Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([C:23]2[O:24][C:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[N:26][N:27]=2)[C:5]([N:8]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[N:6][CH:7]=1.[CH2:34]1[C:38]2([CH2:42][CH2:41][NH:40][CH2:39]2)[CH2:37][N:36]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[CH2:35]1.CCN(C(C)C)C(C)C>CN(C=O)C.CCOC(C)=O>[C:11]([O:10][C:9]([N:8]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:5]1[N:6]=[CH:7][C:2]([N:40]2[CH2:41][CH2:42][C:38]3([CH2:34][CH2:35][N:36]([C:43]([O:45][C:46]([CH3:47])([CH3:48])[CH3:49])=[O:44])[CH2:37]3)[CH2:39]2)=[N:3][C:4]=1[C:23]1[O:24][C:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[N:26][N:27]=1)=[O:15])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)OC(=O)N1CCC2(CCNC2)C1
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1ncc(Br)nc1-c1nnc(-c2ccccc2)o1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC2(CCN(c3cnc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c(-c4nnc(-c5ccccc5)o4)n3)C2)C1
Temperature: 90 °C
Yield: 60.3 %

Procedure:
A mixture of tert-butyl N-[5-bromo-3-(5-phenyl-1,3,4-oxadiazol-2-yl)pyrazin-2-yl]-N-tert-butoxycarbonyl-carbamate (70 mg, 0.14 mmol), tert-butyl 3,7-diazaspiro[4.4]nonane-3-carboxylate (31 mg, 0.14 mmol) and DIEA (35 mg, 47 μL, 0.27 mmol) in DMF (1 mL) was heated at 90° C. for 2 h. The reaction mixture was allowed to cool to room temperature and diluted with EtOAc. The organic layer was washed with brine (2×), dried over Na2SO4, filtered and concentrated under reduced pressure. The crude material was purified by flash chromatography using 0-35% EtOAc in hexanes to yield tert-butyl 7-[5-[bis(tert-butoxycarbonyl)amino]-6-(5-phenyl-1,3,4-oxadiazol-2-yl)pyrazin-2-yl]-3,7-diazaspiro[4.4]nonane-3-carboxylate (56 mg, 62%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 8.15-8.04 (m, 3H), 7.71-7.60 (m, J=7.5 Hz, 3H), 3.74-3.62 (m, 2H), 3.59-3.53 (m, 2H), 3.39 (s, 2H), 2.89 (s, 1H), 2.73 (s, 1H), 2.10-1.99 (m, 2H), 1.98-1.84 (m, 2H), 1.41 (d, J=7.3 Hz, 9H), 1.29 (s, 18H). LC/MS m/z 664.7 [M+H]+.
Reaction SMILES: C[O:2][C:3]([C:5]1([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[CH:19]=[CH:18][C:17]([C:20]4[N:21]=[N:22][N:23]([CH3:41])[C:24]=4[NH:25][C:26]([O:28][CH:29]([C:31]4[CH:36]=[CH:35][CH:34]=[C:33]([C:37]([F:40])([F:39])[F:38])[CH:32]=4)[CH3:30])=[O:27])=[CH:16][CH:15]=3)=[CH:10][CH:9]=2)[CH2:7][CH2:6]1)=[O:4].C1COCC1.[OH-].[Na+]>C(O)C>[CH3:41][N:23]1[C:24]([NH:25][C:26]([O:28][CH:29]([C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([C:37]([F:38])([F:39])[F:40])[CH:32]=2)[CH3:30])=[O:27])=[C:20]([C:17]2[CH:18]=[CH:19][C:14]([C:11]3[CH:10]=[CH:9][C:8]([C:5]4([C:3]([OH:4])=[O:2])[CH2:7][CH2:6]4)=[CH:13][CH:12]=3)=[CH:15][CH:16]=2)[N:21]=[N:22]1
Reactant: COC(=O)C1(c2ccc(-c3ccc(-c4nnn(C)c4NC(=O)OC(C)c4cccc(C(F)(F)F)c4)cc3)cc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CC(OC(=O)Nc1c(-c2ccc(-c3ccc(C4(C(=O)O)CC4)cc3)cc2)nnn1C)c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.1 %

