Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+]([O-])(O)=O.[N+]([O-])([O-])=O.[Zn+2:9].[N+]([O-])([O-])=O.[P:14](=[O:18])([OH:17])([OH:16])[OH:15]>O>[P:14]([O-:18])([O-:17])([O-:16])=[O:15].[Zn+2:9].[P:14]([O-:18])([O-:17])([O-:16])=[O:15].[Zn+2:9].[Zn+2:9]
Reactant: O=P(O)(O)O
Agent: O=[N+]([O-])[O-]
Agent: [Zn+2]
Solvent: O=[N+]([O-])O
Solvent: O
Product: O=P([O-])([O-])[O-]

Procedure:
Phosphating solution based on zinc diacid phosphate, nitric acid, zinc nitrate and phosphoric acid in a percentage amount, diluted in water, of between 5 and 20%, at a temperature of 60-85° C. for a variable between 5 and 15 minutes, so as to produce a compact and homogeneous zinc phosphate coating with a very fine crystalline structure so as to facilitate mechanical deformation of the cold material;
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([S:14](Cl)(=[O:16])=[O:15])[CH:11]=[CH:12][CH:13]=2)=[CH:4][CH:3]=1.[NH2:18][C:19]1[CH:27]=[C:23]([C:24]([OH:26])=[O:25])[C:22]([OH:28])=[CH:21][CH:20]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([S:14]([NH:18][C:19]3[CH:20]=[CH:21][C:22]([OH:28])=[C:23]([CH:27]=3)[C:24]([OH:26])=[O:25])(=[O:16])=[O:15])[CH:9]=2)=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)c1cccc(-c2ccc(Cl)cc2)c1
Reactant: Nc1ccc(O)c(C(=O)O)c1
Product: O=C(O)c1cc(NS(=O)(=O)c2cccc(-c3ccc(Cl)cc3)c2)ccc1O
Yield: 33 %

Procedure:
The product was prepared according to General Procedure 1, described in Example 1, with [[3-(4-chlorophenyl)phenyl]sulfonyl chloride (16 mg, 0.055 mmol) and 5-aminosalicylic acid (7.7 mg, 0.050 mmol) using a modified reaction temperature of 60° C. The title compound was obtained in 33% yield (6.7 mg). MS (ESI+) calcd mass for C19H14ClNO5S 403.028121, found 403.028561.
Reaction SMILES: [CH:1]1([N:4]([CH3:20])[C:5]2[C:6](=[O:19])[NH:7][C:8]3[C:13]([N:14]=2)=[CH:12][C:11]([C:15]([O:17][CH3:18])=[O:16])=[CH:10][CH:9]=3)[CH2:3][CH2:2]1.N1C=CC=CC=1.[O:27](S(C(F)(F)F)(=O)=O)[S:28]([C:31]([F:34])([F:33])[F:32])(=O)=[O:29]>ClCCl>[CH:1]1([N:4]([CH3:20])[C:5]2[C:6]([O:19][S:28]([C:31]([F:34])([F:33])[F:32])(=[O:29])=[O:27])=[N:7][C:8]3[C:13]([N:14]=2)=[CH:12][C:11]([C:15]([O:17][CH3:18])=[O:16])=[CH:10][CH:9]=3)[CH2:2][CH2:3]1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: COC(=O)c1ccc2[nH]c(=O)c(N(C)C3CC3)nc2c1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1ccc2nc(OS(=O)(=O)C(F)(F)F)c(N(C)C3CC3)nc2c1
Temperature: 0 °C

