Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[N:17][C:18]=3[NH2:20])[N:13]([CH2:21][C@H:22]3[CH2:26][CH2:25][CH2:24][NH:23]3)[N:12]=2)=[CH:7][CH:6]=1.[C:32]([CH2:34][C:35](O)=[O:36])#[N:33]>ClCCl>[NH2:20][C:18]1[N:17]=[CH:16][N:15]=[C:14]2[N:13]([CH2:21][C@H:22]3[CH2:26][CH2:25][CH2:24][N:23]3[C:35](=[O:36])[CH2:34][C:32]#[N:33])[N:12]=[C:11]([C:8]3[CH:7]=[CH:6][C:5]([O:4][C:3]4[C:27]([F:31])=[CH:28][CH:29]=[CH:30][C:2]=4[F:1])=[CH:10][CH:9]=3)[C:19]=12
Reactant: Nc1ncnc2c1c(-c1ccc(Oc3c(F)cccc3F)cc1)nn2C[C@H]1CCCN1
Reactant: N#CCC(=O)O
Solvent: ClCCl
Product: N#CCC(=O)N1CCC[C@@H]1Cn1nc(-c2ccc(Oc3c(F)cccc3F)cc2)c2c(N)ncnc21
Temperature: 25 °C
Reaction time: 12 h
Yield: 48.7 %

Procedure:
Into a 100 mL round-bottom flask, was placed a solution of 3-[4-(2,6-difluoro-phenoxy)phenyl]-1-[(2R)-pyrrolidin-2-ylmethyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (200 mg, 0.47 mmol, 1.00 equiv) in dichloromethane (10 mL), 2-cyanoacetic acid (121 mg, 1.42 mmol, 3.00 equiv), and 1,1-carbonyldiimidazole (230 mg, 1.42 mmol, 3.00 equiv). The resulting solution was stirred for 12 h at 25° C. and then washed with water and brine. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was loaded onto a silica gel column and eluted with dichloromethane/methanol (50/1) to give 112 mg (48%) of 3-[(2R)-2-([4-amino-3-[4-(2,6-difluorophenoxy)phenyl]-1H-pyrazolo[3,4-d]pyrimidin-1-yl]methyl)pyrrolidin-1-yl]-3-oxopropanenitrile as a white solid.
Reaction SMILES: C(OC([NH:11][CH2:12][CH2:13][C@H:14]([NH:18]C(OC(C)(C)C)=O)[C:15]([OH:17])=O)=O)C1C=CC=CC=1.[CH3:26][S:27]([Cl:30])(=[O:29])=[O:28].[NH:31]1[CH2:35][CH2:34][CH2:33][CH2:32]1>>[ClH:30].[NH2:18][C@H:14]([C:15](=[O:17])[N:31]1[CH2:35][CH2:34][CH2:33][CH2:32]1)[CH2:13][CH2:12][NH:11][S:27]([CH3:26])(=[O:29])=[O:28]
Reactant: C1CCNC1
Reactant: CC(C)(C)OC(=O)N[C@@H](CCNC(=O)OCc1ccccc1)C(=O)O
Reactant: CS(=O)(=O)Cl
Product: CS(=O)(=O)NCC[C@H](N)C(=O)N1CCCC1
Product: Cl

Procedure:
Starting from (S)-4-[(benzyloxycarbonyl)-amino]-2-[(tert-butyloxycarbonyl)-amino]-butanoic acid, methanesulphonyl chloride and pyrrolidine, the expected product is obtained according to the procedure described in Example 3.
Reaction SMILES: [S:1]([O:5][O:6][S:7]([O-:10])(=[O:9])=[O:8])([O-:4])(=[O:3])=[O:2].[K+:11].[K+].[S:13](=[O:17])(=[O:16])([OH:15])[OH:14]>>[S:1]([O:5][O:6][S:7]([OH:10])(=[O:9])=[O:8])([OH:4])(=[O:3])=[O:2].[S:13]([O-:17])([O-:16])(=[O:15])=[O:14].[K+:11].[K+:11]
Reactant: O=S(=O)(O)O
Reactant: O=S(=O)([O-])OOS(=O)(=O)[O-]
Agent: [K+]
Product: O=S(=O)(O)OOS(=O)(=O)O
Product: O=S(=O)([O-])[O-]

