Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:5][C:6](=[O:35])[CH2:7][N:8]1[C:13]2[CH:14]=[C:15]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:16]=[CH:17][C:12]=2[S:11][CH:10]([CH2:23][CH2:24][CH2:25][C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=2)[C:9]1=[O:34])(C)(C)C.CSC.Cl>ClCCl>[CH2:21]([O:20][C:18]([C:15]1[CH:16]=[CH:17][C:12]2[S:11][CH:10]([CH2:23][CH2:24][CH2:25][C:26]3[CH:27]=[CH:28][C:29]([O:32][CH3:33])=[CH:30][CH:31]=3)[C:9](=[O:34])[N:8]([CH2:7][C:6]([OH:35])=[O:5])[C:13]=2[CH:14]=1)=[O:19])[CH3:22]
Reactant: CCOC(=O)c1ccc2c(c1)N(CC(=O)OC(C)(C)C)C(=O)C(CCCc1ccc(OC)cc1)S2
Agent: Cl
Solvent: CSC
Solvent: ClCCl
Product: CCOC(=O)c1ccc2c(c1)N(CC(=O)O)C(=O)C(CCCc1ccc(OC)cc1)S2
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.1 %

Procedure:
Under ice-cooling, a boron trifluoride-diethyl ether complex (26.6 ml) was added dropwise to a solution of ethyl 4-(2-tert-butoxy-2-oxoethyl)-2-[3-(4-methoxyphenyl)propyl]-3-oxo-3,4-dihydro-2H-1,4-benzothiazine-6-carboxylate (13.16 g) and dimethyl sulfide (26.3 ml) in dichloromethane (250 ml). The resulting mixture was slowly warmed up to room temperature and then stirred overnight. The mixture was poured into a 1N aqueous hydrochloric acid solution and extracted with chloroform. The oil layer was washed twice with a 1N aqueous hydrochloric acid solution, dehydrated over anhydrous sodium sulfate and then concentrated under reduced pressure. {6-(Ethoxycarbonyl)-2-[3-(4-methoxyphenyl)propyl]-3-oxo-2,3-dihydro-4H-1,4-benzothiazin-4-yl}acetic acid (10.64 g) was obtained as a yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([NH:27][CH2:28][CH2:29][NH2:30])[N:17]=[C:18]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[CH3:26])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:31].[C:32]1([N:38]=[C:39]=[O:40])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([NH:27][CH2:28][CH2:29][NH:30][C:39]([NH:38][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[O:40])[N:17]=[C:18]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[CH3:26])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:31]
Reactant: O=C=Nc1ccccc1
Reactant: Cc1cc(F)ccc1-c1nc(NCCN)nc2c1ccc(=O)n2-c1c(F)cccc1F
Product: Cc1cc(F)ccc1-c1nc(NCCNC(=O)Nc2ccccc2)nc2c1ccc(=O)n2-c1c(F)cccc1F
Yield: 79 %

Procedure:
The title compound from Example 157 (42.3 mg, 0.0001 mol) was treated with phenylisocyanate (11.9 mg, 0.00011 mol) in the same manner as described in Example 158. Purification afforded 43 mg (79%) of the title compound as a red solid (m.p. 142°-148°) LC MS (m/e)=545 (MH+). Rt=2.34 min.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([I:9])[CH:5]=[CH:6][C:7]=1[CH3:8].[Br:10]N1C(=O)CCC1=O>C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.C(Cl)(Cl)(Cl)Cl>[Br:10][CH2:8][C:7]1[CH:6]=[CH:5][C:4]([I:9])=[CH:3][C:2]=1[Cl:1]
Reactant: Cc1ccc(I)cc1Cl
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: Clc1cc(I)ccc1CBr
Temperature: 25 °C
Yield: 93.1 %

