Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([NH2:11])[CH:3]=1.CN(C=O)C.[Br:17][CH2:18][C:19](Br)=[O:20]>O1CCOCC1>[F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([NH:11][C:19](=[O:20])[CH2:18][Br:17])[CH:3]=1
Reactant: O=C(Br)CBr
Reactant: Nc1cc(F)ccc1C(=O)O
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: O=C(CBr)Nc1cc(F)ccc1C(=O)O
Temperature: -5 °C
Reaction time: 8 h
Yield: 91.5 %

Procedure:
A solution of 4-fluoro-2-aminobenzoic acid (5.0 g, 32.2 mmol) in a mixture of anhydrous DMF (30 mL) and anhydrous dioxane (30 mL) in a 250 mL 3-necked round-bottomed flask which was equipped with a constant addition funnel (60 mL) was cooled with an ice-bath to -5° C. Bromoacetyl bromide (6.44 g, 2.8 mL, 32.2 mmol) was added dropwise while keeping the internal temperature between -5° and 0° C. over a 1/2 h period. After the addition of the bromoacetyl bromide was completed, the solution was warmed to room temperature and stirred overnight. To this solution was slowly added 150 mL of ice-water, causing a solid to precipitate. The precipitate was filtered, washed with water, and then dried in a vacuum dessicator overnight to afford 8.13 g (91.4%) of the title compound as a white solid, mp 166°-168° C.: 1H NMR (DMSO-d6) δ13.92 (bs, 1H), 11.83 (s, 1H), 8.32 (dd, J=12, J=2.4, 1H), 8.09 (dd, J=9.2, J=6.8, 1H), 7.06 (ddd, J=8.8, J=9.2, J=2.4, 1H), 4.29 (s, 2H); 13C NMR (DMSO-d6) δ168.55, 165.60, 164.80 (d, J=248), 142.29 (d, J=12.9), 133.93 (d, J=10.6), 113.19, 110.42 (d, J=22), 106.43 (d, J=28), 30.54; MS (EI, m/z) 275 (M+).
Reaction SMILES: [CH2:1]([CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][C:11]1=O)[C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=O.[NH2:17][C:18]1[CH:26]=[C:22]([C:23]([OH:25])=[O:24])[C:21]([OH:27])=[CH:20][CH:19]=1>C(O)(=O)C>[C:23]([C:22]1[CH:26]=[C:18]([N:17]2[C:11]3[CH2:12][CH2:13][CH2:14][CH2:15][C:10]=3[CH:1]=[C:2]2[C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:19]=[CH:20][C:21]=1[OH:27])([OH:25])=[O:24]
Reactant: O=C(CC1CCCCC1=O)c1ccccc1
Reactant: Nc1ccc(O)c(C(=O)O)c1
Solvent: CC(=O)O
Product: O=C(O)c1cc(-n2c(-c3ccccc3)cc3c2CCCC3)ccc1O

Procedure:
A solution of 49.7 g. (0.23 mole) of 2-phenacylcyclohexanone, 35.2 g. (0.23 mole) of 5-aminosalicylic acid, and 135 ml. of glacial acetic acid was heated under reflux under nitrogen for 31/2 hours. A solid separated and was collected, washed with water, and recrystallized from acetic acid to provide 46.0 g. (60%) of pale yellow crystals, m.p. 209°-211°.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]([C:12]([OH:14])=O)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.S(Cl)([Cl:17])=O>>[OH:1][C:2]1[CH:11]=[C:10]([C:12]([Cl:17])=[O:14])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1cc(O)nc2ccccc12
Product: O=C(Cl)c1cc(O)nc2ccccc12

