Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:30]=[C:31](F)[CH:32]=1)[C:5]([NH:7][C:8]1[CH:9]=[CH:10][C:11]([CH3:29])=[C:12]([NH:14][C:15](=[O:28])[C:16]2[CH:21]=[CH:20][C:19]([CH2:22][N:23]([CH2:26][CH3:27])[CH2:24][CH3:25])=[CH:18][CH:17]=2)[CH:13]=1)=[O:6].[NH:34]1[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1>>[F:1][C:2]1[CH:3]=[C:4]([CH:30]=[C:31]([N:34]2[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]2)[CH:32]=1)[C:5]([NH:7][C:8]1[CH:9]=[CH:10][C:11]([CH3:29])=[C:12]([NH:14][C:15](=[O:28])[C:16]2[CH:17]=[CH:18][C:19]([CH2:22][N:23]([CH2:24][CH3:25])[CH2:26][CH3:27])=[CH:20][CH:21]=2)[CH:13]=1)=[O:6]
Reactant: C1CCNCC1
Reactant: CCN(CC)Cc1ccc(C(=O)Nc2cc(NC(=O)c3cc(F)cc(F)c3)ccc2C)cc1
Product: CCN(CC)Cc1ccc(C(=O)Nc2cc(NC(=O)c3cc(F)cc(N4CCCCC4)c3)ccc2C)cc1
Yield: 83 %

Procedure:
Using an analogous procedure to that described in Example 67 except that the reaction mixture was heated to 100° C. for 16 hours rather than for 6 days, N-[5-(3,5-difluorobenzamido)-2-methylphenyl]-4-diethylaminomethylbenzamide was reacted with piperidine. There was thus obtained the title compound in 83% yield; NMR Spectrum: (DMSOd6) 0.98 (t, 6H), 1.3-1.7 (m, 8H), 2.2 (s, 3H), 2.4-2.5 (m, 2H), 3.2-3.4 (m, 4H), 6.85-6.95 (m, 1H), 7.0-7.1 (m, 1H), 7.2-7.3 (m, 2H), 7.45 (d, 2H), 7.5-7.6 (m, 1H), 7.8 (m, 1H), 7.9 (d, 2H), 9.8 (s, 1H), 10.13 (broad s, 1H); Mass Spectrum: M+H+ 517.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[C:14]3[C:21]([CH3:24])=[N:22][O:23][C:13]=3[CH2:12][N:11]=2)=[CH:6][CH:5]=1.CC(C1C=C(C(C)C)C(S([N:40]=[N+:41]=[N-:42])(=O)=O)=C(C(C)C)C=1)C.CCOCC>CN(C=O)C>[N:40]([CH:12]1[N:11]=[C:10]([C:7]2[CH:8]=[CH:9][C:4]([Cl:3])=[CH:5][CH:6]=2)[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[C:14]2[C:21]([CH3:24])=[N:22][O:23][C:13]1=2)=[N+:41]=[N-:42]
Reactant: CC(C)c1cc(C(C)C)c(S(=O)(=O)N=[N+]=[N-])c(C(C)C)c1
Reactant: Cc1noc2c1-c1ccccc1C(c1ccc(Cl)cc1)=NC2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: Cc1noc2c1-c1ccccc1C(c1ccc(Cl)cc1)=NC2N=[N+]=[N-]
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
To a round bottom flask was added sodium hydride (0.13 g, 3.3 mmol, 60% in mineral oil). The flask was then purged with nitrogen, DMF (10 mL) was then added and the flask was cooled to 0° C. 6-(4-chlorophenyl)-1-methyl-4H-benzo[c]isoxazolo[4,5-e]azepine (930 mg, 3.0 mmol) in DMF (5 mL) was added and the reaction was allowed to stir for 45 min. Trisyl azide (1.40 g, 4.5 mmol) in DMF (5 mL) was added and the reaction was mixed at 0° C. for 1 h. The reaction poured into ether (100 mL) and washed with brine (3×). The organic layer was dried over Na2SO4, filtered, concentrated to afford crude 4-azido-6-(4-chlorophenyl)-1-methyl-4H-benzo[c]isoxazolo[4,5-e]azepine, which was used directly in the following reaction. LC/MS m/z 350 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[C@@H:19]([NH2:23])[CH2:20][CH2:21][CH3:22])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.C1COCC1.C(N(CC)CC)C.[C:42](Cl)(=[O:47])[C:43]([CH3:46])([CH3:45])[CH3:44]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=4)[C@@H:19]([NH:23][C:42](=[O:47])[C:43]([CH3:46])([CH3:45])[CH3:44])[CH2:20][CH2:21][CH3:22])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: CCC[C@H](N)[C@H](Oc1ccc2c(cnn2-c2ccc(F)cc2)c1)c1ccccc1
Reactant: CC(C)(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCC[C@H](NC(=O)C(C)(C)C)[C@H](Oc1ccc2c(cnn2-c2ccc(F)cc2)c1)c1ccccc1

