Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH3:13])[CH3:12])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH2:14][C:15]1[CH:20]=[CH:19][C:18](B(O)O)=[CH:17][CH:16]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2)CCCCC1>CC([O-])=O.CC([O-])=O.[Pd+2].O1CCOCC1.C1(C)C=CC=CC=1>[CH3:12][N:11]([CH3:13])[S:8]([C:5]1[CH:6]=[CH:7][C:2]([C:18]2[CH:19]=[CH:20][C:15]([NH2:14])=[CH:16][CH:17]=2)=[CH:3][CH:4]=1)(=[O:10])=[O:9]
Reactant: CN(C)S(=O)(=O)c1ccc(Br)cc1
Reactant: Nc1ccc(B(O)O)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Product: CN(C)S(=O)(=O)c1ccc(-c2ccc(N)cc2)cc1
Temperature: 90 °C
Yield: 10 %

Procedure:
To a round bottom flask was added 4-bromo-N,N-dimethyl-benzenesulfonamide (as prepared in the previous step, 539 mg, 2.28 mmol), 4-aminophenylboronic acid (500 mg, 2.28 mmol), Pd(OAc)2 (51 mg, 0.22 mmol), K3PO4 (967 mg, 4.56 mmol) and 2-(dicyclohexyl-phosphino)-biphenyl (319 mg, 0.910 mmol). The flask was charged with toluene (10 mL) and dioxane (10 mL) and heated to 90° C. under Ar. After 5 h the reaction was concentrated in vacuo and the residue was purified by a 10-g silica gel SPE-column eluting with DCM followed by 10% MeOH-DCM to afford 67 mg (10%) of the title compound as a tan solid. Mass spectrum (ESI, m/z): Calcd. for C14H16N2O2S, 277.0 (M+H), found 277.1.
Reaction SMILES: [C:1]1([C@H:11]([NH:13][CH2:14][C@@H:15]2[C@@H:19]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:18][N:17]([C:26]([C:28]3[CH:40]=[CH:39][C:31]([O:32][CH2:33][C:34]([O:36]CC)=[O:35])=[CH:30][CH:29]=3)=[O:27])[CH2:16]2)[CH3:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[OH-].[Li+].[ClH:43]>C1COCC1.O>[ClH:43].[C:1]1([C@H:11]([NH:13][CH2:14][C@@H:15]2[C@@H:19]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:18][N:17]([C:26]([C:28]3[CH:29]=[CH:30][C:31]([O:32][CH2:33][C:34]([OH:36])=[O:35])=[CH:39][CH:40]=3)=[O:27])[CH2:16]2)[CH3:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)COc1ccc(C(=O)N2C[C@H](CN[C@H](C)c3cccc4ccccc34)[C@@H](c3ccccc3)C2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: C[C@@H](NC[C@H]1CN(C(=O)c2ccc(OCC(=O)O)cc2)C[C@@H]1c1ccccc1)c1cccc2ccccc12
Temperature: 25 °C

