Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[CH2:11][O:10][CH2:9][CH:8]([C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=3)[C:6]=2[N:7]=1.Cl.[F:21][C:22]1([F:26])[CH2:25][NH:24][CH2:23]1>>[Cl:1][C:2]1[N:3]=[C:4]([N:24]2[CH2:25][C:22]([F:26])([F:21])[CH2:23]2)[C:5]2[CH2:11][O:10][CH2:9][CH:8]([C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=3)[C:6]=2[N:7]=1
Reactant: FC1(F)CNC1
Reactant: Clc1ccc(C2COCc3c(Cl)nc(Cl)nc32)cc1
Agent: Cl
Product: FC1(F)CN(c2nc(Cl)nc3c2COCC3c2ccc(Cl)cc2)C1
Yield: 67.9 %

Procedure:
2,4-dichloro-8-(4-chlorophenyl)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidine (Preparation K) (500 mg, 1.584 mmol) and 3,3-Difluoroazetidine hydrochloride (308 mg, 2.377 mmol) were combined and purified as per Preparation Ha to give 2-chloro-8-(4-chlorophenyl)-4-(3,3-difluoroazetidin-1-yl)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidine (400 mg, 1.075 mmol, 67.8% yield) as a white solid. LC-MS (M+H)+=372.0. 1H NMR (500 MHz, CDCl3) δ ppm 7.22-7.34 (2 H, m), 7.12 (2 H, d, J=8.24 Hz), 4.63-4.85 (2 H, m), 4.46-4.64 (3 H, m), 4.04-4.17 (1 H, m), 3.91-4.04 (2 H, m).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:15][C:16]([NH2:18])=[S:17])[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1.Br[CH:20]1[C:25](=O)[CH:24]([C:27]2[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:28]=2[F:34])[CH2:23][CH2:22][CH2:21]1>C(O)C>[F:34][C:28]1[CH:29]=[CH:30][C:31]([F:33])=[CH:32][C:27]=1[CH:24]1[C:23]2[N:18]=[C:16]([NH:15][C:5]3[CH:6]=[CH:7][C:8]([N:9]4[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]4)=[C:3]([O:2][CH3:1])[CH:4]=3)[S:17][C:22]=2[CH2:21][CH2:20][CH2:25]1
Reactant: COc1cc(NC(N)=S)ccc1-n1cnc(C)c1
Reactant: O=C1C(Br)CCCC1c1cc(F)ccc1F
Solvent: CCO
Product: COc1cc(Nc2nc3c(s2)CCCC3c2cc(F)ccc2F)ccc1-n1cnc(C)c1
Temperature: 25 °C
Yield: 48.8 %

Procedure:
A suspension of [3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-thiourea (63 mg, 0.24 mmol) and of crude 6-bromo-2-(2,5-difluoro-phenyl)-cyclohexanone (73 mg, 0.25 mmol) in ethanol (2 mL) was heated to reflux under an atmosphere of nitrogen for 2 days. After cooling to room temperature the solvent was evaporated under reduced pressure and the residue was purified by reversed preparative HPLC using acetonitril/water (0.1% formic acid) to yield the title compound (53 mg, 49%) as an off-white solid. MS ISP (m/e): 453.3 (100) [(M+H)+]. 1H NMR (CDCl3, 300 MHz): δ (ppm)=7.88 (s, 1H), 7.50 (s, 1H), 7.09 (d, 1H), 6.99 (m, 1H), 6.80-6.88 (m, 2H), 6.75 (d, 1H), 6.67 (m, 1H), 4.35 (m, 1H), 3.59 (s, 3H), 2.76 (m, 2H), 2.37 (s, 3H), 2.22 (m, 1H), 1.70-1.98 (m, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[C:3]=1[CH:10]1[O:14][C:13](=[O:15])[NH:12][C:11]1=[O:16].[CH3:17][N:18]=[C:19]=[O:20]>C(N(CC)CC)C.ClCCCl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[C:3]=1[CH:10]1[O:14][C:13](=[O:15])[N:12]([C:19](=[O:20])[NH:18][CH3:17])[C:11]1=[O:16]
Reactant: CN=C=O
Reactant: COc1cccc(Cl)c1C1OC(=O)NC1=O
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: CNC(=O)N1C(=O)OC(c2c(Cl)cccc2OC)C1=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
5-(2-Chloro-6-methoxyphenyl)oxazolidin-2,4-dione (1.21 g., 5 mmoles) was suspended in 25 ml. of 1,2-dichloroethane. Triethylamine (1 drop) and then methyl isocyanate (285 mg., 0.29 ml., 5 mmoles) were added and the mixture stirred for 3 hours at room temperature, by which time solution had resulted. The reaction mixture was diluted with 50 ml. of 1,2-dichloroethane, washed with two portions of saturated sodium bicarbonate and then with brine, dried over anhydrous magnesium sulfate, filtered and concentrated to product. Recrystallization from chloroform-hexane afforded purified 5-(2-chloro-6-methoxyphenyl)-3-methylcarbamoyloxazolidin-2,4-dione [1.04 g., 70%; m.p. 124°-127° C. (dec); m/e 300/298].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14](Cl)=[O:15])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18].[NH2:21][CH2:22][CH2:23][N:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1>>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([NH:21][CH2:22][CH2:23][N:24]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)=[O:15])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18]
Reactant: O=C(Cl)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Reactant: NCCN1CCCCC1
Product: O=C(NCCN1CCCCC1)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1

