Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]([CH2:8][C:9]([NH:11][CH:12]1[CH:15](SSC2SC3C=C([N+]([O-])=O)C=CC=3N=2)[N:14]([CH:30]([C:41]([CH3:43])=[CH2:42])[C:31]([O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[O:32])[C:13]1=[O:44])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:45]1([S:51](=[S:66])([O:53]C2SC3C=C([N+]([O-])=O)C=CC=3N=2)=[O:52])[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1.O.C1(S([O-])=O)C=CC=CC=1.[Na+]>CC(C)=O>[O:1]([CH2:8][C:9]([NH:11][CH:12]1[CH:15]([S:53][S:51]([C:45]2[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=2)(=[O:66])=[O:52])[N:14]([CH:30]([C:41]([CH3:43])=[CH2:42])[C:31]([O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[O:32])[C:13]1=[O:44])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=C(C)C(C(=O)OCc1ccccc1)N1C(=O)C(NC(=O)COc2ccccc2)C1SSc1nc2ccc([N+](=O)[O-])cc2s1
Reactant: O=[N+]([O-])c1ccc2nc(OS(=O)(=S)c3ccccc3)sc2c1
Agent: O=S([O-])c1ccccc1
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: C=C(C)C(C(=O)OCc1ccccc1)N1C(=O)C(NC(=O)COc2ccccc2)C1SS(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79 %

Procedure:
A 198 mg quantity of benzyl 2-[3-phenoxyacetamido-4-(6-nitrobenzothiazol-2-yldithio)-2-azetidinon-1-yl]-3-methyl-3-butenoate and 113 mg of 6-nitrobenzothiazol-2-yl benzenethiosulfonate were dissolved in 2.5 ml of acetone. To the solution were added 0.5 ml of water and then 3 mg of sodium benzenesulfinate. The mixture was stirred at room temperature for 8 hours. The precipitated 6-nitrobenzothiazol-2-yl disulfide crystals were filtered and the filtrate was concentrated under reduced pressure. The residue was treated in the same manner as in Example 1, giving benzyl 2-(3-phenoxyacetamido-4-benzenesulfonylthio-2-azetidinon-1-yl)-3-methyl-3-butenoate in a yield of 79%. The NMR spectrum data of the compound thus obtained were identical with those of the compound produced in Example 3.
Reaction SMILES: [C:1]([NH:4][N:5]=[CH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)(=[NH:3])[NH2:2].[CH3:13][O:14][C:15]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][C:16]=1[C:17](=O)[CH2:18]Br>C(O)C>[NH2:3][C:1]1[N:4]([N:5]=[CH:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH:18]=[C:17]([C:16]2[CH:21]=[C:22]([O:25][CH3:26])[CH:23]=[CH:24][C:15]=2[O:14][CH3:13])[N:2]=1
Reactant: N=C(N)NN=Cc1ccccc1
Reactant: COc1ccc(OC)c(C(=O)CBr)c1
Solvent: CCO
Product: COc1ccc(OC)c(-c2cn(N=Cc3ccccc3)c(N)n2)c1

Procedure:
A solution of 1.62 g (0.01 mol) of benzaldehyde guanylhydrazone and 1.34 g of 2,5-dimethoxyphenacyl bromide (Aldrich, Buchs, Switzerland, 97%, Cat. no. 10,458-2) in 5 ml of ethanol is boiled under reflux for 45 minutes. After cooling, the product that has crystallized out is filtered off with suction and recrystallized from ethanol. In that manner there is obtained the title compound, m.p. 180°-181° C., 1H-NMR (DMSO): δ=8.62 (s, 1H); 7.97 (m, 2H); 7.90 (s, 1H); 7.42-7.60 (m, 4H); 6.95 (d, 1H); 6.76 (m, 1H); 6.18 (s, 2H); 3.9 (s, 3H); 3.73 (s, 3H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:9]2[CH:14]=[C:13](O)[N:12]=[C:11]([S:16][CH3:17])[N:10]=2)[CH:6]=[CH:7][CH:8]=1)#[N:2].P(Cl)(Cl)([Cl:20])=O>>[C:1]([C:3]1[CH:4]=[C:5]([C:9]2[CH:14]=[C:13]([Cl:20])[N:12]=[C:11]([S:16][CH3:17])[N:10]=2)[CH:6]=[CH:7][CH:8]=1)#[N:2]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CSc1nc(O)cc(-c2cccc(C#N)c2)n1
Product: CSc1nc(Cl)cc(-c2cccc(C#N)c2)n1
Reaction time: 5 h

