Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][C:8]=2[C:14]2[C:15]3[NH:22][C:21]([CH3:23])=[C:20]([C:24]([NH:26][CH:27]4[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]4)=[O:25])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:4][CH2:3]1.C([O:36][C@@H:37]([CH3:41])[C:38](Cl)=[O:39])(=O)C>>[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][C:8]=2[C:14]2[C:15]3[NH:22][C:21]([CH3:23])=[C:20]([C:24]([NH:26][CH:27]4[CH2:28][CH2:29][N:30]([C:38](=[O:39])[C@@H:37]([OH:36])[CH3:41])[CH2:31][CH2:32]4)=[O:25])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:4][CH2:3]1
Reactant: CC(=O)O[C@@H](C)C(=O)Cl
Reactant: Cc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)NC4CCNCC4)c(C)[nH]c23)c1
Agent: Cl
Product: Cc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)NC4CCN(C(=O)[C@H](C)O)CC4)c(C)[nH]c23)c1

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-5-methylphenyl]-6-methyl-N-(piperidin-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f28) and commercially available (2S)-1-chloro-1-oxopropan-2-yl acetate the title compound is obtained as colorless solid.
Reaction SMILES: [OH-].[Li+].[Cl:3][C:4]1[N:5]=[C:6]([C:11]([N:13]([CH2:29][CH2:30][CH3:31])[CH:14]2[CH2:17][N:16]([C:18]3[S:19][C:20]([C:24]([O:26]CC)=[O:25])=[C:21]([CH3:23])[N:22]=3)[CH2:15]2)=[O:12])[NH:7][C:8]=1[CH2:9][CH3:10].O>CO.C1COCC1>[Cl:3][C:4]1[N:5]=[C:6]([C:11]([N:13]([CH2:29][CH2:30][CH3:31])[CH:14]2[CH2:15][N:16]([C:18]3[S:19][C:20]([C:24]([OH:26])=[O:25])=[C:21]([CH3:23])[N:22]=3)[CH2:17]2)=[O:12])[NH:7][C:8]=1[CH2:9][CH3:10]
Reactant: CCCN(C(=O)c1nc(Cl)c(CC)[nH]1)C1CN(c2nc(C)c(C(=O)OCC)s2)C1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CCCN(C(=O)c1nc(Cl)c(CC)[nH]1)C1CN(c2nc(C)c(C(=O)O)s2)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 54.2 %

Procedure:
A 2 N aqueous lithium hydroxide solution (1.30 mL, 2.59 mmol) was added to a mixed solution of ethyl 2-(3-{[(4-chloro-5-ethyl-1H-imidazol-2-yl)carbonyl](n-propyl)amino}azetidin-1-yl)-4-methyl-1,3-thiazole-5-carboxylate obtained in Example (227d) (114 mg, 0.26 mmol) in methanol/THF (3 mL/0.5 mL), and the mixture was stirred at room temperature for 16 hours. Water was added to the reaction solution, and then the mixture was washed with ethyl acetate. A 1 N aqueous hydrochloric acid solution (4.5 mL) was added to the aqueous layer, followed by extraction with ethyl acetate. The combined organic layers were dried over anhydrous magnesium sulfate and then filtered, and the filtrate was concentrated under reduced pressure. The resulting solid was suspended and washed in diethyl ether to obtain 58 mg of the title compound as a white solid (54%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][NH:6][C:5](=O)[CH:4]=1.O=P(Cl)(Cl)[Cl:12]>>[Cl:12][C:5]1[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=[CH:7][N:6]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1cc[nH]c(=O)c1
Product: COc1ccnc(Cl)c1
Yield: 63 %

