Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: OS(O)(=O)=O.O=S(=O)=O.[C:10]([O:22][CH3:23])(=[O:21])[C:11]1[CH:20]=[CH:19][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][CH:12]=1.[CH2:24]=O>C(O)C>[CH2:23]([O:22][C:10]([C:11]1[CH:20]=[C:19]2[C:14](=[CH:13][CH:12]=1)[C:15](=[O:16])[O:17][CH2:18]2)=[O:21])[CH3:24]
Reactant: C=O
Reactant: COC(=O)c1ccc(C(=O)OC)cc1
Agent: O=S(=O)(O)O
Agent: O=S(=O)=O
Solvent: CCO
Product: CCOC(=O)c1ccc2c(c1)COC2=O
Temperature: 125 °C
Reaction time: 5 h

Procedure:
Oleum (20-25% SO3, 800 g), dimethyl terephthalate (234 g) and paraformaldehyde (48 g) are heated with stirring for 5 hours at 125° C. The reaction mixture is cooled to 70° C. and poured into ethanol (1,6 L) having room temperature. This mixture is heated to reflux for 1½ hour before ice (800 g) is added. The suspension is stirred overnight, filtered off and washed with ethanol (150 ml). The crude product is suspended in water (800 ml) and pH is adjusted to 4 with NaOH (27%). The precipitate is filtered off and washed with water and dried.
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11](/[CH:15]=[CH:16]/[C:17]3[CH:18]=[N:19][CH:20]=[C:21](/[CH:23]=[CH:24]/[C:25]4[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=4)[CH:22]=3)[CH:10]=2)=[N:4][CH:5]=[CH:6][CH:7]=1.[N:31]1[CH:36]=[CH:35][CH:34]=[C:33]([CH2:37][C:38](=O)[C:39](O)=[O:40])[CH:32]=1>C(O)C>[N:31]1[CH:36]=[CH:35][CH:34]=[C:33]([CH2:37][C:38]2[C:39](=[O:40])[N:8]([C:9]3[CH:14]=[CH:13][CH:12]=[C:11](/[CH:15]=[CH:16]/[C:17]4[CH:18]=[N:19][CH:20]=[C:21](/[CH:23]=[CH:24]/[C:25]5[CH:26]=[CH:27][N:28]=[CH:29][CH:30]=5)[CH:22]=4)[CH:10]=3)[C:3]3[N:4]=[CH:5][CH:6]=[CH:7][C:2]=3[N:1]=2)[CH:32]=1
Reactant: O=C(O)C(=O)Cc1cccnc1
Reactant: Nc1cccnc1Nc1cccc(/C=C/c2cncc(/C=C/c3ccncc3)c2)c1
Solvent: CCO
Product: O=c1c(Cc2cccnc2)nc2cccnc2n1-c1cccc(/C=C/c2cncc(/C=C/c3ccncc3)c2)c1
Yield: 60.2 %

Procedure:
A mixture of 3-amino-2-[3-[(E)-2-[5-[(E)-2-(4-pyridyl)vinyl]pyridin-3-yl]vinyl]phenylamino]pyridine (260 mg) and 3-pyridylpyruvic acid (121 mg) in ethanol (5 ml) was stirred under reflux for 5 hours. After removal of the solvent, the residue was chromatographed on silica gel column (chloroform-methanol, 9:1) and crystallized from methanol to give 2-(3-pyridylmethyl)-3-oxo-4-[3-[(E)-2-[5-[(E)-2-(4-pyridyl)vinyl]pyridin-3-yl]vinyl]phenyl]-3,4-dihydropyrido[2,3-b]pyrazine (208 mg).
Reaction SMILES: [CH2:1]([CH:4]([CH2:15][CH:16]=[CH2:17])[CH2:5][O:6][SiH2:7][C:8]1[CH:13]=[CH:12][C:11](I)=[CH:10][CH:9]=1)[CH:2]=[CH2:3].C1COCC1.CCN(CC)CC.[CH3:30][C:31]([OH:38])([CH2:34][CH:35]([CH3:37])[CH3:36])[C:32]#[CH:33]>CCOCC.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.[Cu]I>[CH2:1]([CH:4]([CH2:15][CH:16]=[CH2:17])[CH2:5][O:6][SiH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:33]#[C:32][C:31]([CH3:30])([OH:38])[CH2:34][CH:35]([CH3:37])[CH3:36])=[CH:10][CH:9]=1)[CH:2]=[CH2:3]
Reactant: C=CCC(CC=C)CO[SiH2]c1ccc(I)cc1
Reactant: C#CC(C)(O)CC(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C=CCC(CC=C)CO[SiH2]c1ccc(C#CC(C)(O)CC(C)C)cc1
Yield: 88.3 %

