Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH:3]1([OH:9])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.Br[CH2:11][C:12]([OH:14])=[O:13].O>O1CCCC1>[CH:3]1([O:9][CH2:11][C:12]([OH:14])=[O:13])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: O=C(O)CBr
Reactant: OC1CCCCC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)COC1CCCCC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 842.1 %

Procedure:
To a suspension of 60% sodium hydride (8.79 g) in tetrahydrofuran (500 mL) was added cyclohexanol (10 g) and the mixture was stirred at 0° C. for 0.5 hour. To the mixture was added bromoacetic acid (13.9 g) under ice-water cooling and the mixture was heated under reflux for 2 hours. After adding water to the mixture and organic solvent was evaporated in vacuo. The aqueous solution was diluted with water, washed with ether, acidified with 1 N hydrochloric acid, and extracted with ether. The organic layer was separated, dried over magnesium sulfate, and evaporated in vacuo to give (cyclohexyloxy)acetic acid as colorless oil (133 g).
Reaction SMILES: S(=O)(=O)(O)O.[NH2:6][C@@H:7]([CH:11]1[CH2:13][CH2:12]1)[C:8]([OH:10])=[O:9].[CH2:14](O)[CH3:15]>>[NH2:6][C@@H:7]([CH:11]1[CH2:13][CH2:12]1)[C:8]([O:10][CH2:14][CH3:15])=[O:9]
Reactant: N[C@H](C(=O)O)C1CC1
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)[C@@H](N)C1CC1
Temperature: 25 °C

Procedure:
Sulfuric acid (conc., 1.704 g, 0.926 mL, 17.37 mmol) was added to a solution of (S)-2-amino-2-cyclopropylacetic acid (1 g, 8.69 mmol) in ethanol (12 mL) and heated to reflux for 5 h, then cooled to rt. The reaction mixture was concentrated under vacuum to remove solvent and water (10 mL) was added. The pH of the mixture was adjusted to 10 using 2M aq. sodium hydroxide and was then extracted with DCM (3×15 mL). The organic phase was dried with sodium sulfate and concentrated under vacuum to provide (S)-ethyl 2-amino-2-cyclopropylacetate (862 mg) which was used as is.
Reaction SMILES: [OH-].[K+].O.NN.[CH3:6][O:7][C:8]1([O:28][CH3:29])[CH2:25][CH2:24][C:23]2[C@@H:22]3[C@H:13]([C@H:14]4[C@@:18]([CH2:20][CH2:21]3)([CH3:19])[C:17](=O)[CH2:16][CH2:15]4)[C@H:12]([CH3:27])[CH2:11][C:10]=2[CH2:9]1>C(O)COCCO>[CH3:29][O:28][C:8]1([O:7][CH3:6])[CH2:25][CH2:24][C:23]2[C@@H:22]3[C@H:13]([C@H:14]4[C@@:18]([CH2:20][CH2:21]3)([CH3:19])[CH2:17][CH2:16][CH2:15]4)[C@H:12]([CH3:27])[CH2:11][C:10]=2[CH2:9]1
Reactant: COC1(OC)CCC2=C(C[C@@H](C)[C@@H]3[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]32)C1
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: OCCOCCO
Solvent: O
Product: COC1(OC)CCC2=C(C[C@@H](C)[C@@H]3[C@@H]2CC[C@]2(C)CCC[C@@H]32)C1
Temperature: 130 °C
Reaction time: 0.25 h

