Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [SH:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]2[N:12]=[CH:13][C:14]([C:15]([NH2:17])=[O:16])=[C:4]2[N:3]=1.CC(O[CH2:22][C:23]1[CH2:32][S:31][C@@H:26]2[C@H:27]([NH2:30])[C:28](=[O:29])[N:25]2[C:24]=1[C:33]([OH:35])=[O:34])=O.B(F)(F)F.O>C(#N)C>[NH2:30][C@@H:27]1[C:28](=[O:29])[N:25]2[C@@H:26]1[S:31][CH2:32][C:23]([CH2:22][S:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:9])[F:10])[N:5]3[N:12]=[CH:13][C:14]([C:15](=[O:16])[NH2:17])=[C:4]3[N:3]=1)=[C:24]2[C:33]([OH:35])=[O:34]
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Reactant: NC(=O)c1cnn2c(C(F)(F)F)cc(S)nc12
Agent: FB(F)F
Solvent: CC#N
Solvent: O
Product: NC(=O)c1cnn2c(C(F)(F)F)cc(SCC3=C(C(=O)O)N4C(=O)[C@@H](N)[C@H]4SC3)nc12
Reaction time: 5 h

Procedure:
A mixture of 1.60 g of 5-mercapto-7-(trifluoromethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide and 1.66 g of (7R)-7-aminocephalosporanic acid in 120 ml of acetonitrile was treated while stirring with 20 ml of a 20 percent solution of boron trifluoride in acetonitrile and stirred at 20° for a further 5 hours. 100 ml of water were added and the mixture was concentrated in a vacuum to a volume of about 80 ml. The pH was adjusted to 2.8 with 25 percent aqueous ammonia. After stirring for 1 hour, the precipitate obtained was filtered, washed in succession with water acetone and ether and dried. There was obtained (6R,7R)-7-amino-3-[[(3-carbamoyl-7-(trifluoromethyl)pyrazolo[1,5-a]-pyrimidin-5-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo-[4.2.0]oct-2-ene-2-carboxylic acid.
Reaction SMILES: F[C:2]1[C:9]([F:10])=[CH:8][CH:7]=[C:6]([F:11])[C:3]=1[C:4]#[N:5].[OH-].[NH4+:13]>C(#N)C>[NH2:13][C:2]1[C:9]([F:10])=[CH:8][CH:7]=[C:6]([F:11])[C:3]=1[C:4]#[N:5]
Reactant: [NH4+]
Reactant: N#Cc1c(F)ccc(F)c1F
Agent: [OH-]
Solvent: CC#N
Product: N#Cc1c(F)ccc(F)c1N
Yield: 93 %

Procedure:
2,3,6-Trifluorobenzonitrile (15 g) in ammonium hydroxide solution (28% in water; 80 mL) and acetonitrile (40 mL) was stirred at 70° C. in a pressure vessel for 16 h and the reaction was complete based on GC-MS. Acetonitrile was removed under reduced pressure, and water was added. The white solid precipitate was suction filtered, washed with water and dried under house vacuum over a weekend at room temperature to give 13.7 g (93%) of the crude product; M.P. 90-92° C. GC/MS: m/z 154. 1H NMR (CDCl3): δ 7.07-7.16 (m, 1H), 6.36-6.43 (m, 1H), 4.65 (br s, 2H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=O.[OH:10][CH:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1.[BH4-].[Na+]>CO>[OH:10][CH:11]1[CH2:16][CH2:15][N:14]([CH2:5][C:4]2[CH:3]=[C:2]([OH:1])[CH:9]=[CH:8][CH:7]=2)[CH2:13][CH2:12]1
Reactant: O=Cc1cccc(O)c1
Reactant: OC1CCNCC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Oc1cccc(CN2CCC(O)CC2)c1
Reaction time: 1.5 h
Yield: 66.8 %

