Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[O:12])[NH:4][N:3]=1.O[CH2:14][C:15]([C:17]1[CH:21]=[C:20]([CH3:22])[O:19][N:18]=1)=O.FC(F)(F)C(O)=O>C1(C)C=CC=CC=1>[CH3:22][C:20]1[O:19][N:18]=[C:17]([C:15]2[N:3]3[NH:4][C:5](=[O:12])[C:6]4[C:11]([C:2]3=[N:1][CH:14]=2)=[CH:10][CH:9]=[CH:8][CH:7]=4)[CH:21]=1
Reactant: Nc1n[nH]c(=O)c2ccccc12
Reactant: Cc1cc(C(=O)CO)no1
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Product: Cc1cc(-c2cnc3c4ccccc4c(=O)[nH]n23)no1
Yield: 42.8 %

Procedure:
4-Amino-1-phthalazinone (2.28 g, 14.2 mmol) [Angew. (1967) 6(2) 173-4] and 2-hydroxy-1-(5-methylisoxazol-3-yl)ethanone (2.0 g, 14.2 mmol) were suspended in toluene (100 ml) and trifluoroacetic acid (5 ml) was added. The suspension was heated at reflux under Dean & Stark conditions, for 24 hours. The solvent was then removed in vacuo and the residue was purified by chromatography on silica gel eluting with 10% methanol:dichloromethane, to provide the title product (1.62 g, 43%), 1H NMR (360 MHz, d6-DMSO) 2.50 (3H, s), 5.96 (2H, br s), 7.79-8.22 (4H, m) 11.48 (1H, s).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15]([C:18]3[N:23]=[CH:22][N:21]=[C:20]([C:24](=[O:30])[C:25]([N:27]([CH3:29])[CH3:28])=[O:26])[CH:19]=3)[CH:16]=2)[NH:11][CH:10]=1.[BH4-].[Na+]>C(O)C>[OH:30][CH:24]([C:20]1[CH:19]=[C:18]([C:15]2[CH:16]=[C:17]3[C:9]([C:4]4[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=4[O:2][CH3:1])=[CH:10][NH:11][C:12]3=[N:13][CH:14]=2)[N:23]=[CH:22][N:21]=1)[C:25]([N:27]([CH3:28])[CH3:29])=[O:26]
Reactant: COc1ccccc1-c1c[nH]c2ncc(-c3cc(C(=O)C(=O)N(C)C)ncn3)cc12
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: COc1ccccc1-c1c[nH]c2ncc(-c3cc(C(O)C(=O)N(C)C)ncn3)cc12
Temperature: 25 °C

