Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([CH3:9])[CH:3]=1.II.[CH3:12][C:13]([CH3:15])=O>>[Br:1][C:2]1[CH:8]=[C:7]2[C:5](=[C:4]([CH3:9])[CH:3]=1)[NH:6][CH2:15][CH:13]=[CH:12]2
Reactant: Cc1cc(Br)ccc1N
Reactant: CC(C)=O
Agent: II
Product: Cc1cc(Br)cc2c1NCC=C2

Procedure:
4-Bromo-2-methylaniline (5.58 g, 30 mmol) was treated with iodine (0.2 g, 0.9 mmol) and acetone (150 mL) in a sealed tube at 80° C. for 24 h to provide 6-bromo-1,2-dihydro-8-methylquinoline (Compound 85 of Scheme XXII) in 9% yield as a yellow oil (0.70g). Most of the aniline (>80%) was recovered. A mixture of the 6-bromo-1,2-dihydro-8-methylquinoline (90 mg, 0.33 mmol), 3-nitrobenzeneboronic acid (167 mg, 1.0 mmol), Pd(PPh3)4 (24 mg, 0.02 mmol), K2CO3 (190 mg, 1.38 mmol) in toluene (7 mL) and water (1.5 mL) was heated at 70° C. for 16 h. Standard work-up followed by chromatography afforded 23 mg (23%) of Compound 292 as a yellow oil. Data for Compound 292: IR (neat) 3412, 2966, 1602, 1530, 1348; 1H NMR (400 MHz, CDCl3) 8.38 (t, J=2.0, 1H), 8.08 (dd, J=7.8 and 2.0, 1H), 7.85 (d, J=7.8, 1H), 7.52 (t, J=7.8, 1H), 7.24 (d, J=11.7, 1H), 7.21 (d, J=1.9, 1H), 5.39 (s, 1H), 3.72 (bs, 1H), 2.18 (s, 3H), 2.07 (s, 3H), 1.34 (s, 6H); 13C NMR (100 MHz, CDCl3) 148.9, 143.7, 142.0, 132.2, 129.6, 128.8, 128.7, 128.6, 126.5, 121.3, 121.0, 120.7, 120.6, 120.3, 52.3, 31.9, 19.2, 17.3.
Reaction SMILES: [CH2:1]([N:3]([CH2:11][CH2:12][OH:13])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[CH:5]=1)[CH3:2].S(=O)(=O)(O)O.[N:19](OC(C)C)=[O:20]>O>[CH2:1]([N:3]([CH2:11][CH2:12][OH:13])[C:4]1[CH:9]=[CH:8][C:7]([N:19]=[O:20])=[C:6]([CH3:10])[CH:5]=1)[CH3:2]
Reactant: CCN(CCO)c1cccc(C)c1
Reactant: CC(C)ON=O
Agent: O=S(=O)(O)O
Solvent: O
Product: CCN(CCO)c1ccc(N=O)c(C)c1

Procedure:
360 g of N-ethyl-N-(2-hydroxyethyl)-m-toluidine and 1,250 g of water are initially introduced into a stirred flask. 196 g of concentrated sulfuric acid are added, while stirring and cooling. During this addition, the internal temperature should not rise above 50°. After cooling to 0°, 187 g of isopropyl nitrite is allowed to run in slowly at -2° to +2°. The excess of nitrite is then removed in the customary manner with amidosulfonic acid. The reaction mixture is brought to room temperature and degassed under reduced pressure. 60 g of prereduced Pd/C (5%) is added to this solution as the catalyst and the N-ethyl-N-(2-hydroxyethyl)-3-methyl-4-nitroso-aniline, which has not been isolated, is hydrogenated at 20° to 40° under a gauge pressure of 0.4 bar of hydrogen. When the reaction has ended, the reaction batch is let down, the catalyst is filtered off and the reaction mixture is concentrated.
Reaction SMILES: [I:1][C:2]1[C:6]2[C:7]([O:11][CH3:12])=[N:8][CH:9]=[CH:10][C:5]=2[NH:4][CH:3]=1.[H-].[Na+].CC1C=CC(S(O[CH:26]2[CH2:30][CH2:29][O:28][CH2:27]2)(=O)=O)=CC=1>CN(C=O)C>[I:1][C:2]1[C:6]2[C:7]([O:11][CH3:12])=[N:8][CH:9]=[CH:10][C:5]=2[N:4]([CH:26]2[CH2:30][CH2:29][O:28][CH2:27]2)[CH:3]=1
Reactant: COc1nccc2[nH]cc(I)c12
Reactant: Cc1ccc(S(=O)(=O)OC2CCOC2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1nccc2c1c(I)cn2C1CCOC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.6 %

