Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS[C:3](SC)=[C:4]1[C:13](=[O:14])[C:12]([CH2:19][CH2:20][CH2:21][CH3:22])([CH2:15][CH2:16][CH2:17][CH3:18])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]1=[O:23].[NH2:26][C:27]1[S:28][CH:29]=[C:30]([CH2:36][O:37][CH2:38][O:39][CH3:40])[C:31]=1[S:32]([NH2:35])(=[O:34])=[O:33]>C1(C)C=CC=CC=1>[CH2:15]([C:12]1([CH2:19][CH2:20][CH2:21][CH3:22])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([OH:23])=[C:4]([C:3]2[NH:26][C:27]3[S:28][CH:29]=[C:30]([CH2:36][O:37][CH2:38][O:39][CH3:40])[C:31]=3[S:32](=[O:33])(=[O:34])[N:35]=2)[C:13]1=[O:14])[CH2:16][CH2:17][CH3:18]
Reactant: CCCCC1(CCCC)C(=O)C(=C(SC)SC)C(=O)c2ccccc21
Reactant: COCOCc1csc(N)c1S(N)(=O)=O
Solvent: Cc1ccccc1
Product: CCCCC1(CCCC)C(=O)C(C2=NS(=O)(=O)c3c(COCOC)csc3N2)=C(O)c2ccccc21
Temperature: 25 °C
Yield: 56.3 %

Procedure:
A mixture of the product of Example 5C (66 mg, 0.18 mmol) and the product of Example 10E (44 mg, 0.18 mmol) in toluene (10 mL) was stirred at reflux for 2 h, cooled to 25° C. and concentration in vacuo. The residue was chromatographed on silica gel, eluting with ethyl acetate in hexane to give the title compound (54 mg, 58%). 1H NMR (300 MHz, CDCl3): δ 16.44 (s, 1 H), 15.03, 14.86 (two s, 1 H), 8.27 (m, 1 H), 7.69 (m, 1 H), 7.49 (t, J=7.17 Hz, 1 H), 7.26 (m, 1 H), 7.08 (s, 1 H), 4.84 (s, 2 H), 4.80 (s, 2 H), 3.45 (s, 3 H), 2.33 (m, 2 H), 1.95 (m, 2 H), 1.13 (m, 4 H), 0.86 (m, 2 H), 0.69 (m, 6 H), 0.56 (m, 2 H).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH2:12][C:13]([O:15][CH3:16])=[O:14])[CH:9]=[CH:10][CH:11]=1.[Cl:17][C:18]1[C:39]([C:40]([F:43])([F:42])[F:41])=[CH:38][CH:37]=[CH:36][C:19]=1[CH2:20][NH:21][CH2:22][CH:23]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Cl:17][C:18]1[C:39]([C:40]([F:41])([F:42])[F:43])=[CH:38][CH:37]=[CH:36][C:19]=1[CH2:20][N:21]([CH2:22][CH:23]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH2:12][C:13]([O:15][CH3:16])=[O:14])[CH:9]=[CH:10][CH:11]=1
Reactant: COC(=O)Cc1cccc(OCCCBr)c1
Reactant: FC(F)(F)c1cccc(CNCC(c2ccccc2)c2ccccc2)c1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)Cc1cccc(OCCCN(Cc2cccc(C(F)(F)F)c2Cl)CC(c2ccccc2)c2ccccc2)c1
Reaction time: 96 h
Yield: 81.5 %