Procedure:
A mixture of 174 mg of ethyl (4-{[(3S,4S)-3-({[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-4-phenylpyrrolidin-1-yl]carbonyl}phenoxy)acetate and 3.0 ml of a THF-water (2:1) mixed solvent was mixed with 22 mg of lithium hydroxide and stirred at room temperature. After completion of the reaction, this was neutralized by adding 1 M hydrochloric acid. This was extracted with chloroform, dried with anhydrous sodium sulfate and then concentrated under a reduced pressure. The thus obtained residue was purified by a fractional high performance liquid chromatography (acetonitrile-water) and then treated with hydrochloric acid to obtain 31 mg of (4-{[(3S,4S)-3-({[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-4-phenylpyrrolidin-1-yl]carbonyl}phenoxy)acetic acid hydrochloride as a colorless solid.
Reaction SMILES: [H-].[Na+].[OH:3]/[N:4]=[C:5](/[C:11]1[CH:16]=[CH:15][C:14]([O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:13][CH:12]=1)\[C:6]([O:8]CC)=[O:7].Cl[CH2:25][C:26]1[CH:45]=[CH:44][C:29]([O:30][CH2:31][C:32]2[N:33]=[C:34]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[O:35][C:36]=2[CH3:37])=[CH:28][CH:27]=1.Cl.C(=O)(O)[O-].[Na+]>CN(C)C=O>[CH3:37][C:36]1[O:35][C:34]([C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=2)=[N:33][C:32]=1[CH2:31][O:30][C:29]1[CH:28]=[CH:27][C:26]([CH2:25][O:3]/[N:4]=[C:5](/[C:11]2[CH:12]=[CH:13][C:14]([O:17][C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)=[CH:15][CH:16]=2)\[C:6]([OH:8])=[O:7])=[CH:45][CH:44]=1
Reactant: CCOC(=O)/C(=N\O)c1ccc(Oc2ccccc2)cc1
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(CCl)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [H-]
Solvent: CN(C)C=O
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(CO/N=C(\C(=O)O)c2ccc(Oc3ccccc3)cc2)cc1
Reaction time: 1 h
Yield: 88.6 %

Procedure:
Sodium hydride (60% in oil, 127 mg) was added under a nitrogen atmosphere to a solution of ethyl Z-2-hydroxyimino-2-(4-phenoxylphenyl)acetate (910 mg) and 4-(4-chloromethylphenoxymethyl)-5-methyl-2-phenyloxazole (1.00 g) in N,N-dimethylformamide (10 ml) at room temperature and the mixture was stirred for 1 hour. After adding 1N HCl (5 ml), aqueous sodium bicarbonate was added, and then the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride, dried (MgSO4) and then concentrated. The residue was subjected to column chromatography on silica gel to obtain an oil from a fraction eluted with ethyl acetate-hexane (1:3, v/v). This oil was dissolved in tetrahydrofuran (20 ml)-methanol (10 ml), and 1N aqueous solution of sodium hydroxide (10 ml) was added and the mixture was stirred at 40° C. for 2 hours. 1N HCl (10.5 ml) was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride, dried (MgSO4) and then concentrated. The residual crystal was recrystallized from ethyl acetate-hexane to obtain Z-2-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]-2-(4-phenoxyphenyl)acetic acid (1.51 g, yield 89%) as colorless crystals. m.p. 184-185° C. (decomposition)
Reaction SMILES: Cl.[Br:2][CH2:3][CH2:4][CH2:5][CH2:6][O:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([NH:14][CH3:15])[CH2:10][CH2:9]1.Cl[C:17]([O:19][CH2:20][CH:21]([CH3:23])[CH3:22])=[O:18]>>[CH2:20]([O:19][C:17](=[O:18])[N:14]([C@H:11]1[CH2:12][CH2:13][C@H:8]([O:7][CH2:6][CH2:5][CH2:4][CH2:3][Br:2])[CH2:9][CH2:10]1)[CH3:15])[CH:21]([CH3:23])[CH3:22]
Reactant: CC(C)COC(=O)Cl
Reactant: CN[C@H]1CC[C@H](OCCCCBr)CC1
Agent: Cl
Product: CC(C)COC(=O)N(C)[C@H]1CC[C@H](OCCCCBr)CC1

Procedure:
In analogy to example 11.4, trans-[4-(4-Bromo-butoxy)-cyclohexyl]-methyl-amine hydrochloride and isobutyl chloroformate (with 2.1 eq N,N-diisopropylethylamine) were reacted to yield trans-[4-(4-Bromo-butoxy)-cyclohexyl]-methyl-carbamic acid isobutyl ester which was used directly in the next steps see Example 12.45-12.54.
Reaction SMILES: [C:1](Br)(=[O:3])[CH3:2].C[Si](C)(C)[O:7][C:8]1[CH:13]=[C:12]([O:14][Si](C)(C)C)[C:11]([Cl:19])=[CH:10][N:9]=1.C(N(CC)CC)C>ClCCl>[C:1]([O:7][C:8]1[CH:13]=[C:12]([OH:14])[C:11]([Cl:19])=[CH:10][N:9]=1)(=[O:3])[CH3:2]
Reactant: C[Si](C)(C)Oc1cc(O[Si](C)(C)C)c(Cl)cn1
Reactant: CC(=O)Br
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)Oc1cc(O)c(Cl)cn1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 64 %

