Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[C:5]([C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:10])=[C:4]([NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[S:24]([CH:27]([CH3:29])[CH3:28])(=[O:26])=[O:25])[N:3]=1.[CH:30]([O:33][C:34]1[CH:40]=[C:39]([CH:41]2[CH2:46][CH2:45][N:44]([CH2:47][CH2:48][O:49][CH3:50])[CH2:43][CH2:42]2)[C:38]([CH3:51])=[CH:37][C:35]=1[NH2:36])([CH3:32])[CH3:31]>CCN(C(C)C)C(C)C.CC(O)C>[Cl:8][C:6]1[C:5]([C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:10])=[C:4]([NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[S:24]([CH:27]([CH3:29])[CH3:28])(=[O:26])=[O:25])[N:3]=[C:2]([NH:36][C:35]2[CH:37]=[C:38]([CH3:51])[C:39]([CH:41]3[CH2:42][CH2:43][N:44]([CH2:47][CH2:48][O:49][CH3:50])[CH2:45][CH2:46]3)=[CH:40][C:34]=2[O:33][CH:30]([CH3:32])[CH3:31])[N:7]=1
Reactant: CC(C)S(=O)(=O)c1ccccc1Nc1nc(Cl)nc(Cl)c1C(=O)c1ccccc1
Reactant: COCCN1CCC(c2cc(OC(C)C)c(N)cc2C)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: COCCN1CCC(c2cc(OC(C)C)c(Nc3nc(Cl)c(C(=O)c4ccccc4)c(Nc4ccccc4S(=O)(=O)C(C)C)n3)cc2C)CC1
Temperature: 150 °C
Reaction time: 2 h

Procedure:
To a 10 mL microwave reaction tube, (2,4-dichloro-6-(2-(isopropylsulfonyl)phenylamino)pyrimidin-5-yl)(phenyl)methanone (24.1 mg, 0.0548 mmol), 2-isopropoxy-4-(1-(2-methoxyethyl)piperidin-4-yl)-5-methylaniline (16.8 mg, 0.0548 mmol), 2-propanol (4 mL) and Hunig's Base (3 drops) were added successively. The resulting mixture was stirred at 150° C. for 2 hours by using a microwave machine. The reaction solution concentrated in vacuo to afford crude (4-chloro-2-(2-isopropoxy-4-(1-(2-methoxyethyl)piperidin-4-yl)-5-methylphenylamino)-6-(2-(isopropylsulfonyl)phenylamino)pyrimidin-5-yl)(phenyl)methanone as a slightly yellow sticky oil. MS (ES+): 720.30 (MH+).
Reaction SMILES: C[O:2][P:3]([O:6][CH3:7])[O:4][CH3:5].[C:8]1([CH3:14])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>>[CH3:5][O:4][P:3]([CH2:14][C:8]1[CH:13]=[C:12]2[C:11]([CH:10]=[CH:9][C:8]([CH2:14][P:3](=[O:2])([O:6][CH3:7])[O:4][CH3:5])=[CH:13]2)=[CH:10][CH:9]=1)(=[O:2])[O:6][CH3:7]
Reactant: Cc1ccccc1
Reactant: COP(OC)OC
Product: COP(=O)(Cc1ccc2ccc(CP(=O)(OC)OC)cc2c1)OC

