Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:24])[CH2:9][N:10]([CH3:23])[S:11]([C:14]2[CH:18]=[C:17]([C:19](=[O:21])[CH3:20])[S:16][C:15]=2[NH2:22])(=[O:13])=[O:12])=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:32](Cl)(=[O:35])[CH2:33][CH3:34].O>O1CCCC1>[C:19]([C:17]1[S:16][C:15]([NH:22][C:32](=[O:35])[CH2:33][CH3:34])=[C:14]([S:11](=[O:13])(=[O:12])[N:10]([CH2:9][CH:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[OH:24])[CH3:23])[CH:18]=1)(=[O:21])[CH3:20]
Reactant: CCC(=O)Cl
Reactant: CC(=O)c1cc(S(=O)(=O)N(C)CC(O)c2ccc(F)cc2)c(N)s1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: CCC(=O)Nc1sc(C(C)=O)cc1S(=O)(=O)N(C)CC(O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 5-acetyl-2-amino-thiophene-3-sulfonic acid [2-(4-fluorophenyl)-2-hydroxy-ethyl]-methyl-amide (the compound of Preparation Example 99) (150 mg) and triethylamine (557 μL) in tetrahydrofuran was added propionic acid chloride (195 μL) in small amounts. After stirring at room temperature for 2 hours, triethylamine (557 μL) and propionic acid chloride (195 μL) were further added, and the solution was stirred for 30 minutes. Water was added to the reaction solution, the solution was extracted with ethyl acetate, and the organic layer was dried with anhydrous magnesium sulfate. The residue resulting from the removal of the solvent by evaporation was purified by silica gel column chromatography (hexane/ethyl acetate), and the title compound (75 mg) was obtained as a colorless solid.
Reaction SMILES: [F:1]C1C=CC(COC2CN(C(C3C=CC=CC=3)C3C=CC=CC=3)C2)=CC=1.Cl[C:28]1[CH:45]=[CH:44][C:31]([CH2:32][O:33][CH:34]2[CH2:37][N:36]([C:38]([NH:40][CH2:41][CH:42]=[CH2:43])=[O:39])[CH2:35]2)=[CH:30][CH:29]=1>>[F:1][C:28]1[CH:45]=[CH:44][C:31]([CH2:32][O:33][CH:34]2[CH2:37][N:36]([C:38]([NH:40][CH2:41][CH:42]=[CH2:43])=[O:39])[CH2:35]2)=[CH:30][CH:29]=1
Reactant: Fc1ccc(COC2CN(C(c3ccccc3)c3ccccc3)C2)cc1
Reactant: C=CCNC(=O)N1CC(OCc2ccc(Cl)cc2)C1
Product: C=CCNC(=O)N1CC(OCc2ccc(F)cc2)C1

Procedure:
This material was prepared from compound (9) using the procedure described for compound (2), m.p. 97-99° C. Found: C, 63.57; H, 6.59; N, 10.66. C14H17ClN2O2 requires C, 63.62; H, 6.48; N, 10.59.
Reaction SMILES: S(Cl)([Cl:3])=O.[NH2:5][CH2:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[CH:9][CH:8]=1.[CH3:16]O>>[ClH:3].[NH2:5][CH2:6][C:7]1[CH:8]=[CH:9][C:10]([C:11]([O:13][CH3:16])=[O:12])=[CH:14][CH:15]=1
Reactant: CO
Reactant: O=S(Cl)Cl
Reactant: NCc1ccc(C(=O)O)cc1
Product: COC(=O)c1ccc(CN)cc1
Product: Cl
Temperature: -30 °C
Reaction time: 1 h

