Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([O:5][C:6]2[N:11]=[CH:10][C:9]([F:12])=[CH:8][N:7]=2)[CH2:2]1.C(N(CC)CC)C.Cl[C:21]1[N:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][C:22]=1[C:23]([OH:25])=[O:24]>CO.O1CCCC1>[F:12][C:9]1[CH:10]=[N:11][C:6]([O:5][CH:3]2[CH2:2][N:1]([C:21]3[N:29]=[CH:28][C:27]([C:30]([F:33])([F:31])[F:32])=[CH:26][C:22]=3[C:23]([OH:25])=[O:24])[CH2:4]2)=[N:7][CH:8]=1
Reactant: Fc1cnc(OC2CNC2)nc1
Reactant: O=C(O)c1cc(C(F)(F)F)cnc1Cl
Solvent: CO
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(O)c1cc(C(F)(F)F)cnc1N1CC(Oc2ncc(F)cn2)C1
Temperature: 80 °C
Yield: 23.1 %

Procedure:
To a mixture of 2-(azetidin-3-yloxy)-5-fluoropyrimidine (D51) (108 mg, 0.638 mmol) and triethylamine (0.11 ml, 0.798 mmol) in methanol (1 ml) and tetrahydrofuran (2 ml), 2-chloro-5-(trifluoromethyl)nicotinic acid (120 mg, 0.532 mmol) was added and the mixture was heated 2 h at 80° C. After solvent evaporation the residue was purified by SPE-Si cartridge (25 g) eluting with a mixture dichloromethane/methanol from 95/5 to 80/20. Collected fraction after solvent evaporation afforded the title compound (D131) (44 mg)
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1.[N+:11]([O-])([O-:13])=[O:12].[K+].C(OCC)(=O)C.[NH4+].[OH-]>OS(O)(=O)=O.O>[N+:11]([C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:5]=1[CH:4]=[CH:3][N:2]=[CH:1]2)([O-:13])=[O:12]
Reactant: O=[N+]([O-])[O-]
Reactant: c1ccc2cnccc2c1
Agent: O=S(=O)(O)O
Agent: [K+]
Agent: [NH4+]
Solvent: O
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1cccc2cnccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.9 %

Procedure:
To a solution of isoquinoline (120 g, 0.929 mol) in H2SO4 (1 L) was added KNO3 (112.6 g, 1.115 mol) at −15° C. (dropwise). The mixture was stirred at room temperature for 2 hours. TLC (petroleum ether:ethyl acetate=2:1) showed complete conversion. The mixture was added to water (3 L) at 0° C. The mixture was adjusted to pH 8 by the addition of NH4OH and filtered. The filter cake was washed with methyl tertbutyl ether (1 L×2) and concentrated under vacuum to give 5-nitro-isoquinoline (160 g, 94%) as a yellow solid.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl:7][C:8]1[C:12]([C:13](OCC)=[O:14])=[C:11]([Cl:18])[N:10]([CH2:19][CH3:20])[N:9]=1.C(OCC)(=O)C.O>O1CCCC1>[Cl:7][C:8]1[C:12]([CH2:13][OH:14])=[C:11]([Cl:18])[N:10]([CH2:19][CH3:20])[N:9]=1
Reactant: CCOC(=O)c1c(Cl)nn(CC)c1Cl
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: CCn1nc(Cl)c(CO)c1Cl
Temperature: -50 °C
Reaction time: 3 h
Yield: 100.1 %

