Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[OH:12].C(=O)([O-])[O-].[K+].[K+].Br[CH2:20][CH:21]1[CH2:26][CH2:25][CH2:24][S:23][CH2:22]1>C(#N)C.[I-].[K+]>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[O:12][CH2:20][CH:21]1[CH2:26][CH2:25][CH2:24][S:23][CH2:22]1
Reactant: BrCC1CCCSC1
Reactant: O=[N+]([O-])c1cc(O)c(Cl)cc1F
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: O=[N+]([O-])c1cc(OCC2CCCSC2)c(Cl)cc1F
Temperature: 25 °C
Yield: 28.8 %

Procedure:
47.9 g (250 mmol) of 2-chloro-4-fluoro-5-nitrophenol, 34.6 g (250 mmol) of potassium carbonate, 1 g of potassium iodide and 58.5 g (300 mmol) of 3-bromomethyltetrahydrothiopyran in 500 ml of acetonitrile were refluxed for 5 hours. The mixture was cooled to 25° C. and filtered, the solvent was removed from the filtrate, the residue was taken up in methylene chloride, and the solution was washed with water, dried and concentrated. 22 g (29%) of 2-chloro-4-fluoro-5-nitro-1-(3-tetrahydrothiopyranylmethoxy)benzene (melting point 100° to 103° C.) were obtained.
Reaction SMILES: [O:1]=[C:2]([CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH2:3][CH2:4][NH:5][CH:6]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:7]([O:9]CC)=O.[O-:28][C:29]#[N:30].[K+].Cl>>[CH2:21]([O:20][C:18]([CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH:6]1[N:5]([CH2:4][CH2:3][C:2](=[O:1])[CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[C:29](=[O:28])[NH:30][C:7]1=[O:9])=[O:19])[CH3:22]
Reactant: N#C[O-]
Reactant: CCCCCC(=O)CCNC(CCCCCCC(=O)OCC)C(=O)OCC
Agent: Cl
Agent: [K+]
Product: CCCCCC(=O)CCN1C(=O)NC(=O)C1CCCCCCC(=O)OCC

Procedure:
Diethyl 2-(3-oxooctylamino)nonanedioate (7.7 g) prepared by the method described in Example 1B was treated with potassium cyanate and hydrochloric acid to give 5-(6-ethoxycarbonylhexyl)-1-(3-oxo-octyl)hydantoin. Hydrolysis of this ester using sodium hydroxide solution gave 5-(6-carboxyhexyl)-1-(3-oxooctyl)hydantoin as a viscous oil, which crystallised to a low-melting solid.
Reaction SMILES: [C:1]1([N:7]2[C:12](=[O:13])[N:11]([CH3:14])[C:10](=[O:15])[C:9]([C:16]([OH:18])=O)=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(Cl)([Cl:21])=O>>[C:1]1([N:7]2[C:12](=[O:13])[N:11]([CH3:14])[C:10](=[O:15])[C:9]([C:16]([Cl:21])=[O:18])=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=S(Cl)Cl
Reactant: Cn1c(=O)c(C(=O)O)nn(-c2ccccc2)c1=O
Product: Cn1c(=O)c(C(=O)Cl)nn(-c2ccccc2)c1=O
Yield: 87.5 %

Procedure:
Intermediate e (3 g, 0.012 mol) was added to thionyl chloride (10V/W, 30 mL). The mixture was warmed up to react under reflux for 6 h. The solvent was evaporated off to produce a clear yellow crystal (2.8 g) in a yield of 87.5%.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[Cl:9][C:10]([S:14](Cl)(=[O:16])=[O:15])=[C:11]([Cl:13])[Cl:12]>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][S:14]([C:10]([Cl:9])=[C:11]([Cl:13])[Cl:12])(=[O:16])=[O:15])=[CH:4][CH:3]=1
Reactant: Nc1ccc(Cl)cc1
Reactant: O=S(=O)(Cl)C(Cl)=C(Cl)Cl
Solvent: ClC(Cl)Cl
Product: O=S(=O)(Nc1ccc(Cl)cc1)C(Cl)=C(Cl)Cl

