Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[F:6][C:7]([F:34])([F:33])[C:8]1[N:12]2[N:13]=[C:14]([N:17]3[CH2:22][CH2:21][CH:20]([C:23]4[CH:32]=[CH:31][C:26]([O:27][CH2:28][CH2:29][OH:30])=[CH:25][CH:24]=4)[CH2:19][CH2:18]3)[CH2:15][CH2:16][C:11]2=[N:10][N:9]=1.C(N(CC)CC)C>C(Cl)Cl>[CH3:1][S:2]([O:30][CH2:29][CH2:28][O:27][C:26]1[CH:31]=[CH:32][C:23]([CH:20]2[CH2:21][CH2:22][N:17]([C:14]3[CH2:15][CH2:16][C:11]4[N:12]([C:8]([C:7]([F:6])([F:33])[F:34])=[N:9][N:10]=4)[N:13]=3)[CH2:18][CH2:19]2)=[CH:24][CH:25]=1)(=[O:4])=[O:3]
Reactant: OCCOc1ccc(C2CCN(C3=Nn4c(nnc4C(F)(F)F)CC3)CC2)cc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCCOc1ccc(C2CCN(C3=Nn4c(nnc4C(F)(F)F)CC3)CC2)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 96 %

Procedure:
A solution of methanesulfonyl chloride (0.158 mL, 2.04 mmol) in DCM (1 mL) was added dropwise to a stirred solution of 2-(4-{1-[3-(trifluoromethyl)-7,8-dihydro[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-yl}phenoxy)ethanol (695 mg, 1.70 mmol) and triethylamine (0.473 mL, 3.40 mmol) in DCM (7 mL) cooled to 0° C. under nitrogen. The resulting solution was stirred at 0° C. for 15 minutes, then warmed to room temperature and stirred for a further 15 minutes. The reaction mixture was diluted with DCM (50 mL), and washed with water (50 mL) and saturated brine (25 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford 2-(4-{1-[3-(trifluoromethyl)-7,8-dihydro[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-yl}phenoxy)ethyl methanesulfonate (796 mg, 96%).
Reaction SMILES: [IH:1].[F:2][C:3]([F:8])([F:7])[C:4]([O-:6])=[O:5].[NH2:9][C:10]1[S:11][CH:12]=[C:13]([C:15]([C:49]2[CH:54]=[CH:53][C:52]([OH:55])=[C:51]([OH:56])[CH:50]=2)([O:19][N:20]=[CH:21][C:22]([NH:24][CH:25]2[C:32](=[O:33])[N:31]3[CH:26]2[S:27][CH2:28][C:29]([CH:37]=[CH:38][CH2:39][N+:40]2[CH:45]=[CH:44][C:43]4SC=C[C:42]=4[CH:41]=2)=[C:30]3[C:34]([OH:36])=[O:35])=[O:23])[C:16]([OH:18])=[O:17])[N:14]=1.[CH3:57][C:58]1[N:59](C)[C:60]2N=CC=CC=2[N:62]=1>>[IH:1].[F:2][C:3]([F:8])([F:7])[C:4]([O-:6])=[O:5].[NH2:9][C:10]1[S:11][CH:12]=[C:13]([C:15]([C:49]2[CH:54]=[CH:53][C:52]([OH:55])=[C:51]([OH:56])[CH:50]=2)([O:19][N:20]=[CH:21][C:22]([NH:24][CH:25]2[C:32](=[O:33])[N:31]3[CH:26]2[S:27][CH2:28][C:29]([CH:37]=[CH:38][CH2:39][N:40]2[CH:45]=[CH:44][C:43]4=[NH+:62][CH:58]([CH3:57])[N:59]([CH3:60])[C:42]4=[CH:41]2)=[C:30]3[C:34]([OH:36])=[O:35])=[O:23])[C:16]([OH:18])=[O:17])[N:14]=1
Reactant: Cc1nc2cccnc2n1C
Reactant: Nc1nc(C(ON=CC(=O)NC2C(=O)N3C(C(=O)O)=C(C=CC[n+]4ccc5sccc5c4)CSC23)(C(=O)O)c2ccc(O)c(O)c2)cs1
Agent: I
Agent: O=C([O-])C(F)(F)F
Product: CC1[NH+]=C2C=CN(CC=CC3=C(C(=O)O)N4C(=O)C(NC(=O)C=NOC(C(=O)O)(c5ccc(O)c(O)c5)c5csc(N)n5)C4SC3)C=C2N1C
Yield: 45 %