Procedure:
A solution of 0.16 g (4.2 mmoles) of lithium aluminum hydride dissolved in 70 ml of tetrahydrofuran was cooled to −50° C. Thereto was gradually added dropwise a solution of 1.0 g (4.2 mmoles) of ethyl 3,5-dichloro-1-ethyl-1H-pyrazole-4-carboxylate dissolved in 30 ml of tetrahydrofuran. The mixture was stirred at −50° C. for 3 hours to give rise to a reaction. After confirmation of the completion of the reaction, ethyl acetate was added, followed by stirring for a while. Water was added, followed by stirring for a while. The resulting mixture was filtered under vacuum. The filtrate was extracted with ethyl acetate. The resulting organic layer was washed with water and an aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the solvent contained therein, to obtain 0.82 g (yield: 100%) of (3,5-dichloro-1-ethyl-1H-pyrazol-4-yl)methanol as a brown oily substance.
Reaction SMILES: [CH:1]1(/[CH:7]=[C:8](\[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[OH:24])=[O:17])/C(OC(C)(C)C)=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>NC(N)=S.C1(C)C=CC=CC=1>[CH:1]1([C@H:7]2[CH2:8][C:16](=[O:17])[C:18]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[O:24]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)/C(=C/C1CCCCC1)C(=O)c1ccccc1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: NC(N)=S
Solvent: Cc1ccccc1
Product: O=C1C[C@H](C2CCCCC2)Oc2ccccc21
Yield: 65.1 %

Procedure:
Prepared according to general procedure using (E)-tert-butyl 3-cyclohexyl-2-(2-hydroxyphenylcarbonyl)prop-2-enoate (66 mg, 0.20 mmol), thiourea catalyst III (14 mg, 0.020 mmol) in 2.0 mL toluene for 5 d at −25° C. and p-toluenesulfonic acid (19 mg, 0.10 mmol) for 4 h. Purification via column chromatography with 10% EtOAc/hexanes afforded 30.0 mg (65%) of 16 as a white solid in 80% ee. [α]D: −53.0 (EtOH, c=0.5). Analytical data for 16: IR (film) 2928.8, 1689.6, 1608.8, 1467.1, 1310.1, 1229.6 cm−1; 1H NMR (500 MHz, CDCl3) δ 7.87 (d, J=7.3 Hz, 1H), 7.47 (t, J=7.1 Hz, 1H), 7.01-6.97 (m, 2H), 4.23-4.19 (m, 1H), 2.77-2.65 (m, 2H), 2.01-1.99 (m, 1H), 1.84-1.72 (m, 5H), 1.35-1.11 (m, 5H); 13C NMR (125 MHz, CDCl3) δ 193.4, 162.1, 136.1, 127.1, 121.2 (x2), 118.1, 82.2, 42.0, 40.4, 28.5, 28.4, 26.5, 26.15, 26.09; LRMS (electrospray): Exact mass calcd for C15H18O2 [M]+, 230.13. Found [M+1], 231.7.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([OH:12])=[C:4]([C:13]([OH:15])=O)[N:3]=1.Cl.C[O:18][C:19](=[O:24])[C:20]([NH2:23])([CH3:22])[CH3:21]>>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([OH:12])=[C:4]([C:13]([NH:23][C:20]([CH3:22])([CH3:21])[C:19]([OH:24])=[O:18])=[O:15])[N:3]=1
Reactant: O=C(O)c1nc(Cl)c2ccccc2c1O
Reactant: COC(=O)C(C)(C)N
Agent: Cl
Product: CC(C)(NC(=O)c1nc(Cl)c2ccccc2c1O)C(=O)O

Procedure:
Prepared in analogy to Example A-1 a) and b) from 1-chloro-4-hydroxy-isoquinoline-3-carboxylic acid from Example A-2 d) and 2-amino-2-methyl-propionic acid methyl ester hydrochloride; MS-(+)-ion: M+1=308.9 amu.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([CH2:35][C:36]1[CH:41]=[C:40]([F:42])[C:39]([F:43])=[CH:38][C:37]=1[F:44])[CH2:9][C:10]([N:12]1[CH2:17][CH2:16][N:15]2[C:18]([C:31]([F:34])([F:33])[F:32])=[N:19][C:20]([C:21]([N:23]3[CH2:28][CH2:27][S:26](=[O:30])(=[O:29])[CH2:25][CH2:24]3)=[O:22])=[C:14]2[CH2:13]1)=[O:11])(C)(C)C.[ClH:46]>C(OCC)(=O)C>[ClH:46].[NH2:7][C@H:8]([CH2:35][C:36]1[CH:41]=[C:40]([F:42])[C:39]([F:43])=[CH:38][C:37]=1[F:44])[CH2:9][C:10]([N:12]1[CH2:17][CH2:16][N:15]2[C:18]([C:31]([F:32])([F:33])[F:34])=[N:19][C:20]([C:21]([N:23]3[CH2:24][CH2:25][S:26](=[O:30])(=[O:29])[CH2:27][CH2:28]3)=[O:22])=[C:14]2[CH2:13]1)=[O:11]
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)N1CCn2c(C(F)(F)F)nc(C(=O)N3CCS(=O)(=O)CC3)c2C1)Cc1cc(F)c(F)cc1F
Agent: Cl
Solvent: CCOC(C)=O
Product: N[C@@H](CC(=O)N1CCn2c(C(F)(F)F)nc(C(=O)N3CCS(=O)(=O)CC3)c2C1)Cc1cc(F)c(F)cc1F

