Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([NH:4][C:5]([C:7]2[CH:8]=[CH:9][C:10]([CH3:26])=[C:11]([NH:13][C:14]([C:16]3[CH:24]=[C:23]4[C:19]([CH:20]=[CH:21][N:22]4[CH3:25])=[CH:18][CH:17]=3)=[O:15])[CH:12]=2)=[O:6])[CH2:3][CH2:2]1.ClS([N:31]=[C:32]=O)(=O)=O.CN(C=O)C>C(#N)C>[C:32]([C:20]1[C:19]2[C:23](=[CH:24][C:16]([C:14]([NH:13][C:11]3[CH:12]=[C:7]([C:5](=[O:6])[NH:4][CH:1]4[CH2:2][CH2:3]4)[CH:8]=[CH:9][C:10]=3[CH3:26])=[O:15])=[CH:17][CH:18]=2)[N:22]([CH3:25])[CH:21]=1)#[N:31]
Reactant: Cc1ccc(C(=O)NC2CC2)cc1NC(=O)c1ccc2ccn(C)c2c1
Reactant: O=C=NS(=O)(=O)Cl
Solvent: CN(C)C=O
Solvent: CC#N
Product: Cc1ccc(C(=O)NC2CC2)cc1NC(=O)c1ccc2c(C#N)cn(C)c2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 10.4 %

Procedure:
To N-(5-(cyclopropylcarbamoyl)-2-methylphenyl)-1-methyl-1H-indole-6-carboxamide (0.045 g, 0.129 mmol, example 97, table 5) in anhydrous acetonitrile (2 mL) was added chlorosulfonyl isocyanate (11 μL, 0.129 mmol) at room temperature. The reaction mixture was stirred at room temperature for 30 min. and DMF (11 μL, 0.141 mmol) is added. After another 30 min. at room temperature, the reaction mixture was quenched with methanol (2 mL), concentrated under reduced pressure and subjected to reverse phase preparative HPLC (YMC S5 20×100 mm, 10 min. run, solvent A: 10% MeOH: 90% H2O: 0.1% TFA, solvent B: 90% MeOH, 10% H2O, 0.1% TFA). The desired fractions were collected, and concentrated using speedVac® Plus (SC250DDA) to yield the title compound (Example 223, 0.005 g). HPLC retention time (YMC S5 Combiscreen ODS; 4.6×50 mm (4 min. gradient); Solvent A=10% MeOH, 90% H2O, 0.2% H3PO4; solvent B=90% MeOH, 10% H2O, 0.2% H3PO4): 2.6 min. LCMS [M+H]+ 373.2.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]2[C:9]3([CH2:17][O:18][C:5]=2[CH:4]=1)[CH2:14][CH2:13][CH2:12][NH:11][CH:10]3[CH2:15][NH2:16].[CH3:19]OC(OC)N(C)C>ClCCl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]2[C:9]3([CH2:17][O:18][C:5]=2[CH:4]=1)[CH2:14][CH2:13][CH2:12][N:11]1[CH:19]=[N:16][CH2:15][CH:10]31
Reactant: COC(OC)N(C)C
Reactant: COc1ccc2c(c1)OCC21CCCNC1CN
Solvent: ClCCl
Product: COc1ccc2c(c1)OCC21CCCN2C=NCC21
Temperature: 25 °C

