Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O-:2].[Na+].[F:4][C:5]1[C:10](F)=[C:9]([CH:12]=[O:13])[CH:8]=[CH:7][C:6]=1[C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=1[F:21]>CO>[F:4][C:5]1[C:10]([O:2][CH3:1])=[C:9]([CH:12]=[O:13])[CH:8]=[CH:7][C:6]=1[C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=1[F:21]
Reactant: C[O-]
Reactant: O=Cc1ccc(-c2ccc(F)cc2F)c(F)c1F
Agent: [Na+]
Solvent: CO
Product: COc1c(C=O)ccc(-c2ccc(F)cc2F)c1F
Temperature: 25 °C
Yield: 99.1 %

Procedure:
Sodium methoxide (28% methanol solution, 5.64 g) was added at room temperature to a methanol (120 mL) solution of 2,2′,3,4′-tetrafluorobiphenyl-4-carbaldehyde (4.95 g), and the mixture was heated to reflux for 16 hours in a nitrogen atmosphere. The reaction mixture was cooled to room temperature, and then, the solvent was distilled off under reduced pressure. The obtained residue was diluted with ethyl acetate and water, followed by extraction with ethyl acetate. The obtained organic layer was washed with water and saturated saline in this order and dried over anhydrous magnesium sulfate, and then, the solvent was distilled off under reduced pressure to obtain the title compound (5.14 g).
Reaction SMILES: [Cl:1][C:2]1[CH:37]=[CH:36][C:5]([C:6]([NH:8][CH:9]([CH3:35])[CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][CH:15]([CH:18]3[CH2:27][C:26]4[C:21](=[CH:22][CH:23]=[C:24]([CH3:30])[C:25]=4[O:28][CH3:29])[CH:20]([CH2:31][NH:32]C=O)[O:19]3)[CH2:14][CH2:13]2)=[O:7])=[CH:4][CH:3]=1.[OH-].[Na+]>CO.C1COCC1>[NH2:32][CH2:31][C@H:20]1[C:21]2[C:26](=[C:25]([O:28][CH3:29])[C:24]([CH3:30])=[CH:23][CH:22]=2)[CH2:27][C@@H:18]([CH:15]2[CH2:16][CH2:17][N:12]([CH2:11][CH2:10][CH:9]([NH:8][C:6](=[O:7])[C:5]3[CH:36]=[CH:37][C:2]([Cl:1])=[CH:3][CH:4]=3)[CH3:35])[CH2:13][CH2:14]2)[O:19]1
Reactant: COc1c(C)ccc2c1CC(C1CCN(CCC(C)NC(=O)c3ccc(Cl)cc3)CC1)OC2CNC=O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1c(C)ccc2c1C[C@@H](C1CCN(CCC(C)NC(=O)c3ccc(Cl)cc3)CC1)O[C@H]2CN

Procedure:
Stir and heat at 70° C. a solution of 4-chloro-N-{3-[4-(1-formylaminomethyl-5-methoxy-6-methyl-isochroman-3-yl)-piperidin-1-yl]-1-methylpropyl}-benzamide in CH3OH/THF (10 mL of 1:1 solution) and of 15% NaOH solution (2 mL) for 4 hours. Concentrate the reaction mixture, and extract three times with EtOAc (2 mL). Wash the combined organic phase sequentially with H2O (2 mL), brine (2 mL), and then dry over MgSO4. Concentrate and purify the crude product on a 2 g SCX column.
Reaction SMILES: [NH3:1].O1CCOCC1.[CH2:8]([O:15][C:16]([NH:18][CH2:19][CH2:20][S:21](Cl)(=[O:23])=[O:22])=[O:17])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C(#N)C>[CH2:8]([O:15][C:16]([NH:18][CH2:19][CH2:20][S:21]([NH2:1])(=[O:23])=[O:22])=[O:17])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: N
Reactant: O=C(NCCS(=O)(=O)Cl)OCc1ccccc1
Solvent: C1COCCO1
Solvent: CC#N
Product: NS(=O)(=O)CCNC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 74 %

