Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[C:7]([CH2:14][S:15][CH3:16])[C:6]=1F)(=[O:4])=[O:3].[CH3:18][O:19][CH2:20][CH2:21][NH2:22].Cl>O>[CH3:1][S:2]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[C:7]([CH2:14][S:15][CH3:16])[C:6]=1[NH:22][CH2:21][CH2:20][O:19][CH3:18])(=[O:4])=[O:3]
Reactant: COCCN
Reactant: CSCc1c(C(=O)O)ccc(S(C)(=O)=O)c1F
Agent: Cl
Solvent: O
Product: COCCNc1c(S(C)(=O)=O)ccc(C(=O)O)c1CSC

Procedure:
2 g (7.2 mmol) of 4-methylsulfonyl-3-fluoro-2-methylthiomethylbenzoic acid were refluxed in 20 g (0.266 mol) of a 60% strength 2-methoxyethylamine solution in water for four days. The cold solution was acidified with concentrated HCl to a pH of 1 and extracted with EE. The organic solution was dried with MgSO4 and concentrated to completion. This gives a brown oil.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][C:4]([C:9]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[OH:10])([CH2:5][CH2:6]1)[CH2:3][CH2:2]2.[Br:23]C.[CH2:25](OC)CCC>CC#N>[Br-:23].[OH:10][C:9]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[C:4]12[CH2:5][CH2:6][N+:1]([CH3:25])([CH2:2][CH2:3]1)[CH2:8][CH2:7]2
Reactant: OC(c1ccccc1)(c1ccccc1)C12CCN(CC1)CC2
Reactant: CBr
Reactant: CCCCOC
Solvent: CC#N
Product: C[N+]12CCC(C(O)(c3ccccc3)c3ccccc3)(CC1)CC2
Product: [Br-]
Yield: 88 %

Procedure:
Following the general procedure outlined in Example 3, 1-azabicyclo[2.2.2]oct -4-yl(diphenyl)methanol (0.0638 g, 0.217 mmol) and bromomethane (2.0 M in t -Butylmethyl ether, 0.250 mL, 0.500 mmol) in 2 CH3CN/3CHCl3 (4.0 mL) were reacted to give the desired product (0.0739 g, 88.0%). ELMS m/z 308(M+) Rt (1.58 min).
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([S:14][C:15]([F:18])([F:17])[F:16])=[CH:9][C:8]=2[Cl:19])[N:5]=[C:4]([C:20]#[N:21])[CH:3]=1.[I:22]N1C(=O)CCC1=O>C(#N)C.ClCCl>[NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([S:14][C:15]([F:16])([F:17])[F:18])=[CH:9][C:8]=2[Cl:19])[N:5]=[C:4]([C:20]#[N:21])[C:3]=1[I:22]
Reactant: N#Cc1cc(N)n(-c2c(Cl)cc(SC(F)(F)F)cc2Cl)n1
Reactant: O=C1CCC(=O)N1I
Solvent: CC#N
Solvent: ClCCl
Product: N#Cc1nn(-c2c(Cl)cc(SC(F)(F)F)cc2Cl)c(N)c1I

Procedure:
To a stirred solution of 5-amino-3-cyano-1-(2,6-dichloro-4-trifluoromethylsulphenylphenyl)pyrazole (10 g) in acetonitrile (50 ml) at room temperature was added N-iodosuccinimide (6.4 g) in acetonitrile (25 ml). After 15 minutes the mixture was evaporated to dryness leaving and the residual buff solid taken up in dichloromethane (300 ml). The solution was washed with water (75 ml, ×3), then brine (50 ml), then dried (MgSO4) and evaporated. Trituration with hexane (100 ml, ×2) to provide the title compound as buff solid m.p. 172-174° C.
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7](Cl)=[CH:8][N:9]=1)(=[O:3])[CH3:2].[SH:11][C:12]1[N:16]([CH3:17])[N:15]=[N:14][N:13]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:1]([NH:4][C:5]1[S:6][C:7]([S:11][C:12]2[N:16]([CH3:17])[N:15]=[N:14][N:13]=2)=[CH:8][N:9]=1)(=[O:3])[CH3:2]
Reactant: Cn1nnnc1S
Reactant: CC(=O)Nc1ncc(Cl)s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)Nc1ncc(Sc2nnnn2C)s1
Temperature: 130 °C
Yield: 82.2 %

