Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[S:12][C:11]([NH:13]C(=O)C)=[N:10][C:9]=2[CH3:17])=[CH:4][C:3]=1[NH:18][S:19]([C:22]1[S:26][C:25]([CH3:27])=[N:24][C:23]=1[CH3:28])(=[O:21])=[O:20].Cl>>[NH2:13][C:11]1[S:12][C:8]([C:5]2[CH:4]=[C:3]([NH:18][S:19]([C:22]3[S:26][C:25]([CH3:27])=[N:24][C:23]=3[CH3:28])(=[O:21])=[O:20])[C:2]([Cl:1])=[N:7][CH:6]=2)=[C:9]([CH3:17])[N:10]=1
Reactant: CC(=O)Nc1nc(C)c(-c2cnc(Cl)c(NS(=O)(=O)c3sc(C)nc3C)c2)s1
Agent: Cl
Product: Cc1nc(C)c(S(=O)(=O)Nc2cc(-c3sc(N)nc3C)cnc2Cl)s1

Procedure:
Using an analogous procedure to that described in Example 61, N-{5-[6-chloro-5-(2,4-dimethyl-1,3-thiazol-5-ylsulfonamido)pyridin-3-yl]-4-methyl-1,3-thiazol-2-yl}acetamide was hydrolysed with aqueous hydrochloric acid solution to give the title compound; 1H NMR Spectrum: (DMSOd6) 2.18 (s, 3H), 2.35 (s, 3H), 2.61 (s, 3H), 7.30 (s, 2H), 7.64 (d, 11H), 8.22 (s, 1H), 10.80 (br s, 1H); Mass Spectrum: M+H+ 416.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=5[C:20](=[O:27])[O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[F:28][C:29]1[CH:30]=[C:31](B(O)O)[CH:32]=[CH:33][CH:34]=1>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=5[C:20](=[O:27])[O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][N:8]2[C:33]2[CH:32]=[CH:31][CH:30]=[C:29]([F:28])[CH:34]=2)=[CH:4][CH:3]=1
Reactant: O=C1OC2(CCN(C(=O)c3c[nH]c4cc(Cl)ccc34)CC2)c2ccccc21
Reactant: OB(O)c1cccc(F)c1
Product: O=C1OC2(CCN(C(=O)c3cn(-c4cccc(F)c4)c4cc(Cl)ccc34)CC2)c2ccccc21

Procedure:
Following the general procedure VI as described above, the arylation of 1′-[(6-chloro-1H-indol-3-yl)carbonyl]-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one (prepared according to example 16 above) with commercially available 3-fluorophenylboronic acid gave the title compound. ES-MS m/e (%): 475.0(M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5][PH:6](=[O:9])[O:7]C)=[CH2:4].[I-].[Na+:11]>CC(CC)=O>[CH3:1][O:2][C:3]([CH2:5][PH:6](=[O:7])[O-:9])=[CH2:4].[Na+:11]
Reactant: C=C(C[PH](=O)OC)OC
Agent: [I-]
Agent: [Na+]
Solvent: CCC(C)=O
Product: C=C(C[PH](=O)[O-])OC

Procedure:
A solution of the product of step (a) (0.43 g, 2.87 mmol) and oven dried sodium iodide (0.43 g, 2.87 mol) in distilled ethyl methyl ketone (6 ml) was stirred and refluxed for 16 h.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[C:12]([CH3:14])[CH:11]=[CH:10][C:9]=2[CH3:15])[N:5]=[C:4]([NH2:16])[N:3]=1.[NH2:17][C:18]1[CH:26]=[CH:25][C:21]([CH2:22][CH2:23][OH:24])=[CH:20][CH:19]=1>>[NH2:16][C:4]1[N:3]=[C:2]([NH:17][C:18]2[CH:26]=[CH:25][C:21]([CH2:22][CH2:23][OH:24])=[CH:20][CH:19]=2)[CH:7]=[C:6]([C:8]2[CH:13]=[C:12]([CH3:14])[CH:11]=[CH:10][C:9]=2[CH3:15])[N:5]=1
Reactant: Nc1ccc(CCO)cc1
Reactant: Cc1ccc(C)c(-c2cc(Cl)nc(N)n2)c1
Product: Cc1ccc(C)c(-c2cc(Nc3ccc(CCO)cc3)nc(N)n2)c1

