Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:37])[CH:5]=[CH:6][CH:7]([N:19]([CH3:36])[C:20](=[O:35])[C:21]1[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[C:23]([C:31]([F:34])([F:33])[F:32])[CH:22]=1)[CH2:8][C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=1)[CH3:2]>O1CCCC1.[Pd]>[CH2:1]([O:3][C:4](=[O:37])[CH2:5][CH2:6][CH:7]([N:19]([CH3:36])[C:20](=[O:35])[C:21]1[CH:26]=[C:25]([C:27]([F:28])([F:29])[F:30])[CH:24]=[C:23]([C:31]([F:33])([F:34])[F:32])[CH:22]=1)[CH2:8][C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=1)[CH3:2]
Reactant: CCOC(=O)C=CC(Cc1ccc2ccccc2c1)N(C)C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: [Pd]
Solvent: C1CCOC1
Product: CCOC(=O)CCC(Cc1ccc2ccccc2c1)N(C)C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1

Procedure:
A solution of 20.0 g of 4-[N-methyl-N-(3,5-bistrifluoromethyl-benzoyl)-amino]-5-(naphth-2-yl)-pent-2-enoic acid ethyl ester in 200 ml of tetrahydrofuran is hydrogenated at 20° C. for 2 hours in the presence of 1.0 g of palladium/activated carbon (10%). The reaction mixture is then filtered and concentrated by evaporation. In this way the title compound is obtained in the form of a colourless oil. Rf value=0.50 (hexane/ethyl acetate:1:1). IR(CH2Cl2) cm-1 : 2978, 1729, 1639, 1405, 1339, 1278, 1183, 1141, 903, 849, 820.
Reaction SMILES: [C:1]1(=[O:7])[CH2:6][CH2:5][CH2:4][CH:3]=[CH:2]1.[CH2:8]([PH:12][CH2:13][CH:14]([CH3:16])[CH3:15])[CH:9]([CH3:11])[CH3:10]>>[CH2:8]([P:12]([CH2:13][CH:14]([CH3:16])[CH3:15])[CH:3]1[CH2:4][CH2:5][CH2:6][C:1](=[O:7])[CH2:2]1)[CH:9]([CH3:11])[CH3:10]
Reactant: CC(C)CPCC(C)C
Reactant: O=C1C=CCCC1
Product: CC(C)CP(CC(C)C)C1CCCC(=O)C1
Temperature: 45 °C

Procedure:
A 250 ml round-bottomed flask fitted with a condenser, nitrogen purge, and addition funnel was charged with 29.9 g (0.3 mol) 2-cyclohexen-1-one and heated to 45° C. with stirring. Di-(iso-butyl)phosphine (28.8 g, 0.2 mol) was gradually added to the flask via the addition funnel, over a period of 0.5 hour. When addition was complete, the temperature of the contents of the flask was slowly raised to 70° C. and maintained at that temperature for 3 hours, then cooled. Unreacted starting materials were removed by evaporation under reduced pressure at 120° C.
Reaction SMILES: C[C:2]1[CH:6]=[CH:5][N:4]([CH2:7][O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:3]=1[C:16](=[O:20])[C:17]([O-:19])=[O:18].[OH-].[Na+].Cl>CO>[CH2:9]([O:8][CH2:7][N:4]1[CH:5]=[CH:6][CH:2]=[C:3]1[C:16](=[O:20])[C:17]([OH:19])=[O:18])[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: Cc1ccn(COCc2ccccc2)c1C(=O)C(=O)[O-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)C(=O)c1cccn1COCc1ccccc1
Yield: 47.3 %

