Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][C:5]([OH:12])=[C:4]([N+:13]([O-])=O)[CH:3]=1.C(OCC)(=O)C.C(O)(=O)C>[Fe].O>[NH2:13][C:4]1[CH:3]=[C:2]([Cl:1])[C:7]([C:8]([F:11])([F:9])[F:10])=[CH:6][C:5]=1[OH:12]
Reactant: O=[N+]([O-])c1cc(Cl)c(C(F)(F)F)cc1O
Agent: [Fe]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: O
Product: Nc1cc(Cl)c(C(F)(F)F)cc1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.4 %

Procedure:
A mixture of 2.3 g of 4-chloro-2-nitro 5-trifluoromethylphenol and 10 ml of ethyl acetate was added dropwise to a mixture, which was heated to 80° C., of 2.6 g of electrolytic iron, 10 ml of acetic acid and 20 ml of water, and then the reaction mixture was stirred for one hour. The mixture was cooled to room temperature, and then water was added, followed by extraction with ethyl acetate. The combined organic layers were washed with water, a saturated aqueous solution of sodium hydrogencarbonate and a saturated sodium chloride solution, dried over magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 1.7 g of 2-amino-4-chloro-5-trifluoromethylphenol.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])/[C:5](/[C:11]1[CH:16]=[CH:15][C:14](SC)=[CH:13][CH:12]=1)=[CH:6]/[CH2:7][CH:8]([CH3:10])[CH3:9])[CH3:2].O[O:21][S:22]([O-:24])=O.[K+].[CH3:26]O>>[CH2:1]([O:3][C:4](=[O:19])/[C:5](/[C:11]1[CH:12]=[CH:13][C:14]([S:22]([CH3:26])(=[O:24])=[O:21])=[CH:15][CH:16]=1)=[CH:6]/[CH2:7][CH:8]([CH3:10])[CH3:9])[CH3:2]
Reactant: O=S([O-])OO
Reactant: CO
Reactant: CCOC(=O)/C(=C/CC(C)C)c1ccc(SC)cc1
Agent: [K+]
Product: CCOC(=O)/C(=C/CC(C)C)c1ccc(S(C)(=O)=O)cc1

Procedure:
Following the method of example 54d, oxidation of (E)-5-methyl-2-(4-methylsulfanyl-phenyl)-hex-2-enoic acid ethyl ester (840 mg, 3.01 mmol) with oxone® (2.4 g, 3.9 mmol) in methanol gives the title compound as a yellow oil (848 mg). MS (m/e): 311 (M+H).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH2:8][N:9]=[CH:10][NH:11][C:12]1[CH:13]=[C:14]([C:18]([NH:20][CH2:21][C:22]([NH:24][CH:25]([C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([Br:38])[CH:33]=2)[CH2:26][C:27]([O:29]CC)=[O:28])=[O:23])=[O:19])[CH:15]=[CH:16][CH:17]=1.[Li+].[OH-].C(O)(C(F)(F)F)=O>O.CC#N>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH2:8][N:9]=[CH:10][NH:11][C:12]1[CH:13]=[C:14]([C:18]([NH:20][CH2:21][C:22]([NH:24][CH:25]([C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([Br:38])[CH:33]=2)[CH2:26][C:27]([OH:29])=[O:28])=[O:23])=[O:19])[CH:15]=[CH:16][CH:17]=1
Reactant: CCOC(=O)CC(NC(=O)CNC(=O)c1cccc(NC=NN)c1)c1cccc(Br)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: NN=CNc1cccc(C(=O)NCC(=O)NC(CC(=O)O)c2cccc(Br)c2)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 48.4 %

