Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:6][C:7](=[O:12])[CH2:8][C:9]([CH3:11])=[O:10])([O:3][CH2:4][CH3:5])=[O:2].S(Cl)([Cl:16])(=O)=O>C(Cl)Cl>[C:1]([NH:6][C:7](=[O:12])[CH:8]([Cl:16])[C:9]([CH3:11])=[O:10])([O:3][CH2:4][CH3:5])=[O:2]
Reactant: O=S(=O)(Cl)Cl
Reactant: CCOC(=O)NC(=O)CC(C)=O
Solvent: ClCCl
Product: CCOC(=O)NC(=O)C(Cl)C(C)=O
Yield: 99.8 %

Procedure:
The N-carbethoxyacetoacetamide (12.7 g from above reaction) was dissolved in methylene chloride (50 ml) and cooled in an ice bath. Sulfuryl chloride (10.0 g) was added dropwise to the reaction mixture. After refluxing for 45 minutes the solvent was evaporated under reduced pressure. The resulting colorless oil crystallized over night to give 15.2 g (99%) colorless product. An analytical sample recrystallized from CHCl3 /cyclohexane had mp 69.5°-70.0°; ir (Nujol) 3200, 1760 (broad), 1540 cm-1 ; nmr (CDCl3) 1.35 (t, 3H, J=7), 2.45 (s, 3H), 4.30 (q, 2H, J=7), 5.75 (s, 1H), 9.0 (s, 1H),; and mass spectrum m/e 43 (100%) and 207 (M+).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][C:14]1[CH:22]=[CH:21][C:17]([C:18](O)=[O:19])=[CH:16][CH:15]=1)[O:9][CH2:8][CH2:7][CH:6]2[C:23]([O:25][CH3:26])=[O:24])#[N:2].[CH3:27][O:28][C:29]1[CH:30]=[CH:31][CH:32]=[C:33]2[C:38]=1[N:37]=[CH:36][C:35]([NH2:39])=[CH:34]2.C1C=NC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>CN(C=O)C.O>[C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][C:14]1[CH:15]=[CH:16][C:17]([C:18](=[O:19])[NH:39][C:35]3[CH:36]=[N:37][C:38]4[C:33]([CH:34]=3)=[CH:32][CH:31]=[CH:30][C:29]=4[O:28][CH3:27])=[CH:21][CH:22]=1)[O:9][CH2:8][CH2:7][CH:6]2[C:23]([O:25][CH3:26])=[O:24])#[N:2]
Reactant: COc1cccc2cc(N)cnc12
Reactant: COC(=O)C1CCOc2cc(Oc3ccc(C(=O)O)cc3)c(C#N)cc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)C1CCOc2cc(Oc3ccc(C(=O)Nc4cnc5c(OC)cccc5c4)cc3)c(C#N)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 41.3 %

Procedure:
Dissolved 4-(6-cyano-4-(methoxycarbonyl)chroman-7-yloxy)benzoic acid (0.10 g, 0.29 mmol), 8-methoxyquinolin-3-amine (0.050 g, 0.29 mmol), and HOAT (0.039 g, 0.29 mmol) in dry DMF (1 mL) at ambient temperature. EDCI (0.049 g, 0.32 mmol) was added and the mixture stirred at ambient temperature overnight. The reaction was diluted with excess water, acidified with 10% HCl and extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered and concentrated. The crude material was purified by silica gel column chromatography eluting with 2-5% methanol/dichloromethane to provide the desired product (0.061 g, 42%) as a colorless foam.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([NH:8][C:9]2[S:10][C:11]([CH2:14][NH:15][C:16]3[C:17]([F:29])=[CH:18][C:19]([F:28])=[C:20]([CH:27]=3)[C:21]([NH:23][CH:24]3[CH2:26][CH2:25]3)=[O:22])=[CH:12][N:13]=2)[CH:5]=[CH:4][CH:3]=1.[CH3:30][N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1>C(Cl)Cl>[CH:24]1([NH:23][C:21](=[O:22])[C:20]2[CH:27]=[C:16]([NH:15][CH2:14][C:11]3[S:10][C:9]([NH:8][C:6]4[CH:5]=[CH:4][CH:3]=[C:2]([N:34]5[CH2:35][CH2:36][N:31]([CH3:30])[CH2:32][CH2:33]5)[N:7]=4)=[N:13][CH:12]=3)[C:17]([F:29])=[CH:18][C:19]=2[F:28])[CH2:26][CH2:25]1
Reactant: O=C(NC1CC1)c1cc(NCc2cnc(Nc3cccc(Br)n3)s2)c(F)cc1F
Reactant: CN1CCNCC1
Solvent: ClCCl
Product: CN1CCN(c2cccc(Nc3ncc(CNc4cc(C(=O)NC5CC5)c(F)cc4F)s3)n2)CC1
Temperature: 120 °C
Yield: 55 %

