Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:9][C@@H:10]1[CH2:15][CH:14]=[CH:13][CH2:12][C@@H:11]1[C:16]([OH:18])=[O:17])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+](=[CH2:21])=[N-]>CCOCC>[C:1]([O:9][C@H:10]1[CH2:15][CH:14]=[CH:13][CH2:12][C@H:11]1[C:16]([O:18][CH3:21])=[O:17])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O[C@@H]1CC=CC[C@@H]1C(=O)O)c1ccccc1
Reactant: C=[N+]=[N-]
Solvent: CCOCC
Product: COC(=O)[C@@H]1CC=CC[C@@H]1OC(=O)c1ccccc1
Yield: 100 %

Procedure:
A solution of 1-benzoyloxycyclohex-4-ene-2-carboxylic acid (5, 160 mg, 0.645 mmol) in ether (5 ml) is treated with a solution of diazomethane (excess) in ether. The solvent was removed under vacuum to yield methyl cis-2-benzoyloxy-cyclohex-4-enecarboxylate (6, 168 mg, 100%) as a colorless oil. When enantiomerically pure starting material was used, the product of this reaction was >97% enantiomerically pure. [α]D (c 6.35, acetone)=-89.5 for the 1S,2R isomer).
Reaction SMILES: [Na].[O-]CC.[Na+].[F:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([N+:13]([O-:15])=[O:14])[C:8]=1[CH3:16].[C:17](OCC)(=[O:23])[C:18]([O:20]CC)=[O:19]>CCO.O>[F:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([N+:13]([O-:15])=[O:14])[C:8]=1[CH2:16][C:17](=[O:23])[C:18]([OH:20])=[O:19]
Reactant: CCOC(=O)C(=O)OCC
Reactant: Cc1c(F)cccc1[N+](=O)[O-]
Agent: CC[O-]
Agent: [Na+]
Agent: [Na]
Solvent: O
Solvent: CCO
Product: O=C(O)C(=O)Cc1c(F)cccc1[N+](=O)[O-]
Yield: 21.3 %

Procedure:
Sodium (2.30 g, 100 mmol) was added to anhydrous EtOH (80 mL) at 0-5° C. for 10 min to prepare a fresh sodium ethoxide solution. A solution of 1-fluoro-2-methyl-3-nitrobenzene (14.4 g, 93.0 mmol) and diethyl oxalate (15.3 g, 105 mmol) in EtOH (80 mL) was added to the above solution, and the resulting mixture was then refluxed for 45 min. After cooling down, the red dark solution was diluted with water (100 mL). After removal of the ethanol, the residue was extracted with EtOAc. The aqueous layer was acidified with 2N HCl to pH around 3 to 4, and extracted with DCM. The organic layers were washed with water, dried, and concentrated to afford 4.5 g (21%) of 3-(2-fluoro-6-nitrophenyl)-2-oxopropanoic acid (32) as red oil. LCMS (ESI) m/z: 245.1 [M+NH4]+.
Reaction SMILES: CCCC[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]#[C:15][C:16]([OH:18])=[O:17].S(=O)(=O)(O)O.[CH3:24]O>>[C:16]([O:18][CH3:24])(=[O:17])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][C:6]#[CH:5]
Reactant: CO
Reactant: CCCCCCCCCCCCCC#CC(=O)O
Agent: O=S(=O)(O)O
Product: C#CCCCCCCCCCC(=O)OC
Temperature: 25 °C
Yield: 96 %