Procedure:
In a reaction flask, 100 ml of aqueous ammonia and 100 ml of dioxane were added, and a solution of 17.9 g 2-benzyloxyformamidoethylsulfonyl chloride in acetonitrile (30 ml) was added dropwise under ice-bath condition. The mixture was stirred for 2 h at room temperature. Upon the end of the dropping, the mixture was concentrated under a reduced pressure, and was then filtered, the filter cake was washed with water, and dried to obtain 12.3 g of white solid, yield 74%.
Reaction SMILES: [OH:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=2)[N:5]=[CH:4][CH:3]=1.[F:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22]O)=[C:18]([CH3:24])[CH:17]=1>>[F:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][O:1][C:2]2[N:6]([C:7]3[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=3)[N:5]=[CH:4][CH:3]=2)=[C:18]([CH3:24])[CH:17]=1
Reactant: Cc1cc(F)ccc1CO
Reactant: N#Cc1ccnc(-n2nccc2O)c1
Product: Cc1cc(F)ccc1COc1ccnn1-c1cc(C#N)ccn1

Procedure:
The title compound was prepared from 2-(5-hydroxy-1H-pyrazol-1-yl)pyridine-4-carbonitrile and (4-fluoro-2-methylphenyl)methanol according to the procedure for the preparation of Example 39, part C. 1H NMR (400 MHz, CDCl3): δ 2.38 (3H, s), 5.17 (2H, s), 5.78 (1H, d, J=1.6 Hz), 6.89-6.95 (2H, m), 7.34-7.39 (2H, m), 7.58 (1H, d, J=2.4 Hz), 7.98 (1H, s), 8.67 (1H, d, J=5.2 Hz). [M+H] Calc'd for C17H13FN4O, 309. Found, 309.
Reaction SMILES: [CH3:1][C:2]([O:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15](=[O:32])[NH:16][CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[CH:21][CH:20]=2)=[CH:9][CH:8]=1)[C:3]([OH:5])=[O:4].C(OC(=O)C(OC1C=CC([F:61])=CC=1)(C)CC1C=CC(O)=CC=1)C>>[F:61][C:37]1[CH:36]=[CH:35][C:34]([O:33][C:2]([CH3:1])([CH2:6][C:7]2[CH:8]=[CH:9][C:10]([O:13][CH2:14][C:15](=[O:32])[NH:16][CH2:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=4)=[CH:21][CH:20]=3)=[CH:11][CH:12]=2)[C:3]([OH:5])=[O:4])=[CH:39][CH:38]=1
Reactant: CC(Cc1ccc(OCC(=O)NCCc2ccc(Oc3ccccc3)cc2)cc1)(Oc1ccccc1)C(=O)O
Reactant: CCOC(=O)C(C)(Cc1ccc(O)cc1)Oc1ccc(F)cc1
Product: CC(Cc1ccc(OCC(=O)NCCc2ccc(Oc3ccccc3)cc2)cc1)(Oc1ccc(F)cc1)C(=O)O

Procedure:
The title compound was prepared using same method for 2-Methyl-2-phenoxy-3-(4-{[2-(4-phenoxy-phenyl)-ethylcarbamoyl]-methoxy}-phenyl)-propionic acid from 2-(4-Fluoro-phenoxy)-3-(4-hydroxy-phenyl)-2-methyl-propionic acid ethyl ester.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][CH2:10][N:11]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]2[CH:28]=[CH:27][N:26]=[C:25](Cl)[N:24]=2)[CH:18]=1)[S:12]([CH3:15])(=[O:14])=[O:13])(C)(C)C.[NH:31]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[C:33]([CH2:40][CH2:41][NH2:42])=[CH:32]1>>[NH2:7][CH2:8][CH2:9][CH2:10][N:11]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]2[CH:28]=[CH:27][N:26]=[C:25]([NH:42][CH2:41][CH2:40][C:33]3[C:34]4[C:39](=[CH:38][CH:37]=[CH:36][CH:35]=4)[NH:31][CH:32]=3)[N:24]=2)[CH:18]=1)[S:12]([CH3:15])(=[O:13])=[O:14]
Reactant: NCCc1c[nH]c2ccccc12
Reactant: CC(C)(C)OC(=O)NCCCN(Cc1cccc(-c2ccnc(Cl)n2)c1)S(C)(=O)=O
Product: CS(=O)(=O)N(CCCN)Cc1cccc(-c2ccnc(NCCc3c[nH]c4ccccc34)n2)c1

