Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2](=[N:25][OH:26])[CH2:3][N:4]([C:9]1[C:18]([Cl:19])=[C:17]([Cl:20])[CH:16]=[C:15]2[C:10]=1[N:11]=[C:12]([O:23][CH3:24])[C:13]([O:21][CH3:22])=[N:14]2)[S:5]([CH3:8])(=[O:7])=[O:6].Cl[C:28]([O:30][CH2:31][CH3:32])=[O:29]>N1C=CC=CC=1>[NH2:1][C:2](=[N:25][O:26][C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:3][N:4]([C:9]1[C:18]([Cl:19])=[C:17]([Cl:20])[CH:16]=[C:15]2[C:10]=1[N:11]=[C:12]([O:23][CH3:24])[C:13]([O:21][CH3:22])=[N:14]2)[S:5]([CH3:8])(=[O:6])=[O:7]
Reactant: COc1nc2cc(Cl)c(Cl)c(N(CC(N)=NO)S(C)(=O)=O)c2nc1OC
Reactant: CCOC(=O)Cl
Solvent: c1ccncc1
Product: CCOC(=O)ON=C(N)CN(c1c(Cl)c(Cl)cc2nc(OC)c(OC)nc12)S(C)(=O)=O
Temperature: 0 °C
Reaction time: 16 h
Yield: 76 %

Procedure:
The product of step (a) (852 g, 2.008 mmol) was dissolved in dry pyridine (12 ml) and cooled to 0° C. Ethyl chloroformate (479 mg, 4.418 mmol) was added over 5 minutes. The mixture was stirred at room temperature for 16 hours and poured into ice-cold water (40 ml). The resulting precipitate was collected by filtration and dried under reduced pressure at 60° C. to give N-(2-amino-2-ethoxycarbonyloxyiminoethyl)-N-(6,7-dichloro-2,3-dimethoxyquinoxalin-5-yl)methanesulphonamide (757 mg, 76%).
Reaction SMILES: C(N(CC)CC)C.[CH3:8][C@:9]12[C:15]([CH3:17])([CH3:16])[C@H:12]([CH2:13][CH2:14]1)[CH:11]([C:18](Cl)=[O:19])[C:10]2=[O:21].[C:22]([O:26][C:27]([NH:29][NH:30][C:31]1[CH:36]=[CH:35][C:34]([F:37])=[CH:33][C:32]=1[Cl:38])=[O:28])([CH3:25])([CH3:24])[CH3:23].O>ClCCl>[C:22]([O:26][C:27]([NH:29][N:30]([C:31]1[CH:36]=[CH:35][C:34]([F:37])=[CH:33][C:32]=1[Cl:38])[C:18]([CH:11]1[C:10](=[O:21])[C@@:9]2([CH3:8])[C:15]([CH3:17])([CH3:16])[C@@H:12]1[CH2:13][CH2:14]2)=[O:19])=[O:28])([CH3:25])([CH3:23])[CH3:24]
Reactant: CC1(C)[C@@H]2CC[C@@]1(C)C(=O)C2C(=O)Cl
Reactant: CC(C)(C)OC(=O)NNc1ccc(F)cc1Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NN(C(=O)C1C(=O)[C@]2(C)CC[C@H]1C2(C)C)c1ccc(F)cc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.3 %

