Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]=O.[NH2:9][C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][C:17]=1[NH2:18])[C:13]#[N:14].C1(=O)C=CC(=O)C=C1>C(O)C>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[NH:18][C:17]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][C:10]=2[N:9]=1
Reactant: O=Cc1ccccn1
Reactant: N#Cc1ccc(N)c(N)c1
Agent: O=C1C=CC(=O)C=C1
Solvent: CCO
Product: N#Cc1ccc2[nH]c(-c3ccccn3)nc2c1
Yield: 79.8 %

Procedure:
A mixture comprising 2-pyridinecarboxaldehyde (212 mg, 1.98 mmol, 1 eq), 3,4-diaminobenzonitrile (263 mg, 1.98 mmol, 1 eq) and ethanol (20 mL) was stirred at ambient temperature under nitrogen for 5 to 10 minutes and then 1,4-benzoquinone (233 mg, 2.16 mmol, 1.2 eq) was added. The mixture was heated at reflux for 3 hours and then concentrated. The residue was partitioned between ethyl acetate and saturated sodium bicarbonate. The organic layer was separated, dried (MgSO4), filtered and concentrating to dryness to provide 2-pyridin-2-yl-1H-benzimidazole-5-carbonitrile (348 mg, 1.58 mmol) as an off white solid; ESI LC/MS: 261.9=(MH+ +CH3CN); 1H-NMR (300 Mhz, DMSO-d6): 7.65-7.755 (m, 2H), 7.769 (d, 1H), 8.060 (t, 1H), 8.163 (s, 1H), 8.395 (d, 1H), 8.772 (d, 1H).
Reaction SMILES: [C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24](/[C:26](=[N:30]/[O:31][CH:32]2[CH2:37][CH2:36][CH2:35][CH2:34][O:33]2)/[C:27](O)=[O:28])[N:25]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:38][CH:39]1[C:65](=[O:66])[N:41]2[C:42]([C:53]([O:55][CH2:56][C:57]3[CH:62]=[CH:61][C:60]([O:63][CH3:64])=[CH:59][CH:58]=3)=[O:54])=[C:43](/[CH:46]=[CH:47]\[C:48]3[N:49]=[N:50][S:51][CH:52]=3)[CH2:44][S:45][C@H:40]12.C1CCC(N=C=NC2CCCCC2)CC1>C(Cl)Cl>[C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24](/[C:26](=[N:30]/[O:31][CH:32]2[CH2:37][CH2:36][CH2:35][CH2:34][O:33]2)/[C:27]([NH:38][CH:39]2[C:65](=[O:66])[N:41]3[C:42]([C:53]([O:55][CH2:56][C:57]4[CH:58]=[CH:59][C:60]([O:63][CH3:64])=[CH:61][CH:62]=4)=[O:54])=[C:43](/[CH:46]=[CH:47]\[C:48]4[N:49]=[N:50][S:51][CH:52]=4)[CH2:44][S:45][C@H:40]23)=[O:28])[N:25]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: COc1ccc(COC(=O)C2=C(/C=C\c3csnn3)CS[C@@H]3C(N)C(=O)N23)cc1
Reactant: O=C(O)/C(=N\OC1CCCCO1)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: COc1ccc(COC(=O)C2=C(/C=C\c3csnn3)CS[C@@H]3C(NC(=O)/C(=N\OC4CCCCO4)c4csc(NC(c5ccccc5)(c5ccccc5)c5ccccc5)n4)C(=O)N23)cc1
Yield: 35.5 %

