Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:12]([F:15])([F:14])[F:13])[C:5]([Cl:11])=[CH:6][C:7]=1[N+:8]([O-])=O.Cl[Sn]Cl>C(O)C>[NH2:1][C:2]1[CH:3]=[C:4]([C:12]([F:15])([F:13])[F:14])[C:5]([Cl:11])=[CH:6][C:7]=1[NH2:8]
Reactant: Nc1cc(C(F)(F)F)c(Cl)cc1[N+](=O)[O-]
Agent: Cl[Sn]Cl
Solvent: CCO
Product: Nc1cc(Cl)c(C(F)(F)F)cc1N
Temperature: 90 °C
Yield: 70.3 %

Procedure:
To a stirred mixture of 3-amino-6-chloro-4-nitrobenzotrifluoride (300 mg, 1.25 mmol) in ethanol (5 mL) was added SnCl2 ·2 H2O (1.40 g, 6.20 mmol) in one portion. The mixture was refluxed at 80° C. (oil bath, 90° C.) for 1 h and the solution was cooled to room temperature and ice water (20 g) was added. It was adjusted to pH=7 and extracted with ethyl acetate. The extract was dried over Mg2SO4 and evaporated to give 185 mg (71%) of 3,4-diamino-6-chlorobenzotrifluoride as a brown solid. 1H NMR (CDCl3): δ3.404 (s, 2H); 3.717 (s, 2H); 6.754 (s, 1H); 6.974 (s, 1H).
Reaction SMILES: C[O-].[Na+].Cl.[NH2:5][C:6]([NH2:8])=[NH:7].[C:9]([C:11]1[N:12]([C:16]2[CH:17]=[C:18]([C:26]([O:28]C)=O)[CH:19]=[C:20]([CH:25]=2)[C:21]([O:23]C)=O)[CH:13]=[CH:14][CH:15]=1)#[N:10].O>CO.CN(C)C=O>[C:9]([C:11]1[N:12]([C:16]2[CH:25]=[C:20]([CH:19]=[C:18]([C:26]([N:5]=[C:6]([NH2:8])[NH2:7])=[O:28])[CH:17]=2)[C:21]([N:7]=[C:6]([NH2:8])[NH2:5])=[O:23])[CH:13]=[CH:14][CH:15]=1)#[N:10]
Reactant: COC(=O)c1cc(C(=O)OC)cc(-n2cccc2C#N)c1
Reactant: N=C(N)N
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1cccn1-c1cc(C(=O)N=C(N)N)cc(C(=O)N=C(N)N)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 52.8 %

Procedure:
28% Sodium methoxide in methanol (8.6 ml) was added to guanidine hydrochloride (4.7 g) in dry N,N-dimethylformamide (14 ml), and the mixture was stirred for 20 minutes at ambient temperature. To the mixture was added dimethyl 5-(2-cyanopyrrol-1-yl)isophthalate (1.4 g) and the mixture was stirred for 4 hours at the same temperature. The reaction mixture was poured into a water (150 ml) under stirring. The isolated precipitate was collected by filtration, washed with water and dried to give 2-[3-(2-cyanopyrrol-1-yl)-5-(diaminomethyleneaminocarbonyl)benzoyl]guanidine (0.88 g).
Reaction SMILES: CO[C:3](=O)[C@@H:4]1[CH2:8]CC[NH:5]1.[CH:10]1(N=C=NC2CCCCC2)CCCCC1.C(O[C:28](=[O:31])[CH2:29][NH2:30])C.N>>[C:4]([NH:5][C:28](=[O:31])[CH2:29][NH2:30])([CH3:8])([CH3:10])[CH3:3]
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: CCOC(=O)CN
Reactant: COC(=O)[C@@H]1CCCN1
Agent: N
Product: CC(C)(C)NC(=O)CN

