Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([C:12](=[O:29])[C:13]3[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:28])[C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[Cl:27])=[N:15][CH:14]=3)[CH2:10][CH2:9][CH2:8][CH:7]([CH2:30][CH2:31][OH:32])[C:6]=2[CH:33]=1.[CH3:34][S:35](Cl)(=[O:37])=[O:36].O>N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([C:12](=[O:29])[C:13]3[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:28])[C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[Cl:27])=[N:15][CH:14]=3)[CH2:10][CH2:9][CH2:8][CH:7]([CH2:30][CH2:31][O:32][S:35]([CH3:34])(=[O:37])=[O:36])[C:6]=2[CH:33]=1
Reactant: CS(=O)(=O)Cl
Reactant: O=C(Nc1ccc(C(=O)N2CCCC(CCO)c3cc(Cl)ccc32)cn1)c1ccccc1Cl
Solvent: O
Solvent: c1ccncc1
Product: CS(=O)(=O)OCCC1CCCN(C(=O)c2ccc(NC(=O)c3ccccc3Cl)nc2)c2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 7-chloro-5-(2-hydroxyethyl)-1-[6-(2-chlorobenzoylamino)nicotinoyl]-2,3,4,5-tetrahydro-1H-benzazepine (3.7 g)in pyridine (50 ml) is added with stirring methanesulfonyl chloride (0.71 ml) under ice-cooling, and the mixture is stirred at room temperature for 3 hours. Water is added to the reaction solution, and the mixture is extracted with ethyl acetate. The extract is washed with successively with diluted hydrochloric acid and water, dried over magnesium sulfate, and evaporated under reduced pressure to remove the solvent. The residue is purified by silica gel column chromatography to give 7-chloro-5-(2-methanesulfonyloxyethyl)-1-[6-(2-chlorobenzoylamino)nicotinoyl]-2,3,4,5-tetrahydro-1H-benzazepine (2.8 g) as colorless amorphous.
Reaction SMILES: [N:1]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[N:4]([C:10]1[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=1)[N:16]=[C:15]([C:20]1[CH:25]=[CH:24][C:23]([F:26])=[C:22]([O:27][CH3:28])[CH:21]=1)[N:14]([CH2:29][C:30]([OH:32])=O)[C:13]3=[O:33])[CH2:3][CH2:2]2.[C:34]([NH2:38])([CH3:37])([CH3:36])[CH3:35].C(N(CC)C(C)C)(C)C.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O>C(Cl)Cl.CO>[C:34]([NH:38][C:30](=[O:32])[CH2:29][N:14]1[C:13](=[O:33])[C:12]2[C:17](=[CH:18][CH:19]=[C:10]([N:4]3[CH:5]4[CH2:6][CH2:7][N:1]([CH2:9][CH2:8]4)[CH2:2][CH2:3]3)[CH:11]=2)[N:16]=[C:15]1[C:20]1[CH:25]=[CH:24][C:23]([F:26])=[C:22]([O:27][CH3:28])[CH:21]=1)([CH3:37])([CH3:36])[CH3:35]
Reactant: CC(C)(C)N
Reactant: COc1cc(-c2nc3ccc(N4CCN5CCC4CC5)cc3c(=O)n2CC(=O)O)ccc1F
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: ClCCl
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(-c2nc3ccc(N4CCN5CCC4CC5)cc3c(=O)n2CC(=O)NC(C)(C)C)ccc1F
Temperature: 25 °C
Reaction time: 12 h
Yield: 15.9 %

