Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]([NH:6][C:7]1[C:8]([Cl:18])=[N:9][N:10]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[CH:11]=1)=[O:5].CO.[OH-].[K+].[F:23][C:24]([F:29])([F:28])[CH2:25][CH2:26][SH:27]>O.C(OCC)(=O)C>[Cl:18][C:8]1[C:7]([NH:6][C:4](=[O:5])[CH2:3][CH2:2][S:27][CH2:26][CH2:25][C:24]([F:29])([F:28])[F:23])=[CH:11][N:10]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[N:9]=1
Reactant: O=C(CCCl)Nc1cn(-c2cccnc2)nc1Cl
Reactant: FC(F)(F)CCS
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CO
Product: O=C(CCSCCC(F)(F)F)Nc1cn(-c2cccnc2)nc1Cl
Temperature: 20 °C
Yield: 92.4 %

Procedure:
A 100 mL, 3-neck round bottom flask was charged with 3-chloro-N-(3-chloro-1-(pyridine-3-yl)-1H-pyrazol-4-yl)propanamide (570 mg, 2.00 mmol) and methanol (10 mL), potassium hydroxide (135 mg, 2.40 mmol) was added, followed by 3,3,3-trifluoropropane-1-thiol (312 mg, 2.40 mmol) The mixture was heated at 50° C. for 4 hours, at which point thin layer chromatography analysis [Eluent: ethyl acetate] indicated the reaction was complete to give exclusively a new product. It was cooled to 20° C. and diluted with water (20 mL) and ethyl acetate (20 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (20 mL). The organics were dried over sodium sulfate and concentrated to dryness to afford a light yellow oil, which solidified upon standing to give a light yellow solid (700 mg, 92%): mp 99-102° C.; 1H NMR (400 MHz, DMSO-d6) δ 9.92 (s, 1H), 9.05 (d, J=2.7 Hz, 1H), 8.86 (s, 1H), 8.54 (dd, J=4.5, 1.4 Hz, 1H), 8.21 (ddd, J=8.4, 2.7, 1.4 Hz, 1H), 7.54 (dd, J=8.4, 4.7 Hz, 1H), 2.86 (t, J=7.3 Hz, 2H), 2.74 (td, J=6.5, 5.6, 4.2 Hz, 4H), 2.59 (ddd, J=11.7, 9.7, 7.4 Hz, 2H); 13C NMR (101 MHz, DMSO-d6) δ 169.32, 147.49, 139.44, 135.47, 133.40, 126.60 (q, J=296 Hz), 125.49, 124.23, 122.30, 120.00, 35.18, 33.42 (q, J=27.2 Hz), 26.77, 23.05 (q, J=3.3 Hz); EIMS m/z 378 ([M]+).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([O:15][CH3:16])=[CH:13][C:12]([C:17]2[N:21]=[C:20]([CH3:22])[O:19][N:18]=2)=[C:11](I)[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Mg]Cl)(C)C.[CH:29](=[O:33])[CH:30]([CH3:32])[CH3:31].Cl>O.O1CCCC1>[CH2:1]([O:8][C:9]1[C:14]([O:15][CH3:16])=[CH:13][C:12]([C:17]2[N:21]=[C:20]([CH3:22])[O:19][N:18]=2)=[C:11]([CH:29]([OH:33])[CH:30]([CH3:32])[CH3:31])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)C=O
Reactant: COc1cc(-c2noc(C)n2)c(I)cc1OCc1ccccc1
Agent: CC(C)[Mg]Cl
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(-c2noc(C)n2)c(C(O)C(C)C)cc1OCc1ccccc1
Reaction time: 0.5 h