Procedure:
Triethylamine (21.3 mL, 153 mmol) was added in two portions to a cooled (0° C.) solution of (1R,4R)-4,7,7-trimethyl-3-oxo-bicyclo[2.2.1]heptane-2-carbonyl chloride (Intermediate 20; 10.9 g, 51 mmol) in dichloromethane (100 mL), giving a thick suspension. Dichloromethane (30 mL) was added, followed by N′-(2-chloro-4-fluoro-phenyl)-hydrazinecarboxylic acid tert-butyl ester (Intermediate 33; 9.8 g, 37.6 mmol). The reaction mixture was placed in an oil-bath at 50° C., heated at this temperature for 6 hours and then allowed to cool to room temperature and stir for 1 h. The reaction mixture was poured into water (200 mL) and two layers were separated. The organic layer was washed with water (2×200 mL) and brine (100 mL), dried (magnesium sulfate), filtered, evaporated, and then dried under high vacuum for 90 min to give N′-(2-chloro-4-fluoro-phenyl)-N′-((1R,4R)-4,7,7-trimethyl-3-oxo-bicyclo[2.2.1]heptane-2-carbonyl)-hydrazinecarboxylic acid tert-butyl ester (14.9 g, 90%) as a pale foam.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][CH:10]([NH:17][C:18]1[N:23]=[C:22]([C:24]2[N:28]3[CH:29]=[CH:30][N:31]=[C:32]([N:33]4[CH2:38][CH2:37][N:36]([CH3:39])[CH2:35][CH2:34]4)[C:27]3=[N:26][CH:25]=2)[CH:21]=[CH:20][N:19]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(C)(C)C.Cl>C(O)C>[CH3:39][N:36]1[CH2:35][CH2:34][N:33]([C:32]2[C:27]3[N:28]([C:24]([C:22]4[CH:21]=[CH:20][N:19]=[C:18]([NH:17][CH:10]([C:11]5[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=5)[CH2:9][CH2:8][NH2:7])[N:23]=4)=[CH:25][N:26]=3)[CH:29]=[CH:30][N:31]=2)[CH2:38][CH2:37]1
Reactant: CN1CCN(c2nccn3c(-c4ccnc(NC(CCNC(=O)OC(C)(C)C)c5ccccc5)n4)cnc23)CC1
Agent: Cl
Solvent: CCO
Product: CN1CCN(c2nccn3c(-c4ccnc(NC(CCN)c5ccccc5)n4)cnc23)CC1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of crude (3-{4-[8-(4-methyl-piperazin-1-yl)-imidazo[1,2-a]pyrazin-3-yl]-pyrimidin-2-ylamino}-3-phenyl-propyl)-carbamic acid tert-butyl ester (51 mg, 0.094 mmol) in ethanol (3 mL) was added concentrated hydrochloric acid (3 mL) slowly. The reaction mixture was stirred at room temperature for 15 hours. The solvent was removed under reduced pressure and then the solid was purified by prep-HPLC. Several drops of concentrated HCl were added to the fractions with product. After sonicating for several minutes, solution was concentrated under reduced pressure to afford N1-{4-[8-(4-methyl-piperazin-1-yl)-imidazo[1,2-a]pyrazin-3-yl]-pyrimidin-2-yl}-1-phenyl-propane-1,3-diamine; hydrochloride. (Yield 59 mg, 100%).
Reaction SMILES: C([O:3][C:4]([C@@H:6]1[CH2:10][CH2:9][CH2:8][C@@H:7]1[N:11]([C:17](=[O:36])[CH2:18][C:19]1[NH:24][C:23]2[CH:25]=[CH:26][C:27]([NH:29][S:30]([CH3:33])(=[O:32])=[O:31])=[CH:28][C:22]=2[S:21](=[O:35])(=[O:34])[N:20]=1)[CH2:12][CH2:13][CH:14]([CH3:16])[CH3:15])=O)C.[O-]CC.[Na+].Cl>C(O)C>[OH:3][C:4]1[C@H:6]2[C@H:7]([CH2:8][CH2:9][CH2:10]2)[N:11]([CH2:12][CH2:13][CH:14]([CH3:15])[CH3:16])[C:17](=[O:36])[C:18]=1[C:19]1[NH:24][C:23]2[CH:25]=[CH:26][C:27]([NH:29][S:30]([CH3:33])(=[O:32])=[O:31])=[CH:28][C:22]=2[S:21](=[O:35])(=[O:34])[N:20]=1
Reactant: CCOC(=O)[C@@H]1CCC[C@@H]1N(CCC(C)C)C(=O)CC1=NS(=O)(=O)c2cc(NS(C)(=O)=O)ccc2N1
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CC(C)CCN1C(=O)C(C2=NS(=O)(=O)c3cc(NS(C)(=O)=O)ccc3N2)=C(O)[C@@H]2CCC[C@@H]21
Temperature: 60 °C
Reaction time: 2 h
Yield: 36.3 %

