Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]2[CH:26]=[CH:25][N:24]=[C:23]3[C:18]=2[C:19]2[CH:31]=[CH:30][C:29]([C:32](O)=[O:33])=[CH:28][C:20]=2[C:21](=[O:27])[NH:22]3)=[CH:12][CH:11]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:68][N:69]1[CH2:74][CH2:73][NH:72][CH2:71][CH2:70]1>CN(C=O)C>[CH3:68][N:69]1[CH2:74][CH2:73][N:72]([C:32]([C:29]2[CH:30]=[CH:31][C:19]3[C:18]4[C:23](=[N:24][CH:25]=[CH:26][C:17]=4[NH:16][C:13]4[CH:12]=[CH:11][C:10]([NH:9][C:1](=[O:8])[C:2]5[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=5)=[CH:15][CH:14]=4)[NH:22][C:21](=[O:27])[C:20]=3[CH:28]=2)=[O:33])[CH2:71][CH2:70]1
Reactant: O=C(O)c1ccc2c(c1)c(=O)[nH]c1nccc(Nc3ccc(NC(=O)c4ccccc4)cc3)c12
Reactant: CN1CCNCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN1CCN(C(=O)c2ccc3c(c2)c(=O)[nH]c2nccc(Nc4ccc(NC(=O)c5ccccc5)cc4)c23)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 72.4 %

Procedure:
268 (30 mg, 0.07 mmol), DIEA (25 mg, 0.2 mmol), HATU (31 mg, 0.08 mmol), and 1-methylpiperazine (20 mg, 0.2 mmol) were dissolved in DMF (1 mL), and stirred for 3 h at room temperature. The crude product was purified directlyl via HPLC to provide 269 (27 mg, 63% yield) as a solid. LC-MS (M+H=533, obsd.=533).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:12])[CH3:11])=[CH:5][C:4]=1[C:13]1[N:14]([CH3:18])[N:15]=[CH:16][CH:17]=1.[Br:19]N1C(=O)CCC1=O.O>CN(C)C(=O)C>[Br:19][C:17]1[CH:16]=[N:15][N:14]([CH3:18])[C:13]=1[C:4]1[CH:5]=[C:6]([NH:9][C:10](=[O:12])[CH3:11])[CH:7]=[CH:8][C:3]=1[O:2][CH3:1]
Reactant: COc1ccc(NC(C)=O)cc1-c1ccnn1C
Reactant: O=C1CCC(=O)N1Br
Solvent: CC(=O)N(C)C
Solvent: O
Product: COc1ccc(NC(C)=O)cc1-c1c(Br)cnn1C
Temperature: 50 °C
Yield: 95.6 %

Procedure:
To a solution of N-[4-methoxy-3-(2-methyl-2H-pyrazol-3-yl)phenyl]-acetamide (25.0 kg) in N,N-dimethylacetamide (DMA, 140.5 kg) in a 400 L glass lined jacketed reactor with overhead stirring under nitrogen at 45 to 55° C. internal temperature N-bromosuccinimide (NBS, 19.0 kg) was charged in portions at such a rate as to maintain internal temperature to less than 55° C. The reaction mixture remained a solution at this dilution of DMA and internal temperature of 50.9° C. An “in process check” of the reaction mixture to determine reaction completion after at least 1 hr of stirring at 50° C. showed that the reaction mixture was substantially free of the starting material. Upon cooling of the reaction mixture to an internal temperature of 34° C. water (150 kg) was added in a controlled manner into the reactor to maintain an internal temperature between 40-55° C. A slight exotherm was observed during the reaction quench. The product slurry was then cooled to −5 to 5° C. and filtered through a corrosion resistant filter/dryer. The wetcake was re-slurried, washed with water (2×25 kg), and dried under full house vacuum (˜30 in Hg) with a jacket temperature of 65° C. producing N-[3-(4 bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy phenyl]-acetamide (31.6 kg, 100% purity by HPLC, 96.1% yield).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][C:4](=[O:12])[C:3]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[H-].[Na+].[CH2:21]([N:23]1[C:29](=[O:30])[C:28]([CH3:32])([CH3:31])[C:27](=[O:33])[N:26]([CH3:34])[C:25]2[CH:35]=[C:36]([O:39][CH2:40][CH2:41][CH2:42]I)[CH:37]=[CH:38][C:24]1=2)[CH3:22]>CN(C=O)C>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]([CH2:42][CH2:41][CH2:40][O:39][C:36]2[CH:37]=[CH:38][C:24]3[N:23]([CH2:21][CH3:22])[C:29](=[O:30])[C:28]([CH3:32])([CH3:31])[C:27](=[O:33])[N:26]([CH3:34])[C:25]=3[CH:35]=2)[C:4](=[O:12])[C:3]=1[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(OCCCI)ccc21
Reactant: O=c1[nH]c2ccccc2c(Cl)c1-c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(OCCCn3c(=O)c(-c4ccccc4)c(Cl)c4ccccc43)ccc21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 42.8 %

