Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClCCOC1C=C(C=CC=1)C#N.Cl[CH2:14][CH2:15][CH2:16][O:17][C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][CH:25]=1)[C:21]#[N:22].N1C=NC(S)=N1.[NH:32]1[CH:36]=[CH:35][N:34]=[CH:33]1>>[N:32]1([CH2:14][CH2:15][CH2:16][O:17][C:18]2[CH:19]=[C:20]([CH:23]=[CH:24][CH:25]=2)[C:21]#[N:22])[CH:36]=[CH:35][N:34]=[CH:33]1
Reactant: N#Cc1cccc(OCCCCl)c1
Reactant: c1c[nH]cn1
Agent: N#Cc1cccc(OCCCl)c1
Agent: Sc1nc[nH]n1
Product: N#Cc1cccc(OCCCn2ccnc2)c1

Procedure:
By a method similar to that in Reference Example 2, and using, instead of 3-[(2-chloroethyl)oxy]benzonitrile, 3-[(3-chloropropyl)oxy]benzonitrile obtained in Reference Example 4 and using, instead of 1H-1,2,4-triazole-3-thiol, 1H-imidazole, the title compound was obtained as a colorless oil (1.65 g, 71%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)[N:11](CC3C=CC(C(OC)=O)=CC=3)[N:10]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[CH3:33][OH:34].[OH-:35].[Na+]>C1COCC1>[Cl:8][C:6]1[CH:5]=[C:4]([C:9]2[N:10]([CH2:9][C:4]3[CH:5]=[CH:6][C:7]([C:33]([OH:35])=[O:34])=[CH:2][CH:3]=3)[N:11]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)[CH:13]=2)[CH:3]=[C:2]([Cl:1])[CH:7]=1
Reactant: [OH-]
Reactant: COC(=O)c1ccc(Cn2nc(-c3cc(Cl)cc(Cl)c3)cc2-c2ccc(OC)cc2)cc1
Reactant: CO
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc(-c2cc(-c3cc(Cl)cc(Cl)c3)n(Cc3ccc(C(=O)O)cc3)n2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of the intermediate from example 73 step C (Isomer B, 0.43 g, 0.92 mmol) in THF (30 mL) was added methanol (10 mL) followed by sodium hydroxide solution (2N, 2 mL, 4 mmol). The reaction was stirred at room temperature overnight. The reaction mixture was concentrated in vacuo to remove the organic solvents. The residue was acidified with 1N HCl until the pH was less than 2. The resulting solution was extracted with ethyl acetate (3×) dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give the title compound as a white solid. This material was used in the next step without any further purification. 1H NMR (DMSO, 500 MHz): δ 7.86(d, J=8.5 Hz, 2H), 7.77(d, J=8.7 Hz, 2H), 7.67(s, 1H), 7.5(d, J=1.8 Hz, 2H), 7.14(d, J=8.3 Hz, 2H), 7.04(s, 1H), 6.98(d, J=8.9 Hz, 2H), 5.52(s, 2H), 3.77(s, 3H). LC-MS: 2.55 min; (M+H)=453.1.
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH2:7][C:8]([CH3:10])=[CH2:9])=[C:5]([CH3:11])[S:4][C:3]=1[C:12]([OH:14])=O.[CH3:15][Li]>C(OCC)C>[CH3:1][C:2]1[C:6]([CH2:7][C:8]([CH3:10])=[CH2:9])=[C:5]([CH3:11])[S:4][C:3]=1[C:12](=[O:14])[CH3:15]
Reactant: [Li]C
Reactant: C=C(C)Cc1c(C)sc(C(=O)O)c1C
Solvent: CCOCC
Product: C=C(C)Cc1c(C)sc(C(C)=O)c1C
Reaction time: 1 h

