Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[S:13][C:12]([C:14]([O:16]C)=[O:15])=[C:11]([CH3:18])[C:10]=1[C:19]#[N:20])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>CO.O>[C:1]([O:5][C:6]([NH:8][C:9]1[S:13][C:12]([C:14]([OH:16])=[O:15])=[C:11]([CH3:18])[C:10]=1[C:19]#[N:20])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1sc(NC(=O)OC(C)(C)C)c(C#N)c1C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1c(C(=O)O)sc(NC(=O)OC(C)(C)C)c1C#N
Temperature: 50 °C
Reaction time: 8 h
Yield: 92.9 %

Procedure:
The compound prepared in Example 221 (0.200 g) was suspended in methanol (10 mL) and aqueous sodium hydroxide solution (2 mol/L; 3.375 mL) was added and the reaction mixture stirred at 50° C. overnight. The reaction mixture was cooled to room temperature and concentrated under reduced pressure to afford a solid, which was dissolved in water, acidified to pH 1 and filtered to furnish the title compound (0.177 g) with the following physical properties.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([NH:14][C:15](=O)[CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O1CCCC1>O1CCCC1>[CH2:7]([NH:14][CH2:15][CH2:16][CH2:17][C:18]1[CH:19]=[CH:20][C:21]([OH:24])=[CH:22][CH:23]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: O=C(CCc1ccc(O)cc1)NCc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Oc1ccc(CCCNCc2ccccc2)cc1
Temperature: 0 °C
Yield: 97.6 %

Procedure:
Add lithium aluminum hydride (8.00 g, 211 mmol) to anhydrous tetrahydrofuran (150 mL) and cool to 0° C. under nitrogen. Add N-benzyl-3-(4-hydroxy-phenyl)-propionamide (9.74 g, 38.2 mmol) to anhydrous tetrahydrofuran (80 mL) and add this solution slowly via cannula to the lithium aluminum hydride/tetrahydrofuran mixture at 0° C. under nitrogen. Once this addition is complete, remove the ice bath and heat to reflux for 18 h under nitrogen. Cool the reaction to 0° C. and slowly quench with water (200 mL). Adjust the pH of the solution to pH=8 with 4 M hydrochloric acid. Saturate this solution with sodium chloride, extract with ethyl acetate (3×100 mL), dry the extracts over magnesium sulfate, filter, and concentrate on a rotary evaporator to yield 9.00 g (98%) of 4-(3-benzylamino-propyl)-phenol: mass spectrum (ion spray): m/z=242.1 (M+1); 1H NMR (DMSO-d6): 7.31-7.16 (m, 6H), 6.95-6.92 (m, 2H), 6.66-6.62 (m, 2H), 3.65 (s, 2H), 2.48-2.43 (m, 5H), 1.68-1.60 (m, 2H).
Reaction SMILES: [CH3:1][CH:2]([CH3:30])[CH2:3][CH:4]([NH:20][C:21]1[CH:29]=[CH:28][C:24]([C:25]([OH:27])=O)=[CH:23][N:22]=1)[C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[N:12]2)=[CH:7][CH:6]=1.Cl.[NH2:32][CH2:33][CH2:34][C:35]([O:37][CH3:38])=[O:36].C(N(C(C)C)CC)(C)C>CN(C)C=O.[Cl-].[NH4+]>[CH3:30][CH:2]([CH3:1])[CH2:3][CH:4]([NH:20][C:21]1[CH:29]=[CH:28][C:24]([C:25]([NH:32][CH2:33][CH2:34][C:35]([O:37][CH3:38])=[O:36])=[O:27])=[CH:23][N:22]=1)[C:5]1[CH:6]=[CH:7][C:8]([N:11]2[CH:15]=[C:14]([C:16]([F:18])([F:17])[F:19])[CH:13]=[N:12]2)=[CH:9][CH:10]=1
Reactant: COC(=O)CCN
Reactant: CC(C)CC(Nc1ccc(C(=O)O)cn1)c1ccc(-n2cc(C(F)(F)F)cn2)cc1
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)CCNC(=O)c1ccc(NC(CC(C)C)c2ccc(-n3cc(C(F)(F)F)cn3)cc2)nc1
Reaction time: 0.75 h
Yield: 82.8 %

