Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@:12]([C:24](=[O:26])[NH2:25])([CH2:18][C:19](OCC)=[O:20])[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O-]CC.[Na+].Cl>C(O)C>[CH2:1]([O:8][C:9]([NH:11][C@:12]1([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:18][C:19](=[O:20])[NH:25][C:24]1=[O:26])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C[C@@](NC(=O)OCc1ccccc1)(C(N)=O)C(=O)OCC
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)[C@@]1(NC(=O)OCc2ccccc2)CC(=O)NC1=O
Yield: 85.2 %

Procedure:
A solution of (R)-diethyl 2-benzyloxycarbonylamino-2-carbamoylsuccinate (200 mg) in dehydrated ethanol (10 mL) was added with sodium ethoxide (41 mg) with ice cooling and stirring, the mixture was stirred at the same temperature for 2 hours, then cold 1 mol/L hydrochloric acid was poured into the mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was recrystallized from ethyl acetate/n-hexane to obtain the title compound (149 mg, yield: 85%) as colorless crystals. Optical rotation [α]D28 was −31.8° (c 0.59, ethanol), and optical purity was 99.2% ee.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([NH:14][C:15]([C:17]2[CH:18]=[N:19][N:20]3[CH:25]=[CH:24][C:23](Cl)=[N:22][C:21]=23)=[O:16])=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[CH3:13])[N:6]=1.[NH3:27]>CC(O)C>[CH3:1][C:2]1[S:3][C:4]([NH:14][C:15]([C:17]2[CH:18]=[N:19][N:20]3[CH:25]=[CH:24][C:23]([NH2:27])=[N:22][C:21]=23)=[O:16])=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[CH3:13])[N:6]=1
Reactant: N
Reactant: Cc1nc(-c2ccccc2C)c(NC(=O)c2cnn3ccc(Cl)nc23)s1
Solvent: CC(C)O
Product: Cc1nc(-c2ccccc2C)c(NC(=O)c2cnn3ccc(N)nc23)s1
Temperature: 120 °C
Yield: 16 %

Procedure:
A mixture of 5-chloro-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (2-methyl-4-o-tolyl-thiazol-5-yl)-amide (74.0 mg, 0.19 mmol, 1.0 equiv) and 2M ammonia in propan-2-ol (3 mL) was sealed and heated in a microwave reactor at 120° C. for 1 hour. The solvent was removed under vacuum, and the resultant residue purified by flash column chromatography on silica gel (gradient: 0 to 5% methanol in dichloromethane) to afford 11.0 mg (16%) of 5-amino-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (2-methyl-4-o-tolyl-thiazol-5-yl)-amide. LCMS (ESI) m+H=365.1; 1H NMR (400 MHz, DMSO-d6) δ: 10.35 (s, 1H), 8.66 (d, 1H), 8.23 (s, 1H), 7.47-7.37 (m, 4H), 6.38 (d, 1H), 2.61 (s, 3H), 2.20 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:6]([NH2:7])=[C:5]([C:8]([O:10][CH3:11])=[O:9])[S:4][C:3]=1[CH3:12].C1N=CN([C:18](N2C=NC=C2)=[S:19])C=1.O>CN(C=O)C>[CH3:12][C:3]1[S:4][C:5]([C:8]([O:10][CH3:11])=[O:9])=[C:6]2[C:2]=1[NH:1][C:18](=[S:19])[NH:7]2
Reactant: COC(=O)c1sc(C)c(N)c1N
Reactant: S=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1sc(C)c2[nH]c(=S)[nH]c12
Temperature: 50 °C
Reaction time: 1 h