Procedure:
To a stirring solution of acetylenic acid 3 (37 g, 188 mmol) in 1.1 L of methanol was added 2.2 mL of concentrated sulfuric acid, and the resulting reaction mixture was heated under reflux for 16 h. Upon cooling to room temperature, the reaction mixture was concentrated to one third volume in vacuo, diluted with 1 L of 2:1 hexanes/diethyl ether, and washed with 2×50 mL of saturated aqueous sodium bicarbonate. The combined aqueous washes were further extracted with 2×150 mL of diethyl ether, treated with 50 mL of brine, combined with the previous organic extract and dried sodium sulfate. Concentration in vacuo gave a biphasic residue that was partitioned with 500 mL of hexanes and 50 mL of brine. The aqueous layer was further extracted with 2×50 mL of hexanes, the combined organic layers were dried over sodium sulfate, concentrated in vacuo, and vacuum dried to give methyl ester 4 (38.2 g, 96%) a golden-brown oil:
Reaction SMILES: [NH:1]([C:3]1[CH:4]=[CH:5][C:6]([CH3:9])=[N:7][CH:8]=1)[NH2:2].[CH2:10]([O:12][C:13](=[O:25])[C:14](=O)[CH2:15][C:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1)=O)[CH3:11]>>[CH2:10]([O:12][C:13]([C:14]1[CH:15]=[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)[N:1]([C:3]2[CH:8]=[N:7][C:6]([CH3:9])=[CH:5][CH:4]=2)[N:2]=1)=[O:25])[CH3:11]
Reactant: CCOC(=O)C(=O)CC(=O)c1ccccn1
Reactant: Cc1ccc(NN)cn1
Product: CCOC(=O)c1cc(-c2ccccn2)n(-c2ccc(C)nc2)n1

Procedure:
The general procedure of Referential Example 3-2) was repeated through use of the 5-hydrazino-2-methylpyridine (1.20 g) prepared in Referential Example 63 and the 4-(2-pyridyl)-2,4-dioxobutanoic acid ethyl ester (3.48 g) prepared in Referential Example 31, to thereby give the title compound as an oily product (0.459 g, 15%).
Reaction SMILES: [CH:1]([C:4]1[C:9]([CH2:10][OH:11])=[C:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:7]([CH:18]=[CH:19][CH2:20][CH3:21])=[C:6]([CH:22]([CH3:24])[CH3:23])[N:5]=1)([CH3:3])[CH3:2]>C(OCC)(=O)C.CCCCCC>[CH:1]([C:4]1[C:9]([CH2:10][OH:11])=[C:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:7]([CH2:18][CH2:19][CH2:20][CH3:21])=[C:6]([CH:22]([CH3:23])[CH3:24])[N:5]=1)([CH3:3])[CH3:2]
Reactant: CCC=Cc1c(C(C)C)nc(C(C)C)c(CO)c1-c1ccccc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CCCCc1c(C(C)C)nc(C(C)C)c(CO)c1-c1ccccc1

Procedure:
The title compound was prepared from 2,6-diisopropyl-3-hydroxymethyl-4-phenyl-5-(1-butenyl)pyridine (Example 13) according to the procedure described in Example 1, Step H. 1H NMR (300 MHz, CDCl3): δ7.41 (m, 3 H), 7.17 (m, 2 H), 4.33 (s, 2 H), (sept, J=6.6 Hz, 1 H), 3.24 (sept, J=6.6 Hz, 1 H), 2.28 (m, 2 H), 1.33 (d, J=6.6 Hz, 6 H), 1.31 (d, J=6.6 Hz, 6 H), 1.28 (m, 2 H), 1.14 (m, 3 H), 0.71 (t, J=7 Hz, 3 H). FAB-MS: calculated for (C22H31NO) 325, found 326 (M+H). Anal. Calcd for C22H31NO: C, 81.18; H, 9.60; N, 4.30. Found: C, 81.28; H, 9.87; N, 4.07. mp 83-84° C. Rf=0.4 (20% ethyl acetate/hexane).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[N:17]=[C:18]([NH:21][C:22](=[O:24])[CH3:23])[S:19][CH:20]=2)=[CH:12][CH:11]=1)(C)(C)C.[ClH:26]>C(OCC)(=O)C>[ClH:26].[NH2:7][CH2:8][CH2:9][C:10]1[CH:11]=[CH:12][C:13]([C:16]2[N:17]=[C:18]([NH:21][C:22](=[O:24])[CH3:23])[S:19][CH:20]=2)=[CH:14][CH:15]=1
Reactant: CC(=O)Nc1nc(-c2ccc(CCNC(=O)OC(C)(C)C)cc2)cs1
Agent: Cl
Solvent: CCOC(C)=O
Product: CC(=O)Nc1nc(-c2ccc(CCN)cc2)cs1
Yield: 106 %

