Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:19][CH3:20])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([Cl:11])[CH:9]=2)[NH:4][C:3]1=[O:12].[CH2:21]([N:23]([CH2:37][CH3:38])[C:24](=[O:36])[NH:25][C:26]1[CH:31]=[CH:30][C:29]([S:32](Cl)(=[O:34])=[O:33])=[CH:28][CH:27]=1)[CH3:22]>>[NH2:1][C:2]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:19][CH3:20])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([Cl:11])[CH:9]=2)[N:4]([S:32]([C:29]2[CH:28]=[CH:27][C:26]([NH:25][C:24]([N:23]([CH2:37][CH3:38])[CH2:21][CH3:22])=[O:36])=[CH:31][CH:30]=2)(=[O:34])=[O:33])[C:3]1=[O:12]
Reactant: CCN(CC)C(=O)Nc1ccc(S(=O)(=O)Cl)cc1
Reactant: COc1ccccc1C1(N)C(=O)Nc2ccc(Cl)cc21
Product: CCN(CC)C(=O)Nc1ccc(S(=O)(=O)N2C(=O)C(N)(c3ccccc3OC)c3cc(Cl)ccc32)cc1

Procedure:
This compound is prepared according to the procedure described in EXAMPLE 1 from 0.266 g of 3-amino-5-chloro-1,3-dihydro-3-(2-methoxyphenyl)indol-2-one and 0.280 g of 4-(N',N'-diethylureido)benzenesulfonyl chloride. The expected product is obtained after crystallization from a DCM/iso ether mixture. m=0.160 g. M.p.=214°-217° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4]Cl.[CH2:6]([NH:8][CH2:9][CH3:10])[CH3:7]>>[CH3:1][O:2][CH2:3][CH2:4][N:8]([CH2:9][CH3:10])[CH2:6][CH3:7]
Reactant: CCNCC
Reactant: COCCCl
Product: CCN(CC)CCOC
Reaction time: 10 h

Procedure:
A mixed solution prepared by mixing 200 mL of diethylamine (Kanto Chemical Co., Ltd.) and 85 mL of 2-methoxyethyl chloride (produced by Kanto Chemical) was placed in an autoclave and reacted at 120° C. for 50 hours. The internal pressure at this time was 353 kPa (3.6 kgf/cm2). After 10 hours, the crystals that settled out were removed by filtration, and the filtrate was subjected to normal-pressure distillation, yielding 66 g of 2-methoxyethyldiethylamine.
Reaction SMILES: [Cl:1][C:2]1[C:11]([CH:12]([C:14]2[N:18]3[N:19]=[C:20]([C:23]4[CH:24]=[N:25][N:26]([CH:28]5[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]5)[CH:27]=4)[CH:21]=[CH:22][C:17]3=[N:16][CH:15]=2)[CH3:13])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.C=O.[C:36]([BH3-])#N.[Na+].C(O)(=O)C>CO>[Cl:1][C:2]1[C:11]([CH:12]([C:14]2[N:18]3[N:19]=[C:20]([C:23]4[CH:24]=[N:25][N:26]([CH:28]5[CH2:29][CH2:30][N:31]([CH3:36])[CH2:32][CH2:33]5)[CH:27]=4)[CH:21]=[CH:22][C:17]3=[N:16][CH:15]=2)[CH3:13])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: CC(c1ccc2ncccc2c1Cl)c1cnc2ccc(-c3cnn(C4CCNCC4)c3)nn12
Reactant: [BH3-]C#N
Agent: C=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CC(c1ccc2ncccc2c1Cl)c1cnc2ccc(-c3cnn(C4CCN(C)CC4)c3)nn12
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To (rac)-5-chloro-6-{1-[6-(1-piperidin-4-yl-1H-pyrazol-4-yl)-imidazo[1,2-b]pyridazin-3-yl]-ethyl}-quinoline (131 mg, 0.287 mmol), a 37% aqueous solution of formaldehyde (0.107 mL, 1.434 mmol) and 85% sodium cyanoborohydride (106 mg, 1.434 mmol) in MeOH (5 mL) was added acetic acid to adjust pH at 5-6. The RM was stirred at rt for 2.5 h, filtered and purified by preparative HPLC with acetonitrile and water (+0.1% TFA) to yield the title compound as a white foam (tR 2.29 min (conditions 8), MH+=472).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH2:7].[CH2:8]([N:15]1[CH2:20][CH2:19][CH:18]=[C:17]([CH2:21][CH2:22][C:23](O)=[O:24])[C:16]1=[O:26])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C(Cl)CCl>[CH2:8]([N:15]1[CH2:20][CH2:19][CH:18]=[C:17]([CH2:21][CH2:22][C:23]([NH:7][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)=[O:24])[C:16]1=[O:26])[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: O=C(O)CCC1=CCCN(Cc2ccccc2)C1=O
Reactant: Nc1ccccn1
Solvent: ClCCCl
Product: O=C(CCC1=CCCN(Cc2ccccc2)C1=O)Nc1ccccn1
Yield: 39 %

