Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:5]1[N:17]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:31]([O:33][CH3:34])=[O:32])=[CH:21][CH:20]=2)[C:8]2[CH:9]([C:13]([O:15][CH3:16])=[O:14])[NH:10][CH2:11][CH2:12][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].[C:35](OC(=O)C)(=[O:37])[CH3:36]>N1C=CC=CC=1>[CH2:1]([C:5]1[N:17]([CH2:18][C:19]2[CH:20]=[CH:21][C:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:31]([O:33][CH3:34])=[O:32])=[CH:23][CH:24]=2)[C:8]2[CH:9]([C:13]([O:15][CH3:16])=[O:14])[N:10]([C:35](=[O:37])[CH3:36])[CH2:11][CH2:12][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CC(=O)OC(C)=O
Reactant: CCCCc1nc2c(n1Cc1ccc(-c3ccccc3C(=O)OC)cc1)C(C(=O)OC)NCC2
Solvent: c1ccncc1
Product: CCCCc1nc2c(n1Cc1ccc(-c3ccccc3C(=O)OC)cc1)C(C(=O)OC)N(C(C)=O)CC2
Reaction time: 8 h

Procedure:
To a mixture of the compound obtained in Example 12 (1.70 g) and pyridine (20 ml) is added acetic anhydride (5 ml), and the mixture is stirred overnight. The solvent is distilled off, and to the resulting residue is added chloroform, and the mixture is washed, dried, and evaporated to remove the solvent. The residue is purified by silica gel column chromatography (solvent; chloroform/ethanol=10.1) to give methyl 2-n-butyl-5-acetyl-3-(2'-methoxycarbonylbiphenyl-4-yl)methyl-4,5,6,7-tetrahydroimidazo[4,5 -c]pyridine-4-carboxylate (0.47 g) as an oil.
Reaction SMILES: [F:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][N:7]2[C@@H:11]([CH3:12])[CH2:10][N:9]([C:13]3[S:14][C:15]([C:19]([O:21]CC)=[O:20])=[C:16]([CH3:18])[N:17]=3)[C:8]2=[O:24])=[CH:4][CH:3]=1.FC1C=CC(CN2[C@H](C)CN(C3SC(C(OCC)=O)=C(C)N=3)C2=O)=CC=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C@H:11]([CH3:12])[CH2:10][N:9]([C:13]3[S:14][C:15]([C:19]([OH:21])=[O:20])=[C:16]([CH3:18])[N:17]=3)[C:8]2=[O:24])=[CH:25][CH:26]=1
Reactant: CCOC(=O)c1sc(N2C[C@H](C)N(Cc3ccc(F)cc3)C2=O)nc1C
Agent: CCOC(=O)c1sc(N2C[C@@H](C)N(Cc3ccc(F)cc3)C2=O)nc1C
Product: Cc1nc(N2C[C@@H](C)N(Cc3ccc(F)cc3)C2=O)sc1C(=O)O

Procedure:
Following the procedure as described in Preparation 6, making variations as required to replace (S)-ethyl 2-(3-(4-fluorobenzyl)-4-methyl-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylate with (R)-ethyl 2-(3-(4-fluorobenzyl)-4-methyl-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylate, the title compound was obtained as a colorless solid (87%): 1H NMR (300 MHz, DMSO-d6) δ 12.85 (s, 1H), 7.40-7.35 (m, 2H), 7.21-7.15 (m, 2H), 4.59 (d, J=15.6 Hz, 1H), 4.30 (d, J=15.6 Hz, 1H), 4.19 (t, J=9.6 Hz, 1H), 4.29-4.14 (m, 1H), 3.78-3.71 (m, 1H), 3.56 (dd, J=10.6, 6.3 Hz, 1H), 2.50 (s, 3H), 1.22 (d, J=6.2 Hz, 3H); MS (ES+) m/z 349.9 (M+1).
Reaction SMILES: [Cl:1][CH2:2][C:3]1[C:8]([CH3:9])=[C:7]([O:10][CH3:11])[C:6]([CH3:12])=[CH:5][N:4]=1.O.[NH2:14][NH2:15]>CO>[ClH:1].[CH3:11][O:10][C:7]1[C:6]([CH3:12])=[CH:5][N:4]=[C:3]([CH2:2][NH:14][NH2:15])[C:8]=1[CH3:9]
Reactant: NN
Reactant: COc1c(C)cnc(CCl)c1C
Solvent: CO
Solvent: O
Product: COc1c(C)cnc(CNN)c1C
Product: Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 68 %