Procedure:
(1R,2S)-2-[[2-(7-Methanesulfonylamino-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-acetyl]-(3-methyl-butyl)-amino]-cyclopentanecarboxylic acid ethyl ester (0.3 mmol) was dissolved in ethanol (3 mL), a 21% w/w solution of sodium ethoxide in ethanol (0.56 mL, 1.5 mmol) was added into the above solution. The mixture was stirred at 60° C. for 2 h and allowed to cool to 25° C. The mixture was poured into 0.5 M aqueous hydrochloric acid solution (50 mL). The aqueous layer was extracted with ethyl acetate (2×50 mL). The organic layer was dried over sodium sulfate and concentrated in vacuo to afford the crude product, which was purified by flash column chromatography (Teledyne Isco RediSep Column; 100% ethyl acetate in hexanes) to afford the desired product, (4aR,7aS)-N-{3-[4-hydroxy-1-(3-methyl-butyl)-2-oxo-2,4a,5,6,7,7a-hexahydro-1H-[1]pyrindin-3-yl]-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-7-yl}-methanesulfonamide (0.054 g, 0.109 mmol, 36.3% over two steps), as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ: 0.93 (6H, d, J=6.1 Hz), 1.35-1.65 (7H, m), 2.06-2.18 (2H, m), 3.06 (3H, s), 3.17-3.34 (3H, m), 3.65-3.73 (1H, m), 3.92 (1H, bs), 7.49-7.56 (3H, m), 10.16 (1H, bs). LC-MS (ESI) calcd for C21H28N4O6S2 496.15, found 497.4 [M+H+].
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:16][CH2:15][C:14]2[NH:13][C:12]3[N:17]=[CH:18][C:19](Cl)=[CH:20][C:11]=3[C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:22][O:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([NH2:30])[CH:25]=1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.[OH-].[K+]>C(O)(CC)(C)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:1]([O:5][C:6]([N:8]1[CH2:16][CH2:15][C:14]2[NH:13][C:12]3[N:17]=[CH:18][C:19]([NH:30][C:26]4[CH:27]=[CH:28][CH:29]=[C:24]([O:23][CH3:22])[CH:25]=4)=[CH:20][C:11]=3[C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1cccc(N)c1
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]c3ncc(Cl)cc3c2C1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: CCC(C)(C)O
Product: COc1cccc(Nc2cnc3[nH]c4c(c3c2)CN(C(=O)OC(C)(C)C)CC4)c1
Temperature: 95 °C
Reaction time: 8 h
Yield: 4.8 %

Procedure:
3-Chloro-5,7,8,9-tetrahydro-dipyrido[2,3-b;3′,4′-d]pyrrole-6-carboxylic acid tert-butyl ester (100 mg, 0.32 mmol), m-anisidine (0.04 mL, 0.39 mmol), Pd(OAc)2 (3 mg, 0.01 mmol), X-Phos (12 mg, 0.03 mmol), and KOH (0.03 ml, 0.97 mmol) were suspended in tert-amyl alcohol (2 mL), and stirred overnight at 95° C. The crude mixture was added directly to a Biotage column. The crude product was purified via Biotage eluting with a gradient of 0 to 100% EtOAc in hexanes to provide 46 (6 mg, 5% yield) as a brown oil. LC-MS (M+H=395, obsd.=395).
Reaction SMILES: [NH2:1]/[C:2](/[C:9]([F:12])([F:11])[F:10])=[CH:3]\[C:4]([O:6]CC)=O.[H-].[Na+].[Cl:15][C:16]1[CH:21]=[C:20]([Cl:22])[CH:19]=[C:18]([Cl:23])[C:17]=1[N:24]=[C:25]=[S:26]>CN(C)C=O>[Cl:15][C:16]1[CH:21]=[C:20]([Cl:22])[CH:19]=[C:18]([Cl:23])[C:17]=1[N:24]1[C:4](=[O:6])[CH:3]=[C:2]([C:9]([F:10])([F:11])[F:12])[NH:1][C:25]1=[S:26]
Reactant: S=C=Nc1c(Cl)cc(Cl)cc1Cl
Reactant: CCOC(=O)/C=C(\N)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=c1cc(C(F)(F)F)[nH]c(=S)n1-c1c(Cl)cc(Cl)cc1Cl
Temperature: 5 °C
Yield: 5.7 %