Procedure:
4-Methoxy-2-pyridone (10) (0.805 g, 6.43 mmol) and freshly distilled POCl3 (8 mL) were heated at reflux for 15 h. Excess POCl3 was removed in vacuo and the resultant viscous oil was cooled in ice and carefully neutralised with saturated NaHCO3 solution. The mixture was extracted with EtOAc (×3) and the extracts were worked up in the standard manner to give a brown oil. This material was partially purified by vacuum distillation in a Kugelrohr apparatus (100° C., 0.07 mm Hg). The distillate was triturated with petroleum ether and a white precipitate was filtered off. The filtrate was concentrated and final purification by flash chromatography on silica gel using 30% EtOAc/hexanes as the eluant gave 2-chloro-4-methoxypyridine (11) as a colourless oil (0.586 g, 63%).
Reaction SMILES: [Na][Na].[C:3]([C:5]1[C:9](=[C:10]([C:13]#[N:14])[C:11]#[N:12])[NH:8][C:7](=[O:15])[C:6]=1O)#[N:4].[CH2:17]([N:21]([CH:28]([CH3:34])[CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:18][CH2:19][CH3:20].C(OC(=O)C)(=O)C.P(Cl)(Cl)(Cl)=O>CC(C)=O.O.CN(C)C=O>[CH2:17]([N:21]([C:22]1[CH:23]=[CH:24][C:25]([C:6]2[C:7](=[O:15])[NH:8][C:9](=[C:10]([C:13]#[N:14])[C:11]#[N:12])[C:5]=2[C:3]#[N:4])=[CH:26][CH:27]=1)[CH:28]([CH3:34])[CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[CH2:18][CH2:19][CH3:20]
Reactant: CCCCCC(C)N(CCCC)c1ccccc1
Reactant: N#CC(C#N)=C1NC(=O)C(O)=C1C#N
Agent: [Na][Na]
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: CCCCCC(C)N(CCCC)c1ccc(C2=C(C#N)C(=C(C#N)C#N)NC2=O)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 65 %

Procedure:
A stirred mixture of the disodium salt of 4-cyano-5-dicyanomethylidene-3-hydroxy-2-oxo-2,5-dihydropyrrole (23 parts) and dry N,N-dimethylformamide (180 parts) was cooled to -5° C. to -10° C. and N-n-butyl-N-(1-methylhexyl)aniline containing acetic anhydride (27%, 37 parts) was added followed by the dropwise addition of phosphorus oxychloride (26 parts) whilst maintaining the temperature at less than -5° C. The mixture was allowed to warm to room temperature and stirred for 20 hours. The reaction mixture was poured into a stirred mixture of ice and water (400 parts) and acetone (400 parts) was added before filtering off a solid. The solid was washed repeatedly with warm water (40° C.) and then dried at 50° C. to yield 3-(4-(N-butyl-N-(1-methylhexyl)amino)phenyl)-4-cyano-5-dicyanomethylidene-2-oxo-2,5-dihydropyrrole (26.8 parts, 65%). A small simple this material was slurried in boiling methanol, collected by filtration, washed with methanol and dried at 50° C. to give 3-(4-(N-n-butyl-N-(1-methylhexyl)amino)phenyl)-4-cyano-5-dicyanomethylidene-2-oxo-2,5-dihydropyrrole m.p. 188° C.; λmax (CH2Cl2) 662 nm (εmax 60231); M/Z (EI) 415 (M+, 20%), 400 (15), 372 (12), 344 (100), 288 (33) and 272 (25).
Reaction SMILES: [C:1]([N:4]1[C:11]2[CH:12]=[C:13]([Cl:16])[CH:14]=[CH:15][C:10]=2[CH:9]=[CH:8][C:7]2[N:17]=[C:18](Cl)[C:19]([F:21])=[CH:20][C:6]=2[CH2:5]1)(=[O:3])[CH3:2].CC1(C)C(C)(C)OB([C:31]2[CH:32]=[CH:33][C:34]([N:37]3[CH2:42][CH2:41][O:40][CH2:39][CH2:38]3)=[N:35][CH:36]=2)O1.C(N1C2C=CC=CC=2C=CC2N=C(C3C=NC(OC)=CC=3)C(F)=CC=2C1)(=O)C>>[C:1]([N:4]1[C:11]2[CH:12]=[C:13]([Cl:16])[CH:14]=[CH:15][C:10]=2[CH:9]=[CH:8][C:7]2[N:17]=[C:18]([C:31]3[CH:36]=[N:35][C:34]([N:37]4[CH2:38][CH2:39][O:40][CH2:41][CH2:42]4)=[CH:33][CH:32]=3)[C:19]([F:21])=[CH:20][C:6]=2[CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1Cc2cc(F)c(Cl)nc2C=Cc2ccc(Cl)cc21
Reactant: CC1(C)OB(c2ccc(N3CCOCC3)nc2)OC1(C)C
Agent: COc1ccc(-c2nc3c(cc2F)CN(C(C)=O)c2ccccc2C=C3)cn1
Product: CC(=O)N1Cc2cc(F)c(-c3ccc(N4CCOCC4)nc3)nc2C=Cc2ccc(Cl)cc21
Yield: 51.9 %

