Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([CH:7]=O)=[CH:4][CH:3]=1.[OH-].[Na+].Cl.[N+:12]([CH3:15])([O-:14])=[O:13]>>[CH3:1][C:2]1[O:6][C:5]([CH:7]=[CH:15][N+:12]([O-:14])=[O:13])=[CH:4][CH:3]=1
Reactant: C[N+](=O)[O-]
Reactant: Cc1ccc(C=O)o1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Cc1ccc(C=C[N+](=O)[O-])o1
Temperature: 0 °C
Yield: 57.5 %

Procedure:
5-Methyl-2-furaldehyde (2.75 g) was gradually added by dropping, with stirring under ice cooling, to a solution prepared by dropping 3.05 g of nitromethane into 50 mL of an ice-cooled 20% aqueous solution of sodium hydroxide. After completion of the addition, the mixture was vigorously stirred for 10 minutes more to finish the reaction and the reaction solution was slowly poured over 60 mL of an ice-cooled 6N hydrochloric acid. The mixed solution was stirred for 10 minutes and the resulting separated crystals were filtered, washed with water and dried to give 2.20 g of the objective compound as yellow powder.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]=[CH:7][N:8]=[C:9]([NH:12][CH:13]3[CH2:18][CH2:17]O[CH2:15][CH2:14]3)[C:10]=2[N:11]=1.[Cl:19][C:20]1[C:25]([NH:26][S:27]([C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][C:31]=2[F:37])(=[O:29])=[O:28])=[CH:24][C:23](B2OC(C)(C)C(C)(C)O2)=[CH:22][N:21]=1.C(=O)(O)[O-].[Na+]>O1CCOCC1>[Cl:19][C:20]1[C:25]([NH:26][S:27]([C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][C:31]=2[F:37])(=[O:29])=[O:28])=[CH:24][C:23]([C:2]2[CH:3]=[CH:4][C:5]3[N:6]=[CH:7][N:8]=[C:9]([NH:12][CH:13]4[CH2:18][CH2:17][CH2:15][CH2:14]4)[C:10]=3[N:11]=2)=[CH:22][N:21]=1
Reactant: Clc1ccc2ncnc(NC3CCOCC3)c2n1
Reactant: CC1(C)OB(c2cnc(Cl)c(NS(=O)(=O)c3ccc(F)cc3F)c2)OC1(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: O=S(=O)(Nc1cc(-c2ccc3ncnc(NC4CCCC4)c3n2)cnc1Cl)c1ccc(F)cc1F
Temperature: 25 °C
Yield: 51.4 %

Procedure:
A mixture of 6-chloro-N-(tetrahydro-2H-pyran-4-yl)pyrido[3,2-d]pyrimidin-4-amine (Intermediate 18) (0.043 g, 0.173 mmol), N-(2-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-3-yl)-2,4-difluorobenzenesulfonamide (Intermediate 3) (0.089 g, 0.207 mmol), PdCl2(dppf)-CH2Cl2Adduct (1.41 mg, 1.73 μmol) and 1 N aq. sodium bicarbonate (0.346 ml, 0.346 mmol) in dioxane (0.864 ml) subjected to microwave irradiation for 1 hour at 110° C. After cooling to room temperature, the reaction mixture was filtered through Celite and washed with CH2Cl2. The filtrate was concentrated in vacuo. The residue was purified by column chromatography on SiO2 (Hex:EtOAc=1:1) to give N-(2-chloro-5-(4-(cyclo pentyl amino)pyrido[3,2-d]pyrimidin-6-yl)pyridin-3-yl)-2,4-difluorobenzenesulfonamide (0.046 g, 52%) as a white solid. 1H-NMR (CDCl3, Varian 400 MHz) δ 1.65-1.89 (6H, m), 2.18-2.25 (2H, m), 4.61-4.66 (1H, m), 6.93-7.01 (2H, m), 7.22 (1H, d, J=7.6 Hz), 7.85-7.90 (1H, m), 8.07 (1H, d, J=8.8 Hz), 8.21 (1H, d, J=8.8 Hz), 8.66 (1H, s), 8.74 (1H, d, J=2.0 Hz), 8.82 (1H, d, J=2.0 Hz). m/z=517.2 [M+1]+.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8]([C:13]([NH:15][CH2:16][C:17]1[CH:18]=[C:19]([CH2:23][NH:24]C(=O)OC(C)(C)C)[CH:20]=[CH:21][CH:22]=1)=[O:14])[NH:7][C:6]2=[O:32])#[N:2].[ClH:33].C(OCC)(=O)C>C(OCC)(=O)C>[ClH:33].[NH2:24][CH2:23][C:19]1[CH:18]=[C:17]([CH2:16][NH:15][C:13]([C:8]2[NH:7][C:6](=[O:32])[C:5]3[C:10](=[CH:11][CH:12]=[C:3]([C:1]#[N:2])[CH:4]=3)[N:9]=2)=[O:14])[CH:22]=[CH:21][CH:20]=1
Reactant: CC(C)(C)OC(=O)NCc1cccc(CNC(=O)c2nc3ccc(C#N)cc3c(=O)[nH]2)c1
Agent: Cl
Solvent: CCOC(C)=O
Product: N#Cc1ccc2nc(C(=O)NCc3cccc(CN)c3)[nH]c(=O)c2c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 99 %