Procedure:
Prepared according to the procedure described for example 50 from 5-[(3,5-dichloro-4-pyridyl)sulfanyl]-4-nitro-thiophene-2-carbonyl chloride (120 mg, 0.33 mmol) and N-(2-aminoethyl)piperidine (63 mg, 0.39 mmol). The title compound was obtained as a solid (20 mg, 11% yield). 1H NMR (400 MHz, d6-DMSO) δ: 8.99 (2H, s), 8.83 (1H, m), 8.42 (1H, s), 3.32 (2H, m), 2.42 (3H, m), 2.35 (1H, m), 1.48 (4H, m), 1.37 (2H, m). MS m/z: 459.16, 461.15 [M+H]+.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([S:17](=[O:21])(=[O:20])[NH:18][CH3:19])=[CH:13][C:12]=2[CH3:22])=[O:9])[CH:3]=1.C(NC(C)C)(C)C.[CH:30]1([CH2:33][NH:34][CH2:35][CH2:36][CH3:37])[CH2:32][CH2:31]1>C(O)C>[CH:30]1([CH2:33][N:34]([CH2:35][CH2:36][CH3:37])[C:2]2[N:7]=[CH:6][N:5]=[C:4]([C:8]([NH:10][C:11]3[CH:16]=[CH:15][C:14]([S:17]([NH:18][CH3:19])(=[O:21])=[O:20])=[CH:13][C:12]=3[CH3:22])=[O:9])[CH:3]=2)[CH2:32][CH2:31]1
Reactant: CCCNCC1CC1
Reactant: CNS(=O)(=O)c1ccc(NC(=O)c2cc(Cl)ncn2)c(C)c1
Solvent: CCO
Solvent: CC(C)NC(C)C
Product: CCCN(CC1CC1)c1cc(C(=O)Nc2ccc(S(=O)(=O)NC)cc2C)ncn1
Temperature: 160 °C

Procedure:
A solution of 6-chloro-N-(2-methyl-4-(N-methylsulfamoyl)phenyl)pyrimidine-4-carboxamide (Intermediate 37, 80 mg; 0.235 mmol) and diisopropylamine (82 mL; 0.47 mmol) in ethanol (2.5 ml) was treated with N-(cyclopropylmethyl)propan-1-amine (0.7 ml; 0.29 mmol). The mixture was heated to 160° C. in a microwave for 1 hour and the solvent removed in vacuo. The residue purified by column chromatography (silica) eluting with petroleum ether containing increasing amounts of EtOAc to give the title compound as a white solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]([F:12])([F:11])[F:10].[OH:13][CH:14]1[CH2:18][CH2:17][NH:16][CH2:15]1>>[F:8][C:4]1[C:3]([C:9]([F:12])([F:11])[F:10])=[C:2]([N:16]2[CH2:17][CH2:18][CH:14]([OH:13])[CH2:15]2)[CH:7]=[CH:6][CH:5]=1
Reactant: Fc1cccc(Br)c1C(F)(F)F
Reactant: OC1CCNC1
Product: OC1CCN(c2cccc(F)c2C(F)(F)F)C1
Yield: 24 %

