Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4]([C:6]1[C:11]2=[CH:12][S:13][C:14]([NH2:15])=[C:10]2[C:9](=[O:16])[N:8]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:7]=1)=O)C.O.[NH2:24][NH2:25]>C(O)C>[NH2:15][C:14]1[S:13][CH:12]=[C:11]2[C:10]=1[C:9](=[O:16])[N:8]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[N:7]=[C:6]2[C:4]([NH:24][NH2:25])=[O:3]
Reactant: CCOC(=O)c1nn(-c2ccccc2)c(=O)c2c(N)scc12
Reactant: NN
Solvent: CCO
Solvent: O
Product: NNC(=O)c1nn(-c2ccccc2)c(=O)c2c(N)scc12
Yield: 94.3 %

Procedure:
To a solution of 5-Amino-4-oxo-3-phenyl-3,4-dihydro-thieno[3,4-d]pyridazine-1-carboxylic acid ethyl ester (20 g, 0.063 mol, prepared as described in example 25) in ethanol (400 ml) was added hydrazine hydrate (3.3 g, 0.066 mol). The reaction mixture was stirred at reflux temperature for 6 h at which time an additional portion of hydrazine hydrate (3.3 g, 0.066 mol) was added and the resulting mixture was stirred for an additional 66 h at reflux temperature. An additional portion of hydrazine hydrate (1.5 g, 0.03 mol) was added and the reaction mixture was stirred for an additional 16 h at reflux temperature. The reaction mixture was cooled and the precipitated was filtered off, washed with small portions of ethanol and dried in vacuo at 50° C. for 18 h which afforded 17.9 g (94%) of the title compound as a solid.
Reaction SMILES: [NH2:1][C:2](=[S:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4].Br[CH2:10][C:11](=O)[C:12]([OH:14])=[O:13]>C1COCC1>[CH2:6]([O:5][C:3]([C:2]1[S:8][CH:10]=[C:11]([C:12]([OH:14])=[O:13])[N:1]=1)=[O:4])[CH3:7]
Reactant: CCOC(=O)C(N)=S
Reactant: O=C(O)C(=O)CBr
Solvent: C1CCOC1
Product: CCOC(=O)c1nc(C(=O)O)cs1
Temperature: 50 °C
Reaction time: 8 h
Yield: 48.5 %

Procedure:
A mixture of ethyl 2-amino-2-thioxoacetate (10.1 g), 3-bromo-2-oxopropanoic acid (12.7 g) and THF (200 ml) was stirred at 50° C. overnight. The mixture was concentrated in vacuo, and the resulting solid was suspended in EtOAc. The precipitate was collected by filtration to give the title compound (7.4 g) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10]Cl)=[CH:6][C:5]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C1OCCOCCOCCOCCOCCOC1.[OH:37][C:38]1[CH:39]=[N:40][CH:41]=[CH:42][CH:43]=1.[K]>C1(C)C=CC=CC=1.O>[CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][O:37][C:38]2[CH:39]=[N:40][CH:41]=[CH:42][CH:43]=2)=[CH:6][C:5]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Oc1cccnc1
Reactant: COC(=O)c1ccc(CCl)cc1-c1ccccc1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K]
Solvent: Cc1ccccc1
Solvent: O
Product: COC(=O)c1ccc(COc2cccnc2)cc1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 50.2 %

