Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]12[CH2:8][CH2:7][CH:4]([CH:5]=[CH:6]1)[CH2:3][C:2]2=[O:9]>C1CCCCC1>[CH:5]12[C:2](=[O:9])[CH2:3][CH:4]1[CH2:7][CH:8]=[CH:1][CH2:6]2
Reactant: O=C1CC2C=CC1CC2
Solvent: C1CCCCC1
Product: O=C1CC2CC=CCC12
Reaction time: 50 h

Procedure:
A 4% solution of (+)-bicyclo[2.2.2]oct-5-en-2-one was dissolved in cyclohexane and irradiated in a Pyrex apparatus under argon with a 250 w. medium pressure mercury lamp. After 50 hours, the starting product had been reacted quantitatively. The solution was concentrated by evaporation and the residue subjected to chromatography on 100 g. of silica gel with toluene/1% diethyl ether. Pure (-)-bicyclo[4.2.0]oct-3-en-8-one was obtained.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([NH2:7])=[N:4][CH:3]=1.CC(C)C(O)=O.[CH3:14][N:15]([CH3:18])[CH:16]=O>>[CH3:14][N:15]([CH3:18])[CH:16]=[N:7][C:5]1[S:6][C:2]([CH3:1])=[CH:3][N:4]=1
Reactant: Cc1cnc(N)s1
Reactant: CN(C)C=O
Solvent: CC(C)C(=O)O
Product: Cc1cnc(N=CN(C)C)s1

Procedure:
prepared by reaction of 5-methyl-thiazol-2-ylamine with N,N-dimethylformamide dimethyl acetate. LC-MS: tR=0.52 min; [M+H]+=170.2.
Reaction SMILES: BrC[CH:3]1[CH2:8][CH2:7][CH2:6][N:5]([CH3:9])[CH2:4]1.[CH3:10][C:11]([O:14][C:15]([NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[O:16])([CH3:13])[CH3:12].C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C.[I-].[Li+]>[C:21]([O:20][C:18]([N:17]([C:15]([O:14][C:11]([CH3:13])([CH3:12])[CH3:10])=[O:16])[CH:3]1[CH2:8][CH2:7][CH2:6][N:5]([CH3:9])[CH2:4]1)=[O:19])([CH3:24])([CH3:23])[CH3:22]
Reactant: CN1CCCC(CBr)C1
Reactant: CC(C)(C)OC(=O)NC(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Solvent: CC#N
Product: CN1CCCC(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C1
Temperature: 70 °C
Reaction time: 20 h
Yield: 54.2 %

Procedure:
3-(Bromomethyl)-1-methylpiperidine (1.5 g, 7.81 mmoles) (from Preparative Example 244, Step A above) and di-tert-butyliminodicarboxylate (1.697 g, 7.81 mmoles) were dissolved in anhydrous acetonitrile (25 mL). Cesium carbonate (5.1 g, 15.6 mmoles) and lithium iodide (52 mg, 0.391 mmoles) were added and the mixture was stirred at 70° C. for 20 h. The mixture was evaporated to dryness and the residue was partitioned between dichloromethane and saturated aqueous sodium bicarbonate. The organic layer was dried (MgSO4), filtered and evaporated to dryness. the residue was chromatographed on a silica gel column (30×5 cm) using 3% methanol in dichloromethane as the eluant to give 3-(di-tert-butoxycarbonylamino)-1-methylpiperidine (1.331 g, 52%): FABMS: m/z 329.2 (MH+); HRFABMS: m/z 329.2438 (MH+). Calcd. for C17H33N2O4: m/z 329.2440; δH (CDCl3) 1.10 (1H, m, CH2), 1.54 (18H, s, —COOC(CH3)3), 1.86 (2H, m, CH2), 2.01 (1H, m, CH2), 2.19 (1H m, CH), 2.34 (2H, bm, CH2), 2.59 (3H, —NCH3), 3.19 (2H, m, CH2) and 3.52/3.52 ppm (2H, —CH2N—); δC (CDCl3) CH3: 28.5, 28.5, 28.5, 28.5, 28.5, 28.5, 47.2; CH2: 25.4, 28.3, 50.4, 56.8, 60.8; CH: 37.2; C: 83.0, 83.0, 153.5, 153.5.
Reaction SMILES: C([NH:5][C:6]1[N:11]=[C:10]([N:12]2[C:21]3[C:16](=[CH:17][C:18]([F:24])=[C:19]([F:23])[C:20]=3[Cl:22])[C:15](=[O:25])[CH:14]([C:26]([O:28]CC)=[O:27])[C:13]2=[O:31])[C:9]([C:32]#[N:33])=[CH:8][C:7]=1[F:34])(C)(C)C.Cl>>[NH2:5][C:6]1[N:11]=[C:10]([N:12]2[C:21]3[C:16](=[CH:17][C:18]([F:24])=[C:19]([F:23])[C:20]=3[Cl:22])[C:15](=[O:25])[CH:14]([C:26]([OH:28])=[O:27])[C:13]2=[O:31])[C:9]([C:32]#[N:33])=[CH:8][C:7]=1[F:34]
Reactant: CCOC(=O)C1C(=O)c2cc(F)c(F)c(Cl)c2N(c2nc(NC(C)(C)C)c(F)cc2C#N)C1=O
Agent: Cl
Product: N#Cc1cc(F)c(N)nc1N1C(=O)C(C(=O)O)C(=O)c2cc(F)c(F)c(Cl)c21
Yield: 51.6 %