Procedure:
A solution of 2-{6-[3-(2-Methoxy-phenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-pyrimidin-4-yl}-N,N-dimethyl-2-oxo-acetamide (25 mg, 0.062 mmole), in ethanol (0.4 mL), was cooled to 0° C. in an ice bath and sodium borohydride (7 mg, 0.186 mmole) added in one portion. The solution was removed from the cooling bath, maintained at ambient temperature for 15 min, heated to 50° C., and maintained for an additional 15 min. After cooling to ambient temperature, water (0.2 mL) was added followed by saturated ammonium chloride (0.2 mL). The reaction mixture was concentrated to remove most of the ethanol, diluted with ethyl acetate (10 mL), and the organic layer washed with saturated sodium bicarbonate (5 mL). The resulting organic layer was dried over magnesium sulfate, filtered, and concentrated. The crude product was dissolved in DMSO and purified by mass triggered reverse phase HPLC to afford pure 2-hydroxy-2-{6-[3-(2-methoxy-phenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-pyrimidin-4-yl}-N,N-dimethyl-acetamide as a white solid. (2.3 mg, 9.2%). MS: m/z 404.2 (M+H+). 1H NMR (500 MHz, DMSO-d6) δ 2.87 (s, 3H), 3.13 (s, 3H), 3.83 (s, 3H), 5.57 (d, J=8.0 Hz, 1H), 6.08 (s, J=8.5 Hz, 1H), 7.09 (t, 1H), 7.17 (d, J=8.5 Hz, 1H), 7.34 (t, 1H), 7.58 (d, J=7.5 Hz. 1H), 7.79 (s, 1H), 8.24 (s, 1H), 8.74 (s, 1H), 9.08 (s, 1H), 9.12 (s, 1H), 12.17 (s, 1H).
Reaction SMILES: [N:1]1[NH:2][C:3]([NH2:6])=[N:4][CH:5]=1.[O:7]1[CH2:12][CH2:11][O:10][C:9]2[CH:13]=[C:14]([C:17](=O)[CH2:18][C:19](OCC)=[O:20])[CH:15]=[CH:16][C:8]1=2>C(O)(=O)C>[O:7]1[CH2:12][CH2:11][O:10][C:9]2[CH:13]=[C:14]([C:17]3[NH:6][C:3]4[N:2]([N:1]=[CH:5][N:4]=4)[C:19](=[O:20])[CH:18]=3)[CH:15]=[CH:16][C:8]1=2
Reactant: CCOC(=O)CC(=O)c1ccc2c(c1)OCCO2
Reactant: Nc1ncn[nH]1
Solvent: CC(=O)O
Product: O=c1cc(-c2ccc3c(c2)OCCO3)[nH]c2ncnn12
Temperature: 120 °C
Reaction time: 24 h
Yield: 14.8 %

Procedure:
A mixture of 2H-1,2,4-triazol-3-amine (200 mg, 2.38 mmol, 1.00 equiv), acetic acid (3 mL), and ethyl 3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-3-oxopropanoate (600 mg, 2.40 mmol, 1.01 equiv) was stirred for 24 hr at 120° C. and then concentrated to dryness. The resulting solid was washed with MeOH and collected by filtration. The solid was dissolved in 15 mL of NH4OH (aq.) and filtered. The filtrate was adjusted to pH 5 with HOAc. The resulting solid was collected by filtration and washed with water. The solid was dried to get 95 mg (15%) of 5-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-[1,2,4]triazolo[1,5-α]pyrimidin-7(4H)-one as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]2[O:13][CH:10]2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:14]([NH:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C(O)C>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH:10]([OH:13])[CH:11]([N:21]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:12]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CC2OC2C1
Reactant: c1ccc(CNCc2ccccc2)cc1
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CC(O)C(N(Cc2ccccc2)Cc2ccccc2)C1
Yield: 15.8 %

Procedure:
3.7 g (0.02 mole) of 1-t-butoxycarbonyl-3,4-epoxypyrrolidine (prepared as described in Preparation 8) were dissolved in 15 ml of ethanol. 7.88 g (0.04 mole) of dibenzylamine were added to the solution, and the mixture was heated under reflux for 10 hours. At the end of this time, the solvent was removed by evaporation under reduced pressure, and the residue was subjected to column chromatography through silica gel, eluted with a 12:88 by volume mixture of ethyl acetate and toluene, to give 1.21 g of 1-t-butoxycarbonyl-3-dibenzylamino-4-hydroxypyrrolidine as a pale yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][C:12]1[C:13]([C:25]([O:27][CH3:28])=[O:26])=[C:14]([CH2:18][CH2:19][CH2:20][CH2:21][C:22]([OH:24])=O)[CH:15]=[CH:16][CH:17]=1)(=[O:10])=[O:9].FC(F)(F)C(OC(=O)C(F)(F)F)=O.[O-]S(C(F)(F)F)(=O)=O.[Ga+3].[O-]S(C(F)(F)F)(=O)=O.[O-]S(C(F)(F)F)(=O)=O>ClC(Cl)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][C:12]1[C:13]([C:25]([O:27][CH3:28])=[O:26])=[C:14]2[CH2:18][CH2:19][CH2:20][CH2:21][C:22](=[O:24])[C:15]2=[CH:16][CH:17]=1)(=[O:9])=[O:10]
Reactant: COC(=O)c1c(CCCCC(=O)O)cccc1NS(=O)(=O)c1ccccc1F
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Ga+3]
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: CC(Cl)Cl
Product: COC(=O)c1c(NS(=O)(=O)c2ccccc2F)ccc2c1CCCCC2=O
Temperature: 90 °C
Reaction time: 1.5 h
Yield: 76.4 %

