Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.Br[CH2:14][CH2:15][CH3:16].[H-].[Na+]>CN(C=O)C.C(OCC)(=O)C>[CH2:9]([O:8][C:6](=[O:7])[C:5]1[CH:4]=[CH:3][C:2]([O:1][CH2:14][CH2:15][CH3:16])=[CH:12][CH:11]=1)[CH3:10]
Reactant: CCOC(=O)c1ccc(O)cc1
Reactant: CCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCOc1ccc(C(=O)OCC)cc1
Yield: 90.8 %

Procedure:
(Scheme 1, Compound A) To a solution of ethyl 4-hydroxybenzoate (2.0 g, 12 mmol) and bromopropane (4.0 g, 32.8 mmol) in DMF (50 mL) was added NaH (60% in mineral oil, 0.80 g, 20.8 mmol). The resultant suspension was stirred at room temperature for 1.0 hour. The mixture was diluted with ethyl acetate (EtOAc) (300 mL), washed with H2O, and then was dried over Na2SO4. After filtration and concentration in vacuo, the residue was purified by flash chromatography (SiO2: EtOAc/Hexanes). This compound was obtained as a yellow oil (2.26 g, 10.9 mmol, 91% yield). 1H NMR (DMSO-d6) δ 7.89 (d, 2H, J=8.7 Hz), 7.00 (d, 2H, J=9.0 Hz), 4.24 (q, 2H, J=6.9 Hz), 3.98 (t, 2H, J=6.6 Hz), 1.72 (m, 2H), 1.29 (t, 3H, J=6.6 Hz), 0.97 (t, 3H, J=7.2 Hz); Anal. Calcd for C12H16O3.0.47C6H14: C, 71.54; H, 9.14; N, 0.00. Found: C, 71.57; H, 8.78; N, 0.00; Mass Spec.: 209.04 (MH+).
Reaction SMILES: [C:1]([O:5][C:6](=[O:13])[NH:7][C:8]1[CH:12]=[CH:11][S:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].C([Li])CCC.CN(C)[CH:21]=[O:22].O>O1CCCC1>[C:1]([O:5][C:6](=[O:13])[NH:7][C:8]1[CH:12]=[CH:11][S:10][C:9]=1[CH:21]=[O:22])([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(C)C=O
Reactant: CC(C)(C)OC(=O)Nc1ccsc1
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1ccsc1C=O
Temperature: -78 °C
Reaction time: 1 h

Procedure:
Thiophen-3-yl-carbamic acid tert-butyl ester described in Preparation Example U-1 (1.00 g, 5.02 mmol) was dissolved in tetrahydrofuran (20 mL), to which n-butyl lithium (2.47M hexane solution, 4.47 mL, 11.0 mmol) was added at −78° C., and the mixture was stirred at −78° C. for 1 hour. N,N-dimethylformamide (466 μl, 6.02 mmol) was added to the reaction mixture at −78° C., and the solution was stirred for 1 hour at room temperature. Water was added to the reaction solution, which was then extracted with ethyl acetate, the organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was evaporated in vacuo, the residue was purified by silica gel column chromatography (hexane:ethyl acetate=10:1), and the title compound (1.14 g, quantitatively) was obtained as a colorless oil.
Reaction SMILES: [NH2:1][C:2]([CH3:7])([CH2:5][OH:6])[CH2:3][OH:4].[C:8]1(=O)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1>C1(C)C=CC=CC=1>[CH3:7][C:2]1([CH2:5][OH:6])[NH:1][C:8]2([CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)[O:4][CH2:3]1
Reactant: CC(N)(CO)CO
Reactant: O=C1CCCCC1
Solvent: Cc1ccccc1
Product: CC1(CO)COC2(CCCCC2)N1

