Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=O)[CH:5]=[CH:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH3:14])=[CH:9][C:8]=1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)C.[H-].[Al+3].[Li+].[H-].[H-].[H-]>CCOCC>[CH2:16]([O:15][C:8]1[CH:9]=[C:10]([CH2:13][CH3:14])[CH:11]=[CH:12][C:7]=1[CH:6]=[CH:5][CH2:4][OH:3])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CCOC(=O)C=Cc1ccc(CC)cc1OCc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: CCc1ccc(C=CCO)c(OCc2ccccc2)c1
Reaction time: 4 h
Yield: 71.3 %

Procedure:
A solution of 3-(2-benzyloxy-4-ethyl-phenyl)-acrylic acid ethyl ester (2.9 g, 9.3 mmol) dissolved in ether (7 mL) was added to a cooled 0° C. suspension of lithium aluminium hydride (0.89 g, 23.4 mmol) in ether (20 mL). The reaction mixture was stirred for 4 hours, quenched with H2O (3.6 mL) and 15% NaOH (0.9 mL) and then filtered through glass frit washing with ether. The filtrate was concentrated to a clear oil and purified by flash column chromatography (0% to 30% EtOAc in hexanes) to give the product (1.78 g, 71%). 1H NMR (400 MHz, CDCl3): δ 1.22 (t, J=7.6 Hz, 3H), 2.62 (q, J=7.6 Hz, 2H), 4.29 (m, 2H), 5.10 (s, 2H), 6.35 (dt, J=16.2, 7.6 Hz, 1H), 6.78 (s, 1H), 6.80 (d, J=7.1 Hz, 1H), 6.95 (d, J=16.2 Hz, 1H), 7.32-7.45 (m, 6H).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7](F)=[CH:6][C:5]=1[OH:11])=[O:3].[C:12]1([SH:18])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C([O-])([O-])=O.[K+].[K+].Cl>CN1C(=O)CCC1.O>[OH:11][C:5]1[CH:6]=[C:7]([S:18][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:8]=[CH:9][C:4]=1[C:2](=[O:3])[CH3:1]
Reactant: Sc1ccccc1
Reactant: CC(=O)c1ccc(F)cc1O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN1CCCC1=O
Product: CC(=O)c1ccc(Sc2ccccc2)cc1O
Temperature: 110 °C
Yield: 101.9 %

Procedure:
To a solution of 4-fluoro-2-hydroxyacetophenone (3.083 g, 20 mmol) in NMP (50 mL) were added thiophenol (2.054 ml, 20 mmol) and K2CO3 (8.293 g, 60 mmol). The reaction was heated at 110° C. overnight. Upon cooling the mixture was poured into water, acidified by addition of HCl (diluted) and extracted with Et2O. The combined organic extracts were washed with water and brine, dried over Na2SO4, filtered and concentrated in vacuo to afford 1-(2-hydroxy-4-phenylsulfanyl-phenyl)-ethanone (4.980 g of oil) that was used for the next step without further purification.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]2[N:11]3[CH:12]=[CH:13][C:14]([C:15]([C:17]4[C:25]5[C:20](=[CH:21][C:22]([C:26]6[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=6)=[CH:23][CH:24]=5)[N:19]([CH2:33][CH2:34][NH2:35])[CH:18]=4)=[O:16])=[C:10]3[CH2:9][S:8]2)[CH:2]=1.C(N(CC)CC)C.[CH3:43][S:44](Cl)(=[O:46])=[O:45]>C1COCC1>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]2[N:11]3[CH:12]=[CH:13][C:14]([C:15]([C:17]4[C:25]5[C:20](=[CH:21][C:22]([C:26]6[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=6)=[CH:23][CH:24]=5)[N:19]([CH2:33][CH2:34][NH:35][S:44]([CH3:43])(=[O:46])=[O:45])[CH:18]=4)=[O:16])=[C:10]3[CH2:9][S:8]2)[CH:2]=1
Reactant: CS(=O)(=O)Cl
Reactant: NCCn1cc(C(=O)c2ccn3c2CSC3c2cccnc2)c2ccc(-c3ccc(F)cc3)cc21
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CS(=O)(=O)NCCn1cc(C(=O)c2ccn3c2CSC3c2cccnc2)c2ccc(-c3ccc(F)cc3)cc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 189.9 %