Procedure:
To a solution of 3-iodo-4-methoxy-1H-pyrrolo[3,2-c]pyridine (0.100 g) in DMF (5 mL) was added sodium hydride (60% dispersion in mineral oil, 36.1 mg), and the mixture was stirred at room temperature for 1 hr. Tetrahydrofuran-3-yl 4-methylbenzenesulfonate (221 mg) was added thereto, and the mixture was stirred overnight at room temperature. The reaction mixture was extracted with water and ethyl acetate, and the organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (115 mg).
Reaction SMILES: [C:1]([OH:6])(=[O:5])[C:2]([CH3:4])=[CH2:3].C1(C=CC(O)=CC=1)O.C(C(C)=O)C(C)C.[OH:22][CH2:23][CH2:24][N:25]1[CH2:30][CH2:29][O:28][C:27](=[O:31])[C:26]1=[O:32]>O>[CH2:24]([NH+:25]([CH2:30][CH3:29])[CH2:26][CH3:27])[CH3:23].[C:1]([O:6][CH2:29][CH2:30][N:25]([CH2:24][CH2:23][OH:22])[C:26](=[O:32])[C:27]([OH:31])=[O:28])(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: O=C1OCCN(CCO)C1=O
Reactant: C=C(C)C(=O)O
Agent: Oc1ccc(O)cc1
Solvent: CC(=O)CC(C)C
Solvent: O
Product: C=C(C)C(=O)OCCN(CCO)C(=O)C(=O)O
Product: CC[NH+](CC)CC
Temperature: 120 °C
Reaction time: 2 h

Procedure:
Next, in a flask equipped with a stirrer, a thermometer, a decanter, a nitrogen gas-inlet tube, and a reflux condenser were placed 50 g (0.58 moles) of methacrylic acid, 0.1 g (0.1% by weight) of hydroquinone, and 200 ml of methyl isobutyl ketone (hereinafter, referred to as MIBK) and to this mixture was added 54 g (0.58 moles) of N-hydroxyethylmorpholine-2,3-dione, which was prepared in a way as above. Then, the mixture was warmed at 120° C. and the reaction continued for 2 hours by removing water being formed during the reaction by the decanter by means of azeotropic distillation. Return of the solution temperature to room temperature followed by removal of MIBK under reduced pressure gave 2-(1-morpholyl-2,3-dione)ethyl methacylate, which was placed with 120 ml of water in a flask and hydrolyzed by adding dropwise 59 g (0.58 moles) of TEA at 25° C. during 10 minutes to obtain a triethylammonium salt of (2-methacryloyloxyethyl)2-hydroxyethyoxamic acid 10. ##STR26## This ammonium salt was completely soluble in water and identified by IR, which showed absorption bands at 1720 cm-1 for an ester, 1610 cm31 1 for a carboxylic acid, and 2400~2800 cm-1 for a triethylammonium salt, an acid value of 169 (calcd. 162), and a molecular weight of 332.
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]2[CH:6]([N:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)[C:7]3[N:15]=[CH:14][CH:13]=[CH:12][C:8]=3[CH2:9][N:10]([CH3:11])[C:4]=2[CH:3]=1.[N:24]1[CH:29]=[CH:28][C:27]([CH2:30][C:31](O)=[O:32])=[CH:26][CH:25]=1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1>CN(C=O)C.O>[Cl:1][C:2]1[CH:23]=[CH:22][C:5]2[CH:6]([N:16]3[CH2:21][CH2:20][N:19]([C:31](=[O:32])[CH2:30][C:27]4[CH:28]=[CH:29][N:24]=[CH:25][CH:26]=4)[CH2:18][CH2:17]3)[C:7]3[N:15]=[CH:14][CH:13]=[CH:12][C:8]=3[CH2:9][N:10]([CH3:11])[C:4]=2[CH:3]=1
Reactant: O=C(O)Cc1ccncc1
Reactant: CN1Cc2cccnc2C(N2CCNCC2)c2ccc(Cl)cc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: O
Solvent: CN(C)C=O
Product: CN1Cc2cccnc2C(N2CCN(C(=O)Cc3ccncc3)CC2)c2ccc(Cl)cc21
Reaction time: 0.02 h

