Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:12])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[Cl:20][C:21]1[CH:22]=[C:23]([N:28]=[C:29]=[S:30])[CH:24]=[C:25]([Cl:27])[CH:26]=1>>[Cl:20][C:21]1[CH:22]=[C:23]([NH:28][C:29](=[S:30])[NH:1][C:2]2[CH:3]=[C:4]([NH:10][C:11]([NH:13][C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)=[O:12])[CH:5]=[CH:6][C:7]=2[O:8][CH3:9])[CH:24]=[C:25]([Cl:27])[CH:26]=1
Reactant: S=C=Nc1cc(Cl)cc(Cl)c1
Reactant: COc1ccc(NC(=O)Nc2ccccc2)cc1N
Product: COc1ccc(NC(=O)Nc2ccccc2)cc1NC(=S)Nc1cc(Cl)cc(Cl)c1
Yield: 74 %

Procedure:
Prepared according to the procedure described for Example 78 using 1-(4-methoxy-3-aminophenyl)-3-phenyl-urea from Example 24, Step C (0.390 g, 1.52 mmol) and 3,5-dichlorophenyl isothiocyanate (0.311 g, 1.52 mmol). Filtration without trituration afforded the product (0.5187 g); m.p. 218-219° C.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:4]=[CH:5][C:6]2[CH:12]=[CH:11][C:10](=[O:13])[NH:9][C:7]=2[N:8]=1.[Br:14]N1C(=O)CCC1=O>CN(C)C=O>[Br:14][C:11]1[C:10](=[O:13])[NH:9][C:7]2[N:8]=[C:3]([S:2][CH3:1])[N:4]=[CH:5][C:6]=2[CH:12]=1
Reactant: CSc1ncc2ccc(=O)[nH]c2n1
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Product: CSc1ncc2cc(Br)c(=O)[nH]c2n1
Reaction time: 18 h
Yield: 48.3 %

Procedure:
To a solution of 2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one (1, 1.00 g, 5.18 mmol) in anhydrous dimethylformamide (25 mL) was added N-bromosuccinimide (0.99 g, 5.59 mmol) portionwise at room temperature, and the reaction mixture was stirred for 18 h. The mixture was concentrated, and the solid was triturated with hot water (1×20 mL), filtered, and washed with isopropanol to give title compound as a pale yellow solid (0.68 g, 2.50 mmol, 48%). ESMS m/z 272 (M+H)+; 1H NMR (400 MHz, DMSO-d6) δ ppm 12.88 (br. s., 1H), 8.84 (s, 1H), 8.47 (s, 1H), 2.57 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[N:3]([CH3:30])[C:4](=[O:29])[C:5]([C:20]2[CH:21]=[C:22]([CH:27]=[O:28])[N:23]([CH2:25][CH3:26])[CH:24]=2)([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]3[C:14]([F:19])=[N:15][CH:16]=[CH:17][CH:18]=3)[CH:8]=2)[N:6]=1.[BH4-].[Na+].[CH2:33](O)C>>[NH2:1][C:2]1[N:3]([CH3:30])[C:4](=[O:29])[C:5]([C:20]2[CH:21]=[C:22]([CH2:27][O:28][CH3:33])[N:23]([CH2:25][CH3:26])[CH:24]=2)([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]3[C:14]([F:19])=[N:15][CH:16]=[CH:17][CH:18]=3)[CH:8]=2)[N:6]=1
Reactant: CCn1cc(C2(c3cccc(-c4cccnc4F)c3)N=C(N)N(C)C2=O)cc1C=O
Reactant: CCO
Agent: [BH4-]
Agent: [Na+]
Product: CCn1cc(C2(c3cccc(-c4cccnc4F)c3)N=C(N)N(C)C2=O)cc1COC
Reaction time: 8 h

