Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11][C:10]3[CH:12]=[CH:13][C:14]([CH3:16])=[CH:15][C:9]=3[CH2:8][C:7](=O)[C:6]=2[CH:18]=1.[Cl-:19].[Ca+2].[Cl-].Cl>C1C=CC=CC=1>[Cl:19][CH:7]1[C:6]2[CH:18]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=2[S:11][C:10]2[CH:12]=[CH:13][C:14]([CH3:16])=[CH:15][C:9]=2[CH2:8]1
Reactant: Cc1ccc2c(c1)CC(=O)c1cc(F)ccc1S2
Reactant: [Cl-]
Agent: Cl
Agent: [Ca+2]
Solvent: c1ccccc1
Product: Cc1ccc2c(c1)CC(Cl)c1cc(F)ccc1S2
Reaction time: 8 h

Procedure:
103 G. of 8-fluoro-10,11-dihydro-2-methyl-dibenzo[b,f]thiepin-10-one, 500 ml. of benzene and 38.4 g. of finely pulverized calcium chloride are saturated with hydrochloric acid gas at 15° and stirred overnight. The residue is filtered, washed with benzene and evaporated under reduced pressure, whereby there is obtained 10-chloro-8-fluoro-10,11dihydro-2-methyl-dibenzo[b,f]-thiepin, having a melting point of 63°-64°.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N:9]([CH3:23])[C:10]2[N:11]=[CH:12][C:13]3[N:18]=[C:17]([NH:19][C:20](=[O:22])[CH3:21])[S:16][C:14]=3[N:15]=2)[CH:5]=[CH:6][C:7]=1[F:8].[CH3:24][C:25]([C:29]1[CH:30]=[C:31]([CH:35]=[CH:36][CH:37]=1)[C:32](O)=[O:33])([CH3:28])[C:26]#[CH:27].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(=O)([O-])O.[Na+]>N1C=CC=CC=1>[C:20]([NH:19][C:17]1[S:16][C:14]2[N:15]=[C:10]([N:9]([CH3:23])[C:4]3[CH:5]=[CH:6][C:7]([F:8])=[C:2]([NH:1][C:32](=[O:33])[C:31]4[CH:35]=[CH:36][CH:37]=[C:29]([C:25]([CH3:24])([CH3:28])[C:26]#[CH:27])[CH:30]=4)[CH:3]=3)[N:11]=[CH:12][C:13]=2[N:18]=1)(=[O:22])[CH3:21]
Reactant: CC(=O)Nc1nc2cnc(N(C)c3ccc(F)c(N)c3)nc2s1
Reactant: C#CC(C)(C)c1cccc(C(=O)O)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: c1ccncc1
Product: C#CC(C)(C)c1cccc(C(=O)Nc2cc(N(C)c3ncc4nc(NC(C)=O)sc4n3)ccc2F)c1
Temperature: 90 °C
Reaction time: 3 h
Yield: 62.1 %

Procedure:
A solution of N-{5-[(3-amino-4-fluorophenyl)(methyl)amino][1,3]thiazolo[5,4-d]pyrimidin-2-yl}acetamide (100 mg, 301 μmol) produced in Example D17(iv), 3-(1,1-dimethylprop-2-yn-1-yl)benzoic acid (141 mg, 753 μmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (286 mg, 753 μmol) in pyridine (4 mL) was stirred at 90° C. for 3 hr. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate solution (15 mL), and the mixture was extracted with ethyl acetate (20 mL, 5 mL). The combined organic layer was washed with saturated brine (5 mL), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (hexane/ethyl acetate=40/60→10/90), and the fractions containing the object product were concentrated under reduced pressure. The obtained residue was recrystallized from tetrahydrofuran and hexane to give the title compound (94 mg, 62%) as colorless crystals.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][CH2:6][C:7]1[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)[N:9]([C:19]2[CH:24]=[CH:23][C:22]([S:25](=[O:28])(=[O:27])[NH2:26])=[CH:21][CH:20]=2)[N:8]=1)C.[H-].[H-].[H-].[H-].[Li+].[Al+3].O>C1COCC1>[OH:3][CH2:4][CH2:5][CH2:6][C:7]1[CH:11]=[C:10]([C:12]2[CH:13]=[CH:14][C:15]([CH3:18])=[CH:16][CH:17]=2)[N:9]([C:19]2[CH:24]=[CH:23][C:22]([S:25]([NH2:26])(=[O:28])=[O:27])=[CH:21][CH:20]=2)[N:8]=1
Reactant: CCOC(=O)CCc1cc(-c2ccc(C)cc2)n(-c2ccc(S(N)(=O)=O)cc2)n1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(-c2cc(CCCO)nn2-c2ccc(S(N)(=O)=O)cc2)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 79.8 %