Procedure:
The crude product from Example 27(a), a 1:1 mixture of dibromo and tribromo products (assumed to contain 0.010 mole of each), is dissolved in toluene (25 mL) and trimethylphosphite (10 mL, 0.085 mole). The mixture is heated at reflux temperature for 24 h after which excess toluene and trimethylphosphite are removed under reduced pressure. The dark red residue is chromatographed (400 g of 40-63 μm silica gel, 10% methanol in chloroform, 50 mL fractions), with fractions 31-36 containing 4.90 g of material which is rechromatographed (400 g of 40-63 μM silica gel, ethyl acetate, 50 mL fractions). The column is eluted with ethyl acetate (1 L) and then with 10% methanol in ethyl acetate. Fractions 70-92 (2.09 g) still contained two components (tlc, silica gel, 10% CH3OH--CHCl3, 4% CH3OH--CH2Cl2) and is chromatographed (400 g of 40-63 μM silica gel, CH2Cl2, 50 mL fractions) a third time. Elution is with 4% CH3OH--CH2Cl2 through fraction 80 and then with 10% CH3OH--CH2Cl2. Fractions 41-47 contained the desired diphosphonate (1.418 g) as a viscous oil which slowly solidifies. Crystallization from acetone-hexane give crystals, mp 87°-88° C.
Reaction SMILES: [CH3:1][CH:2]1[C:8](=[O:9])[NH:7][C:6]2=[C:10]3[C:15](=[N:16][C:17]4=[CH:18][CH:19]=[CH:20][C:4](=[C:5]24)[O:3]1)[CH2:14][CH2:13][CH2:12][CH2:11]3.[CH3:21]C(C)([O-])C.[K+].CI>O1CCCC1>[CH3:21][N:7]1[C:6]2=[C:10]3[C:15](=[N:16][C:17]4=[CH:18][CH:19]=[CH:20][C:4](=[C:5]24)[O:3][CH:2]([CH3:1])[C:8]1=[O:9])[CH2:14][CH2:13][CH2:12][CH2:11]3
Reactant: CC1Oc2cccc3nc4c(c(c23)NC1=O)CCCC4
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: CI
Solvent: C1CCOC1
Product: CC1Oc2cccc3nc4c(c(c23)N(C)C1=O)CCCC4
Reaction time: 0.25 h
Yield: 80 %

Procedure:
To a suspension of 1,3,9,10,11,12-hexahydro-3-methyl-2H-quino[4,3,2-ef][1,4]-benzoxazepin-2-one (5.0 g) in dry tetrahydrofuran (150 ml) was added potassium t-butoxide (3.15 g), with stirring. After 15 mins, methyl iodide (1.39 ml) was added, and the reaction mixture was stirred at room temperature overnight. Additional methyl iodide (0.4 ml) was added. The reaction mixture was refluxed for two hrs, cooled, and concentrated. Saturated potassium carbonate solution was added and the mixture was extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated, and the residue was adhered to silica, and flash chromatographed (30-60% ethyl acetate/hexane). The appropriate fractions were concentrated, and the residue was triturated with diethyl ether to give 4.21 g (80%) of 1,3-dimethyl-1,3,9,10,11,12-hexahydro-2H-quino[4,3,2-ef][1,4]benzoxazepin-2-one.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([O:10]C)=[O:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[NH:13][C:14]([C:16]1[CH:17]=[CH:18][C:19]([O:28][CH3:29])=[C:20]2[O:24][C:23]([CH:25]([CH3:27])[CH3:26])=[CH:22][C:21]=12)=[O:15].S(=O)(=O)(O)O>C(O)COCCO.[OH-].[Na+].O>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([OH:10])=[O:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[NH:13][C:14]([C:16]1[CH:17]=[CH:18][C:19]([O:28][CH3:29])=[C:20]2[O:24][C:23]([CH:25]([CH3:27])[CH3:26])=[CH:22][C:21]=12)=[O:15]
Reactant: COC(=O)c1cc(Cl)c(NC(=O)c2ccc(OC)c3oc(C(C)C)cc23)c(Cl)c1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: OCCOCCO
Solvent: O
Product: COc1ccc(C(=O)Nc2c(Cl)cc(C(=O)O)cc2Cl)c2cc(C(C)C)oc12