Procedure:
A 2.09 ml quantity of acetyl bromide and 0.10 ml of stannic chloride were added to a solution of 5.00 g of 2,4-bis(trimethylsilyloxy)-5-chloropyridine in 250 ml of dried dichloromethane. The mixture was stirred at room temperature for 3.5 hours. The mixture was neutralized with triethylamine and the solvent was distilled off. The residue was subjected to silica gel column chromatography using 40% ethyl acetate-benzene as an eluent, giving 2.07 g of the title compound in a yield of 64%.
Reaction SMILES: C[O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[C:8]([C:37]3[CH:42]=[CH:41][N:40]=[C:39]([NH:43][CH3:44])[N:38]=3)[CH:9]=[C:10]2[NH:13][CH:14]2[CH2:19][CH2:18][N:17]([C:20]([O:22][CH2:23][CH:24]3[C:36]4[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=4[C:30]4[C:25]3=[CH:26][CH:27]=[CH:28][CH:29]=4)=[O:21])[CH2:16][CH2:15]2)=[CH:5][CH:4]=1>C(Cl)(Cl)Cl>[OH:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[C:8]([C:37]3[CH:42]=[CH:41][N:40]=[C:39]([NH:43][CH3:44])[N:38]=3)[CH:9]=[C:10]2[NH:13][CH:14]2[CH2:19][CH2:18][N:17]([C:20]([O:22][CH2:23][CH:24]3[C:36]4[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=4[C:30]4[C:25]3=[CH:26][CH:27]=[CH:28][CH:29]=4)=[O:21])[CH2:16][CH2:15]2)=[CH:5][CH:4]=1
Reactant: CNc1nccc(-c2cc(NC3CCN(C(=O)OCC4c5ccccc5-c5ccccc54)CC3)c3cc(OC)ccc3c2)n1
Solvent: ClC(Cl)Cl
Product: CNc1nccc(-c2cc(NC3CCN(C(=O)OCC4c5ccccc5-c5ccccc54)CC3)c3cc(O)ccc3c2)n1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 86.2 %

Procedure:
A round-bottom flask equipped with rubber septum containing solution of (9H-fluoren-9-yl)methyl 4-((7-methoxy-3-(2-(methylamino)pyrimidin-4-yl)naphthalen-1-yl)amino)piperidine-1-carboxylate 205 (0.41 g, 0.69 mmol) in chloroform (10 mL) was cooled to 0° C. Trifluoroborane dimethylsulfide complex (0.73 mL, 27.7 mmol) was added dropwise via syringe. The reaction mixture was stirred at 0° C. for 5 minutes and allowed to warm to room temperature overnight. The reaction mixture was partitioned between water (100 mL) and ethyl acetate (200 mL). The organic layer was extracted with saturated aqueous sodium bicarbonate (100 mL). The organic layer was dried over sodium sulfate, filtered and concentrated (rotary) to afford a brown solid (0.34 g). The crude compound was purified by column chromatography (silica gel) using 3.5% methanol/chloroform as the eluent and triturated with diethyl ether to afford 9H-fluoren-9-ylmethyl 4-({7-hydroxy-3-[2-(methylamino)pyrimidin-4-yl]-1-naphthyl}amino)piperidine-1-carboxylate 206 as an orange-yellow solid (0.28 g). LC/MS (m/z): 573 [M+H].
Reaction SMILES: [C:1]([C:3]1[C:4]([N:26]=CN(C)C)=[N:5][C:6]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)=[C:7]([C:9]2[CH:14]=[CH:13][C:12](=[O:15])[N:11]([CH:16]([CH3:18])[CH3:17])[N:10]=2)[N:8]=1)#[N:2].O.C([O-])(O)=O.[Na+].CCOC(C)=O>Cl.O1CCOCC1>[NH2:26][C:4]1[C:3]([C:1]#[N:2])=[N:8][C:7]([C:9]2[CH:14]=[CH:13][C:12](=[O:15])[N:11]([CH:16]([CH3:18])[CH3:17])[N:10]=2)=[C:6]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)[N:5]=1
Reactant: CC(C)n1nc(-c2nc(C#N)c(N=CN(C)C)nc2-c2ccc(F)cc2)ccc1=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)n1nc(-c2nc(C#N)c(N)nc2-c2ccc(F)cc2)ccc1=O
Yield: 69432.6 %