Procedure:
To a solution of methyl 3-(cyclopropyl(methyl)amino)-2-oxo-1,2-dihydroquinoxaline-6-carboxylate (126.0 mg, 0.46 mmol) in dichloromethane (34 mL) was added pyridine (145.0 mg, 1.84 mmol) and then Tf2O (259 mg, 0.92 mmol) was added dropwise with stirring at 0° C. The resulting solution was stirred for 3 h at room temperature and then quenched by the addition of ice-water (50 mL), extracted with dichloromethane (2×20 mL), dried over anhydrous sodium sulfate and concentrated under vacuum to afford methyl 3-(cyclopropyl(methyl)amino)-2-(trifluoromethylsulfonyloxy)quinoxaline-6-carboxylate as red oil (180 mg, crude).
Reaction SMILES: [N:1]1([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=O.[NH2:16][C@H:17]([C:26]([N:28]([CH3:41])[C@H:29]([C:37]([O:39][CH3:40])=[O:38])[CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:27])[CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22]C=1.C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1>>[N:1]1([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([NH:16][C@H:17]([C:26]([N:28]([CH3:41])[C@H:29]([C:37]([O:39][CH3:40])=[O:38])[CH2:30][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)=[O:27])[CH2:18][C:19]1[CH:20]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:5]
Reactant: COC(=O)[C@H](Cc1ccccc1)N(C)C(=O)[C@@H](N)CCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Product: COC(=O)[C@H](Cc1ccccc1)N(C)C(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H]1CCCN1C(=O)OC(C)(C)C
Yield: 73 %

Procedure:
Condensation of BocPheOPFP (8.63 g.) and MePHeOMe (5.50 g.) by the active ester method gave BocPhe-MePheOMe in 95% yield. De-t-butoxycarbonylation of BocPhe-MePheOMe using hydrogen chloride in ethyl acetate gave HPhe-MePHeOMe in 48% yield. Condensation of BocProOH (0.71 g.) and HPhe-MePheOMe (1.13 g.) by the mixed anhydride method using diphenylphosphinic chloride gave BocPro-Phe-MePheOMe in 73% yield. Hydrazinolysis of BocPro-Phe-MePheOMe (3.10 g.) gave BocPro-Phe-MePheNHNH2 in 84% yield.
Reaction SMILES: Cl.[C:2](Cl)(=[O:9])[C:3]1[CH:8]=[CH:7][CH:6]=[N:5][CH:4]=1.[CH2:11]1[O:17][C@H:16]([C@@H:18]([CH2:20][OH:21])[OH:19])[C@H:14]([OH:15])[C@H:12]1[OH:13]>C(N(CC)CC)C.C(Cl)Cl>[C:2]([O:13][C@@H:12]1[C@@H:14]([O:15][C:2](=[O:9])[C:3]2[CH:8]=[CH:7][CH:6]=[N:5][CH:4]=2)[C@@H:16]([C@@H:18]([CH2:20][O:21][C:2](=[O:9])[C:3]2[CH:8]=[CH:7][CH:6]=[N:5][CH:4]=2)[O:19][C:2](=[O:9])[C:3]2[CH:8]=[CH:7][CH:6]=[N:5][CH:4]=2)[O:17][CH2:11]1)(=[O:9])[C:3]1[CH:8]=[CH:7][CH:6]=[N:5][CH:4]=1
Reactant: O=C(Cl)c1cccnc1
Reactant: OC[C@@H](O)[C@H]1OC[C@H](O)[C@H]1O
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(OC[C@@H](OC(=O)c1cccnc1)[C@H]1OC[C@H](OC(=O)c2cccnc2)[C@H]1OC(=O)c1cccnc1)c1cccnc1