Procedure:
To 280 mg of ethyl 1-(6-t-butylamino-3-cyano-5-fluoropyridin-2-yl)-8-chloro-6,7-difluoro-1,4-dihydro-4-oxoquinolone-3-carboxylate was added 3 ml of 12N hydrochloric acid, and the mixture was heated under reflux for 6 hours and allowed to cool. The solid precipitate was collected by filtration and washed with ethanol and diethylether successively to obtain 120 mg of the title compound as a pale yellow powder.
Reaction SMILES: C(O[C:4](=[NH:11])[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])C.N[C:13]1[CH:14]=[C:15]([CH:28]=[CH:29][C:30]=1[NH2:31])[CH2:16][N:17]1[C:25](=[O:26])[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:18]1=[O:27]>>[O:27]=[C:18]1[C:19]2[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:25](=[O:26])[N:17]1[CH2:16][C:15]1[CH:28]=[CH:29][C:30]2[NH:31][C:4]([CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])=[N:11][C:13]=2[CH:14]=1
Reactant: Nc1ccc(CN2C(=O)c3ccccc3C2=O)cc1N
Reactant: CCOC(=N)CC(=O)OCC
Product: CCOC(=O)Cc1nc2cc(CN3C(=O)c4ccccc4C3=O)ccc2[nH]1
Yield: 71 %

Procedure:
Ethyl 3-ethoxy-3-iminopropionate, prepared as in Example 2(a), was reacted with 2-(3,4-diaminobenzyl)isoindole-1,3-dione under conditions similar to that set forth in Example 2(b) to provide ethyl 5-(1,3-dioxo-1,3-dihydroisoindol-2-ylmethyl)-1H-benzoimidazol-2-ylacetate (71% yield); 1H-NMR (300 Mhz, DMSO-d6): 7.78-7.9 (m, 4H), 7.43-7.47 (m, 2H), 7.12 (d, 1H, J=9.43 Hz), 4.82 (s, 2H), 4.07 (q, 2H, J=7.2 Hz), 3.44 (s, 2H), 1.38 (t, 3H, J=7.2 Hz).
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:7]2[CH:12]=[CH:11][C:10]([CH2:13]O)=[CH:9][CH:8]=2)[CH:4]=[CH:5][N:6]=1.S(Cl)([Cl:17])=O>>[Cl:17][CH2:13][C:10]1[CH:11]=[CH:12][C:7]([N:3]2[CH:4]=[CH:5][N:6]=[C:2]2[CH3:1])=[CH:8][CH:9]=1
Reactant: O=S(Cl)Cl
Reactant: Cc1nccn1-c1ccc(CO)cc1
Product: Cc1nccn1-c1ccc(CCl)cc1

