Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].[NH2:2][C@@H:3]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:4]([O:6][CH3:7])=[O:5].[P:14](Cl)(Cl)(=[O:26])[O:15][C:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][CH:17]=1>C(Cl)Cl>[Cl:1][C:17]1[CH:18]=[CH:19][C:20]2[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:16]=1[O:15][P:14](=[N:2][C@@H:3]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:4]([O:6][CH3:7])=[O:5])=[O:26]
Reactant: COC(=O)[C@@H](N)c1ccccc1
Reactant: Cl
Reactant: O=P(Cl)(Cl)Oc1cccc2ccccc12
Solvent: ClCCl
Product: COC(=O)[C@@H](N=[P+]([O-])Oc1c(Cl)ccc2ccccc12)c1ccccc1

Procedure:
Using the general procedure for synthesizing naphthyl (aminoacid ester) phosphorochloridates, the HCl salt of (S)-methyl 2-amino-2-phenylacetate (2 g), naphthalen-1-yl phosphorodichloridate (2.59 g), TEA (2.76 mL) and DCM (60 mL) were combined to give (2S)-methyl 2-(chloro(naphthalen-1-yloxy)phosphorylamino)-2-phenylacetate as a pale yellow thick oil. The crude compound was taken forward without further purification.
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[OH:15][C:16]1[CH:23]=[C:22]([O:24][CH3:25])[CH:21]=[CH:20][C:17]=1[CH:18]=[O:19]>CC(C)=O>[CH2:1]([O:15][C:16]1[CH:23]=[C:22]([O:24][CH3:25])[CH:21]=[CH:20][C:17]=1[CH:18]=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(C=O)c(O)c1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1ccc(C=O)c(OCc2ccccc2)c1
Yield: 873.2 %

Procedure:
160 ml (1.3 mmol) of benzyl bromide and (1.3 mmol) of potassium carbonate are added to a solution of 2 g (1.3 mmol) of 2-hydroxy-4-methoxybenzaldehyde in 20 ml of acetone. The mixture is stirred at reflux for 6 hours and then evaporated. 50 ml of 1N aqueous solution of sodium hydroxide are added and the medium is extracted with dichloromethane. The organic phase is dried over magnesium sulphate, filtered and evaporated. The residue obtained is precipitated from 1 heptane/ethyl acetate mixture (95/5). 2.75 g of 2-benzyloxy-4-methoxybenzaldehyde are obtained in the form of a white powder with a yield of 86%.
Reaction SMILES: [NH2:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][CH2:4][C:5](NCC)=[O:6].Cl(O)(=O)=[O:14]>>[NH2:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][CH2:4][C:5]([OH:6])=[O:14].[CH2:2]([NH2:1])[CH3:3]
Reactant: CCNC(=O)CC[C@H](N)C(=O)O
Reactant: [O-][Cl+2]([O-])O
Product: CCN
Product: N[C@@H](CCC(=O)O)C(=O)O

Procedure:
The fraction had the same mobilities as standard theanine in amino acid analyzer and in paper chromatography. Hydrolysis of the fraction with chloric acid or glutaminase produced an equal molar ratio of glutamic acid and ethylamine. The hydrolysis of the fraction with glutaminase showed that the ethylamine was located at γ-position. The glutamic acid was shown L-form by glutamic acid hydrogenase (GluDH). IR spectrum of the fraction was identical to that of the standard as shown in FIG. 1. The isolated substance was confirmed theanine by these results.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:34])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][C:14]2[CH:19]=[C:18]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([S:28]([CH3:31])(=[O:30])=[O:29])=[CH:24][CH:23]=3)[CH:17]=[C:16](Br)[CH:15]=2)=[CH:9][C:8]=1[CH3:33])[CH3:2].[C:35]([C:37]1[CH:42]=[CH:41][C:40]([F:43])=[CH:39][CH:38]=1)#[CH:36].C(OC(=O)COC1C=CC(SC2C=C(C#CC3C=CC(CO)=CC=3)C=C(OCCC3C=CC(Cl)=CC=3)C=2)=CC=1C)C>>[CH2:1]([O:3][C:4](=[O:34])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][C:14]2[CH:19]=[C:18]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([S:28]([CH3:31])(=[O:30])=[O:29])=[CH:24][CH:23]=3)[CH:17]=[C:16]([C:36]#[C:35][C:37]3[CH:42]=[CH:41][C:40]([F:43])=[CH:39][CH:38]=3)[CH:15]=2)=[CH:9][C:8]=1[CH3:33])[CH3:2]
Reactant: C#Cc1ccc(F)cc1
Reactant: CCOC(=O)COc1ccc(Sc2cc(Br)cc(OCc3ccc(S(C)(=O)=O)cc3)c2)cc1C
Agent: CCOC(=O)COc1ccc(Sc2cc(C#Cc3ccc(CO)cc3)cc(OCCc3ccc(Cl)cc3)c2)cc1C
Product: CCOC(=O)COc1ccc(Sc2cc(C#Cc3ccc(F)cc3)cc(OCc3ccc(S(C)(=O)=O)cc3)c2)cc1C

