Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO.[C:3]1(O)C=CC=CC=1.[C:10]1([CH3:17])[C:15]([OH:16])=[CH:14][CH:13]=[CH:12][CH:11]=1>N#N>[CH3:17][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]([CH3:3])[C:15]=1[OH:16]
Reactant: Oc1ccccc1
Reactant: Cc1ccccc1O
Agent: N#N
Solvent: CO
Product: Cc1cccc(C)c1O
Yield: 34 %

Procedure:
29.5 g of the catalyst is charged with a 5/1 moles methanol/mole phenol mixture with LHSV of 0.68 h-1. The gaseous mixture, diluted with N2 as the carrier gas after its vaporization at 140° C., is converted to an extent of 83% at 372° C. The yield is 34% of 2,6-dimethylphenol and 47% of o-cresol. After an operating period of 40 hours, the catalyst activity and selectivity decrease sharply.
Reaction SMILES: O1CCCCC1[N:7]1[C:15]2[C:10](=[CH:11][C:12]([C:16]3[N:20]=[CH:19][N:18](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:17]=3)=[CH:13][CH:14]=2)[C:9]([C:40]2[CH:41]=[C:42]([CH:47]=[CH:48][CH:49]=2)[C:43]([O:45]C)=O)=[N:8]1.[OH-].[Li+].O[N:53]1[C:57]2[CH:58]=[CH:59][CH:60]=[CH:61][C:56]=2N=N1.C1(N)CCCCC1.Cl.C(N=C=NCCCN(C)C)C.Cl>O1CCCC1.O.O1CCOCC1>[NH:18]1[CH:19]=[N:20][C:16]([C:12]2[CH:11]=[C:10]3[C:15](=[CH:14][CH:13]=2)[NH:7][N:8]=[C:9]3[C:40]2[CH:41]=[C:42]([C:43]([NH:53][CH:57]3[CH2:58][CH2:59][CH2:60][CH2:61][CH2:56]3)=[O:45])[CH:47]=[CH:48][CH:49]=2)=[N:17]1
Reactant: On1nnc2ccccc21
Reactant: COC(=O)c1cccc(-c2nn(C3CCCCO3)c3ccc(-c4ncn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)cc23)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Solvent: C1COCCO1
Solvent: O
Product: O=C(NC1CCCCC1)c1cccc(-c2n[nH]c3ccc(-c4nc[nH]n4)cc23)c1
Yield: 6 %

Procedure:
The title compound was prepared as described in Example 381, using methyl 3-{1-perhydro-2H-pyran-2-yl-5-[1-(triphenylmethyl)(1,2,4-triazol-3-yl)]-1H-indazol-3-yl}benzoate (0.401 g, 0.62 mmol) and lithium hydroxide (0.046 g, 1.92 mmol) in tetrahydrofuran (3 mL) and water (2 mL); 1-hydroxybenzotriazole (0.252 g, 1.86 mmol), cyclohexylamine (0.213 mL, 1.86 mmol), 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (0.357 g, 1.86 mmol), and additional tetrahydrofuran (2 mL); 4 N hydrochloride solution in dioxane (10 mL). The final crude product was purified by preparative HPLC (10–90% acetonitrile to H2O, 20 min.) (0.015 g, 6% yield over 3 steps): 1H NMR (CD3OD) δ 8.79 (s, 1H), 8.43 (t, 1H), 8.40 (br s, 1H), 8.19 (dt, 1H), 8.12 (d, 1H), 7.88 (dt, 1H), 7.70 (d, 1H), 7.65 (t, 1H), 3.92 (br s, 1H), 2.01 (m, 2H), 1.83 (m, 2H), 1.71 (d, 1H), 1.43 (m, 4H), 1.25 (m, 1H); ES-MS (m/z) 387 [M+1]+.
Reaction SMILES: [CH:1]1([C@:4]2([OH:12])[CH2:8][CH2:7][NH:6][C@H:5]2[CH:9]([CH3:11])[CH3:10])[CH2:3][CH2:2]1.[F:13][C:14]1[CH:21]=[C:20](F)[CH:19]=[CH:18][C:15]=1[C:16]#[N:17].C(=O)([O-])[O-].[Li+].[Li+]>>[CH:1]1([C@:4]2([OH:12])[CH2:8][CH2:7][N:6]([C:20]3[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[C:14]([F:13])[CH:21]=3)[C@H:5]2[CH:9]([CH3:10])[CH3:11])[CH2:3][CH2:2]1
Reactant: CC(C)[C@@H]1NCC[C@@]1(O)C1CC1
Reactant: N#Cc1ccc(F)cc1F
Agent: O=C([O-])[O-]
Agent: [Li+]
Product: CC(C)[C@@H]1N(c2ccc(C#N)c(F)c2)CC[C@@]1(O)C1CC1

