Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].Br[C:14]1[CH:15]=[N:16][CH:17]=[C:18]([CH:23]=1)[C:19]([O:21][CH3:22])=[O:20].C([O-])([O-])=O.[Cs+].[Cs+].O>CN(C=O)C.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>[CH3:22][O:21][C:19](=[O:20])[C:18]1[CH:23]=[C:14]([C:4]2[CH:5]=[CH:6][C:7]([O:8][CH3:9])=[C:2]([Cl:1])[CH:3]=2)[CH:15]=[N:16][CH:17]=1
Reactant: COc1ccc(B(O)O)cc1Cl
Reactant: COC(=O)c1cncc(Br)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: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cncc(-c2ccc(OC)c(Cl)c2)c1
Yield: 37.3 %

Procedure:
6.5 g of 3-chloro-4-methoxyphenylboronic acid, 5.0 g of methyl 5-bromonicotinate, 1.3 g of tetrakis(triphenylphosphine)palladium(0), and 22.6 g of Cs2CO3 were stirred in 325 ml of DMF and 65 ml of water for 3 h at 45° C. The reaction mixture was then poured into 750 ml of water and extracted three times using 300 ml of EA each. The combined organic layers were then washed twice using 150 ml of water each. The organic layer was then dried using MgSO4 and evaporated. Chromatography on silica gel using EA/HEP (gradient) yielded 2.4 g of the title compound, colorless oil.
Reaction SMILES: [CH:1]1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[O:6][C:5]=2[CH:4]=[C:3]([O:14][CH2:15][CH2:16][NH:17][CH2:18][CH:19]([C:28]2[CH:29]=[CH:30][C:31]([O:41][CH2:42][C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)=[C:32]([NH:34][S:35]([N:38]([CH3:40])[CH3:39])(=[O:37])=[O:36])[CH:33]=2)[O:20][Si](CC)(CC)CC)[CH:2]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1.C(O)(=O)C.C(OCC)(=O)C>[CH:1]1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[O:6][C:5]=2[CH:4]=[C:3]([O:14][CH2:15][CH2:16][NH:17][CH2:18][CH:19]([C:28]2[CH:29]=[CH:30][C:31]([O:41][CH2:42][C:43]3[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=3)=[C:32]([NH:34][S:35]([N:38]([CH3:40])[CH3:39])(=[O:36])=[O:37])[CH:33]=2)[OH:20])[CH:2]=1
Reactant: CC[Si](CC)(CC)OC(CNCCOc1ccc2c(c1)oc1ccccc12)c1ccc(OCc2ccccc2)c(NS(=O)(=O)N(C)C)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CN(C)S(=O)(=O)Nc1cc(C(O)CNCCOc2ccc3c(c2)oc2ccccc23)ccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 60.1 mg of Intermediate 43 in 2.9 ml of anhydrous tetrahydrofuran, 36.8 μl of acetic acid and 574 μl of 1 M solution of tetrabutyl ammonium fluoride in tetrahydrofuran were added and the mixture was agitated at room temperature for 1 hour. The reaction mixture was diluted with ethyl acetate and was washed with saturated aqueous sodium bicarbonate solution and then with saturated aqueous sodium chloride solution, followed by drying, whereupon the solvent was distilled off under a reduced pressure. The resulting residue was purified by a silica gel chromatography,whereupon the above-identified compound (50.0 mg) was obtained from eluted fractions with methanol/chloroform (7/100). Rf=0.39 (methanol/chloroform of 1/10).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:14]([C:15]([NH:17][NH2:18])=[O:16])=[N:13][N:12]3[CH:19]=[CH:20][N:21]=[C:11]3[CH:10]=2)=[C:4]([F:22])[CH:3]=1.BrC1C=C[C:27]([NH:30]C2C(C(O)=O)=NN3C=CN=C3C=2)=C(F)C=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.NN.CCN(CC)CC>CC(N(C)C)=O.CCOC(C)=O>[NH2:30][C:27]1[O:16][C:15]([C:14]2[C:9]([NH:8][C:5]3[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][C:4]=3[F:22])=[CH:10][C:11]3[N:12]([CH:19]=[CH:20][N:21]=3)[N:13]=2)=[N:17][N:18]=1
Reactant: NNC(=O)c1nn2ccnc2cc1Nc1ccc(Br)cc1F
Reactant: O=C(O)c1nn2ccnc2cc1Nc1ccc(Br)cc1F
Agent: CCN=C=NCCCN(C)C
Agent: NN
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: Nc1nnc(-c2nn3ccnc3cc2Nc2ccc(Br)cc2F)o1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Preparation of 7-(4-bromo-2-fluorophenylamino)-imidazo[1,2-b]pyridazine-6-carboxylic acid hydrazide: A mixture of 7-(4-bromo-2-fluorophenylamino)-imidazo[1,2-b]pyridazine-6-carboxylic acid (1.00 equiv), EDCI (1.50 equivalents), and HOBt (1.50 equivalents) in DMA is stirred for 30 minutes at room temperature under N2. Hydrazine (3.00 equivalents) is added followed by Et3N (2.50 equivalents). After the reaction mixture is stirred for 16 hours at room temperature, it is diluted with EtOAc and washed with saturated NH4Cl solution, saturated NaHCO3 solution and saturated NaCl. The organic layer is dried (Na2SO4) and concentrated under reduced pressure to yield the desired product. The product may be purified by flash column chromatography if further purification is necessary.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:19]=[CH:18][C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][CH:11]=2)=O)=[CH:4][CH:3]=1.[CH3:20][C:21]1([CH3:30])[CH2:26][C:25](=O)[CH2:24][C:23]([CH3:29])([CH3:28])[O:22]1>>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[C:25]2[CH2:24][C:23]([CH3:29])([CH3:28])[O:22][C:21]([CH3:30])([CH3:20])[CH2:26]2)[C:10]2[CH:19]=[CH:18][C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1
Reactant: CC1(C)CC(=O)CC(C)(C)O1
Reactant: COC(=O)c1ccc(C(=O)c2ccc(O)cc2)cc1
Product: COC(=O)c1ccc(C(=C2CC(C)(C)OC(C)(C)C2)c2ccc(O)cc2)cc1
Yield: 93.5 %

