Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](=[O:4])([O-])[O-].[Cs+].[Cs+].O=[C:8]1[NH:17][CH:16]([C:18]2[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][CH:19]=2)[C:15]2[C:14](=[O:26])[CH2:13][CH2:12][CH2:11][C:10]=2[N:9]1[C:27]1[CH:32]=[CH:31][N:30]=[C:29]([C:33]([F:36])([F:35])[F:34])[CH:28]=1>CN(C)C=O>[CH3:8][N:17]1[CH:16]([C:18]2[CH:19]=[CH:20][C:21]([C:22]#[N:23])=[CH:24][CH:25]=2)[C:15]2[C:14](=[O:26])[CH2:13][CH2:12][CH2:11][C:10]=2[N:9]([C:27]2[CH:32]=[CH:31][N:30]=[C:29]([C:33]([F:35])([F:34])[F:36])[CH:28]=2)[C:1]1=[O:4]
Reactant: N#Cc1ccc(C2NC(=O)N(c3ccnc(C(F)(F)F)c3)C3=C2C(=O)CCC3)cc1
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CN1C(=O)N(c2ccnc(C(F)(F)F)c2)C2=C(C(=O)CCC2)C1c1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Cesium carbonate (39 mg, 0.12 mmol) and methyl idodide (6 μL, 0.10 mmol) are added to a solution of 4-(2,5-dioxo-1-(2-(trifluoromethyl)pyridin-4-yl)-1,2,3,4,5,6,7,8-octahydroquinazolin-4-yl)benzonitrile (example 14, 25 mg, 61 μmol) in N,N-dimethylformamide (1 mL). The mixture is stirred at room temperature for 1 h, diluted with aceontrile and purified by preparative HPLC (Waters SunFire™-C18, gradient of acetonitrile in water, 0.1% TFA). Yield: 13 mg; ESI mass spectrum [M+H]+=427; Retention time HPLC: 1.02 min (Z018_S04).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[N:8]([CH:14]1[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]1=[O:21])[C:7]2=[O:22].[Cl:23][C:24]1[CH:25]=[C:26]([N:31]=[C:32]=[O:33])[CH:27]=[CH:28][C:29]=1[Cl:30].C(N(CC)C(C)C)(C)C>N1C=CC=CC=1>[Cl:23][C:24]1[CH:25]=[C:26]([NH:31][C:32]([NH:2][CH2:3][C:4]2[CH:5]=[C:6]3[C:10](=[CH:11][CH:12]=2)[C:9](=[O:13])[N:8]([CH:14]2[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]2=[O:21])[C:7]3=[O:22])=[O:33])[CH:27]=[CH:28][C:29]=1[Cl:30]
Reactant: O=C=Nc1ccc(Cl)c(Cl)c1
Reactant: NCc1ccc2c(c1)C(=O)N(C1CCC(=O)NC1=O)C2=O
Agent: Cl
Solvent: c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Product: O=C1CCC(N2C(=O)c3ccc(CNC(=O)Nc4ccc(Cl)c(Cl)c4)cc3C2=O)C(=O)N1
Temperature: 40 °C
Reaction time: 8 h
Yield: 16 %

