Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=[O:25])[CH2:5][CH2:6][C:7]1[CH:8]=[N:9][C:10]([O:13][CH2:14][CH:15]2[CH2:24][CH2:23][CH2:22][C:17]3([CH2:21][CH2:20][CH2:19][CH2:18]3)[CH2:16]2)=[CH:11][CH:12]=1)C.O1CCCC1.[OH-].[Na+].[ClH:33]>C(O)C>[ClH:33].[CH2:18]1[C:17]2([CH2:22][CH2:23][CH2:24][CH:15]([CH2:14][O:13][C:10]3[N:9]=[CH:8][C:7]([CH2:6][CH2:5][C:4]([OH:25])=[O:3])=[CH:12][CH:11]=3)[CH2:16]2)[CH2:21][CH2:20][CH2:19]1
Reactant: CCOC(=O)CCc1ccc(OCC2CCCC3(CCCC3)C2)nc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: O=C(O)CCc1ccc(OCC2CCCC3(CCCC3)C2)nc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of 3-[6-(spiro[4.5]dec-7-ylmethoxy)-pyridin-3-yl]-propionic acid ethyl ester (36 mg) obtained in Step 3 in a mixed solvent of tetrahydrofuran (0.36 mL)-ethanol (0.36 mL) was added 1N aqueous sodium hydroxide solution (0.21 mL), followed by stirring the reaction mixture at room temperature for 1.5 hours. Then, to the reaction mixture was added 1N aqueous hydrochloric acid solution, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried and concentrated. The residue was dissolved in a 1,4-dioxane solution of hydrogen chloride (4M, 0.5 mL), and to this was added hexane (0.5 mL) while stirring. The resulting solid was filtered and then dried to give 3-[6-(spiro[4.5]dec-7-ylmethoxy)-pyridin-3-yl]-propionic acid hydrochloride (33 mg).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][CH:3]=1.[Mg].O1CCCC1.[C:15]([N:18]1[CH2:23][CH2:22][CH:21]([C:24](=[O:32])[C:25]2[CH:30]=[CH:29][C:28]([Br:31])=[CH:27][CH:26]=2)[CH2:20][CH2:19]1)(=[O:17])[CH3:16]>CC1C=CC=CC=1.C(O)(=O)C>[C:15]([N:18]1[CH2:19][CH2:20][CH:21]([C:24]([C:25]2[CH:26]=[CH:27][C:28]([Br:31])=[CH:29][CH:30]=2)([C:2]2[CH:7]=[CH:6][C:5]([F:8])=[CH:4][CH:3]=2)[OH:32])[CH2:22][CH2:23]1)(=[O:17])[CH3:16]
Reactant: CC(=O)N1CCC(C(=O)c2ccc(Br)cc2)CC1
Reactant: Fc1ccc(Br)cc1
Agent: [Mg]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: CC(=O)N1CCC(C(O)(c2ccc(F)cc2)c2ccc(Br)cc2)CC1
Reaction time: 5 h

Procedure:
To a stirred and refluxing Grignard-complex previously prepared starting from 52.5 parts of 1-bromo-4-fluorobenzene, 7.5 parts of magnesium and 216 parts of tetrahydrofuran was added dropwise a solution of 94 parts of 1-acetyl-4-(4-bromobenzoyl)piperidine in 450 parts of tetrahydrofuran. Upon completion, stirring was continued for 5 hours at reflux. The reaction mixture was cooled, poured onto a mixture of 300 parts of crushed ice and 40 parts of acetic acid and stirred for 15 minutes. 450 Parts of methylbenzene were added. The organic layer was separated, dried, filtered and evaporated. The residue was taken up in methylbenzene and the whole was evaporated. The residue was purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (90:10 by volume) as eluent. The pure fractions were collected and the eluent was evaporated, yielding 75 parts of 1-acetyl-α-(4-bromophenyl)-α-(4-fluorophenyl)-4-piperidinemethanol as a residue (intermediate 16).
Reaction SMILES: C([N:3]1[C:9]2[N:10]=[CH:11][C:12](C#C)=[CH:13][C:8]=2[C:7](=[O:16])[N:6](C)[C:5]2[CH:18]=[CH:19][CH:20]=[N:21][C:4]1=2)C.BrC1C=NC=NC=1>>[N:21]1[C:4]2[C:5](=[N:6][C:7](=[O:16])[C:8]3[CH:13]=[CH:12][CH:11]=[N:10][C:9]=3[N:3]=2)[CH:18]=[CH:19][CH:20]=1
Reactant: C#Cc1cnc2c(c1)C(=O)N(C)c1cccnc1N2CC
Agent: Brc1cncnc1
Product: O=c1nc2cccnc2nc2ncccc12
Yield: 85.9 %