Procedure:
The general McMurry protocol, described for 14 was followed. Thus, methyl 4-[(4-hydroxyphenyl)carbonyl]benzoate (24) (0.196 g, 0.765 mmol) and 2,2,6,6-tetramethyltetrahydro-4H-pyran-4-one (52) (0.370 g, 2.37 mmol) were subjected for McMurry coupling reaction conditions. Standard work-up followed by purification by column chromatography gave 0.272 g (93%) of the title compound 101 as a white foam. 1H NMR (300 MHz, CDCl3): δ 7.98 (d, J=8.1 Hz, 2H), 7.26 (d, J=8.7 Hz, 2H), 7.05 (d, J=8.7 Hz, 2H), 6.78 (d, J=8.4 Hz, 2H), 3.92 (s, 3H), 2.27 (s, 2H), 2.21 (s, 2H), 1.28 (s, 6H), 1.25 (s, 6H). LCMS (ESI): m/z 379 (M−H)−.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]2[N:6]=[C:7]([NH:9][C:10]3[N:14]([CH3:15])[C:13]4[CH:16]=[CH:17][C:18]([C:20](O)=[O:21])=[CH:19][C:12]=4[N:11]=3)[S:8][C:4]=2[CH:3]=1.[C:25]([O:29][C:30]([N:32]1[CH2:36][CH2:35][C@@H:34]([NH2:37])[CH2:33]1)=[O:31])([CH3:28])([CH3:27])[CH3:26].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[C:25]([O:29][C:30]([N:32]1[CH2:36][CH2:35][C@@H:34]([NH:37][C:20]([C:18]2[CH:17]=[CH:16][C:13]3[N:14]([CH3:15])[C:10]([NH:9][C:7]4[S:8][C:4]5[CH:3]=[C:2]([Cl:1])[CH:24]=[CH:23][C:5]=5[N:6]=4)=[N:11][C:12]=3[CH:19]=2)=[O:21])[CH2:33]1)=[O:31])([CH3:28])([CH3:26])[CH3:27]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](N)C1
Reactant: Cn1c(Nc2nc3ccc(Cl)cc3s2)nc2cc(C(=O)O)ccc21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cn1c(Nc2nc3ccc(Cl)cc3s2)nc2cc(C(=O)N[C@@H]3CCN(C(=O)OC(C)(C)C)C3)ccc21
Yield: 53.5 %

