Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]([CH2:11][C:12]2[NH:13][C:14]3[C:19]([CH:20]=2)=[CH:18][C:17]([S:21]([CH3:24])(=[O:23])=[O:22])=[CH:16][CH:15]=3)=[CH:9][CH:10]=1)=[O:5])[CH3:2].[F:25][C:26]1[CH:33]=[CH:32][C:29]([CH2:30]Br)=[CH:28][CH:27]=1.[Cl-].[NH4+]>O1CCCC1.C([N-]C(C)C)(C)C.[Li+]>[CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]([CH2:11][C:12]2[N:13]([CH2:30][C:29]3[CH:32]=[CH:33][C:26]([F:25])=[CH:27][CH:28]=3)[C:14]3[C:19]([CH:20]=2)=[CH:18][C:17]([S:21]([CH3:24])(=[O:23])=[O:22])=[CH:16][CH:15]=3)=[CH:9][CH:10]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ccc(Cc2cc3cc(S(C)(=O)=O)ccc3[nH]2)o1
Reactant: Fc1ccc(CBr)cc1
Agent: CC(C)[N-]C(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(Cc2cc3cc(S(C)(=O)=O)ccc3n2Cc2ccc(F)cc2)o1
Reaction time: 0.5 h

Procedure:
To a solution of the compound obtained in Example 30 (5) (0.0592 g) in tetrahydrofuran (2 ml), 2.0 M lithium diisopropylamide solution (0.0852 ml) was added dropwise at −78° C. and the mixture was stirred for 30 minutes. 4-Fluorobenzyl bromide (0.02 ml) was then added to the mixture, followed by stirring at the same temperature for 30 minutes. The reaction solution was poured into a saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous NaCl solution, dried over anhydride magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was separated using silica gel preparative thin-layer chromatography (hexane:ethyl acetate=1:1) to obtain 0.005 g of the desired product.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH:10]([NH:29][C:30]([O:32][CH2:33][CH2:34][NH:35][C:36]1[CH:41]=[CH:40][CH:39]=[C:38]([CH3:42])[N:37]=1)=[O:31])[C:11]([NH:13][CH:14]([C:21]1[CH:26]=[C:25]([Cl:27])[CH:24]=[C:23]([Cl:28])[CH:22]=1)[CH2:15][C:16]([O:18]CC)=[O:17])=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)C.[OH-].[Na+]>C(O)(=O)C>[CH2:1]([O:8][CH2:9][CH:10]([NH:29][C:30]([O:32][CH2:33][CH2:34][NH:35][C:36]1[CH:41]=[CH:40][CH:39]=[C:38]([CH3:42])[N:37]=1)=[O:31])[C:11]([NH:13][CH:14]([C:21]1[CH:26]=[C:25]([Cl:27])[CH:24]=[C:23]([Cl:28])[CH:22]=1)[CH2:15][C:16]([OH:18])=[O:17])=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)CC(NC(=O)C(COCc1ccccc1)NC(=O)OCCNc1cccc(C)n1)c1cc(Cl)cc(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CC(=O)O
Product: Cc1cccc(NCCOC(=O)NC(COCc2ccccc2)C(=O)NC(CC(=O)O)c2cc(Cl)cc(Cl)c2)n1

Procedure:
50.00 mg of ethyl 3-{3-benzyloxy-2-[2-(6-methylpyridin-2-ylamino)ethoxycarbonylamino]propanoylamino}-3-(3,5-dichlorophenyl)propionate are reacted with 2 ml of ethanol and 0.50 ml of 1 molar sodium hydroxide solution for 2 hours with stirring, acidified using 0.5 ml of glacial acetic acid and evaporated to dryness, giving 3-{3-benzyloxy-2-[2-(6-methylpyridin-2-ylamino)ethoxycarbonylamino]propanoylamino}-3-(3,5-dichlorophenyl)propionic acid.
Reaction SMILES: [C:1]([OH:12])(=[O:11])[C:2]1[C:3](=[CH:7][CH:8]=[CH:9][CH:10]=1)[C:4]([OH:6])=[O:5].[OH-].[K+]>C(O)C(C)C>[CH2:1]([C:10]1[CH:9]=[CH:8][CH:7]=[C:3]([C:4]([OH:6])=[O:5])[C:2]=1[C:1]([OH:12])=[O:11])[CH:2]([CH3:3])[CH3:10]
Reactant: O=C(O)c1ccccc1C(=O)O
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)CO
Product: CC(C)Cc1cccc(C(=O)O)c1C(=O)O
Temperature: 80 °C

