Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[N:7]1[CH2:12][CH2:11][N:10]([CH2:13][C:14]#[C:15][CH2:16][N:17]2[C:26](=[O:27])[CH2:25][C:20]3([CH2:24][CH2:23][CH2:22][CH2:21]3)[CH2:19][C:18]2=[O:28])[CH2:9][CH2:8]1.[H][H].C1C2(CC(=O)NC(=O)C2)CCC1>S1C=CC=C1.[Pd]>[N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[N:7]1[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][CH2:15][CH2:16][N:17]2[C:26](=[O:27])[CH2:25][C:20]3([CH2:24][CH2:23][CH2:22][CH2:21]3)[CH2:19][C:18]2=[O:28])[CH2:9][CH2:8]1
Reactant: O=C1CC2(CCCC2)CC(=O)N1CC#CCN1CCN(c2ncccn2)CC1
Reactant: [H][H]
Agent: [Pd]
Agent: O=C1CC2(CCCC2)CC(=O)N1
Solvent: c1ccsc1
Product: O=C1CC2(CCCC2)CC(=O)N1CCCCN1CCN(c2ncccn2)CC1
Reaction time: 0 h
Yield: 100.1 %

Procedure:
A solution of 100 g (0.26 mole) of 8-[4-[4-(pyrimidine-2-yl)-piperazine-1-yl]-but-2-inyl]-8-aza-spiro[4.5]decane-7,9-dione in 50 ml thiophen-free benzene is added to a suspension of 2 g of a palladium/carbon catalyst (palladium content about 5% by weight) and 50 ml of thiophen-free benzene under vigorous stirring at 20°-40° C. under the introduction of hydrogen under a pressure of 1 bar at such a rate that the hydrogen uptake of the unsaturated 8-[4-[4-pyrimidine-2-yl)-piperazine-1-yl]-but-2-inyl]-8-aza-spiro[4.5]decane-7,9-dione added is substantially identical with the calculated hydrogen consumption continuously measured with the aid of a gas burette. This practically means that when the addition of the active ingredient is stopped, the hydrogen consumption ceases within 5-10 seconds. The reaction temperature is 20°-40° C. and the reaction time is 1-4 hours. When the reduction has been terminated, the catalyst is filtered off. The catalyst can be directly used in the next hydrogenating operations without any further treatment. The filtrate is evaporated and the residue is suspended in isopropanol and filtered. Thus in the form of white crystals 100.3 g of 8-[4-[4-(pyrimidine-2yl)-piperazine-1-yl]-butyl]-8-aza-spiro[4.5]decane-7.9-dione base are obtained, yield: about 100%.Mp.:105°-106° C. (according to prior art 90°-98° C.). Content: (on the base) 99.8-100.1%. According to HPLC analysis the product contains only 0.1% of contaminations.
Reaction SMILES: [N:1]12[CH2:8][CH:5]([CH2:6][CH2:7]1)[CH:4]=[C:3]([C:9](N(OC)C)=[O:10])[CH2:2]2.[CH3:15][Li].[Br-].[Li+].P(=O)(O)(O)O>O1CCCC1.C(OCC)C>[C:9]([C:3]1[CH2:2][N:1]2[CH2:8][CH:5]([CH:4]=1)[CH2:6][CH2:7]2)(=[O:10])[CH3:15]
Reactant: CON(C)C(=O)C1=CC2CCN(C1)C2
Reactant: [Li]C
Agent: O=P(O)(O)O
Agent: [Br-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(=O)C1=CC2CCN(C1)C2
Temperature: -70 °C

