Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]2[NH:30][C:16]3[N:17]=[CH:18][N:19]=[C:20]([NH:21][C@@H:22]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH3:23])[C:15]=3[CH:14]=2)[CH:8]=1)=[O:4].[CH3:31][NH:32][CH3:33]>O1CCOCC1.C(O)C>[CH3:31][N:32]([CH3:33])[CH2:2][C:3]([NH:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]2[NH:30][C:16]3[N:17]=[CH:18][N:19]=[C:20]([NH:21][C@@H:22]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH3:23])[C:15]=3[CH:14]=2)[CH:8]=1)=[O:4]
Reactant: C[C@@H](Nc1ncnc2[nH]c(-c3cccc(CNC(=O)CCl)c3)cc12)c1ccccc1
Reactant: CNC
Solvent: CCO
Solvent: C1COCCO1
Product: C[C@@H](Nc1ncnc2[nH]c(-c3cccc(CNC(=O)CN(C)C)c3)cc12)c1ccccc1
Temperature: 100 °C

Procedure:
A mixture of 210 mg (0.5 mmol) 2-chloro-N-{3-[4-((R)-1-phenyl-ethylamino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-benzyl}-acetamide in 3 ml dry dioxane is treated with 268 μl (1.5 mmol) of a 5.6 N dimethylamine solution in ethanol (Fluka, Buchs, Switzerland) and then heated to 100° C. for 6 h. The clear yellow solution is cooled and the solvent evaporated. The residue is purified by flash chromatography using a mixture of dichloromethane/methanol with gradually increasing concentrations of methanol starting with 100:2.5 and ending with 100:5 and then switching to dichloromethane/methanol/conc. ammonia starting with 100:5:0.25 and ending with 100:10:0.5. The title compound is obtained as a colorless foam; Rf(dichloromethane/methanol/conc. ammonia 90:10:1)=0.41; MS-ES+: (M+H)+=429.
Reaction SMILES: [OH-].[K+].F[C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[N+:13]([O-:15])=[O:14])[C:7]([OH:9])=[O:8].Cl.[CH2:17]([OH:19])[CH3:18]>>[CH2:17]([O:19][C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[N+:13]([O-:15])=[O:14])[C:7]([OH:9])=[O:8])[CH3:18]
Reactant: CCO
Reactant: O=C(O)c1ccc([N+](=O)[O-])c(F)c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Product: CCOc1cc(C(=O)O)ccc1[N+](=O)[O-]

Procedure:
Potassium hydroxide (0.278 g) was added to a solution of 3-fluoro-4-nitrobenzoic acid (0.4 g) in ethanol (7 ml) and the reaction treated with microwaves (300W, 100° C.) for 5 minutes. The reaction mixture was acidified using 2N HCl and extracted with ethyl acetate. The extracts were combined, washed with water, dried (MgSO4) and evaporated to give 3-ethoxy-4-nitro-benzoic acid (0.325 g).
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([C:21]4[CH:26]=[C:25]([CH:27]([F:29])[F:28])[CH:24]=[CH:23][C:22]=4[O:30][CH2:31][CH:32]4[CH2:34][CH2:33]4)[C:15]=3[NH:14][C:13]=2[CH3:35])=[O:11])[CH2:5][C@H:4]1[F:36].[CH3:37][O:38][CH2:39][C:40](Cl)=[O:41]>>[CH:32]1([CH2:31][O:30][C:22]2[CH:23]=[CH:24][C:25]([CH:27]([F:29])[F:28])=[CH:26][C:21]=2[C:20]2[C:15]3[NH:14][C:13]([CH3:35])=[C:12]([C:10]([NH:9][C@H:6]4[CH2:7][CH2:8][C@H:3]([NH:2][C:40](=[O:41])[CH2:39][O:38][CH3:37])[C@H:4]([F:36])[CH2:5]4)=[O:11])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:33][CH2:34]1
Reactant: COCC(=O)Cl
Reactant: Cc1[nH]c2c(-c3cc(C(F)F)ccc3OCC3CC3)ncnc2c1C(=O)N[C@H]1CC[C@H](N)[C@H](F)C1
Agent: Cl
Product: COCC(=O)N[C@H]1CC[C@H](NC(=O)c2c(C)[nH]c3c(-c4cc(C(F)F)ccc4OCC4CC4)ncnc23)C[C@H]1F