Procedure:
To a solution of 11.1 g (42.3 mmol) of 4-chloromethyl-2-phenylbenzoic acid methyl ester, prepared as in Example 187A, in 150 mL of toluene was added 1.7 g (6.4 mmol) of 18-Crown-6, and 8.40 g (63.1 mmol) of 3-hydroxypyridine, potassium salt. The reaction was stirred at ambient temperature for 20 minutes, then heated to reflux under N2. After 3 hours, the mixture was poured into 100 mL of water. The layers were separated, then the aqueous layer was extracted with ethyl acetate (3×100 mL). The combined organic layers were back extracted with 2M aqueous NaOH (2×30 mL), brine (1×100 mL), dried over magnesium sulfate, filtered, and concentrated to an oil which slowly crystallized. The product was recrystallized from 50 mL of 2-propanol to give 6.78 g of a tan solid. The supernatant was concentrated and purified via silica gel chromatography (50:50 hexanes:ethyl acetate) to give another 2.18 g of product, for a total yield of 8.96 g (66%). 1H NMR (300 MHz, d6-DMSO) δ 3.60 (s, 3H), 5.33 (s, 2H), 7.28-7.54 (m, 8H), 7.57 (dd, J=1.5, 9.0 Hz, 1H), 7.78 (d, J=9 Hz, 1H), 8.18 (dd, J=1.0, 5.5 Hz, 1H), 8.38 (d, J=3.0 Hz, 1H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:12]=[CH:11][CH:10]=[CH:9][C:6]=1[C:7]#[N:8].[H-].[Na+].[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CN(C=O)C.O>[CH2:15]([O:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:12]=[CH:11][CH:10]=[CH:9][C:6]=1[C:7]#[N:8])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: BrCc1ccccc1
Reactant: N#Cc1ccccc1CCCO
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1ccccc1CCCOCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 2-(3-hydroxypropyl)benzonitrile (Example 323c, 3.83 g) in DMF (40 mL) under nitrogen was treated with 60% Sodium hydride (1.140 g) and stirred at room temperature for 1 h before adding benzyl bromide (2.83 mL). The resulting solution was stirred at 20° C. for 60 h. The reaction mixture was diluted with water (200 mL), and extracted with ethyl acetate (200 mL). The organic was dried (MgSO4), filtered and evaporated. The residue was purified (SiO2 chromatography eluting with 30% diethyl ether in isohexane). Pure fractions were evaporated to dryness to afford the subtitle compound as an oil (2.3 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[CH2:4][CH2:5][CH2:6][C:7]1[S:8][C:9]([NH2:12])=[CH:10][CH:11]=1.C([O:16][CH:17]=[C:18]([C:24]#[N:25])[C:19](OCC)=O)C>C1(C)C=CC=CC=1>[C:24]([C:18]1[C:17](=[O:16])[C:10]2[CH:11]=[C:7]([CH2:6][CH2:5][CH2:4][C:3]([O:2][CH3:1])=[O:13])[S:8][C:9]=2[NH:12][CH:19]=1)#[N:25]
Reactant: CCOC=C(C#N)C(=O)OCC
Reactant: COC(=O)CCCc1ccc(N)s1
Solvent: Cc1ccccc1
Product: COC(=O)CCCc1cc2c(=O)c(C#N)c[nH]c2s1
Temperature: 25 °C
Yield: 9.8 %

Procedure:
A mixture of 4-(5-amino-thiophen-2-yl)-butyric acid methyl ester (1.00 g, 5.0 mmol) and ethyl (ethoxymethylene)cyanoacetate (930 mg, 5.5 mmol) in 50 mL of toluene is heated at reflux for 1 hour. The reaction mixture is concentrated and 50 mL of Dowtherm-A is added. The mixture is heated at reflux for 3 hours and cooled to room temperature. The crude reaction mixture is passed through a short pad of silica gel, eluting with dichloromethane followed by 10% methanol in dichloromethane. The crude product is further purified by flash column chromatography eluting with 10% methanol in dichloromethane followed by another flash column chromatography eluting with 10% methanol in ethyl acetate to provide 136 mg of methyl 4-(5-cyano-4-oxo-4,7-dihydrothieno[2,3-b]pyridin-2-yl)butanoate as a tan solid.
Reaction SMILES: [C:1]1([N:7]2[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][CH2:15][C:16]3[N:17]=[N:18][NH:19][CH:20]=3)=[C:9]([OH:21])[C:8]2=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:24].[Al].C(Cl)Cl>CO>[C:1]1([N:7]2[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][CH2:15][C:16]3[N:17]=[N:18][NH:19][CH:20]=3)=[C:9]([OH:21])[C:8]2=[S:24])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=c1c(O)c(CCCc2c[nH]nn2)ccn1-c1ccccc1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Agent: [Al]
Solvent: CO
Solvent: ClCCl
Product: Oc1c(CCCc2c[nH]nn2)ccn(-c2ccccc2)c1=S
Temperature: 175 °C
Yield: 121.9 %