Procedure:
The procedure of Example 1 was employed utilizing 2-amino-2-methyl-1,3-propanediol (42.05 grams; 0.4 mole) and cyclohexanone (39.26 grams; 0.4 mole) in 250 mls of toluene. After removing the toluene, the residue was distilled to obtain 37.7 grams (50.8% of theoretical; b.p. 120° C. at 2.0 mm.) of the desired compound.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:30])=[C:4]([NH:10][C:11]([N:13]2[CH2:17][C@H:16]([O:18][Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20])[CH2:15][C@H:14]2[C:26](OC)=[O:27])=[O:12])[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].[Li+].[BH4-]>C1COCC1>[Cl:1][C:2]1[C:3]([CH3:30])=[C:4]([NH:10][C:11]([N:13]2[CH2:17][C@H:16]([O:18][Si:19]([C:22]([CH3:23])([CH3:24])[CH3:25])([CH3:20])[CH3:21])[CH2:15][C@H:14]2[CH2:26][OH:27])=[O:12])[CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: COC(=O)[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CN1C(=O)Nc1ccc(C#N)c(Cl)c1C
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1c(NC(=O)N2C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]2CO)ccc(C#N)c1Cl
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 92.4 %

Procedure:
To a solution of compound 56C (145 mg, 0.32 mmol) in anhydrous THF (3.0 mL) at 0° C. was added dropwise a solution of 2 M LiBH4 in THF (0.24 ml, 0.48 mmol) as described by Terry Rosen et. al. J. Med. Chem. 31 (8), 1598-1611 (1988). The solution was stirred at 0° C. for 2.5 h, quenched with 1.0 M K2CO3 (1.0 mL) and extracted with EtOAc (2×25 mL). The combined organic phases were washed with 1 M K2CO3, brine, dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was chromatographed (silica gel; EtOAc/hexane gradient) to yield the title compound (125.4 mg, 93%) as a white solid, mp 169-171° C. HPLC: 3.31 min (retention time) (Conditions: YMC S-5 C-18 (4.6×250 mm), eluting with 0-100% B, 4 min gradient. (A=90% H2O—10% CH3CN—0.1% TFA and B=10% H2O—90% CH3CN—0.1% TFA); Flow rate at 4 mL/min. UV detection at 220 nm. Chiral HPLC: retention time=7.01 min (99.96%); Conditions: AD (4.6×250 mm); Eluted with 20% isopropanol in heptane for 30 min at 1 mL/min. MS (ES) m/z 424 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[NH:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1.C1C=CC2N(O)N=NC=2C=1.C(N(C(C)C)C(C)C)C>O.CN(C=O)C>[CH3:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([N:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1)=[O:6]
Reactant: Cc1c(C(=O)O)cccc1[N+](=O)[O-]
Reactant: C1COCCN1
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: Cc1c(C(=O)N2CCOCC2)cccc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 85 %