Procedure:
A mixture of 2-acetylamino-5-chlorothiazole (1.76 g), 5-mercapto-1-methyl-1H-tetrazole (1.2 g) and potassium carbonate (2 g) in N,N-dimethylformamide (40 ml) was heated at 130° C. for 3 hours with stirring. The reaction mixture was concentrated under reduced pressure and the residue was triturated with water. The precipitates were collected by filtration, washed with water and dried in vacuo to give solid. The solid was subjected to column chromatography on silica gel (silica gel 60, 70-230 mesh; Merck: 150 g) and eluted with a mixture of chloroform and methanol (10:1). The fractions containing the objective compound were combined and concentrated under reduced pressure to give 2-acetylamino-5-(1-methyl-1H-tetrazol-5-ylthio)thiazole (2.1 g, yield: 82.0%). mp: 208°-210° C.
Reaction SMILES: [C:1](Cl)(=[O:5])[C:2](Cl)=[O:3].[F:7][C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)=[CH:10][CH:9]=1.[Al+3].[Cl-].[Cl-].[Cl-].C(OCC)(=O)C>C(Cl)Cl.O>[F:7][C:8]1[CH:9]=[CH:10][C:11]([N:14]2[C:15]3[C:16](=[CH:17][C:18]([F:21])=[CH:19][CH:20]=3)[C:1](=[O:5])[C:2]2=[O:3])=[CH:12][CH:13]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: Fc1ccc(Nc2ccc(F)cc2)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=C1C(=O)N(c2ccc(F)cc2)c2ccc(F)cc21
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Oxalyl chloride (9.62 ml, 0.11 mole) was dissolved in 45 ml CH2Cl2. A solution of di-(4-fluorophenyl)amine (19.7 g, 0.096 mole) in 145 ml CH2Cl2 was added over 15 minutes; the temperature rose from 23° to 28°. After stirring 1 hour, AlCl3 (40.8 g) was added portionwise over 15 minutes; the temperature rose from 20° to 30°, and was kept less than 30° by cooling. After stirring for 10 minutes, the reaction mixture was added to 250 ml ethyl acetate and 500 ml ice and water (the temperature rose to 30° C.). The aqueous layer was washed 2×250 ml ethyl acetate. The organic layers were combined, back-washed 1×400 ml H2O, dried over MgSO4, evaporated to solids and triturated with 100 ml 1:1 ether:hexane to recover title product, 19.9 g, m.p. 180°-190°, tlc Rf 0.55 (1:1 ether:hexane).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8][O:9][C:10]2[CH:11]=[C:12]([CH:18]=[CH:19][CH:20]=2)[C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:3][CH2:2]1.C(O)(C(F)(F)F)=O.CCN(C(C)C)C(C)C.[CH:37]([N:40]=[C:41]=[O:42])([CH3:39])[CH3:38]>C(Cl)Cl>[CH:37]([NH:40][C:41]([N:1]1[CH2:2][CH2:3][CH:4]([CH2:7][CH2:8][O:9][C:10]2[CH:11]=[C:12]([CH:18]=[CH:19][CH:20]=2)[C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:5][CH2:6]1)=[O:42])([CH3:39])[CH3:38]
Reactant: CC(C)N=C=O
Reactant: CCOC(=O)c1cccc(OCCC2CCNCC2)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1cccc(OCCC2CCN(C(=O)NC(C)C)CC2)c1
Temperature: 20 °C
Reaction time: 8 h

