Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [SH:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[O:11]([C:13]1[CH:18]=[C:17]([O:19][CH3:20])[N:16]=[C:15](S(C)(=O)=O)[N:14]=1)[CH3:12].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[O:11]([C:13]1[CH:18]=[C:17]([O:19][CH3:20])[N:16]=[C:15]([S:1][C:2]2[N:10]=[CH:9][CH:8]=[CH:7][C:3]=2[C:4]([OH:6])=[O:5])[N:14]=1)[CH3:12]
Reactant: O=C(O)c1cccnc1S
Reactant: COc1cc(OC)nc(S(C)(=O)=O)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(OC)nc(Sc2ncccc2C(=O)O)n1
Temperature: 80 °C
Reaction time: 2 h
Yield: 69.5 %

Procedure:
4.0 g (0.026 mol) of 2-mercaptonicotinic acid, 5.7 g (0.026 mol) of 4,6-dimethoxyl-2-methylsulfonylpyrimidine and 7.2 g (0.052 mol) of potassium carbonate were weighed, and 70 ml of dimethylformamide was added thereto and the mixture was stirred at 80° C. for 2 hours. The resultant mixture was poured into water, and was washed with 100 ml of ethyl acetate. The aqueous layer was then acidified with 10% HCl aqueous solution to precipitate a crystal. The crystal thus precipitated was filtrated out, and was washed with water and was dried. The crystal was then recrystallized with methanol to obtain 5.3 g of a light-yellowish crystal of the aimed product.
Reaction SMILES: C1(C(=[N:14][C:15]2[CH:20]=[CH:19][C:18]([C@H:21]3[CH2:26][CH2:25][C@H:24]([CH:27]([CH3:33])[C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:23][CH2:22]3)=[CH:17][CH:16]=2)C2C=CC=CC=2)C=CC=CC=1>[Pd].C(O)C>[NH2:14][C:15]1[CH:16]=[CH:17][C:18]([C@H:21]2[CH2:22][CH2:23][C@H:24]([CH:27]([CH3:33])[C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:25][CH2:26]2)=[CH:19][CH:20]=1
Reactant: CCOC(=O)C(C)[C@H]1CC[C@H](c2ccc(N=C(c3ccccc3)c3ccccc3)cc2)CC1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)C(C)[C@H]1CC[C@H](c2ccc(N)cc2)CC1
Reaction time: 6 h

Procedure:
10% Palladium on carbon (500 mg) was added in one portion to a stirred solution of trans-ethyl 2-(4-{4-[(diphenylmethylene)amino]phenyl}cyclohexyl)propanoate (2.3 g, 5.23 mmol) in ethanol (50 mL) and the reaction mixture was stirred under a hydrogen atmosphere for 6 h. The reaction mixture was filtered and concentrated in vacuo to leave an oil. The oil was purified by chromatography, using 20-50% EtOAc in isohexane as eluent, to give the title compound (1.0 g, 71%) as an oil; 1H NMR δ (CDCl3) 0.9-1.1 (2H, m), 0.95 (3H, d), 1.1 (3H, t), 1.18-1.32 (2H, m), 1.38-1.5 (1H, m), 1.54-1.64 (1H, m), 1.65-1.8 (3H, m), 2.04-2.15 (1H, m), 2.18-2.3 (1H, m), 3.98 (2H, q), 6.8 (2H, d), 6.92 (2H, d); MS m/e MH+ 276.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([C:20](=[O:26])[CH:21](OCC)O)[C:12]2[O:17][CH2:16][C:15](=[O:18])[NH:14][C:13]=2[CH:19]=1)C1C=CC=CC=1.[NH2:27][C:28]([CH3:43])([CH3:42])[CH2:29][CH2:30][N:31]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH2:34][CH2:33][C:32]1=[O:41]>>[CH3:43][C:28]([NH:27][CH2:21][CH:20]([C:11]1[C:12]2[O:17][CH2:16][C:15](=[O:18])[NH:14][C:13]=2[CH:19]=[C:9]([OH:8])[CH:10]=1)[OH:26])([CH3:42])[CH2:29][CH2:30][N:31]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH2:34][CH2:33][C:32]1=[O:41]
Reactant: CCOC(O)C(=O)c1cc(OCc2ccccc2)cc2c1OCC(=O)N2
Reactant: CC(C)(N)CCN1C(=O)CCc2ccccc21
Product: CC(C)(CCN1C(=O)CCc2ccccc21)NCC(O)c1cc(O)cc2c1OCC(=O)N2

