Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:25])([C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][N:19]=1)[C:3]1[N:12]=[C:11](O)[C:10]2[C:5](=[C:6]([C:14]([F:17])([F:16])[F:15])[CH:7]=[CH:8][CH:9]=2)[N:4]=1.P(Br)(Br)(Br)=O.CCN(C(C)C)C(C)C.[CH3:40][C:41]1[NH:45][N:44]=[C:43]([NH2:46])[CH:42]=1>CN(C=O)C.C1(C)C=CC=CC=1>[F:1][C:2]([F:25])([C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][N:19]=1)[C:3]1[N:12]=[C:11]([NH:46][C:43]2[CH:42]=[C:41]([CH3:40])[NH:45][N:44]=2)[C:10]2[C:5](=[C:6]([C:14]([F:17])([F:16])[F:15])[CH:7]=[CH:8][CH:9]=2)[N:4]=1
Reactant: Oc1nc(C(F)(F)c2ccc(F)cn2)nc2c(C(F)(F)F)cccc12
Reactant: Cc1cc(N)n[nH]1
Agent: O=P(Br)(Br)Br
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(Nc2nc(C(F)(F)c3ccc(F)cn3)nc3c(C(F)(F)F)cccc23)n[nH]1
Temperature: 105 °C
Reaction time: 1.5 h
Yield: 20.1 %

Procedure:
To 2-(difluoro(5-fluoropyridin-2-yl)methyl)-8-(trifluoromethyl)quinazolin-4-ol (121 mg, 0.34 mmol) were added phosphoryl tribromide (890 mg) and toluene (1 mL) followed by DIEA (0.117 mL, 0.67 mmol). The mixture was heated at 105° C. for 1 h. The mixture was cooled and partitioned between EtOAc and saturated aq sodium bicarbonate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. To the residue was added a solution of 5-methyl-1H-pyrazol-3-amine (150 mg, 1.5 mmol) in DMF (4 mL) and the mixture was stirred at rt for 1.5 h. The crude mixture was purified by preparative HPLC (Varian diphenyl reverse phase column, eluting with a gradient of solvent B=0.05% HOAc/ACN and solvent A=0.05% HOAc/H2O) to afford 2-(difluoro(5-fluoropyridin-2-yl)methyl)-N-(5-methyl-1H-pyrazol-3-yl)-8-(trifluoromethyl)quinazolin-4-amine (30 mg, 20%). 1H NMR (300 MHz, DMSO-d6) δ ppm 2.19 (s, 3H) 6.03 (s, 1H) 7.77 (t, J=7.91 Hz, 1H) 7.96-8.06 (m, 2H) 8.27 (d, J=7.53 Hz, 1H) 8.67 (s, 1H) 8.97 (d, J=8.29 Hz, 1H) 11.00 (br s, 1H) 12.18 (br s, 1 H); LC-MS (ESI) m/z 439 (M+H)+.
Reaction SMILES: [CH:1]1[CH:6]=[C:5]2[C:7]([C:9](O)(O)[C:10](=O)[C:4]2=[CH:3][CH:2]=1)=O.Cl.[F:15][C:16]1[CH:17]=[C:18]([NH:22][C:23](=[O:26])[NH:24][NH2:25])[CH:19]=[CH:20][CH:21]=1>>[F:15][C:16]1[CH:17]=[C:18]([NH:22][C:23](=[O:26])[NH:24][N:25]=[C:9]2[CH2:7][C:5]3[C:4](=[CH:3][CH:2]=[CH:1][CH:6]=3)[CH2:10]2)[CH:19]=[CH:20][CH:21]=1
Reactant: O=C1c2ccccc2C(=O)C1(O)O
Reactant: NNC(=O)Nc1cccc(F)c1
Agent: Cl
Product: O=C(NN=C1Cc2ccccc2C1)Nc1cccc(F)c1