Procedure:
Ethyl 3-(2-piperidin-4-yl-ethoxy)-benzoate (1.0 g of the TFA salt, 2.6 mmol) was dissolved in DCM (10 ml), wereupon DIPEA (1.3 ml, 7.7 mmol) and isopropyl isocyanate (0.33 g, 3.8 mmol) was added. The reaction mixture was shaken overnight at 20° C. Silica gel (10 ml) was added, and the solvent removed in vacuo. Flash chromatography (EtOAc/heptan 35:65→55:45) provided 0.67 g of the title compound. LC-MS (m/z): 364 (M+2).
Reaction SMILES: CN(C)CCN.[CH3:7][O:8][CH2:9][CH2:10][O:11][N:12]1[C:16](=O)[C:15]2=[CH:18][CH:19]=[CH:20][CH:21]=[C:14]2C1=O.C(O)(=O)C.C([C:35]1[CH:40]=[C:39]([Cl:41])[CH:38]=[CH:37][C:36]=1[NH:42][S:43]([C:46]([F:49])([F:48])[F:47])(=[O:45])=[O:44])(=O)C1C=CC=CC=1>CCO>[Cl:41][C:39]1[CH:40]=[CH:35][C:36]([NH:42][S:43]([C:46]([F:49])([F:47])[F:48])(=[O:45])=[O:44])=[C:37]([C:16](=[N:12][O:11][CH2:10][CH2:9][O:8][CH3:7])[C:15]2[CH:14]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:38]=1
Reactant: O=C(c1ccccc1)c1cc(Cl)ccc1NS(=O)(=O)C(F)(F)F
Reactant: COCCON1C(=O)c2ccccc2C1=O
Agent: CN(C)CCN
Solvent: CC(=O)O
Solvent: CCO
Product: COCCON=C(c1ccccc1)c1cc(Cl)ccc1NS(=O)(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 7 h
Yield: 74.2 %

Procedure:
N,N-Dimethylethylenediamine (254 μL, 2.20 mmol) was added to a solution of N-(2-methoxyethoxy)phthalimide (332 mg, 1.50 mmol) in EtOH (5 mL), and the reaction allowed to stir at RT for 7 hours. Glacial acetic acid (2 mL) was then added to adjust the mixture to ca. pH 4, followed by the addition of N-(2-benzoyl-4-chlorophenyl)trifluoromethanesulfonamide 25 (364 mg, 1.0 mmol), and the reaction stirred for 15 hours at 30° C. The reaction mixture was concentrated under vacuum, and the residue dissolved in Et2O (50 mL) and washed with water, brine, dried over MgSO4 and the solvent removed under reduced pressure. The residue was purified by radial thin layer chromatography (eluting with CH2Cl2/PE, 1:19) to afford N-{4-chloro-[(2-methoxyethoxyimino)phenylmethyl]phenyl}trifluoromethanesulfonamide 234 (324 mg, 74%), as a colorless oil, 1H n.m.r. (400 MHz, CDCl3) (2:1 mixture of E- and Z-isomers) δ 11.06, br s, 1H, 8.87, br s, 1H, 7.67, d, J=88 Hz, 1H, 7.54-7.31, m, 13H, 7.10, d, J=2.4 Hz, 1H; 6.92, d, J=2.4 Hz, 1H, 4.33, m, 4H, 3.67, m, 4H, 3.46, s, 3H, 3.38, s, 3H. HRMS (M+) 436.0465.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[CH3:12][O:13][C:14](=[O:31])[C:15]1[CH:20]=[CH:19][C:18]([O:21][C:22]2[CH:27]=[CH:26][C:25]([Br:28])=[CH:24][C:23]=2[CH:29]=O)=[CH:17][CH:16]=1.N1CCCC1>CO>[CH3:12][O:13][C:14](=[O:31])[C:15]1[CH:20]=[CH:19][C:18]([O:21][C:22]2[CH:27]=[CH:26][C:25]([Br:28])=[CH:24][C:23]=2/[CH:29]=[C:6]2\[C:7](=[O:11])[NH:8][C:9]3[C:5]\2=[CH:4][CH:3]=[C:2]([Cl:1])[CH:10]=3)=[CH:17][CH:16]=1
Reactant: COC(=O)c1ccc(Oc2ccc(Br)cc2C=O)cc1
Reactant: O=C1Cc2ccc(Cl)cc2N1
Solvent: CO
Solvent: C1CCNC1
Product: COC(=O)c1ccc(Oc2ccc(Br)cc2/C=C2\C(=O)Nc3cc(Cl)ccc32)cc1
Yield: 73.7 %