Procedure:
A mixture of 3-(4-benzyloxy-2-iodo-5-methoxy-phenyl)-5-methyl-[1,2,4]oxadiazole (reference example 4-1) (844 mg) and tetrahydrofuran (6 mL) was cooled in an ice salt bath under an argon atmosphere. Isopropylmagnesium chloride (2.0 mol/L tetrahydrofuran solution, 1.2 mL) was added, and the mixture was stirred under ice-salt-bath cooling for 10 minutes. After an addition of isobutyraldehyde (0.55 mL), the mixture was stirred in an ice salt bath for 10 minutes, and at room temperature for 30 minutes. Water and 2 mol/L hydrochloric acid were added to the mixture, and the mixture was extracted with ethyl acetate. The separated organic layer was washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: 15%-35% ethyl acetate/hexane, gradient elution) to give the title compound (533 mg).
Reaction SMILES: [C:1]1([C:7]#[CH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]>C(Cl)Cl>[C:1]1([C:7]#[C:8][C:11]2[CH:10]=[C:9]([C:3]3[CH:4]=[CH:5][C:6]([C:8]#[C:7][C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)=[C:1]([C:7]#[C:8][C:11]4[CH:10]=[CH:9][CH:14]=[CH:13][CH:12]=4)[CH:2]=3)[CH:14]=[CH:13][C:12]=2[C:8]#[C:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCCCCC
Reactant: C#Cc1ccccc1
Solvent: ClCCl
Product: C(#Cc1ccc(-c2ccc(C#Cc3ccccc3)c(C#Cc3ccccc3)c2)cc1C#Cc1ccccc1)c1ccccc1
Temperature: 85 °C

Procedure:
Analysis of the crude reaction mixture by LC at this point indicated a significant amount of unreacted starting material and products of intermediate conversion. An additional 10 g of phenylacetylene and 1 g of catalyst were added and the reaction mixture was heated at 85° C. for one hour. At this time, the LC indicated conversion was complete. The cooled reaction mixture was diluted with 500 mL of CH2Cl2 and washed with three 1-L portions of 10 percent HCl. The CH2Cl2 solution was isolated and evaporated to provide a crude solid product which was suspended in hexane. The solid was collected by filtration and purified by washing excessively with hot CCL4. This wash removed discoloration and many of the by-products, but it was not sufficiently effective at removing the residual Pd (II) catalyst from the monomer. The monomer was further purified by chromatography over neutral alumina using tetrahydrofuran as an eluent. The resulting monomer was isolated (32.0 g, 58 percent yield) as a light yellow solid with an m.p. of 172° C. to 174° C. with properties:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]2[C:7](=[O:10])[CH2:8][O:9][C:5]=2[C:4]=1[CH2:13][N:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]1.[NH:27]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][N:34]=2)[C:29]([CH:36]=O)=[CH:28]1.N1CCCCC1>CO>[NH:27]1[C:35]2=[N:34][CH:33]=[CH:32][CH:31]=[C:30]2[C:29](/[CH:36]=[C:8]2\[O:9][C:5]3[C:4]([CH2:13][N:14]4[CH2:15][CH2:16][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:18][CH2:19]4)=[C:3]([O:2][CH3:1])[CH:12]=[CH:11][C:6]=3[C:7]\2=[O:10])=[CH:28]1
Reactant: O=Cc1c[nH]c2ncccc12
Reactant: COc1ccc2c(c1CN1CCN(C(=O)OC(C)(C)C)CC1)OCC2=O
Solvent: C1CCNCC1
Solvent: CO
Product: COc1ccc2c(c1CN1CCN(C(=O)OC(C)(C)C)CC1)O/C(=C\c1c[nH]c3ncccc13)C2=O
Temperature: 60 °C
Reaction time: 2 h
Yield: 45.2 %