Procedure:
(R)-[3-[1-(1,1-Dioxo-thiomorpholine-4-carbonyl)-3-trifluoromethyl-5,6-dihydro-8H-imidazo[1,5-a]pyrazin-7-yl]-3-oxo-1-(2,4,5-trifluoro-benzyl)-propyl]-carbamic acid tert-butyl ester 6a (0.15 g, 0.22 mmol) was dissolved in a solution of 3.1 N hydrochloric acid in 4 mL of ethyl acetate. The reaction mixture was reacted at room temperature overnight and monitored by thin layer chromatography until the disappearance of the starting materials. The reaction mixture was concentrated under reduced pressure to obtain the title compound (R)-3-amino-1-[1-(1,1-dioxo-thiomorpholine-4-carbonyl)-3-trifluoromethyl-5,6-dihydro-8H-imidazo[1,5-a]pyrazin-7-yl]-4-(2,4,5-trifluoro-phenyl)-butan-1-one hydrochloride 6 (140 mg) as a light yellow solid.
Reaction SMILES: C(OC([N:11]1[C@H:15]([C:16]([NH:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:14][S:13][CH2:12]1)=O)C1C=CC=CC=1.Br.C(OCC)C>C(O)(=O)C>[C:19]([NH:18][C:16]([C@@H:15]1[CH2:14][S:13][CH2:12][NH:11]1)=[O:17])([CH3:22])([CH3:20])[CH3:21]
Reactant: CC(C)(C)NC(=O)[C@@H]1CSCN1C(=O)OCc1ccccc1
Agent: Br
Solvent: CCOCC
Solvent: CC(=O)O
Product: CC(C)(C)NC(=O)[C@@H]1CSCN1
Temperature: 25 °C
Reaction time: 2 h
Yield: 84 %

Procedure:
A mixture of 3.2 g of 3-(benzyloxycarbonyl)-N-tert.butyl-4(R)-thiazolidinecarboxamide and 10 ml of 32% (w/w) hydrogen bromide in glacial acetic acid was stirred at room temperature for 2 hours. The resulting solution was poured into diethyl ether and the precipitated hydrobromide salt of the product was filtered off, washed with diethyl ether and then dissolved in water. The solution was made alkaline by the addition of 1M sodium hydroxide solution and extracted twice with dichloromethane. The combined dichloromethane extracts were washed with water, dried over anhydrous sodium sulphate, filtered and evaporated to give 1.57 g of N-tert.butyl-4(R)-thiazolidinecarboxamide as a crystalline solid of melting point 68°-71° C.
Reaction SMILES: [C:1]1([C@H:11]([NH:13][CH:14]2[CH2:17][N:16](C(OCC3C=CC=CC=3)=O)[CH2:15]2)[CH3:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1>CO.[C].[Pd]>[C:1]1([C@H:11]([NH:13][CH:14]2[CH2:17][NH:16][CH2:15]2)[CH3:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: C[C@@H](NC1CN(C(=O)OCc2ccccc2)C1)c1cccc2ccccc12
Agent: [Pd]
Solvent: CO
Product: C[C@@H](NC1CNC1)c1cccc2ccccc12
Reaction time: 4 h
Yield: 77.5 %

