Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:11])[CH3:10])=[CH:4][C:3]=1[N:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.[C:18]([C:20]1[O:24][C:23]([C:25](Cl)=[O:26])=[CH:22][CH:21]=1)#[N:19].CCN(C(C)C)C(C)C>>[C:9]([NH:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:25]([C:23]2[O:24][C:20]([C:18]#[N:19])=[CH:21][CH:22]=2)=[O:26])=[C:3]([N:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)[CH:4]=1)(=[O:11])[CH3:10]
Reactant: CC(=O)Nc1ccc(N)c(N2CCCCC2)c1
Reactant: N#Cc1ccc(C(=O)Cl)o1
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)Nc1ccc(NC(=O)c2ccc(C#N)o2)c(N2CCCCC2)c1
Yield: 38 %

Procedure:
Using a procedure similar to Example 3, step (d), N-(4-amino-3-piperidin-1-yl-phenyl)-acetamide (40 mg, 0.17 mmol, as prepared in the previous step) was allowed to react with 5-cyano-furan-2-carbonyl chloride (27 mg, 0.17 mmol) in the presence of DIEA (65 μL, 0.37 mmol) to afford 23 mg (38%) of the title compound as a yellow solid. 1H-NMR (CDCl3; 400 MHz): δ 9.64 (s, 1H),), 8.36 (d, 1H, J=8.5 Hz), 7.70 (br s, 1H), 7.27 (br s, 1H), 7.22 (d, 1H, J=3.8 Hz), 7.14 (br s, 1H), 7.02 (dd, 1H, J=6.6, 8.9 Hz), 2.85 (br s, 4H), 2.18 (s, 3H), 1.80 (br s, 4H), 1.65 (br s, 2H); Mass spectrum (ESI, m/z): Calcd. for C19H20N4O3, 353.1 (M+H), found 353.2.
Reaction SMILES: [ClH:1].[NH2:2][C:3]1[N:8]=[CH:7][C:6](/[CH:9]=[CH:10]/[C:11]([OH:13])=O)=[CH:5][C:4]=1[CH2:14][N:15]1[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]1.Cl.CN1CC2C=C(/C=C/C(O)=O)C=NC=2NC(=O)C1.[CH3:41][NH:42][CH2:43][C:44]1[S:48][C:47]2[CH:49]=[CH:50][CH:51]=[CH:52][C:46]=2[C:45]=1[CH3:53].CNCC1C=CC2C(=CC=CC=2)C=1CCC>>[ClH:1].[NH2:2][C:3]1[N:8]=[CH:7][C:6](/[CH:9]=[CH:10]/[C:11]([N:42]([CH3:41])[CH2:43][C:44]2[S:48][C:47]3[CH:49]=[CH:50][CH:51]=[CH:52][C:46]=3[C:45]=2[CH3:53])=[O:13])=[CH:5][C:4]=1[CH2:14][N:15]1[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]1
Reactant: CNCc1sc2ccccc2c1C
Reactant: CN1CCN(Cc2cc(/C=C/C(=O)O)cnc2N)CC1
Agent: CCCc1c(CNC)ccc2ccccc12
Agent: CN1CC(=O)Nc2ncc(/C=C/C(=O)O)cc2C1
Agent: Cl
Product: Cc1c(CN(C)C(=O)/C=C/c2cnc(N)c(CN3CCN(C)CC3)c2)sc2ccccc12
Yield: 46 %

