Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([CH2:5]3)[CH:3]1[NH2:12])[CH2:9]2.[C:13]1([C:19](Cl)([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>ClCCl>[C:19]([NH:12][CH:3]1[CH:4]2[CH2:5][CH:6]3[CH2:7][CH:8]([CH2:9][C:2]1([OH:1])[CH2:11]3)[CH2:10]2)([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: NC1C2CC3CC(C2)CC1(O)C3
Solvent: ClCCl
Product: OC12CC3CC(CC(C3)C1NC(c1ccccc1)(c1ccccc1)c1ccccc1)C2

Procedure:
To 1-hydroxytricyclo[3.3.1.13,7 ]decan-2-amine (0.47 g; 0.0028 mole), [prepared via a procedure of W. V. Curran and R. B. Angler, J. of Org. Chem., 94(11 ), 3668-70 (1969)] in dichloromethane (45 ml) is added triphenylmethyl chloride (0.78 g; 0.0028 mole) in dichloromethane (5 ml). This mixture is refluxed for 7 hours and then more triphenylmethyl chloride (0.35 g) is added and the reaction refluxed overnight. The reaction is stripped to dryness and the products separated via flash chromatography (eluted with 25% ethyl acetate/hexane) to obtain N-trityl-1-hydroxytricyclo[3.3.1.13,7 ]decan-2-amine which is used directly in step B.
Reaction SMILES: ClC1[CH:41]=[CH:40][C:5]([C:6]2[C:11]([C:12]3[CH:21]=[CH:20][C:19]4[C:14](=[CH:15][CH:16]=[C:17]([C:22]5[N:26]([CH:27]6[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]6)[C:25]6[CH:33]=[CH:34][C:35]([C:37]([OH:39])=[O:38])=[CH:36][C:24]=6[N:23]=5)[CH:18]=4)[N:13]=3)=[CH:10][CH:9]=[CH:8][CH:7]=2)=[CH:4][CH:3]=1.[N:42]1C=CC(B(O)O)=CC=1>>[CH:27]1([N:26]2[C:25]3[CH:33]=[CH:34][C:35]([C:37]([OH:39])=[O:38])=[CH:36][C:24]=3[N:23]=[C:22]2[C:17]2[CH:16]=[C:15]3[C:14](=[CH:19][CH:18]=2)[N:13]=[C:12]([C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]2[CH:4]=[CH:3][N:42]=[CH:41][CH:40]=2)[CH:21]=[CH:20]3)[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]1
Reactant: OB(O)c1ccncc1
Reactant: O=C(O)c1ccc2c(c1)nc(-c1ccc3nc(-c4ccccc4-c4ccc(Cl)cc4)ccc3c1)n2C1CCCCC1
Product: O=C(O)c1ccc2c(c1)nc(-c1ccc3nc(-c4ccccc4-c4ccncc4)ccc3c1)n2C1CCCCC1

Procedure:
The title compound was synthesized as described for Compound 387 except pyridine-4-boronic acid was used instead of 4-chlorophenyl-boronic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([O:9][CH3:10])[C:3]=1[CH2:11][C:12]([O:14]C)=[O:13].[OH-].[K+].O>CO>[Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([O:9][CH3:10])[C:3]=1[CH2:11][C:12]([OH:14])=[O:13]
Reactant: COC(=O)Cc1c(Cl)cc(C)cc1OC
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1cc(C)cc(Cl)c1CC(=O)O

