Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C@H:13]([CH3:14])[CH2:12][CH2:11][C@H:10]([C:15]([OH:17])=O)[CH2:9]2)[CH:5]=[C:4]([C:18]2[CH:26]=[C:25]3[C:21]([CH:22]=[N:23][NH:24]3)=[CH:20][CH:19]=2)[N:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH:60]1([NH2:66])[CH2:65][CH2:64][CH2:63][CH2:62][CH2:61]1>CN(C=O)C.CCOC(C)=O.O>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C@H:13]([CH3:14])[CH2:12][CH2:11][C@H:10]([C:15]([NH:66][CH:60]3[CH2:65][CH2:64][CH2:63][CH2:62][CH2:61]3)=[O:17])[CH2:9]2)[CH:5]=[C:4]([C:18]2[CH:26]=[C:25]3[C:21]([CH:22]=[N:23][NH:24]3)=[CH:20][CH:19]=2)[N:3]=1
Reactant: C[C@@H]1CC[C@H](C(=O)O)CN1c1cc(-c2ccc3cn[nH]c3c2)nc(N)n1
Reactant: NC1CCCCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: C[C@@H]1CC[C@H](C(=O)NC2CCCCC2)CN1c1cc(-c2ccc3cn[nH]c3c2)nc(N)n1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 85.4 %

Procedure:
To a solution of (3S,6R)-1-[2-amino-6-(1H-indazol-6-yl)-4-pyrimidinyl]-6-methyl-3-piperidinecarboxylic acid (95 mg, 0.270 mmol) and HATU (123 mg, 0.324 mmol) in DMF (3 mL) was added Hunig's base (0.094 mL, 0.54 mmol), and the mixture was stirred at room temperature for 15 minutes. Then cyclohexylamine (0.037 mL, 0.324 mmol) was added, and the reaction mixture was stirred at room temperature for 0.5 hours. LCMS showed reaction was completed. The reaction was poured into water, and EtOAc was added to extract the product. The product stayed in the EtOAc layer. The organic layer was concentrated to dryness, and the resulting glass like solid was dissolved in CH3OH. Water was poured into the solution, and a white solid was formed, which was filtered, washed by water, and dried under vacuum to give the title compound (100 mg) as a white solid. LC-MS (ES) m/z=434 [M+H]+. 1H NMR (400 MHz, CD3OD): δ 1.29 (m, 9H), 1.62-2.09 (m, 9H), 2.32-2.45 (m, 1H), 3.06-3.18 (m, 1H), 3.61-3.73 (m, 1H), 4.44-4.84 (m, 1H), 6.53 (s, 1H), 7.65 (dd, J=8.5, 1.4 Hz, 1H), 7.85 (dd, J=8.5, 1.4 Hz, 1H), 8.06 (s, 1H), 8.09 (s, 1H).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][C:5](Cl)=[O:6].[C:8](=[N:21][NH2:22])([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.N1C=CC=CC=1.O>C(Cl)Cl>[C:8](=[N:21][NH:22][C:5](=[O:6])[CH2:4][CH2:3][CH2:2][Cl:1])([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=C(Cl)CCCCl
Reactant: NN=C(c1ccccc1)c1ccccc1
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: O
Product: O=C(CCCCl)NN=C(c1ccccc1)c1ccccc1
Reaction time: 0.5 h

Procedure:
4-Chlorobutyryl chloride (57 mL, 510 mmol) is added to a solution of benzophenone hydrazone (100 g, 510 mmol) and pyridine (41 mL, 510 mmol) in anhydrous CH2Cl2 (520 mL) under nitrogen at a rate that maintained a gentle reflux throughout the addition. The mixture is stirred for 0.5 h and poured into water (1 L). The layers are separated and the organic layer is washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo to yield 4-chloro-butyric acid benzhydrylidene-hydrazide as a residue.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13].[CH3:17][Si]([N-][Si](C)(C)C)(C)C.[Li+].CI>>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH:11]([CH3:17])[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CCOC(=O)Cc1ccc2ccccc2c1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CI
Product: CCOC(=O)C(C)c1ccc2ccccc2c1
Yield: 108.7 %

