Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[C:11]([O:12][CH2:13][CH3:14])=[CH:10][CH:9]=[CH:8][N:7]=1.[CH3:15][S:16][C:17](S(C)=O)=[CH:18][N+:19]([O-:21])=[O:20]>CO>[CH3:15][S:16][C:17]([NH:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[C:11]([O:12][CH2:13][CH3:14])=[CH:10][CH:9]=[CH:8][N:7]=1)=[CH:18][N+:19]([O-:21])=[O:20]
Reactant: CSC(=C[N+](=O)[O-])S(C)=O
Reactant: CCOc1cccnc1CSCCN
Solvent: CO
Product: CCOc1cccnc1CSCCNC(=C[N+](=O)[O-])SC
Reaction time: 8 h
Yield: 49.2 %

Procedure:
2-(2-Aminoethylthiomethyl)-3-ethoxypyridine (2.2 g) in methanol (35 cc) was added over 25 minutes to a stirred solution of 1-methylthio-1-methylsulphinyl-2-nitroethylene (2.07 g) in methanol (85 ml) at 27°-30°, and the mixture was left overnight at room temperature. The mixture was evaporated to a residual oil which was triturated with ethanol/ether to give 1-methylthio-1-[2-(3-ethoxy-2-pyridylmethylthio)ethylamino]-2-nitroethylene (1.68 g) m.p. 126°-127°.
Reaction SMILES: [N:1]1([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][NH2:15])[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.BrCCCCCN1[C:26](=[O:27])[C:25]2=[CH:28][CH:29]=[CH:30][CH:31]=[C:24]2[C:23]1=[O:32].N1C2C=CC=CC=2N=C1>>[C:23]1(=[O:32])[N:15]([CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][N:1]2[C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[N:3]=[CH:2]2)[C:26](=[O:27])[C:25]2=[CH:28][CH:29]=[CH:30][CH:31]=[C:24]12
Reactant: O=C1c2ccccc2C(=O)N1CCCCCBr
Reactant: NCCCCCn1cnc2ccccc21
Agent: c1ccc2[nH]cnc2c1
Product: O=C1c2ccccc2C(=O)N1CCCCCn1cnc2ccccc21

