Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:24]=[N:23][C:5]2[N:6]([CH3:22])[C:7](=[O:21])[N:8]([CH2:11][CH2:12][CH2:13][O:14][CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][O:16]3)[C:9](=[O:10])[C:4]=2[CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].CN(C)CC(O)=O.Br[C:39]1[CH:40]=[N:41][CH:42]=[C:43]([CH3:45])[CH:44]=1>O1CCOCC1.CC(=O)OCC.O.[Cu]I>[CH3:22][N:6]1[C:5]2[N:23]=[CH:24][C:2]([O:1][C:39]3[CH:40]=[N:41][CH:42]=[C:43]([CH3:45])[CH:44]=3)=[CH:3][C:4]=2[C:9](=[O:10])[N:8]([CH2:11][CH2:12][CH2:13][O:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][O:16]2)[C:7]1=[O:21]
Reactant: Cn1c(=O)n(CCCOC2CCCCO2)c(=O)c2cc(O)cnc21
Reactant: Cc1cncc(Br)c1
Agent: [Cu]I
Agent: CN(C)CC(=O)O
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1COCCO1
Product: Cc1cncc(Oc2cnc3c(c2)c(=O)n(CCCOC2CCCCO2)c(=O)n3C)c1
Temperature: 25 °C
Yield: 79.5 %

Procedure:
To a suspension of 6-hydroxy-1-methyl-3-(3-((tetrahydro-2H-pyran-2-yl)oxy)propyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (See Compound 36, step 2, 600 mg, 1.8 mmol), CuI (45 mg, 0.23 mmol), Cs2CO3 (1.69 mg, 5.4 mmol) and 2-(dimethylamino)acetic acid (93 mg, 0.9 mmol) in dioxane (10 mL) was added 3-bromo-5-methylpyridine (0.45 mL, 3.6 mmol). The reaction was heated at 140° C. (MW) in a sealed tube for 2 h, cooled to RT and diluted with EA (50 mL) and water (50 mL). The organic layer was washed with water (30 mL) and brine (50 mL), dried over Na2SO4 and concentrated to a residue which was purified by chromatography eluted with PE/EA (10:1) to give 1-methyl-6-(5-methylpyridin-3-yloxy)-3-(3-(tetrahydro-2H-pyran-2-yloxy)propyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (610 mg, 81% yield) as a yellow solid. LCMS MH+ 427 and TR=1.403 min.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([C:10]2[C:15]([O:16][CH3:17])=[CH:14][NH:13][C:12](=[O:18])[CH:11]=2)[CH:3]=1.[H-].[Na+].[CH:21]1([CH2:25][CH:26](OS(C(F)(F)F)(=O)=O)[C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:24][CH2:23][CH2:22]1>>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([C:10]2[C:15]([O:16][CH3:17])=[CH:14][N:13]([CH:26]([CH2:25][CH:21]3[CH2:22][CH2:23][CH2:24]3)[C:27]([O:29][CH2:30][CH3:31])=[O:28])[C:12](=[O:18])[CH:11]=2)[CH:3]=1
Reactant: COc1c[nH]c(=O)cc1-c1cc(Cl)ccc1C#N
Reactant: CCOC(=O)C(CC1CCC1)OS(=O)(=O)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)C(CC1CCC1)n1cc(OC)c(-c2cc(Cl)ccc2C#N)cc1=O

