Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=1.[H-].[Na+]>CN(C=O)C>[CH:2]([C:11]1[CH:6]=[CH:7][C:8]([O:1][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=3)[CH:5]=[CH:4][C:3]=2[C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=2)=[CH:9][CH:10]=1)=[O:1]
Reactant: COc1cccc(-c2ccc3cc(OC)ccc3c2O)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cccc(-c2ccc3cc(OC)ccc3c2Oc2ccc(C=O)cc2)c1
Temperature: 70 °C

Procedure:
A solution was prepared of 9.8 g (35 mmol) of 1-hydroxy-2-(3-methoxyphenyl)-6-methoxynaphthalene in 490 mL of DMF under a nitrogen atmosphere and to this solution was slowly added 1.47 g (36.8 mmol) of 60% NaH in mineral oil. After ten minutes, 7.5 mL (70 mmol) of 4-fluorobenzaldehdye was added and the reaction mixture was heated to 70° C. for sixty-four hours. The reaction mixture was evaporated to dryness and the residue partioned between water and EtOAc. The EtOAc layer was dried with Na2SO4 and chromatographed on a silica gel column eluted with EtOAc-hexane (1:9)(v/v). The final product was further purified by crystallization from MeOH. This yielded 2.4 g of the title compound as a tan solid, mp 145-146° C.
Reaction SMILES: [C:1]([C:3]1[N:7]2[CH:8]=[C:9]([C:12]3[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=3)[CH:10]=[CH:11][C:6]2=[N:5][CH:4]=1)#[CH:2].Br[C:23]1[S:27][C:26]([S:28]([NH2:31])(=[O:30])=[O:29])=[CH:25][CH:24]=1>>[F:19][C:18]([F:20])([F:21])[C:15]1[CH:16]=[CH:17][C:12]([C:9]2[CH:10]=[CH:11][C:6]3[N:7]([C:3]([C:1]#[C:2][C:23]4[S:27][C:26]([S:28]([NH2:31])(=[O:30])=[O:29])=[CH:25][CH:24]=4)=[CH:4][N:5]=3)[CH:8]=2)=[CH:13][CH:14]=1
Reactant: C#Cc1cnc2ccc(-c3ccc(C(F)(F)F)cc3)cn12
Reactant: NS(=O)(=O)c1ccc(Br)s1
Product: NS(=O)(=O)c1ccc(C#Cc2cnc3ccc(-c4ccc(C(F)(F)F)cc4)cn23)s1

Procedure:
The title compound was prepared from 3-ethynyl-6-(4-trifluoromethyl-phenyl)-imidazo[1,2-a]pyridine (example C.24) (400 mg, 1.3 mmol) and commercially available 5-bromothiophene-2-sulfonamide (338 mg, 1.3 mmol) according to general procedure II. Obtained as a white solid (90 mg, 14%). MS (ISP) 448.1 [(M+H)+]; mp 206-210° C.
Reaction SMILES: Cl.[NH2:2][C:3]1[N:4]=[C:5](Cl)[C:6]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[NH:9][C:7]=2[N:8]=1.[Br:17][C:18]1[CH:19]=[C:20]([CH:22]=[CH:23][CH:24]=1)[NH2:21]>CC(O)C.CO>[NH2:2][C:3]1[N:4]=[C:5]([NH:21][C:20]2[CH:22]=[CH:23][CH:24]=[C:18]([Br:17])[CH:19]=2)[C:6]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[NH:9][C:7]=2[N:8]=1
Reactant: Nc1nc(Cl)c2c(n1)[nH]c1ccccc12
Reactant: Nc1cccc(Br)c1
Agent: Cl
Solvent: CO
Solvent: CC(C)O
Product: Nc1nc(Nc2cccc(Br)c2)c2c(n1)[nH]c1ccccc12
Reaction time: 18 h
Yield: 16 %