Procedure:
ninhydrin, 4-(3-fluorophenyl)-semicarbazide hydrochloride
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH2:8][N:9]2[C:21]3[CH:20]=[CH:19][CH:18]=[C:17]([OH:22])[C:16]=3[C:15]3[C:10]2=[CH:11][CH:12]=[CH:13][C:14]=3[C:23](=[O:25])[NH2:24])[CH:5]=[CH:6][CH:7]=1.Br[CH2:27][C:28]([O:30][CH3:31])=[O:29]>CN(C=O)C.C(OCC)(=O)C>[CH3:1][C:2]1[CH:3]=[C:4]([CH2:8][N:9]2[C:21]3[CH:20]=[CH:19][CH:18]=[C:17]([O:22][CH2:27][C:28]([O:30][CH3:31])=[O:29])[C:16]=3[C:15]3[C:10]2=[CH:11][CH:12]=[CH:13][C:14]=3[C:23](=[O:25])[NH2:24])[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cccc(Cn2c3cccc(O)c3c3c(C(N)=O)cccc32)c1
Reactant: COC(=O)CBr
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)COc1cccc2c1c1c(C(N)=O)cccc1n2Cc1cccc(C)c1
Reaction time: 0.05 h
Yield: 65.7 %

Procedure:
40% Methanolic Triton B (0.45 mL, 0.99 mM) was added to a solution of the 9-[(3-methylphenyl)methyl]-4-hydroxy-5-carbamoyl carbazole (100 mg, 0.30 mM) in 8 mL DMF at room temperature. After 3 minutes, methyl bromoacetate (115 mg, 0.72 mM) was added and the resultant mixture stirred at room temperature for 24 hours. The mixture was diluted with ethyl acetate, washed with H2O, and saturated brine, dried over magnesium sulfate, filtered, and concentrated. The residue was purified by column chromatography on silica gel (elution with ethyl acetate) to afford 80 mg (66%) of the {9-[(3-methylphenyl)methyl]-5-carbamoylcarbazol-4-yl}oxyacetic acid, methyl ester as a white solid. 1H NMR (DMSO-d6) δ 7.6 (d, 1H, J=8 Hz), 7.55 (br s, 1H), 7.45-7.0 (m, 8H), 6.9 (d, 1H, J=8 Hz), 6.6 (d, 1H, J=8 Hz), 5.65 (s, 2H), 4.9 (s, 2H), 3.75 (s, 3H), and 2.2 (s, 3H). IR (KBr, cm−1) 3367, 3157, 1760, 1642, 1589, 1499, 1455, 1424, 1328, 1216, 1151, 1102, 772, and 714. MS (FD) m/e 402.
Reaction SMILES: [S:1]1[CH2:5][C:4](=[O:6])[NH:3][C:2]1=[O:7].[Br:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=1[Br:17])[CH:12]=O.N1CCCCC1>C(O)(=O)C>[Br:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=1[Br:17])[CH:12]=[C:5]1[S:1][C:2](=[O:7])[NH:3][C:4]1=[O:6]
Reactant: O=C1CSC(=O)N1
Reactant: O=Cc1ccc(Br)c(Br)c1
Solvent: CC(=O)O
Solvent: C1CCNCC1
Product: O=C1NC(=O)C(=Cc2ccc(Br)c(Br)c2)S1

Procedure:
A mixture of thiazolidine-2,4-dione (90%, 65 mg, 0.5 mmol), 3,4-dibromobenzaldehyde (132 mg, 0.5 mmol), and piperidine (247 μL, 2.5 mmol) was shaken in acetic acid (2 mL) at 110° C. for 16 hours. After cooling, the mixture was concentrated to dryness in vacuo. The resulting crude product was shaken with water, centrifuged, and the supernatant was discarded. Subsequently the residue was shaken with ethanol, centrifuged, the supernatant was discarded and the residue was further evaporated to dryness to afford the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:10]([OH:15])=[CH:11][CH:12]=[CH:13][CH:14]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:22](Br)[CH:23]=[CH2:24].O>CC(C)=O>[CH2:24]([O:15][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[C:3]1[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=1[Cl:8])[CH:23]=[CH2:22]
Reactant: C=CCBr
Reactant: Oc1ccccc1-c1c(Cl)cccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: C=CCOc1ccccc1-c1c(Cl)cccc1Cl
Reaction time: 1 h
Yield: 92.6 %

