Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[C:25]([O:29][C:30]([NH:32][C:33]1([C:48](O)=[O:49])[CH2:38][CH2:37][N:36]([C:39]2[C:40]3[CH:47]=[CH:46][NH:45][C:41]=3[N:42]=[CH:43][N:44]=2)[CH2:35][CH2:34]1)=[O:31])([CH3:28])([CH3:27])[CH3:26].C(N(CC)C(C)C)(C)C.[NH2:60][CH:61]([C:68]1[CH:73]=[CH:72][C:71]([Cl:74])=[CH:70][CH:69]=1)[CH2:62][CH2:63][S:64]([NH2:67])(=[O:66])=[O:65]>CN1C(=O)CCC1.CO>[Cl:74][C:71]1[CH:70]=[CH:69][C:68]([CH:61]([NH:60][C:48]([C:33]2([NH:32][C:30](=[O:31])[O:29][C:25]([CH3:28])([CH3:26])[CH3:27])[CH2:34][CH2:35][N:36]([C:39]3[C:40]4[CH:47]=[CH:46][NH:45][C:41]=4[N:42]=[CH:43][N:44]=3)[CH2:37][CH2:38]2)=[O:49])[CH2:62][CH2:63][S:64](=[O:65])(=[O:66])[NH2:67])=[CH:73][CH:72]=1
Reactant: CC(C)(C)OC(=O)NC1(C(=O)O)CCN(c2ncnc3[nH]ccc23)CC1
Reactant: NC(CCS(N)(=O)=O)c1ccc(Cl)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: CC(C)(C)OC(=O)NC1(C(=O)NC(CCS(N)(=O)=O)c2ccc(Cl)cc2)CCN(c2ncnc3[nH]ccc23)CC1
Temperature: 50 °C
Reaction time: 0.17 h
Yield: 33.8 %

Procedure:
O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (30.9 mg, 0.08 mmol) was added to 4-(tert-butoxycarbonylamino)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxylic acid (Intermediate 1) (28 mg, 0.08 mmol) and N,N-diisopropylethylamine (0.016 mL, 0.09 mmol) in NMP (5 mL) at 22° C. The resulting suspension was stirred at 50° C. for 10 minutes. The mixture was cooled to ambient temperature and 3-amino-3-(4-chlorophenyl)propane-1-sulfonamide (Intermediate 104) (19.27 mg, 0.08 mmol) was added as a solution in NMP (2 mL). The mixture was stirred at 22° C. for 3 days. The mixture was diluted with methanol and loaded onto an SCX column. The crude product was purified by ion exchange chromatography; the desired product was eluted from the column using 2M NH3/MeOH and pure fractions were evaporated to dryness. The crude product was purified by flash silica chromatography, elution gradient 2 to 6% (10:1 MeOH/conc. NH3 (aq)) in DCM. Pure fractions were evaporated to dryness to afford tert-butyl 4-(1-(4-chlorophenyl)-3-sulfamoylpropylcarbamoyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-4-ylcarbamate (16.00 mg, 34.9%) as a white solid.
Reaction SMILES: CCCCCCCCC.[N+:10]([O-:15])([N+:12]([O-])=O)=[O:11].[C:16](=[O:19])([O-:18])[O-:17].[K+:20].[K+].[Cl:22][C:23]([Cl:45])([Cl:44])[C:24]([N:26]1[CH2:33][CH:32]([N:34]=[O:35])[CH2:31][CH:30]([C:36](=[O:41])[C:37]([Cl:40])([Cl:39])[Cl:38])[NH:29]N(N=O)[NH:27]1)=[O:25].[N+]([O-])(O)=[O:47]>>[C:16](=[O:17])([O-:19])[O-:18].[K+:20].[K+:20].[Cl:22][C:23]([Cl:45])([Cl:44])[C:24]([N:26]1[CH2:33][CH:32]([N+:34]([O-:47])=[O:35])[CH2:31][CH:30]([C:36](=[O:41])[C:37]([Cl:40])([Cl:39])[Cl:38])[NH:29][N:12]([N+:10]([O-:15])=[O:11])[NH:27]1)=[O:25]
Reactant: O=NC1CC(C(=O)C(Cl)(Cl)Cl)NN(N=O)NN(C(=O)C(Cl)(Cl)Cl)C1
Reactant: O=[N+]([O-])O
Reactant: O=[N+]([O-])[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCCCCC
Product: O=C(C1CC([N+](=O)[O-])CN(C(=O)C(Cl)(Cl)Cl)NN([N+](=O)[O-])N1)C(Cl)(Cl)Cl
Temperature: 0 °C
Yield: 89 %