Procedure:
To a solution of 3,5-dimethyl-4-(2-methyl-allyl)-thiophene-2-carboxylic acid (475 mg, 2.26 mmol) in diethyl ether (15 mL), a solution of methyllithium (3.0 mL, 1.6 M in diethyl ether) is added at rt. The mixture is stirred at rt for 1 h before another portion of methyllithium (0.45 mL) is added. Stirring is continued for 1 h. The reaction is quenched by the addition of 1 N aq. NaH2PO4 solution. The mixture is diluted with diethyl ether, washed with 1 N aq. NaOH, dried over Na2SO4 and evaporated to give 1-[3,5-dimethyl-4-(2-methyl-allyl)thiophen-2-yl]-ethanone (395 mg) as a yellow oil; LC-MS: tR=1.03 min, [M+1]=209.14.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:13]=[C:12]([Br:14])[C:11]([OH:15])=[C:6]([C:7]([O:9][CH3:10])=[O:8])[CH:5]=1.C(N(C(C)C)CC)(C)C.[CH3:26][O:27][CH2:28]Cl>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:13]=[C:12]([Br:14])[C:11]([O:15][CH2:26][O:27][CH3:28])=[C:6]([C:7]([O:9][CH3:10])=[O:8])[CH:5]=1
Reactant: COCCl
Reactant: COC(=O)c1cc(Br)c(O)c(C(=O)OC)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: COCOc1c(Br)cc(C(=O)OC)cc1C(=O)OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 60.1 %

Procedure:
To a solution of 5-bromo-4-hydroxyisophthalic acid dimethyl ester (12.3 g) in chloroform (130 mL) were successively added diisopropylethylamine (8.24 g) and methoxymethyl chloride (4.11 g) under ice-cooling, and the mixture was stirred at room temperature overnight. The reaction solution was washed successively with 1N hydrochloric acid, water, and saturated brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=5:1, v/v) to give the title compound (8.52 g).
Reaction SMILES: [O:1]1[CH:7]2[CH:2]1[CH2:3][CH:4]([C:8]([O-:10])=[O:9])[CH2:5][CH2:6]2.[Cl-].[NH4+].[N-:13]=[N+:14]=[N-:15].[Na+]>CN(C)C=O>[N:13]([C@H:7]1[CH2:6][CH2:5][C@@H:4]([C:8]([O:10][CH2:8][C:4]2[CH:5]=[CH:6][CH:7]=[CH:2][CH:3]=2)=[O:9])[CH2:3][C@@H:2]1[OH:1])=[N+:14]=[N-:15]
Reactant: O=C([O-])C1CCC2OC2C1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: [N-]=[N+]=N[C@H]1CC[C@@H](C(=O)OCc2ccccc2)C[C@@H]1O
Temperature: 70 °C
Reaction time: 24 h
Yield: 121.2 %

Procedure:
Benzyl (1R*,3S*, 4R*)-3,4-epoxycyclohexane-1-carboxylate (52.3 g) was dissolved in N,N-dimethylformamide (1000 ml), ammonium chloride (21.9 g) and sodium azide (18.1 g) were added, and the mixture was heated to 70° C. and stirred for 24 hours. The solvent was distilled off under reduced pressure, and water was added to conduct extraction with ethyl acetate. The resultant organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound (61.8 g) as a colorless oil.
Reaction SMILES: [C:1]([C:9]1[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=1[C:11]([NH2:13])=[O:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C=O.[CH2:20]([OH:22])C.C([O-])([O-])=O.[K+].[K+]>O>[OH:22][CH2:20][NH:13][C:11](=[O:12])[C:10]1[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=1[C:1](=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCO
Reactant: NC(=O)c1ccccc1C(=O)c1ccccc1
Agent: C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: O=C(NCO)c1ccccc1C(=O)c1ccccc1

