Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[NH:7][C:6](=[O:8])[CH2:5][CH2:4]1.Br[C:10]1[CH:15]=[C:14]([F:16])[C:13]([C:17]([N:19]2[CH2:24][CH2:23][N:22]([C:25]3[C:30]([CH3:31])=[CH:29][C:28]([CH3:32])=[CH:27][N:26]=3)[CH2:21][CH2:20]2)=[O:18])=[C:12]([F:33])[CH:11]=1>>[CH3:31][C:30]1[C:25]([N:22]2[CH2:23][CH2:24][N:19]([C:17]([C:13]3[C:14]([F:16])=[CH:15][C:10]([N:7]4[C@@H:3]([CH2:2][OH:1])[CH2:4][CH2:5][C:6]4=[O:8])=[CH:11][C:12]=3[F:33])=[O:18])[CH2:20][CH2:21]2)=[N:26][CH:27]=[C:28]([CH3:32])[CH:29]=1
Reactant: O=C1CC[C@H](CO)N1
Reactant: Cc1cnc(N2CCN(C(=O)c3c(F)cc(Br)cc3F)CC2)c(C)c1
Product: Cc1cnc(N2CCN(C(=O)c3c(F)cc(N4C(=O)CC[C@@H]4CO)cc3F)CC2)c(C)c1
Yield: 47.3 %

Procedure:
Using (R)-5-hydroxymethylpyrrolidin-2-one (116 mg) and (4-bromo-2,6-difluorophenyl)[4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (410 mg) described in Preparation Example 111 and by the reaction and treatment in the same manner as in Example 1, the title compound (210 mg) was obtained.
Reaction SMILES: [ClH:1].NC1CNC(=N)CC1.[NH2:10][C:11]1[CH:16]=[C:15]([CH3:17])[C:14]([N+:18]([O-])=O)=[CH:13][N:12]=1>>[ClH:1].[ClH:1].[NH2:18][CH:14]1[CH2:13][NH:12][C:11](=[NH:10])[CH2:16][CH:15]1[CH3:17]
Reactant: Cc1cc(N)ncc1[N+](=O)[O-]
Agent: Cl
Agent: N=C1CCC(N)CN1
Product: CC1CC(=N)NCC1N

Procedure:
The method of preparation of 5-amino-2-iminopiperidine hydrochloride was used to convert 2-amino-4-methyl-5-nitropyridine to the title compound. Product was obtained as a white solid, shown to be two isomers by 1H NMR analysis. Recrystallization from EtOH/H2O gave a white solid, shown to be one isomer (A) by 1H NMR and tentatively assigned the trans configuration. The mother liquor was concentrated in vacuo and redissolved in warm EtOH. Upon cooling, the first crop was obtained which contains more (A). The second crop contains a mixture of (A) and (B). The third crop is pure (B), which was tentatively assigned the cis configuration. The analysis of the product was found to be consistent with the proposed structure. 1H NMR (D2O) of (A): δ3.8-3.7 (m, 1H); 3.68-3.58 (m, 1H); 3.50-3.40 (m, 1H); 2.90-2.75 (m, 1H); 2.45-2.35 (m, 2H); 1.00 (d, J=7 Hz, 3H). 1H NMR (D2O) of (B): 3.75-3.65 (m, 1H); 3.45-3.25 (m, 2H); 2.85-2.70 (m, 1H); 2.50-2.35 (m, 1H); 2.20-2.15 (m, 1H); 1.05 (d, J=7 Hz, 3H).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1.CN(C)C=O.[C@@H:14]12[C:23](=O)[O:22][C:20](=[O:21])[C@@H:15]1[CH2:16][CH2:17][CH2:18][CH2:19]2.[OH-].[K+]>O>[N:6]1[CH:7]=[CH:8][C:3]([CH2:2][N:1]2[C:20](=[O:21])[C@H:15]3[C@H:14]([CH2:19][CH2:18][CH2:17][CH2:16]3)[C:23]2=[O:22])=[CH:4][CH:5]=1
Reactant: NCc1ccncc1
Reactant: O=C1OC(=O)[C@@H]2CCCC[C@H]12
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1[C@H]2CCCC[C@H]2C(=O)N1Cc1ccncc1
Yield: 43.8 %

