Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH:13]=[CH:14][C:15]([SH:17])=[CH:16][C:11]=3[O:10][N:9]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:24]([O:26][C:27](=[O:32])[C:28](Br)([CH3:30])[CH3:29])[CH3:25]>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]3[CH:13]=[CH:14][C:15]([S:17][C:28]([CH3:30])([CH3:29])[C:27]([O:26][CH2:24][CH3:25])=[O:32])=[CH:16][C:11]=3[O:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: Sc1ccc2c(-c3ccc(Cl)cc3)noc2c1
Reactant: CCOC(=O)C(C)(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(C)Sc1ccc2c(-c3ccc(Cl)cc3)noc2c1
Temperature: 60 °C

Procedure:
A mixture of 3.2 g of 3-(4-chlorophenyl)-6-mercapto-1,2-benzisoxazole, 2.52 g of potassium carbonate, 2.39 g of ethyl-2-bromo-2-methylpropionate and 75 ml dimethylformamide is heated at 60° C. for 8 hr. The reaction mixture is poured onto ice/dil hydrochloric acid and extracted with ether. The combined ether extracts are washed with dil sodium hydroxide solution, saturated sodium chloride solution and the solvent is removed in vacuo to afford a yellow oil. The oil is distilled in a Kugelrohr oven at 175° C. and 1.0 mm Hg to give an oil which crystallizes on standing. The solid is recrystallized from isopropyl ether using a brine-chilled Buchner funnel to afford ethyl 2-{[3-(4-chlorophenyl)-1,2-benzisoxazol-6-yl]thio}-2-methylpropionate.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:8][CH2:9][CH2:10]Br.C([O-])([O-])=O.[K+].[K+]>C(#N)C>[Br:8][CH2:9][CH2:10][O:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Oc1ccccc1
Reactant: BrCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: BrCCOc1ccccc1
Temperature: 60 °C
Reaction time: 8 h
Yield: 93.8 %

Procedure:
A suspension of phenol (5 g, 0.053 mol), 1,2-dibromethane (60 g, 0.319 mol) and K2CO3 (22 g, 0.16 mol) in dry acetonitrile (100 ml) was stirred at 60° C. overnight under nitrogen atmosphere. The reaction mixture was filtered and the solvent concentrated under reduced pressure. The residue was purified by column chromatography over silica gel using 10% ethyl acetate in petroleum ether as eluent to yield (10 g) of the sub-title compound as a solid.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][C:9]([CH:13]=[CH2:14])=[CH:10][CH:11]=2)[CH2:6][CH:5]1Cl)(=O)C.[OH-].[Na+].[NH4+].[Cl-:19]>C(O)C>[Cl:19][C:10]1[CH:11]=[C:12]2[C:7]([CH2:6][CH2:5][NH:4]2)=[CH:8][C:9]=1[CH:13]=[CH2:14]
Reactant: [Cl-]
Reactant: C=Cc1ccc2c(c1)CC(Cl)N2C(C)=O
Agent: [NH4+]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: C=Cc1cc2c(cc1Cl)NCC2

Procedure:
1-Acetylchloro-5-vinylindoline (D61) (0.13 g), and 10% aqueous NaOH (5 ml) were heated at reflux in ethanol (20 ml) for 2.5 hours, cooled and treated with an excess of saturated aqueous NH4Cl. The mixture was partitioned between ethyl acetate and brine. The organic extracts were dried (Na2SO4) and evaporated to dryness under reduced pressure affording the title compound as a brown oil (0.13 g) which was used without further purification.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C@H:4](/[CH:5]=[C:6](\[Br:12])/[C:7](=[O:11])[O:8][CH2:9][CH3:10])[C@H:3]1[C:13]([OH:15])=[O:14].[C:17]([C@@H:19](O)[C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([O:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:21]=1)#[N:18]>>[CH3:16][C:2]1([CH3:1])[C@H:4](/[CH:5]=[C:6](\[Br:12])/[C:7](=[O:11])[O:8][CH2:9][CH3:10])[C@H:3]1[C:13]([O:15][C@H:19]([C:17]#[N:18])[C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([O:26][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:21]=1)=[O:14]
Reactant: CCOC(=O)/C(Br)=C/[C@@H]1[C@@H](C(=O)O)C1(C)C
Reactant: N#C[C@@H](O)c1cccc(Oc2ccccc2)c1
Product: CCOC(=O)/C(Br)=C/[C@@H]1[C@@H](C(=O)O[C@H](C#N)c2cccc(Oc3ccccc3)c2)C1(C)C