Procedure:
which comprises the following steps: Condensing N-(5-oxo-L-prolyl)-L-histidine hydrazide by means of the azide method with L-tryptophan benzyl ester and treating the resulting compound with hydrazine hydrate to obtain N-[N-(5-oxo-L-prolyl)-L-histidyl]-L-tryptophan hydrazide (II); treating N-[O-benzyl-N-carboxy-L-tyrosyl]glycine N-benzyl ester with ethyl chloroformate to obtain the corresponding mixed anhydride which is reacted with t-butyl carbazate to obtain the corresponding 2-carboxyhydrazide t-butyl ester which is hydrogenolyzed to N-L-tyrosylglycine 2-carboxyhydrazide t-butyl ester, and condensing the latter with N-carboxy-L-seryl N-benzyl ester 2,4-dinitrophenyl ester followed by hydrogenolysis of the reaction product to obtain N-(N-L-seryl-L-tyrosyl)glycine 2-carboxyhydrazide t-butyl ester (III); condensing N-carboxy-L-proline N-benzyl ester with glycine ethyl ester in the presence of dicyclohexylcarbodiimide, treating the resulting product with ammonia and then hydrogenolyzing, to obtain 2-[(L-prolyl)amino]acetamide, which is condensed with N-carboxy-NG -nitro-L-arginine N-t-butyl ester in the presence of dicyclohexylcarbodiimide and N-hydroxysuccinimide to obtain N-[N-(N-carboxy-NG -nitro-L-arginyl)-L-prolyl)]glycinamide N-t-butyl ester (IV); or alternatively condensing L-proline methyl ester with N-carboxy-NG -nitro-arginine N-t-butyl ester in the presence of dicyclohexylcarbodiimide, condensing the resulting product with glycine ethyl ester in the presence of dicyclohexylcarbodiimide, and treating the resulting product with ammonia to obtain the same compound IV as above; treating said compound IV with acid and then with N-carboxy-L-leucine N-benzyl ester 2,4,5-trichlorophenyl ester and hydrogenolyzing the resulting product in acetic acid, to obtain N-[N-[N-(N-L-leucyl)-L-arginyl]-L-prolyl]-glycinamide diacetate (V); condensing compound II with compound III by means of the azide method to obtain the hexapeptide N-[N-[N-[N-[N-(5-oxo-L-prolyl)-L-histidyl]-L-tryptophyl]-L-seryl]-L-tyrosyl]glycine 2-carboxyhydrazide t-butyl ester, or condensing N-[N-(5-oxo-L-prolyl)-L-histidyl]-L-tryptophan with compound III in the presence of dicyclohexylcarbodiimide to obtain the same hexapeptide as above, and deprotecting and converting the latter to its trifluoroacetate salt (VI); and condensing compound V with compound VI by means of the azide method, to obtain the decapeptide of formula I which is isolated as the diacetate salt and optionally converted to other pharmaceutically acceptable salts.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]([C:22]2[CH:27]=[CH:26][C:25]([C:28]([N:30]([CH2:33][CH3:34])[CH2:31][CH3:32])=[O:29])=[CH:24][CH:23]=2)[N:9]2[CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11][CH2:10]2)[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[CH:42]1([C:48](Cl)=[O:49])[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]1>ClCCl.CN(C1C=CN=CC=1)C>[CH:42]1([C:48]([NH:1][C:2]2[CH:3]=[C:4]([C@@H:8]([N:9]3[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)[C:22]3[CH:27]=[CH:26][C:25]([C:28]([N:30]([CH2:33][CH3:34])[CH2:31][CH3:32])=[O:29])=[CH:24][CH:23]=3)[CH:5]=[CH:6][CH:7]=2)=[O:49])[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]1
Reactant: O=C(Cl)C1CCCCC1
Reactant: CCN(CC)C(=O)c1ccc(C(c2cccc(N)c2)N2CCN(C(=O)OC(C)(C)C)CC2)cc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCN(CC)C(=O)c1ccc([C@@H](c2cccc(NC(=O)C3CCCCC3)c2)N2CCNCC2)cc1
Reaction time: 5 h

