Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](S)=[C:4]([O:9][C:10]([F:13])([F:12])[F:11])[CH:3]=1.IC.[C:16](=O)([O-])[O-].[K+].[K+].BrC1C=CC(SC)=C(OC(F)(F)F)C=1.O[O:37][S:38]([O-:40])=O.[K+]>CC(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:38]([CH3:16])(=[O:40])=[O:37])=[C:4]([O:9][C:10]([F:13])([F:12])[F:11])[CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: O=S([O-])OO
Reactant: FC(F)(F)Oc1cc(Br)ccc1S
Agent: CSc1ccc(Br)cc1OC(F)(F)F
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: CS(=O)(=O)c1ccc(Br)cc1OC(F)(F)F
Temperature: 25 °C

Procedure:
Following the method of example 9a, reaction of 4-bromo-2-trifluoromethoxy-benzenethiol (1.0 g, 3.48 mmol) with iodomethane (0.238 mL, 3.82 mmol) and potassium carbonate (0.528 g, 3.82 mmol) in 13 mL acetone, followed by oxidation as described in example 39c, using 4-bromo-1-methylsulfanyl-2-trifluoromethoxy-benzene (0.78 g, 2.72 mmol) and oxone® (2.17 g, 3.54 mmol), stirring over night at r.t., addition of oxone® (0.84 g, 1.37 mmol), stirring over night at r.t., addition of oxone® (0.84 g, 1.37 mmol) and stirring over three days at r.t. affords the title compound without further chromatography as a white solid (0.81 g). MS (m/e): 320 (M+H).
Reaction SMILES: [CH2:1]([NH:8][C:9](=[O:15])[CH:10]([NH2:14])[CH2:11][O:12][CH3:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.[C:22](OC(=O)C)(=[O:24])[CH3:23]>C1COCC1>[CH2:1]([NH:8][C:9](=[O:15])[CH:10]([NH:14][C:22](=[O:24])[CH3:23])[CH2:11][O:12][CH3:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)OC(C)=O
Reactant: COCC(N)C(=O)NCc1ccccc1
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: COCC(NC(C)=O)C(=O)NCc1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 13 (0.20 g, 0.98 mmol) in dry THF (2.0 mL) is added pyridine (0.086 g, 1.08 mmol), and then acetic anhydride (0.2 g, 1.96 mmol) is added dropwise. The reaction is stirred at room temperature for 18 hours. The solvent is evaporated in vacuo and the residue purified by flash column chromatography to obtain the above compound as the R isomer.
Reaction SMILES: C(OCC1CSC2N(C(=O)C2NC(=O)CC2N=C(C3C=CC=CC=3O)SC=2)C=1C(O)=O)(=O)C.C1(C([O:47][C:48]([C:50]2[N:51]3[CH:54]([S:55][CH2:56][CH:57]=2)[CH:53]([NH:58][C:59](=[O:73])[CH2:60][C:61]2[N:62]=[C:63]([C:66]4[C:71]([OH:72])=[CH:70][CH:69]=[CH:68][N:67]=4)[S:64][CH:65]=2)[C:52]3=[O:74])=[O:49])C2C=CC=CC=2)C=CC=CC=1.[SiH](CC)(CC)CC.FC(F)(F)C(O)=O>C(Cl)CCl>[OH:72][C:71]1[C:66]([C:63]2[S:64][CH:65]=[C:61]([CH2:60][C:59]([NH:58][CH:53]3[C:52](=[O:74])[N:51]4[CH:54]3[S:55][CH2:56][CH:57]=[C:50]4[C:48]([OH:49])=[O:47])=[O:73])[N:62]=2)=[N:67][CH:68]=[CH:69][CH:70]=1
Reactant: O=C(Cc1csc(-c2ncccc2O)n1)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=CCSC12
Agent: CC(=O)OCC1=C(C(=O)O)N2C(=O)C(NC(=O)Cc3csc(-c4ccccc4O)n3)C2SC1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCCl
Product: O=C(Cc1csc(-c2ncccc2O)n1)NC1C(=O)N2C(C(=O)O)=CCSC12
Yield: 85.5 %

Procedure:
