Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH3:13][C:14]1[CH:15]=[N:16][C:17]2[CH2:18][CH2:19][CH2:20][CH2:21][C:22]=2[C:23]=1[CH3:24].C[Si]([N:29]=[C:30]=[S:31])(C)C>C1C=CC=CC=1>[CH3:13][C:14]1[CH:15]=[N:16][C:17]2[CH:18]([C:30](=[S:31])[NH2:29])[CH2:19][CH2:20][CH2:21][C:22]=2[C:23]=1[CH3:24]
Reactant: C[Si](C)(C)N=C=S
Reactant: Cc1cnc2c(c1C)CCCC2
Agent: [Li]CCCC
Solvent: c1ccccc1
Solvent: CC(C)NC(C)C
Product: Cc1cnc2c(c1C)CCCC2C(N)=S
Yield: 5.3 %

Procedure:
By the method described in Example 11 using di-isopropylamine (4.9 ml 0.034 mol) in benzene (50 ml), n-butyl lithium solution (9% w/v, 25 ml, 0.034 mol), 3,4-dimethyl-5,6,7,8-tetrahydroquinoline (5.65g, 0.034 mol) and trimethylsilyl isothiocyanate (4.9 ml, 0.038 mol) was obtained 3,4-dimethyl-5,6,7,8-tetrahydroquinoline-8-thiocarboxamide (0.4 g, 5%) m.p. 163-5° C.
Reaction SMILES: [CH:1]1([CH2:4][C:5]2([C:11]([O:13][CH2:14][CH3:15])=[O:12])SCCCS2)[CH2:3][CH2:2]1.BrN1C(=[O:22])CCC1=O>>[CH:1]1([CH2:4][C:5](=[O:22])[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:3][CH2:2]1
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)C1(CC2CC2)SCCCS1
Product: CCOC(=O)C(=O)CC1CC1

Procedure:
A fifth aspect of this invention is a process for the preparation of ethyl 3-cyclopropyl-2,2-difluoropropanoate, which process comprises: (a) reacting bromomethylcyclopropane with 2-carboethoxy-1,3-dithiane in the presence of strong base to give ethyl 2-(cyclopropylmethyl)-1,3-dithiane-2-carboxylate; (b) reacting the ethyl 2-(cyclopropylmethyl)-1,3-dithiane-2-carboxylate with N-bromosuccinimide to give ethyl 3-cyclopropyl-2-oxopropanoate; and (c) reacting the ethyl 3-cyclopropyl-2-oxopropanoate with a fluorinating agent.
Reaction SMILES: [BH4-].[Na+].[CH3:3][NH:4][CH:5]1[CH2:11][CH2:10][C:9]2[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=2[C:7](=[O:16])[CH2:6]1>O.C(O)C>[CH3:3][NH:4][CH:5]1[CH2:11][CH2:10][C:9]2[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=2[CH:7]([OH:16])[CH2:6]1
Reactant: CNC1CCc2ccccc2C(=O)C1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CNC1CCc2ccccc2C(O)C1
Reaction time: 0.5 h
Yield: 104.2 %

Procedure:
A solution of 47.5g of sodium borohydride in 475 ml of water was slowly added to a solution of 47.5 g of the product of Step A in 2.4 liters of ethanol and the mixture was stirred for 2 1/2 hours and then was concentrated to 500 ml. The mixture was poured into 2 liters of aqueous sodium chloride solution and the mixture was extracted with ethyl acetate. The organic phase was washed with aqueous sodium chloride solution, dried and evaporated to dryness to obtain 50 g of raw 7-methylamino-5-hydroxy-6,7,8,9-tetrahydro [5H] benzocycloheptene which was used as is for the next step.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH:7][C:8]2[CH:9]=[C:10]([OH:14])[CH:11]=[CH:12][CH:13]=2)[S:5][CH:6]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:22][CH:23]=[C:24]([CH3:26])[CH3:25]>CC(C)=O>[CH3:1][C:2]1[N:3]=[C:4]([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH2:22][CH:23]=[C:24]([CH3:26])[CH3:25])[CH:9]=2)[S:5][CH:6]=1
Reactant: Cc1csc(Nc2cccc(O)c2)n1
Reactant: CC(C)=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)=CCOc1cccc(Nc2nc(C)cs2)c1
Yield: 59 %

