Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N(C(OC(C)C)=O)=NC(OC(C)C)=O.[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([C@@H:22]2[O:28][CH2:27][CH2:26][N:25]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:24][C@H:23]2[OH:36])=[CH:18][C:17]=1[F:37].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O=[C:58]1[C:63]([C:64]#[N:65])=[CH:62][CH:61]=[CH:60][NH:59]1>O1CCCC1.O>[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([C@@H:22]2[O:28][CH2:27][CH2:26][N:25]([C:29]([O:31][C:32]([CH3:34])([CH3:33])[CH3:35])=[O:30])[CH2:24][C@@H:23]2[O:36][C:58]2[C:63]([C:64]#[N:65])=[CH:62][CH:61]=[CH:60][N:59]=2)=[CH:18][C:17]=1[F:37]
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(Cl)c(F)c2)[C@H](O)C1
Reactant: N#Cc1ccc[nH]c1=O
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(Cl)c(F)c2)[C@@H](Oc2ncccc2C#N)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 64.3 %

Procedure:
Diisopropyl azodicarboxylate (1.9 M in toluene, 0.69 mL) was added dropwise to a solution of tert-butyl (6R,7S)-7-(4-chloro-3-fluorophenyl)-6-hydroxy-1,4-oxazepane-4-carboxylate (300 mg), triphenylphosphine (340 mg) and 2-oxo-1,2-dihydropyridine-3-carbonitrile (160 mg) in tetrahydrofuran (10 mL), and the mixture was stirred at room temperature for 4 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound (250 mg).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[F:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[Br:12][C:13]([CH3:18])([CH3:17])[C:14](Br)=[O:15]>C(=S)=S>[Br:12][C:13]([CH3:18])([CH3:17])[C:14]([C:9]1[CH:10]=[CH:11][C:6]([F:5])=[CH:7][CH:8]=1)=[O:15]
Reactant: CC(C)(Br)C(=O)Br
Reactant: Fc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: CC(C)(Br)C(=O)c1ccc(F)cc1
Temperature: 20 °C
Reaction time: 0.08 h

Procedure:
A slurry of 14 g. (0.105 mole) of anhydrous aluminum chloride in 14.4 g. (0.150 mole) of fluorobenzene and 24 ml. of carbon disulfide is cooled to 15°C. To it is added 23.8 g. (0.100 mole) of α-bromoisobutyryl bromide over 10-15 minutes at 15°-20°C. The reaction is stirred for 5 minutes at 20°C and then quenched on ice. The product is extracted into chloroform. The chloroform layer is washed with aqueous sodium bicarbonate, dried over anhydrous sodium sulfate and concentrated to give 2-bromo-4'-fluoro-2-methylpropiophenone.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH:10]([NH:13][C:14]([C:16]2[S:17][CH:18]=[CH:19][C:20]=2[NH:21][C:22]2[CH:27]=[CH:26][N:25]=[C:24]3[NH:28][CH:29]=[CH:30][C:23]=23)=[O:15])[CH2:9]1)=O)(C)(C)C.[NH2:31][CH2:32]CC1N=CNC=1>>[NH:31]1[CH:32]=[C:12]([CH2:11][CH2:10][NH:13][C:14]([C:16]2[S:17][CH:18]=[CH:19][C:20]=2[NH:21][C:22]2[CH:27]=[CH:26][N:25]=[C:24]3[NH:28][CH:29]=[CH:30][C:23]=23)=[O:15])[N:8]=[CH:9]1
Reactant: CC(C)(C)OC(=O)N1CCC(NC(=O)c2sccc2Nc2ccnc3[nH]ccc23)C1
Reactant: NCCc1c[nH]cn1
Product: O=C(NCCc1c[nH]cn1)c1sccc1Nc1ccnc2[nH]ccc12