Procedure:
Using the procedure of Step A of Example 20, 1.92 g of the product of Step B of Example 11 and 303 mg of 2,3-dimethyl-4-azabenzimidazole were reacted to obtain 877 mg of the expected product.
Reaction SMILES: [NH2:1][C:2]1[C:7](I)=[CH:6][C:5]([N:9]2[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]2)=[CH:4][C:3]=1[CH3:15].[C-:16]#[N:17].[K+].CC(C)=O>O>[NH2:1][C:2]1[C:7]([C:16]#[N:17])=[CH:6][C:5]([N:9]2[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]2)=[CH:4][C:3]=1[CH3:15]
Reactant: Cc1cn(-c2cc(C)c(N)c(I)c2)cn1
Reactant: [C-]#N
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: Cc1cn(-c2cc(C)c(N)c(C#N)c2)cn1
Reaction time: 72 h
Yield: 66 %

Procedure:
A mixture of 2-amino-3-iodo-5-(4-methylimidazol-1-yl)toluene (391 mg), potassium cyanide (130 mg), PD(OCA) (catalytic amount) and dimethylformaldehyde (4.01 ml) was heated under stirring under nitrogen atmosphere for 3 days. Solvent was removed to give a residue. To the residue was added water and the solution was extracted with chloroform. The extract was dried with MgSO and solvent was removed to give 175 mg (66%) of the title compound.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[N:4][CH:3]=1.[CH3:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=[O:14])=[CH:11][C:10]=1B1OC(C)(C)C(C)(C)O1.C(=O)([O-])[O-].[Na+].[Na+].O1CCOCC1>O>[CH3:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=[O:14])=[CH:11][C:10]=1[C:2]1[CH:7]=[CH:6][N:5]=[N:4][CH:3]=1
Reactant: Cc1ccc(C(=O)O)cc1B1OC(C)(C)C(C)(C)O1
Reactant: Brc1ccnnc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1ccc(C(=O)O)cc1-c1ccnnc1
Temperature: 95 °C
Reaction time: 4 h

Procedure:
To a degassed mixture containing 4-bromopyridazine (0.10 g, 0.63 mmol), 4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid (0.18 g, 0.69 mmol), sodium carbonate (0.27 g, 2.52 mmol), dioxane (5.2 mL) and water (1.01 mL) was added tetrakis(tiphenylphosphine)palladium(0) (0.02 g, 0.02 mmol) in one portion under a nitrogen atmosphere. The mixture was heated with fast stirring at 95° C. for 4 h, cooled to room temperature and filtered. The filtered solution was acidified to below pH 4 with 1N HCl (5.0 mL). The resultant precipitate was recovered by filtration, washed with water (3×3.0 mL) and air dried. The resultant tan solid was suspended in n-pentane (4 mL), stirred for 20 min, recovered by filtration and air dried to afford 4-methyl-3-(pyridazin-4-yl)benzoic acid as a tan solid which was used without further purification. LCMS: retention time: 1.325 min. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Sunfire, 5 micron, C18, 3.0×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 4 mL/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 10% CH3CN/90% H2O/10 mM TFA and solvent B was 10% H2O/90% CH3CN/10 mM TFA. MS data was determined using a Micromass Platform for LC in electrospray mode. m/z 215 (MH+).
Reaction SMILES: [S:1]([NH2:5])([NH2:4])(=[O:3])=[O:2].[CH3:6][S:7]([OH:10])(=[O:9])=[O:8].[Cl:11][CH2:12][CH2:13][C:14]#[N:15]>C(Cl)Cl.CC(C)=O>[CH3:6][S:7]([OH:10])(=[O:9])=[O:8].[S:1]([NH:5][C:14](=[NH:15])[CH2:13][CH2:12][Cl:11])(=[O:3])(=[O:2])[NH2:4]
Reactant: N#CCCCl
Reactant: NS(N)(=O)=O
Agent: CS(=O)(=O)O
Solvent: ClCCl
Solvent: CC(C)=O
Product: N=C(CCCl)NS(N)(=O)=O
Temperature: 57.5 °C
Yield: 47.2 %

