Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:16])[CH2:13][CH2:14][CH3:15])=[C:5]2[NH:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][N:25]([CH3:27])[CH3:26])=[CH:20][CH:19]=1.[Cl:28][C:29]1[CH:34]=[C:33](B2OC(C)(C)C(C)(C)O2)[CH:32]=[C:31]([Cl:44])[C:30]=1[OH:45]>>[Cl:28][C:29]1[CH:34]=[C:33]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][C:6]([C:12](=[O:16])[CH2:13][CH2:14][CH3:15])=[C:5]3[NH:17][C:18]2[CH:23]=[CH:22][C:21]([CH2:24][N:25]([CH3:26])[CH3:27])=[CH:20][CH:19]=2)[CH:32]=[C:31]([Cl:44])[C:30]=1[OH:45]
Reactant: CCCC(=O)c1cnc2ccc(Br)cc2c1Nc1ccc(CN(C)C)cc1
Reactant: CC1(C)OB(c2cc(Cl)c(O)c(Cl)c2)OC1(C)C
Product: CCCC(=O)c1cnc2ccc(-c3cc(Cl)c(O)c(Cl)c3)cc2c1Nc1ccc(CN(C)C)cc1
Yield: 42.9 %

Procedure:
Following general procedure D, 1-(6-bromo-4-((4-((dimethylamino)methyl)phenyl)amino)quinolin-3-yl)butan-1-one (43 mg, 0.10 mmol) was reacted with 2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (47 mg, 0.16 mmol) to afford the desired product (21.8 mg, 43%) as a yellow solid. 1H NMR (500 MHz, MeOD) δ 9.12 (s, 1H), 7.97-7.87 (m, 2H), 7.73 (d, J=1.8 Hz, 1H), 7.46-7.39 (m, 2H), 7.26-7.19 (m, 2H), 7.10 (s, 2H), 3.80 (s, 2H), 3.17 (t, J=7.3 Hz, 2H), 2.39 (s, 6H), 1.81 (h, J=7.4 Hz, 2H), 1.05 (t, J=7.4 Hz, 3H). ESI MS m/z 508 [C28H27Cl2N3O2+H]+; HPLC 99% (AUC), tR=11.22 min.
Reaction SMILES: O1CCCC1.[C:6]([C:10]1[CH:15]=[CH:14][C:13]([CH:16]=[O:17])=[CH:12][C:11]=1[NH:18][C:19](=[O:35])[CH2:20][CH:21]1[C:34]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[O:28][C:27]2[C:22]1=[CH:23][CH:24]=[CH:25][CH:26]=2)([CH3:9])([CH3:8])[CH3:7].[CH:36]1([CH2:42][Mg]Br)[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1>C(OCC)C>[C:6]([C:10]1[CH:15]=[CH:14][C:13]([CH:16]([OH:17])[CH2:42][CH:36]2[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]2)=[CH:12][C:11]=1[NH:18][C:19](=[O:35])[CH2:20][CH:21]1[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:27]=2[O:28][C:29]2[C:34]1=[CH:33][CH:32]=[CH:31][CH:30]=2)([CH3:9])([CH3:7])[CH3:8]
Reactant: CC(C)(C)c1ccc(C=O)cc1NC(=O)CC1c2ccccc2Oc2ccccc21
Reactant: Br[Mg]CC1CCCCC1
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)(C)c1ccc(C(O)CC2CCCCC2)cc1NC(=O)CC1c2ccccc2Oc2ccccc21
Reaction time: 0.33 h
Yield: 76 %

Procedure:
8 ml of a tetrahydrofuran solution containing 100 mg (0.25 mmol) of N-(2-t-butyl-5-formylphenyl)-2-(9H-xanthen-9-yl)acetamide (prepared as described in Preparation 15) were cooled in an ice bath. 0.38 ml (0.38 mmol) of a 1M solution of cyclohexylmethylmagnesium bromide in diethyl ether was then added dropwise to the solution. The resulting mixture was stirred for 20 minutes at this temperature. It was then diluted with diethyl ether, and washed with dilute aqueous hydrochloric acid and then with water. The solvent was then removed by distillation under reduced pressure. The resulting residue was subjected to column chromatography through 20 g of silica gel. Elution with mixtures of methylene chloride and ethyl acetate ranging from 7:1 to 2:1 by volume afforded 95 mg (yield 76%) of the title compound as a foam-like substance.
Reaction SMILES: [NH2:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([C:9](=[O:25])[CH2:10][CH2:11][CH:12]2[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][CH2:13]2)=[C:4]([O:26][CH3:27])[CH:3]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([C:9](=[O:25])[CH2:10][CH2:11][CH:12]2[CH2:13][CH2:14][NH:15][CH2:16][CH2:17]2)=[C:4]([O:26][CH3:27])[CH:3]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)CCC1CCN(C(=O)OC(C)(C)C)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(N)c(Cl)cc1C(=O)CCC1CCNCC1
Yield: 100 %