Procedure:
A mixture of 2-hydroxyquinoline-4-carboxylic acid (V. 2.89 g) and of thionyl chloride (25 ml) is stirred at 80° for 12 hr and then allowed to cool. Excess thionyl chloride is removed under reduced pressure and dichloromethane is added to the residue. The dichloromethane is then removed and the process repeated to remove traces of thionyl chloride. The residue is dried under reduced pressure to give 2-hydroxyquinolin-4-oyl chloride (V-A) as a solid, which is used without further purification, mp: shrinkage and melting from approximately 260°-275°.
Reaction SMILES: [C:1]1([O:7][C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17]Br)=[C:10]([CH2:19][CH2:20][CH3:21])[CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:22][C:23]1[CH:24]=[C:25]([CH2:30][C:31]([O:33][CH3:34])=[O:32])[CH:26]=[CH:27][C:28]=1[OH:29].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[CH2:19]([C:10]1[CH:9]=[C:8]([O:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:13]=[CH:12][C:11]=1[O:14][CH2:15][CH2:16][CH2:17][O:29][C:28]1[CH:27]=[CH:26][C:25]([CH2:30][C:31]([O:33][CH3:34])=[O:32])=[CH:24][C:23]=1[Cl:22])[CH2:20][CH3:21]
Reactant: COC(=O)Cc1ccc(O)c(Cl)c1
Reactant: CCCc1cc(Oc2ccccc2)ccc1OCCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCCc1cc(Oc2ccccc2)ccc1OCCCOc1ccc(CC(=O)OC)cc1Cl

Procedure:
A solution of the product from Step A (2.5 g, 7.18 mmol), methyl 3-chloro-4-hyrdoxyphenylacetate (1.42 g, 7.11 mmol) and cesium carbonate (2.43 g, 7.45 mmol) in DMF (20 mL) was stirred at 40° C. overnight. The reaction mixture was partitioned between ethyl acetate and 0.2N HCl. The organic was washed twice with water, then dried over sodium sulfate. The organic was filtered and evaporated to an oil which was chromatographed over silica gel with 10% of ethyl acetate in hexane to afford the title compound.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6](=[O:15])[CH2:7][CH:8]2[CH2:11][C:12](Cl)=[O:13])=[CH:4][CH:3]=1.[OH-].[NH4+:17]>ClCCl>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6](=[O:15])[CH2:7][CH:8]2[CH2:11][C:12]([NH2:17])=[O:13])=[CH:4][CH:3]=1
Reactant: [NH4+]
Reactant: O=C(Cl)CC1CC(=O)c2ccc(F)cc21
Agent: [OH-]
Solvent: ClCCl
Product: NC(=O)CC1CC(=O)c2ccc(F)cc21
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 2-(6-fluoro-3-oxo-1-indanyl)acetyl chloride (prepared from 0.024 mol of 2-(6-fluoro-3-oxo-1-indanyl)acetic acid) in dichloromethane (150 ml) was cooled to 0° C. and stirred rapidly while 50 ml of ammonium hydroxide, 28-30%, was added. The resulting mixture was allowed to warm to room temperature and stirring was continued for 18 hr. The volatiles from this mixture was removed by spin evaporation in vacuo and the residue was dissolved in dichloromethane (250 ml) and washed with water (3×50 ml). The dichloromethane phase was then slurried with Silica Gel 60 and the volatiles were removed by spin evaporation in vacuo. This silica was then applied to a column of Silica Gel 60 (51×400 mm) wet with dichloromethane and the product was removed by elution with methanol:dichloromethane (3:97) to give, after recrystallization from methanol, 2.4 g (48%) of 2-(6-fluoro-3-oxo-1-indanyl)acetamide as a yellow solid: m.p., 150-152° C.:
Reaction SMILES: [H-].[Na+].[C:3]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:4][C:5]([CH3:7])=[O:6].[Li]CCCC.[S:17]1[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[N:19]=[C:18]1[N:26]1[C:30]([C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=2)=[C:29](/[CH:38]=[CH:39]/[CH:40]=[O:41])[C:28]([CH:42]([CH3:44])[CH3:43])=[N:27]1>C1COCC1>[S:17]1[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[N:19]=[C:18]1[N:26]1[C:30]([C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=2)=[C:29](/[CH:38]=[CH:39]/[CH:40]([OH:41])[CH2:7][C:5](=[O:6])[CH2:4][C:3]([O:9][CH2:10][CH3:11])=[O:8])[C:28]([CH:42]([CH3:44])[CH3:43])=[N:27]1
Reactant: CCOC(=O)CC(C)=O
Reactant: CC(C)c1nn(-c2nc3ccccc3s2)c(-c2ccc(F)cc2)c1/C=C/C=O
Agent: [H-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)CC(=O)CC(O)/C=C/c1c(C(C)C)nn(-c2nc3ccccc3s2)c1-c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 87 %