Procedure:
A suspension of 4-(3-cyanophenyl)-6-hydroxy-2-methylthiopyrimidine in phosphorus oxychloride is stirred for 5 hours at 110°. The reaction mixture is concentrated by evaporation, ice-water is added and the whole is adjusted to pH 5-6 by the addition of 10N sodium hydroxide solution. The undissolved material is filtered off with suction, washed with water and dried in vacuo to give the title compound. [Analogously to J. pharm. Soc. Japan 70, 137 (1950)].
Reaction SMILES: [K].[OH:2][C:3]1[C:7]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[N:6][S:5](=[O:14])[N:4]=1.CN(C=O)C.[Cl:20][C:21]1[CH:29]=[CH:28][C:24]([C:25](Cl)=[O:26])=[CH:23][CH:22]=1.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[Cl:20][C:21]1[CH:29]=[CH:28][C:24]([C:25]([N:4]2[C:3](=[O:2])[C:7]([N:8]3[CH2:13][CH2:12][O:11][CH2:10][CH2:9]3)=[N:6][S:5]2=[O:14])=[O:26])=[CH:23][CH:22]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: O=S1N=C(O)C(N2CCOCC2)=N1
Agent: O=C([O-])O
Agent: [K]
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C1C(N2CCOCC2)=NS(=O)N1C(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a slurry of 2.3 grams of the potassium salt (C) from Example III(a) in 10 ml methylene chloride and 5 ml DMF is added 1.5 ml p-chlorobenzoylchloride. This mixture is allowed to stir for 1 hour at room temperature. After this, saturated sodium bicarbonate solution is added and the product is extracted into methylene chloride. The organic layer is dried and concentrated in vacuo. The crude product (E) is crystallized from ether and hexane to yield 2 grams of the title compound.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])C.[CH3:8][C:9]1[NH:23][CH2:22][CH2:21][C:11]2=[C:12]3[C:17](=[N:18][C:10]=12)[CH:16]=[CH:15][C:14]([O:19][CH3:20])=[CH:13]3>C(O)=O>[CH2:8]=[C:9]1[C:10]2[NH:18][C:17]3[C:12](=[CH:13][C:14]([O:19][CH3:20])=[CH:15][CH:16]=3)[C:11]=2[CH2:21][CH2:22][N:23]1[CH:1]=[O:3]
Reactant: COc1ccc2c(c1)=C1CCNC(C)=C1N=2
Reactant: CC(=O)OC(C)=O
Solvent: O=CO
Product: C=C1c2[nH]c3ccc(OC)cc3c2CCN1C=O
Temperature: 50 °C
Reaction time: 2 h

Procedure:
To acetic anhydride (1 ml) cooled to 0° C. is added dropwise formic acid (0.5 ml). The mixture is heated for 15 min. at 50° C. After cooling rapidly to 0° C., 10-methoxyharmalan (200 mg) is added slowly and portionwise and the medium is left stirring for 2 h. The crude product is then taken to dryness and, after separation by chromatography (eluent: EtOAc/pet. ether; 50/50), 1-methylene-2-formyl-6-methoxy-1,2,3,4-tetrahydro-β-carboline is obtained.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:6]=1[OH:12])[CH3:2].[C:14](=O)([O-])[O-].[Cs+].[Cs+].CI>C(#N)C>[CH2:1]([O:3][C:4](=[O:13])[C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:6]=1[O:12][CH3:14])[CH3:2]
Reactant: CCOC(=O)c1ccc(F)cc1O
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: CI
Product: CCOC(=O)c1ccc(F)cc1OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 92.6 %