Procedure:
A solution of 31 mmol of 1-(6-methoxyspiro[1-benzofuran-3,3′-piperidin]-2′-yl)methanamine and 31 mmol of N,N-dimethyl formamide dimethylacetal in 50 ml of dichloromethane is heated to reflux for 6 hours. The reaction mixture is cooled to room temperature and evaporated. The crude title compound is identified on the basis of the Rf value and reacted further without further purification.
Reaction SMILES: [CH3:1][NH2:2].Br[CH2:4][C:5]1[CH:6]=[CH:7][C:8]2[C:14]3[S:15][C:16]([C:18]([N:20]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[Cl:28])[CH3:21])=[O:19])=[CH:17][C:13]=3[CH2:12][CH2:11][O:10][C:9]=2[CH:29]=1.O>CCO>[Cl:28][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[N:20]([CH3:21])[C:18]([C:16]1[S:15][C:14]2[C:8]3[CH:7]=[CH:6][C:5]([CH2:4][NH:2][CH3:1])=[CH:29][C:9]=3[O:10][CH2:11][CH2:12][C:13]=2[CH:17]=1)=[O:19]
Reactant: CN
Reactant: CN(C(=O)c1cc2c(s1)-c1ccc(CBr)cc1OCC2)c1ccccc1Cl
Solvent: O
Solvent: CCO
Product: CNCc1ccc2c(c1)OCCc1cc(C(=O)N(C)c3ccccc3Cl)sc1-2
Temperature: 60 °C
Reaction time: 2 h
Yield: 42.8 %

Procedure:
To a solution of CH3NH2 in EtOH (0.25 mL) was added TEA (0.5 mL) and 8-(bromomethyl)-N-(2-chlorophenyl)-N-methyl-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxamide (250 mg). The reaction mixture was stirred for 2 h at 60° C. before added water. The mixture was extracted with EtOAc (20 mL×3), dried over Na2SO4 and filtered. The filtrate was concentrated to give the crude product, which was purified by preparative TLC(CH2Cl2: MeOH=10:1) to afford 243 as a light yellow solid (95.6 mg, 42.8%). MS: (ESI+) 412.9
Reaction SMILES: Br[C:2]1[S:10][C:9]2[C:8](=[O:11])[NH:7][C:6]([CH3:13])([CH3:12])[N:5]([CH3:14])[C:4]=2[C:3]=1[CH3:15].CC1(C)C(C)(C)OB([C:24]2[CH:25]=[N:26][N:27](C(OC(C)(C)C)=O)[CH:28]=2)O1.C(=O)([O-])[O-].[Cs+].[Cs+].COCCOC>O>[CH3:14][N:5]1[C:4]2[C:3]([CH3:15])=[C:2]([C:24]3[CH:25]=[N:26][NH:27][CH:28]=3)[S:10][C:9]=2[C:8](=[O:11])[NH:7][C:6]1([CH3:13])[CH3:12]
Reactant: CC(C)(C)OC(=O)n1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: Cc1c(Br)sc2c1N(C)C(C)(C)NC2=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: COCCOC
Product: Cc1c(-c2cn[nH]c2)sc2c1N(C)C(C)(C)NC2=O
Temperature: 90 °C
Reaction time: 8 h
Yield: 47.2 %

Procedure:
A mixture of 6-bromo-1,2,2,7-tetramethyl-2,3-dihydrothieno[3,2-d]pyrimidin-4(1H)-one (145 mg, 0.50 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-pyrazole-1-carboxylate (441 mg, 1.50 mmol), cesium carbonate (815 mg, 2.50 mmol), 1,2-dimethoxyethane (5 mL) and water (1.25 mL) was purged with argon. Then, 1,1′-bis(diphenylphosphino) ferrocenepalladium (II) dichloride dichloromethane adduct (40.8 mg, 0.050 mmol) was added, and the mixture was purged with argon again. The mixture was stirred at 90° C. overnight. The mixture was poured into water (100 mL) and EtOAc (100 mL). The insoluble materials were filtered off, and the organic layer was collected from the filtrate. This organic layer was washed with brine, dried over MgSO4 and concentrated under reduced pressure. The residual oil was purified by column chromatography (Purif, silica gel, 95:5 hexane/EtOAc to EtOAc then to 80:20 EtOAc/MeOH), then triturated with EtOAc/hexane. The solid was collected by filtration to afford the title compound (65.2 mg, 47%) as a white solid:
Reaction SMILES: [CH:1]1([C:7]([C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].Cl.Cl[CH2:24][C:25]1[CH:34]=[CH:33][C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[N:26]=1>CN(C)C=O>[CH:1]1([C:7]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:24][C:25]3[CH:34]=[CH:33][C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[N:26]=3)=[CH:11][CH:10]=2)=[O:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(c1ccc(O)cc1)C1CCCCC1
Reactant: ClCc1ccc2ccccc2n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(c1ccc(OCc2ccc3ccccc3n2)cc1)C1CCCCC1
Temperature: 100 °C
Reaction time: 7 h

