Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1](N(CC)CC)[CH3:2].Br[C:9]1[CH:20]=[CH:19][C:12]([C:13]([CH2:15][C:16](=[O:18])[CH3:17])=[O:14])=[CH:11][CH:10]=1.C=C.Cl>O.CCOCC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.CN(C)C=O>[CH:1]([C:9]1[CH:20]=[CH:19][C:12]([C:13]([CH2:15][C:16](=[O:18])[CH3:17])=[O:14])=[CH:11][CH:10]=1)=[CH2:2]
Reactant: CC(=O)CC(=O)c1ccc(Br)cc1
Reactant: CCN(CC)CC
Agent: [Pd+2]
Agent: C=C
Agent: CC(=O)[O-]
Solvent: CCOCC
Solvent: O
Solvent: CN(C)C=O
Product: C=Cc1ccc(C(=O)CC(C)=O)cc1
Temperature: -196 °C
Reaction time: 12 h
Yield: 54.7 %

Procedure:
Dimethyl formamide (30 mL), palladium acetate (0.022 g, 0.1 mmol), tri-o-tolyl phosphine (0.060 g, 0.2 mmol), triethylamine (9.1 g, 90 mmol), 4-bromobenzoylacetone (2.41 g, 10 mmol) were added to a 100 mL Parr high pressure reactor with an inner glass liner. The solution was degassed with nitrogen for 10 minutes before the reactor was cooled to −196° C. and ethylene (1.7 g, 61 mmol) was condensed for 20 minutes. The reactor was allowed to warm to room temperature before heating to 100° C. in an oil bath. The pressure was bled off until 300 psi was achieved and the reaction was allowed to proceed for 12 hours. The reaction vessel was cooled to room temperature, the extra pressure bled, and the contents dissolved in water (50 mL) and ether (50 mL). The aqueous phase was made acidic by addition of concentrated hydrochloric acid followed by extraction with ether (2×50 mL). The combined organic phase was rinsed with saturated sodium chloride solution, and the organic phase was dried over magnesium sulfate overnight. The solution was filtered, the solvent was removed by vacuum, and the residue dissolved in chloroform (3 mL). The product was isolated by column chromatography from silica gel (Selecto, mesh size 63-200) with chloroform as eluent. The first band collected resulted in a yellow powder (1.03 g, 55% yield) upon solvent removal. 1H-NMR (200 MHz, 25° C., CDCl3): δ 16.12 (s, 1H), 7.83 (d, 2H), 7.45 (d, 2H), 6.70 (dd, 1H), 6.17 (s, 1H), 5.82 (d, 1H), 5.35 (d, 1H), 2.20 (s, 3H).
Reaction SMILES: CCC[C:4]1[C:5]2[N:14]=[C:13](C3C=C(S(N4CCN(C)CC4)(=O)=O)C=CC=3OCC)[NH:12][C:10](=O)[C:6]=2[N:7](C)[N:8]=1.[OH-:34].[Na+]>>[N:7]1[C:6]2[CH:10]=[N:12][CH:13]=[N:14][C:5]=2[C:4](=[O:34])[N:8]=1
Reactant: [OH-]
Reactant: CCCc1nn(C)c2c(=O)[nH]c(-c3cc(S(=O)(=O)N4CCN(C)CC4)ccc3OCC)nc12
Agent: [Na+]
Product: O=C1N=Nc2cncnc21
Yield: 77 %