Procedure:
A 5 ml dimethylformamide solution of 3.7 g ethyl 3-amino-4,4,4-trifluorocrotonate was added dropwise to a 30 ml dimethylformamide solution of 1.0 g of sodium hydride (purity: 55%) with stirring at 5° C. The mixed solution was stirred at room temperature for 15 minutes, then cooled to 5° C. and added dropwise with a 10 ml dimethylformamide solution of 5.0 g of 2,4,6-trichlorophenyl isothiocyanate. The resulting solution was heated to room temperature and further stirred at 130° C. for 2 hours. Then the solvent was distilled away under reduced pressure and the residue was dissolved by adding 200 ml of water and washed with diethyl ether. The obtained aqueous layer was added into a mixed solution of 30 ml of concentrated hydrochloric acid and 100 g of ice and extracted with 200 ml of ethyl acetate. The obtained organic layer was washed with a sodium chloride aqueous solution and dried over anhydrous sodium sulfate. Then the solvent was distilled away under reduced pressure to obtain 2.8 g of a crude product. This product was purified by preparative thin-layer chromatography (developing solvent: a mixed solvent of chloroform and ethyl acetate) to obtain 0.43 g of the objective compound.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH3:17])[N:10]=2)[N:3]=1.[H][H].C(=O)(O)[O-].[Na+]>C(O)C.[C].[Pd]>[CH3:8][C:6]1[CH:7]=[CH:2][N:3]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH3:17])[N:10]=2)[N:5]=1
Reactant: CCCc1cccc(-c2nc(C)cc(Cl)n2)n1
Reactant: [H][H]
Agent: [Pd]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CCCc1cccc(-c2nccc(C)n2)n1
Yield: 88.9 %

Procedure:
To a solution of 4-chloro-6-methyl-2-(6-n-propyl-2-pyridinyl)pyrimidine (2 g) in ethyl alcohol (50 ml), was added 5 % palladium carbon (0.2 g). The mixture was brought into contact with hydrogen gas for two hours. After palladium carbon was filtered off, the reaction solution was concentrated under reduced pressure to give a residue. To the residue, was added saturated aqueous sodium bicarbonate solution (30 ml). The mixture was extracted with chloroform (100 ml) and dried over anhydrous magnesium sulfate. The extract was concentrated under reduced pressure to obtain 4-methyl-2-(6-n-propyl-2-pyridinyl)pyrimidine (1.53 g, yield: 89 %).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[CH:12][C:11]([O:14][CH2:15][CH3:16])=[CH:10][N:9]=2)=[CH:4][CH:3]=1.[C:17]([O:20][CH:21]([CH:23]=[CH2:24])[CH3:22])(=[O:19])[CH3:18].C(N)(C)(C)C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CN1CCCC1=O>[C:17]([O:20][CH:21]([CH3:22])[CH:23]=[CH:24][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[CH:12][C:11]([O:14][CH2:15][CH3:16])=[CH:10][N:9]=2)=[CH:4][CH:3]=1)(=[O:19])[CH3:18]
Reactant: CCOc1cnc(-c2ccc(Br)cc2)nc1
Reactant: C=CC(C)OC(C)=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC(C)(C)N
Solvent: CN1CCCC1=O
Product: CCOc1cnc(-c2ccc(C=CC(C)OC(C)=O)cc2)nc1
Yield: 67 %

