Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[I:11])[C:5](O)=[O:6].C(Cl)(=O)C([Cl:15])=O>C(Cl)Cl.CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[I:11])[C:5]([Cl:15])=[O:6]
Reactant: O=C(O)c1ccc(I)c(F)c1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)c1ccc(I)c(F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.1 %

Procedure:
To a solution of 3-fluoro-4-iodobenzoic acid (1.3 g, 4.9 mmol) in anhydrous CH2Cl2 (20 mL) at 0° C. was added oxalyl chloride (1.2 mL, 15.0 mmol) followed by catalytic DMF (7 drops). The reaction mixture was allowed to warm to room temperature, stirred for 2 h, and then concentrated in vacuo to provide 1.2 g of 3-fluoro-4-iodobenzoyl chloride as a yellow solid. The acid chloride (600 mg, 2.1 mmol) was dissolved in anhydrous CH2Cl2, and dimethylamine (2.1 mL, 4.2 mmol, 2M in THF) was added followed by triethylamine (0.6 mL, 4.2 mmol). The reaction mixture was stirred at room temperature for 2 h and then diluted with CH2Cl2. The organic layer was washed with water, washed with brine, dried (MgSO4), filtered, and concentrated. The resulting solid was stirred with diethyl ether and filtered to afford 353 mg of the title compound as a white solid. 1H NMR (300 MHz, DMSO-d6): δ 7.91 (dd, 1H), 7.32 (dd, 1H), 7.04 (dd, 1H), 2.97 (s, 3H), 2.89 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[C:3]2[N:4]([CH:8]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][S:18]([CH2:21][CH2:22][CH2:23]Cl)(=[O:20])=[O:19])=[CH:13][CH:12]=3)[N:10]=2)[CH:5]=[CH:6][CH:7]=1.[NH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1>>[CH3:1][C:2]1[C:3]2[N:4]([CH:8]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][S:18]([CH2:21][CH2:22][CH2:23][N:25]4[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]4)(=[O:20])=[O:19])=[CH:13][CH:12]=3)[N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: C1CCNCC1
Reactant: Cc1cccn2cc(-c3ccc(NS(=O)(=O)CCCCl)cc3)nc12
Product: Cc1cccn2cc(-c3ccc(NS(=O)(=O)CCCN4CCCCC4)cc3)nc12
Temperature: 25 °C

Procedure:
The product of Step A (65 mg) and piperidine (1.0 mL) were heated at 100° C. for 1.5 hours. The reaction was cooled to ambient temperature and partitioned between ethyl acetate (15 mL) and saturated sodium bicarbonate solution (15 mL). The aqueous portion was extracted with a fresh portion of ethyl acetate (15 mL) (2×) and the organic portions combined and washed with brine (15 mL). The organic portions were dried over magnesium sulfate, filtered and evaporated. The residue was purified via silica gel chromatography (dichloromethane/methanol) to give the title compound (26 mg).). 1H-NMR (CD3OD) δ 1H-NMR (CD3OD) δ8.14 (d, J=7.0 Hz, 1H), 8.00 (s, 1H), 7.81 (m, 2H), 7.23 (m, 2H), 6.98 (m, 1H), 6.70 (t, J=7.0 Hz, 1H), 3.07 (m, 2H), 2.49 (s, 3H), 2.31 (m, 6H), 1.87 (m, 2H), 1.44 (m, 4H), 1.33 (m, 2H).
Reaction SMILES: Br[CH2:2][CH2:3][OH:4].Cl[S:6]([N:9]=[C:10]=[O:11])(=[O:8])=[O:7].[NH:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][CH2:13]1.Cl>ClCCl.C(N(CC)CC)C>[N:12]1([S:6]([N:9]2[CH2:2][CH2:3][O:4][C:10]2=[O:11])(=[O:8])=[O:7])[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][CH2:13]1
Reactant: c1ccc2c(c1)CCN2
Reactant: O=C=NS(=O)(=O)Cl
Reactant: OCCBr
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C1OCCN1S(=O)(=O)N1CCc2ccccc21
Temperature: 25 °C
Reaction time: 24 h