Procedure:
The title compound (16.6 mg, 52%) was prepared from 6D (23.2 mg, 0.0688 mmol) and 5A (22 mg, 0.0722 mmol) by a route analogous to that used for the preparation of 2B. HPLC Rt=2.612 min; LCMS Found: (M+H)+=465.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1.CCN(C(C)C)C(C)C.[N:18]1[CH:23]=[CH:22][C:21]([CH2:24][NH2:25])=[CH:20][CH:19]=1.O>CC(O)C>[Cl:8][C:6]1[N:5]=[CH:4][N:3]=[C:2]([NH:25][CH2:24][C:21]2[CH:22]=[CH:23][N:18]=[CH:19][CH:20]=2)[CH:7]=1
Reactant: NCc1ccncc1
Reactant: Clc1cc(Cl)ncn1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: Clc1cc(NCc2ccncc2)ncn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 77.7 %

Procedure:
To a solution of 4,6-dichloro-pyrimidine (1.5 g, 10.5 mmol) and DIPEA (1.62 g, 12.6 mmol) in iPrOH (40 mL) was added 4-pyridinylmethanamine (1.2 g, 11 mmol) at room temperature. The resulting mixture was stirred at room temperature for 2 hours. Water was added and the mixture was extracted with DCM. The combined extracts were washed with brine, dried over anhydrous Na2SO4, and concentrated to give the crude product, which was purified by flash chromatography on silica to obtain the title compound (1.8 g, yield: 80%). MS (ESI): 221 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[N:6]([C:7]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:5]=[N:4][C:3]=1[CH:26]=[O:27].Cl.[C:29]([O:32][CH2:33][CH3:34])(=[O:31])[CH3:30]>O1CCCC1>[OH:27][CH:26]([C:3]1[N:4]=[CH:5][N:6]([C:7]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:2]=1[CH3:1])[CH2:30][C:29]([O:32][CH2:33][CH3:34])=[O:31]
Reactant: Cc1c(C=O)ncn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCOC(C)=O
Agent: Cl
Solvent: C1CCOC1
Product: CCOC(=O)CC(O)c1ncn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c1C
Reaction time: 2 h
Yield: 80 %

Procedure:
Under argon atmosphere, 3.2 mL (1.70 mmol, 2 equivalents) of the solution of ethyl bromozincacetate in tetrahydrofuran obtained in Example 43 was added dropwise to a solution of 0.3 g. (0.85 mmol) of 5-methyl-1-trityl-1H-imidazol-4-carbaldehyde in 3 mL of THF at 4˜7° C. The mixture was stirred at 2˜5° C. for 2 hours. 5 mL of 1N hydrochloric acid was added dropwise at 20° C. or lower, followed by dilution with 15 mL of ethyl acetate. Then, the layers were separated. The organic layer was washed successively with 5 mL of 1N hydrochloric acid, 5 mL of water, 2.5 mL (×2) of an aqueous saturated sodium bicarbonate solution, and 2.5 mL (×2) of an aqueous saturated sodium chloride solution. After washing, the organic layer was dried with anhydrous magnesium sulfate. After concentration under reduced pressure, recrystallization with 3 mL of IPE afforded 0.30 g of the desired product. (yield 80%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([O:11][CH3:12])[O:9][CH3:10])=[CH:4][N:3]=1.C([Mg]Cl)(C)C.CN(C)[CH:20]=[O:21].O>O1CCCC1>[CH3:10][O:9][CH:8]([O:11][CH3:12])[C:5]1[CH:6]=[CH:7][C:2]([CH:20]=[O:21])=[N:3][CH:4]=1
Reactant: COC(OC)c1ccc(Br)nc1
Reactant: CN(C)C=O
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Solvent: O
Product: COC(OC)c1ccc(C=O)nc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 44.4 %

