Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[Li].C(NC(C)C)(C)C.[Cl:10][C:11]1[CH:12]=[CH:13][C:14]2[N:20]([CH3:21])[C:19](=[O:22])[CH2:18][N:17]=[C:16]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:15]=2[CH:29]=1.[CH3:30][Si:31]([CH3:34])([CH3:33])Cl>C(OCC)C.O1CCCC1>[Cl:10][C:11]1[CH:12]=[CH:13][C:14]2[N:20]([CH3:21])[C:19]([O:22][Si:31]([CH3:34])([CH3:33])[CH3:30])=[CH:18][N:17]=[C:16]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:15]=2[CH:29]=1
Reactant: CN1C(=O)CN=C(c2ccccc2)c2cc(Cl)ccc21
Reactant: C[Si](C)(C)Cl
Agent: [Li]C
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Solvent: CCOCC
Product: CN1C(O[Si](C)(C)C)=CN=C(c2ccccc2)c2cc(Cl)ccc21
Temperature: -70 °C
Reaction time: 3 h
Yield: 95.5 %

Procedure:
A solution of methyllithium in diethyl ether (0.0275 mol, 15.3 ml of 1.8 M solution) was added dropwise to a solution of 3.04 g (0.03 mol) of diisopropylamine in 25 ml of diethyl ether. The reaction mixture was cooled to -70° C. and a solution of 7.12 g (0.025 mol) of 7-chloro-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one in 40 ml of tetrahydrofuran was added dropwise. The reaction mixture became dark red. Trimethylchlorosilane (11.4 ml; 0.09 mol) was added dropwise, after which the reaction mixture was warmed to room temperature, stirred for 3 hours and then filtered. The filtrate was evaporated to dryness and the residue was dissolved in 150 ml of trichlorofluoromethane. This solution was filtered to remove undissolved solid; the filtrate was evaporated to dryness under reduced pressure to give 8.52 g of 7-chloro-1-methyl-5-phenyl-2-trimethylsiloxy-1H-1,4-benzodiazepine as a light orange glass: 1H NMR (CCl3F) δ 0.0 ppm (s, 9H), 2.62 ppm (s, 3H), 5.76 ppm (s, 1H) and 6.4-7.6 ppm (m, 8H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][C:8](=[O:15])OCC(Cl)(Cl)Cl)[N:2]=1.[F:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:23]1[N:24]=[C:25]([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[S:26][CH:27]=1.C(N(C(C)C)CC)(C)C.O>CS(C)=O>[F:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:23]1[N:24]=[C:25]([N:28]2[CH2:29][CH2:30][N:31]([C:8]([NH:7][C:3]3[N:2]=[N:1][CH:6]=[CH:5][CH:4]=3)=[O:15])[CH2:32][CH2:33]2)[S:26][CH:27]=1
Reactant: Fc1ccccc1-c1csc(N2CCNCC2)n1
Reactant: O=C(Nc1cccnn1)OCC(Cl)(Cl)Cl
Solvent: CS(C)=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1cccnn1)N1CCN(c2nc(-c3ccccc3F)cs2)CC1
Temperature: 70 °C
Reaction time: 72 h
Yield: 35.6 %

Procedure:
A mixture of 2,2,2-trichloroethyl pyridazin-3-ylcarbamate (226 mg, 0.835 mmol), 4-[4-(2-fluorophenyl)-1,3-thiazol-2-yl]piperazine (200 mg, 0.760 mmol) and diisopropylethylamine (0.265 ml, 1.52 mmol) in dimethylsulfoxide (2.5 ml) was stirred at 70° C. for 3 days. Water was poured into the reaction solution, and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate) and recrystallized from a mixed solvent of hexane and tetrahydrofuran to give the desired product (104 mg, 35.6%) as a solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][CH2:9]2)=[CH:4][C:3]=1[NH:21][S:22]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)(=[O:24])=[O:23].[C:31]1([CH3:41])[C:32]([S:37](Cl)(=[O:39])=[O:38])=[CH:33][CH:34]=[CH:35][CH:36]=1>>[CH3:41][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[S:37]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:9][CH2:10][NH:11][CH2:12][CH2:13]2)=[CH:4][C:3]=1[NH:21][S:22]([C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)(=[O:23])=[O:24])(=[O:39])=[O:38]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(N)c(NS(=O)(=O)c3ccccc3)c2)CC1