Procedure:
7.1 ml of 2-bromoethanol in 50 ml of dichloromethane are added to a solution of 8.72 ml of chlorosulphonyl isocyanate in 40 ml of dichloromethane. The resulting solution is then added, at 0° C., to a solution of 11.23 ml of indoline and 15.46 ml of triethylamine in 200 ml of dichloromethane. After stirring for 24 hours at ambient temperature, 10N hydrochloric acid is added. The organic phase is then washed with hydrochloric acid and then with water, and is dried, filtered and concentrated, allowing the expected product to be obtained.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][OH:6].N1C=CC=CC=1.[CH2:13]([O:20][C:21](Cl)=[O:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>ClCCl>[OH:6][CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:21](=[O:22])[O:20][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: NCCCCO
Reactant: O=C(Cl)OCc1ccccc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(NCCCCO)OCc1ccccc1
Yield: 27.4 %

Procedure:
A solution of 4-amino-1-butanol (7.68 g) and pyridine (7.00 g) in dichloromethane (100 mL) was chilled in an ice bath and a solution of benzylchloroformate (14.37 g) in dichloromethane (100 mL) was slowly added with stirring over a period of thirty minutes. The ice bath was removed and the reaction was stirred for an additional 16 hours. Hydrochloric acid (1.2 M, 200 mL) was added and phases were separated. The organic phase was dried (MgSO4), filtered and concentrated under reduced pressure. The resulting residue was recrystallized from toluene and dried under vacuum to provide 5.15 g of benzyl (4-hydroxybutyl)carbamate.
Reaction SMILES: [CH2:1]1OCCOCCOCCOCCOCCOC1.CC([O-])(C)C.[K+].[NH:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][C:32]=2[C:34]([N:36]2[CH2:40][C@@H:39]([CH:41]3[CH2:43][CH2:42]3)[C@H:38]([CH2:44][N:45]3[CH2:50][CH2:49][CH:48]([C:51]4[CH:56]=[CH:55][C:54]([F:57])=[CH:53][CH:52]=4)[CH2:47][CH2:46]3)[CH2:37]2)=[O:35])[CH:27]=[CH:26]1.CI>C1COCC1>[CH3:1][N:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][C:32]=2[C:34]([N:36]2[CH2:40][C@@H:39]([CH:41]3[CH2:42][CH2:43]3)[C@H:38]([CH2:44][N:45]3[CH2:50][CH2:49][CH:48]([C:51]4[CH:52]=[CH:53][C:54]([F:57])=[CH:55][CH:56]=4)[CH2:47][CH2:46]3)[CH2:37]2)=[O:35])[CH:27]=[CH:26]1
Reactant: O=C(c1cccc2cc[nH]c12)N1C[C@@H](CN2CCC(c3ccc(F)cc3)CC2)[C@H](C2CC2)C1
Reactant: C1COCCOCCOCCOCCOCCO1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CI
Solvent: C1CCOC1
Product: Cn1ccc2cccc(C(=O)N3C[C@@H](CN4CCC(c5ccc(F)cc5)CC4)[C@H](C4CC4)C3)c21
Reaction time: 1 h

