Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH2:11][CH2:12][N:13]([CH3:15])[CH2:14][C:5]=3[C:4]=2[CH:3]=1.[OH-].[K+].[CH3:18][C:19]1[CH:24]=[N:23][C:22]([CH:25]=[CH2:26])=[CH:21][N:20]=1>CN1CCCC1=O.O>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:26][CH2:25][C:22]3[CH:21]=[N:20][C:19]([CH3:18])=[CH:24][N:23]=3)[C:6]3[CH2:11][CH2:12][N:13]([CH3:15])[CH2:14][C:5]=3[C:4]=2[CH:3]=1
Reactant: C=Cc1cnc(C)cn1
Reactant: CN1CCc2[nH]c3ccc(Cl)cc3c2C1
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Solvent: O
Product: Cc1cnc(CCn2c3c(c4cc(Cl)ccc42)CN(C)CC3)cn1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 48 %

Procedure:
To a solution of 8-Chloro-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (0.11 g, 5.0 mmol) in N-methyl 2-pyrolidone (2.0 mL) was added powdered potassium hydroxide (0.224 g, 4.0 mmol) and allowed to stir for 10 min at RT. 2-methyl-5-vinyl pyrazine (0.065 g, 0.55 mmol) was added and stirred for further 2 h at 60 deg C. After completion (TLC), reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (3×100 mL). The organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure. The crude was purified through column chromatography (6% MeOH:DCM in silica 100-200 mesh, Diameter of column—2.5 cm, Height of silica—approx. 5 inch) to provide the desired compound as yellow oil (0.09 g, 54% yield). 8-Chloro-2-methyl-5-[2-(5-methyl-pyrazin-2-yl)-ethyl]-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (0.09 g, 0.26 mmol) was dissolved in THF (1.0 mL). A solution of oxalic acid dihydrate (0.034 g, 0.26 mmol) in THF (1.0 mL) was added and stirred for 30 min at RT, Precipitate obtained was filtered and dried to give oxalate salt as white solid (0.08 g, 68% yield).
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2([C:15]3[CH:20]=[CH:19][C:18]([I:21])=[CH:17][CH:16]=3)[CH2:14][O:13]2)=[CH:8][CH:7]=1>CC(C)=O.O>[N:1]([CH2:14][C:12]([C:9]1[CH:10]=[CH:11][C:6]([Cl:5])=[CH:7][CH:8]=1)([C:15]1[CH:16]=[CH:17][C:18]([I:21])=[CH:19][CH:20]=1)[OH:13])=[N+:2]=[N-:3]
Reactant: Clc1ccc(C2(c3ccc(I)cc3)CO2)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: [N-]=[N+]=NCC(O)(c1ccc(Cl)cc1)c1ccc(I)cc1
Yield: 100 %

Procedure:
Sodium azide (13.86 g, 213.2 mmol) was added to a mixture of (RS)-2-(4-chlorophenyl)-2-(4-iodophenyl)oxirane (50.66 g, 142.1 mmol) in acetone (400 ml) and water (40 ml) and the mixture was stirred and held at reflux for 4 days. Upon cooling to room temperature the acetone was removed in vacuo, the residue was dissolved in ethyl acetate (500 ml), washed with water (250 ml) and then with brine (250 ml), the organic layer was separated and the solvent removed in vacuo to afford (RS)-2-azido-1-(4-chlorophenyl)-1-(4-iodophenyl)ethanol (56.77 g, 100%) as a pale yellow oil that slowly solidified upon standing to afford an off-white solid. 1H NMR (DMSO-d6) 7.68 (2H, d), 7.44 (2H, d), 7.38 (2H, d), 7.24 (2H, d), 6.38 (1H, br s), 3.99 (2H, s). MS: [M−H]− 398.
Reaction SMILES: C([O:3][C:4](=[O:19])[CH:5]([O:16][CH2:17][CH3:18])[CH2:6][C:7]1[CH:15]=[C:14]2[C:10]([CH:11]=[CH:12][NH:13]2)=[CH:9][CH:8]=1)C.Cl[CH2:21][C:22]1[N:23]=[C:24]([C:27]2[CH:32]=[CH:31][C:30]([CH:33]([CH3:35])[CH3:34])=[CH:29][CH:28]=2)[S:25][CH:26]=1>>[CH2:17]([O:16][CH:5]([CH2:6][C:7]1[CH:15]=[C:14]2[C:10]([CH:11]=[CH:12][N:13]2[CH2:21][C:22]2[N:23]=[C:24]([C:27]3[CH:32]=[CH:31][C:30]([CH:33]([CH3:35])[CH3:34])=[CH:29][CH:28]=3)[S:25][CH:26]=2)=[CH:9][CH:8]=1)[C:4]([OH:3])=[O:19])[CH3:18]
Reactant: CC(C)c1ccc(-c2nc(CCl)cs2)cc1
Reactant: CCOC(=O)C(Cc1ccc2cc[nH]c2c1)OCC
Product: CCOC(Cc1ccc2ccn(Cc3csc(-c4ccc(C(C)C)cc4)n3)c2c1)C(=O)O

