Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([NH2:20])([C:10]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)([NH2:12])[CH3:11])[CH3:9])=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:28]([C:32]1[CH:40]=[CH:39][C:35]([C:36](Cl)=[O:37])=[C:34]([O:41][CH2:42][CH3:43])[CH:33]=1)([CH3:31])([CH3:30])[CH3:29].C(C1C=CC(C(O)=O)=C(OCC)C=1)(C)(C)C.C(Cl)(=O)C(Cl)=O>ClCCl>[NH2:12][C:10]([C:13]1[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=1)([CH3:11])[C:8]([NH:20][C:36](=[O:37])[C:35]1[CH:39]=[CH:40][C:32]([C:28]([CH3:29])([CH3:30])[CH3:31])=[CH:33][C:34]=1[O:41][CH2:42][CH3:43])([C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1)[CH3:9]
Reactant: CCOc1cc(C(C)(C)C)ccc1C(=O)Cl
Reactant: CC(N)(c1ccc(Cl)cc1)C(C)(N)c1ccc(Cl)cc1
Agent: CCOc1cc(C(C)(C)C)ccc1C(=O)O
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOc1cc(C(C)(C)C)ccc1C(=O)NC(C)(c1ccc(Cl)cc1)C(C)(N)c1ccc(Cl)cc1
Yield: 17.3 %

Procedure:
A mixture of meso-2,3-bis-(4-chlorophenyl)-2,3-butanediamine (70 mg, 0.226 mmol, example 1) and triethylamine (62 uL, 0.226 mmol) in 2 mL of dichloromethane was reacted with 0.225 mmol of 4-(tert-butyl)-2-ethoxy-benzoyl chloride (prepared from the reaction of 0.225 mmol of 4-(tert-butyl)-2-ethoxy-benzoic acid and 0.34 mmol of oxalyl chloride) for 30 min at room temperature. The mixture was partitioned between 10% sodium bicarbonate solution and dichloromethane. The dichloromethane extract was washed with water, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the crude amide mixture. Purification by chromatography on silica gel, eluting with hexane-ethyl acetate (3:1) provided 20 mg of N-[2-amino-1,2-bis-(4-chloro-phenyl)-1-methyl-propyl]-4-(tert-butyl)-2-ethoxy-benzamide. The intermediate was refluxed under argon with 0.5 mg of toluenesulfonic acid monohydrate and 7 mL of toluene for 3.5 h, then cooled, taken up in ethyl acetate and washed successively with saturated sodium bicarbonate, water and brine. The ethyl acetate layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Purification by chromatography on silica gel, eluting with ethyl acetate, followed by ethyl acetate-methanol (95:5) provided 9.5 mg of rac-(4S*,5R*)-4,5-bis(4-chlorophenyl)-2-(4-(tert-butyl)-2-ethoxy-phenyl)-4,5-dimethyl-4,5-dihydro-1H-imidazole. LR-MS: 495.0 [(M+H)+]
Reaction SMILES: ClC1C(CCCl)=C(C2C=CC=C(OC)C=2)N=C(N2CCOCC2)N=1.CC1C=C(C)C=CC=1N.[CH3:34][C:35]1[CH:40]=[C:39]([CH3:41])[CH:38]=[CH:37][C:36]=1[N:42]1[C:46]2[N:47]=[C:48]([N:59]3[CH2:64][CH2:63][O:62][CH2:61][CH2:60]3)[N:49]=[C:50]([C:51]3[CH:56]=[CH:55][CH:54]=[C:53]([O:57]C)[CH:52]=3)[C:45]=2[CH2:44][CH2:43]1>>[CH3:34][C:35]1[CH:40]=[C:39]([CH3:41])[CH:38]=[CH:37][C:36]=1[N:42]1[C:46]2[N:47]=[C:48]([N:59]3[CH2:60][CH2:61][O:62][CH2:63][CH2:64]3)[N:49]=[C:50]([C:51]3[CH:52]=[C:53]([OH:57])[CH:54]=[CH:55][CH:56]=3)[C:45]=2[CH2:44][CH2:43]1
Reactant: COc1cccc(-c2nc(N3CCOCC3)nc3c2CCN3c2ccc(C)cc2C)c1
Agent: COc1cccc(-c2nc(N3CCOCC3)nc(Cl)c2CCCl)c1
Solvent: Cc1ccc(N)c(C)c1
Product: Cc1ccc(N2CCc3c(-c4cccc(O)c4)nc(N4CCOCC4)nc32)c(C)c1