Procedure:
Starting from N-[(1S*,3R*,4S*)-4-amino-3-fluorocyclohexyl]-4-[2-(cyclopropylmethoxy)-5-(difluoromethyl)phenyl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f72) and commercially available methoxy-acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[C:11]([C:13]1[CH:21]=[CH:20][CH:19]=[CH:18][C:14]=1[C:15]([OH:17])=[O:16])=O)=[CH:8][C:7]([N+:22]([O-:24])=[O:23])=[CH:6][CH:5]=2.[CH3:25][N:26]([CH3:36])[C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([N:33]([CH3:35])[CH3:34])[CH:28]=1.C(OC(=O)C)(=O)C>>[CH3:34][N:33]([CH3:35])[C:29]1[CH:28]=[C:27]([N:26]([CH3:36])[CH3:25])[CH:32]=[CH:31][C:30]=1[C:11]1([C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[C:7]([N+:22]([O-:24])=[O:23])[CH:8]=3)[NH:3][C:2]=2[CH3:1])[C:13]2[C:14](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:15](=[O:17])[O:16]1
Reactant: CN(C)c1cccc(N(C)C)c1
Reactant: Cc1[nH]c2ccc([N+](=O)[O-])cc2c1C(=O)c1ccccc1C(=O)O
Solvent: CC(=O)OC(C)=O
Product: Cc1[nH]c2ccc([N+](=O)[O-])cc2c1C1(c2ccc(N(C)C)cc2N(C)C)OC(=O)c2ccccc21

Procedure:
Following a procedure similar to that described in part B of Example 18 for interacting 3.24 g (0.01 mole) of 2-[(2-methyl-5-nitro-3-indolyl)carbonyl]benzoic acid, prepared as described in part A above, and 1.6 g (0.01 mole) of N,N,N',N'-tetramethyl-m-phenylenediamine in the presence of 5.0 ml of acetic anhydride, there is obtained 3-[2,4-bis(dimethylamino)phenyl]-3-(2-methyl-5-nitro-3-indolyl)phthalide (Formula III: R0 =R1 =R2 =R3 =R6 =H; R=R5 =CH3 ; R4 =N(CH3)2 ; Y1 =NO2).
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=2[F:17])[C:12]#[N:13])[C:4]1=[O:18].[N:19]1[CH:24]=[CH:23][CH:22]=[C:21]([C:25]2[S:29][C:28]([S:30](Cl)(=[O:32])=[O:31])=[CH:27][CH:26]=2)[CH:20]=1>>[C:12]([C:11]1[CH:14]=[CH:15][C:16]([F:17])=[C:9]([CH:10]=1)[CH2:8][N:5]1[CH2:6][CH2:7][C@H:3]([NH:2][S:30]([C:28]2[S:29][C:25]([C:21]3[CH:20]=[N:19][CH:24]=[CH:23][CH:22]=3)=[CH:26][CH:27]=2)(=[O:31])=[O:32])[C:4]1=[O:18])#[N:13]
Reactant: O=S(=O)(Cl)c1ccc(-c2cccnc2)s1
Reactant: N#Cc1ccc(F)c(CN2CC[C@H](N)C2=O)c1
Agent: Cl
Product: N#Cc1ccc(F)c(CN2CC[C@H](NS(=O)(=O)c3ccc(-c4cccnc4)s3)C2=O)c1

