Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([I:12])[CH:7]=1)=[O:4].[NH:13]1[CH:17]=[CH:16][N:15]=[C:14]1[CH:18]=[O:19].CCN(C(C)C)C(C)C>CN(C=O)C>[CH:18]([C:14]1[N:13]([CH2:2][C:3]([NH:5][C:6]2[CH:11]=[CH:10][CH:9]=[C:8]([I:12])[CH:7]=2)=[O:4])[CH:17]=[CH:16][N:15]=1)=[O:19]
Reactant: O=C(CBr)Nc1cccc(I)c1
Reactant: O=Cc1ncc[nH]1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=Cc1nccn1CC(=O)Nc1cccc(I)c1
Yield: 93.5 %

Procedure:
A solution of 2-bromo-N-(3-iodophenyl)acetamide (2.67 g, 7.83 mmol), 1H-imidazole-2-carbaldehyde (0.752 g, 7.83 mmol) and DIPEA (10 mL) in DMF (20 mL) was stirred at 80° C. for 4 hrs. The solvent was evaporated under reduced pressure to afford a residue, which was purified by Biotage eluting with DCM in hexanes to 10% MeOH in DCM to give 2-(2-formyl-1H-imidazol-1-yl)-N-(3-iodophenyl)acetamide (2.60 g, 94%). 1H NMR (400 MHz, DMSO) 9.64 (s, 1H), 8.17 (brs, 1H), 8.04 (s, 1H), 7.60 (s, 1H), 7.46 (d, J=8.4 Hz, 1H), 7.40 (d, J=8.0 Hz, 1H), 7.28 (s, 1H), 7.10 (t, J=8.0 Hz, 1H), 5.23 (s, 2H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([C:18]1[CH:23]=[C:22]([F:24])[CH:21]=[C:20]([F:25])[CH:19]=1)([CH3:17])[C:10](OC(C)(C)C)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[F:24][C:22]1[CH:23]=[C:18]([C:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:17])[CH:10]=[O:11])[CH:19]=[C:20]([F:25])[CH:21]=1
Reactant: CC(C)(C)OC(=O)NC(C)(C(=O)OC(C)(C)C)c1cc(F)cc(F)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC(C)(C=O)c1cc(F)cc(F)c1
Temperature: -78 °C
Reaction time: 6 h

