Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][CH2:5][N:4]([C@H:7]2[CH2:12][CH2:11][C@@H:10]([N:13]([CH3:15])[CH3:14])[CH2:9][C@H:8]2[NH:16][C:17](=[O:19])[CH3:18])[C:3]1=[O:20].Cl[C:22]1[C:31]2[C:26](=[CH:27][CH:28]=[C:29]([C:32]([F:35])([F:34])[F:33])[CH:30]=2)[N:25]=[CH:24][N:23]=1.C(N(CC)CC)C>C(O)(C)C>[CH3:14][N:13]([CH3:15])[C@H:10]1[CH2:9][C@@H:8]([NH:16][C:17](=[O:19])[CH3:18])[C@@H:7]([N:4]2[CH2:5][CH2:6][C@H:2]([NH:1][C:22]3[C:31]4[C:26](=[CH:27][CH:28]=[C:29]([C:32]([F:34])([F:35])[F:33])[CH:30]=4)[N:25]=[CH:24][N:23]=3)[C:3]2=[O:20])[CH2:12][CH2:11]1
Reactant: CC(=O)N[C@@H]1C[C@H](N(C)C)CC[C@@H]1N1CC[C@H](N)C1=O
Reactant: FC(F)(F)c1ccc2ncnc(Cl)c2c1
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: CC(=O)N[C@@H]1C[C@H](N(C)C)CC[C@@H]1N1CC[C@H](Nc2ncnc3ccc(C(F)(F)F)cc23)C1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 104.5 %

Procedure:
To a solution of N-((1R,2S,5R)-2-((S)-3-amino-2-oxopyrrolidin-1-yl)-5-(dimethylamino)cyclohexyl)acetamide (40 mg, 0.14 mmol) in isopropanol (6 mL) was added 4-chloro-6-(trifluoromethyl)quinazoline (39 mg, 0.17 mmol) and triethylamine (0.02 mL, 0.14 mmol). The mixture was stirred at RT for 16 h and concentrated in vacuo to a crude oil, which was purified by semi-preparative reverse phase HPLC (gradient elution, water/methanol/TFA) to give the title compound (70 mg, 71% yield). LC/MS found [M+H]+=479. 1H-NMR (400 MHz, CD3OD), δ ppm: 8.87 (s, 1H), 8.72 (s, 1H), 8.22 (m, 1H), 7.87 (m, 1H), 5.49 (m, 1H), 4.23 (m, 1H), 4.2 (m, 1H), 4.12 (m, 1H), 3.75 (m, 1H), 3.65 (m, 1H), 3.38 (m, 1H), 2.82 (s, 6H), 2.51 (m, 1H), 2.35 (m, 1H), 2.15 (m, 1H), 2.14-1.86 (m, 5H), 1.84 (s, 3H).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[N:11]=[C:10]([CH:12]=[O:13])[CH:9]=[CH:8][CH:7]=1.S([CH2:24][N:25]=[C:26]=O)(C1C=CC(C)=CC=1)(=O)=O.C(=O)([O-])[O-].[K+].[K+]>CO>[O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[CH:7]=[CH:8][CH:9]=[C:10]([C:12]2[O:13][CH:26]=[N:25][CH:24]=2)[N:11]=1
Reactant: O=Cc1cccc(C2OCCO2)n1
Reactant: Cc1ccc(S(=O)(=O)CN=C=O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: c1cc(-c2cnco2)nc(C2OCCO2)c1

