Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]=[CH:7][C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH:9]=2)=[O:4].[CH3:23][N:24]([CH2:26]N(C)C)[CH3:25]>C(O)(=O)C>[CH3:23][N:24]([CH2:26][C:7]1[C:8]2[C:13](=[CH:12][CH:11]=[C:10]([O:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:9]=2)[C:14]([OH:15])=[C:5]([C:3]([O:2][CH3:1])=[O:4])[N:6]=1)[CH3:25]
Reactant: COC(=O)c1ncc2cc(Oc3ccccc3)ccc2c1O
Reactant: CN(C)CN(C)C
Solvent: CC(=O)O
Product: COC(=O)c1nc(CN(C)C)c2cc(Oc3ccccc3)ccc2c1O
Temperature: 55 °C

Procedure:
A flask was charged with 1a (29.5 g) and acetic acid (44.3 g±5%), and then stirred. Bis-dimethylaminomethane (12.8 g±2%) was slowly added. The mixture was heated to 55±5° C. and maintained until reaction completion. The reaction product was evaluated by MS, HPLC and 1H NMR. 1H NMR (200 MHz, DMSO-d6) δ 11.7 (s, 1H), 8.38 (d, J=9.0 Hz, 1H), 7.61 (dd, J=9.0, 2.7 Hz, 1H), 7.49 (m, 3H), 7.21 (m, 3H), 5.34 (s, 2H), 3.97 (s, 3H), 1.98 (s, 3H); MS-(+)-ion M+1=368.12.
Reaction SMILES: C[C:2]1[C:3]([N:11]=[C:12]=[O:13])=[CH:4][CH:5]=[CH:6][C:7]=1[N:8]=[C:9]=[O:10].[N-]=[C:15]=O.[N-]=C=O.C1(CC2C=CC=CC=2)C=CC=CC=1.C1(N=C=O)C=CC=C(N=C=O)C=1.C(N=C=O)CCCN=C=O.COC1C=C(C2C=CC(N=C=O)=C(OC)C=2)C=CC=1N=C=O.CC1C=C(C2C=CC(N=C=O)=C(C)C=2)C=CC=1N=C=O.C1(N=C=O)C=CC(N=C=O)=CC=1.C1C=C(N=C=O)C2C=CC=C(N=C=O)C=2C=1.C1(CN=C=O)C=CC(CN=C=O)=CC=1.C1(CN=C=O)C=CC=C(CN=C=O)C=1.N(CC1CCCC(CN=C=O)C1)=C=O.N(CC1CCC(CN=C=O)CC1)=C=O.C1C(CC2CCC(N=C=O)CC2)CCC(N=C=O)C1>>[CH3:15][C:4]1[C:3]([N:11]=[C:12]=[O:13])=[CH:2][C:7]([N:8]=[C:9]=[O:10])=[CH:6][CH:5]=1
Reactant: [N-]=C=O
Reactant: Cc1c(N=C=O)cccc1N=C=O
Agent: COc1cc(-c2ccc(N=C=O)c(OC)c2)ccc1N=C=O
Agent: Cc1cc(-c2ccc(N=C=O)c(C)c2)ccc1N=C=O
Agent: O=C=NC1CCC(CC2CCC(N=C=O)CC2)CC1
Solvent: c1ccc(Cc2ccccc2)cc1
Product: Cc1ccc(N=C=O)cc1N=C=O

