Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I-].CS[C:4]1[S:5][CH2:6][C@@H:7]2[CH2:16][C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[CH2:9][N+:8]=12.[NH2:17][C:18]1[CH:27]=[CH:26][CH:25]=[C:24]2[C:19]=1[CH:20]=[C:21]([CH2:28][O:29][CH3:30])[N:22]=[CH:23]2>N1C=CC=CC=1>[CH3:30][O:29][CH2:28][C:21]1[N:22]=[CH:23][C:24]2[C:19]([CH:20]=1)=[C:18]([N:17]=[C:4]1[N:8]3[CH2:9][C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=4[CH2:16][C@H:7]3[CH2:6][S:5]1)[CH:27]=[CH:26][CH:25]=2
Reactant: COCc1cc2c(N)cccc2cn1
Reactant: CSC1=[N+]2Cc3ccccc3C[C@H]2CS1
Agent: [I-]
Solvent: c1ccncc1
Product: COCc1cc2c(N=C3SC[C@@H]4Cc5ccccc5CN34)cccc2cn1
Reaction time: 18 h
Yield: 84.1 %

Procedure:
(S)-3-Methylthio-1,5,10,10a-tetrahydrothiazolo[3,4-b]isoquinolinium iodide (13.0 g) is added to a solution of 5-amino-3-methoxymethylisoquinoline (6.8 g) in pyridine (200 cc). After 18 hours at a temperature of about 20° C., the mixture is concentrated to dryness under reduced pressure (25 mm Hg; 3.3 kPa). The residue is dissolved in a mixture of 4 N sodium hydroxide solution (100 cc) and methylene chloride (200 cc). The organic phase is decanted, washed with water (100 cc), dried over magnesium sulphate and filtered, and the filtrate is then concentrated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at 40° C. The residue is crystallized by trituration with diisopropyl ether (50 cc) and then recrystallised from ethanol (200 cc). (S)-3-[(3-Methoxymethylisoquinol-5-yl)imino]-1,5,10,10a-tetrahydrothiazolo[3,4-b]isoquinoline (11.3 g) is thus obtained in the form of light beige crystals melting at 134° C.
Reaction SMILES: [Br:1][C:2](Br)=[CH:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[C:6]([F:12])[CH:5]=1.CC(C)([O-])C.[K+].C1(C)C=CC=CC=1>O>[Br:1][C:2]#[C:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[C:6]([F:12])[CH:5]=1
Reactant: COc1ccc(C=C(Br)Br)cc1F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: COc1ccc(C#CBr)cc1F
Temperature: 80 °C
Yield: 81.4 %

Procedure:
A mixture of 1-(2,2-dibromo-vinyl)-3-fluoro-4-methoxybenzene (0.5 g, 0.00161 mol), potassium tertbutoxide (0.36 g, 0.00322 mol) and toluene (6 mL) were heated at 80° C. for 4 h. After completion, the reaction mixture was cooled to RT, diluted with water (15 mL), and extracted with EtOAc (3×50 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduce pressure to obtain product as a yellow oil (0.3 g, 81%).
Reaction SMILES: Br[C:2]1[S:11][C:5]2[S:6][C:7](Br)=[C:8]([Br:9])[C:4]=2[C:3]=1[Br:12].C(O)(=O)C>[Zn].O>[Br:9][C:8]1[C:4]2[C:3]([Br:12])=[CH:2][S:11][C:5]=2[S:6][CH:7]=1
Reactant: Brc1sc2sc(Br)c(Br)c2c1Br
Agent: [Zn]
Solvent: CC(=O)O
Solvent: O
Product: Brc1csc2scc(Br)c12
Yield: 72.5 %

