Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][N:8]2[S:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:13])=[O:12])=[CH:4][C:3]=1[OH:20].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[CH2:41][CH2:42][NH:43]C(=O)OC(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][N:8]2[S:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:13])=[O:12])=[CH:4][C:3]=1[O:20][CH2:41][CH2:42][NH2:43]
Reactant: O=S(=O)(c1ccccc1)n1ccc2cc(O)c(F)cc21
Reactant: CC(C)(C)OC(=O)NCCO
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NCCOc1cc2ccn(S(=O)(=O)c3ccccc3)c2cc1F
Temperature: 150 °C
Reaction time: 2 h
Yield: 59.8 %

Procedure:
To 6-fluoro-1-(phenylsulfonyl)-1H-indol-5-ol (Intermediate 28, 3.0 g, 10 mmol), 1,1′-azobis(N,N (3.5 g, 21 mmol), triphenylphosphine (5.4 g, 21 mmol), tert-butyl N-(2-hydroxy-ethyl)carbamate (3.3 g, 21 mmol) and DCM (20 mL) were added. The mixture was heated at 150° C. for 20 minutes in a microwave heater. The reaction mixture was allowed to cool to room temperature and TFA (20 mL) was added. The reaction mixture was allowed to stir at room temperature for 2 hours. The solvent was removed under reduced pressure and the crude material was filtered through a plug of silica gel using DCM as eluent. The solvent was removed under reduced pressure and the crude material was dissolved in ethyl acetate (10 mL) and the HCl salt of the title compound precipitated when 1 M HCl in diethylether (20 mL) was added. The solid was filtered off, dissolved in DCM (100 mL) and organic phase was washed with saturated aqueous NaHCO3 (40 mL) to give the title compound (2.0 g). MS m/z 335 [M+H]+.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([CH:20]([OH:36])[CH2:21][NH:22][C:23]([CH3:35])([CH3:34])[CH2:24][C:25]2[CH:30]=[CH:29][C:28]([CH:31]([CH3:33])[CH3:32])=[CH:27][CH:26]=2)[C:12]2[O:17][CH2:16][C:15](=[O:18])[NH:14][C:13]=2[CH:19]=1)C1C=CC=CC=1>CO.[Pd]>[OH:8][C:9]1[CH:10]=[C:11]([CH:20]([OH:36])[CH2:21][NH:22][C:23]([CH3:34])([CH3:35])[CH2:24][C:25]2[CH:26]=[CH:27][C:28]([CH:31]([CH3:32])[CH3:33])=[CH:29][CH:30]=2)[C:12]2[O:17][CH2:16][C:15](=[O:18])[NH:14][C:13]=2[CH:19]=1
Reactant: CC(C)c1ccc(CC(C)(C)NCC(O)c2cc(OCc3ccccc3)cc3c2OCC(=O)N3)cc1
Agent: [Pd]
Solvent: CO
Product: CC(C)c1ccc(CC(C)(C)NCC(O)c2cc(O)cc3c2OCC(=O)N3)cc1

Procedure:
1.6 g (3.0 mmol) of 6-benzyloxy-8-{1-hydroxy-2-[2-(4-isopropylphenyl)-1,1-dimethylethylamino]ethyl}-4H-benzo[1,4]oxazin-3-one is dissolved in methanol and hydrogenated with palladium on charcoal as catalyst at normal pressure and ambient temperature. The catalyst is suction filtered, the solvent distilled off, and the residue recrystallized from isopropanol. White solid. Yield: 1.1 g (85%, hydrochloride); melting point 248° C.-250° C.; mass spectrometry: [M+H]+=399.
Reaction SMILES: Cl[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4].[C:11]([S-:13])#[N:12].[K+]>C(O)C.O>[S:13]([CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4])[C:11]#[N:12]
Reactant: N#C[S-]
Reactant: O=C(CCl)c1ccccc1
Agent: [K+]
Solvent: O
Solvent: CCO
Product: N#CSCC(=O)c1ccccc1
Temperature: 50 °C
Reaction time: 0.17 h