Procedure:
To a solution of 3-(pyridin-3-yl)-7-[1-(2-aminoethyl)-6-(4-fluorophenyl)indol-3-ylcarbonyl]-1H,3H-pyrrolo[1,2-c]thiazole (0.20 g, 0.062 mmol), prepared according to the method of Example 59, and triethylamine (13 μL, 0.093 mmol) in THF (15 mL) was added methanesulfonyl chloride (6 μL, 0.074 mmol). The reaction mixture was stirred for two hours at ambient temperature. The reaction mixture was quenched with saturated aqueous NH4Cl and extracted with ethyl acetate. The organic phase was washed with brine, dried over MgSO4, filtered, and concentrated in vacuo. 3-(Pyridin-3-yl)-7-[1-(2-methanesulfonylaminoethyl)-6-(4-fluorophenyl)indol-3-ylcarbonyl]-1H,3H-pyrrolo[1,2-c]thiazole (66 mg) was obtained by flash chromatography on silica gel (98:2 CHCl3, methanol), 1H NMR (CDCl3, 300 MHz) δ2.83 (s, 3H), 3.6 (d, 2H, J=6 Hz), 4.42-4.52 (m, 3H), 4.65 (d, 1H, J=15 Hz), 5.57 (bs, 1H), 6.38 (bs, 1H), 6.46 (bs, 1H), 6.8 (d, 1H, J=3 Hz), 7.15 (t, 2H, J=9 Hz, 11 Hz), 7.47 (d, 2H, J=7 Hz), 7.52 7.65 (m, 3H), 7.8 (d, 1H, J=9 Hz), 7.95 (s, 1H), 8.38 (d, 1H, 9 Hz), 8.55 (bs, 2H). MS (DCI/NH3) m/e 561 (M+H)+. Anal calcd for C29H25FN4O3S2 : C, 62.13; H, 4.49; N, 9.99. Found: C, 61.37; H, 4.57; N, 9.58.
Reaction SMILES: [C:1]([O:20][CH2:21][CH2:22][CH:23]1[CH2:28][N:27]([C:29]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:26][CH2:25][NH:24]1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:55]1([N:61]([C:65]2[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=2)[C:62](Cl)=[O:63])[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1>CN(C)C=O>[C:55]1([N:61]([C:65]2[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=2)[C:62]([N:24]2[CH2:25][CH2:26][N:27]([C:29]([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)([C:36]3[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=3)[C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH2:28][CH:23]2[CH2:22][CH2:21][O:20][C:1]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)=[O:63])[CH:56]=[CH:57][CH:58]=[CH:59][CH:60]=1
Reactant: O=C(Cl)N(c1ccccc1)c1ccccc1
Reactant: c1ccc(C(OCCC2CN(C(c3ccccc3)(c3ccccc3)c3ccccc3)CCN2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(N(c1ccccc1)c1ccccc1)N1CCN(C(c2ccccc2)(c2ccccc2)c2ccccc2)CC1CCOC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 50.2 %