Procedure:
122 mg (purity 87%, 0.41 mmol) of 4-chloro-2-(5-methoxy-2-oxo-1,2-dihydropyridin-4-yl)benzonitrile in the presence of 1.3 eq. of sodium hydride and 161 mg (0.53 mmol, 1.3 eq.) of ethyl 3-cyclobutyl-2-{[(trifluoromethyl)sulphonyl]oxy}propanoate (racemate) were reacted at RT according to General 4E. The crude product was purified by flash chromatography (KP-SIL, cyclohexane/ethyl acetate 15-33%). Yield: 140 mg (82% of theory)
Reaction SMILES: [N:1]1([C:8]([C:10]2[CH:14]=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[S:12][C:11]=2Br)=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:22][N:23](C=O)C>[C-]#N.[Zn+2].[C-]#N.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[N:1]1([C:8]([C:10]2[CH:14]=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[S:12][C:11]=2[C:22]#[N:23])=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(c1cc(-c2ccccc2)sc1Br)N1CCCCCC1
Reactant: CN(C)C=O
Agent: [Pd]
Agent: [C-]#N
Agent: [Zn+2]
Product: N#Cc1sc(-c2ccccc2)cc1C(=O)N1CCCCCC1
Temperature: 100 °C

Procedure:
Azepan-1-yl-(2-bromo-5-phenyl-thiophen-3-yl)-methanone (109 mg, 0.30 mmol) was dissolved in DMF (2 mL). Zinc cyanide (0.30 mmol) and tetrakis(triphenylphosphine) palladium (0) (0.15 mmol) were added and the reaction heated at 100° C. for 5 hours. The reaction mixture was cooled to ambient temperature, quenched with a 1:1 mixture of 5% aqueous sodium thiosulfate and 10% aqueous potassium carbonate. The resulting mixture was extracted with ethyl acetate, and the organic solvent separated and then evaporated. The residue was purified by HPLC, eluting with 50%-90% acetonitrile in water (0.1% formic acid) over 30 minutes. The fractions containing the desired product were concentrated under vacuum and freeze-dried to give the title compound (16 mg). LCMS m/z 311.10 [M+H]+ R.T.=11.43 min (Analytical Method 2). 1H NMR (400 MHz, CHCl3-d): δ 7.60 (m, 2H), 7.5 (m, 3H), 7.2 (s, 1H), 3.75 (t, 2H), 3.5 (t, 2H), 1.9 (m, 2H), 1.75-1.6 (m, 6H).
Reaction SMILES: [Si:1]([O:8][CH2:9][C@H:10]([CH3:15])[C:11](OC)=[O:12])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].CCCCCC.[H-].C([Al+]CC(C)C)C(C)C.O>ClCCl>[Si:1]([O:8][CH2:9][C@H:10]([CH3:15])[CH2:11][OH:12])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: COC(=O)[C@@H](C)CO[Si](C)(C)C(C)(C)C
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: CCCCCC
Solvent: ClCCl
Solvent: O
Product: C[C@H](CO)CO[Si](C)(C)C(C)(C)C
Reaction time: 0.5 h
Yield: 89.7 %

Procedure:
Methyl (S)-(+)-3-(t-butyldimethylsilyloxy)-2-methylpropionate (10.0 g; 43.1 mmol) was dissolved in anhydrous dichloromethane (100 ml), and a hexane solution (100 ml) of 1M diisobutylaluminum hydride was dropwise added thereto at a temperature below 0° C. in an argon stream. After stirring for 30 minutes, water (20 ml) was added thereto, and the resultant mixture was stirred for 1 hour, followed by separation of the organic layer. The aqueous layer was extracted with dichloromethane, and the extracts were combined together with the organic layer. The solvent was distilled under reduced pressure to give (R)-(+)-3-(t-butyldimethylsilyloxy)-2-methyl-1-propanol (7.9 g; yield, 90%) as a colorless oil. A portion of the oil was distilled to give a purified product (bath temperature: 112° C./17 mmHg).
Reaction SMILES: [C:1](C1C=CC=CN=1)#[N:2].[NH2:9][C:10]1[S:11][C:12]([CH3:20])=[CH:13][C:14]=1[C:15](OCC)=O.O=P(Cl)(Cl)Cl>>[CH3:20][C:12]1[S:11][C:10]2[N:9]=[CH:1][N:2]=[CH:15][C:14]=2[CH:13]=1
Reactant: N#Cc1ccccn1
Reactant: CCOC(=O)c1cc(C)sc1N
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1cc2cncnc2s1

