Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2([CH:17]=[O:18])[CH2:16][CH2:15][C:10]3([O:14][CH2:13][CH2:12][O:11]3)[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:19][Mg]Br.[Cl-].[NH4+].O>O1CCCC1.C(OCC)(=O)C>[CH3:19][CH:17]([C:7]1([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:8][CH2:9][C:10]2([O:14][CH2:13][CH2:12][O:11]2)[CH2:15][CH2:16]1)[OH:18]
Reactant: C[Mg]Br
Reactant: O=CC1(c2ccccc2)CCC2(CC1)OCCO2
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(O)C1(c2ccccc2)CCC2(CC1)OCCO2
Temperature: 25 °C
Yield: 94.8 %

Procedure:
A solution of 8-phenyl-1,4-dioxaspiro[4.5]decane-8-carboxaldehyde (J. Med. Chem. 1975, 18, 593-599; 4 g, 16.2 mmol) in tetrahydrofuran (100 mL) was added dropwise to a solution of methyl magnesium bromide (3.0M in ether, 8.1 mL, 24.3 mmol) in tetrahydrofuran (50 mL) at 0° C. The mixture was allowed to warm to room temperature over 4 hours, then aqueous ammonium chloride (saturated, 75 mL), water (75 mL) and ethyl acetate (100 mL) were added. The layers were separated and the organic fraction was dried (MgSO4) and the solvent was evaporated under reduced pressure to give the title compound as a colorless solid (4.03 g, 96%). 1H NMR (360 MHz, CDCl3) δ 0.96 (3H, d, J 6.5 Hz), 1.12 (1H, br s), 1.40-1.66 (4H, m), 1.76-1.86 (2H, m), 2.24-2.28 (1H, m), 2.46-2.51 (1H, m), 3.61-3.64 (1H, m), 3.58-3.96 (4H, m), and 7.21-7.38 (5H, m).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([N:11]([O:13][CH3:14])[CH3:12])=[O:10])=[CH:4][CH:3]=1.CN(C)C=O.[H-].[Na+].[CH3:22][C:23]1([CH3:35])[CH2:27][C:26]2[CH:28]=[CH:29][CH:30]=[C:31]([CH2:32][CH2:33]Cl)[C:25]=2[O:24]1>O>[CH3:22][C:23]1([CH3:35])[CH2:27][C:26]2[CH:28]=[CH:29][CH:30]=[C:31]([CH2:32][CH2:33][O:1][C:2]3[CH:7]=[CH:6][C:5]([NH:8][C:9]([N:11]([O:13][CH3:14])[CH3:12])=[O:10])=[CH:4][CH:3]=3)[C:25]=2[O:24]1
Reactant: CON(C)C(=O)Nc1ccc(O)cc1
Reactant: CC1(C)Cc2cccc(CCCl)c2O1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CON(C)C(=O)Nc1ccc(OCCc2cccc3c2OC(C)(C)C3)cc1
Reaction time: 0.5 h
Yield: 66.9 %