Procedure:
[6-(1,4-Diazabicyclo[3.2.2]non-4-yl)-2-(4-fluoro-3-methoxyphenyl)-4-oxo-4H-quinazolin-3-yl]acetic acid (INTERMEDIATE IX.7) (20 mg, 0.44 mmol) was dissolved in DCM (5 mL). Tert-butylamine (6.5 mg, 0.088 mmol) and N,N-diisopropylethylamine (7 mg, 0.053 mmol) were added followed by 1-propanephosphonic acid cyclic anhydride (21 mg, 0.02 mL, 0.066 mmol). The reaction mixture was stirred at room temperature for 12 h. Methanol (5 mL) was added and the solution poured directly onto an SCX cartridge. Elution with 2N NH3/MeOH followed further purification by preparative HPLC afforded N-tert-butyl-2-[6-(1,4-diazabicyclo[3.2.2]non-4-yl)-2-(4-fluoro-3-methoxyphenyl)-4-oxo-4H-quinazolin-3-yl]acetamide (EXAMPLE 9a) (7.3 mg, 0.014 mmol, 33%).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][C:10]3[O:14][CH:13]=[C:12]([CH:15]=[O:16])[C:11]=3[CH:17]=2)=[N:4][N:3]=1.C1(C)C=CC(S([CH2:27][N+:28]#[C-:29])(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+]>CO.C(OCC)(=O)C>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][C:10]3[O:14][CH:13]=[C:12]([C:15]4[O:16][CH:29]=[N:28][CH:27]=4)[C:11]=3[CH:17]=2)=[N:4][N:3]=1
Reactant: Cc1nnc(-c2ccc3occ(C=O)c3c2)o1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CCOC(C)=O
Product: Cc1nnc(-c2ccc3occ(-c4cnco4)c3c2)o1
Yield: 20.2 %

Procedure:
A suspension of 5-(5-methyl-1,3,4-oxadiazol-2-yl)-1-benzofuran-3-carbaldehyde (500 mg, 2.19 mmol), p-toluenesulfonylmethyl isocyanide (471 mg, 2.41 mmol) and potassium carbonate (363 mg, 2.63 mmol) in methanol (10 mL) was heated under reflux for 7 hr. After cooling, the reaction mixture was diluted with ethyl acetate, washed with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (tetrahydrofuran) and recrystallized from methanol to give the title compound (118 mg, yield 20%) as colorless crystals.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([NH2:23])[C:7](=[O:22])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][C:11]([Cl:21])=[CH:10][CH:9]=2)=[O:4].[O:24]1[CH:28]=[CH:27][CH:26]=[C:25]1[CH:29]=O>>[CH3:1][O:2][C:3]([C:5]1[N:6]([N:23]=[CH:29][C:25]2[O:24][CH:28]=[CH:27][CH:26]=2)[C:7](=[O:22])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][C:11]([Cl:21])=[CH:10][CH:9]=2)=[O:4]
Reactant: O=Cc1ccco1
Reactant: COC(=O)c1c(-c2ccccc2)c2cc(Cl)ccc2c(=O)n1N
Product: COC(=O)c1c(-c2ccccc2)c2cc(Cl)ccc2c(=O)n1N=Cc1ccco1

Procedure:
The present compound was synthesized by a method similar to that in Example 210 and using 2-amino-6-chloro-1-oxo-4-phenyl-1,2-dihydroisoquinoline-3-carboxylic acid methyl ester (210 mg) and furan-2-carbaldehyde. A colorless powder (125 mg).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[F:6][C:7]([F:43])([F:42])[C:8]1[CH:9]=[C:10]([CH:35]=[C:36]([C:38]([F:41])([F:40])[F:39])[CH:37]=1)[CH2:11][N:12]1[C:16](Cl)=[C:15]([C:18]([C:20]2[O:24][C:23]([CH:25]3[CH2:27][CH2:26]3)=[N:22][C:21]=2[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[Cl:34])=[O:19])[N:14]=[N:13]1.CCOC(C)=O>CS(C)=O>[F:41][C:38]([F:39])([F:40])[C:36]1[CH:35]=[C:10]([CH:9]=[C:8]([C:7]([F:6])([F:43])[F:42])[CH:37]=1)[CH2:11][N:12]1[C:16]([N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)=[C:15]([C:18]([C:20]2[O:24][C:23]([CH:25]3[CH2:26][CH2:27]3)=[N:22][C:21]=2[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[Cl:34])=[O:19])[N:14]=[N:13]1
Reactant: O=C(c1nnn(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1Cl)c1oc(C2CC2)nc1-c1ccccc1Cl
Reactant: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: O=C(c1nnn(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1-n1ccnc1)c1oc(C2CC2)nc1-c1ccccc1Cl
Temperature: 80 °C
Yield: 88.3 %