Procedure:
By an operation in the same manner as in Example 1 and using (2S,3R)-3-cyclopropyl-2-isopropylpyrrolidin-3-ol 0.5 oxalate (215 mg), 2,4-difluorobenzonitrile (139 mg) and lithium carbonate (163 mg), the title compound was obtained as a pale-brown solid (yield: 114 mg, yield: 40%).
Reaction SMILES: [Br:1]Br.[Br:3][C:4]1[C:5]2[C:6]3[C:10](=[CH:11][CH:12]=1)[NH:9][C:8](=[O:13])[C:7]=3[CH:14]=[CH:15][CH:16]=2>C(O)(=O)C>[Br:3][C:4]1[C:5]2[C:6]3[C:10](=[C:11]([Br:1])[CH:12]=1)[NH:9][C:8](=[O:13])[C:7]=3[CH:14]=[CH:15][CH:16]=2
Reactant: O=C1Nc2ccc(Br)c3cccc1c23
Reactant: BrBr
Solvent: CC(=O)O
Product: O=C1Nc2c(Br)cc(Br)c3cccc1c23
Yield: 66.5 %

Procedure:
A solution of bromine (3.8 g) in glacial acetic acid (15 mL) was added dropwise to a suspension of 6-bromo-benz[cd]indol-2(1H)-one[4 g, 16.1 mmol, described by H. Goldstein and P. Francey, Helv., 15, 1366 (1932)] in glacial acetic acid (30 mL) for 3-4 hr. The precipitate was collected by filtration, washed, dried (any coloration caused by the excess of bromine could be removed by washing with a diluted sodium thiosulfate solution), and crystallized from ethanol-water to give the title compound (3.5 g): mp 280°-290° C.; Anal. Calcd for C11H5Br2NO: C, 40.41% H, 1.54% N, 4.28% and Found: C, 40.52% H, 1.51% N, 4.43%; IR (mineral oil) 3140 and 1700 cm-1 ; UV max (methanol) 345 (ε4370), 329 (2910), 264 (27,680), and 212 nm (30,920); and NMR (DMSO-d6)δ 8.0 (m, 4H), and 11.3 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11]([OH:26])=[C:12]3[CH:18]=[C:17]([CH2:19][N:20]4[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)[S:16][C:13]3=[N:14][CH:15]=2)=[O:9])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].I[CH2:36][CH2:37][CH3:38].O>CN(C=O)C>[Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:26])[C:12]3[CH:18]=[C:17]([CH2:19][N:20]4[CH2:21][CH2:22][O:23][CH2:24][CH2:25]4)[S:16][C:13]=3[N:14]([CH2:36][CH2:37][CH3:38])[CH:15]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: CCCI
Reactant: O=C(NCc1ccc(Cl)cc1)c1cnc2sc(CN3CCOCC3)cc2c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(CN3CCOCC3)sc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 73 %

