Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[N:2](C)/[C:3](=[N:5]/[C:6]([C:8]1[N:17]=[C:16]2[N:10]([CH2:11][CH2:12][O:13][C:14]3[CH:21]=[C:20]([Br:22])[CH:19]=[CH:18][C:15]=32)[CH:9]=1)=O)/[CH3:4].C(O)(=O)C.Cl.[CH:29]([NH:32]N)([CH3:31])[CH3:30]>>[Br:22][C:20]1[CH:19]=[CH:18][C:15]2[C:16]3[N:10]([CH2:11][CH2:12][O:13][C:14]=2[CH:21]=1)[CH:9]=[C:8]([C:6]1[N:32]([CH:29]([CH3:31])[CH3:30])[N:2]=[C:3]([CH3:4])[N:5]=1)[N:17]=3
Reactant: CC(C)NN
Reactant: C/C(=N\C(=O)c1cn2c(n1)-c1ccc(Br)cc1OCC2)N(C)C
Agent: Cl
Solvent: CC(=O)O
Product: Cc1nc(-c2cn3c(n2)-c2ccc(Br)cc2OCC3)n(C(C)C)n1
Temperature: 95 °C
Yield: 83.8 %

Procedure:
To a solution of 8-Bromo-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene-2-carboxylic acid [1-dimethylamino-eth-(E)-ylidene]-amide (0.340 g, 0.000901 mol) in acetic acid (3.0 mL, 0.053 mol) was added isopropylhydrazine hydrochloride (0.1196 g, 0.001082 mol). The reaction was heated to 95° C. for 3 h. The acetic acid was removed in vacuo and the product was loaded as a solid onto silica and purified by flash chromatography (0-10% MeOH in DCM) to give 8-Bromo-2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene (293 mg) as an orange solid. MS(ESI+) 388.1/390.1
Reaction SMILES: C([O:4][C:5]1[C:6]([CH2:22][CH3:23])=[C:7]2[C:15](=[CH:16][C:17]=1[CH:18]([CH3:20])[CH3:19])[O:14][C:10]1([CH2:13][CH2:12][CH2:11]1)[CH2:9][C:8]2=[O:21])(=O)C.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH2:22]([C:6]1[C:5]([OH:4])=[C:17]([CH:18]([CH3:20])[CH3:19])[CH:16]=[C:15]2[C:7]=1[CH:8]([OH:21])[CH2:9][C:10]1([O:14]2)[CH2:13][CH2:12][CH2:11]1)[CH3:23]
Reactant: CCc1c(OC(C)=O)c(C(C)C)cc2c1C(=O)CC1(CCC1)O2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCc1c(O)c(C(C)C)cc2c1C(O)CC1(CCC1)O2
Reaction time: 2 h
Yield: 62.6 %

Procedure:
To a solution of 5-ethyl-7-isopropyl-4-oxospiro[chroman-2,1′-cyclobutane]-6-yl acetate (53 mg) in 5 mL of THF was added LiAlH4 (65 mg) in 3 portions at room temperature. The mixture was stirred for 2 h and quenched by pouring onto ice. The mixture was extracted with EtOAc (3×10 mL) and the organic extract was dried over Na2SO4 and concentrated. The crude product was purified by chromatography to afford 5-ethyl-7-isopropylspiro[chroman-2,1′-cyclobutane]-4,6-diol as an off-white solid (29 mg, 63%).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][O:11][C@H:10]([O:14][CH2:15][C:16]2[CH:21]=[C:20]([Cl:22])[CH:19]=[C:18]([Cl:23])[CH:17]=2)[C@@H:9]1[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)C1C=CC=CC=1.ClC(OC(Cl)C)=O>ClCCCl>[Cl:23][C:18]1[CH:17]=[C:16]([CH:21]=[C:20]([Cl:22])[CH:19]=1)[CH2:15][O:14][C@H:10]1[O:11][CH2:12][CH2:13][NH:8][C@H:9]1[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: Clc1cc(Cl)cc(CO[C@H]2OCCN(Cc3ccccc3)[C@H]2c2ccccc2)c1
Agent: CC(Cl)OC(=O)Cl
Solvent: ClCCCl
Product: Clc1cc(Cl)cc(CO[C@H]2OCCN[C@H]2c2ccccc2)c1
Temperature: 110 °C
Reaction time: 60 h
Yield: 19.6 %