Procedure:
159b (0.062 g, 0.21 mmol) was ground together with P4S10 (0.047 g, 0.105 mmol) in mortar and pestle to form grey powder. The powder was stirred under argon in a flask fitted with condenser and heated to 175° C. for 2 h. The reaction flask was covered with aluminum foil during reaction. After 2 h of reaction, flask was cooled down to room temperature. 25 mL of CH2Cl2:MeOH (10%) mixtures was added and stirred for 15 min. This reaction mixture then washed with water (2×30 mL). Organic layer dried with Na2SO4 and evaporated to yield crude product which was purified by prep-TLC (Eluent —CH2Cl2:MeOH (8%) to give 162b (0.04 g, 60%) as olive green solid. 1H NMR (400 MHz, CDCl3) δ 8.47 (s, 1H), 7.82 (m, 3H), 7.50 (d, J=6.5 Hz, 1H), 7.43 (t, J=7.5 Hz, 2H), 7.34 (t, J=7.4 Hz, 1H), 6.97 (m, 1H), 6.66 (m, 1H), 4.62 (t, J=6.9 Hz, 2H), 4.48 (m, 2H). 13C NMR (100 MHz, CDCl3) δ 168.59, 155.22, 148.03, 131.85, 130.17, 128.84, 128.29, 125.61, 119.84, 113.87, 112.28, 54.99, 46.95, 28.02. HRMS (EI) calcd for C16H16N4OS [M]+ 312.104. found 312.1060.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]([O:12][CH2:13][C:14]([F:20])([F:19])[C:15]([F:18])([F:17])[F:16])[CH:9]=[CH:8][C:3]=1[C:4]([O:6]C)=[O:5].[OH-].[K+].Cl>CO.O>[OH:1][C:2]1[CH:11]=[C:10]([O:12][CH2:13][C:14]([F:19])([F:20])[C:15]([F:16])([F:17])[F:18])[CH:9]=[CH:8][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: COC(=O)c1ccc(OCC(F)(F)C(F)(F)F)cc1O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1ccc(OCC(F)(F)C(F)(F)F)cc1O
Yield: 55 %

Procedure:
To a solution of methyl 2-hydroxy-4-(2,2,3,3,3-pentafluoropropoxy)benzoate (obtained in example 1) (0.72 g, 2.40 mmol) in MeOH (9.7 mL), KOH (0.51 g, 86%; 7.80 mmol) dissolved in H2O (3 mL) was added and the resulting mixture was refluxed for 4 hours. The mixture was allowed to cool and MeOH was evaporated. The residue thus obtained was treated with H2O (5 mL) and the resulting solution was acidified with 6 N HCl. The white solid formed was collected by filtration, washed with cold H2O and dried in vacuo, yielding the title compound (55% yield).
Reaction SMILES: [NH2:1][C:2]1[C:3]([OH:13])=[C:4]([S:9]([NH2:12])(=[O:11])=[O:10])[C:5]([Cl:8])=[CH:6][CH:7]=1.[N:14]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:15]=[O:16]>CN(C)C=O.C(OCC)(=O)C>[NH2:12][S:9]([C:4]1[C:3]([OH:13])=[C:2]([NH:1][C:15]([NH:14][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[O:16])[CH:7]=[CH:6][C:5]=1[Cl:8])(=[O:11])=[O:10]
Reactant: Nc1ccc(Cl)c(S(N)(=O)=O)c1O
Reactant: CCOC(=O)CN=C=O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)CNC(=O)Nc1ccc(Cl)c(S(N)(=O)=O)c1O
Yield: 7.5 %