Procedure:
(Z)-2-(2-tritylaminothiazol-4-yl)-2-tetrahydropyranyloxyiminoacetic acid (0.39 g, 0.76 mmol) and p-methoxybenzyl 7-amino-3-[(Z)-2-(1,2,3-thiadiazol-4-yl)vinyl]-3-cephem-4-carboxylate (1.33 g, 0.76 mmol) were dissolved in methylene chloride (10 ml) and stirred at room temperature for 12 hours by addition of DCC (0.18 g, 0.87 mmol). Insolubles were filtered and then the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography thereby p-methoxybenzyl 7-[(Z)-2-(2-tritylaminothiazol-4-yl)-2-tetrahydropyranyloxyiminoacetamido]-3-[(Z)-2-(1,2,3-thiadiazol-4-yl)vinyl]-3-cephem-4-carboxylate (0.25 g) was obtained as a light yellow powder compound.
Reaction SMILES: [CH2:1]([NH:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[CH2:2][CH2:3][CH2:4][CH3:5].[CH2:12]=O>>[CH3:12][N:6]([CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])[CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: C=O
Reactant: CCCCCNCCCCC
Product: CCCCCN(C)CCCCC
Yield: 96 %

Procedure:
In a similar manner to Example 1, 314.4 g (2.0 mol) of diamylamine (technical mixture of 18.3% by weight of diisopentylamine, 61.0% by weight of di-n/i-pentylamine and 19.2% by weight of di-n-pentylamine, remainder: 1.5% by weight) and 330.2 g (3.2 mol) of formaldehyde (29.1%) are reacted in a 1 l autoclave; a maximum pressure of 2.5 MPa is established at a temperature of 120° C. After the crude amine (aqueous and organic phase) has been degassed at a maximum temperature of 102° C., the water is removed on a water separator. The remaining organic phase is subsequently distilled. 329.1 g of N-methyldiamylamine having a purity of 91.8% are isolated, corresponding to a yield of 88.3% of theory.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:42]([F:45])([F:44])[F:43])[CH:5]=[C:6]2[C:10]=1[N:9]([CH3:11])[N:8]=[C:7]2[CH:12]([C:35]1[CH:40]=[CH:39][C:38]([Cl:41])=[CH:37][CH:36]=1)[CH:13]([C:17]1[CH:34]=[CH:33][C:20]([C:21]([NH:23][CH2:24][CH2:25][C:26]([O:28]C(C)(C)C)=[O:27])=[O:22])=[CH:19][CH:18]=1)[CH2:14][CH2:15][CH3:16].C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C:42]([F:44])([F:43])[F:45])[CH:5]=[C:6]2[C:10]=1[N:9]([CH3:11])[N:8]=[C:7]2[CH:12]([C:35]1[CH:40]=[CH:39][C:38]([Cl:41])=[CH:37][CH:36]=1)[CH:13]([C:17]1[CH:34]=[CH:33][C:20]([C:21]([NH:23][CH2:24][CH2:25][C:26]([OH:28])=[O:27])=[O:22])=[CH:19][CH:18]=1)[CH2:14][CH2:15][CH3:16]
Reactant: CCCC(c1ccc(C(=O)NCCC(=O)OC(C)(C)C)cc1)C(c1ccc(Cl)cc1)c1nn(C)c2c(Cl)cc(C(F)(F)F)cc12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCC(c1ccc(C(=O)NCCC(=O)O)cc1)C(c1ccc(Cl)cc1)c1nn(C)c2c(Cl)cc(C(F)(F)F)cc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of the slower-eluting enantiomer of the product from Step B (4.6 mg, 0.0069 mmol) in DCM (1 mL) was added TFA (1 mL, 13 mmol), and the solution was stirred for 30 minutes at RT. The solution was concentrated, then the residue was purified by reverse phase HPLC eluting with acetonitrile/water+0.1% TFA. Following lyophilization, this afforded the enantiopure title compound as a white solid. 1H NMR (500 MHz, CD3OD): δ 7.92 (s, 1H); 7.62 (d, J=8.5 Hz, 2H); 7.53 (d, J=8.3 Hz, 2H); 7.43 (s, 1H); 7.36 (d, J=8.2 Hz, 2H); 7.33 (d, J=8.5 Hz, 2H); 4.78 (d, 3=11.5 Hz, 1H); 4.26 (s, 3H); 3.72 (td, J=11.4, 3.2 Hz, 1H); 3.52 (t, J=6.9 Hz, 2H); 2.55 (t, J=6.9 Hz, 2H); 1.68-1.57 (m, 1H); 1.50-1.43 (m, 1H); 1.05-0.97 (m, 2H); 0.73 (t, J=7.3 Hz, 3H); LC2 1.31 min. (M+H)+ 606.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([CH2:8][C:9]([NH:11][C@H:12]2[CH2:17][C:16]3[CH:18]=[CH:19][CH:20]=[C:21]([C:22]([OH:24])=[O:23])[C:15]=3[O:14][B:13]2[OH:25])=[O:10])[CH2:4][CH2:3]1.[NH:26]1[C:30]([CH:31]=O)=[CH:29][N:28]=[CH:27]1>>[NH:26]1[C:30]([CH2:31][NH:1][C@H:2]2[CH2:7][CH2:6][C@H:5]([CH2:8][C:9]([NH:11][C@H:12]3[CH2:17][C:16]4[CH:18]=[CH:19][CH:20]=[C:21]([C:22]([OH:24])=[O:23])[C:15]=4[O:14][B:13]3[OH:25])=[O:10])[CH2:4][CH2:3]2)=[CH:29][N:28]=[CH:27]1
Reactant: O=Cc1cnc[nH]1
Reactant: N[C@H]1CC[C@H](CC(=O)N[C@H]2Cc3cccc(C(=O)O)c3OB2O)CC1
Product: O=C(C[C@H]1CC[C@H](NCc2cnc[nH]2)CC1)N[C@H]1Cc2cccc(C(=O)O)c2OB1O