Procedure:
The title product was prepared from {4-[3-Bromo-5-(4-methanesulfonyl-benzyloxy)phenylsulfanyl]-2-methyl-phenoxy}-acetic acid ethyl ester (335 mg; 0.59 mmol), 1-ethynyl-4-fluorobenzene (142.3 mg; 1.19 mmol) applying the procedure described for {4-[3-[2-(4-Chloro-phenyl)-ethoxy]-5-(4-hydroxymethyl-phenylethynyl)-phenylsulfanyl]-2-methylphenoxy}-acetic acid ethyl ester. The crude product was purified by preparative HPLC (method B). Yield: 140 mg (39%). HPLC-MS: m/z: 605.5 (M+H)+; Rt: 2.80 min.
Reaction SMILES: C1(C)C=CC=CC=1.[F:8][C:9]1[CH:15]=[C:14]([F:16])[CH:13]=[C:12]([F:17])[C:10]=1[NH2:11].[C:18]([NH:23][NH:24][C:25](Cl)=[O:26])([O:20][CH2:21][CH3:22])=[O:19]>C(OCC)(=O)C.C1(C)C=CC=CC=1>[F:8][C:9]1[CH:15]=[C:14]([F:16])[CH:13]=[C:12]([F:17])[C:10]=1[NH:11][C:25](=[O:26])[NH:24][NH:23][C:18]([O:20][CH2:21][CH3:22])=[O:19]
Reactant: Nc1c(F)cc(F)cc1F
Reactant: CCOC(=O)NNC(=O)Cl
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CCOC(=O)NNC(=O)Nc1c(F)cc(F)cc1F

Procedure:
A toluene solution of 2,4,6-trifluoroaniline is reacted with 2-carbethoxyhydrazinecarbonyl chloride as described above in Example 1b, mp 177°-178° (ethyl acetate/toluene).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:20])[N:5]([CH:12]1[CH2:17][CH2:16][C:15](=[O:18])[NH:14][C:13]1=[O:19])[C:6]2=[O:11].[F:21][C:22]([F:33])([F:32])[C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=1)[C:26](Cl)=[O:27].CO>C1COCC1.C(OCC)C>[O:19]=[C:13]1[CH:12]([N:5]2[C:4](=[O:20])[C:3]3[C:7](=[CH:8][CH:9]=[CH:10][C:2]=3[NH:1][C:26](=[O:27])[C:25]3[CH:29]=[CH:30][CH:31]=[C:23]([C:22]([F:21])([F:32])[F:33])[CH:24]=3)[C:6]2=[O:11])[CH2:17][CH2:16][C:15](=[O:18])[NH:14]1
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1
Reactant: Nc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: CO
Product: O=C1CCC(N2C(=O)c3cccc(NC(=O)c4cccc(C(F)(F)F)c4)c3C2=O)C(=O)N1
Temperature: 25 °C
Reaction time: 1 h
Yield: 46 %