Procedure:
75 g (328 mmol) of methyl 2-chloro-4-methyl-6-methoxyphenylacetate according to Ex. XXXI-1 are dissolved in 750 ml of methanol and then heated at 80° C. together with 55.20 g (984 mmol) of potassium hydroxide and 250 ml of water for 12 h. The methanol is removed using a rotary evaporator, the residue is adjusted to pH 3 and the precipitated product is filtered off and dried.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([CH:19]=[CH:20][C:21]=1[O:22]C)[O:7][C:8]1[C:13]([CH3:14])=[CH:12][C:11]([N+:15]([O-:17])=[O:16])=[CH:10][C:9]=1[CH3:18])([CH3:3])[CH3:2].B(Br)(Br)Br>C(Cl)Cl>[CH3:18][C:9]1[CH:10]=[C:11]([N+:15]([O-:17])=[O:16])[CH:12]=[C:13]([CH3:14])[C:8]=1[O:7][C:6]1[CH:19]=[CH:20][C:21]([OH:22])=[C:4]([CH:1]([CH3:3])[CH3:2])[CH:5]=1
Reactant: COc1ccc(Oc2c(C)cc([N+](=O)[O-])cc2C)cc1C(C)C
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cc1cc([N+](=O)[O-])cc(C)c1Oc1ccc(O)c(C(C)C)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 4-(3-isopropyl-4-methoxy-phenoxy)-3,5-dimethyl-nitrobenzene (500 mg, 1.59 mmol) in CH2Cl2 (12 mL was added boron tribromide (1 M in CH2Cl2, 3.2 mL, 3.2 mmol). The resulting mixture was stirred 1 h at RT then quenched with water (15 mL) and 1 M HCL (10 mL). After stirring 30 min at RT, the solution was extracted with CH2Cl2 (3×20 mL). Combined extracts were washed with brine (50 ml), dried over anhydrous sodium sulfate, filtered, and concentrated to give the title compound of Step B. The title product of Step B was used in the next step without further purification. MS (APCl−) Calc.: 301, Found: 300.2 (M−1).
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:12]1[C:31]([CH3:32])=[CH:30][C:15]2[N:16]=[C:17]([C:19]3[CH:20]=[C:21]4[C:25](=[CH:26][CH:27]=3)[C:24](=[O:28])[N:23]([CH3:29])[CH2:22]4)[S:18][C:14]=2[C:13]=1[C:33]1[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][CH:34]=1)[C:7]([O:9]CC)=[O:8])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>C1COCC1.CO>[C:1]([O:5][C@@H:6]([C:12]1[C:31]([CH3:32])=[CH:30][C:15]2[N:16]=[C:17]([C:19]3[CH:20]=[C:21]4[C:25](=[CH:26][CH:27]=3)[C:24](=[O:28])[N:23]([CH3:29])[CH2:22]4)[S:18][C:14]=2[C:13]=1[C:33]1[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][CH:34]=1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccc4c(c3)CN(C)C4=O)sc2c1-c1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc2nc(-c3ccc4c(c3)CN(C)C4=O)sc2c(-c2ccc(Cl)cc2)c1[C@H](OC(C)(C)C)C(=O)O

Procedure:
(S)-ethyl 2-tert-butoxy-2-(7-(4-chlorophenyl)-5-methyl-2-(2-methyl-1-oxoisoindolin-5-yl)benzo[d]thiazol-6-yl)acetate (36 mg, 0.064 mmol) dissolved in THF/MeOH (1.25 mL/1.25 mL) and 2N NaOH (0.160 mL) was heated at 50° C. for 2 h and the crude was purified by reverse phase HPLC, eluting by 0-100% acetonitrile in H2O with 0.1% TFA to give the title compound. LCMS-ESI+: calc'd for C29H27ClN2O4S: 535.1 (M+H+); found: 535.2 (M+H+). 1H NMR (400 MHz, DMSO-d6): δ 8.22 (s, 1H), 8.08 (d, J=8.0 Hz, 1H), 7.87 (s, 1H), 7.70 (d, J=8.0 Hz, 1H), 7.65-7.51 (m, 4H), 5.03 (s, 1H), 4.46 (s, 2H), 3.03 (s, 3H), 2.48 (s, 3H), 0.83 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([O:9][CH3:10])[CH:5]=[CH:4][C:3]=1CC#N.S(=O)(=O)(O)O.[C:19]([OH:22])(=[O:21])[CH3:20]>>[Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([O:9][CH3:10])[CH:5]=[CH:4][C:3]=1[CH2:20][C:19]([OH:22])=[O:21]
Reactant: CC(=O)O
Reactant: COc1ccc(CC#N)c(Cl)c1Cl
Agent: O=S(=O)(O)O
Product: COc1ccc(CC(=O)O)c(Cl)c1Cl
Temperature: 110 °C
Reaction time: 8 h

