Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[N:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]3=[N:10][C:9]=2[C:17]2[CH:18]=[CH:19][C:20]([O:34][CH2:35][CH3:36])=[C:21]([CH:33]=2)[C:22]([NH:24][C:25]2[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:26]=2[F:32])=[O:23])[CH:5]=[CH:4][N:3]=1.[CH3:37][O:38][C:39]1[CH:45]=[C:44]([N:46]2[CH2:51][CH2:50][N:49]([CH2:52][CH2:53][O:54][CH3:55])[CH2:48][CH2:47]2)[CH:43]=[CH:42][C:40]=1[NH2:41].C1(C)C=CC(S(O)(=O)=O)=CC=1.C(O)C(F)(F)F.N>CO.C(Cl)Cl>[F:32][C:26]1[CH:27]=[CH:28][CH:29]=[C:30]([F:31])[C:25]=1[NH:24][C:22](=[O:23])[C:21]1[CH:33]=[C:17]([C:9]2[N:10]=[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]3[C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:41][C:40]3[CH:42]=[CH:43][C:44]([N:46]4[CH2:51][CH2:50][N:49]([CH2:52][CH2:53][O:54][CH3:55])[CH2:48][CH2:47]4)=[CH:45][C:39]=3[O:38][CH3:37])[N:7]=2)[CH:18]=[CH:19][C:20]=1[O:34][CH2:35][CH3:36]
Reactant: CCOc1ccc(-c2nc3ccccn3c2-c2ccnc(Cl)n2)cc1C(=O)Nc1c(F)cccc1F
Reactant: COCCN1CCN(c2ccc(N)c(OC)c2)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: N
Solvent: ClCCl
Solvent: OCC(F)(F)F
Solvent: CO
Product: CCOc1ccc(-c2nc3ccccn3c2-c2ccnc(Nc3ccc(N4CCN(CCOC)CC4)cc3OC)n2)cc1C(=O)Nc1c(F)cccc1F
Temperature: 100 °C
Yield: 67.8 %

Procedure:
5-[3-(2-Chloro-4-pyrimidinyl)imidazo[1,2-a]pyridin-2-yl]-N-(2,6-difluorophenyl)-2-(ethyloxy)benzamide (Intermediate Example 6) (100 mg, 0.2 mmol), 2-(methyloxy)-4-{4-[2-(methyloxy)ethyl]-1-piperazinyl}aniline (47 mg, 0.18 mmol), and p-toluenesulfonicacid (90 mg, 0.47 mmol) were weighed into a 20 mL vial. 1 mL of trifluoroethanol was added and the mixture was heated to 100° C. for 72 h. 2 mL of 2 N ammonia in MeOH was added. The solvent was rotovaped down. The residue was taken up in 3 mL of DCM. 1 g of silica gel was added. The solvent was rotovaped down and the pre-absorbed solids were purified by flash chromatography to give the title compound (90 mg, 0.122 mmol, 69%). 1H NMR (400 MHz, DMSO-d6) δ ppm 9.75 (s, 1H), 9.36 (s, 1H), 8.46 (s, 1H), 8.19 (d, J=5.13 Hz, 1H), 8.04 (d, J=1.83 Hz, 1H), 7.74 (dd, J=8.80, 2.20 Hz, 1H), 7.69 (d, J=9.17 Hz, 1H), 7.34-7.46 (m, 3H), 7.26 (d, J=8.43 Hz, 1H), 7.19 (t, J=8.07 Hz, 2H), 6.94 (t, J=6.78 Hz, 1H), 6.67 (d, J=2.20 Hz, 1H), 6.52 (d, J=5.13 Hz, 1H), 6.43-6.50 (m, 1H), 4.26 (q, J=6.97 Hz, 2H), 3.79 (s, 3H), 3.42-3.48 (m, 2H), 3.24 (s, 3H), 3.08-3.17 (m, 4H), 2.53-2.58 (m, 4H), 2.49-2.53 (m, 2H), 1.43 (t, J=6.97 Hz, 3H); MS (ESI): 735 [M+H]+.
Reaction SMILES: [F:1][C:2]1[C:10]2[N:9]=[CH:8][NH:7][C:6]=2[CH:5]=[CH:4][C:3]=1[F:11].C(N(CC)CC)C.Br[CH2:20][C:21]([NH:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=1)=[O:22]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[F:11][C:3]1[CH:4]=[CH:5][C:6]2[N:7]=[CH:8][N:9]([CH2:20][C:21]([NH:23][C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:31])([F:32])[F:33])[CH:25]=3)=[O:22])[C:10]=2[C:2]=1[F:1]
Reactant: Fc1ccc2[nH]cnc2c1F
Reactant: O=C(CBr)Nc1cccc(C(F)(F)F)c1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: O=C(Cn1cnc2ccc(F)c(F)c21)Nc1cccc(C(F)(F)F)c1
Yield: 24.5 %