Procedure:
A solution of (±)1-azabicyclo[3.2.1]oct-3-en-3-yl-N-methoxy-N-methylcarboxamide (D8) (0.40 g, 2.0 mmole) in dry tetrahydrofuran (20 ml) was cooled to -70° C., under a nitrogen atmosphere, and treated dropwise over 15 minutes with methyllithium (1.47 ml of a 1.5 m solution in diethyl ether as the complex with lithium bromide, 2.2 mmole). The temperature was maintained at -70° C. for 30 minutes, and then allowed to warm to 0° C. over 1.75h. The reaction was cooled to -20° C. and poured into a 1M solution of orthophosphoric acid (20 ml) cooled below 0° C. The organic layer was separated, and the aqueous phase was saturated with potassium carbonate, and extracted exhaustively with chloroform. The combined organic extracts were dried (Na2SO4) and concentrated in vacuo to give a pale yellow oil (0.33 g) which was distilled in a kugelrohr at 150° C./0.1 mmHg to give the title compound (D10) as a colourless liquid (0.28 g, 93%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:12])[NH:7][CH2:8][CH:9]1[CH2:11][O:10]1)([CH3:4])([CH3:3])[CH3:2].[CH3:13][NH2:14].C1COCC1>C(O)C>[C:1]([O:5][C:6](=[O:12])[NH:7][CH2:8][CH:9]([OH:10])[CH2:11][NH:14][CH3:13])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN
Reactant: CC(C)(C)OC(=O)NCC1CO1
Solvent: C1CCOC1
Solvent: CCO
Product: CNCC(O)CNC(=O)OC(C)(C)C
Temperature: 40 °C
Reaction time: 5 h

Procedure:
A solution of Oxiranylmethyl-carbamic acid tert-butyl ester (0.64 g, 3.7 mmol) in Ethanol (6 mL) was treated at room temperature with a 2.0M solution of methylamine in THF (5 mL, 10 mmol). The reaction mixture was stirred for 5 hours at 40° C. The solvent was evaporated in vacuo to yield a gum which was used directly into the next step (0.75 g, 98%)
Reaction SMILES: [N:1]1([CH2:15][CH2:16][CH2:17][CH2:18][N:19]2[CH2:24][CH2:23][C:22]3([C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[CH:26]=[CH:25]3)[CH2:21][CH2:20]2)[CH2:6][CH2:5][C:4]2([C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH:8]=[CH:7]2)[CH2:3][CH2:2]1.C(O)(=O)C>C(O)C.[Pd]>[N:1]1([CH2:15][CH2:16][CH2:17][CH2:18][N:19]2[CH2:24][CH2:23][C:22]3([C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[CH2:26][CH2:25]3)[CH2:21][CH2:20]2)[CH2:6][CH2:5][C:4]2([C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH2:8][CH2:7]2)[CH2:3][CH2:2]1
Reactant: C1=CC2(CCN(CCCCN3CCC4(C=Cc5ccccc54)CC3)CC2)c2ccccc21
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCO
Product: c1ccc2c(c1)CCC21CCN(CCCCN2CCC3(CCc4ccccc43)CC2)CC1
Reaction time: 2 h