Procedure:
To a hexane washed suspension of NaH (1.23 g, 30.7 mmol) in THF (20 mL) at 0° C. under an inert atmosphere, was added a solution of ethyl acetoacetate (3.66 mL, 28.7 mmol) in THF (20 mL). The resulting clear solution was stirred at 0° C. for 15 minutes before n-BuLi (13.1 mL, 28.7 mmol) was added dropwise. This orange solution was stirred at 0° C. for 15 minutes before it was cooled to -78° C. and a solution of the unsaturated aldehyde (7.50 g, 19.2 mmol, Step E) in THF (100 mL) was added dropwise. The reaction was stirred at -78° C. for 1 hour and then it was quenched by adding 4 mL glacial acetic acid and removing the cooling bath. The reaction mixture was partitioned between Et2O and saturated aqueous K2CO3 solution. The organic extracts were dried (MgSO4) and evaporated to give an orange solid. Recrystallization from hexanes gave 8.71 g (87%) of product as a pale yellow orange solid.
Reaction SMILES: C(OC(=O)[NH:10][C:11]12[CH2:18][CH:17]3[CH2:19][C:13]([C:20]4[CH:25]=[CH:24][C:23]([N:26]5[CH2:30][CH2:29][CH2:28][C:27]5=[O:31])=[CH:22][CH:21]=4)([CH2:14][CH:15]1[CH2:16]3)[CH2:12]2)C1C=CC=CC=1>CO.[Pd]>[NH2:10][C:11]12[CH2:18][CH:17]3[CH2:19][C:13]([C:20]4[CH:25]=[CH:24][C:23]([N:26]5[CH2:30][CH2:29][CH2:28][C:27]5=[O:31])=[CH:22][CH:21]=4)([CH2:14][CH:15]1[CH2:16]3)[CH2:12]2
Reactant: O=C(NC12CC3CC1CC(c1ccc(N4CCCC4=O)cc1)(C3)C2)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: NC12CC3CC1CC(c1ccc(N4CCCC4=O)cc1)(C3)C2
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.3 %

Procedure:
A mixture of benzyl[2-[4-(2-Oxopyrrolidin-1-yl)phenyl)hexahydro-2,5-methanopentalene-3a(1H)-yl]carbamate (0.73 g, 1.7 mmol) obtained in step I and Pd/C (10%, 0.4 g) in MeOH (17 mL) was stirred at room temperature under H2 atmosphere for 2 h. The reaction mixture was filtered through a pad of celite and the filtrate was concentrated under reduced pressure to obtain 1-[4-(3-aminotricyclo[3.3.1.03,7]non-1-yl)phenyl]pyrrolidin-2-one as an off-white solid (0.43 g, 85% yield). m/z (M+1) 297; 1H NMR (CDCl3) 300 MHz δ 7.52 (d, J=8.6 Hz, 2H), 7.25 (d, J=8.6 Hz, 2H), 3.86 (t, J=6.9 Hz, 2H), 2.62 (t, J=7.9 Hz, 2H), 2.52-2.42 (m, 1H), 2.32-1.60 (m, 13H).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([S:30]([CH3:33])(=[O:32])=[O:31])=[CH:26][CH:25]=2)=[C:5]([CH2:7][CH2:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:11][CH:10]=2)[N:6]=1.Cl[C:35]([O:37][CH2:38][CH3:39])=[O:36]>N1C=CC=CC=1>[CH2:38]([O:37][C:35](=[O:36])[NH:1][C:2]1[S:3][C:4]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([S:30]([CH3:33])(=[O:32])=[O:31])=[CH:26][CH:25]=2)=[C:5]([CH2:7][CH2:8][C:9]2[CH:10]=[CH:11][C:12]([NH:15][C:16]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:22])=[CH:13][CH:14]=2)[N:6]=1)[CH3:39]
Reactant: CC(C)(C)OC(=O)Nc1ccc(CCc2nc(N)sc2Cc2ccc(S(C)(=O)=O)cc2)cc1
Reactant: CCOC(=O)Cl
Solvent: c1ccncc1
Product: CCOC(=O)Nc1nc(CCc2ccc(NC(=O)OC(C)(C)C)cc2)c(Cc2ccc(S(C)(=O)=O)cc2)s1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
tert-Butyl [4-(2-{2-amino-5-[4-(methylsulfonyl)benzyl]-1,3-thiazol-4-yl}ethyl)phenyl]carbamate (140 mg) was dissolved in pyridine (2 ml) under N2 atmosphere. Then, ethyl chloroformate (30.2 ml) was added to the solution at 0° C. The reaction mixture was stirred at r.t. for 2 hours, and concentrated in vacuo. The residue was dissolved in AcOEt, and washed with 1N—HCl, water and brine. The organic layer was dried over anhydrous MgSO4, and concentrated in vacuo to give ethyl{4-(2-{4-[(tert-butoxycarbonyl)amino]phenyl}ethyl)-5-[4-(methylsulfonyl)benzyl]-1,3-thiazol-2-yl}carbamate (155.8 mg) as an off-white amorphous substance.
Reaction SMILES: Cl[C:2]1[NH:3][C:4]2[CH:5]=[CH:6][CH:7]=[C:8]3[C:14]=2[CH:12]([N:13]=1)[CH2:11][CH2:10][CH2:9]3.[NH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>O>[C:16]1([NH:15][C:2]2[NH:3][C:4]3[CH:5]=[CH:6][CH:7]=[C:8]4[C:14]=3[CH:12]([N:13]=2)[CH2:11][CH2:10][CH2:9]4)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: ClC1=NC2CCCc3cccc(c32)N1
Reactant: Nc1ccccc1
Solvent: O
Product: c1ccc(NC2=NC3CCCc4cccc(c43)N2)cc1

