Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[S:5][CH:6]=[CH:7][CH:8]=1)(=[O:3])[CH3:2].CO[CH:11](OC)[N:12](C)[CH3:13].[CH3:17]CCCCC>>[CH3:11][N:12]([CH3:13])[C:2](=[CH2:17])[C:1]([C:4]1[S:5][CH:6]=[CH:7][CH:8]=1)=[O:3]
Reactant: CC(=O)c1cccs1
Reactant: COC(OC)N(C)C
Reactant: CCCCCC
Product: C=C(C(=O)c1cccs1)N(C)C
Yield: 63 %

Procedure:
A mixture of 2-acetylthiophene (10.0 g, 80 mmol) (Aldrich) and dimethylformamide dimethyl acetal (15 g, 126 mmol) is refluxed under nitrogen for 3 hrs, The reaction mixture is cooled and hexane (300 mL) added. The solid is collected by filtration to yield product (1) as an orange solid (9.1 g, 50 mmol, 63%).
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[C:4](=[O:14])[NH:5][C:6](=[O:13])[N:7]([CH2:9][CH2:10][CH:11]=O)[CH:8]=1.[F:17][C:18]([F:32])([F:31])[C:19]1[CH:24]=[CH:23][C:22]([C@:25]23[CH2:30][C@H:29]2[CH2:28][NH:27][CH2:26]3)=[CH:21][CH:20]=1.CC(O)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[Cl:51]CCCl>C(OCC)(=O)C>[ClH:51].[F:1][C:2]([F:16])([F:15])[C:3]1[C:4](=[O:14])[NH:5][C:6](=[O:13])[N:7]([CH2:9][CH2:10][CH2:11][N:27]2[CH2:28][C@H:29]3[C@:25]([C:22]4[CH:21]=[CH:20][C:19]([C:18]([F:17])([F:32])[F:31])=[CH:24][CH:23]=4)([CH2:30]3)[CH2:26]2)[CH:8]=1
Reactant: FC(F)(F)c1ccc([C@@]23CNC[C@@H]2C3)cc1
Reactant: O=CCCn1cc(C(F)(F)F)c(=O)[nH]c1=O
Reactant: ClCCCl
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: Cl
Product: O=c1[nH]c(=O)n(CCCN2C[C@@H]3C[C@]3(c3ccc(C(F)(F)F)cc3)C2)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 51 %

Procedure:
To a solution of 3-(5-trifluoromethyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-propionaldehyde (Prep21, 0.05 g, 0.21 mmol) in DCE (1 mL), (1S,5R)-1-(4-trifluoromethyl-phenyl)-3-aza-bicyclo[3.1.0]hexane (Prep4, 0.08 g, 0.35 mmol) in DCE (1 mL), AcOH (20 μl, 0.36 mmol) and NaBH(AcO)3 (0.09 g, 0.42) were added and the mixture was stirred at room temperature overnight. Ethyl acetate was added and the solution washed with aqueous saturated NaHCO3. The organic phase was dried (Na2SO4) and evaporated. The crude was purified by flash chromatography with DCM-MeOH—NH4OH (97-3-1) to give the title compound (0.04 mg, 51% yield) as a free base.
Reaction SMILES: [CH3:1][CH:2]([CH3:21])[CH2:3][NH:4][C:5]1[C:14]2[C:9](=[N:10][CH:11]=[CH:12][CH:13]=2)[N:8]2[N:15]=[N:16][N:17]=[C:7]2[C:6]=1[N+:18]([O-])=O.[H][H]>[Pt].C(O)C>[CH3:1][CH:2]([CH3:21])[CH2:3][NH:4][C:5]1[C:14]2[C:9](=[N:10][CH:11]=[CH:12][CH:13]=2)[N:8]2[N:15]=[N:16][N:17]=[C:7]2[C:6]=1[NH2:18]
Reactant: CC(C)CNc1c([N+](=O)[O-])c2nnnn2c2ncccc12
Reactant: [H][H]
Agent: [Pt]
Solvent: CCO
Product: CC(C)CNc1c(N)c2nnnn2c2ncccc12

