Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[C:12]([F:18])[C:11]=2[F:19])=[O:9])=[CH:6][N:5]=[C:4]([NH:20][CH:21]2[CH2:26][CH2:25][N:24]([S:27]([CH2:30][CH2:31][CH2:32]Cl)(=[O:29])=[O:28])[CH2:23][CH2:22]2)[N:3]=1.[NH:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1>>[NH2:1][C:2]1[C:7]([C:8]([C:10]2[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[C:12]([F:18])[C:11]=2[F:19])=[O:9])=[CH:6][N:5]=[C:4]([NH:20][CH:21]2[CH2:26][CH2:25][N:24]([S:27]([CH2:30][CH2:31][CH2:32][N:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)(=[O:29])=[O:28])[CH2:23][CH2:22]2)[N:3]=1
Reactant: C1COCCN1
Reactant: COc1ccc(F)c(F)c1C(=O)c1cnc(NC2CCN(S(=O)(=O)CCCCl)CC2)nc1N
Product: COc1ccc(F)c(F)c1C(=O)c1cnc(NC2CCN(S(=O)(=O)CCCN3CCOCC3)CC2)nc1N

Procedure:
The compound was prepared from [4-amino-2-[1-(3-chloro-propane-1-sulfonyl)-piperidin-4-ylamino]-pyrimidin-5-yl]-(2,3-difluoro-6-methoxy-phenyl)-methanone (Example 226) and morpholine (Aldrich) in an analogous manner as described in Example 227. HR-MS (ES, m/z) calculated for C24H33N6O5SF2 [(M+H)+] 555.2196, observed 555.2199.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[NH:18][N:17]=[N:16][N:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[H-].[Na+].[CH2:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CN(C=O)C>[CH2:21]([N:17]1[N:16]=[N:15][C:14]([CH:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)=[N:18]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2nnn[nH]2)CC1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: c1ccc(Cn2nnc(C3CCNCC3)n2)cc1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
A solution of 438 mg (1.7 mmol) of 1-(t-butoxycarbonyl)-4-(1H-tetrazol-5-yl)piperidine (from Step B) in 2 mL of DMF at 0° C. was treated with 83 mg (0.50 mmol) of NaH (60% in mineral oil) and 0.41 mL (3.4 mmol) of benzyl bromide. The resulting mixture was warmed to rt and stirred for 2.5 h. The mixture was partitioned between 50 mL of ether and 50 mL of water and the layers were separated. The organic layer was washed with 50 mL sat'd NaCl, dried over MgSO4 and concentrated. Flash chromatography using 2:1 v/v CH2Cl2/ether, then 1:2 v/v CH2Cl2/ether afforded 85 mg (15%) of 1-butoxycarbonyl)-4-((2-benzyl)tetrazol-5-yl)piperidine. Elution with 2:1 v/v EtOAc/CH2Cl2 afforded 95 mg (17%) of 1-butoxycarbonyl)-4-((1-benzyl)tetrazol-5-yl)piperidine. For 1-(butoxycarbonyl)-4-((2-benzyl)tetrazol-5-yl)piperidine: 1H NMR (500 MHz) δ1.47 (s, 9H), 1.76-1.84 (2H), 2.02-2.05 (2H), 2.91-2.95 (2H), 3.07-3.12 (m, 1H), 4.00-4.20 (2H), 5.71 (s, 2H), 7.35-7.40 (5H). For 1-(butoxycarbonyl)-4-((1-benzyl)tetrazol-5-yl)piperidine: 1H NMR (500 MHz) δ1.45 (s, 9H), 1.59-1.61 (2H), 1.76-1.84 (2H), 2.70-2.80 (2H), 2.85-2.89 (m, 1H), 4.00-4.20 (2H), 5.55 (s, 2H), 7.17-7.19 (2H), 7.36-7.39 (3H).
Reaction SMILES: [C:1]([C:5]1[N:9]=[C:8]([S:10][CH2:11][CH:12]2[O:16][CH2:15][CH2:14][O:13]2)[NH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:17][N:18]([CH3:22])[C:19](Cl)=[O:20].C(N(CC)CC)C>CN(C)C1C=CN=CC=1.O1CCCC1>[CH3:17][N:18]([CH3:22])[C:19]([N:7]1[C:8]([S:10][CH2:11][CH:12]2[O:16][CH2:15][CH2:14][O:13]2)=[N:9][C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])=[N:6]1)=[O:20]
Reactant: CN(C)C(=O)Cl
Reactant: CC(C)(C)c1n[nH]c(SCC2OCCO2)n1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN(C)C(=O)n1nc(C(C)(C)C)nc1SCC1OCCO1