Procedure:
Add imidazole (0.37 g, 5.44 mmol) to a solution of [1-(3,5-bis-trifluoromethyl-benzyl)-5-chloro-1H-[1,2,3]triazol-4-yl]-[4-(2-chloro-phenyl)-2-cyclopropyl-oxazol-5-yl]-methanone (0.16 g, 0.28 mmol) in DMSO (1.0 mL) and heat to 80° C. for 18 h. Dilute reaction mixture with EtOAc and wash with water and brine, then dry, filter, and concentrate. Purify by flash chromatography using a linear gradient of 30% to 70% EtOAc in hexane to give the title compound (0.15 g, 76%). MS (ES) 607.1 (M+H). 1H NMR (400 MHz, CHCl3) δ 7.88 (s, 1H), 7.61 (s, 1H) 7.51 (m, 3H), 7.21–7.33 (m, 4H), 6.92 (s, 1H), 5.43 (s, 2H), 2.20 (m, 1H), 1.17–1.31 (m, 4H).
Reaction SMILES: C(N[C:14](=[O:45])[C:15]1[CH:20]=[C:19]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=2)[C:18]([O:31][CH2:32][CH2:33][OH:34])=[C:17]([C:35]2[CH:40]=[CH:39][CH:38]=[C:37]([C:41]([F:44])([F:43])[F:42])[CH:36]=2)[CH:16]=1)CCCCCCCCCCC.C[N+]1([O-])CC[O:50][CH2:49][CH2:48]1.OS([O-])=O.[Na+].Cl>CC#N.CCC[N+](CCC)(CCC)CCC.[O-][Ru](=O)(=O)=O>[CH2:49]([O:50][C:14](=[O:45])[C:15]1[CH:16]=[C:17]([C:35]2[CH:40]=[CH:39][CH:38]=[C:37]([C:41]([F:44])([F:42])[F:43])[CH:36]=2)[C:18]([O:31][CH2:32][CH2:33][OH:34])=[C:19]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:28])([F:29])[F:30])[CH:22]=2)[CH:20]=1)[CH3:48]
Reactant: CCCCCCCCCCCCNC(=O)c1cc(-c2cccc(C(F)(F)F)c2)c(OCCO)c(-c2cccc(C(F)(F)F)c2)c1
Reactant: C[N+]1([O-])CCOCC1
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: Cl
Solvent: CC#N
Product: CCOC(=O)c1cc(-c2cccc(C(F)(F)F)c2)c(OCCO)c(-c2cccc(C(F)(F)F)c2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 44.6 %