Procedure:
To 17.0 g (157 mmoles) of 4-aminomethylpyridine was added 40 mL of dimethylformamide and 24.2 g (157 mmoles) of cis-1,2-cyclohexanedicarboxylic anhydride. The mixture was heated under reflux for 2 hours. The cooled solution was diluted with water, made basic with aqueous potassium hydroxide, and extracted with ethyl acetate. The organic extracts were washed with saturated sodium bicarbonate solution and saturated sodium chloride solution, dried and evaporated to afford 16.8 g of 2-(4-pyridinylmethyl)-cis-3a,4,5,6,7,7a-hexahydro-1H-isoindole-1,3(2H)-dione, m.p. 91°-92°; NMR (CDCl3): δ8.53-8.63 (d, 2H); 7.19-7.29 (d, 2H); 4.63 (s, 2H); 2.80-3.00 (m, 2H); 1.78-2.00 (m, 2H); 1.63-1.78 (m, 2H); 1.33-1.58 (m, 4H).
Reaction SMILES: N12CCCN=C1CCCCC2.Cl[C:13]1[N:18]=[C:17]([O:19][CH3:20])[C:16]([N+:21]([O-:23])=[O:22])=[C:15]([O:24][CH3:25])[N:14]=1.Cl.[F:27][C:28]([F:40])([F:39])[C:29]1[CH:30]=[C:31]2[C:36](=[CH:37][CH:38]=1)[CH2:35][NH:34][CH2:33][CH2:32]2>CN(C=O)C>[CH3:25][O:24][C:15]1[C:16]([N+:21]([O-:23])=[O:22])=[C:17]([O:19][CH3:20])[N:18]=[C:13]([N:34]2[CH2:33][CH2:32][C:31]3[C:36](=[CH:37][CH:38]=[C:29]([C:28]([F:27])([F:40])[F:39])[CH:30]=3)[CH2:35]2)[N:14]=1
Reactant: COc1nc(Cl)nc(OC)c1[N+](=O)[O-]
Reactant: FC(F)(F)c1ccc2c(c1)CCNC2
Agent: Cl
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: COc1nc(N2CCc3cc(C(F)(F)F)ccc3C2)nc(OC)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 99 %

Procedure:
1,8-diazabicyclo[5.4.0]undec-7-ene (0.669 g, 4.4 mmol) was added to a mixture of 4a (0.438 g, 2 mmol) and 6-(trifluoromethyl)-1,2,3,4-tetrahydroisoquinoline hydrochloride (0.487 g, 2.05 mmol) in DMF (5 ml) at 0° C. over 5 minutes. The mixture was stirred for an additional 5 minutes at room temperature. The mixture was washed with brine, extracted with ethyl acetate and chromatographed to yield 5b (0.76 g, 1.98 mmol, 99%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].I[CH:12]([CH3:14])[CH3:13].C([O-])([O-])=O.[K+].[K+].Cl>O.CC(=O)CC>[CH:12]([O:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6])([CH3:14])[CH3:13]
Reactant: O=C(O)c1cccc(O)c1
Reactant: CC(C)I
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: O
Product: CC(C)Oc1cccc(C(=O)O)c1