Procedure:
According to the procedure of Example 1, except substituting (E)-3-[6-amino-5-(4-methyl-piperazin-1-ylmethyl)pyridin-3-yl]acrylic acid hydrochloride for the (E)-3-(4-methyl-2-oxo-2,3,4,5-tetrahydro-1H-pyrido[2,3-e][1,4]diazepin-7-yl)acrylic acid hydrochloride, and substituting methyl-(3-methyl-benzo[b]thiophen-2-ylmethyl)amine for the methyl-(1-propyl-naphthalen-2-ylmethyl)amine, the title compound (101 mg, 46%) was prepared as a light, yellow powder and as a mixture of amide rotamers: 1H NMR (300 MHz, DMSO-d6) δ 10.6 (br s, 1H), 8.27 (s, 1H), 8.16 (s, 1H), 7.87 (d, J=7.6 Hz, 1H), 7.73 (d, J=7.1 Hz, 1H), 7.52-7.28 (m, 5H), 7.11 (d, J=15.3 Hz, 1H), 5.11-4.89 (m, 2H), 3.55 (br s, 2H), 3.37-3.23 (m, 4H), 3.14 (s, 2H), 3.10-2.92 (m, 5H), 2.72 (s, 3H), 2.42 (s, 3H);
Reaction SMILES: C(#N)C.C(Cl)(=O)C(Cl)=O.[F:10][C:11]1[C:19]([O:20][CH3:21])=[CH:18][CH:17]=[C:16]([F:22])[C:12]=1[C:13]([NH2:15])=O.C(N(CC)CC)C>CN(C=O)C>[F:10][C:11]1[C:19]([O:20][CH3:21])=[CH:18][CH:17]=[C:16]([F:22])[C:12]=1[C:13]#[N:15]
Reactant: COc1ccc(F)c(C(N)=O)c1F
Agent: O=C(Cl)C(=O)Cl
Solvent: CC#N
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1ccc(F)c(C#N)c1F
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 65.7 %

Procedure:
To an ice cold solution of DMF (0.45 ml) and acetonitrile (10 ml) was added oxalyl chloride (0.41 g, 0.28 ml, 3.20 mmol) dropwise while maintaining the temperature to 0° C. The reaction mixture was stirred at 0° C. for 40 min followed by addition of a solution of 2,6-difluoro-3-methoxybenzamide (0.50 g, 2.70 mmol) in DMF (4.5 ml).The resulting reaction mixture was stirred at 0° C. 40 min and then allowed to come to room temperature. After completion of reaction (10 min, TLC monitoring), triethyl amine (0.57 g, 0.80 ml, 5.67 mmol) was added dropwise. The reaction mass was concentrated in vacuo followed by addition of water (100 ml) and extraction with ethyl acetate (3×100 ml). The combined organics was washed with water, brine, dried (Na2SO4), filtered and concentrated. The crude residue was purified over silica gel (60-120 M, 10% EtOAc-Hexane) to get the desired product (0.30 g, 66%) as a white solid.
Reaction SMILES: CC1(C)[O:6][C:5](=O)[C@H:4]([C@@H:8]([C:13]([N:15]2[CH2:20][CH2:19][N:18]([C:21]3[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[CH:23][N:22]=3)[CH2:17][C@H:16]2[CH3:31])=[O:14])[CH2:9][CH:10]([CH3:12])[CH3:11])[O:3]1.[NH2:33][OH:34]>CO.CO.C(#N)C>[OH:34][NH:33][C:5](=[O:6])[C@@H:4]([OH:3])[C@@H:8]([C:13]([N:15]1[CH2:20][CH2:19][N:18]([C:21]2[CH:26]=[C:25]([C:27]([F:28])([F:30])[F:29])[CH:24]=[CH:23][N:22]=2)[CH2:17][C@H:16]1[CH3:31])=[O:14])[CH2:9][CH:10]([CH3:11])[CH3:12]
Reactant: NO
Reactant: CC(C)C[C@H](C(=O)N1CCN(c2cc(C(F)(F)F)ccn2)C[C@H]1C)[C@@H]1OC(C)(C)OC1=O
Solvent: CC#N
Solvent: CO
Product: CC(C)C[C@H](C(=O)N1CCN(c2cc(C(F)(F)F)ccn2)C[C@H]1C)[C@H](O)C(=O)NO
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 29.8 %