Procedure:
To a DMF solution (10 ml) of 2-methyl-3-nitro-benzoic acid (500 mg) and morpholine (361 mg), WSCI (793 mg), HOBt (560 mg) and N-ethyldiisopropylamine (1.44 ml) were added, followed by stirring at room temperature. To this, water was added, followed by extraction with ethyl acetate, which was subsequently washed with saturated aqueous sodium chloride solution, and the organic layer was dried over sodium sulfate. After the sodium sulfate was filtered off, the solvent was distilled off under reduced pressure, followed by purification by silica gel column chromatography (dichloromethane/methanol=40/1 to 10/1), to obtain the desired compound (587 mg, 85%).
Reaction SMILES: [Li+].C[Si]([N-][Si](C)(C)C)(C)C.[C:11]([N:15]1[CH2:20][CH2:19][CH:18](C(OC)=O)[CH2:17][CH2:16]1)([CH3:14])([CH3:13])[CH3:12].ClC1N=C2C(C=CC(=O)[N:33]2C2C(Cl)=CC=CC=2Cl)=C(C2C=CC(F)=CC=2Cl)C=1>C1COCC1>[C:11]([N:15]1[CH2:20][CH2:19][CH:18]([NH2:33])[CH2:17][CH2:16]1)([CH3:14])([CH3:13])[CH3:12]
Reactant: COC(=O)C1CCN(C(C)(C)C)CC1
Reactant: O=c1ccc2c(-c3ccc(F)cc3Cl)cc(Cl)nc2n1-c1c(Cl)cccc1Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)N1CCC(N)CC1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A solution of LHMDS (1.0M in THF, 0.2 mL) was added to methyl 1-tert-butylpiperidine-4-carboxylate (31 mg, 0.16 mmol) in 2 mL THF at −78° C. After 20 minutes the solution was warmed to 0° C. and stirred for an additional 10 minutes. 7-Chloro-5-(2-chloro-4-fluorophenyl)-1-(2,6-dichlorophenyl)-1,8-naphthyridin-2(1H)-one (COMPOUND BBB2) (28.5 mg, 0.063 mmol) was added and the reaction mixture stirred at 45° C. for 30 min. The solution was cooled to rt and quenched with saturated NH4Cl. The mixture was then partitioned between water and ethyl acetate. The organic phase was washed with water, brine and dried over magnesium sulfate. The filtered solution was concentrated and the residue purified by preparative silica gel thin layer chromatography using CHCl3/MeOH/NH4OH (87/12/1) as eluent to give the title compound. Mass spectrum (ESI) 616 (M+1). (Methyl 1-tert-butylpiperidine-4-carboxylate was prepared from 1-tert-butylpiperidin-4-one (COMPOUND PPA-1) by a procedure analogous to that described by Street, L. J.; et al J. Med. Chem. 1990, 33, 2690.)
Reaction SMILES: [C:1]([NH:4][NH:5][C:6]([C:8]1[N:13]=[C:12]([N:14]2[CH2:18][CH2:17][CH2:16][CH:15]2[C:19]2[O:23][N:22]=[C:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=3)[CH:20]=2)[N:11]=[C:10]([NH:30][CH:31]2[CH:35]=[C:34]([CH3:36])[NH:33][N:32]2C(=O)C)[CH:9]=1)=[O:7])(=[O:3])[CH3:2].[OH-].[Na+]>CO>[C:1]([NH:4][NH:5][C:6]([C:8]1[N:13]=[C:12]([N:14]2[CH2:18][CH2:17][CH2:16][CH:15]2[C:19]2[O:23][N:22]=[C:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=3)[CH:20]=2)[N:11]=[C:10]([NH:30][C:31]2[CH:35]=[C:34]([CH3:36])[NH:33][N:32]=2)[CH:9]=1)=[O:7])(=[O:3])[CH3:2]
Reactant: CC(=O)NNC(=O)c1cc(NC2C=C(C)NN2C(C)=O)nc(N2CCCC2c2cc(-c3ccccn3)no2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(=O)NNC(=O)c1cc(Nc2cc(C)[nH]n2)nc(N2CCCC2c2cc(-c3ccccn3)no2)n1
Yield: 96 %

Procedure:
A solution of 6-[N-(acetylamino)carbamoyl]-2-{2-[3-(pyrid-2-yl)isoxazol-5-yl]pyrrolidin-1-yl}-4-(2-acetyl-5-methyl-1H-pyrazol-3-ylamino)pyrimidine (Method 51) (170 mg, 0.32 mmol) in methanol (10 ml) and 2N sodium hydroxide (0.5 ml, 1.0 mmol) was stirred at room temperature for 0.5 hour. The resulting precipitate was collected by filtration to give the title compound (150 mg, 96%).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[F:24][C:25]1[C:33]([OH:34])=[CH:32][CH:31]=[C:30]2[C:26]=1[CH:27]=[CH:28][NH:29]2.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[F:24][C:25]1[C:33]([O:34][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]4[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]4)=[C:9]([O:12][CH3:13])[CH:10]=3)[N:5]=[CH:4][N:3]=2)=[CH:32][CH:31]=[C:30]2[C:26]=1[CH:27]=[CH:28][NH:29]2
Reactant: Oc1ccc2[nH]ccc2c1F
Reactant: COc1cc2c(Cl)ncnc2cc1OCCCN1CCCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3ccc4[nH]ccc4c3F)ncnc2cc1OCCCN1CCCCC1
Temperature: 95 °C
Yield: 67.3 %