Procedure:
To a solution of N-dodecyl-3,5-bis(m-trifluoromethylphenyl)-4-(2-hydroxyethoxy)benzamide (0.254 g, 0.40 mmol) in CH3CN was added NMO (0.145 g, 0.89 mmol) and TPAP (0.014 g, 0.04 mmol). The reaction was stirred at room temperature overnight. Additional NMO (0.045 g, 0.38 mmol) and TPAP (0.013 g, 0.04 mmol) were required as indicated by TLC. After stirring 48 h, 10% NaHSO3 solution was added and the resulting biphasic mixture was stirred vigorously for 30 min. Conc. HCl (2 mL) was added and stirring was continued for 10 min. The layers were separated and the aqueous layer was extracted with EtOAc. The combined organics were washed with brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by flash chromatography (30% EtOAc:Hexane+1% Formic acid) followed by preparatory plate chromatography (30% EtOAc:Hexane+1% Formic acid) to afford the title compound (0.089 g, 34%) as a white solid. mp 154.3-158.2° C.; 1H NMR (DMSO-d6) δ8.55 (t, 1H); 7.98-7.88 (m, 6H); 7.78-7.67 (m, 4H); 3.57 (s, 2H); 3.25 (m, 2H); 1.50 (m, 2H); 1.23 (m, 18H); 0.82 (t, 3H); IR (KBr) 3275, 2900, 1725, 1600, 1575, 1460, 1325, 1190, 1125, 1075, 775, 725, 700, 625 cm−1; mass spectrum [(−)ESI], m/z 650 (M−H)−; Anal. Calcd. for C35H39F6NO4: C, 64.51; H, 6.03; N, 2.15, Found: C, 62.50; H, 5.99; N, 2.01.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:22][C@@H:23]2[CH2:27][CH2:26][O:25][CH2:24]2)=[C:6]([CH:8]2[CH2:12][CH2:11][CH2:10][N:9]2[C:13]2[CH:14]=[CH:15][C:16]([N+:19]([O-])=O)=[N:17][CH:18]=2)[CH:7]=1>C(O)C.[Ni]>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:22][C@@H:23]2[CH2:27][CH2:26][O:25][CH2:24]2)=[C:6]([CH:8]2[CH2:12][CH2:11][CH2:10][N:9]2[C:13]2[CH:14]=[CH:15][C:16]([NH2:19])=[N:17][CH:18]=2)[CH:7]=1
Reactant: O=[N+]([O-])c1ccc(N2CCCC2c2cc(F)ccc2O[C@@H]2CCOC2)cn1
Agent: [Ni]
Solvent: CCO
Product: Nc1ccc(N2CCCC2c2cc(F)ccc2O[C@@H]2CCOC2)cn1
Reaction time: 0.08 h
Yield: 9.3 %

Procedure:
To a stirred solution of 5-(2-(5-fluoro-2-(((R)-tetrahydrofuran-3-yl)oxy)phenyl)pyrrolidin-1-yl)-2-nitropyridine (2.8 g, 75.06 mmol) in ethanol (28 ml) was cooled to 10° C. and added Raney Ni (560 mg, 20% w/w) portion wise and stirred for 5 min, then added N2H4.2H2O drop wise for the period of 5 min, then stirred for 20 min at room temperature. After completion of reaction, reaction mixture was filter through celite bed under N2 atmosphere and filtrate was concentration under reduced pressure, the residue was re-dissolved in DCM and washed with water, brine and dried over anhydrous Na2SO4 and concentrated in vacuo to get desired product as brown solid (2.4 g, yield: 93.3%), MS (ESI): 344.2 (M+H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:15]1(O)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Oc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 66 %

Procedure:
To a solution of 403 mg (2.0 mmol) of N-tert-butoxycarbonyl-4-hydroxypiperidine, 188 mg (2.0 mmol) of phenol, and 525 mg (2.0 mmol) of triphenylphosphine in 50 mL of THF was added 0.315 mL of diethylazodicarboxylate. The resulting solution was stirred at room temperature for 2 days. Concentration in vacuo and purification via silica gel chromatography (10:1 hexane-EtOAc) provided 366 mg of the title compound as a colorless oil.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[I:12][C:13]1[C:14]([O:23][CH3:24])=[N:15][C:16]([S:21][CH3:22])=[C:17]([CH:20]=1)[C:18]#[N:19].C(OCC)(=O)C>ClCCl>[I:12][C:13]1[C:14]([O:23][CH3:24])=[N:15][C:16]([S:21]([CH3:22])=[O:9])=[C:17]([CH:20]=1)[C:18]#[N:19]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COc1nc(SC)c(C#N)cc1I
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COc1nc(S(C)=O)c(C#N)cc1I
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.8 %