Procedure:
To a room temperature solution of INTERMEDIATE 5a (250 mg; 0.54 mmol) in dichloromethane (5 mL) were added triethylamine (0.15 mL; 1.08 mmol), DMAP (cat.) and cyclohexane carbonyl chloride (86 μL; 0.64 mmol). The reaction mixture was stirred for 5 hours then more triethylamine (0.08 mL; 0.58 mmol) and DMAP (cat.) were added. The reaction mixture was stirred overnight then more cyclohexane carbonyl chloride (28 μL; 0.21 mmol) was added. The reaction mixture stirred for 5 hours then was washed with two portions of saturated sodium bicarbonate. The organic phase was dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure. Column chromatography eluting with 2% methanol in dichloromethane gave the desired product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:40]=[CH:39][C:6]([CH2:7][N:8]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=2)[C:9]2[N:14]=[CH:13][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][NH:27][C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:11][N:10]=2)=[CH:5][CH:4]=1.Br[C:42]1[CH:47]=[CH:46][C:45]([C:48]([N:50]2[CH2:55][CH2:54][N:53]([CH2:56][CH3:57])[CH2:52][CH2:51]2)=[O:49])=[CH:44][C:43]=1[CH3:58]>>[CH3:38][O:37][C:34]1[CH:33]=[CH:32][C:31]([CH2:30][N:8]([CH2:7][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:40][CH:39]=2)[C:9]2[N:10]=[CH:11][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][N:27]([C:42]5[CH:47]=[CH:46][C:45]([C:48]([N:50]6[CH2:55][CH2:54][N:53]([CH2:56][CH3:57])[CH2:52][CH2:51]6)=[O:49])=[CH:44][C:43]=5[CH3:58])[C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:13][N:14]=2)=[CH:36][CH:35]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4)cn2)cc1
Reactant: CCN1CCN(C(=O)c2ccc(Br)c(C)c2)CC1
Product: CCN1CCN(C(=O)c2ccc(N3CCc4c(-c5cnc(N(Cc6ccc(OC)cc6)Cc6ccc(OC)cc6)nc5)nc(N5CCOCC5)nc43)c(C)c2)CC1

Procedure:
Using bis-(4-methoxy-benzyl)-[5-(2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl)-pyrimidin-2-yl]-amine (100 mg) and (4-bromo-3-methyl-phenyl)-(4-ethyl-piperazin-1-yl)-methanone (162 mg) instead of 4-chloropicolinic acid t-butylamide, in the same manner as Example 1-D-07, a crude product of [4-(4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidin-7-yl)-3-methyl-phenyl]-(4-ethyl-piperazin-1-yl)-methanone was obtained, and then the PMB groups were removed according to the above Deprotection method 3, to obtain the desired compound (D-146) as a pale yellow powder (25 mg, 12%).
Reaction SMILES: [CH3:1][N:2]([CH3:13])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][C:10]([OH:12])=O.Cl.[C:15]1([C:21]2([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C@H:29]3[C@H:25]([CH2:26][NH:27][CH2:28]3)[C@@H:24]([OH:30])[CH2:23][CH2:22]2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(N(CC)CC)C>ClCCl>[CH3:13][N:2]([CH3:1])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][C:10]([N:27]1[CH2:26][C@H:25]2[C@H:29]([C:21]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH2:22][CH2:23][C@@H:24]2[OH:30])[CH2:28]1)=[O:12]
Reactant: CN(C)c1ccccc1CC(=O)O
Reactant: O[C@H]1CCC(c2ccccc2)(c2ccccc2)[C@@H]2CNC[C@@H]21
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C)c1ccccc1CC(=O)N1C[C@H]2[C@@H](C1)C(c1ccccc1)(c1ccccc1)CC[C@@H]2O
Reaction time: 0.5 h
Yield: 54.6 %