Procedure:
Pyridyl amine was added to organic solvent dissolving 30 mg of 3-(1-benzyl-2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl)-propionic acid (0.12 mM) in EDC. The resulting compound was purified by Silica gel column chromatography with methanol/chloroform (1:20) solvent mixture as an eluant to give 16 mg of the title compound (g1) (yield: 39%).
Reaction SMILES: [CH3:1][N:2]([C:20]1[C:21]2[CH:28]=[CH:27][NH:26][C:22]=2[N:23]=[CH:24][N:25]=1)[C@H:3]1[CH2:8][CH2:7][C@H:6]([CH2:9][S:10]([N:13]2[CH2:18][CH2:17][CH2:16][C@@H:15]([OH:19])[CH2:14]2)(=[O:12])=[O:11])[CH2:5][CH2:4]1.C(N(C(C)C)CC)(C)C.[P:38](OCl)([O:43][CH2:44][CH3:45])([O:40][CH2:41][CH3:42])=[O:39].CO>ClCCl>[P:38]([O:19][C@@H:15]1[CH2:16][CH2:17][CH2:18][N:13]([S:10]([CH2:9][C@H:6]2[CH2:5][CH2:4][C@H:3]([N:2]([CH3:1])[C:20]3[C:21]4[CH:28]=[CH:27][NH:26][C:22]=4[N:23]=[CH:24][N:25]=3)[CH2:8][CH2:7]2)(=[O:12])=[O:11])[CH2:14]1)([O:43][CH2:44][CH3:45])([O:40][CH2:41][CH3:42])=[O:39]
Reactant: CN(c1ncnc2[nH]ccc12)[C@H]1CC[C@H](CS(=O)(=O)N2CCC[C@@H](O)C2)CC1
Reactant: CCOP(=O)(OCl)OCC
Solvent: ClCCl
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: CCOP(=O)(OCC)O[C@@H]1CCCN(S(=O)(=O)C[C@H]2CC[C@H](N(C)c3ncnc4[nH]ccc34)CC2)C1
Reaction time: 8 h

Procedure:
(3R)-1-[({trans-4-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclohexyl}-methyl)sulfonyl]piperidin-3-ol (100 mg, 0.24 mmol) was suspended in dichloromethane (5 mL). Diisopropylethylamine (0.05 mL, 0.3 mmol) was added followed by diethyl chloro phosphate (0.036 mL, 0.24 mmol). The reaction mixture was stirred under nitrogen overnight. Methanol (1 mL) was added to the flask and the reaction mixture was concentrated in vacuo and the resulting residue was purified by preparative reverse phase HPLC. (100 mg, 75%) 1H NMR (400 MHz, DMSO-d6) ppm 1.19 (t, J=6.95 Hz, 6H) 1.23-1.29 (m, 3H) 1.40-1.49 (m, 1H) 1.64-1.76 (m, 5H) 1.80 (d, J=12.81 Hz, 1H) 1.87 (d, J=3.66 Hz, 1H) 2.02 (d, J=10.98 Hz, 2H) 2.58 (dd, J=10.98, 8.42 Hz, 1H) 2.73-2.81 (m, 1H) 2.88-2.99 (m, 2H) 3.15 (s, 3H) 3.44-3.55 (m, 2H) 4.05-4.12 (m, 2H) 4.14-4.21 (m, 2H) 5.00 (d, J=4.03 Hz, 1H) 6.79 (br. s., 1H) 7.27 (dd, J=3.66, 2.20 Hz, 1H) 8.23 (s, 1H). LCMS m/z 544.8 (M+H calcd for C23H38N5O6PS requires 543.2). LCMS (C-18 column, gradient elution 5 minute chromatograph, 95:5 to 5:95 water/acetonitrile, retention time 1.81 min).
Reaction SMILES: [CH3:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][N:5]=[C:4]([C:11]#[N:12])[CH:3]=1.C(OCC)(=O)C>[NH4+].[Cl-].[Zn]>[NH2:8][C:7]1[C:2]([CH3:1])=[CH:3][C:4]([C:11]#[N:12])=[N:5][CH:6]=1
Reactant: Cc1cc(C#N)ncc1[N+](=O)[O-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CCOC(C)=O
Product: Cc1cc(C#N)ncc1N
Temperature: 0 °C
Reaction time: 1 h