Procedure:
In this case, the 1H-benzimidazole-1-pentanamine used as the starting material was obtained by first reacting N-(5-bromopentyl)phthalimide with 1H-benzimidazole to give 1-(5-phthalimidopentyl)-1H-benzimidazole which was then treated with hydrazine to give the amine, all according to general procedures known in the art (Houben-Weyl, Vol. XI/1, page 82, George Thieme Verlag, Stuttgart, 1957).
Reaction SMILES: [CH3:1][C@H:2]1[NH:7][C@@H:6]([CH3:8])[CH2:5][N:4]([C:9]2[CH:10]=[CH:11][C:12]([O:16][CH3:17])=[C:13]([CH:15]=2)[NH2:14])[CH2:3]1.CN1CCOCC1.[Br:25][C:26]1[CH:31]=[CH:30][C:29]([S:32](Cl)(=[O:34])=[O:33])=[C:28]([Cl:36])[CH:27]=1>ClCCl>[Br:25][C:26]1[CH:31]=[CH:30][C:29]([S:32]([NH:14][C:13]2[CH:15]=[C:9]([N:4]3[CH2:3][C@H:2]([CH3:1])[NH:7][C@H:6]([CH3:8])[CH2:5]3)[CH:10]=[CH:11][C:12]=2[O:16][CH3:17])(=[O:33])=[O:34])=[C:28]([Cl:36])[CH:27]=1
Reactant: COc1ccc(N2C[C@@H](C)N[C@@H](C)C2)cc1N
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: COc1ccc(N2C[C@@H](C)N[C@@H](C)C2)cc1NS(=O)(=O)c1ccc(Br)cc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 5-(cis-3,5-dimethyl-1-piperazinyl)-2-(methyloxy)aniline (D4) (1.20 g, 5.09 mmol) in dichloromethane (35 ml) was treated with morpholinomethyl-polystyrene HL resin (2.43 g, 4.2 mmol/g loading, 10.21 mmol) and then the 4-bromo-2-chlorobenzenesulfonyl chloride (2.96 g, 10.21 mmol). The resulting solution was stirred at room temperature overnight. The resin and was filtered, washed with methanol, and the solvent evaporated in vacuo. The residue was then passed through an SCX column eluting first with methanol followed by 2M ammonia in methanol. The basic fractions were collectedand solvent evaporated in vacuo to afford a crude product which was purified further by chromatography using a Flashmaster using an elution gradient of 0 to 5% methanol in dichloromethane. The relevant fractions were collected, combined and the solvent evaporated in vacuo to afford the title compound (E104). MS (ES+) m/e 488/490/492 [M+H]+.
Reaction SMILES: Cl[N:2]1[C:6]2[CH:7]=[CH:8][C:9]([I:11])=[CH:10][C:5]=2[N:4]=[CH:3]1.[NH:12]1[CH2:17][CH2:16][C:15]2([C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:19](=[O:26])[O:18]2)[CH2:14][CH2:13]1.O>CN1C(=O)CCC1>[I:11][C:9]1[CH:8]=[CH:7][C:6]2[NH:2][C:3]([N:12]3[CH2:17][CH2:16][C:15]4([C:25]5[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=5)[C:19](=[O:26])[O:18]4)[CH2:14][CH2:13]3)=[N:4][C:5]=2[CH:10]=1
Reactant: Cln1cnc2cc(I)ccc21
Reactant: O=C1OC2(CCNCC2)c2ccccc21
Solvent: O
Solvent: CN1CCCC1=O
Product: O=C1OC2(CCN(c3nc4cc(I)ccc4[nH]3)CC2)c2ccccc21

Procedure:
Heat a solution of 2 chloro-5-iodo-1H-benzimidazole (3.0 g, 10.7 mmol) and spiro[isobenzofuran-1,4′-piperidin]-3-one (2.63 g, 12.9 mmol) in dry NMP (15 mL) at 100° C. for 14 hours. Pour the cooled mixture into water (50 mL) and extract twice with EtOAc (50 mL). Wash the combined extracts with brine (30 mL), dry, and evaporate in vacuo. Purify by flash column chromatography (50% EtOAc-hexane) to obtain 1′-(5-iodo-1H-benzimidazol-2-yl)-spiro[isobenzofuran-1,4′-piperidin]-3-one as a beige solid. C. 1′-(5-Pyridin-3-yl-1G-benzimidazol-2-yl)-spiro[isobenzofuran-1,44′-piperidin]-3-one
Reaction SMILES: CC(O)=O.[NH2:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[N:12]=[C:11]([CH3:16])[C:10]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:9]2[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[CH2:28]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH2:30][C:29]1=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl>[CH2:28]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH2:30][CH:29]1[NH:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[N:12]=[C:11]([CH3:16])[C:10]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:9]2[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: O=C1Cc2ccccc2C1
Reactant: CCOC(=O)c1c(C)nc2ccc(N)cc2c1-c1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CCOC(=O)c1c(C)nc2ccc(NC3Cc4ccccc4C3)cc2c1-c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 75.3 %