Procedure:
A solution of Example 510E (3.74 g, 9.13 mmol) in dichloroethane (183 mL) was treated with trifluoroacetic anhydride (2.58 mL, 18.3 mmol) and gallium (III) triflate (0.944 g, 1.83 mmol), stirred at 90° C. for 1.5 hours, and cooled to room temperature. The reaction was quenched with saturated aqueous sodium bicarbonate (200 mL), and the aqueous layer was extracted with CH2Cl2 (4×50 mL). The combined organic layers were dried (MgSO4), filtered, and concentrated. The concentrate was purified by flash chromatography (7:3 hexanes/ethyl acetate) to provide the desired product (2.73 g, 76%). MS (ESI(+)) m/e 392 (M+H)+, 409 (M+NH4)+, 414 (M+Na)+; MS (ESI(−)) m/e 390 (M−H)−; 1H NMR (300 MHz, DMSO-d6) δ 10.46 (br s, 1H), 7.74 (m, 2H), 7.52 (d, 1H), 7.43 (dd, 1H), 7.35 (td, 1H), 7.25 (d, 1H), 3.70 (s, 3H), 2.67 (t, 2H), 2.61 (m, 2H), 1.72 (m, 2H), 1.60 (m, 2H).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]2[C:17](=[O:33])[N:18]([C:29]([CH3:32])([CH3:31])[CH3:30])[S:19](=[O:28])(=[O:27])[C:20]=2[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:11][CH:10]=1)C1C=CC=CC=1.B(F)(F)F.CCOCC.CSC>C(Cl)Cl>[C:29]([N:18]1[C:17](=[O:33])[C:16]([NH:15][C:12]2[CH:13]=[CH:14][C:9]([OH:8])=[CH:10][CH:11]=2)=[C:20]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[S:19]1(=[O:27])=[O:28])([CH3:32])([CH3:30])[CH3:31]
Reactant: CC(C)(C)N1C(=O)C(Nc2ccc(OCc3ccccc3)cc2)=C(c2ccccc2)S1(=O)=O
Agent: FB(F)F
Solvent: CCOCC
Solvent: CSC
Solvent: ClCCl
Product: CC(C)(C)N1C(=O)C(Nc2ccc(O)cc2)=C(c2ccccc2)S1(=O)=O
Temperature: 25 °C
Reaction time: 41 h
Yield: 42 %

Procedure:
4-{[4-(Benzyloxy)phenyl]amino}-2-tert-butyl-5-phenylisothiazol-3(2H)-one 1,1-dioxide (0.330 g, 0.71 mmol) was dissolved in dry DCM (40 ml). Boron trifluoride diethyl etherate (1.01 g, 7.13 mmol) and dimethyl sulfide (0.443 g, 7.13 mmol) were added and the reaction mixture was stirred at rt for 41 h. The solvent was evaporated and the residue was dissolved in EtOAc (150 ml) The mixture was washed with water (200 ml), dried (MgSO4), filtered and evaporated. The residue was purified by silica gel column chromatography using a heptane and EtOAc (70:30) as eluant to give the title compound (0.111 g, 42%). 1H NMR (500 MHz, CD3OD): δ 7.21-7.16 (m, 1H), 7.13-7.05 (m 4H), 6.63-6.59 (m, 2H), 6.40-6.36 (m, 2H), 1.74 (s, 9H); 13C NMR (125 MHz, CD3OD): δ 161.2, 155.9, 133.9, 130.7, 130.2, 129.5, 128.8, 126.8, 125.5, 115.7, 62.3, 27.9; Mass Spectrum: M+H+ 373.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[CH:4]=O.COP([CH2:17][C:18](=[O:20])[CH3:19])(=O)OC.C([O-])([O-])=O.[K+].[K+]>O>[F:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1/[CH:4]=[CH:17]/[C:18](=[O:20])[CH3:19]
Reactant: O=Cc1ccc(F)cc1F
Reactant: COP(=O)(CC(C)=O)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CC(=O)/C=C/c1ccc(F)cc1F
Temperature: 0 °C
Yield: 78.1 %