Procedure:
In the same manner as Example 1-A-01, from 4-[4-chloro-5-(2-chloroethyl)-6-(3-methoxyphenyl)-pyrimidin-2-yl]-morpholine and 2,4-dimethylaniline, 7-(2,4-dimethyl-phenyl)-4-(3-methoxy-phenyl)-2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine was obtained, and subsequently, further in the same manner as Example 1-A-09, the desired compound was obtained.
Reaction SMILES: [F:1][C:2]([F:42])([F:41])[C:3]1[CH:4]=[C:5]([C@H:13]([N:15]([CH3:40])[C:16]([N:18]2[CH2:31][CH2:30][C@:21]3([NH:25][CH2:24][CH:23]([C:26]([O:28]C)=[O:27])[CH2:22]3)[CH2:20][C@@H:19]2[C:32]2[CH:37]=[CH:36][C:35]([F:38])=[CH:34][C:33]=2[CH3:39])=[O:17])[CH3:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[OH-].[Na+:44]>CO.O>[F:42][C:2]([F:1])([F:41])[C:3]1[CH:4]=[C:5]([C@H:13]([N:15]([CH3:40])[C:16]([N:18]2[CH2:31][CH2:30][C@:21]3([NH:25][CH2:24][CH:23]([C:26]([O-:28])=[O:27])[CH2:22]3)[CH2:20][C@@H:19]2[C:32]2[CH:37]=[CH:36][C:35]([F:38])=[CH:34][C:33]=2[CH3:39])=[O:17])[CH3:14])[CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=1.[Na+:44]
Reactant: COC(=O)C1CN[C@]2(CCN(C(=O)N(C)[C@H](C)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H](c3ccc(F)cc3C)C2)C1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1cc(F)ccc1[C@H]1C[C@@]2(CCN1C(=O)N(C)[C@H](C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)CC(C(=O)[O-])CN2
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.7 %

Procedure:
Methyl (5S,7R)-8-{[{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl}(methyl)amino]carbonyl}-7-(4-fluoro-2-methylphenyl)-1,8-diazaspiro[4.5]decane-3-carboxylate (Intermediate 36, 22 mg, 0.036 mmol) was dissolved in Methanol (1 ml) and to this solution was added NaOH (1.604 mg, 0.040 mmol) in Water (0.2 ml). The reaction mixture was left stirring at rt overnight. Then the solution was heated at 45° C. for 12 more hrs. The solvents were removed in vacuo and the residue was washed several times with Et2O, the solid was dried under vacuum obtaining the title compound (20.3 mg, 0.033 mmol, 91% yield) as a mixture of diastereoisomers. ratio estimated ca. 2:1, 1H NMR (500 MHz, DMSO-d6) δ ppm 7.99 (s, 1H) 7.70 (s, 2H) 7.04-7.22 (m, 1H) 6.85-6.98 (m, 1H) 6.66-6.82 (m, 1H) 5.20-5.43 (m, 1H) 4.06-4.25 (m, 1H) 2.77 (s, 3H) 2.55-3.57 (m, 5H) 2.33 (s, 3H) 1.46 (d, 3H) 1.06-2.06 (m, 6H);
Reaction SMILES: C(OC([NH:8][CH2:9][C:10]1[N:11]([CH2:33][CH:34]([CH3:36])[CH3:35])[C:12](=[O:32])[C:13]2[C:18]([C:19]=1[C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=1)=[CH:17][C:16](/[CH:27]=[CH:28]/[C:29]([NH2:31])=[O:30])=[CH:15][CH:14]=2)=O)(C)(C)C.[ClH:37]>C(OCC)(=O)C>[ClH:37].[NH2:8][CH2:9][C:10]1[N:11]([CH2:33][CH:34]([CH3:36])[CH3:35])[C:12](=[O:32])[C:13]2[C:18]([C:19]=1[C:20]1[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=1)=[CH:17][C:16](/[CH:27]=[CH:28]/[C:29]([NH2:31])=[O:30])=[CH:15][CH:14]=2
Reactant: CC(C)Cn1c(CNC(=O)OC(C)(C)C)c(-c2ccc(F)cc2)c2cc(/C=C/C(N)=O)ccc2c1=O
Agent: Cl
Solvent: CCOC(C)=O
Product: CC(C)Cn1c(CN)c(-c2ccc(F)cc2)c2cc(/C=C/C(N)=O)ccc2c1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.8 %