Procedure:
To a solution of 0.015 g (0.06 mmol) of 18-crown-6 and 0.060 mL (0.06 mmol) of KOtBu (1M in THF) in 2 mL of THF was added 0.15 g (0.34 mmol) of 1-(7-indolecarbonyl)-3-(R)-(4-(4-fluorophenyl)piperidinylmethyl)-4-(S)-(cyclopropyl)pyrrolidine and the mixture was stirred for 15 min after which 0.0062 mL (0.1 mmol) methyl iodide was added. After 2 h another 0.005 mL of methyl iodide was added and the reaction mixture was stirred for 1 h. The reaction mixture was partitioned between ethyl acetate and sat'd NaHCO3 solution. The organic fraction was dried over MgSO4, filtered and the filtrate was concentrated. The residue was purified by chomatography (silica, Waters RCM 8×10 Novapak) (acetone:hexanes, 1:5) to give the title compound. 1H NMR (CD3OD) d (key peaks) 7.58 (m, 2H), 7.15-6.92 (m, 5H), 7.39 (m, 1H), 6.53 (m, 1H), 3.80 (s, 3H), 0.06 (m, 5H); Mass Spectrum (CI) m/e=460 (M+1).
Reaction SMILES: [CH3:1][C:2]1([CH2:19][CH2:20][CH2:21][C:22]([OH:24])=O)[C:14]2[N:13]3[CH:15]=[CH:16][N:17]=[C:12]3[C:11](=[O:18])[NH:10][C:9]=2[C:8]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]1=2.C(Cl)(=O)C(Cl)=O.C[N:32](C)C=O.N>C(Cl)(Cl)Cl.CO>[CH3:1][C:2]1([CH2:19][CH2:20][CH2:21][C:22]([NH2:32])=[O:24])[C:14]2[N:13]3[CH:15]=[CH:16][N:17]=[C:12]3[C:11](=[O:18])[NH:10][C:9]=2[C:8]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]1=2
Reactant: CC1(CCCC(=O)O)c2ccccc2-c2[nH]c(=O)c3nccn3c21
Reactant: CN(C)C=O
Agent: N
Agent: O=C(Cl)C(=O)Cl
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CC1(CCCC(N)=O)c2ccccc2-c2[nH]c(=O)c3nccn3c21
Reaction time: 3 h

Procedure:
To a very fine suspension of 0.4 g of 4-(10-methyl-4,5-dihydro-4-oxo-10H-imidazo[1,2-a]indeno-[1,2-e]pyrazin-10-yl)butyric acid in 20 ml of chloroform is added, at a temperature in the region of 20° C., 0.13 g of oxalyl chloride followed by a solution of 0.5 ml of dimethylformamide in 5 ml of chloroform, and the stirring is continued for 3 hours. 2 ml of a 5.6N solution of ammonia in methanol are then added and the stirring is continued for 18 hours. The reaction mixture is concentrated on a rotary evaporator and the evaporation residue is stirred for 2 hours with 30 ml of distilled water. The solid is filtered off and purified by chromatography on a column of silica (25 g), eluting under a pressure of 0.5 bar with a mixture of dichloromethane and methanol (9/1 by volume). 0.045 g of 4-(10-methyl-4,5-dihydro-4-oxo-10H-imidazo[1,2-a]indeno[1,2-e]pyrazin-10-yl)butyramide is obtained in the form of a light-beige-coloured solid melting above 260° C. (1H NMR spectrum: (300 MHz; (CD3)2SO-d6 ; δ in ppm): 0.65 (mt, 2H: CH2); 1.53 (s, 3H: CH3); 1.80 (t, J=7.5 Hz, 2H: CH2CON); 2.10 and 2.28 (2 mts, 1H each: hetero-CH2); 6.58 and 7.10 (2 broad s, 1H each: CONH2); 7.27 and 7.33 (2 t, J=7.5 Hz, 1H each: H 7 and H 8); 7.42 and 7.92 (2 broad s, 1H each: H of the imidazole); 7.50 and 7.68 (2 broad d, J=7.5 Hz, 1H each: H 6 and H 8)).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:11])[C:5](=[CH:9][CH:10]=1)[C:6](O)=[O:7].C(Cl)(=O)C(Cl)=O.[OH-].[NH4+:19]>CN(C=O)C.C1COCC1>[F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:19])=[O:7])=[C:4]([OH:11])[CH:3]=1
Reactant: O=C(O)c1ccc(F)cc1O
Reactant: [NH4+]
Agent: O=C(Cl)C(=O)Cl
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: NC(=O)c1ccc(F)cc1O
Reaction time: 2 h

