Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][S:4][CH:3]=1.[Li]CCCC.Br[C:13]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=1>C1COCC1.[Cl-].[Zn+2].[Cl-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd]>[CH3:1][C:2]1[CH:6]=[C:5]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=2)[S:4][CH:3]=1
Reactant: FC(F)(F)c1ccc(Br)cc1
Reactant: Cc1ccsc1
Agent: [Pd]
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1csc(-c2ccc(C(F)(F)F)cc2)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 3-methylthiophene (2.31 ml) in anhydrous THF (75 ml) at −78° C. under N2 was added dropwise n-BuLi (1.6 M in hexanes, 15 ml). Thirty minutes after the addition was complete, the reaction mixture was allowed to warm to 0° C. and stirred for a further 30 minutes. Zinc chloride (0.5 M in THF, 48 ml) was added drop-wise, after a further 15 minutes palladium (0) tetrakis(triphenylphosphine) (100 mg) and 4-bromobenzotrifluoride (3.36 ml) were added and the reaction allowed to attain room temperature. The reaction mixture was warmed to 40° C. and stirred at this temperature for 3 hours. The reaction mixture was then cooled to room temperature and the solvents removed in vacuo. The residue was partitioned between and ether and the aqueous extract further washed with ether. The combined organic extracts were dried (MgSO4), filtered and evaporated to yield a brown oil. Purification by Biotage® chromatography eluting with cyclohexane yielded the title compound as a white solid.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:29])[C@H:15]([CH2:24][CH2:25][C:26](=[O:28])[NH2:27])[NH:16][C:17](OC(C)(C)C)=[O:18])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:30]([O:37][C:38]1[CH:46]=[C:45]([O:47][CH2:48][C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)[CH:44]=[CH:43][C:39]=1C(O)=O)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>>[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:29])[C@H:15]([CH2:24][CH2:25][C:26](=[O:28])[NH2:27])[NH:16][C:17](=[O:18])[C:44]2[CH:43]=[CH:39][C:38]([O:37][CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[CH:46][C:45]=2[O:47][CH2:48][C:49]2[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(OCc2ccccc2)cc1OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@@H](CCC(N)=O)C(=O)N1CCN(Cc2ccccc2)CC1
Product: NC(=O)CC[C@H](NC(=O)c1ccc(OCc2ccccc2)cc1OCc1ccccc1)C(=O)N1CCN(Cc2ccccc2)CC1
Yield: 26.9 %

Procedure:
Condensation of 1-benzyl-4-(N-tert-butoxycarbonyl-L-glutaminyl)piperazine (1.0 g) and 2,4-dibenzyloxybenzoic acid (752 mg) was carried out in the same manner as in Example 7 (i) to obtain colorless crystalline powder 1-benzyl-4-(2,4-dibenzyloxybenzoyl-L-glutaminyl)piperazine (375 mg). Melting point: 133°-135° C.
Reaction SMILES: [CH2:1]([N:4]1[CH2:9][CH2:8][CH:7]([C:10]2[CH:19]=[CH:18][C:13]([C:14]([O:16]C)=O)=[CH:12][CH:11]=2)[CH2:6][CH2:5]1)[C:2]#[CH:3].[CH3:20][O:21][C:22]1[CH:23]=[C:24]([CH2:30][CH2:31][C:32]2[CH:33]=[C:34]([NH2:37])[NH:35][N:36]=2)[CH:25]=[C:26]([O:28][CH3:29])[CH:27]=1.C[Al](C)C>C1(C)C=CC=CC=1>[CH3:29][O:28][C:26]1[CH:25]=[C:24]([CH2:30][CH2:31][C:32]2[CH:33]=[C:34]([NH:37][C:14](=[O:16])[C:13]3[CH:12]=[CH:11][C:10]([CH:7]4[CH2:6][CH2:5][N:4]([CH2:1][C:2]#[CH:3])[CH2:9][CH2:8]4)=[CH:19][CH:18]=3)[NH:35][N:36]=2)[CH:23]=[C:22]([O:21][CH3:20])[CH:27]=1
Reactant: C#CCN1CCC(c2ccc(C(=O)OC)cc2)CC1
Reactant: COc1cc(CCc2cc(N)[nH]n2)cc(OC)c1
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: C#CCN1CCC(c2ccc(C(=O)Nc3cc(CCc4cc(OC)cc(OC)c4)n[nH]3)cc2)CC1
Yield: 51.8 %