Procedure:
10.3 g (0.05 mol) of 2-chloro-3a,4,5,6-tetrahydroperimidine are introduced into 15 ml of aniline, whilst stirring. After the strongly exothermic reaction has subsided (temperature rises to 90° C.), water is added to the mixture and the crystals which have precipitated are isolated by filtration and washed several times with dilute aqueous ammonia solution. 2-Phenylamino-3a,4,5,6-tetrahydro-perimidine is obtained. Yield: 9.5 g (72% of theory) of melting point 233°-235° C.
Reaction SMILES: Cl.[CH3:2][O:3][CH:4]([O:21][CH3:22])[C:5]1[N:14]=[C:13]2[C:8]([CH2:9][CH2:10][CH2:11][NH:12]2)=[CH:7][C:6]=1[CH:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.[F:23][CH:24]([F:27])[CH2:25]I.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[F:23][CH:24]([F:27])[CH2:25][N:18]1[CH2:17][CH2:16][CH:15]([C:6]2[CH:7]=[C:8]3[C:13](=[N:14][C:5]=2[CH:4]([O:3][CH3:2])[O:21][CH3:22])[NH:12][CH2:11][CH2:10][CH2:9]3)[CH2:20][CH2:19]1
Reactant: FC(F)CI
Reactant: COC(OC)c1nc2c(cc1C1CCNCC1)CCCN2
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(OC)c1nc2c(cc1C1CCN(CC(F)F)CC1)CCCN2
Temperature: 70 °C
Reaction time: 16 h