Procedure:
N-(4-Chlorobenzyl)-4-hydroxy-2-(4-morpholinylmethyl)thieno[2,3-b]pyridine-5-carboxamide (418 mg) from Example No. 41 and potassium carbonate (152 mg) are suspended in DMF (10 mL) and to the mixture is added 1-iodopropane (107 μL). The reaction mixture is allowed to stir at room temperature for 4 h. Additional 1-iodopropane (107 μL) is added and the mixture is heated to 60° C. for 2 h. The mixture is allowed to cool to room temperature and stand for 18 h. The resulting suspension is poured into water (25 mL), filtered, and washed with water (5 mL) followed by diethyl ether (5 mL). The resulting crude solid is purified by recrystallization from ethanol to afford 335 mg (73%) of the title compound as a white solid.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][OH:11].[CH2:12]([O:14][C:15](=[O:19])[CH2:16][CH:17]=[CH2:18])[CH3:13]>O1CCCC1>[CH2:12]([O:14][C:15](=[O:19])[CH2:16][CH2:17][CH2:18][O:11][CH2:10][CH2:9][O:8][CH2:7][CH2:6][O:5][CH2:4][CH2:3][O:2][CH3:1])[CH3:13]
Reactant: COCCOCCOCCO
Reactant: C=CCC(=O)OCC
Solvent: C1CCOC1
Product: CCOC(=O)CCCOCCOCCOCCOC
Reaction time: 4 h
Yield: 29.6 %

Procedure:
Triethylene glycol monomethyl ether (4.27 g, 0.026 mol) and But-3-enoic acid ethyl ester (1.5 g, 0.013 mol) were dissolved in tetrahydrofuran (10 mL). Then lump Na0 (0.030 g, 0.013 mol) was added and the reaction was stirred for 4 h. Crude reaction was quenched with 1M HCl (20 mL), washed ethyl acetate (3×20 mL). Organic layers were combined and washed with H2O (2×10 mL), dried MgSO4, and evaporated to dryness to afford 2 a yellowish oil (1.07 g, 30% yield).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:36]=[CH:35][C:12]2[C:13]3[N:17]([CH2:18][CH2:19][O:20][C:11]=2[CH:10]=1)[C:16]1[CH:21]=[C:22]([C:25]([O:27]C)=[O:26])[CH:23]=[CH:24][C:15]=1[C:14]=3[CH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].Cl.O>CO.O1CCCC1>[CH2:1]([O:8][C:9]1[CH:36]=[CH:35][C:12]2[C:13]3[N:17]([CH2:18][CH2:19][O:20][C:11]=2[CH:10]=1)[C:16]1[CH:21]=[C:22]([C:25]([OH:27])=[O:26])[CH:23]=[CH:24][C:15]=1[C:14]=3[CH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CCOc1cc(OCc2ccccc2)ccc1-3
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: O=C(O)c1ccc2c(C3CCCCC3)c3n(c2c1)CCOc1cc(OCc2ccccc2)ccc1-3
Reaction time: 13 h
Yield: 48.1 %

Procedure:
To a solution of methyl 3-benzyloxy-12-cyclohexyl-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carboxylate (173 mg, 0.36 mmol) in methanol (3.5 ml) and tetrahydrofuran (3.5 ml) was added 4N aqueous sodium hydroxide solution (1.7 ml), and the mixture was stirred for 13 hr. To the reaction mixture were added 2N hydrochloric acid (3.7 ml) and water, and the precipitated solid was collected by filtration and dried in vacuo. The obtained solid was purified by silica gel chromatography (hexane:ethyl acetate=1:1) to give 3-benzyloxy-12-cyclohexyl-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carboxylic acid (81 mg, yield 48%).
Reaction SMILES: [C:1]([Si:5]([CH3:14])([CH3:13])[O:6][C@H:7]1[CH2:11][C@@H:10]([OH:12])[CH:9]=[CH:8]1)([CH3:4])([CH3:3])[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].C1(C)C=CC=CC=1>[C:1]([Si:5]([CH3:14])([CH3:13])[O:6][C@@H:7]1[CH2:8][CH2:9][C@H:10]([OH:12])[CH2:11]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1C=C[C@H](O)C1
Agent: [Rh]
Agent: [Cl-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CC(C)(C)[Si](C)(C)O[C@@H]1CC[C@H](O)C1