Procedure:
A solution of methyl [3-(3-bromopropoxy)phenyl]acetate (1.0 g, 3.48 mmole) and N-[2-chloro-3-(trifluoromethyl)benzyl]-2,2-diphenylethanamine (1.63 g, 4.18 mmole) in 20 mL of acetonitrile was treated with potassium carbonate (0.72 g, 5.2 mmol). The reaction mixture was heated to reflux and stirred for 4 days. The reaction mixture was filtered, and the filtrate was concentrated in vacuo. The crude product was purified by flash chromatography (silica gel cartridge, Biotage 32-63 um, 60A) with 10% EtOAc:hexanes as the eluent to afford 1.69 g (81% yield) of the title compound as a viscous oil: 1H NMR (CDCl3, 400 MHz) δ 7.46-7.44 (d, 1 H, J=7.7), 7.25-7.14 (m, 12 H), 6.91-6.84 (m, 2 H), 6.66-6.62 (m, 2 H), 4.15-4.09 (t, 1 H. J=7.6), 3.78 (s, 1 H), 3.69-3.66 (m, 5 H), 3.59(S, 2 H), 3.15-3.13 (d, 2 H, J=7.7), 2.72-2.68 (t, 2 H, J=6.6), 1.87-1.80 (m, 2 H); MS (ESP+) m/e 597 (MH+); TLC (hexanes:EtOAc/9:1) Rf=0.36.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][C:11]2([C:17]3[CH:18]=[N:19][CH:20]=[CH:21][C:16]=3[CH2:15][O:14]2)[CH2:10][CH2:9]1)C1C=CC=CC=1>FC(F)(F)CO.[Pd]>[NH:8]1[CH2:9][CH2:10][C:11]2([C:17]3[CH:18]=[N:19][CH:20]=[CH:21][C:16]=3[CH2:15][O:14]2)[CH2:12][CH2:13]1
Reactant: c1ccc(CN2CCC3(CC2)OCc2ccncc23)cc1
Agent: [Pd]
Solvent: OCC(F)(F)F
Product: c1cc2c(cn1)C1(CCNCC1)OC2
Reaction time: 20 h
Yield: 107.8 %

Procedure:
A solution of 0.22 g (0.78 mmol) 1′-benzyl-1H-spiro[furo[3,4-c]pyridine-3,4′-piperidine] in 8 ml 2,2,2-trifluoroethanol was purged with argon prior to adding 0.08 g (10 mol %) palladium on activated charcoal. The flask was evacuated, refilled with hydrogen gas and stirred under an atmosphere of hydrogen gas for 20 h. The catalyst was filtered off and washed with ethanol. The filtrate was concentrated to dryness to give the title compound (0.16 g, quantitative, purity of approximately 95%) as a light yellow amorphous solid.
Reaction SMILES: [F:1][C@@H:2]1[CH2:6][CH2:5][N:4]([CH:7]2[CH2:12][CH2:11][N:10]([C:13]3[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[C:15]([O:22][CH3:23])[CH:14]=3)[CH2:9][CH2:8]2)[CH2:3]1.FC1(F)CCCN(C2CCN(C3C=CC(N)=C(OC)C=3)CC2)C1>>[F:1][C@@H:2]1[CH2:6][CH2:5][N:4]([CH:7]2[CH2:12][CH2:11][N:10]([C:13]3[CH:18]=[CH:17][C:16]([NH2:19])=[C:15]([O:22][CH3:23])[CH:14]=3)[CH2:9][CH2:8]2)[CH2:3]1
Reactant: COc1cc(N2CCC(N3CC[C@@H](F)C3)CC2)ccc1[N+](=O)[O-]
Agent: COc1cc(N2CCC(N3CCCC(F)(F)C3)CC2)ccc1N
Product: COc1cc(N2CCC(N3CC[C@@H](F)C3)CC2)ccc1N
Yield: 86.1 %