Procedure:
1-(4-Amino-5-chloro-2-methoxyphenyl)-3-[1-(tert-butoxycarbonyl)-piperidin-4-yl]propan-1-one (1.5 g, 3.8 mmol) was dissolved in methylene chloride (20 mL) and trifluoroacetic acid (5 mL) was added to the solution. After 30 minutes the solution was washed with aqueous ammonium hydroxide, and dried over sodium sulfate. Evaporation of the solvents gave 1-(4-amino-5-chloro-2-methoxyphenyl)-3-(piperidin-4-yl)-propan-1-one (1.1 g, 3.8 mmol), m.p. 138°-140° C.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[CH:10]=[CH:9][N:8]([C:11]3[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:13][CH:12]=3)[C:6]=2[N:7]=1.[CH2:21]([O:23][C:24]1[CH:25]=[C:26]([CH:28]=[CH:29][C:30]=1[O:31][CH2:32][CH3:33])[NH2:27])[CH3:22].Cl>C(O)CCC>[CH2:21]([O:23][C:24]1[CH:25]=[C:26]([NH:27][C:2]2[N:3]=[CH:4][C:5]3[CH:10]=[CH:9][N:8]([C:11]4[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:13][CH:12]=4)[C:6]=3[N:7]=2)[CH:28]=[CH:29][C:30]=1[O:31][CH2:32][CH3:33])[CH3:22]
Reactant: CS(=O)(=O)c1ccc(-n2ccc3cnc(Cl)nc32)cc1
Reactant: CCOc1ccc(N)cc1OCC
Agent: Cl
Solvent: CCCCO
Product: CCOc1ccc(Nc2ncc3ccn(-c4ccc(S(C)(=O)=O)cc4)c3n2)cc1OCC
Temperature: 140 °C

Procedure:
To a suspension of 2-chloro-7-(4-methanesulfonyl-phenyl)-7H-pyrrolo[2,3-d]pyrimidine (30.0 mg, 0.093 mmol) in BuOH (1.5 mL) is added 3,4-diethoxyaniline (41.0 mg, 0.220 mmol) and concentrated aqueous HCl (37%, 23.0 μL, 0.232 mmol). The reaction mixture is heated to 140° C. for 24 h, cooled to rt, and concentrated under reduce pressure. The residue is purified by reverse phase prep-HPLC (Waters) to afford the title compound (1) as a yellow solid. HPLC: tR=1.61 min (Method A); MS-ES: (M+H)+=453.
Reaction SMILES: [OH:1][CH2:2][C:3]1([CH2:15][OH:16])[CH2:9][CH2:8][S:7][C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[C:4]1=[O:14].C(N(CC)CC)C.[C:24]1([N:34]=[C:35]=[S:36])[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=[CH:26][CH:25]=1>O1CCCC1>[OH:16][CH2:15][C:3]1([CH2:2][O:1][C:35](=[S:36])[NH:34][C:24]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:27]=[CH:26][CH:25]=2)[CH2:9][CH2:8][S:7][C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[C:4]1=[O:14]
Reactant: S=C=Nc1cccc2ccccc12
Reactant: O=C1c2ccccc2SCCC1(CO)CO
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C1c2ccccc2SCCC1(CO)COC(=S)Nc1cccc2ccccc12

