Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:9]1[C:13]([S:14]C(=O)C2C=CC=CC=2)=[CH:12][N:11]([Si](C(C)C)(C(C)C)C(C)C)[CH:10]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].Cl.[CH2:36]([C:40]1([CH2:43][CH3:44])[CH2:42][NH:41]1)[CH2:37][CH2:38][CH3:39]>C(OCC)(=O)C.CO>[C:1]([C:9]1[C:13]([S:14][CH2:42][C:40]([NH2:41])([CH2:43][CH3:44])[CH2:36][CH2:37][CH2:38][CH3:39])=[CH:12][NH:11][CH:10]=1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1cc(SC(=O)c2ccccc2)c(C(=O)c2ccccc2)c1
Reactant: CCCCC1(CC)CN1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Product: CCCCC(N)(CC)CSc1c[nH]cc1C(=O)c1ccccc1
Yield: 86.3 %

Procedure:
A mixture of the product from step (c) (24.9 g), 250 ml methanol and 106 ml 1N sodium hydroxide was warmed to reflux for 10 minutes then 1N hydrochloric acid (53 ml) was added followed by 2-butyl-2-ethylaziridine (7.7 g, Synthetic Example 1(f)). After one hour the reaction was diluted with ethyl acetate and washed with 1N sodium hydroxide and then water. The organic layer was dried, filtered and concentrated. The residue was chromatographed on silica gel eluting with ethyl acetate-ethanol (3:1) to give a tan viscous oil (15.32 g). 1H NMR is consistent with proposed structure.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[C:6]([Cl:8])[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].CN1CCCC1=O.[Cl:23][C:24]1[C:29](F)=[C:28]([C:31]([F:34])([F:33])[F:32])[CH:27]=[CH:26][N:25]=1>O>[Cl:23][C:24]1[C:29]([O:9][C:4]2[CH:3]=[C:2]([Cl:1])[CH:7]=[C:6]([Cl:8])[CH:5]=2)=[C:28]([C:31]([F:32])([F:33])[F:34])[CH:27]=[CH:26][N:25]=1
Reactant: Oc1cc(Cl)cc(Cl)c1
Reactant: Fc1c(C(F)(F)F)ccnc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: O
Product: FC(F)(F)c1ccnc(Cl)c1Oc1cc(Cl)cc(Cl)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a round bottom flask charged with 3,5-dichlorophenol (1.23 g, 7.52 mmol) and potassium carbonate (1.04 g, 7.52 mmol) was added N-methylpyrrolidinone (5 mL). To this suspension under N2 was added 2-chloro-3-fluoro-4-(trifluoromethyl)pyridine (1.50 g, 7.52 mmol) and the reaction mixture was placed in an oil bath at 120° C. After 60 minutes, the reaction mixture was allowed to cool to room temperature, water (20 mL) was added and the mixture was extracted with ethyl acetate (2×25 mL). The combined organic extracts were washed with brine (3×25 mL), dried (MgSO4), filtered and the solvent was evaporated under reduced pressure. The resulting residue was purified by column chromatography on a pre-packed silica gel Redi Sep 80 gram column, eluting with 0-75% CH2Cl2 in hexanes to afford the title compound. 1H NMR (DMSO-d6) δ 8.52 (d, J=4.5 Hz, 1H), 7.60 (d, J=4.6 Hz, 1H), 7.14-7.10 (m, 1H), 6.72-6.68 (m, 2H). HRMS (M+1)=341.9465.
Reaction SMILES: [Cl:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[C:7]([S:12](=[O:15])(=[O:14])[NH2:13])[CH:6]=1)=[O:4].[CH3:16][NH:17][C:18]([NH:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=1)=[S:19]>>[ClH:1].[Cl:11][C:8]1[CH:9]=[CH:10][C:5]([C:3]2([OH:4])[CH2:2][S:19][C:18](=[N:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=3)[N:17]2[CH3:16])=[CH:6][C:7]=1[S:12](=[O:15])(=[O:14])[NH2:13]
Reactant: NS(=O)(=O)c1cc(C(=O)CCl)ccc1Cl
Reactant: CNC(=S)NCc1ccccn1
Product: CN1C(=NCc2ccccn2)SCC1(O)c1ccc(Cl)c(S(N)(=O)=O)c1
Product: Cl

Procedure:
5.2 g of 2,4'-dichloro-3'-sulfamoylacetophenone and 3.5 g of 1-methyl-3-(2-pyridylmethyl)-thiourea were reacted as prescribed in Example 12 and the end product was precipitated with 400 ml of ethyl acetate while stirring. Colorless crystals, melting point 152° C. (decomposition) γC=N 1620 cm-1.