Procedure:
By a procedure analogous to that described in Example 51b, 5,11-dihydro-11-ethyl-8-ethynyl-5-methyl-6H-dipyrido[3,2-b:2',3'-e][1,4]diazepin-6-one (0.1 g, 0.36 mmol) was coupled with 5-bromopyrimidine (59 mg, 0.37 mmol) to give 65 mg of 5,11-Dihydro-11-ethyl-5-methyl-8-(5-pyrimidyl)ethynyl-(-6H-dipyrido[3,2-b:2',3'-e][1,4]diazepin-6-one (65 mg). A mixture containing this coupled product (65 mg), cyclohexene (0.07 mL), and 10% palladium on carbon (60 mg) in 2 mL of ethanol was heated in a sealed tube at 95° C. for 5 hours. The reaction mixture was filtered through Celite and concentrated. Purification of the residue by flash chromatography, eluting with methanol/dichloromethane, and recrystallization from ethyl acetate/hexanes provided 27 mg of the title compound, m.p. 142°-143° C.
Reaction SMILES: [CH:1]12[CH2:11][CH:6]3[CH2:7][CH:8]([O:10][CH:4]([O:5]3)[C:3](=[O:12])[O:2]1)[CH2:9]2.[Na].O.C(O)(=O)C>C(O)C>[CH:1]12[CH2:11][CH:6]3[CH2:7][CH:8]([O:10][CH:4]([O:5]3)[CH:3]([OH:12])[O:2]1)[CH2:9]2
Reactant: O=C1OC2CC3CC(C2)OC1O3
Agent: [Na]
Solvent: CCO
Solvent: CC(=O)O
Solvent: O
Product: OC1OC2CC3CC(C2)OC1O3

Procedure:
A solution of 340 mg of 2,5,11-trioxatricyclo[4,3,1,14,8 ]undecan-3-one in 10 ml of absolute ethanol is treated with 300 mg of sodium. After the metal has dissolved the reaction mixture is treated with 10 ml of water and 0.7 ml of acetic acid, concentrated under reduced pressure to about 3 ml and the concentrate is extracted with methylene chloride. The solvent is evaporated to leave as residue pure 2,5,11-trioxatricyclo-[4,3,1,14,8 ]undecan-3-ol.
Reaction SMILES: [F:1][C:2]1[CH:17]=[C:16]([CH:18]=O)[CH:15]=[CH:14][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]([NH2:13])=[O:12])=[N:9][CH:10]=1.[CH3:20][CH:21]([CH3:26])[CH2:22][CH2:23][CH2:24][NH2:25].[BH4-].[Na+]>CO>[F:1][C:2]1[CH:17]=[C:16]([CH2:18][NH:25][CH2:24][CH2:23][CH2:22][CH:21]([CH3:26])[CH3:20])[CH:15]=[CH:14][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]([NH2:13])=[O:12])=[N:9][CH:10]=1
Reactant: NC(=O)c1ccc(Oc2ccc(C=O)cc2F)cn1
Reactant: CC(C)CCCN
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)CCCNCc1ccc(Oc2ccc(C(N)=O)nc2)c(F)c1
Reaction time: 8 h
Yield: 54.4 %