Procedure:
2,6-tolylene diisocyanate; diphenylmethane diisocyanate (may be abbreviated as "MDI"); m-phenylene diisocyanate; tetramethylene diisocyanate; 3,3'-dimethoxy-4,4'-biphenylene diisocyanate; 3,3'-dimethyl-4,4'-biphenylene diisocyanate; 4,4'-diphenylene diisocyanate; paraphenylene diisocyanate; 4,4'-diisocyanato diphenyl ether; 1,5-naphthalene diisocyanate; p-xylylene diisocyanate; m-xylylene diisocyanate; 1,3-diisocyanato methyl-cyclohexane; 1,4-diisocyanato methylcyclohexane; 4,4'-diisocyanato dicyclohexane; 4,4'-diisocyanato dicyclohexylmethane; and ieophorone diisocyanate.
Reaction SMILES: SC1N(C)C(=O)C2C(=CC=C(C)C=2)[N:3]=1.ClC1N=C(O)C2C(=CC=C(C)C=2)N=1.[NH:28]([C:30]1[N:39]=[C:38]([OH:40])[C:37]2[C:32](=[CH:33][CH:34]=[C:35]([CH3:41])[CH:36]=2)[N:31]=1)[NH2:29].SC1N=C(O)C2C(=CC=C(C)C=2)N=1.O.NN>O>[NH2:3][N:39]1[C:38](=[O:40])[C:37]2[C:32](=[CH:33][CH:34]=[C:35]([CH3:41])[CH:36]=2)[N:31]=[C:30]1[NH:28][NH2:29]
Reactant: Cc1ccc2nc(S)n(C)c(=O)c2c1
Reactant: Cc1ccc2nc(NN)nc(O)c2c1
Agent: Cc1ccc2nc(Cl)nc(O)c2c1
Agent: Cc1ccc2nc(S)nc(O)c2c1
Agent: NN
Solvent: O
Product: Cc1ccc2nc(NN)n(N)c(=O)c2c1
Temperature: 25 °C
Yield: 95 %

Procedure:
2-mercapto-3,6-dimethylquinazolin-4(3H)-one, 2-chloro-6-methylquinazolin-4-ol, 2-hydrazino-6-methylquinazolin-4-ol or 2-mercapto-6-methylquinazolin-4-ol was stirred in 5 volumes of hydrazine hydrate at reflux for 24 hours and the mixture was diluted with 5 volumes of water. The mixture was cooled to room temperature and was filtered. The product was washed with water and then methanol and dried to obtain a 95% yield of 3-amino-2-hydrazino-6-methylquinazolin-4(3H)-one.
Reaction SMILES: Cl.[CH3:2][N:3]([CH3:7])[CH2:4][CH2:5]Cl.[OH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:17])[CH3:16])=[CH:11][CH:10]=1.C(=O)([O-])[O-].[K+].[K+].Cl>CC(C)=O>[CH3:2][N:3]([CH3:7])[CH2:4][CH2:5][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:17])[CH3:16])=[CH:11][CH:10]=1
Reactant: CC(=O)c1ccc(O)cc1
Reactant: CN(C)CCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(=O)c1ccc(OCCN(C)C)cc1
Yield: 63.6 %

Procedure:
2-(Dimethylamino)ethyl chloride hydrochloride (3.49 g, 23.2 mmol, 1.1 eq.) was added to a solution of 4′-hydroxyacetophenone (3.00 g, 22.0 mmol, 1 eq.) in acetone (100 mL), followed by the addition of potassium carbonate (9.12 g, 66.0 mmol, 3 eq.). The reaction mixture was heated under reflux overnight, cooled, and filtered; and the filtrate was concentrated and water (50 mL) was added, forming a cloudy solution. Hydrochloric acid (0.1N, 20 mL) was added, and the resulting clear solution was extracted three times with ethyl acetate. The aqueous phase was made basic with aqueous sodium hydroxide, forming a cloudy mixture, which was extracted with ethyl acetate (5×50 mL), then the ethyl acetate layer dried over magnesium sulfate and the ethyl acetate evaporated to give 4′-[2-(dimethylamino)ethoxy]acetophenone (2.90 g) as a light yellow oil, with identity and purity verified by LC-MS. Bromine (1.62 g, 10.1 mmol, 1.4 eq.) was added dropwise to a solution of the 4′-[2-(dimethylamino)ethoxy]acetophenone (1.5 g, 7.24 mmol) in acetic acid (5 mL) and the reaction mixture stirred at 24° C. for 3 hours, giving a dark red solution. The reaction mixture was cooled, water (5 mL) was added, and the mixture was lyophilized overnight. The crude 2-bromo-4′-[2-(dimethylamino)ethoxy]acetophenone was purified by preparative HPLC, followed by lyophilization of the appropriate fractions, to give 2-bromo-4′-[2-(dimethylamino)ethoxy]acetophenone (0.7 g) as an off-white solid.
Reaction SMILES: Br[CH2:2][C:3]1[C:4]([Cl:17])=[C:5]([CH:10]=[CH:11][C:12]=1[S:13]([CH3:16])(=[O:15])=[O:14])[C:6]([O:8]C)=[O:7].CC(C)([O-])C.O.[OH-].[Na+].[CH:26]1([OH:32])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1>>[Cl:17][C:4]1[C:3]([CH2:2][O:32][CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)=[C:12]([S:13]([CH3:16])(=[O:15])=[O:14])[CH:11]=[CH:10][C:5]=1[C:6]([OH:8])=[O:7]
Reactant: COC(=O)c1ccc(S(C)(=O)=O)c(CBr)c1Cl
Reactant: OC1CCCCC1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CS(=O)(=O)c1ccc(C(=O)O)c(Cl)c1COC1CCCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1.0 g (2.93 mmol) of methyl 3-bromomethyl-2-chloro-4-methylsulfonylbenzoate was dissolved in 10 ml of cyclohexanol and treated with 0.33 g (2.93 mmol) of potasisum tert-butoxide. The mixture was stirred overnight at room temperature and then concentrated on a rotary evaporator. The residue was dissolved in 16 ml of tetrahydrofuran and 8 ml of water and refluxed for 4 h together with 0.55 g of NaOH (13.74 mmol). It was then allowed to cool and was largely concentrated on a rotary evaporator and the aqueous residue was then treated with 2 M HCl. It was then extracted with methylene chloride, and the combined organic phase was dried over MgSO4 and completely concentrated on a rotary evaporator.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:16]=[CH:15][C:14]([C:17](=[O:19])[CH3:18])=[CH:13][C:11]=3[N:12]=2)=[CH:4][CH:3]=1.[BH4-].[Na+]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:9][C:10]3[CH:16]=[CH:15][C:14]([CH:17]([OH:19])[CH3:18])=[CH:13][C:11]=3[N:12]=2)=[CH:6][CH:7]=1
Reactant: CC(=O)c1ccc2oc(-c3ccc(Cl)cc3)nc2c1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(O)c1ccc2oc(-c3ccc(Cl)cc3)nc2c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 54.3 %