Procedure:
A mixture of 2,3,4,5-tetrabromothieno[2,3-b]thiophene (0.83 g, 1.8 mmol), zinc dust (0.29 g, 4.4 mmol), and acetic acid (30 ml) is refluxed for 2 h. The reaction mixture is poured into water, extracted with DCM, washed with aqueous saturated sodium carbonate solution, dried (Na2SO4), and concentrated under reduced pressure. The product is purified by recrystallisation from hot methanol to obtain white fibrous crystals (389 mg, 72%). M/Z (298, t, M+). Found C, 24.5; H, 0.8. Calc. for C6H2Br2S2C, 24.2; H, 0.7. 1H NMR (300 MHz, CDCl3) δ 7.32 (s, 2H). 13C NMR (300 MHz, CDCl3) δ 139.35, 137.42, 126.44, 102.96.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:9][C:8]([N:10]2[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]2)=[N:7][CH:6]=1)=O.Cl.[NH2:18][OH:19].C[O-].[Na+].CO.Cl>O1CCOCC1>[OH:19][NH:18][C:3]([C:5]1[S:9][C:8]([N:10]2[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]2)=[N:7][CH:6]=1)=[O:2]
Reactant: NO
Reactant: COC(=O)c1cnc(N2CCN(C)CC2)s1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: C1COCCO1
Product: CN1CCN(c2ncc(C(=O)NO)s2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of compound 15a (125 mg, 0.518 mmol) in 1,4-dioxane (2 mL) were added hydroxylamine hydrochloride (360 mg, 5.18 mmol) and a freshly prepared solution of sodium methoxide in methanol (178 mg, 7.72 mmol of sodium dissolved in 1.5 mL of methanol) under a N2 atmosphere. The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was acidified to pH˜6 with 1M HCl and the formed precipitates were filtered off. The filtrate was diluted with ethyl acetate (5 mL) and water (2 mL) and the organic layer was separated. The aqueous layer was washed with ethyl acetate (5 mL) and the combined organic layers were dried on sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC to give 16a. HPLC: (Rt=10.74 min).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:17]=[CH:16][C:6]([C:7]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:8])=[CH:5][C:4]=1[CH2:18][NH2:19].[Cl:20][C:21]1[CH:22]=[C:23]([N:28]=[C:29]=[S:30])[CH:24]=[C:25]([Cl:27])[CH:26]=1>C(N(CC)CC)C>[Cl:20][C:21]1[CH:22]=[C:23]([NH:28][C:29](=[S:30])[NH:19][CH2:18][C:4]2[CH:5]=[C:6]([CH:16]=[CH:17][C:3]=2[O:2][CH3:1])[C:7]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:8])[CH:24]=[C:25]([Cl:27])[CH:26]=1
Reactant: S=C=Nc1cc(Cl)cc(Cl)c1
Reactant: COc1ccc(C(=O)Nc2ccccc2)cc1CN
Solvent: CCN(CC)CC
Product: COc1ccc(C(=O)Nc2ccccc2)cc1CNC(=S)Nc1cc(Cl)cc(Cl)c1
Temperature: 50 °C
Yield: 27 %

Procedure:
A mixture of the product from Step C (0.1585 g, 0.54 mmol), triethylamine (0.5 mL) and 3,5-dichlorophenyl isothiocyanate (Lancaster) (0.138 g, 0.68 mmol) was heated briefly to 50° C. and then allowed to stand at room temperature over-night. The reaction mixture was then re-warmed to 50° C., filtered, and concentrated to an oil which was triturated in hexanes/ethyl acetate (2:1) and filtered through silica gel in ethyl acetate to afford the product (0.067 g); m.p. 208-210° C.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[C:7](Cl)[C:6]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:5][N:4]=1.[Cl:15][C:16]1[CH:17]=[C:18]([CH2:24][NH2:25])[CH:19]=[CH:20][C:21]=1[O:22][CH3:23].C(N(CC)CC)C.O1CCCC1>C(O)(=O)CC(CC(O)=O)(C(O)=O)O>[CH3:1][S:2][C:3]1[N:8]=[C:7]([NH:25][CH2:24][C:18]2[CH:19]=[CH:20][C:21]([O:22][CH3:23])=[C:16]([Cl:15])[CH:17]=2)[C:6]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:5][N:4]=1
Reactant: CCOC(=O)c1cnc(SC)nc1Cl
Reactant: COc1ccc(CN)cc1Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)c1cnc(SC)nc1NCc1ccc(OC)c(Cl)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of 2-methylthio-4-chloro-5-ethoxycarbonylpyrimidine 1.0 g, (3-chloro-4-methoxyphenyl)methylamine 0.81 g, triethylamine 0.66 ml and tetrahydrofuran 12 ml is stirred for 4 hours at room temperature. The reaction mixture is diluted with an aqueous 10% citric acid solution and the mixture is extracted twice with ethyl acetate. The combined organic layer is washed with water and an aqueous saturated sodium chloride solution, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue is purified by silica gel chromatography (solvent; hexane:ethyl acetate=5:1) and concentrated in vacuo to give a colorless oil. The oil is left overnight at room temperature to give 2-methylthio-5-ethoxycarbonyl-4-(3-chloro-4-methoxybenzylamino)pyrimidine as crystals, 1.58 g. mp 82–83° C.
Reaction SMILES: [OH:1][C:2]1[C:3]([O:19][CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][O:21]2)=[CH:4][CH:5]=[C:6]2[C:11]=1[O:10][C:9](=[O:12])[CH:8]=[C:7]2[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.Br[CH2:27][CH2:28][F:29].C([O-])([O-])=O.[Cs+].[Cs+]>CN1C(=O)CCC1.CCOCC>[F:29][CH2:28][CH2:27][O:1][C:2]1[C:3]([O:19][CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][O:21]2)=[CH:4][CH:5]=[C:6]2[C:11]=1[O:10][C:9](=[O:12])[CH:8]=[C:7]2[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=c1cc(-c2ccccc2)c2ccc(OC3CCCCO3)c(O)c2o1
Reactant: FCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOCC
Solvent: CN1CCCC1=O
Product: O=c1cc(-c2ccccc2)c2ccc(OC3CCCCO3)c(OCCF)c2o1
Temperature: 25 °C
Reaction time: 5 h
Yield: 73.7 %