Procedure:
148.2 g of anhydrous phthalic acid and the molar equivalent 74.2 g of isobutyl alcohol were added to a 500 ml glass round-bottomed flask equipped with stirring blades, thermometer and Dimroth condenser, heated while slowly stirring, and after the generated heat at about 80° C. wore off, raised to a temperature of 140° C., which was maintained for 2 hours. The mixture was subsequently cooled to 60° C. The acid value (number of mg of KOH necessary to neutralize 1 g of a sample) of the reaction solution was 257.5. Since the acid value for the case where the reaction is 100% complete is 252.4, the reaction rate was computed to be 98%.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:20][CH2:21][OH:22])[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].F[B-](F)(F)F.[S:28]1[C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=2[S:30][CH+:29]1.N1C=CC=CC=1.C(N(CC)CC)C>ClCCl>[S:28]1[C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=2[S:30][CH:29]1[O:22][CH2:21][CH2:20][C@H:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[C:10]([O:12][CH2:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)=[O:11]
Reactant: c1ccc2s[cH+]sc2c1
Reactant: CC(C)(C)OC(=O)N[C@@H](CCO)C(=O)OCc1ccccc1
Agent: F[B-](F)(F)F
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@@H](CCOC1Sc2ccccc2S1)C(=O)OCc1ccccc1
Reaction time: 8 h

Procedure:
(S)-Benzyl 2-(tert-butoxycarbonylamino)-4-hydroxybutanoate (5.76 g, 18.62 mmol) and 1,3-benzodithiol-2-ylium tetrafluoroborate (4.69 g, 19.55 mmol) were dissolved in dichloromethane (186 mL) and pyridine (4.42 g, 55.86 mmol) was added at room temperature. The mixture was stirred overnight. Upon completion of the reaction, it was quenched with triethylamine (11.5 g, 113.5 mmol) and diluted with dichloromethane. The organic layer was then washed with saturated NaHCO3 and brine. The organic layer was dried over MgSO4 and concentrated down in vacuo. The residue was then purified on normal phase column to obtain a clear oil. 7.6 g (88%).
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH2:7][S:8][C@@H:9]2[C@H:20]([NH2:21])[C:19](=[O:22])[N:10]2[C:11]=1[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])(=[O:3])[CH3:2].C1OC1C.[Cl:27][CH:28]([Cl:42])[C:29]([O:31][NH:32][CH:33]([C:37]1[CH:41]=[CH:40][S:39][CH:38]=1)[C:34](Cl)=[O:35])=[O:30]>C(OCC)(=O)C>[C:1]([O:4][CH2:5][C:6]1[CH2:7][S:8][C@@H:9]2[C@H:20]([NH:21][C:34](=[O:35])[C:33](=[N:32][O:31][C:29](=[O:30])[CH:28]([Cl:27])[Cl:42])[C:37]3[CH:41]=[CH:40][S:39][CH:38]=3)[C:19](=[O:22])[N:10]2[C:11]=1[C:12]([O:14][C:15]([CH3:16])([CH3:17])[CH3:18])=[O:13])(=[O:3])[CH3:2]
Reactant: CC(=O)OCC1=C(C(=O)OC(C)(C)C)N2C(=O)[C@@H](N)[C@H]2SC1
Reactant: O=C(ONC(C(=O)Cl)c1ccsc1)C(Cl)Cl
Agent: CC1CO1
Solvent: CCOC(C)=O
Product: CC(=O)OCC1=C(C(=O)OC(C)(C)C)N2C(=O)[C@@H](NC(=O)C(=NOC(=O)C(Cl)Cl)c3ccsc3)[C@H]2SC1
Temperature: 0 °C