Procedure:
Prepared from 357 mg (1 mmol) of 6-benzyloxy-8-(2-ethoxy-2-hydroxyacetyl)-4H-benzo[1,4]oxazin-3-one and 232 mg (1 mmol) of 1-(3-amino-3-methylbutyl)-3,4-dihydroquinolin-2-one analogously to the method described for Example 5c). The final purification of the product is carried out by preparative HPLC (reverse phase, acetonitrile/water gradient with 0.1% trifluoroacetic acid). Yield: 94 mg (17%, trifluoroacetate); mass spectroscopy: [M]+=440.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C@@:5]1([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[O:10][C:9](=[O:11])[N:8]([C@H:12]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=3)=[CH:16][CH:15]=2)[CH3:13])[CH2:7][CH2:6]1.[NH3:32]>>[O:11]=[C:9]1[N:8]([C@H:12]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=3)=[CH:16][CH:15]=2)[CH3:13])[CH2:7][CH2:6][C@:5]([CH2:4][CH2:3][C:2]([NH2:32])=[O:1])([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[O:10]1
Reactant: N
Reactant: C[C@@H](c1ccc(-c2ccncc2)cc1)N1CC[C@](CCCO)(c2ccccc2)OC1=O
Product: C[C@@H](c1ccc(-c2ccncc2)cc1)N1CC[C@](CCC(N)=O)(c2ccccc2)OC1=O

Procedure:
The title compound was prepared from (R)-6-(3-hydroxypropyl)-6-phenyl-3-((S)-1-(4-(pyridin-4-yl)phenyl)ethyl)-1,3-oxazinan-2-one employing a procedure analogous to that described in Example 12 Step 2, followed by a procedure analogous to that described in Example 8 Step 2 using ammonia. LC-MS Method 2 tR=1.327 min, m/z=430.2; 1H NMR (CDCl3) 1.49 (m, 3H), 1.93 (m, 1H), 2.12-2.34 (m, 5H), 2.44 (m, 1H), 2.94 (m, 1H), 5.46 (m, 2H), 5.67 (m, 1H), 7.08 (m, 2H), 7.19-7.42 (m, 5H), 7.45 (m, 2H), 7.80 (m, 2H), 8.76 (m, 2H).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].C(OC([NH:15][NH:16][C:17]([CH3:21])([CH3:20])[CH2:18][OH:19])=O)(C)(C)C>ClCCl>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH:16]([C:17]([CH3:21])([CH3:20])[CH2:18][OH:19])[NH2:15].[NH:16]([C:17]([CH3:21])([CH3:20])[CH2:18][OH:19])[NH2:15]
Reactant: CC(C)(CO)NNC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(CO)NN
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Trifluoroacetic acid (4 mL) was added to a solution of N′-(2-hydroxy-1,1-dimethyl-ethyl)-hydrazinecarboxylic acid tert-butyl ester (490 mg, 2.4 mmol) in dichloromethane (4 mL). The mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated in vacuo to give the trifluoroacetic acid salt of 2-hydrazino-2-methyl-propan-1-ol (520 mg, quantitative) which was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[C:11]([F:12])=[C:10](F)[C:9]([Cl:14])=[C:8]2[C:3]=1[C:4](=[O:21])[C:5]([C:18]([OH:20])=[O:19])=[CH:6][N:7]2[CH:15]1[CH2:17][CH2:16]1.C(OC([NH:29][CH:30]1[CH2:34][CH2:33][NH:32][CH2:31]1)=O)(C)(C)C.C(N(CC)CC)C>C(#N)C>[NH2:1][C:2]1[C:11]([F:12])=[C:10]([N:32]2[CH2:33][CH2:34][CH:30]([NH2:29])[CH2:31]2)[C:9]([Cl:14])=[C:8]2[C:3]=1[C:4](=[O:21])[C:5]([C:18]([OH:20])=[O:19])=[CH:6][N:7]2[CH:15]1[CH2:17][CH2:16]1
Reactant: Nc1c(F)c(F)c(Cl)c2c1c(=O)c(C(=O)O)cn2C1CC1
Reactant: CC(C)(C)OC(=O)NC1CCNC1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Nc1c(F)c(N2CCC(N)C2)c(Cl)c2c1c(=O)c(C(=O)O)cn2C1CC1
Temperature: 100 °C
Yield: 63 %