Reactant: Cc1ccccc1S(=O)(=O)Cl
Product: Cc1ccccc1S(=O)(=O)Nc1ccc(N2CCNCC2)cc1NS(=O)(=O)c1ccccc1

Procedure:
2-Methyl-N-[2-[(phenylsulfonyl)amino]-4-(1-piperazinyl)phenyl]benzenesulfonamide was synthesized from N-{2-amino-5-(4-t-butyloxycarbonyl-piperazinyl)-phenyl}benzenesulfonamide and o-toluenesulfonylchloride (46 mg, 0.239 mmol) according to general method 3 to give before Boc-deprotection 160 mg of a purple solid. MS (posES-FIA) m/z=Found: 487.1; Calcd 487.14; 1H-NMR δ 7.74-7.16 (m, 8H), 6.78-6.52 (m, 4H), 3.27-3.16 (m, 8H), 2.58 (s, 3H).
Reaction SMILES: [C:1]([O:4][C:5]1[CH:6]=[C:7]([CH2:11][C:12]([OH:14])=O)[CH:8]=[CH:9][CH:10]=1)(=[O:3])[CH3:2].S(Cl)([Cl:17])=O>>[C:1]([O:4][C:5]1[CH:6]=[C:7]([CH2:11][C:12]([Cl:17])=[O:14])[CH:8]=[CH:9][CH:10]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1cccc(CC(=O)O)c1
Reactant: O=S(Cl)Cl
Product: CC(=O)Oc1cccc(CC(=O)Cl)c1

Procedure:
A solution of 6.36 g 3-acetoxyphenylacetic acid and 10 ml of thionyl chloride was refluxed for one hour. The solvent was removed on a rotary evaporator, 15 ml of dry benzene was added and re-evaporated to yield crude 3-acetoxyphenylacetyl chloride. To a cooled solution of the acid chloride in 35 ml benzene was added dropwise a solution 8.9 g of octyl amine and 10 ml of ether. The reaction mixture was stirred at room temperature for three hours, the solids filtered, and the filtrate transferred to a separatory funnel and extracted with 50 ml of 1 N HCl, 50 ml of H2O and 50 ml of brine. The resulting organic solution was dried (MgSO4), filtered, and evaporated to yield 10.14 g of a mixture containing octyl 3-acetoxyphenylacetamide.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([O:8][S:9]([C:12]2[CH:18]=[CH:17][C:15]([CH3:16])=[CH:14][CH:13]=2)(=[O:11])=[O:10])[CH:5]=[C:4]([NH2:19])[N:3]=1.OO.[C:22]([O:25]C(=O)C)(=[O:24])[CH3:23].[O:29]1CC[CH2:31][CH2:30]1>>[C:30]([NH:19][C:4]1[N:3]([O:25][C:22](=[O:24])[CH3:23])[C:2](=[NH:1])[N:7]=[C:6]([O:8][S:9]([C:12]2[CH:18]=[CH:17][C:15]([CH3:16])=[CH:14][CH:13]=2)(=[O:11])=[O:10])[CH:5]=1)(=[O:29])[CH3:31]
Reactant: C1CCOC1
Reactant: CC(=O)OC(C)=O
Reactant: Cc1ccc(S(=O)(=O)Oc2cc(N)nc(N)n2)cc1
Agent: OO
Product: CC(=O)Nc1cc(OS(=O)(=O)c2ccc(C)cc2)nc(=N)n1OC(C)=O
Yield: 68 %

Procedure:
84 g (0.3 mole) of 2,6-diamino-4-tosyloxypyrmidine are added to 1200 ml of anhydrous tetrahydrofuran. 40 ml of a 70% aqueous hydrogen peroxide solution are dropped to the obtained suspension at room temperature while stirring, whereupon the material is dissolved. While stirring 200 ml of acetic anhydride are added to the solution at 40° C. in an hour. After adding the mixture is stirred at 60° C. for further two hours. Then the solvent is evaporated in vacuo and the residue is allowed to stand in a refrigerator for a night. The separated material is filtered, washed with tetrahydrofuran and dried. In this way 77 g (68%) of the aimed compound are obtained.