Procedure:
A mixture of 2-amino-4-chloroindolo[2,3-d]pyrimidine hydrochloride (123 mg, 0.6 mmol) and 3-bromoaniline (0.3 mL, 2.8 mmol) in 2-propanol (6 mL) is heated at reflux for 4 hr, filtered through a celite pad, and concentrated in vacuo. The residue is partitioned between ethyl acetate (25 mL) and water (25 mL). The aqueous phase is extracted with further ethyl acetate (2×20 mL), followed by washing the combined extracts with 1% aqueous sodium hydroxide (25 mL), water (2×40 mL) , saturated brine (40 mL), and drying (Na2SO4). The solution is evaporated to dryness under reduced pressure to afford 105 mg crude product as a tan powder. The solid is dissolved in a minimum amount of methanol, filtered, and further purified by preparative plate chromatography (SiO2; 1:1, EtOAc:CH2Cl2; Rf=0.40). After extraction of the product from the silica gel with ethyl acetate, the volume of the warm solution is reduced to minimum, an d it is filtered through celite, and the solvent is removed under reduced pressure. The oily solid thus obtained is dissolved in a minimum amount of 2-propanol and allowed to crystallize at 3 C. over an 18 h period. The crystals are collected by suction filtration, washed with a small amount of cold 2-propanol, and dried in vacuo to give 2-amino-4-(3-bromoanilino)indolo[2,3-d]pyrimidine (34 mg, 17%). 1HNMR, (DMSO): δbrs), 8.57 (1H, s), 8.11 (1H, d, J=8.0 Hz), 8.01 (1H, s), 7.94 (1H, d, J=8.2 Hz), 7.34-7.12 (5H, m), 6.41 (2H, brs).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C:20]([OH:22])=[O:21])[CH2:10][C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[NH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC1C=CC(S(O[CH2:34][CH2:35][F:36])(=O)=O)=CC=1>>[C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:10][C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]([CH2:34][CH2:35][F:36])[CH:12]=1)[C:20]([OH:22])=[O:21])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1ccc(S(=O)(=O)OCCF)cc1
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1c[nH]c2ccccc12)C(=O)O
Product: CC(C)(C)OC(=O)N[C@H](Cc1cn(CCF)c2ccccc12)C(=O)O
Yield: 66.8 %

Procedure:
The procedure of Referential Example 1(a) was repeated, except that N-tert-butoxycarbonyl-D-tryptophan (700 mg) and 2-fluoroethyl 4-methylbenzenesulfonate (753 mg) were used, whereby the title compound (538 mg) was yielded.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6](=[O:19])[NH:7][CH2:8][CH2:9][CH2:10][C:11]([C:13]1[N:14]([CH3:18])[CH:15]=[CH:16][N:17]=1)=[O:12])([CH3:4])[CH3:3].CB1N2CCC[C@H]2C(C2C=CC=CC=2)(C2C=CC=CC=2)O1.B>O1CCCC1>[CH3:4][C:2]([O:5][C:6](=[O:19])[NH:7][CH2:8][CH2:9][CH2:10][C@@H:11]([OH:12])[C:13]1[N:14]([CH3:18])[CH:15]=[CH:16][N:17]=1)([CH3:1])[CH3:3]
Reactant: Cn1ccnc1C(=O)CCCNC(=O)OC(C)(C)C
Agent: B
Agent: CB1OC(c2ccccc2)(c2ccccc2)[C@@H]2CCCN12
Solvent: C1CCOC1
Product: Cn1ccnc1[C@H](O)CCCNC(=O)OC(C)(C)C
Yield: 41.4 %