Procedure:
To an ice cold solution of t-butyl 3-acetoxymetyl-7β-aminoceph-3-em-4-carboxylate (1.59 g) and propylene oxide (3.5 mls) in ethyl acetate (15 mls) was added with stirring a 1-M solution of 2-dichloroacetoxyamino-2-(thien-3-yl) acetyl chloride (syn-isomer) (5.3 ml) in ethyl acetate. After 11/2 hrs. at 20° C the solution was washed with 2N-HCl, saturated sodium bicarbonate solution and brine. The organic layer was dried and evapoated to give t-butyl 3-acetoxymethyl-7β-[2-dichloroacetoxyimino-2(thien-3-yl)acetamido]ceph-3-em-4-carboxylate (syn-isomer) as a white foam, (2.8 g, 100%), [α]D + 47.0° (c 0.9, DMSO), λmax. (ethanol) 253 nm (ε 13,900), νmax. (CHBr3) 3580 (OH), 3410 (NH), 1790 (β-lactam), 1728 (OCOCH3), 1720 (COO But) and 1700 and 1520 cm-1 (CONH); τ (CDCl3) values include 2.11 to 2.7 (m; thienyl protons), 7.92 (s; OCOCH3), 8.48 (s; But).
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([CH3:18])[N:6]([CH3:17])[C:7]=1[S:8][C:9]1[CH:14]=[C:13]([CH3:15])[CH:12]=[C:11]([CH3:16])[CH:10]=1.[C-:19]#[N:20].[K+]>CN(C)C=O>[CH3:17][N:6]1[C:7]([S:8][C:9]2[CH:14]=[C:13]([CH3:15])[CH:12]=[C:11]([CH3:16])[CH:10]=2)=[C:3]([CH2:2][C:19]#[N:20])[N:4]=[C:5]1[CH3:18]
Reactant: Cc1cc(C)cc(Sc2c(CCl)nc(C)n2C)c1
Reactant: [C-]#N
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(C)cc(Sc2c(CC#N)nc(C)n2C)c1
Temperature: 50 °C
Yield: 42 %

Procedure:
In 5.6 ml of dry dimethylformamide was dissolved 280 mg (1.0 mmol)of 4-chloromethyl-1,2-dimethyl-5-(3,5-dimethylphenylthio)-1H-imidazole (42c). Added was 98 mg (1.5 mmol)of potassium cyanide, and the mixture was heated at 50° C. for 5 hours. To the reaction mixture, ice-water was added, extracted with diethyl ether, the extract was washed with water and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel chromatography (ethyl acetate)to obtain 114 mg of [1,2-dimethyl-5-(3,5-dimethylphenylthio)-1H-imidazol-4-yl]acetonitrile (42d)(yield 42%). mp 81-82° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:13]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][NH:21][C:22]([NH:24]CC3C=CC(OC)=CC=3)=[O:23])=[CH:12][CH:11]=[CH:10][C:4]=2[NH:5][S:6](=[O:9])(=[O:8])[N:7]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:1][C:2]1[C:3]2[C:13]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][NH:21][C:22]([NH2:24])=[O:23])=[CH:12][CH:11]=[CH:10][C:4]=2[NH:5][S:6](=[O:8])(=[O:9])[N:7]=1
Reactant: COc1ccc(CNC(=O)NCCCCCCOc2cccc3c2C(N)=NS(=O)(=O)N3)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC(=O)NCCCCCCOc1cccc2c1C(N)=NS(=O)(=O)N2
Temperature: 25 °C
Reaction time: 4 h
Yield: 0.1 %