Procedure:
3.7 g of N-(2,6-Dichloro-4-methoxycarbonylphenyl)-7-methoxy-2-(1-methylethyl)benzofuran-4-carboxamide are refluxed for 15 min. in 20 ml of diethylene glycol and 30 ml of water in which 0.41 g of caustic soda is dissolved. The solution is diluted with water and acidified to pH 2 using 2 N sulfuric acid. The product precipitates in this process. It is filtered off with suction on a suction filter, washed free of acid with water and dried in vacuo: m.p. 279° C.
Reaction SMILES: C[O:2][C:3]([C@H:5]1[NH:20][C:19](=[O:21])[C@H:18]([CH:22]([CH3:24])[CH3:23])[NH:17][C:16](=[O:25])[C@@H:15]([NH:26][S:27]([C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=2)(=[O:29])=[O:28])[CH2:14][C:13]2=[CH:37][CH:38]=[C:10]([CH:11]=[CH:12]2)[O:9][CH2:8][CH2:7][CH2:6]1)=O.CC(C[AlH]CC(C)C)C.CCOC(C)=O>C(Cl)Cl>[F:36][C:33]1[CH:34]=[CH:35][C:30]([S:27]([NH:26][C@H:15]2[CH2:14][C:13]3=[CH:12][CH:11]=[C:10]([CH:38]=[CH:37]3)[O:9][CH2:8][CH2:7][CH2:6][C@@H:5]([CH:3]=[O:2])[NH:20][C:19](=[O:21])[C@H:18]([CH:22]([CH3:23])[CH3:24])[NH:17][C:16]2=[O:25])(=[O:28])=[O:29])=[CH:31][CH:32]=1
Reactant: COC(=O)[C@@H]1CCCOc2ccc(cc2)C[C@H](NS(=O)(=O)c2ccc(F)cc2)C(=O)N[C@@H](C(C)C)C(=O)N1
Agent: CC(C)C[AlH]CC(C)C
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)[C@@H]1NC(=O)[C@@H](NS(=O)(=O)c2ccc(F)cc2)Cc2ccc(cc2)OCCC[C@@H](C=O)NC1=O
Temperature: -78 °C
Reaction time: 2 h

Procedure:
Ester 68 (39 mg) was dissolved in DCM (6 mL) under an atmosphere of argon. The reaction was cooled to −78° C. To the resultant solution DIBAL (0.39 mL) was added dropwise. This was stirred for 2 h before being allowed to warm to rt overnight. The reaction mixture was partitioned between EtOAc and 1M hydrochloric acid. The aqueous phase was extracted again with EtOAc and the combined organic extracts were dried (MgSO4), filtered and concentrated in vacuo. Purification was achieved using flash chromatography, eluting with a gradient of 1/1 EtOAc/(50/70) petroleum ether to EtOAc to yield a light brown solid, 15 mg, 40%. Rf=0.25 (1/1 EtOAc/(50/70) petroleum ether).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[N:10]=[CH:9][N:8]([CH2:11][CH:12]3[CH2:17][CH2:16][CH2:15][C:14]([CH2:19][NH:20][CH2:21][C:22]([CH3:28])([CH3:27])[C:23]([O:25][CH3:26])=[O:24])([OH:18])[CH2:13]3)[C:7]=2[CH:29]=1)#[N:2].C1N=CN([C:35](N2C=NC=C2)=[O:36])C=1>O1CCOCC1>[C:1]([C:3]1[CH:4]=[CH:5][C:6]2[N:10]=[CH:9][N:8]([CH2:11][C@H:12]3[CH2:17][CH2:16][CH2:15][C@:14]4([O:18][C:35](=[O:36])[N:20]([CH2:21][C:22]([CH3:27])([CH3:28])[C:23]([O:25][CH3:26])=[O:24])[CH2:19]4)[CH2:13]3)[C:7]=2[CH:29]=1)#[N:2]
Reactant: COC(=O)C(C)(C)CNCC1(O)CCCC(Cn2cnc3ccc(C#N)cc32)C1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1COCCO1
Product: COC(=O)C(C)(C)CN1C[C@@]2(CCC[C@H](Cn3cnc4ccc(C#N)cc43)C2)OC1=O
Reaction time: 0.25 h
Yield: 94.9 %