Procedure:
Firstly, a mixture of 4-(diallylethoxysilyl)iodobenzene (147 mg, 0.41 mmol), PdCl2(PPh3)2 (11.5 mg, 0.016 mmol) and CuI (3.1 mg, 0.016 mmol) was added with dist. THF (2 mL), dist. Et3N (3 mL) and 3,5-dimethyl-1-hexyn-3-ol (79 μL, 0.54 mmol). The resultant mixture was stirred under a nitrogen atmosphere at 50° C. for 3 hours to obtain a reaction mixture. Then, the reaction mixture was diluted with ether, and an organic layer was washed with dist. H2O and sat. NaCl. After that, the organic layer was dried with MgSO4, and the dried organic layer was then filtered and concentrated to obtain a crude product. The obtained crude product was separated and purified by silica gel column chromatography (hexane/EtOAc=5/1) to obtain 1-(diallylethoxysilyl)-4-(3,5-dimethyl-3-hydroxy-hexynyl)benzene (129.1 mg, 88% yield).
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([N+:20]([O-:22])=[O:21])[C:18](Cl)=[C:13]3[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:23][C@@H:24]1[CH2:29][CH2:28][CH2:27][C@@H:26]([OH:30])[CH2:25]1>C(O)(C)C>[C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([N+:20]([O-:22])=[O:21])[C:18]([NH:23][C@@H:24]4[CH2:29][CH2:28][CH2:27][C@@H:26]([OH:30])[CH2:25]4)=[C:13]3[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=[N+]([O-])c1cnc2c(ccn2S(=O)(=O)c2ccccc2)c1Cl
Reactant: N[C@@H]1CCC[C@@H](O)C1
Solvent: CC(C)O
Product: O=[N+]([O-])c1cnc2c(ccn2S(=O)(=O)c2ccccc2)c1N[C@@H]1CCC[C@@H](O)C1
Temperature: 82 °C

Procedure:
A stirred suspension of 1-Benzenesulfonyl-4-chloro-5-nitro-1H-pyrrolo[2,3-b]pyridine (2.92 g, 8.65 mmol) and (1R,3R)-3-Amino-cyclohexanol (1.00 g, 8.68 mmol) in isopropyl alcohol (30 ml) was treated with N,N-diisoppropylethylamine (2.27 ml, 13 mmol) and heated at 82° C. overnight. LC/MS shows reaction complete. Reaction cooled to room temperature and used as is for the next step. LCMS (Method M, ESI): RT=2.52 min, m+H=417.3; 1H).
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:11][C:12]([CH3:18])([CH3:17])[CH2:13][C:14](Cl)=[O:15]>N1C=CC=CC=1>[N+:1]([C:4]1[CH:10]=[CH:9][C:7]([NH:8][C:14](=[O:15])[CH2:13][C:12]([CH3:18])([CH3:17])[CH3:11])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: CC(C)(C)CC(=O)Cl
Reactant: Nc1ccc([N+](=O)[O-])cc1
Solvent: c1ccncc1
Product: CC(C)(C)CC(=O)Nc1ccc([N+](=O)[O-])cc1
Temperature: 0 °C
Reaction time: 15 h
Yield: 73.7 %