Procedure:
(8-Chloro-6,11-dihydro-6-methyl-5H-pyrido[3,2-c][1]benzazepin-11-yl)-piperazine (100 mg, 0.305 mmol), 4-pyridine-acetic acid (83.6 mg, 0.61 mmol), EDCl (0.116 g, 0.61 mmol) and HOBT (82.4 mg, 0.61 mmol) were dissolved in DMF (2 ml) and stirred for 1 minute, and then NMM (1 ml) was added. The reaction mixture was stirred at 20° C. for 21 hours and then diluted with water (50 ml), and the aqueous phase was then extracted with EtOAc (about 8 times) until no product was visible in the aqueous layer. The EtOAc phase was then washed with aqueous Na2CO3 and evaporated to a residue (152 mg). This was chromatographed on silica gel to afford partially purified title compound (123 mg), which was rechromatographed on silica gel; two fractions, 51.3 and 50.8 mg, were isolated. The latter gave m.p. 83-87° C.
Reaction SMILES: C(Cl)Cl.[CH3:4][O:5][C:6]1[C@@:7]2([CH2:31][CH:32]=[C:33]([CH3:35])[CH3:34])[CH2:13][CH:11]3[O:12][C@@:8]2([O:29][CH3:30])[C@H:9]([C:21](=[O:28])[C:22]=1[CH2:23][CH:24]=[C:25]([CH3:27])[CH3:26])[C@:10]3([CH3:20])[CH2:14][CH2:15][CH:16]=[C:17]([CH3:19])[CH3:18].BrB(C)C.CCCCCC.CC[O:48]C(C)=O>>[OH:12][C@@H:11]1[C@@:10]([CH3:20])([CH2:14][CH2:15][CH:16]=[C:17]([CH3:18])[CH3:19])[C@@H:9]2[C@:8]([OH:48])([O:29][CH3:30])[C@@:7]([CH2:31][CH:32]=[C:33]([CH3:34])[CH3:35])([C:6]([O:5][CH3:4])=[C:22]([CH2:23][CH:24]=[C:25]([CH3:26])[CH3:27])[C:21]2=[O:28])[CH2:13]1
Reactant: CCOC(C)=O
Reactant: COC1=C(CC=C(C)C)C(=O)[C@H]2[C@]3(OC)OC(C[C@]13CC=C(C)C)[C@@]2(C)CCC=C(C)C
Agent: CB(C)Br
Solvent: ClCCl
Solvent: CCCCCC
Product: COC1=C(CC=C(C)C)C(=O)[C@@H]2[C@](C)(CCC=C(C)C)[C@@H](O)C[C@@]1(CC=C(C)C)[C@@]2(O)OC
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 88 %