Procedure:
In a manner similar to the method described in Example 1a, 6-chlorooxindole (1.6 g, 9.2 mmol) (Crescent) was reacted with 4-(4-bromo-2-formyl-phenoxy)-benzoic acid methyl ester (2.8 g, 8.4 mmol) and pyrrolidine in methanol at 90° C. for 2 h to give E/Z-4-[4-bromo-2-(6-chloro-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-phenoxy]-benzoic acid methyl ester as a bright yellow solid (Yield 3 g, 81%).
Reaction SMILES: [C:1]1([C:7]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC(C)([O-])C.[K+].[Br:22][C:23]1[CH:28]=[C:27]([CH2:29]Br)[CH:26]=[CH:25][C:24]=1[I:31]>O1CCCC1>[Br:22][C:23]1[CH:28]=[C:27]([CH2:29][CH:9]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[O:8])[CH:26]=[CH:25][C:24]=1[I:31]
Reactant: O=C(Cc1ccccc1)c1ccccc1
Reactant: BrCc1ccc(I)c(Br)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: O=C(c1ccccc1)C(Cc1ccc(I)c(Br)c1)c1ccccc1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 99.5 %

Procedure:
A solution of deoxybenzoin (26.4 mg, 0.134 mmol) in tetrahydrofuran (0.66 mL) was cooled to −78° C. and potassium tert-butoxide (0.15 mL, 0.15 mmol, 1.0 M in tetrahydrofuran) was added dropwise. The reaction mixture was stirred at −78° C. for 10 minutes and 2-bromo-4-(bromomethyl)-1-iodobenzene (50.0 mg, 0.133 mmol) in tetrahydrofuran (1 mL) was added dropwise. The reaction mixture was warmed to 25° C. and quenched with saturated ammonium chloride (5 mL) and extracted with ethyl acetate (2×5 mL). The combined organic extracts were washed with brine (5 mL), dried with magnesium sulfate, filtered, and concentrated to a crude yellow oil which was purified by flash column chromatography to yield the desired product (65 mg, 42%). LCMS found for C21H17BrIO (M+H)+: m/z=491, 493.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[NH:10][C:9](=[O:11])[O:8][C:7]([C:16]#[C:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)([C:12]([F:15])([F:14])[F:13])[C:6]=2[CH:24]=1.[C:25]12([CH3:37])[C:31]([CH3:33])([CH3:32])[CH:28]([CH2:29][CH2:30]1)[CH2:27][CH:26]2[C:34](Cl)=[O:35].C(N(CC)CC)C.[Cl:45]CCl>CN(C)C1C=CN=CC=1>[Cl:45][CH:30]1[C@:25]2([CH3:37])[C:31]([CH3:33])([CH3:32])[CH:28]([CH2:27][CH:26]2[C:34]([N:10]2[C:5]3[CH:4]=[CH:3][CH:2]=[CH:24][C:6]=3[C:7]([C:16]#[C:17][C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)([C:12]([F:14])([F:15])[F:13])[O:8][C:9]2=[O:11])=[O:35])[CH2:29]1
Reactant: O=C1Nc2ccc(Cl)cc2C(C#Cc2ccccc2)(C(F)(F)F)O1
Reactant: ClCCl
Reactant: CC1(C)C2CCC1(C)C(C(=O)Cl)C2
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Product: CC1(C)C2CC(Cl)[C@@]1(C)C(C(=O)N1C(=O)OC(C#Cc3ccccc3)(C(F)(F)F)c3ccccc31)C2