Procedure:
A solution of 7.6 g (0.06 mol) p-chloroaniline and 7.0 g (0.03 mol) trichlorovinylsulfonyl chloride in 150 ml chloroform was heated under reflux for 3 hours. The reaction mixture was then cooled, washed with water, dried over magnesium sulfate and evaporated to give an oily residue. The residue was chromatographed on silica gel. N-(p-chlorophenyl)trichlorovinylsulfonamide, m.p. 73°-76° C., was eluted from the silica gel with 30% ether-70% hexane. Elemental analysis for C8H5Cl4NO2S showed: calculated, %S, 9.99, %Cl 44.2; found, %S, 10.1, %Cl 48.2.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([C@@H:12]([CH3:17])[C:13]([F:16])([F:15])[F:14])[C:9]([OH:11])=O)=[CH:4][CH:3]=1.[NH2:18][C:19]1[CH:20]=[C:21]([C:26]2([CH2:29][C:30]([O:32][CH3:33])=[O:31])[CH2:28][CH2:27]2)[CH:22]=[CH:23][C:24]=1[F:25].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.N1C=CC=CC=1>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@H:8]([C@@H:12]([CH3:17])[C:13]([F:16])([F:15])[F:14])[C:9]([NH:18][C:19]2[CH:20]=[C:21]([C:26]3([CH2:29][C:30]([O:32][CH3:33])=[O:31])[CH2:27][CH2:28]3)[CH:22]=[CH:23][C:24]=2[F:25])=[O:11])=[CH:6][CH:7]=1
Reactant: C[C@H]([C@H](C(=O)O)c1ccc(Cl)cc1)C(F)(F)F
Reactant: COC(=O)CC1(c2ccc(F)c(N)c2)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: COC(=O)CC1(c2ccc(F)c(NC(=O)[C@H](c3ccc(Cl)cc3)[C@@H](C)C(F)(F)F)c2)CC1

Procedure:
A solution of 70 mg (0.31 mmol) of (2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbutanoic acid, 84 mg (0.31 mmol) of methyl [1-(3-amino-4-fluorophenyl)cyclopropyl]acetate, 179 mg (0.47 mmol) of 2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU) and 0.6 ml of pyridine in 2.4 ml of DMF was stirred at room temperature overnight. After the reaction had ended, the mixture was separated directly, without further work-up, by preparative HPLC. This gave 106 mg (0.22 mmol, 72% of theory) of the title compound as a colourless oil.
Reaction SMILES: [F:1][C:2]1([F:19])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][C:5]2[CH:13]=[CH:14][CH:15]=[CH:16][C:4]=2[C:3]1([F:18])[F:17].FC(F)(F)C(O)=[O:23]>[O-2].[O-2].[O-2].[Cr+6].C(O)(=O)C>[F:1][C:2]1([F:19])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[C:6](=[O:23])[C:5]2[CH:13]=[CH:14][CH:15]=[CH:16][C:4]=2[C:3]1([F:17])[F:18]
Reactant: O=C(O)C(F)(F)F
Reactant: FC1(F)c2ccccc2Cc2ccccc2C1(F)F
Agent: [Cr+6]
Agent: [O-2]
Solvent: CC(=O)O
Product: O=C1c2ccccc2C(F)(F)C(F)(F)c2ccccc21