Procedure:
The title compound is prepared from 3-(S)-[(3-amino-2-oxo-pyrrolidin-1-yl)-methyl]-4-fluoro-benzonitrile hydrochloride as described in EXAMPLE 17, Part G substituting 5-pyridin-3-yl-thiophene-2-sulfonyl chloride in place of 4,6-dichlorobenzo[b]thiophene-2-sulfonyl chloride. The crude product is triturated with Et2O to give the title compound as a white solid
Reaction SMILES: [NH:1]=[C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:8]=2)[CH:5]=[C:4]([CH2:17][CH3:18])[S:3]1.C(N(CC)CC)C.[C:26](Cl)(=[O:31])[CH2:27][CH:28]([CH3:30])[CH3:29]>C(Cl)(Cl)Cl>[C:26]([N:1]=[C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:14])[F:15])[CH:8]=2)[CH:5]=[C:4]([CH2:17][CH3:18])[S:3]1)(=[O:31])[CH2:27][CH:28]([CH3:30])[CH3:29]
Reactant: CCc1cn(-c2cccc(C(F)(F)F)c2)c(=N)s1
Reactant: CC(C)CC(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCc1cn(-c2cccc(C(F)(F)F)c2)c(=NC(=O)CC(C)C)s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 30.6 %

Procedure:
To a solution of 2-imino-3-(3-trifluoromethylphenyl)-5-ethylthiazoline (0.5 g) and triethylamine (0.6 g) in chloroform (30 ml), isovaleryl chloride (0.8 g) was dropwise added under stirring at room temperature, and stirring was continued for 2 hours. After removal of the solvent under reduced pressure, the concentrated residue was extracted with ethyl acetate (100 ml), washed with water and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was subjected to column chromatography to give 0.2 g of 2-isovalerylimino-3-(3-trifluoromethylphenyl)-5-ethylthiazoline (Compound No. 16).
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]2[C:11]([C:12](=O)[CH3:13])=[CH:10][C:9]([F:15])=[CH:8][CH:7]=2)=[CH:4][CH:3]=1.C([O:20][C:21]([C:23]1[CH:46]=[CH:45][C:26]2[N:27]([CH:39]3[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]3)[C:28]([C:30]3[CH:35]=[CH:34][C:33]([NH2:36])=[C:32]([CH:37]=O)[CH:31]=3)=[N:29][C:25]=2[CH:24]=1)=[O:22])C.[OH-].[K+].Cl>C(O)C>[Cl:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]2[C:11]([C:12]3[CH:13]=[CH:37][C:32]4[C:33](=[CH:34][CH:35]=[C:30]([C:28]5[N:27]([CH:39]6[CH2:40][CH2:41][CH2:42][CH2:43][CH2:44]6)[C:26]6[CH:45]=[CH:46][C:23]([C:21]([OH:22])=[O:20])=[CH:24][C:25]=6[N:29]=5)[CH:31]=4)[N:36]=3)=[CH:10][C:9]([F:15])=[CH:8][CH:7]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1ccc2c(c1)nc(-c1ccc(N)c(C=O)c1)n2C1CCCCC1
Reactant: CC(=O)c1cc(F)ccc1-c1ccc(Cl)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1ccc2c(c1)nc(-c1ccc3nc(-c4cc(F)ccc4-c4ccc(Cl)cc4)ccc3c1)n2C1CCCCC1
Temperature: 75 °C
Reaction time: 8 h
Yield: 58.3 %

Procedure:
1-(4′-Chloro-4-fluoro-biphen-2-yl)-ethanone (62 mg, 0.25 mmol) and 2-(4-amino-3-formyl-phenyl)-1-cyclohexyl-1H-benzoimidazole-5-carboxylic acid ethyl ester (98 mg, 0.25 mmol) were dissolved in 500 μL ethanol and 500 μL 10% ethanolic KOH were added. The reaction was stirred at 75° C. overnight. The reaction was acidified with 4N hydrochloric acid, extracted three times with ethyl acetate, the organic extracts were dried with sodium sulfate and then evaporated. Purification via reverse-phase HPLC gave 84 mg product.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6](=[O:17])[S:7][C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][C:11](Br)=[CH:10][CH:9]=2)=[O:4].[F:18][C:19]([F:34])([F:33])[C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:25]=1>>[CH3:1][O:2][C:3]([C:5]1[C:6](=[O:17])[S:7][C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][C:11]([C:22]1[CH:23]=[C:24]([C:26]([F:29])([F:27])[F:28])[CH:25]=[C:20]([C:19]([F:18])([F:34])[F:33])[CH:21]=1)=[CH:10][CH:9]=2)=[O:4]
Reactant: OB(O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: COC(=O)c1c(O)c2cc(Br)ccc2sc1=O
Product: COC(=O)c1c(O)c2cc(-c3cc(C(F)(F)F)cc(C(F)(F)F)c3)ccc2sc1=O