Procedure:
To a solution of 5.0 g of 1-benzohydrylazetidin-3-one dissolved in 75 ml of toluene was added 2.98 ml of benzyloxycarbonyl chloride, and the mixture was stirred at 80° C. for 4 hours. The reaction mixture was evaporated, and then, to the residue were added water and ethyl acetate, the mixture was stirred and the liquids were separated. The organic layer was washed with water and a saturated brine, dried and concentrated. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=19:1→4:1), and then, hexane was added thereto, and after collecting the precipitate by filtration, it was washed with hexane to obtain 2.73 g of benzyl 3-oxoazetidine-1-carboxylate. (3) To a solution of 8.51 g of benzyl 3-oxoazetidine-1-carboxylate and 7.10 g (R)-(+)-1-(1-naphthyl)ethylamine dissolved in 170 ml of methylene chloride, 7.49 g of magnesium sulfate was added to the solution. The mixture was stirred at room temperature for 3 hours, and then, 9.5 ml of acetic acid and 13.18 g of sodium triacetoxy borohydride were added thereto, and the mixture was stirred at room temperature for 1 hour. To the reaction mixture was added a saturated aqueous sodium bicarbonate solution to make the mixture basic, chloroform was added to the same and the mixture was stirred, and the liquids were separated. The organic layer was dried and concentrated, and the residue was purified by NH silica gel column chromatography (hexane:ethyl acetate=4:1→1:1) to obtain 7.90 g of benzyl 3-[(R)-1-(naphthalen-1-yl)ethylamino]azetidine-1-carboxylate. (4) To a solution of 9.45 g of benzyl 3-[(R)-1-(naphthalen-1-yl)ethylamino]azetidine-1-carboxylate dissolved in 190 ml of methanol, 1 g of palladium carbon (10% wet) was added thereto, and the reaction was carried out under hydrogen atmosphere at room temperature for 4 hours. Palladium carbon was removed, the solvent was evaporated, and the residue was purified by NH silica gel column chromatography (chloroform:methanol=1:0→19:1) to obtain 4.60 g of 3-[(R)-1-(naphthalen-1-yl)ethylamino]azetidine. To a solution of 4.60 g of 3-[(R)-1-(naphthalen-1-yl)ethylamino]azetidine dissolved in 30 ml of ethyl acetate, under ice-cooling, 13 ml of a solution of 4M hydrochloric acid in ethyl acetate was added dropwise, and the mixture was stirred for a while.
Reaction SMILES: [CH3:1][C:2]1[C:7]([NH2:8])=[C:6]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[CH:5]=[CH:4][CH:3]=1.[C:15](Cl)(Cl)=[S:16]>O1CCOCC1.O>[CH3:1][C:2]1[C:7]([N:8]=[C:15]=[S:16])=[C:6]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cccc(N2CCOCC2)c1N
Reactant: S=C(Cl)Cl
Solvent: O
Solvent: C1COCCO1
Product: Cc1cccc(N2CCOCC2)c1N=C=S

Procedure:
Reaction of 6-methyl-2-morpholinoaniline (9.6 g) in dioxan (25 ml) and water (100 ml) with thiophosgene (5.7 ml) at 0° C. for 30 minutes and at room temperature for 3 hours gave 6-methyl-2-morpholinophenyl isothiocyanate as an oil.
Reaction SMILES: [O:1]=[C:2]1[CH2:10][CH2:9][CH2:8][C:7]2[NH:6][CH:5]=[C:4]([CH2:11][CH2:12][C:13]([OH:15])=O)[C:3]1=2.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:28][N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1.C(N(CC)C(C)C)(C)C>ClCCl.O>[CH3:28][N:29]1[CH2:34][CH2:33][N:32]([C:13](=[O:15])[CH2:12][CH2:11][C:4]2[C:3]3[C:2](=[O:1])[CH2:10][CH2:9][CH2:8][C:7]=3[NH:6][CH:5]=2)[CH2:31][CH2:30]1
Reactant: CN1CCNCC1
Reactant: O=C(O)CCc1c[nH]c2c1C(=O)CCC2
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CN1CCN(C(=O)CCc2c[nH]c3c2C(=O)CCC3)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 57.6 %

