Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[CH3:25][C:26]([CH3:39])([CH3:38])[CH2:27][CH2:28][N:29]1[CH2:34][CH2:33][CH:32]([C:35]([OH:37])=O)[CH2:31][CH2:30]1.[NH2:40][CH2:41][C:42]1[CH:61]=[CH:60][C:45]([C:46]([N:48]([CH3:59])[C:49]2[CH:54]=[CH:53][C:52]([C:55]([F:58])([F:57])[F:56])=[CH:51][CH:50]=2)=[O:47])=[CH:44][C:43]=1[CH3:62].CCN(C(C)C)C(C)C>ClCCl>[CH3:62][C:43]1[CH:44]=[C:45]([C:46](=[O:47])[N:48]([CH3:59])[C:49]2[CH:54]=[CH:53][C:52]([C:55]([F:56])([F:57])[F:58])=[CH:51][CH:50]=2)[CH:60]=[CH:61][C:42]=1[CH2:41][NH:40][C:35]([CH:32]1[CH2:31][CH2:30][N:29]([CH2:28][CH2:27][C:26]([CH3:25])([CH3:39])[CH3:38])[CH2:34][CH2:33]1)=[O:37]
Reactant: CC(C)(C)CCN1CCC(C(=O)O)CC1
Reactant: Cc1cc(C(=O)N(C)c2ccc(C(F)(F)F)cc2)ccc1CN
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(C(=O)N(C)c2ccc(C(F)(F)F)cc2)ccc1CNC(=O)C1CCN(CCC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 14 %

Procedure:
PyBroP (188 mg, 0.40 mmol) and 1-(3,3-dimethyl-butyl)-piperidine-4-carboxylic acid (82 mg, 0.38 mmol) were added to a solution of 4-aminomethyl-3,N-dimethyl-N-(4-trifluoromethyl-phenyl)-benzamide from Example E118.3 (100 mg, 0.31 mmol) in dichloromethane (5 ml) and DIEA (0.081 ml, 0.46 mmol). The mixture was stirred at room temperature for 2 days, washed with saturated NaHCO3 then brine, dried and concentrated in vacuo. The residue was purified by preparative HPLC (eluant; 0.5% 35% ammonia:9.5% methanol:90% dichloromethane) to give a off-white powder identified as the title compound (22 mg, 14%).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([C:9]2[N:13]=[C:12]([C:14]3[CH:19]=[C:18]([CH2:20][CH:21]([CH3:23])[CH3:22])[CH:17]=[C:16]([CH3:24])[N:15]=3)[O:11][N:10]=2)[CH:6]=[C:5]([CH3:25])[C:4]=1[OH:26])[CH3:2].[CH2:27]1[O:29][C@@H:28]1[CH2:30]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1.C1(C)C=CC=CC=1>[CH2:1]([C:3]1[CH:8]=[C:7]([C:9]2[N:13]=[C:12]([C:14]3[CH:19]=[C:18]([CH2:20][CH:21]([CH3:23])[CH3:22])[CH:17]=[C:16]([CH3:24])[N:15]=3)[O:11][N:10]=2)[CH:6]=[C:5]([CH3:25])[C:4]=1[O:26][CH2:30][C@@H:28]1[CH2:27][O:29]1)[CH3:2]
Reactant: OC[C@@H]1CO1
Reactant: CCc1cc(-c2noc(-c3cc(CC(C)C)cc(C)n3)n2)cc(C)c1O
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCc1cc(-c2noc(-c3cc(CC(C)C)cc(C)n3)n2)cc(C)c1OC[C@@H]1CO1
Temperature: 25 °C
Reaction time: 4 h
Yield: 50.4 %