Procedure:
Using an analogous procedure to that described in Example 244, 4-chloro-6-methoxy-7-(3-piperidinopropoxy)quinazoline (407 mg, 1.21 mmol), (prepared as described for the starting material in Example 67), 4-fluoro-5-hydroxyindole (220 mg, 1.45 mmol) (prepared as described for the starting material in Example 242), and potassium carbonate (251 mg, 1.82 mmol) in DMF (6 ml) were heated at 95° C. for 90 minutes and purified to give 4-(4-fluoroindol-5-yloxy)-6-methoxy-7-(3-piperidinopropoxy)quinazoline (367 mg, 67%).
Reaction SMILES: [C:1]1([C:7]2[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=2[NH2:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:14]1[C:27]2[C:18](=[N:19][C:20]3[C:21](=O)[CH2:22][CH2:23][CH2:24][C:25]=3[CH:26]=2)[C:17](=O)[CH2:16][CH2:15]1>>[C:1]1([C:7]2[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=2[N:9]=[C:17]2[C:18]3[C:27](=[CH:26][C:25]4[CH2:24][CH2:23][CH2:22][C:21](=[N:9][C:8]5[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=5[C:1]5[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=5)[C:20]=4[N:19]=3)[CH2:14][CH2:15][CH2:16]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Nc1ccccc1-c1ccccc1
Reactant: O=C1CCCc2cc3c(nc21)C(=O)CCC3
Product: c1ccc(-c2ccccc2N=C2CCCc3cc4c(nc32)C(=Nc2ccccc2-c2ccccc2)CCC4)cc1

Procedure:
was synthesized by methods similar to those in Examples 3 and 4: 2-phenylaniline was condensed with 2,3,7,8-tetrahydro-1H,6H-acridine-4,5-dione to yield 4,5-bis(2-phenylphenylimino)-1,2,3,4,5,6,7,8-octahydroacridine (7). The complexation of (7) with FeCl2.4H2O was carried out with azeotropic removal of methanol in benzene. The structure of the final complex was proved by direct probe GC. Exact mass direct probe calculated for C37H31Cl2FeN3: 643.12. Found: 643.12.
Reaction SMILES: [CH:1]1[C:6]([OH:7])=[CH:5][CH:4]=[C:3]([CH3:8])[CH:2]=1.N1C=CC=CC=1.[N+:15]([C:18]1[CH:19]=[C:20]([S:24](Cl)(=[O:26])=[O:25])[CH:21]=[CH:22][CH:23]=1)([O-])=O.[Sn](Cl)Cl>C(Cl)(Cl)Cl.Cl>[NH2:15][C:18]1[CH:19]=[C:20]([S:24]([O:7][C:6]2[CH:5]=[CH:4][C:3]([CH3:8])=[CH:2][CH:1]=2)(=[O:26])=[O:25])[CH:21]=[CH:22][CH:23]=1
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)Cl)c1
Reactant: Cc1ccc(O)cc1
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: Cc1ccc(OS(=O)(=O)c2cccc(N)c2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 71.4 %

Procedure:
To 50 g (0.463 mole) of p-cresol (4-methylphenol) and 37 mL (0.458 mole) of pyridine dissolved in 250 mL of chloroform was added 50 g (0.226 mole) of 3-nitrobenzenesulfonyl chloride. The reaction was allowed to stir at ambient temperature. After 2 hours, the reaction was judged complete by TLC and the volatiles were removed by rotary evaporation. The resulting residue was treated with 400 mL of 0.5 M sodium bicarbonate. The insoluble product was collected and washed with sodium bicarbonate (2 times, 200 mL each) and water (2 times, 300 mL each). The solid was then treated with methanol (200 mL) followed by water (200 mL). The solid was collected by vacuum filtration and washed with water. This solid was treated with 170 g (0.897 mole) of tin (II) chloride dissolved in 250 mL of concentrated HCl. The reaction was allowed to stir at ambient temperature for 40 hours. TLC indicated that the reaction was incomplete, so the reaction was heated at 50 C. for 27 hours. The solid precipitate was collected by vacuum filtration and was washed with 6N HCl. The solid was extracted with ethyl acetate and, water. The ethyl acetate layer was washed with brine, dried with magnesium sulfate, filtered, and the volatiles removed by rotary evaporation to yield 42.5 g of compound as an oil that solidified on standing.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[C:9]([O:13][C:14](=[O:20])[NH:15][C@H:16]([CH3:19])[CH2:17]O)([CH3:12])([CH3:11])[CH3:10].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>C1(C)C=CC=CC=1>[C:9]([O:13][C:14](=[O:20])[NH:15][C@H:16]([CH3:17])[CH2:19][O:8][C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=1)([CH3:12])([CH3:11])[CH3:10]
Reactant: C[C@H](CO)NC(=O)OC(C)(C)C
Reactant: Oc1ccc(Br)cc1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: C[C@H](COc1ccc(Br)cc1)NC(=O)OC(C)(C)C
Temperature: 80 °C
Reaction time: 8 h

