Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:22]=[CH:21][C:10]2[C:11]([C:14]3[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][CH:15]=3)=[N:12][S:13][C:9]=2[CH:8]=1.[C:23]([N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)(=[O:25])[CH3:24]>>[Br:20][C:17]1[CH:18]=[CH:19][C:14]([C:11]2[C:10]3[CH:21]=[CH:22][C:7]([O:6][CH2:5][CH2:4][CH2:3][CH2:2][N:29]4[CH2:30][CH2:31][N:26]([C:23](=[O:25])[CH3:24])[CH2:27][CH2:28]4)=[CH:8][C:9]=3[S:13][N:12]=2)=[CH:15][CH:16]=1
Reactant: BrCCCCOc1ccc2c(-c3ccc(Br)cc3)nsc2c1
Reactant: CC(=O)N1CCNCC1
Product: CC(=O)N1CCN(CCCCOc2ccc3c(-c4ccc(Br)cc4)nsc3c2)CC1

Procedure:
In analogy to example 3.1, 6-(4-Bromo-butoxy)-3-(4-bromo-phenyl)-benzo[d]isothiazole and 1-Acetylpiperazine were converted to yield 1-(4-(4-[3-(4-Bromo-phenyl)-benzo[d]isothiazol-6-yloxy]-butyl)-piperazin-1-yl)-ethanone as white solid, MS: 488(MH+, 1Br).
Reaction SMILES: [CH2:1]([O:3][C:4]([NH:6][C@H:7]([C:11]([OH:13])=O)[CH:8]([CH3:10])[CH3:9])=[O:5])[CH3:2].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[S:28]1[C:32]([C:33]2[CH:38]=[CH:37][C:36]([CH2:39][N:40]([NH2:65])[CH2:41][C@H:42]([OH:64])[C@@H:43]([NH:51][C:52](=[O:63])[C@H:53]([C@H:59]([CH2:61][CH3:62])[CH3:60])[NH:54][C:55]([O:57][CH3:58])=[O:56])[CH2:44][C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)=[CH:35][CH:34]=2)=[CH:31][N:30]=[CH:29]1>CN(C=O)C>[S:28]1[C:32]([C:33]2[CH:34]=[CH:35][C:36]([CH2:39][N:40]([NH:65][C:11](=[O:13])[C@H:7]([CH:8]([CH3:9])[CH3:10])[NH:6][C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH2:41][C@H:42]([OH:64])[C@@H:43]([NH:51][C:52](=[O:63])[C@H:53]([C@H:59]([CH2:61][CH3:62])[CH3:60])[NH:54][C:55]([O:57][CH3:58])=[O:56])[CH2:44][C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)=[CH:37][CH:38]=2)=[CH:31][N:30]=[CH:29]1
Reactant: CCOC(=O)N[C@H](C(=O)O)C(C)C
Reactant: CC[C@H](C)[C@H](NC(=O)OC)C(=O)N[C@@H](Cc1ccccc1)[C@@H](O)CN(N)Cc1ccc(-c2cncs2)cc1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CCOC(=O)N[C@H](C(=O)NN(Cc1ccc(-c2cncs2)cc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)[C@@H](NC(=O)OC)[C@@H](C)CC)C(C)C

Procedure:
Analogously to Example 7, 175 mg (0.92 mmol) of N-ethoxycarbonyl-(L)-valine, 332 mg (1.7 mmol) of EDC and 156 mg (1.15 mmol) of HOBT in 2.5 ml of DMF and 483 μl (3.47 mmol) of TEA are reacted with 0.578 mmol of 1-[4-(thiazol-5-yl)-phenyl]-4(S)-hydroxy-2-amino-5(S)-N-(N-methoxycarbonyl-(L)-iso-leucyl)amino-6-phenyl-2-azahexane (Example 11b) in 5.2 ml of DMF to form the title compound: m.p: 200-203° C.; HPLC20-100 : tRet =14.6; FAB MS (M+H)+ =711.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][CH:9]2[CH2:14][C:13]([CH3:16])([CH3:15])[NH:12][C:11]([CH3:18])([CH3:17])[CH2:10]2)[N:3]=1.[C:19]([CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1)([OH:21])=[O:20]>>[CH3:15][C:13]1([CH3:16])[CH2:14][CH:9]([NH:8][C:4]2[N:3]=[C:2]([C:27]3[CH:28]=[CH:29][C:24]([CH2:23][CH2:22][C:19]([OH:21])=[O:20])=[CH:25][CH:26]=3)[CH:7]=[CH:6][N:5]=2)[CH2:10][C:11]([CH3:18])([CH3:17])[NH:12]1
Reactant: O=C(O)CCc1ccc(B(O)O)cc1
Reactant: CC1(C)CC(Nc2nccc(Cl)n2)CC(C)(C)N1
Product: CC1(C)CC(Nc2nccc(-c3ccc(CCC(=O)O)cc3)n2)CC(C)(C)N1

Procedure:
The title compound was prepared from (4-chloro-pyrimidin-2-yl)-(2,2,6,6-tetramethyl-piperidin-4-yl)-amine and 4-(2-carboxyethyl)phenylboronic acid according to Method C (Example 178). Yield: 1.4 g (100%).