Procedure:
A solution of (−)-(1R,4S)-4-(tert-butyl-dimethyl-silanyloxy)-cyclopent-2-enol (1.2 g, 5.6 mmol) (from Example 27a supra) and Wilkinson's catalyst (520 mg, 0.56 mmol) (Aldrich) in toluene (50 mL) was subjected to hydrogenation at atmospheric pressure for 16 hours. The reaction mixture was filtered and partitioned between ethyl acetate and water. The organic layer was collected, dried over sodium sulfate, filtered and concentrated. The resulting residue was purified by chromatography on a silica gel column using a 0–30% diethyl ether in hexanes gradient to give (−)-(1S,3R)-3-(tert-butyl-dimethyl-silanyloxy)-cyclopentanol as a colorless oil. (Yield 790 mg, 65%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[CH:14]=[C:13]([N:15]2[C:19]3[CH:20]=[CH:21][C:22]([C:24]4[CH:25]=[N:26][N:27]([CH2:29][CH2:30][N:31]5[CH2:36][CH2:35][O:34][CH2:33][CH2:32]5)[CH:28]=4)=[CH:23][C:18]=3[N:17]=[CH:16]2)[CH:12]=[C:11]([NH:37]C(=O)C)[CH:10]=1.[OH-].[Na+]>C(O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[CH:14]=[C:13]([N:15]2[C:19]3[CH:20]=[CH:21][C:22]([C:24]4[CH:25]=[N:26][N:27]([CH2:29][CH2:30][N:31]5[CH2:32][CH2:33][O:34][CH2:35][CH2:36]5)[CH:28]=4)=[CH:23][C:18]=3[N:17]=[CH:16]2)[CH:12]=[C:11]([NH2:37])[CH:10]=1
Reactant: CC(=O)Nc1cc(-c2cc(F)ccc2F)cc(-n2cnc3cc(-c4cnn(CCN5CCOCC5)c4)ccc32)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Nc1cc(-c2cc(F)ccc2F)cc(-n2cnc3cc(-c4cnn(CCN5CCOCC5)c4)ccc32)c1
Temperature: 100 °C
Yield: 90 %

Procedure:
To a solution of the compound of Example 139 (2.2 g, 4.0 mmol) in ethanol (100 ml) was added aqueous solution of NaOH (2.0 g, 50 mmol, 12.5 eq.) and the mixture was heated at 100° C. for 4 h. The mixture was quenched and extracted as in Example 1(d). The solvent was distilled off to afford the product in 90% yield (1.8 g).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[C:7]([C:13]3[CH:21]=[C:20]4[C:16]([CH:17]=[N:18][NH:19]4)=[CH:15][C:14]=3[CH3:22])[CH:8]=[C:9](F)[CH:10]=2)[N:5]=[N:4][C:3]=1[C:23]([NH2:25])=[O:24].CCN(C(C)C)C(C)C.[NH:35]1[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1>CC(N(C)C)=O>[NH2:1][C:2]1[C:11]2[C:6](=[C:7]([C:13]3[CH:21]=[C:20]4[C:16]([CH:17]=[N:18][NH:19]4)=[CH:15][C:14]=3[CH3:22])[CH:8]=[C:9]([N:35]3[CH2:40][CH2:39][O:38][CH2:37][CH2:36]3)[CH:10]=2)[N:5]=[N:4][C:3]=1[C:23]([NH2:25])=[O:24]
Reactant: Cc1cc2cn[nH]c2cc1-c1cc(F)cc2c(N)c(C(N)=O)nnc12
Reactant: C1COCCN1
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc2cn[nH]c2cc1-c1cc(N2CCOCC2)cc2c(N)c(C(N)=O)nnc12
Temperature: 140 °C
Yield: 25.2 %