Procedure:
A solution of 4-{2-amino-4-[3-(2-fluoropyridin-3-yl)phenyl]-1-methyl-5-oxo-4,5-dihydro-1H-imidazol-4-yl}-1-ethyl-1H-pyrrole-2-carbaldehyde in dry ethanol was treated with 2 equivalents of sodium borohydride at 0° C., allowed to come to room temperature, quenched with water and evaporated to dryness under reduced pressure. The resultant residue is dispersed in water and extracted with ethyl acetate. The extracts are combined, dried over MgSO4 and concentrated in vacuo. The resultant residue was dissolved in 0.5M methanolic HCl, stirred overnight and evaporated to dryness under reduced pressure. This residue was dissolved in chloroform, washed with dilute sodium bicarbonate, dried over sodium sulfate and concentrated in vacuo. The resultant residue was purified using flash chromatography and was crystallized from ethylacetate/hexane to give the title compound as a solid, mp 154-157° C., identified by NMR and mass spectral analyses.
Reaction SMILES: Cl[CH2:2][C:3]1[O:7][N:6]=[C:5]([C:8]2[N:9]=[CH:10][N:11]3[C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=4[C:15](=[O:22])[N:14]4[CH2:23][CH2:24][C@H:13]4[C:12]=23)[N:4]=1.[CH2:25]([NH:27][CH2:28][CH3:29])[CH3:26]>CN(C)C=O>[CH2:25]([N:27]([CH2:2][C:3]1[O:7][N:6]=[C:5]([C:8]2[N:9]=[CH:10][N:11]3[C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=4[C:15](=[O:22])[N:14]4[CH2:23][CH2:24][C@H:13]4[C:12]=23)[N:4]=1)[CH2:28][CH3:29])[CH3:26]
Reactant: CCNCC
Reactant: O=C1c2ccccc2-n2cnc(-c3noc(CCl)n3)c2[C@@H]2CCN12
Solvent: CN(C)C=O
Product: CCN(CC)Cc1nc(-c2ncn3c2[C@@H]2CCN2C(=O)c2ccccc2-3)no1
Yield: 92.9 %

Procedure:
1.15 g (3.5 mmol) of (S)-1-(5-chloromethyl-1,2,4-oxadiazol-3-yl)-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepin-9-one were stirred at room temperature overnight with 0.73 g (10 mmol) of diethylamine and 10 ml of N,N-dimethylformamide. By evaporation of the reaction mixture and chromatography of the residue on silica gel while eluting with methylene chloride/methanol 19/1 there were obtained 1.23 g (93%) of (S)-1-(5-diethylaminomethyl-1,2,4-oxadiazol-3-yl)-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepin-9-one, which was converted into the hydrochloride of m.p. 209°-211°.
Reaction SMILES: C([O:3][C:4]([C:6]1([S:16]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)(=[O:18])=[O:17])[CH2:11][CH2:10][N:9]([CH2:12][CH2:13][CH2:14][CH3:15])[CH2:8][CH2:7]1)=[O:5])C>CO.[OH-].[Na+]>[CH2:12]([N:9]1[CH2:8][CH2:7][C:6]([S:16]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)(=[O:18])=[O:17])([C:4]([OH:5])=[O:3])[CH2:11][CH2:10]1)[CH2:13][CH2:14][CH3:15]
Reactant: CCCCN1CCC(C(=O)OCC)(S(=O)(=O)c2ccc(OC)cc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCCN1CCC(C(=O)O)(S(=O)(=O)c2ccc(OC)cc2)CC1

Procedure:
1-Butyl-4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylic acid was prepared starting from 1-butyl-4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylic acid ethyl ester (6.42 g 16.8 mmol) dissolved in methanol (200 ml) and 10 N NaOH (20 ml). The resulting reaction mixture was worked up as outlined in example 83. Yield 1.6 g (27%); white powder; mp 206° C.; MS: 356.4 (M+H)+.
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:14])=[C:10](F)[CH:11]=2)[C:6](=[O:15])[C:5]([C:16]([OH:18])=[O:17])=[CH:4]1)[CH3:2].[CH:19]([CH:21]1[NH:26][CH2:25][CH2:24][NH:23][CH2:22]1)=[CH2:20]>N1C=CC=CC=1>[CH:19]([CH:21]1[NH:26][CH2:25][CH2:24][N:23]([C:10]2[CH:11]=[C:12]3[C:7]([C:6](=[O:15])[C:5]([C:16]([OH:18])=[O:17])=[CH:4][N:3]3[CH2:1][CH3:2])=[CH:8][C:9]=2[F:14])[CH2:22]1)=[CH2:20]
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(F)cc21
Reactant: C=CC1CNCCN1
Solvent: c1ccncc1
Product: C=CC1CN(c2cc3c(cc2F)c(=O)c(C(=O)O)cn3CC)CCN1
Temperature: 100 °C
Yield: 12.2 %