Procedure:
In analogy to the procedure described in example 44, rac-2-ethoxy-3-(1H-indol-6-yl)-propionic acid ethyl ester (preparation 11) was reacted with 4-chloromethyl-2-(4-isopropyl-phenyl)-thiazole to give rac-2-ethoxy-3-{1-[2-(4-isopropyl-phenyl)-thiazol-4-ylmethyl]-1H-indol-6-yl}-propionic acid as yellow viscous oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N+:10]([O-])=O)[C:5]=1[C:13]([O:15][CH3:16])=[O:14].[H][H]>C(OCC)(=O)C.[Pd]>[CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH2:10])[C:5]=1[C:13]([O:15][CH3:16])=[O:14]
Reactant: COC(=O)c1cccc([N+](=O)[O-])c1C(=O)OC
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COC(=O)c1cccc(N)c1C(=O)OC
Yield: 86.9 %

Procedure:
To a solution of methyl-2-(methoxycarbonyl)-3-nitrobenzoate (23.8 g, 99.51 mmol) in ethyl acetate (200 ml) was added 10% Pd/C (1.8 g). The mixture was hydrogenated under 50 psi of hydrogen for 3 hours in a Parr Type Shaker. The mixture was filtered through Celite and the filtrate was concentrated in vacuo to yield an oil. The crude product was purified by flash chromatography (dichloromethane/ethyl acetate 95 to 5) to afford 18.1 g (87%) of the product as a brown oil: 1H NMR (CDCl3) δ 7.22 (t, J=7.6 Hz, 1H), 6.90 (d, J=7.2 Hz, 1H), 6.79 (d, J=8.7 Hz), 5.07 (b, 2H), 3.85 (s, 3H), 3.83 (s, 3H).
Reaction SMILES: [CH2:1]([O:8][CH:9]1[CH2:18][CH2:17][C:12]2(OCC[O:13]2)[CH2:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl>C1COCC1.O>[CH2:1]([O:8][CH:9]1[CH2:18][CH2:17][C:12](=[O:13])[CH2:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc(COC2CCC3(CC2)OCCO3)cc1
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: O=C1CCC(OCc2ccccc2)CC1
Yield: 81.6 %