Procedure:
2.6 g of 1-(4-hydroxyphenyl)-3-methoxy-3-methylurea was dissolved into 20 ml of dried N,N-dimethylformamide, and 0.6 g of 60% sodium hydride was added thereto. After the mixture was stirred for 30 minutes, 1.7 g of 2-(2,3-dihydro-2,2-dimethyl-7-benzofuranyl)ethyl chloride was added dropwise thereto under cooling with ice. After the mixture was stirred at room temperature for 5 hours, it was poured into water and extracted with ethyl acetate. After the organic layer was washed with water, it was dried over anhydrous magnesium sulfate and ethyl acetate was distilled off. The residue was subjected to silica gel column chromatography using ethyl acetate/n-hexane (1/1) as a developer to obtain 2.0 g of Compound No. 10 shown in Table 1.
Reaction SMILES: [H-].[Na+].[C:3]1([CH3:31])[CH:8]=[CH:7][C:6]([S:9]([N:12]2[CH2:30][CH2:29][CH2:28][C@H:13]2[C:14]([NH:16][C@H:17]([C:25]([NH2:27])=[O:26])[CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:15])(=[O:11])=[O:10])=[CH:5][CH:4]=1.[C:32]1([CH3:42])[CH:37]=[CH:36][C:35]([S:38](Cl)(=[O:40])=[O:39])=[CH:34][CH:33]=1>C1COCC1>[C:32]1([CH3:42])[CH:37]=[CH:36][C:35]([S:38]([NH:27][C:25](=[O:26])[C@H:17]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[NH:16][C:14](=[O:15])[C@@H:13]2[CH2:28][CH2:29][CH2:30][N:12]2[S:9]([C:6]2[CH:7]=[CH:8][C:3]([CH3:31])=[CH:4][CH:5]=2)(=[O:11])=[O:10])(=[O:40])=[O:39])=[CH:34][CH:33]=1
Reactant: Cc1ccc(S(=O)(=O)N2CCC[C@H]2C(=O)N[C@@H](Cc2ccccc2)C(N)=O)cc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)NC(=O)[C@H](Cc2ccccc2)NC(=O)[C@@H]2CCCN2S(=O)(=O)c2ccc(C)cc2)cc1
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
N-(Toluene-4-sulfonyl)-L-proline was reacted with L-phenylalanine amide using the procedure described in Method 12 to yield N-(toluene-4-sulfonyl)-L-prolyl-L-phenylalanine amide. To a solution of NaH (60% mineral oil—prewashed with THF) in THF at 0° C. was added N-(toluene-4-sulfonyl)-L-prolyl-L-phenylalanine amide and the reaction was stirred at 0° C. for 45 minutes. Toluene-4-sulfonyl chloride was added and the reaction was stirred for 16 hours at room temperature. The reaction mixture was extracted with EtOAc (3×50 mL) and 0.2 N HCl (50 mL), and the combined organic layers were washed successively with sat. NaHCO3 (50 mL), and sat. NaCl (2×50 mL), dried over MgSO4, filtered, and concentrated to yield the title compound as an oil.
Reaction SMILES: I[CH2:2][CH:3]=[CH2:4].[CH3:5][N:6]([CH3:18])[C:7]1[CH:8]=[C:9]([F:17])[C:10]([N+:14]([O-:16])=[O:15])=[C:11]([OH:13])[CH:12]=1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.CCOCC.O>[CH2:2]([O:13][C:11]1[CH:12]=[C:7]([N:6]([CH3:18])[CH3:5])[CH:8]=[C:9]([F:17])[C:10]=1[N+:14]([O-:16])=[O:15])[CH:3]=[CH2:4]
Reactant: C=CCI
Reactant: CN(C)c1cc(O)c([N+](=O)[O-])c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOCC
Solvent: CS(C)=O
Product: C=CCOc1cc(N(C)C)cc(F)c1[N+](=O)[O-]
Yield: 85.8 %

