Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[CH:6]2.C([BH3-])#N.[Na+].O.[OH-].[Na+]>C(O)(=O)C>[F:13][C:2]([F:1])([F:12])[C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH2:7][CH2:6]2
Reactant: FC(F)(F)c1ccc2[nH]ccc2c1
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: FC(F)(F)c1ccc2c(c1)CCN2
Temperature: 25 °C
Reaction time: 2 h
Yield: 42.2 %

Procedure:
5-Trifluoromethylindole (D5, 1.0 g, 0.0057 mole) in glacial acetic acid (25 ml) was treated with sodium cyanoborohydride (1.7 g, 0.027 mole) under argon and stirred at room temperature for 2 hours. The mixture was poured into water (200 ml), basified with 40% aqueous sodium hydroxide solution, extracted into DCM, dried (Na2SO4) and evaporated in vacuo. The residue was chromatographed on silica gel eluting with 20% ethyl acetate/60-80° petroleum ether to afford the title compound (0.45 g, 45%) as a pale yellow oil.
Reaction SMILES: [C-]#N.[Na+].Br[C:5]1[C:6]2[CH:13]=[CH:12][CH:11]=[CH:10][C:7]=2[S:8][CH:9]=1.[CH3:14][NH:15]CCNC.[OH-].[NH4+]>[Cu]I.O.C(OCC)(=O)C.C1(C)C=CC=CC=1>[S:8]1[CH:9]=[C:5]([C:14]#[N:15])[C:6]2[CH:13]=[CH:12][CH:11]=[CH:10][C:7]1=2
Reactant: Brc1csc2ccccc12
Reactant: CNCCNC
Agent: [Cu]I
Agent: [C-]#N
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: Cc1ccccc1
Product: N#Cc1csc2ccccc12
Temperature: 110 °C
Reaction time: 24 h
Yield: 74.3 %

Procedure:
An oven dried screw cap test tube was charged with NaCN (60 mg, 1.225 mmol), dried KI (34 mg, 0.205 mmol, 20 mol %) and CuI (20 mg, 0.105 mmol, 10 mol %), evacuated and backfilled with argon three times. 3-Bromo-benzo[b]thiophene (135 μL, 1.032 mmol), N,N′-dimethylethylenediamine (110 μL, 1.033 mmol) and anhydrous toluene (700 μL) were added under argon. The tube was sealed and the reaction mixture was stirred magnetically at 110° C. for 24 h. The resulting suspension was cooled to room temperature, 2 mL of ethyl acetate, 1 mL of ammonium hydroxide (30%) and 1 mL of water were added. The mixture was stirred at 25° C. for 10 min, then the organic layer was separated and the aqueous layer was extracted three times with ethyl acetate (3×2 mL). The combined organic layers were washed with 5 mL of water and dried over MgSO4. The solvent was removed at reduced pressure. Purification of the residue by flash chromatography on silica gel (2×15 cm; hexane/ethyl acetate 10:1) provided 122 mg (74% yield) of the title compound as a pale yellow solid.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][N:11]3[N:14]=[C:15]([CH2:17][O:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH:16]=[C:10]3[C:9]2=[O:25])[CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH:32]1(B(O)O)[CH2:34][CH2:33]1>CN(C=O)C.O1CCOCC1.O.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>[CH:32]1([C:2]2[N:7]=[C:6]([N:8]3[CH2:13][CH2:12][N:11]4[N:14]=[C:15]([CH2:17][O:18][C:19]5[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=5)[CH:16]=[C:10]4[C:9]3=[O:25])[CH:5]=[CH:4][CH:3]=2)[CH2:34][CH2:33]1
Reactant: OB(O)C1CC1
Reactant: O=C1c2cc(COc3ccccc3)nn2CCN1c1cccc(Br)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: C1COCCO1
Solvent: O
Product: O=C1c2cc(COc3ccccc3)nn2CCN1c1cccc(C2CC2)n1
Temperature: 150 °C
Reaction time: 0.25 h
Yield: 64.7 %