Procedure:
A catalytic amount of 5% platinum on carbon was added to a suspension of N5-(2-methylpropyl)-4-nitrotetrazolo[1,5-a][1,8]naphthyridine-5-amine (5 g, 17.4 mmoles) in ethanol (300 mL). The reaction mixture was reduced on a Parr apparatus at 50 psi (3.5 Kg/cm2) hydrogen for 2 hours. The reaction mixture was filtered to remove the catalyst. The filtrate was concentrated under vacuum to provide N5-(2-methylpropyl)tetrazolo[1,5-a][1,8]naphthyridin-4,5-diamine as an oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]([N:8]([CH3:24])[C@H:9]2[CH2:14][CH2:13][C@H:12]([C:15]#[C:16][CH2:17][CH2:18]OS(C)(=O)=O)[CH2:11][CH2:10]2)=[N:6][CH:7]=1.[CH3:25][NH:26][CH3:27]>CO>[Br:1][C:2]1[CH:3]=[N:4][C:5]([N:8]([C@H:9]2[CH2:14][CH2:13][C@H:12]([C:15]#[C:16][CH2:17][CH2:18][N:26]([CH3:27])[CH3:25])[CH2:11][CH2:10]2)[CH3:24])=[N:6][CH:7]=1
Reactant: CN(c1ncc(Br)cn1)[C@H]1CC[C@H](C#CCCOS(C)(=O)=O)CC1
Reactant: CNC
Solvent: CO
Product: CN(C)CCC#C[C@H]1CC[C@H](N(C)c2ncc(Br)cn2)CC1
Temperature: 65 °C

Procedure:
A solution of 211 mg (0.51 mmol) of crude trans-Methanesulfonic acid 4-{4-[(5-bromo-pyrimidin-2-yl)-methyl-amino]-cyclohexyl}-but-3-ynyl ester in 5 ml of methanol was treated with 0.91 ml (5.1 mmol) Dimethylamine (33% in EtOH, 5.6M) and heated at 65° C. for 4 h. After cooling and evaporation, the residue was extracted with aqueous saturated NaHCO3/Et2O (3×). The organic phase was dried (Na2SO4), filtered and evaporated. Purification by flash column chromatography on silica gel (CH2Cl2/MeOH 99:1 to 95:5) gave 141 mg (76%) of trans-(5-Bromo-pyrimidin-2-yl)-[4-(4-dimethylamino-but-1-ynyl)-cyclohexyl]-methyl-amine, MS: 365 (MH+, 1Br).
Reaction SMILES: [I-].C[S+](C)(C)=O.[CH3:7]C(C)([O-])C.[K+].O1CCCC1.[CH:18]([CH:20]([NH:42][C:43](=[O:49])[O:44][C:45]([CH3:48])([CH3:47])[CH3:46])[CH2:21][CH:22]([CH2:26][C:27]1[CH:28]=[C:29]2[C:33](=[CH:34][CH:35]=1)[N:32]([CH3:36])[CH:31]=[C:30]2[CH2:37][CH2:38][CH2:39][O:40][CH3:41])[CH:23]([CH3:25])[CH3:24])=[O:19]>CS(C)=O>[CH3:41][O:40][CH2:39][CH2:38][CH2:37][C:30]1[C:29]2[C:33](=[CH:34][CH:35]=[C:27]([CH2:26][CH:22]([CH:23]([CH3:24])[CH3:25])[CH2:21][CH:20]([NH:42][C:43](=[O:49])[O:44][C:45]([CH3:47])([CH3:46])[CH3:48])[CH:18]3[CH2:7][O:19]3)[CH:28]=2)[N:32]([CH3:36])[CH:31]=1
Reactant: CC(C)(C)[O-]
Reactant: COCCCc1cn(C)c2ccc(CC(CC(C=O)NC(=O)OC(C)(C)C)C(C)C)cc12
Agent: C[S+](C)(C)=O
Agent: [I-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: COCCCc1cn(C)c2ccc(CC(CC(NC(=O)OC(C)(C)C)C3CO3)C(C)C)cc12
Temperature: 0 °C