Procedure:
A mixture of 7-(dimethoxymethyl)-6-(piperidin-4-yl)-1,2,3,4-tetrahydro-1,8-naphthyridine hydrochloride (Intermediate 342, 0.78 g, 2.14 mmol), 1,1-difluoro-2-iodoethane (0.63 g, 3.22 mmol) and K2CO3 (0.89 g, 6.43 mmol) in DMF (20 ml) was stirred at 70° C. After 16 h, the reaction mixture was cooled to room temperature, diluted with H2O and extracted with EtOAc (3×). The combined organic phases were washed with brine, dried over Na2SO4 and evaporated. The crude material was purified by reverse phase chromatography (Reprosil C18/250×30 mm/5 um, 35 ml/min, 0.1% TFA in H2O/acetonitrile 95:5 to 40:60 in 25 min, then to 5:95 in 1 min). The product-containing fractions were treated with NaHCO3 and then concentrated to remove acetonitrile. The watery residue was diluted with H2O and extracted with EtOAc (2×). The combined organic phases were dried over Na2SO4 and evaporated to give the title compound as a yellow solid. (UPLC-MS 3) tR 0.41; ESI-MS 356.2 [M+H]+.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1.[B:13](OC)([O:16][CH3:17])[O:14][CH3:15].CCOCC>CCCCCC.C1COCC1>[CH3:15][O:14][B:13]([O:16][CH3:17])[C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1
Reactant: COB(OC)OC
Reactant: Brc1cccnc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: CCCCCC
Product: COB(OC)c1cccnc1
Temperature: 25 °C

Procedure:
n-Butyl lithium (31.3 ml of a 1.6M solution in hexane) was added to a stirred solution of 3-bromopyridine (4.8 ml) and trimethyl borate (6.2 ml) in dry THF (100 ml) at a rate such that the temperature did not exceed -65° C. The mixture was allowed to warm to ambient temperature over 16 hours and was filtered. The solid was washed with ether, combined with more solid obtained from the filtrate and rewashed with ether to give dimethoxy-(3-pyridyl)borane (3.5 g) as a solid, 1H NMR (CD3OD): 3.4 (s, 6 H), 7.2 (m, 1 H), 7.9 (m, 1 H), 8.2 (dd, 1 H), 8.6 (s, 1 H); mass spectrum (+ve CI): 152 (M+H)+.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:14]=[C:13]([O:15]COCC[Si](C)(C)C)[C:12]2[C:7](=[C:8]([N:26]3[CH2:32][CH2:31][CH2:30][N:29]([CH3:33])[CH2:28][CH2:27]3)[CH:9]=[C:10]([O:24][CH3:25])[CH:11]=2)[N:6]=1)=[O:4].O1CCCC1.O.[OH-].[Li+].Cl>O.CO>[CH3:25][O:24][C:10]1[CH:11]=[C:12]2[C:7](=[C:8]([N:26]3[CH2:32][CH2:31][CH2:30][N:29]([CH3:33])[CH2:28][CH2:27]3)[CH:9]=1)[NH:6][C:5]([C:3]([OH:4])=[O:2])=[CH:14][C:13]2=[O:15]
Reactant: COC(=O)c1cc(OCOCC[Si](C)(C)C)c2cc(OC)cc(N3CCCN(C)CC3)c2n1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: COc1cc(N2CCCN(C)CC2)c2[nH]c(C(=O)O)cc(=O)c2c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a light brown solution of 6-methoxy-8-(4-methyl-[1,4]diazepan-1-yl)-4-(2-trimethylsilanyl-ethoxymethoxy)-quinoline-2-carboxylic acid methyl ester (1.00 g, 2.10 mmol) in 18 mL 3:1:1 tetrahydrofuran:methanol:water was added lithium hydroxide monohydrate (0.267 g, 6.35 mmol). The reaction mixture was stirred at room temperature for 5 hours, acidified to pH 4 with 1 N HCl, and stirred an additional 20 minutes. The reaction mixture was concentrated and dried under high vacuum to afford an orange foam. 1H NMR (300 MHz, DMSO, d6) δ 11.06 (s, 1H, NH), 7.53 (s, 1H, C═CH), 7.00 (d, 1H, Jm=2.4 Hz, ArH5), 6.70 (d, 1H, Jm=2.4 Hz, ArH7), 4.05-3.99 (m, 2H, ArNCH2CH2CH2NCH3), 3.87 (s, 3H, OCH3), 3.68-3.60 (m, 2H, ArNCH2CH2NCH3), 3.54-3.47 (m, 2H, ArNCH2CH2NCH3), 3.41-3.26 (m, 2H, ArNCH2CH2CH2NCH3), 2.82 (d, 3H, J=4.8 Hz, NCH3), 2.46-2.41 (m, 1H, ArNCH2CH2CH2NCH3), 2.30-2.25 (m, 1H, ArNCH2CH2CH2NCH3); Mass Spec.: calc. for [C17H21N3O4+H]+ Theor. m/z 332; Obs. 332.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11](=[O:13])[N:10]([CH:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[CH2:9][CH2:8][C:7]=2[CH:20]=1.[CH3:21][N:22]1[C:26]2[C:27]([CH3:42])=[CH:28][C:29]([C:31]([C:33]3[CH:40]=[CH:39][C:36]([C:37]#[N:38])=[C:35](F)[CH:34]=3)=[O:32])=[CH:30][C:25]=2[O:24][C:23]1=[O:43]>CN(C=O)C>[CH3:21][N:22]1[C:26]2[C:27]([CH3:42])=[CH:28][C:29]([C:31]([C:33]3[CH:40]=[CH:39][C:36]([C:37]#[N:38])=[C:35]([N:17]4[CH2:18][CH2:19][CH:14]([N:10]5[CH2:9][CH2:8][C:7]6[CH:20]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=6[NH:12][C:11]5=[O:13])[CH2:15][CH2:16]4)[CH:34]=3)=[O:32])=[CH:30][C:25]=2[O:24][C:23]1=[O:43]
Reactant: Cc1cc(C(=O)c2ccc(C#N)c(F)c2)cc2oc(=O)n(C)c12
Reactant: COc1ccc2c(c1)CCN(C1CCNCC1)C(=O)N2
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)CCN(C1CCN(c3cc(C(=O)c4cc(C)c5c(c4)oc(=O)n5C)ccc3C#N)CC1)C(=O)N2
Temperature: 300 °C