Procedure:
DMF (2 drops) was added to a mixture of 4-fluorosalicylic acid (5 g, 32.0 mmol) and oxalyl chloride (7.11 mL, 80.1 mmol) in THF (35 mL). The mixture was stirred for 2 hours then reduced in vacuo. The residue was dissolved in THF (20 mL) and added dropwise to concentrated ammonium hydroxide solution (30 mL) at 0° C. The reaction was stirred at RT for 20 hours and the THF removed in vacuo. The residue was acidified and a white solid was filtered off. The solid was dissolved in ethyl acetate (80 mL) and the solution washed with water (50 mL), saturated sodium bicarbonate solution (50 mL), dried (MgSO4), and reduced in vacuo to give the desired compound as a yellow solid (2.4 g).
Reaction SMILES: [NH:1]1[C:5]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[CH2:12][NH2:13])=[CH:4][N:3]=[CH:2]1.N1C=CC=CC=1.[C:20](Cl)(=[O:22])[CH3:21]>ClCCl>[NH:3]1[CH:4]=[C:5]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[CH2:12][NH:13][C:20](=[O:22])[CH3:21])[N:1]=[CH:2]1
Reactant: NCc1ccccc1-c1cnc[nH]1
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)NCc1ccccc1-c1c[nH]cn1
Temperature: 25 °C
Reaction time: 16 h
Yield: 12.6 %

Procedure:
To a solution of (2-(1H-imidazol-5-yl)phenyl)methanamine (77 mg, 0.445 mmol) in dichloromethane (3 mL) was added pyridine (0.11 mL, 1.33 mmol) and acetyl chloride (76 μL, 1.07 mmol). The reaction was stirred at room temperature for 16 h. The solvent was removed under reduced pressure. The crude product was dissolved in methanol (4 mL) and refluxed for 2 h. The solution was concentrated and the residue was purified by flash column chromatography (silica gel, 5%-20% MeOH/DCM as eluent) to afford the desired product as a white solid (12 mg, 0.056 mmol, 13%). 1H NMR: 2.01 (s, 3H), 4.44 (d, 2H, J=6.3 Hz), 7.21 (d, 1H, J=1.2 Hz), 7.27-7.30 (m, 2H), 7.41-7.48 (m, 2H), 7.73 (d, 1H, J=0.9 Hz), 7.96 (s, 1H).
Reaction SMILES: [CH2:1]([N:8]1[CH2:24][CH2:23][C:11]2([O:13][C:12]2([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[O:14]C)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.O>CCOCC>[CH2:1]([N:8]1[CH2:9][CH2:10][C:11]([C:12]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)=[O:14])([OH:13])[CH2:23][CH2:24]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC1(c2ccc(F)cc2)OC12CCN(Cc1ccccc1)CC2
Agent: Cl
Solvent: O
Solvent: CCOCC
Product: O=C(c1ccc(F)cc1)C1(O)CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96.2 %

Procedure:
6-Benzyl-2-(4-fluoro-phenyl)-2-methoxy-1-oxa-6-aza-spiro[2.5]octane (0.600 g, 1.83 mmol) was solved in ether (6 mL), 0.6 mL of aqueous HCl was added (37%) and the reaction mixture was stirred at room temperature. After 0.5 h the reaction was finished and water was added and the product precipitate. The mixture was filtrated and the solid was recrystallized ethanol/ether to yield the title compound as a white solid (0.550 g, 1.76 mmol, 96%). MS (m/e): 314.0 (M+H+).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].C[CH:12]([CH:16]([CH3:24])[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)C([O-])=O.[Cl:25][CH2:26][C@@H:27]([OH:34])[CH2:28][C:29](OCC)=[O:30].[C:35]([OH:38])(=[O:37])[CH3:36]>O1CCCC1>[Cl:25][CH2:26][CH:27]([OH:34])[CH2:28][C:29](=[O:30])[CH2:36][C:35]([O:38][C:16]([CH3:12])([CH3:24])[CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)=[O:37]
Reactant: CC(=O)O
Reactant: CC(Cc1ccccc1)C(C)C(=O)[O-]
Reactant: CCOC(=O)C[C@H](O)CCl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(Cc1ccccc1)OC(=O)CC(=O)CC(O)CCl
Temperature: -75 °C
Reaction time: 1 h