Procedure:
To a solution of (5S)-2,2-dimethyl-5-[(1S)-3-methyl-1-({(2R)-2-methyl-4-[4-(trifluoro methyl)pyridin-2-yl]piperazin-1-yl}carbonyl)butyl]-1,3-dioxolan-4-one (142 mg; 0.31 mmol; 1.0 eq.) in MeOH (5.0 mL) was added an aqueous solution of hydroxylamine (50%; 0.046 mL; 1.55 mmol; 5.0 eq.) and the resulting reaction mixture was stirred at RT for 4.5 h. Evaporation of the solvents gave an oil. This residue was taken up in MeOH/ACN (2 mL/1 mL) and purified by reverse-phase chromatography to give the title product (3) as a white powder (40 mg; 29.8%) as a single diastereoisomer. M−(ESI): 431.0; M+(ESI): 433.6. HPLC (condition C): Rt: 10.8 min (HPLC purity: 98.7%).
Reaction SMILES: C(N1C2C(=CC=CC=2)C(CC(O)=O)=C1)(=O)N.C([O:19][C:20](=[O:35])[CH2:21][C:22]1[C:30]2[C:25](=[CH:26][CH:27]=[C:28]([F:31])[CH:29]=2)[N:24]([C:32](=[O:34])[NH2:33])[CH:23]=1)C>>[C:32]([N:24]1[C:25]2[C:30](=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)[C:22]([CH2:21][C:20]([OH:35])=[O:19])=[CH:23]1)(=[O:34])[NH2:33]
Reactant: CCOC(=O)Cc1cn(C(N)=O)c2ccc(F)cc12
Agent: NC(=O)n1cc(CC(=O)O)c2ccccc21
Product: NC(=O)n1cc(CC(=O)O)c2cc(F)ccc21

Procedure:
was prepared in a similar manner as described in Scheme A8 Step B for (1-carbamoyl-1H-indol-3-yl)-acetic acid starting from (1-carbamoyl-5-fluoro-1H-indol-3-yl)-acetic acid ethyl ester. The crude product (yellowish solid) obtained after extractive work-up was used directly in the next step without purification. MS: 236.9 [M+H]+; tR (HPLC conditions b) 2.4 min.
Reaction SMILES: [NH2:1][C:2]1[C:14]([N:15]2[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]2)=[CH:13][C:5]2[N:6]=[C:7]([C:9]([CH3:12])([CH3:11])[CH3:10])[S:8][C:4]=2[CH:3]=1.C(=O)(O)[O-].[Na+].[C:27](Cl)(Cl)=[S:28].[OH-].[Na+]>C(Cl)(Cl)Cl.O>[C:9]([C:7]1[S:8][C:4]2[CH:3]=[C:2]([N:1]=[C:27]=[S:28])[C:14]([N:15]3[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]3)=[CH:13][C:5]=2[N:6]=1)([CH3:12])([CH3:11])[CH3:10]
Reactant: CN1CCN(c2cc3nc(C(C)(C)C)sc3cc2N)CC1
Reactant: S=C(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClC(Cl)Cl
Product: CN1CCN(c2cc3nc(C(C)(C)C)sc3cc2N=C=S)CC1
Reaction time: 4 h

Procedure:
To a stirred mixture of 75 g of 6-Amino-2-tert-butyl-5-(4-methylpiperazin-1-yl)benzothiazole and 29 g of sodium bicarbonate in 1100 ml of chloroform at 0° is added 41 g of thiophosgene and the mixture stirred at 10° for 4 hours. After filtering off the solid, the solution is evaporated to get a yellow solid which is dissolved in water and the pH of the solution is brought to 7 by the addition of dilute sodium hydroxide. The solid separated is extracted with hexane and filtered through 150 g of neutral alumina to give 2-tert-butyl-6-isothiocyanato-5-(4-methyl-piperazin-1-yl)benzothiazole, melting at 124°-126°.
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]2[CH2:7][CH2:8][CH2:9][CH2:10][C:4]=2[C:3]=1[C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[F:19])=O.[C:20]([O:27][CH3:28])(=[O:26])[CH2:21][CH2:22][C:23]([CH3:25])=O.Cl[Si](C)(C)C>CN(C=O)C>[CH3:28][O:27][C:20](=[O:26])[CH2:21][C:22]1[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[F:19])=[C:3]2[C:4]3[CH2:10][CH2:9][CH2:8][CH2:7][C:5]=3[S:6][C:2]2=[N:1][C:23]=1[CH3:25]
Reactant: Nc1sc2c(c1C(=O)c1ccccc1F)CCCC2
Reactant: COC(=O)CCC(C)=O
Agent: C[Si](C)(C)Cl
Solvent: CN(C)C=O
Product: COC(=O)Cc1c(C)nc2sc3c(c2c1-c1ccccc1F)CCCC3
Yield: 86.6 %