Procedure:
Referring to Equation (9), the potassium persulfate and the sulfuric acid react to form peroxydisulfuric acid and potassium sulfate. In Equation (10), the peroxydisulfuric acid oxidizes the manganese dioxide to form hydrogen permanganate and sulfuric acid. The oxidation of Mn2+ to Mn7+ results in the reformation of MnO4− which is visible by the color change in the bath from purple-brown to purple.
Reaction SMILES: [C:1]([O:20][CH3:21])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[CH:22]([N-]C1CCCCC1)(C)C.[Li+].CI.Cl>O1CCCC1>[CH3:22][CH:2]([CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[C:1]([O:20][CH3:21])=[O:19]
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)OC
Reactant: CC(C)[N-]C1CCCCC1
Agent: Cl
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Product: CCCCCCCC/C=C\CCCCCCC(C)C(=O)OC

Procedure:
A solution of methyl oleoate (0.054 mole) in tetrahydrofuran (100 ml) was added dropwise to a freshly prepared cold solution of lithium isopropyl cyclohexyl amide (1.2 eq.) in tetrahydrofuran (400 ml) over 4.75 hrs. Methyl iodide (1.5 eq.) was added dropwise rapidly and the reaction was allowed to come to room temperature. The reaction was stripped of solvent to give an orange oil. The material was added to 1N hydrochloric acid (100 ml) and extracted into ethyl ether. The ethyl ether was washed with water (100 ml), dried over sodium sulfate, filtered and stripped to an oil which was identified as the title compound by spectral analysis and used in Example 67.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[C:2]1/[CH:6]=[C:7]1\[C:8](=[O:16])[NH:9][C:10]2[C:15]\1=[CH:14][CH:13]=[CH:12][CH:11]=2.C=O.[CH2:19]([NH2:23])[CH2:20][CH2:21][CH3:22].[CH3:24]CCCCC>CCO>[CH2:19]([NH:23][CH2:24][N:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:7](=[CH:6][C:2]2[NH:1][CH:5]=[CH:4][CH:3]=2)[C:8]1=[O:16])[CH2:20][CH2:21][CH3:22]
Reactant: CCCCCC
Reactant: CCCCN
Reactant: O=C1Nc2ccccc2/C1=C/c1ccc[nH]1
Agent: C=O
Solvent: CCO
Product: CCCCNCN1C(=O)C(=Cc2ccc[nH]2)c2ccccc21
Temperature: 0 °C

Procedure:
A mixture of Z-(1H-Pyrrol-2-ylmethylene)-1,3-dihydro-indol-2-one (120.0 mg, 0.571 mmol), paraformaldehyde (17.1 mg, 0.571 mmol), and butylamine (56.4 μL, 0.571 mmol) in 5.5 mL of EtOH was heated at reflux for 2.5 h. Then reaction mixture was treated with 2 mL of hexane was and then cooled to 0° C. The reaction mixture was then filtered to remove Z-(1H-Pyrrol-2-ylmethylene)-1,3-dihydro-indol-2-one. The filtrate was partitioned between dilute HCl and ethyl acetate. The organic layer was removed and the aqueous layer washed with 15 mL Ethyl acetate. The aqueous phase was made basic to pH 8 with saturated NaHCO3 and extracted with ethyl acetate. The ethyl acetate layer was washed with H2O, brine and dried over anhydrous Na2SO4. The solvent was removed in vacuo to give 58 mg of yellow oil. The oil was purified by chromatography (silica gel, 1:1/hexane:ethyl acetate) to give the title compound (51.6 mg, 31%) as a yellow solid.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([N:6]1[CH2:10][CH2:9][S:8][CH2:7]1)=[O:5].[Cl:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[NH:17][C:16]([C:21](O)=[O:22])=[CH:15]2.Cl>C(OCC)(=O)C>[O:5]=[C:4]([N:6]1[CH2:10][CH2:9][S:8][CH2:7]1)[CH2:3][NH:2][C:21]([C:16]1[NH:17][C:18]2[C:14]([CH:15]=1)=[CH:13][C:12]([Cl:11])=[CH:20][CH:19]=2)=[O:22]
Reactant: O=C(O)c1cc2cc(Cl)ccc2[nH]1
Reactant: NCC(=O)N1CCSC1
Agent: Cl
Solvent: CCOC(C)=O
Product: O=C(NCC(=O)N1CCSC1)c1cc2cc(Cl)ccc2[nH]1