Procedure:
To a solution of 2-ethyl-4-[5-(4-isobutyl-6-methyl-pyridin-2-yl)-[1,2,4]oxadiazol-3-yl]-6-methyl-phenol (79 mg, 0.224 mmol) in THF (6 mL), (R)-(+)-glycidol (25 mg, 0.335 mmol) and triphenyl phosphine (88 mg, 0.335 mmol) are added. The mixture is stirred and cooled to 0° C. before DEAD (58 mg, 0.335 mmol, as a 40% solution in toluene) is added. The mixture is warmed to rt and stirring is continued for 4 h. Another portion of (R)-(+)-glycidol (8 mg, 0.112 mmol), triphenyl phosphine (30 mg, 0.112 mmol) and DEAD (19 mg, 0.112 mmol) is added. Stirring is continued for 4 h before the solvent is evaporated. The crude product is purified on prep. TLC using heptane:EA 7:3 to give 2-[3-((S)-3-ethyl-5-methyl-4-oxiranylmethoxy-phenyl)-[1,2,4]oxadiazol-5-yl]-4-isobutyl-6-methyl-pyridine (46 mg) as a yellow oil; LC-MS: tR=1.17 min, [M+H]+=408.19.
Reaction SMILES: [N:1]1[C:6]2=[C:7]3[C:16](=[CH:17][CH:18]=[C:5]2[CH:4]=[CH:3][CH:2]=1)[N:15]=[C:14]1[C:9]([C:10]([C:19](O)=[O:20])=[CH:11][CH:12]=[CH:13]1)=[N:8]3.[CH3:22][N:23]([CH3:27])[CH2:24][CH2:25][NH2:26]>>[CH3:22][N:23]([CH3:27])[CH2:24][CH2:25][NH:26][C:19]([C:10]1[C:9]2[C:14](=[N:15][C:16]3[C:7]([N:8]=2)=[C:6]2[N:1]=[CH:2][CH:3]=[CH:4][C:5]2=[CH:18][CH:17]=3)[CH:13]=[CH:12][CH:11]=1)=[O:20]
Reactant: CN(C)CCN
Reactant: O=C(O)c1cccc2nc3ccc4cccnc4c3nc12
Product: CN(C)CCNC(=O)c1cccc2nc3ccc4cccnc4c3nc12

Procedure:
Pyrido[2,3-α]phenazine-11-carboxylic acid (2-dimethylamino-ethyl)-amide was prepared from pyrido[2,3-α]phenazine-11-carboxylic acid (II.1) and N,N-dimethylethylenediamine
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:16])[N:4]([CH3:15])[C:5]([Cl:14])=[N:6][C:7]=1[C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1.C(N(C(C)C)CC)(C)C.[C:26](Cl)(=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>ClCCl>[Cl:14][C:5]1[N:4]([CH3:15])[C:3](=[O:16])[C:2]([NH:1][C:26](=[O:33])[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[C:7]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)[N:6]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Cn1c(Cl)nc(-c2ccncc2)c(N)c1=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cn1c(Cl)nc(-c2ccncc2)c(NC(=O)c2ccccc2)c1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 5-amino-2-chloro-3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one (0.42 mmol) in dichloromethane was added diisopropylethylamine (0.51 mmol) and benzoyl chloride (0.51 mmol). The reaction was stirred overnight at room temperature. The reaction solution was washed with 5% NaHCO3, and the organic layer was purified on silica. M+1=341.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[N:10][N:11]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[CH:12]=2)[N:5]=[C:4]([NH2:21])[CH:3]=1.[CH3:22][N:23]1[CH:27]=[C:26](B2OC(C)(C)C(C)(C)O2)[CH:25]=[N:24]1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:22][N:23]1[CH:27]=[C:26]([C:2]2[N:7]=[C:6]([C:8]3[CH:9]=[N:10][N:11]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[CH:12]=3)[N:5]=[C:4]([NH2:21])[CH:3]=2)[CH:25]=[N:24]1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: C[Si](C)(C)CCOCn1cc(-c2nc(N)cc(Cl)n2)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: Cn1cc(-c2cc(N)nc(-c3cnn(COCC[Si](C)(C)C)c3)n2)cn1
Temperature: 100 °C
Yield: 54.7 %