Procedure:
A mixture of 1.2 g of 1-ethyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, 1.9 g of 3-ethenylpiperazine and 15 ml of pyridine is heated at 100° C. in a pressure bottle for 3 hours, then cooled and evaporated. The residue is purified by silica gel flash chromatography, eluting with chloroform:methanol:water:triethylamine (9:0.5:0.02:0.02), giving 200 mg of the desired product.
Reaction SMILES: [OH:1][C@@:2]1(/[CH:12]=[CH:13]/[C:14](/[CH3:20])=[CH:15]\[C:16]([O:18][CH3:19])=[O:17])[C:7]([CH3:9])([CH3:8])[CH2:6][C:5](=[O:10])[CH:4]=[C:3]1[CH3:11].[CH3:21][Si](C)(C)N[Si](C)(C)C.[Li].CI>O1CCCC1>[OH:1][C@@:2]1(/[CH:12]=[CH:13]/[C:14](/[CH3:20])=[CH:15]\[C:16]([O:18][CH3:19])=[O:17])[C:7]([CH3:9])([CH3:8])[CH2:6][C:5](=[O:10])[C:4]([CH3:21])=[C:3]1[CH3:11]
Reactant: COC(=O)/C=C(C)\C=C\[C@@]1(O)C(C)=CC(=O)CC1(C)C
Reactant: C[Si](C)(C)N[Si](C)(C)C
Agent: [Li]
Solvent: CI
Solvent: C1CCOC1
Product: COC(=O)/C=C(C)\C=C\[C@@]1(O)C(C)=C(C)C(=O)CC1(C)C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of Example 1a (27.8 g, 0.1 mole) in anhydrous tetrahydrofuran (THF, 600 ml) was cooled to 0° C. with an ice bath under an atmosphere of nitrogen. Lithium hexamethyl disilazane (1.0 M solution in THF, 150 ml) was added dropwise via a syringe over about 30 minutes. The resulting solution was stirred at 0° C. for 30 minutes and the ice bath was removed. A solution of methyl iodide (8.09 ml, 18.4 g, 0.13 mole) in anhydrous THF (20 ml) was added via a syringe over 20 minutes. The resulting solution was stirred at ambient temperature overnight. The reaction was quenched with saturated aqueous ammonium chloride solution (200 ml) and water (200 ml) and extracted with ethyl acetate (3×150 ml). The combined organic solution was dried (MgSO4), filtered and concentrated. The residue was purified on a silica gel column eluted with ethyl acetate and hexane. The title compound was obtained as a white solid (17.1 g). 1HNMR (CDCl3): δ7.84 (d, 1H), 6.16 (d, 1H), 5.75 (s, 1H), 3.70 (s, 3H), 2.44 (d, 1H), 2.34 (d, 1H), 2.00 (s, 3H), 1.88 (s, 3H), 1.83 (s, 3H), 1.07 (s, 3H), 1.00 (s, 3H). MS (ESI—): m/e=291.
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:33])=[C:4]([C:8]2[N:9]=[C:10]([CH:20]3[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:22][CH2:21]3)[S:11][C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[C:15]([Cl:19])[N:14]=2)[CH:5]=[CH:6][CH:7]=1.[F:34][C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([F:41])[C:36]=1[S:42](Cl)(=[O:44])=[O:43]>N1C=CC=CC=1>[Cl:19][C:15]1[N:14]=[C:13]([C:12]2[S:11][C:10]([CH:20]3[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:30])([CH3:32])[CH3:31])=[O:27])[CH2:22][CH2:21]3)=[N:9][C:8]=2[C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([NH:1][S:42]([C:36]3[C:37]([F:41])=[CH:38][CH:39]=[CH:40][C:35]=3[F:34])(=[O:44])=[O:43])[C:3]=2[F:33])[CH:18]=[CH:17][N:16]=1
Reactant: O=S(=O)(Cl)c1c(F)cccc1F
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc(-c3cccc(N)c3F)c(-c3ccnc(Cl)n3)s2)CC1
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N1CCC(c2nc(-c3cccc(NS(=O)(=O)c4c(F)cccc4F)c3F)c(-c3ccnc(Cl)n3)s2)CC1
Reaction time: 3 h
Yield: 79.5 %