Procedure:
To a solution of 4,4-bis(hydroxymethyl)-3,4-dihydro-2H-benzo[b]thiepin-5-one (476 mg, 2.0 mmol) in 15 ml of tetrahydrofuran were added, at room temperature, triethylamine (0.31 ml, 2.2 mmol) and 1-naphthyl isothiocyanate (407 mg, 2.2 mmol). The mixture was heated to reflux for 24 hours, concentrated and purified by column chromatography on silica gel (eluent: 1:19 tert-butyl methyl ether/dichloromethane). The product was obtained in a yield of 87 mg (9%).
Reaction SMILES: [OH:1][CH:2]([CH2:23][OH:24])[CH2:3][N:4]1[C:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:11]2[C:6]([N:7]([CH3:22])[C:8](=[O:21])[N:9]([CH3:20])[C:10]2=[O:19])=[CH:5]1.N1C=CN=C1.[Si:30](Cl)([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31]>CN(C1C=CN=CC=1)C.CN(C=O)C.CCOC(C)=O>[Si:30]([O:24][CH2:23][CH:2]([OH:1])[CH2:3][N:4]1[C:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:11]2[C:6]([N:7]([CH3:22])[C:8](=[O:21])[N:9]([CH3:20])[C:10]2=[O:19])=[CH:5]1)([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Cn1c(=O)c2c(-c3ccccc3)n(CC(O)CO)cc2n(C)c1=O
Agent: CN(C)c1ccncc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cn1c(=O)c2c(-c3ccccc3)n(CC(O)CO[Si](C)(C)C(C)(C)C)cc2n(C)c1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
6-(2,3-Dihydroxypropyl)-1,3-dimethyl-5-phenyl-1H-pyrrolo[3,4-d]pyrimidine-2,4(3H,6H)-dione (step 1)(1.66 g, 5.04 mmol), imidazole (0.686 g, 10.08 mmol) and DMAP (0.062 g, 0.504 mmol) were dissolved in DMF (25 ml) and TBS-Cl (0.836 g, 5.54 mmol) was added. The resulting mixture was stirred at RT overnight. Further TBS-Cl (0.836 g, 5.54 mmol) added and stirring continued for 2 hours. The reaction mixture was diluted with EtOAc and washed with sat. NaHCO3(aq) and brine (3×). The organic phase was dried over sodium sulphate and evaporated under vacuum. The residue was redissolved in DCM and evaporated onto silica. The silica was deposited onto a 25 g silica cartridge and the system eluted with 20% EtOAc/hexane, 40% EtOAc/hexane and 60% EtOAc/hexane. The product fractions were combined and evaporated to give tacky yellow solid. This solid was triturated with Et2O/hexane to afford the title compound;
Reaction SMILES: Cl[C:2]1[NH:6][C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[N:3]=1.[CH3:11][O:12][C:13]1[C:21]2[C:16](=[N:17][CH:18]=[CH:19][CH:20]=2)[N:15]([C:22]2[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=2)[N:14]=1.C(N(CC)CC)C>CO>[NH:3]1[C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=[C:2]1[O:28][C:25]1[CH:24]=[CH:23][C:22]([N:15]2[C:16]3=[N:17][CH:18]=[CH:19][CH:20]=[C:21]3[C:13]([O:12][CH3:11])=[N:14]2)=[CH:27][CH:26]=1
Reactant: Clc1nc2ccccc2[nH]1
Reactant: COc1nn(-c2ccc(O)cc2)c2ncccc12
Solvent: CO
Solvent: CCN(CC)CC
Product: COc1nn(-c2ccc(Oc3nc4ccccc4[nH]3)cc2)c2ncccc12
Temperature: 160 °C
Reaction time: 7 h
Yield: 13.2 %

Procedure:
A mixture of 2-chloro-1H-benzimidazole (0.23 g), 4-(3-methoxy-1H-pyrazolo[3,4-b]pyridin-1-yl)phenol (0.24 g) and triethylamine (1.0 ml) was stirred under a nitrogen atmosphere at 160° C. for 7 hr. The reaction mixture was cooled to room temperature, and methanol was added to the reaction mixture. The precipitated solid was filtered off, silica gel was added to the filtrate, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate). Then, it was purified by HPLC(C18) (mobile phase: water/acetonitrile (0.1% TFA-containing eluents)) to give the title compound (0.047 g).
Reaction SMILES: [CH:1]([C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][N:4]=1)=O.[CH3:13][C:14]1[CH:15]=[C:16]([NH2:29])[CH:17]=[N:18][C:19]=1[N:20]1[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[N:21]1>C1(C)C=CC=CC=1>[CH3:13][C:14]1[CH:15]=[C:16]([N:29]=[CH:1][C:3]2[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][N:4]=2)[CH:17]=[N:18][C:19]=1[N:20]1[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[N:21]1
Reactant: COC(=O)c1ccc(C=O)nc1
Reactant: Cc1cc(N)cnc1-n1cc(C(F)(F)F)cn1
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(C=Nc2cnc(-n3cc(C(F)(F)F)cn3)c(C)c2)nc1
Yield: 100 %