Procedure:
To a suspension of 4,5-difluoro-1H-benzimidazole (20 mg, 0.13 mmol) in toluene (260 μL), triethylamine (18 μL, 0.13 mmol) and 2-bromo-N-[3-(trifluoromethyl)phenyl]acetamide (37 mg, 0.13 mmol) were added. The reaction mixture was microwave-irradiated in a sealed vial at 120° C. for 30 min. The vial was cooled, opened and the contents dissolved in 20 mL ethyl acetate. The solution was washed with water (5 mL), saturated aqueous NaHCO3 (5 mL) and brine (5 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. Separation of the isomers in the crude product was performed on flash silica column using neat ethyl acetate to yield the title compound (11.3 mg, 25%). MS (ESI) m/z: 355.8 [M+H] 1H NMR (400 MHz, MeOD) δ ppm 5.31 (s, 2H), 7.20 (ddd, J=11.4, 9.0, 7.5 Hz, 1H), 7.40 (d, J=7.8 Hz, 1H), 7.47 (ddd, J=8.9, 3.7, 1.3 Hz, 1H), 7.52 (t, J=8.1 Hz, 1H), 7.79 (d, J=8.8 Hz, 1H), 7.96 (s, 1H), 8.20 (s, 1H).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH3:12])=[N:7]2.[NH2:13][C:14]1[CH:19]=[C:18]([CH2:20][O:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([Br:28])[CH:23]=2)[CH:17]=[CH:16][C:15]=1[S:29][C:30]1[CH:35]=[CH:34][C:33]([OH:36])=[CH:32][CH:31]=1>>[Br:28][C:24]1[CH:23]=[C:22]([CH:27]=[CH:26][CH:25]=1)[O:21][CH2:20][C:18]1[CH:17]=[CH:16][C:15]([S:29][C:30]2[CH:35]=[CH:34][C:33]([OH:36])=[CH:32][CH:31]=2)=[C:14]([NH:13][C:2]2[C:3]3[C:8](=[N:7][C:6]([CH3:12])=[CH:5][CH:4]=3)[N:9]=[CH:10][CH:11]=2)[CH:19]=1
Reactant: Cc1ccc2c(Cl)ccnc2n1
Reactant: Nc1cc(COc2cccc(Br)c2)ccc1Sc1ccc(O)cc1
Product: Cc1ccc2c(Nc3cc(COc4cccc(Br)c4)ccc3Sc3ccc(O)cc3)ccnc2n1
Temperature: 80 °C