Procedure:
A mixture of 5-aminomethyl-2-(2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione hydrochloride (0.97 g, 3.0 mmol), 3,4-dichlorophenyl isocyanate (0.56 g, 3.0 mmol) and N,N-diisopropylethylamine (1.05 mL, 6.00 mmol) in pyridine (20 mL) was stirred at 40° C. overnight. The reaction mixture was cooled to room temperature, and the solvent was removed under vacuum. The residue was suspended in a biphasic mixture of CH2Cl2 (150 mL) and water (150 mL) and stirred for 2 hours. The solid was filtered, washed with additional water (50 mL), and dried. The resulting solid was stirred in methanol (200 mL) at room temperature for 1 hour, filtered, and dried. This material was refluxed in methanol (2×200 mL) for 3 hours, filtered, and dried. The resulting solid was chromatographed using a methanol-CH2Cl2 (with 0.1% of triethylamine) gradient, eluting 0.23 g of the product at 7:93 methanol-CH2Cl2 (with 0.1% of triethylamine), in 16% yield; mp 290-292° C.; HPLC, Waters Symmetry C-18, 3.9×150 mm, 5 μm, 1 mL/min, 240 nm, 40/60 CH3CN/0.1% H3PO4, 10.50 (97.00%); 1H NMR (DMSO-d6) δ 2.03-2.07 (m, 1H), 2.56-2.62 (m, 2H), 2.82-2.94 (m, 1H), 4.47 (d, J=5.9 Hz, 2H), 5.15 (dd, J=12.6 Hz, J=5.4 Hz, 1H), 7.05 (t, J=6.1 Hz, 1H), 7.29 (dd, J=8.8 Hz, J=2.4 Hz, 1H), 7.46 (d, J=8.8 Hz, 1H), 7.77-7.91 (m, 4H), 9.11 (s, 1H), 11.13 (s, 1H); 13C NMR (DMSO-d6) δ 22.0, 30.9, 42.7, 49.0, 117.9, 118.9, 121.7, 122.4, 123.5, 129.7, 130.4, 130.9, 131.6, 133.3, 140.6, 148.4, 155.0, 167.0, 167.2, 169.8, 172.7; Anal. Calcd for C21H16N4O5Cl2+0.25H2O: C, 52.57; H, 3.47; N, 11.68. Found: C, 52.22; H, 3.25; N, 11.56.
Reaction SMILES: [CH3:1][C:2](=[N:7]O)[C:3](=O)[CH2:4][CH3:5].[C:9]1(=[O:16])[CH2:14][CH2:13][CH2:12][C:11](=O)[CH2:10]1>>[CH3:1][C:2]1[NH:7][C:11]2[CH2:12][CH2:13][CH2:14][C:9](=[O:16])[C:10]=2[C:3]=1[CH2:4][CH3:5]
Reactant: CCC(=O)C(C)=NO
Reactant: O=C1CCCC(=O)C1
Product: CCc1c(C)[nH]c2c1C(=O)CCC2

Procedure:
In yet a further embodiment, the invention provides a method of manufacturing molindone through a 5-step process, wherein in the 1st step 2,3-pentanedione is reacted with hydroxylamine hydrochloride to produce 2,3-pentanedione-2-oxime (SUMO-1); in the 2nd step 2,3-pentanedione-2-oxime and 1,3-cyclohexanedione are reacted to produce 2-methyl-3-ethyl-4-oxo-4,5,6,7-tetrahydroindole (SUMO-2); in the 3rd step 2-methyl-3-ethyl-4-oxo-4,5,6,7-tetrahydroindole reacts with bismorpholinomethane to produce molindone (SUMO-3); in the 4th step molindone is converted into a molindone salt; and in the 5th step the molindone salt is purified/recrystallized, and, optionally, various polymorphic forms of molindone salt are prepared.
Reaction SMILES: Cl[C:2]1[C:7]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:15][CH3:16])=[C:6]([Cl:17])[N:5]=[C:4]([C:18]2[N:23]=[CH:22][CH:21]=[CH:20][N:19]=2)[N:3]=1.[K+].[CH2:25]([S:28]([NH-:31])(=[O:30])=[O:29])[CH2:26][CH3:27].Cl>CS(C)=O>[Cl:17][C:6]1[N:5]=[C:4]([C:18]2[N:23]=[CH:22][CH:21]=[CH:20][N:19]=2)[N:3]=[C:2]([NH:31][S:28]([CH2:25][CH2:26][CH3:27])(=[O:30])=[O:29])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[O:15][CH3:16]
Reactant: COc1ccccc1Oc1c(Cl)nc(-c2ncccn2)nc1Cl
Reactant: CCCS([NH-])(=O)=O
Agent: Cl
Agent: [K+]
Solvent: CS(C)=O
Product: CCCS(=O)(=O)Nc1nc(-c2ncccn2)nc(Cl)c1Oc1ccccc1OC
Reaction time: 240 h
Yield: 99.9 %

