(7-morpholinothieno[2,3-d]pyridazin-2-yl)benzamide (0.016 g) MS (ES+): 395 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:23]=[CH:22][C:5]([NH:6][C:7]2[CH:19]=[C:18]([CH:20]=[CH2:21])[CH:17]=[CH:16][C:8]=2[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[CH:4][CH:3]=1.Br[C:25]1[CH:30]=[CH:29][C:28]([O:31][C:32]([F:35])([F:34])[F:33])=[CH:27][CH:26]=1.C(N(CCCC)CCCC)CCC.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(OCC)(=O)C.CN(C)C(=O)C>[F:1][C:2]1[CH:23]=[CH:22][C:5]([NH:6][C:7]2[CH:19]=[C:18](/[CH:20]=[CH:21]/[C:25]3[CH:26]=[CH:27][C:28]([O:31][C:32]([F:33])([F:34])[F:35])=[CH:29][CH:30]=3)[CH:17]=[CH:16][C:8]=2[C:9]([O:11][C:12]([CH3:15])([CH3:13])[CH3:14])=[O:10])=[CH:4][CH:3]=1
Reactant: FC(F)(F)Oc1ccc(Br)cc1
Reactant: C=Cc1ccc(C(=O)OC(C)(C)C)c(Nc2ccc(F)cc2)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CCCCN(CCCC)CCCC
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: CC(C)(C)OC(=O)c1ccc(/C=C/c2ccc(OC(F)(F)F)cc2)cc1Nc1ccc(F)cc1
Temperature: 110 °C
Reaction time: 6 h

Procedure:
To N,N-dimethylacetamide 3.0 mL solution of tert-butyl 2-(4-fluoroanilino)-4-vinylbenzoate 0.10 g were added 1-bromo-4-(trifluoromethoxy)benzene 0.12 g, tributylamine 0.15 mL and palladium acetate 3.6 mg at room temperature, and it was stirred at 110° C. for 6 hours. Palladium acetate 3.6 mg was added to it, and it was stirred at 130° C. for 6 hours. 1-bromo-4-(trifluoromethoxy)benzene 0.12 g, tributylamine 0.076 mL and (E)-di(μ-acetato)bis(o-(di-o-tolylphosphino)benzyl)dipalladium(II) 6.3 mg were added to it, and it was stirred at 80° C. for 2 hours. After the reaction mixture was cooled to room temperature, ethyl acetate and 10% citric acid aqueous solution were added to it. The organic layer was separated and collected, and the solvent was removed under reduced pressure after sequential washing with 10% citric acid aqueous solution, saturated sodium thiosulfate aqueous solution and saturated sodium chloride aqueous solution. The obtained residue was refined by silica gel column chromatography [Trikonex company, Flash Tube 2008, eluent; hexane:ethyl acetate=10:1] to give tert-butyl 2-(4-fluoroanilino)-4-((E)-2-(4-(trifluoromethoxy)phenyl)vinyl)benzoate.
Reaction SMILES: [C:1]1([C:7]2[CH:16]=[N:15][C:10]3[O:11][CH2:12][CH2:13][NH:14][C:9]=3[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:17][C:18]1[CH:19]=[C:20]([CH:24]=[C:25]([Br:29])[C:26]=1[O:27][CH3:28])[C:21](Cl)=[O:22].C(N(CC)CC)C.Cl>ClCCl>[Br:17][C:18]1[CH:19]=[C:20]([C:21]([N:14]2[CH2:13][CH2:12][O:11][C:10]3[N:15]=[CH:16][C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)=[CH:8][C:9]2=3)=[O:22])[CH:24]=[C:25]([Br:29])[C:26]=1[O:27][CH3:28]
Reactant: c1ccc(-c2cnc3c(c2)NCCO3)cc1
Reactant: COc1c(Br)cc(C(=O)Cl)cc1Br
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1c(Br)cc(C(=O)N2CCOc3ncc(-c4ccccc4)cc32)cc1Br
Temperature: 25 °C
Reaction time: 1 h
Yield: 55.5 %