Procedure:
7.85 g (38.4 mmol) of 4-hydroxyphenyl cyclohexyl ketone are heated under reflux for 2 h after addition of 12 g (86.8 mmol) of potassium carbonate and 200 ml of dimethylformamide. 8.54 g (39.9 mmol) of 2-chloromethylquinoline hydrochloride are then added at room temperature. The reaction mixture is stirred at 100° C. for 7 h and subsequently concentrated in vacuo. The residue is taken up in dichloromethane, and the organic phase is washed with water, dried over sodium sulphate and concentrated in vacuo. A column chromatographic purification on silica gel using dichloromethane/methanol (50:1) follows.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([C:15]2([C:28]([O:30]C)=[O:29])[CH2:20][CH2:19][N:18]([C:21]([C:23]3[S:24][CH:25]=[CH:26][CH:27]=3)=[O:22])[CH2:17][CH2:16]2)(=[O:14])=[O:13])=[CH:8][CH:7]=1)[C:2]#[C:3][CH3:4].[OH-].[Na+]>O1CCCC1.CO>[CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([C:15]2([C:28]([OH:30])=[O:29])[CH2:16][CH2:17][N:18]([C:21]([C:23]3[S:24][CH:25]=[CH:26][CH:27]=3)=[O:22])[CH2:19][CH2:20]2)(=[O:14])=[O:13])=[CH:8][CH:7]=1)[C:2]#[C:3][CH3:4]
Reactant: CC#CCOc1ccc(S(=O)(=O)C2(C(=O)OC)CCN(C(=O)c3cccs3)CC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC#CCOc1ccc(S(=O)(=O)C2(C(=O)O)CCN(C(=O)c3cccs3)CC2)cc1

Procedure:
4-(4-but-2-ynyloxybenzenesulfonyl)-1-(2-thienylcarbonyl)-4-piperidinecarboxylic acid was prepared following the procedure of Example 64 (step 5). Starting from Methyl 4-(4-but-2-ynyloxybenzenesulfonyl)-1-(2-thienylcarbonyl)-4-piperidinecarboxylate (435 mg, 0.94 mmol) in 8 ml of tetrahydrofuran:methanol (1:1), and 1N sodium hydroxide (1.89 ml, 1.89 mmol) to obtain 360 mg (86%) of the acid. HR-MS: m/z Calculated for C21H21NO6S2 448.0883; Found 448.0882.
Reaction SMILES: CCN(CC)CC.[CH2:8]1[C:12]2([CH2:16][CH2:15][NH:14][CH2:13]2)[CH2:11][CH2:10][N:9]1[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18].Cl[C:25]1[N:29]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[N:28]=[N:27][N:26]=1>O1CCOCC1>[C:30]1([N:29]2[C:25]([N:14]3[CH2:15][CH2:16][C:12]4([CH2:8][N:9]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:10][CH2:11]4)[CH2:13]3)=[N:26][N:27]=[N:28]2)[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: CC(C)(C)OC(=O)N1CCC2(CCNC2)C1
Reactant: Clc1nnnn1-c1ccccc1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCC2(CCN(c3nnnn3-c3ccccc3)C2)C1
Temperature: 115 °C