Procedure:
A solution of 1-(6-(4-amino-2,2-dioxo-1H-benzo[c][1,2,6]thiadiazin-5-yloxy)hexyl)-3-(4-methoxybenzyl)urea (122 mmol, 58 mg) (Example 279) in DCM (2.5 mL) was treated with TFA (2.5 mL). The reaction mixture was stirred at room temperature for 4 hours, then the volatiles were removed under a stream of nitrogen. The oily residue was triturated with ether, the precipitate collected, washed with ether, then dissolved in MeOH and evaporated to gives the desired product (44 mg, 100% yield). 1H NMR (400 MHz, DMSO-d6) δ 1.364 (m, 6H), 1.812 (pentet, J=7 Hz, 2H), 2.943 (br t, 2H), 4.154 (d, J=7 Hz, 2H), 4.131 (t, J=7 Hz, 2H), 5.349 (br. s, 2H), 5.894 (br. s, 1H), 6.607 (d, J=8 Hz, 1H), 6.752 (d, J=8 Hz, 1H), 7.456 (t, J=8 Hz, 1H), 7.824 (br. s, 1H), 8.351 (br. s, 1H), 10.945 (s, 1H). MS 356 (MH+).
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14](/[CH:17]=[CH:18]/[C:19](=[O:32])[CH2:20][C:21](=[O:31])/[CH:22]=[CH:23]/[C:24]3[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=3)[CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(OC(NC1C=CC(/C=C/C(=O)CC(=O)/C=C/C2C=CC(O)=CC=2)=CC=1)=O)(C)(C)C>C(Cl)(Cl)Cl.CO>[OH:30][C:27]1[CH:28]=[CH:29][C:24](/[CH:23]=[CH:22]/[C:21](=[O:31])[CH2:20][C:19](=[O:32])/[CH:18]=[CH:17]/[C:14]2[CH:15]=[C:16]3[C:11]([CH2:10][CH2:9][NH:8]3)=[CH:12][CH:13]=2)=[CH:25][CH:26]=1
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(/C=C/C(=O)CC(=O)/C=C/c3ccc(O)cc3)cc21
Agent: CC(C)(C)OC(=O)Nc1ccc(/C=C/C(=O)CC(=O)/C=C/c2ccc(O)cc2)cc1
Solvent: CO
Solvent: ClC(Cl)Cl
Product: O=C(/C=C/c1ccc(O)cc1)CC(=O)/C=C/c1ccc2c(c1)NCC2

Procedure:
The title compound was synthesized using the same procedure employed for Example 281, but with (1E,6E)-1-[1-(tert-butoxycarbony)-indolin-6-yl]-7-(4-hydroxyphenyl)hepta-1,6-diene-3,5-dione (14 mg, 32 μmol, synthesized in Example 292) as the starting material instead of (1E,6E)-1-[4-(tert-butoxycarbonylamino)phenyl]-7-(4-hydroxyphenyl)hepta-1,6-diene-3,5-dione, and was purified by silica gel chromatography (chloroform/methanol=100/0 to 95/5). The product was obtained as a solid (1.4 mg, 13%) having the following characteristic.
Reaction SMILES: [C:1](#[N:4])[CH:2]=[CH2:3].[OH:5][C:6]1([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=2)[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[NH:8][C:7]1=[O:15]>>[C:1]([CH2:2][CH2:3][N:8]1[C:9]2[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]([OH:5])([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=2)[C:7]1=[O:15])#[N:4]
Reactant: O=C1Nc2ccccc2C1(O)c1cccc(C(F)(F)F)c1
Reactant: C=CC#N
Product: N#CCCN1C(=O)C(O)(c2cccc(C(F)(F)F)c2)c2ccccc21