Procedure:
The product from Example 1d (0.034 g, 0.193 mmol) was reacted with the product from Example 225c (0.078 g, 0.193 mmol) for 15 h following the procedure from Example 1g. Consumption of starting material required a second addition of the product from Example 1d (0.019 g, 0.109 mmol) and continued heating at 80° C. (18 h). The crude title compound was purified by HPLC with TFA providing the product as a trifluoroacetic acid salt (0.041 g, 32%). 1H NMR (300 MHz, DMSO-d6) δ ppm: 2.77 (s, 3H) 5.15 (s, 2H) 6.30 (d, J=7.35 Hz, 1H) 6.79 (d, J=8.46 Hz, 2H) 6.95-7.08 (m, 2H) 7.16 (d, 1H) 7.20-7.30 (m, 4H) 7.45-7.55 (m, 2H) 7.81 (d, J=8.82 Hz, 1H) 8.47 (d, J=7.35 Hz, 1H) 9.01 (d, J=8.46 Hz, 1H) 9.98 (s, 1H); Ms (ESI+) m/z 546.0 (M+H)+; (ESI−) m/z 542.0.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[CH:19]=[C:18]([NH:20][C:21]3[CH:30]=[C:29]4[C:24]([CH:25]=[CH:26][CH:27]=[N:28]4)=[CH:23][CH:22]=3)[N:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[N:28]1[C:29]2[C:24](=[CH:23][CH:22]=[C:21]([NH:20][C:18]3[CH:19]=[C:14]([C:11]4[CH2:12][CH2:13][NH:8][CH2:9][CH:10]=4)[N:15]=[CH:16][N:17]=3)[CH:30]=2)[CH:25]=[CH:26][CH:27]=1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2cc(Nc3ccc4cccnc4c3)ncn2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C1=C(c2cc(Nc3ccc4cccnc4c3)ncn2)CCNC1

Procedure:
This compound could be prepared from 4-[6-(quinolin-7-ylamino)-pyrimidin-4-yl]-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester in the presence of TFA and CH2Cl2.
Reaction SMILES: [CH2:1]([N:8]=[C:9]=[S:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:11][NH2:12]>O1CCOCC1>[CH2:1]([NH:8][C:9](=[S:10])[NH:11][NH2:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: S=C=NCc1ccccc1
Reactant: NN
Solvent: C1COCCO1
Product: NNC(=S)NCc1ccccc1
Temperature: 25 °C
Yield: 51.5 %

Procedure:
Benzylisothiocyanate (4.0 g) is slowly added to 1.8 g of anhydrous hydrazine in 50 ml dioxane. The reaction mixture is stirred at room temperature, the dioxane is then removed in vacuo and the residue is recrystallised from ethanol to give 4-benzylthiosemicarbazide as a crystalline solid (2.5 g), m.p. 127.6° C.
Reaction SMILES: COCCOCCOC.[CH2:10]([N:13]1[C:17](=[O:18])[CH2:16][NH:15][C:14]1=[S:19])[CH:11]=[CH2:12].N1CCOCC1.[CH:26](=O)[CH2:27][CH2:28][CH3:29]>C(OCC)(=O)C>[CH2:10]([N:13]1[C:17](=[O:18])[C:16](=[CH:26][CH2:27][CH2:28][CH3:29])[NH:15][C:14]1=[S:19])[CH:11]=[CH2:12]
Reactant: C=CCN1C(=O)CNC1=S
Reactant: CCCC=O
Solvent: COCCOCCOC
Solvent: C1COCCN1
Solvent: CCOC(C)=O
Product: C=CCN1C(=O)C(=CCCC)NC1=S