Procedure:
To a solution of 0.2 mol of 3-hydroxybenzaldehyde in 100 ml of methanol, is added a solution of 0.4 mol of 4-hydroxypiperidine in 80 ml of methanol at about 20° C. To the mixture thus obtained 0.2 mol of sodium borohydride is added portionwise and under stirring, at the temperature of 20°-25° C. within about 90 minutes, then the reaction mixture is stirred 4 hours at room temperature and the solvent is evaporated under reduced pressure to dryness. The residue is taken up with ice and acidified with hydrochloric acid. The acid solution is washed twice with 40 ml of ethyl acetate and concentrated ammonium hydroxide is added thereto up to clearly basic reaction. The product which precipitates is filtered and crystallized from 400 ml of water. The product thus obtained melts at 156°-158° C. Yield: 66.8%.
Reaction SMILES: [S:1]1[C:5]2[C:6](=[O:10])[NH:7][CH2:8][CH2:9][C:4]=2[CH:3]=[CH:2]1.Br[C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[Cu](I)I.O1CCOCC1>[N:14]1[CH:15]=[CH:16][CH:17]=[C:12]([N:7]2[CH2:8][CH2:9][C:4]3[CH:3]=[CH:2][S:1][C:5]=3[C:6]2=[O:10])[CH:13]=1
Reactant: O=C1NCCc2ccsc21
Reactant: Brc1cccnc1
Agent: I[Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: O=C1c2sccc2CCN1c1cccnc1
Yield: 39.3 %

Procedure:
Using analogous reaction conditions as described in example 1, 5,6-dihydro-4H-thieno[2,3-c]pyridin-7-one (I-5d: 110 mg, 0.718 mmol) was reacted with 3-bromo-pyridine (136 mg, 0.861 mmol), 1,4-dioxane (5 mL), copper iodide (13.5 mg, 0.071 mmol), trans-N,N′-dimethyl-cyclohexyl-1,2-diamine (0.033 mL, 0.215 mmol) and potassium phosphate (456 mg, 2.15 mmol) to afford the crude product. Purification by column chromatography on silica gel (1% methanol in DCM) afforded 65 mg of the product (39.3% yield).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]([CH3:11])[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][NH:6]2.C1(C)C=CC(S(O)(=O)=O)=CC=1.[O:23]1[CH:28]=[CH:27][CH2:26][CH2:25][CH2:24]1.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[Cl:1][C:2]1[N:10]=[C:9]([CH3:11])[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH:24]1[CH2:25][CH2:26][CH2:27][CH2:28][O:23]1
Reactant: Cc1nc(Cl)c2nc[nH]c2n1
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1nc(Cl)c2ncn(C3CCCCO3)c2n1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 97 %

Procedure:
6-Chloro-2-methyl-9H-purine (9.45 g, 56 mmol, the material from Step 2) was suspended in DCM (100 mL) and p-toluenesulfonic acid (Acros Organics, Geel, Belgium, 12% in acetic acid, 0.90 mL, 5.6 mmol) and 2,3-dihydropyran (6.6 mL, 73 mmol) were added. The reaction flask was fitted with a reflux condenser and placed in a preheated oil bath (50° C.) and stirred under nitrogen for 30 minutes. Then, the reaction was cooled to room temperature and stirred overnight. After stirring overnight, the reaction was diluted with DCM and treated with saturated sodium bicarbonate (75 mL). The layers were separated, and the aqueous phase was extracted with DCM. The organic extracts were combined, dried over sodium sulfate, filtered, concentrated, and dried under high vacuum at 45° C. (in a water bath) and then at room temperature and then at 60° C. and finally at room temperature again to afford 6-chloro-2-methyl-9-(tetrahydro-2H-pyran-2-yl)-9H-purine (13.73 g, 97% over 3 steps). MS (ESI pos. ion) m/z: 253. Calculated exact mass for C11H13ClN4O: 252. 1H NMR (CDCl3, 400 MHz) δ 8.26 (s, 1H), 5.78 (d, J=10.56 Hz, 1H), 4.19 (d, J=11.93 Hz, 1H), 3.84-3.76 (m, 1H), 2.80 (s, 3H), 2.20-1.96 (m, 3H), 1.89-1.64 (m, 3H).
Reaction SMILES: [SH:1][CH2:2][C:3]1([C:12]([NH:14][CH2:15][C:16]([OH:18])=[O:17])=[O:13])[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4]1.S(=O)(=O)(O)O.[C:24](OC(=O)C)(=[O:26])[CH3:25].C(OCC)C>C(O)(=O)C>[C:24]([S:1][CH2:2][C:3]1([C:12]([NH:14][CH2:15][C:16]([OH:18])=[O:17])=[O:13])[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4]1)(=[O:26])[CH3:25]
Reactant: CC(=O)OC(C)=O
Reactant: O=C(O)CNC(=O)C1(CS)Cc2ccccc2C1
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: CCOCC
Product: CC(=O)SCC1(C(=O)NCC(=O)O)Cc2ccccc2C1