Procedure:
23.8 g of nicotinoyl chloride-hydrochloride are added in portions in the course of 15 minutes to a suspension of 5.0 g of 1,4-anhydro-D-glucitol (Arlitan) in 30 g of triethylamine and 100 ml of methylene chloride, at 40°, whilst stirring and with the exclusion of atmospheric moisture. After the reaction mixture has been allowed to react for a further 30 minutes, it is filtered and the bulk of the methylene chloride is distilled off from the filtrate. The residue which is thus formed from the filtrate is dissolved in methylene chloride and the solution is washed with water. After drying over sodium sulphate, evaporating under a waterpump vacuum and degassing the residue under a high vacuum, pure 2,3,5,6-tetra-O-nicotinoyl-1,4-anhydro-D-glucitol is obtained as a viscous, brownish oil which has an optical rotation [α]D20 = + 16° ± 1° (c = 1.099 in chloroform), IR: carbonyl band at 1,730 cm-1, and a Rf value of 0.26 on silica gel thin layer plates in the system: methylene chloride/ethyl acetate (85:15).
Reaction SMILES: [OH:1][C:2]1[C:3]2[O:23][N:22]=[C:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:4]=2[C:5]([C:13]#[C:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[N:6][C:7]=1[C:8](OCC)=[O:9].[NH2:30][CH2:31][C:32]([OH:34])=[O:33].C[O-].[Na+]>>[OH:1][C:2]1[C:3]2[O:23][N:22]=[C:21]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:4]=2[C:5]([C:13]#[C:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[N:6][C:7]=1[C:8]([NH:30][CH2:31][C:32]([OH:34])=[O:33])=[O:9]
Reactant: CCOC(=O)c1nc(C#Cc2ccccc2)c2c(-c3ccccc3)noc2c1O
Reactant: NCC(=O)O
Agent: C[O-]
Agent: [Na+]
Product: O=C(O)CNC(=O)c1nc(C#Cc2ccccc2)c2c(-c3ccccc3)noc2c1O
Temperature: 25 °C
Yield: 82.1 %

Procedure:
Ethyl 7-hydroxy-3-phenyl-4-(phenylethynyl)isoxazolo[4,5-c]pyridine-6-carboxylate (195 mg, 0.51 mmol) and glycine (1.9 g, 25.3 mmol) were added to sodium methoxide solution (38 mL, 19.0 mmol, 0.5 M in MeOH) and the mixture was refluxed for 3 days. The mixture was cooled to room temperature and the solvent was removed in vacuo. The residue was dissolved in 100 mL of water and hydrochloric acid was added until pH was 3. The precipitate was isolated by filtration and dried under vacuum to give 173 mg of the title compound. MS: (+) m/z 414.32 (M+1).
Reaction SMILES: C(OC(N1CCN([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C@@H:21]3[O:30][C:25]4=[N:26][CH:27]=[CH:28][CH:29]=[C:24]4[O:23][CH2:22]3)=[CH:17][CH:16]=2)CC1)=O)(C)(C)C.Cl.[CH:32]12[NH:39][CH:36]([CH2:37][CH2:38]1)[CH2:35][N:34]([C:40](=[O:42])[CH3:41])[CH2:33]2>>[O:23]1[C:24]2[C:25](=[N:26][CH:27]=[CH:28][CH:29]=2)[O:30][C@@H:21]([C:18]2[CH:19]=[CH:20][C:15]([CH2:14][N:39]3[CH:32]4[CH2:38][CH2:37][CH:36]3[CH2:35][N:34]([C:40](=[O:42])[CH3:41])[CH2:33]4)=[CH:16][CH:17]=2)[CH2:22]1
Reactant: CC(=O)N1CC2CCC(C1)N2
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2ccc([C@H]3COc4cccnc4O3)cc2)CC1
Agent: Cl
Product: CC(=O)N1CC2CCC(C1)N2Cc1ccc([C@H]2COc3cccnc3O2)cc1

Procedure:
Compound 271 is synthesized from Intermediate C and Intermediate U according to General Method H. (LC/MS method 16: ES+ m/z 380.5 [M+H]+, Rt=2.52 min)
Reaction SMILES: [CH3:1][S:2]([CH2:4][CH2:5][CH2:6][NH:7][C:8]1[N:13]=[C:12]2[N:14]=[C:15]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[O:25][CH2:26][CH2:27][CH3:28])[NH:16][C:17](=[O:18])[C:11]2=[CH:10][N:9]=1)=[O:3].ClC1C=C(C=CC=1)C(OO)=[O:34]>ClCCl>[CH3:1][S:2]([CH2:4][CH2:5][CH2:6][NH:7][C:8]1[N:13]=[C:12]2[N:14]=[C:15]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[O:25][CH2:26][CH2:27][CH3:28])[NH:16][C:17](=[O:18])[C:11]2=[CH:10][N:9]=1)(=[O:34])=[O:3]
Reactant: CCCOc1ccccc1-c1nc2nc(NCCCS(C)=O)ncc2c(=O)[nH]1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CCCOc1ccccc1-c1nc2nc(NCCCS(C)(=O)=O)ncc2c(=O)[nH]1