Procedure:
6-Chloro-2-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)pyrimidin-4-amine (1.00 g, 3.07 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.958 g, 4.60 mmol), K3PO4 (1.95 g, 9.21 mmol), and Pd(PPh3)4 (0.355 g, 0.307 mmol) were suspended in dioxane (15.3 mL) and H2O (0.829 mL). After de-gassing with nitrogen, the reaction mixture was heated to 100° C. overnight. After cooling, the reaction mixture was diluted in EtOAc and washed with water and brine. The organics were dried with MgSO4, filtered and concentrated down to an orange oil. Purification of the resulting crude material by silica chromatography using a gradient of 0-10% MeOH/EtOAc afforded 6-(1-methyl-1H-pyrazol-4-yl)-2-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)pyrimidin-4-amine (0.623 g, 1.68 mmol, 54.7% yield) as a thick yellow oil. MS (apci) m/z=372.4 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:11][C:12](=[O:23])[C:13]2[CH:18]=[CH:17][C:16]([C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:15][CH:14]=2)=[S:10])=[CH:4][CH:3]=1.[Br:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][C:32](Cl)=[O:33].C(N(CC)CC)C>C(Cl)Cl>[C:19]([C:16]1[CH:15]=[CH:14][C:13]([C:12]([NH:11][C:9](=[S:10])[NH:8][C:5]2[CH:6]=[CH:7][C:2]([NH:1][C:32](=[O:33])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][Br:24])=[CH:3][CH:4]=2)=[O:23])=[CH:18][CH:17]=1)([CH3:20])([CH3:22])[CH3:21]
Reactant: O=C(Cl)CCCCCCCBr
Reactant: CC(C)(C)c1ccc(C(=O)NC(=S)Nc2ccc(N)cc2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)c1ccc(C(=O)NC(=S)Nc2ccc(NC(=O)CCCCCCCBr)cc2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 59.1 %

Procedure:
8-Bromooctanoic acid (2 g, 8.90 mmol, 1 equiv) was stirred in CH2Cl2 (15 mL) under N2 atmosphere and thionyl chloride (784 μL, 10.68 mmol, 1.2 equiv) added followed by DMF (few drops). The solution was stirred for 16 h and concentrated in vacuo to give 8-bromooctanoyl chloride (2.04 g, 95%) as a yellow oil which was used without further purification. Thiourea 4 (600 mg, 1.84 mmol, 1 equiv.) was stirred in CH2Cl2 (15 mL) under N2 atmosphere. 8-Bromooctanoyl chloride (532 mg, 2.02 mmol, 1.2 equiv.) was added, followed by triethylamine (256 μL, 1.84 mmol, 1 equiv.). The beige suspension was stirred at rt for 16 h and diluted with CH2Cl2 (20 mL). The organic solution was washed with 1 M aqueous hydrochloric acid (1×20 mL), 10% aqueous sodium hydroxide (1×20 mL), and saturated brine (1×20 mL). The organic phase was dried over MgSO4 and concentrated in vacuo. The resulting yellow foam was purified by flash chromatography on silica (50% ethyl acetate/petroleum ether) to give 8-bromo-octanoic acid {4-[3-(4-tert-butyl-benzoyl)-thioureido]-phenyl}-amide (579 mg, 59%) as a yellow oil.
Reaction SMILES: [N:1]1([C:8]([C:10]2[CH:14]=[C:13]([C:15]3[CH2:16][CH2:17][NH:18][CH2:19][CH:20]=3)[S:12][CH:11]=2)=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[C:28](Cl)(=[O:30])[CH3:29]>C(Cl)Cl>[N:1]1([C:8]([C:10]2[CH:14]=[C:13]([C:15]3[CH2:16][CH2:17][N:18]([C:28](=[O:30])[CH3:29])[CH2:19][CH:20]=3)[S:12][CH:11]=2)=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: O=C(c1csc(C2=CCNCC2)c1)N1CCCCCC1
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N1CC=C(c2cc(C(=O)N3CCCCCC3)cs2)CC1
Reaction time: 1 h
Yield: 33.8 %