Procedure:
Lithium bis(trimethylsilyl)amide (190.8 g) was dissolved in tetrahydrofuran (1400 ml) in a main reaction vessel, followed by cooling to −75° C. and nitrogen purging. 2-methyl-1-phenylpropan-2-ylacetate (219.2 g) was charged in a separate reaction vessel and was dissolved by the addition of tetrahydrofuran (300 ml), and the solution was gradually added dropwise to the main reaction vessel over 40 minutes, followed by stirring for 1 hour. (S)-ethyl 4-chloro-3-hydroxybutanoate (50 g) was added and dissolved in tetrahydrofuran (50 ml) and the resulting solution was gradually added dropwise to the main reaction vessel over 20 minutes, followed by stirring for 5 hours. Thereafter, acetic acid (124 ml) was gradually added dropwise thereto, and the temperature was gradually elevated to 0° C. Ethyl acetate (1500 ml) and purified water (1500 ml) were added thereto, followed by stirring for 10 minutes, and the organic layer was separated. The separated organic layer was washed successively with a saturated sodium chloride aqueous solution (1500 ml×2), a saturated sodium bicarbonate aqueous solution (1500 ml) and purified water (1500 ml), dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure to give the crude title compound (299.0 g). A portion of the crude compound was purified by silica gel column (ethyl acetate:n-hexane=3:7(v/v)) to obtain the following NMR data.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@H:9]1[C:16]([OH:18])=O)=[O:7])(C)(C)C.[CH3:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH3:26])[C:21]=1[C:27]1[CH:32]=[CH:31][C:30](C(O)=O)=[CH:29][CH:28]=1.[NH2:36][CH2:37][CH:38]([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[OH:39]>>[CH3:26][C:22]1[CH:23]=[CH:24][CH:25]=[C:20]([CH3:19])[C:21]=1[C:27]1[CH:28]=[CH:29][C:30]([C:6]([N:8]2[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@H:9]2[C:16]([NH:36][CH2:37][CH:38]([OH:39])[C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)=[O:18])=[O:7])=[CH:31][CH:32]=1
Reactant: NCC(O)c1ccccc1
Reactant: CON=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Reactant: Cc1cccc(C)c1-c1ccc(C(=O)O)cc1
Product: CON=C1C[C@@H](C(=O)NCC(O)c2ccccc2)N(C(=O)c2ccc(-c3c(C)cccc3C)cc2)C1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylic acid, 2′,6′-dimethyl[1,1′-biphenyl]-4-carboxylic acid, and (1RS)-2-amino-1-phenylethanol, the title compound was obtained in 95% purity by HPLC. MS(ESI+): m/z=486.
Reaction SMILES: [F:1][C:2]1[C:3]([O:21][CH3:22])=[C:4]([CH:8]([CH2:18][CH2:19][CH3:20])[CH2:9][C:10]([OH:17])([C:13]([F:16])([F:15])[F:14])[CH:11]=O)[CH:5]=[CH:6][CH:7]=1.[NH2:23][C:24]1[CH:33]=[CH:32][CH:31]=[C:30]2[C:25]=1[CH:26]=[N:27][C:28]([CH3:34])=[N:29]2.O>C1(C)C=CC=CC=1.[O-]CC.[O-]CC.[O-]CC.[O-]CC.[Ti+4]>[F:1][C:2]1[C:3]([O:21][CH3:22])=[C:4]([CH:8]([CH2:18][CH2:19][CH3:20])[CH2:9][C:10]([C:13]([F:16])([F:14])[F:15])([OH:17])[CH:11]=[N:23][C:24]2[CH:33]=[CH:32][CH:31]=[C:30]3[C:25]=2[CH:26]=[N:27][C:28]([CH3:34])=[N:29]3)[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ncc2c(N)cccc2n1
Reactant: CCCC(CC(O)(C=O)C(F)(F)F)c1cccc(F)c1OC
Agent: [Ti+4]
Agent: CC[O-]
Solvent: Cc1ccccc1
Solvent: O
Product: CCCC(CC(O)(C=Nc1cccc2nc(C)ncc12)C(F)(F)F)c1cccc(F)c1OC
Yield: 86.8 %