Procedure:
A solution of 0.33 g (0.77 mmole) of 4-benzyl-2-(S)-(3,5-dichlorobenzyloxy)-3-(S)-phenylmorpholine (from Example 44, Step B) and 0.22 g (1.54 mmole) of 1-chloroethyl chloroformate in 4.5 mL of 1,2-dichloroethane was placed in a pressure vial which was lowered into an oil bath which was heated to 110° C. After stirring for 60 hr the solution was cooled and concentrated in vacuo. The residue was dissolved in 7 mL of methanol and the resulting solution was heated at reflux for 30 min. The mixture was cooled and treated with several drops of concentrated aqueous ammonia and the solution was concentrated. The residue was partly purified by flash chromatography on 67 g of silica eluting with 1.5 L of 100:1 methylene chloride: methanol, and the rich cuts were purified by flash chormatography on 32 g of silica eluting with 50:50 hexanes: ethyl acetate and then 50:50:5 hexanes:ethyl acetate:methanol to give 0.051 g (20%)of an oil, which by 1H NMR was pure cis morpholine.
Reaction SMILES: [CH:1]([C:4](=[CH:7][CH2:8][CH:9]([CH3:11])[CH3:10])[CH:5]=[O:6])([CH3:3])[CH3:2].C([O-])(O)=O.[Na+].N#N>[Pd].C(O)C>[CH:1]([CH:4]([CH2:7][CH2:8][CH:9]([CH3:11])[CH3:10])[CH:5]=[O:6])([CH3:3])[CH3:2]
Reactant: CC(C)CC=C(C=O)C(C)C
Agent: [Pd]
Agent: N#N
Agent: O=C([O-])O
Solvent: CCO
Product: CC(C)CCC(C=O)C(C)C
Temperature: 25 °C

Procedure:
To 10 g 2-isopropyl-5-methyl-2-hexenal synthesized above were added 70 ml ethanol, 1 ml saturated NaHCO3 solution and 0.25 g 10% Pd on carbon. N2 was introduced, follwed by H2, and the apparatus was connected with a graduated titration tube filled with H2. The reaction was allowed to continue with stirring at room temperature and atmosphere pressure until the absorption of H2 reached calculation value. The reaction mixture was filtered and the filtrate was used in the next step.
Reaction SMILES: Br[C:2]1[S:3][C:4]([NH:32]C(=O)OC(C)(C)C)=[C:5]([C:7](=[O:31])[NH:8][C:9]2[CH:10]=[N:11][N:12]([CH3:30])[C:13]=2[C@@H:14]2[CH2:20][CH2:19][C@@H:18]([NH:21]C(OC(C)(C)C)=O)[C@H:17]([F:29])[CH2:16][O:15]2)[N:6]=1.[F:40][C:41]1[C:42]([C:50]([F:53])([F:52])[F:51])=[C:43](B(O)O)[CH:44]=[CH:45][CH:46]=1>>[NH2:32][C:4]1[S:3][C:2]([C:43]2[CH:44]=[CH:45][CH:46]=[C:41]([F:40])[C:42]=2[C:50]([F:51])([F:53])[F:52])=[N:6][C:5]=1[C:7]([NH:8][C:9]1[CH:10]=[N:11][N:12]([CH3:30])[C:13]=1[C@@H:14]1[CH2:20][CH2:19][C@@H:18]([NH2:21])[C@H:17]([F:29])[CH2:16][O:15]1)=[O:31]
Reactant: Cn1ncc(NC(=O)c2nc(Br)sc2NC(=O)OC(C)(C)C)c1[C@@H]1CC[C@@H](NC(=O)OC(C)(C)C)[C@H](F)CO1
Reactant: OB(O)c1cccc(F)c1C(F)(F)F
Product: Cn1ncc(NC(=O)c2nc(-c3cccc(F)c3C(F)(F)F)sc2N)c1[C@@H]1CC[C@@H](N)[C@H](F)CO1

