Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2](=[O:37])[C:3](=[O:36])[CH:4]([NH:12][C:13]([C:15]1[C:16]([N:21]2[CH:25]=[C:24]3[CH2:26][N:27](C(OC(C)(C)C)=O)[CH2:28][C:23]3=[N:22]2)=[N:17][CH:18]=[CH:19][CH:20]=1)=[O:14])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[ClH:38]>ClCCl.O1CCOCC1>[ClH:38].[NH2:1][C:2](=[O:37])[C:3](=[O:36])[CH:4]([NH:12][C:13](=[O:14])[C:15]1[CH:20]=[CH:19][CH:18]=[N:17][C:16]=1[N:21]1[CH:25]=[C:24]2[CH2:26][NH:27][CH2:28][C:23]2=[N:22]1)[CH2:5][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: CC(C)(C)OC(=O)N1Cc2cn(-c3ncccc3C(=O)NC(Cc3ccccc3)C(=O)C(N)=O)nc2C1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: NC(=O)C(=O)C(Cc1ccccc1)NC(=O)c1cccnc1-n1cc2c(n1)CNC2
Temperature: 25 °C

Procedure:
To a solution of tert-butyl 2-(3-(4-amino-3,4-dioxo-1-phenylbutan-2-ylcarbamoyl)-pyridin-2-yl)-4,6-dihydropyrrolo[3,4-c]pyrazole-5(2H)-carboxylate (50 mg, 0.099 mmol) in dichloromethane (10 mL) 4004 of 4M HCl in dioxan were added and stirred over night at room temperature. The mixture then was concentrated, the remainder treated with MTB and the remaining solid then further purified by chromatography over Chromabond RP-C18 (eluent: water/acetonitrile) to give 30 mg of the titel compound; ESI-MS [M+H]+: 405.1. 1H-NMR (400 MHz, DMSO), δ[ppm]: 10.41 (broad), 8.93 (m, 1H), 8.54 (m, 1H), 8.21 (m, 1H), 8.06 (m, 1H), 7.85 (m, 1H), 7.71 (m, 1H), 7.49 (m, 1H), 7.26 (m, 5H), 5.33 (m, 1H), 4.35-4.16 (m, 5H), 3.12 (m, 1H), 2.84 (m, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.Cl[CH2:16][CH2:17][N:18]1[C:27](=[O:28])[CH2:26][C:21]2([CH2:25][CH2:24][CH2:23][CH2:22]2)[CH2:20][C:19]1=[O:29]>>[F:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:16][CH2:17][N:18]2[C:19](=[O:29])[CH2:20][C:21]3([CH2:25][CH2:24][CH2:23][CH2:22]3)[CH2:26][C:27]2=[O:28])[CH2:11][CH2:10]1
Reactant: O=C1CC2(CCCC2)CC(=O)N1CCCl
Reactant: Fc1cccc(F)c1N1CCNCC1
Product: O=C1CC2(CCCC2)CC(=O)N1CCN1CCN(c2c(F)cccc2F)CC1
Temperature: 160 °C
Reaction time: 5 h
Yield: 26.4 %

Procedure:
A mixture of 1-(2,6-difluorophenyl)piperazine (23.8 mg, 0.120 mmol) and 8-(2-chloroethyl)-8-azaspiro[4.5]decane-7,9-dione(20 mg, 0.087 mmol) was heated with stirring at 160° C. for 5 hours. The residue was purified by preparative HPLC (see Example 8 for conditions), giving (after removal of the solvent) the title compound as a pale yellow oil (8.9 mg, 0.023 mmol, 26%): ESI-MS m/z 392 (MH+).
Reaction SMILES: [CH2:1]1[CH2:11][C:9](=[O:10])[C:8]2[C:3](=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:2]1.[H-].[Na+].[C:14](=O)([O:18]CC)[O:15][CH2:16][CH3:17].Cl>O>[O:10]=[C:9]1[C:8]2[C:3](=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:2][CH2:1][CH:11]1[C:14]([O:15][CH2:16][CH3:17])=[O:18]
Reactant: O=C1CCCc2ccccc21
Reactant: CCOC(=O)OCC
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: CCOC(=O)C1CCc2ccccc2C1=O
Yield: 57.6 %

Procedure:
A suspension of 10 g (0.0684 mole) of α-tetralone, 3.56 g (0.0890 mole) of 60% sodium hydride and 32 g (0.2709 mole) of diethyl carbonate was heated under reflux for 1 hour, then poured into water, adjusted with conc. hydrochloric acid to a pH of 1 to 2, and extracted with ether. The ether layer was washed with water and then dried over magnesium sulfate. After evaporation of the solvent, the crude product was purified by silica gel column chromatography (hexane/ethyl acetate=9/1) to obtain 8.6 g of ethyl 1,2,3,4-tetrahydro-1-oxo-2-naphthalenecarboxylate, which was dissolved in tetrahydrofuran (220 ml) and then 1.90 g (0.0475 mole) of 60% sodium hydroxide was added under ice-cooling. After stirring for 30 minutes, 10.0 g (0.0599 mole) of ethyl bromoacetate was added, followed by stirring for 3 hours at room temperature. The reaction mixture was poured into ice-water, extracted with ether, and then the extract was subjected to washing with water, drying and solvent evaporation in a conventional manner. The crude product obtained was purified by silica gel column chromatography (hexane/ethyl acetate=5/1) to obtain 9.03 g of the following ethyl 2-ethoxycarbonyl-1,2,3,4-tetrahydro-1-oxo-2-naphthaleneacetate ##STR13##
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[CH2:9][N:10]1[CH:14]=[CH:13][C:12]([NH:15][C:16](=[O:25])[C:17]2[C:22]([F:23])=[CH:21][CH:20]=[CH:19][C:18]=2[F:24])=[N:11]1.CC(C)([O-])C.[K+].Br[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][OH:40]>C(#N)C.CS(C)=O>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][OH:40])[CH:5]=[CH:4][C:3]=1[CH2:9][N:10]1[CH:14]=[CH:13][C:12]([NH:15][C:16](=[O:25])[C:17]2[C:18]([F:24])=[CH:19][CH:20]=[CH:21][C:22]=2[F:23])=[N:11]1
Reactant: O=C(Nc1ccn(Cc2ccc(O)cc2Cl)n1)c1c(F)cccc1F
Reactant: OCCCCCCCBr
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CS(C)=O
Product: O=C(Nc1ccn(Cc2ccc(OCCCCCCCO)cc2Cl)n1)c1c(F)cccc1F
Temperature: 100 °C

Procedure:
To a solution of N-{1-[(2-chloro-4-hydroxyphenyl)methyl]-1H-pyrazol-3-yl}-2,6-difluorobenzamide (for a preparation see Example 31)(30 mg, 0.082 mmol) in acetonitrile (0.5 ml) was added potassium t-butoxide (9.4 mg, 0.084 mmol) and then 7-bromo-1-heptanol (0.015 ml, 0.099 mmol, Aldrich). The reaction vessel was sealed and heated in a Biotage Initiator microwave to 100° C. for 15 min. After cooling the reaction was diluted with DMSO (0.5 ml) and purified by MDAP on Sunfire C18 column using Acetonitrile-Water with a Formic acid modifier (Method B). The solvent was evaporated in vacuo to give the title compound as a colourless gum (6.7 mg);
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][N:6]2[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][C:9]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)=[N:8][C:7]=12)#[CH:2].Br[C:27]1[CH:28]=[CH:29][C:30]([O:42][CH3:43])=[C:31]([S:33]([NH:36][C:37]([CH3:41])([CH3:40])[CH2:38][OH:39])(=[O:35])=[O:34])[CH:32]=1>>[OH:39][CH2:38][C:37]([NH:36][S:33]([C:31]1[CH:32]=[C:27]([C:2]#[C:1][C:3]2[CH:4]=[N:5][N:6]3[C:11]([C:12]([F:14])([F:13])[F:15])=[CH:10][C:9]([C:16]4[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=4)=[N:8][C:7]=23)[CH:28]=[CH:29][C:30]=1[O:42][CH3:43])(=[O:35])=[O:34])([CH3:41])[CH3:40]
Reactant: C#Cc1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Reactant: COc1ccc(Br)cc1S(=O)(=O)NC(C)(C)CO
Product: COc1ccc(C#Cc2cnn3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)cc1S(=O)(=O)NC(C)(C)CO

Procedure:
The title compound was prepared from 3-ethynyl-7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.1) (355 mg, 1.0 mmol) and 5-bromo-N-(2-hydroxy-1,1-dimethyl-ethyl)-2-methoxy-benzenesulfonamide (example B.7) (439 mg, 1.3 mmol) according to general procedure II. Obtained as an orange solid (300 mg, 49%). MS (ISP) 541.3 [(M+H)+]; mp 209-213° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[N:12]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[CH:23]=3)[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([F:20])=[CH:15][CH:14]=3)=[O:10])=[CH:4][CH:3]=1.Br[CH2:30][C:31](=O)[CH2:32][CH3:33]>C(#N)C>[CH2:32]([C:31]1[N:1]=[C:2]2[CH:3]=[CH:4][C:5]([NH:8][C:9]([C:11]3[N:12]([CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[CH:23]=4)[C:13]4[C:18]([CH:19]=3)=[CH:17][C:16]([F:20])=[CH:15][CH:14]=4)=[O:10])=[CH:6][N:7]2[CH:30]=1)[CH3:33]
Reactant: Nc1ccc(NC(=O)c2cc3cc(F)ccc3n2Cc2cccc(F)c2)cn1
Reactant: CCC(=O)CBr
Solvent: CC#N
Product: CCc1cn2cc(NC(=O)c3cc4cc(F)ccc4n3Cc3cccc(F)c3)ccc2n1
Yield: 100.1 %

Procedure:
Compound 5 was prepared according to a process similar to that described in step 4.3, by reacting 0.1 g (0.26 mmol) of N-[6-aminopyrid-3-yl]-5-fluoro-1-[(3-fluorophenyl)-methyl]-1H-indole-2-carboxamide, prepared according to the protocol described in step 4.2, with 0.08 g (0.53 mmol) of 1-bromobutan-2-one in 4 mL of acetonitrile. 0.112 g of the expected product is thus obtained.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[CH2:7][C:8]1[NH:12][C:11]2[CH:13]=[CH:14][C:15]([N+:17]([O-:19])=[O:18])=[CH:16][C:10]=2[N:9]=1>C(Cl)Cl>[N+:17]([C:15]1[CH:14]=[CH:13][C:11]2[NH:12][C:8]([CH2:7][N:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)=[N:9][C:10]=2[CH:16]=1)([O-:19])=[O:18]
Reactant: C1CCNC1
Reactant: O=[N+]([O-])c1ccc2[nH]c(CCl)nc2c1
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc2[nH]c(CN3CCCC3)nc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
9.47 mL (113 mmol) pyrrolidine are added to a solution of 6.00 g (28.4 mmol) 2-chloromethyl-5-nitro-1H-benzimidazole in 100 mL DCM. The reaction is stirred overnight at RT. The reaction solution is washed four times with water. The organic phase is dried over MgSO4 and the solvent is eliminated i.vac.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[CH:10][NH:11][C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.[CH3:20][Si:21]([CH3:28])([CH3:27])[CH2:22][CH2:23][O:24][CH2:25]Cl.[H-].[Na+].C(=O)(O)[O-]>CN(C=O)C>[Cl:19][C:16]1[CH:17]=[CH:18][C:13]([C:12]2[N:11]=[CH:10][N:9]([CH2:25][O:24][CH2:23][CH2:22][Si:21]([CH3:28])([CH3:27])[CH3:20])[C:8]=2[C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)=[CH:14][CH:15]=1
Reactant: C[Si](C)(C)CCOCCl
Reactant: Clc1ccc(-c2nc[nH]c2-c2ccc(Cl)cc2)cc1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCn1cnc(-c2ccc(Cl)cc2)c1-c1ccc(Cl)cc1
Reaction time: 0.33 h

Procedure:
To a solution of 4,5-di-(4-chlorophenyl)imidazole (500 mg, 1.7 mmol) from Example 20, Step A and 2-(trimethylsilyl)ethoxymethyl chloride (SEM-Cl) (0.46 mL, 2.6 mmol) in DMF (8 mL) at rt was added sodium hydride (60% in mineral oil) (135 mg, 3.4 mmol). The reaction was stirred for 20 min, poured into an aq. bicarbonate solution, and extracted twice with ethyl acetate. The organic layers were washed with brine, dried over sodium sulfate, and evaporated. The residue was purified by flash chromatography (25% ethyl acetate in hexanes) to afford the title compound as an oil.
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[C:11]1[CH:16]=[CH:15][C:14]([I:17])=[CH:13][C:12]=1[OH:18])[CH2:8]2.[CH3:19]OS(OC)(=O)=O.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH:3]12[CH2:4][CH:5]3[CH2:6][CH:7]([CH2:8][CH:1]([CH2:10]3)[CH:2]1[C:11]1[CH:16]=[CH:15][C:14]([I:17])=[CH:13][C:12]=1[O:18][CH3:19])[CH2:9]2
Reactant: Oc1cc(I)ccc1C1C2CC3CC(C2)CC1C3
Reactant: COS(=O)(=O)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1cc(I)ccc1C1C2CC3CC(C2)CC1C3
Temperature: 25 °C
Yield: 81.3 %

Procedure:
A solution of 2-adamantyl-5-iodophenol (7.70 g, 21.7 mmol) in acetone (100 mL) was treated with dimethylsulfate (4.11 g, 32.6 mmol) and potassium carbonate (4.50 g, 32.6 mmol). The reaction mixture was stirred at reflux for 24 h, allowed to cool to room temperature, and concentrated in vacuo. The crude product was partitioned between methylene chloride and water. The organic phase was dried over anhydrous magnesium sulfate, filtered, and concentrated to provide 6.5 g (81%) of 2-adamantyl-5-iodoanisole; 1H NMR (300 MHz, CDCl3) δ 7.22 (dd, J=2, 8 Hz, 1H, ArH), 7.10 (d, J=2 Hz, 1H, ArH), 6.89 (d, J=8 Hz, 1H, ArH), 3.79 (s, 3H, OCH3), 2.02 (s, 9H, adamantyl), and 1.73 (s, 6H, adamantyl); 13C NMR (75 MHz, CDCl3) δ 159.35, 138.43, 129.63, 128.25, 120.75, 91.20, 55.22 (OCH3), 40.35, 37.02, 36.92, and 28.97; MS (DCI) m/e 369 (MH+), 368 (M+), 367 (M--H)+, 135 (C10H15+). Anal. Calcd for C17H21OI: C, 55.45; H, 5.75. Found: C, 55.51; H, 5.81.
Reaction SMILES: [C:1]([NH:12][NH2:13])(=[O:11])[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][CH:3]=1.NC1C=CC(C([NH:21][NH2:22])=O)=CC=1.C1C(N)=CC=C(N)C=1.NC1C=CC(C(Cl)=O)=CC=1.C(Cl)(=O)C1C=CC(C(Cl)=O)=CC=1>>[C:6]([NH:21][NH2:22])(=[O:8])[C:5]1[CH:9]=[CH:10][C:2]([C:1]([NH:12][NH2:13])=[O:11])=[CH:3][CH:4]=1
Reactant: NNC(=O)c1ccc(C(=O)O)cc1
Reactant: NNC(=O)c1ccc(N)cc1
Agent: Nc1ccc(C(=O)Cl)cc1
Agent: Nc1ccc(N)cc1
Agent: O=C(Cl)c1ccc(C(=O)Cl)cc1
Product: NNC(=O)c1ccc(C(=O)NN)cc1

Procedure:
Terephthalic acid hydrazide, p-aminobenzoic acid hydrazide, p-phenylenediamine, p-aminobenzoyl chloride and terephthaloyl chloride are properly combined, and a 5 wt% solution of polyamide resin comprising 33 mol% of terephthalhydrazide, 33 mol% of p-benzamide, and 33 mol% of p-phenyleneterephthalamide is obtained by low temperature (about 10° to 35° C.) solution polymerization process. The solvent used for the solution polymerization is preferably dimethylacetamide and calcium chloride is contained in the polymerization solution as a neutralization product. This solution is cast on a metallic belt and dried until the polymer concentration becomes about 30 wt% by heating at about 100° C. for 5 minutes. The film is then dipped for about 2 minutes in water at normal temperatures (about 10° to 35° C.) to remove the solvent and calcium chloride. After further washing with water and drying at 230° C., the resulting film is rolled up. Orientation is conducted by stretching the dried film in the longitudinal direction in a 50° C. dimethylacetamide aqueous solution through the difference in rotating speeds of associated nip rolls, and subsequently stretching it in a lateral direction by guiding it to a tenter and expanding the rail distance. The draw ratio is generally kept from about 1.1 to 2.0 times in both longitudinal and lateral directions. Thus, a 3 μm thick aromatic polyamide film is obtained.
Reaction SMILES: C([N:8]([C@H:16]([C@@H:24]([OH:30])[CH2:25][CH2:26][CH:27]([CH3:29])[CH3:28])[CH2:17][CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1)CC1C=CC=CC=1)C1C=CC=CC=1.C([O-])=O.[NH4+]>CO.[C].[Pd]>[NH2:8][C@H:16]([C@@H:24]([OH:30])[CH2:25][CH2:26][CH:27]([CH3:28])[CH3:29])[CH2:17][CH:18]1[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]1
Reactant: CC(C)CC[C@H](O)[C@H](CC1CCCCC1)N(Cc1ccccc1)Cc1ccccc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: CC(C)CC[C@H](O)[C@@H](N)CC1CCCCC1
Temperature: 25 °C
Yield: 148.1 %

Procedure:
2(S)-(N,N-Dibenzylamino)-1-cyclohexyl-3(S)-hydroxy-6-methylheptane (5 g) was dissolved in methanol (50 ml). Ammonium formate (6.18 g) and then 10% palladium-carbon (50% wet, 0.5 g) were added thereto, and the mixture was vigorously stirred at room temperature. After the completion of the reaction, the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. Ethyl acetate and water were added to the concentrated residue for extraction. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give 4.13 g of 2(S)-amino-1-cyclohexyl-3(S)-hydroxy-6-methylheptane.
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:8][CH2:7][CH:6]([CH2:9][NH:10][C:11]([C:13]2[S:23][C:22]3[N:24]4[C:15](=[CH:16][N:17]=[C:18]4[CH:19]=[CH:20][CH:21]=3)[CH:14]=2)=[O:12])[CH2:5][CH2:4]1.C(N(CC)CC)C.[O:32]([CH2:39][CH2:40][CH2:41][CH2:42]Br)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>C(O)C>[O:32]([CH2:39][CH2:40][CH2:41][CH2:42][N:3]1[CH2:8][CH2:7][CH:6]([CH2:9][NH:10][C:11]([C:13]2[S:23][C:22]3[N:24]4[C:15](=[CH:16][N:17]=[C:18]4[CH:19]=[CH:20][CH:21]=3)[CH:14]=2)=[O:12])[CH2:5][CH2:4]1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: O=C(NCC1CCNCC1)C1=Cc2cnc3cccc(n23)S1
Reactant: BrCCCCOc1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: O=C(NCC1CCN(CCCCOc2ccccc2)CC1)C1=Cc2cnc3cccc(n23)S1

Procedure:
To a solution of 0.58 g (1.5 mM) of N-(piperidin-4-ylmethyl)-5-thia-1,8b-diazaacenaphthylene-4-carboxamide dihydrochloride and 1.0 ml (27.5 mM) of triethylamine in ethanol (6 ml) was added 0.45 g (1.96 mM) of 4-phenoxybutyl bromide at room temperature and the mixture was refluxed under nitrogen for 14 hours. To this reaction mixture was further added 0.23 g (1.0 mM) of 4-phenoxybutyl bromide and the mixture was refluxed for 6 hours. The solvent was then distilled off under reduced pressure and the residue was diluted with water and extracted with chloroform. The organic layer was washed with saturated aqueous solution of sodium chloride and dried over MgSO4. The resulting crude product was purified by column chromatography (methanol/chloroform=1/15-1/10-1/5) to provide the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]([N:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)=[O:18])[CH:15]=3)[C:10]([S:25]([CH3:27])=[O:26])=[CH:9]2)=[N:6][CH:7]=1.Br[C:29]1[CH:34]=[C:33]([Cl:35])[CH:32]=[CH:31][N:30]=1.OC(C1C=CN=C(C2C=NC(N3C4C(=CC=C(C(N5CCOCC5)=O)C=4)C(SC)=C3)=NC=2)C=1)(C)C>>[Cl:35][C:33]1[CH:32]=[CH:31][N:30]=[C:29]([C:2]2[CH:7]=[N:6][C:5]([N:8]3[C:16]4[C:11](=[CH:12][CH:13]=[C:14]([C:17]([N:19]5[CH2:24][CH2:23][O:22][CH2:21][CH2:20]5)=[O:18])[CH:15]=4)[C:10]([S:25]([CH3:27])=[O:26])=[CH:9]3)=[N:4][CH:3]=2)[CH:34]=1
Reactant: CS(=O)c1cn(-c2ncc(Br)cn2)c2cc(C(=O)N3CCOCC3)ccc12
Reactant: Clc1ccnc(Br)c1
Agent: CSc1cn(-c2ncc(-c3cc(C(C)(C)O)ccn3)cn2)c2cc(C(=O)N3CCOCC3)ccc12
Product: CS(=O)c1cn(-c2ncc(-c3cc(Cl)ccn3)cn2)c2cc(C(=O)N3CCOCC3)ccc12

Procedure:
Prepared from (1-(5-bromopyrimidin-2-yl)-3-(methylsulfinyl)-1H-indol-6-yl)(morpholino)-methanone (0.5 g, 1.11 mmol) and 2-bromo-4-chloropyridine (0.23 g, 1.22 mmol) analogously to the experimental procedure for 289a). White solid. Yield: 61 mg (11% of theory)
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:11][CH2:10][C:9]([CH2:12][CH2:13][CH2:14][CH2:15][C:16]([F:28])([F:27])[C:17]([F:26])([F:25])[C:18]([F:24])([F:23])[C:19]([F:22])([F:21])[F:20])=[CH:8][CH2:7]1)=[O:5])C.[OH-].[K+]>O.C(O)C>[F:27][C:16]([F:28])([C:17]([F:25])([F:26])[C:18]([F:23])([F:24])[C:19]([F:22])([F:20])[F:21])[CH2:15][CH2:14][CH2:13][CH2:12][C:9]1[CH2:10][CH2:11][CH:6]([C:4]([OH:5])=[O:3])[CH2:7][CH:8]=1
Reactant: CCOC(=O)C1CC=C(CCCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)CC1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)C1CC=C(CCCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)CC1
Temperature: 25 °C
Yield: 93 %

Procedure:
A solution 4-(5,5,6,6,7,7,8,8,8-nonafluoro-octyl)-cyclohex-3-enecarboxylic acid ethyl ester (41) (1 equi.) and potasium hydroxide (3.5 equi.) in water-ethanol (1:1) (25 mL/mmole) was stirred at 80 C temperature for 2 h., cooled to room temperature and quenched with hydrochloric acid (5%), filtered resulted white solid, washed with water and dried under vacuum to give 4-(5,5,6,6,7,7,8,8,8-nonafluoro-octyl)-cyclohex-3-enecarboxylic acid (42) as a white solid (93%).
Reaction SMILES: [C:1]1(C)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:9]1[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[C:11]([N+:19]([O-:21])=[O:20])[CH:10]=1.OB(O)C1C=CC=CC=1.C(=O)([O-])O.[Na+]>[Pd].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.O.C(O)C>[N+:19]([C:11]1[CH:10]=[C:9]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:18]=[CH:17][C:12]=1[C:13]([O:15][CH3:16])=[O:14])([O-:21])=[O:20]
Reactant: Cc1ccccc1
Reactant: COC(=O)c1ccc(Br)cc1[N+](=O)[O-]
Agent: [Pd]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Solvent: O
Solvent: CCO
Product: COC(=O)c1ccc(-c2ccccc2)cc1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
To a mixed solution of 42 mL of toluene, 16 mL of ethanol and 7.8 mL of water containing 5.2 g of methyl 4-bromo-2-nitrobenzoate, 2.9 g of dihydroxyphenyl borane, 4.2 g of sodium hydrogen carbonate and 1.1 g of tetrakis(triphenylphosphine)-palladium (0) were added sequentially and the resulting mixture was heated to reflux under nitrogen atmosphere for 2 hours. After the reaction mixture was cooled to room temperature, 1.1 g of tetrakis(triphenylphosphine)palladium (0) was added to the reaction mixture and the resulting mixture was heated to reflux under nitrogen atmosphere for 2 hours. After the reaction mixture was cooled to room temperature, 1.1 g of tetrakis(triphenylphosphine)palladium (0) was added to the reaction mixture and the resulting mixture was heated to reflux under nitrogen atmosphere for 2 hours. After the reaction mixture was cooled to room temperature, water was added. The organic layer was separated and dried over anhydrous magnesium sulfate after washed with 1.0 mol/L hydrochloric acid and a saturated sodium chloride aqueous solution sequentially, and the solvent was evaporated under reduced pressure. The obtained residue was purified with silica gel column chromatography [eluent; hexane:ethyl acetate=20:1] to obtain 4.8 g of methyl 2-nitro-4-phenylbenzoate as pale yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][C:3]=1[F:12].[CH2:13]([NH:15][CH2:16][CH3:17])[CH3:14]>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:15]([CH2:16][CH3:17])[CH2:13][CH3:14])(=[O:10])=[O:9])=[CH:4][C:3]=1[F:12]
Reactant: CCNCC
Reactant: O=S(=O)(Cl)c1ccc(Br)c(F)c1
Solvent: ClCCl
Product: CCN(CC)S(=O)(=O)c1ccc(Br)c(F)c1
Yield: 90.5 %

Procedure:
According to general procedure C, 4-Bromo-3-fluoro-benzenesulfonyl chloride (0.40 g, 1.46 mmol) and diethylamine (0.38 mL, 3.65 mmol) were stirred together with dry dichloromethane (5 mL) for 16 hours. 4-bromo-N,N-diethyl-3-fluorobenzenesulfonamide (0.41 g, 90%) was provided after purification. HRMS: calcd for C10H13BrFNO2S, 308.98344; found (EI, M+.), 308.9822. HPLC purity 100.0% at 210-370 nm, 10.9 min.; the Xterra® RP18 column, 3.5μ, 150×4.6 mm column, 1.2 mL/min., 85/15-5/95 (ammonium formate buffer pH=3.5/ACN+MeOH) for 10 min., hold 4 min.
Reaction SMILES: [C:1]([C:3]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[N:5]([CH2:14][CH3:15])[C:4]=1[C:16]1[CH:21]=[CH:20][C:19]([NH:22][S:23]([CH2:26][CH2:27][CH2:28]Cl)(=[O:25])=[O:24])=[CH:18][CH:17]=1)#[N:2].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[O:24]=[S:23]1(=[O:25])[CH2:26][CH2:27][CH2:28][N:22]1[C:19]1[CH:20]=[CH:21][C:16]([C:4]2[N:5]([CH2:14][CH3:15])[C:6]3[C:11]([C:3]=2[C:1]#[N:2])=[CH:10][CH:9]=[C:8]([O:12][CH3:13])[CH:7]=3)=[CH:17][CH:18]=1
Reactant: CCn1c(-c2ccc(NS(=O)(=O)CCCCl)cc2)c(C#N)c2ccc(OC)cc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCn1c(-c2ccc(N3CCCS3(=O)=O)cc2)c(C#N)c2ccc(OC)cc21
Temperature: 70 °C
Yield: 68 %

Procedure:
A solution of 3-chloropropane-1-sulfonic acid [4-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-yl)-phenyl] amide, prepared above (3.65 g, 2.33 mmol) in DMF (100 mL) was treated with K2CO3 and heated at 70° C. for 2 h. After cooling to room temperature, the reaction mixture was diluted with H2O and extracted 3× with hot EtOAc. The hot organic layers were washed with warm H2O (3×) and saturated NaCl and dried and concentrated to a solid. Trituration (CH2Cl2/hexanes) gave 2.27 g (68%) of 2-[4-(1,1-dioxo-1λ6-isothiazolidin-2-yl)phenyl]-1-ethyl-6-methoxy-1H-indole-3-carbonitrile as a light brown solid.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]([CH2:25][CH2:26][OH:27])[C:5]([C:7]1[N:16]2[C:10]([CH2:11][N:12](C(OC)=O)[C:13]3[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=3[CH2:15]2)=[CH:9][CH:8]=1)=[O:6].C(=O)([O-])[O-].[K+].[K+].Cl.[Cl-].[Na+]>CO.O>[OH:1][CH2:2][CH2:3][N:4]([CH2:25][CH2:26][OH:27])[C:5]([C:7]1[N:16]2[C:10]([CH2:11][NH:12][C:13]3[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=3[CH2:15]2)=[CH:9][CH:8]=1)=[O:6]
Reactant: COC(=O)N1Cc2ccc(C(=O)N(CCO)CCO)n2Cc2ccccc21
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: O
Solvent: CO
Product: O=C(c1ccc2n1Cc1ccccc1NC2)N(CCO)CCO
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 10-(methoxycarbonyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxylic acid bis-(2-hydroxy-ethyl)-amide (5 mmol) of Step B in methanol (50 mL) was treated with potassium carbonate and stirred at room temperature overnight. Water was then added to the solution and the pH adjusted to 6 with 6N hydrochloric acid. The solution was saturated with solid sodium chloride and extracted with dichloromethane. The combined organic layers were dried over anhydrous magnesium sulfate and evaporated to dryness to yield the title compound.