Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]([CH3:14])=[C:12]([C:15]([OH:17])=O)[CH:11]=[N:10]2)=[CH:5][CH:4]=1.[NH2:20][C:21]1[CH:22]=[CH:23][C:24]([N:29]2[CH2:34][CH2:33][CH:32]([N:35]3[CH2:40][CH2:39][O:38][CH2:37][CH2:36]3)[CH2:31][CH2:30]2)=[C:25]([CH:28]=1)[C:26]#[N:27]>>[C:26]([C:25]1[CH:28]=[C:21]([NH:20][C:15]([C:12]2[CH:11]=[N:10][N:9]([C:6]3[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:19])[F:18])=[CH:8][CH:7]=3)[C:13]=2[CH3:14])=[O:17])[CH:22]=[CH:23][C:24]=1[N:29]1[CH2:34][CH2:33][CH:32]([N:35]2[CH2:36][CH2:37][O:38][CH2:39][CH2:40]2)[CH2:31][CH2:30]1)#[N:27]
Reactant: N#Cc1cc(N)ccc1N1CCC(N2CCOCC2)CC1
Reactant: Cc1c(C(=O)O)cnn1-c1ccc(C(F)(F)F)cc1
Product: Cc1c(C(=O)Nc2ccc(N3CCC(N4CCOCC4)CC3)c(C#N)c2)cnn1-c1ccc(C(F)(F)F)cc1
Yield: 8.9 %

Procedure:
By the reaction and treatment in the same manner as in Example 64 using 1-(4-trifluoromethylphenyl)-5-methylpyrazole-4-carboxylic acid (0.7 g) and 5-amino-2-(4-morpholinopiperidin-1-yl)benzonitrile (0.6 g), the title compound (0.1 g) was obtained, melting point: 257° C. (decomposition).
Reaction SMILES: [C:1]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)(=[O:4])[CH:2]=[O:3].O.[O:14]=[C:15]1[CH:22]2[CH:17]([CH2:18][CH:19]=[CH:20][CH2:21]2)[NH:16]1>C1C=CC=CC=1>[OH:3][CH:2]([N:16]1[C:15](=[O:14])[CH:22]2[CH:17]1[CH2:18][CH:19]=[CH:20][CH2:21]2)[C:1]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:4]
Reactant: O=CC(=O)OCc1ccccc1
Reactant: O=C1NC2CC=CCC12
Solvent: c1ccccc1
Solvent: O
Product: O=C(OCc1ccccc1)C(O)N1C(=O)C2CC=CCC21
Reaction time: 3 h

Procedure:
Benzyl glyoxylate (2.73 g) was refluxed in benzene (25 ml) with provision for the removal of water. After 45 minutes 8-oxo-7-azabicyclo[4,2,0]oct-3-ene (28) (ref: I. A. Paquette and T. Kakihana, J. Amer. Chem. Soc., 1968, 90, 2897) (1.23 g) was added and refluxing continued for 3 hours. Removal of solvent under reduced pressure followed by chromatography gave two separate isomers of the alcohol (32) (90%) Isomer I, m.p. 92°-93°, νmax (CHCl3) 3450, 1750 (b) cm-1. δppm (CDCl3) 1.76-2.73 (4H, m, 2-CH2), 3.12-3.33 (1H, m, β-lactam proton), 3.76-3.93 (1H, m, β-lactam proton), 4.40 (1H, d, J 6 Hz, exch. D2O), 5.16 (2H, s, CH2), 5.47 (1H, d, J 6 Hz collapsing to s on D2O exch. CH--OH), 5.67-5.83 (2H, m, CH=CH), 7.34 (5H, Ar). M+ at m/e 287 (Found; C, 66.2; H, 5.9; N, 4.9.C16H17NO4 requires C, 66.9; H, 6.0; N, 4.9%). Isomer II, m.p. 100°-101°, νmax (CHCl3) 3450, 1750 (b), δppm (CDCl3) 1.80-2.63 (4H, m, 2-CH2), 3.13-3.36 (1H, m, β-lactam proton), 3.93-4.13 (1H, m, β-lactam proton), 4.20 (1H, bs, exch, D2O), 5.16 (2H, s, CH2), 5.50 (1H, b, sharpening to s on D2O exchange), 5.50-6.00 (2H, m, CH=CH), 7.34 (5H, Ar). (Found; C, 67.2; H, 6.0; N, 4.8. C16H17NO4 requires C, 66.9; H, 6.0; N, 4.9%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[N:8]([CH2:11][C:12]3[CH:20]=[CH:19][CH:18]=[C:17]4[C:13]=3[CH:14]=[CH:15][N:16]4C(OC(C)(C)C)=O)[N:9]=[CH:10][C:5]2=[C:4]([C:28]2[O:29][CH:30]=[CH:31][CH:32]=2)[N:3]=1.C[O-].[Na+]>CO.O>[O:29]1[CH:30]=[CH:31][CH:32]=[C:28]1[C:4]1[N:3]=[C:2]([NH2:1])[N:7]=[C:6]2[N:8]([CH2:11][C:12]3[CH:20]=[CH:19][CH:18]=[C:17]4[C:13]=3[CH:14]=[CH:15][NH:16]4)[N:9]=[CH:10][C:5]=12
Reactant: CC(C)(C)OC(=O)n1ccc2c(Cn3ncc4c(-c5ccco5)nc(N)nc43)cccc21
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: Nc1nc(-c2ccco2)c2cnn(Cc3cccc4[nH]ccc34)c2n1
Yield: 80.1 %