Procedure:
To a solution of 1,1-dimethylethyl 4-[4-(3-amino-2-fluorophenyl)-5-(2-chloro-4-pyrimidinyl)-1,3-thiazol-2-yl]-1-piperidinecarboxylate (300 mg, 0.612 mmol) in pyridine (3 mL) was added 2,6-difluorobenzenesulfonyl chloride (130 mg, 0.612 mmol), and the reaction mixture was stirred for 3 h. The reaction mixture was quenched with water (5 mL) and extracted with EtOAc (3×). The extracts were dried, filtered and concentrated. The residue was purified using column chromatography (40 to 100% EtOAc/hexane) to give 324 mg of the title compound. MS (ESI): 610.1 [M+1-56]+.
Reaction SMILES: C1(C)C=CC(S(Cl)(=O)=[O:8])=CC=1.[Br:12][C:13]1[CH:14]=[N+:15]([O-])[C:16]2[C:21]([CH:22]=1)=[CH:20][CH:19]=[C:18]([O:23][CH3:24])[CH:17]=2>CCOC(C)=O.C([O-])([O-])=O.[K+].[K+]>[Br:12][C:13]1[C:14](=[O:8])[NH:15][C:16]2[C:21]([CH:22]=1)=[CH:20][CH:19]=[C:18]([O:23][CH3:24])[CH:17]=2
Reactant: COc1ccc2cc(Br)c[n+]([O-])c2c1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: COc1ccc2cc(Br)c(=O)[nH]c2c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
p-Toluenesulfonyl chloride (1.68 g, 8.83 mmol) was added to a solution of 3-bromo-7-methoxyquinoline 1-oxide (2.04 g, 8.03 mmol) in EtOAc (50 mL) and 15% aqueous K2CO3 (15 mL) at RT. The reaction mixture was stirred vigorously at RT for 18 h, at which time the product was collected by filtration and washed with EtOAc. The solid was dried under vacuum and used with no further purification. LRMS (M+H)+=254.1.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([F:13])[CH:8]=[CH:9][C:10]=2[F:12])[N:5]=[CH:4][C:3]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15].[NH2:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=1)[C:23]#[N:24]>CC(O)C>[C:23]([C:22]1[CH:21]=[C:20]([NH:19][C:2]2[C:11]3[C:6](=[C:7]([F:13])[CH:8]=[CH:9][C:10]=3[F:12])[N:5]=[CH:4][C:3]=2[C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:27]=[CH:26][CH:25]=1)#[N:24]
Reactant: N#Cc1cccc(N)c1
Reactant: CCOC(=O)c1cnc2c(F)ccc(F)c2c1Cl
Solvent: CC(C)O
Product: CCOC(=O)c1cnc2c(F)ccc(F)c2c1Nc1cccc(C#N)c1
Yield: 50.3 %