Procedure:
A two necked flask was charged with 2,4-difluorobenzaldehyde (4.0 g, 28.1 mmol) and (2-oxo-propyl)-phosphonic acid dimethyl ester (5.78 g, 33.0 mmol) and cooled down at 0° C. K2CO3 (7.62 g, 55.1 mmol) in H2O (14 mL) was added dropwise. Stirring was continued over night at RT. The product was extracted with EtOAc, and the organic phase was dried over Na2SO4. Flash chromatography (SiO2, Heptane/EtOAc 1:3) afforded 4.0 g (79%) of the title compound as alight yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH:13]=[N:14][C:15]([NH:17]C(=O)OCCCC)=[CH:16][C:11]=3[N:10]([C:25]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[N:9]=2)=[CH:4][CH:3]=1>Cl.C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH:13]=[N:14][C:15]([NH2:17])=[CH:16][C:11]=3[N:10]([C:25]([C:38]3[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=3)([C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[N:9]=2)=[CH:4][CH:3]=1
Reactant: CCCCOC(=O)Nc1cc2c(cn1)c(-c1ccc(F)cc1)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: CCOC(C)=O
Product: Nc1cc2c(cn1)c(-c1ccc(F)cc1)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 95.2 %

Procedure:
tent-Butyl (3-(4-fluorophenyl)-1-trityl-1H-pyrazolo[4,3-c]pyridin-6-yl)carbamate (403 mg, 0.706 mmol) was dissolved in HCl (4 M in dioxane, 6 mL) and stirred at room temperature for four hours. The reaction mixture was diluted with ethyl acetate and washed with NaOH (1 N) and brine. The aqueous layer was reextracted with 3:1 chloroform/IPA and the combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo to give 3-(4-fluorophenyl)-1-trityl-1H-pyrazolo[4,3-c]pyridin-6-amine (359.1 mg, 0.672 mmol, 95%), which was carried onto the next step without further purification. MS ESI calc'd. For C31H23FN4 [M+1]+ 471, found 471.
Reaction SMILES: [NH2:1][CH:2]1[CH2:14][CH2:13][C:12]2[NH:11][C:10]3[CH:9]=[CH:8][C:7]([C:15]#[N:16])=[CH:6][C:5]=3[C:4]=2[CH2:3]1.C(N(CC)CC)C.Cl[C:25]([O:27][CH3:28])=[O:26]>CS(C)=O>[CH3:28][O:27][C:25](=[O:26])[NH:1][C@H:2]1[CH2:3][C:4]2[C:5]3[C:10](=[CH:9][CH:8]=[C:7]([C:15]#[N:16])[CH:6]=3)[NH:11][C:12]=2[CH2:13][CH2:14]1
Reactant: COC(=O)Cl
Reactant: N#Cc1ccc2[nH]c3c(c2c1)CC(N)CC3
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: COC(=O)N[C@@H]1CCc2[nH]c3ccc(C#N)cc3c2C1