Procedure:
Following the method described in Example 4, 4-chloro-6-(2,5-dimethyl-phenyl)-pyrimidin-2-yl-amine and 4-aminophenethyl alcohol provided the title compound as hydrochloride salt (85% yield). 1H NMR (DMSO-d6) δ 2.29 (s, 6H, CH3), 6.30 (s, 1H, Ar), 7.24-7.31 (m, 5H, Ar), 7.68 (d, 2H, J=8.0 Hz, Ar), 10.67 (s, 1H), 12.54 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH2:8][N:9]2[C:12](=[O:17])[C:13]([F:16])([F:15])[F:14])=[CH:4][CH:3]=1.[C:18]1([C:24]2[CH:32]=[CH:31][C:27]([C:28](O)=[O:29])=[CH:26][N:25]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.Cl.CN(C)CCCN=C=NCC>C(Cl)Cl.CN(C)C1C=CN=CC=1>[C:18]1([C:24]2[CH:32]=[CH:31][C:27]([C:28]([NH:1][C:2]3[CH:11]=[C:10]4[C:5]([CH2:6][CH2:7][CH2:8][N:9]4[C:12](=[O:17])[C:13]([F:16])([F:14])[F:15])=[CH:4][CH:3]=3)=[O:29])=[CH:26][N:25]=2)[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: Nc1ccc2c(c1)N(C(=O)C(F)(F)F)CCC2
Reactant: O=C(O)c1ccc(-c2ccccc2)nc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: O=C(Nc1ccc2c(c1)N(C(=O)C(F)(F)F)CCC2)c1ccc(-c2ccccc2)nc1
Temperature: 25 °C

Procedure:
To a solution of 7-amino-1-trifluoroacetyl-1,2,3,4-tetrahydroquinoline (D5) (122 mg, 0.5 mmol) in DCM (2 ml) was added 6-phenylnicotinic acid (D48) (119 mg, 0.6 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (111 mg, 0.6 mmol) and 4-dimethylaminopyridine (7 mg, 0.06 mmol) and the reaction stirred at ambient temperature for until complete by tlc. The mixture was then washed with 2M sodium hydroxide solution (1 ml), dried over magnesium sufate and concentrated in vacuo to give the crude product which was purified by silica SPE chromatography. Elution with 20% EtOAc/60-80° C. petroleum ether gave an off-white solid which was recrystallised from EtOAc/60-80° C. petroleum ether giving the title compound as a white solid. 1H NMR (250 MHz, CDCl3) δ (ppm): 9.10 (d, 1H), 8.20 (m, 2H), 8.04 (m, 2H), 7.86 (br, 1H), 7.82 (dd, 1H), 7.72 (br, 1H), 7.50 (m, 3H), 7.19 (1H, d), 3.84 (m, 2H), 2.84 (m, 2H), 2.06 (m, 2H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[N:14]=[CH:13][C:12]([CH:15]=O)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:17]([CH3:20])([O-:19])=[O:18].C([O-])(=O)C.[NH4+]>C(O)(=O)C>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12](/[CH:15]=[CH:20]/[N+:17]([O-:19])=[O:18])=[CH:13][N:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[N+](=O)[O-]
Reactant: O=Cc1ccc(OCc2ccccc2)nc1
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Product: O=[N+]([O-])/C=C/c1ccc(OCc2ccccc2)nc1
Temperature: 110 °C
Reaction time: 2.5 h
Yield: 95.8 %