Procedure:
1.29 g of trimethylsulphoxonium iodide and 0.66 g of potassium tert-butoxide are stirred under high vacuum overnight, admixed with 8 ml of tetrahydrofuran and subsequently cooled to 0° C. A solution of 1.01 g of tert-butyl {1-formyl-3-[3-(3-methoxypropyl)-1-methyl-1H-indol-5-ylmethyl]-4-methylpentyl}carbamate in 8 ml of dimethyl sulphoxide is added dropwise. On completion of reaction (TLC monitoring), the reaction mixture is partitioned between water and tert-butyl methyl ether, and the aqueous phase is extracted once more with tert-butyl methyl ether (2×). The combined organic phases are washed successively with water (3×) and brine, dried over sodium sulphate and concentrated by evaporation. The title compound is identified on the basis of the Rf value from the residue by means of flash chromatography (SiO2 60F).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([O:12][CH3:13])[C:10]=1[Cl:11])[C:5](O)=[O:6].S(Cl)([Cl:16])=O.S(=O)=O.Cl>C1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([O:12][CH3:13])[C:10]=1[Cl:11])[C:5]([Cl:16])=[O:6]
Reactant: O=S(Cl)Cl
Reactant: COc1cc(C(=O)O)cc(Cl)c1Cl
Agent: Cl
Agent: O=S=O
Solvent: c1ccccc1
Product: COc1cc(C(=O)Cl)cc(Cl)c1Cl

Procedure:
3,4-Dichloro-5-methoxybenzoic acid (22.1 g., 0.1 mole) is heated with thionyl chloride (15 g., 0.125 mole) in benzene (100 ml.) until evolution of sulfur dioxide and hydrogen chloride ceases. The benzene and excess thionyl chloride are evaporated and the solid residue is used in the next step.
Reaction SMILES: Br[CH2:2][C:3]1[S:11][C:10]2[C:9]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)=[N:8][C:7](Cl)=[N:6][C:5]=2[CH:4]=1.[NH:19]1[CH:23]=[CH:22][N:21]=[CH:20]1.C([O-])([O-])=O.[K+].[K+].C[N:31]([CH:33]=O)C>>[N:19]1([CH2:2][C:3]2[S:11][C:10]3[C:9]([N:12]4[CH2:17][CH2:16][O:15][CH2:14][CH2:13]4)=[N:8][C:7]([C:5]4[CH:4]=[CH:3][CH:2]=[C:33]5[C:10]=4[CH:9]=[N:8][NH:31]5)=[N:6][C:5]=3[CH:4]=2)[CH:23]=[CH:22][N:21]=[CH:20]1
Reactant: CN(C)C=O
Reactant: c1c[nH]cn1
Reactant: Clc1nc(N2CCOCC2)c2sc(CBr)cc2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: c1cc(-c2nc(N3CCOCC3)c3sc(Cn4ccnc4)cc3n2)c2cn[nH]c2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 6-(bromomethyl)-2-chloro-4-morpholinothieno[3,2-d]pyrimidine 30 from Example 9 (90 mg, 0.3 mmol) in DMF (3 mL) was added imidazole (18 mg, 0.3 mmol) and K2CO3 (50 mg, 0.4 mmol). The resulting solution stirred at room temperature overnight then was concentrated in vacuo. The residue was diluted with water and filtered. The crude product was utilized in a Suzuki coupling using General Procedure A with 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole 7 to provide 312 after reverse phase HPLC purification (32 mg). MS (Q1) 418 (M)+
Reaction SMILES: [CH2:1]([S:3]([OH:6])(=[O:5])=[O:4])[CH3:2].[CH3:7][CH2:8][O:9][C:10]([C:12]1[CH:17]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:23]=2[Cl:24])[C:16]([C:25]([O:27][CH3:28])=[O:26])=[C:15]([CH3:29])[NH:14][C:13]=1[CH2:30][O:31][CH2:32][CH2:33][NH2:34])=[O:11]>CO>[CH3:7][CH2:8][O:9][C:10]([C:12]1[CH:17]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:23]=2[Cl:24])[C:16]([C:25]([O:27][CH3:28])=[O:26])=[C:15]([CH3:29])[NH:14][C:13]=1[CH2:30][O:31][CH2:32][CH2:33][NH2:34])=[O:11].[CH2:1]([S:3]([O-:6])(=[O:5])=[O:4])[CH3:2]
Reactant: CCS(=O)(=O)O
Agent: CCOC(=O)C1=C(COCCN)NC(C)=C(C(=O)OC)C1c1ccccc1Cl
Solvent: CO
Product: CCS(=O)(=O)[O-]
Temperature: 23 °C
Reaction time: 2 h

