Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][C:5]1[C:10]([CH2:11]O)=[C:9]([CH3:13])[N:8]=[C:7]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[N:6]=1.S(Cl)([Cl:26])=O>ClCCl>[Cl:26][CH2:11][C:10]1[C:5]([CH2:4][CH2:3][O:2][CH3:1])=[N:6][C:7]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)=[N:8][C:9]=1[CH3:13]
Reactant: COCCc1nc(-c2ccc(C(F)(F)F)cc2)nc(C)c1CO
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: COCCc1nc(-c2ccc(C(F)(F)F)cc2)nc(C)c1CCl
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.6 %

Procedure:
A solution of [4-(2-methoxy-ethyl)-6-methyl-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-yl]-methanol (2.47 g, 7.48 mmol) in dichloromethane (25 ml) was treated with thionylchloride (0.57 ml, 7.85 mmol). After 2 h stirring at RT, the mixture was partitioned between ether and water. The ether-phase was concentrated under reduced pressure to give 2.42 g (7 mmol, 94%) 5-chloromethyl-4-(2-methoxy-ethyl)-6-methyl-2-(4-trifluoromethyl-phenyl)-pyrimidine.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)[S:5][C:6]=1[CH:7]=[O:8].[CH3:15][Mg]Cl.O.CC(O)=O>C1COCC1>[Cl:1][C:2]1[N:3]=[C:4]([C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)[S:5][C:6]=1[CH:7]([OH:8])[CH3:15]
Reactant: C[Mg]Cl
Reactant: O=Cc1sc(-c2cccnc2)nc1Cl
Solvent: C1CCOC1
Solvent: O
Solvent: CC(=O)O
Product: CC(O)c1sc(-c2cccnc2)nc1Cl
Temperature: -10 °C
Reaction time: 18 h

Procedure:
4-Chloro-2-(3-pyridyl)thiazole-5-carbaldehyde (1.4 g, 6.25 mmol) was dissolved in dry THF (28 ml) and cooled to −10° C. A 3 M solution of methyl magnesiumchloride in THF (2.08 ml, 6.25 mmol) was added dropwise. The reaction mixture was stirred at ambient temperature for 18 hours. Water (1.7 ml) was added, followed by CH3COOH (1 ml). The reaction mixture was extracted with ethyl acetate, the organic layer was separated, dried, filtered, and the solvent was evaporated to dryness to get 1-[4-chloro-2-(3-pyridyl)thiazol-5-yl]ethanol as a brown solid. 1H NMR (300 Mz, DMSO-d6): δ: 9.07 (s, 1H), 8.68 (dd, 1H, J=1.5 Hz), 8.26 (m, 1H), 7.53 (m, 1H), 5.92 (t, 1H, J=6 Hz), 4.67 (d, 3H, J=5.4 Hz).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][CH2:5][CH2:4][C@@H:3]1[NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11].[Br:15][C:16]1[C:17](Cl)=[N:18][C:19]([Cl:22])=[N:20][CH:21]=1.BrC1C(NC(C(C)C)CNC(=O)OC(C)(C)C)=NC(Cl)=NC=1>>[Br:15][C:16]1[C:17]([NH:1][C@H:2]2[CH2:6][CH2:5][CH2:4][C@@H:3]2[NH:7][C:8](=[O:14])[O:9][C:10]([CH3:11])([CH3:13])[CH3:12])=[N:18][C:19]([Cl:22])=[N:20][CH:21]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCC[C@@H]1N
Reactant: Clc1ncc(Br)c(Cl)n1
Agent: CC(C)C(CNC(=O)OC(C)(C)C)Nc1nc(Cl)ncc1Br
Product: CC(C)(C)OC(=O)N[C@H]1CCC[C@@H]1Nc1nc(Cl)ncc1Br