Procedure:
Combine 3-hydroxybenzoic acid (100 mmol), 2-iodopropane (500 mmol), K2CO3 (300 mmol), and 2-butanone (300 mL). Heat at reflux for 72 h. Concentrate in vacuo to obtain a residue. Add water (500 mL) and cool in an ice bath. Adjust to pH 1 by dropwise addition of concentrated HCl. Extract with dichloromethane (3×200 mL). Extract the combined organic layers with water (200 mL), dry over Na2SO4, filter, and concentrate in vacuo to obtain a residue. Purify to obtain the title compound.
Reaction SMILES: [SH:1][C:2]1[O:3][C:4]([C:7]2[O:11][C:10]([N:12]([CH3:14])[CH3:13])=[N:9][N:8]=2)=[N:5][N:6]=1.O1CCOCC1.CN(C)C=O.Br[CH2:27][CH2:28][C:29]([F:33])=[C:30]([F:32])[F:31]>O>[F:33][C:29](=[C:30]([F:32])[F:31])[CH2:28][CH2:27][S:1][C:2]1[O:3][C:4]([C:7]2[O:11][C:10]([N:12]([CH3:14])[CH3:13])=[N:9][N:8]=2)=[N:5][N:6]=1
Reactant: FC(F)=C(F)CCBr
Reactant: CN(C)c1nnc(-c2nnc(S)o2)o1
Solvent: C1COCCO1
Solvent: CN(C)C=O
Solvent: O
Product: CN(C)c1nnc(-c2nnc(SCCC(F)=C(F)F)o2)o1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4.26 g of 2-mercapto-5-(2-dimethylamino-1,3,4-oxadiazol-5-yl)-1,3,4-oxadiazole according to Example H2 are initially introduced into 40 ml of dioxane and stirred with 2.24 g of potassium t-butylate. 4 ml of dimethylformamide and then 4.2 g of 4-bromo-1,1,2-trifluorobut-1-ene are added and the mixture is stirred overnight at room temperature. The mixture is poured into water and the crystals are filtered off with suction. After drying and stirring with ether, 4.6 g of the title compound of melting point 87°-90° C. are obtained.
Reaction SMILES: [F:1][C:2]1[CH:38]=[C:37]([F:39])[CH:36]=[CH:35][C:3]=1[CH2:4][N:5]([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[C:6](=[O:27])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([S:15][CH2:16][C:17]2[CH:26]=[CH:25][CH:24]=[CH:23][C:18]=2[C:19]([O:21]C)=[O:20])=[CH:11][CH:10]=1.[OH-].[K+].CCOC(C)=O>CCO>[F:1][C:2]1[CH:38]=[C:37]([F:39])[CH:36]=[CH:35][C:3]=1[CH2:4][N:5]([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[C:6](=[O:27])[CH2:7][CH2:8][C:9]1[CH:10]=[CH:11][C:12]([S:15][CH2:16][C:17]2[CH:26]=[CH:25][CH:24]=[CH:23][C:18]=2[C:19]([OH:21])=[O:20])=[CH:13][CH:14]=1
Reactant: CCCCCCCN(Cc1ccc(F)cc1F)C(=O)CCc1ccc(SCc2ccccc2C(=O)OC)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCCCCCCN(Cc1ccc(F)cc1F)C(=O)CCc1ccc(SCc2ccccc2C(=O)O)cc1
Yield: 94.1 %

Procedure:
Methyl 2-{[(4-{3-[(2,4-difluorobenzyl)(heptyl)amino]-3-oxopropyl}phenyl)thio]methyl}benzoate (1.05 g, 1.89 mmol) was dissolved in EtOH (95%, 5 ml), potassium hydroxide (0.21 g, 3.77 mmol) was added. The reaction was performed in a single node microwave oven (7 min, 150° C.). Workup was by addition of EtOAc (5 ml) and washing with HCl (2×5 ml, 1M). The organic layer was dried (MgSO4) and the solvent was removed by evaporation to give 0.96 gram of 2-{[(4-{3-[(2,4-difluorobenzyl)(heptyl)amino]-3-oxopropyl}phenyl)thio]methyl}benzoic acid (yield 94.3%).
Reaction SMILES: [CH:1]1([C:4]([C:6]2[CH:7]=[N:8][C:9]3[C:14]([C:15]=2[NH:16][C:17]2[CH:18]=[CH:19][C:20]([N:23]4[CH2:28][CH2:27][CH2:26][C@H:25]([NH:29]C(=O)OC(C)(C)C)[CH2:24]4)=[N:21][CH:22]=2)=[N:13][C:12]([C:37]2[CH:42]=[C:41]([Cl:43])[C:40]([OH:44])=[C:39]([Cl:45])[CH:38]=2)=[CH:11][CH:10]=3)=[O:5])[CH2:3][CH2:2]1.C(O)(C(F)(F)F)=O>>[ClH:43].[ClH:43].[ClH:43].[NH2:29][C@H:25]1[CH2:26][CH2:27][CH2:28][N:23]([C:20]2[N:21]=[CH:22][C:17]([NH:16][C:15]3[C:14]4[C:9](=[CH:10][CH:11]=[C:12]([C:37]5[CH:38]=[C:39]([Cl:45])[C:40]([OH:44])=[C:41]([Cl:43])[CH:42]=5)[N:13]=4)[N:8]=[CH:7][C:6]=3[C:4]([CH:1]3[CH2:3][CH2:2]3)=[O:5])=[CH:18][CH:19]=2)[CH2:24]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCN(c2ccc(Nc3c(C(=O)C4CC4)cnc4ccc(-c5cc(Cl)c(O)c(Cl)c5)nc34)cn2)C1
Solvent: O=C(O)C(F)(F)F
Product: Cl
Product: N[C@H]1CCCN(c2ccc(Nc3c(C(=O)C4CC4)cnc4ccc(-c5cc(Cl)c(O)c(Cl)c5)nc34)cn2)C1
Yield: 171.1 %