Procedure:
6-(3,5-Bis-trifluoromethyl-phenyl)-4-hydroxy-2-oxo-2H-thiochromene-3-carboxylic acid methyl ester was prepared from 6-bromo-4-hydroxy-2-oxo-2H-thiochromene-3-carboxylic acid methyl ester (Example 27 e) under conditions analogous to Example 7(a) using 3,5-Bis-trifluoromethyl-phenylboronic acid. 1H NMR (200 MHz, CDCl3): δ (ppm)=8.572 (s, 1H), 8.037 (s, 2H), 7.908 (s, 1H), 7.820 (d, 1H), 7.510 (d, 1H), 4.04 (s, 3H).
Reaction SMILES: [N:1]1([CH2:6][C@@H:7]([O:14][C:15]2[CH:24]=[CH:23][C:22]3[C:21](=[O:25])[CH2:20][CH2:19][CH2:18][C:17]=3[C:16]=2[CH2:26][S:27][C:28]2[CH:36]=[CH:35][C:31]([C:32](O)=[O:33])=[CH:30][CH:29]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[NH2:37][CH2:38][CH:39]=[CH2:40]>>[CH2:38]([NH:37][C:32](=[O:33])[C:31]1[CH:30]=[CH:29][C:28]([S:27][CH2:26][C:16]2[C:17]3[CH2:18][CH2:19][CH2:20][C:21](=[O:25])[C:22]=3[CH:23]=[CH:24][C:15]=2[O:14][C@@H:7]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:6][N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)=[CH:36][CH:35]=1)[CH:39]=[CH2:40]
Reactant: C=CCN
Reactant: O=C(O)c1ccc(SCc2c(O[C@H](Cn3ccnc3)c3ccccc3)ccc3c2CCCC3=O)cc1
Product: C=CCNC(=O)c1ccc(SCc2c(O[C@H](Cn3ccnc3)c3ccccc3)ccc3c2CCCC3=O)cc1
Yield: 96.7 %

Procedure:
Using the method in Example 172, 4-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfanyl}benzoic acid (50 mg, 0.10 mmol, 0.20M in DMF) and 3-aminopropene (17 mg, 0.30 mmol, 0.6M in DMF) were combined to give 52 mg of the desired compound: Low resolution mass spectrum (LC-MS, APCI) m/z 538 [M+H]+.
Reaction SMILES: [Br:1]Br.[CH3:3][CH:4]([CH3:19])[C:5]([C:7]1[CH:18]=[CH:17][C:10]([O:11][CH2:12][C:13]([O:15][CH3:16])=[O:14])=[CH:9][CH:8]=1)=[O:6]>C(Cl)(Cl)(Cl)Cl>[Br:1][C:4]([CH3:19])([CH3:3])[C:5]([C:7]1[CH:18]=[CH:17][C:10]([O:11][CH2:12][C:13]([O:15][CH3:16])=[O:14])=[CH:9][CH:8]=1)=[O:6]
Reactant: BrBr
Reactant: COC(=O)COc1ccc(C(=O)C(C)C)cc1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)COc1ccc(C(=O)C(C)(C)Br)cc1
Reaction time: 16 h