Procedure:
A mixture of 2.25g. (0.01 mole) of o-benzoylbenzamide, 4 ml. of aqueous formaldehyde solution (38%), 4 ml. of ethanol and 4 ml. of a solution of 1g. K2CO3 in 35 ml. water was refluxed for 20 hours. It was then allowed to cool and the crystalline product was filtered off and washed with water to yield 2.2g. (85%) of analytically pure material, m.p. 166/8°C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][CH:23]=1)[O:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]([CH:12]=[C:13]([NH:15][C:16]([CH:18]3[CH2:20][CH2:19]3)=[O:17])[N:14]=2)[N:11]=1.[C:24]([C:26]([C:29]1[CH:30]=[C:31]([CH:35]=[CH:36][CH:37]=1)[C:32](O)=[O:33])([CH3:28])[CH3:27])#[N:25].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>CN(C)C=O>[C:24]([C:26]([C:29]1[CH:30]=[C:31]([CH:35]=[CH:36][CH:37]=1)[C:32]([NH:1][C:2]1[CH:23]=[CH:22][CH:21]=[C:4]([O:5][C:6]2[CH:7]=[CH:8][C:9]3[N:10]([CH:12]=[C:13]([NH:15][C:16]([CH:18]4[CH2:20][CH2:19]4)=[O:17])[N:14]=3)[N:11]=2)[CH:3]=1)=[O:33])([CH3:28])[CH3:27])#[N:25]
Reactant: Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)c1
Reactant: CC(C)(C#N)c1cccc(C(=O)O)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CC(C)(C#N)c1cccc(C(=O)Nc2cccc(Oc3ccc4nc(NC(=O)C5CC5)cn4n3)c2)c1
Yield: 78 %

Procedure:
Using N-[6-(3-aminophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (100 mg, 0.32 mmol), 3-(1-cyano-1-methylethyl)benzoic acid (62 mg, 0.33 mmol), N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (65 mg, 0.34 mmol), 1-hydroxybenzotriazole (46 mg, 0.34 mmol) and N,N-dimethylformamide (5.0 mL) as starting materials and in the same manner as in Example 318, the title compound (120 mg, 77%) was obtained as a white powder.
Reaction SMILES: [C:1]([NH:9][NH2:10])(=[O:8])[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.ClC1C=CC(C(NN)=O)=CC=1.[CH3:22][N:23]=[C:24]=[O:25].C(N=C=O)C>>[N:5]1[CH:6]=[CH:7][C:2]([C:1]([NH:9][NH:10][C:24]([NH:23][CH3:22])=[O:25])=[O:8])=[CH:3][CH:4]=1
Reactant: NNC(=O)c1ccncc1
Reactant: CN=C=O
Agent: CCN=C=O
Agent: NNC(=O)c1ccc(Cl)cc1
Product: CNC(=O)NNC(=O)c1ccncc1

Procedure:
When, in the procedure of Example 1, isonicotinic acid hydrazide is substituted for 4-chlorobenzoic acid hydrazide and methyl isocyanate is substituted for ethyl isocyanate, the title compound is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][CH:15]=1)[C:12](=[O:16])[C:11]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:17])[C:6]=1[O:5]2.[Br:18]N1C(=O)CCC1=O>>[Br:18][CH2:17][C:7]1[C:6]2[O:5][C:4]3[C:13](=[CH:14][CH:15]=[C:2]([Cl:1])[CH:3]=3)[C:12](=[O:16])[C:11]=2[CH:10]=[CH:9][CH:8]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cccc2c(=O)c3ccc(Cl)cc3oc12
Product: O=c1c2ccc(Cl)cc2oc2c(CBr)cccc12

Procedure:
The above compound (VI: R1 =6-Cl; Z=CH3) was then treated with N-bromosuccinimide as in Example A to give 4-bromomethyl-6-chloroxanthenone (VII: R1 =6-Cl, Z=CH2Br), mp (benzene/petroleum ether) 217°-218° C. Anal. (C14H8BrClO2) C, H,N.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([NH:10][C:11]([CH3:15])([CH3:14])[CH2:12]O)=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.S(Cl)([Cl:18])=O>>[Cl:1][C:2]1[C:7]([C:8]([NH:10][C:11]([CH3:15])([CH3:14])[CH2:12][Cl:18])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: O=S(Cl)Cl
Reactant: CC(C)(CO)NC(=O)c1cccnc1Cl
Product: CC(C)(CCl)NC(=O)c1cccnc1Cl
Temperature: 0 °C