Procedure:
A mixture of methyl 3,4-diamino-2-methylthiophene-5-carboxylate (1.0 g) and N,N'-thiocarbonyldiimidazole (1.1 g) in DMF (5 ml) was stirred at 50° C. for one hour. To the reaction mixture was added water to give crystals. Recrystallization from DMF-water afforded colorless prisms (1.2 g, quantitatively), m.p. 285°-288° C. (dec.)
Reaction SMILES: Br[C:2]1[C:3]([NH:8][C@H:9]([C:14]([NH:16][CH2:17][C:18]#[N:19])=[O:15])[CH2:10][CH:11]([CH3:13])[CH3:12])=[N:4][O:5][C:6]=1[CH3:7].C(OC([N:27]1[CH2:32][CH2:31][N:30]([C:33]2[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=2)[CH2:29][CH2:28]1)=O)(C)(C)C>>[C:18]([CH2:17][NH:16][C:14](=[O:15])[C@H:9]([CH2:10][CH:11]([CH3:13])[CH3:12])[NH:8][C:3]1[C:2]([C:36]2[CH:35]=[CH:34][C:33]([N:30]3[CH2:29][CH2:28][NH:27][CH2:32][CH2:31]3)=[CH:38][CH:37]=2)=[C:6]([CH3:7])[O:5][N:4]=1)#[N:19]
Reactant: Cc1onc(N[C@@H](CC(C)C)C(=O)NCC#N)c1Br
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(B(O)O)cc2)CC1
Product: Cc1onc(N[C@@H](CC(C)C)C(=O)NCC#N)c1-c1ccc(N2CCNCC2)cc1

Procedure:
N2-(4-bromo-5-methylisoxazol-3-yl)-N1-(cyanomethyl)leucinamide was treated with 4-[4-(tert-butoxycarbonyl)-1-piperazinyl]phenylboronic acid (prepared as described in Example 1) as described in Example 1 to afford, after BOC removal with methanesulfonic acid as described in Example 1, N1-(cyanomethyl)-N2-[5-methyl-4-(4-piperazin-1-ylphenyl)isoxazol-3-yl]leucinamide. MS (+APCI): 411.4 [M+1]+
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[NH:7][CH2:8][C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=1)=O)([CH3:4])([CH3:3])[CH3:2].C([O-])(=O)C.[NH4+].C([BH3-])#[N:25].[Na+]>CO>[C:1]([O:5][C:6](=[O:18])[NH:7][CH2:8][CH:9]([NH2:25])[C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: [BH3-]C#N
Reactant: CC(C)(C)OC(=O)NCC(=O)c1cccc(F)c1
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)OC(=O)NCC(N)c1cccc(F)c1
Yield: 91 %

Procedure:
To a flask were added tert-butyl[2-(3-fluorophenyl)-2-oxoethyl]carbamate (0.32 g, 1.3 mmol) and ammonium acetate (2.02 g, 26.2 mmol) and methanol (10 mL) and sodium cyanoborohydride (0.22 g, 3.5 mmol). The mixture was refluxed for 2 h. The solvent was removed under vacuum. To the residue was added EtOAc and 50 mL of 1M NaOH. The aqueous phase was extracted again with fresh EtOAc. The combined organic extracts were dried over sodium sulfate, filtered and dried under vacuum to give 0.301 g (94% yield) of the final product as oil. LC-MS found: 155.1 (M−Boc)+.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1F)([O-:3])=[O:2].[C:14]([NH:17][CH2:18][CH2:19][N:20]1[C:24]([SH:25])=[N:23][N:22]=[N:21]1)(=[O:16])[CH3:15].C(N(CC)CC)C>CC(C)=O>[C:14]([NH:17][CH2:18][CH2:19][N:20]1[C:24]([S:25][C:5]2[CH:6]=[CH:7][C:8]([N+:10]([O-:12])=[O:11])=[CH:9][C:4]=2[N+:1]([O-:3])=[O:2])=[N:23][N:22]=[N:21]1)(=[O:16])[CH3:15]
Reactant: CC(=O)NCCn1nnnc1S
Reactant: O=[N+]([O-])c1ccc(F)c([N+](=O)[O-])c1
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: CC(=O)NCCn1nnnc1Sc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]

Procedure:
A solution of 9.3 g. (0.050 mol.) of 2,4-dinitroflurobenzene in 50 ml. of acetone was added to a solution of 9.35 g. (0.050 mol.) of 1-(2-acetamidoethyl)tetrazole-5-thiol and 6.85 ml. (0.050 mol.) of triethylamine in 100 ml. of acetone and the reaction mixture was stirred for 1 hour. The solid was collected and recrystallized from acetonitrile to give 1-(2-acetamidoethyl)-5-(2,4-dinitrophenylthio)tetrazole, m.p. 197°-198°.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6](B(O)O)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[Cl-].[Li+].C(=O)([O-])[O-].[Na+].[Na+].C(O[CH2:25][CH3:26])(=O)C>COCCOC.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>[C:26]1([C:6]2[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:9]=[CH:8][CH:7]=2)[CH2:25][CH2:8][CH2:9][CH2:4][CH:5]=1
Reactant: CCOC(C)=O
Reactant: O=[N+]([O-])c1cccc(B(O)O)c1
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: [Cl-]
Solvent: COCCOC
Product: O=[N+]([O-])c1cccc(C2=CCCCC2)c1