Procedure:
To a solution of 2-bromo-5-dimethoxymethylpyridine (1.19 g, 5.13 mmol) in tetrahydrofuran (8 mL) was added isopropylmagnesium chloride (2 mol/L in tetrahydrofuran; 4.2 mL, 8.4 mmol) under nitrogen atmosphere, and the mixture was stirred at room temperature for 3 h. Dimethylformamide (0.774 mL, 10.3 mmol) was added, and the mixture was stirred for additional 10 min. Water was added, and the mixture was extracted with ethyl acetate twice. The organic layer was washed with brine and dried on anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (5:1 to 3:1 hexane/ethyl acetate) to afford 5-dimethoxymethyl-2-pyridinecarboxaldehyde (413 mg, 44%).
Reaction SMILES: [CH3:1][S:2]([O:5][CH2:6][C:7]([NH:11][CH2:12][C:13]1[CH:14]=[C:15]2[C:24](=[C:25]3[C:30]=1[CH:29]=[CH:28][CH:27]=[CH:26]3)[CH:23]=[CH:22][C:21]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]2=1)([CH3:10])[CH2:8][OH:9])(=[O:4])=[O:3].[CH2:31](C1C2C=CC=CC=2C2C(=C3C(=C(C=O)C=2)C=CC=C3)C=1)[CH3:32].NC(C)(CO)CO>>[CH3:1][S:2]([O:5][CH2:6][C:7]([NH:11][CH2:12][C:13]1[CH:14]=[C:15]2[C:24](=[C:25]3[C:30]=1[CH:29]=[CH:28][CH:27]=[CH:26]3)[CH:23]=[C:22]([CH2:31][CH3:32])[C:21]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]2=1)([CH3:10])[CH2:8][OH:9])(=[O:4])=[O:3]
Reactant: CCc1cc2c3ccccc3c(C=O)cc2c2ccccc12
Reactant: CC(CO)(COS(C)(=O)=O)NCc1cc2c3ccccc3ccc2c2ccccc12
Agent: CC(N)(CO)CO
Product: CCc1cc2c3ccccc3c(CNC(C)(CO)COS(C)(=O)=O)cc2c2ccccc12

Procedure:
Using the reductive amination procedure outlined in 1C, 12-ethyl-6-chrysenecarbaldehyde (15A) and 2-amino-2-methyl-1,3-propanediol (Aldrich) gave 2-(((12-ethyl-6-chrysenyl)methyl)amino)-2-methyl-1,3-propanediol methanesulfonate mp 189°-192° (dec), (EtOH/Et2O), (C,H,N,S).
Reaction SMILES: [N:1]1([S:7]([C:10]2[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=2)[C:13]([OH:15])=O)(=[O:9])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:19][CH:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:22][CH2:21]1>>[CH:20]1([NH:19][C:13](=[O:15])[C:12]2[CH:16]=[CH:17][CH:18]=[C:10]([S:7]([N:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)(=[O:8])=[O:9])[CH:11]=2)[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:22][CH2:21]1
Reactant: O=C(O)c1cccc(S(=O)(=O)N2CCCCC2)c1
Reactant: NC1CCc2ccccc21
Product: O=C(NC1CCc2ccccc21)c1cccc(S(=O)(=O)N2CCCCC2)c1