Procedure:
To 4-(2-methyl-1H-imidazole-1-yl)benzenemethanol add thionyl chloride. Monitor the progress of the reaction by thin-layer chromatography. Upon completion remove the excess thionyl chloride in vacuo. Partition the residue between 1N NaOH and CH2Cl2. Separate and dry the organic layer. Remove the solvent in vacuo to obtain the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[F:11][C:12]1([F:28])[CH2:17][CH2:16][CH:15]([CH:18]([C:21]2[CH:22]=[N:23][C:24]([CH3:27])=[N:25][CH:26]=2)[CH2:19][NH2:20])[CH2:14][CH2:13]1>>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:20][CH2:19][CH:18]([CH:15]1[CH2:16][CH2:17][C:12]([F:28])([F:11])[CH2:13][CH2:14]1)[C:21]1[CH:22]=[N:23][C:24]([CH3:27])=[N:25][CH:26]=1)=[O:6]
Reactant: Cc1ncc(C(CN)C2CCC(F)(F)CC2)cn1
Reactant: O=C(O)c1ccccc1Cl
Product: Cc1ncc(C(CNC(=O)c2ccccc2Cl)C2CCC(F)(F)CC2)cn1

Procedure:
From 2-chlorobenzoic acid and 2-(4,4-difluorocyclohexyl)-2-(2-methylpyrimidin-5-yl)ethanamine. LCMS (MH+): m/z=394.1, tR (minutes, Method F)=2.1
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([N:10]2[CH2:15][CH2:14][CH:13]([C:16]3[N:17]([CH2:29][CH2:30][NH:31][CH2:32][CH:33]4[CH2:35][CH2:34]4)[CH:18]=[C:19]([C:21]4[CH:26]=[CH:25][C:24]([F:27])=[C:23]([CH3:28])[CH:22]=4)[N:20]=3)[CH2:12][CH2:11]2)[N:5]=[CH:4][N:3]=1.[CH:36]1(N)CCCC1>>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([N:10]2[CH2:11][CH2:12][CH:13]([C:16]3[N:17]([CH2:29][CH2:30][NH:31][CH:32]4[CH2:33][CH2:35][CH2:34][CH2:36]4)[CH:18]=[C:19]([C:21]4[CH:26]=[CH:25][C:24]([F:27])=[C:23]([CH3:28])[CH:22]=4)[N:20]=3)[CH2:14][CH2:15]2)[N:5]=[CH:4][N:3]=1
Reactant: NC1CCCC1
Reactant: Cc1cc(-c2cn(CCNCC3CC3)c(C3CCN(c4ncnc(N)c4C#N)CC3)n2)ccc1F
Product: Cc1cc(-c2cn(CCNC3CCCC3)c(C3CCN(c4ncnc(N)c4C#N)CC3)n2)ccc1F