Procedure:
76.8 g (0.336 mole) of 2-chloro 3-(1,1-dimethyl-2-hydroxy-ethyl)aminocarbonyl pyridine are placed in a reaction vessel immersed in a cooling bath (ice+water). 244 ml (3.36 moles) of thionyl chloride are then added so as to maintain the temperature below 20° C.
Reaction SMILES: [CH2:1]1[CH2:14][O:13][C:12]2[CH:11]=[CH:10][C:5]([C:6](=O)[CH2:7]Br)=[CH:4][C:3]=2[O:2]1.[N:15]1([CH2:21][CH2:22][CH2:23][NH:24][C:25]([NH2:27])=[S:26])[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1.C(N(CC)C(C)C)(C)C.[S:37]1[CH:41]=[CH:40][CH:39]=[C:38]1[C:42](Cl)=[O:43]>C(O)C>[O:13]1[CH2:14][CH2:1][O:2][C:3]2[CH:4]=[C:5]([C:6]3[N:27]=[C:25]([N:24]([CH2:23][CH2:22][CH2:21][N:15]4[CH2:16][CH2:17][O:18][CH2:19][CH2:20]4)[C:42]([C:38]4[S:37][CH:41]=[CH:40][CH:39]=4)=[O:43])[S:26][CH:7]=3)[CH:10]=[CH:11][C:12]1=2
Reactant: NC(=S)NCCCN1CCOCC1
Reactant: O=C(Cl)c1cccs1
Reactant: O=C(CBr)c1ccc2c(c1)OCCO2
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1cccs1)N(CCCN1CCOCC1)c1nc(-c2ccc3c(c2)OCCO3)cs1
Temperature: 25 °C
Yield: 50.9 %

Procedure:
A mixture of 3,4-(ethylenedioxy)phenacyl bromide (77 mg, 0.3 mmol) and (3-morpholin-4-yl-propyl)-thiourea (61 mg, 0.3 mmol) in dry ethanol (3 mL) was heated at reflux for 10 min, cooled to room temperature, and concentrated in vacuo. The resulting residue was suspended in dichloromethane (3 mL) followed by the addition of N,N-diisopropylethylamine (105 μL, 0.6 mmol) and thiophene-2-carbonyl chloride (34 μL, 0.32 mmol). The reaction mixture was maintained at room temperature overnight, then concentrated in vacuo. The resulting residue was dissolved in DMSO (1.5 mL) and subjected to HPLC purification (Method Y). The resulting free amine was dissolved in MeOH (1 mL) and 1M HCl/ether (50 mL) was added. The precipitate was filtered and dried in vacuo to provide the title compound (72 mg) as an off-white solid as the hydrochloride salt. LC/MS (ESI) m/z 472.3 [M+H]. HPLC retention time (Method A)=2.72 min.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([NH:9]C=O)=[C:4]([Cl:12])[N:3]=1.O.P(=O)(O)(O)O>C(O)C>[NH2:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([NH2:9])=[C:4]([Cl:12])[N:3]=1
Reactant: Nc1nc(Cl)c(NC=O)c(Cl)n1
Agent: O=P(O)(O)O
Solvent: O
Solvent: CCO
Product: Nc1nc(Cl)c(N)c(Cl)n1