Reaction SMILES: [CH3:1][O:2][CH2:3][C@H:4]1[O:8][C@@H:7]([N:9]2[C:18]3[N:17]=[CH:16][N:15]=[C:13]([NH2:14])[C:12]=3[N:11]=[CH:10]2)[C@H:6]([OH:19])[C@@H:5]1[OH:20].[N+](=[CH2:23])=[N-]>>[CH3:23][C@@:6]1([OH:19])[C@H:5]([OH:20])[C@@H:4]([CH2:3][O:2][CH3:1])[O:8][C@H:7]1[N:9]1[C:18]2[N:17]=[CH:16][N:15]=[C:13]([NH2:14])[C:12]=2[N:11]=[CH:10]1.[CH3:23][C@@:5]1([OH:20])[C@@H:4]([CH2:3][O:2][CH3:1])[O:8][C@@H:7]([N:9]2[C:18]3[N:17]=[CH:16][N:15]=[C:13]([NH2:14])[C:12]=3[N:11]=[CH:10]2)[C@@H:6]1[OH:19]
Reactant: C=[N+]=[N-]
Reactant: COC[C@H]1O[C@@H](n2cnc3c(N)ncnc32)[C@H](O)[C@@H]1O
Product: COC[C@H]1O[C@@H](n2cnc3c(N)ncnc32)[C@H](O)[C@]1(C)O
Product: COC[C@H]1O[C@@H](n2cnc3c(N)ncnc32)[C@](C)(O)[C@@H]1O

Procedure:
In the same manner as Example 1 [METHOD 1], 5'-O-methyladenosine was methylated by using diazomethane and separated by ion exchange column chromatography to give 2',5'-O-dimethyladenosine (Compound 13) and 3',5'-O-dimethyladenosine (Compound 14).
Reaction SMILES: [C:1]1([CH3:9])[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][OH:8])[CH:2]=1.[C:10](=[O:13])([O-])[O-].[K+].[K+].O.[C:17](OCC)(=O)[CH3:18]>CN(C)C=O>[C:1]1([CH3:9])[CH:6]=[CH:5][CH:4]=[C:3]([N:7]2[C:10](=[O:13])[CH2:18][CH2:17][O:8]2)[CH:2]=1
Reactant: O=C([O-])[O-]
Reactant: CCOC(C)=O
Reactant: Cc1cccc(NO)c1
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cccc(N2OCCC2=O)c1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 73 %

Procedure:
3-Chloro-propionyl (157 μL, 1.65 mmol) was added to a mixture of N-m-tolyl-hydroxylamine (235 mg, 1.69 mmol) and potassium carbonate (223 mg, 1.69 mmol) in N,N-dimethylformamide (1.7 mL) at −10° C. The mixture was stirred at room temperature for 2.5 hours, and water and ethyl acetate were then added. The organic layer and the aqueous layer were separated, and the aqueous layer was repeatedly extracted with ethyl acetate three times. The organic layers were combined, washed with water twice and saturated brine, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give 2-m-tolyl-isoxazolidin-3-one as a pale yellow solid (213 mg, 73%).