Procedure:
To a solution of 4,6-dichloro-5-(2-methoxy-phenoxy)-[2,2′]bipyrimidinyl (prepared as described in [6] and [11]) (1.74 g) in DMSO (5 ml) was added n-propanesulfonamide potassium salt (1.77 g). Stirring was continued for 10 days at rt. The reaction mixture was poured onto ice/water and acidified by 2N HCl. The precipitate was filtered off, washed with water and dried at HV to give n-propanesulfonic acid [6-chloro-5-(2-methoxy-phenoxy)-[2,2′]bipyrimidinyl-4-yl]-amide (2.17 g) as a white powder. LC-MS: tR: 4.14, [M+H]+: 434.13.
Reaction SMILES: [CH2:1]([C:7]1[CH:8]=[C:9]([C:13]2[N:17]([CH3:18])[C:16]([C:19]([N:21]3[CH2:26][CH2:25][CH:24]([N:27]4[CH2:31][CH2:30][CH2:29][CH2:28]4)[CH2:23][CH2:22]3)=[O:20])=[C:15](I)[N:14]=2)[CH:10]=[CH:11][CH:12]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[CH3:33][O:34][C:35]1[CH:40]=[C:39](B(O)O)[CH:38]=[CH:37][N:36]=1>>[CH2:1]([C:7]1[CH:8]=[C:9]([C:13]2[N:17]([CH3:18])[C:16]([C:19]([N:21]3[CH2:26][CH2:25][CH:24]([N:27]4[CH2:31][CH2:30][CH2:29][CH2:28]4)[CH2:23][CH2:22]3)=[O:20])=[C:15]([C:39]3[CH:38]=[CH:37][N:36]=[C:35]([O:34][CH3:33])[CH:40]=3)[N:14]=2)[CH:10]=[CH:11][CH:12]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: COc1cc(B(O)O)ccn1
Reactant: CCCCCCc1cccc(-c2nc(I)c(C(=O)N3CCC(N4CCCC4)CC3)n2C)c1
Product: CCCCCCc1cccc(-c2nc(-c3ccnc(OC)c3)c(C(=O)N3CCC(N4CCCC4)CC3)n2C)c1

Procedure:
In analogy to the procedure described for example 7, [2-(3-hexyl-phenyl)-5-iodo-3-methyl-3H-imidazol-4-yl]-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone (example 2) was reacted with 2-methoxy-pyridin-4-yl-boronic acid to give the title compound as light yellow gum. MS: 530.3 (MH+).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:29])[NH:8][C:9]2[C:14]([C:15]=1[N:16]1[CH2:21][CH2:20][N:19]([C:22]([C:24]3[S:25][CH:26]=[CH:27][CH:28]=3)=[O:23])[CH2:18][CH2:17]1)=[CH:13][N:12]=[CH:11][CH:10]=2)=[O:5])[CH3:2].[F:30][C:31]1[CH:32]=[C:33]([CH:36]=[CH:37][CH:38]=1)[CH2:34]Br>>[CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:29])[N:8]([CH2:34][C:33]2[CH:36]=[CH:37][CH:38]=[C:31]([F:30])[CH:32]=2)[C:9]2[C:14]([C:15]=1[N:16]1[CH2:21][CH2:20][N:19]([C:22]([C:24]3[S:25][CH:26]=[CH:27][CH:28]=3)=[O:23])[CH2:18][CH2:17]1)=[CH:13][N:12]=[CH:11][CH:10]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(N2CCN(C(=O)c3cccs3)CC2)c2cnccc2[nH]c1=O
Reactant: Fc1cccc(CBr)c1
Product: CCOC(=O)c1c(N2CCN(C(=O)c3cccs3)CC2)c2cnccc2n(Cc2cccc(F)c2)c1=O