Procedure:
To 1.57 g (5 mmol) of 5-amino-8-chloro-1-cyclo- propyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinoline carboxylic acid in 20 ml of acetonitrile was added 0.93 g (5 mmol) of 3-[(t-butoxycarbonyl)amino]pyrrolidine and 1.0 g (10 mmol) of triethylamine. The mixture was refluxed for three hours, cooled, and filtered. The solids were washed with acetonitrile and ether, then dissolved in 10 ml of acetic acid and 2 ml of 3 N hydrochloric acid. The mixture was heated at 100° C. for four hours, concentrated, and triturated with 2-propanol. The solid that formed was filtered and washed with ether to give 1.2 g of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:33][CH2:34][C:35]([C:38](OC)=[O:39])([CH3:37])[CH3:36])=[C:6]([CH:8]2[C:13]3([C:21]4[C:16](=[CH:17][C:18]([Cl:22])=[CH:19][CH:20]=4)[NH:15][C:14]3=[O:23])[CH:12]([C:24]3[CH:29]=[C:28]([Cl:30])[CH:27]=[CH:26][C:25]=3[Cl:31])[CH2:11][C:10](=[O:32])[NH:9]2)[CH:7]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:33][CH2:34][C:35]([CH3:37])([CH3:36])[CH2:38][OH:39])=[C:6]([CH:8]2[C:13]3([C:21]4[C:16](=[CH:17][C:18]([Cl:22])=[CH:19][CH:20]=4)[NH:15][C:14]3=[O:23])[CH:12]([C:24]3[CH:29]=[C:28]([Cl:30])[CH:27]=[CH:26][C:25]=3[Cl:31])[CH2:11][C:10](=[O:32])[NH:9]2)[CH:7]=1
Reactant: COC(=O)C(C)(C)COc1ccc(Br)cc1C1NC(=O)CC(c2cc(Cl)ccc2Cl)C12C(=O)Nc1cc(Cl)ccc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(CO)COc1ccc(Br)cc1C1NC(=O)CC(c2cc(Cl)ccc2Cl)C12C(=O)Nc1cc(Cl)ccc12
Yield: 18.2 %

Procedure:
In a manner similar to the method described in Example 231, racemic (2′R,3R,4′S)-2′-[5-bromo-2-(2-methoxycarbonyl-2-methyl-propoxy)-phenyl]-6-chloro-4′-(2,5-dichlorophenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (120 mg, 0.177 mmol) was reacted with LiAlH4 (34 mg, 0.885 mmol) in THF to give title compound as a white solid (21 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10].[CH:12](OC)(OC)OC.OS(O)(=O)=O>CO.CCOC(C)=O>[CH3:12][O:10][C:9](=[O:11])[CH2:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[Cl:1]
Reactant: COC(OC)OC
Reactant: O=C(O)Cc1ccccc1Cl
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(=O)Cc1ccccc1Cl
Temperature: 25 °C
Reaction time: 4 h
Yield: 97.3 %

Procedure:
To a solution of 10.0 g (59 mmol) (2-chlorophenyl)acetic acid in MeOH (10 mL) was added 9.6 mL (88 mmol) of trimethyl orthoformate and 0.32 mL (6.0 mmol) of H2SO4. The reaction was stirred at room temperature for 4 h then diluted with EtOAc and washed with H2O followed by a saturated aqueous solution of NaHCO3. The organic phase was dried over anhydrous Na2SO4 and concentrated under reduced pressure to provide 10.6 g (97%) of (2-chlorophenyl)-acetic acid methyl ester as a clear oil. The crude reaction product was not purified but used immediately.
Reaction SMILES: [Na].[Cl:2][C:3]1[CH:4]=[C:5]([NH:9][NH2:10])[CH:6]=[CH:7][CH:8]=1.[C:11](#[N:20])[CH:12]=[CH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(O)C>[NH2:20][C:11]1[CH2:12][CH:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([Cl:2])[CH:4]=2)[N:10]=1
Reactant: N#CC=Cc1ccccc1
Reactant: NNc1cccc(Cl)c1
Agent: [Na]
Solvent: CCO
Product: NC1=NN(c2cccc(Cl)c2)C(c2ccccc2)C1
Reaction time: 0.08 h