Procedure:
To a stirred solution of (1R,2S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yloxy)-1-phenylpentan-2-amine (91a, 13 mg, 0.03 mmol) dissolved in dry THF (150 μmol) were added, at r.t., triethylamine (27.8 μl, 0.20 mmol) and pivaloyl chloride (12.3 ul, 0.1 mmo). The reaction was stirred over night. The solvent was removed under reduced pressure, and the product purified by preparative HPLC.
Reaction SMILES: Cl[C:2]([N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[C:8](=[O:15])[NH:7][C:6]2[CH:16]=[CH:17][CH:18]=[N:19][C:5]1=2)=[O:3].[CH2:20]([N:23]([CH2:27][CH:28]1[CH2:33][CH2:32][CH2:31][N:30]([CH2:34][CH2:35][NH2:36])[CH2:29]1)[CH2:24][CH2:25][CH3:26])[CH2:21][CH3:22]>C(#N)C>[CH2:20]([N:23]([CH2:27][CH:28]1[CH2:33][CH2:32][CH2:31][N:30]([CH2:34][CH2:35][NH:36][C:2]([N:4]2[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[C:8](=[O:15])[NH:7][C:6]3[CH:16]=[CH:17][CH:18]=[N:19][C:5]2=3)=[O:3])[CH2:29]1)[CH2:24][CH2:25][CH3:26])[CH2:21][CH3:22]
Reactant: CCCN(CCC)CC1CCCN(CCN)C1
Reactant: O=C1Nc2cccnc2N(C(=O)Cl)c2ccccc21
Solvent: CC#N
Product: CCCN(CCC)CC1CCCN(CCNC(=O)N2c3ccccc3C(=O)Nc3cccnc32)C1
Yield: 48 %

Procedure:
Prepared analogously to Example 46 from 11-(chlorocarbonyl)-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one and 2-[3-[(dipropylamino)methyl]-piperidin-1-yl]ethanamine in a yield of 48% of theory. Colourless crystals, m.p. 153°-155° C. (acetonitrile).
Reaction SMILES: [N:1]1[C:6]([C:7]([O:9]CC)=O)=[N:5][C:4]([C:12]([O:14]CC)=O)=[N:3][C:2]=1[C:17]([O:19]CC)=O.[NH2:22][CH:23]1[CH2:28][C:27]([CH3:30])([CH3:29])[N:26]([O:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[C:25]([CH3:41])([CH3:40])[CH2:24]1>>[CH2:32]([O:31][N:26]1[C:27]([CH3:29])([CH3:30])[CH2:28][CH:23]([NH:22][C:17]([C:2]2[N:1]=[C:6]([C:7]([NH:22][CH:23]3[CH2:28][C:27]([CH3:29])([CH3:30])[N:26]([O:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[C:25]([CH3:40])([CH3:41])[CH2:24]3)=[O:9])[N:5]=[C:4]([C:12]([NH:22][CH:23]3[CH2:28][C:27]([CH3:29])([CH3:30])[N:26]([O:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[C:25]([CH3:40])([CH3:41])[CH2:24]3)=[O:14])[N:3]=2)=[O:19])[CH2:24][C:25]1([CH3:40])[CH3:41])[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39]
Reactant: CCOC(=O)c1nc(C(=O)OCC)nc(C(=O)OCC)n1
Reactant: CCCCCCCCON1C(C)(C)CC(N)CC1(C)C
Product: CCCCCCCCON1C(C)(C)CC(NC(=O)c2nc(C(=O)NC3CC(C)(C)N(OCCCCCCCC)C(C)(C)C3)nc(C(=O)NC3CC(C)(C)N(OCCCCCCCC)C(C)(C)C3)n2)CC1(C)C