Procedure:
With the procedure of Example 477, the reaction of 2-cyanopyridine and 2-amino-5-methyl-3-ethoxycarbonyl-thiophene, and the subsequent reaction with POCl3 yields 4-chloro-2-pyridin-2-yl)-6-methyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:13]3[CH:14]=[CH:15][C:16]4[N:17]([C:19]([C:22]5[CH:34]=[CH:33][C:25]([O:26][CH2:27][CH2:28][CH2:29][N:30]=[N+]=[N-])=[CH:24][CH:23]=5)=[CH:20][N:21]=4)[CH:18]=3)=[CH:11][N:10]([C:35]([C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[N:9]=2)=[CH:4][CH:3]=1.C(P)CCC.O.S([O-])([O-])(=O)=O.[Na+].[Na+]>O1CCCC1.C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]([C:13]3[CH:14]=[CH:15][C:16]4[N:17]([C:19]([C:22]5[CH:34]=[CH:33][C:25]([O:26][CH2:27][CH2:28][CH2:29][NH2:30])=[CH:24][CH:23]=5)=[CH:20][N:21]=4)[CH:18]=3)=[CH:11][N:10]([C:35]([C:48]3[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=3)([C:42]3[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=3)[C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[N:9]=2)=[CH:6][CH:7]=1
Reactant: [N-]=[N+]=NCCCOc1ccc(-c2cnc3ccc(-c4cn(C(c5ccccc5)(c5ccccc5)c5ccccc5)nc4-c4ccc(F)cc4)cn23)cc1
Agent: CCCCP
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: NCCCOc1ccc(-c2cnc3ccc(-c4cn(C(c5ccccc5)(c5ccccc5)c5ccccc5)nc4-c4ccc(F)cc4)cn23)cc1
Reaction time: 2 h
Yield: 84.9 %

Procedure:
A solution of 351 mg 3-(4-{6-[3-(4-fluorophenyl)-1-trityl-1H-4-pyrazolyl]imidazo[1,2-a]pyridin-3-yl}phenoxy)-propyl azide obtained in Example 15 in 10 mL tetrahydrofuran was stirred at room temperature in a stream of nitrogen, 0.15 mL n-butyl phosphine was added thereto and stirred for 2 hours. Then, 2 mL water was added thereto and further stirred for 4 hours. Ethyl acetate and anhydrous sodium sulfate were added to the reaction solution and stirred. The drying agent was filtered off, the filtrate was concentrated, and the residue was subjected to silica gel column chromatography. By gradual elution with an eluent from hexane:ethyl acetate=1:1 (v/v) to ethyl acetate:methanol 100:1 (v/v), 287 mg of the title compound was obtained as a pale brown amorphous.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[N+:11]([O-])[C:10]=1[C:16]([O:18][CH3:19])=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:20][N:21](C)[C:22](Cl)=O>ClCCl>[CH2:1]([O:8][C:9]1[C:10]([C:16]([O:18][CH3:19])=[O:17])=[N:11][C:12]([N:21]([CH3:22])[CH3:20])=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1c(OCc2ccccc2)ccc[n+]1[O-]
Reactant: CN(C)C(=O)Cl
Solvent: ClCCl
Product: COC(=O)c1nc(N(C)C)ccc1OCc1ccccc1