Procedure:
To a solution of 1,4-Bis-spiro[ind-2-en-1,4'-piperidin-1'-yl]butane (compound 4a) (3 g) in ethanol (90 ml) were added acetic acid (5 ml) and 5% palladium on carbon (0.9 g). The mixture was hydrogenated in a Parr apparatus for 2 hours ar 3 atm. The catalyst was filtered off and the solvent evaporated. The remaining oil was dissolved in diluted aqueous NH4OH (200 ml, pH>9). The title compound 5a was extracted with ethyl acetate and worked-up as above and finally crystallized from ethyl acetate. Yield 1.6 g. Mp 113-115° C. 1H NMR (CDCl3) δ 1.55-1.65 (m,8H), 1.95-2.10 (m,8H), 2.15 (t,4H), 2.45 (broad s,4H), 2.95 (t,8H), 7.10-7.30 (m,8H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[C:4]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)[CH:3]=1.C(O[B:23]([O:28][CH:29]([CH3:31])[CH3:30])[O:24][CH:25]([CH3:27])[CH3:26])(C)C.C([Li])CCC.OC(C(O)(C)C)(C)C>O1CCCC1.C1(C)C=CC=CC=1>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([B:23]2[O:24][C:25]([CH3:26])([CH3:27])[C:29]([CH3:30])([CH3:31])[O:28]2)=[CH:3][C:4]=1[O:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: COc1ccc(COc2cc(Br)ccc2Cl)cc1
Agent: CC(C)(O)C(C)(C)O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: COc1ccc(COc2cc(B3OC(C)(C)C(C)(C)O3)ccc2Cl)cc1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of 4-bromo-1-chloro-2-(4-methoxy-benzyloxy)-benzene (0.35 g) in tetrahydrofuran (10 ml) under nitrogen was added triisopropylborate (0.29 ml). The mixture was cooled to −78° C. and 2.5M n-butyllithium solution in hexanes was added. The reaction mixture was stirred at −40° C. for 1 hour, then warmed to 20° C. and quenched with 2M hydrochloric acid (aq) (2 ml). The reaction mixture was warmed to room temperature and stirred for 1 hour. The reaction mixture was adjusted to pH 7 using saturated sodium bicarbonate solution, then partitioned between ethyl acetate and water, dried (MgSO4) and the solvents removed in vacuo to yield a crude residue (0.31 g). A mixture of this crude residue and pinacol (0.25 g) in toluene (10 ml) were stirred under reflux overnight in a Dean-Stark apparatus. The solvents were removed in vacuo, the residue was then partitioned between ethyl acetate and water, the combined organics were washed with water then brine and dried (MgSO4), the solvents were removed in vacuo to yield 2-[4-chloro-3-(4-methoxy-benzyloxy)-phenyl]-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (0.28 g).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:9])[CH2:5][CH2:6][CH:7]=[CH2:8])[CH3:2].[Cl:10][C:11]([Cl:16])(Cl)[C:12](Cl)=[O:13]>C(OCC)C.COCCOC.[Cu].[Zn]>[Cl:10][C:11]1([Cl:16])[C:12](=[O:13])[CH2:8][CH:7]1[CH2:6][CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:9]
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Reactant: C=CCCC(=O)OCC
Agent: [Cu]
Agent: [Zn]
Solvent: CCOCC
Solvent: COCCOC
Product: CCOC(=O)CCC1CC(=O)C1(Cl)Cl
Temperature: 25 °C
Reaction time: 72 h
Yield: 79.5 %

Procedure:
A mixture of 4-pentenoic acid ethyl ester (7.07 g, 55.2 mmol) and zinc-copper couple (10.2 g, 140 mmol) in diethyl ether (170 mL) and 1,2-dimethoxyethane (25 mL) was treated dropwise with trichloroacetyl chloride (25 g, 140 mmol). The mixture was stirred at room temperature for 3 days. The reddish heterogeneous reaction mixture was filtered through a pad of celite and the pad was washed with 300 mL Et2O. The filtrate was concentrated to about one half the original volume and the organic phase was washed with two 150 mL portions of H2O and one 150 mL portion of sat NaHCO3. The organic phase was dried over MgSO4, filtered and concentrated to yield a brown liquid. The material was purified by vacuum distillation (90-100° C. @0.044 torr) to yield the title compound (10.49 g, 80%) as a light yellow liquid: GC purity 95.8% (ret. time, 4.92 min).
Reaction SMILES: [N+](C1C=C(S(O[C@@H:14]2[CH2:18][N:17]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C@H:16]([C:26]([O:28][CH3:29])=[O:27])[CH2:15]2)(=O)=O)C=CC=1)([O-])=O.C(#N)CC.[Cl:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[SH:41].C(N(CC)CC)C>C([O-])([O-])=O.[Na+].[Na+]>[Cl:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[S:41][C@H:14]1[CH2:18][N:17]([C:19]([O:21][C:22]([CH3:23])([CH3:24])[CH3:25])=[O:20])[C@H:16]([C:26]([O:28][CH3:29])=[O:27])[CH2:15]1
Reactant: COC(=O)[C@@H]1C[C@H](OS(=O)(=O)c2cccc([N+](=O)[O-])c2)CN1C(=O)OC(C)(C)C
Reactant: Sc1ccccc1Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCC#N
Solvent: CCN(CC)CC
Product: COC(=O)[C@@H]1C[C@@H](Sc2ccccc2Cl)CN1C(=O)OC(C)(C)C
Temperature: 100 °C
Reaction time: 8 h