Procedure:
This compound was prepared according to the procedure B from (2-amino-4,5,6,7-tetrahydrobenzo[b]thiophen-3-yl)(2-fluorophenyl)methanone (0.275 g; 1 mmol), methyl levulinate (0.141 mL; 1.1 mmol), chlorotrimethylsilane (0.511 mL; 4 mmol) in DMF (4 mL) for 48 h. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (5-50%) in heptane furnished 0.320 g (86%) of the title compound as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:16])[CH2:9][C:10](=[O:15])[C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:4][CH:3]=1.CO[CH:19](OC)[N:20]([CH3:22])[CH3:21]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](=[O:16])[C:9](=[CH:19][N:20]([CH3:22])[CH3:21])[C:10](=[O:15])[C:11]([CH3:12])([CH3:13])[CH3:14])=[CH:6][CH:7]=1
Reactant: COC(OC)N(C)C
Reactant: CC(C)(C)C(=O)CC(=O)c1ccc(Cl)cc1
Solvent: Cc1ccccc1
Product: CN(C)C=C(C(=O)c1ccc(Cl)cc1)C(=O)C(C)(C)C
Yield: 65.5 %

Procedure:
17 g of 1-(4-chlorophenyl)-4,4-dimethyl-1,3-pentanedione and 18 g of dimethylformamide dimethylacetal were added to 200 ml of dry toluene, and the mixture was refluxed under heating for 2 hours, and then the methanol was distilled off over 1 hour. The solvent was distilled off, and the residue was purified by silica gel chromatography (developing solvent: chloroform/hexane=6/4) to obtain 13.7 g of the desired product as a pale yellow solid.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][C@@H:6]([OH:8])[C@H:5]([C:9]([CH3:11])=[CH2:10])[CH2:4][CH2:3]1.[H][H]>>[CH3:1][C@H:2]1[CH2:7][C@@H:6]([OH:8])[C@H:5]([CH:9]([CH3:11])[CH3:10])[CH2:4][CH2:3]1
Reactant: [H][H]
Reactant: C=C(C)[C@@H]1CC[C@@H](C)C[C@H]1O
Product: CC(C)[C@@H]1CC[C@@H](C)C[C@H]1O
Temperature: 80 °C

Procedure:
Example 1 was repeated using L-isopulegol with a purity of 99.9% by weight and 99.8% ee, which was introduced at a rate of 12.6 g/h (total amount 303 g) into the reactor at a hydrogen pressure of 40 bar. The main reactor (MR) was heated to 80° C., the postreactor to 75° C. L-menthol (99.8% ee) was obtained in an amount of 306 g corresponding to a rate of 12.8 g/h. The chemical purity of the L-menthol output is compiled in Table 2.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH:4]1[CH2:8][CH2:7][CH2:6][N:5]1[CH3:9].C1(C)C=CC=CC=1.C([O:19][C:20](=O)[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])C.[OH-].[Na+]>C(OCC)(=O)C.O>[CH3:9][N:5]1[CH2:6][CH2:7][CH2:8][CH:4]1[CH2:3][CH2:2][NH:1][C:20](=[O:19])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: CCCCCCCC(=O)OCC
Reactant: CN1CCCC1CCN
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCOC(C)=O
Product: CCCCCCCC(=O)NCCC1CCCN1C
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 74.5 %