Procedure:
Place 5-(2-fluoro-4-formylphenoxy)pyridine-2-carboxamide (Example 403, Part B) (0.650 g, 2.50 mmol), 4-methylpentylamine (Example 433, Part A) (0.278 g, 2.75 mmol) and 3 Å molecular sieves in a vial. Add methanol (12 mL), cap and stir overnight. Add NaBH4 (slight excess) and stir until the gasses stop evolving. Load the reaction mixture directly onto a 25 g ISCO® pre-load column. Dry the column in a vacuum oven at room temperature. Purify by eluting through a 40 g ISCO® column with 0% to 10% (2.0 M NH3 in methanol) in ethyl acetate to give the title compound (0.470 g, 55%): TOF MS ES+ 346.2 (M+H)+, HRMS calcd for C19H25N3O2F 346.1931 (M+H)+, found 346.1922, time 0.48 min; HPLC [YMC-Pro pack C-18 (150×4.6 mm, S-5 microm), 0.05% TFA/acetonitrile in 0.05% TFA/water at 1.0 mL/min, 10-20% over 5 min, 20-95% over 18], tR=11.6 min, 100% purity.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:17])[CH:7]=[C:8]([C:12]([O:14]CC)=[O:13])[NH:9]2)=[C:4]([CH2:18][CH3:19])[CH:3]=1.[OH-].[Na+]>>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:17])[CH:7]=[C:8]([C:12]([OH:14])=[O:13])[NH:9]2)=[C:4]([CH2:18][CH3:19])[CH:3]=1
Reactant: CCOC(=O)c1cc(=O)c2c(CC)cc(Br)cc2[nH]1
Agent: [Na+]
Agent: [OH-]
Product: CCc1cc(Br)cc2[nH]c(C(=O)O)cc(=O)c12

Procedure:
Treatment of ethyl 7-bromo-5-ethyl-4-oxo-1,4-dihydroquinoline-2-carboxylate with sodium hydroxide (0.247 g), as described in Example 1c, gave 7-bromo-5-ethyl-4-oxo-1,4-dihydroquinoline-2-carboxylic acid, mp 278° C. (decomp.). δ (360 MHz, DMSO-d6) 1.14 (3H, t, CH3), 3.24 (2H, q, CH2), 6.55 (1H, s, 3-H), 7.22 (1H, d, 6-H), 8.02 (1H, d, 8-H) and 11.74 (1H, bs, NH).
Reaction SMILES: [F:1][C:2]([F:21])([O:7][Si:8]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)(OCC)[O:9][CH2:10][CH3:11])[C:3]([F:6])([F:5])[F:4].S(Cl)([Cl:24])=O.Cl.[NH+]1C=CC=CC=1>>[F:1][C:2]([F:21])([O:7][Si:8]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([Cl:24])[O:9][CH2:10][CH3:11])[C:3]([F:6])([F:5])[F:4]
Reactant: CCO[Si](OCC)(OC(F)(F)C(F)(F)F)c1ccccc1
Reactant: O=S(Cl)Cl
Agent: Cl
Agent: c1cc[nH+]cc1
Product: CCO[Si](Cl)(OC(F)(F)C(F)(F)F)c1ccccc1
Reaction time: 18 h

Procedure:
152.0 g (0.460 mol) pentafluorophenyltriethoxysilane, 34 mL (0.460 mol, 54.724 g) thionylchloride and 6.910 g (0.0598 mol) pyridinium hydrochloride are refluxed and stirred for 18 h. Pyridinium hydrochloride is precipitated at −78° C. and the solution is filtrated. Pentafluorophenylchlorodiethoxysilane is isolated by vacuum distillation.
Reaction SMILES: [C:1]1(=[O:8])[CH:6]=[CH:5][C:4](=[O:7])[CH:3]=[CH:2]1.[CH2:9]=[CH:10][C:11](=[CH2:13])[CH3:12].[Cr](O)(O)(=O)=O>C(O)(=O)C.O>[CH3:13][C:11]1[CH:12]=[C:6]2[C:5](=[CH:9][CH:10]=1)[C:4](=[O:7])[CH:3]=[CH:2][C:1]2=[O:8]
Reactant: O=C1C=CC(=O)C=C1
Reactant: C=CC(=C)C
Agent: O=[Cr](=O)(O)O
Solvent: O
Solvent: CC(=O)O
Product: Cc1ccc2c(c1)C(=O)C=CC2=O
Temperature: 25 °C
Yield: 31.8 %

