Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([CH2:6][NH:7][C:8](=[O:18])[CH:9]([CH2:16][CH3:17])[N:10]2[CH2:14][CH2:13][CH2:12][C:11]2=[O:15])[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:19]([OH:28])(=[O:27])[C@@H:20]([C@H:22]([C:24]([OH:26])=[O:25])[OH:23])[OH:21].CCCCCCC.CCCCCC.C(O)(C)C>CO>[C:24]([C@@H:22]([C@H:20]([C:19]([OH:28])=[O:27])[OH:21])[OH:23])([OH:26])=[O:25].[N:1]1([CH2:6][NH:7][C:8](=[O:18])[C@H:9]([CH2:16][CH3:17])[N:10]2[CH2:14][CH2:13][CH2:12][C:11]2=[O:15])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCC(C(=O)NCN1CCCC1)N1CCCC1=O
Agent: O=C(O)[C@H](O)[C@@H](O)C(=O)O
Solvent: CO
Solvent: CCCCCC
Solvent: CCCCCCC
Product: CC[C@@H](C(=O)NCN1CCCC1)N1CCCC1=O
Temperature: 60 °C

Procedure:
3.14 g of N-[(1-pyrrolidinyl)methyl]-α-ethyl-2-oxo-1-pyrrolidineacetamide were suspended in 13 ml of methanol. 1.86 g of L-(+)-tartaric acid were added and it was heated at 60° C. 13 ml of heptane were added to the resulting solution, after which it was left to cool to 40° C. It was seeded with a sample of the compound indicated in the example title to start crystallisation. Then it was slowly cooled to 0-5° C. and maintained at this temperature for 4 hours. The crystallised product was separated by filtration and washed twice over the filter with 1 ml of methanol each time, and finally once with 6 ml of hexane. 2.86 g of the compound indicated in the example title was obtained with a diastereoisomeric excess (d.e.): 69% measured by means of HPLC analysis of the free base with a chiral column (Chiralcel OD, hexane/isopropanol, 220 nm).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[NH:14][CH:13]=[CH:12]3)=[C:4]([NH2:18])[CH:3]=1.[CH2:19](OC=C(C#N)C#N)C.C(OCC)(=O)C>C(O)CC.C(Cl)Cl>[NH:14]1[C:15]2[C:11](=[CH:10][C:9]([N:8]3[C:5]4[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][C:4]=4[N:18]=[CH:19]3)=[CH:17][CH:16]=2)[CH:12]=[CH:13]1
Reactant: Cc1ccc(Nc2ccc3[nH]ccc3c2)c(N)c1
Reactant: CCOC=C(C#N)C#N
Solvent: CCOC(C)=O
Solvent: CCCO
Solvent: ClCCl
Product: Cc1ccc2c(c1)ncn2-c1ccc2[nH]ccc2c1
Yield: 81 %