Procedure:
To a suspension of 4-amino-2-(2,6-dioxo(3-piperidyl))isoindoline-1,3-dione (0.55 g, 2 mmol) in THF (30 ml) was added 3-trifluoromethylbenzoyl chloride (0.60 ml, 4 mmol). The mixture was heated to reflux for 18 hours. The reaction was cooled to room temperature, methanol (2 ml) was added, and the mixture stirred for 1 hour. The solvent was evaporated in vacuo leaving a solid that was slurried in diethyl ether (20 ml) and filtered to give 0.41 g (46%) of product as an off-white solid: mp 257–259° C.; 1H NMR (DMSO-d6) d 10.86 (s, 1H), 10.45 (s, 1H), 8.50 (d, J=8.5 Hz, 1H), 8.24–8.25 (m, 2H), 8.02–7.82 (m, 3H), 7.69 (d, J=7.3 Hz, 1H), 5.14 (dd, J=5.7 and 12.8 Hz, 1H), 2.95–2.82 (m, 1H), 2.67–2.48 (m, 2H), 2.14–2.07 (m, 1H); 13C NMR (DMSO-d6) d 171.75, 168.80, 167.31, 166.06, 163.43, 135.80, 135.60, 134.28, 131.16, 130.71, 129.75, 128.35, 128.29, 126.63, 123.59, 123.52, 118.65, 118.55, 48.84, 30.51, 21.62; Anal. Calcd. For C21H14F3N3O5: C, 56.64; H, 3.17; N, 9.44. Found: C, 56.48; H, 3.15; N, 9.41.
Reaction SMILES: S(=O)(=O)(O)O.O[CH:7]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[CH2:11][CH2:10][CH:9]([NH2:18])[CH2:8]1.O1CCOCC1>O>[NH2:18][CH:9]1[CH:8]=[CH:7][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[CH2:11][CH2:10]1
Reactant: NC1CCc2ccccc2C(O)C1
Agent: O=S(=O)(O)O
Solvent: C1COCCO1
Solvent: O
Product: NC1C=Cc2ccccc2CC1
Temperature: 20 °C
Yield: 59.6 %

Procedure:
12 ml of 18N sulfuric acid were added to a refluxing mixture of 5.6 g of the product of Step C and 60 ml of dioxane and the mixture was refluxed for 2 hours and then was cooled to 20° C. The mixture was poured into 300 ml of water and the neutral fraction was extracted with ether. The aqueous phase was made alkaline with sodium hydroxide addition and was extracted with ethyl acetate. The ethyl acetate extracts were washed with aqueous sodium chloride solution, dried, filtered and evaporated to dryness to obtain 5 g of raw product. The latter was chromatographed over silica gel and was eluted with an 8-2-1 ethyl acetate-benzene-triethylamine mixture to obtain 3 g of 7-amino-6,7-dihydro [5H] benzocycloheptene in the form of a brown oil.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][NH:7][C:8](=[O:14])OC(C)(C)C)=[C:4]([F:17])[C:3]=1[C:18](=[O:41])[NH:19][C:20]1[CH:21]=[CH:22][CH:23]=[C:24]2[C:29]=1[N:28]=[CH:27][N:26]=[C:25]2[NH:30][C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([C:37]([F:40])([F:39])[F:38])[CH:32]=1.CCN(C(C)C)C(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[O:78]1[CH2:82][CH2:81][CH2:80][C@H:79]1C(O)=O>Cl.CO.CCOC(C)=O>[Cl:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][NH:7][C:8]([C@@H:79]2[CH2:80][CH2:81][CH2:82][O:78]2)=[O:14])=[C:4]([F:17])[C:3]=1[C:18](=[O:41])[NH:19][C:20]1[CH:21]=[CH:22][CH:23]=[C:24]2[C:29]=1[N:28]=[CH:27][N:26]=[C:25]2[NH:30][C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([C:37]([F:38])([F:40])[F:39])[CH:32]=1
Reactant: O=C(O)[C@@H]1CCCO1
Reactant: CC(C)(C)OC(=O)NCc1ccc(Cl)c(C(=O)Nc2cccc3c(Nc4cccc(C(F)(F)F)c4)ncnc23)c1F
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CO
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1cccc2c(Nc3cccc(C(F)(F)F)c3)ncnc12)c1c(Cl)ccc(CNC(=O)[C@@H]2CCCO2)c1F
Reaction time: 2 h
Yield: 44.1 %