Procedure:
Crude methyl-N-benzyloxymethylpyrrol-2-ylglyoxylate (10 g) in methanol (150 ml) was treated with sodium hydroxide solution (N: 40 ml) at room temperature for 1 hr. Thin-layer chromatography showed complete hydrolysis. Hydrochloric acid (2N: 20 ml) was added and the methanol was removed by evaporation. The residue was shaken with sodium bicarbonate solution and ether. The aqueous layer was acidified under ether and the ether extract was washed with water and dried. Evaporation gave the acid as an orange oil (4.5 g, 55%); this material was used directly to make the synmethoxime described in Preparation 49.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.Cl[S:16]([OH:19])(=[O:18])=[O:17]>C(Cl)(Cl)Cl>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([S:16]([OH:19])(=[O:18])=[O:17])=[CH:11][CH:10]=1
Reactant: Fc1ccc(-c2ccccc2)c(F)c1
Reactant: O=S(=O)(O)Cl
Solvent: ClC(Cl)Cl
Product: O=S(=O)(O)c1ccc(-c2ccc(F)cc2F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 40.3 %

Procedure:
2,4-Difluorobiphenyl (21.2 g, 111 mmol) was dissolved in chloroform (120 mL) and chlorosulfonic acid (12.5 mL, 188 mmol) was added dropwise. The mixture was stirred overnight at room temperature. The reaction mixture was concentrated in vacuo and the residue taken up into EtOAc (100 mL) and washed with water (3×25 mL). The organics were shaken with brine, whereupon a flocculent solid formed. This was filtered and washed with EtOAc and dried to give 2′,4′-difluorobiphenyl-4-sulfonic acid as an off-white solid (12.1 g).
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]#[N:13])=[CH:9][CH:10]=2)[O:5][C:4](=[O:14])[CH:3]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[Cl:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[N:32]=[C:33]=[O:34]>C1COCC1>[C:12]([C:8]1[CH:7]=[C:6]2[C:11]([C:2]([CH2:1][C:33]([NH:32][C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=3[Cl:25])=[O:34])=[CH:3][C:4](=[O:14])[O:5]2)=[CH:10][CH:9]=1)#[N:13]
Reactant: Cc1cc(=O)oc2cc(C#N)ccc12
Reactant: O=C=Nc1ccccc1Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: N#Cc1ccc2c(CC(=O)Nc3ccccc3Cl)cc(=O)oc2c1
Reaction time: 1 h

Procedure:
To a solution of 4-methyl-2-oxo-2H-chromene-7-carbonitrile (670 mg, 3.6 mmol) in dry THF (30 mL) at −20° C. was added drop wise 1.0 M LiHMDS solution in THF (5.4 mL). After 30 minutes 2-chloro-1-isocyanato-benzene (221 mg) was added into the reaction mixture and the reaction mixture was stirred for 1 hour. The reaction mixture was then quenched with saturated aqueous ammonium chloride (25 mL) and extracted with ethyl acetate (50 mL). The organic layer was separated and dried over sodium sulfate, then concentrated and purified on silica gel eluted with 30%-100% ethyl acetate in hexanes to yield 2-(7-cyano-2-oxo-2H-chromen-4-yl)-N-(2-chloro-phenyl)-acetamide as a foam.
Reaction SMILES: [CH:1](=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9]C.[CH:12]([O:19][CH2:20][CH3:21])([O:16][CH2:17][CH3:18])OCC.[N+]([O-])([O-])=O.[NH4+]>C(O)C>[CH2:20]([O:19][CH:12]([O:16][CH2:17][CH3:18])[CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9])[CH3:21]
Reactant: CCOC(OCC)OCC
Reactant: CCCCCCCCCC=O
Agent: O=[N+]([O-])[O-]
Agent: [NH4+]
Solvent: CCO
Product: CCCCCCCCCC(OCC)OCC