Procedure:
To a suspension of 364 mg (0.59 mmol) of (±) 2-(2-trityloxyethyl)-4-N-tritylpiperazine in 10 ml of N,N-dimethylformamide was added 170 ml (1.22 mmol) of triethylamine in one portion and 140 mg (0.60 mmol) of diphenylcarbamyl chloride in portions and the mixture was allowed to stir under nitrogen at room temperature for 20 hours. The solution was cooled and concentrated in vacuo. Flash chromatography on 40 g of silica gel using 25:75 v/v ethyl acetate/hexane as the eluant afforded 240 mg (50%) of a yellow oil.
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([O:7][C:8]2[CH:13]=[CH:12][C:11]([C:14]([Cl:17])(Cl)Cl)=[CH:10][CH:9]=2)=[CH:3][CH:2]=1.[O:18](C1C=CC(C(O)=O)=CC=1)C1C=CC=CC=1.Cl>>[O:7]([C:8]1[CH:13]=[CH:12][C:11]([C:14]([Cl:17])=[O:18])=[CH:10][CH:9]=1)[C:4]1[CH:5]=[CH:6][CH:1]=[CH:2][CH:3]=1
Reactant: O=C(O)c1ccc(Oc2ccccc2)cc1
Reactant: ClC(Cl)(Cl)c1ccc(Oc2ccccc2)cc1
Agent: Cl
Product: O=C(Cl)c1ccc(Oc2ccccc2)cc1
Temperature: 140 °C
Reaction time: 16 h
Yield: 73 %

Procedure:
P-phenoxybenzotrichloride (288 parts) was added to 182 parts of p-phenoxybenzoic acid, with mixing. The mixture was allowed to stand at ambient temperature for about 16 hours, then heated, over a period of about 4 hours, to a temperature of about 140° C., at which point HCl evolution was detected. The mixture was maintained at a temperature of between about 112° and 140° C. for an additional 21 hours, then cooled and analyzed by gas chromatographic techniques. Analysis indicated a 73% yield of p-phenoxybenzoylchloride based on the starting materials.
Reaction SMILES: [CH2:1]([N:8]([S:16]([CH2:19][CH2:20][CH2:21]Cl)(=[O:18])=[O:17])[C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:23][NH:24][CH2:25][CH2:26][NH:27][CH3:28].C([O-])([O-])=O.[K+].[K+]>CC#N>[CH2:1]([N:8]([S:16]([CH2:19][CH2:20][CH2:21][N:24]([CH3:23])[CH2:25][CH2:26][NH:27][CH3:28])(=[O:18])=[O:17])[C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N(Cc1ccccc1)S(=O)(=O)CCCCl
Reactant: CNCCNC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CNCCN(C)CCCS(=O)(=O)N(Cc1ccccc1)C(=O)OC(C)(C)C
Temperature: 65 °C
Reaction time: 8 h

Procedure:
Tert-butyl benzyl[(3-chloropropyl)sulfonyl]carbamate was dissolved in MeCN (0.2M) and N,N′-dimethylethane-1,2-diamine (5 eq.) was added followed by K2CO3 (5 eq.). The mixture was stirred at 65° C. overnight. The solvent was removed under reduced pressure and the residual material was dissolved in EtOAc and washed with water. After drying over Na2SO4, all volatiles were evaporated in vacuo and the residual material used in the next step without purification. (ES+) m/z 400 (M+H)+.
Reaction SMILES: B(Br)(Br)Br.C[O:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][C:15]=1[O:16]C)[CH2:12][CH:11]=[C:10]2[C:18]1[CH:23]=[CH:22][C:21]([O:24]C)=[CH:20][CH:19]=1.CCOC(C)=O.[Na+].[Cl-]>C(Cl)Cl>[OH:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][C:15]=1[OH:16])[CH2:12][CH:11]=[C:10]2[C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=1
Reactant: COc1ccc(C2=CCc3cc(OC)c(OC)cc32)cc1
Agent: BrB(Br)Br
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Oc1ccc(C2=CCc3cc(O)c(O)cc32)cc1
Temperature: -70 °C
Reaction time: 1 h
Yield: 115.7 %