Procedure:
Under an atmosphere of argon, (2S,4S)-1-tert-butyl 2-methyl 4-(3-nitrophenylsulfonyloxy)pyrrolidine-1,2-dicarboxylate (8.5 g, 19.7 mmol, Eq: 1.00) was combined with propionitrile (82.0 ml) to give a light brown solution. Then 2-chlorobenzenethiol (4.28 g, 3.38 ml, 29.6 mmol, Eq: 1.50) and triethylamine (4.00 g, 5.5 ml, 39.5 mmol, Eq: 2.00) were added dropwise. The reaction was stirred overnight at reflux (100° C.). The reaction was cooled to room temperature, and poured in 50 ml Na2CO3 solution (10%), and extracted with 2×100 ml ethyl acetate. The organic layers were washed with 50 ml HCl 0.1M and 50 ml satd. NaCl solution. The organic layer was stirred over Na2SO4, filtered and concentrated in vacuo. The crude material was purified by flash chromatography (70 g column, from 100% to 80% heptane in ethyl acetate). The title compound was obtained as a yellow oil (5.7 g, 77.6%, MS (m/e)=372.1 [M+H+]).
Reaction SMILES: [F:1][C:2]1[C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[C:11]([C:15]([N:17]4[CH2:22][CH2:21][O:20][CH2:19][CH2:18]4)=[O:16])[CH:12]=3)[NH:7][C:6]=2[C:5]([C:23]([NH2:25])=[O:24])=[CH:4][CH:3]=1.C1C(=O)N([Br:33])C(=O)C1>CN(C=O)C>[Br:33][C:3]1[CH:4]=[C:5]([C:23]([NH2:25])=[O:24])[C:6]2[NH:7][C:8]3[C:13]([C:14]=2[C:2]=1[F:1])=[CH:12][C:11]([C:15]([N:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1)=[O:16])=[CH:10][CH:9]=3
Reactant: NC(=O)c1ccc(F)c2c1[nH]c1ccc(C(=O)N3CCOCC3)cc12
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Product: NC(=O)c1cc(Br)c(F)c2c1[nH]c1ccc(C(=O)N3CCOCC3)cc12
Temperature: 80 °C

Procedure:
4-Fluoro-6-(morpholine-4-carbonyl)-9H-carbazole-1-carboxamide (9 mg, 0.026 mmol) was mixed with NBS (5.5 mg, 0.031 mmol) in DMF (1.5 mL). The mixture was stirred at 80° C. for 20 mins More NBS (3 mg, 0.017 mmol) was added to the mixture and heated at 80° C. for another 20 mins. The mixture was concentrated and purified using preparative HPLC to give 3-bromo-4-fluoro-6-(morpholine-4-carbonyl)-9H-carbazole-1-carboxamide. MS (ESI) m/z 420 (M+H)+. 1H NMR (DMSO-d6) δ ppm 11.72 (s, 1H), 8.32 (d, 1H, J=6.5), 8.28 (bs, 1H), 8.13 (s, 1H), 7.85(d, 1H, J=8.3), 7.64 (bs, 1H), 7.58(dd, 1H, J=8.5, 1.6), 3.7-3.5 (bm, 8H).
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[O:7][CH2:6][CH:5]([NH:8][C:9]2[C:14]([N+:15]([O-])=O)=[CH:13][CH:12]=[C:11]([O:18][CH3:19])[N:10]=2)[CH2:4][O:3]1.[H][H]>O1CCOCC1.[Pd]>[CH3:1][C:2]1([CH3:20])[O:7][CH2:6][CH:5]([NH:8][C:9]2[C:14]([NH2:15])=[CH:13][CH:12]=[C:11]([O:18][CH3:19])[N:10]=2)[CH2:4][O:3]1
Reactant: COc1ccc([N+](=O)[O-])c(NC2COC(C)(C)OC2)n1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1COCCO1
Product: COc1ccc(N)c(NC2COC(C)(C)OC2)n1