Procedure:
1 g of 6-[1,3]dioxolan-2-yl-pyridine-2-carbaldehyde (5.58 mmol), 1.10 g of tosylmethyl isocyanate (5.63 mmol) and 0.80 g of potassium carbonate (5.79 mmol) are mixed in 15 ml of methanol. The suspension is heated under reflux for 2 hours. The methanol is separated off, the residue is taken up in a saturated aqueous solution of sodium chloride and the mixture is extracted with ethyl acetate. The organic phase is dried over magnesium sulfate, filtered and then concentrated under vacuum. The title product is isolated by chromatography on a silica column (eluent: hexane/ethyl acetate; 50:50). 1.14 g of a yellow oil are obtained.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][N:6]1[C:15](=[O:16])[CH2:14][C:9]2([CH2:13][CH2:12][CH2:11][CH2:10]2)[CH2:8][C:7]1=[O:17].[N:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][C:19]=1[N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1.C(N(C(C)C)CC)(C)C>CC#N>[N:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][C:19]=1[N:28]1[CH2:33][CH2:32][N:31]([CH2:2][CH2:3][CH2:4][O:5][N:6]2[C:15](=[O:16])[CH2:14][C:9]3([CH2:13][CH2:12][CH2:11][CH2:10]3)[CH2:8][C:7]2=[O:17])[CH2:30][CH2:29]1
Reactant: c1ccc2nc(N3CCNCC3)ccc2c1
Reactant: O=C1CC2(CCCC2)CC(=O)N1OCCCBr
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: O=C1CC2(CCCC2)CC(=O)N1OCCCN1CCN(c2ccc3ccccc3n2)CC1

Procedure:
A mixture of 8-(3-bromopropyloxy)-8-azaspiro[4.5]decan-7,9-dione (5.7 g), 1-(2-quinolinyl)piperazine (4.0 g) and diisopropylethylamine (6.6 ml) in 100 ml of dry CH3CN was heated to 80° with stirring under N2.
Reaction SMILES: [N:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([C:4]3=O)[CH2:2]1)[CH2:8]2.C1(C)C=CC(S([CH2:21][N+:22]#[C-])(=O)=O)=CC=1.CC(C)([O-])C.[K+]>COCCOC.C(O)C>[N:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([C@H:4]3[C:21]#[N:22])[CH2:2]1)[CH2:8]2
Reactant: O=C1C2CC3CC1CN(C3)C2
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCO
Solvent: COCCOC
Product: N#CC1C2CC3CC1CN(C3)C2
Temperature: -78 °C
Reaction time: 5 h

Procedure:
Azaadamantan-4-one (3.76 g, 24.9 mmol; see Becker, D. P.; Flynn, D. L. Synthesis 1992, 1080-1082.) and p-toluenesulfonylmethyl isocyanide (TOSMIC, 6.38 g, 32.3 mmol) were dissolved in a mixture of 1,2-dimethoxyethane (87 mL) and ethanol (3.2 mL) and chilled to −78° C. To the reaction mixture was added potassium tert-butoxide (6.70 g, 59.7 mmol) over a period of 1 minute. The cooling bath was removed and the reaction mixture was stirred at 25° C. for 5 hours and then heated at 40° C. for 0.5 hour. The reaction mixture was cooled and filtered through a glass frit. The filtrate was concentrated, and the residue was purified by silica gel chromatography (10% concentrated NH4OH in acetonitrile, Rf=0.25) to afford the title compound. An aliquot of the solid was then dissolved in 10:1 ether/methanol and treated with fumaric acid (10 mg/mL solution in 10:1 ether/methanol). The precipitate was filtered and dried under vacuum to afford the title compound as a fumarate for characterization: 1H NMR (500 MHz, methanol-d4) δ 2.07-2.14 (m, 2H), 2.22-2.32 (m, 3H), 2.47 (s, 2H), 3.49-3.56 (m, 5 H), 3.59-3.66 (m, 2 H), 6.70 ppm (s, 2.8 H; C4H4O4); MS (DCI/NH3) m/z 163 (M+H)+; Anal. Calcd. for C10H14N2.1.45C4H4O4: C, 57.41; H, 6.04; N, 8.48. Found: C, 57.26; H, 6.04; N, 8.87.
Reaction SMILES: FC(F)(F)C([N:5]([C@@H:13]1[CH2:15][C@H:14]1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:6][CH:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1)=O.[CH:24]([C:26]1[CH:35]=[CH:34][C:29]([C:30]([O:32]C)=[O:31])=[CH:28][N:27]=1)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>ClCCCl.CO>[C:16]1([C@@H:14]2[CH2:15][C@H:13]2[NH:5][CH2:6][CH:7]2[CH2:8][CH2:9][N:10]([CH2:24][C:26]3[CH:35]=[CH:34][C:29]([C:30]([OH:32])=[O:31])=[CH:28][N:27]=3)[CH2:11][CH2:12]2)[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: COC(=O)c1ccc(C=O)nc1
Reactant: O=C(N(CC1CCNCC1)[C@@H]1C[C@H]1c1ccccc1)C(F)(F)F
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCCl
Solvent: CO
Product: O=C(O)c1ccc(CN2CCC(CN[C@@H]3C[C@H]3c3ccccc3)CC2)nc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 75.6 %