Procedure:
To a 5 ml flask, 7-phenyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine (10 mg, 0.05 mmol) and 3,5-dibromo-4-methoxy-benzoyl chloride (17 mg, 0.05 mmol) were dissolved in dichloromethane. Triethylamine (0.02 ml, 0.14 mmol) was added thereto and then stirred at room temperature for 1 hour. After neutralizing with 1N hydrochloric acid solution, the mixture was extracted with dichloromethane and the combined organic layer was dried over anhydrous sodium sulfate (Na2SO4), filtered and evaporated under reduced pressure. The residue was purified by column chromatography on silica eluting with a solvent of dichloromethane:methanol=40:1. The fractions containing the product were collected and evaporated to obtain white solid (14 mg, 59%).
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:21]([OH:23])=O)[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH:19]=[CH2:20])=[CH:13][CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.[CH3:49][O:50][C:51](=[O:57])[C@H:52]([CH:54]([CH3:56])[CH3:55])[NH2:53].CCN(C(C)C)C(C)C>CN(C=O)C.CCOC(C)=O>[CH3:49][O:50][C:51](=[O:57])[C@@H:52]([NH:53][C:21](=[O:23])[C@@H:9]([NH:8][C:1]([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2])[CH2:10][C:11]1[CH:12]=[CH:13][C:14]([O:17][CH2:18][CH:19]=[CH2:20])=[CH:15][CH:16]=1)[CH:54]([CH3:56])[CH3:55]
Reactant: COC(=O)[C@@H](N)C(C)C
Reactant: C=CCOc1ccc(C[C@H](NC(=O)OC(C)(C)C)C(=O)O)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C=CCOc1ccc(C[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@H](C(=O)OC)C(C)C)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
N-BOC-O-allyl-tyrosine (5.0 g, 16.3 mmol), HATU (17.9 mmol) and valine methyl ester hydrochloride (32.6 mmol) were dissolved in anhydrous DMF (25 mL). DIPEA (22.7 mL, 65 mmol) was added and the reaction mixture was stirred at rt for 18 h before being partitioned between EtOAc and 1M hydrochloric acid. The organic phase was then washed sequentially with 1M hydrochloric acid and brine before being dried (MgSO4), filtered and concentrated in vacuo. Purification was achieved using flash chromatography, eluting with a gradient of (50/70) petroleum ether to EtOAc to yield a white solid, 6.08 g, 69%. Rf=0.29 (1/2 EtOAc/(50/70) petroleum ether). m.p. 74-76° C.
Reaction SMILES: [Cl:1][CH2:2][C:3]1[S:4][CH:5]=[CH:6][C:7]=1[CH2:8][Cl:9].S(Cl)([Cl:13])(=O)=O>C(O)(=O)C>[Cl:13][C:5]1[S:4][C:3]([CH2:2][Cl:1])=[C:7]([CH2:8][Cl:9])[CH:6]=1
Reactant: O=S(=O)(Cl)Cl
Reactant: ClCc1ccsc1CCl
Solvent: CC(=O)O
Product: ClCc1cc(Cl)sc1CCl
Temperature: 25 °C
Reaction time: 1 h
Yield: 40.3 %

Procedure:
2,3-Bis-chloromethyl-thiophene (500 mg, 2.76 mmol) was dissolved in acetic acid (10 ml). Sulfuryl chloride (372 mg, 2.76 mmol) was added and the mixture was stirred for 1 h at room temperature. The mixture was partitioned between EA, water and an excess of solid sodium hydrogencarbonate and the aqueous phase extracted with EA. The combined organic extracts were dried over magnesium sulfate, filtered and evaporated to dryness to give 240 mg of the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:7][C:8]2[N:9]=[C:10](Cl)[C:11]([C:29]#[N:30])=[C:12]3[C:17]=2[C:16]=1[NH:15][C:14](=[O:18])[N:13]3[C:19]1[C:27]2[O:26][CH2:25][O:24][C:23]=2[CH:22]=[CH:21][C:20]=1[Cl:28])=[O:5])[CH3:2].[CH3:32][Sn](C)(C)C>CN(C=O)C>[CH2:1]([O:3][C:4]([C:6]1[S:7][C:8]2[N:9]=[C:10]([CH3:32])[C:11]([C:29]#[N:30])=[C:12]3[C:17]=2[C:16]=1[NH:15][C:14](=[O:18])[N:13]3[C:19]1[C:27]2[O:26][CH2:25][O:24][C:23]=2[CH:22]=[CH:21][C:20]=1[Cl:28])=[O:5])[CH3:2]
Reactant: C[Sn](C)(C)C
Reactant: CCOC(=O)c1sc2nc(Cl)c(C#N)c3c2c1NC(=O)N3c1c(Cl)ccc2c1OCO2
Solvent: CN(C)C=O
Product: CCOC(=O)c1sc2nc(C)c(C#N)c3c2c1NC(=O)N3c1c(Cl)ccc2c1OCO2
Temperature: 150 °C

