Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH3:22])[C:7](=[O:21])[C:8]3[CH:18]=[C:17]([CH2:19]Cl)[CH:16]=[N:15][C:9]=3[N:10]([CH2:13][CH3:14])[C:11]=2[N:12]=1.[CH3:23][NH:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH3:22])[C:7](=[O:21])[C:8]3[CH:18]=[C:17]([CH2:19][N:24]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[CH3:23])[CH:16]=[N:15][C:9]=3[N:10]([CH2:13][CH3:14])[C:11]=2[N:12]=1
Reactant: CNc1ccccc1
Reactant: CCN1c2ncc(CCl)cc2C(=O)N(C)c2ccc(Cl)nc21
Product: CCN1c2ncc(CN(C)c3ccccc3)cc2C(=O)N(C)c2ccc(Cl)nc21
Reaction time: 72 h
Yield: 41 %

Procedure:
The 2-chloro-8-chloromethyl-5,11-dihydro-11-ethyl-5-methyl-6H-dipyrido[3,2-b:2',3'-e][1,4]diazepin-6-one (0.050 g, 0.15 mmol) was dissolved in N-methylaniline (1 mL) and stirred for 3 days. The mixture was purified by column chromatography (hexanes to ethyl acetate gradient) to give the title compound (0.025 g, 41%), m.p. 55°-57° C., foam.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9]([N:12]([CH2:14][CH2:15][CH2:16][N:17]([CH3:19])[CH3:18])[CH3:13])(=[O:11])=[O:10])[CH:5]=[N:6][C:7]=1Cl.CC(C)([O-])C.[K+].CN(C)C(=O)C.[CH3:32][N:33]1[CH:37]=[CH:36][C:35]([NH:38][C:39]2[C:48]3[C:43](=[CH:44][CH:45]=[C:46]([OH:49])[CH:47]=3)[N:42]=[CH:41][N:40]=2)=[N:34]1>O>[Cl:1][C:2]1[CH:3]=[C:4]([S:9]([N:12]([CH2:14][CH2:15][CH2:16][N:17]([CH3:19])[CH3:18])[CH3:13])(=[O:11])=[O:10])[CH:5]=[N:6][C:7]=1[O:49][C:46]1[CH:47]=[C:48]2[C:43](=[CH:44][CH:45]=1)[N:42]=[CH:41][N:40]=[C:39]2[NH:38][C:35]1[CH:36]=[CH:37][N:33]([CH3:32])[N:34]=1
Reactant: CN(C)CCCN(C)S(=O)(=O)c1cnc(Cl)c(Cl)c1
Reactant: Cn1ccc(Nc2ncnc3ccc(O)cc23)n1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: CN(C)CCCN(C)S(=O)(=O)c1cnc(Oc2ccc3ncnc(Nc4ccn(C)n4)c3c2)c(Cl)c1
Temperature: 100 °C
Reaction time: 2.5 h
Yield: 67.3 %

Procedure:
5,6-Dichloro-N-[3-(dimethylamino)propyl]-N-methylpyridine-3-sulfonamide (122 mg, 0.37 mmol) and potassium tert-butoxide (58 mg, 0.52 mmol) were added to an N,N-dimethylacetamide solution (1 ml) of 4-[(1-methyl-1H-pyrazol-3-yl)amino]quinazolin-6-ol (50 mg, 0.21 mmol), and stirred under a nitrogen atmosphere at 100° C. for 2.5 hours. The reaction solution was cooled with ice, saline water was added, and extracted with chloroform/methanol (9:1). The organic layer was washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by amine-type silica gel column chromatography (Biotage NH, hexane:ethyl acetate:chloroform to chloroform:methanol=2:4:1 to 100:2) to obtain the entitled compound (75 mg, yield: 68%) as a pale orange amorphous solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]([F:12])([F:11])[F:10].ClC1C=CC(Cl)=CC=1.[C:21]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[O:30]C1C=CC(Cl)=CC=1C(F)(F)F)(=[O:23])[CH3:22].C(C1C=CC=CC=1OC1C=CC(Cl)=CC=1)(=O)C>>[C:21]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[O:30][C:6]1[CH:7]=[CH:2][C:3]([C:9]([F:12])([F:11])[F:10])=[CH:4][C:5]=1[Cl:8])(=[O:23])[CH3:22]
Reactant: FC(F)(F)c1cc(Cl)ccc1Cl
Reactant: CC(=O)c1ccccc1Oc1ccc(Cl)cc1C(F)(F)F
Agent: CC(=O)c1ccccc1Oc1ccc(Cl)cc1
Solvent: Clc1ccc(Cl)cc1
Product: CC(=O)c1ccccc1Oc1ccc(C(F)(F)F)cc1Cl