Procedure:
To the product from Example 184 (1.0 mg, 0.00165 mole) in H2O (15 mL) and CH3CN (10 mL) was added LiOH (210 mg, 0.005 mole). The reaction mixture was stirred at room temperature for 1.5 hours. The pH was lowered to ~2.5 with TFA and the product was isolated by RPHPLC to yield the title compound (460 mg after lyophilization) as a white solid.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([NH:9][CH:10]1[C:35](=[O:36])[N:12]2[CH:13]([C:19]([O:21][CH:22]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[O:20])[C:14]([CH:17]=[O:18])=[CH:15][S:16][C@H:11]12)=[O:8].[CH2:37](O)[CH2:38][OH:39].O.C1(C)C(S(O)(=O)=O)=CC=CC=1>C1C=CC=CC=1>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([NH:9][CH:10]1[C:35](=[O:36])[N:12]2[CH:13]([C:19]([O:21][CH:22]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[O:20])[C:14]([CH:17]3[O:39][CH2:38][CH2:37][O:18]3)=[CH:15][S:16][C@H:11]12)=[O:8]
Reactant: O=CC1=CS[C@@H]2C(NC(=O)Cc3cccs3)C(=O)N2C1C(=O)OC(c1ccccc1)c1ccccc1
Reactant: OCCO
Agent: Cc1ccccc1S(=O)(=O)O
Solvent: c1ccccc1
Solvent: O
Product: O=C(Cc1cccs1)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)C(C3OCCO3)=CS[C@H]12

Procedure:
Benzhydryl 7-(2-thienylacetamido)-3-formyl-2-cephem-4-carboxylate (21.5 g., 41.5 mmol.) was combined with 11.6 ml. of ethylene glycol (0.2 mole) and toluenesulfonic acid monohydrate (0.197 g., 1.04 mmol.) in 500 ml. benzene. The mixture was refluxed for 10 hours using a Dean-Stark trap (1.5 ml. water collected), cooled, and evaporated in vacuo to dryness. The product was taken up in ethyl acetate and washed successively with sodium bicarbonate solution (2X), water (2X) and sodium chloride solution and subsequently dried over Na2SO4. Evaporation in vacuo to dryness gave a product which was chromatographed on 40 g. of silica gel using a benzene-ethyl acetate gradient. Crystallization of the purified product from methylene chloride-hexane gave benzhydryl 7(2-thienylacetamido)-3-(1,3-dioxolan-2-yl)-2-cephem-4-carboxylate as colorless needles (15.07 g., 64.2%): mp 142°-143°; ir (CHCl3) 1780 cm-1 (β-lactam C = 0); nmr (CDCl3) 3.3-3.9 (m, 4, --CH2 --CH2 --), 3.83 (s, 2, side chain CH2), 5.10 (d, 1, J = 4.0 Hz, C6 -H), 5.17 (s, 1, acetal CH), 5.21 (s, 1, C4 -H) and 5.45 ppm (q, 1, J = 4.0 and 8.0 Hz, C7 -H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:16]([CH2:17][C:18]([OH:20])=[O:19])[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.C(N1C=CN=C1)([N:23]1C=CN=C1)=O.N>O1CCCC1>[OH2:19].[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:16]([CH2:17][C:18]([NH2:23])=[O:20])[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:6][CH:7]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: O=C(O)Cn1c(-c2ccc(F)cc2)nc2cccnc21
Agent: N
Solvent: C1CCOC1
Product: NC(=O)Cn1c(-c2ccc(F)cc2)nc2cccnc21
Product: O
Temperature: 25 °C
Reaction time: 8 h
Yield: 63.5 %

Procedure:
A mixture of 2-(4-fluorophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid (4.49 g, 0.0166 mole) and 1,1'-carbonyldiimidazole (2.69 g, 0.0166 mole) was stirred at room temperature in dry tetrahydrofuran (100 ml) for 2.5 hours with a stream of nitrogen bubbling through it. The reaction mixture was cooled in a dry ice/acetone bath and liquid ammonia (50 ml) was added. The mixture was allowed to warm to room temperature and was stirred overnight under nitrogen. The solvents were removed under reduced pressure and the resulting solid was triturated in water (100 ml), collected by filtration, rinsed twice with water, twice with a 5% potassium hydroxide solution and twice again with water. The solid was dissolved in hot methanol, filtered while hot and cooled to room temperature. Water was added to the cloud point. The resulting solid was collected by filtration, rinsed with water, and dried under high vacuum at room temperature to give 3.04 g (68%) of title compound, mp. 246°-248° C.
Reaction SMILES: N[C:2]1[N:7]=[C:6](O)[CH:5]=[C:4](Cl)[N:3]=1.[N+:10]([O-])([OH:12])=[O:11].S(=O)(=O)(O)[OH:15]>>[N+:10]([C:4]1[CH:5]=[CH:6][N:7]=[C:2]([OH:15])[N:3]=1)([O-:12])=[O:11]
Reactant: O=S(=O)(O)O
Reactant: O=[N+]([O-])O
Reactant: Nc1nc(O)cc(Cl)n1
Product: O=[N+]([O-])c1ccnc(O)n1
Temperature: 20 °C
Yield: 98 %