Procedure:
A solution of tert-butyl 4-chloro-2-fluoro-3-((4-((3-(trifluoromethyl)phenyl)amino)quinazolin-8-yl)carbamoyl)benzylcarbamate (Intermediate-16, 80 mg, 0.135 mmol) in HCl in MeOH (2 mL) was stirred at rt for 2 h. The reaction mixture was concentrated and the concentrate was dissolved in DMF (1 mL). The solution was treated with DIPEA (87 mg, 0.675 mmol) and benzotriazole-1-yl-oxy-tris-(dimethylamino)-phosphonium hexafluorophosphate (119 mg, 0.27 mmol) followed by (S)-(−)-tetrahydro-2-furoic acid (24 mg, 0.203 mmol) at rt. The reaction mixture was stirred for 2 h before it was diluted with EtOAc and was washed with H2O and brine. The organic layer was separated, dried, filtered and concentrated. The residue was purified by column chromatography to afford 35 mg of the title product. 1H NMR (300 MHz, DMSO d6): δ 10.67 (s, 1H), 10.14 (s, 1H), 8.79 (d, 1H), 8.71 (s, 1H), 8.47 (br t, 1H), 8.37 (m, 2H), 8.25 (d, 1H), 7.73-7.65 (m, 2H), 7.50 (d, 1H), 7.39 (m, 2H), 4.33 (m, 3H), 3.94 (m, 1H), 3.80 (m, 1H), 2.14 (m, 1H), 1.84 (m, 3H); MS (m/z): 588.34 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:16]=[CH:15][C:14]2[S:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[N:6]([CH2:17][CH2:18][CH2:19][Cl:20])[C:5]=2[CH:4]=1.[NH:23]1[CH2:28][CH2:27][CH:26]([O:29][CH2:30][CH2:31][CH2:32][CH2:33][OH:34])[CH2:25][CH2:24]1>>[ClH:20].[F:1][C:2]([F:22])([F:21])[C:3]1[CH:16]=[CH:15][C:14]2[S:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[N:6]([CH2:17][CH2:18][CH2:19][N:23]3[CH2:28][CH2:27][CH:26]([O:29][CH2:30][CH2:31][CH2:32][CH2:33][OH:34])[CH2:25][CH2:24]3)[C:5]=2[CH:4]=1
Reactant: FC(F)(F)c1ccc2c(c1)N(CCCCl)c1ccccc1S2
Reactant: OCCCCOC1CCNCC1
Product: Cl
Product: OCCCCOC1CCN(CCCN2c3ccccc3Sc3ccc(C(F)(F)F)cc32)CC1
Yield: 38.7 %

Procedure:
Using the procedure of Example XI, 49.7 g (0.145 mole) of 2-trifluoromethyl-10-(3-chloropropyl)-phenothiazine and 25.5 g (0.145 mole) of 4-(4-piperidyloxy)-butanol were reacted to obtain 29 g (39% yield) of 2-trifluoromethyl-10-[3-(4-[4-hydroxybutoxy]-piperidino)-propyl]-phenothiazine hydrochloride in the form of white crystals melting at 67° C.
Reaction SMILES: [CH2:1]([N:5]([CH2:25][CH2:26][CH2:27][CH3:28])[C:6]([C:8]1[C:12]([Cl:13])=[C:11]([CH3:14])[N:10]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:16]=2[C:23]#N)[N:9]=1)=[O:7])[CH2:2][CH2:3][CH3:4].[OH-:29].[K+].Cl.C[OH:33].C(Cl)Cl>C(O)C.O>[Cl:13][C:12]1[C:8]([C:6](=[O:7])[N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[CH2:25][CH2:26][CH2:27][CH3:28])=[N:9][N:10]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:16]=2[C:23]([OH:33])=[O:29])[C:11]=1[CH3:14]
Reactant: CCCCN(CCCC)C(=O)c1nn(-c2ccc(OC)cc2C#N)c(C)c1Cl
Reactant: [OH-]
Reactant: CO
Agent: Cl
Agent: [K+]
Solvent: ClCCl
Solvent: CCO
Solvent: O
Product: CCCCN(CCCC)C(=O)c1nn(-c2ccc(OC)cc2C(=O)O)c(C)c1Cl
Yield: 39 %