Reaction SMILES: C(OC=CC[S:8]C)(=O)C.C(O)C.[C]=O.[C:15]([O:18][CH:19]([CH2:25][CH2:26][S:27][CH3:28])[C:20]([O:22][CH2:23]C)=O)(=[O:17])[CH3:16]>O1CCCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1(C)C=CC=CC=1>[C:15]([O:18][CH:19]([CH2:25][CH2:26][S:27][CH3:28])[C:20]([O:22][CH3:23])=[S:8])(=[O:17])[CH3:16]
Reactant: CSCC=COC(C)=O
Reactant: CCOC(=O)C(CCSC)OC(C)=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [C]=O
Solvent: CCO
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: COC(=S)C(CCSC)OC(C)=O
Temperature: 100 °C
Yield: 10.8 %

Procedure:
0.5 mmoles 1-acetoxy-3-methylthiopropene, (Z: E ratio 43:57), and 2.5 mmoles ethanol were charged into a 71 cc stainless steel bomb equipped with a glass liner and a Teflon coated stir bar. Ten mole percent, based on 1-acetoxy-3-methylthiopropene, of a catalyst comprising bis(triphenylphosphine)dichloropalladium, (φ3P )2PdCl2, was added. Toluene was included as an internal standard. Five milliliters of tetrahydrofuran as a solvent were also included in the reaction system. The reaction mixture was charged under argon. The bomb was sealed and carbon monoxide at a pressure of 1000 psi (at room temperature) was charged to the bomb, and the bomb was heated to 100° C. and allowed to react for 44 hours with stirring. At the termination of the reaction, the reaction products were analyzed by gas chromatography and it was found that 2-acetoxy-4-(methylthio)butanoic acid, ethyl ester was produced in a yield of 10.5 percent, and that 2-acetoxy-4-(methylthio)thiobutanoic acid, methyl ester, was produced in a yield of 10.8 percent, based on the 1-acetoxy-3-methylthiopropene reactant charged. Note that each of the products is hydrolyzable to methionine hydroxy analog.
Reaction SMILES: [F:1][C:2]1([F:46])[CH2:7][CH2:6][CH:5]([C:8]2[C:17]3[C@@H:16]([OH:18])[CH2:15][C:14]([CH3:20])([CH3:19])[CH2:13][C:12]=3[N:11]=[C:10]([CH:21]3[CH2:26][CH2:25][N:24]([C:27]4[N:32]=[CH:31][C:30]([OH:33])=[CH:29][N:28]=4)[CH2:23][CH2:22]3)[C:9]=2[C@@H:34]([F:45])[C:35]2[CH:40]=[CH:39][C:38]([C:41]([F:44])([F:43])[F:42])=[CH:37][CH:36]=2)[CH2:4][CH2:3]1.C1(C)C=CC(S(O[CH2:57][C@@H:58]2[CH2:62][O:61][C:60]([CH3:64])([CH3:63])[O:59]2)(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[F:46][C:2]1([F:1])[CH2:3][CH2:4][CH:5]([C:8]2[C:17]3[C@@H:16]([OH:18])[CH2:15][C:14]([CH3:19])([CH3:20])[CH2:13][C:12]=3[N:11]=[C:10]([CH:21]3[CH2:22][CH2:23][N:24]([C:27]4[N:32]=[CH:31][C:30]([O:33][CH2:57][C@@H:58]5[CH2:62][O:61][C:60]([CH3:64])([CH3:63])[O:59]5)=[CH:29][N:28]=4)[CH2:25][CH2:26]3)[C:9]=2[C@@H:34]([F:45])[C:35]2[CH:36]=[CH:37][C:38]([C:41]([F:43])([F:42])[F:44])=[CH:39][CH:40]=2)[CH2:6][CH2:7]1
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H]2COC(C)(C)O2)cc1
Reactant: CC1(C)Cc2nc(C3CCN(c4ncc(O)cn4)CC3)c([C@@H](F)c3ccc(C(F)(F)F)cc3)c(C3CCC(F)(F)CC3)c2[C@@H](O)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC1(C)Cc2nc(C3CCN(c4ncc(OC[C@@H]5COC(C)(C)O5)cn4)CC3)c([C@@H](F)c3ccc(C(F)(F)F)cc3)c(C3CCC(F)(F)CC3)c2[C@@H](O)C1
Temperature: 90 °C
Reaction time: 5 h
Yield: 82 %

Procedure:
To a solution of 95.0 mg (0.146 mmol) of (5S)-4-(4,4-Difluorocyclohexyl)-3-{(S)-fluoro[4-(trifluoromethyl)phenyl]methyl}-2-[1-(5-hydroxypyrimidin-2-yl)piperidin-4-yl]-7,7-dimethyl-5,6,7,8-tetrahydroquinolin-5-ol, which was prepared by a method similar to that of Reference Example 23, in 0.4 ml of N,N-dimethylformamide, 92.4 mg (0.322 mmol) of (S)-2,2-dimethyl-1,3-dioxolan-4-ylmethyl p-toluenesulfonate and 54.2 mg (0.392 mmol) of potassium carbonate were added, and the mixture was stirred at 90° C. for 5 hours. After completion of the reaction, the reaction solution was poured into water and extracted with toluene twice. The obtained organic phases were combined and washed with saturated sodium chloride aqueous solution, and then the solvent was distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography [n-hexane/ethyl acetate=80/20-59/41 (V/V)] and the fraction including the desired compound was concentrated under reduced pressure to provide 91.3 mg of the title compound as a white solid (yield: 82%).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([NH:9][C:10](=[O:18])[C:11]2[CH:16]=[C:15]([CH3:17])[CH:14]=[N:13][CH:12]=2)[CH:6]=[CH:7][CH:8]=1)=O.Cl.[CH:20]1([NH:26][C:27]([C:29]2([F:35])[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)=[O:28])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1.CCN(C(C)C)C(C)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[CH:20]1([NH:26][C:27]([C:29]2([F:35])[CH2:34][CH2:33][N:32]([CH2:1][C:3]3[CH:4]=[C:5]([NH:9][C:10](=[O:18])[C:11]4[CH:16]=[C:15]([CH3:17])[CH:14]=[N:13][CH:12]=4)[CH:6]=[CH:7][CH:8]=3)[CH2:31][CH2:30]2)=[O:28])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]1
Reactant: Cc1cncc(C(=O)Nc2cccc(C=O)c2)c1
Reactant: O=C(NC1CCCCC1)C1(F)CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1cncc(C(=O)Nc2cccc(CN3CCC(F)(C(=O)NC4CCCCC4)CC3)c2)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of N-(3-formyl-phenyl)-5-methyl-nicotinamide L-1 (60 mg, 0.25 mmol) and 4-fluoro-piperidine-4-carboxylic acid cyclohexylamide hydrochloride (66 mg, 0.25 mmol) in DCM (3 mL) is treated with DIPEA (0.128 mL, 0.75 mmol). Sodium triacetoxyborohydride (132 mg, 0.62 mmol) is added at once and the mixture is stirred at RT for 18 h. The mixture is diluted with DCM (5 mL) and washed twice with aq. sat. NaHCO3 (5 mL). The organic phase is dried over MgSO4 and evaporated. The residue is dissolved in acetonitrile and purified by prep HPLC E, delivering the title compound as a colorless powder, LC-MS A: tR=0.62 min; [M+H]+=453.4. 1H-NMR (CDCl3): δ 1-1.4 (m, 5H), 1.6-1.8 (m, 6H), 1.9-2.1 (m, 2H), 2.2-2.4 (m, 4H), 3.45 (s, 3H), 2.7-2.8 (m, 2H), 3.7-3.8 (m, 1H), 6.28 (t, J=6.5, 1H), 7.15 (d, J=8, 1H), 7.35 (t, J=8, 1H), 7.55 (s, 1H), 7.73 (d, J=8, 1H), 8.05 (s, 1H), 8.12 (s, 1H), 8.61 (s, 1H), 8.93 (s, 1H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][CH:7]([N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)[CH2:6][CH2:5]2.[NH:18]1[CH2:22][CH2:21][CH2:20][C@H:19]1[CH2:23][N:24]1[CH2:28][CH2:27][CH2:26][CH2:25]1.BrC1C=C2C(=CC=1)C[C:35](=[O:40])CC2.N1CCOCC1>>[N:12]1([CH:7]2[CH2:6][CH2:5][C:4]3[CH:3]=[C:2]([C:35]([N:18]4[CH2:22][CH2:21][CH2:20][CH:19]4[CH2:23][N:24]4[CH2:28][CH2:27][CH2:26][CH2:25]4)=[O:40])[CH:11]=[CH:10][C:9]=3[CH2:8]2)[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1
Reactant: C1CN[C@H](CN2CCCC2)C1
Reactant: Brc1ccc2c(c1)CCC(N1CCOCC1)C2
Reactant: O=C1CCc2cc(Br)ccc2C1
Solvent: C1COCCN1