Procedure:
A solution of BBr3 in CH2Cl2 (1.0M, 9.60 ml, 9.60 mmol) is added dropwise to a solution of 5,6-dimethoxy-3-(4-methoxyphenyl)indene (0.60 g, 2.23 mmol) in 2 ml of CH2Cl2, cooled to -70° C. The red solution obtained is heated at room temperature and stirred for 1 h at this temperature. The reaction mixture is poured into a mixture of ice-water and AcOEt. The aqueous phase is saturated with NaCl then extracted twice with AcOEt. The organic phases collected are washed with saturated aqueous NaCl solution, dried over MgSO4 and evaporated to dryness to give a red solid (0.62 g) which is used directly in the following step.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11](=O)[CH2:12][N:13]2[CH2:17][CH2:16][CH2:15][CH:14]2[C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH2:25][CH2:26][CH2:27][N:28]3[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]3)[CH:19]=2)[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.N>CO.C(Cl)Cl>[CH3:10][O:9][C:7]1[CH:6]=[C:5]([C@H:11]2[C:23]3[C:18](=[CH:19][C:20]([O:24][CH2:25][CH2:26][CH2:27][N:28]4[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]4)=[CH:21][CH:22]=3)[C@@H:14]3[CH2:15][CH2:16][CH2:17][N:13]3[CH2:12]2)[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=1
Reactant: COc1cc(OC)cc(C(=O)CN2CCCC2c2cccc(OCCCN3CCCCC3)c2)c1
Agent: N
Solvent: CO
Solvent: ClCCl
Product: COc1cc(OC)cc([C@@H]2CN3CCC[C@H]3c3cc(OCCCN4CCCCC4)ccc32)c1
Yield: 90 %

Procedure:
1-(3,5-Dimethoxy-phenyl)-2-{2-[3-(3-piperidin-1-yl-propoxy)-phenyl]pyrrolidin-1-yl}-ethanone. Prepared as described in Example 8, Step 1, on a 3.80 mmol scale, to give 1.10 g (90%) of the desired product as a pale yellow oil after chromatography (NH3 in MeOH/CH2Cl2). MS: exact mass calcd for C28H38N2O4, 466.3; m/z found, 467.4 [M+H]+. 1H NMR (MeOH-d4): 7.16 (t, J=7.8, 1H), 6.95 (m, 3H), 6.90 (d, J=7.5, 1H), 6.75 (m, 1H), 6.33 (m, 1H), 3.93 (m, 3H), 3.76 (s, 6H), 3.43 (m, 2H), 3.37 (m, 1H), 2.48 (m, 6H), 2.33 (m, 1H), 2.15 (m, 1H), 1.95 (m, 3H), 1.80 (m, 1H), 1.69 (m, 1H), 1.60 (m, 4H), 1.46 (br s, 2H).
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[C:12]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[O:6][CH2:5]1.[CH:28]1([C:32](O)=[O:33])[CH2:31][CH2:30][CH2:29]1>>[O:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[C:12]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:32]([CH:28]5[CH2:31][CH2:30][CH2:29]5)=[O:33])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[O:6][CH2:5]1
Reactant: O=C(O)C1CCC1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3cccc4c3OCO4)CC2)CC1
Agent: Cl
Product: O=C(N[C@H]1CC[C@H](CCN2CCN(c3cccc4c3OCO4)CC2)CC1)C1CCC1