Procedure:
8-Benzyloxy-1,4-dioxa-spiro[4.5]decane (15 g, 60 mmol) was dissolved in THF (150 ml) and 1M aqueous hydrochloric acid (40 ml) is added and the reaction mixture is heated to reflux overnight. The reaction mixture is cooled and diluted with water (200 ml) before being extracted with ethyl acetate (1×200 ml). The organic extract is washed with saturated solution of sodium bicarbonate and then dried over magnesium sulphate, filtered and evaporated under reduced pressure to give an oil. The oil is distilled under vacuum in a kugelrohr to give 4-benzyloxy-cyclohexanone (10 g).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7](OS(C)(=O)=O)[CH:8]=[CH2:9].[O:15]1[C:19]2[CH:20]=[CH:21][C:22]([CH:24]3[CH:30]([CH3:31])[C:29]45[CH2:38][CH:26]([O:27][C:28]4=[CH:35][C:34](=[O:36])[C:33]([OH:37])=[CH:32]5)[CH2:25]3)=[CH:23][C:18]=2[O:17][CH2:16]1>CN(C=O)C.C(Cl)Cl>[O:15]1[C:19]2[CH:20]=[CH:21][C:22]([CH:24]3[CH:30]([CH3:31])[C:29]45[CH2:38][CH:26]([O:27][C:28]4=[CH:35][C:34](=[O:36])[C:33]([OH:37])=[C:32]5[CH2:9][CH:8]=[CH2:7])[CH2:25]3)=[CH:23][C:18]=2[O:17][CH2:16]1
Reactant: C=CCOS(C)(=O)=O
Reactant: CC1C(c2ccc3c(c2)OCO3)CC2CC13C=C(O)C(=O)C=C3O2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: C=CCC1=C(O)C(=O)C=C2OC3CC(c4ccc5c(c4)OCO5)C(C)C21C3
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Potassium carbonate (172.7 mg, 1.25 mmol) and mesyl allyl ether (113 mg, 0.83 mmol) are added to a stirred solution of 4-(1,3-benzodioxol-5-yl)-2,3,4,5-tetrahydro-7-hydroxy-5-methyl-8H-2,5a-methano-1-benzoxepin-8-one (109, as prepared in Example 54) in DMF (4 ml). The reaction is stirred at room temperature overnight, after which time TLC still shows unreacted starting material present. An additional 50 μl mesyl allyl ether is then added to the reaction and the reaction is then starred for another 24 hours. The reaction is diluted with methylene chloride and washed with 10% HCl followed by water. The extract is dried over sodium sulfate and concentrated in vacuo. The reaction is best purified by medium pressure liquid chromatography (MPLC) (i.e., flash chromatography on silica gel (25 g, 1:1 hexane-ethyl acetate as eluant) produces a contaminated product as determined by 1H NMR and flash chromatography on silica gel (30 g silica, 1:1:1 hexane-ethyl ether-methylene chloride) also produces a contaminated product as determined by 1H NMR). M+(CI)=367. 1H NMR: 0.64 (3H, d), 1.67 (1H, dd), 1.89 (1H, d), 2.06 (1H, m), 2.26 (2H, m), 2.49 (3H, m), 2.72 (1H, dd), 3.05 (1H, t), 5.08 (3H, m), 5.92 (2H, s), 6.15 (1H, s), 6.65 (3H, m).
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([N:10]2[C:21]3=[C:22]4[C:16](=[C:17]5[N:26]([CH3:27])[CH:25]=[CH:24][C:23]([NH2:28])=[C:18]5[CH:19]=[CH:20]3)[C:15](=[O:29])[NH:14][C:13]4=[CH:12][CH2:11]2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[CH3:30][C:31]1[S:32][C:33]([CH2:36][C:37](O)=[O:38])=[CH:34][N:35]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)C(C)C)C>CN(C)C(=O)C>[C:1]([N:4]1[CH2:9][CH2:8][CH:7]([N:10]2[C:21]3=[C:22]4[C:16](=[C:17]5[N:26]([CH3:27])[CH:25]=[CH:24][C:23]([NH:28][C:37](=[O:38])[CH2:36][C:33]6[S:32][C:31]([CH3:30])=[N:35][CH:34]=6)=[C:18]5[CH:19]=[CH:20]3)[C:15](=[O:29])[NH:14][C:13]4=[CH:12][CH2:11]2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: Cc1ncc(CC(=O)O)s1
Reactant: CC(=O)N1CCC(N2CC=c3[nH]c(=O)c4c5c(ccc2c3-4)=C(N)C=CN5C)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N1CCC(N2CC=c3[nH]c(=O)c4c5c(ccc2c3-4)=C(NC(=O)Cc2cnc(C)s2)C=CN5C)CC1
Temperature: 25 °C
Reaction time: 22 h
Yield: 95.3 %

