Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[CH:11]=[CH:10][NH:9][C:6]2=[N:7][CH:8]=1.Cl[C:13]1[N:18]=[CH:17][C:16]([O:19][CH:20]2[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:22][CH2:21]2)=[CH:15][CH:14]=1>>[C:29]([O:28][C:26]([N:23]1[CH2:22][CH2:21][CH:20]([O:19][C:16]2[CH:17]=[N:18][C:13]([N:9]3[C:6]4=[N:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=[C:5]4[CH:11]=[CH:10]3)=[CH:14][CH:15]=2)[CH2:25][CH2:24]1)=[O:27])([CH3:32])([CH3:30])[CH3:31]
Reactant: COc1cnc2[nH]ccc2c1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(Cl)nc2)CC1
Product: COc1cnc2c(ccn2-c2ccc(OC3CCN(C(=O)OC(C)(C)C)CC3)cn2)c1

Procedure:
The title compound was prepared by following the similar procedure as described in Intermediate-27 using 5-methoxy-1H-pyrrolo[2,3-b]pyridine and tert-butyl 4-((6-chloropyridin-3-yl)oxy)piperidine-1-carboxylate. (0.09 g, 45%); MS: 425(M+1).
Reaction SMILES: C[O:2][C:3](=[O:31])[CH2:4][CH2:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[N:12]=[C:11]([C:16]1[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=1)[N:10]=[C:9]2[NH:22][C:23]1[CH:28]=[CH:27][C:26]([F:29])=[C:25]([Cl:30])[CH:24]=1.[OH-].[Na+]>CN(C=O)C.O>[Cl:30][C:25]1[CH:24]=[C:23]([NH:22][C:9]2[C:8]3[C:13](=[CH:14][CH:15]=[C:6]([CH2:5][CH2:4][C:3]([OH:31])=[O:2])[CH:7]=3)[N:12]=[C:11]([C:16]3[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=3)[N:10]=2)[CH:28]=[CH:27][C:26]=1[F:29]
Reactant: COC(=O)CCc1ccc2nc(-c3cccnc3)nc(Nc3ccc(F)c(Cl)c3)c2c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(O)CCc1ccc2nc(-c3cccnc3)nc(Nc3ccc(F)c(Cl)c3)c2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 93 %

Procedure:
To a solution of 3-[4-(3-chloro-4-fluoro-phenylamino)-2-pyridin-3-yl-quinazolin-6-yl]-propionic acid methyl ester (1.04 g, 2.39 mmol, 1.0 eq.) in DMF (20 mL) was added a solution of NaOH (0.57 g, 14.3 mmol, 6.0 eq.) in H2O (8 mL). The mixture was stirred at room temperature for 2 h. 50 mL of water was added to the mixture. After filtration, the resulting filter cake was washed with water and dried in vacuo to give 933 mg of xxx-a as a yellow solid (yield 93%). LCMS m/z=423.1, 425.1 (M+1) (Method A) (retention time=1.51 min).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:10][C@@H:9]2[CH2:11][N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[CH:4][CH:3]=1.[N:18]1[NH:19][C:20](=[O:24])[CH:21]=[CH:22][CH:23]=1>>[O:15]1[CH2:16][CH2:17][N:12]([CH2:11][C@H:9]2[CH2:10][C@@H:8]2[C:5]2[CH:6]=[CH:7][C:2]([N:19]3[C:20](=[O:24])[CH:21]=[CH:22][CH:23]=[N:18]3)=[CH:3][CH:4]=2)[CH2:13][CH2:14]1
Reactant: O=c1cccn[nH]1
Reactant: Brc1ccc([C@H]2C[C@@H]2CN2CCOCC2)cc1
Product: O=c1cccnn1-c1ccc([C@H]2C[C@@H]2CN2CCOCC2)cc1