Procedure:
To a solution of 2′,6′-dichloro-1,1′-biphenyl-2-ol (5.4 g, 0.0226 mol) in acetone (100 mL) was added potassium carbonate (3.75 g, 0.0271 mol) followed by allyl bromide (2.58 mL, 0.0298 mol) and the reaction mixture heated to reflux for 24 hours. The cooled reaction mixture was poured into water (300 mL), the mixture stirred vigorously for 1 hour then extracted with ethyl acetate (300 mL). The separated organic extract was washed with water (200 mL) and saturated brine (200 mL), dried over magnesium sulfate and concentrated under reduced pressure to afford a yellow syrup. Purification by flash chromatography using a solvent gradient of 1 to 2% ethyl acetate in hexane gave 5.84 g (93%) of 2′-(allyloxy)-2,6-dichloro-1,1′-biphenyl as a colorless oil. MS (EI) m/z 278 (M+).
Reaction SMILES: C([NH:5]CC(C)C)C(C)C.C(N(CC)CC)C.[CH3:17][C:18]1[CH:31]=[C:30]2[C:21]([S:22][C:23]3[CH:24]=[C:25]([C:33](Cl)=[O:34])[CH:26]=[CH:27][C:28]=3[C:29]2=[O:32])=[CH:20][CH:19]=1>C(Cl)Cl.O>[CH3:17][C:18]1[CH:31]=[C:30]2[C:21]([S:22][C:23]3[CH:24]=[C:25]([C:33]([NH2:5])=[O:34])[CH:26]=[CH:27][C:28]=3[C:29]2=[O:32])=[CH:20][CH:19]=1
Reactant: CC(C)CNCC(C)C
Reactant: Cc1ccc2sc3cc(C(=O)Cl)ccc3c(=O)c2c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: Cc1ccc2sc3cc(C(N)=O)ccc3c(=O)c2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 77.4 %

Procedure:
A solution of 5.0 g (38.8 mmoles) of diisobutyl amine and 5.0 g (49.5 mmoles) of triethyl amine in 40 cc of CH2Cl2 is poured drop by drop in the CH2Cl2 solution containing 7.47 g (25.9 mmoles) of 7-methyl 9-oxo-thioxanthene-3-carbonyl chloride. After approximately 1 hour at room temperature under stirring, the mixture is poured in water, the organic phase is separated and washed again with water. The organic phase is then separated, dehydrated and dried after purification on a flash column (SiO2— eluent: CH2Cl2:AcOEt 9:1). 5.4 g (54.7%) of a yellow solid with the following spectral properties are obtained:
Reaction SMILES: [F:1][CH:2]([F:16])[C:3](=O)[CH2:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=1)=O.[NH2:17][C:18]1[C:22]([C:23]2[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=2)=[CH:21][NH:20][N:19]=1>>[F:1][CH:2]([F:16])[C:3]1[N:19]2[N:20]=[CH:21][C:22]([C:23]3[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=3)=[C:18]2[N:17]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=2)[CH:4]=1
Reactant: COc1ccc(C(=O)CC(=O)C(F)F)cc1
Reactant: Nc1n[nH]cc1-c1ccncc1
Product: COc1ccc(-c2cc(C(F)F)n3ncc(-c4ccncc4)c3n2)cc1
Yield: 68.1 %

Procedure:
Reaction of 4,4-difluoro-1-(4-methoxy-phenyl)-butane-1,3-dione (114 mg, 0.5 mmol), prepared from commercially available 4-methoxy-acetophenone according to general procedure A, and 3-amino-4-(4-pyridinyl)-pyrazole [CAS No. 216661-87-9; prepared from 4-cyanomethyl-pyridine as described in Bioorg. Med. Chem. Lett. 12 (2002) 3537-3541] (80 mg, 0.5 mmol) according to general procedure B yielded the title compound as a yellow solid (120 mg, 68%). MS (ISP) 353.2 [(M+H)+]; mp 206° C.
Reaction SMILES: [CH:1](=O)[CH3:2].[CH2:4]([O:6][C:7]([C:9]1[CH:10]=[N:11][N:12]([C:14]2[N:23]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:22](=[O:32])[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([NH2:33])[CH:20]=3)[N:15]=2)[CH:13]=1)=[O:8])[CH3:5].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(O)C.CCOC(C)=O>[CH2:4]([O:6][C:7]([C:9]1[CH:10]=[N:11][N:12]([C:14]2[N:23]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:22](=[O:32])[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([NH:33][CH2:1][CH3:2])[CH:20]=3)[N:15]=2)[CH:13]=1)=[O:8])[CH3:5]
Reactant: CC=O
Reactant: CCOC(=O)c1cnn(-c2nc3ccc(N)cc3c(=O)n2COCC[Si](C)(C)C)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCNc1ccc2nc(-n3cc(C(=O)OCC)cn3)n(COCC[Si](C)(C)C)c(=O)c2c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 33 %