Procedure:
N-(2,2-Dimethyl-1,3-dioxan-5-yl)-6-(methyloxy)-3-nitro-2-pyridinamine (35.00 g, 123.6 mmol) was divided into 2 aliquots, each of which was taken up in 1,4-dioxane (500 ml) and hydrogenated over 10% Pd on carbon (paste, 1:1 w:w with water, 4.00 g) under 1 atmosphere hydrogen pressure, at room temperature for 18 h. The mixtures were filtered with suction though Celite, using argon blanket and taking care to minimise contact of the product with air. The solids were washed with 1,4-dioxane and the combined filtrate plus washings were evaporated under reduced pressure to give the title compound as a deep purple oil. This was used immediately in the next step.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([NH:12][CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)=[N:7][N:6]=[CH:5]2.[CH:19]1([NH:22][C:23](=[O:40])[C:24]2[CH:29]=[CH:28][C:27]([CH3:30])=[C:26](B3OC(C)(C)C(C)(C)O3)[CH:25]=2)[CH2:21][CH2:20]1.C(=O)([O-])[O-].[K+].[K+]>COCCOC.CCO.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>[CH:13]1([NH:12][C:8]2[C:9]3[C:4](=[CH:3][C:2]([C:26]4[CH:25]=[C:24]([CH:29]=[CH:28][C:27]=4[CH3:30])[C:23]([NH:22][CH:19]4[CH2:20][CH2:21]4)=[O:40])=[CH:11][CH:10]=3)[CH:5]=[N:6][N:7]=2)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1B1OC(C)(C)C(C)(C)O1
Reactant: Brc1ccc2c(NC3CCCCC3)nncc2c1
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: [K+]
Solvent: COCCOC
Solvent: CCO
Product: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc2c(NC3CCCCC3)nncc2c1
Temperature: 90 °C
Reaction time: 2 h
Yield: 65.3 %

Procedure:
The mixture of 6-bromo-N-cyclohexylphthalazin-1-amine (0.2 g, 0.65 mmol), N-cyclopropyl-4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (0.2 g, 0.65 mmol), tetrakis(triphenylphosphine)palladium (38 mg, 0.0325 mmol) and 2M potassium carbonate (1 mL, 1.95 mmol) in 5 mL DME/EtOH (4:1) was stirred at 90° C. for 2 h. (Product MS found to be M+1=401). The mixture was transferred directly to a column and purified via flash chromatography (silica gel) eluting with a gradient of 2% 2 M ammonia in MeOH/DCM to 10% 2 M ammonia in MeOH/DCM to give the title compound (0.17 g) as a yellow solid. Found MS (ES+): 401(M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:17]([NH2:19])=[O:18])=[CH:4][C:5]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[N:7]([CH2:14][CH3:15])[C:6]=2[N:16]=1.C=O.[C:22](O)(=O)C.C([BH3-])#N.[Na+]>CO>[CH2:14]([N:7]1[C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:5]2[CH:4]=[C:3]([C:17]([NH2:19])=[O:18])[C:2]([NH:1][CH3:22])=[N:16][C:6]1=2)[CH3:15]
Reactant: CC(=O)O
Reactant: CCn1c2ccccc2c2cc(C(N)=O)c(N)nc21
Agent: C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CCn1c2ccccc2c2cc(C(N)=O)c(NC)nc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 66.1 %