Procedure:
A solution of tert-butyl 4-[(6-methoxy-3-oxo-2,3-dihydrobenzofuran-7-yl)methyl]piperazine-1-carboxylate (0.107 g, 0.295 mmol) synthesized in Example A40, Step 1 in methanol (1.2 mL) was added with 7-aza-1H-indole-3-carboxaldehyde (0.0517 g, 0.354 mmol) and piperidine (0.00251 g, 0.0295 mmol), and the mixture was stirred at 60° C. for 2 hours. The reaction mixture was cooled to room temperature, and then the precipitated solid was collected by filtration to obtain the objective tert-butyl (Z)-4-({2-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-6-methoxy-3-oxo-2,3-dihydrobenzofuran-7-yl}methyl)piperazine-1-carboxylate (0.0654 g, 45%).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][CH:5]([S:8]([NH2:11])(=[O:10])=[O:9])[CH2:4][CH2:3]1.Cl[C:13]1[CH:14]=[CH:15][C:16]2[N:17]([C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=3)=[CH:20][N:21]=2)[N:18]=1.[F-].[K+]>CS(C)=O.[Cl-].[Na+].O>[Cl:28][C:24]1[CH:23]=[C:22]([C:19]2[N:17]3[N:18]=[C:13]([NH:1][CH:2]4[CH2:7][CH2:6][CH:5]([S:8]([NH2:11])(=[O:9])=[O:10])[CH2:4][CH2:3]4)[CH:14]=[CH:15][C:16]3=[N:21][CH:20]=2)[CH:27]=[CH:26][CH:25]=1
Reactant: Clc1cccc(-c2cnc3ccc(Cl)nn23)c1
Reactant: NC1CCC(S(N)(=O)=O)CC1
Agent: [Cl-]
Agent: [F-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: NS(=O)(=O)C1CCC(Nc2ccc3ncc(-c4cccc(Cl)c4)n3n2)CC1
Temperature: 120 °C

Procedure:
A mixture of 4-aminocyclohexane-1-sulfonamide (200 mg, 1.12 mmol), 6-chloro-3-(3-chlorophenyl)imidazo[1,2-b]pyridazine (200 mg, 0.76 mmol) and KF (500 mg, 8.6 mmol) in DMSO (2 mL) was heated at 120° C. overnight. LCMS showed the reaction was complete. The mixture was poured into brine (80 mL) and extracted with EtOAc (30 mL×3). The combined extracts were dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by to prep. HPLC give two isomers: EX. 8-81 isomer 1 (7.0 mg) and EX. 8-81 isomer 2 (8.1 mg) as white solid.
Reaction SMILES: C([N:8]1[CH2:12][CH:11]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[C:14]=2[N+:21]([O-])=O)[C:10]([C:29](OCC)=[O:30])([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:9]1)C1C=CC=CC=1.[H][H]>CO.[Pd]>[CH3:20][O:19][C:15]1[C:14]2[NH:21][C:29](=[O:30])[C@:10]3([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:9][NH:8][CH2:12][C@@H:11]3[C:13]=2[CH:18]=[CH:17][CH:16]=1
Reactant: [H][H]
Reactant: CCOC(=O)C1(C(=O)OCC)CN(Cc2ccccc2)CC1c1cccc(OC)c1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)[C@@]12CNC[C@@H]1c1cccc(OC)c1NC2=O
Yield: 60.3 %

Procedure:
To a solution of diethyl 1-benzyl-4-(3-methoxy-2-nitrophenyl)pyrrolidine-3,3-dicarboxylate (200 mg, 0.44 mmol) in 20 mL of methanol was added 10% Pd/C catalyst (40 mg, 20% by wt). The mixture was placed on a Parr shaker under 50 psi of hydrogen for 18 h. The reaction was filtered through a pad of Celite and concentrated in vacuo. The residue was purified by flash chromatography (elution with 5% methanol/methylene chloride) to afford 77 mg (60%) of the title compound as a solid. LRMS (ESI): 291.2 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][C:5]=2[N:6]=1.F[C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][C:14]=1[CH3:22].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH3:1][C:2]1[O:3][C:4]2[CH:10]=[CH:9][C:8]([O:11][C:13]3[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][C:14]=3[CH3:22])=[CH:7][C:5]=2[N:6]=1
Reactant: Cc1cc([N+](=O)[O-])ccc1F
Reactant: Cc1nc2cc(O)ccc2o1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1nc2cc(Oc3ccc([N+](=O)[O-])cc3C)ccc2o1
Temperature: 50 °C
Yield: 40.9 %