Procedure:
A mixture of Example 73d (0.02 g, 0.051 mmol), 2-(2-methylthiazol-5-yl)acetic acid (0.012 g, 0.077 mmol), and 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate(V) (0.029 g, 0.077 mmol) in N,N-dimethyl acetamide (0.5 mL) was treated with N-ethyl-N-isopropylpropan-2-amine (0.027 mL, 0.153 mmol) and stirred at ambient temperature for 22 hours. The reaction mixture was partitioned between ethyl acetate and water and washed with saturated aqueous sodium chloride. The aqueous layers were combined, saturated with solid sodium chloride and extracted with ethyl acetate (4×100 mL). The organic layers were combined, dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by flash chromatography (silica gel, 0-15% methanol in dichloromethane). The material was further purified by reverse phase HPLC(C18, acetonitrile/water (0.1% TFA), 10-100%) to provide 0.0258 g (78%) of the title compound as the TFA salt. 1H NMR (400 MHz, PYRIDINE-d5) δ 11.24 (s, 1H), 10.34 (s, 1H), 8.34 (d, J=2.44 Hz, 1H), 7.62 (s, 1H), 7.54 (d, J=2.75 Hz, 1H), 7.35 (s, 1H), 7.21 (d, J=8.54 Hz, 1H), 6.89 (s, 1H), 4.20 (s, 2H), 4.13 (s, 3H), 4.07 (s, 2H), 3.64 (m, 1H), 3.25 (m, 1H), 2.63 (m, 2H), 2.55 (s, 3H), 2.59 (m, 1H), 1.93 (s, 3H), 1.69 (m, 2H), 1.50 (m, 2H). MS (ESI+) m/z 531.1 (M+H)+.
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14](Br)[N:15]=2)[N:10]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:26]([SiH2:30][O:31][C:32]([CH3:56])([CH3:55])[C:33]1[CH:34]=[CH:35][CH:36]=[C:37]2[C:41]=1[NH:40][N:39]=[C:38]2[Sn](CCCC)(CCCC)CCCC)([CH3:29])([CH3:28])[CH3:27]>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I>[C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:38]3[C:37]4[C:41](=[C:33]([C:32]([CH3:56])([CH3:55])[O:31][SiH2:30][C:26]([CH3:29])([CH3:28])[CH3:27])[CH:34]=[CH:35][CH:36]=4)[NH:40][N:39]=3)[N:15]=2)[N:10]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Br)nc12
Reactant: CCCC[Sn](CCCC)(CCCC)c1n[nH]c2c(C(C)(C)O[SiH2]C(C)(C)C)cccc12
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: CC(C)(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3n[nH]c4c(C(C)(C)O[SiH2]C(C)(C)C)cccc34)nc12
Temperature: 80 °C
Reaction time: 8 h
Yield: 33.6 %

Procedure:
In a 25 ml round-bottomed flask, 2-bromo-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid tert-butylamide (180 mg, 0.42 mmol) and 7-(tert-butyldimethyl-silanyloxymethyl)-3-tributylstannanyl-1H-indazole (crude from Step 4, 462 mg, 0.50 mmol) were dissolved in DMF (2.8 ml). The reaction mixture was evacuated and backfilled with argon and tetrakis(triphenylphosphine)palladium (0) (25 mg, 0.022 mmol) and copper (I) iodide (16 mg, 0.084 mmol) were added. The reaction mixture was stirred at 80° C. overnight then cooled to room temperature, quenched with water and extracted with diethyl ether (2×). The combined organic layers were washed twice with water and once with brine then concentrated. The residue was chromatographed over 25 g silica gel with EtOAc/hexanes (gradient: 0-30% EtOAc) to afford 86 mg (34%) of 2-[7-(tert-butyl-dimethyl-silanyloxymethyl)-1H-indazol-3-yl]-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid tert-butylamide as a light yellow solid.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][N:5]=[CH:4][N:3]=1.[CH3:9][O:10][C:11]1[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:12]=1[C:13]#N.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[CH3:9][O:10][C:11]1[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:12]=1[C:13]1[NH:8][C:7]2[C:2](=[N:3][CH:4]=[N:5][CH:6]=2)[N:1]=1
Reactant: COc1ccc(C#N)c(OC)c1
Reactant: Nc1cncnc1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: COc1ccc(-c2nc3ncncc3[nH]2)c(OC)c1
Temperature: 120 °C

Procedure:
A mixture of 2 g of 4,5-diamino-pyrimidine, 4 g of 2,4-dimethoxy-benzonitrile, 6 g of p-toluene sulfonic acid hydrate, and 40 ml of benzene was heated, whereby the benzene was distilled off. The residue was heated for 30 minutes at 120° C. After cooling the residue was triturated with 2 N ammonia and extracted with ethyl acetate. The ethyl acetate phase was extracted with 2 N hydrochloric acid, the aqueous phase was neutralized and again extracted with ethyl acetate, and subsequently the organic phase was extracted with 2 N sodium hydroxide solution. When the aqueous phase was neutralized, the product was precipitated and recrystallized from water.
Reaction SMILES: Cl.[NH2:2][C:3]1[C:12]2[C:7](=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=2)[N:6]=[C:5]([N:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)[N:4]=1.C(N(CC)CC)C.[O:30]1[C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=2[N:32]=[C:31]1S>C(O)CCC>[O:30]1[C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=2[N:32]=[C:31]1[N:20]1[CH2:21][CH2:22][N:17]([C:5]2[N:4]=[C:3]([NH2:2])[C:12]3[C:7](=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=3)[N:6]=2)[CH2:18][CH2:19]1
Reactant: COc1cc2nc(N3CCNCC3)nc(N)c2cc1OC
Reactant: Sc1nc2ccccc2o1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCCCO
Product: COc1cc2nc(N3CCN(c4nc5ccccc5o4)CC3)nc(N)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 6.2 %