Procedure:
A DCM (2 mL) solution of 15 (29 mg, 6.6 μmol, 1 equiv.) was cooled to −78° C. in a 10-mL teardrop-shaped flask, and a DCM solution of bromodimethylborane (2.65 M, 0.25 mL, 0.66 mmol, 10 equiv.) was added dropwise. After stirring the bright yellow solution at −78° C. for 10 min, it was quenched sequentially at −78° C. with 1.25 mL NEt3 and saturated aqueous NaHCO3. The mixture was warmed to room temperature and extracted thrice with EtOAc. The organic extracts were combined, washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo to yield a yellow residue. Flash column chromatography (30 mL SiO2, 9:1 hexane:EtOAc) afforded 26.7 mg (58 μmol, 88% yield) of 17 as a yellow oil. TLC Rf 0.38 (7:3 hexane:EtOAc). 1H NMR (600 MHz; C6D6): δ 5.55 (dq, J=11.5, 1.3 Hz, 1H), 5.35 (t, J=7.3 Hz, 1H), 5.28 (t, J=6.6 Hz, 1H), 3.71 (s, 1H), 3.67 (dd, J=11.8, 5.3 Hz, 1H), 3.53 (s, 3H), 3.34 (dd, J=15.2, 6.4 Hz, 1H), 3.16 (m, 1H), 3.14 (s, 1H), 3.06 (s, 3H), 2.92 (dd, J=14.1, 11.5 Hz, 1H), 2.86 (tdd, J=12.8, 7.7, 5.0 Hz, 1H), 2.26 (d, J=14.1 Hz, 1H), 2.08 (tt, J=12.5, 6.1 Hz, 1H), 2.00 (dd, J=12.8, 12.0 Hz, 1H), 1.84 (s, 3H), 1.72 (s, 3H), 1.72-1.68 (m, 1H), 1.62 (s, 6H), 1.60-1.58 (m, 1H), 1.56 (s, 3H), 1.42 (s, 3H), 1.27 (td, J=12.7, 4.4 Hz, 1H), 1.12 (s, 3H). 13C NMR (126 MHz; C6D6): δ 197.3, 171.2, 136.5, 131.8, 131.1, 125.8, 124.5, 123.36, 123.23, 100.2, 73.4, 61.8, 57.5, 52.4, 48.2, 40.9, 39.7, 37.5, 30.8, 26.0, 25.76, 25.72, 23.7, 22.2, 18.01, 17.90, 17.7, 17.3. FTIR (thin film) νmax: 3464 (br), 2969, 2928, 2859, 1665, 1615, 1450, 1376, 1329, 1235, 1087, 1040, 986, 928, 907, 858, 737 cm-1. HRMS-ESI (m/z): [M+H]+ calculated for C28H44O5, 461.3262. found, 461.3254.
Reaction SMILES: F[C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=O)=[CH:4][C:3]=1[C:11](=O)[CH2:12][CH3:13].[NH2:15][NH2:16].O=P(Cl)(Cl)Cl.[NH2:22][NH:23][C:24]([NH2:26])=[S:25]>>[CH2:12]([C:11]1[C:3]2[C:2](=[CH:10][CH:9]=[C:5]([C:6]3[S:25][C:24]([NH2:26])=[N:23][N:22]=3)[CH:4]=2)[NH:16][N:15]=1)[CH3:13]
Reactant: NN
Reactant: NNC(N)=S
Reactant: CCC(=O)c1cc(C(=O)O)ccc1F
Solvent: O=P(Cl)(Cl)Cl
Product: CCc1n[nH]c2ccc(-c3nnc(N)s3)cc12

Procedure:
4-Fluoro-3-propionylbenzoic acid was synthesized by treating the commercial available 3-bromo-4-fluorobenzoic acid with 1-ethoxyprop-1-ene (6 equivalents), palladium acetate (0.03 equivalents), 1,3-Bis-(diphenylphosphino)-propane (0.06 equivalents) and potassium carbonate (1.2 equivalents) in DMF and water under microwave at 130° C. for 3 hours following with an acid treatment. 3-Ethyl-1H-indazole-5-carboxylic acid was obtained by treating 4-Fluoro-3-propionylbenzoic acid with hydrazine under microwave at 160° C. for half an hour. 5-(3-ethyl-1H-indazol-5-yl)-1,3,4-thiadiazol-2-amine was prepared in a manner similar to that shown in scheme 3 with POCl3 and thiosemicarbazide. MS (API-ES) m/z (%): 246 (100%, M++1).
Reaction SMILES: C(OC([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([CH2:15][C:16]2[C:24]3[O:23][CH:22]=[CH:21][C:20]=3[CH:19]=[C:18]([NH2:25])[CH:17]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[S:26]1[CH:30]=[CH:29][CH:28]=[C:27]1[S:31]([Cl:34])(=[O:33])=[O:32]>>[ClH:34].[ClH:34].[N:11]1([CH2:15][C:16]2[C:24]3[O:23][CH:22]=[CH:21][C:20]=3[CH:19]=[C:18]([NH:25][S:31]([C:27]3[S:26][CH:30]=[CH:29][CH:28]=3)(=[O:33])=[O:32])[CH:17]=2)[CH2:12][CH2:13][CH2:14][NH:8][CH2:9][CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCCN(Cc2cc(N)cc3ccoc23)CC1
Reactant: O=S(=O)(Cl)c1cccs1
Product: Cl
Product: O=S(=O)(Nc1cc(CN2CCCNCC2)c2occc2c1)c1cccs1
Reaction time: 1 h
Yield: 26.9 %