Procedure:
N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-yl]-4-(1-prop-2-ynylpiperidin-4-yl)benzamide was prepared following the procedure as outlined for Example 99, starting from methyl 4-(1-prop-2-ynylpiperidin-4-yl)benzoate (0.257 g, 1.00 mmol) and 5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-amine (0.247 g, 1 mmol) in dry toluene (10 mL) with 2M trimethylaluminium (1.250 mL, 2.50 mmol). The crude product was purified by silica column chromatography, eluting with a gradient of 0 to 5% 2.5M ammonia/methanol in DCM. Pure fractions were evaporated to dryness and the product crystallised from DCM/diethyl ether to give the title compound (0.245 g, 51.8%) as a white solid.
Reaction SMILES: [CH3:1][NH:2][C:3]1[N:8]=[C:7]([C:9]2[NH:10][C:11]3[C:16]([CH:17]=2)=[CH:15][C:14]([C:18]([NH:20][CH:21]([CH2:25][N:26]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:27]2[N:32]=[CH:31][CH:30]=[CH:29][N:28]=2)[C:22](O)=[O:23])=[O:19])=[CH:13][CH:12]=3)[CH:6]=[CH:5][N:4]=1.C1C=NC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[CH2:58]([CH2:60][NH2:61])[OH:59]>CN(C=O)C.C(Cl)CCl>[OH:59][CH2:58][CH2:60][NH:61][C:22]([CH:21]([NH:20][C:18]([C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9]([C:7]1[CH:6]=[CH:5][N:4]=[C:3]([NH:2][CH3:1])[N:8]=1)=[CH:17]2)=[O:19])[CH2:25][N:26]([C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)[C:27]1[N:28]=[CH:29][CH:30]=[CH:31][N:32]=1)=[O:23]
Reactant: NCCO
Reactant: CNc1nccc(-c2cc3cc(C(=O)NC(CN(c4ccccc4)c4ncccn4)C(=O)O)ccc3[nH]2)n1
Agent: On1nnc2cccnc21
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CNc1nccc(-c2cc3cc(C(=O)NC(CN(c4ccccc4)c4ncccn4)C(=O)NCCO)ccc3[nH]2)n1
Temperature: 0 °C
Reaction time: 48 h

Procedure:
200 mg of the acid 48 were dissolved in 2 ml of absolute DMF, 94 mg of HOAt and 158 μl of DIEA were added 56 μl of ethanolamine were then added dropwise and the mixture was cooled down to 0° C.; 195 mg of EDC were then added. After 2 days of stirring at room temperature, the solvent was evaporated and the crude product was purified by means of MPLC (eluent: DCM:MeOH=9:1).
Reaction SMILES: Br[C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[CH2:9]([C:11]1[CH:12]=[C:13](B(O)O)[CH:14]=[CH:15][CH:16]=1)[CH3:10]>>[CH2:9]([C:11]1[CH:16]=[C:15]([C:2]2[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=2)[CH:14]=[CH:13][CH:12]=1)[CH3:10]
Reactant: CCc1cccc(B(O)O)c1
Reactant: Nc1ccc(Br)cc1
Product: CCc1cccc(-c2ccc(N)cc2)c1
Yield: 97.5 %