Procedure:
A flask equipped with a reflux condenser, magnetic stirrer, and nitrogen atmosphere was charged with diglyme (10 mL), 3-allylthiohydantoin (1.0 g, 0.0064 mol), morpholine (0.56 g, 0.0064 mol), and freshly distilled butyraldehyde (0.94 g, 0.13 mol). The mixture was heated in a 70° oil bath for 250 min and, after cooling, was diluted with 20 mL of ethyl acetate. The resulting solution was washed with 2×10 mL 1.2 M HCl, 10 mL of water, and 10 mL of saturated aqueous NaCl. The solution was then filtered through 1 PS paper and concentrated to dryness at aspirator pressure and then high vacuum. The light orange crystalline residue weighed 1.26 g (97%). An HPLC trace at 215 nm indicated that the major product comprised 92% of the mixture. Another component (5%), with a nearly identical ultraviolet spectrum, eluted slightly more slowly. This possibly represents the other geometric isomer. NMR (CDCl3) δ 10 (bs, 1H), 5.2-6.3 (m, 4H), 4.6 (d, 2H), 2.3 (quart., 2H), 1.8 (sex., 2H), 1.0 (t, 3H).
Reaction SMILES: S(Cl)(Cl)=O.[O:5]=[C:6]([CH2:10][C:11]1([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[C:21]([F:24])([F:23])[F:22])[CH2:14][CH2:13][CH2:12]1)[C:7]([OH:9])=O.[O:25]1[C:29]([C:30]2[CH:35]=[CH:34][C:33]([NH2:36])=[CH:32][CH:31]=2)=[CH:28][N:27]=[CH:26]1.C(=O)([O-])[O-].[K+].[K+]>CC(N(C)C)=O>[O:25]1[C:29]([C:30]2[CH:31]=[CH:32][C:33]([NH:36][C:7](=[O:9])[C:6](=[O:5])[CH2:10][C:11]3([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=4[C:21]([F:22])([F:23])[F:24])[CH2:14][CH2:13][CH2:12]3)=[CH:34][CH:35]=2)=[CH:28][N:27]=[CH:26]1
Reactant: O=C(O)C(=O)CC1(c2ccccc2C(F)(F)F)CCC1
Reactant: Nc1ccc(-c2cnco2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O=S(Cl)Cl
Product: O=C(CC1(c2ccccc2C(F)(F)F)CCC1)C(=O)Nc1ccc(-c2cnco2)cc1
Temperature: -5 °C
Reaction time: 0.5 h
Yield: 42.1 %

Procedure:
0.052 ml of thionyl chloride was added to a solution of 0.1 g of 2-Oxo-3-[1-(2-trifluoromethyl-phenyl)-cyclobutyl]-propionic acid in 2 ml of dimethyl acetamide at −5° C., and stirred for 30 min at −5° C. Then 56 mg of 4-oxazol-5-yl-phenylamine was added in solid form and stirred for 1 hour at room temperature. Potassium carbonate was added and stirred overnight at room temperature. The reaction was quenched with water and extracted with ethyl acetate. The combined ethyl acetate extracts were washed twice with water, dried and concentrated by evaporation. The residue was purified by column chromatography on silica-gel (EtOAc-hexane 10%-20%) to yield 63 mg of product.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1C(C)(C=O)CC(O)=O.[OH2:18].[NH2:19][NH2:20]>C(O)C>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:5]2[CH:4]([CH3:9])[CH2:3][C:2](=[O:18])[NH:19][N:20]=2)=[CH:2]1
Reactant: O
Reactant: NN
Reactant: CC(C=O)(CC(=O)O)c1cc2ccccc2[nH]1
Solvent: CCO
Product: CC1CC(=O)NN=C1c1c[nH]c2ccccc12

Procedure:
7.0 g (0.03 mole) of 4-(3-(indolyl)-4-oxo-3-methylbutyric acid and 1.7 ml (0.035 mole) of hydrazine hydrate are heated under reflux in 60 ml of ethanol for 2 hours. After the mixture has been concentrated, the residue is chromatographed over a silica gel column with methylene chloride:methanol=9:1 as the eluant and the product is recrystallised from isopropanol.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[CH:6][C:7]=1[C:8]([O:10][CH3:11])=[O:9].N1C=CC=CC=1.[Cl:21][C:22]1[CH:27]=[C:26]([OH:28])[CH:25]=[CH:24][C:23]=1[CH:29]([CH3:48])[C:30]([C:36]1[CH:47]=[CH:46][C:39]2[N:40]([CH3:45])[C:41](=[O:44])[N:42]([CH3:43])[C:38]=2[CH:37]=1)([OH:35])[C:31]([F:34])([F:33])[F:32]>C(Cl)Cl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH3:11][O:10][C:8](=[O:9])[C:7]1[CH:6]=[CH:5][C:4]([O:28][C:26]2[CH:25]=[CH:24][C:23]([CH:29]([CH3:48])[C:30]([C:36]3[CH:47]=[CH:46][C:39]4[N:40]([CH3:45])[C:41](=[O:44])[N:42]([CH3:43])[C:38]=4[CH:37]=3)([OH:35])[C:31]([F:32])([F:33])[F:34])=[C:22]([Cl:21])[CH:27]=2)=[CH:3][C:2]=1[F:1]
Reactant: CC(c1ccc(O)cc1Cl)C(O)(c1ccc2c(c1)n(C)c(=O)n2C)C(F)(F)F
Reactant: COC(=O)c1ccc(B(O)O)cc1F
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1ccc(Oc2ccc(C(C)C(O)(c3ccc4c(c3)n(C)c(=O)n4C)C(F)(F)F)c(Cl)c2)cc1F
Reaction time: 96 h
Yield: 58.5 %