Procedure:
A solution of tert-butyl 4-(6-amino-4-(2-furyl)-1H-pyrazolo[3,4-d]pyrimidine-1-ylmethyl)indole-1-carboxylate (92 mg, 0.17 mmol) in MeOH (3 mL) was treated with NaOMe (45 mg, 0.84 mmol), refluxed for 2 h, cooled, diluted with water (15 mL) and filtered to give the title compound (45 mg, 82%) as an off white powder.
Reaction SMILES: [CH3:1][N:2]1[C:11]2[C:6](=[CH:7][C:8](/[C:12](/[CH3:24])=[CH:13]/[C:14]3[CH:23]=[CH:22][C:17]([C:18]([O:20]C)=[O:19])=[CH:16][CH:15]=3)=[CH:9][CH:10]=2)[N:5]([CH3:25])[CH2:4][CH2:3]1.[OH-].[K+]>C(O)C.O>[CH3:1][N:2]1[C:11]2[C:6](=[CH:7][C:8](/[C:12](/[CH3:24])=[CH:13]/[C:14]3[CH:23]=[CH:22][C:17]([C:18]([OH:20])=[O:19])=[CH:16][CH:15]=3)=[CH:9][CH:10]=2)[N:5]([CH3:25])[CH2:4][CH2:3]1
Reactant: COC(=O)c1ccc(/C=C(\C)c2ccc3c(c2)N(C)CCN3C)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: C/C(=C\c1ccc(C(=O)O)cc1)c1ccc2c(c1)N(C)CCN2C
Yield: 78.3 %

Procedure:
600 mg of this ester were converted into the free acid by reaction with a solution of 1.5 g of potassium hydroxide in 25 ml of ethanol and 10 ml of water at 50° C. during 4 hours. After recrystallization from ethyl acetate/hexane, there were obtained 450 mg of p-[(E)-2-(1,2,3,4-tetrahydro-1,4-dimethyl-6-quinoxalinyl)propenyl]benzoic acid in the form of orange crystals, melting point 203°-205° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1.[S:11]([C:15]1[CH:21]=[CH:20][C:18]([NH2:19])=[CH:17][CH:16]=1)(=[O:14])(=[O:13])[NH2:12]>>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[N:19][C:18]2[CH:20]=[CH:21][C:15]([S:11](=[O:14])(=[O:13])[NH2:12])=[CH:16][CH:17]=2)=[CH:5][CH:4]=1
Reactant: Nc1ccc(S(N)(=O)=O)cc1
Reactant: COc1ccc(C=O)cc1
Product: COc1ccc(C=Nc2ccc(S(N)(=O)=O)cc2)cc1