Procedure:
Tetrakis(triphenylphosphine)palladium (0) (7 mg, 0.006 mmol), was added to a stirred suspension of 5-(6-bromo-pyridin-2-yl)-2-phenoxymethyl-6,7-dihydro-5H-pyrazolo[1,5-a]pyrazin-4-one (50 mg, 0.12 mmol), potassium carbonate (52 mg, 0.37 mmol), cyclopropylboronic acid (21.5 mg, 0.25 mmol) in a mixture of DMF (0.5 mL) and 1,4-dioxane (0.5 mL) in a sealed tube and under nitrogen. The mixture was stirred at 150° C. for 15 minutes under microwave irradiation. The mixture was diluted with water and extracted with AcOEt. The organic layer was washed with brine, dried (MgSO4), filtered and the solvents evaporated in vacuo. The crude product was purified by flash column chromatography (silica; AcOEt in DCM 0/100 to 20/80). The desired fractions were collected and the solvents evaporated in vacuo. The product was triturated with heptane to yield 5-(6-cyclopropyl-pyridin-2-yl)-2-phenoxymethyl-6,7-dihydro-5H-pyrazolo[1,5-a]pyrazin-4-one (28 mg, 62% yield) as a white solid. 1H NMR (500 MHz, CDCl3) δ ppm 0.93-1.03 (m, 4H), 1.97-2.06 (m, 1H), 4.44-4.58 (m, 4H), 5.12 (s, 2H), 6.93-7.04 (m, 4H), 7.05 (s, 1H), 7.27-7.34 (m, 2H), 7.58 (t, J=7.8 Hz, 1H), 7.74-7.80 (m, 1H).
Reaction SMILES: [CH:1]1([C:6]([OH:8])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.[C:32]([O:36][C:37]([N:39]1[C@@H:44]([C@@H:45]([OH:57])[C@@H:46]([NH2:56])[CH2:47][C:48]2[CH:53]=[C:52]([F:54])[CH:51]=[C:50]([F:55])[CH:49]=2)[CH2:43][O:42][C@@H:41]([O:58][CH2:59][C:60]([CH3:63])([CH3:62])[CH3:61])[CH2:40]1)=[O:38])([CH3:35])([CH3:34])[CH3:33].C(N(CC)CC)C>ClCCl>[C:32]([O:36][C:37]([N:39]1[C@@H:44]([C@@H:45]([OH:57])[C@@H:46]([NH:56][C:6]([CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)=[O:8])[CH2:47][C:48]2[CH:49]=[C:50]([F:55])[CH:51]=[C:52]([F:54])[CH:53]=2)[CH2:43][O:42][C@@H:41]([O:58][CH2:59][C:60]([CH3:63])([CH3:62])[CH3:61])[CH2:40]1)=[O:38])([CH3:33])([CH3:35])[CH3:34]
Reactant: CC(C)(C)CO[C@H]1CN(C(=O)OC(C)(C)C)[C@@H]([C@@H](O)[C@@H](N)Cc2cc(F)cc(F)c2)CO1
Reactant: O=C(O)C1CCCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)(C)CO[C@H]1CN(C(=O)OC(C)(C)C)[C@@H]([C@@H](O)[C@H](Cc2cc(F)cc(F)c2)NC(=O)C2CCCC2)CO1
Yield: 98.3 %