Procedure:
Bromine (2.09 ml) was added dropwise over ten minutes to a stirred solution of the product of step i) above (9.44 g) in carbon tetrachloride (200 ml). The solution was stirred for 16 hours, then the solvent was evaporated in vacuo to give an orange oil. A solution of this oil, in a small volume of dichloromethane, was filtered through silica and the clear filtrate, on evaporation, gave methyl 4-(2-bromo-2,2-dimethylacetyl)phenoxyacetate, 11.3 g, as a white crystalline solid: m.p. 46°-50° C.; NMR (d6DMSO) δ8.09(2H,d), 7.05(2H,d), 4.92(2H,s), 3.72(3H,s), 2.00(6H,s).
Reaction SMILES: S(Cl)(Cl)=O.[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][C:7]=1[S:15]([OH:18])(=O)=[O:16].C[N:20](C)C=O>>[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][C:7]=1[S:15]([NH2:20])(=[O:18])=[O:16]
Reactant: CN(C)C=O
Reactant: O=[N+]([O-])c1ccc(Cl)c(S(=O)(=O)O)c1
Solvent: O=S(Cl)Cl
Product: NS(=O)(=O)c1cc([N+](=O)[O-])ccc1Cl
Reaction time: 2 h
Yield: 42.4 %

Procedure:
To a solution of thionyl chloride (11 mL) and 2-chloro-5-nitro-benzenesulfonic acid (4.78 g, 20.1 mmol) was added N,N-dimethylformamide (0.92 μL) and the reaction mixture was heated to reflux for 4 h. Upon cooling, the reaction mixture was azeotroped with toluene (2-3×). The sulfonyl chloride was dissolved in a minimal amount of toluene and then added to a mixture of concentrated aqueous ammonium hydroxide solution (25 mL) and tetrahydrofuran (25 mL) at −10° C. After stirring for 2 h the reaction was quenched by adding a 6.0 M aqueous hydrochloric acid solution until pH 4 was reached. The layers were separated and the organic layer was concentrated in vacuo to a slurry. Pentane was added and the product was isolated by vacuum filtration to afford the desired product, 2-chloro-5-nitrobenzenesulfonamide (2.0 g, 8.48 mmol, 42.4% yield) as a solid.
Reaction SMILES: CS(O[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]#[N:14])=[C:9]([F:15])[CH:8]=1)(=O)=O.[N-:16]=[N+:17]=[N-:18].[Na+]>O>[N:16]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]#[N:14])=[C:9]([F:15])[CH:8]=1)=[N+:17]=[N-:18]
Reactant: [N-]=[N+]=[N-]
Reactant: CS(=O)(=O)OCc1ccc(C#N)c(F)c1
Agent: [Na+]
Solvent: O
Product: N#Cc1ccc(CN=[N+]=[N-])cc1F
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To an ice cooled solution of 4-cyano-3-fluorobenzyl methanesulfonate (1.8 g, 7.9 mmol; see step (iii) above) was added sodium azide (0.80 g, 0.012 mol). The mixture was stirred overnight and then poured into 200 mL of water and extracted three times with diethyl ether. The combined ethereal phase washed five times with water, dried (Na2SO4) and evaporated. The crude colourless oil could be used without further purification. Yield: 1.2 g (87%).
Reaction SMILES: [C:1]([O:4][CH:5]=[CH2:6])(=[O:3])[CH3:2].OC([C:10]1[NH:15][C:14](=[O:16])[CH:13]=[CH:12][N:11]=1)C>O1CCOCC1>[C:1]([O:4][C@@H:5]([C:10]1[NH:15][C:14](=[O:16])[CH:13]=[CH:12][N:11]=1)[CH3:6])(=[O:3])[CH3:2]
Reactant: C=COC(C)=O
Reactant: CC(O)c1nccc(=O)[nH]1
Solvent: C1COCCO1
Product: CC(=O)O[C@H](C)c1nccc(=O)[nH]1
Temperature: 50 °C
Reaction time: 24 h