Procedure:
1-(4′-{1-Methyl-5-[1-(3-trifluoromethyl-phenyl)-ethoxycarbonylamino]-1H-[1,2,3]triazol-4-yl}-biphenyl-4-yl)-cyclopropanecarboxylic acid methyl ester (410 mg, 0.726 mmol) was dissolved 4 mL of THF and 4 mL of ethanol. To this stirred solution was added 1N sodium hydroxide solution (8 mL). The mixture was stirred at room temperature overnight. TLC indicated complete consumption of the starting material. The mixture was concentrated and the residue was dissolved in 15 mL of water. Dilute hydrochloric acid (1N, 9 mL) was added. The white solid was filtered and dried in the air to give 1-(4′-{1-methyl-5-[1-(3-trifluoromethyl-phenyl)-ethoxycarbonylamino]-1H-[1,2,3]triazol-4-yl}-biphenyl-4-yl)-cyclopropanecarboxylic acid (400 mg, 100% yield). LC/MS calcd for C29H25F3N4O4 (m/e) 550.0, obsd 551.0 (M+H); 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.13-1.29 (m, 2.6H), 1.44-1.52 (m, 2H), 1.60 (br d, 2.4H), 3.86 (s, 3H), 5.75-5.95 (br m, 1H), 7.43 (d, J=8.1 Hz, 2.5H), 7.61 (d, J=8.1 Hz, 2.5H), 7.69 (br m, 3.5H), 7.79 (d, J=7.6 Hz, 3.5H), 9.65 and 10.05 (br s, 1H), 12.35 (s, 1H).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]2[S:13][C:12]3[CH:14]=[C:15]([OH:19])[CH:16]=[C:17]([OH:18])[C:11]=3[CH2:10][CH2:9][C:8]=2[CH:20]=1)(=O)[CH3:2].Cl.[NH2:22][OH:23].C([O-])(=O)C.[Na+]>C(O)C.O>[OH:23][N:22]=[C:1]([C:4]1[CH:5]=[CH:6][C:7]2[S:13][C:12]3[CH:14]=[C:15]([OH:19])[CH:16]=[C:17]([OH:18])[C:11]=3[CH2:10][CH2:9][C:8]=2[CH:20]=1)[CH3:2]
Reactant: CC(=O)c1ccc2c(c1)CCc1c(O)cc(O)cc1S2
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC(=NO)c1ccc2c(c1)CCc1c(O)cc(O)cc1S2
Temperature: 120 °C
Reaction time: 3 h
Yield: 63.3 %

Procedure:
In ethanol, 180 mg of 8-acetyl-10,11-dihydrodibenzo[b,f]thiepin-1,3-diol (63) was dissolved, and an aqueous solution of 49 mg of hydroxylamine hydrochloride and 100 mg of sodium acetate dissolved in 1 mL of water was added thereto. The mixed solution was stirred at 120° C. for 3 hours, concentrated under reduced pressure and then, extracted with ethyl acetate. The organic layer was washed with water and a saturated sodium chloride solution and then, dried with anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (developing solvent; hexane:ethyl acetate=1:1). Upon recrystallization from chloroform-hexane, 120 mg of skin-colored amorphous title compound was obtained (yield 63%). Melting Point: 215.4 to 217.5° C.
Reaction SMILES: [N+:1]([CH:4]([C:8](=O)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:5][CH2:6][CH3:7])([O-])=O.Cl.[N:22]#[C:23][NH2:24]>[Pd]>[C:14]1([CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][C:8]2[N:22]=[C:23]([NH2:24])[NH:1][C:4]=2[CH2:5][CH2:6][CH3:7])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: N#CN
Reactant: CCCC(C(=O)CCCCCc1ccccc1)[N+](=O)[O-]
Agent: [Pd]
Agent: Cl
Product: CCCc1[nH]c(N)nc1CCCCCc1ccccc1