Procedure:
2-Amino-1-thiazolidin-3-yl-ethanone hydrochloride (3.1 mmol) and 5-chloro-1H-indole-2-carboxylic acid (3.4 mmol) were coupled according to Procedure A (0-25° C., 120 hour reaction time) substituting the following work up: the reaction mixture was stirred with ethyl acetate and 2N HCl, filtered, and the filtered solid washed with 2N HCl, 2N NaOH and ether. Yield 988 mg, 98%; HPLC (70/30) 3.25 minutes (99%); mp 253-255° C. (dec, darkening at 243° C.); PBMS 324/326 (MH+, 100%);
Reaction SMILES: [C:1]([CH2:3][CH2:4]C(OC1C2C(=CC=CC=2)C=CC=1)C(O)=O)#[N:2].[OH-].[K+].[CH2:22]([O:24][C:25](=[O:43])[CH:26]([O:32][C:33]1[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH:36]=[CH:35][CH:34]=1)[C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH3:23].C(#N)C=C>C(OCC)(=O)C>[CH2:30]([O:29][C:27](=[O:28])[C:26]([CH2:4][CH2:3][C:1]#[N:2])([O:32][C:33]1[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH:36]=[CH:35][CH:34]=1)[C:25]([O:24][CH2:22][CH3:23])=[O:43])[CH3:31]
Reactant: CCOC(=O)C(Oc1cccc2ccccc12)C(=O)OCC
Reactant: N#CCCC(Oc1cccc2ccccc12)C(=O)O
Agent: [K+]
Agent: [OH-]
Solvent: C=CC#N
Solvent: CCOC(C)=O
Product: CCOC(=O)C(CCC#N)(Oc1cccc2ccccc12)C(=O)OCC
Temperature: 25 °C
Reaction time: 120 h

Procedure:
4-Cyano-2(R,S)-α-naphthoxybutyric acid: 0.11 ml of a 50% aqueous KOH solution is added at 0°, while stirring, to a mixture of 5.0 g of α-naphthoxymalonic acid diethyl ester and 1.09 ml of acrylonitrile. The reaction mixture is stirred for 5 days at room temperature and then dissolved in ethyl acetate. The ethyl acetate solution is washed with 2N sodium bicarbonate solution, 2N hydrochloric acid and brine, dried over sodium sulphate and concentrated by evaporation, leaving (2-cyanoethyl)-α-naphthoxymalonic acid diethyl ester.
Reaction SMILES: [CH2:1](O)[C:2]#[C:3][CH2:4][CH2:5][CH2:6][CH2:7]/[CH:8]=[CH:9]\[CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].P(Br)(Br)[Br:17]>CCOCC.N1C=CC=CC=1>[Br:17][CH2:1][C:2]#[C:3][CH2:4][CH2:5][CH2:6][CH2:7]/[CH:8]=[CH:9]\[CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: BrP(Br)Br
Reactant: CCCCC/C=C\CCCCC#CCO
Solvent: CCOCC
Solvent: c1ccncc1
Product: CCCCC/C=C\CCCCC#CCBr
Yield: 219.3 %