Procedure:
Reaction of acrylonitrile with 3-hydroxy-3-(m-trifluoromethylphenyl)-indolin-2-one by a process analogous to that of Example 1 gives 1-(2-cyanoethyl)-3-hydroxy-3-(m-trifluoromethylphenyl)indolin-2-one. Hydrogenation of the 1-(2-cyanoethyl)-3-hydroxy-3-(m-trifluoromethylphenyl)indolin-2-one gives 1-(3-aminopropyl)-3-hydroxy-3-(m-trifluoromethylphenyl)indolin-2-one. Cyclodehydration of 1-(3-aminopropyl)-3-hydroxy-3-(m-trifluoromethylphenyl)indolin-2-one by a procedure analogous to that of Example 3 gives 10-(m-trifluoromethylphenyl)-2,3,5,10-tetrahydropyrimido [1,2-a] indol-10-ol.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH2:21])(C)(C)C.C(O[C:28](=[O:46])[CH2:29][C:30]([C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([C:38]2[CH:43]=[C:42]([CH3:44])[N:41]=[C:40]([NH2:45])[N:39]=2)[CH:33]=1)=O)(C)(C)C>>[NH2:45][C:40]1[N:39]=[C:38]([C:34]2[CH:33]=[C:32]([C:30]3[CH2:29][C:28](=[O:46])[NH:21][C:9]4[CH:10]=[C:11]([C:17]([F:18])([F:19])[F:20])[C:12]([N:14]([CH3:16])[CH3:15])=[CH:13][C:8]=4[N:7]=3)[CH:37]=[CH:36][CH:35]=2)[CH:43]=[C:42]([CH3:44])[N:41]=1
Reactant: CN(C)c1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F
Reactant: Cc1cc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)nc(N)n1
Product: Cc1cc(-c2cccc(C3=Nc4cc(N(C)C)c(C(F)(F)F)cc4NC(=O)C3)c2)nc(N)n1

Procedure:
The title compound was prepared from (2-amino-5-dimethylamino-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example J1) (96 mg, 0.3 mmol) and 3-[3-(2-amino-6-methyl-pyrimidin-4-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K45) (118 mg, 0.36 mmol) according to the general procedure M and subsequent treatment of the crude product according to the general procedure N. Obtained as a light yellow solid (31 mg).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][O:11][C:12]1[CH:16]=[C:15]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=2[Cl:24])[O:14][N:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:25]I>>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][O:11][C:12]1[CH:16]=[C:15]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([CH3:25])[C:18]=2[Cl:24])[O:14][N:13]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CI
Reactant: CC(C)(C)OC(=O)NCCOc1cc(-c2ccc(Cl)cc2Cl)on1
Product: Cc1c(Cl)ccc(-c2cc(OCCNC(=O)OC(C)(C)C)no2)c1Cl
Yield: 45 %

Procedure:
3-(2-(N-tert-Butoxycarbonylamino)ethoxy)-5-(2,4-dichlorophenyl)isoxazole (0.3 g) and methyl iodide (0.08 ml) were subjected to reaction and post-treatment in a similar manner to that described in Example 14(a) to obtain the title compound (0.14 g, 45%) as a colorless powder.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:19][P:20](=[O:27])([O:24][CH2:25][CH3:26])[O:21][CH2:22][CH3:23])=[N:4][C:5]([N:8]2C(=O)C3C(=CC=CC=3)C2=O)=[CH:6][CH:7]=1.O.NN>C(Cl)Cl>[NH2:8][C:5]1[N:4]=[C:3]([CH2:19][P:20](=[O:27])([O:24][CH2:25][CH3:26])[O:21][CH2:22][CH3:23])[C:2]([Cl:1])=[CH:7][CH:6]=1
Reactant: CCOP(=O)(Cc1nc(N2C(=O)c3ccccc3C2=O)ccc1Cl)OCC
Agent: NN
Solvent: O
Solvent: ClCCl
Product: CCOP(=O)(Cc1nc(N)ccc1Cl)OCC

Procedure:
Following the procedure from Example 16, the product from Example 27 (1.0 g, 2.4 mmol) was reacted with hydrazine monohydrate (0.121 g, 2.4 mmol) in CH2Cl2 (25 mL). Workup produced the crude title product which was used without further purification.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[C:8]([O:12][C:13](=[O:28])[N:14]([C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[CH:22]=1)[C:15](=[O:20])[CH2:16][CH2:17][C:18]#[CH:19])([CH3:11])([CH3:10])[CH3:9]>>[C:8]([O:12][C:13](=[O:28])[N:14]([C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[CH:22]=1)[C:15](=[O:20])[CH2:16][CH2:17][C:18]#[C:19][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1)([CH3:11])([CH3:9])[CH3:10]
Reactant: Brc1ccccn1
Reactant: C#CCCC(=O)N(C(=O)OC(C)(C)C)c1cccc(F)c1
Product: CC(C)(C)OC(=O)N(C(=O)CCC#Cc1ccccn1)c1cccc(F)c1
Yield: 60.5 %