Procedure:
Prepared from (R)-3-(2-(trans-4-aminocyclohexyl)acetamido)-2-hydroxy-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylic acid (Example 6) and 1H-imidazole-5-carbaldehyde following the procedure in Example 27. The product was purified using reverse phase HPLC to afford the titled compound. ESI-MS m/z 427 (MH)+.
Reaction SMILES: COC(=O)C1C=CC(NC(=O)C2C=CC(O)=C(N)C=2)=NC=1.[CH3:22][O:23][C:24](=[O:44])[C:25]1[CH:30]=[CH:29][C:28]([NH:31][C:32]([C:34]2[CH:35]=[CH:36][C:37]3[O:42][CH2:41][CH2:40][NH:39][C:38]=3[CH:43]=2)=[O:33])=[N:27][CH:26]=1.[Cl:45][C:46]1[CH:47]=[CH:48][C:49]([O:56][CH3:57])=[C:50]([S:52](Cl)(=[O:54])=[O:53])[CH:51]=1>>[CH3:22][O:23][C:24](=[O:44])[C:25]1[CH:30]=[CH:29][C:28]([NH:31][C:32]([C:34]2[CH:35]=[CH:36][C:37]3[O:42][CH2:41][CH2:40][N:39]([S:52]([C:50]4[CH:51]=[C:46]([Cl:45])[CH:47]=[CH:48][C:49]=4[O:56][CH3:57])(=[O:53])=[O:54])[C:38]=3[CH:43]=2)=[O:33])=[N:27][CH:26]=1
Reactant: COc1ccc(Cl)cc1S(=O)(=O)Cl
Reactant: COC(=O)c1ccc(NC(=O)c2ccc3c(c2)NCCO3)nc1
Agent: COC(=O)c1ccc(NC(=O)c2ccc(O)c(N)c2)nc1
Product: COC(=O)c1ccc(NC(=O)c2ccc3c(c2)N(S(=O)(=O)c2cc(Cl)ccc2OC)CCO3)nc1