Procedure:
A method of Abdel-Magid et al (J. Org. Chem., 61, 3849, 1996) was used: Glacial AcOH (0.25 ml) was added to a solution of the product of Step 2 (1.46 g, 4.4 mmol), 1H-inden-2(3H)-one (0.46 g, 4.5 mmol) and NaBH(OAc)3 (1.4 g, 6.55 mmol) in anhydrous 1,2-dichloroethane (17 ml). The resulting mixture was stirred overnight at room temperature under N2 and to it more of NaBH(OAc)3 (0.4 g, 1.9 mmol) was added. After 2 h of stirring at room temperature, the mixture was quenched by addition of 1N NaOH aq (5 ml). This was diluted to 60 ml with Et2O and washed with H2O and brine. The organic phase was dried over anhydrous MgSO4, filtered and filtrate evaporated to dryness under reduced pressure. The residue was purified by flash column chromatography (SiO2, CH2Cl2) to give pure product as a creamy solid (1.4 g, 71%). 1H NMR (300 MHz, CDCl3) δ 7.83 (d, J=9.0 Hz, 1H), 7.34-7.5(m, 5H), 7.12-7.21(m, 4H), 7.05(dd, J=2.6, 9.0 Hz, 1H), 6.49(d, J=2.6 Hz, 1H), 4.17(m, 1H), 4.08(m, 1H), 3.19-3.27(m 2H), 2.73-2.83(m, 2H), 2.7(s, 3H), 1.22(s, 9H).
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[C:11]([C:13](OCC)=[O:14])[C:10]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]3[N:29]=[C:30]([C:34]4[O:35][CH:36]=[CH:37][CH:38]=4)[O:31][C:32]=3[CH3:33])=[C:22]([Cl:39])[CH:21]=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Na+].[Na+]>O1CCCC1.C(OCC)(=O)C>[CH2:1]([N:8]1[CH:12]=[C:11]([CH2:13][OH:14])[C:10]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]3[N:29]=[C:30]([C:34]4[O:35][CH:36]=[CH:37][CH:38]=4)[O:31][C:32]=3[CH3:33])=[C:22]([Cl:39])[CH:21]=2)=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cn(Cc2ccccc2)nc1OCc1ccc(OCc2nc(-c3ccco3)oc2C)c(Cl)c1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: Cc1oc(-c2ccco2)nc1COc1ccc(COc2nn(Cc3ccccc3)cc2CO)cc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.5 %

Procedure:
To a solution of ethyl 1-benzyl-3-[(3-chloro-4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}benzyl)oxy]-1H-pyrazole-4-carboxylate (1.30 g) in tetrahydrofuran (30 mL) was added lithium aluminum hydride (0.14 g) at 0° C. and the mixture was stirred at room temperature for 1 hr. Sodium sulfate decahydrate (1.16 g) was added to the reaction mixture, and the mixture was stirred at room temperature for 30 min. The reaction mixture was diluted with ethyl acetate and the precipitate was filtered off. The filtrate was concentrated to give {1-benzyl-3-[(3-chloro-4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}benzyl)oxy]-1H-pyrazol-4-yl]methanol as colorless crystals (1.11 g, yield 92%). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 119-120° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:23](=[CH:24][CH:25]=1)[C:7]1[NH:8][N:9]=[C:10]([C:11]3[C:12]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)=[N:13][O:14][C:15]=3[CH3:16])[C:6]=1[CH2:5]2.BrC1C=C2C(=CC=1)CCC2.[CH3:36][N:37](C=O)C>[C-]#N.[Zn+2].[C-]#N>[CH3:16][C:15]1[O:14][N:13]=[C:12]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:11]=1[C:10]1[NH:9][N:8]=[C:7]2[C:23]3[C:4]([CH2:5][C:6]=12)=[CH:3][C:2]([C:36]#[N:37])=[CH:25][CH:24]=3
Reactant: Cc1onc(-c2ccccc2)c1-c1n[nH]c2c1Cc1cc(Br)ccc1-2
Reactant: CN(C)C=O
Agent: Brc1ccc2c(c1)CCC2
Agent: [C-]#N
Agent: [Zn+2]
Product: Cc1onc(-c2ccccc2)c1-c1[nH]nc2c1Cc1cc(C#N)ccc1-2
Temperature: 80 °C
Yield: 13 %