Procedure:
The title compound (300 mg) was prepared from 4-bromoaniline (270 mg, 1.56 mmol) and 3-ethylphenylboronic acid (300 mg, 2.04 mmol) as a colourless liquid.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([N:12]([CH3:14])[CH3:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[C:15]([O:19][C:20](=[O:29])[NH:21][C@H:22]1[CH2:27][CH2:26][C@@H:25]([NH2:28])[CH2:24][CH2:23]1)([CH3:18])([CH3:17])[CH3:16].C([O-])(O)=O.[Na+]>CC(O)C>[C:15]([O:19][C:20](=[O:29])[NH:21][C@H:22]1[CH2:23][CH2:24][C@@H:25]([NH:28][C:2]2[N:11]=[C:10]([N:12]([CH3:14])[CH3:13])[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]=2)[CH2:26][CH2:27]1)([CH3:18])([CH3:16])[CH3:17]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](N)CC1
Reactant: CN(C)c1nc(Cl)nc2ccccc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Product: CN(C)c1nc(N[C@H]2CC[C@@H](NC(=O)OC(C)(C)C)CC2)nc2ccccc12

Procedure:
A mixture of (2-chloro-quinazolin-4-yl)-dimethyl-amine obtained in step B of example 1 (3.00 g, 14.4 mmol) and cis-(4-amino-cyclohexyl)-carbamic acid tert-butyl ester (3.72 g, 17.4 mmol) in 2-propanol (10 mL) was stirred at reflux for 5.5 days, poured into saturated aqueous NaHCO3, and the aqueous layer was extracted with CHCl3 (three times). The combined organic layer was dried over MgSO4, filtered, concentrated, and purified by flash chromatography (NH-silica, 20% EtOAc in hexane) to give cis-[4-(4-dimethylamino-quinazolin-2-ylamino)-cyclohexyl]-carbamic acid tert-butyl ester including solvent (5.44 g) as a colorless oil. To a solution of the above material (5.44 g) in EtOAc (10 mL) was added 4 M hydrogen chloride in EtOAc (50 mL). The reaction mixture was stirred at ambient temperature for 2 hr, and concentrated. The residue was alkalized with saturated aqueous NaHCO3, and the precipitate was collected by filtration to give cis-N2-(4-amino-cyclohexyl)-N4,N4-dimethyl-quinazoline-2,4-diamine (2.26 g, 55%) as a white solid. The aqueous layer was extracted CHCl3 (three times). The combined organic layer was dried over MgSO4, filtered, and concentrated to give cis-N2-(4-amino-cyclohexyl)-N4,N4-diethyl-quinazoline-2,4-diamine (687 mg, 17%) as a white solid.
Reaction SMILES: C(N([CH2:6][CH3:7])CC)C.C[Si](C#C)(C)C.[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([C@:21]2([O:30][C@H:29]([CH2:31][OH:32])[C@@H:27]([OH:28])[C@H:25]([OH:26])[C@H:23]2[OH:24])[OH:22])=[CH:17][C:16]=1[CH2:33][C:34]1[CH:39]=[CH:38][C:37](OS(C(F)(F)F)(=O)=O)=[CH:36][CH:35]=1.C(=O)([O-])O.[Na+]>CN(C)C=O.[Cu](I)I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([C@:21]2([O:30][C@H:29]([CH2:31][OH:32])[C@@H:27]([OH:28])[C@H:25]([OH:26])[C@H:23]2[OH:24])[OH:22])=[CH:17][C:16]=1[CH2:33][C:34]1[CH:35]=[CH:36][C:37]([C:6]#[CH:7])=[CH:38][CH:39]=1
Reactant: O=S(=O)(Oc1ccc(Cc2cc([C@@]3(O)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)ccc2Cl)cc1)C(F)(F)F
Reactant: CCN(CC)CC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Agent: C#C[Si](C)(C)C
Solvent: CN(C)C=O
Product: C#Cc1ccc(Cc2cc([C@@]3(O)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)ccc2Cl)cc1
Temperature: 90 °C
Reaction time: 8 h