Procedure:
300 mg (0.97 mmol) of 4-(3-fluoro-2-methoxyphenyl)-2-hydroxy-2-(trifluoromethyl)heptanal and 138 mg (0.87 mmol) of 5-amino-2-methylquinazoline are dissolved in 28 ml of toluene and the solution is admixed with 0.48 ml of titanium tetraethoxide. The reaction mixture is heated at 100° for 2 hours, cooled, poured into water and stirred vigorously. The suspension is filtered through Celite, the filter bed being rinsed thoroughly with ethyl acetate. The phases of the filtrate are separated and extraction is carried out again with ethyl acetate. The extracts are washed with saturated sodium chloride solution and dried over sodium sulphate and the solvent is removed in vacuo to give 350 mg of crude 4-(3-fluoro-2-methoxyphenyl)-1-[(2-methylquinazolin-5-yl)imino]-2-(trifluoromethyl)heptan-2-ol as a crude product. The crude imine is dissolved in 35 ml of CH2Cl2 and the solution is cooled to −20° C. 5.8 ml (5.8 mmol) of a 1 M BBr3 solution in dichloromethane are added slowly dropwise over 5 minutes and the mixture is allowed to warm to room temperature over 1.5 hours. The reaction solution is poured onto a mixture of saturated NaHCO3 solution and ice. Extraction is carried out repeatedly with ethyl acetate and the extracts are washed with saturated NaCl solution and dried over Na2SO4. Purification by column chromatography on silica gel (hexane/isopropanol 0-15%) and subsequent HPLC separation on chiral stationary phase afford 16 mg of product and 26 mg of the corresponding (5α,6α,8α) compound (Example 62).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([NH2:14])=[N:8][C:9]([S:12][CH3:13])=[N:10][CH:11]=1)=[O:5])C.[OH-].[Li+]>C(O)C.O>[NH2:14][C:7]1[C:6]([C:4]([OH:5])=[O:3])=[CH:11][N:10]=[C:9]([S:12][CH3:13])[N:8]=1
Reactant: CCOC(=O)c1cnc(SC)nc1N
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CSc1ncc(C(=O)O)c(N)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 98.9 %

Procedure:
To a stirred solution of 4-amino-2-methylsulfanyl-pyrimidine-5-carboxylic acid ethyl ester (24.0 g, 112.5 mmol, Salor) in ethanol (400 mL) and water (200 mL) was added lithium hydroxide (9.536 g, 225.0 mmol). The suspension was stirred at room temperature for 3 hours during which all the solids went into solution. The ethanol was removed in vacuo and additional water was added to make a total volume of 300 mL. The resulting solution was washed with 2×100 mL of ether which was discarded. To the aqueous solution was added concentrated hydrochloric acid (20 mL) to bring the pH of the aqueous solution to about pH 3 during which the desired product precipitated out. The product was filtered, washed with 25 mL of water, suction dried and then dried in a vacuum oven at 50° C. to give 20.6 g (98.8%) of the product as a white solid.
Reaction SMILES: [I-:1].[Na+].[C:3](=[O:12])([O:8][CH:9]([CH3:11])[CH3:10])[O:4][CH2:5][CH2:6]Cl>C(#N)C>[C:3](=[O:12])([O:8][CH:9]([CH3:11])[CH3:10])[O:4][CH:5]([I:1])[CH3:6]
Reactant: CC(C)OC(=O)OCCCl
Reactant: [I-]
Agent: [Na+]
Solvent: CC#N
Product: CC(C)OC(=O)OC(C)I
Temperature: 60 °C
Yield: 68.6 %