Procedure:
3.3 cm3 of thionyl chloride are added over 10 minutes to 30 cm3 of methanol cooled to a temperature in the region of -30° C. Stirring is maintained for 30 minutes at a temperature in the region of -23° C. and then 4.7 g of 4-aminomethylbenzoic acid are added. The mixture is left to return to a temperature in the region of 20° C. over 1 hour. The mixture is treated with 15 cm3 of methanol and stirring is maintained for 15 hours at a temperature in the region of 20° C. The solid is separated by filtration, rinsed with a total of 90 cm3 of methanol and then with a total of 150 cm3 of diethyl ether. The solid is dried under reduced pressure (13.5 Pa) at a temperature in the region of 20° C. 3.2 g of methyl 4-aminomethylbenzoate hydrochloride are thus obtained in the form of a white solid melting at a temperature in the region of 270° C.
Reaction SMILES: [Cl:1]CCl.[OH:4][C:5]1[C:13]([O:14][CH3:15])=[CH:12][C:8]([C:9](O)=[O:10])=[CH:7][C:6]=1[N+:16]([O-:18])=[O:17].S(Cl)(Cl)=O.Cl>CN(C)C=O>[OH:4][C:5]1[C:13]([O:14][CH3:15])=[CH:12][C:8]([C:9]([Cl:1])=[O:10])=[CH:7][C:6]=1[N+:16]([O-:18])=[O:17]
Reactant: COc1cc(C(=O)O)cc([N+](=O)[O-])c1O
Reactant: ClCCl
Agent: Cl
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: COc1cc(C(=O)Cl)cc([N+](=O)[O-])c1O
Temperature: 40 °C

Procedure:
In a reactor 68 kg dichloromethane, 20 kg 5-nitro-vanillic acid of example 1b, 76 gram of N,N-dimethylformamide and 13.4 kg (8 L) thionyl chloride, was charged at 20.2° C. The mixture was heated to 40° C. until all the starting material dissolved and the evolution of HCl and SO2 stopped. When all the starting material was consumed 5-10 L dichloromethane was distilled off at normal pressure at 40° C. then the mixture was cooled to 20-25° C. and the distillation was continued until dry under vacuum at 40° C. The evaporation residue was dissolved in 36 kg dry THF. The THF solution was used in Example 4d.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-])=O.Br[CH2:17][CH2:18][CH2:19][N:20]1C(=O)C2=CC=CC=C2[C:21]1=[O:30].C(=O)([O-])[O-].[K+].[K+].O.NN.C[Si]([N:44]=C=O)(C)C>CN1CCCC1=O.C1COCC1>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][N:13]([CH2:17][CH2:18][CH2:19][NH:20][C:21]([NH2:44])=[O:30])[CH2:12][CH2:11]2)=[CH:6][CH:5]=1
Reactant: C[Si](C)(C)N=C=O
Reactant: O=[N+]([O-])c1ccc(N2CCNCC2)cc1
Reactant: O=C1c2ccccc2C(=O)N1CCCBr
Agent: NN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: O
Solvent: C1CCOC1
Product: NC(=O)NCCCN1CCN(c2ccc(N)cc2)CC1

Procedure:
1-(4-Nitrophenyl)piperazine and N-(3-bromopropyl)phthalimide were allowed to undergo the reaction under heating in 1-methyl-2-pyrrolidone in the presence of potassium carbonate. The resulting compound was allowed to react with hydrazine monohydrate in THF. The resulting compound was allowed to react with trimethylsilyl isocyanate in THF and then subjected to catalytic hydrogenation in the same manner as in Reference Example 3 to obtain {3-[4-(4-aminophenyl)piperazin-1-yl]propyl}urea. F: 276.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([F:11])[CH:3]=1.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1[C:27]2N=CC=[CH:31][C:26]=2[N:25]=N1.C(N(CC)C(C)C)(C)C.CC(N)C>C(Cl)Cl>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:25][CH:26]([CH3:31])[CH3:27])=[O:8])=[C:4]([F:11])[CH:3]=1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: O=C(O)c1ccc(Br)cc1F
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)N
Solvent: ClCCl
Product: CC(C)NC(=O)c1ccc(Br)cc1F
Reaction time: 1.5 h