Procedure:
4-Nitro-10-phenyldecan-5-one (0.084 g, 0.30 mmol) reacted with concentrated HCl (1.50 mmol) and palladium, 5 wt. % on activated carbon (0.129 g, 0.060 mmol) under H2, then reacted with cyanamide (0.064 g, 1.50 mmol) according to the general procedure. Purification by column chromatography gave 0.025 g (30%) over two steps as a yellow oil: 1H NMR (300 MHz, CD3OD) δ 7.20 (m, 2H), 7.15 (m, 3H), 2.60 (t, J=7.2 Hz, 2H), 2.40 (m, 4H), 1.56 (m, 6H), 1.30 (m, 2H), 0.92 (t, J=7.2 Hz, 3H) ppm; 13C NMR (100 MHz, CD3OD) δ 146.4, 142.5, 128.3, 128.1, 125.6, 122.1, 121.9, 35.5, 31.1, 28.8, 28.2, 25.0, 23.0, 22.3, 12.6 ppm; IR νmax (cm−1) 3165, 2931, 1680, 1453, 1031, 747, 699; HRMS (FAB) calcd for C17H25N3 (MH+) 272.2121, found 272.2127.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:10]([C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([OH:19])[C:14]=3[F:20])=[O:12])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.BrC1C=C2C(C([C:33]3[CH:38]=[CH:37][CH:36]=[C:35](O)[C:34]=3C)=O)=CNC2=NC=1.C1(B(O)O)C=CC=CC=1.B(O)O>>[F:20][C:14]1[C:15]([OH:19])=[CH:16][CH:17]=[CH:18][C:13]=1[C:11]([C:10]1[C:4]2[C:5](=[N:6][CH:7]=[C:2]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[CH:3]=2)[NH:8][CH:9]=1)=[O:12]
Reactant: Cc1c(O)cccc1C(=O)c1c[nH]c2ncc(Br)cc12
Reactant: O=C(c1cccc(O)c1F)c1c[nH]c2ncc(Br)cc12
Agent: OB(O)c1ccccc1
Agent: OBO
Product: O=C(c1cccc(O)c1F)c1c[nH]c2ncc(-c3ccccc3)cc12

Procedure:
Additional compounds were prepared following the protocol of Scheme 11, optionally replacing (5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-(2-fluoro-3-hydroxy-phenyl)-methanone P-0067 with (5-Bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-(3-hydroxy-2-methyl-phenyl)-methanone P-0055 (prepared as described in Example 56, Scheme 22) in Step 1 and optionally replacing phenylboronic acid with an appropriate boronic acid in Step 2, The following compounds were made following this procedure:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]([CH2:27][C:28]([OH:30])=O)=[C:10]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([NH:21][CH:22]([CH2:25][CH3:26])[CH2:23][CH3:24])=[O:20])=[CH:15][CH:14]=2)[S:11][CH:12]=1.Cl.[N:32]1([C:37]([NH2:39])=[NH:38])[CH:36]=[CH:35][CH:34]=[N:33]1.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]([CH2:27][C:28](=[O:30])[NH:39][C:37](=[NH:38])[N:32]2[CH:36]=[CH:35][CH:34]=[N:33]2)=[C:10]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([NH:21][CH:22]([CH2:25][CH3:26])[CH2:23][CH3:24])=[O:20])=[CH:15][CH:14]=2)[S:11][CH:12]=1
Reactant: CCC(CC)NC(=O)c1ccc(-c2scc(-c3ccccc3Cl)c2CC(=O)O)cc1
Reactant: N=C(N)n1cccn1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCC(CC)NC(=O)c1ccc(-c2scc(-c3ccccc3Cl)c2CC(=O)NC(=N)n2cccn2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 57.8 %