Product: O=C(c1ccc2c(c1)CCC(N1CCOCC1)C2)N1CCCC1CN1CCCC1

Procedure:
(6-Morpholin-4-yl-5,6,7,8-tetrahydro-naphthalen-2-yl)-(2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-methanone is prepared from 4-(6-bromo-1,2,3,4-tetrahydro-naphthalen-2-yl)-morpholine and (S)-(+)-1-(2-pyrrolidinylmethyl)-pyrrolidine in a manner substantially analogous to Procedure A. (See herein Example 1). Starting material, 4-(6-bromo-1,2,3,4-tetrahydro-naphthalen-2-yl)-morpholine, was prepared from 6-bromo-2-tetralone and morpholine in a manner substantially analogous to Preparation 1. Mass spectrum (APCI): 389 (M++1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]=[C:10]=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8].[NH2:12][C:13]1[S:14][C:15]2[C:21]([Cl:22])=[C:20]([Cl:23])[CH:19]=[C:18]([S:24][C:25]#[N:26])[C:16]=2[N:17]=1>CN(C)C=O>[Cl:23][C:20]1[CH:19]=[C:18]([S:24][C:25]#[N:26])[C:16]2[N:17]=[C:13]([NH:12][C:10]([NH:9][C:4]3[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=3)=[O:11])[S:14][C:15]=2[C:21]=1[Cl:22]
Reactant: O=C=Nc1ccc(Cl)c(Cl)c1
Reactant: N#CSc1cc(Cl)c(Cl)c2sc(N)nc12
Solvent: CN(C)C=O
Product: N#CSc1cc(Cl)c(Cl)c2sc(NC(=O)Nc3ccc(Cl)c(Cl)c3)nc12

Procedure:
3,4-Dichlorophenyl isocyanate (18.8 g., 0.10 mole) was added in portions to a solution of 27.6 g. (0.10 mole) of 2-amino-6,7-dichloro-4-thiocyanatobenzothiazole in 200 ml. of dimethylformamide. The solution was heated at 110° for 5 hours with stirring and cooled at 0° overnight. The solid was collected by filtration to give 28 g. (60%) of product. Two recrystallizations from ethanol gave 13 g. (28%) of analytical material, m.p. 313°-320° (dec.).
Reaction SMILES: Cl.[NH2:2][CH:3]([C:7]([CH3:11])([CH3:10])[CH2:8][CH3:9])[C:4]([OH:6])=[O:5].C(N(C(C)C)CC)(C)C.[CH3:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([S:29](Cl)(=[O:31])=[O:30])=[CH:25][CH:24]=1.CN(C=O)C>C1COCC1>[CH3:21][O:22][C:23]1[CH:24]=[CH:25][C:26]([S:29]([NH:2][CH:3]([C:7]([CH3:11])([CH3:10])[CH2:8][CH3:9])[C:4]([OH:6])=[O:5])(=[O:31])=[O:30])=[CH:27][CH:28]=1
Reactant: CCC(C)(C)C(N)C(=O)O
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCC(C)(C)C(NS(=O)(=O)c1ccc(OC)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 4.1 %

Procedure:
2-amino-3,3-dimethylpentanoic acid hydrochloride (1.63 g), (JCS Chem. Comm. 11, 830-1992) is mixed with diisopropylethylamine (3.6 g, 3.1 equivalent) in dry THF (100 mL). The 4-methoxybenzenesulfonyl chloride (1.86 g, 1 equivalent) is added as a solid. DMF (25 mL) is added to the resulting suspension. After stirring overnight at room temperature the solvents are removed under vacuum. The residue is partitioned between ethyl acetate (200 mL) and 1N HCl (100 mL). The organic phase is separated and the aqueous phase extracted with several more portions of ethyl acetate. The combined organic phases are washed with 1N HCl and then brine. The organic phase are dried (MgSO4), filtered, and concentrated under reduced pressure. The resulting crude product is loaded onto a reverse phase column as a DMSO solution. The column is eluted using a step gradient (10% increments), starting with 30% acetonitrile/water and ending at 90% acetonitrile/water. Combination of the appropriate fractions gave 116 mg of the title compound.