Procedure:
A solution of methyl 3-[({3-[(6-cyano-1H-benzimidazol-1-yl)methyl]-1-hydroxycyclohexaneyl}methyl)amino]-2,2-dimethylpropanoate (1.048 g, 2.63 mmol) and CDI (0.853 g, 5.26 mmol) in 1,4-dioxane (15 mL) was stirred at 100° C. for 1 day. The reaction was then concentrated and purified via silica gel chromatography (ISCO, 40 g silica gel column; solvent A=DCM; solvent B=MeOH (0.1M NH3); 0-5% B over 15 min; then 5% B over 5 min) to give methyl 3-{(5S,7S)-7-[(6-cyano-1H-benzimidazol-1-yl)methyl]-2-oxo-1-oxa-3-azaspiro[4.5]dec-3-yl}-2,2-dimethylpropanoate as a beige solid (1.06 g, 95% yield). MS (m/z) 425.2 (M+H+).
Reaction SMILES: [I:1][C:2]1[CH:8]=[C:7]([N+:9]([O-])=O)[CH:6]=[CH:5][C:3]=1[NH2:4].[OH-].[Na+]>Cl>[I:1][C:2]1[CH:8]=[C:7]([NH2:9])[CH:6]=[CH:5][C:3]=1[NH2:4]
Reactant: Nc1ccc([N+](=O)[O-])cc1I
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Nc1ccc(N)c(I)c1
Yield: 20.9 %

Procedure:
A mixture of concentrated hydrochloric acid (150 ml) and 2-iodo-4-nitroaniline (30.0 g) is stirred and warmed to 45°-50° C. A solution of stannous chloride dihydrate (90.0 g) in concentrated hydrochloric acid (110 ml) is added while maintaining the reaction temperature at 65°-70° C. After the addition is completed, the mixture is cooled in an ice bath and 50% sodium hydroxide (250ml) is added slowly. The mixture is filtered and the isolated damp solid is stirred in 600 ml water at reflux. The solution is decolorized with charcoal, filtered and cooled to afford 5.55 g of title compound, m.p. 95°-99° C.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]([OH:9])=O)[CH:4]=[N:3]1.[CH3:10][NH:11][CH2:12][CH3:13]>>[CH2:12]([N:11]([CH3:10])[C:7]([C:5]1[CH:4]=[N:3][N:2]([CH3:1])[CH:6]=1)=[O:9])[CH3:13]
Reactant: Cn1cc(C(=O)O)cn1
Reactant: CCNC
Product: CCN(C)C(=O)c1cnn(C)c1

Procedure:
This compound was prepared in the same manner as described in example 97, step a from 1-methyl-1H-pyrazole-4-carboxylic acid (1.0 g, 7.93 mmol) and N-methylethanamine (715 μl, 8.33 mmol). Yield: 995 mg (75%); off-white solid; MS: m/z=168.1 [M+H]+.
Reaction SMILES: [O-]P([O-])([O-])=O.[K+].[K+].[K+].Br[C:10]1[C:11](N2CC[C@H](O)C2)=[N:12][CH:13]=[C:14]([CH:29]=1)[C:15]([NH:17]C1C=CC(OC(Cl)(F)F)=CC=1)=[O:16].[O:36]1[CH2:41][CH2:40][CH2:39][CH2:38][CH:37]1[N:42]1[C:46](B2OC(C)(C)C(C)(C)O2)=[CH:45][CH:44]=[N:43]1>C1(C)C=CC=CC=1.CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[O:36]1[CH2:41][CH2:40][CH2:39][CH2:38][CH:37]1[N:42]1[C:46]([C:10]2[CH:11]=[N:12][CH:13]=[C:14]([CH:29]=2)[C:15]([NH2:17])=[O:16])=[CH:45][CH:44]=[N:43]1
Reactant: CC1(C)OB(c2ccnn2C2CCCCO2)OC1(C)C
Reactant: O=C(Nc1ccc(OC(F)(F)Cl)cc1)c1cnc(N2CC[C@H](O)C2)c(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: NC(=O)c1cncc(-c2ccnn2C2CCCCO2)c1
Temperature: 110 °C