Procedure:
2-(Chloromethyl)-4-methoxy-3,5-dimethylpyridine (125.95 g) was added to a mixture of hydrazine monohydrate (360 ml) and methanol (3.3 L) under cooling in an ice bath, and the mixture was stirred for 30 minutes. Then, the ice bath was removed and the mixture was heated with stirring at 60° C. for 2.5 hours. After cooling to room temperature, water (1.5 L) was added to the reaction mixture, and about 3.5 L of the solvent was evaporated under reduced pressure. A 2 N sodium hydroxide solution (1 L) and sodium chloride (300 g) were added to the resulting concentrated residue, followed by extraction with dichloromethane. The organic layer was dried over anhydrous sodium sulfate and filtered. Then, the filtrate was concentrated under reduced pressure. The resulting residue was dissolved in dichloromethane (1.5 L). A 4 N solution of hydrochloric acid in dioxane (550 ml) was added under cooling in an ice bath, and then the mixture was stirred at −2° C. for 13 hours. The precipitated solid was collected by filtration, sequentially washed with dichloromethane, isopropyl ether and dichloromethane, and then dried to obtain the title compound (112.6 g, 68%).
Reaction SMILES: [C:1]([C:3]1([NH:6][C:7]([C@@H:9]2[CH2:13][C@@H:12]([S:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[O:21][C:22]([F:25])([F:24])[F:23])[CH2:11][NH:10]2)=[O:8])[CH2:5][CH2:4]1)#[N:2].[CH2:26]([O:28][C:29]([N:31]1[CH2:36][CH2:35][CH:34]([N:37]2[CH2:40][CH2:39][CH:38]2[C:41]([O-])=[O:42])[CH2:33][CH2:32]1)=[O:30])[CH3:27].[Li+]>>[C:1]([C:3]1([NH:6][C:7]([C@@H:9]2[CH2:13][C@@H:12]([S:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[O:21][C:22]([F:25])([F:23])[F:24])[CH2:11][N:10]2[C:41]([CH:38]2[CH2:39][CH2:40][N:37]2[CH:34]2[CH2:33][CH2:32][N:31]([C:29]([O:28][CH2:26][CH3:27])=[O:30])[CH2:36][CH2:35]2)=[O:42])=[O:8])[CH2:4][CH2:5]1)#[N:2]
Reactant: N#CC1(NC(=O)[C@@H]2C[C@@H](Sc3ccccc3OC(F)(F)F)CN2)CC1
Reactant: CCOC(=O)N1CCC(N2CCC2C(=O)[O-])CC1
Agent: [Li+]
Product: CCOC(=O)N1CCC(N2CCC2C(=O)N2C[C@H](Sc3ccccc3OC(F)(F)F)C[C@H]2C(=O)NC2(C#N)CC2)CC1

Procedure:
The reaction of (2S,4R)-N-(1-cyanocyclopropyl)-4-(2-(trifluoromethoxy)phenylthio)pyrrolidine-2-carboxamide 12D and lithium 1-(1-(ethoxycarbonyl)piperidin-4-yl)azetidine-2-carboxylate 20J carried out according to the general procedure L yielded ethyl 4-(2-((2S,4R)-2-(1-cyanocyclopropylcarbamoyl)-4-(2-(trifluoromethoxy)phenylthio)pyrrolidine-1-carbonyl)azetidin-1-yl)piperidine-1-carboxylate 1:1 epimers as a white solid (70%). MS ISP (m/e): 610.3 (100) [(M+H)]+.
Reaction SMILES: Cl.[O:2]([C:9]1[CH:15]=[C:14]([CH:16]([CH3:18])[CH3:17])[C:12]([NH2:13])=[C:11]([CH:19]([CH3:21])[CH3:20])[CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[S-:22][C:23]#[N:24].[Na+].O.Cl>CC1C=CC=CC=1C>[O:2]([C:9]1[CH:10]=[C:11]([CH:19]([CH3:21])[CH3:20])[C:12]([NH:13][C:23]([NH2:24])=[S:22])=[C:14]([CH:16]([CH3:17])[CH3:18])[CH:15]=1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: N#C[S-]
Reactant: CC(C)c1cc(Oc2ccccc2)cc(C(C)C)c1N
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1C
Product: CC(C)c1cc(Oc2ccccc2)cc(C(C)C)c1NC(N)=S
Temperature: 25 °C
Yield: 95.9 %