Procedure:
25 mg of copper iodide, 44 mg of bis-(triphenylphosphine)-palladium dichloride, 0.30 ml triethylamine and finally 0.14 ml of trimethylsilylacetylene are added under argon to a solution of 0.32 g 1-chloro-4-(β-D-glucopyranos-1-yl)-2-[4-(trifluoromethylsulphonyloxy)-benzyl]-benzene in 3 ml of dimethylformamide. The flask is tightly sealed and stirred for 8 h at 90° C. Then another 25 mg of bis-(triphenylphosphine)-palladium dichloride and 0.1 ml trimethylsilylacetylene are added, and the solution is stirred for a further 10 h at 90° C. Then aqueous sodium hydrogen carbonate solution is added, the mixture is extracted three times with ethyl acetate, and the combined organic phases are dried over sodium sulphate. After the solvent has been eliminated the residue is dissolved in 5 ml of methanol and combined with 0.12 g potassium carbonate. The mixture is stirred for 1 h at ambient temperature and then neutralised with 1 M hydrochloric acid. Then the methanol is evaporated off, the residue is combined with aqueous sodium chloride solution and extracted with ethyl acetate. The organic extracts collected are dried over sodium sulphate, and the solvent is removed. The residue is chromatographed through silica gel (dichloromethane/methanol 1:0->5:1).
Reaction SMILES: [C:1]([O-:4])(=[S:3])[CH3:2].[K+].[Br:6][C:7]1[CH:8]=[CH:9][C:10]2[C:11]3[N:19]([CH2:20][CH2:21][CH2:22][CH2:23]Cl)[C:18]([CH2:25][O:26][CH2:27][CH3:28])=[N:17][C:12]=3[CH:13]=[N:14][C:15]=2[CH:16]=1>CN(C=O)C>[Br:6][C:7]1[CH:8]=[CH:9][C:10]2[C:11]3[N:19]([CH2:20][CH2:21][CH2:22][CH2:23][S:3][C:1](=[O:4])[CH3:2])[C:18]([CH2:25][O:26][CH2:27][CH3:28])=[N:17][C:12]=3[CH:13]=[N:14][C:15]=2[CH:16]=1
Reactant: CC([O-])=S
Reactant: CCOCc1nc2cnc3cc(Br)ccc3c2n1CCCCCl
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOCc1nc2cnc3cc(Br)ccc3c2n1CCCCSC(C)=O
Temperature: 25 °C
Reaction time: 21 h
Yield: 103.4 %

Procedure:
Potassium thioacetate (1.70 g, 14.9 mmol) was added in one portion to a stirred solution of 7-bromo-1-(4-chlorobutyl)-2-ethoxymethyl-1H-imidazo[4,5-c]quinoline (5.37 g, 13.5 mmol) in DMF (65 mL), and the reaction was stirred at ambient temperature for 21 hours. The DMF was removed under reduced pressure, and the residue was partitioned between dichloromethane (300 mL) and water (150 mL). The organic layer was separated, washed with brine (120 mL), dried over magnesium sulfate, filtered, and concentrated to provide 6.09 g of thioacetic acid S-[4-(7-bromo-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]ester as a brown solid.
Reaction SMILES: CO[CH:3](OC)[CH2:4][NH:5][C:6]1[CH2:12][N:11]=[C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[C:9]2[CH:19]=[C:20]([Br:23])[CH:21]=[CH:22][C:8]=2[N:7]=1.S(=O)(=O)(O)O.[OH-].[Na+]>>[Br:23][C:20]1[CH:21]=[CH:22][C:8]2[N:7]3[CH:3]=[CH:4][N:5]=[C:6]3[CH2:12][N:11]=[C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)[C:9]=2[CH:19]=1
Reactant: COC(CNC1=Nc2ccc(Br)cc2C(c2ccccn2)=NC1)OC
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: Brc1ccc2c(c1)C(c1ccccn1)=NCc1nccn1-2
Reaction time: 8 h
Yield: 81 %