Procedure:
Following the general procedure, reaction of 7e (2.59 g assayed, 8.75 mmol) with 3(2H)-pyridazinone (1.09 g, 11.37 mmol) afforded a solution of the free base of 8e in an assayed yield of 2.03 g (50% assay yield, 96% peak area).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1([C:15]2[NH:19][C:18](=[O:20])[O:17][N:16]=2)[CH2:11][CH:10]1[CH:12]([CH3:14])[CH3:13])(C)(C)C.[ClH:22]>O1CCOCC1.CCOCC>[ClH:22].[NH2:7][CH2:8][C:9]1([C:15]2[NH:19][C:18](=[O:20])[O:17][N:16]=2)[CH2:11][CH:10]1[CH:12]([CH3:14])[CH3:13]
Reactant: CC(C)C1CC1(CNC(=O)OC(C)(C)C)c1noc(=O)[nH]1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: CC(C)C1CC1(CN)c1noc(=O)[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 62 %

Procedure:
To a solution of {2-isopropyl-1-(5-oxo-4,5-dihydro-[1,2,4]oxadiazol-3-yl)-cyclopropylmethyl}-carbamic acid tert-butyl ester (3.30 g, 11.1 mmol) in dry 1,4-dioxane (20 ml) was added 4N HCl (40 mL, in 1,4-dioxane). The reaction mixture was stirred at room temperature overnight and diluted with ether (100 mL). The precipitate was collected and dried to give 1.6 g (62%) of 3-(1-aminomethyl-2-isopropyl-cyclopropyl)-4H-[1,2,4]oxadiazol-5-one hydrochloride as a white solid: mp: 178-179° C.; 1H NMR (300 MHz, D2O) δ 1.01 (d, J=5.8 Hz, 3H), 1.10 (d, J=5.8 Hz, 3H), 1.22 (t, J=6.1 Hz, 1H), 1.38-1.46 (m, 2H), 1.56 (m, 1H), 3.12 (d, J=14.2 Hz, 1H), 3.93 (d, J=14.2 Hz, 1H); 13C NMR (75 MHz, D2O) δ 18.1, 20.3, 21.7, 21.9, 29.0, 36.3, 39.3, 162.3, 162.5; MS (APCI) m/z 198 [M+H]+. Anal. Calcd. For C9H15N3O2—HCl: C, 46.26; H, 6.90; N, 17.98; Cl, 15.17. Found: C, 46.39; H. 6.84; N, 17.85; Cl, 14.79.
Reaction SMILES: [Br:1][C:2]1[CH:13]=[CH:12][CH:11]=[CH:10][C:3]=1[O:4][CH:5]1[CH2:9][CH2:8][NH:7][CH2:6]1.Br[CH2:15][CH2:16][O:17][CH3:18].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[Br:1][C:2]1[CH:13]=[CH:12][CH:11]=[CH:10][C:3]=1[O:4][CH:5]1[CH2:9][CH2:8][N:7]([CH2:15][CH2:16][O:17][CH3:18])[CH2:6]1
Reactant: COCCBr
Reactant: Brc1ccccc1OC1CCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COCCN1CCC(Oc2ccccc2Br)C1
Reaction time: 48 h

Procedure:
3-(2-Bromophenoxy)pyrrolidine (1.23 g), 1-bromo-2-methoxyethane (0.526 ml) and potassium carbonate (842 mg) were mixed with dimethylformamide (50 ml) and stirred for two days. The mixture was added to water (100 ml). The mixture was extracted with diethyl ether (3×50 ml), washed with water (2×50 ml), brine (2×30 ml), dried (MgSO4) and concentrated in vacuo. Purification was achieved using cation exchange chromatography eluting with ammonia/methanol/dichloromethane mixtures yielding product as a clear oil (0.8 g).
Reaction SMILES: Cl.[NH2:2][OH:3].C(N(CC)CC)C.[C:11]([C:13]1[CH:14]=[C:15]([NH:19][CH:20]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:21]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([N:30]3[CH2:35][CH2:34][O:33][CH2:32][CH2:31]3)=[CH:26][CH:25]=2)=[O:22])[CH:16]=[CH:17][CH:18]=1)#[N:12]>CO>[OH:3][NH:2][C:11]([C:13]1[CH:14]=[C:15]([NH:19][CH:20]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:21]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([N:30]3[CH2:31][CH2:32][O:33][CH2:34][CH2:35]3)=[CH:26][CH:25]=2)=[O:22])[CH:16]=[CH:17][CH:18]=1)=[NH:12]
Reactant: NO
Reactant: N#Cc1cccc(NC(C(=O)Nc2ccc(N3CCOCC3)cc2)c2ccccc2)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CO
Product: N=C(NO)c1cccc(NC(C(=O)Nc2ccc(N3CCOCC3)cc2)c2ccccc2)c1
Temperature: 70 °C