Procedure:
A suspension of 0.80g of 1,5-di(trichloroacetyl)-1,3,5,7-tetraazabicyclo[3.3.1.]nonane in 5ml. of liquid dinitrogen tetroxide was stirred in a closed container for 20 hours. The reaction mixture was poured into ice water and the solution was neutralized with potassium carbonate to give a solid precipitate which when recrystallized from nitromethane melted at 234°-235°; yield, 0.41 g. (43%) of 1,5-di(trichloroacetyl)-3,7-dinitrosooctahydrotetrazocine. Upon further treatment of the above precipitate with 4 ml. of 99% nitric acid at room temperature with stirring for 12 minutes, followed by quenching in 250 ml. ice and neutralization with potassium carbonate to a pH of about 8, a yield of 89% of 1,5-di(trichloroacetyl)-3,7-dinitrooctahydrotetrazocine was obtained. The melting point of the product when recrystalized from hot nitromethane was 275°-278° C. and the NMR peak was delta 6.05 (in acetone -d6). The calculated elemental analysis is 19.34% carbon, 1.62% hydrogen and 16.91% nitrogen. The analysis of the product showed 19.22% carbon, 1.56% hydrogen and 16.82% nitrogen.
Reaction SMILES: [CH2:1]([NH:7][C:8]1[CH:17]=[CH:16][C:11]2[N:12]=[C:13]([SH:15])[S:14][C:10]=2[CH:9]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[CH3:18][O:19][C:20]1[CH:21]=[C:22]([N:28]=[C:29]=[O:30])[CH:23]=[C:24]([O:26][CH3:27])[CH:25]=1>ClCCl>[CH3:27][O:26][C:24]1[CH:23]=[C:22]([NH:28][C:29](=[O:30])[N:7]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])[C:8]2[CH:17]=[CH:16][C:11]3[N:12]=[C:13]([SH:15])[S:14][C:10]=3[CH:9]=2)[CH:21]=[C:20]([O:19][CH3:18])[CH:25]=1
Reactant: CCCCCCNc1ccc2nc(S)sc2c1
Reactant: COc1cc(N=C=O)cc(OC)c1
Solvent: ClCCl
Product: CCCCCCN(C(=O)Nc1cc(OC)cc(OC)c1)c1ccc2nc(S)sc2c1
Reaction time: 8 h
Yield: 42.8 %

Procedure:
Into 50 ml round bottomed flask were added 6-(hexylamino)-1,3-benzothiazole-2-thiol (58.5 mg, 0.22 mmol), dichloromethane (10 ml) and 3,5-dimethoxyphenyl isocyanate (39.5 mg, 0.22 mmol). The reaction mixture was stirred 8 h, filtered, and the solid that was obtained was triturated with chloroform, followed with chloroform/methanol (9:1 mixture) to give 42 mg (43%) of the title compound. 1H NMR (DMSO-d6) δ=0.79 (t, 3H), 1.19 (br s, 5H), 1.40 (t, 2H), 3.28 (br s, 2H), 3.57 (t, 2H), 3.61 (s, 5H), 6.65 (d, 1H), 7.20 (d, 2H), 7.28 (d, 1H), 7.61 (d, 1H), 7.67 (s, 1H); ESIMS: m/z 444 (M−H).
Reaction SMILES: CCN(CC)CC.[C:8]([NH:11][CH:12](Br)[C:13]([NH:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])(=[O:10])[CH3:9].[CH3:24][SH:25]>C1COCC1>[C:8]([NH:11][CH:12]([S:25][CH3:24])[C:13]([NH:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])(=[O:10])[CH3:9]
Reactant: CS
Reactant: CC(=O)NC(Br)C(=O)NCc1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CSC(NC(C)=O)C(=O)NCc1ccccc1
Reaction time: 0.5 h
Yield: 27 %