Procedure:
Potassium hydroxide (1.5 g, 27 mmol) and hydrazine monohydrate (3 ml, 62 mmol) were added to a suspension of (7α)-3,3-dimethoxy-7-methylestr-5(10)-en-17-one (1 g, 3 mmol) in 17 mL diethyleneglycol at room temperature under a nitrogen atmosphere. The reaction mixture was heated for 1 hour at 130° C. followed by 1 hour and 15 minutes at 230° C. A Dean-Stark trap was used to remove the water and the excess of hydrazine. The reaction mixture was cooled down to room temperature and water was added and extracted with ethyl acetate. The organic layer was washed with brine, dried (Na2SO4) and evaporated to dryness to give the crude product (7α)-3,3-dimethoxy-7-methylestr-5(10)-ene, which was converted into (7α,16α,17β)-7,16-dimethyl-3-methylene-17-(1-propynyl)estr-5(10)-en-17-ol according to the procedures described above, mp 57° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C:11](=[CH2:13])[CH2:10][CH:9]1[C:14]1[NH:15][C:16]([C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:34]=[CH:33][C:32]4[C:27](=[CH:28][CH:29]=[C:30]([C:35]5[NH:36][C:37]([CH:40]6[CH2:44][CH2:43][CH2:42][N:41]6[C:45](=[O:55])[CH:46]([NH:50][C:51]([O:53][CH3:54])=[O:52])[CH:47]([CH3:49])[CH3:48])=[N:38][CH:39]=5)[CH:31]=4)[CH:26]=3)=[CH:21][CH:20]=2)=[CH:17][N:18]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:56]OC(=O)NC(C(N1CCCC1C1NC(C2C=CC3C(=CC=C(Br)C=3)C=2)=CN=1)=O)C(C)C.C(OC(N1C(C2NC(C3C=CC(B4OC(C)(C)C(C)(C)O4)=CC=3)=CN=2)C2CC1CC2)=O)(C)(C)C>>[C:1]([O:5][C:6]([N:8]1[CH:9]([C:14]2[NH:15][C:16]([C:19]3[CH:20]=[CH:21][C:22]([C:25]4[CH:34]=[CH:33][C:32]5[C:27](=[CH:28][CH:29]=[C:30]([C:35]6[NH:36][C:37]([CH:40]7[CH2:44][CH2:43][CH2:42][N:41]7[C:45](=[O:55])[CH:46]([NH:50][C:51]([O:53][CH3:54])=[O:52])[CH:47]([CH3:48])[CH3:49])=[N:38][CH:39]=6)[CH:31]=5)[CH:26]=4)=[CH:23][CH:24]=3)=[CH:17][N:18]=2)[CH:10]2[CH2:56][CH:12]1[CH2:13][CH2:11]2)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc3cc(Br)ccc3c2)[nH]1)C(C)C
Reactant: C=C1CC(c2ncc(-c3ccc(-c4ccc5cc(-c6cnc(C7CCCN7C(=O)C(NC(=O)OC)C(C)C)[nH]6)ccc5c4)cc3)[nH]2)N(C(=O)OC(C)(C)C)C1
Agent: CC(C)(C)OC(=O)N1C2CCC(C2)C1c1ncc(-c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)[nH]1
Product: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc3cc(-c4ccc(-c5cnc(C6C7CCC(C7)N6C(=O)OC(C)(C)C)[nH]5)cc4)ccc3c2)[nH]1)C(C)C
Yield: 63 %

Procedure:
This compound was synthesized using the procedure used to synthesize 2-{5-[4-(6-{2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-naphthalen-2-yl)-phenyl]-1H-imidazol-2-yl}-4-methylene-pyrrolidine-1-carboxylic acid tert-butyl ester using (1-{2-[5-(6-Bromo-naphthalen-2-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (0.200 g, 0.400 mmol) and 3-{5-[4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1H-imidazol-2-yl}-2-azabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (0.224 g, 0.481 mmol) giving 3-{5-[4-(6-{2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-naphthalen-2-yl)-phenyl]-1H-imidazol-2-yl}-2-aza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (0.192 g, 63% yield). LCMS-ESI+: calc'd for C44H51N7O5: 757.40 (M+); Found: 758.78 (M+H+).
Reaction SMILES: C(O)C.[C:4]([C:7]1[C:15]2[S:14][C:13](=[O:16])[NH:12][C:11]=2[C:10]([OH:17])=[CH:9][CH:8]=1)(=[O:6])[CH3:5].I([Cl:21])(=O)=O.I(Cl)(=O)=O.C([N+](C)(C)C)C1C=CC=CC=1>O>[Cl:21][CH2:5][C:4]([C:7]1[C:15]2[S:14][C:13](=[O:16])[NH:12][C:11]=2[C:10]([OH:17])=[CH:9][CH:8]=1)=[O:6]
Reactant: O=I(=O)Cl
Reactant: CC(=O)c1ccc(O)c2[nH]c(=O)sc12
Agent: C[N+](C)(C)Cc1ccccc1
Solvent: CCO
Solvent: O
Product: O=C(CCl)c1ccc(O)c2[nH]c(=O)sc12
Temperature: 78 °C