Procedure:
To 8-hydroxy-4-phenyl-7-(tetrahydro-2H-pyran-2-yloxy)-2H-chromen-2-one (40 mg, 0.12 mmol) and 1-bromo-2-fluoroethane (22 mg, 0.17 mmol) in 0.4 mL NMP was added Cs2CO3 (46 mg, 0.14 mmol). The mixture was stirred at rt for 5 h under Ar atmosphere and diluted with ether (40 mL). It was washed with water (3×30 mL) and dried over MgSO4 and concentrated. The crude product was purified with chromatography (hexane/EtOAc) to afford 8-(2-fluoroethoxy)-4-phenyl-7-(tetrahydro-2H-pyran-2-yloxy)-2H-chromen-2-one as a white solid (34 mg, 73%). MS (ESI) m/z 385 (M+H+).
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][C:6]1[CH:14]=[CH:13][C:9]([C:10](O)=[O:11])=[CH:8][CH:7]=1)[CH3:2].S(Cl)([Cl:17])=O.N1C=CC=CC=1>C1(C)C=CC=CC=1>[CH2:1]([O:3][CH2:4][CH2:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([Cl:17])=[O:11])=[CH:8][CH:7]=1)[CH3:2]
Reactant: O=S(Cl)Cl
Reactant: CCOCCc1ccc(C(=O)O)cc1
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: CCOCCc1ccc(C(=O)Cl)cc1

Procedure:
4-(Ethoxyethyl)benzoic acid (1.4 g, 7.2 mmol) was mixed with thionyl chloride (1.3 g, 10.8 mmol), pyridine (0.1 ml) and toluene (4 ml), followed by reacting them at 80° C. for 2 hours, distilling superfluous thionyl chloride and toluene under reduced pressure, to obtain raw 4-(ethoxy-ethyl)benzoyl chloride.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH:13]=[CH:12][C:11](=[O:14])[N:10]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=3)[C:4]=2[N:5]=[C:6]([S:8][CH3:9])[N:7]=1.C1C=C(Cl)C=C(C(OO)=[O:33])C=1>ClCCl>[Cl:1][C:2]1[C:3]2[CH:13]=[CH:12][C:11](=[O:14])[N:10]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:22])[F:23])=[CH:17][CH:16]=3)[C:4]=2[N:5]=[C:6]([S:8]([CH3:9])=[O:33])[N:7]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1nc(Cl)c2ccc(=O)n(-c3ccc(C(F)(F)F)cc3)c2n1
Solvent: ClCCl
Product: CS(=O)c1nc(Cl)c2ccc(=O)n(-c3ccc(C(F)(F)F)cc3)c2n1
Yield: 82.1 %