Procedure:
Following a procedure similar to that described in Example 1(i), but using 4-methoxybenzaldehyde and 4-sulfamoylaniline as starting materials, the title compound was obtained as a pale yellow powder (yield 95%).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:34]=[CH:33][C:16]([O:17][CH2:18][C:19]2[C:27]3[O:26][C:25]([C:28]([O:30]CC)=[O:29])=[N:24][C:23]=3[CH:22]=[CH:21][CH:20]=2)=[CH:15][CH:14]=1.C(=O)(O)[O-].[Na+]>C(O)C.O>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:14]=[CH:15][C:16]([O:17][CH2:18][C:19]2[C:27]3[O:26][C:25]([C:28]([OH:30])=[O:29])=[N:24][C:23]=3[CH:22]=[CH:21][CH:20]=2)=[CH:33][CH:34]=1
Reactant: CCOC(=O)c1nc2cccc(COc3ccc(OCc4ccc5ccccc5n4)cc3)c2o1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: O=C(O)c1nc2cccc(COc3ccc(OCc4ccc5ccccc5n4)cc3)c2o1

Procedure:
0.66 g of ethyl 7-(4-(quinoline-2-ylmethyloxy)phenoxymethyl)benzoxazole-2-carboxylate and 0.7 g sodium bicarbonate are combined in 50 ml of ethanol and 5 ml of water. After refluxing for 1.5 hours the mixture is concentrated and the residue diluted with ether. The resulting solid is collected, suspended in water and the pH adjusted to 6 with 1 molar hydrochloric acid. The resulting solid is crystallized from aqueous acetic acid, then tetrahydrofuran/hexane to give 7-(4-(quinolin-2-ylmethyloxy)phenoxymethyl)benzoxazole-2-carboxylic acid.
Reaction SMILES: [C:1]([C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][C:4]=1[C:10]([F:13])([F:12])[F:11])#[N:2].[CH2:14]([C:17](=[CH2:21])[C:18](O)=[O:19])[CH2:15][CH3:16]>>[C:1]([C:3]1[CH:9]=[CH:8][C:6]([NH:7][C:18](=[O:19])[C:17]([CH2:14][CH2:15][CH3:16])=[CH2:21])=[CH:5][C:4]=1[C:10]([F:11])([F:12])[F:13])#[N:2]
Reactant: N#Cc1ccc(N)cc1C(F)(F)F
Reactant: C=C(CCC)C(=O)O
Product: C=C(CCC)C(=O)Nc1ccc(C#N)c(C(F)(F)F)c1

Procedure:
Following the procedure described in Example 1, starting from 4-cyano-3-trifluoromethyl-aniline and 2-propyl-acrylic acid, the title compound was prepared as a yellow solid.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[C:11]3[CH:17]=[CH:16][NH:15][C:12]3=[N:13][CH:14]=2)O1.Cl[C:20]1[CH:25]=[N:24][CH:23]=[C:22]([N:26]2[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]2)[N:21]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.C(Cl)(Cl)Cl.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>[CH3:32][N:29]1[CH2:28][CH2:27][N:26]([C:22]2[N:21]=[C:20]([C:9]3[CH:10]=[C:11]4[CH:17]=[CH:16][NH:15][C:12]4=[N:13][CH:14]=3)[CH:25]=[N:24][CH:23]=2)[CH2:31][CH2:30]1
Reactant: CN1CCN(c2cncc(Cl)n2)CC1
Reactant: CC1(C)OB(c2cnc3[nH]ccc3c2)OC1(C)C
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: ClC(Cl)Cl
Product: CN1CCN(c2cncc(-c3cnc4[nH]ccc4c3)n2)CC1
Temperature: 100 °C