Procedure:
Following the procedure for Example 101 starting from tert-butyl N-[2-bromo-4-[[5-[(2S,5R,6S)-5-(tert-butoxycarbonylamino)-6-fluoro-oxepan-2-yl]-1-methyl-pyrazol-4-yl]carbamoyl]thiazol-5-yl]carbamate (Intermediate 95), and replacing 3,6-dihydro-2H-pyran-4-boronic acid pinacol ester with (3-fluoro-2-(trifluoromethyl)phenyl)boronic acid gave 336. 1H NMR (400 MHz, DMSO-d6) δ 9.13 (s, 1H), 7.85-7.77 (m, 1H), 7.72 (s, 1H), 7.66-7.57 (m, 1H), 7.54 (d, J=7.8 Hz, 1H), 7.44 (s, 2H), 4.81-4.73 (m, 1H), 4.63-4.44 (m, 1H), 4.22-4.10 (m, 1H), 4.08-3.91 (m, 1H), 3.76 (s, 3H), 2.10-2.00 (m, 1H), 1.90-1.73 (m, 3H). LCMS (ES+) m/z 517 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[N:5]=[C:4]([NH2:9])[CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].[F:16][C:17]([F:28])([F:27])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1B(O)O.C(Cl)Cl>COCCOC.O.CCOC(C)=O>[Cl:1][C:2]1[CH:7]=[C:6]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[C:17]([F:28])([F:27])[F:16])[N:5]=[C:4]([NH2:9])[CH:3]=1
Reactant: OB(O)c1ccccc1C(F)(F)F
Reactant: Nc1cc(Cl)cc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Solvent: O
Solvent: COCCOC
Product: Nc1cc(Cl)cc(-c2ccccc2C(F)(F)F)n1
Temperature: 80 °C
Reaction time: 0.25 h

Procedure:
A solution of 4,6-dichloro-pyridin-2-ylamine (1.00 g, 6.14 mmol) in DME (75 mL) and water (50 mL) was treated with Cs2CO3 (6.00 g, 18.4 mmol) and 2-(trifluoromethyl)phenylboronic acid (1.52 g, 7.98 mmol). The resulting mixture was degassed by heating under a stream of Ar. Cl2Pd(dppf).DCM (270 mg, 0.368 mmol) was added, and the mixture was heated to 80° C. for 24 h. The cooled mixture was diluted with EtOAc (70 mL) and washed twice with water (50 mL). The combined aqueous layers were extracted twice with EtOAc (50 mL). The combined organic extracts were dried over MgSO4 and concentrated in vacuo. The residue was purified on a 115-g SEPRA Si 35 SPE silica column (Flow rate=30 mL/min; Eluent=EtOAc-hexanes, 1:19 for 15 min, 1:19 to 1:3 over 40 min, then 1:3 until product eluted) to yield 4-chloro-6-(2-trifluoromethyl-phenyl)-pyridin-2-ylamine as an off-white solid. 1H-NMR (400 MHz, CDCl3) δ: 7.74 (d, J=7.6 Hz, 1H), 7.59 (t, J=7.5 Hz, 1H), 7.50 (t, J=7.7 Hz, 1H), 7.45 (d, J=7.6 Hz, 1H), 6.77 (d, J=1.5 Hz, 1H), 6.53 (d, J=1.5 Hz, 1H), 4.59 (br. s., 2H). Mass Spectrum (LCMS, ESI pos.): Calculated for C12H8N2ClF3: 273.0 (M+H); Measured: 273.0.
Reaction SMILES: [NH:1]1[C:12](=[O:13])[C:11]2[N:9]([CH3:10])[CH:8]=[N:7][C:6]=2[N:4]([CH3:5])[C:2]1=[O:3].[Na].CS([CH2:19][CH2:20][CH2:21][C@H:22]([CH3:29])[CH2:23][CH2:24][CH:25]=[C:26]([CH3:28])[CH3:27])(=O)=O.O>CS(C)=O>[CH3:29][C@H:22]([CH2:23][CH2:24][CH:25]=[C:26]([CH3:28])[CH3:27])[CH2:21][CH2:20][CH2:19][N:1]1[C:12](=[O:13])[C:11]2[N:9]([CH3:10])[CH:8]=[N:7][C:6]=2[N:4]([CH3:5])[C:2]1=[O:3]
Reactant: Cn1cnc2c1c(=O)[nH]c(=O)n2C
Reactant: CC(C)=CCC[C@@H](C)CCCS(C)(=O)=O
Agent: [Na]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)=CCC[C@@H](C)CCCn1c(=O)c2c(ncn2C)n(C)c1=O
Temperature: 60 °C
Reaction time: 16 h
Yield: 28 %

