Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[Cl:22][C:23]1[C:28]2[CH2:29][O:30][C:31](=O)[C:27]=2[CH:26]=[CH:25][N:24]=1.Cl>C1COCC1>[Cl:22][C:23]1[C:28]2[CH2:29][O:30][C:31](=[C:5]3[C:4]4[C:8](=[CH:9][CH:10]=[C:2]([F:1])[CH:3]=4)[NH:7][C:6]3=[O:11])[C:27]=2[CH:26]=[CH:25][N:24]=1
Reactant: O=C1OCc2c1ccnc2Cl
Reactant: O=C1Cc2cc(F)ccc2N1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C1Nc2ccc(F)cc2C1=C1OCc2c1ccnc2Cl
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 72.9 %

Procedure:
A solution of 5-fluoro-1,3-dihydro-indol-2-one (825 mg, 5.46 mmol.) in THF (5 mL) is cooled to 0° C. under an Argon atmosphere and treated with a solution of lithium bis(trimethylsilyl)amide (11 mL of a 1 M solution in THF, 11 mmol) dropwise. The resulting solution is stirred at room temperature for 10 min. A solution of 4-chloro-3H-furo[3,4-c]pyridin-1-one (620 mg, 3.67 mmol) in THF (7 mL) is added dropwise to the reaction mixture. The resulting solution is stirred for 4 h. The reaction mixture is poured into aqueous 10% HCl solution (160 mL). The resulting mixture is heated to 90° C. for 2 h and then stirred at room temperature for 36 h. The precipitate which formed is collected by filtration, washed with small volumes of ethyl acetate (10×3 mL) and dried under vacuum to give the title compound as a yellow solid (810 mg, 73%).
Reaction SMILES: [CH2:1]([CH2:10][CH2:11][NH:12][C:13]1[C:21]2[C:16](=[CH:17][C:18]([Cl:23])=[CH:19][C:20]=2[Cl:22])[N:15](C(OC(C)(C)C)=O)[C:14]=1[C:31]([O:33][CH2:34][CH3:35])=[O:32])[C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[O:3].FC(F)(F)C(O)=O.C(=O)([O-])O.[Na+]>C(Cl)Cl>[CH2:1]([CH2:10][CH2:11][NH:12][C:13]1[C:21]2[C:16](=[CH:17][C:18]([Cl:23])=[CH:19][C:20]=2[Cl:22])[NH:15][C:14]=1[C:31]([O:33][CH2:34][CH3:35])=[O:32])[C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[O:3]
Reactant: CCOC(=O)c1c(NCCCC(=O)c2ccccc2)c2c(Cl)cc(Cl)cc2n1C(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1[nH]c2cc(Cl)cc(Cl)c2c1NCCCC(=O)c1ccccc1
Reaction time: 4 h
Yield: 34.9 %

Procedure:
Dissolve 3-[(phenacyl)ethylamino]-2-carbethoxy-4,6-dichloro-1-tert-butyloxycarbonyl-indole (0.79 g, 1.57 mmol) in methylene chloride (5 mL) and add, by dropwise addition, trifluoroacetic acid (5 mL). Stir for 4 hours and pour carefully into saturated sodium hydrogen carbonate (100 mL). Extract into ethyl acetate, dry (MgSO4) and evaporate the solvent in vacuo to give as yellow oil. Recrystallize (ethyl acetate/hexane) to give the title compound (0.23 g, 36%); mp 203°-5° C.
Reaction SMILES: [Si:1]([O:8][CH2:9][C@@H:10]1[C@H:14]2[O:15][C:16]([CH3:19])([CH3:18])[O:17][C@H:13]2[C@H:12]([NH2:20])[CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Cl[C:22]1[N:27]=[C:26]([CH3:28])[N:25]=[C:24]([NH:29][C@@H:30]2[C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[CH2:32][CH2:31]2)[N:23]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1>[Si:1]([O:8][CH2:9][C@H:10]1[C@H:14]2[O:15][C:16]([CH3:19])([CH3:18])[O:17][C@H:13]2[C@H:12]([NH:20][C:22]2[N:23]=[C:24]([NH:29][C@@H:30]3[C:38]4[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=4)[CH2:32][CH2:31]3)[N:25]=[C:26]([CH3:28])[N:27]=2)[CH2:11]1)([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:2])[CH3:3]
Reactant: CC1(C)O[C@@H]2[C@@H](CO[Si](C)(C)C(C)(C)C)C[C@@H](N)[C@@H]2O1
Reactant: Cc1nc(Cl)nc(N[C@H]2CCc3ccccc32)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: Cc1nc(N[C@H]2CCc3ccccc32)nc(N[C@@H]2C[C@@H](CO[Si](C)(C)C(C)(C)C)[C@H]3OC(C)(C)O[C@H]32)n1
Yield: 24.3 %