Procedure:
Into a 1L three-neck flask, ethanesulfonic acid (11.56 g, 1.05 equivalents) and methanol (200 ml) were poured. To the flask, a solution of amlodipine (40.8 g, 0.1 mole) in methanol (300 ml) was added dropwise. The resulting solution was stirred at 23° C. for 2 hours, cooled to 7° C. and stirred again for 1 hour to produce precipitates. They were washed at 5° C. with methanol (100 ml) and n-hexane (100 ml), filtered, and dried at 35° C. in vacuo to afford 46.4 g of amlodipine ethanesulfonate as a white crystalline solid (Yield 90%).
Reaction SMILES: [H-].[Na+].[CH2:3]([C:5]1[N:6]=[CH:7][NH:8][CH:9]=1)[CH3:4].F[C:11]1[CH:16]=[CH:15][C:14]([C:17](=[O:19])[CH3:18])=[CH:13][CH:12]=1>CN(C=O)C.O>[CH2:3]([C:5]1[N:6]=[CH:7][N:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17](=[O:19])[CH3:18])=[CH:13][CH:12]=2)[CH:9]=1)[CH3:4]
Reactant: CC(=O)c1ccc(F)cc1
Reactant: CCc1c[nH]cn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCc1cn(-c2ccc(C(C)=O)cc2)cn1
Temperature: 25 °C

Procedure:
NaH (0.068 g in 60% oil dispersion, 1.7 mmol) was added to a solution of compound 16 (0.180 g, 1.8 mmol) in DMF (6 mL) with stirring at room temperature. The mixture was stirred for 15 min and a solution of 4′-fluoroacetophenone (0.215 g, 1.56 mmol) in DMF (2 mL) was added. The reaction mixture was heated at 80° C. for 1 h, and then cooled, diluted with water, and extracted with EtOAc. The organic layer was washed with brine, dried, and evaporated to a yellow solid. Compound 17 crystallized to form white color needles upon standing at room temperature. The yield was 0.270 g, 67%. The structure was confirmed by 1H NMR in CDCl3. LC-MS: [M+1]=215. Purity was >98%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.[Br:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11]>>[Br-:8].[C:10]([CH2:9][N+:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)([O:12][CH2:13][CH3:14])=[O:11]
Reactant: Clc1ccncc1
Reactant: CCOC(=O)CBr
Product: CCOC(=O)C[n+]1ccc(Cl)cc1
Product: [Br-]

Procedure:
A solution of 1.1 g. (10 mmoles; 0.95 ml.) of 4-chloropyridine in 10 g. (60 mmoles) of ethyl bromoacetate is kept at 5° for 48 hours. The mixture is diluted with 15 ml. of ether, filtered and the solid is washed well with ether.
Reaction SMILES: CO[C:3](=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10]Br)[CH:5]=1.[CH3:13][S:14]([NH2:17])(=[O:16])=[O:15].[F:18][C:19]1[CH:24]=[CH:23][C:22]([C@@H:25]2[C@:27]3([C:35]4[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=4)[NH:29][C:28]3=[O:36])[CH2:26]2)=[CH:21][CH:20]=1>>[F:18][C:19]1[CH:20]=[CH:21][C:22]([C@@H:25]2[C@:27]3([C:35]4[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=4)[N:29]([CH2:10][C:6]4[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=4)[C:3]([NH:17][S:14]([CH3:13])(=[O:16])=[O:15])=[O:12])[C:28]3=[O:36])[CH2:26]2)=[CH:23][CH:24]=1
Reactant: COC(=O)c1cccc(CBr)c1
Reactant: O=C1Nc2ccccc2[C@@]12C[C@@H]2c1ccc(F)cc1
Reactant: CS(N)(=O)=O
Product: CS(=O)(=O)NC(=O)c1cccc(CN2C(=O)[C@]3(C[C@@H]3c3ccc(F)cc3)c3ccccc32)c1