Procedure:
The product of step (a) (0.60 g, 2.24 mmol) was reacted with (3aS)-tetrahydro-1-methyl-3,3-diphenyl-3H-pyrrolo[1,2-c][1,3,2]oxazaborole (1M in toluene, 0.22 ml) and borane:tetrahydrofuran complex (1M, 1.5 ml, 1.5 mmol) in tetrahydrofuran (40 ml) using the procedure described in Example 1 step (a) to give the sub-title compound as a colourless oil (0.25 g, 42%).
Reaction SMILES: Cl[C:2]1[CH:10]=[C:9]([Cl:11])[C:8]([S:12]([CH3:15])(=[O:14])=[O:13])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH2:16]([NH2:22])[C:17]1[O:21][CH:20]=[CH:19][CH:18]=1>Cl>[CH2:16]([NH:22][C:2]1[CH:10]=[C:9]([Cl:11])[C:8]([S:12]([CH3:15])(=[O:14])=[O:13])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5])[C:17]1[O:21][CH:20]=[CH:19][CH:18]=1
Reactant: CS(=O)(=O)c1cc(C(=O)O)c(Cl)cc1Cl
Reactant: NCc1ccco1
Agent: Cl
Product: CS(=O)(=O)c1cc(C(=O)O)c(NCc2ccco2)cc1Cl
Temperature: 125 °C

Procedure:
A mixture of 2,4-dichloro-5-methylsulfonylbenzoic acid (15 g.; 0.055 mole) and furfurylamine (30 ml.) is heated in an oil bath at 125° C. under an atmosphere of nitrogen for 3 hours then poured into cold, dilute hydrochloric acid (200 ml.) to precipitate 17.6 g., (98%) of 2-furfurylamino-4-chloro-5-methylsulfonylbenzoic acid, m.p. 204° C. (dec.) after recrystallization from nitromethane (200 ml.).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][OH:10])=[CH:4][CH:3]=1.CCN(CC)CC.[C:18](Cl)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C1COCC1>[C:18]([O:10][CH2:9][CH2:8][C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=1)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: OCCc1ccc(Br)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(OCCc1ccc(Br)cc1)c1ccccc1
Temperature: 23 °C
Reaction time: 4 h
Yield: 98.9 %

Procedure:
To a mixture of 2-(4-bromophenyl)ethanol (1.00 g, 4.97 mmol, 1.00 equiv) and Et3N (0.763 ml, 0.554 g, 5.47 mmol, 1.10 equiv) in a round-bottom flask in THF (20 ml) was added benzoyl chloride (0.589 mL, 0.713 g, 5.07 mmol, 1.02 equiv). The reaction mixture was stirring for 4 h at 23 ° C. and concentrated in vacuo. The residue was purified by chromatography on silica gel eluting with hexanes/EtOAc 1:1 (v/v) to afford 1.50 g of the title compound as a colorless solid (99%). Rf=0.7 (hexanes/EtOAc 1:1 (v/v)). NMR Spectroscopy: 1H NMR (500 MHz, CDCl3, 23 ° C., δ): 8.00 (d, J=7.2 Hz, 1H), 7.58-7.54 (m, 1H), 7.45-7.42 (m, 4H), 7.16 (d, J=8.4 Hz, 2H), 4.51 (t, J=6.4 Hz, 2H), 3.04 (t, J=6.4 Hz, 2H). 13C NMR (125 MHz, CDCl3, 23 ° C., δ): 166.6, 137.1, 133.1, 131.8, 130.8, 130.3, 129.7, 128.5, 120.6, 65.2, 34.8.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[C:11]([N:15]3[CH2:20][CH2:19][CH2:18][C@@H:17]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:16]3)[CH:12]=[CH:13][CH:14]=2)O1.Cl[C:31]1[C:39]2[C:34](=[CH:35][N:36]=[C:37]([C:40]3[CH:41]=[N:42][N:43]([CH3:45])[CH:44]=3)[CH:38]=2)[N:33]([CH:46]2[CH2:51][CH2:50][CH2:49][CH2:48][O:47]2)[N:32]=1>>[CH3:45][N:43]1[CH:44]=[C:40]([C:37]2[CH:38]=[C:39]3[C:31]([C:9]4[CH:10]=[C:11]([N:15]5[CH2:20][CH2:19][CH2:18][C@@H:17]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:25])([CH3:26])[CH3:27])[CH2:16]5)[CH:12]=[CH:13][CH:14]=4)=[N:32][N:33]([CH:46]4[CH2:51][CH2:50][CH2:49][CH2:48][O:47]4)[C:34]3=[CH:35][N:36]=2)[CH:41]=[N:42]1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCN(c2cccc(B3OC(C)(C)C(C)(C)O3)c2)C1
Reactant: Cn1cc(-c2cc3c(Cl)nn(C4CCCCO4)c3cn2)cn1
Product: Cn1cc(-c2cc3c(-c4cccc(N5CCC[C@@H](NC(=O)OC(C)(C)C)C5)c4)nn(C4CCCCO4)c3cn2)cn1
Yield: 60 %

