Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:15]=[CH:16][C:17]([C:20]([OH:22])=O)=[N:18][CH:19]=3)=[CH:11][CH:12]=2)[C@H:7]([NH:23][C:24]2[CH:29]=[N:28][C:27]([C:30]#[N:31])=[CH:26][N:25]=2)[CH2:6][C@@H:5]1[CH3:32])(=[O:3])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:66][CH2:67][CH2:68][OH:69]>CN(C=O)C>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:15]=[CH:16][C:17]([C:20]([NH:66][CH2:67][CH2:68][OH:69])=[O:22])=[N:18][CH:19]=3)=[CH:11][CH:12]=2)[C@H:7]([NH:23][C:24]2[CH:29]=[N:28][C:27]([C:30]#[N:31])=[CH:26][N:25]=2)[CH2:6][C@@H:5]1[CH3:32])(=[O:3])[CH3:2]
Reactant: CC(=O)N1c2ccc(-c3ccc(C(=O)O)nc3)cc2[C@H](Nc2cnc(C#N)cn2)C[C@@H]1C
Reactant: NCCO
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: CC(=O)N1c2ccc(-c3ccc(C(=O)NCCO)nc3)cc2[C@H](Nc2cnc(C#N)cn2)C[C@@H]1C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 38 %

Procedure:
5-((2S,4R)-1-acetyl-4-((5-cyanopyrazin-2-yl)amino)-2-methyl-1,2,3,4-tetrahydroquinolin-6-yl)picolinic acid (for a preparation see Intermediate 53) (100 mg, 0.233 mmol), HATU (177 mg, 0.467 mmol) and DIPEA (0.122 ml, 0.700 mmol) were combined in DMF (3 mL) and stirred at room temperature for 10 mins. 2-aminoethanol (0.029 ml, 0.350 mmol) was added and the reaction mixture stirred for 1.5 h. The mixture was concentrated in vacuo and purified by MDAP (formate) to give 5-((2S,4R)-1-acetyl-4-((5-cyanopyrazin-2-yl)amino)-2-methyl-1,2,3,4-tetrahydroquinolin-6-yl)-N-(2-hydroxyethyl)picolinamide (42 mg, 0.089 mmol, 38% yield). LCMS: (Formate, 2 min), Rt=0.73 mins, MH+=472
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([OH:28])=O)=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.F[P-](F)(F)(F)(F)F.CN(C(N(C)C)=[N+]1C2C(=NC=CC=2)[N+]([O-])=N1)C.ClCCl.[C:60]([O:64][C:65]([N:67]1[CH2:72][CH2:71][N:70]([CH2:73][CH2:74][CH2:75][NH2:76])[CH2:69][CH2:68]1)=[O:66])([CH3:63])([CH3:62])[CH3:61]>C(N(CC)CC)C>[C:60]([O:64][C:65]([N:67]1[CH2:68][CH2:69][N:70]([CH2:73][CH2:74][CH2:75][NH:76][C:26](=[O:28])[C:25]2[CH:29]=[CH:30][C:22]([NH:21][C:19]3[N:18]=[CH:17][C:8]4[N:9]([CH3:16])[C:10](=[O:15])[C:11]([F:13])([F:14])[CH2:12][N:6]([CH:1]5[CH2:2][CH2:3][CH2:4][CH2:5]5)[C:7]=4[N:20]=3)=[C:23]([O:31][CH3:32])[CH:24]=2)[CH2:71][CH2:72]1)=[O:66])([CH3:63])([CH3:62])[CH3:61]
Reactant: CC(C)(C)OC(=O)N1CCN(CCCN)CC1
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Agent: CN(C)C(N(C)C)=[N+]1N=[N+]([O-])c2ncccc21
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc(C(=O)NCCCN2CCN(C(=O)OC(C)(C)C)CC2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Reaction time: 1.5 h
Yield: 69.6 %