Procedure:
Similarly, by following the same procedure but respectively replacing 3,4-dichlorobenzotrifluoride with 2,5-dichlorobenzotrifluoride and 1,4-dichlorobenzene the compounds 1-acetyl-(2-trifluoromethyl-4-chlorophenoxy)-benzene and 1-acetyl-(4-chlorophenoxy)-benzene are respectively prepared.
Reaction SMILES: C([NH:4][C@:5]1([C:22](NC(C)(C)C)=[O:23])[C@@H:9]([CH2:10][CH2:11][CH2:12][B:13]2[O:17]C(C)(C)C(C)(C)[O:14]2)[CH2:8][NH:7][CH2:6]1)(=O)C.S([O-])([O-])(=O)=O.[Na+].[Na+].[CH3:36][N:37]([CH3:44])[CH2:38][C:39]([CH3:43])([CH3:42])[CH:40]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=[O:47])C.[Na+].C(=O)([O-])[O-].[Na+].[Na+]>ClCCCl.C(O)(=O)C>[NH2:4][C@:5]1([C:22]([OH:23])=[O:47])[C@@H:9]([CH2:10][CH2:11][CH2:12][B:13]([OH:14])[OH:17])[CH2:8][N:7]([CH2:40][C:39]([CH3:43])([CH3:42])[CH2:38][N:37]([CH3:44])[CH3:36])[CH2:6]1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: CC(=O)N[C@@]1(C(=O)NC(C)(C)C)CNC[C@@H]1CCCB1OC(C)(C)C(C)(C)O1
Reactant: CN(C)CC(C)(C)C=O
Agent: O=C([O-])[O-]
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CN(C)CC(C)(C)CN1C[C@H](CCCB(O)O)[C@](N)(C(=O)O)C1
Reaction time: 2 h
Yield: 21.9 %