Procedure:
(E)-3-[3-[[(Tert-butoxycarbonyl)amino]methyl]-4-(4-fluorophenyl)-2-isobutyl-1-oxo-1,2-dihydro-6-isoquinolinyl]-2-propenamide (0.10 g, 0.2 mmol) was dissolved in a solution of 4N hydrogen chloride in ethyl acetate (5 ml) and, the mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated under reduced pressure, and the residue was crystallized from ethyl acetate to give (E)-3-[3-(aminomethyl)-4-(4-fluorophenyl)-2-isobutyl-1-oxo-1.2-dihydro-6-isoquinolinyl]-2-propenamide hydrochloride (0.08 g, 88.8%) as crystals.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([CH:9]2[N:13]([CH2:14][CH2:15][N:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)[C:12](=[O:22])[CH2:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=1.C(=O)(O)[O-].[Na+]>Br>[OH:2][C:3]1[CH:4]=[C:5]([CH:9]2[N:13]([CH2:14][CH2:15][N:16]3[CH2:17][CH2:18][O:19][CH2:20][CH2:21]3)[C:12](=[O:22])[CH2:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(C2CCC(=O)N2CCN2CCOCC2)c1
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Product: O=C1CCC(c2cccc(O)c2)N1CCN1CCOCC1
Temperature: 100 °C
Yield: 27 %