Procedure:
This compound was prepared in an analogous manner as 3-{[3-(1H-Pyrrolo[2,3-b]pyridin-4-ylamino)-thiophene-2-carbonyl]-amino}-pyrrolidine-1-carboxylic acid tert-butyl ester using histamine instead of 1-BOC-3-aminopyrrolidine. LCMS (ESI) 353 (M+H) 1H NMR (400 MHz, DMSO-d6) δ ppm 11.69-11.97 (1H, m) 11.52 (1H, br. s.) 10.35 (1H, s) 8.24 (1H, br. s.) 8.02 (1H, d, J=5.37 Hz) 7.77 (1H, d, J=5.47 Hz) 7.44-7.54 (2H, m) 7.31 (1H, dd, J=3.32, 2.83 Hz) 6.88 (1H, br. s.) 6.82 (1H, d, J=5.37 Hz) 6.44 (1H, dd, J=3.47, 1.71 Hz) 3.41-3.52 (2H, m) 2.71 (2H, t, J=6.98 Hz)
Reaction SMILES: [C:1]1([C:7]2[N:16]3[C:10]([CH2:11][C:12](=[O:21])[NH:13][C:14]4[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=43)=[N:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Br[CH2:25][C:26]([N:28]([CH:35]([CH3:37])[CH3:36])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:27]>CN(C=O)C.[Cl-].[Na+].O>[CH:35]([N:28]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:26](=[O:27])[CH2:25][N:13]1[C:12](=[O:21])[CH2:11][C:10]2[N:16]([C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[N:8][N:9]=2)[C:15]2[CH:17]=[CH:18][CH:19]=[CH:20][C:14]1=2)([CH3:37])[CH3:36]
Reactant: O=C1Cc2nnc(-c3ccccc3)n2-c2ccccc2N1
Reactant: CC(C)N(C(=O)CBr)c1ccccc1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)N(C(=O)CN1C(=O)Cc2nnc(-c3ccccc3)n2-c2ccccc21)c1ccccc1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 72.4 %

Procedure:
To a solution of 1-phenyl-4H,6H-2,3,6,10b-tetraaza-benzo[e]azulen-5-one (Preparation 4(A)) (2.5 g, 9.05 mmol) in DMF (40 mL) at 0° C. was added sodium hydride (60% in oil, 0.36 g, 9.0 mmol). The reaction was warmed to room temperature and was stirred for 40 minutes. The reaction was cooled to −6° C. and a solution of 2-bromo-N-isopropyl-N-phenyl-acetamide (Preparation 1(A)) (2.55 g, 9.95 mmol) in DMF (20 mL) was added to the reaction mixture dropwise over 0.5 hour, maintaining the internal reaction temperature below −3° C. The reaction mixture was stirred for 105 minutes below −3° C. and brine (200 mL) was added. The aqueous solution was washed with ethyl acetate (200 mL). The organic layer was washed with brine, dried over sodium sulfate, and concentrated to ⅓ volume. Hexanes were slowly added until a solid crashed out. The white solid was collected by filtration and was rinsed with ether and hexanes to give 2.96 g of N-isopropyl-2-(5-oxo-1-phenyl-4,5-dihydro-2,3,6,10b-tetraaza-benzo[e]azulen-6-yl)-N-phenyl-acetamide. MS 452 (M+1). This intermediate was carried forward according to Example 3(B), Steps A and B above to afford 2-[4-(1H-indazol-3-ylmethyl)-5-oxo-1-phenyl-4,5-dihydro-2,3,6,10b-tetraaza-benzo[e]azulen-6-yl]-N-isopropyl-N-phenyl-acetamide as a racemic mixture.
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:18][C:17](=[O:19])[N:16]([CH2:20][C:21]3[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[CH:23][C:22]=3I)[C@@H:15]([CH3:32])[CH2:14]2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[C:35]([C:39]1[CH:40]=[CH:41][C:42]([O:48][CH3:49])=[C:43](B(O)O)[CH:44]=1)([CH3:38])([CH3:37])[CH3:36].C([O-])([O-])=O.[K+].[K+].C1COCC1>O>[F:1][C:2]([F:34])([F:33])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:18][C:17](=[O:19])[N:16]([CH2:20][C:21]3[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[CH:23][C:22]=3[C:43]3[CH:44]=[C:39]([C:35]([CH3:36])([CH3:38])[CH3:37])[CH:40]=[CH:41][C:42]=3[O:48][CH3:49])[C@@H:15]([CH3:32])[CH2:14]2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: C[C@H]1C[C@@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC(=O)N1Cc1cc(C(F)(F)F)ccc1I
Reactant: COc1ccc(C(C)(C)C)cc1B(O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(C(C)(C)C)cc1-c1ccc(C(F)(F)F)cc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)C[C@@H]1C
Temperature: 80 °C