Procedure:
To a solution of 6-benzyloxy-pyridin-3-carbaldehyde (4.87 g, 22.8 mmol) described in Manufacturing Example 12-1-2 in acetic acid (30 mL) were added nitromethane (6.96 g, 114 mmol) and ammonium acetate (3.51 g, 45.6 mmol) under nitrogen atmosphere at room temperature, which was stirred for 2.5 hours at 110° C. The reaction mixture was partitioned into water and ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under a reduced pressure to obtain the title compound (5.60 g, 96%) as a crude product.
Reaction SMILES: [Br:1][C:2]1[O:6][C:5]([C:7]([NH:9][NH2:10])=[O:8])=[CH:4][CH:3]=1.[OH-].[K+].CO.[C:15](=S)=[S:16]>O>[Br:1][C:2]1[O:6][C:5]([C:7]2[O:8][C:15]([SH:16])=[N:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: S=C=S
Reactant: NNC(=O)c1ccc(Br)o1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Sc1nnc(-c2ccc(Br)o2)o1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
5-Bromo-furan-2-carboxylic acid hydrazide (20.5 g, 100 mmol) was added to a mixture of potassium hydroxide (6.2 g, 110 mmol) and methanol (125 ml). The mixture was stirred for 30 minutes at room temperature. Carbon disulfide (15.2 g, 200 mmol) was added. The mixture was stirred at reflux for 30 hours. Water (60 ml) was added and the excess of carbon disulfide and methanol was evaporated. The aqueous suspension was acidified by adding concentrated hydrochloric acid (14 ml). The product precipitated and was washed with water (20 ml), dried and evaporated. Yield 8.58 g (35%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:9]2[N:13]([CH2:14][CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]3)[C:12]3[CH:21]=[CH:22][CH:23]=[CH:24][C:11]=3[N:10]=2)=[C:6]([OH:8])[CH:7]=1.Br[CH2:26][C:27]1[CH:34]=[CH:33][C:30]([C:31]#[N:32])=[CH:29][C:28]=1[F:35]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:9]2[N:13]([CH2:14][CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]3)[C:12]3[CH:21]=[CH:22][CH:23]=[CH:24][C:11]=3[N:10]=2)=[C:6]([CH:7]=1)[O:8][CH2:26][C:27]1[CH:34]=[CH:33][C:30]([C:31]#[N:32])=[CH:29][C:28]=1[F:35]
Reactant: Oc1cc(Cl)ccc1-c1nc2ccccc2n1CC1CCCCC1
Reactant: N#Cc1ccc(CBr)c(F)c1
Product: N#Cc1ccc(COc2cc(Cl)ccc2-c2nc3ccccc3n2CC2CCCCC2)c(F)c1

Procedure:
The title compound was prepared in analogy to Example 19, from 5-chloro-2-(1-cyclohexylmethyl-1H-benzoimidazol-2-yl)-phenol and 4-bromomethyl-3-fluoro-benzonitrile (105942-09-4). Brown solid (69%). MS (Turbo Spray): m/z=474.4 (M+H).
Reaction SMILES: Cl[C:2]1[N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[CH:5]=[C:4]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH3:20])[CH:12]=2)[N:3]=1.[NH2:21][CH2:22][C:23]1[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=1.C(N(C(C)C)CC)(C)C>CC(O)C>[CH3:20][O:19][C:13]1[CH:12]=[C:11]([C:4]2[N:3]=[C:2]([NH:21][CH2:22][C:23]3[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=3)[N:7]3[CH:8]=[CH:9][N:10]=[C:6]3[CH:5]=2)[CH:16]=[CH:15][C:14]=1[O:17][CH3:18]
Reactant: COc1ccc(-c2cc3nccn3c(Cl)n2)cc1OC
Reactant: NCc1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: COc1ccc(-c2cc3nccn3c(NCc3ccncc3)n2)cc1OC
Temperature: 90 °C
Reaction time: 20 h
Yield: 52.6 %