Procedure:
3-Iodo-1-Propene (0.30 mL, 3.3 mmol) was added to 5-Dimethylamino-3-fluoro-2-nitro-phenol (0.592 g, 2.96 mmol) and Potassium carbonate (1.1 g, 7.9 mmol) in Dimethyl sulfoxide (15 mL) and the reaction was stirred under an atmosphere of Nitrogen for 45 m. The mixture was diluted with ether (120 mL) and water (50 mL), the layers separated and the aq. back extracted with 25 mL ether. The combined organics were washed with water (60 mL) and brine (60 mL). After drying over sodium sulfate, the solution was conc. in vacuo and the residue chromatographed (ISCO, 52 g SiO2, 0-50% EtOAc:Hex) to afford (3-Allyloxy-5-fluoro-4-nitro-phenyl)-dimethyl-amine as a yellow solid (0.61 g, 86%). 1H-NMR (CDCl3): 6.01 (m, 2H), 5.90 (s, 1H), 5.46 (d, 1H, J=17.2 Hz), 5.32 (d, 1H, J=10.6 Hz), 4.63 (m, 2H), 3.03 (s, 6H); 19F-NMR (CDCl3): −119.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[OH-].[K+].[CH3:11]I.O>CS(C)=O>[CH3:11][O:8][C:5]1[CH:4]=[CH:3][C:2]([CH3:1])=[N:7][CH:6]=1
Reactant: CI
Reactant: Cc1ccc(O)cn1
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: COc1ccc(C)nc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
6-methylpyridin-3-ol (50.0 g, 0.458 mol) was added to a suspension of powdered KOH (103 g, 1.83 mol) in dimethylsulfoxide (750 mL) and the mixture was left to stir at room temperature under nitrogen for 1.5 hours. Methyl iodide (30 mL, 68.3 g, 0.481 mol) was then added dropwise over 1 hour to the dark brown mixture (exothermic). After stirring at room temperature for 1.5 hours water (1.0 L) was added and the mixture was extracted with ethyl acetate (2×300 mL). The combined organic extracts were washed with brine, dried (MgSO4) and evaporated at 40° C. on a rotary evaporator. The residue was purified by column chromatography (silica), eluting with pentane, increasing polarity to ethyl acetate, to give the volatile product as a ˜1:1 mixture with ethyl acetate (40 g, ˜23.3 g product, 41%). 1H NMR (CDCl3, 400 MHz) δ 2.45 (3H, s), 3.79 (3H, s), 7.02 (1H, d), 7.08 (1H, dd), 8.16 (1H, d).
Reaction SMILES: [C:1]1([C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[NH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.I[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[C:9]1([C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[N:8][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: Ic1ccccc1
Reactant: N=C(c1ccccc1)c1ccccc1
Product: c1ccc(N=C(c2ccccc2)c2ccccc2)cc1
Yield: 94 %

Procedure:
Following General Procedure A (90° C., 30 hours), 1,1-diphenyl-methanimine (272 mg, 1.5 mmol) is coupled with iodo-benzene (112 μL, 1.0 mmol) to give 94% N-(diphenylmethylene)aniline.
Reaction SMILES: [Br-].[Br:2][CH:3]([CH3:26])[C:4](=[O:25])[CH2:5][P+:6]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(=O)([O-])[O-].[K+].[K+]>C(OCC)(=O)C.O1CCCC1.O>[Br:2][CH:3]([CH3:26])[C:4](=[O:25])[CH:5]=[P:6]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CC(Br)C(=O)C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Br-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(Br)C(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Yield: 96.8 %

Procedure:
A mixture of (3-bromo-2-oxobutyl)triphenylphosphonium bromide (30 g) in ethyl acetate (150 ml), tetrahydrofuran (50 ml) and water (150 ml) was adjusted to pH 10 with potassium carbonate. The separated organic layer was washed with brine and dried over magnesium sulfate. Evaporation of the solvent gave a residue, which was triturated with diisopropyl ether and collected by filtration to give (3-bromo-2-oxobutylidene)triphenylphosphorane (24.27 g).
Reaction SMILES: [N+:1]([O-:4])([O-])=[O:2].[K+].[OH:6][C:7]1[C:16]([OH:17])=[N:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]3[N:20]=[CH:19][S:18][C:13]3=2)[N:8]=1>S(=O)(=O)(O)O>[OH:6][C:7]1[C:16]([OH:17])=[N:15][C:14]2[C:9](=[CH:10][C:11]([N+:1]([O-:4])=[O:2])=[C:12]3[N:20]=[CH:19][S:18][C:13]3=2)[N:8]=1
Reactant: O=[N+]([O-])[O-]
Reactant: Oc1nc2ccc3ncsc3c2nc1O
Agent: O=S(=O)(O)O
Agent: [K+]
Product: O=[N+]([O-])c1cc2nc(O)c(O)nc2c2scnc12
Temperature: 0 °C
Reaction time: 4 h
Yield: 63.1 %