Procedure:
Following the procedure general for O-alkylation, Method A, a mixture of 3-(4-methylthiazol-2-ylamino)phenol (74 mg, 0.36 mmol) and K2CO3 (55 mg, 0.39 mmol) in acetone (3.6 mL) was treated with 4-bromo-2-methyl-2-butene (0.05 mL, 0.43 mmol). The reaction mixture was heated at reflux for 4 h. The title compound was obtained after purification by flash chromatography on silica gel (hexane:EtOAc 7/3) in 59% yield (58 mg).
Reaction SMILES: Cl.Cl.[S:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[N:5]=[C:4]1[NH:12][C:13]([C:15]1[CH:16]=[CH:17][CH:18]=[C:19]2[C:24]=1[CH2:23][NH:22][CH2:21][CH2:20]2)=[O:14].Cl[C:26]1[S:27][C:28]([CH:32]=[O:33])=[C:29]([Cl:31])[N:30]=1.C([O-])([O-])=O.[Cs+].[Cs+].O>CC(N(C)C)=O>[S:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[N:5]=[C:4]1[NH:12][C:13]([C:15]1[CH:16]=[CH:17][CH:18]=[C:19]2[C:24]=1[CH2:23][N:22]([C:26]1[S:27][C:28]([CH:32]=[O:33])=[C:29]([Cl:31])[N:30]=1)[CH2:21][CH2:20]2)=[O:14]
Reactant: O=C(Nc1nc2ccccc2s1)c1cccc2c1CNCC2
Reactant: O=Cc1sc(Cl)nc1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: O=Cc1sc(N2CCc3cccc(C(=O)Nc4nc5ccccc5s4)c3C2)nc1Cl
Temperature: 60 °C
Yield: 92.3 %

Procedure:
A mixture of compound 1B (3.82 g, 10 mmol), 2,4-dichlorothiazole-5-carbaldehyde (1.82 g, 10 mmol), and Cs2CO3 (9.77 g, 30 mmol) in DMA (30 mL) was heated at 60° C. for 8 hours, cooled to rt and then poured into water (500 mL). The solid was collected by filtration and dried in a vacuum oven overnight (60° C.) to provide 4.2 g of the desired product (45A): 1H NMR (DMSO-d6): δ 12.66 (s, 1H), 9.69 (s, 1H), 8.00 (d, J=7.82 Hz, 1H), 7.77 (d, J=8.06 Hz, 1H), 7.73 (d, J=7.58 Hz, 1H), 7.40-7.49 (m, 3H), 7.33-7.36 (m, 1H), 5.04 (s, 2H), 3.82 (t, J=5.92 Hz, 2H), 3.11 (t, J=6.16 Hz, 2H). MS (ESI(+)): m/z 455 (M+H).
Reaction SMILES: FC(F)(F)C(O)=O.[OH:8][C:9]1[CH:10]=[C:11]([NH:21][C:22]2[N:27]=[C:26]3[N:28](C4CCCCO4)[N:29]=[CH:30][C:25]3=[C:24]([C:37]3[CH:38]=[C:39]([NH:43][C:44](=[O:47])[CH:45]=[CH2:46])[CH:40]=[CH:41][CH:42]=3)[N:23]=2)[CH:12]=[CH:13][C:14]=1[N:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1>C(Cl)Cl>[OH:8][C:9]1[CH:10]=[C:11]([NH:21][C:22]2[N:27]=[C:26]3[NH:28][N:29]=[CH:30][C:25]3=[C:24]([C:37]3[CH:38]=[C:39]([NH:43][C:44](=[O:47])[CH:45]=[CH2:46])[CH:40]=[CH:41][CH:42]=3)[N:23]=2)[CH:12]=[CH:13][C:14]=1[N:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1
Reactant: C=CC(=O)Nc1cccc(-c2nc(Nc3ccc(N4CCOCC4)c(O)c3)nc3c2cnn3C2CCCCO2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C=CC(=O)Nc1cccc(-c2nc(Nc3ccc(N4CCOCC4)c(O)c3)nc3[nH]ncc23)c1
Temperature: 25 °C
Reaction time: 10 h
Yield: 51.9 %