Procedure:
A solution of 3-amino-6-chloro-2-hydroxybenzenesulfonamide (170 mg, 0.76 mmol) and ethyl isocyanatoacetate (103 μL, 0.92 mmol) in 1.5 mL of N,N-dimethyl-formamide was stirred at room temperature for 20 hours. The mixture was diluted with ethyl acetate and washed with water to give the crude. Purification upon column chromatograph on silica gel, eluting with ethyl acetate/hexane (60/40, v/v), followed by Gilson HPLC separation, gave the desired product (20 mg, 7%). LC-MS (m/z) 352.0 (M+).
Reaction SMILES: [Na].[C:2]([OH:7])(=[O:6])[C:3]([OH:5])=[O:4].Cl[C:9]1[C:10]([C:14]2[CH2:15][N:16]([CH3:20])[CH2:17][CH2:18][CH:19]=2)=[N:11][S:12][N:13]=1.[CH3:21][O:22][CH2:23][CH2:24][OH:25]>>[C:2]([OH:7])(=[O:6])[C:3]([OH:5])=[O:4].[CH3:21][O:22][CH2:23][CH2:24][O:25][C:9]1[C:10]([C:14]2[CH2:15][N:16]([CH3:20])[CH2:17][CH2:18][CH:19]=2)=[N:11][S:12][N:13]=1
Reactant: COCCO
Reactant: CN1CCC=C(c2nsnc2Cl)C1
Agent: O=C(O)C(=O)O
Agent: [Na]
Product: COCCOc1nsnc1C1=CCCN(C)C1
Temperature: 50 °C
Reaction time: 18 h

Procedure:
To a solution of sodium (120 mg, 5 mmol) in 2-methoxyethanol (10 ml) was added 3-(4-chloro-1,2,5-thiadiazol-3-yl)-1,2,5,6-tetrahydro-1-methylpyridine oxalate (310 mg, 1 mmol). The mixture was stirred at 50° C. for 18 h and evaporated. The residue was dissolved in water and extracted with ethyl acetate. The combined organic phases were dried and evaporated. The title compound was crystallized as the oxalate salt from acetone to yield 270 mg. (M.p. 152.1° C.; M+ : 253; Compound 15).
Reaction SMILES: [OH:1][C:2]1[CH:14]=[CH:13][C:12]2[NH:11][C:10]3[CH:9]=[C:8](I)[C:7]4[C:16](=[O:20])[NH:17][C:18](=[O:19])[C:6]=4[C:5]=3[C:4]=2[CH:3]=1.CC1(C)C(C)(C)OB([C:29]2[CH:34]=[CH:33][C:32]([NH2:35])=[CH:31][CH:30]=2)O1>>[NH2:35][C:32]1[CH:33]=[CH:34][C:29]([C:8]2[C:7]3[C:16](=[O:20])[NH:17][C:18](=[O:19])[C:6]=3[C:5]3[C:4]4[CH:3]=[C:2]([OH:1])[CH:14]=[CH:13][C:12]=4[NH:11][C:10]=3[CH:9]=2)=[CH:30][CH:31]=1
Reactant: O=C1NC(=O)c2c1c(I)cc1[nH]c3ccc(O)cc3c21
Reactant: CC1(C)OB(c2ccc(N)cc2)OC1(C)C
Product: Nc1ccc(-c2cc3[nH]c4ccc(O)cc4c3c3c2C(=O)NC3=O)cc1
Yield: 57 %