Procedure:
tert-butyl N-[(1S,2S)-2-[(5-bromo-2-chloro-pyrimidin-4-yl)amino]cyclopentyl]carbamate was synthesized by treating tert-butyl N-[(1S,2S)-2-aminocyclopentyl]carbamate with 5-bromo-2,4-dichloro-pyrimidine using analogous reaction conditions as described for tert-butyl N-[2-[(5-bromo-2-chloro-pyrimidin-4-yl)amino]-3-methyl-butyl]carbamate. 1H NMR (600 MHz, DMSO-d6) δ ppm 1.27 (s, 9H) 1.42-1.54 (m, 2H) 1.56-1.65 (m, 2H) 1.80-1.88 (m, 1H) 1.96-2.01 (m, 1H) 3.88-3.96 (m, 1H) 4.03-4.09 (m, 1H) 6.91 (d, J=8.20 Hz, 1H) 7.41 (d, J=7.32 Hz, 1H) 8.18 (s, 1H). LCMS (ESI) 391 (M+H).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[C:8]1([CH:14]([C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)[CH2:15][NH:16][C:17]2[N:25]=[C:24]([N:26]3[CH2:30][CH2:29][C@@H:28]([NH:31][C:32]([NH:34][C@@H:35]4[CH2:39][CH2:38][NH:37][CH2:36]4)=[O:33])[CH2:27]3)[N:23]=[C:22]3[C:18]=2[N:19]=[CH:20][N:21]3[C@@H:40]2[CH2:44][C@H:43]([NH:45][C:46](=[O:49])[CH2:47][CH3:48])[C@@H:42]([OH:50])[C@H:41]2[OH:51])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.CCN(C(C)C)C(C)C.[C:67](Cl)(=[O:77])[C:68]1[CH:76]=[CH:75][C:71]([C:72](Cl)=[O:73])=[CH:70][CH:69]=1>CN1C(=O)CCC1>[C:3]([OH:5])([C:2]([F:7])([F:6])[F:1])=[O:4].[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[OH:51][C@@H:41]1[C@H:42]([OH:50])[C@@H:43]([NH:45][C:46](=[O:49])[CH2:47][CH3:48])[CH2:44][C@H:40]1[N:21]1[CH:20]=[N:19][C:18]2[C:22]1=[N:23][C:24]([N:26]1[CH2:30][CH2:29][C@@H:28]([NH:31][C:32](=[O:33])[NH:34][C@@H:35]3[CH2:39][CH2:38][N:37]([C:67]([C:68]4[CH:76]=[CH:75][C:71]([C:72]([OH:4])=[O:73])=[CH:70][CH:69]=4)=[O:77])[CH2:36]3)[CH2:27]1)=[N:25][C:17]=2[NH:16][CH2:15][CH:14]([C:52]1[CH:53]=[CH:54][CH:55]=[CH:56][CH:57]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=C(Cl)c1ccc(C(=O)Cl)cc1
Reactant: CCC(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(N4CC[C@@H](NC(=O)N[C@@H]5CCNC5)C4)nc32)[C@H](O)[C@@H]1O
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: CCC(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(N4CC[C@@H](NC(=O)N[C@@H]5CCN(C(=O)c6ccc(C(=O)O)cc6)C5)C4)nc32)[C@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of N-((1S,2R,3S,4R)-4-{6-(2,2-diphenyl-ethylamino)-2-[(R)-3-((R)-3-pyrrolidin-3-ylureido)-pyrrolidin-1-yl]-purin-9-yl}-2,3-dihydroxy-cyclopentyl)-propionamide trifluoroacetate (step 1) (0.02 g, 29 μmol) DIPEA (0.0075 g, 58 μmol) in NMP (0.2 ml) is treated with a solution of terephthaloyl chloride (0.006 g, 14.5 μmol) in NMP (0.1 ml). After stirring at room temperature for 1 hour the reaction mixture is purified by C-18 reverse phase column chromatography eluting with acetonitrile:water:TFA (0.1%) (gradient of 0 to 100% acetonitrile) to yield the title compound. (MH+ 831.6)
Reaction SMILES: CC1(C)[O:9][C:8](=[O:10])[C:5]2([CH2:7][CH2:6]2)[C:4](=[O:11])O1.[CH2:13]([C:15]1[CH:16]=[C:17]([CH:19]=[CH:20][CH:21]=1)[NH2:18])[CH3:14]>C(O)C>[CH2:13]([C:15]1[CH:16]=[C:17]([N:18]2[CH2:6][CH2:7][CH:5]([C:8]([OH:9])=[O:10])[C:4]2=[O:11])[CH:19]=[CH:20][CH:21]=1)[CH3:14]
Reactant: CCc1cccc(N)c1
Reactant: CC1(C)OC(=O)C2(CC2)C(=O)O1
Solvent: CCO
Product: CCc1cccc(N2CCC(C(=O)O)C2=O)c1
Yield: 35 %