Procedure:
The title compound was prepared in analogy to Example 60 starting from 3-bromomethyl-benzoic acid methyl ester, methylsulfonamide (commercially available), (1R,2S) and (1S,2R)-2-(4-fluorophenyl)spiro[cyclopropane-1,3′-indolin]-2′-one prepared as in Scheme 1. LC/MS m/e calcd. for C25H21FN2O4S: 470, observed (M+H)+: 471.2 1HNMR (400 MHz, DMSO-d6) δppm 2.10-2.18 (m, 1 H) 2.33-2.42 (m, 1 H) 3.18-3.27 (m, 1 H) 3.38 (s, 3 H) 5.10 (s, 2 H) 6.12 (d, 1 H) 6.71 (t, 1 H) 6.89-6.97 (m, 1 H) 7.03-7.09 (m, 1 H) 7.11-7.18 (m, 2H) 7.31-7.41 (m, 2 H) 7.48-7.55 (m, 1 H) 7.56-7.63 (m, 1 H) 7.82-7.93 (m, 2 H).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3](=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].CO[CH:15](OC)[N:16]([CH3:18])[CH3:17]>C1C=CC=CC=1>[CH3:15][N:16]([CH:18]=[C:4]([C:3](=[O:10])[C:2]([F:11])([F:12])[F:1])[C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH3:17]
Reactant: CCOC(=O)CC(=O)C(F)(F)F
Reactant: COC(OC)N(C)C
Solvent: c1ccccc1
Product: CCOC(=O)C(=CN(C)C)C(=O)C(F)(F)F
Yield: 64.9 %

Procedure:
Ethyl 4,4,4-trifluoroacetoacetate (18.5 g, 77.34 mmol) and N,N-Dimethylformamide dimethyl acetal (9.21 g 77.34 mmol) were dissolved in benzene (10 mL). The mixture was heated under reflux for 1 h. The solvent was evaporated and distilled with a Kugelrohr apparatus to give 12 g of ethyl 2-((dimethylamino)methylene)-4,4,4-trifluoro-3-oxobutanoate (yield 65%).
Reaction SMILES: [CH:1]1[CH2:5][CH:4]=[CH:3][CH:2]=1.[C:6]1(=[O:12])[O:11][C:9](=[O:10])[CH:8]=[CH:7]1.S(=O)(=O)(O)O.[O:18]1CCC[CH2:19]1>>[CH3:19][O:18][C:9]([CH:8]1[CH:7]([C:6]([OH:11])=[O:12])[CH:4]2[CH:5]=[CH:1][CH:2]1[CH2:3]2)=[O:10]
Reactant: O=C1C=CC(=O)O1
Reactant: C1=CCC=C1
Reactant: C1CCOC1
Agent: O=S(=O)(O)O
Product: COC(=O)C1C2C=CC(C2)C1C(=O)O
Yield: 76.6 %

Procedure:
Cyclopentadiene (66 g) and tetrahydrofuran solvent (500 g) are charged in a reactor and the mixture is stirred homogeneously. To the reaction mixture, maleic anhydride (98 g) is added, and the resultant mixture is stirred at 0° C. for about 12 hours. Then, the mixture is filtered to remove the precipitate. To the resultant reactant, a 10% aqueous NaOH solution is added to carry out a hydrolysis reaction. The reactant is neutralized by using a 10% sulfuric acid solution. When reaction is completed, the resultant product is recovered by filtration and dried to obtain 150 g (yield: 86%) of mono-methyl cis 5-norbornene-endo-2,3-dicarboxylate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]([CH3:13])[C:10](O)=[O:11].[NH3:14]>ClCCl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]([CH3:13])[C:10]([NH2:14])=[O:11]
Reactant: N
Reactant: COc1ccccc1C(C)C(=O)O
Solvent: ClCCl
Product: COc1ccccc1C(C)C(N)=O
Reaction time: 0.5 h