Procedure:
A stirred solution of (3R,4S)-3-acetamido-N-tert-butyl-4-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)propyl)pyrrolidine-3-carboxamide (Example 8, step 4) (198 mg, 0.5 mmol) in anhydrous 1,2-dichloroethane (5 mL) was treated with anhydrous sodium sulfate (1 g) and 3-dimethylamino-2,2-dimethylpropionaldehyde (91 mg, 0.7 mmol), stirred for 2 h, then treated with sodium triacetoxyborohydride (212 mg, 1.0 mmol) and glacial acetic acid (2 drops) and stirred for 16 h. Aqueous sodium carbonate (10%, 5 mL) was added and the mixture stirred for a few minutes and extracted with ethyl acetate (30 mL, then 2×10 mL). The combined organic solution was washed with water and saturated aqueous sodium chloride (20 mL each), dried (MgSO4), and concentrated. The crude material was deprotected and isolated using the method described for example 8, step 5 to afford (3R,4S)-3-amino-4-(3-boronopropyl)-1-(3-(dimethylamino)-2,2-dimethylpropyl)pyrrolidine-3-carboxylic acid (36 mg, 16%) as a white granular solid. NMR (D2O) δ 3.80-4.00 (m, 2 H), 3.35-3.50 (m, 3 H), 3.20 (s, 2 H), 2.89 (s, 6 H), 2.50-2.65 (m, 1 H), 1.50-1.65 (m, 1 H), 1.25-1.35 (m, 2 H), 1.21 (s, 6 H), 0.65-0.75 (m, 2 H). MS (m−H2O+1): 312.0; MS (m−2 H2O+1): 294.4.
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[F:28][CH:29]([F:43])[O:30][C:31]1[CH:36]=[CH:35][C:34]([C:37]2([C:40]([OH:42])=O)[CH2:39][CH2:38]2)=[CH:33][CH:32]=1.Cl.Cl.[NH:46]1[CH2:50][CH2:49][C:48]2([C:58]3[CH:57]=[CH:56][N:55]=[CH:54][C:53]=3[C:52](=[O:59])[O:51]2)[CH2:47]1.CN1CCOCC1.[C:67]([OH:73])([C:69]([F:72])([F:71])[F:70])=[O:68]>CN(C=O)C>[OH:73][C:67]([C:69]([F:72])([F:71])[F:70])=[O:68].[F:43][CH:29]([F:28])[O:30][C:31]1[CH:32]=[CH:33][C:34]([C:37]2([C:40]([N:46]3[CH2:50][CH2:49][C:48]4([C:58]5[CH:57]=[CH:56][N:55]=[CH:54][C:53]=5[C:52](=[O:59])[O:51]4)[CH2:47]3)=[O:42])[CH2:38][CH2:39]2)=[CH:35][CH:36]=1
Reactant: O=C1OC2(CCNC2)c2ccncc21
Reactant: O=C(O)C1(c2ccc(OC(F)F)cc2)CC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: O=C1OC2(CCN(C(=O)C3(c4ccc(OC(F)F)cc4)CC3)C2)c2ccncc21
Reaction time: 0.08 h

Procedure:
BOP (0.18 g, 0.42 mmol) was added to a mixture of 1-[4-(difluoromethoxy)phenyl]cyclopropanecarboxylic acid (0.10 g, 0.46 mmol) and 3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-3-one dihydrochloride (0.10 g, 0.38 mmol) in DMF (2.5 mL). After 5 min, 4-methylmorpholine (0.2 mL, 2.0 mmol) was added to the mixture. The resulting mixture was stirred at mom temperature overnight, then was adjusted to be acidic (pH=2.0) with TFA, and then was purified by prep-LCMS to give 1′-({1-[4-(difluoromethoxy)phenyl]cyclopropyl}carbonyl)-3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-3-one TFA salt. The purified salt was neutralized by an addition of NaHCO3 aqueous solution (7.5%). The mixture was extracted with ethyl acetate and the organic phase was concentrated to give 1′-({1-[4-(difluoromethoxy)phenyl]cyclopropyl}carbonyl)-3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-3-one. The desired stereo-isomer was isolated by chiral column to afford (1R)-1′-({1-[4-(difluoromethoxy)phenyl]cyclopropyl}carbonyl)-3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-3-one (49.5 mg, 31%). MS (ESI): (M+H)+=419.1
Reaction SMILES: [N+:1]([CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])([O-:3])=O.[C:10](OC(OC(OC(C)(C)C)=O)=O)(C)(C)[CH3:11]>CN(C)C1C=CN=CC=1>[C:5]([C:4]1[CH:11]=[CH:10][O:3][N:1]=1)([O:7][CH2:8][CH3:9])=[O:6].[NH3:1]
Reactant: CCOC(=O)C[N+](=O)[O-]
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Product: CCOC(=O)c1ccon1
Product: N