Procedure:
To a stirred solution of tert-butyl 2-[(tert-butoxycarbonyl)amino]-2-(3,5-difluorophenyl)propanoate from Step B (2.00 g, 5.60 mmol) in THF (20 mL) at −78° C. was added LiAlH4 (5.60 mL of a 1 M solution in THF, 5.60 mmol), dropwise. The reaction mixture was stirred at −78° C. for 6 h, then quenched with EtOAc (5.6 mL), then H2O (15.6 mL), then 1 N aqueous NaOH (5.6 mL), then EtOAc (17 mL). The reaction mixture was warmed to ambient temperature, stirred for 1 h, filtered, and extracted with EtOAc (2×40 mL). The organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo to afford the title compound in sufficient purity for use in the next step. MS: m/z=186 (M−CO2C4H7).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH:17][C@H:18]4[CH2:23][CH2:22][CH2:21][C:20](=O)[CH2:19]4)[C:14]([F:25])=[CH:13][N:12]=3)=[CH:9][N:8]([S:26]([C:29]3[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=3)(=[O:28])=[O:27])[C:5]2=[N:6][CH:7]=1.Cl.[NH2:37][OH:38]>CCO>[Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH:17][CH:18]4[CH2:23][CH2:22][CH2:21][CH2:20][C:19]4=[N:37][OH:38])[C:14]([F:25])=[CH:13][N:12]=3)=[CH:9][N:8]([S:26]([C:29]3[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=3)(=[O:28])=[O:27])[C:5]2=[N:6][CH:7]=1
Reactant: NO
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(F)c(N[C@H]4CCCC(=O)C4)n3)c3cc(Cl)cnc32)cc1
Agent: Cl
Solvent: CCO
Product: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(F)c(NC4CCCCC4=NO)n3)c3cc(Cl)cnc32)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To solution of (3S)-3-[[2-[5-chloro-1-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridin-3-yl]-5-fluoro-pyrimidin-4-yl]amino]cyclohexanone (0.41 g, 0.81 mmol) in EtOH (8.2 mL) was added hydroxylamine hydrochloride (0.11 g, 1.61 mmol). The reaction mixture was stirred at room temperature overnight. Then the mixture was warmed to 70° C. for 15 min. The reaction mixture was concentrated in vacuo, suspended in EtOAc-DCM, washed with half saturated brine (2×) and filtered through a SiO2 plug. The resulting residue was azeotroped with CH3CN (2×) to provide an off white powder which was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[C:3]([N+:18]([O-])=O)=[C:4]([CH:9]=[C:10]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[N:11]=1)[C:5]([O:7][CH3:8])=[O:6]>CO.CC(O)=O.[Pd]>[NH2:1][C:2]1[C:3]([NH2:18])=[C:4]([CH:9]=[C:10]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[N:11]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1cc(N2CCOCC2)nc(N)c1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Solvent: CC(=O)O
Product: COC(=O)c1cc(N2CCOCC2)nc(N)c1N
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of methyl 2-amino-6-morpholino-3-nitroisonicotinate (4.8 g, 17 mmol) and 10% Pd/C (480 mg) in MeOH (100 mL) and CH3COOH (50 mL) was stirred at room temperature for 16 h with connection to a balloon of H2. LCMS showed no methyl 2-amino-6-morpholino-3-nitroisonicotinate left and the desired product formed. It was then filtered and the filtrate was concentrated in vacuo. The residue (4.3 g) was used for next step without purification. LC/MS: MS (ES+) m/e 253 (MH+).
Reaction SMILES: C1(S([N:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([Cl:19])[C:13]=3[CH:12]=[C:11]2[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)(=O)=O)C=CC=CC=1.CO.[OH-].[Na+]>C1COCC1>[Cl:19][C:18]1[C:13]2[CH:12]=[C:11]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[NH:10][C:14]=2[N:15]=[CH:16][N:17]=1
Reactant: O=S(=O)(c1ccccc1)n1c(-c2ccccc2)cc2c(Cl)ncnc21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Clc1ncnc2[nH]c(-c3ccccc3)cc12
Reaction time: 0.25 h
Yield: 76 %

Procedure:
The product from Method D was dissolved in 10 mL of THF and to this solution was added 5.0 mL of methanol and 1.0 g of NaOH. The reaction mixture was stirred for 15 min., concentrated in vacuo and partitioned between a saturated aqueous solution of ammonium chloride (NH4Cl) and ethyl acetate. The resulting aqueous layer was extracted twice with ethyl acetate. The ethylacetate layers were combined, washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The crude product was purified by silica-gel chromatography (1:5 ethyl- acetate/hexane) to obtain 0.59 g (76%) of the title compound as a pale yellow solid, mp 145° C. (dec). LRMS: 230, 232 (M+2).
Reaction SMILES: [P:1]([O-:44])([O:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][N:39]1[CH2:43][CH2:42][CH2:41][CH2:40]1)([O:3][CH2:4][CH:5]([O:26][C:27](=[O:32])[CH2:28][C:29]([CH3:31])=[O:30])[CH2:6][O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[O:2].[C:45](=O)([O-])O.[Na+]>CC(C)=O>[P:1]([O-:44])([O:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][N+:39]1([CH3:45])[CH2:43][CH2:42][CH2:41][CH2:40]1)([O:3][CH2:4][CH:5]([O:26][C:27](=[O:32])[CH2:28][C:29]([CH3:31])=[O:30])[CH2:6][O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[O:2]
Reactant: CCCCCCCCCCCCCCCCCCOCC(COP(=O)([O-])OCCCCCN1CCCC1)OC(=O)CC(C)=O
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Product: CCCCCCCCCCCCCCCCCCOCC(COP(=O)([O-])OCCCCC[N+]1(C)CCCC1)OC(=O)CC(C)=O
Temperature: 50 °C
Reaction time: 13 h
Yield: 46 %