Procedure:
Combine 6-amino-6,7,8,9-tetrahydro-5H-carbazole-3-carbonitrile (2.4 mmol, 0.5 g) and triethylamine (4.7 mmol, 0.66 mL) in DMSO (10 mL) with 15 stirring. Add methyl chloroformate (3.6 mmol, 275 μL) and stir the resulting mixture at room temperature for 5-10 min. Quench with water (35 mL) and dilute the reaction mixture with ethyl acetate (200 mL). Separate the layers and wash the organic layer with with brine (100 mL). Back wash the brine layer with ethyl acetate (2×100 mL) and dry the combined organic layers with magnesium sulfate. Filter and concentrate in vacuo to provide crude product that is used without further purification. LCMS of the reaction mixture prior to workup gave masses 270.0 (APCI-pos) and 268.0 (APCI-neg) for the desired product.
Reaction SMILES: [CH3:1][C:2]([CH3:9])([CH2:5][CH2:6][CH2:7][CH3:8])[C:3]#[N:4].CCOCC.[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[Na+]>O>[CH3:1][C:2]([CH3:9])([CH2:5][CH2:6][CH2:7][CH3:8])[CH2:3][NH2:4]
Reactant: CCCCC(C)(C)C#N
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCOCC
Product: CCCCC(C)(C)CN
Reaction time: 2 h

Procedure:
A solution of 2,2-dimethylcapronitrile (10.0 g., 0.078 mole) in 100 ml. of ether is added slowly to a suspension of lithium aluminum hydride (6.0 g., 0.158 mole) in 200 ml. of ether while maintaining the reaction at 0°-5°. After stirring the reaction mixture for an additional 2 hr., at 0.5°, the mixture is hydrolyzed by sequentially adding 6.0 ml. of water, 6.0 ml. of 15% sodium hydroxide solution, and finally 18 ml. of water. The hydrolyzed mixture is stirred for an additional hour, filtered and the ether phase concentrated under reduced pressure. Distillation of residual material provides 2,2-dimethylhex-1-ylamine.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[C:12]([F:18])[C:11]=2[F:19])=[O:9])=[CH:6][N:5]=[C:4]([NH:20][CH:21]2[CH2:26][CH2:25][N:24]([S:27]([CH2:30][CH2:31][CH2:32]Cl)(=[O:29])=[O:28])[CH2:23][CH2:22]2)[N:3]=1.[NH2:34][CH:35]([CH2:39][CH2:40][OH:41])[CH2:36][CH2:37][OH:38].CCOC(CC(CC(OCC)=O)=O)=O.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C(OCC)C>[NH2:1][C:2]1[C:7]([C:8]([C:10]2[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[C:12]([F:18])[C:11]=2[F:19])=[O:9])=[CH:6][N:5]=[C:4]([NH:20][CH:21]2[CH2:26][CH2:25][N:24]([S:27]([CH2:30][CH2:31][CH2:32][NH:34][CH:35]([CH2:39][CH2:40][OH:41])[CH2:36][CH2:37][OH:38])(=[O:29])=[O:28])[CH2:23][CH2:22]2)[N:3]=1
Reactant: NC(CCO)CCO
Reactant: COc1ccc(F)c(F)c1C(=O)c1cnc(NC2CCN(S(=O)(=O)CCCCl)CC2)nc1N
Agent: CCOC(=O)CC(=O)CC(=O)OCC
Agent: [Al+3]
Agent: [H-]
Solvent: CCOCC
Product: COc1ccc(F)c(F)c1C(=O)c1cnc(NC2CCN(S(=O)(=O)CCCNC(CCO)CCO)CC2)nc1N