Procedure:
Toluene (1.0 ml), dried using MS 4A, was mixed with 1.48 ml of a n-hexane solution of 15% Me3Al. With the mixture being cooled in an ice-methanol bath, 0.25 ml (1.16 mmols) of 2-(2-aminoethyl)-1-methylpyrrolidine was added dropwise over about 2 minutes. After stirring for 20 minutes, the temperature was raised to room temperature, and 0.5 ml of a toluene solution of 0.2 g (1.16 mmols) of caprylic acid ethyl ester was added dropwise over 1 minute. After stirring for 2 hours at 70° C., the mixture was cooled with ice, and 10 ml of 1N NaOH was added dropwise. The mixture was stirred for 10 minutes, and water and ethyl acetate were added. Then, the mixture was separated into respective layers, and the organic layer was washed twice with 20 ml of a saturated aqueous solution of sodium chloride. After this layer was dried over anhydrous magnesium sulfate, it was concentrated under reduced pressure on a 30° C. water bath to obtain the captioned compound (yield 0.22 g). This compound was subjected to silica gel column chromatography (mobile phase: CHCl3:MeOH (19:1→9:1)) for purification. NMR and mass spectrum confirmed the purified compound to have the following structure:
Reaction SMILES: [SH:1][CH2:2][CH2:3][C:4]([OH:6])=[O:5].O[CH:8]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][S:30][C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([C:37]([F:40])([F:39])[F:38])[CH:32]=1)[CH2:9][C:10]([O:12]C(C)(C)C)=[O:11]>FC(F)(F)C([O-])=O>[C:4]([CH2:3][CH2:2][S:1][CH:8]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][S:30][C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([C:37]([F:39])([F:38])[F:40])[CH:32]=1)[CH2:9][C:10]([OH:12])=[O:11])([OH:6])=[O:5]
Reactant: O=C(O)CCS
Reactant: CC(C)(C)OC(=O)CC(O)c1ccccc1CCCCCCCSc1cccc(C(F)(F)F)c1
Agent: O=C([O-])C(F)(F)F
Product: O=C(O)CCSC(CC(=O)O)c1ccccc1CCCCCCCSc1cccc(C(F)(F)F)c1
Reaction time: 1 h

Procedure:
To trifluoroacetate acid (20 ml), cooled to 0° C., was added 3-mercaptopropionic acid (0.26 ml, 3 mmoles) followed by t-butyl 3-hydroxy-3-[2-(7-(3-trifluoromethylphenylthio)heptyl)phenyl]propanoate. The reaction mixture was stirred for 1 hour and evaporated. The resulting residue was diluted with carbon tetrachloride and washed with ice water. The organic layer was dried over sodium sulfate, filtered and evaporated. The resulting oil was flash chromatographed to give the desired product, -log KB value 6.8.
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[Br:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[C:13](=[O:17])[N:12]([CH2:18][C:19]([CH3:30])([CH3:29])[CH2:20]O[Si](C(C)(C)C)(C)C)[CH:11]=[CH:10]2.CN([CH:34]=[O:35])C>>[Br:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[C:13](=[O:17])[N:12]([CH2:18][C:19]([CH3:29])([CH3:30])[CH2:20][Cl:3])[CH:11]=[C:10]2[CH:34]=[O:35]
Reactant: CC(C)(CO[Si](C)(C)C(C)(C)C)Cn1ccc2cc(Br)ccc2c1=O
Reactant: CN(C)C=O
Reactant: O=P(Cl)(Cl)Cl
Product: CC(C)(CCl)Cn1cc(C=O)c2cc(Br)ccc2c1=O
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Phosphorus oxychloride (104 mL) was added to an ice cooled solution of DMF (180 mL) over 1 h and the resulting mixture stirred at room temperature for 1.5 h before adding dropwise to a solution of 6-bromo-2-(3-{[tert-butyl(dimethyl)silyl]oxy}-2,2-dimethylpropyl)isoquinolin-1(2H)-one (Example 26b, 31.7 g) in DMF (70 mL) under nitrogen. The resulting solution was stirred at 85° C. for 20 h. The cooled reaction mixture was poured onto ice/water (2 L) and stirred for 1 h.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[C:3]=1[CH2:4][C:5]1[CH:12]=[CH:11][C:8]([CH2:9]Br)=[CH:7][CH:6]=1.[N-:18]=[N+:19]=[N-:20].[Na+].C([OH:24])C>>[Cl:1][C:2]1[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[C:3]=1[C:4]([C:5]1[CH:12]=[CH:11][C:8]([CH2:9][N:18]=[N+:19]=[N-:20])=[CH:7][CH:6]=1)=[O:24]
Reactant: Clc1cccc(Cl)c1Cc1ccc(CBr)cc1
Reactant: CCO
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Product: [N-]=[N+]=NCc1ccc(C(=O)c2c(Cl)cccc2Cl)cc1
Yield: 98 %