Procedure:
To a solution of (+/−)-6-(3-methyl-1-(4-(4-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)butylamino)nicotinic acid (50 mg, 0.12 mmol) in N,N-dimethylformamide (5 mL) was added O-(7-Azabenzotriazol-1-yl)-N,N,N′N′-tetramethyluronium hexafluorophosphate (67.7 mg, 0.178 mmol). The mixture was stirred for 45 minutes. Methyl 3-aminopropionate hydrochloride (24.6 mg, 0.178 mmol) and diisopropylethylamine (61.5 mg, 0.476 mmol) were added. The resulting mixture was stirred at room temperature for 2 hours. The mixture was diluted with saturated ammonium chloride. The solution was extracted three times with ethyl acetate. The combined organics were washed with water, dried over sodium sulfate, filtered and concentrated to give methyl 3-(6-(3-methyl-1-(4-(4-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)butylamino)nicotinamido)propanoate (50 mg, 83%) as a brown oil. MS (M+1): 504.1.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][N:10]2[C:14]3[CH2:15][CH2:16][C:17]4[C:18]5[C:19](O)=[N:20][CH:21]=[N:22][C:23]=5[S:24][C:25]=4[C:13]=3[CH:12]=[N:11]2)[CH2:4][CH2:3]1.O=P(Cl)(Cl)[Cl:29]>>[Cl:29][C:19]1[N:20]=[CH:21][N:22]=[C:23]2[C:18]=1[C:17]1[CH2:16][CH2:15][C:14]3[N:10]([CH2:9][CH2:8][N:5]4[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]4)[N:11]=[CH:12][C:13]=3[C:25]=1[S:24]2
Reactant: CN1CCN(CCn2ncc3c2CCc2c-3sc3ncnc(O)c23)CC1
Reactant: O=P(Cl)(Cl)Cl
Product: CN1CCN(CCn2ncc3c2CCc2c-3sc3ncnc(Cl)c23)CC1
Temperature: 105 °C
Yield: 71.4 %

Procedure:
A suspension of 3-[2-(4-methyl-piperazin-1-yl)-ethyl]-4,5-dihydro-3H-10-thia-2,3,7,9-tetraaza-cyclopenta[a]fluorene-6-ol (2 g, 5.4 mmol) in POCl3 (18 ml, 194 mmol) was heated at 105° C. (bath temperature) for 3 h. Analytical HPLC showed no more starting material and a new peak. Excess POCl3 was removed under vacuum and the residue was neutralized with 1N NaOH, extracted with CHCl3:isopropanol (v/v, 3/1). The organic phase was washed with brine, dried over Na2SO4, concentrated to afford a brown syrup, which was purified by silica gel column (CH2Cl2/2N NH3 in MeOH=100/8). The desire product was obtained as a light yellow solid (1.5 g, 71%). 1H-NMR (CD2Cl2-d2) δ 8.66 (s, 1H), 7.60 (s, 1H), 4.19 (t, 2H, J=6.2 Hz), 3.55 (t, 2H, J=8.5 Hz), 3.10 (t, 2H, J=8.3 Hz), 2.80 (t, 2H, J=6.0 Hz), 2.52-2.39 (b, 8H), 2.25 (s, 3H); LCMS RT=1.97 min; [M+H]+=389.4.
Reaction SMILES: [Mg].[CH:2]1(Br)[CH2:4][CH2:3]1.[CH3:6][N:7]1[CH:11]=[CH:10][CH:9]=[C:8]1[C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:13].[Cl-].[NH4+]>O1CCCC1.O>[CH:2]1([C:12]([C:8]2[N:7]([CH3:6])[CH:11]=[CH:10][CH:9]=2)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[OH:13])[CH2:4][CH2:3]1
Reactant: BrC1CC1
Reactant: Cn1cccc1C(=O)c1ccccc1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Product: Cn1cccc1C(O)(c1ccccc1)C1CC1
Yield: 60.5 %