Procedure:
7-chloro-5-(5-chloro-benzo[1,3]dioxol-4-yl)-6-cyano-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triaza-acenaphthylene-2-carboxylic acid ethyl ester Compound 1g (115 mg, 0.242 mmol) was combined with 95% tetramethyltin (0.039 ml, 0.266 mmol), PdCl2(Ph3P)2 (17 mg, 0.024 mmol) and DMF (3 mL) in a sealed microwave vessel. The mixture was heated to 150° C. for 15 mins. The reaction mixture was diluted with 0.5 M NaH2PO4 and extracted with EtOAc, then dried (MgSO4) and evaporated. The resulting residue was purified by flash chromatography (30 to 50% EtOAc/hexane/1% Et3N) to give 5-(5-chloro-benzo[1,3]dioxol-4-yl)-6-cyano-7-methyl-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triaza-acenaphthylene-2-carboxylic acid ethyl ester Compound 2a (57 mg) as a white solid. LC/MS 457 (MH+).
Reaction SMILES: [N:1]([O-])=O.[Na+].[C:5]1([C:11]#[C:12][C:13]2[C:14]([C:19]([F:22])([F:21])[F:20])=[N:15][NH:16][C:17]=2[NH2:18])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[ClH:23]>C(Cl)Cl>[Cl:23][C:12]1[C:11]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)=[N:1][N:18]=[C:17]2[NH:16][N:15]=[C:14]([C:19]([F:21])([F:22])[F:20])[C:13]=12
Reactant: O=N[O-]
Reactant: Cl
Reactant: Nc1[nH]nc(C(F)(F)F)c1C#Cc1ccccc1
Agent: [Na+]
Solvent: ClCCl
Product: FC(F)(F)c1n[nH]c2nnc(-c3ccccc3)c(Cl)c12
Temperature: -15 °C

Procedure:
To a cooled (cooling bath −15° C.) stirred suspension of sodium nitrite (540 mg, 7.8 mmol) in conc. HCl (20 mL) was added a solution of 4-(2-phenylethynyl)-3-(trifluoromethyl)-1H-pyrazol-5-amine (652 mg, 2.6 mmol) in CH2Cl2 (3 mL). The cooling bath was removed and the reaction mixture was stirred at room temperature for 1 h. NaCl (900 mg) was added and the reaction heated at 50° C. for 16 h. CH2Cl2 was added to the cooled reaction mixture. The aqueous phase was extracted with CH2Cl2 twice and the organic phases combined, dried over MgSO4, filtered and evaporated. The residue was purified by column chromatography (silica gel, ethyl acetate/isohexane 1:9 to 1:0) yielding the title compound as a yellow glass (115 mg) which was used in the subsequent step.
Reaction SMILES: C(N(CC)CC)C.[OH:8][CH:9]1[CH2:12][N:11]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:10]1.S(=O)(=O)=O.N1C=CC=CC=1>CS(C)=O>[O:8]=[C:9]1[CH2:12][N:11]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CC(O)C1
Agent: O=S(=O)=O
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CC(=O)C1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 100.7 %

Procedure:
Triethylamine (2.47 mL) was added to a solution of tert-butyl 3-hydroxyazetidine-1-carboxylate (0.5 g, 2.9 mmol) in DMSO (5 mL). To this mixture, a solution of pyridine sulphur trioxide (1.8 g, 11.3 mmol) in DMSO (6.5 mL) was added drop-wise and the mixture was stirred at room temperature for 1.5 hrs. The mixture was poured onto ice-water and extracted with ethyl acetate (3×50 mL), organics combined dried with sodium sulfate, filtered and concentrated to afford tert-butyl 3-oxoazetidine-1-carboxylate as white solid (500 mg, 100%). 1H NMR (300 MHz, CDCl3): δ 4.68 (s, 4H), 1.48 (s, 9H).
Reaction SMILES: C(N(CC)CC)C.[C:8](Cl)(=[O:13])[C:9]([CH3:12])([CH3:11])[CH3:10].[NH2:15][C:16]1[N:21]=[C:20]([C:22]2[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[C:24]([F:30])[CH:23]=2)[CH:19]=[C:18]([N:31]2[C@H:36]([CH3:37])[CH2:35][O:34][C@H:33]([CH2:38][NH2:39])[CH2:32]2)[N:17]=1>C1COCC1>[NH2:15][C:16]1[N:17]=[C:18]([N:31]2[C@H:36]([CH3:37])[CH2:35][O:34][C@H:33]([CH2:38][NH:39][C:8](=[O:13])[C:9]([CH3:12])([CH3:11])[CH3:10])[CH2:32]2)[CH:19]=[C:20]([C:22]2[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[C:24]([F:30])[CH:23]=2)[N:21]=1
Reactant: CC(C)(C)C(=O)Cl
Reactant: C[C@@H]1CO[C@H](CN)CN1c1cc(-c2ccc(C#N)c(F)c2)nc(N)n1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C[C@@H]1CO[C@H](CNC(=O)C(C)(C)C)CN1c1cc(-c2ccc(C#N)c(F)c2)nc(N)n1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 124.5 %