Procedure:
To a solution of 1-(2-(4-chlorophenyl)benzo[d]oxazol-5-yl)ethanone (150 mg, 0.55 mmol) in tetrahydrofuran at 0° C. was added sodium borohydride (52 mg, 1.38 mmol). The resulting mixture was stirred at room temperature for 16 h. The reaction was then quenched at 0° C. with 1M hydrochloric acid solution and extracted three times with ethyl acetate. The combined organic layers were dried over anhydrous MgSO4 and evaporated. The resulting solid was purified by column chromatography eluting using a gradient (ethyl acetate/hexanes 1:3 v/v to ethyl acetate/hexanes 1:2 v/v) to afford 81.7 mg (54%) of the title compound. (LCMS RT=6.47 min, MH+ 274.0)
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([N+:12]([O-:14])=[O:13])[CH:6]=[CH:7][CH:8]=2)[N:3]=1.CC([O-])(C)C.[Na+].[CH2:21]([NH:25][C:26]1[CH:35]=[CH:34][C:33]2[C:28](=[C:29]([N+:36]([O-:38])=[O:37])[CH:30]=[CH:31][CH:32]=2)[N:27]=1)[CH2:22][CH2:23][CH3:24].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl-].[NH4+]>C1(C)C=CC=CC=1>[CH2:21]([N:25]([C:26]1[CH:35]=[CH:34][C:33]2[C:28](=[C:29]([N+:36]([O-:38])=[O:37])[CH:30]=[CH:31][CH:32]=2)[N:27]=1)[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([N+:12]([O-:14])=[O:13])[CH:6]=[CH:7][CH:8]=2)[N:3]=1)[CH2:22][CH2:23][CH3:24]
Reactant: O=[N+]([O-])c1cccc2ccc(Cl)nc12
Reactant: CCCCNc1ccc2cccc([N+](=O)[O-])c2n1
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: Cc1ccccc1
Product: CCCCN(c1ccc2cccc([N+](=O)[O-])c2n1)c1ccc2cccc([N+](=O)[O-])c2n1
Reaction time: 0.5 h
Yield: 38 %