Procedure:
150 g of ω-chloroacetophenone are dissolved at 50° C. in 1000 ml of ethanol, followed by the addition of a solution of 102 g of KSCN in 40 ml of water. After stirring for 10 minutes at 50° C., the ω-thiocyano acetophenone formed is precipitated with water.
Reaction SMILES: [Cl:1][C:2]([Cl:7])([Cl:6])[C:3](Cl)=[O:4].[CH3:8][C:9]1[N:10]=[C:11]2[N:15]([CH:16]=1)[C:14]1[CH:17]=[CH:18][CH:19]=[CH:20][C:13]=1[N:12]2[CH3:21]>C1(C)C(C)=CC=CC=1>[CH3:8][C:9]1[N:10]=[C:11]2[N:15]([C:16]=1[C:3](=[O:4])[C:2]([Cl:7])([Cl:6])[Cl:1])[C:14]1[CH:17]=[CH:18][CH:19]=[CH:20][C:13]=1[N:12]2[CH3:21]
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Reactant: Cc1cn2c3ccccc3n(C)c2n1
Solvent: Cc1ccccc1C
Product: Cc1nc2n(C)c3ccccc3n2c1C(=O)C(Cl)(Cl)Cl

Procedure:
Pour 5.45 g (30 mmol) of freshly distilled trichloroacetyl chloride dropwise into a boiling solution of 2,9-dimethylimidazo[1,2-a]benzimidazole(3.7 g; 20 mmol) obtained as described in Khim. Geterotsikl Soedin, 86, (7), 918-925--in 50 ml of xylene, with vigorous stirring, over a period of 20 to 30 minutes. The mixture is then heated at reflux for wo hours until the product which has initially precipitated is completely dissolved. Cool and filter. Concentrate the mother liquors and add petroleum ehter. Combie with the precipitate obtained earlier and repeat the operation. The combined precipitates are treated with an aqueous solution of sodium hydrogen carbonate and then recrystallised from ethyl acetate.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:9]=[C:10]3[CH:16]=[CH:15][NH:14][C:11]3=[N:12][CH:13]=2)[CH:5]=[CH:4][C:3]=1[CH:17]1[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]1.[I:30]N1C(=O)CCC1=O>C(Cl)Cl>[F:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:9]=[C:10]3[C:16]([I:30])=[CH:15][NH:14][C:11]3=[N:12][CH:13]=2)[CH:5]=[CH:4][C:3]=1[CH:17]1[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]1
Reactant: O=C1CCC(=O)N1I
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(-c3cnc4[nH]ccc4c3)cc2F)CC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(-c3cnc4[nH]cc(I)c4c3)cc2F)CC1
Yield: 94.7 %

Procedure:
Using similar reaction conditions as described in step i of intermediate 1, tert-butyl 4-(2-fluoro-4-(1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)piperidine-1-carboxylate (320 mg, 0.810 mmol) was iodinated with N-iodosuccinimide (219 mg, 0.972 mmol) in DCM (20 ml) to afford 400 mg (94.7% yield) of the pure product. MS: m/z=522.1 (M+1).
Reaction SMILES: [I:1][N:2]([C:7]([O:9][CH2:10][C:11]#[CH:12])=[O:8])[CH2:3][C:4]([OH:6])=[O:5].N12CCCN=C1CCCCC2.[CH2:24](Br)[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]>C(#N)C>[CH2:24]([O:5][C:4](=[O:6])[CH2:3][N:2]([C:7]([O:9][CH2:10][C:11]#[CH:12])=[O:8])[I:1])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]
Reactant: CCCCCCCCBr
Reactant: C#CCOC(=O)N(I)CC(=O)O
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: C#CCOC(=O)N(I)CC(=O)OCCCCCCCC
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
N-Iodopropargyloxycarbonyl glycine (compound 1, 6.50 g., 22.97 mmole) was dissolved in anhydrous acetonitrile (100 ml.), treated with 1,8-diazabicyclo[5.4.0]undec-7-ene (3.5 ml., 23.40 mmole) and stirred at room temperature for 5 minutes. n-Octylbromide (4.00 ml., 23.16 mmole) was added and the reaction mixture was stirred at room temperature for 17 hours, then heated at reflux temperature for 6 hours. The reaction mixture was concentrated under reduced pressure and the resultant residue was dissolved in ethyl acetate. The ethyl acetate solution was washed with water, 5% aqueous citric acid, saturated aqueous sodium bicarbonate, saturated aqueous sodium chloride, dried over magnesium chloride, filtered and concentrated under reduced pressure. The resultant residue was purified utilizing column chromatography (silica gel, 200 g.) and eluted with ethyl acetate/hexane (1:10) to afford N-Iodopropargyloxycarbonyl glycine n-octyl ester (Compound 3) as a clear colorless liquid which crystallized on standing. m.p. 43°-46° C. Elemental Analysis: C14H22NO4 l: Calc'd. C: 42.55, H: 5.61, N: 3.54. Found: C: 43.73, H: 5.62, N: 3.54. (Ethyl acetate was present in 0.5 mole %). 1H-NMR (200 MHz, CDCl3) δppm =0.89, m, 3H (--CH3), 1.30, m, 10H (--(CH2)5 --CH3), 1.64, m, 2H (--CH2 --), 4.0,d, J=3.4 Hz., 2H (--N--CH2 --), 4.1-4.2, m, 2H (--CH2 --), 4.86, s, 2H (C--CH2 --O), 5.32, m, 1H (--NH--). IR (neat) 3460, 2920, 2850, 2200, 1740, 1560, 1480, 1400, 1360, 1200, 1060, 980 cm-1.
Reaction SMILES: [OH:1][C:2]([CH3:17])([CH3:16])[CH2:3][CH2:4]OS(C1C=CC(C)=CC=1)(=O)=O.[Br:18][C:19]1[C:24]([CH3:25])=[CH:23][C:22]([OH:26])=[CH:21][C:20]=1[CH3:27].C(=O)([O-])[O-].[K+].[K+].[NH4+].[Cl-]>CN(C=O)C>[Br:18][C:19]1[C:24]([CH3:25])=[CH:23][C:22]([O:26][CH2:4][CH2:3][C:2]([CH3:17])([OH:1])[CH3:16])=[CH:21][C:20]=1[CH3:27]
Reactant: Cc1cc(O)cc(C)c1Br
Reactant: Cc1ccc(S(=O)(=O)OCCC(C)(C)O)cc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(OCCC(C)(C)O)cc(C)c1Br
Temperature: 50 °C
Reaction time: 16 h