Procedure:
N,N'-Carbonyldiimidazole (16.2 g) is added to a solution of 2-(2-methoxyphenyl)propionic acid (17.5 g) in dry dichloromethane (200 cc), cooled to +5° C. The mixture is stirred for 30 minutes at +5° C. and a stream of ammonia is then passed into the solution for 1 hour, maintaining the same temperature. After stirring for 2 hours at 20° C., the reaction mixture is washed with water (200 cc), dried over magnesium sulphate and then concentrated to dryness under reduced pressure (2.7 kPa). The residue is crystallized from isopropyl ether and the crystals are drained and dried under reduced pressure (2.7 kPa). (RS)-2-(2-Methoxyphenyl)propionamide (12.1 g) is obtained in the form of a white solid melting at 138° C.
Reaction SMILES: O=C1CC([O:8][C@@H:9]2[CH2:13][NH:12][C:11](=[O:14])[CH2:10]2)CCO1.[CH2:15]([NH:22][C:23]([C:25]1[S:29][C:28](Br)=[N:27][C:26]=1[CH3:31])=[O:24])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(=O)([O-])[O-].[Cs+].[Cs+].ClCCl>C1(C)C=CC=CC=1.C(OCC)(=O)C.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>[CH2:15]([NH:22][C:23]([C:25]1[S:29][C:28]([N:12]2[CH2:13][C@@H:9]([OH:8])[CH2:10][C:11]2=[O:14])=[N:27][C:26]=1[CH3:31])=[O:24])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: Cc1nc(Br)sc1C(=O)NCc1ccccc1
Reactant: O=C1C[C@H](OC2CCOC(=O)C2)CN1
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: Cc1nc(N2C[C@@H](O)CC2=O)sc1C(=O)NCc1ccccc1
Temperature: 50 °C
Yield: 52.8 %

Procedure:
A mixture of (4S)-4-(2-oxotetrahydro-2H-pyran-4-yloxy)pyrrolidin-2-one (0.036 g, 0.19 mmol), N-benzyl-2-bromo-4-methylthiazole-5-carboxamide (0.050 g, 0.16 mmol), cesium carbonate (0.079 g, 0.24 mmol), [1,1′-bis(diphenylphosphino)-ferrocene]dichloropalladium(II) complex with dichloromethane (1:1) (0.003 g, 0.003 mmol) and xantphos (0.004 g, 0.006 mmol) in anhydrous toluene (3 mL) was subjected to microwave irradiation at 80° C. for 20 min. The reaction mixture was diluted with ethyl acetate (10 mL) and washed with water (4 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was dissolved in ethanol and a catalytic amount of pyridinium p-toluenesulfonate was added to the solution. The reaction mixture was heated at 50° C. for 6 hours and concentrated in vacuo. The residue was dissolved in dichloromethane (15 mL) and washed with water (5 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The obtained white solid was washed with diethyl ether (25 mL) and dried in air to afford the title compound (0.028 g, 53%): mp 203-204° C. (diethyl ether); 1H NMR (300 MHz, DMSO-d6) δ 8.60 (t, J=6.0 Hz, 1H), 7.33-7.17 (m, 5H), 5.46 (d, J=3.8 Hz, 1H), 4.47-4.41 (m, 1H), 4.35 (d, J=6.0 Hz, 2H), 4.12-4.04 (m, 1H), 3.93-3.85 (m, 1H), 3.00-2.90 (m, 1H), 2.48 (s, 3H), 2.42-2.33 (m, 1H); 13C NMR (75 MHz, DMSO-d6) δ 173.3, 162.1, 155.9, 140.0, 128.7, 127.7, 127.2, 119.4, 63.6, 57.0, 43.1, 41.7, 17.5; MS (ES+) m/z 332.2 (M+1).
Reaction SMILES: [NH2:1][C@H:2]1[C@H:7]2[CH2:8][C@H:4]([C@@H:5]([C:16]([O:18][CH3:19])=[O:17])[N:6]2[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:3]1.[C:20]1([CH3:30])[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1>N1C=CC=CC=1>[CH3:30][C:20]1[CH:25]=[CH:24][C:23]([S:26]([NH:1][C@H:2]2[C@H:7]3[CH2:8][C@H:4]([C@@H:5]([C:16]([O:18][CH3:19])=[O:17])[N:6]3[C:9]([O:11][C:12]([CH3:13])([CH3:14])[CH3:15])=[O:10])[CH2:3]2)(=[O:28])=[O:27])=[CH:22][CH:21]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COC(=O)[C@@H]1[C@@H]2C[C@@H](N)[C@@H](C2)N1C(=O)OC(C)(C)C
Solvent: c1ccncc1
Product: COC(=O)[C@@H]1[C@H]2C[C@H]([C@H](NS(=O)(=O)c3ccc(C)cc3)C2)N1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.3 %