Procedure:
Sulfamide (9.6 g, 0.1 mole) was added to a solution of methanesulfonic acid anhydrous (48.0 g, 0.5 mole) in 3-chloropropionitrile (51.3 g, 0.6 mole). The suspension was heated at 55-60° C., for 18 hours. At the end of the reacting period, the mixture was diluted with methylene chloride (150 ml), and filtered. The solid, thus obtained, was suspended in acetone (50 ml), and the suspension filtered and the product dried, to yield 13.3 g of product.
Reaction SMILES: O1CCC[CH2:2]1.[C:6]([O:9][N:10]([C:17]([O:19][C:20]([CH3:30])([CH3:29])[CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:18])[CH2:11][CH2:12][O:13][CH2:14][CH2:15][OH:16])(=[O:8])[CH3:7].[H-].[Na+].IC>O>[C:6]([O:9][N:10]([C:17]([O:19][C:20]([CH3:30])([CH3:29])[CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:18])[CH2:11][CH2:12][O:13][CH2:14][CH2:15][O:16][CH3:2])(=[O:8])[CH3:7]
Reactant: CC(=O)ON(CCOCCO)C(=O)OC(C)(C)CCc1ccccc1
Reactant: C1CCOC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CI
Product: COCCOCCN(OC(C)=O)C(=O)OC(C)(C)CCc1ccccc1
Reaction time: 0.33 h
Yield: 50 %

Procedure:
Under an argon gas atmosphere, a tetrahydrofuran (20 mL) solution of benzyl{tert-butoxycarbonyl-[2-(2-hydroxyethoxy)ethyl]amino} acetate (5.83 g, 16.5 mmol) was added dropwise to a tetrahydrofuran (10 mL) solution of sodium hydride (1.2 g, 24.8 mmol, 50% in mineral oil) at 0° C. After stirring at the same temperature for 20 minutes, iodomethane (1.6 mL, 24.8 mmol) was added at 0° C. The reaction mixed liquid was stirred at room temperature for 20 hours and then water was added while cooling in an ice bath, thereby terminating the reaction. The reaction liquid was extracted three times with ether and the organic layer was dried, and then the residue was concentrated under reduced pressure and purified by silica gel flash column chromatography (eluent: hexane/ethyl acetate=5/1, 3/1) to obtain benzyl{tert-butoxycarbonyl-[2-(2-methoxyethoxy)ethyl]amino} acetate (3.02 g, 8.21 mmol) as a colorless oily product with a yield of 50%.
Reaction SMILES: [H-].[Na+].[N:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[NH:5][CH:4]=1.Br[C:13]1[C:14](=[O:28])[NH:15][C:16](=[O:27])[C:17]=1[C:18]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[NH:20][CH:19]=1>CN(C=O)C>[N:3]1([C:13]2[C:14](=[O:28])[NH:15][C:16](=[O:27])[C:17]=2[C:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[NH:20][CH:19]=2)[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[N:5]=[CH:4]1
Reactant: c1ccc2[nH]cnc2c1
Reactant: O=C1NC(=O)C(c2c[nH]c3ccccc23)=C1Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1NC(=O)C(n2cnc3ccccc32)=C1c1c[nH]c2ccccc12
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 3.8 %