Procedure:
To a solution of ester 17c (0.11 g, 0.27 mmol) in 5 mL of THF was added LiAlH4 (32 mg, 0.85 mmol). The reaction mixture was stirred for 6 hours at room temperature. EtOAC (10 mL) and water (5 mL) were added successively. The solvent was removed in vacuo and the resulting solid was filtered. The crude product was purified by column chromatography (EtOAc/Hexanes in adequate proportions) to give the titled compound (80 mg, 81%) as a white solid. mp 123.4-125.6° C. 1H NMR (300 MHz, DMSO-d6): δ 7.79 (d, J=9 Hz, 2H), 7.47-7.42 (m, 2H), 7.39 (d, J=9 Hz, 2H), 7.20 (d, J=8 Hz, 2H), 7.13 (d, J=8 Hz, 2H), 6.49 (s, 1H), 4.52 (t, J=5 Hz, 1H), 3.53-3.45 (m, 2H), 2.73-2.59 (m, 2H), 2.31 (s, 3H), 1.87-1.75 (m, 2H).
Reaction SMILES: CO[C:3](=[O:40])[C:4]1[CH:9]=[CH:8][C:7]([C:10]([N:12]2[CH2:39][CH2:38][C:15]3[N:16]=[C:17]([NH:25][C@H:26]([C:28]4[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][CH:29]=4)[CH3:27])[N:18]([CH2:21][CH2:22][C:23]#[CH:24])[C:19](=[O:20])[C:14]=3[CH2:13]2)=[O:11])=[CH:6][CH:5]=1.[OH-].[Na+].[Cl-].[NH4+].C1C=CC2N(O)N=NC=2C=1.C[CH2:56][N:57]=[C:58]=NCCCN(C)C.Cl.CNC>CO.C(Cl)Cl.C(N(CC)CC)C>[CH2:21]([N:18]1[C:19](=[O:20])[C:14]2[CH2:13][N:12]([C:10]([C:7]3[CH:8]=[CH:9][C:4]([C:3]([N:57]([CH3:58])[CH3:56])=[O:40])=[CH:5][CH:6]=3)=[O:11])[CH2:39][CH2:38][C:15]=2[N:16]=[C:17]1[NH:25][C@H:26]([C:28]1[CH:33]=[CH:32][C:31]([C:34]([F:36])([F:35])[F:37])=[CH:30][CH:29]=1)[CH3:27])[CH2:22][C:23]#[CH:24]
Reactant: CCN=C=NCCCN(C)C
Reactant: C#CCCn1c(N[C@@H](C)c2ccc(C(F)(F)F)cc2)nc2c(c1=O)CN(C(=O)c1ccc(C(=O)OC)cc1)CC2
Agent: CNC
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CO
Solvent: CCN(CC)CC
Product: C#CCCn1c(N[C@@H](C)c2ccc(C(F)(F)F)cc2)nc2c(c1=O)CN(C(=O)c1ccc(C(=O)N(C)C)cc1)CC2
Temperature: 25 °C
Reaction time: 20 h
Yield: 65.1 %