Procedure:
To 30 ml of acetone was dissolved 1.17 g (1.8 mmole) of 2-(acetoacetyloxy)-3-(octadecyloxy)propyl 5-(pyrrolidino)pentyl phosphate, and 820 mg (10 mmole) of sodium hydrogen-carbonate previously crushed in a mortar and 410 mg (2.2 mmole) of methyl para-tolanesulrte were added to the solution. The mixture was stirred at 50° C. for 13 hours and acetone was distilled off under reduced pressure. In 30 ml of water was dissolved the residue and the solution was adjusted to pH 4 with 2N HCl, followed by extraction with a mixture of dichloromethane and ethanol (10:1). The solvent was distilled off and the residue was purified by silica gel column chromatography [chloroform-methanol-water (65:25:4)] to give 550 mg yield: 46%) of the desired compound.
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[CH:11]=[CH:10][C:9]([CH3:13])=[CH:8][C:7]=2[C:6](=[O:14])[C:5]2[N:15]([CH3:18])[N:16]=[CH:17][C:4]1=2)[CH3:2].Cl.[CH3:20][N:21]([CH3:26])[CH2:22]CC[Cl:25].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[ClH:25].[CH3:20][N:21]([CH3:26])[CH2:22][CH2:2][CH2:1][N:3]1[C:12]2[CH:11]=[CH:10][C:9]([CH3:13])=[CH:8][C:7]=2[C:6](=[O:14])[C:5]2[N:15]([CH3:18])[N:16]=[CH:17][C:4]1=2
Reactant: CN(C)CCCCl
Reactant: CCn1c2ccc(C)cc2c(=O)c2c1cnn2C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc2c(c1)c(=O)c1c(cnn1C)n2CCCN(C)C
Temperature: 100 °C
Reaction time: 6 h
Yield: 78.8 %

Procedure:
A mixture of 1,7-dimethyl-1,4-dihydro-9H-pyrazolo[4,3-b]quinolin-9-one (UK-264650) (EXAMPLE 47, step 2, 100 mg, 0.375 mmol), 3-(dimethylamino)propyl chloride hydrochloride (178 mg, 1.13 mmol) and potassium carbonate (311 mg, 2.25 mmol) in N,N-dimethylformamide (2 ml) was stirred at 100° C. for 6 h. After cooling to room temperature, water (50 ml) was added and extracted with ethyl acetate (50 ml×3). The combined organic layer was dried over magnesium sulfate and evaporated. To this residue (106 mg) was added methanolic hydrochloric acid and the mixture was concentrated in vacuo. The solid was recrystallized from ethanol/diisopropyl ether to give 99 mg (79%) of the title compound as a yellow solid.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][N:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]2[CH:19]=[C:20]([C:24]([NH2:26])=[O:25])[C:21]([NH2:23])=[N:22][C:11]1=2)(C)(C)C.[ClH:28]>CO>[ClH:28].[NH2:23][C:21]1[C:20]([C:24]([NH2:26])=[O:25])=[CH:19][C:12]2[C:13]3[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:10]([CH2:9][CH2:8][NH2:7])[C:11]=2[N:22]=1
Reactant: CC(C)(C)OC(=O)NCCn1c2ccccc2c2cc(C(N)=O)c(N)nc21
Agent: Cl
Solvent: CO
Product: NCCn1c2ccccc2c2cc(C(N)=O)c(N)nc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of tert-butyl{2-[2-amino-3-(aminocarbonyl)-9H-pyrido[2,3-b]indol-9-yl]ethyl}carbamate (xvi-a, 35.0 mg, 0.095 mmol) in MeOH (2 mL) was added conc. HCl (1 mL). The reaction was stirred at RT. After 2 h, the reaction was concentrated and lyophilized to yield 2-amino-9-(2-aminoethyl)-9H-pyrido[2,3-b]indole-3-carboxamide hydrochloride as a white solid (16, 27 mg, 93%). NH4OAc standard conditions. DAD Retention time =4.48 min. M+H=270. 1H NMR (300 MHz, D2O): Δ8.16 (s, 1), 7.74 (d, J=7.6 Hz, 1H), 7.73-7.42 (m, 1H), 7.36-7.28 (m, 2H), 4.32 (t, J=5.7 Hz, 2H), 3.37 (t, J=5.7 Hz, 2H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]2([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([Br:28])=[CH:24][CH:23]=3)C(=O)OC(C)(C)[O:13][C:12]2=O)=[CH:6][CH:5]=1.[O:30]1[C:35]2=[CH:36][CH:37]=[CH:38][C:34]2=[CH:33][CH:32]=[C:31]1[NH:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>CN1C(=O)CCC1.O>[CH3:1][O:2][C:3](=[O:29])[C:4]1[CH:5]=[CH:6][C:7]([CH2:10][CH:11]([C:12](=[O:13])[N:39]([C:31]2[O:30][C:35]3=[CH:36][CH:37]=[CH:38][C:34]3=[CH:33][CH:32]=2)[C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=2)[CH2:21][C:22]2[CH:23]=[CH:24][C:25]([Br:28])=[CH:26][CH:27]=2)=[CH:8][CH:9]=1
Reactant: c1ccc(Nc2ccc3cccc-3o2)cc1
Reactant: COC(=O)c1ccc(CC2(Cc3ccc(Br)cc3)C(=O)OC(C)(C)OC2=O)cc1
Solvent: O
Solvent: CN1CCCC1=O
Product: COC(=O)c1ccc(CC(Cc2ccc(Br)cc2)C(=O)N(c2ccccc2)c2ccc3cccc-3o2)cc1
Yield: 56.1 %