Procedure:
The title compound (6.2 g, yield 24%) was obtained from 1-bromo-3-fluoro-2-(trifluoromethyl)benzene and 3-hydroxypyrrolidine by a method similar to that in Reference Example 1.
Reaction SMILES: [Br:1][C:2]1[O:6][C:5]([C:7]([OH:9])=O)=[CH:4][CH:3]=1.C(Cl)(=O)C([Cl:13])=O>C(Cl)Cl>[Br:1][C:2]1[O:6][C:5]([C:7]([Cl:13])=[O:9])=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(Br)o1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: O=C(Cl)c1ccc(Br)o1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
At 0° C., to a stirred solution of 5-bromofuran-2-carboxylic acid (3.00 g, 15.7 mmol) in DCM (30 mL) was added dropwise oxalyl dichloride (4.50 mL, 47.1 mmol). Then the resulted mixture was stirred at room temperature for 2 h. TLC and LC-MS showed no starting material. The volatile was removed under reduced pressure and the residual yellow solid was used without further purification (3.20 g, quant.)
Reaction SMILES: C[O:2][C:3](=[O:34])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13]([CH:16]2[CH2:21][CH2:20][N:19]([C:22](=[O:32])[NH:23][C:24]3[C:29]([F:30])=[CH:28][CH:27]=[CH:26][C:25]=3[F:31])[CH2:18][CH2:17]2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:33])[CH:11]=2)[CH:6]=1.O.[OH-].[Li+]>C1COCC1.O>[F:31][C:25]1[CH:26]=[CH:27][CH:28]=[C:29]([F:30])[C:24]=1[NH:23][C:22]([N:19]1[CH2:20][CH2:21][CH:16]([C:13]2[C:12]3[C:7](=[CH:8][CH:9]=[C:10]([F:33])[CH:11]=3)[CH:6]=[C:5]([CH2:4][C:3]([OH:34])=[O:2])[C:14]=2[CH3:15])[CH2:17][CH2:18]1)=[O:32]
Reactant: COC(=O)Cc1cc2ccc(F)cc2c(C2CCN(C(=O)Nc3c(F)cccc3F)CC2)c1C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1c(CC(=O)O)cc2ccc(F)cc2c1C1CCN(C(=O)Nc2c(F)cccc2F)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 63.9 %

Procedure:
To a solution of {4-[1-(2,6-difluoro-phenylcarbamoyl)-piperidin-4-yl]-6-fluoro-3-methyl-naphthalen-2-yl}-acetic acid methyl ester (95.4 mg, 0.203 mmol) in THF (8.0 mL) was added a solution of lithium hydroxide monohydrate (97.2 mg, 2.3 mmol) in water (2.0 mL) at room temperature. The resulting solution was stirred overnight at room temperature under a nitrogen atmosphere. Then, the solvent was removed and the residue was combined with water (25 mL). The mixture was neutralized with 1.0 N HCl. The resulting white precipitate was collected by filtration and dried under high vacuum to provide {4-[1-(2,6-difluoro-phenyl-carbamoyl)-piperidin-4-yl]-6-fluoro-3-methyl-naphthalen-2-yl}-acetic acid (59.2 mg, 64%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.46 (br. s, 1H), 8.38 (br. s, 1H), 7.90 (dd, J=9.00, 6.40 Hz, 1H), 7.75-7.85 (m, 1H), 7.65-7.74 (m, 1H), 7.24-7.42 (m, 2H), 7.14 (m, 2H), 4.17-4.38 (m, 2H), 3.79 (m, 3H), 2.99-3.24 (m, 2H), 2.44 (s, 3H), 2.13-2.36 (m, 1H), 1.57-1.73 (m, 2H). MS cald. for C25H24F3N2O3 [(M+H)+]: 457, obsd. 457.2.
Reaction SMILES: [C:1]([CH:3](O)[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[NH:11][C:12]3[CH:18]=[C:17]([Cl:19])[C:16]([Cl:20])=[CH:15][C:13]=3[N:14]=2)=[CH:6][CH:5]=1)#[N:2].S(Cl)([Cl:24])=O.O>O1CCCC1>[Cl:24][CH:3]([C:1]#[N:2])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[NH:11][C:12]3[CH:18]=[C:17]([Cl:19])[C:16]([Cl:20])=[CH:15][C:13]=3[N:14]=2)=[CH:6][CH:5]=1
Reactant: N#CC(O)c1ccc(-c2nc3cc(Cl)c(Cl)cc3[nH]2)cc1
Reactant: O=S(Cl)Cl
Solvent: C1CCOC1
Solvent: O
Product: N#CC(Cl)c1ccc(-c2nc3cc(Cl)c(Cl)cc3[nH]2)cc1
Temperature: 25 °C
Yield: 25.1 %