Procedure:
The title compound is prepared by the reaction of triethyl 1,3,5-triazine-2,4,6-tricarboxylate and 4-amino-1-octyloxy-2,2,6,6-tetramethylpiperidine.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[CH:20]=[C:12]2[CH:13]=[N+:14]([O-])[CH:15]=[C:16]([O:17][CH3:18])[C:11]2=[N:10]1.P(Br)(Br)([Br:23])=O>ClCCCl>[Br:23][C:13]1[C:12]2=[CH:20][N:9]([C:3]3[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=3[Cl:8])[N:10]=[C:11]2[C:16]([O:17][CH3:18])=[CH:15][N:14]=1
Reactant: O=P(Br)(Br)Br
Reactant: COc1c[n+]([O-])cc2cn(-c3c(Cl)cccc3Cl)nc12
Solvent: ClCCCl
Product: COc1cnc(Br)c2cn(-c3c(Cl)cccc3Cl)nc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 9.1 %

Procedure:
To a cooled (0° C.) solution of 2-(2,6-dichlorophenyl)-7-methoxy-2H-pyrazolo[4,3-c]pyridine 5-oxide (1.3 g, 4.2 mmol) in DCE (30 mL) under nitrogen was added phosphorous oxybromide (2.4 g, 8.4 mmol). The reaction mixture was stirred for 30 minutes, warmed to room temperature, and stirred for a further 4 hours. Further phosphorous oxybromide (1.8 g, 6.3 mmol) was added and the reaction mixture was stirred for a further 16 hours. The temperature was raised to 80° C. and stirred for 2 hours. The resultant mixture was cooled, quenched with sodium carbonate (sat. aq.) and the layers were partitioned. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resultant residue was purified by silica gel flash chromatography (30-40% ethyl acetate in cyclohexane) to afford the title compound as a white solid (143 mg, 9% yield). LCMS (Method D): RT=3.52 min, m/z: 372 [M+H+].
Reaction SMILES: CC1(C)[O:6][C@H:5]([CH2:7][N:8]2[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:35])[C@@H:15]([N:21]3[CH2:25][C:24]([O:26][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[Cl:33])=[CH:23][C:22]3=[O:34])[CH2:16][C:17]([F:20])([F:19])[CH3:18])=[N:9]2)[CH2:4][O:3]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[OH:6][C@@H:5]([CH2:4][OH:3])[CH2:7][N:8]1[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:35])[C@@H:15]([N:21]2[CH2:25][C:24]([O:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[Cl:33])=[CH:23][C:22]2=[O:34])[CH2:16][C:17]([F:19])([F:20])[CH3:18])=[N:9]1
Reactant: CC(F)(F)C[C@@H](C(=O)Nc1ccn(C[C@@H]2COC(C)(C)O2)n1)N1CC(Oc2ccccc2Cl)=CC1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Product: CC(F)(F)C[C@@H](C(=O)Nc1ccn(C[C@@H](O)CO)n1)N1CC(Oc2ccccc2Cl)=CC1=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 82.5 %