Procedure:
Decanal diethyl acetal was prepared by reacting 316 g decanal with 354 g triethyl orthoformate in the presence of 7.6 g ammonium nitrate dissolved in 20 ml. ethanol at a temperature of 50° C. for a period of time of 4 hours. The resulting product was quenched with 32 g sodium methoxide and distilled at 170° C. at 8.0 mm Hg pressure. Then, into a 2 liter reaction flask equipped with stirrer, thermometer, heating mantle, addition funnel, vacuum apparatus, and reflux condenser the following ingredients are added at 20°:
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:15]([OH:17])=O)=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:14][CH2:13]2)[CH2:3][CH2:2]1.[NH2:18][C:19]([CH3:23])([CH3:22])[C:20]#[N:21]>>[C:20]([C:19]([NH:18][C:15](=[O:17])[C:7]1[CH:6]=[CH:5][C:4]([CH:1]2[CH2:2][CH2:3]2)=[C:9]([O:10][CH2:11][CH:12]2[CH2:13][CH2:14]2)[N:8]=1)([CH3:23])[CH3:22])#[N:21]
Reactant: CC(C)(N)C#N
Reactant: O=C(O)c1ccc(C2CC2)c(OCC2CC2)n1
Product: CC(C)(C#N)NC(=O)c1ccc(C2CC2)c(OCC2CC2)n1

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid (Example 42 a) and 2-amino-2-methyl-propanenitrile, (CAN 19355-69-2) as starting materials, LC-MS (UV peak area/ESI) 89%, 300.1702 (M+H)+.
Reaction SMILES: Br[CH2:2][CH2:3][N:4]1[C:8]([CH2:9]Br)=[CH:7][C:6]([N+:11]([O-:13])=[O:12])=[N:5]1.[CH3:14][NH2:15]>C1COCC1>[CH3:14][N:15]1[CH2:2][CH2:3][N:4]2[N:5]=[C:6]([N+:11]([O-:13])=[O:12])[CH:7]=[C:8]2[CH2:9]1
Reactant: O=[N+]([O-])c1cc(CBr)n(CCBr)n1
Reactant: CN
Solvent: C1CCOC1
Product: CN1CCn2nc([N+](=O)[O-])cc2C1
Temperature: 25 °C
Reaction time: 72 h
Yield: 97 %

Procedure:
A 1-L single-neck round-bottomed flask equipped with a magnetic stirrer and nitrogen inlet was charged with THF (350 mL), 101c (10.0 g, 32.2 mmol), 2M methylamine solution in THF (113 mL, 225 mmol) and stirred at room temperature for 72 h. After this time the reaction was concentrated to dryness under reduced pressure, and the resulting solid was stirred with a mixture of ethyl acetate (75 mL) and 10% aqueous potassium carbonate (75 mL). The aqueous layer was separated and extracted with ethyl acetate (2×75 mL). The combined organic extracts were washed with 10% aqueous potassium carbonate (75 mL), followed by brine (50 mL) and dried over sodium sulfate. The drying agent was removed by filtration, and the filtrate concentrated under reduced pressure to afford 101d in 97% yield (5.70 g) as a yellow solid: 1H NMR (300 MHz, CDCl3) δ 6.62 (s, 1H), 4.28 (t, 2H, J=5.4 Hz), 3.67 (s, 2H), 2.95 (t, 2H, J=5.4 Hz), 2.52 (s, 3H); MS (ESI+) m/z 183.0 (M+H)
Reaction SMILES: Br[C:2]1[CH:31]=[CH:30][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20]([N:22]5[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]5)=[N:19][C:18]4=[O:29])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:32]([F:35])([F:34])[F:33])[CH:3]=1.[CH:36]1(B(O)O)[CH2:38][CH2:37]1>>[CH:36]1([C:2]2[CH:31]=[CH:30][C:5]([CH2:6][N:7]3[C:15]4[C:10](=[CH:11][C:12]([CH:16]=[C:17]5[S:21][C:20]([N:22]6[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]6)=[N:19][C:18]5=[O:29])=[CH:13][CH:14]=4)[CH:9]=[N:8]3)=[C:4]([C:32]([F:34])([F:33])[F:35])[CH:3]=2)[CH2:38][CH2:37]1
Reactant: CN1CCN(C2=NC(=O)C(=Cc3ccc4c(cnn4Cc4ccc(Br)cc4C(F)(F)F)c3)S2)CC1
Reactant: OB(O)C1CC1
Product: CN1CCN(C2=NC(=O)C(=Cc3ccc4c(cnn4Cc4ccc(C5CC5)cc4C(F)(F)F)c3)S2)CC1

