Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1.[F:18][C:19]1[CH:20]=[C:21]([CH:25]=[CH:26][C:27]=1[F:28])[C:22](Cl)=[O:23]>>[F:18][C:19]1[CH:20]=[C:21]([CH:25]=[CH:26][C:27]=1[F:28])[C:22]([NH:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1)=[O:23]
Reactant: O=C(Cl)c1ccc(F)c(F)c1
Reactant: CN1CCC(c2c[nH]c3ccc(N)nc23)CC1
Product: CN1CCC(c2c[nH]c3ccc(NC(=O)c4ccc(F)c(F)c4)nc23)CC1
Yield: 85.9 %

Procedure:
Beginning with 0.010 gm (0.044 mMol) 5-amino-3-(1-methylpiperidin-4-yl)pyrrolo[3,2-b]pyridine and 0.007 mL (0.055 mMol) 3,4-difluorobenzoyl chloride, 0.014 gm (80%) of the title compound were prepared essentially by the procedure described in Example 7.
Reaction SMILES: [CH2:1]([N:3]([CH2:37][CH3:38])[CH2:4][CH2:5][CH2:6][NH:7][C:8]1[N:9]=[C:10]([C:27]2[CH:28]=[C:29]([CH:33]=[CH:34][C:35]=2[CH3:36])[C:30](O)=[O:31])[C:11]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([C:19]3[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=3[F:26])[C:12]=2[N:13]=1)[CH3:2].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.Cl.[CH2:71]([S:73][CH2:74][CH2:75][NH2:76])[CH3:72]>CN(C=O)C>[CH2:37]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][CH2:6][NH:7][C:8]1[N:9]=[C:10]([C:27]2[CH:28]=[C:29]([CH:33]=[CH:34][C:35]=2[CH3:36])[C:30]([NH:76][CH2:75][CH2:74][S:73][CH2:71][CH3:72])=[O:31])[C:11]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([C:19]3[C:20]([F:26])=[CH:21][CH:22]=[CH:23][C:24]=3[F:25])[C:12]=2[N:13]=1)[CH3:38]
Reactant: CCN(CC)CCCNc1nc(-c2cc(C(=O)O)ccc2C)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Reactant: CCSCCN
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCSCCNC(=O)c1ccc(C)c(-c2nc(NCCCN(CC)CC)nc3c2ccc(=O)n3-c2c(F)cccc2F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 23 %

Procedure:
To the compound 3-[2-{[3-(diethylamino)propyl]amino}-8-(2,6-difluorophenyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl]-4-methylbenzoic acid (26 mg, 0.05 mmol) in DMF (0.5 mL) were added HBTU (28 mg, 0.075 mmol), triethylamine (21.1 uL, 0.15 mmol) and [2-(ethylthio)ethyl]amine hydrochloride (14.2 mg, 0.1 mmol). The mixture was stirred at rt overnight. Separation by HPLC with TFA, followed by neutralization with SPE amine cartridge afforded the title compound (7 mg, 23%). LC-MS m/z 607 (M+H)+.
Reaction SMILES: [CH2:1]([CH:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:15]([O:17]C)=[O:16])[CH:13]=2)[CH2:8][CH2:7][N:6]1[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:2][CH2:3][CH3:4].O.[OH-].[Li+]>O1CCOCC1.CO.O>[C:22]([O:21][C:19]([N:6]1[CH2:7][CH2:8][C:9]2[C:14](=[CH:13][C:12]([C:15]([OH:17])=[O:16])=[CH:11][CH:10]=2)[CH:5]1[CH2:1][CH2:2][CH2:3][CH3:4])=[O:20])([CH3:25])([CH3:24])[CH3:23]
Reactant: CCCCC1c2cc(C(=O)OC)ccc2CCN1C(=O)OC(C)(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1COCCO1
Solvent: O
Product: CCCCC1c2cc(C(=O)O)ccc2CCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 24 h
Yield: 61.5 %

