Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]([CH2:8][C:9]([OH:11])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:12][CH2:13][CH:14]([OH:26])[CH2:15][N:16]1[CH2:25][CH2:24][C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:17]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[CH2:17]1[C:18]2[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:24][CH2:25][N:16]1[CH2:15][CH:14]([OH:26])[CH2:13][NH:12][C:9](=[O:11])[CH2:8][O:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)COc1ccccc1
Reactant: NCC(O)CN1CCc2ccccc2C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Product: O=C(COc1ccccc1)NCC(O)CN1CCc2ccccc2C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 33.9 %

Procedure:
To a stirred mixture of 2-phenoxyacetic acid (100 mg, 0.658 mmol) in DCM (10 mL) was added TEA (200 mg, 1.98 mmol), 1-amino-3-(3,4-dihydroisoquinolin-2(1H)-yl)propan-2-ol (135 mg, 0.658 mmol) and HATU (250 mg, 0.658 mmol). The mixture was stirred at 25° C. for 16 hours then quenched with water (20 mL) and extracted with DCM (3×20 mL). The combined extracts were washed with brine (20 mL), dried over anhydrous Na2SO4 and concentrated. The residue was then purified by prep-HPLC to afford the title compound (76 mg, 34% yield). 1H NMR (400 MHz, CDCl3): δ 7.31-7.27 (m, 2H), 7.14-7.08 (m, 3H), 7.05-6.98 (m, 2H), 6.93 (d, J=8.0 Hz, 2H), 4.54 (s, 2H), 4.55-4.52 (m, 1H), 4.42 (s, 2H), 4.06-4.00 (m, 1H), 3.71 (s, 2H), 3.48-3.38 (m, 2H), 2.91 (d, J=5.6 Hz, 2H), 2.84 (d, J=5.6 Hz, 2H), 2.60 (d, J=6.8 Hz, 2H) ppm. LCMS (m/z): 341.2 [M+H]+.
Reaction SMILES: C1(C(C2C=CC=CC=2)[N:8]2[CH2:11][CH:10]([CH:12]([C:17]3[CH:18]=[C:19]([CH:25]=[C:26]([F:28])[CH:27]=3)[C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:13]([F:16])([CH3:15])[CH3:14])[CH2:9]2)C=CC=CC=1.OCC1(OC[C@@H](O)[C@@H](O)[C@H]1O)O.[H][H]>CCO.[OH-].[OH-].[Pd+2]>[NH:8]1[CH2:11][CH:10]([CH:12]([C:17]2[CH:18]=[C:19]([CH:25]=[C:26]([F:28])[CH:27]=2)[C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:13]([F:16])([CH3:15])[CH3:14])[CH2:9]1
Reactant: [H][H]
Reactant: CCOC(=O)c1cc(F)cc(C(C2CN(C(c3ccccc3)c3ccccc3)C2)C(C)(C)F)c1
Agent: [Pd+2]
Agent: OCC1(O)OC[C@@H](O)[C@@H](O)[C@H]1O
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)c1cc(F)cc(C(C2CNC2)C(C)(C)F)c1

Procedure:
Ethyl 3-{1-[1-(diphenylmethyl)azetidin-3-yl]-2-fluoro-2-methylpropyl}-5-fluorobenzoate (7.6 g, 16.40 mmol) was hydrogenated in 150 mL of EtOH in the presence 3.4 g of Pd(OH)2 under 50 Psi pressure hydrogen for 24 h. Then it was filtered to remove the solid and washed with CH2Cl2. The combined organic layer was concentrated and washed with hexanes/ether to afford the title compound as an white solid. Mass Spectrum: m/e=298 (M+1).
Reaction SMILES: [NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][C:4]([OH:6])=[O:5].[CH2:10](O)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.O.[C:19]1([CH3:29])[CH:24]=[CH:23][C:22]([S:25]([OH:28])(=[O:27])=[O:26])=[CH:21][CH:20]=1.C1C=CC=CC=1>O>[C:19]1([CH3:29])[CH:20]=[CH:21][C:22]([S:25]([OH:28])(=[O:26])=[O:27])=[CH:23][CH:24]=1.[NH2:1][C@H:2]([C:7]([O:9][CH2:29][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:8])[CH2:3][C:4]([O:6][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:5]
Reactant: N[C@@H](CC(=O)O)C(=O)O
Reactant: OCc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: N[C@@H](CC(=O)OCc1ccccc1)C(=O)OCc1ccccc1
Temperature: 25 °C

