Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[C:9](/[S:11]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[S:21]([NH2:24])(=[O:23])=[O:22])(=[O:13])=[O:12])\[CH3:10])=[CH:4][CH:3]=1.[H][H]>C(OCC)(=O)C.[Pd]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]([S:11]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[S:21]([NH2:24])(=[O:23])=[O:22])(=[O:13])=[O:12])[CH3:10])=[CH:4][CH:3]=1
Reactant: C/C(=C\c1ccc(Cl)cc1)S(=O)(=O)Nc1ccccc1S(N)(=O)=O
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(Cc1ccc(Cl)cc1)S(=O)(=O)Nc1ccccc1S(N)(=O)=O
Yield: 37.6 %

Procedure:
2-[[(E)-1-(4-Chlorophenyl)prop-1-en-2-yl]sulfonylamino]benzenesulfonamide (100 mg, 0.26 mmol) was dissolved in ethyl acetate (3 ml) and subjected to the H-cube (1 ml/min, full hydrogen. 10% Pd/C, 3 runs). The material obtained was purified by preparative HPLC (XTerra MS C8 column, acetonitrile/ammonium acetate buffer) to give the title compound (38 mg, 38%). The compound of Example 8 was also obtained.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH:12]2[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]2)=[CH:4][S:5][C:6]=1[C:7](OCC)=[O:8].C(O)(=O)C.[CH:29](N)=[NH:30]>C(O)C>[O:8]=[C:7]1[NH:30][CH:29]=[N:1][C:2]2[C:3]([CH:12]3[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:22])([CH3:23])[CH3:24])=[O:19])[CH2:14][CH2:13]3)=[CH:4][S:5][C:6]1=2
Reactant: CCOC(=O)c1scc(C2CCN(C(=O)OC(C)(C)C)CC2)c1N
Reactant: N=CN
Solvent: CCO
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCC(c2csc3c(=O)[nH]cnc23)CC1
Yield: 21.4 %

Procedure:
tert-Butyl 4-[4-amino-5-(ethoxycarbonyl)thiophen-3-yl]piperidine-1-carboxylate (307 mg, 0.87 mmol) was dissolved in ethanol (8 mL), and then formamidine acetate (542 mg, 5.20 mmol) was added, followed by heating under reflux for 36 hours. The reaction liquid was concentrated under a reduced pressure, and the obtained residue was dissolved in chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under a reduced pressure. The obtained residue was purified by using silica gel chromatography (chloroform:methanol=10:1) to give tert-butyl 4-(4-oxo-3,4-dihydrothieno[3,2-d]pyrimidin-7-yl)piperidine-1-carboxylate (62.5 mg, 21.5%) as a pale yellow amorphous.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:7][C:8]1[S:9][C:10](Cl)=[N:11][N:12]=1>C(O)C>[NH2:7][C:8]1[S:9][C:10]([N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[N:11][N:12]=1
Reactant: C1CCNCC1
Reactant: Nc1nnc(Cl)s1
Solvent: CCO
Product: Nc1nnc(N2CCCCC2)s1