Procedure:
260 mg of a 60% dispersion of sodium hydride in mineral oil were added to a solution of 295 mg of benzimidazole in 10 ml of DMF and the mixture was stirred under nitrogen for 0.5 hour. 582 mg of 3-bromo-4-(3-indolyl)-1H-pyrrole-2,5-dione were added and the mixture was heated to 50° C. for 18 hours. A solution of 767 mg of benzimidazole and 260 mg of sodium hydride in 10 ml of DMF was added and the mixture was heated to 90° C. for 18 hours under nitrogen. The solvent was evaporated and the residue was partitioned between dichloromethane and 2M hydrochloric acid. The precipitate was purified on silica gel with ethyl acetate/petroleum ether. Recrystallization from ethyl acetate gave 25 mg of 3-(1-benzimidazolyl)-4-(3-indolyl)-1H-pyrrole-2,5-dione, m.p. 310°-320° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH2:12][O:13][CH3:14])[CH2:6][NH2:7].[C:15](Cl)(Cl)=[S:16].C(N(CC)CC)C>C(OCC)(=O)C>[N:7]([CH2:6][C:5]1[CH:8]=[CH:9][C:10]([O:11][CH2:12][O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=1)=[C:15]=[S:16]
Reactant: COCOc1ccc(CN)cc1OC
Reactant: S=C(Cl)Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COCOc1ccc(CN=C=S)cc1OC

Procedure:
A solution of 3-methoxy-4-methoxymethoxybenzylamine (5.3 g, 26.9 mmol) in ethyl acetate (50 mL) was added, via an addition funnel) to a solution of thiophosgene (2.15 mL, 28.2 mmol) and triethylamine (7.87 mL, 56.5 mmol) in ethyl acetate (30 mL) at 0° C. The resultant solution was stirred at ambient temperature overnight. The solution was washed with saturated aqueous sodium bicarbonate and dried over sodium sulfate. The solvent was evaporated in vacuo, and the residue was purified by flash chromatography on silica gel eluted with ethyl acetate/hexanes (1/9 to 3/7) to give the product, 4-isothiocyanatomethyl-2-methoxy-1-methoxymethoxy-benzene, as a waxy tan solid, 4.9 g (76%). 1H NMR (CDCl3): δ 3.51 (s, 3H), 3.91 (s, 3H), 4.64 (s, 2H), 5.23 (s, 2H), 6.83 (m, 2H) and 7.14 (d, J=8 Hz).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:21][CH2:20][C:11]2[C:12]3[C:17](Cl)=[N:16][CH:15]=[N:14][C:13]=3[S:19][C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:22][C:23]1[CH:29]=[CH:28][C:26]([NH2:27])=[C:25]([O:30][CH:31]2[CH2:36][CH2:35][O:34][CH2:33][CH2:32]2)[CH:24]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>O1CCOCC1.CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:21][CH2:20][C:11]2[C:12]3[C:17]([NH:27][C:26]4[CH:28]=[CH:29][C:23]([F:22])=[CH:24][C:25]=4[O:30][CH:31]4[CH2:36][CH2:35][O:34][CH2:33][CH2:32]4)=[N:16][CH:15]=[N:14][C:13]=3[S:19][C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCc2c(sc3ncnc(Cl)c23)C1
Reactant: Nc1ccc(F)cc1OC1CCOCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCc2c(sc3ncnc(Nc4ccc(F)cc4OC4CCOCC4)c23)C1
Temperature: 120 °C
Yield: 19.5 %

Procedure:
A solution of 4-chloro-5,8-dihydro-6H-pyrido[4′,3′:4,5]thieno[2,3-d]pyrimidine-7-carboxylic acid tert-butyl ester (prepared according to WO2007/109279, 0.141 g, 0.43 mmol), 4-fluoro-2-(tetrahydro-2H-pyran-4-yloxy)aniline (0.092 g, 0.44 mmol) and para-toluene sulfonic acid (0.08 g, 0.04 mmol) in 1,4-dioxane (2 mL) was purged with nitrogen and then heated at 120° C. for 5 hours. The reaction mixture was diluted with EtOAc, washed with 10% aqueous K2CO3 and brine. The organic phase was dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by flash column chromatography (100% iso-hexane→66% iso-hexane/EtOAc→100% EtOAc) followed by trituration with MeOH afforded the title compound as white solid (0.042 g, 20%).
Reaction SMILES: CS[C:3]1[NH:12][C:11](=[O:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1.NC1C(C)=CC=CC=1>C(O)C>[N:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:11](=[O:13])[NH:12][CH:3]=1
Reactant: CSc1nc2ccccc2c(=O)[nH]1
Solvent: Cc1ccccc1N
Solvent: CCO
Product: O=c1[nH]cnc2ccccc12
Reaction time: 4 h
Yield: 140.8 %

