Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1([F:33])[O:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]3([C:14]([NH:16][C:17]4[CH:18]=[CH:19][C:20]([CH3:32])=[C:21]([C:23]5[CH:28]=[CH:27][CH:26]=[C:25]([C:29](O)=[O:30])[CH:24]=5)[CH:22]=4)=[O:15])[CH2:13][CH2:12]3)=[CH:10][C:4]=2[O:3]1.[CH3:34][S:35]([NH2:38])(=[O:37])=[O:36].C(Cl)CCl>CN(C1C=CN=CC=1)C.C(Cl)Cl>[F:33][C:2]1([F:1])[O:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]3([C:14]([NH:16][C:17]4[CH:18]=[CH:19][C:20]([CH3:32])=[C:21]([C:23]5[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([NH:38][S:35]([CH3:34])(=[O:37])=[O:36])=[O:30])[CH:24]=5)[CH:22]=4)=[O:15])[CH2:13][CH2:12]3)=[CH:10][C:4]=2[O:3]1
Reactant: CS(N)(=O)=O
Reactant: Cc1ccc(NC(=O)C2(c3ccc4c(c3)OC(F)(F)O4)CC2)cc1-c1cccc(C(=O)O)c1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: ClCCCl
Product: Cc1ccc(NC(=O)C2(c3ccc4c(c3)OC(F)(F)O4)CC2)cc1-c1cccc(C(=O)NS(C)(=O)=O)c1
Reaction time: 18 h

Procedure:
To a mixture of 5′-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-2′-methylbiphenyl-3-carboxylic acid (50 mg, 0.11 mmol), methansulfonamide (7.0 mg, 0.074 mmol), DMAP (13 mg, 0.11 mmol), and CH2Cl2 (1 mL) was added EDC (28 mg, 0.15 mmol) at ambient temperature. The mixture was allowed to stir for 18 h before it was concentrated. The residue was taken up in DMF (1 mL) and was purified by reverse phase preparatory HPLC to provide 5′-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-2′-methyl-N-(methylsulfonyl)biphenyl-3-carboxamide as a white solid. ESI-MS m/z calc. 528.5, found 529.2 (M+1)+. Retention time 1.97 minutes.
Reaction SMILES: [Si](O[C:9]1[N:10]([CH3:19])[C:11]2[CH:16]=[CH:15][N:14]=[C:13](C)[C:12]=2[N:18]=1)(C(C)(C)C)(C)C.[O:20]1CCC[CH2:21]1.C(O)(=O)C>O>[OH:20][CH2:21][C:9]1[N:10]([CH3:19])[C:11]2[CH:16]=[CH:15][N:14]=[CH:13][C:12]=2[N:18]=1
Reactant: C1CCOC1
Reactant: Cc1nccc2c1nc(O[Si](C)(C)C(C)(C)C)n2C
Solvent: O
Solvent: CC(=O)O
Product: Cn1c(CO)nc2cnccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 3.00 g of 2-t-butyldimethylsilyloxy-methyl-1-methylimidazo[4,5-c]pyridine (prepared as described in Preparation 72) in 60 ml of a 1:1:1 by volume mixture of tetrahydrofuran, acetic acid and water was stirred at room temperature for 1 hour and then at 60° C. for 5 hours. At the end of this time, the reaction mixture was freed from the solvent by distillation. The resulting residue was mixed with an aqueous solution of sodium hydrogencarbonate and then concentrated by evaporation under reduced pressure. The concentrate was purified by column chromatography through silica gel, using a 10:1 by volume mixture of ethyl acetate and methanol as the eluent, to give 1.97 g of the title compound, melting at 285-290° C.
Reaction SMILES: [CH:1]1([C:4]2[N:9]3[N:10]=[CH:11][C:12]([C:13]#[CH:14])=[C:8]3[N:7]=[C:6]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=3)[CH:5]=2)[CH2:3][CH2:2]1.Br[C:24]1[S:28][C:27]([S:29]([NH2:32])(=[O:31])=[O:30])=[CH:26][CH:25]=1>>[CH:1]1([C:4]2[N:9]3[N:10]=[CH:11][C:12]([C:13]#[C:14][C:24]4[S:28][C:27]([S:29]([NH2:32])(=[O:31])=[O:30])=[CH:26][CH:25]=4)=[C:8]3[N:7]=[C:6]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=3)[CH:5]=2)[CH2:3][CH2:2]1
Reactant: NS(=O)(=O)c1ccc(Br)s1
Reactant: C#Cc1cnn2c(C3CC3)cc(-c3ccc(Cl)c(Cl)c3)nc12
Product: NS(=O)(=O)c1ccc(C#Cc2cnn3c(C4CC4)cc(-c4ccc(Cl)c(Cl)c4)nc23)s1