Procedure:
A mixture of (3aS,4R,6R,6aR)-6-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-amine (141.8 mg, 0.0004703 mol), 4-chloro-N-[(1S)-2,3-dihydro-1H-inden-1-yl]-6-methyl-1,3,5-triazin-2-amine (127.1 mg, 0.0004876 mol) and potassium carbonate (0.130 g, 0.000940 mol) in 1,4-dioxane (0.77 mL) was subjected to microwave irradiation (300 watts, 160° C.) for 30 minutes. The mixture was filtered with CH2Cl2 and concentrated. The residue was purified by flash chromatography (10 to 100% EtOAc/hexanes) to obtain 60 mg (24%) of the title compound. LC/MS: Rt=2.03 min, ES+ 279 (FA standard).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]2[CH2:11][N:10]([C:12]3[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=3)[C:15](O)=[O:16])[CH2:9][CH2:8][C:6]=2[N:7]=1.C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH:54]([C:57]1[CH:63]=[CH:62][C:60]([NH2:61])=[CH:59][CH:58]=1)([CH3:56])[CH3:55].C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.O>[NH2:1][C:2]1[N:3]=[CH:4][C:5]2[CH2:11][N:10]([C:12]3[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=3)[C:15]([NH:61][C:60]3[CH:62]=[CH:63][C:57]([CH:54]([CH3:56])[CH3:55])=[CH:58][CH:59]=3)=[O:16])[CH2:9][CH2:8][C:6]=2[N:7]=1
Reactant: CC(C)c1ccc(N)cc1
Reactant: Nc1ncc2c(n1)CCN(c1cccc(C(=O)O)c1)C2
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CC(C)c1ccc(NC(=O)c2cccc(N3CCc4nc(N)ncc4C3)c2)cc1
Temperature: 50 °C
Reaction time: 18 h
Yield: 75.7 %

Procedure:
A mixture of 3-(2-amino-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)benzoic acid (41 mg, 0.15 mmol), N,N-diisopropylethylamine (0.105 mL, 0.60 mmol), and HBTU (63 mg, 0.165 mmol) in 1.5 mL DMF was briefly warmed to approx. 50° C. to dissolve solids, then continued stirring at room temperature. After 10 minutes 4-isopropylaniline (0.032 mL, 0.225 mmol) was added and the reaction continued at room temperature for 18 hours. The reaction was added drop wise to a stirring mixture of 35 mL water containing 4 mL brine and 0.3 mL saturated aqueous Na2CO3 solution at room temperature. The resulting precipitate was filtered and rinsed with water. The damp solid was dissolved in 40% MeOH in CHCl3 and evaporated to a dry solid. The solid was triturated with an acetone/hexane mixture to give the title compound as a light beige solid (44 mg, 75%). 1H NMR (DMSO-d6) δ: 10.08 (s, 1H), 8.13 (s, 1H), 7.64-7.70 (m, 2H), 7.49-7.51 (m, 1H), 7.31-7.40 (m, 2H), 7.18-7.25 (m, 3H), 6.40 (s, 2H), 4.29 (s, 2H), 3.65 (t, J=6.0 Hz, 2H), 2.81-2.94 (m, 1H), 2.77 (t, J=5.9 Hz, 2H), 1.20 (d, J=7.0 Hz, 6H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[N:7]([CH2:9][C:10]1[CH:14]=[C:13](Br)[N:12]([S:16]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)(=[O:18])=[O:17])[CH:11]=1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].[F:26][C:27]1[C:32]([O:33][CH3:34])=[CH:31][CH:30]=[CH:29][C:28]=1B(O)O.C(=O)([O-])O.[Na+].COCCOC>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.O>[C:1]([O:5][C:6](=[O:25])[N:7]([CH2:9][C:10]1[CH:14]=[C:13]([C:28]2[CH:29]=[CH:30][CH:31]=[C:32]([O:33][CH3:34])[C:27]=2[F:26])[N:12]([S:16]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)(=[O:18])=[O:17])[CH:11]=1)[CH3:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1cccc(B(O)O)c1F
Reactant: CN(Cc1cc(Br)n(S(=O)(=O)c2cccnc2)c1)C(=O)OC(C)(C)C
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: [Na+]
Solvent: COCCOC
Solvent: O
Product: COc1cccc(-c2cc(CN(C)C(=O)OC(C)(C)C)cn2S(=O)(=O)c2cccnc2)c1F
Temperature: 100 °C
Reaction time: 2 h
Yield: 99.7 %