Procedure:
Ethanol (1500 mL) was added to a mixture of 7-acetyl-4-hydroxy-3H-benzothiazol-2-one (150 g) (WO2004/016578) and benzyltrimethylammonium dichloroiodate (374 g) in a flask fitted with an overhead stirrer. The mixture was heated to 78° C. for 1 h and left to cool to room temperature overnight. The mixture was poured into water (2 L), and the precipitate collected by filtration, washed with water, filtered to near dryness, and suspended in ethyl acetate. The mixture was heated to reflux and allowed to cool to room temperature with stirring. The solid was collected by filtration, washed with cold ethyl acetate (200 mL) then re-suspended in diethyl ether (1 L). The solid was collected, filtered again and washed with ether (200 mL) and dried in vacuo to give the subtitled compound. Yield 164 g.
Reaction SMILES: C(OC([NH:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[N:17](C(OCC1C=CC=CC=1)=O)[C@H:16]([CH3:31])[CH2:15]2)=O)C1C=CC=CC=1.[H][H]>C1COCC1.CO.[Pd]>[CH3:31][C@@H:16]1[CH2:15][C:14]2[C:18](=[CH:19][CH:20]=[C:12]([NH2:11])[CH:13]=2)[NH:17]1
Reactant: [H][H]
Reactant: C[C@@H]1Cc2cc(NC(=O)OCc3ccccc3)ccc2N1C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: C[C@@H]1Cc2cc(N)ccc2N1

Procedure:
A mixture of benzyl (2R)-5-{[(benzyloxy)carbonyl]amino}-2-methyl-2,3-dihydro-1H-indole-1-carboxylate (PCT/US00/08224; WO00/73301, 3.36 g, 8.07 mmol) and 10% palladium-on-carbon (108 mg) in THF/MeOH (1:1, 60 mL) is shaken on a Parr apparatus under a 36 psi hydrogen atmosphere overnight. The catalyst is removed by filtration through a pad of Celite, and the filtrate is concentrated under reduced pressure. Purification by chromatography on a Biotage Flash 40M 90 g silica gel cartridge (1–2% MeOH/CH2Cl2) affords the title compound, MS (ESI+) for C9H12N2 m/z 149 (M+H)+.
Reaction SMILES: [CH2:1]([O:4][C:5](=[O:16])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[C:9]([O:14][CH3:15])[CH:8]=1)[CH2:2][CH3:3].C([O-])([O-])=O.[K+].[K+].Cl[CH2:24][C:25]([N:27]([CH2:30][CH3:31])[CH2:28][CH3:29])=[O:26]>CC(C)=O>[CH2:1]([O:4][C:5](=[O:16])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:24][C:25](=[O:26])[N:27]([CH2:30][CH3:31])[CH2:28][CH3:29])=[C:9]([O:14][CH3:15])[CH:8]=1)[CH2:2][CH3:3]
Reactant: CCN(CC)C(=O)CCl
Reactant: CCCOC(=O)Cc1ccc(O)c(OC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCOC(=O)Cc1ccc(OCC(=O)N(CC)CC)c(OC)c1
Temperature: 60 °C
Yield: 95 %

Procedure:
3-Methoxy-4-hydroxyphenylacetic acid propyl ester (15-A) was dissolved in acetone. To the solution, 2 equivalents of K2CO3 were added, followed by 1.2 equivalent of 2-chloro-N,N-diethylacetamide. Under vigorous stirring, the suspension was warmed to reflux (60° C.) for ˜15 hours. After cooling to room temperature the reaction mixture was filtered and the remaining solvent removed under reduced pressure, giving a 95% yield of a dark yellow oil. The oily product was purified by silica column chromatography to produce the title compound.
Reaction SMILES: [O:1]=[C:2]1[N:8]([CH2:9][C:10]([N:12]([CH:21]([CH3:23])[CH3:22])[C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)=[O:11])[C:7]2[CH:24]=[CH:25][CH:26]=[CH:27][C:6]=2[N:5]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:4](=[O:34])[CH2:3]1.[CH2:35]([N:42]1[C:50]2[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=2)[C:44]([CH2:51]Br)=[N:43]1)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>CN(C=O)C.C1(C)C=CC=CC=1>[CH2:35]([N:42]1[C:50]2[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=2)[C:44]([CH2:51][CH:3]2[C:2](=[O:1])[N:8]([CH2:9][C:10]([N:12]([CH:21]([CH3:23])[CH3:22])[C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)=[O:11])[C:7]3[CH:24]=[CH:25][CH:26]=[CH:27][C:6]=3[N:5]([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[C:4]2=[O:34])=[N:43]1)[C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1
Reactant: BrCc1nn(Cc2ccccc2)c2ccccc12
Reactant: COc1ccc(N(C(=O)CN2C(=O)CC(=O)N(c3ccccc3)c3ccccc32)C(C)C)cc1
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: COc1ccc(N(C(=O)CN2C(=O)C(Cc3nn(Cc4ccccc4)c4ccccc34)C(=O)N(c3ccccc3)c3ccccc32)C(C)C)cc1
Reaction time: 0.17 h
Yield: 84.7 %