Procedure:
By the procedure of example 14, 3.82 g (18.34 mmol) of (Z)-8-tetradecen-2-yn-1-ol, 72 mg of dry pyridine, and 1.66 g (6.12 mmol) of phosphorous tribromide were reacted in 20 ml of ether under reflux for 2.0 h. It was worked up as described in example 14 to give 3.83 g of crude product. It was purified by evaporative distillation at 105° C.-120° C./0.25 mm to yield 3.64 g (73% by weight yield) of (Z)-1-bromo-8-tetradecen-2-yne as a colorless oil.
Reaction SMILES: [H-].[Na+].C1([O:9][C:10](=[O:34])[NH:11][C:12]2[CH:17]=[CH:16][C:15]([S:18]([CH:21]([CH3:23])[CH3:22])(=[O:20])=[O:19])=[C:14]([CH2:24][N:25]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH3:26])[CH:13]=2)C=CC=CC=1.[Br:35][C:36]1[CH:41]=[CH:40][C:39]([CH2:42][CH2:43]O)=[C:38]([CH2:45][CH3:46])[CH:37]=1>C1COCC1>[Br:35][C:36]1[CH:41]=[CH:40][C:39]([CH2:42][CH2:43][O:9][C:10](=[O:34])[NH:11][C:12]2[CH:17]=[CH:16][C:15]([S:18]([CH:21]([CH3:23])[CH3:22])(=[O:20])=[O:19])=[C:14]([CH2:24][N:25]([C:27]([O:29][C:30]([CH3:32])([CH3:33])[CH3:31])=[O:28])[CH3:26])[CH:13]=2)=[C:38]([CH2:45][CH3:46])[CH:37]=1
Reactant: CC(C)S(=O)(=O)c1ccc(NC(=O)Oc2ccccc2)cc1CN(C)C(=O)OC(C)(C)C
Reactant: CCc1cc(Br)ccc1CCO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCc1cc(Br)ccc1CCOC(=O)Nc1ccc(S(=O)(=O)C(C)C)c(CN(C)C(=O)OC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 90.6 %

Procedure:
NaH (190 mg, 4.7 mmol) was added in one portion to a solution of 16G (547 mg, 1.2 mmol) and 36B (1000 mg, 4.4 mmol) in THF (20 mL) at −40° C. The reaction was warmed slowly to ambient temperature over 2 h and stirred for 15 h. The reaction was quenched with saturated citric acid and diluted with EtOAc. The mixture washed with brine, dried over Na2SO4 and concentrated in vacuo. The crude product was purified by flash chromatography (0% to 100% EtOAc in hexanes) to afford 43A (650 mg, 92%) as a yellow solid. MS (ESI) m/z 597.1/599.1 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15](=[O:24])[C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][C:17]=2[OH:23])[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].Br[CH2:27][C:28]1[CH:35]=[CH:34][C:31]([C:32]#[N:33])=[CH:30][CH:29]=1>>[C:1]([O:5][C:6](=[O:25])[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15](=[O:24])[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:27][C:28]3[CH:35]=[CH:34][C:31]([C:32]#[N:33])=[CH:30][CH:29]=3)=[CH:18][C:17]=2[O:23][CH2:27][C:28]2[CH:35]=[CH:34][C:31]([C:32]#[N:33])=[CH:30][CH:29]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1CCC(NC(=O)c2ccc(O)cc2O)CC1
Reactant: N#Cc1ccc(CBr)cc1
Product: CC(C)(C)OC(=O)NC1CCC(NC(=O)c2ccc(OCc3ccc(C#N)cc3)cc2OCc2ccc(C#N)cc2)CC1
Yield: 76.3 %

Procedure:
[4-(2,4-Dihydroxy benzoylamino)cyclohexyl]carbamic acid tert-butyl ester (0.95 g, 2.71 mmol) and 4-bromomethyl-benzonitrile (2.12 g, 10.84 mmol) and other reagents as described in Example 75(a) were used to afford 1.2 g of the required product. 1H NMR (DMSO-d6): δ 1.20 (5H, m), 1.4 (9H, m), 1.75 (4H, m), 3.6 (1H, m), 5.3 (4H, s), 6.7 (1H, s), 6.85 (1H, s), 7.35 (2H, d), 7.5 (1H, s), 7.75 (4H, d), 7.9 (4H, s).
Reaction SMILES: [OH-].[K+].[CH2:3]([O:5][C:6](=[O:28])[CH:7]([CH:13]([CH:15]1[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]1)[CH3:14])[C:8]([O:10]CC)=[O:9])[CH3:4].CCOC(C)=O>CCO.C(Cl)Cl>[CH2:3]([O:5][C:6](=[O:28])[CH:7]([CH:13]([CH:15]1[CH2:16][CH2:17][N:18]([C:21]([O:23][C:24]([CH3:25])([CH3:27])[CH3:26])=[O:22])[CH2:19][CH2:20]1)[CH3:14])[C:8]([OH:10])=[O:9])[CH3:4]
Reactant: CCOC(=O)C(C(=O)OCC)C(C)C1CCN(C(=O)OC(C)(C)C)CC1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCOC(=O)C(C(=O)O)C(C)C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Yield: 119.9 %