Procedure:
A solution of 4-Chloro-2-methylsulfanyl-8-(4-trifluoromethyl-phenyl)-8H-pyrido[2,3-d]pyrimidin-7-one (1.0 g, 2.7 mmol) in dichloromethane (50 mL) was mixed with m-CPBA (0.63 g, 4.0 mmol). The resultant mixture was stirred at room temperature for 10 minutes and concentrated under vacuum. Flash chromatography (EtOAc/Hexane, 3:1) then provided the title compound (0.86 g, 82%): MS (ES) m/z 388 (M+H)+; 1H-NMR(CDCl3) δ 2.80 (s, 3H), 7.03 (d, J=9.9 Hz, 1H), 7.39 (d, J=8.0 Hz, 2H), 7.86 (d, J=8.0 Hz, 2H), 8.19 (d, J=9.9 Hz, 1H).
Reaction SMILES: Br[C:2]1[C:7]([N+:8]([O-])=O)=[C:6]([O:11][CH:12]2[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]2)[C:5]([F:19])=[CH:4][N:3]=1.[H][H]>CO.[Zn+2].[Br-].[Br-].[Pd]>[F:19][C:5]1[C:6]([O:11][CH:12]2[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]2)=[C:7]([NH2:8])[CH:2]=[N:3][CH:4]=1
Reactant: CN1CCC(Oc2c(F)cnc(Br)c2[N+](=O)[O-])CC1
Reactant: [H][H]
Agent: [Pd]
Agent: [Br-]
Agent: [Zn+2]
Solvent: CO
Product: CN1CCC(Oc2c(N)cncc2F)CC1
Reaction time: 8 h

Procedure:
A solution of 2-bromo-5-fluoro-4-[(1-methyl-4-piperidyl)oxy]-3-nitro-pyridine (96 mg, 0.2873 mmol), ZnBr2 (12.94 mg, 3.080 μL, 0.05746 mmol) and Pd on C, wet, Degussa (31 mg) in methanol (5 mL) was flushed with hydrogen and evacuated (3×) and then stirred under a hydrogen atmosphere overnight. The catalyst was filtered off through a celite pad and washed with methanol and ethyl acetate mixtures and the filtrate was concentrated in vacuo to leave a pale yellow oil that was used in next step without further purification. MS (ES+) 226.1.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[S:10][C:9]([CH:11]=O)=[CH:8][C:6]=2[N:7]=1.[CH3:19][N:20]([CH3:29])[C:21]([N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)=[O:22]>>[CH3:19][N:20]([CH3:29])[C:21]([N:23]1[CH2:24][CH2:25][N:26]([CH2:11][C:9]2[S:10][C:5]3[C:4]([N:13]4[CH2:18][CH2:17][O:16][CH2:15][CH2:14]4)=[N:3][C:2]([Cl:1])=[N:7][C:6]=3[CH:8]=2)[CH2:27][CH2:28]1)=[O:22]
Reactant: CN(C)C(=O)N1CCNCC1
Reactant: O=Cc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Product: CN(C)C(=O)N1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1

Procedure:
Reaction between 2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine-6-carbaldehyde 10 from Example 3 and piperazine-1-carboxylic acid dimethylamide using General Procedure Z yielded 4-(2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-piperazine-1-carboxylic acid dimethylamide.
Reaction SMILES: [N:1]1([C:7]([N:9]2[CH2:14][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=3)[CH2:12][CH:11]([C:26]([OH:28])=O)[CH2:10]2)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Cl:29][C:30]1[S:34][C:33]([C:35](=[N:37]O)[NH2:36])=[CH:32][CH:31]=1>>[Cl:29][C:30]1[S:34][C:33]([C:35]2[N:37]=[C:26]([CH:11]3[CH2:12][CH:13]([C:15]4[CH:20]=[CH:19][C:18]([O:21][C:22]([F:23])([F:25])[F:24])=[CH:17][CH:16]=4)[CH2:14][N:9]([C:7]([N:1]4[CH2:2][CH2:3][O:4][CH2:5][CH2:6]4)=[O:8])[CH2:10]3)[O:28][N:36]=2)=[CH:32][CH:31]=1
Reactant: NC(=NO)c1ccc(Cl)s1
Reactant: O=C(O)C1CC(c2ccc(OC(F)(F)F)cc2)CN(C(=O)N2CCOCC2)C1
Product: O=C(N1CCOCC1)N1CC(c2ccc(OC(F)(F)F)cc2)CC(c2nc(-c3ccc(Cl)s3)no2)C1