The procedure used for the preparation of 9a was repeated with 8k (129 mg, 0.221 mmol), Et3SiH (0.353 mL, 2.21 mmol), and trifluoroacetic acid (0.681 mL, 8.84 mmol) in dry ClCH2CH2Cl (6 mL) at 0° C. under nitrogen to give 9k (79.1 mg, 86%) as a yellowish solid after crystallization from THF/CH2Cl2 /hexane. mp 170° C. (dec); IR (KBr) 3600-2800 (br), 3276, 1776, 1723, 1663 cm-1 ; 1H NMR (DMSO-d6) δ3.48 (1H, dd, J=18.9 and 6.0 Hz), 3.58 (1H, dd, J=18.9 and 2.5 Hz), 3.79 (2H, s, CH2), 5.00 (1H, d, J=5.0 Hz), 5.70 (1H, dd, J=8.1 and 5.0 Hz), 6.44 (1H, dd, J=6.0 and 2.5 Hz), 7.37 (1H, dd, J=8.1 and 4.2 Hz), 7.44 (1H, d, J=8.1 Hz), 7.58 (1H, s), 8.14 (1H, d, J=4.2 Hz), 9.15 (1H, d, J=8.1Hz, NH), 11.64 (1H, s, OH), 13.20 (1H, br s, CO2H); FDMS m/z 419 (M+ +1); Anal. Calcd for C17H14N4O5S2.(C4H8O) 0.17: C, 49.30; H, 3.59; N, 13.01. Found: C, 49.13; H, 3.38; N, 12.78.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10](Cl)(=[O:12])=[O:11])=[C:5]([CH3:14])[CH:4]=1.Cl.Cl.Cl.[NH2:18][CH2:19][C:20]1[O:24][C:23]([C:25]([N:27]2[CH2:32][CH2:31][N:30]([CH2:33][CH:34]3[CH2:39][CH2:38][N:37]([CH3:40])[CH2:36][CH2:35]3)[CH2:29][CH2:28]2)=[O:26])=[N:22][N:21]=1.CCN(C(C)C)C(C)C>C(Cl)Cl.C([O-])(O)=O.[Na+]>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10]([NH:18][CH2:19][C:20]2[O:24][C:23]([C:25]([N:27]3[CH2:32][CH2:31][N:30]([CH2:33][CH:34]4[CH2:39][CH2:38][N:37]([CH3:40])[CH2:36][CH2:35]4)[CH2:29][CH2:28]3)=[O:26])=[N:22][N:21]=2)(=[O:12])=[O:11])=[C:5]([CH3:14])[CH:4]=1
Reactant: CN1CCC(CN2CCN(C(=O)c3nnc(CN)o3)CC2)CC1
Reactant: COc1cc(C)c(S(=O)(=O)Cl)c(C)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1cc(C)c(S(=O)(=O)NCc2nnc(C(=O)N3CCN(CC4CCN(C)CC4)CC3)o2)c(C)c1
Temperature: -30 °C
Reaction time: 0.5 h

Procedure:
4-methoxy-2,6-dimethylbenzenesulfonyl chloride (118 mg, 0.5 mmol) was added to a suspension of (5-Amino methyl-1,3,4-oxadiazol-2-yl)-[4-(1-methyl-piperidin-4-ylmethyl)-piperazin-1-yl]-methanone trihydrochloride (200 mg, 0.43 mmol) in DCM, under N2 and the mixture was cooled to −30° C. DIPEA (376 μL, 2.15 mmol) was added over about 3 min and the resultant pink solution was stirred at −30° C. for 30 min and then at ambient temperature for 16 h. The mixture was diluted with saturated aqueous NaHCO3 and extracted with DCM (×2). The combined organic extracts were dried over MgSO4 and concentrated in vacuo to a brown gum which was purified using FCC, eluting with 5% NH3 (2.0 M in MeOH) in DCM, to give the title compound as a clear gum.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[C:6]([CH3:8])[CH:7]=1.[C:10](OC(=O)C)(=[O:12])[CH3:11]>>[C:10]([O:9][C:4]1[CH:5]=[C:6]([CH3:8])[CH:7]=[C:2]([CH3:1])[CH:3]=1)(=[O:12])[CH3:11]
Reactant: Cc1cc(C)cc(O)c1
Reactant: CC(=O)OC(C)=O
Product: CC(=O)Oc1cc(C)cc(C)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 103.1 %

Procedure:
206.5 g (1.69 mol) of 3,5-dimethylphenol and 337.3 g (3.30 mol) of acetic anhydride were refluxed for 1 h and then stirred at RT overnight. The mixture was poured onto water and extracted with methylene chloride. The organic phase was washed with sodium hydroxide solution and water, dried and concentrated under reduced pres-sure. 286 g of 3,5-dimethylphenyl acetate were obtained.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[O-:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[Na+]>>[N+:8]([C:7]1[C:2]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[N:3][CH:4]=[CH:5][CH:6]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1cccnc1Cl
Reactant: [O-]c1ccccc1
Agent: [Na+]
Product: O=[N+]([O-])c1cccnc1Oc1ccccc1

Procedure:
In step (3) of Reaction Scheme I, a 2-chloro-3-nitropyridine of Formula XII is reacted with sodium phenoxide to provide a 3-nitro-2-phenoxypyridine of Formula XIII. Phenol is reacted with sodium hydride in a suitable solvent such as tetrahydrofuran to form the phenoxide. The phenoxide is then reacted at an elevated temperature with a compound of Formula XII.