Procedure:
149 mg (2.15 mmol) of hydroxylamine hydrochloride, 0.30 ml (2.15 mmol) of triethylamine and a few grains of 0.3 nM molecular sieve are added to a solution of 295 mg (0.715 mmol) of 2-(3-cyanophenylamino)-N-(4-morpholin-4-ylphenyl)-2-phenylacetamide in 5 ml of methanol, and the mixture is heated at 70° C. for 18 hours. The reaction mixture is filtered, the filtrate is evaporated, and the residue is taken up in water. The resultant precipitate is filtered off, giving 2-[3-(N-hydroxyamidino)phenylamino]-N-(4-morpholin-4-ylphenyl)-2-phenylacetamide as a colourless solid; ESI 446.
Reaction SMILES: [C:1]([N:8]1[CH2:11][CH2:10][C@H:9]1[CH2:12][O:13][C:14]1[CH:15]=[N:16][C:17]([Cl:22])=[C:18]([C:20]#[N:21])[CH:19]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[H][H]>[Ni]>[NH2:21][CH2:20][C:18]1[CH:19]=[C:14]([O:13][CH2:12][C@@H:9]2[CH2:10][CH2:11][N:8]2[C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH:15]=[N:16][C:17]=1[Cl:22]
Reactant: CC(C)(C)OC(=O)N1CC[C@H]1COc1cnc(Cl)c(C#N)c1
Reactant: [H][H]
Agent: [Ni]
Product: CC(C)(C)OC(=O)N1CC[C@H]1COc1cnc(Cl)c(CN)c1

Procedure:
3-(1-BOC-2-(S)-azetidinylmethoxy)-6-chloro-5-cyanopyridine (0.26 g, 0.80 mmol) from step 92a was stirred in the presence of Raney nickel (0.047 g, 0.80 mmol) under 1 atm of hydrogen at room temperature for 2 hours. The mixture was filtered, and the solvent was removed to give the title compound.
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[C:3]([N:5]1[CH:10]2[CH2:11][CH2:12][CH:6]1[CH2:7][C:8](=[C:13]1[C:26]3[CH:25]=[CH:24][C:23]([C:27]#[N:28])=[CH:22][C:21]=3[O:20][C:19]3[C:14]1=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:9]2)=[O:4].[N-:31]=[N+:32]=[N-:33].[Na+].[NH4+].[Cl-]>CN(C=O)C>[F:30][C:2]([F:29])([F:1])[C:3]([N:5]1[CH:10]2[CH2:11][CH2:12][CH:6]1[CH2:7][C:8](=[C:13]1[C:26]3[CH:25]=[CH:24][C:23]([C:27]4[NH:33][N:32]=[N:31][N:28]=4)=[CH:22][C:21]=3[O:20][C:19]3[C:14]1=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:9]2)=[O:4]
Reactant: N#Cc1ccc2c(c1)Oc1ccccc1C2=C1CC2CCC(C1)N2C(=O)C(F)(F)F
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(N1C2CCC1CC(=C1c3ccccc3Oc3cc(-c4nnn[nH]4)ccc31)C2)C(F)(F)F
Temperature: 120 °C