Procedure:
To a suspension of magnesium turnings (5.29 g, 0.22 mole) in anhydrous tetrahydrofuran (70 ml), cyclopropyl bromide (26.35 g, 0.22 mole) in tetrahydrofuran (50 ml) was added dropwise under nitrogen. The reaction mixture was heated at reflux for one h after the initial exotherm had subsided before (N-methylpyrrol-2-yl)phenylketone (13.3 g, 0.072 mole) (J. White and G. McGillivray, J. Org. Chem., (1977), 42, 4248, R. Greenhouse and C. Ramirez, J. Org. Chem., (1985), 50, 2961) in anhydrous tetrahydrofuran (50 ml ) was introduced dropwise. After heating the reaction mixture at reflux for 3 h it was cooled and saturated, aqueous ammonium chloride solution (95 ml) and water (150 ml) were added. The mixture was extracted with ethyl acetate (3×200 ml) and the combined extracts were dried (MgSO4). Flash chromatography of the residue on evaporation on silica gel eluting with heptane/tetrahydrofuran (9:1) provided the title compound as an oil (9.9 g, 46%) which solidified on standing. T.l.c. rf=0.35 (SiO2, heptane/THF (7:3)).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][CH:13]([C:15]([O:17][CH3:18])=[O:16])[CH2:12][CH2:11][NH:10]2)=[CH:5][C:4]=1[F:19].CCN(C(C)C)C(C)C.[C:29](Cl)(=[O:32])[O:30][CH3:31]>C(Cl)Cl>[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][CH:13]([C:15]([O:17][CH3:18])=[O:16])[CH2:12][CH2:11][N:10]2[C:29]([O:30][CH3:31])=[O:32])=[CH:5][C:4]=1[F:19]
Reactant: COC(=O)Cl
Reactant: COC(=O)C1CCNC(c2ccc(Cl)c(F)c2)C1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C1CCN(C(=O)OC)C(c2ccc(Cl)c(F)c2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.6 %

Procedure:
Methyl 2-(4-chloro-3-fluorophenyl)piperidine-4-carboxylate hydrochloride (1.639 g, 5.32 mmol) and DIPEA (2.316 mL, 13.30 mmol) were dissolved in DCM (10 mL). Methyl carbonochloridate (0.503 mL, 6.38 mmol) was added dropwise and the reaction stirred at room temperature for 2 h. The reaction mixture was diluted with DCM (100 mL) and washed with 0.1 M HCl (2×75 mL), sat. NaHCO3 (100 mL), dried through a phase separator and evaporated in vacuo yielding dimethyl 2-(4-chloro-3-fluorophenyl)piperidine-1,4-dicarboxylate (1.625 g, 93%) as a colorless oil. MS m/z 330 (M+H)+
Reaction SMILES: [CH2:1]1[C:21]2[C:4](=[CH:5][C:6]3[S:12][C:11]4[CH:13]=[C:14]([C:17]([OH:19])=[O:18])[CH:15]=[CH:16][C:10]=4[CH2:9][CH2:8][C:7]=3[CH:20]=2)[CH2:3][CH2:2]1.S(=O)(=O)(O)O.[CH3:27]O>>[CH2:1]1[C:21]2[C:4](=[CH:5][C:6]3[S:12][C:11]4[CH:13]=[C:14]([C:17]([O:19][CH3:27])=[O:18])[CH:15]=[CH:16][C:10]=4[CH2:9][CH2:8][C:7]=3[CH:20]=2)[CH2:3][CH2:2]1
Reactant: O=C(O)c1ccc2c(c1)Sc1cc3c(cc1CC2)CCC3
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc2c(c1)Sc1cc3c(cc1CC2)CCC3