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[C:15]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][C@@H:24]3[CH2:29][CH3:30])[C:16]3[CH2:22][CH2:21][NH:20][CH2:19][C:17]=3[N:18]=2)=[CH:9][CH:8]=1)=[O:5])[CH3:2].CN(C)C=O.C(N(CC)C(C)C)(C)C.[C:45](Cl)(=[O:47])[CH3:46]>>[C:45]([N:20]1[CH2:21][CH2:22][C:16]2[C:15]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][C@@H:24]3[CH2:29][CH3:30])=[N:14][C:13]([C:10]3[CH:9]=[CH:8][C:7]([NH:6][C:4]([NH:3][CH2:1][CH3:2])=[O:5])=[CH:12][CH:11]=3)=[N:18][C:17]=2[CH2:19]1)(=[O:47])[CH3:46]
Reactant: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4CC)n2)CCNC3)cc1
Reactant: CC(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4CC)n2)CCN(C(C)=O)C3)cc1
Reaction time: 8 h

Procedure:
(S)-1-ethyl-3-(4-(4-(3-ethylmorpholino)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)phenyl)urea (0.251 g, 0.611 mmol) in dry N,N-Dimethylformamide (3.00 mL, 38.7 mmol) was added N,N-Diisopropylethylamine (0.310 mL, 1.78 mmol) followed by Acetyl chloride (0.0650 mL, 0.913 mmol). The reaction mixture was stirred for overnight. The reaction mixture was purified by HPLC. 1H NMR (400 MHz, DMSO) δ 8.68 (s, 1H), 8.17 (d, J=7.6, 2H), 7.48 (d, J=7.9, 2H), 6.22 (d, J=6.1, 1H), 4.78-4.63 (m, 1H), 4.44 (dd, J=82.7, 18.2, 1H), 3.97 (s, 1H), 3.85 (d, J=11.1, 1H), 3.78 (d, J=11.6, 1H), 3.67 (d, J=7.4, 2H), 3.45 (dd, J=38.1, 25.8, 3H), 3.29 (m, 1H), 3.16-3.07 (m, 2H), 2.68 (dd, J=47.0, 37.1, 2H), 2.12 (s, 3H), 1.78 (ddd, J=27.5, 13.8, 7.0, 2H), 1.06 (t, J=7.2, 3H), 0.83 (dd, J=12.0, 7.4, 3H). LC/MS-m/z+453.2 (M+H)+.