Procedure:
15 g (58 mmol) of methyl 3-benzyloxypicolinate-N-oxide, 6.7 g (67 mmol) of trimethylsilylnitrile and 8.3 g (61 mmol) of N,N-dimethylcarbamoyl chloride were added to 100 ml of dichloromethane, and the mixture was allowed to stand at room temperature while stirring. The organic layer obtained was washed with water, dried and concentrated, and the residue thus obtained was purified by column chromatography to obtain an aimed compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][C@@:9]([CH3:16])([CH:11]([O:14][CH3:15])[O:12][CH3:13])[C@@H:8]3[O:17][C@@H:7]3[C:6]=2[CH:18]=1.[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([NH:26][CH2:27][C:28]2[N:29]=[N:30][N:31]([CH3:33])[N:32]=2)=[CH:22][CH:21]=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][C@@:9]([CH3:16])([CH:11]([O:14][CH3:15])[O:12][CH3:13])[C@H:8]([OH:17])[C@@H:7]([N:26]([C:23]3[CH:24]=[CH:25][C:20]([Cl:19])=[CH:21][CH:22]=3)[CH2:27][C:28]3[N:29]=[N:30][N:31]([CH3:33])[N:32]=3)[C:6]=2[CH:18]=1
Reactant: Cn1nnc(CNc2ccc(Cl)cc2)n1
Reactant: COC(OC)[C@]1(C)Oc2ccc(Br)cc2[C@H]2O[C@H]21
Product: COC(OC)[C@]1(C)Oc2ccc(Br)cc2[C@H](N(Cc2nnn(C)n2)c2ccc(Cl)cc2)[C@H]1O
Yield: 41.4 %

Procedure:
The same procedure as step 3 of example 1 was accomplished, except for using (2R,3R,4R)-6-bromo-2-methyl-2-dimethoxymethyl-3,4-epoxy-3,4-dihydro-2H-1-benzopyran (232 mg, 0.74 mmol) and N-(4-chlorophenyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amine (164 mg, 0.74 mmol). The crude product was purified by silica gel column chromatography (developing solvent-n-hexane:ethyl acetate=3:1), to give desired compound (165 mg, yield: 41%).
Reaction SMILES: O[Li].O.O.[C:5]([O:9][C:10]([N:12]([CH3:51])[C@@H:13]([CH3:50])[C:14]([NH:16][C@H:17]1[CH2:23][O:22][C:21]2[C:24]([C:28]([O:30]C)=[O:29])=[CH:25][CH:26]=[CH:27][C:20]=2[N:19]([CH2:32][C:33]2[C:42]3[C:37](=[CH:38][C:39]([C:43]([O:45]C)=[O:44])=[CH:40][CH:41]=3)[CH:36]=[CH:35][C:34]=2[O:47][CH3:48])[C:18]1=[O:49])=[O:15])=[O:11])([CH3:8])([CH3:7])[CH3:6]>CO>[C:5]([O:9][C:10]([N:12]([CH3:51])[C@@H:13]([CH3:50])[C:14]([NH:16][C@H:17]1[CH2:23][O:22][C:21]2[C:24]([C:28]([OH:30])=[O:29])=[CH:25][CH:26]=[CH:27][C:20]=2[N:19]([CH2:32][C:33]2[C:42]3[C:37](=[CH:38][C:39]([C:43]([OH:45])=[O:44])=[CH:40][CH:41]=3)[CH:36]=[CH:35][C:34]=2[O:47][CH3:48])[C:18]1=[O:49])=[O:15])=[O:11])([CH3:8])([CH3:7])[CH3:6]
Reactant: COC(=O)c1ccc2c(CN3C(=O)[C@@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)COc4c(C(=O)OC)cccc43)c(OC)ccc2c1
Agent: [Li]O
Solvent: O
Solvent: CO
Product: COc1ccc2cc(C(=O)O)ccc2c1CN1C(=O)[C@@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)COc2c(C(=O)O)cccc21
Temperature: 50 °C
Reaction time: 3.5 h
Yield: 28.9 %