Procedure:
Copper(II)acetate (657 mg), 3-fluoro-4-methoxycarbonylphenylboronic acid (CAS Reg. 505083-04-5, 716 mg), and pyridine (0.3 ml) were added to a solution of 5-[2-(2-chloro-4-hydroxy-phenyl)-1-hydroxy-1-trifluoromethyl-propyl]-1,3-dimethyl-1,3-dihydro-benzoimidazol-2-one (Example 85, 500 mg) in DCM (20 ml). The mixture was stirred with molecular sieves under air atmosphere for 4 days and then concentrated to an oil. The residue was purified by flash chromatography (SiO2, 2:1 EtOAc/heptane) to give the title compound (400 mg) as a light yellow oil. MS (m/e)=567.1 [M+H+].
Reaction SMILES: C([N:8]1[CH2:14][C:13]2[N:15]=[CH:16][C:17]([N:19]([CH3:23])[CH2:20][CH2:21][CH3:22])=[N:18][C:12]=2[O:11][C@@H:10]([CH2:24][O:25][CH3:26])[CH2:9]1)C1C=CC=CC=1.C(OCC)(=O)C.[ClH:33]>CO.[OH-].[OH-].[Pd+2]>[ClH:33].[CH3:26][O:25][CH2:24][C@H:10]1[CH2:9][NH:8][CH2:14][C:13]2[N:15]=[CH:16][C:17]([N:19]([CH3:23])[CH2:20][CH2:21][CH3:22])=[N:18][C:12]=2[O:11]1
Reactant: CCCN(C)c1cnc2c(n1)O[C@@H](COC)CN(Cc1ccccc1)C2
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Product: CCCN(C)c1cnc2c(n1)O[C@@H](COC)CNC2
Temperature: 50 °C
Reaction time: 3 h
Yield: 56 %

Procedure:
To a solution of (6R)-8-benzyl-6-(methoxymethyl)-N-methyl-N-propyl-6,7,8,9-tetrahydropyrazino[2,3-f][1,4]oxazepin-3-amine (465 mg) in methanol (10 mL) was added 20% Pd(OH)2/C (50 mg), and the mixture was stirred under a hydrogen atmosphere at 50° C. for 3 hr. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. To a solution of the obtained crude product in ethyl acetate (10 mL) was added a 4 N hydrogen chloride-ethyl acetate solution (359 μL), and the mixture was stirred for 1 hr. The reaction mixture was filtered, and the obtained crystals were washed with ethyl acetate to give the title compound (223 mg, 56%).
Reaction SMILES: [N+:1]([C:4]1[NH:5][CH:6]=[CH:7][N:8]=1)([O-:3])=[O:2].[CH3:9][O-:10].[Na+].N1C=CN=C1.Br[CH2:18][CH2:19][OH:20]>CN(C=O)C.CO>[N+:1]([C:4]1[N:5]([C:19]([CH2:18][CH2:9][OH:10])=[O:20])[CH:6]=[CH:7][N:8]=1)([O-:3])=[O:2]
Reactant: C[O-]
Reactant: O=[N+]([O-])c1ncc[nH]1
Reactant: OCCBr
Agent: [Na+]
Agent: c1c[nH]cn1
Solvent: CO
Solvent: CN(C)C=O
Product: O=C(CCO)n1ccnc1[N+](=O)[O-]
Temperature: 110 °C