Procedure:
To a suspension of 10 g of the product of step 1 (48 mmol) in dichloromethane(60 mL) was added 9.3 g (57.6 mmol) of 1,1′-carbonyldiimidazole. The mixture was stirred at room temperature for 2 hours and then 5.3 mL (48 mmol) 1-methylpiperazine and 8.4 mL (48 mmol) N,N-diisopropylethylamine was added. The dark red reaction mixture was then stirred at room temperature overnight. The reaction was then poured into water, the organic layer separated and washed with brine, dried and concentrated to give 8 g (57%) of 3-[3-(4-methylpiperazin-1-yl)-3-oxo-propyl]-1,5,6,7-tetrahydroindol-4-one.
Reaction SMILES: C(OC([N:8]([CH2:24][C:25]1([C:29]2[C:34]([F:35])=[CH:33][CH:32]=[CH:31][N:30]=2)[CH2:28][CH2:27][CH2:26]1)[C:9]1[N:14]=[N:13][C:12]([C:15]2[CH:19]=[C:18]([C:20]([O:22]C)=O)[O:17][N:16]=2)=[CH:11][CH:10]=1)=O)(C)(C)C.[OH-].[NH4+:37]>CO>[F:35][C:34]1[C:29]([C:25]2([CH2:24][NH:8][C:9]3[N:14]=[N:13][C:12]([C:15]4[CH:19]=[C:18]([C:20]([NH2:37])=[O:22])[O:17][N:16]=4)=[CH:11][CH:10]=3)[CH2:28][CH2:27][CH2:26]2)=[N:30][CH:31]=[CH:32][CH:33]=1
Reactant: COC(=O)c1cc(-c2ccc(N(CC3(c4ncccc4F)CCC3)C(=O)OC(C)(C)C)nn2)no1
Reactant: [NH4+]
Agent: [OH-]
Solvent: CO
Product: NC(=O)c1cc(-c2ccc(NCC3(c4ncccc4F)CCC3)nn2)no1
Temperature: 100 °C
Reaction time: 0.58 h
Yield: 36 %

Procedure:
Methyl 3-(6-(tert-butoxycarbonyl((1-(3-fluoropyridin-2-yl)cyclobutyl)methyl)amino)pyridazin-3-yl)isoxazole-5-carboxylate (0.53 g, 1.1 mmol), methanol (5 mL) and concentrated ammonium hydroxide (8 mL) were combined in a microwave reactor and heated to 100° C. for 60 min. The reaction mixture was then concentrated and diluted with EtOAc and washed with satd. aq. NaHCO3 and brine. The organic layer was dried over sodium sulfate, filtered, and concentrated. Resultant oil was diluted in 10 mL of DCM and TFA (6 mL) was added and the reaction was stirred for 35 min. The reaction mixture was then concentrated and purified by reverse phase chromatography to give the title compound as a white solid (144 mg, 36%), (m/z [M+H]=369.1).
Reaction SMILES: [F:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][O:7][CH2:8][CH2:9][CH2:10][CH2:11][C@@H:12]([N:28]=[N+:29]=[N-:30])[C:13](N2[C@H](CC3C=CC=CC=3)COC2=O)=[O:14])=[CH:4][C:3]=1[CH3:33].OO.[Li+].[OH-].[O-:38]S([O-])=O.[Na+].[Na+].Cl>C1COCC1.O.O>[F:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][O:7][CH2:8][CH2:9][CH2:10][CH2:11][C@@H:12]([N:28]=[N+:29]=[N-:30])[C:13]([OH:14])=[O:38])=[CH:4][C:3]=1[CH3:33]
Reactant: O=S([O-])[O-]
Reactant: Cc1cc(COCCCC[C@@H](N=[N+]=[N-])C(=O)N2C(=O)OC[C@H]2Cc2ccccc2)ccc1F
Agent: Cl
Agent: OO
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(COCCCC[C@@H](N=[N+]=[N-])C(=O)O)ccc1F
Temperature: 0 °C
Reaction time: 1 h
Yield: 99 %