Procedure:
Intermediate 4 was coupled with 2-(1H-Indol-3-yl)-ethylamine following procedure F and the resulting product deprotected following procedure G. LC-MS showed the product had the expected M+H+ of 479. 1H NMR (Varian 300 MHz, CDCl3-CD3OD, shifts relative to the solvent peak at 7.24 ppm) 8.1 (m, 2H) 7.9 (m, 1H) 7.7 (d, 1H) 7.6 (m, 4H) 7.2 (m, 1H) 7.0 (m, 2H) 4.4 (d, 2H) 3.9 (m, 1H) 3.6 (m, 1H) 3.3 (m, 2H) 3.1 (m, 2H) 2.9 (m, 5H) 1.7 (m, 2H).
Reaction SMILES: Cl.[CH3:2][O:3][CH2:4][C:5]([NH2:7])=[NH:6].C([C:10](CC)([C:14]([O-])=[O:15])[C:11]([O-])=[O:12])C.[H-].[Na+]>CCO>[CH3:2][O:3][CH2:4][C:5]1[N:7]=[C:11]([OH:12])[CH:10]=[C:14]([OH:15])[N:6]=1
Reactant: COCC(=N)N
Reactant: CCC(CC)(C(=O)[O-])C(=O)[O-]
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Product: COCc1nc(O)cc(O)n1
Reaction time: 16 h
Yield: 80.1 %

Procedure:
To a solution of 2-methoxy-acetamidine hydrochloride (20.18 g, 0.16 mol) and diethylmalonate (24.6 mL, 0.16 mol) in EtOH (150 mL) is added 60% dispersion of sodium hydride in oil (14.3 g, 0.36 mol). The mixture is heated to reflux and stirred for 16 hours. The mixture is concentrated in vacuo and the residue is diluted with water (100 mL) and extracted with EtOAc (75 mL). The aqueous layer is acidified to pH 3 with HCl and extracted thrice with EtOAc (75 mL). The organic extracts from acidic solution are combined and dried over magnesium sulfate, filtered and concentrated to afford 2-methoxymethyl-pyrimidine-4,6-diol (20 g, 80%) as an oil.
Reaction SMILES: [F:1][C:2]1[CH:13]=[C:12]([F:14])[CH:11]=[CH:10][C:3]=1[O:4][C:5]([CH3:9])([CH3:8])[C:6]#[N:7].[CH2:15]([OH:17])[CH3:16].[ClH:18]>C(Cl)Cl>[ClH:18].[F:1][C:2]1[CH:13]=[C:12]([F:14])[CH:11]=[CH:10][C:3]=1[O:4][C:5]([CH3:9])([CH3:8])[C:6](=[NH:7])[O:17][CH2:15][CH3:16]
Reactant: CC(C)(C#N)Oc1ccc(F)cc1F
Reactant: CCO
Agent: Cl
Solvent: ClCCl
Product: CCOC(=N)C(C)(C)Oc1ccc(F)cc1F
Reaction time: 60 h

Procedure:
Through a cooled solution of Example 51B (6.5 g, 33 mmol) and ethanol (9.6 mL, 165 mmol) in methylene chloride (10 ml) was bubbled HCl gas at 0° C. for 30 minutes. The reaction was kept in a refrigerator at 4° C. for 60 hours. The reaction mixture was then concentrated and triturated with diethyl ether to obtain a precipitate of the titled compound. MS (ESI+) m/z 244 (M+H)+.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[CH2:5]([N:12]1[C:17](=[O:18])[C:16]2[CH:19]=[CH:20][N:21]=[CH:22][C:15]=2[N:14]=[C:13]1[CH:23](Br)[CH:24]([CH3:26])[CH3:25])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.CCOCC>CN(C=O)C>[N:1]([CH:23]([C:13]1[N:12]([CH2:5][C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:17](=[O:18])[C:16]2[CH:19]=[CH:20][N:21]=[CH:22][C:15]=2[N:14]=1)[CH:24]([CH3:26])[CH3:25])=[N+:2]=[N-:3]
Reactant: CC(C)C(Br)c1nc2cnccc2c(=O)n1Cc1ccccc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CC(C)C(N=[N+]=[N-])c1nc2cnccc2c(=O)n1Cc1ccccc1
Temperature: 65 °C