Procedure:
1.42 g (1.1 eq) of 70% 3-chloroperbenzoic acid is added to a solution of 1.6 g (5.23 mmol) of 5-iodo-6-methoxy-2-(methylthio)nicotinonitrile in 20 ml of dichloromethane. The reaction medium is stirred at room temperature for 1 hour. Ethyl acetate is added and the organic phase is washed with saturated sodium bicarbonate solution, dried on magnesium sulfate, filtered and evaporated to yield 1.63 g (97%) of 5-iodo-6-methoxy-2-(methylsulfinyl)nicotinonitrile in the form of a white powder which may also contain 5-iodo-6-methoxy-2-(methylsulfonyl)nicotinonitrile in small proportions (<20%). If necessary, the mixture is used as-is in the following steps.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([CH:14]=[CH:15][CH:16]=2)[C:11](O)=[O:12])=[CH:4][C:3]=1[C:17](=[O:25])[NH:18][C:19]1[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=1.[CH2:26]([NH:28][CH2:29][CH3:30])[CH3:27]>>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:16]=[CH:15][CH:14]=[C:10]([C:11](=[O:12])[N:28]([CH2:29][CH3:30])[CH2:26][CH3:27])[CH:9]=2)=[CH:4][C:3]=1[C:17]([NH:18][C:19]1[CH:20]=[CH:21][N:22]=[CH:23][CH:24]=1)=[O:25]
Reactant: CCNCC
Reactant: Nc1ncc(-c2cccc(C(=O)O)c2)cc1C(=O)Nc1ccncc1
Product: CCN(CC)C(=O)c1cccc(-c2cnc(N)c(C(=O)Nc3ccncc3)c2)c1

Procedure:
Reaction of 3-[6-amino-5-(pyridin-4-ylcarbamoyl)-pyridin-3-yl]-benzoic acid with diethyl amine gives “A98”; method 1: HPLC/MS: 1.37 min, [M+H]=390;
Reaction SMILES: [H-].[Na+].[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[O:13])[CH:10]=2)[CH:5]=[CH:4]1.[CH3:22]I>O1CCCC1>[CH3:22][N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([O:14][CH2:15][C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)=[O:13])[CH:10]=2)[CH:5]=[CH:4]1
Reactant: CI
Reactant: O=C(OCc1ccccc1)c1ccc2cc[nH]c2c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cn1ccc2ccc(C(=O)OCc3ccccc3)cc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.4 %

Procedure:
Sodium hydride (1.03 g of a 60% dispersion in paraffin oil) was added portionwise to a stirred solution of benzyl 1H-indole-6-carboxylate (from (a), 5.4 g, 21.5 mmol) in tetrahydrofuran (80 ml) at 0° C. under a nitrogen atmosphere. The mixture was stirred for 2 h, then methyl iodide (2.04 ml, 32.6 mmol) was added dropwise. The solution was allowed to warm to room temperature over 12 h. The reaction was quenched by the slow addition of ice cold water and the tetrahydrofuran was removed in vacuo. The product was extracted from saturated sodium chloride solution (300 ml) with dichloromethane (2×300 ml) and the organics were dried (MgSO4). The dried organics were filtered through a 5 cm plug of silica in a sintered funnel and concentrated in vacuo to give the subtitle compound as a white solid (5.1 g).
Reaction SMILES: [CH:1]1([B-](F)(F)F)[CH2:3][CH2:2]1.[K+].C12(C(C34CC5CC(CC(C5)C3)C4)CCCP)CC3CC(CC(C3)C1)C2.C([O-])([O-])=O.[Cs+].[Cs+].Cl[C:41]1[CH:46]=[C:45]([N+:47]([O-:49])=[O:48])[CH:44]=[CH:43][N:42]=1>C1(C)C=CC=CC=1.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH:1]1([C:41]2[CH:46]=[C:45]([N+:47]([O-:49])=[O:48])[CH:44]=[CH:43][N:42]=2)[CH2:3][CH2:2]1
Reactant: O=[N+]([O-])c1ccnc(Cl)c1
Reactant: F[B-](F)(F)C1CC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1ccnc(C2CC2)c1
Temperature: 98 °C