Procedure:
The title compound was prepared from 7-cyclopropyl-5-(3,4-dichloro-phenyl)-3-ethynyl-pyrazolo[1,5-a]pyrimidine (Example C.8) (82 mg, 0.25 mmol) and 5-bromo-thiophene-2-sulfonic acid amide (61 mg, 0.25 mmol) according to general procedure II. Obtained as a yellow solid (35 mg, 28%). MS (ISP) 489.3 [(M+H)+]; mp 213-214° C.
Reaction SMILES: [NH2:1][C:2]1[CH:6]([C:7]2[CH:11]=[CH:10][NH:9][N:8]=2)[C:5](=[O:12])[N:4]([C:13]2[C:18]([Cl:19])=[CH:17][C:16]([Cl:20])=[CH:15][C:14]=2[Cl:21])[N:3]=1.N1C=CC=CC=1.[N+](C1C=CC=CC=1)([O-])=O.[C:37](Cl)(=[O:40])[CH:38]=[CH2:39].[OH-].[Na+]>O1CCCC1.C(O)(=O)C.O>[Cl:21][C:14]1[CH:15]=[C:16]([Cl:20])[CH:17]=[C:18]([Cl:19])[C:13]=1[N:4]1[C:5](=[O:12])[CH:6]([C:7]2[CH:11]=[CH:10][NH:9][N:8]=2)[C:2]([NH:1][C:37](=[O:40])[CH:38]=[CH2:39])=[N:3]1
Reactant: NC1=NN(c2c(Cl)cc(Cl)cc2Cl)C(=O)C1c1cc[nH]n1
Reactant: C=CC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: c1ccncc1
Solvent: O=[N+]([O-])c1ccccc1
Product: C=CC(=O)NC1=NN(c2c(Cl)cc(Cl)cc2Cl)C(=O)C1c1cc[nH]n1
Reaction time: 1.5 h
Yield: 32.1 %

Procedure:
Next, 17 g (0.05 mol) of the 3-amino-1-(2,4,6-trichlorophenyl)-4-pyrazolyl-5-oxo-2-pyrazoline was dissolved in 300 ml qf tetrahydrofuran, to which were added 10 ml (0.13 mol) of pyridine and 1 ml of nitrobenzene. Then, 31.1 g (0.12 mol) of acrylic acid chloride was added under cooling with ice, after which the mixture was stirred for 1.5 hours. Next, 500 ml of water was added, extraction with ethyl acetate was effected, and the extract was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, the residual oil was dissolved in 150 ml of ethanol, and then 60 ml of water containing 3.0 g (0.074 mol) of sodium hydroxide was added at room temperature. After being stirred for 30 min, 3 ml of acetic acid was added to neutralize the solution, the separated oil was extracted with ethyl acetate, the extract was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residual oil was purified by silica gel column chromatography to yield 6.4 g (32%) of the title compound. Melting point: 151° to 154° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][NH:12][C:13](=[O:22])[C:14]1[CH:19]=[CH:18][C:17]([CH2:20]Cl)=[CH:16][CH:15]=1.[C:23]([C:25]1[CH:26]=[C:27](B(O)O)[CH:28]=[CH:29][CH:30]=1)#[N:24].C(=O)([O-])[O-].[Na+].[Na+].[I-].[Na+]>C(COC)OC.O.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>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][NH:12][C:13](=[O:22])[C:14]1[CH:19]=[CH:18][C:17]([CH2:20][C:29]2[CH:28]=[CH:27][CH:26]=[C:25]([C:23]#[N:24])[CH:30]=2)=[CH:16][CH:15]=1
Reactant: O=C(NCc1c[nH]c2ccc(Cl)cc12)c1ccc(CCl)cc1
Reactant: N#Cc1cccc(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: [I-]
Solvent: O
Solvent: COCCOC
Product: N#Cc1cccc(Cc2ccc(C(=O)NCc3c[nH]c4ccc(Cl)cc34)cc2)c1
Yield: 30.2 %