Procedure:
To a solution containing (±) 6-chloro-4-phenylethynyl-4-trifluoromethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one (2.24 g, 6.37 mmol), 4-dimethylaminopyridine (0.10 g, 0.8 mmol), and (-) camphanic acid chloride (2.07 g, 9.55 mmol) in 60 mL of dry dichloromethane, stirred under argon in an ice bath, was added triethylamine (2.22 mL, 15.9 mmol). The cooling bath was removed and the reaction was allowed to proceed at room temperature. When the reaction was complete by thin layer chromatography (SiO2, 4% EtOAc in CHCl3), the solution was diluted with 200 mL of CHCl3 and washed twice with 10% citric acid, then with brine. Upon drying (MgSO4) the solvent was removed on a rotary evaporator and the foamy reside was subjected to flash chromatography, eluting with CHCl3. There was obtained 575 mg of diastereomer I of 6-chloro-(1S)-camphanoyl-4-phenylethynyl-4-trifluoromethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one as an oil, 1H-NMR (CDCl3): δ0.85 (s, 3H), 1.08 (s, 3H), 1.22 (s, 3H), 1.73-1.85 (m, 1H), 1.92-2.08 (m, 1H), 2.50-2.67 (m, 2H), 7.30-7.79 (m, 8H). This was followed by 1.52 g of mixed fractions (diastereomers I and II). Continued elution afforded 680 mg of the slower-moving diastereomer (II) of the title compound which, upon trituration with an ether/hexane mixture, gave clumps of white needles, mp 177°-178.5° C.; 1H-NMR (CDCl3): δ0.83 (s, 3H), 1.12 (s, 3H), 1.23 (s, 3H), 1.73-1.86 (m, 1H), 1.93-2.06 (m, 1H), 2.50-2.63 (m, 2H), 7.38-7.51 (m, 4H), 7.49-7.62 (m, 2H), 7.72 (d, J=9 Hz, 1H), 7.76 (d, J=2 Hz, 1H).
Reaction SMILES: [NH2:1][C:2]1[NH:7][C:6](=[S:8])[C:5]([C:9]#[N:10])=[C:4]([C:11]2[O:12][CH:13]=[CH:14][CH:15]=2)[CH:3]=1.CC[O-].[Na+].Br.Br[CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=1>C(O)C>[NH2:1][C:2]1[CH:3]=[C:4]([C:11]2[O:12][CH:13]=[CH:14][CH:15]=2)[C:5]([C:9]#[N:10])=[C:6]([S:8][CH2:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=2)[N:7]=1
Reactant: BrCCc1ccccn1
Reactant: N#Cc1c(-c2ccco2)cc(N)[nH]c1=S
Agent: Br
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: N#Cc1c(-c2ccco2)cc(N)nc1SCCc1ccccn1
Yield: 75.5 %

Procedure:
To a stirred solution of 100 mg (0.46 mmol) 6-amino-4-furan-2-yl-2-thioxo-1,2-dihydro-pyridine-3-carbonitrile in 3.4 ml ethanol were added 0.60 ml (1.60 mmol) sodium ethylate solution (2.67M in ethanol) and 368 mg (1,38 mmol) 2-(2-bromoethyl)pyridine hydrobromide and the reaction mixture heated at reflux for 1 hour. The reaction mixture was then concentrated in vacuo and the residue partitioned between dichloromethane and water. The organic phase was dried over sodium sulfate and concentrated in vacuo. The residue was triturated in ether to afford 112 mg (76%) 6-amino-4-furan-2-yl-2-(2-pyridin-2-yl-ethylsulfanyl)-nicotinonitrile as a white crystalline solid. ES-MS m/e (%): 323 (M+H+, 100).
Reaction SMILES: O.[C:2]([N:5]([CH2:10][C:11]([OH:13])=[O:12])[CH2:6][C:7]([OH:9])=[O:8])(=O)C.[P:14]([OH:17])([OH:16])[OH:15].S(=O)(=O)(O)O.C=O>O>[P:14]([CH2:2][N:5]([CH2:10][C:11]([OH:13])=[O:12])[CH2:6][C:7]([OH:9])=[O:8])([OH:17])([OH:16])=[O:15]
Reactant: CC(=O)N(CC(=O)O)CC(=O)O
Reactant: OP(O)O
Agent: C=O
Agent: O=S(=O)(O)O
Solvent: O
Product: O=C(O)CN(CC(=O)O)CP(=O)(O)O
Temperature: 110 °C
Yield: 62.3 %