Procedure:
A mixture of 3-chloro-4-methyliodobenzene (9.0 g), N-bromosuccinimide (8.5 g), benzoyl peroxide (0.3 g) and carbon tetrachloride (80 ml) was stirred and heated to reflux for 3 hours. The mixture was cooled to ambient temperature and filtered. The filtrate was evaporated to give 4-bromomethyl-3-chloroiodobenzene (11 g) which was used without further purification.
Reaction SMILES: [CH3:1][N:2]1[C:10]([CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[N:9][C:8]2[CH:7]=[C:6]([N:17]([CH2:21][CH2:22][Cl:23])[CH2:18][CH2:19][Cl:20])[CH:5]=[CH:4][C:3]1=2.Cl.[CH:25]1(O)[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1.C1(N=C=NC2CCCCC2)CCCCC1>CN(C1C=CN=CC=1)C>[CH:25]1([O:15][C:14](=[O:16])[CH2:13][CH2:12][CH2:11][C:10]2[N:2]([CH3:1])[C:3]3[CH:4]=[CH:5][C:6]([N:17]([CH2:18][CH2:19][Cl:20])[CH2:21][CH2:22][Cl:23])=[CH:7][C:8]=3[N:9]=2)[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: Cn1c(CCCC(=O)O)nc2cc(N(CCCl)CCCl)ccc21
Reactant: OC1CCCCC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Agent: Cl
Product: Cn1c(CCCC(=O)OC2CCCCC2)nc2cc(N(CCCl)CCCl)ccc21
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A 250 mL three neck round bottom flask was equipped with an overhead stirrer, thermocouple, temperature controller and nitrogen sweep then charged with 10 g (25.34 mmol) of bendamustine hydrochloride, 2.56 g (2.7 mL, 25.6 mmol, 1.01 eq) of cyclohexanol, 5.3 g (25.6 mmol, 1.01 eq) of dicyclohexylcarbodiimide (DCC), 100 mL of MDC and 0.31 g (2.54 mmol, 0.1 eq) of DMAP. The reaction slurry was stirred at RT for 18 h until an in process analysis indicated the reaction was complete. Two new major product peaks were observed. Solids were removed by vacuum filtration and washed with 5 mL of MDC. The filtrate was washed with 4% aqueous sodium bicarbonate solution (2×100 mL) before drying over sodium sulfate, filtering and concentrating to dryness in vacuo to yield a yellow oil with some solids present. 1H NMR analysis indicated residual DMAP and cyclohexanol was along with DCC by-products were present in addition to the desired product. The residue was slurried with 50 mL of MDC to remove residual cyclohexanol then concentrated in vacuo and chromatographed. The chromatography was carried out using 50 g of silica gel 60, 230-400 mesh, eluting with 1:1 heptane/EtOAc collecting 100 mL fractions. Product containing fractions were combined and concentrated to dryness in vacuo to yield 3.11 g (7.06 mmol, 27.9%) of the product as an off-white solid with an HPLC purity of 97.8 A %. 1H NMR (400 MHz, DMSO-d6) δ 7.31 (d, J=8.76 Hz, 1H), 6.93 (d, J=2.28 Hz, 1H), 6.77 (dd, J=2.40, 8.80 Hz, 1H), 4.65 (m, 1H), 3.7 (s, 8H), 3.65 (s, 3H), 2.83 (t, J=7.4 Hz, 2H), 2.44 (t, J=7.36 Hz, 2H), 2.00 (m, 2H), 1.76 (m, 4H), 1.65 (m, 2H), 1.33 (m, b, 6H).
Reaction SMILES: Cl.[NH2:2][C:3]1[C:11]([CH3:12])=[CH:10][C:6]2[CH:7]=[CH:8][O:9][C:5]=2[CH:4]=1.CO[CH:15]1[CH2:19][CH2:18][CH:17](OC)O1>O1CCOCC1>[CH3:12][C:11]1[C:3]([N:2]2[CH:15]=[CH:19][CH:18]=[CH:17]2)=[CH:4][C:5]2[O:9][CH:8]=[CH:7][C:6]=2[CH:10]=1
Reactant: COC1CCC(OC)O1
Reactant: Cc1cc2ccoc2cc1N
Agent: Cl
Solvent: C1COCCO1
Product: Cc1cc2ccoc2cc1-n1cccc1