Procedure:
In a round bottom flask was placed (S)-2-[4-(2-chloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4,4-difluoro-pentanoic acid [1-((R)-2,2-dimethyl-[1,3]dioxolan-4-yl-methyl)-1H-pyrazol-3-yl]-amide (70 mg, 0.13 mmol), methanol (3 mL) and p-toluenesulfonic acid (5 mg, 0.15 mmol). The mixture was stirred at 25° C. for 24 h and then concentrated in vacuo and dissolved in ethyl acetate and concentrated in vacuo with silica gel (1 g). Purification by Biotage flash chromatography (AnaLogix SF15-12 g column, 100% ethyl acetate to 10% methanol/ethyl acetate) afforded (S)-2-[4-(2-chloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4,4-difluoro-pentanoic acid [1-((R)-2,3-dihydroxy-propyl)-1H-pyrazol-3-yl]-amide (52 mg, 82%) as a white foam: HR-ES-MS m/z calculated for C21H23N4O5ClF2 [M+H]+ 485.1398, observed 485.1396; 1H NMR (300 MHz, DMSO-d6) δ ppm 1.66 (t, J=19.3 Hz, 3H), 3.21-3.33 (m, 2H), 3.69-3.81 (m, 1H), 3.87 (dd, J=13.6, 7.5 Hz, 1H), 4.01-4.17 (m, 1H), 4.30 (d, J=18.4 Hz, 1H), 4.47 (d, J=18.4 Hz, 1H), 4.72 (t, J=5.6 Hz, 1H), 4.81 (s, 1H), 4.95 (d, J=5.1 Hz, 1H), 5.12 (dd, J=9.1, 5.1 Hz, 1H), 6.42 (d, J=2.1 Hz, 1H), 7.32-7.41 (m, 1H), 7.42-7.53 (m, 2H), 7.55 (dd, J=2.1 Hz, 1H), 7.66 (d, J=7.8 Hz, 1H), 10.85 (s, 1H).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH:5][C:6](=[O:18])[C:7]1[CH:12]=[CH:11][C:10]([S:13][CH3:14])=[C:9]([N+:15]([O-])=O)[CH:8]=1.[H][H]>[Pd].C(OCC)(=O)C>[CH3:1][O:2][CH2:3][CH2:4][NH:5][C:6](=[O:18])[C:7]1[CH:12]=[CH:11][C:10]([S:13][CH3:14])=[C:9]([NH2:15])[CH:8]=1
Reactant: [H][H]
Reactant: COCCNC(=O)c1ccc(SC)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COCCNC(=O)c1ccc(SC)c(N)c1
Yield: 94.9 %

Procedure:
A suspension of N-(2-methoxyethyl)-4-methylthio-3-nitrobenzamide (1.6 g) and palladium on charcoal (1.1 g; 5%) in ethyl acetate (60 ml) was shaken under an atmosphere of hydrogen at atmospheric pressure until hydrogen uptake ceased. The mixture was filtered and the residue was rinsed with ethyl acetate. The filtrate was concentrated in vacuo to leave N-(2-methoxyethyl)-4-methylthio-3-aminobenzamide (1.35 g) in the form of an oil that crystallised on standing, m.p. 66°-68° C. [Elemental analysis: C,54.8; H,6.69; N,11.5; S,12.9%; calculated: C,54.98; H,6.71; N,11.66; S,13.34%].
Reaction SMILES: [C:1]([O:5][CH2:6][CH3:7])(=[O:4])[CH:2]=O.[CH2:8]([CH:12]([CH2:15][OH:16])[CH2:13][OH:14])[CH2:9][CH2:10][CH3:11]>>[CH2:8]([CH:12]1[CH2:15][O:16][CH:2]([C:1]([O:5][CH2:6][CH3:7])=[O:4])[O:14][CH2:13]1)[CH2:9][CH2:10][CH3:11]
Reactant: CCCCC(CO)CO
Reactant: CCOC(=O)C=O
Product: CCCCC1COC(C(=O)OCC)OC1

Procedure:
2-(3,5-Difluoro-4-cyanophenyl)-5-butyl-1,3-dioxane is obtained analogously to Example 1 using 5-butyl-1,3-dioxane-2-carboxylic acid chloride (obtainable by reacting ethyl glyoxylate with 2-butylpropane-1,3-diol to give ethyl 5-butyl-1,3-dioxane-2-carboxylate, saponifying the latter and reacting the resulting free acid with SOCl2).
Reaction SMILES: O[CH:2]([CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N+:13]([O-:15])=[O:14])[C:3]([OH:5])=[O:4].CN(C)C=O.S(Cl)([Cl:23])=O>>[Cl:23][CH:2]([CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N+:13]([O-:15])=[O:14])[C:3]([OH:5])=[O:4]
Reactant: O=C(O)C(O)Cc1ccccc1[N+](=O)[O-]
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: O=C(O)C(Cl)Cc1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 30.3 %