Procedure:
To a mixture of 0.105 g (0.23 mmole) of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-benzoic acid (I-22), 0.0988 g (0.26 mmole) of 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxide hexafluorophosphate, 1 mL of dichloromethane, 0.2 mL of triethylamine was added followed by 0.0199 g (0.13 mmole) of 4-(3-amino-propyl)-piperazine-1-carboxylic acid tert-butyl ester. After stirring 1.5 hours, the mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with acetonitrile-water (gradient, 5:95-0:100) to give 0.0609 g of 4-{3-[4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-benzoylamino]-propyl}-piperazine-1-carboxylic acid tert-butyl ester (I-94).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH3:16])=[C:13]([OH:15])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:24][C:25]1[C:33]2[C:28](=[N:29][CH:30]=[N:31][C:32]=2[Cl:34])[N:27]([CH3:35])[N:26]=1>>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH3:16])=[C:13]([CH:14]=1)[O:15][CH2:24][C:25]1[C:33]2[C:28](=[N:29][CH:30]=[N:31][C:32]=2[Cl:34])[N:27]([CH3:35])[N:26]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cn1nc(CBr)c2c(Cl)ncnc21
Reactant: Cc1ccc(OCc2ccccc2)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1ccc(OCc2ccccc2)cc1OCc1nn(C)c2ncnc(Cl)c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 5-benzyloxy-2-methyl-phenol (83.4 mg, 0.389 mmol, 37009-93A) and potassium carbonate (61.8 mg, 0.438 mmole) was stirred at room temperature for 30 minutes before 3-bromomethyl-4-chloro-1-methyl-1H-pyrazolo[3,4-d]pyrimidine (89.8 mg, 0.344 mmole, Example 5) was added. The reaction was stirred at room temperature overnight and then concentrated under reduced pressure to remove dimethylformamide. The residue was dissolved in ethyl acetate, washed with water, dried and concentrated. The crude product was either used directly in the next step or purified by flash chromatography (silica gel, hexanes-ethyl acetate, 90/10 to 60/40) to give pure 3-(5-benzyloxy-2-methyl-phenoxymethyl)-4-chloro-1-methyl-1H-pyrazolo[3,4-d]pyrimidine as a white solid. (Yield 48.0 mg).
Reaction SMILES: [NH2:1][C:2]1[C:15]2[C:6](=[CH:7][C:8]3[C:9]4[C:14]=2[C:13](=[O:16])[N:12]([CH2:17][CH2:18][N:19]([CH3:21])[CH3:20])[C:11](=[O:22])[C:10]=4[CH:23]=[CH:24][CH:25]=3)[CH:5]=[CH:4][CH:3]=1.[N:26]1[S:27][N:28]=[C:29]2[CH:34]=[C:33]([N:35]=[C:36]=[S:37])[CH:32]=[CH:31][C:30]=12>C(#N)C>[N:26]1[S:27][N:28]=[C:29]2[CH:34]=[C:33]([NH:35][C:36]([NH:1][C:2]3[C:15]4[C:6](=[CH:7][C:8]5[C:9]6[C:14]=4[C:13](=[O:16])[N:12]([CH2:17][CH2:18][N:19]([CH3:20])[CH3:21])[C:11](=[O:22])[C:10]=6[CH:23]=[CH:24][CH:25]=5)[CH:5]=[CH:4][CH:3]=3)=[S:37])[CH:32]=[CH:31][C:30]=12
Reactant: CN(C)CCN1C(=O)c2cccc3cc4cccc(N)c4c(c23)C1=O
Reactant: S=C=Nc1ccc2nsnc2c1
Solvent: CC#N
Product: CN(C)CCN1C(=O)c2cccc3cc4cccc(NC(=S)Nc5ccc6nsnc6c5)c4c(c23)C1=O
Temperature: 25 °C
Yield: 89.2 %