Procedure:
The mixture of 5-chloro-7-(3,4-dimethoxyphenyl)-imidazo[1,2-c]pyrimidine (57.94 mg, 0.2 mmol), 4-aminomethylpyridine (23.79 mg, 0.22 mmol), and diisopropylethylamine (38.78, 0.3 mmol) in 2-propanol was stirred at 90° C. for 20 h, and cooled to room temperature. The solvent was evaporated, and 5 ml of ice water was added. Then the resulting product was extracted with 2×10 ml of ethyl acetate. The combined extract was dried over MgSO4. Then the solvent was evaporated and 2 ml of ether was added. The produced solid was collected by filtration and dried to give pure product (38 mg, 52.6%) of [7-(3,4-dimethoxy-phenyl)-imidazo[1,2-c]pyrimidin-5-yl]pyridin-4-ylmethyl-amine.
Reaction SMILES: S(S([O-])=O)([O-])=O.[Na+].[Na+].[N+:9]([C:12]1[C:13]([NH:22][S:23]([CH2:26][CH3:27])(=[O:25])=[O:24])=[N:14][CH:15]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:17]=1)([O-])=O.[Cl-].[Na+]>O.O1CCCC1>[NH2:9][C:12]1[C:13]([NH:22][S:23]([CH2:26][CH3:27])(=[O:25])=[O:24])=[N:14][CH:15]=[C:16]([C:18]([F:21])([F:19])[F:20])[CH:17]=1
Reactant: CCS(=O)(=O)Nc1ncc(C(F)(F)F)cc1[N+](=O)[O-]
Agent: O=S([O-])S(=O)[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCS(=O)(=O)Nc1ncc(C(F)(F)F)cc1N
Yield: 93.4 %

Procedure:
An alternative process will be described. To a solution prepared by dissolving 34.9 g of sodium hydrosulfite in 400 ml of water, a solution prepared by dissolving 5.0 g of N-(3-nitro-5-trifluoromethyl-2-pyridyl)ethanesulfonamide in 80 ml of tetrahydrofuran, was dropwise added at room temperature. After completion of the dropwise addition, the mixture was reacted for further 3 hours. After completion of the reaction, sodium chloride was added until the tetrahydrofuran layer was separated. The separated tetrahydrofuran layer was dried, and tetrahydrofuran was distilled off under reduced pressure to obtain 4.2 g of N-(3-amino-5-trifluoromethyl-2-pyridyl)ethanesulfonamide.
Reaction SMILES: [CH2:1]([C:4]1[C:13]2[O:12][C:11]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:10][C:9](=[O:19])[C:8]=2[C:7]([O:20][CH2:21][CH:22]([OH:24])[CH3:23])=[CH:6][CH:5]=1)[CH:2]=[CH2:3].[H][H]>C(O)C.[Pd]>[OH:24][CH:22]([CH3:23])[CH2:21][O:20][C:7]1[C:8]2[C:9](=[O:19])[CH:10]=[C:11]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[O:12][C:13]=2[C:4]([CH2:1][CH2:2][CH3:3])=[CH:5][CH:6]=1
Reactant: C=CCc1ccc(OCC(C)O)c2c(=O)cc(C(=O)OCC)oc12
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCCc1ccc(OCC(C)O)c2c(=O)cc(C(=O)OCC)oc12

Procedure:
To a suspension of ethyl 8-allyl-5-(2-hydroxypropoxy)-4-oxo-4H-1-benzopyran-2-carboxylate (1.2 g) in ethanol (50 ml) was added 5% palladium on charcoal (0.2 g). The resulting suspension was then hydrogenated at a pressure of 4 atmospheres. After 30 minutes hydrogen uptake had ceased. The reaction mixture was filtered and the filtrate evaporated in vacuo. The residual solid was crystallised from ethanol giving ethyl 5-(2-hydroxypropoxy)-4-oxo-8-propyl-4H-1-benzopyran-2-carboxylate identical in all respects with authentic material.
Reaction SMILES: [CH:1]([N:14]1[CH2:17][CH:16](OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N-:29]=[N+:30]=[N-:31].[Na+]>CN(C=O)C>[N:29]([CH:16]1[CH2:17][N:14]([CH:1]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:15]1)=[N+:30]=[N-:31]
Reactant: Cc1ccc(S(=O)(=O)OC2CN(C(c3ccccc3)c3ccccc3)C2)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: [N-]=[N+]=NC1CN(C(c2ccccc2)c2ccccc2)C1
Temperature: 25 °C