Procedure:
A mixture of 4-Chloro-1-(2-cyano-4-methoxy-phenyl)-5-methyl-1H-pyrazole-3-carboxylic acid dibutylamide (1.3 g, 3.2 mmol) and potassium hydroxide (1.2 g, 21 mmol) in ethanol (5 mL) and water (5 mL) was microwaved at 150° C. for 90 minutes. The pH was adjusted to about 5 with aqueous HCl solution (15 N). The solvent was removed in vacuo. The crude material was eluted through a silica gel column with a 10 to 100% ethyl acetate/heptane and then 1 to 20% methanol/methylene chloride gradient to afford the title compound (0.53 g, 39% yield) as a white solid. MS (ESI) [m/e, (M+H)+]=422.4.
Reaction SMILES: C(N(CC)CC)C.[C:8]1([C:14]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)Cl)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[Br:28][C:29]1[C:33]2[CH:34]=[C:35]([CH3:38])[CH:36]=[CH:37][C:32]=2[O:31][C:30]=1[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=1[C:45]1[NH:49][N:48]=[N:47][N:46]=1>C(Cl)Cl>[Br:28][C:29]1[C:33]2[CH:34]=[C:35]([CH3:38])[CH:36]=[CH:37][C:32]=2[O:31][C:30]=1[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=1[C:45]1[N:49]([C:14]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:48]=[N:47][N:46]=1
Reactant: Cc1ccc2oc(-c3ccccc3-c3nnn[nH]3)c(Br)c2c1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc2oc(-c3ccccc3-c3nnnn3C(c3ccccc3)(c3ccccc3)c3ccccc3)c(Br)c2c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
5.89 g of triethylamine, 8.14 g of triphenylchloromethane and 0.10 g of 4-N,N-dimethylaminopyridine are added in succession to a suspension of 10.37 g of 3-bromo-2-[2'-(1H-tetrazol-5-yl)-phenyl]-5-methylbenzofuran in 300 ml of CH2Cl2 and the batch is stirred for 3 hours at room temperature. The reaction solution is washed with 150 ml of water and 150 ml of brine, concentrated in vacuo to a volume of 50 ml and chromatographed on silica gel 60 (40-63 μm) using CH2Cl2 as eluant. The product, of Rf =0.82 (CH2Cl2 /CH3OH (95:5) ), yields crystalline 3-bromo-2-[2'-(1-trityltetrazol-5-yl)-phenyl]-5-methylbenzofuran, m.p. 199°-200°, from ether.
Reaction SMILES: C(Cl)(=O)C(C)(C)C.[CH2:8]([O:10][C:11]1[CH:12]=[C:13]([CH2:22][C:23]([OH:25])=O)[CH:14]=[CH:15][C:16]=1[C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH3:9].C(N(CC)CC)C.[CH3:33][CH:34]([CH3:50])[CH2:35][C@H:36]([NH2:49])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1[N:43]1[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]1>C1(C)C=CC=CC=1.CCCCCC>[CH2:8]([O:10][C:11]1[CH:12]=[C:13]([CH2:22][C:23]([NH:49][C@H:36]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=2[N:43]2[CH2:44][CH2:45][CH2:46][CH2:47][CH2:48]2)[CH2:35][CH:34]([CH3:50])[CH3:33])=[O:25])[CH:14]=[CH:15][C:16]=1[C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH3:9]
Reactant: CCOC(=O)c1ccc(CC(=O)O)cc1OCC
Reactant: CC(C)C[C@H](N)c1ccccc1N1CCCCC1
Agent: CC(C)(C)C(=O)Cl
Solvent: CCCCCC
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc(CC(=O)N[C@@H](CC(C)C)c2ccccc2N2CCCCC2)cc1OCC
Temperature: 30 °C
Reaction time: 1 h
Yield: 72.8 %