Procedure:
A solution of 7-(3-methylsulphinylpropylamino)-4-oxo-2-(2-propoxyphenyl)-3,4-dihydropyrimido[4,5-d]pyrimidine (0.80 g) and m-chloroperoxybenzoic acid (0.40 g) in dichloromethane (50 ml) was stirred at ambient temperature for 24 hours. During this time further m-chloroperoxybenzoic acid (about 200 mg) was added on 2 occasions. The solution was washed with dilute aqueous sodium bicarbonate (3×25 ml) and the combined washings back-extracted with a little dichloromethane. The combined organic layer was washed with water and then brine, dried (magnesium sulphate) and evaporated under reduced pressure to yield a residue. This was recrystallised three times from methanol to yield the title compound, 0.51 g, m.p. 222°-3° C.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]([CH:6]1[CH2:9][NH:8][CH2:7]1)=[O:5].[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2([C:21](O)=[O:22])[CH2:20][CH2:19][CH2:18]2)=[CH:13][CH:12]=1.C(N(C(C)C)CC)(C)C.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[CH3:2][O:3][C:4]([CH:6]1[CH2:9][N:8]([C:21]([C:17]2([C:14]3[CH:13]=[CH:12][C:11]([Cl:10])=[CH:16][CH:15]=3)[CH2:18][CH2:19][CH2:20]2)=[O:22])[CH2:7]1)=[O:5]
Reactant: COC(=O)C1CNC1
Reactant: O=C(O)C1(c2ccc(Cl)cc2)CCC1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)C1CN(C(=O)C2(c3ccc(Cl)cc3)CCC2)C1
Temperature: 25 °C
Reaction time: 10 h
Yield: 70.6 %

Procedure:
To a stirred solution of azetidine-3-carboxylic acid methyl ester hydrochloride (762 mg, 4.60 mmoles) and 1-(4-chloro-phenyl)-cyclobutane carboxylic acid (2.09 g, 9.90 mmoles) in anhydrous DCM (20 mL) was added di-isopropyl ethyl amine (4.6 mL, 26.4 mmoles) dropwise. After completion of addition solid PyBroP (4.63 g, 9.94 mmoles) was added to the stirring reaction mixture. The reaction mixture continued stirring at RT for 10 h and was quenched with water. The aqueous layer was extracted with EtOAc (3×20 mL). Combined organic layers were dried over Na2SO4 and concentrated to yield an oil. This crude material was purified using silica gel chromatography (9:1 hexanes:EtOAc-1:1 hexane:EtOAc) to yield the desired amide (1.0 g, 65%). 1H NMR (300 MHz, CDCl3): δ 7.38-7.29 (m, 4H), 4.16 (m, 2H), 3.88 (m, 1H), 3.72 (s, 3H), 3.31-1.63 (m, 8H). LRMS: M+309.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([CH3:18])=[C:5]2[C:10]=1[C:9](=[O:11])[N:8]1[CH:12]=[C:13]([C:16]#[N:17])[CH:14]=[CH:15][C:7]1=[N:6]2.[N-:19]=[N+:20]=[N-:21].[Na+].[Cl-].[NH4+].C>CN(C)C=O.N1C=CC=CC=1>[CH3:1][C:2]1[S:3][C:4]([CH3:18])=[C:5]2[C:10]=1[C:9](=[O:11])[N:8]1[CH:12]=[C:13]([C:16]3[NH:21][N:20]=[N:19][N:17]=3)[CH:14]=[CH:15][C:7]1=[N:6]2
Reactant: Cc1sc(C)c2c(=O)n3cc(C#N)ccc3nc12
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: Cc1sc(C)c2c(=O)n3cc(-c4nnn[nH]4)ccc3nc12
Temperature: 120 °C
Yield: 60.4 %