Procedure:
A mixture of 5-{[2-(6-bromo-pyridin-2-ylamino)-thiazol-5-ylmethyl]-amino}-N-cyclopropyl-2,4-difluoro-benzamide (96 mg, 0.20 mmol) in neat N-methyl piperazine (0.4 mL) was heated to 120° C. in a sealed tube for 5 h. The reaction mixture was cooled to RT, diluted with methylene chloride (5 mL), and washed with water (2×5 mL). The organic layer was dried over Na2SO4, concentrated, and the residue was purified by silica gel eluted with 2-10% MeOH/CH3Cl to give the title compound (53 mg, 55%) as a light yellow solid. (M+H)+=500.
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:26][CH2:25][C@H:24]([CH2:27][OH:28])[CH2:23]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([S:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[N:29]1[CH:34]=[C:33](B(O)O)[CH:32]=[N:31][CH:30]=1>>[OH:28][CH2:27][C@H:24]1[CH2:25][CH2:26][N:22]([C:3]2[C:2]([C:33]3[CH:34]=[N:29][CH:30]=[N:31][CH:32]=3)=[CH:21][C:6]([C:7]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([S:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=3)=[O:8])=[CH:5][N:4]=2)[CH2:23]1
Reactant: O=C(Nc1ccc(SC(F)(F)F)cc1)c1cnc(N2CC[C@H](CO)C2)c(Br)c1
Reactant: OB(O)c1cncnc1
Product: O=C(Nc1ccc(SC(F)(F)F)cc1)c1cnc(N2CC[C@H](CO)C2)c(-c2cncnc2)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 185 using (S)-5-bromo-6-(3-(hydroxymethyl)pyrrolidin-1-yl)-N-(4-((trifluoromethyl)thio)phenyl)nicotinamide (Stage 189.1) and pyrimidin-5-ylboronic acid. HPLC (Condition 4) tR=5.13 min, UPLC-MS (Condition 3) tR=1.01 min, m/z=476.3 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.48-1.64 (m, 1H) 1.84 (m, J=6.30 Hz, 1H) 2.15-2.31 (m, 1H) 2.96 (dd, J=10.95, 7.04 Hz, 1H) 3.08-3.42 (m, 5H) 4.60 (t, J=5.28 Hz, 1H) 7.68 (d, J=8.60 Hz, 2H) 7.90 (d, J=8.99 Hz, 2H) 8.08 (d, J=2.35 Hz, 1H) 8.78 (d, J=2.35 Hz, 1H) 8.88 (s, 2H) 9.17 (s, 1H) 10.25 (s, 1H).
Reaction SMILES: [CH3:1]C1C=CC(S(O)(=O)=O)=CC=1.[C:12]1(/[C:18](/[C:26]2[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=2)=[CH:19]\[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][OH:25])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.O>C[O-].[Na+]>[CH3:1][O:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]/[CH:19]=[C:18](\[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)/[C:26]1[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: OCCCCC/C=C(\c1ccccc1)c1cccnc1
Agent: C[O-]
Agent: [Na+]
Solvent: O
Product: COCCCCC/C=C(\c1ccccc1)c1cccnc1
Reaction time: 72 h
Yield: 75 %