Procedure:
5-(3-Methoxyphenyl)-1-[2-(4-morpholinyl)ethyl]-2-pyrrolidinone (12.8 g) was dissolved in 48% hydrobromic acid (100 ml) and warmed at 100° C. for 4.5 hrs. The reaction mixture was cooled to ambient temperature, neutralized with saturated sodium bicarbonate solution, and the mixture was extracted with dichloromethane (6 times). The combined organic extracts were washed with brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by flash column chromatography (silica gel, ether). The appropriate fractions were collected and concentrated to give 3.3 g (55%) of 5-(3-hydroxyphenyl)-1-[2-(4-morpholinyl)ethyl]-2-pyrrolidinone.
Reaction SMILES: Cl.C([O:5][C:6]1[CH:7]=[CH:8][C:9]2[C:13]([C:14](=[O:30])[C:15]3[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23][N:24]4[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]4)=[CH:17][CH:16]=3)=[C:12]([C:31]3[CH:36]=[CH:35][C:34]([O:37]C(=O)C)=[CH:33][CH:32]=3)[S:11][C:10]=2[CH:41]=1)(=O)C.[OH-].[Na+]>CO>[OH:5][C:6]1[CH:7]=[CH:8][C:9]2[C:13]([C:14](=[O:30])[C:15]3[CH:16]=[CH:17][C:18]([O:21][CH2:22][CH2:23][N:24]4[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]4)=[CH:19][CH:20]=3)=[C:12]([C:31]3[CH:32]=[CH:33][C:34]([OH:37])=[CH:35][CH:36]=3)[S:11][C:10]=2[CH:41]=1
Reactant: CC(=O)Oc1ccc(-c2sc3cc(OC(C)=O)ccc3c2C(=O)c2ccc(OCCN3CCCCC3)cc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(c1ccc(OCCN2CCCCC2)cc1)c1c(-c2ccc(O)cc2)sc2cc(O)ccc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The oily product of Example 1 above, 6-acetoxy-2-(4-acetoxyphenyl)-3-[4-(2-piperidinoethoxy)benzoyl]benzo[b]thiophene, hydrochloride, was dissolved in 700 ml. of methanol and 100 ml. of 5 N sodium hydroxide. The mixture was stirred at ambient temperature for two hours, and was then evaporated to an oil under vacuum at a temperature below 40° C. The residue was dissolved in 500 ml. of water and washed twice with 500 ml. portions of diethyl ether. The aqueous layer was acidified to pH 2 with cold 50% aqueous methanesulfonic acid, diluted to about 3 liters, and washed twice with 1 liter portions of diethyl ether. The aqueous layer was then separated, thoroughly degassed under vacuum, and made basic with aqueous ammonia. The resulting solids were collected by filtration and vacuum dried at 40° C. to obtain 14.2 g. of crude product which was chromatographed over a 5×5 cm. column of Activity I silica gel, eluting with 15% methanol in chloroform. The product-containing fractions were evaporated to dryness to obtain a yellow foam, which was recrystallized from acetone to obtain 11.9 g. of product, which was substantially identical to the product of Example 3 above by nmr, ultraviolet and infrared analysis.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]2[NH:6][C:7]([CH2:9][C:10]([O:12]C)=[O:11])=[N:8][C:4]=2[CH:3]=1>Cl>[ClH:1].[Cl:1][C:2]1[CH:15]=[CH:14][C:5]2[NH:6][C:7]([CH2:9][C:10]([OH:12])=[O:11])=[N:8][C:4]=2[CH:3]=1
Reactant: COC(=O)Cc1nc2cc(Cl)ccc2[nH]1
Agent: Cl
Product: O=C(O)Cc1nc2cc(Cl)ccc2[nH]1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
0.68 g (2.27 mmol) of 75% methyl (5-chloro-1H-benzimidazol-2-yl)acetate is suspended in 20 mL of concentrated hydrochloric acid solution and stirred for 16 hours at ambient temperature. The precipitate formed is suction filtered and the filtrate concentrated in vacuo at 50° C. The residue is taken up twice in toluene and twice in diethyl ether, the volatile constituents are eliminated in vacuo. The residue is washed with diethyl ether. Yield: 0.23 g (41%) (hydrochloride); Rf value: 0.15 (silica gel; dichloromethane/ethanol=8:2+1% glacial acetic acid); C9H7ClN2O2 x HCl (210.62/247.08); mass spectrum: (M+H)+=211/213 (chlorine isotope).
Reaction SMILES: Br[C:2]1[S:6][C:5]([S:7]([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH:17]3[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]3)[C:12](=[O:30])[CH2:11]2)(=[O:9])=[O:8])=[CH:4][CH:3]=1.[Cl:31][C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC>[C:26]([O:25][C:23]([N:20]1[CH2:21][CH2:22][CH:17]([CH2:16][N:13]2[CH2:14][CH2:15][N:10]([S:7]([C:5]3[S:6][C:2]([C:35]4[CH:36]=[CH:37][C:32]([Cl:31])=[CH:33][CH:34]=4)=[CH:3][CH:4]=3)(=[O:9])=[O:8])[CH2:11][C:12]2=[O:30])[CH2:18][CH2:19]1)=[O:24])([CH3:29])([CH3:28])[CH3:27]
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(CN2CCN(S(=O)(=O)c3ccc(Br)s3)CC2=O)CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CC(C)(C)OC(=O)N1CCC(CN2CCN(S(=O)(=O)c3ccc(-c4ccc(Cl)cc4)s3)CC2=O)CC1
Yield: 92.6 %

