Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:9]=[C:10]([C:13]([NH:15][NH2:16])=[O:14])[NH:11][N:12]=1.[OH:17][C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][C:25]=1[O:26][CH3:27])[CH:21]=O>C(O)C>[OH:17][C:18]1[CH:19]=[C:20]([CH:21]=[N:16][NH:15][C:13]([C:10]2[NH:11][N:12]=[C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])[CH:9]=2)=[O:14])[CH:23]=[CH:24][C:25]=1[O:26][CH3:27]
Reactant: NNC(=O)c1cc(-c2ccccc2Cl)n[nH]1
Reactant: COc1ccc(C=O)cc1O
Solvent: CCO
Product: COc1ccc(C=NNC(=O)c2cc(-c3ccccc3Cl)n[nH]2)cc1O
Yield: 68.1 %

Procedure:
In ethanol (3 ml), 5-(2-chlorophenyl)-2H-pyrazole-3-carboxylic acid hydrazide (30 mg) prepared in the Step 22-1-3 and 3-hydroxy-4-methoxybenzaldehyde (25 mg) was heated under reflux for 24 hours. After the mixture was allowed to cool, the precipitated crystal was separated by filtration and dried to give the title compound (32 mg, 68%).
Reaction SMILES: [N+]([NH:4][C:5]1[NH:10][C:9](=[O:11])[C:8]([CH2:12][C:13]2[CH:18]=[CH:17][N:16]=[C:15]([O:19][CH3:20])[CH:14]=2)=[CH:7][N:6]=1)([O-])=O.[CH3:21][C:22]1[NH:26][CH:25]=[N:24][C:23]=1[CH2:27][S:28][CH2:29][CH2:30]N>C(O)C>[CH3:21][C:22]1[NH:26][CH:25]=[N:24][C:23]=1[CH2:27][S:28][CH2:29][CH2:30][NH:4][C:5]1[NH:10][C:9](=[O:11])[C:8]([CH2:12][C:13]2[CH:18]=[CH:17][N:16]=[C:15]([O:19][CH3:20])[CH:14]=2)=[CH:7][N:6]=1
Reactant: COc1cc(Cc2cnc(N[N+](=O)[O-])[nH]c2=O)ccn1
Reactant: Cc1[nH]cnc1CSCCN
Solvent: CCO
Product: COc1cc(Cc2cnc(NCCSCc3nc[nH]c3C)[nH]c2=O)ccn1
Yield: 51 %

Procedure:
An equimolar mixture of 2-nitroamino-5-(2-methoxy-4-pyridylmethyl)-4-pyrimidone and 2-(5-methyl-4-imidazolyl methylthio)ethylamine was heated under reflux in ethanol for 18 hours. The solid which crystallised out on cooling was recrystallised from methanol to give 2-[2-(5-methyl-4-imidazolylmethylthio)ethylamino]-5-(2-methoxy-4-pyridylmethyl)-4-pyrimidone, m.p. 177-178° in 51% yield. The latter compound was heated under reflux in 2N hydrogen chloride in ethanol for 24 hours and the mixture was evaporated to dryness. The residue was recrystallised from 2-propanol/ethanol containing hydrogen chloride to give 2-[2-(5-methyl-4-imidazolylmethylthio)ethylamino]-5-(2-hydroxy-4-pyridylmethyl)-4-pyrimidone trihydrochloride, m.p. 172-176°.
Reaction SMILES: [S:1]1[CH:5]=[C:4]([C:6]2[N:10]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([C:18]4[C:19]([C:24]([O:26]C(C)(C)C)=[O:25])=[CH:20][CH:21]=[CH:22][CH:23]=4)=[CH:14][CH:13]=3)[C:9]3[CH:31]=[CH:32][CH:33]=[CH:34][C:8]=3[N:7]=2)[N:3]=[CH:2]1.FC(F)(F)C(O)=O>>[S:1]1[CH:5]=[C:4]([C:6]2[N:10]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([C:18]4[C:19]([C:24]([OH:26])=[O:25])=[CH:20][CH:21]=[CH:22][CH:23]=4)=[CH:14][CH:13]=3)[C:9]3[CH:31]=[CH:32][CH:33]=[CH:34][C:8]=3[N:7]=2)[N:3]=[CH:2]1
Reactant: CC(C)(C)OC(=O)c1ccccc1-c1ccc(Cn2c(-c3cscn3)nc3ccccc32)cc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)c1ccccc1-c1ccc(Cn2c(-c3cscn3)nc3ccccc32)cc1

