Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[C:9]([F:12])([F:11])[F:10])=[CH:4][CH:3]=1.[O-][CH2:15][CH3:16].[Na+]>[Cl-].C([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)C1C=CC=CC=1.C(O)C>[C:15]1([CH:16]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[C:9]([F:12])([F:11])[F:10])[CH:6]=[CH:7][CH:2]=[CH:3][CH:4]=1
Reactant: CC[O-]
Reactant: O=C(c1ccc(F)cc1)C(F)(F)F
Agent: [Cl-]
Agent: [Na+]
Agent: c1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCO
Product: Fc1ccc(C(=Cc2ccccc2)C(F)(F)F)cc1
Yield: 91 %

Procedure:
4'-Fluoro-2,2,2-trifluoroacetophenone (F. E. Herkes et al.: J. Org. Chem. 32, 1311-18 (1967)) is reacted with benzyl-triphenyl-phosphonium chloride in the presence of an ethanol solution of sodium ethoxide. 1-Phenyl-3,3,3-trifluoro-2-(4-fluorophenyl)-propene is obtained with a yield of 91%; b.p.: 110°-114° C./0.2 mm Hg, m.p.: 43°-45° C.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[S:10][C:9]([CH:11]=O)=[CH:8][C:6]=2[N:7]=1.[CH3:19][N:20]([CH3:30])[C:21](=[O:29])[CH2:22][N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1>>[Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[S:10][C:9]([CH2:11][N:26]3[CH2:25][CH2:24][N:23]([CH2:22][C:21]([N:20]([CH3:30])[CH3:19])=[O:29])[CH2:28][CH2:27]3)=[CH:8][C:6]=2[N:7]=1
Reactant: CN(C)C(=O)CN1CCNCC1
Reactant: O=Cc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Product: CN(C)C(=O)CN1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1

Procedure:
Reaction between 2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine-6-carbaldehyde 10 (Example 3) and N,N-dimethyl-2-piperazin-1-yl-acetamide using General Procedure B-3 yielded 2-[4-(2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-piperazin-1-yl]-N,N-dimethyl-acetamide.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]2([C:16]3=[CH:17][C:18]4[O:22][CH2:21][O:20][C:19]=4[CH:23]=[C:15]3[O:14][CH2:13]2)[C:5]1=[O:24].Br[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]Br.C(N(CC)CC)C>C1COCC1>[N:1]1([CH2:2][CH2:3][N:4]2[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6]3([C:16]4=[CH:17][C:18]5[O:22][CH2:21][O:20][C:19]=5[CH:23]=[C:15]4[O:14][CH2:13]3)[C:5]2=[O:24])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: BrCCCCCBr
Reactant: NCCN1C(=O)C2(COc3cc4c(cc32)OCO4)c2ccccc21
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C1N(CCN2CCCCC2)c2ccccc2C12COc1cc3c(cc12)OCO3