Procedure:
4-methyl-5-nitropicolinonitrile (7.0 g, 43 mmol) was suspended in aq. NH4Cl (200 mL) and cooled to 0° C. Zinc was added portionwise for 30 min and stirred for 1 hr. The reaction was added with ethyl acetate (200 mL) and stirred for 2 hrs. The reaction was filtered and the organic layer was taken up, dried over MgSO4, and concentrated over vacuum. The solid was triturated with 50% ethyl acetate in hexane to give 5-amino-4-methylpicolinonitrile in 67% (4.56 g). 1HNMR (CDCl3, 400 MHz) δ 7.98 (s, 1H), 7.21 (s, 1H), 5.42˜5.48 (b, 2H), 2.54 (s, 3H). Exact mass calculated for C7H7N3 133.15. found 134.21 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=O.[NH:20]1[C:24]([CH2:25][C:26](O)=[O:27])=[N:23][N:22]=[N:21]1.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O.O>C(OCC)(=O)C>[C:14]1([C:12]2[C:3]3[C:2](=[CH:7][CH:6]=[C:5]([C:8]([F:11])([F:10])[F:9])[CH:4]=3)[NH:1][C:26](=[O:27])[C:25]=2[C:24]2[NH:23][N:22]=[N:21][N:20]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Nc1ccc(C(F)(F)F)cc1C(=O)c1ccccc1
Reactant: O=C(O)Cc1nnn[nH]1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCOC(C)=O
Solvent: O
Product: O=c1[nH]c2ccc(C(F)(F)F)cc2c(-c2ccccc2)c1-c1nnn[nH]1
Temperature: 50 °C
Yield: 94.1 %

Procedure:
(2-Amino-5-(trifluoromethyl)phenyl)(phenyl)methanone (300 mg, 1.13 mmol) and 2-(1H-tetrazol-5-yl)acetic acid (145 mg, 1.13 mmol) were suspended in ethyl acetate (10 ml). Then 1-propanephosphonic acid cyclic anhydride (2.02 g, 1.89 ml, 50% solution in EtOAc, 3.18 mmol) was added and the mixture was heated to 50° C. overnight. Then water was added at room temperature and the resulting precipitate was filtered, washed with water and heptane and dried at 50° C. and 15 mbar to afford the title compound (380 mg, 94%) as yellow solid. MS (ESI): 356.5 (M−H)−.
Reaction SMILES: Br[C:2](Br)=[CH:3][C:4]12[CH2:11][N:8]([CH2:9][CH2:10]1)[CH2:7][CH2:6][CH2:5]2.C([Li])CCC>C1COCC1.CCCCCC>[C:3]([C:4]12[CH2:11][N:8]([CH2:9][CH2:10]1)[CH2:7][CH2:6][CH2:5]2)#[CH:2]
Reactant: BrC(Br)=CC12CCCN(CC1)C2
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: C#CC12CCCN(CC1)C2
Temperature: 25 °C
Reaction time: 1 h
Yield: 54.5 %