Procedure:
4-{3-(3-Butynyl)-4-oxo-2-[(S)-1-(4-trifluoromethylphenyl)ethylamino]-3,5,7,8-tetrahydro-4H-pyrido[4,3-d]pyrimidine-6-carbonyl}benzoic acid methyl ester (360 mg) was dissolved in MeOH (6 ml), and 5N NaOH solution (0.65 ml) was added. The reaction mixture was stirred at room temperature for 20 hr. The reaction mixture was acidified with aqueous ammonium chloride. The mixture was extracted with methylene chloride and ethyl acetate successively, and the organic layer was dried over sodium sulfate. The organic layer was filtrated and concentrated under reduced pressure to afford the crude acid (0.40 g). The crude acid was suspended in methylene chloride (12 ml), and to the suspension HOBT (0.15 g), WSC (0.19 g), dimethylamine hydrochloride (0.11 g) and triethylamine (0.18 ml) were added. The reaction mixture was stirred at room temperature for 12 hr. The reaction solution was quenched with aqueous NaHCO3, and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified medium-pressure silica gel column chromatography (solvent; ethyl acetate:hexane=2:3 to 0:100). The titled compound (0.24 g) was obtained as a colorless amorphous substance.
Reaction SMILES: Cl([O-])=O.[Na+].O.P([O-])(O)(O)=O.[Na+].[OH:12][C:13]1[C:20]([C:21]([F:24])([F:23])[F:22])=[CH:19][CH:18]=[C:17]([CH3:25])[C:14]=1[CH:15]=[O:16].CC(=CC)C.S([O-])([O-])(=[O:33])=S.[Na+].[Na+].Cl>C(O)(C)(C)C.O1CCOCC1>[OH:12][C:13]1[C:20]([C:21]([F:22])([F:23])[F:24])=[CH:19][CH:18]=[C:17]([CH3:25])[C:14]=1[C:15]([OH:33])=[O:16]
Reactant: Cc1ccc(C(F)(F)F)c(O)c1C=O
Reactant: O=S([O-])([O-])=S
Agent: CC=C(C)C
Agent: Cl
Agent: O=P([O-])(O)O
Solvent: O
Solvent: C1COCCO1
Solvent: CC(C)(C)O
Product: Cc1ccc(C(F)(F)F)c(O)c1C(=O)O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
After an aqueous solution (40 ml) of sodium chlorite (6.0 g, 66.3 mmol) and sodium dihydrogenphosphate monohydrate (6.0 g, 43.5 mmol) was added dropwise to a solution of 2-hydroxy-6-methyl-3-(trifluoromethyl)benzaldehyde (4.65 g, 22.8 mmol) obtained in Example (28-2) in a mixture of tert-butyl alcohol (90 ml), 1,4-dioxane (30 ml) and 2-methyl-2-butene (30 ml), the mixture was stirred at room temperature for 1 hour. After the reaction mixture was cooled with ice and a 5% aqueous sodium thiosulfate solution was added thereto, the mixture was poured into 0.5N hydrochloric acid and extracted with ethyl acetate (twice). The organic layer was successively washed with water and a saturated aqueous NaCl solution and dried with anhydrous sodium sulfate. The residue obtained by removing the solvent under reduced pressure was crystallized using ethyl acetate and n-hexane to give 2-hydroxy-6-methyl-3-(trifluoromethyl)benzoic acid as a colorless compound (4.21 g, yield: 84%).
Reaction SMILES: [CH2:1]([O:9][C:10]1[CH:11]=[C:12](C(O)=O)[C:13](C2C=CC=CC=2)=[CH:14][CH:15]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]CC.CC(CCC)CCCOC1C=CC(O)=CC=1.[CH3:41][CH:42]([CH2:62][CH2:63][CH2:64][CH3:65])[CH2:43][CH2:44][CH2:45][O:46][C:47]1[CH:48]=[C:49]([C:59]([OH:61])=[O:60])[C:50]([C:53]2[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=2)=[CH:51][CH:52]=1.C(OC1C=CC(O)=CC=1)CCCCC>>[CH2:1]([O:9][C:10]1[CH:15]=[CH:14][C:13]([O:60][C:59]([C:49]2[C:50]([C:53]3[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=3)=[CH:51][CH:52]=[C:47]([O:46][CH2:45][CH2:44][CH2:43][C@@H:42]([CH3:41])[CH2:62][CH2:63][CH2:64][CH3:65])[CH:48]=2)=[O:61])=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCC(C)CCCOc1ccc(-c2ccccc2)c(C(=O)O)c1
Reactant: CCCCCCCCOc1ccc(-c2ccccc2)c(C(=O)O)c1
Agent: CCCC(C)CCCOc1ccc(O)cc1
Agent: CCCCCCOc1ccc(O)cc1
Product: CCCCCCOc1ccc(OC(=O)c2cc(OCCC[C@@H](C)CCCC)ccc2-c2ccccc2)cc1