Procedure:
To a suspension of sodium theobromine (4.05 g, 20.0 mmol) in dimethylsulfoxide (50 mL) was added 1-methanesulfonyl-4-(R)-methyl-8-methylnon-7-ene and the reaction stirred for 16 hours at 60° C. The mixture was then poured into water (100 mL) and extracted with ethyl acetate (100 mL, 2×50 mL). The organic portions were combined, dried using magnesium sulfate and the solvent evaporated to give a residue which was purified by column chromatography using ethyl acetate/hexane to yield 1.70 g (28% yield) 1-(4-(R)-Methyl-8-methylnon-7-enyl)-3,7-dimethylxanthine (inventive compound no. 2536R) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH:13]([CH:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)[CH2:14][OH:15])[C:11]3[CH:22]=[C:23]([F:27])[C:24]([F:26])=[CH:25][C:10]=3[N:9]=2)=[CH:4][CH:3]=1.[F:28][C:29]1[CH:30]=[C:31]([CH:34]=[CH:35][C:36]=1O)[C:32]#[N:33].N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH:13]([CH:16]3[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]3)[CH2:14][O:15][C:36]3[CH:35]=[CH:34][C:31]([C:32]#[N:33])=[CH:30][C:29]=3[F:28])[C:11]3[CH:22]=[C:23]([F:27])[C:24]([F:26])=[CH:25][C:10]=3[N:9]=2)=[CH:4][CH:3]=1
Reactant: N#Cc1ccc(O)c(F)c1
Reactant: OCC(C1CCCCC1)n1c(-c2ccc(Cl)cc2)nc2cc(F)c(F)cc21
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Product: N#Cc1ccc(OCC(C2CCCCC2)n2c(-c3ccc(Cl)cc3)nc3cc(F)c(F)cc32)c(F)c1
Yield: 89 %