Procedure:
To a stirring solution of 490 mg (1.08 mmol) of 2-(2,4-Dioxo-5-phenyl-2,3,4,5-tetrahydro-benzo[b][1,4]diazepin-1-yl)-N-isopropyl-N-(4-methoxy-phenyl) acetamide, prepared as in Intermediate 4, in 12 mL DMF at 0° C. is added dropwise over 5 min 2.35 mL (1.18 mmol, 1.1 equiv) of a 0.5M solution of KN(TMS)2 in toluene. The resulting solution is stirred 10 min, then a solution of 355 mg (1.18 mmol, 1.1 equiv) of 1-Benzyl-3-bromomethyl-1H-indazole in 3 mL DMF is added. The resulting solution is stirred 4.5 h at RT and then quenched with 5 mL of H2O. The reaction mixture is then poured into 50 mL of EtOAc and extracted with H2O (2×50 mL). The organic layer is separated, dried (MgSO4), and the solvents removed in vacuo. Purification of the material by silica gel flash column chromatography using hexane/EtOAc 3/2 as eluent followed by lyophilization in acetonitrile/H2O afforded 620 mg of the title compound as a white amorphous solid: 1H NMR (CDCl3, 300 MHz) δ7.86 (d, 1H, J=8.1), 7.40 (d, 1H, J=7.9), 7.33-6.88 (m, 20H), 5.43 (s, 2H), 5.00 (m, 1H), 4.25 (m, 3H), 3.85 (m,4H), 3.58 (dd, 1H, J=5.1, 16.0), 1.06 (d, 6H, J=6.6); low resolution MS (FAB)m/e 678 (MH+), 677 (M+),
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[S:10]([NH:13][C:14]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=1[S:21][CH2:22][CH2:23][C:24]([O:26][CH3:27])=[O:25])(=[O:12])=[O:11].C1C=C(Cl)C=C(C(OO)=[O:36])C=1>C(Cl)Cl.CCOC(C)=O>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[S:10]([NH:13][C:14]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=1[S:21]([CH2:22][CH2:23][C:24]([O:26][CH3:27])=[O:25])=[O:36])(=[O:11])=[O:12]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COC(=O)CCSc1ccc(Cl)cc1NS(=O)(=O)c1cc2ccccc2o1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COC(=O)CCS(=O)c1ccc(Cl)cc1NS(=O)(=O)c1cc2ccccc2o1
Temperature: 25 °C
Reaction time: 1 h
Yield: 45.8 %

Procedure:
To a solution of methyl 3-({2-[(1-benzofuran-2-ylsulfonyl)amino]-4-chlorophenyl}sulfanyl)propanoate (181 mg, 0.43 mmol) in CH2Cl2 (4 ml) was added mCPBA (153 mg, ˜0.64 mmol). The reaction was stirred at room temperature for 1 hour, diluted with EtOAc, extracted with saturated aqueous NaHCO3 and brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (25-100% EtOAc in hexane, then 10% MeOH in CH2Cl2) to yield the title compound (87 mg, 46%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:16]=[C:17]([Cl:19])[CH:18]=1)[O:5][NH:6][C:7](=[O:15])OC1C=CC=CC=1.[C:20]([NH2:29])([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([CH3:22])[CH3:21].C(N(CC)CC)C>O1CCCC1>[Br:1][C:2]1[CH:3]=[C:4]([CH:16]=[C:17]([Cl:19])[CH:18]=1)[O:5][NH:6][C:7]([NH:29][C:20]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([CH3:22])[CH3:21])=[O:15]
Reactant: CC(C)(N)c1ccccc1
Reactant: O=C(NOc1cc(Cl)cc(Br)c1)Oc1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(NC(=O)NOc1cc(Cl)cc(Br)c1)c1ccccc1
Reaction time: 5 h
Yield: 86 %