Procedure:
(2,3-Dichloro-4-methoxyphenyl)acetonitrile (770 mg) was dissolved in a 50% aqueous acetic acid solution (8.00 mL), and then concentrated sulfuric acid (4.00 mL) was added thereto, followed by stirring at 110° C. overnight. The reaction mixture was cooled to room temperature, then ice water was added to the mixture, and the resulting solid was collected by filtration and washed with water to obtain (2,3-dichloro-4-methoxyphenyl)acetic acid (737 mg).
Reaction SMILES: [C:1]1([C:7]2[O:8][C:9]([C:15]([F:18])([F:17])[F:16])=[C:10]([C:12]([OH:14])=O)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:19]([N:22]([CH3:30])[C:23]1[CH:28]=[CH:27][C:26]([NH2:29])=[CH:25][N:24]=1)([CH3:21])[CH3:20]>>[CH:19]([N:22]([CH3:30])[C:23]1[N:24]=[CH:25][C:26]([NH:29][C:12]([C:10]2[N:11]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[O:8][C:9]=2[C:15]([F:18])([F:17])[F:16])=[O:14])=[CH:27][CH:28]=1)([CH3:21])[CH3:20]
Reactant: O=C(O)c1nc(-c2ccccc2)oc1C(F)(F)F
Reactant: CC(C)N(C)c1ccc(N)cn1
Product: CC(C)N(C)c1ccc(NC(=O)c2nc(-c3ccccc3)oc2C(F)(F)F)cn1

Procedure:
With a procedure similar to example 1 above, 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [6-(isopropyl-methyl-amino)-pyridin-3-yl]-amide was prepared from 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid and N2-isopropyl-N2-methyl-pyridine-2,5-diamine. LCMS calcd for C20H19F3N4O2 (m/e) 404, obsd 405 (M+H).
Reaction SMILES: [CH2:1]([C:3]1[N:16]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])=[CH:20][CH:19]=2)[C:6]2[CH:7]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[NH:8][CH2:9][CH2:10][C:5]=2[N:4]=1)[CH3:2].[C:37](OC(=O)C)(=[O:39])[CH3:38].C(=O)([O-])O.[Na+].C(Cl)(Cl)Cl>O>[CH2:1]([C:3]1[N:16]([CH2:17][C:18]2[CH:19]=[CH:20][C:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[C:30]([O:32][C:33]([CH3:34])([CH3:36])[CH3:35])=[O:31])=[CH:22][CH:23]=2)[C:6]2[CH:7]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[N:8]([C:37](=[O:39])[CH3:38])[CH2:9][CH2:10][C:5]=2[N:4]=1)[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: CCOC(=O)C1NCCc2nc(CC)n(Cc3ccc(-c4ccccc4C(=O)OC(C)(C)C)cc3)c21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O
Product: CCOC(=O)C1c2c(nc(CC)n2Cc2ccc(-c3ccccc3C(=O)OC(C)(C)C)cc2)CCN1C(C)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of ethyl 2-ethyl-3-[2'-(t-butoxycarbonyl)biphenyl-4-yl]methyl-4,5,6,7-tetrahydroimidazo[4,5-c]pyridine-4-carboxylate (2.26 g), acetic anhydride (0.94 g), sodium hydrogen carbonate (2.33 g), chloroform (18 ml) and water (18 ml) is stirred overnight at room temperature. The organic layer is separated, washed with brine, dried, and evaporated. The residue is purified by silica gel column chromatography (solvent; chloroform/methanol) to give ethyl 2-ethyl-5-acetyl-3-[2'-(t-butoxycarbonyl)biphenyl-4-yl]methyl-4,5,6,7-tetrahydroimidazo [4,5-c]pyridine-4-carboxylate (2.10 9) as a white foam.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:11])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].S(Cl)(Cl)=O.[CH3:16]O>>[OH:1][C:2]1[C:3]([CH3:11])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([O:7][CH3:16])=[O:6]
Reactant: CO
Reactant: Cc1c(O)cccc1C(=O)O
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cccc(O)c1C
Temperature: 25 °C
Yield: 84 %

