Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][O:10][C:11]2[CH:16]=[CH:15][N:14]3[C:17]([C:20]([O-:22])=O)=[CH:18][N:19]=[C:13]3[CH:12]=2)[CH2:4][CH2:3]1.[Li+].ClC1C=C(Cl)C=C(Cl)C=1C(Cl)=O.[CH:36]1([C:39]2[C:47]3[C:46]([NH2:48])=[CH:45][CH:44]=[CH:43][C:42]=3[N:41]([CH2:49][C:50]3[CH:54]=[CH:53][N:52]([CH2:55][CH3:56])[N:51]=3)[N:40]=2)[CH2:38][CH2:37]1>CN1C(=O)CCC1>[CH:36]1([C:39]2[C:47]3[C:42](=[CH:43][CH:44]=[CH:45][C:46]=3[NH:48][C:20]([C:17]3[N:14]4[CH:15]=[CH:16][C:11]([O:10][CH2:9][CH2:8][N:5]5[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]5)=[CH:12][C:13]4=[N:19][CH:18]=3)=[O:22])[N:41]([CH2:49][C:50]3[CH:54]=[CH:53][N:52]([CH2:55][CH3:56])[N:51]=3)[N:40]=2)[CH2:37][CH2:38]1
Reactant: CN1CCN(CCOc2ccn3c(C(=O)[O-])cnc3c2)CC1
Reactant: CCn1ccc(Cn2nc(C3CC3)c3c(N)cccc32)n1
Agent: O=C(Cl)c1c(Cl)cc(Cl)cc1Cl
Agent: [Li+]
Solvent: CN1CCCC1=O
Product: CCn1ccc(Cn2nc(C3CC3)c3c(NC(=O)c4cnc5cc(OCCN6CCN(C)CC6)ccn45)cccc32)n1
Temperature: 0 °C
Reaction time: 1 h
Yield: 66.8 %

Procedure:
To lithium 7-(2-(4-methylpiperazin-1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxylate (100 mg, 0.316 mmol; prepared as in Example 56, step A) was added NMP (60 mL). The reaction mixture was cooled to 0° C. and 2,4,6-trichlorobenzoyl chloride (50.4 μL, 0.316 mmol) was added dropwise. The cold bath was removed once the addition was complete. The reaction mixture was stirred for 1 hour. The reaction mixture became cloudy. 3-Cyclopropyl-1-((1-ethyl-1H-pyrazol-3-yl)methyl)-1H-indazol-4-amine (59.4 mg, 0.211 mmol) was added and the mixture was heated to 88° C. for 11 hours. The mixture was cooled to ambient temperature. Vacuum distillation was set up and NMP was removed until the reaction mixture became a thick oily residue, to which 10% NaOH aqueous solution (100 mL) was added and the resulting clear solution was stirred at 80° C. for 30 minutes. The mixture was cooled to ambient temperature and extracted with DCM. The organic phases were combined, dried (Na2SO4) and concentrated under vacuum (bath temperature at 80° C. to remove left over NMP) to a thick residue, which was triturated with Et2O (500 mL) to give the final product (80 mg). MS (ES+APCI) m/z=568 (M+H).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8](OO)=O)[CH:3]=1.C1C2CC=CCC=2C=CC=1.[C:22]([O:25][CH2:26][CH3:27])(=O)C.C(=O)(O)[O-].[Na+]>C(OCC)C>[O:25]1[CH:26]2[CH:22]1[CH2:8][C:4]1[CH:5]=[CH:6][CH:7]=[CH:2][C:3]=1[CH2:27]2
Reactant: CCOC(C)=O
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: C1=CCc2ccccc2C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Product: c1ccc2c(c1)CC1OC1C2