Procedure:
2-amino-9-ethyl-9H-pyrido[2,3-b]indole-3-carboxamide (1, 36 mg, 0.141 mmol), formaldehyde (37 wt % in water, 0.011 mL, 0.155 mmol) and acetic acid (0.0084 mL, 0.148 mmol) in methanol (2.6 mL) were stirred at room temperature for 1 h then sodium cyanoborohydride (13 mg, 0.212 mmol) was added. The reaction stirred at room temperature for 16 h, then was quenched with aqueous saturated sodium bicarbonate (2.6 mL). The resulting mixture was diluted with ethyl acetate (100 mL), washed with water (2×50 mL) and brine (50 mL), dried over magnesium sulfate, filtered and then concentrated in vacuo. The residue was adsorbed onto silica gel using methanol and purified by silica gel chromatography (5-10% methanol in methylene chloride gradient) to afford the title compound (48, 25 mg, 66%). NH4OAc standard conditions. DAD Retention time=7.84 min. M+H=269. 1H NMR (300 MHz, CDCl3): δ 8.60 (br s, 1H), 8.19 (s, 1H), 7.79 (d, J=7.9 Hz, 1H), 7.36-7.32 (m, 2H), 7.21-7.17 (m, 1H), 5.65 (br s, 2H), 4.38 (q, J=7.3 Hz, 2H), 3.12 (s, 3H), 1.42 (t, J=7.3 Hz, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([S:11]([C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=1)(=[O:13])=[O:12])[CH:6]=[C:5]2[CH2:21]Cl.[NH:23]1[CH2:29][CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([S:11]([C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=1)(=[O:13])=[O:12])[CH:6]=[C:5]2[CH2:21][N:23]1[CH2:29][CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1
Reactant: C1CNCCNC1
Reactant: Cc1ccc(S(=O)(=O)n2cc(CCl)c3cc(Br)ccc32)cc1
Product: Cc1ccc(S(=O)(=O)n2cc(CN3CCCNCC3)c3cc(Br)ccc32)cc1

Procedure:
Using essentially the same procedure as described in example 127, 5-Bromo-1-(4-methylbenzenesulfonyl)-3-chloromethyl-1H-indole was reacted with homopiperazine to obtain the above derivative.
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[C@@:37]2([CH3:38])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:36]2[CH2:35][CH2:34][C@@:33]2([CH3:39])[C@H:17]3[CH2:18][CH:19]=[C:20]2[C@@H:21]([S:23][C:24](OC2C=CC=CC=2)=O)[CH3:22])[CH2:12][C@@H:11]([O:40][Si:41]([C:44]([CH3:47])([CH3:46])[CH3:45])([CH3:43])[CH3:42])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].BrC/[CH:50]=[CH:51]\[C:52]([CH3:62])([O:54][Si:55]([CH2:60][CH3:61])([CH2:58][CH3:59])[CH2:56][CH3:57])[CH3:53].O1CCCC1.[OH-].[K+]>CO>[Si:1]([O:8][C@@H:9]1[C@@:37]2([CH3:38])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:36]2[CH2:35][CH2:34][C@@:33]2([CH3:39])[C@H:17]3[CH2:18][CH:19]=[C:20]2[C@@H:21]([S:23][CH2:24]/[CH:50]=[CH:51]\[C:52]([CH3:53])([O:54][Si:55]([CH2:60][CH3:61])([CH2:56][CH3:57])[CH2:58][CH3:59])[CH3:62])[CH3:22])[CH2:12][C@@H:11]([O:40][Si:41]([C:44]([CH3:46])([CH3:45])[CH3:47])([CH3:43])[CH3:42])[CH2:10]1)([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:2])[CH3:3]
Reactant: C[C@H](SC(=O)Oc1ccccc1)C1=CC[C@H]2C3=CC=C4C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C
Reactant: CC[Si](CC)(CC)OC(C)(C)/C=C\CBr
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC[Si](CC)(CC)OC(C)(C)/C=C\CS[C@@H](C)C1=CC[C@H]2C3=CC=C4C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C
Yield: 64.3 %