Procedure:
2,2,2-trifluoroacetic acid (526 mg, 4.62 mmol) was added to a solution of N-(3-(6-((3-hydroxy-4-morpholinophenyl)amino)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)phenyl)acrylamide (100 mg, 0.185 mmol) in DCM (10 ml). The reaction mixture was stirred at room temperature overnight (about 8-12 h), after which the solvent was removed in vacuo. The residue was purified by flash chromatography (MeOH/DCM 5%) to yield the title compound (45 mg, 0.096 mmol, 52.2% yield) as a solid. 1NMR (CD3OD, 400 MHz): 8.98 (s, 1H), 8.39 (s, 1H), 8.05 (d, 1H, J=7.2 Hz), 7.94 (s, 1H), 7.62 (d, 1H, J=8.4 Hz), 7.56 (t, 1H, J=8.0 Hz), 7.36-7.29 (m, 2H), 6.54-6.43 (m, 2H), 5.85 (dd, 1H, J=2.8 & 9.6 Hz), 4.03 (m, 4H), 3.54 (m, 4H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([CH3:14])([CH2:12][OH:13])[CH2:10][OH:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:15](OC=C)(=[O:21])[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]>C(OC(C)C)(C)C>[C:1]([O:5][C:6]([NH:8][C@@:9]([CH3:14])([CH2:10][O:11][C:15](=[O:21])[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH2:12][OH:13])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(CO)(CO)NC(=O)OC(C)(C)C
Reactant: C=COC(=O)CCCCC
Solvent: CC(C)OC(C)C
Product: CCCCCC(=O)OC[C@@](C)(CO)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 84.6 %

Procedure:
2-t-Butoxycarbonylamino-2-methylpropane-1,3-diol (20.0 g, 97.4 mmol) was suspended in isopropyl ether (200 mL), and 16.3 mL (0.100 mol) of vinyl hexanoate and lipase [Immobilized lipase from Pseudomonas sp., manufactured by TOYOBO Co., Inc., 0.67 U/mg] (0.8 g) were added thereto, followed by stirring of the mixture at room temperature for 2 hours. After the reaction mixture was filtered, the filtrate was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate, 10:1-2:1) to obtain the title compound (25.0 g, yield: 85%).
Reaction SMILES: [CH:1]1[C:14]2[CH2:13][C@H:12]3[NH:15][CH2:16][CH2:17][C@:6]4([C@H:11]3[CH2:10][CH2:9][CH2:8][CH2:7]4)[C:5]=2[CH:4]=[C:3]([C:18](=[O:20])[CH3:19])[CH:2]=1.C(N(CC)CC)C.[C:28](#[N:31])[CH:29]=[CH2:30]>C(O)C>[C:18]([C:3]1[CH:2]=[CH:1][C:14]2[CH2:13][C@H:12]3[N:15]([CH2:30][CH2:29][C:28]#[N:31])[CH2:16][CH2:17][C@@:6]4([C:5]=2[CH:4]=1)[C@H:11]3[CH2:10][CH2:9][CH2:8][CH2:7]4)(=[O:20])[CH3:19]
Reactant: CC(=O)c1ccc2c(c1)[C@@]13CCCC[C@H]1[C@@H](C2)NCC3
Reactant: C=CC#N
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC(=O)c1ccc2c(c1)[C@@]13CCCC[C@H]1[C@@H](C2)N(CCC#N)CC3
Yield: 94.7 %