Procedure:
tert-Butyl{[5-bromo-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate (431 mg), (2-fluoro-3-methoxyphenyl)boronic acid (256 mg), sodium hydrogencarbonate (253 mg) and tetrakis(triphenylphosphine)palladium (88 mg) were added to a mixture of 1,2-dimethoxyethane (8 mL) and water (2 mL), and the mixture was stirred under a nitrogen atmosphere 100° C. for 2 hr. The reaction mixture was allowed to cool, a saturated aqueous sodium hydrogencarbonate solution was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=1:1) to give the title compound as a colorless oil (yield 475 mg, about 100%).
Reaction SMILES: CCCC[N+](CCCC)(CCCC)CCCC.[F-].[F:19][C:20]([F:39])([F:38])[C:21]1[CH:26]=[CH:25][C:24]([CH2:27][C:28]([O:30][CH3:31])=[O:29])=[C:23]([C:32]#[C:33][Si](C)(C)C)[CH:22]=1>C1COCC1.CCOC(C)=O>[C:32]([C:23]1[CH:22]=[C:21]([C:20]([F:19])([F:39])[F:38])[CH:26]=[CH:25][C:24]=1[CH2:27][C:28]([O:30][CH3:31])=[O:29])#[CH:33]
Reactant: COC(=O)Cc1ccc(C(F)(F)F)cc1C#C[Si](C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C#Cc1cc(C(F)(F)F)ccc1CC(=O)OC

Procedure:
TBAF (1.0 M in THF; 7.16 mL, 7.15 mmol) was added to a stirred solution of methyl 2-(4-(trifluoromethyl)-2-((trimethylsilyl)ethynyl)phenyl)acetate (A58) (1.50 g, 4.77 mmol) in THF (50 mL) at 0° C. After 5 minutes the resulting mixture was diluted with EtOAc (50 mL) then washed with 10% NaHCO3 (50 mL). The organic layer was dried (MgSO4) and evaporated under reduced pressure. The residue was adsorbed onto silica gel and purified by column chromatography (Biotage Isolera, SiO2 cartridge, 0-10% EtOAc in petroleum benzine 40-60° C.) to give the title compound A59 as a dark red liquid (956 mg, 83%); 1H NMR (400 MHz, CDCl3) δ 7.77 (d, J=1.2 Hz, 1H), 7.57 (dd, J=8.1, 1.4 Hz, 1H), 7.43 (d, J=8.1 Hz, 1H), 3.90 (s, 2H), 3.72 (s, 3H), 3.36 (s, 1H). LCMS-A: rt 6.099 min; m/z 243.1 [M+H]+.
Reaction SMILES: Br[C:2]1[C:3]([N:21]2[CH2:26][CH2:25][C:24]([CH3:28])([CH3:27])[CH2:23][CH2:22]2)=[C:4]([C@H:10]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:5]([CH3:9])=[N:6][C:7]=1[CH3:8].[CH3:29][O:30][C:31]1[CH:47]=[CH:46][CH:45]=[CH:44][C:32]=1[CH2:33][O:34][C:35]1[CH:40]=[CH:39][C:38](B(O)O)=[CH:37][CH:36]=1.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)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>[C:17]([O:16][C@@H:10]([C:4]1[C:5]([CH3:9])=[N:6][C:7]([CH3:8])=[C:2]([C:38]2[CH:37]=[CH:36][C:35]([O:34][CH2:33][C:32]3[CH:44]=[CH:45][CH:46]=[CH:47][C:31]=3[O:30][CH3:29])=[CH:40][CH:39]=2)[C:3]=1[N:21]1[CH2:26][CH2:25][C:24]([CH3:28])([CH3:27])[CH2:23][CH2:22]1)[C:11]([O:13][CH2:14][CH3:15])=[O:12])([CH3:20])([CH3:19])[CH3:18]
Reactant: COc1ccccc1COc1ccc(B(O)O)cc1
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)nc(C)c(Br)c1N1CCC(C)(C)CC1
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: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)nc(C)c(-c2ccc(OCc3ccccc3OC)cc2)c1N1CCC(C)(C)CC1
Temperature: 110 °C
Reaction time: 2 h
Yield: 68.4 %