Procedure:
To a suspension of 2-nitroimidazole (4.00 g, 35.4 mmol) in 40 mL dry DMF was added dropwise 3N NaOMe in MeOH until the imidazole had dissolved completely and the solution had just turned red. Further imidazole was added until the color just returned to yellow. The MeOH was then removed by heating to 110° C., removing the condenser, and continuing heating up to a bath temperature of 152° C. After cooling the solution to 110° C., 2-bromoethanol (2.74 mL, 4.82 g, 38.6 mmol, Aldrich, redistilled) was added and the bath temperature maintained at 110° C. for 1-1/2 h. The yellow solution was then flash-evaporated at 40° C., under a high vacuum until a yellow paste was obtained. This was subsequently extracted five times with 20 mL acetone and the acetone solutions evaporated to a yellow solid, which was treated with 25 mL EtOAc and the solvent again evaporated. The resulting material was extracted with 10 mL saturated Na2CO3, twice with 20 mL half-saturated Na2CO3, and finally twice with 10 mL water. The remaining crystalline material, 2.96 g, was free of 2-nitroimidazole by TLC (Eastman silica gel, DME). The aqueous solutions were extracted twice with 25 mL EtOAc, and the organic layers then washed with 5 mL half-saturated Na2CO3, 5 mL water, and then dried over anhydrous MgSO4. Concentration to 20 mL and cooling yielded 0.586 g of product, mp 112°-116.5° C. The two crystalline products were recrystallized from EtOH to yield 1.92 g (34.5%) of the desired 2-(2-Nitro-1-imidazoyl)ethanol as yellow-green needles.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:12]2[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[N:15]3[N:22]=[CH:23][C:24]([C:25](O)=[O:26])=[C:14]3[N:13]=2)[CH:5]=[CH:6][C:7]=1[C:8]([F:11])([F:10])[F:9].[CH3:28][S:29]([C:32]1[CH:33]=[C:34]([NH2:38])[CH:35]=[CH:36][CH:37]=1)(=[O:31])=[O:30].Cl>>[CH3:28][S:29]([C:32]1[CH:33]=[C:34]([NH:38][C:25]([C:24]2[CH:23]=[N:22][N:15]3[C:16]([C:18]([F:21])([F:20])[F:19])=[CH:17][C:12]([C:4]4[CH:5]=[CH:6][C:7]([C:8]([F:11])([F:9])[F:10])=[C:2]([CH3:1])[CH:3]=4)=[N:13][C:14]=23)=[O:26])[CH:35]=[CH:36][CH:37]=1)(=[O:30])=[O:31]
Reactant: CS(=O)(=O)c1cccc(N)c1
Reactant: Cc1cc(-c2cc(C(F)(F)F)n3ncc(C(=O)O)c3n2)ccc1C(F)(F)F
Agent: Cl
Product: Cc1cc(-c2cc(C(F)(F)F)n3ncc(C(=O)Nc4cccc(S(C)(=O)=O)c4)c3n2)ccc1C(F)(F)F

Procedure:
The title compound was prepared from 5-(3-methyl-4-trifluoromethyl-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.8) and 3-methanesulfonyl-phenylamine [commercially available as hydrochloride] according to general procedure II. Yellow solid. MS (ISP) 543.3 [(M+H)+]; mp 233° C.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[CH:6][CH:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:16]([SH:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CN(C)C=O>[C:17]1([CH2:16][S:23][C:2]2[C:7]([C:8]#[N:9])=[CH:6][CH:5]=[CH:4][N:3]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: SCc1ccccc1
Reactant: N#Cc1cccnc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#Cc1cccnc1SCc1ccccc1
Temperature: 120 °C
Reaction time: 2 h