Procedure:
Using the procedure of Step B of Example 43, (1R,trans,Z) 2,2-dimethyl-3-(2-bromo-3-oxo-3-ethoxy-1-propenyl)-cyclopropane carboxylic acid and (S)α-cyano-3-phenoxy-benzyl alcohol were reacted to obtain (S)α-cyano-3-phenoxy-benzyl (1R,trans,Z) 2,2-dimethyl-3-(2-bromo-3-oxo-3-ethoxy-1-propenyl)-cyclopropanecarboxylate melting at 97° C. and having a specific rotation of [α]D20 =+5°±1° (c=1% in chloroform).
Reaction SMILES: ClC(Cl)(Cl)[C:3]([C:5]1[NH:6][CH:7]=[C:8]([Cl:10])[CH:9]=1)=[O:4].[NH4+:13]>C1COCC1>[Cl:10][C:8]1[CH:9]=[C:5]([C:3]([NH2:13])=[O:4])[NH:6][CH:7]=1
Reactant: [NH4+]
Reactant: O=C(c1cc(Cl)c[nH]1)C(Cl)(Cl)Cl
Solvent: C1CCOC1
Product: NC(=O)c1cc(Cl)c[nH]1
Yield: 92 %

Procedure:
A solution of 2,2,2-trichloro-1-(4-chloro-1H-Pyrrol-2-yl)ethanone (14.0 g, 56.7 mmol) in THF (100 mL) was bubbled with ammonium gas for 2 h at room temperature. TLC analysis indicated that there was complete conversion of starting material. The reaction mixture was concentrated in vacuo to yield 7.5 g of the above compound (51.88 mmol, yield 92%). 1H-NMR (Acetone-d6) δ 10.92 (br s, 1H), 7.21 (br s, 1H), 7.02 (s, 1H), 6.84 (s, 1H), 6.57 (br s, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[NH:12][CH2:13][C:14]([CH3:17])([OH:16])[CH3:15])=[CH:9][CH:8]=[CH:7][CH:6]=2.[CH3:18][O:19][C:20]([NH:22][C:23](=NC(OC)=O)OC)=[O:21].C(O)(=O)C.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[OH:16][C:14]([CH3:17])([CH3:15])[CH2:13][N:12]1[C:11]2[C:10]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[N:4]=[CH:3][C:2]=2[N:1]=[C:23]1[NH:22][C:20](=[O:21])[O:19][CH3:18]
Reactant: COC(=O)N=C(NC(=O)OC)OC
Reactant: CC(C)(O)CNc1c(N)cnc2ccccc12
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: CC(=O)O
Product: COC(=O)Nc1nc2cnc3ccccc3c2n1CC(C)(C)O