Procedure:
A mixture of 4-amino-6-fluoro-8-(5-methyl-1H-indazol-6-yl)cinnoline-3-carboxamide (200 mg, 0.59 mmol), DIPEA (1000 mg), morpholine (500 mg,) and DMA (4 mL) was heated at 140° C. in a microwave under N2 for 3 hours. The mixture was cooled, concentrated, and purified via preparative HPLC to give the title compound (60 mg, 25%). 1H NMR (400 MHz, DMSO-d6) δ ppm 12.95 (1H, s), 8.93 (1H, br s), 8.30 (1H, d, J=2.4 Hz), 8.03 (1H, s), 7.81 (1H, br s), 7.60 (1H, s), 7.54-7.51 (3H, m), 7.35 (1H, s), 3.79 (4H, t, J=4.8 Hz), 3.42 (4H, t, J=4.8 Hz), 2.00 (3H, s); LC-MS (5-95% ACN in H2O gradient with 0.02% NH4OAc, tR 3.053 minutes); ESI+APCI m/z [M+H]+ 404.
Reaction SMILES: [P:1]([OH:5])([O-:4])([O-:3])=[O:2].[NH4+:6].[NH4+].N.[P:9](=[O:13])([OH:12])([OH:11])[OH:10]>>[P:1]([OH:5])([OH:4])([O-:3])=[O:2].[NH4+:6].[P:9]([OH:13])([O-:12])([O-:11])=[O:10].[NH4+:6].[NH4+:6]
Reactant: O=P(O)(O)O
Agent: N
Agent: O=P([O-])([O-])O
Agent: [NH4+]
Product: O=P([O-])(O)O

Procedure:
The process for the manufacture of granular diammonium phosphate according to the present invention is defined by the appended claims with specific embodiments shown in the attached drawing. For purposes of summarizing the invention, the invention relates to a process for the manufacture of solid diammonium phosphate having granular particle size in a range of 2 mm to 4 mm where about 75 to 85 percent of the granules produced are in a range of the desired granule size of 2 mm to 4 mm. The solid granular diammonium phosphate is prepared by reacting anhydrous ammonia with phosphoric acid in a reactor to form a partially reacted aqueous slurry of monoammonium phosphate and diammonium phosphate. The partially reacted slurry is pumped to a granulator-reactor and further reacted with anhydrous ammonia to form a moisture containing solid granular diammonium phosphate mixture having a range of particle sizes consisting of oversize, undersize and product. The moisture containing solid granular diammonium phosphate mixture is introduced to a dryer dried. Upon discharging the drier a portion of the dried solid granular diammonium phosphate mixture is diverted back to the granulator-reactor. The portion not diverted is separated or classified by a separating means to separate the oversize and undersize from the desired product size diammonium phosphate. Separation is attained by setting to a narrow size separation (difference between oversize and product screen) an oversized screen to separate oversized granular particles and a product screen to separate undersized granular particles from the product granular particles. The oversize product granular particles are milled and recycled along with the undersized granular particles obtained during the classifying process to the granulator-reactor. The desired granular product is collected wherein about 90% of the granules collected by the classifying means are in a range of the desired granule size of 2 mm to 4 mm and about 10% of the granules collected by the classifying means are off size (roughly about 2% oversize and 8% undersize) where 40% of the dryer discharge is diverted to the granulator-reactor and the screens are set at +5 oversize and +7 product.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@H:12]([CH3:13])[C:11]3[CH:14]=[C:15](/[CH:20]=[CH:21]/[CH3:22])[CH:16]=[C:17]([O:18][CH3:19])[C:10]=3[O:9]2)=[CH:4][C:3]=1[O:23][CH3:24].Cl.[CH3:26][N:27]([CH2:29][CH2:30]Cl)[CH3:28].[OH-].[K+]>C1(C)C=CC=CC=1>[CH3:19][O:18][C:17]1[C:10]2[O:9][C@@H:8]([C:5]3[CH:6]=[CH:7][C:2]([O:1][CH2:30][CH2:29][N:27]([CH3:28])[CH3:26])=[C:3]([O:23][CH3:24])[CH:4]=3)[C@H:12]([CH3:13])[C:11]=2[CH:14]=[C:15](/[CH:20]=[CH:21]/[CH3:22])[CH:16]=1
Reactant: CN(C)CCCl
Reactant: C/C=C/c1cc(OC)c2c(c1)[C@@H](C)[C@H](c1ccc(O)c(OC)c1)O2
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: C/C=C/c1cc(OC)c2c(c1)[C@@H](C)[C@H](c1ccc(OCCN(C)C)c(OC)c1)O2
Reaction time: 6 h
Yield: 61.3 %

