Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:5]([O:6][CH2:7][C:8]([CH3:12])([OH:11])[CH2:9][OH:10])=[CH:4][CH:3]=1.[CH3:15][C:16]([CH3:18])=O.O1CCCC1.C(=O)([O-])[O-].[Na+].[Na+]>O.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH2:7][C:8]2([CH3:12])[CH2:9][O:10][C:16]([CH3:18])([CH3:15])[O:11]2)=[CH:13][CH:14]=1
Reactant: CC(C)=O
Reactant: CC(O)(CO)COc1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: CC1(COc2ccc(Br)cc2)COC(C)(C)O1
Temperature: 25 °C
Reaction time: 67 h
Yield: 40.2 %

Procedure:
3-(4-Bromophenoxy)-2-methylpropane-1,2-diol (261 mg, 1.00 mmol), acetone (77 mg, 1.3 mmol), tetrahydrofuran (5 mL), and a boron trifluoride diethyl ether complex (3 drops) were mixed. The mixture was stirred at room temperature for 67 hours, and acetone (102 mg, 1.76 mmol) was added thereto, followed by stirring for 2 hours. Sodium carbonate, ethyl acetate, and water were added to the reaction mixture to conduct extraction. The organic layer was washed with a saline solution twice. A residue was obtained by concentrating the organic layer under reduced pressure, and the residue was subjected to chromatography refining (methylene chloride) using silica gel, obtaining 121 mg of the objective compound (yield: 40%).
Reaction SMILES: [CH:1]([Mg]Cl)=[CH2:2].CN1C(=O)N(C)CCC1.P(OCC)(OCC)OCC.[Si:24]([O:31][C@H:32]([CH2:39]I)[CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25]>C1COCC1.[Cu]I>[Si:24]([O:31][C@H:32]([CH2:39][CH:1]=[CH2:2])[CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25]
Reactant: C=C[Mg]Cl
Reactant: CCOC(=O)C[C@@H](CI)O[Si](C)(C)C(C)(C)C
Agent: [Cu]I
Agent: CCOP(OCC)OCC
Solvent: C1CCOC1
Solvent: CN1CCCN(C)C1=O
Product: C=CC[C@H](CC(=O)OCC)O[Si](C)(C)C(C)(C)C
Temperature: 11 °C
Reaction time: 0.25 h
Yield: 67.9 %

Procedure:
To a suspension of CuI (83.64 g, 437.0 mmol) in dry THF (875 mL), vinylmagnesium chloride (1.9 M in THF, 460.0 mL, 874.0 mmol) is added under argon atmosphere at 44 to −31° C. in 15 minutes under vigorous stirring. The resulting dark slurry is stirred for 15 minutes, and DMPU (112 g, 874.0 mmol) is added at 42° C. in one portion followed by the dropwise addition (5 minutes) of P(OEt)3 (160.1 mL, 874.0 mmol) at 40° C. The resulting mixture is stirred for 30 minutes and a THF (220 mL) solution of (S)-ethyl 3-(tert-butyldimethylsilyloxy)-4-iodobutyrate (3) (162.7 g, 437.0 mmol) is added at −40 to −36° C. in 15 minutes. The stirring is continued for 1 hour at −40 to −35° C. before allowing the mixture to warm to 11° C. over a period of 3.5 hours. The reaction is quenched at −2° C. (saturated NH4Cl, 1.0 L) and stirred at 10° C. for 30 minutes. The product is extracted with i-Pr2O or t-BuMeO. Partial evaporation of the solvent under reduced pressure gives a yellow solution which is washed with 0.1 M H2SO4, water and dried (MgSO4). Ether is removed completely under reduced pressure (15 mbar) at 80° C. to produce a yellow oily residue. This residue is purified further by vacuum distillation (64-72° C. at 0.10-0.44 mbar) to give 80.8 g (67.8%) of ethyl 3(R)-(tert-butyldimethylsilyloxy)-5-hexenoate (4) as a colorless oil (GC purity 96%). 1H NMR (300 MHz, CDCl3): δ 5.81 (ddt, J=17.8, 9.6 and 7.2 Hz, 1H), 5.11-5.03 (m, 2H), 4.21 (quint., J=6.8 Hz, 1H), 4.12 (qt, J=7.1 and 1.5 Hz, 2H), 2.43 (d, J=7.1 Hz, 1H), 2.43 (d, J=5.4 Hz, 1H), 2.31−2.25 (m, 2H), 1.26 (t, J=7.2 Hz, 3H), 0.87 (s, 9H), 0.07 (s, 3H), 0.04 (s, 3H). 13C NMR (75 MHz, CDCl3): δ 171.7, 134.1, 117.6, 68.9, 60.2, 42.1, 42.1, 25.7, 17.9, 14.1, −4.6, −5.0.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][CH3:12])=[C:6]([CH:10]=1)[C:7](Cl)=[O:8].Cl.[NH2:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][C:23]([OH:25])=[O:24])=[CH:18][CH:17]=1>CC(C)=O.[OH-].[Na+].O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][CH3:12])=[C:6]([CH:10]=1)[C:7]([NH:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][C:23]([OH:25])=[O:24])=[CH:18][CH:17]=1)=[O:8]
Reactant: NCc1ccc(CC(=O)O)cc1
Reactant: COc1ccc(Cl)cc1C(=O)Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Product: COc1ccc(Cl)cc1C(=O)NCc1ccc(CC(=O)O)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 22.1 %