Procedure:
250 mL (5 volumes) of concentrated sulfuric acid was stirred in a 1000 mL round bottom flask (22° C.). To this, 2-amino-6-chloro-4-pyrimidinol (50 g) was added in portions. The temperature increased rapidly with early additions, stabilizing at a temperature of 40° C. Later additions had less effect on the temperature, a maximum of approx. 45° C. being recorded. Prior to addition of fuming nitric acid (45 mL, 0.9 volumes), the mixture was cooled (using an ice bath) to 20° C. In portions of roughly 1.5 mL (reflecting pipette volume), nitric acid was added dropwise at a steady rate (ca. 1 min between each portion). Early portions had the greatest effect on the temperature, the controlled exotherms reaching a temperature of approx. 26° C. before returning to 20° C. under the influence of the ice bath. Later portions had little effect, and the temperature was maintained at approx. 21° C. After 45 mL of fuming nitric acid had been added in this way, the mixture was allowed to stir for 2 hr (during this period the ice bath was removed and the temperature stabilised at room temperature ca. 22° C.). The entire mixture was poured onto stirred ice/water (1200 mL) and the resulting yellow solid filtered under vacuum. The product was washed in succession with water (600 mL), ethanol (600 mL) and diethylether (600 mL). This method gave 63.5 g (98% yield) of the required nitro-pyrimidinol.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[CH:10](O)=[O:11].O>C1(C)C=CC=CC=1>[CH:10]([N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1)=[O:11]
Reactant: O=CO
Reactant: c1ccc2c(c1)CCN2
Solvent: Cc1ccccc1
Solvent: O
Product: O=CN1CCc2ccccc21
Temperature: 25 °C
Yield: 91.7 %

Procedure:
A mixture of indoline (145 g, 1.2 mol) and formic acid (90%, 92 g, 1.8 mol) was brought to reflux in toluene with removal of water via a Dean-Stark apparatus. After 6 hours the reaction mixture was cooled to room temperature, washed with water and concentrated in vacuo. N-formylindoline (158 g, 1.1 mol, 88% yield) was isolated as an off-white solid and used in the next step without further purification. Mixture of rotamers: 1H-NMR (CDCl3) δ 8.92 (s, 0.85H), 8.51 (s, 0.15H), 8.06 (d, J=8.3 Hz, 0.15H), 7.26-7.16 (m, 3.85H), 7.16-7.02 (m, 1H), 4.13-4.02 (m, 2H), 3.21-3.12 (dt, 2H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[C:4]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=2)[CH:3]=1.[Li][CH2:22]CCC.C[Si](C)(C)[O:28][C@@H:29]1[C@@H:34]([O:35][Si](C)(C)C)[C@H:33]([O:40][Si](C)(C)C)[C@@H:32]([CH2:45][O:46][Si](C)(C)C)[O:31][C:30]1=[O:51].CS(O)(=O)=O>CO.CCCCCC.C1COCC1>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([C@@:30]2([O:51][CH3:22])[C@H:29]([OH:28])[C@@H:34]([OH:35])[C@H:33]([OH:40])[C@@H:32]([CH2:45][OH:46])[O:31]2)=[CH:3][C:4]=1[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1
Reactant: FC(F)(F)Oc1ccc(Cc2cc(Br)ccc2Cl)cc1
Reactant: [Li]CCCC
Reactant: C[Si](C)(C)OC[C@H]1OC(=O)[C@H](O[Si](C)(C)C)[C@@H](O[Si](C)(C)C)[C@@H]1O[Si](C)(C)C
Agent: CS(=O)(=O)O
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CO
Product: CO[C@@]1(c2ccc(Cl)c(Cc3ccc(OC(F)(F)F)cc3)c2)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Temperature: -78 °C
Reaction time: 1.5 h