Procedure:
To a solution of Compound 5e (0.232 g, 0.56 mmol) in DMF (5 mL) were added NaN3 (0.11 g, 1.69 mmol) and NH4Cl (0.09 g, 1.68 mmol). The reaction mixture was heated at 120° C. for 14 h, and then cooled to room temperature. An insoluble material was collected by filtration and washed with DMF (5 mL). The filtrate was acidified with 2N HCl (10 mL) and extracted with EtOAc (3×10 mL). The combined organic layers were washed with H2O (10 mL), dried (MgSO4), and concentrated to give the title compound 5f which was used for subsequent reactions without further purification. MS m/z (MH+) 453.9.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[C:4]1[CH:9]=[C:8](I)[C:7]([C:11]([F:14])([F:13])[F:12])=[CH:6][C:5]=1[NH:15][C:16](=[O:18])[CH3:17].C([Sn](CCCC)(CCCC)[C:25]1[O:26][CH2:27][CH2:28][CH:29]=1)CCC.CCN(CC)CC>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][O:2][C:3](=[O:19])[C:4]1[CH:9]=[C:8]([C:25]2[O:26][CH2:27][CH2:28][CH:29]=2)[C:7]([C:11]([F:14])([F:13])[F:12])=[CH:6][C:5]=1[NH:15][C:16](=[O:18])[CH3:17]
Reactant: CCCC[Sn](CCCC)(CCCC)C1=CCCO1
Reactant: COC(=O)c1cc(I)c(C(F)(F)F)cc1NC(C)=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: COC(=O)c1cc(C2=CCCO2)c(C(F)(F)F)cc1NC(C)=O
Temperature: 25 °C
Yield: 85.9 %

Procedure:
To a solution of 2-acetylamino-5-iodo-4-trifluoromethyl-benzoic acid methyl ester (10 g, 25.8 mmol) in dioxane were added tributyl-(4,5-dihydro-furan-2-yl)-stannane (13.9 g, 38.7 mmol), (Ph3P)4Pd then Et3N (4.52 mL, 32.3 mmol). The reaction mixture was heated at reflux for 18 h to give a brown suspension that was allowed to cool to r.t. The reaction mixture was filtered through a sintered funnel and the filtrate was concentrated under in vacuo. The residue was purified by flash column chromatography (silica gel, 1:4 EtOAc/hexanes) to give the title compound (7.3 g, 86%) as beige crystals, m.p.: 120-125° C., API-ES: m/z 330 [M+H]+
Reaction SMILES: Cl.Cl.[O:3]1[CH2:8][CH2:7][CH:6]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH2:5][CH2:4]1.C([O-])(O)=O.[Na+].[N:20]#[C:21]Br.C(Cl)Cl>C(O)C>[O:3]1[CH2:8][CH2:7][CH:6]([N:9]2[CH2:14][CH2:13][N:12]([C:21]#[N:20])[CH2:11][CH2:10]2)[CH2:5][CH2:4]1
Reactant: N#CBr
Reactant: C1CN(C2CCOCC2)CCN1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: ClCCl
Product: N#CN1CCN(C2CCOCC2)CC1
Temperature: 25 °C
Yield: 131.3 %