Procedure:
3-t-Butyl-5-(1,3-dioxolan-2-yl-methylthio)-1H-1,2,4-triazole (7 g, 28.8 mmole), 2.8 ml (30.5 mmole) of dimethylcarbamoyl chloride, 8 ml (57 mmole) of triethylamine and 0.5 g (4.1 mmole) of 4-dimethylaminopyridine were dissolved in 50 ml of tetrahydrofuran (THF). The mixture was refluxed for four hours, concentrated in vacuo and partitioned between methylene chloride and dilute hydrochloric acid. The organic layer was separated, dried over magnesium sulfate, filtered and concentrated. Chromatography on silica gel using ethyl ether/hexane gave 1-dimethylcarbamoyl-3-t-butyl-5-(1,3-dioxolan-2-yl-methylthio)-1H-1,2,4triazole, an oil.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13](=[S:19])[CH:14]=[CH:15][NH:16]2)=[CH:11][C:10]=1[O:20][CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:23]1[S:24][C:25]([N+:28]([O-:30])=[O:29])=[CH:26][N:27]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([S:19][C:23]3[S:24][C:25]([N+:28]([O-:30])=[O:29])=[CH:26][N:27]=3)=[CH:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[O:20][CH3:21])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc2c(=S)cc[nH]c2cc1OCc1ccccc1
Reactant: O=[N+]([O-])c1cnc(Br)s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2c(Sc3ncc([N+](=O)[O-])s3)ccnc2cc1OCc1ccccc1

Procedure:
7-(Benzyloxy)-6-methoxy-1,4-dihydro-4-quinolinethione (14.8 g), 2-bromo-5-nitro-1,3-thiazole (10.4 g), potassium carbonate (10.3 g) and dimethylformamide (150 ml) were stirred together at room temperature for 50 minutes. After adding 800 ml of water to the reaction solution, the precipitated solid was filtered out and washed with ethyl acetate to obtain 13.4 g of a light ochre powder.
Reaction SMILES: [C:1](N1C=CN=C1)(N1C=CN=C1)=[O:2].[F:13][C:14]1[CH:39]=[CH:38][C:17]([NH:18][C:19]2[CH:35]=[C:34]([F:36])[C:33]([F:37])=[CH:32][C:20]=2[C:21]([NH:23][O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:22])=[CH:16][CH:15]=1>>[F:13][C:14]1[CH:15]=[CH:16][C:17]([N:18]2[C:19]3[C:20](=[CH:32][C:33]([F:37])=[C:34]([F:36])[CH:35]=3)[C:21](=[O:22])[N:23]([O:24][CH2:25][C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:1]2=[O:2])=[CH:38][CH:39]=1
Reactant: O=C(NOCc1ccccc1)c1cc(F)c(F)cc1Nc1ccc(F)cc1
Reactant: O=C(n1ccnc1)n1ccnc1
Product: O=c1c2cc(F)c(F)cc2n(-c2ccc(F)cc2)c(=O)n1OCc1ccccc1
Yield: 49.1 %