Procedure:
A solution of 4-[5-(4-Bromobenzyl)-2,2-dimethyl-4,6-dioxo-[1,3]dioxan-5-ylmethyl]-benzoic acid methyl ester (1.35 g, 2.93 mmol) and 4-benzofuran-2-ylphenylamine (736 mg, 3.52 mmol) in dry NMP (10 mL) was heated at 220° C. for 5 min in the microwave. The reaction mixture was diluted with water then extracted with EtOAc. After concentrating, the crude material was purified by flash chromatography on silica gel (ISCO cartridge, 40 g), eluting with a gradient of zero to 35% ethyl acetate in hexane over 30 minutes to afford 4-[2-(4-Benzofuran-2-ylphenylcarbamoyl)-3-(4-bromophenyl)-propyl]-benzoic acid methyl ester (935 mg, 56%). 1H NMR (300 MHz, DMSO-d6): δ 9.92 (s, 1H), 7.86 (d, J=8.4 Hz, 2H), 7.80 (d, J=8.7 Hz, 2H), 7.64-7.17 (m, 13H), 3.81 (s, 3H), 3.10-2.93 (m, 3H), 2.85-2.71 (m, 2H).
Reaction SMILES: [C:1]1([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:6]=[CH:5][C:4]([S:7]([NH2:10])(=[O:9])=[O:8])=[CH:3][CH:2]=1.[H-].[Na+].[CH2:19]([C:21]1[N:31]([C:32]2[CH:37]=[CH:36][C:35]([CH2:38][CH2:39][NH:40][C:41](=O)[O:42]C3C=CC=CC=3)=[CH:34][CH:33]=2)[C:24]2=[N:25][C:26]([CH3:30])=[CH:27][C:28]([CH3:29])=[C:23]2[N:22]=1)[CH3:20].O>CN(C=O)C>[C:1]1([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:6]=[CH:5][C:4]([S:7]([NH:10][C:41]([NH:40][CH2:39][CH2:38][C:35]2[CH:36]=[CH:37][C:32]([N:31]3[C:24]4=[N:25][C:26]([CH3:30])=[CH:27][C:28]([CH3:29])=[C:23]4[N:22]=[C:21]3[CH2:19][CH3:20])=[CH:33][CH:34]=2)=[O:42])(=[O:8])=[O:9])=[CH:3][CH:2]=1
Reactant: CCc1nc2c(C)cc(C)nc2n1-c1ccc(CCNC(=O)Oc2ccccc2)cc1
Reactant: NS(=O)(=O)c1ccc(-c2ccccc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCc1nc2c(C)cc(C)nc2n1-c1ccc(CCNC(=O)NS(=O)(=O)c2ccc(-c3ccccc3)cc2)cc1
Reaction time: 0.08 h
Yield: 49.7 %