Procedure:
A stirred mixture of L-aspartic acid (399 g.; 3.00 moles), benzyl alcohol (1.95 kg.; 18.0 moles), p-toluenesulfonic acid monohydrate (582 g.; 3.06 moles), and dry benzene (1.2 l.) was heated at reflux for 16 hours. The water formed in the reaction (145 ml.) was removed by means of a Dean-Stark trap. The resulting solution was cooled to room temperature, then diluted with benzene (1.2 l.) and ether (3.6 l.). The resulting solid was collected on a filter, washed with ether (7.0 l.), and dried; yield, 1195 g. (82%). The crude product was recrystallized from methanol (1720 ml.) to give 959 g. (80% recovery) of purified (I): m.p., 158°-159.5°; literature m.p., 158°-160°. Additional reactions were carried out to give a total of 4.27 kg. of product suitable for further transformation.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#N)=[CH:6][N:5]=[C:4]([S:10][CH3:11])[N:3]=1.[H-].C([Al+]CC(C)C)C(C)C.Cl.C([O-])([O-])=[O:24].[Na+].[Na+]>C1COCC1>[NH2:1][C:2]1[C:7]([CH:8]=[O:24])=[CH:6][N:5]=[C:4]([S:10][CH3:11])[N:3]=1
Reactant: O=C([O-])[O-]
Reactant: CSc1ncc(C#N)c(N)n1
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: C1CCOC1
Product: CSc1ncc(C=O)c(N)n1
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 53.1 %

Procedure:
To a solution of 4-amino-2-(methylthio)pyrimidine-5-carbonitrile (3.0 g, 18.05 mmol) in THF (100 mL) is added diisobutylaluminum hydride (41.52 mL, 1.0 M in CH2Cl2, 41.52 mmol) at 0° C. After the mixture is stirred for 2.5 hours at 0° C., hydrochloric acid (2N, 30 mL) is added and stirring is continued for 20 minutes. To the reaction mixture is added saturated Na2CO3 until a pH of 8 is achieved. The suspended material is filtered through Celit pad and washed with K2CO3 solution. The solution is diluted with EtOAc and washed with saturated K2CO3, brine and dried, filtered and concentrated to give crude product, which is purified by flash silica gel column, eluting with hexane (100%) gradient to hexane/ether (60/40%), to give the title intermediate as a solid (1.62 g, 53.1%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:13][CH3:14])=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][C:8]([Cl:12])=[CH:7]2.[CH:15](OCC)(OCC)OCC>>[CH3:14][N:13]1[C:3]2[CH:4]=[CH:5][C:6]3[CH:7]=[C:8]([Cl:12])[CH:9]=[N:10][C:11]=3[C:2]=2[N:1]=[CH:15]1
Reactant: CCOC(OCC)OCC
Reactant: CNc1ccc2cc(Cl)cnc2c1N
Product: Cn1cnc2c3ncc(Cl)cc3ccc21
Temperature: 0 °C