Procedure:
A mixture of 6,6-dimethyl-5,7-dioxaspiro[2.5]octane-4,8-dione (0.500 g; 2.94 mmol) and 3-ethylaniline (1.1 mL; 8.82 mmol) in ethanol (3 mL) was irradiated in a microwave oven for 3 minutes at 100° C. The mixture was concentrated under reduced pressure and the residue was dissolved in a solution of sodium hydroxide 6N, washed with dichloromethane, acidified with a solution of hydrochloric acid 6N to pH=2, extracted with ethyl acetate dried and concentrated under reduced pressure to yield 0.240 g (35%) of a yellow oil which was used in the next step without further purification.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[N:8][N:7]2[CH:10]=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:12]=[C:6]2[C:5]=1[NH:19][C@H:20]1[CH2:25][CH2:24][CH2:23][N:22]([C:26]([O:28]C(C)(C)C)=O)[CH2:21]1)(=[O:3])[NH2:2].[C:33](OC(=O)C)(=O)C.CCN(C(C)C)C(C)C>C(Cl)Cl>[C:26]([N:22]1[CH2:23][CH2:24][CH2:25][C@H:20]([NH:19][C:5]2[C:6]3[N:7]([CH:10]=[C:11]([C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=4)[CH:12]=3)[N:8]=[CH:9][C:4]=2[C:1]([NH2:2])=[O:3])[CH2:21]1)(=[O:28])[CH3:33]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](Nc2c(C(N)=O)cnn3cc(-c4ccccc4)cc23)C1
Reactant: CC(=O)OC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)N1CCC[C@H](Nc2c(C(N)=O)cnn3cc(-c4ccccc4)cc23)C1
Reaction time: 1 h

Procedure:
A suspension of (S)-6-phenyl-4-(piperidin-3-ylamino)pyrrolo[1,2-b]pyridazine-3-carboxamide hydrochloride salt (Example 44, 12.2 mg, 0.033 mmol) in CH2Cl2 (0.3 mL) was added acetic anhydride (3.72 μL, 0.04 mmol) followed by DIPEA (0.017 mL, 0.1 mmol). The reaction was stirred for 1 h at which time the starting material had been consumed as judged by HPLC. The solvents were removed and the product purified via reverse phase preparative HPLC. LCMS: 378 (M+H)+; HPLC (conditions E): retention time=7.41 min; 1H NMR (MeOD, 400 MHz) δ 8.17 (d, J=13 Hz, 1H), 7.97 (dd, J=1.7, 12.3 Hz, 1H), 7.75 (m, 3H), 7.40 (m, 3H), 7.27 (m, 1H), 4.38 (m, 1H), 3.83-3.94 (m, 2H), 3.42 (m, 2H), 2.21 (s, 3H), 1.98 (m, 1H), 1.87 (m, 1H), 1.75 (m, 1H).
Reaction SMILES: [CH3:1][C:2]([CH3:6])=[CH:3][CH2:4]O.[C:7]([O-:13])([O-])([O:9][CH2:10][CH3:11])[CH3:8]>B(O)(O)O.C(O)C>[CH3:1][C:2]([CH3:6])([CH:3]=[CH2:4])[CH2:8][C:7]([O:9][CH2:10][CH3:11])=[O:13]
Reactant: CC(C)=CCO
Reactant: CCOC(C)([O-])[O-]
Agent: OB(O)O
Solvent: CCO
Product: C=CC(C)(C)CC(=O)OCC
Yield: 80.1 %