Procedure:
The starting material 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (124) (50 mg, 0.2 mmol, 1 eq) and 2-chloro-6-(4-methylpiperazin-1-yl)pyrazine (63) (44 mg, 0.2 mmol, 1 eq) in DMF (5 mL) was degassed and purged under argon atmosphere for 10 min. To this reaction mixture was charged Cs2CO3 (133 mg, 0.4 mmol, 2 eq) followed by addition of Pd(PPh3)4 (0.01 mg, 0.04 mmol) and degassing and purging under argon for an additional 10 min. The reaction mixture was heated at 100° C. for 12 h in a sealed tube. After completion of the reaction, the reaction mixture was diluted with CHCl3 and filtered through Celite. The solvents were distilled off and the crude material was submitted for flash column purification in neutral alumina using 2% MeOH/CHCl3 to obtain pale yellow solid compound 5-(6-(4-methylpiperazin-1-yl)pyrazin-2-yl)-1H-pyrrolo[2,3-b]pyridine 125 in 20 mg quantity. The compound 125 was confirmed by 1HNMR and LCMS. 1H NMR (400 MHz, CDCl3) δ: 8.96 (d, J=1.5 Hz 1H), 8.55 (d, J=1.70 Hz, 1H), 8.30 (s, 1H), 8.08 (s, 1H), 7.35 (m, J=3.04, 1H), 6.60 (m, J=1.95 1H), 3.75 (m, J=5.00, 4H), 2.58 (m, J=5.12, 4H), 2.38 (s, 3H); MS m/z 294.9 (M+H)+.
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[C:11](=[C:12](OS(C(F)(F)F)(=O)=O)[N:13]([CH:18]([CH3:20])[CH3:19])[N:14]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[CH:29]([C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1)([CH3:31])[CH3:30]>>[CH:18]([N:13]1[C:12]([C:35]2[CH:36]=[CH:37][C:32]([CH:29]([CH3:31])[CH3:30])=[CH:33][CH:34]=2)=[C:11]2[C:15]([CH2:16][CH2:17][NH:8][CH2:9][CH2:10]2)=[N:14]1)([CH3:19])[CH3:20]
Reactant: CC(C)c1ccc(B(O)O)cc1
Reactant: CC(C)n1nc2c(c1OS(=O)(=O)C(F)(F)F)CCN(C(=O)OC(C)(C)C)CC2
Product: CC(C)c1ccc(-c2c3c(nn2C(C)C)CCNCC3)cc1
Yield: 94.2 %

Procedure:
The title compound (177 mg) was prepared according to Example 189 using 270 mg of 2-isopropyl-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 189, Step A) and 311 mg of 4-isopropylphenylboronic acid. MS (ESI): exact mass calculated for C19H27N3, 297.44; found, m/z 298.5 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.35-7.34 (m, 2H), 7.19-7.17 (m, 2H), 4.57 (br s, 1H), 4.38-4.32 (m, 1H), 3.36-3.34 (m, 1H), 3.15-3.13 (m, 1H), 2.90 (m, 1H), 2.79-2.70 (m, 2H), 1.31 (d, J=13.3 Hz, 6H), 1.20 (d, J=6.9 Hz, 6H).
Reaction SMILES: Cl[C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]1[O:17][C:16]([C:18]2[CH:23]=[CH:22][C:21]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)=[CH:20][C:19]=2[O:30][CH3:31])=[N:15][N:14]=1.[NH:32]1[CH:36]=[CH:35][CH:34]=[N:33]1>>[CH3:31][O:30][C:19]1[CH:20]=[C:21]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[CH:22]=[CH:23][C:18]=1[C:16]1[O:17][C:13]([C:3]2[C:4]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)=[N:5][O:6][C:2]=2[N:32]2[CH:36]=[CH:35][CH:34]=[N:33]2)=[N:14][N:15]=1
Reactant: c1cn[nH]c1
Reactant: COc1cc(N2CCOCC2)ccc1-c1nnc(-c2c(-c3ccccc3)noc2Cl)o1
Product: COc1cc(N2CCOCC2)ccc1-c1nnc(-c2c(-c3ccccc3)noc2-n2cccn2)o1
Yield: 79 %

Procedure:
As described for example 106, 4-{4-[5-(5-chloro-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-3-methoxy-phenyl}-morpholine (100 mg, 0.23 mmol) using pyrazole instead of dimethylamine hydrochloride was converted to the title compound (85 mg, 79%) which was obtained as an off-white solid. MS: m/e=471.3 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[C:18]=2F)=[N:15][OH:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC(C)([O-])C.[K+]>C1COCC1.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[C:18]=3[O:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1cccc(C(=NO)C2CCN(C(=O)OC(C)(C)C)CC2)c1F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1cccc2c(C3CCN(C(=O)OC(C)(C)C)CC3)noc12
Temperature: 25 °C
Yield: 64.4 %