Procedure:
To a mixture of 1.5 g of (-)-1-(morphinan-3-yl)ethanone, 2.3 g of triethylamine and 35 ml of absolute ethanol, was added 0.35 g of acrylonitrile. After the mixture had been heated at reflux for 16 hours the solvent and excess of reagents were removed under reduced pressure to give 1.7 g (94%) of crude (-)-3-acetyl-17-morphinanpropanenitrile. For analysis, a sample of this compound was distilled, bp 220°-230° (0.05 mm), [α]25D-65.5° (c 1.03, MeOH).
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][C:3]=1[N:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:25][CH2:26][O:27][CH3:28].Cl>C(#N)C>[F:1][C:2]1[C:7]([C:8]([F:9])([F:10])[F:11])=[CH:6][CH:5]=[CH:4][C:3]=1[N:12]1[CH2:13][CH2:14][N:15]([CH2:25][CH2:26][O:27][CH3:28])[CH2:16][CH2:17]1
Reactant: COCCBr
Reactant: Fc1c(N2CCNCC2)cccc1C(F)(F)F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COCCN1CCN(c2cccc(C(F)(F)F)c2F)CC1

Procedure:
Preparation according to Example 1: 1-[2-fluoro-3-(trifluoro-methyl)phenyl]piperazine (0.5 g, 2.0 mmol), acetonitrile (25 ml), potassium carbonate (0.42 g, 3.0 mmol) and 1-bromo-2-methoxyethane (0.189 ml, 2.0 mmol). Yield: 0.26 g (42%). The amine was converted to the hydrochloric acid salt and recrystallized from ethanol/diethyl ether: M.p. 170-171° C. MS m/z (relative intensity, 70 eV) 306 (M+, 9), 262 (13), 261 (bp), 218 (23), 190 (23).
Reaction SMILES: Cl.[C:2]1([C:8]2[CH:9]=[C:10]3[C:14](=[C:15]([C:17]([NH2:19])=[O:18])[CH:16]=2)[NH:13][N:12]=[C:11]3[CH:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:26]([S:29](Cl)(=[O:31])=[O:30])([CH3:28])[CH3:27].C(N(CC)CC)C>CN(C1C=CN=CC=1)C.CN(C=O)C>[CH3:27][CH:26]([S:29]([N:23]1[CH2:24][CH2:25][CH:20]([C:11]2[C:10]3[C:14](=[C:15]([C:17]([NH2:19])=[O:18])[CH:16]=[C:8]([C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)[CH:9]=3)[NH:13][N:12]=2)[CH2:21][CH2:22]1)(=[O:31])=[O:30])[CH3:28]
Reactant: CC(C)S(=O)(=O)Cl
Reactant: NC(=O)c1cc(-c2ccccc2)cc2c(C3CCNCC3)n[nH]c12
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)S(=O)(=O)N1CCC(c2n[nH]c3c(C(N)=O)cc(-c4ccccc4)cc23)CC1
Yield: 20.7 %

Procedure:
This compound was prepared in a fashion analogous to the procedure described in Example 3. Thus, 5-phenyl-3-(4-piperidinyl)-1H-indazole-7-carboxamide hydrochloride (0.057 g, 0.17 mmol) was reacted with isopropylsulfonyl chloride (0.02 mL, 0.17 mmol) in the presence of triethylamine (0.1 mL, 0.71 mmol) and DMAP (0.0021 g, 0.017 mmol) in DMF (3 mL) to give 0.015 g of a white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([NH2:14])[C:7]([NH2:13])=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11])([O-:3])=[O:2].[F:15][C:16]([F:23])([F:22])[CH:17]([OH:21])[C:18](O)=O.Cl.C(=O)(O)[O-].[Na+]>O.C(OCC)(=O)C>[N+:1]([C:4]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][C:7]2[NH:13][C:18]([CH:17]([OH:21])[C:16]([F:23])([F:22])[F:15])=[N:14][C:6]=2[CH:5]=1)([O-:3])=[O:2]
Reactant: Nc1cc([N+](=O)[O-])c([N+](=O)[O-])cc1N
Reactant: O=C(O)C(O)C(F)(F)F
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1cc2nc(C(O)C(F)(F)F)[nH]c2cc1[N+](=O)[O-]
Temperature: 108 °C