Procedure:
440 mg (1.60 mmol) 7-methoxy-3-piperidin-4-yl-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one and 124 mg (0.400 mmol) 4-(3,4-dimethyl-2-oxo-2,3-dihydro-benzoxazole-6-carbonyl)-2-fluoro-benzonitrile were combined and heated to 300° C. for approx. 10 min. Then the mixture was dissolved in DMF and purified by preparative HPLC-MS. The fractions containing the product were combined and the organic solvent was evaporated down. The residue was neutralised with 1N aqueous sodium hydroxide solution, the precipitate formed was suction filtered, washed with water and dried.
Reaction SMILES: [CH:1]1([CH:7]([C:9]2[C:10]([CH2:24][CH2:25][CH3:26])=[N:11][N:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][N:15]=3)[CH:13]=2)O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]([N:36]([CH3:44])[CH2:37][CH2:38][C:39]([O:41]CC)=[O:40])=[O:35])=[CH:30][CH:29]=1>>[CH:1]1([CH:7]([NH:27][C:28]2[CH:29]=[CH:30][C:31]([C:34]([N:36]([CH3:44])[CH2:37][CH2:38][C:39]([OH:41])=[O:40])=[O:35])=[CH:32][CH:33]=2)[C:9]2[C:10]([CH2:24][CH2:25][CH3:26])=[N:11][N:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][N:15]=3)[CH:13]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCCc1nn(-c2ccc(C(F)(F)F)cn2)cc1C(O)C1CCCCC1
Reactant: CCOC(=O)CCN(C)C(=O)c1ccc(N)cc1
Product: CCCc1nn(-c2ccc(C(F)(F)F)cn2)cc1C(Nc1ccc(C(=O)N(C)CCC(=O)O)cc1)C1CCCCC1
Yield: 33.8 %

Procedure:
Using cyclohexyl{3-propyl-1-[5-(trifluoromethyl)pyridin-2-yl]-1H-pyrazol-4-yl}methanol (0.65 g) synthesized in Example 5(3) and ethyl 3-{[(4-aminophenyl)carbonyl](methyl)amino}propanoate (0.44 g) synthesized in Example 2(2) and in the same manner as in Example 1(7), the title object compound (0.34 g, 34%) was obtained as a white solid.
Reaction SMILES: [C:1]([N:9]1[CH2:15][CH2:14][CH2:13][CH:12]([Cl:16])[CH2:11][C:10]1=[O:17])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:18]C1(Cl)CCCNC(=O)C1>>[C:1]([N:9]1[CH2:15][CH2:14][CH2:13][C:12]([Cl:18])([Cl:16])[CH2:11][C:10]1=[O:17])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CC(Cl)(Cl)CCCN1
Reactant: O=C1CC(Cl)CCCN1C(=O)c1ccccc1
Product: O=C1CC(Cl)(Cl)CCCN1C(=O)c1ccccc1