Procedure:
Using General Method 3, the reaction of carbonyldiimidazole (3.0 g, 18.4 mmol) and crude 2-(4-fluoro-anilino)-N-benzyloxy-4,5-difluoro-benzamide (Example U, 3.43 g, 9.2 mmol) provided 1.8 g of the title compound as a solid, mp 201-202° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][C:15]=2[CH:21]=O)[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[CH3:2].[CH2:24]([NH2:26])[CH3:25]>>[CH2:1]([O:3][C:4](=[O:23])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][C:15]=2[CH2:21][NH:26][CH2:24][CH3:25])[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[CH3:2]
Reactant: CCN
Reactant: CCOC(=O)Cc1ccc(OC)c(-c2cc(C)ccc2C=O)c1
Product: CCNCc1ccc(C)cc1-c1cc(CC(=O)OCC)ccc1OC

Procedure:
Prepared according to the procedure described in Example 33, Step 4, using the following starting materials: (2′-formyl-6-methoxy-5′-methyl-biphenyl-3-yl)-acetic acid ethyl ester and ethylamine (2M in THF).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[C:4]([F:11])[CH:3]=1>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:10])[CH3:9])=[C:4]([F:11])[CH:3]=1
Reactant: CC(=O)c1ccc(Br)cc1F
Solvent: ClCCl
Product: CC(O)c1ccc(Br)cc1F
Temperature: -30 °C
Reaction time: 0.25 h
Yield: 336.3 %

Procedure:
An oven dried 500 mL flask, was charged under nitrogen with (S)-2-methyl-CBS-oxazaborolidine 1M in toluene (5.02 mL) and dissolved in CH2Cl2 (250 mL). Me2-BH3 (30 mL, 60.27 mmol) was then added and cooled to −30° C. and reaction stirred for 15 minutes. (1-(4-Bromo-2-fluoro-phenyl)-ethanone (10.9 g, 50.23 mmol) from step 2 below was dissolved in CH2Cl2 (10 mL) and slowly added via addition funnel to the previous solution. The resulting reaction was stirred at 25° C. overnight. The solution was carefully quenched with MeOH, the solvent was removed in vacuo and the residue was purified by flash column chromatography (20% EtOAc in hexanes) to provide the desired product (9 37 g, 90%) as a clear oil. 1H NMR (400 MHz, CDCl3): δ 1.49 (d, J=6.6 Hz, 3H), 5.15 (q, J=12, 6.4 Hz, 1H), 7.15–7.45 (m, 3H).
Reaction SMILES: [Na].Cl[C:3]1[C:8]([O:9][CH:10]([CH3:12])[CH3:11])=[CH:7][CH:6]=[CH:5][N:4]=1.[CH3:13][OH:14]>>[CH:10]([O:9][C:8]1[C:3]([O:14][CH3:13])=[N:4][CH:5]=[CH:6][CH:7]=1)([CH3:12])[CH3:11]
Reactant: CO
Reactant: CC(C)Oc1cccnc1Cl
Agent: [Na]
Product: COc1ncccc1OC(C)C
Temperature: 150 °C

Procedure:
To a solution of methanolate obtained by dissolving sodium (534 mg, 23.25 mmol) in MeOH (8 ml) was added a solution of 2-chloro-3-isopropoxy-pyridine (Stage 93.1.4, 1.14 g, 6.64 mmol) in MeOH (2 ml). The reaction mixture was heated at 150° C. by microwave irradiation for 25 min then concentrated and quenched with EtOAc and brine. The organic layer was dried over Na2SO4, filtered and evaporated to give the title compound as an oil (HPLC: tR 2.66 min (Method A); M+H=264 MS-ES)
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][NH:6][S:7]([C:10]1[CH:15]=[CH:14][C:13](Br)=[CH:12][C:11]=1[Cl:17])(=[O:9])=[O:8].[F:18][C:19]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=1B(O)O>>[OH:1][CH2:2][CH2:3][CH2:4][CH2:5][NH:6][S:7]([C:10]1[CH:15]=[CH:14][C:13]([C:22]2[CH:21]=[CH:20][C:19]([F:18])=[CH:24][C:23]=2[F:25])=[CH:12][C:11]=1[Cl:17])(=[O:9])=[O:8]
Reactant: O=S(=O)(NCCCCO)c1ccc(Br)cc1Cl
Reactant: OB(O)c1ccc(F)cc1F
Product: O=S(=O)(NCCCCO)c1ccc(-c2ccc(F)cc2F)cc1Cl