Procedure:
15 g of trans-2,3-dihydro-2-(4-hydroxy-3-methoxyphenyl)-7-methoxy-3-methyl-5-(E)-propenylbenzofurane("Dehydrodiisoeugenol") are dissolved in 150 ml abs. toluene at 80° . 9.5 g of N,N-dimethyl-2-chloroethylamine-hydrochloride and 15.5 g KOH in solid form are added. After 6 h at 80°, the solution is cooled down and decanted from solid KOH, whereafter the toluene solution is washed with water to remove dissolved KOH. After drying over sodium sulfate, the solution is evaporated in vacuo. The residue is cristallized in vacuo, and the still present non-cristalline part is dissolved in petroleum ether. One obtains 11.2 g of N-2-[4-(trans-2,3-dihydro-7-methoxy-3-methyl-5-(E)-propenylbenzofurane-2-yl)-2-methoxyphenoxy]ethyl-N,N,-dimethylamine, as slightly yellow cristals of mp 58°-60° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C@H:9]1[O:14][C:13](=[O:15])[NH:12][CH2:11][CH2:10]1.C(OC(=O)CCC(C1C=CC=CC=1OC)=O)C.CC1C=C([C@H]2OC(=O)NCC2)C=C(C)C=1.[H-].[Na+].Br[CH2:51][C:52]1[CH:57]=[C:56]([C:58]([F:61])([F:60])[F:59])[CH:55]=[CH:54][C:53]=1[C:62]1[CH:67]=[C:66]([CH:68]([CH3:70])[CH3:69])[CH:65]=[CH:64][C:63]=1[Cl:71]>>[Cl:71][C:63]1[CH:64]=[CH:65][C:66]([CH:68]([CH3:69])[CH3:70])=[CH:67][C:62]=1[C:53]1[CH:54]=[CH:55][C:56]([C:58]([F:59])([F:60])[F:61])=[CH:57][C:52]=1[CH2:51][N:12]1[CH2:11][CH2:10][C@@H:9]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[O:2][CH3:1])[O:14][C:13]1=[O:15]
Reactant: COc1ccccc1[C@@H]1CCNC(=O)O1
Reactant: CC(C)c1ccc(Cl)c(-c2ccc(C(F)(F)F)cc2CBr)c1
Agent: CCOC(=O)CCC(=O)c1ccccc1OC
Agent: Cc1cc(C)cc([C@@H]2CCNC(=O)O2)c1
Agent: [H-]
Product: COc1ccccc1[C@@H]1CCN(Cc2cc(C(F)(F)F)ccc2-c2cc(C(C)C)ccc2Cl)C(=O)O1

Procedure:
(6S)-6-(2-methoxyphenyl) 1,3-oxazinan-2-one (prepared from ethyl-4-(2-methoxyphenyl)-4-oxobutyrate by a procedure analogous to that reported for Intermediate 21; 20 mg; 0.10 mmol) was treated with sodium hydride (60% in oil; 8.0 mg; 0.20 mmol) and 2-(bromomethyl)-2′-chloro-5′-isopropyl-4-(trifluoromethyl)-biphenyl (Intermediate 27; 39 mg; 0.10 mmol) as described in Example 11 to afford (6S)-3-{[2′-chloro-5′-isopropyl-4-(trifluoromethyl)biphenyl-2-yl]methyl}-6-(2-methoxyphenyl)-1,3-oxazinan-2-one as a white solid. LCMS=518.1 (M+1)+. 1H NMR (CDCl3, 500 MHz, mixture of atropisomers): δ 7.76 (s, 1H), 7.64 (d, J=8.1 Hz, 1H), 7.50 (d, J=6.4 Hz, 1H), 7.44 (s, 1H), 7.37-7.35 (m, 1H), 7.34-30 (m, 1H), 7.26-7.24 (m, 1H), 7.09 (dd, J=7.8, 2.3 Hz, 1H), 7.06-7-7.00 (m, 1H), 6.90 (d, J=8.2 Hz, 1H), 5.66 (dd, J=8.7, 3.0 Hz, 1H), 4.71 (d, J=15.8 Hz, 1H), 4.39 (d, J=15.8 Hz, 1H), 3.85 (s, 3H), 3.25-3.17 (m, 1H), 3.09-3.04 (m, 1H), 2.97-2.92 (m, 1H), 2.31-2.25 (m, 1H), 2.06-1.99 (m, 1H) 1.28 (d, J=7.1 Hz, 6H).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[NH2:10][OH:11].Cl.C([O-])(O)=O.[Na+]>O>[F:1][C:2]1[CH:9]=[CH:8][C:5](/[C:6](=[N:10]\[OH:11])/[NH2:7])=[CH:4][CH:3]=1
Reactant: N#Cc1ccc(F)cc1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: N/C(=N/O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.9 %