Procedure:
The above product (1.3 g) is dissolved in ethylene glycol dimethyl ether (10 ml), and thereto are added 3-nitrophenylboronic acid (1.3 g), tetrakis(triphenylphosphine)palladium (0) (330 mg), lithium chloride (720 mg) and 2M aqueous sodium carbonate (8 ml), and the mixture is heated under reflux for 3 hours. To the mixture is added ethyl acetate, and the organic layer is washed with water, and the solvent is evaporated under reduced pressure. The residue is purified by silica gel column chromatography (eluent: gradient from 0% to 100% hexane/ethyl acetate) to give 3-(cyclohexen-1-yl)-1-nitrobenzene (700 mg).
Reaction SMILES: [NH3:1].[C:2]1([S:8]([C:11]2[C:12]([S:25][CH3:26])=[N:13][N:14]3[C:19](Cl)=[CH:18][C:17]([CH2:21][N:22]([CH3:24])[CH3:23])=[N:16][C:15]=23)(=[O:10])=[O:9])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CO.CN(C=O)C>[C:2]1([S:8]([C:11]2[C:12]([S:25][CH3:26])=[N:13][N:14]3[C:19]([NH2:1])=[CH:18][C:17]([CH2:21][N:22]([CH3:24])[CH3:23])=[N:16][C:15]=23)(=[O:10])=[O:9])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CSc1nn2c(Cl)cc(CN(C)C)nc2c1S(=O)(=O)c1ccccc1
Reactant: N
Solvent: CO
Solvent: CN(C)C=O
Product: CSc1nn2c(N)cc(CN(C)C)nc2c1S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 78 %

Procedure:
20 ml of a 50% solution of NH3 in MeOH were added to a solution of 1.20 g (3 mmol) of (3-benzenesulphonyl-7-chloro-2-methylsulphanyl-pyrazolo[1,5-a]pyrimidin-5-ylmethyl)-dimethyl-amine in 30 ml of DMF and stirred at RT for 4 hrs. The reaction solution was evaporated and the residue was partitioned between 2N NaOH and CH2Cl2. The aqueous phase was extracted three times with CH2Cl2, and the combined organic phases were dried (MgSO4), filtered and evaporated. Subsequent chromatography (silica gel, CH2Cl2/MeOH 6:1) yielded 0.90 g (78%) of 3-benzenesulphonyl-5-dimethylaminomethyl-2-methylsulphanyl-pyrazolo[1,5-a]pyrimidin-7-ylamine as colorless crystals, m.p. 216-218°.
Reaction SMILES: CC1(C)COB([C:8]2[CH:22]=[CH:21][C:11]([O:12][CH2:13][CH2:14][N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:10][CH:9]=2)OC1.Br[C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][C:33]=1[Cl:34])[NH:30][CH:29]=[C:28]2[CH:35]=[O:36].C(=O)([O-])[O-].[K+].[K+].C1(C)C=CC=CC=1>C(O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(OCC)(=O)C>[Cl:34][C:33]1[CH:32]=[C:31]2[C:27]([C:28]([CH:35]=[O:36])=[CH:29][NH:30]2)=[CH:26][C:25]=1[C:8]1[CH:9]=[CH:10][C:11]([O:12][CH2:13][CH2:14][N:15]2[CH2:16][CH2:17][O:18][CH2:19][CH2:20]2)=[CH:21][CH:22]=1
Reactant: CC1(C)COB(c2ccc(OCCN3CCOCC3)cc2)OC1
Reactant: O=Cc1c[nH]c2cc(Cl)c(Br)cc12
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: Cc1ccccc1
Product: O=Cc1c[nH]c2cc(Cl)c(-c3ccc(OCCN4CCOCC4)cc3)cc12
Temperature: 110 °C
Yield: 56.3 %