Procedure:
A solution of 1,4-benzoquinone (13.9 g, 128 mmol) and isoprene (13.1 ml, 131 mmol) was stirred in glacial acetic acid (44 ml) for 68 hours at room temperature. The mixture was diluted with water (44 ml) and refluxed for 11/2 hours. The mixture was cooled to room temperature and acetic acid (84 ml) and chromic acid [chromium trioxide (29.4 g) in water (30 ml)] was added sequentially, before refluxing for a further 11/2 hours. After cooling, the mixture was diluted with water (200 ml) and extracted with ether (3×50 ml). The combined ether fractions were washed with dilute sodium hydroxide solution (2M; 2 15×50 ml), water (2×50 ml), saturated sodium chloride solution (50 ml) and dried over magnesium sulphate. Filtration and evaporation of solvent under reduced pressure, and repeated recrystallisation from petroleum ether yielded the title compound (7 g).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[F:17])=[N:9][N:8]([CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][O:19]3)[C:5]2=[CH:6][N:7]=1.[O:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH:25]1[N:30]1[C:34](B2OC(C)(C)C(C)(C)O2)=[CH:33][N:32]=[CH:31]1.[F-].[Cs+].CN(C=O)C>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.[Cu]I.O>[F:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[C:10]1[C:4]2[C:5](=[CH:6][N:7]=[C:2]([C:34]3[N:30]([CH:25]4[CH2:26][CH2:27][CH2:28][CH2:29][O:24]4)[CH:31]=[N:32][CH:33]=3)[CH:3]=2)[N:8]([CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][O:19]2)[N:9]=1
Reactant: Fc1ccccc1-c1nn(C2CCCCO2)c2cnc(Br)cc12
Reactant: CC1(C)OB(c2cncn2C2CCCCO2)OC1(C)C
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: Fc1ccccc1-c1nn(C2CCCCO2)c2cnc(-c3cncn3C3CCCCO3)cc12
Temperature: 90 °C
Yield: 55.9 %

Procedure:
To a 100 mL of round bottom flask was added 5-bromo-3-(2-fluorophenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridine (150 mg, 0.40 mmol), 1-(tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-imidazole (222 mg, 0.80 mmol), Pd(PPh3)4(33 mg, 0.04 mmol), CsF (152 mg, 1 mmol), CuI (8 mg, 0.04 mmol) and DMF (6 mL). The reaction mixture was heated at 90° C. under nitrogen for overnight. The resulting mixture was poured into 50 mL of water and extracted with ethyl acetate (50 mL×3). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified via flash chromatography eluting with 5% to 10% CH3OH in CH2Cl2 to afford 3-(2-fluorophenyl)-1-(tetrahydro-2H-pyran-2-yl)-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-imidazol-5-yl)-1H-pyrazolo[3,4-c]pyridine as a brown oil (100 mg, 84%). ESI MS m/z=448 (M+1).
Reaction SMILES: [CH3:1][C:2]1[N:7]2[C:8](=[O:15])[C:9]([C:12]([OH:14])=O)=[CH:10][N:11]=[C:6]2[CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.ClC(OC)=O.[CH2:28]([NH2:34])[CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]>C(Cl)(Cl)Cl>[CH2:28]([NH:34][C:12]([C:9]1[C:8](=[O:15])[N:7]2[C:2]([CH3:1])=[CH:3][CH:4]=[CH:5][C:6]2=[N:11][CH:10]=1)=[O:14])[CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]
Reactant: CCCCCCN
Reactant: Cc1cccc2ncc(C(=O)O)c(=O)n12
Agent: COC(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCCCCCNC(=O)c1cnc2cccc(C)n2c1=O
Reaction time: 0.08 h
Yield: 71.3 %

Procedure:
A mixture containing 16.32 g (0.08 mol) of 6-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-3-carboxylic acid and 12.4 ml (0.088 mol) of triethylamine in 480 ml of chloroform is cooled below -10° C. by ice-salt. A solution of 6.5 ml (0.08 mol) of methyl chloroformate in 40 ml of chloroform is dropped to the above mixture at a temperature between -11° C. and -12° C. during 20 minutes. After stirring for 5 minutes, 8.9 g (0.088 mol) of hexylamine dissolved in 80 ml of dried chloroform are dropped to the above solution at -12° C. during 35 minutes. The reaction mixture is stirred at the same temperature for 1 hour and then let to stand under cooling by ice. For working up, the reaction mixture is washed 3 times with 150 ml of 5% sodium hydrogen carbonate solution each and then 3 times with 150 ml of water each. The organic phase is dried over anhydrous sodium sulfate, filtered and evaporated to give 16.4 g (71.3%) of the named product as yellow crystals after recrystallization from ethanol, m.p.: 116°-118° C.
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)[C:12]2N=CC=[CH:16][C:11]=2[N:10]=N1.[NH2:25][C:26]1[N:27]=[C:28]([C:38]2[CH:43]=[C:42]([O:44][CH2:45][C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)[C:41]([Cl:52])=[CH:40][C:39]=2[Cl:53])[C:29]2[CH:34]=[C:33]([C:35]([OH:37])=O)[S:32][C:30]=2[N:31]=1.C(N)(C)C>CN(C=O)C>[CH:11]([NH:10][C:35]([C:33]1[S:32][C:30]2[N:31]=[C:26]([NH2:25])[N:27]=[C:28]([C:38]3[CH:43]=[C:42]([O:44][CH2:45][C:46]4[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=4)[C:41]([Cl:52])=[CH:40][C:39]=3[Cl:53])[C:29]=2[CH:34]=1)=[O:37])([CH3:16])[CH3:12]
Reactant: Nc1nc(-c2cc(OCc3ccccc3)c(Cl)cc2Cl)c2cc(C(=O)O)sc2n1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CC(C)N
Product: CC(C)NC(=O)c1cc2c(-c3cc(OCc4ccccc4)c(Cl)cc3Cl)nc(N)nc2s1
Temperature: 60 °C