Procedure:
Following the Suzuki coupling procedure in Example 172, (R)-tert-butyl 1-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperidin-3-ylcarbamate and 3-chloro-5-(1-methyl-1H-pyrazol-4-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridine were reacted to give tert-butyl (3R)-1-(3-(5-(1-methyl-1H-pyrazol-4-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazo-lo[3,4-c]pyridin-3-yl)phenyl)piperidin-3-ylcarbamate as a solid (60%). 1H NMR (400 MHz, CDCl3) δ 9.12 (s, 1H), 7.97 (s, 1H), 7.95 (s, 1H), 7.93 (s, 1H), 7.34 (t, J=7.8 Hz, 1H), 7.26 (s, 1H), 7.19 (s, 1H), 6.73 (d, J=8.4 Hz, 1H), 5.90-5.83 (m, 1H), 4.09-4.00 (m, 2H), 3.97 (s, 3H), 3.88-3.76 (m, 2H), 3.67 (s, 1H), 3.52 (s, 1H), 3.17 (s, 1H), 3.03 (s, 1H), 2.64-2.52 (m, 1H), 2.17 (d, J=10.1 Hz, 2H), 2.09-1.99 (m, 1H), 1.84-1.70 (m, 5H), 1.65-1.54 (m, 1H), 1.41 (s, 9H). LC/MS: m/z 558.2 [M+1].
Reaction SMILES: [CH:1]([C@H:3]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4]1)=[CH2:2].Br[C:16]1[CH:17]=[N:18][CH:19]=[C:20]([O:22][CH:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[CH:21]=1.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.C(N(C(C)C)CC)(C)C>CN1CCCC1=O.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[O:26]1[CH2:27][CH2:28][CH:23]([O:22][C:20]2[CH:21]=[C:16](/[CH:2]=[CH:1]/[C@H:3]3[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4]3)[CH:17]=[N:18][CH:19]=2)[CH2:24][CH2:25]1
Reactant: C=C[C@H]1CCN(C(=O)OC(C)(C)C)C1
Reactant: Brc1cncc(OC2CCOCC2)c1
Agent: [Pd+2]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: CC(=O)[O-]
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN1CCCC1=O
Product: CC(C)(C)OC(=O)N1CC[C@H](/C=C/c2cncc(OC3CCOCC3)c2)C1
Temperature: 130 °C
Reaction time: 17 h
Yield: 82.7 %