Procedure:
To a solution of azepan-1-yl-[5-(1,2,3,6-tetrahydro-pyridin-4-yl)-thiophen-3-yl]-methanone (0.023 g, 0.08 mmol) in DCM (1 mL) was added triethylamine (0.27 mmol) and acetyl chloride (0.11 mmol). The reaction mixture was stirred for 1 hour, and then the solvent evaporated. The product was purified by HPLC, eluting with 10%-98% acetonitrile in water (0.1% formic acid). The fractions containing the desired product were concentrated under vacuum to give the title compound as a colourless oil (0.009 g). LCMS m/z 333.11 [M+H]+ RT=8.18 min (Analytical Method 2).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10].[CH3:12][O:13][C:14]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][C:15]=1[NH2:16]>>[CH3:12][O:13][C:14]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][C:15]=1[NH:16][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10]
Reactant: COc1ccc([N+](=O)[O-])cc1N
Reactant: O=C(O)Cc1ccccc1Br
Product: COc1ccc([N+](=O)[O-])cc1Nc1ccccc1CC(=O)O

Procedure:
In the manner described in example 3, 2-bromophenylacetic acid is condensed with 2-methoxy-5-nitroaniline to yield 2-[(2-methoxy-5-nitrophenyl)amino]phenylacetic acid.
Reaction SMILES: [CH2:1]([O:8][N:9]([C@H:22]1[CH2:27][N:26]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[C@H:25]([C:35](=[NH:38])[NH:36][OH:37])[CH2:24][CH2:23]1)[S:10]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[N+:19]([O-:21])=[O:20])(=[O:12])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:39]C1C=CC(S([O-])(=O)=O)=CC=1.C1C=C[NH+]=CC=1>COC(OC)OC>[CH2:1]([O:8][N:9]([C@H:22]1[CH2:27][N:26]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[C@H:25]([C:35]2[N:38]=[CH:39][O:37][N:36]=2)[CH2:24][CH2:23]1)[S:10]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[N+:19]([O-:21])=[O:20])(=[O:12])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1C[C@H](N(OCc2ccccc2)S(=O)(=O)c2ccccc2[N+](=O)[O-])CC[C@H]1C(=N)NO
Reactant: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: COC(OC)OC
Product: CC(C)(C)OC(=O)N1C[C@H](N(OCc2ccccc2)S(=O)(=O)c2ccccc2[N+](=O)[O-])CC[C@H]1c1ncon1
Temperature: 70 °C
Reaction time: 4 h
Yield: 1178.8 %

Procedure:
A mixture of (2S,5R)-tert-butyl 5-(N-(benzyloxy)-2-nitrophenylsulfonamido)-2-(N-hydroxycarbamimidoyl)piperidine-1-carboxylate (3.0 g, 5.46 mmol), trimethoxymethane (60 mL), and PPTS (0.08 g) was stirred at 70° C. for 4 hrs. The solvent was then removed under vacuum. The residue was purified by silica gel column chromatography (gradient elution 0˜35% petroleum ether/EtOAc) to give (2S,5R)-tert-butyl 5-(N-(benzyloxy)-2-nitrophenylsulfonamido)-2-(1,2,4-oxadiazol-3-yl)piperidine-1-carboxylate (2.1 g, 69%) as a yellow solid. ESI-MS (EI+, m/z): 582 [M+Na]+.
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([CH3:7])[C:3]=1[Br:8].[F:9][C:10]([F:22])([F:21])[C:11]1[CH:16]=[CH:15][C:14]([S:17](Cl)(=[O:19])=[O:18])=[CH:13][CH:12]=1>>[F:22][C:10]([F:9])([F:21])[C:11]1[CH:12]=[CH:13][C:14]([S:17]([NH:1][C:2]2[O:6][N:5]=[C:4]([CH3:7])[C:3]=2[Br:8])(=[O:19])=[O:18])=[CH:15][CH:16]=1
Reactant: Cc1noc(N)c1Br
Reactant: O=S(=O)(Cl)c1ccc(C(F)(F)F)cc1
Product: Cc1noc(NS(=O)(=O)c2ccc(C(F)(F)F)cc2)c1Br
Yield: 72 %