Procedure:
215 mg of 11-amino-2-[2-(dimethylamino)ethyl]-1H-dibenzo[de,h]isoquinoline-1,3(2H)-dione (obtained in example 3) (0.645 mmole) were dissolved in 10 ml of acetonitrile. 250 mg (2 molar equivalents) of 2,1,3-benzothiadiazol-5-yl isothiocyanate was added and the reaction mixture was maintained at room temperature for 16 hours. The solvent was then evaporated under reduced pressure and the residue was submitted to a flash chromatography (SiO2, CH2Cl2/MeOH 95/5). 303 mg of the desired product (formula shown hereinabove) were isolated as a red powder (yield=89%) which was characterized as follows:
Reaction SMILES: [O:1]([P:8]([CH2:17][S:18](OC1C=CC=CC=1)(=[O:20])=[O:19])([O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:28]([O:32][C:33]([N:35]1[CH2:40][CH2:39][CH:38]([CH2:41][NH2:42])[CH2:37][CH2:36]1)=[O:34])([CH3:31])([CH3:30])[CH3:29]>C1(C)C=CC=CC=1>[O:10]([P:8]([CH2:17][S:18]([NH:42][CH2:41][CH:38]1[CH2:39][CH2:40][N:35]([C:33]([O:32][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:34])[CH2:36][CH2:37]1)(=[O:20])=[O:19])([O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:9])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CN)CC1
Reactant: O=P(CS(=O)(=O)Oc1ccccc1)(Oc1ccccc1)Oc1ccccc1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC(CNS(=O)(=O)CP(=O)(Oc2ccccc2)Oc2ccccc2)CC1

Procedure:
A solution of 2.405 g (5.947 mM) of phenyl di-phenoxyphosphorylmethanesulfonate and 1.66 g (7.73 mM) of 1-(tert-butoxycarbonyl)piperidine-4-ylmethylamine in 50 ml of toluene was refluxed overnight. The solvent was then distilled off under reduced pressure and the residue was purified by silica gel column chromatography (hexane-ethyl acetate:2/1 to 1/1) to provide the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([C:12]([OH:14])=[O:13])=[CH:7][CH:6]=[CH:5]2.[Cl:15][C:16]1[N:21]=[C:20](Cl)[CH:19]=[CH:18][N:17]=1.O.Cl>CC(C)=O.[OH-].[Na+]>[Cl:15][C:16]1[N:21]=[C:20]([O:1][C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[C:8]([C:12]([OH:14])=[O:13])=[CH:7][CH:6]=[CH:5]3)[CH:19]=[CH:18][N:17]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: O=C(O)c1cccc2cc(O)ccc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Product: O=C(O)c1cccc2cc(Oc3ccnc(Cl)n3)ccc12
Temperature: 50 °C
Reaction time: 2 h

Procedure:
To a mixture of 7.4 g (39.5 mMol) 6-hydroxy-1-naphthoic acid and 5.9 g (39.5 mMol) 2,4-dichloropyrimidin in 104 ml of acetone, 79 ml NaOH (1 M in H2O) are added dropwise. The mixture is stirred for 19 h at rt and finally 2 h at 50° C. Then it is poured into 1.3 l water and acidified by addition of 40 ml of a 2 M HCl solution. Filtration of the suspension, washing with water and drying gives the title compound: MS: [M+1]+=301.
Reaction SMILES: [CH:1]([CH:3]([CH3:14])[C:4]([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][CH:7]=1)=O)=O.O.[NH2:16][NH2:17]>C(O)C>[CH3:13][O:12][C:9]1[CH:10]=[CH:11][C:6]([C:4]2[C:3]([CH3:14])=[CH:1][NH:17][N:16]=2)=[CH:7][CH:8]=1
Reactant: NN
Reactant: COc1ccc(C(=O)C(C)C=O)cc1
Solvent: CCO
Solvent: O
Product: COc1ccc(-c2n[nH]cc2C)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 88 %