Procedure:
K3PO4 (41.3 mg, 0.195 mmol) was added to a solution of (S)-5-bromo-N-(4-(chlorodifluoromethoxy)phenyl)-6-(3-hydroxypyrrolidin-1-yl)nicotinamide (Stage 8.1, 30 mg, 0.067 mmol) and 1-(tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (36.2 mg, 0.13 mmol) in toluene (0.32 mL) in a vial which was flushed with argon. Pd(PPh3)4 (3.75 mg, 0.032 mmol) was added. The vial was sealed and heated at 110° C. for 18 h. After cooling at RT, the RM was dissolved in EtOAc, washed with brine, dried over Na2SO4 and the solvent was evaporated off under reduced pressure to give a crude product was purified by flash chromatography (RediSep® Silica gel column, DCM/MeOH from 2% to 5% MeOH) to afford N-(4-(chlorodifluoromethoxy)phenyl)-6-(S)-3-hydroxypyrrolidin-1-yl)-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)nicotinamide, a portion of which (21 mg, 0.039 mmol) was dissolved in DCM (0.5 mL), treated with TFA (0.141 mL, 1.82 mmol) and stirred at RT for 3 h. The RM was poured into 10% aq. Na2CO3 (10 mL) and extracted with EtOAc. The combined extracts were dried over Na2SO4 and the solvent was evaporated off under reduced pressure to give the crude product which was purified by flash chromatography (RediSep® Silica gel column, DCM/MeOH from 2% to 5% MeOH) to afford the title compound. HPLC (Condition 4) tR=4.49 min, HPLC Chiral (CHIRALCEL® OD-H, 250×4.6 mm, eluent:n-heptane/EtOH/MeOH (85:10:5), 1 mL/min, UV DAD, tR=13.32 min, UPLC-MS (Condition 3) tR=0.92 min, m/z=450.3 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.65-1.76 (m, 1H) 1.77-1.92 (m, 1H) 2.86-2.97 (m, 1H) 3.18-3.35 (m, 2H) 3.34-3.47 (m, 1H) 4.10-4.24 (m, 1H) 4.66-4.93 (m, 1H) 6.28-6.42 (m, 1H) 7.31 (d, J=8.99 Hz, 2H) 7.85 (d, J=8.99 Hz, 3H) 7.96-8.05 (m, 1H) 8.64-8.81 (m, 1H) 10.17 (s, 1H) 12.80-13.14 (m, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][NH2:9])=[CH:4][CH:3]=1.[Br:10][C:11]1[CH:12]=[C:13]([CH:27]=[CH:28][CH:29]=1)[C:14]([C:16](=[CH:19]NC1C=CC=CC=1)[C:17]#[N:18])=[O:15]>C(O)C.CCCCCC>[NH2:18][C:17]1[N:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[N:9]=[CH:19][C:16]=1[C:14](=[O:15])[C:13]1[CH:27]=[CH:28][CH:29]=[C:11]([Br:10])[CH:12]=1
Reactant: N#CC(=CNc1ccccc1)C(=O)c1cccc(Br)c1
Reactant: NNc1ccc(F)cc1
Solvent: CCCCCC
Solvent: CCO
Product: Nc1c(C(=O)c2cccc(Br)c2)cnn1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 87.7 %

Procedure:
A mixture of 4-fluorophenylhydrazine (4.25 g, 33.7 mmol) and 2-(3-bromobenzoyl)-3-phenylaminoacrylonitrile (10.0 g, 30.7 mmol) in ethanol (100 ml) was heated at reflux under a nitrogen atmosphere. After 4 h, the reaction mixture was cooled to room temperature, diluted with hexane to give 5-amino-4-(3-bromobenzoyl)-1-(4-fluorophenyl)pyrazole (9.7 g) as a solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:26]=[C:25]([CH2:27][CH3:28])[CH:24]=[CH:23][C:10]=1[O:11][C:12]1[CH:17]=[CH:16][C:15]([S:18](Cl)(=[O:20])=[O:19])=[CH:14][C:13]=1[F:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N.[CH2:30]([NH2:33])[CH2:31][CH3:32]>>[CH2:1]([O:8][C:9]1[CH:26]=[C:25]([CH2:27][CH3:28])[CH:24]=[CH:23][C:10]=1[O:11][C:12]1[CH:17]=[CH:16][C:15]([S:18]([NH:33][CH2:30][CH2:31][CH3:32])(=[O:20])=[O:19])=[CH:14][C:13]=1[F:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCN
Reactant: CCc1ccc(Oc2ccc(S(=O)(=O)Cl)cc2F)c(OCc2ccccc2)c1
Agent: N
Product: CCCNS(=O)(=O)c1ccc(Oc2ccc(CC)cc2OCc2ccccc2)c(F)c1
Yield: 41 %