Procedure:
To a stirred solution of 4-biphenylsulfonamide (Greenlee, W. J.; Walsh, T. F.; et al. Eur. Pat. Appl., EP 617001 (1994)., 56 mg, 0.24 mmol) in DMF (3 mL) was added NaH (60% oil dispersion, 20 mg, 0.5 mmol) at room temperature. After 5 min, phenyl 2-[4-(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]ethylcarbamate (step 1, 100 mg, 0.24 mmol) was added, and the mixture was stirred for an additional 1 h. The mixture was poured into water (50 mL) and extracted with diethyl ether (2×50 mL). The combined extracts were washed with water (50 mL), brine (50 mL) and dried (MgSO4). Removal of solvent gave white oily solids. Purification by preparative TLC (ethyl acetate) gave 66 mg (50%) of the title compound as a colorless oil: MS (ESI) m/z 554 (M+H)+; 1H-NMR (CDCl3) δ 8.06 (2H, d, J=8.6 Hz), 7.13 (2H, d, J=8.6 Hz), 7.60–7.53 (2H, m), 7.48–7.36 (3H, m), 7.21 (2H, d, J=8.4 Hz), 7.12 (2H, d, J=8.3 Hz), 6.92 (1H, s), 6.11 (1H, br.t, J=5.5 Hz), 3.54 (2H, dt, J=5.9, 6.0 Hz), 2.89 (2H, J=6.0 Hz), 2.64 (2H, q, J=7.5 Hz), 2.66 (3H, s), 2.40 (3H, s), 1.18 (3H, t, J=7.5 Hz).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[C:14]([O:16][C:17]3[C:22]([CH3:23])=[CH:21][C:20]([N+:24]([O-])=O)=[CH:19][C:18]=3[CH3:27])[CH:13]=[CH:12][C:11]=2[OH:28])=[O:9])=[CH:4][CH:3]=1>C(OCC)(=O)C.[Pd]>[NH2:24][C:20]1[CH:21]=[C:22]([CH3:23])[C:17]([O:16][C:14]2[CH:13]=[CH:12][C:11]([OH:28])=[C:10]([C:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)=[O:9])[CH:15]=2)=[C:18]([CH3:27])[CH:19]=1
Reactant: Cc1cc([N+](=O)[O-])cc(C)c1Oc1ccc(O)c(C(=O)c2ccc(F)cc2)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Cc1cc(N)cc(C)c1Oc1ccc(O)c(C(=O)c2ccc(F)cc2)c1

Procedure:
A solution of 2.77 g (7.3 mmol) of (4-fluorophenyl)[2-hydroxy-5-(2,6-dimethyl-4-nitrophenoxy) phenyl]methanone in 200 ml ethyl acetate with 1.0 g of 10% palladium on carbon is hydrogenated on a Parr apparatus for 2.5 hours at 50 psi and room temperature, then filtered and evaporated to give [5-(4-amino-2,6-dimethylphenoxy)-2-hydroxyphenyl](4-fluorophenyl)methanone.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5](I)=[N:6][CH:7]=1.C([Li])CCC.[O:14]1[CH2:17][C:16](=[O:18])[CH2:15]1>C1(C)C=CC=CC=1.O>[Br:1][C:2]1[CH:3]=[N:4][C:5]([C:16]2([OH:18])[CH2:17][O:14][CH2:15]2)=[N:6][CH:7]=1
Reactant: O=C1COC1
Reactant: Brc1cnc(I)nc1
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Solvent: O
Product: OC1(c2ncc(Br)cn2)COC1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 42.4 %