Procedure:
A solution of 9 (11.5 g, 31.8 mmol) and sodium azide (4.12 g, 64 mmol) in 250 ml of DMF was heated to 70° C. for 24 hours. After cooling to room temperature the solvent was removed in vacuo and the residue partitioned between chloroform and water. The organics were dried over MgSO4, filtered and the solvent removed in vacuo. The crude product was purified by chromatography on silica gel (8:1 hexane: ethyl acetate) afforded the title compound.
Reaction SMILES: C1C=CC2N(O)N=[N:7]C=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.CCN(C(C)C)C(C)C.[CH3:33][C:34]1[C:35]([CH2:47][CH2:48][C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][C:50]=2[CH2:55][C:56]([OH:58])=O)=[N:36][C:37]([NH:40][C:41]2[CH:42]=[N:43][N:44]([CH3:46])[CH:45]=2)=[N:38][CH:39]=1.C(=O)([O-])[O-].[NH4+].[NH4+]>CN(C=O)C>[CH3:33][C:34]1[C:35]([CH2:47][CH2:48][C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][C:50]=2[CH2:55][C:56]([NH2:7])=[O:58])=[N:36][C:37]([NH:40][C:41]2[CH:42]=[N:43][N:44]([CH3:46])[CH:45]=2)=[N:38][CH:39]=1
Reactant: On1nnc2ccccc21
Reactant: Cc1cnc(Nc2cnn(C)c2)nc1CCc1ccccc1CC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cnc(Nc2cnn(C)c2)nc1CCc1ccccc1CC(N)=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 60.1 %

Procedure:
HOBt (0.074 g, 0.55 mmol), EDCl.HCl (0.117 g, 0.610 mmol) and DIPEA (0.16 mL, 0.94 mmol) were added to a solution of 2-(2-(2-(5-methyl-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)ethyl)phenyl)acetic acid (A117) (0.066 g, 0.19 mmol) in dry DMF (5 mL) under an atmosphere of nitrogen. After 10 minutes ammonium carbonate (0.180 g, 1.88 mmol) was added in one portion and the resulting mixture stirred for 18 hours at room temperature. The volatiles were removed in vacuo and the residue partitioned between EtOAc (50 mL) and aqueous saturated NaHCO3 (50 mL). The aqueous layer was extracted with EtOAc (2×25 mL). The combined organic layers were washed with brine (25 mL) and dried over Na2SO4. The solvent was removed in vacuo and the residue purified by silica gel column chromatography (Biotage Isolera, 24 g SiO2 cartridge, 0-100% EtOAc in petroleum benzine 40-60° C. followed by 0-30% MeOH in EtOAc) to give the title compound 28 as a yellow solid (0.040 g, 61%); 1H NMR (400 MHz, d6-DMSO) δ 9.18 (s, 1H), 8.10 (s, 1H), 7.86 (s, 1H), 7.43 (s, 2H), 7.28-7.10 (m, 4H), 6.93 (s, 1H), 3.78 (s, 3H), 3.49 (s, 2H), 3.07-2.98 (m, 2H), 2.90-2.81 (m, 2H), 2.04 (s, 3H). LCMS-A: rt 4.464 min; m/z 351 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:12])[C:9]([OH:11])=O)=[CH:4][CH:3]=1.[NH2:13][CH2:14][CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][CH:20]([C:23]2[CH:24]=[C:25]([NH:29][C:30](=[O:34])[CH2:31][CH2:32][CH3:33])[CH:26]=[CH:27][CH:28]=2)[CH2:19][CH2:18]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([CH3:12])[C:9]([NH:13][CH2:14][CH2:15][CH2:16][N:17]2[CH2:22][CH2:21][CH:20]([C:23]3[CH:24]=[C:25]([NH:29][C:30](=[O:34])[CH2:31][CH2:32][CH3:33])[CH:26]=[CH:27][CH:28]=3)[CH2:19][CH2:18]2)=[O:11])=[CH:6][CH:7]=1
Reactant: CC(C(=O)O)c1ccc(Cl)cc1
Reactant: CCCC(=O)Nc1cccc(C2CCN(CCCN)CC2)c1
Product: CCCC(=O)Nc1cccc(C2CCN(CCCNC(=O)C(C)c3ccc(Cl)cc3)CC2)c1