Procedure:
According to the procedure of example 65(b) except substituting 4-(4-ethyl-2-methoxyphenoxy)-3-fluorobenzene sulfonyl chloride for 4-[2-(benzyloxy)-4-ethylphenoxy]-3-fluorobenzene sulfonyl chloride and NH3 for propylamine (1.7 mmol; 0.14 mL), the title compound (140 mg; 0.32 mmol; 41%) was obtained as a brown oil after purification on preparative TLC (dichloromethane).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1.[Br:11]N1C(C)(C)C(=O)N(Br)C1=O>C1COCC1>[Br:11][CH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1
Reactant: CC1(C)C(=O)N(Br)C(=O)N1Br
Reactant: Cc1ccc(C(=O)O)cn1
Solvent: C1CCOC1
Product: O=C(O)c1ccc(CBr)nc1
Yield: 52 %

Procedure:
1st step: To a stirred suspension of 6-methylnicotinic acid (commercially available) (500 mg, 3.64 mmol) in THF (14 mL) at RT, was added 1,3-dibromo-5,5-dimethylhydantoin (DDH) (1.06 g, 3.71 mmol). Stirring was continued over night and concentrated under vacuo. Column chromatography (SiO2, CH2Cl2/MeOH: 8/2) yielded 410 mg (52%) of 6-bromomethyl-nicotinic acid as a light orange solid. ES-MS m/e: 214.2-216.3 (M+H+).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13](I)[CH:12]=[CH:11][C:10]=1[N:16]1[S:20](=[O:22])(=[O:21])[NH:19][C:18](=[O:23])[CH2:17]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:24][O:25][C:26](=[O:33])[C:27]([NH:29][C:30](=[O:32])[CH3:31])=[CH2:28].C(N(CC)CC)C>CC#N.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:24][O:25][C:26](=[O:33])/[C:27](/[NH:29][C:30](=[O:32])[CH3:31])=[CH:28]\[C:13]1[CH:12]=[CH:11][C:10]([N:16]2[CH2:17][C:18](=[O:23])[NH:19][S:20]2(=[O:22])=[O:21])=[C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:14]=1
Reactant: O=C1CN(c2ccc(I)cc2OCc2ccccc2)S(=O)(=O)N1
Reactant: C=C(NC(C)=O)C(=O)OC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COC(=O)/C(=C\c1ccc(N2CC(=O)NS2(=O)=O)c(OCc2ccccc2)c1)NC(C)=O
Temperature: 100 °C

Procedure:
A mixture of 5-(2-benzyloxy-4-iodophenyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one (200 mg, 0.4 mmol), 2-acetylaminoacrylic acid methyl ester (16.6 mg, 0.54 mmol), triethylamine (0.75 mL, 5.4 mmol) and Pd(OAc)2 (15 mg) in MeCN (5 mL) in a pressure vessel is heated at 100° C. for 18 h. The mixture is filtered and the solvent is removed under reduced pressure to give the title compound which is used directly in the next step.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[CH3:15][O:16][C:17]1[CH:22]=[C:21]([NH2:23])[CH:20]=[CH:19][N:18]=1.N1C=CC=CC=1.Cl>ClCCl>[F:1][C:2]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[CH:7][C:3]=1[C:4]([NH:23][C:21]1[CH:20]=[CH:19][N:18]=[C:17]([O:16][CH3:15])[CH:22]=1)=[O:5]
Reactant: COc1cc(N)ccn1
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1F
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1cc(NC(=O)c2ccc(C(F)(F)F)cc2F)ccn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.1 %