Procedure:
5-Bromo-2-iodopyrimidine (2 g, 7.02 mmol) was dissolved in dry toluene (30 mL) and cooled to −78° C. under N2. n-Butyllithium (2.5M solution in hexanes, 2.95 mL) was added dropwise, and the reaction mixture was aged for 30 minutes prior to dropwise addition of oxetan-3-one (0.452 mL, 7.72 mmol). The reaction mixture was stirred at −78° C. for 30 minutes, then allowed to warm to room temperature for 1 h. The reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (3×100 mL). The combined organic extracts were successively washed with water and brine, then dried over magnesium sulphate and filtered. The solvent was removed under reduced pressure. The resulting crude brown oily solid was absorbed onto a 25 g KP-Sil Biotage column with minimal DCM, and eluted using a Biotage Isolera 4 with 10-100% ethyl acetate in heptanes, to afford the title compound (687 mg, 42%) as a crystalline yellow solid. δH (500 MHz, DMSO-d6) 9.07 (s, 2H), 6.43 (s, 1H), 4.94 (d, J 6.5 Hz, 2H), 4.67 (d, J 6.5 Hz, 2H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([C:10]([CH3:13])([CH3:12])[CH3:11])[CH:7]=[C:6]([N+:14]([O-:16])=[O:15])[C:5]=1Cl)([O-:3])=[O:2].[CH3:18][NH:19][CH3:20].C(O)C>O>[CH3:18][N:19]([CH3:20])[C:5]1[C:4]([N+:1]([O-:3])=[O:2])=[CH:9][C:8]([C:10]([CH3:13])([CH3:12])[CH3:11])=[CH:7][C:6]=1[N+:14]([O-:16])=[O:15]
Reactant: CNC
Reactant: CC(C)(C)c1cc([N+](=O)[O-])c(Cl)c([N+](=O)[O-])c1
Solvent: CCO
Solvent: O
Product: CN(C)c1c([N+](=O)[O-])cc(C(C)(C)C)cc1[N+](=O)[O-]
Reaction time: 1 h

Procedure:
Two and six-tenths grams (.01 mole) of 2,6-dinitro-4-t-butylchlorobenzene was reacted with 3.1 grams of 40% aqueous solution of dimethylamine in 50 ml. ethanol. The temperature was slowly increased as follows: 30° C. for 1 hour, 40° C. for 1 hour, 50° C. for one hour, then 80° C. for five hours. When the reaction was complete, about 100 ml. H2O was added, precipitating the product. This was filtered, washed with portions of H2O and upon recrystallization from ethanol yielded 2.5 grams of N,N-dimethyl-2,6-dinitro-4-t-butylaniline in the form of orange-yellow needles melting at 101-102° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([O:15][C:16]2[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][N:17]=2)[CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([C:11]([O:13][CH3:14])=[O:12])=[CH:7]2.O.O1CCC[CH2:28]1>CO>[CH3:28][O:1][C:2]1[CH:3]=[C:4]([O:15][C:16]2[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][N:17]=2)[CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([C:11]([O:13][CH3:14])=[O:12])=[CH:7]2
Reactant: C1CCOC1
Reactant: COC(=O)c1cc2cc(Oc3ccc(S(C)(=O)=O)cn3)cc(O)c2[nH]1
Solvent: CO
Solvent: O
Product: COC(=O)c1cc2cc(Oc3ccc(S(C)(=O)=O)cn3)cc(OC)c2[nH]1
Temperature: 0 °C
Reaction time: 1 h
Yield: 86 %