Procedure:
12 g of 2-(4-bromophenyl)-5-(ethoxy)pyrimidine, 12 g of 2-acetoxy-3-butene, 10 g of N-tert.butylamine, 20 ml of N-methylpyrrolidone, 0.12 g of palladium(II) acetate and 0.3 g of triphenylphosphine were reacted in analogous manner to Example 1(d) to give 9 g of 2-[4-(3-acetoxy-1-butenyl)phenyl]-5-ethoxypyrimidine.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([C:9]2[CH2:10][N:11]([CH2:15][CH3:16])[CH2:12][CH2:13][CH:14]=2)[CH:6]=[CH:7][CH:8]=1.Cl.[NH+]1C=CC=CC=1.[OH-].[NH4+]>O>[CH2:15]([N:11]1[CH2:12][CH2:13][CH:14]=[C:9]([C:5]2[CH:4]=[C:3]([OH:2])[CH:8]=[CH:7][CH:6]=2)[CH2:10]1)[CH3:16]
Reactant: CCN1CCC=C(c2cccc(OC)c2)C1
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Product: CCN1CCC=C(c2cccc(O)c2)C1
Temperature: 200 °C
Yield: 81.2 %

Procedure:
A mixture of 5.2 g of the product of Step A and 10.4 g of pyridinium hydrochloride was heated at 200° C. for 21/2 hours and the mixture was cooled and diluted with water. Ammonium hydroxide was added to the mixture which was then extracted with methylene chloride. The organic phase was washed with water, dried and evaporated to dryness under reduced pressure. The residue was chromatographed over silica gel and was eluted with a 6-3-1 cyclohexane-chloroform-triethylamine mixture to obtain 3.95 g of 3-(1-ethyl-1,2,5,6-tetrahydropyridin-3-yl)-phenol. 3.85 g of the latter were dissolved in 40 ml of isopropanol and 2.4 g of oxalic acid were added thereto. The mixture was cooled and filtered and the product was washed with isopropanol and dried to obtain 3.57 g of 3-(1-ethyl-1,2,5,6-tetrahydropyridin-3-yl)-phenol oxalate melting at 240° C.
Reaction SMILES: C[O:2][C:3](=O)[CH:4]([NH:8][C:9](=[O:24])[C:10]1[CH:15]=[CH:14][C:13]([C:16]#[C:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:12][CH:11]=1)[CH:5]([OH:7])[CH3:6].Cl.[NH2:27][OH:28].C[O-].[Na+].Cl>CO.C(Cl)Cl.CCOC(C)=O>[OH:7][CH:5]([CH3:6])[CH:4]([NH:8][C:9](=[O:24])[C:10]1[CH:15]=[CH:14][C:13]([C:16]#[C:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:12][CH:11]=1)[C:3](=[O:2])[NH:27][OH:28]
Reactant: COC(=O)C(NC(=O)c1ccc(C#Cc2ccccc2)cc1)C(C)O
Reactant: NO
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: ClCCl
Product: CC(O)C(NC(=O)c1ccc(C#Cc2ccccc2)cc1)C(=O)NO
Reaction time: 2 h
Yield: 54.9 %