Procedure:
A mixture of 4.3 g of 3-methyl-2-buten-1-ol, 16.2 g of ethyl orthoacetate and 86 mg of boric acid was heated for 2 hours at 120° with stirring, during which ethanol was evolved and removed. The temperature was then increased to 145°-150° where it was maintained for an additional 8 hours. When ethanol evolution ceased, the mixture was distilled to separate unreacted ethyl orthoacetate from 6.25 g (80% yield) of ethyl 3,3-dimethyl-4-pentenoate, b.p. 78°-80°/51 mm.
Reaction SMILES: [F:1][C:2]([F:25])([C:21]([F:24])([F:23])[F:22])[C:3](=O)[CH:4]=[CH:5][C:6]1[CH:7]=[C:8]([C:12]2[CH:17]=[CH:16][C:15]([S:18][CH3:19])=[CH:14][CH:13]=2)[CH:9]=[CH:10][CH:11]=1.Cl.[Cl:27][C:28]1[CH:33]=[C:32]([Cl:34])[CH:31]=[CH:30][C:29]=1[NH:35][NH2:36].Cl>C(O)C>[Cl:27][C:28]1[CH:33]=[C:32]([Cl:34])[CH:31]=[CH:30][C:29]=1[N:35]1[CH:5]([C:6]2[CH:7]=[C:8]([C:12]3[CH:17]=[CH:16][C:15]([S:18][CH3:19])=[CH:14][CH:13]=3)[CH:9]=[CH:10][CH:11]=2)[CH2:4][C:3]([C:2]([F:25])([F:1])[C:21]([F:24])([F:23])[F:22])=[N:36]1
Reactant: CSc1ccc(-c2cccc(C=CC(=O)C(F)(F)C(F)(F)F)c2)cc1
Reactant: NNc1ccc(Cl)cc1Cl
Agent: Cl
Solvent: CCO
Product: CSc1ccc(-c2cccc(C3CC(C(F)(F)C(F)(F)F)=NN3c3ccc(Cl)cc3Cl)c2)cc1
Temperature: 100 °C
Reaction time: 18 h
Yield: 32.1 %

Procedure:
4,4,5,5,5-Pentafluoro-1-(4′-methylsulfanyl-biphenyl-3-yl)-pent-1-en-3-one (200.0 mg, 0.54 mmol) prepared in Step 3 of Preparation 4, 2,4-dichlorophenylhydrazine hydrochloride (127.0 mg, 0.59 mmol) and conc. hydrochloric acid (200.0 uL) were added to ethanol (5.0 mL). The reaction mixture was stirred at 100° C. for 18 hours, quenched with a saturated solution of sodium hydrogen carbonate, and then extracted with ethyl acetate three times. The combined extract was washed with brine, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give a yellow liquid residue. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/60) to give 92.0 mg of the titled compound as a yellow liquid.
Reaction SMILES: [NH2:1][C:2]1[C:7](=[O:8])[C:6]2[CH:9]=[C:10]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:11]([NH:13][S:14]([CH3:17])(=[O:16])=[O:15])=[CH:12][C:5]=2[O:4][CH:3]=1.CO[CH:27](OC)[N:28]([CH3:30])[CH3:29]>>[CH3:27][N:28]([CH:30]=[N:1][C:2]1[C:7](=[O:8])[C:6]2[CH:9]=[C:10]([O:18][C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:11]([NH:13][S:14]([CH3:17])(=[O:15])=[O:16])=[CH:12][C:5]=2[O:4][CH:3]=1)[CH3:29]
Reactant: CS(=O)(=O)Nc1cc2occ(N)c(=O)c2cc1Oc1ccccc1
Reactant: COC(OC)N(C)C
Product: CN(C)C=Nc1coc2cc(NS(C)(=O)=O)c(Oc3ccccc3)cc2c1=O

Procedure:
3-Amino-7-methylsulfonylamino-6-phenoxy-4H-1-benzopyran-4-one was reacted with N,N-dimethylformamide dimethylacetal to obtain 3-(N,N-dimethylamino)methyleneamino-7-methylsulfonylamino-6-phenoxy-4H-1-benzopyran-4-one.
Reaction SMILES: [C:1]([O:4]CC(=O)CC1C=CC(Cl)=C(Cl)C=1)(=[O:3])[CH3:2].[S:17]1[CH:21]=[C:20]([CH2:22][C:23](=[O:26])[CH2:24]Cl)[C:19]2[CH:27]=[CH:28][CH:29]=[CH:30][C:18]1=2.C(O)(=O)C.C(N(CC)CC)C>>[C:1]([O:4][CH2:24][C:23](=[O:26])[CH2:22][C:20]1[C:19]2[CH:27]=[CH:28][CH:29]=[CH:30][C:18]=2[S:17][CH:21]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OCC(=O)Cc1ccc(Cl)c(Cl)c1
Reactant: O=C(CCl)Cc1csc2ccccc12
Solvent: CC(=O)O
Solvent: CCN(CC)CC
Product: CC(=O)OCC(=O)Cc1csc2ccccc12
Yield: 51 %