Procedure:
A mixture of tert-butyl (R)-3-vinylpyrrolidine-1-carboxylate 9 (7.00 g, 35.5 mmol), 3-bromo-5-(tetrahydro-2H-pyran-4-yloxy)pyridine 12 (10.0 g, 38.8 mmol), palladium acetate (0.40 g, 1.8 mmol), tricyclohexylphosphine (1.0 g, 3.57 mmol) and diisopropylethylamine (15 mL) in 1-methyl-2-pyrrolidinone (130 mL) was stirred at 130° C. for 17 h. The reaction was cooled to ambient temperature, diluted with water (800 mL) and extracted with ethyl acetate (2×200 mL). The combined organic extracts were dried over sodium sulfate, concentrated, and purified by silica gel column chromatography using 60-100% ethyl acetate in hexanes. This product was further purified on reverse phase HPLC using 0.05% trifluoroacetic acid in acetonitrile and 0.05% trifluoroacetic acid in water to obtain tert-butyl (R)-(E)-3-(2-(5-(tetrahydro-2H-pyran-4-yloxy)pyridin-3-yl)vinyl)pyrrolidine-1-carboxylate (11.0 g) as a gum. 1H-NMR (CDCl3, 400 MHz): δ 8.41 (s, 1 H), 8.37 (d, J=2.3 Hz, 1 H), 7.68 (s, 1 H), 6.48 d, J=16.1 Hz, 1 H), 6.43 (dd, J=16.0, 6.4 Hz, 1 H), 4.71-4.66 (m, 1 H), 4.02-3.96 (m, 2 H), 3.68-3.52 (m, 4 H), 3.44-3.34 (m, 1 H), 3.28-3.15 (m, 1 H), 3.09-2.98 (m, 1 H), 2.18-2.04 (m, 3 H), 1.90-1.78 (m, 3 H), 1.48 (s, 9 H)
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH:13][CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][C:23](=[O:32])[N:24]([CH3:31])[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[CH:18][CH:17]=2)(=[O:12])=[O:11])=[CH:6][CH:5]=1)([O-])=O>[Pd].C(O)C>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH:13][CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][C:23](=[O:32])[N:24]([CH3:31])[C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)=[CH:18][CH:17]=2)(=[O:12])=[O:11])=[CH:6][CH:5]=1
Reactant: CN(C(=O)Oc1ccc(CCNS(=O)(=O)c2ccc([N+](=O)[O-])cc2)cc1)c1ccccc1
Agent: [Pd]
Solvent: CCO
Product: CN(C(=O)Oc1ccc(CCNS(=O)(=O)c2ccc(N)cc2)cc1)c1ccccc1
Yield: 94 %

Procedure:
Methyl-phenyl-carbamic acid 4-[2-(4-nitro-benzenesulfonylamino)-ethyl]-phenyl ester, 5% palladium on carbon, and ethanol were stirred under hydrogen at 1 bar and rt for 16 h. Filtration and removal of ethanol produced the title compound in 94% yield as an oil. HPLC-MS: m/z=426.1 (M+1); Rt=3.61 min.
Reaction SMILES: S(=O)(=O)(O)O.[N+:6]([O-:9])([O-])=[O:7].[Na+].[Br:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[OH:18]>O.C(OCC)(=O)C>[Br:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([N+:6]([O-:9])=[O:7])[C:13]=1[OH:18]
Reactant: O=[N+]([O-])[O-]
Reactant: Oc1ccccc1Br
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: O=[N+]([O-])c1cccc(Br)c1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 42.5 %

Procedure:
A solution of 60 mL of concentrated sulfuric acid diluted with 186 mL of water was cooled to room temperature. Sodium nitrate (79.2 g, 0.93 mol) was added to the solution. 2-Bromo-phenol 1a (60 mL, 0.52 mol) was added dropwise at such a rate that the reaction temperature was kept below 25° C. The reaction mixture was stirred at room temperature for 2 hours. The precipitate was dissolved in 320 mL of ethyl acetate. The mixture was washed with water and saturated brine, dried over anhydrous magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound 2-bromo-6-nitro-phenol 1b (48.2 g, yield 42.8%) as a yellow solid.
Reaction SMILES: [I-].[K+].CS(O[CH2:8][CH2:9][O:10][C:11]1[C:19]2[C:14](=[N:15][CH:16]=[N:17][C:18]=2[NH:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][C:28]3[CH:29]=[N:30][C:31]([CH3:34])=[CH:32][CH:33]=3)=[C:23]([F:35])[CH:22]=2)[NH:13][N:12]=1)(=O)=O.[OH:36][CH:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1>>[F:35][C:23]1[CH:22]=[C:21]([NH:20][C:18]2[N:17]=[CH:16][N:15]=[C:14]3[NH:13][N:12]=[C:11]([O:10][CH2:9][CH2:8][N:40]4[CH2:41][CH2:42][CH:37]([OH:36])[CH2:38][CH2:39]4)[C:19]=23)[CH:26]=[CH:25][C:24]=1[O:27][C:28]1[CH:29]=[N:30][C:31]([CH3:34])=[CH:32][CH:33]=1
Reactant: OC1CCNCC1
Reactant: Cc1ccc(Oc2ccc(Nc3ncnc4[nH]nc(OCCOS(C)(=O)=O)c34)cc2F)cn1
Agent: [I-]
Agent: [K+]
Product: Cc1ccc(Oc2ccc(Nc3ncnc4[nH]nc(OCCN5CCC(O)CC5)c34)cc2F)cn1
Yield: 39 %