Reaction SMILES: C(O)(=O)C.[N:5]1([C:14]2([CH2:19][C:20]([NH2:22])=[NH:21])[CH2:18][CH2:17][CH2:16][CH2:15]2)[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[CH:7]=[CH:6]1.[C:23]([O:27][C:28](=[O:43])/[C:29](/O)=[C:30](\[O:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)/[C:31](O)=[O:32])([CH3:26])([CH3:25])[CH3:24].C[O-].[Na+].C(OCC)(=O)C>CO>[C:23]([O:27][C:28]([C:29]1[C:30]([O:34][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[C:31]([OH:32])[N:22]=[C:20]([CH2:19][C:14]2([N:5]3[C:9]4=[N:10][CH:11]=[CH:12][CH:13]=[C:8]4[CH:7]=[CH:6]3)[CH2:18][CH2:17][CH2:16][CH2:15]2)[N:21]=1)=[O:43])([CH3:26])([CH3:24])[CH3:25]
Reactant: CC(C)(C)OC(=O)/C(O)=C(\OCc1ccccc1)C(=O)O
Reactant: N=C(N)CC1(n2ccc3cccnc32)CCCC1
Agent: C[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)c1nc(CC2(n3ccc4cccnc43)CCCC2)nc(O)c1OCc1ccccc1
Temperature: 25 °C
Yield: 75.4 %

Procedure:
To a stirred solution of 2-(1-pyrrolo[2,3-b]pyridin-1-yl-cyclopentyl)-acetamidine; compound with acetic acid (402) (800 mg, 2.65 mmol) and (E)-3-benzyloxy-2-hydroxy-4-oxo-pent-2-enoic acid tert-butyl ester (4) (978 mg, 3.18 mmol) in methanol (80 mL) was added sodium methoxide solution (25% in methanol) (1.7 mL, 7.94 mmol) at 0° C. The reaction mixture was allowed to warm slowly to room temperature and was stirred for 16 h (TLC, ethyl acetate, Rf=0.3). After completion of the reaction, methanol was evaporated to get a crude product which was purified by Combi-Flash column (eluted at 60-70% ethyl acetate in hexane) to get 5-benzyloxy-6-hydroxy-2-(1-pyrrolo[2,3-b]pyridin-1-yl-cyclopentylmethyl)-pyrimidine-4-carboxylic acid tert-butyl ester (403) (1 g, 75%) as a light yellow solid.
Reaction SMILES: Br[C:2]1[CH:21]=[CH:20][C:5]([CH2:6][C:7]2[N:12]=[C:11]([C:13]3[CH:18]=[CH:17][C:16](Br)=[CH:15][CH:14]=3)[CH:10]=[CH:9][N:8]=2)=[CH:4][CH:3]=1.[Cu][C:23]#[N:24].[CH3:25][N:26]1CCCC1=O>>[C:25]([C:2]1[CH:21]=[CH:20][C:5]([CH2:6][C:7]2[N:12]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([C:23]#[N:24])=[CH:15][CH:14]=3)[CH:10]=[CH:9][N:8]=2)=[CH:4][CH:3]=1)#[N:26]
Reactant: Brc1ccc(Cc2nccc(-c3ccc(Br)cc3)n2)cc1
Reactant: N#C[Cu]
Reactant: CN1CCCC1=O
Product: N#Cc1ccc(Cc2nccc(-c3ccc(C#N)cc3)n2)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A mixture of 2-(4-bromobenzyl)-4-(4-bromophenyl)pyrimidine (8.8 g, 0.02 mole) and copper(I) cyanide (4.45 g, 0.05 mole) in 25 mL dry N-methyl-2-pyrrolidone is heated under nitrogen for 3-4 hr (TLC followed), during which time the color changes to dark brown. The mixture is poured into 250 mL ice cold water and a brown solid precipitated. The mixture is stirred for 2 hr with 200 mL of 10% NaCN solution; the solid is filtered, washed with water (1 L) and dried. The brown solid is placed in a soxlet device and treated with ethanol for 36 hr. The solvent is removed, the light brown solid chromatographed over neutral aluminumoxide, elution is with ether:CHCl3 (8:2) (20×50 mL fractions). Evaporation of the solvent yields a white solid which is dried in vacuo at 100° C. for 6-7 hr to give 2.3 g (39%), mp 155°-156° C.