Procedure:
A mixture of 2-amino-4,6-dichloro-5-[(dimethylamino)methylene]amino}pyrimidine (Example 2, 500 mg, 2.14 mmol), pH 3.2 aqueous potassium phosphate buffer (1.5 M, 6 mL, prepared as described in Example 3), water (1 mL), and ethanol (5 mL) was refluxed gently for 28 hours. During the reflux period, pH was maintained at ca. 3 by addition of 85% phosphoric acid. Volatiles were evaporated in vacuo and the residual solids partitioned between water (30 mL, adjusted to ph 8 with dilute ammonium hydroxide) and chloroform (75 mL). The chloroform layer was dried (sodium sulfate) and the chloroform evaporated to leave off-white solid (0.30 g). Crystallization of this solid from ethanol:water/4:1 gave the title compound (IV) as light pink needles (332 mg, 61%); darkens and shrinks to black solid above 185° C., does not become fluid below 300° C.; 1H-NMR (DMSO-d6) and mass spectra identical to those described in Example 4.
Reaction SMILES: [CH:1]1([N:5]2[CH2:10][CH:9]3[CH:7]([CH:8]3[C:11]([O:13]CC)=[O:12])[CH2:6]2)[CH2:4][CH2:3][CH2:2]1.O1CCCC1.O.[OH-].[Li+].Cl>O>[CH:1]1([N:5]2[CH2:10][CH:9]3[CH:7]([CH:8]3[C:11]([OH:13])=[O:12])[CH2:6]2)[CH2:2][CH2:3][CH2:4]1
Reactant: CCOC(=O)C1C2CN(C3CCC3)CC21
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)C1C2CN(C3CCC3)CC21
Temperature: 0 °C
Reaction time: 24 h
Yield: 92 %

Procedure:
To a stirred mixture of ethyl 3-cyclobutyl-3-aza bicyclo[3.1.0]hexane-6-carboxylate (218 mg, 1.04 mmol, obtained in the above step), tetrahydrofuran (2 mL) and water (2.0 mL) cooled at 0° C., lithium hydroxide monohydrate (133 mg, 3.19 mmol) was added in a single lot. The reaction mixture was stirred at room temperature for 24 hours. The reaction mixture was cooled again to 0° C. and acidified with 2N hydrochloric acid to pH: 2-3. The volatiles were removed under reduced pressure and the traces of water were removed by azeotropic distillation with toluene to obtain 3-cyclobutyl-3-aza bicyclo[3.1.0]hexane-6-carboxylic acid (180 mg).
Reaction SMILES: [C:1]1([CH2:7][C:8]([NH:10][C@@H:11]2[C:38](=[O:39])[N:13]3[C:14]([C:26]([O:28][CH2:29][C:30]4[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=4)=[O:27])=[C:15](OS(C(F)(F)F)(=O)=O)[CH2:16][S:17][C@H:12]23)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:40][C:41]#[C:42][CH3:43].C(N(C(C)C)CC)(C)C>ClCCl>[CH3:40][C:41]1[C:15]2[C@H:16]([C:42]=1[CH3:43])[S:17][C@H:12]1[N:13]([C:38](=[O:39])[C@H:11]1[NH:10][C:8](=[O:9])[CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:14]=2[C:26]([O:28][CH2:29][C:30]1[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=1)=[O:27]
Reactant: COc1ccc(COC(=O)C2=C(OS(=O)(=O)C(F)(F)F)CS[C@@H]3[C@H](NC(=O)Cc4ccccc4)C(=O)N23)cc1
Reactant: CC#CC
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(COC(=O)C2=C3C(C)=C(C)[C@@H]3S[C@@H]3[C@H](NC(=O)Cc4ccccc4)C(=O)N23)cc1
Temperature: 25 °C
Yield: 56.8 %