Procedure:
This compound was prepared from 2-oxo-4-[4-(thiophene-2-carbonyl)-piperazin-1-yl]-1,2-dihydro-[1,6]-naphthyridin-3-carboxylic acid ethyl ester (121) and 3-fluorobenzyl bromide according to General Procedure B. Yield 113 mg (22%), MP 135° C.; 1H-NMR (DMSO-d6): δ 1.28 (t, J=7.2 Hz, 3H), 3.22 (m, 4H), 3.92 (m, 4H), 4.32 (q, J=7.2 Hz, 2H), 5.44 (s, 2H), 6.98 (d, J=7.6 Hz, 1H), 7.10 (m, 2H), 7.16 (dd, J=3.6, 4.8 Hz, 1H), 7.34 (m, 2H), 7.47 (dd, J=1.2, 3.6 Hz, 1H), 7.80 (dd, J=1.2, 4.8 Hz, 1H), 8.56 (d, J=6.0 Hz, 1H), 9.09 (s, 1H); EIMS: 521 (M+1). Anal. (C27H25FN4O4S) C, H, N.
Reaction SMILES: OC(C(F)(F)F)=O.[CH:8]([N:11]1[C:15]([C:16]2[S:17][C:18]3[CH2:19][CH2:20][O:21][C:22]4[CH:29]=[CH:28][C:27]([CH:30]5[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]5)=[CH:26][C:23]=4[C:24]=3[N:25]=2)=[N:14][CH:13]=[N:12]1)([CH3:10])[CH3:9].Br[CH2:37][C:38]([NH2:40])=[O:39]>>[CH:8]([N:11]1[C:15]([C:16]2[S:17][C:18]3[CH2:19][CH2:20][O:21][C:22]4[CH:29]=[CH:28][C:27]([CH:30]5[CH2:35][CH2:34][N:33]([CH2:37][C:38]([NH2:40])=[O:39])[CH2:32][CH2:31]5)=[CH:26][C:23]=4[C:24]=3[N:25]=2)=[N:14][CH:13]=[N:12]1)([CH3:10])[CH3:9]
Reactant: CC(C)n1ncnc1-c1nc2c(s1)CCOc1ccc(C3CCNCC3)cc1-2
Reactant: NC(=O)CBr
Solvent: O=C(O)C(F)(F)F
Product: CC(C)n1ncnc1-c1nc2c(s1)CCOc1ccc(C3CCN(CC(N)=O)CC3)cc1-2

Procedure:
Following the procedure for 319, 2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-9-piperidin-4-yl-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene TFA salt was alkylated with bromoacetamide to give 357 isolated as a white solid (167 mg, 86%). LCMS: RT=7.55 min, [M+H]+=453. 1H NMR δ (ppm) (DMSO-d6): 8.23 (1 H, d, J=2.30 Hz), 8.06 (1 H, s), 7.14 (1 H, dd, J=8.34, 2.37 Hz), 7.10 (2 H, s), 6.95 (1 H, d, J=8.26 Hz), 5.79-5.68 (1 H, m), 4.33-4.27 (2 H, m), 3.41-3.35 (2 H, m), 2.92-2.81 (4 H, m), 2.50 (1 H, m), 2.17 (2 H, dd, J=12.36, 10.20 Hz), 1.78 (2 H, d, J=12.48 Hz), 1.73-1.61 (2 H, m), 1.53 (6 H, d, J=6.61 Hz)
Reaction SMILES: O[CH2:2][C:3]1([CH3:10])[CH2:7][N:6]([CH3:8])[C:5](=[O:9])[NH:4]1.N1C=CC=CC=1.S(Cl)([Cl:19])=O>ClCCCl>[Cl:19][CH2:2][C:3]1([CH3:10])[CH2:7][N:6]([CH3:8])[C:5](=[O:9])[NH:4]1
Reactant: CN1CC(C)(CO)NC1=O
Reactant: O=S(Cl)Cl
Solvent: c1ccncc1
Solvent: ClCCCl
Product: CN1CC(C)(CCl)NC1=O
Yield: 24.3 %