Procedure:
A mixture of 1-[(3-amino-4-quinolinyl)amino]-2-methyl-2-propanol (1.0 g, 4.3 mmol), 1,3-dimethoxycarbonyl-O-methylisourea (prepared according to the general method of Viswanathan, N. Indian Patent No. 168,784, 1.64 g, 8.64 mmol), acetic acid (1.3 g, 22 mmol), and p-toluenesulfonic acid (0.82 g, 4.3 mmol) in methanol (20 mL) was heated at reflux for 16 hours. The volatiles were removed under reduced pressure, and the residue was dissolved in chloroform (100 mL). The solution was washed sequentially with water (100 mL), aqueous sodium carbonate (100 mL of 4% w/w), water (100 mL), and brine (100 mL) and then concentrated under reduced pressure. The residue was purified by automated flash chromatography (40+M silica cartridge, eluting with 0% to 25% CMA in chloroform) followed by recrystallization from acetonitrile to provide 0.64 g of methyl [1-(2-hydroxy-2-methylpropyl)-1H-imidazo[4,5-c]quinolin-2-yl]carbamate as a white solid, mp 225° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[C:5]([CH:7]1[CH2:12][CH2:11][N:10]([CH3:13])[CH2:9][CH2:8]1)=[O:6].[Br:17][C:18]1[CH:26]=[CH:25][C:21]([C:22](Cl)=[O:23])=[CH:20][CH:19]=1>>[Br:17][C:18]1[CH:26]=[CH:25][C:21]([C:22]([NH:1][C:2]2[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=2)[C:5]([CH:7]2[CH2:8][CH2:9][N:10]([CH3:13])[CH2:11][CH2:12]2)=[O:6])=[O:23])=[CH:20][CH:19]=1
Reactant: O=C(Cl)c1ccc(Br)cc1
Reactant: CN1CCC(C(=O)c2cccc(N)c2)CC1
Product: CN1CCC(C(=O)c2cccc(NC(=O)c3ccc(Br)cc3)c2)CC1
Yield: 112 %

Procedure:
Beginning with 4-[3-aminobenzoyl]-1-methylpiperidine (25 mg, 0.115 mmol) and 4-bromobenzoyl chloride (50 mg, 0.229 mmol), 51.7 mg (>100%) of the title compound were recovered.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:12]2[CH2:17][CH2:16][CH:15]([N:18]3[CH2:23][C@@H:22]4[CH2:24][C@H:19]3[CH2:20][NH:21]4)[CH2:14][CH2:13]2)[CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10].C([O-])([O-])=O.[K+].[K+].I[CH2:32][CH2:33][F:34]>CN(C=O)C>[F:34][CH2:33][CH2:32][N:21]1[CH2:20][C@@H:19]2[CH2:24][C@H:22]1[CH2:23][N:18]2[CH:15]1[CH2:16][CH2:17][N:12]([C:5]2[CH:6]=[CH:7][C:8]([N+:9]([O-:11])=[O:10])=[C:3]([O:2][CH3:1])[CH:4]=2)[CH2:13][CH2:14]1
Reactant: COc1cc(N2CCC(N3C[C@@H]4C[C@H]3CN4)CC2)ccc1[N+](=O)[O-]
Reactant: FCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(N2CCC(N3C[C@@H]4C[C@H]3CN4CCF)CC2)ccc1[N+](=O)[O-]
Reaction time: 8 h
Yield: 50.8 %

Procedure:
To (1S,4S)-2-{1-[3-(methyloxy)-4-nitrophenyl]-4-piperidinyl}-2,5-diazabicyclo-[2.2.1]heptane (0.40 g, 1.2 mmol) and K2CO3 (0.38 g, 2.8 mmol) in DMF (10 mL) was added 1-iodo-2-fluoroethane (0.26 g, 1.5 mmol), and the reaction was stirred overnight. More 1-iodo-2-fluoroethane (50 mg, 0.29 mmol) was added, and the solution stirred an additional 4 h. The solvent was removed under vacuum, and the residue was taken up in DCM. Silica was added, and the solvent removed under vacuum. Silica gel chromatography provided the title compound of step C as a yellow oil (230 mg, 0.61 mmol, 49% yield). 1H NMR (400 MHz, CDCl3) δ 7.96 (d, J=9.3 Hz, 1H), 6.38 (dd, J=9.3, 2.4 Hz, 1H), 6.27 (d, J=2.4 Hz, 1H), 4.58-4.39 (m, 2H), 3.91 (s, 3H), 3.82-3.73 (m, 2H), 3.51 (br s, 1H), 3.34 (br s, 1H), 3.08-2.98 (m, 2H), 2.96-2.53 (m, 7H), 1.96-1.65 (m, 4H), 1.59-1.46 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[C:5]([CH3:11])=[CH:4][C:3]=1[O:12][CH2:13][CH:14]1[CH2:16][CH:15]1[CH2:17][CH2:18][CH3:19].C(O)(=O)C>[Fe].O>[CH3:11][C:5]1[CH:4]=[C:3]([O:12][CH2:13][CH:14]2[CH2:16][CH:15]2[CH2:17][CH2:18][CH3:19])[C:2]([CH3:1])=[CH:7][C:6]=1[NH2:8]
Reactant: CCCC1CC1COc1cc(C)c([N+](=O)[O-])cc1C
Agent: [Fe]
Solvent: CC(=O)O
Solvent: O
Product: CCCC1CC1COc1cc(C)c(N)cc1C
Temperature: 80 °C
Reaction time: 1 h
Yield: 64.3 %