Procedure:
Using a method analogous to that described in Example 40, 4-bromo-2-chlorophenyl-sulfonic acid-(4-hydroxybutyl)-amide and 2,4-difluorophenyl boronic acid were reacted to give the title compound as a white solid. δC (CDCl3, 62.9 MHz): 26.4, 29.5, 41.2, 62.1, 104.9 (t, J 26.0), 112.3 (dd, J 21.3, 2.9), 122.3 (dd, J 12.7, 3.9), 127.5, 131.3, 131.5, 131.5, 131.7 (d, J 2.0), 136.2, 140.6, 159.9 (dd, J 252.0, 11.7) and 163.3 (dd, J 252.0, 11.7).
Reaction SMILES: FC1C(O[C:9](=[O:24])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[NH:16][CH2:17][C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)=C(F)C(F)=C(F)C=1F.[CH2:29]([C:33]1[CH2:37][CH:36]([CH2:38][O:39][NH2:40])[O:35][N:34]=1)[CH2:30][CH2:31][CH3:32]>>[CH2:29]([C:33]1[CH2:37][CH:36]([CH2:38][O:39][NH:40][C:9](=[O:24])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[NH:16][CH2:17][C:18]2[CH:19]=[CH:20][N:21]=[CH:22][CH:23]=2)[O:35][N:34]=1)[CH2:30][CH2:31][CH3:32]
Reactant: CCCCC1=NOC(CON)C1
Reactant: O=C(Oc1c(F)c(F)c(F)c(F)c1F)c1ccccc1NCc1ccncc1
Product: CCCCC1=NOC(CONC(=O)c2ccccc2NCc2ccncc2)C1

Procedure:
Prepared by a similar method as described for example 415. Starting materials: 2-[(Pyridin-4-ylmethyl)-amino]-benzoic acid pentafluorophenyl ester (preparation 7C) and O-(3-butyl-4,5-dihydro-isoxazol-5-ylmethyl)-hydroxylamine (see preparation 91).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[N:18]3[C:13]([CH:14]=[C:15]([CH:19]([CH3:21])[CH3:20])[CH:16]=[CH:17]3)=[C:12]([C:22](=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24])[C:11]=2[CH2:28][C:29]([CH3:34])([CH3:33])[C:30](O)=[O:31])=[O:9])=[CH:4][CH:3]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)[C:46]2[N:47]=[CH:48]C=CC=2N=N1.Cl.CNC>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([C:10]2[N:18]3[C:13]([CH:14]=[C:15]([CH:19]([CH3:21])[CH3:20])[CH:16]=[CH:17]3)=[C:12]([C:22](=[O:27])[C:23]([CH3:25])([CH3:26])[CH3:24])[C:11]=2[CH2:28][C:29]([CH3:33])([CH3:34])[C:30]([N:47]([CH3:48])[CH3:46])=[O:31])=[O:9])=[CH:6][CH:7]=1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: CC(C)c1ccn2c(C(=O)c3ccc(Cl)cc3)c(CC(C)(C)C(=O)O)c(C(=O)C(C)(C)C)c2c1
Agent: CNC
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Product: CC(C)c1ccn2c(C(=O)c3ccc(Cl)cc3)c(CC(C)(C)C(=O)N(C)C)c(C(=O)C(C)(C)C)c2c1
Reaction time: 16 h
Yield: 34.2 %