Procedure:
A suspension of 1-(tetrahydro-2H-pyran-4-yl)piperazine dihydrochloride (600 mg, 2.467 mmol) in anhydrous Ethanol (10 mL) was added solid NaHCO3 (1555 mg, 18.51 mmol) followed by cyanic bromide (523 mg, 4.93 mmol) and the mixture was stirred at ambient temperature. The mixture was diluted by 50 mL of CH2Cl2 and the solids were filtered off. The filtrated was concentrated in vacuo to afford to give the title compound (632 mg, 3.24 mmol, >100% yield). 1H NMR (400 MHz, Chloroform-d) δ ppm=4.02 (dd, J=3.8, 11.2 Hz, 2H), 3.42-3.31 (m, 2H), 3.31-3.22 (m, 4H), 2.74-2.61 (m, 4H), 2.59-2.47 (m, 1H), 1.73 (d, J=11.5 Hz, 2H), 1.67-1.49 (m, 2H); LC/MS (m/z) ES+ (ELSD)=196.1 (M+1).
Reaction SMILES: [NH2:1][C:2]1[C:10]([Cl:11])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([OH:12])[CH:3]=1.C[O-].[Na+].CO.S(OC)(O[CH3:22])(=O)=O>CO.O>[NH2:1][C:2]1[C:10]([Cl:11])=[CH:9][C:5]([C:6]([O:8][CH3:22])=[O:7])=[C:4]([OH:12])[CH:3]=1
Reactant: Nc1cc(O)c(C(=O)O)cc1Cl
Reactant: COS(=O)(=O)OC
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COC(=O)c1cc(Cl)c(N)cc1O
Reaction time: 0.5 h
Yield: 86.8 %

Procedure:
A solution of 4-amino-5-chloro-2-hydroxybenzoic acid (1.88 g, 0.010 mole) in absolute methanol (20 ml) was treated with 25% sodium methoxide/methanol (2.16 g, 0.010 mole), stirred for 30 minutes, and concentrated in vacuo. The solid residue was taken up in anhydrous acetone (30 ml), treated with dimethyl sulfate (1.64 g, 0.013 mole) and refluxed for 2 hours. The resultant solution was diluted with water (100 ml), and the precipitate was filtered, washed with water, and dried exhaustively in vacuo to afford 1.75 g (87%) of the title compound as fine colorless needles. The material was recrystallized from ethyl acetate/hexane; mp 138°-139° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:14][C:15](=[O:17])[CH3:16])[CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:7]=1.[Br:18][C:19]1[CH:24]=[CH:23][C:22](F)=[C:21]([N+:26]([O-:28])=[O:27])[CH:20]=1.[F-].[K+]>CN(C=O)C>[Br:18][C:19]1[CH:24]=[CH:23][C:22]([NH:1][C:2]2[CH:3]=[C:4]([NH:14][C:15](=[O:17])[CH3:16])[CH:5]=[C:6]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH:7]=2)=[C:21]([N+:26]([O-:28])=[O:27])[CH:20]=1
Reactant: O=[N+]([O-])c1cc(Br)ccc1F
Reactant: CC(=O)Nc1cc(N)cc(-c2ccccc2)c1
Agent: [F-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)Nc1cc(Nc2ccc(Br)cc2[N+](=O)[O-])cc(-c2ccccc2)c1
Yield: 52 %

Procedure:
A solution of N-(5-aminobiphenyl-3-yl)acetamide (1 g, 4.54 mmol), 4-bromo-1-fluoro-2-nitrobenzene (1.03 g, 4.54 mmol, 1.0 eq.) and potassium fluoride (0.26 g, 4.54 mmol, 1.0 eq.) in DMF (5 ml) was heated at 100° C. for 12 h. The mixture was quenched and extracted as in Example 1(d). The solvent was distilled off and the residue was purified by column chromatography (60-120 silica gel, 50% ethyl acetate in hexane) to give the product in 52% yield (1 g).
Reaction SMILES: CI.[C:3](=[O:6])([O-])[O-].[K+].[K+].[Cl:9][C:10]1[C:15]2[N:16]=[C:17]([O:19][CH2:20][CH2:21][CH3:22])[S:18][C:14]=2[C:13]([N:23]2[C:28](=[O:29])[CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[NH:25][C:24]2=O)=[C:12]([F:35])[CH:11]=1>CC(CC)=O>[Cl:9][C:10]1[C:15]2[N:16]=[C:17]([O:19][CH2:20][CH2:21][CH3:22])[S:18][C:14]=2[C:13]([N:23]2[C:28](=[O:29])[CH:27]=[C:26]([C:30]([F:31])([F:33])[F:32])[N:25]([CH3:24])[C:3]2=[O:6])=[C:12]([F:35])[CH:11]=1
Reactant: CCCOc1nc2c(Cl)cc(F)c(-n3c(=O)cc(C(F)(F)F)[nH]c3=O)c2s1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CCC(C)=O
Product: CCCOc1nc2c(Cl)cc(F)c(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)c2s1
Reaction time: 12 h