Procedure:
To a room temperature mixture of 4-[(2-Fluoro-3-methoxy-phenyl)-hydroxyimino-methyl]-piperidine-1-carboxylic acid tert-butyl ester (5.00 g, 14.2 mmol) in THF (50 mL) under nitrogen was added potassium tert-butoxide (15.0 mL of a 1M THF solution, 15.0 mmol) rapidly and the reaction refluxed for 4 h. After cooling to room temperature, the reaction was diluted with ethyl acetate (250 mL) and washed with water (100 mL) and brine (100 mL) successively. The organics were dried over magnesium sulfate, filtered, and concentrated to give a waxy solid. Recrystallization of the solid did not remove impurities so the crude product was chromatographed on silica using a step gradient elution of 10% ethyl acetate/dichloromethane to 40% ethyl acetate/dichloromethane to afford 3.04 g (64%) of the desired product as a white powder, mp:130–132° C.
Reaction SMILES: [CH2:1]([C:3](O)([CH:6]([CH3:13])[CH2:7][CH:8]=[C:9]([CH3:12])[CH2:10][CH3:11])[CH:4]=[CH2:5])[CH3:2].P(Br)(Br)[Br:16]>>[Br:16][CH2:2][CH:1]=[C:3]([CH2:4][CH3:5])[CH:6]([CH3:13])[CH2:7][CH:8]=[C:9]([CH3:12])[CH2:10][CH3:11]
Reactant: BrP(Br)Br
Reactant: C=CC(O)(CC)C(C)CC=C(C)CC
Product: CCC(C)=CCC(C)C(=CCBr)CC

Procedure:
Following the procedure of Example 9, 3-ethyl-4,7-dimethyl-1,6-nonadien-3-ol and phosphorus tribromide are reacted to form 1-bromo-3-ethyl-4,7-dimethyl-2,6-nonadiene.
Reaction SMILES: [CH:1]1[C:14]2[S:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[O:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[C:15](Cl)(=[O:17])[CH3:16].[Cl-].[Al+3].[Cl-].[Cl-].Cl>C(=S)=S.O>[C:15]([C:10]1[CH:9]=[CH:8][C:7]2[O:6][C:5]3[C:14](=[CH:1][CH:2]=[CH:3][CH:4]=3)[S:13][C:12]=2[CH:11]=1)(=[O:17])[CH3:16]
Reactant: CC(=O)Cl
Reactant: c1ccc2c(c1)Oc1ccccc1S2
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Solvent: O
Product: CC(=O)c1ccc2c(c1)Sc1ccccc1O2
Reaction time: 2 h

Procedure:
Phenoxathiin (22.9 g.) and acetyl chloride (8.8 ml) were dissolved in carbon disulphide (120 ml) and mechanically stirred while aluminium chloride (15.5 g) was added in small portions. The red mixture was stirred for 2 hr. at room temperature, then boiled under reflux on the water bath for a further 21/4 hr. The mixture was cooled and poured on to ice and hydrochloric acid, and the precipitated product filtered off, washed with water, and recrystallised once from ethanol and twice from petroleum ether (b.p. 80°-100° C.) to give the product m.p. 112° C.
Reaction SMILES: I[C:2]1[C:10]2[O:9][CH2:8][C:7](=[O:11])[C:6]=2[CH:5]=[CH:4][C:3]=1[O:12][CH3:13].[CH2:14]([CH:17]1[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]1)[C:15]#[CH:16]>C(N(CC)CC)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH3:13][O:12][C:3]1[CH:4]=[CH:5][C:6]2[C:7](=[O:11])[CH2:8][O:9][C:10]=2[C:2]=1[C:16]#[C:15][CH2:14][CH:17]1[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]1
Reactant: C#CCC1CCN(C(=O)OC(C)(C)C)CC1
Reactant: COc1ccc2c(c1I)OCC2=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: COc1ccc2c(c1C#CCC1CCN(C(=O)OC(C)(C)C)CC1)OCC2=O
Temperature: 50 °C
Reaction time: 8 h
Yield: 60.8 %