Procedure:
A solution of 15 g. (37 mmol) of [[7-bromo-5-(2-pyridyl)-3H-1,4-benzodiazepine-2-yl]amino]acetaldehyde dimethyl-acetal in 50 ml. of concentrated sulfuric acid is allowed to stirat room temperature under nitrogen overnight, poured onto crushed ice and neutralized with an aqueous sodium hydroxide solution. The product is extracted with chloroform and the chloroform washed with brine, dried oversodium sulfate and concentrated to an oil in vacuo. On trituration, 10.2 g.(81%) of 8-bromo-6-(2-pyridyl)-4H-imidazo[1,2-a][1,4]benzodiazepine, a yellow crystalline product of melting point 208°-210°, is obtained.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH:7]1([CH2:12][CH2:13][C:14]([N:16]2[C@@H:24]3[C@@H:19]([C:20]4[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH3:30])[C:21]=4[CH2:22][CH2:23]3)[CH2:18][CH2:17]2)=O)[CH2:11][CH2:10][CH2:9][CH2:8]1.C1COCC1.O.[OH-].[Na+]>C1COCC1.O>[CH:7]1([CH2:12][CH2:13][CH2:14][N:16]2[C@@H:24]3[C@@H:19]([C:20]4[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH3:30])[C:21]=4[CH2:22][CH2:23]3)[CH2:18][CH2:17]2)[CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: COc1cccc2c1CC[C@H]1[C@@H]2CCN1C(=O)CCC1CCCC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: COc1cccc2c1CC[C@H]1[C@@H]2CCN1CCCC1CCCC1
Yield: 97.8 %

Procedure:
0.71 g (0.0187 mol) of lithium aluminum hydride was suspended in 20 ml of THF under argon. A solution of 4.7 g (0.01435 mol) of rac-cis-3-(3-cyclopentyl-propionyl)-2,3,3a,4,5,9b-hexahydro-6-methoxy-1H-benzo[e]indole in 50 ml of THF was added dropwise thereto and the mixture was boiled under reflux for 1/2 hour. 10 ml of THF/water 4:1, 4 ml of a 15% aqueous NaOH solution and 2 ml of water were cautiously added dropwise thereto in succession, whereupon the mixture was boiled under reflux for 10 minutes until a complete white precipitate had resulted. After filtration and concentration there was obtained an oil which was chromatographed over silica gel with n-hexane/ethyl acetate 1:1. There were obtained 4.40 g (98%) of rac-cis-3-(3-cyclopentylpropyl)-2,3,3a,4,5,9b-hexahydro-6-methoxy-1H-benzo[e]indole as a yellowish, oily material.
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH2:7].[C:9]([CH2:11][C:12](OCC)=O)#[N:10]>C(OCCC)(=O)C>[N:7]1[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=2[NH:8][C:12]=1[CH2:11][C:9]#[N:10]
Reactant: CCOC(=O)CC#N
Reactant: Nc1ccccc1N
Solvent: CCCOC(C)=O
Product: N#CCc1nc2ccccc2[nH]1

Procedure:
Benzimidazole-2-acetonitrile was prepared as follows. A mixture of o-phenylenediamine (1 mole) and ethyl cyanoacetate (2 moles) was refluxed for about 30 hours, cooled, diluted with propyl acetate (225 mL), filtered, washed and dried, to provide benzimidazole-2-acetonitrile in a 60-70% yield. Benzimidazole-2-acetonitrile is also available commercially from Aldrich Chemical Company.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:14]=[CH:13][N:12]([CH2:15][C@@H:16]([NH:18][C:19]([C:21]3[NH:25][N:24]=[C:23]([CH:26]([OH:28])[CH3:27])[CH:22]=3)=[O:20])[CH3:17])[N:11]=2)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].[C:29](OC(=O)C)(=[O:31])[CH3:30]>CN(C1C=CN=CC=1)C.N1C=CC=CC=1>[C:29]([O:28][CH:26]([C:23]1[CH:22]=[C:21]([C:19](=[O:20])[NH:18][C@@H:16]([CH3:17])[CH2:15][N:12]2[CH:13]=[CH:14][C:10]([C:4]3[CH:5]=[CH:6][C:7]([C:8]#[N:9])=[C:2]([Cl:1])[CH:3]=3)=[N:11]2)[NH:25][N:24]=1)[CH3:27])(=[O:31])[CH3:30]
Reactant: CC(O)c1cc(C(=O)N[C@@H](C)Cn2ccc(-c3ccc(C#N)c(Cl)c3)n2)[nH]n1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: CC(=O)OC(C)c1cc(C(=O)N[C@@H](C)Cn2ccc(-c3ccc(C#N)c(Cl)c3)n2)[nH]n1
Temperature: 0 °C
Reaction time: 8 h
Yield: 58.9 %