Procedure:
A 0.6 g. amount of sodium metal is dissolved in 100 ml. of absolute ethanol, then 14.76 g. of m-chlorophenylhydrazine is added followed in 5 minutes by 12.92 g. of cinnamonitrile. The reaction mixture is refluxed for 6 hours, then cooled in an ice-bath. The precipitate formed is collected by filtration, then is dissolved in dichloromethane. This solution is passed through a short column of a hydrous magnesium silicate. The effluent is heated to reflux on a steam bath and hexane is added until a precipitate occurs. The product is collected, then is recrystallized from dichloromethane-hexane to give 7.55 g. of the product of the Example as salmon colored needles, m.p. 164°-165° C.
Reaction SMILES: CO[C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7](I)=[CH:6][CH:5]=1.[N:12]1[CH:17]=[CH:16][CH:15]=[C:14](B(O)O)[CH:13]=1.C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>C(OCC)(=O)C.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CO>[N:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:7]2[CH:6]=[CH:5][C:4]([CH:3]=[O:11])=[CH:9][CH:8]=2)[CH:13]=1
Reactant: OB(O)c1cccnc1
Reactant: COC(=O)c1ccc(I)cc1
Agent: Cl[Pd]Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CO
Solvent: CCOC(C)=O
Product: O=Cc1ccc(-c2cccnc2)cc1
Temperature: 80 °C
Yield: 98.2 %

Procedure:
To a mixture of 1.18 g 4-iodobenzoic acid methyl ester, 830 mg pyridine-3-boronic acid, and 158 mg bis(triphenylphosphine) palladium(II) chloride was added solvent (18 mL toluene and 5 mL methanol) followed by 4.5 mL of 2M sodium carbonate and the mixture heated to 80° C. on an oil bath. After 16 hours the mixture was cooled to room temperature diluted with ethyl acetate and filtered through diatomaceous earth. The organic portion was washed sequentially with 1.25N sodium hydroxide and brine, dried over magnesium sulfate and concentrated in vacuo. Purification by flash chromatography on silica gel (hexane:ethyl acetate, 80:20; then 70:30; then 60:40) gave the title compound (810 mg).
Reaction SMILES: [CH2:1]([N:5]1[C:9]2=[C:10](Cl)[N:11]=[N:12][CH:13]=[C:8]2[C:7]([CH3:15])=[C:6]1[CH3:16])[CH:2]=[CH:3][CH3:4].[CH2:17]([OH:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[CH2:17]([O:24][C:10]1[N:11]=[N:12][CH:13]=[C:8]2[C:7]([CH3:15])=[C:6]([CH3:16])[N:5]([CH2:1][CH:2]=[CH:3][CH3:4])[C:9]=12)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CC=CCn1c(C)c(C)c2cnnc(Cl)c21
Reactant: OCc1ccccc1
Product: CC=CCn1c(C)c(C)c2cnnc(OCc3ccccc3)c21
Yield: 78.6 %

Procedure:
The title compound (cis/trans=21/79) was prepared as pale brown crystals in 78.6 % yield in a similar procedure to that described in Example 1 by using 1-(2-butenyl)-7-chloro-2,3-dimethylpyrrolo[2,3-d]pyridazine [cis/trans (18/82)] and benzyl alcohol.
Reaction SMILES: CS(NCCCCCCC(OCC)=O)(=O)=O.C([O:20][CH:21]([CH2:43][CH2:44][CH2:45][CH2:46][CH3:47])[CH2:22][CH2:23][CH2:24][N:25]([CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][C:38]([O:40]CC)=[O:39])[S:26]([CH:29](C)C)(=[O:28])=[O:27])(=O)C>>[OH:20][C@H:21]([CH2:43][CH2:44][CH2:45][CH2:46][CH3:47])[C:22]#[C:23][CH2:24][N:25]([CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][C:38]([OH:40])=[O:39])[S:26]([CH3:29])(=[O:27])=[O:28]
Reactant: CCCCCC(CCCN(CCCCCCC(=O)OCC)S(=O)(=O)C(C)C)OC(C)=O
Agent: CCOC(=O)CCCCCCNS(C)(=O)=O
Product: CCCCC[C@@H](O)C#CCN(CCCCCCC(=O)O)S(C)(=O)=O