Procedure:
A mixture of methyl 6-formylnicotinate (251.3 mg, 1.52 mmol) and 5-methyl-6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyridin-3-amine (369 mg, 1.52 mmol) in toluene (8 mL) was heated at reflux under nitrogen overnight. The reaction mixture was concentrated to give methyl 6-((5-methyl-6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyridin-3-ylimino)methyl)nicotinate (592 mg, 100%). 1H NMR (400 MHz, (CD3)2SO, δ): 9.09 (d, 1H), 8.83 (s, 1H), 8.72 (s, 1H), 8.35-8.30 (m, 2H), 8.20-8.17 (m, 1H), 8.11 (s, 1H), 7.90 (d, 1H), 3.79 (s, 3H), 2.32 (s, 3H).
Reaction SMILES: [N:1]1([C:7]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:8]=2[C:9]([NH2:18])=[N:10][C:11]([NH2:17])=[N:12]3)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21][C:20]=1[C:29](Cl)=[O:30]>>[NH2:17][C:11]1[N:10]=[C:9]([NH2:18])[C:8]2[C:13](=[CH:14][CH:15]=[CH:16][C:7]=2[N:1]2[CH2:6][CH2:5][N:4]([C:29]([C:20]3[CH:21]=[CH:22][C:23]4[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH:19]=3)=[O:30])[CH2:3][CH2:2]2)[N:12]=1
Reactant: O=C(Cl)c1ccc2ccccc2c1
Reactant: Nc1nc(N)c2c(N3CCNCC3)cccc2n1
Product: Nc1nc(N)c2c(N3CCN(C(=O)c4ccc5ccccc5c4)CC3)cccc2n1
Yield: 77 %

Procedure:
Title compound was prepared via Resin Method using 5-piperazin-1-yl-quinazoline-2,4-diamine (50 mg; 0.2 mmol) and 2-Naphthoyl chloride (78.2 mg; 0.41 mmol) to obtain 61.6 mg. (77% yield). 1H NMR (500 MHz, DMSO-d6) δ 9.06 (s, 1H), 8.59 (s, 1H), 8.02 (m, 8H), 7.6 (m, 5H), 7.5 (t, J=8.0 Hz, 1H), 7.09 (d, J=8.5 Hz, 1H), 6.99 (d, J=7.5 Hz, 1H), 6.67 (br s, 2H), 4.64 (br s, 1H), 3.76 (br s, 1H), 3.42 (m, 4H), 2.85 (m, 2H).
Reaction SMILES: C1C2C(CO[C:16]([N:18](C)[C@H:19]([C:23]([NH:25][C@H:26]([C:30]([N:32]([C@@H:34]([C@@H:62]([CH3:65])[CH2:63][CH3:64])[C@H:35]([O:60][CH3:61])[CH2:36][C:37]([N:39]3[CH2:43][CH2:42][CH2:41][C@H:40]3[C@H:44]([O:58][CH3:59])[C@@H:45]([CH3:57])[C:46]([NH:48][CH2:49][CH2:50][C:51]3[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=3)=[S:47])=[O:38])[CH3:33])=[O:31])[CH:27]([CH3:29])[CH3:28])=[O:24])[CH:20]([CH3:22])[CH3:21])=O)C3C(=CC=CC=3)C=2C=CC=1>ClCCl.C(NCC)C>[CH3:16][NH:18][C@H:19]([C:23]([NH:25][C@H:26]([C:30]([N:32]([C@@H:34]([C@@H:62]([CH3:65])[CH2:63][CH3:64])[C@H:35]([O:60][CH3:61])[CH2:36][C:37]([N:39]1[CH2:43][CH2:42][CH2:41][C@H:40]1[C@H:44]([O:58][CH3:59])[C@@H:45]([CH3:57])[C:46]([NH:48][CH2:49][CH2:50][C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)=[S:47])=[O:38])[CH3:33])=[O:31])[CH:27]([CH3:29])[CH3:28])=[O:24])[CH:20]([CH3:22])[CH3:21]
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=S)NCCc1ccccc1)OC)N(C)C(=O)[C@@H](NC(=O)[C@H](C(C)C)N(C)C(=O)OCC1c2ccccc2-c2ccccc21)C(C)C
Solvent: CCNCC
Solvent: ClCCl
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=S)NCCc1ccccc1)OC)N(C)C(=O)[C@@H](NC(=O)[C@@H](NC)C(C)C)C(C)C
Yield: 87.7 %