Procedure:
To a solution of 4-{2-[4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)phenoxy]ethyl}morpholine (190 mg, 0.6 mmol) in ethanol (2.4 mL) were added 5-bromo-6-chloro-1H-indole-3-carbaldehyde (187 mg, 0.72 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (45 mg, 0.06 mmol), 2M aqueous potassium carbonate (1.2 mL, 2.4 mmol) and toluene (7 mL). The mixture was degassed with nitrogen for 3 min and heated to 110° C. by microwave irradiation for 1 h. The mixture was concentrated in vacuo to give a residue, which was dissolved with ethyl acetate (50 mL) and washed with brine (2×15 mL). The organic layer was dried over Na2SO4 and concentrated in vacuo to give a residue, which was purified by flash chromatography to give 6-chloro-5-{4-[2-(morpholin-4-yl)ethoxy]phenyl}-1H-indole-3-carbaldehyde (130 mg, 57%) as a yellow oil.
Reaction SMILES: [F:1][C:2]1[C:3]([F:26])=[C:4]2[O:9][CH2:8][C:7]3([CH2:13][CH2:12][CH2:11][CH2:10]3)[N:6]3[CH:14]=[C:15]([C:23]([OH:25])=[O:24])[C:16](=[O:22])[C:17]([C:18]=1[N+:19]([O-])=O)=[C:5]23.CN(C=O)C>C(O)C.C(O)(=O)C.[Pd]>[NH2:19][C:18]1[C:17]2[C:16](=[O:22])[C:15]([C:23]([OH:25])=[O:24])=[CH:14][N:6]3[C:7]4([CH2:13][CH2:12][CH2:11][CH2:10]4)[CH2:8][O:9][C:4]([C:5]=23)=[C:3]([F:26])[C:2]=1[F:1]
Reactant: O=C(O)c1cn2c3c(c(F)c(F)c([N+](=O)[O-])c3c1=O)OCC21CCCC1
Agent: [Pd]
Solvent: CCO
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: Nc1c(F)c(F)c2c3c1c(=O)c(C(=O)O)cn3C1(CCCC1)CO2
Yield: 84748.2 %

Procedure:
A solution of 9′,10′-difluoro-8′-nitro-7′-oxospiro[cyclopentane-1,3′(2′H)-[7H]pyrido[1,2,3-de][1,4]benzoxazine]-6′-carboxylic acid (3.9 g, 0.01 mmol) in ethanol/acetic acid (1:1, v/v, 100 mL) was hydrogenated under atmospheric pressure over 10% Pd/C (390 mg) at 80° C. for 18 h. Then 200 mL of DMF were added and the reaction mixture was heated until it became clear. The catalyst was removed by filtration over Celite, which was washed two times with hot DMF and the combined filtrates were concentrated in vacuo to dryness to yield the title compound (2.85 g, 73%) which was used crude in the next step.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][NH:23][CH3:24])=[CH:12][CH:11]=2)=[O:9])=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.Br[CH2:35][CH:36]1[CH2:38][CH2:37]1>CC(N(C)C)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][N:23]([CH2:35][CH:36]3[CH2:38][CH2:37]3)[CH3:24])=[CH:12][CH:11]=2)=[O:9])=[CH:6][CH:7]=1
Reactant: CNCCCCCCOc1ccc(C(=O)c2ccc(Br)cc2)cc1
Reactant: BrCC1CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: CN(CCCCCCOc1ccc(C(=O)c2ccc(Br)cc2)cc1)CC1CC1
Temperature: 50 °C
Reaction time: 24 h

Procedure:
A mixture of 0.1 g of (4-bromo-phenyl)-[4-(6-methylamino-hexyloxy)-phenyl]-methanone, 0.13 ml of diisopropylethylamine and 0.06 ml of bromomethyl-cyclopropane in 20 ml of dimethyl-acetamide is stirred at 50° C. for 24 hrs., concentrated and the residue is treated with sodium hydrogen carbonate solution and extracted with methylene chloride. The organic phases are washed with saturated sodium chloride solution, dried and evaporated. The residue is purified over silica gel with CH2Cl2 /MeOH/NH4OH (94/5.410.6 to 85/12.5/2.5). There is obtained 0.68 g of (4-bromo-phenyl)-[4-[6-(cyclopropylmethyl-methyl-amino)-hexyloxy]-phenyl]-methanone which is converted into the fumarate, MS: m/e 443 (M+H+, 1Br).
Reaction SMILES: Br[C:2]1[N:6]2[N:7]=[C:8]([Cl:11])[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.[CH3:12][O:13][C:14]1[N:15]=[N:16][CH:17]=[CH:18][C:19]=1[Sn](CCCC)(CCCC)CCCC>[Cu]I.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.CN(C=O)C>[Cl:11][C:8]1[CH:9]=[CH:10][C:5]2[N:6]([C:2]([C:19]3[CH:18]=[CH:17][N:16]=[N:15][C:14]=3[O:13][CH3:12])=[CH:3][N:4]=2)[N:7]=1
Reactant: Clc1ccc2ncc(Br)n2n1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccnnc1OC
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: COc1nnccc1-c1cnc2ccc(Cl)nn12
Temperature: 100 °C
Reaction time: 20 h
Yield: 64.2 %