Procedure:
To a solution of methyl 7-hydroxy-5-{[5-(methylsulfonyl)pyridin-2-yl]oxy}-1H-indole-2-carboxylate (3.12 g) in a mixture of tetrahydrofuran (30 mL) and methanol (5 mL) was added dropwise 2M trimethylsilyldiazomethane diethyl ether solution (4.3 mL) at 0° C. The mixture was stirred at 0° C. for 1 h, 2M trimethylsilyldiazomethane diethyl ether solution (8.0 mL) was added dropwise to the mixture again, and the mixture was stirred at 0° C. for 2.5 h. Furthermore, 2M trimethylsilyldiazomethane diethyl ether solution (4.0 mL) was added dropwise to the mixture, and the mixture was stirred at room temperature for 1 h. To quench the reaction, 6M hydrochloric acid (9 mL) was added to the mixture. Water was added and the mixture was extracted with ethyl acetate. The organic layer was washed successively with saturated aqueous sodium carbonate solution and saturated brine, dried over magnesium sulfate, filtered and concentrated. The residual solid was washed with diethyl ether to give the title compound (2.78 g, 86%) as a brown solid. MS 377 (MH+).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][O:4][C:3](/[C:7](/[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[OH:16])=[N:8]\[OH:9])=[N:2]1.[C:17](=O)([O-])[O-].[Na+].[Na+].S(OC)(OC)(=O)=O.Cl>CN(C)C=O>[CH3:17][O:9]/[N:8]=[C:7](/[C:3]1[O:4][CH2:5][CH2:6][O:1][N:2]=1)\[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[OH:16]
Reactant: O=C([O-])[O-]
Reactant: O/N=C(\C1=NOCCO1)c1ccccc1O
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: COS(=O)(=O)OC
Product: CO/N=C(/C1=NOCCO1)c1ccccc1O
Reaction time: 16 h
Yield: 62.7 %

Procedure:
1.2 g (0.0054 mol) of Z-(5,6-dihydro-1,4,2-dioxazin-3-yl)-(2-hydroxy-phenyl)-methanone oxime (V-1) in 5 ml of dimethylformamide are stirred at 20° C. together with 0.66 g (0.0062 mol) of sodium carbonate initially for 30 minutes. 0.83 g (0.00658 mol) of dimethyl sulphate is then added and stirring is continued at 20° C. for a further 16 hours. The reaction mixture is adjusted to a slightly acidic pH using 2 N aqueous hydrochloric acid and extracted with ethyl acetate. The organic phase is dried over sodium sulphate and the solvent is distilled off under reduced pressure. 0.8 g (50.35% of theory) of Z-(5,6-dihydro-1,4,2-dioxazin-3-yl)-(2-hydroxy-phenyl)-methanone O-methyl-oxime (1) of a purity of 80.3% (HPLC) is obtained.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[CH:7][C:6]=1[F:13].[C:14]([O:18][C:19]([N:21]1[CH2:28][CH:27]2[O:29][CH:23]([CH2:24][NH:25][CH2:26]2)[CH2:22]1)=[O:20])([CH3:17])([CH3:16])[CH3:15].C([O-])([O-])=O.[K+].[K+]>C(#N)C>[C:14]([O:18][C:19]([N:21]1[CH2:22][CH:23]2[O:29][CH:27]([CH2:26][N:25]([CH2:2][CH2:3][O:4][C:5]3[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[CH:7][C:6]=3[F:13])[CH2:24]2)[CH2:28]1)=[O:20])([CH3:17])([CH3:15])[CH3:16]
Reactant: CC(C)(C)OC(=O)N1CC2CNCC(C1)O2
Reactant: N#Cc1ccc(OCCBr)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CC2CN(CCOc3ccc(C#N)cc3F)CC(C1)O2
Temperature: 60 °C
Reaction time: 120 h
Yield: 65.8 %