Procedure:
Example 77 was prepared from 2-(4-chlorophenyl)propanoic acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}butanamide according to the procedures described in Scheme 10: 1H NMR (400 MHz, CDCl3) δ 7.56 (s, 1H), 7.41 (s, 1H), 7.30–7.27 (m, 6H), 6.96 (m, 2H), 3.51 (q, 1H, J=7.2 Hz), 3.50–3.30 (m, 2H), 3.02 (d, 1H, J=10.8 Hz), 2.92 (d, 1H, J=13.6 Hz), 2.50 (m, 1H), 2.41–2.34 (m, 4H), 1.99–1.94 (m, 2H), 1.86–1.58 (m, 8H), 1.51 (d, 3H, J=7.2 Hz), 1.02 (t, 3H, J=7.6 Hz); ESMS m/e: 470.3 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]([O:12][C:13]([F:16])([F:15])[F:14])=[CH:8][C:4]=1[C:5]([OH:7])=O.S(Cl)(Cl)=O.[CH3:21][O:22][C:23]1[CH:24]=[C:25]([CH:27]=[CH:28][C:29]=1[C:30]1[S:31][C:32]2[CH:38]=[C:37]([O:39][CH3:40])[CH:36]=[CH:35][C:33]=2[N:34]=1)[NH2:26]>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]([O:12][C:13]([F:16])([F:15])[F:14])=[CH:8][C:4]=1[C:5]([NH:26][C:25]1[CH:27]=[CH:28][C:29]([C:30]2[S:31][C:32]3[CH:38]=[C:37]([O:39][CH3:40])[CH:36]=[CH:35][C:33]=3[N:34]=2)=[C:23]([O:22][CH3:21])[CH:24]=1)=[O:7]
Reactant: COc1ccc2nc(-c3ccc(N)cc3OC)sc2c1
Reactant: COc1ccc(OC(F)(F)F)cc1C(=O)O
Solvent: O=S(Cl)Cl
Solvent: c1ccncc1
Product: COc1ccc2nc(-c3ccc(NC(=O)c4cc(OC(F)(F)F)ccc4OC)cc3OC)sc2c1
Temperature: 25 °C
Yield: 73.4 %

Procedure:
A stirred mixture of 2-methoxy-5-trifluoromethoxybenzoic acid (0.248 g, 1.05 mmol) and thionyl chloride (4 ml) was heated under reflux for 4 h. After cooling to room temperature, the excess reagent was removed under reduced pressure to give the crude acid chloride. The amide was prepared as described in the Amide Coupling section using the crude acid chloride and 3-methoxy-4-(6-methoxy-1,3-benzothiazol-2-yl)aniline (0.30 g, 1.05 mmol) in dry pyridine (8 ml) to give the title compound (0.389 g, 73%) as an almost colourless solid after work-up and recrystallisation from acetic acid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][CH2:8][CH2:9][CH2:10][NH:11][C:12]([N:14]=[CH:15]N(C)C)=[S:13])([CH3:4])([CH3:3])[CH3:2].[F:20][C:21]([F:33])([F:32])[C:22]1[CH:31]=[CH:30][CH:29]=[CH:28][C:23]=1[C:24](=[O:27])[CH2:25]Br>>[C:1]([O:5][C:6](=[O:19])[NH:7][CH2:8][CH2:9][CH2:10][NH:11][C:12]1[S:13][C:25]([C:24](=[O:27])[C:23]2[CH:28]=[CH:29][CH:30]=[CH:31][C:22]=2[C:21]([F:20])([F:32])[F:33])=[CH:15][N:14]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: O=C(CBr)c1ccccc1C(F)(F)F
Reactant: CN(C)C=NC(=S)NCCCNC(=O)OC(C)(C)C
Product: CC(C)(C)OC(=O)NCCCNc1ncc(C(=O)c2ccccc2C(F)(F)F)s1