Procedure:
The reaction mixture of 106.0 mg (0.37 mmol) of 4-chloro-3-ethoxycarbonyl-5,8-difluoroquinoline and 51.5 mg (0.44 mmol) of 3-amino-benzonitrile in 2.0 mL of 2-propanol was refluxed for 2 h and cooled down. The pale yellow precipitate was filtered, washed with cold 2-propanol, and dried in oven at 40° C. overnight to give 65.7 mg (50%) of the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:14]2[CH2:15][O:16][CH2:17][CH:9]1[CH2:10][NH:11][C:12](=[O:18])[CH2:13]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[C:20]1[CH:21]=[CH:22][C:23]([N+:26]([O-:28])=[O:27])=[N:24][CH:25]=1>>[C:1]([O:5][C:6]([N:8]1[CH:14]2[CH2:15][O:16][CH2:17][CH:9]1[CH2:10][N:11]([C:20]1[CH:25]=[N:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=1)[C:12](=[O:18])[CH2:13]2)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=[N+]([O-])c1ccc(Br)cn1
Reactant: CC(C)(C)OC(=O)N1C2CNC(=O)CC1COC2
Product: CC(C)(C)OC(=O)N1C2COCC1CN(c1ccc([N+](=O)[O-])nc1)C(=O)C2
Yield: 60.2 %

Procedure:
Following general N—C coupling procedure 1, 4-Oxo-8-oxa-3,10-diaza-bicyclo[4.3.1]decane-10-carboxylic acid tert-butyl ester (0.776 g, 3.03 mmol) was combined with 5-Bromo-2-nitro-pyridine (0.676 g, 3.33 mmol) which gave 3-(6-Nitro-pyridin-3-yl)-4-oxo-8-oxa-3,10-diaza-bicyclo[4.3.1]decane-10-carboxylic acid tert-butyl ester (0.69 g, 1.732) in 57.2 yield. MS m/z 379.4 (M+H)
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[S:24](=[O:26])(=[O:25])[CH2:23][CH2:22][C:21]([C:27]([NH:29][C:30]4[CH:35]=[CH:34][C:33]([CH:36]([OH:43])[C:37]5[CH:42]=[CH:41][CH:40]=[CH:39][N:38]=5)=[CH:32][CH:31]=4)=[O:28])=[CH:20][C:19]=3[CH:44]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].ClC1C=CC=C(C(OO)=[O:53])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[S:24](=[O:26])(=[O:25])[CH2:23][CH2:22][C:21]([C:27]([NH:29][C:30]4[CH:31]=[CH:32][C:33]([CH:36]([OH:43])[C:37]5[CH:42]=[CH:41][CH:40]=[CH:39][N+:38]=5[O-:53])=[CH:34][CH:35]=4)=[O:28])=[CH:20][C:19]=3[CH:44]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(C(O)c4ccccn4)cc2)CCS3(=O)=O)cc1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(C(O)c4cccc[n+]4[O-])cc2)CCS3(=O)=O)cc1
Yield: 41.6 %

Procedure:
To a solution of 7-[4-(2-butoxyethoxy)phenyl]-N-[4-[hydroxy(2-pyridyl)methyl]phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (Compound 152) (157 mg) in dichloromethane (10 ml) was added at 0° C. 3-chloroperbenzoic acid (70%, 98 mg), and the mixture was stirred at room temperature for 2 days. To the reaction mixture was added sodium thiosulfate solution, and the mixture was stirred for a few minutes and extracted with ethyl acetate. The organic layer was washed with sodium bicarbonate solution and saturated brine, dried with magnesium sulfate and concentrated under reduced pressure, and the residue was purified with column chromatography (ethanol/ethyl acetate=1:9→1:4) to give pale yellow crystals of 7-[4-(2-butoxyethoxy)phenyl]-N-[4-[hydroxy(1-oxidopyridin-2-yl)methyl]phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (Compound 153) (67 mg).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:17]2[C:18]([CH3:34])([CH3:33])[C:19](=[O:32])[N:20]([CH:22]3[CH2:27][CH2:26][N:25]([C:28](=[O:31])[CH2:29]Cl)[CH2:24][CH2:23]3)[N:21]=2)[CH:12]=[CH:13][C:14]=1[O:15][CH3:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:35]1(=[O:41])[NH:39][C:38](=[O:40])[CH2:37][CH2:36]1>>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:17]2[C:18]([CH3:34])([CH3:33])[C:19](=[O:32])[N:20]([CH:22]3[CH2:27][CH2:26][N:25]([C:28](=[O:31])[CH2:29][N:39]4[C:35](=[O:41])[CH2:36][CH2:37][C:38]4=[O:40])[CH2:24][CH2:23]3)[N:21]=2)[CH:12]=[CH:13][C:14]=1[O:15][CH3:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(C2=NN(C3CCN(C(=O)CCl)CC3)C(=O)C2(C)C)cc1OCc1ccccc1
Reactant: O=C1CCC(=O)N1
Product: COc1ccc(C2=NN(C3CCN(C(=O)CN4C(=O)CCC4=O)CC3)C(=O)C2(C)C)cc1OCc1ccccc1