Procedure:
24.9 g (0.12 mol) of 8-amino-3-chloro-7-methylaminoquinoline and 107 g (0.72 mol) of triethyl orthoformate are heated at 100° C. for 30 min. The mixture is then cooled to 0° C., and the precipitate (32 g) is filtered off with suction. The mother liquor is concentrated under reduced pressure, and the residue is recrystallized from ethyl acetate/petroleum ether. The two solids obtained in this way are identical. Yield: 48.5 g (82%); melting point 188° to 189° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[C:5]([OH:7])=[O:6].C(=O)(O)[O-].[Na+].[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[C:5]([O:7][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:6]
Reactant: BrCc1ccccc1
Reactant: O=C(O)c1ccc([N+](=O)[O-])c(F)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(OCc1ccccc1)c1ccc([N+](=O)[O-])c(F)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A suspension of 3-fluoro-4-nitroberizoic acid (33.0 g) in anhydrous DMF (300 ml) was cooled to 0° C., treated with sodium bicarbonate (13.5 g) and stirred for 30 min. The mixture was treated dropwise with benzyl bromide (19.0 ml) stirred for a further 30 min then allowed to warm to room temperature while stirring overnight (18 h). The resulting orange solution was evaporated under reduced pressure and the residue partitioned between ethyl acetate (1200 ml) and saturated aqueous sodium carbonate (1600 ml). The organic layer was split into 2×600 ml portions and each was washed with water (2×500 ml), brine (200 ml), dried over anhydrous magnesium sulfate then filtered. The filtrates were combined and evaporated under reduced pressure to give the title compound (38.2 g) as an orange oil which crystallised on standing overnight.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=O)[CH:5]=[N:6][CH:7]=1.C(O)(=O)[CH2:11][C:12]([OH:14])=[O:13].N1CCCCC1>N1C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:11][C:12]([OH:14])=[O:13])[CH:5]=[N:6][CH:7]=1
Reactant: O=Cc1cncc(F)c1
Reactant: O=C(O)CC(=O)O
Solvent: C1CCNCC1
Solvent: c1ccncc1
Product: O=C(O)C=Cc1cncc(F)c1
Temperature: 110 °C
Reaction time: 2 h
Yield: 34 %

Procedure:
A mixture of 1.1 g of the crude 5-fluoro-3-pyridinecarbaldehyde, 1.8 g of malonic acid, 0.15 ml of piperidine, and 7 ml of pyridine is stirred at 110° C. for 2 hours. The reaction mixture is concentrated, and 20 ml of water is added. The resulting precipitate is collected and washed with cold water to give 0.5 g of the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:18]([O:19][CH3:20])=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([CH2:11][C:12]([N:14]([CH3:16])[CH3:15])=[O:13])[CH2:9][CH2:10][C:4]=2[CH:3]=1.Cl[C:22]1[N:27]=[C:26]([NH:28][C:29]2[CH:30]=[CH:31][C:32]([N:40]3[CH2:45][CH2:44][N:43]([CH:46]([CH3:48])[CH3:47])[CH2:42][CH2:41]3)=[C:33]3[C:37]=2[C:36](=[O:38])[N:35]([CH3:39])[CH2:34]3)[C:25]([Cl:49])=[CH:24][N:23]=1>>[Cl:49][C:25]1[C:26]([NH:28][C:29]2[CH:30]=[CH:31][C:32]([N:40]3[CH2:45][CH2:44][N:43]([CH:46]([CH3:47])[CH3:48])[CH2:42][CH2:41]3)=[C:33]3[C:37]=2[C:36](=[O:38])[N:35]([CH3:39])[CH2:34]3)=[N:27][C:22]([NH:1][C:2]2[C:18]([O:19][CH3:20])=[CH:17][C:5]3[CH2:6][CH2:7][N:8]([CH2:11][C:12]([N:14]([CH3:16])[CH3:15])=[O:13])[CH2:9][CH2:10][C:4]=3[CH:3]=2)=[N:23][CH:24]=1
Reactant: CC(C)N1CCN(c2ccc(Nc3nc(Cl)ncc3Cl)c3c2CN(C)C3=O)CC1
Reactant: COc1cc2c(cc1N)CCN(CC(=O)N(C)C)CC2
Product: COc1cc2c(cc1Nc1ncc(Cl)c(Nc3ccc(N4CCN(C(C)C)CC4)c4c3C(=O)N(C)C4)n1)CCN(CC(=O)N(C)C)CC2