Procedure:
The title compound was prepared according to the procedure of Example 106, Step 3, starting from 4-(5-amino-benzofuran-7-ylmethyl)-1,4-diazepane-1-carboxylic acid tert-butyl ester (36 mg, 0.10 mmol; obtained in Example 109, Step 2) and 2-thiophenesulfonyl chloride (29 mg, 0.16 mmol). Additional 2-thiophenesulfonyl chloride (10 mg, 0.06 mmol) was added with continuous stirring for 1 h. The title compound (10 mg, 22%) was obtained as a colorless solid. HPLC 100%, RT=1.20 min (System A; 10-97% MeCN over 3 min), 100%, RT=1.06 min (System B; 10-97% MeCN over 3 min). 1H NMR (400 MHz, methanol-d4) δ ppm 2.20-2.29 (m, 2H) 3.34-3.41 (m, 2H) 3.41-3.55 (m, 2H) 3.63-3.69 (m, 2H) 3.69-3.77 (m, 2H) 4.66 (s, 2H) 6.84 (d, J=2.26 Hz, 1H) 6.98 (dd, J=5.02, 3.76 Hz, 1H) 7.32 (d, J=2.01 Hz, 1H) 7.42 (dd, J=3.76, 1.25 Hz, 1H) 7.47 (d, J=2.26 Hz, 1H) 7.63 (dd, J=5.02, 1.25 Hz, 1H) 7.82 (d, J=2.26 Hz, 1H). MS (ESI+) for C18H21N3O3S2 m/z 392 (M+H)+.
Reaction SMILES: [CH2:1]([C:8]1[CH:17]=[CH:16][C:11]2[NH:12][C:13](=[S:15])[NH:14][C:10]=2[CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:18][C:19]([CH:21]=[CH2:22])=[O:20]>>[CH2:1]([C:8]1[CH:17]=[CH:16][C:11]2[N:12]([CH2:22][CH2:21][C:19](=[O:20])[CH3:18])[C:13](=[S:15])[NH:14][C:10]=2[CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=CC(C)=O
Reactant: S=c1[nH]c2ccc(Cc3ccccc3)cc2[nH]1
Product: CC(=O)CCn1c(=S)[nH]c2cc(Cc3ccccc3)ccc21

Procedure:
16 g (66.7 mmoles) of 5-benzyl-benzimidazoline-2-thione are stirred in 30 ml of methylvinylketone for 25 hours. The excess of the detone is distilled off under vacuum (0.1 to 0.2 bars), 50 ml of isopropanol are poured onto the residue, then the solvent is distilled off. Upon pouring ether onto the residue, crystalls are obtained. These are filtered off, and recrystallized from acetonitrile, then ethanol. The title product thus obtained melts at a temperature of 141°-142° C.
Reaction SMILES: C[O:2][C:3](=[O:30])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:18]=[C:17]([C:19]([CH3:22])([CH3:21])[CH3:20])[C:16]([O:23][CH3:24])=[C:15]([C:25]([CH3:28])([CH3:27])[CH3:26])[CH:14]=2)=[CH:7][C:6]=1[F:29].[OH-].[Na+].C(O)C.O>C(#N)C>[C:19]([C:17]1[CH:18]=[C:13]([CH2:12][CH2:11][C:8]2[CH:9]=[CH:10][C:5]([CH2:4][C:3]([OH:30])=[O:2])=[C:6]([F:29])[CH:7]=2)[CH:14]=[C:15]([C:25]([CH3:26])([CH3:28])[CH3:27])[C:16]=1[O:23][CH3:24])([CH3:20])([CH3:21])[CH3:22]
Reactant: COC(=O)Cc1ccc(C#Cc2cc(C(C)(C)C)c(OC)c(C(C)(C)C)c2)cc1F
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: CC#N
Product: COc1c(C(C)(C)C)cc(CCc2ccc(CC(=O)O)c(F)c2)cc1C(C)(C)C