Procedure:
5 g (23 mmol) of ethyl 2-naphthylacetate, 23.3 mL (1.0 M, 23 mmol) of lithium bis (trimethylsilyl) amide, and 1.5 mL (24 mmol) of methyl iodide were reacted as described in Preparation 11 to yield 5.71 g of a dark oil.
Reaction SMILES: [C:1]([Si:5]([CH3:24])([CH3:23])[O:6][CH:7]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:8][CH2:9][CH:10]1[NH:14][C:13](=[O:15])[CH2:12][CH2:11]1)([CH3:4])([CH3:3])[CH3:2].C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH2:35]([O:37][C:38](=[O:49])[C:39]1[CH:44]=[CH:43][C:42]([O:45][CH2:46][CH2:47]Br)=[CH:41][CH:40]=1)[CH3:36]>>[CH2:35]([O:37][C:38](=[O:49])[C:39]1[CH:44]=[CH:43][C:42]([O:45][CH2:46][CH2:47][N:14]2[C:13](=[O:15])[CH2:12][CH2:11][CH:10]2[CH2:9][CH2:8][CH:7]([O:6][Si:5]([C:1]([CH3:3])([CH3:2])[CH3:4])([CH3:24])[CH3:23])[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:41][CH:40]=1)[CH3:36]
Reactant: CCOC(=O)c1ccc(OCCBr)cc1
Reactant: CC(C)(C)[Si](C)(C)OC(CCC1CCC(=O)N1)Cc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Product: CCOC(=O)c1ccc(OCCN2C(=O)CCC2CCC(Cc2ccccc2)O[Si](C)(C)C(C)(C)C)cc1
Temperature: 50 °C
Yield: 17.1 %

Procedure:
Analogous to the procedure described for Example 1A, Step D, 5-[3-(tert-butyl-dimethyl-silanyloxy)-4-phenyl-butyl]-pyrrolidin-2-one (prepared in Example 1A, Step C) (250 mg, 0.719 mmol) was alkylated with NaHMDS (1M in THF, 0.86 mL, 0.86 mmol) and 4-(2-bromo-ethoxy)-benzoic acid ethyl ester (216 mg, 0.791 mmol). The reaction temperature was maintained at 50° C. over 24 h. Purification by radial chromatography (hexanes to 4:1 hexanes:EtOAc) provided 4-(2-{2-[3-(tert-butyl-dimethyl-silanyloxy)-4-phenyl-butyl]-5-oxo-pyrrolidin-1-yl}-ethoxy)-benzoic acid ethyl ester (66.4 mg). 1H NMR (CDCl3) (selected peaks) δ7.96 (m, 2H), 7.29-7.13 (m, 5H), 6.84 (m, 2H), 4.33 (q, 2H), 4.12 (m, 2H), 3.90 (m, 2H), 3.68 (m, 1H), 3.34 (m, 1H), 2.73 (m, 2H), 2.32 (m, 2H), 1.36 (t, 3H), 0.85 (s, 9H, −0.03 (s, 3H), −0.15 (d, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C@H:6]1[CH2:11][CH2:10][CH2:9][N:8]([CH2:12][C@@H:13]([O:22][Si:23]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24])[C:14]2[CH:19]=[CH:18][C:17]([C:20]#[N:21])=[CH:16][CH:15]=2)[CH2:7]1)=[O:5])[CH3:2].[NH2:30][OH:31]>CCO>[Si:23]([O:22][C@@H:13]([C:14]1[CH:15]=[CH:16][C:17](/[C:20](=[N:30]/[OH:31])/[NH2:21])=[CH:18][CH:19]=1)[CH2:12][N:8]1[CH2:9][CH2:10][CH2:11][C@H:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH2:7]1)([C:26]([CH3:28])([CH3:27])[CH3:29])([CH3:25])[CH3:24]
Reactant: NO
Reactant: CCOC(=O)[C@H]1CCCN(C[C@@H](O[Si](C)(C)C(C)(C)C)c2ccc(C#N)cc2)C1
Solvent: CCO
Product: CCOC(=O)[C@H]1CCCN(C[C@@H](O[Si](C)(C)C(C)(C)C)c2ccc(/C(N)=N/O)cc2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.6 %