Procedure:
Reaction of a 5,8-dihydronaphthalene of formula III or formula IV with m-chloroperbenzoic acid yields a 5,6,7,8-tetrahydro-6,7-epoxynaphthalene having the structure ##STR6## The reaction can be carried out by mixing m-chloroperbenzoic acid with a solution of a 5,8-dihydronaphthalene in an organic solvent, e.g., ethyl acetate. The resulting mixture is added to a mixture of ethyl ether and aqueous sodium bicarbonate, and mixed to form a 5,6,7,8-tetrahydro-6,7-epoxynaphthalene of formula V.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[C:22]3[S:21][C:20]([NH:23][C:24]([O:26][CH3:27])=[O:25])=[N:19][C:18]=3[C:17]([O:28][CH3:29])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C>Cl.CO>[CH3:27][O:26][C:24](=[O:25])[NH:23][C:20]1[S:21][C:22]2[C:14]([C:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH:10]=3)=[CH:15][CH:16]=[C:17]([O:28][CH3:29])[C:18]=2[N:19]=1
Reactant: COC(=O)Nc1nc2c(OC)ccc(C3=CCN(C(=O)OC(C)(C)C)CC3)c2s1
Agent: Cl
Solvent: CO
Product: COC(=O)Nc1nc2c(OC)ccc(C3=CCNCC3)c2s1
Yield: 17.4 %

Procedure:
0.03 g (0.072 mMol) 4-(4-methoxy-2-methoxycarbonylamino-benzothiazol-7-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester were dissolved in 0.75 ml 2.5 M HCl/MeOH and heated to reflux for 1.5 h. The reaction mixture was concentrated in vacuo, taken up in 3 ml water and the pH was adjusted to 8 with sat. aqueous sodium bicarbonate. The suspension formed was filtered and the material on the filter was washed with water and dried in vacuo. The residue was subjected to column chromatography (dichloro methane/methanol 9:1+1%) NH4OH) to yield 4 mg (18%) [4-methoxy-7-(1,2,3,6-tetrahydro-pyridin-4-yl)-benzothiazol-2-yl]-carbamic acid methyl ester as a beige solid. ES-MS m/e (%): 320 ([M+H]+, 100).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][C@H:11]([C:13]2[CH:17]=[CH:16][S:15][CH:14]=2)[C@@H:10]([CH:18]=O)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:20][C:21]1([CH2:27][CH2:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>>[CH2:1]([N:8]1[CH2:12][C@H:11]([C:13]2[CH:17]=[CH:16][S:15][CH:14]=2)[C@@H:10]([CH2:18][N:24]2[CH2:25][CH2:26][C:21]([OH:20])([CH2:27][CH2:28][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH2:22][CH2:23]2)[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C[C@H]1CN(Cc2ccccc2)C[C@@H]1c1ccsc1
Reactant: OC1(CCCc2ccccc2)CCNCC1
Product: OC1(CCCc2ccccc2)CCN(C[C@H]2CN(Cc3ccccc3)C[C@@H]2c2ccsc2)CC1

Procedure:
The title compound was prepared from 1-Benzyl-3-(R)-formyl-4-(S)-(3-thienyl)pyrrolidine [which was prepared from (S)-N-(1-benzyl-4-(S)-(3-thienyl)-3-(R)-pyrrolidinylcarbonyl)-4-benzyl-2-oxazolidinone (Example 241 Step 2)] and 4-hydroxy-4-(3-phenylpropyl)piperidine (Example 122, Step 1) by procedures analogous to those described in Example 241.
Reaction SMILES: O[Li].O.C[O:5][C:6](=[O:47])[CH2:7][C:8]1[CH:45]=[CH:44][C:43]([CH3:46])=[CH:42][C:9]=1[CH2:10][CH2:11][C:12]1[C:17]([C:18]([F:21])([F:20])[F:19])=[CH:16][N:15]=[C:14]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([CH:29]3[CH2:34][CH2:33][N:32]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:31][CH2:30]3)=[CH:25][CH:24]=2)[N:13]=1>C1COCC1.O.CO>[C:38]([O:37][C:35]([N:32]1[CH2:33][CH2:34][CH:29]([C:26]2[CH:27]=[CH:28][C:23]([NH:22][C:14]3[N:13]=[C:12]([CH2:11][CH2:10][C:9]4[CH:42]=[C:43]([CH3:46])[CH:44]=[CH:45][C:8]=4[CH2:7][C:6]([OH:47])=[O:5])[C:17]([C:18]([F:20])([F:19])[F:21])=[CH:16][N:15]=3)=[CH:24][CH:25]=2)[CH2:30][CH2:31]1)=[O:36])([CH3:41])([CH3:39])[CH3:40]
Reactant: COC(=O)Cc1ccc(C)cc1CCc1nc(Nc2ccc(C3CCN(C(=O)OC(C)(C)C)CC3)cc2)ncc1C(F)(F)F
Agent: [Li]O
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: Cc1ccc(CC(=O)O)c(CCc2nc(Nc3ccc(C4CCN(C(=O)OC(C)(C)C)CC4)cc3)ncc2C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 27 h