Procedure:
A mixture of 4.4 g (0.0172 mol) of 1,3-dimethyl-10-oxo-10H-pyrido-[1,2-a]thieno[3,4-d]pyrimidine-7-carbonitrile (Example 51), 6.5 g (0.1 mol) of sodium azide and 5.3 g (0.1 mol) of ammonium chloride in 180 ml of dimethylformamide is stirred and heated in a wax bath at 120° C. for seventeen hours under nitrogen. The reaction mixture is cooled, filtered and the filtrate evaporated. The residue is treated with 250 ml of water and acidified with concentrated hydrochloric acid. This mixture is warmed on a steam bath, cooled and filtered to give 5.1 g of crude product. This material is dissolved in hot pyridine, activated charcoal (Darco-G60, Matheson, Coleman and Bell) is added and the hot suspension is filtered through Supercell Hyflo® (Johns-Mansville). The filtrate is cooled to give 3.1 g of 1,3-dimethyl-7-(1H-tetrazol-5-yl)-10H-pyrido[1,2-a]thieno-[3,4-d]pyrimidin-10-one; mp 292° C. (dec).
Reaction SMILES: [NH2:1][C:2]1[C:3]([OH:13])=[C:4]([CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11])[C:5]#[N:6].[C:14]([O-])([O-])=O.[K+].[K+].IC>CN(C=O)C>[NH2:1][C:2]1[C:3]([O:13][CH3:14])=[C:4]([CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11])[C:5]#[N:6]
Reactant: N#Cc1ccc([N+](=O)[O-])c(N)c1O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COc1c(C#N)ccc([N+](=O)[O-])c1N
Temperature: 25 °C
Reaction time: 16 h
Yield: 61.2 %

Procedure:
To a stirring suspension of 11A (0.34 g, 1.86 mmol) and K2CO3 (0.283 g, 2.05 mmol) in DMF (3 mL) was added iodomethane (0.127 mL, 2.05 mmol). After the addition, the reaction mixture was stirred at rt for 16 h, then partitioned between H2O and CH2Cl2. The separated CH2Cl2 layer was washed with water, brine, dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was chromatographed (silica gel) eluting with 5% to 40% EtOAc/hexane to yield the title compound (0.22 g) as a solid.
Reaction SMILES: [CH3:1][Mg]Br.[F:4][C:5]1[C:27]([CH:28]=[O:29])=[CH:26][C:8]2[C:9]3[N:13]([CH2:14][CH2:15][O:16][C:7]=2[CH:6]=1)[CH:12]=[C:11]([C:17]1[N:18]([CH:23]([CH3:25])[CH3:24])[N:19]=[C:20]([CH3:22])[N:21]=1)[N:10]=3>C1COCC1.C1(C)C=CC=CC=1.C1COCC1>[F:4][C:5]1[C:27]([CH:28]([OH:29])[CH3:1])=[CH:26][C:8]2[C:9]3[N:13]([CH2:14][CH2:15][O:16][C:7]=2[CH:6]=1)[CH:12]=[C:11]([C:17]1[N:18]([CH:23]([CH3:25])[CH3:24])[N:19]=[C:20]([CH3:22])[N:21]=1)[N:10]=3
Reactant: Cc1nc(-c2cn3c(n2)-c2cc(C=O)c(F)cc2OCC3)n(C(C)C)n1
Reactant: C[Mg]Br
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: Cc1nc(-c2cn3c(n2)-c2cc(C(C)O)c(F)cc2OCC3)n(C(C)C)n1
Temperature: 0 °C
Reaction time: 1 h
Yield: 34 %