Procedure:
4-Trifluoromethyl-N-(4-bromo-3-methyl-5-isoxazolyl)benzenesulfonamide was prepared from 5-amino-4-bromo-3-methylisoxazole and 4-trifluoromethylbenzenesulfonyl chloride according to the procedures described in Example 30. The crude product was purified by recrystallization from ethyl acetate/hexanes to give a crystalline solid, m.p. 155-158° C., yield 72%.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][N:6]2[C:11]1[CH:16]=[CH:15][N:14]=[C:13](S(C)=O)[N:12]=1.[CH2:20]([O:22][C:23]([CH:25]1[CH2:30][CH2:29][CH:28]([NH2:31])[CH2:27][CH2:26]1)=[O:24])[CH3:21]>O1CCOCC1>[CH2:20]([O:22][C:23]([CH:25]1[CH2:30][CH2:29][CH:28]([NH:31][C:13]2[N:12]=[C:11]([N:6]3[C:7]4[C:3](=[C:2]([Br:1])[CH:10]=[CH:9][CH:8]=4)[CH:4]=[CH:5]3)[CH:16]=[CH:15][N:14]=2)[CH2:27][CH2:26]1)=[O:24])[CH3:21]
Reactant: CCOC(=O)C1CCC(N)CC1
Reactant: CS(=O)c1nccc(-n2ccc3c(Br)cccc32)n1
Solvent: C1COCCO1
Product: CCOC(=O)C1CCC(Nc2nccc(-n3ccc4c(Br)cccc43)n2)CC1
Temperature: 110 °C
Reaction time: 5.5 h
Yield: 88.6 %

Procedure:
A mixture of 4-bromo-1-(2-methylsulfinyl-pyrimidin-4-yl)-1H-indole (4.98 g) and 4-amino-cyclohexanecarboxylic acid ethyl ester (5.07 g) in 1,4-dioxane (100 mL) was stirred at 110° C. under N2 for 5.5 h. The solvent was removed in vacuo to provide an oil, which solidified at RT. The product was flash chromatographed on silica, eluting with hexanes/EtOAc (7:3 to 6:4) to provide 4-[4-(4-bromoindol-1-yl)-pyrimidin-2-ylamino]-cyclohexanecarboxylic acid ethyl ester (5.82 g, 89%) as a white powder.
Reaction SMILES: [O:1]=[C:2]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[Li+].[CH3:16]C([N-]C(C)C)C.CI.Cl>CCOCC>[CH3:16][CH:9]([C:2](=[O:1])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: CCOC(=O)CC(=O)CC(=O)OCC
Reactant: CC(C)[N-]C(C)C
Agent: Cl
Agent: [Li+]
Solvent: CCOCC
Solvent: CI
Product: CCOC(=O)CC(=O)C(C)C(=O)OCC
Temperature: -15 °C
Reaction time: 3 h
Yield: 23 %