Procedure:
To a solution of sodium azide (1.41 g, 21.7 mmol) in DMF (12 mL) was added 3-benzyl-2-(1-bromo-2-methylpropyl)pyrido[3,4-d]pyrimidin-4(3H)-one (5.4 g, 14.50 mmol) in DMF (12 mL). The reaction was heated to 65° C. for 1.5 h, and then the solution was cooled to room temperature. The reaction contents were poured into a separatory funnel filled with ether and ice water. The organic solution was washed with brine and dried over sodium sulfate. Filtration and concentration afforded the title compound as a brown oil. 1H NMR (500 MHz, CDCl3) δ 0.61 (d, J=6.5 Hz, 3H), 1.09 (d, J=6.5 Hz, 3H), 2.67-2.73 (m, 1H), 3.71 (d, J=10 Hz, 1H), 5.10 (d, J=16.5 Hz, 1H), 5.83 (d, J=16 Hz, 1H), 7.16 (d, J=8 Hz, 2H), 7.32-7.38 (m, 3H), 8.12 (d, J=6.5 Hz, 1H), 8.75 (d, J=5.5 Hz, 1H), 9.13 (s, 1H). MS [M+H] C18H18N6O=335.1.
Reaction SMILES: [C:1]1([C:7]2[NH:8][C:9]3[C:14]([C:15]=2[C:16]2[CH2:21][CH2:20][CH:19]([C:22]([OH:24])=[O:23])[CH2:18][CH:17]=2)=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CO.[CH3:27]S(O)(=O)=O>C(Cl)Cl>[C:1]1([C:7]2[NH:8][C:9]3[C:14]([C:15]=2[C:16]2[CH2:21][CH2:20][CH:19]([C:22]([O:24][CH3:27])=[O:23])[CH2:18][CH:17]=2)=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)C1CC=C(c2c(-c3ccccc3)[nH]c3ccccc23)CC1
Reactant: CS(=O)(=O)O
Solvent: CO
Solvent: ClCCl
Product: COC(=O)C1CC=C(c2c(-c3ccccc3)[nH]c3ccccc23)CC1
Yield: 71 %

Procedure:
A solution of 70.0 g (0.22 mol) of 4-(2-phenyl-1H-indol-3-yl)-3-cyclohexene-1-carboxylic acid (Example 1), 35.2 g (1.1 mol) of methanol, 350 mL of methylene dichloride, and 0.5 mL of methanesulfonic acid was heated under reflux for 21 h. The reaction mixture was cooled, washed with water, dried over sodium sulfate, concentrated in vacuo, and crystallized from ethyl acetate:hexane to give 51.8 g (71%) of methyl 4-(2-phenyl-1H-indol-3-yl)-3-cyclohexene-1-carboxylate in two crops: m.p. 175°-177° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[N:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1.[F:17][C:18]([F:42])([F:41])[CH2:19][NH:20][C:21]([C:23]1([CH2:36][CH2:37][CH2:38][CH2:39]Br)[C:35]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[C:29]2[C:24]1=[CH:25][CH:26]=[CH:27][CH:28]=2)=[O:22]>>[F:17][C:18]([F:41])([F:42])[CH2:19][NH:20][C:21]([C:23]1([CH2:36][CH2:37][CH2:38][CH2:39][N:14]2[CH2:13][CH2:12][N:11]([C:4]3[CH:5]=[CH:6][C:7]([O:9][CH3:10])=[CH:8][C:3]=3[O:2][CH3:1])[CH2:16][CH2:15]2)[C:35]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[C:29]2[C:24]1=[CH:25][CH:26]=[CH:27][CH:28]=2)=[O:22]
Reactant: O=C(NCC(F)(F)F)C1(CCCCBr)c2ccccc2-c2ccccc21
Reactant: COc1ccc(N2CCNCC2)c(OC)c1
Product: COc1ccc(N2CCN(CCCCC3(C(=O)NCC(F)(F)F)c4ccccc4-c4ccccc43)CC2)c(OC)c1