Procedure:
0.49 g of N,N'-carbonyldiimidazole is added to a solution of 0.52 g of 2-dimethylaminophenylacetic acid in 20 cm3 of dry dichloromethane. The mixture is stirred for 30 minutes at +5° C. and then a solution of 0.93 g of (3aR,4S,7aR)-7,7-diphenyl-4-perhydroisoindolol hydrochloride and 0.84 cm3 of triethylamine in 10 cm3 of dichloromethane is added. The reaction mixture is stirred for 2 hours at +5° C. and then washed with 10 cm3 of water, dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2.7 kPa). The residue obtained is chromatographed on a silica gel column (0.04 mm -0.06 mm, diameter 2 cm, height 35 cm), eluting with ethyl acetate and collecting fractions of 30 cm3. Fractions 8 to 27 are pooled and concentrated to dryness under reduced pressure (2.7 kPa). The residue is crystallized from a mixture of 4 cm3 of acetonitrile and 20 cm3 of ethyl ether. The crystals are drained and dried under reduced pressure (2.7 kPa). 0.70 g of (3aR,4S,7aR)-2-[(2-dimethylaminophenyl)acetyl]-7,7-diphenyl-4-perhydroisoindolol is obtained in the form of a white solid; melting point 160° C., [α]20D =-162° (c =0.5, methanol).
Reaction SMILES: [C:1]([CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13](=[O:18])[CH:12]=[CH:11]2)([OH:3])=O.C1[CH2:29][CH2:28][N:27]2[C:22](=[N:23][CH2:24][CH2:25][CH2:26]2)[CH2:21]C1.ClC(OCC(C)C)=O.C(NC1C=CC=CN=1)C>C(Cl)(Cl)Cl>[CH2:28]([N:27]([C:22]1[CH:21]=[CH:26][CH:25]=[CH:24][N:23]=1)[C:1]([CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13](=[O:18])[CH:12]=[CH:11]2)=[O:3])[CH3:29]
Reactant: C1CCC2=NCCCN2CC1
Reactant: O=C(O)CCCOc1ccc2[nH]c(=O)ccc2c1
Agent: CC(C)COC(=O)Cl
Agent: CCNc1ccccn1
Solvent: ClC(Cl)Cl
Product: CCN(C(=O)CCCOc1ccc2[nH]c(=O)ccc2c1)c1ccccn1
Reaction time: 1 h

Procedure:
Into 300 ml of chloroform were added 9.9 g of 6-(3-carboxypropoxy)carbostyril and 6.5 ml of DBU. The outside of the reaction vessel containing the abovementioned mixture was ice-cooled and 5.7 ml of isobutyl chloroformate was added dropwise under stirring condition. After the addition operation, stirring was continued for 1 hour at a room temperature and 5.4 g of 2-ethylaminopyridine was added dropwise, then the reaction was continued for 5 hours under stirring condition. The reaction mixture was washed with a diluted NaHCO3 aqueous solution and water, and was concentrated. The residue thus obtained was treated by a silica-gel column chromatography (solvent used was a mixture of chloroform:methanol=20:1) and the elute thus obtained was concentrated then was recrystallized from methanol, to obtain 4.5 g of 6-{3-[N-ethyl-N-(2-pyridyl)aminocarbonyl]propoxy}carbostyril in the form of colorless needle-like crystals. Melting point: 148°-149° C.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][NH:8]2)=[C:4]([N+:11]([O-:13])=[O:12])[CH:3]=1.[B-](F)(F)(F)[F:15].[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+](F)(CC2)C1>C(#N)C.C(O)(=O)C>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([F:15])=[N:7][NH:8]2)=[C:4]([N+:11]([O-:13])=[O:12])[CH:3]=1
Reactant: O=[N+]([O-])c1cc(Br)cc2[nH]ncc12
Reactant: F[B-](F)(F)F
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Solvent: CC#N
Solvent: CC(=O)O
Product: O=[N+]([O-])c1cc(Br)cc2[nH]nc(F)c12
Reaction time: 8 h

Procedure:
To a solution of 6-bromo-4-nitro-1H-indazole (10 g, 41.3 mmol, available from Sinova) in acetonitrile (100 ml) and acetic acid (20.00 ml) was added Selectfluor® (22.10 g, 83 mmol). The resultant mixture was heated to 100° C. and stirred overnight. The resultant orange solution was concentrated under vacuum then partitioned between ethyl acetate and water. The layers were separated and the aqueous extracted again with ethyl acetate. The combined organics were dried over MgSO4, filtered and concentrated. The solid was then dissolved in 20 ml DCM, loaded onto a 330 g silica column and purified on a 0-100% EtOAc/Cyclohexane gradient. The relevant fractions were combined and concentrated to yield the title compound as an orange solid (6.9 g).
Reaction SMILES: C(OCC)C.C([O:8][C:9](=O)[CH2:10][C:11]1([CH2:31][C:32](O)=[O:33])[S:15][C:14]2[CH:16]=[C:17]3[S:21][C:20]([CH2:26][C:27](O)=[O:28])([CH2:22][C:23](O)=[O:24])[S:19][C:18]3=[CH:30][C:13]=2[S:12]1)C.C(O)C>O>[OH:28][CH2:27][CH2:26][C:20]1([CH2:22][CH2:23][OH:24])[S:19][C:18]2[CH:30]=[C:13]3[S:12][C:11]([CH2:31][CH2:32][OH:33])([CH2:10][CH2:9][OH:8])[S:15][C:14]3=[CH:16][C:17]=2[S:21]1
Reactant: CCOC(=O)CC1(CC(=O)O)Sc2cc3c(cc2S1)SC(CC(=O)O)(CC(=O)O)S3
Solvent: CCOCC
Solvent: CCO
Solvent: O
Product: OCCC1(CCO)Sc2cc3c(cc2S1)SC(CCO)(CCO)S3
Temperature: 25 °C