Procedure:
The title compound was prepared in analogy to Example 4, intermediate, from 2-[2-(4-chloro-phenyl)-5,6-difluoro-benzoimidazol-1-yl]-2-cyclohexyl-ethanol (Ex. 1, int. c) and 3-fluoro-4-hydroxybenzonitrile (commercially available) and replacing di-ethyl azodicarboxylate by di-tert-butyl azodicarboxylate. The resulting solid was purified by silica gel chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of n-heptane and ethyl acetate (100:0 to 50:50) to give the desired compound as a colorless foam (89%). MS (Turbo Spray): m/z=510.3 [M+H].
Reaction SMILES: [CH:1]12[CH2:9][CH:5]([NH:6][C:7]1=O)[CH2:4][CH2:3][CH2:2]2.P(Cl)(Cl)(Cl)=O.[Cl:15][C:16]1[CH:17]=[C:18]([NH2:26])[C:19](=[C:23]([Cl:25])[CH:24]=1)[C:20](O)=[O:21].N1C2C(=CC=CC=2)C(=O)C1=O.OO.ClC1C=CC=C(C(O)=O)C=1N.C([O-])([O-])=O.[K+].[K+]>C(Cl)(Cl)Cl.C(N(CC)CC)C>[Cl:25][C:23]1[CH:24]=[C:16]([Cl:15])[CH:17]=[C:18]2[C:19]=1[C:20](=[O:21])[N:6]1[CH:5]3[CH2:9][CH:1]([CH2:2][CH2:3][CH2:4]3)[C:7]1=[N:26]2
Reactant: O=C1NC2CCCC1C2
Reactant: Nc1cc(Cl)cc(Cl)c1C(=O)O
Agent: Nc1c(Cl)cccc1C(=O)O
Agent: O=C([O-])[O-]
Agent: O=C1Nc2ccccc2C1=O
Solvent: CCN(CC)CC
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Product: O=c1c2c(Cl)cc(Cl)cc2nc2n1C1CCCC2C1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 3.82 g of 6-azabicyclo[3,2,1]-octan-7-one (R. L. Augustine and L. A. Bag, J. Org. Chem., 40:1074 (1975)) in 25 mL of chloroform was added 4 mL of phosphorus oxychloride. After the mildly exothermic reaction ceased, the mixture was stirred at room temperature for 4 hours. 6.3 g of 4,6-dichloroanthranilic acid (prepared from the corresponding isatine: T. Sandmeyer, Helv. Chim. Acta, 2:234 (1919), by oxidation with alkaline hydrogen peroxide, following the procedure described by Baker, et al., J. Org. Chem., 17:141 (1952) for the synthesis of 3-chloroanthranilic acid) was dissolved in a mixture of 50 mL of chloroform and 10 mL of triethylamine. This solution was added to the stirred above solution of the imidoyl chloride at such a rate as to prevent boiling over (exothermic!), approximately 2 minutes. Then the mixture was stirred at room temperature for 4 hours and then refluxed for 3 days. Then the dark brown mixture was treated with 200 mL of 10% aqueous K2CO3. The chloroform layer was separated, aqueous layer was extracted two times with 50 mL of chloroform. The combined chloroform extract was dried with anhydrous potassium carbonate, filtered, and concentrated in vacuo. The residue was chromatographed on silica gel, using 8:1 chloroform-ethyl acetate as eluent. The corresponding fractions were concentrated in vacuo, giving a crystalline solid. This was recrystallized from ethyl acetate-hexane, giving colorless crystals.
Reaction SMILES: C(OC([N:11]1[CH:16]=[CH:15][CH:14]([C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)[CH2:13][CH2:12]1)=O)C1C=CC=CC=1.[H][H]>C(O)C.[Pd]>[N:19]1[CH:20]=[CH:21][CH:22]=[C:17]([CH:14]2[CH2:15][CH2:16][NH:11][CH2:12][CH2:13]2)[CH:18]=1
Reactant: O=C(OCc1ccccc1)N1C=CC(c2cccnc2)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: c1cncc(C2CCNCC2)c1
Reaction time: 16 h

Procedure:
A solution of 1-benzyloxycarbonyl-4-(3-pyridyl)-1,2,3,4-tetrahydropyridine (0.714 in ethanol (50 mL) was treated with 10% palladium on carbon (0.1 g) and hydrogenated under a hydrogen atmosphere at room temperature and 3.44 bar for 16 hours. The reaction mixture was filtered through diatomaceous earth to remove the catalyst, and the resulting filtrate was evaporated to afford the piperidine (0.393 g); NMR (CDCl3): 1.7 (m, 4), 2.8 (m, 4), 3.2 (m, 2), 7.3 (m, 1), 7.5 (m, 1), 8.5 (m, 2); MS: m/z=162(M+1).
Reaction SMILES: CC1(C)[O:7][CH2:6][CH:5]([CH2:8][O:9][C:10]2[C:15]([CH3:16])=[CH:14][C:13]([C:17]3[N:21]=[C:20]([C:22]4[S:29][C:28]([CH3:30])=[C:27]5[C:23]=4[CH2:24][C@H:25]4[C:31]([CH3:33])([CH3:32])[C@H:26]45)[O:19][N:18]=3)=[CH:12][C:11]=2[CH3:34])[CH2:4][O:3]1.Cl.C(NCC)C>C(O)(=O)C.O.C1COCC1.C(O)(C)C>[CH3:16][C:15]1[CH:14]=[C:13]([C:17]2[N:21]=[C:20]([C:22]3[S:29][C:28]([CH3:30])=[C:27]4[C:23]=3[CH2:24][C@H:25]3[C:31]([CH3:32])([CH3:33])[C@H:26]34)[O:19][N:18]=2)[CH:12]=[C:11]([CH3:34])[C:10]=1[O:9][CH2:8][CH:5]([CH2:4][OH:3])[CH2:6][OH:7]
Reactant: Cc1cc(-c2noc(-c3sc(C)c4c3C[C@@H]3[C@H]4C3(C)C)n2)cc(C)c1OCC1COC(C)(C)OC1
Agent: Cl
Solvent: O
Solvent: CC(C)O
Solvent: C1CCOC1
Product: Cc1cc(-c2noc(-c3sc(C)c4c3C[C@@H]3[C@H]4C3(C)C)n2)cc(C)c1OCC(CO)CO
Temperature: 25 °C
Reaction time: 3 h
Yield: 40.3 %