Procedure:
A mixture of 1′-(2-aminoethyl)spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one (0.20 g, 0.62 mmol), 1,5-dibromopentane (0.08 mL, 0.62 mmol) and triethyl amine (0.17 mL, 1.23 mmol) in THF (10.0 mL) was refluxed for 15 hrs and concentrated in vacuo to dryness. The residue was subjected to flash chromatography eluting with 10% methanol in ethyl acetate to give 1′-(2-piperidin-1-ylethyl)spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one, which was treated with 4.0 M HCl in dioxane to give the title compound (28%): mp >240° C.; 1H NMR (300 MHz, CD3OD) δ 7.40 (t, 1H), 7.27-7.11 (m, 3H), 6.51 (s, 1H), 6.17 (s, 1H), 5.86 (s, 2H), 4.91 (d, 1H), 4.71 (d, 1H), 4.40-4.13 (m, 2H), 3.95-3.84 (m, 1H), 3.66-3.37 (m, 3H), 3.14-2.96 (m, 2H), 2.06-1.45 (m, 6H); 13C NMR (75 MHz, CD3OD) δ 180.4, 157.5, 150.5, 143.8, 142.5, 133.9, 130.3, 125.3, 125.1, 120.6, 110.2, 103.9, 102.9, 94.2, 81.4, 59.7, 55.4, 54.9, 53.9, 36.4, 24.2, 22.6; MS (ES+) m/z 393 (M+1).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[C:5]([C:7]([O:9][CH3:10])=[O:8])[N:6]=1.[C:17](Cl)(=[O:19])[CH3:18].O>N1C=CC=CC=1>[C:17]([NH:1][C:2]1[S:3][C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[C:5]([C:7]([O:9][CH3:10])=[O:8])[N:6]=1)(=[O:19])[CH3:18]
Reactant: CC(=O)Cl
Reactant: COC(=O)c1nc(N)sc1-c1ccccc1
Solvent: c1ccncc1
Solvent: O
Product: COC(=O)c1nc(NC(C)=O)sc1-c1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Methyl 2-amino-5-phenyl-1,3-thiazole-4-carboxylate (3 g) was dissolved in pyridine (30 ml), and then acetyl chloride (2.73 ml) was added dropwise to the solution at 0° C. under N2 atmosphere. The reaction mixture was stirred at r.t. for 1.5 hours. Water was added to the solution at 0° C. The precipitate was filtered in vacuo, and the solid was washed with ethyl ether to give methyl 2-(acetylamino)-5-phenyl-1,3-thiazole-4-carboxylate (2.37 g) as a pale brown solid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[CH:4][C:3]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH3:18].C(=O)([O-])[O-].[K+].[K+].[CH2:25](Br)[CH3:26]>C(#N)C>[CH2:25]([O:1][C:2]1[CH:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[CH:4][C:3]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH3:18])[CH3:26]
Reactant: COC(=O)c1ccc(-c2ccccc2C)c(O)c1
Reactant: CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOc1cc(C(=O)OC)ccc1-c1ccccc1C
Temperature: 50 °C
Yield: 98.8 %

Procedure:
To a stirred solution of methyl 2-hydroxy-2′-methyl-1,1′-biphenyl-4-carboxylate (10 g, 41.2 mmol) in anhydrous ACN (100 mL) was added anhydrous potassium carbonate (17.1 g, 123.6 mmol) followed by ethyl bromide (15.4 mL, 206 mmol). The reaction mixture was heated at 50° C. for 48 hours, and then cooled to RT and filtered. The filtrate was concentrated under vacuum to afford of the title compound as brown liquid (11 g, 98%). 1H NMR (DMSO-d6, 400 MHz) δ 7.70 (1H, d), 7.62 (1H, s), 7.16-7.29 (5H, m), 4.09 (2H, q), 3.95 (3H, s), 2.15 (3H, s), 1.30 (3H, t).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[S:10])=[CH:4][CH:3]=1.[CH:11]1([N:17]=[C:18]=[O:19])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1>C1C=CC=CC=1.C(N(CC)CC)C.C([O-])(=O)CCCCCCCCCCC.C([O-])(=O)CCCCCCCCCCC.C([Sn+2]CCCC)CCC>[CH:11]1([NH:17][C:18]([O:1][C:2]2[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[S:10])=[CH:4][CH:3]=2)=[O:19])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: Oc1ccc(N=C=S)cc1
Reactant: O=C=NC1CCCCC1
Agent: CCCCCCCCCCCC(=O)[O-]
Agent: CCCC[Sn+2]CCCC
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: O=C(NC1CCCCC1)Oc1ccc(N=C=S)cc1