Procedure:
The synthesis of this compound is carried out as described in Example 1 except that, in Step A, the ethyl 7-(methanesulfonamido)heptanoate is replaced by an equimolar amount of ethyl 7-[(1-methylethane)sulfonamido]heptanoate (Example R). The product of Step A is thus ethyl 7-[N-(4-acetoxynonyl)-1-methylethanesulfonamido]heptanoate. The subsequent step yields 7-[N-(4-hydroxynonyl)-1-methylethanesulfonamido]heptanoic acid (B).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:4][C@H:3]1[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15].CCN(C(C)C)C(C)C.[C:30](C1CC(=O)NC1=O)([O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:31]>CN(C)C=O>[CH2:33]([O:32][C:30]([NH:1][C@H:2]1[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:4][C@H:3]1[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[O:31])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: CC(C)(C)OC(=O)[C@@H]1CN(C(=O)OC(C)(C)C)C[C@@H]1N
Reactant: O=C1CC(C(=O)OCc2ccccc2)C(=O)N1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)[C@@H]1CN(C(=O)OC(C)(C)C)C[C@@H]1NC(=O)OCc1ccccc1
Reaction time: 3 h
Yield: 105.1 %

Procedure:
To a solution of (3R,4R)-di-tert-butyl 4-aminopyrrolidine-1,3-dicarboxylate (Org. Biomol. Chem. 2004, 2, 2763-2776) (765 mg, 2.67 mmol) and Hunig's base (465 uL, 2.67 mmol) in N,N-dimethylformamide (5 mL) was added Cbz succinimide (665 mg, 2.67 mmol). The mixture was stirred for 3 hours and partitioned between EtOAc and water. The organic layer was washed repeatedly with brine, dried (Na2SO4) and concentrated to a clear oil (1.18 g, quantitative yield). MS (DCI/NH4) m/z=438 (M+NH4)+.
Reaction SMILES: I[C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:19]=[CH:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[N:7][N:8]2[CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])=[CH:4][CH:3]=1.[C:27]1(B(O)O)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.C(OCC)(=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>[C:27]1([C:2]2[CH:10]=[C:9]3[C:5]([C:6]([CH:19]=[CH:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[N:7][N:8]3[CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])=[CH:4][CH:3]=2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: OB(O)c1ccccc1
Reactant: C[Si](C)(C)CCOCn1nc(C=Cc2ccccc2)c2ccc(I)cc21
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: CCOC(C)=O
Solvent: C1COCCO1
Product: C[Si](C)(C)CCOCn1nc(C=Cc2ccccc2)c2ccc(-c3ccccc3)cc21
Temperature: 90 °C
Yield: 80.9 %

Procedure:
A solution of 476 mg (1.0 mmol) of 6-iodo-3-styryl-1-[2-(trimethyl-silanyl)ethoxymethyl]-1H-indazole, from Example 14 step (i), in dioxane (3 ml, degassed by sonication and bubbling argon), Pd(PPh3)4 (23 mg, 0.05 mmol), phenylboronic acid (302 mg, 2.5 mmol), and Na2CO3 (1.25 ml of a 2M aqueous solution, degassed as above) was heated at 90° C. for 2 h. The solution was then diluted with ethyl acetate (100 ml) and washed with brine (2×20 ml). The organic layer was dried over MgSO4, and concentrated under reduced pressure. Purification by silica gel chromatography gave of 6-phenyl-3-styryl-1-[2-(trimethyl-silanyl)ethoxymethyl]-1H-indazole as a brown oil (345 mg, 81%). 1H NMR (300 MHz, CDCl3) δ 8.09 (dd, 1H, J=8.5, 0.7 Hz), 7.75 (s, 1H), 7.70 (d, 1H, J=7.0 Hz), 7.64-7.58 (m, 2H), 7.56-7.51 (m, 2H), 7.50-7.45 (m, 2H), 7.45-7.36 (m, 4H), 7.34-7.27 (m, 1H), 5.80 (s, 2H), 3.73 (t, 2H, J=8.3 Hz), 1.12 (t, 2H, J=8.3 Hz).
Reaction SMILES: C(OP([CH:9]([F:11])[F:10])(=O)OCC)C.C([N-]C(C)C)(C)C.[Li+].[CH3:20][O:21][C:22]1[CH:40]=[CH:39][C:38]2[C@@H:37]3[C@H:27]([C@H:28]4[C@@:32]([CH2:35][CH2:36]3)([CH2:33][CH3:34])[C:31](=O)[CH2:30][CH2:29]4)[CH2:26][CH2:25][C:24]=2[CH:23]=1>O1CCCC1.C(OCC)(=O)C>[F:11][C:9]([F:10])=[C:31]1[CH2:30][CH2:29][C@H:28]2[C@H:27]3[C@H:37]([CH2:36][CH2:35][C@:32]12[CH2:33][CH3:34])[C:38]1[CH:39]=[CH:40][C:22]([O:21][CH3:20])=[CH:23][C:24]=1[CH2:25][CH2:26]3
Reactant: CCOP(=O)(OCC)C(F)F
Reactant: CC[C@]12CC[C@@H]3c4ccc(OC)cc4CC[C@H]3[C@@H]1CCC2=O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC[C@]12CC[C@@H]3c4ccc(OC)cc4CC[C@H]3[C@@H]1CCC2=C(F)F
Reaction time: 1 h
Yield: 80.8 %