Procedure:
A solution of crude (±) 5-(2,2-dibromoethenyl)-1-azabicyclo[3.2.1]octane (10 g, 34 mM) (D5) in dry THF (200 ml) was cooled to -78° C. under nitrogen and treated with n-butyl lithium in hexane (49 ml of a 1.6 molar solution, 0.078 mol). The solution was stirred at this temperature for 1 h and then allowed to warm to room temperature over a period of 1 h. The reaction mixture was then cooled to -70° C. and quenched by the addition of acetic acid (10 ml). The solution was then concentrated in vacuo to a gum and the residue partitioned between chloroform and saturated aqueous potassium carbonate solution. The organic phase was separated, dried (Na2SO4) and concentrated in vacuo to a gum which was distilled in vacuo to afford the title compound (D6, 2.5 g, 51%) as a colourless oil (B.pt 110°-120° at 0.5 mM) which crystallised on standing m.p. 41°-42° C.
Reaction SMILES: [Cl:1][C:2]1[O:3][CH:4]=[C:5]([C:7]([O:9]CC)=O)[N:6]=1.[Cl:12][C:13]1[CH:19]=[CH:18][C:16]([NH2:17])=[CH:15][CH:14]=1.N>>[Cl:1][C:2]1[O:3][CH:4]=[C:5]([C:7]([NH:17][C:16]2[CH:18]=[CH:19][C:13]([Cl:12])=[CH:14][CH:15]=2)=[O:9])[N:6]=1
Reactant: CCOC(=O)c1coc(Cl)n1
Reactant: Nc1ccc(Cl)cc1
Agent: N
Product: O=C(Nc1ccc(Cl)cc1)c1coc(Cl)n1

Procedure:
Prepared from ethyl 2-chlorooxazole-4-carboxylate (83.5 mg, 0.475 mmol) and 4-chloroaniline (60.5 mg, 0.475 mmol) as described in Example 154A: 1H NMR (500 MHz, DMSO-D6) δ ppm 7.37-7.45 (m, 2H), 7.81-7.89 (m, 2H), 8.91 (s, 1H), 10.45 (s, 1H). MS (DCI/NH3) m/z=274 (M+NH4)+.
Reaction SMILES: [F:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][NH:7][C:8]([C:10]2([C:13]([F:16])([F:15])[F:14])[CH2:12][CH2:11]2)=[O:9])=[CH:4][C:3]=1[N:19]=[C:20]=S.[NH2:22][C:23]1[C:24]([NH:44][CH3:45])=[CH:25][C:26]([O:39][CH2:40][CH:41]([F:43])[F:42])=[C:27]([CH:38]=1)[C:28]([NH:30][C:31]1[CH:36]=[CH:35][C:34]([Br:37])=[CH:33][CH:32]=1)=[O:29].CC(C)N=C=NC(C)C>CN(C=O)C>[Br:37][C:34]1[CH:35]=[CH:36][C:31]([NH:30][C:28]([C:27]2[C:26]([O:39][CH2:40][CH:41]([F:42])[F:43])=[CH:25][C:24]3[N:44]([CH3:45])[C:20]([NH:19][C:3]4[CH:4]=[C:5]([CH2:6][NH:7][C:8]([C:10]5([C:13]([F:16])([F:15])[F:14])[CH2:12][CH2:11]5)=[O:9])[CH:17]=[CH:18][C:2]=4[F:1])=[N:22][C:23]=3[CH:38]=2)=[O:29])=[CH:32][CH:33]=1
Reactant: O=C(NCc1ccc(F)c(N=C=S)c1)C1(C(F)(F)F)CC1
Reactant: CNc1cc(OCC(F)F)c(C(=O)Nc2ccc(Br)cc2)cc1N
Agent: CC(C)N=C=NC(C)C
Solvent: CN(C)C=O
Product: Cn1c(Nc2cc(CNC(=O)C3(C(F)(F)F)CC3)ccc2F)nc2cc(C(=O)Nc3ccc(Br)cc3)c(OCC(F)F)cc21