Procedure:
N-((5-Chloro-1H-indol-3-yl)methyl)-4-(3-cyanobenzyl)benzamide was prepared following method B starting from N-((5-Chloro-1H-indol-3-yl)methyl)-4-(chloromethyl)benzamide (0.080 g, 0.240 mmol), 3-cyanophenylboronic acid (0.038 g; 0.252 mmol); Tetrakis(triphenylphosphine)palladium(0) (0.014 g; 0.012 mmol), sodium carbonate (0.051 g; 0.480 mmol) and sodium iodide (0.109 g; 0.720 mmol), in dimethoxyethane (3 mL) and water (1 mL), irradiated in a microwave oven at 130° C. for 15 minutes. Flash chromatography on silica gel (eluent 2 to 20% ethyl acetate in dichloromethane) furnished 0.029 g (30%) of the title compound as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](CC([O-])=O)=[CH:5][C:4]=1[N+:13]([O-:15])=[O:14].[O-:16]CC.[Na+].Cl>C(O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([OH:16])=[CH:5][C:4]=1[N+:13]([O-:15])=[O:14]
Reactant: CC[O-]
Reactant: COc1ccc(CC(=O)[O-])cc1[N+](=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: COc1ccc(O)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
4-Methoxy-3-nitrophenylacetate (2.46 g, 11.7 mmol) was dissolved in anhydrous ethanol (80 ml) and sodium ethoxide (1.19 g, 17.5 mmol) was added. The reaction was stirred at room temperature for 0.5 h. The dark red solution was acidified with 2M HCl and concentrated under reduced pressure. The residue was taken up into water and extracted with dichloromethane. The combined organics were washed with 2M HCl and brine, then dried over sodium sulfate. Evaporation of the solvent under reduced pressure gave the title compound as a yellow solid.
Reaction SMILES: Cl.[F:2][C:3]([F:14])([F:13])[CH:4]1[C:9]2[N:10]=[CH:11][NH:12][C:8]=2[CH2:7][CH2:6][NH:5]1.[Cl:15][C:16]1[C:24]([C:25]([F:28])([F:27])[F:26])=[CH:23][CH:22]=[CH:21][C:17]=1[C:18](O)=[O:19].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.CCOC(C)=O>[Cl:15][C:16]1[C:24]([C:25]([F:27])([F:28])[F:26])=[CH:23][CH:22]=[CH:21][C:17]=1[C:18]([N:5]1[CH2:6][CH2:7][C:8]2[NH:12][CH:11]=[N:10][C:9]=2[CH:4]1[C:3]([F:2])([F:13])[F:14])=[O:19]
Reactant: FC(F)(F)C1NCCc2[nH]cnc21
Reactant: O=C(O)c1cccc(C(F)(F)F)c1Cl
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1cccc(C(F)(F)F)c1Cl)N1CCc2[nH]cnc2C1C(F)(F)F
Yield: 34.3 %

Procedure:
A solution of 4-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine hydrochloride (0.10 g, 0.44 mmol), 2-chloro-3-trifluoromethyl benzoic acid (0.10 g, 0.44 mmol), HATU (0.18 g, 0.48 mmol, and DIPEA (0.19 mL, 1.1 mmol) in DMF (2 mL) was stirred for 30 min. The reaction was diluted with EtOAc (15 mL) and washed with H2O (3×10 mL). The organic layers were combined, dried (Na2SO4), and concentrated. Chromatography of the resulting residue (SiO2; MeOH(NH3):DCM) gave the title compound (0.06 g, 34%). 1H NMR (500 MHz, CDCl3) δ 8.02-7.94 (m, 1H), 7.80-7.58 (m, 1H), 7.51-7.39 (m, 1H), 6.60-6.50 (m, 1H), 4.42 (q, J=7.6 Hz, 1H), 2.95 (s, 4H). MS (ESI): mass calculated for C15H10ClF6N3O, 397.042. m/z found 398.1 [M+H]+.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][CH:9]1[C:21]([OH:23])=O)([O:3]C(C)(C)C)=O.CN(C(O[N:32]1N=N[C:34]2C=CC=C[C:33]1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)CC)(C)C.Cl.COC(=O)[C@@H](C)N>ClCCl.CN(C=O)C>[CH3:34][C@@H:33]1[C:1](=[O:3])[N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH:9]2[C:21](=[O:23])[NH:32]1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)OC(C)(C)C)C(C(=O)O)C1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: COC(=O)[C@@H](C)N
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H]1NC(=O)C2CNCCN2C1=O
Reaction time: 0.75 h