Procedure:
Finely powdered potassium nitrate (92 mg, 0.9 mmol) was added to a stirred and ice-cooled solution of 7,8-dihydroxythiazolo[5,4-f]quinoxaline (0.20 g, 0.9 mmol) in 5 ml of conc. sulfuric acid. The mixture was stirred at 0° C. for 30 min, then at room temperature for 4 h, and finally poured into ice/water. The resulting precipitate was isolated by filtration, washed with water, and dried giving 0.15 g (62%) of the nitro compound; m.p. >360° C., IR (KBr): 1680 cm-1 ; 1H-NMR (DMSO-d6): 8.06 (s, 1H, ArH), 9.53 (s, 1H, ArH), 12.23 (broad s, 1H, OH), 12.76 (broad s, 1H, OH).
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[N:21]=[C:22]([S:33][CH:34]([CH3:37])[CH2:35][OH:36])[NH:23][C:24]=2[C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)=[CH:16][CH:15]=1>C(Cl)(Cl)Cl>[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[N:21]=[C:22]([S:33]([CH:34]([CH3:37])[CH2:35][OH:36])=[O:9])[NH:23][C:24]=2[C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)=[CH:16][CH:15]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COc1ccc(-c2nc(SC(C)CO)[nH]c2-c2ccc(OC)cc2)cc1
Solvent: ClC(Cl)Cl
Product: COc1ccc(-c2nc(S(=O)C(C)CO)[nH]c2-c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
At room temperature, a solution of 2.16 g. of 3-chloroperbenzoic acid in 150 ml. of chloroform is added dropwise to a solution of 3.71 g. of [4,5-bis(4-methoxyphenyl)]-2-(2-hydroxy-1-methylethylthio)imidazole in 200 ml. of chloroform. The mixture is stirred overnight at room temperature and washed with saturated sodium bicarbonate solution. The organic solution is dried over sodium sulfate and concentrated under vacuum. The residue is purified by chromatography on 200 g. of silica gel with ethyl acetate as the eluent. After evaporation of the solvent, 2.67 g. of [4,5-bis(4-methoxyphenyl)]-2-(2-hydroxy-1-methylethylsulfinyl)imidazole is obtained as an amorphous foam.
Reaction SMILES: O=S(Cl)[Cl:3].[NH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18].[CH3:20]O>>[ClH:3].[CH3:20][O:18][C:17](=[O:19])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][NH2:5]
Reactant: CO
Reactant: NCCCCCCCCCCCC(=O)O
Reactant: O=S(Cl)Cl
Product: COC(=O)CCCCCCCCCCCN
Product: Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 60 %

Procedure:
MeOH (40 ml) was cooled to 0-50° C., and SOCl2 (4 ml) was added drop wise with stirring during 30 minutes. 12-Aminododecanoic acid (3 g, 13.9 mmol) was added and the resulting suspension was stirred at 0-5° C. while the ice in cooling bath melted and allowed to warm to room temperature during 16 hours. The mixture was filtered and the solid was dried by suction to afford 2.23 g (60%) of 12-aminododecanoic acid methyl ester hydrochloride. From the mother liquor a further batch of 0.92 g (25%) was isolated.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]([C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH3:22])[CH:14]=1)([CH:10]([CH3:12])[CH3:11])[C:6]([O:8][CH3:9])=[O:7].[CH3:23][NH:24][CH2:25][CH2:26][C:27]1[CH:37]=[CH:36][C:30]([C:31]([O:33][CH2:34][CH3:35])=[O:32])=[CH:29][CH:28]=1>>[CH3:22][O:21][C:15]1[CH:14]=[C:13]([C:5]([C:6]([O:8][CH3:9])=[O:7])([CH:10]([CH3:12])[CH3:11])[CH2:4][CH2:3][CH2:2][N:24]([CH3:23])[CH2:25][CH2:26][C:27]2[CH:37]=[CH:36][C:30]([C:31]([O:33][CH2:34][CH3:35])=[O:32])=[CH:29][CH:28]=2)[CH:18]=[CH:17][C:16]=1[O:19][CH3:20]
Reactant: CCOC(=O)c1ccc(CCNC)cc1
Reactant: COC(=O)C(CCCCl)(c1ccc(OC)c(OC)c1)C(C)C
Product: CCOC(=O)c1ccc(CCN(C)CCCC(C(=O)OC)(c2ccc(OC)c(OC)c2)C(C)C)cc1