Procedure:
Drug preparation: Sildenafil was synthesized in 6 steps according to reported procedures (Terrett et al., 1996) (U.S. Pat. No. 5,346,901.1994). Briefly, commercially available 2-ethoxybenzoic acid was converted to 2-ethoxybenzoyl chloride with thionyl chloride. Reaction of 2-ethoxybenzoyl chloride with 4-amino-1-methyl-3-N-propylpyrazole-5-carboxamide yielded the amide in 90% yield. Cyclization of the amide using NaOH afforded pyrazolopyrimidinone in 77% yield. Chlorosulfonylation of the pyrazolopyrimidinone in chlorosulfonic acid, followed by reaction with N-methylpiperazine provided sildenafil in 90% yield. Tadalafil was also synthesized according to reported procedures (Daugan et al., 2003b). Briefly, D-tryptophan methyl ester reacted with piperonal under Pictet-Spengler reaction condition (TFA/CH2Cl2/MeOH) and the resulting product condensed with chloroacetyl chloride to provide acylated intermediate. Reaction of the intermediate with N-methyl amine provided tadalafil. Tadalafil was diluted in 0.1% DMSO.
Reaction SMILES: [OH:1][C:2]1[CH:6]=[C:5]([CH3:7])[N:4]([C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][C:14]=3[O:18][CH3:19])[CH:9]=2)[N:3]=1.C([O-])([O-])=O.[K+].[K+].[Na+].[I-].Cl[CH2:29][CH2:30][N:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1>CN(C)C=O>[CH3:19][O:18][C:14]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:15]=1[CH:16]=[CH:17][C:8]([N:4]1[C:5]([CH3:7])=[CH:6][C:2]([O:1][CH2:29][CH2:30][N:31]3[CH2:36][CH2:35][O:34][CH2:33][CH2:32]3)=[N:3]1)=[CH:9]2
Reactant: ClCCN1CCOCC1
Reactant: COc1cccc2cc(-n3nc(O)cc3C)ccc12
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cccc2cc(-n3nc(OCCN4CCOCC4)cc3C)ccc12
Temperature: 90 °C
Yield: 94 %

Procedure:
To a solution of 3-hydroxy-5-methyl-1-(5-methoxynaphthalen-2-yl)-1H-pyrazol (150 mg, 0.59 mmol) in dimethylformamide (10 ml), 2-chloroethylmorpholine chlorhydrate (136 mg, 0.71 mmol), K2CO3 (245 mg, 1.77 mmol), and NaI (catalytic quantity) were added. The mixture was heated, in an inert nitrogen atmosphere, at 90° C. during 8 hrs. Subsequently it was cooled, filtered, and the filtered product was evaporated to dryness in a rotavapor. The residue was divided between water and ethylic ether. The organic phase was washed with water and afterwards with an aqueous solution of HCl 2N several times. The collection of the acidic aqueous phases were basified with a solution of NaOH 20% and it was extracted with ethyl acetate, which was washed with water, dried over sodium sulfate, filtered, and evaporated to dryness yielding 204 mg (94%) of 4-{2-[1-(5-methoxynaphthalen-2-yl)-5-methyl-1H-pyrazol-3-yloxy]ethyl}morpholine in the form of an oil.
Reaction SMILES: C([O:4][CH2:5][CH:6]([OH:30])[CH:7]([OH:29])[CH2:8][N:9]1[C:15]2[CH:16]=[CH:17][C:18]([Cl:20])=[CH:19][C:14]=2[C:13]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[F:27])=[N:12][CH2:11][C:10]1=[O:28])(=O)C.N>CO>[Cl:20][C:18]1[CH:17]=[CH:16][C:15]2[N:9]([CH2:8][CH:7]([OH:29])[CH:6]([OH:30])[CH2:5][OH:4])[C:10](=[O:28])[CH2:11][N:12]=[C:13]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[F:27])[C:14]=2[CH:19]=1
Reactant: CC(=O)OCC(O)C(O)CN1C(=O)CN=C(c2ccccc2F)c2cc(Cl)ccc21
Agent: N
Solvent: CO
Product: O=C1CN=C(c2ccccc2F)c2cc(Cl)ccc2N1CC(O)C(O)CO
Temperature: 25 °C
Reaction time: 16 h