Procedure:
Pivaloyl chloride (5.4 g, 45 mmol) was added to a mixture of 3-ethoxy-4-ethoxycarbonyl phenylacetic acid (10.0 g, 40 mmol), toluene (50 ml) and triethylamine (5.0 g, 49 mmol) at −5° C. and stirred for 1 hour. A solution of (S)-3-methyl-1-(2-piperidinophenyl)-1-butylamine (9.8 g, 40 mmol) in toluene (20 ml) was then added at below 10° C. The temperature of the reaction mixture was raised to 30° C. and the mixture stirred overnight. It was then washed with water and saturated sodium bicarbonate solution. Toluene was distilled off under reduced pressure to get the crude product. The crude product was dissolved in toluene (35 ml), hexane (200 ml) was added and the mixture cooled at 0° C. The solid product so obtained was filtered and dried to give 14.0 g of the title compound (Yield: 73%, HPLC Purity 99%).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][CH:10]([OH:13])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:21][S:22](Cl)(=[O:24])=[O:23]>C1(C)C=CC=CC=1>[CH3:21][S:22]([O:13][CH:10]1[CH2:11][CH2:12][N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:9]1)(=[O:24])=[O:23]
Reactant: OC1CCN(Cc2ccccc2)C1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CS(=O)(=O)OC1CCN(Cc2ccccc2)C1
Temperature: 25 °C

Procedure:
1-Benzyl-3-pyrrolidinol (1.1 g) in toluene (10 mL) at 0° C. was treated with triethylamine (1 mL) and methanesulfonyl chloride (0.53 mL), warmed to room temperature, washed with saturated aqueous sodium bicarbonate, water, and brine, dried over anhydrous sodium sulfate, and concentrated. 1H NMR (300 MHz, DMSO-d6) δ 7.31 (s, 5H), 5.21 (m, 1H), 3.65 (q, 2H), 2.82 (m, 2H), 2.5 (m, 2H), 2.36 (m, 2H), 2.1 (m, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@H:9]2[C@@H:15]([OH:16])[C:14](=[O:17])[N:13]([CH2:18][CH2:19][N:20]([CH3:22])[CH3:21])[C:12]3[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:11]=3[S:10]2)=[CH:5][CH:4]=1.[CH:28]([OH:30])=[O:29].[C:31]([O:34]C(=O)C)(=[O:33])C>N1C=CC=CC=1>[C:31]([OH:34])(=[O:33])[C:28]([OH:30])=[O:29].[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C@H:9]2[C@@H:15]([O:16][CH:28]=[O:29])[C:14](=[O:17])[N:13]([CH2:18][CH2:19][N:20]([CH3:22])[CH3:21])[C:12]3[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:11]=3[S:10]2)=[CH:7][CH:8]=1
Reactant: O=CO
Reactant: COc1ccc([C@@H]2Sc3cc(Cl)ccc3N(CCN(C)C)C(=O)[C@@H]2O)cc1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: COc1ccc([C@@H]2Sc3cc(Cl)ccc3N(CCN(C)C)C(=O)[C@@H]2OC=O)cc1
Product: O=C(O)C(=O)O
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A mixture of 0.8 g of (+)-cis-2-(4-methoxyphenyl)-3-hydroxy-5-[2-(dimethylamino)ethyl]-8-chloro-2,3-dihydro-1,5-benzothiazepin-4(5H)-one, 9 ml of formic acid, 3 ml of acetic anhydride and one ml of pyridine is stirred at room temperature for 3 days. The reaction mixture is evaporated under reduced pressure to remove solvent. The residue is converted into its oxalate and recrystallized from a mixture of ethanol and ether. 0.725 g of (+)-cis-2-(4-methoxyphenyl)-3-formyloxy-5-[2-(dimethylamino)ethyl]-8-chloro-2,3-dihydro-1,5-benzothiazepin-4(5H)-one oxalate is obtained.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:6]([CH3:13])[N:5]=[C:4]2[S:14][C:15]([Br:17])=[CH:16][C:3]=12.CC(C)([O-])C.[Na+].[C:24]1([S:30](Cl)(=[O:32])=[O:31])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C1COCC1.CN(C=O)C>[Br:17][C:15]1[S:14][C:4]2=[N:5][C:6]([CH3:13])=[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:2]([NH:1][S:30]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)(=[O:32])=[O:31])=[C:3]2[CH:16]=1
Reactant: CCOC(=O)c1c(C)nc2sc(Br)cc2c1N
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(C)nc2sc(Br)cc2c1NS(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 74.3 %