Procedure:
A solution of KOH (84 mg, 1.16 mmol) in EtOH (2 mL) was added dropwise to a solution of 2-[1-(1-tert-butoxycarbonyl-piperidin-4-yl)-ethyl]-malonic acid diethyl ester (0.39 g, 1.01 mmol) in methylene chloride (4 mL) and EtOH (10 mL) at 0° C. The resulting mixture was stirred at room temperature over night. EtOAc was added and the mixture was washed with 0.5 M HCl and brine, dried and concentrated under reduced pressure to give 416 mg of crude 2-[1-(1-tert-butoxycarbonyl-piperidin-4-yl)-ethyl]-malonic acid monoethyl ester.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12]C[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:14]1([S:20]([C:23]2[C:24]([S:34][CH3:35])=[N:25][N:26]3[C:31](Cl)=[CH:30][C:29]([CH3:33])=[N:28][C:27]=23)(=[O:22])=[O:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C[N:37](C=O)C>>[C:14]1([S:20]([C:23]2[C:24]([S:34][CH3:35])=[N:25][N:26]3[C:31]([N:37]4[CH2:10][CH2:9][N:8]([CH2:1][C:2]5[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=5)[CH2:13][CH2:12]4)=[CH:30][C:29]([CH3:33])=[N:28][C:27]=23)(=[O:22])=[O:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CSc1nn2c(Cl)cc(C)nc2c1S(=O)(=O)c1ccccc1
Reactant: CN(C)C=O
Reactant: c1ccc(CN2CCCCC2)cc1
Product: CSc1nn2c(N3CCN(Cc4ccccc4)CC3)cc(C)nc2c1S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 73 %

Procedure:
0.35 g (2 mmol) of N-benzyl-piperidine was added to a solution of 0.35 g (1 mmol) of 3-benzenesulphonyl-7-chloro-5-methyl-2-methylsulphanyl-pyrazolo[1,5-a]pyrimidine in 5 ml of DMF and stirred at 60° for 2 hrs. The reaction solution was cooled to RT and evaporated in a high vacuum. The residue was partitioned between 2N NaOH and CH2Cl2. The aqueous phase was extracted three times with CH2Cl2, and the combined organic phases were dried (MgSO4), filtered and evaporated. Subsequent chromatography (SiO2, CH2Cl2/MeOH 19:1) and crystallization from EtOH yielded 0.36 g (73%) of 3-benzenesulphonyl-7-(4-benzyl-piperazin-1-yl)-5-methyl-2-methylsulphanyl-pyrazolo[1,5-a]pyrimidine as colorless crystals m.p. 156-158°.
Reaction SMILES: C1(C([O:9][C:10]2[C:15]([CH3:16])=[CH:14][C:13]([Cl:17])=[CH:12][C:11]=2[C:18](=[O:20])[CH3:19])=O)CCCCC1.[OH-:21].[K+].Cl>N1C=CC=CC=1>[Cl:17][C:13]1[CH:14]=[C:15]([CH3:16])[C:10]([OH:9])=[C:11]([C:18](=[O:20])[CH2:19][C:18]([CH:11]2[CH2:12][CH2:13][CH2:14][CH2:15][CH2:10]2)=[O:21])[CH:12]=1
Reactant: CC(=O)c1cc(Cl)cc(C)c1OC(=O)C1CCCCC1
Reactant: [OH-]
Agent: Cl
Agent: [K+]
Solvent: c1ccncc1
Product: Cc1cc(Cl)cc(C(=O)CC(=O)C2CCCCC2)c1O
Temperature: 50 °C
Reaction time: 1 h
Yield: 154.2 %