Procedure:
305 g (1 mol) of 4-phenoxy-2,6-diisopropylaniline hydrochloride, 97 g (1.2 mol) of sodium thiocyanate, 10 ml of water and 10 ml of concentrated hydrochloric acid are suspended in 800 ml of o-xylene. The mixture is heated to 90° C. over 6 hours, during which time 2 ml of concentrated hydrochloric acid are added after 3 hours and then after each further hour. Thereafter the reaction mixture is cooled to room temperature and the product is isolated by filtration, washed with water and dried, giving 315 g (96% of theory) of N-(4-phenoxy-2,6-diisopropylphenyl)thiourea in the form of pale grey crystals which melt at 219°-221° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([NH:8][NH2:9])[N:3]=1.C(N(CC)CC)C.C(O[CH:20]=[C:21]([C:27](=O)[C:28]([F:31])([F:30])[F:29])[C:22]([O:24][CH2:25][CH3:26])=[O:23])C>C(#N)C>[CH2:25]([O:24][C:22]([C:21]1[CH:20]=[N:9][N:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[N:3]=2)[C:27]=1[C:28]([F:29])([F:30])[F:31])=[O:23])[CH3:26]
Reactant: CCOC=C(C(=O)OCC)C(=O)C(F)(F)F
Reactant: NNc1cccc(Cl)n1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCOC(=O)c1cnn(-c2cccc(Cl)n2)c1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution 2-chloro-6-hydrazinopyridine (1.00 g, 6.97 mmol) and triethylamine (0.971 mL, 6.97 mmol) in acetonitrile (35 mL) was added ethyl 2-(ethoxymethylene)-4,4,4-trifluoro-3-oxobutyrate (1.36 mL, 6.97 mmol). After 20 min, the reaction mixture was placed in a 60° C. oil bath. After 30 min, the reaction mixture was allowed to cool to ambient temperature, then was concentrated in vacuo. Purification by flash chromatography on silica gel (0 to 30% EtOAc in hexanes, then 30 to 100% EtOAc in hexanes) gave the title compound: LCMS m/z 319.9 [M+H]+; 1H NMR (500 MHz, CDCl3) δ 8.10 (s, 1 H),7.88 (t, J=7.5 Hz, 1 H),7.58 (d, J=8.0 Hz, 1 H),7.47 (d, J=8.0 Hz, 1 H),4.38 (q, J=7.0 Hz, 2 H),1.38 (t, J=7.0 Hz, 3 H).
Reaction SMILES: [C:1]([Si:5]([CH3:25])([CH3:24])[O:6][CH:7]([C:9]([CH3:23])([CH:21]=[CH2:22])[C:10](N1[C@@H](C(C)C)COC1=O)=[O:11])[CH3:8])([CH3:4])([CH3:3])[CH3:2].[OH:26]O.O.[OH-].[Li+]>O1CCCC1.O>[C:1]([Si:5]([CH3:25])([CH3:24])[O:6][CH:7]([C:9]([CH3:23])([CH:21]=[CH2:22])[C:10]([OH:11])=[O:26])[CH3:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: OO
Reactant: C=CC(C)(C(=O)N1C(=O)OC[C@@H]1C(C)C)C(C)O[Si](C)(C)C(C)(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: C=CC(C)(C(=O)O)C(C)O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 48 h
Yield: 38.4 %