Procedure:
(S)-Ethyl-1-((S)-2-(tert-butyldimethylsilyloxy)-2-(4-cyanophenyl)ethyl)piperidine-3-carboxylate (31.0 g, 74.4 mmol) was dissolved in EtOH (248 mL). Hydroxylamine (50% aq) (6.84 ml, 112 mmol) was added and stirred at room temperature overnight. Then all volatiles were removed with ROTAVAPOR®. The residue was purified with on a silica gel cartridge (330 g silica, 0-50% EtOAc/hexanes gradient) to give (S)-ethyl 1-((S)-2-(tert-butyldimethylsilyloxy)-2-(4-((Z)-N′-hydroxycarbamimidoyl)phenyl)ethyl)piperidine-3-carboxylate (31 g, 68.9 mmol, 93% yield) as a white foam. 1H NMR (400 MHz, CDCl3) δ ppm 8.38 (1H, br s), 7.58 (2H, d), 7.37 (2H, d), 4.88 (2H, br s), 4.81 (1H, m), 4.13 (2H, m), 2.96 (1H, m), 2.82 (1H, m), 2.61 (1H, dd), 2.51 (1H, m), 2.42 (1H, dd), 2.32 (1H, tt), 2.13 (1H, dt), 1.91 (1H, m), 1.66 (1H, dt), 1.58 (1H, m), 1.48 (1H, m), 1.27 (3H, t), 0.89 (9H, s), 0.08 (3H, s), −0.09 (3H, s).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[OH:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][S:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15].C(N(CC)CC)C>C(Cl)Cl>[CH3:1][S:2]([O:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][S:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])(=[O:4])=[O:3]
Reactant: CCOC(=O)CSCCCCCO
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)CSCCCCCOS(C)(=O)=O

Procedure:
A solution of 16.7 g. (0.146 mol) methanesulphonyl chloride and 150 ml. methylene chloride is added dropwise at -5° C., within the course of 30 minutes, to a mixture of 30.1 g. (0.146 mol) ethyl 8-hydroxy-3-thiaoctanoate, 200 ml. methylene chloride and 22,2 g. (0.219 mol) anhydrous triethylamine and the reaction mixture then stirred at 0° C. for a further 30 minutes. It is then extracted with ice-cold 2N sulphuric acid and subsequently with ice water, dried with anhydrous sodium sulphate and subsequently evaporated. Yield 38.3 g. (93% of theory) in the form of a colourless oil.
Reaction SMILES: [CH3:1][Si:2]([CH3:10])([CH3:9])[O:3][C:4]([CH3:8])([C:6]#[CH:7])[CH3:5].[Li]CCCC.CON(C)[C:19]([C:21]1[N:22]=[CH:23][S:24][CH:25]=1)=[O:20]>C1COCC1>[CH3:5][C:4]([O:3][Si:2]([CH3:10])([CH3:9])[CH3:1])([CH3:8])[C:6]#[C:7][C:19]([C:21]1[N:22]=[CH:23][S:24][CH:25]=1)=[O:20]
Reactant: CON(C)C(=O)c1cscn1
Reactant: C#CC(C)(C)O[Si](C)(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C#CC(=O)c1cscn1)O[Si](C)(C)C
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 31.5 %