Procedure:
(R)-3-{[2-(6-Chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carbonyl]amino}-pyrrolidine-1-carboxylic acid tert-butyl ester (55 mg) was prepared by following General Procedure F starting from 2-(6-chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carboxylic acid (70 mg), (R)-3-amino-pyrrolidine-1-carboxylic acid tert-butyl ester (45 mg), HBTU (95 mg), and DIEA (70 uL) in DMF (1 mL).
Reaction SMILES: [CH2:1]([C:3]1([CH2:15][CH3:16])[O:8][C:7](=[O:9])[NH:6][C:5]2[CH:10]=[CH:11][C:12](I)=[CH:13][C:4]1=2)[CH3:2].[Cl:17][C:18]1[CH:19]=[C:20](B(O)O)[CH:21]=[CH:22][CH:23]=1>>[Cl:17][C:18]1[CH:23]=[C:22]([C:12]2[CH:11]=[CH:10][C:5]3[NH:6][C:7](=[O:9])[O:8][C:3]([CH2:15][CH3:16])([CH2:1][CH3:2])[C:4]=3[CH:13]=2)[CH:21]=[CH:20][CH:19]=1
Reactant: CCC1(CC)OC(=O)Nc2ccc(I)cc21
Reactant: OB(O)c1cccc(Cl)c1
Product: CCC1(CC)OC(=O)Nc2ccc(-c3cccc(Cl)c3)cc21

Procedure:
6-(3-Chlorophenyl)-4,4-diethyl-1,4-dihydrobenzo[d][1,3]oxazin-2-one was prepared, from 4,4-diethyl-6-iodo-1,4-dihydrobenzo[d][1,3]oxazin-2-one and 3-chlorophenyl boronic acid according to the procedure of Example 4, as a white solid: mp 150–151° C.; 1H-NMR (CDCl3) δ 8.52 (s, 1H, D2O exchangeable), 7.50 (s, 1H), 7.31–7.44 (m, 4H), 7.16 (d, 1H, J=1.5 Hz), 6.89 (d, 1H, J=8.2 Hz), 2.03 (m, 4H), 0.94 (t, 6H, J=7.4 Hz); MS (EI) m/z 315 (M+, 53%). Anal. Calc. For C18H18ClNO2: C, 68.46, H, 5.75, N, 4.44. Found: C, 68.16, H, 5.81, N, 4.32.
Reaction SMILES: C[O:2][C:3](=O)[C:4]([N:7]1[CH:11]=[C:10]([NH:12][C:13](=[O:30])[CH:14]([NH:18][C:19](=[O:29])[CH2:20][C:21]2[CH:26]=[C:25]([F:27])[CH:24]=[C:23]([F:28])[CH:22]=2)[CH2:15][CH2:16][CH3:17])[N:9]=[CH:8]1)([CH3:6])[CH3:5].[H-].[H-].[H-].[H-].[Li+].[Al+3]>>[OH:2][CH2:3][C:4]([N:7]1[CH:11]=[C:10]([NH:12][C:13](=[O:30])[CH:14]([NH:18][C:19](=[O:29])[CH2:20][C:21]2[CH:26]=[C:25]([F:27])[CH:24]=[C:23]([F:28])[CH:22]=2)[CH2:15][CH2:16][CH3:17])[N:9]=[CH:8]1)([CH3:6])[CH3:5]
Reactant: CCCC(NC(=O)Cc1cc(F)cc(F)c1)C(=O)Nc1cn(C(C)(C)C(=O)OC)cn1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: CCCC(NC(=O)Cc1cc(F)cc(F)c1)C(=O)Nc1cn(C(C)(C)CO)cn1