Reaction SMILES: C(OC(=O)[NH:7][C@@H:8]1[CH2:12][CH2:11][N:10]([C:13]2[N:21]=[C:20]3[C:16]([N:17]=[CH:18][N:19]3[C@@H:22]3[CH2:26][C@H:25]([NH:27][C:28](=[O:39])[C@H:29]([O:31][CH2:32][C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[CH3:30])[C@@H:24]([OH:40])[C@H:23]3[OH:41])=[C:15]([NH:42][CH2:43][CH:44]([C:51]3[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=3)[C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)[N:14]=2)[CH2:9]1)(C)(C)C.Cl>CO.O1CCOCC1>[NH2:7][C@@H:8]1[CH2:12][CH2:11][N:10]([C:13]2[N:21]=[C:20]3[C:16]([N:17]=[CH:18][N:19]3[C@@H:22]3[CH2:26][C@H:25]([NH:27][C:28](=[O:39])[C@H:29]([O:31][CH2:32][C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[CH3:30])[C@@H:24]([OH:40])[C@H:23]3[OH:41])=[C:15]([NH:42][CH2:43][CH:44]([C:45]3[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=3)[C:51]3[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=3)[N:14]=2)[CH2:9]1
Reactant: C[C@@H](OCc1ccccc1)C(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(N4CC[C@@H](NC(=O)OC(C)(C)C)C4)nc32)[C@H](O)[C@@H]1O
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: C[C@@H](OCc1ccccc1)C(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(N4CC[C@@H](N)C4)nc32)[C@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of {(R)-1-[9-[(1R,2S,3R,4S)-4-((R)-2-Benzyloxy-propionylamino)-2,3-dihydroxy-cyclopentyl]-6-(2,2-diphenyl-ethylamino)-9H-purin-2-yl]-pyrrolidin-3-yl}-carbamic acid tert-butyl ester in MeOH (˜0.5M) is treated with an equal volume of 4M HCl in dioxane and stirred at room temperature for 2 hours. The solvent is removed in vacuo and purification is carried out by column chromatography/crystallisation to afford the title compound.
Reaction SMILES: CS(O[CH2:6][C:7]1[O:11][N:10]=[C:9]([C@@H:12]2[CH2:16][CH2:15][CH2:14][N:13]2[C:17](=[O:32])[C:18]([F:31])([F:30])[C:19]2([OH:29])[CH2:24][C:23]([CH3:26])([CH3:25])[CH2:22][C:21]([CH3:28])([CH3:27])[CH2:20]2)[CH:8]=1)(=O)=O.C1COCC1.[CH3:38]COC(C)=O.C[C:45]#[N:46]>>[CH3:38][N:46]([CH2:6][C:7]1[O:11][N:10]=[C:9]([C@@H:12]2[CH2:16][CH2:15][CH2:14][N:13]2[C:17](=[O:32])[C:18]([F:30])([F:31])[C:19]2([OH:29])[CH2:24][C:23]([CH3:25])([CH3:26])[CH2:22][C:21]([CH3:28])([CH3:27])[CH2:20]2)[CH:8]=1)[CH3:45]
Reactant: CC#N
Reactant: CCOC(C)=O
Reactant: CC1(C)CC(C)(C)CC(O)(C(F)(F)C(=O)N2CCC[C@H]2c2cc(COS(C)(=O)=O)on2)C1
Solvent: C1CCOC1
Product: CN(C)Cc1cc([C@@H]2CCCN2C(=O)C(F)(F)C2(O)CC(C)(C)CC(C)(C)C2)no1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
The compound (160 mg) obtained in Example 3-(5) was dissolved in MeCN and after adding a THF solution of dimethyllamine (2 M, 250 μL), the mixture was stirred at room temperature for 3 hours. To the reaction mixture, AcOEt (50 ml) and a saturated aqueous solution of NaCO3 (50 ml) were added to separate the organic layer. The resulting organic layer was washed with brine (50 ml), dried (MgSO4), filtered and concentrated to give a crude product, which was further purified by silica gel chromatography (AcOEt/hexane) to give the titled compound (83 mg, colorless amorphous.)