Procedure:
The title compound was prepared in an analogous manner as 4-Amino-6-{4-[1-[2-(cyclopropylmethyl-amino)-ethyl]-4-(4-fluoro-3-methyl-phenyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carbonitrile using cyclopentylamine instead of cyclopropylmethylamine. LC-MS: (M+1=489, obsd.=489).
Reaction SMILES: [CH2:1]([C:3]1([C:41]([OH:43])=[O:42])[CH2:8][CH2:7][N:6]([C:9]([C@:11]23[CH2:37][CH2:36][C@@H:35]([C:38]([CH3:40])=[CH2:39])[C@@H:12]2[C@@H:13]2[C@@:26]([CH3:29])([CH2:27][CH2:28]3)[C@@:25]3([CH3:30])[C@@H:16]([C@:17]4([CH3:34])[C@@H:22]([CH2:23][CH2:24]3)[C:21]([CH3:32])([CH3:31])[C@@H:20]([OH:33])[CH2:19][CH2:18]4)[CH2:15][CH2:14]2)=[O:10])[CH2:5][CH2:4]1)[CH3:2].N1C=CC=CC=1.[CH3:50][C:51]1([CH3:58])[CH2:55][C:54](=[O:56])[O:53][C:52]1=[O:57]>C(OCC)(=O)C>[C:52]([C:51]([CH3:58])([CH3:50])[CH2:55][C:54]([O:33][C@H:20]1[CH2:19][CH2:18][C@@:17]2([CH3:34])[C@@H:22]([CH2:23][CH2:24][C@:25]3([CH3:30])[C@@H:16]2[CH2:15][CH2:14][C@H:13]2[C@@:26]3([CH3:29])[CH2:27][CH2:28][C@@:11]3([C:9]([N:6]4[CH2:5][CH2:4][C:3]([CH2:1][CH3:2])([C:41]([OH:43])=[O:42])[CH2:8][CH2:7]4)=[O:10])[CH2:37][CH2:36][C@@H:35]([C:38]([CH3:40])=[CH2:39])[C@@H:12]32)[C:21]1([CH3:32])[CH3:31])=[O:56])([OH:57])=[O:53]
Reactant: C=C(C)[C@@H]1CC[C@]2(C(=O)N3CCC(CC)(C(=O)O)CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Reactant: CC1(C)CC(=O)OC1=O
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: C=C(C)[C@@H]1CC[C@]2(C(=O)N3CCC(CC)(C(=O)O)CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](OC(=O)CC(C)(C)C(=O)O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12

Procedure:
To a stirred solution of 4-ethyl-1-((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-9-hydroxy-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysene-3a-carbonyl)piperidine-4-carboxylic acid (Example 84, 0.5 g, 0.80 mmol) in pyridine (5 ml) dimethyl amino pyridine (0.2 g, 1.6 mmol) and 3,3-dimethyldihydrofuran-2,5-dione (0.82 ml) were added. The contents were refluxed for about 16 hours. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with ethyl acetate (30 ml). The organic layer was washed with 5% aqueous HCl, water followed by brine then dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using 5% MeOH in DCM as eluent to furnish the title compound (0.25 g) as a white solid. 1H NMR (300 MHz, CDCl3): 0.95-1.16 (m, 19H); 1.23-1.78 (m, 23H); 2.15-2.59 (m, 11H); 2.77-3.58 (m, 16H); 4.33-4.70 (m, 4H); 5.58-5.60 (s, 1H); 5.78-5.80 (s, 1H); 7.44-7.47 (s, 1H); ES Mass: 725 (100%), [M+1].
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]([N:6]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[C:10](=[O:17])[NH:9][C:8]2[CH:18]=[CH:19][CH:20]=[N:21][C:7]1=2)=[O:5].[CH3:22][N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1>>[CH3:22][N:23]1[CH2:28][CH2:27][N:26]([CH2:2][CH2:3][C:4]([N:6]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[C:10](=[O:17])[NH:9][C:8]3[CH:18]=[CH:19][CH:20]=[N:21][C:7]2=3)=[O:5])[CH2:25][CH2:24]1
Reactant: O=C1Nc2cccnc2N(C(=O)CCCl)c2ccccc21
Reactant: CN1CCNCC1
Product: CN1CCN(CCC(=O)N2c3ccccc3C(=O)Nc3cccnc32)CC1
Yield: 51 %

Procedure:
Using the procedure of Example 2, 11-(3-chloropropionyl)-5,11-dihydro-6H-pyrido-[2,3-b][1,4]-benzodiazepine-6-one and 1-methyl-piperazine were reacted to obtain a 51% yield of 5,11-dihydro-11-[3-(4-methyl-1-piperazinyl)-propionyl]-6H-pyrido-[2,3-b][1,4]-benzodiazepine-6-one which melted at 232°-233° C. after crystallization from an ethyl acetate-ethanol mixture. The dihydrochloride thereof melted at 235° C. after crystallization from ethanol.
Reaction SMILES: [CH3:1][C:2]1[CH:15]=[CH:14][N:5]2[C:6](=[O:13])[C:7]([C:10]([OH:12])=O)=[CH:8][N:9]=[C:4]2[CH:3]=1.C(N(CC)CC)C.ClC(OC)=O.[CH:28]1([NH2:33])[CH2:32][CH2:31][CH2:30][CH2:29]1>C(Cl)(Cl)Cl>[CH:28]1([NH:33][C:10]([C:7]2[C:6](=[O:13])[N:5]3[CH:14]=[CH:15][C:2]([CH3:1])=[CH:3][C:4]3=[N:9][CH:8]=2)=[O:12])[CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: Cc1ccn2c(=O)c(C(=O)O)cnc2c1
Reactant: NC1CCCC1
Agent: COC(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: Cc1ccn2c(=O)c(C(=O)NC3CCCC3)cnc2c1
Reaction time: 0.08 h
Yield: 55.3 %