Procedure:
(4S,6S)-6-[3,5-bis(trifluoromethyl)phenyl]-3-[2-iodo-5-(trifluoromethyl)benzyl]-4-methyl-1,3-oxazinan-2-one (Intermediate 23; 25 mg; 0.041 mmol), (5-tert-butyl-2-methoxyphenyl)boronic acid (11.1 mg; 0.053 mmol), 1-1′-bis(di tert-butylphosphino)ferrocene palladium dichloride (2.7 mg; 0.0041 mmol), 1 N K2CO3 (1.2 mL) and THF (1.2 mL) were combined in a sealed tube and heated at 80° C. for 1.5 h. The reaction was diluted with H2O (10 mL) and extracted with EtOAc (3×10 mL). The combined extracts were washed with brine (10 mL), dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by flash silica gel chromatography (0-30% EtOAc/hexanes gradient) to afford (4S,6S)-6-[3,5-bis(trifluoromethyl)phenyl]-3-{[5′-tert-butyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-4-methyl-1,3-oxazinan-2-one as a white solid. LCMS=648.0 (M+1)+. 1H NMR (CDCl3, 500 MHz, mixture of atropisomers): δ 7.86-7.83 (m, 2H), 7.78 (s, 1H), 7.68 (s, 1H), 7.63-7.59 (m, 1H), 7.44-7.36 (m, 2H), 7.18 (dd, J=6.7, 2.4 Hz, 1H), 6.94 (d, J=8.7 Hz, 1H), 5.20 (d, J=16 Hz, 1H), 5.16 (d, J=11.2 Hz, 1H), 4.38 (d, J=15.8 Hz, 1H), 3.80 (s, 3H), 3.41-3.34 (m, 1H), 2.29-2.24 (m, 1H), 1.88-1.81 (m, 1H), 1.32 (s, 9H), 1.02 (d, J=6.2 Hz, 3H).
Reaction SMILES: Cl.[NH:2]1[C:7]2[N:8]=[CH:9][CH:10]=[CH:11][C:6]=2[C:5]2([CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[O:4][C:3]1=[O:17].[Cl:18][C:19]1[C:24]2[NH:25][C:26]([CH:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)=[N:27][C:23]=2[CH:22]=[C:21]([O:34][C:35]2[CH:40]=[C:39](Cl)[N:38]=[CH:37][N:36]=2)[CH:20]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:18][C:19]1[C:24]2[NH:25][C:26]([CH:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)=[N:27][C:23]=2[CH:22]=[C:21]([O:34][C:35]2[N:36]=[CH:37][N:38]=[C:39]([N:14]3[CH2:13][CH2:12][C:5]4([O:4][C:3](=[O:17])[NH:2][C:7]5[N:8]=[CH:9][CH:10]=[CH:11][C:6]4=5)[CH2:16][CH2:15]3)[CH:40]=2)[CH:20]=1
Reactant: Clc1cc(Oc2cc(Cl)c3[nH]c(C4CCOCC4)nc3c2)ncn1
Reactant: O=C1Nc2ncccc2C2(CCNCC2)O1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C1Nc2ncccc2C2(CCN(c3cc(Oc4cc(Cl)c5[nH]c(C6CCOCC6)nc5c4)ncn3)CC2)O1