Procedure:
Et3N (5 mL) was added into a solution of tert-butyl 2,7-diazaspiro[4.4]nonane-2-carboxylate (1 g) and 5-chloro-1-phenyl-1H-tetrazole (1 g) in dioxane (50 mL). The mixture was heated to 115° C. for 24 hours. The reaction was quenched with water (50 mL). The aqueous layer was extracted with EtOAc (3×50 mL). The combined organic phase was dried over MgSO4 and concentrated to give a residue which was purified by silica gel chromatography to give tert-butyl 7-(1-phenyl-1H-tetrazol-5-yl)-2,7-diazaspiro[4.4]nonane-2-carboxylate.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:12]3[CH2:17][CH2:16][N:15]([C:18]([NH:20][CH:21]4[CH2:27][CH2:26][CH2:25][CH2:24][CH:23]([OH:28])[CH2:22]4)=[O:19])[CH2:14][CH2:13]3)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.[H-].[Na+].Br[C:32]1[C:37]([CH3:38])=[CH:36][CH:35]=[CH:34][N:33]=1>>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:12]3[CH2:17][CH2:16][N:15]([C:18]([NH:20][CH:21]4[CH2:27][CH2:26][CH2:25][CH2:24][CH:23]([O:28][C:32]5[C:37]([CH3:38])=[CH:36][CH:35]=[CH:34][N:33]=5)[CH2:22]4)=[O:19])[CH2:14][CH2:13]3)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: Cc1cccnc1Br
Reactant: O=C(NC1CCCCC(O)C1)N1CCN(c2ccnc3cc(Cl)ccc23)CC1
Agent: [H-]
Agent: [Na+]
Product: Cc1cccnc1OC1CCCCC(NC(=O)N2CCN(c3ccnc4cc(Cl)ccc34)CC2)C1

Procedure:
As described for example 138, 4-(7-chloro-4-quinolinyl)-N-(3-hydroxycycloheptyl)-1-piperazinecarboxamide, NaH, and 2-bromo-3-picoline are reacted to give the product. LC-MS: 494 (M++1). 1H NMR (CDCl3) δ 8.75 (d, 1H), 8.05 (s, 1H), 7.98 (d, 1H), 7.85 (m, 1H), 7.45 (d, 1H), 7.40 (m, 1H), 6.85 (d, 1H), 6.78 (m, 1H), 6.10 (d, 1H), 5.20 (m, 1H), 4.10 (m, 1H), 3.76 (m, 4H), 3.25 (m, 4H), 2.26 (m, 1H), 2.18 (s, 3H), 2.12 (m, 2H), 1.45–1.90 (m, 7H).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:7]([OH:10])[CH2:8][OH:9].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)(O)[O-].[Na+]>C1C=CC=CC=1>[O:9]1[C:4]2([CH2:5][CH2:6][O:1][CH2:2][CH2:3]2)[O:10][CH2:7][CH2:8]1
Reactant: C1CCOCC1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccccc1
Solvent: O
Product: C1CC2(CCO1)OCCO2
Yield: 90.1 %

Procedure:
Tetrahydro-4H-pyran (6.00 g, 60.0 mmol) was dissolved in benzene (120 mL), to which ethylene glycol (11.2 g, 180 mmol) and p-toluenesulfonic acid monohydrate (1.14 g, 6.00 mmol) were added. Using a Dean-Stark tube, the resulting mixture was refluxed for two hours while removing water generated. To the resulting reaction liquid, a saturated aqueous solution of sodium bicarbonate was added, followed by extraction with ethyl acetate. The resulting organic layer was washed with saturated brine, and dried over sodium sulfate. The solvent was distilled off under reduced pressure. The residue thus obtained was purified by basic silica gel column chromatography (hexane:ethyl acetate, 100:0-0:100, V/V) to give the desired title compound (7.79 g, yield 90%).
Reaction SMILES: Br[CH:2]([C:12]1[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:14][CH:13]=1)[C:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1)=O.[C:22]([NH2:30])(=[S:29])[C:23]1[CH:28]=[CH:27][CH:26]=[N:25][CH:24]=1>C(#N)C>[F:11][C:8]1[CH:9]=[CH:10][C:5]([C:3]2[N:30]=[C:22]([C:23]3[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=3)[S:29][C:2]=2[C:12]2[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:14][CH:13]=2)=[CH:6][CH:7]=1
Reactant: NC(=S)c1cccnc1
Reactant: CS(=O)(=O)c1ccc(C(Br)C(=O)c2ccc(F)cc2)cc1
Solvent: CC#N
Product: CS(=O)(=O)c1ccc(-c2sc(-c3cccnc3)nc2-c2ccc(F)cc2)cc1
Temperature: 25 °C
Yield: 43.4 %