Procedure:
To a solution of 2-tert-butyl 7-methyl 1-butyl-3,4-dihydroisoquinoline-2,7(1H)-dicarboxylate prepared in step 2 (347 mg, 1.0 mmol) in 2:1:1 dioxane/methanol/water (6.6 mL) was added lithium hydroxide monohydrate (125 mg, 3.0 mmol) and the reaction mixture stirred 24 h at room temperature. The reaction mixture was concentrated under reduced pressure and the solid residue partitioned between ethyl acetate and water. The aqueous phase was acidified with 1 N hydrochloric acid to pH 1 and extracted several times with 3:1 chloroform/2-propanol. The combined organic phases were washed with water and saturated sodium chloride, dried (sodium sulfate), filtered, and concentrated under reduced pressure to provide 2-(tert-butoxycarbonyl)-1-butyl-1,2,3,4-tetrahydroisoquinoline-7-carboxylic acid (205 mg). ESI MS m/z 332 [M−H]−.
Reaction SMILES: [CH:1]([C:4]1[C:5]([O:13][CH3:14])=[CH:6][C:7]([CH3:12])=[C:8]([CH:11]=1)[CH:9]=O)([CH3:3])[CH3:2].[Cl:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][C:20](=[O:25])[CH2:19]2>>[Cl:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][C:20](=[O:25])[C:19]2=[CH:9][C:8]1[CH:11]=[C:4]([CH:1]([CH3:3])[CH3:2])[C:5]([O:13][CH3:14])=[CH:6][C:7]=1[CH3:12]
Reactant: COc1cc(C)c(C=O)cc1C(C)C
Reactant: O=C1Cc2cc(Cl)ccc2N1
Product: COc1cc(C)c(C=C2C(=O)Nc3ccc(Cl)cc32)cc1C(C)C

Procedure:
5-Isopropyl-4-methoxy-2-methylbenzaldehyde was condensed with 5-chloro-2-oxindole to give 0.3 g of 5-Chloro-3-(5-isopropyl-4-methoxy-2-methylbenzylidene)-1,3-dihydroindol-2-one as a yellow-orange solid.
Reaction SMILES: C([O:4][C@@H:5]1[CH2:9][C:8](=O)[N:7]([C@@H:11]2[CH2:16][CH2:15][CH2:14][CH2:13][C@H:12]2[O:17][CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[C:22]([O:34][CH3:35])[CH:21]=2)[C:6]1=O)(=O)C.B.C1COCC1.CO>C1COCC1>[CH2:27]([O:26][C:23]1[CH:24]=[CH:25][C:20]([CH2:19][CH2:18][O:17][C@@H:12]2[CH2:13][CH2:14][CH2:15][CH2:16][C@H:11]2[N:7]2[CH2:8][CH2:9][C@@H:5]([OH:4])[CH2:6]2)=[CH:21][C:22]=1[O:34][CH3:35])[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: COc1cc(CCO[C@@H]2CCCC[C@H]2N2C(=O)C[C@@H](OC(C)=O)C2=O)ccc1OCc1ccccc1
Agent: B
Solvent: C1CCOC1
Solvent: CO
Product: COc1cc(CCO[C@@H]2CCCC[C@H]2N2CC[C@@H](O)C2)ccc1OCc1ccccc1
Temperature: 80 °C
Reaction time: 3 h
Yield: 119.4 %