Procedure:
LiOH.H2O (0.028 g, 0.65 mmol) was added to a solution of tert-butyl 4-(4-((4-(2-(2-methoxy-2-oxoethyl)-5-methylphenethyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperidine-1-carboxylate (A88) (0.133 g, 0.217 mmol) in THF (7 mL), water (1.5 mL) and MeOH (1 mL) and the resulting mixture stirred at room temperature for 27 hours. The volatiles were removed in vacuo and the residue was partitioned between EtOAc (50 mL) and saturated aqueous NaHCO3 (50 mL). The layers were separated and the aqueous layer was extracted with EtOAc (2×50 mL). The combined organic layers were washed with brine (50 mL), dried over MgSO4 and the volatiles removed in vacuo to give the title compound A89 as a white solid (0.124 g, 95%); 1H NMR (400 MHz, d4-MeOH) δ 8.49 (s, 1H), 7.61 (d, J=8.5 Hz, 2H), 7.15 (d, J=8.5 Hz, 2H), 7.09 (d, J=7.7 Hz, 1H), 7.00 (s, 1H), 6.96 (d, J=7.7 Hz, 1H), 4.18 (d, J=13.1 Hz, 2H), 3.65 (s, 2H), 3.13-2.90 (m, 4H), 2.92-2.71 (m, 2H), 2.64 (tt, J=12.0, 3.1 Hz, 1H), 2.26 (s, 3H), 1.78 (d, J=12.5 Hz, 2H), 1.61-1.49 (m, 2H), 1.47 (s, 9H). LCMS-A: rt 6.736 min; m/z 599.3 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:21]=[CH:20][CH:19]=[CH:18][C:3]=1[C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:17])[CH2:13][C:14]([OH:16])=O)[CH2:8][CH2:7]1)=[O:5].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[S:43]1[CH:47]=[CH:46][C:45]([C:48]2[CH:53]=[CH:52][C:51]([NH2:54])=[CH:50][CH:49]=2)=[CH:44]1>CN(C1C=CN=CC=1)C.CN(C=O)C.O>[Br:1][C:2]1[CH:21]=[CH:20][CH:19]=[CH:18][C:3]=1[C:4]([N:6]1[CH2:7][CH2:8][N:9]([C:12](=[O:17])[CH2:13][C:14]([NH:54][C:51]2[CH:50]=[CH:49][C:48]([C:45]3[CH:46]=[CH:47][S:43][CH:44]=3)=[CH:53][CH:52]=2)=[O:16])[CH2:10][CH2:11]1)=[O:5]
Reactant: Nc1ccc(-c2ccsc2)cc1
Reactant: O=C(O)CC(=O)N1CCN(C(=O)c2ccccc2Br)CC1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: O=C(CC(=O)N1CCN(C(=O)c2ccccc2Br)CC1)Nc1ccc(-c2ccsc2)cc1
Reaction time: 0.03 h
Yield: 19.1 %