Procedure:
To a solution of N,N′-diboc-piperazine-2-carboxylic acid (2 g, 6.06 mmol) in 50 mL of dichloromethane and was added TBTU (2.138 g, 6.66 mmol) and diisopropylethyl amine (1.3 mL, 7.26 mmol). The reaction was stirred for 45 min. In the meantime, a suspension of D-alanine methyl ester hydrochloride (1.249 g, 12.11 mmol) and diisopropylethylamine (3.27 mL, 18.76 mmol) in 20 mL of dichloromethane and 5 mL of DMF was stirred and finally added to the reaction mixture. The reaction was left stirring at room temperature overnight. UPLC-MS analysis showed the expected product (peak at 0.72 min, m/z=416 (M+1), 360 (M−t-Bu+1). The reaction was diluted with dichloromethane and extracted with sat. NaHCO3, dried (Na2SO4), and the solvent removed. The crude (4.242 g) was taken to the next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]#N)=[CH:4][C:3]=1[F:11].O.[S-2].[Na+].[Na+].CI>C(O)C.O>[F:11][C:3]1[CH:4]=[C:5]([S:8][CH3:9])[CH:6]=[CH:7][C:2]=1[NH2:1]
Reactant: N#CSc1ccc(N)c(F)c1
Agent: [Na+]
Agent: [S-2]
Solvent: CI
Solvent: O
Solvent: CCO
Product: CSc1ccc(N)c(F)c1
Temperature: 50 °C
Reaction time: 4 h
Yield: 87.2 %

Procedure:
A solution of the product of Example 26, Step A, 4-amino-3-fluorophenyl thiocyanate (500 mg, 2.97 mmol), in ethanol (7.5 mL) was added to a solution of sodium sulfide monohydrate (714 mg, 2.97 mmol) in water (1.5 mL) and the mixture heated at 50° C. for 2 hours. Methyl iodide (464 mg, 3.27 mmol) in ethanol (0.5 mL) was added and heating continued for a further 4 hours. The reaction mixture was then diluted with water (15 mL) and extracted with Et2O (4×5 mL). The combined Et2O extracts were washed with water (3×10 mL), saturated NaCl (10 mL), and dried (Na2SO4), followed by removal of the solvent under reduced pressure to afford a pale yellow oil. This material was purified by dry flash column chromatography on silica (5% Et2O/hexanes as eluant) to give 2-fluoro-4-methylthioaniline as a pale yellow oil (407 mg, 87%); 1H NMR (400 MHz, CDCl3) δ 7.01 (dd, J=11.3, 2.1 Hz, 1 H), 6.94 (ddd, J=8.2, 2.1, 0.9 Hz, 1 H), 6.71 (dd, J=9.3, 8.2 Hz, 1 H), 3.67 (br s, 2 H), 2.42 (s, 3 H). Step C: Preparation of 3,4-difluoro-2-[[2-fluoro-4-(methylthio)phenyl]amino]-benzoic acid
Reaction SMILES: F[C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:14])[C:7]([OH:13])=[CH:8][N:9]2[CH3:12])=[CH:4][CH:3]=1.[OH-].[Na+].[CH3:17][S:18](Cl)(=[O:20])=[O:19]>O>[CH3:17][S:18]([O:13][C:7]1[C:6](=[O:14])[C:5]2[C:10](=[CH:11][CH:2]=[CH:3][CH:4]=2)[N:9]([CH3:12])[CH:8]=1)(=[O:20])=[O:19]
Reactant: Cn1cc(O)c(=O)c2ccc(F)cc21
Reactant: CS(=O)(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cn1cc(OS(C)(=O)=O)c(=O)c2ccccc21
Temperature: 0 °C