Procedure:
Piperidine (100 μl) was added to a solution of 2-amino-5-chloro-1,3,4-thiadiazole (50 mg) in ethanol (1 ml) and the mixture heated in a sealed vial at 70° C. for 6 hours The ethanol was evaporated from the cooled reaction under vacuum, the residue diluted with water and the solid product filtered off to give 2-amino-5-piperid-1-yl-1,3,4-thiadiazole.
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[CH:10]([C:12]1[C:20]2[C:15](=[N:16][CH:17]=[C:18]([C:21]3[CH2:22][CH2:23][NH:24][CH2:25][CH:26]=3)[CH:19]=2)[NH:14][CH:13]=1)[CH3:11].[CH:27](O)=[O:28].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[CH:10]([C:12]1[C:20]2[C:15](=[N:16][CH:17]=[C:18]([C:21]3[CH2:22][CH2:23][N:24]([CH:27]=[O:28])[CH2:25][CH:26]=3)[CH:19]=2)[NH:14][CH:13]=1)[CH3:11]
Reactant: CC(c1c(Cl)ccc(F)c1Cl)c1c[nH]c2ncc(C3=CCNCC3)cc12
Reactant: O=CO
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(c1c(Cl)ccc(F)c1Cl)c1c[nH]c2ncc(C3=CCN(C=O)CC3)cc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 3-[1-(2,6-dichloro-3-fluorophenyl)ethyl]-5-(1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrrolo[2,3-b]pyridine (12.0 mg, 0.0307 mmol), formic acid (2.3 μL, 0.0615 mmol), TBTU (19.7 mg, 0.0615 mmol), DIPEA (26.8 μL, 0.154 mmol) and DCM (1 mL) was stirred at rt for 30 min. The solution was concentrated in vacuo, redissolved in MeOH (0.5 mL) and purified via HPLC. The fractions containing the pure product were concentrated in vacuo to afford the title compound as a white solid. 1H NMR (400 MHz, CD3OD): δ=1.87 (d, J=7.3 Hz, 3 H), 2.36-2.58 (m, 2H), 3.63-3.80 (m, 2 H), 4.05-4.15 (m, 2 H), 5.26 (q, J=7.2 Hz, 1 H), 5.86-5.97 (m, 1 H), 7.18 (t, J=8.7 Hz, 1 H), 7.24-7.31 (m, 1 H), 7.32-7.54 (m, 2 H), 8.09-8.17 (m, 1 H), 8.22 (d, J=2.0 Hz, 1 H). MS (ES+): m/z 418.04 (100) [MH+]. HPLC: tR=3.40 min (ZQ3, polar—5 min).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([N+:14]([O-])=O)[C:11]=1[NH:12][CH3:13])[C:5]([O:7][CH3:8])=[O:6]>C(O)(=O)C.C(O)C.[Fe]>[NH2:14][C:10]1[CH:9]=[C:4]([CH:3]=[C:2]([Br:1])[C:11]=1[NH:12][CH3:13])[C:5]([O:7][CH3:8])=[O:6]
Reactant: CNc1c(Br)cc(C(=O)OC)cc1[N+](=O)[O-]
Agent: [Fe]
Solvent: CC(=O)O
Solvent: CCO
Product: CNc1c(N)cc(C(=O)OC)cc1Br

Procedure:
Prepared analogously to example 91a from methyl 3-bromo-4-(methylamino)-5-nitrobenzoate using iron powder in acetic acid and ethanol.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:9])=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[CH:10]([C:12]1[N:13]=[CH:14][NH:15][CH:16]=1)=O.[BH4-].[Na+].O>CO>[Cl:1][C:2]1[C:3]([F:9])=[C:4]([NH:5][CH2:10][C:12]2[NH:13][CH:14]=[N:15][CH:16]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: Nc1cccc(Cl)c1F
Reactant: O=Cc1c[nH]cn1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: Fc1c(Cl)cccc1NCc1cnc[nH]1
Temperature: 60 °C
Reaction time: 8 h
Yield: 0.1 %

Procedure:
To a solution of 3-chloro-2-fluoroaniline (0.44 g, 3 mmol) in methanol (5 ml) was added 4-formylimidazole (0.29 g, 3 mmol). After stirring the mixture overnight at 60° C. the solution was cooled and sodium borohydride (0.57 g, 15 mmol) was added. The reaction mixture was stirred at room temperature for 4 hours. Then water was added and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with water, dried over magnesium sulfate and evaporated. The residue was purified by column filtration (heptane/ethyl acetate=1:1) to yield a light yellow liquid (0.55 mg, 81%); MS (ISP): 226.3 ((M+H)+.).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[CH:9]1([C:12](Cl)=[O:13])[CH2:11][CH2:10]1>>[F:1][C:2]1[CH:3]=[C:4]([O:8][C:12]([CH:9]2[CH2:11][CH2:10]2)=[O:13])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cl)C1CC1
Reactant: Oc1cccc(F)c1
Product: O=C(Oc1cccc(F)c1)C1CC1
Temperature: 80 °C
Reaction time: 1 h
Yield: 98 %