Procedure:
6-{[4-(5-Chloro-2-methoxy-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-nicotinic acid, MS (ISP): m/e=502.1 (M−H), was prepared as described for example 14, steps 1 to 8. Step 4 was performed using 6-amino-nicotinic acid methyl ester, yielding 6-(4-benzyloxy-3-nitro-benzoylamino)-nicotinic acid methyl ester, which was reduced to 6-(3-amino-4-hydroxy-benzoylamino)-nicotinic acid methyl ester in step 5 and cyclized to 6-[(3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl)-amino]-nicotinic acid methyl ester in step 6. Step 7 was performed using 5-chloro-2-methoxy-benzenesulfonyl chloride and yielded 6-{[4-(5-chloro-2-methoxy-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-nicotinic acid methyl ester, which was hydrolyzed in step 8.
Reaction SMILES: [Cl:1][C:2]1[C:7](=[O:8])[C:6](Cl)=[N:5][S:4][N:3]=1.C(N(CC)CC)C.[C:17]1([SH:23])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(OCC)C>[Cl:1][C:2]1[C:7](=[O:8])[C:6]([S:23][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[N:5][S:4][N:3]=1
Reactant: O=c1c(Cl)nsnc1Cl
Reactant: Sc1ccccc1
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: O=c1c(Cl)nsnc1Sc1ccccc1
Reaction time: 2 h

Procedure:
A mixture of 3.66 g of 3,5-dichloro-4H-1,2,6-thiadiazin-4-one, 30 ml of ethyl ether, and 2.02 g of triethylamine is stirred at 0°-5° C. while a solution of 2.20 g of thiophenol in 20 ml of ethyl ether is added dropwise to it. This mixture is stirred 2 hours longer while it is allowed to return to ambient temperature. Then it is filtered to remove triethylamine hydrochloride, and the filtrate is concentrated on a rotary evaporator. The solid residue is recrystallized from hexane to yield yellow prisms, mp 100°-2°.
Reaction SMILES: [C:1]1([N:7]([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[C:8](=[O:42])[O:9][CH2:10][C:11]2([OH:41])[CH2:17][CH2:16][CH2:15][C:14]3[C:18]([O:22][Si](C(C)(C)C)(C4C=CC=CC=4)C4C=CC=CC=4)=[CH:19][CH:20]=[CH:21][C:13]=3[CH:12]2[OH:40])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(N(C2C=CC=CC=2)C(=O)OCC2(O)C(O)CCC3C(O[Si](C(C)(C)C)(C4C=CC=CC=4)C4C=CC=CC=4)=CC=CC=3C2)C=CC=CC=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.Cl>C1COCC1>[C:43]1([N:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:8](=[O:42])[O:9][CH2:10][C:11]2([OH:41])[CH2:17][CH2:16][CH2:15][C:14]3[C:18]([OH:22])=[CH:19][CH:20]=[CH:21][C:13]=3[CH:12]2[OH:40])[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1
Reactant: CC(C)(C)[Si](Oc1cccc2c1CCCC(O)(COC(=O)N(c1ccccc1)c1ccccc1)C2O)(c1ccccc1)c1ccccc1
Agent: CC(C)(C)[Si](Oc1cccc2c1CCC(O)C(O)(COC(=O)N(c1ccccc1)c1ccccc1)C2)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Solvent: C1CCOC1
Product: O=C(OCC1(O)CCCc2c(O)cccc2C1O)N(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of a mixture of [(5SR,6SR)-1-(tert-butyldiphenylsilyloxy)-5,6-dihydroxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl]methyl N,N-diphenylcarbamate and [(6RS,7RS)-1-(tert-butyldiphenylsilyloxy)-6,7-dihydroxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl]methyl N,N-diphenylcarbamate (1.04 g) in THF (10 ml) was added tetrabutylammonium fluoride (1M THF solution, 2.38 ml) at 5° C. The mixture was stirred at room temperature for 1 hour. After addition of 1N-hydrochloric acid (3 ml) under ice-cooling, the mixture was extracted with EtOAc. The organic layer was washed with water, saturated sodium hydrogencarbonate solution, water, and then brine. It was dried over magnesium sulfate and evaporated in vacuo. The residue was purified by silica gel column chromatography (hexane-EtOAc 4:5) to give first [(5SR,6SR)-1,5,6-trihydroxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl]methyl N,N-diphenylcarbamate (468.4 mg) as an amorphous solid and then [(6RS,7RS)-1,6,7-trihydroxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl]methyl N,N-diphenylcarbamate (195.9 mg) as an amorphous solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:34])[CH2:6][N:5]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)[C@@H:4]([C:18]([NH:20][C:21]2([C:24]3[CH:33]=[CH:32][C:27]([C:28]([O:30]C)=[O:29])=[CH:26][CH:25]=3)[CH2:23][CH2:22]2)=[O:19])[CH2:3]1.O1CCOCC1.O[Li].O>O>[CH3:1][C:2]1([CH3:34])[CH2:6][N:5]([CH2:7][C:8]2[CH:9]=[CH:10][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:12][CH:13]=2)[C@@H:4]([C:18]([NH:20][C:21]2([C:24]3[CH:25]=[CH:26][C:27]([C:28]([OH:30])=[O:29])=[CH:32][CH:33]=3)[CH2:22][CH2:23]2)=[O:19])[CH2:3]1
Reactant: COC(=O)c1ccc(C2(NC(=O)[C@H]3CC(C)(C)CN3Cc3ccc(C(F)(F)F)cc3)CC2)cc1
Agent: [Li]O
Solvent: C1COCCO1
Solvent: O
Product: CC1(C)C[C@H](C(=O)NC2(c3ccc(C(=O)O)cc3)CC2)N(Cc2ccc(C(F)(F)F)cc2)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 36.7 %