Procedure:
The starting acetylene was obtained as described in Example 118. The 3-carboethoxy isoxazole intermediate was obtained by cycloaddition of the nitrile oxide generated in situ from ethyl nitroacetate, di-t-butyldicarbonate and 4-dimethylaminopyridine. The amide was obtained from the 3-carboethoxy isoxazole intermediate by hydrolysis to the acid, conversion to the acyl chloride and reaction with ammonia. LRMS (ESI+) m/z: 358.0 (M−H+ C15H14F3N3O4 requires 358.0)
Reaction SMILES: [F:1][C:2]([F:17])([O:6][C:7]1[CH:8]=[C:9]([CH:14]=[CH:15][CH:16]=1)[C:10]([O:12]C)=[O:11])[CH:3]([F:5])[Cl:4].[OH-].[K+].O.Cl>O1CCCC1>[F:1][C:2]([F:17])([O:6][C:7]1[CH:8]=[C:9]([CH:14]=[CH:15][CH:16]=1)[C:10]([OH:12])=[O:11])[CH:3]([F:5])[Cl:4]
Reactant: COC(=O)c1cccc(OC(F)(F)C(F)Cl)c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1cccc(OC(F)(F)C(F)Cl)c1
Temperature: 95 °C
Reaction time: 0.25 h

Procedure:
40 Parts by weight of methyl 3-(1',1',2'-trifluoro-2'-chloroethoxy)-benzoate, in a mixture of 8.4 parts by weight of potassium hydroxide, 100 parts by weight of water and 5 parts by weight of tetrahydrofuran, are stirred for 15 minutes at 95° C. The resulting solution is acidified with concentrated hydrochloric acid and the precipitate formed is filtered off and dried; 35 parts of 3-(1',1',2'-trifluoro-2'-chloroethoxy)benzoic acid of melting point 79°-85° C. are obtained.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15]([CH:18]=[O:19])=[CH:14][C:13]=2[CH:20]=O)[S:8][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].C(OC(=O)C)(=O)C>C1(C)C(C)=CC=CC=1>[C:1]([C:5]1[N:6]=[C:7]([C:10]2[O:11][C:12]3[CH:17]=[CH:16][C:15]([CH:18]=[O:19])=[CH:14][C:13]=3[CH:20]=2)[S:8][CH:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1csc(COc2ccc(C=O)cc2C=O)n1
Solvent: Cc1ccccc1C
Solvent: CC(=O)OC(C)=O
Product: CC(C)(C)c1csc(-c2cc3cc(C=O)ccc3o2)n1
Temperature: 130 °C
Reaction time: 27 h
Yield: 1232.1 %

Procedure:
A mixture of 4-tert-butyl-2-(2,4-diformylphenoxymethyl)thiazole (0.95 g) and acetic anhydride (12.9 ml) in dried xylene (100 ml) was stirred at 130° C. for 27 hours. After being cooled, the resulting mixture was concentrated in reduced pressure to give a residue. The residue was crystallized with diisopropyl ether. The resulting crystals were collected by filtration and washed with diisopropyl ether to give 4-tert-butyl-2-(5-formylbenzofuran-2-yl)thiazole (11.01 g).
Reaction SMILES: Cl.[CH2:2]([NH:4][C:5]([N:7]1[CH2:11][C:10]([CH3:13])([CH3:12])[CH:9]=[N:8]1)=[NH:6])[CH3:3].CCN(P1(N(C)CCCN1C)=NC(C)(C)C)CC.[Br:32][C:33]1[CH:34]=[C:35]([S:46](Cl)(=[O:48])=[O:47])[CH:36]=[CH:37][C:38]=1[NH:39][C:40](=[O:45])[C:41]([F:44])([F:43])[F:42].Cl>C1COCC1>[Br:32][C:33]1[CH:34]=[C:35]([S:46](=[O:48])(=[O:47])[N:6]=[C:5]([N:7]2[CH2:11][C:10]([CH3:12])([CH3:13])[CH:9]=[N:8]2)[NH:4][CH2:2][CH3:3])[CH:36]=[CH:37][C:38]=1[NH:39][C:40](=[O:45])[C:41]([F:43])([F:44])[F:42]
Reactant: O=C(Nc1ccc(S(=O)(=O)Cl)cc1Br)C(F)(F)F
Reactant: CCNC(=N)N1CC(C)(C)C=N1
Agent: CCN(CC)P1(=NC(C)(C)C)N(C)CCCN1C
Agent: Cl
Solvent: C1CCOC1
Product: CCNC(=NS(=O)(=O)c1ccc(NC(=O)C(F)(F)F)c(Br)c1)N1CC(C)(C)C=N1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 78.4 %