Reaction SMILES: [CH3:1][C:2]1[N:6]2[C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=3[NH:9][CH2:10][CH2:11][C:5]2=[N:4][N:3]=1.[CH3:16][C:17]1[CH:34]=[CH:33][CH:32]=[CH:31][C:18]=1[C:19]([NH:21][C:22]1[CH:30]=[CH:29][C:25]([C:26](Cl)=[O:27])=[CH:24][CH:23]=1)=[O:20].C(N(CC)CC)C>ClCCl>[CH3:1][C:2]1[N:6]2[C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=3[N:9]([C:26]([C:25]3[CH:24]=[CH:23][C:22]([NH:21][C:19](=[O:20])[C:18]4[CH:31]=[CH:32][CH:33]=[CH:34][C:17]=4[CH3:16])=[CH:30][CH:29]=3)=[O:27])[CH2:10][CH2:11][C:5]2=[N:4][N:3]=1
Reactant: Cc1ccccc1C(=O)Nc1ccc(C(=O)Cl)cc1
Reactant: Cc1nnc2n1-c1ccccc1NCC2
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2CCc3nnc(C)n3-c3ccccc32)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 5 mmol of 5,6-dihydro-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,5]benzodiazepine in 20 ml of dichloromethane is added 5.5 mmol of 4-[(2-methylbenzoyl)amino]benzoyl chloride and 7.5 mmol of triethylamine. The mixture is stirred at room temperature for 8 hours and then washed with water, aqueous NaHCO3 and brine. The organic layer is dried (Na2SO4) and the solvent removed in vacuo to give a solid. The solid is purified by chromatography on silica gel with ethyl acetate-hexane as solvent to give the desired product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]([C:11]1[O:12][C:13]2[CH:20]=[C:19](B3OC(C)(C)C(C)(C)O3)[CH:18]=[CH:17][C:14]=2[C:15]=1[CH3:16])=[O:10].Br[C:31]1[N:36]=[C:35]([CH2:37][NH:38][C:39](=[O:41])[CH3:40])[CH:34]=[CH:33][CH:32]=1>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]([C:11]1[O:12][C:13]2[CH:20]=[C:19]([C:31]3[N:36]=[C:35]([CH2:37][NH:38][C:39](=[O:41])[CH3:40])[CH:34]=[CH:33][CH:32]=3)[CH:18]=[CH:17][C:14]=2[C:15]=1[CH3:16])=[O:10]
Reactant: Cc1c(C(=O)c2ccc(Cl)cc2Cl)oc2cc(B3OC(C)(C)C(C)(C)O3)ccc12
Reactant: CC(=O)NCc1cccc(Br)n1
Product: CC(=O)NCc1cccc(-c2ccc3c(C)c(C(=O)c4ccc(Cl)cc4Cl)oc3c2)n1

Procedure:
N-{6-[2-(2,4-dichloro-benzoyl)-3-methyl-benzofuran-6-yl]-pyridin-2-ylmethyl}-acetamide was prepared via a Suzuki coupling of ((2,4-dichlorophenyl)-[3-methyl-6-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)-benzofuran-2-yl]-methanone and N-(6-Bromo-pyridin-2-ylmethyl)-acetamide as described in method 6 step 2. 1H-NMR (CD3OD) δ 8.19 (s, 1H), 8.05 (dd, J=9 Hz, J=2 Hz, 1H), 7.99-7.89 (m, 3H), 7.64 (d, J=2 Hz, 1H), 7.57-7.51 (m, 2H), 7.40 (d, J=7 Hz, 1H), 4.59 (s, 2H), 2.62 (s, 3H), 2.07 (s, 3H).