Procedure:
To a solution of vinyl acetate (4.3 g, 50 mmol) in dioxane (63 mL) was added 2-(1-hydroxy-ethyl)-3H-pyrimidin-4-one (prepared according to the method of Preparation Twelve, 2.1 g, 15.1 mmol), and the mixture was heated to 50° C. To the resulting solution was added lipase P30 (0.21 g, 10 wt %) and the heating was continued for 24 h. The reaction mixture was filtered and the filtrate was evaporated to obtain a thick syrupy liquid residue. The residue was purified by flash column chromatography (95:5 dichloromethane:methanol) to give the title compound as a colorless liquid, 0.97 g (92% of theory). 1H NMR (CDCl3, 300 MHz) δ 1.61 (d, 3H), 2.20 (s, 3H), 5.65 (q, 1H), 6.35 (d, 1H), 7.97 (d, 1H), 11.94 (s, 1H); [α]D+39.9 (c 1.0, MeOH).
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:12]1[C:13]([CH3:38])=[N:14][C:15]2[N:16]([N:30]=[C:31]([C:33]([O:35]CC)=[O:34])[CH:32]=2)[C:17]=1[C:18]1[C:19]([CH3:29])=[C:20]2[C:25](=[C:26]([F:28])[CH:27]=1)[O:24][CH2:23][CH2:22][CH2:21]2)[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].O.Cl>C1COCC1>[C:1]([O:5][C@@H:6]([C:12]1[C:13]([CH3:38])=[N:14][C:15]2[N:16]([N:30]=[C:31]([C:33]([OH:35])=[O:34])[CH:32]=2)[C:17]=1[C:18]1[C:19]([CH3:29])=[C:20]2[C:25](=[C:26]([F:28])[CH:27]=1)[O:24][CH2:23][CH2:22][CH2:21]2)[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)c1cc2nc(C)c([C@H](OC(C)(C)C)C(=O)OCC)c(-c3cc(F)c4c(c3C)CCCO4)n2n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)nc2cc(C(=O)O)nn2c1-c1cc(F)c2c(c1C)CCCO2
Temperature: 25 °C
Reaction time: 16 h
Yield: 89.1 %

Procedure:
To a solution of ethyl 6-((S)-1-(tert-butoxy)-2-ethoxy-2-oxoethyl)-7-(8-fluoro-5-methylchroman-6-yl)-5-methylpyrazolo[1,5-a]pyrimidine-2-carboxylate (4 g, 6.07 mmol) in THF (40 mL) was added 1N NaOH (6.07 mL, 6.07 mmol) and the resulting mixture was stirred at rt for 16 h. At this point LCMS indicated about 70% conversion, so additional NaOH (2.5 mL, 2.5 mmol) was added and the mixture was stirred for another 2 h. At this point LCMS indicated progression of reaction (approx 90% coversion) along with small amount of di-acid. Water (20 mL) was then added and the mixture was acidified with 1N HCl (10 mL) and extracted with ether (2×100 mL), washed with brine (50 mL), dried (Na2SO4), filtered and concentrated to afford 6-((S)-1-(tert-butoxy)-2-ethoxy-2-oxoethyl)-7-(8-fluoro-5-methylchroman-6-yl)-5-methylpyrazolo[1,5-a]pyrimidine-2-carboxylic acid (2.7 g, 5.41 mmol, 89% yield) as off-white solid. 1H NMR (500 MHz, CDCl3) δ: 7.21 (s, 1H), 6.85 (d, J=10.7 Hz, 1H), 5.00 (s, 1H), 4.36 (t, J=4.4 Hz, 2H), 4.19-4.12 (m, 2H), 2.81 (s, 3H), 2.80-2.74 (m, 2H), 2.20 (dd, J=6.3, 4.1 Hz, 2H), 1.83 (s, 3H), 1.24-1.20 (m, 3H), 1.18 (s, 9H). LCMS (M+H)=500.4.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:4]=1[CH:5]=O.[CH:13]([C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1)([CH3:15])[CH3:14]>>[CH3:1][O:2][C:3]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:4]=1[CH2:5][NH:20][C:19]1[CH:21]=[CH:22][C:16]([CH:13]([CH3:15])[CH3:14])=[CH:17][CH:18]=1
Reactant: CC(C)c1ccc(N)cc1
Reactant: COc1ccc(C=O)c(OC)c1
Product: COc1ccc(CNc2ccc(C(C)C)cc2)c(OC)c1
Yield: 372.3 %