Procedure:
A cooled (0° C.) solution of recovered (S)-3-{2-[1-(tert-butyl-dimethyl-silanyloxy)-ethyl]-2-methyl-but-3-enoyl}-4-isopropyl-oxazolidin-2-one (431.5 mg, 1.167 mmol) in tetrahydrofuran/water (15 mL, 2:1) was subsequently treated with hydrogen peroxide (30% aqueous, 600 μL, 5.835 mmol) and lithium hydroxide monohydrate (98 mg, 2.335 mmol). After stirring for 2 days at room temperature, hydrogen peroxide (30% aqueous, 600 μL, 5.835 mmol) and lithium hydroxide monohydrate (175 mg, 4.171 mmol) were added at 0° C. After stirring at room temperature for 17 days, the reaction was quenched with solid sodium metabisulfite (4.4 g). After stirring for 1 h at room temperature, the pH was adjusted with hydrochloric acid (1 M) to pH 2 at 0° C. The aqueous layer was extracted with ethyl acetate (2×). The organics were combined, dried over anhydrous sodium sulfate, filtered and the volatiles were removed in vacuo. The residue was purified by silica gel chromatography using a 50 g Isolute cartridge eluted with a continuous gradient of iso-hexanes/diethyl ether 1:0 to 7:3 to afford the title compound (115.8 mg, 38%) as a white solid and as a single diastereoisomer. 1H NMR (300 MHz, CDCl3) δ 0.14 (s, 3H), 0.16 (s, 3H), 0.92 (s, 9H), 1.20-1.26 (m, 6H), 3.97 (q, J=6.5 Hz, 1H), 5.16-5.26 (m, 2H), 5.88 (dd, J=17.4, 10.7 Hz, 1H), 10.33 (br s, 1H).
Reaction SMILES: [N+:1]([C:4]1[CH:16]=[CH:15][C:7]2[O:8][C:9]([CH3:14])([CH3:13])[O:10][C:11](=[O:12])[C:6]=2[CH:5]=1)([O-])=O>CCO.[Pd]>[NH2:1][C:4]1[CH:16]=[CH:15][C:7]2[O:8][C:9]([CH3:13])([CH3:14])[O:10][C:11](=[O:12])[C:6]=2[CH:5]=1
Reactant: CC1(C)OC(=O)c2cc([N+](=O)[O-])ccc2O1
Agent: [Pd]
Solvent: CCO
Product: CC1(C)OC(=O)c2cc(N)ccc2O1
Reaction time: 12 h
Yield: 98.6 %

Procedure:
To a solution of 6-nitro-2,2-dimethyl-4H-1,3-benzodioxin-4-one (4.1 g) in EtOH (30 mL) was added Pd/C (1.947 g) under nitrogen atmosphere. Hydrogenation was performed for 12 hrs at rt using 10 bars of H2. The reaction mixture was filtered through X bed of celite, washed with EtOH and THF. The filtrates were concentrated under vacuum to give the title compound as a pale yellow solid (3.5 g, 98%). 1H NMR (CDCl3) δ 7.71 (d, J=8.7 Hz, 1H), 7.15 (d, J=2.6 Hz, 1H), 6.83 (dd, J=8.7 Hz, 2.6 Hz, 1H), 3.44 (brs, 2H), 2.63 (s, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:37]=[CH:38][C:39]=1[F:40])[CH2:5][N:6]1[CH2:15][CH2:14][C:13]2[C:8](=[C:9]([O:34][CH3:35])[C:10](=[O:33])[N:11]3[CH2:21][CH2:20][CH2:19][CH2:18][N:17]([CH2:22][CH2:23][O:24]CC4C=CC=CC=4)[C:16](=[O:32])[C:12]3=2)[C:7]1=[O:36].[H][H]>C(OCC)(=O)C.[Rh]>[Cl:1][C:2]1[CH:3]=[C:4]([CH:37]=[CH:38][C:39]=1[F:40])[CH2:5][N:6]1[CH2:15][CH2:14][C:13]2[C:8](=[C:9]([O:34][CH3:35])[C:10](=[O:33])[N:11]3[CH2:21][CH2:20][CH2:19][CH2:18][N:17]([CH2:22][CH2:23][OH:24])[C:16](=[O:32])[C:12]3=2)[C:7]1=[O:36]
Reactant: [H][H]
Reactant: COc1c2c(c3n(c1=O)CCCCN(CCOCc1ccccc1)C3=O)CCN(Cc1ccc(F)c(Cl)c1)C2=O
Agent: [Rh]
Solvent: CCOC(C)=O
Product: COc1c2c(c3n(c1=O)CCCCN(CCO)C3=O)CCN(Cc1ccc(F)c(Cl)c1)C2=O