Procedure:
To a solution of 1.20 g N-ethyl-4,4-dimethyl-4,5-dihydro-pyrazole-1-carboxamidine hydrochloride in 35 mL dry THF was added 5.1 mL (3.0 equiv.) BEMP and the reaction mixture was stirred for 10 minutes at room temperature. 2.15 g (1.0 equiv.) 3-Bromo-4-(2,2,2-trifluoro-acetylamino)-benzenesulfonyl chloride was added in one portion and the resulting bright yellow solution was stirred overnight at room temperature. The reaction mixture was acidified with 1N HCl and extracted twice with EA. The combined organic layers were dried over Na2SO4, filtered and evaporated under reduced pressure. Purification by flash chromatography (Et2O/PA 1:1→Et2O) afforded 2.29 g (78%) of product. 1H NMR (400 MHz, CDCl3) δ 1.18 (t, J=7.3 Hz, 3H), 1.24 (s, 6H), 3.43-3.51 (m, 2H), 3.79 (br.s, 2H), 6.78 (s, 1H), 7.93 (dd, J=8.6, 2.0 Hz, 1H), 8.19 (d, J=2.0 Hz, 1H), 8.39 (d, J=8.6 Hz, 1H), 8.61 (br.s., 1H).
Reaction SMILES: [CH2:1]([C:4]1[CH:5]=[N:6][C:7]([N:10]2[CH2:15][CH2:14][CH:13]([OH:16])[CH2:12][CH2:11]2)=[N:8][CH:9]=1)[CH2:2][CH3:3].CCN(CC)CC.[CH3:24][S:25](Cl)(=[O:27])=[O:26]>C(Cl)Cl>[CH3:24][S:25]([O:16][CH:13]1[CH2:14][CH2:15][N:10]([C:7]2[N:8]=[CH:9][C:4]([CH2:1][CH2:2][CH3:3])=[CH:5][N:6]=2)[CH2:11][CH2:12]1)(=[O:27])=[O:26]
Reactant: CCCc1cnc(N2CCC(O)CC2)nc1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCc1cnc(N2CCC(OS(C)(=O)=O)CC2)nc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.9 %

Procedure:
To a stirring solution of 1-(5-propylpyrimidin-2-yl)piperidin-4-ol (9.2 g, 41.6 mmol), Et3N (12.85 mL, 91 mmol, Aldrich) in CH2Cl2 (80 mL) at 0° C. was added a solution of Methanesulfonyl chloride (3.54 mL, 45.7 mmol, Acros) in CH2Cl2 (20 mL) dropwise. The reaction mixture was stirred at room temperature for 1 h and washed with 1N HCl in H2O, saturated NaHCO3 in H2O and brine. The organic layer was dried over Na2SO4 and concentrated in vacuo to yield 11.7 g of the desired product as an off-white solid. MS (ESI) 300 (M+H).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH:16]=[CH:15][C:14]([O:17][CH:18]3[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]4[CH:32]=[CH:31][C:30]([CH:33]=[C:34]([CH3:36])[CH3:35])=[CH:29][CH:28]=4)=[O:25])[CH2:20][CH2:19]3)=[CH:13][C:12]2=[O:37])=[CH:7][CH:6]=1)(=[O:4])=[O:3]>[Pd].CO.CN(C=O)C.C(Cl)Cl>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH:16]=[CH:15][C:14]([O:17][CH:18]3[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]4[CH:28]=[CH:29][C:30]([CH2:33][CH:34]([CH3:35])[CH3:36])=[CH:31][CH:32]=4)=[O:25])[CH2:20][CH2:19]3)=[CH:13][C:12]2=[O:37])=[CH:7][CH:6]=1)(=[O:3])=[O:4]
Reactant: CC(C)=Cc1ccc(OC(=O)N2CCC(Oc3ccn(-c4ccc(S(C)(=O)=O)cc4)c(=O)c3)CC2)cc1
Agent: [Pd]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CO
Product: CC(C)Cc1ccc(OC(=O)N2CCC(Oc3ccn(-c4ccc(S(C)(=O)=O)cc4)c(=O)c3)CC2)cc1
Reaction time: 2 h