Procedure:
To a mixture of potassium cyclopropyltrifluoroborate (0.943 g, 6.37 mmol), palladium (II) acetate (0.0285 g, 0.126 mmol), di-1-adamantylbutylphosphine [CAS 321921-71-5] (0.0678 g, 0.189 mmol) and Cs2CO3 (6.165 g, 18.922 mmol) in toluene (20 ml) and water (4 ml) under a nitrogen atmosphere was added 2-chloro-4-nitropyridine (1 g, 6.307 mmo). The reaction mixture was heated at 98° C. for 2 days. After cooling, the mixture was washed with water. The organic phase was separated and dried (Na2SO4). The filtrate was concentrated in vacuo and the residue was purified by column chromatography (silica gel; Heptane/DCM from 100/0 to 50/50 as eluent). The desired fractions were collected and concentrated in vacuo to yield intermediate compound D52 (0.800 g, 77%) as yellow oil which crystallized upon standing
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[NH:7][CH2:8][CH2:9][N:10]([C:24](=[O:27])[CH:25]=[CH2:26])[CH:11]1[CH2:16][CH2:15][N:14]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:13][CH2:12]1)([CH3:4])([CH3:3])[CH3:2].CC(C)([O-])C.[K+]>CN(C=O)C>[C:1]([O:5][C:6]([N:7]1[CH2:26][CH2:25][C:24](=[O:27])[N:10]([CH:11]2[CH2:16][CH2:15][N:14]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:13][CH2:12]2)[CH2:9][CH2:8]1)=[O:28])([CH3:4])([CH3:2])[CH3:3]
Reactant: C=CC(=O)N(CCNC(=O)OC(C)(C)C)C1CCN(Cc2ccccc2)CC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(=O)N(C2CCN(Cc3ccccc3)CC2)CC1
Reaction time: 2 h
Yield: 75.3 %

Procedure:
To a solution of {2-[Acryloyl-(1-benzyl-piperidin-4-yl)-amino]-ethyl}-carbamic acid tert-butyl ester (4.6 g, 12 mmol) in DMF (40 ml) was added potassium tert-butoxide (0.1 g, 1 mmol) and the reaction stirred for 2 h after which time it was concentrated, the residue dissolved in CH2Cl2, washed with saturated NaHCO3, dried (Na2SO4), and concentrated. The product was isolated by flash column chromatography (CH2Cl2:MeOH 9:1) to afford the title compound (3.5 g, 75%) as a white solid. MS: 388.3 (MH+)
Reaction SMILES: [O:1]=[C:2]1[N:7]2[CH:8]=[C:9]([C:12]([OH:14])=O)[CH:10]=[CH:11][C:6]2=[N:5][C:4]2[S:15][C:16]([CH2:18][CH2:19][CH3:20])=[CH:17][C:3]1=2.C(N1C=CN=C1)(N1C=CN=C1)=O.O.[NH2:34][C:35]1[NH:39][N:38]=[N:37][N:36]=1.Cl[Si](C)(C)C.C(N(CC)CC)C.[N-]1C=CN=C1>CN(C)C=O>[O:1]=[C:2]1[N:7]2[CH:8]=[C:9]([C:12]([NH:34][C:35]3[NH:39][N:38]=[N:37][N:36]=3)=[O:14])[CH:10]=[CH:11][C:6]2=[N:5][C:4]2[S:15][C:16]([CH2:18][CH2:19][CH3:20])=[CH:17][C:3]1=2
Reactant: CCCc1cc2c(=O)n3cc(C(=O)O)ccc3nc2s1
Reactant: Nc1nnn[nH]1
Agent: C[Si](C)(C)Cl
Agent: O=C(n1ccnc1)n1ccnc1
Agent: c1c[n-]cn1
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCCc1cc2c(=O)n3cc(C(=O)Nc4nnn[nH]4)ccc3nc2s1