Procedure:
The procedure described in Example 23 was repeated (except that potassium iodide was not used) using 2-{[4-({3-fluoro-4-[(6-methylpyridin-3-yl)oxy]phenyl}amino)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]oxy}ethyl methanesulfonate and 4-hydroxypiperidine to give the title compound in 39% yield; NMR Spectrum: 1.37 (m, 1H), 1.67 (d, 1H), 2.16 (t, 1H), 2.45 (s, 3H), 2.78 (t, 2H), 4.42 (t, 2H), 4.54 (d, 1H), 7.23 (m, 3H), 7.56 (dd, 1H), 8.01 (dd, 1H), 8.24 (d, 1H), 8.36 (s, 1H), 8.66 (br s, 1H); Mass Spectrum: 480 (MH+).
Reaction SMILES: [C:1]([Si:4]([CH3:7])([CH3:6])[CH3:5])(=O)[CH3:2].[C:8](#[N:12])[CH2:9][C:10]#[N:11].C([O-])(=O)C.[NH4+].C(O)(=O)C>CCOC(C)=O.C1C=CC=CC=1>[CH3:5][Si:4]([CH3:7])([CH3:6])[C:1](=[C:9]([C:8]#[N:12])[C:10]#[N:11])[CH3:2]
Reactant: N#CCC#N
Reactant: CC(=O)[Si](C)(C)C
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: c1ccccc1
Product: CC(=C(C#N)C#N)[Si](C)(C)C
Temperature: 95 °C
Yield: 80 %

Procedure:
To a mixture of acetyltrimethylsilane (1.0 g, 8.6 mmol), malononitrile (625 mg, 9.46 mmol) and ammonium acetate (126 mg, 1.64 mmol), acetic acid (394 μL, 6.88 mmol) and benzene (30 mL) were added. The reaction flask was attached to a Dean-Stark trap filled with benzene and the solution was heated to 95° C. for 3 h. The orange reaction mixture was cooled, diluted with EtOAc, washed with saturated aqueous NaHCO3 and brine, dried over anhydrous MgSO4, and concentrated. The residue was purified by column chromatography on silica gel (using a solvent gradient from 1% to 30% EtOAc in hexanes) to give 2-(1-(trimethylsilyl)ethylidene) malononitrile as colorless oil (1.13 g, 79.8%).
Reaction SMILES: [CH:1]1([N:7]([CH2:17][CH:18]2[CH2:20][CH2:19]2)[C:8]2[N:13]=[CH:12][N:11]=[C:10]([C:14]([OH:16])=O)[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:21][C:22]1[CH:30]=[CH:29][C:25]([C:26]([NH2:28])=[O:27])=[CH:24][CH:23]=1>C(Cl)Cl>[NH2:28][C:26]([C:25]1[CH:29]=[CH:30][C:22]([NH:21][C:14]([C:10]2[CH:9]=[C:8]([N:7]([CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)[CH2:17][CH:18]3[CH2:20][CH2:19]3)[N:13]=[CH:12][N:11]=2)=[O:16])=[CH:23][CH:24]=1)=[O:27]
Reactant: O=C(O)c1cc(N(CC2CC2)C2CCCCC2)ncn1
Reactant: NC(=O)c1ccc(N)cc1
Solvent: ClCCl
Product: NC(=O)c1ccc(NC(=O)c2cc(N(CC3CC3)C3CCCCC3)ncn2)cc1
Yield: 85 %