Procedure:
The reaction of 9-hydroxy-4-iodopyrrolo[3,4-c]carbazole-1,3(2H,6H)-dione prepared as in example 7 with 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenylamine according to the procedure described in example 8 gave 4-(4-Aminophenyl)-9-hydroxypyrrolo[3,4-c]carbazole-1,3(2H,6H)-dione (16) (I, Ar=4-aminophenyl) in a 57% yield; mp 256–258° C. 1H NMR δ [(CD3)2SO] 11.60 (s, 1H), 10.92 (s, 1H), 9.19 (s, 1H), 8.31 (d, J=2.3 Hz, 1H), 7.48 (s, 1H), 7.39 (d, J=8.6 Hz, 1H), 7.30 (d, J=8.4 Hz, 2H), 7.02 (dd, J=8.6, 2.3 Hz, 1H), 6.62 (d, J=8.4 Hz, 2H), 5.29 (br s, 2H). Found: C, 68.09; H, 4.34; N, 11.03. C20H13N3O3.1/2H2O requires C, 68.17; H, 4.00; N, 11.92.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[C:10](=[O:14])[NH:9][CH2:8][CH2:7]2.Br[CH2:16][CH2:17][CH3:18]>CN(C=O)C>[Br:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[C:10](=[O:14])[N:9]([CH2:16][CH2:17][CH3:18])[CH2:8][CH2:7]2
Reactant: O=C1NCCc2cc(Br)ccc21
Reactant: CCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCN1CCc2cc(Br)ccc2C1=O
Temperature: 25 °C
Yield: 71.1 %

Procedure:
Sodium hydride (60% w/w suspension in oil) (1.17 mmol, 46.7 mg) was suspended in DMF (0.5 ml) under argon. The mixture was cooled to 0° C. before dropwise addition of 6-bromo-3,4-dihydroisoquinolin-1(2H)-one (1K2) (1.06 mmol, 240 mg) in DMF (1.5 ml) The reaction was stirred at 0° C. for 30 min before addition of 3-bromopropane (1K3) (1.592 mmol, 196 mg) in DMF (1 ml). Once addition was complete the reaction was allowed to warm to room temperature then heated at 60° C. for 4hrs. The reaction mixture was cooled, quenched with water and extracted three times with diethyl ether. The combined organics were washed with brine, dried (MgSO4) and evaporated to dryness. The residue was purified on silica eluting with 30-100% EtOAc/heptane to give 6-bromo-2-propyl-3,4-dihydroisoquinolin-1(2H)-one (1K4) 202 mg (70.9%); 1H NMR (400 MHz, CDCl3) δ 7.94 (d, 1H) 7.47 (d, 1H) 7.33 (s, 1H) 3.54 (m, 4H) 2.96 (t, 2H) 1.65 (m, 2H) 0.96 (t, 3H).
Reaction SMILES: [CH3:1][C:2]1[N:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:18])[C:10](=[O:19])[C:9]2[C:4](=[N:5][CH:6]=[CH:7][N:8]=2)[N:3]=1.[F:20][C:21]1[CH:28]=[CH:27][CH:26]=[CH:25][C:22]=1[CH:23]=O.C(OC(=O)C)(=O)C>O1CCOCC1>[F:20][C:21]1[CH:28]=[CH:27][CH:26]=[CH:25][C:22]=1[CH:23]=[CH:1][C:2]1[N:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:18])[C:10](=[O:19])[C:9]2[C:4](=[N:5][CH:6]=[CH:7][N:8]=2)[N:3]=1
Reactant: Cc1ccccc1-n1c(C)nc2nccnc2c1=O
Reactant: O=Cc1ccccc1F
Solvent: CC(=O)OC(C)=O
Solvent: C1COCCO1
Product: Cc1ccccc1-n1c(C=Cc2ccccc2F)nc2nccnc2c1=O
Yield: 55.4 %