Procedure:
Prepared analogously to Example 2 b from 1-(2,4-dimethoxy-phenyl)-piperazine and 9-(4-bromo-butyl)-9H-fluorene-9-carboxylic acid-(2,2,2-trifluoroethyl)-amide.
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]([O:25]C(C)(C)C)=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[CH:30]=[C:31]([NH:35][C:36]([N:38]3[CH2:43][CH2:42][O:41][CH2:40][CH2:39]3)=[O:37])[CH:32]=[C:33]([CH3:34])[C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]([OH:25])=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[CH:30]=[C:31]([NH:35][C:36]([N:38]3[CH2:39][CH2:40][O:41][CH2:42][CH2:43]3)=[O:37])[CH:32]=[C:33]([CH3:34])[C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2c(C)cc(NC(=O)N3CCOCC3)cc2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCCc1nc2c(C)cc(NC(=O)N3CCOCC3)cc2n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
Prepared analogously to Example 1 from tert.butyl 4'-[[2-n-butyl-4-methyl-6-(morpholinocarbonylamino)-benzimidazol-1-yl]methyl]-biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([OH:8])[C:3]=1[C:9](=[O:11])[CH3:10].C(=O)([O-])[O-].[K+].[K+].Br[CH2:19][CH2:20][CH2:21][Cl:22].O>CN(C)C=O>[Cl:22][CH2:21][CH2:20][CH2:19][O:1][C:2]1[C:3]([C:9](=[O:11])[CH3:10])=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1
Reactant: ClCCCBr
Reactant: CC(=O)c1c(O)cccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)c1c(O)cccc1OCCCCl
Temperature: 70 °C
Reaction time: 4 h
Yield: 46.4 %

Procedure:
To a solution of 2′,6′-dihydroxy-acetophenone (500 mg, 3.28 mmol) in dimethylformamide (20 ml) were added potassium carbonate (680 mg, 4.93 mmol) and 1-bromo-3-chloropropane (0.34 ml, 3.45 mmol) and the mixture was stirred at 70° C. for 4 h. Water was added and the organics were extracted with ethylacetate, washed with brine, dried over sodium sulfate and concentrated to dryness. The residue was purified by flash chromatography over silica gel (gradient cyclohexane/ethyl acetate: 0-15%) to yield 6′-(3-chloropropoxy)-2′-hydroxy-acetophenone (348 mg, 46%) as a pale yellow solid. To a solution of 6′-(3-chloropropoxy)-2′-hydroxy-acetophenone (345 mg, 1.50 mmol) in acetonitrile (15 ml) was added potassium carbonate (416 mg, 3.0 mmol) and morpholine (0.396 ml, 4.52 mmol). The mixture was stirred for 18 hours at room temperature then 60° C. for 3 days. Water was added and the organics were extracted with ethylacetate, washed with brine, dried over sodium sulfate and concentrated to dryness. The residue was purified by flash chromatography over silica gel (gradient ethyl acetate/methanol: 0-10%) to yield 2′-hydroxy-6′-(3-morpholino-4-yl-propoxy)-acetophenone (171 mg, 40%) as an orange oil that solidified.
Reaction SMILES: FC(F)(F)C(O)=O.Cl[C:9]1[N:14]=[C:13]([F:15])[C:12]2[O:16][C:17]3[C:22]([C@@:23]4([C:31]5[C:26](=[N:27][CH:28]=[CH:29][CH:30]=5)[C:25]([NH2:32])=[N:24]4)[C:11]=2[CH:10]=1)=[CH:21][C:20]([C:33]1[C:34]([F:39])=[N:35][CH:36]=[CH:37][CH:38]=1)=[CH:19][CH:18]=3.[O:40]1[CH2:45][CH2:44][CH:43]=[C:42](B2OC(C)(C)C(C)(C)O2)[CH2:41]1.C(O)(C(F)(F)F)=O>>[O:40]1[CH2:45][CH2:44][CH:43]=[C:42]([C:9]2[N:14]=[C:13]([F:15])[C:12]3[O:16][C:17]4[C:22]([C@@:23]5([C:31]6[C:26](=[N:27][CH:28]=[CH:29][CH:30]=6)[C:25]([NH2:32])=[N:24]5)[C:11]=3[CH:10]=2)=[CH:21][C:20]([C:33]2[C:34]([F:39])=[N:35][CH:36]=[CH:37][CH:38]=2)=[CH:19][CH:18]=4)[CH2:41]1
Reactant: NC1=N[C@]2(c3cc(-c4cccnc4F)ccc3Oc3c2cc(Cl)nc3F)c2cccnc21
Reactant: CC1(C)OB(C2=CCCOC2)OC1(C)C
Solvent: O=C(O)C(F)(F)F
Product: NC1=N[C@]2(c3cc(-c4cccnc4F)ccc3Oc3c2cc(C2=CCCOC2)nc3F)c2cccnc21