Procedure:
4-[(3R)-3-fluoro-1-pyrrolidinyl]-1-[3-(methyloxy)-4-nitrophenyl]piperidine (1.33 g, 4.0 mmol) was reduced in a manner analogous to 4-(3,3-difluoro-1,4′-bipiperidin-1′-yl)-2-(methyloxy)aniline (Intermediate B38) above. The filtrate was washed with water, dried over magnesium sulfate and concentrated to give 4-{4-[(3R)-3-fluoro-1-pyrrolidinyl]-1-piperidinyl}-2-(methyloxy)aniline (1.01 g, 86% yield). 1H NMR (400 MHz, d6-DMSO) δ 6.48-6.45 (m, 2H), 6.26 (dd, J=8.4 and 2.4 Hz, 1H), 5.24-5.07 (m, 1H), 4.16 (s, 2H), 3.70 (s, 3H), 3.33-3.30 (m, 2H), 2.88-2.76 (m, 2H), 2.69-2.56 (m,1H), 2.54-2.46 (m under DMSO peak, 2H), 2.37-2.31 (m, 1H), 2.14-1.99 (m, 2H), 1.90-1.75 (m, 3H), 1.51-1.41 (m, 2H).
Reaction SMILES: C[Si]([C:5]#[C:6][C:7]1[N:11]([C@@H]2O[C@H](COC(=O)C)[C@@H](OC(=O)C)[C@H]2OC(=O)C)[CH:10]=[N:9][C:8]=1[C:30]#[N:31])(C)C.[OH-].[Na+]>Cl.CO>[C:6]([C:7]1[NH:11][CH:10]=[N:9][C:8]=1[C:30]#[N:31])#[CH:5]
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cnc(C#N)c2C#C[Si](C)(C)C)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: C#Cc1[nH]cnc1C#N
Temperature: 100 °C
Yield: 95.7 %

Procedure:
A solution of 447 mg (1 mmol) of 5-trimethylsilylethynyl-1-(2,3,5-tri-O-acetyl-β-D-ribofuranosyl) imidazole-4-carbonitrile in a 1N hydrochloric acid-methanol (10 ml: 5 ml) solvent mixture was heated under reflux at 100° C. for 4 hours. After the reaction, the reaction solution was neutralized with 1N sodium hydroxide solution, silica gel powder was added, and the solvent was evaporated. The residue was adsorbed onto a silica gel column (2.7×13 cm), eluted with a 0-8% ethanol-chloroform solvent mixture, and crystallized from water-containing methanol to obtain 112 mg of pale yellow crystals of 5-ethynylimidazole-4-carbonitrile (yield: 95.7%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[CH:7]2.[H-].[Na+].[CH:13]1([CH2:19]Br)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([CH2:19][CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)[CH:8]=[CH:7]2
Reactant: BrCC1CCCCC1
Reactant: Clc1cccc2cc[nH]c12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Clc1cccc2ccn(CC3CCCCC3)c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.8 %

Procedure:
To a solution of 7-chloroindole (4.91 g, 32.4 mmol) in dimethylformamide (60 ml) at 0° C. under nitrogen was added sodium hydride (60% dispersion in mineral oil, 1.43 g, 35.6 mmol). The mixture was stirred for 1 h at room temperature. Cyclohexylmethyl bromide (5.0 ml, 35.6 mmol) was added at 0° C. The mixture was stirred for 18 h at room temperature. To the reaction mixture was added sodium hydride (60% dispersion in mineral oil, 358 mg, 8.94 mmol). After stirring for 15 mins, cyclohexylmethyl bromide (1.25 ml, 8.96 mmol) was added. The mixture was heated at 70° C. with stirring for 1.5 h. After cooling to room temperature, the mixture was partitioned between dichloromethane and water. The aqueous layer was extracted with dichloromethane and combined organic layers were washed with brine, dried over sodium sulfate and concentrated in vacuo. The obtained residue was purified by column chromatography eluting with 0-5% (v/v) ethyl acetate in n-heptane to afford 7-chloro-1-cyclohexylmethylindole (8.1 g, 32.0 mmol).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:17](=[O:18])[C:16]2[C:19]3[N:8]([N:9]([CH3:45])[CH2:10][O:11][C:12]=3[C:13]([N:21]3[CH2:26][CH2:25][N:24]([C:27]4[CH:32]=[CH:31][C:30]([N:33]5[CH2:37][C@H:36]([CH2:38][NH:39][C:40](=[O:42])[CH3:41])[O:35][C:34]5=[O:43])=[CH:29][C:28]=4[F:44])[CH2:23][CH2:22]3)=[C:14]([F:20])[CH:15]=2)[CH:7]=1)=[O:5])C.Cl.C(O)(=O)C>C(Cl)Cl.C(O)(C(F)(F)F)=O>[C:40]([NH:39][CH2:38][C@@H:36]1[O:35][C:34](=[O:43])[N:33]([C:30]2[CH:31]=[CH:32][C:27]([N:24]3[CH2:23][CH2:22][N:21]([C:13]4[C:12]5=[C:19]6[C:16]([C:17](=[O:18])[C:6]([C:4]([OH:5])=[O:3])=[CH:7][N:8]6[N:9]([CH3:45])[CH2:10][O:11]5)=[CH:15][C:14]=4[F:20])[CH2:26][CH2:25]3)=[C:28]([F:44])[CH:29]=2)[CH2:37]1)(=[O:42])[CH3:41]
Reactant: CCOC(=O)c1cn2c3c(c(N4CCN(c5ccc(N6C[C@H](CNC(C)=O)OC6=O)cc5F)CC4)c(F)cc3c1=O)OCN2C
Agent: Cl
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)NC[C@H]1CN(c2ccc(N3CCN(c4c(F)cc5c(=O)c(C(=O)O)cn6c5c4OCN6C)CC3)c(F)c2)C(=O)O1