Procedure:
Mix N-[[2-(mercaptomethyl)-2,3-dihydro-1H-indene-2-yl]carbonyl]-glycine (17.8 g, 67.2 mmol) and sulfuric acid (0.3 mL of a 10% solution in acetic acid). Add acetic anhydride (6.34 mL, 67.2 mmol) over 10 minutes. Allow to cool, pour into ethyl ether and wash with water three times. Separate the organic phase, dry (MgSO4) and evaporate the solvent in vacuo to give the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[CH2:10](I)[CH2:11][CH:12]([CH3:14])[CH3:13].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:13][CH:12]([CH3:14])[CH2:11][CH2:10][O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: CC(C)CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)CCOc1ccc(C=O)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 94.5 %

Procedure:
A mixture of 1.00 g of p-hydroxybenzaldehyde, 1.46 g of isoamyl iodide and 1.80 g of potassium carbonate in 15 ml of N,N-dimethylformamide was stirred at room temperature for 2 days. Water was added to the reaction mixture, and the product was extracted with ethyl acetate. The ethyl acetate layer was washed in sequence with 1N sodium hydroxide, water and saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 1.34 g of p-(3-methylbutoxy)benzaldehyde.
Reaction SMILES: [CH3:1][N:2]1[CH2:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[C:5](=[O:13])[C:4]2[CH:14]=[CH:15][C:16]([CH2:18][C:19]([OH:21])=[O:20])=[CH:17][C:3]1=2.[CH3:22]O.S(=O)(=O)(O)O>>[CH3:1][N:2]1[CH2:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[C:5](=[O:13])[C:4]2[CH:14]=[CH:15][C:16]([CH2:18][C:19]([O:21][CH3:22])=[O:20])=[CH:17][C:3]1=2
Reactant: CO
Reactant: CN1Cc2ccccc2C(=O)c2ccc(CC(=O)O)cc21
Agent: O=S(=O)(O)O
Product: COC(=O)Cc1ccc2c(c1)N(C)Cc1ccccc1C2=O

Procedure:
5,6-Dihydro-5-methyl-11-oxodibenz[b,e]azepine-3-acetic acid was esterified with methanol-sulfuric acid in a customary manner to afford methyl 5,6-dihydro-5-methyl-11-oxodibenz[b,e]azepine-3-acetate having a melting point of 88.4°-90.5° C.
Reaction SMILES: Br[C:2]1[C:3]([C:8]([O:10][CH3:11])=[O:9])=[N:4][CH:5]=[CH:6][N:7]=1.[CH3:12][O-:13].[Na+]>CO>[CH3:12][O:13][C:2]1[C:3]([C:8]([O:10][CH3:11])=[O:9])=[N:4][CH:5]=[CH:6][N:7]=1
Reactant: COC(=O)c1nccnc1Br
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1nccnc1OC
Reaction time: 0.5 h