Procedure:
2 ml of 6N hydrochloric acid are added to a mixture of 2.95 g (20 mmole) of 6-amino-5-methylbenzofuran, 3.17 g (24 mmole) of 2,5-dimethoxytetrahydrofuran and 50 ml of dioxane and the whole is boiled under reflux for 40 minutes. The whole is then concentrated in vacuo, the residue is taken up in methylene chloride and the organic phase is washed three times with water. The crude product remaining after drying and removal of the methylene chloride is chromatographed over silica gel with ether/petroleum ether. Subsequent distillation of the pure fractions in a bulb tube (105°, 5.10-2 torr) yields 5-methyl-6-(pyrrol-1-yl)-benzofuran in the form of a pale yellow oil.
Reaction SMILES: [Si:1]([O:8][CH2:9][C@@H:10]([NH:12][C:13]([C:15]1[N:16]=[C:17]([N:20]2[CH2:23][CH:22]([OH:24])[CH2:21]2)[S:18][CH:19]=1)=[O:14])[CH3:11])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:25][S:26](Cl)(=[O:28])=[O:27].C(N(CC)CC)C>C(Cl)Cl>[Si:1]([O:8][CH2:9][C@@H:10]([NH:12][C:13]([C:15]1[N:16]=[C:17]([N:20]2[CH2:21][CH:22]([O:24][S:26]([CH3:25])(=[O:28])=[O:27])[CH2:23]2)[S:18][CH:19]=1)=[O:14])[CH3:11])([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: C[C@@H](CO[Si](C)(C)C(C)(C)C)NC(=O)c1csc(N2CC(O)C2)n1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@@H](CO[Si](C)(C)C(C)(C)C)NC(=O)c1csc(N2CC(OS(C)(=O)=O)C2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 103.2 %

Procedure:
To a solution of 1-{4-[(1S)-2-(t-butyldimethylsilyloxy)-1-methylethylcarbamoyl]-1,3-thiazol-2-yl}-3-hydroxyazetidine (930 mg, 2.50 mmol) (obtained as described in Reference Example 35(4)) in methylene chloride (47 ml) were added methanesulfonyl chloride (480 μl, 6.20 mmol) (obtained as described in Reference Example 35(4)) and triethylamine (869 μl, 6.20 mmol) in an ice bath. After stirring the mixture in the ice bath for 10 minutes, the mixture was stirred at room temperature for 1 hour. After checking the completion of the reaction, the reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate solution. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using n-hexane:ethyl acetate (2:1→1:2) as the eluant to afford 1-{4-[(1S)-2-(t-butyldimethylsilyloxy)-1-methylethylcarbamoyl]-1,3-thiazol-2-yl}-3-methanesulfonyloxyazetidine (1.16 g, yield 100%) as a pale yellow oil.
Reaction SMILES: [CH2:1]([C:7]1([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[C:19]2[CH:18]=[C:17]3[CH:20](O)[CH:21]([CH3:23])[CH2:22][C:16]3=[CH:15][C:14]=2[C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH2:25]([C:7]1([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])[C:19]2[CH:18]=[C:17]3[CH:20]=[C:21]([CH3:23])[CH2:22][C:16]3=[CH:15][C:14]=2[C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]
Reactant: CCCCCCC1(CCCCCC)c2ccccc2-c2cc3c(cc21)C(O)C(C)C3
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CCCCCCC1(CCCCCC)c2ccccc2-c2cc3c(cc21)C=C(C)C3
Temperature: 25 °C
Yield: 96.8 %