Procedure:
The title compound was prepared in accordance with the general method of Example 1, from 2-bromo-pyridine (137 mg, 0.86 mmol) and (3-fluoro-phenyl)-pent-4-ynoyl-carbamic acid tert-butyl ester (250 mg, 0.86 mmol). Reaction time: 3 hours. The crude residue was purified by flash chromatography (cyclohexane/AcOEt 4:1) to yield 190 mg (0.52 mmol, 60%) of (3-fluoro-phenyl)-(5-pyridin-2-yl-pent-4-ynoyl)-carbamic acid tert-butyl ester as a white solid.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[C:12]([N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13]>>[CH3:8][C:5]1[CH:6]=[CH:7][C:2]([N:22]2[CH2:21][CH2:20][N:19]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:24][CH2:23]2)=[C:3]([N+:9]([O-:11])=[O:10])[CH:4]=1
Reactant: Cc1ccc(F)c([N+](=O)[O-])c1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Product: Cc1ccc(N2CCN(C(=O)OC(C)(C)C)CC2)c([N+](=O)[O-])c1
Yield: 90 %

Procedure:
Method 1 was followed using 4-fluoro-3-nitrotoluene (1.0 eq), 1-Boc-piperazine (1.2 eq), and TEA (1.5 eq) at 55° C. for 48 hours yielding tert-butyl 4-(4-methyl-2-nitrophenyl)piperazine-1-carboxylate (90%). LCMS (m/z): 322.1 (MH+); LC Rt=3.46 min.
Reaction SMILES: [CH2:1]([C:3]1[S:7][C:6](=[N:8][C:9]([C:11]2[CH2:15][CH2:14][CH2:13][C:12]=2[C:16]([OH:18])=[O:17])=[O:10])[N:5]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[C:32]3[NH:36][N:35]=[N:34][N:33]=3)=[CH:22][CH:21]=2)[N:4]=1)[CH3:2].[OH-].[K+:38]>C(O)C>[K+:38].[K+:38].[CH2:1]([C:3]1[S:7][C:6](=[N:8][C:9]([C:11]2[CH2:15][CH2:14][CH2:13][C:12]=2[C:16]([O-:18])=[O:17])=[O:10])[N:5]([CH2:19][C:20]2[CH:21]=[CH:22][C:23]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[C:32]3[NH:33][N:34]=[N:35][N:36]=3)=[CH:24][CH:25]=2)[N:4]=1)[CH3:2].[CH2:1]([C:3]1[S:7][C:6](=[N:8][C:9]([C:11]2[CH2:15][CH2:14][CH2:13][C:12]=2[C:16]([O-:18])=[O:17])=[O:10])[N:5]([CH2:19][C:20]2[CH:21]=[CH:22][C:23]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[C:32]3[NH:33][N:34]=[N:35][N:36]=3)=[CH:24][CH:25]=2)[N:4]=1)[CH3:2]
Reactant: CCc1nn(Cc2ccc(-c3ccccc3-c3nnn[nH]3)cc2)c(=NC(=O)C2=C(C(=O)O)CCC2)s1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCc1nn(Cc2ccc(-c3ccccc3-c3nnn[nH]3)cc2)c(=NC(=O)C2=C(C(=O)[O-])CCC2)s1