Procedure:
2-Methylthio-4-quinazolone (10.0 g, 0.052 mol) was fused with o-toluidine (8.35 g, 0.078 mol) at 160°. After 4 hours, the solid was treated with ethanol, and filtered to give 2-methylphenylamino)-4-quinazolone (10.7 g, 82%) m.p. 278°-280°.
Reaction SMILES: N1C=CC=CC=1.[O:7]1[CH:11]=[CH:10][CH:9]=[C:8]1[CH:12]([NH2:14])[CH3:13].[CH:15]([C:18]([CH3:25])([CH:22]([CH3:24])[CH3:23])[C:19](Cl)=[O:20])([CH3:17])[CH3:16]>O1CCCC1>[CH:15]([C:18]([CH3:25])([CH:22]([CH3:24])[CH3:23])[C:19]([NH:14][CH:12]([C:8]1[O:7][CH:11]=[CH:10][CH:9]=1)[CH3:13])=[O:20])([CH3:17])[CH3:16]
Reactant: CC(N)c1ccco1
Reactant: CC(C)C(C)(C(=O)Cl)C(C)C
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CC(NC(=O)C(C)(C(C)C)C(C)C)c1ccco1
Reaction time: 8 h
Yield: 45.5 %

Procedure:
In a 25 mL round bottom flask, fitted with magnetic stirrer, 15 mL of tetrahydrofuran, 2.1 mmol (1.5 eq.) of pyridine and 1.54 mmol (1.1 eq.) of 1-(furan-2-yl)ethanamine were added. 1.4 mmol of 2-isopropyl-2,3-dimethylbutanoyl chloride (prepared by hydrolysis of 2-isopropyl-N,2,3-trimethylbutanamide, WS-23 with NaNO2 in H2SO4 and subsequent acid chloride formation with SOCl2) were added and the mixture was stirred at room to temperature for 16 hours, overnight. The reaction mixture was extracted with MTBE and HCl (1N in water). The organic layer was washed with NaOH (1N in water) and brine, dried over MgSO4 and concentrated. The crude product was purified by column chromatography, obtaining 160 mg of a beige solid, mp 57-60° C.
Reaction SMILES: [OH:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]([NH:8][CH2:9][CH:10]2[CH2:15][CH2:14][CH2:13][NH:12][CH2:11]2)=[O:7])=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH2:25]([O:32][C:33](ONC(=O)CCC(N)=O)=[O:34])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>O1CCCC1>[CH2:25]([O:32][C:33]([N:12]1[CH2:13][CH2:14][CH2:15][CH:10]([CH2:9][NH:8][C:6](=[O:7])[C:5]2[CH:4]=[CH:3][C:2]([OH:1])=[CH:17][CH:16]=2)[CH2:11]1)=[O:34])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: NC(=O)CCC(=O)NOC(=O)OCc1ccccc1
Reactant: O=C(NCC1CCCNC1)c1ccc(O)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(NCC1CCCN(C(=O)OCc2ccccc2)C1)c1ccc(O)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a mixture of 4-hydroxy-N-piperidin-3-ylmethyl-benzamide (135 mg, 0.580 mmol) in tetrahydrofuran (5 mL) was added triethylamine (100 μL) and N-benzyloxycarbonyloxysuccinamide (144 mg, 0.580 mmol) and the mixture stirred at rt for 3 h. The reaction was concentrated in vacuo and chromatographed on silica using 50–100% ethyl acetate/hexane to give 3-[(4-hydroxy-benzoylamino)-methyl]-piperidine-1-carboxylic acid benzyl ester as a foam.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C@@H:10]([CH:14]([CH3:16])[CH3:15])[C:11]([OH:13])=O)[CH3:9])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:18][O:19][C:20](=[O:26])[C@@H:21]1[CH2:25][CH2:24][CH2:23][NH:22]1>>[CH3:18][O:19][C:20]([CH:21]1[CH2:25][CH2:24][CH2:23][N:22]1[C:11](=[O:13])[CH:10]([N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH3:9])[CH:14]([CH3:16])[CH3:15])=[O:26]
Reactant: COC(=O)[C@@H]1CCCN1
Reactant: CC(C)[C@@H](C(=O)O)N(C)C(=O)OC(C)(C)C
Agent: Cl
Product: COC(=O)C1CCCN1C(=O)C(C(C)C)N(C)C(=O)OC(C)(C)C
Yield: 93.1 %