Procedure:
[4-(2-Chlorophenyl)-2-(4-{[(1-ethylpropyl)amino]carbonyl}phenyl)thien-3-yl]acetic acid (0.125 g, 0.282 mmol) was dissolved in CH2Cl2 (2 mL) and carbonyldiimidizole (0.229 g, 1.41 mmol) was added. The solution was stirred under argon at room temperature for 30 min. 1-H-Pyrazole-1-carboxamidine hydrochloride (0.413 g, 2.82 mmol) and diisopropyl ethylamine (0.737 mL, 4.23 mmol) were added to the solution and stirred overnight. The solvent was removed and the mixture was absorbed onto silica gel and purified by flash chromatography (20:1 CHCl3:MeOH) to yield 4-(4-(2-chloro-phenyl)-3-{[(imino-pyrazol-1-yl-methyl)-carbamoyl]-methyl}-thiophen-2-yl)-N-(1-ethyl-propyl)-benzamide (0.087 g) as a white solid.
Reaction SMILES: [CH3:1][O:2][C@H:3]1[C@@H:7]2[CH2:8][C@H:9]3[C@H:14]([C:15](=[CH2:16])[C@@H:6]2[C@@H:5]([CH3:17])[O:4]1)[CH2:13][CH2:12][CH2:11][CH2:10]3.[OH:18]O.[OH-:20].[Na+]>>[OH:18][CH2:16][C@@H:15]1[C@H:6]2[C@H:7]([C@H:3]([O:2][CH3:1])[O:4][C@@H:5]2[CH3:17])[CH2:8][C@H:9]2[C@H:14]1[CH2:13][CH2:12][CH2:11][CH2:10]2.[OH:20][CH2:16][C@H:15]1[C@H:6]2[C@H:7]([C@H:3]([O:2][CH3:1])[O:4][C@@H:5]2[CH3:17])[CH2:8][C@H:9]2[C@H:14]1[CH2:13][CH2:12][CH2:11][CH2:10]2
Reactant: [OH-]
Reactant: OO
Reactant: C=C1[C@H]2[C@@H](C[C@@H]3CCCC[C@@H]13)[C@H](OC)O[C@@H]2C
Agent: [Na+]
Product: CO[C@@H]1O[C@H](C)[C@@H]2[C@H]1C[C@@H]1CCCC[C@H]1[C@@H]2CO
Product: CO[C@@H]1O[C@H](C)[C@H]2[C@H](CO)[C@@H]3CCCC[C@H]3C[C@@H]12
Yield: 8 %
Yield: 75 %

Procedure:
Similarly to Example 8, after 663.7 mg(2.81 mmol) of (1R,3R,3aR,4aR,8aS,9aR)-1-methoxy-3-methyl-4-methylene-dodecahydronaphtho[2,3-c]furan were reacted with 4.21 ml (1.5 equivalents) of borane-tetrahydrofuran complex(1M), it was oxidized by adding 3.00 ml of 30% hydrogen peroxide solution and 3.00 ml of 10% aqueous solution of sodium hydroxide to obtain 538.2 mg of (1R,3R,3aS,4S,4aR,8aS,9aR)-4-hydroxymethyl-1-methoxy-3-methyl-dodecahydronaphtho[2,3-c]furan(yield 75%) and 55.2 mg of (1R,3R,3aS,4R,4aR,8aS,9aR)-4-hydroxymethyl-1-methoxy-3-methyl-dodecahydronaphtho[2,3-c]furan(8%). (1R,3R,3aS,4S,4aR,8aS,9aR)-4-hydoxymethyl-1-methoxy-3-methyl-dodecahydronaphtho[2,3-c]furan
Reaction SMILES: [OH:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([CH3:9])=[CH:4][C:3]=1B(O)O.Br[C:14]1(Br)[NH:19][C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)=[CH:17][CH:16]=[CH:15]1.[C:27](=[O:30])([O-])[O-].[Na+].[Na+]>COCCOC.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[OH:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([CH3:9])=[CH:4][C:3]=1[C:16]1[CH:15]=[CH:14][N:19]=[C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[C:17]=1[C:7]1[CH:6]=[C:5]([CH3:9])[CH:4]=[C:3]([CH3:2])[C:27]=1[OH:30]
Reactant: BrC1(Br)C=CC=C(c2ccccn2)N1
Reactant: O=C([O-])[O-]
Reactant: Cc1cc(C)c(O)c(B(O)O)c1
Agent: [Pd]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: COCCOC
Product: Cc1cc(C)c(O)c(-c2ccnc(-c3ccccn3)c2-c2cc(C)cc(C)c2O)c1
Yield: 68 %