Procedure:
A solution of p-methoxybenzyl (6R,7R)-7-phenylacetamido-3-(trifluoromethyl-sulphonyloxy)ceph-3-em-4-carboxylate (60 mg, 0.102 mmol) in dichloromethane (10 ml) was cooled to 0° C., 2-Butyne (1.2 ml, 15.3 mmol) was added followed by diisopropylethylamine (18 μl, 0.102 mmol). The mixture was stirred and allowed to warm to room temperature over 15 min. Chromatography gave the title compound (28.4 mg, 57%), (Found: M+, 490.1562. C27H26N2O5S requires M, 490.1562); νmax (CH2Cl2) 1783, 1716, 1684 cm-1 ; δH (CDCl3) 1.79 (3H, s), 1.97 (3H, s), 3.62 (2H, ABq, J 16.1), 3.79 (3H, s), 4.07 (1H, br s), 4.79 (1H, d, J 4.8), 5.21 (2H, ABq, J 11.8), 5.89 (1H, dd, J 8.6, 4.8), 6.06 (1H, d, J 8.6), 6.86 (2H, d, J 8.6), 7.30 (7H, m); δc (CDCl3) 12.5, 13.2, 43.3, 45.6, 55.3, 59.8, 62.3, 67.1, 111.8, 113.9 (2c), 127.4, 127.7, 129.2 (2c) 129.5 (2c), 130.8 (2c), 133.7, 135.4, 142.5, 149.1, 159.9, 161.4, 164.4, 171.2.
Reaction SMILES: [C:1]([NH2:4])(=[S:3])[CH3:2].Br[CH2:6][C:7]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=1)=O>O>[CH3:16][O:15][C:12]1[CH:13]=[CH:14][C:9]([C:7]2[N:4]=[C:1]([CH3:2])[S:3][CH:6]=2)=[CH:10][CH:11]=1
Reactant: CC(N)=S
Reactant: COc1ccc(C(=O)CBr)cc1
Solvent: O
Product: COc1ccc(-c2csc(C)n2)cc1
Temperature: 140 °C
Yield: 69.6 %

Procedure:
The mixture of thioacetamide (16.0 g, 213 mmol) and 2-bromo-1-(4-methoxy-phenyl)-ethanone (4.0 g, 17.5 mmol) was heated at 140° C. for 24 h under nitrogen atmosphere. After the completion of the reaction mixture (TLC monitoring), water (100 mL) was added and extracted with ethyl acetate (3×100 mL). The combined organics was washed with water, brine, dried (Na2SO4), filtered and concentrated. The crude residue was purified over silica gel (230-400 M, 1% EtOAc-Hexane) to get the desired product (2.5 g, 69%).
Reaction SMILES: CN(C)[C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][CH:5]=1.P(Cl)(Cl)(Cl)=O.[CH3:18][S:19][C:20]1[NH:21][CH:22]=[CH:23][CH:24]=1.C([O-])(=O)C.[Na+]>ClCCCl.O>[CH3:18][S:19][C:20]1[NH:21][C:22]([C:3](=[O:11])[C:4]2[CH:5]=[CH:6][C:7]([F:10])=[CH:8][CH:9]=2)=[CH:23][CH:24]=1
Reactant: CSc1ccc[nH]1
Reactant: CN(C)C(=O)c1ccc(F)cc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCCl
Solvent: O
Product: CSc1ccc(C(=O)c2ccc(F)cc2)[nH]1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 54.4 %

Procedure:
A solution of N,N-dimethyl-4-fluorobenzamide (8.4 g, 0.05 moles) in anhydrous 1,2-dichloroethane (170 ml) containing phosphorous oxychloride (7.7 g, 0.05 moles) was heated at reflux temperature for 1 hour. At the end of this time 2-methylthiopyrrole (2.82 g, 0.025 moles) was added and heating was continued for an additional 0.5 hour. The solution was cooled to room temperature, and to the cooled solution was cautiously added, with good agitation, a solution of sodium acetate (12.3 g, 0.15 moles) in water (50 ml) and the mixture was then boiled under reflux for 1 hour. The organic phase was separated, washed with water, dried, and evaporated. The residue was subjected to column chromatography on silica gel suing ethyl acetate-hexane (1:9) as the eluting solvent. A yellow colored solid 2-(methylthio)-5-(4-fluorobenzoyl)pyrrole (3.2 g, 54%) was obtained which after crystallization from ether-hexane had m.p. 112°-113° C.
Reaction SMILES: [SH:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([O:10]CC)=[O:9])[N:6]=1.[OH-].[Na+].C(OCC)(=O)C.Cl>O1CCOCC1.O>[SH:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([OH:10])=[O:9])[N:6]=1
Reactant: CCOC(=O)Cc1csc(S)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)Cc1csc(S)n1
Reaction time: 2 h
Yield: 68.6 %