Procedure:
5-(4-Methyl-2-nitrophenylamino)-1H-indole (0.47 g, 2.0 mmoles) was reduced by catalytic hydrogenation to form 5-(4-methyl-2-aminophenylamino)-1H-indole (0.41 g, 2.0 mmoles). The 5-(4-methyl-2-aminophenylamino)-1H-indole was cyclized with ethoxymethylenemalononitrile (0.49 g, 2.0 mmole) in propanol, while being heated for 14 hours. Column chromatography using 10% ethyl acetate in methylene chloride afforded the title compound (81%) as a yellow solid. Mp, 215.0°-216.0° C.; Rf =0.3 in 10% ethyl acetate in methylene chloride; 1H NMR (DMSO-d6) δ11.43 (br s, NH), 8.42 (s, 1H), 7.76 (d, J=1.4 Hz, 1H), 7.61 (d, J=8.4 Hz, 1H), 7.56 (d, J=0.5 Hz, 1H), 7.52 (t, J=2.6 Hz, 1H), 7.42 (d, J=8.3 Hz, 1H), 7.30 (dd, J=8.5 and 1.7 Hz, 1H), 7.12 (br d, J=8.3 Hz, 1H), 6.56 (dd, J=2.7 and 0.9 Hz, 1H), 2.44 (s, 3H); 13C NMR (DMSO-d6) δ156.5, 144.3, 143.8, 137.2, 134.0, 130.0, 129.1, 128.0, 126.4, 119.7, 119.0, 117.3, 113.4, 111.7, 103.0, 21.6; FAB LRMS (m/z, relative intensity) 249 (23), 248 ([MH]+, 100); HRMS calculated for C16H13N3 247.1107, found 247.1092.
Reaction SMILES: [H-].[Na+].[CH3:3][CH:4]([C@H:6]1[CH2:10][N:9]([C:11]2[CH:12]=[N:13][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:15][CH:16]=2)[C:8](=[O:21])[NH:7]1)[CH3:5].Br[CH2:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25].C(=O)([O-])O.[Na+]>CN(C=O)C.O>[O:21]=[C:8]1[N:9]([C:11]2[CH:12]=[N:13][C:14]([C:17]([F:19])([F:18])[F:20])=[CH:15][CH:16]=2)[CH2:10][C@H:6]([CH:4]([CH3:3])[CH3:5])[N:7]1[CH2:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: CC(C)[C@H]1CN(c2ccc(C(F)(F)F)nc2)C(=O)N1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)[C@H]1CN(c2ccc(C(F)(F)F)nc2)C(=O)N1CC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Sodium hydride (0.53 g) was added to a solution of (4S)-4-(propan-2-yl)-1-[6-(trifluoromethyl)pyridin-3-yl]imidazolidin-2-one (5.6 g) in DMF (20 mL), and the mixture was stirred at room temperature for 10 min. Thereafter, tert-butyl bromoacetate (2.0 mL) was added portionwise thereto, and the mixture was stirred at room temperature for 2 hr. Water and saturated aqueous sodium hydrogen carbonate solution were added thereto, and the mixture was extracted with chloroform. The organic layer was separated out by phase-separation cartridge (Biotage, Isolute Phase Separator) and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel cartridge, hexane/ethyl acetate) to afford tert-butyl {(5S)-2-oxo-5-(propan-2-yl)-3-[6-(trifluoromethyl)pyridin-3-yl]imidazolidin-1-yl}acetate (802 mg).
Reaction SMILES: Cl[S:2]([C:5]1[CH:14]=[CH:13][CH:12]=[CH:11][C:6]=1[C:7]([O:9][CH3:10])=[O:8])(=[O:4])=[O:3].[N:15]1[CH:20]=[CH:19][CH:18]=[C:17]([NH2:21])[CH:16]=1>CC#N.CCOC(C)=O.CCOCC>[N:15]1[CH:20]=[CH:19][CH:18]=[C:17]([NH:21][S:2]([C:5]2[CH:14]=[CH:13][CH:12]=[CH:11][C:6]=2[C:7]([O:9][CH3:10])=[O:8])(=[O:4])=[O:3])[CH:16]=1
Reactant: COC(=O)c1ccccc1S(=O)(=O)Cl
Reactant: Nc1cccnc1
Solvent: CCOCC
Solvent: CCOC(C)=O
Solvent: CC#N
Product: COC(=O)c1ccccc1S(=O)(=O)Nc1cccnc1
Reaction time: 1 h

Procedure:
Methyl 2-(chlorosulfonyl)benzoate (14.1 g, 60.0 mmol) was added to a stirred solution of 3-pyridinamine (15.0 g, 159.4 mmol) in CH3CN (0.4 M). The temperature rose to 25° C. and a small amount of reddish oil separated out. CHCl3 (2.0 M, protected with amylenes) was added to return all materials to solution. After 1 h, the solvents were evaporated and the residual oil was partitioned between EtOAc and water. The organic layer was washed with water and was evaporated to give the crude product. The crude product was dissolved in the minimum amount of hot EtOAc and was diluted with ether. The product rapidly crystallized out and after 1 hour filtered off and washed with ether to provide the title compound. 1H NMR (400 MHz, CDCl3) δ 8.38 (d, 1H) 8.31 (d, 2H) 7.93 (d, 2H) 7.80 (d, 2H) 7.76 (t, 1H) 7.64 (t, 1H) 7.53 (t, 1H) 7.25 (m, 1H) 4.12 (s, 3H).
Reaction SMILES: [CH2:1]([N:8]([CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([Br:27])=[CH:23][CH:22]=1)[CH2:9][C@@H:10]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=1)[OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CN=C1.[Si:33](Cl)([C:36]([CH3:39])([CH3:38])[CH3:37])([CH3:35])[CH3:34]>CN(C)C=O>[CH2:1]([N:8]([CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([Br:27])=[CH:23][CH:22]=1)[CH2:9][C@H:10]([O:11][Si:33]([C:36]([CH3:39])([CH3:38])[CH3:37])([CH3:35])[CH3:34])[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O[C@@H](CN(CCc1ccc(Br)cc1)Cc1ccccc1)c1cccc(Cl)c1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)O[C@@H](CN(CCc1ccc(Br)cc1)Cc1ccccc1)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 14 h
Yield: 90.3 %