Procedure:
A mixture of 4-(5-bromo-2-thiophenesulfonyl)-1-[1-(tert-butoxycarbonyl)piperidin-4-ylmethyl]-2-piperazinone (115 mg), 4-chlorophenylboronic acid (52 mg), tetrakistriphenylphosphine palladium (25 mg), 2M sodium carbonate solution (0.25 ml) and dimethoxyethane (10 ml) was refluxed for 15 hours. The reaction solution was concentrated, and to the residue was sodium bicarbonate solution. The mixture was extracted with ethyl acetate, washed with brine, dried, and concentrated, and the residue was purified with silica gel column chromatography (hexane:ethyl acetate=1:3) to give colorless solid of 1-[1-(tert-butoxycarbonyl)piperidin-4-ylmethyl]-4-[5-(4-chlorophenyl)-2-thiophenesulfonyl]-2-piperazinone (113 mg).
Reaction SMILES: [Cl:1][C:2]1[N:6]([CH:7]([CH3:9])[CH3:8])[N:5]=[CH:4][C:3]=1[N+:10]([O-])=O.[Cl-].[NH4+]>CCO.[Fe]>[Cl:1][C:2]1[N:6]([CH:7]([CH3:9])[CH3:8])[N:5]=[CH:4][C:3]=1[NH2:10]
Reactant: CC(C)n1ncc([N+](=O)[O-])c1Cl
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Product: CC(C)n1ncc(N)c1Cl
Temperature: 80 °C
Yield: 76 %

Procedure:
To a suspension of 5-chloro-1-isopropyl-4-nitro-1H-pyrazole (1 equiv) and iron dust (3 equiv) in EtOH (0.26 M) was added ammonium chloride (3 equiv). The mixture was heated to 80° C. for 20 h then cooled to room temperature. The reaction was quenched with solid sodium bicarbonate and treated with ethyl acetate (0.09 M) with continuous stirring. The mixture was filtered and the filter cake was rinsed with ethyl acetate. The combined filtrate was dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (1.5% MeOH in DCM) to provide the desired product (76% yield) as a brown oil. MS (ESI) m/z 160.1 [M+H]+.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:18]([OH:20])=O)=[N:8][C:9]=2[CH2:10][C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[CH2:3][CH2:2]1.[NH:21]1[C:25]2([CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:27][CH2:26]2)[CH2:24][CH2:23][CH2:22]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>>[C:34]([O:33][C:31]([N:28]1[CH2:27][CH2:26][C:25]2([N:21]([C:18]([C:7]3[CH:6]=[CH:5][C:4]([CH:1]4[CH2:2][CH2:3]4)=[C:9]([CH2:10][C:11]4[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=4)[N:8]=3)=[O:20])[CH2:22][CH2:23][CH2:24]2)[CH2:30][CH2:29]1)=[O:32])([CH3:37])([CH3:35])[CH3:36]
Reactant: O=C(O)c1ccc(C2CC2)c(Cc2ccc(F)cc2)n1
Reactant: CC(C)(C)OC(=O)N1CCC2(CCCN2)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCC2(CCCN2C(=O)c2ccc(C3CC3)c(Cc3ccc(F)cc3)n2)CC1

Procedure:
In analogy to the procedure described in Example 47 b), 5-cyclopropyl-6-(4-fluoro-benzyl)-pyridine-2-carboxylic acid (Example 5 g)) was reacted with tert-butyl 1,8-diazaspiro[4.5]decane-8-carboxylate (937729-06-1) in the presence of TBTU and DIEA to obtain the title compound as colorless oil; MS (EI): m/e=494.6 [MH+].
Reaction SMILES: [CH2:1]([N:5]1[C:13]2[C:12](=[O:14])[NH:11][C:10]([Cl:15])=[N:9][C:8]=2[N:7]=[C:6]1[N:16]1[CH2:21][CH2:20][CH2:19][CH:18]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:17]1)[C:2]#[C:3][CH3:4].CI.[C:32](=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[CH2:1]([N:5]1[C:13]2[C:12](=[O:14])[N:11]([CH3:32])[C:10]([Cl:15])=[N:9][C:8]=2[N:7]=[C:6]1[N:16]1[CH2:21][CH2:20][CH2:19][CH:18]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:17]1)[C:2]#[C:3][CH3:4]
Reactant: CC#CCn1c(N2CCCC(NC(=O)OC(C)(C)C)C2)nc2nc(Cl)[nH]c(=O)c21
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Solvent: CI
Product: CC#CCn1c(N2CCCC(NC(=O)OC(C)(C)C)C2)nc2nc(Cl)n(C)c(=O)c21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 74.7 %

