Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC(OC([N:8](C(OC(C)(C)C)=O)[N:9]([C:17]1[C:22]([F:23])=[C:21]([NH:24][CH2:25][CH2:26][C:27]2[CH:31]=[CH:30][S:29][CH:28]=2)[N:20]=[C:19]([Cl:32])[N:18]=1)C(OC(C)(C)C)=O)=O)(C)C.Cl>CO>[Cl:32][C:19]1[NH:20][C:21]([NH:24][CH2:25][CH2:26][C:27]2[CH:31]=[CH:30][S:29][CH:28]=2)=[C:22]([F:23])[C:17](=[N:9][NH2:8])[N:18]=1
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)N(C(=O)OC(C)(C)C)c1nc(Cl)nc(NCCc2ccsc2)c1F
Agent: Cl
Solvent: CO
Product: NN=c1nc(Cl)[nH]c(NCCc2ccsc2)c1F
Reaction time: 72 h
Yield: 12 %

Procedure:
Tris(1,1-dimethylethyl)2-(2-chloro-5-fluoro-6-{[2-(3-thienyl)ethyl]amino}-4-pyrimidinyl)-1,1,2-hydrazinetricarboxylate (2.389 g, 4.07 mmol) was dissolved in MeOH (25 mL) and HCl (4M in 1,4-dioxane) (25 mL) at room temperature. The reaction mixture was left to stir over 3 days, evaporated and purified by RP-HPLC to provide 2-chloro-5-fluoro-6-{[2-(3-thienyl)ethyl]amino}-4(1H)-pyrimidinone hydrazone as a brown sticky solid (0.1401 g). LCMS: (M+H)+=288.0.
Reaction SMILES: [OH:1][C:2]1[C:6]([CH2:7][C:8]([O:10][CH3:11])=[O:9])=[CH:5][N:4]([CH3:12])[N:3]=1.Cl[CH2:14][C:15]1[CH:34]=[CH:33][C:18]([O:19][CH2:20][C:21]2[N:22]=[C:23]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[O:24][C:25]=2[CH3:26])=[C:17]([O:35][CH3:36])[CH:16]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH3:36][O:35][C:17]1[CH:16]=[C:15]([CH:34]=[CH:33][C:18]=1[O:19][CH2:20][C:21]1[N:22]=[C:23]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[O:24][C:25]=1[CH3:26])[CH2:14][O:1][C:2]1[C:6]([CH2:7][C:8]([O:10][CH3:11])=[O:9])=[CH:5][N:4]([CH3:12])[N:3]=1
Reactant: COc1cc(CCl)ccc1OCc1nc(-c2ccccc2)oc1C
Reactant: COC(=O)Cc1cn(C)nc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)Cc1cn(C)nc1OCc1ccc(OCc2nc(-c3ccccc3)oc2C)c(OC)c1
Temperature: 60 °C
Reaction time: 5 h
Yield: 57.2 %

Procedure:
A mixture of methyl (3-hydroxy-1-methyl-1H-pyrazol-4-yl)acetate (340 mg), 4-(4-chloromethyl-2-methoxyphenoxymethyl)-5-methyl-2-phenyloxazole (687 mg), potassium carbonate (553 mg) and N,N-dimethylformamide (10 ml) was stirred at 60° C. for 5 hrs. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and methyl [3-[3-methoxy-4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxy]-1-methyl-1H-pyrazol-4-yl]acetate (546 mg, yield 57%) was obtained as a colorless oil from a fraction eluted with ethyl acetate-hexane (2:1, volume ratio).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:9]#[N:10])[CH:6]=[CH:5][C:4]=1[C:11]1[NH:19][C:18]2[CH:17]=[N:16][C:15](=[O:20])[NH:14][C:13]=2[N:12]=1.S(=O)(=O)(O)[OH:22]>>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:9]([NH2:10])=[O:22])[CH:6]=[CH:5][C:4]=1[C:11]1[NH:19][C:18]2[CH:17]=[N:16][C:15](=[O:20])[NH:14][C:13]=2[N:12]=1
Reactant: COc1cc(C#N)ccc1-c1nc2[nH]c(=O)ncc2[nH]1
Reactant: O=S(=O)(O)O
Product: COc1cc(C(N)=O)ccc1-c1nc2[nH]c(=O)ncc2[nH]1