Procedure:
The title compound was prepared in accordance with the procedure in Example 72, step (a) using N-(4-fluoro-3-isothiocyanatobenzyl)-1-(trifluoromethyl)cyclopropane carboxamide (160 mg; 0.50 mmol), 5-amino-N-(4-bromophenyl)-2-(2,2-difluoroethoxy)-4-(methylamino)benzamide (200 mg; 0.50 mmol), DIC (63 mg; 0.50 mmol) and DMF (4 mL). Yield: 25 mg (7%). 400 MHz 1H-NMR (DMSO-d6, ppm) 10.06 (1H, s) 8.61 (1H, s) 8.39 (1H, t, J=5.8 Hz) 7.87-7.81 (1H, m) 7.73-7.65 (3H, m) 7.52-7.48 (2H, m) 7.29-7.26 (1H, m) 7.21-7.14 (1H, m) 6.91-6.86 (1H, m) 6.65-6.36 (1H, m) 4.55-4.46 (2H, m) 4.24 (2H, d, J=5.8 Hz) 3.71 (3H, s) 1.39-1.32 (2H, m) 1.23-1.20 (2H, m). MS m/z: 684, 686 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:18]([NH:21]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:19][CH:20]=1)[C:5]([OH:17])([C:10]#[C:11][C:12]1[O:13][CH:14]=[CH:15][CH:16]=1)[C:6]([F:9])([F:8])[F:7].Cl.C(=O)(O)[O-]>CO>[NH2:21][C:18]1[C:4]([C:5]([OH:17])([C:10]#[C:11][C:12]2[O:13][CH:14]=[CH:15][CH:16]=2)[C:6]([F:7])([F:8])[F:9])=[CH:3][C:2]([Cl:1])=[CH:20][CH:19]=1
Reactant: OC(C#Cc1ccco1)(c1cc(Cl)ccc1NC(c1ccccc1)(c1ccccc1)c1ccccc1)C(F)(F)F
Agent: Cl
Agent: O=C([O-])O
Solvent: CO
Product: Nc1ccc(Cl)cc1C(O)(C#Cc1ccco1)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 2.0 g of 3-Chloro-6-(triphenylmethy)amino-α-(2-furanyl)ethynyl-α-(trifluoromethyl)benzyl alcohol (Example 9, Part B) in 20 mL of methanol was added 0.125 mL of 12 N aqueous hydrochloric acid, and the resulting solution was stirred at ambient temperature for 30 min. The reaction mixture was poured onto aqueous bicarbonate and extracted with ether. The ether layer was washed with brine, dried and evaporated. The residue was dissolved in methanol after cooling in ice for 1 h, the precipitated methyl trityl ether was filtered off. After evaporation of the filtrate, the residue was chromatographed over silica gel (elution with hexanes/ethyl acetate 3:1) affording after crystalization from hexane/ethyl acetate 280 mg of the title compound.
Reaction SMILES: [C:1]([CH2:4][O:5][C:6]1[CH:19]=[CH:18][C:9]([CH2:10][CH:11]2[S:15][C:14](=[O:16])[NH:13][C:12]2=[O:17])=[CH:8][CH:7]=1)(O)=O.[CH3:20][NH:21][C:22](=[O:30])[C:23]1[C:24](=[CH:26][CH:27]=[CH:28][CH:29]=1)[NH2:25].C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[CH3:20][N:21]1[C:22](=[O:30])[C:23]2[C:24](=[CH:26][CH:27]=[CH:28][CH:29]=2)[N:25]=[C:1]1[CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]([CH2:10][CH:11]2[S:15][C:14](=[O:16])[NH:13][C:12]2=[O:17])=[CH:18][CH:19]=1
Reactant: O=C(O)COc1ccc(CC2SC(=O)NC2=O)cc1
Reactant: CNC(=O)c1ccccc1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Product: Cn1c(COc2ccc(CC3SC(=O)NC3=O)cc2)nc2ccccc2c1=O
Temperature: 175 °C

Procedure:
A suspension of 5-[4-[(carboxy)methoxy]benzyl]thiazolidine-2-4-dione obtained by following a procedure described in any of Examples 25-28 (100 g, 0.356 M), N-methyl anthranilamide (58.7 g, 0.391 M), and p-toluenesulphonic acid (200 mg) was taken in a round bottom flask fitted with a mechanical stirrer, oil bath and Dean-Stark condenser. The reaction mixture was heated to reflux (internal temperature 150-155° C., oil bath temperature 170-180° C.) for a period of 12-15 h while monitoring the reaction by TLC. After completion of the reaction, the reaction mass was cooled to 80° C. and methanol (700 ml) was added slowly through a dropping funnel. The reaction mass was allowed to attain room temperature while stirring and the solid thus obtained was filtered and washed with methanol (150 ml) and dried at 100-120° C. for 1 h to afford 5-[4-[[3-methyl-4-oxo-3,4-dihydroquinazolin-2-yl]methoxy]benzyl]thiazolidine-2,4-dione as a white solid (100 g , Y=71%, P=98%).
Reaction SMILES: C([O:3][C:4](=[O:35])[CH:5]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[N:6]1[CH:10]=[C:9]([NH:11][C:12](=[O:28])[C:13]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:14][CH3:15])[N:8]=[CH:7]1)C.[OH-].[Na+]>CO>[CH2:29]([CH:5]([N:6]1[CH:10]=[C:9]([NH:11][C:12](=[O:28])[C:13]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:14][CH3:15])[N:8]=[CH:7]1)[C:4]([OH:35])=[O:3])[CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]
Reactant: CCCCCCC(C(=O)OCC)n1cnc(NC(=O)C(CC)(c2ccccc2)c2ccccc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCCCCC(C(=O)O)n1cnc(NC(=O)C(CC)(c2ccccc2)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 42.5 %