Procedure:
A mixture containing 1.22 g (0.006 mol) of 8-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-3-carboxylic acid and 0.84 ml (0.006 mol) of triethylamine in 40 ml of chloroform is cooled below -10° C. by ice-salt. A solution of 0.46 ml (0.006 mol) of methyl chloroformate in 3 ml of chloroform is dropped to the above mixture at -15° C. during 10 minutes. After stirring for 5 minutes, 0.56 g (0.0066 mol) of cyclopentylamine dissolved in 6 ml of chloroform is dropped to the above solution. The reaction mixture is stirred at -10° C. for 1 hour, then allowed to stand overnight under cooling by ice. For working up, the reaction mixture is washed 3 times with 15 ml of 5% sodium hydrogen carbonate solution each, then 3 times with 15 ml of water each. The organic phase is dried over anhydrous sodium sulfate, filtered and evaporated to yield 0.9 g (55%) of the named compound as a crystalline substance after recrystallization from ethanol, m.p.: 220°-222° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[C:3]=1[C:10]([O:12][CH2:13][CH3:14])=[O:11].[C:15]1(B(O)O)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.N1C=CC=CC=1>O1CCOCC1>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:4](=[O:9])[C:3]=1[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: CCOC(=O)c1c(C)cc(C)[nH]c1=O
Reactant: OB(O)c1ccccc1
Solvent: C1COCCO1
Solvent: c1ccncc1
Product: CCOC(=O)c1c(C)cc(C)n(-c2ccccc2)c1=O
Temperature: 80 °C
Yield: 28.6 %

Procedure:
A suspension of ethyl 4,6-dimethyl-2-oxo-1,2-dihydropyridine-3-carboxylate (7.5 g, 0.038 mol), phenylboronic acid (14.1 g, 0.115 mol), cupric acetate (1.38 g, 0.008 mol), pyridine (7.5 mL) in 1,4-dioxane (80 mL) is heated at 80° C. for 96 hours. The solid is filtered off and the filtrate is concentrated. The residue is partitioned with EtOAc (50 mL) and 2N HCl (70 mL), and the precipitate is collected by filtration and washed with EtOAc to give the title product (2.95 g). The EtOAc solution is separated, dried and concentrated. The residue is purified by silica gel column chromatography eluting with PE:acetone (2:1) to give another portion of (0.3 g). (3.25 g, 31.2% yield). MS (m/z): 272.0 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[CH2:8][OH:9].[H-].[Na+].F[C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16]([N+:23]([O-:25])=[O:24])=[CH:15][CH:14]=1.CO>C1COCC1>[N+:23]([C:16]1[C:17]2[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:13]([O:9][CH2:8][C:7]2[CH:6]=[CH:5][N:4]=[CH:3][C:2]=2[NH2:1])=[CH:14][CH:15]=1)([O-:25])=[O:24]
Reactant: O=[N+]([O-])c1ccc(F)c2ccccc12
Reactant: Nc1cnccc1CO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: Nc1cnccc1COc1ccc([N+](=O)[O-])c2ccccc12
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 82 %