Procedure:
A solution of 9.4 g of diethyl-(difluoromethyl)-phosphonate in 150 ml of tetrahydrofuran is slowly mixed with 25 ml of 2 M lithium diisopropylamide solution at a bath temperature of -50° C., and it is stirred for 1 hour. Then, a solution of 6 g of 3-methoxy-18-methyl-estra-1,3,5(10)-trien-17-one in 173 ml of tetrahydrofuran is slowly added, stirred for 15 minutes, slowly heated at a bath temperature of from -50° C. to 100° C. and refluxed for 6 hours. For working-up, it is diluted with ethyl acetate, washed with water as well as with saturated sodium chloride solution, dried on sodium sulfate, concentrated by evaporation in a vacuum and chromatographed on silica gel with hexane/ethyl acetate. 5.4 g of 17-difluoromethylene-3-methoxy-18-methyl-estra -1,3,5(10)-triene is obtained as colorless crystals with a melting point of 145-146° C., [α]D22 =+40.2° (c=0.515% in pyridine).
Reaction SMILES: ClC(OC([N:7]1[CH2:12][CH2:11][C:10]([CH2:19][NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:9][CH2:8]1)=O)C>CO>[C:24]([O:23][C:21](=[O:22])[NH:20][CH2:19][C:10]1([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:11][CH2:12][NH:7][CH2:8][CH2:9]1)([CH3:27])([CH3:25])[CH3:26]
Reactant: CC(Cl)OC(=O)N1CCC(CNC(=O)OC(C)(C)C)(c2ccccc2)CC1
Solvent: CO
Product: CC(C)(C)OC(=O)NCC1(c2ccccc2)CCNCC1
Temperature: 60 °C
Reaction time: 5 h

Procedure:
A mixture of 4-(tert-butoxycarbonylaminomethyl)-4-phenylpiperidine-1-carboxylic acid 1-chloroethyl ester in MeOH is stirred at 60° C. for 5 h, then the reaction mixture is concentrated in vacuo to give (4-phenylpiperidin-4-ylmethyl) carbamic acid tert-butyl ester, which is directly used for the next reaction without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][C:9]2=[O:14])=[CH:6][C:5]([C:15]#[N:16])=[CH:4][C:3]=1[NH:17][C:18]1[N:23]=[C:22]([N:24]([CH:34]2[CH2:36][CH2:35]2)CC2C=CC(OC)=CC=2)[C:21]2=[N:37][CH:38]=[C:39]([C:40]#[N:41])[N:20]2[N:19]=1.[CH:42](=O)[CH3:43].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(C(F)(F)F)=O>C(Cl)Cl.ClCCCl.C1(OC)C=CC=CC=1>[Cl:1][C:2]1[C:7]([N:8]2[CH2:13][CH2:12][N:11]([CH2:42][CH3:43])[CH2:10][C:9]2=[O:14])=[CH:6][C:5]([C:15]#[N:16])=[CH:4][C:3]=1[NH:17][C:18]1[N:23]=[C:22]([NH:24][CH:34]2[CH2:36][CH2:35]2)[C:21]2=[N:37][CH:38]=[C:39]([C:40]#[N:41])[N:20]2[N:19]=1
Reactant: CC=O
Reactant: COc1ccc(CN(c2nc(Nc3cc(C#N)cc(N4CCNCC4=O)c3Cl)nn3c(C#N)cnc23)C2CC2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Solvent: COc1ccccc1
Product: CCN1CCN(c2cc(C#N)cc(Nc3nc(NC4CC4)c4ncc(C#N)n4n3)c2Cl)C(=O)C1
Temperature: 60 °C
Reaction time: 0.25 h
Yield: 69.9 %