Procedure:
Synthesized as for N-benzoyl-3-chlorocaprolactam (Example VI) using 3,3-dichlorocaprolactam (prepared from caprolactam according to J. Am. Chem. Soc. 1958, 80, 6238) in place of 3-chlorocaprolactam.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[NH2:21])[C:5]([NH:7][C:8]1[CH:9]=[N:10][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:12][CH:13]=1)=[O:6].C([O:24][P:25]([CH2:30]/[CH:31]=[CH:32]/[C:33]1[CH:38]=[C:37]([CH3:39])[C:36]([CH:40]=O)=[C:35]([CH3:42])[CH:34]=1)(=[O:29])[O:26]CC)C>>[CH3:42][C:35]1[CH:34]=[C:33]([CH2:32][CH2:31][CH2:30][P:25](=[O:24])([OH:29])[OH:26])[CH:38]=[C:37]([CH3:39])[C:36]=1[C:40]1[NH:1][C:2]2[CH:3]=[C:4]([C:5](=[O:6])[NH:7][C:8]3[CH:9]=[N:10][C:11]([C:14]([F:17])([F:15])[F:16])=[CH:12][CH:13]=3)[CH:18]=[CH:19][C:20]=2[N:21]=1
Reactant: CCOP(=O)(C/C=C/c1cc(C)c(C=O)c(C)c1)OCC
Reactant: Nc1ccc(C(=O)Nc2ccc(C(F)(F)F)nc2)cc1N
Product: Cc1cc(CCCP(=O)(O)O)cc(C)c1-c1nc2ccc(C(=O)Nc3ccc(C(F)(F)F)nc3)cc2[nH]1

Procedure:
The title compound was prepared from 3,4-diamino-N-(6-trifluoromethylpyridin-3-yl)-benzamide and [(E)-3-(4-formyl-3,5-dimethylphenyl)-allyl]-phosphonic acid diethyl ester analogous to Example 6-32. 1H NMR (Methanol-d4, 400 MHz): δ 9.09 (d, 1H), 8.57 (dd, 1H), 8.34 (dd, 1H), 8.00 (dd, 1H), 7.87 (d, 1H), 7.76 (dd, 1H), 7.09 (s, 2H), 2.76 (t, 2H), 2.16 (s, 6H), 2.00 (m, 2H), 1.71 (m, 2H). MS (m/z) 533.1 (M+1); Retention time: 1.13 min (Method 10).
Reaction SMILES: C(O)(C(F)(F)F)=[O:2].[OH:8][C:9]1[C:22]2[C:21](=[O:23])[C:20]3[C:15](=[C:16]([O:24][CH3:25])[CH:17]=[CH:18][CH:19]=3)[O:14][C:13]=2[CH:12]=[C:11]([O:26][CH2:27][CH:28]2[CH2:30][O:29]2)[CH:10]=1>>[OH:29][CH:28]([CH2:30][OH:2])[CH2:27][O:26][C:11]1[CH:10]=[C:9]([OH:8])[C:22]2[C:21](=[O:23])[C:20]3[C:15]([O:14][C:13]=2[CH:12]=1)=[C:16]([O:24][CH3:25])[CH:17]=[CH:18][CH:19]=3
Reactant: COc1cccc2c(=O)c3c(O)cc(OCC4CO4)cc3oc12
Reactant: O=C(O)C(F)(F)F
Product: COc1cccc2c(=O)c3c(O)cc(OCC(O)CO)cc3oc12
Temperature: 50 °C
Reaction time: 4 h
Yield: 47.3 %