Procedure:
To a solution of (1R,2R)-1-{2-[2-(4-benzyloxy-3-methoxyphenyl)ethoxy]-cyclohexyl}-(3R)-2,5-dioxopyrrolidin-3-yl acetate (49.0 g, 100 mmol) in anhydrous THF (100 mL) under nitrogen was added slowly BH3.THF (1.0 M solution in THF, 400 mmol, 400 mL). The solution was heated to 80° C. and stirred for 3 hours. The solution was cooled to ambient temperature and methanol (100 mL) was added slowly until no more bubbling was observed. The solution was concentrated and methanolic HCl (1.25 M solution in CH3OH, 500 mL) was added. The solution was heated to 80° C. and stirred for 1 hour. The cooled solution was then concentrated to afford (1R,2R)-1-{2-[2-(4-benzyloxy-3-methoxyphenyl)ethoxy]cyclohexyl}-(3R)-pyrrolidin-3-ol (50.8 g, quantitative yield) as a yellow syrup. The crude product was used in the next step without further purification; 1H NMR (400 MHz, CDCl3) δ 11.45 (br, s, 1H), 7.50-7.10 (m, 5H), 6.90-6.60 (m, 3H), 4.22 (br, s, 1H), 4.00-3.85 (m, 5H), 3.75-3.55 (m, 2H), 3.35-2.50 (m, 7H), 2.45-2.20 (m, 2H), 2.08 (br, s, 1H), 1.90-1.50 (m, 3H), 1.35-1.05 (m, 6H); MS (ESI): 426.2 [M+H]+
Reaction SMILES: C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(O[C:40]([C@H:42]1[C@@H:47]([NH:48][CH2:49][C:50]2[CH:55]=[CH:54][C:53]([F:56])=[CH:52][CH:51]=2)[C@H:46]2[CH2:57][C@@H:43]1[CH2:44][CH2:45]2)=[O:41])C.[I:58][C:59]1[CH:74]=[CH:73][C:62]2[NH:63][C:64]([CH2:69][C:70](O)=[O:71])=[N:65][S:66](=[O:68])(=[O:67])[C:61]=2[CH:60]=1.[O-]CC.[Na+].C(O)C>CN(C)C=O>[F:56][C:53]1[CH:52]=[CH:51][C:50]([CH2:49][N:48]2[C:70](=[O:71])[C:69]([C:64]3[NH:63][C:62]4[CH:73]=[CH:74][C:59]([I:58])=[CH:60][C:61]=4[S:66](=[O:68])(=[O:67])[N:65]=3)=[C:40]([OH:41])[C@H:42]3[C@@H:47]2[C@H:46]2[CH2:57][C@@H:43]3[CH2:44][CH2:45]2)=[CH:55][CH:54]=1
Reactant: CCOC(=O)[C@@H]1[C@H]2CC[C@H](C2)[C@@H]1NCc1ccc(F)cc1
Reactant: O=C(O)CC1=NS(=O)(=O)c2cc(I)ccc2N1
Agent: CC[O-]
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCO
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C1C(C2=NS(=O)(=O)c3cc(I)ccc3N2)=C(O)[C@@H]2[C@H]3CC[C@H](C3)[C@@H]2N1Cc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 19 h
Yield: 49.3 %