Procedure:
Prepared in analogous manner to Example 9 from tert.butyl 4'-[(2-(thiazol-4-yl)-benzimidazol-1-yl)-methyl]biphenyl-2-carboxylate and trifluoroacetic acid
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]([CH2:12][O:13][C:14]2[CH:19]=[CH:18][C:17]([S:20]([NH:23][CH:24]3[CH2:29][CH2:28][NH:27][CH2:26][CH:25]3[C:30]([OH:32])=[O:31])(=[O:22])=[O:21])=[CH:16][CH:15]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.C(N(CC)CC)C.[C:40]([N:44]=[C:45]=[O:46])([CH3:43])([CH3:42])[CH3:41]>C1COCC1>[C:40]([NH:44][C:45]([N:27]1[CH2:28][CH2:29][C@@H:24]([NH:23][S:20]([C:17]2[CH:18]=[CH:19][C:14]([O:13][CH2:12][C:10]3[C:9]4[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=4)[N:3]=[C:2]([CH3:1])[CH:11]=3)=[CH:15][CH:16]=2)(=[O:21])=[O:22])[C@@H:25]([C:30]([OH:32])=[O:31])[CH2:26]1)=[O:46])([CH3:43])([CH3:42])[CH3:41]
Reactant: CC(C)(C)N=C=O
Reactant: Cc1cc(COc2ccc(S(=O)(=O)NC3CCNCC3C(=O)O)cc2)c2ccccc2n1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1cc(COc2ccc(S(=O)(=O)N[C@@H]3CCN(C(=O)NC(C)(C)C)C[C@@H]3C(=O)O)cc2)c2ccccc2n1
Temperature: 25 °C
Reaction time: 19 h
Yield: 82 %

Procedure:
To a solution of 0.5 g (1.1 mmol) of 4-[4-(2-methyl-quinolin-4-ylmethoxy)-benzenesulfonylamino]-piperidine-3-carboxylic acid (Example 29, Step 1) and triethylamine (0.3 mL, 2.197 mmol) in THF (10 mL) at 0° C. was added tert-butylisocyanate (0.130 g, 1.32 mmol). The reaction mixture was allowed to warm to 25° C. and then stirred for 19 h. The THF was removed in vacuo and the resulting oil was diluted with ethyl acetate (100 mL). The organics were washed with saturated aqueous sodium chloride (2×30 mL), dried over MgSO4, filtered and concentrated to obtain a crude solid (0.580 g). The crude product was purified by reverse phase HPLC (Gilson) on a Phenomex C-18 semi-prep column eluting an acetonitrile:water gradient, to afford (3S,4R)-1-tert-butylcarbamoyl-4-[4-(2-methyl-quinolin-4-yl methoxy)-benzenesulfonylamino]-piperidine-3-carboxylic acid as an amorphous white solid (0.5 g, 88.5%). MS: 555 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:8]=[CH:9][CH:10]=1)[NH2:7])([O-:3])=[O:2].[F:11][C:12]([F:25])([O:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=1)[CH:20]=O)[CH:13]([F:15])[F:14].C(O)(=O)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClC(Cl)C>[N+:1]([C:4]1[CH:5]=[C:6]([NH:7][CH2:20][C:19]2[CH:22]=[CH:23][CH:24]=[C:17]([O:16][C:12]([F:11])([F:25])[CH:13]([F:14])[F:15])[CH:18]=2)[CH:8]=[CH:9][CH:10]=1)([O-:3])=[O:2]
Reactant: O=Cc1cccc(OC(F)(F)C(F)F)c1
Reactant: Nc1cccc([N+](=O)[O-])c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: O=[N+]([O-])c1cccc(NCc2cccc(OC(F)(F)C(F)F)c2)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 69.9 %