Procedure:
Acetaldehyde (1 mL) was added to 1-[6-amino-4-oxo-3-(2-trimethylsilanyl-ethoxymethyl)-3,4-dihydro-quinazolin-2-yl]-1H-pyrazole-4-carboxylic acid ethyl ester (0.250 g, 0.582 mol) and 4 Å molecular sieves (0.35 g) in ethanol (1.9 g). The reaction mixture was stirred at room temperature for 18 h and was then filtered. Ethanol and acetaldehyde were removed under high vacuum. The residue was redissolved in DCE (1.5 mL) and sodium triacetoxyborohydride (0.308 g, 1.46 mmol) was added. The reaction mixture was stirred at room temperature for 6 d, then diluted with EtOAc (30 mL) and washed with saturated aqueous sodium bicarbonate (20 mL). The aqueous layer was extracted with EtOAc (30 mL) and the combined organic layers were washed with brine (20 mL), dried (MgSO4), and concentrated. The residue was purified via FCC (5-65% EtOAc/hexanes) to yield the titled compound (87.0 mg, 33% yield). MS (ESI/Cl): mass calcd. for C22H31N5O4Si, 457.2; m/z found, 458.2 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][C:5]2[N:6]=[C:7]([C@@H:9]3[CH2:12][C@H:11](O)[CH2:10]3)[S:8][C:4]=2[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.C([C@@H]([C@H](C(O)=O)O)O)(O)=O.[CH3:47][C@@H:48]1[CH2:52][CH2:51][CH2:50][NH:49]1>ClCCl>[Br:1][C:2]1[CH:15]=[CH:14][C:5]2[N:6]=[C:7]([C@H:9]3[CH2:12][C@H:11]([N:49]4[CH2:50][CH2:51][CH2:52][C@H:48]4[CH3:47])[CH2:10]3)[S:8][C:4]=2[CH:3]=1
Reactant: C[C@@H]1CCCN1
Reactant: O[C@H]1C[C@@H](c2nc3ccc(Br)cc3s2)C1
Agent: O=C(O)[C@H](O)[C@@H](O)C(=O)O
Agent: O=C([O-])[O-]
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Product: C[C@@H]1CCCN1[C@H]1C[C@H](c2nc3ccc(Br)cc3s2)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The product of Example 1D (2.52 mmole) was dissolved in anhydrous dichloromethane (20 ml). Potassium carbonate (696 mg, 5.04 mmole) was added followed by trifluoromethanesulfonic anhydride (551 μl, 3.27 mmole). The mixture was allowed to stir at room temperature for 2 hours, then another portion of potassium carbonate (1.74 g, 12.6 mmole) was added, followed by 2-(R)-methylpyrrolidine L-tartrate (prepared according to the procedure that described in: R. Altenbach et al., WO 2004043458, and Y. Pu et al., Organic Process Research & Development, 9(1), 45-50, 2005) (1.18 g, 5.04 mmole). The resulting mixture was stirred at room temperature overnight. It was then quenched with water, and extracted three times with dichloromethane. The organic layers were combined, washed with brine, dried over sodium sulfate, and concentrated. The crude product was purified by column chromatography (0.5% ammonium hydroxide and 5% methanol in dichloromethane) to give 394 mg (45%) of title compound. 1H NMR (400 MHz, CDCl3) δ ppm 7.97 (d, J=1.84 Hz, 1H), 7.83 (d, J=8.90 Hz, 1H), 7.55 (dd, J=8.75, 1.99 Hz, 1H), 3.75-3.88 (m, 1H), 3.40-3.56 (m, 1H), 3.00-3.10 (m, 1H), 2.61-2.79 (m, 3H), 2.42-2.57 (m, 2H), 2.23-2.37 (m, 1H), 1.88-2.02 (m, 1H), 1.77-1.88 (m, 1H), 1.61-1.76 (m, 1H), 1.39-1.54 (m, 1H), 1.11 (d, J=6.14 Hz, 3H). MS: (M+H)+=351/353.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@:9]1([CH2:12][N:13]2[CH:17]=[N:16][CH:15]=[N:14]2)[CH2:11][O:10]1.O.[NH2:19][NH2:20]>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:10])([CH2:12][N:13]1[CH:17]=[N:16][CH:15]=[N:14]1)[CH2:11][NH:19][NH2:20]
Reactant: NN
Reactant: Fc1ccc([C@@]2(Cn3cncn3)CO2)c(F)c1
Solvent: O
Product: NNCC(O)(Cn1cncn1)c1ccc(F)cc1F