Procedure:
To a magnetically stirred solution of α-hydroxy-2-nitrobenzenepropanoic acid (1.00 g, 4.74 mmol) in N,N-dimethylformamide (2 ml, 25.85 mmol) cooled in ice was added thionyl chloride (12 ml, 164.5 mmol) slowly dropwise. The cooling bath was removed and the solution was left at room temperature (20° C.) overnight. The solution was evaporated to a solid. Ice and dichloromethane were added and the mixture was stirred magnetically for one hour, during which time it warmed to room temperature. The layers were separated and the organic phase was washed six times with water. The dried (MgSO4) solution was evaporated to a syrup which was subjected to an oil pump vacuum; yield 1.09 g Examination of the syrup on the μ-Bondapak C18 chromatographic column (Waters Associates) using a solvent system containing 90% of 0.1N ammonium acetate, pH 4.0 buffer and 10% acetonitrile revealed three components. The major component, which was present to the extent of 74% of the mixture, was separated on a Waters Associates Prep. 500 unit using a C18 cartridge and the solvent system mentioned above. Appropriate fractions were evaporated to a syrup below room temperature. The syrup was mixed with dilute hydrochloric acid and chloroform. The organic phase was washed twice with saturated brine and dried (MgSO4). The solution was evaporated to a syrup which crystallized spontaneously (0.48 g, 44%). Crystallization from chloroform-cyclohexane gave 0.33 g (31%) of the titled product; m.p. 108°-109°; MH+ 230 (1 Cl, CI mode); λmaxKBr 1707, 1725 (COOH), pmr (CDCl3) δ3.22-3.96 (8 lines, AB part of an ABX system, --CH2 --), 4.60-4.88 (q centered at 4.76, width 14 Hz, "J" 6 Hz, X part of ABX system, >CH), 7.32-8.16 (m, aromatic).
Reaction SMILES: [F:1][C:2]1[C:13]([O:14][CH3:15])=[CH:12][CH:11]=[CH:10][C:3]=1[C:4](N(OC)C)=[O:5]>C1COCC1.C1(C)C=CC=CC=1>[F:1][C:2]1[C:13]([O:14][CH3:15])=[CH:12][CH:11]=[CH:10][C:3]=1[CH:4]=[O:5]
Reactant: COc1cccc(C(=O)N(C)OC)c1F
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: COc1cccc(C=O)c1F
Temperature: -78 °C
Reaction time: 3 h
Yield: 84.7 %

Procedure:
To a solution of 2-fluoro-3,N-dimethoxy-N-methyl-benzamide (2.30 g, 10.8 mmol) in THF (20 mL) at −78° C. was added 1M DEBAL-H in toluene.(12 mL, 12 mmol). The reaction stirred at −78° C. for 3 h and then the remaining 1M DIDAL-H in toluene (4.2 mL, 4.2 mmol) was added to the reaction. The reaction was allowed to stir at −78° C. for 30 min and was then warmed to rt. The reaction was quenched slowly with saturated aqueous NH4Cl. The organic phase was separated and the aqueous phase was extracted with 2×50 mL ethyl acetate. The combined organic phases were washed successively with 1N HCl and brine. The organic phase was dried (MgSO4) and concentrated in vacuo. The residue was purified by flash chromatography eluting silica gel with EtOAc:hexane [0:100 to 1:1] to yield the title compound (1.41 g, 85%): δH (300 MHz, CDCl3): 10.38 (1H, s), 7.43-7.40 (1H, m), 7.24-7.15 (2H, m), 3.95 (3H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:9][CH3:10])=[C:6]([NH2:8])[CH:7]=1.[CH3:11][C:12]1[CH:17]=[CH:16][C:15]([S:18](Cl)(=[O:20])=[O:19])=[CH:14][C:13]=1[N+:22]([O-:24])=[O:23]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:9][CH3:10])=[C:6]([NH:8][S:18]([C:15]2[CH:16]=[CH:17][C:12]([CH3:11])=[C:13]([N+:22]([O-:24])=[O:23])[CH:14]=2)(=[O:19])=[O:20])[CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1[N+](=O)[O-]
Reactant: CSc1ccc(Cl)cc1N
Product: CSc1ccc(Cl)cc1NS(=O)(=O)c1ccc(C)c([N+](=O)[O-])c1
Yield: 60.7 %