Procedure:
44 mg of 9-(4-{4-[(5S)-5-(acetylamino-methyl)-2-oxo-oxazolidin-3-yl]-2-fluoro-phenyl}-piperazin-1-yl)-8-fluoro-3-methyl-6-oxo-2,3-dihydro-6H-1-oxa-3,3a-diaza-phenalene-5-carboxylic acid ethyl ester (0.32 mmol) were heated at 80° C. in 2 ml of a 1/1 conc. HCl and acetic acid mixture. The reaction was monitored by HPLC. The HCl/AcOH mixture was evaporated, the residue dissolved in a methanol/dichloromethane 1/1 mixture, treated with triethylamine and evaporated. The deacetylated residue was dissolved in a 1/1 mixture acetic acid and acetic anhydride, and the reaction monitored by HPLC. The solvents were evaporated and the residue was purified by preparative HPLC.
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]3[C:26]([N:27]([CH3:31])[CH:28]([CH3:30])[CH3:29])=[N:25][C:24]4[C:19](=[CH:20][CH:21]=[C:22]([C:32]([O:34][CH3:35])=[O:33])[CH:23]=4)[N:18]=3)=[CH:14][CH:15]=2)[CH:10]=[N:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O.O>ClCCl>[NH:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]3[C:26]([N:27]([CH3:31])[CH:28]([CH3:30])[CH3:29])=[N:25][C:24]4[C:19](=[CH:20][CH:21]=[C:22]([C:32]([O:34][CH3:35])=[O:33])[CH:23]=4)[N:18]=3)=[CH:14][CH:15]=2)[CH:10]=[N:9]1
Reactant: COC(=O)c1ccc2nc(-c3ccc4c(cnn4C(=O)OC(C)(C)C)c3)c(N(C)C(C)C)nc2c1
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1ccc2nc(-c3ccc4[nH]ncc4c3)c(N(C)C(C)C)nc2c1

Procedure:
A solution of methyl 2-[1-[(tert-butoxy)carbonyl]-1H-indazol-5-yl]-3-[methyl(propan-2-yl)amino]quinoxaline-6-carboxylate (624 mg, 1.31 mmol) and trifluoroacetic acid (4 ml) in dichloromethane (20 ml) was stirred for 1 h at room temperature. The resulting solution was added water (200 ml) and adjusted to pH 8, extracted with dichloromethane (5×50 ml), dried over anhydrous magnesium and concentrated in vacuo to afford methyl 2-(1H-indazol-5-yl)-3-[methyl(propan-2-yl)amino]quinoxaline-6-carboxylate as a yellow solid (442 mg, crude).
Reaction SMILES: [CH:1]([O:4][C:5]([NH:7][C:8]1[CH:17]=[C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:15]=[C:14]([CH3:26])[C:9]=1[C:10]([O:12]C)=[O:11])=[O:6])([CH3:3])[CH3:2]>[OH-].[Na+].COCCOC>[CH:1]([O:4][C:5]([NH:7][C:8]1[CH:17]=[C:16]([O:18][CH2:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:15]=[C:14]([CH3:26])[C:9]=1[C:10]([OH:12])=[O:11])=[O:6])([CH3:3])[CH3:2]
Reactant: COC(=O)c1c(C)cc(OCc2ccccc2)cc1NC(=O)OC(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: COCCOC
Product: Cc1cc(OCc2ccccc2)cc(NC(=O)OC(C)C)c1C(=O)O
Reaction time: 8 h
Yield: 58 %