Procedure:
To a suspension of 1,1-dimethylethyl {[3-({[(6-cyano-4-oxo-3,4-dihydroquinazolin-2-yl)carbonyl]amino}methyl)phenyl]methyl}carbamate obtained in Reference Example 46 (2.14 g, 4.94 mmol) in ethyl acetate (5 mL) was added 4N hydrogen chloride/ethyl acetate (60 mL), and the mixture was stirred at room temperature for 15 hr. The reaction mixture was concentrated under reduced pressure, and the residue was crystallized from toluene. The obtained crude crystals were suspended in ethyl acetate, and the suspension was stirred under heating for 3 hr to give the title compound as a white powder (1.86 g, 99%).
Reaction SMILES: [F:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[C:4]([F:9])[C:3]=1[CH:10]([O:12][C:13]1[CH:19]=[CH:18][C:16]([NH2:17])=[CH:15][CH:14]=1)[CH3:11].[S-:20][C:21]#[N:22].[K+].BrBr>>[F:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[C:4]([F:9])[C:3]=1[CH:10]([O:12][C:13]1[CH:14]=[CH:15][C:16]2[N:17]=[C:21]([NH2:22])[S:20][C:18]=2[CH:19]=1)[CH3:11]
Reactant: N#C[S-]
Reactant: Cc1ccc(F)c(C(C)Oc2ccc(N)cc2)c1F
Agent: BrBr
Agent: [K+]
Product: Cc1ccc(F)c(C(C)Oc2ccc3nc(N)sc3c2)c1F
Yield: 98.6 %

Procedure:
6-[1-(2,6-Difluoro-3-methylphenyl)ethoxy]-1,3-benzothiazol-2-amine was prepared according to the method described in Example 20d but from 3.5 g of 4-[1-(2,6-difluoro-3-methylphenyl)ethoxy]aniline, 5.2 g of potassium thiocyanate and 0.681 cm3 of dibromine. We obtain 4.2 g of 6-[1-(2,6-difluoro-3-methylphenyl)ethoxy]-1,3-benzothiazol-2-amine in the form of a brown-coloured solid, which has the following characteristics:
Reaction SMILES: [CH:1]1([C:7]2([C:20]([OH:22])=O)[CH2:13][CH:12]3[N:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:9]([CH2:10][CH2:11]3)[CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)(=O)C(Cl)=O.[C:29]([NH2:33])([CH3:32])([CH3:31])[CH3:30]>C(Cl)(Cl)Cl.CN(C=O)C>[C:29]([NH:33][C:20]([C:7]1([CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[CH2:13][CH:12]2[N:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:9]([CH2:10][CH2:11]2)[CH2:8]1)=[O:22])([CH3:32])([CH3:31])[CH3:30]
Reactant: CC(C)(C)N
Reactant: CCOC(=O)N1C2CCC1CC(C(=O)O)(C1CCCCC1)C2
Agent: O=C(Cl)C(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: CCOC(=O)N1C2CCC1CC(C(=O)NC(C)(C)C)(C1CCCCC1)C2
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
To a solution of 3-cyclohexyl-8-(ethoxycarbonyl)-8-azabicyclo[3.2.1]octane-3-carboxylic acid (1-7) (1.50 g, 4.85 mmol) in CHCl3 (60.0 mL) was slowly added oxalyl chloride (2.67 mL, 5.33 mmol, 2.0 N), followed by addition of DMF (3 drops) as a catalyst. After the bubbling ceased, the mixture was stirred for 30 min and the solvents were removed under vacuum. To the mixture was added t-BuNH2 (5.32 g, 72.7 mmol) and the resulting suspension was warmed up to 80° C. overnight. The solvents were removed under vacuum; the reaction was quenched with 1 N HCl, and then extracted with EtOAc (3×100 mL). The combined organic layers were washed with brine, dried over anhydrous MgSO4, and concentrated to give a crude residue. Purification of the crude residue by flash chromatography over silica gel (10% ethyl acetate/hexanes as eluent) afforded (1-8) as a white solid.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:21]=4[O:28][CH2:29][CH2:30][O:31][CH3:32])[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1.Cl[C:34]([CH2:36][O:37]C(=O)C)=[O:35]>>[OH:37][CH2:36][C:34]([NH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:21]=4[O:28][CH2:29][CH2:30][O:31][CH3:32])[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1)=[O:35]
Reactant: CC(=O)OCC(=O)Cl
Reactant: COCCOc1cc(OC)ccc1-c1ncnc2c(C(=O)N[C@H]3CC[C@H](N)CC3)c[nH]c12
Product: COCCOc1cc(OC)ccc1-c1ncnc2c(C(=O)N[C@H]3CC[C@H](NC(=O)CO)CC3)c[nH]c12