Procedure:
A process according to claim 1 which comprises reacting (R)-1-[2-(2,4-difluorophenyl)oxiran-2-ylmethyl]-1H-1,2,4-triazole with hydrazine hydrate to form 2-(2,4-difluorophenyl)-1-hydrazino-3-(1H-1,2,4-triazol-1-yl)propan-2-ol, reacting this product with methyl (E)-4-(2,2,3,3)-tetrafluoropropoxy)cinnamimidate, and subsequently reacting the (E)-N-[2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propyl]-4-(2,2,3,3-tetrafluoropropoxy)cinnamamidrazone product with ethyl orthoformate to form (R)-2-(2,4-difluorophenyl)-1-(3-[(E)-4-(2,2,3,3-tetrafluoropropoxy)styryl]-1H-1,2,4-triazol-1-yl)-3-(1H-1,2,4-triazol-1-yl)propan-2-ol.
Reaction SMILES: [CH2:1]([C@H:6]1[CH2:11][CH2:10][C@H:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][C:21]([C:24](Cl)=[O:25])=[CH:20][CH:19]=3)=[CH:14][CH:13]=2)[CH2:8][CH2:7]1)[CH2:2][CH2:3][CH2:4][CH3:5].[CH2:27]([C:30]1[CH:35]=[CH:34][C:33]([C@H:36]2[CH2:41][CH2:40][C@H:39]([OH:42])[CH2:38][CH2:37]2)=[CH:32][CH:31]=1)[CH2:28][CH3:29]>C1C=CC=CC=1.N1C=CC=CC=1>[CH2:27]([C:30]1[CH:35]=[CH:34][C:33]([C@H:36]2[CH2:37][CH2:38][C@H:39]([O:42][C:24]([C:21]3[CH:20]=[CH:19][C:18]([C:15]4[CH:14]=[CH:13][C:12]([C@H:9]5[CH2:8][CH2:7][C@H:6]([CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])[CH2:11][CH2:10]5)=[CH:17][CH:16]=4)=[CH:23][CH:22]=3)=[O:25])[CH2:40][CH2:41]2)=[CH:32][CH:31]=1)[CH2:28][CH3:29]
Reactant: CCCCC[C@H]1CC[C@H](c2ccc(-c3ccc(C(=O)Cl)cc3)cc2)CC1
Reactant: CCCc1ccc([C@H]2CC[C@H](O)CC2)cc1
Solvent: c1ccncc1
Solvent: c1ccccc1
Product: CCCCC[C@H]1CC[C@H](c2ccc(-c3ccc(C(=O)O[C@H]4CC[C@H](c5ccc(CCC)cc5)CC4)cc3)cc2)CC1
Temperature: 65 °C
Reaction time: 8 h

Procedure:
The crude 4'-(trans-4-pentylcyclohexyl)-4-biphenylcarboxylic acid chloride obtained was dissolved in 40 ml of benzene and then added dropwise to a solution of 0.90 g of trans-4-(p-propylphenyl)cyclohexanol in 20 ml of pyridine. The mixture was stirred at a bath temperature of 65° C. overnight, then poured into ice-water and extracted with diethyl ether. The extract was washed four times with 25 ml of 3N hydrochloric acid each time, then washed with 25 ml of 2N sodium carbonate solution and several times with water, dried over sodium sulphate and concentrated. The crude 4'-(trans-4-pentylcyclohexyl)-4-biphenylcarboxylic acid trans-4-(p-propylphenyl)cyclohexyl ester obtained was recrystallized once from ethanol containing a small amount of ethyl acetate and once from ethyl acetate. Yield 1.1 g; m.p. (C-S) 131.2° C.; phase transition S-N 143.3° C.; cl.p. (N-I) 337.5° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)[CH:9]=2)[C:4]=1Br.[C:22]1([Mg]Br)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.Cl>C1COCC1.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>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)[CH:9]=2)[C:4]=1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: COc1ccc(-c2ccc3c(Br)c(OC)ccc3c2)cc1
Reactant: Br[Mg]c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Solvent: C1CCOC1
Product: COc1ccc(-c2ccc3c(-c4ccccc4)c(OC)ccc3c2)cc1
Temperature: 25 °C
Yield: 53 %