Procedure:
2-Methylbenzo[d]oxazol-5-ol (0.86 g, 5.77 mmol), 1-fluoro-2-methyl-4-nitrobenzene (0.98 g, 6.34 mmol) and K2CO3 (1.59 g, 11.53 mmol) were combined in DMF and heated to 50° C. for 16 hours. The reaction mixture was cooled to room temperature and poured into ice water. The mixture was extracted with ethyl acetate (3×). The combined organics were washed with brine, dried, and concentrated under reduced pressure. The residue was chromatographed (20% to 40% ethyl acetate in hexanes) to provide the product (0.671 g, 41%) as yellow solid.
Reaction SMILES: Br[C:2]1[C:10]2[C:9]([NH:11][C@H:12]([C:14]3[N:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:18](=[O:26])[C:17]4=[C:27]([CH3:30])[CH:28]=[CH:29][N:16]4[N:15]=3)[CH3:13])=[N:8][CH:7]=[N:6][C:5]=2[N:4]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH:3]=1.CC1(C)C(C)(C)OB([C:47]2[CH:55]=[C:54]([NH2:56])[CH:53]=[C:52]3[C:48]=2[CH:49]=[CH:50][NH:51]3)O1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O>[NH2:56][C:54]1[CH:53]=[C:52]2[C:48]([CH:49]=[CH:50][NH:51]2)=[C:47]([C:2]2[C:10]3[C:9]([NH:11][C@H:12]([C:14]4[N:19]([C:20]5[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=5)[C:18](=[O:26])[C:17]5=[C:27]([CH3:30])[CH:28]=[CH:29][N:16]5[N:15]=4)[CH3:13])=[N:8][CH:7]=[N:6][C:5]=3[N:4]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH:3]=2)[CH:55]=1
Reactant: CC1(C)OB(c2cc(N)cc3[nH]ccc23)OC1(C)C
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(Br)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(-c3cc(N)cc5[nH]ccc35)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Yield: 61.9 %

Procedure:
(S)-2-(1-((5-Bromo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (125 mg, 0.21 mmol) was treated with 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indol-6-amine (110 mg, 0.43 mmol), sodium carbonate (55 mg, 0.52 mmols) and 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (52 mg, 0.06 mmol) in 1,2-dimethoxyethane (5.0 ml) and water (0.125 ml) according to the method described in Preparation 62. The residue was purified using SP1® Purification System (0% to 50%, hexane-ethyl acetate) to give 84 mg (56% yield) of the title compound.
Reaction SMILES: [CH:1]1([C:6]2[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:13]([CH:15]1[O:17][CH2:16]1)Cl>>[CH:1]1([C:6]2[CH:7]=[CH:8][C:9]([O:12][CH2:13][CH:15]3[CH2:16][O:17]3)=[CH:10][CH:11]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: Oc1ccc(C2CCCC2)cc1
Reactant: ClCC1CO1
Product: c1cc(C2CCCC2)ccc1OCC1CO1

Procedure:
The title compound was prepared from 4-cyclopentyl-phenol and epichlorohydrin employing the procedures as set forth in Step 1 of Example 2.
Reaction SMILES: [O:1]=[CH:2][C:3](=[CH2:5])[CH3:4].[OH2:6].[CH3:7]O>>[C:2]([O:6][CH3:7])(=[O:1])[C:3]([CH3:4])=[CH2:5].[O:1]=[CH:2][C:3](=[CH2:4])[CH3:5]
Reactant: CO
Reactant: O
Agent: C=C(C)C=O
Product: C=C(C)C(=O)OC