Procedure:
1.7 g of methyl iodide were added dropwise at about 20° C. to a mixture of 200 ml of absolute ethyl methyl ketone, 1.7 g of potassium carbonate and 5.0 g of 3-[4-chloro-6-fluoro-2-propoxybenzothiazol-7-yl]-6-trifluoromethyl-2,4(1H,3H)-pyrimidinedione (compound I.8). Stirring was carried out for 12 hours at room temperature, after which the insoluble components were filtered off. The clear solution obtained was evaporated down. The residue was then taken up in water, after which the solution was neutralized with dilute hydrochloric acid. The product was then extracted with ethyl acetate. The ester phase was finally dried over sodium sulfate and then evaporated down. The purification of the crude product thus obtained was carried out by chromatography over silica gel (eluent: 9:1 cyclohexane/methyl tert-butyl ether). Yield: 1.0 g.
Reaction SMILES: [CH3:1][S:2]([N:5]([S:7]([NH2:10])(=[O:9])=[O:8])[CH3:6])(=[O:4])=[O:3].[CH3:11][O:12][C:13]1[CH:18]=[C:17]([CH3:19])[N:16]=[C:15]([NH:20][C:21](=O)[O:22]C2C=CC=CC=2)[N:14]=1>ClC1C=CC=CC=1>[CH3:1][S:2]([N:5]([S:7]([NH:10][C:21]([NH:20][C:15]1[N:14]=[C:13]([O:12][CH3:11])[CH:18]=[C:17]([CH3:19])[N:16]=1)=[O:22])(=[O:9])=[O:8])[CH3:6])(=[O:4])=[O:3]
Reactant: CN(S(C)(=O)=O)S(N)(=O)=O
Reactant: COc1cc(C)nc(NC(=O)Oc2ccccc2)n1
Solvent: Clc1ccccc1
Product: COc1cc(C)nc(NC(=O)NS(=O)(=O)N(C)S(C)(=O)=O)n1
Temperature: 100 °C
Reaction time: 5 h
Yield: 96.4 %

Procedure:
37.6 g of (N-methylsulfonyl-N-methylamino)sulfonamide are dissolved in 500 ml of chlorobenzene, 51.8 g of phenyl 4-methoxy-6-methyl-2-pyrimidylcarbamate are added dropwise at room temperature to the solution, and the mixture is stirred for 5 hours at 100° C. The mixture is cooled to 0° C., the precipitate is then filtered off, and, after washing with 100 ml of chlorobenzene, 68.8 g of the desired product of a purity of 98.7% are obtained. This corresponds to a yield of 96.4% of theory. The melting point of the product is 118-120° C.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1.[CH2:21]([N:23]([CH2:26][CH:27]1[O:32][CH2:31][CH2:30][NH:29][CH2:28]1)[CH2:24][CH3:25])[CH3:22]>>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11]([N:29]4[CH2:30][CH2:31][O:32][CH:27]([CH2:26][N:23]([CH2:24][CH3:25])[CH2:21][CH3:22])[CH2:28]4)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: O=C(O)c1cn(C2CC2)c2c(F)c(F)c(F)cc2c1=O
Reactant: CCN(CC)CC1CNCCO1
Product: CCN(CC)CC1CN(c2c(F)cc3c(=O)c(C(=O)O)cn(C4CC4)c3c2F)CCO1