Procedure:
5-[1-(4-Cyclopropyl-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(4-methyl-piperazin-1-yl)-thiazol-4-one was prepared from 5-[1-(4-Bromo-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(4-methyl-piperazin-1-yl)-thiazol-4-one and cyclopropyl boronic acid following General Procedure F.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([N+:12]([O-:14])=[O:13])=[CH:7][C:3]=1[C:4](O)=[O:5].C(Cl)(=O)C([Cl:18])=O>CN(C)C=O.ClCCCl>[Cl:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([N+:12]([O-:14])=[O:13])=[CH:7][C:3]=1[C:4]([Cl:18])=[O:5]
Reactant: O=C(O)c1cc([N+](=O)[O-])c(F)cc1Cl
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: O=C(Cl)c1cc([N+](=O)[O-])c(F)cc1Cl

Procedure:
A mixture of 2-chloro-4-fluoro-5-nitrobenzoic acid (50.0 g, 0.228 mol) and N,N-dimethylformamide (5 drops) in 1,2-dichloroethane is treated dropwise with oxalyl chloride (30.8 mL, 0.353 mol), refluxed for 3 hours, cooled, and concentrated in vacuo to obtain the title product as an orange solid which is identified by NMR spectral analyses.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH:10]([CH3:12])[CH3:11])[CH:5]=[C:4](Br)[CH:3]=1.[Li]CCCC.C([O:23][B:24](OCC(C)C)[O:25]CC(C)C)C(C)C>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([B:24]([OH:25])[OH:23])[CH:5]=[C:6]([O:8][CH2:9][CH:10]([CH3:12])[CH3:11])[CH:7]=1
Reactant: CC(C)COB(OCC(C)C)OCC(C)C
Reactant: CC(C)COc1cc(Br)cc(Br)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)COc1cc(Br)cc(B(O)O)c1
Temperature: -70 °C