Procedure:
In the method of the present invention, it is preferred that the contents of the liquid methacrolein and the liquid methanol in the liquid mixture (I) are 5 to 60% by weight and 40 to 95% by weight, respectively, more advantageously, 10 to 50% by weight and 40 to 75% by weight, respectively, based on the weight of the liquid mixture (I). In the method of the present invention, as the liquid mixture (I) which is introduced into the dehydration tower, use can be made of a liquid mixture (IV) containing liquid methacrolein and liquid methanol, which liquid mixture (IV) is obtained by separation from the reaction mixture (containing methyl methacrylate, water, methacrolein and methanol) obtained by the direct ML-to-MMA synthesis reaction, that is, the liquid mixture (IV) may be recycled to the dehydration tower as the liquid mixture (I).
Reaction SMILES: [BrH:1].[C:2]([O:5][CH2:6][C:7]1([CH2:29][O:30][C:31](=[O:33])[CH3:32])[O:16][CH:11](OC(=O)C)[C@H:10]([O:17][C:18](=[O:20])[CH3:19])[C@@H:9]([O:21][C:22](=[O:24])[CH3:23])[C@H:8]1[O:25][C:26](=[O:28])[CH3:27])(=[O:4])[CH3:3]>C(O)(=O)C>[C:2]([O:5][CH2:6][C:7]1([CH2:29][O:30][C:31](=[O:33])[CH3:32])[O:16][C@@H:11]([Br:1])[C@H:10]([O:17][C:18](=[O:20])[CH3:19])[C@@H:9]([O:21][C:22](=[O:24])[CH3:23])[C@H:8]1[O:25][C:26](=[O:28])[CH3:27])(=[O:4])[CH3:3]
Reactant: CC(=O)OCC1(COC(C)=O)OC(OC(C)=O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Reactant: Br
Solvent: CC(=O)O
Product: CC(=O)OCC1(COC(C)=O)O[C@@H](Br)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
Glacial acetic acid (60 ml) is saturated with dry gaseous HBr for 30 minutes at 18°-20° C. This solution is mixed with 5-C-acetoxymethyl-1,2,3,4,6-penta-O-acetyl-L-arabino-hexopyranose (7) (6.0 g, 0.013ml) and is stirred at an ambient temperature for 3.5 hours. Workup of the reaction mixture involves: dilution with methylene chloride (150 ml), washing with ice-water, sat. sodium bicarbonate solution, and water again. After drying the methylene chloride solution with sodium sulfate (anhydrous), evaporation of the solvent produces crude 5-C-acetoxymethyl-2,3,4,6-tetra-O-acetyl-α-L-arabino-hexopyranosyl bromide (18) (3 g) which is dried under high vacuum for 30 minutes and is used for the glycosidation reactions without further purification.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[C:15]3[C:10](=[N:11][CH:12]=[CH:13][CH:14]=3)[NH:9][C:8]2=[O:16])[CH2:3][CH2:2]1.Cl[C:18]1[N:23]=[CH:22][N:21]=[C:20]([O:24][C:25]2[CH:26]=[C:27]([CH3:39])[C:28]3[N:32]=[C:31]([C@@H:33]4[CH2:37][CH2:36][CH2:35][O:34]4)[NH:30][C:29]=3[CH:38]=2)[CH:19]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:39][C:27]1[C:28]2[N:32]=[C:31]([C@@H:33]3[CH2:37][CH2:36][CH2:35][O:34]3)[NH:30][C:29]=2[CH:38]=[C:25]([O:24][C:20]2[N:21]=[CH:22][N:23]=[C:18]([N:1]3[CH2:2][CH2:3][CH:4]([N:7]4[C:15]5[C:10](=[N:11][CH:12]=[CH:13][CH:14]=5)[NH:9][C:8]4=[O:16])[CH2:5][CH2:6]3)[CH:19]=2)[CH:26]=1
Reactant: O=c1[nH]c2ncccc2n1C1CCNCC1
Reactant: Cc1cc(Oc2cc(Cl)ncn2)cc2[nH]c([C@@H]3CCCO3)nc12
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(Oc2cc(N3CCC(n4c(=O)[nH]c5ncccc54)CC3)ncn2)cc2[nH]c([C@@H]3CCCO3)nc12