Procedure:
To a suspension of 4-amino-6,7-dimethoxy-2-(1-piperazinyl)quinazoline hydrochloride (3.26 g) in 250 ml of butanol, 1.01 g of triethylamine was added. The mixture was stirred at room temperature for 2 hr and 1.51 g of benzoxazole-2-thiol was added. The mixture was refluxed for 72 hr and evaporated. The solids were triturated with water and filtered to give 2.7 g of crude product. This was chromatographed over silica gel using 7% methanolmethylene chloride as eluent. Appropriate fractions were mixed together to give 0.25 g of the title compound, which was crystallized from hexanemethylene chloride; mp >250° C.; ir (nujol mull) 3420, 3320 and 3200 cm-1 ; uv max (MeOH) 341 (ε=6,650), 282 (ε=28,900), 278 (ε 29,300) and 252 nm (ε=73,000); and Anal. Calcd for C21H22N6O3 : C, 62.06% H, 5.45% N, 20.68% and Found: C, 61.38% H, 5.59% N, 20.78%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[Cl:13])[CH:5]=[CH:6][C:7]([OH:9])=O.C(Cl)(=O)C(Cl)=O.[CH3:20][N:21]([CH3:37])[CH:22]1[CH2:26][CH2:25][N:24]([C:27]2[S:28][C:29]3[CH:35]=[C:34]([NH2:36])[CH:33]=[CH:32][C:30]=3[N:31]=2)[CH2:23]1>CN(C=O)C.C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]([NH:36][C:34]2[CH:33]=[CH:32][C:30]3[N:31]=[C:27]([N:24]4[CH2:25][CH2:26][CH:22]([N:21]([CH3:37])[CH3:20])[CH2:23]4)[S:28][C:29]=3[CH:35]=2)=[O:9])[CH:10]=[CH:11][C:12]=1[Cl:13]
Reactant: CN(C)C1CCN(c2nc3ccc(N)cc3s2)C1
Reactant: O=C(O)C=Cc1ccc(Cl)c(Cl)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CN(C)C1CCN(c2nc3ccc(NC(=O)C=Cc4ccc(Cl)c(Cl)c4)cc3s2)C1
Yield: 32.4 %

Procedure:
Combine 3,4-dichlorocinnamic acid (0.083 g, 0.381 mmol), CH2Cl2 (5.0 mL), and DMF (3 drops) with stirring. Add oxalyl chloride (0.10 mL, 1.14 mmol) and stir the mixture for 3 h at room temperature. Concentrate the mixture in vacuo, add hexane (approximately 10 mL), re-concentrate in vacuo, and add CH2Cl2 (5.0 mL). Transfer the mixture to a 40 mL reaction vial and add a mixture of 2-(3-dimethylamino-pyrrolidin-1-yl)-benzothiazol-6-ylamine (0.100 g, 0.381 mmol) (Example 1, step 3) in CH2Cl2 (5.0 mL). Shake the reaction vial overnight at room temperature. Dilute the reaction mixture with CH2Cl2 (30 mL), wash with saturated NaHCO3 (aqueous) (2×25 mL), dry over sodium sulfate, filter, and concentrate in vacuo. Purify the residue using silica gel chromatography (12 g column, 5-15% MeOH/CH2Cl2 over 45 min) to yield a yellow residue. Dilute the residue with CH2Cl2 (25 mL) and wash with 1 M NaOH (25 mL). Filter a yellow solid which precipitates in the separatory funnel. Concentrate the mother liquor in vacuo and filter, washing with cold CH2Cl2 to obtain a second crop. Combine the precipitate from the separatory funnel, and the second crop, to afford the title compound (57 mg, 32%). mass spectrum (m/e): 461.2 [M+1], 459.2 [M−1]. 1H NMR (400 MHz, CDCl3): δ8.31 (d, 1H, J=1.6 Hz), 7.65 (d, 1H, J=15.6 Hz), 7.64 (m, 1H), 7.52 (d, 1H, J=8.4 Hz), 7.46 (d, 1H, J=8.4 Hz), 7.37 (m, 1H), 7.35 (m, 1H), 7.16 (dd, 1H, J=8.8, 2.4 Hz), 6.53 (d, 1H, J=15.6 Hz), 3.86 (t, 1H, J=9.2 Hz), 3.74 (t, 1H, J=9.2 Hz), 3.56 (m, 1H), 3.50-3.42 (m, 1H), 2.98 (m, 1H), 2.36 (s, 6H), 2.29 (m, 1H), 2.07 (m, 1H).
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH2:10])[N:7]([CH2:11][CH3:12])[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].Cl[C:16]([O:18][CH2:19][C:20]([Cl:23])([Cl:22])[Cl:21])=[O:17]>C(OCC)(=O)C.O>[Cl:21][C:20]([Cl:23])([Cl:22])[CH2:19][O:18][C:16](=[O:17])[NH:10][C:8]1[N:7]([CH2:11][CH3:12])[N:6]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[CH:9]=1
Reactant: CCn1nc(C(C)(C)C)cc1N
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Product: CCn1nc(C(C)(C)C)cc1NC(=O)OCC(Cl)(Cl)Cl
Reaction time: 0.75 h
Yield: 7.6 %