Procedure:
To a solution of (1R)-2-[benzyl[2-(4-bromophenyl)ethyl]amino]-1-(3-chlorophenyl)ethanol (18.5 g) in N,N-dimethylformamide (40 ml) were successively added imidazole (3.96 g) and tert-butyldimethylsilyl chloride (7.52 g) and the solution was stirred at room temperature for 14 hours. The reaction mixture was quenched by the addition of water (100 ml) and extracted with ethyl acetate (100 ml×1). The extract was washed with water (100 ml×2), brine (100 ml×1), and dried over magnesium sulfate. Filtration followed by evaporation gave a colorless oil, which was chromatographed on silica gel (eluent: hexane/ethyl acetate) to give (2R)-N-benzyl-N-[2-(4-bromophenyl)ethyl]-2-[[tert-butyl(dimethyl)silyl]oxy]-2-(3-chlorophenyl)ethanamine (21.0 g) as a colorless oil.
Reaction SMILES: [CH3:1][N:2]([CH3:19])[CH2:3][CH2:4][N:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[N+:15]([O-])=O)[C:6]1=[O:18].[Sn](Cl)Cl>C1COCC1>[NH2:15][C:11]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:12]=1[CH:13]=[CH:14][N:5]([CH2:4][CH2:3][N:2]([CH3:19])[CH3:1])[C:6]2=[O:18]
Reactant: CN(C)CCn1ccc2c([N+](=O)[O-])cccc2c1=O
Agent: Cl[Sn]Cl
Solvent: C1CCOC1
Product: CN(C)CCn1ccc2c(N)cccc2c1=O

Procedure:
2-(2-Dimethylamino-ethyl)-5-nitro-2H-isoquinolin-1-one (0.67 g, 2.6 mmol) and dehydrate tin dichloride (2 g, 10 mml) were stirred in THF (10 mL) at room temperature for 24 hours. The volatiles were removed via rotovapor, and the residue was dissolved in CH2Cl2 (1 L), washed with aqueous saturated NaHCO3 solution (30 mL×3). The organic layer was dried over Na2SO4, filtered and concentrated to dryness gave 5-Amino-2-(2-dimethylamino-ethyl)-2H-isoquinolin-1-one as a yellow solid. The compound was used for next steps without further purification.
Reaction SMILES: C([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20](=[O:30])[NH:21][C:22]3[CH:27]=[CH:26][C:25]([CH3:28])=[C:24]([I:29])[CH:23]=3)=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[CH3:31][C:32]1([CH3:39])[CH2:37]C(=O)[O:35][C:33]1=[O:34].IC1C=CC(NC(C2C=CC(N3CCN(C(=O)CC(C)(C)C(O)=O)CC3)=NC=2)=O)=CC=1C>>[I:29][C:24]1[CH:23]=[C:22]([NH:21][C:20]([C:17]2[CH:18]=[CH:19][C:14]([N:11]3[CH2:12][CH2:13][N:8]([C:6](=[O:5])[CH2:31][C:32]([CH3:39])([CH3:37])[C:33]([OH:35])=[O:34])[CH2:9][CH2:10]3)=[N:15][CH:16]=2)=[O:30])[CH:27]=[CH:26][C:25]=1[CH3:28]
Reactant: CC1(C)CC(=O)OC1=O
Reactant: Cc1ccc(NC(=O)c2ccc(N3CCN(C(=O)OC(C)(C)C)CC3)nc2)cc1I
Agent: Cc1cc(NC(=O)c2ccc(N3CCN(C(=O)CC(C)(C)C(=O)O)CC3)nc2)ccc1I
Product: Cc1ccc(NC(=O)c2ccc(N3CCN(C(=O)CC(C)(C)C(=O)O)CC3)nc2)cc1I