Procedure:
The title compound was synthesized by procedures and steps analogous to those described in Example 5 above, but using (S)-3-Chloro-1-fluoro-7-(2-fluoropyridin-3-yl)spiro[chromeno[2,3-c]pyridine-5,5′-pyrrolo[3,4-b]pyridin]-7′-amine 2,2,2-trifluoroacetate and 2-(5,6-dihydro-2H-pyran-3-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane in step 4. MS m/z=496.0 [M+H]+. Calculated for: C28H0F2N5O2.C2HF3O2: 609.50 (TFA salt)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[Cl:21])[CH2:5][CH:6]1[C:13]2[CH:12]=[C:11]([C:14]([O:16]C)=[O:15])[NH:10][C:9]=2[CH2:8][CH2:7]1.[OH-].[Li+].CO>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[Cl:21])[CH2:5][CH:6]1[C:13]2[CH:12]=[C:11]([C:14]([OH:16])=[O:15])[NH:10][C:9]=2[CH2:8][CH2:7]1
Reactant: COC(=O)c1cc2c([nH]1)CCC2Cc1ccc(Cl)c(Cl)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1cc2c([nH]1)CCC2Cc1ccc(Cl)c(Cl)c1
Yield: 23 %

Procedure:
The title compound was synthesized from methyl 4-(3,4-dichlorobenzyl)-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylate (0.064 g, 0.2 mmol) and lithium hydroxide (0.084 g, 2.0 mmol in 3 mL water), according to General Procedure 7. A 1:1 mixture of methanol (MeOH) and THF (6 mL) was used. The resulting product was purified by column chromatography (Isco CombiFlash) eluting with a gradient of 0-100% EtOAc/heptane to afford a light brown solid: 14 mg, 23% yield. 1H NMR (400 MHz, METHANOL-d4) δ ppm 2.00-2.15 (m, 1H), 2.46-2.67 (m, 3H), 2.69-2.84 (m, 2H), 3.19-3.29 (m, 1H), 6.31 (s, 1H), 7.11 (dd, J=8.20, 2.00 Hz, 1H), 7.34 (d, J=1.95 Hz, 1H), 7.37-7.45 (m, 1H); HPLC (UV=96.1%), (ELSD=100%).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH3:12])[N:9]=[C:10]([I:11])[C:3]=12.[F:13][CH:14]1[CH2:17][NH:16][CH2:15]1.C(=O)(O)[O-].[Na+]>O1CCCC1>[F:13][CH:14]1[CH2:17][N:16]([C:2]2[N:7]=[CH:6][N:5]=[C:4]3[N:8]([CH3:12])[N:9]=[C:10]([I:11])[C:3]=23)[CH2:15]1
Reactant: FC1CNC1
Reactant: Cn1nc(I)c2c(Cl)ncnc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: Cn1nc(I)c2c(N3CC(F)C3)ncnc21
Temperature: 25 °C
Reaction time: 18 h