Procedure:
4-Chloro-3-phenyl-1H-quinoline-2-one (0.3 g) was suspended in DMF (6 ml). Sodium hydride (60% in oil) (51 mg) was added, and the mixture was stirred for 15 minutes at room temperature. 1-Ethyl-7-(3-iodopropoxy)-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione (0.55 g) was added thereto and the mixture was stirred at room temperature for 7 days. The reaction mixture was poured to ice water (50 ml), and the generated insoluble matter was separated. The insoluble matter was dissolved in ethyl acetate. The liquid was dried over sodium sulfate and condensed under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1→1:3). The purified product was condensed under reduced pressure, and the residue was recrystallized from ether, thereby obtaining the title compound (0.28 g) as a white powder.
Reaction SMILES: Br[C:2]1[CH:20]=[CH:19][C:5]([C:6]([NH:8][C:9]2[CH:18]=[C:17]3[C:12]([CH:13]=[CH:14][CH:15]=[N:16]3)=[CH:11][CH:10]=2)=[O:7])=[CH:4][CH:3]=1.[CH3:21][O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1B(O)O>>[CH3:21][O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[C:2]1[CH:20]=[CH:19][C:5]([C:6]([NH:8][C:9]2[CH:18]=[C:17]3[C:12]([CH:13]=[CH:14][CH:15]=[N:16]3)=[CH:11][CH:10]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(Nc1ccc2cccnc2c1)c1ccc(Br)cc1
Reactant: COc1ccccc1B(O)O
Product: COc1ccccc1-c1ccc(C(=O)Nc2ccc3cccnc3c2)cc1

Procedure:
Using the procedure outlined in Example 58, the title compound was prepared from 4-bromo-N-quinolin-7-ylbenzamide (Example 82) (50 mg, 0.153 mmol) and 2-methoxy-phenylboronic acid (25 mg, 0.168 mmol) as a colourless gum. 1H NMR (400 MHz, CDCl3) δ (ppm): 8.91 (dd, 1H), 8.17 (d, 1H), 8.14 (m, 3H), 7.98, (d, 2H), 7.86 (d, 1H), 7.70 (d, 2H), 7.36 (m, 3H), 7.30 (d, 1H), 7.07 (t, 1H), 3.85 (s, 3H).
Reaction SMILES: [CH2:1]1[CH2:5][C:4]2([CH2:12][C:10](=[O:11])[NH:9][C:7](=[O:8])[CH2:6]2)[CH2:3][CH2:2]1.[Br-].[N:14]1[CH:19]=[CH:18][CH:17]=[N:16][C:15]=1[N:20]1[CH2:29][CH2:28][N+:23]2([CH2:27][CH2:26][CH2:25][CH2:24]2)[CH2:22][CH2:21]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[N:14]1[CH:19]=[CH:18][CH:17]=[N:16][C:15]=1[N:20]1[CH2:29][CH2:28][N:23]([CH2:24][CH2:25][CH2:26][CH2:27][N:9]2[C:7](=[O:8])[CH2:6][C:4]3([CH2:5][CH2:1][CH2:2][CH2:3]3)[CH2:12][C:10]2=[O:11])[CH2:22][CH2:21]1
Reactant: O=C1CC2(CCCC2)CC(=O)N1
Reactant: c1cnc(N2CC[N+]3(CCCC3)CC2)nc1
Agent: O=C([O-])[O-]
Agent: [Br-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1CC2(CCCC2)CC(=O)N1CCCCN1CCN(c2ncccn2)CC1