Procedure:
A solution of methyl 2-isopropoxycarbonylamino-4-benzyloxy-6-methyl-benzoate (171 mg, 0.000487 mol) in sodium hydroxide (4% solution, 10 ml) and 1,2-dimethoxyethane (10 ml) was refluxed for 4 hours and then left at room temperature overnight. The organic solvent was removed under reduced pressure, the aqueous extract was acidified to pH 3 with 5% hydrochloric acid. A white suspension was formed which was extracted with ethyl acetate. The ethyl acetate layer was dried over magnesium sulphate and evaporated to give a solid. This solid was further purified by column chromatography (50% ethyl acetate: pet. ether) to give 2-(isopropoxy)carbonylamino-4-benzyloxy-6-methyl-benzoic acid (97 mg), m.p. 137°-139° C., IR (CHCl3): 2500-3200, 1721, 1660, 1610, 1585, 1520 cm-1 ; H-NMR (acetone-d6): 1.9 (d, 6H, CH3CHCH3), 3.10 (s, 3H, Me), 5.4 (m, 1H, CH3CHCH3), 5.4 (s, 2H, PhCH2), 7.2 (m, 1H, ArH), 8.0 (m, 5H, Ph).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:7]([C:12]([O:14][CH3:15])=[O:13])=[C:8]([OH:11])[C:9]=1[OH:10])=[O:4].N1C=CC=C1.[CH2:28]([C:30]([CH2:35][CH3:36])([CH2:33]O)[CH2:31]O)[CH3:29].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:7]([C:12]([O:14][CH3:15])=[O:13])=[C:8]2[C:9]=1[O:10][CH2:33][C:30]([CH2:35][CH3:36])([CH2:28][CH3:29])[CH2:31][O:11]2)=[O:4]
Reactant: COC(=O)c1c(O)c(O)c(C(=O)OC)n1Cc1ccccc1
Reactant: CCC(CC)(CO)CO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1cc[nH]c1
Solvent: C1CCOC1
Product: CCC1(CC)COc2c(c(C(=O)OC)n(Cc3ccccc3)c2C(=O)OC)OC1