Procedure:
The title compound, white solid (22.1 mg, 65.5%), MS (ISP) m/z=414.2 [(M+H)+], was prepared in accordance with the general method of example 1 from Trans-4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexylamine hydrochloride (Intermediate A) (30 mg, 81.5 mmol) and cyclobutanecarboxylic acid.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:7]=[C:8]([CH3:14])[C:9]([CH:12]=C)=[N:10][CH:11]=1)[C:2]#[C:3][CH3:4].CC(C)=[O:17].O>O=[Os](=O)(=O)=O>[CH2:1]([O:5][C:6]1[CH:7]=[C:8]([CH3:14])[C:9]([CH:12]=[O:17])=[N:10][CH:11]=1)[C:2]#[C:3][CH3:4]
Reactant: CC(C)=O
Reactant: C=Cc1ncc(OCC#CC)cc1C
Agent: O=[Os](=O)(=O)=O
Solvent: O
Product: CC#CCOc1cnc(C=O)c(C)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
OsO4 (2.5 wt. % sol. in tert-Butanol) (0.86 mL, 0.0027 mol) was added to a stirred solution of 5-(but-2-yn-1-yloxy)-3-methyl-2-vinylpyridine (5.1 g, 0.027 mol) in acetone/water (100:100 mL) at 0° C. The reaction mixture was allowed to stir for 30 min at ambient temperature. Then NaIO4 (23.2 g, 0.108 mol) was added and the reaction mixture was allowed to stir for additional 4 h at ambient temperature. The reaction mixture was diluted with ice cold water (200 mL) and extracted with EtOAc (3×200 mL). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The crude residue was purified by flash column chromatography on silica gel, eluting with 5-10% EtOAc in petroleum ether to give 5-(but-2-yn-1-yloxy)-3-methylpicolinaldehyde as an off white solid (3.6 g, 69.9%). MS m/z=189.9 [M+H]+.
Reaction SMILES: [O:1]([C:8]1[CH:12]=[CH:11][S:10][C:9]=1[CH:13]=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:15][CH:16]([CH3:32])[C:17]([NH:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[CH:21]=1)=[O:18]>>[CH3:15][CH:16]([CH3:32])[C:17]([NH:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH:26]2[CH2:31][CH2:30][N:29]([CH2:13][C:9]3[S:10][CH:11]=[CH:12][C:8]=3[O:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH2:28][CH2:27]2)[CH:21]=1)=[O:18]
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Reactant: O=Cc1sccc1Oc1ccccc1
Product: CC(C)C(=O)Nc1cccc(C2CCN(Cc3sccc3Oc3ccccc3)CC2)c1

Procedure:
Prepared by Procedure F and Scheme R using 3-phenoxy-2-thiophenecarbaldehyde and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 435.0 (M+H)+.
Reaction SMILES: Cl.[N:2]1[C:11]2[C:6](=[CH:7][C:8]([NH:12][NH2:13])=[CH:9][CH:10]=2)[CH:5]=[CH:4][CH:3]=1.[CH3:14][C:15]([CH3:22])([CH3:21])[C:16](=O)[CH2:17][C:18]#[N:19]>CCO.Cl>[C:15]([C:16]1[CH:17]=[C:18]([NH2:19])[N:12]([C:8]2[CH:7]=[C:6]3[C:11](=[CH:10][CH:9]=2)[N:2]=[CH:3][CH:4]=[CH:5]3)[N:13]=1)([CH3:22])([CH3:21])[CH3:14]
Reactant: NNc1ccc2ncccc2c1
Reactant: CC(C)(C)C(=O)CC#N
Agent: Cl
Solvent: CCO
Product: CC(C)(C)c1cc(N)n(-c2ccc3ncccc3c2)n1
Yield: 51.3 %