Procedure:
9.8 g (51.0 mmol) of the 2-formyl-4′-methoxypropiophenone synthesized in Step 1 was dissolved in 150 ml of ethanol. At room temperature, 3.8 g (61.2 mmol) of 80% hydrazine hydrate was dropwise added to the solution, followed by stirring at the same temperature for 1 hour and further by heating under reflux for 2 hours. After reaction had been completed, the reaction mixture was cooled to room temperature and the solvent was distilled away. As a result, 8.4 g (44.9 mmol) of 3-(4′-methoxyphenyl)-4-methylpyrazole was obtained as an orange oily matter. The yield was 88%. The product synthesized was subjected to the next reaction without purification.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:5](=[O:14])[CH2:6][CH2:7][CH2:8][C:9]=2[C:10]=1[C:11]([OH:13])=O.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.C(N(CC)CC)C.[CH2:43]([N:45]([CH2:49][CH3:50])[CH2:46][CH2:47][NH2:48])[CH3:44]>CN(C=O)C>[CH2:43]([N:45]([CH2:49][CH3:50])[CH2:46][CH2:47][NH:48][C:11]([C:10]1[C:9]2[CH2:8][CH2:7][CH2:6][C:5](=[O:14])[C:4]=2[NH:3][C:2]=1[CH3:1])=[O:13])[CH3:44]
Reactant: Cc1[nH]c2c(c1C(=O)O)CCCC2=O
Reactant: CCN(CC)CCN
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCN(CC)CCNC(=O)c1c(C)[nH]c2c1CCCC2=O
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 78.9 %

Procedure:
A mixture of 2-methyl-7-oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxylic acid (S4) 0.2 g (1.0 mmol), HOBt 0.16 g (1.2 mmol), EDCI 0.24 g (1.2 mmol) and triethylamine 0.2 g (2.0 mmol) in 10 ml DMF was stirred at room temperature for 20 min, then N1,N1-diethylethane-1,2-diamine 0.24 g (2.1 mmol) was added. After stirred at room temperature for 24 hours, the mixture was poured into the ice water and extracted with CH2Cl2. The organic layer separated was washed with water and saturated sodium chloride solution, then dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by a silica gel column, eluted with CH2Cl2/MeOH (30:1), to give 0.23 g (79%) of the titled compound as a white solid.
Reaction SMILES: C([N:8]1[CH2:12][CH2:11][C@H:10]([NH:13][C@@H:14]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH3:23])[CH:17]=2)[CH3:15])[CH2:9]1)C1C=CC=CC=1.[ClH:24]>CO.O1CCOCC1.[OH-].[Pd+2].[OH-]>[ClH:24].[ClH:24].[CH3:23][O:22][C:18]1[CH:17]=[C:16]([C@H:14]([NH:13][C@H:10]2[CH2:11][CH2:12][NH:8][CH2:9]2)[CH3:15])[CH:21]=[CH:20][CH:19]=1
Reactant: COc1cccc([C@@H](C)N[C@H]2CCN(Cc3ccccc3)C2)c1
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CO
Product: COc1cccc([C@@H](C)N[C@H]2CCNC2)c1
Reaction time: 72 h

Procedure:
To a solution of 3.67 g of (S)-(1-benzylpyrrolidin-3-yl)-[(R)-1-(3-methoxyphenyl)ethyl]amine dissolved in 100 ml of methanol were added 830 mg of palladium hydroxide and 8.85 ml of a solution of 4M hydrochloric acid in dioxane, and the mixture was shaked under hydrogen atmosphere at 3 atm at room temperature for 3 days. Palladium hydroxide was removed, and the solvent was evaporated. To the residue was added methanol, and the resulting precipitates were collected by filtration, washed with methanol and dried to obtain 1.14 g of (S)-3-[(R)-1-(3-methoxyphenyl)ethylamino]pyrrolidine dihydrochloride (the following Reference example Table, Reference example 1.001).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([NH:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=1)=[O:13])=[C:5]2[OH:23].ClC1C=CC(CNC(C2C=NC3C(C=2O)=CC=C(N[S:47]([CH3:50])(=[O:49])=[O:48])C=3)=O)=CC=1.NC1C=C2C(C(O)=C(C(NCC3C=CC(Cl)=CC=3)=O)C=N2)=CC=1>>[Cl:22][C:19]1[CH:20]=[CH:21][C:16]([CH2:15][NH:14][C:12]([C:6]2[CH:7]=[N:8][C:9]3[C:4]([C:5]=2[OH:23])=[CH:3][C:2]([NH:1][S:47]([CH3:50])(=[O:49])=[O:48])=[CH:11][CH:10]=3)=[O:13])=[CH:17][CH:18]=1
Reactant: Nc1ccc2ncc(C(=O)NCc3ccc(Cl)cc3)c(O)c2c1
Reactant: CS(=O)(=O)Nc1ccc2c(O)c(C(=O)NCc3ccc(Cl)cc3)cnc2c1
Agent: Nc1ccc2c(O)c(C(=O)NCc3ccc(Cl)cc3)cnc2c1
Product: CS(=O)(=O)Nc1ccc2ncc(C(=O)NCc3ccc(Cl)cc3)c(O)c2c1