Procedure:
LiOH.H2O (22.0 mg, 523 μmol, Eq: 2.00) and H2O (0.5 mL) was added to a solution of (S)-methyl 3-((S)-2-(tert-butoxycarbonyl(methyl)amino)propanamido)-5-((2-methoxy-6-(methoxycarbonyl)naphthalen-1-yl)methyl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-9-carboxylate (170 mg, 262 μmol, Eq: 1.00) in MeOH (5 mL). The mixture was heated to 50° C. After 3.5 h, LiOH.H2O (44 mg, 1.04 mmol) was added and temperature increased to 60° C. After 1.5 h, the MeOH was removed under vacuum, the aqueous mixture diluted with water and extracted with Et2O. The aqueous mixture was acidified to pH 2.0 with 1 N HCl and extracted with EtOAc. The combined organic extracts were washed brine and concentrated to give a residue that was triturated with Et2O to afford (S)-3-((S)-2-(tert-butoxycarbonyl(methyl)amino)propanamido)-5-((6-carboxy-2-methoxynaphthalen-1-yl)methyl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-9-carboxylic acid (47 mg) as a white solid.
Reaction SMILES: [Mg].II.BrC(Br)C.[CH2:8]([C:13]1[CH:26]=[CH:25][C:16]([O:17][C:18]2[CH:23]=[CH:22][C:21](Br)=[CH:20][CH:19]=2)=[CH:15][CH:14]=1)[C:9]([CH3:12])([CH3:11])[CH3:10].[N:27]1[CH:32]=[CH:31][C:30]([CH:33]=[O:34])=[CH:29][CH:28]=1.[Cl-].[NH4+]>CCOCC.O1CCCC1>[CH2:8]([C:13]1[CH:26]=[CH:25][C:16]([O:17][C:18]2[CH:23]=[CH:22][C:21]([CH:33]([C:30]3[CH:31]=[CH:32][N:27]=[CH:28][CH:29]=3)[OH:34])=[CH:20][CH:19]=2)=[CH:15][CH:14]=1)[C:9]([CH3:12])([CH3:11])[CH3:10]
Reactant: O=Cc1ccncc1
Reactant: CC(C)(C)Cc1ccc(Oc2ccc(Br)cc2)cc1
Agent: CC(Br)Br
Agent: II
Agent: [Cl-]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)(C)Cc1ccc(Oc2ccc(C(O)c3ccncc3)cc2)cc1
Reaction time: 8 h