Procedure:
1,3-Dibromo-5-isobutoxy-benzene (1. g; 3.3 mmol) was dissolved in dry THF (30 ml) in a dry reaction under stirring. The reaction mixture was cooled to −70° C. and n-BuLi (2M; 2.44 ml) was added. The reaction mixture was stirred for 15 min. and triisobutylborate (1.50 ml; 6.5 mmol) was added at −70° C. The temperature was raised to −30° C. and stirred for 1½ hour followed by a temperature increase to room temperature. The reaction mixture was quenched with saturated aqueous sodium hydrogen carbonate (about 3 ml) and evaporated to dryness. The crude product was purified by prep HPLC (method B). Yield: 430 mg; 49%. HPLC-MS: m/z: 272.9 (M+); Rt: 2.08 min
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[O:11][CH2:12][CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([C:21](=[O:25])[C:22]([OH:24])=[O:23])=[CH:17][CH:16]=1.[OH:26][CH2:27][CH:28]([CH2:30]O)[OH:29]>ClCCl.O1CCCC1>[OH:29][CH:28]([CH2:27][OH:26])[CH2:30][O:23][C:22](=[O:24])[C:21](=[O:25])[C:18]1[CH:19]=[CH:20][C:15]([O:14][CH2:13][CH2:12][O:11][C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH:1]=2)=[CH:16][CH:17]=1
Reactant: O=C(O)C(=O)c1ccc(OCCOc2ccc3ccccc3c2)cc1
Reactant: OCC(O)CO
Solvent: C1CCOC1
Solvent: ClCCl
Product: O=C(OCC(O)CO)C(=O)c1ccc(OCCOc2ccc3ccccc3c2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The acid chloride, prepared from 4-[[2-(2-naphthalenyloxy)ethyl]oxy]-alpha-oxobenzene-acetic acid (0.5 g) as described in Example 6, was dissolved in dichloromethane (10 mL) and added dropwise to a stirred, cold (<-50° C.) mixture of glycerine (0.9 mL) in tetrahydrofuran (10 mL). The cooling bath was removed and the mixture stirred for 1 hour at room temperature. The mixture was diluted with dichloromethane and washed once with saturated aqueous sodium bicarbonate, once with water, and the organic solution was dried (Na2SO4), filtered, and evaporated to give crude product. The material was purified by HPLC (ethyl acetate) to provide, after crystallization from ethyl acetate-hexane, 0.25 g of rac.-4-[[2-(2-naphthalenyloxy)ethyl]oxy]-alpha-oxobenzeneacetic acid 2,3-dihydroxypropyl ester as a colorless solid, mp 124°-125° C.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[Cl-].[Al+3].[Cl-].[Cl-].[C:9]([O:17][C:18]1[C:26]2[CH:25]=[CH:24][S:23][C:22]=2[CH:21]=[CH:20][CH:19]=1)(=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>ClCCl>[C:9]([O:17][C:18]1[C:26]2[CH:25]=[C:24]([C:1](=[O:3])[CH3:2])[S:23][C:22]=2[CH:21]=[CH:20][CH:19]=1)(=[O:16])[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: CC(=O)Cl
Reactant: O=C(Oc1cccc2sccc12)c1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC(=O)c1cc2c(OC(=O)c3ccccc3)cccc2s1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of acetyl chloride (0.25 ml) in dichloromethane (1.5 ml) was added dropwise under nitrogen at ambient temperature to a stirred suspension of anhydrous aluminium chloride (0.94 g) in dichloromethane (10 ml) and the mixture was stirred at ambient temperature for 15 minutes. A solution of benzo[b]thiophen-4-yl benzoate (0.6 g) in dichloromethane (4 ml) was added, the mixture was stirred at ambient temperature for 18 hours, then it was poured onto ice-water (60 ml). The product was extracted into dichloromethane (2×50 ml), the combined extracts were washed with water (50 ml), saturated aqueous sodium hydrogencarbonate solution (20 ml), water (2×50 ml) and saturated aqueous sodium chloride solution (40 ml), then they were dried (MgSO4) and the solvent was removed in vacuo. The residue was purified by flash chromatography over silica using a 7:3 mixture of dichloromethane and petroleum ether (b.p. 60-80° C.) as eluant. Appropriate fractions were combined and the solvents removed in vacuo to give 2-acetylbenzo[b]thiophen-4-yl benzoate (0.13 g) as a cream solid which was used without further purification.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([N:5]2[CH:9]=[CH:8][C:7]([C:10]3[N:22]([CH2:23][C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[CH:25]=4)[C:13]4[CH:14]=[CH:15][C:16]5[N:17]([C:18]([CH3:21])=[N:19][N:20]=5)[C:12]=4[CH:11]=3)=[N:6]2)[CH2:2]1.[CH3:31][S:32](Cl)(=[O:34])=[O:33].C(N(CC)CC)C>C(Cl)Cl>[Cl:30][C:26]1[CH:25]=[C:24]([CH:29]=[CH:28][CH:27]=1)[CH2:23][N:22]1[C:13]2[CH:14]=[CH:15][C:16]3[N:17]([C:18]([CH3:21])=[N:19][N:20]=3)[C:12]=2[CH:11]=[C:10]1[C:7]1[CH:8]=[CH:9][N:5]([CH:3]2[CH2:2][N:1]([S:32]([CH3:31])(=[O:34])=[O:33])[CH2:4]2)[N:6]=1
Reactant: Cc1nnc2ccc3c(cc(-c4ccn(C5CNC5)n4)n3Cc3cccc(Cl)c3)n12
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1nnc2ccc3c(cc(-c4ccn(C5CN(S(C)(=O)=O)C5)n4)n3Cc3cccc(Cl)c3)n12
Reaction time: 0.03 h
Yield: 67.7 %