Procedure:
3.00 g of phenyl 3-bromo-5-chlorophenoxycarbamate was dissolved in 50 ml of tetrahydrofuran. The resulting solution was added to a mixture of 1.54 g of cumylamine and 1.15 g of triethylamine, followed by stirring for 5 hours, while being heated to reflux. The reaction solvent was then distilled off under reduced pressure. The resulting residue was partially purified by silica gel column chromatography (eluent: hexane:ethyl acetate=3:1). The resulting crude crystal was washed with hexane to obtain 1-(3-Bromo-5-chlorophenoxy)-3-(2-phenylpropan-2-yl)urea (2.89 g, yield: 86%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[NH:14][C:13](=O)[CH:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.CN(C)C1C=CC=CC=1.P(Cl)(Cl)([Cl:27])=O.[OH-].[Na+]>C1(C)C=CC=CC=1>[Cl:27][C:13]1[CH:12]=[CH:11][N:10]=[C:9]([NH:8][C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[N:14]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1ccnc(Nc2cccc(Cl)c2)[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)c1ccccc1
Solvent: Cc1ccccc1
Product: Clc1cccc(Nc2nccc(Cl)n2)c1
Yield: 61 %

Procedure:
To 2-(3-chlorophenylamino)pyrimidin-4(3H)-one, 2, (3.00 g, 13.5 mmol) in toluene (30 mL) is added N,N-dimethyl-aniline (3.57 mL, 28.4 mmol) and phosphorus oxychloride (1.24 mL, 13.5 mmol). The resulting mixture is heated to reflux for 15 minutes, cooled to room temperature and neutralized to pH 7 with 1M NaOH (aqueous). The organic layer is extracted with EtOAc (3×250 mL). The combined organic layers are dried (MgSO4) and concentrated in vacuo. The residue is purified over silica (5% EtOAc in hexanes) to afford 2.0 g (61% yield) of the desired compound. 1H NMR (DMSO-d6, 300 MHz): δ 7.06-7.04 (m, 2H), 7.34 (t, J=8.1, 1H), 7.65-7.61 (m, 1H), 7.93 (m, 1H), 8.50 (d, J=5.1 Hz, 1H), 10.26 (s, 1H).
Reaction SMILES: O.O.O.[C:4]1([O-:10])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[Na+].[CH2:12](Cl)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CO>[CH2:12]([O:10][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: ClCc1ccccc1
Reactant: [O-]c1ccccc1
Agent: [Na+]
Solvent: CO
Solvent: O
Product: c1ccc(COc2ccccc2)cc1
Yield: 66.9 %

Procedure:
A mixture of sodium phenolate trihydrate (10.2 g; 60 mmole) and benzyl chloride (6.4 ml; 56 mmole) in methanol (150 ml) was pumped through the system (15 ml/minute; 146°-7° C.; 1000-1050 kPa). The MeOH was rotary evaporated off and the residue recrystallised from EtOH to afford colourless needles of phenyl benzyl ether (6.9 g; 67% yield), m.p. 36°-36.3° C.
Reaction SMILES: Cl[C:2]1[C:3]([N+:11]([O-:13])=[O:12])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].[OH-:14].[K+].Cl>O>[OH:14][C:2]1[C:3]([N+:11]([O-:13])=[O:12])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6]
Reactant: [OH-]
Reactant: O=C(O)c1cccc(Cl)c1[N+](=O)[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Product: O=C(O)c1cccc(O)c1[N+](=O)[O-]
Yield: 150.2 %