Procedure:
Reaction of 1e with 2c produced 3w. MS found M+H=500. The oxalate salt of 3w was recrystallized from ethyl acetate; mp 121-123° C.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([Cl:19])[CH:13]=2)[CH:3]=1.[NH2:20][CH2:21][CH:22]([OH:25])[CH2:23][OH:24]>>[ClH:1].[Cl:19][C:14]1[CH:13]=[C:12]([C:4]2[CH:3]=[C:2]([NH:20][CH2:21][CH:22]([OH:25])[CH2:23][OH:24])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=2)[CH:17]=[CH:16][C:15]=1[Cl:18]
Reactant: Clc1ccc(-c2cc(Cl)c3ccccc3n2)cc1Cl
Reactant: NCC(O)CO
Product: Cl
Product: OCC(O)CNc1cc(-c2ccc(Cl)c(Cl)c2)nc2ccccc12

Procedure:
The title compound, m.p. 234-236° C., and MS: m/e=362 (M+), was prepared from 4-chloro-2-(3,4-dichloro-phenyl)-quinoline and (RS)-3-amino-1,2-propandiol.
Reaction SMILES: [OH:1][C:2]([C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1)([C:6]1[N:7]=[CH:8][N:9]([C:11]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:10]=1)[CH:3]([CH3:5])[CH3:4].Br[C:40]1[N:45]=[C:44]([C:46]([NH:48][CH3:49])=[O:47])[CH:43]=[CH:42][CH:41]=1>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>[OH:1][C:2]([C:30]1[CH:35]=[CH:34][C:33]([C:40]2[N:45]=[C:44]([C:46]([NH:48][CH3:49])=[O:47])[CH:43]=[CH:42][CH:41]=2)=[CH:32][CH:31]=1)([C:6]1[N:7]=[CH:8][N:9]([C:11]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:10]=1)[CH:3]([CH3:5])[CH3:4]
Reactant: CC(C)C(O)(c1ccc(B(O)O)cc1)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: CNC(=O)c1cccc(Br)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: CNC(=O)c1cccc(-c2ccc(C(O)(c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)C(C)C)cc2)n1
Yield: 31.7 %

Procedure:
By the reaction in the same manner as in Example 33-(ii) using 4-[1-hydroxy-2-methyl-1-(1-trityl-1H-imidazol-4-yl)propyl]phenylboronic acid (2.97 g), 6-bromo-N-methyl-2-pyridinecarboxamide (1.30 g) and tetrakis(triphenylphosphine)palladium(0) (0.110 g), the title compound (1.11 g) was obtained as colorless powder crystals.
Reaction SMILES: [CH3:1][C@@H:2]1[NH:7][CH2:6][CH2:5][N:4]([CH2:8][C:9]([NH:11][C:12]2[CH:21]=[CH:20][CH:19]=[C:18]3[C:13]=2[CH:14]=[CH:15][CH:16]=[N:17]3)=[O:10])[CH2:3]1.[C:22]([C:24]1[CH:29]=[CH:28][C:27]([S:30](Cl)(=[O:32])=[O:31])=[CH:26][CH:25]=1)#[N:23]>>[C:22]([C:24]1[CH:25]=[CH:26][C:27]([S:30]([N:7]2[CH2:6][CH2:5][N:4]([CH2:8][C:9]([NH:11][C:12]3[CH:21]=[CH:20][CH:19]=[C:18]4[C:13]=3[CH:14]=[CH:15][CH:16]=[N:17]4)=[O:10])[CH2:3][C@@H:2]2[CH3:1])(=[O:32])=[O:31])=[CH:28][CH:29]=1)#[N:23]
Reactant: C[C@H]1CN(CC(=O)Nc2cccc3ncccc23)CCN1
Reactant: N#Cc1ccc(S(=O)(=O)Cl)cc1
Product: C[C@H]1CN(CC(=O)Nc2cccc3ncccc23)CCN1S(=O)(=O)c1ccc(C#N)cc1