Procedure:
Five grams of 4-nitroaniline was stirred in 25 ml of pyridine and 4.95 g of 3,3-dimethylbutyryl chloride was added. The mixture was stirred 15 hours and poured into ice-water. The resultant solid was collected on a filter and dissolved in 200 ml of ethyl acetate and the solution was treated with activated charcoal and concentrated to yield 6.3 g of 4-nitro-3,3-dimethylbutyrylaminobenzene, m.p. 192°-194°. This material was reduced in 200 ml of methanol, at 3 atmospheres of hydrogen in the presence of 5% Pd/carbon. After removal of the catalyst by filtration, concentration of the filtrate gives 5.3 g of product (3,3-dimethylbutyrylamino)aniline, m.p. 138°-140° C.
Reaction SMILES: [N+](C1C=CC(C([O:10][CH2:11][C@@:12]2([CH3:26])[O:16][C:15](=[O:17])[N:14]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=3)[CH2:13]2)=O)=CC=1)([O-])=O.[N+](C1C=CC(C(OC[C@H]2OC(=O)N(C3C=CC(OC)=CC=3)[C@H]2C)=O)=CC=1)([O-])=O>>[CH3:25][O:24][C:21]1[CH:20]=[CH:19][C:18]([N:14]2[CH2:13][C@:12]([CH2:11][OH:10])([CH3:26])[O:16][C:15]2=[O:17])=[CH:23][CH:22]=1
Reactant: COc1ccc(N2C[C@@](C)(COC(=O)c3ccc([N+](=O)[O-])cc3)OC2=O)cc1
Agent: COc1ccc(N2C(=O)O[C@H](COC(=O)c3ccc([N+](=O)[O-])cc3)[C@@H]2C)cc1
Product: COc1ccc(N2C[C@@](C)(CO)OC2=O)cc1
Yield: 95 %

Procedure:
The reaction was conducted in a similar manner to Referential Example 9 except that Compound [78] obtained in Referential Example 8 was used instead of Compound [76], whereby the title compound was obtained in a yield of 95%.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:12]([NH2:13])=[CH:11][C:9](=[O:10])[N:8]([CH2:14][CH:15]3[CH2:17][CH2:16]3)[C:6]2=[O:7])[CH2:3][CH2:2]1.N([O-])=O.[Na+].C(O)=O.S(S([O-])=O)([O-])=O.[Na+].[Na+].[CH:33]([NH2:35])=O>>[CH:15]1([CH2:14][N:8]2[C:9](=[O:10])[C:11]3[NH:35][CH:33]=[N:13][C:12]=3[N:5]([CH2:4][CH:1]3[CH2:3][CH2:2]3)[C:6]2=[O:7])[CH2:17][CH2:16]1
Reactant: Nc1cc(=O)n(CC2CC2)c(=O)n1CC1CC1
Reactant: NC=O
Agent: O=N[O-]
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O=CO
Product: O=c1c2[nH]cnc2n(CC2CC2)c(=O)n1CC1CC1
Temperature: 100 °C