Procedure:
A solution of 4-bromo-2-fluorobenzoic acid (1.50 g, 6.85 mmol, Combi-Blocks: Cat. # CA-4096), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (2.86 g, 7.53 mmol), and N,N-diisopropylethylamine (2.4 mL, 14 mmol) in methylene chloride (20. mL) was stirred for 10 minutes. 2-Propanamine (2.3 mL, 27 mmol) was then added and stirring was continued for 1.5 hours LC/MS data indicated that the major reaction component was the desired product. The reaction mixture was diluted with methylene chloride (40 mL) and H2O (3 mL). The layers were separated and the organic layer was washed with water (3×3 mL) and 1N HCl (3×3 mL). The combined aqueous phases were extracted with methylene chloride (5 mL). The combined organic layers were washed with brine (3 mL), dried over Na2SO4, filtered and concentrated in-vacuo. The crude product was purified by flash chromatography on a silica gel column eluting with ethyl acetate in hexanes (0-15%) to afford the desired product. LCMS (M+H)+: m/z=260.0/262.0.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[C:5]2[N:11]=[C:10]([CH2:12][CH:13]3[CH2:18][CH2:17][N:16]([C:19](=[O:23])[CH:20]([CH3:22])[CH3:21])[CH2:15][CH2:14]3)[CH:9]=[CH:8][C:6]=2[N:7]=1.[Si]([N:37]1[C:45]2[C:40](=[C:41](B3OC(C)(C)C(C)(C)O3)[C:42]([F:46])=[CH:43][CH:44]=2)[CH:39]=[CH:38]1)(C(C)(C)C)(C)C>>[F:46][C:42]1[C:41]([C:2]2[N:3]=[C:4]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[C:5]3[N:11]=[C:10]([CH2:12][CH:13]4[CH2:18][CH2:17][N:16]([C:19](=[O:23])[CH:20]([CH3:22])[CH3:21])[CH2:15][CH2:14]4)[CH:9]=[CH:8][C:6]=3[N:7]=2)=[C:40]2[C:45](=[CH:44][CH:43]=1)[NH:37][CH:38]=[CH:39]2
Reactant: CC(C)C(=O)N1CCC(Cc2ccc3nc(Cl)nc(N4CCOCC4)c3n2)CC1
Reactant: CC1(C)OB(c2c(F)ccc3c2ccn3[Si](C)(C)C(C)(C)C)OC1(C)C
Product: CC(C)C(=O)N1CCC(Cc2ccc3nc(-c4c(F)ccc5[nH]ccc45)nc(N4CCOCC4)c3n2)CC1

Procedure:
1-(4-((2-Chloro-4-morpholinopyrido[3,2-d]pyrimidin-6-yl)methyl)piperidin-1-yl)-2-methylpropan-1-one (60 mg) was reacted with 1-(tert-butyldimethylsilyl)-5-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole via General Procedure A to produce 19.9 mg of 149 following reverse phase HPLC purification.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)=[CH:10][C:9]=1[NH:21][C:22](=[O:35])[CH2:23][C:24]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([N+:32]([O-:34])=[O:33])[CH:27]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:20][C:17]1[CH:18]=[CH:19][C:14]([C:11]2[CH:12]=[CH:13][C:8]3[N:7]=[C:24]([C:26]4[CH:31]=[CH:30][CH:29]=[C:28]([N+:32]([O-:34])=[O:33])[CH:27]=4)[CH2:23][C:22](=[O:35])[NH:21][C:9]=3[CH:10]=2)=[CH:15][CH:16]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccc(F)cc2)cc1NC(=O)CC(=O)c1cccc([N+](=O)[O-])c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1CC(c2cccc([N+](=O)[O-])c2)=Nc2ccc(-c3ccc(F)cc3)cc2N1