Procedure:
The procedure described above for the synthesis of 3-(3,4-dichlorophenyl)-2-oxopropyl acetate was followed, reacting 1-(benzo[b]thiophen-3-yl)-3-chloropropan-2-one (0.661 g, 2.94 mmol) with acetic acid (0.34 mL, 0.35 g, 5.9 mmol) and triethylamine (0.82 mL, 0.59 g, 5.9 mmol). Flash chromatography over silica gel (10-40% ethyl acetate in hexanes) gave pure product (0.372 g, 51% yield): 1H NMR (400 MHz, CDCl3) δ 2.14 (s, 3H) 3.98 (s, 2H) 4.71 (s, 2H) 7.34-7.44 (m, 3H) 7.67-7.70 (m, 1H) 7.86-7.89 (m, 1H).
Reaction SMILES: [C-:1]#[N:2].[Na+].Br[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12](=[O:17])[C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:8][CH:7]=1>O.C(O)C>[C:12]([C:9]1[CH:10]=[CH:11][C:6]([CH2:5][C:1]#[N:2])=[CH:7][CH:8]=1)(=[O:17])[C:13]([CH3:16])([CH3:15])[CH3:14]
Reactant: [C-]#N
Reactant: CC(C)(C)C(=O)c1ccc(CBr)cc1
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC(C)(C)C(=O)c1ccc(CC#N)cc1
Temperature: 50 °C

Procedure:
A solution of 34.3 g (0.700 mole) sodium cyanide in 40 ml of water is warmed to 50° C and a solution of α-bromo-p-pivaloyl toluene in 85 ml ethanol is then added dropwise at such a rate as to maintain the temperature at 50° C. After the addition is complete the mixture is refluxed for four hours. The excess ethanol is removed in vacuo and the resulting residue is treated with ether/water. The layers are separated and the ether is washed with cold 50% sulfuric acid, water and sodium bicarbonate, then the ether layer is dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo. The residue is distilled in vacuo to give p-pivaloyl phenyl acetonitrile (b.p. 143-148° C/0.75 mm n22 =1.5244.)
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[CH:28]1([CH2:34][C@H:35]([N:39]2[CH2:47][C:46]3[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=3)[C:40]2=[O:48])[C:36]([OH:38])=O)[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1.[NH2:49][C:50]1[CH:55]=[CH:54][C:53]([Br:56])=[CH:52][N:51]=1.C1(C[C@@H](N2CC3C(=CC=CC=3)C2=O)C(NC2SC=CN=2)=O)CCCCC1>>[Br:56][C:53]1[CH:54]=[CH:55][C:50]([NH:49][C:36](=[O:38])[C@@H:35]([N:39]2[CH2:47][C:46]3[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=3)[C:40]2=[O:48])[CH2:34][CH:28]2[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]2)=[N:51][CH:52]=1
Reactant: O=C(O)[C@H](CC1CCCCC1)N1Cc2ccccc2C1=O
Reactant: Nc1ccc(Br)cn1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C(Nc1nccs1)[C@@H](CC1CCCCC1)N1Cc2ccccc2C1=O
Product: O=C(Nc1ccc(Br)cn1)[C@H](CC1CCCCC1)N1Cc2ccccc2C1=O
Yield: 54.9 %