Procedure:
The entitled compound was produced according to the method of Example 73 but using 3-(piperidin-1-ylsulfonyl)benzoic acid and 1-aminoindane as the starting materials.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][OH:11])=[CH:9][C:4]=2[N:3]=[CH:2]1>C1C=CC=CC=1.O=[Mn]=O>[NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]=[O:11])=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: OCc1ccc2[nH]cnc2c1
Agent: O=[Mn]=O
Solvent: c1ccccc1
Product: O=Cc1ccc2[nH]cnc2c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 40.7 %

Procedure:
To a stirring solution of (1H-benzo[d]imidazol-5-yl)methanol (501 mg, 3.38 mmol) in benzene (35 mL) was added MnO2 (2.35, 27.0 mmol). After stirring at room temperature for 12 h the reaction was then filtered through celite and the filter cake was washed with THF (200 mL). The Filtrate was concentrated to give the title compound (1H-benzo[d]imidazole-5-carbaldehyde)(201 mg, 41%) as a white solid: 1H NMR (400 MHz, DMSO-d6) δ 12.90 (bs, 1H), 10.04 (s, 1H), 8.43 (s, 1H), 8.19 (s, 1H), 7.75 (s, 2H).
Reaction SMILES: [K+].[C:2]([C:4]1[N:5]=[C:6]([C:17]([O-:19])=O)[N:7](COCC[Si](C)(C)C)[CH:8]=1)#[N:3].[CH2:20]([O:22][C:23](=[O:40])[CH2:24][C:25]1[CH:30]=[CH:29][C:28]([NH2:31])=[C:27]([C:32]2[CH2:37][CH2:36][C:35]([CH3:39])([CH3:38])[CH2:34][CH:33]=2)[N:26]=1)[CH3:21]>>[CH2:20]([O:22][C:23](=[O:40])[CH2:24][C:25]1[CH:30]=[CH:29][C:28]([NH:31][C:17]([C:6]2[NH:5][C:4]([C:2]#[N:3])=[CH:8][N:7]=2)=[O:19])=[C:27]([C:32]2[CH2:37][CH2:36][C:35]([CH3:39])([CH3:38])[CH2:34][CH:33]=2)[N:26]=1)[CH3:21]
Reactant: C[Si](C)(C)CCOCn1cc(C#N)nc1C(=O)[O-]
Reactant: CCOC(=O)Cc1ccc(N)c(C2=CCC(C)(C)CC2)n1
Agent: [K+]
Product: CCOC(=O)Cc1ccc(NC(=O)c2ncc(C#N)[nH]2)c(C2=CCC(C)(C)CC2)n1