Procedure:
(R)-methyl 4-(1-(4,4-dimethyl-1-(4-(trifluoromethyl)benzyl)pyrrolidine-2-carboxamido)cyclopropyl)benzoate (D151) (100 mg, 0.21 mmol) was partitioned between dioxane (2 ml) and water (2 ml) prior addition of LiOH H2O (35 mg, 0.84 mmol) and the resulting mixture was stirred at RT for 18 hrs. Dioxane was evaporated off and the aqueous solution acidified with acetic acid to pH˜4-5. A white solid precipitated which was filtered, dried under vacuum, then re-dissolved in dioxane (2 ml) and water (2 ml) and hydrolysed for additional 5 hrs after addition of LiOH H2O (18 mg, 0.42 mmol). Dioxane was evaporated off and the aqueous solution acidified with acetic acid to pH˜4-5. A white solid precipitated which was filtered and dried under vacuum, to afford the title compound (E34) (35.5 mg).
Reaction SMILES: [H-].[Na+].[C:3]([SiH2:7][O:8][C:9]([CH3:19])([CH3:18])[C:10]1[C:15]([CH3:16])=[CH:14][N:13]=[C:12]([NH2:17])[CH:11]=1)([CH3:6])([CH3:5])[CH3:4].Cl[C:21]1[S:22][C:23]([C:26]#[N:27])=[CH:24][N:25]=1.Cl>O.C1COCC1>[C:3]([SiH2:7][O:8][C:9]([CH3:19])([CH3:18])[C:10]1[C:15]([CH3:16])=[CH:14][N:13]=[C:12]([NH:17][C:21]2[S:22][C:23]([C:26]#[N:27])=[CH:24][N:25]=2)[CH:11]=1)([CH3:6])([CH3:5])[CH3:4]
Reactant: Cc1cnc(N)cc1C(C)(C)O[SiH2]C(C)(C)C
Reactant: N#Cc1cnc(Cl)s1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cnc(Nc2ncc(C#N)s2)cc1C(C)(C)O[SiH2]C(C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
An oven dried flask under N2 was charged with NaH (60% dispersion, 185 mg, 4.63 mmol). 5 mL of anhydrous THF was added followed by addition of 4-(tert-butyl-dimethyl-silanyloxymethyl)-5-methyl-pyridin-2-ylamine (9-6, 0.487 g, 1.93 mmol) and 2-chloro-5-cyanothiazole (1-2, 0.391 g, 2.70 mmol). The resulting solution was heated to reflux. After 1 hour the reaction was allowed to cool to room temperature and was then diluted with water. The pH was adjusted to 7 with 1 M HCl. The resulting precipitate was filtered and washed with water to afford 9-7.
Reaction SMILES: [OH-].[OH:2][C:3]1[N+:7]2[CH2:8][CH2:9][C:10]3[CH:14]=[CH:13][S:12][C:11]=3[C:6]=2S[C:4]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[C:21]([O:25][CH3:26])(=[O:24])[C:22]#[CH:23]>C1(C)C=CC=CC=1>[O:2]=[C:3]1[C:4]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:23][C:22]([C:21]([O:25][CH3:26])=[O:24])=[C:6]2[N:7]1[CH2:8][CH2:9][C:10]1[CH:14]=[CH:13][S:12][C:11]=12
Reactant: C#CC(=O)OC
Reactant: Oc1c(-c2ccccc2)sc2[n+]1CCc1ccsc1-2
Agent: [OH-]
Solvent: Cc1ccccc1
Product: COC(=O)c1cc(-c2ccccc2)c(=O)n2c1-c1sccc1CC2