Procedure:
To a stirred solution trimethyl (2-methylbut-3-yn-2-yloxy)silane (0.56 g, 3.57 mmol) in dry THF (10 mL) was added n-BuLi (1.3 mL, 2.1 mmol, 1.6 M in hexane) dropwise at −78° C. under an inert atmosphere for a period of 5 min. After being stirred for 30 min at −78° C., a solution of N-methoxy-N-methylthiazole-4-carboxamide (0.25 g, 1.78 mmol) in dry THF (5 mL) was added to reaction mixture and stirring was continued for an additional 1 h at −78° C. The reaction mixture was quenched with a saturated NH4Cl solution and extracted with EtOAc (2×30 mL). The combined organic layers were washed with water (20 mL), brine (20 mL), dried over Na2SO4, filtered and concentrated in vacuo to obtain the crude product. The crude material was purified via silica gel column chromatography eluting with 2-4% EtOAc in Hexane to afford 4-methyl-1-(thiazol-4-yl)-4-(trimethylsilyloxy)pent-2-yn-1-one (0.15 g, 31.44%) as an oil.
Reaction SMILES: Br[C:2]1[C:11](=[O:12])[N:10]([CH3:13])[C:9]2[C:8]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=3[F:21])=[N:7][N:6]=[CH:5][C:4]=2[CH:3]=1.C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+].[F:70][C:71]1[CH:76]=[C:75]([F:77])[CH:74]=[CH:73][C:72]=1[NH2:78]>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:21][C:15]1[CH:16]=[C:17]([F:20])[CH:18]=[CH:19][C:14]=1[C:8]1[C:9]2[N:10]([CH3:13])[C:11](=[O:12])[C:2]([NH:78][C:72]3[CH:73]=[CH:74][C:75]([F:77])=[CH:76][C:71]=3[F:70])=[CH:3][C:4]=2[CH:5]=[N:6][N:7]=1
Reactant: Nc1ccc(F)cc1F
Reactant: Cn1c(=O)c(Br)cc2cnnc(-c3ccc(F)cc3F)c21
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: Cc1ccccc1
Product: Cn1c(=O)c(Nc2ccc(F)cc2F)cc2cnnc(-c3ccc(F)cc3F)c21
Temperature: 110 °C

Procedure:
To a suspension of 3-bromo-8-(2,4-difluorophenyl)-1-methylpyrido[3,2-d]pyridazin-2(1H)-one (8) (60.0 mg, 0.170 mmol) in toluene (2 mL) was added palladium (II) acetate (1.91 mg, 0.00852 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos) (9.86 mg, 0.0170 mmol) and cesium carbonate (83.3 mg, 0.256 mmol) followed by 2,4-difluorobenzenamine (0.0260 mL, 0.256 mmol). The reaction mixture was stirred and heated in a microwave at 110° C. for 75 min and then cooled to RT to afford a suspension. The solid was collected by suction filtration, washed with toluene and water, and dried in vacuo to give 8-(2,4-difluorophenyl)-3-(2,4-difluorophenylamino)-1-methylpyrido[3,2-d]pyridazin-2(1H)-one as a pale yellow solid. MS (ESI, pos. ion) m/z: 401 (M+1).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][CH:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:13][CH2:12]1.Cl[CH:23]1[C:27]2=[N:28][CH:29]=[CH:30][CH:31]=[C:26]2[CH2:25][CH2:24]1.C(=O)([O-])[O-].[K+].[K+].O>C(#N)C>[N:28]1[C:27]2[CH:23]([N:1]3[C:5]4[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=4[N:3]=[C:2]3[NH:10][CH:11]3[CH2:16][CH2:15][N:14]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:13][CH2:12]3)[CH2:24][CH2:25][C:26]=2[CH:31]=[CH:30][CH:29]=1
Reactant: CCOC(=O)N1CCC(Nc2nc3ccccc3[nH]2)CC1
Reactant: ClC1CCc2cccnc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CCOC(=O)N1CCC(Nc2nc3ccccc3n2C2CCc3cccnc32)CC1
Yield: 68.3 %

Procedure:
A mixture of ethyl 4-(1H-benzimidazol-2-ylamino)-1-piperidine-carboxylate (0.0289 mol), 7-chloro-6,7-dihydro-5H-cyclopenta[b]pyridine (0.0289 mol) and potassium carbonate (0.0867 mol) in acetonitrile (250 ml) was stirred and refluxed for 48 hours and then brought to room temperature. The reaction was carried out again using the same quantities. The mixtures were combined, poured out into H2O and extracted with EtOAc. The organic layer was separated, washed with H2O, dried (MgSO4), filtered and the solvent was evaporated. The residue (25 g) was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH NH4OH 97/3/0.5; 20-45 μm). Two fractions were collected and their solvents were evaporated, yielding 8 g of ethyl 4-[[1-(6,7-dihydro-5H-1-pyrindin-7-yl) 1H-benzimidazol-2-yl]amino]-1-piperidinecarboxylate (interm. 22).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][S:9]([C:12]2[CH:17]=[CH:16][C:15](F)=[CH:14][CH:13]=2)(=[O:11])=[O:10])=[CH:4][C:3]=1[N+:19]([O-:21])=[O:20].[CH2:22]([CH2:24][NH2:25])[OH:23]>CCOCCO.Cl>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][S:9]([C:12]2[CH:17]=[CH:16][C:15]([NH:25][CH2:24][CH2:22][OH:23])=[CH:14][CH:13]=2)(=[O:11])=[O:10])=[CH:4][C:3]=1[N+:19]([O-:21])=[O:20]
Reactant: Nc1ccc(OS(=O)(=O)c2ccc(F)cc2)cc1[N+](=O)[O-]
Reactant: NCCO
Agent: Cl
Solvent: CCOCCO
Product: Nc1ccc(OS(=O)(=O)c2ccc(NCCO)cc2)cc1[N+](=O)[O-]