Procedure:
2-Acetyl-4-chloro-6-methylphenyl cyclohexanecarboxylate (12 g, 0.0408 mole) was dissolved in pyridine (60 ml) and to the solution was added KOH powder (3 g, 0.0536 mole) with stirring at 50° C. The stirring was continued for 1 hour. The reaction mixture was cooled and poured into diluted hydrochloric acid and extracted with hexane-ethyl acetate (2:1). The extract was washed with water and dried (MgSO4). The solvent was distilled off under reduced pressure. The residue was treated with cold methanol to obtain the title compound (9.27 g) as crystals, yield 77.3%. The crystals were recrystallized from ethyl acetate and hexane to obtained prisms, m.p. 76°-77° C.
Reaction SMILES: [CH3:1][S:2]([CH3:4])=O.S(=O)(=O)(O)O.[C:10]1([N:16]=C=O)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[OH-].[Na+]>C(O)(=O)C>[NH2:16][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[CH3:1][S:2][CH2:4][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[NH2:16]
Reactant: O=C=Nc1ccccc1
Reactant: CS(C)=O
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: CSCc1ccccc1N
Product: Nc1ccccc1
Temperature: 50 °C
Yield: 55.8 %
Yield: 22.4 %

Procedure:
To a solution of 7.60 g (0.0974 moles) of dry dimethyl sulfoxide in 70 ml of dry acetic acid at 0° C. and under a nitrogen atmosphere, was slowly added 9.76 g (0.0959 moles) of 100% sulfuric acid. The temperature rose to 15° C. The ice bath was removed and 9.9843 g (0.0838 moles) of phenyl isocyanate was added dropwise. An immediate evolution of gas began, which subsided after approximately fifteen minutes. After thirty minutes at room temperature, the reaction mixture was warmed to 50° C. for an additional hour. The entire solution was then poured into 100 ml of 10% aqueous sodium hydroxide solution and this was extracted with methylene chloride. The organic layer was dried over anhydrous sodium carbonate and filtered. Due to the instability of this sulfilimine, 0.33 g of succnimide was added and the solution was then concentrated to 150 ml and refluxed for sixteen hours. The solution was then washed with 10% aqueous sodium hydroxide, dried over anhydrous magnesium sulfate and filtered. To this was added dodecane as an internal standard and the solution was analyzed by gas chromatography. In this manner, there was obtained 1.751 g (22.4%) of aniline and 7.166 g (55.8%) of 2-methylthiomethylaniline. Other examples of the preparation and rearrangement of unstable N-aryl-S,S-dimethylsulfilimines were performed and these results can be found in Table II.
Reaction SMILES: [Na].C(O)C.[Cl:5][C:6]1[CH:11]=[N:10][CH:9]=[C:8]([NH:12][NH2:13])[N:7]=1.[C:14](#[N:18])/[CH:15]=[CH:16]/[CH3:17]>C1C=CC=CC=1>[NH2:18][C:14]1[CH2:15][CH:16]([CH3:17])[N:12]([C:8]2[CH:9]=[N:10][CH:11]=[C:6]([Cl:5])[N:7]=2)[N:13]=1
Reactant: C/C=C/C#N
Reactant: NNc1cncc(Cl)n1
Agent: [Na]
Solvent: c1ccccc1
Solvent: CCO
Product: CC1CC(N)=NN1c1cncc(Cl)n1