Procedure:
This compound was synthesized according to U.S. Pat. No. 6,833,471. To 20 mL of dry THF that had been purged with Ar(gas) was added diethyl 3-oxopentanedioate (5 mL, 27.54 mmol) and the solution was cooled to −15° C. prior to the dropwise addition of LDA (2M) (15 mL, 30 mmol). The reaction was maintained under Ar(gas) at −15° C., and MeI (3 mL, 48.2 mmol) was added slowly. The reaction was allowed to reach room temperature gradually over 3 hours, and the stirring was continued overnight. After 18 hours, the reaction mixture was poured into 140 mL of a 1:1 mixture of 0.5 N HCl (aq) and Et2O. The organic layer was separated, and the aqueous layer was extracted twice with Et2O (15 mL×2). The organic layers were combined, washed with brine, dried (MgSO4) and concentrated to give an yellow oil, which was flash chromatography purified (SiO2, Hexane:EtOAc=8:2 (v:v)) to afford a colorless/light yellow oil as the title compound. (1.37 g, 23% yield). MW m/z: 215.3 (MW−1, low intensity). 1H NMR (CDCl3, 300 Hz) δ ppm 4.20 (q, 4H), 3.68 (q, 1H), 3.60 (dd, 2H), 1.37 (d, 3H), 1.26 (t, 6H).
Reaction SMILES: [CH:1]([C:3]1[CH:18]=[CH:17][C:6]([O:7][C:8]2[N:9]=[CH:10][C:11]([C:14]([NH2:16])=[O:15])=[N:12][CH:13]=2)=[C:5]([O:19][CH3:20])[CH:4]=1)=O.[O:21]1[CH2:26][CH2:25][CH:24]([CH2:27][CH2:28][NH2:29])[CH2:23][CH2:22]1.[BH4-].[Na+]>CO>[CH3:20][O:19][C:5]1[CH:4]=[C:3]([CH2:1][NH:29][CH2:28][CH2:27][CH:24]2[CH2:25][CH2:26][O:21][CH2:22][CH2:23]2)[CH:18]=[CH:17][C:6]=1[O:7][C:8]1[N:9]=[CH:10][C:11]([C:14]([NH2:16])=[O:15])=[N:12][CH:13]=1
Reactant: NCCC1CCOCC1
Reactant: COc1cc(C=O)ccc1Oc1cnc(C(N)=O)cn1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COc1cc(CNCCC2CCOCC2)ccc1Oc1cnc(C(N)=O)cn1
Reaction time: 8 h
Yield: 59.4 %

Procedure:
Place 5-(4-Formyl-2-methoxyphenoxy)pyrazine-2-carboxamide (Example 719, Part A) (0.200 g, 0.732 mmol), 2-(tetrahydropyran-4-yl)ethylamine (0.0993 g, 0.769 mmol) and 3 Å molecular sieves in a vial. Add methanol (3.6 mL), cap and stir overnight. Add NaBH4 (ca. 3-5 eq in two portions) and stir until the gasses stop evolving. Load the reaction mixture directly onto a 25 g ISCO® C. pre-load column. Dry the column in a vacuum oven at room temperature. Purify by eluting through a 40 g ISCO® column 5% to 20% (2.0 M NH3 in methanol) in ethyl acetate. Concentrate the fractions containing the product. Take the solid up in ethyl acetate (50 mL) and wash with 1.0 N NaOH to give the title compound (0.168 g, 59.4%): TOF MS ES+ 387.2031 (M+H)+, HRMS calcd for C20H27N4O4 387.2032 (M+H)+, found 387.2031, time 0.52 min; HPLC [Waters XTerra™ C-18 (150×4.6 mm, S-5 microm), 0.1% TFA/acetonitrile in 0.1% TFA/water at 1.0 mL/min, 5-95% over 23 min], tR=8.7 min, 100% purity.
Reaction SMILES: Br[C:2]1([CH2:10][C:11]([O:13][Si:14]([C:27]([CH3:30])([CH3:29])[CH3:28])([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])[C:6](=[O:7])[O:5][C:4]([CH3:9])([CH3:8])[O:3]1.N12CCCN=C1CCCCC2>O1CCCC1>[CH3:8][C:4]1([CH3:9])[O:5][C:6](=[O:7])/[C:2](=[CH:10]/[C:11]([O:13][Si:14]([C:27]([CH3:30])([CH3:29])[CH3:28])([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])/[O:3]1
Reactant: CC1(C)OC(=O)C(Br)(CC(=O)O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)O1
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: CC1(C)OC(=O)/C(=C/C(=O)O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)O1
Temperature: 5 °C
Reaction time: 1.5 h