Procedure:
Methylmagnesium bromide (10.1 mL of a 1.4 M solution in THF/PhMe) was added to a solution of 8-fluoro-2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulene-9-carbaldehyde (968 mg, 2.83 mmol) in THF (20 mL) at 0° C. The reaction mixture was stirred at 0° C. for 1 h and then quenched by addition of sat. NH4Cl (10 mL). The mixture was extracted with EtOAc (3×25 mL) and the combined organics were washed (brine), dried (Na2SO4) and concentrated in vacuo. Compound purified by column chromatography (Si-PPC, gradient 0-5% MeOH in DCM) to give the title compound (361 mg, 0.97 mmol, 34%) as a pale brown solid. LCMS (Method J): RT=2.53 min, [M+H]+=372
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=3)[C:9]3[N:10]([CH:11]=[CH:12][N:13]=3)[C:3]=12.CC(C)([O-])C.[K+].[CH3:27][O:28][CH2:29][CH2:30][N:31]1[C:35]2=[N:36][CH:37]=[CH:38][CH:39]=[C:34]2[N:33]=[C:32]1S(C)(=O)=O.O>CC(N(C)C)=O>[CH3:27][O:28][CH2:29][CH2:30][N:31]1[C:35]2=[N:36][CH:37]=[CH:38][CH:39]=[C:34]2[N:33]=[C:32]1[O:20][C:17]1[CH:18]=[CH:19][C:14]([N:8]2[C:4]3=[N:5][CH:6]=[CH:7][C:2]([CH3:1])=[C:3]3[N:10]3[CH:11]=[CH:12][N:13]=[C:9]23)=[CH:15][CH:16]=1
Reactant: COCCn1c(S(C)(=O)=O)nc2cccnc21
Reactant: Cc1ccnc2c1n1ccnc1n2-c1ccc(O)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: COCCn1c(Oc2ccc(-n3c4nccc(C)c4n4ccnc34)cc2)nc2cccnc21
Reaction time: 0.17 h
Yield: 86.3 %

Procedure:
To a solution of 4-(5-methyl-9H-imidazo[1′,2′:1,2]imidazo[4,5-b]pyridin-9-yl)phenol (370 mg) obtained in Example 15, step E) in DMA (3 ml) was added potassium tert-butoxide (168 mg) at room temperature. After stirring for 10 min, a solution of 3-(2-methoxyethyl)-2-(methylsulfonyl)-3H-imidazo[4,5-b]pyridine (383 mg) in DMA (3 ml) was added, and the obtained mixture was stirred at 150° C. for 1 hr. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by basic silica gel column chromatography (hexane/THF) and recrystallized from acetone to give the title compound (531 mg).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[H-].[Na+].Br[CH2:11][CH2:12][Cl:13].[Na+].[Cl-]>CN(C)C=O.O>[Cl:13][CH2:12][CH2:11][O:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: ClCCBr
Reactant: Oc1cccnc1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: ClCCOc1cccnc1
Temperature: 25 °C
Yield: 119.7 %

Procedure:
Under a nitrogen atmosphere, a solution of 3-hydroxypyridine (2.00 g, 21.0 mmol) in N,N-dimethylformamide (DMF) (10 mL) was added drop-wise over 5 min to a cold (0-5° C.), stirring slurry of sodium hydride (0.756 g of an 80% dispersion in mineral oil, 27.5 mmol) in DMF (15 mL). The mixture was allowed to stir and warm to ambient temperature over 1 h. Next, 1-bromo-2-chloroethane (3.60 g, 25.2 mmol) was added drop-wise over 5 min. The resulting dark-brown mixture was stirred at ambient temperature for 4 h. Water (30 mL) was added, followed by saturated NaCl solution (25 mL), and the mixture was extracted with ether (4×50 mL). The combined ether extracts were dried (Na2SO4), filtered, and concentrated by rotary evaporation to a residue that was dried briefly under high vacuum to give 3.96 g (66.1%) of a light-brown oil.
Reaction SMILES: CS[C:3]1[N:4]=[C:5]([CH2:12][C:13]2[CH:17]=[CH:16][S:15][CH:14]=2)[NH:6][C:7](=[O:11])[C:8]=1[C:9]#[N:10].[NH:18]1[CH2:23][CH2:22][CH:21]([CH2:24][CH2:25][OH:26])[CH2:20][CH2:19]1>>[OH:26][CH2:25][CH2:24][CH:21]1[CH2:22][CH2:23][N:18]([C:3]2[N:4]=[C:5]([CH2:12][C:13]3[CH:17]=[CH:16][S:15][CH:14]=3)[NH:6][C:7](=[O:11])[C:8]=2[C:9]#[N:10])[CH2:19][CH2:20]1
Reactant: OCCC1CCNCC1
Reactant: CSc1nc(Cc2ccsc2)[nH]c(=O)c1C#N
Product: N#Cc1c(N2CCC(CCO)CC2)nc(Cc2ccsc2)[nH]c1=O