Procedure:
p-Toluenesulfonate of (E)-7-phenyl-7-(3-pyridyl)-6-hepten-1-ol (0.2 g, 0.5 mmole) was dissolved in a methanolic solution (1 ml) of 28% sodium methoxide and the solution was allowed to stand at room temperature for 3 days. To the reaction mixture was added water (10 ml) and the product was extracted twice with ethyl acetate. The organic layer was washed with water, dried and concentrated under reduced pressure. The residue was then subjected to silica gel column chromatography using isopropyl ether-ethyl acetate (1:1) as the developing solvent to give (E)-1-methoxy-7-phenyl-7-(3-pyridyl)-6-heptene (0.1 g, 75%) (Compound I-37) as an oil.
Reaction SMILES: [NH2:1][S:2]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[CH2:8]2)(=[O:4])=[O:3].[CH2:15]([NH:17][C:18]([C:20]([C:22]1[NH:23][CH:24]=[CH:25][CH:26]=1)=O)=[O:19])[CH3:16].N1CCCCC1>ClCCl>[NH2:1][S:2]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[C:8]2=[C:20]([C:22]1[NH:23][CH:24]=[CH:25][CH:26]=1)[C:18]([NH:17][CH2:15][CH3:16])=[O:19])(=[O:4])=[O:3]
Reactant: CCNC(=O)C(=O)c1ccc[nH]1
Reactant: NS(=O)(=O)c1ccc2c(c1)CC(=O)N2
Solvent: ClCCl
Solvent: C1CCNCC1
Product: CCNC(=O)C(=C1C(=O)Nc2ccc(S(N)(=O)=O)cc21)c1ccc[nH]1

Procedure:
Alternatively, a mixture of 5-aminosulfonylindolin-2-one (0.22 g, 1.0 mmol), 2-(ethylamino)carbonylcarbonylpyrrole (0.33 g, 2.0 mmol) and piperidine (0.2 mL, 2.0 mmol) was irradiated in a microwave at 160° C. for 5 minutes. The reaction mixture was dissolved in dichloromethane (25 mL). The resulting mixture was washed with 0.2 N HCl (25 mL) and saturated sodium bicarbonate (25 mL), dried (magnesium sulfate) and concentrated. Chromatography on SiO2 (10 g) using hexane/ethyl acetate afforded 5-aminosulfonyl-3-[(pyrrol-2-yl)(ethylaminocarbonyl)methylene]indolin-2-one; (45 mg), 1H NMR (400 MHz, DMSO-d6) δ 1.16 (t, 3H), 3.36 (q, 2H), 6.40 (s, 1H), 6.64 (s, 1H), 7.02 (d, 1H), 7.20 (brs, 2H), 7.42 (s, 1H), 7.64 (d, 1H), 7.75 (s, 1H), 8.85 (t, 1H), 11.40 (s, 1H) ppm.
Reaction SMILES: Cl.[CH3:2][N:3]1[C:9](=[O:10])[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.C(N(CC)CC)C.Cl[CH2:19][C:20]1[N:25]=[C:24]([NH:26][C:27]2[S:28][C:29]([C:32]#[N:33])=[CH:30][N:31]=2)[CH:23]=[CH:22][CH:21]=1>CS(C)=O>[CH3:2][N:3]1[C:9](=[O:10])[CH2:8][CH2:7][N:6]([CH2:19][C:20]2[N:25]=[C:24]([NH:26][C:27]3[S:28][C:29]([C:32]#[N:33])=[CH:30][N:31]=3)[CH:23]=[CH:22][CH:21]=2)[CH2:5][CH2:4]1
Reactant: CN1CCNCCC1=O
Reactant: N#Cc1cnc(Nc2cccc(CCl)n2)s1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CN1CCN(Cc2cccc(Nc3ncc(C#N)s3)n2)CCC1=O
Reaction time: 2 h