Procedure:
N,N-diisopropylethylamine (1.79 mL, 10.3 mmol) and (benzotriazol-1yloxy)-tris(dimethylamino)-phosphoniumhexafluorophosphate (1.52 g, 3.44 mmol) were added sequentially to a solution of (1S,2R,3S,4R)-3-(4-fluoro-benzylamino)-bicyclo[2.2.1]heptane-2-carboxylic acid ethyl ester (prepared as described in Example 6l, 1.0 g, 3.43 mmol) and (7-iodo-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-acetic acid (prepared as described in US patent application US 2008/0031852, 1.26 g, 3.44 mmol) in N,N-dimethylformamide (25 mL) at 25° C. The resulting solution was stirred at 25° C. for 19 h, and then was concentrated in vacuo. The residue was partitioned between 1.0M aqueous hydrochloric acid solution (150 mL) and ethyl acetate (2×150 mL). The organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The resulting orange oil was dissolved in ethanol (50 mL) at 25° C. A 21 wt. % solution of sodium ethoxide in ethanol (3.33 mL, 10.3 mmol) was added and the reaction mixture was heated at 60° C. for 3 h. After cooling to 25° C., the reaction mixture was concentrated in vacuo to approximately 5 mL volume and was then partitioned between 1.0M aqueous hydrochloric acid solution (150 mL) and ethyl acetate (2×150 mL). The organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography (Teledyne Isco RediSep column; 0 to 60% ethyl acetate in hexanes) to afford the desired product, (1R,2S,7R,8S)-3-(4-fluoro-benzyl)-6-hydroxy-5-(7-iodo-1,1-dioxo-1, 4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-3-aza-tricyclo[6.2.1.02,7]undec-5-en-4-one (1.0 g, 1.69 mmol, 49%), as a pale yellow foam. 1H NMR (400 MHz, DMSO-d6) δ: 1.15-1.21 (3H, m), 1.38-1.41 (1H, m), 1.46-1.61 (3H, m), 2.62 (1H, d, J=2.4 Hz), 2.98 (1H, d, J=9.4 Hz), 3.52 (1H, d, J=9.3 Hz), 4.40 (1H, d, J=15.7 Hz), 4.95 (1H, d, J=15.6 Hz), 7.14 (2H, d, J=17.9 Hz), 7.11-7.16 (2H, m), 7.30-7.34 (3H, m), 7.97 (1H, dd, J1=2.3 Hz, J2=8.6 Hz), 8.07 (1H, d, J=1.5 Hz). LC-MS (ESI) calcd for C24H21FIN3O4S 593.03, found 594.2 [M+H+].
Reaction SMILES: Br[CH2:2][C:3]1[N:8]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=2)[C:7](=[O:19])[NH:6][CH:5]([C:20]2[CH:25]=[CH:24][C:23]([C:26]#[N:27])=[CH:22][C:21]=2[S:28]([CH3:31])(=[O:30])=[O:29])[C:4]=1[C:32](OCC)=[O:33].[NH2:37][CH2:38][CH2:39][OH:40]>C(#N)C>[OH:40][CH2:39][CH2:38][N:37]1[C:32](=[O:33])[C:4]2[CH:5]([C:20]3[CH:25]=[CH:24][C:23]([C:26]#[N:27])=[CH:22][C:21]=3[S:28]([CH3:31])(=[O:30])=[O:29])[NH:6][C:7](=[O:19])[N:8]([C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:16])[F:17])[CH:10]=3)[C:3]=2[CH2:2]1
Reactant: CCOC(=O)C1=C(CBr)N(c2cccc(C(F)(F)F)c2)C(=O)NC1c1ccc(C#N)cc1S(C)(=O)=O
Reactant: NCCO
Solvent: CC#N
Product: CS(=O)(=O)c1cc(C#N)ccc1C1NC(=O)N(c2cccc(C(F)(F)F)c2)C2=C1C(=O)N(CCO)C2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(rac)-Ethyl 6-(bromomethyl)-4-[4-cyano-2-(methylsulfonyl)phenyl]-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carboxylate (200 mg, 0.34 mmol; Example 13A) was dissolved in acetonitrile (5 ml), 2-aminoethanol (62.5 mg, 1.02 mmol) was added and the mixture was stirred at RT overnight. The reaction mixture was then purified directly by preparative HPLC (column: Kromasil C18, 125 mm×20 mm, 5 μm, 100 Å; mobile phase A: water with 0.01% formic acid, mobile phase B: acetonitrile; gradient: 0 min 10% B→2 min 10% B→9 min 90% B→12 min 90% B→12.1 min 10% B→15 min 10% B; flow rate: 0.35 ml/min; UV detection: 254 nm). This gave 98 mg (54% of theory) of the title compound.
Reaction SMILES: C([O:8][C:9](=[O:24])[C@@H:10]1[CH2:14][C@@H:13]([C:15]#[N:16])[CH2:12][N:11]1[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])C1C=CC=CC=1.C(OC(N1C[C@H](CN)C[C@H]1C(O)=O)=O)(C)(C)C>>[C:20]([O:19][C:17]([N:11]1[CH2:12][C@@H:13]([CH2:15][NH2:16])[CH2:14][C@H:10]1[C:9]([OH:24])=[O:8])=[O:18])([CH3:23])([CH3:22])[CH3:21]
Reactant: CC(C)(C)OC(=O)N1C[C@H](C#N)C[C@H]1C(=O)OCc1ccccc1
Agent: CC(C)(C)OC(=O)N1C[C@H](CN)C[C@H]1C(=O)O
Product: CC(C)(C)OC(=O)N1C[C@@H](CN)C[C@H]1C(=O)O
Yield: 67 %

Procedure:
Cyano acid benzyl acid ester 36 (3.0 g, 9.1 mmol) was hydrogenated as for the synthesis of 12, and the product was crystallized from water/ethanol/ether to give 1.5 g (67% yield), m.p.=230°-231° C. 1H NMR (D2O) δ1.41/1.46 (2s, 9H), 2.11 (m, 1H), 2.60 (m, 1H), 3.12 (m, 2H), 3.73 (m, 1H), 4.17 (dd, J=9.0/3.9,1H).
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[CH:10]=[C:9]3[C:12](=[O:15])[CH2:13][O:14][C:8]3=[CH:7][C:6]=2[CH2:5][C:4]1=[O:16])[CH3:2].[BH4-].[Na+].[H-]>CO>[CH2:1]([N:3]1[C:11]2[CH:10]=[C:9]3[CH:12]([OH:15])[CH2:13][O:14][C:8]3=[CH:7][C:6]=2[CH2:5][C:4]1=[O:16])[CH3:2]
Reactant: CCN1C(=O)Cc2cc3c(cc21)C(=O)CO3
Agent: [BH4-]
Agent: [H-]
Agent: [Na+]
Solvent: CO
Product: CCN1C(=O)Cc2cc3c(cc21)C(O)CO3
Reaction time: 0.5 h