Procedure:
To a solution 2,2,2-trifluoro-N-(trans-2-phenylcyclopropyl)-N-(piperidin-4-ylmethyl)acetamide (130 mg, 0.398 mmol) in 1,2-dichloroethane (DCE) (2 mL) were added methyl 6-formylnicotinate (86 mg, 0.518 mmol) and sodium triacetoxyborohydride (127 mg, 0.598 mmol), and the reaction mixture was stirred at room temperature for 18 h. The mixture was quenched with water (2 mL) and extracted with DCM (3×). The extract was dried (Na2SO4) and concentrated to give a crude product. The product was dissolved in methanol (2.000 mL) and sodium hydroxide (3M, 0.664 mL, 1.992 mmol) was added. The mixture was stirred at room temperature for 3 h and concentrated. The residue was treated with methanol and filtered. The filtrate was purified using reverse-phase HPLC under the acidic conditions to give 110 mg of product as pale yellow solid (HCl salt). MS: (M+H)+=366.4. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.24 (m, 1H),1.54-1.73 (m, 3H), 1.98-2.12 (m, 3H), 2.59-2.72 (m, 1H), 2.94 (m, 4H), 3.45 (br. s., 2H), 4.54 (br. s., 2H), 7.16-7.25 (m, 3H), 7.27-7.35 (m, 2H), 7.81 (d, J=8.08 Hz, 1H), 8.38 (dd, J=8.08, 2.27 Hz, 1H), 9.12 (d, J=1.52 Hz, 1H), 9.78 (br. s., 2H), 10.72 (br. s., 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([OH:19])=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:8](=[O:12])[NH:9]2)=[CH:4][CH:3]=1.C(=O)([O-])O.[Na+].Br[CH2:26][C:27]#[N:28].O>CN(C)C=O>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([O:19][CH2:26][C:27]#[N:28])=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:8](=[O:12])[NH:9]2)=[CH:4][CH:3]=1
Reactant: N#CCBr
Reactant: O=c1[nH]c2cc(Cl)ccc2c(O)c1-c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: N#CCOc1c(-c2ccccc2)c(=O)[nH]c2cc(Cl)ccc12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 7-chloro-4-hydroxy-3-phenyl-2(1H)-quinolone (0.50 g, 1.84 mmol) in dimethyl formamide (50 ml) under nitrogen at room temperature, was added sodium hydrogen carbonate (1.50 g) followed by bromoacetonitrile (1.9 ml). The reaction mixture was stirred at room temperature for 16 h, then poured into water and extracted with ethyl acetate (3×50 ml). The combined organic layers were washed with water (2×50 ml), dried (MgSO4), filtered and the solvent was removed in vacuo to leave an oily residue. Trituration with diethyl ether, followed by recrystallisation from an ethyl acetate, petrol (60-80) mixture, gave the title compound as a white solid (0.15 g). Mp 209°-211° C. Found: C, 65.60; H, 3.74; N, 8.75; C17H11N2O2Cl requires C, 65.71; H, 3.57; N, 9.02%. δ (360 MHz, DMSO-d6) 4.59 (2H, s, OCH2CN), 7.31 (1H, dd, J=8.63 Hz, J=2.10 Hz, 6-H), 7.40-7.49 (6H, m, Ph+8-H), 7.83 (1H, d, J=88.63 Hz, 5-H), 12.10 (1H, bs, NH). m/z (CI+), 311, (M+1).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH2:4][CH2:3]1.[N:18]1[C:23]2[O:24][CH2:25][CH2:26][O:27][C:22]=2[CH:21]=[C:20]([CH:28]=O)[N:19]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>C(Cl)Cl.CO>[N:18]1[C:23]2[O:24][CH2:25][CH2:26][O:27][C:22]=2[CH:21]=[C:20]([CH2:28][NH:1][CH:2]2[CH2:3][CH2:4][N:5]([C:8]([O:10][CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[O:9])[CH2:6][CH2:7]2)[N:19]=1
Reactant: O=Cc1cc2c(nn1)OCCO2
Reactant: NC1CCN(C(=O)OCc2ccccc2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: O=C(OCc1ccccc1)N1CCC(NCc2cc3c(nn2)OCCO3)CC1
Reaction time: 2 h
Yield: 62 %