Procedure:
A solution of N′-[3-cyano-6-(4-fluorophenyl)-5-(1-isopropyl-6-oxo-1,6-dihydro-3-pyridazinyl)-2-pyrazinyl]-N,N-dimethylimidoformamide (100 mg) in 4N HCl in dioxane (2 ml) and water (2 ml) was stirred at 25° C. for 15 hours. Water, aq. NaHCO3 and EtOAc were added to the reaction mixture. The organic layer was separated, and dried over MgSO4. The solvent was removed in vacuo. The residue was purified by silica gel column chromatography eluted with a mixture of n-hexane and EtOAc. The fractions were concentrated in vacuo to obtain 3-amino-5-(4-fluorophenyl)-6-(1-isopropyl-6-oxo-1,6-dihydro-3-pyridazinyl)-2-pyrazinecarbonitrile (60 g) as white powder.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([I:20])=[CH:16][CH:15]=1)[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Cl)CCl.N1C2C(=NC=CC=2)N(O)N=1.Cl.[CH3:36][Si:37]1([CH3:55])[CH2:41][C@@H:40]([C:42]([NH:44][C@H:45]2[C:54]3[C:49](=[CH:50][CH:51]=[CH:52][CH:53]=3)[CH2:48][CH2:47][CH2:46]2)=[O:43])[NH:39][CH2:38]1.CCN(C(C)C)C(C)C>CN(C=O)C.C(OCC)(=O)C.[Cl-].[Na+].O>[CH3:36][Si:37]1([CH3:55])[CH2:41][C@@H:40]([C:42](=[O:43])[NH:44][C@H:45]2[C:54]3[C:49](=[CH:50][CH:51]=[CH:52][CH:53]=3)[CH2:48][CH2:47][CH2:46]2)[N:39]([C:10](=[O:12])[C@@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH2:13][C:14]2[CH:19]=[CH:18][C:17]([I:20])=[CH:16][CH:15]=2)[CH2:38]1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(I)cc1)C(=O)O
Reactant: C[Si]1(C)CN[C@H](C(=O)N[C@@H]2CCCc3ccccc32)C1
Agent: Cl
Agent: On1nnc2cccnc21
Agent: [Cl-]
Solvent: O
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(I)cc1)C(=O)N1C[Si](C)(C)C[C@H]1C(=O)N[C@@H]1CCCc2ccccc21
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 88.8 %