Procedure:
A solution of 4-(hydroxymethyl)-1,4-dimethylimidazolidin-2-one (3.3 g, 22.7 mmol), anhydrous pyridine (8.25 ml, 102 mmol), and thionyl chloride (8.26 ml, 114 mmol) in 46 ml of 1,2-dichloroethane was heated at reflux temperature for 8 hours. The reaction mixture was concentrated under reduced pressure, diluted with dichloromethane, and filtered to remove solids. The organic layer was washed with once 2 N HCl, which was back-extracted three times with dichloromethane, and the combined organic fractions were dried over sodium sulfate and concentrated to 2.2 g of yellow oil. The crude product was purified by column chromatorgraphy, eluting from silica gel with a gradient of 0-10% methanol in dichloromethane to give 897 mg of desired product as a white solid (25% yield). 1H NMR (400 MHz, CDCl3) δ 1.42 (s, 3H), 2.79 (s, 3H), 3.17-3.20 (d, J=9.2 Hz, 1H), 3.36-3.39 (d, J=9.2 Hz, 1H), 3.50 (s, 2H). 13C NMR (100 MHz, CDCl3) δ 24.2, 30.3, 51.5, 55.0, 57.0, 160.6. LRMS (ESI/APCI): 163 [M+H]+.
Reaction SMILES: [CH3:1][N:2]([CH3:20])[CH2:3][CH2:4][NH:5][C:6]([C:8]1[NH:9][C:10]2[C:15]([CH:16]=1)=[CH:14][CH:13]=[C:12]([N+:17]([O-])=O)[CH:11]=2)=[O:7]>C(O)C.C(OC(=O)C)C.[Pd]>[CH3:1][N:2]([CH3:20])[CH2:3][CH2:4][NH:5][C:6]([C:8]1[NH:9][C:10]2[C:15]([CH:16]=1)=[CH:14][CH:13]=[C:12]([NH2:17])[CH:11]=2)=[O:7]
Reactant: CN(C)CCNC(=O)c1cc2ccc([N+](=O)[O-])cc2[nH]1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CN(C)CCNC(=O)c1cc2ccc(N)cc2[nH]1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 82.9 mg (0.3 mmole) 125 in a mixture of ethanol/ethylacetate 1:1 10% Pd/C (40 mg) was added. The flask was flushed 3 times with hydrogen and filled with hydrogen at 30 to 35 psi. The suspension was stirred vigorously at room temperature for 30 minutes. The catalyst was filtered off, the filtrate was evaporated in vacuo to dryness. The solid 126 was used for the next step without purification
Reaction SMILES: COC1C=CC(C(O)=[CH:10][C:11]2[N:20]=[CH:19][CH:18]=[CH:17][C:12]=2[C:13]([NH:15][CH3:16])=[O:14])=CC=1.N>O1CCOCC1>[CH3:10][C:11]1[N:20]=[CH:19][CH:18]=[CH:17][C:12]=1[C:13]([NH:15][CH3:16])=[O:14]
Reactant: CNC(=O)c1cccnc1C=C(O)c1ccc(OC)cc1
Agent: N
Solvent: C1COCCO1
Product: CNC(=O)c1cccnc1C
Temperature: 170 °C
Yield: 127.8 %

Procedure:
2-[2-(4-Methoxyphenyl)-2-hydroxyethenyl]-N-methylnicotinamide (2.509 g) was added to a 29% aqueous solution of ammonia (100 ml) and dioxane (50 ml), which was then heated in a sealed tube at 170° C. overnight. After cooling as it was, the resulting insoluble matters were collected by filtration, to give the title compound as a dark green solid (1.694 g, yield; 73%).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C@H:13]([O:17][CH3:18])[C:14]([OH:16])=[O:15])=[CH:8][CH:7]=1.[CH3:19][CH2:20][CH2:21][CH2:22][C:23]1[CH:24]=[CH:25][C:26](O)=[CH:27][CH:28]=1>>[CH2:22]([C:23]1[CH:24]=[CH:25][C:26]([O:1][CH2:2][CH2:3][CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([CH2:12][C@H:13]([O:17][CH3:18])[C:14]([OH:16])=[O:15])=[CH:8][CH:7]=2)=[CH:27][CH:28]=1)[CH2:21][CH2:20][CH3:19]
Reactant: CCCCc1ccc(O)cc1
Reactant: CO[C@@H](Cc1ccc(OCCCO)cc1)C(=O)O
Product: CCCCc1ccc(OCCCOc2ccc(C[C@H](OC)C(=O)O)cc2)cc1

Procedure:
The title compound was prepared from (2S)-3-[4-(3-hydroxy-propoxy)-phenyl]-2-methoxy-propionic acid linked to Wang's Resin (Example 94, Step D) via Mitsunobu coupling with 4-n-butylphenol and cleavage from the resin (Standard Procedure G) gave an oily solid (7%). 1H-NMR (200.15 MHz, CDCl3): δ 7.11 (dd, 4H, J=12.7, 8.6), 6.82 (dd, 4H, J=8.6, 3.2), 4.12 (t, 4H, J=6.2), 3.97 (dd, 1H, J=7.7, 4.4), 3.38 (s, 3H), 3.30 (dd, 1H, J=14.5, 4.4), 2.94 (dd, 1H, J=14.5, 7.7), 2.54 (t, 2H, J=7.7), 2.23 (qn, 2H, J=6.2), 1.63–1.48 (m, 2H), 1.42–1.24 (m, 2H), 0.91 (t, 3H, J=7.2).
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[Cl:11][C:12]1[CH:19]=[C:18]([OH:20])[CH:17]=[CH:16][C:13]=1[C:14]#N.Cl.[O:22]1CCCC1>O>[Cl:11][C:12]1[CH:19]=[C:18]([OH:20])[CH:17]=[CH:16][C:13]=1[CH:14]=[O:22]
Reactant: C1CCOC1
Reactant: N#Cc1ccc(O)cc1Cl
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: O
Product: O=Cc1ccc(O)cc1Cl
Temperature: -78 °C
Reaction time: 1 h
Yield: 84 %