Procedure:
In the present method, 1-Benzyl-3,4-dihydroxy-1H-pyrrole-2,5-dicarboxylic acid dimethyl ester, the pyrrole derivative labeled A4 in FIG. 4 (hereinafter referred to as compound A4) is first synthesized from commercially available chemicals according to prior art techniques (see A. Merz, R. Schropp, E. Dotterl, “3,4-Dialkoxypyrroles and 2,3,7,8,12,13,17,18-Octaalkoxyporphyrins”, Synthesis, 7, pp. 795-800, (1995)). Then, a solution of compound A4, 2,2-diethyl-1,3-propanediol (labeled B4 in FIG. 4), triphenylphosphine (PPh3; labeled C4 in FIG. 4), and diethyl azodicarboxylate (DEAD; labeled D4 in FIG. 4) is refluxed in tetrahydrofuran (THF) for about 10-20 hours (preferably under an inert atmosphere). The reaction mixture is then quenched using a small amount of water, mixed with silica gel, and evaporated to dryness. The resulting material is loaded into a silica gel column and eluded by hexane and dichloromethane (1:1 volume ratio) to yield 2-Benzyl-6,6-diethyl-6,7-dihydro-2H,5H-4,8-dioxa-2-aza-azulene-1,3-dicarboxylic acid dimethyl ester, the pyrrole derivative labeled E4 in FIG. 4 (hereinafter referred to as compound E4).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([N:17]2[CH2:20][CH:19]([C@@H:21]([C:26]3[CH:31]=[C:30]([F:32])[CH:29]=[C:28]([F:33])[CH:27]=3)[C:22]([OH:25])([CH3:24])[CH3:23])[CH2:18]2)[C:9]2[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=2)[C:12]#[N:13])=[CH:4][CH:3]=1.[CH3:34][Si]([N-][Si](C)(C)C)(C)C.[Na+].IC>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@H:8]([N:17]2[CH2:20][CH:19]([C@@H:21]([C:26]3[CH:31]=[C:30]([F:32])[CH:29]=[C:28]([F:33])[CH:27]=3)[C:22]([O:25][CH3:34])([CH3:24])[CH3:23])[CH2:18]2)[C:9]2[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=2)[C:12]#[N:13])=[CH:6][CH:7]=1
Reactant: CC(C)(O)[C@H](c1cc(F)cc(F)c1)C1CN([C@@H](c2ccc(Cl)cc2)c2cccc(C#N)c2)C1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CI
Solvent: C1CCOC1
Product: COC(C)(C)[C@H](c1cc(F)cc(F)c1)C1CN([C@@H](c2ccc(Cl)cc2)c2cccc(C#N)c2)C1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A solution of 46.6 mg (0.1 mmole) of 3-((S)-(4-chlorophenyl){3-[(1S)-1-(3,5-difluorophenyl)-2-hydroxy-2-methylpropyl]azetidin-1-yl}methyl)benzonitrile in THF was cooled to −78° C. To this was added 0.3 mL of a 1M solution of NaHMDS in THF. After 10 minutes, 20 uL of iodomethane was added and the solution was allowed to warm to rt. The solution was partitioned between ethyl acetate and water and the organic layer was washed with brine, dried over MgSO4 and concentrated. The residue was filtered through silica gel using 10% ethyl acetate-hexane to afford the title compound; 1H-NMR(CDCl3) δ 1.07 (s, 3H), 1.14 (S, 3H), 2.28 (t, 1H, J=7.5 Hz), 2.74 (d, 1H, J=10.7 Hz), 2.82 (t, 1H, J=7.5 Hz), 3.10-3.16 (m, 2H), 3.19 (s, 1H), 3.62 (m, 1H), 4.29 (s, 1H), 6.67-6.73 (m, 3H), 7.21-7.4 (m, 8H);); Mass Spectrum: m/e=481 (M+1, 35Cl) and 483 (M+1, 37Cl).
Reaction SMILES: O.[NH2:2][NH2:3].[C:4]([NH:7][C:8]1[CH:9]=[CH:10][C:11]([O:22][CH2:23][CH:24]([OH:31])[CH2:25][NH:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[C:12]([CH:21]=1)[C:13]([CH2:15][CH2:16][C:17](OC)=[O:18])=O)(=[O:6])[CH3:5]>C(O)(=O)C>[C:4]([NH:7][C:8]1[CH:9]=[CH:10][C:11]([O:22][CH2:23][CH:24]([OH:31])[CH2:25][NH:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[C:12]([C:13]2[CH2:15][CH2:16][C:17](=[O:18])[NH:2][N:3]=2)[CH:21]=1)(=[O:6])[CH3:5]
Reactant: NN
Reactant: COC(=O)CCC(=O)c1cc(NC(C)=O)ccc1OCC(O)CNC(C)(C)C
Solvent: CC(=O)O
Solvent: O
Product: CC(=O)Nc1ccc(OCC(O)CNC(C)(C)C)c(C2=NNC(=O)CC2)c1