Procedure:
Using General Procedure I Method A, (2S)-(tert-Butoxycarbonyl-methyl-amino)-3-methyl-butyric acid (0.37 g, 1.6 mmol) is coupled to L-proline methyl ester hydrochloride (0.26 g, 1.6 mmol) to give 1-[2-(tert-butoxycarbonyl-methyl-amino)-3-methyl-butyryl]-pyrrolidine-2-carboxylic acid methyl ester (0.51 g, 93%) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[N:9]=[C:10]([O:12][C@H:13]3[CH2:18][CH2:17][C@H:16]([NH2:19])[CH2:15][CH2:14]3)[S:11][C:7]=2[CH:6]=[CH:5][CH:4]=1.[O:20]=[C:21]1[NH:26][C:25]2[CH:27]=[C:28]([CH:31]=O)[CH:29]=[CH:30][C:24]=2[O:23][CH2:22]1.[BH4-].[Na+]>ClCCCl.CO>[CH3:1][O:2][C:3]1[C:8]2[N:9]=[C:10]([O:12][C@H:13]3[CH2:18][CH2:17][C@H:16]([NH:19][CH2:31][C:28]4[CH:29]=[CH:30][C:24]5[O:23][CH2:22][C:21](=[O:20])[NH:26][C:25]=5[CH:27]=4)[CH2:15][CH2:14]3)[S:11][C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: O=Cc1ccc2c(c1)NC(=O)CO2
Reactant: COc1cccc2sc(O[C@H]3CC[C@H](N)CC3)nc12
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCCl
Solvent: CO
Product: COc1cccc2sc(O[C@H]3CC[C@H](NCc4ccc5c(c4)NC(=O)CO5)CC3)nc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
trans-4-(4-methoxy-benzothiazol-2-yloxy)-cyclohexylamine (0.5 mmol, intermediate 25.b) and 3-oxo-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbaldehyde (0.5 mmol) were dissolved in DCE (4 ml) and MeOH (4 ml). The mixture was stirred at RT overnight, NaBH4 (1 eq) was added and stirring continued for 1 h. The reaction mixture was partitioned between DCM and NH4OH. The organic layer was dried over MgSO4 and concentrated under reduced pressure. Purification by chromatography (EtOAc/MeOH 9:1 +1% NH4OH) and crystallisation from ether gave 36 mg (16%) of the title compound as a colourless solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[C:10]1[CH2:19][CH2:18][C:13]2([O:17][CH2:16][CH2:15][O:14]2)[CH2:12][CH:11]=1>CO.C(OCC)(=O)C.[Pd]>[F:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[CH:10]1[CH2:11][CH2:12][C:13]2([O:14][CH2:15][CH2:16][O:17]2)[CH2:18][CH2:19]1
Reactant: Fc1cc(F)c(C2=CCC3(CC2)OCCO3)cc1F
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: Fc1cc(F)c(C2CCC3(CC2)OCCO3)cc1F
Reaction time: 8 h