Procedure:
O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (1.176 g; 3.07 mmol) was added to 2-Amino-4-(5-benzyloxy-2,4-dichloro-phenyl)-thieno[2,3-d]pyrimidine-6-carboxylic acid. 2NaCl (1.33 g; 2.38 mmol) then DMF (25 ml) was added to afford a turbid brown solution. Isopropylamine (1.01 ml; 11.9 mmol) was added and reaction mixture was heated at 60° C. (oil bath temperature) for 18 hours. Reaction mixture was allowed to cool to room temperature and DMF was removed in vacuo. The residue was partitioned between ethyl acetate (200 ml) and water (200 ml). The phases were separated and the organic phase was washed with saturated aqueous sodium chloride solution (200 ml) the dried over anhydrous sodium sulphate, filtered and the filtrate solvents removed in vacuo to afford a yellow solid. The crude product was purified by flash chromatography on silica gel (50 g IST Flash Si cartridge) eluting with a solvent gradient of 20 to 50% ethyl acetate in hexane. This affords product as a colourless solid (0.612 g; 53%)
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.CS(C)=O.[CH2:12](Cl)[C:13]#[CH:14]>O.C(=O)([O-])[O-].[Ag+2]>[C:12]([O:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1)#[C:13][CH3:14]
Reactant: C#CCCl
Reactant: Oc1ccncc1
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Solvent: CS(C)=O
Solvent: O
Product: CC#COc1ccncc1
Temperature: 25 °C
Yield: 3.6 %

Procedure:
To a solution of 20.0 g (0.21 mole) 4-hydroxypyridine and 200 ml dimethyl sulfoxide was added 102 g (0.1 mole) silver carbonate. Propargyl chloride (22.5 g, 0.3 mole) was added to this suspension and the mixture heated at 50° for 6 hrs. After cooling to room temperature, the reaction mixture was diluted with water and extracted two times with ether. The combined ether extract was dried, filtered and concentrated as before to give 1.0 g of 4-(propynyloxy)pyridine. The product was 95% pure by vpc. The nmr and ir were compatible with the structure.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([C:14]([C:16]2[C:21]([Cl:22])=[CH:20][N:19]=[C:18]3[N:23]([Si](C(C)C)(C(C)C)C(C)C)[CH:24]=[CH:25][C:17]=23)=O)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:36][NH2:37].CC(O)=O>CCO>[CH2:1]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([C:14](=[N:36][NH2:37])[C:16]2[C:21]([Cl:22])=[CH:20][N:19]=[C:18]3[NH:23][CH:24]=[CH:25][C:17]=23)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NN
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc2c(C(=O)C3CCCN(Cc4ccccc4)C3)c(Cl)cnc21
Solvent: CC(=O)O
Solvent: CCO
Product: NN=C(c1c(Cl)cnc2[nH]ccc12)C1CCCN(Cc2ccccc2)C1
Temperature: 25 °C
Yield: 99.5 %