Procedure:
Prepared from {4′-fluoro-3-[3-(3-nitro-phenyl)-3-oxo-propionylamino]-biphenyl-4-yl}-carbamic acid tert.-butyl ester (Example K42) by treatment with TFA in CH2Cl2 according to the general procedure M. Obtained as a light yellow solid (719 mg).
Reaction SMILES: [CH:1]1[C:6]2[C:7]([O:9][C:10](=[O:11])[C:5]=2[CH:4]=[C:3]2[C:12]([O:14][C:15](=[O:16])[C:2]=12)=[O:13])=[O:8].[Cl-].[Al+3].[Cl-].[Cl-].C(N(CC)[CH:25]([CH3:27])[CH3:26])(C)C.Cl.[CH3:31][C:32]1[CH:33]=[CH:34][C:35]([CH3:38])=[CH:36][CH:37]=1>ClCCCl>[CH3:15][C:2]1[CH:3]=[CH:27][C:25]([CH3:26])=[CH:6][C:1]=1[C:15]([C:2]1[CH:1]=[C:6]([C:7]([OH:9])=[O:8])[C:5]([C:10](=[O:11])[C:33]2[CH:34]=[C:35]([CH3:38])[CH:36]=[CH:37][C:32]=2[CH3:31])=[CH:4][C:3]=1[C:12]([OH:14])=[O:13])=[O:16]
Reactant: O=c1oc(=O)c2cc3c(=O)oc(=O)c3cc12
Reactant: CCN(C(C)C)C(C)C
Reactant: Cc1ccc(C)cc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: Cc1ccc(C)c(C(=O)c2cc(C(=O)O)c(C(=O)c3cc(C)ccc3C)cc2C(=O)O)c1
Temperature: 15 °C
Reaction time: 8 h

Procedure:
A mixture of 144 grams of benzene-1,2,4,5-tetracarboxylic acid dianhydride (pyromellitic dianhydride), 439 grams of aluminum chloride, and 915 grams of 1,2-dichloroethane was cooled to 15° C. To this was added a mixture of 140 grams of p-xylene, 109 grams of N,N-diisopropylethylamine, and 426 mL of 1,2-dichloroethane over a period of 3.5 hours keeping the temperature between 15° C. and 20° C. The resulting mixture was stirred overnight at room temperature, poured into 2876 grams of ice and 1078 mL concentrated hydrochloric acid and stirred for one hour. The organic layer was washed with 7 L of water. Three liters of water was poured off and the mixture allowed to stand for 4 days, after which the remaining 3 L of water was poured off. To the resulting residue was added 7 L of ethyl acetate and 3 L of tetrahydrofuran. The organic phase was separated and concentrated in vacuo. To 92 grams of the residue was added 1910 mL of ethyl acetate and the mixture was heated to 77° C. for one hour. The mixture was cooled to room temperature and the solid was collected by filtration and dried to give 2,5-bis(2,5-dimethybenzoyl)terephthalic acid.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([O:8][CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)=[CH:4][CH:3]=1.[CH2:22]([NH:24][C:25]([C:27]1[CH:28]=[C:29]2[C:33](=[CH:34][CH:35]=1)[NH:32][CH:31]=[CH:30]2)=[O:26])[CH3:23]>>[C:18]([O:17][C:15]([N:12]1[CH2:13][CH2:14][CH:9]([O:8][C:5]2[CH:6]=[N:7][C:2]([N:32]3[C:33]4[C:29](=[CH:28][C:27]([C:25](=[O:26])[NH:24][CH2:22][CH3:23])=[CH:35][CH:34]=4)[CH:30]=[CH:31]3)=[CH:3][CH:4]=2)[CH2:10][CH2:11]1)=[O:16])([CH3:21])([CH3:20])[CH3:19]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(Cl)nc2)CC1
Reactant: CCNC(=O)c1ccc2[nH]ccc2c1
Product: CCNC(=O)c1ccc2c(ccn2-c2ccc(OC3CCN(C(=O)OC(C)(C)C)CC3)cn2)c1