Procedure:
A suspension of crude 2,3,10,11-tetrahydro-1H-benzo[b]indeno[5,6-f]thiepin-7-carboxylic acid (8.276 g, 28 mmole) in methanol (200 ml) containing concentrated sulfuric acid was stirred under reflux for 20 hours. The suspension was evaporated, water was added and the product was extracted with chloroform. The crude ester was purified by chromatography (250 g Merck silica gel eluted with 1:1 hexane/methylene chloride) The title compound had m.p. 110°-111° C. (from acetonitrile).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([F:10])[C:5]([C:8]#[N:9])=[N:6][CH:7]=1.[Br-].[CH:12]1([Zn+])[CH2:14][CH2:13]1>C1COCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:12]1([C:2]2[CH:3]=[C:4]([F:10])[C:5]([C:8]#[N:9])=[N:6][CH:7]=2)[CH2:14][CH2:13]1
Reactant: [Zn+]C1CC1
Reactant: N#Cc1ncc(Br)cc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Solvent: C1CCOC1
Product: N#Cc1ncc(C2CC2)cc1F
Temperature: 80 °C

Procedure:
To solution of 5-bromo-3-fluoropicolinonitrile (603 mg, 3.0 mmol) and Pd(PPh3)4 (173 mg, 0.15 mmol) in 10 mL of THF was added cyclopropyl zinc bromide (0.5 M, 10 mL) under N2. After being heated 80° C. for 4 h, the mixture was cooled to room temperature and quenched with sat. NH4Cl(aq). The mixture was extracted with EtOAc (3×) and the combined organic layers were washed with sat. NaHCO3 (aq.) and brine, dried (MgSO4), and concentrated. The crude product was purified by silica gel chromatography (elution with 0-8% EtOAc/Hex) to afford 5-cyclopropyl-3-fluoropicolinonitrile (406 mg).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][C:5](Cl)=[O:6].[CH2:8]([N:15]1[CH2:20][CH2:19][CH:18]([NH:21][CH:22]([CH3:24])[CH3:23])[CH2:17][CH2:16]1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.CCN(C(C)C)C(C)C>ClCCl>[CH2:8]([N:15]1[CH2:20][CH2:19][CH:18]([N:21]([CH:22]([CH3:24])[CH3:23])[C:5](=[O:6])[CH2:4][CH2:3][CH2:2][Cl:1])[CH2:17][CH2:16]1)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: CC(C)NC1CCN(Cc2ccccc2)CC1
Reactant: O=C(Cl)CCCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)N(C(=O)CCCCl)C1CCN(Cc2ccccc2)CC1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 34.5 %

Procedure:
A solution of 4-chlorobutyryl chloride (5.3 mL, 47.4 mmol) in dichloromethane (400 mL) was added dropwise to a mixture of 1-benzyl-4-(isopropylamino)piperidine (10 g, 43.07 mmol) and DIPEA (9.0 mL, 51.7 mmol) in dichloromethane (200 mL) at 0° C. The reaction mixture was stirred at 0° C. for 15 min and then at room temperature for 2 h. The solution was then washed with saturated sodium bicarbonate, brine, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography (ethyl acetate/hexane/triethylamine: 42.5/56.5/1) to give 5.0 g of the title intermediate as viscous oil (35% yield).
Reaction SMILES: [CH2:1]([C:3]1[S:17][C:6]2=[N:7][CH:8]=[C:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:10]([OH:11])=[C:5]2[CH:4]=1)[CH3:2].[N+:18]([O-])([O-:20])=[O:19].[Na+]>S(=O)(=O)(O)O>[CH2:1]([C:3]1[S:17][C:6]2=[N:7][CH:8]=[C:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:10]([OH:11])=[C:5]2[C:4]=1[N+:18]([O-:20])=[O:19])[CH3:2]
Reactant: CCOC(=O)c1cnc2sc(CC)cc2c1O
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CCOC(=O)c1cnc2sc(CC)c([N+](=O)[O-])c2c1O
Temperature: 0 °C
Reaction time: 1 h
Yield: 81 %