Procedure:
A mixture of 6 g of α-hexyl-4-[(1-oxo-2,2-diphenylbutyl)amino]-1H-imidazole-1-acetic acid ethyl ester, 50 ml of 1N sodium hydroxide, and 100 ml of methanol were stirred at room temperature for 1 hour. The mixture was concentrated in vacuo, taken up in water, and the pH adjusted to 4.0. The aqueous solution was extracted with ethyl acetate. The organic extract was washed twice with water, dried over sodium sulfate, and concentrated in vacuo. The residue was dissolved in methylene chloride, filtered, and concentrated in vacuo to provide 2.4 g of the desired titled product.
Reaction SMILES: [CH:1]1([N:7]([CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:8](=[O:23])[NH:9][C:10]2[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[C:12]([C:18]([CH3:21])([CH3:20])[CH3:19])[C:11]=2[OH:22])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:31](OC(=O)C)(=[O:33])[CH3:32].C(N(CC)CC)C>ClCCl>[C:31]([O:22][C:11]1[C:12]([C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:13][C:14]([O:16][CH3:17])=[CH:15][C:10]=1[NH:9][C:8]([N:7]([CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1)[CH2:24][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)=[O:23])(=[O:33])[CH3:32]
Reactant: COc1cc(NC(=O)N(Cc2ccccc2)C2CCCCC2)c(O)c(C(C)(C)C)c1
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc(NC(=O)N(Cc2ccccc2)C2CCCCC2)c(OC(C)=O)c(C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of 4.00 g of 2-(3-cyclohexyl-3-phenylmethylureido)-4-methoxy-6-tert-butylphenol, 2.0 ml of acetic anhydride, 3.2 ml of triethylamine and 80 ml of dichloromethane was stirred at room temperature for 24 hours. The reaction mixture was washed and dried, and the solvent was removed under reduced pressure. The residue was applied to silica gel column chromatography (solvent; chloroform:ethyl acetate=9:1) to give 735 mg of O-acetyl-2-(3-cyclohexyl-3-phenylmethylureido)-4-methoxy-6-tert-butylphenol (Rf=0.75, melting point: 129°-132° C. (recrystallized from hexane)).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:9]([C:12]2[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=2[C:14](O)=[O:15])(=[O:11])=[O:10])=[C:4]([C:21]([F:24])([F:23])[F:22])[CH:3]=1.Cl.[CH2:26]([O:28][C:29](=[O:33])[C@H:30]([CH3:32])[NH2:31])[CH3:27].O.OC1C2N=NNC=2C=CC=1.C(N(CC)CC)C.C1(N=C=NC2CCCCC2)CCCCC1>>[CH2:26]([O:28][C:29](=[O:33])[CH:30]([NH:31][C:14](=[O:15])[C:13]1[CH:17]=[CH:18][CH:19]=[CH:20][C:12]=1[S:9](=[O:11])(=[O:10])[NH:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=1[C:21]([F:22])([F:23])[F:24])[CH3:32])[CH3:27]
Reactant: CCOC(=O)[C@H](C)N
Reactant: O=C(O)c1ccccc1S(=O)(=O)Nc1ccc(F)cc1C(F)(F)F
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: O
Solvent: CCN(CC)CC
Product: CCOC(=O)C(C)NC(=O)c1ccccc1S(=O)(=O)Nc1ccc(F)cc1C(F)(F)F

Procedure:
Under the conditions of Example 2(a), 3.633 g (10 mmol) of 2-[N-(4-fluoro-2-trifluoromethylphenyl)sulfamoyl]benzoic acid, 1.536 g (10 mmol) of L-alanine ethyl ester hydrochloride, 1.531 g (10 mmol) of hydroxybenzotriazole, hydrate, as well as 1.012 g (10 mmol) of triethylamine and 2.063 g (10 mmol) of dicyclohexylcarbodiimide are reacted and worked up analogously. The crude product is chromatographed on silica gel. The title compound is eluted with ethyl acetate.
Reaction SMILES: Cl.[NH2:2][OH:3].[OH-].[Na+].[C:6](#[N:15])[CH:7]=[CH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C(O)C>[OH:3][NH:2][C:6](=[NH:15])/[CH:7]=[CH:8]/[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: N#CC=Cc1ccccc1
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: N=C(/C=C/c1ccccc1)NO
Reaction time: 0.5 h