Procedure:
4-Methyl-[1,4]diazepan-5-one hydrochloride (0.092 g, 0.028 mmol) was dissolved in 1 mL DMSO. Triethylamine (0.12 mL, 0.84 mmol) was added followed by the addition 2-(6-Chloromethyl-pyridin-2-ylamino)-thiazole-5-carbonitrile (0.070 g, 0.28 mmol). The solution as stirred for 2 h. The reaction mixture was purified directly by loading the solution onto a reverse phase preparative column. The fractions containing pure product were concentrated and the white solid that resulted was characterized as the TFA salt. 1H NMR (CD3OD) δ 8.07 (s, 1H), 7.91 (dd, 1H, J=7.5, 8.2 Hz), 7.30 (d, 1H, J=7.3 Hz), 7.19 (d, 1H, J=8.4 Hz), 4.56 (s, 2H), 3.83 (bs, 2H), 3.64 (bs, 4H), 3.01 (s, 3H), 2.93 (bs, 2H). MS [M+H]+=343.2.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13]([C:18]([OH:20])=[O:19])=[CH:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl-].[CH:22](=[N+:29]([CH3:31])[CH3:30])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13]([C:18]([OH:20])=[O:19])=[C:12]2[CH:22]([N:29]([CH3:31])[CH3:30])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[N+](C)=Cc1ccccc1
Reactant: O=C(O)c1cc2cc(OCc3ccccc3)ccc2[nH]1
Agent: [Cl-]
Product: CN(C)C(c1ccccc1)c1c(C(=O)O)[nH]c2ccc(OCc3ccccc3)cc12

Procedure:
The preparation was carried out in accordance with general synthesis instructions 4 from 5-benzyloxy-1H-indole-2-carboxylic acid and benzylidene-dimethyl-ammonium chloride, which had been prepared in accordance with example 1.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10]O)=[CH:4][CH:3]=1.[ClH:12]>O>[Cl:12][CH2:10][CH2:9][CH2:8][C:5]1[CH:6]=[CH:7][C:2]([OH:1])=[CH:3][CH:4]=1
Reactant: Cl
Reactant: OCCCc1ccc(O)cc1
Solvent: O
Product: Oc1ccc(CCCCl)cc1
Yield: 90 %

Procedure:
3-(4-Hydroxyphenyl)-1-propanol (0.97 g, 0.006374 mol) and concentrated HCl (20 ml) were heated at 100° C. for 14 h. After being cooled, the reaction mixture was poured into water and extracted with ethyl acetate. The extracts were washed with water, dried and concentrated in vacuo to give a raw product. Purification by flash chromatography (heptane/ethyl acetate 9:1) gave a pure product (0.98 g, 90%).
Reaction SMILES: [OH-].[Na+].[C:3]([NH:7][NH:8][C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1)=[O:10])([CH3:6])([CH3:5])[CH3:4].[Br:17][C:18]1[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=1[C:20](Cl)=[O:21]>C1(C)C=CC=CC=1>[C:3]([N:7]([C:20](=[O:21])[C:19]1[CH:23]=[CH:24][CH:25]=[CH:26][C:18]=1[Br:17])[NH:8][C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1)=[O:10])([CH3:6])([CH3:4])[CH3:5]
Reactant: O=C(Cl)c1ccccc1Br
Reactant: CC(C)(C)NNC(=O)c1ccccn1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: CC(C)(C)N(NC(=O)c1ccccn1)C(=O)c1ccccc1Br
Temperature: 23 °C
Reaction time: 8 h
Yield: 49.3 %