Procedure:
700 mg of t-butyl [1-[7-(2-butynyl)-2-chloro-6-oxo-6,7-dihydro-1H-purin-8-yl]piperidin-3-yl]carbamate was dissolved in 7.0 ml of dimethyl sulfoxide, and then 114 μl of methyl iodide and 299 mg of potassium carbonate were added thereto. The mixture was stirred at room temperature for 30 minutes, and 40 ml of water was added to the reaction solution. The mixture was stirred at room temperature for 30 minutes, and the white precipitate was collected by filtration. The resulting white solid was washed with water and then with hexane to give 540 mg of the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[C:8]#[N:9].[Cl-].[OH:11][NH3+:12].C(N(CC)CC)C>>[OH:11][N:12]=[C:8]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:2]=1[CH3:1])[NH2:9]
Reactant: Cc1ccncc1C#N
Reactant: [NH3+]O
Agent: [Cl-]
Solvent: CCN(CC)CC
Product: Cc1ccncc1C(N)=NO

Procedure:
850 mg (7.20 mmol) of 4-methylpyridine-3-carbonitrile, 750 mg (10.79 mmol) of hydroxylammonium chloride and 1.2 ml (8.6 mmol) of triethylamine were reacted according to the General Method 5A. Yield: 666 mg (61% of theory)
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]2[NH:8][N:9]=[C:10]([OH:11])[C:5]2=[C:4]([CH3:12])[CH:3]=1.[N:13]([CH:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:19][CH2:18][CH2:17]1)=[C:14]=[O:15]>C1COCC1.CN(C=O)C>[CH:16]1([NH:13][C:14]([N:9]2[C:10](=[O:11])[C:5]3[C:6](=[N:7][C:2]([Cl:1])=[CH:3][C:4]=3[CH3:12])[NH:8]2)=[O:15])[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:19][CH2:18][CH2:17]1
Reactant: O=C=NC1CCCc2ccccc21
Reactant: Cc1cc(Cl)nc2[nH]nc(O)c12
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Cc1cc(Cl)nc2[nH]n(C(=O)NC3CCCc4ccccc43)c(=O)c12

Procedure:
In analogy to example 1c, 200 mg (1.089 mmol) of 6-chloro-4-methyl-1H-pyrazolo-[3,4-b]pyridin-3-ol were reacted with 226.4 mg (1.2 mmol) of 1-isocyanato-1,2,3,4-tetrahydronaphthalene in THF/DMF at RT. Yield: 142 mg (37%), M+H+: 357.35.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[CH2:6][C:7]#[N:8])[CH3:2].Cl[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[OH-].[Na+].O>CS(C)=O.CCOCC>[CH2:1]([O:3][C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[CH:6]([CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[C:7]#[N:8])[CH3:2]
Reactant: CCCCCCl
Reactant: CCOc1ccccc1CC#N
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: CCOCC
Solvent: O
Product: CCCCCC(C#N)c1ccccc1OCC
Temperature: 25 °C
Yield: 47.7 %