Procedure:
Following General Procedure B, the title compound (197 mg, 61%) was prepared from 5-Chloro-2-methylsulfanyl-phenylamine (150 mg, 0.87 mmol) and 4-Methyl-3-nitro-benzenesulfonyl chloride (235 mg, 0.87 mmol).
Reaction SMILES: [CH:1]1[C:14]2[C:5](=[CH:6][C:7]3[C:12]([C:13]=2[C:15]([OH:17])=O)=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH:4]=[CH:3][CH:2]=1.C(Cl)(Cl)[Cl:19]>S(Cl)(Cl)=O>[CH:1]1[C:14]2[C:5](=[CH:6][C:7]3[C:12]([C:13]=2[C:15]([Cl:19])=[O:17])=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH:4]=[CH:3][CH:2]=1
Reactant: ClC(Cl)Cl
Reactant: O=C(O)c1c2ccccc2cc2ccccc12
Solvent: O=S(Cl)Cl
Product: O=C(Cl)c1c2ccccc2cc2ccccc12
Temperature: 25 °C
Yield: 59 %

Procedure:
Anthracene-9-carboxylic acid (recrystallized from ethanol, 12.05 g, 54.3 mmol) was suspended in a mixture of chloroform (60 mL, Aldrich, amylenes-stabilized) and thionyl chloride (12 mL) and heated under reflux until a clear solution was obtained (about 30 minutes). The solvent was removed by distillation under reduced pressure and the residual hot oil was dissolved in toluene (20 mL) and hexane (100 mL) was added. After cooling to ambient temperature the crystalline product was collected by filtration and dried in a stream of nitrogen then under high vacuum to give the title compound as a yellow solid (7.69 g, 59%). Non-commercially available carboxylic acids referred to in this section were prepared as described below. If desired they were converted to the corresponding carbonyl chloride using thionyl chloride as described above.
Reaction SMILES: C(N1C=CN=C1)([N:3]1C=CN=C1)=O.[Cl:13][C:14]1[CH:15]=[C:16]([CH3:35])[C:17]([OH:34])=[C:18]([C:20](=[N:28][CH2:29][CH2:30][C:31](O)=[O:32])[C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)[CH:19]=1.N>O1CCCC1>[Cl:13][C:14]1[CH:15]=[C:16]([CH3:35])[C:17]([OH:34])=[C:18]([C:20](=[N:28][CH2:29][CH2:30][C:31]([NH2:3])=[O:32])[C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)[CH:19]=1
Reactant: Cc1cc(Cl)cc(C(=NCCC(=O)O)c2ccc(Cl)cc2)c1O
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: N
Solvent: C1CCOC1
Product: Cc1cc(Cl)cc(C(=NCCC(N)=O)c2ccc(Cl)cc2)c1O

Procedure:
Under a hood, carbonyldiimidazole (5.56 g; 0.0312 mol) is added gradually to a stirred solution of the acid obtained in Example 1 (11 g; 0.0312 mol) in 150 ml of dry tetrahydrofuran. The stirring is continued for 11/2 hours at ambient temperature, and the solution is then poured into 100 ml of liquid NH3 and the whole is stirred until the evaporation of the ammonia has ended (about 3 hours). The residue is evaporated to dryness in vacuo. The residue is dissolved in CH2Cl2 and the methylene chloride solution is washed with water and with a saturated solution of sodium bicarbonate and then dried over MgSO4. Evaporation gives a solid, which is chromatographed on a column (SiO2, AcOEt). The solid obtained is recrystallised from AcOEt (i.e. ethyl acetate) to give a yellow solid.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH:2]1[C:7]([OH:9])=[O:8].[CH2:10]=O>[Pd]>[CH3:10][N:1]1[CH2:6][CH2:5][O:4][CH2:3][CH:2]1[C:7]([OH:9])=[O:8]
Reactant: C=O
Reactant: O=C(O)C1COCCN1
Agent: [Pd]
Product: CN1CCOCC1C(=O)O
Yield: 96.1 %