Procedure:
49 mg (0.19 mmol) spiro[piperidin-4,4′-pyrido[2,3-d][1,3]oxazin]-2′(1′H)-one hydrochloride, 70 mg (0.19 mmol) 7-chloro-5-(6-chloropyrimidin-4-yloxy)-2-(tetrahydro-2H-pyran-4-yl)-1H-benzo[d]imidazole and 70 μL (0.40 mmol) DIPEA in 2.0 mL DMF were stirred for 3 h at RT and for 3 h at 40° C. The reaction mixture was purified by chromatography. The fractions containing product were combined and evaporated down i.vac.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[CH:6]=[C:5]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][N:10]=2)[N:4]=[C:3]1[O:15][CH:16]1[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][CH:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[CH2:18][CH2:17]1.[CH:30](=O)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(O)(=O)C.ClCCCl>[CH2:30]([N:27]1[CH2:26][CH2:25][CH:24]([CH2:23][CH2:22][N:19]2[CH2:18][CH2:17][CH:16]([O:15][C:3]3[N:2]([CH3:1])[C:7](=[O:8])[CH:6]=[C:5]([C:9]4[CH:14]=[CH:13][N:12]=[CH:11][N:10]=4)[N:4]=3)[CH2:21][CH2:20]2)[CH2:29][CH2:28]1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: O=Cc1ccccc1
Reactant: Cn1c(OC2CCN(CCC3CCNCC3)CC2)nc(-c2ccncn2)cc1=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: Cn1c(OC2CCN(CCC3CCN(Cc4ccccc4)CC3)CC2)nc(-c2ccncn2)cc1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 710 %

Procedure:
To a mixture of 1-methyl-2-[1-(2-piperidin-4-yl-ethyl)piperidin-4-yloxy]-1H-[4,4′]bipyrimidinyl-6-one (40 mg, 0.10 mmol), benzaldehyde (16 mg, 0.15 mmol) and acetic acid (one drop) in 1,2-dichloroethane (0.5 ml) was added sodium triacetoxyborohydride (53 mg, 0.25 mmol). The mixture was stirred at room temperature overnight. The mixture was partitioned between water and dichloromethane. The organic layer was washed with brine, dried over sodium sulfate, and concentrated in vacuo. The residue was purified by NH-silica gel column chromatography (eluent; hexane/ethyl acetate=20/80) to afford 2-{1-[2-(1-benzyl-piperidin-4-yl)ethyl]piperidin-4-yloxy}-1-methyl-1H-[4,4′]bipyrimidinyl-6-one as a colorless solid (35 mg, 0.71 mmol, 71%).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([O:57][CH:58]([CH3:60])[CH3:59])[C:7]([F:56])=[C:8]([CH:10]([NH:43][C:44]2[CH:49]=[CH:48][C:47]([C:50]3[N:54]=[C:53]([CH3:55])[O:52][N:51]=3)=[CH:46][CH:45]=2)[C:11]2[N:12]([C:24]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH:13]=[C:14]([C:16]3[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=3[CH:18]=[O:19])[N:15]=2)[CH:9]=1)[CH3:2].[CH3:61][CH2:62][Mg+].[Br-].CCOC(C)=O.[Na+].[Cl-]>C1COCC1>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([O:57][CH:58]([CH3:59])[CH3:60])[C:7]([F:56])=[C:8]([CH:10]([NH:43][C:44]2[CH:45]=[CH:46][C:47]([C:50]3[N:54]=[C:53]([CH3:55])[O:52][N:51]=3)=[CH:48][CH:49]=2)[C:11]2[N:12]([C:24]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH:13]=[C:14]([C:16]3[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=3[CH:18]([OH:19])[CH2:61][CH3:62])[N:15]=2)[CH:9]=1)[CH3:2]
Reactant: CCOc1cc(OC(C)C)c(F)c(C(Nc2ccc(-c3noc(C)n3)cc2)c2nc(-c3ccccc3C=O)cn2C(c2ccccc2)(c2ccccc2)c2ccccc2)c1
Reactant: CC[Mg+]
Agent: [Br-]
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOc1cc(OC(C)C)c(F)c(C(Nc2ccc(-c3noc(C)n3)cc2)c2nc(-c3ccccc3C(O)CC)cn2C(c2ccccc2)(c2ccccc2)c2ccccc2)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of Intermediate 122.1 (50 mg, 0.06 mmol) in THF (1 mL) was added EtMgBr dropwise at 0° C. under N2 atmosphere, the reaction mixture was stirred at 0° C. for 30 min. The reaction mixture was then partionated between EtOAc and sat. NaCl, the organic layer was collected and dried over (Na2SO4), filtered and concentrated. The crude material Intermediate 122.2 was used as is in the following step. LCMS (2 min gradient) RT=2.23 min, 828.4 (M+H).
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[H-].[Na+].[C:14]([C:16]1[CH:21]=[CH:20][C:19](Br)=[CH:18][CH:17]=1)#[N:15].Cl>O1CCOCC1>[C:14]([C:16]1[CH:21]=[CH:20][C:19]([CH:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:1]([O:9][CH2:10][CH3:11])=[O:8])=[CH:18][CH:17]=1)#[N:15]
Reactant: N#Cc1ccc(Br)cc1
Reactant: CCOC(=O)CC(=O)OCC
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CCOC(=O)C(C(=O)OCC)c1ccc(C#N)cc1
Temperature: 100 °C
Reaction time: 0.17 h