Procedure:
5.77 g (0.02 mol) of 4-oxo-2-propyl-4H-pyrido[1,2-a]thieno[2,3-d]pyrimidine-7-carboxylic acid (Example 3) and 6.49 g (0.04 mol) of 1,1'carbonyldiimidazole (Aldrich Chemical Company) in 100 ml of dimethylformamide are stirred at 50° C. for one hour. To 2.5 g (0.024 mol) of 5-aminotetrazole monohydrate (Aldrich Chemical Company) in 50 ml of dimethylformamide cooled to 0°-5° C. is added 9.14 ml (0.072 mol) of chlorotrimethylsilane (Aldrich Chemical Company) and 10 ml (0.072 mol) of triethylamine. The mixture is stirred and allowed to reach room temperature. After two hours the mixture is combined with the previous imidazolide mixture and stirred for fourteen hours at room temperature. The resulting precipitate 0.9 g, of 4-oxo-2-propyl-N-1H-tetrazol-5-yl-4H-pyrido[1,2-a]thieno[2,3-d]pyrimidine-7-carboxamide is collected; mp 306°-308° C. (dec) after recrystallization from pyridine.
Reaction SMILES: [CH:1]1([NH:4][C:5]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([O:14][C:15]3[CH:20]=[CH:19][N:18]=[C:17]4[CH:21]=[C:22]([C:24]5[N:25]([CH3:35])[C:26]([CH2:29][NH:30][CH2:31][CH2:32][O:33][CH3:34])=[CH:27][N:28]=5)[S:23][C:16]=34)=[C:10]([F:36])[CH:9]=2)=[O:6])[CH2:3][CH2:2]1.[CH3:37][S:38](Cl)(=[O:40])=[O:39].CCN(C(C)C)C(C)C>C(Cl)Cl.CCOC(C)=O>[CH:1]1([NH:4][C:5](=[O:6])[NH:7][C:8]2[CH:13]=[CH:12][C:11]([O:14][C:15]3[CH:20]=[CH:19][N:18]=[C:17]4[CH:21]=[C:22]([C:24]5[N:25]([CH3:35])[C:26]([CH2:29][N:30]([CH2:31][CH2:32][O:33][CH3:34])[S:38]([CH3:37])(=[O:40])=[O:39])=[CH:27][N:28]=5)[S:23][C:16]=34)=[C:10]([F:36])[CH:9]=2)[CH2:3][CH2:2]1
Reactant: COCCNCc1cnc(-c2cc3nccc(Oc4ccc(NC(=O)NC5CC5)cc4F)c3s2)n1C
Reactant: CS(=O)(=O)Cl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COCCN(Cc1cnc(-c2cc3nccc(Oc4ccc(NC(=O)NC5CC5)cc4F)c3s2)n1C)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 48.5 %

Procedure:
To a suspension of the amine 348 (61 mg, 0.119 mmol) in DCM (5 ml) was added methanesulfonyl chloride (20.53 mg, 1.5 eq, 0.179 mmol) and iPr2NEt (46.3 mg, 3 eq, 0.358 mmol) and the reaction mixture was stirred at RT for 3 hours. The mixture was diluted with EtOAc then washed with saturated NH4Cl solution, saturated NaHCO3 solution and brine. The organic phase was collected, dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography (eluent 25% MeOH in EtOAc) to afford the desired compound 349 as a pale yellow solid (34 mg, 48%). 1H NMR (d6 DMSO) 8.27 (s, 1H), 8.10 (d, J=5.48 Hz, 1H), 7.53 (s, 1H), 7.25 (m, 1H), 6.95 (t, J=9.0 Hz, 1H), 6.76 (m, 1H), 6.71 (s, 1H), 6.24 (d, J=5.48 Hz, 1H), 6.14 (s, 1H), 4.06 (s, 2H), 3.49 (s, 3H), 2.72 (s, 3H), 2.63 (s, 3H), 2.12 (m, 3H), 0.23 (m, 2H), 0.00 (s, 2H).
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[CH:10][C:9]([C:12](=[O:28])[CH2:13][C:14]([C:20]3[CH:25]=[C:24]([Cl:26])[CH:23]=[C:22]([Cl:27])[CH:21]=3)(O)[C:15]([F:18])([F:17])[F:16])=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.S(Cl)(Cl)=O.N1C=CC=CC=1.Cl>O.C1(C)C=CC=CC=1>[N:1]1([C:6]2[CH:7]=[CH:8][C:9]([C:12](=[O:28])[CH:13]=[C:14]([C:20]3[CH:25]=[C:24]([Cl:26])[CH:23]=[C:22]([Cl:27])[CH:21]=3)[C:15]([F:17])([F:18])[F:16])=[CH:10][CH:11]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: O=C(CC(O)(c1cc(Cl)cc(Cl)c1)C(F)(F)F)c1ccc(-n2ccnc2)cc1
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Solvent: O=S(Cl)Cl
Product: O=C(C=C(c1cc(Cl)cc(Cl)c1)C(F)(F)F)c1ccc(-n2ccnc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 81.5 %