Procedure:
A flask containing N—((S)-1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)-propan-2-yl)-3-(1-hydroxyethyl)-1H-pyrazole-5-carboxamide (400 mg, 1.003 mmol) and DMAP (12.25 mg, 0.100 mmol) was put under nitrogen atmosphere. Pyridine (10 ml) was added, the reaction mixture cooled down to 0° C. and acetic anhydride (0.099 ml, 108 mg) was added dropwise. The mixture was allowed to warm to RT and stirred overnight. Next day the mixture was evaporated and purified by flash chromatography. Yield 58.9%. 1H-NMR (400 MHz; DMSO-d6): δ 1.15 (d, 3H), 1.51 (d, 3H), 2.02 (s, 3H), 4.25-4.37 (m, 2H), 4.39-4.49 (m, 1H), 5.88 (q, 1H), 6.64 (s, 1H), 6.90 (dd, 1H), 7.80 (dd, 1H), 7.91-7.96 (m, 2H), 8.04-8.07 (m, 1H), 8.15 (s, 1H), 13.24 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][C:5]([CH2:6][NH:7][C:8]([CH:10]2[CH2:12][CH2:11]2)=[O:9])=[CH:4][C:3]=1[N+:15]([O-])=O.Cl>[Fe].CO>[NH2:15][C:3]1[CH:4]=[C:5]([CH:13]=[CH:14][C:2]=1[Cl:1])[CH2:6][NH:7][C:8]([CH:10]1[CH2:12][CH2:11]1)=[O:9]
Reactant: O=C(NCc1ccc(Cl)c([N+](=O)[O-])c1)C1CC1
Agent: [Fe]
Agent: Cl
Solvent: CO
Product: Nc1cc(CNC(=O)C2CC2)ccc1Cl
Yield: 56.7 %

Procedure:
The title compound was prepared by following the procedure as described in step-2 of Intermediate-28 by using N-(4-chloro-3-nitrobenzyl)cyclopropanecarboxamide (0.400 g), methanol (10 mL), iron powder (catalytic) and conc.HCl (5 mL). The reaction mass was refluxed for 2 h. The reaction mass was quenched in water and basified with NaHCO3 and extracted with DCM. The organic layer was dried over anhydrous sodium sulphate and concentrated to afford 0.200 g of desired product. 1H NMR (300 MHz, DMSO d6): δ 0.65 (d, J=8.4 Hz, 4H), 1.57 (m, 1H), 4.11 (d, J=5.4 Hz, 2H), 5.34 (s, 2H), 6.41 (d, J=7.2 Hz, 1H), 7.10 (d, J=7.8 Hz, 1H), 8.50 (br s, 1H); MS (m/z): 225.07 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([OH:10])[C:3]=1[CH:4]=[O:5].C([O-])([O-])=O.[Cs+].[Cs+].Cl.Cl[CH2:19][C:20]1[C:21]([C:26]2[N:30]([CH:31]([CH3:33])[CH3:32])[N:29]=[CH:28][CH:27]=2)=[N:22][CH:23]=[CH:24][CH:25]=1>CN(C=O)C>[OH:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH2:19][C:20]2[C:21]([C:26]3[N:30]([CH:31]([CH3:33])[CH3:32])[N:29]=[CH:28][CH:27]=3)=[N:22][CH:23]=[CH:24][CH:25]=2)[C:3]=1[CH:4]=[O:5]
Reactant: CC(C)n1nccc1-c1ncccc1CCl
Reactant: O=Cc1c(O)cccc1O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)n1nccc1-c1ncccc1COc1cccc(O)c1C=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 38.4 %