Procedure:
ba) A suspension of 31.65 g of 5,6-dihydro -3-hydroxy-2-phenylthiazolo[3,2-a]thieno[2,3-c]pyridinium hydroxide (internal salt) in 770 ml of toluene was treated with 10.94 g of methyl propiolate, the mixture was heated under reflux until the reaction has finished, the reaction mixture was evaporated in vacuo and the residue was chromatographed on silica gel with toluene/ethyl acetate (9:1). There was obtained methyl 4,5-dihydro-7-oxo-8-phenyl-7H-thieno[2,3-a]quinolizine-10-carboxylate as yellow crystals of m.p. 116° (from ethyl acetate).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.[Li]CCCC.[C:15]([O:19][C:20](=[O:34])[NH:21][C@H:22]1[CH2:27][CH2:26][C@H:25]([C:28](=[O:33])N(OC)C)[CH2:24][CH2:23]1)([CH3:18])([CH3:17])[CH3:16].O>C1COCC1>[C:15]([O:19][C:20](=[O:34])[NH:21][CH:22]1[CH2:23][CH2:24][CH:25]([C:28]([C:2]2[S:1][C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[N:3]=2)=[O:33])[CH2:26][CH2:27]1)([CH3:18])([CH3:16])[CH3:17]
Reactant: c1ccc2scnc2c1
Reactant: CON(C)C(=O)[C@H]1CC[C@H](NC(=O)OC(C)(C)C)CC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)NC1CCC(C(=O)c2nc3ccccc3s2)CC1
Yield: 82.1 %

Procedure:
To a solution of benzothiazole (675 mg, 0.55 ml, 5 mmol) in THF (20 ml) at −78° C. was added dropwise n-BuLi (2.5M in Hex, 2 ml) such that the temperature did not exceed −70° C. The brown solution was stirred at this temperature for 15 min before dropwise addition of a solution of [trans-4-(methoxy-methyl-carbamoyl)-cyclohexyl]-carbamic acid tert-butyl ester (716 mg, 2.5 mmol, prepared according to WO 03/053933) in THF (2 ml). The temperature was kept below −70° C. The brown solution was then gradually allowed to reach RT (over 3 h). Mixture was poured into water and extracted with EtOAc. The combined organic extracts were washed with brine and dried over MgSO4 and concentrated under reduced pressure. The residue was purified by chromatography over SiO2 (Hex/EtOAc 4:1 then DCM). The relevant fractions were pooled, evaporated under reduced pressure, digested with Hex and filtered to give 740 mg (82%) of [4-(benzothiazole-2-carbonyl)-cyclohexyl]-carbamic acid tert-butyl ester.
Reaction SMILES: [OH:1][C:2]1[CH:37]=[CH:36][C:5]2[CH:6]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][S:27][CH2:28][CH2:29][N:30]3[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]3)[C:7]([C:11]3[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=3)([CH3:10])[CH2:8][O:9][C:4]=2[CH:3]=1.C[OH:39]>O>[OH:1][C:2]1[CH:37]=[CH:36][C:5]2[CH:6]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][S:27]([CH2:28][CH2:29][N:30]3[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]3)=[O:39])[C:7]([C:11]3[CH:12]=[CH:13][C:14]([OH:17])=[CH:15][CH:16]=3)([CH3:10])[CH2:8][O:9][C:4]=2[CH:3]=1
Reactant: CC1(c2ccc(O)cc2)COc2cc(O)ccc2C1CCCCCCCCCSCCN1CCCCC1
Reactant: CO
Solvent: O
Product: CC1(c2ccc(O)cc2)COc2cc(O)ccc2C1CCCCCCCCCS(=O)CCN1CCCCC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 74 %