Procedure:
A mixture of 1.45 g. (0.00544 mole) of 10,11-dihydro-10,10,11,11-tetrafluoro-5H-dibenzo[a,d]cycloheptene, 0.73 g. (0.0073 mole) of chromium trioxide, 25 ml. of trifluoroacetic acid and 2 ml. of glacial acetic acid is stirred at reflux for 21/4 hours. During this period, almost all of the chromium trioxide dissolves. Solvents are evaporated under reduced pressure and the residue is partitioned between benzene and water. The aqueous layer is separated and re-extracted twice with benzene. The combined benzene extracts are washed thoroughly with water, dried over anhydrous magnesium sulfate, and evaporated to dryness under reduced pressure. The crude product is left as the residual oily solid and is purified by column chromatography on 75 g. of silica gel, eluting the product with 1:1 benzene-carbon tetrachloride. The fractions that show one spot of Rf 0.75 on a silica thin layer plate developed with benzene are combined. Evaporation of the solvent under reduced pressure leaves the white crystalline product, m.p. 70°-75°C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[N:8]=[C:9]3[NH:18][C:13]4([CH2:17][CH2:16][NH:15][CH2:14]4)[CH2:12][CH2:11][N:10]3[C:19](=[O:21])[CH:20]=2)=[N:3][CH:2]=1.C(N(CC)CC)C.[F:29][C:30]1[CH:31]=[C:32]([CH:36]=[CH:37][CH:38]=1)[C:33](Cl)=[O:34].[Cl-].[NH4+]>O1CCCC1>[F:29][C:30]1[CH:31]=[C:32]([CH:36]=[CH:37][CH:38]=1)[C:33]([N:15]1[CH2:16][CH2:17][C:13]2([CH2:12][CH2:11][N:10]3[C:19](=[O:21])[CH:20]=[C:7]([C:4]4[CH:5]=[CH:6][N:1]=[CH:2][N:3]=4)[N:8]=[C:9]3[NH:18]2)[CH2:14]1)=[O:34]
Reactant: O=C(Cl)c1cccc(F)c1
Reactant: O=c1cc(-c2ccncn2)nc2n1CCC1(CCNC1)N2
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(c1cccc(F)c1)N1CCC2(CCn3c(nc(-c4ccncn4)cc3=O)N2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 72.3 %

Procedure:
To a solution of 0.3 g (1.055 mmol) of 8-pyrimidin-4-yl-3,4-dihydrospiro [pyrimido[1,2-a]pyrimidine-2,3′-pyrrolidin]-6(1H)-one dissolved in 5 ml of tetrahydrofuran at room temperature were added 0.18 ml (1.27 mmol) of triethylamine and 0.152 ml (1.27 mmol) of 3-fluoro-benzoyl chloride. The resulting mixture was stirred at room temperature under nitrogen atmosphere for 2h. The reaction mixture was added to a saturated aqueous solution of ammonium chloride, extracted with a mixture of dichloromethane/menthanol in the proportions of 100/0 to 80/20, dried and evaporated. The residue was purified by chromatography on silica gel eluting with a mixture of dichloromethane/menthanol in the proportions of 100/0 to 70/30 to give 0.310 g (72%) of pure product as grey solid. Mp: 296-298° C.
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([O:18][C:19]3[C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[CH:22]=[CH:21][CH:20]=3)[CH:13]=[N:12]2)[C:8]([OH:10])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:29][C:30]1[CH:34]=[CH:33][N:32]([CH2:35][C:36]([CH3:39])([OH:38])[CH3:37])[N:31]=1>>[OH:38][C:36]([CH3:39])([CH3:37])[CH2:35][N:32]1[CH:33]=[CH:34][C:30]([NH:29][C:8](=[O:10])[CH:7]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([O:18][C:19]3[C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[CH:22]=[CH:21][CH:20]=3)[CH:13]=[N:12]2)[CH2:6][CH2:1][CH2:5][CH2:4][CH2:3][CH3:2])=[N:31]1
Reactant: CC(C)(O)Cn1ccc(N)n1
Reactant: O=C(O)C(CC1CCCC1)n1ncc(Oc2cccc3ccccc23)cc1=O
Product: CCCCCCC(C(=O)Nc1ccn(CC(C)(C)O)n1)n1ncc(Oc2cccc3ccccc23)cc1=O
Yield: 11 %