Procedure:
To a slurry of 30 g. (0.138 mole) of 5-ethyl-3,6-dioxo-2,3,6,7-tetrahydro-furo[2,3-f]indole (Preparation A) in 1 l. of methanol cooled to 0° C. was added 5.24 g. (0.138 mole) of sodium borohydride. After 30 minutes an additional 2.6 g. (68.4 moles) of hydride was added and the reaction mixture allowed to stir for 1.5 hours. The reaction mixture was quenched by the addition of 50 ml. of a saturated brine solution and the resulting solution concentrated in vacuo. The residue was partitioned between 1 l. of a saturated brine solution and 1 l. of dichloromethane. The organic layer was separated and held, and the aqueous layer was extracted (4×300 ml.) with fresh dichloromethane. The organic extracts were combined, dried over magnesium sulfate and concentrated to give a quantitative yield of product. A small sample was recrystallized from diethyl ether, m.p. 144°-145° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][C:9]([C@@H:11]2[CH2:15][CH2:14][N:13](C(OCC3C=CC=CC=3)=O)[N:12]2[C:26](=[O:46])[C@@H:27]([CH2:34][N:35]([CH:44]=[O:45])[O:36]CC2C=CC=CC=2)[CH2:28][CH:29]2[CH2:33][CH2:32][CH2:31][CH2:30]2)=[O:10])[CH:5]=[CH:4][CH:3]=1>CO.[OH-].[OH-].[Pd+2]>[Cl:1][C:2]1[N:7]=[C:6]([NH:8][C:9]([C@@H:11]2[CH2:15][CH2:14][NH:13][N:12]2[C:26](=[O:46])[C@@H:27]([CH2:34][N:35]([CH:44]=[O:45])[OH:36])[CH2:28][CH:29]2[CH2:33][CH2:32][CH2:31][CH2:30]2)=[O:10])[CH:5]=[CH:4][CH:3]=1
Reactant: O=CN(C[C@@H](CC1CCCC1)C(=O)N1[C@H](C(=O)Nc2cccc(Cl)n2)CCN1C(=O)OCc1ccccc1)OCc1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: O=CN(O)C[C@@H](CC1CCCC1)C(=O)N1NCC[C@H]1C(=O)Nc1cccc(Cl)n1
Reaction time: 0.33 h
Yield: 31.2 %