Procedure:
In a 500 mL round flask, 9,9-dihexyl-2-methyl-1,2,3,9-tetrahydrocyclopenta[b]fluoren-1-ol (80 g, 197.7 mmol) and p-toluene sulfonic acid (0.2 g) were dissolved in 320 mL of toluene, and then water was completely removed under reflux with Dean-Stark. The resultant material was cooled to room temperature, and then an aqueous ammonium chloride solution (150 mL) and 200 mL of diethyl ether were injected thereto, followed by separation of the organic layer. The organic layer collected by extracting the residue with diethyl ether was dried over magnesium sulfate, followed by removal of volatile materials, and then purified by using silica gel column chromatography tube, to thereby obtain 74.0 g of 9,9-dihexyl-2-methyl-3,9-dihydrocyclopenta[b]fluorene (yield: 96.8%).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:12]=[C:11]([C:13]([NH:15][C:16]3[CH:17]=[C:18]([NH:22][C:23](=[O:34])[C:24]4[CH:29]=[C:28](Cl)[CH:27]=[CH:26][C:25]=4[N+:31]([O-:33])=[O:32])[CH:19]=[CH:20][CH:21]=3)=[O:14])[CH:10]=[CH:9][N:8]=2)[CH2:3][CH2:2]1.[CH3:35][N:36]1[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1>>[O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:12]=[C:11]([C:13]([NH:15][C:16]3[CH:17]=[C:18]([NH:22][C:23](=[O:34])[C:24]4[CH:29]=[C:28]([N:39]5[CH2:40][CH2:41][N:36]([CH3:35])[CH2:37][CH2:38]5)[CH:27]=[CH:26][C:25]=4[N+:31]([O-:33])=[O:32])[CH:19]=[CH:20][CH:21]=3)=[O:14])[CH:10]=[CH:9][N:8]=2)[CH2:3][CH2:2]1
Reactant: CN1CCNCC1
Reactant: O=C(Nc1cccc(NC(=O)c2cc(Cl)ccc2[N+](=O)[O-])c1)c1ccnc(N2CCOCC2)c1
Product: CN1CCN(c2ccc([N+](=O)[O-])c(C(=O)Nc3cccc(NC(=O)c4ccnc(N5CCOCC5)c4)c3)c2)CC1
Yield: 89 %

Procedure:
In an analogous procedure to that described in the fifth paragraph of the portion of Note c) which is concerned with the preparation of starting materials, N-[3-(2-morpholinopyrid-4-ylcarbonylamino)phenyl]-5-chloro-2-nitrobenzamide was reacted with 1-methylpiperazine to give N-[3-(2-morpholinopyrid-4-ylcarbonylamino)phenyl]-5-(4-methylpiperazin-1-yl)-2-nitrobenzamide in 89% yield; NMR Spectrum: (DMSOd6) 2.2 (s, 3H), 2.41 (m, 4H) )3.5 (m, 8H), 3.71 (t, 4H), 7.07 (m, 3H), 7.31 (m, 3H), 7.48 (d, 1H), 8.03 (d, 1H), 8.16 (s, 1H), 8.26 (d, 1H), 10.35 (broad s, 1H), 10.44 (broad s, 1H); Mass Spectrum: M+H+ 546.
Reaction SMILES: [C:1]1([CH2:7][S:8]([C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[NH:16][C:15](=[O:20])[CH2:14]3)(=[O:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH:21][CH:22]1[CH2:27][CH2:26][N:25]([C:28](=[O:39])[CH2:29][C:30]2[C:31]([CH3:38])=[C:32]([CH:36]=O)[NH:33][C:34]=2[CH3:35])[CH2:24][CH2:23]1.N1CCCCC1>C(O)C>[OH:21][CH:22]1[CH2:27][CH2:26][N:25]([C:28](=[O:39])[CH2:29][C:30]2[C:31]([CH3:38])=[C:32](/[CH:36]=[C:14]3\[C:15](=[O:20])[NH:16][C:17]4[C:13]\3=[CH:12][C:11]([S:8]([CH2:7][C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)(=[O:10])=[O:9])=[CH:19][CH:18]=4)[NH:33][C:34]=2[CH3:35])[CH2:24][CH2:23]1
Reactant: Cc1[nH]c(C=O)c(C)c1CC(=O)N1CCC(O)CC1
Reactant: O=C1Cc2cc(S(=O)(=O)Cc3ccccc3)ccc2N1
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4ccccc4)cc32)c(C)c1CC(=O)N1CCC(O)CC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of 5-phenylmethanesulfonyl-1,3-dihydro-indol-2-one (100 mg, 0.35 mmol), 4-[2-(4-hydroxy-piperidin-1-yl)-2-oxo-ethyl]-3,5-dimethyl-1H-pyrrole-2-carbaldehyde (180 mg, 0.68 mmol) and piperidine (0.5 eq.) in ethanol (2 mL) was stirred at rt for 48 hours. The reaction was concentrated and triturated with methanol to give the titled compound as an orangish-red solid.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]2[CH2:8][CH2:9][N:10]([C:12](=[O:17])[CH2:13][CH2:14][CH:15]=[CH2:16])[CH2:11][C:4]=2[CH:3]=1.[CH3:18][NH:19][NH2:20]>>[CH3:18][N:19]([C:2]1[N:7]=[N:6][C:5]2[CH2:8][CH2:9][N:10]([C:12](=[O:17])[CH2:13][CH2:14][CH:15]=[CH2:16])[CH2:11][C:4]=2[CH:3]=1)[NH2:20]
Reactant: CNN
Reactant: C=CCCC(=O)N1CCc2nnc(Cl)cc2C1
Product: C=CCCC(=O)N1CCc2nnc(N(C)N)cc2C1