Procedure:
Prepared by partial saponification of 8-(2-methoxy-4-cyanophenyl)-3H-purin-2-one with concentrated sulfuric acid at ambient temperature.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:6]([O:10][C:11]([N:13]1[CH2:18][CH2:17][N:16]([CH2:19][C:20]([N:22]2[C:30]3[C:25](=[CH:26][CH:27]=[C:28]([C:31]([OH:33])=O)[CH:29]=3)[CH2:24][CH2:23]2)=[O:21])[CH2:15][C@H:14]1[CH3:34])=[O:12])([CH3:9])([CH3:8])[CH3:7]>>[C:6]([O:10][C:11]([N:13]1[CH2:18][CH2:17][N:16]([CH2:19][C:20](=[O:21])[N:22]2[C:30]3[C:25](=[CH:26][CH:27]=[C:28]([C:31]([N:1]4[CH2:5][CH2:4][CH2:3][CH2:2]4)=[O:33])[CH:29]=3)[CH2:24][CH2:23]2)[CH2:15][C@H:14]1[CH3:34])=[O:12])([CH3:7])([CH3:8])[CH3:9]
Reactant: C[C@@H]1CN(CC(=O)N2CCc3ccc(C(=O)O)cc32)CCN1C(=O)OC(C)(C)C
Reactant: C1CCNC1
Product: C[C@@H]1CN(CC(=O)N2CCc3ccc(C(=O)N4CCCC4)cc32)CCN1C(=O)OC(C)(C)C

Procedure:
Starting with pyrrolidine and 1-[2-((R)-4-tert-butoxycarbonyl-3-methyl-piperazin-1-yl)-acetyl]-2,3-dihydro-1H-indole-6-carboxylic acid, the title compound was prepared by using similar methods to those described in General Procedure 1. 1H NMR (Me-d3-OD): 8.31 (1H, s), 7.34 (1H, d), 7.22 (1H, dd), 4.32 (2H, t), 4.24 (1H, s), 3.83 (1H, d), 3.67-3.54 (2H, m), 3.54-3.41 (2H, m), 3.31-3.09 (5H, m), 2.93 (1H, d), 2.83 (1H, d), 2.41-2.23 (1H, m), 2.23-2.09 (1H, m), 2.02-1.98 (2H, m), 1.96-1.84 (2H, m), 1.48 (9H, s), 1.30 (3H, d).
Reaction SMILES: [I-].[C:2]1([S+:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])(OCC)C.[C:28]12([CH2:38][S:39]([OH:42])(=[O:41])=[O:40])[C:35]([CH3:37])([CH3:36])[CH:32]([CH2:33][CH2:34]1)[CH2:31][C:29]2=[O:30].N>C(Cl)Cl>[C:28]12([CH2:38][S:39]([O-:42])(=[O:40])=[O:41])[C:35]([CH3:37])([CH3:36])[CH:32]([CH2:33][CH2:34]1)[CH2:31][C:29]2=[O:30].[C:15]1([S+:8]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Agent: CCOC(C)([O-])[O-]
Agent: N
Agent: [I-]
Solvent: ClCCl
Product: CC1(C)C2CCC1(CS(=O)(=O)[O-])C(=O)C2
Yield: 82.9 %