Procedure:
A suspension of 3-[4-(2,2-dimethyl-[1,3]dioxan-5-ylmethoxy)-3,5-dimethyl-phenyl]-5-((1aS,5aR)-1,1,2-trimethyl-1,1a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalen-4-yl)-[1,2,4]oxadiazole (135 mg, 0.273 mmol) in acetic acid/water 4:1 (4 mL) and THF (2 mL) is stirred at rt for 3 h. Then, approx. 6 N HCl in isopropanol (1 mL) is added and stirring is continued for 30 min. Diethylamine (0.2 mL) is added to the mixture which is then purified by prep. HPLC (Grom-Sil 120 ODS-4-HE, 30×75 mm, 10 um, acetonitile/water (0.5% HCOOH), 20% to 95% acetonitrile) to give 2-{2,6-dimethyl-4-[5-((1aS,5aR)-1,1,2-trimethyl-1,1a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalen-4-yl)-[1,2,4]oxadiazol-3-yl]-phenoxymethyl}-propane-1,3-diol (50 mg) as a colourless resin; LC-MS: tR=1.12 min, [M+1]+=455.22; 1H NMR (CDCl3): δ 7.78 (s, 2H), 4.05-4.00 (m, 4H), 3.98-3.94 (m, 2H), 3.11 (dd, J=6.4, 18.8 Hz, 1H), 2.94 (d, J=18.8 Hz, 1H), 2.43 (s, 3H), 2.35 (s, 6H), 2.32-2.23 (m, 1H), 2.14 (s br, 2H), 2.00-1.92 (m, 2H), 1.15 (s, 3H), 0.76 (s, 3H).
Reaction SMILES: [CH3:1][N:2]([CH:18]1[CH2:23][CH2:22][N:21]([CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:20][CH2:19]1)[C:3](=[O:17])[C:4]1[CH:9]=[C:8]([Cl:10])[C:7]([NH:11]C(=O)C)=[CH:6][C:5]=1[O:15][CH3:16].Cl>O>[ClH:10].[CH3:1][N:2]([CH:18]1[CH2:23][CH2:22][N:21]([CH2:24][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH2:20][CH2:19]1)[C:3](=[O:17])[C:4]1[CH:9]=[C:8]([Cl:10])[C:7]([NH2:11])=[CH:6][C:5]=1[O:15][CH3:16]
Reactant: COc1cc(NC(C)=O)c(Cl)cc1C(=O)N(C)C1CCN(Cc2ccccc2)CC1
Agent: Cl
Solvent: O
Product: COc1cc(N)c(Cl)cc1C(=O)N(C)C1CCN(Cc2ccccc2)CC1
Yield: 169.7 %

Procedure:
A mixture of N-methyl-N-(1-benzylpiperid-4-yl)-2-methoxy-4-acetamido-5-chlorbenzamide (12.9 g; 0.03 moles), prepared as described in Example 1, concentrated hydrochloric acid (10 ml) and water (30 ml) was boiled under reflux for 2 hours. The solution was concentrated in vacuo and the residue recrystallized from ethanol. The N-methyl-N-(1-benzylpiperid-4-yl)-2-methoxy-4-amino-5-chloro-benzamide hydrochloride (10.8 g) was obtained, m.p. 259°-260° C. (dec.)
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.O.C(=[N:16][N:17]1[C:22]([S:23][CH2:24][CH3:25])=[N:21][C:20](=[O:26])[N:19]([CH2:27][C:28]([CH3:31])([CH3:30])[CH3:29])[C:18]1=[O:32])(C)C>C(O)(C)C>[NH2:16][N:17]1[C:22]([S:23][CH2:24][CH3:25])=[N:21][C:20](=[O:26])[N:19]([CH2:27][C:28]([CH3:31])([CH3:30])[CH3:29])[C:18]1=[O:32]
Reactant: CCSc1nc(=O)n(CC(C)(C)C)c(=O)n1N=C(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)O
Solvent: O
Product: CCSc1nc(=O)n(CC(C)(C)C)c(=O)n1N
Temperature: 60 °C
Reaction time: 1 h
Yield: 91 %