Procedure:
15.6 g of 2-amino-5-(4-fluorophenylsulfonyloxy)nitrobenzene were combined with 25 ml ethanolamine in 100 ml ethyl glycol in a round bottom flask. The reaction mixture was heated to reflux for 90 min and then cooled on ice. Reaction mixture was then diluted with 250 ml of 2N aqueous HCl, the compound precipitated and was filtered off with suction. The preciptate was the washed with water and dried, yielding 15.5 g of 2-amino-5-(4-[2-hydroxyethyl]aminophenylsulfonyloxy)nitrobenzene (melting point 180° C.).
Reaction SMILES: [H-].[Na+].[N:3]1[C:11]([NH2:12])=[C:10]2[C:6]([NH:7][CH:8]=[N:9]2)=[N:5][CH:4]=1.Cl[CH2:14][C:15]1[N:19]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:18]2[CH:26]=[C:27]([F:30])[CH:28]=[CH:29][C:17]=2[N:16]=1>CN(C=O)C>[F:30][C:27]1[CH:28]=[CH:29][C:17]2[N:16]=[C:15]([CH2:14][N:7]3[CH:8]=[N:9][C:10]4[C:6]3=[N:5][CH:4]=[N:3][C:11]=4[NH2:12])[N:19]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:18]=2[CH:26]=1
Reactant: Fc1ccc2nc(CCl)n(-c3ccccc3)c2c1
Reactant: Nc1ncnc2[nH]cnc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Nc1ncnc2c1ncn2Cc1nc2ccc(F)cc2n1-c1ccccc1
Temperature: 70 °C
Reaction time: 0.25 h

Procedure:
Sodium hydride, NaH (60% in mineral oil, 23 mg, 0.69 mmol) was added to a suspension of 9H-purin-6-ylamine (93 mg, 0.69 mmol) in DMF (1 mL) under a nitrogen atmosphere. The reaction mixture was stirred for 15 min then 2-chloromethyl-6-fluoro-1-phenyl-1H-benzoimidazole (148 mg, 0.57 mmol) in DMF (1 mL) added. After 30 min stirring at RT, the temperature was increased to 70° C. and stirring continued for 3 h. The volatiles were removed under reduced pressure and the resulting residue partitioned between DCM and water. The aqueous phase was extracted with DCM (×3) and the combined organic fractions dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, gradient 0-10% 2N NH3/MeOH in DCM) to afford still impure 9-(6-fluoro-1-phenyl-1H-benzoimidazol-2-ylmethyl)-9H-purin-6-ylamine. Impure 9-(6-fluoro-1-phenyl-1H-benzoimidazol-2-ylmethyl)-9H-purin-6-ylamine was purified by reverse phase HPLC (Phenomenex Gemini 5 μm C18 on a gradient 20-98%, 0.1% HCO2H in acetonitrile/water) to afford pure 376 as a white solid (45 mg, 22%). LCMS (Method K): RT 3.18 min [M+H]+ 360.0. 1H NMR (DMSO-d6, 400 MHz): δ 8.06 (1H, s), 8.04 (1H, s), 7.68-7.55 (6H, m), 7.21 (2H, br s), 7.15-7.08 (1H, m), 6.97 (1H, dd, J=8.98, 2.55 Hz), 5.58 (2H, s)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:36][CH2:35][C:11]3[NH:12][C:13]4[CH:14]=[CH:15][C:16]([C:19]([NH:21][CH:22]5[CH2:27][CH2:26][N:25]([C:28]([O:30]C(C)(C)C)=O)[CH2:24][CH2:23]5)=[O:20])=[CH:17][C:18]=4[C:10]=3[CH2:9]2)=[CH:4][CH:3]=1.[F:37][C:38]1[CH:46]=[CH:45][C:41](C(Cl)=O)=[CH:40][CH:39]=1.C(N(CC)CC)C.C(=O)(O)[O-].[Na+]>Cl.O1CCOCC1>[F:37][C:38]1[CH:46]=[CH:45][C:41]([C:28]([N:25]2[CH2:26][CH2:27][CH:22]([NH:21][C:19]([C:16]3[CH:15]=[CH:14][C:13]4[NH:12][C:11]5[CH2:35][CH2:36][N:8]([C:5]6[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=6)[CH2:9][C:10]=5[C:18]=4[CH:17]=3)=[O:20])[CH2:23][CH2:24]2)=[O:30])=[CH:40][CH:39]=1
Reactant: CC(C)(C)OC(=O)N1CCC(NC(=O)c2ccc3[nH]c4c(c3c2)CN(c2ccc(F)cc2)CC4)CC1
Reactant: O=C(Cl)c1ccc(F)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: O=C(NC1CCN(C(=O)c2ccc(F)cc2)CC1)c1ccc2[nH]c3c(c2c1)CN(c1ccc(F)cc1)CC3
Temperature: 25 °C
Reaction time: 2 h
Yield: 46 %

