Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][C:5]([NH2:7])=[O:6].[CH3:8][N:9]([CH3:14])[CH2:10][CH2:11][CH2:12]N.N>>[CH3:8][N:9]([CH3:14])[CH2:10][CH2:11][CH2:12][NH:7][C:5](=[O:6])[CH2:4][CH2:3][O:2][CH3:1]
Reactant: CN(C)CCCN
Reactant: COCCC(N)=O
Agent: N
Product: COCCC(=O)NCCCN(C)C

Procedure:
103.1 g (1.0 mole) of 3-methoxypropionamide are heated with 107.3 g (1.05 mole) of 3-dimethylaminopropylamine for 6 hours in a temperature range of 145°-170° C. until the evolution of ammonia is complete. In the subsequent distillation in a high vacuum 176 g (0.93 mole=93.5% of the theoretical yield) of a colorless liquid are obtained having Bp0.1 of 97°-99° C.
Reaction SMILES: [CH2:1]([NH:3][NH2:4])[CH3:2].[F:5][C:6]1[CH:15]=[C:14]2[C:9]([CH:10]=[CH:11][CH:12]=[N:13]2)=[CH:8][C:7]=1[CH2:16][C:17]1[N:21]2[N:22]=[C:23]([C:26](=O)[CH3:27])[CH:24]=[CH:25][C:20]2=[N:19][CH:18]=1>>[CH2:1]([NH:3]/[N:4]=[C:26](/[C:23]1[CH:24]=[CH:25][C:20]2[N:21]([C:17]([CH2:16][C:7]3[CH:8]=[C:9]4[C:14](=[CH:15][C:6]=3[F:5])[N:13]=[CH:12][CH:11]=[CH:10]4)=[CH:18][N:19]=2)[N:22]=1)\[CH3:27])[CH3:2]
Reactant: CCNN
Reactant: CC(=O)c1ccc2ncc(Cc3cc4cccnc4cc3F)n2n1
Product: CCN/N=C(\C)c1ccc2ncc(Cc3cc4cccnc4cc3F)n2n1
Yield: 32 %

Procedure:
The title compound was prepared from ethyl hydrazine and 1-[3-(7-fluoro-quinolin-6-ylmethyl)-imidazo[1,2-b]pyridazin-6-yl]-ethanone in analogy to the synthesis of example 1 in 32% yield. 1H-NMR (400 MHz, MeOH -d4) δ ppm 8.81 (dd, 1H), 8.27 (d, 1H), 7.92 (d, 1H), 7.88 (d, 1H), 7.78 (d, 1H), 7.69 (d, 1H), 7.54 (s, 1H), 7.47 (q, 1H), 4.59 (s, 2H), 3.38 (q, 2H), 2.13 (s, 3H), 1.22 (t, 3H). LCMS (method A): [MH]+=363, tR=5.32 min.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9]([NH:12][C:13]2[CH:21]=[C:20]3[C:16]([C:17]([C:23](=[O:27])[C:24](Cl)=[O:25])=[CH:18][N:19]3[CH3:22])=[CH:15][CH:14]=2)(=[O:11])=[O:10])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[NH3:28]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([S:9]([NH:12][C:13]2[CH:21]=[C:20]3[C:16]([C:17]([C:23](=[O:27])[C:24]([NH2:28])=[O:25])=[CH:18][N:19]3[CH3:22])=[CH:15][CH:14]=2)(=[O:11])=[O:10])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: N
Reactant: Cn1cc(C(=O)C(=O)Cl)c2ccc(NS(=O)(=O)c3cc(Cl)cc(Cl)c3)cc21
Solvent: C1CCOC1
Product: Cn1cc(C(=O)C(N)=O)c2ccc(NS(=O)(=O)c3cc(Cl)cc(Cl)c3)cc21
Reaction time: 3.5 h