Procedure:
A solution of tolanoic-Thr methyl ester (4) (2.34 g, 7.0 mmol) in MeOH (20 ml) and DCM (30 ml) was added to a cooled (−10° C. bath) suspension of hydroxylamine HCl salt (4.81 g, 70.0 mmol) and NaOMe (4.16 g, 77.0 mmol) in MeOH (30 ml). Follow reaction by LCMS. After stirring for 2 hours, the reaction seems to stall at 50% completion. Add an additional 1 equivalent of NaOMe (0.416 g). After 3 hours, the reaction was 75% complete. Add an additional 0.5 equivalent of NaOMe (0.21 g). After 4 hours, the reaction was 90% complete. Add an additional 0.15 equivalent of NaOMe (0.064 g) for a total of 12.65 equivalents of NaOMe. The pH of the reaction was between 11-12 and had reacted about 95% completion. The reaction was diluted with EtOAc (500 ml) and washed with sat aq. NaHCO3 (2×60 ml), 50% diluted brine (60 ml), sat brine (60 ml), dried with Na2SO4, filtered and concentrated under reduced pressure. The residue was dissolved in minimal DMA. The product was purified by prep. HPLC using a reverse phase Ultro 120 C18 column running a 2% gradient (AcCN/water, 0.1% TFA). The purified fractions were lyophilized to dryness. The product as the TFA salt was dissolved in AcCN/water (50:50) (80 ml), 1N aq. HCl (13 equivalent) and lyophilized again to give 1.3 g of white powder in 55% yield and >97% purity.
Reaction SMILES: [F:1][C:2]([F:42])([F:41])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:18][C:17](=[O:19])[N:16]([CH2:20][C:21]3[C:26]([C:27]4[CH:32]=[C:31]([CH:33]([CH3:35])[CH3:34])[C:30]([F:36])=[CH:29][C:28]=4[O:37][CH3:38])=[CH:25][CH:24]=[C:23](Cl)[N:22]=3)[C@@H:15]([CH3:40])[CH2:14]2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[C:43](B(O)O)([CH3:45])=[CH2:44]>C(=O)([O-])[O-].[K+].[K+].C1COCC1>[F:1][C:2]([F:42])([F:41])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:18][C:17](=[O:19])[N:16]([CH2:20][C:21]3[C:26]([C:27]4[CH:32]=[C:31]([CH:33]([CH3:35])[CH3:34])[C:30]([F:36])=[CH:29][C:28]=4[O:37][CH3:38])=[CH:25][CH:24]=[C:23]([C:43]([CH3:45])=[CH2:44])[N:22]=3)[C@@H:15]([CH3:40])[CH2:14]2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: COc1cc(F)c(C(C)C)cc1-c1ccc(Cl)nc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)C[C@@H]1C
Reactant: C=C(C)B(O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: C=C(C)c1ccc(-c2cc(C(C)C)c(F)cc2OC)c(CN2C(=O)O[C@H](c3cc(C(F)(F)F)cc(C(F)(F)F)c3)C[C@@H]2C)n1
Temperature: 25 °C

Procedure:
A mixture of (4S,6S)-6-[3,5-bis(trifluoromethyl)phenyl]-3-{[6-chloro-3-(4-fluoro-5-isopropyl-2-methoxyphenyl)pyridin-2-yl]methyl)}-4-methyl-1,3-oxazinan-2-one (Example 4, 16 mg, 0.026 mmol), isopropenyl boronic acid (22 mg, 0.26 mmol) and 1,1-bis(ditbutylphosphino)ferrocene palladium dichloride (2 mg, 0.0026 mmol) in aqueous potassium carbonate/THF (1 mL, 1 mL) was heated at reflux for 2.5 h under N2. After cooling to room temperature, the aqueous phase was separated and extracted with EtOAc (3×20 mL). The combined organic layers were dried (Na2SO4) and concentrated in vacuo to give the crude product. This was purified by flash chromatography on silica gel (0-15% EtOAc in hexanes gradient) to afford (4S,6S)-6-[3,5-bis(trifluoromethyl)phenyl]-3-{[3-(4-fluoro-5-isopropyl-2-methoxyphenyl)-6-isopropenylpyridin-2-yl]methyl}-4-methyl-1,3-oxazinan-2-one. LCMS=625.2 (M+1)+. 1H NMR (CDCl3, 500 MHz): δ 7.85 (br s, 3H), 7.51 (m, 2H), 7.05 (m, 1H), 6.71 (d, J=11.9 Hz, 1H), 5.98 (br s, 1H), 5.35 (br s, 1H), 5.31 (br m, 1H), 4.32 (br m, 1H), 3.79 (s, 3H), 3.22 (br m, 1H), 2.28 (s, 3H), 1.89 (m, 2H), 1.27 (br m, 9H).
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]21[CH2:14][CH2:13][C:12](=[O:15])[CH2:11][CH2:10]2.[BH4-].[Na+]>C(O)C>[CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]21[CH2:10][CH2:11][CH:12]([OH:15])[CH2:13][CH2:14]2
Reactant: O=C1CCC2(CC1)Cc1ccccc1C2
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: OC1CCC2(CC1)Cc1ccccc1C2