Procedure:
12.3 G of 3-chloro-5,6,7,8-tetrahydro-6-(4-pentenoyl)pyrido[4,3-c]pyridazine and 50 cc of methylhydrazine are stirred at a bath temperature of 90° for 30 minutes. The crude title compound is obtained in crystalline form upon cooling the mixture with ice. The title compound has a M.P. of 128°-130° (decomp., from isopropanol).
Reaction SMILES: [CH3:1][CH:2]([O:4][C:5](=[O:30])[NH:6][C@H:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14](B3OC(C)(C)C(C)(C)O3)[CH:15]=2)[N:10]([C:26](=[O:28])[CH3:27])[C@@H:9]([CH3:29])[CH2:8]1)[CH3:3].Br[C:32]1[CH:37]=[CH:36][C:35]([CH2:38][C:39]([O:41][CH2:42][CH3:43])=[O:40])=[CH:34][CH:33]=1.C(=O)([O-])[O-].[K+].[K+]>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>[C:26]([N:10]1[C:11]2[C:16](=[CH:15][C:14]([C:32]3[CH:37]=[CH:36][C:35]([CH2:38][C:39]([O:41][CH2:42][CH3:43])=[O:40])=[CH:34][CH:33]=3)=[CH:13][CH:12]=2)[C@H:7]([NH:6][C:5]([O:4][CH:2]([CH3:3])[CH3:1])=[O:30])[CH2:8][C@@H:9]1[CH3:29])(=[O:28])[CH3:27]
Reactant: CC(=O)N1c2ccc(B3OC(C)(C)C(C)(C)O3)cc2[C@H](NC(=O)OC(C)C)C[C@@H]1C
Reactant: CCOC(=O)Cc1ccc(Br)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCOC(=O)Cc1ccc(-c2ccc3c(c2)[C@H](NC(=O)OC(C)C)C[C@H](C)N3C(C)=O)cc1
Temperature: 100 °C
Yield: 31 %

Procedure:
A mixture of 1-methylethyl[(2S,4R)-1-acetyl-2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahydro-4-quinolinyl]carbamate (for a preparation see Intermediate 52) (100 mg, 0.240 mmol), ethyl (4-bromophenyl)acetate (70.1 mg, 0.288 mmol), potassium carbonate (100 mg, 0.721 mmol) and tetrakis(triphenylphosphine)palladium(0) (13.88 mg, 0.012 mmol) was degassed under house vacuum and quenched several times with nitrogen, and then was heated at 100° C. for 1 h before being cooled to room temperature and partitioned between AcOEt (60 mL) and water (30 mL). The layers were separated and the organic phase was washed with brine, dried on MgSO4 and concentrated in vacuo. Purification of the residue by flash chromatography on silica gel (gradient: 5 to 25% AcOEt in hexanes) gave ethyl {4-[(2S,4R)-1-acetyl-2-methyl-4-({[(1-methylethyl)oxy]carbonyl}amino)-1,2,3,4-tetrahydro-6-quinolinyl]phenyl}acetate (33.9 mg, 0.075 mmol, 31%) as a colourless solid.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH:6]1[CH2:9][N:8](C(OC(C)(C)C)=O)[CH2:7]1>C(Cl)Cl>[NH:8]1[CH2:9][CH:6]([C:2]2[NH:1][CH:5]=[CH:4][N:3]=2)[CH2:7]1
Reactant: CC(C)(C)OC(=O)N1CC(c2ncc[nH]2)C1
Solvent: ClCCl
Product: c1c[nH]c(C2CNC2)n1