Procedure:
A mixture of 1-(quinolin-6-yl)hydrazine hydrochloride (4.0 g, 20.5 mmol) and 4,4-dimethyl-3-oxo-pentanenitrile (3.6 g, 30 mol) in EtOH (50 mL) and conc. HCl (5 mL) was heated at reflux overnight. After removal of the solvent, the residue was purified by column chromatography to yield 3-t-butyl-1-(quinolin-6-yl)-1H-pyrazol-5-amine (2.8 g, 51% yield). 1H NMR (300 MHz, DMSO-d6): δ 8.84 (d, J=4.2 Hz, 1H), 8.37 (d, J=7.5 Hz, 1H), 8.09 (s, 1H), 8.04 (s, 2H), 7.52 (m, 1H), 5.46 (s, 1H), 5.40 (brs, 2H), 1.29 (s, 9H).
Reaction SMILES: [C:1]([O:9][C:10]1([CH2:27][C:28]2[CH:33]=[CH:32][C:31](OC)=[CH:30][C:29]=2[OH:36])[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([CH3:19])[CH:17]=2)[N:12]([CH2:20][CH2:21][CH2:22][CH:23]([CH3:25])[CH3:24])[C:11]1=[O:26])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:37](OC1C2C(=CC=C(C)C=2)N(CCCC(C)C)C1=O)(=[O:44])C1C=CC=CC=1>>[C:1]([O:9][C:10]1([CH2:27][C:28]2[CH:33]=[C:32]([O:44][CH3:37])[CH:31]=[CH:30][C:29]=2[OH:36])[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([CH3:19])[CH:17]=2)[N:12]([CH2:20][CH2:21][CH2:22][CH:23]([CH3:25])[CH3:24])[C:11]1=[O:26])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc2c(c1)C(OC(=O)c1ccccc1)C(=O)N2CCCC(C)C
Reactant: COc1ccc(CC2(OC(=O)c3ccccc3)C(=O)N(CCCC(C)C)c3ccc(C)cc32)c(O)c1
Product: COc1ccc(O)c(CC2(OC(=O)c3ccccc3)C(=O)N(CCCC(C)C)c3ccc(C)cc32)c1

Procedure:
This compound was prepared in a similar manner to 3-(2-hydroxy-4-methoxybenzyl)-5-methyl-1-(4-methylpentyl)-2-oxoindolin-3-yl benzoate by reacting 5-methyl-1-(4-methylpentyl)-2-oxoindolin-3-yl benzoate with tert-butyl (2-(hydroxymethyl)-4-methoxyphenyl)carbonate. 1H-NMR δ 8.06 (d, 2H), 7.58 (t, 1H), 7.45 (t, 2H), 7.13 (d, 2H), 6.85 (d, 1H), 6.65 (m, 2H), 6.02 (bs, H), 5.88 (bs, OH), 3.70 (m, 2H), 3.47 (s, 3H), 3.38 (m, 2H), 2.32 (s, 3H), 1.48 (m, 1H), 1.27 (m, 2H), 1.12 (m, 2H), 0.84 (d, 6H). Calculated mass for C30H33NO5, 487.24, observed, 510.3 (M+Na).
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[N:8]([C:20]3[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][C:21]=3[F:27])[C:9]3[C:14]([C:15]=2/[C:16](=[N:18]/O)/[NH2:17])=[CH:13][CH:12]=[CH:11][CH:10]=3)=[C:5]([CH3:28])[O:4][N:3]=1.C(OC(=O)C)(=O)C>C(O)(=O)C.[Pd]>[CH3:1][C:2]1[C:6]([C:7]2[N:8]([C:20]3[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][C:21]=3[F:27])[C:9]3[C:14]([C:15]=2[C:16](=[NH:17])[NH2:18])=[CH:13][CH:12]=[CH:11][CH:10]=3)=[C:5]([CH3:28])[O:4][N:3]=1
Reactant: Cc1noc(C)c1-c1c(/C(N)=N/O)c2ccccc2n1-c1ccc(O)cc1F
Agent: [Pd]
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: Cc1noc(C)c1-c1c(C(=N)N)c2ccccc2n1-c1ccc(O)cc1F