Procedure:
According to general procedure A, from #35 (465 mg, 0.502 mmol, 1 eq.) in dichloromethane (5 mL, 0.1 M) and diethylamine (5 mL) was synthesized the crude desired material, which was purified by silica gel chromatography (Gradient: 0% to 10% methanol in dichloromethane) to give #36 (310 mg, 88%) as a solid. LC-MS: m/z 704.6 [M+H+], retention time=0.74 minutes; HRMS: m/z calculated for C38H66N5O5S: 704.4779. found: 704.477 [M+H+]; 1H NMR (400 MHz, CD3OD), presumed to be a mixture of rotamers, characteristic signals: δ 7.23-7.30 (m, 4H), 7.15-7.22 (m, 1H), [4.68 (d, J=8.6 Hz) and 4.74 (d, J=8.0 Hz), total 1H], 3.39 and 3.40 (2 s, total 3H), 3.12 and 3.22 (2 br s, total 3H), [2.82 (d, J=6.0 Hz) and 2.84 (d, J=6.0 Hz), total 1H], 2.29 and 2.30 (2 s, total 3H), [1.27 (d, J=6.8 Hz) and 1.29 (d, J=6.6 Hz), total 3H], [0.84 (t, J=7.4 Hz) and 0.87 (t, J=7.4 Hz), total 3H].
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[F:6][C:7]([F:41])([F:40])[C:8]1[CH:9]=[C:10]([CH:33]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:35]=1)[C:11]([N:13]1[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][CH2:21][OH:22])[CH2:15][C@H:14]1[CH2:23][C:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[NH:26][CH:25]=1)=[O:12].C(N(CC)CC)C>ClCCl>[F:41][C:7]([F:6])([F:40])[C:8]1[CH:9]=[C:10]([CH:33]=[C:34]([C:36]([F:37])([F:38])[F:39])[CH:35]=1)[C:11]([N:13]1[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][CH2:21][O:22][S:2]([CH3:1])(=[O:4])=[O:3])[CH2:15][C@H:14]1[CH2:23][C:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[NH:26][CH:25]=1)=[O:12]
Reactant: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCN(CCCO)C[C@H]1Cc1c[nH]c2ccccc12
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCCCN1CCN(C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H](Cc2c[nH]c3ccccc23)C1
Reaction time: 1 h
Yield: 75.9 %

Procedure:
A solution of methanesulfonyl chloride (1.1 g) in dichloromethane (4 ml) was added to a stirred solution of (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-4-(3-hydroxypropyl)-2-(1H-indol-3-ylmethyl)piperazine (4.99 g) and triethylamine (1.1 g) in dichloromethane (50 ml) at ice-bath temperature over a 20-minute period. After being stirred at the same temperature for 1 hour, the reaction mixture was diluted with dichloromethane (50 ml) and then washed with water and aqueous sodium bicarbonate solution. The dichloromethane layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using dichloromethane-methanol (30:1) as an eluent to give (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(1H-indol-3-ylmethyl)-4-(3-methylsulfonyloxypropyl)piperazine (4.31 g) as a powder.
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[C:4]#[N:5].[NH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1.O>COCCO>[C:4]([C:3]1[CH:6]=[C:7]([N+:10]([O-:12])=[O:11])[CH:8]=[CH:9][C:2]=1[N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)#[N:5]
Reactant: C1CNCCN1
Reactant: N#Cc1cc([N+](=O)[O-])ccc1Cl
Solvent: COCCO
Solvent: O
Product: N#Cc1cc([N+](=O)[O-])ccc1N1CCNCC1
Temperature: 60 °C
Yield: 99.8 %

Procedure:
A mixture of 2-chloro-5-nitrobenzonitrile (1 g) and piperazine (2.12 g) in ethylene glycol monomethyl ether (5 mL) was heated at 60° C. for 30 minutes. After cooling to room temperature, H2O was added (50 mL) and the solution extracted with CH2Cl2 (3×25 mL). The combined organic layers were washed with H2O, dried over Na2SO4 and evaporated to dryness to give 1.27 g (99%) of the desired compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].Br[CH2:12][CH:13]([O:17][CH2:18][CH3:19])[O:14][CH2:15][CH3:16]>CN(C)C=O.C(OCC)(=O)C>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH2:12][CH:13]([O:17][CH2:18][CH3:19])[O:14][CH2:15][CH3:16])[CH:3]=1
Reactant: CCOC(CBr)OCC
Reactant: Oc1cccc(Br)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(COc1cccc(Br)c1)OCC
Temperature: 0 °C
Reaction time: 8 h
Yield: 94.4 %