Procedure:
This compound is prepared from 6-amino-N-[(4-chlorophenyl)methyl]-4-hydroxy-3-quinolinecarboxamide using a procedure similar to that used to prepare N-[(4-chlorophenyl)methyl]-4-hydroxy-7-[(methylsulfonyl)amino]3-quinoline-carboxamide from 7-amino-N-[(4-chlorophenyl)methyl]-4-hydroxy-3-quinoline-carboxamide. The product is obtained as a tan powder.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2[C:20]3[C:15](=[C:16]([F:22])[CH:17]=[CH:18][C:19]=3[F:21])[O:14][CH2:13][CH:12]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH2:23][CH2:24][CH2:25][CH2:26][OH:27].C([O-])([O-])=O.[Na+].[Na+].C(OCC)(=O)C>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([CH:11]2[C:20]3[C:15](=[C:16]([F:22])[CH:17]=[CH:18][C:19]=3[F:21])[O:14][CH2:13][CH:12]2[NH:23][CH2:24][CH2:25][CH2:26][OH:27])(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: NCCCO
Reactant: O=S(=O)(C1=CCOc2c(F)ccc(F)c21)c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=S(=O)(c1ccc(Cl)cc1)C1c2c(F)ccc(F)c2OCC1NCCCO
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
4-(4-Chloro-benzenesulfonyl)-5,8-difluoro-2H-chromene (0.3 g, 0.88 mmole) was dissolved in 15 ml THF and 3-aminopropanol (1 ml) was added. The mixture was stirred at room temperature for 30 minutes. 50 saturated Na2CO3 solution and 50 ml EtOAc were added. The organic layer washed with water (50 ml), brine (50 ml), dried over Na2SO4 and concentrated. The product was purified by column (EtOAc/hexane from 50/50 to 100/0 in 45 minutes). Yield: 0.31 g, 84%. 1H NMR (CDCl3 400 MHz) δ 7.69 (d, J=8.8 Hz, 2H), 7.48 (d, J=8.1 Hz), 6.99 (td, J=9.5, 5.1 Hz, 1H), 6.38 (td, J=9.5, 3.7 HZ, 1H), 4.80 (dd, J=12.5, 2.9 Hz, 1H), 4.53 (s, 1H), 4.43 (d, J=11.8 Hz, 1H), 3.78 (s, 1H), 3.61 (t, J=5.9 Hz, 2H), 2.86-2.71 (m, 2H), 2.25 (bs, 1H), 1.57 (p, J=5.9 Hz, 2H).
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][C:10]2[CH:18]=[CH:17][CH:16]=[C:15]3[C:11]=2[C:12](=[O:32])[N:13]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([CH2:27][C:28](SC)=[NH:29])=[CH:23][CH:22]=2)[C:14]3=[O:19])=[O:8])=[CH:4][CH:3]=1.C([O-])(=O)C.[NH4+:37].[Cl-].[NH4+]>CO.C(Cl)Cl>[NH2:29][C:28](=[NH:37])[CH2:27][C:24]1[CH:25]=[CH:26][C:21]([CH2:20][N:13]2[C:12](=[O:32])[C:11]3[C:15](=[CH:16][CH:17]=[CH:18][C:10]=3[NH:9][C:7]([C:5]3[S:6][C:2]([Cl:1])=[CH:3][CH:4]=3)=[O:8])[C:14]2=[O:19])=[CH:22][CH:23]=1
Reactant: [NH4+]
Reactant: CSC(=N)Cc1ccc(CN2C(=O)c3cccc(NC(=O)c4ccc(Cl)s4)c3C2=O)cc1
Agent: CC(=O)[O-]
Agent: [Cl-]
Solvent: CO
Solvent: ClCCl
Product: N=C(N)Cc1ccc(CN2C(=O)c3cccc(NC(=O)c4ccc(Cl)s4)c3C2=O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
320 mg (0.661 mmol) of methyl 2-{4-[(4-{[(5-chloro-2-thienyl)carbonyl]amino}-1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]phenyl}ethaneimidothioate are suspended in 40 ml of methanol, and 153 mg (1.98 mmol) of ammonium acetate and 106 mg (1.98 mmol) of ammonium chloride are added. The mixture is stirred at room temperature overnight, diluted with methanol and methylene chloride until a clear solution is formed and adsorbed on silica gel. Chromatography on silica gel (CH2Cl2/EtOH=10/1 to 3/1) gives the desired compound. The product is dissolved in methanol and methylene chloride, and trifluoroacetic acid is added. Removal of the solvent under reduced pressure gives 298 mg (80% of theory) of the desired product as trifluoroacetic acid salt.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[C:8]([C:10]([OH:12])=[O:11])[CH:7]=[CH:6][C:3]=1[CH2:4][NH2:5].C([O-])([O-])=O.[Na+].[Na+].[C:19](ON1C(=O)CCC1=O)([O:21][CH2:22][CH:23]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:29]2[C:24]1=[CH:25][CH:26]=[CH:27][CH:28]=2)=[O:20]>O1CCOCC1>[C:19]([NH:5][CH2:4][C:3]1[CH:6]=[CH:7][C:8]([C:10]([OH:12])=[O:11])=[CH:9][C:2]=1[Br:1])([O:21][CH2:22][CH:23]1[C:24]2[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:30]2[C:35]1=[CH:34][CH:33]=[CH:32][CH:31]=2)=[O:20]
Reactant: NCc1ccc(C(=O)O)cc1Br
Reactant: O=C(OCC1c2ccccc2-c2ccccc21)ON1C(=O)CCC1=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: O=C(NCc1ccc(C(=O)O)cc1Br)OCC1c2ccccc2-c2ccccc21
Temperature: 10 °C
Yield: 66.8 %