Procedure:
A dry flask under argon atmosphere was charged with diethyl ether (2600 ml) and LiAlH, (21.2 g 0.56 mol). Benzo[1,2-d:4,5-d']bis(1,3)dithiole-2,2,6,6-tetraacetic acid ethyl ester (80.2 g, 0.139 mol) was added and the mixture was refluxed for 26 h. The mixture was cooled to ambient temperature and ethanol (165 ml) was carefully added followed by water (410 ml). The ether was decanted off and the white precipitate was stirred with water (3300 ml) to give a slurry. After acidification with hydrochloric acid the slurry was filtered and the crude product was washed with water and dried. Yield: 55.0 g (97%)
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH2:8])[CH:3]=1.CO[C:11]1[N:16]=[CH:15][C:14](B(O)O)=[CH:13]N=1.[C:20]([O-])([O-])=O.[Na+].[Na+]>COCCOC.CCO.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[N:16]1[CH:11]=[CH:20][CH:13]=[C:14]([C:2]2[N:7]=[CH:6][N:5]=[C:4]([NH2:8])[CH:3]=2)[CH:15]=1
Reactant: Nc1cc(Cl)ncn1
Reactant: COc1ncc(B(O)O)cn1
Reactant: O=C([O-])[O-]
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Na+]
Solvent: CCO
Solvent: COCCOC
Solvent: O
Product: Nc1cc(-c2cccnc2)ncn1
Temperature: 125 °C
Yield: 51 %

Procedure:
6-Chloropyrimidin-4-amine (0.35 g, 2.70 mmol), 2-methoxypyrimidin-5-ylboronic acid (0.520 g, 3.38 mmol), Na2CO3 (0.859 g, 8.11 mmol) and bis(triphenylphosphine)palladium(II) chloride (0.038 g, 0.054 mmol) were suspended in a mixture of DME/EtOH/water. (15:2:3 mL). The mixture was heated in the microwave synthesizer at 125° C. for 20 min and concentrated. The residue was purified by silica gel chromatography (0-5% 9:1 methanol:ammonium hydroxide-ethyl acetate) to afford 6-(pyridin-3-yl)pyrimidin-4-amine (0.28 g, 1.378 mmol, 51% yield) as an off-white solid. LCMS R.T.=0.53; [M+H]+=204.11.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5]2([C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[NH:9][CH2:8]2)[CH2:4][CH2:3]1.CCN(CC)CC.Cl[C:24]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25]>C(Cl)Cl>[CH2:27]([O:26][C:24]([N:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:5]2([CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]2)[CH2:8]1)=[O:25])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CN1CCC2(CC1)CNc1ccccc12
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN1CCC2(CC1)CN(C(=O)OCc1ccccc1)c1ccccc12
Reaction time: 2 h
Yield: 71.1 %