Procedure:
Sodium iodide (20.69 g, 138.0 mmol) was added to the crude solution of chloroethyl isopropyl carbonate (5.11 g, 30.67 mmol) in acetonitrile (50 mL). The resulting mixture was heated to 60° C. for 2 hours and then allowed to cool to 25° C. The reaction mixture was concentrated under reduced pressure and the resulting mixture was treated with diethyl ether. The solids were filtered off and the filtrate was concentrated under reduced pressure to obtain 1-iodoethyl isopropyl carbonate as a dark orange oil (5.43 g, 69% yield).
Reaction SMILES: [C:1]([CH2:5][N:6]1[C:12](=[O:13])[CH:11]([N:14]([C:24]([O:26]CC)=[O:25])[CH2:15][CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:10][S:9][CH2:8][CH2:7]1)([O:3]C)=[O:2].O>CO.[OH-].[Na+]>[C:1]([CH2:5][N:6]1[C:12](=[O:13])[CH:11]([N:14]([C:24]([OH:26])=[O:25])[CH2:15][CH2:16][CH2:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:10][S:9][CH2:8][CH2:7]1)([OH:3])=[O:2]
Reactant: CCOC(=O)N(CCCc1ccccc1)C1CSCCN(CC(=O)OC)C1=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)CN1CCSCC(N(CCCc2ccccc2)C(=O)O)C1=O
Yield: 94.8 %

Procedure:
4-[Carbomethoxymethyl]-6-[carboethoxy-3-phenyl propylamino]-perhydro-1,4-thiazepin-5-one (0.1 g) is dissolved in 1.5 ml of methanol and 0.5 ml of 1M sodium hydroxide. At the end of 4 hours at room temperature, 2 ml of water is added. The resulting solution is loaded onto a column of Dowex-50 resin (on the proton cycle). After thorough washing with water, the column is developed with 5% pyridine. The eluent is lyophilized to yield the product as a white solid (0.085 g). The sample analyzes for C17H23N2O5S.1/2H2O.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([C:22]2[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:23]=2[Cl:29])[C@H:12]([CH3:21])[CH2:13][CH2:14][CH2:15][S:16]([NH:19][CH3:20])(=[O:18])=[O:17])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH2:30](S(Cl)(=O)=O)[CH2:31]CCC.[CH2:39](NCC)C>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([C:22]2[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:23]=2[Cl:29])[C@H:12]([CH3:21])[CH2:13][CH2:14][CH2:15][S:16]([N:19]([CH2:30][CH3:31])[CH2:20][CH3:39])(=[O:17])=[O:18])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: CCNCC
Reactant: CNS(=O)(=O)CCC[C@@H](C)N(c1cc(Cl)ccc1Cl)S(=O)(=O)c1ccc(Cl)cc1
Reactant: CCCCCS(=O)(=O)Cl
Product: CCN(CC)S(=O)(=O)CCC[C@@H](C)N(c1cc(Cl)ccc1Cl)S(=O)(=O)c1ccc(Cl)cc1
Yield: 59 %