Procedure:
14 g of 1-(4-acetoxy-2,3-dihydroxybutyl)-7-chloro-5-(2-fluorophenyl)-1, 3-dihydro-2H-1,4-benzodiazepin-2-one are dissolved in 30 ml of methanol, treated with 15 ml of 25% aqueous ammonia and stirred at room temperature for 16 hours. The mixture is then evaporated to dryness and chromatographed on silica gel with ethyl acetate/methanol (9:1 ). The pure fractions are combined and evaporated. There is obtained 7-chloro-5-(2-fluorophenyl)-1,3-dihydro-1-(2,3,4-trihydroxybutyl)-2H-1,4-benzodiazepin-2-one in the form of a foam.
Reaction SMILES: C([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([NH:11][C:12]([N:14]2[CH2:19][CH2:18][N:17]([C:20]3[S:24][N:23]=[C:22]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[N:21]=3)[CH2:16][CH2:15]2)=[O:13])[CH:6]=1)(=O)C.[OH-].[Na+].O>CO.O1CCCC1>[OH:4][C:5]1[CH:6]=[C:7]([NH:11][C:12]([N:14]2[CH2:19][CH2:18][N:17]([C:20]3[S:24][N:23]=[C:22]([C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=4)[N:21]=3)[CH2:16][CH2:15]2)=[O:13])[CH:8]=[CH:9][CH:10]=1
Reactant: CC(=O)Oc1cccc(NC(=O)N2CCN(c3nc(-c4ccccc4)ns3)CC2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: O=C(Nc1cccc(O)c1)N1CCN(c2nc(-c3ccccc3)ns2)CC1
Temperature: 70 °C
Reaction time: 3 h
Yield: 62.9 %

Procedure:
To a solution of 3-({[4-(3-phenyl-1,2,4-thiadiazol-5-yl)piperazin-1-yl]carbonyl}amino)phenyl acetate (635 mg, 1.50 mmol) in methanol/tetrahydrofuran (2:1) (60 ml) was added an aqueous 1 N sodium hydroxide solution (1.5 ml), and the mixture was stirred at 70° C. for 3 hours. Water was poured to the reaction mixture, and the resulting solution was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1) and recrystallized from a mixed solvent of hexane and tetrahydrofuran to give 360 mg (62.9%) of the desired product as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12](=[O:13])[CH:11]=[C:10]([CH3:14])[NH:9]2)=[CH:4][CH:3]=1.[F:15][C:16]([F:24])([F:23])[C:17](=[O:22])[C:18]([O:20][CH3:21])=[O:19]>C(Cl)(Cl)Cl>[CH3:21][O:20][C:18](=[O:19])[C:17]([OH:22])([C:16]([F:24])([F:23])[F:15])[C:11]1[C:12](=[O:13])[N:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[NH:9][C:10]=1[CH3:14]
Reactant: Cc1cc(=O)n(-c2ccc(Cl)cc2)[nH]1
Reactant: COC(=O)C(=O)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: COC(=O)C(O)(c1c(C)[nH]n(-c2ccc(Cl)cc2)c1=O)C(F)(F)F
Temperature: 80 °C
Reaction time: 2 h

Procedure:
To a chloroform solution (5 ml) of 1-(4-chlorophenyl)-3-methyl-5-pyrazolone (104 mg, 0.5 mmol), methyl trifluoropyruvate (78 mg, 0.5 mmol) was added at room temperature and the mixture was stirred at 80° C. for 2 hours. After removing the solvent under reduced pressure, the title compound was obtained as a colorless solid (182 mg).
Reaction SMILES: [NH:1]([C:3]1[N:8]=[CH:7][C:6]([C:9]2[CH:10]=[CH:11][C:12](=[O:16])[N:13]([CH3:15])[CH:14]=2)=[CH:5][CH:4]=1)[NH2:2].N(C1C=CC=CC=1)=[C:18]=[S:19]>CN1C(=O)CCC1.ClC1C=CC=C(Cl)C=1>[NH:1]([C:3]1[N:8]=[CH:7][C:6]([C:9]2[CH:10]=[CH:11][C:12](=[O:16])[N:13]([CH3:15])[CH:14]=2)=[CH:5][CH:4]=1)[NH2:2].[SH:19][C:18]1[N:8]2[CH:7]=[C:6]([C:9]3[CH:10]=[CH:11][C:12](=[O:16])[N:13]([CH3:15])[CH:14]=3)[CH:5]=[CH:4][C:3]2=[N:1][N:2]=1
Reactant: S=C=Nc1ccccc1
Agent: Cn1cc(-c2ccc(NN)nc2)ccc1=O
Solvent: Clc1cccc(Cl)c1
Solvent: CN1CCCC1=O
Product: Cn1cc(-c2ccc3nnc(S)n3c2)ccc1=O
Temperature: 160 °C
Yield: 86.3 %