Procedure:
Following General Procedure I and using [4-(3,5-di-tert-butyl-4-methoxy-phenylethynyl)-2-fluoro-phenyl]-acetic acid methyl ester (Compound 144, 0.122 g, 0.29 mmol), 5M aqueous sodium hydroxide solution (1 mL) and ethanol (4 mL), followed preparative reverse phase HPLC using 10% water in acetonitrile as the mobile phase, the title compound was obtained as a white solid (0.077 g, 65%).
Reaction SMILES: C1(S[CH2:8][N:9]2[C:13](=[O:14])[CH:12]([CH2:15][CH2:16][CH3:17])[NH:11][S:10]2(=[O:19])=[O:18])C=CC=CC=1.S(Cl)([Cl:23])(=O)=O>C(Cl)Cl>[Cl:23][CH2:8][N:9]1[C:13](=[O:14])[CH:12]([CH2:15][CH2:16][CH3:17])[NH:11][S:10]1(=[O:19])=[O:18]
Reactant: CCCC1NS(=O)(=O)N(CSc2ccccc2)C1=O
Reactant: O=S(=O)(Cl)Cl
Solvent: ClCCl
Product: CCCC1NS(=O)(=O)N(CCl)C1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 38 %

Procedure:
To a solution of 2-phenylthiomethyl-4-propyl-1,2,5-thiadiazolidin-3-one 1,1-dioxide (1.1 g, 3.6 mmol) in 10 ml of methylene chloride was added sulfuryl chloride (0.44 ml, 5.5 mmol) and the mixture was stirred for 3 hours at room temperature. The mixture was concentrated in vacuo, the residue triturated in hexane (50ml) for 1 hour, the resulting solid filtered and purified by silica gel flash column chromatography (20-25% of ethyl acetate in hexane) to afford 0.31 g of 2-chloromethyl-4-propyl-1,2,5-thiadiazolidin-3-one 1,1-dioxide (Formula II: R1 =H; R2 =propyl; R3 =H; X'=Cl) as a solid, m.p. 62°-63.5° C.
Reaction SMILES: Cl.[NH2:2][CH:3]([C:9](=O)[CH3:10])[C:4]([O:6][CH2:7][CH3:8])=[O:5].[C:12](=[NH:17])(OCC)[CH3:13].C(N(CC)CC)C>C(O)C>[CH3:13][C:12]1[NH:2][C:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])=[C:9]([CH3:10])[N:17]=1
Reactant: CCOC(C)=N
Reactant: CCOC(=O)C(N)C(C)=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCOC(=O)c1[nH]c(C)nc1C
Reaction time: 8 h
Yield: 23.8 %

Procedure:
Ethyl 2-amino-3-oxobutanoate hydrochloride (5 g) was added portionwise to a solution of ethyl ethaneimidate (34.0 g) and triethylamine (42 ml) in ethanol (500 ml), and the resulting yellow solution was stirred overnight. Solvent was removed in vacuo and the residue partitioned between water (200 ml) and ether (200 ml). The organic layer was separated and the aqueous phase further extracted with ether (2×200 ml). The dried organic extracts were evaporated in vacuo and the residue washed with cold ether and filtered to give the title compound as a white solid (1.1 g). m.p. 165-166° C.
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4](=[S:16])[C:5]([C:14]#[N:15])=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:7]=1.[CH:17](Br)([CH3:19])[CH3:18].CC[O-].[Na+]>C(O)C>[NH2:1][C:2]1[N:3]=[C:4]([S:16][CH:17]([CH3:19])[CH3:18])[C:5]([C:14]#[N:15])=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:7]=1
Reactant: CC(C)Br
Reactant: N#Cc1c(-c2ccccc2)nc(N)[nH]c1=S
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CC(C)Sc1nc(N)nc(-c2ccccc2)c1C#N