Procedure:
Cycle 1: A reactor was charged with N-acetyliminodiacetic acid monohydrate (17.0 g), water (5 g), phosphorous acid (11.39 g) and 98% sulfuric acid (15 g). The mixture was heated to 110° C. and 42.2% formaldehyde (5.6 mL) was added drop wise over a one hour period. After another 1¾ hour at 110° C. the mixture was cooled to 25° C. The mixture was filtered and the solid was washed with water to give 12.46 g of N-(phosphonomethyl)iminodiacetic acid.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[S:7])=[CH:4][CH:3]=1.Br[CH2:12][C:13]([C:15]1[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][CH:16]=1)=O>CCO>[F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]2[S:7][CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][CH:16]=3)[N:8]=2)=[CH:4][CH:3]=1
Reactant: O=C(CBr)c1ccc(Br)cc1
Reactant: NC(=S)c1ccc(F)cc1
Solvent: CCO
Product: Fc1ccc(-c2nc(-c3ccc(Br)cc3)cs2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 185.5 %

Procedure:
To a solution of p-fluorothiobenzamide (0.39 g, 2.5 mmol) in 20 ml of abs. EtOH is added 2,4'-dibromoacetophenone (0.7 g, 2.5 mmol) all at once. The reaction mixture is stirred at room temperature for 3 hours and then chilled in ice bath. The precipitate is collected by filtration, washed with cold EtOH (5 ml×2) and dried in vacuum to give 2-(4'-fluorophenyl)-4-(4'-bromophenyl)thiazole as a white fluffy crystaline solid (1.55 g, 93%). mp.158-9° C.
Reaction SMILES: Br[C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([CH3:9])[C:3]=1[F:10].[C:11]([Cu])#[N:12].C(OCC)(=O)C>CCCCCC>[NH2:6][C:5]1[CH:7]=[CH:8][C:2]([C:11]#[N:12])=[C:3]([F:10])[C:4]=1[CH3:9]
Reactant: Cc1c(N)ccc(Br)c1F
Reactant: N#C[Cu]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: Cc1c(N)ccc(C#N)c1F
Temperature: 140 °C
Yield: 67.3 %

Procedure:
A mixture of 4-bromo-3-fluoro-2-methylaniline (23 g, 113 mmol) and cyanocopper (20.19 g, 225 mmol) N,N-dimethylformamide (200 mL) was heated to 140° C. for 7 h. After the mixture was cooled to room temperature filtered and poured into a separatory funnel containing water and ethyl acetate (1:1). Layers were separated and the organic layer was concentrated under reduced pressure. Flash chromatography (0-50% ethyl acetate in hexane) gave the desired product (11.4 g, 76 mmol, 67% yield) as a brown solid. 1H NMR (400 MHz, CHLOROFORM-d) δ (ppm) 7.22 (t, 1H), 6.45 (d, J=8.59 Hz, 1H), 4.23 (br. s., 2H), 2.07 (s, 3H); MS (ESI) m/z 151.1[M+1]+.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=2)[N:5]=[C:4]2[CH2:15][CH2:16][CH2:17][C:3]=12.[NH2:18][C:19]1[CH:31]=[CH:30][C:22]([O:23][CH:24]([CH3:29])[C:25]([O:27][CH3:28])=[O:26])=[CH:21][CH:20]=1>>[Cl:14][C:10]1[CH:9]=[C:8]([C:6]2[N:5]=[C:4]3[CH2:15][CH2:16][CH2:17][C:3]3=[C:2]([NH:18][C:19]3[CH:20]=[CH:21][C:22]([O:23][CH:24]([CH3:29])[C:25]([O:27][CH3:28])=[O:26])=[CH:30][CH:31]=3)[CH:7]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: Clc1cccc(-c2cc(Cl)c3c(n2)CCC3)c1
Reactant: COC(=O)C(C)Oc1ccc(N)cc1
Product: COC(=O)C(C)Oc1ccc(Nc2cc(-c3cccc(Cl)c3)nc3c2CCC3)cc1
Yield: 60.6 %