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH:5]=[CH:6][CH:7]=1.[F:17][C:18]([F:44])([F:43])[CH:19]([CH3:42])[CH:20]([C:24]1[CH:29]=[CH:28][C:27]([CH2:30][N:31]2[CH2:39][C:38]3[C:33](=[CH:34][CH:35]=[CH:36][C:37]=3[F:40])[C:32]2=[O:41])=[CH:26][CH:25]=1)[C:21](O)=[O:22].O.ON1C2C=CC=CC=2N=N1.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>CN(C=O)C.O>[F:44][C:18]([F:17])([F:43])[CH:19]([CH3:42])[CH:20]([C:24]1[CH:25]=[CH:26][C:27]([CH2:30][N:31]2[CH2:39][C:38]3[C:33](=[CH:34][CH:35]=[CH:36][C:37]=3[F:40])[C:32]2=[O:41])=[CH:28][CH:29]=1)[C:21]([NH:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH:5]=[CH:6][CH:7]=1)=[O:22]
Reactant: CC(C(C(=O)O)c1ccc(CN2Cc3c(F)cccc3C2=O)cc1)C(F)(F)F
Reactant: CC(C)(C)OC(=O)CCc1cccc(N)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C(C(=O)Nc1cccc(CCC(=O)OC(C)(C)C)c1)c1ccc(CN2Cc3c(F)cccc3C2=O)cc1)C(F)(F)F
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
215.3 mg (0.89 mmol) of tert-butyl 3-(3-aminophenyl)propanoate were added to a solution of 280.0 mg (0.71 mmol) of 4,4,4-trifluoro-2-{4-[(4-fluoro-1-oxo-1,3-dihydro-2H-isoindol-2-yl)methyl]phenyl}-3-methylbutanoic acid and 114.8 mg (0.85 mmol) of 1-hydroxy-1H-benzotriazole hydrate in 1.4 ml of DMF. At 0° C., 308 μl (1.77 mmol) of DIEA and then, a little at a time, 296.2 mg (0.78 mmol) of HATU were added to the resulting mixture. The reaction mixture was then slowly warmed to RT and subsequently stirred at RT for 2.5 h. The mixture was added to water and extracted three times with ethyl acetate. The combined organic phases were dried over magnesium sulfate and concentrated under reduced pressure. The crude product was purified by preparative RP-HPLC (mobile phase: acetonitrile/water gradient). This gave 333 mg (78.6% of theory) of the title compound.