Procedure:
A solution of 8-(2,4,5-trifluorophenyl)-1,4-dioxaspiro[4.5]dec-7-ene in methanol (240 mL) and ethyl acetate (5 mL) was treated with 10% palladium on carbon (7.0 g) and stirred under an atmosphere of hydrogen gas (40 psig) overnight. The reaction mixture was filtered over Celite. The filtrate was concentrated and chromatographed (silica gel, gradient 5-7% ethyl acetate in hexane) to yield the title compound.
Reaction SMILES: [H-].[Na+].Cl[C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[C:6]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[N:15]=2)[N:5]=1.[CH3:21][S:22]([CH3:24])=[O:23]>O1CCCC1>[CH3:20][C:16]1[N:15]=[C:14]([C:6]2[N:5]=[C:4]([CH2:21][S:22]([CH3:24])=[O:23])[C:13]3[C:8]([CH:7]=2)=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH:19]=[CH:18][CH:17]=1
Reactant: Cc1cccc(-c2cc3ccccc3c(Cl)n2)n1
Reactant: CS(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cccc(-c2cc3ccccc3c(CS(C)=O)n2)n1
Temperature: 70 °C
Reaction time: 2 h

Procedure:
A suspension of 6 g of sodium hydride (55-60% in paraffin) in 80 ml of anhydrous dimethyl sulphoxide was stirred for 2 hours at 70° C. A solution of 8.8 g of 1-chloro-3-(6-methyl-2-pyridyl)isoquinoline (prepared as described in Example XI) in anhydrous tetrahydrofuran was added dropwise to the mixture with ice-cooling, to obtain a deep red-coloured reaction mixture. The mixture was stirred for 2 hours at 50° C. and was then extracted with dichloromethane, after addition of ice-water. The organic layer was washed with a saturated aqueous sodium chloride solution and with water and the solvent was then distilled off. The residue was dissolved in diethyl ether and ethereal hydrogen chloride was added to the solution. The precipitate obtained was filtered off and dissolved in water. The solution was made alkaline with aqueous sodium hydroxide and extracted with diethyl ether. The ether was distilled off and the residue was crystallised from a mixture of ethanol and pentane. 3-(-6-Methyl-2-pyridyl)-1-methylsulphinylmethylisoquinoline was obtained, melting point 198.0° -198.5° C. A portion of the base was converted into the hydrochloride which, after crystallisation from isopropyl alcohol, melted at 120°-121° C. (decomp.).
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([C:15]3[NH:16][CH:17]=[C:18]([C:20](O)=[O:21])[N:19]=3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH2:35]([CH2:37][NH2:38])[OH:36].O>CN(C=O)C>[OH:36][CH2:35][CH2:37][NH:38][C:20]([C:18]1[N:19]=[C:15]([C:9]2[CH:10]=[CH:11][C:12]([O:13][CH3:14])=[C:7]([O:6][CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5]3)[CH:8]=2)[NH:16][CH:17]=1)=[O:21]
Reactant: NCCO
Reactant: COc1ccc(-c2nc(C(=O)O)c[nH]2)cc1OC1CCCC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(-c2nc(C(=O)NCCO)c[nH]2)cc1OC1CCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 43.3 %

Procedure:
To a solution of 2-(3-Cyclopentyloxy-4-methoxyphenyl)-imidazole-4-carboxylic acid (500 mg, 1.65 mmol) in DMF (15 ml) at room temperature was added carbonyldiimidazole (295 mg, 1.8 mmol). The resultant solution was stirred for 30 minutes and then ethanolamine (180 μl, 1.8 mmol) was added and the reaction mixture stirred at room temperature overnight. Water (75 ml) was added and the mixture extracted with ethyl acetate (2×75 ml). The combined organics were washed with brine (40 ml), dried over Na2SO4 and the volatiles removed in vacuo. Flash chromatography (SiO2; CH2Cl2:EtOH (95:5) (1% NH3)) afforded 2-(3-cyclopentyloxy-4-methoxyphenyl)-imidazole-4-carboxylic acid, N-(2-hydroxyethyl) amide (247 mg, 43%) as a white solid, mp 206-208° C.