Procedure:
The compound was prepared from [4-amino-2-[1-(3-chloro-propane-1-sulfonyl)-piperidin-4-ylamino]-pyrimidin-5-yl]-(2,3-difluoro-6-methoxy-phenyl)-methanone (Example 226) and 3-amino-pentane-1,5-diol (prepared from the methyl oxime of diethyl 1,3-acetonedicarboxylate, Aldrich, by reduction with lithium aluminum hydride in diethyl ether) in an analogous manner as described in Example 227. HR-MS (ES, m/z) calculated for C25H37N6O6SF2 [(M+H)+] 587.2458, observed 587.2464.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][S:8](Cl)(=[O:10])=[O:9].C(OCC)C.[CH3:17][NH:18][CH3:19]>C(#N)C>[CH3:17][N:18]([CH3:19])[S:8]([CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][Cl:1])(=[O:10])=[O:9]
Reactant: CNC
Reactant: O=S(=O)(Cl)CCCCCCCl
Solvent: CC#N
Solvent: CCOCC
Product: CN(C)S(=O)(=O)CCCCCCCl
Reaction time: 0.33 h
Yield: 96.4 %

Procedure:
6-Chlorohexanesulfonyl chloride (6.57g, 30 mmol) was added dropwise to a solution of diethyl ether (60 ml) and a 12% acetonitrile solution of dimethylamine (24.8 g, 66 mmol) with stirring under ice-cooling. Thereafter, the mixture was stirred at the same temperature for 20 minutes. The reaction mixture was concentrated in vacuo. Thereafter, the concentrate was diluted with diethyl ether (60 ml). The resulting solution was washed twice with water (10 ml) and then with brine (10 ml), and thereafter dried over anhydrous magnesium sulfate. Subsequently, the solvent was removed by evaporation in vacuo. The crude product was purified by column chromatography on silica gel with ethyl acetate-n-hexane (1:4), to give N,N-dimethyl-6-chlorohexanesulfonamide (6.59 g) as a pale yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([C:14](=O)[CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:5]([CH:9]=[C:10]([O:12][CH3:13])[CH:11]=1)[C:6](O)=[O:7].O.[NH2:24][NH2:25]>>[CH2:15]([C:14]1[C:4]2[C:5](=[CH:9][C:10]([O:12][CH3:13])=[CH:11][C:3]=2[O:2][CH3:1])[C:6](=[O:7])[NH:25][N:24]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: COc1cc(OC)c(C(=O)Cc2ccccc2)c(C(=O)O)c1
Reactant: NN
Solvent: O
Product: COc1cc(OC)c2c(Cc3ccccc3)n[nH]c(=O)c2c1

Procedure:
This compound is obtained according to the procedure described in 1.2. by reacting unpurified 3,5-dimethoxy-2-(phenylacetyl)benzoic acid with hydrazine hydrate.
Reaction SMILES: [CH2:1]([NH:4][C:5]1[C:6]2[S:14][CH:13]=[C:12]([CH2:15][CH3:16])[C:7]=2[N:8]=[C:9](Cl)[N:10]=1)[CH:2]=[CH2:3].[CH2:17]([NH2:20])[CH:18]=[CH2:19].C(=O)([O-])O.[Na+]>>[CH2:17]([NH:20][C:9]1[N:10]=[C:5]([NH:4][CH2:1][CH:2]=[CH2:3])[C:6]2[S:14][CH:13]=[C:12]([CH2:15][CH3:16])[C:7]=2[N:8]=1)[CH:18]=[CH2:19]
Reactant: C=CCN
Reactant: C=CCNc1nc(Cl)nc2c(CC)csc12
Agent: O=C([O-])O
Agent: [Na+]
Product: C=CCNc1nc(NCC=C)c2scc(CC)c2n1
Yield: 86.3 %

Procedure:
304 mg (1.2 mmol) of 4-allylamino-2-chloro-7-ethylthieno[3,2-d]pyrimidine and 1.10 g (19.2 mmol) of allylamine were heated in a sealed tube at 140° C. for 16 hours. After completion of the reaction, the reaction mixture was allowed to resume room temperature, followed by adding a saturated aqueous sodium hydrogen carbonate solution thereto and extraction with ethyl acetate (50 ml×2). After the organic layer was washed with brine and dried over anhydrous sodium sulfate, the solvent was distilled off. The residue was purified by silica gel chromatography (eluent: ethyl acetate-hexane=1/4) to give 284 mg (yield: 86.3%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:22])[C:12]3[S:19][C:18]([CH2:20]Cl)=[CH:17][C:13]=3[N:14]([CH3:16])[CH:15]=2)=[O:9])=[CH:4][CH:3]=1.[NH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1.C(N(C(C)C)CC)(C)C>CN(C=O)C.O>[Cl:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:22])[C:12]3[S:19][C:18]([CH2:20][N:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[CH:17][C:13]=3[N:14]([CH3:16])[CH:15]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2sc(CCl)cc21
Reactant: C1COCCN1
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2sc(CN3CCOCC3)cc21
Temperature: 60 °C
Reaction time: 3 h
Yield: 85.5 %