Procedure:
To a solution of 2 g of methyl 3-bromopyrazine-2-carboxylate (prepared as described by J. H. Jones, W. H. Holtz, E. J. C. Cragoe, J. Med. Chem., 1969, 12, 285-287) in 50 mL of methanol was added 4 mL of 30% NaOMe in methanol. After stirring 30 min the reaction was quenched with 6 mL of acetic acid and concentrated under reduced pressure. The residue was partitioned between 50 mL ethyl acetate and 50 mL saturated NaHCO3, the extract dried over MgSO4. Concentration under reduced pressure gave a white crystalline solid: MS (m+1)=169.1; 1H NMR (400 MHz, CDCl3) 8.3 (m, 2H), 4.1 (s, 3H), 4.0 (s, 3H).
Reaction SMILES: [C:1]12[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=1)[NH:6]C(=O)[O:4][C:2]2=O.[N:13]1([CH2:18][CH2:19][CH2:20][CH2:21][NH2:22])[CH:17]=[CH:16][N:15]=[CH:14]1>C(O)C>[NH2:6][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:1]=1[C:2]([NH:22][CH2:21][CH2:20][CH2:19][CH2:18][N:13]1[CH:17]=[CH:16][N:15]=[CH:14]1)=[O:4]
Reactant: NCCCCn1ccnc1
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Solvent: CCO
Product: Nc1ccccc1C(=O)NCCCCn1ccnc1
Temperature: 25 °C
Reaction time: 22 h

Procedure:
A mixture of 1.63 g of isatoic anhydride, 1.39 g of 1H-imidazole-1-butanamine and 25 ml of ethanol was stirred at room temperature for 22 hours. The reaction mixture was concentrated and the residue was dissolved in ethyl acetate and cooled. The desired product was isolated by filtration, mp 91°-93° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][C:3]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13].[F:17][C:18]([F:35])([F:34])[C:19]1[CH:24]=[CH:23][C:22]([C:25]2[C:26]([C:31](Cl)=[O:32])=[CH:27][CH:28]=[CH:29][CH:30]=2)=[CH:21][CH:20]=1.C(=O)(O)[O-].[Na+]>>[CH2:15]([O:14][C:12]([C:3]1[CH:4]=[C:5]([CH2:8][C:9]([OH:11])=[O:10])[CH:6]=[CH:7][C:2]=1[NH:1][C:31]([C:26]1[C:25]([C:22]2[CH:23]=[CH:24][C:19]([C:18]([F:17])([F:34])[F:35])=[CH:20][CH:21]=2)=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:32])=[O:13])[CH3:16]
Reactant: O=C(Cl)c1ccccc1-c1ccc(C(F)(F)F)cc1
Reactant: CCOC(=O)c1cc(CC(=O)O)ccc1N
Agent: O=C([O-])O
Agent: [Na+]
Product: CCOC(=O)c1cc(CC(=O)O)ccc1NC(=O)c1ccccc1-c1ccc(C(F)(F)F)cc1
Yield: 58.6 %

Procedure:
The 4-amino-3-ethoxycarbonylphenylacetic acid (1.51 g) obtained in Example 9-4d) and 4′-trifluoromethylbiphenyl-2-carboxylic acid chloride (1.99 g) were subjected to reactions similar to those in Example 7a) with the proviso that sodium bicarbonate was used as a base, thereby the title compound (1.87 g) was given as a pale yellow amorphous powder.
Reaction SMILES: C[O:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH:5]=[C:6]([CH3:19])[N:7]2[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.B(Br)(Br)Br.C(Cl)Cl>C(Cl)Cl>[OH:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH:5]=[C:6]([CH3:19])[N:7]2[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: COc1cccc2c1cc(C)n2Cc1ccccc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cc1cc2c(O)cccc2n1Cc1ccccc1
Yield: 48.6 %