Procedure:
A solution of 5.0 g 5-chloro-2-methoxybenzoyl chloride in 10 ml acetone is added, with ice cooling, to a solution of 5.0 g 4-aminomethyl-phenylacetic acid hydrochloride in 25 ml 2 N aqueous sodium hydroxide solution and 25 ml acetone. The reaction mixture is then stirred for 3 hours at ambient temperature, diluted with water, filtered with charcoal and the filtrate acidified with 2 N hydrochloric acid. The precipitate obtained is filtered off with suction and dried and then recrystallized from ethyl acetate/petroleum ether. There is obtained 1.8 g (21% of theory) 4-(5-chloro-2-methoxybenzamidomethyl)-phenylacetic acid; m.p. 140°-141° C.
Reaction SMILES: CC1(C)O[C:6](=[O:8])[C:5](=[CH:9][NH:10][C:11]2[CH:25]=[CH:24][C:14]([C:15]([O:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:16])=[C:13]([OH:26])[CH:12]=2)C(=O)O1.[CH2:29](Br)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C(=O)([O-])[O-].[K+].[K+].C(OCC)C.O1CCCC1>CN(C)C=O.C(O)C.CCCCCC.C1C=CC(C2C=CC=CC=2)=CC=1.C1C=CC(OC2C=CC=CC=2)=CC=1.C(OCC)C.O>[CH2:29]([O:26][C:13]1[CH:12]=[C:11]2[C:25]([C:6](=[O:8])[CH:5]=[CH:9][NH:10]2)=[CH:24][C:14]=1[C:15]([O:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)=[O:16])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: CC1(C)OC(=O)C(=CNc2ccc(C(=O)Oc3ccccc3)c(O)c2)C(=O)O1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Solvent: CCCCCC
Product: O=C(Oc1ccccc1)c1cc2c(=O)cc[nH]c2cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 10766.7 %

Procedure:
Phenyl 4-(((2,2-dimethyl-4,6-dioxo-1,3-dioxan-5-ylidene)methyl)amino)-2-hydroxybenzoate (11.5 g, 0.030 mmol), benzyl bromide (5.64 g, 0.033 mmol) and potassium carbonate (4.56 g, 0.033 mmol) were stirred in dimethylformamide (45 ml) at 80° C. for 3 hours. The reaction solution was distributed between a diethyl ether-tetrahydrofuran mixed solvent and water, the organic layer was washed with water and saturated brine and dried over anhydrous magnesium sulfate, and the drying agent was filtered out and the filtrate distilled off under reduced pressure. The obtained crude product was suspended in ethanol, the suspension was diluted with hexane, and the crystals were filtered out, washed with hexane and blow-dried to obtain white crystals. The crystals were then heated and stirred for 1 hour in Dowtherm A (50 ml) at 200° C. After allowing the reaction solution to cool to room temperature, diethyl ether (25 ml) was added and the mixture was further stirred overnight. The precipitated crystals were filtered out, washed with diethyl ether and blow-dried to obtain the title compound (1.20 g, 3.23 mmol, 11%) as white crystals.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:5]=[CH:4][C:3]=1[C:15]1[C:23]2[C:22]([NH2:24])=[N:21][CH:20]=[N:19][C:18]=2[N:17]([CH2:25][CH:26]2[CH2:30][CH2:29][CH2:28][NH:27]2)[CH:16]=1.[C:31]([C:33](=[CH:37][CH:38]1[CH2:40][CH2:39]1)[C:34](O)=[O:35])#[N:32].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[NH2:24][C:22]1[C:23]2[C:15]([C:3]3[CH:4]=[CH:5][C:6]([O:8][C:9]4[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=4)=[CH:7][C:2]=3[F:1])=[CH:16][N:17]([CH2:25][CH:26]3[CH2:30][CH2:29][CH2:28][N:27]3[C:34]([C:33](=[CH:37][CH:38]3[CH2:40][CH2:39]3)[C:31]#[N:32])=[O:35])[C:18]=2[N:19]=[CH:20][N:21]=1
Reactant: N#CC(=CC1CC1)C(=O)O
Reactant: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1F)cn2CC1CCCN1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: N#CC(=CC1CC1)C(=O)N1CCCC1Cn1cc(-c2ccc(Oc3ccccc3)cc2F)c2c(N)ncnc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 54.3 %