Procedure:
To a solution of 2-bromo-4-carboxybenzylamine (20 g, 0.086 mol) in dioxane (250 mL), was added an aqueous solution of Na2CO3 (10%, 350 mL) with stirring. The reaction mixture was cooled to 10° C., added Fmoc-OSu (32 g, 0.096 mol) in portions and allowed to stir at RT for 8 h. The solid precipitate was filtered off and washed with diethyl ether (2×200 mL). The solid was acidified with 3N HCl and filtered under suction. The crude solid was recrystalised from methanol/diethyl ether to give N-(Fmoc)-2-bromo-4-carboxybenzylamine (26 g, 67%) as a solid.
Reaction SMILES: [F:1][C:2]1[N:3]([C:11]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:4]=[C:5]([CH2:7][CH2:8][CH2:9][OH:10])[N:6]=1.[CH3:30][S:31](Cl)(=[O:33])=[O:32]>N1C=CC=CC=1>[F:1][C:2]1[N:3]([C:11]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:4]=[C:5]([CH2:7][CH2:8][CH2:9][O:10][S:31]([CH3:30])(=[O:33])=[O:32])[N:6]=1
Reactant: CS(=O)(=O)Cl
Reactant: OCCCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c(F)n1
Solvent: c1ccncc1
Product: CS(=O)(=O)OCCCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c(F)n1