Procedure:
50% TFA (5 mL) was added to 1-hydroxy-5-methoxy-3-(oxiran-2-ylmethoxy)-9H-xanthen-9-one (20 mg, 0.06 mmol) synthesized in Step 2 of Example 1, and the reaction mixture was stirred at 50° C. for 4 hours. The solvent was removed, and the resulting residue was dried under reduced pressure to give the title compound (10 mg, 47.3%) as a white solid.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:15]=[C:14]([CH:16]=[CH:17][NH:18][C:19]([O:21][CH3:22])=[O:20])[CH:13]=[CH:12][C:6]=1[O:7][CH2:8][CH:9]1[O:11][CH2:10]1)[CH:2]=[CH2:3].[CH:23]([NH2:26])([CH3:25])[CH3:24]>C(O)(C)C>[CH2:1]([O:4][C:5]1[CH:15]=[C:14]([CH:16]=[CH:17][NH:18][C:19]([O:21][CH3:22])=[O:20])[CH:13]=[CH:12][C:6]=1[O:7][CH2:8][CH:9]([OH:11])[CH2:10][NH:26][CH:23]([CH3:25])[CH3:24])[CH:2]=[CH2:3]
Reactant: CC(C)N
Reactant: C=CCOc1cc(C=CNC(=O)OC)ccc1OCC1CO1
Solvent: CC(C)O
Product: C=CCOc1cc(C=CNC(=O)OC)ccc1OCC(O)CNC(C)C
Temperature: 80 °C

Procedure:
4.45 g (0.0146 mol) of 1-[2-allyloxy-4-(2-methoxycarbonylaminovinyl)-phenoxy]-2,3-epoxy-propane are heated with a solution of 1.26 ml (0.0146 mol) of isopropylamine in 100 ml of isopropanol for 3 hours under reflux to 80°C. The mixture is then evaporated under reduced pressure and the resulting crude base is crystallised from acetone-ether. 1-[2-Allyloxy-4-(2-methoxycarbonylaminovinyl)-phenoxy]-2-hydroxy-3-isopropylamino-propane of melting point 91°-92° is obtained. From this, the fumarate, melting point 169°-170° (after recrystallisation from methanol-isopropanol) is obtained after dissolving in isopropanol and adding the calculated amount of fumaric acid.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([S:10]([N:13]2[CH2:18][CH2:17][CH:16]([C:19]([O:21]CC)=[O:20])[CH2:15][CH2:14]2)(=[O:12])=[O:11])=[CH:6][C:5]=1[C:24]1[NH:25][C:26](=[O:37])[C:27]2[N:33]=[CH:32][CH:31]=[C:30]([CH2:34][CH2:35][CH3:36])[C:28]=2[N:29]=1)[CH3:2].[OH-].[K+]>C(O)C>[C:19]([CH:16]1[CH2:15][CH2:14][N:13]([S:10]([C:7]2[CH:8]=[CH:9][C:4]([O:3][CH2:1][CH3:2])=[C:5]([C:24]3[NH:25][C:26](=[O:37])[C:27]4[N:33]=[CH:32][CH:31]=[C:30]([CH2:34][CH2:35][CH3:36])[C:28]=4[N:29]=3)[CH:6]=2)(=[O:12])=[O:11])[CH2:18][CH2:17]1)([OH:21])=[O:20]
Reactant: CCCc1ccnc2c(=O)[nH]c(-c3cc(S(=O)(=O)N4CCC(C(=O)OCC)CC4)ccc3OCC)nc12
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCCc1ccnc2c(=O)[nH]c(-c3cc(S(=O)(=O)N4CCC(C(=O)O)CC4)ccc3OCC)nc12
Yield: 18 %

Procedure:
A mixture of 2-[2-ethoxy-5-(4-ethoxycarbonyl-piperidinosulphonyl)phenyl]-8-n-propylpyrido[3,2-d]pyrimidin-4(3H)-one (Example 4; 0.55 g, 0.001 mol), potassium hydroxide (0.146 g, 0.0026 mol) and ethanol (35 ml) was stirred under reflux for 5 hours, then allowed to cool. The solvent was evaporated under vacuum, and the residue chromatographed twice on ion-exchange resin (Bio-rad AG50W-X8 H+, 27.5 g) using a pyridine in water elution gradient (2-50% pyridine). Crystallization of the product from aqueous ethanol gave the title compound as a colourless solid (0.09 g, 8%), m.p. 262-264° C.