Procedure:
5-(3-mercapto-[1,2,4]triazolo[4,3-a]pyridin-6-yl)-1-methylpyridin-2(]H)-one: A mixture of 5-(6-hydrazinylpyridin-3-yl)-1-methylpyridin-2(1 H)-one (600 mg, 2.78 mmol) and isothiocyanatobenzene (450 mg, 3.33 mmol) in NMP-1,3-dichlorobenzene (1:1, 10 mL) was heated in a microwave at 160° C. for 1 hr and then purified by preparative LCMS to provide the title compound, 5-(3-mercapto-[1,2,4]triazolo[4,3-a]pyridin-6-yl)-1-methylpyridin-2(1H)-one (310 mg, 43% yield).
Reaction SMILES: [O:1]=[C:2]1[NH:7][CH:6]=[C:5]([NH:8][C:9]([CH:11]2[CH:15]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[C:17]=3[F:23])[C:14]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][C:27]=3[F:33])([C:24]#[N:25])[CH:13]([CH2:34][C:35]([CH3:38])([CH3:37])[CH3:36])[NH:12]2)=[O:10])[CH:4]=[CH:3]1>CO>[O:1]=[C:2]1[NH:7][CH:6]=[C:5]([NH:8][C:9]([C@@H:11]2[C@@H:15]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[C:17]=3[F:23])[C@@:14]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][C:27]=3[F:33])([C:24]#[N:25])[C@@H:13]([CH2:34][C:35]([CH3:38])([CH3:37])[CH3:36])[NH:12]2)=[O:10])[CH:4]=[CH:3]1
Reactant: CC(C)(C)CC1NC(C(=O)Nc2ccc(=O)[nH]c2)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Solvent: CO
Product: CC(C)(C)C[C@H]1N[C@H](C(=O)Nc2ccc(=O)[nH]c2)[C@@H](c2cccc(Cl)c2F)[C@]1(C#N)c1ccc(Cl)cc1F

Procedure:
Rac (2R,3S,4R,5S)-3-(3-Chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (6-oxo-1,6-dihydro-pyridin-3-yl)-amide (168 mg) was resolved on a Berger SFC machine under 100 bar, 30° C. with 40% of methanol at a rate of 2 mL/min give two separated peaks. Peak 1, 62 mg (desired), peak 2, 64 mg (undesired).
Reaction SMILES: [Si:1]([N:8]1[C:11](=[O:12])[CH2:10][C@@H:9]1[C:13]([OH:15])=O)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].ClC(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl.CC1C=C(C)C=C(C)N=1.[F:37][C:38]1[CH:39]=[C:40]([C@:46]([C:55]2[CH:60]=[C:59]([O:61][C:62]([F:67])([F:66])[CH:63]([F:65])[F:64])[CH:58]=[C:57]([F:68])[CH:56]=2)([NH2:54])[CH2:47][C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[CH:41]=[CH:42][C:43]=1[O:44][CH3:45].C(N(CC)C(C)C)(C)C>C1COCC1.O>[Si:1]([N:8]1[C:11](=[O:12])[CH2:10][C@@H:9]1[C:13]([NH:54][C@:46]([C:40]1[CH:41]=[CH:42][C:43]([O:44][CH3:45])=[C:38]([F:37])[CH:39]=1)([C:55]1[CH:60]=[C:59]([O:61][C:62]([F:67])([F:66])[CH:63]([F:65])[F:64])[CH:58]=[C:57]([F:68])[CH:56]=1)[CH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)=[O:15])([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:2])[CH3:3]
Reactant: COc1ccc([C@](N)(Cc2ccccc2)c2cc(F)cc(OC(F)(F)C(F)F)c2)cc1F
Reactant: CC(C)(C)[Si](C)(C)N1C(=O)C[C@@H]1C(=O)O
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1cc(C)nc(C)c1
Solvent: O
Product: COc1ccc([C@@](Cc2ccccc2)(NC(=O)[C@H]2CC(=O)N2[Si](C)(C)C(C)(C)C)c2cc(F)cc(OC(F)(F)C(F)F)c2)cc1F
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 55 %