Procedure:
Stir cyclopentanecarboxylic acid (0.01 mL, 0.12 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCl) (0.02 g, 0.12 mmol) and 1-hydroxybenzotriazole monohydrate (HOBT) (0.02 g, 0.12 mmol) in dichloromethane (1 mL) at room temperature for 30 minutes. Add (2R,5R)-5-[(1S,2S)-2-amino-3-(3,5-difluorophenyl)-1-hydroxypropyl]-2-(2,2-dimethylpropoxy)-morpholine-4-carboxylic acid tert-butyl ester (0.05 g, 0.11 mmol) in dichloromethane (1 mL) and triethylamine (0.06 mL, 0.44 mmol) and stir at room temperature overnight. Wash with saturated aqueous sodium bicarbonate, dry (magnesium sulfate), filter, concentrate and purify (silica gel chromatography, eluting with 80:20 hexane:ethyl acetate), to give the desired compound as white solid (0.06 g, 98%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:31])[C:5]([NH:9][C:10]([C:12]1[CH:21]=[C:20]([Cl:22])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]=1[O:23][CH2:24][CH:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1)=[O:11])([CH3:8])[CH2:6][CH3:7])[CH3:2].[C:32](Cl)(=[O:34])[CH3:33].CCN(CC)CC>ClCCl>[CH2:1]([O:3][C:4](=[O:31])[C:5]([NH:9][C:10]([C:12]1[CH:21]=[C:20]([Cl:22])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]=1[O:23][CH2:24][CH:25]1[CH2:26][CH2:27][N:28]([C:32](=[O:34])[CH3:33])[CH2:29][CH2:30]1)=[O:11])([CH3:8])[CH2:6][CH3:7])[CH3:2]
Reactant: CCOC(=O)C(C)(CC)NC(=O)c1cc(Cl)c2ccccc2c1OCC1CCNCC1
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)C(C)(CC)NC(=O)c1cc(Cl)c2ccccc2c1OCC1CCN(C(C)=O)CC1
Reaction time: 8 h

Procedure:
To a solution of 70 mg of 2-{[4-chloro-1-(piperidin-4-yl-methoxy)-naphthalene-2-carbonyl]-amino}-2-methyl-butyric acid ethyl ester in 4 mL dichloromethane was added 0.026 ml of acetyl chloride followed by addition of 0.13 mL Et3N. This mixture was stirred overnight. The mixture was concentrated and chromatographed on silica with 7 N NH3 in MeOH/dichloromethane to give 76 mg of 2-{[1-(1-acetyl-piperidin-4-ylmethoxy)-4-chloro-naphthalene-2-carbonyl]-amino}-2-methyl-butyric acid ethyl ester.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[C:8]3[NH:16][N:15]=[N:14][C:9]=3[N:10]=[C:11]([NH2:13])[N:12]=2)=[CH:4][CH:3]=1.Br[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH2:25][O:26][CH2:27][CH:28]2[CH2:32][CH2:31][O:30][CH2:29]2)[N:20]=1>>[O:30]1[CH2:31][CH2:32][CH:28]([CH2:27][O:26][CH2:25][C:21]2[N:20]=[C:19]([CH2:18][N:14]3[C:9]4[N:10]=[C:11]([NH2:13])[N:12]=[C:7]([C:5]5[O:6][C:2]([CH3:1])=[CH:3][CH:4]=5)[C:8]=4[N:16]=[N:15]3)[CH:24]=[CH:23][CH:22]=2)[CH2:29]1
Reactant: BrCc1cccc(COCC2CCOC2)n1
Reactant: Cc1ccc(-c2nc(N)nc3nn[nH]c23)o1
Product: Cc1ccc(-c2nc(N)nc3c2nnn3Cc2cccc(COCC3CCOC3)n2)o1

Procedure:
Prepared from 7-(5-methyl-2-furyl)-1H-[1,2,3]triazolo[4,5-d]pyrimidin-5-ylamine and 2-bromomethyl-6-(tetrahydrofuran-3-ylmethoxymethyl)pyridine by the alkylation method described for Example 36.
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:15]=[CH:14][N:13]([C:16]3[CH:21]=[CH:20][C:19]([O:22][C:23]([F:29])([F:28])[C:24]([F:27])([F:26])[F:25])=[CH:18][CH:17]=3)[N:12]=2)=[CH:7][CH:6]=1)=[N+]=[N-]>C(OCC)(=O)C.[Pd]>[F:29][C:23]([F:28])([O:22][C:19]1[CH:20]=[CH:21][C:16]([N:13]2[CH:14]=[N:15][C:11]([C:8]3[CH:9]=[CH:10][C:5]([CH2:4][NH2:1])=[CH:6][CH:7]=3)=[N:12]2)=[CH:17][CH:18]=1)[C:24]([F:27])([F:26])[F:25]
Reactant: [N-]=[N+]=NCc1ccc(-c2ncn(-c3ccc(OC(F)(F)C(F)(F)F)cc3)n2)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: NCc1ccc(-c2ncn(-c3ccc(OC(F)(F)C(F)(F)F)cc3)n2)cc1
Reaction time: 12 h
Yield: 98.5 %