Procedure:
DMAP (104 mg, 0.85 mmol) was added to 3-[4-(2-bromo-benzoyl)-piperazin-1-yl]-3-oxo-propionic acid (167 mg, 0.47 mmol) in DMF (2 mL) followed by EDCI (90 mg, 0.47 mmol) and HOBT (63 mg, 0.47 mmol). After 2 minutes, 4-thiophen-3-yl-phenylamine (75 mg, 0.43 mmol) was added and stirring was continued at room temperature overnight. Cold water was added and the formed precipitate was collected. Purification by preparative HPLC afforded 42 mg (19.2% yield) of 3-[4-(2-bromo-benzoyl)-piperazin-1-yl]-3-oxo-N-(4-thiophen-3-yl-phenyl)-propionamide. LC/MS [M+H]+: 512.06, 93.02%. 1H NMR (300 MHz, CDCl3): δ 9.6 (d, 1H), 7.85-7.5 (m, 5H), 7.46-7.34 (m, 4H), 7.34-7.26 (m, 2H), 4.09-3.9 (m, 2H), 3.82-3.64 (m, 4H), 3.58-3.52 (s, 1H), 3.5-3.44 (s, 1H), 3.42-3.32 (m, 1H), 3.3-3.18 (m, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[O:13][C:12]=2[CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH2:31]([N:33]([CH2:38][CH3:39])[CH2:34][CH2:35][CH2:36]Cl)[CH3:32]>>[CH2:31]([N:33]([CH2:38][CH3:39])[CH2:34][CH2:35][CH2:36][O:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([C:11]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[O:13][C:12]=2[CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=2)(=[O:10])=[O:9])=[CH:6][CH:7]=1)[CH3:32]
Reactant: O=S(=O)(c1ccc(O)cc1)c1c(Cc2cccc(C(F)(F)F)c2)oc2ccccc12
Reactant: CCN(CC)CCCCl
Product: CCN(CC)CCCOc1ccc(S(=O)(=O)c2c(Cc3cccc(C(F)(F)F)c3)oc3ccccc23)cc1

Procedure:
Reaction of 3-(4-hydroxyphenylsulfonyl)-2-(3-trifluoromethylbenzyl)benzofuran with 3-diethylaminopropyl chloride as described above gives the title compound.
Reaction SMILES: [C:1]([CH2:6][N:7]1[C:11]([SH:12])=[N:10][N:9]=[N:8]1)([C:3]([OH:5])=[O:4])=O.Cl.[CH3:14][O:15][NH2:16].C(=O)(O)[O-].[Na+]>O>[C:3]([C:1](=[N:16][O:15][CH3:14])[CH2:6][N:7]1[C:11]([SH:12])=[N:10][N:9]=[N:8]1)([OH:5])=[O:4]
Reactant: CON
Reactant: O=C(O)C(=O)Cn1nnnc1S
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: CON=C(Cn1nnnc1S)C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.9 %

Procedure:
A solution of 1-oxalomethyl-1H-tetrazole-5-thiol (1.09 g) and methoxyamine hydrochloride (0.47 g) in water (15 ml) was adjusted to pH 6.5 with sodium bicarbonate and stirred at room temperature for 2 hours. After washing with ethyl acetate, the aqueous solution was adjusted to pH 1.8 with 10% hydrochloric acid, extracted with ethyl acetate, dried over magnesium sulfate and evaporated to give 1-(2-carboxy-2-methoxyiminoethyl)-1H-tetrazole-5-thiol (1.05 g), mp 84° to 86° C.
Reaction SMILES: [CH2:1]([N:3]([CH2:10][CH2:11][CH3:12])[C:4](=[O:9])[C:5]([O:7]C)=[O:6])[CH3:2].[OH-].[Na+:14]>CO.O>[CH2:1]([N:3]([CH2:10][CH2:11][CH3:12])[C:4](=[O:9])[C:5]([O-:7])=[O:6])[CH3:2].[Na+:14]
Reactant: CCCN(CC)C(=O)C(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCCN(CC)C(=O)C(=O)[O-]
Yield: 98.2 %