Reaction SMILES: [Cl:1][C:2]([Cl:6])([Cl:5])[C:3]#[N:4].[CH2:7]([O:9][C:10](=[O:14])[CH2:11][C:12]#[N:13])[CH3:8]>C(O)C.C(N(CC)CC)C>[NH2:4]/[C:3](/[C:2]([Cl:6])([Cl:5])[Cl:1])=[C:11](/[C:12]#[N:13])\[C:10]([O:9][CH2:7][CH3:8])=[O:14]
Reactant: N#CC(Cl)(Cl)Cl
Reactant: CCOC(=O)CC#N
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOC(=O)/C(C#N)=C(\N)C(Cl)(Cl)Cl
Temperature: 0 °C
Reaction time: 0.02 h
Yield: 87.3 %

Procedure:
To a mixture of trichloroacetonitrile (38 mL, 0.38 mol) and cyanoacetic acid ethyl ester (20 mL, 0.2 mol) in ethanol (63 mL) was added triethylamine (1 mL, 7 mmol). The reaction mixture began to turn red and an exotherm occurred after ˜1 minute. The reaction mixture was cooled to 0° C., then stirred for two hours while slowly warming to room temperature. The reaction mixture was concentrated in vacuo to a red oil, which was taken up in DCM, filtered through a plug of silica gel, and concentrated in vacuo to afford 44.95 g (90%) of (Z)-ethyl 3-amino-4,4,4-trichloro-2-cyanobut-2-enoate as a colorless oil that slowly solidified to a white solid. 1H NMR (400 MHz, CDCl3) δ 10.19 (s, 1H), 6.85 (s, 1H), 4.31 (q, J=7.1, 1H), 1.37 (t, J=7.1, 3H).
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[CH:6][CH:5]=1.[CH3:12][CH:13]([CH2:18][C:19]([O:21]C)=[O:20])[C:14]([O:16]C)=[O:15].CO>C1(C)C=CC=CC=1>[F:3][C:4]1[CH:11]=[CH:10][C:7](/[CH:8]=[C:18](\[CH:13]([CH3:12])[C:14]([OH:16])=[O:15])/[C:19]([OH:21])=[O:20])=[CH:6][CH:5]=1
Reactant: COC(=O)CC(C)C(=O)OC
Reactant: O=Cc1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: Cc1ccccc1
Product: CC(C(=O)O)/C(=C\c1ccc(F)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of sodium hydride (60% in paraffin oil, 31g, 686 mmol) in toluene (150 mL) was added a solution of 4-fluorobenzaldehyde (30 g, 214 mmol) and dimethyl methylsuccinate (58 g, 312 mmol) in toluene (150 mL) over 1 hour at 0° C. under nitrogen. The reaction was initiated by addition of a drop of methanol at room temperature and was stirred at room temperature for 2 hours. The reaction was quenched by slow addition of 2.0 N aqueous NaOH (300 mL) at 0° C. The resulting mixture was stirred at 110° C. for 4 hours. The mixture was then cooled to room temperature and the aqueous layer was diluted with water (300 mL) and washed with Et2O (2×300 mL). The aqueous phase was cooled in an ice-water bath. Addition of concentrated HCl was followed by extraction with ethyl acetate (2×100 mL). The combined organic extracts were washed with water (50 mL) followed by brine (50 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated. The residue was crystallized from ethyl acetate-hexanes to give 2-[1-(4-fluoro-phenyl)-meth-(E)-ylidene]-3-methyl succinic acid. The procedure above was repeated using a separate amount of 4-fluorobenzaldehyde (30 g, 214 mmol). The products of the two reactions were combined to provide 2-[1-(4-fluoro-phenyl)-meth-(E)-ylidene]-3-methyl succinic acid as a pale yellow solid (28g, 27.5% overall). MS cald. for C12H12FO4 [(M+H)+]: 239, obsd. 239.2.