Procedure:
A suspension of 6-bromo-3-(5-methyl-3-phenylisoxazol-4-yl)-1,4-dihydroindeno[1,2-c]pyrazole (500 mg, 1.3 mmol) (prepared from 5-bromoindane in the same manner as Example 1) and zinc cyanide (912 mg, 7.8 mmol) in DMF (5 ml) was degassed with N2 for 0.5 hr, tetrakis(triphenylphosphine)palladium(0) (100 mg) was added and heated to 80° C. for 3 days. The reaction mixture was cooled, poured into 10% ammonium hydroxide solution and extracted into EtOAc. The organic layer was washed with H2O(×3) then dried (MgSO4), evaporated and the residue chromatographed on silica, eluting with dichloromethane and recrystallised from hot dichloromethane to give the title compound as a white solid (55 mg, 13%). 1H NMR (400 MHz, CDCl3) δ 7.84 (d, J=8.4 Hz, 1H), 7.68 (d, J=7.6 Hz, 2H), 7.51–7.37 (m, 5H), 3.35 (s, 2H), 2.59 (s, 3H), m/z (ES+) 339 (M+H)+.
Reaction SMILES: FC(F)(F)C1C=CC=C(C(F)(F)F)C=1.[F:15][C:16]1[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=1)[C:19](Cl)=[O:20].[H][H]>O>[F:15][C:16]1[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=1)[CH:19]=[O:20]
Reactant: [H][H]
Reactant: O=C(Cl)c1cccc(F)c1
Agent: FC(F)(F)c1cccc(C(F)(F)F)c1
Solvent: O
Product: O=Cc1cccc(F)c1
Temperature: 85 °C
Yield: 57 %

Procedure:
0.5 g of 5% palladium on barium sulfate (recovered from Example 1) and 50 g of 3-fluorobenzoyl chloride were placed in a reaction vessel at room temperature with exclusion of water. A gentle stream of hydrogen gas was then introduced at atmospheric pressure. The mixture was subsequently heated to 80-90° C. and hydrogen gas was introduced continuously at atmospheric pressure. After liberation of acidic offgases had ceased (9.5 hours), the mixture was cooled to room temperature, the catalyst was removed by filtration and the filtrate was distilled at 28 mbar. At a boiling point of 73° C., 3-fluorobenzaldehyde was obtained in a yield of 23.0 g. This corresponds to a yield of 57% of theory.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[O:12])[O:4][C:3]=1[CH:13]([OH:15])[CH3:14].[F:16][C:17]1[CH:18]=[C:19](B(O)O)[CH:20]=[CH:21][CH:22]=1.C([O-])([O-])=O.[Cs+].[Cs+]>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:16][C:17]1[CH:22]=[C:21]([C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5](=[O:12])[O:4][C:3]=2[CH:13]([OH:15])[CH3:14])[CH:20]=[CH:19][CH:18]=1
Reactant: OB(O)c1cccc(F)c1
Reactant: CC(O)c1oc(=O)c2ccccc2c1Br
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: [Cs+]
Product: CC(O)c1oc(=O)c2ccccc2c1-c1cccc(F)c1
Yield: 46.2 %

Procedure:
The title compound was made in a similar way as that of the intermediate B1 using 4-bromo-3-(1-hydroxyethyl)-1H-isochromen-1-one (Intermediate A2, 0.8 g, 2.97 mmol), 3-fluorophenylboronic acid (0.62 g, 4.46 mmol), Pd(PPh3)4 (0.17 g, 0.149 mmol) and Cs2CO3 (0.97 g, 2.9 mmol) to afford the title compound (0.39 g, 46%).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]([NH:15][NH2:16])=[O:14].[F:17][C:18]1[CH:26]=[C:25]([F:27])[C:24]([F:28])=[CH:23][C:19]=1[C:20](O)=O>>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]1[O:14][C:20]([C:19]2[CH:23]=[C:24]([F:28])[C:25]([F:27])=[CH:26][C:18]=2[F:17])=[N:16][N:15]=1
Reactant: Cc1onc(-c2ccccc2)c1C(=O)NN
Reactant: O=C(O)c1cc(F)c(F)cc1F
Product: Cc1onc(-c2ccccc2)c1-c1nnc(-c2cc(F)c(F)cc2F)o1
Yield: 46 %