Procedure:
To 31.4 parts of 3-fluorophenol were added dropwise 29.3 parts of cyclopropanecarbonyl chloride at 80° C. Upon completion, the whole was stirred for 1 hour at 80° C. The reaction mixture was distilled, yielding 49.7 parts (98%) of (3-fluorophenyl)cyclopropanecarboxylate; bp. 75°-85° C. at 0.5 mm. pressure (intermediate 86).
Reaction SMILES: Cl[CH2:2][C:3]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10](=[O:15])[CH2:9][CH2:8]2)=O.C([O:18][C:19]([NH:21][NH2:22])=[S:20])C>C(#N)C>[NH:11]1[C:12]2[C:7](=[CH:6][C:5]([C:3]3[CH2:2][S:20][C:19](=[O:18])[NH:21][N:22]=3)=[CH:14][CH:13]=2)[CH2:8][CH2:9][C:10]1=[O:15]
Reactant: CCOC(=S)NN
Reactant: O=C1CCc2cc(C(=O)CCl)ccc2N1
Solvent: CC#N
Product: O=C1CCc2cc(C3=NNC(=O)SC3)ccc2N1
Reaction time: 2 h
Yield: 66.4 %

Procedure:
To a solution of acetonitrile (100 ml) were added 6-chloroacetyl-3,4-dihydrocarbostyril (6.7 g) and ethoxythiocarbonylhydrazine (5.4 g) and the mixture was stirred for 2 hours, cooled and then filtered off. The filtrate was recrystallized from dimethylformamide (30 ml) and water (10 ml) to obtain pale yellowish 5-(3,4-dihydrocarbostyril-6-yl)-3,6-dihydro-1,3,4-thiadiazin-2-one (5.2 g), m.p. 271°-272° C. (decomposition).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([O:11][C:12]2[N:17]=[CH:16][C:15]([N+:18]([O-])=O)=[CH:14][N:13]=2)[CH:7]=[CH:8][C:9]=1[CH3:10])[CH3:2].C1COCC1.O.[Cl-].[NH4+]>[Fe].O>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([O:11][C:12]2[N:17]=[CH:16][C:15]([NH2:18])=[CH:14][N:13]=2)[CH:7]=[CH:8][C:9]=1[CH3:10])[CH3:2]
Reactant: CCOc1cc(Oc2ncc([N+](=O)[O-])cn2)ccc1C
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Product: CCOc1cc(Oc2ncc(N)cn2)ccc1C
Reaction time: 8 h
Yield: 95.9 %

Procedure:
Fe powder (89 mg, 1.598 mmol) was added to a solution of 2-{[3-(ethyloxy)-4-methylphenyl]oxy}-5-nitropyrimidine (Intermediate 91, 110 mg) in a mixture THF/water (9 mL/3 mL) followed by ammonium chloride (86 mg, 1.598 mmol). The reaction mixture was stirred overnight under nitrogen. The reaction mixture was poured into water and the iron was filtrated. Ethyl acetate was used to wash the solid filtrated. The filtrate was extracted with ethyl acetate (3 times). The combined ethyl acetate layers were dried over sodium sulphate and concentrated to give the title compound (94 mg) which was directly used in the next step.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][C:5]1[C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[C:8]([CH3:15])[NH:7][C:6]=1[C:16]([O:18][CH2:19][CH3:20])=[O:17].[C:21]1(B(O)O)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.N1C=CC=CC=1>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.ClCCl>[CH3:1][O:2][CH2:3][CH2:4][C:5]1[C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[C:8]([CH3:15])[N:7]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:6]=1[C:16]([O:18][CH2:19][CH3:20])=[O:17]
Reactant: OB(O)c1ccccc1
Reactant: CCOC(=O)c1[nH]c(C)c(C(=O)OCC)c1CCOC
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)c1c(CCOC)c(C(=O)OCC)n(-c2ccccc2)c1C
Reaction time: 8 h
Yield: 39.7 %

Procedure:
A mixture of diethyl 3-(2-methoxyethyl)-5-methyl-1H-pyrrole-2,4-dicarboxylate (100 mg, 0.35 mmol), phenyl boronic acid (130 mg, 1.06 mmol), copper acetate (130 mg, 0.71 mmol), dry pyridine (110 mg, 1.40 mmol), molecular sieves (400 mg) and dichloromethane (10 mL) was purged with argon gas for 30 min and stirred overnight. The mixture was filtered through a celite bed, washed with dichloromethane (15 mL) and concentrated under reduced pressure. The crude compound was purified by column chromatography over silica gel (100-200 mesh) using 20% ethyl acetate/pet ether as eluent to afford diethyl 3-(2-methoxyethyl)-5-methyl-1-phenyl-pyrrole-2,4-dicarboxylate (50 mg, 40%) as a colourless oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([C:12](=O)[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:19][CH3:20])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+].C(=O)(O)[O-].[Na+].CCOC(C)=O>CO>[C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:19][CH3:20])[CH2:9]1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: COc1ccccc1C(=O)C1CN(C(=O)OC(C)(C)C)C1
Agent: O=C([O-])O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Product: COc1ccccc1CC1CN(C(=O)OC(C)(C)C)C1
Reaction time: 36 h
Yield: 18.5 %