Procedure:
4-bromo-1-chloro-2-[[4-(trifluoromethoxy)phenyl]methyl]benzene 6h (2.33 g, 6.38 mmol) was dissolved in 40 mL of mixed solution (THF and n-hexane, v:v=1:3) and cooled to −78° C., followed by dropwise addition of a solution of nBuLi in n-hexane (3.83 mL, 9.57 mmol). After stirring for 1.5 hours at −78° C., a solution (30 mL) of (3R,4S,5R,6R)-3,4,5-tris(trimethylsilyloxy)-6-(trimethylsilyloxymethyl)tetrahydropyran-2-one 2f (4.47 g, 9.57 mmol) in mixed solution (THF and n-hexane, v:v=1:3) was dropwise added before the reaction mixture was stirred for 2 hours at −78° C. A solution (32 mL) of 0.6 M methanesulfonic acid in methanol was added before the reaction mixture was warmed and stirred for 16 hours at room temperature. Thereafter, the reaction mixture was partitioned after 150 mL of saturated sodium carbonate solution were added. The aqueous phase was extracted with ethyl acetate (100 mL×3) and the organic extracts were combined, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography with elution system A to obtain the title compound (2S,3R,4S,5S,6R)-2-[4-chloro-3-[[4-(trifluoromethoxy)phenyl]methyl]phenyl]-6-(hydroxymethyl)-2-methoxy-tetrahydropyran-3,4,5-triol 61 (1.38 g, white solid), yield: 45.2%. 1H NMR (400 MHz, CD3OD): δ 7.61 (d, 1H), 7.51 (dd, 1H), 7.40 (d, 1H), 7.31-7.29 (m, 2H), 7.17 (d, 2H), 4.23-4.12 (m, 2H), 3.94 (d, 1H), 3.86-3.75 (m, 2H), 3.95-3.59 (m, 2H), 3.47-3.42 (m, 1H), 3.10 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2/[C:10](=[CH:18]/[C:19]2[NH:23][C:22]([CH3:24])=[C:21]([C:25](O)=[O:26])[C:20]=2[CH3:28])/[C:11](=[O:17])[NH:12]3)[CH:5]=[CH:6][CH:7]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[CH:43]1([CH2:46][NH:47][CH2:48][C@@H:49]2[CH2:53][CH2:52][CH2:51][NH:50]2)[CH2:45][CH2:44]1>CN(C=O)C.C(Cl)Cl>[CH:43]1([CH2:46][NH:47][CH2:48][C@@H:49]2[CH2:53][CH2:52][CH2:51][N:50]2[C:25]([C:21]2[C:20]([CH3:28])=[C:19](/[CH:18]=[C:10]3\[C:11](=[O:17])[NH:12][C:13]4[C:9]\3=[C:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=3)[CH:16]=[CH:15][CH:14]=4)[NH:23][C:22]=2[CH3:24])=[O:26])[CH2:44][CH2:45]1
Reactant: Cc1[nH]c(/C=C2\C(=O)Nc3cccc(-c4cccc(F)c4)c32)c(C)c1C(=O)O
Reactant: C1CN[C@H](CNCC2CC2)C1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: Cc1[nH]c(/C=C2\C(=O)Nc3cccc(-c4cccc(F)c4)c32)c(C)c1C(=O)N1CCC[C@H]1CNCC1CC1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of 5-[4-(3-fluoro-phenyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (70 mg, 0.185 mmol), EDC (70 mg, 0.37 mmol), HOBt (26 mg, 0.19 mmol) in DMF (4 mL) was added TEA (0.08 mL) and cyclopropylmethyl-(S)-1-pyrrolidin-2-ylmethyl-amine (0.05 mL, 0.37 mmol). The mixture was stirred at rt for 20 hours. The reaction was diluted with DCM, washed with water, NaHCO3, dried and concentrated. The residue was purified on a silica gel column to give the titled compound.
Reaction SMILES: Cl[C:2]1[C:7]2[CH2:8][N:9]([CH2:12][C:13]3[CH:18]=[C:17]([CH3:19])[C:16]([O:20][CH2:21][CH:22]([F:24])[F:23])=[CH:15][N:14]=3)[C:10](=[O:11])[C:6]=2[CH:5]=[CH:4][N:3]=1.[CH:25]([O:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:26]>>[F:23][CH:22]([F:24])[CH2:21][O:20][C:16]1[C:17]([CH3:19])=[CH:18][C:13]([CH2:12][N:9]2[C:10](=[O:11])[C:6]3[CH:5]=[CH:4][N:3]=[C:2]([C:25]([O:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[O:26])[C:7]=3[CH2:8]2)=[N:14][CH:15]=1
Reactant: Cc1cc(CN2Cc3c(ccnc3Cl)C2=O)ncc1OCC(F)F
Reactant: O=COc1ccccc1
Product: Cc1cc(CN2Cc3c(ccnc3C(=O)Oc3ccccc3)C2=O)ncc1OCC(F)F
Yield: 68 %