Procedure:
(11') A spiro(cyclohexane-1,2'-indan)-4-one [11] obtained in step (10) has its 4-keto function reduced, e.g., by mixing said compound in ethanol with sodium borohydride at moderate (room) temperature for from about 3 to about 8 hours, to produce a corresponding spiro(cyclohexane-1,2'-indan)-4-ol [14].
Reaction SMILES: [CH3:1][N:2]([CH3:19])[C:3]([C@@H:5]1[CH2:10][O:9][CH2:8][C:7](=O)[N:6]1[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=O.[H-].[H-].[H-].[H-].[Li+].[Al+3].O.[OH-].[Na+]>C1COCC1>[CH3:1][N:2]([CH3:19])[CH2:3][C@@H:5]1[CH2:10][O:9][CH2:8][CH2:7][N:6]1[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CN(C)C(=O)[C@@H]1COCC(=O)N1Cc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CN(C)C[C@@H]1COCCN1Cc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 145.1 %

Procedure:
(3S)—N,N-Dimethyl-5-oxo-4-(phenylmethyl)-3 morpholinecarboxamide (390 mg, 1.5 mmol) was dissolved in THF (20 mL) and the solution was cooled to 0° C. LiAlH4 (225 mg, 5.9 mmol) was added and the resulting mixture was refluxed overnight. Upon cooling to 0° C., water (1.4 mL) was added followed by 15% (w/w) NaOH (aq) (1.4 mL) and finally another portion of water (4.2 mL). Stirring for 30 min followed by filtration and concentration in vacuo yielded a crude mixture which was purified by RP-HPLC to provide dimethyl{[(3R)-4-(phenylmethyl)-3-morpholinyl]methyl}amine (510 mg, 41%). LCMS: (M+H)+: 235.2.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]([NH:11][CH2:12][CH3:13])=[O:10])[CH:3]=1.[F:14][C:15]1[CH:20]=[CH:19][C:18](B2OC(C)(C)C(C)(C)O2)=[CH:17][N:16]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>>[CH2:12]([NH:11][C:9]([NH:8][C:4]1[CH:3]=[C:2]([C:18]2[CH:17]=[N:16][C:15]([F:14])=[CH:20][CH:19]=2)[CH:7]=[CH:6][N:5]=1)=[O:10])[CH3:13]
Reactant: CC1(C)OB(c2ccc(F)nc2)OC1(C)C
Reactant: CCNC(=O)Nc1cc(Br)ccn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CCNC(=O)Nc1cc(-c2ccc(F)nc2)ccn1
Yield: 84.3 %