Procedure:
Triphenylsulfonium iodide (390 mg; 1 mmol), ethyl orthoacetate (486 mg; 3 mmol), and camphorsulfonic acid (278 mg; 1.2 mmol) were dissolved in anhydrous methylene chloride (10 ml), and the resultant mixture was stirred for 12 hours at room temperature. The reaction mixture was alkalinized by adding 1% aqueous ammonia (10 ml), and subjected to extraction with methylene chloride three times, followed by drying. The solvent was removed through distillation, and the thus-obtained semi-solid matter was washed with ether, to thereby yield 410 mg of the target compound as white crystals (yield: 82%).
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:8]=[C:9]([C:19]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=3)=[O:20])[C:10]3[N:14]=[C:13]([O:15][CH2:16][CH3:17])[NH:12][C:11]=3[CH:18]=2)=[C:5]([CH3:27])[O:4][N:3]=1.[CH:28]([Mg]Br)([CH2:30][CH3:31])[CH3:29]>C1COCC1>[CH3:1][C:2]1[C:6]([C:7]2[CH:8]=[C:9]([C:19]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=3)([OH:20])[CH:28]([CH3:29])[CH2:30][CH3:31])[C:10]3[N:14]=[C:13]([O:15][CH2:16][CH3:17])[NH:12][C:11]=3[CH:18]=2)=[C:5]([CH3:27])[O:4][N:3]=1
Reactant: CCC(C)[Mg]Br
Reactant: CCOc1nc2c(C(=O)c3ccccn3)cc(-c3c(C)noc3C)cc2[nH]1
Solvent: C1CCOC1
Product: CCOc1nc2c(C(O)(c3ccccn3)C(C)CC)cc(-c3c(C)noc3C)cc2[nH]1
Reaction time: 0.17 h

Procedure:
(6-(3,5-dimethylisoxazol-4-yl)-2-ethoxy-1H-benzo[d]imidazol-4-yl)(pyridin-2-yl)methanone (20 mg, 0.055 mmol) was dissolved in dry THF (0.55 mL) under argon. Sec-butylmagnesium bromide (1.0 M in THF, 0.27 mL, 0.28 mmol) was added dropwise and the reaction was allowed to stir for 10 minutes. The reaction was quenched with water, concentrated and purified by reverse-phase HPLC to give 1-(6-(3,5-dimethylisoxazol-4-yl)-2-ethoxy-1H-benzo[d]imidazol-4-yl)-2-methyl-1-(pyridin-2-yl)butan-1-ol intermediate. Intermediate was taken up in 0.5 mL EtOH and 0.3 mL 4.0M HCl/dioxane and heated to 65° C. for 1 hr. Reaction was concentrated and purified by reverse phase HPLC to afford the desired product
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:13])=[C:4]([CH:9]=[C:10]([Cl:12])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[CH3:14][C:15]([O:18][C:19]([NH:21][CH:22]1[CH2:28][CH2:27][C:25](=O)[CH2:24][CH2:23]1)=[O:20])([CH3:17])[CH3:16].C([BH3-])#N.[Na+]>CO.[Cl-].[Zn+2].[Cl-]>[C:15]([O:18][C:19]([NH:21][C@@H:22]1[CH2:28][CH2:27][C@H:25]([NH:1][C:2]2[C:3]([CH3:13])=[C:4]([CH:9]=[C:10]([Cl:12])[CH:11]=2)[C:5]([O:7][CH3:8])=[O:6])[CH2:24][CH2:23]1)=[O:20])([CH3:17])([CH3:14])[CH3:16]