Reaction SMILES: [ClH:1].C(OC([N:9]1[CH2:14][CH2:13][C:12]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)([CH2:15][NH:16][CH3:17])[CH2:11][CH2:10]1)=O)(C)(C)C>O1CCOCC1.CO>[ClH:24].[ClH:1].[Cl:24][C:21]1[CH:22]=[CH:23][C:18]([C:12]2([CH2:15][NH:16][CH3:17])[CH2:13][CH2:14][NH:9][CH2:10][CH2:11]2)=[CH:19][CH:20]=1
Reactant: CNCC1(c2ccc(Cl)cc2)CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: CNCC1(c2ccc(Cl)cc2)CCNCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
A 4M solution of hydrochloric acid in dioxane (10 ml) was added dropwise to a solution of 4-(4-chlorophenyl)-4-methylaminomethyl-piperidine-1-carboxylic acid tert-butyl ester (142 mg, 0.42 mmol) in methanol (10 ml). The reaction was stirred overnight at room temperature. After this period of time, the solvents were concentrated to give [4-(4-chlorophenyl)-piperidin-4-ylmethyl]-methylamine bis-hydrochloride (132 mg, 0.42 mmol, 100%). This compound was used in the subsequent step without further purification. LC-MS (LCT2) m/z 239 [M+H+], Rt 0.53 min.
Reaction SMILES: [S:1]([O-:4])([O-:3])=[O:2].[Na+:5].[Na+].Br[CH2:8][CH:9]1[CH2:11][CH2:10]1>O>[CH:9]1([CH2:8][S:1]([O-:4])(=[O:3])=[O:2])[CH2:11][CH2:10]1.[Na+:5]
Reactant: BrCC1CC1
Reactant: O=S([O-])[O-]
Agent: [Na+]
Solvent: O
Product: O=S(=O)([O-])CC1CC1
Temperature: 100 °C
Yield: 128.9 %

Procedure:
Sodium sulfite (1.43 g, 11.3 mmol) was dissolved in water (8.00 mL). To this, (bromomethyl)cyclopropane (1.00 mL, 10.3 mmol) was added and the mixture was stirred with heat at 100° C. for 24 hours. The solvent in the reaction mixture was evaporated off under reduced pressure, and the residue was subjected to slurry purification using diisopropyl ether, to give sodium cyclopropanemethanesulfonate (2.10 g, yield: 99%).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=2N)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:23][C:24]([F:30])([F:29])[CH2:25][C:26](O)=[O:27].C[N:32]1CCOCC1>ClCCl.C(OCC)(=O)C>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([NH2:32])[C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=2[C:26](=[O:27])[CH2:25][C:24]([F:30])([F:29])[F:23])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN1CCOCC1
Reactant: Nc1cc(F)ccc1NC1CCN(Cc2ccccc2)CC1
Reactant: O=C(O)CC(F)(F)F
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: NN(c1ccc(F)cc1C(=O)CC(F)(F)F)C1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 9.1 g 1-Benzyl-4-(2-amino-4-fluoro-phenylamino)-piperidine, 2.7 ml 3,3,3-trifluoropropionic acid and 18.6 ml N-methyl-morpholine in 350 ml dichloromethane was dropped 36.4 ml of a 50% solution of PPA in ethyl acetate. The mixture was stirred for 12 h at r.t., extracted 3× with 250 ml water, and the aqueous layers were extracted with 150 ml dichloromethane. After drying the combined organic layers with MgSO4, the solution was evaporated and purified by flash chromatography with dichloromethane/methanol 19:1. The yield was 11.9 g of the desired product.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH:4]1[O:24][C@:23]2([C:25]([CH2:27][OH:28])=[O:26])[C@@H:6]([CH2:7][C@@H:8]3[C@:22]2([CH3:29])[CH2:21][C@H:20]([OH:30])[C@H:19]2[C@H:9]3[CH2:10][CH2:11][C:12]3[C@:18]2([CH3:31])[CH:17]=[CH:16][C:14](=[O:15])[CH:13]=3)[O:5]1.