Procedure:
To a stirred mixture of 3-tert-butyl-1-ethyl-1H-pyrazole-5-amine (0.500 g, 2.99 mmol) in ethyl acetate (7.5 mL) and 1 M aqueous NaOH (7.5 mL, 7.5 mmol), cooled in an ice bath, was added 2,2,2-trichloroethyl chloroformate (0.453 mL, 3.29 mmol) and the mixture was stirred for 45 min. The mixture was diluted with water and extracted twice with ethyl acetate. The combined organic extracts were dried (MgSO4) and evaporated. The residue was crystallised from pentane-diethyl ether (1:1) to give the title compound (0.078 g) as a white solid. The mother liquors were evaporated and purified by column chromatography (0-40% EtOAc/cyclohexane) to give the title compound (0.817 g) as a colorless oil (Total yield 0.895 g, 87%). LCMS (Method 3): Rt 4.09 min, m/z 342/344/346 [MH+]. 1H NMR (300 MHz, CDCl3): 1.44 (12H, m), 4.78-4.83 (2H, m), 4.88 (2H, s), 6.53 (1H, s), 9.82 (1H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1.[CH3:15][S:16]([C:19]1[CH:20]=[C:21]([CH:25]=[CH:26][CH:27]=1)[C:22](O)=[O:23])(=[O:18])=[O:17]>>[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:22](=[O:23])[C:21]2[CH:25]=[CH:26][CH:27]=[C:19]([S:16]([CH3:15])(=[O:18])=[O:17])[CH:20]=2)=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1
Reactant: CS(=O)(=O)c1cccc(C(=O)O)c1
Reactant: Nc1ccc(Cl)c(-c2ccccn2)c1
Product: CS(=O)(=O)c1cccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)c1

Procedure:
Procedure G was used to couple 4-chloro-3-(pyridin-2-yl)aniline and 3-(methanesulfonyl)benzoic acid to produce N-(4-chloro-3-(pyridin-2-yl)phenyl)-3-(methylsulfonyl)benzamide. MS (Q1) 387.2 (M)+.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:20]Br.[CH3:22][O:23][C:24]1[CH:32]=[C:31]2[C:27]([C:28]([CH2:33][CH2:34]O)=[CH:29][NH:30]2)=[CH:26][CH:25]=1>C(#N)C.C(OCC)C>[CH3:22][O:23][C:24]1[CH:32]=[C:31]2[C:27]([C:28]([CH2:33][CH2:34][Br:20])=[CH:29][NH:30]2)=[CH:26][CH:25]=1
Reactant: COc1ccc2c(CCO)c[nH]c2c1
Reactant: BrBr
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: CC#N
Product: COc1ccc2c(CCBr)c[nH]c2c1
Reaction time: 0.33 h