Procedure:
To a solution of compound 4 (19.9 g, 0.109 mol) in acetonitrile (200 mL) was added cesium carbonate (42.0 g, 0.129 mol). The resulting mixture was stirred at rt for 30 min. followed by addition of methyl iodide (13.5 mL, 0.218 mol). The resulting mixture was stirred at rt O/N and filtered through Celite. The solvent was removed under reduced pressure to give crude product 5 (20.0 g, 93%) and used in the next step without further purification. 1H NMR 400 MHz (CDCl3) δ: 7.81-7.78 (m, 1H), 6.60-6.58 (m, 2H), 4.38 (q, J=7.0 Hz, 2H), 3.82 (s, 3H), 1.39 (t, J=7.0 Hz, 3H); MS (ES) m/z: 199 (M+1)+.
Reaction SMILES: C[O:2][C:3]([C@@H:5]1[CH2:9][C:8](=[O:10])[N:7]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)=[CH:13][CH:12]=2)[CH2:6]1)=[O:4].Cl>O1CCOCC1>[F:25][C:22]1[CH:21]=[CH:20][C:19]([CH2:18][O:17][C:14]2[CH:13]=[CH:12][C:11]([N:7]3[C:8](=[O:10])[CH2:9][C@@H:5]([C:3]([OH:4])=[O:2])[CH2:6]3)=[CH:16][CH:15]=2)=[CH:24][CH:23]=1
Reactant: COC(=O)[C@@H]1CC(=O)N(c2ccc(OCc3ccc(F)cc3)cc2)C1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(O)[C@@H]1CC(=O)N(c2ccc(OCc3ccc(F)cc3)cc2)C1
Temperature: 52 °C

Procedure:
A solution of 3.7 mmol of (R)-1-[4-(4-fluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidine-3-carboxylic acid methyl ester in 77 ml of dioxane was treated with 8.64 ml of hydrochloric acid (37%). The mixture was heated at 52° C. for 18 h in a closed flask. The solution was evaporated under reduced pressure to yield the crude acid as a yellowish solid. The crude acid was triturated at −5° C. in 10 ml of ethyl acetate. The solid was collected on a filter funnel and then dried under high vacuum to yield (R)-1-[4-(4-fluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidine-3-carboxylic acid as a white solid; MS: m/e=330 (M+H)+.
Reaction SMILES: [NH2:1][CH2:2][C:3]1([N:7](CC2C=CC=CC=2)CC2C=CC=CC=2)[CH2:6][O:5][CH2:4]1.C1CCCCC=1.[ClH:28]>C(O)C.[Pd].CO.C(OCC)C>[ClH:28].[ClH:28].[NH2:1][CH2:2][C:3]1([NH2:7])[CH2:6][O:5][CH2:4]1
Reactant: NCC1(N(Cc2ccccc2)Cc2ccccc2)COC1
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: CCO
Solvent: CCOCC
Product: NCC1(N)COC1

Procedure:
585 mg (2.07 mmol) of 3-(aminomethyl)-N,N-dibenzyloxetane-3-amine [synthesis described in: US2008/103183 A1, 2008; p. 48] were initially charged in ethanol (29.2 ml), and 441 mg (0.41 mmol) of 10% palladium on activated carbon and 6.3 ml (62.2 mmol) of cyclohexene were added. The reaction mixture was stirred under reflux for 8 h. The mixture was then filtered through a Millipore® filter, the filter cake was washed with methanol, 2.6 ml (5.2 mmol) of 2 M hydrogen chloride in diethyl ether were added to the filtrate and the mixture was concentrated and dried under high vacuum. This gave 423 mg (87% of theory, purity 75%) of the target compound.
Reaction SMILES: C1(C)C=CC=CC=1.C[Mg]Cl.[CH3:11][C:12]([OH:15])([CH3:14])[CH3:13].[Cl:16][C:17]1[N:22]=C(C(OC)=O)[CH:20]=[CH:19][N:18]=1>C1COCC1.CCOC(C)=O>[Cl:16][C:17]1[N:22]=[C:11]([C:12]([OH:15])([CH3:14])[CH3:13])[CH:20]=[CH:19][N:18]=1
Reactant: CC(C)(C)O
Reactant: COC(=O)c1ccnc(Cl)n1
Agent: C[Mg]Cl
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(O)c1ccnc(Cl)n1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 71 %