Procedure:
A mixture of (S)-ethyl 2-(5-bromo-4-(4,4-dimethylpiperidin-1-yl)-2,6-dimethylpyridin-3-yl)-2-(tert-butoxy)acetate (0.0433 g, 0.095 mmol), (4-((2-methoxybenzyl)oxy)phenyl)boronic acid (0.037 g, 0.143 mmol) and 2M Na2CO3 (0.119 ml, 0.238 mmol) in DMF (2 mL) was degassed for 10 min. Then, Pd(Ph3P)4 (10.99 mg, 9.51 μmol) was added, degassed for 5 min and placed in a oil bath pre-heated to 110° C. After 2 h, cooled and purified by pre-HPLC to afford (S)-ethyl 2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-5-(4-((2-methoxybenzyl)oxy)phenyl)-2,6-dimethylpyridin-3-yl)acetate (0.038 g, 0.065 mmol, 67.9% yield) as white solid. 1H NMR (500 MHz, CDCl3) δ 7.51 (dd, J=1.6, 7.4 Hz, 1H), 7.34 (dt, J=1.7, 7.8 Hz, 1H), 7.15-7.18 (m, 1H), 7.04-7.10 (m, 3H), 7.01 (dt, J=0.9, 7.5 Hz, 1H), 6.96 (d, J=8.2 Hz, 1H), 6.03 (br. s., 1H), 5.17-5.25 (m, 2H), 4.23-4.31 (m, 1H), 4.19 (qd, J=7.1, 10.7 Hz, 1H), 3.91 (s, 3H), 3.05-3.28 (m, 1H), 2.87 (br. s., 1H), 2.66 (br. s., 3H), 2.28 (br. s., 3H), 1.95-2.15 (m, 1H), 1.27 (t, J=7.1 Hz, 3H), 1.20 (s, 9H), 0.9 (br.s., 3H), 0.68 (br. s., 3H). 5H of piperidine were not resolved. LCMS (M+H)=589.4.
Reaction SMILES: N1C=CC=CC=1.Cl.Cl.[CH3:9][N:10]([CH3:26])[CH2:11][CH2:12][NH:13][N:14]=[CH:15][NH:16][C:17]1[CH:25]=[CH:24][C:20]([C:21]([OH:23])=[O:22])=[CH:19][CH:18]=1.Cl.[C:28]([C:31]1[CH:32]=[C:33]2[C:38](=[CH:39][CH:40]=1)[C:37]([CH2:41][C:42](=[O:44])[NH2:43])=[C:36](O)[CH:35]=[CH:34]2)(=[NH:30])[NH2:29].C1CCC(N=C=NC2CCCCC2)CC1>CN(C1C=CN=CC=1)C.C(C(C)=O)C.O.C(O)(=O)C>[CH3:9][N:10]([CH3:26])[CH2:11][CH2:12][NH:13][N:14]=[CH:15][NH:16][C:17]1[CH:25]=[CH:24][C:20]([C:21]([O:23][C:36]2[CH:35]=[CH:34][C:33]3[C:38](=[CH:39][CH:40]=[C:31]([C:28](=[NH:29])[NH2:30])[CH:32]=3)[C:37]=2[CH2:41][C:42](=[O:44])[NH2:43])=[O:22])=[CH:19][CH:18]=1
Reactant: N=C(N)c1ccc2c(CC(N)=O)c(O)ccc2c1
Reactant: CN(C)CCNN=CNc1ccc(C(=O)O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CC(=O)O
Solvent: CCC(C)=O
Solvent: c1ccncc1
Product: CN(C)CCNN=CNc1ccc(C(=O)Oc2ccc3cc(C(=N)N)ccc3c2CC(N)=O)cc1
Reaction time: 2 h
Yield: 86.8 %