Reaction SMILES: [H-].[Na+:2].[CH3:3][C:4]([CH3:33])([CH3:32])[C:5]#[C:6][C:7]1[S:11][C:10]([C:12]([OH:14])=[O:13])=[C:9]([N:15]([CH:25]2[CH2:30][CH2:29][CH:28]([OH:31])[CH2:27][CH2:26]2)[C:16]([CH:18]2[CH2:23][CH2:22][CH:21]([CH3:24])[CH2:20][CH2:19]2)=[O:17])[CH:8]=1.[N:34]1([C:38]([C:40]2[CH:45]=[CH:44][N:43]=[C:42](Cl)[CH:41]=2)=[O:39])[CH2:37][CH2:36][CH2:35]1.[OH-].[Na+]>CN(C=O)C>[N:34]1([C:38]([C:40]2[CH:45]=[CH:44][N:43]=[C:42]([O:31][CH:28]3[CH2:29][CH2:30][CH:25]([N:15]([C:9]4[CH:8]=[C:7]([C:6]#[C:5][C:4]([CH3:32])([CH3:3])[CH3:33])[S:11][C:10]=4[C:12]([O-:14])=[O:13])[C:16]([CH:18]4[CH2:23][CH2:22][CH:21]([CH3:24])[CH2:20][CH2:19]4)=[O:17])[CH2:26][CH2:27]3)[CH:41]=2)=[O:39])[CH2:37][CH2:36][CH2:35]1.[Na+:2]
Reactant: O=C(c1ccnc(Cl)c1)N1CCC1
Reactant: CC1CCC(C(=O)N(c2cc(C#CC(C)(C)C)sc2C(=O)O)C2CCC(O)CC2)CC1
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CC1CCC(C(=O)N(c2cc(C#CC(C)(C)C)sc2C(=O)[O-])C2CCC(Oc3cc(C(=O)N4CCC4)ccn3)CC2)CC1
Temperature: 25 °C
Yield: 77 %

Procedure:
NaH (60 mg of a 60% oil dispersion, 1.50 mmol) was added in portions to a solution of 5-(3,3-dimethyl-but-1-ynyl)-3-[(4-hydroxy-cyclohexyl)-(4-methyl-cyclohexanecarbonyl)-amino]-thiophene-2-carboxylic acid (130 mg, 0.291 mmol) and azetidin-1-yl-(2-chloro-pyridin-4-yl)-methanone from the previous step (290 mg, 1.47 mmol) in DMF (3.0 mL) at 0° C. After 30 min the reaction was warmed to room temperature and then heated at 85° C. for 3.5 h. The reaction was cooled, aqueous NaOH (0.5 mL of a 1.0 N solution) was added and the reaction evaporated to dryness to give a solid residue. The solid was purified by column chromatography on reverse phase C18 silica gel (100% water to 20% acetonitrile/water). Fractions containing product were pooled and lyophilized to give the desired product as a colorless solid (140 mg, 77%). HPLC retention time: 6.41 min (2-98% acetonitrile:water with 0.05% trifluoroacetic acid).