Procedure:
A three neck 300 ml flask fitted with a reflux condenser, thermometer and dropping funnel was charged with 18.52 grams (0.15 moles) of commercially available 2-ethoxy benzylcyanide in 50 ml of dimethyl sulfoxide (DMSO). To the reaction was added 17.6 grams (0.165 moles, 1.1 ec.) of 1-chloropentane. While stirring at room temperature, 13.2 grams (0.165 moles) of 50% NaOH in 20 ml of DMSO was added over 20 minutes. A slight exotherm occurred and the reaction mixture was stirred at room temperature for 2 hours after which gas-liquid chromatoqraphy (GLC) indicated the reaction was 92% complete. The reaction was stirred for an additional 3 hours, then water was added followed by 200 ml of ether. After washing with acid and brine, the solvent was concentrated and gave an oil which was distilled under vacuum (160°-165° C. at 0.5 mm) and gave 15.82 grams (47.7% yield) of product.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH3:7][C:8]1[C:9]2[C:10]3([CH2:19][CH:20](C(C)(C)C(=O)C4C=CN=CC=4)[NH:21][CH:22]=2)[C:14](=[CH:15][CH:16]=1)[NH:13][CH:12]([CH:17]=O)C3.[CH2:34]1[CH2:38][O:37][CH2:36][CH2:35]1>>[CH3:36][O:37]/[C:38](/[C:34]1[CH:35]=[CH:14][N:13]=[CH:12][CH:17]=1)=[C:12](\[N:13]1[C:14]2[CH:15]=[CH:16][C:8]([CH3:7])=[CH:9][C:10]=2[C:19]2[CH2:20][N:21]([CH3:22])[CH2:16][CH2:8][C:7]1=2)/[CH3:17]
Reactant: CC1=CC=C2NC(C=O)CC23CC(C(C)(C)C(=O)c2ccncc2)NC=C13
Reactant: C1CCOC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: CO/C(=C(/C)n1c2c(c3cc(C)ccc31)CN(C)CC2)c1ccncc1
Reaction time: 0.17 h

Procedure:
LAH (87 mg, 52.63 mmol) was taken in dry THF (10 mL) under inert atmosphere stirred for 10 min, 8-methyl-5-(2-methyl-1-oxo-1-(pyridin-4-yl)propan-2-yl)-3,4-dihydro-1H-pyrido[4,3-d]indole-2(5H)-carbaldehyde (0.33 g, 0.914 mmol) was added portionwise and stirred at RT for 1 h. The reaction was monitored by TLC. LAH was quenched with sat. sodium sulfate (aqueous) at 0° C., filtered the reaction mass. The filtrate was extracted with EtOAc, dried over anhydrous sodium sulfate and evaporated to dryness to afford 0.24 g of the title compound as a yellow sticky solid. 1H NMR (CDCl3, free base) δ (ppm): 8.36 (d, 2H), 7.20 (s, 1H), 7.10 (d, 1H), 7.0 (d, 1H), 6.78 (d, 2H), 3.78 (s, 2H), 3.60 (s, 3H), 2.82 (m, 1H), 2.74 (m, 1H), 2.60 (m, 1H), 2.50 (s, 3H), 2.42 (s, 3H), 2.30 (m, 1H), 2.19 (s, 3H).
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][O:11][C:12]1[CH:17]=[C:16]([N+:18]([O-:20])=[O:19])[C:15]([CH:21]=[O:22])=[CH:14][C:13]=1[O:23][CH3:24])(=[O:3])[CH3:2].[BH4-].[Na+].[Cl-].[NH4+].C(N(CC)CC)C>C(O)C.ClCCl>[C:1]([O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][O:11][C:12]1[CH:17]=[C:16]([N+:18]([O-:20])=[O:19])[C:15]([CH2:21][OH:22])=[CH:14][C:13]=1[O:23][CH3:24])(=[O:3])[CH3:2]
Reactant: COc1cc(C=O)c([N+](=O)[O-])cc1OCCCCCCOC(C)=O
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCO
Product: COc1cc(CO)c([N+](=O)[O-])cc1OCCCCCCOC(C)=O
Temperature: 0 °C
Reaction time: 3 h