Procedure:
A cooled (-78° C.) solution or Et3N (4.85 g, 48.0 mmol) in THF (20 mL) was added to a cooled (-78° C.) solution of 2-acetamido-N-benzyl-2-bromoacetamide (prepared from 2-acetamido-N-benzyl-2-ethoxyacetamide (4.00 g, 16.0 mmol) and BBr3 (1M in CH2Cl2, 20.0 mL, 20.0 mmol)) in THF (275 mL). A cooled (-78° C.) solution of excess MeSH (5-6 equiv) in THF (55 mL) was then added. The reaction mixture was stirred at this temperature (30 min) and then at room temperature (1 h). The insoluble materials were filtered and the filtrate was evaporated to dryness in vacuo. The oily residue obtained was purified by flash column chromatography on SiO2 gel (2% MeOH/CHCl3) to give 1.10 g (27%) of the desired product as a yellow orange oil. The product was purified by a second flash column chromatography on SiO2 gel (2% MeOH/CHCl3) to give 0.72 g of the pure product as a white solid.
Reaction SMILES: [Br:1][C:2]1[C:7](Cl)=[CH:6][C:5]([N:9]2[C:18]3[C:13](=[CH:14][C:15]([S:19]([O:22][C:23]4[C:28]([F:29])=[C:27]([F:30])[C:26]([F:31])=[C:25]([F:32])[C:24]=4[F:33])(=[O:21])=[O:20])=[CH:16][CH:17]=3)[CH:12]=[CH:11][C:10]2=[O:34])=[C:4]([O:35][CH3:36])[CH:3]=1.BrC1C=CC(I)=C(OC)C=1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:9]2[C:18]3[C:13](=[CH:14][C:15]([S:19]([O:22][C:23]4[C:24]([F:33])=[C:25]([F:32])[C:26]([F:31])=[C:27]([F:30])[C:28]=4[F:29])(=[O:20])=[O:21])=[CH:16][CH:17]=3)[CH:12]=[CH:11][C:10]2=[O:34])=[C:4]([O:35][CH3:36])[CH:3]=1
Reactant: COc1cc(Br)c(Cl)cc1-n1c(=O)ccc2cc(S(=O)(=O)Oc3c(F)c(F)c(F)c(F)c3F)ccc21
Agent: COc1cc(Br)ccc1I
Product: COc1cc(Br)ccc1-n1c(=O)ccc2cc(S(=O)(=O)Oc3c(F)c(F)c(F)c(F)c3F)ccc21

Procedure:
Perfluorophenyl 1-(4-bromo-2-methoxyphenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonate was synthesized in a manner similar to that described for perfluorophenyl 1-(4-bromo-5-chloro-2-methoxyphenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonate, except using 5-bromo-2-iodoanisole (Oakwood) instead of 1-bromo-2-chloro-4-iodo-5-methoxybenzene in step 1. m/z (ESI) 575.7 (M+H)+.
Reaction SMILES: [CH:1]([N-]C(C)C)(C)C.[Li+].C([Li])CCC.C(NC(C)C)(C)C.[CH3:21][N:22]([CH3:31])[CH2:23][CH2:24][C:25]1[CH:30]=[N:29][CH:28]=[CH:27][N:26]=1.CI>O1CCCC1>[CH3:31][N:22]([CH3:21])[CH2:23][CH:24]([C:25]1[CH:30]=[N:29][CH:28]=[CH:27][N:26]=1)[CH3:1]
Reactant: CC(C)[N-]C(C)C
Reactant: CN(C)CCc1cnccn1
Agent: [Li+]
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Solvent: CI
Product: CC(CN(C)C)c1cnccn1
Temperature: -30 °C
Reaction time: 0.5 h
Yield: 98.3 %