Procedure:
tert-Butyl(2-{4-[2-(acetylamino)-1,3-thiazol-4-yl]phenyl}ethyl)carbamate (250 mg) was dissolved in ethyl acetate (4 mL) and 4 N hydrogen chloride in ethyl acetate (2 mL). The solvent was evaporated in vacuo. The solid was washed with ethyl acetate and ethyl ether to give N-{4-[4-(2-aminoethyl)phenyl]-1,3-thiazol-2-yl}acetamide hydrochloride (220 mg, 106%).
Reaction SMILES: [OH:1]OS([O-])=O.[K+].CO.[CH3:9][S:10]([C:12]1[CH:13]=[C:14]([N:18]2[C:23]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:22][C:21](=[O:30])[C:20]([CH3:31])=[C:19]2[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:15]=[CH:16][CH:17]=1)=[O:11]>O>[CH3:9][S:10]([C:12]1[CH:13]=[C:14]([N:18]2[C:23]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:22][C:21](=[O:30])[C:20]([CH3:31])=[C:19]2[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:15]=[CH:16][CH:17]=1)(=[O:1])=[O:11]
Reactant: Cc1c(-c2ccccc2)n(-c2cccc(S(C)=O)c2)c(-c2ccccc2)cc1=O
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: CO
Solvent: O
Product: Cc1c(-c2ccccc2)n(-c2cccc(S(C)(=O)=O)c2)c(-c2ccccc2)cc1=O
Reaction time: 2 h
Yield: 74.1 %

Procedure:
In 5 ml of water was dissolved 1.2 g (0.0019 mole) of Oxone. The resulting solution was then added dropwise to 5 ml of a methanol solution of 0.5 g (0.0013 mole) of 1-(3-methanesulfinylphenyl)-3-methyl-2,6-diphenyl-4(1H)-pyridinone. After stirring the reaction mixture for 2 hours, it was poured into water, followed by extraction with chloroform. The organic layer was washed with water and was thereafter dried over anhydrous sodium sulfate. The solvent was distilled off and the residue was crystallized form a 2:1 mixed solvent of acetone and hexane, affording 0.4 g of 1-(3-methanesulfonylphenyl)-3-methyl-2,6-diphenyl-4(1H)-pyridinone having a melting point of 246°-248° C.
Reaction SMILES: [I:1]N1C(=O)CCC1=O.[CH2:9]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([N:22]2[CH2:26][C@H:25]3[O:27][CH2:28][O:29][C@H:24]3[CH2:23]2)[N:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.CN(C)C=O>O>[CH2:9]([C:16]1[C:21]([I:1])=[CH:20][CH:19]=[C:18]([N:22]2[CH2:23][C@H:24]3[O:29][CH2:28][O:27][C@H:25]3[CH2:26]2)[N:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: c1ccc(Cc2cccc(N3C[C@@H]4OCO[C@@H]4C3)n2)cc1
Reactant: O=C1CCC(=O)N1I
Solvent: O
Solvent: CN(C)C=O
Product: Ic1ccc(N2C[C@@H]3OCO[C@@H]3C2)nc1Cc1ccccc1
Reaction time: 8 h
Yield: 53.5 %