Procedure:
475 mg (2.75 mmole) of methyl N-ethyl-N-n-propyloxamate was dissolved in 10 ml of methanol. The resulting mixture was stirred under ice-cooling. 109 mg (2.75 mmole) of sodium hydroxide was dissolved in 5 ml of water, and the resulting solution was added dropwise to said mixture. After completion of the dropwise addition, the reaction mixture was stirred for 3 hours at room temperature. Methanol was distilled off from the reaction solution under reduced pressure and the remaining aqueous layer was washed with 5 ml of methylene chloride. The aqueous layer was then separated and distilled under reduced pressure, to afford 495 mg (2.7 mmole) of sodium N-ethyl-N-n-propyloxamate as white solids.
Reaction SMILES: COC1C=CC(CN2CCN(CC3N=CC([NH:21][C:22]([C:24]4[CH:25]=[CH:26][C:27]([C:34]5[C:39]([Cl:40])=[C:38]([O:41][CH3:42])[CH:37]=[C:36]([O:43][CH3:44])[C:35]=5[Cl:45])=[C:28]5[C:33]=4[N:32]=[CH:31][CH:30]=[CH:29]5)=[O:23])=CC=3)CC2)=CC=1.N[C:49]1[N:54]=[CH:53][C:52]([CH2:55][N:56]([CH3:62])[CH2:57][CH2:58][N:59]([CH3:61])[CH3:60])=[CH:51][CH:50]=1>C(Cl)Cl.CO>[CH3:60][N:59]([CH3:61])[CH2:58][CH2:57][N:56]([CH2:55][C:52]1[CH:51]=[CH:50][C:49]([NH:21][C:22]([C:24]2[CH:25]=[CH:26][C:27]([C:34]3[C:39]([Cl:40])=[C:38]([O:41][CH3:42])[CH:37]=[C:36]([O:43][CH3:44])[C:35]=3[Cl:45])=[C:28]3[C:33]=2[N:32]=[CH:31][CH:30]=[CH:29]3)=[O:23])=[N:54][CH:53]=1)[CH3:62]
Reactant: COc1ccc(CN2CCN(Cc3ccc(NC(=O)c4ccc(-c5c(Cl)c(OC)cc(OC)c5Cl)c5cccnc45)cn3)CC2)cc1
Reactant: CN(C)CCN(C)Cc1ccc(N)nc1
Solvent: ClCCl
Solvent: CO
Product: COc1cc(OC)c(Cl)c(-c2ccc(C(=O)Nc3ccc(CN(C)CCN(C)C)cn3)c3ncccc23)c1Cl
Temperature: 25 °C
Reaction time: 14 h

Procedure:
The title compound was prepared in analogy to the procedure described in Step 14.1 but using 5-(2,6-dichloro-3,5-dimethoxy-phenyl)-quinoline-8-carboxylic acid (6-piperazin-1-ylmethyl-pyridin-3-yl)-amide (Example 170), N-(6-amino-pyridin-3-ylmethyl)-N,N′,N′-trimethylethane-1,2-diamine (prepared as described in Example 26 but using N,N,N′-trimethyl-ethane-1,2-diamine in Step 26.2), and stirring the reaction mixture for 14 h at rt. Title compound: ESI-MS: 568.0 [M+H]+; TLC: Rf=0.15 (DCM/MeOH, 9:1).
Reaction SMILES: [C:1]([C:3]1[C:4]([NH2:9])=[N:5][CH:6]=[CH:7][CH:8]=1)#[CH:2].[O:10]1[CH:14]=[CH:13][CH:12]=[C:11]1[CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][C:24](Cl)=[N:25][OH:26])=[CH:19][CH:18]=1.C(N(CC)CC)C>O1CCCC1>[O:10]1[CH:14]=[CH:13][CH:12]=[C:11]1[CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][C:24]2[CH:2]=[C:1]([C:3]3[C:4]([NH2:9])=[N:5][CH:6]=[CH:7][CH:8]=3)[O:26][N:25]=2)=[CH:19][CH:18]=1
Reactant: ON=C(Cl)Cc1ccc(CCc2ccco2)cc1
Reactant: C#Cc1cccnc1N
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Nc1ncccc1-c1cc(Cc2ccc(CCc3ccco3)cc2)no1
Temperature: 60 °C
Reaction time: 1.5 h
Yield: 40.8 %

Procedure:
To an anhydrous tetrahydrofuran (5 mL) solution of 3-ethynyl-pyridin-2-ylamine (33.1 mg, 0.281 mmol) described in Manufacturing Example 1-2-3 was added (4-(2-furan-2-yl-ethyl)phenyl)-acetohydroximoyl chloride (224 mg, 0.85 mmol) described in Manufacturing Example 80-1-7 under nitrogen atmosphere at room temperature. Triethylamine (0.24 mL, 1.7 mmol) was then added dropwise, followed by 1.5 hours of stirring at 60° C. The reaction mixture was partitioned into water and ethyl acetate at room temperature. The organic layer was washed with water and saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, and the solvent was evaporated under a reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate:heptane=1:9 then 3:7) to obtain the title compound (39.6 mg, 40.8%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH2:11][C@@H:12]2[CH2:14][O:13]2)=[C:6]([CH:9]=1)C=O.C1C=C(Cl)C=C([C:22]([O:24]O)=[O:23])C=1>C(Cl)Cl>[CH:22]([O:24][C:6]1[CH:9]=[C:2]([Br:1])[CH:3]=[CH:4][C:5]=1[O:10][CH2:11][C@@H:12]1[CH2:14][O:13]1)=[O:23]
Reactant: O=Cc1cc(Br)ccc1OC[C@@H]1CO1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: O=COc1cc(Br)ccc1OC[C@@H]1CO1