Procedure:
To 0.56 mole of lithium diisopropylamide, prepared from n-butyllithium and diisopropylamine in tetrahydrofuran, was added at -10° C. 84.6 g (0.56 mole) of β-dimethylaminoethylpyrazine in 1200 ml of tetrahydrofuran over a period of 30 minutes. The reaction mixture was stirred for additional 30 minutes. The deep red-coloured reaction mixture was cooled to -30° C. and 95.4 g (0.56 mole) of methyl iodide was added over a period of 20 minutes and the reaction mixture was stirred for three additional hours at room temperature. The mixture was poured onto ice and extracted with ether. The combined extracts were dried over sodium sulphate and the ether removed by distillation. The residue was distilled to give 91.0 g of β-dimethylamino-α-methylethylpyrazine, b.p. 90°-93° C. at 9 mm Hg.
Reaction SMILES: [CH2:1]([C:3]1[N:7]([C:8]2[N:9]=[C:10]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)[C:11]3[N:16]=[C:15]([CH2:17]O)[S:14][C:12]=3[N:13]=2)[C:6]2[CH:25]=[CH:26][CH:27]=[CH:28][C:5]=2[N:4]=1)[CH3:2].P(Br)(Br)[Br:30]>C(Cl)Cl>[Br:30][CH2:17][C:15]1[S:14][C:12]2[N:13]=[C:8]([N:7]3[C:6]4[CH:25]=[CH:26][CH:27]=[CH:28][C:5]=4[N:4]=[C:3]3[CH2:1][CH3:2])[N:9]=[C:10]([N:19]3[CH2:20][CH2:21][O:22][CH2:23][CH2:24]3)[C:11]=2[N:16]=1
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CO)sc2n1
Reactant: BrP(Br)Br
Solvent: ClCCl
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CBr)sc2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 49.3 %

Procedure:
To a suspension of [5-(2-ethylbenzoimidazol-1-yl)-7-morpholin-4-ylthiazolo[5,4-d]pyrimidin-2-yl]methanol (1.18 g, 2.97 mmol) in DCM (60 mL) was added PBr3 (3.36 mL, 3.36 mmol, 1M solution in DCM) and the resulting mixture allowed to stir at r.t. for 1 h. The reaction mixture was diluted with DCM and the organic phase washed with H2O and brine, then dried (MgSO4) and concentrated in vacuo affording the title compound as a yellow solid (673 mg, 49%). LCMS (method H): RT 3.24 min, [M+H]+ 459.1 and 461.1 (1:1)
Reaction SMILES: NC1C2C(=CC(OC)=C(OC)C=2)N=C([NH:16][CH2:17][CH2:18][NH:19][S:20]([C:23]2[CH:28]=[CH:27][C:26]([C:29]([CH3:32])([CH3:31])[CH3:30])=[CH:25][CH:24]=2)(=[O:22])=[O:21])N=1.C(N)CN.C(C1C=CC=CC=1S(Cl)(=O)=O)(C)(C)C>CO>[NH2:16][CH2:17][CH2:18][NH:19][S:20]([C:23]1[CH:28]=[CH:27][C:26]([C:29]([CH3:32])([CH3:31])[CH3:30])=[CH:25][CH:24]=1)(=[O:22])=[O:21]
Reactant: COc1cc2nc(NCCNS(=O)(=O)c3ccc(C(C)(C)C)cc3)nc(N)c2cc1OC
Agent: CC(C)(C)c1ccccc1S(=O)(=O)Cl
Solvent: CO
Solvent: NCCN
Product: CC(C)(C)c1ccc(S(=O)(=O)NCCN)cc1
Reaction time: 3 h