Procedure:
To a stirring mixture of ethyl 4-amino-2-bromo-6-methylthieno[2,3-b]pyridine-5-carboxylate (Description 66) (5.84 g, 18.53 mmol) in THF (110 mL) and DMF (55 mL) was added sodium tert-butoxide (4.45 g, 46.3 mmol) and benzenesulfonyl chloride (4.75 mL, 37.1 mmol). The resulting mixture was stirred at RT for 30 min. The reaction mixture was quenched with saturated ammonium chloride solution (ca. 150 mL) and extracted with DCM (80 mL×3). The combined organic layers were dried and concentrated. The residue was purified via normal phase chromatography, eluting with 0-30% ethyl acetate in DCM, to give the title compound (6.27 g). LCMS (A) m/z: 455/457 [M+1]+, Rt 1.35 min (acidic).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@H:9]2[C@@H:15]([O:16][C:17](=[O:19])[CH3:18])[C:14](=[O:20])[NH:13][C:12]3[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:11]=3[S:10]2)=[CH:5][CH:4]=1.Cl.[CH3:27][N:28]([CH2:32][CH2:33]Cl)[CH2:29][CH2:30][CH3:31].C(=O)([O-])[O-].[K+].[K+].[C:41]([O-:46])(=[O:45])[C:42]([O-:44])=[O:43]>CC(C)=O>[C:41]([OH:46])(=[O:45])[C:42]([OH:44])=[O:43].[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C@H:9]2[C@@H:15]([O:16][C:17](=[O:19])[CH3:18])[C:14](=[O:20])[N:13]([CH2:33][CH2:32][N:28]([CH3:27])[CH2:29][CH2:30][CH3:31])[C:12]3[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:11]=3[S:10]2)=[CH:7][CH:8]=1
Reactant: CCCN(C)CCCl
Reactant: O=C([O-])C(=O)[O-]
Reactant: COc1ccc([C@@H]2Sc3cc(Cl)ccc3NC(=O)[C@@H]2OC(C)=O)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCN(C)CCN1C(=O)[C@H](OC(C)=O)[C@H](c2ccc(OC)cc2)Sc2cc(Cl)ccc21
Product: O=C(O)C(=O)O

Procedure:
A mixture of 1 g of (±)-cis-2-(4-methoxyphenyl)-3-acetoxy-8-chloro-2,3-dihydro-1,5-benzothiazepin-4(5H)-one, 0.55 g of 2-(N-methyl-N-n-propylamino)ethyl chloride hydrochloride, 0.95 g of potassium carbonate and 20 ml of acetone is treated in the same manner as described in Example 1. The product thus obtained is converted into its oxalate and recrystallized from a mixture of chloroform and ethanol. 1.1 g of (±)-cis-2-(4-methoxyphenyl)-3-acetoxy-5-[2-(N-methyl-N-n-propylamino)ethyl]-8-chloro-2,3-dihydro-1,5-benzothiazepin-4(5H)-one oxalate are thereby obtained as colorless needles.
Reaction SMILES: N#N.[CH2:3]([N:10]1[CH2:14][CH2:13][C@H:12]([C@@H:15]([OH:20])[CH2:16][CH:17]([CH3:19])[CH3:18])[C:11]1=O)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.COCCO[AlH2-]OCCOC.[Na+]>C1(C)C=CC=CC=1>[CH2:3]([N:10]1[CH2:14][CH2:13][C@H:12]([C@@H:15]([OH:20])[CH2:16][CH:17]([CH3:18])[CH3:19])[CH2:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CC(C)C[C@H](O)[C@H]1CCN(Cc2ccccc2)C1=O
Agent: COCCO[AlH2-]OCCOC
Agent: N#N
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC(C)C[C@H](O)[C@H]1CCN(Cc2ccccc2)C1
Temperature: 0 °C
Reaction time: 16 h
Yield: 101.5 %