Procedure:
A suspension of 4-(2-methylprop-1-enyl)phenyl 4-(1-(4-(methylsulfonyl)phenyl)-2-oxo-1,2-dihydropyridin-4-yloxy)piperidine-1-carboxylate (30 mg, 0.057 mmol) and palladium on carbon (10 wt. %, wet) (20 mg, 0.188 mmol, Aldrich) in MeOH (4.0 mL) and DMF (0.5 mL) was placed under hydrogen (balloon) for 2 hrs and additional palladium on carbon (20 mg) was added. The resulting mixture was continuously stirred under hydrogen (balloon) for 1.5 hrs, diluted with CH2Cl2, filtrated through a pad of CELITE® 545 filter aid and concentrated in vacuo. The residue was purified by preparative HPLC (C18 column; 30-100% methanol in water containing 0.05% trifluoroacetic acid) to give Example 144 (21.4 mg, yellow solid, 71%) upon lyophilization. 1H NMR (500 MHz, CDCl3) 8.10 (d, J=8.25 Hz, 2 H), 7.61 (d, J=8.25 Hz, 2H), 7.38 (d, J=7.70 Hz, 1H), 7.14 (d, J=8.80 Hz, 2H), 7.00 (d, J=8.25 Hz, 2H), 6.56 (d, J=2.20 Hz, 1H), 6.33 (dd, J=7.42, 2.47 Hz, 1H), 4.62-4.74 (m, 1H), 3.89-4.04 (m, 1H), 3.85 (app brs, 1H), 3.85 (app brs, 1H), 3.57 (app brs, 1H), 3.12 (s, 3H), 2.46 (d, J=7.15 Hz, 2H), 2.13 (app brs, 2H), 1.89-1.98 (m, 2H), 1.80-1.89 (m, 1H), 0.90 (d, J=6.60 Hz, 6H). MS (ESI) 525 (M+H).
Reaction SMILES: [BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[NH:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1.[CH3:20][O:21][C:22]1[C:29]([OH:30])=[CH:28][C:25]([CH:26]=O)=[CH:24][CH:23]=1.Cl>C(Cl)Cl>[CH3:20][O:21][C:22]1[CH:23]=[CH:24][C:25]([CH2:26][N:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)=[CH:28][C:29]=1[OH:30]
Reactant: COc1ccc(C=O)cc1O
Reactant: C1CCNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Product: COc1ccc(CN2CCCC2)cc1O
Yield: 84.9 %

Procedure:
NaB(OAc)3H (32 g, 0.15 mol) was added in portions for 15 min to a mixture of pyrrolidine (9.1 mL, 0.11 mol) and 4-methoxy-5-hydroxybenzaldehyde (15.2 g, 0.1 mol) in CH2Cl2 (100 mL) under vigorous stirring and cooling with an ice bath in an atmosphere of argon Ar. The mixture was stirred for 20 h and cooled with an ice bath. Concentrated HCl (21 mL) was added. The organic layer was separated and discarded. The aqueous one was alkalized with K2CO3 to pH 9 (60 mL) and extracted with chloroform (3×100 mL). The combined extracts were dried with Na2SO4, and evaporated to give the title compounds (17.6 g, 85%) as white crystals. LCMS-data: 208.1 and 209.1 (M+H)+, (calculated for C12H17NO2 207.1). 1H NMR (400 MHz)-data (DMSO-d6, J, Hz): 8.81 (br s, 1H, OH); 6.80 (d, 1H, ArH, J=8.3 Hz); 6.73 (d, 1H, ArH, J=2 Hz); 6.65 (dd, 1H, ArH, J1=2 Hz, J2=8 Hz); 3.72 (s, 3H, OCH3); 3.40 (s, 2H, CH2Ar); 2.41-2.33 (m, 4H, CH2CH2CH2CH2); 1.70-1.62 (m, 4H, CH2CH2CH2CH2,).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[OH:7][C@@:8]([CH3:16])([C:12]([F:15])([F:14])[F:13])[C:9](O)=[O:10].[CH2:17]([S:19][C:20]1[CH:26]=[CH:25][C:23]([NH2:24])=[C:22]([Cl:27])[C:21]=1[Cl:28])[CH3:18].C1(C2C=CC=C(C3C=CC=CC=3)N=2)C=CC=CC=1>C(Cl)Cl.CN(C=O)C>[Cl:27][C:22]1[C:21]([Cl:28])=[C:20]([S:19][CH2:17][CH3:18])[CH:26]=[CH:25][C:23]=1[NH:24][C:9](=[O:10])[C@:8]([OH:7])([CH3:16])[C:12]([F:15])([F:14])[F:13]
Reactant: CCSc1ccc(N)c(Cl)c1Cl
Reactant: C[C@@](O)(C(=O)O)C(F)(F)F
Agent: O=C(Cl)C(=O)Cl
Agent: c1ccc(-c2cccc(-c3ccccc3)n2)cc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCSc1ccc(NC(=O)[C@@](C)(O)C(F)(F)F)c(Cl)c1Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 67.7 %