Procedure:
400 mg [6-(3,5-dichloro-phenylsulphonylamino)-1-methyl-1H-indol-3-yl]-oxo-acetyl-chloride are dissolved in 1.5 ml tetrahydrofuran, combined with 550 μl concentrated ammonia (32% solution in water) and stirred for 3.5 hours. The solvent is eliminated in vacuo and the residue is extracted from a little methanol. The solid is suction filtered and dried in vacuo.
Reaction SMILES: [C:1]1([CH:7]([CH:14]2[CH2:19][CH2:18][N:17]([O:20][C:21]([C:23]([CH3:26])([CH3:25])[CH3:24])=[O:22])[CH2:16][CH2:15]2)[CH2:8][C:9](OCC)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[Na+]>C1COCC1>[C:1]1([CH:7]([CH:14]2[CH2:19][CH2:18][N:17]([O:20][C:21]([C:23]([CH3:26])([CH3:25])[CH3:24])=[O:22])[CH2:16][CH2:15]2)[CH2:8][CH:9]=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)CC(c1ccccc1)C1CCN(OC(=O)C(C)(C)C)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)ON1CCC(C(CC=O)c2ccccc2)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 99.3 %

Procedure:
To a solution of ethyl 3-phenyl-3-(1-tert-butylcarbonyloxypiperidin-4-yl)propionoate (5.3 g, 14.6 mmol) in THF (100 mL) was added lithium aluminium hydride (14.6 mL, 1M, 14.6 mmol) dropwise over 20 min. The resulting mixture was stirred at 0° C. for 1 h. 2M aqueous sodium hydroxide (20 mL) was added dropwise. The mixture was filtered through Celite®, washing with ethyl acetate (3×25 mL). The filtrate and washings were combined and evaporated. The residue was dissolved in ethyl acetate (100 mL) and the resulting solution washed with water (3×50 mL), dried and evaporated to give the sub-titled compound (4.6 g); NMR: 0.9-1 (m, 2H) 1.25 (m, 1H) 1.35 (s, 9H) 1.5-2 (m, 5H) 2.6 (m, 2H) 3.1 (m, 2H) 3.8-4 (m, 2H) 4.2 (t, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:16]3[C:11]([CH2:12][CH2:13][CH2:14][CH2:15]3)=[CH:10][C:9]2=[O:17])=[CH:4][CH:3]=1.CC(C)([O-])C.[K+].[CH3:24][N:25]([CH3:29])[CH2:26][CH2:27]Cl>>[CH3:24][N:25]([CH3:29])[CH2:26][CH2:27][O:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH:16]3[C:11]([CH2:12][CH2:13][CH2:14][CH2:15]3)=[CH:10][C:9]2=[O:17])=[CH:6][CH:7]=1
Reactant: O=C1C=C2CCCCC2N1c1ccc(O)cc1
Reactant: CN(C)CCCl
Agent: CC(C)(C)[O-]
Agent: [K+]
Product: CN(C)CCOc1ccc(N2C(=O)C=C3CCCCC32)cc1
Temperature: 60 °C
Yield: 58.3 %

Procedure:
In accordance with the procedure described in Example 1b), 22.9 g (0.1 mol) of 1-(4-hydroxyphenyl)2-oxo-2,4,5,6,7,7 a-hexahydro-indole were added to a solution of potassium tertiary-butoxide [potassium metal: 3.9 g (1.1 mol); tertiary-butanol, 100 cm3 ], and this solution was added to 11.8 g (0.11 mole) of 2-dimethylamino-1-chloroethane. After heating for 6 hours at 60° C, the crude product of the reaction was isolated as in Example 1b), and purified by crystallisation from hexane. 17.5 g (yield 57%) of 1-[4-(2-dimethylaminoethoxy)-phenyl]-2-oxo-2,4,5,6,7,7a-hexahydro-indole, m.p. 90° C, were obtained.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:10][CH2:9][CH:8]([CH2:11][O:12]CC2C=CC=CC=2)[CH2:7][CH2:6]1)=[O:4]>CO.[Pd]>[CH3:1][O:2][C:3]([CH:5]1[CH2:10][CH2:9][CH:8]([CH2:11][OH:12])[CH2:7][CH2:6]1)=[O:4]
Reactant: COC(=O)C1CCC(COCc2ccccc2)CC1
Agent: [Pd]
Solvent: CO
Product: COC(=O)C1CCC(CO)CC1