Procedure:
Following General Procedure B2, 4-chloro-2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridine (0.150 g, 0.57 mmol) was reacted with methyl 2-(4-aminophenoxy)propanoate (0.133 g, 0.68 mmol) to afford the title compound (0.146 g, 97%) as an off-white solid. MW=422.90. 1H NMR (DMSO-d6, 500 MHz) δ 7.98 (s, 1H), 7.88-7.86 (m, 1H), 7.74-7.69 (m, 1H), 7.46-7.38 (m, 2H), 7.22-7.17 (m, 2H), 7.02 (s, 1H), 6.96-6.89 (m, 2H), 4.96 (q, J=6.8 Hz, 1H), 3.69 (s, 3H), 2.89 (t, J=7.6 Hz, 2H), 2.80 (t, J=7.6 Hz, 2H), 2.13-2.03 (m, 2H), 1.51 (d, J=6.7 Hz, 3H); APCI MS m/z 423 [M+H]+.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH3:5])[CH3:2].[CH2:6](Cl)[C:7]1[CH:15]=[CH:14][C:13]2[O:12][CH2:11][O:10][C:9]=2[CH:8]=1.[O:17]1CCCC1>>[CH2:1]([N:3]([CH2:4][CH3:5])[C:6](=[O:17])[C:7]1[CH:15]=[CH:14][C:13]2[O:12][CH2:11][O:10][C:9]=2[CH:8]=1)[CH3:2]
Reactant: CCNCC
Reactant: ClCc1ccc2c(c1)OCO2
Reactant: C1CCOC1
Product: CCN(CC)C(=O)c1ccc2c(c1)OCO2
Reaction time: 0.17 h

Procedure:
A solution of diethylamine (56.2 mL, 0.543 mol) in tetrahydrofuran is added dropwise to a solution of piperonyl chloride (33.4 g, 0.181 mol) in tetrahydrofuran at 0° C. The reaction mixture is stirred for 10 minutes and filtered through diatomaceous earth. The filtrate is concentrated in vacuo to give a solid residue which is recrystalized from ether to afford the title product, 36.7 g (91.8%).
Reaction SMILES: Cl[CH:2]([C:8]([CH3:10])=O)[C:3]([O:5][CH2:6][CH3:7])=[O:4].[C:11]([S-:13])#[N:12].[K+].[CH3:15][O:16][C:17]1[CH:18]=[C:19]([NH2:29])[CH:20]=[CH:21][C:22]=1[N:23]1[CH:27]=[C:26]([CH3:28])[N:25]=[CH:24]1>C(O)C>[CH2:6]([O:5][C:3]([C:2]1[S:13][C:11]([NH:29][C:19]2[CH:20]=[CH:21][C:22]([N:23]3[CH:27]=[C:26]([CH3:28])[N:25]=[CH:24]3)=[C:17]([O:16][CH3:15])[CH:18]=2)=[N:12][C:8]=1[CH3:10])=[O:4])[CH3:7]
Reactant: N#C[S-]
Reactant: COc1cc(N)ccc1-n1cnc(C)c1
Reactant: CCOC(=O)C(Cl)C(C)=O
Agent: [K+]
Solvent: CCO
Product: CCOC(=O)c1sc(Nc2ccc(-n3cnc(C)c3)c(OC)c2)nc1C
Yield: 17.7 %