Procedure:
The title compound was prepared by following the similar procedure as described in Example-1 by using tert-butyl 4-((6-chloropyridin-3-yl)oxy)piperidine-1-carboxylate (intermediate-6) and N-ethyl-1H-indole-5-carboxamide (intermediate-15).
Reaction SMILES: F[C:2]1[C:11]2[C:10](=[O:12])[O:9][C:8](=[O:13])[NH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.NC1C=CC=C([Cl:24])C=1C(O)=O>>[Cl:24][C:2]1[C:11]2[C:10](=[O:12])[O:9][C:8](=[O:13])[NH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: Nc1cccc(Cl)c1C(=O)O
Reactant: O=c1[nH]c2cccc(F)c2c(=O)o1
Product: O=c1[nH]c2cccc(Cl)c2c(=O)o1

Procedure:
Prepared analogously to Compound 27E replacing 2-amino-6-fluorobenzoic acid with 2-amino-6-chlorobenzoic acid. 1H NMR (DMSO-d6, 400 MHz) δ=7.07 (dd, J=0.8, 8 Hz, 1H), 7.24-7.27 (m, 1H), 7.58-7.63 (m, 1H), 11.81 (brs, 1H).
Reaction SMILES: Cl[C:2]1[C:3]2[S:20][C:19]([NH2:21])=[N:18][C:4]=2[N:5]=[C:6]([S:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[C:11]=2[F:17])[N:7]=1.CCN(C(C)C)C(C)C.[NH2:31][C:32]([CH3:37])([CH3:36])[CH:33]([OH:35])O.[OH2:38]>CN1C(=O)CCC1>[NH2:21][C:19]1[S:20][C:3]2[C:2]([NH:31][C:32]([CH3:37])([CH2:33][OH:35])[CH2:36][OH:38])=[N:7][C:6]([S:8][CH2:9][C:10]3[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[C:11]=3[F:17])=[N:5][C:4]=2[N:18]=1
Reactant: Nc1nc2nc(SCc3cccc(F)c3F)nc(Cl)c2s1
Reactant: O
Reactant: CC(C)(N)C(O)O
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(CO)(CO)Nc1nc(SCc2cccc(F)c2F)nc2nc(N)sc12
Temperature: 110 °C
Yield: 42 %

Procedure:
The product from step (d) (1.5 g) was suspended in NMP (10 ml), then Hunigs base (1.5 ml) and 2-Amino-2-methylpropanediol (1.37 g) added. Reaction mixture heated to 110° C. under N2 for 4 hrs. A further aliquot of 2-Amino-2-methylpropanediol (0.685 g) was added and mixture heated at 110° C. for 5 hrs. Mixture poured in to water (400 ml) and solid was collected by filtration. Purified by column chromatography (EtOAc: Methanol (95:5)) to give 0.756 g of product. 42% yield.
Reaction SMILES: Cl[C:2]1[C:3]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=2.[CH3:23][C@H:24]1[CH2:28][CH2:27][CH2:26][NH:25]1.[CH2:29](O)[CH2:30][CH2:31]C>>[F:22][C:19]1[CH:20]=[CH:21][C:16]([C:3]2[C:2]([N:25]3[CH2:26][CH2:27][CH2:28][C@@H:24]3[CH3:23])=[N:11][C:10]3[C:5](=[CH:6][CH:7]=[C:8]([C:12]([O:14][CH2:15][CH2:29][CH2:30][CH3:31])=[O:13])[CH:9]=3)[N:4]=2)=[CH:17][CH:18]=1
Reactant: C[C@H]1CCCN1
Reactant: COC(=O)c1ccc2nc(-c3ccc(F)cc3)c(Cl)nc2c1
Reactant: CCCCO
Product: CCCCOC(=O)c1ccc2nc(-c3ccc(F)cc3)c(N3CCC[C@@H]3C)nc2c1
Temperature: 110 °C
Reaction time: 8 h