Procedure:
4,5-Dinitro-benzene-1,2-diamine (2.01 g; 10.2 mmoles) and 3,3,3-trifluoro-2-hydroxy-propionic acid (2.22 g; 15.4 mmoles) were suspended in 6N HCl (5 mL; 30 mmoles) and water (4 mL) under a nitrogen atmosphere. The reaction was stirred vigorously and heated to 108° C. for 18 hrs, then cooled to room temperature. The reaction was diluted with water (40 mL) and with ethyl acetate (40 mL), then sodium bicarbonate (3.79 g; 45.0 mmoles) was added slowly and in portions to quench the reaction. The aqueous layer was separated and extracted with ethyl acetate (3×30 mL). The extracts were combined, washed with water (30 mL) and brine (40 mL), then dried over Na2SO4. The filtrate was concentrated in vacuo to yield a crude brown solid which was then purified by column chromatography (SiO2; 30% ethyl acetate/CH2Cl2) to yield the title compound as a brown solid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[CH:4][CH:3]=1.CCOCC>C(O)C>[OH:1][C@H:2]1[CH2:3][CH2:4][C@H:5]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15])[CH2:6][CH2:7]1
Reactant: O=C(O)CCCCCCc1ccc(O)cc1
Solvent: CCO
Solvent: CCOCC
Product: O=C(O)CCCCCC[C@H]1CC[C@H](O)CC1
Yield: 34.1 %

Procedure:
7-(4-Hydroxyphenyl)heptanoic acid (20 g) is subjected to similar catalytic reduction as Reference Example 5 in 80% ethanol. Ether is added to the crude product to give crystals. Recrystallization from ethanol-water and then from i-propanol-ether give trans-7-(4-hydroxycyclohexyl)heptanoic acid (7 g) as colorless needles, m.p. 123°-128° C.
Reaction SMILES: [NH2:1][C:2]1[NH:3][CH2:4][CH2:5][CH:6]=1.C([O:9][CH:10]=[C:11]([C:17](OCC)=O)[C:12]([O:14][CH2:15][CH3:16])=[O:13])C>C(O)C>[O:9]=[C:10]1[C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:17][N:3]2[CH2:4][CH2:5][CH2:6][C:2]2=[N:1]1
Reactant: NC1=CCCN1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Solvent: CCO
Product: CCOC(=O)c1cn2c(nc1=O)CCC2
Temperature: 0 °C
Reaction time: 1 h
Yield: 48.4 %

Procedure:
42 g. of 2-amino-pyrroline are dissolved in 400 ml. of ethanol and at 0°-7° C. a solution of 108 g. of diethyl ethoxy-methylene-malonate in 200 ml. ethanol is added dropwise. After the addition is completed the mixture is stirred for 1 hour at 0° C., and allowed to stand for 12 hours at -5° C. The precipitated crystals are filtered. After evaporation of the alcohol the residue is boiled with 200 ml. of benzene. After cooling the insoluble crystals are filtered off. The filtered crystals are combined and recrystallized from ethanol. 50.3 g. (48.4%) ethyl 2-oxo-2,6,7,8-tetrahydro-pyrrolo[1,2-a]pyrimidine-3-carboxylate are obtained, melting at 193° C.
Reaction SMILES: ClCCl.C([N:11]1[CH2:16][CH2:15][CH:14]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[NH:25][C:26](=[O:40])[C:27]4[N:32]([CH:33]5[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]5)[N:31]=[C:30]([CH3:39])[C:28]=4[N:29]=3)=[C:20]([O:41][CH3:42])[CH:19]=2)[CH2:13][CH2:12]1)C1C=CC=CC=1.ClC(OC(Cl)C)=O>ClCCCl>[CH:33]1([N:32]2[C:27]3[C:26](=[O:40])[NH:25][C:24]([C:21]4[CH:22]=[CH:23][C:18]([NH:17][CH:14]5[CH2:15][CH2:16][NH:11][CH2:12][CH2:13]5)=[CH:19][C:20]=4[O:41][CH3:42])=[N:29][C:28]=3[C:30]([CH3:39])=[N:31]2)[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38]1
Reactant: COc1cc(NC2CCN(Cc3ccccc3)CC2)ccc1-c1nc2c(C)nn(C3CCCCC3)c2c(=O)[nH]1
Agent: CC(Cl)OC(=O)Cl
Solvent: ClCCCl
Solvent: ClCCl
Product: COc1cc(NC2CCNCC2)ccc1-c1nc2c(C)nn(C3CCCCC3)c2c(=O)[nH]1
Temperature: 25 °C
Reaction time: 4 h
Yield: 62.3 %