Procedure:
To a solution of 3-(2-methoxy-benzoyl)-azetidine-1-carboxylic acid tert-butyl ester (2.1 g, 7.2 mmol) in methanol (50 mL) was added sodium borohydride (1.08 g, 28.8 mmol). After stirring for 36 h, saturated sodium bicarbonate solution and EtOAc were added. The aqueous portion was extracted three times with EtOAc and the combined organic were dried (Na2SO4) and concentrated. To a solution of this material in ethanol (50 mL) was added 10% Pd/C. This reaction was then placed on a Parr hydrogenation apparatus with 60 psi of hydrogen gas. After 72 h, the reaction mixture was filtered through a pad of Celite and the filtrate concentrated. The crude product was purified by RP HPLC (basic conditions) to provide the title compound (370 mg, 19%). MS (ESI): mass calcd. for C16H23NO3, 277.2; m/z found, 222.2 [M-t-Bu]+. 1H NMR (CDCl3): 7.23-7.10 (m, 1H), 7.06 (d, J=7.3 Hz, 1H), 6.92-6.77 (m, 2H), 3.96 (t, J=8.0 Hz, 2H), 3.81 (s, 3H), 3.65-3.63 (m, 2H), 2.94-2.78 (m, 5H), 1.44 (s, 9H).
Reaction SMILES: [CH3:1][CH:2]1[CH2:18][CH2:17][N:5]2[C:6](=[O:16])[CH:7]=[C:8]([C:10]3[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=3)[N:9]=[C:4]2[NH:3]1.[H-].[Na+].[N:21]1[C:29]2[CH2:28][C@H:27]([CH2:30]OS(C)(=O)=O)[CH2:26][C:25]=2[CH:24]=[CH:23][CH:22]=1.O>CN(C)C=O>[N:21]1[C:29]2[CH2:28][C@H:27]([CH2:30][N:3]3[C:4]4=[N:9][C:8]([C:10]5[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=5)=[CH:7][C:6](=[O:16])[N:5]4[CH2:17][CH2:18][CH:2]3[CH3:1])[CH2:26][C:25]=2[CH:24]=[CH:23][CH:22]=1
Reactant: CS(=O)(=O)OC[C@@H]1Cc2cccnc2C1
Reactant: CC1CCn2c(nc(-c3ccncc3)cc2=O)N1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC1CCn2c(nc(-c3ccncc3)cc2=O)N1C[C@@H]1Cc2cccnc2C1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 60.5 %

Procedure:
To a solution of 0.15 g (0.62 mmol) of 8-methyl-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one in 3 ml of anhydrous dimethylformamide was added 0.032 g (0.81 mmol) of sodium hydride (60% suspension in mineral oil). The mixture was allowed to stir at 50° C. for 30 min. 0.184 g (0.81 mmol) of methanesulfonic acid 6,7-dihydro-5H-[1]pyrindin-6-(R)-ylmethyl ester was added and the stirring continued at 85° C. for 18 h. Water was added and the mixture extracted with trichloromethane/methanol 90/10. The extracts were washed with a saturated aqueous solution of sodium chloride, dried and evaporated to give crude product. Purification by chromatography on silica gel, eluting with a mixture of ethylacetate/ethanol in the proportions 100/0 to 74/26, gives 0.14 g (60%) of the compound in the form of free base.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]([OH:16])=O)=[CH:12][CH:11]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.[NH2:41][C:42]1[CH:47]=[CH:46][C:45]([NH2:48])=[CH:44][CH:43]=1>CN(C=O)C.C(N(CC)CC)C>[C:1]([O:5][C:6](=[O:7])[NH:8][CH2:9][C:10]1[CH:11]=[CH:12][C:13]([C:14](=[O:16])[NH:41][C:42]2[CH:47]=[CH:46][C:45]([NH2:48])=[CH:44][CH:43]=2)=[CH:17][CH:18]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)NCc1ccc(C(=O)O)cc1
Reactant: Nc1ccc(N)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCc1ccc(C(=O)Nc2ccc(N)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 54.1 %