Procedure:
The title compound is prepared in 68% yield (200 mg, pale brown solid) from 4-chloro-2-((5-(2,2-difluoroethoxy)-4-methylpyridin-2-yl)methyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (240 mg, 0.68 mmol, Intermediate-69) and phenyl formate (170 mg, 1.4 mmol) in a similar manner to Intermediate-91.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10]3([CH2:14][C:13](=[O:15])[N:12]([CH2:16][C:17]4[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[CH:18]=4)[C:11]3=[O:24])[C:9](=[O:25])[N:8]([CH2:26][C:27]([O:29]C)=[O:28])[C:5]2=[CH:6][CH:7]=1.I[Si](C)(C)C.Cl.C(OCC)(=O)C>C(Cl)(Cl)Cl.C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:10]3([CH2:14][C:13](=[O:15])[N:12]([CH2:16][C:17]4[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[CH:18]=4)[C:11]3=[O:24])[C:9](=[O:25])[N:8]([CH2:26][C:27]([OH:29])=[O:28])[C:5]2=[CH:6][CH:7]=1
Reactant: COC(=O)CN1C(=O)C2(CC(=O)N(Cc3cccc(Cl)c3)C2=O)c2cc(Cl)ccc21
Agent: C[Si](C)(C)I
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: ClC(Cl)Cl
Product: O=C(O)CN1C(=O)C2(CC(=O)N(Cc3cccc(Cl)c3)C2=O)c2cc(Cl)ccc21

Procedure:
Alternatively, a solution of methyl [5-chloro-1′-(3-chlorobenzyl)-2,2′,5′-trioxospiro[indole-3,3′-pyrrolidin]-1(2H)-yl)acetate, intermediate 48, (250 mg, 0.56 mmol) in chloroforme or acetonitrile (10 ml) was treated with iodotrimethylsilane (0.31 ml, 2.24 mmol) and heated up to reflux until completion. Addition of 1.0 N HCl (10 ml), product extraction with ethyl acetate or chloroforme (3×5 ml), washing of the combined extracts with sat. sodium thiosulfate (10 ml) and drying (MgSO4) gave the title compound as in quant.yield as slightly yellow solid (75% purity by HPLC using chloroform; 68% purity by HPLC using acetonitrile). MS (ESI+): 434.3; MS (ESI−): 431.4.
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([CH:7]([OH:10])[CH2:8][NH2:9])=[CH:3][CH:2]=1.[ClH:11].C=O.[C-]#[N:15].[K+].C(O[CH2:20][CH3:21])C>O>[ClH:11].[OH:10][CH:7]([C:4]1[CH:5]=[CH:6][CH:1]=[CH:2][CH:3]=1)[CH2:8][NH:9][CH2:21][C:20]#[N:15]
Reactant: NCC(O)c1ccccc1
Reactant: [C-]#N
Reactant: CCOCC
Agent: C=O
Agent: Cl
Agent: [K+]
Solvent: O
Product: N#CCNCC(O)c1ccccc1

Procedure:
Combine dl-2-amino-1-phenylethanol (5.49 g.; 0.04 moles) with water (60 ml)and 5 N aqueous HCl (8 ml; 0.04 moles) then stir until clear. Add 37% aqueous formaldehyde solution (4 ml), then with stirring drip in a solution of potassium cyanide (2.61 g.; 0.04 moles) in water (20 ml). Stira further 3 hours at room temperature then add diethyl ether and let stand overnight. Extract with diethyl ether, wash, dry and evaporate the solventin vacuo. Purify the resulting oil and convert to the HCl salt as in the preceding paragraph to obtain 4.10 g. of the title product, m.p.=146°-148° C.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([Cl:9])[C:3]=1[NH2:4].Cl.N([O-])=O.[Na+].[N-:15]=[N+:16]=[N-].[Na+]>C(OCC)(=O)C.O>[N:4]([C:3]1[C:2]([Cl:1])=[CH:8][CH:7]=[CH:6][C:5]=1[Cl:9])=[N+:15]=[N-:16]
Reactant: [N-]=[N+]=[N-]
Reactant: Nc1c(Cl)cccc1Cl
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: [N-]=[N+]=Nc1c(Cl)cccc1Cl
Reaction time: 0.17 h
Yield: 90.9 %