Procedure:
A suspension of 4-(2-Bromo-ethoxy)-3-fluoro-benzonitrile (21.6 g, 0.0885 mol, from step (v) above), 9-oxa-3,7-diaza-bicyclo[3.3.1]nonane-3-carboxylic acid tert-butyl ester (21.1 g, 0.07965 mol; see WO 01/28992) and dry K2CO3 (48.9 g, 0.354 mol) in 200 ml of dry acetonitrile was stirred at 60° C. for five days under N2 atmosphere. The reaction mixture was filtered through celite and filtrate was concentrated under reduced pressure. The residue was purified by column chromatography over silica gel using 27% ethyl acetate in petroleum ether, as eluent to yield the sub-title compound (20.5 g) as a solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH:9]2[CH2:17][CH:16]3[N:12]([CH2:13][CH2:14][CH2:15]3)[C:11]([CH3:19])([CH3:18])[CH2:10]2)[C:5]([C:20]#[N:21])=[CH:4][N:3]=1.[CH:22]1([C:25]2[C:30]([N:31]3[CH:35]=[N:34][N:33]=[N:32]3)=[CH:29][C:28]([NH2:36])=[C:27]([F:37])[CH:26]=2)[CH2:24][CH2:23]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)(C)C>[CH:22]1([C:25]2[C:30]([N:31]3[CH:35]=[N:34][N:33]=[N:32]3)=[CH:29][C:28]([NH:36][C:2]3[N:7]=[C:6]([NH:8][CH:9]4[CH2:17][CH:16]5[N:12]([CH2:13][CH2:14][CH2:15]5)[C:11]([CH3:19])([CH3:18])[CH2:10]4)[C:5]([C:20]#[N:21])=[CH:4][N:3]=3)=[C:27]([F:37])[CH:26]=2)[CH2:24][CH2:23]1
Reactant: CC1(C)CC(Nc2nc(Cl)ncc2C#N)CC2CCCN21
Reactant: Nc1cc(-n2cnnn2)c(C2CC2)cc1F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)O
Solvent: O
Product: CC1(C)CC(Nc2nc(Nc3cc(-n4cnnn4)c(C4CC4)cc3F)ncc2C#N)CC2CCCN21
Temperature: 80 °C
Reaction time: 4 h

Procedure:
A mixture of (±)-2-chloro-4-(octahydro-5,5-dimethylindolizin-7-ylamino)pyrimidine-5-carbonitrile (60 mg of 70% pure material from previous step), 4-cyclopropyl-2-fluoro-5-(1H-tetrazol-1-yl)benzeneamine (65 mg, 0.3 mmol; prepared according to U.S. patent application Ser. No. 13/188,222, filed Jul. 21, 2011, now U.S. patent application publication US2012/0022092) and para-toluenesulfonic acid monohydrate (37 mg, 0.2 mmol) in isopropyl alcohol (3 ml) were combined in a sealed vial, heated to 80° C. and stirred for 4 hours. After cooling, a precipitate emerged which was filtered. The filter cake was suspended in EtOAc (30 ml) and 1N NaOH (50 ml). The aqueous and organic layers were partitioned and the aqueous layer was extracted with EtOAc (2×25 ml). The combined organic extracts were dried (MgSO4), filtered and the solvent removed under vacuum to leave a solid. The solid was freeze-dried from MeCN/H2O to give the product (26 mg) as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[Cl:8].[C:10](N1C=CN=C1)([N:12]1[CH:16]=[CH:15][N:14]=[CH:13]1)=[O:11]>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([O:9][C:10]([N:12]2[CH:16]=[CH:15][N:14]=[CH:13]2)=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Oc1ccc(Cl)c(Cl)c1
Solvent: ClCCl
Product: O=C(Oc1ccc(Cl)c(Cl)c1)n1ccnc1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 63.7 %

Procedure:
A solution of 5.00 g (30.7 mmol) of 3,4-dichlorophenol in 160 ml of dichloromethane was treated with 6.47 g (39.9 mmol) of 1,1′-carbonyldiimidazol. The reaction was stirred at room temperature over 3.5 h, then partitioned between aq. 0.5 M citric acid and dichloromethane (3×). The organic phase was dried over Na2SO4 evaporated and crystallized from diethyl ether to yield 5.03 g (64%) of the title compound as white crystals. MS: 256.8 (MH+, 2Cl).