[CH2:32]([N:36]=[C:37]=[O:38])[CH2:33][CH2:34][CH3:35].[OH2:39]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:1][CH2:2][CH2:3][CH:4]1[O:24][C@:23]2([C:25]([CH2:27][OH:28])=[O:26])[C@@H:6]([CH2:7][C@@H:8]3[C@:22]2([CH3:29])[CH2:21][C@H:20]([OH:30])[C@H:19]2[C@H:9]3[CH2:10][CH2:11][C:12]3[C@:18]2([CH3:31])[CH:17]=[CH:16][C:14](=[O:15])[CH:13]=3)[O:5]1.[CH2:32]([NH:36][C:37](=[O:38])[O-:39])[CH2:33][CH2:34][CH3:35]
Reactant: CCCCN=C=O
Reactant: O
Agent: CCCC1O[C@@H]2C[C@H]3[C@@H]4CCC5=CC(=O)C=C[C@]5(C)[C@H]4[C@@H](O)C[C@]3(C)[C@]2(C(=O)CO)O1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCCCNC(=O)[O-]
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To the solution of budesonide (500 mg, 1.16 mmol) in DCM (5.0 mL) was added butyl isocyanate (144 μL, 1.28 mmol) and DMAP (312 mg, 2.55 mmol) at room temperature. The reaction mixture was stirred at room temperature for 24 hours. During this 24 hours more butyl isocyanate (72 μL, 0.64 mmol) and DMAP (156 mg, 1.27 mmol). The reaction was followed by HPLC. The reaction mixture was poured into water (20 mL) and DCM (10 mL); the aqueous phase was extracted with DCM (10 mL). The combined organic phases were washed with water (10 mL) and brine (10 mL), dried over Na2SO4, filtered, and concentrated in vacuo to provide crude budesonide butylcarbamate. The product was purified by chromatography, eluted with Hexane: AcOEt=9:1 to 3:1 to provide 560 mg of 1:1 mixture of epimers (originated from budesonide) (99.22 area % purity on HPLC). 1H NMR (CDCl3) δ 0.82-2.7 (m, 30H), 3.06-3.20 (m, 3H), 4.45 (m, 1H), 4.58 (t, 1H, 4.5 Hz), 4.75-5.36 (m, 5H), 5.99 (s, 1H), 6.24 (d, 1H, 10.1 Hz), 7.29 (d, 1H, 10.1 Hz). 13C NMR (CDCl3) δ 13.98, 14.08, 14.22, 17.09, 17.30, 17.37, 17.73, 20.09, 20.28, 21.26, 30.56, 31.22, 32.11, 32.59, 33.13, 33.65, 34.27, 35.23, 37.34, 40.30, 40.73, 40.99, 41.17, 44.37, 46.09, 47.49, 50.01, 53.15, 55.43, 55.52, 67.82, 69.82, 69.93, 82.11, 83.37, 97.84, 98.75, 104.66, 108.43, 122.61, 127.97, 155.94, 156.03, 156.79, 170.45, 170.56, 186.95, 203.89 and 205.21.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([OH:17])([CH3:16])[CH3:15])[N:11]3[N:18]=[CH:19][C:20]([C:21]#[CH:22])=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.Br[C:24]1[S:28][C:27]([S:29]([NH2:32])(=[O:31])=[O:30])=[CH:26][CH:25]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([OH:17])([CH3:16])[CH3:15])[N:11]3[N:18]=[CH:19][C:20]([C:21]#[C:22][C:24]4[S:28][C:27]([S:29]([NH2:32])(=[O:31])=[O:30])=[CH:26][CH:25]=4)=[C:10]3[N:9]=2)=[CH:4][CH:3]=1
Reactant: C#Cc1cnn2c(C(C)(C)O)cc(-c3ccc(Cl)cc3)nc12
Reactant: NS(=O)(=O)c1ccc(Br)s1
Product: CC(C)(O)c1cc(-c2ccc(Cl)cc2)nc2c(C#Cc3ccc(S(N)(=O)=O)s3)cnn12

Procedure:
The title compound was prepared from 2-[5-(4-chloro-phenyl)-3-ethynyl-pyrazolo[1,5-a]pyrimidin-7-yl]-propan-2-ol (example C.13) (78 mg, 0.25 mmol) and 5-bromo-thiophene-2-sulfonic acid amide (61 mg, 0.25 mmol) according to general procedure II. Obtained as a yellow solid (76 mg, 64%). MS (ISP) 473.0 [(M+H)+]; mp 206-208° C.