Procedure:
3-nitroaniline (1.87 g, 13.51 mmol) and 3-(1,1,2,2-tetrafluoroethoxy)-benzaldehyde (3 g, 13.5 mmol) were dissolved in 25 mL of dichloroethane and acetic acid (0.85 mL, 14.9 mmol), then solid NaBH(OAc)3 (3.73 g 17.6 mmol) was added. The mixture was stirred at room temperature for 48 hours, then quenched with aqueous saturated sodium bicarbonate and diluted with ethyl acetate. The organic layer was dried over MgSO4, and concentrated in vacuo. The crude product was purified by flash column chromatography on silica gel eluting with ethyl acetate:hexane 1:7 to give 3.25 g (70%) of the desired N-(3-nitrophenyl)-3-(1,1,2,2-tetrafluoroethoxy) benzenemethan-amine product as a brown oil. HRMS calcd. for C15H13F4N2O3: 345.0862[M+H]+, found: 345.0864. 1H NMR (CDCl3) δ4.4 (s, 2H), 4.5 (s, 1H), 5.9 (tt, 1H), 6.9 (d, 1H), 7.1 (d, 1H), 7.2-7.3 (m, 3H), 7.4(m, 2H), 7.5 (d, 1H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([NH2:9])[CH:3]=1.[I:10]Cl.S([O-])([O-])=O.[Na+].[Na+]>CO>[Cl:1][C:2]1[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([NH2:9])[C:3]=1[I:10]
Reactant: ClI
Reactant: Cc1nc(N)cc(Cl)n1
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: CO
Product: Cc1nc(N)c(I)c(Cl)n1
Temperature: 2.5 °C
Reaction time: 16 h
Yield: 79.9 %

Procedure:
Combine 6-chloro-2-methylpyrimidin-4-amine (708 g, 4.93 mol) and MeOH (7.08 L) in a 20 L round bottom flask equipped with a mechanical stirrer. Cool to 0-5° C. Add iodine monochloride (4.806 kg, 29.6 mol) dissolved in MeOH (6 L) using an addition funnel over a period of 1 h. Warm the reaction mixture to RT and stir at RT for 16 h. Cool the reaction mixture to 0-5° C. and add sodium sulfite (46 L, 20% aqueous solution). Filter the resulting solid and wash with water (2 L) followed by hexane (3 L). Dry the solid under vacuum to afford the title compound as a white solid (1061 g, 80%). LC-ES/MS m/z 269.9 (M+1).
Reaction SMILES: [CH:1]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8][N:7]([C:16](=[NH:20])[O:17][CH2:18][CH3:19])[CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[F:21][C:22]1[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:23]=1[C:24](Cl)=[O:25]>>[F:21][C:22]1[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:23]=1[C:24]([N:20]=[C:16]([N:7]1[CH2:6][C:5]2[CH:4]=[CH:3][CH:2]=[CH:1][C:11]=2[C:10]2[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=2[CH2:8]1)[O:17][CH2:18][CH3:19])=[O:25]
Reactant: CCOC(=N)N1Cc2ccccc2-c2ccccc2C1
Reactant: O=C(Cl)c1ccc(F)cc1F
Product: CCOC(=NC(=O)c1ccc(F)cc1F)N1Cc2ccccc2-c2ccccc2C1