Procedure:
To a solution of 3-hydroxy-2-methylbenzoic acid (3.80 g, 25.0 mmol) in methanol (3.0 mL) at 0° C. was added thionyl chloride (3.00 mL, 41.2 mmol) dropwise. The reaction was allowed to warm to room temperature and was then heated at 50° C. for 2 hours. The solvent was removed under vacuum and the resulting solids were dissolved in ethyl acetate and washed with NaHCO3 (sat. aq.). The ethyl acetate layer was dried over Na2SO4, filtered, and concentrated under vacuum to give methyl 3-hydroxy-2-methylbenzoate (114a, 3.49 g, 84% yield) as a light tan solid.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[C:16]2[CH2:15][C@@H:14]([CH2:17][NH2:18])[N:13]([C@H:19]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH3:20])[CH2:12][C:11]=2[S:10][C:9]=1[NH2:27])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.C[O:36][C:37](=O)[C:38]1[C:43]([O:44][CH3:45])=[CH:42][CH:41]=[CH:40][C:39]=1[CH2:46]Cl>C(#N)C>[C:1]([O:5][C:6]([C:8]1[C:16]2[CH2:15][C@@H:14]([CH2:17][N:18]3[CH2:46][C:39]4[C:38](=[C:43]([O:44][CH3:45])[CH:42]=[CH:41][CH:40]=4)[C:37]3=[O:36])[N:13]([C@H:19]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH3:20])[CH2:12][C:11]=2[S:10][C:9]=1[NH2:27])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: C[C@@H](c1ccccc1)N1Cc2sc(N)c(C(=O)OC(C)(C)C)c2C[C@H]1CN
Reactant: COC(=O)c1c(CCl)cccc1OC
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COc1cccc2c1C(=O)N(C[C@@H]1Cc3c(sc(N)c3C(=O)OC(C)(C)C)CN1[C@@H](C)c1ccccc1)C2
Temperature: 25 °C
Reaction time: 16 h
Yield: 52.8 %

Procedure:
2-Amino-5-(S)-aminomethyl-6-(1-(S)-phenyl-ethyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid tert-butyl ester (0.55 g, 1.42 mmol) and triethylamine (396 μl, 2.84 mmol) was heated in acetonitrile (15 ml) under an atmosphere of nitrogen to 60° C. whereupon a solution of 2-chloromethyl-6-methoxy-benzoic acid methyl ester (0.32 g, 1.49 mmol) in acetonitrile (5 ml) was added dropwise over the course of 3 hours, keeping the reaction mixture at 60° C. The reaction was allowed to cool to room temperature and was left for 16 hours before the solvent was evaporated in vacuo. The product was purified by column chromatography (SiO2, Flash 40, ethyl acetate-petrol ether) to give 400 mg (53%) of 2-amino-5-(S)-(7-methoxy-1-oxo-1,3-dihydro-isoindol-2-ylmethyl)-6-((S)-1-phenyl-ethyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid tert-butyl ester as an oil.
Reaction SMILES: [C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH3:23])=[CH:13][CH:12]=[CH:11][C:10]=2[N:24]1C(=O)C2=CC=CC=C2C1=O)(=[O:5])[CH2:2][CH2:3][CH3:4].O.NN>C(O)C>[NH2:24][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]2[C:9]=1[N:8]=[CH:7][C:6]([C:1](=[O:5])[CH2:2][CH2:3][CH3:4])=[C:15]2[NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH3:23]
Reactant: CCCC(=O)c1cnc2c(N3C(=O)c4ccccc4C3=O)cccc2c1Nc1ccccc1C
Agent: NN
Solvent: CCO
Solvent: O
Product: CCCC(=O)c1cnc2c(N)cccc2c1Nc1ccccc1C
Yield: 86.1 %

Procedure:
3-Butyryl-4-(2-methylphenylamino)-8-phthalimidoquinoline (9.0 g, 0.02 moles) and hydrazine hydrate (1.5 ml) were heated together under reflux in ethanol (100 ml) for 2 hours. The solvent was evaporated and the residue was stirred in chloroform, filtered and the filtrate concentrated and chromatographed (silica gel chloroform) to give 8-amino-3-butyryl-4-(2-methylphenylamino)quinoline (5.5 g, 86%), as a bright yellow oil which crystallized on standing, m.p. 108°-10° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8](=O)[CH2:9][C@H:10]([C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH2:29][CH2:28][NH:27][C:26](=[O:30])[CH:25]=3)=[CH:20][CH:19]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH3:17])[CH:5]=[CH:4][N:3]=1.Cl.[NH2:33][OH:34].C(=O)([O-])O.[Na+]>>[OH:34]/[N:33]=[C:8](/[C:6]1[CH:5]=[CH:4][N:3]=[C:2]([CH3:1])[CH:7]=1)\[CH2:9][C@H:10]([C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH2:29][CH2:28][NH:27][C:26](=[O:30])[CH:25]=2)=[CH:20][CH:19]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH3:17]
Reactant: NO
Reactant: Cc1cc(C(=O)C[C@H](c2ccc(C3=CC(=O)NCC3)cc2)c2ccccc2C)ccn1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1cc(/C(C[C@H](c2ccc(C3=CC(=O)NCC3)cc2)c2ccccc2C)=N/O)ccn1