Procedure:
By the reaction and treatment in the same manner as in Preparation Example 1 using 2,4-dimethoxybenzaldehyde (8.0 g) and 4-isopropylaniline (1.4 g) as starting materials, [(2,4-dimethoxyphenyl)methyl](4-isopropylphenyl)amine (11 g) was obtained.
Reaction SMILES: [F:1][C:2]1[C:7]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:25][CH2:26][CH:27]1[O:31][CH2:30][CH2:29][O:28]1.Cl>C(#N)C>[O:28]1[CH2:29][CH2:30][O:31][CH:27]1[CH2:26][CH2:25][N:15]1[CH2:16][CH2:17][CH:12]([C:3]2[CH:4]=[CH:5][CH:6]=[C:7]([S:8]([CH3:11])(=[O:10])=[O:9])[C:2]=2[F:1])[CH2:13][CH2:14]1
Reactant: BrCCC1OCCO1
Reactant: CS(=O)(=O)c1cccc(C2CCNCC2)c1F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CS(=O)(=O)c1cccc(C2CCN(CCC3OCCO3)CC2)c1F

Procedure:
Preparation according to Example 1: 4-[2-fluoro-3-(methylsulfonyl)phenyl]piperidine (0.42 g, 1.63 mmol), acetonitrile (20 ml), potassium carbonate (0.45 g, 3.2 mmol) and 2-(2-bromoethyl)-1,3-dioxolan (0.205 ml, 1.65 mmol). Yield: 0.18 g (31%). The amine was converted to the hydrochloric acid salt and recrystallized from ethanol/diethyl ether: M.p. 224-225° C. MS m/z (relative intensity, 70 eV) 357 (M+, 3), 270 (bp), 257 (59), 256 (27), 178 (90).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH3:21])=[C:5]([C:18]([O-:20])=[O:19])[CH:6]([CH3:17])[C:7]=1[C:8]([O:10]CC(C#N)C#N)=[O:9]>CC(C)=O.[OH-].[Na+].O>[CH3:21][C:4]1[NH:3][C:2]([CH3:1])=[C:7]([C:8]([OH:10])=[O:9])[CH:6]([CH3:17])[C:5]=1[C:18]([OH:20])=[O:19]
Reactant: CC1=C(C(=O)[O-])C(C)C(C(=O)OCC(C#N)C#N)=C(C)N1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Product: CC1=C(C(=O)O)C(C)C(C(=O)O)=C(C)N1
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.7 %

Procedure:
In 12 0 ml of acetone containing 240 ml of 1N sodium hydroxide was dissolved 12 . 7 g of the dicyanoethyl 1,4-dihydro-2,4,6-trimethyl-3,5-pyridinedicarboxylate obtained in (1) above, and the solution was stirred at a room temperature for 2 hours. After the reaction, the reaction mixture was diluted with 240 ml of water and washed twice with dichloromethane. The separated aqueous layer was rendered acidic (pH=1-2) with concentrated hydrochloric acid under ice-cooling and stirred for 3 hours- The thus formed crystal was collected by suction filtration. The filtrate was dried under reduced pressure to yield 4.55 g (yield: 54%) of 1,4-dihydro- 2,4,6-trimethyl-3,5-pyridinedicarboxylic acid as a pale yellows powder.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:22])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17](I)[CH:16]=1.[C:23]([C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1)#[N:24].C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.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>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14]([C:15]1[CH:16]=[C:17]([C:28]2[CH:29]=[CH:30][C:25]([C:23]#[N:24])=[CH:26][CH:27]=2)[CH:18]=[CH:19][CH:20]=1)=[O:22]
Reactant: N#Cc1ccc(B(O)O)cc1
Reactant: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1cccc(I)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: N#Cc1ccc(-c2cccc(C(=O)NCCc3c[nH]c4ccc(Cl)cc34)c2)cc1
Yield: 24.2 %