Procedure:
7-Fluoro-3-hydroxy-1 -methyl-4-quinolone (4.5 g) was added to a solution of sodium hydroxide (12 g) in water (56 ml) and the mixture stirred at 0 to 5° with ice/water cooling. Methanesulphonyl chloride (4 ml) was added over a period of 1 5 minutes followed by aqueous sodium hydroxide (5M, 3 ml). The resultant solid was collected by filtration, washed with water (2×20 ml), and crystallised from industrial methylated spirit (220 ml) to give the novel compound 7-fluoro-]-methyl-4-oxo-1,4-dihydroquinol-3-yl methanesulphonate, m.p. 212°-213°.
Reaction SMILES: [S:1]1[C:5]([CH:6]=[O:7])=[CH:4][C:3]2[S:8][CH:9]=[CH:10][C:2]1=2.[CH2:11](O)[CH2:12][OH:13]>S(C1C=CC(C)=CC=1)([O-])(=O)=O.[NH+]1C=CC=CC=1.C1C=CC=CC=1>[O:7]1[CH2:11][CH2:12][O:13][CH:6]1[C:5]1[S:1][C:2]2[CH:10]=[CH:9][S:8][C:3]=2[CH:4]=1
Reactant: OCCO
Reactant: O=Cc1cc2sccc2s1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: c1ccccc1
Product: c1cc2sc(C3OCCO3)cc2s1
Temperature: 25 °C
Yield: 84.1 %

Procedure:
A mixture of thieno[3,2-b]thiophene-2-carboxaldehyde (8) (23.30 g., 138.5 mmole); ethylene glycol (31 mL., 34.39 g., 554.0 mmole); pyridinium tosylate (2.5 g., 10 mmole); and benzene (200 mL) was stirred and refluxed and the water (3.2 mL) was removed by a Dean-Stark trap (~4 hours). The reaction was cooled to room temperature, extracted with water three times and then with a saturated solution of sodium bicarbonate. The organic layer was dried (MgSO4), filtered, and the solvent was evaporated to leave a crystalline mass. Trituration with a small amount of ether removed the color to give 24.72 g of a white crystalline product, mp. 88°-90° C. An additional 1.43 g of product was collected from the ether washing, mp 88°-89° C., yielding a total of 26.15 g of 2-(2-dioxolanyl)thieno[3,2-b]thiophene (9). This product was used in the next step without further purification.
Reaction SMILES: [CH2:1]([NH:8][C:9]([N:11]1[C:19]2[C:14](=[CH:15][C:16]([NH:20][S:21]([C:24]3[CH:29]=[C:28]([Cl:30])[CH:27]=[C:26]([Cl:31])[CH:25]=3)(=[O:23])=[O:22])=[CH:17][CH:18]=2)[CH:13]=[CH:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:39][C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41].O>CN(C)C=O.C(OCC)(=O)C>[CH2:1]([NH:8][C:9]([N:11]1[C:19]2[C:14](=[CH:15][C:16]([N:20]([CH2:39][C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[S:21]([C:24]3[CH:29]=[C:28]([Cl:30])[CH:27]=[C:26]([Cl:31])[CH:25]=3)(=[O:23])=[O:22])=[CH:17][CH:18]=2)[CH:13]=[CH:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)CBr
Reactant: O=C(NCc1ccccc1)n1ccc2cc(NS(=O)(=O)c3cc(Cl)cc(Cl)c3)ccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)CN(c1ccc2c(ccn2C(=O)NCc2ccccc2)c1)S(=O)(=O)c1cc(Cl)cc(Cl)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
150 mg 5-(3,5-dichloro-phenylsulphonylamino)-indole-1-carboxylic acid-benzylamide are dissolved in 5 ml dimethylformamide. 109 mg potassium carbonate and 51 μl tert.butyl bromoacetate are added thereto. The mixture is stirred for 4 hours at ambient temperature, the solvent is eliminated in vacuo and the residue is divided between water and ethyl acetate. The aqueous phase is extracted with ethyl acetate and the combined organic phases are dried on magnesium sulphate. The solvents are eliminated in vacuo and the residue is purified by chromatography on silica gel (cyclohexane/ethyl acetate 10:1 to 1:3).
Reaction SMILES: Br[C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[NH2:11][C:12]1[CH:17]=[C:16]([Br:18])[C:15]([Br:19])=[CH:14][C:13]=1[NH2:20]>>[Br:18][C:16]1[C:15]([Br:19])=[CH:14][C:13]2[NH:20][C:2]3[N:10]=[CH:9][CH:8]=[CH:7][C:3]=3[C:4](=[O:6])[NH:11][C:12]=2[CH:17]=1
Reactant: Nc1cc(Br)c(Br)cc1N
Reactant: O=C(O)c1cccnc1Br
Product: O=C1Nc2cc(Br)c(Br)cc2Nc2ncccc21
Temperature: 150 °C