Procedure:
143 mg of N-iodosuccinic acid imide was added little by little to a mixture of 150 mg of 2-benzyl-6-(cis-3,4-methylenedioxypyrrolidine-1-yl)pyridine and 5.0 ml of N,N-dimethylformamide under ice-cooling, followed by stirring overnight as it was. The reaction solution was poured into water, and then extracted with ethyl acetate. The organic phase was washed with sodium thiosulfate, water and brine, and the solvent was removed. The residue was subjected to silica gel column chromatography and eluted with hexane and then with hexane/ethyl acetate (4:1), to give 116 mg of the target compound.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([CH:18]4[CH2:23][CH2:22][O:21][CH2:20][CH2:19]4)[CH2:14][CH2:13]3)=[CH:8][C:6]=2[N:7]=1.[NH:30]1[C:38]2[CH:37]=[CH:36][CH:35]=[C:34](B(O)O)[C:33]=2[CH:32]=[CH:31]1>>[NH:30]1[C:38]2[C:33](=[C:34]([C:2]3[N:3]=[C:4]([N:24]4[CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)[C:5]4[S:10][C:9]([CH2:11][N:12]5[CH2:17][CH2:16][N:15]([CH:18]6[CH2:23][CH2:22][O:21][CH2:20][CH2:19]6)[CH2:14][CH2:13]5)=[CH:8][C:6]=4[N:7]=3)[CH:35]=[CH:36][CH:37]=2)[CH:32]=[CH:31]1
Reactant: Clc1nc(N2CCOCC2)c2sc(CN3CCN(C4CCOCC4)CC3)cc2n1
Reactant: OB(O)c1cccc2[nH]ccc12
Product: c1cc(-c2nc(N3CCOCC3)c3sc(CN4CCN(C5CCOCC5)CC4)cc3n2)c2cc[nH]c2c1
Yield: 64 %

Procedure:
A mixture of 2-chloro-4-morpholin-4-yl-6-[4-(tetrahydro-pyran-4-yl)-piperazin-1-ylmethyl]-thieno[3,2-d]pyrimidine (100 mg, 0.23 mmol) and indole-4-boronic acid was reacted using Suzuki coupling Method B, to give after silica chromatography, the title compound as a white solid (76 mg, 64%).
Reaction SMILES: [NH2:1][C:2]1[N:12]=[C:11]([NH:13]C(=O)C(C)(C)C)[C:10]([Cl:20])=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].Cl[CH2:22][CH:23]=O.C>C(O)C>[NH2:13][C:11]1[N:12]2[CH:22]=[CH:23][N:1]=[C:2]2[C:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])=[CH:9][C:10]=1[Cl:20]
Reactant: CCOC(=O)c1cc(Cl)c(NC(=O)C(C)(C)C)nc1N
Reactant: O=CCCl
Solvent: CCO
Product: CCOC(=O)c1cc(Cl)c(N)n2ccnc12
Reaction time: 8 h
Yield: 43.3 %

Procedure:
To a solution of ethyl 2-amino-5-chloro-6-[(2,2-dimethylpropanoyl)amino]nicotinate (Example 1, METHOD A, Step 2, 685 mg, 2.12 mmol) in ethanol (10 mL) was added 50% aqueous chloroacetaldehyde (430 μL, 3.4 mmol), and the mixture was refluxed with stirring overnight. The mixture was treated with charcoal and filtered. The filtrate was dry-loaded onto silica gel and chromatographed on a column of silica gel eluting with dichloromethane/methanol/25% aqueous ammonia (97:3:1 to 95:5:0.5) to give 220 mg (40%) of the title compound as a white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[C:10]([NH2:12])[C:9](Cl)=[CH:8][C:5]=1[NH:6][CH3:7])([O-:3])=[O:2].[SH:14][CH2:15][CH:16]([OH:18])[CH3:17]>>[N+:1]([C:4]1[CH:11]=[C:10]([NH2:12])[C:9]([S:14][CH2:15][CH:16]([OH:18])[CH3:17])=[CH:8][C:5]=1[NH:6][CH3:7])([O-:3])=[O:2]
Reactant: CC(O)CS
Reactant: CNc1cc(Cl)c(N)cc1[N+](=O)[O-]
Product: CNc1cc(SCC(C)O)c(N)cc1[N+](=O)[O-]
Yield: 97.5 %