Procedure:
To a 3 ml dichloromethane solution of 120 mg (0.228 mmol) of the compound obtained in Example 223, 50 μl (0.456 mmol) of 1-chloroethyl chloroformate was added, and the mixture was stirred at room temperature for 4 hours. Further, 50 μl (0.456 mmol) of 1-chloroethyl chloroformate and 3 ml of 1,2-dichloroethane were added, and the mixture was heated under reflux for 5 hours. Then, the reaction mixture was distilled under reduced pressure, 3 ml of methanol was added to the residue, and the mixture was heated under reflux for 1.5 hours. The reaction mixture was cooled to room temperature, and the solvent was distilled off under reduced pressure. An aqueous solution of sodium hydrogen carbonate was added to the residue, and the mixture was extracted with dichloromethane. The organic layer was washed with water and a saturated aqueous solution of sodium chloride, and dried over anhydrous sodium sulfate, whereafter the solvent was distilled off under reduced pressure. The residue was purified by basic silica gel column chromatography (dichloromethane/methanol=20/1) to obtain 62 mg (62%) of the captioned compound.
Reaction SMILES: [CH3:1][C:2]1([CH3:59])[C:10]2[C:5](=[CH:6][C:7]([CH2:11][O:12][CH:13]3[CH:18]([C:19]4[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][CH2:28][O:29][CH2:30][C:31]5[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=5[O:37][CH3:38])=[CH:21][CH:20]=4)[CH2:17][CH2:16][N:15]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:14]3)=[CH:8][CH:9]=2)[N:4]([CH2:46][CH2:47]OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:3]1.[N-:60]=[N+:61]=[N-:62].[Na+].O>CN(C)C=O>[N:60]([CH2:47][CH2:46][N:4]1[C:5]2[C:10](=[CH:9][CH:8]=[C:7]([CH2:11][O:12][CH:13]3[CH:18]([C:19]4[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][CH2:28][O:29][CH2:30][C:31]5[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=5[O:37][CH3:38])=[CH:21][CH:20]=4)[CH2:17][CH2:16][N:15]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:14]3)[CH:6]=2)[C:2]([CH3:1])([CH3:59])[CH2:3]1)=[N+:61]=[N-:62]
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCc2ccc3c(c2)N(CCOS(=O)(=O)c2ccc(C)cc2)CC3(C)C)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCc2ccc3c(c2)N(CCN=[N+]=[N-])CC3(C)C)cc1
Temperature: 65 °C
Reaction time: 1.5 h

Procedure:
The solution of 0.455 g of tert-butyl 3-{3,3-dimethyl-1-[2-(toluene-4-sulphonyloxy)ethyl]-2,3-dihydro-1H-indol-6-ylmethoxy}-4-{4-[3-(2-methoxybenzyloxy)propoxy]phenyl}piperidine-1-carboxylate in 5.0 ml of N,N-dimethylformamide is admixed with 0.286 g of sodium azide and stirred at 65° C. over 1.5 hours. The reaction mixture is cooled, admixed with water (40 ml) and extracted with tert-butyl methyl ether (2×40 ml). The organic phases are washed successively with water (40 ml) and brine (40 ml), dried over sodium sulphate, filtered and concentrated by evaporation. The title compound is obtained as a yellowish oil from the residue by means of flash chromatography (SiO2 60F). Rf=0.33 (1:2 EtOAc-heptane); Rt=6.56.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:20]2[C:21](=[O:25])[NH:22][C:23](=[O:24])[C:19]=2[C:18]2[C:17]3[CH:16]=[C:15]([O:26][CH3:27])[C:14]([CH2:28][CH2:29][CH2:30][CH2:31]I)=[CH:13][C:12]=3[NH:11][C:10]=2[CH:9]=1.[NH:33]1[CH2:37][CH2:36][CH2:35][CH2:34]1>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:20]2[C:21](=[O:25])[NH:22][C:23](=[O:24])[C:19]=2[C:18]2[C:17]3[CH:16]=[C:15]([O:26][CH3:27])[C:14]([CH2:28][CH2:29][CH2:30][CH2:31][N:33]4[CH2:37][CH2:36][CH2:35][CH2:34]4)=[CH:13][C:12]=3[NH:11][C:10]=2[CH:9]=1
Reactant: C1CCNC1
Reactant: COc1cc2c(cc1CCCCI)[nH]c1cc(-c3ccccc3Cl)c3c(c12)C(=O)NC3=O
Product: COc1cc2c(cc1CCCCN1CCCC1)[nH]c1cc(-c3ccccc3Cl)c3c(c12)C(=O)NC3=O
Reaction time: 2 h
Yield: 75 %