Procedure:
To a 0° C. solution of 2,6-dichloroaniline (2.00 g) in ethyl acetate (40 mL) is added concentrated hydrochloric acid (12 mL). The reaction is stirred for 10 minutes. To this solution is added a solution of sodium nitrite (2.55 g) in water (7.5 mL) over 3 minutes. Upon completion of the addition, the reaction is stirred for an additional 30 minutes. A solution of sodium azide (2.41 g) in water (8 mL) is added over 5 minutes. After 30 minutes, pH 7 buffer (50 mL) is added and the reaction is transferred to a separatory funnel. The layers are separated and the aqueous layer is extracted with ethyl acetate. The organic layers are combined and washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound (2.11 g). 1H NMR (400 MHz, CDCl3) δ 7.3-7.27 (d, 2H), 7.07-7.02 (t, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([CH:9]2[CH2:11][CH2:10]2)[CH:3]=1.N([O-])=O.[Na+].[N-:16]=[N+:17]=[N-].[Na+].[OH-].[Na+]>C(O)(=O)C.O>[N:6]([C:5]1[CH:7]=[CH:8][C:2]([Cl:1])=[CH:3][C:4]=1[CH:9]1[CH2:11][CH2:10]1)=[N+:16]=[N-:17]
Reactant: [N-]=[N+]=[N-]
Reactant: Nc1ccc(Cl)cc1C1CC1
Agent: O=N[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: [N-]=[N+]=Nc1ccc(Cl)cc1C1CC1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A solution of 4-chloro-2-cyclopropylaniline (182 mg, 1.086 mmol) in acetic acid (15 ml) and water (15 ml) was stirred and cooled to 0° C. A solution of sodium nitrite (74.9 mg, 1.086 mmol) in water (1.4 ml) was added dropwise and the mixture was stirred under ice cooling for 10 mins. A solution of sodium azide (70.6 mg, 1.086 mmol) in water (1.5 ml) was added dropwise and was stirred under ice cooling for 1 hr and then at RT 30 mins. To the product mixture was added 2M NaOH (aq) until basic and this was extracted with EtOAc. The organic extract was washed with sat. NaHCO3(aq) and dried over MgSO4, filtered and concentrated under reduced pressure to give the title compound as a dark yellow/brown oil. The crude product was used in the next step without further purification.
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:16])[O:4][C:5]1[C:13]2[O:12][C:11]([CH3:15])([CH3:14])[CH2:10][C:9]=2[CH:8]=[CH:7][CH:6]=1.[C:17]([CH2:19][CH2:20][N:21]([CH2:24][CH2:25][C:26]#[N:27])[S:22]Cl)#[N:18].N1C=CC=CC=1>C(Cl)Cl>[C:17]([CH2:19][CH2:20][N:21]([CH2:24][CH2:25][C:26]#[N:27])[S:22][N:2]([CH3:1])[C:3](=[O:16])[O:4][C:5]1[C:13]2[O:12][C:11]([CH3:14])([CH3:15])[CH2:10][C:9]=2[CH:8]=[CH:7][CH:6]=1)#[N:18]
Reactant: N#CCCN(CCC#N)SCl
Reactant: CNC(=O)Oc1cccc2c1OC(C)(C)C2
Solvent: ClCCl
Solvent: c1ccncc1
Product: CN(SN(CCC#N)CCC#N)C(=O)Oc1cccc2c1OC(C)(C)C2
Reaction time: 20 h