Procedure:
Using the method described in Example 17, 3-cyclopentyl-2-[4-(naphthalen-1-yloxy)-6-oxo-6H-pyridazin-1-yl]-propionic acid (Intermediate 38) and 1-(3-amino-pyrazol-1-yl)-2-methyl-propan-2-ol (Intermediate 1) afforded 2-[4-(naphthalen-1-yloxy)-6-oxo-6H-pyridazin-1-yl]-octanoic acid [1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-amide as a white solid (0.15 g, 11%); ES+-HRMS m/e calcd for C29H33N5O4 [M+H+] 516.2606 found 516.2604. 1H-NMR (300 MHz, DMSO-d6) δ ppm 1.10-1.20 (br.s., 7H), 1.22-1.83 (m, 8H), 1.93 (m, 1H), 2.29 (m, 1H), 3.89 (s, 2H), 4.67 (s, 1H), 5.45 (m, 1H), 5.63 (s, 1H), 6.40 (s, 1H), 7.44-7.74 (m, 5H), 7.87-8.16 (m, 3H), 8.29 (s, 1H), 10.79 (s, 1H).
Reaction SMILES: [OH:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:12]/[O:13][CH3:14])/[C:8]([O:10]C)=[O:9])[N:6]=1.[OH-].[K+].Cl>C(O)C>[OH:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:12]/[O:13][CH3:14])/[C:8]([OH:10])=[O:9])[N:6]=1
Reactant: CO/N=C(\C(=O)OC)c1csc(O)n1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CO/N=C(\C(=O)O)c1csc(O)n1
Reaction time: 4 h

Procedure:
In 3 ml of ethanol is dissolved 1.0 g of methyl 2-(2-hydroxy-4-thiazolyl)-(Z)-2-methoxyiminoacetate, and under ice-cooling 5 ml of an aqueous solution of potassium hydroxide (1.3 g) is added dropwise. The mixture is allowed to stand for 4 hours, adjusted to pH 2-3 with 1N hydrochloric acid, and extracted three times with n-butanol. The extracts are combined, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The procedure gives a light-brown powder of 2-(2-hydroxy-4-thiazolyl)-(Z)-2-methoxyiminoacetic acid, m.p. 143°-144° C. (decomp.).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[O:3][C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=O.CN(C=O)C.C(Cl)(=O)C(Cl)=O.[CH2:26]([NH:28][CH2:29][CH3:30])[CH3:27]>C(Cl)Cl>[CH2:26]([N:28]([CH2:29][CH3:30])[C:6](=[O:8])[C:5]1[CH:9]=[CH:10][CH:11]=[CH:12][C:4]=1[O:3][C:2]([F:1])([F:14])[F:13])[CH3:27]
Reactant: O=C(O)c1ccccc1OC(F)(F)F
Reactant: CCNCC
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCN(CC)C(=O)c1ccccc1OC(F)(F)F
Reaction time: 4 h
Yield: 94.1 %

Procedure:
To a stirring solution of 2-trifluoromethoxybenzoic acid (3.6 g, 17.5 mmol, Avocado) in dry CH2Cl2 (150 mL) with DMF (0.5 mL) was added a 2M solution of oxalyl chloride in CH2Cl2 (17.5 mL) dropwise over 30 min. The reaction was stirred for 4 h and then conc. in vacuo to a white solid. The solid was dissolved in CH2Cl2 (150 mL) and reacted with diethylamine (3.2 g, 43.8 mmol, Aldrich) the reaction was stirred for 16 h and then conc. in vacuo to a yellow solid. The solid was purified by radial chromatography (SiO2, 1:5, EtOAc:hexanes) to yield 4.3 grams (94%) of the product as a colorless oil. MS (ESI) 262 (M+H).
Reaction SMILES: CN(C)[CH:3]=[CH:4][C:5]([C:7]1(C)[CH:11]([S:12][CH3:13])[S:10][C:9]([C:14]#[N:15])=[C:8]1[CH3:16])=O.[C:19]1([NH:25][C:26]([NH2:28])=[NH:27])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(#N)C.CO>[CH3:16][C:8]1[C:7]([C:5]2[CH:4]=[CH:3][N:28]=[C:26]([NH:25][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[N:27]=2)=[C:11]([S:12][CH3:13])[S:10][C:9]=1[C:14]#[N:15]
Reactant: N=C(N)Nc1ccccc1
Reactant: CSC1SC(C#N)=C(C)C1(C)C(=O)C=CN(C)C
Solvent: CC#N
Solvent: CO
Product: CSc1sc(C#N)c(C)c1-c1ccnc(Nc2ccccc2)n1