Procedure:
To a solution of (S)-2-((tert-butoxycarbonyl)amino)-3-(4-iodophenyl)propanoic acid (0.77 g, 2.0 mmol) in DMF (4 mL) was added EDC (0.53 g, 2.8 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 5 min, followed by addition of 3H-[1,2,3]-triazolo[4,5-b]pyridin-3-ol (0.22 g, 1.6 mmol) and a solution of (R)-3,3-dimethyl-N—((R)-1,2,3,4-tetrahydronaphthalen-1-yl)-1,3-azasilolidine-5-carboxamide HCl (0.53 g, 1.6 mmol) in DMF (3 mL) and DIEA (0.8 mL, 4.6 mmol). The resulting mixture was then stirred at rt for 1 h and diluted with ethyl acetate and brine. The organic layer was separated, washed with aq. NaHCO3 solution, dried over MgSO4 and concentrated in vacuo. The resulting oil was purified by flash chromatography (eluting with 20% EtOAc/DCM) to afford the title compound as a white solid (0.94 g, 87%). 1H NMR (CDCl3) δ 7.76-7.45 (m, 2H), 7.22-7.05 (m, 3.5H), 6.89 (d, J=8.1 Hz, 2H), 6.50 (d, J=8.1 Hz, 0.5H), 5.27-5.06 (m, 3H), 4.96-4.71 (m, 1H), 3.10 (d, J=13.4 Hz, 0.5H), 2.96-2.45 (m, 4.5H), 2.16-1.98 (m, 1H), 1.85 (dd, J=11.3, 5.8 Hz, 3H), 1.44-1.16 (m, 10H), 0.98 (dd, J=14.7, 10.1 Hz, 1H), 0.44 (s, 3H), 0.27 (s, 3H); MS(ESI+) m/z 662.4 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:13])[C:5](=[CH:11][CH:12]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7].C(=O)([O-])[O-].[K+].[K+].Cl[CH:21]([CH3:26])[C:22]([O:24][CH3:25])=[O:23].O>CN(C)C=O>[Cl:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[C:4]([O:13][CH:21]([C:22]([O:24][CH3:25])=[O:23])[CH3:26])[CH:3]=1
Reactant: COC(=O)C(C)Cl
Reactant: CCOC(=O)c1ccc(Cl)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1ccc(Cl)cc1OC(C)C(=O)OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.2 %

Procedure:
To a solution of ethyl 4-chlorosalicylate (9.45 g) and potassium carbonate (10.3 g) in N,N-dimethylformamide (100 ml) was added methyl 2-chloropropionate (6.9 g), followed by stirring overnight at room temperature. The reaction mixture was poured into water (200 ml) and extracted with ether (200 ml×2). The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was subjected to chromatography on silica gel to give ethyl 4-chloro-2-(1(methoxycarbonyl)ethoxy)benzoate (yield, 8.4 g).
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][CH:6]1[S:10][C:9]([C:11]2[NH:12][C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([O:20][C:21]2[CH:26]=[CH:25][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:23][N:22]=2)=[CH:15][C:14]=3[O:31][CH:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)=[N:8][CH2:7]1)C.[BH4-].[Li+].O.C(OCC)(=O)C>O1CCCC1.CO.CCCCCC>[CH3:30][S:27]([C:24]1[CH:25]=[CH:26][C:21]([O:20][C:16]2[CH:17]=[C:18]3[C:13](=[C:14]([O:31][CH:32]4[CH2:37][CH2:36][O:35][CH2:34][CH2:33]4)[CH:15]=2)[NH:12][C:11]([C:9]2[S:10][CH:6]([CH2:5][CH2:4][OH:3])[CH2:7][N:8]=2)=[CH:19]3)=[N:22][CH:23]=1)(=[O:28])=[O:29]
Reactant: CCOC(=O)CC1CN=C(c2cc3cc(Oc4ccc(S(C)(=O)=O)cn4)cc(OC4CCOCC4)c3[nH]2)S1
Agent: [BH4-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: CO
Product: CS(=O)(=O)c1ccc(Oc2cc(OC3CCOCC3)c3[nH]c(C4=NCC(CCO)S4)cc3c2)nc1
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 51.7 %