Procedure:
80 mg (0.20 mmol) of 1-(morpholin-4-ylcarbonyl)-5-[4-(trifluoromethoxy)phenyl]piperidine-3-carboxylic acid (Example 44A) and 39 mg (0.22 mmol, 1.1 eq.) of 5-chloro-N′-hydroxythiophene-2-carboximidamide were reacted according to the General Method 1. Yield: 57 mg (53% of theory)
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:8](=[O:10])[CH3:9])=[N:6][CH:7]=1.O1CCO[CH2:13][CH2:12]1>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH2:12]([C:2]1[CH:3]=[CH:4][C:5]([C:8](=[O:10])[CH3:9])=[N:6][CH:7]=1)[CH3:13]
Reactant: CC(=O)c1ccc(Br)cn1
Reactant: C1COCCO1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Product: CCc1ccc(C(C)=O)nc1
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
A mixture of 1-(5-bromopyridin-2-yl)ethanone (6.30 g, 31.5 mmol; Supplier=Kalexsyn; Lot=90) and [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (560 mg, 0.76 mmol) in dioxane (120 ml) was degassed by sparging with N2 for 10 minutes. Added a solution (15% w/w) of diethyl zinc in hexane (50 ml) slowly, dropwise and heated to 50° C. The orange mixture turned dark, ultimately generating a dark orange with yellow solids as it stirred at 50° C. for 30 minutes. Allowed to cool to room temperature. The reaction mixture was partitioned between EtOAc (200 ml) and water (200 ml), and the aqueous phase was extracted 2×with EtOAc. The combined organic phases were washed with brine (500 ml), dried (Na2SO4), filtered and evaporated in vacuo to give 4.14 g brown oil. Distilled under high vac using short-path distillation apparatus. BP=55° C. @ 0.32 torr to give 2.249 g of slightly tinted oil. 1H-NMR (CDCl3): δ 8.50 (d, J=1.9 Hz, 1H), 7.96 (d, J=7.9 Hz, 1H), 7.63 (dd, J=8.0, 2.2 Hz, 1H), 2.71 (m, 2H), 2.69 (s, 3H), 1.27 (t, J=7.6 Hz, 3H). HPLC: 2.011 min., 57 area % @ 210 nm; 2.012 min., 75 area % @ 254 nm. LCMS: MS (ESI−) for C10H12O m/z 150.1 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4](C(OCC)=O)=[C:5]([CH3:14])[C:6]=1[CH2:7][CH2:8][C:9]([O:11]CC)=[O:10].[OH-].[Na+].Cl>>[C:9]([CH2:8][CH2:7][C:6]1[C:5]([CH3:14])=[CH:4][NH:3][C:2]=1[CH3:1])([OH:11])=[O:10]
Reactant: CCOC(=O)CCc1c(C)[nH]c(C(=O)OCC)c1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Cc1c[nH]c(C)c1CCC(=O)O
Temperature: 50 °C
Yield: 101.2 %

Procedure:
2,4-Dimethyl-5-ethoxycarbonyl-3-(2-ethoxycarbonylethyl)-pyrrole (1.07 kg) and 3.2 L 5 N sodium hydroxide were mechanically stirred in a 12 L three-neck round bottom flask equipped with a reflux condenser and an addition funnel and heated in an oil bath. The mixture was refluxed for 3 hours after which time the internal temperature was 96° C., all solids were dissolved and thin layer chromatography showed hydrolysis to be complete. The heating bath was removed and the mixture cooled to 50° C. in a water bath. 12N Hydrochloric acid (˜1.3 L) was slowly added. After about 50% of the acid was added gas evolution began and the temperature reached 60° C. As more acid was added, gas evolution increased and a yellow precipitate formed. The final pH was adjusted to 3.5 with hydrochloric acid. The mixture was cooled in an ice bath to 8° C. The solids were collected by vacuum filtration, washed twice with 0.5 L of distilled water and dried for 48 hours in a vacuum oven at 55-60° C. to give 677 g (101% yield) of 3-(2-carboxyethyl)-2,4-dimethylpyrrole.
Reaction SMILES: [CH3:1][C:2](=[CH:19][CH2:20][CH2:21][C:22]([CH3:25])=[CH:23][CH3:24])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11](=[CH:16][O:17][CH3:18])[C:12]([O:14][CH3:15])=[O:13].[H][H]>CO.[Pd]>[CH3:1][CH:2]([CH2:19][CH2:20][CH2:21][CH:22]([CH3:25])[CH2:23][CH3:24])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11](=[CH:16][O:17][CH3:18])[C:12]([O:14][CH3:15])=[O:13]
Reactant: [H][H]
Reactant: CC=C(C)CCC=C(C)COc1ccccc1C(=COC)C(=O)OC
Agent: [Pd]
Solvent: CO
Product: CCC(C)CCCC(C)COc1ccccc1C(=COC)C(=O)OC