Procedure:
To a solution of 4-(tert-butoxycarbonylamino-methyl)-benzoic acid (1.005 g) and N-hydroxy-benzotriazole (HOBt)(0.642 g) in DMF (30 ml) are added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC)(2.76 g) and triethylamine (2.005 ml). The mixture is stirred for 1 h at ambient temperature. This solution is added at 0° C. slowly to a solution of 1,4-diaminobenzene (0.43 g) and triethylamine (0.45 ml) in DMF (5 ml). After completion of the chemical reaction the mixture is evaporated at high vacuum and the residue is partitioned between ethyl acetate and an aqueous saturated sodium bicarbonate solution. The organic phase is dried over sodium sulfate and the crude product is purified by silica gel flash chromatography. A colorless solid (0.735 g) is obtained in 55% yield.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][CH2:10][NH2:11].C[O:13][C:14](=O)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH2:21]Br.C([O-])([O-])=O.[K+].[K+].C(OCC)(=O)C>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][CH2:10][N:11]1[CH2:21][C:16]2[C:15](=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:14]1=[O:13]
Reactant: COC(=O)c1ccccc1CBr
Reactant: NCCCc1ccccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: O=C1c2ccccc2CN1CCCc1ccccc1F
Temperature: 100 °C
Reaction time: 16 h
Yield: 51.1 %

Procedure:
A mixture of 3-(2-fluorophenyl)-propylamine (306 mg, 2 mmol), 2-bromomethyl-benzoic acid methyl ester (458 mg, 2 mmol), and K2CO3 (200 mg, 1.45 mmol) in toluene (10 mL) was heated with stirring at 100° C. for 16 h. Workup and silica gel column chromatography using a gradient of hexanes to 50% ethyl acetate in hexanes afforded 2-[3-(2-fluorophenyl)-propyl]-2,3-dihydroisoindol-1-one (275 mg, 51%). GC/MS gave: m/z (rel.int.) 269 (M+, 32), 147 (89), 146 (100), 119 (29), 109 (25) and 91 (40).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2(O)[CH2:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:12]2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl>C1COCC1.O>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH2:19][C:18]3[C:13]([CH:12]=2)=[CH:14][CH:15]=[CH:16][CH:17]=3)=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(C2(O)Cc3ccccc3C2)cc1
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)c1ccc(C2=Cc3ccccc3C2)cc1
Yield: 63.3 %

Procedure:
To a solution of 2-(4-t-butyl-phenyl)-2-indanol (23.0 g, 86.5 mmol) in THF (200 mL) was added a solution of concentrated hydrochloric acid (40 mL) in water (60 mL). The solid was collected and washed with pentane (50 mL) and then tetrahydrofuran (50 mL) to give 13.6 g of 2-(4-t-butyl-phenyl)-1H-indene. 1H-N.M.R. (CDCl3) d 1.35 (s, 9H), d 3.78(br s, 2H), d 7.13-7.19(m, 2H),d 7.26 (br tt, J=7.4, 0.6 Hz, 1H), d 7.36-7.47(m, 4H), d 7.55-7.6(br d, J=6.7 Hz, 2H).
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]3[O:15][C:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[CH:13][CH:12]=3)[CH:9]=2)[NH:4][N:3]=1.[Cl:23][C:24]1[S:28][C:27]([C:29](Cl)=[O:30])=[CH:26][CH:25]=1>CN(C)C1C=CN=CC=1.N1C=CC=CC=1.O1CCOCC1>[Cl:23][C:24]1[S:28][C:27]([C:29]([NH:1][C:2]2[C:10]3[C:5](=[CH:6][CH:7]=[C:8]([C:11]4[O:15][C:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[CH:13][CH:12]=4)[CH:9]=3)[NH:4][N:3]=2)=[O:30])=[CH:26][CH:25]=1
Reactant: CC(C)(C)OC(=O)c1ccc(-c2ccc3[nH]nc(N)c3c2)o1
Reactant: O=C(Cl)c1ccc(Cl)s1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)c1ccc(-c2ccc3[nH]nc(NC(=O)c4ccc(Cl)s4)c3c2)o1