Procedure:
starting from ethyl 5,7-dihydro-6H-dibenz[c,e]azepine-6-carboximidate and 2,4-difluorobenzoyl chloride, there is obtained ethyl N-(2,4-difluorobenzoyl)-5,7-dihydro-6H-dibenz[c,e]azepine-6-carboximidate as a syrup, mass spectrum m/e: M+ 406 (8), 377 (22), 194 (100), 141 (74);
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:18][CH2:19][CH3:20])[CH2:5][N:6]1[C:10]([NH2:11])=[CH:9][C:8]([C:12]2[CH:13]=[N:14][CH:15]=[N:16][CH:17]=2)=[N:7]1)[CH3:2].Br[C:22]1[C:23]([CH3:32])=[CH:24][C:25]([CH3:31])=[C:26]([N+:28]([O-:30])=[O:29])[CH:27]=1>>[CH2:19]([O:18][CH:4]([O:3][CH2:1][CH3:2])[CH2:5][N:6]1[C:10]([NH:11][C:22]2[CH:27]=[C:26]([N+:28]([O-:30])=[O:29])[C:25]([CH3:31])=[CH:24][C:23]=2[CH3:32])=[CH:9][C:8]([C:12]2[CH:13]=[N:14][CH:15]=[N:16][CH:17]=2)=[N:7]1)[CH3:20]
Reactant: CCOC(Cn1nc(-c2cncnc2)cc1N)OCC
Reactant: Cc1cc(C)c([N+](=O)[O-])cc1Br
Product: CCOC(Cn1nc(-c2cncnc2)cc1Nc1cc([N+](=O)[O-])c(C)cc1C)OCC

Procedure:
Analogously to Example 13A/Step 1, 3.01 g (10.8 mmol) of the compound of Example 78A and 2.75 g (11.9 mmol) of 5-bromo-2,4-dimethylnitrobenzene gave, after 3 h of heating under reflux, a crude product which was purified by chromatography on a Biotage system (100 g Snap column; mobile phase gradient ethyl acetate/0-8% methanol). This gave 3.70 g (65% of theory) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:11]([C:12]#[N:13])=[C:10](O)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([N:15]3[CH2:20][CH2:19][N:18]([CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH2:17][CH2:16]3)[CH:8]=2)[N:3]=1.P(Cl)(Cl)([Cl:30])=O.[OH-].[Na+]>>[NH2:1][C:2]1[C:11]([C:12]#[N:13])=[C:10]([Cl:30])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([N:15]3[CH2:20][CH2:19][N:18]([CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH2:17][CH2:16]3)[CH:8]=2)[N:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: N#Cc1c(N)nc2ccc(N3CCN(Cc4ccccc4)CC3)cc2c1O
Agent: [Na+]
Agent: [OH-]
Product: N#Cc1c(N)nc2ccc(N3CCN(Cc4ccccc4)CC3)cc2c1Cl
Temperature: 120 °C
Reaction time: 6 h

Procedure:
The mixture of 14 g of 2-amino-3-cyano-4-hydroxy-6-(4-benzylpiperazin-1-yl)quinoline and 28 mL of phosphoryl chloride is stirred at 120° C. for 6 hours. The cooled reaction mixture is poured onto 500 g of ice, the pH of the mixture is adjusted to 8 with 10% NaOH solution, and the precipitated material is filtered off. After drying 14.5 g of the title compound is obtained, m.p.: 206° C.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([C:9]([N:11]2[CH2:16][CH2:15][CH:14]([N:17]3[CH2:21][CH2:20][CH2:19][C@H:18]3[CH2:22][OH:23])[CH2:13][CH2:12]2)=[O:10])=[C:4]([CH3:24])[CH:3]=1.CC1(C)C(C)(C)OB([C:33]2[CH:34]=[N:35][CH:36]=[C:37]([C:39]([F:42])([F:41])[F:40])[CH:38]=2)O1>>[CH3:8][C:6]1[CH:7]=[C:2]([C:33]2[CH:34]=[N:35][CH:36]=[C:37]([C:39]([F:42])([F:41])[F:40])[CH:38]=2)[CH:3]=[C:4]([CH3:24])[C:5]=1[C:9]([N:11]1[CH2:16][CH2:15][CH:14]([N:17]2[CH2:21][CH2:20][CH2:19][C@H:18]2[CH2:22][OH:23])[CH2:13][CH2:12]1)=[O:10]
Reactant: Cc1cc(Br)cc(C)c1C(=O)N1CCC(N2CCC[C@H]2CO)CC1
Reactant: CC1(C)OB(c2cncc(C(F)(F)F)c2)OC1(C)C
Product: Cc1cc(-c2cncc(C(F)(F)F)c2)cc(C)c1C(=O)N1CCC(N2CCC[C@H]2CO)CC1