Procedure:
To 3-(4-(azidomethyl)phenyl)-1-(4-(perfluoroethoxy)phenyl)-1H-1,2,4-triazole (0.015 g, 0.037 mmol) in ethyl acetate (10 mL) was added palladium on carbon (10 wt %, 0.010 g, 0.037 mmol). The mixture was stirred under a hydrogen atmosphere (balloon) for 12 hours. The mixture was purged with nitrogen, filtered, and concentrated to provide the title compound as a white solid (0.014 g, 85%): 1H NMR (400 MHz, CDCl3) δ 8.56 (s, 1H), 8.12 (d, J=8.2 Hz, 2H), 7.80 (d, J=9.1 Hz, 2H), 7.39 (d, J=9.1 Hz, 4H), 3.87 (s, 2H), 2.42 (s, 2H); 19F NMR (376 MHz, CDCl3) δ −85.90, −87.86; ESIMS m/z 385 ([M+H]+).
Reaction SMILES: [C:1]([C:4]1[N:5]=[C:6]2[C:11]([C:12]([NH2:14])=O)=[CH:10][CH:9]=[CH:8][N:7]2[C:15]=1[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=1)(=[O:3])[CH3:2].C(N(CC)CC)C.ClC(Cl)(Cl)C(Cl)=O>ClCCl>[C:1]([C:4]1[N:5]=[C:6]2[C:11]([C:12]#[N:14])=[CH:10][CH:9]=[CH:8][N:7]2[C:15]=1[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1nc2c(C(N)=O)cccn2c1-c1cccc(F)c1
Agent: O=C(Cl)C(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)c1nc2c(C#N)cccn2c1-c1cccc(F)c1
Temperature: -15 °C
Reaction time: 1 h
Yield: 101.7 %

Procedure:
A solution of 2-acetyl-3-(3-fluorophenyl)imidazo[1,2-a]pyridine-8-carboxamide (0.24 g, 0.81 mmol) in dichloromethane (12 mL) was treated with triethylamine (0.34 mL, 2.4 mmol) and cooled to −15° C. The reaction mixture was treated with trichloroacetyl chloride (0.18 mL, 1.6 mmol) dropwise and stirred between −15° C. to −10° C. for 1 h. The reaction mixture was diluted with dichloromethane (100 mL) and washed with water (2×50 mL) and brine (50 mL), dried with sodium sulfate, filtered, and concentrated to give the desired product (0.23 g, quantitative). This material was used without further purification. LCMS for C16H11FN3O (M+H)+: m/z=280.1.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N:8]([CH3:25])[C:9](=[O:24])[C:10]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([C:20]([F:23])([F:22])[F:21])[CH:11]=1.[F:26][C:27]1[CH:28]=[C:29](B(O)O)[C:30]([O:33][CH3:34])=[N:31][CH:32]=1>CN(C=O)C>[F:26][C:27]1[CH:28]=[C:29]([C:2]2[CH:7]=[CH:6][N:5]=[CH:4][C:3]=2[N:8]([CH3:25])[C:9](=[O:24])[C:10]2[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([C:20]([F:23])([F:22])[F:21])[CH:11]=2)[C:30]([O:33][CH3:34])=[N:31][CH:32]=1
Reactant: CN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnccc1Br
Reactant: COc1ncc(F)cc1B(O)O
Solvent: CN(C)C=O
Product: COc1ncc(F)cc1-c1ccncc1N(C)C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1