Procedure:
To a suspension of 2-[4-[cyano(hydroxy)methyl]phenyl]-5,6-dichlorobenzimidazole (275 mg, 0.865 mmol) in tetrahydrofuran (20 mL) was added thionyl chloride (0.38 mL, 5.2 mmol), and the mixture was heated to reflux for 3 h. After cooling to room temperature, water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried on anhydrous sodium sulfate. The solvent was removed under reduced pressure. The residue was purified by column chromatography (14:1 chloroform/acetonitrile) to afford of 2-[4-[chloro(cyano)methyl]phenyl]-5,6-dichlorobenzimidazole (73 mg, 25%).
Reaction SMILES: [OH:1][C:2]1([CH2:12][NH:13][C:14]([C:16]2[C:17]3[CH:18]=[CH:19][C:20](Cl)=[N:21][C:22]=3[CH:23]=[CH:24][C:25]=2[Cl:26])=[O:15])[CH2:7][CH2:6][CH2:5][CH:4]([C:8]([F:11])([F:10])[F:9])[CH2:3]1.CCN(C(C)C)C(C)C.[CH3:37][N:38]([CH3:44])[CH:39]1[CH2:43][CH2:42][NH:41][CH2:40]1>>[OH:1][C:2]1([CH2:12][NH:13][C:14]([C:16]2[C:17]3[CH:18]=[CH:19][C:20]([N:41]4[CH2:42][CH2:43][CH:39]([N:38]([CH3:44])[CH3:37])[CH2:40]4)=[N:21][C:22]=3[CH:23]=[CH:24][C:25]=2[Cl:26])=[O:15])[CH2:7][CH2:6][CH2:5][CH:4]([C:8]([F:9])([F:10])[F:11])[CH2:3]1
Reactant: O=C(NCC1(O)CCCC(C(F)(F)F)C1)c1c(Cl)ccc2nc(Cl)ccc12
Reactant: CN(C)C1CCNC1
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)C1CCN(c2ccc3c(C(=O)NCC4(O)CCCC(C(F)(F)F)C4)c(Cl)ccc3n2)C1

Procedure:
The title compound was synthesized according to the procedure described in example 1 using 2,6-dichloro-quinoline-5-carboxylic acid (1-hydroxy-3-trifluoromethyl-cyclohexylmethyl)-amide, DIPEA and 3-dimethylamino-pyrrolidine. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.75 (1H), 7.85 (m, 1H), 7.58 (2H), 7.05 (1H), 4.76 (s, 1H), 3.83 (t, 1H), 3.75 (m, 2H), 3.46 (m, 2H), 3.26 (m, 2H), 2.84 (m, 1H), 2.22 (s, 6H), 2.12 (m, 2H), 1.85-1.72 (m, 4H), 1.27 (t, 1H), 1.07 (t, 1H), 0.83 (d, 3H). m/z: 499 [M+H]
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]2[N:14]([C:15]([O:17][C:18]3[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=3)=[O:16])[C:13]([O:27]C)=[N:12][C:11]([CH3:29])=[C:10]2[C:30]([O:32][CH3:33])=[O:31])[CH:5]=[CH:6][C:7]=1[F:8].[Br:34]Br>C(Cl)(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([CH:9]2[N:14]([C:15]([O:17][C:18]3[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=3)=[O:16])[C:13](=[O:27])[NH:12][C:11]([CH2:29][Br:34])=[C:10]2[C:30]([O:32][CH3:33])=[O:31])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: BrBr
Reactant: COC(=O)C1=C(C)N=C(OC)N(C(=O)Oc2ccc([N+](=O)[O-])cc2)C1c1ccc(F)c(F)c1
Solvent: ClC(Cl)Cl
Product: COC(=O)C1=C(CBr)NC(=O)N(C(=O)Oc2ccc([N+](=O)[O-])cc2)C1c1ccc(F)c(F)c1
Reaction time: 1.5 h
Yield: 102.6 %