Procedure:
A mixture of fused zinc chloride (0.17 g, 1.25 mmol), dioxane (15 mL), 2-methyl-3-(2-methyl-phenyl)-3H-pteridin-4-one (0.174 g, 0.69 mmol, preparation 8), and 2-fluorobenzaldehyde (0.22 mL, 2.07 mmol), and acetic anhydride 0.195 mL, 2.07 mmol) was refluxed overnight. The reaction was cooled and concentrated. The residual material was partitioned between saturated aqueous sodium bicarbonate and methylene chloride. The layers were carefully shaken and separated. The organic layer was washed with brine, dried and concentrated. The residue was flash chromatographed on silica gel (0.75×4 inches) with elution proceeding as follows: 50% ethyl acetate/hexane (300 mL), forerun; 60% ethyl acetate/hexane (400 mL). 2-[2-(2-Fluoro-phenyl)-vinyl]-3-o-tolyl-3H-pteridin-4-one (0.137 g, 55%) was isolated as a yellow crystalline solid. A sample was recrystallized from ethyl acetate.
Reaction SMILES: [Cl:1][C:2]1[CH:35]=[CH:34][CH:33]=[C:32]([F:36])[C:3]=1[CH2:4][N:5]1[C:13]2[C:12](=[O:14])[N:11]([CH2:15][CH3:16])[C:10](=[O:17])[N:9]([CH2:18][C:19]([O:21]C(C)(C)C)=[O:20])[C:8]=2[N:7]=[C:6]1[N:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:35]=[CH:34][CH:33]=[C:32]([F:36])[C:3]=1[CH2:4][N:5]1[C:13]2[C:12](=[O:14])[N:11]([CH2:15][CH3:16])[C:10](=[O:17])[N:9]([CH2:18][C:19]([OH:21])=[O:20])[C:8]=2[N:7]=[C:6]1[N:26]1[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]1
Reactant: CCn1c(=O)c2c(nc(N3CCCCC3)n2Cc2c(F)cccc2Cl)n(CC(=O)OC(C)(C)C)c1=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCn1c(=O)c2c(nc(N3CCCCC3)n2Cc2c(F)cccc2Cl)n(CC(=O)O)c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 89 %

Procedure:
A solution of tert-butyl [7-(2-chloro-6-fluorobenzyl)-1-ethyl-2,6-dioxo-8-piperidin-1-yl-1,2,6,7-tetrahydro-3H-purin-3-yl]acetate (24 mg, 0.046 mmol) in 230 μL CH2Cl2 was treated with 230 μL TFA. The reaction was stirred at room temperature for 1 hr and then the solvent was removed by reduced pressure. The crude product was filtered through a silica plug and rinsed with 20% MeOH/EtOAc. The solvent was removed affording the title compound (19 mg, 90% yield) as a white solid: 1H NMR (CDCl3, 400 MHz) 7.22-7.16 (m, 1H), 7.14-7.10 (m, 1H), 6.98-6.91 (m, 1H), 5.51 (s, 2H), 4.80 (s, 2H), 3.95 (q, 2H, J=7.0 Hz), 3.11-3.01 (m, 4H), 1.54-1.41 (m, 6H), 1.12 (t, 3H, J=7.0 Hz); MS (ESP+) m/e 464 (MH+).
Reaction SMILES: [OH:1][C@H:2]1[C:8](=[O:9])[NH:7][C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[S:4][C@H:3]1[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1.C(OCC)(=O)C.[CH3:28][N:29]([CH2:31][CH2:32]Cl)[CH3:30].C([O-])([O-])=O.[K+].[K+]>O>[CH3:28][N:29]([CH3:30])[CH2:31][CH2:32][N:7]1[C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[S:4][C@@H:3]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[C@@H:2]([OH:1])[C:8]1=[O:9]
Reactant: COc1ccc([C@@H]2Sc3ccccc3NC(=O)[C@@H]2O)cc1
Reactant: CN(C)CCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Product: COc1ccc([C@@H]2Sc3ccccc3N(CCN(C)C)C(=O)[C@@H]2O)cc1
Temperature: 25 °C
Yield: 69.6 %