Procedure:
40 Milliliters of 20% hydrous pyridine was added to 1.5 g of 4-[(2-dimethylaminoethyl)aminoiminomethylamino]benzoic acid.dihydrochloride, 1.03 g of 6-amidino-1-carbamoylmethyl-2-naphthol.hydrochloride, 1.44 g of DCC and 56 mg of DMAP, followed by stirring for 2 hours under cooling with ice and then 24 hours at room temperature. The precipitate was filtered and the filtrate was concentrated under reduced pressure. To the residue was added 15 ml of methanol, and this solution was added dropwise to 400 ml of acetone, followed by stirring for 24 hours under cooling with ice. Then, the precipitate was collected by filtration to obtain a crude product. Then, the product was subjected to silica gel column chromatography using methyl ethyl ketone-water-acetic acid (80:15:5) as an eluent, and the desired fractions were collected and the solvent was distilled off under reduced pressure. To the residue were added 15 ml of methanol and 1.41 ml of concentrated hydrochloric acid, and the solution was added dropwise to 400 ml of acetone, followed by stirring for 24 hours under cooling with ice. Then, the precipitate was collected by filtration to obtain 1.52 g of the desired product.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:31][C@@H:32]([C:34]1[CH:35]=[N:36][C:37]([Cl:40])=[CH:38][CH:39]=1)[OH:33])[CH2:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([O:26]CC)=[O:25])=[CH:20][C:19]=2[O:29][CH3:30])=[CH:14][CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>C(O)C.C(OCC)(=O)C.Cl>[C:1]([O:5][C:6]([N:8]([CH2:31][C@@H:32]([C:34]1[CH:35]=[N:36][C:37]([Cl:40])=[CH:38][CH:39]=1)[OH:33])[CH2:9][CH2:10][CH2:11][C:12]1[CH:13]=[CH:14][C:15]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([OH:26])=[O:25])=[CH:20][C:19]=2[O:29][CH3:30])=[CH:16][CH:17]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)c1ccc(-c2ccc(CCCN(C[C@H](O)c3ccc(Cl)nc3)C(=O)OC(C)(C)C)cc2)c(OC)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCO
Product: COc1cc(C(=O)O)ccc1-c1ccc(CCCN(C[C@H](O)c2ccc(Cl)nc2)C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of ethyl 4′-[3-[(tert-butoxycarbonyl)-[(2R)-2-(6-chloro-3-pyridyl)-2-hydroxyethyl]amino]propyl]-2-methoxy-1,1′-biphenyl-4-carboxylate in ethanol (5.0 ml) was added 1N sodium hydroxide (1.0 ml) and the mixture was stirred for 2 hours at room temperature. The mixture was diluted with ethyl acetate and 1N hydrochloric acid. The organic layer was separated, washed with brine, dried over magnesium sulfate and evaporated. The residue was purified by column chromatography on silica gel (hexane/ethyl acetate=1/1) to give 4′-[3-[(tert-butoxycarbonyl)[(2R)-2-(6-chloro-3-pyridyl)-2-hydroxyethyl]amino]propyl]-2-methoxy-1,1′-biphenyl-4-carboxylic acid (100 mg).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([O:12][C:13]3[CH:14]=[CH:15][C:16]([N:19]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[C:20]([C:22]4([C:25]([NH2:27])=[O:26])[CH2:24][CH2:23]4)=[O:21])=[N:17][CH:18]=3)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.CS(O[CH2:39][CH2:40][CH2:41][N:42]1[CH2:48][CH:47]([OH:49])[C:44]2([CH2:46][CH2:45]2)[CH2:43]1)(=O)=O.C([O-])([O-])=O.[Cs+].[Cs+]>CC(N(C)C)=O>[OH:49][CH:47]1[C:44]2([CH2:46][CH2:45]2)[CH2:43][N:42]([CH2:41][CH2:40][CH2:39][O:1][C:2]2[CH:11]=[C:10]3[C:5]([C:6]([O:12][C:13]4[CH:14]=[CH:15][C:16]([N:19]([C:28]5[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=5)[C:20]([C:22]5([C:25]([NH2:27])=[O:26])[CH2:24][CH2:23]5)=[O:21])=[N:17][CH:18]=4)=[CH:7][CH:8]=[N:9]3)=[CH:4][CH:3]=2)[CH2:48]1
Reactant: CS(=O)(=O)OCCCN1CC(O)C2(CC2)C1
Reactant: NC(=O)C1(C(=O)N(c2ccccc2)c2ccc(Oc3ccnc4cc(O)ccc34)cn2)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Product: NC(=O)C1(C(=O)N(c2ccccc2)c2ccc(Oc3ccnc4cc(OCCCN5CC(O)C6(CC6)C5)ccc34)cn2)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 74.1 %