Procedure:
2-chloro-8-nitroquinoline (122 mg; 0.59 mmol) and NaOtBu (77.5 mg; 0.81 mmol) are added to a violet suspension of N-butyl-8-nitro-2-quinoline amine (0.17 g; 0.69 mmol), tris(dibenzylidene-acetone)-dipalladium(0) (13 mg; 0.014 mmol) and rac-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (17 mg; 0.027 mmol) in 5 ml of toluene under argon. The medium is heated under reflux for 3 hours, then 2-chloro-8-nitroquinoline (22 mg; 0.11 mmol) is again added. Heating is continued for 2 hours 30 minutes then 10 ml of a saturated ammonium chloride solution are added. The product is extracted with 3×30 ml of CH2Cl2 and the solvent is evaporated under reduced pressure. The product is purified by silica gel chromatography, eluted with CH2Cl2/hexane (80/20, v/v) to yield N-butyl-2,2′-imino-bis(8-nitroquinoline) in the form of a yellow powder (0.11 g; 0.26 mmol, yield=38%). NMR-1H (250 MHz, CDCl3) δ, ppm: 8.14 (d, 3J (H, H)=9.0 Hz, 2H); 7.99 (dd, 3J (H, H)=7.5 Hz, 4J (H, H)=1.5 Hz, 2H); 7.93 (dd, 3J (H, H)=8.0 Hz, 4J (H, H)=1.5 Hz, 2H); 7.73 (d, 3J (H, H)=9.0 Hz, 2H); 7.43 (m, 2H); 4.45 (t, 3J (H, H)=7.5 Hz, 2H); 1.83 (m, 2H); 1.47 (m, 2H); 0.98 (t, 3J (H, H)=7.5 Hz, 3H). NMR-13C (63 MHz, CDCl3) δ, ppm: 156.2 (Cq); 146.4 (Cq); 138.7 (Cq); 137.0 (CH); 131.5 (CH); 126.2 (Cq); 124.2 (CH); 122.8 (CH); 117.3 (CH); 48.9 (CH2); 30.4 (CH2); 20.3 (CH2); 13.9 (CH3). MS (CID, NH3): m/z=418 (MH+). Analysis (%) for C22H19N5O4: calculated C, 63.30; H, 4.59; N, 16.78. found C, 63.18; H, 4.49; N, 16.39. UV/vis [CH3OH/20 mM Tris-HCl pH=7.4 containing 150 mM NaCl (1/1, v/v)]: λ nm (ε M−1 cm−1)=210 (91,400), 226 (53,500, shoulder), 270 (42,100), 294 (26,700, shoulder), 383 (28,400).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[CH2:13][CH2:12][C@:11]([CH:17]([CH3:19])[CH3:18])([C:14]([OH:16])=O)[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.Cl.[F:22][C:23]([F:37])([F:36])[C:24]1[CH:29]=[CH:28][N:27]=[C:26]([C:30]2[CH2:31][CH2:32][NH:33][CH2:34][CH:35]=2)[CH:25]=1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>C(Cl)Cl>[CH:17]([C@:11]1([C:14]([N:33]2[CH2:34][CH:35]=[C:30]([C:26]3[CH:25]=[C:24]([C:23]([F:37])([F:22])[F:36])[CH:29]=[CH:28][N:27]=3)[CH2:31][CH2:32]2)=[O:16])[CH2:12][CH2:13][C@@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH2:10]1)([CH3:19])[CH3:18]
Reactant: FC(F)(F)c1ccnc(C2=CCNCC2)c1
Reactant: CC(C)[C@]1(C(=O)O)CC[C@@H](NC(=O)OC(C)(C)C)C1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)[C@]1(C(=O)N2CC=C(c3cc(C(F)(F)F)ccn3)CC2)CC[C@@H](NC(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (1S,3R)-3-[(tert-butoxycarbonyl)amino]-1-isopropylcyclopentanecarboxylic acid (0.288 g, 1.06 mmol) and 4-(trifluoromethyl)-1′,2′,3′,6′-tetrahydro-2,4′-bipyridine dihydrochloride (0.320 g, 1.06 mmol) in dry methylene chloride (11.5 mL) was added triethylamine (0.592 mL, 4.25 mmol) followed by benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (0.517 g, 1.17 mmol). After being stirred at room temperature overnight, the brown reaction mixture was washed with NaHCO3 and brine, dried (MgSO4), filtered, and concentrated. The residue was purified by column chromatography on silica gel (30:70 EtOAc/hexanes) to provide a light yellow solid product: 265 mg (52%). LC-MS calculated for C25H34F3N3O3: (M+H) 482; found 382.2 (M-Boc+1).
Reaction SMILES: CO[C:3](=[O:12])[C:4]([C:10]#[N:11])=[C:5]([S:8][CH3:9])SC.[C:13]([CH2:15][C:16]([NH2:18])=[S:17])#[N:14].C([O-])([O-])=O.[K+].[K+].Cl>CS(C)=O>[OH:12][C:3]1[NH:18][C:16](=[S:17])[C:15]([C:13]#[N:14])=[C:5]([S:8][CH3:9])[C:4]=1[C:10]#[N:11]
Reactant: COC(=O)C(C#N)=C(SC)SC
Reactant: N#CCC(N)=S
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CSc1c(C#N)c(O)[nH]c(=S)c1C#N
Reaction time: 18 h