Procedure:
A mixture 3,3-tetramethyleneglutarimide (16.7 g., 0.1 mole) , 8-(2-pyrimidinyl)-8-aza-5-azoniaspiro[4.5]decane bromide (29.9 g., 0.1 mole) and potassium carbonate (16.6 g., 0.12 mole) in 190 ml. of dimethylformamide is maintained at 150°-155° C. for a reaction period of 24 hours and then evaporated to dryness under reduced pressure. The resulting solid is triturated with 90 ml. of water, taken up in 10% hydrochloric acid and filtered. The acid filtrate is made basic with 10% aqueous sodium hydroxide and precipitated free base collected and dried to provide 8-[4-[4-(2-pyrimidinyl)-1-piperazinyl]butyl]-8-azaspiro[4.5]decane-7,9-dione.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[C:4]([NH2:9])[N:3]=1.[F:10][C:11]1[CH:19]=[CH:18][C:14]([C:15](O)=O)=[CH:13][CH:12]=1>>[F:10][C:11]1[CH:19]=[CH:18][C:14]([C:15]2[NH:8][C:7]3[C:2]([N:1]=2)=[N:3][C:4]([NH2:9])=[CH:5][CH:6]=3)=[CH:13][CH:12]=1
Reactant: Nc1ccc(N)c(N)n1
Reactant: O=C(O)c1ccc(F)cc1
Product: Nc1ccc2[nH]c(-c3ccc(F)cc3)nc2n1

Procedure:
2,3,6-Triaminopyridine (Austin Products; 372 mg 3 mmol) and 4-fluorobenzoic acid (420 mg 3 mmol) are treated with polyphosphoric acid (30 g) at 150° C. for 1 h. The reaction mixture is poured on ice-water/NH3conc. and extracted with ethyl acetate three times. The combined organic phases are dried over Na2SO4, filtered and evaporated to dryness to yield the crude product, which is purified by SiO2 chromatography (acetone/cyclohexane 20/80 to 50/80) and rendered the title compound as pale yellow crystals (200 mg 29%)
Reaction SMILES: [CH2:1]([N:3]1[C:15]2[C:14](=[O:16])[NH:13][CH:12]([CH3:17])[CH2:11][C:10]=2[C:9]2[C:4]1=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH3:2].Br[C:19]1[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[Cu](I)I.O1CCOCC1>[CH2:1]([N:3]1[C:15]2[C:14](=[O:16])[N:13]([C:19]3[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=3)[CH:12]([CH3:17])[CH2:11][C:10]=2[C:9]2[C:4]1=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH3:2]
Reactant: Brc1cccnc1
Reactant: CCn1c2c(c3ccccc31)CC(C)NC2=O
Agent: I[Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: CCn1c2c(c3ccccc31)CC(C)N(c1cccnc1)C2=O
Yield: 34.3 %

Procedure:
Using analogous reaction conditions as described in Example 1, 9-ethyl-3-methyl-2,3,4,9-tetrahydro-b-carbolin-1-one (I-42d: 0.1 g, 0.4386 mmol) was reacted with 3-bromo-pyridine (0.069 g, 0.4386 mmol), 1,4-dioxane (15 mL), copper iodide (0.008 g, 0.0438 mmol), trans-N,N′-dimethyl-cyclohexyl-1,2-diamine (0.018 mg, 0.1315 mmol) and potassium phosphate (0.232 g, 1.096 mmol) to afford the crude product. Purification by column chromatography on silica gel (70% ethylacetate in hexane) afforded 46 mg of the product (34% yield).
Reaction SMILES: [CH2:1]([O:4][C@@H:5]([CH3:18])[C:6]([O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13](O)=[O:14])=[CH:11][CH:10]=1)=[O:7])[CH2:2][CH3:3].S(Cl)([Cl:21])=O>N1C=CC=CC=1>[CH2:1]([O:4][C@@H:5]([CH3:18])[C:6]([O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([Cl:21])=[O:14])=[CH:11][CH:10]=1)=[O:7])[CH2:2][CH3:3]
Reactant: CCCO[C@@H](C)C(=O)Oc1ccc(C(=O)O)cc1
Reactant: O=S(Cl)Cl
Solvent: c1ccncc1
Product: CCCO[C@@H](C)C(=O)Oc1ccc(C(=O)Cl)cc1