Procedure:
In analogy to the procedure described for example 1, (4-bromo-2,6-dimethyl-phenyl)-[4-((S)-2-hydroxymethyl-pyrrolidin-1-yl)-piperidin-1-yl]-methanone (intermediate 4) was reacted with 3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-5-trifluoromethyl-pyridine (intermediate 6) to give the title compound as light yellow solid. MS: 462.4 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:17]=[C:16]([N+:18]([O-])=O)[CH:15]=[CH:14][C:4]=1[O:5][CH2:6][C:7]([N:9]1[CH2:13][CH2:12][CH2:11][CH2:10]1)=[O:8]>CCO>[NH2:18][C:16]1[CH:15]=[CH:14][C:4]([O:5][CH2:6][C:7]([N:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)=[O:8])=[C:3]([O:2][CH3:1])[CH:17]=1
Reactant: COc1cc([N+](=O)[O-])ccc1OCC(=O)N1CCCC1
Solvent: CCO
Product: COc1cc(N)ccc1OCC(=O)N1CCCC1
Reaction time: 5 h
Yield: 85 %

Procedure:
A suspension of 2-(2-methoxy-4-nitrophenoxy)-1-(pyrrolidin-1-yl)ethanone (2.03 g; 7.24 mmol) and 10% Pd(C) (1.54 g; 1.45 mmol) in EtOH (20 mL) was hydrogenated at 55 psi of H2 for 5 h. After filtration through fiberglass filter paper, the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, CH2Cl2/CH3OH, 100:0 to 19:1 gradient) to afford the title compound (1.54 g; 85%) as an orange gum. 1H NMR (CDCl3) δ 1.81-1.86 (m, 2H), 1.91-1.96 (m, 2H), 3.49-3.56 (m, 6H), 3.81 (s, 3H), 4.58 (s, 2H), 6.19 (dd, J=8.80 Hz, 2.20 Hz, 1H), 6.30 (d, J=2.75 Hz, 1H), 6.81 (d, J=8.80 Hz, 1H); 13C NMR (CDCl3) δ 23.78, 26.22, 45.90, 46.10, 55.73, 70.47, 100.70, 106.54, 117.06, 140.41, 142.01, 150.69, 167.13; HPLC a) column: PHENOMENEX® C18 4.6×50 mm, 4 min gradient, 10% MeOH/90% H2O/0.2% H3PO4 to 90% MeOH/10% H2O/0.2% H3PO4; 1 min hold, 4 mL/min UV detection at 220 nm, 0.19, 0.66 min retention time, (98%); HPLC b) column: PHENOMENEX® C18 4.6×50 mm, 4 min gradient, 10% MeOH/90% H2O/0.1% TFA to 90% MeOH/10% H2O/0.1% TFA, 1 min hold; 4 mL/min, UV detection at 220 nm, 0.99 min retention time; MS (ES): m/z 251 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([O:10][CH3:11])[CH:3]=1.[Cl:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][C:20]=1[Cl:21])[CH2:16]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(C)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[Cl:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][C:20]=1[Cl:21])[CH2:16][O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([O:10][CH3:11])[CH:3]=1
Reactant: OCc1ccc(Cl)c(Cl)c1
Reactant: COc1cc(O)ccc1C=O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: COc1cc(OCc2ccc(Cl)c(Cl)c2)ccc1C=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.1 %