Procedure:
Under the same conditions as in Example 3, 1α,3β-bis(tert-butyldimethylsilyloxy)-20(S)-phenoxycarbonylthiopregna-5,7,16-triene (91.2 mg, 0.131 mmol), (Z)-1-bromo-4-methyl-4-triethylsilyloxy-2-pentene (192 mg, 0.655 mmol), tetrahydrofuran (1.5 ml) and 1M KOH solution in methanol (1.5 ml) were reacted and worked up, and then the residue was purified by preparative thin layer chromatography (0.5 mm×2, hexane:dichloromethane:ethyl acetate=160:40:1, developed once) to give the title compound as a colorless oil (66.3 mg, 64%).
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH2:7][CH3:8])[N:5]=[CH:4][CH:3]=1.[CH2:9]([O:11][C:12](=[O:23])[C:13](=[CH:19]OCC)[C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH3:10].O>C(OCC)(=O)C>[CH2:7]([N:6]1[C:2]([NH:1][CH:19]=[C:13]([C:12]([O:11][CH2:9][CH3:10])=[O:23])[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:3][CH:4]=[N:5]1)[CH3:8]
Reactant: CCn1nccc1N
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)C(=CNc1ccnn1CC)C(=O)OCC
Temperature: 120 °C
Reaction time: 1 h

Procedure:
A mixture of 5-amino-1-ethylpyrazole (1 gm, 0.0089 mole) and diethylethoxymethylenemalonate (1.9 ml, 0.0089 mole) was stirred at 120° C. for about 1 hour. The reaction mixture was poured into water and extraction was done with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo to give yellow oil. Yield: 2.5 g. m/z: (M++1) 282.0.
Reaction SMILES: CON(C)[C:4](=[O:28])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]2[CH:12]=[CH:13][C:14]3[O:18][C:17]([CH2:19][CH2:20][N:21]4[CH2:25][CH2:24][CH2:23][C@H:22]4[CH3:26])=[CH:16][C:15]=3[CH:27]=2)[CH:6]=1.[CH2:30]([Mg]Cl)[CH:31]([CH3:33])[CH3:32]>>[CH3:30][CH:31]([CH3:33])[CH2:32][C:4]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]2[CH:27]=[CH:15][C:14]3[O:18][C:17]([CH2:19][CH2:20][N:21]4[CH2:25][CH2:24][CH2:23][C@H:22]4[CH3:26])=[CH:16][C:13]=3[CH:12]=2)[CH:6]=1)=[O:28]
Reactant: CC(C)C[Mg]Cl
Reactant: CON(C)C(=O)c1cccc(-c2ccc3oc(CCN4CCC[C@H]4C)cc3c2)c1
Product: CC(C)CC(=O)c1cccc(-c2ccc3oc(CCN4CCC[C@H]4C)cc3c2)c1
Reaction time: 8 h
Yield: 19 %