Procedure:
Ethyl{2-[5-{[5-(methylsulfonyl)pyridin-2-yl]oxy}-7-(tetrahydro-2H-pyran-4-yloxy)-1H-indol-2-yl]-4,5-dihydro-1,3-thiazol-5-yl}acetate (207 mg) was dissolved in tetrahydrofuran (5 mL)-methanol (2 mL), lithium tetrahydroborate (22 mg) was added under ice-cooling, and the mixture was stirred at room temperature for 50 min. To the reaction solution were added lithium tetrahydroborate (32 mg) and methanol (1 mL), and the mixture was stirred at room temperature for 1 hr. Furthermore, lithium tetrahydroborate (15 mg) was added, and the mixture was stirred at room temperature for 1 hr. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The obtained crude product was subjected to silica gel column chromatography (methanol:ethyl acetate:hexane=0:50:50 to 20:80:0, volume ratio) to give the title compound as a yellow amorphous solid (99 mg, yield 52%). The obtained amorphous solid was crystallized from diethyl ether, and the obtained crystals were recrystallized from ethyl acetate-diethyl ether to give the title compound as colorless crystals.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]3[CH:26]=[CH:25][N:24]=[C:23](Cl)[N:22]=3)[CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:28][CH2:29][CH2:30][C:31]1[CH:36]=[CH:35][C:34]([OH:37])=[C:33]([O:38][CH3:39])[CH:32]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]3[CH:26]=[CH:25][N:24]=[C:23]([NH:28][CH2:29][CH2:30][C:31]4[CH:36]=[CH:35][C:34]([OH:37])=[C:33]([O:38][CH3:39])[CH:32]=4)[N:22]=3)[CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2cccc(-c3ccnc(Cl)n3)c2)CC1
Reactant: COc1cc(CCN)ccc1O
Product: COc1cc(CCNc2nccc(-c3cccc(NC4CCN(C(=O)OC(C)(C)C)CC4)c3)n2)ccc1O

Procedure:
Intermediate 7 was coupled with 4-(2-Amino-ethyl)-2-methoxy-phenol following procedure F. LC-MS showed the product had the expected M+H+ of 520. 1H NMR (Varian 300 MHz, CDCl3, shifts relative to the solvent peak at 7.24 ppm) δ 8.30 (d, 1H) 7.25-7.4 (m, 3H) 6.8-7.0 (m, 2H) 6.65-6.78 (m, 3H) 5.45 (m, 1H) 4.0 (m, 2H) 3.82 (s, 3H) 3.7 (m, 4H) 3.49 (m, 1H) 2.85 (m, 4H) 2.0 (m, 2H) 1.5 (s, 9H).
Reaction SMILES: [H][H].[C:3]([O:11][CH3:12])(=[O:10])[CH2:4][CH2:5][C:6](OC)=O>[Mn].[Cu]>[OH:10][CH2:3][CH2:4][CH2:5][CH2:12][O:11][CH:3]1[CH2:4][CH2:5][CH2:6][O:10]1
Reactant: [H][H]
Reactant: COC(=O)CCC(=O)OC
Agent: [Cu]
Agent: [Mn]
Product: OCCCCOC1CCCO1

Procedure:
This second intermediate reaction product stream is then passed on through lines 20, 21, and 22 to third hydrogenation reactor 10. Additional hydrogen at an appropriate temperature can, if desired, be added from line 23 to the second intermediate reaction product mixture in line 21 in order to adjust the temperature of the resulting stream prior to entry to third hydrogenation reactor 10. This third hydrogenation reactor 10 contains a charge 24 of the manganese promoted copper hydrogenation catalyst DRD92/89A which is also available from Kvaerner Process Technology Limited. This catalyst is highly active for the conversion of the remaining dimethyl succinate but exhibits the surprising result that the content of the cyclic acetal, i.e. 2-(4′-hydroxybutoxy)-tetrahydrofuran, in the final product stream in line 25 is much reduced compared with the content of this compound in the second intermediate reaction product stream in line 19.
Reaction SMILES: C([O:4][CH2:5][C:6]1[N:7]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[Cl:26])[C:8](=[O:19])[C:9]2[CH:14]=[C:13]([S:15](=[O:18])(=[O:17])[NH2:16])[S:12][C:10]=2[N:11]=1)(=O)C.CO.Cl>O>[Cl:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[N:7]1[C:8](=[O:19])[C:9]2[CH:14]=[C:13]([S:15](=[O:17])(=[O:18])[NH2:16])[S:12][C:10]=2[N:11]=[C:6]1[CH2:5][OH:4]
Reactant: CC(=O)OCc1nc2sc(S(N)(=O)=O)cc2c(=O)n1-c1ccccc1Cl
Agent: Cl
Solvent: O
Solvent: CO
Product: NS(=O)(=O)c1cc2c(=O)n(-c3ccccc3Cl)c(CO)nc2s1
Yield: 74.2 %