Procedure:
Into a 10-mL sealed tube, was placed methyl 3-chloro-2-(4-fluorophenyl)quinoxaline-6-carboxylate (150 mg, 0.47 mmol, 1.00 equiv), (S)-2-methylpyrrolidine (403 mg, 4.74 mmol, 9.99 equiv), butan-1-ol (2 mL). The resulting solution was stirred overnight at 110° C. in an oil bath. The resulting mixture was concentrated under vacuum. This resulted in 150 mg (crude) of (S)-butyl 2-(4-fluorophenyl)-3-(2-methylpyrrolidin-1-yl)quinoxaline-6-carboxylate as a yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH:12]=[O:13])[CH2:10][CH2:9][C:8]([C:14]([O:16]CC)=[O:15])=[CH:7][C:6]=2[CH:19]=1>[OH-].[Na+].C1COCC1.C(O)C.Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH:12]=[O:13])[CH2:10][CH2:9][C:8]([C:14]([OH:16])=[O:15])=[CH:7][C:6]=2[CH:19]=1
Reactant: CCOC(=O)C1=Cc2cc(Br)ccc2N(C=O)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: O=CN1CCC(C(=O)O)=Cc2cc(Br)ccc21
Temperature: 25 °C
Reaction time: 15 h
Yield: 99.6 %

Procedure:
In 1N sodium hydroxide (13.0 ml) and THF:ethanol (1:1, 50 ml) was dissolved ethyl 7-bromo-1-formyl-2,3-dihydro-1-benzazepine-4-carboxylate (2.77 g), and the mixture was stirred at room temperature for 15 hours. To the mixture was added IN hydrochloric acid (12.5 ml), and the mixture was concentrated. To the residue was added water (200 ml), and the mixture was adjusted to pH 2 with 1N hydrochloric acid. The mixture was extracted with ethyl acetate (300 ml×3), and the organic layer was dried with magnesium sulfate. The solvent was evaporated under reduced pressure to give 7-bromo-1-formyl-2,3-dihydro-1-benzazepine-4-carboxylic acid (2.52 g, 100%).
Reaction SMILES: [N:1]([C:38]([CH2:40][O:41][CH2:42][C:43]([OH:45])=O)=[O:39])([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].Cl.CN(C)CCCN=C=NCC.[NH2:58][CH2:59][C:60]([O:62][CH2:63][C:64]1[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=1)=[O:61].CC1C=CC(S(O)(=O)=O)=CC=1>C(Cl)Cl.CCN(CC)CC>[N:1]([C:38]([CH2:40][O:41][CH2:42][C:43]([NH:58][CH2:59][C:60]([O:62][CH2:63][C:64]1[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=1)=[O:61])=[O:45])=[O:39])([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]
Reactant: CCCCCCCCCCCCCCCCCCN(CCCCCCCCCCCCCCCCCC)C(=O)COCC(=O)O
Reactant: NCC(=O)OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCCCCN(CCCCCCCCCCCCCCCCCC)C(=O)COCC(=O)NCC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 70 %