Procedure:
A mixture of 0.1 mole of 2-bromonicotinic acid and 0.1 mole of 1,2-diamino-4,5-dibromobenzene is heated in an open vessel to 150° C. with vigorous stirring. After 3 minutes the source of heat is removed, and the reaction mixture is allowed to cool to room temperature and to crystallizes to give a solid. The solid is removed from the vessel, powdered, washed with dilute sodium hydroxide, and then with boiling water, and finally recrystallized from dioxane to give 6,11-dihydro-8,9-dibromo-5H-pyrido[2,3-b][1,5]benzodiazepin-5-one.
Reaction SMILES: Cl.Cl.[CH3:3][O:4][C:5]1[CH:6]=[C:7]([CH:15]=[C:16]([O:20][CH3:21])[C:17]=1[O:18][CH3:19])[CH2:8][N:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.C(=O)(O)[O-].[Na+].C(OCC)(=O)C.[CH3:33][O:34][C:35]1[CH:36]=[C:37]([CH:41]=[C:42]([O:46][CH3:47])[C:43]=1[O:44][CH3:45])[C:38]([Cl:40])=[O:39]>O>[ClH:40].[CH3:33][O:34][C:35]1[CH:36]=[C:37]([CH:41]=[C:42]([O:46][CH3:47])[C:43]=1[O:44][CH3:45])[C:38]([N:12]1[CH2:11][CH2:10][N:9]([CH2:8][C:7]2[CH:15]=[C:16]([O:20][CH3:21])[C:17]([O:18][CH3:19])=[C:5]([O:4][CH3:3])[CH:6]=2)[CH2:14][CH2:13]1)=[O:39]
Reactant: COc1cc(CN2CCNCC2)cc(OC)c1OC
Reactant: COc1cc(C(=O)Cl)cc(OC)c1OC
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: COc1cc(CN2CCN(C(=O)c3cc(OC)c(OC)c(OC)c3)CC2)cc(OC)c1OC
Temperature: 25 °C
Yield: 68.3 %

Procedure:
To a mixture of 1-(3,4,5-trimethoxybenzyl)piperazine dihydrochloride (0.6 g), sodium bicarbonate (5 g), ethyl acetate (20 ml) and water (20 ml) is added, with stirring at room temperature, 3,4,5-trimethoxybenzoyl chloride (0.61 g), followed by stirring for 30 minutes. The ethyl acetate layer is separated, washed with water, dried, and concentrated under reduced pressure. The residue is dissolved in ethanol (10 ml). To the solution is added a solution of hydrogen chloride - ethanol (1 ml). The mixture is diluted with ethyl ether (100 ml) to give 1-(3,4,5-trimethoxybenzoyl)-4-(3,4,5-trimethoxybenzyl)piperazine hydrochloride (0.6 g) as colorless needles, m.p. 200°-205° C. (decomp.).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:14][CH:13]3[N:15](C)[CH:10]([CH2:11][CH2:12]3)[CH:9]2[O:17][CH2:18][C:19]2[CH:28]=[CH:27][C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:20]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl[C:36]([O:38][CH2:39][C:40]([Cl:43])([Cl:42])[Cl:41])=[O:37]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:14][CH:13]3[N:15]([C:36]([O:38][CH2:39][C:40]([Cl:43])([Cl:42])[Cl:41])=[O:37])[CH:10]([CH2:11][CH2:12]3)[CH:9]2[O:17][CH2:18][C:19]2[CH:28]=[CH:27][C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:20]=2)=[CH:4][CH:3]=1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Reactant: CN1C2CCC1C(OCc1ccc3ccccc3c1)C(c1ccc(Cl)cc1)C2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: O=C(OCC(Cl)(Cl)Cl)N1C2CCC1C(OCc1ccc3ccccc3c1)C(c1ccc(Cl)cc1)C2
Temperature: 100 °C
Reaction time: 12 h
Yield: 79.2 %