Procedure:
Diethyl malonate (0.49 mol) was added at approximately 60° C. over 2 hours to a suspension of sodium hydride (0.51 mol) in 140 ml of 1,4-dioxane. After stirring for a further 10 min, 0.05 mol of CuBr were added. After 15 min, 0.25 mol of 4-cyanobromobenzene in 10 ml of dioxane were added. The reaction mixture was maintained at 100° C. for approximately 14 hours and then, at approximately 15° C., 35 ml of 12N hydrochloric acid were slowly added. The precipitate was filtered off and the filtrate was extracted with diethyl ether. After phase separation, the organic phase was dried and then freed from the solvent. 32 g of the title compound remained.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:27]=[CH:26][C:16]([CH2:17][P:18](=[O:25])([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21])=[CH:15][CH:14]=2)[N:3]=1.[NH2:28][C:29]1[CH:38]=[CH:37][C:36]([C:39]#[N:40])=[CH:35][C:30]=1[C:31]([NH:33][CH3:34])=[O:32]>>[C:39]([C:36]1[CH:37]=[CH:38][C:29]([NH:28][C:2]2[C:7]([C:8]([F:10])([F:9])[F:11])=[CH:6][N:5]=[C:4]([NH:12][C:13]3[CH:14]=[CH:15][C:16]([CH2:17][P:18](=[O:25])([O:19][CH2:20][CH3:21])[O:22][CH2:23][CH3:24])=[CH:26][CH:27]=3)[N:3]=2)=[C:30]([C:31](=[O:32])[NH:33][CH3:34])[CH:35]=1)#[N:40]
Reactant: CNC(=O)c1cc(C#N)ccc1N
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)cc1)OCC
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(C#N)cc3C(=O)NC)n2)cc1)OCC
Yield: 21.8 %