Procedure:
4.4 g (0.02 mole) of 2,3-dihydro-2,2-dimethylbenzofuran-7-yl N-methyl-carbamate, 3.8 g (0.02 mole) of bis(cyanoethyl)aminosulfenyl chloride obtained in Example 31, and 4.7 g (0.06 mole) of pyridine were dissolved in 35 ml of methylene chloride, and the resulting solution was stirred for 20 hours at 25° to 30° C. After completion of the reaction, the reaction solution was washed successively with water, diluted hydrochloric acid and water. The methylene chloride layer was dried over sodium sulfate and concentrated under reduced pressure to obtain an oily product which was almost entirely composed of the desired product although containing small amounts of the starting materials and impurities. Yield: 6.2 g (82.7%).
Reaction SMILES: [CH:1]([C:4]1[N:5]=[C:6]([CH2:9][CH2:10][C:11]2[CH:29]=[CH:28][N:14]3[C:15](=[O:27])[C:16]([CH:25]=O)=[C:17]([N:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)[N:18]=[C:13]3[CH:12]=2)[S:7][CH:8]=1)([CH3:3])[CH3:2].[S:30]1[CH2:34][C:33](=[O:35])[NH:32][C:31]1=[O:36]>N1CCCCC1.C(O)(=O)C.C1C=CC=CC=1>[CH:1]([C:4]1[N:5]=[C:6]([CH2:9][CH2:10][C:11]2[CH:29]=[CH:28][N:14]3[C:15](=[O:27])[C:16]([CH:25]=[C:34]4[S:30][C:31](=[O:36])[NH:32][C:33]4=[O:35])=[C:17]([N:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)[N:18]=[C:13]3[CH:12]=2)[S:7][CH:8]=1)([CH3:3])[CH3:2]
Reactant: O=C1CSC(=O)N1
Reactant: CC(C)c1csc(CCc2ccn3c(=O)c(C=O)c(N4CCOCC4)nc3c2)n1
Solvent: C1CCNCC1
Solvent: c1ccccc1
Solvent: CC(=O)O
Product: CC(C)c1csc(CCc2ccn3c(=O)c(C=C4SC(=O)NC4=O)c(N4CCOCC4)nc3c2)n1
Yield: 76.1 %

Procedure:
8-[2-(4-Isopropyl-1,3-thiazol-2-yl)ethyl]-2-morpholino-4-oxo-4H-pyrido[1,2-a]-pyrimidine-3-carbaldehyde (18 mg) and 2,4-thiazolidinedione (53 mg) were added with benzene (10 ml), piperidine (one drop) and acetic acid (two drops) and refluxed by heating for 3 hours in a vessel provided with a Dean-Stark trap. After the solvent was evaporated under reduced pressure, the residue was purified by silica gel column chromatography to obtain the title compound (17 mg) as yellow powder.
Reaction SMILES: N[C:2]1[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[C:5]2[N:6]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[Cl:16])[C:7](=[O:9])[NH:8][C:4]=2[CH:3]=1.[C:23]([Cu])#[N:24].N(OC(C)(C)C)=O.O>CS(C)=O>[Cl:16][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[N:6]1[C:5]2[C:17]([C:19]([F:21])([F:22])[F:20])=[CH:18][C:2]([C:23]#[N:24])=[CH:3][C:4]=2[NH:8][C:7]1=[O:9]
Reactant: N#C[Cu]
Reactant: Nc1cc(C(F)(F)F)c2c(c1)[nH]c(=O)n2-c1ccccc1Cl
Agent: CC(C)(C)ON=O
Solvent: O
Solvent: CS(C)=O
Product: N#Cc1cc(C(F)(F)F)c2c(c1)[nH]c(=O)n2-c1ccccc1Cl
Temperature: 55 °C
Reaction time: 1 h
Yield: 37 %

Procedure:
5-Amino-1-(2-chlorophenyl)-7-(trifluoromethyl)-1,3-dihydro-2H-benzimidazole-2-one (46.2 mg) was dissolved in dimethyl sulfoxide (1 ml), and to the solution was added CuCN (16.4 mg). The mixture was heated at 55° C. At the same temperature, a solution of t-butyl nitrite (43.6 mg) in dimethyl sulfoxide (0.5 ml) was added dropwise during about 1.5 hours. After the addition was completed, the mixture was stirred at about 60° C. for 1 hour. After allowing to cool, to the reaction mixture was added water, and the mixture was extracted 2 times with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo. The resultant residue was purified by silica gel column (20 g, CHCl3-methanol=20:1) to give the title compound (17.6 mg).