Procedure:
General Procedure for the Synthesis of Sulfonamides (Scheme 3). N-[2-(4-Amino-6,7-dimethoxy-quinazolin-2-ylamino)-ethyl]-4-tert-butyl-benzene sulfonamide (41): A mixture of ethylenediamine (0.36 g, 6.0 mmol) and t-butylbenzenesulfonyl chloride (0.464 g, 2.0 mmol) in methanol (15 mL) was stirred for 3 h, concentrated, and purified by silica gel chromatography to yield N-(2-amino-ethyl)-4-t-butyl-benzenesulfonamide. Following the procedure for the synthesis of compound 14, compound 42 was obtained. 1HNMR (DMSO-d6) δ 1.17 (s, 9H), 3.11 (s, 2H), 3.48 (s, 2H), 3.86 (s, 3H), 3.93 (s, 3H), 6.90 (s, 1H), 7.50 (d, J=8.4 Hz, 2H), 7.55 (s, 1H), 7.70 (d, J=8.4 Hz, 2H). HRMS (M+H)+ calcd for C22H30N5O4S 460.2013, found 460.2010. Anal. (C22H29N5O4S.HCl) C, H, N.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:13]([OH:15])=[O:14])=[CH:4][CH:5]=[C:6]2[C:11]=1[S:10][CH2:9][CH2:8][C:7]2=[O:12].OO.[OH2:18].C(O)(=[O:21])C>[O-][W]([O-])(=O)=O.[Na+].[Na+]>[CH3:1][C:2]1[C:3]([C:13]([OH:15])=[O:14])=[CH:4][CH:5]=[C:6]2[C:11]=1[S:10](=[O:21])(=[O:18])[CH2:9][CH2:8][C:7]2=[O:12]
Reactant: CC(=O)O
Reactant: O
Reactant: Cc1c(C(=O)O)ccc2c1SCCC2=O
Agent: O=[W](=O)([O-])[O-]
Agent: OO
Agent: [Na+]
Product: Cc1c(C(=O)O)ccc2c1S(=O)(=O)CCC2=O
Reaction time: 1 h

Procedure:
20 g (0.09 mol) of 8-methylthiochroman-4-one-7-carboxylic acid are dissolved in 100 ml of acetic acid. One spatula-tip full of sodium tungstate is added. 24.9 g (0.22 mol) of 30% strength hydrogen peroxide solution are then added dropwise at 50° C. Stirring is continued for one hour at RT. The reaction solution is then poured into water, during which process a precipitate is formed, which is filtered off with suction. The product is washed with water and then dried.
Reaction SMILES: [H][H].[N+:3]([C:6]1[CH:7]=[C:8]([C:23]([O:25][CH3:26])=[O:24])[C:9]2[CH2:10][N:11]([CH:16]([CH2:20][CH2:21][CH3:22])[CH2:17][CH2:18][CH3:19])[C:12](=[O:15])[C:13]=2[CH:14]=1)([O-])=O>CO.[Pd]>[NH2:3][C:6]1[CH:7]=[C:8]([C:23]([O:25][CH3:26])=[O:24])[C:9]2[CH2:10][N:11]([CH:16]([CH2:20][CH2:21][CH3:22])[CH2:17][CH2:18][CH3:19])[C:12](=[O:15])[C:13]=2[CH:14]=1
Reactant: CCCC(CCC)N1Cc2c(C(=O)OC)cc([N+](=O)[O-])cc2C1=O
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CCCC(CCC)N1Cc2c(C(=O)OC)cc(N)cc2C1=O
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 75.9 %