Procedure:
A flame-dried, 250 mL round bottom flask was charged, under argon, with 4 (8 g, 23.6 mmol) and this was suspended in 35 mL of anhydrous ethanol. The flask was protected from light and then placed in an ice bath. Sodium borohydride (2.06 g, 54.3 mmol) was added in small portions and the reaction was allowed to stir at 0° C. for 180 minutes. At this time, saturated ammonium chloride (30 mL) was added slowly to the reaction mixture over a period of 20 minutes to minimize the gas evolution. Ethanol was evaporated in vacuo and the mixture was diluted with water (100 ml) and extracted with dichloromethane (3×100 mL). The combined organic layers were dried with magnesium sulfate, filtered, and the solvent was evaporated in vacuo to give orange oil. This oil was subjected to column chromatography (SiO2, 75×200 mm, 1% triethylamine in dichloromethane) to give, following solvent evaporation, 7.25 g (90%) of 5 as a yellow solid. Rf=0.30 (33% ethyl acetate/hexane). Mp >220° C. 1H NMR (400 MHz, DMSO-d6): δ7.67 (s, 1), 7.38 (s, 1), 5.55 (t, J=6.4 Hz, 1), 4.81 (d, J=6.4 Hz, 2), 4.04 (t, J=7.2 Hz, 2), 4.00 (t, J=7.6 Hz, 2), 3.91 (s, 3), 1.99 (s, 3), 1.76-1.72 (m, 2), 1.61-1.57 (m, 2), 1.45-1.37 (m, 4) ppm.
Reaction SMILES: F[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([S:18][CH3:19])=[CH:14][C:13]=2[F:20])[C:3]=1[CH:21]=O.O.[NH2:24][NH2:25]>COCCOC>[F:20][C:13]1[CH:14]=[C:15]([S:18][CH3:19])[CH:16]=[CH:17][C:12]=1[NH:11][C:4]1[C:5]([C:6]([OH:8])=[O:7])=[CH:9][CH:10]=[C:2]2[C:3]=1[CH:21]=[N:24][NH:25]2
Reactant: NN
Reactant: CSc1ccc(Nc2c(C(=O)O)ccc(F)c2C=O)c(F)c1
Solvent: COCCOC
Solvent: O
Product: CSc1ccc(Nc2c(C(=O)O)ccc3[nH]ncc23)c(F)c1
Temperature: 90 °C
Yield: 82 %

Procedure:
To a suspension of 4-fluoro-2-(2-fluoro-4-methylsulfanyl-phenylamino)-3-formyl-benzoic acid (105 mg, 0.32 mmol) in DME (5 mL) was added hydrazine hydrate (5 mL) and the reaction mixture heated at 90° C. for 18 hours. The volatile solvent was removed in vacuo and the residue acidified with concentrated HCl whilst applying cooling. The resultant precipitate was collected by filtration and washed with water to give the title compound as a tan solid (85 mg, 82%). LCMS (Method B) RT 3.12 [M+H]+ 318.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:24])=[C:4]2[C:9](=[C:10]([CH3:13])[C:11]=1[CH3:12])[O:8][C:7]([CH3:23])([C:14]([NH:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][OH:22])=[O:15])[CH2:6][CH2:5]2.[O:25]=[N+]([O-])[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[Ce+4].[NH4+].[NH4+]>>[OH:25][C:7]([CH3:23])([CH2:6][CH2:5][C:4]1[C:9](=[O:8])[C:10]([CH3:13])=[C:11]([CH3:12])[C:2](=[O:1])[C:3]=1[CH3:24])[C:14]([NH:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][OH:22])=[O:15]
Reactant: O=[N+]([O-])[O-]
Reactant: Cc1c(C)c2c(c(C)c1O)CCC(C)(C(=O)NCCCCCO)O2
Agent: [Ce+4]
Agent: [NH4+]
Product: CC1=C(C)C(=O)C(CCC(C)(O)C(=O)NCCCCCO)=C(C)C1=O
Yield: 92.3 %

Procedure:
Oxidation as described in protocol B, using 96 mg (0.286 mmol) of 6-hydroxy-N-(5-hydroxypentyl)-2,5,7,8-tetramethylchroman-2-carboxamide and 345 mg CAN (0.629 mmol) yielded 92.8 mg of 2-hydroxy-N-(5-hydroxypentyl)-2-methyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide as a yellow oil.