Procedure:
A mixture of 3-chloro-2-nitrobenzoic acid (40 g, 0.20 mol) and KOH (160 g, 2.86 mol) in water (200 mL) was heated to reflux for 16 hr. 6N aqueous hydrochloric acid was added to the mixture to pH=3, then extracted with ethyl acetate (500 mL×4). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated to give 3-hydroxy-2-nitrobenzoic acid (55 g), LC-MS (ESI) m/z 184 [M+1]−.
Reaction SMILES: [C-:1]#[N:2].[K+].Br[CH2:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([Br:14])=[CH:10][CH:9]=1)=[O:7].C.Cl>O.C(O)C>[Br:14][C:11]1[CH:12]=[CH:13][C:8]([C:6](=[O:7])[CH2:5][C:1]#[N:2])=[CH:9][CH:10]=1
Reactant: O=C(CBr)c1ccc(Br)cc1
Reactant: [C-]#N
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CCO
Product: N#CCC(=O)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 47.3 %

Procedure:
A solution containing 9.4 g of KCN in 20 ml of water is prepared and then it is poured dropwise over a mixture containing 20 g of 2-bromo-1-(4-bromophenyl)ethanone dissolved in 800 ml of 90% ethanol. After stirring for 5 hours at RT, the solid formed is filtered and then it is rinsed with ice-cold water. The solid obtained is dissolved in 400 ml of water and then activated charcoal is added, the mixture is kept stirring for 20 minutes, and then filtered on Celite®. The filtrate obtained is treated with HCl at 10% and the white precipitate formed is filtered, washed with water and then dried under vacuum. 7.63 g of the expected compound are obtained. m.p.=164° C.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][N:3]=1.[C-:9]#[N:10].[Na+]>CS(C)=O.C(OCC)(=O)C>[C:9]([C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][N:3]=1)#[N:10]
Reactant: [C-]#N
Reactant: Fc1cc(I)ccn1
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: N#Cc1cc(I)ccn1
Temperature: 100 °C
Yield: 5 %

Procedure:
2-Fluoro-4-iodopyridine (4.99 g, 22.4 mmol) prepared according to a known method (WO2005/041663) was dissolved in dimethyl sulfoxide (75 mL), and the mixture was stirred at 100° C. after adding sodium cyanide (1.21 g, 24.7 mmol). The reaction mixture was diluted with ethyl acetate, and the organic layer was washed with an aqueous sodium bicarbonate solution and saturated brine. The organic layer was dried over anhydrous magnesium sulfate. The residue obtained upon concentration under reduced pressure was purified by silica gel column chromatography to give 2-cyano-4-iodopyridine (258 mg, 5%).
Reaction SMILES: N#N.[C:3]1(=[O:10])[CH2:8][CH2:7][CH2:6][CH2:5][C:4]1=O.[NH:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1>C1(C)C=CC=CC=1>[N:11]1([C:4]2[C:3](=[O:10])[CH2:8][CH2:7][CH2:6][CH:5]=2)[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1
Reactant: O=C1CCCCC1=O
Reactant: C1COCCN1
Agent: N#N
Solvent: Cc1ccccc1
Product: O=C1CCCC=C1N1CCOCC1
Yield: 95.4 %

Procedure:
Synthesis based on literature modified procedure (Ōhashi, M.; Takahashi, T.; Inoue, S.; Sato, K. Bulletin Chemical Society of Japan, 1975; 48:1892). A 500-mL round-bottomed flask is equipped with a Dean Stark, condenser, stir bar and gas inlet (N2 gas atmosphere). The flask is charged with of 1,2-cyclohexanedione (15.14 g, 135.00 mmol), morpholine (14.82 g, 170.10 mmol) and toluene (330 mL). The resulting yellow solution is heated to reflux for 5 hours. Heating is stopped and about 3.0 mL of water are collected on the Dean Stark. The brown solution is decanted away from a thick oil and rinsed with toluene. The solution is concentrated under high vacuum to afford 23.33 g (95.34% yield) of title compound of Preparation 2 as a brown solid.
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([C:13]#[N:14])[CH:8]=2)=[CH:4][CH:3]=1.[N-:17]=[N+:18]=[N-:19].[Na+].[Cl-].[NH4+]>CN(C=O)C>[NH:17]1[C:13]([C:9]2[CH:8]=[C:7]([O:6][C:5]3[CH:15]=[CH:16][C:2]([NH2:1])=[CH:3][CH:4]=3)[CH:12]=[CH:11][N:10]=2)=[N:14][N:19]=[N:18]1
Reactant: N#Cc1cc(Oc2ccc(N)cc2)ccn1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Nc1ccc(Oc2ccnc(-c3nnn[nH]3)c2)cc1
Temperature: 70 °C