Procedure:
4-Benzyloxymethyl-cyclohexanecarboxylic acid methyl ester (340 mg, 1.30 mmol) is dissolved in MeOH (15 mL). In the presence of catalytic amount of 10% Pd/C, the reaction mixture is stirred for 3 hours under H2 (10 bar). After removal of 10% Pd/C, solvent is evaporated. The desired product, 4-hydroxymethyl-cyclohexanecarboxylic acid methyl ester, is obtained (160 mg, 72%) after purification using silica gel column chromatography (eluent: EtOAc/hexane).
Reaction SMILES: [OH:1][CH:2]([C:5]1[CH:9]=[CH:8][S:7][CH:6]=1)[C:3]#[CH:4].C([Mg]Cl)#C.S1C=CC(C=O)=C1.Br[C:22]1[CH:30]=[CH:29][CH:28]=[C:27]2[C:23]=1/[C:24](=[CH:32]/[C:33]1[NH:34][CH:35]=[CH:36][C:37]=1[O:38][CH3:39])/[C:25](=[O:31])[NH:26]2>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.CN(C=O)C.CCN(CC)CC>[OH:1][CH:2]([C:5]1[CH:9]=[CH:8][S:7][CH:6]=1)[C:3]#[C:4][C:22]1[CH:30]=[CH:29][CH:28]=[C:27]2[C:23]=1/[C:24](=[CH:32]/[C:33]1[NH:34][CH:35]=[CH:36][C:37]=1[O:38][CH3:39])/[C:25](=[O:31])[NH:26]2
Reactant: C#CC(O)c1ccsc1
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2cccc(Br)c21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: C#C[Mg]Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cc[nH]c1/C=C1\C(=O)Nc2cccc(C#CC(O)c3ccsc3)c21

Procedure:
Using Method D above, 3-hydroxy-3-(thiophen-3-yl)-1-propyne (131 mg, 0.95 mmol) (prepared by the addition of ethynylmagnesium chloride (Aldrich) to 3-thiophenecarboxaldehyde (Aldrich) according to Method A above) was coupled to (Z)-4-bromo-1,3-dihydro-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (107 mg, 0.34 mmol) (Starting Material 1) using (Ph3P)2PdCl2 (32 mg) (Aldrich) and CuI (17 mg) (Aldrich) as catalyst in DMF (3 mL) and Et3N (3 mL) as solvent at 70° C. or 18 h, yielding rac-(Z)-1,3-dihydro-4-[3-hydroxy-3-(thiophen-3-yl)-1-propynyl]-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one. (Yield 93 mg, 72%).
Reaction SMILES: [ClH:1].C([O:6][C:7]([C:9]1[CH:10]=[N:11][C:12]([N:15]2[C:19](=[O:20])[C:18]([N:21]3[CH:25]=[CH:24][N:23]=[N:22]3)=[CH:17][NH:16]2)=[CH:13][CH:14]=1)=[O:8])(C)(C)C>C(Cl)Cl.C(O)(C(F)(F)F)=O>[ClH:1].[O:20]=[C:19]1[N:15]([C:12]2[N:11]=[CH:10][C:9]([C:7]([OH:8])=[O:6])=[CH:14][CH:13]=2)[NH:16][CH:17]=[C:18]1[N:21]1[CH:25]=[CH:24][N:23]=[N:22]1
Reactant: CC(C)(C)OC(=O)c1ccc(-n2[nH]cc(-n3ccnn3)c2=O)nc1
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)c1ccc(-n2[nH]cc(-n3ccnn3)c2=O)nc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
50 mg (0.1 mmol) of the compound from Example 62 are dissolved in 1 ml of a 1:1 mixture of methylene chloride and TFA and the mixture is stirred at RT for 1 h. The reaction solution is concentrated in vacuo, the residue is suspended in 2 ml 1 N hydrochloric acid and the suspension is then lyophilized.
Reaction SMILES: C(Br)C.[Mg].[CH:5]1[C:10]([OH:11])=[CH:9][CH:8]=[CH:7][C:6]=1[CH3:12].[CH2:13]=[O:14].Cl>C1COCC1.C1(C)C=CC=CC=1.CN1CCCN(C)C1=O>[OH:11][C:10]1[CH:5]=[C:6]([CH3:12])[CH:7]=[CH:8][C:9]=1[CH:13]=[O:14]
Reactant: Cc1cccc(O)c1
Reactant: C=O
Agent: Cl
Agent: [Mg]
Solvent: C1CCOC1
Solvent: CN1CCCN(C)C1=O
Solvent: CCBr
Product: Cc1ccc(C=O)c(O)c1
Yield: 21.1 %