Procedure:
4-{4-[5-(3-Iodo-4-methyl-phenylcarbamoyl)-pyridin-2-yl]-piperazin-1-yl}-2,2-dimethyl-4-oxo-butyric acid was prepared from 4-[5-(3-iodo-4-methyl-phenylcarbamoyl)-pyridin-2-yl]-piperazine-1-carboxylic acid tert-butyl ester and 2,2-dimethysuccinic anhydride following a procedure similar to the one described in the synthesis of 4-{4-[5-(4-iodo-3-methyl-phenylcarbamoyl)-pyridin-2-yl]-piperazin-1-yl}-dimethyl-4-oxo-butyric acid above. HRMS m/z calcd for C23H27N4O4I [M+H]+: 551.1150. Found: 551.1152.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[CH2:3][N:4]=[C:5]([NH2:22])[NH:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([S:13][CH2:14][CH2:15][CH2:16][C:17]([O:19]CC)=O)[N:8]=1.[CH2:25]([CH2:27][NH2:28])[OH:26]>CO>[OH:26][CH2:25][CH2:27][NH:28][C:17](=[O:19])[CH2:16][CH2:15][CH2:14][S:13][C:9]1[N:8]=[C:7]([NH:6][C:5]([NH2:22])=[N:4][CH2:3][C:2]([F:1])([F:23])[F:24])[CH:12]=[CH:11][N:10]=1
Reactant: CCOC(=O)CCCSc1nccc(NC(N)=NCC(F)(F)F)n1
Reactant: NCCO
Solvent: CO
Product: NC(=NCC(F)(F)F)Nc1ccnc(SCCCC(=O)NCCO)n1

Procedure:
A mixture of ethyl 4-[4-(2-[2,2,2-trifluoroethyl]guanidino)pyrimid-2-ylthio]butyrate (0.2 g.), ethanolamine (0.5 ml.) and MeOH (5 ml.) was heated under reflux for 48 hours and then evaporated to dryness. Water was added to the residue, and the mixture extracted with EtOAc. The extract was dried and evaporated to dryness and the residue recrystallised from a small volume of EtOAc to give N-(2-hydroxyethyl)-4-[4-(2-[2,2,2-trifluoroethyl]guanidino)pyrimid-2-ylthio]butyramide (0.12 g.), m.p. 148°-150°.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:8](O)[CH:9](O)[CH3:10]>>[CH3:10][C:9]1[C:7]2[C:2](=[CH:3][CH:4]=[CH:5][CH:6]=2)[NH:1][CH:8]=1
Reactant: CC(O)CO
Reactant: Nc1ccccc1
Product: Cc1c[nH]c2ccccc12

Procedure:
Aniline and propylene glycol were reacted at a molar ratio shown in Table 17 in the same manner as described in Example 1, whereby 3-methylindole was obtained as a main product. The results are shown in the following Table 17.
Reaction SMILES: CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[CH3:23][O:24][C:25]1[CH:26]=[CH:27][C:28]2[NH:34][C:33](=[O:35])[N:32]([CH:36]3[CH2:41][CH2:40][N:39]([C:42]4[N:47]=[CH:46][N:45]=[C:44]([C:48](O)=[O:49])[CH:43]=4)[CH2:38][CH2:37]3)[CH2:31][CH2:30][C:29]=2[CH:51]=1.Cl.[CH3:53][C:54]1([CH3:67])[CH2:59][NH:58][CH2:57][C:56]2[C:60]([C:63]([F:66])([F:65])[F:64])=[N:61][NH:62][C:55]1=2>CN(C=O)C>[CH3:53][C:54]1([CH3:67])[CH2:59][N:58]([C:48]([C:44]2[N:45]=[CH:46][N:47]=[C:42]([N:39]3[CH2:38][CH2:37][CH:36]([N:32]4[CH2:31][CH2:30][C:29]5[CH:51]=[C:25]([O:24][CH3:23])[CH:26]=[CH:27][C:28]=5[NH:34][C:33]4=[O:35])[CH2:41][CH2:40]3)[CH:43]=2)=[O:49])[CH2:57][C:56]2[C:60]([C:63]([F:66])([F:64])[F:65])=[N:61][NH:62][C:55]1=2
Reactant: CC1(C)CNCc2c(C(F)(F)F)n[nH]c21
Reactant: COc1ccc2c(c1)CCN(C1CCN(c3cc(C(=O)O)ncn3)CC1)C(=O)N2
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)CCN(C1CCN(c3cc(C(=O)N4Cc5c(C(F)(F)F)n[nH]c5C(C)(C)C4)ncn3)CC1)C(=O)N2
Temperature: 25 °C
Reaction time: 4 h