Procedure:
Into a 3-L three neck round-bottom flask, was placed a solution of 3-bromophenol (50.00 g, 289.0 mmol) in N,N-dimethylformamide (1 L). The system was purged with nitrogen and the solution was cooled to 0° C., then sodium hydride (60%, 12.8 g, 320 mmol) was added portion-wise. To the resulting mixture was added 2-bromo-1,1-diethoxyethane (53.1 mL, 345 mmol) drop-wise at 0° C. The resulting mixture was stirred overnight at 120° C., behind a blast shield (CAUTION: NaH and DMF can become a runaway reaction. All necessary safety precautions were performed). The mixture was cooled to room temperature, then diluted with ethyl acetate (3 L). The mixture was washed with brine (4×500 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with ethyl acetate/petroleum ether (1/50-1/30) as the eluent to yield the title compound as a light yellow oil (78.9 g, 94%).
Reaction SMILES: O.NN.[C:4]([O:8][C:9]([NH:11][O:12][CH2:13][CH2:14][CH2:15][CH2:16][N:17]1C(=O)C2C(=CC=CC=2)C1=O)=[O:10])([CH3:7])([CH3:6])[CH3:5]>C(O)C>[C:4]([O:8][C:9](=[O:10])[NH:11][O:12][CH2:13][CH2:14][CH2:15][CH2:16][NH2:17])([CH3:7])([CH3:5])[CH3:6]
Reactant: CC(C)(C)OC(=O)NOCCCCN1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)NOCCCCN
Temperature: 80 °C
Reaction time: 65 h
Yield: 30.7 %

Procedure:
Hydrazine hydrate (1.0 ml, 20 mmol) was added to a solution of 2-(4-(tert-butoxycarbonylaminoxy)butyl)isoindole-1,3-dione (2.08 g, 6.22 mmol) in ethanol (8.0 ml). The reaction mixture was stirred at 80° C. for 65 h. The solvent was removed in vacuo. The residue was dissolved in toluene (10 ml) and the solvent was removed in vacuo. The residue was suspended in 1 N hydrochloric acid (10 ml). The precipitation was removed by filtration and was washed with water (2 ml). The filtrate and the wash-liquids were combined and made basic with potassium carbonate. The solution was extracted with dichloromethane (4×20 ml). The organic layer was dried over magnesium sulphate. The solvent was removed in vacuo to give 0.39 g of N-(4-aminobutoxy)carbamic acid tert-butyl ester. Potassium carbonate (3 g) was added to the aqueous phase, which was extracted with dichloromethane (3×20 ml). These combined organic layers were dried over magnesium sulphate. The solvent was removed in vacuo to give another 0.39 g of N-(4-aminobutoxy)carbamic acid tert-butyl ester.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH2:11][N:12]2[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]2)[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].[NH2:19][C:20]1[S:24][C:23]([C:25]([O:27][CH3:28])=[O:26])=[C:22]([O:29][C@@H:30]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2[C:38]([F:41])([F:40])[F:39])[CH3:31])[CH:21]=1.C([O-])([O-])=O.[K+].[K+].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>C(O)(C)(C)C>[CH3:18][N:15]1[CH2:16][CH2:17][N:12]([CH2:11][C:4]2[CH:5]=[CH:6][C:7]([N+:8]([O-:10])=[O:9])=[C:2]([NH:19][C:20]3[S:24][C:23]([C:25]([O:27][CH3:28])=[O:26])=[C:22]([O:29][C@@H:30]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=4[C:38]([F:41])([F:39])[F:40])[CH3:31])[CH:21]=3)[CH:3]=2)[CH2:13][CH2:14]1
Reactant: CN1CCN(Cc2ccc([N+](=O)[O-])c(Cl)c2)CC1
Reactant: COC(=O)c1sc(N)cc1O[C@H](C)c1ccccc1C(F)(F)F
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Product: COC(=O)c1sc(Nc2cc(CN3CCN(C)CC3)ccc2[N+](=O)[O-])cc1O[C@H](C)c1ccccc1C(F)(F)F
Temperature: 80 °C
Yield: 79.6 %