Procedure:
In analogy to example 132, step 6, from (R)-4-(4-(3-(2-methylpyridin-4-yl)-3-oxo-1-o-tolylpropyl)phenyl)-5,6-dihydropyridin-2(1H)-one and hydroxylamine hydrochloride in the presence of sodium hydrogencarbonate was prepared the title compound as a light yellow foam, MS (ESI+): m/z=426.1 ([M+H]+).
Reaction SMILES: [NH3:1].CS(O[CH:7]1[CH2:10][N:9]([CH:11]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)[C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[CH2:8]1)(=O)=O>CO>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([CH:11]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)[N:9]2[CH2:10][CH:7]([NH2:1])[CH2:8]2)=[CH:13][CH:14]=1
Reactant: CS(=O)(=O)OC1CN(C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)C1
Reactant: N
Solvent: CO
Product: NC1CN(C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)C1
Temperature: -60 °C
Reaction time: 24 h

Procedure:
1-[Bis(4-chlorophenyl)methyl]azetidin-3-yl-amine may be obtained in the following manner: 400 cm3 of a mixture of methanol and liquid ammonia (50/50 by volume) are added to 27 g of 1-[bis(4-chlorophenyl)methyl]azetidin-3-yl methylsulfonate contained in an autoclave previously cooled to around −60° C. The reaction medium is then stirred at 60° C. for 24 hours and then abandoned in the open air to allow the evaporation of the ammonia and finally concentrated under reduced pressure (2.7 kPa). The residue is taken up in 500 cm3 of a 0.37 N aqueous sodium hydroxide solution and extracted with four times 500 cm3 of ethyl ether. The combined organic phases are washed successively with twice 100 cm3 of distilled water and 100 cm3 of a saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated under reduced pressure (2.7 kPa). The residue obtained is purified by flash chromatography on silica gel [eluant: dichloromethane/methanol (95/5 by volume)]. 14.2 g of 1-[bis(4-chlorophenyl)methyl]azetidin-3-ylamine are obtained in the form of an oil which solidifies into a cream-colored solid.
Reaction SMILES: C([N:5]([C:15]1[N:16]([C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=2)[N:17]=[C:18]2[C:23]=1[CH:22]=[CH:21][CH:20]=[CH:19]2)C(NC1CCCCC1)=O)CCC.N=[C:32]1[CH:37]=[CH:36][CH:35]=[N:34][CH2:33]1>CN1CCCC1=O>[Cl:30][C:27]1[CH:26]=[CH:25][C:24]([N:16]2[C:15]([NH:5][C:32]3[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=3)=[C:23]3[C:18]([CH:19]=[CH:20][CH:21]=[CH:22]3)=[N:17]2)=[CH:29][CH:28]=1
Reactant: N=C1C=CC=NC1
Reactant: CCCCN(C(=O)NC1CCCCC1)c1c2ccccc2nn1-c1ccc(Cl)cc1
Solvent: CN1CCCC1=O
Product: Clc1ccc(-n2nc3ccccc3c2Nc2cccnc2)cc1

Procedure:
In analogy to the procedure described in example 4.1, 3-chloro-2-(4-chloro-phenyl)-2H-indazole (Ardakani, Manouchehr; Smalley, Robert K.; Smith, Richard H., Synthesis (1979), (4), 308-9) was reacted with 3-iminopyridine ([462-08-8]) in N-methyl 2-pyrrolidone for 4 days at 175° C. in a sealed tube to give the title compound as yellow solid. MS: m/e=321.1 [M+H+].
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][CH3:11])[N:5]=[C:4]([NH:12][CH2:13][CH2:14][CH3:15])[N:3]=1.Cl.[NH2:17][OH:18]>>[CH2:13]([NH:12][C:4]1[N:5]=[C:6]([NH:8][CH2:9][CH2:10][CH3:11])[N:7]=[C:2]([NH:17][OH:18])[N:3]=1)[CH2:14][CH3:15]
Reactant: CCCNc1nc(Cl)nc(NCCC)n1
Reactant: NO
Agent: Cl
Product: CCCNc1nc(NO)nc(NCCC)n1