Procedure:
4-(3-Dimethylamino-acryloyl)-3,4-dimethyl-5-methylsulfanyl-4,5-dihydro-thiophene-2-carbonitrile (0.2 mmol) was combined with N-phenyl-guanidine (0.2 mmol) in acetonitrile (0.25 mL) and the resulting mixture heated at reflux for 24 hours. The reaction mixture was diluted with methanol (3mL) and the resulting slurry filtered and the solid was washed with methanol (2 mL) then dried under nitrogen to afford IIa-37. M+H=507.1, HPLC: Rt=6.196 minutes, 1H NMR (500 Mz, DMSO) 9.77(s, 1H), 8.25(d, 1H, J=5.3 Hz), 7.69(s, 1H), 7.48(m, 2H), 7.48(m, 4H), 7.41(t, 2H, J=7.3 Hz), 7.34(t, 1H, J=7.2 Hz), 7.25(d, 1H, J=8.3 Hz), 7.21 (t, 1H, J=8.0 Hz), 6.67(d, 1H, J=6.7 Hz), 6.01(d, 1H, J=5.3 Hz), 5.11(s, 2H), 3.32(s, 3H, CH3), 2.68(s, 3H, CH3).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:20]Br.N1C=CN=C1.[CH:27]1([CH:33]([CH2:48][CH2:49]O)[C:34]([NH:36][CH2:37][C:38]2[C:43]([Cl:44])=[CH:42][C:41]([O:45][CH3:46])=[CH:40][C:39]=2[Cl:47])=[O:35])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1>C(Cl)Cl>[Br:20][CH2:49][CH2:48][CH:33]([CH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1)[C:34]([NH:36][CH2:37][C:38]1[C:43]([Cl:44])=[CH:42][C:41]([O:45][CH3:46])=[CH:40][C:39]=1[Cl:47])=[O:35]
Reactant: BrBr
Reactant: COc1cc(Cl)c(CNC(=O)C(CCO)C2CCCCC2)c(Cl)c1
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1cc(Cl)c(CNC(=O)C(CCBr)C2CCCCC2)c(Cl)c1

Procedure:
Stir a mixture of triphenylphosphine (3.16 g, 12.06 mmol), bromine (1.91 g, 12.06) and methylene chloride (150 mL) at room temperature for 20 minutes. To the mixture, add a solution of imidazole (0.98 g, 14.48 mmol), 2-Cyclohexyl-N-(2,6-dichloro-4-methoxy-benzyl)-4-hydroxy-butyramide (4.5 g, 12.06 mmol) in methylene chloride (100 mL). Stir the reaction at room temperature for 3.5 hours. Wash the reaction with HCl (1 N), water and brine. After drying the organic layer over sodium sulfate, filter and concentrate under vacuum. Purify the residue by silica gel chromatography with 1:3 ethyl acetate/hexane to afford 2.5 g. of the title compound. MS (m/z): 436 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:7](=[O:8])[N:6]2[N:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:14][CH:13]=3)[S:11][C:5]2=[N:4][C:3]=1[NH2:22].[N:23]([O-])=O.[Na+]>Cl.O>[C:18]([C:15]1[CH:14]=[CH:13][C:12]([C:10]2[S:11][C:5]3=[N:4][C:3]4[N:22]=[N:23][NH:1][C:2]=4[C:7](=[O:8])[N:6]3[N:9]=2)=[CH:17][CH:16]=1)([CH3:19])([CH3:21])[CH3:20]
Reactant: CC(C)(C)c1ccc(-c2nn3c(=O)c(N)c(N)nc3s2)cc1
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: CC(C)(C)c1ccc(-c2nn3c(=O)c4[nH]nnc4nc3s2)cc1