Procedure:
Starting from trans-4-[4-methoxy-2-(2-methoxy-ethoxy)-phenyl]-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (4-amino-cyclohexyl)-amide (example A182) and acetic acid chlorocarbonyl-methyl ester the title compound was obtained as colorless solid.
Reaction SMILES: [H-].[Na+].[C:3](Cl)(=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[N:12]1([C:18]2[N:19]=[C:20]3[NH:28][C@H:27]([C:29]([F:32])([F:31])[F:30])[CH2:26][CH2:25][N:21]3[C:22](=[O:24])[CH:23]=2)[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1.C(=O)(O)[O-].[Na+]>O1CCCC1.C(OCC)(=O)C>[C:3]([N:28]1[C:20]2=[N:19][C:18]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)=[CH:23][C:22](=[O:24])[N:21]2[CH2:25][CH2:26][C@H:27]1[C:29]([F:30])([F:31])[F:32])(=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=c1cc(N2CCOCC2)nc2n1CC[C@@H](C(F)(F)F)N2
Reactant: O=C(Cl)c1ccccc1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C(c1ccccc1)N1c2nc(N3CCOCC3)cc(=O)n2CC[C@H]1C(F)(F)F
Temperature: 25 °C
Reaction time: 6 h

Procedure:
35.7 mg of sodium hydride and then, after 10 minutes of stirring, 0.135 ml de of benzoyl chloride are added, under an argon atmosphere, to a solution of 300 mg of (S)-2-morpholin-4-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one (Example 1e) in 3 ml of tetrahydrofuran. After stirring for six hours at ambient temperature, a saturated solution of sodium bicarbonate and ethyl acetate are added to the reaction mixture. The organic phase is separated and then successively washed with a saturated solution of sodium chloride, dried over magnesium sulphate, filtered and concentrated under reduced pressure. The residue obtained is purified by silica chromatography (eluent: CH2Cl2) so as to give 74 mg of (S)-9-benzoyl-2-morpholin-4-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one, in the form of a white solid, the characteristics of which are the following:
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][C:11]([OH:13])=O)=[CH:2]1.[CH:14]1([N:20]([CH3:24])[CH2:21][CH2:22][NH2:23])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1>>[CH:14]1([N:20]([CH3:24])[CH2:21][CH2:22][NH:23][C:11](=[O:13])[CH2:10][C:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[NH:1][CH:2]=2)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: CN(CCN)C1CCCCC1
Reactant: O=C(O)Cc1c[nH]c2ccccc12
Product: CN(CCNC(=O)Cc1c[nH]c2ccccc12)C1CCCCC1