Procedure:
A solution of ethyl bromide (13.8 ml) in THF (100 ml) was added dropwise, under nitrogen to a stirred mixture of magnesium turnings (4.44 g) in dry THF (50 ml). After complete Grignard formation a solution of m-cresol (20 g) in THF (100 ml) was added dropwise. The resulting suspension was stirred for 15 mins before a solution of 1,3-dimethyl-3,4,5,6-tetrahydropyrimidin-2-one (23.7 g) in dry toluene (300 ml) was added dropwise followed by paraformaldehyde (13.85 g). The resulting suspension was heated at reflux overnight. After cooling the suspension was treated with 10% HCl (200 ml) and filtered before separating the organic phase. The organic extracts were washed with water (4×100 ml), dried and evaporated to a yellow crystalline solid (11 g). Low temperature crystallisation from ether gave the title compound as a white crystalline solid (5.31 g). A second crop (0.695 g) was also obtained.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][NH:15][C:16]1[CH:21]=[CH:20][N:19]=[C:18]([NH:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[CH:24]=2)[N:17]=1)=O)(C)(C)C>FC(F)(F)C(O)=O>[Cl:29][C:25]1[CH:24]=[C:23]([NH:22][C:18]2[N:17]=[C:16]([NH:15][CH2:14][CH:9]3[CH2:10][CH2:11][CH2:12][CH2:13][NH:8]3)[CH:21]=[CH:20][N:19]=2)[CH:28]=[CH:27][CH:26]=1
Reactant: CC(C)(C)OC(=O)N1CCCCC1CNc1ccnc(Nc2cccc(Cl)c2)n1
Solvent: O=C(O)C(F)(F)F
Product: Clc1cccc(Nc2nccc(NCC3CCCCN3)n2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 7 %

Procedure:
2-{[2-(3-chlorophenylamino)pyrimidin-4-ylamino]methyl}-piperidine-1-carboxylic acid tert-butyl ester, 15, is dissolved in neat trifluoroacetic acid (3 mL) and stirred at room temperature for 3 hours. The reaction is concentrated in vacuo and the residue partitioned between EtOAc and sat. NaHCO3. The organic layer is dried (MgSO4), concentrated in vacuo, and purified over silica (MeOH/CH2Cl2) to afford 7 mg (7% yield) of the desired compound: 1H NMR (CDCl3, 300 MHz) δ 1.50-1.63 (m, 1H), 1.70-1.92 (m, 4H), 1.95-2.10 (m, 2H), 2.88 (dt, J=12.0, 3.6 Hz, 1H), 3.30-3.40 (m, 1H), 3.52 (d, J=12.0 Hz, 1H), 3.61-3.70 (m, 1H), 3.87 (d, J=15.3 Hz, 1H) 6.01 (d, J=6.6 Hz, 1H), 7.02 (dt, J=7.5, 1.8 Hz, 1H), 7.22 (t, J=7.8 Hz, 1H), 7.25 (t, J=1.8 Hz, 1H), 7.75 (d, J=6.6 Hz, 1H), 7.96 (t, J=1.8 Hz, 1H); HRMS calcd for C16H20ClN5, 318.1485 m/z (M+H)+; observed 318.1481 m/z.
Reaction SMILES: [NH2:1][C:2]1[CH:19]=[CH:18][C:5]([O:6][C:7]2[C:16]3[NH:15][C:14](=[O:17])[CH:13]=[N:12][C:11]=3[N:10]=[CH:9][CH:8]=2)=[CH:4][C:3]=1[S:20][CH3:21].[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([N:29]=[C:30]=[O:31])=[CH:25][C:24]=1[C:32]([F:35])([F:34])[F:33]>>[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([NH:29][C:30]([NH:1][C:2]2[CH:19]=[CH:18][C:5]([O:6][C:7]3[C:16]4[NH:15][C:14](=[O:17])[CH:13]=[N:12][C:11]=4[N:10]=[CH:9][CH:8]=3)=[CH:4][C:3]=2[S:20][CH3:21])=[O:31])=[CH:25][C:24]=1[C:32]([F:33])([F:34])[F:35]
Reactant: CSc1cc(Oc2ccnc3ncc(=O)[nH]c23)ccc1N
Reactant: O=C=Nc1ccc(Cl)c(C(F)(F)F)c1
Product: CSc1cc(Oc2ccnc3ncc(=O)[nH]c23)ccc1NC(=O)Nc1ccc(Cl)c(C(F)(F)F)c1
Yield: 29 %