Reaction SMILES: [CH3:1][N:2]([CH3:7])[S:3](Cl)(=[O:5])=[O:4].[CH3:8][N:9]1[C:21]2[CH2:20][CH2:19][CH:18]([CH2:22][C:23]3[N:24]=[CH:25][NH:26][C:27]=3[CH3:28])[C:17](=[O:29])[C:16]=2[C:15]2[C:10]1=[CH:11][CH:12]=[CH:13][CH:14]=2.C(N(CC)CC)C.CCCCCC>ClCCl>[CH3:1][N:2]([CH3:7])[S:3]([N:26]1[C:27]([CH3:28])=[C:23]([CH2:22][CH:18]2[C:17](=[O:29])[C:16]3[C:15]4[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=4)[N:9]([CH3:8])[C:21]=3[CH2:20][CH2:19]2)[N:24]=[CH:25]1)(=[O:5])=[O:4]
Reactant: Cc1[nH]cnc1CC1CCc2c(c3ccccc3n2C)C1=O
Reactant: CN(C)S(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCCCCC
Solvent: CCN(CC)CC
Product: Cc1c(CC2CCc3c(c4ccccc4n3C)C2=O)ncn1S(=O)(=O)N(C)C

Procedure:
A solution of dimethylsulphamoyl chloride (0.16 ml) in dry dichloromethane was added to a stirred solution of 1,2,3,9-tetrahydro-9-methyl -3-[(5-methyl-1H-imidazol-4-yl)methyl]-4H-carbazol-4-one (438 mg) and triethylamine (0.25 ml) in dry dichloromethane (30 ml) and the mixture was heated at reflux for 18 h. After cooling the reaction mixture was adsorbed onto FCC silica which was then applied to a column and FCC eluting with System A (150:8:1) gave an oil, which solidified to a powder on trituration with dry hexane (30 ml). This powder was then further purified by dissolution in dry dichloromethane (30 ml) and crystallisation by addition of dry hexane (10 ml) to give the title compound (518 mg), m.p. 122°-124°.
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7](O)=O)=[CH:5][CH:4]=1)#[N:2].[CH3:12][N:13]([C:15]([NH2:17])=[S:16])[NH2:14].O=P(Cl)(Cl)Cl.C([O-])(O)=O.[Na+]>O1CCOCC1>[CH:3]1([N:17]=[C:15]2[S:16][C:7]([C:6]3[CH:10]=[CH:11][C:3]([C:1]#[N:2])=[CH:4][CH:5]=3)=[N:14][N:13]2[CH3:12])[CH2:11][CH2:10][CH2:6][CH2:5][CH2:4]1
Reactant: CN(N)C(N)=S
Reactant: N#Cc1ccc(C(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: C1COCCO1
Product: Cn1nc(-c2ccc(C#N)cc2)sc1=NC1CCCCC1
Temperature: 95 °C
Yield: 76.2 %

Procedure:
To a mixture of 4-cyanobenzoic acid (74.8 mmol, 11 g), 2-methylthiosemicarbazide (5a) (74.8 mmol, 13.42 g) in anhydrous dioxane (110 mL) at 70° C., POCl3 (89.65 mmol, 76.76 mL) was added, and the mixture was warmed at 95° C. for 4 hours. The solvent was removed by distillation under reduced pressure to give a crude material which was basified at pH 8-7 with a saturated solution of NaHCO3. The aqueous phase was extracted with dichloromethane. The organic layer was washed with water and saturated solution of NaCl, dried over magnesium sulfate, filtered, and distilled to give a residue which was purified by silica gel chromatography (eluted with a gradient of cyclohexane/ethyl acetate finishing with the ratio 90:10) to afford 8.5 g of the title compound. Yield: 42%.