Procedure:
To a well stirred solution of (+)-6-(3,4-difluorophenyl)-1,6-dihydro-2-methoxy-5-methoxycarbonyl-4-methyl-1-[(4-nitrophenyloxy) carbonyl]pyrimidine (1.5 mmol, 0.66 g) in 5 mL of chloroform was added a solution of bromine (1.5 mmol, 0.09 mL) in 3 mL of chloroform at 0° C. and the solution was allowed to attain room temperature over 1.5 h. The solvent was removed in vacuo and the residue was again dissolved in CHCl3 (20 mL) and washed with brine. The organic layer was separated, dried over Na2SO4, filtered and the solvent was removed in vacuo to get 0.81 g of (+)-6-(3,4-difluorophenyl)-1,6-dihydro-2-oxo-5-methoxycarbonyl-4-bromomethyl-1-[(4-nitrophenyloxy) carbonyl-]pyrimidine as a yellow foam. It was used in the next step without any purification.
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[C:11]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=O)[C:10]([O:19]CC2C=CC=CC=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:27]1CCCC1>[C].[Pd].C(O)C>[C:17]([O:16][CH2:14][CH2:13][C:11]1[C:10]([OH:19])=[N:9][N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:12]=1)(=[O:27])[CH3:18]
Reactant: CCOC(=O)Cc1cn(Cc2ccccc2)nc1OCc1ccccc1
Reactant: C1CCOC1
Agent: [Pd]
Solvent: CCO
Product: CC(=O)OCCc1cn(Cc2ccccc2)nc1O
Reaction time: 2 h
Yield: 88 %

Procedure:
A mixture of ethyl 1-benzyl-3-benzyloxy-1H-pyrazol-4-ylacetate (14.9 g), 5% palladium-carbon (15.0 g), tetrahydrofuran (150 ml) and ethanol (150 ml) was stirred under a hydrogen atmosphere for 2 hrs. Palladium-carbon was filtered off and the filtrate was concentrated to give 1-benzyl-3-hydroxy-1H-pyrazol-4-ylethyl acetate (9.76 g, yield 88%) as colorless crystals. The crystals were recrystallized from tetrahydrofuran-hexane. melting point: 156–157° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:17][C@H:18]1[CH2:23][CH2:22][C@H:21]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[CH2:20][CH2:19]1.[C:32]([C:34]1[S:38][C:37](B(O)O)=[CH:36][CH:35]=1)#[N:33]>>[C:32]([C:34]1[S:38][C:37]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][C:6]([C:12]([CH:14]2[CH2:15][CH2:16]2)=[O:13])=[C:5]3[NH:17][C@H:18]2[CH2:23][CH2:22][C@H:21]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:29])([CH3:28])[CH3:30])[CH2:20][CH2:19]2)=[CH:36][CH:35]=1)#[N:33]
Reactant: N#Cc1ccc(B(O)O)s1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](Nc2c(C(=O)C3CC3)cnc3ccc(Br)cc23)CC1
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@H](Nc2c(C(=O)C3CC3)cnc3ccc(-c4ccc(C#N)s4)cc23)CC1