Procedure:
As described for example 2, 5-methyl-3-phenyl-isoxazole-4-carboxylic acid hydrazide (4.18 g, 19.2 mmol) was converted using 2,4,5-trifluorobenzoic acid instead of o-toluic acid to the title compound (3.16 g, 46%) which was obtained as a white solid. MS: m/e=358.1 [M+H]+.
Reaction SMILES: F[C:2]1[C:19]([F:20])=[C:18]([F:21])[C:17]([F:22])=[CH:16][C:3]=1[C:4]([C:6](=[CH:12]OCC)[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5].[CH3:23][O:24][C:25]1[CH:30]=[CH:29][C:28]([NH2:31])=[CH:27][CH:26]=1>C(O)C>[F:22][C:17]1[CH:16]=[C:3]2[C:2](=[C:19]([F:20])[C:18]=1[F:21])[N:31]([C:28]1[CH:29]=[CH:30][C:25]([O:24][CH3:23])=[CH:26][CH:27]=1)[CH:12]=[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[C:4]2=[O:5]
Reactant: CCOC=C(C(=O)OCC)C(=O)c1cc(F)c(F)c(F)c1F
Reactant: COc1ccc(N)cc1
Solvent: CCO
Product: CCOC(=O)c1cn(-c2ccc(OC)cc2)c2c(F)c(F)c(F)cc2c1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 80.5 %

Procedure:
A mixture of ethyl 2-(2,3,4,5-tetrafluorobenzoyl)-3-ethoxyacrylate (0.4 g), p-anisidine (0.15 g) and ethanol (4 ml) is stirred at room temperature for 30 minutes. After the reaction, the solvent is distilled off under reduced pressure. To the resulting residue is added anhydrous dioxane (10 ml) and further added portionwise 60% sodium hydride (60 mg). The mixture is stirred at room temperature for 30 minutes. Thereafter, the reaction mixture is poured into saturated aqueous ammonium chloride and then extracted with dichloromethane to give ethyl 6,7,8-trifluoro-1-(4-methoxyphenyl)- 1,4-dihydro-4-oxoquinoline-3-carboxylate (0.37 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH3:14][O:15][C:16]1[C:21]([C:22]2[CH:31]=[CH:30][CH:29]=[C:28]3[C:23]=2[CH2:24][CH2:25][NH:26][CH:27]3[CH3:32])=[CH:20][CH:19]=[CH:18][N:17]=1>>[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:26]3[CH2:25][CH2:24][C:23]4[C:28](=[CH:29][CH:30]=[CH:31][C:22]=4[C:21]4[C:16]([O:15][CH3:14])=[N:17][CH:18]=[CH:19][CH:20]=4)[CH:27]3[CH3:32])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: O=C(O)c1cc2ncc(Cl)cn2n1
Reactant: COc1ncccc1-c1cccc2c1CCNC2C
Product: COc1ncccc1-c1cccc2c1CCN(C(=O)c1cc3ncc(Cl)cn3n1)C2C

Procedure:
In close analogy to the procedure described in Example 1, 6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 5-(2-Methoxy-pyridin-3-yl)-1-methyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
Reaction SMILES: [OH-].[Na+].BrBr.Br[O-].[O:7]=[S:8]1(=[O:25])[CH2:12][CH2:11][CH2:10][N:9]1[C:13]12[CH2:21][CH:17]3[CH2:18][CH:19]([CH2:20]1)[C:15]([C:22](=[O:24])C)([CH2:16]3)[CH2:14]2.CC(O)=[O:28]>O1CCOCC1.O>[O:7]=[S:8]1(=[O:25])[CH2:12][CH2:11][CH2:10][N:9]1[C:13]12[CH2:21][CH:17]3[CH2:18][CH:19]([CH2:20]1)[C:15]([C:22]([OH:28])=[O:24])([CH2:16]3)[CH2:14]2
Reactant: CC(=O)C12CC3CC1CC(N1CCCS1(=O)=O)(C3)C2
Reactant: CC(=O)O
Agent: BrBr
Agent: [Na+]
Agent: [O-]Br
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)C12CC3CC1CC(N1CCCS1(=O)=O)(C3)C2
Reaction time: 0.08 h
Yield: 89.3 %