Procedure:
The resulting carboxylic acid (2.45 g) was reacted with 10 ml of thionyl chloride and 0.2 ml of pyridine to obtain 2.61 g of 4-[(S)-2-propoxypropanoyloxy]benzoyl chloride.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:14][CH2:13][CH2:12][N:11]3[C:15]([C:18]4[CH:23]=[CH:22][C:21]([C:24]5[O:28][C:27]([CH3:29])=[N:26][CH:25]=5)=[C:20]([O:30][CH3:31])[CH:19]=4)=[N:16][N:17]=[C:10]23)[CH:5]=[CH:6][C:7]=1[F:8].[H-].[Na+].[CH2:34](I)[CH3:35]>CN(C=O)C.O>[F:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:34][CH3:35])[CH2:14][CH2:13][CH2:12][N:11]3[C:15]([C:18]4[CH:23]=[CH:22][C:21]([C:24]5[O:28][C:27]([CH3:29])=[N:26][CH:25]=5)=[C:20]([O:30][CH3:31])[CH:19]=4)=[N:16][N:17]=[C:10]23)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: COc1cc(-c2nnc3n2CCCC3c2ccc(F)c(F)c2)ccc1-c1cnc(C)o1
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCC1(c2ccc(F)c(F)c2)CCCn2c(-c3ccc(-c4cnc(C)o4)c(OC)c3)nnc21
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 8-(3,4-difluorophenyl)-3-[3-methoxy-4-(2-methyl-1,3-oxazol-5-yl)phenyl]-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyridine (200 mg) in DMF (4 mL) was added sodium hydride (60%, 28.4 mg) at room temperature, and the mixture was stirred at 60° C. for 30 min under a nitrogen atmosphere. Ethyl iodide (45.2 μL) was added to the reaction mixture at room temperature, and the mixture was stirred at room temperature for 30 min. The reaction mixture was diluted with water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (methanol/ethyl acetate) to give the title compound (37.1 mg).
Reaction SMILES: [OH:1][CH2:2][C:3]1([C:6]2([CH3:11])[O:10][CH2:9][CH2:8][O:7]2)[CH2:5][CH2:4]1.C(N(CC)CC)C.[C:19]1([CH3:29])[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1>CN(C1C=CN=CC=1)C.ClCCl>[CH3:11][C:6]1([C:3]2([CH2:2][O:1][S:25]([C:22]3[CH:23]=[CH:24][C:19]([CH3:29])=[CH:20][CH:21]=3)(=[O:27])=[O:26])[CH2:4][CH2:5]2)[O:7][CH2:8][CH2:9][O:10]1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC1(C2(CO)CC2)OCCO1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)OCC2(C3(C)OCCO3)CC2)cc1
Temperature: 0 °C

Procedure:
To a stirred and ice-cooled solution of 3 (5.0 g, 31.6 mmol), N,N-dimethyl-4-aminopyridine (386 mg, 8.16 mmol) and triethylamine (22 mL, 158 mmol) in dichloromethane (25 mL) was added p-toluenesulfonyl chloride (7.23 g, 37.9 mmol) portionwise and the mixture was stirred in a cold room at 4° C. overnight. The mixture was poured into ice water, and the organic layer was separated. The aqueous layer was extracted with diethyl ether. The combined organic layers were washed with water and brine, and dried over sodium sulfate. Filtration and concentration gave 16.70 g of crude 4, as a pale yellow oil, which was used in the next step without further purification.
Reaction SMILES: [C:1]([CH2:3][C:4]([NH2:6])=[S:5])#[N:2].O=[C:8]([CH2:14][C:15](=O)[CH3:16])[C:9]([O:11][CH2:12][CH3:13])=[O:10].C(N(CC)CC)C>CCO>[CH2:12]([O:11][C:9](=[O:10])[C:8]1[CH:14]=[C:15]([CH3:16])[N:6]=[C:4]([SH:5])[C:3]=1[C:1]#[N:2])[CH3:13]
Reactant: N#CCC(N)=S
Reactant: CCOC(=O)C(=O)CC(C)=O
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCOC(=O)c1cc(C)nc(S)c1C#N
Reaction time: 8 h
Yield: 63.8 %