Procedure:
Preparation according to Preparation 2 using 5-bromo-2-[(2S)-oxiran-2-ylmethoxy]benzaldehyde (8.3 g, 32 mmol), DCM (100 ml) and m-CPBA (77%, 10.9 g, 48.6 mmol). The mixture was heated at reflux for 3 h. Crude yield: 8.5 g. MS m/z (rel. intensity, 70 eV) 274 (M+, 10), 273 (M+, 9), 189 (98), 188 (bp), 57 (77).
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]([CH:6]=[N:7][N:8]([CH3:22])[C:9]([N:11]([N:13]=[CH:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[CH3:12])=[NH:10])=[CH:4][CH:3]=1.[C:25](OC(=O)C)(=[O:27])[CH3:26]>>[C:25]([N:10]=[C:9]([N:11]([N:13]=[CH:14][C:15]1[CH:16]=[CH:17][C:18]([Cl:21])=[CH:19][CH:20]=1)[CH3:12])[N:8]([N:7]=[CH:6][C:5]1[CH:23]=[CH:24][C:2]([Cl:1])=[CH:3][CH:4]=1)[CH3:22])(=[O:27])[CH3:26]
Reactant: CN(N=Cc1ccc(Cl)cc1)C(=N)N(C)N=Cc1ccc(Cl)cc1
Reactant: CC(=O)OC(C)=O
Product: CC(=O)N=C(N(C)N=Cc1ccc(Cl)cc1)N(C)N=Cc1ccc(Cl)cc1

Procedure:
When 1,3-bis(p-chlorobenzylideneamino)-1,3-dimethylguanidine free base is submitted to the above reaction conditions with acetic anhydride, there is obtained the corresponding 2-acetyl-1,3-bis(4-chlorobenzylideneamino)-1,3-dimethylguanidine.
Reaction SMILES: O[CH2:2][CH2:3][CH:4]1[O:18][C:7]2=[C:8]3[C:13](=[C:14]([CH3:16])[CH:15]=[C:6]2[CH2:5]1)[NH:12][C:11](=[O:17])[CH:10]=[CH:9]3.N1C=CC=CC=1.CS([Cl:29])(=O)=O.CO>CN(C)C=O.O>[Cl:29][CH2:2][CH2:3][CH:4]1[O:18][C:7]2=[C:8]3[C:13](=[C:14]([CH3:16])[CH:15]=[C:6]2[CH2:5]1)[NH:12][C:11](=[O:17])[CH:10]=[CH:9]3
Reactant: CS(=O)(=O)Cl
Reactant: Cc1cc2c(c3ccc(=O)[nH]c13)OC(CCO)C2
Solvent: CO
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: Cc1cc2c(c3ccc(=O)[nH]c13)OC(CCCl)C2
Reaction time: 6 h
Yield: 98.6 %