Procedure:
4-Bromophenol (0.2 g, 1.14 mmol), ((R)-2-hydroxy-1-methyl-ethyl)-carbamic acid tert-butyl ester (0.2 g, 1.14 mmol) and triphenylphosphine (0.45 g, 1.71 mmol) were dissolved in anhydrous toluene (10 ml) under an atmosphere of nitrogen. A solution of di-tert-butyl azodicarboxylate (0.39 g, 1.71 mmol) in toluene (5 ml) was added slowly ensuring that the temperature did not exceed 35° C. The reaction mixture was heated to 80° C. and stirred overnight. The solvent was removed in vacuo and the residue was dissolved in ethyl acetate and subsequently washed with 1M HCl, water, brine then dried over magnesium sulfate, filtered and concentrated in vacuo. Purification by Flash Chromatography using 10% ethyl acetate/cyclohexane as the elutant gave the final product. Yield 80 mg, 21%. LCMS method: 2, RT: 6.17 min; MI: 330-332 [M+1].
Reaction SMILES: ClC(C1C(C)CC(C)(C)C(=[O:18])C1)C1C=CC=CC=1.[Cl:19][C:20]1[CH:36]=[CH:35][C:23]([CH2:24][C:25]2[CH:30]([CH3:31])[CH2:29][C:28]([CH3:33])([CH3:32])[C:27](=[O:34])[CH:26]=2)=[CH:22][CH:21]=1.[OH-].[Na+].OO>CO>[Cl:19][C:20]1[CH:21]=[CH:22][C:23]([CH2:24][C:25]23[O:18][CH:26]2[C:27](=[O:34])[C:28]([CH3:33])([CH3:32])[CH2:29][CH:30]3[CH3:31])=[CH:35][CH:36]=1
Reactant: CC1CC(C)(C)C(=O)C=C1Cc1ccc(Cl)cc1
Reactant: CC1CC(C)(C)C(=O)CC1C(Cl)c1ccccc1
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC1CC(C)(C)C(=O)C2OC12Cc1ccc(Cl)cc1
Temperature: 40 °C
Reaction time: 8 h

Procedure:
The 1-(chlorobenzyl)-4,4,6-trimethylcyclohexan-3-one (315 g, 1.2 mol) obtained in (b) above was added to methanol (1500 ml) and the mixture warmed to 40° C. to give a clear yellow solution. The solution was then cooled to 10° C. and aqueous sodium hydroxide (25 g in 112 ml water) was added over a period of 10 minutes. Whilst maintaining the temperature of the reaction mixture between 15° and 20° C., 30% (w/v) aqueous hydrogen peroxide (138 ml, 1.2 mol) was added over a period of 30 minutes and the mixture was then stirred overnight. A further 30 ml was then added and the mixture stirred for 21/2 hours. The reaction mixture was then concentrated under reduced pressure and diluted with water (2 liters) and diethyl ether (1.5 liters). The aqueous layer was then extracted with diethyl ether (2×0.5 liters), dried and the solvent flashed off to give 1-(4 -chlorobenzyl)-1,2-epoxy-4,4,6-trimethylcyclohexan-3-one as a crystalline white solid (271 g), m.pt. 58°-59° C.
Reaction SMILES: [NH2:1][C:2](=[S:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4].N1C=CC=CC=1.Br[CH2:16][C:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=O>C(O)C>[C:19]1([C:17]2[N:1]=[C:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[S:8][CH:16]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CCOC(=O)C(N)=S
Reactant: O=C(CBr)c1ccccc1
Solvent: CCO
Solvent: c1ccncc1
Product: CCOC(=O)c1nc(-c2ccccc2)cs1
Yield: 75.4 %