Procedure:
To a solution of 3-{3-[(4-chlorophenyl)carbonyl]-1-(2,2-dimethylpropanoyl)-7-(propan-2-yl)indolizin-2-yl}-2,2-dimethylpropanoic acid (100 mg, 0.207 mmol), O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (157.7 mg, 0.415 mmol), and dimethylamine-HCl (18.6 mg, 0.228 mmol) is added TEA (0.173 mL, 1.245 mmol). The reaction is stirred for 16 h then purified by HPLC to give the title compound (36 mg, 34%).
Reaction SMILES: [C:1]([N:4]1[C:8]2[CH:9]=[C:10]([CH3:13])[CH:11]=[CH:12][C:7]=2[NH:6][C:5]1=[O:14])([CH3:3])=[CH2:2].[Cl:15][C:16]1[CH:17]=[C:18]2[C:22](=[C:23]([CH2:25]O)[CH:24]=1)[N:21]([CH3:27])[C:20]([CH3:28])=[C:19]2[CH3:29].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1.C(OCC)(=O)C>[Cl:15][C:16]1[CH:17]=[C:18]2[C:22](=[C:23]([CH2:25][N:6]3[C:7]4[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][C:8]=4[N:4]([C:1]([CH3:3])=[CH2:2])[C:5]3=[O:14])[CH:24]=1)[N:21]([CH3:27])[C:20]([CH3:28])=[C:19]2[CH3:29]
Reactant: C=C(C)n1c(=O)[nH]c2ccc(C)cc21
Reactant: Cc1c(C)n(C)c2c(CO)cc(Cl)cc12
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C=C(C)n1c(=O)n(Cc2cc(Cl)cc3c(C)c(C)n(C)c23)c2ccc(C)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 56.4 %

Procedure:
To a solution of 1-Isopropenyl-6-methyl-1,3-dihydro-benzimidazol-2-one (50 mg, 0.27 mmol) and (5-Chloro-1,2,3-trimethyl-1H-indol-7-yl)-methanol (60 mg, 0.27 mmol), triphenylphosphine (84 mg, 0.32 mmol) in THF (2 mL) was added dropwise DIAD (0.06 mL, 0.32 mmol). The mixture was stirred at room temperature for 1 h. The reaction mixture was diluted with ethyl acetate and washed with water (×2). The organic phase was dried over Na2SO4 and concentrated. The resulting residue was purified by silica gel prep TLC using 4:1 Hexanes:ethyl acetate as an eluent to afford 60 mg of the desired product as a brownish oil. LCMS (ESMS): m/z 394.28 (M+H+).
Reaction SMILES: [C:1]1([C:7]2[N:12]=[C:11]([C:13]([O:15][CH3:16])=[O:14])[CH:10]=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.ClC1C=CC=C(C(OO)=[O:25])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl>[C:1]1([C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([C:13]([O:15][CH3:16])=[O:14])[N+:12]=2[O-:25])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COC(=O)c1cccc(-c2ccccc2)n1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)c1cccc(-c2ccccc2)[n+]1[O-]
Temperature: 25 °C
Reaction time: 72 h
Yield: 9.9 %

Procedure:
To a solution of methyl 6-phenylpyridine-2-carboxylate (509 mg, 6.24 mmol) in dichloromethane (5 mL) was added m-chloroperbenzoic acid (purity: 69-75%, 2.87 g, 12.5 mmol), and the mixture was stirred at room temperature for 3 days. Saturated sodium thiosulfate aqueous solution was added to the reaction mixture, and the mixture was extracted 3 times with ethyl acetate. The combined organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and filtered. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (NH silica gel, ethyl acetate/hexane=1/2→1/1) to give the title compound (142 mg, 10%) as a colorless oil.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:16]=[C:15]3[C:10]([N:11]=[CH:12][CH:13]=[N:14]3)=[C:9]([O:17][C@@H:18]3[CH2:23][CH2:22][C@H:21]([N:24]4C(=O)C5C(=CC=CC=5)C4=O)[CH2:20][CH2:19]3)[CH:8]=2)[CH2:3][CH2:2]1.NN.CCOCC>CO>[O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:16]=[C:15]3[C:10]([N:11]=[CH:12][CH:13]=[N:14]3)=[C:9]([O:17][C@@H:18]3[CH2:23][CH2:22][C@H:21]([NH2:24])[CH2:20][CH2:19]3)[CH:8]=2)[CH2:3][CH2:2]1
Reactant: O=C1c2ccccc2C(=O)N1[C@H]1CC[C@@H](Oc2cc(N3CCOCC3)cc3nccnc23)CC1
Agent: NN
Solvent: CCOCC
Solvent: CO
Product: N[C@H]1CC[C@@H](Oc2cc(N3CCOCC3)cc3nccnc23)CC1
Reaction time: 0.5 h