Procedure:
A solution of 2-fluoro-4-(trifluoromethyl)benzoyl chloride (25.0 g, 110.3 mmol) in dichloromethane (125.0 mL) was added drop-wise to a mixture of 2-methoxypyridin-4-amine (13.7 g, 110.3 mmol), pyridine (26.8 mL, 330.9 mmol) and dichloromethane (500.0 mL) at 0° C. The mixture was allowed to warm to room temperature and was stirred at that temperature overnight. The mixture was poured into 1N HCl (200 mL) and dichloromethane (200 mL). The layers were separated and the organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The product was slurried in hexane, the hexane was decanted and the product was dried under reduced pressure to yield 2-fluoro-N-(2-methoxy-4-pyridyl)-4-(trifluoromethyl)benzamide (25.7 g, 74%) as a cream solid. ESI-MS m/z calc. 314.07. found 315.3 (M+1)+; Retention time: 1.49 minutes (3 minutes run). 1H NMR (400 MHz, DMSO-d6) δ 10.96 (s, 1H), 8.15-8.04 (m, 1H), 8.00-7.85 (m, 2H), 7.76 (d, J=8.1 Hz, 1H), 7.26-7.15 (m, 2H), 3.85 (s, 3H) ppm.
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[H-].[Na+].Cl[CH2:15][C:16](=[O:18])[CH3:17]>O1CCCC1>[O:18]=[C:16]([CH3:17])[CH2:15][N:5]1[C:1](=[O:11])[C:2]2[C:3](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4]1=[O:6]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CC(=O)CCl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(=O)CN1C(=O)c2ccccc2C1=O
Temperature: 40 °C
Reaction time: 15 h
Yield: 70 %

Procedure:
Phthalimide (3 g) was dissolved in dry tetrahydrofuran (70 ml) and added dropwise at room temperature to a suspension of sodium hydride (539 mg) in tetrahydrofuran (15 ml). This was followed by heating at 40° C. for one hour, and then a solution of chloroacetone (1.99 g) dissolved in tetrahydrofuran (15 ml) was added dropwise. The mixture was then kept at the reflux temperature for 15 hours. After cooling, it was added to an ice/water mixture and extracted three times with ethyl acetate. The combined organic phases were washed once with saturated sodium chloride solution and then dried over magnesium sulfate. The solvent was removed in vacuo and the residue was chromatographed on silica gel (n-heptane/ethyl acetate 2:1). 2.9 g of the title compound were isolated.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]=[C:10]=[O:11].[CH2:12]([NH:19][CH2:20][CH2:21][CH2:22][CH3:23])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CCCCCC>[CH2:12]([N:19]([CH2:20][CH2:21][CH2:22][CH3:23])[C:10]([NH:9][C:3]1[CH:4]=[CH:5][C:6]([CH3:8])=[CH:7][C:2]=1[CH3:1])=[O:11])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Cc1ccc(N=C=O)c(C)c1
Reactant: CCCCNCc1ccccc1
Solvent: CCCCCC
Product: CCCCN(Cc1ccccc1)C(=O)Nc1ccc(C)cc1C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 4.89 g of 2,4-dimethylphenylisocyanate in 100 ml of hexane is added to a solution of 4.41 g of N-benzyl-n-butylamine in 150 ml of hexane, and the solution is stirred at room temperature for 2 hours and then evaporated. The residual solid is recrystallized from pentane to yield 1-benzyl-1-(n-butyl)-3-(2,4-dimethylphenyl)urea, m.p. 70°-71° C.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:14]([OH:16])=[O:15])[S:6][C:7]=1[N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)#[N:2].C([Li])CCC.[Cl:22][C:23]1[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=1[CH:25]=[O:26]>C1COCC1>[Cl:22][C:23]1[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=1[CH:25]([OH:26])[C:4]1[C:3]([C:1]#[N:2])=[C:7]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[S:6][C:5]=1[C:14]([OH:16])=[O:15]
Reactant: O=Cc1ccccc1Cl
Reactant: N#Cc1cc(C(=O)O)sc1N1CCOCC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: N#Cc1c(N2CCOCC2)sc(C(=O)O)c1C(O)c1ccccc1Cl
Temperature: -70 °C
Reaction time: 2 h
Yield: 18.9 %