Procedure:
To a solution of 4-fluorobenzonitrile (1.21 g, 10 mmol) and NH2OH.HCl (0.83 g, 12 mmol) in H2O (5 mL) was added NaHCO3 in portions. The reaction mixture was stirred at room temperature overnight. The mixture was then diluted with H2O (50 mL) and extracted with ethyl acetate (2×50 mL). The combined organic layers were washed with brine and dried over Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to give the desired product (1.2 g). MS (ESI): 155 (MH+).
Reaction SMILES: [N+](C1C=CC([O:10][C:11]([N:13]2[C:18](=[O:19])[CH2:17][O:16][CH:15]([CH3:20])[CH:14]2[C:21]2[CH:26]=[CH:25][C:24]([F:27])=[C:23]([F:28])[CH:22]=2)=[O:12])=CC=1)([O-])=O.CO>C(Cl)Cl>[F:28][C:23]1[CH:22]=[C:21]([CH:14]2[CH:15]([CH3:20])[O:16][CH2:17][C:18](=[O:19])[N:13]2[C:11]([OH:12])=[O:10])[CH:26]=[CH:25][C:24]=1[F:27]
Reactant: CC1OCC(=O)N(C(=O)Oc2ccc([N+](=O)[O-])cc2)C1c1ccc(F)c(F)c1
Solvent: CO
Solvent: ClCCl
Product: CC1OCC(=O)N(C(=O)O)C1c1ccc(F)c(F)c1

Procedure:
3-(3,4-Difluorophenyl)-2-methyl-5-oxo-morpholine-4-carboxylic acid-4-nitro-phenyl ester (section II, part 1) was coupled to 3-[4-(cyano-4-phenyl-piperidin-1-yl]-propylamine in the same manner as described in section I, part 3c. White powder. M.P.=191-194° C.; Mass spec. 497 (M+1, 100%); [α]D=+23.1 (c=0.09, MeOH) Analysis calculated for C33H36N3O4F2Cl.0.35 CH2Cl2: C, 58.38; H, 5.68; N, 9.96. Found: C, 58.57; H, 6.03; N, 9.72.
Reaction SMILES: B.C1COCC1.[CH2:7]([N:14]([C:19]1[CH:24]=[C:23]([C:25](=[O:28])[CH2:26][Br:27])[CH:22]=[CH:21][C:20]=1[O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[S:15]([CH3:18])(=[O:17])=[O:16])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.CO>C1(C)C=CC=CC=1.C1COCC1>[CH2:7]([N:14]([C:19]1[CH:24]=[C:23]([C@@H:25]([OH:28])[CH2:26][Br:27])[CH:22]=[CH:21][C:20]=1[O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[S:15]([CH3:18])(=[O:17])=[O:16])[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CS(=O)(=O)N(Cc1ccccc1)c1cc(C(=O)CBr)ccc1OCc1ccccc1
Agent: B
Solvent: CO
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CS(=O)(=O)N(Cc1ccccc1)c1cc([C@@H](O)CBr)ccc1OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 94.8 %