Procedure:
0.5 mmol (Z)-2-(3,5-dimethylisoxazol-4-yl)-1-(2-fluoro-4-hydroxyphenyl)-N′-hydroxy-1H-indole-3-carboximidamide (Example 235) was dissolved in 5 ml acetic acid. Acetic acid anhydride (4 eq) was slowly added and the mixture was stirred over night. A Pd—C catalyst (10% on carbon) was added and the mixture was placed in a hydrogenation apparatus under 50 psi H2 over night. The mixture was filtered through celite and concentrated. The crude product was purified on HPLC: (Column: Sunfire, 20 min acidic gradient: 5-50% MeCN. ES/MS m/z: 365.15 (M+H), 363.18 (M−H); 1H NMR (MeOD, 500 MHz): 7.86 (m, 1H), 7.41-7.31 (m, 2.5H), 7.25-7.13 (m, 1.5H), 6.76 (m, 1H), 6.67 (m, 1H), 2.21, 2.15 (two s, 3H) and 2.08, 2.06 (two s, 3H).
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C@@H:19]3[CH2:23][N:22](C(OC(C)(C)C)=O)[C@H:21]([C:31](=[O:43])[NH:32][C@H:33]4[C:42]5[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=5)[CH2:36][CH2:35][CH2:34]4)[CH2:20]3)=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[C@H:33]1([NH:32][C:31]([C@H:21]2[NH:22][CH2:23][C@@H:19]([NH:18][C:16](=[O:17])[O:15][CH2:14][CH:12]3[C:11]4[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=4[C:5]4[C:13]3=[CH:1][CH:2]=[CH:3][CH:4]=4)[CH2:20]2)=[O:43])[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH2:36][CH2:35][CH2:34]1
Reactant: CC(C)(C)OC(=O)N1C[C@@H](NC(=O)OCC2c3ccccc3-c3ccccc32)C[C@H]1C(=O)N[C@@H]1CCCc2ccccc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(N[C@@H]1CN[C@H](C(=O)N[C@@H]2CCCc3ccccc32)C1)OCC1c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
To a solution of (2S,4S)-tert-butyl 4-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-2-(((R)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)pyrrolidine-1-carboxylate (6.70 g, 11.5 mmol) in CH2Cl2 (50 mL) at rt was added TFA (15 mL) dropwise. The reaction mixture was stirred at rt for 2 h, and then concentrated in vacuo. The residue was dissolved in CH2Cl2 (200 mL) and washed with aq. K2HPO4 solution (50 mL). The organic layer was dried over MgSO4, filtered and concentrated in vacuo to give crude (9H-fluoren-9-yl)methyl ((3S,5S)-5-(((R)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)pyrrolidin-3-yl)carbamate (5.54 g, 100%), which was used directly in the next step.
Reaction SMILES: [N:1]1([CH:7]2[CH2:30][N:29]([CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][C:37]([O:39]CC)=[O:38])[C:10]3=[N:11][C:12]([C:22]4[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=4)=[C:13]([C:15]4[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=4)[N:14]=[C:9]3[CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+].O.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CCO>[N:1]1([CH:7]2[CH2:30][N:29]([CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][C:37]([OH:39])=[O:38])[C:10]3=[N:11][C:12]([C:22]4[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=4)=[C:13]([C:15]4[CH:16]=[CH:17][C:18]([CH3:21])=[CH:19][CH:20]=4)[N:14]=[C:9]3[CH2:8]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCOC(=O)CCCCCCN1CC(N2CCCCC2)Cc2nc(-c3ccc(C)cc3)c(-c3ccc(C)cc3)nc21
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1ccc(-c2nc3c(nc2-c2ccc(C)cc2)N(CCCCCCC(=O)O)CC(N2CCCCC2)C3)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of ethyl 7-(7-(piperidin-1-yl)-2,3-di-p-tolyl-7,8-dihydropyrido[2,3-b]pyrazin-5(6H)-yl)heptanoate (step 8) (39 mg, 0.070 mmol) in EtOH (1 ml) was treated with 2M NaOH (0.105 mL, 0.211 mmol) and stirred at room temperature overnight. The resulting mixture was added to water (30 ml) and the pH was adjusted to pH4 by addition of 10% aqueous citric acid solution. The aqueous portion was extracted with DCM (×3) and the combined extracts were passed through a phase separating column. The solvent was removed under reduced pressure to afford the titled compound;
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@H:12]([CH2:13][CH:14]=[O:15])[CH2:11][O:10][C:9]1([CH3:17])[CH3:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:18][Mg]Br>C(OCC)C>[C:1]([O:5][C:6]([N:8]1[C@@H:12]([CH2:13][C@H:14]([OH:15])[CH3:18])[CH2:11][O:10][C:9]1([CH3:17])[CH3:16])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1[C@@H](CC=O)COC1(C)C
Reactant: C[Mg]Br
Solvent: CCOCC
Product: C[C@@H](O)C[C@H]1COC(C)(C)N1C(=O)OC(C)(C)C
Reaction time: 8 h