Procedure:
By a procedure similar to that of Example I, the above compound (3.9 g., m.p. 170°-173° C.) was prepared from 3.8 g. (0.025 m.) of p-hydroxyphenylisothiocyanate and 3.2 g. (0.025 m.) of cyclohexylisocyanate, using 50 mls. of benzene as a solvent and 3 drops each of triethylamine and dibutyltin dilaurate as catalysts.
Reaction SMILES: [N:1]1([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:6][CH2:5][O:4][C@@H:3]2[CH2:7][NH:8][CH2:9][CH2:10][C@@H:2]12.Cl[C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20].C(N(CC)CC)C>C(Cl)Cl>[N:1]1([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:6][CH2:5][O:4][C@@H:3]2[CH2:7][N:8]([C:19]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[O:20])[CH2:9][CH2:10][C@@H:2]12
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H]2CNCC[C@H]21
Reactant: O=C(Cl)OCc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCO[C@@H]2CN(C(=O)OCc3ccccc3)CC[C@H]21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To tert-butyl (4aR,8aR)-octahydro-1H-pyrido[3,4-b][1,4]oxazine-1-carboxylate (250 mg, 1.03 mmol) dissolved in DCM (2 mL) was added benzyl chloroformate (0.21 mL, 1.44 mmol). Triethylamine (0.4 mL, 2.89 mmol) was added slowly and stirred for 3 hours at room temperature. The reaction was quenched with saturated aqueous sodium bicarbonate. The aqueous layer was extracted with DCM, and the combined organic layers were dried over sodium sulfate, filtered, and concentrated to afford (4aR,8aR)-6-benzyl 1-tert-butyl hexahydro-1H-pyrido[3,4-b][1,4]oxazine-1,6(7H)-dicarboxylate. 1H NMR (500 MHz, CDCl3) δ 7.40-7.30 (m, 5H), 5.12 (s, 2H), 4.40-4.15 (m, 1H), 3.93-3.87 (m, 1H), 3.86-3.79 (m, 1H), 3.77-3.71 (m, 1H), 3.42-3.29 (m, 2H), 3.19-3.13 (m, 1H), 2.81-2.48 (m, 2H), 1.76-1.66 (m, 1H), 1.58 (s, 2H), 1.45 (s, 9H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][CH2:10][C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:23][N:24]([CH3:29])[S:25](Cl)(=[O:27])=[O:26]>ClCCl>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]([CH2:10][C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1)[S:25]([N:24]([CH3:29])[CH3:23])(=[O:27])=[O:26]
Reactant: CN(C)S(=O)(=O)Cl
Reactant: Fc1ccc(NCc2cccnc2)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CN(C)S(=O)(=O)N(Cc1cccnc1)c1ccc(F)cc1F
Temperature: 25 °C

Procedure:
A 3.3 g. portion of 3-(2,4-difluorophenylaminomethyl)pyridine was dissolved in 15 ml. of dichloromethane, and 2.8 g. of potassium carbonate and 3.6 g. of dimethylsulfamoyl chloride were added. The mixture was stirred at ambient temperature for several days, and was then stirred under reflux for 4 hours. The mixture was then cooled, and extracted with 20 ml. of aqueous sodium bicarbonate and with 20 ml. of water, and was dried and evaporated to an oil. The oil was dissolved in dichloromethane and chromatographed over silica gel, eluting with 9:1 dichloromethane:ethyl acetate to obtain 2.1 g. of the desired product.
Reaction SMILES: S(=O)(=O)(O)O.C(OC[O:10][C:11]1[CH:12]=[C:13]([CH:22]=[CH:23][C:24]2[CH:25]=[C:26]([CH:30]=[CH:31][CH2:32][CH2:33][CH2:34][CH:35]([OH:39])[CH:36]([CH3:38])[CH3:37])[CH:27]=[CH:28][CH:29]=2)[CH:14]=[C:15]([O:17]COCC)[CH:16]=1)C>CO.C1COCC1>[OH:39][CH:35]([CH:36]([CH3:38])[CH3:37])[CH2:34][CH2:33][CH2:32][CH:31]=[CH:30][C:26]1[CH:25]=[C:24]([CH:23]=[CH:22][C:13]2[CH:12]=[C:11]([OH:10])[CH:16]=[C:15]([OH:17])[CH:14]=2)[CH:29]=[CH:28][CH:27]=1
Reactant: CCOCOc1cc(C=Cc2cccc(C=CCCCC(O)C(C)C)c2)cc(OCOCC)c1
Agent: O=S(=O)(O)O
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)C(O)CCCC=Cc1cccc(C=Cc2cc(O)cc(O)c2)c1