Procedure:
To a solution of THF (0.25 mL) and toluene (1 mL) at −20° C. under a nitrogen atmosphere was added methyl magnesium chloride (3.0 M in THF, 1 mL, 2.90 mmol) followed by t-BuOH (0.050 mL in 0.750 mL THF, 0.579 mmol) and left to stir for 30 min at 0° C. The solution was cooled back down to −20° C. and methyl 2-chloropyrimidine-4-carboxylate (100 mg, 0.58 mmol) in THF (1 mL) was added. The solution was warmed to room temperature and stirred for an additional 30 min. The solution was diluted with EtOAc, washed with brine, dried with MgSO4, filtered, and concentrated to dryness to afford 2-(2-chloropyrimidin-4-yl)propan-2-ol (71 mg, 0.41 mmol, 71% yield. MS ESI: [M+H]+ m/z 173.1. 1H NMR (500 MHz, CDCl3) δ 8.60 (dd, J=1.8, 5.1, 1H), 7.44 (d, J=5.1 1H), 1.56 (d, J=1.8, 6H).
Reaction SMILES: [C:1]([CH2:3][C:4]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH:5]=[CH:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])#[N:2]>C(O)C.[Pd]>[C:1]([CH2:3][C:4]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:5][CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])#[N:2]
Reactant: CCOC(=O)C=CC(CC#N)(c1ccccc1)c1ccccc1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CCC(CC#N)(c1ccccc1)c1ccccc1
Yield: 85.2 %

Procedure:
To a solution of ethyl 5-cyano-4,4-diphenyl-2-pentenoate (0.7 g) in ethanol (20 ml) was added 10% palladium-on-carbon (0.24 g), and the mixture was subjected to catalytic hydrogenation at atmospheric pressure and temperature. The catalyst in the reaction mixture was filtered off and the filtrate was concentrated to dryness. The group was purified by silica gel column chromatography to provide the title compound (0.6 g) as colorless oil.
Reaction SMILES: [CH2:1]1[CH2:6][C@H:5]([C:7]([OH:9])=[O:8])[CH2:4][CH2:3][C@H:2]1[CH2:10][NH2:11].[C:12]([O:15][CH:16]([O:20][C:21](ON1C(=O)CCC1=O)=[O:22])[CH2:17][CH2:18][CH3:19])(=[O:14])[CH3:13]>CC(OC)(C)C.CC(C)=O.O>[C:12]([O:15][CH:16]([O:20][C:21]([NH:11][CH2:10][C@H:2]1[CH2:3][CH2:4][C@H:5]([C:7]([OH:9])=[O:8])[CH2:6][CH2:1]1)=[O:22])[CH2:17][CH2:18][CH3:19])(=[O:14])[CH3:13]
Reactant: NC[C@H]1CC[C@H](C(=O)O)CC1
Reactant: CCCC(OC(C)=O)OC(=O)ON1C(=O)CCC1=O
Solvent: O
Solvent: COC(C)(C)C
Solvent: CC(C)=O
Product: CCCC(OC(C)=O)OC(=O)NC[C@H]1CC[C@H](C(=O)O)CC1