Procedure:
The title compound was prepared from the product of step (i) (1.4 g) and 4-cyanobenzenesulphonyl chloride (1 g) by the method of Example 58 step (ii) as a white solid. Yield: 0.53 g
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C@@H:4]([O:6][C:7]1[CH:12]=[CH:11][C:10]([F:13])=[C:9]([NH2:14])[CH:8]=1)[CH3:5].C[O:17][C:18](=O)[CH:19]([CH2:24][C:25]1[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][C:26]=1[Cl:32])[C:20](=O)[CH2:21][CH3:22]>>[CH3:1][O:2][C:3](=[O:15])[C@@H:4]([O:6][C:7]1[CH:12]=[CH:11][C:10]([F:13])=[C:9]2[C:8]=1[C:18](=[O:17])[C:19]([CH2:24][C:25]1[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][C:26]=1[Cl:32])=[C:20]([CH2:21][CH3:22])[NH:14]2)[CH3:5]
Reactant: COC(=O)[C@H](C)Oc1ccc(F)c(N)c1
Reactant: CCC(=O)C(Cc1ccc(Cl)cc1Cl)C(=O)OC
Product: CCc1[nH]c2c(F)ccc(O[C@@H](C)C(=O)OC)c2c(=O)c1Cc1ccc(Cl)cc1Cl

Procedure:
The title compounds were prepared by the method of Preparation 65c using (S)-2-(3-amino-4-fluorophenoxy)propionic acid methyl ester and 2-(2,4-dichlorobenzyl)-3-oxopentanoic acid methyl ester.
Reaction SMILES: [CH:1]1([N:6]2[C:14]3[C:9](=[CH:10][CH:11]=[C:12]([C:15]([OH:17])=O)[CH:13]=3)[C:8]([CH2:18][CH3:19])=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[CH2:21]([O:23][C:24](=[O:28])[CH2:25][CH2:26][NH2:27])[CH3:22]>>[CH2:21]([O:23][C:24](=[O:28])[CH2:25][CH2:26][NH:27][C:15]([C:12]1[CH:13]=[C:14]2[C:9]([C:8]([CH2:18][CH3:19])=[N:7][N:6]2[CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)=[CH:10][CH:11]=1)=[O:17])[CH3:22]
Reactant: CCOC(=O)CCN
Reactant: CCc1nn(C2CCCC2)c2cc(C(=O)O)ccc12
Agent: Cl
Product: CCOC(=O)CCNC(=O)c1ccc2c(CC)nn(C3CCCC3)c2c1
Yield: 90.5 %

Procedure:
This compound was prepared according to the method of Example 35, using 297 mg (1.15 mmol, 1.0 equiv) 1-cyclopentyl-3-ethyl-1H-indazole-6-carboxylic acid and 177 mg (1.15 mmol, 1.0 equiv) beta-alanine ethyl ester hydrochloride as starting materials to give 372 mg (90%) of white crystals: mp 74-76° C.; Anal. calcd for C20H27N3O3: C, 67.21; H, 7.61; N, 11.76. Found: C, 67.40; H, 7.56; N, 11.99.
Reaction SMILES: [Mg].[CH3:2][C:3]1[CH:10]=[C:9]([CH3:11])[CH:8]=[C:7]([CH3:12])[C:4]=1[CH2:5]Cl.CC1C=C(C)C=C(C)C=1C[Mg]Cl.[CH3:25][O:26][C:27]1[CH:32]=[CH:31][C:30]([S:33]([C:36]2[CH:37]=[N:38][C:39]([CH3:42])=[N:40][CH:41]=2)(=[O:35])=[O:34])=[CH:29][CH:28]=1>CCOCC.C1COCC1>[CH3:25][O:26][C:27]1[CH:28]=[CH:29][C:30]([S:33]([C:36]2[CH:41]([CH2:5][C:4]3[C:3]([CH3:2])=[CH:10][C:9]([CH3:11])=[CH:8][C:7]=3[CH3:12])[NH:40][C:39]([CH3:42])=[N:38][CH:37]=2)(=[O:35])=[O:34])=[CH:31][CH:32]=1
Reactant: Cc1cc(C)c(CCl)c(C)c1
Reactant: COc1ccc(S(=O)(=O)c2cnc(C)nc2)cc1
Agent: Cc1cc(C)c(C[Mg]Cl)c(C)c1
Agent: [Mg]
Solvent: CCOCC
Solvent: C1CCOC1
Product: COc1ccc(S(=O)(=O)C2=CN=C(C)NC2Cc2c(C)cc(C)cc2C)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 50.9 %