Procedure:
N-(4-bromopyridin-2-yl)-N′-ethylurea (Intermediate 33, 0.40 g, 1.64 mmol), 2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (1.057 g, 4.92 mmol), tetrakis triphenyl phosphine palladium (0.189 g, 0.16 mmol), and cesium carbonate (1.16 g, 4.92 mmol) were taken in a microwave vial and degassed with nitrogen. A dioxane:water (4:1, 10 mL) solution was added to the vial and the mixture was microwaved at 110° C. for half an hour. The palladium was filtered off, and the reaction was partitioned between water and ethyl acetate. The layers were separated, and the organic layer was washed with saturated sodium bicarbonate solution, water and brine, then dried over magnesium sulfate, and concentrated. The residue obtained was washed with acetonitrile to give the title compound as a white solid (360 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH2:12][CH2:13][CH2:14][CH3:15])[N:6]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[C:29]3[N:33]([C:34]([C:47]4[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=4)([C:41]4[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=4)[C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)[N:32]=[N:31][N:30]=3)=[CH:19][CH:18]=1)[C:5]2=[O:53].[CH:54](=O)[C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1.[BH3-]C#N.[Na+]>CCO.C1COCC1>[CH2:54]([NH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH2:12][CH2:13][CH2:14][CH3:15])[N:6]([CH2:16][C:17]1[CH:18]=[CH:19][C:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[C:29]3[N:33]([C:34]([C:35]4[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=4)([C:41]4[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=4)[C:47]4[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=4)[N:32]=[N:31][N:30]=3)=[CH:21][CH:22]=1)[C:5]2=[O:53])[C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1
Reactant: CCCCc1nc2ccc(N)cc2c(=O)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: O=Cc1ccccc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: CCCCc1nc2ccc(NCc3ccccc3)cc2c(=O)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Temperature: 60 °C
Reaction time: 8 h
Yield: 42.9 %

Procedure:
To 100 mg (0.14 mmol) of the amine from Example 40 in 2 mL of EtOH was added 16 mg (0.15 mmol) of benzaldehyde. The reaction mixture was heated to 60° C. for 1 hour, cooled to 0° C. and treated with 0.29 mL (0.29 mmol) of a 1M solution of NaCNBH3 in THF. The reaction mixture was stirred overnight, concentrated in vacuo, and the residue partitioned between 25 mL of EtOAc and 15 mL of water. The phases were separated and the organic phase was washed with brine (1×25 mL) and dried over MgSO4. The mixture was filtered and concentrated in vacuo and the residue was purified by flash chromatography over silica gel eluting with 25% EtOAc/hexanes to give 45 mg (0.06 mmol) of a yellow foam. 1H-NMR (CDCl3 300 MHz): 0.88 (t, 3H, J=7.4 Hz), 1.31 (m, 2H), 1.66 (m, 2H), 2.61 (3 line m, 2H, J=7.8 Hz), 4.32 (bs, 1H), 4.43 (bs, 2H), 5.28 (bs, 2H), 6.88 (m, 8H), 7.08 (m, 3H), 7.20-7.53 (m, 19H), 7.91 (d, 1H).
Reaction SMILES: [C:1]([OH:12])(=[O:11])[C:2]1[C:3](=[CH:7][CH:8]=[CH:9][CH:10]=1)C(N)=O.C[N:14](C)[CH:15]=[O:16].C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.[Pb+4]>O>[C:2]12[C:3](=[CH:7][CH:8]=[CH:9][CH:10]=1)[NH:14][C:15](=[O:16])[O:12][C:1]2=[O:11]
Reactant: NC(=O)c1ccccc1C(=O)O
Reactant: CN(C)C=O
Agent: CC(=O)[O-]
Agent: [Pb+4]
Solvent: O
Product: O=c1[nH]c2ccccc2c(=O)o1
Reaction time: 0.67 h

Procedure:
A 100 ml. flask was charged with 2.0 g. phthalamic acid suspended in 20 ml. dimethylformamide at room temperature. A 5.4 g. portion of lead tetra-acetate was added to the suspension, and the reaction mixture was held at room temperature for 40 minutes. The reaction mixture was poured into 30 ml. water. Isatoic anhydride was filtered from the water, recrystallized from dioxane, and dried in vacuo for 2 hours. The final yield of isatoic anhydride amounted to 1.07 g. tan solids, melting point 243°, and represented 54 percent of theory based on the phthalamic acid.