Procedure:
To a mixture of 5-(2-fluoro-4-phenoxy-phenyl)-7-pyrrolidin-2-ylmethyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine (100 mg, 0.25 mmol, 1.0 eq), 2-cyano-3-cyclopropyl-acrylic acid (42 mg, 0.3 mmol, 1.2 eq) and DIEA (97 mg, 0.75 mmol, 3.0 eq) in 10 ml of DCM was added HATU (145 mg, 0.38 mmol, 1.5 eq). The mixture was stirred for 4 h at RT under N2. LCMS showed the reaction was completed. The reaction mixture was concentrated and purified by Pre-TLC to provide 71 mg (54%) of the title compound. LCMS: m/z 523.2 (M+H)+. 1HNMR (400 MHz, DMSO-d6): δ 0.866˜0.920 (m, 2H), 1.177˜1.194 (m, 2H), 1.569 (m, 1H), 1.721 (m, 2H), 1.883 (m, 2H), 3.200 (m, 2H), 3.511 (m, 1H), 4.360˜4.475 (m, 2H), 6.125 (m, 2H), 6.642˜6.664 (m, 1H), 6.898˜6.920 (m, 1H), 6.977˜7.010 (m, 1H), 7.150˜7.232 (m, 4H), 7.371˜7.471 (m, 3H) and 8.131 (m, 1H).
Reaction SMILES: [CH:1]([N-]C(C)C)(C)C.[Li+].O1CCCC1.[C:14]1([C:19]([C:21]2[CH:26]=[CH:25][C:24]([CH2:27][C:28]([O:30][CH3:31])=[O:29])=[CH:23][CH:22]=2)=[O:20])[S:18][CH:17]=[CH:16][CH:15]=1.CI>CN(C)P(N(C)C)(N(C)C)=O>[C:14]1([C:19]([C:21]2[CH:26]=[CH:25][C:24]([CH:27]([CH3:1])[C:28]([O:30][CH3:31])=[O:29])=[CH:23][CH:22]=2)=[O:20])[S:18][CH:17]=[CH:16][CH:15]=1
Reactant: CC(C)[N-]C(C)C
Reactant: COC(=O)Cc1ccc(C(=O)c2cccs2)cc1
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: COC(=O)C(C)c1ccc(C(=O)c2cccs2)cc1
Temperature: -78 °C
Reaction time: 0.67 h

Procedure:
A mixture of 4.27 parts of lithium diisopropylamide and 50 parts of tetrahydrofuran is cooled to -78° C. Then there are added 10.4 parts of methyl 2-[p-(2-thenoyl)phenyl]acetate and the mixture is stirred for 40 minutes. 6.25 Parts of methyl iodide dissolved in 2.15 parts of hexamethylphosphoramide are added at -78° C and the mixture is further stirred for 1 hour after which it is allowed to warm up to room temperature. The whole is poured onto water. The resulting mixture is extracted with diisopropylether. The organic phase is washed with water, dried and evaporated. The residue is crystallized from diisopropylether at 0° C, yielding methyl p-(2-thenoyl)hydratropate.
Reaction SMILES: [CH3:1][C:2]1[CH2:6][CH2:5][CH2:4][CH:3]=1.ClS([N:11]=[C:12]=[O:13])(=O)=O.S([O-])([O-])=O.[Na+].[Na+].[OH-].[K+]>C(OCC)C.O>[CH3:1][C:2]12[NH:11][C:12](=[O:13])[CH:6]1[CH2:5][CH2:4][CH2:3]2
Reactant: O=C=NS(=O)(=O)Cl
Reactant: CC1=CCCC1
Agent: O=S([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Product: CC12CCCC1C(=O)N2
Temperature: 25 °C