Procedure:
(3RS,4RS)-7-Hydroxy-3-(4-hydroxyphenyl)-3-methyl-4-[9-(2-piperidinoethylthio)nonyl]-2,3-dihydro-4H-benzopyran (126 mg, 0.24 mmol) was dissolved in methanol (5 ml)and water (1.2 ml), and NaIO4 (62 mg, 0.29 mmol) was added thereto. The reaction was stirred for 4 hours at room temperature and then filtered. The filtrate was concentrated and the residue was purified with flash column chromatography (dichloromethane:ethanol=13:1→10:1) to obtain 96 mg (yield: 74%) of the title compound as a white foamy solid.
Reaction SMILES: [CH3:1][N:2]([CH3:6])[CH2:3][CH2:4][OH:5].C[Si]([N-][Si](C)(C)C)(C)C.[Na+].Cl[C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][N:19]=1>CN(C=O)C.O.CCOC(C)=O>[N+:24]([C:21]1[CH:22]=[CH:23][C:18]([O:5][CH2:4][CH2:3][N:2]([CH3:6])[CH3:1])=[N:19][CH:20]=1)([O-:26])=[O:25]
Reactant: CN(C)CCO
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)CCOc1ccc([N+](=O)[O-])cn1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 44.2 %

Procedure:
Microwave heating. To a solution of 2-(dimethylamino)ethanol (339 mg, 3.80 mmol) in DMF (5 mL) was added sodium bis(trimethylsilyl)amide (4.75 mL, 1M solution in THF, 4.75 mmol). The mixture was stirred at room temperature for 15 min. 2-Chloro-5-nitropyridine (500 mg, 3.16 mmol) was then added. The vial was capped and subjected to microwave irradiation (150° C. for 10 minutes). The mixture was diluted with water (250 mL) and EtOAc (250 mL). The two layers were separated, and the aqueous layer extracted two more times with EtOAc. The organic extracts were combined, washed with water and brine, dried over sodium sulfate and evaporated to give the crude material as brown oil. Purification by column chromatography on silica gel using 5% methanol/methylene chloride yielded 2-(5-nitropyridin-2-yloxy)-N,N-dimethylethanamine as a light yellow solid (295 mg, 44%).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][N:9]=2)[C:4](O)=[CH:3][CH:2]=1.[Br-:12].[Br-].[Br-].[P+3]=O.N>C(#N)C>[Br:12][C:4]1[C:5]2[C:10](=[N:9][CH:8]=[CH:7][CH:6]=2)[N:1]=[CH:2][CH:3]=1
Reactant: Oc1ccnc2ncccc12
Reactant: [Br-]
Agent: N
Agent: O=[P+3]
Solvent: CC#N
Product: Brc1ccnc2ncccc12
Reaction time: 1 h