Procedure:
To a solution of (3-amino-pyridin-4-yl)-methanol (5) (4.00 g, 32.2 mmol) in anhydrous THF (160 mL) at 0° C. was added sodium hydride (1.55 g, 38.7 mmol, 60 wt %). After stirring for 20 min, 1-fluoro-4-nitronaphthalene (6.16 g, 32.2 mmol) was added, the ice bath removed and the reaction mixture left to warm to RT and stir for 12 hr. The reaction mixture was partitioned between EtOAc (200 mL) and saturated aq NaHCO3 solution (150 mL). The remaining yellow solid was collected by filtration and washed sequentially with water (50 mL), MeOH (50 mL) and diethyl ether (100 mL) and was identified as the desired product by LC-MS and 1H NMR. The filtrate was returned to a separating funnel; the organic phase was collected and washed with brine (100 mL), dried and concentrated in vacuo to afford an orange residue. Trituration of the orange residue with MeOH (200 mL) afforded an orange solid which was washed with diethyl ether (200 mL). LC-MS and 1H NMR analysis of the orange solid were identical to that observed for the insoluble solid obtained earlier. The two products were combined to afford 4-((4-nitronaphthalen-1-yloxy)methyl)pyridin-3-amine (6) (7.80 g, 77%): m/z 296 (M+H)+ (ES+).
Reaction SMILES: S(=O)(=O)(O)O.[NH2:6][C:7]1[CH:8]=[C:9]([N:13]2[C:18](=[O:19])[CH2:17][C:16]([CH3:21])([CH3:20])[CH2:15][C:14]2=[O:22])[CH:10]=[CH:11][CH:12]=1>C(OC(=O)CC)(=O)CC.O>[C:18]([NH:6][C:7]1[CH:8]=[C:9]([N:13]2[C:14](=[O:22])[CH2:15][C:16]([CH3:20])([CH3:21])[CH2:17][C:18]2=[O:19])[CH:10]=[CH:11][CH:12]=1)(=[O:19])[CH2:17][CH3:16]
Reactant: CC1(C)CC(=O)N(c2cccc(N)c2)C(=O)C1
Agent: CCC(=O)OC(=O)CC
Agent: O=S(=O)(O)O
Solvent: O
Product: CCC(=O)Nc1cccc(N2C(=O)CC(C)(C)CC2=O)c1

Procedure:
Five and one-half g. of propionic anhydride containing one drop of concentrated sulfuric acid was added to 9.3 g. of N-(m-aminophenyl)-3,3-dimethyl glutarimide in a small beaker. The mixture became warm and liquified. Upon cooling, the reaction mixture solidifed and was treated with water, collected by filtration and dried. Yield was 10.7 g. of a product having a m.p. of 199°-203° C. The product was identified as the title compound by analysis of infrared spectra.
Reaction SMILES: [CH3:1][C:2]1[N:3]([CH2:20][C:21]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH:24]=[CH:23][CH:22]=2)[C:4]2[CH:10]=[C:9]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)[CH:8]=[C:7]([N+:17]([O-])=O)[C:5]=2[N:6]=1>C(O)C.O.[Fe]>[CH3:1][C:2]1[N:3]([CH2:20][C:21]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH:24]=[CH:23][CH:22]=2)[C:4]2[CH:10]=[C:9]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)[CH:8]=[C:7]([NH2:17])[C:5]=2[N:6]=1
Reactant: Cc1nc2c([N+](=O)[O-])cc(N3CCOCC3)cc2n1Cc1cccc2ccccc12
Agent: [Fe]
Solvent: O
Solvent: CCO
Product: Cc1nc2c(N)cc(N3CCOCC3)cc2n1Cc1cccc2ccccc12
Temperature: 25 °C
Yield: 96.8 %