Procedure:
To a cooled (0° C.) solution of (R)-3-((R)-6-(4-fluoro-3-methylbenzyloxy)-2-azidohexanoyl)-4-benzyloxazolidin-2-one (0.251 g, 0.552 mmol) in 11 mL of THF/H2O (8:3), were added stepwise 30% H2O2 (0.22 mL, 2.208 mmol) and LiOH (0.046 g, 1.105 mmol). The reaction mixture was stirred at 0° C. for 1 h then room temperature for overnight. Then a solution of Na2SO3 (0.304 g, 2.412 mmol) in 3 mL of water was added. After stirred at room temperature for 10 min, the reaction mixture was acidified with 4N HCl to pH=2 and extracted with dichloromethane (30 mL×3). The combined organic extracts dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was used directly in the next step without further purification (0.163 g, >99% yield).
Reaction SMILES: C[O:2][C:3]([C:5]1[N:13]([CH2:14][C:15]2[CH:19]=[C:18]([C:20]3[S:21][C:22]([Cl:25])=[CH:23][CH:24]=3)[O:17][N:16]=2)[C:12]2[CH:11]=[CH:10][C:9](=[O:26])[NH:8][C:7]=2[CH:6]=1)=[O:4].[OH-].[Li+]>O1CCCC1.O>[Cl:25][C:22]1[S:21][C:20]([C:18]2[O:17][N:16]=[C:15]([CH2:14][N:13]3[C:12]4[CH:11]=[CH:10][C:9](=[O:26])[NH:8][C:7]=4[CH:6]=[C:5]3[C:3]([OH:4])=[O:2])[CH:19]=2)=[CH:24][CH:23]=1
Reactant: COC(=O)c1cc2[nH]c(=O)ccc2n1Cc1cc(-c2ccc(Cl)s2)on1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1cc2[nH]c(=O)ccc2n1Cc1cc(-c2ccc(Cl)s2)on1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 20 mg) 1-[5-(5-Chloro-thiophen-2-yl)-isoxazol-3-ylmethyl]-5-oxo-4,5-dihydro-1H-pyrrolo[3,2-b]pyridine-2-carboxylic acid methyl ester and 1.9 mg lithium hydroxide in a mixture of 2 ml tetrahydrofuran and 1 mL water was stirred for 2 hours at room temperature. The solvent was removed under reduced pressure and the residue was coevaporated twice with toluene. The residue was directly subjected to the subsequent reaction without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]2[N:6]([CH:11]3[CH2:15][CH2:14][C:13]([F:17])([F:16])[CH2:12]3)[C:7]([CH2:9]Cl)=[N:8][C:4]=2[CH:3]=1.[CH3:20][S:21]([C:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[NH:26][N:25]=1)(=[O:23])=[O:22].CS(C1C2C(=CN=CC=2)NN=1)(=O)=O>>[Cl:1][C:2]1[CH:19]=[CH:18][C:5]2[N:6]([CH:11]3[CH2:15][CH2:14][C:13]([F:17])([F:16])[CH2:12]3)[C:7]([CH2:9][N:26]3[C:27]4[C:32](=[CH:31][CH:30]=[CH:29][CH:28]=4)[C:24]([S:21]([CH3:20])(=[O:22])=[O:23])=[N:25]3)=[N:8][C:4]=2[CH:3]=1
Reactant: CS(=O)(=O)c1n[nH]c2ccccc12
Reactant: FC1(F)CCC(n2c(CCl)nc3cc(Cl)ccc32)C1
Agent: CS(=O)(=O)c1n[nH]c2cnccc12
Product: CS(=O)(=O)c1nn(Cc2nc3cc(Cl)ccc3n2C2CCC(F)(F)C2)c2ccccc12