Procedure:
Prepared analogously as described for example 1 using 5-[3-(benzyloxy)-4-methoxyphenyl]-2-[1-(chloroacetyl)piperidin-4-yl]-4,4-dimethyl-2,4-dihydro-3H-pyrazol-3-one (see below) and succinimide as starting compounds.
Reaction SMILES: C1C2C(COC([NH:18][C@@H:19]([CH2:23][S:24][CH2:25][C@H:26]([O:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH3:53])[CH2:27][O:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])[C:20]([OH:22])=O)=O)C3C(=CC=CC=3)C=2C=CC=1.Cl.[NH2:55][CH2:56][CH2:57][O:58][CH2:59][CH2:60][O:61][CH2:62][CH2:63][C:64]([P:67](=[O:74])([O:71]CC)[O:68]CC)([F:66])[F:65]>>[NH2:18][C@@H:19]([CH2:23][S:24][CH2:25][C@H:26]([O:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH3:53])[CH2:27][O:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])[C:20](=[O:22])[NH:55][CH2:56][CH2:57][O:58][CH2:59][CH2:60][O:61][CH2:62][CH2:63][C:64]([P:67](=[O:68])([OH:74])[OH:71])([F:65])[F:66]
Reactant: CCCCCCCCCCCCOC[C@H](CSC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O)OCCCCCCCCCCCC
Reactant: CCOP(=O)(OCC)C(F)(F)CCOCCOCCN
Agent: Cl
Product: CCCCCCCCCCCCOC[C@H](CSC[C@H](N)C(=O)NCCOCCOCCC(F)(F)P(=O)(O)O)OCCCCCCCCCCCC

Procedure:
The title product was prepared from (R)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(((R)-2,3-bis(dodecyloxy)propyl)thio)propanoic acid (1 eq, from example 20, step 5) and diethyl 3-(2-(2-aminoethoxy)ethoxy)-1,1-difluoropropylphosphonate hydrochloride (1.2 eq) by following the procedure described for example 19, step 4-6. 1H NMR (CDCl3): δ 9.15 (br s, 1H), 4.16 (br s, 1H), 3.48-3.77 (m, 9H), 3.34-3.48 (m, 4H), 3.07-3.17 (m, 2H), 2.93-3.07 (m, 2H), 2.67-2.82 (m, 2H), 2.25-2.41 (m, 2H), 1.62-1.71 (m, 2H), 1.45-1.60 (m, 4H), 1.04-1.35 (m, 36H), 0.87 (t, 6H). LRMS [M+H]=777.5.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([Cl:11])=[CH:8][CH:9]=2)[N:4]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:3]=1[C:17](=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[Cl:25][CH2:26][C:27](Cl)=[O:28]>>[C:17]([C:3]1[N:4]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:5]2[C:10]([C:2]=1[NH:1][C:27](=[O:28])[CH2:26][Cl:25])=[CH:9][CH:8]=[C:7]([Cl:11])[CH:6]=2)(=[O:24])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CCOC(=O)n1c(C(=O)c2ccccc2)c(N)c2ccc(Cl)cc21
Reactant: O=C(Cl)CCl
Product: CCOC(=O)n1c(C(=O)c2ccccc2)c(NC(=O)CCl)c2ccc(Cl)cc21