Procedure:
Oxalyl chloride (0.75 ml) was added to a stirred suspension of (R)-(+)-2-hydroxy-2-methyl-3,3,3-trifluoropropanoic acid (Method 25) (1.37 g) in DCM (10 ml) containing DMF (1 drop). The mixture was stirred at ambient temperature for 18 hours and was then added to a solution of 4-ethylsulphanyl-2,3-dichloroaniline (Method 7) (1.92 g) and 2,6-diphenylpyridine (2.0 g) in DCM (50 ml). The mixture was stirred for 3 hours at room temperature, volatile material was removed by evaporation and the residue was purified by chromatography eluting with 0-20% EtOAc/isohexane to give the title compound (2.12 g) as a solid. NMR (CDCl3) 1.35 (t, 3H), 1.76 (s, 3H), 2.97 (q, 2H), 3.61 (s, 1H), 7.22 (d, 1H), 8.27 (d, 1H), 8.91 (s, 1H); m/z: 360.
Reaction SMILES: [F:1][C:2]1[CH:20]=[CH:19][C:5]2[NH:6][C:7](=O)[C:8]3[C:13]4[CH2:14][CH2:15][CH2:16][CH2:17][C:12]=4[S:11][C:9]=3[S:10][C:4]=2[CH:3]=1.P(Cl)(Cl)(Cl)=O.CN(C)C1C=CC=CC=1.[CH3:35][N:36]1[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1>>[F:1][C:2]1[CH:20]=[CH:19][C:5]2[N:6]=[C:7]([N:39]3[CH2:40][CH2:41][N:36]([CH3:35])[CH2:37][CH2:38]3)[C:8]3[C:13]4[CH2:14][CH2:15][CH2:16][CH2:17][C:12]=4[S:11][C:9]=3[S:10][C:4]=2[CH:3]=1
Reactant: O=C1Nc2ccc(F)cc2Sc2sc3c(c21)CCCC3
Reactant: CN1CCNCC1
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)c1ccccc1
Product: CN1CCN(C2=Nc3ccc(F)cc3Sc3sc4c(c32)CCCC4)CC1

Procedure:
In the same manner as in Example 80 and using 8-fluoro-1,2,3,4-tetrahydro-[1]benzothieno[2,3-b][1,5]benzothiazepin-12(11H)-one, phosphorus oxychloride, N,N-dimethylaniline and 1-methylpiperazine, 8-fluoro-1,2,3,4-tetrahydro-12-(4-methylpiperazin-1-yl)-[1]benzothieno[2,3-b][1,5]benzothiazepine is obtained.
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)Cl.S[C:8]1[O:9][C:10]2[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[CH:14]=[CH:13][C:11]=2[N:12]=1.[CH3:20][N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>C1(C)C=CC=CC=1>[CH3:20][N:21]1[CH2:26][CH2:25][N:24]([C:8]2[O:9][C:10]3[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[CH:14]=[CH:13][C:11]=3[N:12]=2)[CH2:23][CH2:22]1
Reactant: CN1CCNCC1
Reactant: O=[N+]([O-])c1ccc2nc(S)oc2c1
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: CN1CCN(c2nc3ccc([N+](=O)[O-])cc3o2)CC1
Temperature: 100 °C