Procedure:
To a solution of phenylmethyl (3S)-3-{[(6-chloro-2-pyridinyl)amino]carbonyl}-2-[(2R)-3-cyclopentyl-2-({formyl[(phenylmethyl)oxy]amino}methyl)propanoyl]-1-pyrazolidinecarboxylate (268 mg, 0.413 mmol) in methanol (8 ml) was added 20% palladium hydroxide on carbon (80 mg, 0.413 mmol). The mixture was hydrogenated under balloon pressure for 1 h 20 min. and then filtered. The filtrate was purified by reverse-phase HPLC to yield (3S)—N-(6-chloro-2-pyridinyl)-2-((2R)-3-cyclopentyl-2-{[formyl(hydroxy)amino]methyl}propanoyl)-3-pyrazolidinecarboxamide (55 mg, 0.129 mmol, 31% yield). LC/MS: (M+H)+: 423.9. 1H NMR (400 MHz, METHANOL-d4) δ ppm 1.06-1.31 (m, 2H) 1.31-1.47 (m, 1H) 1.47-1.69 (m, 4H) 1.69-1.98 (m, 4H) 2.11-2.37 (m, 1H) 2.40-2.66 (m, 1H) 2.79-3.01 (m, 1H) 3.17-3.31 (m, 1H) 3.51 (dd, J=14.15, 4.55 Hz, 1H) 3.61-3.85 (m, 2H) 3.95 (td, J=9.54, 4.93 Hz, 1H) 4.60-4.76 (m, 1H) 7.14 (d, J=7.83 Hz, 1H) 7.75 (t, J=7.96 Hz, 1H) 7.88 (s, 1H) 8.08 (d, J=8.08 Hz, 1H).
Reaction SMILES: Cl.Cl.[CH3:3][NH:4][NH:5][CH3:6].C(=O)([O-])[O-].[K+].[K+].O1CCCC1.[Br:18][C:19]1[CH:20]=[C:21]([Br:43])[C:22]2[N:27]=[C:26]([C:28]3[N:29]([C:34]4[C:39]([Cl:40])=[CH:38][CH:37]=[CH:36][N:35]=4)[CH:30]=[C:31]([Br:33])[CH:32]=3)[O:25][C:24](=[O:41])[C:23]=2[CH:42]=1>O>[Br:33][C:31]1[CH:32]=[C:28]([C:26]([NH:27][C:22]2[C:21]([Br:43])=[CH:20][C:19]([Br:18])=[CH:42][C:23]=2[C:24]([N:4]([CH3:3])[NH:5][CH3:6])=[O:41])=[O:25])[N:29]([C:34]2[C:39]([Cl:40])=[CH:38][CH:37]=[CH:36][N:35]=2)[CH:30]=1
Reactant: O=c1oc(-c2cc(Br)cn2-c2ncccc2Cl)nc2c(Br)cc(Br)cc12
Reactant: CNNC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CNN(C)C(=O)c1cc(Br)cc(Br)c1NC(=O)c1cc(Br)cn1-c1ncccc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 79.6 %

Procedure:
To a mixture of 0.42 g of N,N′-dimethylhydrazine dihydrochloride, five drops of water, 0.87 g of potassium carbonate and 10 ml of tetrahydrofuran was added 0.59 g of 6,8-dibromo-2-[4-bromo-1-(3-chloro-2-pyridinyl)-1H-pyrrol-2-yl]-4H-3,1-benzoxazine-4-one. The resulting mixture was stirred at room temperature for 2 hours. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and an aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting residue was subjected to silica gel chromatography to obtain 0.52 g of 4-bromo-N-[4,6-dibromo-2-(N,N′-dimethylhydrazinocarbonyl)phenyl]-1-(3-chloro-2-pyridinyl)-1H-pyrrole-2-carboxamide of the formula:
Reaction SMILES: [CH3:1][NH:2][O:3][CH3:4].[CH3:5][C:6]1[C:11]([C:12](=[O:20])[C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)=[CH:10][CH:9]=[CH:8][C:7]=1[CH2:21][C:22]([OH:24])=O.C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)(Cl)Cl>[CH3:4][O:3][N:2]([CH3:1])[C:22](=[O:24])[CH2:21][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]([C:12](=[O:20])[C:13]2[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=2)[C:6]=1[CH3:5]
Reactant: Cc1c(CC(=O)O)cccc1C(=O)c1ccc(Cl)cc1
Reactant: CNOC
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClC(Cl)Cl
Product: CON(C)C(=O)Cc1cccc(C(=O)c2ccc(Cl)cc2)c1C
Temperature: 25 °C
Reaction time: 4 h

Procedure:
1 ml of N,O-dimethylhydroxylamine was added progressively to a mixture of 2.88 g of 2-methyl-3-(p-chlorobenzoyl)-phenylacetic acid and 2.06 g of dicyclohexylcarbodiimide in 50 ml of chloroform and the mixture was stirred for 4 hours at room temperature. The precipitate was filtered off and the filtrate was evaporated to dryness to obtain N-methoxy-N,2-dimethyl-3-(p-chlorobenzoyl)-phenylacetamide.
Reaction SMILES: [OH-].[Na+].[CH2:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][CH2:5][N:4]1[C:13]1[N:18]=[C:17]([CH3:19])[C:16]([CH:20]([CH2:25][CH2:26][CH3:27])[C:21]([O:23]C)=[O:22])=[C:15]([C:28]2[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=2)[N:14]=1>CO>[CH2:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][CH2:5][N:4]1[C:13]1[N:18]=[C:17]([CH3:19])[C:16]([CH:20]([CH2:25][CH2:26][CH3:27])[C:21]([OH:23])=[O:22])=[C:15]([C:28]2[CH:29]=[CH:30][C:31]([CH3:34])=[CH:32][CH:33]=2)[N:14]=1
Reactant: CCCC(C(=O)OC)c1c(C)nc(N2CCc3ccccc3C2)nc1-c1ccc(C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCC(C(=O)O)c1c(C)nc(N2CCc3ccccc3C2)nc1-c1ccc(C)cc1
Temperature: 100 °C
Yield: 71.6 %