Procedure:
To a stirred mixture of NaOH (2.1 g, 53.0 mmol), H2O (14 mL), and 1,4 dioxane (4 mL) at ice bath temperature was added Br2 (1.0 mL, 19.8 mmol) and the mixture was stirred for 5 minutes. Thus formed hypobromite solution was added drop-wise to a stirred solution of the compound obtained in step I (1.0 g, 3.53 mmol) in 1,4-dioxane (7 mL) at 10° C. The temperature of the reaction was gradually brought to room temperature and the reaction was stirred for 1 h, then it was cooled to ice bath temperature and quenched by adding AcOH (3.9 mL, 65.7 mmol). The reaction mixture was diluted with water and extracted with EtOAc. The combined organic layer was washed with brine, dried over Na2SO4, and the solvent was removed under reduced pressure to obtain 1-(1,1-dioxido iso thiazolidin-2-yl)tricyclo[3.3.1.03,7]nonane-3-carboxylic acid as a viscous liquid (0.9 g) in 90% yield. m/z (M+1) 286; 1H NMR (CDCl3) 300 MHz δ 3.37 (t, J=6.6 Hz, 2H), 3.16 (t, J=7.8 Hz, 2H), 2.84-2.76 (m, 1H), 2.52-2.41 (m, 2H), 2.38-2.26 (m, 2H), 2.25-1.98 (m, 6H), 1.85-1.72 (m, 2H), 1.61 (dd, J=2.2, 11.3 Hz, 1H).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:27]=[CH:26][C:16]([CH2:17][P:18](=[O:25])([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21])=[CH:15][CH:14]=2)[N:3]=1.[NH2:28][C:29]1[CH:30]=[CH:31][CH:32]=[C:33]2[C:38]=1[C:37](=[O:39])[N:36]([CH3:40])[CH2:35][CH2:34]2>>[CH3:40][N:36]1[CH2:35][CH2:34][C:33]2[C:38](=[C:29]([NH:28][C:2]3[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]4[CH:14]=[CH:15][C:16]([CH2:17][P:18](=[O:25])([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21])=[CH:26][CH:27]=4)[N:3]=3)[CH:30]=[CH:31][CH:32]=2)[C:37]1=[O:39]
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)cc1)OCC
Reactant: CN1CCc2cccc(N)c2C1=O
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3cccc4c3C(=O)N(C)CC4)n2)cc1)OCC