Procedure:
To a solution of 2-tert-butyl 3-methyl (1R,3S,4R,6R)-6-amino-2-azabicyclo[2.2.1]heptane-2,3-dicarboxylate obtained in Example 29-3 (321 mg) in pyridine (4 mL), was added p-toluenesulfonyl chloride (249 mg). The mixture was stirred at room temperature for 1 hr. The resulting mixture was evaporated in vacuo, and the residue chromatographed on silica gel eluting with hexane and ethyl acetate (1:1) to give the target compound (440 mg)
Reaction SMILES: FC(F)(F)C1CO[C:6]2[CH:19]=[CH:18][C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:7]=2C=1C(O)=O.[F:22][C:23]([F:44])([F:43])[C:24]1COC2C=CC3C(=CC=CC=3)[C:28]=2[C:29]=1[C:30]([O:32]CC)=[O:31].[OH-:45].[Na+].Cl>C(O)C.O1CCCC1>[F:22][C:23]([F:44])([F:43])[CH:24]1[O:45][C:7]2[C:12]3[C:17]([CH:18]=[CH:19][C:6]=2[CH:28]=[C:29]1[C:30]([OH:32])=[O:31])=[CH:16][CH:15]=[CH:14][CH:13]=3
Reactant: CCOC(=O)C1=C(C(F)(F)F)COc2ccc3ccccc3c21
Reactant: [OH-]
Reactant: O=C(O)C1=C(C(F)(F)F)COc2ccc3ccccc3c21
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Product: O=C(O)C1=Cc2ccc3ccccc3c2OC1C(F)(F)F
Temperature: 25 °C
Reaction time: 16 h
Yield: 95 %

Procedure:
Preparation of 2-trifluoromethyl-3H-naphthopyran-carboxylic acid. A solution of the ester from Step 1 (0.8 g, 2.5 mmol) was dissolved in 40 mL of ethanol and 10 mL of tetrahydrofuran, treated with sodium hydroxide (2.5 N, 10 mL, 25 mmol) and stirred at room temperature for 16 hours. The reaction mixture was acidified with 1.0 N HCl, whereupon a solid formed that was isolated by filtration. The solid was washed with 20 mL of water to afford 0.7 g (95%) of the title compound as a yellow solid: mp 245.9–248.6° C. 1H NMR (acetone-d6/300 MHz) 8.57 (s, 1H), 8.28 (d, 1H, J=8.7 Hz), 8.03 (d, 1H, J=9.0 Hz), 7.93 (d, 1H, J=8.7), 7.67 (m, 1H), 7.50 (m, 1H), 7.28 (d, 1H, J=9.0), 5.96 (qH-F, 1H, J=7.2 Hz). FABHRMS m/z 295.0561 (M+H, Calc'd 295.0582). Anal. Calc'd for C15H9O3F3+3.31% H2O: C, 59.21; H, 3.35. Found: C, 59.17; H, 3.07.
Reaction SMILES: CN([CH:4]=[O:5])C.P(Cl)(Cl)(Cl)=O.[CH3:11][C:12]1[N:19]2[C:15]([S:16][CH:17]=[CH:18]2)=[CH:14][N:13]=1.[OH-].[Na+]>ClCCl.O>[CH:4]([C:14]1[N:13]=[C:12]([CH3:11])[N:19]2[CH:18]=[CH:17][S:16][C:15]=12)=[O:5]
Reactant: CN(C)C=O
Reactant: Cc1ncc2sccn12
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: O
Product: Cc1nc(C=O)c2sccn12
Temperature: 0 °C