Procedure:
The title compound was prepared by coupling 4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylate potassium salt (as prepared in Example 1, step (d)) and [5-amino-6-(4,4-dimethyl-cyclohex-1-enyl)-pyridin-2-yl]-acetic acid ethyl ester (as prepared in the previous step) according to the procedure in Example 34, step (c), followed by SEM deprotection according to the procedure in Example 34, step (d). Mass spectrum (ESI, m/z): Calcd. for C22H25ClN5O3, 408.2 (M+H). found 408.2.
Reaction SMILES: [C:1](=O)([O:3]CC)[NH2:2].CC([O-])(C)C.[K+].[CH3:13][C@:14]1([CH2:22][N:23]2[C:27]3[CH:28]=[C:29]([C:32]#[N:33])[CH:30]=[CH:31][C:26]=3[N:25]=[CH:24]2)[CH2:21][CH2:20][CH2:19][C@:16]2([O:18][CH2:17]2)[CH2:15]1.[OH-].[Na+]>CN1C(=O)CCC1.CCOC(C)=O>[CH3:13][C@:14]1([CH2:22][N:23]2[C:27]3[CH:28]=[C:29]([C:32]#[N:33])[CH:30]=[CH:31][C:26]=3[N:25]=[CH:24]2)[CH2:21][CH2:20][CH2:19][C@:16]2([O:18][C:1](=[O:3])[NH:2][CH2:17]2)[CH2:15]1
Reactant: C[C@]1(Cn2cnc3ccc(C#N)cc32)CCC[C@@]2(CO2)C1
Reactant: CCOC(N)=O
Agent: CC(C)(C)[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: C[C@]1(Cn2cnc3ccc(C#N)cc32)CCC[C@@]2(CNC(=O)O2)C1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
A mixture of ethyl carbamate (0.237 g, 2.67 mmol) and KOtBu (0.259 g, 2.310 mmol) in NMP (8.89 mL) was heated at 100° C. for 15 min. 1-(((3S,5S)-5-methyl-1-oxaspiro[2.5]octan-5-ylmethyl)-1H-benzo[d]imidazole-6-carbonitrile (0.500 g, 1.777 mmol) was then added. The reaction mixture was stirred overnight (stopped heating at some point because of storm power outage). The reaction mixture was heated at 100° C. and stirred for an additional 6 h. Additional ethyl carbamate (0.237 g, 2.67 mmol) and KOtBu (0.065 g, 0.578 mmol) were added and stirred for 16 h. Additional ethyl carbamate (0.237 g, 2.67 mmol) and KOtBu (0.130 g, 1.156 mmol) were then added and heated at 110° C. for 16 h. The reaction mixture was heated at 130° C. for 2 days. Additional ethyl carbamate (0.237 g, 2.67 mmol) and KOtBu (0.065 g, 0.578 mmol) were added and mixture stirred for additional 3 h. The reaction mixture was heated at 110° C. for an additional 3 days, followed by the addition of 2N NaOH (30 mL) and EtOAc (75 mL). The layers were then separated and the organic layer washed with water (3×50 mL). The organic layer was dried over Na2SO4, filtered, and concentrated. The compound was loaded onto florisil and purified using silica gel chromatography CISCO): 1-3.5% MeOH/DCM (18 min), 3.5% (7 min), 25 g silica. Product eluted at 13 min. The product was dried under high vacuum at 40° C. overnight. 1-{[(5S,7S)-7-methyl-2-oxo-1-oxa-3-azaspiro[4.5]dec-7-yl]methyl}-1H-benzimidazole-6-carbonitrile was obtained as a white solid (336 mg, 55.4% yield). MS (m/z) 325 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][CH:3]=1.[C:10](Cl)([Cl:12])=[O:11]>>[Cl:12][C:10]([O:7][CH2:6][C:5]1[CH:8]=[CH:9][C:2]([Cl:1])=[CH:3][CH:4]=1)=[O:11]
Reactant: O=C(Cl)Cl
Reactant: OCc1ccc(Cl)cc1
Product: O=C(Cl)OCc1ccc(Cl)cc1

Procedure:
Prepared according to the procedure described in Example 56, Step 1, using the following starting materials: 4-chlorobenzyl alcohol and phosgene (20% in toluene).
Reaction SMILES: CO[C:3]1[CH:8]=[CH:7][C:6]([O:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[Cl:16])=[CH:5][C:4]=1[CH:17]([CH3:21])[C:18]([OH:20])=[O:19]>C(OC(=O)C)(=O)C.I>[CH3:21][CH:17]1[C:4]2[CH:5]=[C:6]([O:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[Cl:16])[CH:7]=[CH:8][C:3]=2[O:19][C:18]1=[O:20]
Reactant: COc1ccc(Oc2ccccc2Cl)cc1C(C)C(=O)O
Agent: I
Solvent: CC(=O)OC(C)=O
Product: CC1C(=O)Oc2ccc(Oc3ccccc3Cl)cc21
Yield: 73.3 %