Procedure:
1.1 g of p-toluenesulphonic acid and 5.4 ml of water were added to a solution of 34.1 g (0.114 mol) of 1-isopropylideneamino-6-ethylthio-3-neopentyl-1,3,5-triazine-2,4(1H, 3H)-dione (the compound of formula (V-1)) in 150 ml of isopropanol at 60° C., and the mixture was stirred for one hour at 60° C., the bulk of the reaction product crystallizing out. Approximately 80 ml of the mixture were distilled off at 200 to 300 mbars, the mixture was cooled to 0° C. and was filtered under suction, and the residue was washed with a little methanol. 26.8 g (91% of theory) of 1-amino-6-ethylthio-3-neopentyl-1,3,5-triazine-2,4(1H, 3H)-dione of melting point 202° to 204° C. were obtained.
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[C:5]([NH:10][CH:11]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:12]([OH:14])=[O:13])[CH:6]=[CH:7][C:8]=1[CH3:9].C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[N:40]12[CH2:47][CH2:46][CH:43]([CH2:44][CH2:45]1)[C@@H:42](O)[CH2:41]2>C(#N)C>[N:40]12[CH2:47][CH2:46][CH:43]([CH2:44][CH2:45]1)[C@@H:42]([O:13][C:12](=[O:14])[CH:11]([NH:10][C:5]1[CH:6]=[CH:7][C:8]([CH3:9])=[C:3]([F:2])[CH:4]=1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[CH2:41]2
Reactant: O[C@H]1CN2CCC1CC2
Reactant: Cc1ccc(NC(C(=O)O)c2ccccc2)cc1F
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(NC(C(=O)O[C@H]2CN3CCC2CC3)c2ccccc2)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.5 %

Procedure:
(3-Fluoro-4-methyl-phenylamino)-phenyl-acetic acid hydrochloride (I48) (250 mg, 0.84 mmol), 2-(1H-benzo[d][1,2,3]triazol-1-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate(V) (321 mg, 0.84 mmol), and HOBT (129 mg, 0.84 mmol) are dissolved in acetonitrile (6 mL). DIPEA (0.29 mL, 1.69 mmol) is added, followed by (R)-quinuclidin-3-ol (215 mg, 1.69 mmol) and the resulting yellow solution is stirred at RT overnight (Conversion complete by UPLC/MS-UV). MeCN is evaporated, the residue is dissolved in EtOAc and washed with sat. NaHCO3, water and brine. The organic layer is recovered, dried over Na2SO4, filtered and evaporated. The crude compound is purified by filtration through a pad of silica using DCM/MeOH=9/1 as the eluent to obtain the title compound as a yellow oil (311 mg, quantitative yield, mixture of diastereoisomers).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].[F-].[Cs+].[CH2:15](B1OC(C)(C)C(C)(C)O1)[CH:16]=[CH2:17].O>C1COCC1.CCCCCC.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>[CH2:17]([C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11])[CH:16]=[CH2:15]
Reactant: COc1ccc(I)c([N+](=O)[O-])c1
Reactant: C=CCB1OC(C)(C)C(C)(C)O1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: O
Product: C=CCc1ccc(OC)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 51.8 %