Procedure:
Using Method F2 with 8-(4-amino-3-(methylthio)phenoxy)pyrido[2,3-b]pyrazin-2(1H)-one and 4-chloro-3-trifluoromethylphenyl isocyanate, the title compound (15 mg, 29%) was obtained as a pale brown powder.
Reaction SMILES: C([C@H]([C@@H](C(O)=O)O)O)(O)=O.[NH2:11][C@@H:12]1[CH2:16][CH2:15][NH:14][CH2:13]1.[OH-].[Na+].[Cl-:19].[K+].[Pt+2:21].[Cl-:22].[Cl-]>O>[Pt+2:21].[Cl:19][C@@H:13]1[C@H:12]([NH2:11])[CH2:16][CH2:15][N:14]1[Cl:22]
Reactant: [Cl-]
Reactant: N[C@@H]1CCNC1
Agent: [Pt+2]
Agent: O=C(O)[C@@H](O)[C@H](O)C(=O)O
Agent: [K+]
Solvent: O
Product: N[C@@H]1CCN(Cl)[C@@H]1Cl
Temperature: 25 °C
Yield: 57.2 %

Procedure:
(3R)-3-Aminopyrrolidine D(-)-tartrate (236 mg) prepared in Reference Example 1-(1) is dissolved in water (40 ml) and thereto is added sodium hydroxide (80 mg), and the mixture is stirred at room temperature. To the solution is added platinum (II) potassium chloride (415 mg), and the mixture is stirred at room temperature overnight. The precipitated solid is removed by filtration, and the filtrate is concentrated under reduced pressure. To the residue is added water (2 ml), and the resulting crystals are separated by filtration and washed with water and acetone to give cis-dichloro-(3R)-3-aminopyrrolidine platinum (II) (200 mg) as pale yellow crystal.
Reaction SMILES: CN(C=O)C.Cl[CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:12]=[CH:13][C:14]([N+:19]([O-:21])=[O:20])=[C:15]([CH2:17][OH:18])[CH:16]=1.[N-:22]=[N+:23]=[N-:24].[Na+]>C(OCC)(=O)C>[N:22]([CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:12]=[CH:13][C:14]([N+:19]([O-:21])=[O:20])=[C:15]([CH2:17][OH:18])[CH:16]=1)=[N+:23]=[N-:24]
Reactant: O=[N+]([O-])c1ccc(OCCCCl)cc1CO
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: [N-]=[N+]=NCCCOc1ccc([N+](=O)[O-])c(CO)c1
Temperature: 70 °C
Reaction time: 8 h
Yield: 88 %

Procedure:
DMF (7.5 mL) was added to (5-(3-chloropropoxy)-2-nitrophenyl)methanol (635 mg, 0.00258 moles) and sodium azide (252 mg, 0.00387 moles) in a flask, and the resulting mixture was heated to 70° C. and stirred overnight. The reaction was diluted in ethyl acetate (100 mL) and washed twice with water (75 mL each) and once with brine (75 mL). The organic layer was dried with anhydrous magnesium sulfate, which was filtered out. The filtrate was concentrated on a rotary evaporator and dried in vacuo overnight to yield (5-(3-azidopropoxy)-2-nitrophenyl)methanol as a yellow solid (yield 88%). H NMR (400 MHz, CD2Cl2) δ 8.16 (d, J=9.1 Hz, 1H), 7.27 (d, J=2.8 Hz, 1H), 6.91 (dd, J=9.1, 2.8 Hz, 1H), 4.98 (s, 2H), 4.18 (t, J=6.0 Hz, 2H), 3.53 (t, J=6.6 Hz, 2H), 2.12-2.06 (m, 2H). 13C-NMR (100 MHz, CD2Cl2) δ 163.99, 141.22, 128.43, 114.97, 113.93, 66.15, 63.26, 48.68, 29.13 HRMS m/z: calculated for C10H12N4O4 [M+H]+, 253.0931. found, 253.0939.
Reaction SMILES: [NH2:1][C:2]1[C:10]([NH2:11])=[CH:9][CH:8]=[C:7]2[C:3]=1/[C:4](=[CH:13]/[C:14]1[NH:15][CH:16]=[CH:17][C:18]=1[O:19][CH3:20])/[C:5](=[O:12])[NH:6]2.[CH3:21][C:22](=O)[C:23](=O)[CH3:24]>C(O)C>[CH3:21][C:22]1[C:23]([CH3:24])=[N:11][C:10]2[CH:9]=[CH:8][C:7]3[NH:6][C:5](=[O:12])/[C:4](=[CH:13]\[C:14]4[NH:15][CH:16]=[CH:17][C:18]=4[O:19][CH3:20])/[C:3]=3[C:2]=2[N:1]=1
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2ccc(N)c(N)c21
Reactant: CC(=O)C(C)=O
Solvent: CCO
Product: COc1cc[nH]c1/C=C1\C(=O)Nc2ccc3nc(C)c(C)nc3c21
Yield: 100 %