Procedure:
To a solution of (C18H37)2NCOCH2OCH2COOH (1.0 g, 1.5 mmol) in CH2Cl2 (30 mL) was added 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride (0.31 g, 1.6 mmol) and the reaction was stirred at room temperature. After 0.5 h, Gly-OCH2Ph.TsOH (0.53 g, 1.5 mmol) and Et3N (0.6 mL) were added and the mixture was stirred overnight. The reaction mixture was washed with water (20 mL), 0.5 M aqueous HCl (20 mL), water (20 mL), 10% aqueous Na2CO3 (20 mL), and brine (20 mL) then dried over MgSO4, evaporated and the residue crystallized from MeOH yielding (C18H37)2NCOCH2OCH2CO-Gly-OCH2Ph as a deliquescent white solid (0.86 g, 70%), mp 38–40° C. 1H-NMR (300 MHz, δ, CDCl3) 0.86 (6H, t, J=6.9 Hz), 1.24 (64H, m), 1.50 (4H, bs), 3.06 (2H, t, J=7.5 Hz), 3.28 (2H, t, J=7.5 Hz), 4.10 (2H, s), 4.12 (2H, s), 4.25 (2H, s), 5.15 (2H, s), 7.33 (5H, m), 8.20 (1H, t, J=5.7 Hz). 13C-NMR (75 MHz, 6, CDCl3): 14.2, 22.7, 26.9, 27.1, 27.6, 29.0, 29.39, 29.44, 29.5, 29.6, 29.7, 29.8, 32.0, 40.8, 46.3, 47.0, 67.1, 69.7, 71.8, 128.5, 128.6, 128.8, 135.3, 168.5, 169.8, 170.6.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH:10]=[N:9][C:8]([OH:12])=[CH:7]2.IC.O.[C:16](OCC)(=O)C>CN(C=O)C.C(=O)([O-])[O-].[Ag+2]>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH:10]=[N:9][C:8]([O:12][CH3:16])=[CH:7]2
Reactant: CCOC(C)=O
Reactant: Oc1cc2cccc(Br)c2cn1
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Solvent: CI
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc2cccc(Br)c2cn1
Temperature: 50 °C
Reaction time: 24 h
Yield: 22 %

Procedure:
To a suspension of 8-bromoisoquinolin-3-ol (Description 53; 7.3 g, 0.03 mol) and silver carbonate (13.6 g, 0.05 mol) in dry DMF (380 ml) under nitrogen was added iodomethane (2.25 ml, 0.04 mol). The mixture was stirred at 50° C. for 24 hours. Further iodomethane (1 ml, 0.015 mol) was added and the mixture heated for 64 hours at 50° C. The mixture was cooled, water (300 ml) and ethyl acetate (300 ml) were added and shaken well. The mixture was filtered through Celite™, the layers separated and the aqueous layer was extracted with ethyl acetate (3×50 ml). The organic layers were combined, evaporated to ˜150 ml, washed twice with water and then brine. The organic extract was then evaporated to give the title compound (1.7 g, 22%).
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([N+:17]([O-:19])=[O:18])[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1.[F:20]C1C=C(O)C=CC=1[N+]([O-])=O.FC1C=C(C=CC=1)CBr>>[F:20][C:5]1[CH:6]=[C:7]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=2)[CH:2]=[CH:3][C:4]=1[N+:17]([O-:19])=[O:18]
Reactant: O=[N+]([O-])c1ccc(OCc2cccc(F)c2)c(F)c1
Reactant: O=[N+]([O-])c1ccc(O)cc1F
Agent: Fc1cccc(CBr)c1
Product: O=[N+]([O-])c1ccc(OCc2cccc(F)c2)cc1F

Procedure:
Prepared in analogy to 3-fluoro-4-(3-fluoro-benzyloxy)-nitrobenzene, starting from 3-fluoro-4-nitrophenol and 3-fluorobenzyl bromide. Yield after recrystallisation from diethyl ether/hexane: 100% of a white solid. MS: m/e=265.0 (M+).
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[CH2:5][C@@:4]1([CH2:12][N:13]([CH3:23])[S:14]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)(=[O:16])=[O:15])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[OH-].[Na+]>C(Cl)Cl.CC(O)(C)C.C(OCC)C>[CH:2]([C@@H:3]1[CH2:5][C@@:4]1([CH2:12][N:13]([CH3:23])[S:14]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)(=[O:15])=[O:16])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:1]
Reactant: CN(C[C@@]1(c2ccccc2)C[C@H]1CO)S(=O)(=O)c1ccccc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCOCC
Solvent: CC(C)(C)O
Product: CN(C[C@@]1(c2ccccc2)C[C@H]1C=O)S(=O)(=O)c1ccccc1
Yield: 45.1 %