Procedure:
To a stirred solution of 2-cyanothioacetamide (3.52 g, 35 mmol) and ethyl 2,4-dioxovalerate (5.0 g, 32 mmol) in anhydrous EtOH (75 mL) at room temperature was added triethylamine (0.5 mL) and the reaction was stirred overnight. Filtration and washing of the precipitates with EtOH gave 3-cyano-2-mercapto-6-methyl-isonicotinic acid ethyl ester as a yellow solid (4.54 g, 64.5%). A mixture of this ester (3.54 g, 16 mmol), bromoacetamide (2.15 g, 16 mmol) and sodium ethoxide (2.18 g, 32 mmol) in MeOH was heated at reflux overnight. It was then allowed to cool to room temperature. Filtration and washing of the precipitates with EtOH provided 3-amino-2-carbamoyl-6-methyl-thieno[2,3-b]pyridine-4-carboxylic acid ethyl ester as a solid (0.94 g, 21.1%).
Reaction SMILES: C(OC(OCC)[N:5]1[CH:9]=[CH:8][N:7]=[CH:6]1)C.C([Li])CCC.[Cl:18][C:19]1[CH:26]=[CH:25][CH:24]=[C:23]([CH2:27][CH3:28])[C:20]=1[CH:21]=[O:22]>O1CCCC1.CCCCCC>[Cl:18][C:19]1[CH:26]=[CH:25][CH:24]=[C:23]([CH2:27][CH3:28])[C:20]=1[CH:21]([C:6]1[NH:5][CH:9]=[CH:8][N:7]=1)[OH:22]
Reactant: CCc1cccc(Cl)c1C=O
Reactant: CCOC(OCC)n1ccnc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCc1cccc(Cl)c1C(O)c1ncc[nH]1
Temperature: 0 °C
Reaction time: 1 h
Yield: 95.9 %

Procedure:
To a solution of 1.60 ml (9.79 mmol) 1-(diethoxymethyl)imidazole in 6 ml tetrahydrofuran at −78° C. was added dropwise 6.67 ml (10.7 mmol) of a 1.6 M solution of n-butyllithium in hexane. The resulting solution of 2-(1-diethoxymethyl-1H-imidazol-2-yl)-lithium was stirred at −78° C., and then added dropwise to a solution of 1.50 g (8.90 mmol) 2-chloro-6-ethyl-benzaldehyde in 6 ml tetrahydrofuran at 0° C. The reaction mixture was then stirred at 0° C. for 30 min and at room temperature for 1 h, before being quenched by dropwise addition of 1 M aqueous hydrochloric acid. The mixture was made basic by addition of aqueous sodium bicarbonbate solution and diluted with ethyl acetate. The phases were separated and the organic phase was washed with saturated brine, dried over Na2SO4, filtered and concentrated in vacuo to afford 2.02 g (96%) of the title compound as a yellow oil which was used in the next step without further purification.
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH3:7])=[C:5]([C:8]([OH:10])=O)[CH:4]=[N:3]1.S(Cl)(Cl)=O.[NH2:15][C:16]1[CH:17]=[C:18]([CH:31]=[CH:32][CH:33]=1)[C:19]([C:21]1[CH:29]=[C:28]2[C:24]([CH2:25][C:26](=[O:30])[NH:27]2)=[CH:23][CH:22]=1)=[O:20]>C1COCC1>[O:30]=[C:26]1[CH2:25][C:24]2[C:28](=[CH:29][C:21]([C:19]([C:18]3[CH:17]=[C:16]([NH:15][C:8]([C:5]4[CH:4]=[N:3][N:2]([CH3:1])[C:6]=4[CH3:7])=[O:10])[CH:33]=[CH:32][CH:31]=3)=[O:20])=[CH:22][CH:23]=2)[NH:27]1
Reactant: Nc1cccc(C(=O)c2ccc3c(c2)NC(=O)C3)c1
Reactant: Cc1c(C(=O)O)cnn1C
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Product: Cc1c(C(=O)Nc2cccc(C(=O)c3ccc4c(c3)NC(=O)C4)c2)cnn1C
Temperature: 79 °C
Reaction time: 3 h
Yield: 45.6 %