Procedure:
A solution of 1.25 g (5 mmol) of 4-methoxy-2-methyl-1-(phenylmethyl)-1H-indole and 20 mL of 1M BBr3 /CH2Cl2 in 50 mL of methylene chloride was stirred at room temperature for 5 hours and concentrated at reduced pressure. The residue was dissolved in ethyl acetate, washed with brine and dried (MgSO4). After concentrating at reduced pressure, the residue was chromatographed on silica gel eluting with 20% EtOAc/hexane to give 577 mg (49% yield) of 4-hydroxy-2-methyl-1-(phenylmethyl)-1H-indole, 125-127° C.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:11]=[CH:10][C:9]([C:12]([N:14]3[C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=4[CH2:18][N:17]4[CH:25]=[CH:26][CH:27]=[C:16]4[CH2:15]3)=[O:13])=[CH:8][CH:7]=2)=[N:2]1.[C:28](Cl)(=[O:32])[CH2:29][CH2:30][CH3:31]>N1C=CC=CC=1>[CH:27]1[CH:26]=[CH:25][N:17]2[CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[N:14]([C:12]([C:9]3[CH:10]=[CH:11][C:6]([C:3]4[CH:4]=[CH:5][N:1]([C:28](=[O:32])[CH2:29][CH2:30][CH3:31])[N:2]=4)=[CH:7][CH:8]=3)=[O:13])[CH2:15][C:16]=12
Reactant: CCCC(=O)Cl
Reactant: O=C(c1ccc(-c2cc[nH]n2)cc1)N1Cc2cccn2Cc2ccccc21
Solvent: c1ccncc1
Product: CCCC(=O)n1ccc(-c2ccc(C(=O)N3Cc4cccn4Cc4ccccc43)cc2)n1
Yield: 63.5 %

Procedure:
In the manner of Example 32, employing [4-(1H-pyrazol-3-yl)-phenyl]-(5H,11H-pyrrolo[2,1-c][1,4]benzodiazepin-10-yl)-methanone (0.71 g) in dry pyridine (10 ml) and butyryl chloride (0.32 g), the title compound (0.54 g) was obtained as a solid, m.p. 105-110° C.; MS, m/z: 424 (M)+.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][S:5]([O:8][CH2:9][C:10]([CH3:25])([CH3:24])[CH:11]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)[CH:12]=C)(=[O:7])=[O:6].O=O.[O:28]=[O+][O-].CSC>ClCCl>[Cl:1][CH2:2][CH2:3][CH2:4][S:5]([O:8][CH2:9][C:10]([CH3:24])([CH3:25])[CH:11]([O:14][CH2:15][C:16]1[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=1)[CH:12]=[O:28])(=[O:6])=[O:7]
Reactant: C=CC(OCc1ccc(OC)cc1)C(C)(C)COS(=O)(=O)CCCCl
Reactant: O=[O+][O-]
Agent: O=O
Solvent: CSC
Solvent: ClCCl
Product: COc1ccc(COC(C=O)C(C)(C)COS(=O)(=O)CCCCl)cc1
Yield: 77 %