Procedure:
4-Chloro-3-iodo-1-methyl-1H-pyrazolo[3,4-d]pyrimidine (C9) (2.00 g, 6.79 mmol), 3-fluoroazetidine (833 mg, 7.46 mmol), saturated aqueous sodium bicarbonate solution (30 mL), and tetrahydrofuran (40 mL) were combined and allowed to stir at room temperature for 18 hours. After removal of volatiles in vacuo, the residue was diluted with water. Filtration provided the product as a tan solid. Yield: 1.91 g, 5.73 mmol, 84%. LCMS m/z 334.0 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 3.91 (s, 3H), 4.47-4.63 (m, 2H), 4.75-4.90 (m, 2H), 5.44-5.64 (m, 1H, JHF=58.0 Hz), 8.31 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([C:9]2[N:13]3[CH2:14][CH2:15][CH2:16][C@@:17]([C:28]([OH:31])([CH3:30])[CH3:29])([O:18][C:19]4[CH:24]=[C:23]([F:25])[C:22]([F:26])=[C:21]([F:27])[CH:20]=4)[C:12]3=[N:11][N:10]=2)[CH:6]=[CH:5][C:4]=1[N:32]1[CH:36]=[C:35]([CH3:37])[N:34]=[CH:33]1.[P:38](=O)([OH:41])([OH:40])[OH:39]>CC(O)C>[P:38]([O:31][C:28]([C@@:17]1([O:18][C:19]2[CH:24]=[C:23]([F:25])[C:22]([F:26])=[C:21]([F:27])[CH:20]=2)[CH2:16][CH2:15][CH2:14][N:13]2[C:9]([C:7]3[CH:6]=[CH:5][C:4]([N:32]4[CH:36]=[C:35]([CH3:37])[N:34]=[CH:33]4)=[C:3]([O:2][CH3:1])[N:8]=3)=[N:10][N:11]=[C:12]12)([CH3:30])[CH3:29])([OH:41])([OH:40])=[O:39]
Reactant: O=P(O)(O)O
Reactant: COc1nc(-c2nnc3n2CCC[C@]3(Oc2cc(F)c(F)c(F)c2)C(C)(C)O)ccc1-n1cnc(C)c1
Solvent: CC(C)O
Product: COc1nc(-c2nnc3n2CCC[C@]3(Oc2cc(F)c(F)c(F)c2)C(C)(C)OP(=O)(O)O)ccc1-n1cnc(C)c1
Reaction time: 0.5 h
Yield: 93.5 %

Procedure:
To a mixture of 2-{(8R)-3-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]-8-(3,4,5-trifluorophenoxy)-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyridin-8-yl}propan-2-ol (1.0 g) in 2-propanol (4 mL) was added a mixture of phosphoric acid (0.27 g) in 2-propanol (2 mL) at 50° C., and the mixture was stirred for 30 min. To the reaction mixture was added IPE (6 mL) at 50° C., and the mixture was stirred for 30 min. To the reaction mixture was added IPE (2 mL) at room temperature, and the mixture was stirred for 30 min. The crystals were collected by filtration, washed with IPE (2 mL) and dried to give the title compound (1.08 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16](Br)=[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][N:10]3[N:9]=2)=[CH:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:23]1[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=1)CCC.[F-].[K+]>C1(C)C=CC=CC=1.C(OCC)C.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>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]([C:23]3[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=3)=[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][N:10]3[N:9]=2)=[CH:4][CH:3]=1
Reactant: Fc1ccc(-c2nn3ccccc3c2Br)cc1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccncc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [F-]
Agent: [K+]
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: Fc1ccc(-c2nn3ccccc3c2-c2ccncc2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2-(4-fluorophenyl)-3-bromopyrazolo[1,5-a]pyridine (0.2 g. 0.68 mmol) and 4-(tributylstannyl)pyridine (0.38 g, 1 mmol) in dry toluene (10 mL) was added tetrakis(triphenylphosphine)palladium (0) (0.03 g, 0.03 mmol) and the mixture was heated at reflux temperature under a nitrogen atmosphere for about 48 hours. The mixture was cooled to room temperature and diluted with diethyl ether (40 mL). The mixture was poured into a 10% aqueous solution of potassium fluoride (20 mL) and the mixture was stirred for 1 hour. The biphasic mixture was filtered through a pad (1 cm) of diatomaceous earth and the organic phase was separated. The aqueous phase was extracted with diethyl ether (10 mL) and the combined organic phases are washed with brine, dried over anhydrous magnesium sulfate, filtered and the solvent evaporated under reduced pressure. The residue was purified using silica gel chromatography with 20% ethyl acetate in hexanes, followed by 50% ethyl acetate in hexanes, as eluent to give the title compound as an off white solid, 0.16 g (80%). 1H NMR (CDCl3) δ 8.58 (br s, 2H), 8.50 (d, 1H, J=7.2 Hz), 7.63 (d, 1H, 9 Hz), 7.52 (m, 2H), 7.27–7.20 (m, 3H), 7.06 (t, 2H, 8.7 Hz), 6.86 dt, 1H J=7, 1 Hz). MS (+ve ion electrospray) 290 (100), (MH+).
Reaction SMILES: [F:1][C:2]1[CH:29]=[CH:28][C:5]([C:6]([CH:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][N:16]3[C:25](=[O:26])[C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[NH:18][C:17]3=[O:27])[CH2:10][CH2:9]2)=[O:7])=[CH:4][CH:3]=1.CO.[BH4-].[Na+]>O>[F:1][C:2]1[CH:29]=[CH:28][C:5]([CH:6]([OH:7])[CH:8]2[CH2:9][CH2:10][N:11]([CH2:14][CH2:15][N:16]3[C:25](=[O:26])[C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[NH:18][C:17]3=[O:27])[CH2:12][CH2:13]2)=[CH:4][CH:3]=1
Reactant: O=C(c1ccc(F)cc1)C1CCN(CCn2c(=O)[nH]c3ccccc3c2=O)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: O=c1[nH]c2ccccc2c(=O)n1CCN1CCC(C(O)c2ccc(F)cc2)CC1
Reaction time: 8 h