Procedure:
A mixture of 4-(2-methyl-3-(naphthalen-1-ylmethyl)-7-nitro-3H-benzo[d]imidazol-5-yl)morpholine (804 mg), prepared as described in Example 2, iron powder (168 mg) and FeSO4 (84 mg) in ethanol (30 mL) and H2O (30 mL) was stirred at reflux temperature overnight. The mixture was cooled to room temperature and the solvent was removed in-vacuo. The residue was dissolved in DCM and filtered. The filtrate was then washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in-vacuo to afford the desired product as a solid (720 mg, 97%). 1H NMR (300 MHz, DMSO-d6) δ ppm 2.33 (s, 3H), 2.91 (t, 4H J=4.8 Hz), 3.64 (t, 4H J=4.8 Hz), 5.15 (br s, 2H), 5.83 (s, 2H), 6.10 (d, 1H, J=2.1 Hz), 6.12 (d, 1H, J=2.1 Hz), 6.38 (d, 1H, J=7.5 Hz), 7.34 (t, 1H, J=7.5 Hz), 7.58-7.68 (m, 2H), 7.84 (d, 1H, J=8.4 Hz), 8.01 (d, 1H, J=7.5 Hz), 8.23 (d, 1H, J=8.4 Hz); LC-MS: m/e=373 [M+1]+
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:7]=[O:8])[S:5][CH:6]=1.[F:9][C:10]1[C:15](B(O)O)=[CH:14][CH:13]=[CH:12][N:11]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:9][C:10]1[C:15]([C:2]2[CH:3]=[C:4]([CH:7]=[O:8])[S:5][CH:6]=2)=[CH:14][CH:13]=[CH:12][N:11]=1
Reactant: OB(O)c1cccnc1F
Reactant: O=Cc1cc(Br)cs1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: O=Cc1cc(-c2cccnc2F)cs1
Temperature: 80 °C
Reaction time: 20 h
Yield: 53.5 %

Procedure:
A suspension of 4-bromothiophene-2-carbaldehyde (10.0 g), 2-fluoro-3-pyridineboronic acid (9.1 g), tetrakis(triphenylphosphine)palladium (0) (3.1 g) and sodium carbonate (13.7 g) in 1,2-dimethoxyethane (100 mL) and water (50 mL) was stirred at 80° C. for 20 hr under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=2:1) to give the title compound as a pale-yellow solid (yield 5.8 g, yield 53%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11](=[O:26])[NH:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH:14]=1)[C:5](O)=[O:6].[C:27]1([CH:33]([NH2:35])[CH3:34])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]([NH:35][CH:33]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH3:34])=[O:6])[CH:8]=[CH:9][C:10]=1[C:11]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH:14]=1)=[O:26]
Reactant: O=C(O)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)c(Cl)c1
Reactant: CC(N)c1ccccc1
Product: CC(NC(=O)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)c(Cl)c1)c1ccccc1

Procedure:
62 mg of 3-chloro-4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzoic acid was coupled to 1-phenylethanamine via Procedure G. The crude product was purified on reverse phase HPLC to yield 2-chloro-N1-(4-chloro-3-(pyridin-2-yl)phenyl)-N4-(1-phenylethyl)terephthalamide. MS (Q1) 490.1 (M)+.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][CH2:5][CH2:4][C@H:3]1[C:7]([OH:9])=[O:8].Cl.[CH3:11]O>O1CCOCC1>[NH2:1][C@H:2]1[CH2:6][CH2:5][CH2:4][C@H:3]1[C:7]([O:9][CH3:11])=[O:8]
Reactant: N[C@H]1CCC[C@H]1C(=O)O
Reactant: CO
Agent: Cl
Solvent: C1COCCO1
Product: COC(=O)[C@@H]1CCC[C@@H]1N