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH2:11][C@@H:10]([NH:12]CC=C)[C@H:9]([OH:16])[C@H:8]([O:17][CH:18]([CH2:21][CH3:22])[CH2:19][CH3:20])[CH:7]=1)=[O:5])[CH3:2].C(CN)O.S(=O)(=O)(O)O>C(O)C.[Pd]>[CH2:1]([O:3][C:4]([C:6]1[CH2:11][C@@H:10]([NH2:12])[C@H:9]([OH:16])[C@H:8]([O:17][CH:18]([CH2:19][CH3:20])[CH2:21][CH3:22])[CH:7]=1)=[O:5])[CH3:2]
Reactant: C=CCN[C@@H]1CC(C(=O)OCC)=C[C@@H](OC(CC)CC)[C@H]1O
Agent: [Pd]
Agent: O=S(=O)(O)O
Solvent: NCCO
Solvent: CCO
Product: CCOC(=O)C1=C[C@@H](OC(CC)CC)[C@@H](O)[C@H](N)C1
Temperature: 78 °C

Procedure:
In a 2.5 l 4-necked round bottom flask equipped with a reflux condenser, a thermometer, a mechanical stirrer and an inert gas supply 312.8 g of (3R,4S,5R)-5-allylamino-3-(1-ethyl-propoxy)-4-hydroxy-cyclohex-1-enecarboxylic acid ethyl ester obtained according to (a) were dissolved at room temperature and stirring under argon in 1560 ml of ethanol. To the clear, dark yellow solution were added 66.2 ml of ethanolamine (d=1.015, 1.10 mol) and 31.3 g of palladium on charcoal 10%. The black suspension was heated to 78° C. in the course of 25 min and refluxed for 3 h. The suspension was cooled below 40° C., filtered through a filter paper and the filter cake was washed with 100 ml of ethanol. The combined orange filtrates were cooled to 0 to 5° C., treated with 59.0 ml of sulfuric acid (d=1.83, 1.10 mol) keeping the temperature below 30° C. The yellow suspension (pH=2.5) was evaporated in a rotary evaporator at 48° C./160 to 50 mbar and the remaining oily, yellow crystals (956 g) were dissolved in 1000 ml of deionized water and the orange solution was extracted with a mixture of 500 ml of tert.-butyl methyl ether and 500 ml of n-hexane. The organic phase was extracted with 260 ml of 0.5M aqueous sulfuric acid and the combined aqueous phases (pH=2.3) were cooled to 10° C. and treated with stirring with about 128 ml of 50% aqueous potassium hydroxide until pH=9.5 was reached keeping the temperature in the range of 5° C. to 20° C. The organic phase was separated and the aqueous phase was extracted first with 1000 ml, then twice with 500 ml, in total with 2000 ml of tert.-butyl methyl ether. The combined organic extracts were dried over 1000 g of sodium sulfate and filtered. The filter cake was washed with about 300 ml of tert.-butyl methyl ether and the combined filtrates were evaporated in a rotary evaporator at 48° C./360 to 20 mbar and dried at 48° C./15 mbar for 2 h to yield crude (3R,4S,5R)-5-amino-3-(1-ethyl-propoxy)-4-hydroxy-cyclohex-1-enecarboxylic acid ethyl ester (271.4 g) as a red oil containing about 4% of the 4-amino-5-hydroxy isomer.