Reaction SMILES: [NH2:1][C@H:2]1[C@H:13]2[C:14]3[C:5](=[CH:6][C:7]([O:23]C)=[C:8]([O:21]C)[C:9]=3[CH2:10][C@@H:11]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH2:12]2)[CH2:4][CH2:3]1.B(Br)(Br)[Br:26]>C(Cl)Cl>[BrH:26].[NH2:1][C@H:2]1[C@H:13]2[C:14]3[C:5](=[CH:6][C:7]([OH:23])=[C:8]([OH:21])[C:9]=3[CH2:10][C@@H:11]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:12]2)[CH2:4][CH2:3]1
Reactant: COc1cc2c3c(c1OC)C[C@@H](c1ccccc1)C[C@H]3[C@H](N)CC2
Reactant: BrB(Br)Br
Solvent: ClCCl
Product: Br
Product: N[C@@H]1CCc2cc(O)c(O)c3c2[C@H]1C[C@H](c1ccccc1)C3
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 0.4 g (1.2 mmol) of [1R,8S,9aR]-1-amino-5,6-dimethoxy-2,3,7,8,9,9a-hexahydro-8 phenyl-phenalene, from Step 7, in 9 mL of methylene chloride was treated with 4.4 mL of a 1M solution of boron tribromide in methylene chloride (4.4 mmol), added dropwise at -78° C. The reaction mixture was warmed to ambient temperature for 1 h and recooled to 78° C. and quenched with 5 mL of methanol. The reaction mixture was allowed to warm to ambient temperature and stirred at ambient temperature for 1 h. The solvent was removed in vacuo. Methanol (5 mL) was added and the solution was concentrated to remove methyl borate by azeotropic distillation. The title compound was obtained after recrystallization from ethanol/diethyl ether as a white solid.
Reaction SMILES: F[C:2]1[C:3]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[C:4]([CH3:19])[C:5]([C:17]#[N:18])=[C:6]2[C:10]=1[O:9][C:8]([N:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)=[N:7]2.C(N(CC)CC)C.[CH3:33][N:34]([CH3:40])[C@H:35]1[CH2:39][CH2:38][NH:37][CH2:36]1>CS(C)=O.ClCCl>[CH3:33][N:34]([CH3:40])[C@H:35]1[CH2:39][CH2:38][N:37]([C:2]2[C:3]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[C:4]([CH3:19])[C:5]([C:17]#[N:18])=[C:6]3[C:10]=2[O:9][C:8]([N:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)=[N:7]3)[CH2:36]1
Reactant: Cc1c(-c2ccccc2)c(F)c2oc(N3CCCCC3)nc2c1C#N
Reactant: CN(C)[C@H]1CCNC1
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1c(-c2ccccc2)c(N2CC[C@H](N(C)C)C2)c2oc(N3CCCCC3)nc2c1C#N
Temperature: 150 °C
Reaction time: 4 h
Yield: 44.3 %

Procedure:
7-Fluoro-5-methyl-6-phenyl-2-(piperidin-1-yl)-1,3-benzoxazole-4-carbonitrile (I-136) (0.21 g, 0.63 mmol) was suspended in dimethyl sulfoxide (5 ml), then triethylamine (0.91 ml, 1.37 mmol) and (3S)-3-(dimethylamino)pyrrolidine (0.16 ml, 1.26 mmol) were added, followed by stirring in a sealed tube at an external temperature of about 150° C. for 4 hours. This was diluted with dichloromethane, washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated away under reduced pressure, and the resulting residue was purified by silica gel column chromatography (silica gel 10 g, dichloromethane:methanol=30:1) and preparative thin-layer chromatography (dichloromethane:methanol=20:1), then isopropyl ether was added, and the insoluble matter was collected by filtration to obtain a beige solid (0.12 g, 44%).
Reaction SMILES: [OH:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[O:26][CH3:27])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:3]1.Cl[CH2:36][C:37]1[CH:38]=[C:39]([N:43]([CH2:47][CH2:48][CH2:49][O:50][CH3:51])[C:44](=[O:46])[CH3:45])[CH:40]=[CH:41][CH:42]=1>>[C:44]([N:43]([CH2:47][CH2:48][CH2:49][O:50][CH3:51])[C:39]1[CH:38]=[C:37]([CH:42]=[CH:41][CH:40]=1)[CH2:36][O:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[O:26][CH3:27])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:3]1)(=[O:46])[CH3:45]
Reactant: COCCCN(C(C)=O)c1cccc(CCl)c1
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2O)cc1
Product: COCCCN(C(C)=O)c1cccc(COC2CN(C(=O)OC(C)(C)C)CCC2c2ccc(OCCCOCc3ccccc3OC)cc2)c1

Procedure:
Analogously to Method D, 0.238 g of tert-butyl 3-hydroxy-4-{4-[3-(2-methoxybenzyloxy)-propoxy]phenyl}piperidine-1-carboxylate and 0.128 g of N-(3-chloromethylphenyl)-N-(3-methoxypropyl)acetamide are reacted. The title compound is obtained as a slightly yellowish oil. Rf=0.20 (2:1 EtOAc-heptane); Rt=5.80.