Procedure:
N-(4,6-Bis-n-propylamino-[1,3,5]triazin-2-yl)-hydroxylamine (XLV) was prepared from 2-chloro-N-(4,6-bis-(n-propylamino)-[1,3,5]triazine (XXXIV) and hydroxylamine hydrochloride as described in Example 13 (99% yield). 400 MHz 1H NMR (DMSO-d6, ppm) 9.0-8.6 (1H, br s), 8.39-8.14 (1H, s), 6.89-6.55 (2H, m), 3.23-3.06 (4H, m), 1.54-1.40 (4H, m), 0.84 (6H, t, J=7.4 Hz). ESI-MS (m/z): 227 [M+H]+. MP: 138-141° C.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]([C:19]2[NH:23][C:22]([C:24]3[CH:29]=[C:28]([CH:30]=O)[CH:27]=[CH:26][N:25]=3)=[CH:21][CH:20]=2)[CH2:12][CH:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[C:32]([N:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1)(=[O:34])[CH3:33].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.C(OCC)(=O)C>[C:32]([N:35]1[CH2:40][CH2:39][N:38]([CH2:30][C:28]2[CH:27]=[CH:26][N:25]=[C:24]([C:22]3[NH:23][C:19]([CH:11]([C:8]4[CH:7]=[CH:6][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:10][CH:9]=4)[CH2:12][CH:13]4[CH2:14][CH2:15][O:16][CH2:17][CH2:18]4)=[CH:20][CH:21]=3)[CH:29]=2)[CH2:37][CH2:36]1)(=[O:34])[CH3:33]
Reactant: CS(=O)(=O)c1ccc(C(CC2CCOCC2)c2ccc(-c3cc(C=O)ccn3)[nH]2)cc1
Reactant: CC(=O)N1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCCl
Product: CC(=O)N1CCN(Cc2ccnc(-c3ccc(C(CC4CCOCC4)c4ccc(S(C)(=O)=O)cc4)[nH]3)c2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 84.3 %

Procedure:
To a solution of 2-(5-{1-[4-(methylsulfonyl)phenyl]-2-(tetrahydro-2H-pyran-4-yl)ethyl}-1H-pyrrol-2-yl)pyridine-4-carbaldehyde (170 mg) in 1,2-dichloroethane (5 mL) was added 1-acetylpiperazine (115 mg), and the mixture was stirred at room temperature for 30 min. To the reaction mixture was added sodium triacetoxyborohydride (250 mg), and the mixture was stirred overnight at room temperature. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate and saturated brine, dried (MgSO4) and concentrated. The residue was subjected to basic silica gel column chromatography, and the title compound (180 mg, yield 85%) was obtained as a pale-yellow amorphous solid from a fraction eluted with ethyl acetate-methanol (19:1, volume ratio). MS: 551 (MH+).
Reaction SMILES: [NH2:1][C:2]([C@H:4]1[C:13]2[C:8](=[CH:9][C:10]([Cl:15])=[CH:11][C:12]=2[Cl:14])[NH:7][C@@H:6]([C:16]([O:18]C)=[O:17])[CH2:5]1)=[O:3].[OH-].[Na+].Cl>CO.O>[NH2:1][C:2]([C@H:4]1[C:13]2[C:8](=[CH:9][C:10]([Cl:15])=[CH:11][C:12]=2[Cl:14])[NH:7][C@@H:6]([C:16]([OH:18])=[O:17])[CH2:5]1)=[O:3]
Reactant: COC(=O)[C@H]1C[C@@H](C(N)=O)c2c(Cl)cc(Cl)cc2N1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: NC(=O)[C@@H]1C[C@H](C(=O)O)Nc2cc(Cl)cc(Cl)c21
Temperature: 25 °C
Reaction time: 14 h
Yield: 71.6 %