Procedure:
In analogy to the preparation of Example 1, 100 mg (0.38 mmol) of 4-(methylsulphanyl)-6-oxo-2-(3-thienylmethyl)-1,6-dihydropyrimidine-5-carbonitrile are reacted with 491 mg (3.80 mmol) of 2-(4-piperidinyl)ethan-1-ol to give 64 mg (49% of theory) of the title compound.
Reaction SMILES: [H-].[Na+].[C:3]([O:11]CC)(=[O:10])[CH2:4][C:5](OCC)=O.[Br:14][C:15]1[CH:22]=[CH:21][C:18](CBr)=[CH:17][CH:16]=1>CN(C)C=O.O>[Br:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:5][CH2:4][C:3]([OH:11])=[O:10])=[CH:17][CH:16]=1
Reactant: CCOC(=O)CC(=O)OCC
Reactant: BrCc1ccc(Br)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(O)CCc1ccc(Br)cc1
Reaction time: 0.08 h

Procedure:
A mixture of a 60% suspension of sodium hydride in mineral oil (4.8 g, 120 mmol) in N,N-dimethylformamide (50 mL) at about 5° C. was treated with diethyl malonate (36.4 mL, 240 mmol). The mixture was stirred for about 5 minutes, slowly treated with a solution of 4-bromobenzyl bromide (20.0 g, 80 mmol) in N,N-dimethylformamide (20 mL), stirred at room temperature overnight, diluted with water, and extracted with ethyl acetate. The combined organic extracts were dried (MgSO4), filtered, and concentrated under high vacuum. The residue was dissolved in a mixture of acetic acid (46 mL), water (30 mL), and concentrated sulfuric acid (13 mL) and was heated to reflux for 18 hours. The reaction mixture was cooled, concentrated under high vacuum, and diluted with water. The formed crystalline solid was collected by filtration, washed with water and diethyl ether, and was dried under high vacuum to provide the desired product. MS (DCI-NH3): m/z 246, 248 (M+NH4)+.
Reaction SMILES: [NH2:1][C:2]1[N:7]([CH2:8][CH3:9])[C:6](=[O:10])[C:5]([C:11]2[CH:16]=[CH:15][C:14](=[O:17])[NH:13][CH:12]=2)=[C:4]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=2)[N:3]=1.[C:25](=O)([O-])[O-].[K+].[K+].IC>CS(C)=O>[NH2:1][C:2]1[N:7]([CH2:8][CH3:9])[C:6](=[O:10])[C:5]([C:11]2[CH:16]=[CH:15][C:14](=[O:17])[N:13]([CH3:25])[CH:12]=2)=[C:4]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=2)[N:3]=1
Reactant: O=C([O-])[O-]
Reactant: CCn1c(N)nc(-c2cccc(F)c2)c(-c2ccc(=O)[nH]c2)c1=O
Agent: [K+]
Solvent: CI
Solvent: CS(C)=O
Product: CCn1c(N)nc(-c2cccc(F)c2)c(-c2ccc(=O)n(C)c2)c1=O
Temperature: 50 °C
Reaction time: 16 h
Yield: 19.6 %