Procedure:
To a solution of (R)-1-(tert-butyldimethylsilyl)-4-oxoazetidine-2-carboxylic acid (126 mg, 0.55 mmol) in THF (1.5 mL) was added to a solution of triphosgene (54 mg, 0.18 mmol). The reaction mixture was stirred for 5 min at rt, followed by addition of 2,4,6-trimethylpyridine (203 μL, 1.54 mmol), a solution of (R)-1-(3-fluoro-4-methoxyphenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethanamine, prepared as described in Procedure 3, 62, 5 and 6, (50 mg, 0.11 mmol) in THF (0.6 mL), and N,N-diisopropylethylamine (268 μL, 1.54 mmol). The reaction mixture was stirred at room temperature for 40 min. Water (10 mL) was added and the reaction mixture was extracted with dichloromethane (3×15 mL) and the combined organic layers were washed with 2 N potassium carbonate and then sat. NaCl. The organic layers were dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by ISCO Flash chromatography (Analogix column 4.2 g, eluting with hexane/EtOAc) to yield (R)-1-(tert-Butyldimethylsilyl)-N—((R)-1-(3-fluoro-4-methoxyphenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)-4-oxoazetidine-2-carboxamide (Example 343, 41 mg, 55% yield). LCMS: RT=4.18 min [M+H] 667.1 (Phenominex, Luna C18, 4.6×50 mm, 10%-90% MeOH/H2O containing 0.1% TFA, flow rate 4 mL/min, 4 min gradient, monitoring at 220 nm); 1H NMR (500 MHz, CDCl3) δ ppm −0.04 (s, 3H), 0.24 (s, 3H), 0.91 (s, 9H), 2.79 (dd, J=15.4, 2.7 Hz, 1H), 3.32 (dd, J=15.4, 6.6 Hz, 1H), 3.79-3.85 (m, 1H), 3.86-3.90 (m, 2H), 3.91 (s, 3H), 5.87 (none, 2H), 6.59 (s, 1H), 6.64 (d, J=7.1 Hz, 2H), 6.75 (s, 1H), 6.80 (d, J=9.3 Hz, 1H), 6.87-6.94 (m, 4H), 7.15 (t, J=7.4 Hz, 2H), 7.20 (d, J=7.1 Hz, 1H).
Reaction SMILES: C1([O:7][C:8](=O)[NH:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[N:21]=[C:20]([C:22]4[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:23]=4[S:29]([CH3:32])(=[O:31])=[O:30])[CH:19]=[C:18]([N:33]4[CH2:38][CH2:37][O:36][CH2:35][C@@H:34]4[CH3:39])[N:17]=3)=[CH:12][CH:11]=2)C=CC=CC=1.[CH:41]1([NH2:44])[CH2:43][CH2:42]1>>[CH:41]1([NH:44][C:8]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[N:21]=[C:20]([C:22]4[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:23]=4[S:29]([CH3:32])(=[O:30])=[O:31])[CH:19]=[C:18]([N:33]4[CH2:38][CH2:37][O:36][CH2:35][C@@H:34]4[CH3:39])[N:17]=3)=[CH:12][CH:11]=2)=[O:7])[CH2:43][CH2:42]1
Reactant: NC1CC1
Reactant: C[C@H]1COCCN1c1cc(-c2cc(F)ccc2S(C)(=O)=O)nc(-c2ccc(NC(=O)Oc3ccccc3)cc2)n1
Product: C[C@H]1COCCN1c1cc(-c2cc(F)ccc2S(C)(=O)=O)nc(-c2ccc(NC(=O)NC3CC3)cc2)n1