Procedure:
To a solution of 1-methylcyclopent-1-ene (CAS number 693-89-0; 38.5 mL, 365 mmol) in diethyl ether (220 ml) at 0° C. was added drop wise [(chlorosulfonyl)imino]methanone (CAS number 1189-71-5; 33.3 ml, 383 mmol). The reaction was then allowed to warm to room temperature and then heated to 36° C. for 72 hours. The reaction was then cooled to room temperature and a solution of sodium sulfite (73.5 g) in water (400 ml) was added drop wise, followed by the addition of 15% w/v potassium hydroxide (500 ml) to obtain pH 7-8. The phases were separated and aqueous phase was extracted with diethyl ether (2×200 ml). The combined organics were dried over magnesium sulfate and concentrated in vacuo to afford the title compound.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][CH2:5][C:4]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=2)([C:8](O)=[O:9])[CH2:3]1.[ClH:19]>C1COCC1.O1CCOCC1>[ClH:19].[NH2:1][CH:2]1[CH2:7][CH2:6][CH2:5][C:4]([CH2:8][OH:9])([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=2)[CH2:3]1
Reactant: NC1CCCC(Oc2cccc(F)c2)(C(=O)O)C1
Agent: Cl
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: NC1CCCC(CO)(Oc2cccc(F)c2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To the solution of 3-amino-1-(3-fluorophenoxy)cyclohexanecarboxylic acid (0.2 mmol, 50.6 mg) in THF was added a solution of borane dimethylsulfide complex in THF (1 mmol, 2 M, 0.5 mL). The reaction mixture was stirred at room temperature for overnight. A solution of HCl in dioxane was added dropwise. The product, HCl salt of (3-amino-1-(3-fluorophenoxy)cyclohexyl)methanol, was obtained after removal of solvent.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][C:25]=1[Cl:26])[CH2:5][NH:6][C:7]([NH:9][C:10]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:11]=1[CH:12]=[N:13][N:14]2C(OC)=O)=[O:8].[OH-].[K+].C(Cl)Cl.O>CO>[Cl:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][C:25]=1[Cl:26])[CH2:5][NH:6][C:7]([NH:9][C:10]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:11]=1[CH:12]=[N:13][NH:14]2)=[O:8]
Reactant: COC(=O)n1ncc2c(NC(=O)NCc3ccc(Cl)c(Cl)c3)cccc21
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Solvent: CO
Product: O=C(NCc1ccc(Cl)c(Cl)c1)Nc1cccc2[nH]ncc12
Temperature: 25 °C

Procedure:
The product of Example 90C (0.25 g, 0.6 mmol) was heated at reflux in methanol (5 mL) and 0.5N KOH (1 mL) for 0.5 hours. The reaction mixture was allowed to cool to ambient temperature, pH was adjusted to 5, and volume was reduced under reduced pressure. Methylene chloride and water was added, the phases were separated, and the organic phase concentrated under reduced pressure to provide the title compound. 1H NMR (300 MHz, DMSO-d6) δ 4.38 (d, 2H), 6.9 (t, 1H), 7.05 (d, 1H), 7.19 (t, 1H), 7.35 (dd, 1H), 7.6 (m, 2H), 8.06 (s, 1H), 8.82 (s, 1H). MS (DCI+) m/z 336 (M+H)+; Anal. Calcd. For C15H13N4Cl2O: C, 53.75; H, 3.62; N, 16.72. Found: C, 53.84; H, 3.44; N, 16.88.
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@@H:13]([CH2:23][O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[O:12][C@H:11]([CH2:32][I:33])[C@@H:10]1[OH:34])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C(C)=CC=CC=1C.[Si:43](OS(C(F)(F)F)(=O)=O)([C:46]([CH3:49])([CH3:48])[CH3:47])([CH3:45])[CH3:44]>C(Cl)Cl>[CH2:1]([O:8][C@H:9]1[C@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@@H:13]([CH2:23][O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[O:12][C@H:11]([CH2:32][I:33])[C@@H:10]1[O:34][Si:43]([C:46]([CH3:49])([CH3:48])[CH3:47])([CH3:45])[CH3:44])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O[C@@H]1[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@@H](COCc2ccccc2)O[C@@H]1CI
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: CC(C)(C)[Si](C)(C)O[C@@H]1[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@@H](COCc2ccccc2)O[C@@H]1CI
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 87.6 %