Procedure:
Following the general nucleophilic carbamoylation procedure, tranexamic acid (472 mg, 3.0 mmol) and 1-[(2,5-dioxopyrrolidinyl)oxycarbonyloxy]butyl acetate (620 mg, 2.27 mmol) were reacted in the MTBE/acetone/water mixture (16 mL) to yield the title compound 33 (174 mg, 24% yield) as a waxy white solid after work-up and mass-guided preparative HPLC purification. 1H NMR (400 MHz, DMSO-d6): δ=0.82-0.94 (br. m, 5H), 1.17-1.38 (br. m, 5H), 1.63-1.73 (br. m, 4H), 1.83-1.91 (br. m, 2H), 2.05 (s, 3H), 2.10 (tt, J=11.6, 3.6 Hz, 1H), 2.74-2.88 (m, 2H), 6.58 (t, J=5.6 Hz, 1H), 7.42 (t, J=6.0 Hz, 1H), 11.97 (br. s, 1H). MS (ESI) m/z 338.16 (M+Na)+; 314.12 (M−H)−.
Reaction SMILES: FC(F)(F)C(O)=O.[F:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][N:16]2[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=3[N:18]=[C:17]2[C:25]([CH:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)=[O:26])=[CH:11][CH:10]=1.Cl[CH2:34][CH2:35][CH2:36][C:37]([C:39]1[CH:44]=[CH:43][C:42]([C:45]([CH3:48])([CH3:47])[CH3:46])=[CH:41][CH:40]=1)=[O:38].C(=O)(O)[O-].[K+].[I-].[K+]>C1(C)C=CC=CC=1.O>[CH3:48][C:45]([C:42]1[CH:41]=[CH:40][C:39]([C:37](=[O:38])[CH2:36][CH2:35][CH2:34][N:30]2[CH2:31][CH2:32][CH:27]([C:25]([C:17]3[N:16]([CH2:15][C:12]4[CH:13]=[CH:14][C:9]([F:8])=[CH:10][CH:11]=4)[C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=4[N:18]=3)=[O:26])[CH2:28][CH2:29]2)=[CH:44][CH:43]=1)([CH3:46])[CH3:47]
Reactant: O=C(c1nc2ccccc2n1Cc1ccc(F)cc1)C1CCNCC1
Reactant: CC(C)(C)c1ccc(C(=O)CCCCl)cc1
Agent: O=C([O-])O
Agent: [I-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)(C)c1ccc(C(=O)CCCN2CCC(C(=O)c3nc4ccccc4n3Cc3ccc(F)cc3)CC2)cc1

Procedure:
[1-[(4-fluorophenyl)methyl]-1H-benzimidazol-2-yl]-4-piperidinylmethanone mono (trifluoroacetate) (5.0 g, 11 mmol), 4-chloro-4'-tert-butylbutyrophenone (6.2, 26 mmol), potassium bicarbonate (2.5 g, 25 mmol), and potassium iodide (catalytic amount) were combined and refluxed in toluene (50 ml) and water (5 ml) for 3 days. The cooled layers were separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with water, brine, dried (MgSO4), and concentrated. The resulting oil was chromatographed on silica gel (75×160 mm), eluting with ethyl acetate. The appropriate fractions were combined, concentrated, and the resulting oil crystallized from cyclohexane to afford 1-[4-(1,1-dimethylethyl)phenyl]-4-[4-[[1-[(4-fluorophenyl)methyl]-1H-benzimidazol-2-yl]carbonyl]-1-piperdinyl]-1-butanone: 3.4 g (57%), m.p. 105°-106° C.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[C:7]([C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][N:13]=[CH:12]2)#[N:8]>C1COCC1>[NH2:8][CH2:7][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][N:13]=[CH:12]2
Reactant: N#Cc1ccc2[nH]ncc2c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: NCc1ccc2[nH]ncc2c1
Temperature: 0 °C