Procedure:
The title compound was prepared in analogy to Example 2-1 by using 5-chloro-2-chloromethyl-1-(3,3-difluoro-cyclopentyl)-1H-benzoimidazole and 3-methanesulfonyl-1H-indazole instead of 5-chloro-2-chloromethyl-1-((S)-1,1-dioxo-tetrahydro-1λ6-thiophen-3-yl)-1H-benzoimidazole and 3-(methylsulfonyl)-1H-pyrazolo[3,4-c]pyridine.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][CH:2]1[CH:11]([OH:14])[CH2:12]Br.Cl.[NH:16]1[CH2:21][CH2:20][CH:19]([N:22]2[C:30](=[O:31])[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:23]2=[O:32])[CH2:18][CH2:17]1.C(N(CC)CC)C>C(O)C>[O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][CH:2]1[CH:11]([OH:14])[CH2:12][N:16]1[CH2:21][CH2:20][CH:19]([N:22]2[C:23](=[O:32])[C:24]3[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:30]2=[O:31])[CH2:18][CH2:17]1
Reactant: OC(CBr)C1COc2ccccc2O1
Reactant: O=C1c2ccccc2C(=O)N1C1CCNCC1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: O=C1c2ccccc2C(=O)N1C1CCN(CC(O)C2COc3ccccc3O2)CC1

Procedure:
Erythro, 1-(1,4-benzodioxan-2-yl)-2-bromoethanol (1.29 g, 0.005 m) and 2-(piperid-4-yl)-1H-isoindole-1,3-(2H)dione hydrochloride (1.33 g, 0.005 cm3) in ethanol (75 cm3) with triethylamine (3.03 g, 0.03 cm3) were refluxed for 18 hours. The solution was cooled and the solvent evaporated. the residue was dissolved in chloroform and then washed twice with water, dried (MgSO4) and evaporated. The residue was dissolved in isopropyl alcohol and acidified with ethanolic HCl. The crystallised material was filtered to give the title compound as the hydrochloride salt m.p. 235°-237° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([OH:7])=[O:6].OS(O)(=O)=O.[CH3:17][CH2:18]O>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([O:7][CH2:17][CH3:18])=[O:6]
Reactant: CCO
Reactant: Cc1ccc(C(=O)O)cc1F
Agent: O=S(=O)(O)O
Solvent: Cc1ccccc1
Product: CCOC(=O)c1ccc(C)c(F)c1
Yield: 92 %

Procedure:
A solution of 10.2 g (66.2 mmol) of 3-fluoro-4-methylbenzoic acid in 50 mL of EtOH and 25 mL of toluene containing 0.2 mL of H2SO4 was heated gradually to 120° C. (oil bath temperature), and the solvent was removed by distillation over a period of 2.25 h through a 10-cm Vigreux column. The residue was cooled, treated with a further 50 mL of EtOH and 25 mL of toluene, and the distillation was repeated. The residual solution, containing some white solid, was poured into 75 mL of aqueous NaHCO3 and extracted with hexane (75 mL, then 50 mL). The extract was washed with water (2×75 mL), dried (Na2SO4), and concentrated. The pale-yellow liquid was distilled, bp 49°-58° C. (0.01-0.05 mm) to give 11.1 g (92% yield) of ethyl 3-fluoro-4-methylbenzoate as a colorless liquid: IR (CHCl3) 1720 (C=O), 1580, 1420, 1370, 1290, 1190, 1130, 1090, 1020, 940, 895 cm-1 ; 1H NMR (CDCl3) δ 1.40 (t, J=7 Hz, 3, CO2CH2CH3), 2.32 (d, J=2 Hz, 3, ArCH3), 4.37 (q, J=7 Hz, 2, CO2CH2CH3), 7.22 (dd, J=8 Hz, J=8 Hz, 1, 6' H), 7.68 (m, 2, 3', 5' H); MS calcd for C10H11FO2 182.0743, found 182.0729.
Reaction SMILES: C(O/[CH:4]=[CH:5]/[C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=1)=[O:7])C>S(=O)(=O)(O)O>[F:18][C:15]([F:16])([F:17])[C:12]1[CH:13]=[C:14]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:6](=[O:7])[CH:5]=[CH:4]2
Reactant: CCO/C=C/C(=O)Nc1ccc(C(F)(F)F)cc1
Agent: O=S(=O)(O)O
Product: O=c1ccc2cc(C(F)(F)F)ccc2[nH]1
Temperature: 0 °C
Reaction time: 2 h
Yield: 55.9 %