Procedure:
A mixture of (1-benzylpiperidin-3-yl)(5-chloro-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)methanone (1.45 g, 2.84 mmol), anhydrous hydrazine (0.273 g, 8.53 mmol) and AcOH (0.163 mL, 2.84 mmol) was heated in EtOH (35 mL) at reflux for about 16 h. The reaction mixture was cooled to room temperature, the solvent was removed under reduced pressure and the residue partitioned between saturated aqueous NaHCO3 (50 mL) and EtOAc (60 mL). The organic phase was washed with brine (40 mL) and concentrated to yield 4-((1-benzylpiperidin-3-yl)(hydrazono)methyl)-5-chloro-1H-pyrrolo[2,3-b]pyridine (1.04 g, quantitative) as a brown amorphous solid that was used directly in the next step without further purification: LC/MS (Table 2, Method a) Rt=1.57 min; MS m/z: 368 (M+H)+.
Reaction SMILES: O=O.[CH2:3]([O:6][CH2:7][CH:8]([OH:11])[CH2:9][OH:10])[C:4]#[CH:5]>Cl[Cu].[NH4+].[Cl-]>[OH:11][CH:8]([CH2:9][OH:10])[CH2:7][O:6][CH2:3][C:4]#[C:5][C:5]#[C:4][CH2:3][O:6][CH2:7][CH:8]([OH:11])[CH2:9][OH:10]
Reactant: C#CCOCC(O)CO
Agent: Cl[Cu]
Agent: O=O
Agent: [Cl-]
Product: OCC(O)COCC#CC#CCOCC(O)CO
Yield: 75.9 %

Procedure:
An aqueous NH4Cl solution was saturated at 5° C. CuCl (1.0 g, 18.7 mmol) was added to 20 ml of the saturated aqueous NH4Cl solution. The reaction vessel was filled with O2 and the mixture was vigorously stirred during the whole reaction time. 3-(2-propynyloxy)-propane-1,2-diol (4, 13.01 g, 100 mmol) was added at room temperature in 5 portions during 2.5 hours. The reaction mixture was stirred at 40° for 1 hour and then evaporated to dryness. The residue was dissolved in 50 ml CH3CN:H2O=1:1 and filtered through 20 g silica 60. The filter column was washed with 100 ml CH3CN:H2O=1:1 and the filtrate was evaporated to dryness. The residue was suspended in MeOH (70 ml) and insoluble inorganic components removed by filtration. The filtrate was diluted with water (500 ml) and stirred with ion exchangers (IRA 67, 110 ml; AMB 200 C, 110 ml) and activated carbon (0.1 g). The ion exchangers were filtered off and washed with water (2×250 ml). The combined filtrates were evaporated and gave 9.8 g 17 as a light yellow oil in 76% yield. TLC on silica; H2O:CH3CN=1:1, Rf=0.79; CH3CN, Rf=0.26.
Reaction SMILES: C([Li])CCC.C([O:13][C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][CH:22]=1)[N:19]([S:23]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)(=[O:25])=[O:24])[CH:18]=[C:17]2[CH2:32][C@H:33]1[CH2:37][CH2:36][CH2:35][N:34]1[CH3:38])C1C=CC=CC=1.[CH2:39](Br)[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>C1COCC1>[CH2:39]([C:18]1[N:19]([S:23]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)(=[O:24])=[O:25])[C:20]2[C:16]([C:17]=1[CH2:32][C@H:33]1[CH2:37][CH2:36][CH2:35][N:34]1[CH3:38])=[CH:15][C:14]([OH:13])=[CH:22][CH:21]=2)[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1
Reactant: CN1CCC[C@@H]1Cc1cn(S(=O)(=O)c2ccccc2)c2ccc(OCc3ccccc3)cc12
Reactant: BrCc1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CN1CCC[C@@H]1Cc1c(Cc2ccccc2)n(S(=O)(=O)c2ccccc2)c2ccc(O)cc12
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 52.2 %