Procedure:
The title compound was prepared from 2-(7-amino-8-methoxy-1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-N,N-dimethylacetamide (41 mg, 0.15 mmol) and 7-(2,5-dichloropyrimidin-4-ylamino)-4-(4-isopropylpiperazin-1-yl)-2-methyl-2,3-dihydroisoindol-1-one (60 mg, 0.1 mmol) in an analogous manner to Example 946 to afford a tan foam (79 mg, 80%). Mp: 78-80° C. LCMS (m/e) 676 (M+1); 1H-NMR (CDCl3, 400 MHz) δ 10.58 (s, 1H), 8.68 (d, J=9 Hz, 1H), 8.10 (s, 2H), 7.39 (s, 1H), 7.09 (d, J=9 Hz, 1H), 6.68 (s, 1H), 4.40 (s, 2H), 3.91 (s, 3H), 3.54 (s, 3H), 3.35 (s, 2H), 3.24 (s, 3H), 3.20 (s, 3H), 3.11-2.88 (m, 6H), 2.80-2.65 (m, 8H), 1.82 (m, 1H), 1.12 (d, J=6 Hz, 6H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11](=[O:13])[N:10]([CH:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[CH2:9][CH2:8][C:7]=2[CH:20]=1.Cl[C:22]1[CH:27]=[CH:26][N:25]=[C:24]([C:28]([N:30]2[C:38]3[C:33](=[C:34]([F:40])[C:35]([F:39])=[CH:36][CH:37]=3)[CH2:32][CH2:31]2)=[O:29])[CH:23]=1.C(=O)([O-])[O-].[K+].[K+]>CN1C(=O)CCC1>[F:40][C:34]1[C:35]([F:39])=[CH:36][CH:37]=[C:38]2[C:33]=1[CH2:32][CH2:31][N:30]2[C:28]([C:24]1[CH:23]=[C:22]([N:17]2[CH2:18][CH2:19][CH:14]([N:10]3[CH2:9][CH2:8][C:7]4[CH:20]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=4[NH:12][C:11]3=[O:13])[CH2:15][CH2:16]2)[CH:27]=[CH:26][N:25]=1)=[O:29]
Reactant: COc1ccc2c(c1)CCN(C1CCNCC1)C(=O)N2
Reactant: O=C(c1cc(Cl)ccn1)N1CCc2c1ccc(F)c2F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: COc1ccc2c(c1)CCN(C1CCN(c3ccnc(C(=O)N4CCc5c4ccc(F)c5F)c3)CC1)C(=O)N2

Procedure:
0.18 g (0.67 mmol) 7-methoxy-3-piperidin-4-yl-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one, 0.20 g (0.68 mmol) (4-chloro-pyridin-2-yl)-(4,5-difluoro-2,3-dihydro-indol-1-yl)-methanone and 97 mg (0.70 mmol) potassium carbonate were stirred in 3 mL of NMP for 4 h at 130° C. and overnight at RT. The reaction mixture was purified by HPLC. The product-containing fractions were combined and freeze-dried.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][N:9]=[C:8]([C:11]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=3)[C:7]=2[CH:18]=1.[C-:19]#[N:20].[Na+]>CN(C)C=O>[Cl:17][C:14]1[CH:15]=[CH:16][C:11]([C:8]2[C:7]3[CH:18]=[C:3]([CH2:2][C:19]#[N:20])[CH:4]=[CH:5][C:6]=3[O:10][N:9]=2)=[CH:12][CH:13]=1
Reactant: [C-]#N
Reactant: Clc1ccc(-c2noc3ccc(CBr)cc23)cc1
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#CCc1ccc2onc(-c3ccc(Cl)cc3)c2c1