Procedure:
11.5 g (0.057 mol) of 2-nitro-4-amino-5-chloro-N-(methyl)aniline and 7.8 g (0.085 mol) of 1-mercaptopropan-2-ol were used as the starting materials to give dark brown crystals (14.3 g) melting at 152° C. (recrystallization from 96° ethanol) whose elemental analysis calculated for C10H15N3O3S was:
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:3]=1C=O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(O[CH:27]([O:31][CH2:32]C)[O:28][CH2:29]C)C>CO>[Br:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:3]=1[CH:27]([O:28][CH3:29])[O:31][CH3:32]
Reactant: COc1ccc(Br)c(C=O)c1
Reactant: CCOC(OCC)OCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CO
Product: COc1ccc(Br)c(C(OC)OC)c1
Yield: 53 %

Procedure:
Step AH (2): 2-Bromo-5-methoxybenzaldehyde (1069 mg, 4.975 mmol) was dissolved in a mixture of methanol (20 mL) and triethylorthoformate (20 mL). p-Toluenesulfonic acid monohydrate (180.0 mg, 0.946 mmol) was added and the reaction mixture was stirred under reflux for 5 h. The reaction was quenched with aqueous NaHCO3 and extracted with DCM. The combined organic phases were dried over Na2SO4, filtered and concentrated in vacuum at the temperature, not exceeding 35° C. The residue was purified by silica gel chromatography to give 1-bromo-2-(dimethoxymethyl)-4-methoxybenzene (688.5 mg, 53%) as colorless oil. LC-MS (M+H)+=261.00. 1H NMR (CDCl3, 500 MHz) δ 7.42 (d, J=7.0 Hz, 1H) 7.16 (d, J=3.0 Hz, 1H) 6.76 (dd, J1=10 Hz, J2=3.0 Hz, 1H) 5.50 (s, 1H) 3.80 (s, 3H) 3.39 (s, 6H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=1)[C:10]#[N:11].Cl[CH2:20][N:21]1[CH:25]=[N:24][CH:23]=[N:22]1.CS(C)=O.[OH-].[Na+]>O>[C:10]([C:9]([C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[O:2][CH3:1])([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=1)[CH2:20][N:21]1[CH:25]=[N:24][CH:23]=[N:22]1)#[N:11]
Reactant: COc1ccccc1C(C#N)Cc1ccccn1
Reactant: ClCn1cncn1
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: COc1ccccc1C(C#N)(Cc1ccccn1)Cn1cncn1
Reaction time: 2 h

Procedure:
To a flask was added 5.0 g. (0.021 mole) of 2-(2-methoxyphenyl)-3-(2-pyridyl)propionitrile, 5.0 g. (0.031 mole) of 1-(chloromethyl)-1,2,4-triazole, and 150 ml. of DMSO, followed by 10 g. (0.125 mole) of 50% aqueous sodium hydroxide over 30 minutes. The reaction exothermed to 40° C. and was stirred for an additional two hours. After cooling, water was added and the organic material extracted with ether. The combined ether extracts were then washed with water, dried using magnesium sulfate, filtered, and the ether removed by rotary evaporation to obtain 3.0 g. of organic residue which was recrystallized from ether yielding 1.3 g. of the product as a grey solid, melting point 155°-158° C.
Reaction SMILES: [Cl:1][C:2]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[O:12]1[CH2:17][CH2:16][CH:15]([CH:18]([C:21]2[CH:22]=[N:23][C:24]([C:27]([F:30])([F:29])[F:28])=[N:25][CH:26]=2)[CH2:19][NH2:20])[CH2:14][CH2:13]1>>[Cl:1][C:2]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:20][CH2:19][CH:18]([CH:15]1[CH2:16][CH2:17][O:12][CH2:13][CH2:14]1)[C:21]1[CH:22]=[N:23][C:24]([C:27]([F:29])([F:30])[F:28])=[N:25][CH:26]=1)=[O:6]
Reactant: O=C(O)c1cccc(F)c1Cl
Reactant: NCC(c1cnc(C(F)(F)F)nc1)C1CCOCC1
Product: O=C(NCC(c1cnc(C(F)(F)F)nc1)C1CCOCC1)c1cccc(F)c1Cl