Procedure:
The title compound was prepared in analogy to example 25, from N-(4-bromo-pyridin-3-yl)-N-methyl-3,5-bis-trifluoromethyl-benzamide (example 25, intermediate a) and 5-fluoro-2-methoxypyridine-3-boronic acid (CAS RN 957120-32-0) and using DMF as reaction solvent. Off-white solid (27%). MS (ESI): m/z=474.1 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][N+:13]([O-:15])=[O:14])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[CH3:16][O:17][C:18]1[CH:19]=[C:20]([C:26]([CH2:32][CH2:33][CH:34]=[O:35])([CH:29]([CH3:31])[CH3:30])[C:27]#[N:28])[CH:21]=[CH:22][C:23]=1[O:24][CH3:25].[F-].[K+]>CC(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH:12]([N+:13]([O-:15])=[O:14])[CH:34]([OH:35])[CH2:33][CH2:32][C:26]([C:27]#[N:28])([CH:29]([CH3:30])[CH3:31])[C:20]2[CH:21]=[CH:22][C:23]([O:24][CH3:25])=[C:18]([O:17][CH3:16])[CH:19]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(CC[N+](=O)[O-])cc1OC
Reactant: COc1ccc(C(C#N)(CCC=O)C(C)C)cc1OC
Agent: [F-]
Agent: [K+]
Solvent: CC(C)O
Product: COc1ccc(CC(C(O)CCC(C#N)(c2ccc(OC)c(OC)c2)C(C)C)[N+](=O)[O-])cc1OC
Temperature: 25 °C
Yield: 73.9 %

Procedure:
A mixture of 2-(3,4-dimethoxyphenyl)-1-nitroethane (4, 135 g, 0.64 mol), 2-(3,4-dimethoxyphenyl)-2-(3-oxopropyl)-2-isopropylacetonitrile (7, 156 g, 0.57 mol) and KF (19.3 g, anhydrous, Aldrich) in 2-propanol (2.0 L) was heated to 50°-55° C. for about 40 hours. The mixture was then cooled to room temperature and the isopropanol removed in vacuo. The residue was dissolved in CH2Cl2 (1.6 L) and filtered through Celite (50 g). The filtrate was extracted with saturated aqueous NaHCO3 (2×500 mL), the organic layer evaporated, and the product recrystallized from ethyl acetate-hexane (1:1) to yield 1-(3,4-dimethoxyphenyl)-2-nitro-6-cyano-6-(i-propyl)-6-(3,4-dimethoxyphenyl)-hexan-3-ol (8, 205 g, m.p. 171°-173° C., MS m/e 486(M+)).
Reaction SMILES: [F:1][C:2]1([F:20])[C:15]([F:17])([F:16])[C:14]2[CH:13]=[C:12](Br)[CH:11]=[CH:10][C:9]=2[C:8]2[C:3]1=[CH:4][C:5](Br)=[CH:6][CH:7]=2.[CH2:21]([Mg]Br)[CH2:22][CH2:23][CH2:24][CH2:25][CH3:26].Cl.[Na+].[Cl-]>C1COCC1>[F:1][C:2]1([F:20])[C:15]([F:17])([F:16])[C:14]2[CH:13]=[C:12]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH:11]=[CH:10][C:9]=2[C:8]2[C:3]1=[CH:4][C:5]([CH2:14][CH2:15][CH2:2][CH2:3][CH2:4][CH3:5])=[CH:6][CH:7]=2
Reactant: CCCCCC[Mg]Br
Reactant: FC1(F)c2cc(Br)ccc2-c2ccc(Br)cc2C1(F)F
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCCCc1ccc2c(c1)C(F)(F)C(F)(F)c1cc(CCCCCC)ccc1-2
Temperature: 0 °C
Reaction time: 4 h