Procedure:
A solution of 2-[2-methoxy-5-(2-chlorophenoxy)phenyl]propionic acid (3.2 g) in acetic anhydride (10 ml) and hydriodic acid (55-58%, 20 ml) were treated in a similar manner to that of Example 14-(8) to give oily 3-methyl-5-(2-chlorophenoxy)2,3-dihydrobenzofuran-2-one (2.1 g).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[C:12]([CH3:25])=[N:13][N:14]([CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=4)[C:15]=3[CH3:16])=[CH:9][N:8]([S:26]([C:29]3[CH:35]=[CH:34][C:32]([CH3:33])=[CH:31][CH:30]=3)(=[O:28])=[O:27])[C:5]2=[N:6][CH:7]=1.CC1(C)C(C)(C)OB([C:44]2[CH:49]=[CH:48][C:47]([C:50]3[CH:55]=[CH:54][N:53]=[CH:52][CH:51]=3)=[CH:46][CH:45]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.O>[F:24][C:20]1[CH:19]=[C:18]([CH:23]=[CH:22][CH:21]=1)[CH2:17][N:14]1[C:15]([CH3:16])=[C:11]([C:10]2[C:4]3[C:5](=[N:6][CH:7]=[C:2]([C:44]4[CH:45]=[CH:46][C:47]([C:50]5[CH:51]=[CH:52][N:53]=[CH:54][CH:55]=5)=[CH:48][CH:49]=4)[CH:3]=3)[N:8]([S:26]([C:29]3[CH:30]=[CH:31][C:32]([CH3:33])=[CH:34][CH:35]=3)(=[O:28])=[O:27])[CH:9]=2)[C:12]([CH3:25])=[N:13]1
Reactant: CC1(C)OB(c2ccc(-c3ccncc3)cc2)OC1(C)C
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3c(C)nn(Cc4cccc(F)c4)c3C)c3cc(Br)cnc32)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: Cc1ccccc1
Product: Cc1ccc(S(=O)(=O)n2cc(-c3c(C)nn(Cc4cccc(F)c4)c3C)c3cc(-c4ccc(-c5ccncc5)cc4)cnc32)cc1
Yield: 70.8 %

Procedure:
Using similar reaction conditions as described in step-ii of example-1, 5-bromo-3-(1-(3-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine (step-i of example-14) (150 mg, 0.27 mmol) was coupled with 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyridine (intermediate 45) (91.44 mh, 0.32 mmol) in sodium carbonate (85.86, 0.81 mmol), toluene/ethanol/water (5/5/2 ml). This afforded 120 mg (70.5% yield) of the titled compound.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH:14]=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:16][Mg]Br.O>O1CCCC1>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH:14]([OH:15])[CH3:16])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[Mg]Br
Reactant: CC(C)(C)OC(=O)NCCCCCC=O
Solvent: O
Solvent: C1CCOC1
Product: CC(O)CCCCCNC(=O)OC(C)(C)C
Reaction time: 2 h

Procedure:
Under argon atmosphere, a solution of 650 mg of 6-tert-butoxycarbonylaminohexanal in 10 mL of anhydrous tetrahydrofuran was cooled to −78° C., and treated dropwise with 6.8 mL of methylmagnesium bromide (a 1.0 M solution in tetrahydrofuran). After 2 hours, the reaction solution was combined with water, extracted with ethyl acetate, and dried. After concentrating, the residue was purified by column chromatography on silica gel (n-hexane:ethyl acetate=2:1) to obtain 280 mg of the desirable compound.
Reaction SMILES: [C:1]12([C:11]3[C:12]([OH:32])=[CH:13][C:14]([OH:31])=[C:15]([CH:30]=3)[C:16]([NH:18][CH2:19][C:20]3[CH:25]=[C:24]([O:26][CH3:27])[CH:23]=[C:22]([O:28]C)[CH:21]=3)=[O:17])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.B(Br)(Br)Br.CO>ClCCl>[C:1]12([C:11]3[C:12]([OH:32])=[CH:13][C:14]([OH:31])=[C:15]([CH:30]=3)[C:16]([NH:18][CH2:19][C:20]3[CH:25]=[C:24]([O:26][CH3:27])[CH:23]=[C:22]([OH:28])[CH:21]=3)=[O:17])[CH2:8][CH:7]3[CH2:9][CH:3]([CH2:4][CH:5]([CH2:6]3)[CH2:10]1)[CH2:2]2
Reactant: COc1cc(CNC(=O)c2cc(C34CC5CC(CC(C5)C3)C4)c(O)cc2O)cc(OC)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CO
Product: COc1cc(O)cc(CNC(=O)c2cc(C34CC5CC(CC(C5)C3)C4)c(O)cc2O)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 17.2 %