Procedure:
From 2-chloro-3-fluorobenzoic acid and 2-(tetrahydro-2H-pyran-4-yl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)ethanamine. LCMS (MH+): m/z=432.1, tR (minutes, Method F)=2.48
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][NH:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][OH:19])=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].C1([O:26][C:27](=O)[NH:28][C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][C:30]=2[F:36])C=CC=CC=1>C1(C)C=CC=CC=1>[CH2:1]([C:5]1[CH:6]=[CH:7][C:8]([CH2:11][N:12]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][OH:19])[C:27]([NH:28][C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][C:30]=2[F:36])=[O:26])=[CH:9][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ccc(CNCCCCCCO)cc1
Reactant: O=C(Nc1ccc(F)cc1F)Oc1ccccc1
Solvent: Cc1ccccc1
Product: CCCCc1ccc(CN(CCCCCCO)C(=O)Nc2ccc(F)cc2F)cc1
Reaction time: 16 h
Yield: 37 %

Procedure:
A mixture of 1.58 g of 6-[[(4-butylphenyl)methyl]amino]-1-hexanol and 1.5 g of phenyl-N-(2,4-difluorophenyl)carbamate in 40 ml of toluene was heated at reflux for 5 hours. The reaction mixture was cooled and allowed to stand at room temperature for 16 hours. The solution was washed with 3N aqueous hydrochloric acid, brine, 1N aqueous sodium hydroxide and brine again, then was dried over anhydrous magnesium sulfate and filtered. The filtrate was evaporated in vacuo and gave a yellow oil. The oil was treated by preparative high pressure liquid chromatography and gave 0.93 g (37%) of the desired product as a colorless oil.
Reaction SMILES: [CH2:1]([N:4]([CH2:20][CH2:21][CH3:22])[C:5]([CH2:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH3:18])[CH:15]=2)[N:10]([CH3:19])[CH:9]=1)=[O:6])[CH2:2][CH3:3].C([BH3-])#N.[Na+].[OH-].[Na+]>FC(F)(F)C(O)=O.C(OCC)C>[CH2:20]([N:4]([CH2:1][CH2:2][CH3:3])[C:5]([CH2:7][CH:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH3:18])[CH:15]=2)[N:10]([CH3:19])[CH2:9]1)=[O:6])[CH2:21][CH3:22]
Reactant: CCCN(CCC)C(=O)Cc1cn(C)c2ccc(OC)cc12
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: O=C(O)C(F)(F)F
Product: CCCN(CCC)C(=O)CC1CN(C)c2ccc(OC)cc21
Reaction time: 12 h
Yield: 66.8 %

Procedure:
To a solution of 3-(di-n-propylaminocarbonylmethyl)-5-methoxy-1-methylindole (78.5 mg, 0.310 mmol) in 0.75 mL of trifluoroacetic acid was added sodium cyanoborohydride (79 mg, 1.3 mmol) at room temperature. After the reaction mixture was stirred at the same temperature for 12 h, the reaction mixture was diluted with diethyl ether, and neutralized by 40% sodium hydroxide aqueous solution. The separated organic layer was washed with saturated NaHCO3 aqueous solution and brine, and dried over MgSO4. After filtration, the filtrate was concentrated in vacuo, and the residue was purified by silica gel column chromatography to obtain the title compound (63 mg, 83%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:36]=[CH:37][C:38]=1[OH:39])[C:5]([N:7]([CH:33]([CH3:35])[CH3:34])[C:8]1[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[CH:10][C:9]=1[C@@H:16]1[CH2:25][CH2:24][C:23]2[CH:22]=[C:21]([O:26]C(=O)C(C)(C)C)[CH:20]=[CH:19][C:18]=2[CH2:17]1)=O.Cl[CH2:41][C:42]([N:44]([CH2:46][CH2:47][O:48][CH3:49])[CH3:45])=O>>[F:1][C:2]1[CH:3]=[C:4]([CH:36]=[CH:37][C:38]=1[O:39][CH2:41][CH2:42][N:44]([CH2:46][CH2:47][O:48][CH3:49])[CH3:45])[CH2:5][N:7]([CH:33]([CH3:35])[CH3:34])[C:8]1[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[CH:10][C:9]=1[C@@H:16]1[CH2:25][CH2:24][C:23]2[CH:22]=[C:21]([OH:26])[CH:20]=[CH:19][C:18]=2[CH2:17]1
Reactant: COc1ccc([C@@H]2CCc3cc(OC(=O)C(C)(C)C)ccc3C2)c(N(C(=O)c2ccc(O)c(F)c2)C(C)C)c1
Reactant: COCCN(C)C(=O)CCl
Product: COCCN(C)CCOc1ccc(CN(c2cc(OC)ccc2[C@@H]2CCc3cc(O)ccc3C2)C(C)C)cc1F
Yield: 33.2 %