Procedure:
Compound 11a was prepared using the amino acid coupling procedure described in Example 10 using (1H-indol-3-yl)-acetic acid and N1-Cyclohexyl-N1-methyl-ethane-1,2-diamine as the starting materials: LC-MS (Method B, retention time=0.516 min. MS calc'd for C19H28N3O (MH+): 314.2. Found 314.5.
Reaction SMILES: [C:1]([C:3]1[CH:12]=[CH:11][C:10](F)=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6])#[N:2].[Br:14][C:15]1[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][C:16]=1[CH:17]=[O:18].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Br:14][C:15]1[CH:22]=[CH:21][C:20]([O:23][C:10]2[CH:11]=[CH:12][C:3]([C:1]#[N:2])=[C:4]([CH:9]=2)[C:5]([O:7][CH3:8])=[O:6])=[CH:19][C:16]=1[CH:17]=[O:18]
Reactant: COC(=O)c1cc(F)ccc1C#N
Reactant: O=Cc1cc(O)ccc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cc(Oc2ccc(Br)c(C=O)c2)ccc1C#N
Temperature: 80 °C
Reaction time: 8 h
Yield: 59.4 %

Procedure:
A mixture of methyl 2-cyano-5-fluorobenzoate (4.48 g, 25.0 mmol), 2-bromo-5-hydroxybenzaldehyde (5.03 g, 25.0 mmol), and potassium carbonate (4.14 g, 30.0 mmol) in N,N-dimethylformamide (50 mL) was stirred at 80° C. overnight. Water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried on anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue was purified by silica gel chromatography (chloroform) to give methyl 5-(4-bromo-3-formylphenoxy)-2-cyanobenzoate (5.35 g, 71%).
Reaction SMILES: [C:1]1(=[O:14])[O:13][CH:4]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[CH2:3][CH2:2]1.[CH:15]([C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH:24]([CH3:26])[CH3:25])[C:19]=1[N:27]=[C:28]=[O:29])([CH3:17])[CH3:16].C([N-]C(C)C)(C)C.[Li+]>>[CH3:17][CH:15]([C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH:24]([CH3:25])[CH3:26])[C:19]=1[NH:27][C:28]([CH:2]1[CH2:3][CH2:4][CH:5]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[O:13][C:1]1=[O:14])=[O:29])[CH3:16]
Reactant: CC(C)c1cccc(C(C)C)c1N=C=O
Reactant: CCCCCCCCC1CCC(=O)O1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Product: CCCCCCCC1CCC(C(=O)Nc2c(C(C)C)cccc2C(C)C)C(=O)O1

Procedure:
The title compound was prepared from (±)-δ-dodecanolactone (5.0 g, 0.025 mol), 2,6-diisopropylphenyl isocyanate (5.12 g, 0.025 mol), and lithium diisopropylamide (0.025 mol) using the procedure described in Example 1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[NH:8][CH:9]=[CH:10][C:3]=12.C1N2CN3CN(C2)CN1C3.[C:21](O)(=[O:23])C>>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[NH:8][CH:9]=[C:10]([CH:21]=[O:23])[C:3]=12
Reactant: Clc1ccnc2[nH]ccc12
Reactant: CC(=O)O
Agent: C1N2CN3CN1CN(C2)C3
Product: O=Cc1c[nH]c2nccc(Cl)c12
Temperature: 100 °C

Procedure:
A mixture of 4-chloro-1H-pyrrolo[2,3-b]pyridine (15 g, 98 mmol) and hexamethylenetetramine (25.00 g, 178 mmol) in aqueous acetic acid (33%, 15 mL) was heated at 100° C. overnight. After cooling, the mixture was poured into ice-water and stirred for several minutes. The solid material was collected by filtration, washed with water, and dried in vacuo to provide the title compound. MS (ESI+) m/z 181 (M+H)+.
Reaction SMILES: C([O:3][C:4]([C@@H:6]1[CH2:11][CH2:10][CH2:9][N:8]([CH2:12][CH2:13][O:14]/[CH:15]=[C:16](/[C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[CH:25]=2)\[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[CH3:23])[CH2:7]1)=[O:5])C.[OH-].[Na+].Cl.[Cl:34]CCl>C(O)C>[ClH:34].[F:30][C:26]1[CH:25]=[C:24](/[C:16](/[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[CH3:23])=[CH:15]/[O:14][CH2:13][CH2:12][N:8]2[CH2:9][CH2:10][CH2:11][C@@H:6]([C:4]([OH:5])=[O:3])[CH2:7]2)[CH:29]=[CH:28][CH:27]=1
Reactant: CCOC(=O)[C@@H]1CCCN(CCO/C=C(/c2cccc(F)c2)c2ccccc2C)C1
Reactant: ClCCl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1ccccc1/C(=C\OCCN1CCC[C@@H](C(=O)O)C1)c1cccc(F)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 24 %