Procedure:
4-Hydroxy-2-methoxybenzaldehyde (408 mg, 2.68 mmol), 3,4-dichlorobenzyl alcohol (665 mg, 3.76 mmol), and triphenylphosphine (980 mg, 3.74 mmol) were dissolved in tetrahydrofuran (8 mL), and a diethyl azodicarboxylate toluene solution (2.2 M, 1.71 mL, 3.76 mmol) was slowly added dropwise thereto at room temperature, and then, the resulting mixture was stirred under a nitrogen atmosphere at room temperature for 2 hours. The solvent in the reaction solution was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=100:0 to 90:10 (v/v)), whereby the objective title compound was obtained as a white solid (801 mg, yield: 96%).
Reaction SMILES: C([O:4][C@H:5]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([N:20]([CH3:22])[CH3:21])[CH:13]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])(=O)C.[C:23]1(C)[CH:28]=[CH:27]C(S(O)(=O)=O)=[CH:25][CH:24]=1>C(O)C1C=CC=CC=1.C1C=CC=CC=1>[OH:4][C@H:5]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([N:20]([CH3:21])[CH3:22])[CH:13]=1)[C:6]([O:8][CH2:9][C:10]1[CH:27]=[CH:28][CH:23]=[CH:24][CH:25]=1)=[O:7]
Reactant: CCOC(=O)[C@@H](Cc1ccc(OC)c(N(C)C)c1)OC(C)=O
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: OCc1ccccc1
Solvent: c1ccccc1
Product: COc1ccc(C[C@@H](O)C(=O)OCc2ccccc2)cc1N(C)C
Yield: 59.3 %

Procedure:
To a solution of ethyl (R)-2-acetoxy-3-(4-methoxy-3-dimethylaminophenyl)propionate(1.56 g) in benzyl alcohol (3.7 ml)and benzene (7.4 ml) was added p-toluenesulfonic acid (0.82 g)and heated under reflux for 6 hours. After cooling, the solvent wasevaporated in vacuo, and the gained crude product was purified bysilica gel column chromatography. The residue was eluted withmixed solvent of hexane, ethyl acetate, and ethanol (60:35:5, v/v).The fractions containing the desired product were combined andevaporated in vacuo to obtain benzyl (R)-2-hydroxy-3-(4-methoxy-3-dimethylaminophenyl)propionate(0.93 g).
Reaction SMILES: [O:1]=[C:2]1[CH2:10][C:9]2[C:4](=[C:5]([S:11]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[CH:6]=[CH:7][CH:8]=2)[NH:3]1.[O:21]1CCOCC1.[OH-].[Na+]>O>[NH2:3][C:4]1[C:5]([S:11]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)(=[O:13])=[O:12])=[CH:6][CH:7]=[CH:8][C:9]=1[CH2:10][C:2]([OH:21])=[O:1]
Reactant: O=C1Cc2cccc(S(=O)(=O)c3ccc(Cl)cc3)c2N1
Reactant: C1COCCO1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Nc1c(CC(=O)O)cccc1S(=O)(=O)c1ccc(Cl)cc1
Reaction time: 6 h

Procedure:
A mixture of 2-oxo-7-(4-chlorophenylsulfonyl)indoline (3.3 g) and dioxane (20 ml) was added to a solution of sodium hydroxide (2.0 g) in water (20 ml), and the mixture was refluxed with stirring for 6 hrs. The reaction mixture was concentrated in vacuo, and the residue was dissolved in water. The aqueous solution was washed with diethyl ether, adjusted to pH 4 with 5% sulfuric acid and extracted with diethyl ether. The extract was washed with saline, dried over magnesium sulfate, treated with charcoal and then evaporated in vacuo to give 2-[2-amino-3-(4-chlorophenylsulfonyl)phenyl]acetic acid (2.8 g). mp 139°-141° C.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:34]=[CH:33][C:11]([NH:12]/[C:13](=[C:20]3\[C:21](=[O:32])[NH:22][C:23]4[C:28]\3=[CH:27][CH:26]=[C:25]([C:29]([OH:31])=[O:30])[CH:24]=4)/[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:10][CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:35](O)[CH2:36][CH3:37]>>[N:1]1([CH2:7][C:8]2[CH:9]=[CH:10][C:11]([NH:12]/[C:13](=[C:20]3\[C:21](=[O:32])[NH:22][C:23]4[C:28]\3=[CH:27][CH:26]=[C:25]([C:29]([O:31][CH2:35][CH2:36][CH3:37])=[O:30])[CH:24]=4)/[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)=[CH:33][CH:34]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCCO
Reactant: O=C1Nc2cc(C(=O)O)ccc2/C1=C(/Nc1ccc(CN2CCCCC2)cc1)c1ccccc1
Product: CCCOC(=O)c1ccc2c(c1)NC(=O)/C2=C(\Nc1ccc(CN2CCCCC2)cc1)c1ccccc1