Procedure:
4.1 g of 9,9,10,10-tetrafluoro-2,7-dibromo-9,10-dihydrophenanthrene are dissolved in 250 ml of THF and the solution is cooled to 0° C. 120 mg of 1,3-bis(diphenylphosphine)propanenickel(lI) chloride are added, and, at 0° C., 50 mmol of hexylmagnesium bromide in 100 ml of THF are added dropwise. Stirring is continued for 4 hours, and then for a further 18 hours at 50° C. The mixture is acidified with 1N HCl, the aqueous phase is saturated with NaCl and the phases are separated. The aqueous phase is subsequently subjected to extraction a number of times with tert-butyl methyl ether. The crude product is purified by chromatography on silica gel. This gives 3.45 g of 9,9,10,10-tetrafluoro-2,7-dihexyl-9,10-dihydrophenanthrene.
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[C:9]2[C:5]([CH2:6][C:7]([CH:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)([CH3:13])[C:8]2=[O:12])=[CH:4][C:3]=1[CH2:19][C:20]([NH2:22])=[O:21].[C:23](OCC)(=[O:29])[C:24](OCC)=[O:25].CC(C)([O-])C.[K+].Cl>CN(C)C=O.O>[Cl:1][C:2]1[C:10]([Cl:11])=[C:9]2[C:5]([CH2:6][C:7]([CH:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)([CH3:13])[C:8]2=[O:12])=[CH:4][C:3]=1[C:19]1[C:20](=[O:21])[NH:22][C:24](=[O:25])[C:23]=1[OH:29]
Reactant: CC1(C2CCCC2)Cc2cc(CC(N)=O)c(Cl)c(Cl)c2C1=O
Reactant: CCOC(=O)C(=O)OCC
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC1(C2CCCC2)Cc2cc(C3=C(O)C(=O)NC3=O)c(Cl)c(Cl)c2C1=O

Procedure:
In a nitrogen atmosphere, (+)-(6,7-dichloro-2-cyclopentyl-2,3-dihydro-2-methyl-1-oxo-1H-inden-5-yl)acetamide (19.8 g., 0.0582 mole) and diethyl oxalate (9.14 g., 0.0626 mole) are dissolved in dimethylformamide (100 ml.) and stirred in an ice bath. Potassium tert. butoxide (15.2 g, 0.136 mole) is added in two portions at a 10 minute interval. The reaction mixture is stirred at 25° C. for 18 hours, poured into water (600 ml) acidified with hydrochloric acid, extracted with ether, washed with water and brine and dried over MgSO4. Evaporation of the ether at reduced pressure gives (+)3-(6,7-dichloro-2-cyclopentyl-2,3-dihydro-2-methyl-1-oxo-1H-inden-5-yl)-4-hydroxy-1H-pyrrole-2,5-dione as the hemietherate in the form of a foam. Upon drying at reduced pressure, the analysis of the hemietherate is as follows:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]2=[C:8]([CH3:14])[N:9]=[C:10]([CH2:11][CH2:12][CH3:13])[N:4]2[N:3]=1.[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([C:23](=[O:25])[CH3:24])=[CH:19][CH:18]=1.[ClH:26]>C(O)C>[ClH:26].[NH2:1][C:2]1[NH:7][CH:6]([CH2:24][C:23]([C:20]2[CH:21]=[CH:22][C:17]([O:16][CH3:15])=[CH:18][CH:19]=2)=[O:25])[C:5]2=[C:8]([CH3:14])[N:9]=[C:10]([CH2:11][CH2:12][CH3:13])[N:4]2[N:3]=1
Reactant: COc1ccc(C(C)=O)cc1
Reactant: CCCc1nc(C)c2cnc(N)nn12
Agent: Cl
Solvent: CCO
Product: CCCc1nc(C)c2n1N=C(N)NC2CC(=O)c1ccc(OC)cc1