Procedure:
N-(2-(5-chloro-1H-indol-3-yl)ethyl)-4′-cyanobiphenyl-3-carboxamide was prepared according to method B with N-(2-(5-chloro-1H-indol-3-yl)ethyl)-3-iodobenzamide (0.075 g; 0.176 mmol), 4-cyanophenylboronic acid (0.027 g; 0.180 mmol), tetrakis(triphenylphosphine)palladium (0.010 g; 0.009 mmol), sodium carbonate (0.037 g; 0.353 mmol), in dimethoxyethane (3 mL) and water (1 mL), irradiated in a microwave oven at 130° C. for 15 minutes. Flash chromatography on silica gel (eluent 2 to 20% ethyl acetate in dichloromethane) furnished 0.017 g (24%) of N-(2-(5-chloro-1H-indol-3-yl)ethyl)-4′-cyanobiphenyl-3-carboxamide as a white solid.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[H-].[Na+].CN(C=O)C.Br[CH2:17][CH2:18][CH:19]1[CH2:24][CH2:23][CH:22]2[CH2:25][CH:20]1[C:21]2([CH3:27])[CH3:26]>>[I:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:17][CH2:18][CH:19]2[CH2:24][CH2:23][CH:22]3[CH2:25][CH:20]2[C:21]3([CH3:26])[CH3:27])=[CH:4][CH:3]=1
Reactant: CC1(C)C2CCC(CCBr)C1C2
Reactant: Oc1ccc(I)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1(C)C2CCC(CCOc3ccc(I)cc3)C1C2
Temperature: 25 °C
Reaction time: 3 h
Yield: 190.4 %

Procedure:
To a stirred suspension of 4-iodophenol (0.5 g; 2.27 mmol) and 60% NaH (0.16 g, 2.3 mmol) in anhydrous DMF (5 ml) 2-(2-bromoethyl)-6,6-dimethylbicyclo[3.1.1]heptane (0.5 g, 2.2 mmol) was added the and mixture was stirred for 3 h at room temperature. After addition of more of 2-(2-bromoethyl)-6,6-dimethylbicyclo[3.1.1]heptane (0.2 g) the mixture was stirred for additional 2 h, quenched with NH4Cl solution and diluted to 20 ml with EtOAc. The organic layer was separated, dried over MgSO4 and filtered. The filtrate was evaporated to dryness and the residue was purified by FCC (SiO2, hexane/EtOAc) to give the title compound (0.61 g, 73%), as a colourless paste. 1H-NMR (CDCl3) 7.51 (d, 2H, J=8.91 Hz); 6.64 (d, 2H, J=8.88 Hz); 3.88 (t, 2H, J=3.21 Hz); 2.34-1.84 (m, 10H); 1.17 (s, 3H); 1.01 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8](=O)[CH2:9][CH:10]2[C:15](=[O:16])[CH2:14][C:13]([CH3:18])([CH3:17])[CH2:12][C:11]2=O)[CH:5]=[CH:6][CH:7]=1.COC1C=CC(P2(=S)SP(=S)(C3C=CC(OC)=CC=3)[S:30]2)=CC=1>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2[S:30][C:11]3[CH2:12][C:13]([CH3:18])([CH3:17])[CH2:14][C:15](=[O:16])[C:10]=3[CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC1(C)CC(=O)C(CC(=O)c2cccc(Br)c2)C(=O)C1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: CC1(C)CC(=O)c2cc(-c3cccc(Br)c3)sc2C1
Yield: 33.1 %

Procedure:
2-(2-(3-Bromophenyl)-2-oxoethyl)-5,5-dimethylcyclohexane-1,3-dione (2.77 g, 8.2 mmol) and 2,4-bis(4-methoxyphenyl)-1,3,2,4-dithiadiphosphetane-2,4-disulfide (Lawesson's reagent) (2.29 g, 5.4 mmol) were refluxed in toluene (100 mL) for 6 hr. The reaction mixture was concentrated in vacuo and purified on silica gel using a gradient elution of 0-10% ethyl acetate in 40-60 petroleum ether to afford the title compound (0.6 g, 22%).