Procedure:
2-(4-{2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoylamino}-imidazol-1-yl)-2-methyl-propionic acid methyl ester was reduced with LAH to afford the title compound: C13 NMR (100 MHz, CDCl3) 13.9, 18.9, 24.7, 24.8, 35.5, 42.8, 53.2, 59.5, 70.1, 102.5, 102.8, 103.0, 105.6, 112.3, 112.4, 112.5, 112.6, 131.8, 137.1, 138.6, 138.7, 161.8, 161.9, 164.3, 164.4, 169.4, 169.8; MS 409.2 m/z (M+1).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][N:11]=1)[C:5]([O:7][CH3:8])=[O:6].[Br-].[F:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][C:21]=1[C:22]([F:25])([F:24])[F:23])[CH2:17][Zn+].Cl>O1CCCC1.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>[F:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][C:21]=1[C:22]([F:23])([F:24])[F:25])[CH2:17][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][N:11]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1ccnc(Cl)c1
Reactant: Fc1cc(C[Zn+])ccc1C(F)(F)F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: [Br-]
Solvent: C1CCOC1
Product: COC(=O)c1ccnc(Cc2ccc(C(F)(F)F)c(F)c2)c1
Temperature: 60 °C
Reaction time: 1 h
Yield: 87.9 %

Procedure:
To a solution of methyl 2-chloroisonicotinate (5.15 g, 30 mmol) and Pd(PPh3)4 (0.693 g, 0.60 mmol) in tetrahydrofuran (40 mL) under nitrogen in a dried flask was added freshly prepared (3-fluoro-4-(trifluoromethyl)benzyl)zinc(II) bromide (12.55 g, 38.91 mmol) in tetrahydrofuran (50 mL). The resulting bright yellow mixture was heated to 60° C. for 2 h 20 min, then cooled to room temperature. The reaction was quenched by the addition of 10% NH4Cl. It was diluted with ethyl acetate. After phase separation, the organic layer was washed with brine, dried over MgSO4 and evaporated. The residue was suspended in 150 mL MTBE and sonicated, then the yellow insolubles were filtered off and washed with MTBE. The volume of the filtrate was increased to ca. 200 mL, then hydrogen chloride (7.50 mL, 30.00 mmol) (4M in dioxane) was added dropwise. A colorless precipitate formed. The resulting suspension was stirred for ca. 1 h, then sonicated for 2 min. The formed solid was collected and washed with MTBE and dried. The solid was dissolved in DCM and washed with 10% K2CO3. After phase separation, the aqueous layer was extracted with DCM. The combined organic layers were dried over MgSO4 and evaporated. Methyl 2-(3-fluoro-4-(trifluoromethyl)benzyl)isonicotinate (8.26 g, 88%) was isolated as a pale orange oil. 1H NMR (400 MHz, cdcl3) δ 3.94 (s, 3H), 4.24 (s, 2H), 7.06-7.18 (m, 2H), 7.52 (t, 1H), 7.69-7.75 (m, 2H), 8.68-8.75 (m, 1H). MS m/z 314 (M+H)+
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:42])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[C:18]([CH3:19])=[CH:17][C:16]([C:20]([CH2:38][CH3:39])([C:23]3[CH:28]=[CH:27][C:26](/[CH:29]=[CH:30]/[C:31]([CH2:35][CH3:36])([OH:34])[CH2:32][CH3:33])=[C:25]([CH3:37])[CH:24]=3)[CH2:21][CH3:22])=[CH:15][C:14]=2[CH3:40])=[CH:9][C:8]=1[F:41].[Cl-].[NH4+]>CO.O1CCCC1>[CH2:21]([C:20]([C:16]1[CH:17]=[C:18]([CH3:19])[C:13]([C:10]2[CH:11]=[CH:12][C:7]([CH2:6][C:5]([OH:42])=[O:4])=[C:8]([F:41])[CH:9]=2)=[C:14]([CH3:40])[CH:15]=1)([C:23]1[CH:28]=[CH:27][C:26](/[CH:29]=[CH:30]/[C:31]([CH2:32][CH3:33])([OH:34])[CH2:35][CH3:36])=[C:25]([CH3:37])[CH:24]=1)[CH2:38][CH3:39])[CH3:22]
Reactant: CCC(O)(/C=C/c1ccc(C(CC)(CC)c2cc(C)c(-c3ccc(CC(=O)OC)c(F)c3)c(C)c2)cc1C)CC
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CCC(O)(/C=C/c1ccc(C(CC)(CC)c2cc(C)c(-c3ccc(CC(=O)O)c(F)c3)c(C)c2)cc1C)CC
Temperature: 25 °C
Reaction time: 10 h
Yield: 74.7 %