Procedure:
A mixture of N-(4-chlorobenzyl)-2-(chloromethyl)-4-methyl-7-oxo-4,7-dihydrothieno[3,2-b]pyridine-6-carboxamide (50 mg, 0.13 mmol), morpholine (17.4 mg, 0.20 mmol) and diisopropylethylamine (35 μL, 0.20 mmol) in dry DMF (2.7 mL) was heated to 60° C., becoming a solution. The reaction was stirred for 3 hours at that temperature. After cooling to room temperature, the solution was diluted with water (5 mL). The resulting milky suspension was stirred vigorously for 30 minutes, and then left standing overnight at room temp. The mixture was filtered, and the collected solid was washed with water and dried in vacuo, leaving a white solid. Recrystallization from acetonitrile (10 mL) gave the title compound (48 mg) as a flocculent white solid.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([N:15]1[C@@H:23]2[C@@H:18]([CH2:19][CH2:20][CH2:21][CH2:22]2)[CH2:17][C@H:16]1[CH2:24][NH:25][CH2:26][C:27]1[O:28][C:29]2[CH:35]=[CH:34][CH:33]=[CH:32][C:30]=2[CH:31]=1)=O)(C)(C)C.C(N(CC)CC)C.[CH3:43][O:44][C:45]1[C:50]2[O:51][C:52]([CH3:55])([CH3:54])[O:53][C:49]=2[CH:48]=[C:47]([C:56](Cl)=[O:57])[CH:46]=1.FC(F)(F)C(O)=O>ClCCl>[O:28]1[C:29]2[CH:35]=[CH:34][CH:33]=[CH:32][C:30]=2[CH:31]=[C:27]1[CH2:26][N:25]([CH2:24][C@@H:16]1[CH2:17][C@H:18]2[C@H:23]([CH2:22][CH2:21][CH2:20][CH2:19]2)[NH:15]1)[C:56]([C:47]1[CH:46]=[C:45]([O:44][CH3:43])[C:50]2[O:51][C:52]([CH3:55])([CH3:54])[O:53][C:49]=2[CH:48]=1)=[O:57]
Reactant: CC(C)(C)OC(=O)N1[C@H](CNCc2cc3ccccc3o2)C[C@@H]2CCCC[C@@H]21
Reactant: COc1cc(C(=O)Cl)cc2c1OC(C)(C)O2
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Product: COc1cc(C(=O)N(Cc2cc3ccccc3o2)C[C@@H]2C[C@@H]3CCCC[C@@H]3N2)cc2c1OC(C)(C)O2
Temperature: 25 °C
Reaction time: 1 h
Yield: 29.4 %