Procedure:
A mixture of phenylmethyl 4-amino-1-piperidinecarboxylate (for a synthesis see WO 2004/058144 Example 99(e)) (14.4 g crude, equivalent to 11 g, 47 mmol) and 6,7-dihydro[1,4]dioxino[2,3-c]pyridazine-3-carbaldehyde (for a preparation see Example 6(e)) (6.46 g, 39 mmol) in DCM (200 ml) and MeOH (10 ml) was stirred for 4 h at rt, then cooled in ice as sodium triacetoxyborohydride (12.4 g) was added over 15 min. After stirring for another 2 h, the mixture was treated with aqueous sodium bicarbonate to neutralise. The aqueous phase was extracted with DCM and the organic fractions were dried and evaporated. Chromatography on silica (750 g), eluting with 0-10% MeOH/DCM, gave the product (11.1 g, 62%).
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([NH:17][CH2:18][CH2:19][OH:20])[C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:21])[C:6]([C:22]([OH:24])=[O:23])=[CH:5]2)[CH2:3][CH2:2]1.[Br:25][C:26]1[CH:34]=[CH:33][CH:32]=[C:31]2[C:27]=1[CH2:28][NH:29][CH2:30]2.C1CCN2C(=NCCC2)CC1>CN(C=O)C>[Br:25][C:26]1[CH:34]=[CH:33][CH:32]=[C:31]2[C:27]=1[CH2:28][N:29]([C:11]1[C:12]([F:14])=[C:13]3[C:8]([C:7](=[O:21])[C:6]([C:22]([OH:24])=[O:23])=[CH:5][N:4]3[CH:1]3[CH2:2][CH2:3]3)=[C:9]([NH:17][CH2:18][CH2:19][OH:20])[C:10]=1[F:16])[CH2:30]2
Reactant: O=C(O)c1cn(C2CC2)c2c(F)c(F)c(F)c(NCCO)c2c1=O
Reactant: Brc1cccc2c1CNC2
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: O=C(O)c1cn(C2CC2)c2c(F)c(N3Cc4cccc(Br)c4C3)c(F)c(NCCO)c2c1=O
Yield: 32.7 %