Procedure:
The title product was prepared according to the procedure for Example 102 using diethyl (4-{[4-chloro-5-(trifluoromethyl)pyrimidin-2-yl]amino}benzyl)phosphonate (52.9 mg, 0.125 mmol) and 8-amino-2-methyl-3,4-dihydroisoquinolin-1(2H)-one (Compound 132A, 25 mg, 0.14 mmol). The crude material was adsorbed onto a pre-filled solid loading cartridge and purified using the Teledyne/ISCO Combiflash system, eluting with 0-5% MeOH:CH2Cl2. The desired fractions were pooled together and concentrated in vacuo, giving the title material as a white solid, 42.0 mg (59%). 1H NMR (400 MHz, DMSO-d6) δ ppm 12.55 (br s, 1H), 9.82 (br s, 1H), 8.44 (s, 1H), 8.56 (br s, 1H), 7.58 (d, J=7.8 Hz, 2H), 7.40 (t, J=8.0 Hz, 1H), 7.19 (dd, J=8.6, 2.3 Hz, 2H), 6.97 (d, J=7.3 Hz, 1H), 3.95 (qd, J=7.4, 7.2 Hz, 4H), 3.56 (t, J=6.7 Hz, 2H), 3.18 (d, J=21.2 Hz, 2H), 3.06 (s, 3H), 2.97 (t, J=6.6 Hz, 2H), 1.18 (t, J=7.1 Hz, 6H). MS (ES+): m/z 564.16 (100) [MH+]. HPLC: tR=3.50 min (ZQ3, polar—5 min).
Reaction SMILES: [F:1][C:2]1[C:11]([C@H:12]2[CH2:14][O:13]2)=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([O:15][CH3:16])=[N:9]2)=[N:4][CH:3]=1.[C:17]1([CH2:23][O:24][C:25](=[O:33])[NH:26][CH2:27][C@@H:28]2[CH2:32][CH2:31][NH:30][CH2:29]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.Cl([O-])(=O)(=O)=O.[Li+]>C(#N)C>[C:17]1([CH2:23][O:24][C:25](=[O:33])[NH:26][CH2:27][C@@H:28]2[CH2:32][CH2:31][N:30]([CH2:14][C@@H:12]([C:11]3[C:10]4[C:5](=[CH:6][CH:7]=[C:8]([O:15][CH3:16])[N:9]=4)[N:4]=[CH:3][C:2]=3[F:1])[OH:13])[CH2:29]2)[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: COc1ccc2ncc(F)c([C@H]3CO3)c2n1
Reactant: O=C(NC[C@@H]1CCNC1)OCc1ccccc1
Agent: [Li+]
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: CC#N
Product: COc1ccc2ncc(F)c([C@@H](O)CN3CC[C@@H](CNC(=O)OCc4ccccc4)C3)c2n1
Temperature: 43 °C
Yield: 55 %

Procedure:
To a solution of 7-fluoro-2-(methyloxy)-8-[(2S)-2-oxiranyl]-1,5-naphthyridine (220 mg, 1.0 mmol) in acetonitrile (5 mL) were added phenylmethyl[(3R)-3-pyrrolidinylmethyl]carbamate (235 mg, 1.0 mmol) followed by Lithium perchlorate (106 mg, 1.0 mmol). After heated at 43° C. for 48 h, the resulting mixture was cooled down to room temperature, concentrated and purified with column chromatography (silica, 1-5% methanol in DCM (1% NH4OH)) to provide the title compound as an off-white solid (250 mg, 55%): LC/MS (ES) m/e 455 (M+H)+.
Reaction SMILES: C([Li])CCC.[CH2:6]([OH:10])[CH2:7][CH2:8][OH:9].Br[CH2:12][CH:13]=[C:14]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[CH3:28])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH3:21]>O>[CH3:28][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[C:14]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH3:21])=[CH:13][CH2:12][O:9][CH2:8][CH2:7][CH2:6][OH:10]
Reactant: Cc1ccccc1C(=CCBr)c1ccccc1C
Reactant: OCCCO
Agent: [Li]CCCC
Solvent: O
Product: Cc1ccccc1C(=CCOCCCO)c1ccccc1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 31 %

Procedure:
A solution of n-butyllithium in hexanes (15.2 ml, 2.5 M) was added dropwise under a nitrogen atmosphere to 1,3- propanediol (31 ml) on an ice-bath. When addition was complete the mixture was stirred 0.5 h at room temperature. 3-Bromo-1,1-bis(2-methylphenyl)-1-propene (11.5 g, 38 mmol, prepared in a similar way to the method described in Example 23) was added and the reaction mixture was stirred at room temperature for 48 h and at 75° C. for 36 h. Water (100 ml) was added and the mixture was extracted with ethyl acetate (100 ml). The phases were separated and the organic phase was washed with water (2×50 ml), dried over magnesium sulphate and the solvent evaporated in vacuo. Flash chromatography of the residue on silica gel (300 g) using a gradient of n-heptane in ethyl acetate as eluent provided 3.5 g (31 %) of 3-(3,3-bis(2-methyl phenyl)-2-propen-1-yloxy)-1-propanol.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7]O[C:9]2=[O:14])([O-:3])=[O:2].Cl.[CH3:16][S:17]([CH2:20][CH2:21][NH2:22])(=[O:19])=[O:18].CO>>[CH3:16][S:17]([CH2:20][CH2:21][N:22]1[CH:7]=[CH:6][C:5]2[C:10](=[CH:11][CH:12]=[CH:13][C:4]=2[N+:1]([O-:3])=[O:2])[C:9]1=[O:14])(=[O:19])=[O:18]
Reactant: CS(=O)(=O)CCN
Reactant: O=c1occc2c([N+](=O)[O-])cccc12
Agent: Cl
Solvent: CO
Product: CS(=O)(=O)CCn1ccc2c([N+](=O)[O-])cccc2c1=O
Temperature: 25 °C