Procedure:
The title compound was prepared using the procedure from Example 102 (Diethyl (4-{[4-{[4-fluoro-2-(methylcarbamoyl)phenyl]amino}-5-(trifluoromethyl)pyrimidin-2-yl]amino}-3-benzyl)phosphonate) with diethyl (4-{[4-chloro-5-(trifluoromethyl)pyrimidin-2-yl]amino}benzyl)phosphonate (10.0 mg, 0.0236 mmol) and 2-amino-5-cyano-N-methylbenzamide (Compound 150A, 8.3 mg, 0.0472 mmol). The crude mixture was purified by MDP to obtain the title compound as white solid (2.9 mg, 22% yield). 1H NMR (400 MHz, CD3OD) δ=1.28 (t, J=7.1 Hz, 6 H), 2.92 (s, 3 H), 3.26 (d, J=21.5 Hz, 2 H), 4.07 (qd, J=7.3, 7.1 Hz, 4 H), 7.28 (dd, J=8.8, 2.5 Hz, 2 H), 7.56 (d, J=6.3 Hz, 2 H), 7.76 (d, J=8.6 Hz, 1 H), 8.04 (d, J=1.8 Hz, 1 H), 8.42 (s, 1 H), 8.88 (br. s., 1 H). MS (ES+): m/z 563.17 (100) [MH+]; HPLC: tR=1.04 min (UPLC, purity).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)[CH:5]=[C:4]([C:18]([F:21])([F:20])[F:19])[N:3]=1.IC1C=C(C2C=CC(C(F)(F)F)=CC=2)C=C(C(F)(F)F)N=1.[Br:43][C:44]1[CH:45]=[C:46](B(O)O)[CH:47]=[CH:48][CH:49]=1>>[Br:43][C:44]1[CH:49]=[C:48]([C:2]2[CH:7]=[C:6]([C:8]3[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=3)[CH:5]=[C:4]([C:18]([F:21])([F:20])[F:19])[N:3]=2)[CH:47]=[CH:46][CH:45]=1
Reactant: OB(O)c1cccc(Br)c1
Reactant: FC(F)(F)c1ccc(-c2cc(Cl)nc(C(F)(F)F)c2)cc1
Agent: FC(F)(F)c1ccc(-c2cc(I)nc(C(F)(F)F)c2)cc1
Product: FC(F)(F)c1ccc(-c2cc(-c3cccc(Br)c3)nc(C(F)(F)F)c2)cc1

Procedure:
The title compound was prepared from a mixture of 2-chloro-6-trifluoromethyl-4-(4-trifluoromethyl-phenyl)-pyridine (example A.26) (65%) and 2-iodo-6-trifluoromethyl-4-(4-trifluoromethyl-phenyl)-pyridine (example A.49) (35%) (5.5 g, 4.62 mmol) and commercially available 3-bromo-benzene-boronic acid (1.02 g, 5.1 mmol) according to the general procedure IVb. Obtained as a white solid (1.43 g, 69%). MS (ISP) 446.0 [(M+H)+] and 448 [(M+2+H)+]
Reaction SMILES: [OH-].[Na+].[S:3]1[C:7]([NH2:8])=[N:6][CH:5]=[N:4]1.[C:9]([C:11]1[CH:12]=[C:13]([S:18](Cl)(=[O:20])=[O:19])[CH:14]=[CH:15][C:16]=1[F:17])#[N:10].Cl>O.O1CCOCC1>[C:9]([C:11]1[CH:12]=[C:13]([S:18]([NH:8][C:7]2[S:3][N:4]=[CH:5][N:6]=2)(=[O:20])=[O:19])[CH:14]=[CH:15][C:16]=1[F:17])#[N:10]
Reactant: Nc1ncns1
Reactant: N#Cc1cc(S(=O)(=O)Cl)ccc1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: N#Cc1cc(S(=O)(=O)Nc2ncns2)ccc1F
Reaction time: 0.08 h

Procedure:
Sodium hydroxide (5.08 g, 0.127 mmol) was dissolved in water (60 mL) and 1,4-dioxane (300 mL). 1,2,4-thiadiazol-5-amine (10 g, 100 mmol) was added and the reaction stirred for 5 minutes. 3-Cyano-4-fluorobenzene-1-sulfonyl chloride (8.25 g, 37.6 mmol) was added and the reaction was allowed to stir for 3 hours at 20° C. After this time, the reaction was poured into a 1M aqueous solution of hydrogen chloride (150 mL). This solution was extracted with ethyl acetate (3×50 mL). The combined organics were dried over sodium sulfate, filtered and concentrated to give the title compound as a brown solid.
Reaction SMILES: [C:1](#[N:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:9][C:10]1[CH:16]=[CH:15][C:13]([NH2:14])=[CH:12][CH:11]=1>>[CH3:9][C:10]1[CH:16]=[CH:15][C:13]([NH:14][C:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[NH:8])=[CH:12][CH:11]=1
Reactant: Cc1ccc(N)cc1
Reactant: N#Cc1ccccc1
Product: Cc1ccc(NC(=N)c2ccccc2)cc1
Yield: 55 %