Procedure:
A 5-L three-necked flask equipped with a heating mantle, a mechanical stirrer and a condenser was charged with 162 g (0.54 mol) of (+)-(2S,3S)-2,3-dihydro-3-hydroxy-2-(4-methoxyphenyl)-1,5-benzothiazepin-4(5H)-one and then 1 L of ethyl acetate. After stirring to dissolve the solution, 100 g (0.694 mol) of dimethylaminoethyl chloride.HC1 was added in one portion followed by 300 g (2.16 mol) of finely ground K2CO3 and 5 mL of H2O. (The 5 ml. of water was essential to cause a reaction between the phases, while addition of much more water would have resulted in gummy mixture that was difficult to filter.) This heterogeneous mixture was rapidly stirred at reflux for 5 hours. By thin layer chromatography (8:1, CH2C12 -MeOH, short wave UV), reaction was complete and therefore the mixture was allowed to cool to room temperature, filtered through a sintered glass funnel and washed with 100 mL 1:1 hexanes-ethyl acetate. The solvent was evaporated and on standing the oil crystallized. Recrystallization from ether gave 140 g (70%) of colorless crystalline (+)-(2S,3S)-5-[2-(dimethylamino)ethyl]-2,3-dihydro-3-hydroxy-2-(4-methoxyphenyl)-1,5-benzothiazepin-4(5H)-one, m.p. 79-81° C., [α]D20=+ 156.4°(C=1.0; CHC13).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:4]=[C:5]([CH:30]=[C:31]([S:33][CH3:34])[CH:32]=1)[CH2:6][O:7][C:8]1[CH:9]=[C:10]([CH:15]=[C:16]([O:18][CH2:19][C:20]2[CH:25]=[C:24]([S:26][CH3:27])[CH:23]=[C:22]([S:28][CH3:29])[CH:21]=2)[CH:17]=1)[C:11](OC)=[O:12].Cl>O1CCCC1>[CH3:34][S:33][C:31]1[CH:30]=[C:5]([CH:4]=[C:3]([S:2][CH3:1])[CH:32]=1)[CH2:6][O:7][C:8]1[CH:9]=[C:10]([CH:15]=[C:16]([O:18][CH2:19][C:20]2[CH:25]=[C:24]([S:26][CH3:27])[CH:23]=[C:22]([S:28][CH3:29])[CH:21]=2)[CH:17]=1)[CH2:11][OH:12]
Reactant: COC(=O)c1cc(OCc2cc(SC)cc(SC)c2)cc(OCc2cc(SC)cc(SC)c2)c1
Agent: Cl
Solvent: C1CCOC1
Product: CSc1cc(COc2cc(CO)cc(OCc3cc(SC)cc(SC)c3)c2)cc(SC)c1
Reaction time: 5 h

Procedure:
To sodium dihydrobis(2-methoxyethoxy)aluminate (70% in toluene, 22.7 g, 0.078 mol), was added dropwise a solution of methyl 3,5-bis(3,5-dimethylthiobenzyloxy)benzoate (21.0 g) in tetrahydrofuran (180 ml) in a stream of nitrogen at 5-10° C. during 30 minutes. After completion of the addition, the mixture was stirred for 5 hours and then poured into 2L of diluted hydrochloric acid, followed by extraction with 1L of chloroform. The extract was evaporated to dryness, and the residue was purified by means of chromatography using chloroform as the developing solvent, giving 3,5-bis(3,5-dimethylthiobenzyloxy)benzyl alcohol. The yield was 17.5 g (85.6%).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].CS(C)=O.C(=O)([O-])[O-].[K+].[K+].[NH2:21][C@@H:22]([CH3:25])[CH2:23][OH:24]>O>[N+:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:21][C@@H:22]([CH3:25])[CH2:23][OH:24])([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: C[C@H](N)CO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: C[C@@H](CO)Nc1ccccc1[N+](=O)[O-]
Temperature: 60 °C
Yield: 104.5 %