Procedure:
To a solution of hydroxylamine hydrochloride (690 mg, 10 mmol) in ethanol was added NaOH (400 mg, 10 mmol), followed by cinnamonitrile (1.3 g, 10 mmol). This mixture was heated to reflux for 16 h. The ethanol was removed in vacuo, the residue was acidified with 3M HCl (5 mL) and the solution was boiled for 30 minutes. The cooled solution was made basic (pH 8) with NH4OH, and partitioned between water and ethyl acetate. The organics were concentrated to give a sticky white mass which was used without further purification.
Reaction SMILES: [Br-].[Cl:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][CH:7]=[N+:8]2[CH2:13][C:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:15].BrCC(C1C=CC=CC=1)=O.ClC1C=C2C(=CC=1)[N:39]=[CH:38][CH:37]=[CH:36]2>C(#N)C>[C:14]([C:13]1[N:8]2[C:9]3[C:4]([CH:5]=[CH:6][C:7]2=[C:37]([C:38]#[N:39])[CH:36]=1)=[C:3]([Cl:2])[CH:12]=[CH:11][CH:10]=3)(=[O:15])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C(C[n+]1cccc2c(Cl)cccc21)c1ccccc1
Reactant: Clc1ccc2ncccc2c1
Agent: O=C(CBr)c1ccccc1
Agent: [Br-]
Solvent: CC#N
Product: N#Cc1cc(C(=O)c2ccccc2)n2c1ccc1c(Cl)cccc12

Procedure:
5-Chloro-1-phenacyl-quinolinium bromide: The title compound was prepared from 2-bromo-1-phenyl-ethanone (490 mg, 2.46 mmol), 6-chloro-quinoline (314 mg, 1.92 mmol) and acetonitrile (5 mL), similar to Example 1a, and yielded 394 mg (57%) as a light tan solid: 1H NMR (CDCl3) 10.55 (dd, J=1.2, 6.0 Hz, 1H), 9.41 (d, J=8.7 Hz, 1H), 8.32 (m, 1H), 8.30 (m, 1H), 8.23 (dd, J=6.0, 9.0 Hz, 1H), 8.05–7.99 (m, 3H), 7.70 (m, 3H), 7.55 (m, 2H).
Reaction SMILES: Cl.[C:2]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][CH2:12][C:13]2[N:17]([CH3:18])[C:16]3[CH:19]=[CH:20][C:21]([C@@:23]([NH:32][CH2:33][C:34]([O:36]CCC)=[O:35])([C:25]([N:27]4[CH2:31][CH2:30][CH2:29][CH2:28]4)=[O:26])[CH3:24])=[CH:22][C:15]=3[N:14]=2)=[CH:7][CH:6]=1)(=[NH:4])[NH2:3].C(O)CC.[OH-].[Na+].Cl[Si](C)(C)C>CO.CS(C)=O>[C:2]([C:5]1[CH:6]=[CH:7][C:8]([NH:11][CH2:12][C:13]2[N:17]([CH3:18])[C:16]3[CH:19]=[CH:20][C:21]([C@@:23]([NH:32][CH2:33][C:34]([OH:36])=[O:35])([C:25]([N:27]4[CH2:31][CH2:30][CH2:29][CH2:28]4)=[O:26])[CH3:24])=[CH:22][C:15]=3[N:14]=2)=[CH:9][CH:10]=1)(=[NH:3])[NH2:4]
Reactant: CCCOC(=O)CN[C@@](C)(C(=O)N1CCCC1)c1ccc2c(c1)nc(CNc1ccc(C(=N)N)cc1)n2C
Agent: C[Si](C)(C)Cl
Agent: Cl
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CO
Solvent: CCCO
Product: Cn1c(CNc2ccc(C(=N)N)cc2)nc2cc([C@@](C)(NCC(=O)O)C(=O)N3CCCC3)ccc21
Temperature: 20 °C
Reaction time: 3 h