Procedure:
A solution of tert-butyl 4-(2-(4-fluorophenyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole-8-carboxamido)piperidine-1-carboxylate (Compound 38, 50 mg, 100 μmol) in 4 N HCl/dioxane (3.0 mL) was allowed to stir at room temperature for 2 h. The reaction mixture was then concentrated, MeOH (5.0 mL) was added and the volatiles were evaporated (2×). The resulting residue was dissolved in DMF (2.0 mL) and 4-fluorobenzoyl chloride (15 μL, 20 mg, 130 μmol) and triethylamine (0.5 mL, 0.36 g, 3.6 mmol) were added. The resulting reaction mixture was allowed to stir at room temperature overnight, poured into saturated sodium bicarbonate solution (20 mL) to give a yellow solid which was triturated with ethyl ether and then purified by reverse phase HPLC to provide N-(1-(4-fluorobenzoyl)piperidin-4-yl)-2-(4-fluorophenyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole-8-carboxamide (Compound 39) (46%). 1H NMR (DMSO-d6, 300 MHZ) 11.13 (s, 1H), 8.09 (d, J=7.7 Hz, 1H), 8.03 (s, 1H), 7.58 (dd, J=8.4, 1.5 Hz, 1H), 7.45 (dd, J=8.5, 5.5 Hz, 2H), 7.28 (t, J=8.8 Hz, 3H), 7.10 (m, 4H), 4.43 (s, 3H), 4.18-4.03 (m, 2H), 3.70-3.54 (m, 3H), 3.16 (br s, 1H), 2.92 (br s, 2H), 1.87 (br s, 2H), 1.54 (br s, 2H) ppm; MS (ES) 515 (M+H).
Reaction SMILES: [Cl:1][C:2]1[C:7](Cl)=[CH:6][CH:5]=[C:4]([N+:9]([O-:11])=[O:10])[C:3]=1[O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[Cl:19][C:20]1[CH:25]=[C:24]([CH3:26])[C:23]([Cl:27])=[CH:22][C:21]=1[SH:28].[OH-].[Na+]>CS(C)=O>[Cl:1][C:2]1[C:3]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1[S:28][C:21]1[CH:22]=[C:23]([Cl:27])[C:24]([CH3:26])=[CH:25][C:20]=1[Cl:19]
Reactant: O=[N+]([O-])c1ccc(Cl)c(Cl)c1Oc1ccccc1
Reactant: Cc1cc(Cl)c(S)cc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: Cc1cc(Cl)c(Sc2ccc([N+](=O)[O-])c(Oc3ccccc3)c2Cl)cc1Cl
Temperature: 100 °C
Reaction time: 5 h