Procedure:
A solution of ethyl 2-ethyl-4-hydroxythieno[2,3-b]pyridine-5-carboxylate (1.0 g, 4.0 mmol) in conc. sulfuric acid (10 ml) was cooled to -5° C. and a solution of sodium nitrate (370 mg, 4.3 mmol) in conc. sulfuric acid (5 ml) was added dropwise to the chilled solution. The reaction mixture was stirred at -3° C. to -5° C. for 1 hour and poured into ice-water. The precipitated product was collected by filtration and washed with cold water and then ethanol. The resulting precipitate was dissolved in chloroform, washed with a saturated aqueous sodium chloride, dried (MgSO4) and evaporated in vacuo. The resulting yellow solid was washed with a mixture of ether/hexane, and dried to give 960 mg (81%) of the title compound.
Reaction SMILES: [CH3:1][O-:2].[Na+].Cl[C:5]1[N:9]([C:10]2[C:11]([C:15]([O:17][CH3:18])=[O:16])=[CH:12][O:13][CH:14]=2)[C:8](=[O:19])[N:7]([CH3:20])[N:6]=1.[NH4+].[Cl-]>CO.C(COC)OC>[CH3:1][O:2][C:5]1[N:9]([C:10]2[C:11]([C:15]([O:17][CH3:18])=[O:16])=[CH:12][O:13][CH:14]=2)[C:8](=[O:19])[N:7]([CH3:20])[N:6]=1
Reactant: COC(=O)c1cocc1-n1c(Cl)nn(C)c1=O
Reactant: C[O-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Solvent: COCCOC
Product: COC(=O)c1cocc1-n1c(OC)nn(C)c1=O
Temperature: 40 °C

Procedure:
A solution of sodium methoxide (11.4 mL, 30% in methanol) was added to a solution of the title compound of Step D (5.34 g) in methanol/dimethoxyethane (26 mL/26 mL) while stirring under nitrogen. The yellow solution was heated to 40° C. for 5 h, cooled to room temperature and left to stir overnight under nitrogen. The reaction mixture was poured into saturated aqueous NH4Cl (50 mL) and the resulting mixture was extracted three times with ethyl acetate. The combined organic extracts were dried (MgSO4), filtered and concentrated to a yellow solid. The yellow solid was dried under vacuum to afford 4.7 g of the title compound of Step E melting at 131-133° C. 1H NMR (CDCl3): δ 8.04 (d,1H), 7.68 (d,1H), 3.94 (s,3H), 3.78 (s,3H), 3.43 (s,3H).
Reaction SMILES: O.[C:2]1([CH3:19])[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:18][CH2:17][CH2:16][C@H:12]2[C:13]([OH:15])=O)(=[O:10])=[O:9])=[CH:4][CH:3]=1.Cl.C[O:22][C:23](=[O:33])[C@H:24]([CH2:26][CH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1)[NH2:25].[Li+].[OH-]>C1COCC1.O>[C:2]1([CH3:19])[CH:3]=[CH:4][C:5]([S:8]([N:11]2[CH2:18][CH2:17][CH2:16][C@H:12]2[C:13]([NH:25][C@H:24]([C:23]([OH:33])=[O:22])[CH2:26][CH:27]2[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]2)=[O:15])(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)N2CCC[C@H]2C(=O)O)cc1
Reactant: COC(=O)[C@@H](N)CC1CCCCC1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)N2CCC[C@H]2C(=O)N[C@@H](CC2CCCCC2)C(=O)O)cc1