Procedure:
1.0 of 6,7-diamino-2-(4-tert-butylphenyl)-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-5-one was suspended in a mixture of 20 ml of concentrated hydrochloric acid and 20 ml of water, and 2 ml of an aqueous solution containing 0.70 g of sodium nitrite was added dropwise thereto while cooling below 5° C. and stirring. The mixture was stirred at that temperature for 1.5 hours and then diluted with water. The resulting precipitate was filtered and recrystallized from chloroform-ethanol to obtain 0.88 g of the titled compound as pale yellow prisms. Melting Point: 293°-296° C. (decomposition).
Reaction SMILES: C([O:5][C:6](=[O:45])[C:7]([O:10]/[N:11]=[C:12](/[C:32]1[N:33]=[C:34]([NH:37]C(OC(C)(C)C)=O)[S:35][CH:36]=1)\[C:13]([NH:15][C@@H:16]1[C:19](=[O:20])[N:18]([S:21]([OH:24])(=[O:23])=[O:22])[C@@H:17]1[CH2:25][N:26]1[N:30]=[C:29]([CH3:31])[CH:28]=[N:27]1)=[O:14])([CH3:9])[CH3:8])(C)(C)C>C(O)=O>[NH2:37][C:34]1[S:35][CH:36]=[C:32](/[C:12](=[N:11]/[O:10][C:7]([CH3:9])([CH3:8])[C:6]([OH:45])=[O:5])/[C:13]([NH:15][C@@H:16]2[C:19](=[O:20])[N:18]([S:21]([OH:24])(=[O:22])=[O:23])[C@@H:17]2[CH2:25][N:26]2[N:30]=[C:29]([CH3:31])[CH:28]=[N:27]2)=[O:14])[N:33]=1
Reactant: Cc1cnn(C[C@@H]2[C@H](NC(=O)/C(=N\OC(C)(C)C(=O)OC(C)(C)C)c3csc(NC(=O)OC(C)(C)C)n3)C(=O)N2S(=O)(=O)O)n1
Solvent: O=CO
Product: Cc1cnn(C[C@@H]2[C@H](NC(=O)/C(=N\OC(C)(C)C(=O)O)c3csc(N)n3)C(=O)N2S(=O)(=O)O)n1
Yield: 26.5 %

Procedure:
(2R,3S)-3-((Z)-2-(((1-(tert-butoxy)-2-methyl-1-oxopropan-2-yl)oxy)imino)-2-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)acetamido)-2-((4-methyl-2H-1,2,3-triazol-2-yl)methyl)-4-oxoazetidine-1-sulfonic acid (67 mg, 0.10 mmol) was stirred with formic acid (1.5 mL) at rt for 3.5 h then concentrated in vacuo. The crude residue was purified by reverse phase prep HPLC (XBridge, 30×100 mm, 5 μm, C18 column; ACN-water with 0.1% formic acid modifier, 1 mL/min), affording the title compound (13.7 mg, 27%) as a white solid. LCMS: m/z=514.9 (M−1); 1H NMR (400 MHz, D2O): δ 7.39 (s, 1H), 6.94 (s, 1H), 5.38 (d, J=5.6 Hz, 1H), 4.80-4.60 (m, 3H assumed; obscured by solvent residual peak), 2.10 (s, 3H), 1.26 (s, 3H), 1.25 (s, 3H).
Reaction SMILES: [CH2:1]([N:3]([CH2:31][CH3:32])[C:4]([CH2:6][O:7][C:8]1[CH:9]=[CH:10][CH:11]=[C:12]2[C:16]=1[NH:15][CH:14]=[C:13]2[CH2:17][C@H:18]([N:20]1C(=O)C2=CC=CC=C2C1=O)[CH3:19])=[O:5])[CH3:2].O.NN>C(O)C>[CH2:31]([N:3]([CH2:1][CH3:2])[C:4]([CH2:6][O:7][C:8]1[CH:9]=[CH:10][CH:11]=[C:12]2[C:16]=1[NH:15][CH:14]=[C:13]2[CH2:17][C@H:18]([NH2:20])[CH3:19])=[O:5])[CH3:32]
Reactant: CCN(CC)C(=O)COc1cccc2c(C[C@@H](C)N3C(=O)c4ccccc4C3=O)c[nH]c12
Agent: NN
Solvent: O
Solvent: CCO
Product: CCN(CC)C(=O)COc1cccc2c(C[C@@H](C)N)c[nH]c12
Temperature: 85 °C
Reaction time: 3 h
Yield: 96 %