Procedure:
Bis(2-hydroxy-3,5-dimethylphenyl)-2,2′-bipyridine was prepared by reaction of 2-hydroxy-3,5-dimethylphenylboronic acid (321 mg, 1.92 mmol) with 6,6-dibromo-2,2′-bipyridyl (260 mg, 0.82 mmol), sodium carbonate (2N solution, 2 ml) and tetrakis(triphenylphosphine) palladium (20 mg) in ethylene glycol dimethyl ether (8 ml) at reflux under nitrogen for 88 hours. The solid was filtered from the cooled reaction and washed with acetone and water to give the desired product as a yellow solid (220 mg, 68%); δH [21H6]-DMSO 8.39,(2H, d), 8.31,(2H, t), 8.10,(2H, 7.78,(2H, s), 7.10,(2H, s), 2.31,(6H, s), 2.24,(6H, s).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8](O)=[O:9])=[CH:6][N:5]=[C:4]2[NH:11][CH:12]=[CH:13][C:3]=12.O[N:15]1C2C=CC=CC=2N=N1.CN(C)CCCN=C=NCC.[OH-].[NH4+]>CN(C)C=O.C(Cl)(Cl)Cl.O>[Cl:1][C:2]1[C:7]([C:8]([NH2:15])=[O:9])=[CH:6][N:5]=[C:4]2[NH:11][CH:12]=[CH:13][C:3]=12
Reactant: On1nnc2ccccc21
Reactant: O=C(O)c1cnc2[nH]ccc2c1Cl
Agent: CCN=C=NCCCN(C)C
Agent: [NH4+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: CN(C)C=O
Product: NC(=O)c1cnc2[nH]ccc2c1Cl
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 10.8 %

Procedure:
To a solution of 4-chloro-1H-pyrrolo[2,3-b]pyridine-5-carboxylicacid (840 mg) in N,N-dimethylformamide (8.4 mL) were added 1-hydroxybenzotriazole (808 mg) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (929 mg). The mixture was stirred at 60° C. for 30 minutes. The solution was cooled to ambient temperature and added 28% ammonium hydroxide aqueous solution (1.2 mL). The mixture was stirred at ambient temperature for 1 hour. To the solution were added water and chloroform and the mixture was extracted with chloroform. The extract was dried over MgSO4, filtrated and evaporated. The residue was purified by column chromatography on silica gel with chloroform and methanol (100:0 to 90:10) to give 4-chloro-1H-pyrrolo[2,3-b]pyridine-5-carboxamide (90 mg) as a pale yellow powder.
Reaction SMILES: [NH:1]1[C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[C:3](=[O:10])[C:2]1=[O:11].N1C2=NC=[CH:19][CH:20]=[C:15]2[CH:14]=[CH:13]1>>[CH2:13]([N:1]1[C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[C:3](=[O:10])[C:2]1=[O:11])[CH2:14][CH2:15][CH2:20][CH3:19]
Reactant: c1cnc2[nH]ccc2c1
Reactant: O=C1Nc2ccncc2C1=O
Product: CCCCCN1C(=O)C(=O)c2cnccc21