Procedure:
To a solution of N-(5-(7-hydroxyquinolin-4-yloxy)pyridin-2-yl)-N-phenylcyclopropane-1,1-dicarboxamide (110 mg, 0.25 mmol) in DMA (2 mL) was added 3-(7-hydroxy-5-azaspiro[2.4]heptane-5-yl)propyl methanesulfonate (125 mg, 0.50 mmol) and Cs2CO3 (243 mg, 0.75 mmol). The reaction was then stirred at rt for 24 hrs. The solvent was removed and the residue was partioned between saturated NaHCO3 aqueous solution (10 mL) and CHCl3 (30 mL). The organic layer was separated, dried over anhydrous Na2SO4, filtered and the filtrate was concentrated in vacuo. The residue was purified by a silica gel column chromatography (100:15:1(v/v/v)EtOAc/CH3OH/Et3N) to afford the desired compound as a pale yellow solid (110 mg, 75%).
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]([O:6][CH2:7][C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.[CH2:13](O)[CH2:14][OH:15].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH3:9][C:8]1([CH2:7][O:6][C:5]2[CH:11]=[CH:12][C:2]([OH:1])=[CH:3][CH:4]=2)[O:15][CH2:14][CH2:13][O:10]1
Reactant: OCCO
Reactant: CC(=O)COc1ccc(O)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CC1(COc2ccc(O)cc2)OCCO1

Procedure:
A solution of 1-(4-hydroxyphenoxy)propan-2-one (3.2 g), 1,2-ethanediol (3.0 ml) and p-toluenesulphonic acid (50 mg) in toluene (100 ml) was stirred under reflux in a Dean and Stark apparatus for 3 1/2 hours in an atmosphere of argon. The reaction mixture was cooled, washed with 5% aqueous sodium bicarbonate (100 ml), washed with water (2×50 ml), washed with brine (50 ml) and dried. Toluene was removed under reduced pressure to give 4-[(2-methyl-1,3-dioxolan-2-yl)methoxy]phenol as an oil (3.4 g).
Reaction SMILES: [OH:1][C@@H:2]1[CH2:19][N:5]2[C:6](=[O:18])[CH2:7][CH2:8][N:9]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:10][C@@H:4]2[CH2:3]1.Br[C:21]1[CH:26]=[N:25][C:24]([CH:27]2[CH2:29][CH2:28]2)=[CH:23][N:22]=1.CC(C)([O-])C.[K+]>O1CCCC1.ClCCl>[CH:27]1([C:24]2[N:25]=[CH:26][C:21]([O:1][C@@H:2]3[CH2:19][N:5]4[C:6](=[O:18])[CH2:7][CH2:8][N:9]([C:11]([O:13][C:14]([CH3:15])([CH3:16])[CH3:17])=[O:12])[CH2:10][C@@H:4]4[CH2:3]3)=[N:22][CH:23]=2)[CH2:29][CH2:28]1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)N2C[C@@H](O)C[C@H]2C1
Reactant: Brc1cnc(C2CC2)cn1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(=O)N2C[C@@H](Oc3cnc(C4CC4)cn3)C[C@H]2C1
Temperature: 25 °C
Reaction time: 72 h
Yield: 65.6 %