Procedure:
A mixture of 1-[(3-chloro-4-nitrophenyl)methyl]-4-methylpiperazine (0.313 g, 1.16 mmol), methyl 5-amino-3-({(1R)-1-[2-(trifluoromethyl)phenyl]ethyl}oxy)-2-thiophenecarboxylate (0.401 g, 1.16 mmol), K2CO3 (0.401 g, 2.90 mmol), X-Phos (0.0587 g, 0.12 mmol), tris(benzylideneacetone)dipalladium(0) (0.0531 g, 0.06 mmol) and tert-butanol (4.6 mL) in a sealed tube was heated at 80° C. for 18 h. The crude reaction mixture was filtered through celite, washing with toluene and then purified by flash column chromatography (EtOAc:MeOH:NEt3) to give the title compound (0.534 g, 70%) as a red amorphous solid.
Reaction SMILES: [C:1](Br)([CH3:4])([CH3:3])[CH3:2].[Mg].[CH3:7][C:8]([CH3:12])([CH3:11])[CH:9]=[O:10]>CCOCC>[C:8]([CH:9]([OH:10])[C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:12])([CH3:11])[CH3:7]
Reactant: CC(C)(C)C=O
Reactant: CC(C)(C)Br
Agent: [Mg]
Solvent: CCOCC
Product: CC(C)(C)C(O)C(C)(C)C

Procedure:
A solution of t-butyl bromide in ether is added slowly to magnesium stirrings until the Grignard reagent begins to form. The remainder of the alkyl bromide is then added and the mixture is stirred until all the magnesium dissolves. At 0° C., a solution of 2,2-dimethylpropionaldehyde is added and the resulting product is quenched with 1M HCl and extracted with ether and the solvent is evaporated to afford di-t-butylmethyl alcohol.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]1=2.C(O)(=O)C.[N+:19]([O-])([OH:21])=[O:20]>C(OC(=O)C)(=O)C>[N+:19]([CH:10]1[CH2:11][C:2]([CH3:14])([CH3:1])[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:8]=2[C:9]1([CH3:13])[CH3:12])([O-:21])=[O:20]
Reactant: O=[N+]([O-])O
Reactant: CC1(C)CCC(C)(C)c2ccccc21
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: CC1(C)CC([N+](=O)[O-])C(C)(C)c2ccccc21
Temperature: 25 °C
Yield: 97 %

Procedure:
A solution of 5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalene (20.0 g, 106.2 mmole) in 85 ml of acetic anhydride at 0° C. was treated with 12.2 mL of acetic acid followed by 11.1 mL of nitric acid (70%) and was allowed to warm to room temperature. After 24 hours the reaction mixture was poured onto 300 mL of ice-water and extracted with three 150 mL portions of ether. The combined organic extracts were washed with four 100 mL portions of 15% aqueous sodium hydroxide solution, two 200 mL portions of water and one 200 mL portion of saturated aqueous sodium chloride solution. The organic phase was dried, filtered and concentrated in vacuo to provide 23.93 g (97%) of 6-nitro-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalene (3) as a pale yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([CH:10]=[CH:11][C:12]([CH3:22])=[CH:13][CH:14]=[CH:15][C:16]([CH3:21])=[CH:17][C:18](Cl)=[O:19])=[C:5]([CH3:23])[C:4]=1[CH3:24].[CH2:25]([NH:27]CC)[CH3:26]>>[CH2:25]([NH:27][C:18](=[O:19])[CH:17]=[C:16]([CH3:21])[CH:15]=[CH:14][CH:13]=[C:12]([CH3:22])[CH:11]=[CH:10][C:6]1[C:7]([CH3:9])=[CH:8][C:3]([O:2][CH3:1])=[C:4]([CH3:24])[C:5]=1[CH3:23])[CH3:26]
Reactant: COc1cc(C)c(C=CC(C)=CC=CC(C)=CC(=O)Cl)c(C)c1C
Reactant: CCNCC
Product: CCNC(=O)C=C(C)C=CC=C(C)C=Cc1c(C)cc(OC)c(C)c1C

Procedure:
9-(4-methoxy-2,3,6-trimethyl-phenyl)-3,7-dimethyl-nona-2,4,6,8-tetraen-1-oic acid chloride and diethylamine are converted to