Procedure:
A mixture of 5-bromomethyl-3-(4-chlorophenyl)-1,2-benzisoxazole (45 g.) and sodium cyanide (7.4 g.) in dry dimethylformamide (800 ml.) was heated on a steam bath for 3 hours. The mixture was filtered and the filtrate was evaporated to dryness, to give 3-(4-chlorophenyl)-1,2-benzisoxazol-5-ylacetonitrile (m.p. 118°C.).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH:12]([C:14]2[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][CH:15]=2)[O:11][CH2:10][C:9]1=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B.C1COCC1.CO>C1COCC1>[CH2:1]([N:8]1[CH2:9][CH2:10][O:11][CH:12]([C:14]2[CH:15]=[CH:16][C:17]([Br:20])=[CH:18][CH:19]=2)[CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1COC(c2ccc(Br)cc2)CN1Cc1ccccc1
Agent: B
Solvent: CO
Solvent: C1CCOC1
Product: Brc1ccc(C2CN(Cc3ccccc3)CCO2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.6 %

Procedure:
To a solution of 4-benzyl-6-(4-bromo-phenyl)-morpholin-3-one (21.3 g; 62 mmol) in THF (350 mL) was added BH3.THF in THF (1M, 155 mL; 155 mmol) dropwise, at 0° C. After 1 hour the mixture was allowed to warm to RT and stirred for another 2 hours. To the reaction mixture was added MeOH (300 mL), at 0° C., the resulting mixture was stirred at RT for 3 days, and subsequently concentrated in vacuo. The residue was partitioned between EtOAc and 1 M aqueous NaOH-solution. The organic layer was dried (Na2SO4), filtered, and concentrated in vacuo to afford 4-benzyl-2-(4-bromo-phenyl)-morpholine (20.1 g), which was used as such in the next step.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[C:5]([C:12]([N:14]2[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=3[CH2:18][N:17]3[CH:25]=[CH:26][CH:27]=[C:16]3[CH2:15]2)=[O:13])=[CH:4][N:3]=1.[H-].[Na+].[CH3:30][C:31]1[CH:32]=[N:33][NH:34][CH:35]=1>CN(C)C=O>[CH3:30][C:31]1[CH:32]=[N:33][N:34]([C:2]2[N:7]=[C:6]([C:8]([F:9])([F:11])[F:10])[C:5]([C:12]([N:14]3[C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=4[CH2:18][N:17]4[CH:25]=[CH:26][CH:27]=[C:16]4[CH2:15]3)=[O:13])=[CH:4][N:3]=2)[CH:35]=1
Reactant: Cc1cn[nH]c1
Reactant: O=C(c1cnc(Cl)nc1C(F)(F)F)N1Cc2cccn2Cc2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cnn(-c2ncc(C(=O)N3Cc4cccn4Cc4ccccc43)c(C(F)(F)F)n2)c1
Yield: 66.7 %

Procedure:
In the manner of Example 9's Method 1, employing (2-chloro-4-trifluoromethyl-pyrimidin-5-yl)-(5H,11H-pyrrolo[2,1-c][1,4]benzodiazepin-10-yl)-methanone (0.98 g), 60% sodium hydride in oil (0.15 g), 4-methylpyrazole (0.42 g) and dimethylformamide (25 ml), the title compound (0.73 g) was obtained as a crystalline solid, m.p. 214-217° C.
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][C:5]([O:31][CH3:32])=[C:6]2[C:10]([C:11](=[O:30])[C:12]([N:14]3[CH2:23][CH2:22][C:21]4[C:16](=[CH:17][CH:18]=[CH:19][C:20]=4[C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=4)[CH2:15]3)=[O:13])=[CH:9][NH:8][C:7]=12.[F:33][C:34]([F:41])([F:40])[C:35]1[N:39]=[CH:38][NH:37][N:36]=1.CN[C@@H]1CCCC[C@@H]1NC.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.[Cu]I>[CH3:32][O:31][C:5]1[CH:4]=[N:3][C:2]([N:37]2[CH:38]=[N:39][C:35]([C:34]([F:41])([F:40])[F:33])=[N:36]2)=[C:7]2[NH:8][CH:9]=[C:10]([C:11](=[O:30])[C:12]([N:14]3[CH2:23][CH2:22][C:21]4[C:16](=[CH:17][CH:18]=[CH:19][C:20]=4[C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=4)[CH2:15]3)=[O:13])[C:6]=12
Reactant: FC(F)(F)c1nc[nH]n1
Reactant: COc1cnc(Br)c2[nH]cc(C(=O)C(=O)N3CCc4c(cccc4-c4ccccn4)C3)c12
Agent: [Cu]I
Agent: CN[C@H]1CCCC[C@H]1NC
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: COc1cnc(-n2cnc(C(F)(F)F)n2)c2[nH]cc(C(=O)C(=O)N3CCc4c(cccc4-c4ccccn4)C3)c12
Temperature: 100 °C