Procedure:
40.7 g (157 mmol) of toluene-4-sulfonic acid 3-hydroxy-3-methylbutyl ester (product of step 1), 34.0 g (169 mmol) of 4-bromo-3,5-dimethylphenol and 25.0 g (180 mmol) of potassium carbonate are dissolved in 114 ml DMF. The reaction mixture is stirred at 50° C. for 16 h. The reaction mixture is poured into aq. NH4Cl solution and stirred. Then the layers are separated. The aq. layer is extracted with DCM. The combined organic layers are washed with water and dried. The solvent is evaporated and the residue is chromatographed on silica gel (PE/EtOAc) to give the title compound. Yield: 38.3 g; Mass spectrum (ESI+): m/z=287 [M+H]+.
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:27])[F:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:29]=[C:30]1[NH:34][C:33](=[O:35])[C:32](=[CH:36][C:37]2[CH:44]=[CH:43][C:40]([CH:41]=O)=[CH:39][CH:38]=2)[S:31]1>>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH:24][CH2:41][C:40]3[CH:39]=[CH:38][C:37](/[CH:36]=[C:32]4/[C:33](=[O:35])[NH:34][C:30](=[O:29])[S:31]/4)=[CH:44][CH:43]=3)[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:26])[F:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1ccc(C=C2SC(=O)NC2=O)cc1
Reactant: Nc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Product: O=C1NC(=O)/C(=C/c2ccc(CNc3cccc(-c4c(Cc5ccccc5)cnc5c(C(F)(F)F)cccc45)c3)cc2)S1

Procedure:
The title compound was prepared from {3-[3-benzyl-8-(trifluoromethyl)quinolin-4-yl]phenyl}amine and 4-(2,4-dioxo-thiazolidin-5-ylidenemethyl)-benzaldehyde according to the procedure of Example 66. MS (ES) m/z 594.1.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12]C)=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:14][C:15]2[CH:19]=[C:18]([CH3:20])[NH:17][N:16]=2)[N:3]=1.[BrH:21]>C(O)(=O)C>[Br:21][C:2]1[C:11]2[C:6](=[CH:7][C:8]([OH:12])=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:14][C:15]2[CH:19]=[C:18]([CH3:20])[NH:17][N:16]=2)[N:3]=1
Reactant: COc1ccc2c(Cl)nc(Nc3cc(C)[nH]n3)cc2c1
Reactant: Br
Solvent: CC(=O)O
Product: Cc1cc(Nc2cc3cc(O)ccc3c(Br)n2)n[nH]1
Temperature: 25 °C