Procedure:
Following general procedure D, tert-butyl trans-4-[6-bromo-3-(cyclopropanecarbonyl)quinolin-4-ylamino]cyclohexylcarbamate (49 mg, 0.100 mmol) was reacted with 5-cyanothiophen-2-ylboronic acid (31 mg, 0.200 mmol) to afford the desired product (24 mg, 47%) as a brown solid: ESI MS m/z 517 [C29H32N4O3S+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([OH:17])=O)[CH3:14])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.Cl.[NH2:19][N:20]1[C:26](=[O:27])[CH:25]([C:28](=[O:32])[CH2:29][O:30][CH3:31])[C:24]2[CH:33]=[CH:34][CH:35]=[CH:36][C:23]=2[C:22]2[CH:37]=[CH:38][CH:39]=[CH:40][C:21]1=2>>[F:8][C:6]1[CH:5]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([NH:19][N:20]2[C:26](=[O:27])[CH:25]([C:28](=[O:32])[CH2:29][O:30][CH3:31])[C:24]3[CH:33]=[CH:34][CH:35]=[CH:36][C:23]=3[C:22]3[CH:37]=[CH:38][CH:39]=[CH:40][C:21]2=3)=[O:17])[CH3:14])=[O:11])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: COCC(=O)C1C(=O)N(N)c2ccccc2-c2ccccc21
Reactant: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Agent: Cl
Product: COCC(=O)C1C(=O)N(NC(=O)[C@H](C)NC(=O)Cc2cc(F)cc(F)c2)c2ccccc2-c2ccccc21

Procedure:
Following General Procedure D and using N-(3,5-difluorophenylacetyl)-L-alanine (Example B) and 5-amino-7-(methoxyacetyl)-5,7-dihydro-6H-dibenz[b,d]azepin-6-one hydrochloride (Example 7-G), the title compound was prepared as a colorless solid. The product was purified by flash chromatography.
Reaction SMILES: [C:1]([O:5][C:6]([CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[C:17]3[NH:21][C:20]([CH:22]=[C:23]4[N:46]=[C:26]([C:27]([CH:39]([CH2:43][CH2:44]Br)[CH2:40][CH2:41]Br)=[C:28]5[NH:38][C:31](=[CH:32][C:33]6[CH:34]=[CH:35][C:36]=2[N:37]=6)[CH:30]=[CH:29]5)[CH:25]=[CH:24]4)=[CH:19][CH:18]=3)=[CH:12][CH:11]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C[O:48][P:49]([O:52][CH3:53])[O:50][CH3:51]>>[C:1]([O:5][C:6]([CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[C:17]3[NH:21][C:20]([CH:22]=[C:23]4[N:46]=[C:26]([C:27]([CH:39]([CH2:43][CH2:44][P:49]([O:52][CH3:53])([O:50][CH3:51])=[O:48])[CH2:40][CH2:41][P:49]([O:52][CH3:53])([O:50][CH3:51])=[O:48])=[C:28]5[NH:38][C:31](=[CH:32][C:33]6[CH:34]=[CH:35][C:36]=2[N:37]=6)[CH:30]=[CH:29]5)[CH:25]=[CH:24]4)=[CH:19][CH:18]=3)=[CH:12][CH:11]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)COc1ccc(-c2c3nc(cc4ccc([nH]4)c(C(CCBr)CCBr)c4nc(cc5ccc2[nH]5)C=C4)C=C3)cc1
Reactant: COP(OC)OC
Product: COP(=O)(CCC(CCP(=O)(OC)OC)c1c2nc(cc3ccc([nH]3)c(-c3ccc(OCC(=O)OC(C)(C)C)cc3)c3nc(cc4ccc1[nH]4)C=C3)C=C2)OC
Yield: 65 %