Procedure:
A 200-mL round bottomed flask equipped with a magnetic stir bar was charged with 1-fluoro-2-nitrobenzene (8.25 g, 58.5 mmol), DMSO (29 mL), potassium carbonate (8.89 g, 64.3 mmol), and (S)-2-aminopropane-1-ol (4.83 g, 64.3 mmol). The mixture was heated to 60° C. for 6 h and then cooled to room temperature. The reaction mixture was diluted with water (60 mL). The mixture was stirred for several minutes, then extracted with ethyl acetate (ca. 200-250 mL). The ethyl acetate extract was washed thrice with 5 wt % aqueous sodium chloride (3×50 mL) and concentrated under reduced pressure to afford crude (S)-2-(2-nitrophenylamino)propane-1-ol (12.0 g, 105%) as a bright orange syrup. MS (ESI, pos. ion) m/z 197 [M+1]+.
Reaction SMILES: [CH:1]1([C:4]2[C:5]([O:24][CH2:25][C:26]([F:29])([F:28])[F:27])=[CH:6][C:7]([C:10]([NH:12][C:13]([C:18]3[N:22]=[C:21]([CH3:23])[O:20][N:19]=3)([CH3:17])[C:14](O)=[O:15])=[O:11])=[N:8][CH:9]=2)[CH2:3][CH2:2]1.[NH:30]1[CH2:33][CH2:32][CH2:31]1>>[N:30]1([C:14](=[O:15])[C:13]([NH:12][C:10]([C:7]2[CH:6]=[C:5]([O:24][CH2:25][C:26]([F:27])([F:28])[F:29])[C:4]([CH:1]3[CH2:2][CH2:3]3)=[CH:9][N:8]=2)=[O:11])([C:18]2[N:22]=[C:21]([CH3:23])[O:20][N:19]=2)[CH3:17])[CH2:33][CH2:32][CH2:31]1
Reactant: Cc1nc(C(C)(NC(=O)c2cc(OCC(F)(F)F)c(C3CC3)cn2)C(=O)O)no1
Reactant: C1CNC1
Product: Cc1nc(C(C)(NC(=O)c2cc(OCC(F)(F)F)c(C3CC3)cn2)C(=O)N2CCC2)no1

Procedure:
The title compound was synthesized in analogy to Example 112e, using 2-[[5-cyclopropyl-4-(2,2,2-trifluoroethoxy)pyridine-2-carbonyl]amino]-2-(5-methyl-1,2,4-oxadiazol-3-yl)propanoic acid (example 147c) and azetidine (CAN 503-29-7) as starting materials and isolated (23 mg, 51%); MS (ESI, m/z): 454.5 (M+H+).
Reaction SMILES: Cl.[C:2]1([CH:8]2[CH:13]=[CH:12][NH:11][CH2:10][CH2:9]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(C(C)C)C(C)C)C.[C:23]1([C:29]2([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[O:33][C:32]3[CH:34]=[CH:35][C:36]([S:38](Cl)(=[O:40])=[O:39])=[CH:37][C:31]=3[O:30]2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.Cl>C(Cl)Cl>[C:42]1([C:29]2([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[O:33][C:32]3[CH:34]=[CH:35][C:36]([S:38]([N:11]4[CH2:10][CH:9]=[C:8]([C:2]5[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=5)[CH2:13][CH2:12]4)(=[O:39])=[O:40])=[CH:37][C:31]=3[O:30]2)[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1
Reactant: C1=CC(c2ccccc2)CCN1
Reactant: O=S(=O)(Cl)c1ccc2c(c1)OC(c1ccccc1)(c1ccccc1)O2
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=S(=O)(c1ccc2c(c1)OC(c1ccccc1)(c1ccccc1)O2)N1CC=C(c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 47.6 %

Procedure:
4-Phenyl-1,2,3,4-tetrahydropyridine hydrochloride (15.92 mg, 0.10 mmol) was suspended in methylene chloride (2 ml). Ethyldiisopropylamine (0.035 ml, 0.20 mmol) was added and the solution was shaken for 10 minutes at room temperature. 2,2-Diphenyl-benzo[1,3]dioxole-5-sulfonyl chloride (37.28 mg, 0.10 mmol) was added and the reaction was shaken at room temperature for 12 hours. Aqueous HCl (0.1 N, 1.0 ml) was added and the mixture shaken for 30 minutes, the aqueous layer removed and the organic phase concentrated and purified by preparative reverse phase HPLC (YMC, ODS-AQ packing; 20%→95% CH3CN/H2O) to yield the sulfonamide (23.6 mg, 48%).