Procedure:
A mixture of 11-(3-chloro-4-fluorobenzyl)-9-methoxy-2-[2-(benzyloxy)ethyl]-3,4,5,6,12,13-hexahydro-2H[1,4]diazocino[2,1-a]-2,6-naphthyridine-1,8,10(1H)-trione (0.55 g, 0.97 mmol) and 5% rhodium on carbon (1.10 g) in ethyl acetate (22 mL) was stirred under a balloon of hydrogen at room temperature overnight. The product mixture was filtered through a pad of Celite. The filtrate was concentrated under vacuum to afford the title compound. This material was used in the following reaction without further purification.
Reaction SMILES: [Cl-].[Cl-].[Cl-].[Al+3].C[N+]([O-])=O.[F:9][C:10]1[C:27]([NH:28][S:29]([CH2:32][CH2:33][CH3:34])(=[O:31])=[O:30])=[CH:26][CH:25]=[C:24]([F:35])[C:11]=1[C:12]([NH:14][C:15]1[CH:16]=[C:17]2[CH:23]=[CH:22][NH:21][C:18]2=[N:19][CH:20]=1)=[O:13].[Cl:36][CH2:37][C:38](Cl)=[O:39]>C(Cl)Cl.[Cl-].[NH4+]>[Cl:36][CH2:37][C:38]([C:23]1[C:17]2[C:18](=[N:19][CH:20]=[C:15]([NH:14][C:12](=[O:13])[C:11]3[C:24]([F:35])=[CH:25][CH:26]=[C:27]([NH:28][S:29]([CH2:32][CH2:33][CH3:34])(=[O:31])=[O:30])[C:10]=3[F:9])[CH:16]=2)[NH:21][CH:22]=1)=[O:39]
Reactant: O=C(Cl)CCl
Reactant: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)Nc2cnc3[nH]ccc3c2)c1F
Agent: [Al+3]
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: C[N+](=O)[O-]
Product: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)Nc2cnc3[nH]cc(C(=O)CCl)c3c2)c1F
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 49.3 %

Procedure:
A solution of aluminum trichloride (0.266 g, 2.00 mmol) in 1:1 DCM:CH3NO2 (5 mL) was added slowly to a slurry of 2,6-difluoro-3-(propylsulfonamido)-N-(1H-pyrrolo[2,3-b]pyridin-5-yl)benzamide (0.100 g, 0.254 mmol) in 1:1 DCM:CH3NO2 (2 mL) at 0° C. The solution was stirred at 0° C. for 40 minutes. A solution of 2-chloroacetyl chloride (0.0307 mL, 0.380 mmol) in DCM (1 mL) was added, and the reaction mixture was allowed to warm to room temperature overnight. Additional 2-chloroacetyl chloride (5 eq.) was added, and the reaction mixture was warmed to 50° C. for 20 hours. The solution was cooled and diluted with saturated aqueous ammonium chloride and extracted with EtOAc (3 X). The organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. They were then purified via column chromatography (5% MeOH/DCM) to afford N-(3-(2-chloroacetyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-2,6-difluoro-3-(propylsulfonamido)benzamide (59 mg, 50%) as a solid.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)[N:3]=1.CN(C)[C:20](=[O:22])[CH3:21]>O>[N:15]1[CH:16]=[CH:17][C:12]([C:4]2[N:3]=[C:2]([NH:3][C@H:2]3[C:11]4[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=4)[CH2:21][C@H:20]3[OH:22])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=2)=[CH:13][CH:14]=1
Reactant: CC(=O)N(C)C
Reactant: Clc1nc(-c2ccncc2)nc2ccccc12
Solvent: O
Product: O[C@@H]1Cc2ccccc2[C@@H]1Nc1nc(-c2ccncc2)nc2ccccc12
Temperature: 85 °C
Reaction time: 2 h