Procedure:
To a solution of (1R,2S)-2-aminocyclopentanecarboxylic acid (0.15 g, 0.9 mmol) in methanol (5 mL) was added 4N HCl in dioxane (1 mL) and the reaction mixture was stirred at reflux overnight. The reaction mixture was concentrated in vacuo to afford an oil which was used directly for the next step.
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@H:6]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:7]([OH:9])=O)=[O:4].CCOC(C(C#N)=NOC(N1CCOCC1)=[N+](C)C)=O.F[P-](F)(F)(F)(F)F.[CH3:43][O:44][CH2:45][C@@H:46]1[CH2:50][N:49](C(OC(C)(C)C)=O)[C@H:48]([C:58]2[NH:59][C:60]([C:63]3[CH:68]=[C:67]4[CH2:69][O:70][C:71]5[CH:88]=[C:87]6[C:74]([CH:75]=[CH:76][C:77]7[N:81]=[C:80]([C@@H:82]8[CH2:86][CH2:85][CH2:84][NH:83]8)[NH:79][C:78]=76)=[CH:73][C:72]=5[C:66]4=[CH:65][CH:64]=3)=[CH:61][N:62]=2)[CH2:47]1>CCN(C(C)C)C(C)C.CN(C=O)C>[CH3:1][O:2][C:3](=[O:4])[NH:5][C@H:6]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:7]([N:83]1[CH2:84][CH2:85][CH2:86][C@H:82]1[C:80]1[NH:79][C:78]2[C:87]3[C:74]([CH:75]=[CH:76][C:77]=2[N:81]=1)=[CH:73][C:72]1[C:66]2[C:67]([CH2:69][O:70][C:71]=1[CH:88]=3)=[CH:68][C:63]([C:60]1[NH:59][C:58]([C@@H:48]3[CH2:47][C@H:46]([CH2:45][O:44][CH3:43])[CH2:50][NH:49]3)=[N:62][CH:61]=1)=[CH:64][CH:65]=2)=[O:9]
Reactant: COC[C@H]1C[C@@H](c2ncc(-c3ccc4c(c3)COc3cc5c(ccc6nc([C@@H]7CCCN7)[nH]c65)cc3-4)[nH]2)N(C(=O)OC(C)(C)C)C1
Reactant: COC(=O)N[C@@H](C(=O)O)c1ccccc1
Agent: CCOC(=O)C(C#N)=NOC(N1CCOCC1)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC[C@@H]1CN[C@H](c2ncc(-c3ccc4c(c3)COc3cc5c(ccc6nc([C@@H]7CCCN7C(=O)[C@H](NC(=O)OC)c7ccccc7)[nH]c65)cc3-4)[nH]2)C1
Reaction time: 1.5 h

Procedure:
A mixture of (R)-2-(methoxycarbonylamino)-2-phenylacetic acid (22 mg, 0.105 mmol), COMU (45 mg, 0.069 mmol), and tert-butyl(2S,4S)-4-(methoxymethyl)-2-(5-{2-[(2S)-pyrrolidin-2-yl]-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-9-yl}-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (65 mg, 0.105 mmol) in 1.5 mL 10% DIPEA in DMF was stirred for 1.5 h. The reaction mixture was partitioned between ethyl acetate and saturated sodium bicarbonate. The organic phase was dried over sodium sulphate, filtered and concentrated under reduced pressure. The crude intermediate was treated with 8 mL 1.25N HCl in ethanol at 50° C. for 4 h. Added saturated sodium bicarbonate and extracted the free base into dichloromethane. (106 mg).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11](=[O:15])[CH2:12][C:13]#[N:14].[NH4+].[Cl-].[N-:18]=[N+:19]=[N-:20].[Na+]>CN(C)C=O>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11](=[O:15])[CH2:12][C:13]1[N:18]=[N:19][NH:20][N:14]=1
Reactant: N#CCC(=O)Nc1nc2ccccc2s1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(Cc1nn[nH]n1)Nc1nc2ccccc2s1
Temperature: 120 °C
Yield: 17.5 %

Procedure:
N-(benzo[d]thiazole-2-yl)-2-cyanoacetamide (0.1 g), NH4Cl (5.0 eq, 0.1 g), and NaN3 (5.2 eq, 0.13 g) were dissolved on 2.1 mL of DMF (dimethylformamide), and heated at 120° C. for 6 hours. DMF was removed under reduced pressure distillation, and 10 ml of water and 5% NaOH solution were added thereto. The aqueous layer was washed with 15 ml of Et2O, and treated with activated carbon. To the obtained reaction mixture, 10% aqueous hydrochloric acid, making the solution with pH 2. The obtained reaction mixture was extracted with methylene chloride, to produce N-(benzo[d]thiazole-2-yl)-2-(2H-tetrazole-5-yl)acetamide (20%, 21 mg) in light yellow solid phase.