Procedure:
(R)-7-Diethylaminocarbonylmethyloxy-3-(2-phthalimidopropyl)indole 10.27 g was suspended in 100 ml of ethanol, and 2.5 ml of hydrazine monohydrate was added thereto. The suspension was heated to reflux in an oil bath of 85° C. For 3 hours. After cooling down, the resulting deposited insoluble materials were filtered off, and the filtrate was concentrated under reduced pressure. Ethyl acetate and a sodium hydroxide aqueous solution were added to the residue and distributed in liquid-liquid, and the organic layer was further washed with a sodium hydroxide aqueous solution and dried. The solution was evaporated under reduced pressure. The resulting residue was slowly crystallized, and dried under reduced pressure, whereby 6.90 g of the title compound was obtained in the form of a pale brownish white substance.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[CH2:10]([OH:14])[CH2:11][C:12]#[CH:13].C(N(CC)CC)C>CN(C)C=O.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[OH:14][CH2:10][CH2:11][C:12]#[C:13][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5]
Reactant: C#CCCO
Reactant: O=Cc1ccccc1Br
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=Cc1ccccc1C#CCCO
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.4 %

Procedure:
To a solution of 2-bromobenzaldehyde (10 g, 54 mmol) in anhydrous N,N-dimethylformamide (150 ml) was added 3-butyn-1-ol (6.13 ml, 81 mmol) and triethylamine (11.3 ml, 81 mmol), followed by copper (I) iodide (490 mg, 5.4 mmol) and Pd(PPh3)2Cl2 (1.9 g, 2.7 mmol), and the mixture degassed three times and stirred at room temperature overnight. The mixture was poured into water (600 ml) and extracted with EtOAc (3×150 ml); the combined EtOAc layers were washed with water (2×250 ml), sat NaCl (100 ml), then dried over Na2SO4, filtered and evaporated. The residue was purified by column chromatography on silica eluting with 50% Et2O in isohexanes to give the title compound (8.5 g, 90%) as an orange oil.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([CH2:14][OH:15])[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].N1C=CC=CC=1.[CH3:22][S:23](Cl)(=[O:25])=[O:24]>C(Cl)Cl>[C:4]([O:3][C:1]([N:8]1[CH2:13][CH2:12][CH2:11][C@@H:10]([CH2:14][O:15][S:23]([CH3:22])(=[O:25])=[O:24])[CH2:9]1)=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCCC(CO)C1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC[C@@H](COS(C)(=O)=O)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of N-BOC-3-piperidinemethanol (0.50 g, 0.002 mmole) in DCM (10 mL) was added dropwise pyridine (2.42 mL, 0.03 mmole) followed by the addition of methanesulfonyl chloride (0.774 mL, 0.01 mmole). The reaction mixture continued stirring at RT overnight. The reaction mixture was quenched with water. The aqueous layer was extracted with EtOAc (3×5 mL). Combined organic layers were dried over Na2SO4 and concentrated to yield a crude oil, 68, which was used in the next step without further purification. LRMS: 193 (M+-BOC group).
Reaction SMILES: Cl.[N:2]1[C:7]2[NH:8][CH:9]=[CH:10][C:6]=2[C:5]([N:11]2[CH2:15][CH2:14][C@@H:13]([NH2:16])[CH2:12]2)=[N:4][CH:3]=1.[CH:17](=O)[CH2:18][CH3:19]>C1COCC1>[CH2:17]([NH:16][C@@H:13]1[CH2:14][CH2:15][N:11]([C:5]2[C:6]3[CH:10]=[CH:9][NH:8][C:7]=3[N:2]=[CH:3][N:4]=2)[CH2:12]1)[CH2:18][CH3:19]
Reactant: CCC=O
Reactant: N[C@@H]1CCN(c2ncnc3[nH]ccc23)C1
Agent: Cl
Solvent: C1CCOC1
Product: CCCN[C@@H]1CCN(c2ncnc3[nH]ccc23)C1
Temperature: 25 °C