Procedure:
The title compound was synthesised from [3-(3-Dimethylaminomethylene-thioureido)-propyl]-carbamic acid tert-butyl ester and 2-trifluoromethyl phenacylbromide (literature: EP 432040) according to the procedure described for Example 25. MS (m/e): 429.9 (MH+, 100%).
Reaction SMILES: [N:1]([O-:3])=O.[Na+].[CH:5](=[C:12]1[NH:16][C:15](=[O:17])[CH:14]=[C:13]1[OH:18])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>C(O)(=O)C>[CH:5](=[C:12]1[NH:16][C:15](=[O:17])[C:14](=[N:1][OH:3])[C:13]1=[O:18])[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: O=C1C=C(O)C(=Cc2ccccc2)N1
Reactant: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: O=C1NC(=Cc2ccccc2)C(=O)C1=NO
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
An aqueous solution of 1.1 mmol (0.075 g) sodium nitrite was added dropwise to an ice-cooled solution of 2 mmol 5-benzylidene 4-hydroxy-1,5-dihydropyrrol-2-one (prepared in accordance with H. Poschenrieder et al (Arch. Pharm. Pharm. Med. Chem. 1998, 331, 389-394) and H.-D. Stachel et al (J. Heterocycl. Chem. 1980, vol. 17, pp. 1195-1199 and Liebigs Ann. Chem. 1985, pp. 1692-1696)) in 5 ml glacial acetic acid, while stirring. The resulting solution was then stirred at room temperature for 30 minutes and concentrated in vacuo. The residue is purified by recrystallization from ethanol. The yield of 5-benzylidene-pyrrolidine-2,3,4-trione 3-oxime was 65%, with a melting point of 205° C.
Reaction SMILES: [Cl:1][C:2]1[C:6]2[CH:7]=[N:8][CH:9]=[CH:10][C:5]=2[NH:4][CH:3]=1.C(N(CC)CC)C.Cl[C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20]>ClCCl>[Cl:1][C:2]1[C:6]2[CH:7]=[N:8][CH:9]=[CH:10][C:5]=2[N:4]([C:19]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:20])[CH:3]=1
Reactant: Clc1c[nH]c2ccncc12
Reactant: O=C(Cl)OCc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(OCc1ccccc1)n1cc(Cl)c2cnccc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 128.9 %

Procedure:
To a stirred solution of 3-chloro-1H-pyrrolo[3,2-c]pyridine (1 g, 6.55 mmol) in dichloromethane (10 mL), triethylamine (2.3 ml, 16.38 mmol) was added. The mixture was cooled to 0° C. and benzyl chloroformate (2.3 mL, 50% solution in dichloromethane, 9.83 mmol) was added drop wise. After complete addition, the reaction mixture was stirred at room temperature for about 1 hour. On completion, the reaction was quenched by addition of saturated aq. sodium bicarbonate solution and the organic layer was separated, washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum to afford benzyl 3-chloro-1H-pyrrolo[3,2-c]pyridine-1-carboxylate (2.42 g, 100%) as viscous liquid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:9]=[CH:8][C:7]([S:10](=[O:20])(=[O:19])[NH:11][C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)=[CH:6][CH:5]=1.Br[CH2:23][CH:24]([CH3:26])[CH3:25].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CCOC(C)=O>[CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:9]=[CH:8][C:7]([S:10](=[O:20])(=[O:19])[N:11]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[CH2:23][CH:24]([CH3:26])[CH3:25])=[CH:6][CH:5]=1
Reactant: CC(C)CBr
Reactant: COC(=O)c1ccc(S(=O)(=O)Nc2ccc(F)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(S(=O)(=O)N(CC(C)C)c2ccc(F)cc2)cc1
Temperature: 90 °C
Yield: 143.2 %