Procedure:
2-cyano-3,3-bis-methylsulfanyl-acrylic acid methyl ester Compound 1a (25.0 g, 123 mmol) was combined with 97% 2-cyano-thioacetamide (12.7 g, 123 mmol) and K2CO3 (51.0 g, 369 mmol) in DMSO (300 mL) at room temperature. The reaction was stirred for 18 hrs. The cooled reaction mixture (0° C.) was slowly acidified with 1N HCl. The resultant yellow precipitate was collected by filtration and sequentially washed with 1N HCl, water, MeOH and hexane to give 6-hydroxy-4-methylsulfanyl-2-thioxo-1,2-dihydro-pyridine-3,5-dicarbonitrile Compound 1b (24.7 g, 90% yield). 1H NMR (DMSOd6) δ 2.66 (s, 3H). 13C NMR (DMSOd6) δ 118.1 (CN), 117.3 (CN), 17.4 (SMe). MS 222 (M−).
Reaction SMILES: C([O:5][C:6](=[O:35])[CH2:7][N:8]1[C:12]2[CH:13]=[CH:14][C:15]([N:17]([CH2:28][CH:29]=[CH:30][CH3:31])[S:18]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)(=[O:20])=[O:19])=[CH:16][C:11]=2[N:10]=[C:9]1[CH2:32][CH2:33][CH3:34])(C)(C)C.C(O)(C(F)(F)F)=O>>[CH2:28]([N:17]([S:18]([C:21]1[CH:22]=[CH:23][C:24]([F:27])=[CH:25][CH:26]=1)(=[O:19])=[O:20])[C:15]1[CH:14]=[CH:13][C:12]2[N:8]([CH2:7][C:6]([OH:35])=[O:5])[C:9]([CH2:32][CH2:33][CH3:34])=[N:10][C:11]=2[CH:16]=1)[CH:29]=[CH:30][CH3:31]
Reactant: CC=CCN(c1ccc2c(c1)nc(CCC)n2CC(=O)OC(C)(C)C)S(=O)(=O)c1ccc(F)cc1
Solvent: O=C(O)C(F)(F)F
Product: CC=CCN(c1ccc2c(c1)nc(CCC)n2CC(=O)O)S(=O)(=O)c1ccc(F)cc1

Procedure:
{5-[But-2-enyl-(4-fluoro-benzenesulfonyl)-amino]-2-propyl-benzoimidazol-1-yl}-acetic acid tert-butyl ester was treated with TFA (2 mL) for 2 hours, concentrated, and purified by preparative LCMS to give the title compound. MS calculated for C22H24FN3O4S—H: 444, observed: 444.
Reaction SMILES: CS(Cl)(=O)=O.ClC1(C(O)=O)N(C2C(Cl)=CC=CN=2)NC=C1.[Cl:22][C:23]1[CH:27]=[C:26]([C:28]([OH:30])=O)[N:25]([C:31]2[C:36]([Cl:37])=[CH:35][CH:34]=[CH:33][N:32]=2)[N:24]=1.N1C=CC=CC=1.[NH2:44][C:45]1[C:53]([CH3:54])=[CH:52][C:51]([Cl:55])=[CH:50][C:46]=1[C:47](O)=[O:48]>C(#N)C.O>[Cl:55][C:51]1[CH:52]=[C:53]([CH3:54])[C:45]2[N:44]=[C:28]([C:26]3[N:25]([C:31]4[C:36]([Cl:37])=[CH:35][CH:34]=[CH:33][N:32]=4)[N:24]=[C:23]([Cl:22])[CH:27]=3)[O:30][C:47](=[O:48])[C:46]=2[CH:50]=1
Reactant: O=C(O)c1cc(Cl)nn1-c1ncccc1Cl
Reactant: Cc1cc(Cl)cc(C(=O)O)c1N
Agent: CS(=O)(=O)Cl
Agent: O=C(O)C1(Cl)C=CNN1c1ncccc1Cl
Solvent: CC#N
Solvent: c1ccncc1
Solvent: O
Product: Cc1cc(Cl)cc2c(=O)oc(-c3cc(Cl)nn3-c3ncccc3Cl)nc12
Temperature: -5 °C
Reaction time: 0.08 h