Reaction SMILES: [CH2:1]([C:8]1[S:9][C:10]([CH3:29])=[C:11]([CH3:28])[C:12]=1[C:13]([C:15]1[CH:20]=[CH:19][C:18]([O:21]C)=[C:17]([CH:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)[CH:16]=1)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B(Br)(Br)Br.O>C(Cl)Cl>[CH:23]1([C:17]2[CH:16]=[C:15]([C:13]3[C:12]4[C:11]([CH3:28])=[C:10]([CH3:29])[S:9][C:8]=4[CH:1]=[C:2]4[C:7]=3[CH:6]=[CH:5][CH:4]=[CH:3]4)[CH:20]=[CH:19][C:18]=2[OH:21])[CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: COc1ccc(C(=O)c2c(Cc3ccccc3)sc(C)c2C)cc1C1CCCC1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: Cc1sc2cc3ccccc3c(-c3ccc(O)c(C4CCCC4)c3)c2c1C
Temperature: 25 °C
Reaction time: 22 h
Yield: 78 %

Procedure:
To (2-benzyl4,5-dimethyl-thiophen-3-yl)-(3-cyclopentyl-4-methoxy-phenyl)-methanone (4.8 g, 11.7 mmol) in anhydrous methylene chloride (70 mL) at -78° C. under nitrogen was added dropwise over a period of 20 min boron tribromide (3.6 mL, 37.6 mmol). The reaction mixture was then allowed to stir at room temperature for 22 h. The solution was poured onto a mixture of ice and water (600 mL) and extracted with diethyl ether (800 mL). The diethyl ether layer was washed twice with water (500 mL) and once with brine (500 mL). Concentration under reduced pressure and chromatography with petroleum ether:ethyl acetate (97:3) gave the title compound as a white solid (3.4 g, 78%): mp 156-158° C.; (DMSO-d6) δ 9.48 (s, 1 H), 8.42 (s, 1 H), 7.93 (d, 1 H), 7.46-7.41 (m, 2 H), 7.35-7.30 (m, 1 H), 7.00 (s, 1 H), 6.95-6.90 (m, 2 H), 3.38-3.28 (m, 1 H), 2.39 (s, 3 H), 1.99-1.90 (m, 2 H), 1.68-1.47 (m, 6 H), 1.60 (s, 3 H). MS(EI): [M+] 372. Anal. Calc. for C25H24OS: C, 80.60, H, 6.49, N, 0.00. Found: C, 80.39, H, 6.43, N, 0.04.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:11]2[CH2:15][CH2:14][NH:13][C:12]2=[O:16])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].ClS([N:21]=[C:22]=[O:23])(=O)=O.O>C(OCC)(=O)C>[NH2:21][C:22]([N:13]1[CH2:14][CH2:15][N:11]([C:5]2[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=2)[C:12]1=[O:16])=[O:23]
Reactant: COc1ccc(N2CCNC2=O)cc1OC
Reactant: O=C=NS(=O)(=O)Cl
Solvent: CCOC(C)=O
Solvent: O
Product: COc1ccc(N2CCN(C(N)=O)C2=O)cc1OC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 13.33 g (60 mmol) of 1-(3,4-dimethoxyphenyl)-2-imidazolidinone in 150 ml of ethyl acetate was cooled to 0° C., and 8.92 g (63 mmol) of chlorosulfonylisocyanate was added dropwise. The mixture was stirred for one hour at room temperature. To the resulting thick suspension was added 50 ml of water, and the mixture was stirred until two clear layers were formed. The aqueous phase was separated and stored in the refrigerator overnight. The precipitate was filtered off by suction, washed with water and dried in vacuo; yield: 11.04 g; melting point 240° C.