Procedure:
To ethyl 2-amino-2-thioxoacetate (4 g, 30 mmol) in ethanol (50 mL) was added pyridine (0.24 g, 3 mmol). 2-Bromo-1-phenylethanone (5 g, 25 mmol) was added after 10 minutes and the mixture was then heated at reflux for 6 hours. The resulting mixture was washed with water and extracted with EtOAc and dried over anhydrous sodium sulfate. The solution was then concentrated under vacuum to give a crude product, which was purified by column chromatography to afford the title compound as a white solid (4.4 g). MS (ESI) m/z 233 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[C:11]([O:13][CH3:14])[CH:12]=1)[CH:9]=[N:8][C:7]([C:15]1[CH:20]=[C:19]([CH3:21])[C:18]([OH:22])=[C:17]([CH3:23])[CH:16]=1)=[CH:6]2.O[CH2:25][CH2:26][N:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1.C(N(CC)C(C)C)(C)C.CCOC(/N=N/C(OCC)=O)=O>C1COCC1.C(OCC)(=O)C>[CH3:23][C:17]1[CH:16]=[C:15]([C:7]2[N:8]=[CH:9][C:10]3[C:5]([CH:6]=2)=[CH:4][C:3]([O:2][CH3:1])=[CH:12][C:11]=3[O:13][CH3:14])[CH:20]=[C:19]([CH3:21])[C:18]=1[O:22][CH2:25][CH2:26][N:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1
Reactant: COc1cc(OC)c2cnc(-c3cc(C)c(O)c(C)c3)cc2c1
Reactant: OCCN1CCOCC1
Agent: CCOC(=O)/N=N/C(=O)OCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(OC)c2cnc(-c3cc(C)c(OCCN4CCOCC4)c(C)c3)cc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 63.9 %

Procedure:
To a solution of 4-(6,8-dimethoxyisoquinolin-3-yl)-2,6-dimethylphenol (0.309 g, 1.0 mol) in anhydrous THF (20 mL), triphenyl phosphene (0.52 g, 2.0 mmol), 4-(2-hydroxyethyl)morpholine (0.262 g, 2.0 mmol) and N,N-diisopropylethylamine (0.387 g, 3.0 mmol) were added. To this stirred solution was added diethylazodicarboxylate (0.348 g, 2.0 mmol). The reaction mixture was stirred at room temperature overnight under nitrogen, then diluted with ethyl acetate (100 mL). The organic layer was washed with water and brine, and dried over anhydrous Na2SO4. The solvent was removed under reduced pressure. The crude material was purified by column chromatography to give 3-[3,5-dimethyl-4-(2-morpholin-4-ylethoxy)phenyl]-6,8-dimethoxyisoquinoline (0.54 g) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[N+:23]([C:26]1[CH:27]=[C:28]([S:32](Cl)(=[O:34])=[O:33])[CH:29]=[CH:30][CH:31]=1)([O-:25])=[O:24]>O1CCCC1>[N+:23]([C:26]1[CH:27]=[C:28]([S:32]([NH:1][C:2]2[CH:3]=[C:4]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:12])([CH3:14])[CH3:13])[CH:5]=[CH:6][CH:7]=2)(=[O:34])=[O:33])[CH:29]=[CH:30][CH:31]=1)([O-:25])=[O:24]
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)Cl)c1
Reactant: CC(C)(C)OC(=O)Nc1cccc(N)c1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)Nc1cccc(NS(=O)(=O)c2cccc([N+](=O)[O-])c2)c1
Temperature: 0 °C
Yield: 39.7 %