Procedure:
3.2 g of methyl α-(2-(2,6-dimethylocta-2,6-dienyloxy)phenyl)-β-methoxyacrylate are dissolved in 70 ml of methanol, and 0.2 g of palladium on active carbon is added. At room temperature, hydrogen is passed with stirring through the suspension until no further gas is absorbed. The solution is separated from the catalyst and evaporated. This give 3.1 g of an oil.
Reaction SMILES: Cl[CH2:2][C:3]1[N:7]([C:8]2[CH:9]=[C:10]([CH:14]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:16]=2)[C:11]([NH2:13])=[O:12])[N:6]=[N:5][N:4]=1.Cl.[C@H:22]12[CH2:28][C@H:25]([NH:26][CH2:27]1)[CH2:24][O:23]2>C(#N)C>[C@H:22]12[CH2:28][C@H:25]([N:26]([CH2:2][C:3]3[N:7]([C:8]4[CH:9]=[C:10]([CH:14]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:16]=4)[C:11]([NH2:13])=[O:12])[N:6]=[N:5][N:4]=3)[CH2:27]1)[CH2:24][O:23]2
Reactant: NC(=O)c1cc(-n2nnnc2CCl)cc(C(F)(F)F)c1
Reactant: C1O[C@@H]2CN[C@H]1C2
Agent: Cl
Solvent: CC#N
Product: NC(=O)c1cc(-n2nnnc2CN2C[C@@H]3C[C@H]2CO3)cc(C(F)(F)F)c1
Temperature: 140 °C

Procedure:
To a solution of 3-[5-(chloromethyl)-1H-tetrazol-1-yl]-5-(trifluoromethyl)benzamide (Intermediate 31, 300 mg, 0.982 mmol) in acetonitrile (0.5 mL) was added (1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptane hydrochloride (160 mg, 1.18 mmol) and di-idopropylethylamine (0.377 mL, 2.16 mmol). The reaction was heated to 140° C. for 20 minutes in a microwave reactor.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][C:28]=1[F:29])[NH:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([O:24][CH3:25])=[CH:13][C:14]=2[O:16][CH2:17][C@H:18]2[NH:22][CH2:21][C@@H:20]([OH:23])[CH2:19]2)[N:9]=[CH:8][N:7]=1.[C:30](O)(=[O:33])[CH2:31][OH:32]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][C:28]=1[F:29])[NH:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([O:24][CH3:25])=[CH:13][C:14]=2[O:16][CH2:17][C@H:18]2[N:22]([C:31](=[O:32])[CH2:30][OH:33])[CH2:21][C@@H:20]([OH:23])[CH2:19]2)[N:9]=[CH:8][N:7]=1
Reactant: O=C(O)CO
Reactant: COc1cc(OC[C@@H]2C[C@H](O)CN2)c2c(Nc3ccc(F)c(Cl)c3)ncnc2c1
Product: COc1cc(OC[C@@H]2C[C@H](O)CN2C(=O)CO)c2c(Nc3ccc(F)c(Cl)c3)ncnc2c1
Yield: 81 %

Procedure:
The procedure described in Example 20 was repeated using (3S,5S)-5-[({4-[3-chloro-4-fluoroanilino]-7-methoxyquinazolin-5-yl}oxy)methyl]pyrrolidin-3-ol (157 mg) with glycolic acid (31 mg) to give the title compound as a white solid in 81% yield; NMR spectrum (DMSO-d6) 10.01 (s, 1H), 8.48 (s, 1H), 8.22 (dd, 1H), 7.74-7.69 (m, 1H), 7.43 (t, 1H), 6.84 (d, 1H), 6.78 (d, 1H), 5.29-5.28 (m, 1H), 4.73-4.68 (m, 1H), 4.64-4.59 (m, 2H), 4.44-4.42 (m, 1H), 4.34-4.31 (m, 1H), 4.06-4.05 (m, 2H), 3.93 (s, 3H), 3.64 (dd, 1H), 3.45 (s, 1H), 2.25-2.12 (m, 1H), 1.99-1.95 (m, 1H); Mass spectrum MH+ 477.
Reaction SMILES: [H-].[Na+].[N:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH:10]2[C:23]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[S:17][C:16]3[C:11]2=[CH:12][CH:13]=[CH:14][CH:15]=3)=[CH:5][CH:4]=1.[N:24]1[CH:29]=[CH:28][C:27]([CH2:30]Cl)=[CH:26][CH:25]=1>CS(C)=O>[N:3]1[CH:4]=[CH:5][C:6]([CH2:9][C:10]2([CH2:30][C:27]3[CH:28]=[CH:29][N:24]=[CH:25][CH:26]=3)[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=3[S:17][C:18]3[C:23]2=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:7][CH:8]=1
Reactant: c1ccc2c(c1)Sc1ccccc1C2Cc1ccncc1
Reactant: ClCc1ccncc1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: c1ccc2c(c1)Sc1ccccc1C2(Cc1ccncc1)Cc1ccncc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 65.7 %