Reaction SMILES: [C:1]1([CH2:7][C:8](=[O:14])[C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:15](OC(=O)C)(=[O:17])[CH3:16].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>>[C:15]([O:14]/[C:8](=[CH:7]\[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)/[C:9]([O:11][CH2:12][CH3:13])=[O:10])(=[O:17])[CH3:16]
Reactant: CCOC(=O)C(=O)Cc1ccccc1
Reactant: CC(=O)OC(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: CCOC(=O)/C(=C/c1ccccc1)OC(C)=O

Procedure:
A solution containing 22 g. of ethyl phenylpyruvate, 65 g. of acetic anhydride and 20 mg. of p-toluenesulfonic acid monohydrate was refluxed for 2.5 hours. Excess acetic anhydride was stripped from the reaction mass and the product, crude (Z)-ethyl 2-acetyloxy-3-phenyl-2-propenoate, was distilled at about 1.6 mm. Hg. (b.p. 120°-135° C.). The recovered product crystallized on standing in refrigeration and was recovered by filtration and recrystallized from ethanol; recovered 12.1 g., m.p. 41°-47° C.; second recrystallization, 10.5 g., m.p. 47°-49° C.; third recrystallization, 9.2 g., m.p., 47°-49° C.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:13]([O:15][CH3:16])=[O:14])=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[NH:5][CH:6]=1.C1C(=O)N([Br:24])C(=O)C1>>[Br:24][C:6]1[NH:5][C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[C:3]([C:13]([O:15][CH3:16])=[O:14])[C:2]=1[CH3:1]
Reactant: COC(=O)c1c(C)c[nH]c1-c1ccccc1
Reactant: O=C1CCC(=O)N1Br
Product: COC(=O)c1c(-c2ccccc2)[nH]c(Br)c1C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 96.7 %

Procedure:
To a solution of methyl 4-methyl-2-phenylpyrrole-3-carboxylate (74 mg, 0.341 mmol) in TEF (1.5 mL) was added NBS (67 mg, 0.375 mmol) at −78° C. After being stirred for 0.25 hour at the same temperature, the mixture was allowed to warm to room temperature. The mixture was poured into ice-water (5 mL). The whole was extracted with ethyl acetate (20 mL), dried over Na2SO4 and concentrated in vacuo. The residual oil was purified by flash chromatography eluting with ethyl acetate-hexane (1:8) to afford the subtitle compound (97 mg, 96% yield) as crystals.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:15]([N:17]4[CH2:22][CH2:21][CH:20]([CH2:23][O:24][CH3:25])[CH2:19][CH2:18]4)=[N:14][C:13]([CH2:26][CH2:27]O)=[N:12][C:11]=3[S:10][CH:9]=2)=[CH:4][CH:3]=1.[CH2:29]([N:31](CC)[CH2:32][CH3:33])[CH3:30].CS(Cl)(=O)=O.N1CCCC1>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:15]([N:17]4[CH2:22][CH2:21][CH:20]([CH2:23][O:24][CH3:25])[CH2:19][CH2:18]4)=[N:14][C:13]([CH2:26][CH2:27][N:31]4[CH2:32][CH2:33][CH2:30][CH2:29]4)=[N:12][C:11]=3[S:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: CCN(CC)CC
Reactant: COCC1CCN(c2nc(CCO)nc3scc(-c4ccc(F)cc4)c23)CC1
Agent: CS(=O)(=O)Cl
Solvent: C1CCNC1
Solvent: C1CCOC1
Product: COCC1CCN(c2nc(CCN3CCCC3)nc3scc(-c4ccc(F)cc4)c23)CC1
Temperature: 50 °C
Reaction time: 2 h
Yield: 44 %

Procedure:
2-[5-(4-Fluorophenyl)-4-[4-(methoxymethyl)-1-piperidyl]thieno[2,3-d]pyrimidin-2-yl]ethanol (20 mg, 0.05 mmol) was dissolved in THF (1 mL) to which was added triethylamine (0.021 mL, 0.15 mmol) and methanesulfonyl chloride (0.1 mmol). The reaction was stirred at 50° C. for 2 hrs then pyrrolidine (18 mg, 0.25 mmol) was added and the reaction stirred at 50° C. overnight. The reaction was partitioned between water and DCM. The organics wre concentrated in vacuo and the residue purified by preparative TLC, eluting with 7.5% 7M ammonia in methanol/DCM v/v to give 5-(4-fluorophenyl)-4-[4-(methoxymethyl)-1-piperidyl]-2-(2-pyrrolidin-1-ylethyl)thieno[2,3-d]pyrimidine (10 mg). LCMS RT=3.28 min. M+1=455.