Procedure:
A solution of sodium hydroxide 5N (1 mL) was added to a mixture of methyl 2-(2-(3,4-dihydroisoquinolin-2(1H)-yl)-4-methyl-6-p-tolylpyrimidin-5-yl)pentanoate (0.072 g; 0.168 mmol) in methanol (1 mL). The mixture was heated in a sealed tube at 100° C. for 18 h and then concentrated under reduced pressure. The residue was dissolved in water and the pH of the solution was adjusted between 2 and 3 by addition of a solution of hydrochloric acid 6N. The precipitate was collected by filtration and dried under reduced pressure over phosphorus pentoxide to give 0.050 g (72%) of the title compound as a yellow solid.
Reaction SMILES: [OH:1][C:2]1[C:9]([CH3:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.Cl.[NH2:12]O.C([O-])(=O)C.[Na+]>C(O)=O>[OH:1][C:2]1[C:9]([CH3:10])=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:12]
Reactant: Cc1cccc(C=O)c1O
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O=CO
Product: Cc1cccc(C#N)c1O

Procedure:
A solution of 2-hydroxy-3-methyl-benzaldehyde (1.13 g, 8.29 mmol), hydroxylamine hydrochloride (0.69 g, 9.9 mmol) and sodium acetate (0.8 g, 9.9 mmol) in formic acid (20 ml) is heated at reflux over night. The solvent is evaporated under reduced pressure and the residue is partitioned between water and ethyl acetate. The organic phase is dried and evaporated to dryness. Chromatography yields the title compound. (CDCl3, 400 MHz): 7.32 (m, 2H); 6.89 (t, 1H); 5.65 (s, 1H); 2.23 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH:8][C@H:9]([C:11]2[N:16]=[C:15]3[CH:17]=[CH:18][N:19]([CH3:20])[C:14]3=[CH:13][C:12]=2[N:21]2[CH2:26][CH2:25][CH2:24][C@@H:23]([N:27]3C(=O)C4C(=CC=CC=4)C3=O)[CH2:22]2)[CH3:10])[C:5]([C:38]#[N:39])=[C:4]([CH3:40])[N:3]=1.O.NN.NN>C(O)C.C(#N)C>[NH2:1][C:2]1[N:7]=[C:6]([NH:8][C@H:9]([C:11]2[N:16]=[C:15]3[CH:17]=[CH:18][N:19]([CH3:20])[C:14]3=[CH:13][C:12]=2[N:21]2[CH2:26][CH2:25][CH2:24][C@@H:23]([NH2:27])[CH2:22]2)[CH3:10])[C:5]([C:38]#[N:39])=[C:4]([CH3:40])[N:3]=1
Reactant: Cc1nc(N)nc(N[C@@H](C)c2nc3ccn(C)c3cc2N2CCC[C@@H](N3C(=O)c4ccccc4C3=O)C2)c1C#N
Agent: NN
Solvent: CCO
Solvent: CC#N
Solvent: O
Product: Cc1nc(N)nc(N[C@@H](C)c2nc3ccn(C)c3cc2N2CCC[C@@H](N)C2)c1C#N
Temperature: 60 °C
Yield: 26.7 %