Procedure:
BOP coupling of (S)-3-Cyclohexyl-2-(1-oxo-1,3-dihydro-isoindol-2-yl)-propionic acid (prepared in Example 1, Step A; 287 mg; 1.00 mmol) and 2-amino-5-bromopyridine (173 mg; 1.00 mmol) in a manner similar to that used for the preparation of (R)-3-cyclohexyl-2-(1-oxo-1,3-dihydro-isoindol-2-yl)-N-thiazol-2-yl-propionamide (outlined in Example 9, Step B) provided after flash chromatography (Merck Silica gel 60, 230-400 mesh, eluent: 30% ethyl acetate/hexanes) 243 mg (55%)of (S)-N-(5-Bromo-pyridin-2-yl)-3-cyclohexyl-2-(1-oxo-1,3-dihydro-isoindol-2-yl)-propionamide as a white foam: EI-HRMS m/e calcd for C22H24BrN3O2 (M+) 441.1052, found 441.1036.
Reaction SMILES: [H-].[Na+].[CH3:3][S:4]([NH-:7])(=[O:6])=[O:5].[C:8]([C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][C:19]=1[O:20][CH2:21][CH2:22][O:23][CH3:24])[N:16]=[CH:15][CH:14]=[C:13]2[O:25][C:26]1[CH:31]=[CH:30][C:29]([NH:32][C:33](=O)[O:34]C2C=CC=CC=2)=[CH:28][CH:27]=1)#[N:9]>O1CCCC1>[C:8]([C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][C:19]=1[O:20][CH2:21][CH2:22][O:23][CH3:24])[N:16]=[CH:15][CH:14]=[C:13]2[O:25][C:26]1[CH:27]=[CH:28][C:29]([NH:32][C:33]([NH:7][S:4]([CH3:3])(=[O:6])=[O:5])=[O:34])=[CH:30][CH:31]=1)#[N:9]
Reactant: COCCOc1cc2nccc(Oc3ccc(NC(=O)Oc4ccccc4)cc3)c2cc1C#N
Reactant: CS([NH-])(=O)=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCCOc1cc2nccc(Oc3ccc(NC(=O)NS(C)(=O)=O)cc3)c2cc1C#N
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 74.5 %

Procedure:
After suspending sodium hydride (11 mg, 0.275 mmol) in tetrahydrofuran (8 ml) under a nitrogen atmosphere, methanesulfonylamide (31.4 mg, 0.330 mmol) was added while cooling in an ice water bath, and the mixture was stirred at room temperature for 10 minutes. Phenyl N-(4-(6-cyano-7-(2-methoxyethoxy)-4-quinolyl)oxyphenyl)carbamate (50 mg, 0.110 mmol) was added and the mixture was stirred at 60° C. for 1 hour. The insoluble portion was filtered off, and after concentration under reduced pressure, tetrahydrofuran-hexane (1:2) was added for crystallization to obtain the title compound (37.6 mg, 0.082 mmol, 75.0%) as gray crystals.
Reaction SMILES: C[O:2][C:3](=[O:34])[C@@H:4]([O:31][CH2:32][CH3:33])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]2[N:15]=[C:16]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH:27]([CH3:29])[CH3:28])=[CH:22][CH:21]=3)[O:17][C:18]=2[CH3:19])=[CH:8][C:7]=1[Cl:30].[Li+].[OH-]>>[Cl:30][C:7]1[CH:8]=[C:9]([O:12][CH2:13][C:14]2[N:15]=[C:16]([C:20]3[CH:21]=[CH:22][C:23]([O:26][CH:27]([CH3:29])[CH3:28])=[CH:24][CH:25]=3)[O:17][C:18]=2[CH3:19])[CH:10]=[CH:11][C:6]=1[CH2:5][C@H:4]([O:31][CH2:32][CH3:33])[C:3]([OH:34])=[O:2]
Reactant: CCO[C@@H](Cc1ccc(OCc2nc(-c3ccc(OC(C)C)cc3)oc2C)cc1Cl)C(=O)OC
Agent: [Li+]
Agent: [OH-]
Product: CCO[C@@H](Cc1ccc(OCc2nc(-c3ccc(OC(C)C)cc3)oc2C)cc1Cl)C(=O)O