Procedure:
A solution of 2-fluoro-4-(3-hydroxypropyl)-1-triphenylmethylimidazole in pyridine was treated with methanesulphonyl chloride. Work-up as for the starting material of Example 9 gave 2-fluoro-4-(3-methanesulphonyloxypropyl)-1-triphenylmethylimidazole, having the following n.m.r. spectrum in CDCl3 : 2.03 (m, 2H); 2.52 (t, 2H); 2.94 (s, 3H); 4.21 (t, 2H); 6.27 (s, 1H); 7.0-7.5 (m, 15H).
Reaction SMILES: [OH-].[Na+].[CH2:3]([N:5]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[C:12]([CH3:17])[CH:11]=2)[N:7]=[C:6]1CC#N)[CH3:4].[C:21]([OH:24])(=[O:23])[CH3:22]>O.CS(C)=O>[CH2:3]([N:5]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[C:12]([CH3:17])[CH:11]=2)[N:7]=[C:6]1[CH2:22][C:21]([OH:24])=[O:23])[CH3:4]
Reactant: CCn1cc(-c2ccc(F)c(C)c2)nc1CC#N
Reactant: CC(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: CCn1cc(-c2ccc(F)c(C)c2)nc1CC(=O)O
Temperature: 100 °C
Reaction time: 4 h

Procedure:
930 mg sodium hydroxide in 6 mL water was added to 525 mg (1-ethyl-4-(4-fluoro-3-methyl-phenyl)-1H-imidazol-2-yl)-acetonitrile in 2 mL DMSO. The reaction was stirred 4 h at 100° C. The mixture was diluted with water acidified with concentrated acetic acid and extracted with ethylacetate. The organic layer was dried and evaporated. The residue was crystallized with diethyl ether to give 60 mg of the desired product. Rt: 0.94 min (method K), (M+H)+: 263
Reaction SMILES: [CH3:1][C:2]([CH3:15])([S:4]([NH:6][C:7]1(/[C:11](=[N:13]/[OH:14])/[NH2:12])[CH2:10][CH2:9][CH2:8]1)=[O:5])[CH3:3].[CH3:16]OC(OC)N(C)C>O1CCOCC1>[O:14]1[CH:16]=[N:12][C:11]([C:7]2([NH:6][S:4]([C:2]([CH3:15])([CH3:1])[CH3:3])=[O:5])[CH2:10][CH2:9][CH2:8]2)=[N:13]1
Reactant: COC(OC)N(C)C
Reactant: CC(C)(C)S(=O)NC1(/C(N)=N/O)CCC1
Solvent: C1COCCO1
Product: CC(C)(C)S(=O)NC1(c2ncon2)CCC1
Temperature: 70 °C
Yield: 14.7 %