Procedure:
To a solution of 1,8-naphthyridin-4-ol (59 g, 400 mmol) in acetonitrile (500 ml) was added phosphorus oxide tribromide. The reaction mixture was heated to reflux. After 1 hour, the reaction mixture was carefully diluted with ice and the resulting solution was basified with ammonia solution (25%) to pH>7. The reaction mixture was partially concentrated in vacuo, then extracted with chloroform (4×500 ml). The organics were dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by column chromatography on silica gel (ethyl acetate/petroleum ether gradient) to afford 4-bromo-1,8-naphthyridine.
Reaction SMILES: C([Li])CCC.Br[C:7]1[C:12]([CH3:13])=[C:11]([O:14][CH3:15])[C:10]([CH3:16])=[C:9]([CH3:17])[C:8]=1[O:18][CH3:19].[CH2:20]([N:27]1[CH2:32][CH2:31][CH:30]([C:33](=[O:43])[C:34]2[CH:39]=[CH:38][C:37]([CH:40]([CH3:42])[CH3:41])=[CH:36][CH:35]=2)[CH2:29][CH2:28]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.O>O1CCCC1>[CH2:20]([N:27]1[CH2:28][CH2:29][CH:30]([C:33]([C:7]2[C:12]([CH3:13])=[C:11]([O:14][CH3:15])[C:10]([CH3:16])=[C:9]([CH3:17])[C:8]=2[O:18][CH3:19])([C:34]2[CH:35]=[CH:36][C:37]([CH:40]([CH3:42])[CH3:41])=[CH:38][CH:39]=2)[OH:43])[CH2:31][CH2:32]1)[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: COc1c(C)c(C)c(OC)c(Br)c1C
Reactant: CC(C)c1ccc(C(=O)C2CCN(Cc3ccccc3)CC2)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: COc1c(C)c(C)c(OC)c(C(O)(c2ccc(C(C)C)cc2)C2CCN(Cc3ccccc3)CC2)c1C
Reaction time: 0.5 h
Yield: 83.6 %

Procedure:
n-Butyllithium (1.6 M, 12.0 mL, 19.2 mmol) was added to a solution of 1-bromo-2,5-dimethoxy-3,4,6-trimethylbenzene (4.89 g, 18.87 mmol) in tetrahydrofuran (100 mL) at −78° C., and the mixture was stirred for 30 minutes at the same temperature. To the reaction mixture was added 1-benzyl-4-(4-isopropylbenzoyl)piperidine (5.02 g, 15.6 mmol). The mixture was stirred for 30 minutes at the same temperature, then poured into the water, and extracted twice with ethyl acetate. The organic layers were combined, washed with an aqueous saturated sodium hydrogencarbonate, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was crystallized from ethyl acetate-hexane to obtain the title compound (6.54 g, yield 83%).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]([NH:15][NH2:16])=[O:14].[F:17][C:18]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:19]=1[C:20](O)=O>>[F:17][C:18]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:19]=1[C:20]1[O:14][C:13]([C:3]2[C:4]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)=[N:5][O:6][C:2]=2[CH3:1])=[N:15][N:16]=1
Reactant: O=C(O)c1ccc(F)cc1F
Reactant: Cc1onc(-c2ccccc2)c1C(=O)NN
Product: Cc1onc(-c2ccccc2)c1-c1nnc(-c2ccc(F)cc2F)o1
Yield: 64 %

Procedure:
As described for example 2, 5-methyl-3-phenyl-isoxazole-4-carboxylic acid hydrazide (200 mg, 0.92 mmol) was converted using 2,4-difluorobenzoic acid instead of o-toluic acid to the title compound (SiO2, heptane:ethyl acetate:dichloromethane=70:10:20 to 40:40:20, 199 mg, 64%) which was obtained as a white solid. MS: m/e=340.2 [M+H]+.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1)#[N:2].[Na].[CH3:10][NH:11][NH:12][C:13](=O)[C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1>CO>[CH3:10][N:11]1[C:1]([C:3]2[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=2)=[N:2][C:13]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)=[N:12]1
Reactant: N#Cc1ccncc1
Reactant: CNNC(=O)c1ccc(Cl)cc1
Agent: [Na]
Solvent: CO
Product: Cn1nc(-c2ccc(Cl)cc2)nc1-c1ccncc1
Reaction time: 0.5 h

Procedure:
To 4-cyanopyridine (2 g.) in methanol (30 ml.) is added sodium (0.1 g.). After standing at room temperature 0.5 hour the solution is added to 1-methyl-2-p-chlorobenzoylhydrazine (3.6 g.) in methanol (40 ml.). The reaction mixture is refluxed for 5 hours and concentrated to an oil which is solidified. After recrystallization from ethyl alcohol 0.5 g. of 1-methyl-3-(p-chlorophenyl)-5-(4-pyridyl)-1,2,4-triazole m.p. 191° C. is obtained.