Procedure:
To a mixture of 2-methoxy-6-(4-methoxyphenyl)-1-bromonaphthalene (0.80 g, 2.33 mmol) and tetrakis(triphenylphosphine)palladium (0.13 g, 0.12 mmol) in THF (10 mL) was added phenylmagnesiumbromide (2.2 mL of 3 N in ether). The reaction mixture was stirred at reflux overnight, cooled to room temperature, poured into 1 N HCl (100 mL), and extracted with ethyl acetate (3×200 mL). The combined organic layers were washed with sodium bicarbonate solution, dried over magnesium sulfate, filtered, evaportation of the solvent, and purification by silica column chromatography (10% ethyl acetate-hexanes) yielded 0.42 g (53%) of a gray solid: mp 157-160° C.; 1H NMR (CDCl3): δ 3.85 (3H, s), 3.87 (3H, s), 7.01 (2H, d, J=8.64 Hz), 7.38-7.46 (4H, m), 7.49-7.57 (4H, m), 7.64 (2H, d, J=8.64 Hz), 7.92 (1H, d, J=9.05 Hz), 7.97 (1H, s); MS (ESI) m/z 341 (M+H)+.
Reaction SMILES: [CH:1]1([C@H:7]2[NH:12][C:11]3[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=3[O:9][CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[N:17]([O-])=O.[Na+].Cl.[H-].[Al+3].[Li+].[H-].[H-].[H-].O1CCCC1>CN(C)C=O.O>[NH2:17][N:12]1[C:11]2[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=2[O:9][CH2:8][C@H:7]1[CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=N[O-]
Reactant: c1ccc2c(c1)N[C@H](C1CCCCC1)CO2
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: NN1c2ccccc2OC[C@H]1C1CCCCC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 50.6 %

Procedure:
(R)-3-cyclohexyl-3,4-dihydro-2H-1,4-benzoxazine (2.72 g, 12.5 mmol) was dissolved in N,N-dimethylformamide (20 ml) and a solution of sodium nitrite (949 mg, 13.8 mmol) in water (3.0 ml) was added at 0° C. Then, 5 N hydrochloric acid (6.0 ml) was added at 0° C. The reaction mixture was stirred at 0° C. for 1 h, then partitioned between ethyl acetate and water. The aqueous layer was extracted with ethyl acetate and the combined organic layers were washed with brine, dried over sodium sulfate and concentrated. The obtained residue was dissolved in diethyl ether (50 ml), and lithium aluminum hydride in tetrahydrofuran (1.0 M; 9.51 ml, 9.51 mmol) was added at 0° C. The reaction mixture was stirred at 0° C. for 1 h, then quenched with ice water. Ethyl acetate was added to the mixture and the mixture was filtered through a plug of Celite, and the filter cake washed with ethyl acetate. The filtrate was partitioned and the aqueous layer extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate and concentrated. The residue was purified by flash chromatography eluting with 0-17% (v/v) ethyl acetate in heptane to afford (R)-4-amino-3-cyclohexyl-3,4-dihydro-2H-1,4-benzoxazine (1.47 g, 6.33 mmol).
Reaction SMILES: [CH3:1][C:2]([CH3:31])([CH3:30])[CH2:3][C:4]([NH:6][C:7]1[C:8]([CH3:29])=[C:9](B(O)O)[C:10]2[O:14][CH2:13][CH:12]([C:15]3[CH:20]=[CH:19][C:18]([CH:21]([CH3:23])[CH3:22])=[CH:17][CH:16]=3)[C:11]=2[C:24]=1[CH3:25])=[O:5].Br[C:33]1[CH:34]=[N:35][CH:36]=[N:37][CH:38]=1>>[CH:21]([C:18]1[CH:19]=[CH:20][C:15]([CH:12]2[C:11]3[C:24]([CH3:25])=[C:7]([NH:6][C:4](=[O:5])[CH2:3][C:2]([CH3:31])([CH3:30])[CH3:1])[C:8]([CH3:29])=[C:9]([C:33]4[CH:34]=[N:35][CH:36]=[N:37][CH:38]=4)[C:10]=3[O:14][CH2:13]2)=[CH:16][CH:17]=1)([CH3:23])[CH3:22]
Reactant: Cc1c(NC(=O)CC(C)(C)C)c(C)c2c(c1B(O)O)OCC2c1ccc(C(C)C)cc1
Reactant: Brc1cncnc1
Product: Cc1c(NC(=O)CC(C)(C)C)c(C)c2c(c1-c1cncnc1)OCC2c1ccc(C(C)C)cc1
Yield: 77 %