Procedure:
E or Z-(R)-1-[2-[[2-(3-Fluorophenyl)-2-(2-methylphenyl)-ethenyl] oxy]ethyl]-3-piperidine carboxylic acid ethyl ester (0.40 g, 0.00097 mol) (prepared as described in Method A) was dissolved in ethanol (5 ml) and 12 N sodium hydroxide solution (0.3 ml) was introduced. After stirring the solution at room temperature for 5 h, 37% hydrochloric acid solution was added until the pH was measured as ca. 1. Dichloromethane (250 ml) was introduced, and the resultant precipitate was dissolved by addition of ice portionwise with vigorous stirring. The organic phase was separated, dried (Na ) and evaporated to a residue, which was co-evaporated with acetone. Recrystallization from acetone provided the title compound (0.10 g, 24%) as a white solid, m.p. 193°-195°.
Reaction SMILES: [N:1]1([CH2:10][CH2:11][C:12]([OH:14])=O)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.[C:15]([C:19]1[CH:25]=[CH:24][C:22]([NH2:23])=[CH:21][CH:20]=1)([CH3:18])([CH3:17])[CH3:16]>>[N:1]1([CH2:10][CH2:11][C:12]([NH:23][C:22]2[CH:24]=[CH:25][C:19]([C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:20][CH:21]=2)=[O:14])[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: CC(C)(C)c1ccc(N)cc1
Reactant: O=C(O)CCn1cnc2ccccc21
Product: CC(C)(C)c1ccc(NC(=O)CCn2cnc3ccccc32)cc1

Procedure:
Part C. The title compound was synthesized according to a procedure described in Example 98 starting from 3-benzoimidazol-1-yl-propanoic acid and 4-tert-butyl-aniline. Calculated for C16H23N3O m/z: 321.18, found 322.1 [M+H]+.
Reaction SMILES: Br[C:2]1[C:10]2[NH:9][C:8]3[CH:11]4[CH2:17][CH2:16][N:14]([CH2:15][C:7]=3[C:6]=2[CH:5]=[CH:4][CH:3]=1)[CH2:13][CH2:12]4.[C:18]1(/[CH:24]=[CH:25]/B(O)O)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[C:18]1(/[CH:24]=[CH:25]/[C:2]2[C:10]3[NH:9][C:8]4[CH:11]5[CH2:17][CH2:16][N:14]([CH2:15][C:7]=4[C:6]=3[CH:5]=[CH:4][CH:3]=2)[CH2:13][CH2:12]5)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: OB(O)/C=C/c1ccccc1
Reactant: Brc1cccc2c3c([nH]c12)C1CCN(CC1)C3
Product: C(=C/c1cccc2c3c([nH]c12)C1CCN(CC1)C3)\c1ccccc1

Procedure:
The product of Example 1B (100 mg, 0.34 mmol) and (E)-phenylethenylboronic acid (56 mg, 0.38 mmol; Aldrich) were processed as described in Example 4 to provide the title compound: 1H NMR (400 MHz, methanol-d4) δ ppm 2.03-2.18 (m, 4 H), 3.04-3.13 (m, 2 H), 3.13-3.18 (m, 1 H), 3.21-3.28 (m, 2 H), 4.24 (s, 2 H), 7.01 (t, J=7.6 Hz, 1 H), 7.19-7.28 (m, 3 H), 7.32-7.41 (m, 3 H), 7.60 (d, J=12.2 Hz, 1 H), 7.62-7.65 (m, 2 H); MS (DCI) m/z 315 (M+H)+.
Reaction SMILES: [C:1]([O:4][C:5]1[C:6](=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:7](Cl)=[O:8])(=[O:3])[CH3:2].[OH2:14]>C1(C)C=CC=CC=1>[C:1]([O:4][C:5]1[CH:13]=[CH:12][CH:11]=[CH:10][C:6]=1[C:7]([OH:14])=[O:8])(=[O:3])[CH3:2]
Reactant: O
Reactant: CC(=O)Oc1ccccc1C(=O)Cl
Solvent: Cc1ccccc1
Product: CC(=O)Oc1ccccc1C(=O)O
Temperature: 7.5 °C
Yield: 80 %