Procedure:
Synthesized from pivalic acid (R)-6-{2-[(3-fluoro-4-hydroxybenzoyl)isopropylamino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (21 mg) and 2-chloro-N-(2-methoxyethyl)-N-methylacetamide (13 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (7.2 mg) was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](/[C:12](=[N:16]\[O:17][CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)/[C:13](O)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].[CH3:24][C:25]1[N:29]=[C:28]([NH2:30])[S:27][N:26]=1.C(N(CC)C(C)C)(C)C>C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4](/[C:12](=[N:16]\[O:17][CH:18]2[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]2)/[C:13]([NH:30][C:28]2[S:27][N:26]=[C:25]([CH3:24])[N:29]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:9])=[O:10]
Reactant: CS(=O)(=O)c1ccc(/C(=N\OC2CCCCC2)C(=O)O)cc1Cl
Reactant: Cc1nsc(N)n1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nsc(NC(=O)/C(=N/OC2CCCCC2)c2ccc(S(C)(=O)=O)c(Cl)c2)n1
Reaction time: 2 h
Yield: 40.2 %

Procedure:
(E)-(3-Chloro-4-methanesulfonyl-phenyl)-cyclohexyloxyimino-acetic acid (prepared as in Example 9, 112 mg, 0.31 mmol), 3-methyl-[1,2,4]thiadiazol-5-ylamine (36 mg, 0.31 mmol) and N,N-diisopropylethylamine (163 μL, 0.93 mmol) were combined in acetonitrile (1.25 mL) and cooled in an ice bath. O-(7-Azabenzotriazole-1-yl)-N,N,N′N′-tetramethyluronium hexafluorophosphate (118 mg, 0.31 mmol) was added and the ice bath was removed. After stirring 2 h, the reaction mixture was evaporated in vacuo. The residue was treated with saturated aqueous sodium bicarbonate solution (1 mL) and extracted with chloroform (2×3 mL). The combined organic phases were dried over sodium sulfate and evaporated in vacuo. The residue was purified by flash column chromatography (Merck silica gel 60, 40-63 μm; 40% ethyl acetate/hexanes) to afford (E)-2-(3-chloro-4-methanesulfonyl-phenyl)-2-cyclohexyloxyimino-N-(3-methyl-[1,2,4]thiadiazol-5-yl)-acetamide (57 mg, 40%) as a white solid after lyophilization from aqueous acetonitrile: LC-MS (ESI) m/e calcd for C18H21ClN4O4S2 [M+] 456.07, found 457 [M+H+]; H1-NMR (400 MHz, CDCl3) δ ppm 1.25-1.64 (m, 6H, 3×CH2), 1.73 (m, 2H, 2×CH of CH2), 2.00 (m, 2H, 2×CH of CH2), 2.60 (s, 3 H, ArCH3), 3.31 (s, 3 H, SO2CH3), 4.37 (m, 1 H, OCH), 7.64 (dd, Jo=8.2, Jm=1.5 Hz, 1 H, Ar), 7.74 (d, Jm=1.5 Hz, 1 H, Ar), 8.23 (d, Jo=8.2 Hz, 1 H, Ar), 10.35 (s, 1 H, NH).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH2:11][CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[C:3]=1[C:4]#[N:5].[OH:18][C:19]1[CH:20]=[C:21]([CH:25]=[CH:26][CH:27]=1)[C:22](O)=[O:23]>>[NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH2:11][CH:12]2[CH2:17][CH2:16][N:15]([C:22](=[O:23])[C:21]3[CH:25]=[CH:26][CH:27]=[C:19]([OH:18])[CH:20]=3)[CH2:14][CH2:13]2)[C:3]=1[C:4]#[N:5]
Reactant: O=C(O)c1cccc(O)c1
Reactant: N#Cc1c(N)cccc1OCC1CCNCC1
Product: N#Cc1c(N)cccc1OCC1CCN(C(=O)c2cccc(O)c2)CC1