Procedure:
A mixture of 1.58 g of 2,5-dimethyl-4-nitro-1-[(2-propylcyclopropyl)methoxy]benzene, 1.68 g of iron powder, 20 mL of acetic acid and 20 mL of water was stirred at 80° C. for 1 hour. The reaction mixture was cooled to around room temperature, and then concentrated under reduced pressure. The resulting residue was converted into basic with an aqueous 1 N sodium hydroxide solution, then ethyl acetate was added, and the mixture was filtered. The filtrate was extracted with ethyl acetate, and then the organic layer was washed with water and saturated salt water, and dried over anhydrous magnesium sulfate. The resulting residue was subjected to silica gel column chromatography to obtain 0.90 g of 2,5-dimethyl-4-[(2-propylcyclopropyl)methoxy]phenylamine.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:11][CH:12]3[C:18](=[O:19])[N:17]([CH2:20][C:21]([N:23]([C:27]4[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=4)[CH:24]([CH3:26])[CH3:25])=[O:22])[C:16]4[CH:34]=[CH:35][CH:36]=[CH:37][C:15]=4[N:14]([C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)[C:13]3=[O:44])=[N:7][NH:8]2)=[CH:4][CH:3]=1.[C:45](OC(=O)C)(=[O:47])[CH3:46]>>[C:45]([N:8]1[C:9]2[C:5](=[CH:4][CH:3]=[C:2]([F:1])[CH:10]=2)[C:6]([CH2:11][CH:12]2[C:18](=[O:19])[N:17]([CH2:20][C:21]([N:23]([C:27]3[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=3)[CH:24]([CH3:25])[CH3:26])=[O:22])[C:16]3[CH:34]=[CH:35][CH:36]=[CH:37][C:15]=3[N:14]([C:38]3[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=3)[C:13]2=[O:44])=[N:7]1)(=[O:47])[CH3:46]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)N(C(=O)CN1C(=O)C(Cc2n[nH]c3cc(F)ccc23)C(=O)N(c2ccccc2)c2ccccc21)c1ccc(F)cc1
Product: CC(=O)n1nc(CC2C(=O)N(CC(=O)N(c3ccc(F)cc3)C(C)C)c3ccccc3N(c3ccccc3)C2=O)c2ccc(F)cc21