Procedure:
A quantity of 0.38 g (8.0 mmole) of 50% sodium hydride oil dispersion was added slowly during 15 minutes to 20 ml of dimethyl sulfoxide at room temperature. After completion of addition, the reaction mixture was heated at 45° for 30 minutes. It was cooled to 15° and a solution of 2.3 g (8.0 mmole) of 9-(4-pyridinylmethyl)thioxanthene in 10 ml of dimethylsulfoxide was added dropwise during 15 minutes at room temperature. After completion of addition, the reaction mixture was stirred 30 minutes at room temperature. Then a solution of 4-picolylchloride (8.75 mmole) in 5 ml of dimethylsulfoxide was added dropwise during 30 minutes at ambient temperature. The reaction was then heated at 40° for 30 minutes. The reaction was quenched by addition of water (50 ml). Trituration of the precipitated oil yielded a crystalline solid, which was filtered off, washed with water and dried. The tan solid was dissolved in benzene and decolorized by stirring with 1 g of Magnesol® for 30 minutes. Filtration and evaporation yielded a colorless product (2.0 g) which was recrystallized from ethylacetate, m.p., 201.4°-203.4°.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:42])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][C@H:9]2[C:28]([NH:30][C:31]2[CH:39]=[CH:38][C:34]([C:35]([OH:37])=[O:36])=[CH:33][C:32]=2[O:40][CH3:41])=[O:29])[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CN(C)C=O.Cl[CH2:55][C:56]([N:58]1[CH2:63][CH2:62][O:61][CH2:60][CH2:59]1)=[O:57]>O>[N:58]1([C:56](=[O:57])[CH2:55][O:36][C:35](=[O:37])[C:34]2[CH:38]=[CH:39][C:31]([NH:30][C:28]([C@H:9]3[C@H:8]([C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=4[F:42])[C@:12]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=4[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:26])([CH3:27])[CH3:25])[NH:10]3)=[O:29])=[C:32]([O:40][CH3:41])[CH:33]=2)[CH2:63][CH2:62][O:61][CH2:60][CH2:59]1
Reactant: O=C(CCl)N1CCOCC1
Reactant: COc1cc(C(=O)O)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2F)[C@H]1c1cccc(Cl)c1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(C(=O)OCC(=O)N2CCOCC2)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2F)[C@H]1c1cccc(Cl)c1F
Temperature: 50 °C
Reaction time: 1.5 h
Yield: 86.3 %

Procedure:
In a 15 mL pressure tube, 4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoic acid (prepared as described in US20100152190A1, 100 mg, 162 μmol) and cesium carbonate (63.4 mg, 195 μmol) were combined with dry dimethyl formamide (5 mL). 2-Chloro-1-morpholinoethanone (26.5 mg, 21.1 μL, 162 μmol) was added to the mixture with stirring. The tube was capped and heated at 50° C. After 1.5 h, the reaction mixture was cooled down to room temperature. It was poured into water and extracted with ethyl acetate (2×). The ethyl acetate layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified with flash chromatography (24 g pre-packed silica gel column, eluted with ethyl acetate in hexanes) to give 4-{[(2R,3S,4R,5S)-4-(4-chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-3-methoxy-benzoic acid 2-morpholin-4-yl-2-oxo-ethyl ester as an off-white solid (104 mg, 86% yield) as product. LCMS (ES+) m/z calcd. for C37H39Cl2F2N4O6 [(M+H)+]: 743. found: 743.