Procedure:
A mixture of 4-(4-fluoro-phenylsulfamoyl)-benzoic acid methyl ester (1.00 g, 3.23 mmol), 1-bromo-2-methyl propane (527 μL, 4.85 mmol), and K2CO3 (891 mg, 6.46 mmol) in DMF (10 mL) was heated at 90° C. for 18 hours. The cooled mixture was diluted with EtOAc, washed with water and brine, dried over Na2SO4 and concentrated under vacuum. Purification by silica gel column chromatography (0-50% EtOAc in cyclohexane) gave 4-[(4-fluoro-phenyl)-isobutyl-sulfamoyl]-benzoic acid methyl ester (1.69 g, 77%). 1H NMR (300 MHz, CDCl3) δ 8.12 (d, J=8.3 Hz, 2H), 7.63 (d, J=8.3 Hz, 2H), 6.99 (d, J=6.5 Hz, 4H), 3.96 (s, 3H), 3.31 (d, J=7.3 Hz, 2H), 1.58-1.56 (m, 1H), 0.92 (d, J=6.7 Hz, 6H). LCMS (m/z, Method A) ES+ 366.1 [M+1]+.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([OH:12])=O.C(N(CC)CC)C.ClC(OCC)=O.[C:26]1([N:32]2[C:36]3([CH2:41][CH2:40][NH:39][CH2:38][CH2:37]3)[C:35](=[O:42])[NH:34][CH2:33]2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>O1CCCC1.CN1CCOCC1>[CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([N:39]1[CH2:38][CH2:37][C:36]2([N:32]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH2:33][NH:34][C:35]2=[O:42])[CH2:41][CH2:40]1)=[O:12]
Reactant: O=C(O)C1=Cc2ccccc2C1
Reactant: O=C1NCN(c2ccccc2)C12CCNCC2
Agent: CCOC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CN1CCOCC1
Product: O=C(C1=Cc2ccccc2C1)N1CCC2(CC1)C(=O)NCN2c1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Indene-2-carboxylic acid (12.8g) is dissolved in dry tetrahydrofuran (300 ml), cooled to 0° C, treated with N-methylmorpholine (40 drops), triethylamine (12 ml) and ethyl chloroformate (8.6g) and stirred for 30 minutes. To this mixture is added a suspension of 1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one (20.0g) in dry tetrahydrofuran (200 ml) and the mixture is stirred at 0° C for 30 minutes. The mixture is allowed to warm to room temperature and stirred for 16 hours. The precipitated solids are filtered off, washed with additional tetrahydrofuran, and the filtrate is concentrated. The semi-solid residue is dissolved in chloroform, washed with water and saturated sodium bicarbonate solution, dried, and concentrated to give the crude product.
Reaction SMILES: C([O:3][C:4](=[O:27])[CH2:5][N:6]([C:21]([O:23][CH2:24][CH:25]=[CH2:26])=[O:22])[CH:7]([C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)C.O.CO.O.[OH-].[Li+]>C1COCC1>[CH2:24]([O:23][C:21]([N:6]([CH2:5][C:4]([OH:27])=[O:3])[CH:7]([C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:22])[CH:25]=[CH2:26]
Reactant: C=CCOC(=O)N(CC(=O)OCC)C(c1ccccc1)c1ccc(Cl)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: C=CCOC(=O)N(CC(=O)O)C(c1ccccc1)c1ccc(Cl)cc1
Yield: 66.4 %

Procedure:
(RS)-{Allyloxycarbonyl-[(4-chloro-phenyl)-phenyl-methyl]-amino}-acetic acid ethyl ester (18 g, 46.4 mmol) was dissolved in THF (60 mL), water (60 mL), and MeOH (60 mL) and treated with lithium hydroxide monohydrate (3.9 g, 92 mmol) at 20° C. for 2 h. The mixture was evaporated and extracted with AcOEt, 1 N HCl and 50% NaCl. The crude product was crystallized from heptane/ethyl acetate 10:1 (100 mL). One obtained 11.08 g (66%) of white crystals. MS: m/z=358 [M+H]+.