Procedure:
Phosphorus pentachloride (764 mg) was dissolved in anhydrous toluene (9 ml), the resulting solution was mixed with 2-mercapto-6-nitrobenzoxazole (600 mg) which has been obtained in the same manner as described in Reference Example 1, and the mixture was then stirred with heating at 100° C. for 3 hours. With cooling in an ice bath, to this was added dropwise N-methylpiperazine (3.4 ml). After 20 minutes of stirring, the thus obtained mixture was extracted with ethyl acetate, and the organic layer was washed with saturated sodium bicarbonate aqueous solution and saturated brine in that order. After drying with magnesium sulfate, the solvent was evaporated under a reduced pressure, and the resulting residue was purified by a silica gel column chromatography (methylene chloride:methanol=20:1) to obtain 2-(4-methyl-1-piperazinyl)-6-nitrobenzoxazole (668.9 mg) in the form of yellow crystalline powder.
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]=2[N+:22]([O-])=O)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C1COCC1.CO.[Pt]>[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]=2[NH2:22])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1cc(F)ccc1NC1CCN(Cc2ccccc2)CC1
Agent: [Pt]
Solvent: CO
Solvent: C1CCOC1
Product: Nc1cc(F)ccc1NC1CCN(Cc2ccccc2)CC1
Yield: 99.1 %

Procedure:
1-Benzyl-4-(4-fluoro-2-nitrophenylamino)-piperidine (10.1 g) were dissolved in 1:1 THF-methanol (150 ml) and hydrogenated with Pt/C (1.5 g, 10%) at room temperature for 1.5 h. The catalyst was then removed by filtration, and the filtrate evaporated to yield 9.1 g of the title compound as an oil. The compound was used without further purification.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[C:13]([O:17][C:18]([NH:20][C@@H:21]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:22]([O:24]C)=O)=[O:19])([CH3:16])([CH3:15])[CH3:14].[Br:33][CH2:34][Br:35]>O1CCCC1>[CH2:26]([C@H:21]([NH:20][C:18](=[O:19])[O:17][C:13]([CH3:14])([CH3:15])[CH3:16])[C:22](=[O:24])[CH:34]([Br:35])[Br:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: COC(=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Reactant: BrCBr
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)C(Br)Br
Temperature: -70 °C
Reaction time: 0.5 h
Yield: 20.8 %

Procedure:
Under nitrogen gas, a solution of diisopropylamine (2.4 g, 21.6 mmol) in tetrahydrofuran (10 mL) was added to n-butyllithium (in 1.6 M hexane, 13.5 mL, 21.6 mmol) at 5° C. and the mixture was stirred for 30 minutes (liquor A). Separately, under nitrogen gas in another vessel, a solution was prepared from methyl (S)-2-tert-butyloxycarbonylamino-3-phenylpropanoate (2.0 g, 7.2 mmol), dibromomethane (2.5 g, 14.4 mmol) and tetrahydrofuran (10 mL) and cooled to −70° C. (liquor B). To this liquor B was added said liquor A over 30 minutes at −70° C., and the mixture was stirred for 30 minutes at the same temperature and then warmed to 20° C. This reaction mixture was poured in 25 mL of2N-HCl for hydrolysis and, then, extracted with 10 mL of ethyl acetate. The organic layer was washed with 20 mL of water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to recover 2.670 g of black solid. This solid was recrystallized from ethyl acetate/hexane to provide brown crystals of tert-butyl (S)-(1-benzyl-3,3-dibromo-2-oxo-propyl)carbamate (630 mg, 92.2 area %, yield 19%).