Procedure:
To a solution of (2S,3R,4R,5R,6R)-4,5-bis(benzyloxy)-6-((benzyloxy)methyl)-2-(iodomethyl)tetrahydro-2H-pyran-3-ol (1.0 g, 1.74 mmol, 1.0 equiv) in dry DCM (10 mL) under nitrogen atmosphere, was added 2,6-lutidine (0.41 mL, 3.5 mmol, 2.0 equiv) at room temperature. The resulting mixture was stirred for 5 minutes. The reaction was cooled to 0° C. and TBSOTf (0.6 mL, 2.6 mmol, 1.5 equiv) was added dropwise. The mixture was then slowly allowed to warm to room temperature. After 1 hour, the mixture was diluted with DCM (20 mL) and washed with water (2×20 mL). The organic layer was dried over Na2SO4 and over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give an oil. The oil was then purified by silica gel chromatography, eluting with 5% EtOAc in petroleum ether to give (((2S,3R,4S,5R,6R)-4,5-bis(benzyloxy)-6-((benzyloxy)methyl)-2-(iodomethyl)tetrahydro-2H-pyran-3-yl)oxy)(tert-butyl)dimethylsilane as a colorless oil (1.05 g, 94%). 1H NMR (400 MHz, CDCl3) δ 7.40-7.22 (m, 13H), 7.09-7.04 (m, 2H), 4.90-4.77 (m, 2H), 4.77-4.68 (m, 2H), 4.53 (d, J=12.1 Hz, 1H), 4.47 (d, J=10.7 Hz, 1H), 4.09 (ddd, J=12.2, 5.9, 3.4 Hz, 1H), 3.91 (dd, J=9.2, 5.9 Hz, 1H), 3.81 (dd, J=10.7, 3.2 Hz, 1H), 3.75 (dd, J=10.7, 2.1 Hz, 1H), 3.69 (dd, J=9.9, 8.7 Hz, 1H), 3.63-3.56 (m, 2H), 3.51 (dt, J=9.9, 2.6 Hz, 1H), 3.41 (t, J=11.8 Hz, 1H), 0.91 (s, 9H), 0.09 (s, 3H), 0.07 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@H:11]2[CH2:15][O:14][C@@H:13]([CH2:16][O:17][C:18](=[O:25])[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[O:12]2)=[C:4](Cl)[N:3]=1.[CH:27]1([NH2:30])[CH2:29][CH2:28]1>C(O)C>[NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@H:11]2[CH2:15][O:14][C@@H:13]([CH2:16][O:17][C:18](=[O:25])[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[O:12]2)=[C:4]([NH:30][CH:27]2[CH2:29][CH2:28]2)[N:3]=1
Reactant: NC1CC1
Reactant: Nc1nc(Cl)c2ncn([C@H]3CO[C@@H](COC(=O)c4ccccc4)O3)c2n1
Solvent: CCO
Product: Nc1nc(NC2CC2)c2ncn([C@H]3CO[C@@H](COC(=O)c4ccccc4)O3)c2n1
Reaction time: 0.5 h
Yield: 97.6 %

Procedure:
Benzoic acid 4(R)-(2-amino-6-chloro-purin-9-yl)-[1,3]dioxolan-2(R)-ylmethyl ester (1266 g, cis/trans:1.9/1), ethanol (20 L), and cyclopropylamine (643 g) were refluxed for 16 hours. The reaction mixture was cooled and concentrated to a residue. The residue was dissolved in dichloromethane (3.6 L) and agitated with an aqueous solution of sodium bicarbonate for 30 minutes. After settling the organic layer was separated and the aqueous was back-extracted with dichloromethane (2×750 mL). The combined organic layers were concentrated to give a yellow-brown foam (1304 g) of material (9) which is suitable for reaction in the subsequent deprotection step in NH3/MeOH.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:17]3[CH:16]=[CH:15][S:14][C:13]=3[CH:12]=[C:11]([C:18]([OH:20])=O)[CH:10]=2)=[CH:5][CH:4]=1.[CH2:21]([N:23](CC)[CH2:24][CH3:25])[CH3:22]>C1(C)C=CC=CC=1.S(Cl)(Cl)=O.C(NCC)C>[CH2:21]([N:23]([CH2:24][CH3:25])[C:18]([C:11]1[CH:10]=[C:9]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[C:17]2[CH:16]=[CH:15][S:14][C:13]=2[CH:12]=1)=[O:20])[CH3:22]
Reactant: COc1ccc(-c2cc(C(=O)O)cc3sccc23)cc1
Reactant: CCN(CC)CC
Solvent: O=S(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CCNCC
Product: CCN(CC)C(=O)c1cc(-c2ccc(OC)cc2)c2ccsc2c1