Procedure:
4-Chloro-2-pyridin-4-ylquinazoline (1 mmol) was dissolved into N,N-dimethylacetamide (0.5 M), followed by addition of diispropylethylamine (2 mmol) and 1S, 2R-(−)-cis-1-amino-2-indanol (1.2 mmol) and was stirred at 85° C. for 2 h. The reaction was poured into water and back-extracted with ethyl acetate (3×). The combined organic layers were washed with 1N HCl, followed by a brine wash, and dried over magnesium sulfate. The final product was purified by MPLC and lyophilized to a yellow powder. (78%) 1H NMR (400 MHz, d6-DMSO): δ 8.75 (d, 2H), 8.55 (d, 1H), 8.35 (m, 2H), 7.85 (d, 2H), 7.55 (m, 1H), 7.35 (d, 2H), 7.25 (m, 2H), 6.15 (m, 1H), 4.85 (m, 1H), 3.25 (dd, 1H), 3.00 (d, 1H). MS (EI) for C22H18N4O: 355 (MH+).
Reaction SMILES: [N:1]1([CH2:7][CH2:8][CH2:9][CH2:10][NH2:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:12]([C:14]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([CH2:23][CH2:24][NH:25][C:26](=[O:40])[C:27]3[CH:32]=[CH:31][C:30]([C:33]4[CH:38]=[CH:37][N:36]=[C:35](Cl)[N:34]=4)=[CH:29][CH:28]=3)[CH:21]=2)[NH:16][CH:15]=1)#[N:13]>>[C:12]([C:14]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([CH2:23][CH2:24][NH:25][C:26](=[O:40])[C:27]3[CH:32]=[CH:31][C:30]([C:33]4[CH:38]=[CH:37][N:36]=[C:35]([NH:11][CH2:10][CH2:9][CH2:8][CH2:7][N:1]5[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]5)[N:34]=4)=[CH:29][CH:28]=3)[CH:21]=2)[NH:16][CH:15]=1)#[N:13]
Reactant: NCCCCN1CCCCC1
Reactant: N#Cc1c[nH]c2ccc(CCNC(=O)c3ccc(-c4ccnc(Cl)n4)cc3)cc12
Product: N#Cc1c[nH]c2ccc(CCNC(=O)c3ccc(-c4ccnc(NCCCCN5CCCCC5)n4)cc3)cc12

Procedure:
Using 4-piperidin-1-ylbutylamine (reference example 93 g) and N-[2-(3-Cyano-1H-indol-5-yl)-ethyl]-4-[2-chloro-pyrimidin-4-yl]-benzamide (reference example 1az) as substrates. MS (ion spray) m/z 522 (M+H)+.
Reaction SMILES: [NH2:1][C:2]([CH3:6])([CH3:5])[CH2:3][OH:4].C(OCC)C.[C:12]([NH:16][C:17]1[O:18][C:19]([C:26](Cl)=[O:27])=[C:20]([C:22]([F:25])([F:24])[F:23])[N:21]=1)([CH3:15])([CH3:14])[CH3:13]>CCCCCC>[CH3:15][C:12]([NH:16][C:17]1[O:18][C:19]([C:26]([NH:1][C:2]([CH3:6])([CH3:5])[CH2:3][OH:4])=[O:27])=[C:20]([C:22]([F:24])([F:25])[F:23])[N:21]=1)([CH3:13])[CH3:14]
Reactant: CC(C)(C)Nc1nc(C(F)(F)F)c(C(=O)Cl)o1
Reactant: CC(C)(N)CO
Solvent: CCOCC
Solvent: CCCCCC
Product: CC(C)(C)Nc1nc(C(F)(F)F)c(C(=O)NC(C)(C)CO)o1