Procedure:
To the above prepared solution of morpholine-3-carboxylic acid (140 mg, 0.86 mmol, 1 eq) was added aqueous formaldehyde (0.1 g, 1 mmol, 37%, 1.2 equiv), and the solution was stirred under hydrogen atmosphere at room temperature for 24 h in the presence of 10% palladium on carbon (150 mg, 50% water). After completion of the reaction, the catalyst was filtered off and the filtrate was concentrated under vacuum to give 120 mg of the desired 4-methylmorpholine-3-carboxylic acid. The crude material was used in the next step without further purification. 1H NMR (CD3OD, 400 MHz): δ 4.24-4.22 (m, 1H), 4.00-3.99 (m, 1H), 3.74-3.64 (m, 3H), 3.42-3.38 (m, 1H), 3.20-3.19 (m, 1H), 2.95 (s, 3H)
Reaction SMILES: C[O:2][C:3]1[CH:8]=[C:7]([O:9]C)[CH:6]=[CH:5][C:4]=1[C:11]1[C:19]2[C:14](=[C:15]([C:20]([F:23])([F:22])[F:21])[CH:16]=[CH:17][CH:18]=2)[N:13]([CH:24]([CH3:26])[CH3:25])[N:12]=1.B(Br)(Br)Br.C1CCCCC=1>>[CH:24]([N:13]1[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][C:15]=2[C:20]([F:23])([F:22])[F:21])[C:11]([C:4]2[CH:5]=[CH:6][C:7]([OH:9])=[CH:8][C:3]=2[OH:2])=[N:12]1)([CH3:26])[CH3:25]
Reactant: COc1ccc(-c2nn(C(C)C)c3c(C(F)(F)F)cccc23)c(OC)c1
Agent: BrB(Br)Br
Solvent: C1=CCCCC1
Product: CC(C)n1nc(-c2ccc(O)cc2O)c2cccc(C(F)(F)F)c21
Yield: 66.4 %

Procedure:
Prepared according to Method D step C from 3-(2,4-dimethoxyphenyl)-1-isopropyl-7-(trifluoromethyl)-1H-indazole (0.442 g, 1.2 mmol), boron tribromide (0.688 mL, 7.27 mmol) and 1.0 mL of cyclohexene to give the product (0.268 g) as an off-white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:32]=[CH:33][C:34]=1[O:35][CH3:36])[CH2:6][CH:7]1[C:13]2[CH:14]=[C:15]([O:20][CH3:21])[C:16]([O:18][CH3:19])=[CH:17][C:12]=2[CH2:11][CH2:10][CH2:9][N:8]1[CH:22]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:23](O)=[O:24].[CH2:37]([O:39][CH2:40][CH2:41][CH2:42][NH2:43])[CH3:38]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:32]=[CH:33][C:34]=1[O:35][CH3:36])[CH2:6][CH:7]1[C:13]2[CH:14]=[C:15]([O:20][CH3:21])[C:16]([O:18][CH3:19])=[CH:17][C:12]=2[CH2:11][CH2:10][CH2:9][N:8]1[CH:22]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:23]([NH:43][CH2:42][CH2:41][CH2:40][O:39][CH2:37][CH3:38])=[O:24]
Reactant: CCOCCCN
Reactant: COc1ccc(CC2c3cc(OC)c(OC)cc3CCCN2C(C(=O)O)c2ccccc2)cc1OC
Product: CCOCCCNC(=O)C(c1ccccc1)N1CCCc2cc(OC)c(OC)cc2C1Cc1ccc(OC)c(OC)c1