Procedure:
To a mechanically stirred mixture of 18.3 g (69.7 mmol) triphenylphosphine and 200 ml acetonitrile, 11.15 g (69.7 mmol) bromine is added dropwise over 20 minutes. The mixture is stirred 20 minutes at 0° and the ice bath is removed. A solution of 12.1 g (63.4 mmol) 6-methoxy-3-(2-hydroxyethyl)indole in 60 ml acetonitrile is added over 30 minutes. After stirring 2 hours at room temperature the mixture is diluted with 250 ml diethyl ether. The liquid is decanted from precipitated tar. The residue is washed with an additional 250 ml diethyl ether. The volume of the ethereal extracts is reduced to about 60 ml and the solution is filtered through 75 g silica gel with diethyl ether. The solvent is removed to yield 6-methoxy-3-(2-bromoethyl)indole, 4.1 g, yellow waxy solid, mp 98°-101°, which turns green on standing.
Reaction SMILES: [H-].[Na+].[C:3]([C:7]1[N:12]=[C:11]([N:13]2[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][CH2:21][OH:22])[CH2:15][CH2:14]2)[CH:10]=[C:9]([CH:23]2[CH2:26][CH2:25][CH2:24]2)[N:8]=1)([CH3:6])([CH3:5])[CH3:4].Cl[C:28]1[CH:33]=[CH:32][N:31]=[C:30]([S:34][CH3:35])[N:29]=1>CCCCC.O1CCOCC1>[C:3]([C:7]1[N:8]=[C:9]([CH:23]2[CH2:26][CH2:25][CH2:24]2)[CH:10]=[C:11]([N:13]2[CH2:14][CH2:15][N:16]([CH2:19][CH2:20][CH2:21][O:22][C:28]3[CH:33]=[CH:32][N:31]=[C:30]([S:34][CH3:35])[N:29]=3)[CH2:17][CH2:18]2)[N:12]=1)([CH3:6])([CH3:4])[CH3:5]
Reactant: CC(C)(C)c1nc(C2CCC2)cc(N2CCN(CCCO)CC2)n1
Reactant: CSc1nccc(Cl)n1
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCCCC
Product: CSc1nccc(OCCCN2CCN(c3cc(C4CCC4)nc(C(C)(C)C)n3)CC2)n1
Yield: 85.2 %

Procedure:
0.36 g of sodium hydride (9 mmol, 60% in paraffin) were washed oil-free with pentane before 1.5 g of 3-[4-(2-tert-butyl-6-cyclobutyl-pyrimidin-4-yl)-piperazin-1-yl]-propan-1-ol (4.5 mmol) dissolved in 20 ml of dioxane were added. The reaction was heated to reflux for 1 h. After cooling, 0.75 g of 4-chloro-2-methylsulfanyl-pyrimidine (4.67 mmol) dissolved in 10 ml of dioxane were added. The reaction mixture was stirred under reflux for 2 h. The reaction mixture was partitioned between water and ethyl acetate. The organic layer was extracted with 5% aqueous citric acid, the pH of the aqueous phase was adjusted to basic pH with 2 N sodium hydroxide solution. The aqueous layer was re-extracted with ethyl acetate, the organic layer was dried over magnesium sulfate, filtered, and the solvent was evaporated to yield 1.75 g of the title compound as a yellowish oil.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:12])[CH:8]=2)[N:3]=1.[K].[OH:14][C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=1)[C:18]([OH:20])=[O:19]>CS(C)=O>[Cl:12][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([O:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:17]([CH:16]=1)[C:18]([OH:20])=[O:19])[CH:11]=[CH:10]2
Reactant: Clc1ccc2nc(Cl)ccc2c1
Reactant: O=C(O)c1cccc(O)c1
Agent: [K]
Solvent: CS(C)=O
Product: O=C(O)c1cccc(Oc2ccc3cc(Cl)ccc3n2)c1

Procedure:
Substantially equimolar amounts of 2,6-dichloroquinoline and the potassium salt of 3-hydroxybenzoic acid are reacted, in an inert organic solvent, e.g., dimethylsulfoxide giving 5-(6-chloro-2-quinolinoxy)benzoic acid which is nitrated, with, for example, potassium nitrate in the presence of concentrated sulfuric acid to give the corresponding 2-nitrobenzoic acid. The 2-nitrobenzoic acid is then reacted with a suitably substituted--halo compound, e.g., 2-chloropropionate, as described hereinabove.