Procedure:
A mixture of 2,6-dihydroxybenzaldehyde (1.96 g, 14.2 mmol, 2 eq.) and Cs2CO3 (7.5 g, 21.3 mmol, 3 eq.) in DMF (180 mL) was stirred at rt for 30 min. To this mixture was added 3-(chloromethyl)-2-(1-isopropyl-1H-pyrazol-5-yl)pyridine hydrochloride (1.93 g, 7.1 mmol, 1 eq.) at rt. The mixture was continued to stir at rt O/N, filtered, concentrated and purified on silica gel using a mixture of EtOAc and hexanes as eluent to give 2-hydroxy-6-((2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)benzaldehyde (920 mg, 37%) as a pale yellow oil. 1H NMR (400 MHz, CDCl3) δ 11.96 (s, 1H), 10.40 (s, 1H), 8.77 (dd, J=4.8, 1.5 Hz, 1H), 8.00 (d, J=7.8 Hz, 1H), 7.63 (d, J=1.8 Hz, 1H), 7.49-7.34 (m, 2H), 6.59 (d, J=8.5 Hz, 1H), 6.37 (d, J=1.8 Hz, 1H), 6.29 (d, J=8.2 Hz, 1H), 5.10 (s, 2H), 4.67 (sep, J=6.7 Hz, 1H), 1.50 (d, J=6.6 Hz, 6H). LRMS (M+H+) m/z 338.1
Reaction SMILES: O[NH:2][C:3](=[NH:30])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[C:23]2[C:22]3[CH:21]=[C:20]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH:19]=[CH:18][C:17]=3[N:16]=[CH:15][C:14]=2[N:13]=[CH:12]1>Cl.[Ni]>[C:24]1([C:20]2[CH:19]=[CH:18][C:17]3[N:16]=[CH:15][C:14]4[N:13]=[CH:12][N:11]([C:6]5[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=5[CH2:4][C:3]([NH2:30])=[NH:2])[C:23]=4[C:22]=3[CH:21]=2)[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: N=C(Cc1ccccc1-n1cnc2cnc3ccc(-c4ccccc4)cc3c21)NO
Agent: [Ni]
Agent: Cl
Product: N=C(N)Cc1ccccc1-n1cnc2cnc3ccc(-c4ccccc4)cc3c21

Procedure:
The title compound is prepared in analogy to Example 69 starting from 220 mg (0.559 mmol) N-hydroxy-2-[2-(8-phenyl-imidazo[4,5-c]quinolin-1-yl)-phenyl]-acetamidine (Example 68) and 120 mg Raney-Ni in 6 ml 0.5 N HCl at 50° C. for 9 h. The compound is purified by chromatography (THF-H2O-1N HCl 90:10:0.25) and precipitated from ethyl acetate. mp: 261-263° C.; MS: 378 (M++1); HPLC: tret=6.66 min (Grad 1).
Reaction SMILES: [CH2:1]([CH:4]1[S:9](=[O:11])(=[O:10])[C:8]([CH3:13])([CH3:12])[C:7]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[N:6][C:5]1([C:23]1[CH:28]=[C:27]([N+:29]([O-:31])=[O:30])[CH:26]=[CH:25][C:24]=1[F:32])[CH3:22])[CH:2]=C.C(=O)(O)[O-:34].[Na+].[BH4-].[Na+]>C(Cl)Cl.CO>[F:32][C:24]1[CH:25]=[CH:26][C:27]([N+:29]([O-:31])=[O:30])=[CH:28][C:23]=1[C:5]1([CH3:22])[CH:4]([CH2:1][CH2:2][OH:34])[S:9](=[O:11])(=[O:10])[C:8]([CH3:13])([CH3:12])[C:7]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[N:6]1
Reactant: O=C([O-])O
Reactant: C=CCC1C(C)(c2cc([N+](=O)[O-])ccc2F)N=C(NC(=O)OC(C)(C)C)C(C)(C)S1(=O)=O
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: CC(C)(C)OC(=O)NC1=NC(C)(c2cc([N+](=O)[O-])ccc2F)C(CCO)S(=O)(=O)C1(C)C
Reaction time: 0.17 h
Yield: 98.8 %