Procedure:
A reaction vessel fitted with a calcium sulfate drying tube was charged with 4.9 g (55 mmol) of 2-amino-2-methyl-1-propanol and 50 ml of anhydrous ethyl ether. With this mixture stirred at 0°-5° C., there was added dropwise over a period of 45 minutes a solution of 50 ml anhydrous ethyl ether containing 6.5 g (25 mmol) of 2-(tert-butylamino)-4-trifluoromethyl-5-oxazolecarbonyl chloride. The reaction mixture was stirred at ambient temperature for 11/2 hours, then filtered to remove the HCl salt of 2-amino-2-methyl1-propanol. The ether filtrate was washed successively with one molar oxalic acid and saturated brine, then dried under magnesium sulfate, and concentrated under reduced pressure to yield 8.2 g of a colorless, viscous oil. This oil was mixed with hexane and heated to reflux to yield a white solid material. The material was cooled and filtered to yield 7.7 g of a white crystalline product (m.p.=140°-144° C.) identified in Table I.
Reaction SMILES: [CH3:1][C@@H:2]1[C@H:33]([OH:34])[C@@H:32]([CH3:35])[C@@H:31]([OH:36])[C@@H:30]([CH3:37])[C@H:29]([O:38][C:39]([CH3:41])=[O:40])[C@H:28]([CH3:42])[C@@H:27]([O:43][CH3:44])[CH:26]=[CH:25][O:24][C@:21]2([CH3:45])[C:22](=[O:23])[C:14]3=[C:15]([O:20]2)[C:16]([CH3:19])=[C:17]([OH:18])[C:12]2=[C:13]3[C:46]([OH:50])=[C:47]([CH:48]=O)[C:10](=[C:11]2[OH:51])[NH:9][C:7](=[O:8])[C:6]([CH3:52])=[CH:5][CH:4]=[CH:3]1.[NH2:53][N:54]1[CH2:59][CH2:58][N:57]([CH:60]2[CH2:64][CH2:63][CH2:62][CH2:61]2)[CH2:56][CH2:55]1>O1CCCC1>[CH3:1][C@@H:2]1[C@H:33]([OH:34])[C@@H:32]([CH3:35])[C@@H:31]([OH:36])[C@@H:30]([CH3:37])[C@H:29]([O:38][C:39]([CH3:41])=[O:40])[C@H:28]([CH3:42])[C@@H:27]([O:43][CH3:44])[CH:26]=[CH:25][O:24][C@@:21]2([CH3:45])[O:20][C:15]3[C:14]([C:22]2=[O:23])=[C:13]2[C:46](/[C:47](=[CH:48]/[NH:53][N:54]4[CH2:55][CH2:56][N:57]([CH:60]5[CH2:64][CH2:63][CH2:62][CH2:61]5)[CH2:58][CH2:59]4)/[C:10](=[C:11]([OH:51])[C:12]2=[C:17]([OH:18])[C:16]=3[CH3:19])[NH:9][C:7](=[O:8])[C:6]([CH3:52])=[CH:5][CH:4]=[CH:3]1)=[O:50]
Reactant: CO[C@H]1C=CO[C@@]2(C)Oc3c(C)c(O)c4c(O)c(c(C=O)c(O)c4c3C2=O)NC(=O)C(C)=CC=C[C@H](C)[C@H](O)[C@@H](C)[C@@H](O)[C@@H](C)[C@H](OC(C)=O)[C@@H]1C
Reactant: NN1CCN(C2CCCC2)CC1
Agent: CO[C@H]1/C=C/O[C@@]2(C)Oc3c(C)c(O)c4c(O)c(c(C=O)c(O)c4c3C2=O)NC(=O)/C(C)=C\C=C\[C@H](C)[C@H](O)[C@@H](C)[C@@H](O)[C@@H](C)[C@H](OC(C)=O)[C@@H]1C
Agent: CO[C@H]1/C=C/O[C@@]2(C)Oc3c(C)c(O)c4c(c3C2=O)C(=O)/C(=C/NN2CCN(C3CCCC3)CC2)C(=C4O)NC(=O)/C(C)=C\C=C\[C@H](C)[C@H](O)[C@@H](C)[C@@H](O)[C@@H](C)[C@H](OC(C)=O)[C@@H]1C
Solvent: C1CCOC1
Product: CO[C@H]1C=CO[C@@]2(C)Oc3c(C)c(O)c4c(c3C2=O)C(=O)/C(=C/NN2CCN(C3CCCC3)CC2)C(=C4O)NC(=O)C(C)=CC=C[C@H](C)[C@H](O)[C@@H](C)[C@@H](O)[C@@H](C)[C@H](OC(C)=O)[C@@H]1C
Reaction time: 0.5 h

Procedure:
0.01 Mole of 3-formylrifamycin SV is dissolved in tetrahydrofuran and to the obtained solution 0.011 mole of 1-amino-4-cyclopentylpiperazine is added to the reaction mixture at room temperature. After 30 minutes, the reaction is completed since thin layer chromatography of the mixture shows disappearance of the starting 3-formylrifamycin SV. The solvent is then evaporated off and the residue is crystallized from ethyl acetate. The title product, which melts at 179°-80° C, is obtained in a 55% yield.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=O)[C:5]2=[O:12].F[C:14]1C=[C:18]2C(O[C:22](=[O:24])[NH:23][C:17]2=[CH:16][CH:15]=1)=O.FC1C=C2[NH:35]C(=O)OC(=O)C2=CC=1>>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]=[C:6]1[C:5](=[O:12])[C:18]3[C:17]([N:23]1[C:22]2=[O:24])=[CH:16][CH:15]=[CH:14][N:35]=3
Reactant: O=C1Nc2ccc(F)cc2C1=O
Reactant: O=c1[nH]c2cc(F)ccc2c(=O)o1
Reactant: O=c1[nH]c2ccc(F)cc2c(=O)o1
Product: O=C1c2ncccc2-n2c1nc1ccc(F)cc1c2=O