Procedure:
To a solution-of LiAlH4 (0.76 g, 20.1 mmol) in THF (10 mL) cooled to 0° C. was added a solution of 5-cyanoindazole (0.64 g, 4.47 mmol) in THF (10 mL) dropwise. After 0.5 h the reaction mixture was warmed to reflux for 2 h, then cooled to 0° C. and quenched by the careful addition of water (0.76 mL), 1.0 N sodium hydroxide (0.76 mL), and water (2.28 mL). This mixture was filtered through a pad of celite and washed with THF/MeOH (3:1, 300 mL). Removal of the solvent in vacuo provided a solid which was purified via flash column chromatography (25×150 mm column; elution with MeOH:CH2Cl2:CH2Cl2 saturated with NH3, 10:60:30). This afforded the title compound as a light yellow solid:
Reaction SMILES: [Cl:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:5]=[C:4]([CH3:13])[C:3]=1[CH:14]=O.[CH3:16][CH:17]([CH3:33])[C:18]([NH:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[CH:22]=1)=[O:19]>>[Cl:1][C:2]1[N:6]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:5]=[C:4]([CH3:13])[C:3]=1[CH2:14][N:30]1[CH2:31][CH2:32][CH:27]([C:23]2[CH:22]=[C:21]([NH:20][C:18](=[O:19])[CH:17]([CH3:16])[CH3:33])[CH:26]=[CH:25][CH:24]=2)[CH2:28][CH2:29]1
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Reactant: Cc1nn(-c2ccccc2)c(Cl)c1C=O
Product: Cc1nn(-c2ccccc2)c(Cl)c1CN1CCC(c2cccc(NC(=O)C(C)C)c2)CC1

Procedure:
Prepared by Procedure F and Scheme R using 5-chloro-3-methyl-1-phenyl-1H-pyrazole-4-carbaldehyde and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 451.2 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:12](C(OC(C)(C)C)=O)/[C:11](=[C:26]3/[C:27]([CH:39]([CH3:41])[CH3:40])=[N:28][N:29](C(OC(C)(C)C)=O)[C:30]/3=[O:31])/[CH:10]=2)=[CH:4][CH:3]=1.[CH2:42]([S:44](Cl)(=[O:46])=[O:45])[CH3:43]>>[CH:39]([C:27]1=[N:28][NH:29][C:30](=[O:31])/[C:26]/1=[C:11]1\[NH:12][C:13]2[C:18]([C:9]([S:8][C:5]3[CH:6]=[CH:7][C:2]([NH:1][S:44]([CH2:42][CH3:43])(=[O:46])=[O:45])=[CH:3][CH:4]=3)=[CH:10]\1)=[CH:17][CH:16]=[CH:15][CH:14]=2)([CH3:41])[CH3:40]
Reactant: CC(C)C1=NN(C(=O)OC(C)(C)C)C(=O)/C1=C1/C=C(Sc2ccc(N)cc2)c2ccccc2N1C(=O)OC(C)(C)C
Reactant: CCS(=O)(=O)Cl
Product: CCS(=O)(=O)Nc1ccc(SC2=C/C(=C3/C(=O)NN=C3C(C)C)Nc3ccccc32)cc1

Procedure:
Example 22 was synthesized from (Z)-tert-butyl 4-(4-aminophenylthio)-2-(1-(tert-butoxycarbonyl)-3-isopropyl-5-oxo-1H-pyrazol-4(5H)-ylidene)quinoline-1(2H)-carboxylate and ethanesulfonyl chloride according to the procedure described in Example 21. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.99 (d, J=6.82 Hz, 6H) 1.27 (t, J=7.33 Hz, 3H) 2.57 (bs, 1H) 3.27 (q, J=7.33 Hz, 2H) 7.30 (d, J=8.34 Hz, 1H) 7.44 (d, J=8.59 Hz, 2H) 7.59-7.65 (m, 1H) 7.71 (d, J=8.59 Hz, 2H) 7.85-7.91 (m, 2H) 8.13 (d, J=8.34 Hz, 1H) 10.41 (s, 1H); ESI-MS: m/z calc'd for C23H24N4O3S2 468.59. found 469.2 (M+H)+.
Reaction SMILES: [C:1]1([C:11](Cl)=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C[O:15][P:16]1[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[C:19]2[CH:26]=[CH:27][CH:28]=[CH:29][C:18]=2[O:17]1>C1(C)C=CC=CC=1>[C:1]1([C:11]([P:16]2(=[O:15])[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[C:19]3[CH:26]=[CH:27][CH:28]=[CH:29][C:18]=3[O:17]2)=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: COP1Oc2ccccc2-c2ccccc21
Reactant: O=C(Cl)c1cccc2ccccc12
Solvent: Cc1ccccc1
Product: O=C(c1cccc2ccccc12)P1(=O)Oc2ccccc2-c2ccccc21
Temperature: 125 °C