Procedure:
From 2-amino-4-phenyl-6-thioxo-1,6-dihydro-pyrimidine-5-carbonitrile, isopropyl bromide and sodium ethylate in ethanol. EI-MS m/e (%): 270 (M+, 30), 269 ([M—H]+, 100).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[C:5]([OH:7])=O.C(N1C=CN=C1)(N1C=CN=C1)=O.[Mg+].[C:25]([O:31][CH2:32][CH3:33])(=[O:30])[CH2:26]C([O-])=O.Cl>O1CCCC1.O.C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[C:4]([C:5](=[O:7])[CH2:26][C:25]([O:31][CH2:32][CH3:33])=[O:30])[CH:8]=[CH:9][C:10]=1[F:11]
Reactant: O=C(O)c1ccc(F)c(F)c1
Reactant: CCOC(=O)CC(=O)[O-]
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [Mg+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)CC(=O)c1ccc(F)c(F)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 129.7 %

Procedure:
To a solution of 3,4-difluorobenzoic acid (10 g, 63.3 mmol) in tetrahydrofuran (300 ml) was added 1,1′-carbonylbis-1H-imidazole (11.3 g, 69.6 mmol) and the mixture was stirred at room temperature for 30 min. To the reaction solution was added monoethyl malonate magnesium salt (10 g, 34.8 mmol) and the mixture was stirred at room temperature for 2 hrs. To the reaction solution were added ethyl acetate (50 ml) and water (50 ml), and conc. hydrochloric acid was added until the aqueous layer showed acidic pH. The reaction solution was extracted with ethyl acetate (200 ml×2). The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1) to give ethyl 3-(3,4-difluorophenyl)-3-oxopropionate (10.3 g, 77%) as a brown oil.
Reaction SMILES: CCCCCC.C([Li])CCC.[CH3:12][C:13]1[CH:25]=[C:24]([CH3:26])[C:23]([O:27][CH3:28])=[C:22]2[C:14]=1[CH:15]1[C:20](=[CH:21]2)[CH2:19][CH2:18][CH2:17][CH2:16]1.[CH2:29]([O:31][CH:32]([O:35][CH2:36][CH3:37])[CH2:33]Br)[CH3:30].[Cl-].[NH4+]>O1CCCC1.C(OCC)C>[CH3:12][C:13]1[CH:25]=[C:24]([CH3:26])[C:23]([O:27][CH3:28])=[C:22]2[C:14]=1[C:15]1[CH2:16][CH2:17][CH2:18][CH2:19][C:20]=1[CH:21]2[CH2:33][CH:32]([O:35][CH2:36][CH3:37])[O:31][CH2:29][CH3:30]
Reactant: COc1c(C)cc(C)c2c1C=C1CCCCC12
Reactant: CCOC(CBr)OCC
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: CCCCCC
Product: CCOC(CC1C2=C(CCCC2)c2c(C)cc(C)c(OC)c21)OCC
Reaction time: 0.67 h

Procedure:
19 Milliliters of a 15% n-butyl lithium n-hexane solution was added dropwise to a tetrahydrofuran solution containing 5.0 g of 5,7-dimethyl-8-methoxy-2,3,4,4a-tetrahydro-1H-fluorene in 50 ml of tetrahydrofuran at -50° C. After stirring at the same temperature for 40 minutes, thereto was added dropwise 6 ml of bromoacetoaldehyde diethyl acetal at the same temperature, followed by stirring at the same temperature for 1.5 hour. To the reaction mixture was added a saturated aqueous ammonium chloride solution and this was diluted with diethyl ether, washed with water twice and then with a saturated aqueous sodium chloride solution and then dried with magnesium sulfate. The solvent was distilled off and the residue was purified by a silica gel column chromatography (eluent: ethyl acetate:n-hexane=1:30) to obtain 5.68 g of 5,7-dimethyl-8-methoxy-9-(2,2-diethoxyethyl)-1,2,3,4-tetrahydro-9H-fluorene.
Reaction SMILES: [C:1]1(N=C=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:10][C:11]([NH2:13])=[S:12].C[N:15](C)[CH:16]=[O:17]>>[C:1]1([NH:10][C:11]([NH:13][C:16]([NH2:15])=[O:17])=[S:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NC(N)=S
Reactant: O=C=Nc1ccccc1
Reactant: CN(C)C=O
Product: NC(=O)NC(=S)Nc1ccccc1
Temperature: 0 °C