Procedure:
300 mg (0.505 mmol) 2-[3-(6-Fluoro-1H-indazol-3-ylmethyl)-2,4-dioxo-5-phenyl-2,3,4,5,-tetrahydro-benzo[b][1,4]diazepin-1-yl]-N-(4-fluoro-phenyl)-N-isopropyl-acetamide, prepared as in Example 63, is dissolved in 15 mL Acetic anhydride and heated at reflux 1 h. The solvent is removed in vacuo and the residue purified by preparative HPLC on a Delta-Pak C-18 column eluted from 35% to 60% CH3CN in H2O with 0.1% TFA buffer over 30 minutes at 150 mL/min. The appropriate fraction is frozen and lyophilized to give 144 mg (0.226 mmol) of the title compound as a white lyophilizate: 1H NMR (CDCl3, 300 MHz) δ8.04 (m, 1H), 7.76 (m, 1H), 7.50 (d, 1H, J=8.0), 7.39-7.08 (m, 12H), 6.98 (d, 1H, J=7.8), 5.02 (m, 1H), 4.32 (d, 1H, J=16.6), 4.30 (t, 1H), 4.10 (d, 1H, J=16.6), 3.75 (m, 1H), 3.57 (m, 1H), 2.63 (s, 3H), 1.08 (m, 6H); low resolution MS (FAB) m/e 636.1 (MH+); TLC Rf =0.30 (EtOAc/Hexanes, 1:2).
Reaction SMILES: [CH3:1][S:2]([NH2:5])(=[O:4])=[O:3].[OH-].[Na+].Cl[CH2:9][C@@H:10]1[CH2:12][O:11]1.Cl>O>[O:11]1[CH2:12][C@@H:10]1[CH2:9][CH2:1][S:2]([NH2:5])(=[O:4])=[O:3]
Reactant: ClC[C@@H]1CO1
Reactant: CS(N)(=O)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: NS(=O)(=O)CC[C@H]1CO1
Reaction time: 2 h
Yield: 15.7 %

Procedure:
To a cold solution of methanesulfonamide (10 g, 0.105 mol) in water (100 mL) in an ice bath was added sodium hydroxide as pellets (8.4 g, 0.21 mol) and then (S)-2-chloromethyloxirane (12.4 g, 0.158 mol). The mixture was stirred at the same temperature for 2 h, and at room temperature for 12 h and then concentrated hydrochloric acid (18 mL) was added. The product was isolated by extracting the aqueous layer with dichloromethane (2×300 mL). The organic layer was dried over MgSO4 and then evaporated to dryness, yielding a colorless liquid (2.5 g), which was used directly in the next step.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][O:9][C:10]1[NH:11][C:12]2[C:17]([N:18]=1)=[C:16]([NH2:19])[N:15]=[C:14]([O:20][CH2:21][CH2:22][O:23][CH3:24])[N:13]=2.C(=O)([O-])[O-].[K+].[K+].CS(O[CH2:36][CH:37]1[CH2:41][CH2:40][O:39][CH2:38]1)(=O)=O>CN(C=O)C>[CH3:8][O:9][C:10]1[N:11]([CH2:36][CH:37]2[CH2:41][CH2:40][O:39][CH2:38]2)[C:12]2[C:17]([N:18]=1)=[C:16]([NH2:19])[N:15]=[C:14]([O:20][CH2:21][CH2:22][O:23][CH3:24])[N:13]=2
Reactant: COCCOc1nc(N)c2nc(OC)[nH]c2n1
Reactant: CS(=O)(=O)OCC1CCOC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: COCCOc1nc(N)c2nc(OC)n(CC3CCOC3)c2n1
Temperature: 60 °C
Yield: 44.9 %

Procedure:
8-(Methoxy)-2-{[2-(methoxy)ethyl]oxy}-9H-purin-6-amine trifluoroacetate salt (0.30 g) was dissolved in dry DMF (5 mL). To this was added anhydrous potassium carbonate (0.47 g) and then heated to 60° C. for 1.5 hours. The reaction mixture was cooled to room temperature and tetrahydro-3-furanylmethyl methanesulfonate (0.168 g) was added. The reaction mixture was then heated to 90° C. for 3.5 hours. The reaction mixture was then quenched into water (100 mL) and extracted into ethyl acetate (50 mL, 3 times). The organic was separated and dried by passing through a hydrophobic frit and then evaporated under reduced pressure to give a glassy solid. This was purified by C18 reverse phase chromatography using water (containing 0.1% formic acid)-acetonitrile (containing 0.05% formic acid) as eluent (10-45%). This gave the title compound as a white solid (0.1233 g).
Reaction SMILES: [NH:1]1[C:5]2=[N+:6]([O-])[CH:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[CH:2]1.CN(C)C=O.CS([Cl:20])(=O)=O.[OH-].[Na+]>O>[Cl:20][C:9]1[CH:8]=[CH:7][N:6]=[C:5]2[NH:1][CH:2]=[CH:3][C:4]=12
Reactant: CS(=O)(=O)Cl
Reactant: [O-][n+]1cccc2cc[nH]c21
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: Clc1ccnc2[nH]ccc12
Temperature: 40 °C
Yield: 135.4 %