Procedure:
The reaction is carried out as in Example 1, starting with 4-(4-methoxyphenyl)benzo[b]thiophene-6-carboxylic acid (2.9 g) in toluene (30 cc) and thionyl chloride (2.3 cc) and triethylamine (4.3 cc) and diethylamine (1.1 cc) in anhydrous toluene (30 cc). After chromatography of the residue on silica gel using a cyclohexane:ethyl acetate (80:20 by volume) mixture as the eluent and recrystallization in isopropyl ether, N,N-diethyl-4-(4-methoxyphenyl)benzo[b]thiophene-6-carboxamide (1.12 g), m.p. 88° C., is isolated.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[C:10]([C:11]([NH:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[CH:9][N:8]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[C:5]2=[N:6][CH:7]=1.[F:26][C:27]1[CH:35]=[C:34]2[C:30]([CH:31]=[N:32][NH:33]2)=[CH:29][CH:28]=1.CC(C)([O-])C.[Na+]>O1CCOCC1.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[C:14]([NH:13][C:11]([C:10]1[C:4]2[C:5](=[N:6][CH:7]=[C:2]([N:33]3[C:34]4[C:30](=[CH:29][CH:28]=[C:27]([F:26])[CH:35]=4)[CH:31]=[N:32]3)[N:3]=2)[N:8]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[CH:9]=1)=[O:12])([CH3:17])([CH3:16])[CH3:15]
Reactant: Fc1ccc2cn[nH]c2c1
Reactant: CC(C)(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Br)nc12
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CC(C)(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-n3ncc4ccc(F)cc43)nc12
Temperature: 125 °C

Procedure:
To a stirred solution of 2-bromo-N-tert-butyl-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (140 mg, 328 μmol), 6-fluoro-1H-indazole (43.0 mg, 316 mmol) in dioxane (2 mL) was added sodium tert-butoxide (66.8 mg, 695 μmol) and bis(tri-tert-butylphosphine)palladium(0) (16.1 mg, 31.6 μmol). The mixture was degassed then heated in sealed tube at 125° C. for two days. The mixture was cooled, filtered through celite, the cake washed with ethyl acetate, and the combined filtrates were concentrated in vacuo. Purification by chromatography (silica, 24 g Analogix column, 0-40% ethyl acetate in hexanes) gave N-tert-Butyl-2-(6-fluoro-1H-indazol-1-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide. 1H NMR (CDCl3) δ: 9.17 (s, 1H), 8.36 (s, 1H), 8.29 (dd, J=9.3, 2.3 Hz, 1H), 8.26 (d, J=1.0 Hz, 1H), 7.80 (dd, J=8.8, 5.0 Hz, 1H), 7.66 (s, 1H), 7.12 (td, J=8.9, 2.3 Hz, 1H), 5.72 (s, 2H), 3.54-3.63 (m, 2H), 1.62 (s, 9H), 0.90-1.00 (m, 2H), −0.03 (s, 9H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([S:8]([C:11]2[CH:12]=[N:13][C:14]3[C:19]([CH:20]=2)=[CH:18][CH:17]=[CH:16][C:15]=3I)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[CH2:22]([N:29]1[CH2:33][CH2:32][C@H:31]2[CH2:34][NH:35][CH2:36][C@@H:30]12)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[CH2:22]([N:29]1[CH2:33][CH2:32][C@H:31]2[CH2:34][N:35]([C:15]3[CH:16]=[CH:17][CH:18]=[C:19]4[C:14]=3[N:13]=[CH:12][C:11]([S:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=3)(=[O:10])=[O:9])=[CH:20]4)[CH2:36][C@@H:30]12)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=S(=O)(c1cccc(F)c1)c1cnc2c(I)cccc2c1
Reactant: c1ccc(CN2CC[C@H]3CNC[C@H]32)cc1
Product: O=S(=O)(c1cccc(F)c1)c1cnc2c(N3C[C@@H]4CCN(Cc5ccccc5)[C@@H]4C3)cccc2c1