Procedure:
2-(2-Hydroxyethyl)-5-methyl-2,3,6,7-tetrahydrofuro[2,3-f]quinoline-7-one (1.65 g) was suspended in dimethylformamide (20 ml). To the suspension, pyridine (20 ml) and methanesulfonyl chloride (1.5 ml) were added thereto, and the mixture was stirred for 6 hours. When the reaction was completed, methanol (20 ml) was added while cooling the mixture on ice, followed by mixing for 20 minutes. Subsequently, the reaction mixture was condensed under reduced pressure, to which water was added and extracted with chloroform. The chloroform phase was dried and condensed under reduced pressure. The resultant residue was recrystallized from a solvent mixture of chloroform-ether to obtain 1.75 of 2-(2-chloroethyl)-5-methyl-2,3,6,7-tetrahydrofuro[2,3-f]quinoline-7-one as pale yellow needles (98.6%).
Reaction SMILES: Cl[C:2]1[N:9]=[C:8]([CH3:10])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[H-].[Na+].[CH:13]([OH:16])([CH3:15])[CH3:14]>>[CH:13]([O:16][C:2]1[C:3]([C:4]#[N:5])=[CH:6][CH:7]=[C:8]([CH3:10])[N:9]=1)([CH3:15])[CH3:14]
Reactant: Cc1ccc(C#N)c(Cl)n1
Reactant: CC(C)O
Agent: [H-]
Agent: [Na+]
Product: Cc1ccc(C#N)c(OC(C)C)n1
Temperature: 50 °C

Procedure:
The 2-chloro-6-methyl-nicotinonitrile (0.8 g, 5.2 mmol) was added in small portion to a mixture of NaH 60% (4 mol eq, 0.8 g) in isopropanol (30 mL). The reaction mixture was heated at 50° C. overnight. The solvent was distilled and water was added to the residue. The aqueous solution was extracted with EtOAc (3×30 mL) and the organic phases were evaporated at reduced pressure to give 32a as a pale yellow deliquescent solid (1.25 g, quantitative yield). 1HNMR (DMSO, 200 MHz) δ 1.24 (s, 3H), 1.32 (s, 3H), 2.25 (s, 3H), 5.02 (m, 1H), 7.31 (d, 1H), 7.69 (m, 1H).
Reaction SMILES: Cl[CH:2]([CH:14]1[CH2:19][CH2:18][N:17]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]3[N:28]=[N:29][N:30]([CH2:32][CH3:33])[N:31]=3)=[CH:23][CH:22]=2)[CH2:16][CH2:15]1)[C:3]1[CH:13]=[CH:12][C:6]([O:7][C:8]([F:11])([F:10])[F:9])=[CH:5][CH:4]=1.[F:34][C:35]([F:45])([F:44])[O:36][C:37]1[CH:42]=[CH:41][C:40]([OH:43])=[CH:39][CH:38]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH2:32]([N:30]1[N:29]=[N:28][C:27]([C:24]2[CH:25]=[CH:26][C:21]([CH2:20][N:17]3[CH2:18][CH2:19][C:14](=[C:2]([C:3]4[CH:13]=[CH:12][C:6]([O:7][C:8]([F:11])([F:10])[F:9])=[CH:5][CH:4]=4)[O:43][C:40]4[CH:41]=[CH:42][C:37]([O:36][C:35]([F:34])([F:44])[F:45])=[CH:38][CH:39]=4)[CH2:15][CH2:16]3)=[CH:22][CH:23]=2)=[N:31]1)[CH3:33]
Reactant: Oc1ccc(OC(F)(F)F)cc1
Reactant: CCn1nnc(-c2ccc(CN3CCC(C(Cl)c4ccc(OC(F)(F)F)cc4)CC3)cc2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCn1nnc(-c2ccc(CN3CCC(=C(Oc4ccc(OC(F)(F)F)cc4)c4ccc(OC(F)(F)F)cc4)CC3)cc2)n1

Procedure:
A solution of {4-[chloro(1-{[4-(2-ethyl(1,2,3,4-tetraazol-5-yl))phenyl]methyl}(4-piperidyl))methyl]phenoxy}trifluoromethane, 4-(trifluoromethoxy)phenol and potassium carbonate in DMF is stirred at ambient temperature for about two hours. After this time the reaction mixture is poured into water and the mixture is extracted with ethyl acetate. The extract is dried with magnesium sulfate and filtered. The filtrate is concentrated under reduced pressure, yielding compound 137.
Reaction SMILES: Br[C:2]1[N:3]([CH2:9][CH3:10])[C:4]([Br:8])=[C:5]([Br:7])[N:6]=1.[C:11]1(OB(C2C=CC=CC=2)O)[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.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>[Br:7][C:5]1[N:6]=[C:2]([C:19]2[C:20]3[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH:16]=[CH:17][CH:18]=2)[N:3]([CH2:9][CH3:10])[C:4]=1[Br:8]
Reactant: OB(Oc1cccc2ccccc12)c1ccccc1
Reactant: CCn1c(Br)nc(Br)c1Br
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: [K+]
Solvent: Cc1ccccc1
Product: CCn1c(-c2cccc3ccccc23)nc(Br)c1Br
Temperature: 90 °C
Reaction time: 16 h