Reaction SMILES: [C:1]([C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]([CH2:13][C:14]([OH:16])=O)[N:5]=1)(=[O:3])[NH2:2].[Br:17][C:18]1[N:23]=[C:22]([NH:24][C:25]([C@@H:27]2[CH2:32][C@@H:31]3[C@@H:29]([CH2:30]3)[NH:28]2)=[O:26])[CH:21]=[CH:20][CH:19]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[Br:17][C:18]1[N:23]=[C:22]([NH:24][C:25]([C@@H:27]2[CH2:32][C@@H:31]3[C@@H:29]([CH2:30]3)[N:28]2[C:14](=[O:16])[CH2:13][N:6]2[C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[C:4]([C:1]([NH2:2])=[O:3])=[N:5]2)=[O:26])[CH:21]=[CH:20][CH:19]=1
Reactant: O=C(Nc1cccc(Br)n1)[C@@H]1C[C@H]2C[C@H]2N1
Reactant: NC(=O)c1nn(CC(=O)O)c2ccccc12
Agent: CN(C)C(On1nnc2ccccc21)=[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: NC(=O)c1nn(CC(=O)N2[C@@H]3C[C@@H]3C[C@H]2C(=O)Nc2cccc(Br)n2)c2ccccc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(3-Carbamoyl-indazol-1-yl)-acetic acid (130 mg, 0.59 mmol, prepared as described in Scheme A25), (1R,3S,5R)-2-aza-bicyclo[3.1.0]hexane-3-carboxylic acid (6-bromo-pyridin-2-yl)-amide (2 TFA salt, 303 mg, 0.59 mmol) and HBTU (337 mg, 0.89 mmol) were dissolved in DMF (3 mL). DIPEA (406 μL, 2.37 mmol) was added and the reaction mixture was stirred at 25° C. for 1 h. The crude reaction mixture was purified by preparative HPLC (Waters Sunfire C18-OBD, 5 μm, 30×100 mm, flow: 40 mL/min, eluent: 20% to 100% CH3CN in H2O in 25 min, CH3CN and H2O containing 0.1% TFA). The pure fractions were combined, neutralized with an aqueous saturated solution of NaHCO3 and extracted with CH2Cl2 to give the desired compound. TLC, Rf (CH2Cl2/MeOH 9:1)=0.55; MS: 483.1/485.1 [M+H]+, 965.4/967.4 [2M+H]+, 982.4/984.3 [2M+NH4]+, 481.1/483.2 [M−H]−, 527.2/529.1 [M+HCOO]−; tR (HPLC conditions a): 2.79 min. Alternatively, for final compounds containing a basic residue: the pure HPLC fractions were combined, CH3CN was evaporated under reduced pressure, the resulting aqueous solution was adjusted to pH 8-9 by addition of an aqueous saturated solution of NaHCO3, extracted with CH2Cl2 (×3), the combined organic extracts were dried (Na2SO4) and concentrated under vacuum.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:16]3[C:11](=[CH:12][C:13]([CH:17]=O)=[CH:14][CH:15]=3)[CH2:10][O:9]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl.[NH2:27][OH:28].O>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:16]3[C:11](=[CH:12][C:13]([CH:17]=[N:27][OH:28])=[CH:14][CH:15]=3)[CH2:10][O:9]2)=[CH:4][CH:3]=1
Reactant: O=Cc1ccc2c(c1)COC2c1ccc(F)cc1
Reactant: NO
Agent: Cl
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: ON=Cc1ccc2c(c1)COC2c1ccc(F)cc1
Temperature: 2.5 °C
Yield: 79.2 %

Procedure:
1-(4′-Fluorophenyl)-1,3-dihydroisobenzofuran-5-carbaldehyde (5.96 g) was dissolved in toluene (30 ml) and triethylamine (2.75 g) was flown in. Thereto was added hydroxylamine hydrochloride (1.88 g) and the mixture was reacted at 80-90° C. for 1 hr. Hot water (30 ml) was added to the reaction mixture and the mixture was partitioned while hot at 90° C. The organic layer was cooled to 0-5° C. and the resulting crystals were collected by filtration to give the title compound (5.02 9, yield:79.2%).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[N:6][C:7]([C@@H:17]([NH2:19])[CH3:18])=[C:8]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)[CH:9]=2)[CH:4]=[CH:3]1.Cl[C:21]1[N:29]=[C:28]([NH2:30])[N:27]=[C:26]2[C:22]=1[N:23]=[CH:24][NH:25]2.CCN(CC)CC>CN(C=O)C>[CH3:1][N:2]1[C:10]2[C:5](=[N:6][C:7]([C@@H:17]([NH:19][C:21]3[N:29]=[C:28]([NH2:30])[N:27]=[C:26]4[C:22]=3[N:23]=[CH:24][NH:25]4)[CH3:18])=[C:8]([N:11]3[CH2:12][CH2:13][O:14][CH2:15][CH2:16]3)[CH:9]=2)[CH:4]=[CH:3]1