Procedure:
0.11 g (0.28 mmol) TBTU were added to 0.10 g (0.25 mmol) 6-[4-(7-methoxy-2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidin-1-yl]-pyrimidine-4-carboxylic acid, 90 mg (0.32 mmol) 7,7-dimethyl-3-trifluoromethyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine hydrochloride and 0.12 mL TEA in 1.0 mL DMF and the mixture was stirred for 4 h at RT. Then the reaction mixture was purified by preparative HPLC-MS. The product-containing fractions were combined and freeze-dried.
Reaction SMILES: [C:1]1([SH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[F:15][C:16]([F:20])=[C:17]([F:19])[Cl:18].FC(Cl)(F)C(Cl)(Cl)F>CN(C)C=O.C(O)C.[Zn]>[F:15][C:16]([S:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)([F:20])[CH:17]([F:19])[Cl:18]
Reactant: FC(F)=C(F)Cl
Reactant: Sc1ccccc1
Agent: [Zn]
Solvent: CN(C)C=O
Solvent: FC(F)(Cl)C(F)(Cl)Cl
Solvent: CCO
Product: FC(Cl)C(F)(F)Sc1ccccc1

Procedure:
In 300 ml of dimethylformamide was dissolved 55 g of thiophenol, and 55 g of triethylamine was added to the solution. Trifluorochloroethylene was passed into the mixture over the period of 2 hours under heating with stirring at 60° C. (trifluorochloroethylene was generated by reacting 187 g of 1,1,2-trifluorotrichloroethane with 130 g of powdered zinc in ethanol in accordance with the conventional method). After the conclusion of the reaction, the reaction mixture was concentrated to dryness under reduced pressure, and the resulting oily material was distilled under reduced pressure to give 55 g of (1,1,2-trifluoro-2-chloroethyl)phenylsulfide as a colorless liquid having a boiling point of 52°-53° C./0.2 mmHg.
Reaction SMILES: [OH:1][CH:2]([C:7]1[S:8][C:9]2[CH:15]=[C:14]([N:16]3[CH2:20][CH:19]([CH2:21][O:22][CH3:23])[O:18][C:17]3=[O:24])[CH:13]=[CH:12][C:10]=2[N:11]=1)[CH2:3][CH:4]=NO.FC(F)(F)C([C:29]1[NH:30]C=CN=1)=O.C(=O)([O-])O.[Na+]>O1CCCC1>[OH:1][C@H:2]([C:7]1[S:8][C:9]2[CH:15]=[C:14]([N:16]3[CH2:20][C@H:19]([CH2:21][O:22][CH3:23])[O:18][C:17]3=[O:24])[CH:13]=[CH:12][C:10]=2[N:11]=1)[CH2:3][CH2:4][C:29]#[N:30]
Reactant: COCC1CN(c2ccc3nc(C(O)CC=NO)sc3c2)C(=O)O1
Reactant: O=C(c1ncc[nH]1)C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: COC[C@H]1CN(c2ccc3nc([C@@H](O)CCC#N)sc3c2)C(=O)O1
Temperature: 25 °C
Reaction time: 4 h
Yield: 70.7 %