Procedure:
N-{[(1S,2R)-2-(hydroxymethyl)-1-phenylcyclopropyl]methyl}-N-methylbenzenesulfonamide (600 mg, 1.82 mmol), accessed via the method of preparation 7A, was dissolved in 18 mL DCM with 270 uL 2-methylpropan-2-ol and treated with Dess-Martin Periodinane (1.23 g, 2.90 mmol, 1.6 eq) at ambient temperature for 16 h. The reaction mixture was diluted with 42 mL diethyl ether and treated with 22 mL 1N NaOH at ambient temperature for 15 min. The organic phase was separated, the aqueous phase extracted twice with diethyl ether, the organic phases combined, washed with brine, dried over MgSO4, filtered and concentrated to a colorless oil. The crude material was purified by flash chromatography (SiO2, eluted successively with DCM, EtOAc/hexanes (1:4)) to the title product (270 mg, 0.82 mmol, 45%) as a colorless oil. 1H NMR (300 MHz, CDCl3) δ 9.82 (d, J=3.8 Hz, 1H), 7.65-7.28 (m, 10H), 3.53-3.43 (m, 2H), 2.42 (s, 3H), 2.34-2.32 (m, 1H), 1.90-1.87 (m, 1H), 1.70-1.66 (m, 1H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14](=[O:15])[N:13]2[CH2:16][CH2:17][N:18]([CH:19]([CH3:21])[CH3:20])[C:12]2=[N:11][C:10]=1[C:22]([OH:24])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[F:26][C:27]1[CH:32]=[CH:31][C:30]([CH2:33][NH2:34])=[C:29]([N:35]2[CH:39]=[N:38][CH:37]=[N:36]2)[CH:28]=1>>[F:26][C:27]1[CH:32]=[CH:31][C:30]([CH2:33][NH:34][C:22]([C:10]2[N:11]=[C:12]3[N:18]([CH:19]([CH3:20])[CH3:21])[CH2:17][CH2:16][N:13]3[C:14](=[O:15])[C:9]=2[O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:24])=[C:29]([N:35]2[CH:39]=[N:38][CH:37]=[N:36]2)[CH:28]=1
Reactant: NCc1ccc(F)cc1-n1cncn1
Reactant: CC(C)N1CCn2c1nc(C(=O)O)c(OCc1ccccc1)c2=O
Agent: Cl
Product: CC(C)N1CCn2c1nc(C(=O)NCc1ccc(F)cc1-n1cncn1)c(OCc1ccccc1)c2=O
Yield: 76.2 %

Procedure:
Coupling of 6-(benzyloxy)-1-isopropyl-5-oxo-1,2,3,5-tetrahydroimidazo[1,2-a]pyrimidine-7-carboxylic acid (0.300 g, 0.91 mmol) and (4-fluoro-2-(1H-1,2,4-triazol-1-yl)phenyl)methanamine hydrochloride (0.210 g, 0.96 mmol) as described for the synthesis of intermediate 3 gave 0.349 g (76% yield) of the title amide as white crystals; mp 171-172° C. (ethyl acetate). 1HNMR 400 MHz (CDCl3) δ (ppm): 1.24 (6H, d, J=6.8 Hz, 2×CH3), 3.66 (2H, t, J=9 Hz, CH2), 4.13 (2H, t, J=9 Hz, CH2), 4.41 (2H, d, J=6.3 Hz, NCH2), 4.43 (1H, m, CH), 5.10 (2H, s, OCH2), 7.06 (1H, dd, J=2.6 Hz and J=8.6 Hz, aromatic), 7.17 (1H, m, aromatic), 7.29-7.31 (3H, m, aromatics), 7.45-7.48 (2H, m, aromatics), 7.71 (1H, dd, J=5.9 Hz and J=8.6 Hz, aromatic), 8.0 (1H, s, CH), 8.36 (1H, broad t, NH), 8.39 (1H, s, CH). Anal. Calcd for C26H26FN7O3: C, 62.01; H, 5.20; N, 19.47. Found: C, 62.00; H, 5.20; N, 19.50.