Procedure:
205 mg of 1-cyclopropyl-5-(2-hydroxyethylamino)-6,7,8- trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, 131 mg of 4-bromoisoindoline, 182 mg of DBU, and 1.5 ml of are anhydrous DMF were processed in the same manner as in Example 20 to produce 102 mg of the target compound.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[NH:11][CH:10]=2)=[CH:3][CH:2]=1.[CH2:18]([C:25]1([N:32]([CH3:34])[CH3:33])[CH2:30][CH2:29][C:28](=O)[CH2:27][CH2:26]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.FC(F)(F)S(O)(=O)=O>ClCCl>[CH2:18]([C:25]1([N:32]([CH3:34])[CH3:33])[CH2:30][CH2:29][C:28]([C:10]2[NH:11][C:12]3[C:17]([C:9]=2[CH2:8][CH2:7][C:4]2[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=2)=[CH:16][CH:15]=[CH:14][CH:13]=3)([C:10]2[NH:11][C:12]3[C:17]([C:9]=2[CH2:8][CH2:7][C:4]2[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=2)=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH2:27][CH2:26]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CN(C)C1(Cc2ccccc2)CCC(=O)CC1
Reactant: c1ccc2c(CCc3ccncc3)c[nH]c2c1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: ClCCl
Product: CN(C)C1(Cc2ccccc2)CCC(c2[nH]c3ccccc3c2CCc2ccncc2)(c2[nH]c3ccccc3c2CCc2ccncc2)CC1
Temperature: 25 °C
Reaction time: 67 h

Procedure:
3-(2-pyridin-4-ylethyl)-1H-indole (667 mg, 3 mmol, synthesis cf. WO2008009415, indole unit Ind-14) together with 4-benzyl-4-(dimethylamino)cyclohexanone (652 mg, 3 mmol, synthesis cf. WO2008009415, ketone unit Ket-3) was dissolved in abs. dichloromethane (45 ml) and mixed with trifluoromethane sulphonic acid (0.553 ml, 6.3 mmol). The batch was stirred for 67 h at RT, and a brown oil separated out. For work up the reaction solution was mixed with 1N NaOH (10 ml) and THF (10 ml). The mixture was stirred a further 60 min. After separation of the phases the aqueous phase was extracted with dichloromethane (3×10 ml). The combined organic extracts were dried over Na2SO4 and then concentrated to low volume. The raw product obtained (1.22 g) was purified by column chromatography [silica gel 60 (100 g); ethyl acetate/methanol (10:1, 1100 ml), ethyl acetate/methanol (2:1, 500 ml) ethyl acetate/methanol (1:2, 750 ml)].
Reaction SMILES: [CH2:1]([N:6]([C:10]1[CH:19]=[CH:18][C:17]2[C:16]([CH3:21])([CH3:20])[CH2:15][CH2:14][C:13]([CH3:23])([CH3:22])[C:12]=2[CH:11]=1)[C:7](Cl)=[O:8])[CH2:2][CH2:3][CH2:4][CH3:5].[NH2:24][C:25]1[CH:35]=[CH:34][C:28]([C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:27][CH:26]=1>N1C=CC=CC=1.O>[CH2:1]([N:6]([C:10]1[CH:19]=[CH:18][C:17]2[C:16]([CH3:21])([CH3:20])[CH2:15][CH2:14][C:13]([CH3:23])([CH3:22])[C:12]=2[CH:11]=1)[C:7](=[O:8])[NH:24][C:25]1[CH:26]=[CH:27][C:28]([C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:34][CH:35]=1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCN(C(=O)Cl)c1ccc2c(c1)C(C)(C)CCC2(C)C
Reactant: CCOC(=O)c1ccc(N)cc1
Solvent: O
Solvent: c1ccncc1
Product: CCCCCN(C(=O)Nc1ccc(C(=O)OCC)cc1)c1ccc2c(c1)C(C)(C)CCC2(C)C
Temperature: 40 °C
Reaction time: 15 h
Yield: 21.5 %