Procedure:
A mixture of 1-(7-bromo-4-methoxy-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-(5-(pyridin-2-yl)-3,4-dihydroisoquinolin-2(1H)-yl)ethane-1,2-dione (100 mg, 0.204 mmol), 3-(trifluoromethyl)-1H-1,2,4-triazole (55.8 mg, 0.407 mmol), (1R,2S)—N1,N2-dimethylcyclohexane-1,2-diamine (5.79 mg, 0.041 mmol), copper (I) iodide (19.38 mg, 0.102 mmol) and potassium carbonate (84 mg, 0.611 mmol) in dioxane (1 mL) was heated at 100° C. for 4 hours. LCMS indicated that the desired product was generated. The reaction mixture was filtered and the clear solution was purified by prep. HPLC to give 1-(4-methoxy-7-(3-(trifluoromethyl)-1H-1,2,4-triazol-1-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-(5-(pyridin-2-yl)-3,4-dihydroisoquinolin-2(1H)-yl)ethane-1,2-dione as white solid (35 mg, 30%). LCMS: m/e 548.18 (M+H)+, 2.50 min (method 10). 1H NMR (500 MHz, MeOD) δ ppm 2.85-3.08 (m, 2H) 3.74-4.04 (m, 5H) 4.81-5.09 (m, 2H) 7.37-7.71 (m, 3H) 7.88-7.96 (m, 1H) 7.97-8.18 (m, 2H) 8.33-8.43 (m, 1H) 8.52-8.70 (m, 1H) 8.82-8.96 (m, 1H) 9.51 (s, 1H).
Reaction SMILES: [H-].[Al+3].[H-].[H-].[CH2:5]([O:12][C:13]1[CH:22]=[CH:21][C:20]([CH:23]([O:26][CH3:27])[O:24][CH3:25])=[CH:19][C:14]=1[C:15](OC)=[O:16])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.O.[OH-].[Na+]>O1CCCC1>[CH2:5]([O:12][C:13]1[CH:22]=[CH:21][C:20]([CH:23]([O:24][CH3:25])[O:26][CH3:27])=[CH:19][C:14]=1[CH2:15][OH:16])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: COC(=O)c1cc(C(OC)OC)ccc1OCc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COC(OC)c1ccc(OCc2ccccc2)c(CO)c1
Reaction time: 0.08 h
Yield: 98.7 %