Procedure:
To a stirred solution of tert-butyl 3-(1H-imidazol-2-yl)azetidine-1-carboxylate (36 mg, 0.16 mmol) in DCM (1 mL) is added boron trifluoride diethyl ether complex (40 μL, 0.318 mmol). After 2 h the reaction mixture is quenched with water (11 μL). MeOH is added and the reaction mixture is concentrated under reduced pressure to give crude 2-(azetidin-3-yl)-1H-imidazole.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:3]=1[C:4](Cl)=[O:5].C[O:13][C:14]([C:16]1[C:20]([NH2:21])=[CH:19][NH:18][N:17]=1)=[O:15].C(N(CC)CC)C>O1CCOCC1>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:3]=1[C:4]([NH:21][C:20]1[C:16]([C:14]([OH:15])=[O:13])=[N:17][NH:18][CH:19]=1)=[O:5]
Reactant: O=C(Cl)c1c(Cl)cccc1Cl
Reactant: COC(=O)c1n[nH]cc1N
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: O=C(O)c1n[nH]cc1NC(=O)c1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 5 h
Yield: 94.3 %

Procedure:
2,6-Dichlorobenzoyl chloride (8.2 g; 39.05 mmol) was added cautiously to a solution of 4-amino-1H-pyrazole-3-carboxylic acid methyl ester (5 g; 35.5 mmol) and triethylamine (5.95 ml; 42.6 mmol) in dioxan (50 ml) then stirred at room temperature for 5 hours. The reaction mixture was filtered and the filtrate treated with methanol (50 ml) and 2M sodium hydroxide solution (100 ml), heated at 50° C. for 4 hours, and then evaporated. 100 ml of water was added to the residue then acidified with concentrated hydrochloric acid. The solid was collected by filtration, washed with water (100 ml) and sucked dry to give 10.05 g of 4-(2,6-dichloro-benzoylamino)-1H-pyrazole-3-carboxylic acid as a pale violet solid.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][CH2:5][N:4]([C:7](=[O:38])[CH:8]([N:15]2[C:19]3[CH:20]=[C:21]([C:24]#[N:25])[CH:22]=[CH:23][C:18]=3[N:17]([S:26]([C:29]3[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=3)(=[O:28])=[O:27])[C:16]2=[O:37])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:3]1.[CH3:39][N:40]1[CH2:45][CH2:44][C:43](=O)[CH2:42][CH2:41]1>C1COCC1>[CH3:36][O:35][C:32]1[CH:31]=[CH:30][C:29]([S:26]([N:17]2[C:18]3[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[CH:20][C:19]=3[N:15]([CH:8]([C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:7]([N:4]3[CH2:5][CH2:6][C@H:2]([NH:1][CH:43]4[CH2:44][CH2:45][N:40]([CH3:39])[CH2:41][CH2:42]4)[CH2:3]3)=[O:38])[C:16]2=[O:37])(=[O:27])=[O:28])=[CH:34][CH:33]=1
Reactant: CN1CCC(=O)CC1
Reactant: COc1ccc(S(=O)(=O)n2c(=O)n(C(C(=O)N3CC[C@H](N)C3)c3ccccc3)c3cc(C#N)ccc32)cc1
Solvent: C1CCOC1
Product: COc1ccc(S(=O)(=O)n2c(=O)n(C(C(=O)N3CC[C@H](NC4CCN(C)CC4)C3)c3ccccc3)c3cc(C#N)ccc32)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 69.9 %