Procedure:
1,3-Di-cyclopropylmethyl xanthine was prepared using an analogous procedure to that described in Chem. Berichte 88, 1306-1312, 1955: 20.2 g (0.0855 mol) of 1,3-di-cyclopropylmethyl-6-amino-uracil was dissolved in 100 ml of formamide, then 5.9 g sodium nitrite was added and at 60° C. 13.4 ml formic acid was added slowly with stirring. After the colour had changed from yellow to violet, the mixture was heated up to 100° C. and 3.1 g of sodium dithionite (Na2S2O4) was added in small portions.
Reaction SMILES: [CH2:1]([C:3]([S:11][CH2:12]Cl)([CH3:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH3:2].P([S-])(=S)([O-])[O-].[P:19]([SH:27])([O:24][CH2:25][CH3:26])([O:21][CH2:22][CH3:23])=[S:20].CCOCC>C(N(CC)CC)C>[P:19]([S:27][CH2:12][S:11][C:3]([CH2:1][CH3:2])([CH3:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=[S:20])([O:24][CH2:25][CH3:26])[O:21][CH2:22][CH3:23]
Reactant: CCOP(=S)(S)OCC
Reactant: CCC(C)(SCCl)c1ccccc1
Agent: [O-]P([O-])(=S)[S-]
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CCOP(=S)(OCC)SCSC(C)(CC)c1ccccc1
Temperature: 25 °C

Procedure:
To 0.091 mole of chloromethyl α-ethyl-α-methylbenzyl sulfide and 16.9 grams (0.091 mole) of the phosphorodithioate of the formula (C2H5O)2PSSH in 100 ml. of ether is added 9.2 grams of triethylamine, dropwise, maintaining the temperature at 25° C. The mixture is stirred for several hours and then washed with water and 5% sodium hydroxide solution. Evaporation of the solvent from the dried (magnesium sulfate) solution gives 31.3 grams (95%) of a colorless liqiuid. This material is chromatographically purified on a silica gel dry-column using 10 volume percent methylene chloride in hexane as the eluant.
Reaction SMILES: [C:1]([C:3]1[CH:8]([C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[NH:14][N:13]=[C:12]3[C:18]([OH:20])=O)[C:7]([C:21]#[N:22])=[C:6]([CH3:23])[NH:5][C:4]=1[CH3:24])#[N:2].CCN(CC)CC.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:56][N:57]([CH3:61])[CH2:58][CH2:59][NH2:60]>CN(C=O)C>[C:1]([C:3]1[CH:8]([C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[NH:14][N:13]=[C:12]3[C:18]([NH:60][CH2:59][CH2:58][N:57]([CH3:61])[CH3:56])=[O:20])[C:7]([C:21]#[N:22])=[C:6]([CH3:23])[NH:5][C:4]=1[CH3:24])#[N:2]
Reactant: CN(C)CCN
Reactant: CC1=C(C#N)C(c2ccc3[nH]nc(C(=O)O)c3c2)C(C#N)=C(C)N1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC1=C(C#N)C(c2ccc3[nH]nc(C(=O)NCCN(C)C)c3c2)C(C#N)=C(C)N1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 33.1 %

Procedure:
To a solution of 5-(3,5-dicyano-1,4-dihydro-2,6-dimethyl-4-pyridinyl)-1H-indazole-3-carboxylic acid (300 mg, 0.94 mmol), from Synthetic Example 3, in DMF (5 mL) was added Et3N (476 mg, 4.7 mmol) and HATU (430 mg, 1.13 mmol). The mixture was stirred at rt for 30 min, then N,N-dimethylethylenediamine (167.2 mg, 1.9 mmol) was added. The mixture was kept at rt overnight, and then quenched with water. The reaction mixture was extracted with CH2Cl2, dried, and concentrated. The residue was purified by flash chromatography followed by HPLC to afford 5-(3,5-dicyano-1,4-dihydro-2,6-dimethyl-4-pyridinyl)-N-[2-(dimethylamino)ethyl]-1H-indazole-3-carboxamide (121 mg, 33.7%) (Cpd. No. 103.2, Table 2). 1H-NMR (400 MHz, DMSO-D6): δ=8.16 (s, 1H), 7.63 (d, 1H), 7.41 (d, 1H), 4.55 (s, 1H), 3.82 (t, 2H), 3.43 (t, 2H), 3.01 (s, 6H), 2.14 (s, 6H) ppm.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[CH2:10][C@H:9]([CH3:11])[N:8]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[CH2:7][C@H:6]1[CH3:20])=[O:4].[CH2:21]([O:23][C:24](=[O:34])[CH2:25][C:26]1[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:27]=1[OH:33])[CH3:22].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CC(=O)CC.C(OCC)(=O)C>[CH2:21]([O:23][C:24](=[O:34])[CH2:25][C:26]1[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:27]=1[O:33][CH2:2][C:3]([N:5]1[CH2:10][C@H:9]([CH3:11])[N:8]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[CH2:7][C@H:6]1[CH3:20])=[O:4])[CH3:22]
Reactant: CCOC(=O)Cc1cc(Cl)ccc1O
Reactant: C[C@@H]1CN(Cc2ccc(F)cc2)[C@@H](C)CN1C(=O)CCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: CCOC(C)=O
Product: CCOC(=O)Cc1cc(Cl)ccc1OCC(=O)N1C[C@H](C)N(Cc2ccc(F)cc2)C[C@H]1C
Yield: 97.8 %