Reaction SMILES: [Cl:1][C:2]1[C:3](B(O)O)=[CH:4][C:5]([O:8][CH3:9])=[N:6][CH:7]=1.Br[C:14]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=1[C:21]([F:24])([F:23])[F:22]>CC(C1C=C(C(C)C)C(C2C(P(C3CCCCC3)C3CCCCC3)=CC=CC=2)=C(C(C)C)C=1)C.C1C=[C-]C(CCN)=CC=1.Cl[Pd+]>[Cl:1][C:2]1[C:3]([C:16]2[CH:17]=[C:18]([Cl:20])[CH:19]=[CH:14][C:15]=2[C:21]([F:22])([F:23])[F:24])=[CH:4][C:5]([O:8][CH3:9])=[N:6][CH:7]=1
Reactant: COc1cc(B(O)O)c(Cl)cn1
Reactant: FC(F)(F)c1ccc(Cl)cc1Br
Agent: Cl[Pd+]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: NCCc1[c-]cccc1
Product: COc1cc(-c2cc(Cl)ccc2C(F)(F)F)c(Cl)cn1

Procedure:
443 mg (2.20 mmol) of 5-chloro-2-methoxypyridin-4-ylboronic acid and 571 mg (2.20 mmol) of 2-bromo-4-chloro-1-(trifluoromethyl)benzene in the presence of XPhos precatalyst were reacted according to General Method 2B. Yield: 193 mg (purity 93%, 25% of theory)
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH3:5].NC(N)=O.S(=O)(=O)(O)O.NC(N)=O.S(=O)(=O)(O)O.[CH:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH2:2]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH2:3][CH2:4][CH3:5]
Reactant: CCCCCl
Reactant: c1ccccc1
Agent: NC(N)=O
Agent: O=S(=O)(O)O
Product: CCCCc1ccccc1
Reaction time: 0.17 h

Procedure:
Normal-butylbenzene is prepared by heating equal molar amounts of 1-chlorobutane and benzene in a molten urea-sulfuric acid component containing 42.6 weight percent urea and 75.4 weight percent sulfuric acid having a urea/sulfuric acid molar ratio of 1.2 at a temperature of 140° F. and a pressure of 100 psig. for a period of 10 minutes. The n-butylbenzene product is recovered by cooling the reaction mixture to solidify the urea-sulfuric acid component melt and extracting the resulting mixture with toluene. The n-butylbenzene product is removed from the toluene solvent by distilling the solvent, and the urea-sulfuric acid component is re-melted and recycled to the process.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](Cl)=[N:7][C:8]([Cl:12])=[N:9]2)=[CH:4][C:3]=1[F:14].[NH:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1>ClCCl>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[N:7][C:8]([Cl:12])=[N:9]2)=[CH:4][C:3]=1[F:14]
Reactant: Fc1cc2c(Cl)nc(Cl)nc2cc1Br
Reactant: C1COCCN1
Solvent: ClCCl
Product: Fc1cc2c(N3CCOCC3)nc(Cl)nc2cc1Br
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 53.9 %

Procedure:
To an ice cold solution of 7-bromo-2,4-dichloro-6-fluoro-quinazoline (0.35 g, 1.178 mmol) in dichloromethane (15 mL), morpholine (0.566 mL, 0.0066 mol) was slowly added and the reaction was continued for 20 minutes. The reaction mixture was diluted with dichloromethane and washed with water. The organic layer was dried over sodium sulphate and evaporated to provide crude solid. The crude material was purified using column chromatography (60-120 silica gel, 30% ethyl acetate in hexane) to provide the title compound (220 mg, 57%). 1H NMR (300 MHz, DMSO-d6): δ 8.16 (d, J=6.6 Hz, 1H), 8.01 (d, J=9.6 Hz, 1H), 3.83-3.86 (m, 4H), 3.76-3.73 (m, 4H); LC-MS (ESI): Calculated mass: 345.0; Observed mass [M+H]+: 347.8 (RT: 1.70 min).