Procedure:
A sample of 15a (38.7 mg, 0.048 mmol) was dissolved in trimethylphosphite (5.0 mL). The solution was refluxed under argon for 1.5 days. The P(OMe)3 was evaporated at reduced pressure. The residue was chromatographed (silica, CH2Cl2/MeOH, 0→5%) to yield a dark purple solid (24.6 mg, 65%): 1H NMR δ 1.64 (s, 9H), 3.15 (m, 2H), 3.32-3.36 (m, 2H), 3.43 (s, 3H), 3.47 (s, 6H), 3.50 (s, 3H), 3.81-3.87 (m, 4H), 4.84 (s, 2H), 5.44 (m, 1H), 7.35 (d, J=8.1 Hz, 2H), 8.17 (d, J=8.1 Hz, 2H), 9.10 (s, 2H), 9.40 (s, 2H), 9.50-9.51 (m, 1H), 9.73-9.74 (m, 2H), 10.30-10.31 (m, 2H); LD-MS obsd 803.7, calcd 800.3104 (C41H48N4O9P2); λabs (log ε) 407 (4.90), 504 nm; λem (λexc 407 nm) 636 nm, 702 nm. Varying amounts of a less polar purple solid (16a-Br) were isolated along with small amounts of the starting material 15a (limited characterization). Data for 16a-Br: 1H NMR δ 0.86-0.95 (m, 1H), 1.65 (s, 9H), 1.91-2.00 (m, 1H), 3.13-3.40 (m, 6H), 3.44 (s, 3H), 3.48 (s, 3H), 3.55-3.85 (m, 2H), 4.83 (s, 2H), 5.51-5.61 (m, 1H), 7.34 (d, J=8.1 Hz, 2H), 8.17 (d, J=8.1 Hz, 2H), 9.08-9.10 (m, 2H), 9.37-9.41 (m, 2H), 9.49-9.51 (m, 2H), 9.67-9.68 (m, 1H), 9.84-9.85 (m, 1H), 10.30 (s, 2H); LD-MS obsd 773.6, calcd 773.2 [(M+H)+, M=C39H42BrN4O6P2]; λabs 407, 502 nm; λem (λexc 407 nm) 634, 702 nm.
Reaction SMILES: CC(C)(OC([N:7]1[CH2:12][CH2:11][N:10]([C:13]2[C:18]([N:19]3[CH2:23][CH2:22][CH2:21][CH2:20]3)=[CH:17][CH:16]=[CH:15][N:14]=2)[CH2:9][CH2:8]1)=O)C.FC(F)(F)C(O)=O.[OH-].[Na+]>C1COCC1>[N:19]1([C:18]2[C:13]([N:10]3[CH2:9][CH2:8][NH:7][CH2:12][CH2:11]3)=[N:14][CH:15]=[CH:16][CH:17]=2)[CH2:20][CH2:21][CH2:22][CH2:23]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncccc2N2CCCC2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: c1cnc(N2CCNCC2)c(N2CCCC2)c1
Reaction time: 0.33 h

Procedure:
1-[1,1-Dimethylethoxycarbonyl]-4-[3-(1-pyrrolidinyl)-2-pyridinyl]piperazine (PREPARATION 47, 0.26 g) is dissolved in 1.3 ml of THF and cooled to 0°. Trifluoroacetic acid (1.3 ml) is added and the reaction is stirred at 0° for 20 min, and then warmed to 20°-25° for 20 min. Then the reaction is poured into 1N aqueous sodium hydroxide and extracted with methanol/chloroform (10/90, 2×50 ml), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the title compound, NMR (300 MHz, CDCl3) 7.64, 6.81, 6.61, 3.05-2.94, 2.86-2.79 and 1.78-1.65 δ.
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][NH:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([N:24]3[CH:28]=[CH:27][CH:26]=[N:25]3)=[CH:20][CH:19]=2)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:30][N:31]1[CH:35]=[C:34]([S:36](Cl)(=[O:38])=[O:37])[N:33]=[CH:32]1>>[C:1]([O:5][C:6](=[O:29])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][N:16]([S:36]([C:34]2[N:33]=[CH:32][N:31]([CH3:30])[CH:35]=2)(=[O:38])=[O:37])[CH2:17][C:18]2[CH:19]=[CH:20][C:21]([N:24]3[CH:28]=[CH:27][CH:26]=[N:25]3)=[CH:22][CH:23]=2)[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cn1cnc(S(=O)(=O)Cl)c1
Reactant: CC(C)(C)OC(=O)COc1cccc(CNCc2ccc(-n3cccn3)cc2)c1
Product: Cn1cnc(S(=O)(=O)N(Cc2ccc(-n3cccn3)cc2)Cc2cccc(OCC(=O)OC(C)(C)C)c2)c1