Procedure:
A 1 N sodium hydroxide aqueous solution (0.180 mL, 0.180 mmol) was added to a solution of (E)-(4′-{1-ethyl-1-[4-(3-ethyl-3-hydroxy-1-pentenyl)-3-methyl-phenyl]-propyl}-3-fluoro-2′,6′-dimethyl-biphenyl-4-yl)acetic acid methyl ester (Example 118-(1); 32.5 mg, 0.060 mmol) in methanol-tetrahydrofuran (1:1, 4 mL), and the mixture was stirred at room temperature for 10 hours. The reaction mixture was then poured into a saturated aqueous ammonium chloride solution, followed by extraction with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (hexane:ethyl acetate=1:1) to give the target compound as a colorless oil (23.8 mg, 75%).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6](F)[N:5]=[CH:4][N:3]=1.[CH2:10]([OH:14])[C:11]#[C:12][CH3:13].C(N(CC)C(C)C)(C)C>CCCCCC>[CH2:10]([O:14][C:6]1[C:7]([F:8])=[C:2]([F:1])[N:3]=[CH:4][N:5]=1)[C:11]#[C:12][CH3:13]
Reactant: Fc1ncnc(F)c1F
Reactant: CC#CCO
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCCC
Product: CC#CCOc1ncnc(F)c1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 80.1 %

Procedure:
0.5 g of 4,5,6-trifluoropyrimidine, 0.31 g of 2-butyn-1-ol and 0.62 ml of N,N-diisopropylethylamine were added to 1 ml of hexane, then the mixture was stirred at room temperature for 1 hour. Then the reaction mixture was subjected to silica gel column chromatography to obtain 0.55 g of 4-(2-butynyloxy)-5,6-difluoropyrimidine.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[N:13]1[C:17]([C:18]([OH:20])=O)=[C:16]([C:21]#[N:22])[CH:15]=[N:14]1.S(Cl)([Cl:25])=O>>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:9])([F:11])[F:10])[CH:5]=[C:4]([Cl:12])[C:3]=1[N:13]1[C:17]([C:18]([Cl:25])=[O:20])=[C:16]([C:21]#[N:22])[CH:15]=[N:14]1
Reactant: N#Cc1cnn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c1C(=O)O
Reactant: O=S(Cl)Cl
Product: N#Cc1cnn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c1C(=O)Cl
Yield: 58.5 %

Procedure:
A slurry of 12.0 g (0.0343 mole) of 1-(2,6-dichloro-4-trifluoromethylphenyl)-4-cyano-1H-5-pyrazolylcarboxylic acid in 30 mL (49 g, 0.41 mole) of thionyl chloride was heated at gentle reflux for approximately 62 hours, after which it had become a dark solution. This solution was cooled, and the excess thionyl chloride was evaporated under reduced pressure, leaving a residue. Petroleum ether was added to this residue, causing a precipitate, which, upon filtration, yielded 7.4 g of 1-(2,6-dichloro-4-trifluoromethylphenyl)-4-cyano-1H-5-pyrazolylcarboxylic acid chloride as a solid, mp 100°-102° C. The NMR spectrum was consistent with the proposed structure. A second crop of tacky crystals was obtained by chilling the filtrate obtained when the product was isolated by filtration. The NMR spectrum of the second crop of crystals was consistent with the proposed structure, but showed also that it was contaminated with some starting material.
Reaction SMILES: [CH:1]1([C:7]2[C:15]3[C:10](=[CH:11][N:12]=[CH:13][CH:14]=3)[NH:9][C:8]=2[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[CH2:23][C:24]1[O:28][N:27]=[C:26]([C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][C:30]=2[C:36]([F:39])([F:38])[F:37])[CH:25]=1.[OH-].[Na+].C(N(CC)CC)C>CN(C=O)C>[CH:1]1([C:7]2[C:8]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[N:9][C:10]3[C:15]=2[CH:14]=[CH:13][N:12]([CH2:23][C:24]2[O:28][N:27]=[C:26]([C:29]4[CH:34]=[CH:33][C:32]([F:35])=[CH:31][C:30]=4[C:36]([F:39])([F:37])[F:38])[CH:25]=2)[CH:11]=3)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: Fc1ccc(-c2cc(CCl)on2)c(C(F)(F)F)c1
Reactant: c1ccc(-c2[nH]c3cnccc3c2C2CCCCC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Fc1ccc(-c2cc(Cn3ccc4c(C5CCCCC5)c(-c5ccccc5)nc-4c3)on2)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 26.2 %