Procedure:
A mixture of 14.2 gm of 2,3-dichloro-6-nitro-1-phenoxy-benzene, 10.2 gm of 2,5-dichloro-4-methylthiophenol, 5.0 ml of 10 N sodium hydroxide and 40 ml of dimethylsulfoxide was stirred for 5 hours at 100° C. and then allowed to stand overnight at room temperature. Thereafter, the reaction mixture was admixed with 400 ml of 1 N sodium hydroxide, and the product precipitated thereby was collected and recrystallized from 150 ml of ethanol. 20.5 gm (90% of theory) of the light yellow crystalline title compound, m.p. 138°-144° C., were obtained.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:14][CH:13]3[O:15][CH:10]([CH2:11][CH2:12]3)[CH2:9]2)[N:5]=[C:4]([N:16]2[CH2:22][CH:21]3[O:23][CH:18]([CH2:19][CH2:20]3)[CH2:17]2)[N:3]=1.[F:24][CH:25]([F:35])[C:26]1[NH:30][C:29]2[CH:31]=[CH:32][CH:33]=[CH:34][C:28]=2[N:27]=1.C([O-])([O-])=O.[K+].[K+].Cl.C12OC(CC1)CNC2>CN(C=O)C>[F:35][CH:25]([F:24])[C:26]1[N:27]([C:2]2[N:3]=[C:4]([N:16]3[CH2:22][CH:21]4[O:23][CH:18]([CH2:19][CH2:20]4)[CH2:17]3)[N:5]=[C:6]([N:8]3[CH2:9][CH:10]4[O:15][CH:13]([CH2:12][CH2:11]4)[CH2:14]3)[N:7]=2)[C:28]2[CH:34]=[CH:33][CH:32]=[CH:31][C:29]=2[N:30]=1
Reactant: FC(F)c1nc2ccccc2[nH]1
Reactant: Clc1nc(N2CC3CCC(C2)O3)nc(N2CC3CCC(C2)O3)n1
Agent: C1CC2CNCC1O2
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: FC(F)c1nc2ccccc2n1-c1nc(N2CC3CCC(C2)O3)nc(N2CC3CCC(C2)O3)n1

Procedure:
A solution of cyanuric chloride (922 mg, 5 mmol) in acetone (5 mL) was added to ice. A solution of 8-oxa-3-azabicyclo[3.2.1]octane hydrochloride (750 mg, 5 mmol) and triethylamine (2.1 mL, 15 mmol) in aqueous acetone was then added. After 20 min the precipitate was collected to give 1.0 g of a white powder which was a 7:3 mixture of 3-(4,6-dichloro-1,3,5-triazine-2,4-diyl)-8-oxa-3-azabicyclo[3.2.1]octane and 3,3′-(6-chloro-1,3,5-triazine-2,4-diyl)bis(8-oxa-3-azabicyclo[3.2.1]octane). Treatment of the mixture (400 mg) with 2-(difluoromethyl)-1H-benzo[d]imidazole (146 mg, 0.87 mmol) and K2CO3 (967 mg, 7 mmol) in DMF (2.5 mL) for 18 hours, followed by addition of 8-oxa-3-azabicyclo[3.2.1]octane hydrochloride (150 mg) gave, after 1 h, 3,3′-(6-(2-(difluoromethyl)-1H-benzo[d]imidazol-1-yl)-1,3,5-triazine-2,4-diyl)bis(8-oxa-3-azabicyclo[3.2.1]octane) after purification by HPLC. (M+H) 475.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:22](=O)[CH2:23][CH3:24])[C:5]2[C:10]([CH3:11])=[C:9]([CH3:12])[N:8]([C:13]3[C:18]([CH3:19])=[CH:17][C:16]([CH3:20])=[CH:15][C:14]=3[CH3:21])[C:6]=2[N:7]=1.[OH:26][NH:27]Cl.C([O-])(=O)C.[Na+]>CO>[CH3:1][C:2]1[N:3]=[C:4]([C:22](=[N:27][OH:26])[CH2:23][CH3:24])[C:5]2[C:10]([CH3:11])=[C:9]([CH3:12])[N:8]([C:13]3[C:18]([CH3:19])=[CH:17][C:16]([CH3:20])=[CH:15][C:14]=3[CH3:21])[C:6]=2[N:7]=1
Reactant: ONCl
Reactant: CCC(=O)c1nc(C)nc2c1c(C)c(C)n2-c1c(C)cc(C)cc1C
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CO
Product: CCC(=NO)c1nc(C)nc2c1c(C)c(C)n2-c1c(C)cc(C)cc1C
Temperature: 25 °C
Reaction time: 24 h
Yield: 105.1 %