Procedure:
In a manner similar to Example 1(j), by reacting 0.3 ml of concentrated sulphuric acid in 2.5 ml of methanol with 126 mg (0.27 mmol) of 8-{3-[2-(3,5-bis-ethoxymethoxyphenyl)vinyl]phenyl}-2-methyloct-7-en-3-ol in 2.5 ml of THF, after purification on a silica column (ethyl acetate 40-heptane 60), a beige powder (m=60 mg; Y=63%) is obtained.
Reaction SMILES: [C:1]1([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:6]=[CH:5][C:4]([O:7][CH2:8][CH2:9][CH2:10][C:11]#[C:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][C@H:20]([O:24][CH3:25])[C:21]([OH:23])=[O:22])=[CH:15][CH:14]=2)=[CH:3][CH:2]=1.[H][H]>CO.[Pd]>[C:1]1([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:2]=[CH:3][C:4]([O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][C@H:20]([O:24][CH3:25])[C:21]([OH:23])=[O:22])=[CH:15][CH:14]=2)=[CH:5][CH:6]=1
Reactant: CO[C@@H](Cc1ccc(C#CCCCOc2ccc(-c3ccccc3)cc2)cc1)C(=O)O
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CO[C@@H](Cc1ccc(CCCCCOc2ccc(-c3ccccc3)cc2)cc1)C(=O)O

Procedure:
The title compound was prepared as follows: (2S)-3-{4-[5-(Biphenyl-4-yloxy)-pent-1-ynyl]-phenyl}-2-methoxy-propionic acid from Example 21 (0.08 mmol) was dissolved in methanol (10 mL). Palladium 10% on activated carbon (0.004 g, 0.004 mmol) was added and the solution saturated with hydrogen (1 Atm) and stirred for 5 hours. The mixture was filtered through a pad of celite and concentrated under vacuum. The residue was purified by column chromatography. MS (ES) for C27H30O4 [M−H]−: 417.3.
Reaction SMILES: [S:1]1[C:5]([C:6]([OH:8])=O)=[CH:4][C:3]2[CH:9]=[CH:10][CH:11]=[CH:12][C:2]1=2.[NH2:13][C:14]1[CH:15]=[CH:16][C:17]([N:22]2[CH2:27][CH2:26][CH:25]([CH2:28][CH2:29][OH:30])[CH2:24][CH2:23]2)=[C:18]([CH:21]=1)[C:19]#[N:20]>>[C:19]([C:18]1[CH:21]=[C:14]([NH:13][C:6]([C:5]2[S:1][C:2]3[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=3[CH:4]=2)=[O:8])[CH:15]=[CH:16][C:17]=1[N:22]1[CH2:27][CH2:26][CH:25]([CH2:28][CH2:29][OH:30])[CH2:24][CH2:23]1)#[N:20]
Reactant: N#Cc1cc(N)ccc1N1CCC(CCO)CC1
Reactant: O=C(O)c1cc2ccccc2s1
Product: N#Cc1cc(NC(=O)c2cc3ccccc3s2)ccc1N1CCC(CCO)CC1
Yield: 34.6 %

Procedure:
By the reaction and treatment in the same manner as in Example 6 using benzo[b]thiophene-2-carboxylic acid (1.5 g) and 5-amino-2-[4-(2-hydroxyethyl)piperidin-1-yl]benzonitrile (1.4 g), the title compound (0.8 g) was obtained. melting point: 218° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:9]2[S:13][C:12]([N:14]3[CH2:20][CH2:19][CH2:18][NH:17][C:16](=[O:21])[CH2:15]3)=[N:11][CH:10]=2)[CH:5]=[C:6]([CH3:8])[CH:7]=1.Cl[C:23]1[N:28]=[C:27]([CH:29]2[CH2:31][CH2:30]2)[CH:26]=[CH:25][N:24]=1.C(=O)([O-])[O-].[K+].[K+].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>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]>[CH:29]1([C:27]2[CH:26]=[CH:25][N:24]=[C:23]([NH:1][C:2]3[CH:3]=[C:4]([C:9]4[S:13][C:12]([N:14]5[CH2:20][CH2:19][CH2:18][NH:17][C:16](=[O:21])[CH2:15]5)=[N:11][CH:10]=4)[CH:5]=[C:6]([CH3:8])[CH:7]=3)[N:28]=2)[CH2:31][CH2:30]1
Reactant: Clc1nccc(C2CC2)n1
Reactant: Cc1cc(N)cc(-c2cnc(N3CCCNC(=O)C3)s2)c1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: Cc1cc(Nc2nccc(C3CC3)n2)cc(-c2cnc(N3CCCNC(=O)C3)s2)c1
Temperature: 90 °C
Yield: 69.2 %