Procedure:
In analogy to the procedure described in example 1 g], (S)-3-{2-chloro-4-[2-(4-isopropoxy-phenyl)-5-methyl-oxazol-4-ylmethoxy]-phenyl}-2-ethoxy-propionic acid methyl ester was treated with LiOH to obtain (S)-3-{2-chloro-4-[2-(4-isopropoxy-phenyl)-5-methyl-oxazol-4-ylmethoxy]-phenyl}-2-ethoxy-propionic acid as colorless foam.
Reaction SMILES: [O:1]=[C:2]1[C:6]2([CH2:11][CH2:10][NH:9][CH2:8][CH2:7]2)[N:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:4][N:3]1[CH2:18][C:19]1[CH:20]=[C:21]([CH:29]=[CH:30][CH:31]=1)[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23].I[CH2:33][CH2:34][CH2:35][C:36]([C:38]1[CH:43]=[CH:42][C:41]([O:44][CH3:45])=[CH:40][CH:39]=1)=[O:37].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:45][O:44][C:41]1[CH:42]=[CH:43][C:38]([C:36](=[O:37])[CH2:35][CH2:34][CH2:33][N:9]2[CH2:10][CH2:11][C:6]3([N:5]([C:12]4[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=4)[CH2:4][N:3]([CH2:18][C:19]4[CH:20]=[C:21]([CH:29]=[CH:30][CH:31]=4)[C:22]([O:24][C:25]([CH3:28])([CH3:26])[CH3:27])=[O:23])[C:2]3=[O:1])[CH2:7][CH2:8]2)=[CH:39][CH:40]=1
Reactant: COc1ccc(C(=O)CCCI)cc1
Reactant: CC(C)(C)OC(=O)c1cccc(CN2CN(c3ccccc3)C3(CCNCC3)C2=O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(C(=O)CCCN2CCC3(CC2)C(=O)N(Cc2cccc(C(=O)OC(C)(C)C)c2)CN3c2ccccc2)cc1
Temperature: 68 °C
Reaction time: 16 h
Yield: 23.6 %

Procedure:
A mixture of tert-butyl 3-((4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate (300 mg, 0.71 mmol, 1 equiv), 4-iodo-1-(4-methoxyphenyl)butan-1-one (216.5 mg, 0.71 mmol, 1 equiv), and potassium carbonate (285.2 mg, 2.136 mmol, 3 equiv) in N,N-dimethylformamide was stirred at 68° C. for 16 h. After cooling the reaction mixture, the crude mixture was partitioned between ethyl acetate and water. The organic layer was dried over MgSO4, filtered, concentrated, and the crude residue was purified using the Biotage flash chromatography system (SNAP 10 g cartridge, Rf=0.4, gradient—1%-8% methanol in dichloromethane) to afford the title compound as an oil (100 mg, 25%); MS for C36H43N3O5 m/z 598.3 (M+H)+.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].B1(C=C)OB([CH:13]=[CH2:14])OB(C=C)O1.C1C=CN=CC=1.[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([NH:32][C:33]([C:35]2[N:39]([CH3:40])[N:38]=[C:37]([C:41]([F:47])([F:46])[C:42]([F:45])([F:44])[F:43])[C:36]=2I)=[O:34])=[CH:28][C:27]=1[C:49](=[O:54])[NH:50][CH:51]1[CH2:53][CH2:52]1>O.C(COC)OC.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:25][C:26]1[CH:31]=[CH:30][C:29]([NH:32][C:33]([C:35]2[N:39]([CH3:40])[N:38]=[C:37]([C:41]([F:47])([F:46])[C:42]([F:45])([F:44])[F:43])[C:36]=2[CH:13]=[CH2:14])=[O:34])=[CH:28][C:27]=1[C:49](=[O:54])[NH:50][CH:51]1[CH2:53][CH2:52]1
Reactant: C=CB1OB(C=C)OB(C=C)O1
Reactant: Cn1nc(C(F)(F)C(F)(F)F)c(I)c1C(=O)Nc1ccc(Cl)c(C(=O)NC2CC2)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: [K+]
Solvent: COCCOC
Solvent: c1ccncc1
Solvent: O
Product: C=Cc1c(C(F)(F)C(F)(F)F)nn(C)c1C(=O)Nc1ccc(Cl)c(C(=O)NC2CC2)c1