Procedure:
n-Butyllithium (0.10 mL, 1.45M in hexane, 0.14 mmol) was added to a solution of (R)-5-benzyloxy-3-(1-methyl-2-pyrrolidinylmethyl)-1-phenylsulfonylindole (Example 7e, 24 mg, 0.052 mmol) in THF (2 mL) at -78° C.; the temperature was raised to 0° C. and the mixture was stirred for 20 min. After recooling to -78° C., benzyl bromide (18 μL, 0.15 mmol) was added and the mixture was stirred for 1 h at 78° C.; then 15 min. without cooling prior to quenching with water and extraction with ethyl acetate. The organic layer was washed sequentially with water and brine, and dried over sodium sulfate. Palladium on carbon (10%) was added to a solution of the crude product in methanol (2 mL) and the mixture was stirred under an atmosphere of hydrogen for 1.5 h. Removal of the catalyst by filtration followed by flash chromatography (silica gel, 0-10% 2M methanolic ammonia in dichloromethane) yielded (R)-2-benzyl-5-hydroxy-3-(1-methyl-2-pyrrolidinylmethyl)-1-phenylsulfonylindole (12.5 mg, 40%; HRMS-FAB+ for C27H28N2O3S calculated MH+ :461.18988; found MH+ :461.18724).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]2[C:15]([N+:27]([O-:29])=[O:28])=[CH:16][C:17]3[NH:22][C:21](=[O:23])[O:20][C:19]([CH3:25])([CH3:24])[C:18]=3[CH:26]=2)=[CH:4][CH:3]=1.[OH:30]O>>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]2[C:15]([N+:27]([O-:29])=[O:28])=[CH:16][C:17]3[NH:22][C:21](=[O:23])[O:20][C:19]([CH3:25])([CH3:24])[C:18]=3[CH:26]=2)=[O:30])=[CH:6][CH:7]=1
Reactant: Cc1ccc(SCCCCOc2cc3c(cc2[N+](=O)[O-])NC(=O)OC3(C)C)cc1
Reactant: OO
Product: Cc1ccc(S(=O)CCCCOc2cc3c(cc2[N+](=O)[O-])NC(=O)OC3(C)C)cc1

Procedure:
Prepared analogously to Example 2 from 6-[4-(4-methylphenylmercapto)-butoxy]-7-nitro-4,4-dimethyl-4H-3,1-benzoxazin-2-one and hydrogen peroxide.
Reaction SMILES: C(OP([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])(OCC)=O)C.[H-].[Na+].[N:17]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[CH:29]([CH:33]([C:42]([NH2:44])=[O:43])[C:34]2[CH:41]=[CH:40][C:37]([CH:38]=O)=[CH:36][CH:35]=2)[CH2:30][CH2:31][CH3:32])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1>CN(C)C=O>[N:17]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[CH:29]([CH:33]([C:42]([NH2:44])=[O:43])[C:34]2[CH:35]=[CH:36][C:37]([CH:38]=[CH:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:40][CH:41]=2)[CH2:30][CH2:31][CH3:32])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Reactant: CCCC(c1ccccc1N1CCCCC1)C(C(N)=O)c1ccc(C=O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCC(c1ccccc1N1CCCCC1)C(C(N)=O)c1ccc(C=CC(=O)OCC)cc1
Reaction time: 0.25 h

Procedure:
A solution of 2.80 gm (12.5 m mol) of ethyl diethylphosphonoacetate in 10 ml of absolute dimethylformamide was added dropwise, at ambient temperature, to 0.60 gm (12.5 m mol) of sodium hydride (50% in oil) in 15 ml of absolute dimethylformamide. The mixture was stirred for 15 minutes (until the development of gas ceased), and then a solution of 2.4 gm (6.34 m mol) of 4-[(1-(2-piperidino-phenyl)-1-butyl)-aminocarbonylmethyl]-benzaldehyde in 10 ml of absolute dimethylformamide was added thereto dropwise. The mixture was stirred for two hours at ambient temperature, concentrated by evaporation in vacuo, and distributed between water and ether. The ether phase was dried, filtered, and then evaporated in vacuo. The evaporation residue was purified by column chromatography on silica gel [toluene/acetone (10:1)].
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[CH3:5][C:6]1([CH3:13])[NH:10][C:9](=[O:11])[CH2:8][C:7]1=[O:12].C(N(CC)CC)C>C(Cl)Cl>[C:1]([O:12][C:7]1[C:6]([CH3:13])([CH3:5])[NH:10][C:9](=[O:11])[CH:8]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: CC1(C)NC(=O)CC1=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)OC1=CC(=O)NC1(C)C
Reaction time: 24 h
Yield: 18.7 %

Procedure:
At 0 to 5° C., a solution of 4.08 g of acetyl chloride in 20 of methylene chloride is added dropwise to a solution of 6.36 g of 5,5-dimethylpyrrolidine-2,4-dione and 5.57 g of triethylamine in 50 ml of methylene chloride. The mixture is then left to reach room temperature over the course of approximately one hour and then stirred for a further 24 hours. The reaction mixture is then diluted with 50 ml of methylene chloride, and extracted by shaking twice with in each case 50 ml of water, twice with in each case 25 ml of 5% strength sodium hydroxide solution and once with 50 ml of saturated aqueous NaCl solution. Drying and concentration by evaporation gives 1.58 g of the title compound in a purity according to HPLC of 97%.