Procedure:
85 g of 2-chloro-3-cyanopyridine, 98.2 g potassium carbonate anhydrous powder and 600 g of dimethyl formamide were mixed to obtain a suspension. To this suspension, a solution of 79.2 g benzyl mercaptan in 250 ml dimethyl formamide was added dropwise over a period of approx. 3 hours at 80-90° C. The reaction mass was agitated for 2 hours at the same temperature. The temperature was slowly raised to 120° C. Then, the reaction mixture was reacted at 120-130° C. for about 1.5 hours. Afterwards, heating was stopped and reaction mass was allowed to attain the room temperature. Inorganic cake was separated by filtration. Dimethyl formamide was distilled under reduced pressure, and the residue left at bottom was 2-(phenyl methyl thio)-3-cyano pyridine 150 g, sufficiently pure to be used in the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:10][C:11]2[C:16]([F:17])=[CH:15][CH:14]=[C:13]([CH3:18])[C:12]=2[F:19])[CH:9]=1)[C:5]#[N:6].C1C(=O)N([Br:27])C(=O)C1>C(Cl)(Cl)(Cl)Cl.CC(N=NC(C#N)(C)C)(C#N)C>[Br:27][CH2:18][C:13]1[C:12]([F:19])=[C:11]([O:10][C:8]2[CH:7]=[C:4]([CH:3]=[C:2]([Cl:1])[CH:9]=2)[C:5]#[N:6])[C:16]([F:17])=[CH:15][CH:14]=1
Reactant: Cc1ccc(F)c(Oc2cc(Cl)cc(C#N)c2)c1F
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: N#Cc1cc(Cl)cc(Oc2c(F)ccc(CBr)c2F)c1
Temperature: 90 °C
Reaction time: 0.08 h
Yield: 55.9 %

Procedure:
A solution of 3-chloro-5-[(2,6-difluoro-3-methylphenyl)oxy]benzonitrile (4.05 g, 14.48 mmol) and NBS (3.09 g, 17.38 mmol) in carbon tetrachloride (500 mL) was degassed and heated to 90° C. under a nitrogen atmosphere. After ca. 5 min, AIBN (0.119 g, 0.724 mmol) was added and the solution was heated for 6 h. The solution was cooled to 0° C. then filtered through Celite. The filtrate was concentrated and the crude material was purified on silica gel (hexanes/ethyl acetate) to give the title compound (2.9 g, 56%) as a white solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.31-7.40 (m, 2H), 7.21 (t, 1H), 7.04-7.11 (m, 2H), 4.51 (s, 2H).
Reaction SMILES: [OH-].[Na+].C1COCC1.[CH3:8][O:9][C:10]1[CH:11]=[CH:12][C:13]([CH2:32][NH:33][C:34]2[CH:39]=[CH:38][C:37]([C:40]3[CH:45]=[CH:44][C:43]([C:46]([F:49])([F:48])[F:47])=[CH:42][CH:41]=3)=[CH:36][CH:35]=2)=[C:14]([C:16]2[CH:17]=[CH:18][C:19]([C:22]([NH:24][CH2:25][CH2:26][C:27]([O:29]CC)=[O:28])=[O:23])=[N:20][CH:21]=2)[CH:15]=1>CO>[CH3:8][O:9][C:10]1[CH:11]=[CH:12][C:13]([CH2:32][NH:33][C:34]2[CH:39]=[CH:38][C:37]([C:40]3[CH:41]=[CH:42][C:43]([C:46]([F:48])([F:49])[F:47])=[CH:44][CH:45]=3)=[CH:36][CH:35]=2)=[C:14]([C:16]2[CH:17]=[CH:18][C:19]([C:22]([NH:24][CH2:25][CH2:26][C:27]([OH:29])=[O:28])=[O:23])=[N:20][CH:21]=2)[CH:15]=1
Reactant: CCOC(=O)CCNC(=O)c1ccc(-c2cc(OC)ccc2CNc2ccc(-c3ccc(C(F)(F)F)cc3)cc2)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(CNc2ccc(-c3ccc(C(F)(F)F)cc3)cc2)c(-c2ccc(C(=O)NCCC(=O)O)nc2)c1
Temperature: 25 °C