Procedure:
Method as for example 58 using (S)-phenyl(4-(4-(5-fluoro-2-(methylsulfonyl)phenyl)-6-(3-methylmorpholino)pyrimidin-2-yl)phenyl)carbamate (intermediate 34) and cyclopropyl amine as starting materials. The solvent removed in vacuo and the crude material purified by prep HPLC at low pH to yield the title compound.
Reaction SMILES: [H-].[Na+].[C:3]([O:7][CH2:8][CH3:9])(=[O:6])[CH:4]=[CH2:5].Cl[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13].O>C1(C)C=CC=CC=1.C(O)C>[C@@H:4]1([C:3]([O:7][CH2:8][CH3:9])=[O:6])[CH2:5][C@@H:11]1[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CCOC(=O)CCl
Reactant: C=CC(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCO
Product: CCOC(=O)[C@H]1C[C@H]1C(=O)OCC
Temperature: 25 °C
Yield: 35.1 %

Procedure:
To a stirred suspension of 32.8 g (818.8 mmol) of 60% sodium hydride mineral oil dispersion in 200 mL of toluene under nitrogen, was added between 10 to 20 mL of a blend of ethyl acrylate (81.2 g, 810.7 mmol) and ethyl chloroacetate (99.4 g, 810.7 mmol) followed by several drops of ethanol. After an induction period of about 1 h, steady gas and heat evolution began with the reaction mixture temperature reaching 35° C. The remaining mixed ester reagent was carefully added dropwise with ice-bath cooling so as to maintain a reaction temperature of 30°-80° C. After the addition was complete (4 h), the mixture was cooled to room temperature and carefully poured into water (300 mL). The organic layer was separated and dried (MgSO4) and evaporated to a dry residue. The dry residue was chromatographed on silica gel using 10% ethyl acetate in hexane as the eluant. The fractions containing the desired compound were combined and evaporated to dryness under reduced pressure to give 53.0 g of the title compound of Step A as a clear oil (35% yield). IR (neat, cm-1): 1728.9 (C=O);
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:22]=[CH:21][C:10]2[C:11]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)=[N:12][S:13][C:9]=2[CH:8]=1.[CH3:23][O:24][CH2:25][CH2:26][NH:27][CH2:28][CH3:29]>>[CH2:28]([N:27]([CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:22]=[CH:21][C:10]2[C:11]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)=[N:12][S:13][C:9]=2[CH:8]=1)[CH2:26][CH2:25][O:24][CH3:23])[CH3:29]
Reactant: Fc1ccc(-c2nsc3cc(OCCCCBr)ccc23)cc1
Reactant: CCNCCOC
Product: CCN(CCCCOc1ccc2c(-c3ccc(F)cc3)nsc2c1)CCOC

Procedure:
In analogy to example 3.1, 6-(4-Bromo-butoxy)-3-(4-fluoro-phenyl)-benzo[d]isothiazole and N-(2-Methoxyethyl)ethylamine were converted to yield Ethyl-{4-[3-(4-fluoro-phenyl)-benzo[d]isothiazol-6-yloxy]-butyl}-(2-methoxy-ethyl)-amine which was transferred into its salt by treatment with formic acid, MS: 403 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[N:12]([CH3:13])[CH:11]=[CH:10][C:5]2=[N:6][C:7]=1[C:8]#[N:9].[CH3:14][Mg]Cl.C1COCC1.C[O-].[Na+].[BH4-].[Na+].[BH4-]>CO.C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]2[N:12]([CH3:13])[CH:11]=[CH:10][C:5]2=[N:6][C:7]=1[CH:8]([NH2:9])[CH3:14]
Reactant: Cn1ccc2nc(C#N)c(Br)cc21
Reactant: C[Mg]Cl
Agent: C[O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Solvent: Cc1ccccc1
Product: CC(N)c1nc2ccn(C)c2cc1Br
Temperature: 7.5 °C
Reaction time: 2 h