Procedure:
Hydrazine hydrate (0.0785 ml, 0.00157 mole) was added to a stirred solution of methyl 3-[5-acetamido-2-(3-t-butylamino-2-hydroxypropoxy)benzoyl]propionate (0.21 g, 0.0005 mole) in glacial acetic acid (2 ml) and the solution was heated under reflux for 90 minutes. The residue after evaporation was treated with an excess of sodium bicarbonate solution and the solution evaporated to dryness under reduced pressure. The residue was extracted with dichloromethane and the dried extract evaporated to dryness. An aqueous solution of the residue was washed with two small portions of dichloromethane and then evaporated to an oily residue, which with ethyl acetate gave 6-[5-acetamido-2-(3-t-butylamino-2-hydroxypropoxy)phenyl]-4,5-dihydro-3(2H)-pyridazinone
Reaction SMILES: [CH:1]([N:5]1[CH:9]=[CH:8][C:7]([C:10]2[S:11][CH:12]=[C:13]([CH3:15])[CH:14]=2)=[N:6]1)([CH2:3][CH3:4])[CH3:2].[I:16]N1C(=O)CCC1=O.S([O-])([O-])(=O)=S.[Na+].[Na+].C(=O)([O-])[O-].[Na+].[Na+]>>[CH:1]([N:5]1[CH:9]=[C:8]([I:16])[C:7]([C:10]2[S:11][CH:12]=[C:13]([CH3:15])[CH:14]=2)=[N:6]1)([CH2:3][CH3:4])[CH3:2]
Reactant: O=C1CCC(=O)N1I
Reactant: CCC(C)n1ccc(-c2cc(C)cs2)n1
Agent: O=C([O-])[O-]
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Product: CCC(C)n1cc(I)c(-c2cc(C)cs2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.2 %

Procedure:
To a solution of 1-sec-butyl-3-(4-methyl-2-thienyl)-1H-pyrazole (4.9 mmol) in 14 mL dry 1V, N-dimethylformamide under argon atmosphere was added N-iodosuccinimide (5.1 mmol) in small portions at 0° C. The reaction mixture was allowed to warm to room temperature and was stirred overnight. 5% aqueous sodium thiosulfate solution and saturated aqueous sodium carbonate solution were added and the mixture was stirred at room temperature for 1 h, then extracted with MTBE. The combined organic extracts were successively washed with water and brine, dried over MgSO4, filtered and concentrated. The residue was purified by chromatography on silica gel (cyclohexane:dichloromethane 100:0 to 0:100) to afford 1.36 g 1-sec-butyl-4-iodo-3-(4-methyl-2-thienyl)-1H-pyrazole (78% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]([CH:17]([CH:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)[C:18](O)=[O:19])=[C:15]3[C:10]([CH:11]=[C:12]([F:28])[C:13]([F:27])=[CH:14]3)=[N:9]2)=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[CH:33]1([NH2:39])[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1>CN(C1C=CN=CC=1)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]([CH:17]([CH:21]3[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]3)[C:18]([NH:39][CH:33]3[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]3)=[O:19])=[C:15]3[C:10]([CH:11]=[C:12]([F:28])[C:13]([F:27])=[CH:14]3)=[N:9]2)=[CH:4][CH:3]=1
Reactant: NC1CCCCC1
Reactant: O=C(O)C(c1c2cc(F)c(F)cc2nn1-c1ccc(Cl)cc1)C1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: O=S(Cl)Cl
Product: O=C(NC1CCCCC1)C(c1c2cc(F)c(F)cc2nn1-c1ccc(Cl)cc1)C1CCCCC1

Procedure:
In analogy to the procedure described in example 6, [rac]-[2-(4-chloro-phenyl)-5,6-difluoro-2H-indazol-3-yl]-cyclohexyl-acetic acid was converted into the corresponding acid chloride with thionyl chloride which subsequently reacted with cyclohexylamine (CAS Reg. No. 108-91-8) in the presence of DMAP to give the title compound as off-white solid. MS: m/e=486.4 [M+H+].
Reaction SMILES: S(O[CH2:6][C@@:7]12[CH2:22][O:21][C@@H:9]([C@H:10]([N:12]3[CH:19]=[C:18]([CH3:20])[C:16](=[O:17])[NH:15][C:13]3=[O:14])[O:11]1)[C@@H:8]2[OH:23])(C)(=O)=O.[N-:24]=[N+:25]=[N-:26].[Na+]>CN(C)C=O>[N:24]([CH2:6][C@@:7]12[CH2:22][O:21][C@@H:9]([C@H:10]([N:12]3[CH:19]=[C:18]([CH3:20])[C:16](=[O:17])[NH:15][C:13]3=[O:14])[O:11]1)[C@@H:8]2[OH:23])=[N+:25]=[N-:26]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1cn([C@@H]2O[C@@]3(COS(C)(=O)=O)CO[C@@H]2[C@@H]3O)c(=O)[nH]c1=O
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cn([C@@H]2O[C@@]3(CN=[N+]=[N-])CO[C@@H]2[C@@H]3O)c(=O)[nH]c1=O