Procedure:
A mixture of 3-bromo-6-chloroimidazo[1,2-b]pyridazine (Preparation 1b, 182 mg, 0.78 mmol), 3-methoxy-4-(tributylstannyl)pyridazine (Preparation 8b, 313 mg, 0.78 mmol), copper(I) iodide (15 mg, 0.08 mmol) and dry N,N′-dimethylformamide (4 mL) in a Schlenk vial was subjected to three cycles of evacuation backfilling with argon. Tetrakis(triphenylphosphine)palladium(0) (91 mg, 0.08 mmol) was then added and the resulting mixture was subjected to three further cycles of evacuation backfilling with argon before being stirred at 100° C. for 20 hours. The reaction mixture was cooled down, the solvent was removed under reduced pressure and the residue was purified by flash chromatography (1:1 hexanes/ethyl acetate to 100% ethyl acetate) to give the title compound (131 mg, 64%) as a beige solid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH2:13][CH2:14][N:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1)[CH:8]=[CH:7]2)([O-])=O>C(O)C.[Pd]>[N:15]1([CH2:14][CH2:13][N:9]2[C:10]3[C:6](=[CH:5][C:4]([NH2:1])=[CH:12][CH:11]=3)[CH:7]=[CH:8]2)[CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: O=[N+]([O-])c1ccc2c(ccn2CCN2CCCC2)c1
Agent: [Pd]
Solvent: CCO
Product: Nc1ccc2c(ccn2CCN2CCCC2)c1
Reaction time: 8 h

Procedure:
Dissolve 5-nitro-1-(2-pyrrolidin-1-yl-ethyl)-1H-indole (375 mg, 1.45 mmol) in ethanol (15 mL) and add 5% Pd/C (149 mg). Purge the black mixture with hydrogen (1 atm) and stir overnight under a hydrogen atmosphere. Filter the black mixture through Celite® and wash the solids with additional ethanol (˜10 mL). Concentrate the filtrate to give the title compound as a yellow solid. MS (ES+) 230.2 (M+1)+. 1H NMR (400 MHz, CDCl3): δ: 7.17 (d, 1H, J=8.8 Hz), 7.05 (d, 1H, J=3.1 Hz), 6.92 (d, 1H, J=2.2 Hz), 6.67 (dd, 1H, J=8.3, 2.2 Hz), 6.29 (d, 1H, J=3.1 Hz), 4.21 (t, 2H, J=7.5 Hz), 3.37 (s, 2H), 2.86 (t, 2H, J=7.5 Hz), 2.55 (m, 4H), 1.79 (m, 4H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH2:9][CH2:8][CH:7]([N:15]([CH3:17])[CH3:16])[CH2:6][C:5]2=1.[CH3:18][C:19]1[O:23][CH:22]=[C:21]([C:24](O)=[O:25])[CH:20]=1>>[CH3:18][C:19]1[O:23][CH:22]=[C:21]([C:24]([NH:1][C:2]2[CH:3]=[C:4]3[C:12](=[CH:13][CH:14]=2)[NH:11][C:10]2[CH2:9][CH2:8][CH:7]([N:15]([CH3:17])[CH3:16])[CH2:6][C:5]3=2)=[O:25])[CH:20]=1
Reactant: CN(C)C1CCc2[nH]c3ccc(N)cc3c2C1
Reactant: Cc1cc(C(=O)O)co1
Product: Cc1cc(C(=O)Nc2ccc3[nH]c4c(c3c2)CC(N(C)C)CC4)co1
Yield: 61.6 %