Procedure:
50 mg (0.23 mmol) 1-piperidin-4-yl-1,3-dihydroimidazo[4,5-b]pyridin-2-one, 70 mg (0.21 mmol) (S)-6-(6-chloropyrimidin-4-yloxy)-4-methyl-2-(tetrahydrofuran-2-yl)-1H-benzo[d]-imidazole and 0.08 mL (0.46 mmol) DIPEA in 2.0 mL DMF were stirred overnight at RT and for 2 h at 40° C. The reaction mixture was purified by preparative HPLC-MS. The fractions containing product were partially evaporated down i.vac. and neutralised with 1M sodium hydroxide solution. The precipitate formed was suction filtered, washed and dried.
Reaction SMILES: [SH:1][CH2:2][CH2:3][C:4]([NH:7][C:8](=[O:17])[O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([CH3:6])[CH3:5].[CH2:18]1[O:20][CH:19]1[CH2:21][OH:22].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[OH:20][CH:19]([CH2:21][OH:22])[CH2:18][S:1][CH2:2][CH2:3][C:4]([NH:7][C:8](=[O:17])[O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([CH3:6])[CH3:5]
Reactant: CC(C)(CCS)NC(=O)OCc1ccccc1
Reactant: OCC1CO1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(CCSCC(O)CO)NC(=O)OCc1ccccc1
Temperature: 70 °C
Yield: 60 %

Procedure:
To a solution of benzyl 4-mercapto-2-methylbutan-2-ylcarbamate (17.4 g, 68.7 mmol) in N,N-dimethylformamide (200 ml) was added glycidol (5.0 ml, 75 mmol) and cesium carbonate (1.55 g, 4.76 mmol). The suspension was heated to 70° C. for 17 hours, then cooled to room temperature and concentrated in vacuo. The residue was purified by flash chromatography (20% to 100% ethyl acetate in hexanes) to afford the title compound as a clear oil (13.48 g, 41.22 mmol, 60%). 1H NMR (400 MHz, CDCl3) δ 1.30 (m, 6H), 2.0-2.1 (m, 2H), 2.24 (m, 1H), 2.49-2.62 (m, 3H), 2.71 (m, 1H), 3.5 (m, 1H), 3.7 (m, 2H), 4.75 (s, 1H), 5.06 (s, 2H), 7.3-7.4 (m, 5H); LRMS (ESI/APCI) m/z 328 [M+H]+, 350 [M+Na]+.
Reaction SMILES: [SH:1][C:2]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[C:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1)#[N:14]>N1C=CC=CC=1>[CH3:12][O:11][C:9]1[CH:8]=[CH:7][C:3]2[C:4](=[O:6])[N:14]=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=3)[S:1][C:2]=2[CH:10]=1
Reactant: COc1ccc(C(=O)O)c(S)c1
Reactant: N#Cc1ccccn1
Solvent: c1ccncc1
Product: COc1ccc2c(=O)nc(-c3ccccn3)sc2c1
Yield: 46.8 %