Procedure:
As the first step in the reaction, phenyl isocyanate, 119 grams (1 mole) is added in one portion with swirling to a warm solution of 83.73 grams (1.1 mole) of thiourea in 120 milliliters of dry dimethylformamide and the resulting solution heated for three hours. Thereafter, the solution is cooled, a mixture of ice and ice water cautiously added and the vessel scratched to induce crystallization of the desired intermediate N-phenylthioimidodicarbonic diamide. After crystallization starts, additional ice water (to about 1 liter) is added. The crystals which form are then recovered, washed with water and recrystallized from methanol to obtain 127 grams of a N-phenylthioimidodicarbonic diamide intermediate product, m.p. 176°-180° C.
Reaction SMILES: Br.[CH2:2]([C:4]1[S:8][C:7](=[NH:9])[N:6]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]#[N:24])=[CH:13][CH:12]=2)[N:5]=1)[CH3:3].C[Sn]([N:29]=[N+:30]=[N-:31])(C)C.Cl>C1(C)C=CC=CC=1>[CH2:2]([C:4]1[S:8][C:7](=[NH:9])[N:6]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]3[NH:31][N:30]=[N:29][N:24]=3)=[CH:13][CH:12]=2)[N:5]=1)[CH3:3]
Reactant: C[Sn](C)(C)N=[N+]=[N-]
Reactant: CCc1nn(Cc2ccc(-c3ccccc3C#N)cc2)c(=N)s1
Agent: Br
Agent: Cl
Solvent: Cc1ccccc1
Product: CCc1nn(Cc2ccc(-c3ccccc3-c3nnn[nH]3)cc2)c(=N)s1
Yield: 3.1 %

Procedure:
In 20 ml of toluene, 2.0 g of 5-ethyl-2-imino-3-(2'-cyanobiphenyl-4-yl)methyl-1,3,4-thiadiazoline.hydrobromide and 1.1 g of trimethyltin azide were suspended, followed by heating under reflux for 6 hours. After cooling, the reaction mixture was subjected to column chromatography on a silica gel and eluted using chloroform:methanol (20:1)→chloroform:methanol:acetic acid (20:10:1). The eluate fraction thus obtained were then distilled off under reduced pressure. To the residue, 40 ml of 2N sodium hydroxide and 40 ml of ethyl acetate were added. The aqueous layer so obtained was neutralized with 12N hydrochloric acid and powders so precipitated were collected by filtration. The powders were washed successively with water, ethanol and then diethyl ether and then dried, whereby 56 mg of the title compound was obtained.
Reaction SMILES: C(OC(=O)[N:7](C)[C@@H:8]([C:16](=[O:24])[NH:17][CH2:18][CH:19]1[CH2:23][CH2:22][CH2:21][O:20]1)[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(C)(C)C.F[C:28](F)(F)C(O)=O.C(=O)([O-])O.[Na+].C(=O)([O-])[O-].[Na+].[Na+].C(=O)([O-])O.[Na+]>C(Cl)Cl>[CH3:28][C@@:8]([NH2:7])([CH2:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[C:16]([NH:17][CH2:18][CH:19]1[CH2:23][CH2:22][CH2:21][O:20]1)=[O:24]
Reactant: CN(C(=O)OC(C)(C)C)[C@H](Cc1ccccc1)C(=O)NCC1CCCO1
Reactant: O=C(O)C(F)(F)F
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: C[C@@](N)(Cc1ccccc1)C(=O)NCC1CCCO1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Methyl-((1R)-2-phenyl-1-((tetrahydrofuran-2-ylmethyl)carbamoyl)ethyl)carbamic acid tert-butyl ester (5.5 g; 15.2 mmol) was dissolved in methylene chloride (20 mL) and trifluoroacetic acid (20 mL) was added. The reaction mixture was stirred for 1 hour at room temperature. Methylene chloride (100 mL) and an aqueous solution of sodium hydrogen carbonate/sodium carbonate (pH 9, 50 mL) were added and solid sodium hydrogen carbonate was added until pH 8. The aquous phase was extracted with methylene chloride (100 mL) and the combined organic phases were dried (magnesium sulfate). The solvent was removed in vacuo to afford 3.62 g of (2R)-2-Methyl-amino-3-phenyl-N-((2-tetrahydrofuranyl)methyl)propionamide.