Procedure:
To a stirred solution of (S)-2,2-dimethyl-4-(2-oxo-ethyl)-oxazolidine-3-carboxylic acid tert-butyl ester (12.0 g; CAS 147959-19-1) in dry diethyl ether (200 ml) under an argon atmosphere at room temperature was added dropwise a solution of methylmagnesium bromide in diethyl ether (49.3 ml, 3 M solution) and stirring continued overnight. The reaction mixture was then quenched by careful addition of water and extracted twice with ethyl acetate. The combined organic phases were dried over sodium sulphate, filtered and concentrated in vacuo. The reside was purified by column chromatography (SiO2; gradient: heptane/EtOAc 100:0→50:50) to give (S)-4-((R)-2-hydroxy-propyl)-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (5.89 g) from fractions eluting first and (S)-4-((S)-2-hydroxy-propyl)-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (4.07 g) from fractions eluting later, both compounds as light yellow oils. (S)-4-((R)-2-hydroxy-propyl)-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester: 1H NMR δ (CDCl3, 300 MHz): 4.60 (1H, br. D, J=3.3 Hz), 4.23 (1H, m), 4.00 (1H, dd, J=8.7 & 5.4 Hz), 3.71 (1H, m), 3.65 (1H, d, J=8.7 Hz), 1.76 (1H, td, J=11.4 & 2.1 Hz), 1.61-1.46 (16H, m), 1.20 (3H, d, J=6.3 Hz). (S)-4-((S)-2-hydroxy-propyl)-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester: 1H NMR δ (CDCl3, 300 MHz): 4.13 (1H, m), 3.98 (1H, m), 3.85-3.60 (2H, m), 2.50 (1H, br. s), 1.80 (1H, m), 1.60-1.49 (16H, m), 1.22 (3H, d, J=6.3 Hz).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:13]#[N:14])[C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[C:7]([OH:12])[CH:6]=2.[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][CH:18]=1>>[OH:12][C:7]1[CH:6]=[C:5]2[C:10]([CH:11]=[C:2]([C:20]3[CH:21]=[CH:22][C:17]([O:16][CH3:15])=[CH:18][CH:19]=3)[CH:3]=[C:4]2[C:13]#[N:14])=[CH:9][CH:8]=1
Reactant: N#Cc1cc(Br)cc2ccc(O)cc12
Reactant: COc1ccc(B(O)O)cc1
Product: COc1ccc(-c2cc(C#N)c3cc(O)ccc3c2)cc1

Procedure:
The title compound was prepared by. reacting 3-bromo-7-hydroxy-1-naphthonitrile (0.249 g, 1.00 mmol) with 4-methoxyphenylboronic acid (0.21 g, 1.4 mmol) according to Method A to yield 0.19 (69%) of a light yellow solid: mp 226° C.; 1H NMR (DMSO-d6): δ 3.82 (3H, s), 7.07 (2H, d, J=8.82 Hz), 7.26 (1H, dd, J=2.32 Hz, J=8.90 Hz), 7.37 (1H, d, J=2.27 Hz), 7.80 (2H, d, J=8.80 Hz), 8.02 (1H, d, J=8.96 Hz), 8.37 (1H, d, J=1.85 Hz), 8.44 (1H, d, J=1.43 Hz), 10.48 (1H, bs); MS (ESI) m/z 274 (M−H)−.