Procedure:
A 0.30 g. amount of sodium metal is dissolved in 100 ml. of absolute ethanol, then 6.72 g. of 2-chloro-6-hydrazinopyrazine (prepared as described above) is added and after 5 minutes, 4.6 g. of distilled crotononitrile is added. The reaction mixture is refluxed for 6 hours. The solvent is removed in vacuo and water is added to the residue to separate a gum. The gum is dissolved in dichloromethane, dried over magnesium sulfate and filtered. The filtrate is evaporated to give a gum. The gum is treated with benzene to separate yellow crystals. The crystals are collected, dried and recrystallized from acetone-hexane to give 1.4 g of the desired product as yellow crystals, m.p. 147°-148° C.
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][CH:14]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:13][CH2:12]1)=O)C1C=CC=CC=1.[CH:22]([N-]C(C)C)(C)C.[Li+]>C1COCC1.C(OCC)(=O)C.O>[CH3:22][C:14]1([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:13][CH2:12][NH:11][CH2:16][CH2:15]1
Reactant: CCOC(=O)C1CCN(C(=O)OCc2ccccc2)CC1
Reactant: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)C1(C)CCNCC1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
4-Methyl-4-ethoxycarbonyl-piperidine was prepared by alkylation of 1-(benzyloxycarbonyl)-4-ethoxycarbonyl-piperidine (J.Med.Chem 1994, 37, p 368)-2.6 g (10 mmol) 1. in 25 ml dry THF at -70° C., under argon, treated with 7 ml lithium di-isopropylamide solution (2M). Stirred 1.5 hours then a solution of 1.5 equivalents of alkyl halide in 5 ml of THF added dropwise. Reaction allowed to warm to ambient temperature over several hours, diluted with ethyl acetate and water. Aqueous layer extracted twice with ethyl acetate, organic solution washed with brine and dried. Evaporated to give the liquid product.
Reaction SMILES: [F:1][C:2]1[CH:24]=[CH:23][C:5]([O:6][C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][C:15]=2[C:16]([NH2:18])=[O:17])[N:12]([CH2:19][CH:20]([CH3:22])[CH3:21])[N:11]=[CH:10]3)=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.N1[CH2:42][CH2:41][O:40][CH2:39][CH2:38]1>C1COCC1>[F:1][C:2]1[CH:24]=[CH:23][C:5]([O:6][C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][C:15]=2[C:16]([N:18]2[CH2:42][CH2:41][O:40][CH2:39][CH2:38]2)=[O:17])[N:12]([CH2:19][CH:20]([CH3:22])[CH3:21])[N:11]=[CH:10]3)=[CH:4][CH:3]=1
Reactant: CC(C)Cn1ncc2cc(Oc3ccc(F)cc3)c(C(N)=O)cc21
Reactant: C1COCCN1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CC(C)Cn1ncc2cc(Oc3ccc(F)cc3)c(C(=O)N3CCOCC3)cc21
Reaction time: 18 h
Yield: 93 %

Procedure:
A solution of 5-(4-fluorophenoxy)-1-isobutyl-1H-indazole-6-carboxylic acid (compound 10g, prepared as described in Example 46) in THF was treated with carbonyldiimidazole (1.2 equivalents) at room temperature under nitrogen atmosphere. After stirring for 18 hours, the reaction was treated with morpholine (1 equivalent). After an additional 18 hours, the solvent was allowed to slowly evaporate and the residue was purified in a Sep Pak cartridge eluting with a gradient of 100% CH2Cl2 to MeOH/CH2Cl2 to provide compound 11g-2 as an oil in 93% yield.
Reaction SMILES: C(=O)(O)[O-].[Na+].[Cl-].[OH:7][NH3+:8].[Br:9][C:10]1[CH:11]=[CH:12][C:13]2[NH:19][C:18](=S)[CH2:17][N:16]=[C:15]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=3)[C:14]=2[CH:27]=1.[CH3:28][N:29](C)[CH:30]=[O:31]>O1CCOCC1>[Br:9][C:10]1[CH:11]=[CH:12][C:13]2[N:19]=[C:18]([NH:8][O:7][C:30](=[O:31])[NH:29][C:28]3[CH:12]=[CH:11][CH:10]=[CH:27][CH:14]=3)[CH2:17][N:16]=[C:15]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=3)[C:14]=2[CH:27]=1
Reactant: S=C1CN=C(c2ccccn2)c2cc(Br)ccc2N1
Reactant: CN(C)C=O
Reactant: [NH3+]O
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: C1COCCO1
Product: O=C(Nc1ccccc1)ONC1=Nc2ccc(Br)cc2C(c2ccccn2)=NC1
Reaction time: 8 h