Procedure:
A solution of (1-Chloro-6-methoxy-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine (100 mg), 40% HBr (2 ml) and acetic acid (5 ml) was heated at 120° C. overnight. After cooled to room temperature, the reaction mixture was concentrated to oil, and the residue was treated with 50 ml water. The mixture was extracted by ethyl acetate (50 ml×3), and the organic layer was evaporated to give 1-Bromo-3-(5-methyl-1H-pyrazol-3-ylamino)-isoquinolin-6-ol as solid (80 mg). LC-MS: m/e 319 (MH+).
Reaction SMILES: Cl[C:2]1[CH:11]=[N:10][C:9]2[C:4](=[C:5]3[CH:19]=[CH:18][CH:17]=[CH:16][C:6]3=[C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]3=2)[N:3]=1.[CH:20]1[C:28]2[C:27]3[CH:29]=[CH:30][CH:31]=[CH:32][C:26]=3[S:25][C:24]=2[C:23]([C:33]2[CH:34]=[C:35](B(O)O)[CH:36]=[CH:37][CH:38]=2)=[CH:22][CH:21]=1.C1(C)C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+]>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(O)C>[CH:20]1[C:28]2[C:27]3[CH:29]=[CH:30][CH:31]=[CH:32][C:26]=3[S:25][C:24]=2[C:23]([C:33]2[CH:34]=[C:35]([C:2]3[CH:11]=[N:10][C:9]4[C:4](=[C:5]5[CH:19]=[CH:18][CH:17]=[CH:16][C:6]5=[C:7]5[CH:15]=[CH:14][CH:13]=[CH:12][C:8]5=4)[N:3]=3)[CH:36]=[CH:37][CH:38]=2)=[CH:22][CH:21]=1
Reactant: Clc1cnc2c3ccccc3c3ccccc3c2n1
Reactant: OB(O)c1cccc(-c2cccc3c2sc2ccccc23)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: [K+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: c1cc(-c2cnc3c4ccccc4c4ccccc4c3n2)cc(-c2cccc3c2sc2ccccc23)c1
Temperature: 25 °C

Procedure:
First, 5.3 g (20 mmol) of 2-chlorodibenzo[f,h]quinoxaline, 6.1 g (20 mmol) of 3-(dibenzothiophen-4-yl)phenylboronic acid, 460 mg (0.4 mmol) of tetrakis(triphenylphosphine)palladium(0), 300 mL of toluene, 20 mL of ethanol, and 20 mL of a 2M aqueous solution of potassium carbonate were put in a 2-L three-neck flask. The mixture was degassed by being stirred under reduced pressure, and the air in the three-neck flask was replaced with nitrogen. This mixture was stirred under a nitrogen stream at 100° C. for 7.5 hours. After cooled to room temperature, the obtained mixture was filtered to give a white residue. The obtained residue was washed with water and ethanol in this order, and then dried. The obtained solid was dissolved in about 600 mL of hot toluene, followed by suction filtration through Celite and Florisil, whereby a clear colorless filtrate was obtained. The obtained filtrate was concentrated and purified by silica gel column chromatography using about 700 mL of silica gel. The chromatography was carried out using hot toluene as a developing solvent. Acetone and ethanol were added to the solid obtained here, followed by irradiation with ultrasonic waves. Then, the generated suspended solid was collected by filtration and the obtained solid was dried, so that 7.85 g of white powder was obtained in 80% yield.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[C:10]([F:13])([F:12])[F:11].[CH3:14][CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][NH:16]1>CS(C)=O.CCOCC>[CH3:14][CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][N:16]1[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[C:10]([F:13])([F:12])[F:11]
Reactant: CC1CCCCN1
Reactant: N#Cc1ccc(F)c(C(F)(F)F)c1
Solvent: CCOCC
Solvent: CS(C)=O
Product: CC1CCCCN1c1ccc(C#N)cc1C(F)(F)F
Temperature: 100 °C