Reaction SMILES: [C:1]([N:5]1[CH2:29][CH2:28][CH2:27][CH2:26][C:8]2[CH:9]=[C:10]3[C:19]4[CH:18]=[C:17]([S:20]([CH2:22][CH3:23])=[O:21])[C:16]([O:24][CH3:25])=[CH:15][C:14]=4[CH2:13][CH2:12][N:11]3[C:7]=2[C:6]1=[O:30])([CH3:4])([CH3:3])[CH3:2].C1C(=O)N([Br:38])C(=O)C1>CN(C=O)C.O>[C:1]([N:5]1[CH2:29][CH2:28][CH2:27][CH2:26][C:8]2[C:9]([Br:38])=[C:10]3[C:19]4[CH:18]=[C:17]([S:20]([CH2:22][CH3:23])=[O:21])[C:16]([O:24][CH3:25])=[CH:15][C:14]=4[CH2:13][CH2:12][N:11]3[C:7]=2[C:6]1=[O:30])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCS(=O)c1cc2c(cc1OC)CCn1c-2cc2c1C(=O)N(C(C)(C)C)CCCC2
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Solvent: O
Product: CCS(=O)c1cc2c(cc1OC)CCn1c3c(c(Br)c1-2)CCCCN(C(C)(C)C)C3=O
Reaction time: 0.17 h
Yield: 86.9 %

Procedure:
A solution of 350 mg of 23c in 4 ml of DMF was treated with 155 mg of NBS. After stirring for 10 min. the reaction was diluted with 25 ml of water and extracted with ethyl acetate. The organic extract was washed with water, dried and concentrated, and the residue was treated with diisopropyl ether, to give 360 mg of 23d, Mp: 140-145° C. Rf 0.18 (heptane/ethyl acetate 1/1). LC-MS-ESI: [M+1] 506.97 and 524.99. NMR (CDCl3) δ 1.24 (t, 3, ethyl), 2.82 and 3.08 (2×m, 2, ethyl), 3.88 (s, 3, OCH3), 6.77, 8.78 (2×s, 2, Ar—H).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([C@@H:10]2[C:14]3[C:15]([CH3:28])=[C:16]([NH:20][C:21](=[O:27])[CH2:22][C:23]([CH3:26])([CH3:25])[CH3:24])[C:17]([CH3:19])=[CH:18][C:13]=3[O:12][CH2:11]2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[C:29](OCC)(=[O:31])C.CCCCCC>C(Cl)(Cl)Cl>[CH:29]([C:18]1[C:13]2[O:12][CH2:11][C@H:10]([C:7]3[CH:6]=[CH:5][C:4]([CH:1]([CH3:2])[CH3:3])=[CH:9][CH:8]=3)[C:14]=2[C:15]([CH3:28])=[C:16]([NH:20][C:21](=[O:27])[CH2:22][C:23]([CH3:26])([CH3:25])[CH3:24])[C:17]=1[CH3:19])=[O:31]
Reactant: CCOC(C)=O
Reactant: Cc1cc2c(c(C)c1NC(=O)CC(C)(C)C)[C@@H](c1ccc(C(C)C)cc1)CO2
Solvent: ClC(Cl)Cl
Solvent: CCCCCC
Product: Cc1c(C=O)c2c(c(C)c1NC(=O)CC(C)(C)C)[C@@H](c1ccc(C(C)C)cc1)CO2
Yield: 83 %

Procedure:
Using (+)-N-((3R)-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide obtained in Example 37, the title compound was synthesized in the same manner as in Example 20. Yield: 83%. Melting point: 179-180° C. (ethyl acetate-hexane). [α]D°=−25.80° (c=0.48, chloroform).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH:10]([C:14]([OH:16])=O)[C:11]([OH:13])=O)[CH3:2].[NH2:18][C:19]1[CH:20]=[CH:21][CH:22]=[C:23]2[C:28]=1[N:27]=[CH:26][CH:25]=[CH:24]2.[CH2:29](Cl)[CH2:30]Cl>CN(C1C=CN=CC=1)C.C1COCC1>[CH2:1]([O:3][C:4](=[O:17])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH:10]([C:11](=[O:13])[NH:27][C:26]1[CH:25]=[CH:24][CH:23]=[C:30]2[C:29]=1[N:18]=[CH:19][CH:20]=[CH:21]2)[C:14](=[O:16])[NH:18][C:19]1[CH:20]=[CH:21][CH:22]=[C:23]2[C:28]=1[N:27]=[CH:26][CH:25]=[CH:24]2)[CH3:2]