Procedure:
To a stirred mixture of 2.6 parts of 3-[2-[4-(4-fluorobenzoyl)-1-piperidinyl]ethyl]-2,4(1H,3H)-quinazolinedione and 120 parts of methanol are added portionwise 2 parts of sodium borohydride. Upon completion, stirring is continued overnight at room temperature. Water is added and the whole is evaporated. The residue is stirred in water. The solid product is filtered off and crystallized from 2-propanone, yielding 1.2 parts of 3-[2-[4-[(4-fluorophenyl)hydroxymethyl]-1-piperidinyl]ethyl]-2,4(1H,3H)-quinazolinedione; mp. 212.8° C.
Reaction SMILES: [C:1]([NH:4][C@H:5]1[CH2:10][CH2:9][C@H:8]([C:11]([N:13]2[CH2:18][CH2:17][N:16]([S:19]([C:22]3[CH:31]=[CH:30][C:29]4[C:24](=[CH:25][CH:26]=[C:27]([Cl:32])[CH:28]=4)[CH:23]=3)(=[O:21])=[O:20])[CH2:15][CH2:14]2)=[O:12])[CH2:7][CH2:6]1)(=[NH:3])[CH3:2].C(N(CC)CC)C.[C:40](Cl)(=[O:43])[O:41][CH3:42]>ClCCl>[CH3:42][O:41][C:40]([CH2:2][C:1]([NH:4][C@H:5]1[CH2:10][CH2:9][C@H:8]([C:11]([N:13]2[CH2:18][CH2:17][N:16]([S:19]([C:22]3[CH:31]=[CH:30][C:29]4[C:24](=[CH:25][CH:26]=[C:27]([Cl:32])[CH:28]=4)[CH:23]=3)(=[O:21])=[O:20])[CH2:15][CH2:14]2)=[O:12])[CH2:7][CH2:6]1)=[NH:3])=[O:43]
Reactant: COC(=O)Cl
Reactant: CC(=N)N[C@H]1CC[C@H](C(=O)N2CCN(S(=O)(=O)c3ccc4cc(Cl)ccc4c3)CC2)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)CC(=N)N[C@H]1CC[C@H](C(=O)N2CCN(S(=O)(=O)c3ccc4cc(Cl)ccc4c3)CC2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1-(trans-4-acetimidoylaminocyclohexane-1-ylcarbonyl)-4-(6-chloronaphthalene-2-sulfonyl)piperazine (300 mg) and triethylamine (199 mg) in dichloromethane (30 ml) was added methyl chlorocarbonate (192 mg), and the mixture was stirred at room temperature for 30 minutes. The reaction solution was concentrated, and the residue was purified with silica gel column chromatography (ethyl acetate) to give colorless crystals of the title compound (171 mg).