Procedure:
To a solution of ethyl 2-mercapto-4-thiazole acetate (203 mg) in 1,4-dioxane (1.0 ml) was added 1N-sodium hydroxide solution (2.0 ml) at room temperature. After stirring at the same temperature for 2 hours, the solution was poured into a mixture of ethyl acetate and water, and adjusted to pH 8.0 with 1N-hydrochloric acid. The separated aqueous solution was adjusted to pH 3.0 with 1N-hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried over magnesium sulfate and evaporated under reduced pressure to give 2-mercapto-4-thiazole acetic acid (120 mg).
Reaction SMILES: O1CCOC1[C:6]1[C:15]([CH:16]([C:18]2[CH:22]=[CH:21][S:20][CH:19]=2)[OH:17])=[CH:14][C:13]2[C:12]([CH3:24])([CH3:23])[CH2:11][CH2:10][C:9]([CH3:26])([CH3:25])[C:8]=2[CH:7]=1.BrC1C(C2OCCO2)=CC2C(C)(C)CCC(C)(C)C=2C=1.S1C=CC(C=O)=C1.O1CCOC1C1C(C(C2SC=CC=2)O)=CC2C(C)(C)CCC(C)(C)C=2C=1>ClCCl>[S:20]1[CH:21]=[CH:22][C:18]([C:16](=[O:17])[C:15]2[CH:6]=[CH:7][C:8]3[C:9]([CH3:26])([CH3:25])[CH2:10][CH2:11][C:12]([CH3:23])([CH3:24])[C:13]=3[CH:14]=2)=[CH:19]1
Reactant: CC1(C)CCC(C)(C)c2cc(C(O)c3ccsc3)c(C3OCCO3)cc21
Agent: CC1(C)CCC(C)(C)c2cc(C(O)c3cccs3)c(C3OCCO3)cc21
Agent: CC1(C)CCC(C)(C)c2cc(C3OCCO3)c(Br)cc21
Agent: O=Cc1ccsc1
Solvent: ClCCl
Product: CC1(C)CCC(C)(C)c2cc(C(=O)c3ccsc3)ccc21
Temperature: 0 °C
Reaction time: 4 h
Yield: 33.5 %

Procedure:
A solution of 2-(1,3-dioxolane-2-yl)-3-[(thiophen-3-yl)hydroxymethyl]-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene (1.31 g, 3.86 mmol) [prepared from 3-bromo-2-(1,3-dioxolane-2-yl)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene and 3-thiophenecarboxaldehyde as previously described for the preparation of 2-(1,3-dioxolane-2-yl)-3-[(thiophene-2-yl)hydroxymethyl)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene] in 13 ml of anhydrous dichloromethane was cooled to 0° C. and Des-Martin periodinane (1.80 g, 4.25 mmol) was added over 3 minutes. The reaction was warmed to rt and stirred for 4 hours. The cloudy solution was diluted with 200 ml of dichloromethane and washed with sodium bicarbonate solution. The organic layer was washed with brine, dried over magnesium sulfate and concentrated in vacuo. This residue was then dissolved in 10 ml of tetrahydrofuran and stirred vigorously while adding 10 ml of an aqueous 1N HCl solution. Mixture was stirred for two hours and partitioned between ethyl acetate and water. The resulting organic layer was washed with brine, dried over magnesium sulfate and dried in vacuo. Chromatographic separation was achieved using a silica gel column eluting with a gradient starting with 2% ethyl acetate/hexanes to 8% ethyl acetate/hexanes to give 2-formyl-[3-((thiophen-3-yl)oxomethyl)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene (386 mg).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:15]#[N:16])[CH:13]=2)[N:8](C2CCCCO2)[N:7]=1.[N:23]([Sn](CCCC)(CCCC)CCCC)=[N+:24]=[N-:25].Cl>C1(C)C=CC=CC=1.O1CCOCC1>[N:23]1[NH:24][N:25]=[N:16][C:15]=1[C:12]1[CH:13]=[C:14]2[C:9](=[CH:10][CH:11]=1)[NH:8][N:7]=[C:6]2[C:2]1[O:1][CH:5]=[CH:4][CH:3]=1
Reactant: N#Cc1ccc2c(c1)c(-c1ccco1)nn2C1CCCCO1
Reactant: CCCC[Sn](CCCC)(CCCC)N=[N+]=[N-]
Agent: Cl
Solvent: Cc1ccccc1
Solvent: C1COCCO1
Product: c1coc(-c2n[nH]c3ccc(-c4nn[nH]n4)cc23)c1
Yield: 4.7 %