Procedure:
To the so obtained solution, a solution of the acetylsalicylic acid chloride (16 g, 0.08 moles) in toluene (50 ml) is added under stirring at the temperature of 5-10° C. The mixture is maintained at a temperature within the above range, under stirring for 2 hours, then poured into water and then extracted with dichloromethane (2×100 ml). The organic phase is separated, washed in sequence with a solution of potassium carbonate at 25% w/v, with water, with a 3% hydrochloric acid solution and finally again with water, then anhydrified with sodium sulphate and the solvent evaporated under reduced pressure. The residue is crystallized from isopropanol. 3-hydroxymethyl phenyl ester of the 2-acetoxybenzoic acid (45.8 g, 0.16 moles, yield 80%) is obtained.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])[C:11]([C:20]([F:23])([F:22])[F:21])=[CH:10][C:9]=1[NH:24][C:25](=[O:41])[CH2:26][C:27](=O)[C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([C:34]2[CH:39]=[CH:38][N:37]=[CH:36][CH:35]=2)[CH:29]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[N:37]1[CH:36]=[CH:35][C:34]([C:30]2[CH:29]=[C:28]([C:27]3[CH2:26][C:25](=[O:41])[NH:24][C:9]4[CH:10]=[C:11]([C:20]([F:23])([F:21])[F:22])[C:12]([O:14][CH2:15][C:16]([F:19])([F:17])[F:18])=[CH:13][C:8]=4[N:7]=3)[CH:33]=[CH:32][CH:31]=2)=[CH:39][CH:38]=1
Reactant: CC(C)(C)OC(=O)Nc1cc(OCC(F)(F)F)c(C(F)(F)F)cc1NC(=O)CC(=O)c1cccc(-c2ccncc2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1CC(c2cccc(-c3ccncc3)c2)=Nc2cc(OCC(F)(F)F)c(C(F)(F)F)cc2N1

Procedure:
The title compound was prepared from [2-[3-oxo-3-(3-pyridin-4-yl-phenyl)-propionylamino]-5-(2,2,2-trifluoro-ethoxy)-4-trifluoromethyl-phenyl]-carbamic acid tert-butyl ester (Example M33) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light yellow solid (175 mg).
Reaction SMILES: CON(C)[C:4]([C:6]1[C:7]([NH2:15])=[N:8][C:9]([S:12][CH2:13][CH3:14])=[N:10][CH:11]=1)=[O:5].Br[C:18]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=1[CH3:25]>>[NH2:15][C:7]1[C:6]([C:4]([C:18]2[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=2[CH3:25])=[O:5])=[CH:11][N:10]=[C:9]([S:12][CH2:13][CH3:14])[N:8]=1
Reactant: Cc1ccc(F)cc1Br
Reactant: CCSc1ncc(C(=O)N(C)OC)c(N)n1
Product: CCSc1ncc(C(=O)c2cc(F)ccc2C)c(N)n1

Procedure:
The compound was prepared from 4-amino-2-ethylsulfanyl-pyrimidine-5-carboxylic acid methoxy-methyl-amide, Example 1, and 2-bromo-4-fluorotoluene (Aldrich) in an analogous manner as described in Example 169.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:8]([F:11])([F:10])[F:9])=[N:6][CH:7]=1.[CH:12]([Sn](CCCC)(CCCC)CCCC)=[CH2:13]>CN(C=O)C.C1COCC1>[F:9][C:8]([F:11])([F:10])[C:5]1[CH:4]=[CH:3][C:2]([CH:12]=[CH2:13])=[CH:7][N:6]=1
Reactant: FC(F)(F)c1ccc(Br)cn1
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: C=Cc1ccc(C(F)(F)F)nc1
Temperature: 100 °C
Yield: 1324.9 %

Procedure:
2 g of 5-bromo-2-(trifluoromethyl)pyridine was dissolved in DMF:THF (3:1, 12 mL). vinyltributyltin (3 g) and tetrakis (triphenylphosphine)palladium (135 mg) were added to this solution. The reaction mixture was degassed and purged with nitrogen for 5 min and then heated at 100° C. for 2 h. at which point the reaction was found complete (monitored by TLC). The reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layer was dried over anhydrous sodium sulfate and evaporated under reduced pressure (Caution: product may be volatile) and the residue was purified by SiO2 chromatography (100-200 mesh, eluent: hexane-ethyl acetate gradient). The requisite fractions were concentrated below 40° C. under reduced pressure to obtain 20.3 g of 2-(trifluoromethyl)-5-vinylpyridine as oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[Cl:11])[C:5](Cl)=[O:6].[CH2:12]([NH:19][C:20]([C:22]1[S:26][C:25]([NH2:27])=[N:24][C:23]=1[CH3:28])=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[CH2:12]([NH:19][C:20]([C:22]1[S:26][C:25]([NH:27][C:5](=[O:6])[C:4]2[CH:8]=[CH:9][C:10]([Cl:11])=[C:2]([Cl:1])[CH:3]=2)=[N:24][C:23]=1[CH3:28])=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Cc1nc(N)sc1C(=O)NCc1ccccc1
Reactant: O=C(Cl)c1ccc(Cl)c(Cl)c1
Product: Cc1nc(NC(=O)c2ccc(Cl)c(Cl)c2)sc1C(=O)NCc1ccccc1
Yield: 15 %