Procedure:
In an oven-dried vial was added 4-[5-(3-amino-5-methylphenyl)-1,3-thiazol-2-yl]-1,4-diazepan-2-one (Intermediate XX, 77 mg, 0.26 mmol), 2-chloro-4-cyclopropylpyrimidine (44 mg, 0.26 mmol), potassium carbonate (70 mg, 0.51 mmol), XPhos (61 mg, 0.13 mmol), and Pd2(dba)3 (23 mg, 0.025 mmol). The tube was evacuated and backfilled with argon 3×. Degassed t-amyl alcohol (0.85 ml) was added, and the tube was sealed and heated to 90° C. for 15 h. The mixture was then cooled to room temperature and purified by Combiflash (0-70% ethyl acetate/hexanes followed by 0-20% methanol/dichloromethane) to provide 77 mg (0.18 mmol, 72%) of 4-(5-{3-[(4-cyclopropylpyrimidin-2-yl)amino]-5-methylphenyl}-1,3-thiazol-2-yl)-1,4-diazepan-2-one as a yellow foam. MS APCI: [M+H]+ m/z 421.2. 1H NMR (500 MHz, CDCl3) δ 8.16 (d, J=5.6 Hz, 1H), 7.75 (s, 1H), 7.44 (s, 2H), 7.13 (s, 1H), 6.91 (s, 1H), 6.65 (d, J=5.5 Hz, 1H), 6.00 (s, 1H), 4.27 (d, J=13.9 Hz, 2H), 3.98-3.79 (m, 2H), 3.38 (dd, J=5.6 Hz, 11.2 Hz, 2H), 2.33 (s, 3H), 2.04 (d, J=4.0 Hz, 3H), 1.26 (t, J=7.3 Hz, 2H), 1.11 (dd, J=3.2 Hz, 8.3 Hz, 2H). rhSyk=+++.
Reaction SMILES: [F:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[CH:4][C:3]=1[C:12]1[C:21]2[N:20]=[CH:19][CH:18]=[N:17][C:16]=2[C:15]([C:22](O)=[O:23])=[CH:14][CH:13]=1.[NH2:25][C:26]1[N:31]=[CH:30][C:29]([CH2:32][N:33]([CH3:39])[CH2:34][CH2:35][N:36]([CH3:38])[CH3:37])=[CH:28][CH:27]=1>>[CH3:37][N:36]([CH3:38])[CH2:35][CH2:34][N:33]([CH2:32][C:29]1[CH:28]=[CH:27][C:26]([NH:25][C:22]([C:15]2[C:16]3[N:17]=[CH:18][CH:19]=[N:20][C:21]=3[C:12]([C:3]3[CH:4]=[C:5]([O:10][CH3:11])[CH:6]=[C:7]([O:8][CH3:9])[C:2]=3[F:1])=[CH:13][CH:14]=2)=[O:23])=[N:31][CH:30]=1)[CH3:39]
Reactant: COc1cc(OC)c(F)c(-c2ccc(C(=O)O)c3nccnc23)c1
Reactant: CN(C)CCN(C)Cc1ccc(N)nc1
Product: COc1cc(OC)c(F)c(-c2ccc(C(=O)Nc3ccc(CN(C)CCN(C)C)cn3)c3nccnc23)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
The title compound was prepared in analogy to the procedure described in Step 14.1 but using 8-(2-fluoro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylic acid (Step 94.1), N-(6-amino-pyridin-3-ylmethyl)-N,N′,N′-trimethyl-ethane-1,2-diamine (prepared as described in Example 26 but using N,N,N′-trimethyl-ethane-1,2-diamine in Step 26.2) and stirring the reaction mixture for 18 h at rt. The crude product was purified by silica gel column chromatography (DCM/MeOH/NH3aq, 94:5:1). Title compound: ESI-MS: 519.2 [M+H]+; tR=3.26 min (System 1); TLC: Rf=0.13 (DCM/MeOH/NH3aq, 94:5:1).
Reaction SMILES: [CH2:1]1[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH2:6][CH2:5][CH2:4][N:3]3[C:2]1=[O:13].[Cl:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19](Cl)=[O:20]>>[Cl:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([C:9]1[CH:8]=[C:7]2[C:12]3=[C:11]([CH2:1][C:2](=[O:13])[N:3]3[CH2:4][CH2:5][CH2:6]2)[CH:10]=1)=[O:20]
Reactant: O=C1Cc2cccc3c2N1CCC3
Reactant: O=C(Cl)CCCCCl
Product: O=C(CCCCCl)c1cc2c3c(c1)CC(=O)N3CCC2
Yield: 64.9 %