Procedure:
To 2-[[5-ethyl-3-[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl-1,3,4-thiadiazolin-2-yliden]aminocarbonyl]-1-cyclopentenecarboxylic acid (10 g) were added 0.1N potassium hydroxide in ethanol solution (400 ml) and ethanol (600 ml) to dissolve the former in the latter. The resulting solution was concentrated to about 200 ml in total. The crystals so precipitated were collected by filtration, washed with ethanol and then dried, whereby 11 g of the title compound was obtained.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:10]1[C:11]([C:30]2[CH:35]=[CH:34][C:33](Cl)=[CH:32][CH:31]=2)=[C:12]2[C:17](=[CH:18][C:19]=1[CH3:20])[N:16]=[C:15]([CH2:21][N:22]([CH3:29])[C:23]1C=CC=CC=1)[CH:14]=[CH:13]2)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:3])[CH3:2].C(O[C@@H](C1C(C2CCCCC=2)=C2C(=CC=1C)N=C(CN(C)C)C=C2)C(OCC)=O)(C)(C)C>>[C:1]([O:5][C@@H:6]([C:10]1[C:11]([C:30]2[CH2:35][CH2:34][CH2:33][CH2:32][CH:31]=2)=[C:12]2[C:17](=[CH:18][C:19]=1[CH3:20])[N:16]=[C:15]([CH2:21][N:22]([CH3:29])[CH3:23])[CH:14]=[CH:13]2)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cc2nc(CN(C)c3ccccc3)ccc2c(-c2ccc(Cl)cc2)c1[C@H](OC(C)(C)C)C(=O)O
Agent: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(CN(C)C)ccc2c1C1=CCCCC1
Product: Cc1cc2nc(CN(C)C)ccc2c(C2=CCCCC2)c1[C@H](OC(C)(C)C)C(=O)O

Procedure:
(S)-2-tert-Butoxy-2-(5-cyclohexenyl-2-((dimethylamino)methyl)-7-methylquinolin-6-yl)acetic acid was prepared following the procedure used to prepare compound (S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-((methyl(phenyl)amino) methyl)quinolin-6-yl)acetic acid of Example 14, except that (S)-ethyl 2-tert-butoxy-2-(5-cyclohexenyl-2-((dimethylamino) methyl)-7-methylquinolin-6-yl)acetate was used instead of (S)-ethyl 2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-((methyl(phenyl)amino)methyl)quinolin-6-yl)acetate. 1H-NMR 300 MHz, (CD3OD) 8.40-8.30 (m, 1H), 7.85-7.78 (m, 1H), 7.42 (d, 1H), 6.04, 5.70 (br, br, 1H), 5.80, 5.64 (s, s, 1H), 4.65 (s, 2H), 3.04 (s, 6H), 2.68-2.56 (m, 4H), 2.40-1.80 (m, 6H), 1.30-1.20 (m, 9H); LCMS-ESI+ (m/z): [M-1-11]+ calcd for C25H34N2O3: 411.6. Found: 411.3.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][C:23]=1[O:24][CH3:25])[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][CH2:15]2)=[CH:10][CH:9]=1)=[O:6].C([O:28][C:29]([C:31]1[CH:36]=[CH:35][C:34](B(O)O)=[CH:33][CH:32]=1)=[O:30])C.COCCOC.C(=O)([O-])[O-].[Cs+].[Cs+]>O>[CH3:25][O:24][C:23]1[CH:22]=[CH:21][C:4]([C:5](=[O:6])[NH:7][C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][CH2:15]3)=[CH:10][CH:9]=2)=[CH:3][C:2]=1[C:34]1[CH:35]=[CH:36][C:31]([C:29]([OH:30])=[O:28])=[CH:32][CH:33]=1
Reactant: CCOC(=O)c1ccc(B(O)O)cc1
Reactant: COc1ccc(C(=O)Nc2ccc(N3CCN(C)CC3)cc2)cc1Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: COCCOC
Solvent: O
Product: COc1ccc(C(=O)Nc2ccc(N3CCN(C)CC3)cc2)cc1-c1ccc(C(=O)O)cc1
Reaction time: 16 h