Procedure:
7 g of aluminum hydride was suspended in 200 ml tetrahydrofuran under ice-cooling, and a solution of 39.08 g of methyl 2-(benzyloxy)-5-(dimethoxymethyl)benzoate in 100 ml tetrahydrofuran was added thereto. After stirring for 5 minutes, water, 15% sodium hydroxide and water were added thereto and filtered. The filtrate was evapoarated, to give 35.15 g of 2-(benzyloxy)-5-(dimethoxymethyl)benzyl alcohol. This crude product was dissolved in 250 ml toluene, and 40 g of diphenyl phosphoryl azide and 22 ml diazabicylo[5.4.0]undecene were added, followed by stirring overnight at room temperature. Water was added to the reaction product, followed by extracting with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and the solvent was evapoarated. The residue was purified by silica gel column chromatography, and from fractions eluted with hexane-ethyl acetate (15:1), 17.4 g of 4-(benzyloxy)-3-(azidomethyl)dimethoxymethylbenzene was obtained. This product was left for 1 month at room temperature and purified by silica gel column chromatography, and from fractions eluted with hexane-ethyl acetate (12:1), 9.39 g of 4-(benzyloxy)-3-(azidomethyl)benzaldehyde was obtained.
Reaction SMILES: [S:1](Cl)([CH3:4])(=[O:3])=[O:2].Cl.[NH2:7][C:8]1[CH:9]=[CH:10][C:11]2[N:12]([C:14]([C:17]([C:19]3[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[C:21]([O:28][CH3:29])[CH:20]=3)=[O:18])=[N:15][CH:16]=2)[CH:13]=1>N1C=CC=CC=1.Cl>[CH3:29][O:28][C:21]1[CH:20]=[C:19]([CH:24]=[CH:23][C:22]=1[N+:25]([O-:27])=[O:26])[C:17]([C:14]1[N:12]2[CH:13]=[C:8]([NH:7][S:1]([CH3:4])(=[O:3])=[O:2])[CH:9]=[CH:10][C:11]2=[CH:16][N:15]=1)=[O:18]
Reactant: COc1cc(C(=O)c2ncc3ccc(N)cn23)ccc1[N+](=O)[O-]
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Product: COc1cc(C(=O)c2ncc3ccc(NS(C)(=O)=O)cn23)ccc1[N+](=O)[O-]
Temperature: 5 °C
Reaction time: 18 h
Yield: 91.6 %

Procedure:
0.107 ml (1.38 mmol) of mesyl chloride is added to 0.40 g (1.15 mmol) of (6-aminoimidazo[1,5-a]pyridin-3-yl) (3-methoxy-4-nitrophenyl)methanone hydrochloride in 10 ml of pyridine cooled to 5° C. and the mixture is allowed to return to ambient temperature and is stirred for 18 hours. The medium is taken up in 130 ml of 1N hydrochloric acid and extracted with ethyl acetate. The organic phase is washed with a saturated aqueous sodium chloride solution, then dried over sodium sulfate and concentrated under reduced pressure. The residue is taken up in isopropyl ether, filtered off, washed with isopropyl ether and then dried. 411 mg of a yellow solid are obtained. Melting point: 249° C.; 1H NMR (d6-DMSO): 3.14 (3H, s), 4.02 (3H, s), 7.39 (1H, d), 7.94 (1H, s), 8.02-8.11 (3H, m), 8.13 (1H, s), 9.88 (1H, s)
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[N:12][C:13](Cl)=[CH:14][CH:15]=2)[CH:10]=[C:9]1[C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:28]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[NH:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31].C([O-])([O-])=O.[Cs+].[Cs+]>C1(C)C=CC=CC=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.NC1C=CC=CC=1C1C=CC=CC=1[Pd]Cl>[CH2:1]([N:8]1[C:16]2[C:11](=[N:12][C:13]([N:28]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[NH:29][C:30]([O:32][C:33]([CH3:34])([CH3:35])[CH3:36])=[O:31])=[CH:14][CH:15]=2)[CH:10]=[C:9]1[C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(OCc1ccccc1)c1cc2nc(Cl)ccc2n1Cc1ccccc1
Reactant: CC(C)(C)OC(=O)NNC(=O)OC(C)(C)C
Agent: Nc1ccccc1-c1ccccc1[Pd]Cl
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)NN(C(=O)OC(C)(C)C)c1ccc2c(cc(C(=O)OCc3ccccc3)n2Cc2ccccc2)n1
Temperature: 110 °C
Reaction time: 5 h