Procedure:
73 g of the 3-[2-(1-hydroxy-3-hydroxyiminopropyl)benzothiazol-6-yl]-5-methoxymethyl-2 -oxazolidinone obtained in the Example 8 was dissolved in 800 ml of tetrahydrofuran. 90 g of trifluoroacetylimidazole was added dropwise to the solution under cooling with ice and the mixture was stirred at room temperature for 4 h. The reaction liquid was poured into an aqueous sodium hydrogencarbonate solution. After extraction with ethyl acetate followed by washing with an aqueous common salt solution, drying over magnesium sulfate and concentration under reduced pressure, the obtained solid was recrystallized from acetone/water to give 51 g of the titled compound.
Reaction SMILES: N[N:2]1[C:7](=[O:8])[C:6]2[C:9]3[CH2:15][CH2:14][N:13]([C:16]([O:18]C(C)(C)C)=O)[CH2:12][C:10]=3[S:11][C:5]=2[N:4]=[C:3]1[CH2:23][CH2:24][CH2:25][CH2:26][N:27]1[CH2:32][CH2:31][N:30]([C:33]2[CH:42]=[CH:41][C:40]3[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=3)[N:34]=2)[CH2:29][CH2:28]1.N([O-])=O.[Na+].[C:47](=O)([O-])O.[Na+]>C(O)(=O)C.O>[C:16]([N:13]1[CH2:14][CH2:15][C:9]2[C:6]3[C:7](=[O:8])[NH:2][C:3]([CH2:23][CH2:24][CH2:25][CH2:26][N:27]4[CH2:28][CH2:29][N:30]([C:33]5[CH:42]=[CH:41][C:40]6[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=6)[N:34]=5)[CH2:31][CH2:32]4)=[N:4][C:5]=3[S:11][C:10]=2[CH2:12]1)(=[O:18])[CH3:47]
Reactant: O=C([O-])O
Reactant: CC(C)(C)OC(=O)N1CCc2c(sc3nc(CCCCN4CCN(c5ccc6ccccc6n5)CC4)n(N)c(=O)c23)C1
Agent: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CC(=O)N1CCc2c(sc3nc(CCCCN4CCN(c5ccc6ccccc6n5)CC4)[nH]c(=O)c23)C1
Reaction time: 0.5 h
Yield: 99 %

Procedure:
In a mixture of 5 ml of acetic acid with 2 ml of water 60 mg of 3-amino-7-tert-butoxycarbonyl-2-[4-(4-quinolin-2-ylpiperazin-1-yl)butyl]-5,6,7,8-tetrahydro-3H-pyrido[4′3′:4,5]thieno[2,3-d]pyrimidin-4-one was dissolved, and into the solution, a solution of 10 mg of sodium nitrite in 2 ml of water was dropped under cooling with ice. After 30 minutes' stirring, the reaction mixture was neutralized with saturated aqueous sodium hydrogencarbonate solution, and the resulting precipitate was extracted with chloroform, washed with water and dried over anhydrous sodium sulfate. Distilling the solvent off under reduced pressure, the residue was purified on silica gel column chromatography to provide 52 mg (99%) of 7-acetyl-2-[4-(4-quinolin-2-ylpiperazin-1-yl)butyl]-5,6,7,8-tetrahydro-3H-pyrido[4′3′:4,5]thieno-[2,3-d]pyrimidin-4-one.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:27]=[CH:26][C:14]([O:15][CH:16]([CH3:25])[CH2:17][NH:18][S:19]([CH:22]([CH3:24])[CH3:23])(=[O:21])=[O:20])=[CH:13][CH:12]=2)=[CH:7][CH:6]=1.C(N(CC)CC)C.[CH3:35][S:36](Cl)(=[O:38])=[O:37]>C(Cl)Cl>[CH3:24][CH:22]([S:19]([NH:18][CH2:17][CH:16]([O:15][C:14]1[CH:26]=[CH:27][C:11]([C:8]2[CH:7]=[CH:6][C:5]([CH2:4][CH2:3][NH:2][S:36]([CH3:35])(=[O:38])=[O:37])=[CH:10][CH:9]=2)=[CH:12][CH:13]=1)[CH3:25])(=[O:21])=[O:20])[CH3:23]
Reactant: CS(=O)(=O)Cl
Reactant: CC(CNS(=O)(=O)C(C)C)Oc1ccc(-c2ccc(CCN)cc2)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(CNS(=O)(=O)C(C)C)Oc1ccc(-c2ccc(CCNS(C)(=O)=O)cc2)cc1
Yield: 105.3 %