Procedure:
The titled compound was prepared according to the procedure described in step 1 of Example 2 (Method A) from 3-amino-2-benzoyl-6-chloro-1-(ethoxycarbonyl)indole (Example 1, step 2) and chloroacetyl chloride.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([C:8]2[C:13]3[S:14][CH:15]=[CH:16][C:12]=3[CH2:11][CH2:10][N:9]=2)[CH2:4][CH2:3]1.[CH3:17][O:18][C:19]1[CH:27]=[CH:26][C:22]([C:23](Cl)=[O:24])=[CH:21][CH:20]=1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([CH:8]2[C:13]3[S:14][CH:15]=[CH:16][C:12]=3[CH2:11][CH2:10][N:9]2[C:23]([C:22]2[CH:26]=[CH:27][C:19]([O:18][CH3:17])=[CH:20][CH:21]=2)=[O:24])[CH2:4][CH2:3]1
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: CN1CCC(C2=NCCc3ccsc32)CC1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: COc1ccc(C(=O)N2CCc3ccsc3C2C2CCN(C)CC2)cc1
Yield: 90 %

Procedure:
7-(1-Methylpiperidin-4-yl)-4,5,-dihydrothieno[2,3-c]pyridine (0.1 g), 4-methoxybenzoyl chloride (0.086 g), and triethylamine (0.112 ml ) were reacted in toluene (5 ml) exactly as described in example 4. Yield 90% of crude [7-(1-Methylpiperidin-4-yl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-6-yl]-(4-methoxyphenyl)-methanone. MS: M+=370.
Reaction SMILES: [NH2:1][N:2]1[CH:6]=[N:5][CH:4]=[N:3]1.[Cl:7][C:8]1[CH:24]=[CH:23][C:11]([O:12][CH2:13][C:14]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)=O)=[CH:10][CH:9]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[Cl:7][C:8]1[CH:9]=[CH:10][C:11]([O:12][CH2:13][C:14](=[N:1][N:2]2[CH:6]=[N:5][CH:4]=[N:3]2)[C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)=[CH:23][CH:24]=1
Reactant: O=C(COc1ccc(Cl)cc1)c1ccc(F)cc1
Reactant: Nn1cncn1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: Fc1ccc(C(COc2ccc(Cl)cc2)=Nn2cncn2)cc1

Procedure:
To a stirred solution of 1-amino-1H-1,2,4-triazole (75% purity, 5.6 g, 0.05 mmol) and 2-(4-chlorophenoxy)-4'-fluoroacetophenone (13.2 g, 0.05 mmol) in 100 mL dry toluene is added a catalytic amount (1.0 g) p-toluene sulfonic acid. The mixture is heated at reflux with azeotropic removal of water for 4 days. Solvent is evaporated and the residue taken up in 200 mL ethyl acetate. The organic solution is washed with 2×100 mL 10% aqueous Na2CO3 and 1×100 mL brine. The dried (MgSO4) solution is filtered and concentrated to give the desired product which can be purified by chromatography or crystallization from an appropriate solvent.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([S:9][CH3:10])[N:3]=1.C(NC(C)C)(C)C.[Li].[CH:19]1([CH:24]=[O:25])[CH2:23][CH2:22][CH2:21][CH2:20]1>C1COCC1>[CH:19]1([CH:24]([C:7]2[C:2]([Cl:1])=[N:3][C:4]([S:9][CH3:10])=[N:5][C:6]=2[Cl:8])[OH:25])[CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: O=CC1CCCC1
Reactant: CSc1nc(Cl)cc(Cl)n1
Agent: [Li]
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CSc1nc(Cl)c(C(O)C2CCCC2)c(Cl)n1
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
4,6-Dichloro-2-methylsulfanyl-pyrimidine (8.0 g, 41.01 mmol) was dissolved in 500 mL dry THF and cooled to −78° C. Lithium diisopropylamine (36.9 mL of 2.0 M solution in hexanes) was added dropwise, and the reaction mixture was stirred for 20 minutes at −78° C. Cyclopentane-carboxaldehyde (8.05 g, 82.02 mmol was added, and the reaction mixture was stirred for 45 minutes at −78° C. The reaction was quenched by addition of saturated aqueous ammonium chloride. The aqueous mixture was extracted with ethyl acetate, and the combined organic layers were washed with water, washed with brine, dried (MgSO4), filtered, and evaporated under reduced pressure. The residue was purified by flash chromatography (5% to 40% EtOAc in hexanes) to yield 9.76 g of cyclopentyl-(4,6-dichloro-2-methylsulfanyl-pyrimidin-5-yl)-methanol. Mass Spec. M+H=294.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[N:10][N:11]([CH3:18])[C:12]=2[C:13]2[N:14]=[CH:15][NH:16][CH:17]=2)=[CH:4][CH:3]=1.[CH3:19][C:20]([C:22]1[CH:27]=[CH:26][C:25](F)=[CH:24][CH:23]=1)=[O:21].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[N:10][N:11]([CH3:18])[C:12]=2[C:13]2[N:14]=[CH:15][N:16]([C:25]3[CH:26]=[CH:27][C:22]([C:20](=[O:21])[CH3:19])=[CH:23][CH:24]=3)[CH:17]=2)=[CH:4][CH:3]=1
Reactant: Cn1nnc(-c2ccc(F)cc2)c1-c1c[nH]cn1
Reactant: CC(=O)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)c1ccc(-n2cnc(-c3c(-c4ccc(F)cc4)nnn3C)c2)cc1
Temperature: 120 °C
Yield: 47 %