Procedure:
Methanesulfonyl chloride (1.0 mL, 1.5 g 13 mmol) was dissolved in acetonitrile (10 mL) and the mixture was cooled to −5° C. A solution of 5-chloro-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxylic acid (i.e. the carboxylic acid product of Example 8, Step D) (2.58 g, 10 mmol) and pyridine (1.4 mL, 1.4 g, 17 mmol) in acetonitrile (10 mL) was added dropwise over 5 minutes at −5 to 0° C. A slurry formed during the addition. The mixture was stirred 5 minutes at this temperature, and then 2-amino-3-methyl-5-chlorobenzoic acid (i.e. the product from Example 6, Step A) (1.86 g, 10 mmol) was added all at once. Then a solution of pyridine (2.8 mL, 2.7 g, 35 mmol) in acetonitrile (10 mL) was added dropwise in 5 min at −5 to 0° C. The mixture was stirred 15 minutes at −5 to 0° C., and then methanesulfonyl chloride (1.0 mL, 1.5 mL, 13 mmol) in acetonitrile (5 mL) was added dropwise in 5 min at −5 to 0° C. The reaction mixture was stirred 15 minutes at this temperature, then allowed to warm slowly to room temperature, and stirred 4 h. Water (15 mL) was added dropwise, and the mixture was stirred 15 minutes. Then the mixture was filtered, and the solids were washed with 2:1 acetonitrile-water (3×3 mL), then with acetonitrile 2×5 mL), and dried under nitrogen to afford the title product as a pale yellow powder, 3.83 g (94.0% crude yield), melting at 199-201° C. HPLC or the product using a Zorbax® RX-C8 chromatography column (4.5 mm×25 cm, eluent 25-95% acetonitrile/pH 3 water) showed a major peak corresponding to the title compound and having 97.8% of total chromatogram peak area.
Reaction SMILES: C[N:2](C)C=O.C(Cl)(=O)C(Cl)=O.[F:12][C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[CH:16][CH:17]=[C:18]([O:27][CH3:28])[C:19]=2[C:23]([F:26])([F:25])[F:24])[C:14]=1[C:29]([N:31]([C:36]([O:38][CH3:39])=[O:37])[CH2:32][C:33]([OH:35])=O)=[O:30]>C(Cl)Cl>[F:12][C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[CH:16][CH:17]=[C:18]([O:27][CH3:28])[C:19]=2[C:23]([F:25])([F:24])[F:26])[C:14]=1[C:29]([N:31]([CH2:32][C:33]([NH2:2])=[O:35])[C:36]([O:38][CH3:39])=[O:37])=[O:30]
Reactant: CN(C)C=O
Reactant: COC(=O)N(CC(=O)O)C(=O)c1c(F)ccc2c(C(F)(F)F)c(OC)ccc12
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: COC(=O)N(CC(N)=O)C(=O)c1c(F)ccc2c(C(F)(F)F)c(OC)ccc12
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 54 %