Procedure:
Using Method A above, (Z)-4,5-diamino-1,3-dihydro-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (60 mg, 0.22 mmol) (Starting Material 5) was condensed with 2,3-butanedione (135 μL) (Aldrich) in ethanol (3 ml) at reflux to give (Z)-7,9-dihydro-2,3-dimethyl-9-[(3-methoxy-1H-pyrrol-2-yl)methylene]-8H-pyrrolo-[3,2-f]quinoxalin-8-one in 100% yield.
Reaction SMILES: [CH3:1][N:2]1[C:6]([N:7]2[CH2:12][CH2:11][CH:10]([NH:13]C(=O)OC(C)(C)C)[CH2:9][CH2:8]2)=[C:5]([NH2:21])[CH:4]=[N:3]1.C(OC([NH:29][C:30]1[S:34][C:33]([C:35]2[C:40]([F:41])=[CH:39][CH:38]=[CH:37][C:36]=2[F:42])=[N:32][C:31]=1[C:43](O)=[O:44])=O)(C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>>[NH2:29][C:30]1[S:34][C:33]([C:35]2[C:40]([F:41])=[CH:39][CH:38]=[CH:37][C:36]=2[F:42])=[N:32][C:31]=1[C:43]([NH:21][C:5]1[CH:4]=[N:3][N:2]([CH3:1])[C:6]=1[N:7]1[CH2:8][CH2:9][CH:10]([NH2:13])[CH2:11][CH2:12]1)=[O:44]
Reactant: Cn1ncc(N)c1N1CCC(NC(=O)OC(C)(C)C)CC1
Reactant: CC(C)(C)OC(=O)Nc1sc(-c2c(F)cccc2F)nc1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: Cn1ncc(NC(=O)c2nc(-c3c(F)cccc3F)sc2N)c1N1CCC(N)CC1
Yield: 21 %

Procedure:
Following the procedures as described in Example 113, tert-butyl 1-(1-methyl-4-amino-1H-pyrazol-5-yl)piperidin-4-ylcarbamate, 5-(tert-butoxycarbonylamino)-2-(2,6-difluorophenyl)thiazole-4-carboxylic acid, and HATU were reacted to give 108 as a white solid (27 mg, 21%) over two steps. 1H NMR (400 MHz, DMSO) δ 8.70 (s, 1H), 7.60-7.37 (m, 4H), 7.27 (t, J=8.7, 2H), 3.62 (s, 3H), 3.12-2.92 (m, 4H), 2.66 (dd, J=11.9, 8.2, 1H), 1.77 (d, J=9.5, 2H), 1.36 (td, J=15.3, 4.7, 2H). ESIMS m/z=434.1 (M+1).
Reaction SMILES: [BH4-].[Na+].[CH2:3]([N:10]1[CH2:17][CH:16]2[CH:12]([C:13](=[O:21])[C:14]3[CH:20]=[CH:19][S:18][C:15]=32)[CH2:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>CO>[CH2:3]([N:10]1[CH2:17][CH:16]2[CH:12]([CH:13]([OH:21])[C:14]3[CH:20]=[CH:19][S:18][C:15]=32)[CH2:11]1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: O=C1c2ccsc2C2CN(Cc3ccccc3)CC12
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OC1c2ccsc2C2CN(Cc3ccccc3)CC12
Reaction time: 8 h