Procedure:
After adding 2.69 g of toluene to 0.90 g (2.09 mmol) of 1-(4-(1H-imidazol-1-yl)phenyl)-3-(3,5-dichlorophenyl)-4,4,4-trifluoro-3-hydroxybutan-1-one, 0.50 g (4.19 mmol) of thionyl chloride and 0.33 g (4.19 mmol) of pyridine were added at 80° C., and stirred for 1 hour. The reaction solution was cooled to room temperature, and separated by adding 35 ml of chloroform and 20 ml of water. After washing the organic phase with an aqueous solution of 0.37 g of sodium hydroxide dissolved into 2.0 g of water, the organic phase was washed with an aqueous solution prepared by 0.44 g (4.19 mmol) of 35% hydrochloric acid and 20 ml of water, and then washed with water. The solvent was distilled off under reduced pressure to obtain 0.70 g of 1-(4-(1H-imidazol-1-yl)phenyl)-3-(3,5-dichlorophenyl)-4,4,4-trifluoro-2-buten-1-one (yield 81.7%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([O:17][CH2:18][CH2:19][OH:20])=[N:10][CH:11]=[C:12]([CH:16]=2)[C:13]([OH:15])=O)=[CH:4][CH:3]=1.[F:21][C:22]([F:31])([F:30])[C:23]1[N:27]=[C:26]([CH2:28][NH2:29])[O:25][N:24]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:9]([O:17][CH2:18][CH2:19][OH:20])=[N:10][CH:11]=[C:12]([CH:16]=2)[C:13]([NH:29][CH2:28][C:26]2[O:25][N:24]=[C:23]([C:22]([F:31])([F:30])[F:21])[N:27]=2)=[O:15])=[CH:6][CH:7]=1
Reactant: NCc1nc(C(F)(F)F)no1
Reactant: O=C(O)c1cnc(OCCO)c(-c2ccc(Cl)cc2)c1
Product: O=C(NCc1nc(C(F)(F)F)no1)c1cnc(OCCO)c(-c2ccc(Cl)cc2)c1

Procedure:
The title compound was synthesized in analogy to Example 1 using 5-(4-chlorophenyl)-6-(2-hydroxyethoxy)nicotinic acid (example CI) and 3-trifluoromethyl-[1,2,4]oxadiazol-5-methanamine (example AK) as starting materials; LC-MS (UV peak area/ESI) 100.0%, 443.1 (M+H)+.
Reaction SMILES: [CH:1]([O:4][CH2:5][CH2:6][CH2:7][NH2:8])([CH3:3])[CH3:2].[C:9]([N:12]1[C:21]2[C:16](=[CH:17][C:18]([C:22](O)=[O:23])=[CH:19][CH:20]=2)[C:15]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)([CH3:25])[CH2:14][C:13]1([CH3:33])[CH3:32])(=[O:11])[CH3:10].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>ClCCl>[C:9]([N:12]1[C:21]2[C:16](=[CH:17][C:18]([C:22]([NH:8][CH2:7][CH2:6][CH2:5][O:4][CH:1]([CH3:3])[CH3:2])=[O:23])=[CH:19][CH:20]=2)[C:15]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)([CH3:25])[CH2:14][C:13]1([CH3:33])[CH3:32])(=[O:11])[CH3:10]
Reactant: CC(C)OCCCN
Reactant: CC(=O)N1c2ccc(C(=O)O)cc2C(C)(c2ccccc2)CC1(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)N1c2ccc(C(=O)NCCCOC(C)C)cc2C(C)(c2ccccc2)CC1(C)C

Procedure:
Condensation of 3-isopropoxypropylamine (5.2 mg) with 1-acetyl-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline-6-carboxylic acid (10 mg), under the agency of HATU (23 mg) and N,N-diisopropylethylamine (19 μl) in dichloromethane (2 ml) was performed according to the method described in example 11.