Procedure:
To a mixture of magnesium (240 mg, 10 mmol) and ether (20 mL) was added 2,4,6-trimethylbenzyl chloride (1.69 g, 10 mmol) in ether (20 mL) dropwise at reflux under N2. The freshly prepared solution of 2,4,6-trimethylbenzylmagnesium chloride in ether was added to a solution of 5-(4-methoxy-benzenesulfonyl)-2-methylpyrimidine (264 mg, 1.0 mmol) in THF (10 mL) dropwise at 0° C. The mixture was stirred under N2 at 0° C. for 1 h and then quenched by addition of saturated aqueous NH4Cl. The organic layer was separated and the aqueous layer was extracted three times with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel (EtOAc) to provide 5-(4-methoxy-benzenesulfonyl)-2-methyl-6-(2,4,6-trimethylbenzyl)-1,6-dihydro-pyrimidine (203 mg, 51%) as a light yellow solid: 1H NMR (500 MHz, CDCl3) δ 7.86 (d, J=9.0 Hz, 2H), 7.45 (s, 1H), 6.99 (d, J=9.0 Hz, 2H), 6.83 (s, 2H), 4.40 (dd, J=10.8, 3.2 Hz, 1H), 3.86 (s, 3H), 2.96 (dd, J=14.2, 10.8 Hz, 1H), 2.87 (dd, J=14.2, 3.2 Hz, 1H), 2.25 (s, 6H), 2.24 (s, 3H), 1.91 (s, 3H); ESI MS m/z 399 [(M+H)+, calcd for C22H27N2O3S, 399.2].
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[CH:7]=1)[CH2:4][OH:5].[C:18](O)(=[O:27])[CH:19]=[CH:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(Cl)CCl.C(N(CC)CC)C>CN(C1C=CN=CC=1)C.ClCCl>[OH:5][CH2:4][C@H:3]([NH:2][C:18](=[O:27])[CH:19]=[CH:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[CH:7]=1
Reactant: N[C@@H](CO)c1cccc(N2CCOCC2)c1
Reactant: O=C(O)C=Cc1ccccc1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: ClCCCl
Product: O=C(C=Cc1ccccc1)N[C@@H](CO)c1cccc(N2CCOCC2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.4 %