Procedure:
A dry flask was charged with 1,5-Dimethyl-1H-pyrazole-4-carboxylic acid (0.144 g, 1.03 mmol) and thionyl chloride (5 mL) and allowed to stir at 79° C. for 3 h. The thionyl chloride was then removed by concentration in vacuo. The crude acid chloride was cooled to room temperature, and then dissolved in THF (101 mL). 6-(3-Amino-benzoyl)-1,3-dihydro-indol-2-one (as prepared in Example 40, 0.260 g, 1.03 mmol) was added to the THF solution of the acid chloride, and the mixture was allowed to reflux overnight. The reaction mixture was then allowed to cool to room temperature and filtered. The solid residue was washed with 0° C. THF and collected to afford the 1,5-Dimethyl-1H-pyrazole-4-carboxylic acid [3-(2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide as a solid (0.177 g, 0.47 mmol, 46%).
Reaction SMILES: [OH:1][CH2:2][C@@H:3]([NH:5][C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9])[CH3:4].[S:13](Cl)([C:16]1[CH:22]=[CH:21][C:19]([CH3:20])=[CH:18][CH:17]=1)(=[O:15])=[O:14].Cl>N1C=CC=CC=1>[CH3:20][C:19]1[CH:21]=[CH:22][C:16]([S:13]([O:1][CH2:2][C@@H:3]([NH:5][C:6]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:12])[CH3:4])(=[O:15])=[O:14])=[CH:17][CH:18]=1
Reactant: C[C@@H](CO)NC(=O)OC(C)(C)C
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OC[C@H](C)NC(=O)OC(C)(C)C)cc1
Reaction time: 0.5 h
Yield: 71.8 %

Procedure:
A mixture of tert-butyl [(1S)-2-hydroxy-1-methylethyl]carbamate (10.0 g), tosyl chloride (12.0 g) and pyridine (100 mL) was stirred for 30 min under ice-cooling, and at room temperature for 2 hr. Tosyl chloride (6.0 g) was further added to the reaction mixture, and the mixture was stirred at room temperature overnight. 0.5M Hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound as a white solid (13.5 g).
Reaction SMILES: [C:1]([CH2:3][CH2:4][S:5][C:6]([Cl:10])=[CH:7][C:8]#[N:9])#[N:2].C([O-])(=O)C.[Na+].[Br:16]Br>ClC(Cl)C>[C:1]([CH2:3][CH2:4][S:5][C:6]([Cl:10])=[C:7]([Br:16])[C:8]#[N:9])#[N:2]
Reactant: N#CC=C(Cl)SCCC#N
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: N#CCCSC(Cl)=C(Br)C#N
Yield: 40.5 %

Procedure:
17.3 g of 1-chloro-2-cyano-vinyl 2-cyano-ethyl sulphide were dissolved in 100 ml of dichloroethane, and 9.8 g of sodium acetate were added. 16 g of bromine were then added dropwise at 20° C. The organic phase was washed with water, concentrated and chromatographed. 10.2 g of 2-bromo-1-chloro-2-cyano-vinyl 2-cyano-ethyl sulphide were obtained as an oil, 1H-NMR: δ=2.6-2.9 (2H) and 3.1-3.5 (2H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([O:15]CC1C=CC=CC=1)=[CH:10][CH:9]=2)=[O:5])[CH3:2]>C(O)C.CCOC(C)=O.[Pd]>[CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([OH:15])=[CH:10][CH:9]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc2cc(OCc3ccccc3)ccc2[nH]1
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cc2cc(O)ccc2[nH]1
Yield: 100.3 %

Procedure:
A solution of 5-benzyloxyindole-2-carboxylic acid ethyl ester (10 g, 34 mmol) in ethanol (250 mL) was treated with 10% Pd/C and hydrogenated under atmospheric pressure (double-walled balloon) for 20 h. The reaction mixture was diluted with EtOAc and filtered through Celite®. Evaporation of the filtrate in vacuo gave the title compound as a tan solid (7 g, 99%). 1H NMR (400 MHz, CDCl3)·8.86 (br s, 1H), 7.29 (d, J=8.80 Hz, 1H), 7.11 (s, 1H), 7.06 (s, 1H), 6.94 (d, J=8.70 Hz, 1H), 4.83 (br s, 1H), 4.42 (q, J=7.09 Hz, 2H), 1.41 (t, J=7.08 Hz 3H).
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[CH2:4][O:5][C:6]([CH3:11])([CH2:9][OH:10])[CH2:7][OH:8].[CH:16](=O)[CH2:17][CH2:18][CH2:19][CH3:20]>C1C=CC=CC=1>[CH2:17]([CH:16]1[O:10][CH2:9][C:6]([O:5][CH2:4][C:3]2[CH:12]=[CH:13][CH:14]=[CH:15][C:2]=2[F:1])([CH3:11])[CH2:7][O:8]1)[CH2:18][CH2:19][CH3:20]
Reactant: CC(CO)(CO)OCc1ccccc1F
Reactant: CCCCC=O
Solvent: c1ccccc1
Product: CCCCC1OCC(C)(OCc2ccccc2F)CO1