Procedure:
An aqueous solution of sodium hydroxide (1.24 g of 50% NaOH diluted with 5 ml of water) was added to a solution of N'-t-butyl-N-(2-pyridinecarbonyl)hydrazine (1.0 g, 0.00518 mol) in 20 ml of toluene at 23° C. The mixture was cooled and treated with 2-bromobenzoyl chloride (1.137 g, 0.00518 mol). The mixture was then stirred at 23° C. overnight. The solids were removed by filtration, washed with water and dried to afford 0.96 g of N'-t-butyl-N-(2-pyridinecarbonyl)-N'-(2-bromobenzoyl)hydrazine as a white solid. m.p. 179°-180° C.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([Cl:12])[CH:10]=2)[N:5]([CH3:13])[C:4](=[O:14])[C:3]=1[C:15]#[N:16].[NH:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1>ClCCl>[Cl:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]([CH3:13])[C:4](=[O:14])[C:3]([C:15]#[N:16])=[C:2]2[N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1
Reactant: Cn1c(=O)c(C#N)c(Cl)c2cc(Cl)ccc21
Reactant: C1CNCCN1
Solvent: ClCCl
Product: Cn1c(=O)c(C#N)c(N2CCNCC2)c2cc(Cl)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.3 %

Procedure:
A solution of Compound 70 (0.8 g, 3.16 mmol) in dichloromethane was added slowly to a stirred solution of piperazine (819 mg, 9.50 mmol) in dichloromethane at room temperature. The solution was stirred overnight at room temperature. The solvent was then removed under reduced pressure. The residue was taken in water, sonicated briefly, and filtered. The solids were dissolved in ethyl acetate and washed by water. The organic layer was dried over Na2SO4 and concentrated to yield 950 mg (99%) of yellow solids. M.P. 223° C. 1H NMR (DMSO-d6): δ 2.92 (m, 4H), 3.48 (m, 4H), 3.55 (s, 3H), 7.60 (d, J=8.8 Hz, 1H), 7.77 (m, 2H). EIMS m/z 303 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=2[CH2:23][NH:24][CH2:25][CH3:26])[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1.[CH2:28]([N:30]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:31](Cl)=[O:32])[CH3:29].C(N(CC)CC)C>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:1][O:2][C:3](=[O:27])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:21])([F:20])[F:22])=[CH:15][C:14]=2[CH2:23][N:24]([CH2:25][CH3:26])[C:31]([N:30]([CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH2:28][CH3:29])=[O:32])[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1
Reactant: CCNCc1cc(C(F)(F)F)ccc1-c1cc(CC(=O)OC)ccc1OC
Reactant: CCN(Cc1ccccc1)C(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCN(Cc1ccccc1)C(=O)N(CC)Cc1cc(C(F)(F)F)ccc1-c1cc(CC(=O)OC)ccc1OC

Procedure:
(2′-Ethylaminomethyl-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid methyl ester (0.130 g, 0.34 mmol), N-ethyl-N-benzylcarbamoyl chloride (0.081 g, 0.41 mmol), 4-dimethylaminopyridine (0.010 g, 0.08 mmol), and triethylamine (0.12 mL, 0.85 mmol) were combined in CH2Cl2 (5 mL) and stirred at reflux overnight. The mixture was purified by silica gel chromatography (0-100% EtOAc in hexanes) to give the title compound.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11](Cl)=[O:12])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].C(N(CC)CC)C.[CH3:21][S:22][C:23]1[S:27][C:26]([NH2:28])=[N:25][CH:24]=1>C1COCC1>[C:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11](=[O:12])[NH:28][C:26]2[S:27][C:23]([S:22][CH3:21])=[CH:24][N:25]=2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1ccc(C(=O)Cl)cc1
Reactant: CSc1cnc(N)s1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CSc1cnc(NC(=O)c2ccc(OC(C)=O)cc2)s1
Yield: 84.1 %