Procedure:
Following the procedure as described in Example 2, making variations only as required to use 3,4-dichlorobenzoyl chloride in place of benzoyl chloride to react with 2-amino-4-methylthiazole-5-carboxylic acid benzylamide, the title compound was obtained as a white solid in 15% yield; m.p. 212-214° C.; 1H NMR (CD3OD, 300 MHz) δ 8.21 (d, J=2.0 Hz, 1H), 7.93 (dd, J=2.0, 8.4 Hz, 1H), 7.68 (d, J=8.4 Hz, 1H), 7.33-7.23 (m, 5H), 4.50 (s, 2H), 2.54 (s, 3H); MS (ES+) m/z 420.0 (M+1).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[S:6](Cl)(=[O:8])=[O:7].[CH2:10]([N:17]1[CH2:24][CH:23]2[C:25]([CH3:27])([CH3:26])[CH:19]([CH2:20][NH:21][CH2:22]2)[CH2:18]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>ClCCl>[CH2:10]([N:17]1[CH2:18][CH:19]2[C:25]([CH3:27])([CH3:26])[CH:23]([CH2:22][N:21]([S:6]([C:2]3[S:1][CH:5]=[CH:4][CH:3]=3)(=[O:8])=[O:7])[CH2:20]2)[CH2:24]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=S(=O)(Cl)c1cccs1
Reactant: CC1(C)C2CNCC1CN(Cc1ccccc1)C2
Solvent: ClCCl
Product: CC1(C)C2CN(Cc3ccccc3)CC1CN(S(=O)(=O)c1cccs1)C2
Temperature: 25 °C
Reaction time: 3 h
Yield: 73.2 %

Procedure:
A solution of 2.87 g (=0.015 mol) thiophene-2-sulfonyl chloride in 20 ml dichloromethane was added dropwise with ice cooling to a solution of 3.5 g (=0.014 mol) 7-benzyl-9,9-dimethyl-3,7-diazabicyclo[3,3,1]nonane (=substance No. C8 in the following Table C) in 40 ml dichloromethane. Then the ice bath was removed and the reaction mixture stirred further for 3 hours at room temperature. The reaction mixture was then made alkaline by adding aqueous sodium hydroxide solution, the aqueous phase was separated and extracted twice with dichloromethane. The combined dichloromethane phases were dried over magnesium sulfate and the solvent was evaporated. 4.0 g of the title compound (base) were thereby obtained as an oil.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:10])[CH3:9].[CH3:11][C:12]([CH3:14])=O.N1CCCC1>CO>[CH3:11][C:12]1([CH3:14])[CH2:9][C:8](=[O:10])[C:3]2[C:2](=[CH:7][CH:6]=[CH:5][CH:4]=2)[O:1]1
Reactant: CC(C)=O
Reactant: CC(=O)c1ccccc1O
Solvent: CO
Solvent: C1CCNC1
Product: CC1(C)CC(=O)c2ccccc2O1

Procedure:
A solution of 2′-hydroxyacetophenone (5.0 mL), acetone (4.7 mL), and pyrrolidine (5.4 mL) in 150 mL of methanol was stirred for 66 hours. The mixture was concentrated and treated with aqueous HCl (pH<1). The acidic layer was extracted twice with ethyl ether, which was dried and concentrated to provide 2,2-dimethylchroman-4-one. The 2,2-dimethylchroman-4-one was dissolved in 300 mL of methanol and treated with ammonium acetate (65 g) and sodium cyanoborohydride (2.5 g) for 24 hours. The resulting mixture was concentrated to 100 mL and diluted with 300 mL water. Concentrated HCl was carefully added until the pH was less than 1 and the acidic mixture was extracted with ethyl ether. The acidic phase was made basic with KOH and then extracted twice with ethyl ether. The basic extracts were dried and concentrated to provide the title compound.