Procedure:
To a pink solution of 1H-pyrrolo[2,3-b]pyridine 7-oxide (2.47 g, 0.0184 mol) in dimethylformamide (DMF) (13.3 mL, 0.172 mol) was added methanesulfonyl chloride (4.0 mL, 0.052 mol) at 50° C., and the pink color changed to orange. The reaction mixture was heated at 73° C. for 2h, then cooled to 40° C. Water (35 mL) was added, and the resulting suspension was cooled at 0° C. NaOH was added to adjust the pH of the mixture to about 7. The mixture was filtered and washed with water (×3) to give 3.8 g of a wet pale orange solid that was dried at 40° C. overnight to give the product (2.35 g, 82.2% yield).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]([NH:8][CH2:9][C:10]2[C:11]([CH3:25])=[CH:12][C:13]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[N:14][C:15]=2[CH3:16])=[O:7])[CH:3]=[N:2]1.CS(O[CH2:31][C:32]1[CH:33]=[C:34]2[C:39](=[CH:40][CH:41]=1)[N:38]=[CH:37][C:36]([Cl:42])=[CH:35]2)(=O)=O.C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[Cl:42][C:36]1[CH:37]=[N:38][C:39]2[C:34]([CH:35]=1)=[CH:33][C:32]([CH2:31][N:1]1[CH:5]=[C:4]([C:6]([NH:8][CH2:9][C:10]3[C:11]([CH3:25])=[CH:12][C:13]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[N:14][C:15]=3[CH3:16])=[O:7])[CH:3]=[N:2]1)=[CH:41][CH:40]=2
Reactant: CS(=O)(=O)OCc1ccc2ncc(Cl)cc2c1
Reactant: Cc1cc(NC(=O)OC(C)(C)C)nc(C)c1CNC(=O)c1cn[nH]c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Cc1cc(NC(=O)OC(C)(C)C)nc(C)c1CNC(=O)c1cnn(Cc2ccc3ncc(Cl)cc3c2)c1

Procedure:
A solution of tert-Butyl 5-((1H-pyrazole-4-carboxamido)methyl)-4,6-dimethylpyridin-2-ylcarbamate (145 mg, 0.421 mmol), (3-Chloroquinolin-6-yl)methyl methanesulfonate (143 mg, 0.421 mmol 80%) and K2CO3 (291 mg, 2.105 mmol) in Acetone (3 ml) was stirred for 20 h at 50° C. The reaction was quenched with H2O and extracted twice with DCM. The organic layer was dried with Na2SO4, filtered and evaporated to dryness to afford crude title compound. The crude product was purified by preparative HPLC (Macherey-Nagel Nucleosil 250×40 mm, 5 to 100% ACN and 0.1% TFA, flow 40 ml/min) to afford pure title compound. MS (Method V) [M+H]+=521.4.
Reaction SMILES: CO[C:3](=[O:24])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[C:13]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[N:14][O:15][C:16]=2[CH3:17])=[N:6][CH:5]=1.[NH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][OH:32]>>[OH:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][NH:25][C:3](=[O:24])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[C:13]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)=[N:14][O:15][C:16]=2[CH3:17])=[N:6][CH:5]=1
Reactant: COC(=O)c1ccc(OCc2c(-c3ccccc3)noc2C)nc1
Reactant: NCCCCCCO
Product: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)NCCCCCCO)cn1
Yield: 20 %