Procedure:
Beginning with 8.7 mg (0.038 mMol) 6-amino-3-(dimethyl)amino-1,2,3,4-tetrahydro-9H-carbazole and 10.0 mg (0.090 mMol) 5-methylfuran-3-carboxylic acid, 7.9 mg (62%) of the title compound were recovered as a beige solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[CH2:4][CH2:5][S:6](=[O:14])(=[O:13])[NH:7][CH2:8][CH2:9][CH2:10][CH:11]=[CH2:12].[C:16]([O-])([O-])=O.[K+].[K+].CI>CN(C=O)C.CCOC(C)=O>[CH3:1][O:2][C:3](=[O:15])[CH2:4][CH2:5][S:6](=[O:14])(=[O:13])[N:7]([CH3:16])[CH2:8][CH2:9][CH2:10][CH:11]=[CH2:12]
Reactant: C=CCCCNS(=O)(=O)CCC(=O)OC
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C=CCCCN(C)S(=O)(=O)CCC(=O)OC

Procedure:
To a stirred suspension of 1.03 g (12.0 mmol) pent-4-enylamine, 8 ml DCM and 5 ml 10% aqueous Na2CO3 at 0° C. are added dropwise 2.25 g (12.0 mmol) 3-chlorosulfonyl-propionic acid methyl ester. After stirring for 2 h at 25° C. the phases are separated and the organic phase is dried with sodium sulfate and evaporated. Chromatography on silica gel (EtOAc, hexane 1:2) gives the 3-pent-4-enylsulfamoyl-propionic acid methyl ester. This ester is dissolved in 2 ml DMF and heated to 65° C. in the presence of 1.58 g (11.5 mmol) K2CO3 and 0.716 ml methyl iodide for 5 h. The mixture is diluted with EtOAc and washed with water, dried with sodium sulfate and evaporated. Chromatography on silica gel (EtOAc, hexane 1:4) gives the 3-(methyl-pent-4-enyl-sulfamoyl)-propionic acid methyl ester. Hydrolysis of this ester with LiOH in water/MeOH gives the title compound.
Reaction SMILES: [OH:1][NH:2][C:3]([C:5]1[CH:6]=[N:7][C:8]([CH2:11][N:12]=[N+]=[N-])=[CH:9][CH:10]=1)=[NH:4].C1COCC1.O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>>[OH:1][NH:2][C:3]([C:5]1[CH:6]=[N:7][C:8]([CH2:11][NH2:12])=[CH:9][CH:10]=1)=[NH:4]
Reactant: [N-]=[N+]=NCc1ccc(C(=N)NO)cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: N=C(NO)c1ccc(CN)nc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of the azide (11-4) of Example 52 in THF/water (80 ml/5 ml) (7.8 g, 40.6 mmol) was added triphenylphosphine (12.8 g, 48.72 mmol). The reaction mixture was stirred overnight at room temperature. The solvent was removed to dryness and the remaining residue was diluted with 100 ml 1N HCl and 100 ml water. The aqueous layer was extracted several times with dichloromethane. The aqueous layer was made basic (pH˜9) with an alkaline resin (Bio Rad AG 1-X8). The resin was filtered and washed thoroughly with water. The combined washings were dried under reduced pressure to give a white solid (6.60 g).
Reaction SMILES: [CH:1]([C:5]1[CH:6]=[C:7]([NH2:14])[C:8]([O:12][CH3:13])=[C:9]([NH2:11])[CH:10]=1)([CH2:3][CH3:4])[CH3:2].N1C=CC=CC=1.[CH3:21][S:22](Cl)(=[O:24])=[O:23]>ClCCl>[NH2:14][C:7]1[C:8]([O:12][CH3:13])=[C:9]([NH:11][S:22]([CH3:21])(=[O:24])=[O:23])[CH:10]=[C:5]([CH:1]([CH2:3][CH3:4])[CH3:2])[CH:6]=1
Reactant: CCC(C)c1cc(N)c(OC)c(N)c1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCC(C)c1cc(N)c(OC)c(NS(C)(=O)=O)c1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
1.46 g of 5-sec-butyl-2-methoxy-1,3-diamino-benzene are dissolved in 20 ml dichloromethane, combined with 1.21 ml of pyridine and cooled to 0° C. 600 μl of methanesulphonic acid chloride are added, the mixture is allowed to come up to ambient temperature and stirred for 2 hours. The solvents are eliminated in vacuo and the residue is chromatographed on silica gel (cyclohexane/ethyl acetate 80:20 to 20:80).
Reaction SMILES: [C:1]1([O:9][CH3:10])[C:2](=[CH:5][CH:6]=[CH:7][CH:8]=1)[O:3][CH3:4].[Cl-].[Al+3].[Cl-].[Cl-].[F:15][C:16]1[CH:24]=[CH:23][C:19]([C:20](Cl)=[O:21])=[CH:18][CH:17]=1.O.Cl>>[CH3:4][O:3][C:2]1[CH:5]=[C:6]([CH:7]=[CH:8][C:1]=1[O:9][CH3:10])[C:20]([C:19]1[CH:23]=[CH:24][C:16]([F:15])=[CH:17][CH:18]=1)=[O:21]
Reactant: COc1ccccc1OC
Reactant: O=C(Cl)c1ccc(F)cc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Product: COc1ccc(C(=O)c2ccc(F)cc2)cc1OC
Temperature: 0 °C
Reaction time: 12 h