Procedure:
DMF (8 ml) was added to 40 ml of dichloromethane. The mixture was cooled in an argon atmosphere to 0° C. A solution of 9 ml of phosphorus oxychloride in 40 ml of dichloromethane was added dropwise thereto. Further, a solution of 1.2 g of 5-methylimidazo[5,1-b]thiazole in 20 ml of dichloromethane was added dropwise thereto. The mixture was heated under reflux for 5 hr. The reaction solution was poured into iced water, and then adjusted to pH 10 by the addition of an aqueous sodium hydroxide solution. The mixture was extracted with dichloromethane. The extract was dried over magnesium sulfate. The solvent was then concentrated under the reduced pressure. The residue was purified by chromatography on silica gel to give 1.5 g of 7-formyl-5-methylimidazo[5,1-b]thiazole.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.Cl[C:10]1[C:19]2[C:14](=[C:15]([O:22][CH3:23])[C:16]([O:20][CH3:21])=[CH:17][CH:18]=2)[CH:13]=[C:12]([NH:24][C:25]2[CH:29]=[C:28]([CH3:30])[NH:27][N:26]=2)[N:11]=1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:10]2[C:19]3[C:14](=[C:15]([O:22][CH3:23])[C:16]([O:20][CH3:21])=[CH:17][CH:18]=3)[CH:13]=[C:12]([NH:24][C:25]3[CH:29]=[C:28]([CH3:30])[NH:27][N:26]=3)[N:11]=2)=[CH:4][CH:3]=1
Reactant: Oc1ccc(F)cc1
Reactant: COc1ccc2c(Cl)nc(Nc3cc(C)[nH]n3)cc2c1OC
Product: COc1ccc2c(Oc3ccc(F)cc3)nc(Nc3cc(C)[nH]n3)cc2c1OC

Procedure:
Similar procedure as described in example 10 was used, starting from 4-fluoro-phenol and (1-chloro-5,6-dimethoxy-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine to give [1-(4-fluoro-phenoxy)-5,6-dimethoxy-isoquinolin-3-yl]-(5-methyl-1H-pyrazol-3-yl)-amine. LC-MS m/e 395(MH+).
Reaction SMILES: BrC1C=CC(OC)=C([N+]([O-])=O)C=1.[CH3:13][O:14][CH:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.[CH3:21][O:22][C:23]1[C:28]2[N:29]=[C:30]([NH:32][C:33]([N:35]3[CH2:40][CH2:39][O:38][CH2:37][CH2:36]3)=[O:34])[S:31][C:27]=2[C:26](N2CCOCC2)=[CH:25][CH:24]=1>>[CH3:21][O:22][C:23]1[C:28]2[N:29]=[C:30]([NH:32][C:33]([N:35]3[CH2:40][CH2:39][O:38][CH2:37][CH2:36]3)=[O:34])[S:31][C:27]=2[C:26]([N:18]2[CH2:19][CH2:20][CH:15]([O:14][CH3:13])[CH2:16][CH2:17]2)=[CH:25][CH:24]=1
Reactant: COC1CCNCC1
Reactant: COc1ccc(N2CCOCC2)c2sc(NC(=O)N3CCOCC3)nc12
Agent: COc1ccc(Br)cc1[N+](=O)[O-]
Product: COc1ccc(N2CCC(OC)CC2)c2sc(NC(=O)N3CCOCC3)nc12

Procedure:
The title compound was prepared strarting from 4-bromo-1-methoxy-2-nitro-benzene and 4-methoxy-piperidine as described for morpholine-4-carboxylic acid (4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-amide (Example 136) and obtained as a light yellow solid in about 10% overall yield, MS: m/e=407 (M+H+).
Reaction SMILES: C[O-].[Na+].CO.Cl[CH2:7][C:8]([NH:10][C:11]1[CH:17]=[C:16]([OH:18])[CH:15]=[CH:14][C:12]=1[OH:13])=[O:9].O>CN(C)C=O>[OH:18][C:16]1[CH:15]=[CH:14][C:12]2[O:13][CH2:7][C:8](=[O:9])[NH:10][C:11]=2[CH:17]=1
Reactant: O=C(CCl)Nc1cc(O)ccc1O
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: CN(C)C=O
Product: O=C1COc2ccc(O)cc2N1

Procedure:
30% sodium methoxide in methanol (18.4 g, 0.075 mole) was added under stirring to the 2-(α-chloroacetamido)-hydroquinone (13.4 g, 0.075 mole) in dimethylformamide (DMF 10 ml). The resulting solution was poured into water (150 ml) and the separated solid was Coupler (1) (9 g, 73%).