Procedure:
A mixture of 4-fluoro-3-(trifluoromethyl)benzonitrile (50.0 g, 0.26 mol, Combi-Blocks AN-1049) and 2-methylpiperidine (156 mL, 1.32 mol) in DMSO (500 mL) was heated at 100° C. under nitrogen for 12 hours. The reaction mixture was diluted with Et2O and washed with water, a saturated aqueous solution of NaHCO3 and a saturated aqueous solution of NH4Cl. The organic layer was dried (MgSO4) and the solvent was removed under reduced pressure to give the title compound as a beige powder. UPLC/MS, M−(ESI): 269.2. 1H NMR (DMSO-d6, 300 MHz) δ 8.19 (d, J=2.0 Hz, 1H), 8.12 (dd, J=8.4, 2.0 Hz, 1H), 7.75 (d, J=8.2 Hz, 1H), 3.13 (m, 1H), 2.88 (m, 1H), 2.56 (m, 1H), 1.77-1.25 (m, 6H), 0.72 (d, J=6.0 Hz, 3H).
Reaction SMILES: [CH:1]1[C:9]([NH2:10])=[CH:8][C:7]2[CH2:11][CH2:12][N:5]3[C:6]=2[C:2]=1[C:3]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][C:4]=13.[C:19](Cl)(=[O:26])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]>ClCCl>[CH:1]1[C:9]([NH:10][C:19](=[O:26])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[CH:8][C:7]2[CH2:11][CH2:12][N:5]3[C:6]=2[C:2]=1[C:3]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][C:4]=13
Reactant: CCCCCCC(=O)Cl
Reactant: Nc1cc2c3c(c1)c1c(n3CC2)CCCCCC1
Solvent: ClCCl
Product: CCCCCCC(=O)Nc1cc2c3c(c1)c1c(n3CC2)CCCCCC1
Yield: 19.4 %

Procedure:
Following the procedure of Example 1, Step 4, 4,5,7,8,9,10,11,12-octahydrocycloocta[b]pyrrolo[3,2,1-hi]indol-2-amine (0.15 g, 0.54 mmol), heptanoyl chloride (0.084 mL, 0.54 mmol) and poly-(4-vinylpyridine) (500 mg) in dichloromethane (12 mL) provided N-4,5,7,8,9,10,11,12-octahydrocycloocta[b]pyrrolo[3,2,1-hi]indol-2-ylheptanamide (37 mg). MS (ESI) m/z 353; HPLC purity 100% at 210-370 nm, 11.6 min.; 100% at 250 nm, 11.6 min.; Xterra RP18, 3.5 u, 150×4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. pH=3.5/ACN and MeOH) for 10 min, hold 4 min); HRMS: calcd for C23H32N2O+H+, 353.25874; found (ESI, [M+H]+), 353.2575.
Reaction SMILES: [ClH:1].[OH:2][NH:3][C:4]([C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH2:8][CH2:9][C:10]2=[N:15]O)=[NH:5].N[N:18]1[CH:22]=[C:21]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=2)[N:20]=[C:19]1[NH2:31]>C(O)(C)C>[ClH:1].[ClH:1].[OH:2][NH:3][C:4]([C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH2:8][CH2:9][C:10]2=[N:15][N:18]1[CH:22]=[C:21]([C:23]2[CH:24]=[CH:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=2)[N:20]=[C:19]1[NH2:31])=[NH:5]
Reactant: N=C(NO)c1cccc2c1CCC2=NO
Reactant: COc1ccc(-c2cn(N)c(N)n2)cc1
Agent: Cl
Solvent: CC(C)O
Product: COc1ccc(-c2cn(N=C3CCc4c(C(=N)NO)cccc43)c(N)n2)cc1