Reactant: CC(C)(C)OC(=O)NC1CCC(=O)CC1
Reactant: COC(=O)c1cc(Cl)cc(N)c1C
Agent: [BH3-]C#N
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1cc(Cl)cc(N[C@H]2CC[C@@H](NC(=O)OC(C)(C)C)CC2)c1C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of methyl 3-amino-5-chloro-2-methylbenzoate (500 mg, 2.505 mmol) and 4-N-Boc-aminocyclohexanone (2.0 g, 9.38 mmol) in methanol (20 mL) was added zinc chloride (1.0 g, 7.34 mmol). The reaction was stirred for 2 h at room temperature, then sodium cyanoborohydride (700 mg, 11.14 mmol) was added portionwise over 2 h. The reaction was then heated to 40° C. and stirred for 24 h. LCMS showed that the reaction was mostly complete (11% starting amine remained with two product peaks 40% and 49% corresponding to the trans and cis products). The reaction was evaporated to dryness, taken up in EtOAc, washed with aq. NH4Cl, 1 N Na2CO3, brine, dried (Na2SO4), filtered and concentrated under vacuum. The residue was purified by silica gel chromatography (Analogix, SF25-80 g, 10 to 30% EtOAc in hexanes). The cis-diastereomer was contaminated with 27% of the methyl 3-amino-5-chloro-2-methylbenzoate starting material. Trituration and filtration from a small volume of 10% EtOAc in hexanes gave the pure cis-diastereomer methyl 3-(((cis)-4-((tert-butoxycarbonyl)amino)cyclohexyl)amino)-5-chloro-2-methylbenzoate (305 mg, 0.730 mmol, 29.1% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ=6.85 (d, J=2.3 Hz, 1 H), 6.74 (d, J=2.0 Hz, 1 H), 6.62 (d, J=7.1Hz, 1 H), 4.66 (d, J=6.8 Hz, 1 H), 3.81 (s, 3 H), 3.47 (br. s., 2 H), 2.19 (s, 3 H), 1.75-1.51 (m, 8 H), 1.39 (s, 9 H). MS(ES) [M+H]+ 397.2.
Reaction SMILES: [NH2:1][C:2]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[C:7]2[CH2:13][CH2:14][NH:15][C:16](=[O:25])[O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:3].[H-].[Na+].Br[CH2:29][CH2:30][CH2:31][CH3:32]>>[NH2:1][C:2]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH2:29][CH2:30][CH2:31][CH3:32])[CH:8]=[C:7]2[CH2:13][CH2:14][NH:15][C:16](=[O:25])[O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:3]
Reactant: NC(=O)c1ccc2[nH]cc(CCNC(=O)OCc3ccccc3)c2c1
Reactant: CCCCBr
Agent: [H-]
Agent: [Na+]
Product: CCCCn1cc(CCNC(=O)OCc2ccccc2)c2cc(C(N)=O)ccc21