Procedure:
To form a Grignard reagent, to 3.6 g. of magnesium metal and a crystal of iodine are added, all at once, 25 ml. of a solution of 9.0 g. dibromoethane and 25.0 g. of p-(4-neopentylphenoxy)-bromobenzene in 150 ml. of absolute tetrahydrofuran (THF). After initiating the Grignard reaction, the rest of the above THF solution is added dropwise to maintain gentle reflux. The (Grignard reagent) reaction mixture is thereafter refluxed for half an hour; cooled and to it is added, dropwise, a solution of 8.3 g. of 4-pyridine-carboxaldehyde in 20 ml. of absolute THF. The reaction mixture is then stirred overnight, decomposed with saturated ammonium chloride aqueous solution and 100 ml. ether added. The organic phase is separated, dried over anhydrous sodium sulfate, filtered, and evaporated under vacuum to dryness to yield a residue. The residue is chromatographed on silica gel, first with toluene as the eluent and subsequently with toluene containing increasing concentrations of chloroform. The desired fractions are collected and evaporated under vacuum to dryness to yield a residue. From the residue is crystallized (from ether) the title product, m.p. 120°-122° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:3]=1.CCCCCC.C([Li])CCC.[O:25]1CCC[CH2:26]1>>[CH:26]([C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:3]=1)=[O:25]
Reactant: C1CCOC1
Reactant: Brc1cccc(-c2ccccc2)n1
Agent: [Li]CCCC
Solvent: CCCCCC
Product: O=Cc1cccc(-c2ccccc2)n1
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
A tetrahydrofuran (20 ml) solution of 2-bromo-6-phenylpyridine (1.3 g, 5.5 mmol) was cooled to −78° C., then a hexane solution of n-butyllithium (3.5 ml, 1.58 M, 5.6 mmol) was dropwise added thereto while 20 minutes. The reaction mixture was additionally stirred at −78° C. for 1 hour, then a tetrahydrofuran (5 ml) solution of 2-formyl-6-phenylpyridine (1.0 g, 5.5 mmol) obtained by Reference Example 11 was dropwise added thereto while 10 minutes, the reaction temperature was allowed to warm to 0° C. while 30 minutes. Then the reaction mixture was poured into an aqueous ammonium chloride-saturated solution, an organic layer was separated, furthermore an aqueous layer was extracted with toluene. The organic layer was combined, and the solvent was distilled off, and the residue was purified by silica gel column chromatography and recrystallization, thereby obtaining 1.1 g of 1,1-bis(6-phenylpyridine-2-yl)methanol as white powder. Yield: 61.2%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]3[CH:13]=[C:14]4[C@:19]([C:21]([OH:23])=[O:22])([CH2:20][C:11]=3[CH:10]=[N:9]2)[CH2:18][N:17]([S:24]([C:27]2[CH:28]=[N:29][C:30]([N:33]3[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)=[CH:31][CH:32]=2)(=[O:26])=[O:25])[CH2:16][CH2:15]4)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:45][C:46]1([CH3:51])[CH2:49][O:48][CH:47]1Br>CN(C)C=O.O>[CH3:45][C:46]1([CH2:51][O:22][C:21]([C@@:19]23[CH2:18][N:17]([S:24]([C:27]4[CH:28]=[N:29][C:30]([N:33]5[CH2:38][CH2:37][O:36][CH2:35][CH2:34]5)=[CH:31][CH:32]=4)(=[O:25])=[O:26])[CH2:16][CH2:15][C:14]2=[CH:13][C:12]2[N:8]([C:5]4[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=4)[N:9]=[CH:10][C:11]=2[CH2:20]3)=[O:23])[CH2:49][O:48][CH2:47]1
Reactant: CC1(C)COC1Br
Reactant: O=C(O)[C@]12Cc3cnn(-c4ccc(F)cc4)c3C=C1CCN(S(=O)(=O)c1ccc(N3CCOCC3)nc1)C2
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CC1(COC(=O)[C@]23Cc4cnn(-c5ccc(F)cc5)c4C=C2CCN(S(=O)(=O)c2ccc(N4CCOCC4)nc2)C3)COC1
Yield: 19.2 %

Procedure:
A solution of (R)-1-(4-fluorophenyl)-6-(6-morpholin-4-yl-pyridine-3-sulfonyl]-1,4,5,6,7,8-hexahydro-1,2,6-triaza-cyclopenta[b]naphthalene-4a-carboxylic acid (0.09 g) in N,N-dimethylformamide (1 mL) was treated with cesium carbonate (0.16 g) and 3-methyl-3-methylbromo-oxetane (0.14 g) at room temperature for 30 minutes. The reaction mixture was diluted with water and the precipitate collected by filtration and dried under vacuum. The solid was purified by preparative reverse-phase HPLC eluting with a mixture of methanol and water containing 0.1% formic acid (3:2 to 4:1 by volume) to give the title compound as a white solid (0.02 g). 1H NMR (400 MHz, CHCl3-d): δ 8.53 (d, 1H), 7.78 (dd, 1H), 7.49-7.41 (m, 3H), 7.16 (t, 2H), 6.62 (d, 1H), 6.45 (s, 1H), 4.49-4.38 (m, 3H), 4.34 (dd, 2H), 4.15 (s, 2H), 3.81 (t, 4H), 3.67 (t, 4H), 3.32 (d, 1H), 2.91 (d, 1H), 2.62 (d, 1H), 2.52 (d, 1H), 2.40 (d, 2H), 1.28 (s, 3H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:30])[NH:7][C:8]([CH3:29])([CH3:28])[C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:17]2[CH:18]=[N:19][C:20]3[C:25]([CH:26]=2)=[N:24][C:23](Cl)=[CH:22][CH:21]=3)[CH2:13][CH2:12]1)=[O:10])([CH3:4])([CH3:3])[CH3:2].[NH2:31][C:32]1[O:33][C:34]2[CH:40]=[CH:39][C:38](B(O)O)=[CH:37][C:35]=2[N:36]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([O:5][C:6](=[O:30])[NH:7][C:8]([CH3:29])([CH3:28])[C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:17]2[CH:18]=[N:19][C:20]3[C:25]([CH:26]=2)=[N:24][C:23]([C:38]2[CH:39]=[CH:40][C:34]4[O:33][C:32]([NH2:31])=[N:36][C:35]=4[CH:37]=2)=[CH:22][CH:21]=3)[CH2:13][CH2:12]1)=[O:10])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NC(C)(C)C(=O)N1CCN(c2cnc3ccc(Cl)nc3c2)CC1
Reactant: Nc1nc2cc(B(O)O)ccc2o1
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: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)NC(C)(C)C(=O)N1CCN(c2cnc3ccc(-c4ccc5oc(N)nc5c4)nc3c2)CC1
Yield: 37.2 %