Procedure:
Diisobutylaluminium hydride (1M in hexane, 240 mL, 240 mmol) was added to a solution of 2-chloro-4-hydroxybenzonitrile (15 g, 97.7 mmol) in tetrahydrofuran (200 mL), cooled to −78° C., and the mixture was stirred at this temperature for 1 hour then at room temperature for 18 hours. The mixture was then cooled to 0° C. and 1M hydrochloric acid (80 mL) was added dropwise. The reaction mixture was diluted with water (200 mL) and filtered, washing through with ethyl acetate (×2). The layers of the filtrate were separated and the organic solution was dried over magnesium sulfate and concentrated in vacuo. Trituration of the residue with dichloromethane afforded the title compound as a solid in 84% yield, 12.92 g.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:4][C:3]=1[C:15]1[CH:20]=[C:19]([CH2:21][CH2:22][CH2:23][C:24]([O:26][CH3:27])=[O:25])[CH:18]=[CH:17][C:16]=1[OH:28].[F:29][C:30]1[CH:37]=[C:36]([Br:38])[CH:35]=[CH:34][C:31]=1[CH2:32]Br.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[F:29][C:30]1[CH:37]=[C:36]([Br:38])[CH:35]=[CH:34][C:31]=1[CH2:32][O:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:4][C:3]=1[C:15]1[CH:20]=[C:19]([CH2:21][CH2:22][CH2:23][C:24]([O:26][CH3:27])=[O:25])[CH:18]=[CH:17][C:16]=1[OH:28]
Reactant: Fc1cc(Br)ccc1CBr
Reactant: COC(=O)CCCc1ccc(O)c(-c2cc(CCCC(=O)OC)ccc2O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)CCCc1ccc(O)c(-c2cc(CCCC(=O)OC)ccc2OCc2ccc(Br)cc2F)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 5 ml of a DMF solution containing 200 mg (0.5181 mmol) of 2,2'-dihydroxy-5,5'-bis (3-methoxycarbonylpropyl) biphenyl and 0.731 ml (5.181 mmol) of 2-fluoro-4-bromobenzyl bromide, there were added 85.8 mg (0.6217 mmol) of anhydrous potassium carbonate and the resulting mixture was agitated for 2 hours at room temperature. The reaction mixture was filtered by suction through Celite to remove the solid matter and the filtrate was washed with ethyl acetate. After the solvent in the filtrate was evaporated off under reduced pressure, the evaporated residue was dissolved in chloroform. This solution was washed with dilute hydrochloric acid, dilute aqueous sodium bicarbonate, water and aqueous sodium chloride solution in this sequence and was dried by adding anhydrous sodium sulfate. The residue obtained after the solvent had been evaporated off was purified by silica gel column chromatography (with 15 g of WAKO-gel C-200, eluent: toluene and toluene/ethyl acetate of 100/1) to obtain 248.1 mg (0.4322 mmol), 83%) of 2-(2-fluoro-4-bromobenzyloxy)-2'-hydroxy-5, 5'-bis(3-methoxycarbonylpropyl) biphenyl as an oily product. 1H-NMR (CDCl3) δ (ppm): 1.7-2.2 (4H, m, 2CH3), 2.35 (4H, t, 2CH2), 2.67 (4H, t, 2CH2), 3.66 (6H, s, 2CH3), 5.03 (2H, s, CH2), 6.87 (1H, s, OH), 6.8-7.3 (9H, m, arom-H), MS (FAB): 573 (M-H)-
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH2:20])=[C:4]([CH2:17][CH2:18][CH3:19])[C:5]2[O:10][C:9]([C:11]([O:13][CH3:14])=[O:12])=[CH:8][C:7](=[O:15])[C:6]=2[CH:16]=1.O=[C:22]([C:28](OCC)=[O:29])[C:23]([O:25][CH2:26][CH3:27])=[O:24]>C(O)C>[OH:29][C:28]1[C:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[N:20][C:3]2[C:4]([CH2:17][CH2:18][CH3:19])=[C:5]3[O:10][C:9]([C:11]([O:13][CH3:14])=[O:12])=[CH:8][C:7](=[O:15])[C:6]3=[CH:16][C:2]=2[N:1]=1
Reactant: CCOC(=O)C(=O)C(=O)OCC
Reactant: CCCc1c(N)c(N)cc2c(=O)cc(C(=O)OC)oc12
Solvent: CCO
Product: CCCc1c2nc(C(=O)OCC)c(O)nc2cc2c(=O)cc(C(=O)OC)oc12