Procedure:
A solution of 7-iodo-6-methoxybenzofuran-3(2H)-one (0.348 g, 1.20 mmol) synthesized in Example B46, Step 2 in triethylamine (10 mL) was added with tert-butyl 4-(prop-2-ynyl)piperidine-1-carboxylate (0.269 g, 1.20 mmol), dichlorobis(triphenylphosphine)palladium(II) (0.0842 g, 0.120 mmol) and copper(I) iodide (0.0114 g, 0.0600 mmol), and the mixture was stirred overnight at 50° C. The reaction mixture was concentrated, and then added with water, and the mixture was extracted with methylene chloride. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated, and the resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain tert-butyl 4-[3-(6-methoxy-3-oxo-2,3-dihydrobenzofuran-7-yl)prop-2-ynyl]piperidine-1-carboxylate (0.281 g, 61%).
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][CH2:5][CH:4]([C:8]([O:10][CH3:11])=[O:9])[CH2:3]1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.[CH2:29](O)[CH2:30][OH:31].C(N(CC)CC)C>C1(C)C=CC=CC=1>[O:31]1[C:2]2([CH2:7][CH2:6][CH2:5][CH:4]([C:8]([O:10][CH3:11])=[O:9])[CH2:3]2)[O:1][CH2:29][CH2:30]1
Reactant: OCCO
Reactant: COC(=O)C1CCCC(=O)C1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: COC(=O)C1CCCC2(C1)OCCO2
Temperature: 25 °C

Procedure:
Methyl 3-oxocyclohexanecarboxylate (930 mg) and pyridinium p-toluenesulfonate (299 mg) were combined in toluene (29.8 mL) to give a colorless solution. Ethylene glycol (0.996 mL) was added and the reaction was refluxed under Dean-Stark conditions for 2 days. The reaction was cooled to room temperature, triethylamine was added, and then the mixture was concentrated by rotary evaporation. The residue was purified by regular phase flash column chromatography (Analogix 0-40% hexane/ethyl acetate).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:15][CH2:14][CH2:13][CH:12]2[CH2:16][OH:17])(=[O:10])=[O:9])=[CH:4][CH:3]=1.N1C=CN=C1.[C:23]([Si:27](Cl)([CH3:29])[CH3:28])([CH3:26])([CH3:25])[CH3:24]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([N:11]2[CH2:15][CH2:14][CH2:13][CH:12]2[CH2:16][O:17][Si:27]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:29])[CH3:28])(=[O:10])=[O:9])=[CH:6][CH:7]=1
Reactant: O=S(=O)(c1ccc(Br)cc1)N1CCCC1CO
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCC1CCCN1S(=O)(=O)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.8 %

Procedure:
To a solution of [1-(4-bromo-benzenesulfonyl)-pyrrolidin-2-yl]-methanol (50.0 g, 0.16 mol) and 1H-imidazole (21.3 g, 0.31 mol) in CH2Cl2 (500 mL) was added tert-butylchlorodimethylsilane (35.5 g, 0.24 mol) in portions. After addition, the mixture was stirred for 1 hour at room temperature. The reaction was quenched with water (200 mL) and the separated aqueous layer was extracted with CH2Cl2 (100 mL×3). The combined organic layers were washed with brine, dried over Na2SO4 and evaporated under vacuum to give 1-(4-bromo-benzenesulfonyl)-2-(tert-butyldimethylsilanyloxymethyl)pyrrolidine (68.0 g, 99%). 1H NMR (300 MHz, CDCl3) δ 7.63-7.71 (m, 4H), 3.77-3.81 (m, 1H), 3.51-3.63 (m, 2H), 3.37-3.43 (m, 1H), 3.02-3.07 (m, 1H), 1.77-1.91 (m, 2H), 1.49-1.57 (m, 2H), 0.87 (s, 9H), 0.06 (d, J=1.8 Hz, 6H).
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:14]#[N:15])[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[F:16][C:17]([F:22])([F:21])[CH2:18][CH2:19]Br.C([O-])([O-])=O.[K+].[K+]>CC#N.CCOC(C)=O>[I:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:14]#[N:15])[CH2:13][CH2:12][N:11]([CH2:19][CH2:18][C:17]([F:22])([F:21])[F:16])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: FC(F)(F)CCBr
Reactant: N#CC1(c2ccc(I)cc2)CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: N#CC1(c2ccc(I)cc2)CCN(CCC(F)(F)F)CC1
Temperature: 60 °C
Yield: 97.9 %