Procedure:
Using 5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-2(1H)-one (3.46 g) and 5-chlorovaleryl chloride (3.4 g) according to the same method as that of Reference Example 1, the title compound (3.78 g) was obtained as pale yellow crystals having a melting point of 89 to 90° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([O:9][CH3:10])[C:3]=1[CH2:11][C:12]([O:14]C)=[O:13].[OH-].[K+].O>CO>[Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([O:9][CH3:10])[C:3]=1[CH2:11][C:12]([OH:14])=[O:13]
Reactant: COC(=O)Cc1c(Cl)cc(C)cc1OC
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1cc(C)cc(Cl)c1CC(=O)O

Procedure:
75 g (328 mmol) of methyl 2-chloro-4-methyl-6-methoxyphenylacetate according to Ex. XXXI-1 are dissolved in 750 ml of methanol and then heated at 80° C. together with 55.20 g (984 mmol) of potassium hydroxide and 250 ml of water for 12 h. The methanol is removed using a rotary evaporator, the residue is adjusted to pH 3 and the precipitated product is filtered off and dried.
Reaction SMILES: [N:1]([C:4]1[N:12]=[C:11]2[C:7]([N:8]=[CH:9][N:10]2[CH2:13][O:14][CH2:15][CH2:16][OH:17])=[C:6]([NH2:18])[N:5]=1)=[N+]=[N-]>[Pd].C(O)C>[NH2:1][C:4]1[N:12]=[C:11]2[C:7]([N:8]=[CH:9][N:10]2[CH2:13][O:14][CH2:15][CH2:16][OH:17])=[C:6]([NH2:18])[N:5]=1
Reactant: [N-]=[N+]=Nc1nc(N)c2ncn(COCCO)c2n1
Agent: [Pd]
Solvent: CCO
Product: Nc1nc(N)c2ncn(COCCO)c2n1
Reaction time: 3.5 h

Procedure:
A mixture of 2-azido-9-(2-hydroxyethoxymethyl)adenine (0.41g) and 10% palladium on charcoal (80mg) in ethanol (41ml) was shaken under hydrogen at 50 psi for 3.5 hours. The catalyst was removed by filtration through a celite pad and washed thoroughly with ethanol and water. The solvent was removed by evaporation under reduced pressure giving a quantitative yield (0.37g) of nearly pure (one spot on TLC) 2-amino-9-(2-hydroxyethoxymethyl)adenine, m.p. 183°-184° C. after recrystallization from n-propanol.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:17]3[C:12](=[CH:13][C:14]([F:20])=[C:15](F)[C:16]=3[F:18])[C:11](=[O:21])[C:10]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:9]2)=[CH:4][CH:3]=1.Cl.[N:28]1([CH:33]2[CH2:37][CH2:36][NH:35][CH2:34]2)[CH:32]=[CH:31][N:30]=[N:29]1.C1CCN2C(=NCCC2)CC1>C(#N)C>[F:20][C:14]1[CH:13]=[C:12]2[C:17](=[C:16]([F:18])[C:15]=1[N:35]1[CH2:36][CH2:37][CH:33]([N:28]3[CH:32]=[CH:31][N:30]=[N:29]3)[CH2:34]1)[N:8]([C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1)[CH:9]=[C:10]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:11]2=[O:21]
Reactant: CCOC(=O)c1cn(-c2ccc(F)cc2)c2c(F)c(F)c(F)cc2c1=O
Reactant: c1cn(C2CCNC2)nn1
Agent: Cl
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: CCOC(=O)c1cn(-c2ccc(F)cc2)c2c(F)c(N3CCC(n4ccnn4)C3)c(F)cc2c1=O
Temperature: 25 °C
Reaction time: 15 h