Procedure:
As shown in step 9-iii of Scheme 9, to a suspension of 2-[(cis)-4-(7-morpholinoquinoxalin-5-yl)oxycyclohexyl]isoindoline-1,3-dione (2.3 g, 5.02 mmol) in MeOH (25 mL) was added hydrazine (321 mg, 315 μL, 10.0 mmol) and the reaction mixture stirred for 18 hours at RT, over which time the initial suspension became homogenenous followed by the appearance of a precipitate. Et2O (30 mL) was added and the reaction mixture stirred an additional 30 minutes. The precipitates were filtered off, the filtrate concentrated under reduced pressure, the residue treated with DCM (30 mL), and any remaining solids removed by filtration. The filtrate was concentrated under reduced pressure to provide (cis)-4-((7-morpholinoquinoxalin-5-yl)oxy)cyclohexanamine (compound 1030), which was used as is in subsequent reactions: 1H-NMR (300 MHz, CDCl3) δ 8.69 (d, J=1.9 Hz, 1H), 8.62 (d, J=1.9 Hz, 1H), 6.95 (d, J=2.5 Hz, 1H), 6.90 (d, J=2.5 Hz, 1H), 5.00-4.67 (m, 3H), 4.03-3.81 (m, 4H), 3.49 (s, 1H), 3.43-3.25 (m, 4H), 2.88 (q, J=6.2 Hz, 2H), 2.36-1.96 (m, 6H).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH:27]=O)=[C:5]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[N+:19]([O-:21])=[O:20])[C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9].[NH2:29][CH2:30][CH2:31][OH:32].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1C=CC=CC=1>[CH3:1][C:2]1[NH:3][C:4]([CH:27]=[N:29][CH2:30][CH2:31][OH:32])=[C:5]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[N+:19]([O-:21])=[O:20])[C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CCOC(=O)C1=C(C)NC(C=O)=C(C(=O)OCC)C1c1ccccc1[N+](=O)[O-]
Reactant: NCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: CCOC(=O)C1=C(C)NC(C=NCCO)=C(C(=O)OCC)C1c1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 95.8 %

Procedure:
A mixture of diethyl 2-methyl-4-(2-nitrophenyl)-6-formyl-1,4-dihydropyridine-3,5-dicarboxylate (1.1651 g), 2-aminoethanol (185 mg) and p-toluenesulfonic acid (catalytic amount) in dried benzene (20 ml) was refluxed under azeotropic dehydration for 1.5 hours. After cooling to room temperature, water was added to the resultant solution. The mixture was washed twice with water. The aqueous layer was extracted with diethyl ether and the extract was combined with the benzene solution. The mixed solution was dried over magnesium sulfate and then the solvent was removed from the solution to give viscous oil (1.2397 g) of diethyl 2-methyl-4-(2-nitrophenyl)-6-(2-hydroxyethyl)iminomethyl-1,4-dihydropyridine-3,5-dicarboxylate.
Reaction SMILES: FC(F)(F)S(O)(=O)=O.[Cl:9][C:10]1[CH:16]=[CH:15][C:13]([OH:14])=[CH:12][C:11]=1[OH:17].[Cl:18][CH2:19][CH2:20][C:21](O)=[O:22]>O>[Cl:18][CH2:19][CH2:20][C:21]([C:15]1[CH:16]=[C:10]([Cl:9])[C:11]([OH:17])=[CH:12][C:13]=1[OH:14])=[O:22]
Reactant: Oc1ccc(Cl)c(O)c1
Reactant: O=C(O)CCCl
Agent: O=S(=O)(O)C(F)(F)F
Solvent: O
Product: O=C(CCCl)c1cc(Cl)c(O)cc1O
Temperature: 6 °C
Yield: 98.6 %