Procedure:
NaBH4 (1664 mg, 44 mmol) was added in portions to a solution of the product of step e) (1183 mg, 4.40 mmol) in methanol at 0° C. The reaction mixture was allowed to come to room temperature and was stirred overnight. The solvent was evaporated and the residue was diluted with brine (50 ml) and extracted with ethyl acetate (2×50 mL). The combined organic extracts were dried with MgSO4 and solvent evaporated in vacuo to afford the subtitle compound (1192 mg, quantitative conversion) that was used without further purification. MS calculated for C16H17NOS +H: 272, observed: 272.
Reaction SMILES: [CH:1]1([N:6]2[C:10]3[N:11]=[C:12]([NH2:15])[N:13]=[CH:14][C:9]=3[C:8]3[CH:16]=[CH:17][N:18]=[C:19]([F:20])[C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.[Si:21]([O:28][CH2:29][CH:30]1[CH2:35][CH2:34][N:33]([C:36]2[CH:37]=[CH:38][C:39](Cl)=[N:40][CH:41]=2)[CH2:32][CH2:31]1)([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.CC(C)([O-])C.[Na+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[Si:21]([O:28][CH2:29][CH:30]1[CH2:31][CH2:32][N:33]([C:36]2[CH:37]=[CH:38][C:39]([NH:15][C:12]3[N:13]=[CH:14][C:9]4[C:8]5[CH:16]=[CH:17][N:18]=[C:19]([F:20])[C:7]=5[N:6]([CH:1]5[CH2:2][CH2:3][CH2:4][CH2:5]5)[C:10]=4[N:11]=3)=[N:40][CH:41]=2)[CH2:34][CH2:35]1)([C:24]([CH3:27])([CH3:25])[CH3:26])([CH3:23])[CH3:22]
Reactant: CC(C)(C)[Si](C)(C)OCC1CCN(c2ccc(Cl)nc2)CC1
Reactant: Nc1ncc2c3ccnc(F)c3n(C3CCCC3)c2n1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: C1COCCO1
Product: CC(C)(C)[Si](C)(C)OCC1CCN(c2ccc(Nc3ncc4c5ccnc(F)c5n(C5CCCC5)c4n3)nc2)CC1
Temperature: 120 °C
Yield: 0.1 %

Procedure:
A 10 mL reaction vessel was charged with compound 245 (100 mg, 369 mmol), compound 281 (126 mg, 369 mmol), tris(dibenzylideneacetone)dipalladium (0) (25.3 mg, 27.6 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethyl-9H-xanthene (32.0 mg, 55.3 mmol), sodium t-butoxide (70.8 mg, 737 mmol), and dioxane (1.5 mL).). The reaction was purged with argon and heated with microwave energy (300 W) for 2 hours at 120° C. The resulting solution was added to ethyl acetate (40 mL) and washed with water (30 mL) and brine (30 mL). The organic phase was dried (MgSO4) and evaporated to give an orange oil. Silica gel chromatography (gradient elution hexanes+2.5% TEA/0-35% ethyl acetate+2.5% TEA) afforded compound 282 as a yellow solid (121 mg, 57%).
Reaction SMILES: CO[C:3]([CH2:5][CH2:6][C@H:7]([NH2:11])[C:8]([OH:10])=[O:9])=[O:4].C(CC(=O)C)(=O)C.[C:19]([NH2:23])(C)(C)[CH3:20].C(N)C>CO>[NH2:11][C@H:7]([C:8]([OH:10])=[O:9])[CH2:6][CH2:5][C:3]([NH:23][CH2:19][CH3:20])=[O:4]
Reactant: CC(C)(C)N
Reactant: COC(=O)CC[C@H](N)C(=O)O
Agent: CCN
Solvent: CO
Solvent: CC(=O)CC(C)=O
Product: CCNC(=O)CC[C@H](N)C(=O)O
Temperature: 60 °C
Yield: 66.7 %

Procedure:
First, 5.0 g (31 mmol) of L-glutamic acid-γ-methyl ester was suspended in 15 mL of methanol. To this, 3.4 g (34 mmol) of acetylacetone and 2.3 g (31 mmol) of t-butylamine were added. The mixture was heated at 60° C. for 2 hours. Subsequently, 20 g (310 mmol) of 70% ethylamine was added to the mixture and the same procedure as in Example 1 was performed to obtain 3.6 g of theanine (yield: 66.7%). The obtained theanine had the same purity as high as in Example 1.
Reaction SMILES: [C:1]([O:5][C:6](=[O:49])[N:7]([C:10]1[C:14]2[CH:15]=[N:16][C:17]([NH:19]C(OCC3C=CC=CC=3)=O)=[CH:18][C:13]=2[N:12]([C:30]([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[N:11]=1)[CH2:8][CH3:9])([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[C:1]([O:5][C:6](=[O:49])[N:7]([C:10]1[C:14]2[CH:15]=[N:16][C:17]([NH2:19])=[CH:18][C:13]=2[N:12]([C:30]([C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=2)([C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)[C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[N:11]=1)[CH2:8][CH3:9])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCN(C(=O)OC(C)(C)C)c1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2cc(NC(=O)OCc3ccccc3)ncc12
Agent: [Pd]
Solvent: CO
Product: CCN(C(=O)OC(C)(C)C)c1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2cc(N)ncc12
Reaction time: 5 h
Yield: 74.5 %