Procedure:
2-Amino-5-methyl-7-propylimidazo[5,1-f]-as-triazine (Example 4) (1.9 g.), p-methoxyacetophenone (1.65 g.) and concentrated hydrochloric acid (2 ml.) in ethanol (50 ml.) were heated under reflux for 1.5 hours. The solvent was distilled off and the residue was treated with 2N sodium carbonate. The mixture was extracted with ethyl acetate and the extract was dried over magnesium sulphate, filtered and evaporated. The residue was crystallised from a mixture of ethyl acetate and light petroleum and had m.p. 193°-195°. The solid in ethanol (20 ml.) was treated with hydrogen chloride in ether. The mixture was further diluted with ether and the solid that crystallised from a mixture of isopropanol and ether and had m.p. 122°.
Reaction SMILES: Cl[C:2]1[C:3]2[CH2:16][CH2:15][N:14]([C:17]3[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=3)[C:4]=2[N:5]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:7]=1.[CH2:23]([O:30][C:31]1[C:32]([F:41])=[C:33](B(O)O)[C:34]([F:37])=[CH:35][CH:36]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.B(O)O>>[CH2:23]([O:30][C:31]1[C:32]([F:41])=[C:33]([C:2]2[C:3]3[CH2:16][CH2:15][N:14]([C:17]4[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=4)[C:4]=3[N:5]=[C:6]([N:8]3[CH2:13][CH2:12][O:11][CH2:10][CH2:9]3)[N:7]=2)[C:34]([F:37])=[CH:35][CH:36]=1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: Clc1nc(N2CCOCC2)nc2c1CCN2c1ccncc1
Reactant: OB(O)c1c(F)ccc(OCc2ccccc2)c1F
Agent: OBO
Product: Fc1ccc(OCc2ccccc2)c(F)c1-c1nc(N2CCOCC2)nc2c1CCN2c1ccncc1

Procedure:
In the same manner as Example 1-B-10, using 4-chloro-2-morpholin-4-yl-7-pyridin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine, and 3-benzyloxy-2,6-difluorophenylboronic acid as a boronic acid, the desired compound was obtained.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][CH2:11][C:12]1[C:13]([O:30][CH3:31])=[C:14]2[C:18](=[C:19]([F:21])[CH:20]=1)[N:17]([CH2:22][CH3:23])[CH:16]=[C:15]2[CH2:24][C:25]([N:27]([CH3:29])[CH3:28])=O.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][CH2:11][C:12]1[C:13]([O:30][CH3:31])=[C:14]2[C:18](=[C:19]([F:21])[CH:20]=1)[N:17]([CH2:22][CH3:23])[CH:16]=[C:15]2[CH2:24][CH2:25][N:27]([CH3:29])[CH3:28]
Reactant: CCn1cc(CC(=O)N(C)C)c2c(OC)c(CCc3nc4ccccc4[nH]3)cc(F)c21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCn1cc(CCN(C)C)c2c(OC)c(CCc3nc4ccccc4[nH]3)cc(F)c21
Temperature: 25 °C
Reaction time: 8 h
Yield: 22.4 %