Procedure:
A mixture of 2-mercapto-4-methoxybenzoic acid (1.4 g, 7.9 mmol), 2-cyanopyridine (0.89 g, 8.5 mmol) and pyridine (10 ml) was refluxed for 10 hrs as described in Example 9. After cooling, the precipitated crystals were collected by filtration and recrystallized from hexane-tetrahydrofuran to give the titled compound (1.0 g, 47%) as crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([F:30])[C:5]([C:24]2[N:25]=[N:26][N:27]([CH3:29])[N:28]=2)=[C:6]([C:8]2[CH:9]=[N:10][C:11]3[CH:12]([NH:17][C:18]([C:20]4([NH2:23])[CH2:22][CH2:21]4)=[O:19])[CH2:13][CH2:14][C:15]=3[CH:16]=2)[CH:7]=1.[CH3:31][O:32][C:33]1[CH:37]=[C:36]([C:38](O)=[O:39])[O:35][N:34]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([F:30])[C:5]([C:24]2[N:25]=[N:26][N:27]([CH3:29])[N:28]=2)=[C:6]([C:8]2[CH:9]=[N:10][C:11]3[CH:12]([NH:17][C:18]([C:20]4([NH:23][C:38]([C:36]5[O:35][N:34]=[C:33]([O:32][CH3:31])[CH:37]=5)=[O:39])[CH2:22][CH2:21]4)=[O:19])[CH2:13][CH2:14][C:15]=3[CH:16]=2)[CH:7]=1
Reactant: Cn1nnc(-c2c(F)cc(Cl)cc2-c2cnc3c(c2)CCC3NC(=O)C2(N)CC2)n1
Reactant: COc1cc(C(=O)O)on1
Product: COc1cc(C(=O)NC2(C(=O)NC3CCc4cc(-c5cc(Cl)cc(F)c5-c5nnn(C)n5)cnc43)CC2)on1

Procedure:
In analogy to the procedures described for the preparation of intermediate A-1 [B], 1-amino-cyclopropanecarboxylic acid{(rac)-3-[5-chloro-3-fluoro-2-(2-methyl-2H-tetrazol-5-yl)-phenyl]-6,7-dihydro-5H-[1]pyrindin-7-yl}-amide (example 55) was coupled with 3-methoxy-isoxazole-5-carboxylic acid to yield the title compound as light yellow solid. MS: 553.2 (MH+, 1Cl).
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:13]=[C:14]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:15]=2)[C:10]([OH:12])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:24][N:25]1[CH:29]=[CH:28][C:27]([NH2:30])=[N:26]1.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>CN(C=O)C>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:13]=[C:14]([O:16][CH2:17][C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:15]=2)[C:10]([NH:30][C:27]2[CH:28]=[CH:29][N:25]([CH3:24])[N:26]=2)=[O:12])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C(O)c1cc(OCc2ccccc2)cc(OC2CCCC2)c1
Reactant: Cn1ccc(N)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cn1ccc(NC(=O)c2cc(OCc3ccccc3)cc(OC3CCCC3)c2)n1
Yield: 47.8 %

Procedure:
3-(Cyclopentyloxy)-5-[(phenylmethyl)oxy]benzoic acid (3.14 g, 10.0 mmol), 1-methyl-1H-pyrazol-3-amine (1.95 g, 20 mmol) and HATU (4.95 g, 13 mmol) were dissolved in DMF (12.5 mL) then DIPEA (3.49 mL, 20 mmol) was added. The resultant mixture was stirred at RT for 20 hours. The mixture was quenched with water (150 mL) and extracted with ethyl acetate (2×75 mL), washed with brine, dried (MgSO4), filtered and concentrated in vacuo to leave a yellow oil. The residue was chromatographed on silica, eluting with 0-30% ethyl acetate in isohexane, to give the desired product as a clear gum (1.87 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:16][C:15]3[C:14](=[O:17])[N:13]([C:18]4[CH:23]=[CH:22][C:21]([O:24][CH2:25][C@@H:26]([CH:28]5[CH2:30][CH2:29]5)[OH:27])=[C:20]([O:31][CH3:32])[CH:19]=4)[CH:12]=[N:11][C:10]=3[CH:9]=2)=[CH:4][CH:3]=1.C(N=C=NC(C)C)(C)C.C(OC([NH:49][C@H:50]([C:54](O)=[O:55])[CH:51]([CH3:53])[CH3:52])=O)(C)(C)C>CN(C)C1C=CN=CC=1.C(Cl)Cl>[NH2:49][C@@H:50]([CH:51]([CH3:53])[CH3:52])[C:54]([O:27][C@H:26]([CH:28]1[CH2:29][CH2:30]1)[CH2:25][O:24][C:21]1[CH:22]=[CH:23][C:18]([N:13]2[C:14](=[O:17])[C:15]3[S:16][C:8]([C:5]4[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=4)=[CH:9][C:10]=3[N:11]=[CH:12]2)=[CH:19][C:20]=1[O:31][CH3:32])=[O:55]
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: COc1cc(-n2cnc3cc(-c4ccc(Cl)cc4)sc3c2=O)ccc1OC[C@H](O)C1CC1
Agent: CC(C)N=C=NC(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: COc1cc(-n2cnc3cc(-c4ccc(Cl)cc4)sc3c2=O)ccc1OC[C@H](OC(=O)[C@@H](N)C(C)C)C1CC1
Temperature: 25 °C
Reaction time: 19 h