Procedure:
7.2 ml of 32% hydrochloric acid (Merck, Darmstadt, Germany; p.a.) are added, with stirring, to a mixture of 4.92 g (0.024 mol) of 4-(N-hydroxyamidino)-2,3-dihydro-1H-inden-1-one oxime, 4.9 g (0.024 mol) of 1,2-diamino-4-(4-methoxyphenyl)-imidazole (see Hetzheim A. et al., Chem. Ber. 100, 3418 (1967)) and 120 ml of isopropanol, and the reaction mixture is stirred at 80° C. for 19 hours. The reaction mixture is filtered while hot and the filtrate is cooled. The pale-yellow title product that has crystallised out is filtered off with suction and dried. It crystallizes in the form of the monohydrate, m.p. >220° C., MS (FAB): (M+H)+ =377, 1H-NMR (DMSO/D2O): δ=8.23 (d, 1H); 7.74 (s, 1H); 7.72 (d, 1H); 7.57-7.63 (m, 3H); 7.02 (d, 2H); 3.75 (s, 3H), 3.26 (s, 4H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:42])[C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][C:17]3[CH2:22][CH2:21][C:20]([CH3:24])([CH3:23])[CH2:19][C:18]=3[C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)[CH2:12][CH2:11]2)=[CH:6][C:5]=1[O:32][C:33]1[CH:41]=[CH:40][CH:39]=[C:38]2[C:34]=1[CH:35]=[N:36][NH:37]2.[Cl:43]N1C(=O)CCC1=O>C(#N)C>[NH:37]1[C:38]2[C:34](=[C:33]([O:32][C:5]3[CH:6]=[C:7]([N:10]4[CH2:15][CH2:14][N:13]([CH2:16][C:17]5[CH2:22][CH2:21][C:20]([CH3:24])([CH3:23])[CH2:19][C:18]=5[C:25]5[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=5)[CH2:12][CH2:11]4)[C:8]([Cl:43])=[CH:9][C:4]=3[C:3]([O:2][CH3:1])=[O:42])[CH:41]=[CH:40][CH:39]=2)[CH:35]=[N:36]1
Reactant: COC(=O)c1ccc(N2CCN(CC3=C(c4ccc(Cl)cc4)CC(C)(C)CC3)CC2)cc1Oc1cccc2[nH]ncc12
Reactant: O=C1CCC(=O)N1Cl
Solvent: CC#N
Product: COC(=O)c1cc(Cl)c(N2CCN(CC3=C(c4ccc(Cl)cc4)CC(C)(C)CC3)CC2)cc1Oc1cccc2[nH]ncc12

Procedure:
A mixture of EXAMPLE 400D (0.5 g) and 1-chloropyrrolidine-2,5-dione (0.126 g) in acetonitrile (10 mL) was stirred at room temperature for 4 hours. The solvent was removed, and the residue was purified by flash column chromatography on silica gel to give the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](Br)[CH:6]=[CH:7][CH:8]=1.[OH-:10].[Cs+]>C(OCC)(=O)C.CCCCCCC>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([OH:10])[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(Br)c1
Reactant: [OH-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: COc1cccc(O)c1
Yield: 85 %

Procedure:
Following general operating mode B, 3-methoxybromobenzene (127 μL, 1.0 mmol) was reacted with cesium hydroxide to give the expected product in the form of an oil with a yield of 85% (eluent: ethyl acetate/heptane 10:90).
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][N:6]=1.[Li]CCCC.CCCCCC.[Sn:18](Cl)([CH2:27][CH2:28][CH2:29][CH3:30])([CH2:23][CH2:24][CH2:25][CH3:26])[CH2:19][CH2:20][CH2:21][CH3:22].O>CCOCC>[CH2:27]([Sn:18]([CH2:19][CH2:20][CH2:21][CH3:22])([CH2:23][CH2:24][CH2:25][CH3:26])[C:2]1[S:3][CH:4]=[CH:5][N:6]=1)[CH2:28][CH2:29][CH3:30]
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: Brc1nccs1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: O
Solvent: CCOCC
Product: CCCC[Sn](CCCC)(CCCC)c1nccs1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90 %

Procedure:
To a mixture of 2-bromothiazole (4.6 mL, 50 mmol) and anhydrous ether (50 mL), there was added an n-BuLi hexane solution (22 mL, 55 mmol) dropwise at −70° C. under nitrogen atmosphere, and the mixture was stirred for 30 minutes. A solution of n-Bu3SnCl (14 mL, 50 mmol) in ether (20 mL) was then added at −70° C., and after stirring for 4 hours, the mixture was raised to room temperature and stirred for another hour. After adding water (50 mL), the organic layer was extracted three times with ether (50 mL), and the solvent was distilled away. It was then purified by silica gel chromatography (hexane:ethyl acetate=20:1) to yield the title compound (17g, 90%).
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][NH2:7])(=[O:3])[CH3:2].[CH2:8]([C:10]1[CH:27]=[CH:26][C:13]([O:14][C:15]2[CH:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[CH:17][C:16]=2[F:25])=[C:12]([O:28][CH3:29])[CH:11]=1)[CH3:9]>C1COCC1>[CH2:8]([C:10]1[CH:27]=[CH:26][C:13]([O:14][C:15]2[CH:20]=[CH:19][C:18]([S:21]([NH:7][CH2:6][CH2:5][NH:4][C:1](=[O:3])[CH3:2])(=[O:23])=[O:22])=[CH:17][C:16]=2[F:25])=[C:12]([O:28][CH3:29])[CH:11]=1)[CH3:9]
Reactant: CC(=O)NCCN
Reactant: CCc1ccc(Oc2ccc(S(=O)(=O)Cl)cc2F)c(OC)c1
Solvent: C1CCOC1
Product: CCc1ccc(Oc2ccc(S(=O)(=O)NCCNC(C)=O)cc2F)c(OC)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 37.2 %