Procedure:
A solution of 4-bromo-2,2-dimethyl-5-oxo-1,3-dioxolane-4-acetic acid, tert-butyldiphenylsilyl ester (˜26 g, 52.4 mmol) in dry tetrahydrofuran (160 ml) was cooled to 0° C. and treated dropwise over 5 minutes with 1,8-diazabicyclo[5,4,0]undec-7-ene (12.7 g, 78.8 mmol) and the resulting mixture was stirred at 5° C. for 1.5 hour. The solid formed was filtered and washed with a small amount of tetrahydrofuran. The filtrate was used as such for the next step.
Reaction SMILES: [CH3:1][C:2]1[O:3][CH:4]=[CH:5][C:6]=1[C:7](Cl)=[O:8].[NH2:10][C:11]1[CH:33]=[CH:32][C:14]([C:15]([N:17]2[CH2:23][C:22]3[CH:24]=[CH:25][CH:26]=[CH:27][C:21]=3[CH2:20][C:19]3[CH:28]=[CH:29][CH:30]=[CH:31][C:18]2=3)=[O:16])=[CH:13][CH:12]=1>>[CH:28]1[C:19]2[CH2:20][C:21]3[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=3[CH2:23][N:17]([C:15]([C:14]3[CH:13]=[CH:12][C:11]([NH:10][C:7]([C:6]4[CH:5]=[CH:4][O:3][C:2]=4[CH3:1])=[O:8])=[CH:33][CH:32]=3)=[O:16])[C:18]=2[CH:31]=[CH:30][CH:29]=1
Reactant: Nc1ccc(C(=O)N2Cc3ccccc3Cc3ccccc32)cc1
Reactant: Cc1occc1C(=O)Cl
Product: Cc1occc1C(=O)Nc1ccc(C(=O)N2Cc3ccccc3Cc3ccccc32)cc1

Procedure:
As described for Example 9, 2-methyl-3-furanecarbonyl chloride is reacted with 5-(4-aminobenzoyl)-6,11-dihydro-5H-dibenz[b,e]azepine to give the product. Recrystallization from dichloromethane-hexane gives crystals, m.p. 202°-204° C.
Reaction SMILES: [CH:1]([CH:3]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=1)[C:4]([O:6][CH2:7][CH3:8])=[O:5])=O.Cl.[CH3:18][NH:19][CH3:20].C(=O)([O-])[O-].[K+].[K+]>C(O)C>[CH3:16][O:15][C:12]1[CH:13]=[CH:14][C:9]([C:3](=[CH:1][N:19]([CH3:20])[CH3:18])[C:4]([O:6][CH2:7][CH3:8])=[O:5])=[CH:10][CH:11]=1
Reactant: CNC
Reactant: CCOC(=O)C(C=O)c1ccc(OC)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CCOC(=O)C(=CN(C)C)c1ccc(OC)cc1
Yield: 98.7 %

Procedure:
21 g (0.0945 mol) of ethyl α-formyl-p-methoxyphenylacetate, 80 ml of ethanol and 31,1 g (0.38 mol) of dimethylamine hydrochloride were mixed in a 250 ml balloon flask provided with magnetic stirring and thermometer under a gentle nitrogen flow. Subsequently 7.4 g (0.054 mol) of potassium carbonate were added. The thus obtained solution was stirred at room temperature for 3 days. The solvent was evaporated to dryness in the rotary evaporator and 120 ml of water were added over the thus obtained solid residue. The pH was adjusted to 5-6 with 5N hydrochloric acid and the product of the aqueous phase was extracted with 2×80 ml of dichloromethane. The organic extracts were dried with sodium sulfate and the solvent was removed under vacuum, to give a residue weighing 23.26 g and solidifying at room temperature (Yield: 98.7%)
Reaction SMILES: C(OC(C1C(=O)NC2C=CSC=2C=1Cl)=O)C.[CH3:17][O:18][C:19]([C:21]1[S:22][CH:23]=[CH:24][C:25]=1[NH2:26])=[O:20].[CH3:27][O:28][C:29]1[CH:36]=[CH:35][C:32]([CH2:33]Cl)=[CH:31][CH:30]=1>>[CH3:27][O:28][C:29]1[CH:36]=[CH:35][C:32]([CH2:33][NH:26][C:25]2[CH:24]=[CH:23][S:22][C:21]=2[C:19]([O:18][CH3:17])=[O:20])=[CH:31][CH:30]=1
Reactant: COC(=O)c1sccc1N
Reactant: COc1ccc(CCl)cc1
Agent: CCOC(=O)c1c(Cl)c2sccc2[nH]c1=O
Product: COC(=O)c1sccc1NCc1ccc(OC)cc1