Procedure:
To a solution of 2-bromo-1-(4-fluorophenyl)-2-(4-methylsulfonylphenyl)ethanone from Step 2 (0.732 g, 1.97 mmol) in acetonitrile (20 mL) in a 50 mL round bottom flask was added thionicotinamide (0.273 g, 1.97 mmol) with stirring. The resulting solution was heated to reflux for 1 hour and additional 2-bromo-1-(4-fluorophenyl)-3-(methylsulfonylphenyl)ethanone (0.031 g, 0.05 mmol) was added and stirred at ruflux for an additional hour. The reaction was cooled to room temperature and concentrated in vacuo yielding an orange semi-solid. This was purified by flash chromatography (2:1 hexane:ethyl acetate with 1% acetic acid). The product fractions were combined, toluene added, and the resulting solution reconcentrated in vacuo yielding 4-(4-fluorophenyl)-5-(4-methylsulfonylphenyl)-2-(3-pyridyl) thiazole as a pale yellow crystalline solid (0.351 g, 43%): mp 143°-146° C. 1H NMR (CDCl3) 400 mHz δ9.20 (d, J=1.81 Hz, 1H), 8.68 (dd, J=1.46, 4.89 Hz, 1H), 8.30 (dr, J=2.00, 9.42 Hz, 1H), 7.91 (d, J=8.55 Hz, 2H), 7.60-7.52 (m, 4H), 7.42 (m, 1), 7.05 (t, J=8.70 Hz, 2H), 3.10 (s, 3H). MS (EI): m/z 410 (M+). HRMS Δ=-4.3
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][CH:16]([C:19]4[C:24]([O:25][CH3:26])=[CH:23][CH:22]=[CH:21][C:20]=4[O:27][CH3:28])[CH2:15][CH2:14]3)=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.Cl[CH2:30][C:31]([NH:33][CH3:34])=[O:32]>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:14][CH2:15][CH:16]([C:19]4[C:24]([O:25][CH3:26])=[CH:23][CH:22]=[CH:21][C:20]=4[O:27][CH3:28])[CH2:17][CH2:18]3)=[O:12])=[CH:7][N:8]2[CH2:30][C:31]([NH:33][CH3:34])=[O:32])=[CH:4][CH:3]=1
Reactant: CNC(=O)CCl
Reactant: COc1cccc(OC)c1C1CCN(C(=O)c2c[nH]c3cc(Cl)ccc23)CC1
Product: CNC(=O)Cn1cc(C(=O)N2CCC(c3c(OC)cccc3OC)CC2)c2ccc(Cl)cc21

Procedure:
Analogous to general procedure II, the alkylation of (6-chloro-1H-indol-3-yl)-[4-(2,6-dimethoxy-phenyl)-piperidin-1-yl]-methanone (prepared herein) with (commercially available) 2-chloro-N-methyl-acetamide gave the title compound.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]#[C:14][C:15]1[CH:20]=[N:19][CH:18]=[CH:17][N:16]=1>C(O)C.[Pd]>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]1[CH:20]=[N:19][CH:18]=[CH:17][N:16]=1
Reactant: BrCCCCCCOCCCCC#Cc1cnccn1
Agent: [Pd]
Solvent: CCO
Product: BrCCCCCCOCCCCCCc1cnccn1
Reaction time: 11 h
Yield: 87.7 %