Procedure:
To a solution of 2-chloro-1-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazin-1-yl]-ethanone (3.3 g, 11.0 mmol) in 2-butanone (100 mL) was added (5-chloro-2-hydroxy-phenyl)-acetic acid ethyl ester (2.3 g, 11.0 mmol), potassium carbonate (3.05 g, 22.1 mmol), and potassium iodide (1.83 g, 11.0 mmol). The reaction was heated at reflux for 48 hrs. The solution was cooled, diluted with ethyl acetate and washed with brine. The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. The crude product was purified by dissolving in dichloromethane and passing through a pad of silica gel. Concentration in vacuo gave the title compound (5.13 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5](B2OC(C)(C)C(C)(C)O2)=[CH:4][C:3]=1[NH:18][C:19]([NH:21][CH2:22][CH2:23][C:24]([O:27][CH3:28])([CH3:26])[CH3:25])=[O:20].FC(F)(F)S(O[C:35]1[C:46]([CH3:47])=[N:45][C:38]2[N:39]=[C:40]([NH:43][CH3:44])[N:41]=[CH:42][C:37]=2[CH:36]=1)(=O)=O.C([O-])(O)=O.[Na+]>O1CCOCC1.O.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>[F:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([C:35]2[C:46]([CH3:47])=[N:45][C:38]3[N:39]=[C:40]([NH:43][CH3:44])[N:41]=[CH:42][C:37]=3[CH:36]=2)=[CH:4][C:3]=1[NH:18][C:19]([NH:21][CH2:22][CH2:23][C:24]([O:27][CH3:28])([CH3:25])[CH3:26])=[O:20]
Reactant: CNc1ncc2cc(OS(=O)(=O)C(F)(F)F)c(C)nc2n1
Reactant: COC(C)(C)CCNC(=O)Nc1cc(B2OC(C)(C)C(C)(C)O2)c(C)cc1F
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: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CNc1ncc2cc(-c3cc(NC(=O)NCCC(C)(C)OC)c(F)cc3C)c(C)nc2n1
Temperature: 55 °C
Yield: 21.1 %