Procedure:
To a solution of 93.9 g (0.15 mol) of (R)-2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(n-propyloxycarbonylmethylamino)-1-(pyrrolidinocarbonyl)-ethyl]-benzimidazole-hydrochloride ×1 equivalent n-propanol in 470 mL methanol are added 13.3 g (0.33 mol) of solid sodium hydroxide and this mixture is refluxed for 1.5 hours under an inert gas atmosphere. It is allowed to cool to 50° C. and within 10 minutes 22.8 mL (0.18 mmol) of chlorotrimethylsilan are added dropwise thereto. The mixture is diluted with 470 mL of dimethylsulphoxide and 370 mL of methanol are distilled off at 300 mbar/80° C. To eliminate sodium chloride the suspension is filtered hot. The filtrate is cooled to 20° C. and stirred for 3 hours at 20° C. The suspension formed is suction filtered and the filter cake is washed with 50 mL dimethylsulphoxide and 100 mL acetone. The filter cake is dried at 50° C. in the circulating air drier. The title compound is obtained as a colourless solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:41])=[C:6]([CH2:8][CH:9]([NH:11][C:12]2[CH:17]=[CH:16][NH:15][C:14](=[O:18])[C:13]=2[C:19]2[NH:40][C:22]3=[CH:23][C:24]4[C:25](=O)[N:26]([CH:32]5[CH2:37][CH2:36][N:35]([CH3:38])[CH2:34][CH2:33]5)[C:27](=[O:31])[C:28]=4[C:29]([CH3:30])=[C:21]3[N:20]=2)[CH3:10])[CH:7]=1>[Zn].C(O)(=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:41])=[C:6]([CH2:8][CH:9]([NH:11][C:12]2[CH:17]=[CH:16][NH:15][C:14](=[O:18])[C:13]=2[C:19]2[NH:40][C:22]3=[CH:23][C:24]4[CH2:25][N:26]([CH:32]5[CH2:37][CH2:36][N:35]([CH3:38])[CH2:34][CH2:33]5)[C:27](=[O:31])[C:28]=4[C:29]([CH3:30])=[C:21]3[N:20]=2)[CH3:10])[CH:7]=1
Reactant: Cc1ccc(F)cc1CC(C)Nc1cc[nH]c(=O)c1-c1nc2c(C)c3c(cc2[nH]1)C(=O)N(C1CCN(C)CC1)C3=O
Agent: [Zn]
Solvent: CC(=O)O
Product: Cc1ccc(F)cc1CC(C)Nc1cc[nH]c(=O)c1-c1nc2c(C)c3c(cc2[nH]1)CN(C1CCN(C)CC1)C3=O
Yield: 15.1 %

Procedure:
A mixture of 2-(4-(1-(5-fluoro-2-methylphenyl)propan-2-ylamino)-2-oxo-1,2-dihydropyridin-3-yl)-4-methyl-6-(1-methylpiperidin-4-yl)imidazo[4,5-f]isoindole-5,7(1H,6H)-dione (0.81 g, 1.46 mmol), zinc dust (0.95 g, 14.55 mmol), and 25 mL of acetic acid was heated at reflux for 13-14 h under an argon atmosphere. Product was separated by a silica gel column using methylene chloride and methanol (85:15 v/v) as eluent to afford 0.12 g of the designed compound as yellowish solid. 1H NMR (500 MHz, DMSO-d6) δ 12.98 (s, 1H, NH), 11.32 (d, J=8.0 Hz, 1H, NH), 11.16 (d, J=4.5 Hz, 1H, NH), 7.80 (s, 1H, ArH), 7.29-7.26 (m, 1H, ArH), 7.15-7.12 (2H, ArH), 6.91-6.85 (m, 1H, ArH), 6.14 (d, J=7.5 Hz, 1H, ArH), 4.43 (s, 2H, CH2), 4.21-4.15 (m, 1H, CH), 4.04-3.99 (m, 1H, CH), 2.97 (d, J=6.5 Hz, 2H, CH2), 2.89-2.87 (m, 2H, CH2), 2.54 (s, 2H, CH2), 2.28 (s, 3H, CH3), 2.21 (s, 3H, CH3), 2.04-1.99 (m, 2H, CH2), 1.89 (s, 3H, CH3), 1.89-1.82 (m, 2H, CH2), 1.70-1.67 (m, 2H, CH2), 1.34 (d, J=6.0 Hz, 3H, CH3); Mass (ESI, positive) m/z 543.2 [M+H]+, 565.2 [M+Na]+.