Procedure:
prepared by reaction of [1-(3,4-dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-phenyl-acetic acid with 3-ethoxypropylamine.
Reaction SMILES: [NH2:1][C:2]1[N:7]([CH:8]2[CH2:10][CH2:9]2)[C:6](=[O:11])[NH:5][C:4](=[O:12])[CH:3]=1.Cl.[N:14]([O-])=[O:15].[Na+]>O>[NH2:1][C:2]1[N:7]([CH:8]2[CH2:10][CH2:9]2)[C:6](=[O:11])[NH:5][C:4](=[O:12])[C:3]=1[N:14]=[O:15]
Reactant: O=N[O-]
Reactant: Nc1cc(=O)[nH]c(=O)n1C1CC1
Agent: Cl
Agent: [Na+]
Solvent: O
Product: Nc1c(N=O)c(=O)[nH]c(=O)n1C1CC1
Reaction time: 2 h

Procedure:
31.7 g (0.19 mol) of 6-amino-1-cyclopropyl-2,4-(1H,3H)-pyrimidinedione (II) was suspended in 250 ml water. To this was added 45 ml of 5N HCl and 15 g of NaNO2 (0.22 mol) which was dissolved in water. The reaction mixture was stirring for 2 hours and after cooling, the red crystals were filtered off and washed with water. Yield 31.9 g (86%) (III) NMR.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[C:17](=[O:18])[C:16]3[C:15]4[C:10](=[CH:11][C:12]([C:19]#[N:20])=[CH:13][CH:14]=4)[NH:9][C:8]=3[C:7]([CH3:22])([CH3:21])[C:6]=2[CH:23]=1.O[CH2:25][CH2:26][N:27]1[CH2:31][CH2:30][NH:29][C:28]1=[O:32]>>[CH3:22][C:7]1([CH3:21])[C:8]2[NH:9][C:10]3[C:15](=[CH:14][CH:13]=[C:12]([C:19]#[N:20])[CH:11]=3)[C:16]=2[C:17](=[O:18])[C:5]2[CH:4]=[CH:3][C:2]([O:1][CH2:25][CH2:26][N:27]3[CH2:31][CH2:30][NH:29][C:28]3=[O:32])=[CH:23][C:6]1=2
Reactant: CC1(C)c2cc(O)ccc2C(=O)c2c1[nH]c1cc(C#N)ccc21
Reactant: O=C1NCCN1CCO
Product: CC1(C)c2cc(OCCN3CCNC3=O)ccc2C(=O)c2c1[nH]c1cc(C#N)ccc21

Procedure:
Under the same conditions as the method for synthesizing Compound A7-1, the title compound was prepared from Compound A6 and 1-(2-hydroxy-ethyl)-imidazolidin-2-one.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:20]([O:21][CH3:22])=[CH:19][C:12]2[CH2:13][CH2:14][CH2:15][CH2:16][C:17](=[O:18])[C:11]=2[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[O-].[Na+].[C:26](=O)([O:29]C)[O:27][CH3:28]>>[CH3:28][O:27][C:26]([CH:16]1[CH2:15][CH2:14][CH2:13][C:12]2[CH:19]=[C:20]([O:21][CH3:22])[C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[CH:10][C:11]=2[C:17]1=[O:18])=[O:29]
Reactant: COC(=O)OC
Reactant: COc1cc2c(cc1OCc1ccccc1)C(=O)CCCC2
Agent: C[O-]
Agent: [Na+]
Product: COC(=O)C1CCCc2cc(OC)c(OCc3ccccc3)cc2C1=O
Temperature: 0 °C

Procedure:
A mixture of 3-benzyloxy-2-methoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-one (3.2 g), sodium methoxide (2.8 g) and dimethyl carbonate (100 ml) is heated for four hours under reflux in a stream of nitrogen. The reaction mixture is poured into ice-water containing concentrated hydrochloric acid (10 ml), and extracted with ethyl acetate. The organic layer is washed with water, dried and concentrated under reduced pressure to afford 3-benzyloxy-2-methoxy-5-oxo-6,7,8,9-tetrahydro-5H-benzocycloheptene-6-carboxylic acid methyl ester (3.7 g) as a pale yellow oily product.