Procedure:
A solution of BH3.THF in THF (1 M, 30.70 mmol) was added to a mixture of N-benzyl-N-[2-benzyloxy-5-(2-bromoacetyl)phenyl]methanesulfonamide (131) (25.00 g, 51.20 mmol) and R-methyl-CBS-oxazoborolidine (1 M in toluene, 5.10 mL, 5.10 mmol) in anhydrous THF (150 mL). The reaction mixture was stirred at 0° C. for 15 min and then at rt for 16 h. Methanol (100 mL) was then slowly added to quench the reaction. After removal of solvent by rotary evaporation, the resulting residue was purified by column chromatography (silica gel, dichloromethane only) to give desired bromo alcohol 132 as an orange oil (23.80 g, 95% yield): 1H NMR (500 MHz, CDCl3) δ 2.86 (s, 3H), 3.30-3.38 (m, 2H), 4.70 (m, 3H), 5.11 (s, 2H), 7.00 (m, 2H), 7.21 (m, 5H), 7.28 (d, 1H), 7.42 (m, 5H).
Reaction SMILES: [C:1]([CH2:6][C:7]([O:9]CC)=O)(=O)[CH:2]([CH3:4])[CH3:3].[CH3:12][NH:13][NH2:14]>C(O)C>[OH:9][C:7]1[N:13]([CH3:12])[N:14]=[C:1]([CH:2]([CH3:4])[CH3:3])[CH:6]=1
Reactant: CNN
Reactant: CCOC(=O)CC(=O)C(C)C
Solvent: CCO
Product: CC(C)c1cc(O)n(C)n1
Yield: 88 %

Procedure:
To a solution of 30.0 grams of ethyl isobutyrylacetate in 130 ml of ethanol (anhydrous, 5% methanol) at 10° C. was added dropwise over 30 minutes a solution of 8.7 grams of methyl hydrazine in 30 mls of ethanol. The reaction temperature did not exceed 20° C. After twenty minutes of additional stirring the cooling bath was removed and 2 ml of glacial acetic acid was added. After one hour of stirring at room temperature the reaction was then refluxed for four hours. After stirring overnight at room temperature the reaction was concentrated to yield a yellowish solid. This solid was stirred with 100 ml of hexanes for 30 minutes and the off-white solid was collected and rinsed with 75 ml of hexanes. The solid was dried in a vacuum oven at 45° C. overnight to yield 23.3 g of the desired product, mp 120°-122° C.
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)[CH:8]=[CH:7][N:6]=1)(=O)=O.[CH3:17][C:18]1[C:23]([NH2:24])=[CH:22][C:21]([N+:25]([O-:27])=[O:26])=[CH:20][N:19]=1.[H-].[Na+].C(Cl)(Cl)Cl>CN(C=O)C.O>[N+:25]([C:21]1[CH:22]=[C:23]([NH:24][C:5]2[N:10]=[C:9]([C:11]3[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=3)[CH:8]=[CH:7][N:6]=2)[C:18]([CH3:17])=[N:19][CH:20]=1)([O-:27])=[O:26]
Reactant: Cc1ncc([N+](=O)[O-])cc1N
Reactant: CS(=O)(=O)c1nccc(-c2cccnc2)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Solvent: O
Product: Cc1ncc([N+](=O)[O-])cc1Nc1nccc(-c2cccnc2)n1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a stirred solution of 2-methylsulfonyl-4-(pyridin-3-yl)pyrimidine (3.0 g) and 2-methyl-3-amino-5-nitropyridine (5.0 g) in DMF (50 mL) at 0-5° C. was added sodium hydride (60%, 2.3 g). The reaction mixture was naturally warmed to room temperature and stirred for 6 hours. Chloroform (50 mL) and water (50 mL) were added to the reaction and the phases were separated, the aqueous phase was extracted with Chloroform (2×100 mL). The organic extracts were combined, dried, filtered, concentrated and the residue was purified by chromatography to provide_N-(5-nitro-2-methylpyrid-3-yl)-4-(pyrid-3-yl)-2-pyrimidinamine (5.2 g).