Procedure:
300 mg of tert-butyl 5-(3-amino-1H-indazol-5-yl)furan-2-carboxylate, 199 mg of 5-chlorothiophene-2-carbonyl chloride and 8 mg of 4-(dimethylamino)pyridine are stirred at 90° C. for 24 hours in 2 ml of pyridine and 100 μl of dioxane. The reaction mixture is evaporated, and the residue is purified by column chromatography. Yield: 260 mg (58%) of tert-butyl 5-{3-[(5-chlorothiophene-2-carbonyl)amino]-1H-indazol-5-yl}furan-2-carboxylate.
Reaction SMILES: C1O[C:8]2[CH:7]=[CH:6][C:5]([N+:10]([O-:12])=[O:11])=[CH:4][C:3]=2[O:2]1.[NH3:13].COCCOCCOC>O>[NH2:13][C:8]1[CH:7]=[CH:6][C:5]([N+:10]([O-:12])=[O:11])=[CH:4][C:3]=1[OH:2]
Reactant: O=[N+]([O-])c1ccc2c(c1)OCO2
Reactant: N
Solvent: COCCOCCOC
Solvent: O
Product: Nc1ccc([N+](=O)[O-])cc1O
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
A solution of 0.18 mol (30 g) of 3,4-methylenedioxynitrobenzene in a mixture of 240 ml of 28% strength ammonia solution and 240 ml of diethylene glycol dimethyl ether is heated at 100° C. for 28 hours in an autoclave. After cooling, 480 ml of water are added. The unreacted initial product precipitates. It is recovered by filtration and the filtrate is then neutralised with hydrochloric acid. After filtration, the filtrate is extracted with ethyl acetate. The ethyl acetate is driven off in vacuo. The residue is treated with 25 ml of acetic anhydride and then kept in a boiling water-bath for 30 minutes. After cooling, the expected product is isolated in the form of the acetyl derivative. This acetyl derivative is hydrolysed with 45 ml of hydrochloric acid of density 1.17, at 90° C. for one hour. After dilution and neutralisation of the solution containing hydrochloric acid, 2-amino-5-nitrophenol is isolated by filtration. Melting point=207° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[S:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17](=[O:19])[CH3:18])=[CH:12][CH:11]=1.Br[CH2:21][C:22]#[N:23].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[NH2:1][C:2]1[CH:7]=[C:6]([O:8][CH2:21][C:22]#[N:23])[CH:5]=[CH:4][C:3]=1[S:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17](=[O:19])[CH3:18])=[CH:12][CH:11]=1
Reactant: CC(=O)Nc1ccc(Sc2ccc(O)cc2N)cc1
Reactant: N#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)Nc1ccc(Sc2ccc(OCC#N)cc2N)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 99.5 %

Procedure:
A mixture of the product from Example 38b (56 mg, 0.17 mmol), 2-Bromoacetonitrile (20 mg, 0.17 mmol) and potassium carbonate (26 mg, 0.19 mmol) in DMF (1 mL) was stirred at room temperature 15 hr. The next day, the reaction mixture was poured onto ice and the solid collected by filtration providing the title compound (53 mg, 100%).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH:18]=[CH:17][CH:16]=[CH:15]2)=[CH:10][C:9]=1[NH:19][C:20](=[O:35])[CH2:21][C:22]([C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([N:30]2[CH:34]=[CH:33][N:32]=[CH:31]2)[CH:25]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[N:30]1([C:26]2[CH:25]=[C:24]([C:22]3[CH2:21][C:20](=[O:35])[NH:19][C:9]4[CH:10]=[C:11]([N:14]5[CH:18]=[CH:17][CH:16]=[CH:15]5)[CH:12]=[CH:13][C:8]=4[N:7]=3)[CH:29]=[CH:28][CH:27]=2)[CH:34]=[CH:33][N:32]=[CH:31]1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-n2cccc2)cc1NC(=O)CC(=O)c1cccc(-n2ccnc2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1CC(c2cccc(-n3ccnc3)c2)=Nc2ccc(-n3cccc3)cc2N1