Procedure:
Dimethyl formamide (6 μL, 0.067 eq) and oxalyl chloride (130 μL, 1.2 eq) were added to a stirred solution of N-[[2-fluoro-6-methoxy-5-(trifluoromethyl)-1-naphthalenyl]carbonyl]-N-(methoxycarbonyl)glycine in anhydrous methylene chloride (2.5 mL) at 0° C. under a dry nitrogen atmosphere. After 5 minutes, the reaction was warmed to room temperature. After 13/4 hours, the organics were removed. The residue was dissolved in anhydrous ether (30 mL) at 0° C. and ammonia gas was bubbled in for 1 minute. The reaction was immediately quenched with hexane (30 mL). The solid was collected by suction filtration and suspended in ethyl acetate (75 mL). The ethyl acetate phase was washed with water (2×25 mL), dried with magnesium sulfate, and the ethyl acetate was removed. The solid was combined with that from another run and recrystallized in chloroform:petroleum ether to provide the title compound as a white solid (325 mg, 54% combined yield), m.p. 199°-202° C.
Reaction SMILES: C[N:2](C)[CH:3]=[CH:4][C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N+:13]([O-:15])=[O:14])=[O:6].Cl.NO>C(O)C>[N+:13]([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[C:5]1[O:6][N:2]=[CH:3][CH:4]=1)([O-:15])=[O:14]
Reactant: CN(C)C=CC(=O)c1ccccc1[N+](=O)[O-]
Agent: Cl
Agent: NO
Solvent: CCO
Product: O=[N+]([O-])c1ccccc1-c1ccno1
Yield: 70.2 %

Procedure:
A suspension containing 99 g of 3-(dimethylamino)-1-(2-nitrophenyl)-2-propen-1-one, prepared in Example 1, and 63 g of hydroxylamine hydrochloride in 250 ml of ethanol was refluxed for 16 hours, then concentrated to dryness in vacuo. Water (400 ml) was added to the residue, and the resulting suspension was filtered. The solid was recrystallized from 2-propanol to give 60 g of the title compound; m.p. 66°-69° C.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][CH:9]=[C:10]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:11]([O:12][CH2:13][CH3:14])=[C:6]2[CH:5]=[N:4]1)[CH3:2].BrN1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[CH2:13]([O:12][C:11]1[C:10]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:9][N:8]=[C:7]2[N:3]([CH:1]=[CH2:2])[N:4]=[CH:5][C:6]=12)[CH3:14]
Reactant: CCOC(=O)c1cnc2c(cnn2CC)c1OCC
Agent: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: C=Cn1ncc2c(OCC)c(C(=O)OCC)cnc21

Procedure:
A suspension of ethyl 1-ethyl-4-ethoxy-1H-pyrazolo[3,4-b]pyridine-5-carboxylate (which may be prepared as described in U.S. Pat. No. 3,755,340, for example, Example 1c) (14.24 g.) and N-bromosuccinimide (21.2 g.) in carbon tetrachloride (109 ml.) was stirred and heated under reflux while being irradiated with a sun lamp (Westinghouse 250 watt). After 1.5 hours the mixture was cooled (ice-bath) and filtered. The filtrate was washed with aqueous sodium bicarbonate and water, dried (MgSO4) and evaporated to give ethyl 4-ethoxy-1-vinyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylate as a yellow oil.
Reaction SMILES: C([O:5][C:6]([CH:8]1[CH2:12][CH2:11][N:10]2[C:13]([C:23](=[O:31])[C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=3)=[CH:14][C:15](C(OC(C)(C)C)=O)=[C:9]12)=[O:7])(C)(C)C>FC(F)(F)C(O)=O>[F:30][C:27]1[CH:28]=[CH:29][C:24]([C:23]([C:13]2[N:10]3[CH2:11][CH2:12][CH:8]([C:6]([OH:7])=[O:5])[C:9]3=[CH:15][CH:14]=2)=[O:31])=[CH:25][CH:26]=1
Reactant: CC(C)(C)OC(=O)c1cc(C(=O)c2ccc(F)cc2)n2c1C(C(=O)OC(C)(C)C)CC2
Solvent: O=C(O)C(F)(F)F
Product: O=C(c1ccc(F)cc1)c1ccc2n1CCC2C(=O)O

Procedure:
t-Butyl-5-(p-fluorobenzoyl)-7-t-butoxycarbonyl-1,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-1-carboxylate (1 mmole) is dissolved in 5 ml of trifluoroacetic acid. The reaction mixture is heated at reflux for 5 hours before it is evaporated in vacuo to remove most of the solvent. The resulting oil is triturated with about 10 ml of water, filtered and dried in vacuo to afford 5-(p-fluorobenzoyl)-1,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-1-carboxylic acid.
Reaction SMILES: [O:1]=[P:2]12[O:13]P3(OP(OP(O3)([O:9]1)=O)(=O)[O:3]2)=O.C[Si](C)(C)O[Si](C)(C)C.[CH2:24]([S:36][CH2:37][CH:38]([O:41][CH2:42][CH2:43][CH2:44]CCCCCCC)[CH2:39]O)[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35]>N1C=CC=CC=1>[CH2:24]([S:36][CH:37]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH:38]([O:41][CH2:42][CH2:43][CH2:44][O:3][P:2](=[O:1])([OH:13])[OH:9])[CH3:39])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35]
Reactant: CCCCCCCCCCCCSCC(CO)OCCCCCCCCCC
Reactant: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: C[Si](C)(C)O[Si](C)(C)C
Solvent: c1ccncc1
Product: CCCCCCCCCCCCSC(CCCCCCC)C(C)OCCCOP(=O)(O)O
Temperature: 100 °C