Procedure:
Using the procedure of Example 51, 2-(2-fluorobenzyloxy)-2-methyl-1,3-propanediol and valeraldehyde were reacted, using benzene as solvent, to give, after separation by column chromatography, r-2-butyl-t-5-(2-fluorobenzyloxy)-5-methyl-1,3-dioxane, b.p. 105°/0.05 mm, nD25 1.4840; and r-2-butyl-c-5-(2-fluorobenzyloxy)-5-methyl-1,3-dioxane, b.p. 105°/0.025 mm, nD25 1.4865. The ir and nmr spectra were consistent with the assigned structures.
Reaction SMILES: F[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([F:11])[N:3]=1.[CH2:12]([N:19]1[CH2:24][CH2:23][CH:22]([NH:25][CH2:26][CH3:27])[CH2:21][CH2:20]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+].O>C(#N)C>[CH2:12]([N:19]1[CH2:24][CH2:23][CH:22]([N:25]([CH2:26][CH3:27])[C:2]2[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([F:11])[N:3]=2)[CH2:21][CH2:20]1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=[N+]([O-])c1ccc(F)nc1F
Reactant: CCNC1CCN(Cc2ccccc2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CCN(c1nc(F)ccc1[N+](=O)[O-])C1CCN(Cc2ccccc2)CC1
Reaction time: 0.17 h

Procedure:
2,6-Difluoro-3-nitropyridine (5.00 g) is dissolved in acetonitrile (10 ml) and 1-benzyl-4-ethylaminopiperidine (EXAMPLE 11, 6.81 g) dissolved in 10 ml of acetonitrile is added via cannula. Then an additional 58 ml of acetonitrile is added and the reaction is cooled to 0°. Then 5.1 g of potassium carbonate is added and the reaction is stirred 10 min and allowed to warm to 20°-25°. After 6 hrs, the reaction is poured into water, extracted with ethyl acetate, washed with saline and dried over sodium sulfate. Flash column chromatography (silica gel; 5% ethyl acetate/hexane to 10% ethyl acetate/hexane) gives the title compound, NMR (300 MHz, CDCl3) 8.22, 7.37-7.23, 6.25, 3.66, 3.55, 3.50, 3.01, 2.10, 1.95, 1.83 and 1.09δ.
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:4]=[C:5]([CH:9]2[NH:13][N:12]=[C:11]3[C:14](=[CH:20][C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=4)[CH2:15][S:16](=[O:19])(=[O:18])[CH2:17][CH:10]23)[CH:6]=[CH:7][CH:8]=1.O.[C:34](OC(=O)C)(=[O:36])[CH3:35]>C(O)(=O)C>[C:34]([N:13]1[CH:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:31])([F:1])[F:32])[CH:4]=2)[CH:10]2[CH2:17][S:16](=[O:19])(=[O:18])[CH2:15][C:14](=[CH:20][C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:28])([F:29])[F:30])[CH:22]=3)[C:11]2=[N:12]1)(=[O:36])[CH3:35]
Reactant: O=S1(=O)CC(=Cc2cccc(C(F)(F)F)c2)C2=NNC(c3cccc(C(F)(F)F)c3)C2C1
Reactant: CC(=O)OC(C)=O
Solvent: CC(=O)O
Solvent: O
Product: CC(=O)N1N=C2C(=Cc3cccc(C(F)(F)F)c3)CS(=O)(=O)CC2C1c1cccc(C(F)(F)F)c1
Temperature: 25 °C

Procedure:
A suspension of 2,3,3a,4,6,7-hexahydro-3-[3-(trifluoromethyl)phenyl]-7-[[3-(trifluoromethyl)phenyl]methylene]thiopyrano[4,3-c]pyrazole-5,5-dioxide in 2ml of acetic anhydride and 25ml of acetic acid is heated on a steam bath for 15 minutes with occasional swirling. About 10ml of hot water is added and the solution is allowed to cool to room temperature. The solids are collected and washed with acetic acid/water (3/2) and water, and dried in vacuo over phosphorus pentoxide at 50°C to give 1.56g of the title compound, melting point 200°-202.5°C.