Procedure:
Following general procedure IV-2, (S)-tert-butyl 1-{5-[3-(cyclopropanecarbonyl)-6-(3,5-dichloro-4-hydroxyphenyl)-1,5-naphthyridin-4-ylamino]pyridin-2-yl}piperidin-3-ylcarbamate (73 mg, 0.11 mmol) was reacted with TFA (3 mL) followed by formation of the trihydrochloride salt to afford the desired product (31 mg, 42%) as an orange solid: 1H NMR (500 MHz, CD3OD) δ 9.52 (br s, 1H), 8.51 (d, J=9.0 Hz, 1H), 8.42 (d, J=9.0 Hz, 1H), 8.23 (d, J=2.6 Hz, 1H), 7.88 (dd, J=9.4, 2.7 Hz, 1H), 7.69 (br s, 2H), 7.24 (d, J=9.5 Hz, 1H), 4.37 (d, J=10.9 Hz, 1H), 4.05-3.95 (m, 1H), 3.50-3.33 (m, 3H), 2.90 (br s, 1H), 2.27-2.17 (m, 1H), 2.06-1.96 (m, 1H), 1.86-1.74 (m, 2H), 1.37-1.18 (m, 4H); ESI MS m/z 549 [M+H]+; HPLC 95.4% (AUC), tR=10.09 min.
Reaction SMILES: [CH2:1]([CH:5]([C:11]([O:13]CC)=O)[C:6]([O:8]CC)=O)[CH2:2][CH2:3][CH3:4].[Na].[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([NH:25][NH:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:21][CH:20]=1>C(O)C>[CH2:1]([CH:5]1[C:6](=[O:8])[N:25]([C:22]2[CH:21]=[CH:20][C:19]([O:18][CH3:17])=[CH:24][CH:23]=2)[N:26]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:11]1=[O:13])[CH2:2][CH2:3][CH3:4]
Reactant: COc1ccc(NNc2ccccc2)cc1
Reactant: CCCCC(C(=O)OCC)C(=O)OCC
Agent: [Na]
Solvent: CCO
Product: CCCCC1C(=O)N(c2ccccc2)N(c2ccc(OC)cc2)C1=O
Temperature: 142.5 °C
Yield: 56.7 %

Procedure:
Diethyl butylmalonate (4.33 g; 20.0 mmol) was added to a stirred solution of sodium (0.46 g; 20.0 mmol) in absolute ethanol (20 ml), followed by crude 1-(4-methoxyphenyl)-2-phenylhydrazine (4.3 g; 20 mmol max.) in absolute ethanol (5 ml). About ⅔ of the ethanol was distilled off and xylene (20 ml) was added to the residue. The reaction mixture was heated to 140-145° C. (bath temperature) for 15 h to distill off the rest of the ethanol. The reaction mixture was cooled to 0° C. (bath temperature) and poured into ice water (ca. 100 ml). The aqueous layer was extracted with CH2Cl2 (2×15 ml); the extracts were discarded. The cold aqueous layer was acidified with 6 H HCl (5 ml) and extracted with CH2Cl2 (3×10 ml). The combined extracts were washed with water (2×10 ml) and dried (MgSO4). Filtration and evaporation gave 3.84 g amber oil. Purified by flash chromatography on a 130×65 mm silica gel 60 column eluted with ethyl acetate-heptane (1:3) to give 1.45 g (21%) colourless oil.
Reaction SMILES: [CH:1]([C:3]1[S:7][CH:6]=[C:5]([C:8]2[CH:9]=[C:10]3[C:14](=[C:15]([C:17]([NH2:19])=[O:18])[CH:16]=2)[NH:13][CH:12]=[C:11]3[CH:20]2[CH2:25][CH2:24][N:23]([S:26]([CH2:29][CH2:30][CH2:31][O:32][CH3:33])(=[O:28])=[O:27])[CH2:22][CH2:21]2)[CH:4]=1)=O.[CH3:34][C:35]([NH2:38])([CH3:37])[CH3:36].[BH4-].[Na+]>>[CH3:34][C:35]([NH:38][CH2:1][C:3]1[S:7][CH:6]=[C:5]([C:8]2[CH:9]=[C:10]3[C:14](=[C:15]([C:17]([NH2:19])=[O:18])[CH:16]=2)[NH:13][CH:12]=[C:11]3[CH:20]2[CH2:21][CH2:22][N:23]([S:26]([CH2:29][CH2:30][CH2:31][O:32][CH3:33])(=[O:27])=[O:28])[CH2:24][CH2:25]2)[CH:4]=1)([CH3:37])[CH3:36]
Reactant: CC(C)(C)N
Reactant: COCCCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4csc(C=O)c4)cc23)CC1
Agent: [BH4-]
Agent: [Na+]
Product: COCCCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4csc(CNC(C)(C)C)c4)cc23)CC1