Procedure:
Combine 1-(2-fluoro-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-3-(3-methoxy-3-methylbutyl)urea (0.17 g, 0.431 mmol), 7-methyl-2-(methylamino)pyrido[2,3-d]pyrimidin-6-yl trifluoromethanesulfonate (0.139 g, 0.431 mmol) and NaHCO3 (0.109 g, 1.293 mmol) in dioxane (6 mL) and H2O (1.5 mL). Sparge the mixture with argon. Treat with tetrakis(triphenylphosphine)palladium (0.025 g, 0.022 mmol), sparge again with argon and heat at 55° C. overnight. Add an additional portion of tetrakis(triphenylphosphine)palladium (25 mg, 0.022 mmol) and heat at 65° C. overnight. Cool the mixture to RT, remove solids by filtration, and wash solids with dioxane. Combine filtrates, dilute with EtOAc, wash with saturated NaHCO3 and brine, dry over Na2SO4, concentrate to dryness and purify via silica gel chromatography (EtOAc/Hex). Dissolve in DCM, wash with saturated NaHCO3 and brine, dry over Na2SO4, concentrate to dryness. Treat with 1:1 MeCN/H2O, freeze in −78° C. bath and lyophilize to obtain the title compound (40 mg, 21% yield) as a pale yellow solid. MS (ESI) m/z: 441.2 (M+1).
Reaction SMILES: CN1CCOCC1.Cl[C:9]([O:11][CH:12]([CH3:14])[CH3:13])=[O:10].[NH2:15][CH:16]1[CH2:20][CH2:19][CH2:18][CH:17]1[CH2:21][C:22]([NH:24][CH:25]([CH3:36])[CH2:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]#[N:35])=[CH:30][CH:29]=1)=[O:23].O>C(Cl)Cl>[C:34]([C:31]1[CH:30]=[CH:29][C:28]([O:27][CH2:26][CH:25]([NH:24][C:22](=[O:23])[CH2:21][CH:17]2[CH2:18][CH2:19][CH2:20][CH:16]2[NH:15][C:9]([O:11][CH:12]([CH3:14])[CH3:13])=[O:10])[CH3:36])=[CH:33][CH:32]=1)#[N:35]
Reactant: CC(COc1ccc(C#N)cc1)NC(=O)CC1CCCC1N
Reactant: CC(C)OC(=O)Cl
Solvent: CN1CCOCC1
Solvent: O
Solvent: ClCCl
Product: CC(COc1ccc(C#N)cc1)NC(=O)CC1CCCC1NC(=O)OC(C)C
Temperature: 25 °C
Reaction time: 15 h
Yield: 90.7 %

Procedure:
0.4 g of N-methyhnorpholine, and subsequently 0.5 g of isopropyl chloroformate were added to a suspension containing 1.2 g of 2-amino-N-[2-(4-cyanophenoxy)-1-methylethyl]cyclopentylacetic acid amide suspended in 40 ml of methylene chloride at -15° C. The mixture was allowed to sit and warm naturally to room temperature and stirred for 15 hours at room temperature. Water was subsequently added to the reaction mixture. After the methylene chloride layer was washed with water, the organic layer was dried over anhydrous magnesium sulfate and then the methylene chloride was removed under reduced pressure. The residue was purified by column chromatography on silica gel, thus obtaining 1.4 g of the desired product in the form of a colorless plated crystal (yield: 90%).
Reaction SMILES: ClC(Cl)(Cl)COC([N:7]1[C:19]2[CH2:18][N:17]([S:20]([CH2:23][CH:24]([CH:29]3[CH2:34][CH2:33][N:32]([C:35]([O:37][CH2:38][C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)=[O:36])[CH2:31][CH2:30]3)[C:25](=[O:28])[NH:26][OH:27])(=[O:22])=[O:21])[CH2:16][CH2:15][C:14]=2[C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)=O.[OH-].[Na+]>CO>[CH2:38]([O:37][C:35]([N:32]1[CH2:33][CH2:34][CH:29]([CH:24]([C:25](=[O:28])[NH:26][OH:27])[CH2:23][S:20]([N:17]2[CH2:16][CH2:15][C:14]3[C:13]4[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=4)[NH:7][C:19]=3[CH2:18]2)(=[O:22])=[O:21])[CH2:30][CH2:31]1)=[O:36])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: O=C(NO)C(CS(=O)(=O)N1CCc2c(n(C(=O)OCC(Cl)(Cl)Cl)c3ccccc23)C1)C1CCN(C(=O)OCc2ccccc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(NO)C(CS(=O)(=O)N1CCc2c([nH]c3ccccc23)C1)C1CCN(C(=O)OCc2ccccc2)CC1
Yield: 80.4 %