Procedure:
Reaction of the iodide (173) prepared as described in example 312 with pyrrolidine using the procedure described in example 179 except that the reaction conditions were 2 h at room temperature gave (176) (75%) as an orange powder, which was used without further purification, mp 173–178° C. 1H NMR δ [(CD3)2SO] 11.85 (s, 1H), 11.04 (br s, 1H), 8.42 (s, 1H), 7.57 (dd, J=8.0, 2.2 Hz, 1H), 7.55 (s, 1H), 7.51–7.43 (m, 3H), 7.42 (s, 1H), 3.93 (s, 3H), 2.77 (t, J=7.4 Hz, 2H), 2.24 (t, J=7.3 Hz, 2H), 2.11 (s, 6H), 1.63 (m, 2H), 1.47 (m, 2H).
Reaction SMILES: Br[CH2:2][C:3]1[CH:15]=[CH:14][C:6]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])=[CH:5][C:4]=1[N+:16]([O-:18])=[O:17].[NH:19]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C:20]([O:22][CH3:23])=[O:21].[K].O>CN(C)C=O>[C:27]([O:26][C:24]([N:19]([CH2:2][C:3]1[CH:15]=[CH:14][C:6]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])=[CH:5][C:4]=1[N+:16]([O-:18])=[O:17])[C:20]([O:22][CH3:23])=[O:21])=[O:25])([CH3:30])([CH3:29])[CH3:28]
Reactant: CC(C)(C)OC(=O)c1ccc(CBr)c([N+](=O)[O-])c1
Reactant: COC(=O)NC(=O)OC(C)(C)C
Agent: [K]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)N(Cc1ccc(C(=O)OC(C)(C)C)cc1[N+](=O)[O-])C(=O)OC(C)(C)C
Reaction time: 1 h
Yield: 72.8 %

Procedure:
To a solution of tert-butyl 4-bromomethyl-3-nitrobenzoate (2.27 g, 7.2 mmol) (Int. J. Peptide Res. 1990, 36, 31) in dimethylformamide (25 mL) was added a suspension of potassium tert-butyl methyl iminodicarboxylate (J.C.S. Perkin I 1977, 1088-90) (1.56 g, 7.3 mmol) in dimethylformamide (20 mL). The dark brown solution was stirred 1 h and poured into water (400 mL), extracted with ethyl acetate (3×100 mL) and the combined organic layers were washed with water (5×75 mL), dried (sodium sulfate) and concentrated to give a pale orange oil which was purified by flash chromatography on silica gel (20% ethyl acetate/hexane) to give the title compound (2.15 g, 73%): 1H NMR (400 MHz, CDCl3) δ 8.65 (s, 1H), 8.2 (d, 1H), 7.45 (d, 1H), 5.3 (s, 2H), 3.8 (s, 3H), 1.6 (s, 9H), 1.45 (s, 9H).
Reaction SMILES: C(N(CC)CC)C.[CH3:8][S:9](Cl)(=[O:11])=[O:10].[OH:13][CH:14]1[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][CH2:15]1.[Cl-].[Na+]>O1CCCC1>[CH3:8][S:9]([O:13][CH:14]1[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][CH2:15]1)(=[O:11])=[O:10]
Reactant: CS(=O)(=O)Cl
Reactant: CN1CCC(O)CC1
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CN1CCC(OS(C)(=O)=O)CC1
Reaction time: 2 h