Procedure:
As described for example 220, 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid methyl ester (180 mg, 0.55 mmol) was converted, using 6-amino-1-hexanol instead of 3-amino-1-propanol, to the title compound (45 mg, 20%) which was obtained as a white solid. MS: m/e=410.3 [M+H]+.
Reaction SMILES: ClC1C=C(CC[CH2:10][N:11]([C@H:25]2[CH2:30][CH2:29][C@H:28]([CH3:31])[CH2:27][CH2:26]2)[C:12](=[O:24])[NH:13][C:14]2[S:15][C:16]([S:19][CH2:20][C:21]([OH:23])=[O:22])=[CH:17][N:18]=2)C=CC=1.[Cl:32][C:33]1[CH:34]=[CH:35][C:36]2[O:40][CH:39]=[C:38]([CH2:41][CH2:42]C(O)=O)[C:37]=2[CH:46]=1.C(OC(=O)CSC1SC(N)=NC=1)C>>[Cl:32][C:33]1[CH:34]=[CH:35][C:36]2[O:40][CH:39]=[C:38]([CH2:41][CH2:42][CH2:10][N:11]([C@H:25]3[CH2:30][CH2:29][C@H:28]([CH3:31])[CH2:27][CH2:26]3)[C:12](=[O:24])[NH:13][C:14]3[S:15][C:16]([S:19][CH2:20][C:21]([OH:23])=[O:22])=[CH:17][N:18]=3)[C:37]=2[CH:46]=1
Reactant: C[C@H]1CC[C@H](N(CCCc2cccc(Cl)c2)C(=O)Nc2ncc(SCC(=O)O)s2)CC1
Reactant: O=C(O)CCc1coc2ccc(Cl)cc12
Agent: CCOC(=O)CSc1cnc(N)s1
Product: C[C@H]1CC[C@H](N(CCCc2coc3ccc(Cl)cc23)C(=O)Nc2ncc(SCC(=O)O)s2)CC1

Procedure:
The compound was prepared following an analogous procedure to the one described for the synthesis of {2-[-3-[3-(3-chloro-phenyl)-propyl]-3-(trans-4-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid using 3-(5-chloro-benzofuran-3-yl)-propionic acid and (2-aminothiazol-5-ylsulfanyl) acetic acid ethyl ester.
Reaction SMILES: C(N(CC)CC)C.[OH:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)=[CH:11][CH:10]=1.Cl[CH2:22][C:23]1[S:24][C:25]2[CH:31]=[CH:30][CH:29]=[CH:28][C:26]=2[N:27]=1>C(COC)OC>[OH:8][C:9]1[CH:10]=[CH:11][C:12]([N:15]2[CH2:20][CH2:19][N:18]([CH2:22][C:23]3[S:24][C:25]4[CH:31]=[CH:30][CH:29]=[CH:28][C:26]=4[N:27]=3)[CH2:17][CH2:16]2)=[CH:13][CH:14]=1
Reactant: ClCc1nc2ccccc2s1
Reactant: Oc1ccc(N2CCNCC2)cc1
Solvent: CCN(CC)CC
Solvent: COCCOC
Product: Oc1ccc(N2CCN(Cc3nc4ccccc4s3)CC2)cc1
Reaction time: 5 h
Yield: 81.1 %

Procedure:
A solution of 1.05 g of triethylamine in 20 ml of absolute dimethoxyethane was added dropwise within 15 minutes with stirring to a mixture of 1.78 g (10 mmol) of 1-(4-hydroxyphenyl)piperazine, 2.48 g (13.5 mmol) of 2-chloromethylbenzothiazole and 80 ml of absolute 1,2-dimethoxyethane under reflux. The mixture was stirred for a further 5 hours under reflux, the solvent was evaporated in vacuo, the residue was taken up in CH2Cl2 /H2O, the phases were separated, and the aqueous phase was extracted three times with CH2Cl2. The combined CH2Cl2 extracts were dried, filtered and evaporated. The crystalline residue (3.2 g) was recrystallized from methanol. 2.64 g (81.2% of theory) of pure 1-(4-hydroxyphenyl)-4-(benzothiazol-2-ylmethyl)piperazine, melting point 175°-76° C., were obtained.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[C:11]([C:12]#[N:13])=[CH:10][CH:9]=[C:8]2[C:4]=1[CH:5]=[CH:6][NH:7]2.Cl[CH2:17][C:18]1[N:22]=[C:21]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[O:29][CH3:30])[O:20][N:19]=1>>[CH3:30][O:29][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1[C:21]1[O:20][N:19]=[C:18]([CH2:17][N:7]2[C:8]3[C:4](=[C:3]([C:2]([F:14])([F:1])[F:15])[C:11]([C:12]#[N:13])=[CH:10][CH:9]=3)[CH:5]=[CH:6]2)[N:22]=1
Reactant: COc1ccccc1-c1nc(CCl)no1
Reactant: N#Cc1ccc2[nH]ccc2c1C(F)(F)F
Product: COc1ccccc1-c1nc(Cn2ccc3c(C(F)(F)F)c(C#N)ccc32)no1