Procedure:
In an autoclave, 1.52 g of methyl 6-nitro-1-oxo-2-(1-propylbutyl)isoindoline-4-carboxylate are dissolved in 15 cm3 of methanol. 100 mg of 5% palladium-on-carbon in suspension in 1 cm3 of methanol are added. The autoclave is placed under 2 bar of hydrogen pressure and the mixture is stirred for 5 min at a temperature in the vicinity of 25° C. The reaction medium is filtered through a celite pellet. The celite is rinsed using 2×10 cm3 of methanol, then the organic phase is concentrated using a rotary evaporator under reduced pressure (5 kPa). The residual yellow oil is purified by column chromatography (silica 60 column—particle size 15-40 μm—150 g—eluent: 60% cyclohexane/40% ethyl acetate). The fractions are concentrated under reduced pressure (5 kPa). 1.05 g of methyl 6-amino-1-oxo-2-(1-propylbutyl)isoindoline-4-carboxylate are obtained in the form of a pale yellow solid.
Reaction SMILES: C(NC1C=C(C(OCC)=O)C(C2[C:12]([C:17]3[CH:22]=[C:21]([C:23](F)(F)F)[CH:20]=[CH:19][C:18]=3[O:27][CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[CH:13]C=CC=2)=CC=1)(=O)C.C1(COC2C=CC=CC=2C2C=CC=CC=2B(O)O)C=CC=CC=1.Br[C:64]1[CH:69]=CC=C[C:65]=1[C:70]1[C:71]([C:77]([O:79][CH2:80][CH3:81])=[O:78])=[CH:72][C:73]([CH3:76])=[CH:74][CH:75]=1>>[CH3:76][C:73]1[CH:72]=[C:71]([C:77]([O:79][CH2:80][CH3:81])=[O:78])[C:70]([C:65]2[C:22]([C:17]3[CH:12]=[CH:13][CH:20]=[CH:19][C:18]=3[O:27][CH2:28][C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)=[CH:21][CH:23]=[CH:69][CH:64]=2)=[CH:75][CH:74]=1
Reactant: CCOC(=O)c1cc(NC(C)=O)ccc1-c1ccccc1-c1cc(C(F)(F)F)ccc1OCc1ccccc1
Reactant: CCOC(=O)c1cc(C)ccc1-c1ccccc1Br
Agent: OB(O)c1ccccc1-c1ccccc1OCc1ccccc1
Product: CCOC(=O)c1cc(C)ccc1-c1ccccc1-c1ccccc1OCc1ccccc1

Procedure:
Prepared in a similar way to ethyl 4-(acetylamino)-2″-[(phenylmethyl)oxy]-5″-(trifluoromethyl)-1,1′:2′,1″-terphenyl-2-carboxylate but using {2′-[(phenylmethyl)oxy]-2-biphenylyl}boronic acid instead of [2-[(phenylmethyl)oxy]-5-(trifluoromethyl)phenyl]boronic acid and ethyl 2′-bromo-4-methyl-2-biphenylcarboxylate instead of ethyl 4-(acetylamino)-2′-bromo-2-biphenylcarboxylate. LC/MS t=4.11, [MH+] 423.1
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:15][CH2:14][CH2:13][C@H:9]1[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N:16]1([C:21]2[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][C:22]=2[CH2:31][NH2:32])[CH:20]=[N:19][N:18]=[N:17]1.C(Cl)CCl.C1C=NC2N(O)N=NC=2C=1>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:15][CH2:14][CH2:13][C@H:9]1[C:10]([NH:32][CH2:31][C:22]1[CH:23]=[C:24]([C:27]([F:28])([F:29])[F:30])[CH:25]=[CH:26][C:21]=1[N:16]1[CH:20]=[N:19][N:18]=[N:17]1)=[O:12])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: NCc1cc(C(F)(F)F)ccc1-n1cnnn1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)NCc1cc(C(F)(F)F)ccc1-n1cnnn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 1-(tert-butoxycarbonyl)-L-proline (39 mg, 0.18 mmol), 1-[2-(1H-tetraazol-1-yl)-5-(trifluoromethyl)phenyl]methanamine (42 mg, 0.17 mmol), EDC (49 mg, 0.26 mmol) and HOAt (12 mg, 0.09 mmol) in DMF (1 mL) was stirred at room temperature for 2 h. The crude product was purified by reverse phase HPLC followed by neutralization of an aqueous slurry of the compound with saturated aqueous K2CO3 and repeated extraction of the resulting aqueous mixture with EtOAc (the aqueous layer was saturated with NaCl before each extraction). The combined organic extracts were dried (anhydrous Na2SO4) and concentrated to afford the title compound as an oil which was carried on directly to the deprotection step (Step D below). LCMS (M+H): 441.2.
Reaction SMILES: Cl.[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C@H:19]4[CH2:24][CH2:23][C@H:22]([NH2:25])[CH2:21][CH2:20]4)[CH2:13][CH2:12]3)[C:5]=2[O:4][CH2:3]1.C(N(CC)C(C)C)(C)C.[CH3:35][S:36](Cl)(=[O:38])=[O:37].C([O-])(O)=O.[Na+]>ClCCl>[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C@H:19]4[CH2:20][CH2:21][C@H:22]([NH:25][S:36]([CH3:35])(=[O:38])=[O:37])[CH2:23][CH2:24]4)[CH2:13][CH2:12]3)[C:5]=2[O:4][CH2:3]1
Reactant: N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3OCO4)CC2)CC1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CS(=O)(=O)N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3OCO4)CC2)CC1
Temperature: 25 °C