Procedure:
Into a 1-neck round-bottom flask were added tert-butyl (3-aminophenyl)carbamate (2.0 g, 9.6 mmol) and tetrahydrofuran (30 mL) and triethylamine (2.0 mL, 14 mmol). The mixture was stirred at 0° C. and m-nitrobenzenesulfonyl chloride (2.1 g, 9.6 mmol) was slowly added. The reaction was warmed to rt and stirred for 1 h. The solvent was removed under vacuum and EtOAc and water were added. The aqueous phase was extracted again with EtOAc. The organics were combined, dried over Na2SO4 and the solvents were removed under vacuum. The crude was purified by combi-flash column chromatography to give the desired product (1.5 g, 39%). LCMS for C17H19N3O6S (M-tBu+H)+: m/z=338.0. 1H NMR (400 MHz, DMSO-d6): δ 10.47 (s, 1H), 9.35 (s, 1H), 8.51 (t, J=2.0 Hz, 1H), 8.43 (ddd, J=8.2, 2.2, 1.0 Hz, 1H), 8.12 (ddd, J=7.8, 1.8, 1.0 Hz, 1H), 7.84 (t, J=8.0 Hz, 1H), 7.35 (br, 1H), 7.07 (m, 1H), 7.06 (s, 1H), 6.68 (dt, J=7.0, 2.0 Hz, 1H), 1.42 (s, 9H).
Reaction SMILES: [C:1]([C:3]1([NH:6][C:7]([C@@H:9]2[CH2:13][C@@H:12]([S:14]([C:17]3[CH:22]=[CH:21][C:20](F)=[CH:19][C:18]=3[C:24]([F:27])([F:26])[F:25])(=[O:16])=[O:15])[CH2:11][N:10]2[C:28]2[N:29]([CH:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)[N:30]=[C:31]([CH3:33])[CH:32]=2)=[O:8])[CH2:5][CH2:4]1)#[N:2].[CH3:40][N:41]1[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]1>>[C:1]([C:3]1([NH:6][C:7]([C@@H:9]2[CH2:13][C@@H:12]([S:14]([C:17]3[CH:22]=[CH:21][C:20]([N:44]4[CH2:45][CH2:46][N:41]([CH3:40])[CH2:42][CH2:43]4)=[CH:19][C:18]=3[C:24]([F:27])([F:26])[F:25])(=[O:15])=[O:16])[CH2:11][N:10]2[C:28]2[N:29]([CH:34]3[CH2:35][CH2:36][O:37][CH2:38][CH2:39]3)[N:30]=[C:31]([CH3:33])[CH:32]=2)=[O:8])[CH2:4][CH2:5]1)#[N:2]
Reactant: Cc1cc(N2C[C@H](S(=O)(=O)c3ccc(F)cc3C(F)(F)F)C[C@H]2C(=O)NC2(C#N)CC2)n(C2CCOCC2)n1
Reactant: CN1CCNCC1
Product: Cc1cc(N2C[C@H](S(=O)(=O)c3ccc(N4CCN(C)CC4)cc3C(F)(F)F)C[C@H]2C(=O)NC2(C#N)CC2)n(C2CCOCC2)n1

Procedure:
In analogy to the procedure described in example 389, (2S,4R)-4-(4-fluoro-2-trifluoromethyl-benzenesulfonyl)-1-[5-methyl-2-(tetrahydro-pyran-4-yl)-2H-pyrazol-3-yl]-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-amide (example 396c) was reacted with 1-methylpiperazine (CAS Reg. No. 109-01-3) to give the title compound as colorless foam. MS (ESI): m/z=650.4 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][NH:8]2)=[C:4]([NH:11][C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)=[O:13])[CH:3]=1.[NH:20]1[C:28]2[C:23](=[CH:24][CH:25]=[C:26](B(O)O)[CH:27]=2)[CH:22]=[CH:21]1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[NH:20]1[C:28]2[C:23](=[CH:24][CH:25]=[C:26]([C:2]3[CH:10]=[C:9]4[C:5]([CH:6]=[N:7][NH:8]4)=[C:4]([NH:11][C:12]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=4)=[O:13])[CH:3]=3)[CH:27]=2)[CH:22]=[CH:21]1
Reactant: OB(O)c1ccc2cc[nH]c2c1
Reactant: O=C(Nc1cc(Br)cc2[nH]ncc12)c1ccccn1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: O=C(Nc1cc(-c2ccc3cc[nH]c3c2)cc2[nH]ncc12)c1ccccn1
Temperature: 150 °C
Yield: 11.6 %

Procedure:
A mixture of N-(6-bromo-1H-indazol-4-yl)-2-pyridinecarboxamide (70 mg, 0.22 mmol), 1H-indol-6-ylboronic acid (42 mg, 0.26 mmol), Pd(dppf)Cl2 (10 mol %, 22 mg, 0.027 mmol), aqueous sodium carbonate solution (2M, 0.328 ml, 0.656 mmol) in dioxane/water 1:1 (3 ml) was heated at 150° C. for 15 mins under microwave irradiation. The reaction mixture was filtered through a silica cartridge eluting with MeOH. The solvent was removed in vacuo. The crude compound obtained was purified by mass directed preparative HPLC (Method B) to afford the title compound (9 mg).