Procedure:
A mixture of (R)-6-(4-chlorophenyl)-3-(4-(2-cyclopropyl-2-hydroxyethoxy)-3-methoxyphenyl)-thieno[3,2-d]pyrimidin-4(3H)-one described in Example 1 (1.3 g, 2.33 mmol), diisopropylcarbodiimide (0.88 g, 6.99 mmol), 4-dimethylaminopyridine (142 mg, 1.16 mmol) and N-(t-butoxycarbonyl)-L-valine (1.52 g, 6.99 mmol) in CH2Cl2 (10 mL) was stirred at rt for 19 h. By LCMS analysis no starting alcohol remained. The suspension was diluted with CH2Cl2 and washed with aq NaHCO3. After extracting the aqueous layer with CH2Cl2, the combined organic layers were washed sequentially with water and brine, dried over Na2SO4, filtered and the filtrate concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, EtOAC/hexane 0 to 40% gradient) to afford the title compound (1.12 g) as a white solid. 1H NMR (CDCl3) δ 0.41-0.46 (m, 1H), 0.49-0.53 (m, 1H), 0.58-0.63 (m, 1H), 0.64-0.68 (m, 1H), 0.925 (d, J=7 Hz), 3H), 0.99 (d, J=7 Hz), 1.16-1.19 (m, 1H), 1.44 (s, 9H), 2.19-2.23 (m, 1H), 3.86 (s, 3H), 4.23-4.32 (m, 3H), 4.67-4.71 (m, 1H), 5.06 (d, J=2 Hz, 1H), 6.92-6.95 (m, 2H), 7.04 (d, J=2 Hz, 1H), 7.26 (s, 2H), 7.45 (d, J=2 Hz), 7.54 (s, 1H), 7.66 (d, J=2 Hz, 2H), 8.16 (s, 1H). LCMS (ES): m/z 669 [M+H].
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[S:9]([N:12]([C:22]1[C:27]([O:28][CH3:29])=[N:26][C:25](Cl)=[CH:24][N:23]=1)COCCO[Si](C)(C)C)(=[O:11])=[O:10].[C:31]([O:35][CH3:36])(=[O:34])[CH2:32][OH:33].[H-].[Na+]>CN(C)C=O>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[S:9]([NH:12][C:22]1[N:23]=[CH:24][C:25]([O:33][CH2:32][C:31]([O:35][CH3:36])=[O:34])=[N:26][C:27]=1[O:28][CH3:29])(=[O:10])=[O:11]
Reactant: COC(=O)CO
Reactant: COc1nc(Cl)cnc1N(COCCO[Si](C)(C)C)S(=O)(=O)c1cccc(Cl)c1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)COc1cnc(NS(=O)(=O)c2cccc(Cl)c2Cl)c(OC)n1

Procedure:
Procedure as for Example 115 using 2,3-dichloro-N-(5-chloro-3-methoxy-2-pyrazinyl)-N-({2-[(trimethylsilyl)oxy]ethoxy}methyl)benzenesulphonamide (Example 115a) (0.26 g), methyl glycolate (0.075 mL) and sodium hydride (0.035 g of a 60% dispersion in oil) in N,N-dimethylformamide (5 mL). Yield 0.1 g