Reactant: C[C@H](N)c1nc2ccn(C)c2cc1N1CCOCC1
Reactant: Nc1nc(Cl)c2nc[nH]c2n1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C[C@H](Nc1nc(N)nc2[nH]cnc12)c1nc2ccn(C)c2cc1N1CCOCC1
Temperature: 90 °C
Reaction time: 8 h
Yield: 25.2 %

Procedure:
To a 10 mL vial were added (S)-1-(1-methyl-6-morpholino-1H-pyrrolo[3,2-b]pyridin-5-yl)ethanamine (100 mg, 0.384 mmol), 6-chloro-9H-purin-2-amine (65.1 mg, 0.384 mmol) and Et3N (0.11 mL, 0.77 mmol) in DMF (3 mL). The resulting yellow solution was heated to 90° C. and stirred overnight. The reaction mixture was purified by preparative HPLC eluting with 20-40% ACN in water (with 0.05% ammonium formate). The fractions containing the desired product were combined and lyophilized to give the title compound as a white solid (38 mg, 25%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.38-1.52 (m, 4 H), 2.68-2.86 (m, 3 H), 3.01-3.18 (m, 3 H), 3.69-3.95 (m, 9 H), 5.62-5.82 (m, 2 H), 5.88-6.08 (m, 1 H), 6.46-6.59 (m, 2 H), 6.74-6.92 (m, 1 H), 7.52-7.59 (m, 1 H), 7.59-7.74 (m, 1 H), 7.76-7.90 (m, 1 H), 12.00-12.22 (m, 1 H); ESI-MS m/z [M+H]+ calc'd for C19H23N9O, 394. found 394.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[O:6][CH2:7][C:8]3[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=3[CH:10]([C:11]#[N:12])[C:4]=2[CH:3]=1.[H-].[Na+].[CH3:21][N:22]([CH3:27])[CH2:23][CH2:24][CH2:25]Cl>CN(C)C=O>[ClH:1].[Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[O:6][CH2:7][C:8]3[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=3[C:10]([C:11]#[N:12])([CH2:25][CH2:24][CH2:23][N:22]([CH3:27])[CH3:21])[C:4]=2[CH:3]=1
Reactant: CN(C)CCCCl
Reactant: N#CC1c2ccccc2COc2ccc(Cl)cc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C)CCCC1(C#N)c2ccccc2COc2ccc(Cl)cc21
Product: Cl
Temperature: 5 °C
Reaction time: 0.08 h
Yield: 31.2 %

Procedure:
2-Chloro-11-cyano-6,11-dihydrodibenz[b,e]oxepin (4.6 g; 0.017 mole) of Example 25B is dissolved in dry dimethylformamide (DMF) [40 ml] under nitrogen and cooled to 5° C. Sodium hydride (99%) (0.45 g; 0.018 mole) is added in one portion and stirred for five minutes. It is then brought to ambient temperature and stirred for thirty minutes. After cooling to 3° C. 3-dimethylaminopropyl chloride (2.18 g; 0.018 mole) in dry DMF (20 ml) is added dropwise. Upon completion of the addition, the reaction mixture is brought to ambient temperature for thirty minutes and then heated at 60° C. for eight hours. The reaction mixture is cooled and poured with stirring into 600 ml ice water. The resulting solid is filtered, dissolved in ether and extracted with 2 N HCl. The acidic aqueous portion is basified with 10% NaOH and the precipitate filtered and dried. The solid is dissolved in ether and treated with ethereal HCl. After filtering, the solid is washed with ether and dried. Recrystallization from acetonitrile provides 1.0 g (16%) of crystals of 2-chloro-11-cyano-11-[3(dimethylamino)propyl]-6,11-dihydrodibenz[b,e]oxepin hydrochloride, m.p. 217°-219° C.