Procedure:
1 g of sodium bicarbonate and 0.8 g of hydroxylammonium chloride are added to 3 g of 7-bromo-5-(2-pyridyl)-1,3-dihydro-2H-1,4-benzodiazepine-2-thione in 60 ml of dioxane containing dimethylformamide and the mixture is stirred for 8 hours. 0.3 g of sodium bicarbonate and 0.25 g of hydroxylammonium chloride are again added and the mixture is stirred for 30 minutes at 50° C. The mixture is filtered off under suction when cold, and 1.0 ml of phenylisocyanate is added to the filtrate which is stirred for 1 hour. After the usual working up process, 1.6 g of colorless crystals are precipitated and are recrystallized from ethanol. Melting point 190° to 192° C.
Reaction SMILES: ClC(N(C)C)=C(C)C.[CH3:9][C@H:10]([O:14][C:15]1[CH:16]=[C:17]([CH:21]=[C:22]([O:24][C:25]2[CH:36]=[CH:35][C:28]3[C:29](=[O:34])[N:30]([CH3:33])[CH2:31][O:32][C:27]=3[CH:26]=2)[CH:23]=1)[C:18]([OH:20])=O)[CH2:11][O:12][CH3:13].[NH2:37][C:38]1[CH:42]=[CH:41][N:40]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[N:39]=1.N1C=CC=CC=1>C(Cl)Cl>[CH3:9][C@H:10]([O:14][C:15]1[CH:16]=[C:17]([C:18]([NH:37][C:38]2[CH:42]=[CH:41][N:40]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[N:39]=2)=[O:20])[CH:21]=[C:22]([O:24][C:25]2[CH:36]=[CH:35][C:28]3[C:29](=[O:34])[N:30]([CH3:33])[CH2:31][O:32][C:27]=3[CH:26]=2)[CH:23]=1)[CH2:11][O:12][CH3:13]
Reactant: CC(C)(C)OC(=O)n1ccc(N)n1
Reactant: COC[C@H](C)Oc1cc(Oc2ccc3c(c2)OCN(C)C3=O)cc(C(=O)O)c1
Agent: CC(C)=C(Cl)N(C)C
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC[C@H](C)Oc1cc(Oc2ccc3c(c2)OCN(C)C3=O)cc(C(=O)Nc2ccn(C(=O)OC(C)(C)C)n2)c1
Reaction time: 1 h
Yield: 52.9 %

Procedure:
1-Chloro-N,N,2-trimethyl-1-propenylamine (0.13 mL, 0.97 mmol) was added to a solution of 3-{[(1S)-1-methyl-2-(methyloxy)ethyl]oxy}-5-[(3-methyl-4-oxo-3,4-dihydro-2H-1,3-benzoxazin-7-yl)oxy]benzoic acid (0.25 g, 0.65 mmol) in DCM (10 mL) and stirred for 1 hour. 1,1-Dimethylethyl 3-amino-1H-pyrazole-1-carboxylate (0.18 g, 0.97 mmol) then pyridine (0.11 mL, 1.29 mmol) were added and the reaction stirred for a further 45 mins then reduced in vacuo and partitioned between ethyl acetate (50 mL) and water (50 mL). The aqueous layer was further extracted into ethyl acetate (50 mL) and the combined organics washed with water (50 mL), brine (50 mL), dried (MgSO4), and reduced in vacuo. The crude oil was chromatographed on silica, eluting with 40-100% ethyl acetate in isohexane, to give the desired compound as a golden oil (0.19 g). 1H NMR δ (CDCl3): 1.32 (d, 3H), 1.63 (s, 9H), 3.10 (s, 3H), 3.40 (s, 3H), 3.48-3.60 (m, 2H), 4.56-4.60 (m, 1H), 5.18 (s, 2H), 6.54 (d, 1H), 6.73-6.76 (m, 1H), 6.83 (t, 1H), 7.07-7.08 (m, 2H), 7.25-7.26 (m, 1H), 7.95 (d, 1H), 8.00 (d, 1H), 8.65 (s, 1H); m/z 551 (M−H)−