Procedure:
Synthesized as described in Example 23 using 4-(trifluoromethyl)-1H-indole-5-carbonitrile and 3-(chloromethyl)-5-[2-(methyloxy)phenyl]-1,2,4-oxadiazole: MS (ES) m/z 399 (M+1).
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[CH:5][N:6]=1.Cl[C:8]1[N:9]=[C:10]([NH:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)[C:11]2[CH:16]=[C:15]([CH3:17])[S:14][C:12]=2[N:13]=1>>[CH3:1][C:2]1[N:3]([C:8]2[N:9]=[C:10]([NH:18][CH2:19][C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[C:11]3[CH:16]=[C:15]([CH3:17])[S:14][C:12]=3[N:13]=2)[CH:4]=[CH:5][N:6]=1
Reactant: Cc1ncc[nH]1
Reactant: Cc1cc2c(NCc3ccc(F)cc3)nc(Cl)nc2s1
Product: Cc1cc2c(NCc3ccc(F)cc3)nc(-n3ccnc3C)nc2s1

Procedure:
Following the procedure of Example 97, the reaction of 2-methylimidazole with 2-chloro-6-methyl-4-(4-fluorobenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(2-methylimidazol-1-yl)-6-methyl-4-(4-fluorobenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([CH3:7])=[C:4]([C:8]([OH:10])=O)[CH:3]=1.C(Cl)(=O)C(Cl)=O.[C:17]1([O:23][CH3:24])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[Al+3].[Cl-].[Cl-].[Cl-]>C(Cl)Cl.CN(C=O)C>[Br:1][C:2]1[S:6][C:5]([CH3:7])=[C:4]([C:8]([C:20]2[CH:21]=[CH:22][C:17]([O:23][CH3:24])=[CH:18][CH:19]=2)=[O:10])[CH:3]=1
Reactant: Cc1sc(Br)cc1C(=O)O
Reactant: COc1ccccc1
Agent: O=C(Cl)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1ccc(C(=O)c2cc(Br)sc2C)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of acid 8 (10 g, 45.2 mmol) in CH2Cl2 (200 mL) were added oxalyl chloride (4.8 mL, 54.3 mmol) and catalytic amounts of DMF at room temperature. The mixture was stirred at room temperature for 2 hours. The mixture was concentrated in vacuo and dried under high vacuum. The crude acid chloride was dissolved with CH2Cl2 (200 mL) and cooled to 0° C. To the mixture was added anisole (5.0 mL, 45.2 mmol) at 0° C. and stirred at 0° C. for 5 min. To the reaction mixture was added AlCl3 (6.0 g, 45.2 mmol) portionwise at 0° C. The mixture was stirred at 0° C. for 2 hours, warmed up to room temperature and stirred at room temperature for 15 hours. The mixture was poured into ice-water and extracted with CH2Cl2 (100 mL×2). The combined organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The crude product was tritulated with MeOH (100 mL) and stirred at 0° C. for 1 hour. The precipitated solid was filtered and washed with MeOH (50 mL). The solid was dried under high vacuum and used without further purification (11.7 g, 83%).