Procedure:
The product of step (c) above (0.6 g) was suspended in ethanol (25 ml), and diethyl ketomalonate (0.382 g) was added. The mixture was refluxed for 18 hours, and the resulting precipitate was collected (0.29 g) and identified as the sub-title compound by NMR and MS: δDMSO : 1.0 (3H,t), 1.4 (3H, t), 1.6 (2H, m), 3.0 (2H, t), 4.0 (3H, s), 4.4 (2H, q), 6.95 (1H, s), 8.2 (1H, s).
Reaction SMILES: [Si]([O:8][CH:9]1[CH2:14][C:13]([CH3:16])([CH3:15])[C:12]([CH:17]=[CH:18][C:19](=[O:22])[CH2:20][CH3:21])=[C:11]([CH3:23])[CH2:10]1)(C(C)(C)C)(C)C.[OH:24]C1(C)CC(O)CC(C)(C)C1C=CC(O)C>>[OH:24][C:11]1([CH3:23])[CH2:10][CH:9]([OH:8])[CH2:14][C:13]([CH3:16])([CH3:15])[CH:12]1[CH:17]=[CH:18][CH:19]([OH:22])[CH2:20][CH3:21]
Reactant: CCC(=O)C=CC1=C(C)CC(O[Si](C)(C)C(C)(C)C)CC1(C)C
Reactant: CC(O)C=CC1C(C)(C)CC(O)CC1(C)O
Product: CCC(O)C=CC1C(C)(C)CC(O)CC1(C)O

Procedure:
The entitled compound was prepared from 1-[4-(t-butyldimethylsilyl)oxy-2,6,6-trimethylcyclohex-1-enyl]pent-1-en-3-one in the same manner as described in Example 1-(4), (5), and (6).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[N:3]=1.CC1(C)C(C)(C)OB([C:17]2[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=2[C:19]#[N:20])O1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CN(C)C=O.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>[Br:8][C:4]1[N:3]=[C:2]([C:17]2[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=2[C:19]#[N:20])[CH:7]=[CH:6][CH:5]=1
Reactant: Brc1cccc(Br)n1
Reactant: CC1(C)OB(c2ccccc2C#N)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1ccccc1-c1cccc(Br)n1
Temperature: 80 °C
Yield: 100 %

Procedure:
2,6-Dibromopyridine (0.47 g, 2.0 mmol), 2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)benzonitrile (0.69 g, 3.0 mmol) and potassium phosphate (0.85 g, 4.0 mmol) were dissolved in N,N-dimethylformamide (10 ml) and degassed with nitrogen for 15 min. Tetrakis(triphenylphosphine)palladium(0) (70 mg, 0.06 mmol) was added then the mixture heated at 80° C. for 16 h. The mixture was allowed to cool to ambient temperature, diluted with water (200 ml) and extracted into ethyl acetate (2×150 ml). The combined organics were washed with brine (200 ml), dried over anhydrous sodium sulfate and evaporated to give a yellow oil. Purification by flash column chromatography on silica eluting with isohexane on a gradient of ethyl acetate (10-30%) gave 2-(6-bromopyridin-2-yl)benzonitrile (0.518 g, 100%) as a waxy solid: δH (360 MHz, CDCl3) 7.53-7.57 (2H, m), 7.68-7.72 (2H, m), 7.80 (1H, d, J 8), 7.86-7.90 (1H, m).
Reaction SMILES: Br[C:2]1([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=2)[C:10]2[C:5](=[CH:6][C:7]([Cl:11])=[CH:8][CH:9]=2)[NH:4][C:3]1=[O:12].[F:21][C:22]([F:36])([F:35])[C:23]1[CH:28]=[CH:27][C:26]([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)=[CH:25][CH:24]=1.CCN(C(C)C)C(C)C>C(#N)C>[Cl:11][C:7]1[CH:6]=[C:5]2[C:10]([C:2]([CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=3)([N:32]3[CH2:31][CH2:30][N:29]([C:26]4[CH:25]=[CH:24][C:23]([C:22]([F:35])([F:36])[F:21])=[CH:28][CH:27]=4)[CH2:34][CH2:33]3)[C:3](=[O:12])[NH:4]2)=[CH:9][CH:8]=1
Reactant: O=C1Nc2cc(Cl)ccc2C1(Br)Cc1cccc(Cl)c1
Reactant: FC(F)(F)c1ccc(N2CCNCC2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: O=C1Nc2cc(Cl)ccc2C1(Cc1cccc(Cl)c1)N1CCN(c2ccc(C(F)(F)F)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 54.1 %