Procedure:
Benzyl 1-benzyl-5-chloro-1H-pyrrolo[3,2-b]pyridine-2-carboxylate (1.13 g, 3.00 mmol, from Step 1) and di-tert-butyl hydrazine-1,2-dicarboxylate (0.77 g, 3.3 mmol, Aldrich), dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine-(2′-aminobiphenyl-2-yl)(chloro)palladium (1:1) (0.24 g, 0.30 mmol, Aldrich) and Cs2CO3 (0.98 g, 3.0 mmol, Aldrich) were combined in toluene (27 mL) and the mixture was degassed by bubbling a stream of nitrogen through the solution for 10 minutes. The reaction was stirred at 110° C. for 5 hours. The reaction mixture was partitioned between water and ethyl acetate, the aqueous was extracted three times, the combined organic extracts were dried over sodium sulfate, filtered and concentrated. Flash chromatography, eluting with a gradient from 0-40% EtOAc in hexanes was used to purify the product. Yield: (1.12 g, 65%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:11]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=2)[N:10]2[CH:21]=[CH:22][N:23]=[C:9]2[NH:8][C:7]=1[CH:24]=[N:25]O)=[O:5])[CH3:2].C([O-])(=O)C.[Na+].C(OC(=O)C)(=O)C.O>C(O)(=O)C>[C:24]([C:7]1[NH:8][C:9]2[N:10]([CH:21]=[CH:22][N:23]=2)[CH:11]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=2)[C:6]=1[C:4]([O:3][CH2:1][CH3:2])=[O:5])#[N:25]
Reactant: CCOC(=O)C1=C(C=NO)Nc2nccn2C1c1cccc([N+](=O)[O-])c1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: CCOC(=O)C1=C(C#N)Nc2nccn2C1c1cccc([N+](=O)[O-])c1
Yield: 42.1 %

Procedure:
A solution of 6-ethoxycarbonyl-7-hydroxyiminomethyl-5-(3-nitrophenyl)-5,8-dihydroimidazo[1,2-a]pyrimidine (1.25 g), 0.29 g of sodium acetate and 0.4 ml of acetic anhydride in 15 ml of acetic acid is stirred with heating at 80°-90° C. for 30 minutes. The reaction solution is poured into water and precipitated crystals are collected by filtration. Recrystallization from a mixture of chloroform and ethanol gives 0.5 g of 7-cyano-6-ethoxycarbonyl-5-(3-nitrophenyl)-5,8-dihydroimidazo[1,2-a]pyrimidine, melting at 260°-261° C. with decomposition.
Reaction SMILES: BrC1C=[C:4]([C@@H:8]2[C@@H:12]([C:13]3[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=3F)[O:11][C:10](=[O:21])[NH:9]2)C=NC=1.Cl.Cl.N[C@H](C1[N:40]=[C:39]([Cl:41])[CH:38]=[CH:37][N:36]=1)[C@@H](C1C=CC=C(F)C=1)O.O.C(O)(C(F)(F)F)=O>CC#N>[Cl:41][C:39]1[CH:38]=[CH:37][N:36]=[C:4]([C@@H:8]2[C@@H:12]([C:13]3[CH:14]=[CH:15][CH:16]=[C:17]([F:19])[CH:18]=3)[O:11][C:10](=[O:21])[NH:9]2)[N:40]=1
Reactant: O=C1N[C@H](c2cncc(Br)c2)[C@@H](c2cc(F)ccc2F)O1
Reactant: N[C@H](c1nccc(Cl)n1)[C@H](O)c1cccc(F)c1
Agent: Cl
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: O=C1N[C@H](c2nccc(Cl)n2)[C@@H](c2cccc(F)c2)O1

Procedure:
Prepared according to the same procedure as (4R,5R)-4-(5-bromopyridin-3-yl)-5-(2,5-difluorophenyl)oxazolidin-2-one, starting with (1R,2R)-2-amino-2-(4-chloropyrimidin-2-yl)-1-(3-fluorophenyl)ethanol 2HCl, Analytical HPLC method: Phenomenex LUNA C18, 50×2 3μ, A=90% H2O/10% CH3CN, B=90% CH3CN/10% H2O, Modifier 0.1% TFA, 0.00 min=0% B, 4.0 min=100% B, 5.0 min=100% B, Flow rate=0.8 mL/min., TR=2.483 min, Mass spec.: 294.1 (MH)+.