Procedure:
Following the general procedure for the preparation of aldehydes from alkenes of Description 11, (3R/S)-3-[(4-methoxyphenyl)methoxy]-2,2-dimethylpent-4-enyl (3-chloropropyl)sulfonate (14a) (4.0 g, 10.2 mmol) dissolved in 100 mL of dichloromethane (DCM) was treated with a mixture of oxygen and ozone (O2/O3). Upon completion of the reaction, 2 mL (1.69 g, 27.2 mmol) of dimethyl sulfide (DMS) was added. After work-up, the crude material was purified by silica gel column chromatography using a mixture of ethyl acetate (EtOAc) and hexane (Hxn) (EtOAc/Hxn=1:2) as eluent to provide 3.1 g (77% yield) of the title compound (14b) as a colorless oil. The analytical data was consistent with the proposed structure and with the data obtained for the enantiopure compound (13b).
Reaction SMILES: [Cl-].[CH3:2][O:3][CH2:4][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[NH2-].[Na+].[CH2:26]([C:33]1[CH:37]=[CH:36][S:35][C:34]=1[C:38](=O)[C:39]([O:41][CH3:42])=[O:40])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.O>C1COCC1>[CH2:26]([C:33]1[CH:37]=[CH:36][S:35][C:34]=1/[C:38](=[CH:2]\[O:3][CH3:4])/[C:39]([O:41][CH3:42])=[O:40])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COC(=O)C(=O)c1sccc1Cc1ccccc1
Agent: [Cl-]
Agent: [NH2-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CO/C=C(/C(=O)OC)c1sccc1Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of (methoxymethyl)triphenylphosphonium chloride and sodamide (0.4 g of a 1:1 molar mixture) in dry THF was added a solution of methyl 2-(3-benzyl-2-thienyl)-2-oxoacetate (220 mg, 0.8 mmol) in dry THF (5 ml). The reaction mixture was stirred at room temperature for 30 minutes. More (methoxymethyl)triphenylphosphonium chloride and sodamide (0.2 g of a 1:1 molar mixture) were added and stirring was continued for a further one hour. The reaction mixture was poured into water and then extracted with ether. The combined ether layers were washed with water and brine and then dried. Filtration through a pad of silica gel to remove triphenylphosphine oxide, followed by HPLC (eluent dichloromethane) afforded (Z)-methyl 2-(3-benzyl-2-thienyl)-3-methoxypropenoate, an oil (100 mg), 1H nmr: delta 3.64 (3H, s), 3.78 (6H, s), 6.75 (1H, d), 7.0-7.4 (6H, m), 7.60 (1H, s) ppm; and (E)-methyl 2-(3-benzyl- 2-thienyl)-3-methoxypropenoate, an oil (30 mg), 1H nmr: delta 3.64 (3H, s), 3.80 (3H, s), 3.82 (3H, s), 6.56 (1H, s), 6.75 (1H, d), 7.0-7.3 (6H, m) ppm.
Reaction SMILES: [OH:1][CH:2]([CH2:25][OH:26])[CH2:3][NH:4][C:5]1[N:13]=[C:12]2[C:8]([N:9]=[C:10]([O:22][CH3:23])[N:11]2[CH2:14][C:15]2[CH:16]=[N:17][C:18]([CH3:21])=[CH:19][CH:20]=2)=[C:7]([NH2:24])[N:6]=1.C(N(CC)CC)C.[C:34](OC(OC(C)(C)C)=O)(OC(C)(C)C)=[O:35]>CN(C)C=O>[CH3:23][O:22][C:10]1[N:11]([CH2:14][C:15]2[CH:16]=[N:17][C:18]([CH3:21])=[CH:19][CH:20]=2)[C:12]2[C:8]([N:9]=1)=[C:7]([NH2:24])[N:6]=[C:5]([NH:4][CH2:3][CH:2]1[CH2:25][O:26][C:34](=[O:35])[O:1]1)[N:13]=2
Reactant: COc1nc2c(N)nc(NCC(O)CO)nc2n1Cc1ccc(C)nc1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1nc2c(N)nc(NCC3COC(=O)O3)nc2n1Cc1ccc(C)nc1
Reaction time: 14 h
Yield: 26.6 %

Procedure:
2-(2,3-Dihydroxypropylamino)-8-methoxy-9-{(6-methyl-3-pyridyl)methyl}adenine (230 mg, 0.64 mmol) obtained by Reference example 18, 4-dimethylaminopyridine (5 mg, 0.04 mmol) and triethylamine (0.02 ml, 0.14 mmol) were dissolved in dimethylformamide (2 ml). Thereto was added di-t-butyl dicarbonate (410 mg, 1.9 mmol) in the oil bath kept at 50° C. and the mixture was stirred for 14 hours. The reaction mixture was concentrated and the residue was purified by preparative thin layer chromatography to give the captioned compound (64 mg, 0.17 mmol, yield 26%) as a white solid.
Reaction SMILES: [CH3:1]I.[N:3]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9]2[CH:16]=[CH:15][C:12]([CH:13]=[O:14])=[CH:11][CH:10]=2)[CH:4]=1.[BH4-].[Na+]>ClCCl>[OH:14][CH2:13][C:12]1[CH:15]=[CH:16][C:9]([C:5]2[CH2:4][N:3]([CH3:1])[CH2:8][CH2:7][CH:6]=2)=[CH:10][CH:11]=1
Reactant: CI
Reactant: O=Cc1ccc(-c2cccnc2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Product: CN1CCC=C(c2ccc(CO)cc2)C1
Temperature: 25 °C
Reaction time: 48 h
Yield: 72.1 %