Procedure:
N-(Toluene-4-sulfonyl)-L-proline hydrate was coupled to β-cyclohexylalanine methyl ester hydrochloride using the procedure described in Method 3. The title compound was prepared via hydrolysis of the methyl ester using LiOH in THF/water.
Reaction SMILES: [CH2:1]([C:4]1[N:5]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C:6]2[C:11]([C:12]=1[CH2:13][C:14](O)=[O:15])=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH:2]=[CH2:3].Cl.[NH2:25][C@@H:26]([CH2:31][C:32]1[CH:37]=[C:36]([F:38])[CH:35]=[C:34]([Br:39])[CH:33]=1)[C:27]([O:29][CH3:30])=[O:28].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH2:1]([C:4]1[N:5]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C:6]2[C:11]([C:12]=1[CH2:13][C:14]([NH:25][C@@H:26]([CH2:31][C:32]1[CH:37]=[C:36]([F:38])[CH:35]=[C:34]([Br:39])[CH:33]=1)[C:27]([O:29][CH3:30])=[O:28])=[O:15])=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH:2]=[CH2:3]
Reactant: C=CCc1c(CC(=O)O)c2ccccc2n1C(=O)OC(C)(C)C
Reactant: COC(=O)[C@@H](N)Cc1cc(F)cc(Br)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C=CCc1c(CC(=O)N[C@@H](Cc2cc(F)cc(Br)c2)C(=O)OC)c2ccccc2n1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 65.5 %

Procedure:
2-(2-allyl-1-(tert-butoxycarbonyl)-1H-indol-3-yl)acetic acid (850 mg, 2.7 mmol) and (S)-methyl 2-amino-3-(3-bromo-5-fluorophenyl)propanoate hydrochloride (720 mg, 2.61 mmol) were combined in DCM (13 mL) and treated with HATU (1.49 g, 3.9 mmol) and iPr2NEt (1.13 mL, 6.5 mmol). After stirring for 16 h at room temperature, the reaction was partitioned between DCM and H2O. The organics were separated and dried over sodium sulfate. After removal of solvent, the crude product was purified by silica gel chromatography to provide (S)-tert-butyl 2-allyl-3-(2-(3-(3-bromo-5-fluorophenyl)-1-methoxy-1-oxopropan-2-ylamino)-2-oxoethyl)-1H-indole-1-carboxylate (0.98 g, 63%). MS (m/z) 573 [M+H]+.
Reaction SMILES: C(O[C:4](=[O:17])[CH2:5][N:6]1[CH2:10][C@@H:9]2C[CH2:12][CH2:13][CH2:14][CH2:15][C@@H:8]2[C:7]1=[O:16])C.[NH3:18]>CO>[O:16]=[C:7]1[C@H:8]2[C@@H:9]([CH2:12][CH2:13][CH2:14][CH2:15]2)[CH2:10][N:6]1[CH2:5][C:4]([NH2:18])=[O:17]
Reactant: CCOC(=O)CN1C[C@@H]2CCCCC[C@@H]2C1=O
Reactant: N
Solvent: CO
Product: NC(=O)CN1C[C@@H]2CCCC[C@H]2C1=O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
For example, trans-octahydro-1-oxo-cyclohexa[c]pyrrole-2(1H)acetic acid ethyl ester (V) (6.6 g, 0.031 mole) in methanol is saturated with anhydrous ammonia and the mixture is stirred at room temperature 24 hours. The solution is concentrated at reduced pressure to yield a solid. Recrystallization from acetonitrile yields pure trans-octahydro-1-oxo-2H-isoindole-2-acetic acid amide (VI).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][N:10]1[C:18]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[C:17]2[C:12]([N:13]([CH3:28])[C:14](=[O:27])[N:15]([CH3:26])[C:16]2=[O:25])=[CH:11]1)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:7][CH2:8][CH2:9][N:10]1[C:18]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[C:17]2[C:12]([N:13]([CH3:28])[C:14](=[O:27])[N:15]([CH3:26])[C:16]2=[O:25])=[CH:11]1
Reactant: Cn1c(=O)c2c(-c3ccccc3)n(CCNC(=O)OC(C)(C)C)cc2n(C)c1=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cn1c(=O)c2c(-c3ccccc3)n(CCN)cc2n(C)c1=O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
[2-(1,3-Dimethyl-2,4-dioxo-5-phenyl-1,2,3,4-tetrahydro-pyrrolo[3,4-d]pyrimidin-6-yl)-ethyl]-carbamic acid tert-butyl ester (step 4) (1.11 g, 2.79 mmol) was dissolved in DCM (10 mL) and treated with trifluoroacetic acid (2.1 mL, 25.1 mmol). The reaction was stirred at RT for 4 h. The reaction was quenched by pouring into stirring 2M NaOH and further NaOH added until alkaline to pH paper. The layers were separated and the aqueous phase extracted with DCM (3×75 mL). The combined organic phases were washed with water (100 mL), brine (75 mL) and passed through a hydrophobic frit. The solvent was removed under reduced pressure, affording the title compound as an off-white solid.
Reaction SMILES: [Br:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH2:16])[CH:11]=[CH:12][C:13]=1[O:14][CH3:15].[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]=[C:25]=[O:26])=[CH:20][C:19]=1[C:27]([F:30])([F:29])[F:28]>C(Cl)Cl>[Br:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH:16][C:25]([NH:24][C:21]2[CH:22]=[CH:23][C:18]([Cl:17])=[C:19]([C:27]([F:29])([F:28])[F:30])[CH:20]=2)=[O:26])[CH:11]=[CH:12][C:13]=1[O:14][CH3:15]
Reactant: O=C=Nc1ccc(Cl)c(C(F)(F)F)c1
Reactant: COc1ccc(N)cc1-c1c(Br)cnn1C
Solvent: ClCCl
Product: COc1ccc(NC(=O)Nc2ccc(Cl)c(C(F)(F)F)c2)cc1-c1c(Br)cnn1C
Yield: 83.3 %