Procedure:
To a solution of 45 mg (0.09 mmol) of (2S,3aS,7aS)-2-{[(benzofuran-2-ylmethyl)-amino]-methyl}-octahydro-indole-1-carboxylic acid tert-butyl ester trifluoroacetic acid salt in 1 mL dichloromethane, 28 μL (0.20 mmol) of triethylamine and 23 mg (0.10 mmol) of 7-methoxy-2,2-dimethyl-benzo[1,3]dioxole-5-carbonyl chloride were added at r.t. Stirring at r.t. for 1 hour was followed by the addition of 0.1 mL trifluoroacetic acid; 2 hours thereafter the solution was evaporated in vacuum and purified using reverse phase HPLC, mobile phase with a gradient 15-80% acetonitrile in 50 min. Fractions containing pure product were evaporated, the residue was dissolved in dichloromethane, which was washed with aqueous sodium bicarbonate, dried with anhydrous magnesium sulfate and evaporated in vacuum to yield 13 mg of the product as the free base off-white Solid. LC-MSD, m/z for C29H34N2O5 [M+H]+: 491.2. 1H NMR (400 MHz, CDCl3): δ 1.2-2.3 (m, 11 H), 1.7 (s, 6 H), 3.2-3.9 (m, 4 H), 3.9 (s, 3 H), 4.7-4.9 (m, 1 H), 4.9-5.0 (m, 1 H), 6.7 (s, 1H), 6.7-6.9 (m, 2H), 7.2-7.3 (m, 2H), 7.4-7.5 (m, 1 H), 7.5-7.6 (m, 1 H).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:9]=[C:8]([C:10]2[CH:11]=[N:12][NH:13][CH:14]=2)[S:7][CH:6]=1)=[O:4].[OH-].[Na+]>CO>[NH:12]1[CH:11]=[C:10]([C:8]2[S:7][CH:6]=[C:5]([C:3]([OH:4])=[O:2])[CH:9]=2)[CH:14]=[N:13]1
Reactant: COC(=O)c1csc(-c2cn[nH]c2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1csc(-c2cn[nH]c2)c1
Yield: 68.5 %

Procedure:
5-(1H-Pyrazol-4-yl)-thiophene-3-carboxylic acid methyl ester (2.8 g, 13.3 mmol) was dissolved in a mixture of methanol (18 mL) and a solution of aqueous sodium hydroxide (1 N, 18 mL) and the mixture stirred at 50° C. for 1.5 hours. The mixture was concentrated under vacuum and acidified with aqueous hydrochloric acid (1N). The resulting precipitate was isolated by filtration and washed with water before drying under vacuum to give the title compound as a white solid (1.77 g). LCMS m/z 195.1 [M+H]+. R.T.=3.23 min (Analytical Method 4). 1H NMR (400 MHz, d6-DMSO): δ 8.1 (s, 1H), 8.0 (m, 2H), 7.45 (s, 1H).
Reaction SMILES: C[O-].[Na+].[CH3:4][O:5][C:6]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][C:7]=1[CH:8]=O.[N:16]([CH2:19][C:20]([O:22][CH3:23])=[O:21])=[N+:17]=[N-:18].[Cl-].[NH4+]>CO>[CH3:4][O:5][C:6]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][C:7]=1[C:8]([C:6]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:7]=1)=[C:19]([N:16]=[N+:17]=[N-:18])[C:20]([O:22][CH3:23])=[O:21]
Reactant: COC(=O)CN=[N+]=[N-]
Reactant: COc1ccc(OC)c(C=O)c1
Agent: C[O-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Product: COC(=O)C(N=[N+]=[N-])=C(c1ccccc1)c1cc(OC)ccc1OC
Reaction time: 2 h
Yield: 86.6 %

Procedure:
While 23 ml of sodium methoxide (28% solution in methanol) in 40 ml of anhydrous methanol was stirred vigorously, 40 ml of a mixed methanol solution containing 4.0 g (21.1 mmol) of 2,5-dimethoxybenzaldehyde and 9.7 g (84.2 mmol) of methyl azidoacetate was added dropwise at -15° C. After completion of the addition, the reaction mixture was stirred for 2 hours. Then the reaction mixture was poured into a saturated ammonium chloride solution and extracted with ethyl acetate. The extract was washed with water and dried over magnesium sulfate. After distilling off the solvent, the residue was purified by silica gel chromatography (hexane:ethyl acetate=10:1) to provide 3.1 g of methyl 2,5-dimethoxyphenyl-α-azidocinnamate.