Procedure:
The mixture of rac-3-bromo-6-chloro-3-(3-chloro-benzyl)-1,3-dihydro-indol-2-one (100 mg, 0.270 mmol), 1-(4-trifluoromethyl-phenyl)-piperazine (75 mg, 0.324 mmol) and DIPEA (42 mg, 0.324 mmol) In acetonitrile (3 mL) was stirred at room temperature for overnight. The crude was concentrated and the residue was purified with preparative HPLC to give 76 mg of rac-6-chloro-3-(3-chloro-benzyl)-3-[4-(4-trifluoromethyl-phenyl)-piperazin-1-yl]-1,3-dihydro-indol-2-one as a white solid. MS: 520 (M+H)+. H1-NMR (400 MHz, CDCl3) δ 7.584 (s, 1H), 7.493 (d, 2H), 7.240 (d, 1H), 7.081 (t, 2H), 7.011 (t, 1H), 6.908 (d, 3H), 6.766 (d, 1H), 6.684 (d, 1H), 3.431 (d, 1H), 3.329-3.206 (m, 5H), 2.947 (t, 4H).
Reaction SMILES: Br[CH2:2][C:3]1[O:4][C:5]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:7]=1.[OH:20][C:21]1[CH:22]=[C:23]([CH2:27][CH2:28][C:29]([O:31][CH3:32])=[O:30])[CH:24]=[CH:25][CH:26]=1>>[C:8]1([C:6]2[N:7]=[C:3]([CH2:2][O:20][C:21]3[CH:22]=[C:23]([CH2:27][CH2:28][C:29]([O:31][CH3:32])=[O:30])[CH:24]=[CH:25][CH:26]=3)[O:4][C:5]=2[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: BrCc1nc(-c2ccccc2)c(-c2ccccc2)o1
Reactant: COC(=O)CCc1cccc(O)c1
Product: COC(=O)CCc1cccc(OCc2nc(-c3ccccc3)c(-c3ccccc3)o2)c1
Reaction time: 0.5 h
Yield: 833.6 %

Procedure:
A mixture of 2-bromomethyl-4,5-diphenyloxazole (10.00 g, 3 mmol), methyl 3-(3-hydroxyphenyl)propanoate (5.73 g, 3 mmol) potassium carbonate (4.83 g, 3.5 mmol) potassium iodide (catalytic amount) and acetonetrile (150 mL) was stirred at reflux temperature. After 30 minutes, the mixture was filtered, concentrated in vacuo and the residual oil chromatographed on a column of silica gel. Elution with a mixture of hexanes and diethyl ether (3:1) furnished methyl 3-[3-((4,5-diphenyl-2-oxazolyl)methoxy]phenyl]propanoate (10.34 g, 78%) as an oil. An analytical sample was prepared by subjecting a 4 g sample to chromatography under the conditions described above to furnish pure material as an oil.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:22])([F:21])[CH2:17]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][CH3:15])[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(N2CCC(F)(F)C2)C2N=NNC=2N=1)(C)(C)C.Br.BrCC1[C:47]([Cl:52])=[N:48][CH:49]=[CH:50][CH:51]=1>>[C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:21])([F:22])[CH2:17]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[C:47]([Cl:52])=[N:48][CH:49]=[CH:50][CH:51]=3)[C:9]=2[N:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: Clc1ncccc1CBr
Reactant: CCn1nnc2c(N3CCC(F)(F)C3)nc(C(C)(C)C)nc21
Agent: Br
Agent: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1
Product: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nnn(Cc3cccnc3Cl)c2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3-ethyl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 61), the title compound was prepared from 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 3-(bromomethyl)-2-chloropyridine hydrobromide and isolated as light-yellow gum. MS(m/e): 408.3 (MH+).