Procedure:
The title compound was prepared from 3-(2-furyl)-1-perhydro-2H-pyran-2-yl-1H-indazole-5-carbonitrile (0.095 g, 0.307 mmol), azidotributyl tin (0.245 g, 0.202 mL, 0.74 mmol) in toluene (8 mL) as described for the preparation of compound 167. Deprotection was effected by treating a dioxane solution (5 mL) with 8 mL of 4.0N solution of hydrogen chloride in 1,4-dioxane. The compound was purified by preparative HPLC (10-100% acetonitrile in H2O, 20 min) (0.008 g, 0.032 mmol, 4.7% yield over 2 steps): 1H NMR (DMSO-d6) δ 13.6 (br s, 1H), 8.8 (s, 1H), 8.1 (d, 1H), 7.9 (d, 1H), 7.8 (d, 1H), 7.1 (d, 1H), 6.7 (dd, 1H); ES-MS (m/z) 253 [M+1]+.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[H-].[Na+].[F:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17]Cl)=[CH:15][CH:14]=1.O>CS(C)=O>[F:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17][N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[CH:3]=[CH:2]2)=[CH:15][CH:14]=1
Reactant: Fc1ccc(CCl)cc1
Reactant: c1ccc2[nH]ccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: Fc1ccc(Cn2ccc3ccccc32)cc1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
A solution of 11.72 g (0.1 mol) of indole in 50 ml of dimethyl sulfoxide is added to a mixture of 2.64 g of sodium hydride (0.11 mol, mineral oil suspension) in 100 ml of dimethyl sulfoxide. The mixture is heated for 1.5 hours at 60° C., then allowed to cool and 15.9 g (0.11 mol) of 4-fluorobenzyl chloride are added dropwise. The solution is warmed to 60° C., allowed to stand overnight and then poured into 400 ml of water with stirring. The mixture is extracted several times with a total of 150 ml of methylene chloride, the organic phase is dried using anhydrous sodium sulfate and filtered, and the filtrate is concentrated in vacuo. The residue is distilled in a high vacuum: 21.0 g (96% of theory)
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[C:6](=[O:14])[CH2:7][C:8]2=[O:13])([O-])=O.[H][H].[O:17]1CC[CH2:19][CH2:18]1>C(O)C.[Pd]>[C:18]([CH:7]1[C:6](=[O:14])[C:5]2[C:9](=[CH:10][CH:11]=[CH:12][C:4]=2[NH2:1])[C:8]1=[O:13])(=[O:17])[CH3:19]
Reactant: [H][H]
Reactant: O=C1CC(=O)c2c1cccc2[N+](=O)[O-]
Reactant: C1CCOC1
Agent: [Pd]
Solvent: CCO
Product: CC(=O)C1C(=O)c2cccc(N)c2C1=O

Procedure:
To a suspension of 20.0 g of 4-nitro-1,3-indanedione in 100 mL tetrahydrofuran and 20 mL of ethanol, 1.0 g of 10% Pd/C catalyst was added and the mixture hydrogenated at 50 psi until three molar equivalents of hydrogen were taken up. The catalyst was filtered off and solvent was removed from the filtrate under reduced pressure. Recrystallization from ethanol afforded 14.8 g of the title compound, m.p. 126°-128°.