Reactant: Nc1cccc2cccnc12
Reactant: ClCCCl
Reactant: CCOC(=O)CCCCCC(C(=O)O)C(=O)O
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: CCOC(=O)CCCCCC(C(=O)Nc1cccc2cccnc12)C(=O)Nc1cccc2cccnc12
Reaction time: 8 h

Procedure:
Diacid 62 (150 mg, 0.609 mmol), 8-aminoquinoline (211 mg, 1.462 mmol), and DMAP (5 mg) were dissolved in THF (6 mL). To this solution was added EDC (350 mg, 1.827 mmol) and the reaction allowed to proceed overnight. The mixture was concentrated under reduced pressure and the product purified by flash chromatography (40% EtOAc/hexanes). Evaporation of the combined product fractions left 63 as a light brown solid (100 mg, 0.201 mmol, 14%). 1H-NMR (400 MHz, DMSO-d6) δ 10.85 (s, 2H), 8.92 (dd, 2H), 8.64 (dd, 2H), 8.40 (dd, 2H), 7.68 (dd, 2H), 7.62 (dd, 2H), 7.57 (t, 2H), 4.35 (t, 1H), 3.98 (q, 2H), 2.24 (t, 2H), 2.00 (m, 2H), 1.51 (m, 2H), 1.37 (m, 4H), 1.12 (t, 3H).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[N:4]=[C:5]2[CH2:10][NH:9][CH2:8][CH2:7][N:6]2[CH:11]=1.CCN(CC1C=CC=CC=1)CC.C=CC1C=CC=CC=1.C=CC1C=CC(C=C)=CC=1.[Cl:44][C:45]1[CH:53]=[C:52]([Cl:54])[CH:51]=[CH:50][C:46]=1[C:47](Cl)=[O:48]>ClCCl>[Cl:44][C:45]1[CH:53]=[C:52]([Cl:54])[CH:51]=[CH:50][C:46]=1[C:47]([N:9]1[CH2:8][CH2:7][N:6]2[CH:11]=[C:3]([C:2]([F:12])([F:1])[F:13])[N:4]=[C:5]2[CH2:10]1)=[O:48]
Reactant: FC(F)(F)c1cn2c(n1)CNCC2
Reactant: O=C(Cl)c1ccc(Cl)cc1Cl
Agent: C=Cc1ccc(C=C)cc1
Agent: CCN(CC)Cc1ccccc1
Solvent: ClCCl
Solvent: C=Cc1ccccc1
Product: O=C(c1ccc(Cl)cc1Cl)N1CCn2cc(C(F)(F)F)nc2C1
Temperature: 25 °C
Reaction time: 24 h
Yield: 97.8 %

Procedure:
2-(Trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine (0.096 g, 0.5 mmol, intermediate 4) and diethylaminomethyl polystyrene (0.469 g, 1.500 mmol) were slurried in dichloromethane (DCM) (5 ml). 2,4-Dichlorobenzoyl chloride (0.084 ml, 0.600 mmol) was added and the mixture stirred at room temperature for 24 h. The resin was filtered, washed with dichloromethane and the filtrate concentrated in vacuo to afford crude product which was purified by flash chromatography (Biotage SP4, 25+S, eluting with a 0-100% gradient of ethyl acetate/iso-hexane) to afford 7-[(2,4-dichlorophenyl)carbonyl]-2-(trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine (0.178 g, 0.489 mmol, 98% yield).