Procedure:
The product from Example 145 and isobutylmagnesium chloride were processed as described in Example 146, except that after reacting overnight additional isobutylmagnesium chloride (400 mol %) was added and the reaction mixture was stirred for four more hours, to provide the title compound (19% yield). MS (ESI APCI) m/z 390 (M+H)+; 1HNMR (300 MHz, CD3OD) δ 1.01 (d, 6 H), 1.17 (d, 3 H), 1.37-1.53 (m, 1 H), 1.73-1.86 (m, 2 H), 1.94-2.07 (m, 1 H), 2.20-2.35 (m, 2 H), 2.41-2.59 (m, 2 H), 2.95 (d, 2 H), 2.95-3.14 (m, 2 H), 3.19-3.34 (m, 2 H), 6.62 (s, 1 H), 7.49-7.52 (m, 2 H), 7.57 (dd, 1 H), 7.77 (dd, 1 H), 7.86 (ddd, 1 H), 7.93 (ddd, 1 H), 8.19 (dd, 1 H).
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[CH2:15][C@H:14]([N:16]3[CH:20]=[C:19]([CH2:21][CH3:22])[CH:18]=[N:17]3)[C@@H:13]([OH:23])[C@H:12]2[OH:24])=[C:4]([NH:25][CH2:26][CH:27]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[N:3]=1.[F:40][C:41]([F:46])([F:45])[C:42]([OH:44])=[O:43].C1(C(C2C=CC=CC=2)CN[C:56]2[N:64]=[C:63](NCCN3CCCCC3)N=[C:61]3[C:57]=2N=C[N:60]3[C@@H:74]2[CH2:78][C@H:77](N3C=C(CO)C=N3)[C@@H:76](O)[C@H]2O)C=CC=CC=1.N1([C@@H]2CCNC2)CCCC1>>[F:40][C:41]([F:46])([F:45])[C:42]([OH:44])=[O:43].[N:60]1([C@@H:61]2[CH2:57][CH2:56][N:64]([C:2]3[N:10]=[C:9]4[C:5]([N:6]=[CH:7][N:8]4[C@@H:11]4[CH2:15][C@H:14]([N:16]5[CH:20]=[C:19]([CH2:21][CH3:22])[CH:18]=[N:17]5)[C@@H:13]([OH:23])[C@H:12]4[OH:24])=[C:4]([NH:25][CH2:26][CH:27]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)[C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[N:3]=3)[CH2:63]2)[CH2:74][CH2:78][CH2:77][CH2:76]1
Reactant: CCc1cnn([C@H]2C[C@@H](n3cnc4c(NCC(c5ccccc5)c5ccccc5)nc(Cl)nc43)[C@H](O)[C@@H]2O)c1
Reactant: OCc1cnn([C@H]2C[C@@H](n3cnc4c(NCC(c5ccccc5)c5ccccc5)nc(NCCN5CCCCC5)nc43)[C@H](O)[C@@H]2O)c1
Agent: C1CCN([C@@H]2CCNC2)C1
Solvent: O=C(O)C(F)(F)F
Product: CCc1cnn([C@H]2C[C@@H](n3cnc4c(NCC(c5ccccc5)c5ccccc5)nc(N5CC[C@@H](N6CCCC6)C5)nc43)[C@H](O)[C@@H]2O)c1

Procedure:
This compound is prepared from (1R,2S,3R,5S)-3-[2-chloro-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-5-(4-ethyl-pyrazol-1-yl)-cyclopentane-1,2-diol (Intermediate BA8) using a procedure analogous to that of (1R,2S,3R,5S)-3-[6-(2,2-diphenyl-ethylamino)-2-(2-piperidin-1-yl-ethylamino)-purin-9-yl]-5-(4-hydroxymethyl-pyrazol-1-yl)-cyclopentane-1,2-diol trifluoro-acetate (Example 461 by replacing 1-(2-amino-ethyl)piperidine with (R)-[1,3′]bipyrrolidinyl (intermediate EB). MS (ES+) m/e 648.44 (MH+).
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:22])([F:21])[CH2:17]2)[C:8]2[C:9](=[N:11][N:12]([CH2:14][CH3:15])[N:13]=2)[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(N2CCC(F)(F)C2)C2N=NNC=2N=1)(C)(C)C.BrCC1[C:50]([Cl:51])=[C:49]([F:52])[CH:48]=[CH:47][C:46]=1[Cl:53]>>[C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:21])([F:22])[CH2:17]2)[C:8]2[C:9](=[N:11][N:12]([CH2:14][C:15]3[C:46]([Cl:53])=[CH:47][CH:48]=[C:49]([F:52])[C:50]=3[Cl:51])[N:13]=2)[N:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: Fc1ccc(Cl)c(CBr)c1Cl
Reactant: CCn1nc2nc(C(C)(C)C)nc(N3CCC(F)(F)C3)c2n1
Agent: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1
Product: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn(Cc3c(Cl)ccc(F)c3Cl)nc2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoro-pyrrolidin-1-yl)-2-ethyl-2H-[1,2,3]triazolo[4,5-d]pyrimidine (example 3, step b), the title compound was prepared from 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 2-(bromomethyl)-1,3-dichloro-4-fluorobenzene and isolated as white solid. MS (m/e): 459.2 (MH+).