Procedure:
Triethylamine (0.05 mL, 0.36 mmol) and pivaloyl chloride (0.04 mL, 0.33 mmol) were added to a solution of 4-{2-amino-6-[(2R,5R)-2-(aminomethyl)-5-methyl-4-morpholinyl]-4-pyrimidinyl}-2-fluorobenzonitrile (99 mg, 0.29 mmol) in THF (5 mL), and the mixture was stirred at room temperature under nitrogen for 45 minutes. The mixture was quenched with saturated aqueous NaHCO3 (10 mL) and extracted with EtOAc (2×10 mL). The extracts were washed with brine (15 mL), dried (Na2SO4), filtered, and concentrated in vacuo to give the title compound as a yellow foam (154 mg, about 75% pure). LC-MS (ES) m/z=427 [M+H]+.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1)#[N:2].C(N(CC)CC)C.[F:22][C:23]([F:38])([F:37])[C:24]1[CH:25]=[C:26]([N:34]=[C:35]=[O:36])[CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=1>ClCCl.O>[F:22][C:23]([F:37])([F:38])[C:24]1[CH:25]=[C:26]([NH:34][C:35]([N:12]2[CH2:13][CH2:14][N:9]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[C:1]#[N:2])[CH2:10][CH2:11]2)=[O:36])[CH:27]=[C:28]([C:30]([F:33])([F:31])[F:32])[CH:29]=1
Reactant: N#Cc1ccccc1N1CCNCC1
Reactant: O=C=Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: N#Cc1ccccc1N1CCN(C(=O)Nc2cc(C(F)(F)F)cc(C(F)(F)F)c2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1-(2-Cyanophenyl)piperazine (1.0 g, 5.34 mmol) was dissolved in 25 mL of dichloromethane. Then, triethylamine (820 μL, 5.88 mmol) was added, followed by 3,5-bis(trifluoromethyl)phenyl isocyanate (1020 μL, 5.87 mmol). The reaction stirred at room temperature overnight. The reaction mixture was diluted with 50 mL of water and extracted three times with 25 mL portions of ethyl acetate. The combined organic fractions were washed twice with 25 mL of 0.1 M HCl, once with 25 mL of water, and once with 25 mL of saturated sodium bicarbonate. The organic fraction was dried with magnesium sulfate and concentrated under vacuum. The crude product was used without further purification.
Reaction SMILES: [H-].[Na+].O[CH:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](=[O:13])[N:5]1[C:14]1[CH:23]=[CH:22][C:21]2[C:16](=[N:17][C:18]([O:24][CH3:25])=[CH:19][CH:20]=2)[N:15]=1.[CH3:26][C:27]([CH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1)=[O:28].C(OCC)C>CN(C)C=O>[CH:29]1([C:27](=[O:28])[CH2:26][CH:4]2[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6](=[O:13])[N:5]2[C:14]2[CH:23]=[CH:22][C:21]3[C:16](=[N:17][C:18]([O:24][CH3:25])=[CH:19][CH:20]=3)[N:15]=2)[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1
Reactant: CC(=O)C1CCCCC1
Reactant: COc1ccc2ccc(N3C(=O)c4ccccc4C3O)nc2n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: COc1ccc2ccc(N3C(=O)c4ccccc4C3CC(=O)C3CCCCC3)nc2n1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 35.5 %

Procedure:
An oily suspension (50% by weight; 3.1 g) of sodium hydride is added at a temperature in the region of -5° C. to a solution, maintained under a nitrogen atmosphere, of 3-hydroxy-2-(7-methoxy-1,8-naphthyridin-2-yl)-1-isoindolinone (10 g) in anhydrous dimethylformamide (180 cc), and the suspension obtained is stirred for 30 minutes at a temperature in the region of 0° C. A solution of cyclohexyl methyl ketone (8.2 g) in anhydrous dimethylformamide (20 cc) is then added and stirring is continued for 6 hours at a temperature in the region of 0° C. and then for 16 hours at a temperature in the region of 20° C. The reaction mixture is then poured into distilled water (800 cc). The solid obtained is separated by filtration, washed with water, dried in the air, and then recrystallized in acetonitrile and finally purified by chromatography under pressure (50 kPa) on silica gel (0.04-0.063 mm; 140 g) contained in a column 2.8 cm in diameter. Elution is performed with methylene chloride, collecting 20-cc fractions. Fractions 25 to 62 are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 40° C. The solid obtained is taken up with ethyl ether (100 cc) and separated by filtration. 3-(2-Cyclohexyl-2- oxoethyl)-2-(7-methoxy-1,8-naphthyridin-2-yl)-1-isoindolinone (4.8 g), m.p. 140° C., is obtained.