Procedure:
To a solution of 2-((2-chloro-5-cyano-3-(2-oxopiperazin-1-yl)phenyl)amino)-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (17 mg, 0.030 mmol) in DCM (2 mL) was added acetaldehyde (13.16 mg, 0.299 mmol) and acetic acid (3.42 μl, 0.060 mmol). After stirring for 15 min, sodium triacetoxyborohydride (12.66 mg, 0.060 mmol) was added. After stirring at room temperature for 2 h, LC-MS indicated completion. After concentration, purification via flash chromatography (0-10% MeOH in DCM, 12 g) gave 20 mg of the PMB protected product. This was dissolved in 1 mL of DCE and then 1 drop of anisole was added followed by 0.5 mL of TFA. The solution was heated at 60° C. for 2.5 h. LC-MS indicated completion, and then it was cooled and concentrated. The crude was dissolved in methanol and neutralized with 7N ammonia in methanol. After stirring for 10 min it was concentrated, purification via preparative HPLC gave the title compound as a yellow solid (10 mg).
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][CH3:9])=[N:6][C:5](Br)=[CH:4][N:3]=1.[Na].[CH3:12][OH:13]>O>[NH2:1][C:2]1[C:7]([O:8][CH3:9])=[N:6][C:5]([O:13][CH3:12])=[CH:4][N:3]=1
Reactant: CO
Reactant: COc1nc(Br)cnc1N
Agent: [Na]
Solvent: O
Product: COc1cnc(N)c(OC)n1

Procedure:
A mixture of 0.1 mole of 2-amino-3-methoxy-5-bromopyrazine and 0.1 mole of sodium in 160 ml. of anhydrous methanol is refluxed 5-10 hours and poured into water. The product is extracted with ether or chloroform and recrystallized from a suitable solvent such as ethanol to give 2-amino-3,5-dimethoxypyrazine.
Reaction SMILES: [N+]([O-])([O-])=O.[Ce+4].[NH4+].[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[I:23]I.[CH3:25][N:26]1[C:30]([C:31]([OH:33])=[O:32])=[CH:29][C:28]([C:34]([F:40])([F:39])[C:35]([F:38])([F:37])[F:36])=[N:27]1.ClCCl>C(#N)C>[CH3:25][N:26]1[C:30]([C:31]([OH:33])=[O:32])=[C:29]([I:23])[C:28]([C:34]([F:39])([F:40])[C:35]([F:37])([F:36])[F:38])=[N:27]1
Reactant: Cn1nc(C(F)(F)C(F)(F)F)cc1C(=O)O
Reactant: II
Agent: O=[N+]([O-])[O-]
Agent: [Ce+4]
Agent: [NH4+]
Solvent: CC#N
Solvent: ClCCl
Product: Cn1nc(C(F)(F)C(F)(F)F)c(I)c1C(=O)O

Procedure:
1.34 g (2.46 mmol) of ammonium cerium(IV) nitrate and then 0.75 g (2.95 mmol) of iodine are added to a solution of 1.20 g (4.91 mmol) of 1-methyl-3-pentafluoroethyl-1H-pyrazole-5-carboxylic acid in 4.3 ml of acetonitrile and the reaction mixture is heated under reflux for 18 hours. After adding 20 ml of dichloromethane, washing is carried out firstly with water, with sodium disulphite solution and finally with saturated sodium chloride solution. The organic phase is dried over sodium sulphate and the solvent is distilled off at reduced pressure on a rotary evaporator. This gives 1.28 g of 4-iodo-1-methyl-3-pentafluoroethyl-1H-pyrazole-5-carboxylic acid (47%) as an oil.