Procedure:
The title compound (318 mg, 100%, slow crystallizing-foam) was prepared from (2-{4-[4-(2-aminoethyl)phenyl]phenoxy}propyl)[(methylethyl)sulfonyl]amine hydrochloride (250 mg, 0.664 mmol, prepared in example 39), methylene chloride (4.5 mL, anhydrous), triethylamine (0.09 mL, 0.664 mmol), and methanesulfonyl chloride (0.05 mL, 0.664 mmol) in a manner analogous to the procedure described in Example 40.
Reaction SMILES: [F:1][C:2]1[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[C:3]=1[CH2:4][O:5][C:6]1[C:7]2[N:8]([C:13]([C:17](O)=[O:18])=[C:14]([CH3:16])[N:15]=2)[CH:9]=[C:10]([CH3:12])[CH:11]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CN1CCOCC1.Cl.[NH2:55][CH2:56][CH:57]1[CH2:66][CH2:65][C:64]2[C:59](=[CH:60][CH:61]=[CH:62][CH:63]=2)[N:58]1[C:67]([O:69][C:70]([CH3:73])([CH3:72])[CH3:71])=[O:68]>CN(C=O)C.O>[F:1][C:2]1[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[C:3]=1[CH2:4][O:5][C:6]1[C:7]2[N:8]([C:13]([C:17]([NH:55][CH2:56][CH:57]3[CH2:66][CH2:65][C:64]4[C:59](=[CH:60][CH:61]=[CH:62][CH:63]=4)[N:58]3[C:67]([O:69][C:70]([CH3:73])([CH3:72])[CH3:71])=[O:68])=[O:18])=[C:14]([CH3:16])[N:15]=2)[CH:9]=[C:10]([CH3:12])[CH:11]=1
Reactant: CC(C)(C)OC(=O)N1c2ccccc2CCC1CN
Reactant: Cc1cc(OCc2c(F)cccc2F)c2nc(C)c(C(=O)O)n2c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: O
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: Cc1cc(OCc2c(F)cccc2F)c2nc(C)c(C(=O)NCC3CCc4ccccc4N3C(=O)OC(C)(C)C)n2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
120 mg (0.36 mmol) of 8-[(2,6-difluorobenzyl)oxy]-2,6-dimethylimidazo[1,2-a]pyridine-3-carboxylic acid Example 21A, 139 mg (0.43 mmol) of TBTU and 0.20 ml (1.81 mmol) of 4-methylmorpholine in DMF (2.3 ml) were stirred at RT for 10 min, 119 mg (0.40 mmol) of rac-tert-butyl 2-(aminomethyl)-3,4-dihydroquinoline-1(2H)-carboxylate hydrochloride were added and the reaction mixture was stirred at RT overnight. Water was added, and the mixture was stirred at RT for 30 min. The solid formed was filtered off, washed with water and dried under high vacuum. This gave 182 mg (85% of theory, purity 98%) of the target compound.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[C:7]1([C:13]2[N:14]=[C:15]([C:18]3([C:24]#[N:25])[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[S:16][CH:17]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>C1COCC1>[C:7]1([C:13]2[N:14]=[C:15]([C:18]3([CH2:24][NH2:25])[CH2:19][CH2:20][O:21][CH2:22][CH2:23]3)[S:16][CH:17]=2)[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: N#CC1(c2nc(-c3ccccc3)cs2)CCOCC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: NCC1(c2nc(-c3ccccc3)cs2)CCOCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 37.2 %