Procedure:
Following the general procedure in example 281, 5-(5-formyl-3-thienyl)-3-(1-{[3-(methyloxy)propyl]sulfonyl}-4-piperidinyl)-1H-indole-7-carboxamide (40 mg, 0.08 mmol), (1,1-dimethylethyl)amine (70 mg, 0.8 mmol) and NaBH4 (30.26 mg, 0.8 mmol) were reacted to form the desired product which was purified by Gilson HPLC (CH3CN/Water, 0.1% TFA) (8.4 mg, 19%).
Reaction SMILES: [H-].[Na+].[Br-].[OH:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[CH3:30][C:31](=O)[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40]>CS(C)=O>[CH3:40][CH:39]([CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH3:30])[CH2:10][CH2:9][CH2:8][CH2:7][CH:6]=[CH:5][OH:4]
Reactant: OCCCCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCCCCCCCCC(C)=O
Agent: [Br-]
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CCCCCCCCCC(C)CCCCC=CO
Temperature: 70 °C
Reaction time: 18 h

Procedure:
Into a dried 5 L, 3 neck round bottom flask fitted with mechanical stirring, nitrogen inlet, dropping funnel, thermometer and nitrogen outlet is added 70.2 g of 60% sodium hydride (1.76 mol) in mineral oil. The mineral oil is removed by washing with hexanes. Anhydrous dimethyl sulfoxide (500ml) is added to the flask and the mixture is heated to 70° C. until evolution of hydrogen stops. The reaction mixture is cooled to room temperature followed by addition of 1 L of anhydrous tetrahydrofuran. (6-hydroxyhexyl) triphenylphosphonium bromide (443.4 g, 1 mol) is slurried with warm anhydrous dimethyl sulfoxide (50° C., 500 ml) and slowly added to the reaction mixture through the dropping funnel while keeping it at 25-30° C. The mixture is stirred for 30 minutes at room temperature at which time 2-undecanone (187 g, 1.1 mol) is slowly added through a dropping funnel. Reaction is slightly exothermic and cooling is needed to maintain 25-30° C. The mixture is stirred for 18 hr. and then poured into a 5 L beaker containing 1 L purified water with stirring. The oil phase (top) is allowed to separate out in a separatory funnel and the water phase is removed. The water phase is washed with hexanes (500 ml) and the organic phase is separated and combined with the oil phase from the water wash. The organic mixture is then extracted with water 3 times (500 ml each) followed by vacuum distillation to collect the clear, oily product (132 g) at 140° C. and 1 mm Hg.
Reaction SMILES: S(Cl)([Cl:3])=O.[F:5][C:6]1[C:11]([CH:12]([CH3:16])[C:13](O)=[O:14])=[C:10]([F:17])[C:9]([F:18])=[C:8]([F:19])[C:7]=1[F:20]>>[F:5][C:6]1[C:11]([CH:12]([CH3:16])[C:13]([Cl:3])=[O:14])=[C:10]([F:17])[C:9]([F:18])=[C:8]([F:19])[C:7]=1[F:20]
Reactant: CC(C(=O)O)c1c(F)c(F)c(F)c(F)c1F
Reactant: O=S(Cl)Cl
Product: CC(C(=O)Cl)c1c(F)c(F)c(F)c(F)c1F
Temperature: 80 °C
Reaction time: 10 h