Procedure:
The procedure of Example 1 was followed except that the 4-n-octoxybiphenylcarboxylic acid and 4-(4'-methylheptyloxy)phenol were replaced by 4-(4'-methyloctoxy) biphenylcarboxylic acid and 4-n-hexyloxyphenol and the title compound was obtained.
Reaction SMILES: [C:1]([O:4][CH:5]([C:7]1[S:11][C:10]2[C:12](=[O:20])[C:13]3[CH:17]=[CH:16][S:15][C:14]=3[C:18](=[O:19])[C:9]=2[CH:8]=1)[CH3:6])(=[O:3])[CH3:2].[K+].[Br-]>C(Cl)(Cl)Cl>[C:1]([O:4][CH:5]([C:7]1[S:11][C:10]2[C:12](=[O:20])[C:13]3[C:17]([CH:5]([O:4][C:1](=[O:3])[CH3:2])[CH3:6])=[CH:16][S:15][C:14]=3[C:18](=[O:19])[C:9]=2[CH:8]=1)[CH3:6])(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)c1cc2c(s1)C(=O)c1ccsc1C2=O
Agent: [Br-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Product: CC(=O)OC(C)c1cc2c(s1)C(=O)c1c(C(C)OC(C)=O)csc1C2=O
Yield: 72 %

Procedure:
Compound 15 was prepared from 14 in an identical manner to that compound 11. Yield 72%; yellow solid; mp 180-182° C.; UV (CHCl3) λmax 245 (log ε 4.32); IR (KBr) 1640, 1720 (C═O) cm−1; 1H NMR (CDCl3) δ 1.58 (d, J=6.6 Hz, 3H, C-7-CHCH3), 1.67 (d, J=6.6 Hz, 3H, C-2-CHCH3), 2.12 (s, 6H, COCH3×2), 6.10-6.16 (q, J=6.6 Hz, 1H, C-2-CH), 6.50-6.56 (q, J=6.6 Hz, 1H, C-7-CH), 7.50 (s, 1H, H-3), 7.62 (s, 1H, H-6); 13C NMR (CDCl3): δ 21.0, 21.1, 21.3, 22.0 (CH3×4), 67.4, 67.8 (CH×2), 123.2 (C-3), 128.6 (C-6), 154.0 (C-7), 154.1 (C-2), 169.6, 169.7 (C-2-C═O, C-7-C═O), 174.3, 174.8 (C-4, C-8); MS m/z 392 (M+); Anal. (C18H16O6S2) C, H.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C:10]([C:12]2[C:21](=[O:22])[C:20]3[C:15](=[C:16]([F:25])[C:17](F)=[C:18]([F:23])[CH:19]=3)[N:14](COCC[Si](C)(C)C)[CH:13]=2)=[O:11])=[CH:4][CH:3]=1.[OH:34][CH2:35][C:36]1[CH:41]=[CH:40][C:39]([OH:42])=[CH:38][CH:37]=1.[H-].[Na+].[Cl-].[NH4+]>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C:10]([C:12]2[CH:13]=[N:14][C:15]3[C:20]([C:21]=2[OH:22])=[CH:19][C:18]([F:23])=[C:17]([O:42][C:39]2[CH:40]=[CH:41][C:36]([CH2:35][OH:34])=[CH:37][CH:38]=2)[C:16]=3[F:25])=[O:11])=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)CCOCn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(F)c(F)c(F)c21
Reactant: OCc1ccc(O)cc1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: O=C(NCc1ccc(Cl)cc1)c1cnc2c(F)c(Oc3ccc(CO)cc3)c(F)cc2c1O
Temperature: 140 °C
Yield: 15.3 %