Reaction SMILES: [CH3:1][N:2]=[C:3]=[O:4].[ClH:5].Cl.[Cl:7][C:8]1[CH:24]=[CH:23][C:11]([CH2:12][N:13]2[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][CH2:21][SH:22])[CH2:15][CH2:14]2)=[CH:10][CH:9]=1.C(N(CC)CC)C>C(Cl)Cl>[ClH:7].[ClH:5].[CH3:1][NH:2][C:3](=[SH:22][CH2:21][CH2:20][CH2:19][N:16]1[CH2:17][CH2:18][N:13]([CH2:12][C:11]2[CH:10]=[CH:9][C:8]([Cl:7])=[CH:24][CH:23]=2)[CH2:14][CH2:15]1)[OH:4]
Reactant: CN=C=O
Reactant: SCCCN1CCN(Cc2ccc(Cl)cc2)CC1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CNC(O)=[SH]CCCN1CCN(Cc2ccc(Cl)cc2)CC1
Yield: 64.4 %

Procedure:
The procedure described in Example 2 was followed, using 0.4 g of methyl isocyanate, 2.0 g of 3-[4-(4-chlorobenzyl)piperazin- 1-yl]propanethiol dihydrochloride, 0.7 g of triethylamine and 50 ml of methylene chloride, to give 0.75 g (32% of theory) of N-methyl-S-{3-[4-(4-chlorobenzyl)piperazin-1-yl]propyl}thiocarbamate dihydrochloride as a white crystalline solid, M.p. 240°-243° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:20][C:21]([O:23]C2C(F)=C(F)C(F)=C(F)C=2F)=O)[CH:6]=[CH:7][C:8]=1[NH:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:19])=[O:11].[Cl:35][C:36]1[C:37]([O:46][CH2:47][CH:48]2[CH2:52][CH2:51][CH2:50][NH:49]2)=[N:38][CH:39]=[C:40]([C:42]([O:44][CH3:45])=[O:43])[CH:41]=1>CN(C=O)C.CCOC(C)=O>[Cl:35][C:36]1[C:37]([O:46][CH2:47][CH:48]2[CH2:52][CH2:51][CH2:50][N:49]2[C:21](=[O:23])[CH2:20][C:5]2[CH:6]=[CH:7][C:8]([NH:9][C:10]([NH:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[CH3:19])=[O:11])=[C:3]([O:2][CH3:1])[CH:4]=2)=[N:38][CH:39]=[C:40]([C:42]([O:44][CH3:45])=[O:43])[CH:41]=1
Reactant: COc1cc(CC(=O)Oc2c(F)c(F)c(F)c(F)c2F)ccc1NC(=O)Nc1ccccc1C
Reactant: COC(=O)c1cnc(OCC2CCCN2)c(Cl)c1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1cnc(OCC2CCCN2C(=O)Cc2ccc(NC(=O)Nc3ccccc3C)c(OC)c2)c(Cl)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The mixture of pentafluorophenyl 3-methoxy-4-[N′-(2-methylphenyl)ureido]phenylacetate (317.0 mg, 0.660 mmol), methyl 3chloro-2-[(2-pyrrolidinyl)methoxy]pyridine-5-carboxylate (172.0 mg, 0.635 mmol), Et3 N (105 ul, 0.756 mmol) in DMF (2.0 mL) was stirred for 1 hr at room temp. The mixture was diluted with EtOAc, washed with brine, and dried over Na2SO4. The solvent was removed under a reduced pressure to afford methyl 3chloro-2-[[1-[3-methoxy-4-[N′-(2-methylphenyl)ureido]phenylacetyl]-2-pyrrolidinyl]methoxy]pyridine-5-carboxylate as a brownish oil. To a stirred solution of this compound in THF (6.0 mL) and H2O (2.0. mL) was added LiOH (45.3 mg, 1.89 mmol), and the reaction mixture was stirred for 5 hr at room temp. The mixture was diluted with n-hexane and extracted with 1N-NaOH. The aqueous layer was acidified by