Procedure:
To 7-(1-azetidin-3-yl-1H-pyrazol-3-yl)-6-(3-chlorobenzyl)-1-methyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyridine (6.0 mg, 0.014 mmol, from Example 108, Step 1) was added methanesulfonyl chloride (1.3 μL, 0.017 mmol, Aldrich) in DCM (0.50 mL). This was followed by triethylamine (4.0 μL, 0.029 mmol) and the reaction was stirred for 2 minutes. Purification via preparative HPLC-MS (C18 eluting with a gradient of MeCN/H2O containing 0.15% NH4OH) afforded clean product (4.7 mg, 66%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[C:24]([N:27]1[CH2:31][CH2:30][NH:29][C:28]1=[O:32])(=[O:26])[CH3:25]>>[C:24]([N:27]1[CH2:31][CH2:30][N:29]([C:2]2[CH:7]=[CH:6][C:5]([C:8]([N:10]3[CH2:15][CH2:14][N:13]([C:16]4[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][N:17]=4)[CH2:12][CH2:11]3)=[O:9])=[CH:4][CH:3]=2)[C:28]1=[O:32])(=[O:26])[CH3:25]
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Br)cc3)CC2)c(C)c1
Reactant: CC(=O)N1CCNC1=O
Product: CC(=O)N1CCN(c2ccc(C(=O)N3CCN(c4ncc(C)cc4C)CC3)cc2)C1=O
Yield: 70.2 %

Procedure:
Using (4-bromophenyl)[4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (225 mg) described in Preparation Example 165 and 1-acetylimidazolidin-2-one (115 mg) and by the reaction and treatment in the same manner as in Example 1, the title compound (178 mg) was obtained.
Reaction SMILES: [S:1]1(=[O:7])(=[O:6])[CH2:5][CH2:4][CH2:3][NH:2]1.Br[C:9]1[CH:10]=[CH:11][C:12]([C:15]([N:17]2[CH2:22][CH2:21][N:20]([C:23]3[C:28]([CH3:29])=[CH:27][C:26]([CH3:30])=[CH:25][N:24]=3)[CH2:19][CH2:18]2)=[O:16])=[N:13][CH:14]=1>>[CH3:29][C:28]1[C:23]([N:20]2[CH2:21][CH2:22][N:17]([C:15]([C:12]3[CH:11]=[CH:10][C:9]([N:2]4[CH2:3][CH2:4][CH2:5][S:1]4(=[O:7])=[O:6])=[CH:14][N:13]=3)=[O:16])[CH2:18][CH2:19]2)=[N:24][CH:25]=[C:26]([CH3:30])[CH:27]=1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Br)cn3)CC2)c(C)c1
Reactant: O=S1(=O)CCCN1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4CCCS4(=O)=O)cn3)CC2)c(C)c1
Yield: 37.1 %

Procedure:
Using isothiazolidine 1,1-dioxide (121 mg) and (5-bromopyridin-2-yl) [4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (375 mg) described in Preparation Example 134 and by the reaction and treatment in the same manner as in Example 1, the title compound (154 mg) was obtained.
Reaction SMILES: Br[C:2]1C=C(C=CC=1)C(O)=O.C[Al](C)C.[CH3:15][C:16]([C:18]1[CH:19]=[C:20]([Br:24])[CH:21]=[CH:22][CH:23]=1)=[CH2:17]>CCCCCC>[C:16]([C:18]1[CH:19]=[C:20]([Br:24])[CH:21]=[CH:22][CH:23]=1)([CH3:2])([CH3:15])[CH3:17]
Reactant: C=C(C)c1cccc(Br)c1
Reactant: O=C(O)c1cccc(Br)c1
Agent: C[Al](C)C
Solvent: CCCCCC
Product: CC(C)(C)c1cccc(Br)c1
Temperature: 145 °C
Reaction time: 3 h