Procedure:
13.3 ml of triethylamine and subsequently 7.4 ml of methanesulfonyl chloride were added, whilst ice-cooling, to a solution of 10 g of 4-hydroxy-1-methylpiperidine dissolved in 100 ml of dry tetrahydrofuran. The mixture was then stirred at 0° to 5° C. for 2 hours and then at room temperature for 1.5 hours, after which it was poured into an aqueous solution of sodium chloride and extracted with ethyl acetate. The extract was washed with an aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. The solvent was then distilled off under reduced pressure, to afford 12.74 g of the title compound as an oil.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]#[N:5].[CH3:6][C:7]1[O:13]C(C)(C)O[C:9](=[O:10])[CH:8]=1>C(N(CC)CC)C>[C:9]([O:1][CH2:2][CH2:3][C:4]#[N:5])(=[O:10])[CH2:8][C:7]([CH3:6])=[O:13]
Reactant: N#CCCO
Reactant: CC1=CC(=O)OC(C)(C)O1
Solvent: CCN(CC)CC
Product: CC(=O)CC(=O)OCCC#N

Procedure:
A mixture of 16.33 g (0.23 mole) of 3-hydroxy-propionitrile and 28.4 g (0.20 mole) of 2,2,6-trimethyl-1,3-dioxen-4-one in the presence of 0.1 ml of triethylamine is heated to 90°-100° C. for 4 hrs 30 mins.
Reaction SMILES: [CH2:1]([C:3]1[CH:11]=[CH:10][C:9]2[NH:8][C:7]3[CH2:12][CH2:13][N:14]([CH3:16])[CH2:15][C:6]=3[C:5]=2[CH:4]=1)[CH3:2].[OH-].[K+].[CH3:19][C:20]1[CH:25]=[CH:24][C:23]([CH:26]=[CH2:27])=[CH:22][N:21]=1>CN1CCCC1=O.O>[CH2:1]([C:3]1[CH:11]=[CH:10][C:9]2[N:8]([CH2:27][CH2:26][C:23]3[CH:22]=[N:21][C:20]([CH3:19])=[CH:25][CH:24]=3)[C:7]3[CH2:12][CH2:13][N:14]([CH3:16])[CH2:15][C:6]=3[C:5]=2[CH:4]=1)[CH3:2]
Reactant: CCc1ccc2[nH]c3c(c2c1)CN(C)CC3
Reactant: C=Cc1ccc(C)nc1
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Solvent: O
Product: CCc1ccc2c(c1)c1c(n2CCc2ccc(C)nc2)CCN(C)C1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 20.4 %

Procedure:
To a solution of 8-Ethyl-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (0.107 g, 0.5 mmol) in N-methyl 2-pyrolidone (2 mL) was added powdered potassium hydroxide (0.224 g, 4.0 mmol) and allowed to stir for 10 min at RT. 2-methyl-5-vinyl pyridine (0.065 g, 0.55 mmol) was added and stirred for further 24 h. at 120 deg C., After completion of TLC, Reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (3×50 mL). The organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure. The crude was purified through column chromatography (8% MeOH:DCM in silica 100-200 mesh, Diameter of column—2.5 cm, Height of silica—approx. 5 inch) to provide the desired compound as brown oil (0.034 g, 20% yield). 8-Ethyl-2-methyl-5-[2-(6-methyl-pyridin-3-yl)-ethyl]-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (0.034 g, 0.102 mmol) was dissolved in THF (0.5 mL). A solution of oxalic acid dihydrate (0.013 g, 0.102 mol) in THF (0.5 mL) was added and stirred for 30 min at RT, Precipitate obtained was filtered and dried to give oxalate salt as off white solid (0.015 g, 32% yield).