Procedure:
A mixture of 4.8 ml of thionyl chloride and 8.10 g of (-)-2-(pentafluorophenyl)propionic acid obtained in Example 4 was stirred for 10 hours at 80° C. Excess thionyl chloride was distilled off under reduced pressure, and the subsequent distillation under reduced pressure gave 6.61 g of (-)-2-(pentafluorophenyl)propionyl chloride having the aforementioned physical properties.
Reaction SMILES: [CH:1]([O:4][S:5]([C:8]1[C:17]([N:18]=[N:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)=[C:16]([OH:28])[C:15]2[C:10](=[CH:11][C:12]([NH:29][C:30]3[N:35]=[C:34](Cl)[N:33]=[C:32]([Cl:37])[N:31]=3)=[CH:13][CH:14]=2)[CH:9]=1)(=[O:7])=[O:6])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Na+].[Na+].[NH:44]([CH2:48][CH2:49][OH:50])[CH2:45][CH2:46][OH:47]>CC(C)=O.Cl>[CH:1]([O:4][S:5]([C:8]1[C:17]([N:18]=[N:19][C:20]2[CH:21]=[CH:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=2)=[C:16]([OH:28])[C:15]2[C:10](=[CH:11][C:12]([NH:29][C:30]3[N:35]=[C:34]([N:44]([CH2:48][CH2:49][OH:50])[CH2:45][CH2:46][OH:47])[N:33]=[C:32]([Cl:37])[N:31]=3)=[CH:13][CH:14]=2)[CH:9]=1)(=[O:6])=[O:7])([CH3:3])[CH3:2]
Reactant: COc1ccc(N=Nc2c(S(=O)(=O)OC(C)C)cc3cc(Nc4nc(Cl)nc(Cl)n4)ccc3c2O)cc1
Reactant: OCCNCCO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)=O
Product: COc1ccc(N=Nc2c(S(=O)(=O)OC(C)C)cc3cc(Nc4nc(Cl)nc(N(CCO)CCO)n4)ccc3c2O)cc1
Reaction time: 60 h
Yield: 77.8 %

Procedure:
7-(4,6-Dichloro-[1,3,5]-triazin-2-ylamino)-4-hydroxy-3-(4-methoxy-phenylazo)-napthalene-2-sulfonic acid isopropyl ester (Example 7, 200 mg, 0.36 mmol) in acetone (3 mL) was stirred under nitrogen with sodium carbonate (38 mg, 0.36 mmol). Diethanolamine (35 μL, 40 mg, 0.36 mmol) was added to the stirred suspension, and the reaction mixture was allowed to stir 60 h. The reaction mixture was diluted with hydrochloric acid (3 mL, 1 N) and filtered. The solid was triturated in methanol/ether (1:3) for 1 h and filtered to provide the title compound (179 mg, 0.28 mmol, 79%) as a red solid: NMR (DMSO-d6): δ 16.28 (s, 1H), 10.61 (s, 1H), 8.45 (s, 1H ), 8.30 (d, J=9 Hz, 1H), 7.88 (m, 2H), 7.76 (d, J=9 Hz, 2H), 7.15 (d, J=9 Hz, 2H), 4.78 (m, 1H), 3.90 (m, 13H), 1.23 (d, J=6 Hz, 6H); Analytical HPLC: 87%.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH2:5][CH2:6][N:7]([CH2:12][C:13]#[C:14][C:15]3[CH:20]=[CH:19][C:18]([C:21]#[N:22])=[CH:17][CH:16]=3)[CH2:8][CH2:9][C:10]=2[N:11]=1.O.[H][H].CCOCC>CN(C)C=O.[Pd].CC([O-])=O.CC([O-])=O.[Pb+2]>[NH2:1][C:2]1[S:3][C:4]2[CH2:5][CH2:6][N:7]([CH2:12]/[CH:13]=[CH:14]\[C:15]3[CH:16]=[CH:17][C:18]([C:21]#[N:22])=[CH:19][CH:20]=3)[CH2:8][CH2:9][C:10]=2[N:11]=1
Reactant: [H][H]
Reactant: N#Cc1ccc(C#CCN2CCc3nc(N)sc3CC2)cc1
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Pb+2]
Solvent: CCOCC
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1ccc(/C=C\CN2CCc3nc(N)sc3CC2)cc1
Yield: 29.5 %