Procedure:
5-Adamantan-1-yl-N-(3,5-dimethoxybenzyl)-2,4-dihydroxybenzamide (0.27 g) is dissolved in dichloromethane (3 mL). After adding BBr3 (1.7 mL in CH2Cl2 1.0 M solution, 3 eq.) and stirring at room temperature for 2 hours, methanol (5 mL) is added and extraction is carried out using water and dichloromethane. The organic layer is dried with anhydrous magnesium sulfate, filtered, concentrated under reduced pressure and separated by column chromatography to obtain 0.045 g of the target compound as white solid.
Reaction SMILES: CS(Cl)(=O)=O.[F:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]([CH2:18]O)[C:14]([O:16][CH3:17])=[O:15])=[CH:9][CH:8]=1.FC1C=CC(C(=C)C(OC)=O)=CC=1.[CH:33]([NH2:36])([CH3:35])[CH3:34]>C1COCC1.CCOCC.CCOC(C)=O>[F:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]([CH2:18][NH:36][CH:33]([CH3:35])[CH3:34])[C:14]([O:16][CH3:17])=[O:15])=[CH:9][CH:8]=1
Reactant: COC(=O)C(CO)c1ccc(F)cc1
Reactant: CC(C)N
Agent: C=C(C(=O)OC)c1ccc(F)cc1
Agent: CS(=O)(=O)Cl
Solvent: CCOCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)C(CNC(C)C)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 99.4 %

Procedure:
Methanesulfonyl chloride (1.230 mL, 15.89 mmol) and TEA (4.642 mL, 33.30 mmol) was added to a stirred solution of methyl 2-(4-fluorophenyl)-3-hydroxypropanoate (3 g, 15.14 mmol) in THF (150 mL) at 0° C. under nitrogen. The reaction mixture was allowed to warm to room temperature and stirred at room temperature for 2 days. The resulting suspension was diluted with Et2O (200 mL), filtered and concentrated in vacuo to give a colorless oil containing the intermediate compound, methyl 2-(4-fluorophenyl)acrylate. 1H NMR (CDCl3, 400 MHz) 7.39 (dd, J 8.4 and 5.4 Hz, 2H), 7.04 (app. t, J=8.6 Hz, 2H), 6.36 (s, 1H), 5.87 (s, 1H), 3.83 (s, 1H.) The methyl 2-(4-fluorophenyl)acrylate was taken up into THF (150 mL) and treated with isopropylamine (6.446 mL, 75.68 mmol). The reaction mixture was stirred at room temperature for 2 hours, diluted with EtOAc (200 mL), washed with saturated aqueous bicarbonate (100 mL), dried over Na2SO4 and concentrated in vacuo to give pure methyl 2-(4-fluorophenyl)-3-(isopropylamino)propanoate (3.6 g, 99.39% yield). LCMS (APCI+) [M+H]+ 240.
Reaction SMILES: [CH2:1]([N:8]([CH2:19][C:20]1[CH:33]=[CH:32][C:23]([O:24][C:25]2[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=2)=[CH:22][CH:21]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[C:10]=1[CH3:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:34]([O:38][CH2:39][CH3:40])(=[O:37])[CH2:35]O>>[CH2:1]([N:8]([CH2:19][C:20]1[CH:33]=[CH:32][C:23]([O:24][C:25]2[CH:26]=[CH:27][C:28]([O:31][CH2:35][C:34]([O:38][CH2:39][CH3:40])=[O:37])=[CH:29][CH:30]=2)=[CH:22][CH:21]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[C:10]=1[CH3:18])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)CO
Reactant: Cc1c(N(Cc2ccccc2)Cc2ccc(Oc3ccc(O)cc3)cc2)cccc1[N+](=O)[O-]
Product: CCOC(=O)COc1ccc(Oc2ccc(CN(Cc3ccccc3)c3cccc([N+](=O)[O-])c3C)cc2)cc1

Procedure:
The product from Example 60E and ethyl glycolate were processed as described in Example 62A to provide the title compound. MS (ESI+) m/z 527 (M+H)+.