Procedure:
A solution of 1.02 g (2.6 mmol) of (1RS,2RS,3RS,5SR)-3-(4-chloro-phenyl)-8-methyl-2-(naphthalen-2-ylmethoxy)-8-aza-bicyclo[3.2.1]octane in 40 ml of toluene was treated with 150 mg of potassium carbonate and heated to 100° C. Subsequently, 0.635 g (0.400 ml) (3 mmol) of 2,2,2-trichloroethyl chloro-formate was added thereto and the mixture was stirred at 100° C. for 12 hours. The reaction solution was evaporated under reduced pressure, the residue was taken up in 70 ml of ethyl acetate and washed with 30 ml of water and 30 ml of saturated sodium hydrogen carbonate solution. Drying over magnesium sulphate, filtration and evaporation yielded a colourless oil which was chromatographed on silica gel using a 3:2 mixture of hexane and ethyl acetate. There were obtained 1.14 g (79% of theory) of 2,2,2-trichloroethyl (1RS,2RS,3RS,5SR)-3-(4-chloro-phenyl)-2-(naphthalen-2-ylmethoxy)-8-aza-bicyclo[3.2.1]octane-8-carboxylate as a colourless oil, Rf : 0.38 (silica gel, hexane:ethyl acetate=3:2).
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]2[N:6]=[C:7]([NH:9][CH2:10][CH:11]3[CH2:15][CH2:14][NH:13][CH2:12]3)[O:8][C:4]=2[CH:3]=1.Cl.C(OC(N1CC[C@@H](CN)C1)=O)(C)(C)C.ClC1OC2C=C(Cl)C=CC=2N=1>O1CCOCC1>[ClH:1].[Cl:1][C:2]1[CH:17]=[CH:16][C:5]2[N:6]=[C:7]([NH:9][CH2:10][C@@H:11]3[CH2:15][CH2:14][NH:13][CH2:12]3)[O:8][C:4]=2[CH:3]=1
Reactant: Clc1ccc2nc(NCC3CCNC3)oc2c1
Agent: CC(C)(C)OC(=O)N1CC[C@@H](CN)C1
Agent: Cl
Agent: Clc1ccc2nc(Cl)oc2c1
Solvent: C1COCCO1
Product: Clc1ccc2nc(NC[C@@H]3CCNC3)oc2c1

Procedure:
In analogy to the procedure described for the synthesis of (6-Chloro-benzooxazol-2-yl)-pyrrolidin-3-ylmethyl-amine; hydrochloride (example 1, step 2) the title compound was prepared from (S)-3-aminomethyl-pyrrolidine-1-carboxylic acid tert-butyl ester and 2,6-dichloro-benzooxazole (commercially available) and subsequent cleavage of the tert-butyloxy carbonyl-protecting group through treatment with HCl in dioxane. MS (m/e): 252.2 (MH+).
Reaction SMILES: [CH2:1]([C:3]1([CH2:19][C:20]([O:22][CH3:23])=[O:21])[C:8]2[NH:9][C:10]3[C:15]([C:7]=2[CH2:6][CH2:5][O:4]1)=[CH:14][CH:13]=[CH:12][C:11]=3[C:16]#[C:17][CH3:18])[CH3:2].[H][H]>[Pd].CC([O-])=O.CC([O-])=O.[Pb+2].CO>[CH2:1]([C:3]1([CH2:19][C:20]([O:22][CH3:23])=[O:21])[C:8]2[NH:9][C:10]3[C:15]([C:7]=2[CH2:6][CH2:5][O:4]1)=[CH:14][CH:13]=[CH:12][C:11]=3/[CH:16]=[CH:17]\[CH3:18])[CH3:2]
Reactant: [H][H]
Reactant: CC#Cc1cccc2c3c([nH]c12)C(CC)(CC(=O)OC)OCC3
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Pb+2]
Solvent: CO
Product: C/C=C\c1cccc2c3c([nH]c12)C(CC)(CC(=O)OC)OCC3
Temperature: 25 °C
Reaction time: 8 h
Yield: 44.7 %

Procedure:
A mixture of 1-ethyl-8-(1-propynyl)-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetic acid, methyl ester (155 mg, 0.5 mmol), Lindlar catalyst (15 mg), and methanol (10 mL) was charged with 1 atmosphere of hydrogen and allowed to stir at room temperature overnight. The catalyst was then removed by filtration through a celite plug, and the filtrate concentrated to give 170 mg of the crude product. This material was purified by flash chromatography (10% ethyl acetate/hexane, silica gel) to give the pure title compound as a yellow oil (70 mg).