Procedure:
The title compound was prepared from {2-[3-(3-imidazol-1-yl-phenyl)-3-oxo-propionylamino]-4-pyrrol-1-yl-phenyl}-carbamic acid tert.-butyl ester (Example M17) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a yellow solid (1.03 g).
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[C:11]2[C:6](=[CH:7][C:8](Br)=[CH:9][CH:10]=2)[N:5]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:4][CH2:3]1.C(N(CC)CC)C.[CH3:27][Si:28]([C:31]#[CH:32])([CH3:30])[CH3:29].[Cl-]>[Cu]I.C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(Cl)Cl>[CH3:1][C:2]1([CH3:19])[C:11]2[C:6](=[CH:7][C:8]([C:32]#[C:31][Si:28]([CH3:30])([CH3:29])[CH3:27])=[CH:9][CH:10]=2)[N:5]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:4][CH2:3]1
Reactant: C#C[Si](C)(C)C
Reactant: CC1(C)CCN(c2ccccc2)c2cc(Br)ccc21
Agent: [Cu]I
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1(C)CCN(c2ccccc2)c2cc(C#C[Si](C)(C)C)ccc21
Temperature: 70 °C

Procedure:
To a solution of 0.10 g (0.32 mmol) of 4,4-dimethyl-1,2,3,4-tetrahydro-N-phenyl-7-bromoquinoline (Compound 6) and 5.0 g (4.0 mL, 36 mmol) triethylamine were added 0.032 g (0.17 mmol) of copper(I) iodide, 0.70 g (1.0 mL, 7.1 mmol) of (trimethylsilyl)acetylene, and 0.050 g (0.07 mmol) of bis(triphenylphosphine)palladium(ID chloride. The resulting mixture was heated at 70° C. for 22 hours. The reaction was cooled, methylene chloride was added, and the mixture was adsorbed onto silica gel. The mixture was purified by flash chromatography (hexanes) to give the title compound as a yellow solid. PNMR (300 MHz, CDCl3) d 0.17 (9 H, s), 1.32 (6 H, s), 1.82 (2 H, t, J=6.0 Hz), 3.61 (2 H, t, J=6.0 Hz), 6.85 (2 H, overlapping d's), 7.15-7.41 (6 H, m).
Reaction SMILES: C(O)(C(F)(F)F)=O.C(OC([N:15]1[CH2:18][CH:17]([C:19]([N:21]2[CH2:24][CH2:23][CH2:22]2)=[O:20])[CH2:16]1)=O)(C)(C)C>C(Cl)Cl>[NH:15]1[CH2:18][CH:17]([C:19]([N:21]2[CH2:24][CH2:23][CH2:22]2)=[O:20])[CH2:16]1
Reactant: CC(C)(C)OC(=O)N1CC(C(=O)N2CCC2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(C1CNC1)N1CCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 37 %

Procedure:
Azetidine hydrochloride salt (515 mg, 5.50 mmol) was added to a solution of azetidine-1,3-dicarboxylic acid mono-tert-butyl ester (1.0 g, 4.97 mmol), HATU (2.09 g, 5.50 mmol) and DIPEA (2.18 mL, 12.52 mmol) in DMF (100 mL) and the resulting mixture stirred at ambient temperature for 1 h, then concentrated in vacuo. The resulting oil was partitioned between EtOAc and water. The organic layer was separated, washed with water and brine, then dried (MgSO4) and concentrated in vacuo to give 3-(azetidine-1-carbonyl)azetidine-1-carboxylic acid tert-butyl ester as a colourless oil. TFA (3 mL) was added to a solution of 3-(azetidine-1-carbonyl)-azetidine-1-carboxylic acid tert-butyl ester in DCM (15 mL) and the mixture stirred at ambient temperature for 1 h, then loaded onto an Isolute® SCX-2 cartridge (25 g). The cartridge was then washed with methanol and the desired product was subsequently eluted using 2 M NH3 in MeOH. The product was collected and concentrated in vacuo to afford the title compound as a colourless oil (260 mg, 37%). 1H NMR (CD3OD, 400 MHz) δ 4.19-4.08 (m, 2H); 4.07-3.92 (m, 2H); 3.91-3.78 (m, 2H); 3.72-3.52 (m, 3H) and 2.36-2.21 (m, 2H).