Procedure:
Charge a 1 L, 3-neck round bottom flask equipped with a magnetic stirrer, thermal couple, addition funnel and N2 inlet with crude (R)-1-benzyl-3-((S)-1-hydroxy-3-methylbutyl)pyrrolidin-2-one (38.26 mmoles, assumed) and toluene (100 mL). Cool the slightly heterogeneous stirring solution to 0° C. (salt/ice bath) and add a solution of Vitride™ (Rohm & Haas) (65 wt % in toluene, 24 mL, 86.085 mmoles) and toluene (70 mL) drop wise while maintaining a temperature at or below 5° C. Rinse the addition funnel with toluene (10-20 mL). Stir at room temperature overnight (˜16 hr). Cool the reaction mixture to 0° C. (salt/ice bath) and quenched with saturated Rochell's salt solution (200 mL) followed by MTBE (200 mL). Allow the mixture to warm to room temperature with stirring and then stir at this temperature for 1 hour. Separate the organic and aqueous layers and wash the organic layer with H2O (2×200 mL), then brine (200 mL), and then dry over Na2SO4. Filter and concentrate to give the desired intermediate as a brown oil (9.61 g, 38.85 mmoles, >100% yield). 1H NMR (300 MHz, CDCl3) δ 7.36-7.18 (m, 5H), 3.82-3.72 (m, 1H), 3.58 (dd, 2H, 7.61, 20.51 Hz), 2.87 (td, 1H, J=4.10, 8.79 Hz), 2.79-2.70 (m, 1H), 2.48-2.38 (m, 1H), 2.26-2.04 (m, 2H), 1.98-1.64 (m, 3H), 1.46-1.32 (m, 1H), 1.14-0.98 (m, 1H), 0.92 (d, 3H, J=1.18 Hz), 0.89 (d, 3H, J=1.76 Hz). LC/MS=248.1 (M+1).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][CH:8]1[CH2:12][CH2:11][CH:10]([CH3:13])[N:9]1[C:14]1[CH:22]=[CH:21][C:17]([C:18]([OH:20])=O)=[CH:16][C:15]=1[N+:23]([O-:25])=[O:24].O[N:27]=[C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[O:36][C:37]([F:40])([F:39])[F:38])[NH2:29].CCN(C(C)C)C(C)C>>[CH3:13][CH:10]1[CH2:11][CH2:12][CH:8]([CH3:7])[N:9]1[C:14]1[CH:22]=[CH:21][C:17]([C:18]2[O:20][N:29]=[C:28]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[O:36][C:37]([F:38])([F:39])[F:40])[N:27]=2)=[CH:16][C:15]=1[N+:23]([O-:25])=[O:24]
Reactant: CC1CCC(C)N1c1ccc(C(=O)O)cc1[N+](=O)[O-]
Reactant: NC(=NO)c1ccccc1OC(F)(F)F
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Product: CC1CCC(C)N1c1ccc(-c2nc(-c3ccccc3OC(F)(F)F)no2)cc1[N+](=O)[O-]

Procedure:
Oxalyl chloride (152 μL; 1.2 mmol; 3 eq.), Intermediate 25 (106 mg; 0.4 mmol; 1 eq.), Intermediate 2 (88 mg; 0.4 mmol, 1 eq.) and DIEA (155 μL; 1.2 mmol; 3 eq.) were reacted according to general procedure 2. Purification by crystallisation from ethyl acetate/n-pentane afforded the title compound as a yellow solid.