the addition of 1 N HCl and extracted with CHCl3. The extract was washed with brine, dried over Na2SO4. The solvent was removed under a reduced pressure and the obtained crude solid was recrystallized from n-hexane-EtOAc-EtOH to afford 242.2 mg (70%/0) 47 as an orange crystalline powder. mp 122–125; IR (KBr) 3354, 1709, 1593, 1535, 1454, 1257 cm−1; 1H-NMR (400 MHz, DMSO-d6) δ 1.67–2.03 (m, 4H), 2.50 (s, 3H), 3.33–3.42 (m, 1H), 3.52 (m, 2H), 3.58 (d, J=4.4 Hz, 1H), 3.83 (s, 3H), 4.27–4.31 (m, 2H), 4.42–4.47 (m, 1H), 6.73 (d, J=7.8 Hz, 1H), 6.87–6.95 (m, 3H), 7.11–7.17 (m, 2H), 7.79 (d, J=8.3 Hz, 1H), 7.99 (d, J=8.3 Hz, 1H), 8.14 (dd, J=2.0, 8.8 Hz, 1H), 8.46 (s, 1H), 8.56 (s, 1H), 8.69 (d, J=2.0 Hz, 1H), 13.06 (br s, 1H); MS (FAB) m/z 553 (M++1); Anal. Calcd for C28H29ClN4O6: C, 60.81; H, 5.29; N, 10.31. Found: C, 60.98; H, 5.50; N, 9.46.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([S:10]([N:13]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:21]=2[O:28][CH3:29])[C:14]2[S:18][N:17]=[CH:16][N:15]=2)(=[O:12])=[O:11])[CH:6]=[CH:7][C:8]=1F)#[N:2].[N:30]1[CH:35]=[CH:34][C:33]([C:36]2[CH:37]=[C:38]([C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=3[C:49]([F:52])([F:51])[F:50])[CH:39]=[CH:40][C:41]=2[OH:42])=[CH:32][N:31]=1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[C:1]([C:3]1[CH:4]=[C:5]([S:10]([N:13]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:21]=2[O:28][CH3:29])[C:14]2[S:18][N:17]=[CH:16][N:15]=2)(=[O:11])=[O:12])[CH:6]=[CH:7][C:8]=1[O:42][C:41]1[CH:40]=[CH:39][C:38]([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=2[C:49]([F:50])([F:51])[F:52])=[CH:37][C:36]=1[C:33]1[CH:34]=[CH:35][N:30]=[N:31][CH:32]=1)#[N:2]
Reactant: COc1ccc(CN(c2ncns2)S(=O)(=O)c2ccc(F)c(C#N)c2)c(OC)c1
Reactant: Oc1ccc(-c2ccccc2C(F)(F)F)cc1-c1ccnnc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: COc1ccc(CN(c2ncns2)S(=O)(=O)c2ccc(Oc3ccc(-c4ccccc4C(F)(F)F)cc3-c3ccnnc3)c(C#N)c2)c(OC)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 115.5 %

Procedure:
To a solution of 3-cyano-N-(2,4-dimethoxybenzyl)-4-fluoro-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide (Preparation 19, 206 mg, 0.474 mmol) and 3-pyridazin-4-yl-2′-(trifluoromethyl)biphenyl-4-ol (Preparation 9, 150 mg, 0.474 mmol) in dimethylsulfoxide (5 mL) was added potassium carbonate (196 mg, 1.42 mmol). The reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was quenched with a 1M aqueous solution of sodium hydroxide whereupon a precipitate formed. The precipitate was collected by filtration and washed with water to afford the title compound as a solid (400 mg, 115%, contains residual dimethylsulfoxide). The material was used without purification in the next step.