Procedure:
Following the procedure for the synthesis of example 512, intermediate 510 (0.815 g, 4.10 mmol) dissolved in dry THF (25.0 mL), triethylamine (0.572 mL, 4.10 mmol), and 514 (0.500 g, 3.42 mmol) dissolved in dry THF (10.0 mL) gave 515 (0.887 g, 84%) as a tan solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH:9]2[CH2:14][CH2:13][C:12]3([CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]3)[CH2:11][CH2:10]2)[C:5]([Cl:27])=[CH:4][N:3]=1.[NH2:28][C:29]1[CH:30]=[N:31][N:32]([CH2:34][CH2:35][OH:36])[CH:33]=1.Cl.CCOC(C)=O>CC(O)C>[Cl:27][C:5]1[C:6]([NH:8][CH:9]2[CH2:14][CH2:13][C:12]3([CH2:15][CH2:16][N:17]([C:20]([O:22][C:23]([CH3:24])([CH3:25])[CH3:26])=[O:21])[CH2:18][CH2:19]3)[CH2:11][CH2:10]2)=[N:7][C:2]([NH:28][C:29]2[CH:30]=[N:31][N:32]([CH2:34][CH2:35][OH:36])[CH:33]=2)=[N:3][CH:4]=1
Reactant: CC(C)(C)OC(=O)N1CCC2(CCC(Nc3nc(Cl)ncc3Cl)CC2)CC1
Reactant: Nc1cnn(CCO)c1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CC(C)O
Product: CC(C)(C)OC(=O)N1CCC2(CCC(Nc3nc(Nc4cnn(CCO)c4)ncc3Cl)CC2)CC1
Temperature: 140 °C
Reaction time: 1 h
Yield: 81.7 %

Procedure:
To a solution of tert-butyl 3-[(2,5-dichloropyrimidin-4-yl)amino]-9-azaspiro[5.5]undecane-9-carboxylate (501.5 mg, 1.21 mmol) and 2-(4-aminopyrazol-1-yl)ethanol (306.5 mg, 2.411 mmol) in propan-2-ol (6 mL) was added a solution of HCl in EtOAc (1 mL, 4 mmol). The mixture stirred in a sealed tube under the microwave radiation at 140° C. for 1 h and then concentrated in vacuo. The residue was purified by silica gel column chromatography (MeOH/DCM (v/v)=1/100 to 1/20 to 1/7) to give the product as a light yellow solid (500.0 mg, 0.9881 mmol, 81.85%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.C[Al](C)C.[N:14]1([C:20]2[N:21]=[C:22]([CH2:33][C:34](OCC)=[O:35])[N:23]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:24](=[O:26])[CH:25]=2)[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1>C1(C)C=CC=CC=1.O1CCCC1>[N:1]1([C:34](=[O:35])[CH2:33][C:22]2[N:23]([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:24](=[O:26])[CH:25]=[C:20]([N:14]3[CH2:15][CH2:16][O:17][CH2:18][CH2:19]3)[N:21]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: c1ccc2c(c1)CCN2
Reactant: CCOC(=O)Cc1nc(N2CCOCC2)cc(=O)n1-c1ccccc1
Agent: C[Al](C)C
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: O=C(Cc1nc(N2CCOCC2)cc(=O)n1-c1ccccc1)N1CCc2ccccc21
Temperature: 90 °C
Yield: 3.8 %

Procedure:
56 mg of indoline and 0.36 ml of 2M trimethyl aluminum in toluene are successively added to a solution of 65 mg of ethyl (4-morpholin-4-yl-6-oxo-1-phenyl-1,6-dihydropyrimidin-2-yl)acetate in 3 ml of tetrahydrofuran and 1.5 ml of toluene. The reaction mixture is heated at 90° C. for 4 hours and then concentrated under reduced pressure. The residue is purified twice by silica column chromatography, elution being carried out with a mixture of dichloromethane and methanol (98/2, V/V) and then with ethyl acetate, so as to give 3 mg of 2-[2-(2,3-dihydroindol-1-yl)-2-oxoethyl]-6-morpholin-4-yl-3-phenyl-3H-pyrimidin-4-one in the form of a solid, the characteristics of which are the following:
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.I[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>>[C:7]1([N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: Ic1ccccc1
Reactant: c1c[nH]cn1
Product: c1ccc(-n2ccnc2)cc1