Procedure:
To a solution of tert-butyl(6-(((benzyloxy)carbonyl)amino)-1-trityl-1H-pyrazolo[4,3-c]pyridin-3-yl)(ethyl)carbamate (0.2 g, 0.31 mmol) in MeOH (50 mL) was added Pd on carbon (10%, 0.2 g) and the contents were stirred under an atmosphere of H2 (3.0 Kg/cm2). After 5 h, the suspension was filtered through a pad of celite, and the solvent was evaporated under reduced pressure to afford the title compound (0.12 g, 75% yield) and was taken directly for the next step. MS ESI calc'd. for C32H33N5O2 [M+H]+ 520. Found 520.
Reaction SMILES: CS(O)(=O)=O.[NH2:6][CH2:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[C:13](=[O:17])[N:12]([CH:18]1[CH2:23][CH2:22][C:21](=[O:24])[NH:20][C:19]1=[O:25])[CH2:11]2.[C:26]([C:30]1[CH:38]=[CH:37][C:33]([C:34](Cl)=[O:35])=[CH:32][CH:31]=1)([CH3:29])([CH3:28])[CH3:27].Cl>C(#N)C>[C:26]([C:30]1[CH:31]=[CH:32][C:33]([C:34]([NH:6][CH2:7][C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[C:13](=[O:17])[N:12]([CH:18]2[CH2:23][CH2:22][C:21](=[O:24])[NH:20][C:19]2=[O:25])[CH2:11]3)=[O:35])=[CH:37][CH:38]=1)([CH3:29])([CH3:27])[CH3:28]
Reactant: NCc1ccc2c(c1)CN(C1CCC(=O)NC1=O)C2=O
Reactant: CC(C)(C)c1ccc(C(=O)Cl)cc1
Agent: CS(=O)(=O)O
Agent: Cl
Solvent: CC#N
Product: CC(C)(C)c1ccc(C(=O)NCc2ccc3c(c2)CN(C2CCC(=O)NC2=O)C3=O)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 89 %

Procedure:
To a stirred mixture of 3-(5-aminomethyl-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione methanesulfonate (0.50 g, 1.4 mmol) and 4-tert-butylbenzoyl chloride (0.28 g, 1.4 mmol) in acetonitrile (30 mL) at 0° C. was added TEA (0.28 g, 2.8 mmol) dropwise over 10 min. The mixture was stirred at ambient temperature for 2 h and then 10% aqueous HCl solution (30 mL) was added. The solid precipitate was filtered, washed with water (30 mL) and dried in vacuo providing 4-tert-butyl-N-[2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-ylmethyl]-benzamide as a white solid (0.54 g, 92% yield); mp 238-240° C.; HPLC, Waters Symmetry C-18, 3.9×150 mm, 5 μm, 1 ml/min, 240 nm, 40/60 CH3CN/0.1% H3PO4, 4.89 (99.23%); 1H NMR (DMSO-d6) δ 1.30 (s, 9H, t-butyl), 1.91-2.08 (m, 1H, CHH), 2.27-2.45 (m, 1H, CHH), 2.54-2.67 (m, 1H, CHH), 2.81-3.01 (m, 1H, CHH), 4.30 (d, 1H, CHH), 4.44 (d, 1H, CHH), 4.59 (d, J=5.5 Hz, 2H, CH2 and CHH), 5.10 (dd, 1H, CH), 7.40-7.58 (m, 4H, Ar), 7.69 (d, 1H, Ar), 7.85 (d, J=8.1 Hz, 2H, Ar), 9.08 (t, 1H, NH), 10.99 (s, 1H, NH); 13C NMR (DMSO-d6) δ 22.49, 30.92, 31.20, 34.59, 42.63, 47.12, 51.56, 121.95, 122.91, 125.08, 125.35, 126.97, 127.11, 129.17, 130.32, 131.38, 142.36, 144.10, 154.11, 166.12, 167.93, 170.98, 172.85; LCMS: MH=434; Anal. Calcd for C25H27N3O4+3.0H2O: C, 68.41; H, 6.34; N, 9.57. Found: C, 68.54; H, 6.47; N, 9.18.