Procedure:
4-chloro-N-[2,5-dichlorophenyl]-N-[4-(diethylaminosulfonyl)-1(R)-methylbutyl]-benzenesulfonamide was prepared analogous to 4-chloro-N-[2,5-dichlorophenyl]-N-[4-[(methylamino)sulfonyl]-1(R)-methylbutyl]benzenesulfonamide by reacting (4R)-4-[2,5-dichlorophenyl][4-chlorophenyl)sulfonyl]-amino]pentylsulfonyl chloride with diethylamine. Yield=59%; MS (ESI+), 541 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12](=[O:51])[C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH2:24][CH2:23][N:22]([CH2:25][C:26]4[CH2:31][CH2:30][C:29]([CH3:33])([CH3:32])[CH2:28][C:27]=4[C:34]4[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][CH:35]=4)[CH2:21][CH2:20]3)=[CH:15][C:14]=2[O:41][C:42]2[CH:43]=[C:44]3[CH:50]=[CH:49][NH:48][C:45]3=[N:46][CH:47]=2)(=[O:10])=[O:9])=[CH:4][C:3]=1[N+:52]([O-:54])=[O:53].[CH3:55][O:56][C:57]1[CH:62]=[CH:61][C:60]([CH2:63][NH2:64])=[CH:59][CH:58]=1.CCN(C(C)C)C(C)C>CS(C)=O.CO>[Cl:40][C:37]1[CH:38]=[CH:39][C:34]([C:27]2[CH2:28][C:29]([CH3:32])([CH3:33])[CH2:30][CH2:31][C:26]=2[CH2:25][N:22]2[CH2:23][CH2:24][N:19]([C:16]3[CH:17]=[CH:18][C:13]([C:12]([NH:11][S:8]([C:5]4[CH:6]=[CH:7][C:2]([NH:64][CH2:63][C:60]5[CH:61]=[CH:62][C:57]([O:56][CH3:55])=[CH:58][CH:59]=5)=[C:3]([N+:52]([O-:54])=[O:53])[CH:4]=4)(=[O:10])=[O:9])=[O:51])=[C:14]([O:41][C:42]4[CH:43]=[C:44]5[CH:50]=[CH:49][NH:48][C:45]5=[N:46][CH:47]=4)[CH:15]=3)[CH2:20][CH2:21]2)=[CH:35][CH:36]=1
Reactant: CC1(C)CCC(CN2CCN(c3ccc(C(=O)NS(=O)(=O)c4ccc(Cl)c([N+](=O)[O-])c4)c(Oc4cnc5[nH]ccc5c4)c3)CC2)=C(c2ccc(Cl)cc2)C1
Reactant: COc1ccc(CN)cc1
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: COc1ccc(CNc2ccc(S(=O)(=O)NC(=O)c3ccc(N4CCN(CC5=C(c6ccc(Cl)cc6)CC(C)(C)CC5)CC4)cc3Oc3cnc4[nH]ccc4c3)cc2[N+](=O)[O-])cc1

Procedure:
A suspension of EXAMPLE 53A (120 mg), (4-methoxyphenyl)methanamine (31 mg) and Hunig's Base (0.159 mL) in dimethylsulfoxide (2 mL) was heated for 2 hours at 150° C. in a Biotage Initiator microwave reactor. The reaction mixture was diluted with methanol (2 mL) and purified by reverse phase HPLC (C8, 30%-100% CH3CN/water/0.1% trifluoroacetic acid). 1H NMR (500 MHz, pyridine-d5) δ 13.07 (s, 1H), 9.32 (d, 1H), 9.17 (t, 1H), 8.43 (d, 1H), 8.28 (dd, 1H), 8.08 (d, 1H), 7.64-7.68 (m, 2H), 7.44 (d, 2H), 7.38 (d, 2H), 7.07 (d, 2H), 6.97-7.02 (m, 2H), 6.90 (d, 1H), 6.74 (dd, 1H), 6.52 (d, 1H), 6.49 (dd, 1H), 4.55 (d, 2H), 3.68 (s, 3H), 3.03-3.09 (m, 4H), 2.77 (s, 2H), 2.26 (t, 2H), 2.10-2.17 (m, 4H), 1.97 (s, 2H), 1.39 (t, 2H), 0.93 (s, 6H).