Procedure:
The title compound was prepared from benzonitrile (0.96 g, 9 mmol) and 4-methylaniline (1 g, 9 mmol) by following the procedure described in preparation 10 (1.08 g, yield 55%, purity 98.42% by HPLC). 1H-NMR (CDCl3):δ 2.33 (s, 3H), 5 (bs, 2H, D2O exchangeable), 6.89-6.91 (d, 2H), 7.15-7.17 (d, 2H), 7.44-7.46 (m, 3H), 8 (bs, 2H). MS m/z:211.2 (M+).
Reaction SMILES: [CH:1]1[C:11]2[CH:10]=[CH:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[CH:6]([CH:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH3:22][C:23]([CH3:25])=O.[Al].N>CO>[CH:12]1[C:8]2[CH:9]=[CH:10][C:11]3[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=3[CH:6]([CH:16]3[CH2:17][CH2:18][N:19]([CH:23]([CH3:25])[CH3:22])[CH2:20][CH2:21]3)[C:7]=2[CH:15]=[CH:14][CH:13]=1
Reactant: CC(C)=O
Reactant: C1=Cc2ccccc2C(C2CCNCC2)c2ccccc21
Agent: N
Agent: [Al]
Solvent: CO
Product: CC(C)N1CCC(C2c3ccccc3C=Cc3ccccc32)CC1
Reaction time: 48 h

Procedure:
0.50 gram (1.8 millimoles) of 4-(5H-dibenzo[a,d]cyclohepten-5-yl)piperidine (prepared in a manner described in the preceding example), 3.96 grams (68.1 millimoles) of acetone and 5 milliliters of methanol were warmed gently to start dissolution. To this was added 0.30 gram (11 millimoles) of aluminum bits and a catalytic amount (0.01 gram; 0.04 millimole) of mercuric chloride and the resulting mixture stirred for 2.5 hours. A TLC analysis of the reaction mixture showed presence of some but minor amount of product. The mixture was stirred for 48 hours. A TLC analysis at this time (1 percent methanol/99 percent chloroform saturated with ammonia) indicated consumption of the starting material with the formation of a new product which was determined by 1H NMR to be a 4-(5H-dibenzo[a,d]cyclohepten-5-yl)-1-isopropylpiperidine product. The reaction mixture was filtered through a pad of celite and the solvent removed in vacuo to obtain a residue which after recrystallization from a minimum amount of hot acetonitrile and drying for 3.5 hours at 100° C./1 mm. Hg, was a white powder, m.p. 124°-126° C. The product had elemental analyses as follows:
Reaction SMILES: [C:1]1([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][C:4]([O:7][CH2:8][CH2:9][CH2:10][OH:11])=[CH:3][CH:2]=1.C[O:19][C:20](=[O:33])[CH:21]([O:30][CH2:31][CH3:32])[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25](O)[CH:24]=1.C1(C2C=CC=CC=2)C=CC(OCCOC2C=CC(C[C@H](OC)C(O)=O)=CC=2)=CC=1>>[C:1]1([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:6]=[CH:5][C:4]([O:7][CH2:8][CH2:9][CH2:10][O:11][C:27]2[CH:28]=[C:23]([CH2:22][CH:21]([O:30][CH2:31][CH3:32])[C:20]([OH:33])=[O:19])[CH:24]=[CH:25][CH:26]=2)=[CH:3][CH:2]=1
Reactant: OCCCOc1ccc(-c2ccccc2)cc1
Reactant: CCOC(Cc1cccc(O)c1)C(=O)OC
Agent: CO[C@@H](Cc1ccc(OCCOc2ccc(-c3ccccc3)cc2)cc1)C(=O)O
Product: CCOC(Cc1cccc(OCCCOc2ccc(-c3ccccc3)cc2)c1)C(=O)O