Procedure:
(2E)-3-ethoxy-N-(4-trifluoromethylphenyl)prop-2-enamide (3.44 g, 16.8 mmol) was added in several batches to sulfuric acid (20 ml) at 0° C. and then stirred for 2 hours at 0° C. The resulting mixture was quenched with ice-water (100 ml). The product was precipitated from water and collected by filtration to afford 6-(trifluoromethyl)-1,2-dihydroquinolin-2-one as a yellow solid (2.0 g, 56%). (ES, m/z): [M+H]+ 214. 1H NMR (300 MHz, DMSO): δ 8.14 (s, 1H), 8.03 (d, J=9.6 Hz, 1H), 7.80-7.83 (m, 1H), 7.45 (d, J=8.4 Hz, 1H), 6.61-6.65 (t, J=9.6 Hz, 1H).
Reaction SMILES: [Si]([O:18][CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][CH2:24][N:23]([C:27]2[CH:32]=[CH:31][C:30]([N:33]3[CH2:37][C@H:36]([CH2:38][NH:39][C:40]([C:42]4[S:43][C:44]([Cl:47])=[CH:45][CH:46]=4)=[O:41])[O:35][C:34]3=[O:48])=[CH:29][C:28]=2[CH3:49])[C:22]1=[O:50])(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O.[Cl-].[Na+]>C1COCC1.C(OCC)(=O)C>[Cl:47][C:44]1[S:43][C:42]([C:40]([NH:39][CH2:38][C@@H:36]2[O:35][C:34](=[O:48])[N:33]([C:30]3[CH:31]=[CH:32][C:27]([N:23]4[CH2:24][CH2:25][CH2:26][N:21]([CH2:20][CH2:19][OH:18])[C:22]4=[O:50])=[C:28]([CH3:49])[CH:29]=3)[CH2:37]2)=[O:41])=[CH:46][CH:45]=1
Reactant: Cc1cc(N2C[C@H](CNC(=O)c3ccc(Cl)s3)OC2=O)ccc1N1CCCN(CCO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)C1=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1cc(N2C[C@H](CNC(=O)c3ccc(Cl)s3)OC2=O)ccc1N1CCCN(CCO)C1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 232 mg (0.32 mmol) of the product from example 67A in 6 ml of THF is admixed with 195 mg (0.74 mmol) of a 1 molar solution of tetrabutylammonium fluoride in THF. The mixture is stirred at RT for 2 h. Then it is admixed with 60 ml of water, 30 ml of ethyl acetate and 6 ml of sodium chloride solution, and the phases are separated. The organic phase is extracted three times with ethyl acetate and the combined organic phases are dried over sodium sulfate. After filtration, the mixture is freed of the solvent and the residue is prepurified by chromatography on silica gel (20:1 dichloromethane/methanol). Subsequent purification by means of preparative HPLC with an acetonitrile/water mixture affords 29 mg (18% of theory) of the desired product.
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[CH2:6][C:5]2[C:7]([CH3:19])=[C:8]([N:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)[C:9]([CH3:12])=[C:10]([CH3:11])[C:4]=2[O:3]1.Br[C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=1>>[Cl:28][C:25]1[CH:26]=[CH:27][C:22]([N:16]2[CH2:15][CH2:14][N:13]([C:8]3[C:9]([CH3:12])=[C:10]([CH3:11])[C:4]4[O:3][C:2]([CH3:20])([CH3:1])[CH2:6][C:5]=4[C:7]=3[CH3:19])[CH2:18][CH2:17]2)=[CH:23][CH:24]=1
Reactant: Cc1c(C)c(N2CCNCC2)c(C)c2c1OC(C)(C)C2
Reactant: Clc1ccc(Br)cc1
Product: Cc1c(C)c(N2CCN(c3ccc(Cl)cc3)CC2)c(C)c2c1OC(C)(C)C2
Yield: 26 %

Procedure:
By using 1-(2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-yl)piperazine (274 mg, 1.00 mmol) synthesized in Reference example 61 and 1-bromo-4-chlorobenzene (287 mg, 1.50 mmol), the reaction was carried out in the same manner as Example 23 to obtain the title compound 100 mg (yield 26%).