Procedure:
3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine (0.035 g, 0.12 mmol) was treated with 4-chloro-3-(trifluoromethyl)phenyl isocyanate (0.027 g, 0.12 mmol, 1.0 equiv.) in CH2Cl2 (2 mL), in a similar manner as described in Example 1.2 to afford Compound 6 (0.051 g, 0.10 mmol, 81%) as a white solid. LCMS m/z (%)=503 (M+H79Br35Cl, 78), 505 (M+H81Br35Cl, 100), 507 (M+H81Br37Cl, 28). 1H NMR (400 MHz, acetone-d6) δ: 8.52 (s, 1H), 8.27 (s, 1H), 8.13 (s, 1H), 7.74 (d, J=8.7 Hz, 1H), 7.68 (d, J=9.0 Hz, 1H), 7.53 (d, J=8.7 Hz, 1H), 7.49 (s, 1H), 7.43 (s, 1H), 7.14 (d, J=9.0 Hz, 1H), 3.82 (s, 3H), 3.68 (s, 3H).
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH2:10][CH:11](S(C)=O)SC)=[CH:4][C:3]=2[O:2]1.C[O:18]CCOC>>[CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH2:10][CH:11]=[O:18])=[CH:4][C:3]=2[O:2]1
Reactant: COCCOC
Reactant: CSC(Cc1ccc2c(c1)OCO2)S(C)=O
Product: O=CCc1ccc2c(c1)OCO2
Yield: 45 %