Procedure:
By the use of 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid and 2-(diethylaminomethyl)morpholine, the reaction is similarly carried out as Example 11 to give 1-cyclopropyl-7-[2-(diethylaminomethyl)morpholino]-6,8-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, melting at 155°-157° C.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9](/[CH:11]=[CH:12]/[CH:13]([C:18]2[CH:23]=[C:22]([Cl:24])[C:21]([Cl:25])=[C:20]([Cl:26])[CH:19]=2)[C:14]([F:17])([F:16])[F:15])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].Cl.C(N=C=NCCCN(C)C)C.Cl.[NH2:40][C:41]1([C:44]#[N:45])[CH2:43][CH2:42]1.Cl>ClCCCl.CN(C1C=CN=CC=1)C.CCOC(C)=O>[Br:1][C:2]1[CH:10]=[C:9](/[CH:11]=[CH:12]/[CH:13]([C:18]2[CH:19]=[C:20]([Cl:26])[C:21]([Cl:25])=[C:22]([Cl:24])[CH:23]=2)[C:14]([F:17])([F:15])[F:16])[CH:8]=[CH:7][C:3]=1[C:4]([NH:40][C:41]1([C:44]#[N:45])[CH2:43][CH2:42]1)=[O:5]
Reactant: O=C(O)c1ccc(/C=C/C(c2cc(Cl)c(Cl)c(Cl)c2)C(F)(F)F)cc1Br
Reactant: N#CC1(N)CC1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: ClCCCl
Product: N#CC1(NC(=O)c2ccc(/C=C/C(c3cc(Cl)c(Cl)c(Cl)c3)C(F)(F)F)cc2Br)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 11.5 %

Procedure:
To a stirred solution of (E)-2-bromo-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)benzoic acid (100 mg, 0.205 mmol) in DCE (10.0 mL) at RT was added 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDC hydrochloride) (58.9 mg, 0.307 mmol), 1-amino-1-cyclopropanecarbonitrile hydrochloride (24.3 mg, 0.296 mmol), DMAP (catalytic) and TEA (22.79 mg, 0.225 mmol). The resulting reaction mixture was stirred at RT for 18 h. To the reaction mixture was added EtOAc (50 mL) and 0.1N HCl (10 mL) and the layers were separated. The aqueous layer was extracted with EtOAc (1×). The combined organic layers were washed with aq NaHCO3 (1×), dried (MgSO4), filtered and concentrated under reduce pressure to give an oil. Purification by flash chromatography (SiO2, 230-400 mesh; eluting with 35% EtOAc in hexanes) afforded the title compound as a white solid (13 mg, 11.5%). Characterization data for this molecule is listed in Table 2.
Reaction SMILES: [O:1]=[C:2]1[N:7]2[CH2:8][CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[N:11]=[C:6]2[N:5]([C:18]2[CH:23]=[CH:22][N:21]=[C:20]([NH:24][CH:25]([CH3:35])[CH2:26][C:27]3[CH:34]=[CH:33][C:30]([CH:31]=O)=[CH:29][CH:28]=3)[N:19]=2)[CH2:4][CH2:3]1.C([O-])(=O)C.[NH4+].[N+:41]([CH2:44][CH3:45])([O-:43])=[O:42]>>[CH3:35][CH:25]([NH:24][C:20]1[N:19]=[C:18]([N:5]2[CH2:4][CH2:3][C:2](=[O:1])[N:7]3[CH2:8][CH:9]=[C:10]([C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=4)[N:11]=[C:6]23)[CH:23]=[CH:22][N:21]=1)[CH2:26][C:27]1[CH:34]=[CH:33][C:30]([CH:31]=[C:44]([N+:41]([O-:43])=[O:42])[CH3:45])=[CH:29][CH:28]=1
Reactant: CC[N+](=O)[O-]
Reactant: CC(Cc1ccc(C=O)cc1)Nc1nccc(N2CCC(=O)N3CC=C(c4ccccc4)N=C32)n1
Agent: CC(=O)[O-]
Agent: [NH4+]
Product: CC(=Cc1ccc(CC(C)Nc2nccc(N3CCC(=O)N4CC=C(c5ccccc5)N=C43)n2)cc1)[N+](=O)[O-]