Procedure:
To a solution of the crude 4-(4-iodo-phenyl)-piperidine-4-carbonitrile (0.60 g, ˜1.9 mmol) in CH3CN (6 mL) was added (3,3,3-trifluoro)-propyl bromide (1.02 mL, 9.6 mmol, 5 eq.) and K2CO3 (1.33 g, 9.6 mmol, 5 eq.) and the resulting mixture was stirred and heated to 60° C. for 16 h. The reaction was cooled to room temperature, diluted with EtOAc (20 mL) and washed with H2O (25 mL) and saturated brine (2×25 mL). The organic phase was dried over anhydrous Na2SO4, filtered and concentrated by rotary evaporation to give the crude 4-(4-iodo-phenyl)-1-(3,3,3-trifluoro-propyl)-piperidine-4-carbonitrile as a red solid (0.761 g, 1.86 mmol, 98%). 1H NMR (300 MHz, CDCl3): δ 7.83 (dd, 2H), 7.33 (dd, 2H), 3.09 (d, 2H), 2.82 (dd, 2H), 2.66 (td, 2H), 2.45 (m, 2H), 2.18 (m, 4H); MS (ESI): 409.1/410.2 (M +1).
Reaction SMILES: [CH:1]([NH:4][C:5]([C:7]1[C:15]2[C:11](=[CH:12][NH:13][N:14]=2)[CH:10]=[C:9]([CH3:16])[C:8]=1[NH:17][C:18]([C:20]1[N:21]([C:27]2[C:32]([Cl:33])=[CH:31][CH:30]=[CH:29][N:28]=2)[N:22]=[C:23]([O:25][CH3:26])[CH:24]=1)=[O:19])=[O:6])([CH3:3])[CH3:2].C(N(CC)CC)C.Cl[C:42]([S:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH3:52])=[O:43]>ClCCl>[CH2:45]([S:44][C:42]([N:13]1[CH:12]=[C:11]2[C:15]([C:7]([C:5](=[O:6])[NH:4][CH:1]([CH3:3])[CH3:2])=[C:8]([NH:17][C:18]([C:20]3[N:21]([C:27]4[C:32]([Cl:33])=[CH:31][CH:30]=[CH:29][N:28]=4)[N:22]=[C:23]([O:25][CH3:26])[CH:24]=3)=[O:19])[C:9]([CH3:16])=[CH:10]2)=[N:14]1)=[O:43])[CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH3:52]
Reactant: CCCCCCCCSC(=O)Cl
Reactant: COc1cc(C(=O)Nc2c(C)cc3c[nH]nc3c2C(=O)NC(C)C)n(-c2ncccc2Cl)n1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCCSC(=O)n1cc2cc(C)c(NC(=O)c3cc(OC)nn3-c3ncccc3Cl)c(C(=O)NC(C)C)c2n1
Temperature: 20 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 6-{[2-(3-chloro-pyridin-2-yl)-5-methoxy-2H-pyrazole-3-carbonyl]-amino}-5-methyl-2H-indazole-7-carboxylic acid isopropylamide (0.300 g, 0.64 mmol) in dichloromethane (3.0 mL) was added triethylamine (90 μL, 0.65 mmol), then S-octyl chlorothioformate (0.133 g, 0.64 mmol). The resulting homogeneous reaction mixture was stirred for 0.5 h at 20° C. The reaction mixture was then concentrated in vacuo and the residue was purified by flash-chromatography (SiO2, CH2Cl2/ethyl acetate 9:1) affording the title compound as yellow crystals with a melting point of 98-102° C.
Reaction SMILES: C1(COC([NH:11][CH2:12][C@H:13]2[CH2:17][CH2:16][CH2:15][N:14]2[CH:18]([C:24]([O:26]CC)=O)[C:19]([O:21][CH2:22][CH3:23])=[O:20])=O)C=CC=CC=1>CCO.[Pd]>[O:26]=[C:24]1[CH:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[N:14]2[CH2:15][CH2:16][CH2:17][C@@H:13]2[CH2:12][NH:11]1
Reactant: CCOC(=O)C(C(=O)OCC)N1CCC[C@@H]1CNC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)C1C(=O)NC[C@H]2CCCN12
Temperature: 50 °C
Reaction time: 2.5 h
Yield: 106.9 %