Procedure:
To 3-cyclohexyl-2-phenyl-1H-pyrrolo[2,3-c]pyridine (9 mg, 33 μmol) and 5-(chloromethyl)-3-(4-fluoro-2-(trifluoromethyl)phenyl)isoxazole (11 mg, 39 μmol) in DMF (326 μL) was added 10% aqueous NaOH (16 mL, 39 μmol). After stirring 12 h at room temperature, the reaction was neutralized with triethylamine and the crude purified by reverse phase HPLC to provide 4.5 mg (27%) of the title compound: 1H NMR (CD3OD, 300 MHz) δ 9.2 (s, 1H), 8.36 (s, 2H), 7.55-7.72 (m, 8H), 6.82 (s, 1H), 6.12 (s, 2H), 3.04 (m, 1H), 1.78-2.06 (m, 7H), 1.30-1.50 (m, 3H); LCMS found 520.3 (M++H, C30H26F4N3O requires 520.5).
Reaction SMILES: [H-].[Na+].[CH2:3](Br)[C:4]#[CH:5].[ClH:7].[CH2:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11][CH2:10][N:9]1[C:18]1[N:19]=[CH:20][CH:21]=[C:22]2[C:26]([CH3:27])=[C:25]([CH3:28])[NH:24][C:23]=12>O1CCCC1>[ClH:7].[CH:3]([N:24]1[C:23]2=[C:18]([N:9]3[CH2:10][CH2:11][C:12]4[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:8]3)[N:19]=[CH:20][CH:21]=[C:22]2[C:26]([CH3:27])=[C:25]1[CH3:28])=[C:4]=[CH2:5]
Reactant: C#CCBr
Reactant: Cc1[nH]c2c(N3CCc4ccccc4C3)nccc2c1C
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=C=Cn1c(C)c(C)c2ccnc(N3CCc4ccccc4C3)c21
Temperature: 25 °C
Reaction time: 12 h
Yield: 6.6 %

Procedure:
Sodium hydride (60%; 80 mg, 1.80 mmol) and propargyl bromide (35.6 μl, 1.40 mmol) were added at 0° C. to a solution of 7-(1,2,3,4-tetrahydroisoquinolin-2-yl)-2,3-dimethyl-1H-pyrrolo[2,3-c]pyridine hydrochloride (92,3 mg, 0.33 mol) prepared in Example 468 in anhydrous tetrahydrofuran (10 ml). The reaction mixture was stirred for 12 hours at room temperature. Ice was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was dried on anhydrous magnesium sulfate and then concentrated under reduced pressure. The resulting residue was purified with silica gel column chromatography (n-hexane/ethyl acetate=1/1, v/v). The resulting product was dissolved in ethyl acetate, saturated with hydrochloric acid gas, and then filtered to give 32.5 mg of the titled compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([C:14](N(OC)C)=[O:15])[CH2:10][CH2:9]2)=[CH:4][C:3]=1[O:20][CH3:21].[CH2:22]([Mg]Br)[CH3:23].Cl>CCOCC.C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:9][CH2:10][CH:11]([C:14](=[O:15])[CH2:22][CH3:23])[CH2:12][CH2:13]2)=[CH:4][C:3]=1[O:20][CH3:21]
Reactant: CC[Mg]Br
Reactant: COc1cc(N2CCC(C(=O)N(C)OC)CC2)ccc1Cl
Agent: Cl
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCC(=O)C1CCN(c2ccc(Cl)c(OC)c2)CC1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 93 %