Procedure:
A solution of ethyl 1-(4-fluorophenyl)-6,7,8-trifluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylate (180 mg, 0.5 mmol), 3-(1,2,3-triazol-1-yl)-pyrrolidine hydrochloride (259 mg, 1.4 mmol) and DBU (384 mg, 2.5 mmol) in acetonitrile (20 ml) was heated at 75° C for 3 h, cooled to r.t. and stirred for another 15 h. The separated solid was filtered, successively washed with acetonitrile and ether. The white crystalline solid thus obtained was dried in vac-oven at 40° C. Yield: 135 mg, 56.7%. 1H NMR (CDCl3) δ: 1.35 (t, 3H), 2.50 (m, 2H), 3.70 (m, 1H), 3.85 (m, 2H), 4.10 (m, 1H), 4.35 (q, 2H), 5.25 (m, 1H), 7.20 (m, 2H), 7.40 (m, 2H), 7.63 (d, 1H), 7.72 (d, 1H), 7.90 (dd, 1H), 8.25 (s, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C@H:6]1[C@@H:11]([NH2:12])[CH2:10][CH2:9][N:8]([CH2:13][CH2:14][O:15][C:16]2[CH:25]=[N:24][C:23]3[C:18](=[CH:19][C:20]([O:26][CH3:27])=[CH:21][CH:22]=3)[N:17]=2)[CH2:7]1)=[O:5])[CH3:2].[O:28]=[C:29]1[NH:34][C:33]2[CH:35]=[C:36]([C:39](O)=[O:40])[CH:37]=[CH:38][C:32]=2[S:31][CH2:30]1>>[CH2:1]([O:3][C:4]([C@H:6]1[C@@H:11]([NH:12][C:39]([C:36]2[CH:37]=[CH:38][C:32]3[S:31][CH2:30][C:29](=[O:28])[NH:34][C:33]=3[CH:35]=2)=[O:40])[CH2:10][CH2:9][N:8]([CH2:13][CH2:14][O:15][C:16]2[CH:25]=[N:24][C:23]3[C:18](=[CH:19][C:20]([O:26][CH3:27])=[CH:21][CH:22]=3)[N:17]=2)[CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)[C@@H]1CN(CCOc2cnc3ccc(OC)cc3n2)CC[C@@H]1N
Reactant: O=C1CSc2ccc(C(=O)O)cc2N1
Product: CCOC(=O)[C@@H]1CN(CCOc2cnc3ccc(OC)cc3n2)CC[C@@H]1NC(=O)c1ccc2c(c1)NC(=O)CS2

Procedure:
The title compound is prepared as a yellow oil (135 mg, 71% yield) following Scheme 1 and in analogy to Example 1 using (3R,4S)-4-amino1-[2-(7-methoxy-quinoxalin-2-yloxy)-ethyl]-piperidine-3-carboxylic acid ethyl ester and 3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid as starting materials.
Reaction SMILES: C([O:5][C:6](=[O:22])[C:7]1[CH:12]=[C:11]([NH:13][CH2:14][CH2:15][CH2:16][CH:17]=[CH2:18])[N:10]=[C:9]([O:19][CH2:20][CH3:21])[CH:8]=1)(C)(C)C>FC(F)(F)C(O)=O>[CH2:20]([O:19][C:9]1[CH:8]=[C:7]([CH:12]=[C:11]([NH:13][CH2:14][CH2:15][CH2:16][CH:17]=[CH2:18])[N:10]=1)[C:6]([OH:22])=[O:5])[CH3:21]
Reactant: C=CCCCNc1cc(C(=O)OC(C)(C)C)cc(OCC)n1
Solvent: O=C(O)C(F)(F)F
Product: C=CCCCNc1cc(C(=O)O)cc(OCC)n1