Procedure:
A solution of 4-cyano-5-morpholin-4-ylthiophene-2-carboxylic acid (0.1 g, 0.42 mmol) in anhydrous THF (1.5 mL) was cooled down to −70° C. To this cooled solution was added a 2.5 M solution of n-butyl lithium in hexanes (0.672 mL, 1.68 mmol) dropwise under nitrogen. The resulting solution was stirred at −70° C. for 2 h and 2-chlorobenzaldehyde (0.142 mL, 1.26 mmol) was added. The reaction mixture was stirred at −70° C. for a further 2 h and was quenched with water. The mixture was concentrated to a small volume and the aqueous residue was washed with EtOAc. The aqueous solution was separated, acidified with 1N HCl and extracted with EtOAc. The organic solutions were combined, washed with brine, dried over MgSO4, filtered and concentrated. The crude material was purified by column chromatography to give 3-[(2-chlorophenyl)(hydroxy)methyl]-4-cyano-5-morpholin-4-ylthiophene-2-carboxylic acid (61) (0.03 g, 19%). LCMS: (FA) ES+ 319.0. 1H NMR (400 MHz, d6-DMSO) δ: 7.39-7.41 m, 1H), 7.31-7.33 (m, 1H), 7.23-7.27 (m, 2H), 6.19 (s, 1H), 5.74 (s, 1H), 3.70-3.72 m, 4H) and 3.38-3.40 (m, 4H).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH:12]=[CH2:13].ClC1C=CC=C(C(OO)=[O:22])C=1>C(Cl)Cl>[O:22]1[CH:12]([CH2:11][CH2:10][CH2:9][CH2:8][O:7][CH:2]2[CH2:3][CH2:4][CH2:5][CH2:6][O:1]2)[CH2:13]1
Reactant: C=CCCCCOC1CCCCO1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: C(CCC1CO1)COC1CCCCO1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 11.57 g of 6-(2-tetrahydropyranyloxy)-hex-1-ene in 200 mL of methylene chloride is added 10.8 g m-chloroperbenzoic acid and the mixture is stirred at room temperature for 18 hours. The reaction is quenched by the addition of saturated aqueous sodium bicarbonate solution followed by saturated sodium sulfite solution. The organic phase is dried, filtered and evaporated to give a clear oil which is purified by chromatography over silica gel using hexane/ether (4:1) as eluent to obtain 1,2-epoxy-6-(2-tetrahydropyranyloxy)-hexane; IR (CH2CH2): 1450, 1135, 1033 cm-1.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[CH3:8][C:9]1[N:10]=[C:11]([NH2:26])[S:12][C:13]=1[C:14]1[CH:19]=[CH:18][N:17]=[C:16]([N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)[N:15]=1>>[CH3:8][C:9]1[N:10]=[C:11]([NH:26][C:1](=[O:3])[CH3:2])[S:12][C:13]=1[C:14]1[CH:19]=[CH:18][N:17]=[C:16]([N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)[N:15]=1
Reactant: Cc1nc(N)sc1-c1ccnc(N2CCOCC2)n1
Reactant: CC(=O)OC(C)=O
Product: CC(=O)Nc1nc(C)c(-c2ccnc(N3CCOCC3)n2)s1
Temperature: 60 °C

Procedure:
Acetic anhydride (3 ml) is added to 4-methyl-5-(2-morpholin-4-yl-pyrimidin-4-yl)-thiazol-2-ylamine (25d)(0.045 g, 0.162 mmol) and the reaction mixture is heated to 60° C. for 1 hour. The solvent is removed in vacuo and the crude residue is dissolved in ethyl acetate (50 ml) and water (50 ml) The layers are separated and the organic layer is washed with sodium carbonate solution, brine, dried over MgSO4 and concentrated in vacuo to yield a brown oil. The crude residue is purified by chromatography on silica eluting with ethyl acetate-hexane (3:2) to afford the titled compound.