Procedure:
A solution of 1-(4-chloro-3-methoxyphenyl)-N-methoxy-N-methylpiperidine-4-carboxamide (450 mg, 1.439 mmol) in anhydrous Et2O (10 mL) and THF (5 mL) was placed under nitrogen and cooled to −78° C. The solution was treated with ethylmagnesium bromide (2.16 mL of a 2.0 M solution in Et2O, 4.32 mmol) within 2 minutes and the stirred at for 20 minutes before warming the reaction to 0° C. The reaction was continued at 0° C. for 30 min and then poured into 0.5 M HCl (15 mL) and stirred vigorously for 5 min. The mixture was adjusted to pH 6 and extracted with Et2O. The extract was washed with brine, dried (MgSO4) and concentrated on a rotary evaporator to give 1-(1-(4-chloro-3-methoxyphenyl)piperidin-4-yl)propan-1-one (375 mg, 1.331 mmol, 93% yield) as a white solid.
Reaction SMILES: C[O:2][C:3](=[O:29])[C@@H:4]([O:26][CH2:27][CH3:28])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]2[N:15]=[C:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[O:17][CH:18]=2)=[CH:8][C:7]=1[CH3:25].[Li+].[OH-]>>[CH2:27]([O:26][C@@H:4]([CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]2[N:15]=[C:16]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[O:17][CH:18]=2)=[CH:8][C:7]=1[CH3:25])[C:3]([OH:29])=[O:2])[CH3:28]
Reactant: CCO[C@@H](Cc1ccc(OCc2coc(-c3ccccc3)n2)cc1C)C(=O)OC
Agent: [Li+]
Agent: [OH-]
Product: CCO[C@@H](Cc1ccc(OCc2coc(-c3ccccc3)n2)cc1C)C(=O)O

Procedure:
In analogy to the procedure described in example 1 g], (S)-2-ethoxy-3-[2-methyl-4-(2-phenyl-oxazol-4-ylmethoxy)-phenyl]-propionic acid methyl ester was treated with LiOH to obtain (S)-2-ethoxy-3-[2-methyl-4-(2-phenyl-oxazol-4-ylmethoxy)-phenyl]-propionic acid as colorless solid.
Reaction SMILES: [Na].[N+]([O-])(O)=O.[NH2:6][C:7]([NH2:9])=[NH:8].N[C:11]1[N:16]([CH2:17][CH3:18])[C:15](=[O:19])[N:14]([CH2:20][CH3:21])[C:13](=[O:22])[C:12]=1[CH:23]=O>C(O)C>[NH2:8][C:7]1[N:9]=[C:11]2[N:16]([CH2:17][CH3:18])[C:15](=[O:19])[N:14]([CH2:20][CH3:21])[C:13](=[O:22])[C:12]2=[CH:23][N:6]=1
Reactant: CCn1c(N)c(C=O)c(=O)n(CC)c1=O
Reactant: N=C(N)N
Agent: [Na]
Solvent: O=[N+]([O-])O
Solvent: CCO
Product: CCn1c(=O)c2cnc(N)nc2n(CC)c1=O
Reaction time: 0.17 h
Yield: 86.9 %