Procedure:
A solution of pentyl-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-carbamoyl chloride (35) (900 mg, 2.6 mmole) in 20 mL pyridine was treated with 481 mg of ethyl p-aminobenzoate (3 eq.) and stirred at 40° C. for 15 hours. The reaction mixture was diluted with 100 mL of cold water and extracted with two 100 mL portions of ethyl acetate. The combined organic extracts were dried over MgSO4, filtered and concentrated in vacuo to give an orange oil, which was purified by flash chromatography (SiO2, 5% ethyl acetate/hexanes) to provide 260 mg of ethyl 4-[3-pentyl-3-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-ureido]-benzoate (37) as a pale yellow oil.
Reaction SMILES: [O:1]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][Mg]Br)[Si:2]([C:5]([CH3:8])([CH3:7])[CH3:6])([CH3:4])[CH3:3].BrCCCCCCCCO[Si](C(C)(C)C)(C)C.[Mg].BrCCBr.[CH3:41][Si:42]([CH3:51])([CH3:50])[C:43]1[O:47][CH:46]=[C:45]([CH:48]=[O:49])[CH:44]=1>O1CCCC1>[OH:49][CH:48]([C:45]1[CH:44]=[C:43]([Si:42]([CH3:51])([CH3:50])[CH3:41])[O:47][CH:46]=1)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][O:1][Si:2]([C:5]([CH3:8])([CH3:7])[CH3:6])([CH3:4])[CH3:3]
Reactant: C[Si](C)(C)c1cc(C=O)co1
Reactant: CC(C)(C)[Si](C)(C)OCCCCCCCC[Mg]Br
Agent: CC(C)(C)[Si](C)(C)OCCCCCCCCBr
Agent: [Mg]
Solvent: BrCCBr
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCCCCCCCCC(O)c1coc([Si](C)(C)C)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 8-t-butyldimethylsiloxyoctylmagnesium bromide (5.63 mmol prepared from 1-bromo-8-t-butyldimethylsiloxyoctane 1.82 g, 5.63 mmol and 6.19 mmol magnesium; with a catalytic amount of 1,2-dibromoethane as initiator) in tetrahydrofuran (2 ml) at 0° under argon was added dropwise 5-trimethylsilyl-3-furaldehyde (0.866 g, 5.15 mmol) in tetrahydrofuran (10 ml). The solution was warmed to room temperature, stirred for one hour, quenched with cold 10% hydrochloric acid and extracted into ethyl ether. The organic portion was washed with saturated sodium bicarbonate, water saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated to give a pale oil. Purification by flash chromatography (silica, 5 to 10% ethyl acetate/hexane) gave the desired alcohol.
Reaction SMILES: N[C:2]1[C:3]([CH3:13])=[CH:4][C:5]([Br:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].N([O-])=O.[Na+].[ClH:18]>O.[Cu]Cl>[Br:12][C:5]1[CH:4]=[C:3]([CH3:13])[C:2]([Cl:18])=[CH:11][C:6]=1[C:7]([O:9][CH3:10])=[O:8]
Reactant: Cl
Reactant: COC(=O)c1cc(N)c(C)cc1Br
Agent: Cl[Cu]
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: COC(=O)c1cc(Cl)c(C)cc1Br
Temperature: 25 °C
Reaction time: 1 h
Yield: 64.4 %

Procedure:
To a solution of methyl 5-amino-2-bromo-4-methylbenzoate (4.86 g, 20 mmol) in hydrochloric acid (6N, 50 mL) was added sodium nitrite (1.38 g, 20 mmol) carefully at −5° C. After one hour, the obtained mixture was added to a boiling solution of copper(I) chloride (3.96 g, 40 mmol) in water (50 mL) dropwise and the resulting mixture was refluxed with stirring for 2 h. The mixture was cooled to rt and extracted with ethyl acetate (2×50 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel column chromatography eluted with PE to give methyl 2-bromo-5-chloro-4-methylbenzoate (3.4 g, yield 64.4%). 1H NMR (400 MHz, DMSO-d6): δ 7.82 (s, 1H), 7.81 (s, 1H), 3.85 (s, 3H), 2.51 (s, 3H) ppm; MS: m/z=265.0 (M+1, ESI+).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][NH:7][CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11].[CH:15](OCC)=[O:16]>C1(C)C=CC=CC=1>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][N:7]([CH:15]=[O:16])[CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: CCOC=O
Reactant: CCOC(=O)CCNCc1cccs1
Solvent: Cc1ccccc1
Product: CCOC(=O)CCN(C=O)Cc1cccs1
Yield: 99.9 %