Procedure:
Tert-butyl(1-(4-(6-chloro-1,5-naphthyridin-3-yl)piperazin-1-yl)-2-methyl-1-oxopropan-2-yl)carbamate (20) (190 mg, 0.44 mmol, 1.0 eq) and (2-aminobenzo[d]oxazol-5-yl)boronic acid (94 mg, 0.53 mmol, 1.2 eq) were dissolved in a mixture of 1,4-dioxane (10 mL) and water (10 mL). To this mixture, Pd(PPh3)4 (51 mg, 0.044 mmol, 0.1 eq) and sodium carbonate (140 mg, 1.32 mmol, 3.0 eq) were added sequentially. The resulting mixture was heated at reflux for 2 h with stirring under an argon atmosphere. The reaction was complete based on TLC analysis. The reaction mixture was concentrate in vacuo, and purified by silica gel column chromatography (1-5% MeOH—CH2Cl2) to afford the desired product, tert-butyl(1-(4-(6-(2-aminobenzo[d]oxazol-5-yl)-1,5-naphthyridin-3-yl)piperazin-1-yl)-2-methyl-1-oxopropan-2-yl)carbamate (D-21) (87 mg, 37.2%) as a yellow solid. ESI-MS m/z: 532.22[M+H]+.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[N:15]([CH2:23][C:24]([F:27])([F:26])[F:25])[N:16]=[C:17]3[C:22]=2[CH2:21][CH2:20][CH2:19][CH2:18]3)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[F:27][C:24]([F:25])([F:26])[CH2:23][N:15]1[C:14]([CH:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)=[C:22]2[C:17]([CH2:18][CH2:19][CH2:20][CH2:21]2)=[N:16]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2c3c(nn2CC(F)(F)F)CCCC3)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: FC(F)(F)Cn1nc2c(c1C1CCNCC1)CCCC2

Procedure:
A solution of 500 mg (1.3 mmol) of 1-tert-butoxycarbonyl-4-(2-(2,2,2-trifluoroethyl)-4,5,6,7-tetrahydro-(2H)-indazol-3-yl)piperidine (from Step B) in 4.1 mL of CH2Cl2 at 0° C. was treated with 2.7 mL of trifluoroacetic acid. After 30 min volatiles were removed under reduced pressure. The residue was partitioned between 25 mL of CH2Cl2 and 25 mL of 1 N NaOH. After separating phases, the aqueous layer was extracted with 25 mL of 1 N NaOH. The combined organic layers were dried over Na2SO4 and concentrated to afford the title compound, which was used without further purification. 1H-NMR (500 MHz) δ 1.68–1.95 (m, 9H), 2.61–2.71 (m, 7H), 3.17–3.20 (m, 2H), 4.61 (q, J=8.3, 2H).
Reaction SMILES: [O-]CC.[Na+].[Cl:5]/[C:6](=[C:9](\[Cl:12])/[CH:10]=[O:11])/[CH:7]=[O:8].Cl.[CH3:14][NH2:15].O>C(O)(=O)C>[Cl:5][C:6]1[C:7]([N:15]([CH3:14])[C:10](=[O:11])[C:9]=1[Cl:12])=[O:8]
Reactant: CN
Reactant: O=C/C(Cl)=C(/Cl)C=O
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CN1C(=O)C(Cl)=C(Cl)C1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 63.7 %