Procedure:
A mixture of 1-[-2,5,6-trimethyl-7-(2,4,6-trimethylphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-propan-1-one (0.598 g, 1.783 mmol), hydroxylamino hydrochloride (0.370 g, 5.35 mmol), sodium acetate (0.439 g, 5.35 mmol) in MeOH (30 ml) was stirred at room temperature for 24 hours. The mixture was concentrated to dryness. The residue was diluted with water and extracted with ethyl acetate. The organic layer was dried and concentrated to give 0.657 g of a white glassy foam. The glassy foam was purified through silica gel column chromatography to separated both E (white crystals, mp 162-164° C., confirmed by X-ray structural analysis) and Z (white crystals, mp 84-87° C.) isomers and a mixture of E and Z isomers (mp −150-190° C.).
Reaction SMILES: C([O:8][C:9]1[C:10]([O:25][CH3:26])=[CH:11][C:12]2[C:18](=[O:19])[N:17]3[CH2:20][CH2:21][CH2:22][CH2:23][C@@H:16]3[CH:15]=[N:14][C:13]=2[CH:24]=1)C1C=CC=CC=1>C(Cl)Cl.C([O-])(O)=O.[Na+]>[OH:8][C:9]1[C:10]([O:25][CH3:26])=[CH:11][C:12]2[C:18](=[O:19])[N:17]3[CH2:20][CH2:21][CH2:22][CH2:23][C@@H:16]3[CH:15]=[N:14][C:13]=2[CH:24]=1
Reactant: COc1cc2c(cc1OCc1ccccc1)N=C[C@H]1CCCCN1C2=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COc1cc2c(cc1O)N=C[C@H]1CCCCN1C2=O
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 76.3 %

Procedure:
To (R,Z)-3-(benzyloxy)-2-methoxy-7,8,9,10-tetrahydrobenzo[e]pyrido[1,2-a][1,4]diazepin-12(6aH)-one (241) (215 mg, 0.614 mmol) in 25 ml of CH2Cl2 at 0° C. was added 25 ml of CH2SO3H. The mixture was stirred at 0° C. for 10 min and then at RT for 2 h, diluted with CH2Cl2, neutralized with cold 1.0 M NaHCO3, extracted with CH2Cl2, dried over Na2SO4, filtered, evaporated and purified on SiO2 chromatography eluted with CH3OH/CH2Cl2 (1:15) to afford 122 mg (70%) of the title product. 1H NMR (CDCl3), 7.75 (d, 1H, J=5.7 Hz), 7.28 (s, 1H), 6.70 (s, 1H), 4.08 (m, 1H), 3.83 (d, 3H), 3.61 (m, 1H), 3.08 (m, 1H), 1.91 (m, 1H), 1.81 (m, 1H), 1.71˜1.55 (m, 4H); 13C NMR 167.81, 163.46, 148.53, 145.71, 140.84, 121.23, 111.89, 111.39, 56.45, 49.83, 39.96, 24.71, 23.22, 18.60; MS m/z+ 283.7 (M+Na).
Reaction SMILES: CC([N+]1(C)[C@@H]2[CH2:9][C@@H:10]([O:12][C:13]([CH:15](C3C=CC=CC=3)[CH2:16][OH:17])=[O:14])C[C@H]1CC2)C.[OH2:25].[Br-]>C(O)C>[CH2:10]([OH:12])[CH3:9].[OH:17][CH2:16][CH:15]([CH2:13][OH:14])[OH:25]
Reactant: O
Reactant: CC(C)[N+]1(C)[C@@H]2CC[C@H]1C[C@@H](OC(=O)C(CO)c1ccccc1)C2
Agent: [Br-]
Solvent: CCO
Product: OCC(O)CO

Procedure:
The solubility of ipratropium bromide in ethanol is 42.48 mg/g.