Procedure:
A mixture of 4-(4-fluoro-phenyl)-5-(1H-imidazol-4-yl)-1-methyl-1H-[1,2,3]triazole (73 mg, 0.30 mmol), 4-fluoroacetophenone (37 μL, 0.30 mmol) and potassium carbonate (83 mg, 0.60 mmol) in DMF (1.5 mL) was stirred under Ar in a sealed flask and heated at 120° C. for 16 h. After cooling to room temperature the mixture was poured into water and extracted with ethyl acetate and the combined extracts washed with water, brine, dried over sodium sulphate, filtered and evaporated. Purification by chromatography (silica, 0 to 100% ethyl acetate in heptane) afforded the title compound (51 mg, 47%) as an off white solid after recrystallisation from ethyl acetate. MS: m/e=362.2 [M+H]+.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[NH3:12]>CO>[NH2:12][C:2]1[N:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: N
Reactant: Cc1ccc(C(=O)O)c(Cl)n1
Solvent: CO
Product: Cc1ccc(C(=O)O)c(N)n1
Yield: 54 %

Procedure:
A solution of 2-Chloro-6-methyl-nicotinic acid (3.00 g, 17.5 mmol) in ammonia in MeOH (7M, 60 mL) in a bomb was heated to 120° C. overnight. After cooling, the solvent was removed and the residue was neutralized with 2N HCl. The precipitate was filtered, washed with water and dried to afford 2-Amino-6-methyl-nicotinic acid (1.44 g, 54%). 1H NMR (CD3OD, 400 MHz) δ 8.21 (d, J=7.6 Hz, 1H), 6.60 (d, J=7.6 Hz, 1H), 2.41 (s, 3H). MS (APCI+) [M+H]+153.
Reaction SMILES: [Na].Cl[C:3]1[N:8]=[C:7]([NH2:9])[N:6]=[C:5]([NH2:10])[CH:4]=1.[CH2:11]([OH:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[NH2:9][C:7]1[N:6]=[C:5]([NH2:10])[CH:4]=[C:3]([O:18][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:8]=1
Reactant: OCc1ccccc1
Reactant: Nc1cc(Cl)nc(N)n1
Agent: [Na]
Product: Nc1cc(OCc2ccccc2)nc(N)n1

Procedure:
A solution of 3.8 g sodium in 100 mL benzylalcohol is heated in an oil bath with 21.6 g 6-chloro-2,4-diamino-pyrimidine (6) for 3 hours at 160° C. The surplus alcohol is distilled off in vacuum.