Procedure:
2-[2-(1-Benzyloxycarbonyl-piperidin-4-yl)-2-hydroxycarbamoyl-ethane sulfonyl]-1,2,3,4-tetrahydro-β-carboline-9-carboxylic acid 2,2,2-trichloro-ethyl ester (135 mg) and 0.1N sodium hydroxide (4.2 ml) in methanol were stirred at room temperature for 3.5 h. The methanol was removed under reduced pressure and the residue partitioned between dichloromethane (20 ml) and 5% citric acid solution (5 ml). The aqueous was extracted with 10% methanol in dichloromethane (2×20 ml) and the combined organics washed with water (2×30 ml) and evaporated under reduced pressure to give the title compound (82 mg, 80%) as a white solid.
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([N+:15]([O-])=O)=[CH:10][CH:9]=2)=O)C.[AlH4-].[Li+].O.[OH-].[Na+]>C1COCC1>[NH2:15][C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([CH2:4][OH:3])=[CH:14]2
Reactant: CCOC(=O)c1cc2cc([N+](=O)[O-])ccc2[nH]1
Agent: [AlH4-]
Agent: [Li+]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Nc1ccc2[nH]c(CO)cc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.5 %

Procedure:
2-Ethoxycarbonyl-5-nitroindole (500 mg, 0.002 mol) was dissolved in 50 mL THF, added lithium tetrahydroaluminate (341 mg, 0.00898 mol) in 3 portions and stirred at room temperature overnight. Water (341 μL), 15% NaOH solution (341 μL), and water (1.1 mL) were added cautiously and the mixtured was filtered. The filtrate was concentrated under vacuum to give the product (300 mg, 98%) as an oil. m/z=162.9.
Reaction SMILES: [CH3:1][C:2]1[C:9]([CH3:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][NH2:5].Cl[CH2:12][CH2:13][N:14]=[C:15]=[O:16].[OH-].[Na+]>O1CCOCC1.C(OCC)(=O)C>[CH3:1][C:2]1[C:9]([CH3:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][NH:5][C:15]1[O:16][CH2:12][CH2:13][N:14]=1
Reactant: O=C=NCCCl
Reactant: Cc1cccc(CN)c1C
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: Cc1cccc(CNC2=NCCO2)c1C
Temperature: 25 °C
Reaction time: 18 h
Yield: 53.6 %

Procedure:
A mixture of 1.0 gram (0.0074 mole) of 2,3-dimethylbenzylamine and 0.69 gram (0.0081 mole) of 2-chloroethylisocyanate in 10 mL of 1,4-dioxane was heated to reflux where it stirred for about 18 hours. The reaction mixture was allowed to cool and an aqueous solution of sodium hydroxide (4.0 mL of a 3.0 molar solution) was added. The reaction mixture was heated to reflux for about 18 hours then allowed to cool to ambient temperature. The reaction mixture was concentrated under reduced pressure to leave a viscous oil residue. The residue was suspended in 50 mL of ethyl acetate and washed with 20 mL of water. The organic phase was extracted with 20 mL of 3.0 molar aqueous hydrochloric acid. The aqueous extract was made basic by adding 3.0 molar aqueous sodium hydroxide and the basic mixture was extracted with 50 mL of ethyl acetate. The extract was dried with sodium sulfate, filtered and the filtrate concentrated under reduced pressure to yield 0.81 gram of the title compound as an oil. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1F.[C:12]([O:19][CH3:20])(=[O:18])[CH2:13][C:14]([O:16][CH3:17])=[O:15].[OH-].[Na+].Cl>CN1CCCC1=O.O>[CH3:17][O:16][C:14](=[O:15])[CH:13]([C:7]1[CH:6]=[CH:5][C:4]([N+:9]([O-:11])=[O:10])=[CH:3][C:2]=1[Cl:1])[C:12]([O:19][CH3:20])=[O:18]
Reactant: O=[N+]([O-])c1ccc(F)c(Cl)c1
Reactant: COC(=O)CC(=O)OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CN1CCCC1=O
Product: COC(=O)C(C(=O)OC)c1ccc([N+](=O)[O-])cc1Cl
Temperature: 80 °C
Reaction time: 0.25 h
Yield: 67.1 %