Procedure:
Veratrole (29.3 g) was added, while stirring, to a mixture of aluminum chloride (34 g) and 4-fluorobenzoyl chloride (35 g) which had been cooled to 0° C., and the resulting mixture allowed to stand for 12 hours at room temperature. It was then boiled for 1 hour. The reaction mixture was then decomposed with water/HCl and extracted with chloroform.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][CH:5]=1)=[O:3].[CH:12](=O)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[OH-].[Na+]>C(O)C>[CH3:11][O:10][C:7]1[CH:8]=[CH:9][C:4]([C:2](=[O:3])[CH:1]=[CH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:5][CH:6]=1
Reactant: COc1ccc(C(C)=O)cc1
Reactant: O=Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc(C(=O)C=Cc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91 %

Procedure:
50.1 g. (0.333 m) 4-methoxyacetophenone and 35.4 g (0.333 m) benzaldehyde were combined in a 500 ml Erlenmeyer flask, with the 4-methoxyacetophenone being previously melted. Then 80 ml 5N NaOH solution (appr.) (1.2 × 0.333 m) was added to the mixture. Approximately 40 ml absolute ethanol was added to the stirred mixture in small portions to keep the mixture homogeneous. It was let stir at room temperature overnight, and a solid white cake resulted. The solid was filtered, washed with water, and then recrystallized from methanol/water to give 72.3 g (91%) of 1-(4-methoxyphenyl)-3-phenyl-2-propen-1-one. 10 g (0.0420 m) of this compound and 160 mg Pd on C (10%) were combined with about 200 ml ethyl acetate and placed under 1 atm of hydrogen. Upon stirring, the mixture absorbed 950 ml H2 (calc. 940 ml) and stopped. The reaction mixture was filtered and the clear solution was concentrated to obtain 9.8 g (98%) of 1-(4-methoxyphenyl)-3-phenyl-1-propanone.
Reaction SMILES: O=[C:2]1[CH2:10][CH2:9][CH:8]2[CH:4]([CH2:5][N:6]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7]2)[CH2:3]1.[NH3:18].CO.[BH4-].[Na+]>CCO.CC(O[Ti](OC(C)C)(OC(C)C)OC(C)C)C>[NH2:18][CH:2]1[CH2:10][CH2:9][CH:8]2[CH:4]([CH2:5][N:6]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7]2)[CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CC2CCC(=O)CC2C1
Reactant: N
Agent: CC(C)O[Ti](OC(C)C)(OC(C)C)OC(C)C
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: CO
Product: CC(C)(C)OC(=O)N1CC2CCC(N)CC2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
To a solution of tert-butyl 5-oxohexahydro-1H-isoindole-2(3H)-carboxylate (11.97 g, 50 mmol) in EtOH (100 mL) were added a solution of NH3 in MeOH (7 M, 100 mL, 700 mmol) and Ti(OiPr)4 (28.42 g, 100 mmol). After addition, the reaction mixture was stirred at rt overnight and NaBH4 (3.78 g, 100 mmol) was added portionwise, then the resulting mixture was stirred at rt for another 5 h. The reaction was quenched with water (100 mL), stirred at rt for 1 h and filtered. The filter cake was washed with DCM (100 mL×3) and the filtrate was concentrated in vacuo. The residue was dissolved in a mixture of EtOAc (100 mL) and water (100 mL), and extracted with EtOAc (250 mL×3). The combined organic phases were washed with brine (250 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give the title compound as brown oil (12.02 g, 100%).