Procedure:
To a first vessel charged with toluene (5.1 L) was added 6-bromo-1-methyl-1H-pyrrolo[3,2-b]pyridine-5-carbonitrile (300 g, 1.27 mol) under nitrogen. The solution was cooled to 5-10° C. A 3M solution of CH3MgCl in THF (637 mL, 1.91 mol) was added slowly over a 35 minute period while maintaining the temperature of the reaction mixture below 30° C. The reaction mixture was stirred for 2 hours at 15-20° C. To a second vessel charged with methanol at 0-5° C. was added sodium methylate (24.4 mL) under nitrogen. Sodium borohydride (72.2 g, 1.91 mol) was added to the methanol solution portion-wise over a 20 minute period at 0-5° C. The borohydride solution was stirred for 1 hour. The contents of the first vessel were then transferred into the second vessel slowly over a 2 hour period while maintaining the temperature of the reaction mixture in the second vessel below 30° C. Following the transfer of the Grignard solution, the first vessel was rinsed with toluene (0.60 L) which was added to the second vessel. The first vessel was next charged with methanol (0.60 L) over a 10 minute period at a temperature less than 30° C. The methanol solution was subsequently transferred to the second vessel, and the reaction mixture was stirred at 0-5° C. for an additional 2 hours. The reaction mixture was then transferred into a third vessel charged with a 2M HCl solution (2.40 L) at 5-15° C. over a period of 1.25 hours. Following the transfer, the second vessel was rinsed with toluene (0.60 L), which was added to the third vessel, and the reaction mixture was stirred for 16 hours. The mixture was warmed to 40-45° C. and 2M NaOH (1.0 L) was added slowly over a 20 minute period until the pH of the aqueous phase was 8.5. The reaction mixture was stirred for an additional 40 minutes, and the pH of the aqueous phase was confirmed to be 8.5. The organic and aqueous phases were separated. The aqueous phase was extracted with toluene (2×3.0 L). The organic layers were combined and screened to remove particulates. The filtrate was concentrated under vacuum at 50° C. until distillation ceased. Isopropanol (3.0 L) was added, and the reaction mixture concentrated under vacuum at 50° C. Additional isopropanol (300 mL) was added to give the title compound as a solution in IPA (230.7 g by gravimetric assay).
Reaction SMILES: F[C:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][C:9]=2[O:17][CH3:18])=[CH:6][CH:5]=[CH:4][N:3]=1.C(=O)([O-])[O-:20].[Na+].[Na+]>O1CCOCC1.Cl>[CH3:18][O:17][C:9]1[CH:10]=[C:11]([N+:14]([O-:16])=[O:15])[CH:12]=[CH:13][C:8]=1[C:7]1[C:2](=[O:20])[NH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C([O-])[O-]
Reactant: COc1cc([N+](=O)[O-])ccc1-c1cccnc1F
Agent: Cl
Agent: [Na+]
Solvent: C1COCCO1
Product: COc1cc([N+](=O)[O-])ccc1-c1ccc[nH]c1=O

Procedure:
1.50 g (6.04 mmol) of the product from example 54A are heated overnight in a mixture of 75 ml of dioxane and 75 ml of 4-molar hydrochloric acid. The mixture is then alkalized with sodium carbonate solution. The precipitate is filtered off with suction, washed with water and dried. This affords 1.43 g (96% of theory) of the desired compound.
Reaction SMILES: [OH:1][CH2:2][C:3]1[C:4]([CH2:10][CH2:11][CH3:12])=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1.CO.[Br-:15].[Br-].[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC>ClCCl>[Br:15][C:8]1[CH:7]=[CH:6][C:5]([OH:9])=[C:4]([CH2:10][CH2:11][CH3:12])[C:3]=1[CH2:2][OH:1]
Reactant: CCCc1c(O)cccc1CO
Reactant: [Br-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CO
Solvent: ClCCl
Product: CCCc1c(O)ccc(Br)c1CO
Reaction time: 1 h
Yield: 67.1 %