Procedure:
Ethyl 3-[(thiophen-2-ylmethyl)amino]propionate (13.8 g) prepared in the step 1 and 47.8 g of ethyl formate were dissolved in 100 mL of toluene and heated to reflux overnight. After the reaction solution was cooled, the solvent was evaporated therefrom in vacuo to give 15.6 g of the objective compound as light yellow liquid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([CH3:10])[N:3]=1.[C:11]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[S:17]([N:20]=[C:21]=[O:22])(=[O:19])=[O:18]>ClCCl.C1(C)C=CC=CC=1>[C:11]1([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[S:17]([NH:20][C:21]([NH:1][C:2]1[N:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([CH3:10])[N:3]=1)=[O:22])(=[O:19])=[O:18]
Reactant: O=C=NS(=O)(=O)c1ccccc1-c1ccccc1
Reactant: COc1cc(C)nc(N)n1
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: COc1cc(C)nc(NC(=O)NS(=O)(=O)c2ccccc2-c2ccccc2)n1
Temperature: 25 °C
Reaction time: 10 h
Yield: 86.9 %

Procedure:
13.9 g of 2-amino-4-methoxy-6-methylpyrimidine were dissolved in 150 ml of dry dichloromethane. To this solution was added dropwise a solution of 28.5 g of 2-biphenylylsulfonyl isocyanate in 40 ml of toluene over an hour. During this addition, the internal temperature was maintained at room temperature. When the addition was finished, the mixture was stirred at room temperature for 10 hours to complete the reaction. After completion of the reaction, the mixture was concentrated to about half the volume by evaporating dichloromethane under reduced pressure. The resultant colorless crystals were filtered. The crystals were then washed with a small amount of ether and dried to obtain 34.6 g of N-2-biphenylylsulfonyl-N'-(4-methoxy-6-methylpyrimidin-2-yl) urea; m.p. 199°-202° C.
Reaction SMILES: C1(C)C=CC=CC=1.[CH:8]12[O:17][CH:14]([CH2:15][CH2:16]1)[CH:13]1[CH:9]2[C:10](=[O:19])[CH2:11][C:12]1=[O:18].C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.[Br:32][C:33]1[CH:38]=[CH:37][C:36]([Pb+3])=[C:35]([CH2:40][CH3:41])[CH:34]=1.Cl>CN(C)C1C=CN=CC=1.C(Cl)(Cl)Cl>[Br:32][C:33]1[CH:38]=[CH:37][C:36]([CH:11]2[C:10](=[O:19])[CH:9]3[CH:13]([CH:14]4[O:17][CH:8]3[CH2:16][CH2:15]4)[C:12]2=[O:18])=[C:35]([CH2:40][CH3:41])[CH:34]=1
Reactant: CCc1cc(Br)ccc1[Pb+3]
Reactant: O=C1CC(=O)C2C3CCC(O3)C12
Agent: CC(=O)[O-]
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: ClC(Cl)Cl
Product: CCc1cc(Br)ccc1C1C(=O)C2C3CCC(O3)C2C1=O
Temperature: 80 °C
Reaction time: 4 h