Procedure:
To a solution of 2-amino-3-ethyl-6-(3-fluorophenyl)-5-(6-oxo-1,6-dihydro-3-pyridinyl)-3,4-dihydro-4-pyrimidinone (20 mg, 0.06 mmol) in dimethyl sulfoxide (1 mL) were added potassium carbonate (20 mg, 0.12 mmol) and iodomethane (20 μL, 0.30 mmol), followed by stirring at 50° C. for 16 hours. After filtering off the insoluble matters, the filtrate was purified by HPLC, to give the title compound (4 mg).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[C:5]2[Cl:12].[Li]CCCC.CON(C)[C:21]([C:23]1[N:24]=[CH:25][S:26][CH:27]=1)=[O:22]>C1COCC1>[Cl:12][C:5]1[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([C:21]([C:23]3[N:24]=[CH:25][S:26][CH:27]=3)=[O:22])[CH:3]=2)[N:8]=[CH:7][CH:6]=1
Reactant: Clc1ccnc2ccc(Br)cc12
Reactant: CON(C)C(=O)c1cscn1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=C(c1ccc2nccc(Cl)c2c1)c1cscn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 6-bromo-4-chloroquinoline (0.459 g, 1.89 mmol) in THF (8 mL) was added n-BuLi (1.12 mL, 1.80 mmol, 1.6M in hexane) at −78° C. under argon and the resulting mixture was stirred for 2 hr. A solution of N-methoxy-N-methylthiazole-4-carboxamide (0.39 g, 2.27 mmol) in THF (2 mL) was added and the resulting mixture was allowed to warm to room temperature and stirred at room temperature for 2 hr. The reaction mixture was quenched with ice and saturated NH4Cl. The aqueous layer was extracted with CH2Cl2. The combined organics were concentrated and purified by column chromatography (40-50% EtOAc/hexanes) to yield (4-chloroquinolin-6-yl)(thiazol-4-yl)methanone. (ES, m/z) [M+H]+ 275, 277.
Reaction SMILES: [F:1][CH:2]([F:36])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:7][C:6]=1[C:15]1[C:16]2[N:17]([N:21]=[C:22]([NH:24][C:25]3[CH:35]=[CH:34][C:28]4[CH2:29][CH2:30][NH:31][CH2:32][CH2:33][C:27]=4[CH:26]=3)[N:23]=2)[CH:18]=[CH:19][CH:20]=1.Cl[CH2:38][C:39]([N:41]([CH3:43])[CH3:42])=[O:40]>>[F:36][CH:2]([F:1])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:7][C:6]=1[C:15]1[C:16]2[N:17]([N:21]=[C:22]([NH:24][C:25]3[CH:35]=[CH:34][C:28]4[CH2:29][CH2:30][N:31]([CH2:38][C:39]([N:41]([CH3:43])[CH3:42])=[O:40])[CH2:32][CH2:33][C:27]=4[CH:26]=3)[N:23]=2)[CH:18]=[CH:19][CH:20]=1
Reactant: CS(=O)(=O)c1ccc(OCC(F)F)c(-c2cccn3nc(Nc4ccc5c(c4)CCNCC5)nc23)c1
Reactant: CN(C)C(=O)CCl
Product: CN(C)C(=O)CN1CCc2ccc(Nc3nc4c(-c5cc(S(C)(=O)=O)ccc5OCC(F)F)cccn4n3)cc2CC1

Procedure:
2-(7-{8-[2-(2,2-Difluoro-ethoxy)-5-methanesulfonyl-phenyl]-[1,2,4]triazolo[1,5-a]pyridin-2-ylamino}-1,2,4,5-tetrahydro-3-benzazepin-3-yl)-N,N-dimethyl-acetamide was prepared from {8-[2-(2,2-difluoro-ethoxy)-5-methanesulfonyl-phenyl]-[1,2,4]triazolo[1,5-a]pyridin-2-yl}-(2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)-amine (0.127 g, 0.247 mmol) and 2-chloro-N,N-dimethyl-acetamide (0.038 mL, 0.371 mmol) in a manner analogous to Example 313 to give product (0.060 g, 40%). MP=128-130° C. 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 9.50 (s, 1H), 8.81 (d, 1H), 8.20 (s, 1H), 8.00 d, 1H), 7.65 (d, 1H), 7.50 (m, 2H), 7.32 (s, 1H), 7.10 (t, 1H), 6.98 (d, 1H), 6.28 (br m, 1H), 4.54 (m, 2H), 3.25 (m, 5H), 3.10 (s, 3H), 2.80 (m, 7H), 2.60 (m, 4H). MS=599 (MH)+.