Procedure:
To a solution of 3-[2-((S)-3-amino-pyrrolidin-1-yl)-2-oxo-1-phenyl-ethyl]-1-(4-methoxy-benzenesulfonyl)-2-oxo-2,3-dihydro-1H-benzoimidazole-5-carbonitrile (Example 171, 200 mg, 0.38 mmol) and 1-methyl-4-piperidone (0.087 mL, 0.75 mmol) in THF (5 mL) MP-(OAc)3BH resin (Argonaut; 2.55 mmol/g; 369 mg, 0.94 mmol) was added. The reaction mixture was agitated at room temperature for 24 hours, then filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel using 15% methanol in CH2Cl2 to afford 1-(4-methoxy-benzenesulfonyl)-3-{2-[(S)-3-(1-methyl-piperidin-4-ylamino)-pyrrolidin-1-yl]-2-oxo-1-phenyl-ethyl}-2-oxo-2,3-dihydro-1H-benzoimidazole-5-carbonitrile (167 mg, 71%) as a white solid.
Reaction SMILES: [CH:1]1(/[CH:7]=[C:8](\[CH2:14][P:15]([O:21][CH2:22][CH3:23])([CH2:17][CH:18]([CH3:20])[CH3:19])=[O:16])/[C:9]([O:11]CC)=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+]>C(O)C.O>[CH:1]1(/[CH:7]=[C:8](\[CH2:14][P:15]([O:21][CH2:22][CH3:23])([CH2:17][CH:18]([CH3:19])[CH3:20])=[O:16])/[C:9]([OH:11])=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCOC(=O)/C(=C/C1CCCCC1)CP(=O)(CC(C)C)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCOP(=O)(C/C(=C\C1CCCCC1)C(=O)O)CC(C)C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 176 mg (0.51 millimole) of ethyl (Z)-3-cyclohexyl-2-(ethoxyisobutylphosphinoyl)methylpropenoate in 2 ml of ethanol was added 1 N sodium hydroxide (0.51 ml) and the solution was stirred at room temperature for 3 hours, and then refluxed for 30 minutes. After cooling, the reaction mixture was diluted with 30 ml of water, and extracted with 20 ml of ether. The aqueous layer was acidified with 4 N hydrochloric acid, and extracted three times with 20 ml of ether each time. The combined organic layers were washed with 10 ml of a saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give 143 mg (yield of the captioned compound as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[C:7]([Cl:8])=[C:6]([C:9]([F:12])([F:11])[F:10])[CH:5]=[CH:4][C:3]=1[OH:13].[C:14](O)(=[O:21])[C:15]1[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=1.CCN=C=NCCCN(C)C.N1C=CC=CC=1>O>[Cl:8][C:7]1[C:6]([C:9]([F:12])([F:10])[F:11])=[CH:5][CH:4]=[C:3]([OH:13])[C:2]=1[NH:1][C:14](=[O:21])[C:15]1[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=1
Reactant: O=C(O)c1ccncc1
Reactant: Nc1c(O)ccc(C(F)(F)F)c1Cl
Agent: CCN=C=NCCCN(C)C
Solvent: O
Solvent: c1ccncc1
Product: O=C(Nc1c(O)ccc(C(F)(F)F)c1Cl)c1ccncc1
Temperature: 80 °C
Yield: 59 %