Procedure:
A mixture of 4-(4-amino-phenoxy)-pyridine-2-carbonitrile (Example 102) (2.6 g, 12.3 mmol), sodium azide (6.6 g, 102 mmol, 8.3 equiv), and ammonium chloride in DMF abs. (180 mL) is heated to 70° C. for 7.5 h, under an argon atmosphere. The reaction mixture is allowed to cool to rt, filtered through a glass sintered funnel and concentrated in vacuo. The residue is purified by silica gel (390 g) column chromatography (CH2Cl2/MeOH, 80/20) to afford the title compound as a beige solid: ES-MS: 255.0 [M+H]+; single peak at tR=3.98 min (System 2); Rf=0.20 (CH2Cl2/MeOH, 75/25).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]=[CH:7][NH:8]2)([O-:3])=[O:2].[OH-].[K+].[Br:15][CH2:16][CH2:17][CH2:18]Br>CN(C=O)C.O>[Br:15][CH2:16][CH2:17][CH2:18][N:8]1[C:9]2[C:5](=[C:4]([N+:1]([O-:3])=[O:2])[CH:12]=[CH:11][CH:10]=2)[CH:6]=[CH:7]1
Reactant: BrCCCBr
Reactant: O=[N+]([O-])c1cccc2[nH]ccc12
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1cccc2c1ccn2CCCBr
Temperature: 25 °C
Reaction time: 12 h
Yield: 93.2 %

Procedure:
To a solution of 4-nitroindole (5 g, 31 mmol) in anhydrous N,N′-dimethylformamide (200 mL) was added grounded potassium hydroxide (1.74 g, 31 mmol) in portions. Then a solution of 1,3-dibromopropane (18 g, 89 mmol) in N,N′-dimethylformamide was added dropwise. The mixture was stirred at room temperature for 12 hours, diluted with water and extracted with ethyl acetate. The organic phases were combined, washed by brine, dried over anhydrous sodium sulfate, filtrated and evaporated. The residue was purified by silica gel chromatography to afford the product 1-(3-bromopropyl)-4-nitro-1H-indole as brown-red oil (8.18 g, yield 94%).
Reaction SMILES: [Si:1]([O:8][CH2:9][C@H:10]([N:25]1[CH:29]=[C:28]([C:30]([NH2:32])=[O:31])[N:27]=[CH:26]1)[CH2:11][CH2:12][N:13]1[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([N+:22]([O-])=O)[CH:20]=2)[CH:15]=[CH:14]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Cl-].[NH4+]>C(O)C.O.[Fe]>[NH2:22][C:19]1[CH:20]=[C:21]2[C:16]([CH:15]=[CH:14][N:13]2[CH2:12][CH2:11][C@@H:10]([N:25]2[CH:29]=[C:28]([C:30]([NH2:32])=[O:31])[N:27]=[CH:26]2)[CH2:9][O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])=[CH:17][CH:18]=1
Reactant: CC(C)(C)[Si](C)(C)OC[C@@H](CCn1ccc2ccc([N+](=O)[O-])cc21)n1cnc(C(N)=O)c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: CC(C)(C)[Si](C)(C)OC[C@@H](CCn1ccc2ccc(N)cc21)n1cnc(C(N)=O)c1
Temperature: 90 °C
Reaction time: 0.67 h
Yield: 94.7 %

Procedure:
To a mechanically stirred mixture of 1-[(R)-1-(tert-butyldimethylsilyloxy)-4-(6-nitroindol-1-yl)-2-butyl]imidazole-4-carboxamide (450 mg, 0.98 mmol) and ammonium chloride (45 mg) in ethanol (10 ml) and water (5 ml) was added portionwise iron powder (450 mg) at 90° C. The resulting mixture was stirred for 40 minutes at 90° C. After cooling, the insoluble material was filtered through Celite and washed with ethanol and ethyl acetate. The filtrate and the washing were combined and concentrated in vacuo. The resulting residue was extracted with ethyl acetate and washed with brine. The organic layer was dried (sodium sulfate) and concentrated in vacuo to give 1-[(R)-4-(6-aminoindol-1-yl)-1-(tert-butyldimethylsilyloxy)-2-butyl]imidazole-4-carboxamide (397 mg, 94.7%). This material was used for the next reaction without further purification.