Procedure:
Following the method of Example 16(i), [2-[5-(aminocarbonyl)-1H-indol-3-yl]ethyl]carbamic acid, phenylmethyl ester (1.5 g), sodium hydride (0.16 g) and 1-bromobutane (1 ml) gave a pale brown oily solid (1.5 g). Chromatography on a silica column (Kieselgel 60, 60 g) eluted with chloroform containing 1% methanol gave the title compound (1.0 g) as a colourless crystalline solid m.p. 138°-9° (ethyl acetate).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH3:23])[CH:15]=2)[OH:13])[CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10]>C(Cl)Cl.O=[Mn]=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH3:23])[CH:15]=2)=[O:13])[CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10]
Reactant: COc1ccc(C(O)c2ccc([N+](=O)[O-])c(OC)c2)cc1OC
Agent: O=[Mn]=O
Solvent: ClCCl
Product: COc1ccc(C(=O)c2ccc([N+](=O)[O-])c(OC)c2)cc1OC
Reaction time: 48 h
Yield: 63 %

Procedure:
A suspension of (3-methoxy-4-nitro-phenyl)-(3,4-dimethoxy-phenyl)-methanol (1.9 g, 6.0 mmol) and MnO2 (9.1 g, 104.7 mmol) in CH2Cl2 (100 mL) was stirred for 2 days. The mixture was filtered through Celite and the Celite was washed with CH2Cl2. The filtrate was concentrated and the residue was purified by flash chromatography (silica gel, CH2Cl2:EtOAc 95:5) to afford (3-methoxy-4-nitro-phenyl)-(3,4-dimethoxy-phenyl)-methanone (1.2 g, 64%) of yellow solid: 1H NMR (CDCl3) δ 7.87 (d, J=8 Hz, 1H), 7.50-7.46 (dd, J=2, 5.7 Hz, 2H), 7.36-7.30 (m, 2H), 6.93 (d, J=8 Hz, 1H), 4.01 (s, 3H), 3.98 (s, 3H), 3.96 (s, 3H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]2[CH2:13][CH2:12][C:11]([CH3:15])([CH3:14])[CH2:10][CH:9]=2)[C:3]=1[NH:16][C:17]([C:19]1[NH:20][CH:21]=[C:22]([C:24]#[N:25])[N:23]=1)=[O:18].[O:26]1[CH2:31][CH2:30][C:29](=[O:32])[CH2:28][CH2:27]1>>[CH3:14][C:11]1([CH3:15])[CH2:12][CH2:13][C:8]([C:4]2[C:3]([NH:16][C:17]([C:19]3[NH:20][CH:21]=[C:22]([C:24]#[N:25])[N:23]=3)=[O:18])=[CH:2][CH:7]=[C:6]([C:29]3([OH:32])[CH2:30][CH2:31][O:26][CH2:27][CH2:28]3)[N:5]=2)=[CH:9][CH2:10]1
Reactant: CC1(C)CC=C(c2nccc(Br)c2NC(=O)c2nc(C#N)c[nH]2)CC1
Reactant: O=C1CCOCC1
Product: CC1(C)CC=C(c2nc(C3(O)CCOCC3)ccc2NC(=O)c2nc(C#N)c[nH]2)CC1

Procedure:
The title compound was prepared as described in Example 1 step (h) using 4-cyano-1H-imidazole-2-carboxylic acid [4-bromo-2-(4,4-dimethyl-cyclohex-1-enyl)-pyridine-3-yl]-amide (as prepared in the Example 32 steps (d)) and tetrahydropyran-4-one. Mass spectrum (ESI, m/z): Calcd. for C25H27N5O3, 422.2 (M+H). found 422.2.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][CH:3]=1.[NH2:12][C@H:13]([C:17]([OH:19])=[O:18])[CH:14]([CH3:16])[CH3:15].C(=O)([O-])[O-].[K+].[K+].S1(CCCC1)(=O)=O>[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[F:9][C:8]([F:11])([F:10])[C:5]1[CH:6]=[CH:7][C:2]([NH:12][CH:13]([CH:14]([CH3:16])[CH3:15])[C:17]([OH:19])=[O:18])=[CH:3][CH:4]=1
Reactant: Fc1ccc(C(F)(F)F)cc1
Reactant: CC(C)[C@H](N)C(=O)O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: O=S1(=O)CCCC1
Product: CC(C)C(Nc1ccc(C(F)(F)F)cc1)C(=O)O
Temperature: 140 °C
Yield: 53 %

Procedure:
A mixture of 80 parts of p-fluorobenzotrifluoride, 114 parts of valine, 135 parts of potassium carbonate, 65 parts of tetra(n-butyl)ammonium iodide, and 630 parts of sulfolane was placed in a pressure reactor. The reactor was degassed, placed under an argon atmosphere, sealed, and then heated and maintained at about 140° C. for about 18 hours. Analysis of the reaction product indicated 53.0% yield of 2-(4-trifluoromethylphenylamino)-3-methylbutanoic acid, based on p-fluorobenzotrifluoride starting materials.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].C([Sn](CCCC)(CCCC)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1)CCC.[F-].[Cs+]>CN(C=O)C.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.[Cu]I>[CH3:12][C:9]1[CH:10]=[CH:11][C:2]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)=[C:3]([CH:8]=1)[C:4]([O:6][CH3:7])=[O:5]
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Reactant: COC(=O)c1cc(C)ccc1Br
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc(C)ccc1-c1ccccn1
Temperature: 130 °C