Procedure:
To a stirred mixture of Trans-4-[2-(4-Benzo[1,3]dioxol-4-yl-piperidin-1-yl)-ethyl]-cyclohexylamine hydrochloride (intermediate A) (30 mg, 0.0818 mmol, Eq: 1.00) in dichloromethane (500 μl) was added at room temperature N,N-diisopropylethylamine (31.6 mg, 42.7 μl, 245 μmol, Eq: 3) and methanesulfonyl chloride (14.1 mg, 123 μmol). The mixture was allowed to stir at room temperature over night. The crude reaction diluted with 5 mL sat NaHCO3 and extracted with DCM (2×10 mL). The organic layers were dried over MgSO4 and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 10 g, 0% to 10% MeOH in DCM) to yield the title compound as an white solid (16.2 mg, 48.5%), MS (ISP) m/z=409.3 [(M+H)+].
Reaction SMILES: [OH:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([C:10](=[O:12])[CH3:11])=[CH:4][C:3]=1[O:13][CH3:14].[NH:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17]([CH:24]=O)=[CH:16]1.N1CCCCC1>C(O)C>[OH:1][C:2]1[C:3]([O:13][CH3:14])=[CH:4][C:5]([C:10](=[O:12])/[CH:11]=[CH:24]/[C:17]2[C:18]3[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=3)[NH:15][CH:16]=2)=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: O=Cc1c[nH]c2ccccc12
Reactant: COc1cc(C(C)=O)cc(OC)c1O
Solvent: CCO
Solvent: C1CCNCC1
Product: COc1cc(C(=O)/C=C/c2c[nH]c3ccccc23)cc(OC)c1O
Yield: 19.2 %

Procedure:
4'-Hydroxy-3',5'-dimethoxyacetophenone (1.96 g) and indole-3-carboxaldehyde (1.45 g) were dissolved in ethanol (20 ml), and piperidine (0.85 g) was added thereto, followed by heating under reflux for 32 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography. The obtained crude crystals were recrystallized from ethyl acetate to give Compound 70 (0.62 g).
Reaction SMILES: [CH3:1][C:2]1[CH:7]2[C:8]([CH3:10])(C)[CH:5]([CH2:6]2)[CH2:4][CH:3]=1.[C:11]1(O)C=CC=CC=1.C1(=O)OC(=O)C=C1.C=O>>[CH2:10]1[CH:8]2[CH:5]3[CH:4]=[CH:3][CH:2]([CH:7]2[CH:6]=[CH:11]1)[CH2:1]3
Reactant: CC1=CCC2CC1C2(C)C
Reactant: Oc1ccccc1
Agent: C=O
Agent: O=C1C=CC(=O)O1
Product: C1=CC2C3C=CC(C3)C2C1
Temperature: 120 °C
Yield: 2044.7 %