Procedure:
0.157 g of 8-((3aS,6aS)-1-benzylhexahydropyrrolo[3,4-b]pyrrol-5(1H)-yl)-3-(3-fluorophenylsulfonyl)quinoline were prepared by analogy to the method of Example 27 by coupling of 3-(3-fluorophenylsulfonyl)-8-iodoquinoline with (3aS,6aS)-1-benzyloctahydropyrrolo[3,4-b]pyrrole
Reaction SMILES: Cl.[C:2]([C:4]1([NH:7][C:8]([C@@H:10]2[CH2:14][C@@H:13]([S:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[C:24]([F:27])([F:26])[F:25])(=[O:17])=[O:16])[CH2:12][NH:11]2)=[O:9])[CH2:6][CH2:5]1)#[N:3].[F:28][C:29]1[CH:37]=[CH:36][C:32]([C:33](O)=[O:34])=[CH:31][CH:30]=1>>[C:2]([C:4]1([NH:7][C:8]([C@@H:10]2[CH2:14][C@@H:13]([S:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[C:24]([F:27])([F:25])[F:26])(=[O:17])=[O:16])[CH2:12][N:11]2[C:33](=[O:34])[C:32]2[CH:36]=[CH:37][C:29]([F:28])=[CH:30][CH:31]=2)=[O:9])[CH2:5][CH2:6]1)#[N:3]
Reactant: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3ccccc3C(F)(F)F)CN2)CC1
Reactant: O=C(O)c1ccc(F)cc1
Agent: Cl
Product: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3ccccc3C(F)(F)F)CN2C(=O)c2ccc(F)cc2)CC1

Procedure:
L54. (2S,4R)-4-(2-trifluoromethyl-benzenesulfonyl)-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-amide hydrochloride from experiment K5 was coupled with 4-fluorobenzoic acid in analogy to experiment A1 to give (2S,4R)-1-(4-fluoro-benzoyl)-4-(2-trifluoromethyl-benzenesulfonyl)-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-amide as a pale yellow solid. MS: 510.2 [M+H]+.
Reaction SMILES: COC1C=CC2C(=O)C3C(OC=2C=1)=CC=CC=3.[CH3:18][O:19][C:20]1[CH:35]=[C:34]([O:36][CH3:37])[C:23]([C:24]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2OC)=[O:25])=[C:22]([OH:38])[CH:21]=1>>[CH3:37][O:36][C:34]1[C:23]2[C:24](=[O:25])[C:26]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[O:38][C:22]=2[CH:21]=[C:20]([O:19][CH3:18])[CH:35]=1
Reactant: COc1cc(O)c(C(=O)c2ccccc2OC)c(OC)c1
Agent: COc1ccc2c(=O)c3ccccc3oc2c1
Product: COc1cc(OC)c2c(=O)c3ccccc3oc2c1
Yield: 83 %

Procedure:
Based on the method of producing 3-methoxyxanthone (5M), 2.20 g (7.75 mmol) of 4 6-dimethoxy-2-hydroxy-2'-methoxybenzophenone (11a) and 2,4,6-trimethoxy-2'-hydroxyphenone (11b) were reacted to give 1.65g (6.45 mmol) of 1,3-dimethoxyxanthone (12M) as colorless powder. The yield was 83%. The physical properties of the compound were measured and are listed below.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[S:11]([O-:13])=[O:12].[Na+:14].[CH2:15]([CH2:17][NH2:18])[OH:16].Cl>O>[OH:16][CH2:15][CH2:17][NH:18][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[S:11]([O-:13])=[O:12].[Na+:14]
Reactant: NCCO
Reactant: O=[N+]([O-])c1ccc(Cl)c(S(=O)[O-])c1
Agent: Cl
Agent: [Na+]
Solvent: O
Product: O=[N+]([O-])c1ccc(NCCO)c(S(=O)[O-])c1
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
122 g of sodium 2-chloro-5-nitrobenzenesulphinate are kneaded together with 150 g of ethanolamine, and the mixture is gradually heated to 100° C. After 30 minutes at 100° C. 500 ml of water are added, the reaction solution is neutralised with hydrochloric acid, and the sodium 2-(2-hydroxyethyl)amino-5-nitrobenzenesulphinate is isolated as above, by salting out.