Procedure:
N-((4-Chlorophenyl)methyl)-4-oxo-6,7,8-trifluoro-1-(2-(trimethylsilyl)ethoxy) methyl-3-quinolinecarboxamide (1.00 g) from Preparation No. 13 and 4-hydroxymethyl phenol (500 mg) are dissolved in DMF (20 mL). Sodium hydride (60% dispersion, 80 mg) is added and the mixture is heated to 140° C. for 1 h. The reaction mixture is allowed to cool to rt, is poured into sat. aq. ammonium chloride (100 mL), and is extracted with ethyl acetate (3×50 mL). The organic layer is washed with brine (10 mL), dried (MgSO4), and concentrated. The crude product is purified by column chromatography (heptane/ethyl acetate, 1/1; 1/5) followed by recrystallization to afford 145 mg of the title compound as a white solid.
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][CH2:11][C@@:12]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[O:17][C:16](=[O:18])[N:15]([C@H:19]([C:21]2[CH:26]=[CH:25][C:24]([CH:27]=[CH2:28])=[CH:23][CH:22]=2)[CH3:20])[CH2:14][CH2:13]1)(C(C)(C)C)(C)C.[OH2:35].[OH-].[Na+].OO>C1COCC1.Cl>[OH:35][CH2:28][CH2:27][C:24]1[CH:25]=[CH:26][C:21]([C@@H:19]([N:15]2[CH2:14][CH2:13][C@:12]([CH2:11][CH2:10][CH2:9][OH:8])([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[O:17][C:16]2=[O:18])[CH3:20])=[CH:22][CH:23]=1
Reactant: C=Cc1ccc([C@H](C)N2CC[C@](CCCO[Si](C)(C)C(C)(C)C)(c3ccccc3)OC2=O)cc1
Reactant: O
Agent: Cl
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Product: C[C@@H](c1ccc(CCO)cc1)N1CC[C@](CCCO)(c2ccccc2)OC1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 20 %

Procedure:
To a solution of (R)-6-(3-(tert-butyldimethylsilyloxy)propyl)-6-phenyl-3-((S)-1-(4-vinylphenyl)ethyl)-1,3-oxazinan-2-one (20 mg, 0.042 mmol) in dry THF (10 mL) was added BH3 THF (0.5 ml, 0.5 mmol) dropwise at 0° C. After stirring for 2 h at rt, the mixture was cooled to 0° C., and H2O (0.5 mL), 3 M aqueous NaOH (0.5 mL) and 30% H2O2 (0.5 mL) were added successively added. The mixture was stirred overnight at rt. The mixture was diluted with 1 M HCl, and the pH of the mixture was adjusted to 6-7 with 1 M HCl. The layers were separated, and the aqueous phase was extracted with EtOAc (3×5 mL). The combined organic layer was washed with a saturated aqueous NaHCO3 solution (5 mL) and brine (5 mL), dried over Na2SO4, and concentrated in vacuo to give the crude product, which was purified by TLC and preparative HPLC to afford (R)-3-((S)-1-(4-(2-hydroxyethyl)phenyl)ethyl)-6-(3-hydroxy propyl)-6-phenyl-1,3-oxazinan-2-one (7.02 mg, 20%). LC-MS Method 2 tR=1.757, min, m/z=406.2; 1H NMR (CDCl3): 1.31 (m, 1H), 1.47 (d, 3H), 1.68 (m, 1H), 1.89 (m, 2H), 2.18 (m, 2H), 2.70 (m, 1H), 2.83 (m, 1H), 3.49 (m, 2H), 3.71 (m, 2H), 5.58 (m, 1H), 6.75 (m, 2H), 6.88 (m, 2H), 7.23 (m, 5H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[N:9][C:10]2[CH:15]=[CH:14][C:13]([N:16]=[N:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:12][CH:11]=2)=[CH:4][C:3]=1[CH3:24].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[CH2:45][CH2:46][CH2:47][CH2:48][O:49][C:50](=[O:53])[CH:51]=[CH2:52].N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[C:50]([O:49][CH2:48][CH2:47][CH2:46][CH2:45][O:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[N:9][C:10]2[CH:15]=[CH:14][C:13]([N:16]=[N:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:12][CH:11]=2)=[CH:4][C:3]=1[CH3:24])(=[O:53])[CH:51]=[CH2:52]
Reactant: Cc1cc(N=Nc2ccc(N=Nc3ccccc3)cc2)ccc1O
Reactant: C=CC(=O)OCCCCO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C=CC(=O)OCCCCOc1ccc(N=Nc2ccc(N=Nc3ccccc3)cc2)cc1C
Temperature: -30 °C
Reaction time: 0.75 h