Procedure:
2.08 g of methyl 2-(3,4-methylenedioxyphenyl)-1-methylthioethyl sulfoxide was dissolved in 20 ml. of 1,2-dimethoxyethane, and with the addition of 1.71 g of cupric chloride dihydrate, the solution was refluxed for 15 minutes. The solvent was removed by evaporation at reduced pressure, and 50 ml. of methylene chloride was added. The insoluble water was removed by filtration. The filtrate was concentrated at reduced pressure, and subjected to column chromatography (silica gel, benzene) to give 722 mg of (3,4-methylenedioxyphenyl)acetaldehyde in a yield of 45%.
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:7]=[CH:6][S:5][C:4]=1[CH2:8][N:9]1[C:14]2[CH:15]=[C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[S:17][C:13]=2[C:12](=[O:24])[N:11]([CH:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[C:10]1=[O:31].[CH2:32]([O:34][C:35]1[C:44]([O:45][CH3:46])=[CH:43][C:42]2[C:41]([C:47]3[CH:55]=[CH:54][C:50]([C:51](O)=[O:52])=[CH:49][CH:48]=3)=[N:40][C@@H:39]3[CH2:56][CH2:57][S:58][CH2:59][C@@H:38]3[C:37]=2[CH:36]=1)[CH3:33].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH2:32]([O:34][C:35]1[C:44]([O:45][CH3:46])=[CH:43][C:42]2[C:41]([C:47]3[CH:48]=[CH:49][C:50]([C:51]([N:28]4[CH2:27][CH2:26][CH:25]([N:11]5[C:12](=[O:24])[C:13]6[S:17][C:16]([C:18]7[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=7)=[CH:15][C:14]=6[N:9]([CH2:8][C:4]6[S:5][CH:6]=[CH:7][C:3]=6[CH3:2])[C:10]5=[O:31])[CH2:30][CH2:29]4)=[O:52])=[CH:54][CH:55]=3)=[N:40][C@@H:39]3[CH2:56][CH2:57][S:58][CH2:59][C@@H:38]3[C:37]=2[CH:36]=1)[CH3:33]
Reactant: CCOc1cc2c(cc1OC)C(c1ccc(C(=O)O)cc1)=N[C@@H]1CCSC[C@H]21
Reactant: Cc1ccsc1Cn1c(=O)n(C2CCNCC2)c(=O)c2sc(-c3ccccc3)cc21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOc1cc2c(cc1OC)C(c1ccc(C(=O)N3CCC(n4c(=O)c5sc(-c6ccccc6)cc5n(Cc5sccc5C)c4=O)CC3)cc1)=N[C@@H]1CCSC[C@H]21

Procedure:
1-[(3-methylthiophen-2-yl)methyl]-6-phenyl-3-(piperidin-4-yl)thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione hydrochloride (191 mg; compound B96) is reacted with 4-[(4aR,10bR)-9-ethoxy-8-methoxy-3,4,4a,10b-tetrahydro-1H-thiopyrano[4,3-c]isoquinolin-6-yl]benzoic acid (159 mg; compound C10) and HBTU (167 mg) in DCM (4 ml) in the presence of DIPEA (0.28 ml) according to the procedure described in example 55 to afford the title compound after purification by flash column chromatography as a solid.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4]Br.[Cl:6][C:7]1[CH:8]=[C:9]([OH:28])[CH:10]=[CH:11][C:12]=1[CH:13]([CH3:27])[C:14]([OH:26])([C:19]1[CH:24]=[N:23][C:22]([CH3:25])=[CH:21][N:20]=1)[C:15]([F:18])([F:17])[F:16]>>[Cl:6][C:7]1[CH:8]=[C:9]([O:28][CH2:4][CH2:3][O:2][CH3:1])[CH:10]=[CH:11][C:12]=1[CH:13]([CH3:27])[C:14]([C:19]1[CH:24]=[N:23][C:22]([CH3:25])=[CH:21][N:20]=1)([OH:26])[C:15]([F:18])([F:16])[F:17]
Reactant: Cc1cnc(C(O)(C(C)c2ccc(O)cc2Cl)C(F)(F)F)cn1
Reactant: COCCBr
Product: COCCOc1ccc(C(C)C(O)(c2cnc(C)cn2)C(F)(F)F)c(Cl)c1

Procedure:
The title compound was prepared in analogy to Example 74 from 2-bromoethyl methyl ether and 3-chloro-4-[3,3,3-trifluoro-2-hydroxy-1-methyl-2-(5-methyl-pyrazin-2-yl)-propyl]-phenol (Example 72). MS (m/e)=405.3 (MH+).