Procedure:
Prepared analogously to Example 12 by catalytic hydrogenation of 1.30 g (4.21 mmol) of 2-amino-6-(3-(4-cyano-phenyl)-2-propyn-1-yl)-4,5,7,8-tetrahydro-6H-thiazolo[5,4-d]azepine. 0.3 H2O in anhydrous dimethylformamide under 1 bar of hydrogen pressure using Lindlar catalyst (5% palladium on calcium carbonate, contaminated with lead) at ambient temperature. Yield: 29.5% of theory, Melting point: 186°-188° C. (ether).
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([C:15](=[O:17])[CH3:16])=[CH:11][C:10]=2[NH2:18])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:19][S:20](Cl)(=[O:22])=[O:21]>N1C=CC=CC=1>[C:1]1([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([C:15](=[O:17])[CH3:16])=[CH:11][C:10]=2[NH:18][S:20]([CH3:19])(=[O:22])=[O:21])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CS(=O)(=O)Cl
Reactant: CC(=O)c1ccc(OCc2ccccc2)c(N)c1
Solvent: c1ccncc1
Product: CC(=O)c1ccc(OCc2ccccc2)c(NS(C)(=O)=O)c1
Reaction time: 0.65 h
Yield: 77.6 %

Procedure:
To a mechanically stirred 16° C. pyridine (270 mL) solution of 1-[4-phenylmethoxy-3-aminophenyl]ethanone (57.4 g, 238 mmol) under N2, was added methanesulfonyl chloride (18.6 mL, 240 mmol). After 39 minutes, the completed reaction was quenched with 1.8 L H2O and the resulting suspension stirred for ~2 hours before filtration. The collected solids were washed with H2O (2×250 mL=500 mL) and partially air dried. These solids were dissolved in CHCl3 (450 mL), the water phase removed and heptane (475 mL) added with stirring. The resulting fine suspension was filtered after ~15 minutes, washed with hexane and dried in vacuo at 55° C. to give 59 g (78%) of the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12]1[NH:13][C:14]([CH:19]([CH3:21])[CH3:20])([CH3:18])[C:15](=[O:17])[N:16]=1)=[O:5])[CH3:2].[CH2:22]([N:24]=[C:25]=[O:26])[CH3:23].C1CCN2C(=NCCC2)CC1>C(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12]1[N:13]([C:25](=[O:26])[NH:24][CH2:22][CH3:23])[C:14]([CH:19]([CH3:20])[CH3:21])([CH3:18])[C:15](=[O:17])[N:16]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ccccc1C1=NC(=O)C(C)(C(C)C)N1
Reactant: CCN=C=O
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: CCNC(=O)N1C(c2ccccc2C(=O)OCC)=NC(=O)C1(C)C(C)C
Yield: 98.7 %

Procedure:
9 g (0.031 mole) of 2-(2-ethoxycarbonylphenyl)-5-isopropyl-5-methyl-4-oxo-2-imidazoline are dissolved in 30 ml of absolute methylene chloride, and 2.7 g (0.038 mole) of ethyl isocyanate and 0.5 ml of DBU are added at room temperature. After a reaction time of 1 hour, the mixture is poured onto ice and the organic phase is washed twice with water, dried and evaporated. 11.0 g (98% of theory) of 2-(2-ethoxycarbonylphenyl)-1-N-ethylcarbamoyl-5-isopropyl-5-methyl-4-oxo-2-imidazoline are obtained as colorless tablets of melting point 85°-87° C.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[C:5]([C:7]([F:10])([F:9])[F:8])[N:6]=1.C(OC(=O)[NH:17][C@@H:18]1[CH2:22][CH2:21][N:20](C2C(C(F)(F)F)=CC=CN=2)[CH2:19]1)(C)(C)C.FC(F)(F)C1C(N2CC[C@@H](N)C2)=NC=CC=1>>[F:8][C:7]([F:10])([F:9])[C:5]1[N:6]=[C:2]([N:20]2[CH2:21][CH2:22][C@@H:18]([NH2:17])[CH2:19]2)[S:3][CH:4]=1
Reactant: FC(F)(F)c1csc(Br)n1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCN(c2ncccc2C(F)(F)F)C1
Agent: N[C@@H]1CCN(c2ncccc2C(F)(F)F)C1
Product: N[C@@H]1CCN(c2nc(C(F)(F)F)cs2)C1