Procedure:
A 3M aqueous solution of NaOH (0.15 mL, 0.44 mmol) was added to a THF (1.8 mL) and MeOH (2 mL) solution of ethyl 3-(5-(5-methoxy-2-(((4′-(trifluoromethyl)-[1,1′-biphenyl]-4-yl)amino)methyl)phenyl)picolinamido)propanoate (85 mg, 0.15 mmol) and the resulting mixture was stirred at room temperature. After 2 h the resulting mixture was concentrated in vacuo, suspended in water, and acidified with 2 M HCl. The resulting precipitate was filtered off and dried in vacuo to yield the title compound.
Reaction SMILES: [CH3:1][C:2]1[C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:15])[C:6]=2[CH:5]=[C:4]([C:16]([OH:18])=[O:17])[CH:3]=1.[C:19](=O)([O-])[O-].[K+].[K+].CN(C)C=O.CI>O>[CH3:1][C:2]1[C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:15])[C:6]=2[CH:5]=[C:4]([C:16]([O:18][CH3:19])=[O:17])[CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: Cc1cc(C(=O)O)cc2c1-c1ccccc1C2=O
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Solvent: O
Product: COC(=O)c1cc(C)c2c(c1)C(=O)c1ccccc1-2
Reaction time: 0.25 h
Yield: 96.2 %

Procedure:
Under anhydrous calcium chloride drying conditions, 4-methyl-9-oxo-9H-fluorene-2-carboxylic acid (1.745 g), potassium carbonate (3.03 g) and dimethylformamide (20 ml) were mixed. To this mixture was added methyl iodide (0.92 ml) at room temperature, and the mixture was stirred for 3 hr 15 min. To the reaction mixture was added water (60 ml), and the mixture was stirred at room temperature for 30 min. The mixture was filtered and the obtained solid was air-dried and dried under reduced pressure at 80° C. to give the title compound (1.778 g, 96%).
Reaction SMILES: C(N(CC)CC)C.[N:8]1([C:13](Cl)=[O:14])[CH2:12][CH2:11][CH2:10][CH2:9]1.[C:16]([O:20][C:21]([N:23]1[CH2:27][C@@H:26]([CH2:28][N:29]([CH:46]([CH3:48])[CH3:47])[C:30](=[O:45])[C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[C:33]([O:39][CH2:40][CH2:41][CH2:42][O:43][CH3:44])[CH:32]=2)[C@H:25]([CH2:49][NH:50][CH:51]2[CH2:53][CH2:52]2)[CH2:24]1)=[O:22])([CH3:19])([CH3:18])[CH3:17]>C(Cl)Cl>[C:16]([O:20][C:21]([N:23]1[CH2:27][C@@H:26]([CH2:28][N:29]([CH:46]([CH3:47])[CH3:48])[C:30](=[O:45])[C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[C:33]([O:39][CH2:40][CH2:41][CH2:42][O:43][CH3:44])[CH:32]=2)[C@H:25]([CH2:49][N:50]([CH:51]2[CH2:52][CH2:53]2)[C:13]([N:8]2[CH2:12][CH2:11][CH2:10][CH2:9]2)=[O:14])[CH2:24]1)=[O:22])([CH3:18])([CH3:19])[CH3:17]
Reactant: O=C(Cl)N1CCCC1
Reactant: COCCCOc1cc(C(=O)N(C[C@@H]2CN(C(=O)OC(C)(C)C)C[C@H]2CNC2CC2)C(C)C)ccc1OC
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCCCOc1cc(C(=O)N(C[C@@H]2CN(C(=O)OC(C)(C)C)C[C@H]2CN(C(=O)N2CCCC2)C2CC2)C(C)C)ccc1OC
Temperature: 60 °C
Reaction time: 24 h

Procedure:
Triethylamine (99 μL, 0.714 mmol) followed by 1-pyrrolidinecarbonyl chloride is added to a solution of ((3R*,4R*)-3-cyclopropylaminomethyl-4-({isopropyl-[4-methoxy-3-(3-methoxy-propoxy)-benzoyl]-amino}-methyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (254 mg, 0.476 mmol) in CH2Cl2 (20 mL). The resulting solution is stirred at RT for 2 h and at 60° C. for another 24 h. Evaporation of the solvent affords the crude product which is purified by preparative HPLC (Waters C18 ODB, eluent: H2O/CH3CN 20 to 100%) to give the title compound. MS (LC-MS): 631.1 [M+H]+; tR (HPLC, Macherey-Nagel Nucleosil C18 column, 10-100% CH3CN/H2O/5 min, 100% CH3CN/3 min, CH3CN and H2O containing 0.1% TFA, flow: 1.5 ml/min): 6.31 min.