Procedure:
A solution of [6-[(6-bromohexyl)oxy]-1-hexynyl]pyrazine (2.76 g) in ethanol (70 ml) was added to a pre-hydrogenated suspension of 10% palladium on carbon (2.00 g) in ethanol (50 ml) and hydrogenated at room temperature and pressure for 11 h. The mixture was filtered through hyflo and evaporated in vacuo to afford the title compound as a colourless oil (2.45 g), t.l.c. (ether) Rf 0.55.
Reaction SMILES: [CH2:1]([C:3]1[CH:7]=[C:6]([CH2:8]P(OCC)(=O)OCC)[O:5][N:4]=1)[CH3:2].COC([O:21][C:22]1[CH:29]=[CH:28][CH:27]=[CH:26][C:23]=1[CH:24]=O)C>>[CH2:1]([C:3]1[CH:7]=[C:6]([CH:8]=[CH:24][C:23]2[CH:26]=[CH:27][CH:28]=[CH:29][C:22]=2[OH:21])[O:5][N:4]=1)[CH3:2]
Reactant: COC(C)Oc1ccccc1C=O
Reactant: CCOP(=O)(Cc1cc(CC)no1)OCC
Product: CCc1cc(C=Cc2ccccc2O)on1

Procedure:
Using the method described in Example I, 6 g (0.02 mole) of diethyl (3-ethyl-isoxazol-5-yl)-methanephosphonate and 4.4 g (0.02 mole) of o-(1-methoxyethoxy)-benzaldehyde are reacted and the product is recrystallized from isopropanol. 1.7 g (32% of theory) of colorless crystals, of melting point 175°-176° C., are obtained.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7](F)=[C:8]([S:10]([NH2:13])(=[O:12])=[O:11])[CH:9]=1)(=[O:3])[CH3:2].[CH2:15]([NH2:17])[CH3:16]>C(O)C>[C:1]([C:4]1[CH:5]=[CH:6][C:7]([NH:17][CH2:15][CH3:16])=[C:8]([S:10]([NH2:13])(=[O:12])=[O:11])[CH:9]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1ccc(F)c(S(N)(=O)=O)c1
Reactant: CCN
Solvent: CCO
Product: CCNc1ccc(C(C)=O)cc1S(N)(=O)=O

Procedure:
A solution of 5-acetyl-2-fluorobenzenesulphonamide (6.0 g) and ethylamine (70% solution in water, 25 ml) in absolute ethanol (100 ml) was heated at 100° for 16 hours in a bomb. The resulting yellow solution was evaporated to small volume to deposit the title compound as an off-white crystalline solid, 6.0 g, m.p. 201°-204° (from ethanol).
Reaction SMILES: N1C=CC=CC=1.[F:7][C:8]1[CH:14]=[CH:13][C:11]([NH2:12])=[CH:10][CH:9]=1.[Br:15][C:16]1[CH:25]=[C:24]2[C:19]([CH2:20][CH2:21][N:22]([C:26](=[O:31])[C:27]([F:30])([F:29])[F:28])[CH2:23]2)=[CH:18][C:17]=1[S:32](Cl)(=[O:34])=[O:33].Cl>C(Cl)(Cl)Cl>[Br:15][C:16]1[CH:25]=[C:24]2[C:19]([CH2:20][CH2:21][N:22]([C:26](=[O:31])[C:27]([F:29])([F:28])[F:30])[CH2:23]2)=[CH:18][C:17]=1[S:32]([NH:12][C:11]1[CH:13]=[CH:14][C:8]([F:7])=[CH:9][CH:10]=1)(=[O:33])=[O:34]
Reactant: Nc1ccc(F)cc1
Reactant: O=C(N1CCc2cc(S(=O)(=O)Cl)c(Br)cc2C1)C(F)(F)F
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: O=C(N1CCc2cc(S(=O)(=O)Nc3ccc(F)cc3)c(Br)cc2C1)C(F)(F)F
Temperature: 25 °C
Reaction time: 13 h
Yield: 94.2 %

Procedure:
Pyridine (3.09 mL, 38.4 mmol) was added to a solution of 4-fluoroaniline (3.73 g, 33.6 mmol) in chloroform (107 mL), and 7-bromo-2-(trifluoroacetyl)-1,2,3,4-tetrahydroisoquinoline-6-sulfonyl chloride (13.0 g, 32.0 mmol) was added thereto while cooling in ice. The mixture was warmed to room temperature and stirred for 13 hr. To the mixture was added 1 mol/L hydrochloric acid, and the mixture was extracted with chloroform. The organic layer was concentrated under reduced pressure and the concentrate was powdered with hexane and ethyl acetate (4:1) and then collected by filtration to afford 7-bromo-N-(4-fluorophenyl)-2-(trifluoroacetyl)-1,2,3,4-tetrahydroisoquinoline-6-sulfonamide as an orange powder (14.5 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[OH:9].C(N(CC)CC)C.Cl[C:18]([O:20][CH2:21][CH3:22])=[O:19]>ClCCl>[CH2:21]([O:20][C:18](=[O:19])[O:9][C:3]1[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=1[Cl:1])[CH3:22]
Reactant: Oc1ccc(F)cc1Cl
Reactant: CCOC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)Oc1ccc(F)cc1Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 98.8 %

Procedure:
To a solution of 2-chloro-4-fluoro-phenol (0.8 mL, 7.64 mmol) and triethylamine (1.3 mL, 9.16 mmol) in dichloromethane (10 mL) at 0° C. was added ethyl chloroformate (0.9 mL, 9.16 mmol) dropwise. The ice bath was removed and the solution was allowed to warm to room temperature and stirred for an additional 16 hours. Afterwards dichloromethane (20 mL) was added to the mixture, the organic solution was washed with brine (50 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated under vacuum to provide the title product as an oil (1.65 g, 100%).
Reaction SMILES: [C:1]([SiH2:5][O:6][C:7]([CH3:23])([CH3:22])[C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH:15]([O:19][CH2:20][CH3:21])[C:16]([OH:18])=[O:17])=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[Cl:24][C:25]([Cl:29])([Cl:28])[CH2:26]O>C(Cl)Cl.CN(C1C=CN=CC=1)C>[Cl:24][C:25]([Cl:29])([Cl:28])[CH2:26][O:17][C:16](=[O:18])[CH:15]([O:19][CH2:20][CH3:21])[CH2:14][C:11]1[CH:12]=[CH:13][C:8]([C:7]([CH3:22])([CH3:23])[O:6][SiH2:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[CH:9][CH:10]=1
Reactant: OCC(Cl)(Cl)Cl
Reactant: CCOC(Cc1ccc(C(C)(C)O[SiH2]C(C)(C)C)cc1)C(=O)O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCOC(Cc1ccc(C(C)(C)O[SiH2]C(C)(C)C)cc1)C(=O)OCC(Cl)(Cl)Cl
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Under nitrogene atmosphere 3-[4-(tert-butyl-dimethyl-silanyloxymethyl)-phenyl]-2-ethoxy-propionic acid (0.135 g, 0.4 mmol) and 2,2,2-trichloro ethanol (0.06 g, 0 4 mmol) were dissolved in dry DCM (5 mL) and DMAP (2 mg, 0.02 mmol) was added followed by EDCxHCl (0.092 g, 0.48 mmol) at 0° C. The mixture was stirred for 18 h at ambient temperature, then diluted with DCM and extracted with aq. HCl (2N) and water. The organic layer was separated, dried (MgSO4) and evaporated to afford the crude product which was used in the next step without further purification (0.176 g, 93.6%). 1H NMR (400 MHz, CDCl3): δ 7.12-7.19 (m, 4H), 4.62-4.71 (q, 2H), 4.63 (s, 2H), 4.05-4.08 (m, 1H), 3.55-3.59 (m, 1H), 3.27-3.31 (m, 1H), 2.92-3.03 (m, 2H), 1.08 (t, 3H).
Reaction SMILES: Br[C:2]1[S:6][C:5]([CH:7]=[O:8])=[CH:4][CH:3]=1.[C:9]1(B(O)O)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C([O-])([O-])=O.[K+].[K+]>C(O)(C)C.O.[Pd]>[C:9]1([C:2]2[S:6][C:5]([CH:7]=[O:8])=[CH:4][CH:3]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=Cc1ccc(Br)s1
Reactant: OB(O)c1ccccc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Solvent: O
Product: O=Cc1ccc(-c2ccccc2)s1
Yield: 96.1 %

Procedure:
A mixture of 5-bromo-thiophene-2-carbaldehyde (2.0 g, 10.5 mmol), phenylboronic acid (17 g, 11 mmol), K2CO3 (8.7 g, 62.8 mmol) and 10% Pd/C (0.56 g) in isopropanol/H2O (1:1, 40 mL) was refluxed for 5 h. The reaction mixture was filtered through a pad of Celite. After the isopropanol was removed, the product was collected on a filter, washed with hexane and dried in vacuo to yield the title compound (1.9 g, 82%).
Reaction SMILES: [CH2:1]([N:4]([CH2:19][CH2:20][CH3:21])[CH:5]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][C:12]=2C(OC)=O)[O:7][CH2:6]1)[CH2:2][CH3:3].[OH-].[Na+].C1(P([N:38]=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1>CO.O>[CH2:1]([N:4]([CH2:19][CH2:20][CH3:21])[CH:5]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][C:12]=2[NH2:38])[O:7][CH2:6]1)[CH2:2][CH3:3]
Reactant: CCCN(CCC)C1COc2cccc(C(=O)OC)c2C1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCCN(CCC)C1COc2cccc(N)c2C1
Reaction time: 4 h

Procedure:
3-Dipropylamino-5-methyloxycarbonylchroman (Example 2; 1.0 g, 3.4 mmol) was dissolved in methanol (20 ml). Sodium hydroxide (0.16 g, 4.1 mmol) in water (1.0 ml) was added and the solution was refluxed with nitrogen overnight. The solution was evaporated to dryness, toluene (20 ml) was added and again the solution was evaporated to dryness. The residue was dissolved in toluene 20 ml, diphenylphosphoryl azid (1.87 g, 6.8 mmol) was added and the solution was refluxed for 2 hours. Methanol (2.0 ml) was added and reflux was continued for 4 hours. The solution was cooled, washed with water and extracted with dilute HCl (aq.). The acidic water phase was neutralized NaOH (aq.) and extracted with toluene. The toluene-phase was dried with sodium sulphate and evaporated to dryness. The residue was dissolved in ethanol containing 10% NaOH (20 ml) and the solution was refluxed overnight. The solution was cooled and diluted with toluene. Washing with water, drying of the organic phase and evaporation to dryness afforded the title compound as an oil, which was converted to a dihydrochloride salt. Mp 173°-174° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)[N:3]=1.[Br:22][C:23]1[N:24]=[CH:25][NH:26][CH:27]=1>>[Br:22][C:23]1[N:24]=[CH:25][N:26]([C:2]2[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([C:12]3[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=3)[N:3]=2)[CH:27]=1
Reactant: Brc1c[nH]cn1
Reactant: FC(F)(F)c1ccc(-c2cc(C(F)(F)F)nc(Cl)n2)cc1
Product: FC(F)(F)c1ccc(-c2cc(C(F)(F)F)nc(-n3cnc(Br)c3)n2)cc1

Procedure:
The title compound was prepared from 2-chloro-4-trifluoromethyl-6-(4-trifluoromethylphenyl)-pyrimidine (example A.2) (0.98 g, 3.0 mmol) and commercially available 4-bromo-imidazole (0.66 g, 4.50 mmol) according to the general procedure IVa. Obtained as a white solid (0.78 g, 59%). MS (EI) 438.0 [(M)+]; mp 184.5° C.