Procedure:
To a solution of 1-iodo-4-methoxy-2-nitrobenzene (5 g, 18 mmol) in. THF (500 mL) are added cesium fluoride (11 g, 72 mmol) and Pd(PPh3)4(0.56 g, 48 mmol). The resulting mixture is stirred for 30 min at room temperature. A solution of allylboronic acid pinacol ester (5.6 mL, 33 mmol) in THF (15 mL) is added dropwise. The resulting mixture is refluxed for 24 h then diluted with hexane (100 mL) followed by water (100 mL). The product is extracted with hexane (2×100 mL). The combined organic layers are washed with water (150 mL) then brine (150 mL) and dried over Na2SO4. The solvent is removed under reduced pressure and the residue is purified by column chromatography using hexane as eluent affording 1.8 g (48%) of the title compound as a brown liquid. 1H NMR (DMSO-d6, 400 MHz) δ 7.93-7.91 (m, 1), 7.59-7.50 (m, 1H), 7.04-7.01 (m, 1H), 5.0-4.9 (m, 2H), 3.89-3.85 (m, 1H), 3.81 (s, 3H), 3.53-3.51 (m, 2H).
Reaction SMILES: [Cl-].[NH4+].O.[CH2:4]([O:8][C:9]1[CH:14]=[C:13]([Cl:15])[C:12]([O:16][CH2:17][CH2:18][CH2:19][CH3:20])=[CH:11][C:10]=1[N+:21]([O-])=O)[CH2:5][CH2:6][CH3:7]>C(O)(C)C>[CH2:4]([O:8][C:9]1[CH:14]=[C:13]([Cl:15])[C:12]([O:16][CH2:17][CH2:18][CH2:19][CH3:20])=[CH:11][C:10]=1[NH2:21])[CH2:5][CH2:6][CH3:7]
Reactant: CCCCOc1cc([N+](=O)[O-])c(OCCCC)cc1Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CC(C)O
Solvent: O
Product: CCCCOc1cc(Cl)c(OCCCC)cc1N

Procedure:
To a mixture of 84 parts of reduced iron, 8 parts of ammonium chloride, 35 parts of water and 160 parts of isopropanol was gradually added 60.3 parts of 2,5-dibutoxy-4-chloronitrobenzene under reflux to reduce the nitro compound. Post-treatment was carried out in a conventional manner to obtain 53 parts of 2,5-dibutoxy-4-chloroaniline (m.p.: 43° to 44° C.).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:25][C@H:24]([CH3:26])[O:23][C@H:22]([CH3:27])[CH2:21]3)=[CH:16][C:15]=2[CH:28]2[CH2:33][CH2:32][C:31]([CH3:35])([CH3:34])[CH2:30][CH2:29]2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(OCC)(=O)C.Cl.C(=O)([O-])[O-].[Na+].[Na+]>O.ClCCl>[CH3:34][C:31]1([CH3:35])[CH2:30][CH2:29][CH:28]([C:15]2[CH:16]=[C:17]([N:20]3[CH2:25][C@H:24]([CH3:26])[O:23][C@H:22]([CH3:27])[CH2:21]3)[CH:18]=[CH:19][C:14]=2[N:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)[CH2:33][CH2:32]1
Reactant: C[C@@H]1CN(c2ccc(N3CCN(C(=O)OC(C)(C)C)CC3)c(C3CCC(C)(C)CC3)c2)C[C@H](C)O1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: ClCCl
Product: C[C@@H]1CN(c2ccc(N3CCNCC3)c(C3CCC(C)(C)CC3)c2)C[C@H](C)O1
Temperature: 25 °C
Yield: 87.9 %

Procedure:
To cis-4-[2-(4,4-dimethylcyclohexyl)-4-(2,6-dimethylmorpholin-4-yl)phenyl]piperazine-1-carboxylic acid t-butyl ester (648 mg, 1.33 mmol) produced in Example (61a) was added a mixed solvent of ethyl acetate (5 mL)-dichloromethane (1 mL), followed by stirring at room temperature under a nitrogen atmosphere. A 4N solution of hydrogen chloride in ethyl acetate (5 mL, 20 mmol) was added dropwise thereto, followed by stirring for 17 hours under the same conditions. Saturated aqueous solution of sodium carbonate was added to the reaction mixture to make the mixture basic. Dichloromethane and water were added thereto and extraction was performed with dichloromethane. The separated organic layer was washed with brine and then dried over anhydrous sodium sulfate. The desiccant was filtered off and the filtrate was concentrated under reduced pressure. The resultant residue was purified by NH silica gel column chromatography (ethyl acetate/hexane) to give 451 mg of the title compound as light yellow crystals.