Procedure:
Using the procedure in Example 36 and substituting 4-azaisatin (Example 11) for 5-fluoroisatin and 5-fluoroisatoic anhydride for 4-fluoroisatoic anhydride gives the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:26]=[CH:25][C:6]([C:7]([NH:9][C:10]2[C:11]([NH2:24])=[CH:12][C:13]([O:16][Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18])=[CH:14][CH:15]=2)=[O:8])=[CH:5][CH:4]=1.[CH2:27]([C:29]1[CH:37]=[CH:36][C:32]([C:33](Cl)=[O:34])=[CH:31][CH:30]=1)[CH3:28]>>[CH3:1][O:2][C:3]1[CH:26]=[CH:25][C:6]([C:7]([NH:9][C:10]2[C:11]([NH:24][C:33](=[O:34])[C:32]3[CH:36]=[CH:37][C:29]([CH2:27][CH3:28])=[CH:30][CH:31]=3)=[CH:12][C:13]([O:16][Si:17]([C:20]([CH3:23])([CH3:21])[CH3:22])([CH3:19])[CH3:18])=[CH:14][CH:15]=2)=[O:8])=[CH:5][CH:4]=1
Reactant: COc1ccc(C(=O)Nc2ccc(O[Si](C)(C)C(C)(C)C)cc2N)cc1
Reactant: CCc1ccc(C(=O)Cl)cc1
Product: CCc1ccc(C(=O)Nc2cc(O[Si](C)(C)C(C)(C)C)ccc2NC(=O)c2ccc(OC)cc2)cc1
Yield: 88.1 %

Procedure:
Using the procedure described in Example 68, Part A, N1-(4-methoxybenzoyl)-4-(tert-butyldimethylsilyloxy)-1,2-benzenediamine (300 mg, 0.81 mmol) was reacted with 4-ethylbenzoyl chloride (0.13 mL, 0.89 mmol) to yield 360 mg (88%) of the title compound as a white solid.
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([C:8]([OH:10])=[O:9])[CH2:4][CH2:3]1.[H-].[Na+].Cl[C:14]1[CH:23]=[N:22][C:21]2[C:16](=[CH:17][C:18]([O:26][CH3:27])=[C:19]([O:24][CH3:25])[CH:20]=2)[N:15]=1>C1COCC1.CN(C=O)C>[CH3:25][O:24][C:19]1[CH:20]=[C:21]2[C:16](=[CH:17][C:18]=1[O:26][CH3:27])[N:15]=[C:14]([O:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([C:8]([OH:10])=[O:9])[CH2:4][CH2:3]1)[CH:23]=[N:22]2
Reactant: O=C(O)[C@H]1CC[C@H](O)CC1
Reactant: COc1cc2ncc(Cl)nc2cc1OC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COc1cc2ncc(O[C@H]3CC[C@H](C(=O)O)CC3)nc2cc1OC

Procedure:
A mixture of cis/trans-4-hydroxy-cyclohexanecarboxylic acid (144 mg, 1 mmol) and NaH (60%, 160 mg, 4 mmol) in anhydrous THF/DMF (10 mL/2 mL) is refluxed for one hour before addition of 2-chloro-6,7-dimethoxyquinoxaline (225 mg, 1 mmol). The resulting mixture is continued to refluxed for four hours. The reaction mixture is neutralized to pH 5 and extracted with ethyl acetate (2×50 mL). The combined organic solutions are dried over magnesium sulfate and filtered. The residue after concentration is chromatographed on silica gel (ethyl acetate, followed by methanol) to provide the desired product as a white solid (m.p. 90-93° C.). Anal. Calcd. for C17H20N2O5.0.5 H2O: C, 59.89; H, 6.19; N, 8.22; Found: C, 59.91; H, 6.62; N, 7.90.