Procedure:
A suspension of 4.02 g (20 mmol) of m-bromobenzoic acid (Compound 23) in 10 ml hexane was cooled in an ice-bath under nitrogen and then treated slowly with 40 ml of 2M (80 mmol) trimethylaluminum in hexane. The hexane was removed by distillation under nitrogen and the apparatus modified for reflux. The reaction mixture was then heated in an oil bath at 140-150 degrees C. for 3 hours. The oil bath was then replaced by an ice-water bath and the reaction mixture was quenched by the slow dropwise addition of water. The mixture was acidified with dilute HCl and mixture heated at reflux until the aluminum salts were dissolved. The reaction mixture was allowed to cool and extracted with 3×8 ml ether. The ether extracts were combined, washed with dil. HCl, water and saturated NaCl and then dried (MgSO4). The solvent was removed in-vacuo and the residue distilled to give a mixture of the title compound and 3-(1-methyl-ethenyl)bromobenzene as a colorless oil. A small portion (200 mg) of this mixture was dissolved in 1 ml of methylene chloride and then treated with a solution of 200 mg of m-chloroperbenzoic acid in 4 ml of methylene chloride. The mixture was stirred at room temperature for 1 hour and the methylene chloride removed in-vacuo. The residue was dissolved in hexane and filtered through a short silica column and the filtrate concentrated in-vacuo to give pure title compound as a colorless oil. PMR (CDCl3): & 1.30 (9H, s), 7.25 (1H, m), 7.41 (2H, m), 7.65 (H, t, J-2.1 Hz).
Reaction SMILES: [CH:1]1([NH:4][C:5]([C:7]2[CH:8]=[CH:9][C:10]([CH3:32])=[C:11]([NH:13][C:14](=[O:31])[C:15]3[CH:20]=[CH:19][C:18]([N:21]4[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]4)=[CH:17][C:16]=3[N+:28]([O-])=O)[CH:12]=2)=[O:6])[CH2:3][CH2:2]1.[CH2:33](O)C>[Pd]>[CH:1]1([NH:4][C:5](=[O:6])[C:7]2[CH:8]=[CH:9][C:10]([CH3:32])=[C:11]([N:13]3[C:14](=[O:31])[C:15]4[C:16](=[CH:17][C:18]([N:21]5[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]5)=[CH:19][CH:20]=4)[N:28]=[CH:33]3)[CH:12]=2)[CH2:3][CH2:2]1
Reactant: CCO
Reactant: Cc1ccc(C(=O)NC2CC2)cc1NC(=O)c1ccc(N2CCN(C)CC2)cc1[N+](=O)[O-]
Agent: [Pd]
Product: Cc1ccc(C(=O)NC2CC2)cc1-n1cnc2cc(N3CCN(C)CC3)ccc2c1=O
Reaction time: 16 h