Procedure:
A mixture of 4-(2,6-dichlorobenzyl)benzyl bromide (7.49 g, 21.8 mmol) and sodium azide (4.19 g, 64.5 mmol) in absolute ethanol (100 ml) was refluxed 5 hours, cooled, and evaporated under vacuum. The residue was triturated wit diethyl ether (100 ml), filtered, and evaporated under vacuum to provide 6.5 g (98%) 4-(2,6-dichlorobenzoyl)benzyl azide, m.p. 92°-94° C.
Reaction SMILES: [O:1]([CH2:8][C@H:9]([OH:12])[CH2:10][OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)(O)[O-:14].[Na+]>C(O)(=O)C.O.[Pt]=O>[OH:12][C@@H:9]([CH2:8][O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:10]([OH:14])=[O:11]
Reactant: O=C([O-])O
Reactant: OC[C@@H](O)COc1ccccc1
Agent: O=[Pt]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: O=C(O)[C@@H](O)COc1ccccc1
Yield: 83 %

Procedure:
Platinum oxide (1.0 g) in acetic acid (20 ml) was hydrogenated at 1 atmosphere for 1.5 h. The platinum was filtered off, washed with water and added to a solution of (R)-3-phenoxy-1,2-propanediol (1.0 g, 6 mmol) and sodium bicarbonate (0.5 g) in water (120 ml). Air was blown through the vigorously stirred mixture overnight. The mixture was filtered, the aqueous solution acidified with hydrochloric acid and extracted with ethyl acetate. The organic extracts were dried (Na2SO4) and the solvent evaporated to give the sub-title acid (0.9 g).
Reaction SMILES: [CH2:1]([O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][O:10][C:11]1[CH:20]=[CH:19][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][CH:12]=1)[CH:2]=C.OCCOCC[O:27][C:28]1C=CC(C([O-])=O)=[CH:30][CH:29]=1.[H-].[Na+].[H][H].C(Br)C=C>O1CCCC1.O>[CH2:28]([O:27][CH2:2][CH2:1][O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][O:10][C:11]1[CH:20]=[CH:19][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][CH:12]=1)[CH:29]=[CH2:30]
Reactant: O=C([O-])c1ccc(OCCOCCO)cc1
Reactant: C=CCOCCOCCOc1ccc(C(=O)OC)cc1
Reactant: [H][H]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: C=CCBr
Product: C=CCOCCOCCOCCOc1ccc(C(=O)OC)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
These compounds were synthesized by similar methods. The representative synthesis of methyl 4-(2-(2-allyloxy-ethoxy)ethoxy)benzoate (7) is presented. The obtained methyl 4-(2-(2-hydroxyethoxy) ethoxy) benzoate (3) 8.4 grams (0.035 mole) was added to a suspension of 3.15 grams (0.105 mole) sodium hydride in 100 ml dried tetrahydrofuran at 4° C. After the hydrogen was completely released, allyl bromide 3.94 ml (0.0456 mole) was added dropwise to the reaction mixture and then stirred at room temperature overnight. The excess sodium hydride was treated with distilled water and extracted with ethyl acetate. The organic phase was washed with 10% aqueous hydrochloric acid solution, dried over anhydrous MgSO4, and the solvent evaporated on a rotary evaporator. The yellow oil product was purified by flash chromatography on silica gel with 4% diethyl ether in dischloromethane. Yield 8.39 grams (86%). 1H-NMR (CDCl3, TMS): d=3.81-4.25 (m, 10H, --CH2 --(OCH2CH2)2 --), 3.85 (s, 3H, --COOCH3), 5.23 and 5.9 (m, 3H, CH=CH--), 6.95 and 8.05 (2d, 4 aromatic protons).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][CH2:10][CH2:11]Br)=[CH:4][CH:3]=1.Cl.[F:14][C:15]1([F:21])[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][CH2:10][CH2:11][N:18]2[CH2:19][CH2:20][C:15]([F:21])([F:14])[CH2:16][CH2:17]2)=[CH:4][CH:3]=1
Reactant: FC1(F)CCNCC1
Reactant: BrCCCOc1ccc(Br)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: FC1(F)CCN(CCCOc2ccc(Br)cc2)CC1
Temperature: 60 °C
Yield: 50.9 %