Procedure:
Following the procedure as described in PREPARATION 1A, and making non-critical variations using 1H-pyrrolo[3,2-c]pyridine-2,3-dione (see Rivalle, C., et al, J. Heterocyclic Chem. (1997), 34:441) to replace 1H-pyrrolo[2,3-b]pyridine, the title compound was obtained (36%): 1H NMR (300 MHz, CDCl3) δ 8.71-8.64 (m, 2H), 6.90 (d, 1H), 3.71 (t, 2H), 1.74-1.62 (m, 2H), 1.41-1.27 (m, 4H), 0.89 (t, 3H); MS (ES+) m/z 219.3 (M+1).
Reaction SMILES: S(O)(O)(=O)=O.CS[C:8](=[NH:10])[NH2:9].Cl[C:12]([O:14][CH3:15])=[O:13].[OH-].[Na+].[CH:18]1([CH2:21][S:22][C:23]2[CH:28]=[CH:27][C:26]([NH2:29])=[C:25](N)[CH:24]=2)[CH2:20][CH2:19]1>O.CO.C(O)(=O)C>[CH:18]1([CH2:21][S:22][C:23]2[CH:28]=[CH:27][C:26]3[NH:29][C:8]([NH:9][C:12](=[O:13])[O:14][CH3:15])=[N:10][C:25]=3[CH:24]=2)[CH2:19][CH2:20]1
Reactant: Nc1ccc(SCC2CC2)cc1N
Reactant: COC(=O)Cl
Reactant: CSC(=N)N
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Solvent: CO
Product: COC(=O)Nc1nc2cc(SCC3CC3)ccc2[nH]1
Reaction time: 0.25 h

Procedure:
To a mixture of 9 g of 2-methyl-2-thiopseudourea sulfate in 6 ml of water there is added 5.7 ml of methyl chloroformate at 0° C and the mixture is stirred for 15 minutes. Then there is added 12 ml of 25% NaOH dropwise and the mixture is stirred for 15 minutes. Then there is added 6 ml of acetic acid dropwise and the mixture is stirred for 15 minutes. The total amount of 4-(cyclopropylmethyl)thio-o-phenylenediamine from above in 50 ml of methanol is then added and the mixture is refluxed for 2 hours. The alcohol is removed in vacuo and water is added. The resulting solid is filtrated off and crystallized from glyme-acetonitrile to yield, 3.9 g, m.p. 228°-231°.
Reaction SMILES: CN([CH:4]=[C:5]1[C:13](=O)[C:9]2=[N:10][O:11][N:12]=[C:8]2[CH2:7][CH2:6]1)C.[OH:15][C:16]1[CH:17]=[C:18]([NH:22][C:23]([NH2:25])=[NH:24])[CH:19]=[CH:20][CH:21]=1>CN(C=O)C>[N:10]1[O:11][N:12]=[C:8]2[CH2:7][CH2:6][C:5]3[C:13](=[N:24][C:23]([NH:22][C:18]4[CH:17]=[C:16]([OH:15])[CH:21]=[CH:20][CH:19]=4)=[N:25][CH:4]=3)[C:9]=12
Reactant: CN(C)C=C1CCc2nonc2C1=O
Reactant: N=C(N)Nc1cccc(O)c1
Solvent: CN(C)C=O
Product: Oc1cccc(Nc2ncc3c(n2)-c2nonc2CC3)c1

Procedure:
The DMF solution of 5-dimethylaminomethylene-6,7-dihydro-5H-benzo[1,2,5]oxadiazol-4-one 0.1 g (0.00052 mol) and 3 equivalents of N-(3-hydroxy-phenyl)-guanidine was stirred at 110° C. for overnight, the final product was purified by directly injecting the DMF reaction solution into prep HPLC.
Reaction SMILES: [C:1]1([S:7][C:8]2C=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][C:9]=2C#N)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-:20].[Na+].[CH2:22]([OH:24])[CH3:23]>O>[C:1]1([S:7][C:8]2[CH:9]=[CH:12][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:14][C:23]=2[C:22]([OH:20])=[O:24])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCO
Reactant: [OH-]
Reactant: N#Cc1cc(C(F)(F)F)ccc1Sc1ccccc1
Agent: [Na+]
Solvent: O
Product: O=C(O)c1cc(C(F)(F)F)ccc1Sc1ccccc1
Temperature: 0 °C