Procedure:
Mixture of (R)-2-Amino-2-(3-morpholin-4-yl-phenyl)-ethanol hydrochloride (70 mg, 0.24 mmol), cinnamic acid (35 mg, 0.24 mmol), EDC (91 mg, 0.47 mmol), DMAP (29 mg, 0.24 mmol), triethyl amine (0.13 mL, 0.95 mmol) in dichloromethane (1 mL) was stirred at room temperature overnight. The reaction mixture was concentrated under vacuum and purified by flash chromatography with 60% acetone/hexanes to provide the title compound as a white solid (57 mg, 68% yield).
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][N:4]=[C:5]([NH:7][S:8]([C:11]2[CH:12]=[CH:13][C:14]([NH2:17])=[CH:15][CH:16]=2)(=[O:10])=[O:9])[CH:6]=1.[CH:18]1[CH:19]=CC2C(=O)C=CC(=O)[C:22]=2[CH:23]=1.CCN(C(C)C)C(C)C.CI>CN(C=O)C>[CH2:19]([NH:17][C:14]1[CH:13]=[CH:12][C:11]([S:8]([NH:7][C:5]2[CH:6]=[CH:1][CH:2]=[CH:3][N:4]=2)(=[O:10])=[O:9])=[CH:16][CH:15]=1)[CH2:18][CH2:23][CH3:22]
Reactant: O=C1C=CC(=O)c2ccccc21
Reactant: Nc1ccc(S(=O)(=O)Nc2ccccn2)cc1
Solvent: CN(C)C=O
Solvent: CI
Solvent: CCN(C(C)C)C(C)C
Product: CCCCNc1ccc(S(=O)(=O)Nc2ccccn2)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Sulfapyridine Naphthoquinone Derivatives (6a, 6b, 6c). (YL1-018-1, YL1-018-2, YL1-018-9). DIPEA (52.9 mg, 0.41 mmol) was added to solution of 4-(3-Chloro-1,4-dioxo-1,4-dihydro-naphthalen-2-ylamino-N-pyridin-2-yl-benzenesulfonamide (150 mg, 0.34 mmol) in anhydrous DMF (3 ml) under inert conditions. Methyl iodide (58 mg, 0.41 mmol) was added to the reaction mixture after 5 min. and the reaction was stirred at r.t. for two days. The reaction mixture was dried under reduced pressure and purified by flash chromatography (SiO2, EtOAC in Hexane, gradient elution).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[F:9].[OH:10][C:11]1[CH:15]=[C:14]([N:16]2[C:20]3[CH:21]=[N:22][CH:23]=[CH:24][C:19]=3[N:18]=[CH:17]2)[S:13][C:12]=1[C:25]([O:27][CH3:28])=[O:26].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[F:9][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[CH2:2][O:10][C:11]1[CH:15]=[C:14]([N:16]2[C:20]3[CH:21]=[N:22][CH:23]=[CH:24][C:19]=3[N:18]=[CH:17]2)[S:13][C:12]=1[C:25]([O:27][CH3:28])=[O:26]
Reactant: COC(=O)c1sc(-n2cnc3ccncc32)cc1O
Reactant: Fc1ccccc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1sc(-n2cnc3ccncc32)cc1OCc1ccccc1F

Procedure:
In a similar manner as described for example B11, 81.7 mg of 1-(bromomethyl)-2-fluorobenzene, 100 mg of methyl 3-hydroxy-5-(3H-imidazo[4,5-c]pyridin-3-yl)thiophene-2-carboxylate, and 59.7 mg of potassium carbonate in 3 ml anhydrous DMF give methyl 3-[(2-fluorobenzyl)oxy]-5-(3H-imidazo[4,5-c]pyridin-3-yl)thiophene-2-carboxylate as crude material that is used for step 2 without further purification.
Reaction SMILES: [O-]S(C(F)(F)F)(=O)=O.[CH2:9]([O:11][C:12]([CH:14]1[CH2:23][C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16]([CH3:25])([CH3:24])[NH:15]1)=[O:13])[CH3:10].C[Si](C=[N+]=[N-])(C)C.[CH3:33][OH:34]>C(Cl)Cl>[CH2:9]([O:11][C:12]([CH:14]1[CH2:23][C:22]2[C:17](=[CH:18][CH:19]=[C:20]([O:34][CH3:33])[CH:21]=2)[C:16]([CH3:24])([CH3:25])[NH:15]1)=[O:13])[CH3:10]
Reactant: CO
Reactant: CCOC(=O)C1Cc2ccccc2C(C)(C)N1
Agent: C[Si](C)(C)C=[N+]=[N-]
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)C1Cc2cc(OC)ccc2C(C)(C)N1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96 %

Procedure:
To a solution of the triflate salt of 1,1-dimethyl-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid ethyl ester (1.5 g, 3.76 mmol, 1.0 eq.) in MeOH (20 mL) and CH2Cl2 (2 mL) at 0° C. was added a solution of (trimethylsilyl)diazomethane (2.0 M in hexane, 3.7 mL, 2.0 eq.). The resulting mixture was warmed to r.t. and stirred overnight, and then the solution was concentrated. Purification by flash chromatography (125 g SiO2 linear gradient, 40 mL/min, 1:1 EtOAc/hexane for 33 minutes) afforded about 900 mg of the final compound (96%). LRMS (electrospray): 250.2 (M+1).