Procedure:
Prepared from 3-Z-[1-(4-(piperidin-1-yl-methyl)-anilino)-1-phenyl-methylene]-6-carboxy-2-indolinone and n-propanol Rf value: 0.7 (silica gel, methylene chloride/methanol=5:1) C31H33N3O3
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:27])[F:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:29]1([N:35]([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[C:36]2[CH:43]=[CH:42][C:39]([CH:40]=O)=[CH:38][CH:37]=2)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH:24][CH2:40][C:39]3[CH:38]=[CH:37][C:36]([N:35]([C:44]4[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=4)[C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[CH:43][CH:42]=3)[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:26])[F:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Reactant: O=Cc1ccc(N(c2ccccc2)c2ccccc2)cc1
Product: FC(F)(F)c1cccc2c(-c3cccc(NCc4ccc(N(c5ccccc5)c5ccccc5)cc4)c3)c(Cc3ccccc3)cnc12

Procedure:
This compound was prepared according to the procedure of example 66, substituting 3-(3-benzyl-8-trifluoromethyl-quinolin-4-yl)-phenylamine and 4-diphenylamino-benzaldehyde. MS (ESI) m/z 636.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][CH2:11][C:12]#[N:13])[CH:6]=[CH:7][CH:8]=1.[H][H]>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][CH2:11][CH2:12][NH2:13])[CH:6]=[CH:7][CH:8]=1
Reactant: [H][H]
Reactant: COc1cccc(CCCC#N)c1
Solvent: CCO
Product: COc1cccc(CCCCN)c1
Reaction time: 72 h
Yield: 78 %

Procedure:
To a Parr bottle flushed with nitrogen was added ~1.0 g of Raney Nickel (50% suspension in H2O), ethanol (125 mL), ammonium hydroxide (30 mL), and a solution of 4-(3-methoxyphenyl)butyronitrile (8.49 g, 48.4 mmol) in ethanol (150 mL). The bottle was charged with hydrogen (60 psi) and rocked 3 d. The suspension was filtered through Celite, the cake rinsed with fresh ethanol (400 mL), and the combined filtrate concentrated in vacuo. The resulting suspension was treated with dichloromethane (200 mL) and water (200 mL), the layers separated, and the aqueous portion back-extracted with fresh dichloromethane (2×50 mL). The combined organic portions were washed with saturated sodium chloride solution (300 mL), dried (K2CO3), filtered, and concentrated in vacuo. Kugelrohr distillation (0.1 torr, 120° C.) provided the desired product as a clear liquid (6.77 g, 78%) which was identical spectroscopically to that previously reported. Venit, J. J.; DiPierro, M.; Magnus, P. J. Org. Chem. 1989, 54, 4298-4301. 1H NMR (CDCl3) δ 7.20 (t, J=8 Hz, 1H), 6.79-6.70 (m, 3H), 3.80 (s, 3H), 2.75-2.68 (m, 2H), 2.61 t J=8 Hz, 2H), 1.82-1.45 (m, 6H).
Reaction SMILES: Cl[C:2]1[CH:10]=[C:9]([F:11])[C:8]([F:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[F:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1>>[F:11][C:9]1[C:8]([F:12])=[CH:7][C:3]([C:4]([OH:6])=[O:5])=[C:2]([O:20][C:17]2[CH:18]=[CH:19][C:14]([F:13])=[CH:15][CH:16]=2)[CH:10]=1
Reactant: Oc1ccc(F)cc1
Reactant: O=C(O)c1cc(F)c(F)cc1Cl
Product: O=C(O)c1cc(F)c(F)cc1Oc1ccc(F)cc1