Procedure:
To a 25 mL pear flask were added 2-amino-4-(((S)-1-(6-((R)-3-(1,3-dioxoisoindolin-2-yl)piperidin-1-yl)-1-methyl-1H-pyrrolo[3,2-b]pyridin-5-yl)ethyl)amino)-6-methylpyrimidine-5-carbonitrile (20 mg, 0.037 mmol) and hydrazine monohydrate (0.027 mL, 0.56 mmol) in ethanol (1 mL). The mixture was heated to 60° C. for 8 hours and then at room temperature overnight. Additional hydrazine (30 eq, 0.054 mL) was added and the mixture was heated for another 4 hours. The crude reaction mixture was diluted with acetonitrile and was then purified by preparative HPLC (basic mode, 20-45% ACN/water gradient). The product-containing fractions were combined and lyophilized to give the title compound as a light brown solid (4.0 mg, 28%). The absolute configuration of the stereocenter on the piperidine ring was not determined, but was assigned the opposite configuration of EXAMPLE 5. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.41 (d, J=6.57 Hz, 3H), 1.72-1.99 (m, 3H), 2.09-2.22 (m, 1H), 2.27-2.36 (m, 3H), 2.56-2.73 (m, 3H), 3.47 (ddd, J=9.09, 7.20, 4.93 Hz, 1H), 3.59-3.66 (m, 1H), 3.67-3.73 (m, 3H), 5.19 (br s, 2H), 5.77-5.95 (m, 1H), 6.57 (d, J=3.28 Hz, 1H), 6.93-7.07 (m, 1H), 7.12-7.16 (m, 1H), 7.17-7.23 (m, 2H), 7.40 (s, 1H); ESI-MS m/z [M+H]+ calc'd for C21H27N9, 406. found 406.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([C:22]2[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:23]=2[Cl:29])[C@H:12]([CH3:21])[CH2:13][CH2:14][CH2:15][S:16]([NH:19][CH3:20])(=[O:18])=[O:17])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH2:30](S(Cl)(=O)=O)CCCC.CNC>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([C:22]2[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:23]=2[Cl:29])[C@H:12]([CH3:21])[CH2:13][CH2:14][CH2:15][S:16]([N:19]([CH3:30])[CH3:20])(=[O:17])=[O:18])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: CCCCCS(=O)(=O)Cl
Reactant: CNS(=O)(=O)CCC[C@@H](C)N(c1cc(Cl)ccc1Cl)S(=O)(=O)c1ccc(Cl)cc1
Agent: CNC
Product: C[C@H](CCCS(=O)(=O)N(C)C)N(c1cc(Cl)ccc1Cl)S(=O)(=O)c1ccc(Cl)cc1
Yield: 65 %

Procedure:
4-chloro-N-[2,5-dichlorophenyl]-N-[4-(dimethylaminosulfonyl)-1(R)-methylbutyl]-benzenesulfonamide was prepared analogous to 4-chloro-N-[2,5-dichlorophenyl]-N-[4-[(methylamino)sulfonyl]-1(R)-methylbutyl]benzenesulfonamide by reacting (4R)-4-[2,5-dichlorophenyl][4-chlorophenyl)sulfonyl]-amino]pentylsulfonyl chloride with dimethylamine. Yield=65%; MS (ESI+), 513 (M+H)+.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:27]=[CH:26][C:9]2[N:10]=[C:11]([NH:14][CH:15]3[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][C:22]=4[O:24][CH3:25])[CH2:17][CH2:16]3)[O:12][CH2:13][C:8]=2[CH:7]=1)=[O:4].[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1>C(#N)C>[CH3:25][O:24][C:22]1[CH:21]=[CH:20][CH:19]=[C:18]2[C:23]=1[CH:15]([NH:14][C:11]1[O:12][CH2:13][C:8]3[CH:7]=[C:6]([NH:5][C:3](=[O:4])[CH2:2][N:28]4[CH2:33][CH2:32][O:31][CH2:30][CH2:29]4)[CH:27]=[CH:26][C:9]=3[N:10]=1)[CH2:16][CH2:17]2
Reactant: COc1cccc2c1C(NC1=Nc3ccc(NC(=O)CCl)cc3CO1)CC2
Reactant: C1COCCN1
Solvent: CC#N
Product: COc1cccc2c1C(NC1=Nc3ccc(NC(=O)CN4CCOCC4)cc3CO1)CC2
Yield: 97.3 %

Procedure:
Prepared from the above described rac-2-chloro-N-[2-(7-methoxy-indan-1-ylamino)-4H-benzo[d][1,3]oxazin-6-yl]-acetamide (100 mg, 0.259 mmol) and morpholine (226 ul, 2.59 mmol) in acetonitrile (1 ml) according to the procedure described for Example 3 step B. Obtained the title compound as an off-white foam (110 mg, 97%), MS (ISP) m/e=437.2 [(M+H)+].