Procedure:
Prepared from 2-bromo4-trifluoromethylthiazole (J. A. Edwards Ger. Offen., 2252070, 1973) in a manner similar to that described in D1 and D2.
Reaction SMILES: C([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11](=[O:33])[NH:12][C:13]2[C:14](=[O:32])[O:15][C:16]3[C:21]([CH:22]=2)=[CH:20][CH:19]=[C:18]([O:23][CH:24]2[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]2)[C:17]=3[CH3:31])=[CH:7][C:6]=1[CH2:34][CH:35]=[C:36]([CH3:38])[CH3:37])(=O)C>C(N(CC)CC)C.CO>[OH:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]([NH:12][C:13]2[C:14](=[O:32])[O:15][C:16]3[C:21]([CH:22]=2)=[CH:20][CH:19]=[C:18]([O:23][CH:24]2[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]2)[C:17]=3[CH3:31])=[O:33])=[CH:7][C:6]=1[CH2:34][CH:35]=[C:36]([CH3:38])[CH3:37]
Reactant: CC(=O)Oc1ccc(C(=O)Nc2cc3ccc(OC4CCN(C)CC4)c(C)c3oc2=O)cc1CC=C(C)C
Solvent: CO
Solvent: CCN(CC)CC
Product: CC(C)=CCc1cc(C(=O)Nc2cc3ccc(OC4CCN(C)CC4)c(C)c3oc2=O)ccc1O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
General procedure IV for the preparation of compounds 31a-g: Compound 29a (52 mg, 0.1 mmol) was dissolved in 10% triethylamine/methanol (3 mL). The solution was stirred at room temperature overnight and concentrated. The residue was purified by column chromatography on silica by using methylene chloride and methanol (10:1) to give 31a as a white, amorphous solid (37 mg, 73%). 1H NMR (500 MHz, DMSOd6) δ 9.22 (s, 1H), 8.47 (s, 1H), 7.68˜7.66 (m, 2H), 7.53 (d, J=8.7, 1H), 7.11 (d, J=8.9, 1H), 6.90 (d, J=8.7, 1H), 5.30 (m, 1H), 4.57 (m, 1H), 3.27 (d, J=7.3, 2H), 2.62˜2.54 (m, 2H), 2.34˜2.28 (m, 2H), 2.22 (s, 3H), 2.21 (s, 3H), 1.96˜1.92 (m, 2H), 1.76˜1.72 (m, 2H), 1.71 (s, 3H), 1.69 (s, 3H). 13C NMR (125 MHz, DMSOd6) δ 165.3, 158.8, 158.4, 156.6, 149.5, 131.9, 129.2, 127.8, 127.7, 126.8, 126.0, 124.0, 122.3, 121.3, 114.6, 113.4, 112.7, 110.8, 72.1, 51.8, 45.7, 30.2, 27.9, 25.6, 17.7, 8.2. IR (film) νmax 3421, 1703, 1666, 1601, 1528, 1504, 1366, 1248, 1178, 1150, 1094, 1040 cm−1. HRMS (ESI+) m/z Calc for [M+H+] C28H33N2O5 477.2389. found: 477.2397.
Reaction SMILES: [CH2:1]([NH:4][C:5](=[O:13])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[NH2:12])[CH:2]=[CH2:3].[CH2:14]([NH2:17])[CH:15]=C.[C:18]12[C:24](=CC=CC=1)[NH:23]C(=O)OC2=O>>[CH2:1]([NH:4][C:5](=[O:13])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[NH:12][CH2:15][C:14]1[NH:17][CH2:18][CH2:24][N:23]=1)[CH:2]=[CH2:3]
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Reactant: C=CCN
Reactant: C=CCNC(=O)c1ccccc1N
Product: C=CCNC(=O)c1ccccc1NCC1=NCCN1

Procedure:
N-Allyl-2-amino benzamide (prepared from allylamine and isatoic anhydride, using the methods described in Example 17) and CMI were reacted using conditions described in the general procedure for CMI coupling to give N-allyl-2-[(4,5-dihydro-1H-imidazol-2-ylmethyl)amino]benzamide, isolated as the hydrochloride salt.