Procedure:
In succession, 18.5 mg (0.016 mmol) of tetrakis(triphenylphosphine)palladium, 0.044 g (0.320 mmol) of potassium carbonate in 1 ml of water, and 0.077 g (320 μmol of 2,4,6-trivinylcyclotriboroxane pyridine complex are added to a solution of 180 mg (0.32 mmol) of N-[4-chloro-3-(cyclopropylcarbamoyl)phenyl]-1-methyl-3-(pentafluoroethyl)-4-iodo-1H-pyrazole-5-carboxamide from Example Ik-4 in 3 ml of dimethoxyethane, and the reaction mixture is heated under reflux for 20 hours. The solvent is completely distilled off at reduced pressure on a rotary evaporator and the residue is purified by means of flash chromatography on silica gel (eluent: cyclohexane/ethyl acetate; gradient: 2 hours, from 0% to 100% ethyl acetate). This gives 0.107 g of N-[4-chloro-3-(cyclopropylcarbamoyl)phenyl]-1-methyl-3-(pentafluoroethyl)-4-ethenyl-1H-pyrazole-5-carboxamide (70%) as an oil.
Reaction SMILES: [Cl:1][C:2]1[C:3]([I:15])=[CH:4][C:5]2[N:9]=[C:8]([S:10]([CH3:13])(=[O:12])=[O:11])[NH:7][C:6]=2[CH:14]=1.[H-].[Na+].Br[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[CH:22][CH:21]=1>CN(C=O)C>[C:23]1([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:22]=[CH:21][C:20]([CH2:19][N:7]2[C:6]3[CH:14]=[C:2]([Cl:1])[C:3]([I:15])=[CH:4][C:5]=3[N:9]=[C:8]2[S:10]([CH3:13])(=[O:12])=[O:11])=[CH:25][CH:24]=1
Reactant: BrCc1ccc(-c2ccccc2)cc1
Reactant: CS(=O)(=O)c1nc2cc(I)c(Cl)cc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1nc2cc(I)c(Cl)cc2n1Cc1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 6-chloro-5-iodo-2-methanesulfonyl-1H-benzoimidazole (1.53 g, 4.3 mmol) in DMF (21 ml) at 0° C. was added sodium hydride (60% dispersion in mineral oil, 190 mg, 4.7 mmol). After 15 minutes, the reaction was warmed to rt and stirred for 1 hour. The mixture was then cooled to 0° C. and 4-bromomethyl-biphenyl (1.2 g, 4.7 mmol) was slowly added. The mixture was then warmed to rt and stirred overnight. The volatiles were removed on a rotary evaporator and the residue was partitioned between EtOAc and half-saturated ammonium chloride. The aqueous layer was extracted a second time and the organic extracts were combined. The combined EtOAc extracts were washed with H2O, brine, and then dried with MgSO4. The crude oil obtained upon rotary evaporation was triturated in Et2O and filtered to yield the title compound as a beige solid.
Reaction SMILES: [F:1][C:2]1([F:33])[CH2:6][CH2:5][C@@H:4]([C@@:7]([OH:32])([C:24]2[CH:29]=[CH:28][C:27]([CH2:30][OH:31])=[CH:26][CH:25]=2)[C:8]([O:10][CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]2)=[O:9])[CH2:3]1.CN(C1C=CC=CN=1)C.[C:43](OC(=O)C)(=[O:45])[CH3:44]>C(Cl)(Cl)Cl.C(N(CC)CC)C.C(OCC)(=O)C>[F:33][C:2]1([F:1])[CH2:6][CH2:5][C@@H:4]([C@@:7]([OH:32])([C:24]2[CH:29]=[CH:28][C:27]([CH2:30][O:31][C:43](=[O:45])[CH3:44])=[CH:26][CH:25]=2)[C:8]([O:10][CH:11]2[CH2:12][CH2:13][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:15][CH2:16]2)=[O:9])[CH2:3]1
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)(C)OC(=O)N1CCC(OC(=O)[C@](O)(c2ccc(CO)cc2)[C@@H]2CCC(F)(F)C2)CC1
Agent: CN(C)c1ccccn1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Product: CC(=O)OCc1ccc([C@@](O)(C(=O)OC2CCN(C(=O)OC(C)(C)C)CC2)[C@@H]2CCC(F)(F)C2)cc1
Temperature: 25 °C

Procedure:
To a solution of 42 mg of t-butyl 4-((2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-(4-(hydroxymethyl)phenyl)-ethanoyloxy)tetrahydropyridine-1(2H)-carboxylate in 2 ml of chloroform, 0.015 ml of triethylamine, 0.01 ml of acetic anhydride and 2 mg of dimethylaminopyridine were added successively, followed by an hour's stirring at room temperature. The reaction liquid was diluted with ethyl acetate, washed successively with water and saturated brine, and dried over anhydrous sodium sulfate. Distilling the solvent off under reduced pressure, the resulting residue was purified on preparative thin layer chromatography (Kieselgel™ 60F254, Art 5744 (Merck), hexane/ethyl acetate=2/1) to provide 42 mg of the title compound as a colorless oily substance.