Procedure:
Following the general method as outlined in Example 1, starting from 6-[cyclohexyhcyclopropylmethyl)amino]pyrimidine-4-carboxylic acid (Intermediate 13) and 4-aminobenzamide (Aldrich), the title compound was obtained as a brown solid in 85% yield after trituration in DCM.
Reaction SMILES: [F:1][C:2]1([F:35])[CH2:8][N:7]([CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:6]2[N:17]=[C:18]([NH:21][C:22]3[CH:30]=[CH:29][C:25]([C:26]([OH:28])=O)=[CH:24][C:23]=3[O:31][CH3:32])[N:19]=[CH:20][C:5]=2[N:4]([CH3:33])[C:3]1=[O:34].C(N(C(C)C)C(C)C)C.[O:45]1[CH2:50][CH2:49][CH:48]([NH2:51])[CH2:47][CH2:46]1>CN(C)C=O>[F:35][C:2]1([F:1])[CH2:8][N:7]([CH2:9][CH2:10][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:6]2[N:17]=[C:18]([NH:21][C:22]3[CH:30]=[CH:29][C:25]([C:26]([NH:51][CH:48]4[CH2:49][CH2:50][O:45][CH2:46][CH2:47]4)=[O:28])=[CH:24][C:23]=3[O:31][CH3:32])[N:19]=[CH:20][C:5]=2[N:4]([CH3:33])[C:3]1=[O:34]
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(CCc1ccccc1)CC(F)(F)C(=O)N2C
Reactant: NC1CCOCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cc(C(=O)NC2CCOCC2)ccc1Nc1ncc2c(n1)N(CCc1ccccc1)CC(F)(F)C(=O)N2C
Temperature: 25 °C
Reaction time: 1 h
Yield: 72.7 %

Procedure:
To a mixture of 0.08 g (0.17 mmole) of 4-(7,7-difluoro-5-methyl-6-oxo-9-phenethyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-benzoic acid (I-275), 0.12 mL (0.64 mmole) of ethyldiisopropyl amine and 0.018 g (0.19 mmole) of tetrahydro-pyran-4-ylamine in 2.0 mL of dimethylformamide was added 0.079 g (0.19 mmole) of 1-(di-1-pyrrolidinylmethylene)-1H-benzotriazolium 3-oxide hexafluorophosphate. The mixture was stirred at room temperature for 1 hour, then diluted with 10 mL of ice water. The mixture was extracted with dichloromethane 3 times. The combined organic layers were washed three times with sodium carbonate, three times with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification by silica gel chromatography, eluting with dichloromethane-methanol (gradient, 100:0-95:5) gave 0.070 g of 4-(7,7-difluoro-5-methyl-6-oxo-9-phenethyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-(tetrahydro-pyran-4-yl)-benzamide (I-280) as a white solid.
Reaction SMILES: [CH:1]([O:4][C:5]1[C:14]([CH3:15])=[CH:13][CH:12]=[C:11]2[C:6]=1[CH2:7][C@@H:8]([CH:20]1[CH2:25][CH2:24][N:23]([C:26](=O)[CH:27]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH2:28][CH3:29])[CH2:22][CH2:21]1)[O:9][C@H:10]2[CH2:16][NH:17][CH:18]=O)([CH3:3])[CH3:2].C(Cl)Cl.[OH-].[Na+].O>[H-].[Al+3].[Li+].[H-].[H-].[H-].C(OCC)C>[CH:1]([O:4][C:5]1[C:14]([CH3:15])=[CH:13][CH:12]=[C:11]2[C:6]=1[CH2:7][C@@H:8]([CH:20]1[CH2:21][CH2:22][N:23]([CH2:26][CH:27]([C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH2:28][CH3:29])[CH2:24][CH2:25]1)[O:9][C@H:10]2[CH2:16][NH:17][CH3:18])([CH3:2])[CH3:3]
Reactant: CCC(C(=O)N1CCC([C@@H]2Cc3c(ccc(C)c3OC(C)C)[C@H](CNC=O)O2)CC1)c1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: ClCCl
Solvent: CCOCC
Product: CCC(CN1CCC([C@@H]2Cc3c(ccc(C)c3OC(C)C)[C@H](CNC)O2)CC1)c1ccccc1
Temperature: 25 °C