Procedure:
A dimethylformamide (3.0 ml) solution of Compound 3 (27 mg, 0.078 mmol) and sodium azide was stirred for 1.5 hours at room temperature and for 2 hours at 100° C. in a stream of nitrogen. The solvent was distilled off under reduced pressure, and then a small amount of water was added to the residue, followed by extracting the mixture with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride, and dried over anhydrous sodium sulfate. Then, the solvent was distilled off under reduced pressure to obtain Compound 4 (28 mg, quant. in 2 steps) as a yellow oily substance.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:31])[CH2:10][N:11]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[NH:15][CH2:14][C@H:13]([NH:22][C:23]([O:25]C(C)(C)C)=O)[C:12]1=[O:30])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])(O)=O.[Na+].Cl[C:38]([O:40][CH3:41])=[O:39]>C1COCC1>[CH2:1]([O:8][C:9](=[O:31])[CH2:10][N:11]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[N:15]([C:38]([O:40][CH3:41])=[O:39])[CH2:14][C@H:13]([NH:22][C:23](=[O:25])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:12]1=[O:30])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)Cl
Reactant: CC(C)(C)OC(=O)N[C@H]1CNc2ccccc2N(CC(=O)OCc2ccccc2)C1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)N1C[C@H](NC(=O)c2ccccc2)C(=O)N(CC(=O)OCc2ccccc2)c2ccccc21
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A vigorously-stirred, 0° C. solution of (3S)-2-oxo-3-(benzoylamino)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine-1-acetic acid benzyl ester (600b) (461 mg, 1.07 mmol, in THF (5 ml) and sat. aq. NaHCO3 (2.5 ml) was treated with a THF solution (0.35 ml) of methyl chloroformate (151 mg, 1.6 mmol) and the reaction was stirred for 45 min at RT. The reaction was poured onto CH2Cl2 and washed with H2O, dried over Na2SO4 and concentrated in vacuo. Chromatography (flash, SiO2, 0% to 10% MeOH/CH2Cl2) gave 525 mg of 602j as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:29])[C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH:15]=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[OH:22])[C:13]([C:23]#[N:24])=[CH:12]2)=[CH:7][C:6]=1[O:25]COC)[CH3:2].O1CCCC1.C(O)C.Cl>O>[CH2:1]([O:3][C:4](=[O:29])[C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH:15]=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[OH:22])[C:13]([C:23]#[N:24])=[CH:12]2)=[CH:7][C:6]=1[OH:25])[CH3:2]
Reactant: CCOC(=O)c1ccc(-n2cc(C#N)c(-c3ccccc3O)c2)cc1OCOC
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: CCOC(=O)c1ccc(-n2cc(C#N)c(-c3ccccc3O)c2)cc1O
Temperature: 70 °C
Reaction time: 18 h
Yield: 50.7 %

Procedure:
To a solution of 4-[3-cyano-4-(2-hydroxyphenyl)pyrrole-1-yl]-2-methoxymethoxy benzoic acid ethyl ester (0.12 g) in a mixed solvent of tetrahydrofuran (3 mL) and ethanol (5 mL) was added 2 mol/L hydrochloric acid (2 mL), and this mixture was stirred at 70° C. for 18 hours. To this reaction mixture was added water, the precipitated solid was collected by filtration, and this solid was washed with water, dried under reduced pressure at 50° C. to give the title compound (0.054 g).