Procedure:
A suspension of N-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-4-(4-methylpiperazin-1-yl)-2-nitrobenzamide (0.23 g) and 10% palladium on carbon (0.04 g) in ethanol (30 ml) was agitated under a hydrogen atmosphere for 16 hours. The reaction mixture was filtered through diatomaceous earth (Celite®) and the filtrate evaporated to dryness to give the title compound as a glass (0.16 g); NMR Spectrum: (DMSOd6) 0.57 (m, 2H), 0.68 (m, 2H), 2.22 (s, 3H), 2.24 (s, 3H), 2.43 (m, 4H), 2.85 (m, 1H), 3.19 (m, 4H), 6.18 (s, 1H), 6.25 (m, 1H), 6.44 (s, 2H), 7.30 (d, 1H), 7.59 (m, 1H), 7.64 (d, 1H), 7.76 (s, 1H), 8.35 (d, 1H), 9.37 (s, 1H); Mass Spectrum: M+H+ 408.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[CH2:5][C:6]1[CH:7]=[C:8]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][C:13]=2[CH2:22][NH:23][CH2:24][CH3:25])[CH:9]=[CH:10][CH:11]=1)[CH3:2].[CH:27]1([C:30](Cl)=[O:31])[CH2:29][CH2:28]1>>[CH2:1]([O:3][C:4](=[O:26])[CH2:5][C:6]1[CH:7]=[C:8]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:19])([F:20])[F:21])=[CH:14][C:13]=2[CH2:22][N:23]([C:30]([CH:27]2[CH2:29][CH2:28]2)=[O:31])[CH2:24][CH3:25])[CH:9]=[CH:10][CH:11]=1)[CH3:2]
Reactant: O=C(Cl)C1CC1
Reactant: CCNCc1cc(C(F)(F)F)ccc1-c1cccc(CC(=O)OCC)c1
Product: CCOC(=O)Cc1cccc(-c2ccc(C(F)(F)F)cc2CN(CC)C(=O)C2CC2)c1

Procedure:
Prepared according to the procedure described in Example 1, Step 6, using the following starting materials: (2′-ethylaminomethyl-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid ethyl ester and cyclopropanecarbonyl chloride.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[NH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:18][CH:17]=1>[Cu]>[C:5]1([CH3:8])[CH:6]=[CH:7][C:2]([N:15]([C:2]2[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=2)[C:16]2[CH:17]=[CH:18][C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:20][CH:21]=2)=[CH:3][CH:4]=1
Reactant: Cc1ccc(I)cc1
Reactant: Nc1ccc(-c2ccccc2)cc1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1ccc(N(c2ccc(C)cc2)c2ccc(-c3ccccc3)cc2)cc1
Temperature: 220 °C

Procedure:
A mixture of 65.4 grams of p-iodotoluene, 11.3 grams of copper bronze powder and 55.3 grams of potassium carbonate in 150 milliliters of Soltrol 220 was mechanically stirred in a 250 milliliter round-bottomed flask fitted with a reflux condenser. The mixture was first heated to 160° C. with a heating mantle before 16.92 grams of 4-aminobiphenyl was added. After the addition, the reaction mixture was heated under reflux at 220° C. for five hours. After cooling, the reaction mixture was filtered, and the resulting filter cake was washed with 50 milliliters of heptane. The filtrate was distilled under reduced pressure to remove Soltrol 220. The resulting solid residue was purified by column chromatography on silica gel to afford a white solid. Further purification by recrystallization from isopropanol yielded 16.2 grams of analytically pure bis(p-tolyl)-4-biphenylylamine, melting point, 94° to 95° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([S:9][C:10](=N)N)[CH:5]=[CH:6][C:7]=1[OH:8].C[O-].[Na+].[Na].S(C1C=CC(C)=CC=1)(O[CH2:21][CH:22](C)[CH2:23][CH3:24])(=O)=O>CO>[CH3:21][CH:22]([CH2:23][CH3:24])[CH2:10][S:9][C:4]1[CH:3]=[C:2]([OH:1])[C:7](=[CH:6][CH:5]=1)[OH:8]
Reactant: CCC(C)COS(=O)(=O)c1ccc(C)cc1
Reactant: N=C(N)Sc1ccc(O)c(O)c1
Agent: C[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CO
Product: CCC(C)CSc1ccc(O)c(O)c1

Procedure:
22 g (0.1 mole) of S-(3,4-dihydroxyphenyl)-isothiourea were dissolved in 50 ml of anhydrous methanol in a 1 litre flask equipped with a magnetic stirrer and under a nitrogen flow. The solution was heated and a solution of sodium methoxide containing 9.2 g of sodium (4 equivalents) in 150 ml of anhydrous methanol was added. 24.2 g (0.1 mole) of 2-methylbutyl tosylate in solution in 50 ml of methanol were poured into the reaction mixture at the boiling point of methanol.