Procedure:
To tert-butyl (8S,9aS)-8-hydroxy-5-oxohexahydro-1H-pyrrolo[1,2-a][1,4]diazepine-2(3H)-carboxylate (270 mg, 1 mmol, Part B) and 2-bromo-5-cyclopropylpyrazine (299 mg, 1.5 mmol) in tetrahydrofuran (3 mL) and dichloromethane (1 mL) was added potassium t-butoxide (3 mL, 3 mmol, 1 M in tetrahydrofuran). The mixture was stirred at room temperature for three days, and then concentrated. The residue was purified by chromatography on silica gel (ethyl acetate) to give 255 mg (65.6% yield) of the title compound as a solid. 1H NMR (400 MHz, CDCl3) δ ppm 0.98 (m, 4H), 1.47 (s, 9H), 2.01 (m, 2H), 2.61 (m, 3H), 3.01 (m, 2H), 3.80-3.98 (m, 3H), 4.22 (m, 2H), 5.40 (m, 1H), 7.95 (d, J=1 Hz, 1H), 8.02 (d, J=1 Hz, 1H); MS (ESI) m/z 389.0 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([F:9])[CH:3]=1.[CH3:10][N:11]1[C:15]([CH3:16])=[C:14]([C:17](O)=[O:18])[C:13](=[O:20])[N:12]1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.CCN=C=NCCCN(C)C.C1C=NC2N(O)N=NC=2C=1>C(Cl)Cl>[F:9][C:4]1[CH:3]=[C:2]([NH:1][C:17]([C:14]2[C:13](=[O:20])[N:12]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[N:11]([CH3:10])[C:15]=2[CH3:16])=[O:18])[CH:7]=[CH:6][C:5]=1[OH:8]
Reactant: Nc1ccc(O)c(F)c1
Reactant: Cc1c(C(=O)O)c(=O)n(-c2ccccc2)n1C
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2cccnc21
Solvent: ClCCl
Product: Cc1c(C(=O)Nc2ccc(O)c(F)c2)c(=O)n(-c2ccccc2)n1C
Temperature: 45 °C
Reaction time: 12 h
Yield: 93.3 %

Procedure:
To a suspension of 4-amino-2-fluorophenol (2.54 g, 20 mmol) and 1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxylic acid (4.74 g, 20.4 mmol) in DCM (60 mL) were added EDCI (4.6 g, 24 mmol) and HOAT (0.54 g, 4 mmol). The reaction was stirred at 45° C. for 12 hours, then cool to rt, quenched with H2O (10 mL), and stirred for another 4 hours. The solid was obtained by filtration and washed with DCM (20 mL×3), then dried at 60° C. in vacuo for 12 hours to give the title compound as a pale yellow solid (6.37 g, 93.4%).
Reaction SMILES: Cl[C:2]1[C:3]([C:8]2[C:9]([F:15])=[C:10]([NH2:14])[CH:11]=[CH:12][CH:13]=2)=[N:4][CH:5]=[CH:6][CH:7]=1.Br[C:17]1C(C)=CC=CN=1>>[F:15][C:9]1[C:8]([C:3]2[C:2]([CH3:17])=[CH:7][CH:6]=[CH:5][N:4]=2)=[CH:13][CH:12]=[CH:11][C:10]=1[NH2:14]
Reactant: Nc1cccc(-c2ncccc2Cl)c1F
Reactant: Cc1cccnc1Br
Product: Cc1cccnc1-c1cccc(N)c1F

Procedure:
was prepared by using the same procedures as described for the preparation of 3-(3-chloro-pyridin-2-yl)-2-fluoro-phenylamine in Scheme C6, starting from 2-bromo-3-methylpyridine [3430-17-9]. MS (LC-MS): 203 [M+H]+; tR (HPLC conditions k): 1.36 min.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10].[C:11](OC(=O)C)(=[O:13])[CH3:12]>>[C:11]([N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10])(=[O:13])[CH3:12]
Reactant: O=C1Cc2ccccc2N1
Reactant: CC(=O)OC(C)=O
Product: CC(=O)N1C(=O)Cc2ccccc21
Temperature: 0 °C

Procedure:
Oxindole (1 equivalent) was dissolved in acetic anhydride and the resulting mixture was heated under reflux for 3 days. After cooling, the reaction mixture was poured into ice water. The resulting precipitate was collected by filtration, washed with water and dried, whereby 1-acetyloxindole was obtained. From the thus obtained 1-acetyloxindole and diformylfuran, a target compound was obtained in the same manner as in Example 1.