Procedure:
A mixture of methyl 2-bromo-5-methylbenzoate (0.629 g, 2.747 mmol), 2-(tributylstannyl)pyridine (1.32 g, 3.585 mmol), CsF (0.834 g, 5.494 mmol), Pd(PPh3)4 (0.4 g, 0.27 mmol), and CuI (0.105 g, 0.549 mmol) in DMF (20 mL) was degassed for 10 min and then heated in the microwave reactor for 30 min at 130° C. The mixture was cooled and the solvent was removed in vacuo. The crude was dissolved with EtOAc and then washed with saturated NaHCO3 and dried over Na2SO4. The solvent was removed in vacuo to obtain the crude, which was purified by silica gel to obtain the title compound. ESI-MS (m/z): 228 [M+1]+.
Reaction SMILES: [CH3:1][N:2]([CH3:19])[S:3]([CH2:6][CH2:7][NH:8][C:9]1[C:10]([C:15]([O:17]C)=O)=[N:11][CH:12]=[CH:13][CH:14]=1)(=[O:5])=[O:4].[H-].[Na+].Cl[C:23](=[O:29])[CH2:24][C:25]([O:27][CH3:28])=[O:26]>C1COCC1.CO>[CH3:19][N:2]([CH3:1])[S:3]([CH2:6][CH2:7][N:8]1[C:9]2[C:10](=[N:11][CH:12]=[CH:13][CH:14]=2)[C:15]([OH:17])=[C:24]([C:25]([O:27][CH3:28])=[O:26])[C:23]1=[O:29])(=[O:4])=[O:5]
Reactant: COC(=O)c1ncccc1NCCS(=O)(=O)N(C)C
Reactant: COC(=O)CC(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)c1c(O)c2ncccc2n(CCS(=O)(=O)N(C)C)c1=O
Temperature: 0 °C
Reaction time: 8 h

Procedure:
Methyl 3-({2-[(dimethylamino)sulfonyl]ethyl}amino)pyridine-2-carboxylate (0.877 g, 3.05 mmol) was dissolved in dry THF (10 mL) and cooled to 0° C. NaH (338 mg, 60% suspension in oil, 8.45 mmol) was added and a precipitate formed. The slurry was treated with methyl 3-chloro-3-oxopropionate (0.410 mL, 3.82 mmol) and 3 drops of MeOH and allowed to warm and stir overnight. The reaction was concentrated somewhat in vacuo, then poured into water. The mixture was extracted once with CHCL3, then acidified and extracted repeatedly with CHCl3 until only a trace of UV active material is removed. The acidic organic extracts were dried over Na2SO4, filtered and evaporated to give the product as a pink foam.
Reaction SMILES: Br[CH2:2]/[CH:3]=[CH:4]\[CH2:5][CH2:6][CH2:7][C:8]([O:10][CH3:11])=[O:9].[Na+].[I-:13]>CC(C)=O>[I:13][CH2:2]/[CH:3]=[CH:4]\[CH2:5][CH2:6][CH2:7][C:8]([O:10][CH3:11])=[O:9]
Reactant: [I-]
Reactant: COC(=O)CCC/C=C\CBr
Agent: [Na+]
Solvent: CC(C)=O
Product: COC(=O)CCC/C=C\CI
Reaction time: 0.08 h
Yield: 100.4 %

Procedure:
To a solution of bromide 40 (0.29 g, 1.30 mmol) in dry acetone (10 mL) was added NaI (0.26 g, 1.70 mmol). The reaction mixture was stirred for 5 min, filtered, and poured into Et2O (50 mL) and water (20 mL). The ether layer was separated, washed with three 20-mL portions of water, dried over Na2SO4, and concentrated by rotary evaporation to yield the iodide 34 (0.35 g, 100%). The iodide was used immediately without further purification. If the reaction mixture was stirred for longer than 5 min, isomerization of the cis- to the transallyl iodide began to take place.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4](=[O:26])[C:5]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=3)=[CH:14][CH:13]=2)=[C:6]([CH2:8][CH2:9][CH3:10])[N:7]=1.[F:27][C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1.N1C=CC=CC=1.C(N(CC)CC)C>C(OCC)(=O)C.C([O-])(=O)C.[Cu+2].C([O-])(=O)C.ClCCl>[F:27][C:28]1[CH:33]=[CH:32][C:31]([N:3]2[C:4](=[O:26])[C:5]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([C:18]4[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=4)=[CH:14][CH:13]=3)=[C:6]([CH2:8][CH2:9][CH3:10])[N:7]=[C:2]2[CH3:1])=[CH:30][CH:29]=1
Reactant: CCCc1nc(C)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: OB(O)c1ccc(F)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCCc1nc(C)n(-c2ccc(F)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reaction time: 96 h
Yield: 36.9 %