Procedure:
6 g of 2-(phenylthio)-5-trifluoromethyl-benzonitrile, 40 ml of 15% aqueous sodium hydroxide solution and 12 ml of ethanol are heated under reflux for 12 hours and then cooled. After the addition of 100 ml of water, the mixture is extracted with 80 ml of benzene. The aqueous phase is cooled to 0° C and acidified with concentrated hydrochloric acid. The precipitate which separates out is extracted with methylene chloride. The organic phase is washed with water until neutral, dried over sodium sulphate, filtered and evaporated. There is obtained 2-(phenylthio)-5-trifluoromethyl-benzoic acid which melts at 140°-145° C.
Reaction SMILES: [CH:1]([C:3]1[CH:21]=[CH:20][C:6]([CH2:7][CH2:8][NH:9][S:10]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)(=[O:12])=[O:11])=[CH:5][CH:4]=1)=O.C1(P(C2C=CC=CC=2)(C2C=CC=CC=2)=[CH:29][C:30](=[O:32])[CH3:31])C=CC=CC=1>C1(C)C=CC=CC=1>[O:32]=[C:30]([CH3:31])[CH:29]=[CH:1][C:3]1[CH:21]=[CH:20][C:6]([CH2:7][CH2:8][NH:9][S:10]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)(=[O:12])=[O:11])=[CH:5][CH:4]=1
Reactant: O=Cc1ccc(CCNS(=O)(=O)c2ccc(Cl)cc2)cc1
Reactant: CC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Product: CC(=O)C=Cc1ccc(CCNS(=O)(=O)c2ccc(Cl)cc2)cc1

Procedure:
A mixture of 3.2 g. (10 mnole) 4-chlorobenzenesulphonic acid-(4-formylphenethylamide), 50 ml. anhydrous toluene and 3.2 g. (10 mmole) 1-triphenylphosphoranylidene-2-propanone is refluxed for 5 hours, then cooled, stirred with silica gel and filtered off with suction. The filtrate is evaporated and purified by column chromatography (silica gel/methylene chloride). Yield 1.3 g. (36% of theory); m.p. 111°-113° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:46][C:47]([F:50])([F:49])[F:48])[C:9]1[CH:14]=[C:13]([C:15]2[O:16][CH:17]=[C:18]([C:20]([NH:22][C:23]3[C:24]([N:29]4[C:33](=[O:34])[CH2:32][C@H:31]([NH:35]C(=O)OCC5C=CC=CC=5)[CH2:30]4)=[N:25][N:26]([CH3:28])[CH:27]=3)=[O:21])[N:19]=2)[CH:12]=[CH:11][N:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1COCC1>[C].[Pd].CO>[NH2:35][C@@H:31]1[CH2:30][N:29]([C:24]2[C:23]([NH:22][C:20]([C:18]3[N:19]=[C:15]([C:13]4[CH:12]=[CH:11][N:10]=[C:9]([N:8]([CH2:46][C:47]([F:49])([F:48])[F:50])[C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[CH:14]=4)[O:16][CH:17]=3)=[O:21])=[CH:27][N:26]([CH3:28])[N:25]=2)[C:33](=[O:34])[CH2:32]1
Reactant: Cn1cc(NC(=O)c2coc(-c3ccnc(N(CC(F)(F)F)C(=O)OC(C)(C)C)c3)n2)c(N2C[C@@H](NC(=O)OCc3ccccc3)CC2=O)n1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: Cn1cc(NC(=O)c2coc(-c3ccnc(N(CC(F)(F)F)C(=O)OC(C)(C)C)c3)n2)c(N2C[C@@H](N)CC2=O)n1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 101.1 %

Procedure:
To a mixture of benzyl ((3S)-1-(4-(((2-(2-((tert-butoxycarbonyl)(2,2,2-trifluoroethyl)amino)pyridin-4-yl)-1,3-oxazol-4-yl)carbonyl)amino)-1-methyl-1H-pyrazol-3-yl)-5-oxopyrrolidin-3-yl)carbamate (1.0 g), THF (7.2 mL) and methanol (7.2 mL) was added 10% palladium-carbon (154 mg), and the mixture was stirred at room temperature for 1.5 hr under hydrogen atmosphere. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure to give the title compound (817 mg).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH2:8][CH3:9])[N:5]=[CH:4][N:3]=1.C1C(=O)N([I:17])C(=O)C1>C(O)(=O)C>[CH2:8]([C:6]1[N:5]=[CH:4][NH:3][C:2](=[O:1])[C:7]=1[I:17])[CH3:9]
Reactant: CCc1cc(O)ncn1
Reactant: O=C1CCC(=O)N1I
Solvent: CC(=O)O
Product: CCc1nc[nH]c(=O)c1I
Temperature: 25 °C
Reaction time: 30 h