Procedure:
The title compound was prepared from 3-(biphenyl-4-yloxy)-propan-1-ol (Example 291, Step 6) and 2-ethoxy-3-(3-hydroxy-phenyl)-propionic acid methyl ester (Example 378, Step 4) via the same procedure used for the preparation of (2S)-3-{4-[2-(biphenyl-4-yloxy)-ethoxy]-phenyl}-2-methoxy-propionic acid (Example 283, Step 3) to produce a white solid. The crude material was submitted to chiral HPLC separation to afford the single enantiomer isomer 2. MS (ES) for C26H28O5 [M+NH4]+: 438.0, [M+Na]+: 443.0.
Reaction SMILES: [F:1][C:2]([O:6][C:7]1[CH:14]=[CH:13][C:10]([CH:11]=[O:12])=[CH:9][CH:8]=1)=[C:3]([F:5])[F:4].[BH4-].[Na+]>C1C=CC=CC=1.C(O)C>[F:1][C:2]([O:6][C:7]1[CH:14]=[CH:13][C:10]([CH2:11][OH:12])=[CH:9][CH:8]=1)=[C:3]([F:5])[F:4]
Reactant: O=Cc1ccc(OC(F)=C(F)F)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: c1ccccc1
Product: OCc1ccc(OC(F)=C(F)F)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 70 %

Procedure:
To a solution of 4-(trifluorovinyloxy)benzaldehyde (about 35 mmol) in benzene/ethanol (75/75 mL) at room temperature was added sodium borohydride (1.8 g, 1.3 eq). The resulting mixture was stirred at room temperature for 3 h. Under reduced pressure, all the solvent was evaporated. The residue was extracted by CH2Cl2 for 1 h and dried over sodium sulfate. The product was purified by chromatography using CH2Cl2 as the eluent to afford 4-(trifluorovinyloxy)benzyl alcohol as colorless oil (5.0 g, yield 68%). 1H NMR (CDCl3): δ 7.36 (d, J=8.8 Hz, 2H), 7.09 (d, J=8.8 Hz, 2H), 4.67 (s, 2H), 2.03 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[C:14]([CH2:22][N:23]([CH3:25])[CH3:24])[CH:15]=[C:16]([N+:19]([O-])=O)[CH:17]=3)[N:12]=[CH:11][C:10]=2[C:26]#[N:27])[CH:5]=[CH:6][CH:7]=1.C(O)(=O)C>[Fe].CO>[NH2:19][C:16]1[CH:17]=[C:18]2[C:13](=[C:14]([CH2:22][N:23]([CH3:24])[CH3:25])[CH:15]=1)[N:12]=[CH:11][C:10]([C:26]#[N:27])=[C:9]2[NH:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=1
Reactant: CN(C)Cc1cc([N+](=O)[O-])cc2c(Nc3cccc(Br)c3)c(C#N)cnc12
Agent: [Fe]
Solvent: CO
Solvent: CC(=O)O
Product: CN(C)Cc1cc(N)cc2c(Nc3cccc(Br)c3)c(C#N)cnc12
Yield: 59.8 %

Procedure:
A stirred mixture of 4-[(3-bromophenyl)amino]-8-dimethylaminomethyl-6-nitro-quinoline-3-carbonitrile (5.98 g, 14.1 mmol), iron powder (2.76 g, 49 mg-atoms), acetic acid (5.67 ml, 99 mmol), and 70 ml of methanol was refluxed for 2 h and then evaporated to remove methanol. The residue was stirred with water for 10 m, and the orange solid was filtered off and washed with 2% acetic acid. The total filtrate was basified to pH 10 with 5 N sodium hydroxide. The resulting precipitate was extracted with methylene chloride. The extract was washed with water, dried, and concentrated. The residue was subjected to chromatography on silica gel with ethyl acetate-methanol-triethylamine to give 3.34 g of amber solid; mass spectrum (electrospray, m/e) M+H 396.2, 398.1.