Procedure:
A 2-liter 4-neck round-bottom flask was charged with trifluoromethanesulfonic acid (500 g, 3.33 mol) and the flask contents were cooled below 10° C. 4-Chlororesorcinol (100 g, 0.69 mol) was added in portions over 20-30 minutes, maintaining the temperature at 4 to 8° C. The reaction mixture was stirred at or below 10° C. until a clear solution formed (40 minutes). 3-Chloropropanoic acid (78.8 g, 0.73 mol) was warmed until melted and then added in liquid form dropwise over 45 minutes to the flask, maintaining the temperature at or below 10° C. The reaction mixture was stirred for an additional 10 minutes at or below 10° C., then slowly heated to 50-55° C. and maintained there for 6 hours. The reaction mixture was cooled to ambient temperature and added dropwise to water (1.1 L) contained in a 3-liter 4-neck round-bottom flask. The resulting mixture was stirred at ambient temperature for 30 minutes. The resulting precipitate was collected by filtration, washed with water (3×540 mL), and dried in a fan dryer at 40° C. until the moisture content fell below 0.5%, to afford 3-chloro-1-(5-chloro-2,4-dihydroxyphenyl)propan-1-one as an orange solid (160 g, 98.4% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:12]=[C:13]([O:15][CH3:16])[CH:14]=1)[CH:6]([OH:11])[C:7]([O:9]C)=[O:8].CO[C:19]1[CH:30]=CC(C(O)C(OC)=O)=C[CH:20]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:6]2([C:7]([OH:9])=[O:8])[CH2:30][CH2:19][CH2:20][O:11]2)[CH:12]=[C:13]([O:15][CH3:16])[CH:14]=1
Reactant: COC(=O)C(O)c1ccc(OC)cc1
Reactant: COC(=O)C(O)c1cc(OC)cc(OC)c1
Product: COc1cc(OC)cc(C2(C(=O)O)CCCO2)c1

Procedure:
2-(3,5-Dimethoxyphenyl)-2-tetrahydrofuroic acid was prepared according to the procedures described in Reference Example 27 substituting 3,5-dimethoxymandelic acid, methyl ester for 4-methoxymandelic acid, methyl ester in Step A.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][CH3:16])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH:21][C:22](=[O:42])[CH2:23][C:24]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:32]2[CH:33]=[N:34][C:35]([CH:39]3[CH2:41][CH2:40]3)=[CH:36][C:37]=2[CH3:38])[CH:27]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:39]1([C:35]2[N:34]=[CH:33][C:32]([C:28]3[CH:27]=[C:26]([C:24]4[CH2:23][C:22](=[O:42])[NH:21][C:9]5[CH:10]=[C:11]([C:17]([F:19])([F:20])[F:18])[C:12]([O:14][CH2:15][CH3:16])=[CH:13][C:8]=5[N:7]=4)[CH:31]=[CH:30][CH:29]=3)=[C:37]([CH3:38])[CH:36]=2)[CH2:41][CH2:40]1
Reactant: CCOc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3cnc(C4CC4)cc3C)c2)cc1C(F)(F)F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOc1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-c3cnc(C4CC4)cc3C)c1)=N2

Procedure:
The title compound was prepared from (2-{3-[3-(6-cyclopropyl-4-methyl-pyridin-3-yl)-phenyl]-3-oxo-propionylamino}-5-ethoxy-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example M227) (305 mg, 0.51 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as an off-white solid (160 mg, 65%).
Reaction SMILES: [C:1]1(=[N:12]O)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](=[N:10]O)[CH2:2]1.[Na].O>C(O)C>[NH2:10][CH:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH:1]([NH2:12])[CH2:2]1
Reactant: ON=C1CC(=NO)c2ccccc21
Agent: [Na]
Solvent: CCO
Solvent: O
Product: NC1CC(N)c2ccccc21
Yield: 69.5 %