Procedure:
To a stirred solution of 70 g (0.56 mol) 4-hydroxy-6-ethyl pyrimidine in acetic acid is added 127 g (0.56 mol) NIS portion wise at RT within 15 min. The reaction is stirred for 30 h at RT until all starting material is consumed. The reaction mixture is diluted with water and the solid product is filtered off and washed with sodium thiosulfate solution to remove excess iodine. After drying, the desired product is obtained as a solid (90 g; 64%) which is used without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[N:10][C:11]=1[O:12][CH3:13])[N:8]([CH2:14][CH3:15])[CH:7]=[C:6]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:5]2=[O:21].[F:22][B-:23]([F:26])([F:25])[F:24].[H+].[N:28](OCCC(C)C)=O>C(O)C.CCOCC>[F:22][B-:23]([F:26])([F:25])[F:24].[CH2:19]([O:18][C:16]([C:6]1[C:5](=[O:21])[C:4]2[C:9](=[N:10][C:11]([O:12][CH3:13])=[C:2]([N+:1]#[N:28])[CH:3]=2)[N:8]([CH2:14][CH3:15])[CH:7]=1)=[O:17])[CH3:20]
Reactant: CC(C)CCON=O
Reactant: CCOC(=O)c1cn(CC)c2nc(OC)c(N)cc2c1=O
Agent: F[B-](F)(F)F
Agent: [H+]
Solvent: CCOCC
Solvent: CCO
Product: CCOC(=O)c1cn(CC)c2nc(OC)c([N+]#N)cc2c1=O
Reaction time: 0.5 h

Procedure:
A solution of 12.0 g of ethyl 6-amino-1-ethyl-1,4-dihydro-7-methoxy-4-oxo-1,8-naphthyridine-3-carboxylate in 120 ml of ethanol and 60 ml of aqueous 42% tetrafluoroboric acid was cooled to 0° C. To the solution kept at 0°-3° C. was added 6.0 g of isoamyl nitrite. The mixture was stirred for 30 minutes at the same temperature, and then diluted with 600 ml of ether to give a precipitate which was collected and washed with ether to give 12.8 g of 3-ethoxycarbonyl-1-ethyl-1,4-dihydro-7-methoxy-4-oxo-1,8-naphthyridine-6-diazonium tetrafluoroborate, decomposing at 142°-147° C.
Reaction SMILES: [CH:1](=[O:4])CC.[C:5]([O:9][CH3:10])(=[O:8])[CH:6]=O.N([CH2:13][C:14](O)=O)C>CO>[CH:1](/[C:6](=[CH:13]\[CH3:14])/[C:5]([O:9][CH3:10])=[O:8])=[O:4]
Reactant: COC(=O)C=O
Reactant: CNCC(=O)O
Reactant: CCC=O
Solvent: CO
Product: C/C=C(\C=O)C(=O)OC
Temperature: 80 °C
Reaction time: 1 h
Yield: 16.4 %

Procedure:
174 g (3 mol) of propionaldehyde were added within 1 h to a mixture of 264 g (3 mol) of methyl glyoxylate, 96 g of methanol and 2.7 g (0.03 mol) of sarcosine at 80° C. After the addition was complete the reaction mixture was stirred at 80° C. for 1 h and then distilled under a pressure of 1 mbar in a thin-film evaporator. 417 g of distillate which contained 50.8% methyl 2-hydroxy-3-formylbutanoate and 16.4% methyl formylcrotonate were obtained.