Procedure:
A mixture of (R)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrrolidin-3-amine hydrochloride (50 mg, 0.24 mmol), propionaldehyde (15 mg, 0.26 mmol) and NaBH(OAC)3 (61 mg, 1.2 mmol) in THF (5 mL) was stirred at the ambient temperature for minutes. It was then quenched with water (2 mL) and extracted with EtOAc (3×10 mL). The combined extracts were washed with brine (3×5 mL), dried over anhydrous Na2SO4, filtered, and concentrated to give the title compound. MS (m/z): 246 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1([CH3:24])[C:11]2[CH:10]=[C:9]3[NH:12][C:13]([C:15]4[CH:20]=[CH:19][C:18]([C:21]#[N:22])=[CH:17][CH:16]=4)=[N:14][C:8]3=[CH:7][C:6]=2[NH:5][C:4](=[O:23])[CH2:3]1.S(=O)(=O)(O)[OH:26].N>>[CH3:1][C:2]1([CH3:24])[C:11]2[CH:10]=[C:9]3[NH:12][C:13]([C:15]4[CH:20]=[CH:19][C:18]([C:21]([NH2:22])=[O:26])=[CH:17][CH:16]=4)=[N:14][C:8]3=[CH:7][C:6]=2[NH:5][C:4](=[O:23])[CH2:3]1
Reactant: O=S(=O)(O)O
Reactant: CC1(C)CC(=O)Nc2cc3nc(-c4ccc(C#N)cc4)[nH]c3cc21
Agent: N
Product: CC1(C)CC(=O)Nc2cc3nc(-c4ccc(C(N)=O)cc4)[nH]c3cc21

Procedure:
3.6 g. of the compound obtained in Example 26 were introduced into 70 ml. concentrated sulphuric acid and stirred for 24 hours at 25° C. Subsequently, the reaction mixture was poured on to ice, neutralized with a concentrated aqueous solution of ammonia, filtered off with suction and well washed with water to give 1.8 g. of the title compound which, after crystallization from ethanol/water, had a melting point of 317°-319° C.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([Cl:9])[CH:6]=[CH:5][C:3]=1[NH2:4].[H-].[Na+].Cl[C:13]1[C:22]2[C:17](=[CH:18][C:19]3[CH:26]=[C:25]([O:27][CH3:28])[CH:24]=[CH:23][C:20]=3[CH:21]=2)[N:16]=[CH:15][C:14]=1[C:29]#[N:30]>CN(C=O)C>[Cl:1][C:2]1[CH:8]=[C:7]([Cl:9])[CH:6]=[CH:5][C:3]=1[NH:4][C:13]1[C:22]2[C:17](=[CH:18][C:19]3[CH:26]=[C:25]([O:27][CH3:28])[CH:24]=[CH:23][C:20]=3[CH:21]=2)[N:16]=[CH:15][C:14]=1[C:29]#[N:30]
Reactant: COc1ccc2cc3c(Cl)c(C#N)cnc3cc2c1
Reactant: Nc1ccc(Cl)cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc2cc3c(Nc4ccc(Cl)cc4Cl)c(C#N)cnc3cc2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 82.1 %

Procedure:
According to the procedure of Example 14, a reaction mixture of 487.7 mg (3.01 mmol) of 2,4-dichloroaniline and 120.6 mg (3.01 mmol) of sodium hydride in 15 mL of anhydrous DMF is stirred at room temperature for 0.5 hour. To the mixture is added 367.0 mg (1.37 mmol) of 4-chloro-8-methoxybenzo[g]quinoline-3-carbonitrile. The resulting mixture is heated at 55° C. for 0.5 hour. After work up, 443.3 mg (82.1%) of 4-(2,4-dichloroanilino)-8-methoxybenzo[g]quinoline-3-carbonitrile is obtained as a yellow solid, mp>260° C.