Procedure:
Methyl iodide (0.8 ml, 12.9 mmol) was added to a solution of 4-(3-pyridyl)benzaldehyde (0.78 g, 4.3 mmol) in dichloromethane and stirred 2 days. Additional methyl iodide (0.8 ml, 12.9 mmol) was added and stirred for 3 hr. After removal of the solvent, methanol was added to the residue and ice-cooled. Sodium tetrahydroborate (6.4 g, 17.0 mmol) was added to the solution and stirred for 1.5 hr with warming to room temperature. Organic solvents were removed under reduced pressure after addition of water and extracted with ethyl acetate, washed with water and brine and dried over sodium sulfate. After removal of the solvent under reduced pressure, residue was purified by silica gel chromatography (eluent ethyl acetate to methanol) to give 3-(4-hydroxymethylphenyl)-1-methyl-1,2,5,6-tetrahydropyridine (0.63 g, 72%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:39][CH3:40])=[C:6]([C:8]([CH3:38])([CH3:37])[CH2:9][C:10]([OH:36])([C:32]([F:35])([F:34])[F:33])[CH2:11][NH:12][C:13]2[CH:21]=[C:20]([CH3:22])[CH:19]=[C:18]3[C:14]=2[CH:15]=[N:16][N:17]3[C:23]2[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=2)[C:26]([OH:28])=O)[CH:7]=1.Cl.[NH2:42][C@H:43]([C:45]([NH2:47])=[O:46])[CH3:44]>>[NH2:47][C:45](=[O:46])[C@@H:43]([NH:42][C:26](=[O:28])[C:25]1[CH:29]=[CH:30][CH:31]=[C:23]([N:17]2[C:18]3[C:14](=[C:13]([NH:12][CH2:11][C:10]([OH:36])([C:32]([F:34])([F:33])[F:35])[CH2:9][C:8]([C:6]4[CH:7]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=4[O:39][CH3:40])([CH3:38])[CH3:37])[CH:21]=[C:20]([CH3:22])[CH:19]=3)[CH:15]=[N:16]2)[CH:24]=1)[CH3:44]
Reactant: C[C@H](N)C(N)=O
Reactant: COc1ccc(F)cc1C(C)(C)CC(O)(CNc1cc(C)cc2c1cnn2-c1cccc(C(=O)O)c1)C(F)(F)F
Agent: Cl
Product: COc1ccc(F)cc1C(C)(C)CC(O)(CNc1cc(C)cc2c1cnn2-c1cccc(C(=O)N[C@@H](C)C(N)=O)c1)C(F)(F)F

Procedure:
Prepared similarly to Example 1 from 3-(4-{[4-[5-fluoro-2-(methyloxy)phenyl]-2-hydroxy-4-methyl-2-(trifluoromethyl)pentyl]amino}-6-methyl-1H-indazol-1-yl)benzoic acid and L-alaninamide hydrochloride with System A used for purification by mass directed autopreparation.
Reaction SMILES: [CH2:1]([C@:3]12[CH2:11][CH2:10][C@@H:9]3[C:12]4[CH:13]=[CH:14][C:15]([O:20][CH3:21])=[CH:16][C:17]=4[CH2:18][CH2:19][C@H:8]3[C@@H:7]1[CH2:6][CH2:5][C@@H:4]2[OH:22])[CH3:2].[H-].[Na+].[CH2:25](I)[CH3:26]>C1(C)C(C)=CC=CC=1>[CH2:25]([O:22][C@@H:4]1[C@:3]2([CH2:1][CH3:2])[C@H:7]([C@@H:8]3[CH2:19][CH2:18][C:17]4[CH:16]=[C:15]([O:20][CH3:21])[CH:14]=[CH:13][C:12]=4[C@H:9]3[CH2:10][CH2:11]2)[CH2:6][CH2:5]1)[CH3:26]
Reactant: CC[C@]12CC[C@@H]3c4ccc(OC)cc4CC[C@H]3[C@@H]1CC[C@@H]2O
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1C
Product: CCO[C@H]1CC[C@H]2[C@@H]3CCc4cc(OC)ccc4[C@H]3CC[C@]12CC