Procedure:
A mixture of 4′-[(2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile (1.0 g), 4-fluorophenylboronic acid (0.82 g), copper(II) acetate (1.1 g), pyridine (1.2 mL), triethylamine (2.0 mL), molecular sieves 4 A (2.0 g) and dichloromethane (10 mL) was stirred for 4 days. The reaction mixture was diluted with ethyl acetate, and the insoluble material was filtered off. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound (0.47 g, 37%) as a colorless liquid.
Reaction SMILES: C([O:8][C:9](=[O:30])[C@@H:10]([CH2:14][C:15]([N:17]1[C:29]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[C:23]2[C:18]1=[CH:19][CH:20]=[CH:21][CH:22]=2)=[O:16])[CH2:11][CH2:12][CH3:13])C1C=CC=CC=1>CCOC(C)=O.[Pd]>[CH:28]1[C:29]2[N:17]([C:15](=[O:16])[CH2:14][C@@H:10]([CH2:11][CH2:12][CH3:13])[C:9]([OH:30])=[O:8])[C:18]3[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:24]=2[CH:25]=[CH:26][CH:27]=1
Reactant: CCC[C@H](CC(=O)n1c2ccccc2c2ccccc21)C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCC[C@H](CC(=O)n1c2ccccc2c2ccccc21)C(=O)O
Reaction time: 3 h
Yield: 84.4 %

Procedure:
A stirred solution of (2R)-2-(2-Carbazol-9-yl-2-oxo-ethyl)-pentanoic acid benzyl ester (4.50 g, 11.26 mmol) in EtOAc (60 mL) was treated with 10% Pd on carbon (˜400 mg) and the reaction mixture then placed under an atmosphere of hydrogen. After 1 h further 10% Pd on carbon (˜300 mg) was added and the reaction mixture was placed under hydrogen, with stirring, for a further 3 h after which the reaction mixture was filtered through a celite pad and concentrated to give the sub-title compound (2.94 g, 84%) as a white solid which also contained carbazole: 1H NMR (400 MHz, CDCl3) δ 0.92-1.04 (3H, m), 1.32-2.00 (4H, m), 3.19-3.34 (2H, m), 3.58-3.70 (1H, m), 7.30-7.53 (4H, m), 8.00-8.30 (4H, m).
Reaction SMILES: CN(C)C=O.C(Cl)(=O)C(Cl)=O.[CH3:12][C:13]([C:16]1[C:21]([O:22][CH2:23][O:24][CH2:25][CH2:26][O:27][CH3:28])=[C:20]([C:29]([CH3:32])([CH3:31])[CH3:30])[N:19]=[C:18]([CH:33]=[N:34]O)[N:17]=1)([CH3:15])[CH3:14].N1C=CC=NC=1>C(#N)C>[CH3:15][C:13]([C:16]1[C:21]([O:22][CH2:23][O:24][CH2:25][CH2:26][O:27][CH3:28])=[C:20]([C:29]([CH3:32])([CH3:31])[CH3:30])[N:19]=[C:18]([C:33]#[N:34])[N:17]=1)([CH3:12])[CH3:14]
Reactant: COCCOCOc1c(C(C)(C)C)nc(C=NO)nc1C(C)(C)C
Agent: O=C(Cl)C(=O)Cl
Solvent: c1cncnc1
Solvent: CN(C)C=O
Solvent: CC#N
Product: COCCOCOc1c(C(C)(C)C)nc(C#N)nc1C(C)(C)C
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 0 %