Procedure:
To a solution of 0.63 g of 4-hydroxy-3-methyl4′-phenylazo-azobenzene, 1.05 g of triphenylphosphine and 0.58 g of 4-hydroxybutylacrylate in 10 ml THF; which was cooled to −30° C., was added dropwise a solution of 0.70 g of diethyl azodicarboxylate in 5 ml THF. After complete addition, the reaction mixture was stirred for further 45 min at room temperature, and then concentrated to dryness. The obtained yellow-red residue was purified by filtration on silica using methylenechloride as the eluent to give 0.65 g of pure yellow-orange crystalys; λmax. (CB 483): 395 nm.
Reaction SMILES: [Br:1][C:2]1[C:7]2[C:8](=O)[N:9]3[CH2:21][CH2:20][CH2:19][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3C(O)=O)[C:6]=2[CH:5]=[CH:4][CH:3]=1.[OH2:23]>CN(C)C=O>[Br:1][C:2]1[C:7]2[CH2:8][N:9]3[CH2:21][CH2:20][CH2:19][C@H:10]3[CH:11]3[C:15](=[O:23])[N:14]=[CH:13][N:12]3[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1ncn2c1[C@@H]1CCCN1C(=O)c1c(Br)cccc1-2
Reactant: O
Solvent: CN(C)C=O
Product: O=C1N=CN2c3cccc(Br)c3CN3CCC[C@H]3C12
Reaction time: 0.5 h

Procedure:
109.03 g (300 mmol) of (S)-8-bromo-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-1-carboxylic acid was decarboxylated at 290°. The melt was dissolved in about 400 ml of N,N-dimethylformamide and the solution was poured into 2.5 l of water. After stirring for 30 minutes the precipitated product was filtered off, rinsed with water and dried. There was obtained (S)-8-bromo-11,12,13,13a-tetrahydro-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-one of melting point 232°-233°.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:9]=[N:10][N:11]([CH2:13][CH:14]3[CH2:16][CH:15]3[C:17]([O:19]CC)=[O:18])[CH:12]=2)=[CH:4][C:3]=1[O:22][CH:23]([C:25]1[C:30]([Cl:31])=[CH:29][CH:28]=[C:27]([F:32])[C:26]=1[Cl:33])[CH3:24].[OH-].[Na+]>CO>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:9]=[N:10][N:11]([CH2:13][CH:14]3[CH2:16][CH:15]3[C:17]([OH:19])=[O:18])[CH:12]=2)=[CH:4][C:3]=1[O:22][CH:23]([C:25]1[C:30]([Cl:31])=[CH:29][CH:28]=[C:27]([F:32])[C:26]=1[Cl:33])[CH3:24]
Reactant: CCOC(=O)C1CC1Cn1cc(-c2cnc(N)c(OC(C)c3c(Cl)ccc(F)c3Cl)c2)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(Oc1cc(-c2cnn(CC3CC3C(=O)O)c2)cnc1N)c1c(Cl)ccc(F)c1Cl
Temperature: 80 °C
Reaction time: 3 h
Yield: 91.6 %