Procedure:
To a solution of 3-(hydroxymethyl)-2-propylphenol (1.05 g, 6.32 mmol) in dichloromethane (50 mL)-methanol (30 mL) mixtures, tetrabutylammonium tribromide (3.20 g, 6.64 mmol) was added at 0° C. The mixture was stirred at the same temperature for 1 hour. Solvent was evaporated under reduced pressure. The residue was added with water and extracted with ethyl acetate. Subsequently, the organic layer was washed with saturated saline, dried using anhydrous sodium sulfate, and concentrated in vacuum. The obtained residue was purified using silica-gel column chromatography (hexane/ethyl acetate) and the title compound (1.04 g, 67%) was obtained as colorless crystalline powder.
Reaction SMILES: [CH:1]1([NH2:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:8][C:9]1[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=1[C:11](Cl)=[O:12].C(N(CC)CC)C>C1C=CC=CC=1>[CH:1]1([NH:7][C:11](=[O:12])[C:10]2[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=2[CH3:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1ccccc1C(=O)Cl
Reactant: NC1CCCCC1
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: Cc1ccccc1C(=O)NC1CCCCC1
Temperature: 60 °C
Reaction time: 3 h

Procedure:
9.9 PARTS OF CYCLOHEXYLAMINE IS DISSOLVED IN 100 PARTS OF BENZENE AND THE MIXTURE IS REACTED WITH 15.5 PARTS OF 2-METHYLBENZOYL CHLORIDE IN THE PRESENCE OF 12 PARTS OF TRIETHYLAMINE AT 10°C. The whole is stirred for 3 hours at 60°C and then cooled; the precipitated triethylamine chloride is filtered, the filtrate is concentrated under vacuum and the residue is recrystallized from a mixture of methanol and water.
Reaction SMILES: [F:1][C:2]([F:8])([F:7])[CH2:3][C:4](=O)[CH3:5].[C:9]([S@:13]([NH2:15])=[O:14])([CH3:12])([CH3:11])[CH3:10]>C1COCC1.[Cl-].[Na+].O.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[CH3:10][C:9]([S@:13]([N:15]=[C:4]([CH2:3][C:2]([F:8])([F:7])[F:1])[CH3:5])=[O:14])([CH3:12])[CH3:11]
Reactant: CC(=O)CC(F)(F)F
Reactant: CC(C)(C)[S@](N)=O
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: O
Product: CC(CC(F)(F)F)=N[S@](=O)C(C)(C)C
Temperature: 25 °C
Yield: 64.3 %

Procedure:
To a solution of 4,4,4-trifluorobutan-2-one (12 g, 95 mmol) in THF (150 ml) was added titanium (IV) isopropoxide (42 ml, 142 mmol) and (R)-tert-butanesulfinamide (17.3 g, 142 mmol). The solution was heated to reflux for 22 h, cooled to RT, and poured into a vigorously-stirred brine solution. The mixture was filtered through a pad of Celite, the filter cake washed with EtOAc, and the filtrate separated. The aqueous layer was extracted with EtOAc, the organic layers combined and washed with brine, dried on Na2SO4, and concentrated in vacuo. The residue was purified by column chromatography (15% to 60% EtOAc in hexanes) to afford the title compound as a yellow oil (14.0 g, 65%). 1H NMR (CDCl3, 400 MHz) δ 1.25 (s, 9H), 2.45 (s, 3H), 3.19 (q, J=14.4 Hz, 2H). 19F NMR (CDCl3, 376 MHz) δ −61.03 (t, J=10.5 Hz), −62.8 (t, J=10.5 Hz).