Procedure:
Sodium ethoxide (3.56 g, 50 mmol) was added to a solution containing 2,3-dichloromaleic hydride (5.56 g, 33.3 mmol) and methylamine hydrochloride (3.50 g, 55.0 mmol) in 40 mL of acetic acid. The mixture was stirred under a CaCl2 drying tube at 25° C. for 16 hours and then refluxed for 4 hours. The cooled mixture was poured into water (350 mL) and extracted with EtOAc (3×75 mL). The combined organic extracts were washed with 100 mL portions of saturated aqueous NaHCO3, water and brine and dried (MgSO4). The solvent was evaporated under reduced pressure. The residue was recrystallized from ethanol to give 3.82 g (64%) of 2,3-dichloro N-methylmaleimide as white crystals. Concentration of the mother liquor and chromatography of the residue by radial preparative layer chromatography (Chromatotron, Harrison Research), gave an additional 0.81 g of 2,3-dichloro N-methylmaleimide, raising the yield to 77%.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]([N:5]([C@@H:13]1[CH2:15][C@H:14]1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:6][CH:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1)=[O:4].O=[CH:25][CH2:26][CH2:27][C:28]1[CH:29]=[C:30]([CH:35]=[CH:36][CH:37]=1)[C:31]([O:33][CH3:34])=[O:32].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[F:23][C:2]([F:1])([F:22])[C:3]([N:5]([CH2:6][CH:7]1[CH2:8][CH2:9][N:10]([CH2:25][CH2:26][CH2:27][C:28]2[CH:29]=[C:30]([CH:35]=[CH:36][CH:37]=2)[C:31]([O:33][CH3:34])=[O:32])[CH2:11][CH2:12]1)[C@@H:13]1[CH2:15][C@H:14]1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:4]
Reactant: COC(=O)c1cccc(CCC=O)c1
Reactant: O=C(N(CC1CCNCC1)[C@@H]1C[C@H]1c1ccccc1)C(F)(F)F
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: COC(=O)c1cccc(CCCN2CCC(CN(C(=O)C(F)(F)F)[C@@H]3C[C@H]3c3ccccc3)CC2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 63.7 %

Procedure:
To a solution of 2,2,2-trifluoro-N-(trans-2-phenylcyclopropyl)-N-(piperidin-4-ylmethyl)acetamide (100 mg, 0.306 mmol) in 1,2-dichloroethane (DCE) (2 mL) were added methyl 3-(3-oxopropyl)benzoate (70.7 mg, 0.368 mmol) and sodium triacetoxyborohydride (104 mg, 0.490 mmol), and the mixture was stirred at room temperature for 18 h. The reaction was then quenched with water (5 mL) and extracted with DCM (3×). The extract was dried (Na2SO4) and concentrated. The residue was purified using column chromatography (silica gel, 0 to 100% EtOAc/hexanes then 0 to 15% MeOH/EtOAc) to give 98 mg of product as pale yellow solid. MS: (M+H)+=503.1. 1H NMR (400 MHz, METHANOL-d4) δ ppm 1.32-1.53 (m, 3H), 1.57-1.69 (m, 1H), 1.75-1.90 (m, 2H), 1.91-2.08 (m, 4H), 2.26-2.56 (m, 3H), 2.65-2.88 (m, 4H), 3.13-3.29 (m, 2H), 3.45-3.65 (m, 2H), 3.89-3.95 (m, 3H), 7.05-7.36 (m, 5H), 7.39-7.57 (m, 2H), 7.83-8.00 (m, 2H).