Procedure:
To a suspension of LiAlH4 (220 mg, 5.9 mmol) in dry THF (10 mL) was added a solution of 4-(4-phenylthiazol-2-yl)tetrahydro-2H-pyran-4-carbonitrile (400 mg, 1.47 mmol) in dry THF (10 mL) at 0° C. The reaction mixture was stirred at room temperature for 1 h and then quenched carefully with water and diluted with EtOAc. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (neutral alumina, eluent 5% MeOH in CHCl3) to afford (4-(4-phenylthiazol-2-yl)tetrahydro-2H-pyran-4-yl)methanamine (150 mg, yield 37%): 1H NMR (400 MHz, CDCl3) δ 7.89-7.91 (m, 2H), 7.48 (s, 1H), 7.33-7.46 (m, 3H), 3.89-3.93 (m, 2H), 3.63-3.69 (m, 2H), 3.03 (s, 2H), 2.30-2.33 (m, 2H), 1.90-1.97 (m, 2H). MS (ESI) m/z: Calculated for C15H18N2OS: 274.11. found: 275.2 (M+H)+.
Reaction SMILES: [C:1]1([C:7]2[NH:11][C:10]3[CH:12]=[C:13]([C:15]([O:17][CH3:18])=[O:16])[S:14][C:9]=3[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(OC(=O)C)(=O)C.[C:26]1(=O)[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1.P(=O)(O)(O)O>C(O)(=O)C>[C:26]1([C:8]2[C:9]3[S:14][C:13]([C:15]([O:17][CH3:18])=[O:16])=[CH:12][C:10]=3[NH:11][C:7]=2[C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:31][CH2:30][CH2:29][CH2:28][CH:27]=1
Reactant: O=C1CCCCC1
Reactant: COC(=O)c1cc2[nH]c(-c3ccccc3)cc2s1
Agent: O=P(O)(O)O
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: COC(=O)c1cc2[nH]c(-c3ccccc3)c(C3=CCCCC3)c2s1
Temperature: 80 °C
Yield: 69 %

Procedure:
A solution (0.2 M) of methyl 5-phenyl-4H-thieno[3,2-b]pyrrole-2-carboxylate in acetic acid was treated with acetic anhydride (10 eq.), cyclohexanone (10 eq.) and 85% phosphoric acid (2.3 eq.). The mixture was heated at 80° C. for 3 h, then was poured into ice cold ammonium hydroxide. The product was extracted with AcOEt and the combined organic layers were washed sequentially with aqueous HCl (1 N), aqueous NaHCO3 (saturated solution) and brine then dried and concentrated. The crude was purified by flash chromatography on silica gel (1:4 AcOEt/petroleum ether) affording the title compound (69%) as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:13][NH:12][CH2:11][CH:10]2[N:14]([CH3:25])[C:15](=[O:24])[CH2:16][C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].[CH3:26][C:27]1[N:31]=[C:30]([C:32]2[CH:40]=[CH:39][C:35]([C:36](O)=[O:37])=[CH:34][CH:33]=2)[O:29][N:28]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:13][N:12]([C:36](=[O:37])[C:35]3[CH:34]=[CH:33][C:32]([C:30]4[O:29][N:28]=[C:27]([CH3:26])[N:31]=4)=[CH:40][CH:39]=3)[CH2:11][CH:10]2[N:14]([CH3:25])[C:15](=[O:24])[CH2:16][C:17]2[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: Cc1noc(-c2ccc(C(=O)O)cc2)n1
Reactant: CN(C(=O)Cc1ccc(F)cc1)C1CNCC1c1ccc(Cl)c(Cl)c1
Product: Cc1noc(-c2ccc(C(=O)N3CC(c4ccc(Cl)c(Cl)c4)C(N(C)C(=O)Cc4ccc(F)cc4)C3)cc2)n1

Procedure:
In analogy to the procedure described for the synthesis of example 87 (step c), the title compound N-{(3RS,4SR)-4-(3,4-dichloro-phenyl)-1-[4-(3-methyl-[1,2,4]oxadiazol-5-yl)-benzoyl]-pyrrolidin-3-yl}-2-(4-fluoro-phenyl)-N-methyl-acetamide was prepared from N-[(3RS,4SR)-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-2-(4-fluoro-phenyl)-N-methyl-acetamide using 4-(3-methyl-1,2,4-oxadiazol-5-yl)-benzoic acid instead of 1-(1-methyl-cyclopropanecarbonyl)-piperidine-4-carboxylic acid and was obtained as a light yellow oil. MS m/e: 567.1 [M]+.