Procedure:
Dimethylformamide (0.05 g, 0.6 mmoles) is cooled to 0° C. in 10 mL of acetonitrile under argon. Oxalyl chloride (0.1 g, 0.9 mmoles) is added and the reaction mixture is stirred at 0° C. for 10 minutes. 4,6-Bis(1,1-dimethylethyl)-5-[(2-methoxyethoxy)-methoxy] -2-pyrimidinecarboxaldehyde oxime (0.2 g, 0.6 moles) is dissolved in 10 mL of acetonitrile and cooled to 0° C. The vilsmier reagent prepared above is added to the pyrimidine solution at 0° C. After 3 hours at 0° C., the reaction is quenched by the addition of 10 mL of saturated sodium bicarbonate and extracted with ether (3×10 mL). The organic extract is washed with 50 mL of brine and dried over magnesium sulfate. Evaporation of the solvent gives a red oil which is purified by flash chromatography (silica, 10% ether/chloroform) to give 4,6-bis(1,1-dimethylethyl)-5-[(2-methoxyethoxy)-methoxy]-2-pyrimidinecarbonitrile (43 mg, 22% ) as an oil. H1 -NMR (CDCl3) δ 5.04 (s, 2H, O--CH2 --O), 3.95 (m, 2H), 3.62 (m, 2H), 3.41 (s, 3H, OCH3), 1.44 (s, 18H, C(CH3)3 ).
Reaction SMILES: [C:1]([N:8]1[CH2:12][C@H:11]([OH:13])[CH2:10][C@H:9]1[CH2:14][OH:15])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].N1C=CN=C1.[Si:21](Cl)([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22]>CN(C=O)C>[C:1]([N:8]1[CH2:12][C@H:11]([OH:13])[CH2:10][C@H:9]1[CH2:14][O:15][Si:21]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CC(C)(C)OC(=O)N1C[C@H](O)C[C@H]1CO
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1C[C@H](O)C[C@H]1CO[Si](C)(C)C(C)(C)C
Reaction time: 1.5 h
Yield: 49.2 %

Procedure:
To N-Boc-(2S,4R)-4-hydroxy-2-hydroxymethylpyrrolidine (0.199 g, 0.92 mmol) in DMF (2 ml) was added imidazole (0.125 g) and t-butyldimethylsilyl chloride (0.14 g). After 1.5 h, the reaction was concentrated by evaporation under reduced pressure, and the residue dissolved in diethyl ether, washed with water and brine, dried and evaporated. Purification by chromatography on silica gel eluting with 0-30% ethyl acetate in hexane gave the title material, (0.15 g, 49%). NMR (CDCl3) 0.02 (s, 3H), 0.03 (s, 3H), 0.9 (s, 9H), 1.45 (s, 9H), 1.9 (bm, 9H), 2.2 (bm, 1H), 3.3-4.0 (bm, 5H), 4.5 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=2)=[CH:4][CH:3]=1.[CH2:19]=O.Cl>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:9][CH2:10][C:11]3[C:16](=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=3)[CH2:19]2)=[CH:6][CH:7]=1
Reactant: C=O
Reactant: COc1cccc(CCNc2ccc(Cl)cc2)c1
Agent: Cl
Solvent: CO
Product: COc1ccc2c(c1)CCN(c1ccc(Cl)cc1)C2

Procedure:
14.4 g of the product described under (a), 6 ml of 35% strength aqueous formaldehyde solution and 10 ml of concentrated hydrochloric acid in 20 ml of methanol are heated under reflux for 1 day. On distilling off the methanol, the product crystallizes out. After cooling, it is filtered off with suction and the resulting product (13.5 g, 91% of theory) is reacted further under (c) without further purification.