Procedure:
To 9.3 g of 3,4-dihydro-2-acetoxymethyl-3-(2-chlorophenyl)-4-oxo-6-sulfamoylthieno[2,3-d]pyrimidine were added 200 ml of methanol, 30 ml of water and 14.3 ml of conc. hydrochloric acid, and the mixture was stirred under reflux for 2 hours. The reaction mixture was concentrated, and the residue was crystallized from methanol to give 6.2 g of pale yellow crystals, which was recrystallized from methanol to afford 2.6 g of the title compound, m.p. 259° C. (decomposition).
Reaction SMILES: C([Li])CCC.[O:6]1[CH2:10][CH2:9][O:8][CH:7]1[C:11]1[O:12][CH:13]=[CH:14][CH:15]=1.[F:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=1)[CH2:20]Br.[Cl-].[NH4+]>O1CCCC1>[F:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=1)[CH2:20][C:13]1[O:12][C:11]([CH:7]2[O:8][CH2:9][CH2:10][O:6]2)=[CH:15][CH:14]=1
Reactant: Fc1cccc(CBr)c1
Reactant: c1coc(C2OCCO2)c1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: Fc1cccc(Cc2ccc(C3OCCO3)o2)c1
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
n-Butyl lithium (2.66M hexane solution, 25.5 mL, 67.88 mmol) was added dropwise to a solution of 2-(1,3-dioxolan-2-yl)furan (8272 mg, 59.03 mmol) in tetrahydrofuran (160 mL) that had been cooled to −78° C. solution under nitrogen atmosphere, which was then stirred for 10 minutes. To this solution was added a solution of 3-fluorobenzyl bromide (14.50 g, 76.73 mmol) in tetrahydrofuran (60 mL) dropwise, which was then stirred for 1 hour at −78° C., and for 1.25 hours at room temperature. An aqueous solution of saturated ammonium chloride was added to the reaction mixture, which was extracted with diethyl ether. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and then, concentrated in vacuo. The obtained residue was purified by silica gel chromatography (hexane-ethyl acetate), and a mixture of the title compound and 2-(1,3-dioxolane-2-yl)furan (8033 mg), which is the starting material, was obtained.
Reaction SMILES: [C:1]([O:5][C:6]([C@H:8]([CH2:13]I)[C:9]([O:11][CH3:12])=[O:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[C:16]1[S:20][C:19]([Si:21]([CH:28]([CH3:30])[CH3:29])([CH:25]([CH3:27])[CH3:26])[CH:22]([CH3:24])[CH3:23])=[N:18][CH:17]=1>>[C:1]([O:5][C:6]([C@@H:8]([CH2:13][C:16]1[S:20][C:19]([Si:21]([CH:25]([CH3:27])[CH3:26])([CH:28]([CH3:30])[CH3:29])[CH:22]([CH3:23])[CH3:24])=[N:18][CH:17]=1)[C:9]([O:11][CH3:12])=[O:10])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)[Si](c1ncc(Br)s1)(C(C)C)C(C)C
Reactant: COC(=O)[C@@H](CI)C(=O)OC(C)(C)C
Product: COC(=O)[C@H](Cc1cnc([Si](C(C)C)(C(C)C)C(C)C)s1)C(=O)OC(C)(C)C