Procedure:
A solution of 99 g (489 mmol) of 1'-methylspiro(indoline-3,4'-piperidine) (prepared according to Ong, H. H. et al, J. Med. Chem., 1983, 26, 981-986) in 1 L of CH2Cl2 and 82 mL (539 mmol) of Et3N was cooled to 0-5° C. with an ice bath and 77 mL (539 mmol) of benzyl chloroformate was added over 30 min keeping the reaction temperature below 10° C. After stirring for 2 h 19 mL (136 mmol) of Et3N and 15 mL (105 mmol) of benzyl chloroformate were added since the reaction was incomplete and stirred for 2 h. At this time, additional 19 mL (136 mmol) of Et3N and 15 mL (105 mmol) of benzyl chloroformate were added. After 1 h, when a TLC indicated a complete reaction, the solution was concentrated in vacuo and the residue was partitioned between ether and saturated NaHCO3. The layers were separated, the organic layer was washed with saturated NaHCO3 and brine, and dried over MgSO4. The filtrate was concentrated and the residue was chromatographed on 2 kg of silica gel using 1-5% MeOH/CH2Cl2 to obtain 117 g (71%) of 1-benzyloxycarbonyl-1'-methylspiro(indoline-3,4'-piperidine) as a yellow oil. The yellow oil was dissolved in 800 mL of 1,2-dichloroethane and cooled in ice bath as 50 mL (463 mmol) of 1-chloroethyl chloroformate keeping the temperature below 10° C. The resulting solution was heated to reflux. Gas evolution was noticed when the reaction temperature reached 70-75° C. After 1 h the solution was cooled, concentrated to ca. 250 mL in vacuo and 700 mL of methanol was added. The mixture was refluxed for 1.5 h and gas evolution was observed. The reaction was cooled to room temperature and concentrated in vacuo to a wet solid. The solid was slurried with cold methanol, the solid was filtered, washed with cold methanol and dried. The filtrates and the washing were combined and concentrated to a brown foam. The brown foam and the filtered solid were suspended in CH2Cl2, washed with 2.5 N NaOH and the CH2Cl2 solution was dried. The residue was chromatographed on 2 kg of silica gel using a gradient of 94:5:1 to 89:10:1 CH2Cl2, methanol, NH4OH to isolate 91.3 g of free base as a brown oil. The oil was dissolved in 1 L of EtOAc by adding methanol (ca. 10 mL) and HCl gas was passed through the solution. After stirring the acidic solution for 10 min, it was concentrated to a foam. The foam was triturated with ether and the solid was filtered, washed with more ether and dried to furnish 91.5 g (73%) of title compound as a light yellow solid.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([C@H:10]2[CH2:15][CH2:14][C@H:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH2:12][CH2:11]2)[CH:7]=[CH:6][C:5]=1[OH:24])([O-])=O.O.NN>C(O)C>[NH2:1][C:4]1[CH:9]=[C:8]([C@H:10]2[CH2:11][CH2:12][C@H:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH2:14][CH2:15]2)[CH:7]=[CH:6][C:5]=1[OH:24]
Reactant: CCCCCCCC[C@H]1CC[C@H](c2ccc(O)c([N+](=O)[O-])c2)CC1
Agent: NN
Solvent: O
Solvent: CCO
Product: CCCCCCCC[C@H]1CC[C@H](c2ccc(O)c(N)c2)CC1
Temperature: 70 °C

Procedure:
Step ii) In a 50 ml-three-necked flask, 1.90 g (5.70 mM) of 2-nitro-4-(trans-4-octylcyclohexyl)phenol, 0.35 g of activated carbon, 0.04 g of FeCl3.6H2O and 15 ml of ethanol were placed and heated to 55°-65° C. under stirring. To the mixture, 1.8 ml of 80% hydrazine hydrate was gradually added dropwise and heated to 70° C., followed by stirring for 20 min at 70° C. After the reaction, the reaction mixture was filtered under heating to remove the activated carbon and the filtrate was cooled to room temperature to precipitate a crystal. The crystal was recovered by filtration and recrystallized from ethanol to obtain 1.49 g of 2-amino-4-(trans-4-octylcyclohexyl)phenol (yield: 86.2%).
Reaction SMILES: CC1C(C)=CC=CC=1OC1N=CC(N)=CC=1.[CH3:17][CH:18]([C:20]1[CH:21]=[C:22]([O:26][C:27]2[N:32]=[CH:31][C:30]([NH2:33])=[CH:29][CH:28]=2)[CH:23]=[CH:24][CH:25]=1)[CH3:19].C[O:35][C:36]([NH:38][N:39]=[CH:40]OC)=O>>[CH3:19][CH:18]([C:20]1[CH:21]=[C:22]([O:26][C:27]2[N:32]=[CH:31][C:30]([N:33]3[CH:40]=[N:39][NH:38][C:36]3=[O:35])=[CH:29][CH:28]=2)[CH:23]=[CH:24][CH:25]=1)[CH3:17]
Reactant: CC(C)c1cccc(Oc2ccc(N)cn2)c1
Reactant: COC=NNC(=O)OC
Agent: Cc1cccc(Oc2ccc(N)cn2)c1C
Product: CC(C)c1cccc(Oc2ccc(-n3cn[nH]c3=O)cn2)c1