Procedure:
The preferred intermediate in the preparation of compounds of structure (I), 7-chloro-5-oxo-4,5-dihydro-thieno[3,2-b]pyridine-6-carboxylic acid ethyl ester depicted by formula (4) below, was also prepared by an alternative route as shown in Scheme 34. In this method, methyl-3-amino-thiophene-2-carboxylate was reacted with 4-methoxy benzylchloride to yield methyl 3-(4-methoxybenzylamino)thiophene-2-carboxylate, depicted by formula (65). This intermediate was reacted with ethylmalonyl chloride followed by a cyclization reaction to yield 7-hydroxy-4-(4-methoxybenzyl)-5-oxo-4,5-dihydro-thieno[3,2-b]pyridine-6-carboxylic acid ethyl ester, depicted by formula (67). Chlorination of 7-hydroxy-4-(4-methoxybenzyl)-5-oxo-4,5-dihydro-thieno[3,2-b]pyridine-6-carboxylic acid ethyl ester, depicted by formula (67) by reacting with oxalyl chloride followed by deprotection yielded the intermediate 7-chloro-5-oxo-4,5-dihydro-thieno[3,2-b]pyridine-6-carboxylic acid ethyl ester, depicted by formula (4), as shown in Scheme 34.
Reaction SMILES: C([Li])CCC.C([C:8]([CH2:19][CH3:20])([C:13]1[N:14]=[C:15]([CH3:18])[S:16][CH:17]=1)P([O-])(=O)[O-])C.[Si:21]([O:28][C@@H:29]([CH2:33][CH2:34][O:35][Si:36]([C:39]([CH3:42])([CH3:41])[CH3:40])([CH3:38])[CH3:37])C(=O)C)([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22]>C1COCC1>[Si:21]([O:28][CH2:29][CH2:33][C@H:34]([O:35][Si:36]([C:39]([CH3:42])([CH3:41])[CH3:40])([CH3:37])[CH3:38])/[C:19](/[CH3:20])=[CH:8]/[C:13]1[N:14]=[C:15]([CH3:18])[S:16][CH:17]=1)([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22]
Reactant: CCC(CC)(c1csc(C)n1)P(=O)([O-])[O-]
Reactant: CC(=O)[C@H](CCO[Si](C)(C)C(C)(C)C)O[Si](C)(C)C(C)(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C/C(=C\c1csc(C)n1)[C@H](CCO[Si](C)(C)C(C)(C)C)O[Si](C)(C)C(C)(C)C
Temperature: -78 °C
Reaction time: 1 h
Yield: 78.9 %

Procedure:
(see D. Schinzer et al., Chem. Eur. J. 2, 1477-1482 (1996)) n-Butyl lithium (23,5 ml [58.7 mmol, 1.2 equiv] of a 2.5 M solution in hexanes) is added dropwise to a stirred solution of diethyl-(2-methylthiazol-4-yl)-methanephosphonate 10 (14,64 g, 58.7 mmol, 1.2 equiv) in THF (150 ml) cooled to −78° C. After stirring at −78° C. for 1 h, a solution of (S)-3,5-di-(tertbutyidimethylsilyloxy)-pentan-2-one 14 (16.96 g, 48,9 mmol, 1.0 equiv) in 100 ml of THF is added dropwise at −78° C. The mixture is warmed to r.t. within 12 h. The reaction is quenched with saturated aqueous ammonium chloride solution (100 ml). The organic layer is seperated and the aqueous layer is extracted with diethyl ether (3×100 ml). The combined organic extracts are dried over magnesium sulfate and concentrated in vacuo. Purification of the residue by flash column chromatography (gradient elution with pentane/dichloromethane 4:1→dichloromethane→diethyl ether→diethyl ether/methanol 10:1) affords (S,4E)-1,3di-(tert-butyldimethylsilyloxy)-4-methyl-5-(2-methylthiazol-4-yl)-pent-4-ene 15 (17,07 g, 38.6 mmol, 79%) as a colourless oil and some starting material (10 and 14). Alternatively, the crude product obtained after extraction can be directly used in the next step.