Reaction SMILES: C1(C2C=CC=CC=2CO)C2C(=CC=CC=2)C=CC=1.[CH3:19][O:20][C:21]1[CH:36]=[CH:35][C:24]([C:25]([C:27]2[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=2)=[O:26])=[CH:23][CH:22]=1.[BH4-].[Na+]>>[CH3:34][O:33][C:30]1[CH:29]=[CH:28][C:27]([CH:25]([C:24]2[CH:35]=[CH:36][C:21]([O:20][CH3:19])=[CH:22][CH:23]=2)[OH:26])=[CH:32][CH:31]=1
Reactant: COc1ccc(C(=O)c2ccc(OC)cc2)cc1
Agent: OCc1ccccc1-c1cccc2ccccc12
Agent: [BH4-]
Agent: [Na+]
Product: COc1ccc(C(O)c2ccc(OC)cc2)cc1

Procedure:
With the same method as for Compound 13, 4,4′-dimethoxybenzophenone (Aldrich) and sodium borohydride (Wako Pure Chemical Industries, ltd.) were used, to thereby obtain the title compound.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]([Cl:11])[C:8]([F:12])=[C:7]([CH3:13])[C:3]=1[C:4](O)=[O:5].CN(C)C=O.C(Cl)(=O)C([Cl:22])=O>ClCCl>[Cl:1][C:2]1[N:10]=[C:9]([Cl:11])[C:8]([F:12])=[C:7]([CH3:13])[C:3]=1[C:4]([Cl:22])=[O:5]
Reactant: O=C(Cl)C(=O)Cl
Reactant: Cc1c(F)c(Cl)nc(Cl)c1C(=O)O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1c(F)c(Cl)nc(Cl)c1C(=O)Cl
Reaction time: 1 h
Yield: 88.7 %

Procedure:
A slurry of 30.8 g (0.147 moles) of 2,6-dichloro-4-methyl-5-fluoronicotinic acid in 200 mL of dichloromethane, containing a catalytic amount of dimethyl formamide, was treated dropwise over a 1-hour period with 19.2 mL (0.22 moles) oxalyl chloride. After 1 hour, the homogenous solution was evaporated in vacuo, diluted with an equal volume of dichloromethane, and evaporated in vacuo to yield 31.6 g of the title compound as an oil.
Reaction SMILES: [OH:1][C@@H:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C@@:3]1([CH2:20][C:21]1[CH:29]=[CH:28][C:24]([C:25](O)=[O:26])=[CH:23][CH:22]=1)[C:11]1[CH2:12][C:13]2[C:18]([CH:19]=1)=[CH:17][CH:16]=[CH:15][CH:14]=2.CC(OC(OC(OC(C)(C)C)=O)=O)(C)C.[N:45]1C=CC=CC=1.C(=O)(O)[O-].[NH4+]>CS(C)=O.O>[OH:1][C@@H:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C@@:3]1([CH2:20][C:21]1[CH:29]=[CH:28][C:24]([C:25]([NH2:45])=[O:26])=[CH:23][CH:22]=1)[C:11]1[CH2:12][C:13]2[C:18]([CH:19]=1)=[CH:17][CH:16]=[CH:15][CH:14]=2
Reactant: O=C(O)c1ccc(C[C@@]2(C3=Cc4ccccc4C3)Cc3ccccc3[C@H]2O)cc1
Reactant: c1ccncc1
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [NH4+]
Solvent: O
Solvent: CS(C)=O
Product: NC(=O)c1ccc(C[C@@]2(C3=Cc4ccccc4C3)Cc3ccccc3[C@H]2O)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 57.5 %

Procedure:
To a solution of 4-(((1S,2S)-1-hydroxy-2,3-dihydro-1H,1′H-[2,2′-biinden]-2-yl)methyl)benzoic acid (100 mg, 0.26 mmol) in DMSO (5 mL) was added Boc anhydride (69 mg, 0.31 mmol) followed by pyridine (24 mg, 0.26 mmol) and stirred at room temperature for 5 min. Ammonium bicarbonate (62 mg, 0.78 mmol) was added and stirred for additional 1 h. Reaction mixture was poured into water (25 mL) and extracted with ethyl acetate (3×25 mL). The organic layer was washed with brine (25 mL), dried over anhydrous Na2SO4 and evaporated under reduced pressure. The residue was purified by CombiFlash using 20% ethyl acetate in chloroform as an eluent to yield 57 mg (57%) of the title compound as an off white solid.