Procedure:
The title compound was prepared in a similar way with respect to Example 50 replacing 6-[(2,3-dimethylphenyl)oxy]-3-pyridinamine with 6-{[3-(1-methylethyl)phenyl]oxy}-3-pyridinamine and methyl (2E/Z)-2-(1-methoxyethylidene)hydrazinecarboxylate (Intermediate 21) with methyl-2-[1-(methyloxy)methylidene]hydrazinecarboxylate (Intermediate 28). The title compound, 21 mg, was obtained by preparative HPLC.
Reaction SMILES: C[O-].[Na+].[NH:4]1[CH:8]=[CH:7][N:6]=[CH:5]1.[C:9]1([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:14]=[CH:13][C:12]([C:15]2([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:24])[CH2:17][O:16]2)=[CH:11][CH:10]=1>CO.CN(C)C=O>[C:9]1([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:14]=[CH:13][C:12]([C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[Cl:24])([OH:16])[CH2:17][N:4]2[CH:8]=[CH:7][N:6]=[CH:5]2)=[CH:11][CH:10]=1
Reactant: c1c[nH]cn1
Reactant: Clc1ccccc1C1(c2ccc(-c3ccccc3)cc2)CO1
Agent: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: OC(Cn1ccnc1)(c1ccc(-c2ccccc2)cc1)c1ccccc1Cl
Temperature: 80 °C
Yield: 78.4 %

Procedure:
3.5 g (0.065 mol) of sodium methylate are dissolved in 20 ml of methanol, and 7.5 g (0.11 mole) of imidazole are added. A solution of 15 g (0.05 mol) of 2-(4-biphenylyl)-2-(2-chlorophenyl)-oxirane in 75 ml of dimethylformamide is added dropwise to this mixture and the reaction mixture is heated to 80° C. for 1.5 hours. Thereafter, it is poured onto water and the crystals which form are filtered off and dried. 14.7 g (79% of theory) of 1-(4-biphenylyl)-1-(2-chlorophenyl)-2-imidazol-1-yl-ethanol of melting point 222° C. are obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4](F)[CH:3]=1.[H-].[Na+].Cl[C:13]1[C:14]2[CH:15]=[C:16]3[O:32][CH2:31][CH2:30][O:29][CH2:28][CH2:27][O:26][CH2:25][CH2:24][O:23][C:17]3=[CH:18][C:19]=2[N:20]=[CH:21][N:22]=1.[CH3:33]N(C=O)C>CCOC(C)=O>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:13]2[C:14]3[CH:15]=[C:16]4[O:32][CH2:31][CH2:30][O:29][CH2:28][CH2:27][O:26][CH2:25][CH2:24][O:23][C:17]4=[CH:18][C:19]=3[N:20]=[CH:21][N:22]=2)=[C:4]([CH3:33])[CH:3]=1
Reactant: CN(C)C=O
Reactant: Clc1ncnc2cc3c(cc12)OCCOCCOCCO3
Reactant: Nc1ccc(O)c(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: Cc1cc(N)ccc1Oc1ncnc2cc3c(cc12)OCCOCCOCCO3
Temperature: 25 °C
Yield: 100 %

Procedure:
4-amino-2-fluoro-phenol (1.53 g, 12.0 mmol) was dissolved in dry DMF (30 ml) to which was added 60% NaH (774 mg, 19.3 mmol). After the mixture was stirred at room temperature for several minutes, a suspension of 4-Chloro-7,8,10,11,13,14-hexahydro-6,9,12,15-tetraoxa-1,3-diaza-cyclododeca[b]naphthalene (2.08 g, 6.7 mmol) in dry DMF (40 ml) was added. The reaction mixture was stirred at room temperature for 1-2 hrs, then diluted with EtOAc and washed with sat'd NaHCO3 (3×), H2O (1×), sat'd NaCl (1×), dried (Na2SO4), and concentrated in vacuo to give crude title compound (2.68 g, −100%) which was used in the next reaction without further purification. 1H-NMR (400 MHz, DMSO): 8.58 (s, 1H), 7.80 (s, 1H), 7.50 (s, 1H), 7.04 (t, 1H), 6.50 (dd, 2H), 5.40 (br s, 2H), 4.35 (s, 4H), 3.87 (d, 4H), 3.62 (s, 4H). LC/MS Calcd for (M+H)′ 401.4. found 402.5.