Procedure:
Into a round bottom flask was combined 5-nitro-isochromen-1-one (1.5 g, 0.0071 mol), 2-(methylsulfonyl)ethanamine hydrochloride (2.2 g, 0.014 mol) and methanol (45 mL, 1.1 mol). The mixture was heated at reflux for 1.5 hours. The mixture was cooled to room temperature and was concentrated to yield a yellow solid. The solid was taken onto the next step without further purification.
Reaction SMILES: [H-].[Na+].[Si:3]([O:10][CH2:11][C@@H:12]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH3:13])([C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:5])[CH3:4].[CH3:22]I>CN(C=O)C>[Si:3]([O:10][CH2:11][C@@H:12]([N:14]([CH3:22])[C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH3:13])([C:6]([CH3:9])([CH3:7])[CH3:8])([CH3:5])[CH3:4]
Reactant: C[C@@H](CO[Si](C)(C)C(C)(C)C)NC(=O)OC(C)(C)C
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[C@@H](CO[Si](C)(C)C(C)(C)C)N(C)C(=O)OC(C)(C)C
Reaction time: 0.5 h

Procedure:
To a solution of NaH (60% dispersed in mineral oil, 60 mg, 1.49 mmol, 1.15 equiv.) in DMF (2.0 mL) was added (S)-tert-butyl 1-(tert-butyldimethylsilyloxy)propan-2-ylcarbamate (360 mg, 1.3 mmol). The reaction mixture was stirred for 30 min followed by addition of methyl iodide (93 μL, 1.49 mmol, 1.15 equiv.) and stirred for 1 h. LC/MS indicated the reaction was complete. The reaction mixture was quenched with saturated NH4Cl and diluted with EtOAc. The organic layer was separated, washed with brine, dried over Na2SO4, and filtered. The filtrate was concentrated under reduced pressure to give (S)-tert-butyl 1-(tert-butyldimethylsilyloxy)propan-2-yl(methyl)carbamate as an oil, which was used in the next step without further purification. LRMS (M-Boc+H+) m/z 204.1.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH3:8])[CH:5]=[N:6][CH:7]=1.C([Li])CCC.[B:14](OC(C)C)([O:19]C(C)C)[O:15]C(C)C>CCOCC>[CH3:8][C:4]1[CH:5]=[N:6][CH:7]=[C:2]([B:14]([OH:19])[OH:15])[CH:3]=1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: Cc1cncc(Br)c1
Agent: [Li]CCCC
Solvent: CCOCC
Product: Cc1cncc(B(O)O)c1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of 5-bromo-3-picoline (0.25 g, 1.45 mmol) in Et2O (5 mL) at −78° C., was added n-butyl lithium (1.6 M in hexanes, 0.92 mL, 1.48 mmol) dropwise. The mixture was stirred at −78° C. for 1 hour and then triisopropyl borate was added quickly. The mixture was stirred at −78° C. for 1 hour and then quenched with water (2 mL). The mixture was warmed up to room temperature overnight. Solvent was removed under reduced pressure to yield a yellow solid (0.25 g).