Procedure:
Following General Procedure A (90° C., 30 hours), 1H-imidazole (102 mg, 1.5 mmol) is coupled with iodo-benzene (112 μL, 1.0 mmol). The crude brown oil is purified by flash chromatography on silica gel (eluent: hexane/ethylacetate=20/80) to provide 130 mg (90% isolated yield) of the desired product as a light yellow oil.
Reaction SMILES: C([NH:4][C:5]1[C:13]([CH3:14])=[CH:12][C:11]([N+:15]([O-:17])=[O:16])=[CH:10][C:6]=1[C:7]([OH:9])=[O:8])(=O)C.[OH-].[K+].CO.Cl>O>[NH2:4][C:5]1[C:13]([CH3:14])=[CH:12][C:11]([N+:15]([O-:17])=[O:16])=[CH:10][C:6]=1[C:7]([OH:9])=[O:8]
Reactant: CC(=O)Nc1c(C)cc([N+](=O)[O-])cc1C(=O)O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1cc([N+](=O)[O-])cc(C(=O)O)c1N
Temperature: 80 °C
Yield: 75.6 %

Procedure:
A mixture of 0.45 g of 2-acetylamino-3-methyl-5-nitrobenzoic acid, 0.45 g of potassium hydroxide, 5 ml of methanol and 20 ml of water was heated to reflux at 80° C. for 2 hours. The reaction mixture was allowed to cool to room temperature, and water was poured into the mixture. The mixture was adjusted to pH 3 by an addition of 2N hydrochloric acid. A deposited precipitate was collected by filtration to obtain 0.28 g of 2-amino-3-methyl-5-nitrobenzoic acid of the formula:
Reaction SMILES: CN(C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([S:20]([N:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)(=[O:22])=[O:21])[CH:15]=2)[N:8]=1)=O.[F:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[NH:37][NH2:38]>>[F:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[N:37]1[C:5]([C:7]2[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([S:20]([N:23]4[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]4)(=[O:21])=[O:22])[CH:15]=3)[N:8]=2)=[CH:4][CH:3]=[N:38]1
Reactant: NNc1ccccc1F
Reactant: CN(C)/C=C/C(=O)c1nn(-c2cccc(S(=O)(=O)N3CCCCC3)c2)ccc1=O
Product: O=c1ccn(-c2cccc(S(=O)(=O)N3CCCCC3)c2)nc1-c1ccnn1-c1ccccc1F

Procedure:
The product was obtained starting from 3-((E)-3-Dimethylamino-acryloyl)-1-[3-(piperidine-1-sulfonyl)-phenyl]-1H-pyridazin-4-one (A-26) and 2-fluoro-phenylhydrazine according to the method described for example 91. MS: M=480.1 (M+H)+
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:24])[N:8]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:9]2[C:14]([C:15]=1Cl)=[CH:13][CH:12]=[CH:11][N:10]=2)=[O:5])[CH3:2].[NH:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1>ClCCl>[CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:24])[N:8]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:9]2[C:14]([C:15]=1[N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1)=[CH:13][CH:12]=[CH:11][N:10]=2)=[O:5])[CH3:2]
Reactant: C1CNCCN1
Reactant: CCOC(=O)c1c(Cl)c2cccnc2n(Cc2ccccc2)c1=O
Solvent: ClCCl
Product: CCOC(=O)c1c(N2CCNCC2)c2cccnc2n(Cc2ccccc2)c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.5 %