Procedure:
The title compound is prepared by stirring 2-ethoxy-6-pent-4-enylamino-isonicotinic acid tert-butyl ester 18 h in neat trifluoroacetic acid. Evaporation of the TFA gives the title compound that is used in the next step without purification.
Reaction SMILES: N#N.[O-]CC.[Na+].[C:7]([O:14][CH2:15][CH3:16])(=[O:13])[C:8]([O:10]CC)=O.[CH3:17][C:18]1[C:23]([N+:24]([O-:26])=[O:25])=[CH:22][CH:21]=[CH:20][N:19]=1.[NH4+].[Cl-]>CC(O)C.O.CC#N.C1COCC1>[CH2:15]([O:14][C:7](=[O:13])[C:8]([OH:10])=[CH:17][C:18]1[C:23]([N+:24]([O-:26])=[O:25])=[CH:22][CH:21]=[CH:20][N:19]=1)[CH3:16]
Reactant: CCOC(=O)C(=O)OCC
Reactant: Cc1ncccc1[N+](=O)[O-]
Agent: CC[O-]
Agent: N#N
Agent: [Cl-]
Solvent: O
Solvent: CC#N
Solvent: CC(C)O
Product: CCOC(=O)C(O)=Cc1ncccc1[N+](=O)[O-]
Temperature: 2 °C
Reaction time: 0.33 h

Procedure:
Add tetrahydrofuran (2.7 L) to a 22-L, 3-neck flask fitted with a stirrer, temperature probe and an addition funnel fitted with a gas inlet adapter for N2, and cool to about 2° C. Add sodium ethoxide (0.409 kg, 6.02 mol, 2.0 equiv.) in one portion. One observes a slight exotherm to 2.7° C. Stir the mixture for 20 min, add diethyl oxalate (1.22 L, 9.03 mol, 3.0 equiv.) at −0.34° C. over 50 min (slightly exothermic) and then stir the mixture for 10 min. Add a solution of 2-methyl-3-nitropyridine (2a-1, 0.415 kg, 3.01 mol, 1.0 equiv.) and THF (0.625 L) at 4-9° C. over 22 min without cooling. Allow the mixture to warm to rt over 1 h. Monitor progress of the reaction by HPLC (Agilent series 1100 using the following conditions: Waters Symmetry C8 (5μ) column (3.9×150 mm), flow rate at 1.0 mL/min; CH3CN/0.1% aq. TFA, 55/45; λ=210 nm; RT: 2-methyl-3-nitropyridine 2a-1=1.8 min, 3a-1=2.7 min). Typically one observes >99% conversion to product within 2-3 h. During the reaction, a thick red precipitate forms. Cool the reaction mixture to about 1° C. and add saturated NH4Cl solution (2.0 L) at 1° C. to 9° C. Add water (5.9 L) (pH 7.4) and then add IPA (3.5 L). Stir the mixture for 1 h and collect the red colored solid by filtration. Wash the filter cake with IPA/H2O (1:4, 8.0 L), H2O (15 L) and air dry. Dry the filter cake (40° C./0.1 in Hg) to give 3a-1 (0.635 kg, 89%). 1H NMR (CDCl3) δ 1.40 (t, 3H, J=7 Hz), 4.38 (q, 2H, J=7 Hz), 7.36 (m, 2H), 8.42 (dd, 1H J=1.5, 8.4 Hz), 8.66 (dd, 1H, J=1.5, 4.8 Hz), 14.52 (2, 1H, OH).