Procedure:
Prepared as in Example 24a from 2-amino-6-(piperidin-4-ylmethoxy)benzonitrile (Example 34c) and 3-hydroxybenzoic acid as an orange glass (66%). 1H NMR (400 MHz, DMSO-d6) δ 1.29 (m, 2H), 1.66-1.92 (m, 2H), 2.06 (m, 1H), 2.80 (brs, 1H), 3.05 (brs, 1H), 3.62 (brs, 1H), 3.91 (d, J=8.0 Hz, 2H), 4.49 (brs, 1H), 5.99 (s, 2H), 6.22 (d, J=8.0 Hz, 1H), 6.34 (d, J=8.0 Hz, 1H), 6.72-6.83 (m, 3H), 7.15-7.24 (m, 2H), 9.65 (s, 1H). MS 352 (MH+).
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)=[N:4][C:5]([N:8]2C(=O)C3C(=CC=CC=3)C2=O)=[CH:6][CH:7]=1>C(O)C.C(N)CN>[CH3:1][C:2]1[C:3]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)=[N:4][C:5]([NH2:8])=[CH:6][CH:7]=1
Reactant: Cc1ccc(N2C(=O)c3ccccc3C2=O)nc1-c1ccccn1
Solvent: CCO
Solvent: NCCN
Product: Cc1ccc(N)nc1-c1ccccn1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-(3-methyl-2,2′-bipyridin-6-yl)isoindoline-1,3-dione (129 mg, 0.41 mmol) in ethanol (2 ml) is added a couple of drops of ethylenediamine at room temperature. The solution is stirred at room temperature for 30 minutes. The solvents are removed by rotary evaporation and the crude product is purified by silica gel flash chromatography, eluted with 3% methanol in dichloromethane to afford 3-methyl-2,2′-bipyridin-6-amine as an off-white solid. LC-MS m/z: 186.1 (M+1).
Reaction SMILES: [C:1]([NH:9][CH2:10][C:11]([OH:13])=O)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:14]([NH2:26])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25].C>C(OCC)(=O)C>[CH2:14]([NH:26][C:11](=[O:13])[CH2:10][NH:9][C:1](=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: O=C(O)CNC(=O)c1ccccc1
Reactant: CCCCCCCCCCCCN
Solvent: CCOC(C)=O
Product: CCCCCCCCCCCCNC(=O)CNC(=O)c1ccccc1
Temperature: 160 °C

Procedure:
A mixture consisting of 10 gm (0.056 mol) of N-benzoyl-glycine and 10.5 gm (0.056 mol) of n-dodecyl-amine was heated for 90 minutes at 160°C., while stirring. Thereafter, ethyl acetate and activated charcoal were added to the reaction mixture, and the mixture was vacuum-filtered while still hot. Upon cooling of the filtrate, a crystalline substance separated out which was collected and again recrystallized from ethyl acetate, yielding 11.9 gm (58% of theory) of the compound of the formula ##EQU4## having a melting point of 124°C.