Procedure:
Reflux a suspension of 5.0 g. of dl-13-ethyl-3-methoxygona-1,3,5(10)-trien-17β-ol and 3.83 g. of sodium hydride (50% in oil) for 1.5 hours in xylene (100 ml). Add 14.5 ml. of ethyl iodide and reflux for 22 hours. Acidify with 2N hydrochloric acid and extract the material with benzene. Chromatograph the residue on alumina (Grade I neutral). Elute the product with benzene-ether (1:1). Recrystallize the product from 60 ml. of methanol to obtain dl-17β-ethoxy-13-ethyl-3-methoxygona-1,3,5(10)-triene (2.3 g); m.p. 74°-77°C.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][C:12]#[C:13][C:14]1[CH2:31][C@@:29]2([CH3:30])[C@@H:25]([CH2:26][CH2:27][C@@H:28]2[O:32][CH:33]2[CH2:38][CH2:37][CH2:36][CH2:35][O:34]2)[C@@:24]2([C:39]#[N:40])[C:15]=1[C:16]1[CH:17]=[CH:18][C:19]([O:41][CH3:42])=[CH:20][C:21]=1[CH2:22][CH2:23]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>O1CCCC1.CO.[Pd]>[CH2:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]1[CH2:31][C@@:29]2([CH3:30])[C@@H:25]([CH2:26][CH2:27][C@@H:28]2[O:32][CH:33]2[CH2:38][CH2:37][CH2:36][CH2:35][O:34]2)[C@@:24]2([C:39]#[N:40])[C:15]=1[C:16]1[CH:17]=[CH:18][C:19]([O:41][CH3:42])=[CH:20][C:21]=1[CH2:22][CH2:23]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc2c(c1)CC[C@]1(C#N)C2=C(C#CCCCOCc2ccccc2)C[C@]2(C)[C@@H](OC3CCCCO3)CC[C@H]21
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc2c(c1)CC[C@]1(C#N)C2=C(CCCCCOCc2ccccc2)C[C@]2(C)[C@@H](OC3CCCCO3)CC[C@H]21
Temperature: 25 °C
Yield: 100.2 %

Procedure:
A solution of 15.26 g of alkyne 3 in 300 ml of tetrahydrofuran/methanol (3:1) is mixed with 2.7 g of palladium (10% on magnesium carbonate) and stirred at room temperature under a hydrogen atmosphere (1 bar) until the reaction is completed. For working-up, it is filtered on Celite and concentrated by evaporation in a vacuum. 15.4 g of a colorless foam 4 is obtained, which is used without further purification in the next stage (GC-MS: m/z theor.: 569, pract.: 569).
Reaction SMILES: [F:1][C:2]1[C:7]2[NH:8]C(=O)O[C:11](=[O:12])[C:6]=2[CH:5]=[CH:4][CH:3]=1.O1CCCC1.[CH2:19]([NH2:22])[C:20]#[CH:21]>>[NH2:8][C:7]1[C:2]([F:1])=[CH:3][CH:4]=[CH:5][C:6]=1[C:11]([NH:22][CH2:19][C:20]#[CH:21])=[O:12]
Reactant: O=c1[nH]c2c(F)cccc2c(=O)o1
Reactant: C#CCN
Solvent: C1CCOC1
Product: C#CCNC(=O)c1cccc(F)c1N
Reaction time: 2 h
Yield: 79 %

Procedure:
8-Fluoro-1H-benzo[d][1,3]oxazine-2,4-dione (3.00 g, 16.6 mmol) was dissolved in tetrahydrofuran (100 mL, 1.23 mol) and prop-2-ynylamine (1.70 mL, 24.8 mmol) was added. The reaction was stirred for 2 hours and then concentrated under reduced pressure onto silica gel. Purification by silica gel chromatography (dry loaded) using a gradient of 0-60% EtOAc/hex as the eluting solvent to obtain 2-amino-3-fluoro-N-prop-2-ynyl-benzamide as a white solid (2.52 g, 79%). m.p.=89-91° C.; LCMS (m/e) 138 (M-NHCH2CCH); 1H-NMR (CDCl3, 400 MHz) δ 7.14 (d, 1H, J=8.0 Hz), 7.12-7.05 (m, 1H), 6.64-6.56 (m, 1H), 6.28-6.14 (m, 1H), 5.67 (bs, 2H), 4.27-4.19 (m, 2H), 2.34-2.27 (m, 1H).