Procedure:
A solution of tert-butyl ((5RS,6RS)-6-allyl-5-(2-fluoro-5-nitrophenyl)-2,2,5-trimethyl-1,1-dioxido-5,6-dihydro-2H-1,4-thiazin-3-yl)carbamate (120 mg, 0.256 mmol) in DCM (1.8 ml) and MeOH (0.6 ml) was cooled to −78° C., and sodium bicarbonate (42.9 mg, 0.511 mmol) was added and the mixture was ozonolyzed for 10 min. Oxygen was bubbled through the solution for 2 min, then solid sodium borohydride (14.5 mg, 0.383 mmol) was added to the mixture and the mixture was removed from the cooling bath and was allowed to reach RT and stirred for 30 min. The reaction was quenched with sat. solution of NH4Cl and extracted with EtOAc. The organic layer was washed with brine, dried over MgSO4 and concentrated to afford crude racemic tert-butyl ((5RS,6RS)-5-(2-fluoro-5-nitrophenyl)-6-(2-hydroxyethyl)-2,2,5-trimethyl-1,1-dioxido-5,6-dihydro-2H-1,4-thiazin-3-yl)carbamate (120 mg, 0.253 mmol, 99% yield) which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1Br.[F:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[C:12]=1B(O)O>COCCOC.O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:12]1[C:13]([O:17][CH3:18])=[CH:14][CH:15]=[CH:16][C:11]=1[F:10]
Reactant: Clc1ccc(Br)c(Cl)c1
Reactant: COc1cccc(F)c1B(O)O
Solvent: COCCOC
Solvent: O
Product: COc1cccc(F)c1-c1ccc(Cl)cc1Cl
Yield: 62.7 %

Procedure:
Treatment of 2,4-dichlorobromobenzene (13.8 g, 61.2 mmol) with 2-fluoro-6-methoxybenzene boronic acid (5.0 g, 29.4 mmol) in DME-water (5:1, 150 mL) according to the procedure described for Example 69, Step 1 provided 5.0 g (63%) of 2,4-dichloro-2′-fluoro-6′-methoxybiphenyl as a colorless oil.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[Br:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]Br.[OH-].[Na+]>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.C(Cl)Cl>[Br:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][O:1][CH:2]1[CH2:3][CH2:4][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:6][CH2:7]1
Reactant: BrCCCCCCBr
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(OCCCCCCBr)CC1
Temperature: 25 °C
Reaction time: 120 h

Procedure:
A mixture of 7 g of tert-butyl (4-hydroxy)-piperidine-1-carboxylate and 210 ml of 1,6-dibromohexane is treated firstly with 3.5 g of tetrabutylammonium hydrogen sulphate and then with 210 ml of 50% aqueous sodium hydroxide solution. After stirring at room temperature for 5 days the reaction mixture is diluted with methylene chloride, the organic phase is separated and the aqueous phase is extracted with methylene chloride. The combined organic phases are washed with saturated sodium chloride solution, dried and concentrated. The brown oil is chromatographed on silica gel with ethyl acetate-hexane. 10.9 g of tert-butyl 4-(6-bromo-hexyloxy)-piperidine-1-carboxylate are obtained.