Procedure:
4-Dimethylaminopyridine (3.67 g, 30.0 mmol) and toluene (10 ml) are added to a solution of (1RS,2SR,6RS,7SR)-10-oxatricyclo[5.2.1.02,6]decane-3,5-dione (1.0 g, 6.0 mmol) in chloroform (40 ml) and the reaction mixture is heated to 80° C. 4-Bromo-2-ethylphenyllead triacetate (5.13 g, 9.04 mmol) is added portionwise over 20 minutes, and once the addition is complete the reaction mixture is stirred at 80° C. for a further 4 hours. The mixture is cooled to room temperature, 2 M aqueous hydrochloric acid (40 ml) is added, and the mixture is stirred vigorously for 15 minutes, then filtered through a small plug of diatomaceous earth, washing with 40 ml dichloromethane. The organic phase is separated, and the aqueous phase is extracted with dichloromethane (2×20 ml). The organic solutions are combined, dried over anhydrous magnesium sulfate, filtered and the filtrate is concentrated under reduced pressure. The residue is purified by column chromatography on silica gel to give (1RS,2SR,6RS,7SR)-4-(4-bromo-2-ethylphenyl)-10-oxatricyclo-[5.2.1.02,6]decane-3,5-dione.
Reaction SMILES: [N:1]([C@@H:4]([C@@H:8]([C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=1)[C:9]1[CH:14]=[CH:13][N:12]=[CH:11][C:10]=1[F:15])[C:5]([OH:7])=O)=[N+]=[N-].[NH2:23][C:24]1[CH:54]=[CH:53][CH:52]=[C:51]([F:55])[C:25]=1[CH2:26][CH2:27][C@H:28]1[O:33][CH2:32][C@@H:31]([CH2:34][O:35][C:36](=[O:43])[NH:37][CH2:38][C:39]([F:42])([F:41])[F:40])[N:30](C(OC(C)(C)C)=O)[CH2:29]1>>[Cl:22][C:19]1[CH:20]=[CH:21][C:16]([C@@H:8]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][C:10]=2[F:15])[C@@H:4]([C:5]([NH:23][C:24]2[CH:54]=[CH:53][CH:52]=[C:51]([F:55])[C:25]=2[CH2:26][CH2:27][C@H:28]2[O:33][CH2:32][C@@H:31]([CH2:34][O:35][C:36](=[O:43])[NH:37][CH2:38][C:39]([F:42])([F:41])[F:40])[NH:30][CH2:29]2)=[O:7])[NH2:1])=[CH:17][CH:18]=1
Reactant: [N-]=[N+]=N[C@H](C(=O)O)[C@@H](c1ccc(Cl)cc1)c1ccncc1F
Reactant: CC(C)(C)OC(=O)N1C[C@@H](CCc2c(N)cccc2F)OC[C@H]1COC(=O)NCC(F)(F)F
Product: N[C@H](C(=O)Nc1cccc(F)c1CC[C@@H]1CN[C@H](COC(=O)NCC(F)(F)F)CO1)[C@@H](c1ccc(Cl)cc1)c1ccncc1F

Procedure:
The title compound was prepared from (2S,3S)-2-azido-3-(4-chlorophenyl)-3-(3-fluoropyridin-4-yl)propanoic acid (Example 1040, step 1) and the product from step 4 of Example 99 using the procedures given in steps 2-4 of Example 93. MS (ES) m/z=656 (M+H)+.
Reaction SMILES: C(O[C:4](=[O:19])[NH:5][S:6]([C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH3:18])[CH2:13][CH2:12]2)(=[O:8])=[O:7])C.[Cl:20][C:21]1[CH:27]=[CH:26][C:24]([NH2:25])=[CH:23][CH:22]=1>>[Cl:20][C:21]1[CH:27]=[CH:26][C:24]([NH:25][C:4]([NH:5][S:6]([C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[N:14]([CH3:18])[CH2:13][CH2:12]3)(=[O:7])=[O:8])=[O:19])=[CH:23][CH:22]=1
Reactant: Nc1ccc(Cl)cc1
Reactant: CCOC(=O)NS(=O)(=O)c1ccc2c(c1)CCN2C
Product: CN1CCc2cc(S(=O)(=O)NC(=O)Nc3ccc(Cl)cc3)ccc21
Yield: 60 %

Procedure:
Following the procedure of Example 3B, the title product was prepared in 60% yield from [(2,3-dihydro-1-methyl-1H-indol-5-yl)sulfonyl]carbamic acid ethyl ester and 4-chloroaniline, m.p. 145°-147° C.