Procedure:
The solution of diethyl {(2R)-2-[({[(phenylmethyl)oxy]carbonyl}amino)methyl]-1-pyrrolidinyl}propanedioate (D110, 1.07 g, 2.72 mmol) in EtOH (ca. 20 ml) was degassed, (10%) Pd/C (580 mg) was added and the reaction mixture was stirred under a H2 atmosphere for 2.5 hrs. The catalyst was filtered off and the volume of the filtrated solution was reduced in vacuo. The solution was warmed-up to 50° C. and it was stirred at this temperature for 6 hrs and at room temperature for 12 hrs. The solvent was evaporated to dryness to give the title compound (617 mg) as a mixture of diastereoisomers (ratio ca. 70:30). This crude was used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:18][CH3:19])=[C:4]([C:9]([CH3:17])([CH3:16])[CH2:10][C:11](=[O:15])[C:12]([OH:14])=[O:13])[CH:5]=[CH:6][C:7]=1[CH3:8].S(=O)(=O)(O)O.[CH2:25](O)[CH3:26]>>[CH2:25]([O:13][C:12](=[O:14])[C:11](=[O:15])[CH2:10][C:9]([C:4]1[CH:5]=[CH:6][C:7]([CH3:8])=[C:2]([Cl:1])[C:3]=1[O:18][CH3:19])([CH3:17])[CH3:16])[CH3:26]
Reactant: CCO
Reactant: COc1c(C(C)(C)CC(=O)C(=O)O)ccc(C)c1Cl
Agent: O=S(=O)(O)O
Product: CCOC(=O)C(=O)CC(C)(C)c1ccc(C)c(Cl)c1OC
Yield: 81.6 %

Procedure:
5.37 g (18.86 mmol) of 4-(3-chloro-2-methoxy-4-methylphenyl)-4-methyl-2-oxo-pentanoic acid is dissolved in 112 ml of ethanol, mixed with 2 ml of concentrated sulfuric acid and refluxed for five hours. The ethanol is drawn off in a rotary evaporator, and the residue is carefully mixed with saturated sodium bicarbonate solution after 50 ml of water is added. It is extracted twice with ethyl acetate. The combined organic extracts are washed with water and with brine. After drying, and after the dessicant is filtered off and the solvent is spun in, the residue is chromatographed on silica gel (mobile solvent:ethyl acetate/hexane). 4.81 g (81.6%) of the desired compound is isolated.
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:10](=O)[CH2:9][CH2:8][CH2:7][C:6]=2[O:5][C:4](=[O:13])[CH:3]=1.[CH2:14]([NH2:18])[CH2:15][CH2:16][CH3:17]>>[CH2:14]([N:18]1[C:10]2[CH2:9][CH2:8][CH2:7][C:6](=[O:5])[C:11]=2[C:2]([CH3:1])=[CH:3][C:4]1=[O:13])[CH2:15][CH2:16][CH3:17]
Reactant: Cc1cc(=O)oc2c1C(=O)CCC2
Reactant: CCCCN
Product: CCCCn1c2c(c(C)cc1=O)C(=O)CCC2

Procedure:
Prepared analogously to Example 5(b) from 4-methyl- 5,6,7,8-tetrahydro-cumarin-5-one and n-butylamine.