Procedure:
0.92 g of sodium was dissolved in 50 ml of absolute ethanol, and 6.40 g (53 mmol) of guanidine nitrate was added thereto. The solution was stirred for 10 minutes and filtered with Celite filter aid. 0.98 g (4.6 mmol) of 6-amino-1,3-diethyl-5-formyluracil was added to the filtrate and the reaction mixture was refluxed for 24 hours. After removal of the solvent under reduced pressure, 30 ml of water was added thereto. The crystalline precipitate was filtered off and recrystallized from ethanol to give 0.94 g of 7-amino-1,3-diethyl-pyrimido[4,5-d]pyrimidine-2,4-dione (compound 17) in a 87% yield.
Reaction SMILES: C(O[C:6](=O)[N:7]([CH:9]([C:11](=[O:42])[NH:12][C:13]1[CH:18]=[C:17]([C:19]2[C:20]3[N:27]([CH3:28])[N:26]=[C:25]([CH3:29])[C:21]=3[N:22]=[CH:23][N:24]=2)[CH:16]=[C:15]([C:30]#[C:31][C:32]2[CH:33]=[C:34]3[C:38](=[CH:39][CH:40]=2)[N:37]([CH3:41])[N:36]=[CH:35]3)[N:14]=1)[CH3:10])C)(C)(C)C.C(O)(C(F)(F)F)=O.C(=O)([O-])O.[Na+]>C(Cl)Cl>[CH3:28][N:27]1[C:20]2[C:19]([C:17]3[CH:16]=[C:15]([C:30]#[C:31][C:32]4[CH:33]=[C:34]5[C:38](=[CH:39][CH:40]=4)[N:37]([CH3:41])[N:36]=[CH:35]5)[N:14]=[C:13]([NH:12][C:11](=[O:42])[CH:9]([NH:7][CH3:6])[CH3:10])[CH:18]=3)=[N:24][CH:23]=[N:22][C:21]=2[C:25]([CH3:29])=[N:26]1
Reactant: Cc1nn(C)c2c(-c3cc(C#Cc4ccc5c(cnn5C)c4)nc(NC(=O)C(C)N(C)C(=O)OC(C)(C)C)c3)ncnc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNC(C)C(=O)Nc1cc(-c2ncnc3c(C)nn(C)c23)cc(C#Cc2ccc3c(cnn3C)c2)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of tert-butyl-N-{1-[(4-{1,3-dimethyl-1H-pyrazolo[4,3-d]pyrimidin-7-yl}-6-[2-(1-methyl-1H-indazol-5-yl)ethynyl]pyridin-2-yl)carbamoyl]ethyl}-N-methylcarbamate H1 (246 mg, 0.42 mmol), DCM (5 ml) and TFA (1 ml) is stirred at RT for 1 h. 50 ml of a saturated aqueous sodium hydrogencarbonate solution is added and the mixture extracted with DCM. The combined organic layers are dried over MgSO4 and concentrated in vacuo. The product is purified by RP HPLC. Yield: 99 mg (49%). HPLC-MS: M+H=480; tR=1.16 min (METHOD—1).
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][C:8]([C:11]3[CH:12]=[CH:13][C:14]([N:17]4[CH2:21][CH:20]([CH2:22][O:23][CH3:24])[O:19][C:18]4=[O:25])=[N:15][CH:16]=3)=[CH:7][CH2:6]2)[O:4][CH2:3][CH2:2]1>CO.[Pd]>[O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([C:11]3[CH:12]=[CH:13][C:14]([N:17]4[CH2:21][CH:20]([CH2:22][O:23][CH3:24])[O:19][C:18]4=[O:25])=[N:15][CH:16]=3)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1
Reactant: COCC1CN(c2ccc(C3=CCC4(CC3)OCCO4)cn2)C(=O)O1
Agent: [Pd]
Solvent: CO
Product: COCC1CN(c2ccc(C3CCC4(CC3)OCCO4)cn2)C(=O)O1
Yield: 38.7 %

Procedure:
A solution of 0.9 g of (RS)-3-[5-(1,4-dioxa-spiro[4,5]dec-7-en-8-yl)-pyridin-2-yl]-5-methoxymethyl-oxazolidin-2-one and 0.4 g of palladium-on-charcoal (10%) in 150 ml of methanol was hydrogenated at room temperature and normal pressure. After filtering off the catalyst the filtrate was concentrated and the residue was recrystallized from diethyl ether. There was obtained 0.35 g of (RS)-3-[5-(1,4-dioxa-spiro[4,5]decan-8-yl)-pyridin-2-yl]-5-methoxymethyl-oxazolidin-2-one. M.p.: 117°-121°.