Procedure:
A solution of 1-benzyl-4-chloro-2-oxo-1,2-dihydro-[1,8]-naphthyridine-3-carboxylic acid ethyl ester (4) (1.2 g, 3.5 mmol) in dichloromethane was added slowly to a stirred solution of piperazine (0.9 g, 10.5 mmol) in dichloromethane at room temperature. The solution was stirred overnight at room temperature. The solvent was evaporated and the residue was suspended in water, sonicated briefly, and extracted with dichloromethane. The combined organic phase was subsequently washed by water and brine, dried over Na2SO4, and evaporated to yield 1.12 g (82%) of 1-benzyl-2-oxo-4-piperazin-1-yl-1,2-dihydro-[1,8]-naphthyridine-3-carboxylic acid ethyl ester (5) as yellow solids. MP: 120° C.; 1H-NMR (DMSO-d6): δ 1.30 (t, J=6.9 Hz, 3H), 2.28 (m, 4H), 3.03 (m, 4H), 4.28 (q, J=6.9 Hz, 2H), 5.55 (s, 2H), 7.16-7.28 (m, 5H), 7.36 (m, 1H), 8.25 (dd, J=1.5, 7.5 Hz, 1H), 8.63 (dd, J=1.5, 7.5 Hz, 1H); EIMS: 393 (M+1), 415 (M+23).
Reaction SMILES: [Na].[C:2]1([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][O:17][C:18]3[CH:27]=[CH:26][CH:25]=[C:24]4[C:19]=3[CH2:20][CH2:21][C:22](=[O:28])[NH:23]4)[CH2:10][CH2:9]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:29](Cl)(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.O>C(O)C>[C:29]([N:23]1[C:24]2[C:19](=[C:18]([O:17][CH2:16][CH2:15][CH2:14][N:11]3[CH2:10][CH2:9][N:8]([C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)[CH2:13][CH2:12]3)[CH:27]=[CH:26][CH:25]=2)[CH2:20][CH2:21][C:22]1=[O:28])(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: O=C1CCc2c(cccc2OCCCN2CCN(c3ccccc3)CC2)N1
Reactant: O=C(Cl)c1ccccc1
Agent: [Na]
Solvent: O
Solvent: CCO
Product: O=C1CCc2c(OCCCN3CCN(c4ccccc4)CC3)cccc2N1C(=O)c1ccccc1
Yield: 84.3 %

Procedure:
0.3 Gram of sodium metal is dissolved in 80 ml of ethanol and to this solution is added 3.6 g of 5-[3-(4-phenylpiperazinyl)propoxy]-3,4-dihydrocarbostyril, then 1.5 g of benzoyl chloride are added and the solution is heated for 5 hours under refluxing conditions. The reaction mixture is concentrated under reduced pressure to dryness. To the residue thus obtained is added water and the insoluble matter is collected by filtration, washed with water and dried. The crude crystals are recrystallized from ligroin to obtain 3.9 g (yield: 86%) of 1-benzoyl-5-[3-(4-phenylpiperazinyl)propoxy]-3,4-dihydrocarbostyril in the form of pale yellowish needle-like crystals with a melting point of 113° C.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[C:8]1([C:14]2[N:19]=[C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=4[OH:32])[N:21]=3)[CH:17]=[CH:16][CH:15]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>N1C=CC=CC=1>[C:1]([O:32][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=1[C:22]1[N:21]=[C:20]([C:18]2[CH:17]=[CH:16][CH:15]=[C:14]([C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:19]=2)[CH:25]=[CH:24][CH:23]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: Oc1ccccc1-c1cccc(-c2cccc(-c3ccccc3)n2)n1
Solvent: c1ccncc1
Product: CC(=O)Oc1ccccc1-c1cccc(-c2cccc(-c3ccccc3)n2)n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 92.4 %

Procedure:
Acetic anhydride (580 μL, 6.2 mmol) was dropwise added to a pyridine (20 ml) solution of 2-(6′-phenyl-2,2′-bipyridine-6-yl)phenol (1.0 g, 3.1 mmol) obtained by Example 14, then the mixture was stirred for 24 hours at room temperature. The solvent was distilled off from the reaction mixture, and the residue was purified by silica gel column chromatography and recrystallization, thereby obtaining 1.05 g of 6-(2-acetoxyphenyl)-6′-phenyl-2,2′-bipyridine as yellow crystal. Yield: 93.0%.