Procedure:
A mixture of 0.17 g of 2-amino-3-chloro-4-trifluoromethylphenol, 0.99 g of isonicotinic acid, 0.19 g of WSC and 3 ml of pyridine was stirred while heating at 80° C. for two hours. The mixture was cooled to room temperature, and then water was poured, followed by extraction with ethyl acetate three times. The combined organic layers were washed with water and a saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 0.15 g of N-[2-chloro-6-hydroxy-3-(trifluoromethyl)phenyl]isonicotinamide.
Reaction SMILES: [OH:1][C:2]1[C:3]2[CH:10]=[C:9]([CH2:11][CH2:12][NH:13][C:14](=[O:16])[CH3:15])[S:8][C:4]=2[N:5]=[CH:6][N:7]=1.C=O.[C:19](O)(C(F)(F)F)=O>ClCCCl>[OH:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[C:3]=1[C:10]1[CH2:19][N:13]([C:14](=[O:16])[CH3:15])[CH2:12][CH2:11][C:9]=1[S:8]2
Reactant: CC(=O)NCCc1cc2c(O)ncnc2s1
Reactant: O=C(O)C(F)(F)F
Agent: C=O
Solvent: ClCCCl
Product: CC(=O)N1CCc2sc3ncnc(O)c3c2C1
Temperature: 25 °C
Reaction time: 12 h
Yield: 63 %

Procedure:
To a solution of N-(2-[4-hydroxythieno[2,3-d]pyrimidin-6-yl]ethyl)acetamide (300 mg, 1.26 mmol, 1.00 equiv) and paraformaldehyde (300 mg, 10.00 mmol, 7.91 equiv) in 50 mL of 1,2-dichloroethane at 0° C. was added CF3COOH (6 mL). The solution was stirred for 12 h at room temperature. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with dichloromethane/methanol (10:1) to afford the desired 1-[3-hydroxy-8-thia-4,6,12-triazatricyclo[7.4.0.0-[2,7]]trideca-1(9),2,4,6-tetraen-12-yl]ethan-1-one (200 mg, 63%) as a light yellow solid. MS (ES): m/z 250 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.Br[C:15]1[CH:16]=[C:17]([CH:46]=[CH:47][CH:48]=1)[CH2:18][N:19]1[C:23]2[CH:24]=[C:25]([O:28][CH2:29][C:30]3[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][N:31]=3)[CH:26]=[CH:27][C:22]=2[N:21]=[C:20]1[CH2:37][C:38]([CH2:44][CH3:45])([CH2:42][CH3:43])[C:39]([OH:41])=[O:40]>>[CH2:42]([C:38]([CH2:37][C:20]1[N:19]([CH2:18][C:17]2[CH:16]=[C:15]([C:6]3[CH:7]=[CH:8][C:3]([C:2]([F:13])([F:12])[F:1])=[CH:4][CH:5]=3)[CH:48]=[CH:47][CH:46]=2)[C:23]2[CH:24]=[C:25]([O:28][CH2:29][C:30]3[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][N:31]=3)[CH:26]=[CH:27][C:22]=2[N:21]=1)([CH2:44][CH3:45])[C:39]([OH:41])=[O:40])[CH3:43]
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: CCC(CC)(Cc1nc2ccc(OCc3ccc(C)cn3)cc2n1Cc1cccc(Br)c1)C(=O)O
Product: CCC(CC)(Cc1nc2ccc(OCc3ccc(C)cn3)cc2n1Cc1cccc(-c2ccc(C(F)(F)F)cc2)c1)C(=O)O

Procedure:
The title compound was prepared using similar methods to those in Example 144 using (4-(trifluoromethyl)phenyl)boronic acid and 2-((1-(3-bromobenzyl)-6-((5-methylpyridin-2-yl)methoxy)-1H-benzo[d]imidazol-2-yl)methyl)-2-ethylbutanoic acid. MS (ESI): mass calcd. for C35H34F3N3O3, 602.26; m/z found, 603.2 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 8.37-8.32 (m, 1H), 7.70-7.65 (m, 2H), 7.65-7.61 (d, J=8.8, 1H), 7.58-7.50 (m, 3H), 7.49-7.44 (m, 1H), 7.43-7.35 (m, 2H), 7.06-7.02 (dd, J=8.9, 2.4, 1H), 7.02-6.97 (d, J=8.1, 1H), 6.90-6.86 (d, J=2.3, 1H), 5.39-5.32 (s, 2H), 5.19-5.14 (s, 2H), 3.04-2.98 (s, 2H), 2.32-2.27 (s, 3H), 1.73-1.54 (m, 4H), 0.84-0.74 (t, J=7.4, 6H), 7.26-7.24 (s, 1H).