Procedure:
50 g (0.262 mol) of 1-naphthoyl chloride were warmed to 80° to 85° C. under a nitrogen atmosphere. 60.3 g (0.262 mol) of 6-methoxy-(6H)-dibenz[c,e][1,2]oxaphosphorin were added dropwise while stirring. The reaction proceeded exothermically. The temperature was then increased in steps to 125° C. When the reaction was complete, 90 ml of toluene were added at 40° C. After crystallization 77 g (80% of theory) of the above-mentioned compound of melting point 149° to 151° C. were obtained.
Reaction SMILES: C([BH3-])#N.[Na+].[CH3:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[NH:8][CH:7]=1.[OH-].[Na+]>C(O)(=O)C>[CH3:5][CH:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[NH:8][CH2:7]1
Reactant: Cc1c[nH]c2ccccc12
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: CC1CNc2ccccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Under a nitrogen atmosphere 0.58 g (9.2 mmol) sodium cyanoborohydride were added batchwise to 1.0 g (7.6 mmol) 3-methylindole in 5.0 mL glacial acetic acid and the mixture was stirred for 60 min at RT. Then the reaction mixture was poured onto a 4N aqueous sodium hydroxide solution and extracted with EtOAc. The combined organic phases were washed several times with saturated sodium hydrogen carbonate solution, dried on sodium sulphate and evaporated down.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:12][C:11](I)=[N:10][C:9]=1[C:14]([NH2:16])=[O:15].[CH3:17][C:18]1[C:19]([Sn](C)(C)C)=[CH:20][C:21]([NH:24][C:25]([CH:27]2[CH2:29][CH2:28]2)=[O:26])=[N:22][CH:23]=1.[Cl-].[Li+]>O1CCOCC1.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.[Cu]I>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:12][C:11]([C:19]2[C:18]([CH3:17])=[CH:23][N:22]=[C:21]([NH:24][C:25]([CH:27]3[CH2:29][CH2:28]3)=[O:26])[CH:20]=2)=[N:10][C:9]=1[C:14]([NH2:16])=[O:15]
Reactant: NC(=O)c1nc(I)oc1-c1ccccc1Cl
Reactant: Cc1cnc(NC(=O)C2CC2)cc1[Sn](C)(C)C
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Solvent: C1COCCO1
Product: Cc1cnc(NC(=O)C2CC2)cc1-c1nc(C(N)=O)c(-c2ccccc2Cl)o1
Temperature: 100 °C
Reaction time: 5 h
Yield: 64.8 %