Procedure:
The mixture of 4-{2-[4-(4-oxo-8-phenyl-3,4-dihydro-2H,6H-pyrimido[1,2-a]pyrimidin-1-yl) -pyrimidin-2-ylamino]-propyl}-benzaldehyde (35 mg, 0.08 mmol), ammonium acetate (10 mg, 0.16 mmol) in nitroethane (5 mL) was heated to reflux for 4 h. The mixture was brought to room temperature and concentrated. The residue was dissolved in ethylacetate (20 mL), washed with water, saturated sodium bicarbonate, brine, dried over magnesium sulfate and concentrated. M+1=524.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][N:3]=[N:2]1.[Cl:6][C:7]1[CH:8]=[C:9]([CH:14](O)[CH:15]2[CH2:18][N:17]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:16]2)[CH:10]=[CH:11][C:12]=1[Cl:13].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[Cl:6][C:7]1[CH:8]=[C:9]([CH:14]([N:2]2[N:3]=[N:4][CH:5]=[N:1]2)[CH:15]2[CH2:18][N:17]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:16]2)[CH:10]=[CH:11][C:12]=1[Cl:13]
Reactant: CC(C)(C)OC(=O)N1CC(C(O)c2ccc(Cl)c(Cl)c2)C1
Reactant: c1nnn[nH]1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC(C(c2ccc(Cl)c(Cl)c2)n2ncnn2)C1
Temperature: 0 °C
Reaction time: 24 h
Yield: 88 %

Procedure:
Tetrazole (90.0 mg, 1.28 mmol) was added to tertiary butyl 3-((3,4-dichlorophenyl)(hydroxy)methyl)azetidine-1-carboxylate (200 mg, 0.638 mmol) and triphenylphosphine (335 mg, 1.28 mmol) dissolved in the distilled tetrahydrofuran solution (15.0 mL), and diisopropyl azocarboxylate (0.25 mL, 1.28 mmol) was slowly added thereto at 0° C., and the mixture was stirred at room temperature for one day. The solvent of the reaction mixture was removed by reduced pressure evaporation to obtain a yellow liquid, which was purified by flash chromatography (n-hexane:ethyl acetate (4:1, v/v)). The product was identified as a single compound by TLC (n-hexane:ethyl acetate (4:1, v/v)) (yield: 88%, white solid). This white solid was dissolved in 10 mL of methanol solution, and 1 N HCl (3.0 mL) was added thereto, and heated to reflux at 60° C. for one day. Thereafter, the solvent of the reaction mixture was removed by reduced pressure evaporation to obtain the title compound (KHG27280).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH:14]([C:16]2[N:17]=[N:18][N:19]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=3)[CH:20]=2)[OH:15])=[CH:4][CH:3]=1.[CH2:32]([O:34][C:35]([C:37]1([C:40]2[CH:45]=[CH:44][C:43](B3OC(C)(C)C(C)(C)O3)=[CH:42][CH:41]=2)[CH2:39][CH2:38]1)=[O:36])[CH3:33]>>[CH2:32]([O:34][C:35]([C:37]1([C:40]2[CH:45]=[CH:44][C:43]([C:2]3[CH:3]=[CH:4][C:5]([C:8]4[O:12][N:11]=[C:10]([CH3:13])[C:9]=4[CH:14]([OH:15])[C:16]4[N:17]=[N:18][N:19]([CH2:21][C:22]5[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:29])([F:30])[F:31])[CH:23]=5)[CH:20]=4)=[CH:6][CH:7]=3)=[CH:42][CH:41]=2)[CH2:38][CH2:39]1)=[O:36])[CH3:33]
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C(O)c1cn(Cc2cccc(C(F)(F)F)c2)nn1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4C(O)c4cn(Cc5cccc(C(F)(F)F)c5)nn4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 1, Step 10, using [5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-[1-(3-trifluoromethyl-benzyl)-1H-[1,2,3]triazol-4-yl]-methanol and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.