Procedure:
To a solution of 20 g of a 1,3-indandione dioxime in 2 L of absolute ethanol was cautiously added 160 g of sodium in portions during 1 hr (at such a rate to maintain reflux). After disappearance of the sodium, 300 mL of water was slowly added and the solution concentrated in vacuo to remove most of the ethanol. The resulting solution was acidified with conc. hydrochloric acid to pH 1-2 followed by extraction with methylene chloride to recover unreacted started material. The aqueous layer was basified with 10% sodium hydroxide to pH 12 and extracted with methylene chloride which gave 11.7 grams of crude 1,3-diaminoindan upon solvent removal in vacuo. Purification of this material by flash column chromatography eluting with 95% ethanol/ammonium hydroxide (400:16) gave 8.75 g of the title compound as an approximately 60/40 mixture of cis to trans isomers.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](F)[CH:5]=[CH:4][C:3]=1[C:9]([N:11]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[CH2:15][N:14]2[CH:22]=[CH:23][CH:24]=[C:13]2[CH2:12]1)=[O:10].[H-].[Na+].CCCCCC.[NH:33]1[CH:37]=[N:36][CH:35]=[N:34]1>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[C:6]([N:33]2[CH:37]=[N:36][CH:35]=[N:34]2)[CH:5]=[CH:4][C:3]=1[C:9]([N:11]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[CH2:15][N:14]2[CH:22]=[CH:23][CH:24]=[C:13]2[CH2:12]1)=[O:10]
Reactant: c1nc[nH]n1
Reactant: O=C(c1ccc(F)cc1Cl)N1Cc2cccn2Cc2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: O=C(c1ccc(-n2cncn2)cc1Cl)N1Cc2cccn2Cc2ccccc21
Yield: 26.2 %

Procedure:
In the manner of Example 9's Method 1, employing (2-chloro-4-fluorophenyl)-(5H,11H-pyrrolo[2,1-c][1,4]benzodiazepin-10-yl)-methanone (1.7 g), 60% sodium hydride in oil (0.5 g, degreased with hexane), 1,2,4-triazole (0.70 g) and dimethylformamide (50 ml), the title compound (0.51 g) was obtained as an amorphous solid, MS, m/z: 390.3 (M+H)+, 779.3 (2M+H)+.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH:15]([O:16]C(=O)C3C=CC=CC=3)[CH2:14][CH:13]([CH:25]=[CH:26][P:27]([OH:30])([OH:29])=[O:28])[O:12]2)=[C:4](Br)[N:3]=1.[CH3:32][NH2:33]>O>[NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[O:12][CH:13]([CH:25]=[CH:26][P:27](=[O:28])([OH:30])[OH:29])[CH2:14][CH:15]2[OH:16])=[C:4]([NH:33][CH3:32])[N:3]=1
Reactant: CN
Reactant: Nc1nc(Br)c2ncn(C3OC(C=CP(=O)(O)O)CC3OC(=O)c3ccccc3)c2n1
Solvent: O
Product: CNc1nc(N)nc2c1ncn2C1OC(C=CP(=O)(O)O)CC1O
Temperature: 25 °C
Reaction time: 3 h
Yield: 35 %

Procedure:
Compound 46.2 (250 mg, crude) was dissolved in 40 wt % methylamine in water and stirred at rt for 3 h. The solution was concentrated under reduced pressure and the residue was subjected to a reverse phase HPLC to give compound 46.3 (60 mg, 35% yield). 1H NMR (CDCl3, 300 MHz): δ 2.05-2.18 (m, 2H), 2.83 (s, 3H), 4.54-4.55 (m, 1H), 4.84 (s, 1H), 5.73 (d, 1H, J=1.5), 5.89-5.95 (m, 1H), 6.22 (m, 1H), 7.64 (s, 1H). 31PNMR: 10.23 ppm. LRMS [M−H]− C12H17N6O5P requires 355.1. Found 355.1.