Procedure:
Dissolve N-{(1R,3S)-5-isopropoxy-6-methyl-3-[1-(2-phenyl-butyryl)-piperidin-4-yl]-isochroman-1-ylmethyl}formamide (0.10 g, 0.20 mmole) in 1M lithium aluminum hydride in diethyl ether (1.5 mL) and bring to reflux. After 3.5 hr cool to room temperature, add methylene chloride (2 mL) followed by dropwise addition of 10% NaOH until no further reaction is observed. Add 2 mL of methylene chloride and 4 mL of water and filter reaction mixture and wash the filter cake with additional methylene chloride and water. Combine the organic phases and dry over Na2SO4. Purify the crude product on a 4 g silica gel column (eluting with methylene chloride and then methylene chloride:methanol:ammonium hydroxide 89:10:1). Collect the appropriate fractions and concentrate to obtain the title compound. It was used without further purification in the next step.
Reaction SMILES: C(OC(=O)[NH:10][C:11]1([C:14]2[N:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[O:16][N:15]=2)[CH2:13][CH2:12]1)C1C=CC=CC=1.[BrH:24]>C(O)(=O)C.CCOCC>[BrH:24].[F:22][C:19]([F:20])([F:21])[C:17]1[O:16][N:15]=[C:14]([C:11]2([NH2:10])[CH2:12][CH2:13]2)[N:18]=1
Reactant: O=C(NC1(c2noc(C(F)(F)F)n2)CC1)OCc1ccccc1
Agent: Br
Solvent: CCOCC
Solvent: CC(=O)O
Product: NC1(c2noc(C(F)(F)F)n2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
[1-(5-Trifluoromethyl-1,2,4-oxadiazol-3-yl)-cyclopropyl]-carbamic acid benzyl ester (0.22 g, 0.67 mmol) was dissolved in 33% HBr in acetic acid (0.5 mL) and the reaction allowed to stir for 30 min at RT. The mixture was diluted with Et2O resulting is formation of a white precipitate. The majority of the liquid was decanted off and the residue concentrated under reduce pressure to give 1-(5-trifluoromethyl-1,2,4-oxadiazol-3-yl)-cyclopropylamine hydrobromide (0.19 g, 0.69 mmol) as an orange solid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([O:18][CH3:19])=[CH:15][CH:16]=3)[O:11][C:10](=[O:20])[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.C[O-].[Na+].[CH2:24](Br)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>CO>[CH2:24]([O:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([O:18][CH3:19])=[CH:15][CH:16]=3)[O:11][C:10](=[O:20])[CH:9]=2)[CH:5]=[CH:6][CH:7]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: COc1ccc2c(-c3cccc(O)c3)cc(=O)oc2c1
Reactant: BrCc1ccccc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc2c(-c3cccc(OCc4ccccc4)c3)cc(=O)oc2c1
Temperature: 45 °C
Reaction time: 3 h
Yield: 89 %

Procedure:
4-[3′-(hydroxy)phenyl]-7-methoxycoumarin (prepared as in Example 1 (ii) (268 g) and 95% sodium methoxide (102 g) were dissolved in methanol (3.00 L) and stirred while heating to 45° C. Benzyl bromide (314 g) was added and the reaction was heated to 60° C. A thick precipitate formed in the pink reaction mixture. After 3 hours, the slurry was cooled in an ice-water bath and filtered to collect the product, which was washed with methanol (500 mL) and water (1.0 L), then dried under vacuum (20 inches of Hg) at 70° C. to give 4-[3-(benzyloxy)phenyl]-7-methoxycoumarin (320 g, 89%).