Procedure:
3-Chloro 4-fluoro nitrobenzene (5.0 g, 28.48 mmol) and dimethyl malonate (3.3 mL, 36.17 mmol) were dissolved in N-methylpyrrolidinone (131.5 mL). Sodium hydroxide (2.4 g, 60 mmol) was added at RT and the solution was heated at 80° C. for 2 hours. The reaction mixture was cooled to 5° C. and 1N HCl solution was added to give a pH of 2. Water (526 mL) was added and the resulting mixture was stirred for 15 minutes during which a pale yellow solid precipitated out. The precipitate was collected by filtration and then washed with water (2×10 mL). The resulting solid mass was dissolved in DCM (50 mL), dried (Na2SO4) and then the volatiles were removed under reduced pressure to afford the title compound (5.5 g, 67%). The product was used as such in the next step without purification.
Reaction SMILES: [NH2:1][C:2]1[C:7]([OH:8])=[C:6]([F:9])[C:5]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[C:4]([CH3:16])[C:3]=1[C:17]#[N:18].CO[CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23]>CCCCCC>[CH2:25]([O:24][C:22]([C:21]1[O:8][C:7]2[C:6]([F:9])=[C:5]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:4]([CH3:16])=[C:3]([C:17]#[N:18])[C:2]=2[N:1]=1)=[O:23])[CH3:26]
Reactant: Cc1c(C#N)c(N)c(O)c(F)c1-c1ccccc1
Reactant: CCOC(=O)COC
Solvent: CCCCCC
Product: CCOC(=O)c1nc2c(C#N)c(C)c(-c3ccccc3)c(F)c2o1
Temperature: 25 °C
Reaction time: 17 h
Yield: 95.5 %

Procedure:
4-Amino-6-fluoro-5-hydroxy-2-methylbiphenyl-3-carbonitrile (I-41) (5.0 g, 20.64 mmol) and ethyl methoxyacetate (18.18 g, 82.56 mmol) were stirred at 100° C. for 23 hours under nitrogen atmosphere. The reaction liquid was cooled to room temperature, and left at the same temperature for 17 hours. At 0° C., hexane was added to the suspension, and left at the same temperature for 1 hour. With washing with hexane, the precipitated crystal was collected by filtration. The crystal was collected, dried at 50° C. under reduced pressure for 4 hours, and then at room temperature for 12 hours to obtain the entitled compound (6.39 g, 96%) as a pale brown powder.
Reaction SMILES: [F:1][CH2:2][C:3]([CH2:9][F:10])([CH2:7][CH3:8])[CH2:4][CH:5]=[O:6].[OH:11]OS([O-])=O.[K+]>CN(C)C=O>[F:1][CH2:2][C:3]([CH2:9][F:10])([CH2:7][CH3:8])[CH2:4][C:5]([OH:11])=[O:6]
Reactant: O=S([O-])OO
Reactant: CCC(CF)(CF)CC=O
Agent: [K+]
Solvent: CN(C)C=O
Product: CCC(CF)(CF)CC(=O)O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of 3,3-bis(fluoromethyl)pentanal (6.8 g, 45 mmol) and Oxone® (27.9 g, 45 mmol) in N,N-dimethylformamide (120 mL) was stirred at rt for 4 h. The reaction was quenched with 2N hydrochloric acid (200 mL) and extracted with ethyl acetate (4×100 mL). The extracts were washed with 2 N hydrochloric acid (150 mL) and 5% aqueous lithium chloride (150 mL), dried over sodium sulfate and concentrated to give 3,3-bis(fluoromethyl)pentanoic acid.