Procedure:
A solution of 46 mg (0.25 mmol) ethyl 2-chloroacetoacetate and of 36 mg (0.375 mmol) potassium rhodanide in ethanol (0.75 ml) was stirred at room temperature for 1 hour. 51 mg (0.25 mmol) 3-methoxy-4-(4-methyl-imidazol-1-yl)-phenylamine was added and the reaction was heated to reflux for 3 hours. A solid precipitated. The reaction was diluted with water and extracted twice with ethyl acetate. The insoluble precipitate was filtered off, washed with ethyl acetate and dried to yield the 16.5 mg of the title compound. The organic layer was dried over sodium sulphate, filtered and the solvent was evaporated in vacuo. The residue was purified on silica gel with methylene chloride/methanol 19/1. The fraction with the product was stirred with diethyl ether at room temperature and the solid was filtered off. The product was combined yielding 32 mg (35%) 2-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenylamino]-4-methyl-thiazole-5-carboxylic acid ethyl ester as a yellow solid. MS ISP (m/e): 373.2 (100) (M+H)+. 1H NMR (DMSO-D6, 250 MHz): δ (ppm)=10.93 (s, 1H), 8.49 (s, 1H), 7.61 (s, 1H), 7.43 (d, 1H), 7.37 (s, 1H), 7.31 (s, 1H), 4.22 (q, 2H), 3.84 (s, 3H), 2.55 (s, 3H), 2.24 (s, 3H), 1.27 (t, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:20](=[NH:21])[N:19]([CH2:22][CH3:23])[C:12]2[N:13]=[C:14]([S:17][CH3:18])[N:15]=[CH:16][C:11]=2[CH:10]=1.[C:24](OC(=O)C)(=[O:26])[CH3:25]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:20](=[N:21][C:24](=[O:26])[CH3:25])[N:19]([CH2:22][CH3:23])[C:12]2[N:13]=[C:14]([S:17][CH3:18])[N:15]=[CH:16][C:11]=2[CH:10]=1
Reactant: CC(=O)OC(C)=O
Reactant: CCn1c(=N)c(-c2c(Cl)cccc2Cl)cc2cnc(SC)nc21
Product: CCn1c(=NC(C)=O)c(-c2c(Cl)cccc2Cl)cc2cnc(SC)nc21

Procedure:
A mixture of 2.70 g (7.40 mmol) of 6-(2,6-dichlorophenyl)-8-ethyl-2-methylsulfanyl-8H-pyrido[2,3-d]pyrimidin-7-ylideneamine of Example 65 and 15 mL of acetic anhydride was heated with stirring to the boiling point. The resulting solution was heated at reflux for 5 minutes and concentrated at reduced pressure to ca. 8 mL volume. The solution was cooled and ether (8 mL) was added. The well-defined crystals that separated were filtered and washed with 5 mL of ether and 10 mL of petroleum ether; wt 2.68 g; mp 175°-177° C.
Reaction SMILES: C12N(C3C=NC4C(=CC=CC=4)N=3)CC1CCNC2.[C:19]1([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:25]([N:27]1[CH2:33][CH:32]2[CH:29]([CH2:30][NH:31]2)[CH2:28]1)=[O:26].Cl[C:41]1[N:46]=[C:45]([O:47][CH3:48])[CH:44]=[CH:43][N:42]=1>>[C:19]1([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:25]([N:27]1[CH2:33][CH:32]2[CH:29]([CH2:30][N:31]2[C:41]2[N:46]=[C:45]([O:47][CH3:48])[CH:44]=[CH:43][N:42]=2)[CH2:28]1)=[O:26]
Reactant: COc1ccnc(Cl)n1
Reactant: O=C(c1ccccc1-c1ccccc1)N1CC2CNC2C1
Agent: c1ccc2nc(N3CC4CCNCC43)cnc2c1
Product: COc1ccnc(N2CC3CN(C(=O)c4ccccc4-c4ccccc4)CC32)n1

Procedure:
The title compound was prepared in a manner analogous to for Intermediate 2, Step A, using Intermediate 19 and 2-chloro-4-methoxypyrimidine. MS (ESI) mass calcd. for C23H22N4O2, 386.46; m/z found, 387.2 [M+H]+.