Procedure:
Cis-4-aminocarbonyl-5,7-dichloro-2-methoxycarbonyl-1,2,3,4-tetrahydroquinoline (0.12 g) was dissolved in 50% aqueous methanol (20 ml) and 1N sodium hydroxide solution (0.6 ml) was added. The reaction mixture was stirred at room temperature for 14 h then the solvents were evaporated in vacuo to leave a residue which was redissolved in water (20 ml) and acidified to pH 1 with concentrated hydrochloric acid. The aqueous solution was extracted with ethyl acetate (3×40 ml), dried (Na2SO4), filtered and concentrated under vacuum to give an off white solid which was triturated with diethyl ether and collected by filtration to give the title compound (0.082 g, m.p. 220°-222° C.); δ (360 MHz, DMSO) 2.28 (2H, m, CHACHBHCCHD), 3.71 (1H, m, CHACHBHCCHD), 3.89 (1H, m, CHACHBHCCHD), 6.62 (1 H, d, J=2.1 Hz, 6-H or 8-H), 6.64 (1H, br, s, NH), 6.74 (1H, d, J=2.1 Hz, 6-H or 8-H), 6.81 (1H, s, br, NH), 7.26 (1H, s, br, NH); m/e (FAB) 289 (M+1); Found: C, 44.84; H, 3.67; N, 8.95. C11H10Cl2N2O3.0.4H2O requires C, 44.59; H, 3.67; N, 9.45%.
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[C:26]([N+:28]([O-])=O)[CH:25]=[C:24]([Cl:31])[C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([OH:23])=[C:9]([CH:22]=1)[C:10]([NH:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[O:11]>CCO.CCOC(C)=O.[Pd]>[NH2:28][C:26]1[CH:25]=[C:24]([Cl:31])[C:3]([O:4][C:5]2[CH:6]=[CH:7][C:8]([OH:23])=[C:9]([CH:22]=2)[C:10]([NH:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[O:11])=[C:2]([Cl:1])[CH:27]=1
Reactant: CCCCCCCCCNC(=O)c1cc(Oc2c(Cl)cc([N+](=O)[O-])cc2Cl)ccc1O
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCCCCCCCCNC(=O)c1cc(Oc2c(Cl)cc(N)cc2Cl)ccc1O
Reaction time: 1.5 h
Yield: 72.7 %

Procedure:
To a solution of 5-(2,6-dichloro-4-nitro-phenoxy)-2-hydroxy-N-nonyl-benzamide (168 mg, 0.36 mmol) in a mixture of EtOH (3 ml) and EtOAc (3 ml) was added catalyst (10% Pd/C, 100 mg). The resulting mixture was hydrogenated at 55 psi for 1.5 h at RT. The mixture was filtered through Celite® and concentrated to give the title compound of Step E (115 mg) as a tan solid. The title product of Step E was used without further purification in the next step. MS (APCl+) Calc.: 438.1. Found: 439.3 (M+1).
Reaction SMILES: [CH3:1][S:2][CH2:3][CH2:4][CH2:5][CH2:6][OH:7].C(N(CC)CC)C.[CH3:15][S:16](Cl)(=[O:18])=[O:17]>C1COCC1>[CH3:15][S:16]([O:7][CH2:6][CH2:5][CH2:4][CH2:3][S:2][CH3:1])(=[O:18])=[O:17]
Reactant: CSCCCCO
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CSCCCCOS(C)(=O)=O

Procedure:
The 4-(methylthio)-1-butanol (Aldrich, 0.15 g, 1.2 mmol), triethylamine (0.56 mL, 4.1 mmol), and methanesulfonyl chloride (0.15 mL, 1.9 mmol) in 10 mL THF were processed as described in Example 1C to give the title compound that was used directly in the next reaction.
Reaction SMILES: [C:1]([CH:4]1[CH2:9][CH2:8][CH2:7][C:6]([CH3:11])([CH3:10])[CH2:5]1)(=[O:3])[CH3:2].[CH2:12](O)[CH:13]=[CH2:14].C([O-])(=O)C.[Na+]>>[C:1]([CH:4]1[CH2:9][CH2:8][CH2:7][C:6]([CH3:11])([CH3:10])[CH2:5]1)(=[O:3])[CH2:2][CH2:14][CH:13]=[CH2:12]
Reactant: CC(=O)C1CCCC(C)(C)C1
Reactant: C=CCO
Agent: CC(=O)[O-]
Agent: [Na+]
Product: C=CCCC(=O)C1CCCC(C)(C)C1

Procedure:
Into a 2 liter autoclave is placed 700 grams of the diethyl ketal of 1-acetyl-3,3-dimethyl cyclohexane prepared according to Example II; 360 grams of allyl alcohol; and 10 grams of sodium acetate. The autoclave is sealed and heated to 150° and maintained at that temperature for a period of five hours. At the end of the five hour period, the autoclave is opened and the contents are filtered, washed with water and distilled on a 12" Goodloe column yielding the following fractions: