Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Sn](CCCC)(CCCC)[C:6]1[O:7][C:8]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:9]=2[CH:10]=1)CCC.[CH2:24]([O:26][CH2:27][CH2:28][CH2:29][NH:30][C:31](=[O:55])[CH:32]([NH:37][C:38]1[CH:43]=[C:42]([CH2:44][CH2:45][CH2:46]C)[N:41]=[C:40]([C:48]2[CH:49]=[N:50][CH:51]=[C:52](Br)[CH:53]=2)[N:39]=1)[CH2:33][CH:34]([CH3:36])[CH3:35])[CH3:25]>CN(C)C=O.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>[CH2:24]([O:26][CH2:27][CH2:28][CH2:29][NH:30][C:31](=[O:55])[CH:32]([NH:37][C:38]1[CH:43]=[C:42]([CH2:44][CH2:45][CH3:46])[N:41]=[C:40]([C:48]2[CH:49]=[N:50][CH:51]=[C:52]([C:6]3[O:7][C:8]4[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:9]=4[CH:10]=3)[CH:53]=2)[N:39]=1)[CH2:33][CH:34]([CH3:35])[CH3:36])[CH3:25]
Reactant: CCCCc1cc(NC(CC(C)C)C(=O)NCCCOCC)nc(-c2cncc(Br)c2)n1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cc2cc(F)ccc2o1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Product: CCCc1cc(NC(CC(C)C)C(=O)NCCCOCC)nc(-c2cncc(-c3cc4cc(F)ccc4o3)c2)n1
Yield: 21.3 %

Procedure:
Under an atmosphere of argon, a solution of tributyl(5-fluorobenzofuran-2-yl)stannane (17 mg), 2-[2-(5-bromopyridin-3-yl)-6-butylpyrimidin-4-ylamino]-4-methylpentanoic acid (3-ethoxypropyl)amide (20 mg) and (PPh3)2PdCl2 (2 mg) in N,N-dimethylformamide (1 mL) was heated at 80° C. for 12 h and then quenched with water (10 mL). The mixture was extracted with ethyl acetate (3×20 mL) and the combined organic extracts were dried over sodium sulfate and concentrated. The crude product was purified by semi-preparative HPLC to give 4.6 mg of 2-{2-[5-(5-fluorobenzofuran-2-yl)pyridin-3-yl]-6-propylpyrimidin-4-ylamino}-4-methylpentanoic acid (3-ethoxypropyl) amide as a TFA salt. ESI-MS (m/z) 562 [M+H]+.
Reaction SMILES: [OH-].[K+].[Br:3][C:4]1[CH:13]=[C:12]2[C:7]([C:8]([CH3:16])([CH3:15])[CH2:9][C:10](=[O:14])[NH:11]2)=[CH:6][C:5]=1[CH3:17].[CH3:18]I.O>CS(C)=O>[Br:3][C:4]1[CH:13]=[C:12]2[C:7]([C:8]([CH3:15])([CH3:16])[CH2:9][C:10](=[O:14])[N:11]2[CH3:18])=[CH:6][C:5]=1[CH3:17]
Reactant: CI
Reactant: Cc1cc2c(cc1Br)NC(=O)CC2(C)C
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: Cc1cc2c(cc1Br)N(C)C(=O)CC2(C)C
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 101.3 %

Procedure:
A mixture of powdered KOH (14.06 g, 0.250 mol) in DMSO (150 mL) was stirred at 0° C. for 10 min. 7-Bromo-4,4,6-trimethyl-3,4-dihydro-1H-quinoline-2-one (33.59 g, 0.125 mol) was added cautiously, followed immediately by the addition of methyl iodide (39 mL, 0.625 mol). The reaction mixture was kept at 0° C. for 30 min then slowly warmed up to room temperature and stirred overnight at room temperature. The reaction mixture was poured into water and extracted with dichloromethane washed with water and brine, dried (Mg2SO4), filtered and evaporated to give 35.74 g of 7-bromo-1,4,4,6-tetramethyl-3,4-dihydro-1H-quinoline-2-one (99%) and used without further purification in the Suzuki coupling (step a). 1H NMR (300 MHz; CDCl3): 1.27 (s, 6 H), 2.37 (s, 3 H), 2.48 (s, 2 H), 3.35 (s, 3 H), 7.12 (s, 1 H), 7.16 (s, 1 H).
Reaction SMILES: [N+:1]([O-:4])([O-])=[O:2].[K+].[CH3:6][C:7]1[CH:15]=[C:14]2[C:10]([C:11]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[N:12][NH:13]2)=[CH:9][CH:8]=1.S(=O)(=O)(O)O>>[CH3:6][C:7]1[CH:15]=[C:14]2[C:10]([C:11]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)=[N:12][NH:13]2)=[CH:9][C:8]=1[N+:1]([O-:4])=[O:2]
Reactant: O=[N+]([O-])[O-]
Reactant: Cc1ccc2c(-c3ccccc3)n[nH]c2c1
Agent: O=S(=O)(O)O
Agent: [K+]
Product: Cc1cc2[nH]nc(-c3ccccc3)c2cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 47.3 %

Procedure:
6-Methyl-5-nitro-3-phenyl-1H-indazole can be obtained in the following way: 0.43 g of potassium nitrate is added over 5 minutes to a solution, cooled to a temperature in the region of 0° C., of 0.8 g of 6-methyl-3-phenyl-1H-indazole in 8 ml of an aqueous 98% sulfuric acid solution. The reaction mixture is stirred at a temperature in the region of 0° C. for 5 minutes and is then heated at a temperature in the region of 35-40° C. for 10 minutes and again cooled to a temperature in the region of 0° C. and stirred for 1 hour. The mixture is then poured into 50 g of ice, stirred at a temperature in the region of 0° C. for 1 hour, then filtered through sintered glass. The solid obtained is washed with 3 times 30 ml of water and partially dried and is then redissolved in 100 ml of ethyl acetate and the mixture is dried over magnesium sulfate, filtered and then concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40° C. The residue thus obtained is purified by chromatography on a silica column (particle size 40-63 μm), eluting successively with cyclohexane/ethyl acetate (90/10; 80/20 by volume) mixtures. The fractions containing the expected product are pooled and concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40° C. 0.46 g of 6-methyl-5-nitro-3-phenyl-1H-indazole is thus obtained in the form of a yellow crystalline solid melting at 164° C.
Reaction SMILES: [CH:1]1([N:8]([C:25]2[CH:30]=[CH:29][C:28]([N:31]([CH3:33])[CH3:32])=[CH:27][CH:26]=2)[C:9](=[O:24])[NH:10][C:11]2[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[C:13]([C:19]([CH3:22])([CH3:21])[CH3:20])[C:12]=2[OH:23])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:34]([O:41][C:42]([NH:44][C@H:45]([C:47](O)=[O:48])[CH3:46])=[O:43])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.Cl.C(N=C=NCCCN(C)C)C>CN(C)C1C=CN=CC=1.CN(C)C=O>[CH2:34]([O:41][C:42]([NH:44][C@H:45]([C:47]([O:23][C:12]1[C:13]([C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:14][C:15]([O:17][CH3:18])=[CH:16][C:11]=1[NH:10][C:9]([N:8]([CH:1]1[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)[C:25]1[CH:30]=[CH:29][C:28]([N:31]([CH3:33])[CH3:32])=[CH:27][CH:26]=1)=[O:24])=[O:48])[CH3:46])=[O:43])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: COc1cc(NC(=O)N(c2ccc(N(C)C)cc2)C2CCCCCC2)c(O)c(C(C)(C)C)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Product: COc1cc(NC(=O)N(c2ccc(N(C)C)cc2)C2CCCCCC2)c(OC(=O)[C@H](C)NC(=O)OCc2ccccc2)c(C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 59.7 %

Procedure:
A mixture of 1.5 g of 2-[3-cycloheptyl-3-(4-dimethylaminophenyl)ureido]-4-methoxy-6-tert-butylphenol, 2.16 g of N-benzyloxycarbonyl-L-alanine, 1.95 g of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (WSC), 0.62 g of 4-dimethylaminopyridine (DMPA) and 30 ml of dimethylformamide (DMF) was stirred at room temperature for 5 hours. A saturated saline solution was added to the mixture and the mixture was extracted with ethyl acetate. The extract was washed and dried. The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography (solvent; hexane:ethyl acetate=4:1) to give 1.3 g of O-(N-benzyloxycarbonyl-L-alanyl)-2-[3-cycloheptyl-3-(4-dimethylaminophenyl)ureido]-4-methoxy-6-tert-butylphenol (yield: 60%, melting point: 126° C.).
Reaction SMILES: [OH-].[Na+].[CH3:3][C:4]1[O:8][C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:6][C:5]=1[CH2:15][O:16][C:17]1[CH:41]=[CH:40][C:20]([CH2:21][O:22]/[N:23]=[C:24](/[C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)\[CH2:25][CH2:26][CH2:27][CH2:28][C:29]([O:31]CC)=[O:30])=[CH:19][CH:18]=1.CO.Cl>O1CCCC1>[CH3:3][C:4]1[O:8][C:7]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)=[N:6][C:5]=1[CH2:15][O:16][C:17]1[CH:18]=[CH:19][C:20]([CH2:21][O:22]/[N:23]=[C:24](/[C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)\[CH2:25][CH2:26][CH2:27][CH2:28][C:29]([OH:31])=[O:30])=[CH:40][CH:41]=1
Reactant: CCOC(=O)CCCC/C(=N\OCc1ccc(OCc2nc(-c3ccccc3)oc2C)cc1)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(CO/N=C(\CCCCC(=O)O)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.9 %

Procedure:
A 1N aqueous saturated solution of sodium hydroxide (3 ml) was added to a solution of ethyl E-6-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]-6-phenylhexanoate (530 mg) in tetrahydrofuran (6 ml)-methanol (3 ml) and stirred at room temperature for 1 hour. 1N hydrochloric acid (3.3 ml) was added to the reaction mixture and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated solution of sodium chloride, dried (MgSO4) and concentrated. The residue was recrystallized from ethyl acetate-hexane to obtain E-6-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]-6-phenylhexanoic acid (451 mg, yield 90%) as colorless crystals. m.p. 112-113° C.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([Cl:11])=[CH:8][CH:9]=2)[N:4](C(OCC)=O)[C:3]=1[C:17](=[O:26])[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([C:24]#[N:25])[CH:19]=1.C(=O)([O-])[O-:28].[K+].[K+].NC1C2C(=CC(Cl)=CC=2)NC=1C(=O)C1C=CC=C(C#N)C=1>C(O)C.O>[NH2:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([Cl:11])=[CH:8][CH:9]=2)[NH:4][C:3]=1[C:17](=[O:26])[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([NH2:25])=[O:28])[CH:19]=1
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)n1c(C(=O)c2cccc(C#N)c2)c(N)c2ccc(Cl)cc21
Agent: N#Cc1cccc(C(=O)c2[nH]c3cc(Cl)ccc3c2N)c1
Agent: [K+]
Solvent: O
Solvent: CCO
Product: NC(=O)c1cccc(C(=O)c2[nH]c3cc(Cl)ccc3c2N)c1

Procedure:
A mixture of 3-amino-6-chloro-2-(3-cyanobenzoyl)-1-(ethoxycarbonyl)indole (step 1, 10.4 g, 28 mmol) and potassium carbonate (20 g, 140 mmol) in ethanol (100 ml) and water (100 ml) was heated at reflux for 4 h. The mixture was cooled and concentrated, and the residue partitioned between water (100 ml) and ethyl acetate (250). The organic layer was dried (MgSO4) and concentrated. The residual oil was purified by flash column chromatography eluting with hexane/ethyl acetate (2/1) to give; 3-Amino-6-chloro-2-(3-cyanobenzoyl)indole (Example 127):
Reaction SMILES: Cl.[C:2]([C:5]1[CH:12]=[CH:11][C:8]([CH2:9][NH2:10])=[CH:7][CH:6]=1)(=[O:4])[CH3:3].C(N(CC)CC)C.[CH3:20][C:21]1[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1>ClCCl>[C:2]([C:5]1[CH:12]=[CH:11][C:8]([CH2:9][NH:10][S:27]([C:24]2[CH:25]=[CH:26][C:21]([CH3:20])=[CH:22][CH:23]=2)(=[O:29])=[O:28])=[CH:7][CH:6]=1)(=[O:4])[CH3:3]
Reactant: CC(=O)c1ccc(CN)cc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)c1ccc(CNS(=O)(=O)c2ccc(C)cc2)cc1
Temperature: 4 °C
Reaction time: 0.25 h

Procedure:
To a stirred suspension under argon of 4-acetylbenzylamine hydrochloride (700 mg) in dichloromethane (20 ml) was added triethylamine (1.15 ml) and stirring continued for 15 minutes. The mixture was cooled to 4° C., then 4-methylphenylsulphonyl chloride (790 mg) in dichloromethane (5 ml) added dropwise over 30 minutes. The reaction mixture was stirred for 18 hours at ambient temperature, then diluted with further dichloromethane (50 ml), washed with water, dried (MgSO4) and evaporated. Trituration of the residue gave N-([4-acetylphenyl]methyl)4-methylphenylsulphonamide (A), 1.02 g., as an off-white solid: m.p. 125°-128° C.; NMR (d6DMSO) δ8.13(1H,t), 7.86(2H,d), 7.68(2H,d), 7.37(4H,dd), 4.03(2H,d), 2.55(3H,s), 2.39(3H,s); m/e304(M+H)+.
Reaction SMILES: Br[CH:2]([C:4]1[N:13]([CH3:14])[C:12](=[O:15])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:16]#[N:17])[CH:10]=2)[N:5]=1)[CH3:3].[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([S:26]([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)(=[O:28])=[O:27])=[CH:22][CH:21]=1>C(#N)C>[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([S:26]([N:29]2[CH2:34][CH2:33][N:32]([CH:2]([C:4]3[N:13]([CH3:14])[C:12](=[O:15])[C:11]4[C:6](=[CH:7][CH:8]=[C:9]([C:16]#[N:17])[CH:10]=4)[N:5]=3)[CH3:3])[CH2:31][CH2:30]2)(=[O:28])=[O:27])=[CH:22][CH:21]=1
Reactant: CC(Br)c1nc2ccc(C#N)cc2c(=O)n1C
Reactant: COc1ccc(S(=O)(=O)N2CCNCC2)cc1
Solvent: CC#N
Product: COc1ccc(S(=O)(=O)N2CCN(C(C)c3nc4ccc(C#N)cc4c(=O)n3C)CC2)cc1
Yield: 8.4 %

Procedure:
In a test tube containing of 2-(1-bromo-ethyl)-3-methyl-4-oxo-3,4-dihydro-quinazoline-6-carbonitrile (40.0 mg, 0.14 mmol) in acetonitrile (2 ml) was added KI (34.0 mg, 0.21 mmol), and (1-(4-Methoxy-benzenesulfonyl)-piperazine (46.4 mg, 0.21 mmol). The reaction was heated for 18 hours. The solution was concentrated under reduced pressure. The residue was partitioned between water (2 ml) and dichloromethane (5 ml). The organic layer was dried over magnesium sulfate, filtered and concentrated under reduced pressure. The solvent was removed under vacuum. The resulting residue was dissolvent in DMSO (2 ml) and purified by HPLC (Gilson-215, 0.035% TFA in acetonitrile and 0.05% water as mobile phase). The product was collected and dried under reduced pressure to give the 2-{1-[4-(4-Methoxy-benzenesulfonyl)-piperazin-1-yl]-ethyl}-3-methyl-4-oxo-3,4-dihydro-quinazoline-6-carbonitrile compound (Yield 5.52 mg, 8.2%). 1H NMR (400 MHz, CDCl3): δ 1.64 (d, 3H, J=6.57 Hz), 3.29-3.10 (m, 6H), 3.48-3.37 (m, 2H), 3.68 (s, 3H), 3.90 (s, 3H), 4.53 (q, 1H, J=13.14, 5.81 Hz), 6.97 (d, 2H, J=2.02 Hz), 7.66 (d, 2H, J=8.84, Hz), 7.76 (d, 1H, J=8.59 Hz), 7.94 (dd, 1H J=8.59, 2.02 Hz), 8.57 (d, 1H, J=2.02 Hz). MS m/z calc. 467.16, found (ESI); 468.4 (M+1)+. Retention time 2.75 minutes.
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:13][C:12]([C:14]3[C:15]([NH2:26])=[N:16][CH:17]=[C:18]([C:20]4[CH2:21][CH2:22][NH:23][CH2:24][CH:25]=4)[N:19]=3)=[N:11][N:10]=2)=[CH:5][CH:4]=1.CCN(C(C)C)C(C)C.[C:36](Cl)(=[O:39])[CH2:37][CH3:38]>C(Cl)Cl>[NH2:26][C:15]1[N:16]=[CH:17][C:18]([C:20]2[CH2:21][CH2:22][N:23]([C:36](=[O:39])[CH2:37][CH3:38])[CH2:24][CH:25]=2)=[N:19][C:14]=1[C:12]1[O:13][C:9]([C:6]2[CH:5]=[CH:4][C:3]([CH2:2][Br:1])=[CH:8][CH:7]=2)=[N:10][N:11]=1
Reactant: Nc1ncc(C2=CCNCC2)nc1-c1nnc(-c2ccc(CBr)cc2)o1
Reactant: CCC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCC(=O)N1CC=C(c2cnc(N)c(-c3nnc(-c4ccc(CBr)cc4)o3)n2)CC1
Reaction time: 0.25 h
Yield: 60.9 %

Procedure:
To a solution of 3-[5-[4-(bromomethyl)phenyl]-1,3,4-oxadiazol-2-yl]-5-(1,2,3,6-tetrahydropyridin-4-yl)pyrazin-2-amine (34 mg, 0.07 mmol) in anhydrous DCM (500 μL) cooled in an ice water bath under an atmosphere of nitrogen was added DIEA (49 mg, 66 μL, 0.38 mmol) followed by the dropwise addition of a solution of propanoyl chloride (8 mg, 7 μL, 0.08 mmol) in DCM (0.2 mL). The reaction mixture was stirred for 15 minutes. The reaction mixture was diluted with DCM and washed three times with 1M aqueous HCl solution, twice with saturated aqueous NaHCO3 solution and then twice with a solution of brine. The layers were separated and the organic layer was dried over Na2SO4, filtered and concentrated to dryness under reduced pressure to yield 1-[4-[5-amino-6-[5-[4-(bromomethyl)phenyl]-1,3,4-oxadiazol-2-yl]pyrazin-2-yl]-3,6-dihydro-2H-pyridin-1-yl]propan-1-one (20 mg, 57%). LC/MS m/z 471.3 [M+H]+.
Reaction SMILES: SCCO.[CH3:5][N:6]([C@@H:19]1[C@@H:26]2[C@@H:22]([CH2:23][N:24]([S:27]([C:30]3[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][CH:31]=3)(=[O:29])=[O:28])[CH2:25]2)[CH2:21][CH2:20]1)S(C1C=CC=CC=1[N+]([O-])=O)(=O)=O.N12CCCN=C1CCCCC2.C([O-])(O)=O.[Na+]>CN(C)C=O>[CH3:5][NH:6][C@@H:19]1[C@@H:26]2[C@@H:22]([CH2:23][N:24]([S:27]([C:30]3[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:37])[F:38])=[CH:32][CH:31]=3)(=[O:29])=[O:28])[CH2:25]2)[CH2:21][CH2:20]1
Reactant: CN([C@H]1CC[C@@H]2CN(S(=O)(=O)c3ccc(C(F)(F)F)cc3)C[C@@H]21)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Agent: O=C([O-])O
Agent: OCCS
Agent: [Na+]
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: CN[C@H]1CC[C@@H]2CN(S(=O)(=O)c3ccc(C(F)(F)F)cc3)C[C@@H]21
Reaction time: 0.5 h

Procedure:
2-Mercaptoethanol (0.056 mL, 0.793 mmol) was added dropwise to a mixture of N-methyl-2-nitro-N-((3aR,4S,6aS)-2-(4-(trifluoromethyl)phenylsulfonyl)octahydrocyclopenta[c]pyrrol-4-yl)benzenesulfonamide (235 mg, 0.440 mmol) from Example 300 and 1,8-diazabicyclo[5.4.0]undec-7-ene (0.166 mL, 1.101 mmol) in N,N-dimethylformamide (1 mL) at room temperature. The reaction mixture was stirred for 30 minutes, and 1 N NaHCO3 solution was added, The mixture was extracted with dichloromethane, and the separated the organic layer was concentrated. The resultant crude material was purified using a SF15-12g cartridge (Analogix®, Burlington, Wis.) with a gradient of 0-5.5% methanol (2 N NH3)/dichloromethane over 20 minutes to give the title compound: 1H NMR (500 MHz, pyridine-d5) δ ppm 8.17 (d, J=8.1, 2H), 7.94 (d, J=8.2, 2H), 4.93-4.86 (m, 1H), 3.34 (dd, J=9.8, 3.3, 1H), 3.14 (dd, J=9.7, 3.2, 1H), 3.06 (dd, J=9.7, 8.2, 1H), 2.65 (q, J=5.7, 1H), 2.57-2.46 (m, 1H), 2.29 (s, 3H), 2.25 (ddd, J=8.6, 5.0, 2.5, 1H), 1.86 (ddd, J=12.0, 8.6, 6.1, 1H), 1.80-1.72 (m, 1H), 1.61-1.32 (m, 1H), 1.32-1.19 (m, 2H); MS (ESI+) m/z 349 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH2:5][OH:6].[H-].[Na+].[CH3:13][N:14]([CH3:30])[S:15]([NH:18][C:19](=[O:29])[C:20]1[CH:25]=[C:24]([F:26])[C:23](F)=[CH:22][C:21]=1[F:28])(=[O:17])=[O:16]>O1CCCC1.CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH2:5][O:6][C:23]1[C:24]([F:26])=[CH:25][C:20]([C:19]([NH:18][S:15]([N:14]([CH3:30])[CH3:13])(=[O:17])=[O:16])=[O:29])=[C:21]([F:28])[CH:22]=1
Reactant: CN(C)S(=O)(=O)NC(=O)c1cc(F)c(F)cc1F
Reactant: OCc1ccc(Cl)c(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: CN(C)S(=O)(=O)NC(=O)c1cc(F)c(OCc2ccc(Cl)c(Cl)c2)cc1F
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 36 %

Procedure:
To a solution of 3,4-dichlorobenzyl alcohol (157 mg, 0.884 mmol) in tetrahydrofuran (3 mL) was added sodium hydride (60% dispersion in oil, 37 mg, 0.92 mmol). The reaction was stirred at room temperature for 45 minutes and heated to 55° C. for 30 minutes. The reaction mixture was cooled to room temperature and concentrated in vacuo. To the residue was added a solution of N-[(dimethylamino)sulfonyl]-2,4,5-trifluorobenzamide (Preparation 3, 100 mg, 0.354 mmol) in dimethyl sulfoxide (2 mL). The reaction mixture was stirred at room temperature for 3 hours and then partitioned between aqueous 2M hydrochloric acid (5 mL) and ethyl acetate (10 mL). The organic phase was separated and washed with a saturated aqueous solution of sodium chloride (10 mL), dried over magnesium sulfate, filtered and concentrated in vacuo. The crude material was triturated with diethyl ether, filtered and dried in vacuo to afford the title compound as a white solid (56 mg, 29%).
Reaction SMILES: [CH:1]1([CH2:7][NH2:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.F[C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17](=[O:19])[CH3:18])=[CH:12][C:11]=1[N+:20]([O-:22])=[O:21].C(=O)([O-])[O-].[Na+].[Na+]>CCO.O>[CH:1]1([CH2:7][NH:8][C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17](=[O:19])[CH3:18])=[CH:12][C:11]=2[N+:20]([O-:22])=[O:21])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(=O)Nc1ccc(F)c([N+](=O)[O-])c1
Reactant: NCC1CCCCC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC(=O)Nc1ccc(NCC2CCCCC2)c([N+](=O)[O-])c1
Temperature: 60 °C
Yield: 113.3 %

Procedure:
Cyclohexylmethylamine (2.86 mL, 2.49 g, 22.0 mmol) was added to a mixture of N-(4-fluoro-3-nitrophenyl)acetamide (3.96 g, 20.0 mmol) and sodium carbonate (4.66 g, 44 mmol) in EtOH (50 mL) at room temperature. The reaction mixture was heated for 48 h at 60° C., and diluted with H2O (800 mL). The orange solid was precipitated out and collected to give the desired product (6.60 g, 100%). MS (ESI) (M+H)+: 292.32.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[NH:9][CH:8]=2)[CH2:3][CH2:2]1.Cl[C:17]([O:19][CH2:20][CH3:21])=[O:18].O>ClCCl>[CH2:20]([O:19][C:17]([N:1]1[CH2:6][CH2:5][CH:4]([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[NH:9][CH:8]=2)[CH2:3][CH2:2]1)=[O:18])[CH3:21]
Reactant: CCOC(=O)Cl
Reactant: c1ccc2c(C3CCNCC3)c[nH]c2c1
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)N1CCC(c2c[nH]c3ccccc23)CC1
Reaction time: 2 h

Procedure:
To a suspension of 30 g (0.15 mol) of 3-piperidin-4-yl-1H-indole and 28 mL (0.2 mol) in 185 mL of anhydrous dichloromethane, 17 mL (0.18 mol) of ethyl chloroformate was added dropwise keeping the temperature of the reaction below 20° C. After 2 h at room temperature, the crude mixture was poured into 100 mL of water. The organic layer was separated and dried with sodium sulfate. After filtration, the solvent was removed under reduced pressure affording 39 g (95% of yield) of the expected product.
Reaction SMILES: [CH2:1]([SH:3])[CH3:2].[CH2:4]([CH:9]1[CH2:14][CH2:13][CH:12]([CH:15]2[CH2:20][CH2:19][C:18]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])(O)[CH2:17][CH2:16]2)[CH2:11][CH2:10]1)[CH2:5][CH2:6][CH2:7][CH3:8].C(OC(=O)C)(=O)C.Cl(O)(=O)(=O)=O.[Cl-].[Na+]>C(O)(=O)C>[CH2:4]([CH:9]1[CH2:14][CH2:13][CH:12]([CH:15]2[CH2:20][CH2:19][C:18]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])([S:3][CH2:1][CH3:2])[CH2:17][CH2:16]2)[CH2:11][CH2:10]1)[CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCS
Reactant: CCCCCCCC1(O)CCC(C2CCC(CCCCC)CC2)CC1
Agent: [Cl-]
Agent: [Na+]
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: CCCCCCCC1(SCC)CCC(C2CCC(CCCCC)CC2)CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
7.2 g of ethanethiol and 35 g of 4-pentyl-4'heptyl-4'-hydroxybicyclohexane in 70 ml of glacial acetic acid are added dropwise to a mixture of 30 ml of glacial acetic acid, 11.1 g of acetic anhydride and 7 g of 72% aqueous perchloric acid solution at -20°. The mixture is stirred at room temperature for 24 hours, poured into 250 ml of saturated sodium chloride solution, extracted with petroleum ether and worked up in the customary manner. 4-Pentyl-4'-heptyl-4'-ethylthiobicyclohexane is obtained.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[P:8](Cl)([Cl:10])[Cl:9]>C(N(CC)CC)C>[O:7]([P:8]([Cl:10])[Cl:9])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: ClP(Cl)Cl
Reactant: Oc1ccccc1
Solvent: CCN(CC)CC
Product: ClP(Cl)Oc1ccccc1

Procedure:
Further starting compounds HalPnR1R2 and HalPnR3R4 are obtainable by stepwise synthesis. Thus, for example, reaction of phenol with phosphorus trichloride in the presence of a tertiary amine, e.g. triethylamine, produces phenoxyphosphorus dichloride which can be reacted with one equivalent of the appropriate pyrrole compound, e.g. pyrrole, in the presence of a tertiary amine to give phenoxypyrrolylphosphorus chloride.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][CH:9]([OH:12])[CH2:8][CH2:7]1)=[O:5])[CH3:2].N1C=CN=C1.[Si:18](Cl)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19].C(OCC)C>CN(C)C=O>[CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][CH:9]([O:12][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19])[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1CCC(O)CC1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CCOC(=O)C1CCC(O[Si](C)(C)C(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 4-hydroxy-cyclohexanecarboxylic acid ethyl ester (10.32 g, 59.92 mmol) in dimethylformamide (50 mL) was added imidazole (8.16 g, 119.8 mmol), followed by tert-butyldimethylsilyl chloride (9.94 g, 65.9 mmol). The resulting mixture was stirred at room temperature for 16 hours. Diethyl ether was added (150 mL), and the mixture was washed with 1M HCl (150 mL). The aqueous layer was extracted with diethyl ether (150 mL). The combined organic layers were washed with 1M HCl (100 mL) and saturated sodium chloride solution (100 mL), dried over magnesium sulfate, filtered and concentrated to afford a clear oil. MS (CI) m/z 287 (M+1)+