Procedure:
The title compound was prepared according to the procedure described in step 1 of Example 66 from 2-chloro-4,5-difluorobenzoic acid and 4-fluorophenol: MS (ESI) m/z 222 (M−H)−.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:22])=[C:8]2[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[N:14][S:13][C:9]2=[C:10](Br)[N:11]=1)=[O:5])[CH3:2].C([Sn](CCCC)(CCCC)[C:28]1[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=1)CCC>>[CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:22])=[C:8]2[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[N:14][S:13][C:9]2=[C:10]([C:28]2[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=2)[N:11]=1)=[O:5])[CH3:2]
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccncc1
Reactant: CCOC(=O)c1nc(Br)c2snc(-c3ccccc3)c2c1O
Product: CCOC(=O)c1nc(-c2ccncc2)c2snc(-c3ccccc3)c2c1O

Procedure:
The title compound was synthesized in analogy to Example 3 from 7-bromo-4-hydroxy-3-phenyl-isothiazolo[5,4-c]pyridine-5-carboxylic acid ethyl ester and 4-(tributylstannyl)pyridine: MS (m/z) 378.1 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C:11](=[O:13])[CH2:10][CH:9]1[CH2:14][CH2:15][NH:16][C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18])=[O:7])([CH3:4])([CH3:3])[CH3:2].C[Si]([N-][Si](C)(C)C)(C)C.[Na+].C1COCC1.[CH3:42][C:43]([Si:46](Cl)([CH3:48])[CH3:47])([CH3:45])[CH3:44]>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:12][C:11]([O:13][Si:46]([C:43]([CH3:45])([CH3:44])[CH3:42])([CH3:48])[CH3:47])=[CH:10][CH:9]1[CH2:14][CH2:15][NH:16][C:17]([O:19][CH2:20][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)=[O:18])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CC(C)(C)OC(=O)N1CC(=O)CC1CCNC(=O)OCc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC(O[Si](C)(C)C(C)(C)C)=CC1CCNC(=O)OCc1ccccc1
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 83.9 %

Procedure:
To a pre-cooled (−78° C.) solution containing 6 (400 mg, 1.10 mmol) in THF (10 mL) was added 1M NaHMDS/THF (2.43 mL) in a dropwise fashion. After 45 min, a solution containing TBSCl (348 mg, 2.31 mmol) in THF (5 mL) was added to the heterogeneous reaction mixture. After 30 min, the homogeneous reaction mixture was quenched with saturated aqueous NH4Cl. The solution was diluted with EtOAc and the layers were separated. The organic phase was washed with brine then dried over anhydrous Na2SO4, filtered, and concentrated. The crude product was purified by flash silica gel chromatography (4:1 hexanes/EtOAc) to afford 440 mg (83%) of 7 as a white foam. 1H NMR (CDCl3, 300 MHz), mixture of rotomers: δ7.26 (m, 5H), 5.87 (m, 0.25H), 5.70 (m, 0.25H), 5.48 (m, 0.5H), (app dd, J=16.4, 12.8 Hz, 2H), 4.92 (m, 0.3H), 4.55 (br s, 0.7H), 4.49 (m, 0.7H), 4.39 (m, 0.3H), 3.99 (m, 0.2H), 3.92 (m, 0.4H), 3.86 (br s, 0.4H), 3.76 (m, 1H), 3.28 (m, 0.5H), 3.13 (m, 0.5H), 3.03 (m, 0.5H), 2.92 (m, 0.5H), 1.78 (m, 1H), 1.64 (m, 1H), 1.38 (s, 9H), 0.85 (s, 9H), 0.11 (s, 6H) ppm. Mass spectrum, m/z [499.2] (M+Na)+.