Procedure:
The title compound was synthesized in a manner analogous to that described Example 475, using (R)-methyl 2-(tert-butoxycarbonyl)-3-iodopropanoate and 5-bromo-2-(triisopropylsilyl)thiazole (prepared according to Stangeland, Eric L.; Sammakia, Tarek, Use of Thiazoles in the Halogen Dance Reaction: Application to the Total Synthesis of WS75624 B, Journal of Organic Chemistry (2004), 69(7), 2381-2385.). MS m/z: 443.3 (100%, M+1).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7](=[O:23])[NH:8][C:9]2[CH:14]=[CH:13][N:12]3[N:15]=[C:16]([N:18]4[CH2:22][CH2:21][CH2:20][CH2:19]4)[N:17]=[C:11]3[CH:10]=2)=[C:5]([C:24](O)=[O:25])[CH:4]=[N:3]1.[NH:27]1[CH2:30][CH2:29][CH2:28]1.CCCP(=O)=O.C(N(CC)C(C)C)(C)C>O1CCCC1>[N:18]1([C:16]2[N:17]=[C:11]3[CH:10]=[C:9]([NH:8][C:7]([C:6]4[N:2]([CH3:1])[N:3]=[CH:4][C:5]=4[C:24]([N:27]4[CH2:30][CH2:29][CH2:28]4)=[O:25])=[O:23])[CH:14]=[CH:13][N:12]3[N:15]=2)[CH2:19][CH2:20][CH2:21][CH2:22]1
Reactant: C1CNC1
Reactant: Cn1ncc(C(=O)O)c1C(=O)Nc1ccn2nc(N3CCCC3)nc2c1
Agent: CCCP(=O)=O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Cn1ncc(C(=O)N2CCC2)c1C(=O)Nc1ccn2nc(N3CCCC3)nc2c1
Reaction time: 18 h
Yield: 81.7 %

Procedure:
A mixture of 1-methyl-5-(2-(pyrrolidin-1-yl)-[1,2,4]triazolo[1,5-a]pyridin-7-ylcarbamoyl)-1H-pyrazole-4-carboxylic acid (150 mg, 422 μmol), azetidine (85.4 μl, 1.27 mmol), propylphosphonic anhydride (50% in ethyl acetate, 622 μl, 1.06 mmol) and N,N-diisopropylethylamine (287 μl, 1.69 mmol) in tetrahydrofuran (6 ml) was stirred for 18 hours at 70°. The solvent was evaporated, the residue was triturated with sodium hydrogencarbonate solution. The precipitated solid was filtered off, washed with water and dried affording 4-(azetidine-1-carbonyl)-2-methyl-2H-pyrazole-3-carboxylic acid (2-pyrrolidin-1-yl-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-amide (136 mg, 81.7%) as a light brown solid. mp: >250° C., MS: m/z=395.4 (M+H+).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][C:7]1[CH2:12][CH2:11][N:10](C(OC(C)(C)C)=O)[CH2:9][CH:8]=1.[ClH:20]>C(Cl)Cl.C(OCC)C>[ClH:20].[NH:10]1[CH2:9][CH:8]=[C:7]([CH2:6][C:2]2[S:1][CH:5]=[CH:4][N:3]=2)[CH2:12][CH2:11]1
Reactant: CC(C)(C)OC(=O)N1CC=C(Cc2nccs2)CC1
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Product: C1=C(Cc2nccs2)CCNC1
Temperature: 27.5 °C
Reaction time: 2 h

Procedure:
To a stirred solution of tert-butyl 4-(thiazol-2-ylmethyl)-5,6-dihydropyridine-1(2H)-carboxylate (F) (1.5 g, 5.36 mmol) in CH2Cl2 (20 mL) was added 2M HCl in diethyl ether (5 mL) dropwise at 0° C. and the reaction mixture was allowed to stir at 20-35° C. for 2 h. Then the reaction mixture was rotary evaporated under vacuum to get the desired compound as a brown liquid (1.6 g); 1H NMR (400 MHz, DMSO-d6) δ 9.23 (bs, 2H), 7.77 (d, J=2.5 Hz, 1H), 7.68 (d, J=3.2 Hz, 1H), 5.61 (s, 1H), 3.80 (s, 2H), 3.58-3.54 (m, 2H), 3.15-3.11 (m, 2H), 2.27-2.23 (m, 2H).