Procedure:
The title compound of Step A was prepared from {3-[(4-pyrazol-1-yl-benzylamino)-methyl]-phenoxy}-acetic acid tert-butyl ester, prepared in Step A of Example 13h, and 1methyl-1H-imidazole-4-sulfonyl chloride following the method described in Example 3, Step B with a reaction time of 2 h. 1H NMR (400 MHz, CDCl3) δ 7.87 (d, 1H), 7.67 (d, 1H), 7.52 (d, 2H), 7.48 (d, 1H), 7.37 (d, 1H), 7.23 (d, 2H), 7.10 (t, 1H), 6.73 (m, 3H), 6.42 (m, 1H), 4.41 (s, 4H), 4.36 (s, 2H), 3.70 (s, 3H), 1.46 (s, 9H); MS 538 (M+1).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:20]([Br:24])(Br)(Br)Br.[CH2:25](O)[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47]C>ClCCl>[CH2:20]([Br:24])[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43][CH2:42][CH2:41][CH2:40][CH2:39][CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH3:25]
Reactant: CCCCCCCCCCCCCCCCCCCCCCCCO
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCCCCCCCCCCBr
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A series of n-alkyl bromides (CnH2n+1Br) were purchased from TCI (n=3, 6, 9, 12, 15, and 18) and Aldrich (n=22), and used as received. 1-Tetracosyl bromide (n-C24H49Br) was prepared from the corresponding alcohol (Aldrich) according to the following procedure. Triphenylphosphine (95 mg, 0.36 mmol) and carbontetrabromide (120 mg, 0.36 mmol) were sequentially introduced into a dichloromethane solution (50 ml) dissolved with 1-tetracosanol (60 mg, 0.17 mmol), and the mixture was stirred at room temperature for 12 hr. The solvent was then removed by evacuation, and the produced 1-tetracosyl bromide was isolated from the reaction mixture by column chromatography. 4-[4-(Dimethylamino)styryl]pyridin (Aldrich), tetraethylorthosilicate (TEOS, Acros), sodium aluminate (NaAlO2, Kanto) and tetrapropylammonium hydroxide (TPAOH, Aldrich) were purchased, and used as received. n-Octadecane and n-heptadecane were purchased from PolyScience Corporation and used as such. 4-Nitroaniline was purchased from Aldrich, and used as such.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[CH:7][C:8]([S:12]([CH3:14])=[O:13])=[C:9]([NH2:11])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].C[O:16][C:17](=O)[C:18]1[CH:23]=[CH:22][C:21]([CH3:24])=[C:20]([N:25]2[CH:29]=[C:28]([C:30]3[CH:31]=[N:32][N:33]([C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)[C:34]=3[CH2:35][CH3:36])[N:27]=[CH:26]2)[CH:19]=1>>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([S:12]([CH3:14])=[O:13])=[C:9]([NH:11][C:17](=[O:16])[C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[C:20]([N:25]3[CH:29]=[C:28]([C:30]4[CH:31]=[N:32][N:33]([C:37]5[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=5)[C:34]=4[CH2:35][CH3:36])[N:27]=[CH:26]3)[CH:19]=2)[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CS(=O)c1ccc(C(C)(C)C)cc1N
Reactant: CCc1c(-c2cn(-c3cc(C(=O)OC)ccc3C)cn2)cnn1-c1ccccc1
Product: CCc1c(-c2cn(-c3cc(C(=O)Nc4cc(C(C)(C)C)ccc4S(C)=O)ccc3C)cn2)cnn1-c1ccccc1

Procedure:
Example 156 was prepared from 5-tert-butyl-2-methanesulfinyl-phenylamine and 3-[4-(5-ethyl-1-phenyl-1H-pyrazol-4-yl)-imidazol-1-yl]-4-methyl-benzoic acid methyl ester (Example 151) in the same manner as Example 151. ESI MS m/z 566 [C33H35N5O2S+H]+.