Procedure:
A suspension of 4.26 g P4O10 in 60 ml absolute pyridine was admixed at room temperature with 13 ml hexamethyldisiloxane and heated to 100° C. for 1 hour. It was then slightly cooled, admixed with 25 g 3-dodecylmercapto-2-decyloxy-1-propanol and heated for a further 2.5 hours to 100° C.
Reaction SMILES: [C:1]([OH:13])(=[O:12])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH:9]=[CH:10][CH3:11].C(O)(=O)CCCCCCCCC=C>>[C:1]([OH:13])(=[O:12])[CH2:2][CH2:3][CH2:4][CH2:5][CH:6]=[CH:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: CC=CCCCCCCCC(=O)O
Agent: C=CCCCCCCCCC(=O)O
Product: CCCCC=CCCCCC(=O)O

Procedure:
9-undecenoic acid; 10-undecenoic acid;
Reaction SMILES: [Cl:1][C:2]1[C:21]([Cl:22])=[CH:20][C:5]2[N:6]([C@@H:9]3[O:14][C@H:13]([CH3:15])[C@@:11]([C:16](=[O:18])[CH3:17])([OH:12])[C@H:10]3[F:19])[CH:7]=[N:8][C:4]=2[CH:3]=1.C1C(=O)N([Br:30])C(=O)C1>C1(C)C=CC=CC=1>[Br:30][C:7]1[N:6]([C@@H:9]2[O:14][C@H:13]([CH3:15])[C@@:11]([C:16](=[O:18])[CH3:17])([OH:12])[C@H:10]2[F:19])[C:5]2[CH:20]=[C:21]([Cl:22])[C:2]([Cl:1])=[CH:3][C:4]=2[N:8]=1
Reactant: CC(=O)[C@@]1(O)[C@@H](C)O[C@@H](n2cnc3cc(Cl)c(Cl)cc32)[C@@H]1F
Reactant: O=C1CCC(=O)N1Br
Solvent: Cc1ccccc1
Product: CC(=O)[C@@]1(O)[C@@H](C)O[C@@H](n2c(Br)nc3cc(Cl)c(Cl)cc32)[C@@H]1F
Temperature: 85 °C
Reaction time: 0.17 h

Procedure:
5,6-Dichloro-1-(3-acetyl-2,5-dideoxy-2-fluoro-beta-D-ribofuranosyl)-1H-benzimidazole (0.45 g, 1.3 mmoles) was boiled in toluene to remove water. Excess toluene was removed in vacuo. THF (Aldrich, Sure Seal, 20 mL) was added and the solution heated to reflux in an 85° C. oil bath. NBS (Aldrich, 0.46 g, 2.6 mmoles, 2 eq.) was added and the reaction refluxed 7 mins. A second portion (0.23 g, 1.3 mmoles, 1 eq.) was added and reflux continued 10 mins. The reaction was removed from the heat, diluted with chloroform (40 mL) and cooled to room temperature. The solution was washed with sat. sodium bicarbonate (2×), dried with MgSO4 and filtered. The solvents were removed in vacuo and the residue purified by chromatography on 75 g of silica gel eluted with ethyl acetate/hexane (1:4, v/v). The product containing fractions were combined and the solvents removed in vacuo. The yield was 0.42 g, 75%. MS (FAB+): m/z, 425; 1H NMR (DMSO-d6) δ7.99 (s,1H, Ar—H), 7.97 (s, 1H, Ar—H), 6.27 (d, 1H, H-1′, J=19 Hz), 5.69 (d, 1H, H-2′, J=53 Hz), 5.1 (m, 1H), 4.25 (m, 1H), 2.13 (s, 3H, acetyl), 1.45 (d, 3H, H-5′, J=6 Hz).