Procedure:
(Z)-1-(1,1-dimethylethylsulfinamido)-N′-hydroxycyclobutanecarboximidamide (300 mg, 1.29 mmol) was taken up in dioxane (6 ml) and treated with N,N-Dimethylformamide dimethyl acetal (2.6 ml, 19 mmol) at rt. The reaction was then heated to 70° C. for 4 h. LCMS showed that starting material had been consumed. The expected M+H of 244 was observed in one of the minor peaks. The reaction was concentrated under high vacuum and the residue was purified by preparative reverse phase HPLC on a C18 column using a NH4OAc buffered H2O/CH3CN gradient, and concentrated to give N-(1-(1,2,4-oxadiazol-3-yl)cyclobutyl)-2-methylpropane-2-sulfinamide (45 mg, 0.19 mmol, 14% yield) as a light brown oil consistent by LCMS. LC-MS retention time: 1.31 min; m/z (MH+): 244. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna 3u C18 2.0×30 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 1 mL/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 10% acetonitrile/90% H2O/0.1% trifluoroacetic acid and solvent B was 10% H2O/90% acetonitrile/0.1% trifluoroacetic acid. MS data was determined using a Micromass Platform for LC in electrospray mode.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH3:9][O:10][C:11]([C:13]1[CH:21]=[C:20]2[C:16]([C:17]3[CH:25]=[C:24]([CH3:26])[CH:23]=[N:22][C:18]=3[NH:19]2)=[C:15]([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([S:33]([CH2:36][CH3:37])(=[O:35])=[O:34])[CH:28]=2)[CH:14]=1)=[O:12]>C(Cl)Cl>[CH3:9][O:10][C:11]([C:13]1[CH:21]=[C:20]2[C:16]([C:17]3[CH:25]=[C:24]([CH3:26])[CH:23]=[N:22][C:18]=3[NH:19]2)=[C:15]([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([S:33]([CH2:36][CH3:37])(=[O:35])=[O:34])[CH:28]=2)[C:14]=1[Br:1])=[O:12]
Reactant: CCS(=O)(=O)c1cccc(-c2cc(C(=O)OC)cc3[nH]c4ncc(C)cc4c23)c1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Product: CCS(=O)(=O)c1cccc(-c2c(Br)c(C(=O)OC)cc3[nH]c4ncc(C)cc4c23)c1
Temperature: 30 °C
Reaction time: 18 h
Yield: 23.8 %

Procedure:
N-Bromosuccinimide (59 mg, 0.33 mmol) was added to a solution of Compound 132 (128 mg, 0.31 mmol) in CH2Cl2 (3 mL) at r.t. The reaction was stirred for 18 h at 30° C. and was then concentrated in vacuo. Purification by prep-HPLC gave 36 mg (24%) of the title compound as a white solid. 1H NMR (400 MHz, CDCl3) δ 12.28 (br s, 1H), 8.23 (s, 1H), 8.15-8.19 (m, 2H), 7.98 (s, 1H), 7.87 (t, 1H, J=7.6 Hz), 7.72 (d, 1H, J=7.6 Hz), 7.08 (s, 1H), 4.03 (s, 3H), 3.22 (q, 2H, J=7.2 Hz), 2.34 (s, 3H), 1.33 (t, 3H, J=7.2 Hz). MS (ES) [m+H] calc'd for C22H19BrN2O4S, 487, 489; found 487, 489.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[N:6]([CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C:5]2=[O:20].N1C=CC=CC=1.[CH3:27][S:28](Cl)(=[O:30])=[O:29]>C1COCC1>[CH3:27][S:28]([NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[N:6]([CH2:12][C:13]([O:15][C:16]([CH3:17])([CH3:19])[CH3:18])=[O:14])[C:5]2=[O:20])(=[O:30])=[O:29]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)CN1C(=O)c2ccc(N)cc2C1=O
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)CN1C(=O)c2ccc(NS(C)(=O)=O)cc2C1=O
Yield: 14.5 %

Procedure:
To a solution of tert-butyl 2-(5-amino-1,3-dioxoisoindolin-2-yl)acetate (14 g, 50.7 mmol) in THF (100 ml), pyridine (8.20 ml, 101 mmol) was added followed by methanesulfonyl chloride (7.74 ml, 101 mmol), and the resulting mixture was heated to reflux for 5 hours. The volatiles were removed under vacuum, the residue was dissolved in DCM (200 ml) and washed with 0.2M HCl (3×50 ml) and brine; the organic phase was dried over Na2SO4 and evaporated to dryness. The resulting solid was triturated with ethyl acetate, and the title compound was recovered by filtration (12.5 g). The mother liquors were evaporated in vacuo and purified by silica gel chromatography (DCM:AcOEt 10:1), affording additional 2.6 g of the title compound. These two batches were dissolved in DCM, combined, and the solvent was evaporated in vacuo to afford tert-butyl 2-(5-(methylsulfonamido)-1,3-dioxoisoindolin-2-yl)acetate (15.1 g, 42.6 mmol, 84% yield, MS/ESI+ 354.9 [MH]+).