Procedure:
To a solution of 29-3 (100 mg, 0.24 mmol) in THF (10 mL) was added lithium aluminum hydride (19 mg, 0.48 mmol). The mixture was stirred at room temperature overnight. Na2SO4.10H2O was added and the reaction mixture was filtered and the filtrate was evaporated to give the crude product which was purified by preparative HPLC (basic condition, water/CH3CN, 43-53% CH3CN in 7.5 min, RT=7.3 min) to afford 29-4 (22 mg, 23%) as a yellow solid. 1H-NMR (400 MHz, CDCl3): δ (ppm) 7.52-7.50 (br.s, 2H), 7.20-7.16 (m, 2H), 6.76 (s, 1H), 6.66 (d, J=12.8 Hz, 1H), 3.96 (q, J=7.2 Hz, 2H), 3.81 (s, 3H), 3.14 (t, J=7.2 Hz, 2H), 3.06-2.98 (m, 4H), 2.69 (t, J=7.6 Hz, 2H), 2.38 (s, 6H) 1.30 (t, J=7.2 Hz, 3H). LRMS: calc 408.5 and found: 409.2 [M+1].
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@@H:10]([C@H:13]([OH:20])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C=O)C.[H-].[Na+].[Cl:28][C:29]1[CH:30]=[C:31](F)[CH:32]=[C:33]([Cl:35])[CH:34]=1.Cl>CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@@H:10]([C@H:13]([O:20][C:31]2[CH:30]=[C:29]([Cl:28])[CH:34]=[C:33]([Cl:35])[CH:32]=2)[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H]([C@H](O)c2ccccc2)C1
Reactant: Fc1cc(Cl)cc(Cl)c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC[C@@H]([C@H](Oc2cc(Cl)cc(Cl)c2)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
(R)-3-((S)-hydroxyphenylmethyl)pyrrolidine-1-carboxylic acid t-butyl ester (10.0 g, 36.0 mmol) was dissolved in anhydrous DMF (65 mL, 840 mmol). Washed and dried sodium hydride (1.0 g, 43 mmol) was added, and the mixture stirred at room temperature for 15 minutes. 3,5-Dichlorofluorobenzene (10 mL, 80 mmol) was then added, and the mixture stirred at 70° C. for 3 hours. The mixture was cooled to room temperature. EtOAc (200 mL) and 1M HCl (200 mL) was added, mixed, and the phases separated. The organic layer was washed with 2×200 mL of diluted aqueous NaCl, dried over Na2SO4, and concentrated to dryness to yield 19 g of crude product. The crude product was purified on a 300 g SiG column to yield (R)-3-[(S)-(3,5-dichlorophenoxy)phenylmethyl]pyrrolidine-1-carboxylic acid t-butyl ester as a white sticky foam (14.1 g, 91.67% purity).
Reaction SMILES: [C:1]1([CH3:12])[CH:6]=[CH:5][C:4]([O:7][CH2:8][C:9]([OH:11])=O)=[CH:3][CH:2]=1.[NH2:13][C:14]1[CH:15]=[C:16]([CH:20]=[CH:21][N:22]=1)[C:17]([NH2:19])=[O:18].CCN(C(C)C)C(C)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>CN(C=O)C>[C:1]1([CH3:12])[CH:2]=[CH:3][C:4]([O:7][CH2:8][C:9]([NH:13][C:14]2[CH:15]=[C:16]([CH:20]=[CH:21][N:22]=2)[C:17]([NH2:19])=[O:18])=[O:11])=[CH:5][CH:6]=1
Reactant: Cc1ccc(OCC(=O)O)cc1
Reactant: NC(=O)c1ccnc(N)c1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(OCC(=O)Nc2cc(C(N)=O)ccn2)cc1
Yield: 66.7 %

Procedure:
A solution of 4 p-tolyloxy-acetic acid (60.1 mg, 0.36 mmol), 2-amino-isonicotinamide (74.1 mg, 0.54 mmol), DIPEA (0.12 ml, 0.72 mmol) and PyBOP (374.4 mg, 0.72 mmol) in DMF 5.0 mL was stirred, then partitioned between ethyl acetate and water. The organic phase was washed with brine, dried over anhydrous MgSO4, and concentrated. The residue was purified by Prep-TLC(CH2Cl2:MeOH=10:1) to give 2-(2-p-tolyloxy-acetylamino)-isonicotinamide as a white solid (68.5 mg, 66.8% yield).
Reaction SMILES: [CH:1]1([CH2:7][C@H:8]2[CH2:10][O:9]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:11][C:12]([CH3:17])([CH3:16])[CH2:13][CH2:14][OH:15]>CN(C=O)C.[H-].[Na+]>[CH:1]1([CH2:7][C@H:8]([OH:9])[CH2:10][O:15][CH2:14][CH2:13][C:12]([CH3:17])([CH3:16])[CH3:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)CCO
Reactant: C1CCC(C[C@H]2CO2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)CCOC[C@@H](O)CC1CCCCC1
Yield: 61 %

Procedure:
The product from Example 1308C (435 mg, 3.1 mmol) in DMF (2.0 mL), 3,3-dimethylbutanol (400 μL, 3.3 mmol) in DMF (3.0 mL) and NaH, 60% dispersion in mineral oil, (145 mg, 3.6 mmol) in DMF (7.0 mL) were allowed to react in a manner similar to that described in Example 1308D. The residue was chromatographed (silica gel; EtOAc/hexanes, 1:20) to afford a light yellow oil (458 mg, 57%). 1H NMR (CDCl13, 300 MHz) δ0.78-1.01 (m, 2H), 0.92 (s, 9H), 1.11-1.57 (m, 8H), 1.62-1.85 (m, 5H), 3.21 (dd, J=8, 9 Hz, 1H), 3.40-3.66 (m, 3H), 3.89 (m, 1H); MS (CI/NH3) m/z: (M+NH4)+ 260.