Procedure:
To a solution of 2,4,5-tribromo-1-ethyl-1H-imidazole (13.19 g, 40 mmol) and 1-naphthylphenylboronic acid (6.88 g, 40 mmol, 1.0 eq.) in toluene (100 ml) is added aqueous potassium carbonate solution (2.0 N, 40 ml, 2.0 eq.), followed by the addition of Pd(PPh3)4 (1.154 g, 1 mmol, 0.025 eq.). The resulting mixture is degassed with nitrogen, and then stirred at 90° C. for 16 hr. After cooling to rt, the reaction mixture is diluted with EtOAc (100 ml), washed with water and brine, and dried over sodium sulfate. After the solvent is removed, the crude product is purified through flash chromatography to afford the title product LCMS 380 (M+1).
Reaction SMILES: [C:1]([NH:6][N:7]=[C:8]([CH3:18])[CH2:9][CH2:10][C:11]([O:13][CH2:14][CH2:15][CH2:16][CH3:17])=[O:12])([CH2:4][CH3:5])([CH3:3])[CH3:2].[Cl:19]Cl>CCCCC>[C:1]([N:6]=[N:7][C:8]([Cl:19])([CH3:18])[CH2:9][CH2:10][C:11]([O:13][CH2:14][CH2:15][CH2:16][CH3:17])=[O:12])([CH2:4][CH3:5])([CH3:3])[CH3:2]
Reactant: CCCCOC(=O)CCC(C)=NNC(C)(C)CC
Reactant: ClCl
Solvent: CCCCC
Product: CCCCOC(=O)CCC(C)(Cl)N=NC(C)(C)CC
Temperature: -20 °C
Reaction time: 0.25 h
Yield: 104 %

Procedure:
To a solution of 90 grams (.316 moles) of butyl levulinate t-amylhydrazone in 150 mls. of pentane in a 500 ml. round bottom flask was passed 10.9 grams (.154 moles) of chlorine holding the temperature at -20°C with a dry ice- isopropanol bath. The chlorine was added over 30 minutes and then the reaction was stirred an additional 15 minutes at -20°C and filtered. The filtrate was dried and the pentane evaporated leaving 46.6 grams of crude butyl 4-t-amylazo-4-chlorovalerate.
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][C:7]([O:11][C:12](=[O:21])[NH:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[Cl:20])=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[H-].[Na+].[CH3:24]I>O1CCOCC1>[CH3:24][N:1]1[C:10]2[C:5](=[CH:6][C:7]([O:11][C:12](=[O:21])[NH:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[Cl:20])=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: CI
Reactant: O=C(Nc1ccccc1Cl)Oc1ccc2c(c1)CCCN2
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CN1CCCc2cc(OC(=O)Nc3ccccc3Cl)ccc21
Reaction time: 0.33 h

Procedure:
A solution of 1 of 2-chloro-phenyl -carbamic acid-1, 2, 3, 4-tetrahydro-quinolin-6-yl ester (0.302 g., 1.5 mmol) in dry dioxane (5 ml) was added to a stirred suspension of sodium hydride (0.036 g., 1.5 mmol) in dry dioxane (5 ml) at −10° C. during 5 min. The reaction mixture was stirred for 20 min. Then methyl iodide (0.122 ml, 1.8 mmol) was added to the stirring reaction mixture. Stirring was continued for additional 1.5 hours during which the temperature was allowed to rise to room temperature (34° C.). The reaction mixture was quenched with water (0.2 ml), concentrated under vaccum, diluted with water (5 ml), extracted with chloroform (2×5 ml) and dried over sodium sulphate. The combined fractions of chloroform were concentrated under vaccum. The residue was chromatographed on silica gel using 30:70 chloroform: hexane (30:70) as eluant to give 2o; yield: 0.50 g. (47.5%).