Procedure:
A mixture of 5-(2-chlorophenyl)-2-iodo-1,3-oxazole-4-carboxamide (0.051 g, 0.14 mmol), N-[5-methyl-4-(trimethylstannyl)pyridine-2-yl]cyclopropanecarboxamide (0.064 g, 0.19 mmol), tetrakis(triphenylphosphine)palladium(0) (0.008 g, 0.007 mmol), copper(I) iodide (0.008 g, 0.043 mmol), and lithium chloride (0.018 g, 0.43 mmol) in 1,4-dioxane (1.5 mL) was degassed with argon three times and then allowed to stir at 100° C. under an atmosphere of argon for 5 h. The reaction mixture was filtered while hot and the filtrate was concentrated. The residue was purified by column chromatography to give 5-(2-chlorophenyl)-2-{2-[(cyclopropylcarbonyl)amino]-5-methylpyridin-4-yl}-1,3-oxazole-4-carboxamide (Compound I-86) (0.036 g, 62%). LCMS (AA): m/z=397 (M+H).
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([CH3:12])[C:5]([N+:9]([O-:11])=[O:10])=[C:6]([NH2:8])[CH:7]=1.[CH3:13][C:14]([O:17][C:18]([NH:20][CH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1)=[O:19])([CH3:16])[CH3:15].C([O-])(O)=O.[Na+]>CS(C)=O>[C:14]([O:17][C:18](=[O:19])[NH:20][CH:21]1[CH2:26][CH2:25][N:24]([C:2]2[CH:3]=[C:4]([CH3:12])[C:5]([N+:9]([O-:11])=[O:10])=[C:6]([NH2:8])[CH:7]=2)[CH2:23][CH2:22]1)([CH3:16])([CH3:13])[CH3:15]
Reactant: Cc1cc(F)cc(N)c1[N+](=O)[O-]
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CS(C)=O
Product: Cc1cc(N2CCC(NC(=O)OC(C)(C)C)CC2)cc(N)c1[N+](=O)[O-]
Temperature: 85 °C
Reaction time: 3 h

Procedure:
5-Fluoro-3-methyl-2-nitro-phenylamine (0.97 g, 5.7 mmol), 4-N-BOC-aminopiperidine (1.60 g, 8.0 mmol), diusopropylethylamine (2.5 ml, 14 mmol) and DMSO (10 ml) are combined and stirred at 85° C. for 3 hours. The reaction mixture was poured on saturated aqueous NaHCO3 solution and extracted with ethyl acetate. The organic layers were washed with water (3×) and brine, dried over Na2SO4 and concentrated. Flash column chromatography on silica (eluent hexanes-ethyl acetate-triethylamine 50-50-1, then 33-66-1) gave the title compound as a yellow solid. (1.57 g, 79%). LCMS (M+H)+ m/z 351 (t=1.55 min.). 1H NMR (500 MHz, CD3OD) δ 6.70 (1H, broad s), 6.22 (1H, d, J=2.5 Hz)), 6.13 (1H, d, J=2.5 Hz), 3.88 (2H, d, J=13.3 Hz), 3.58 (1H, broad s), 2.98 (2H, t, J=11.8 Hz), 2.48 (3H, s), 1.92 (2H, d, J=11.3 Hz), 1.48 (2H, m), 1.45 (9H, s).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[O:11]([C:18]1[S:22][C:21]([CH2:23][NH2:24])=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.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(N(CC)CC)C>CN(C)C=O.O>[Cl:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:24][CH2:23][C:21]1[S:22][C:18]([O:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[CH:19][CH:20]=1)=[O:6]
Reactant: O=C(O)c1cccnc1Cl
Reactant: NCc1ccc(Oc2ccccc2)s1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: O=C(NCc1ccc(Oc2ccccc2)s1)c1cccnc1Cl
Temperature: 60 °C
Reaction time: 48 h
Yield: 46 %

Procedure:
To a solution of 2-chloro nicotinic acid (1182 mg, 7.50 mmol) in N,N-dimethylformamide (3 mL) were added C-(5-phenoxy-thiophen-2-yl)methylamine described in Preparation Example 24 (1693 mg, 8.25 mmol), benzotriazol-1-yloxy tris(dimethylamino)phosphonium hexafluorophosphate (3987 mg, 9.0 mmol) and triethylamine (2.5 mL, 18.0 mmol), and the solution was stirred at 60° C. for 2 days. Water was added to the reaction mixture, which was then extracted with ethyl acetate, and then concentrated. The residue was purified by silica gel column chromatography, and the title compound (1181 mg, 3.43 mmol, 46%) was obtained.