Procedure:
Using (5-((3,3-dimethylbutanoyl)amino)-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-7-yl)boronic acid obtained in Example 116 and 5-bromopyrimidine, the title compound was obtained in the same manner as in Example 107. Yield: 77%. Melting point: 167-169° C. (ethyl acetate-hexane).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[N:8]=[N:7][C:6]([CH2:9][O:10][CH2:11][C:12]2[NH:13][C:14]([CH3:35])=[C:15]([C:31]([O:33][CH3:34])=[O:32])[CH:16]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[C:24]=3[Cl:30])[C:17]=2[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[N:5]1.C(N(CC)CC)C.[Cl:43][C:44]1[CH:49]=[C:48](Cl)[N:47]=[CH:46][N:45]=1>C(O)C>[Cl:43][C:44]1[N:45]=[CH:46][N:47]=[C:48]([NH:1][CH2:2][CH2:3][N:4]2[N:8]=[N:7][C:6]([CH2:9][O:10][CH2:11][C:12]3[NH:13][C:14]([CH3:35])=[C:15]([C:31]([O:33][CH3:34])=[O:32])[CH:16]([C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[C:24]=4[Cl:30])[C:17]=3[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[N:5]2)[CH:49]=1
Reactant: CCOC(=O)C1=C(COCc2nnn(CCN)n2)NC(C)=C(C(=O)OC)C1c1cccc(Cl)c1Cl
Reactant: Clc1cc(Cl)ncn1
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCOC(=O)C1=C(COCc2nnn(CCNc3cc(Cl)ncn3)n2)NC(C)=C(C(=O)OC)C1c1cccc(Cl)c1Cl
Yield: 80.8 %

Procedure:
A solution of 2-(2-aminoethyl)-5-{[4-(2,3-dichlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyridin-2-yl]methoxymethyl}tetrazole (0.52 g), triethylamine (0.5 ml) and 4,6-dichloropyrimidine (0.16 g) in ethanol (20 ml) was heated under reflux for 23 hours and then evaporated. The residue was purified by chromatography on silica (8 g) using dichloromethane plus from 0 to 100% by volume of ethyl acetate as eluant. Appropriate fractions were combined and evaporated to give 2-{[(6-chloro-4-pyrimidinyl)amino]ethyl}-5-{[4-(2,3-dichlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyridin-2-yl]methoxymethyl}tetrazole (0.51 g) as a colourless foam. A solution of this crude product in morpholine (3 ml) was heated on a steam-bath for 90 minutes and then partitioned between 2M hydrochloric acid and dichloromethane. The acidic layer was extracted into dichloromethane and the combined organic layers were washed with water and 10% aqueous sodium carbonate solution, dried over anhydrous sodium sulphate and evaporated. The residue was purified by chromatography on silica (10 g) using dichloromethane plus from 0 to 50% by volume of ethyl acetate followed by dichloromethane plus from 1 to 5% by volume of methanol as eluant. Appropriate fractions were combined and evaporated. The residual oil was triturated with diethyl ether and the resulting solid collected, washed with diethyl ether and dried to give the title compound (0.51 g), m.p. 160°-162° C. Found: C,52.24; H,5.20; N,18.24. C30H35Cl2N9O6 requires: C,52.33; H,5.09; N,18.31%.