Procedure:
1350 g of dicyclopentadiene are polymerized in the presence of 150 g of α-pinene at 230° C under a pressure of 4 atmospheres. A semisolid, yellow paste is obtained. 100 g of this product and 47 g of phenol are heated to 120° C. Simultaneously 15 g of maleic anhydride and 4 g of paraformaldehyde are added. After maintaining the mixture for 30 minutes at 120° C heating takes place for 6 hours to 220° C, the pressure being reduced for the last 30 minutes of the reaction. 145 g (=87.5%) of a yellow resin having a melting point of 76° to 78° C and a viscosity of 70 cP are obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[C:15]([O:19][CH2:20][CH3:21])(=[O:18])[C:16]#[CH:17]>O1CCCC1.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>[CH2:20]([O:19][C:15](=[O:18])[C:16]#[C:17][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)[CH3:21]
Reactant: C#CC(=O)OCC
Reactant: Clc1ccc(I)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Product: CCOC(=O)C#Cc1ccc(Cl)cc1
Temperature: 35 °C
Reaction time: 41 h

Procedure:
A mixture of 1-chloro-4-iodobenzene (120.4 g, 0.50 mol) and cesium carbonate (352.8 g, 1.0 mol) in tetrahydrofuran (1.275 L) was evaporated and flushed with argon. Then cuprous iodide (3.81 g, 20.0 mmol) and bis(triphenylphosphine)palladium(II) chloride (7.02 g, 10.0 mmol) were added and then ethyl propiolate (100 g, 1.01 mol) was added dropwise over a period of 20 min. The resulting dark brown suspension was stirred for 41 h at 35° C., then filtrated over Hyflo® and washed with THF (5 L). The solution was concentrated and treated with toluene/heptane 1:2 (1.5 L) and stirred for 1 h at 45° C. under reduced pressure (250 mbar). The resulting suspension was filtered and the residue was washed with further toluene/heptane 1:2 (1.5 L). The solid was dried affording 181.64 g (MS m/e: 209.0/211.2 [M+H]+) of a dark brown oil as crude product which was used without further purification.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([CH2:11][C:12]#[N:13])[CH:7]=[CH:8][C:9]=1[Cl:10].Br[CH2:15][CH2:16][CH:17]=[CH2:18].O>CN(C)C=O>[Cl:3][C:4]1[CH:5]=[C:6]([CH:11]([CH2:18][CH2:17][CH:16]=[CH2:15])[C:12]#[N:13])[CH:7]=[CH:8][C:9]=1[Cl:10]
Reactant: N#CCc1ccc(Cl)c(Cl)c1
Reactant: C=CCCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C=CCCC(C#N)c1ccc(Cl)c(Cl)c1
Temperature: 60 °C
Reaction time: 3 h
Yield: 21.4 %

Procedure:
To a solution of sodium hydride (14.8 g, 60% dispersion in mineral oil) in dimethylformamide (DMF, 150 ml) at 0° C. under nitrogen was added a solution of 3,4-dichlorophenylacetonitrile (68.9 g, 1 mol. equivalent) in DMF (300 ml) and the mixture was stirred for 3 hours. A solution of 4-bromobut-1-ene (50 g, 1 mol. eq.) in DMF (100 ml) was then added, and the mixture was stirred at room temperature for one hour, then heated to 60° C. for 5 hours. The reaction mixture was cooled and water (1 liter) was added. The mixture was then extracted with ethyl acetate (2×500 ml). The combined organic extracts were then washed with water (2×1 liter), dried over MgSO4 and the solvent was removed under reduced pressure. The residue was then purified by column chromatography using silica gel, eluting with a solvent gradient of ethyl acetate:hexane (1:19 to 1:6, by volume) to give the title compound (51.5 g).