Procedure:
To a reaction solution of compound (4-6) (377 mg, 0.76 mmol) in 5.0 mL of MeOH at room temperature under N2 was added another solution of 2.0 N NaOH (2) (1.5 mL, 3.04 mmol). The resulting mixture was stirred at 80° C. for 3 hours. The reaction mixture was concentrated by vacuum to remove most of the MeOH and acidified by 2 M HCl to pH 4.0. The mixture was extracted with CH2Cl2 (2×200 mL); the organic layers were washed with brine (50 mL), and dried (Na2SO4) and concentrated by vacuum to give 324 mg of (4-7) as a yellow solid. (92% yield). 1H NMR (400 MHz, DMSO-D6) δ ppm 0.92-1.04 (m, 2H) 1.57-1.72 (m, 2H) 1.76-1.90 (m, 3H) 3.98-4.18 (m, 2H) 6.46 (s, 2H) 6.89-7.02 (m, 1H) 7.29-7.52 (m, 2H) 7.52-7.63 (m, 2H) 7.73 (d, J=1.52 Hz, 1H) 7.94 (s, 1H) 12.19 (s, 1H). LCMS calcd for C21H19Cl2FN4O3 (M−H) 463, found 463. HPLC purity 87%.
Reaction SMILES: FC(F)(F)C(O)=O.FC(F)(F)C(O)=O.[CH3:15][C:16]1[CH:25]=[C:24]([CH2:26][O:27][C:28]2[CH:52]=[CH:51][C:31]([C:32]([NH:34][CH2:35][C:36]3([CH:45]4[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]4)[C:41](=[O:42])[NH:40][C:39](=[O:43])[NH:38][C:37]3=[O:44])=[O:33])=[CH:30][CH:29]=2)[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:17]=1.[O:53]1[CH2:58][CH2:57][C:56](=O)[CH2:55][CH2:54]1>>[CH3:15][C:16]1[CH:25]=[C:24]([CH2:26][O:27][C:28]2[CH:29]=[CH:30][C:31]([C:32]([NH:34][CH2:35][C:36]3([CH:45]4[CH2:50][CH2:49][N:48]([CH:56]5[CH2:57][CH2:58][O:53][CH2:54][CH2:55]5)[CH2:47][CH2:46]4)[C:37](=[O:44])[NH:38][C:39](=[O:43])[NH:40][C:41]3=[O:42])=[O:33])=[CH:51][CH:52]=2)[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:17]=1
Reactant: Cc1cc(COc2ccc(C(=O)NCC3(C4CCNCC4)C(=O)NC(=O)NC3=O)cc2)c2ccccc2n1
Reactant: O=C1CCOCC1
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(COc2ccc(C(=O)NCC3(C4CCN(C5CCOCC5)CC4)C(=O)NC(=O)NC3=O)cc2)c2ccccc2n1
Yield: 22 %

Procedure:
Following the procedure analogous to that used in reaction (9), the compound from Example 29 was reacted with tetrahydro-4H-pyran-4-one for 5 days to provide the title compound (5 mg, 22%). MS found: (M+H)+=600.4.
Reaction SMILES: [Cl:1][CH2:2][CH2:3]C(O)=O.[Br:7][C:8]1[CH:17]=[CH:16][C:15]([OH:18])=[C:14]2[C:9]=1[CH:10]=[CH:11][CH:12]=[N:13]2.[BH4-].[Na+]>C1COCC1.C(OCC)(=O)C>[Br:7][C:8]1[CH:17]=[CH:16][C:15]([OH:18])=[C:14]2[C:9]=1[CH2:10][CH2:11][CH2:12][N:13]2[CH2:3][CH2:2][Cl:1]
Reactant: O=C(O)CCCl
Reactant: Oc1ccc(Br)c2cccnc12
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Oc1ccc(Br)c2c1N(CCCl)CCC2
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
In a round bottom flask, 3-chloropropanoic acid (8.44 g, 89.3 mmol, 20 eq.) was added to 5-bromoquinolin-8-ol (1 g, 4.46 mmol, 1 eq.) in 15 mL THF at 0° C. NaBH4 (759 mg, 20 mmol, 4.5 eq.) was added portionwise in 50 minutes at 0° C. The reaction was stirred at 0° C. for 30 minutes then heated to 80° C. for 2 hours. The reaction was cooled down. Reaction mixture was diluted with ethyl acetate and washed with brine, dried (MgSO4), filtered, concentrated to give 5-bromo-1-(2-chloroethyl)-1,2,3,4-tetrahydroquinolin-8-ol crude. LCMS-ESI+ (m/z): [M+H]+ calcd for C11H14BrClNO: 291.58. found: 292.0.
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=1.II.Cl[P:22]([C:27]([CH3:30])([CH3:29])[CH3:28])[C:23]([CH3:26])([CH3:25])[CH3:24]>CCOCC>[C:23]([P:22]([C:27]([CH3:30])([CH3:29])[CH3:28])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=1)([CH3:26])([CH3:25])[CH3:24]
Reactant: CC(C)(C)P(Cl)C(C)(C)C
Reactant: FC(F)(F)c1ccc(-c2ccccc2Br)cc1
Agent: II
Agent: [Mg]
Solvent: CCOCC
Product: CC(C)(C)P(c1ccccc1-c1ccc(C(F)(F)F)cc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 14 h
Yield: 10.7 %