Procedure:
N-Acetylethylenediamine (1.1 mmol; 0.10 mL) was slowly added to a solution of 4-(4-ethyl-2-methoxyphenoxy)-3-fluorobenzenesulfonyl chloride (0.94 mmol; 325 mg) and TEA (2.8 mmol; 0.40 mL) in anhydrous THF (5 mL), under argon at 0° C. The reaction was stirred overnight with progressive warming to room temperature. Concentrated, the mixture was purified by chromatography (dichloromethane/methanol/ammonia gradient) to yield the title compound as a yellow oil (142 mg; 0.35 mmol; 37%) used as such in the following reaction.
Reaction SMILES: O1CCCCC1[N:7]1[C:15]2[C:10](=[CH:11][C:12]([NH:16][C:17]([C:19]3[CH:28]=[CH:27][C:22]([C:23]([O:25][CH3:26])=[O:24])=[CH:21][CH:20]=3)=[O:18])=[CH:13][CH:14]=2)[C:9]([C:29]2[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=2)=[N:8]1>O1CCCC1.Cl>[N:32]1[CH:31]=[CH:30][C:29]([C:9]2[C:10]3[C:15](=[CH:14][CH:13]=[C:12]([NH:16][C:17]([C:19]4[CH:20]=[CH:21][C:22]([C:23]([O:25][CH3:26])=[O:24])=[CH:27][CH:28]=4)=[O:18])[CH:11]=3)[NH:7][N:8]=2)=[CH:34][CH:33]=1
Reactant: COC(=O)c1ccc(C(=O)Nc2ccc3c(c2)c(-c2ccncc2)nn3C2CCCCO2)cc1
Agent: Cl
Solvent: C1CCOC1
Product: COC(=O)c1ccc(C(=O)Nc2ccc3[nH]nc(-c4ccncc4)c3c2)cc1

Procedure:
The title compound was prepared using methyl 4-[N-(1-perhydro-2H-pyran-2-yl-3-(4-pyridyl)-1H-indazol-5-yl)carbamoyl]benzoate (0.158 g, 035 mmol) as a solution in tetrahydrofuran (3 mL) and 6.0 N aqueous HCl (5 mL). The intermediate was isolated and used without further purification (0.129 g, quantitative): ES-MS (m/z) 373 [M+1]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=2)[N:6]=[C:5]([C:20]([OH:22])=O)[CH:4]=1.S(Cl)(Cl)=O.C1C=CC=CC=1.[CH2:33]([NH:35][CH2:36][CH3:37])[CH3:34]>C(OCC)(=O)C.CN(C=O)C>[CH2:33]([N:35]([CH2:36][CH3:37])[C:20]([C:5]1[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=[C:7]([O:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:17])([F:18])[F:19])[CH:11]=2)[N:6]=1)=[O:22])[CH3:34]
Reactant: CCNCC
Reactant: COc1cc(Oc2cccc(C(F)(F)F)c2)nc(C(=O)O)c1
Solvent: O=S(Cl)Cl
Solvent: c1ccccc1
Solvent: CN(C)C=O
Product: CCN(CC)C(=O)c1cc(OC)cc(Oc2cccc(C(F)(F)F)c2)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
0.40 g (0.00128 mol) of 4-methoxy-6-{3-(trifluoromethyl)phenoxy}-2-pyridine carboxylic acid was mixed with 0.3 g (0.00128×2.0 mol) of thionyl chloride and then with about 10 ml of benzene and a small amount of DMF, followed by treating the obtained mixture under reflux for about 30 minutes. The reaction solution was concentrated and mixed with methylene chloride and then with 0.23 g (0.00128×2.5 mol) of diethyl amine, followed by stirring at room temperature for about one hour. The reaction solution was distributed in ethyl acetate-saturated sodium bicarbonate water, and washed with saturated brine. The organic phase of the solution was dried with anhydrous sodium sulfate, concentrated and purified by silica gel column chromatography (eluting solution: ethyl acetate/hexane), thereby obtaining an aimed product.