Procedure:
A mixture of 3-Bromo-4-methoxy-N-[4-(4-methyl-piperazin-1-yl)-phenyl]-benzamide (748 mg) and 4-(ethoxycarbonyl)-phenyl boronic acid (538 mg) in 2:1 DME:water (15 ml) containing cesium carbonate (1.21 mg) and tetrakis(triphenylphosphine)palladium0 (220 mg) was heated to reflux for 18 h. The mixture was cooled and then evaporated. The residue was then stirred in ethanol (8 ml) and 2M NaOH (4 ml) at room temp for 16 h. The ethanol was then evaporated and the residue acidified with 2M HCl. The resulting solid was collected by filtration and dried (528 mg)
Reaction SMILES: [C:1]1(=[O:31])[N:5]([CH2:6][CH2:7][C:8]#[C:9][C:10]2[C:11](=[O:25])[NH:12][C:13](=[O:24])[N:14]([CH:23]=2)[C@@H:15]2[O:22][C@H:19]([CH2:20][OH:21])[C@@H:17]([OH:18])[CH2:16]2)[C:4](=[O:26])[C:3]2=[CH:27][CH:28]=[CH:29][CH:30]=[C:2]12>CCO.[Ni]>[C:4]1(=[O:26])[N:5]([CH2:6][CH2:7][CH2:8][CH2:9][C:10]2[C:11](=[O:25])[NH:12][C:13](=[O:24])[N:14]([CH:23]=2)[C@@H:15]2[O:22][C@H:19]([CH2:20][OH:21])[C@@H:17]([OH:18])[CH2:16]2)[C:1](=[O:31])[C:2]2=[CH:30][CH:29]=[CH:28][CH:27]=[C:3]12
Reactant: O=C1c2ccccc2C(=O)N1CCC#Cc1cn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]c1=O
Agent: [Ni]
Solvent: CCO
Product: O=C1c2ccccc2C(=O)N1CCCCc1cn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]c1=O
Reaction time: 48 h
Yield: 97 %

Procedure:
1.00 Gram of 5-(4-Phthalimidobut-1-yn-1-yl)-2′-deoxyuridine was dissolved in 95% EtOH and about 3 g of neutral Raney nickel was added. After 48 hours, the catalyst was removed by cautious filtration and the filtrate was evaporated to a solid which was recrystallized from methanol-water to give 960 mg (97%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][CH2:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])=[C:4]([CH:17](O)[CH3:18])[CH:3]=1.CCN(C(C)C)C(C)C.CS([Cl:33])(=O)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][CH2:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])=[C:4]([CH:17]([Cl:33])[CH3:18])[CH:3]=1
Reactant: CC(O)c1cc(Cl)ccc1OCC(=O)OC(C)(C)C
Reactant: CS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(Cl)c1cc(Cl)ccc1OCC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To the product of step b) (0.34 g) in DCM (5 ml) was added Hunigs base (1 ml) followed by methanesulfonyl chloride (0.46 ml) and the reaction stirred at room temperature for 2 h followed by heating at 45° C. for 2 h. After cooling to 0° C. the bulk of the volatiles were removed in vacuo. Diethyl ether and water were added and the organic layer separated.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:23][CH2:24][CH:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[C:17]([N+:20]([O-])=O)[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[F:8].[H][H]>O1CCCC1.[Pt](=O)=O>[NH2:20][C:17]1[CH:18]=[C:19]2[C:14](=[CH:15][C:16]=1[O:23][CH2:24][CH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1)[N:13]=[CH:12][N:11]=[C:10]2[NH:9][C:4]1[CH:5]=[CH:6][C:7]([F:8])=[C:2]([Cl:1])[CH:3]=1
Reactant: O=[N+]([O-])c1cc2c(Nc3ccc(F)c(Cl)c3)ncnc2cc1OCC1CCOCC1
Reactant: [H][H]
Agent: O=[Pt]=O
Solvent: C1CCOC1
Product: Nc1cc2c(Nc3ccc(F)c(Cl)c3)ncnc2cc1OCC1CCOCC1

Procedure:
22.80 g of 4-[(3-chloro-4-fluorophenyl)amino]-6-nitro-7-[(tetrahydropyran-4-yl)methoxy]quinazoline are hydrogenated in 300 ml of tetrahydrofuran in the presence of 3.50 g of platinum dioxide at ambient temperature until the calculated amount of hydrogen has been taken up. The catalyst is filtered off and the filtrate is evaporated to dryness using the rotary evaporator. The residue is stirred with diethylether, suction filtered, washed with diethylether and dried at ambient temperature. Yield: 19.95 g (93% of theory); mass spectrum (ESI+): m/z=403, 405 [M+H]+; melting point: 221° C.