Procedure:
An oven dried Schlenk tube was evacuated and backfilled with argon and charged with magnesium turnings (90 mg, 3.69 mmol), 2-bromo-4′-(trifluoromethyl)biphenyl (1.01 g, 3.35 mmol), and a crystal of iodine. The tube was purged with argon for 5 minutes, then THF (6 mL) was added through a rubber septum and the reaction mixture was heated to reflux for 1 hour. The reaction mixture was cooled to room temperature and cuprous chloride (365 mg, 3.69 mmol) and chloro-di-t-butylphosphine (0.765 mL, 4.03 mmol) were added. Heating was resumed for 14 hours. The reaction mixture was then cooled to room temperature and diluted with ether (40 mL). The suspension was filtered to isolate the solid. The solid was partitioned between ethyl acetate (60 mL) and 38% ammonium hydroxide (75 mL). The aqueous layer was extracted with ethyl acetate (60 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, decanted, and concentrated in vacuo. The product was crystallized from MeOH (10 mL) to afford 131 mg (11%) of pale yellow needles. A second crop was isolated by concentrating the mother liquor and recrystallizing the solid from MeOH (20 mL) and water (2 mL) to afford 260 mg (21%) of the product.
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[NH:15][C:14](=[O:19])[C:13]2=[O:20]>>[CH2:1]([C:13]1([OH:20])[C:12]2[C:16](=[CH:17][CH:18]=[C:10]([Cl:9])[CH:11]=2)[NH:15][C:14]1=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1Nc2ccc(Cl)cc2C1=O
Reactant: BrCc1ccccc1
Product: O=C1Nc2ccc(Cl)cc2C1(O)Cc1ccccc1
Yield: 37.3 %

Procedure:
With 5.00 g of benzyl bromide and 1.50 g of 5-chloroisatin as starting material, 844 mg of the title compound (white solid) was obtained by a similar method to Step 21-1.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:24])=[C:6]([C@:8]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][C:15]=2[O:22][CH3:23])([CH3:11])[CH2:9][OH:10])[CH:7]=1.N1C=CC=CC=1.[S:31](Cl)(Cl)=[O:32]>ClCCl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:24])=[C:6]([C:8]2([CH3:11])[CH2:9][O:10][S@@:31](=[O:32])[N:12]2[CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][C:15]=2[O:22][CH3:23])[CH:7]=1
Reactant: COc1ccc(CN[C@@](C)(CO)c2cc(Br)ccc2F)c(OC)c1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1ccc(CN2[S@](=O)OCC2(C)c2cc(Br)ccc2F)c(OC)c1
Temperature: 23 °C
Reaction time: 0.08 h
Yield: 99.7 %

Procedure:
To a solution of (R)-2-(5-bromo-2-fluorophenyl)-2-(2,4-dimethoxybenzylamino)propan-1-ol (14.1 g, 35.4 mmol, Eq: 1.00) and pyridine (14.0 g, 14.3 ml, 177 mmol, Eq: 5.0) in dichloromethane (258 ml) at 78° C. was dropwise added thionyl chloride (5.05 g, 3.1 ml, 42.5 mmol, Eq: 1.2), stirring was continued at 78° C. for 5 min, the cooling bath was removed and the mixture was slowly warmed up to 23° C. and stirring was continued for 20 min. Extracted with 5% citric acid and sat NaHCO3-sol., dried the organic layer over Na2SO4, filtered off and evaporated totally to give the (R)-4-(5-bromo-2-fluoro-phenyl)-3-(2,4-dimethoxy-benzyl)-4-methyl-[1,2,3]oxathiazolidine 2-oxide (15.7 g, 35.3 mmol, 99.8% yield) as a light yellow oil, which needed no further purification. MS (ISP): m/z=444.1 [M+H]+ and 446.0 [M+2+H]+.