Procedure:
A suspension of 1-bromo-4-(3-bromopropoxy)benzene (1.85 g, 6.29 mmol), 4,4-difluoropiperidine hydrochloride (1.0 g, 6.34 mmol) and potassium carbonate (2.17 g, 15.7 mmol) in acetonitrile (100 mL) was heated to 60° C. overnight, then concentrated in vacuo. The residue was partitioned between ether and saturated aqueous sodium bicarbonate. The layers were separated; the organic layer was washed with saturated aqueous sodium bicarbonate, water and brine. The organic layer was dried (Na2SO4), filtered and concentrated. Purification by flash column chromatography on an analogix SF40-80g column (hexanes/ethyl acetate=7:3) afforded the title compound as a clear oil (1.07 g, 50%). LCMS m/z 334.3 (M+1). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.90-2.08 (m, 6 H) 2.47-2.64 (m, 6 H) 3.99 (t, J=6.34 Hz, 2 H) 6.75-6.81 (m, 2 H) 7.34-7.40 (m, 2 H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]2[N:5]([N:9]=[C:10]([C:12]3([CH2:15][NH2:16])[CH2:14][CH2:13]3)[N:11]=2)[CH:6]=[CH:7][CH:8]=1.CCN(CC)CC.[N:24]1([C:29](Cl)=[O:30])[CH2:28][CH2:27][CH2:26][CH2:25]1.C([O-])(O)=O.[Na+]>C1COCC1.O>[CH3:1][O:2][C:3]1[C:4]2[N:5]([N:9]=[C:10]([C:12]3([CH2:15][NH:16][C:29]([N:24]4[CH2:28][CH2:27][CH2:26][CH2:25]4)=[O:30])[CH2:14][CH2:13]3)[N:11]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: O=C(Cl)N1CCCC1
Reactant: COc1cccn2nc(C3(CN)CC3)nc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: COc1cccn2nc(C3(CNC(=O)N4CCCC4)CC3)nc12
Reaction time: 24 h

Procedure:
Under an argon atmosphere C-[1-(8-Methoxy-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-cyclopropyl]-methylamine (0.050 g, 0.23 mmol) was dissolved in THF (1 mL) and Et3N (0.048 mL, 0.35 mmol). 1-Pyrrolidinecarbonyl chloride (0.032 mL, 0.29 mmol) was added. Stirring was performed at RT for 24 h. Aq. NaHCO3 and H2O were added. The aqueous phase was extracted with DCM (×3). The combined organic phases were dried over Na2SO4, filtered and concentrated in vacuo to afford Pyrrolidine-1-carboxylic acid [1-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-cyclopropylmethyl]-amide as a crude product.
Reaction SMILES: [C:1](Cl)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[CH3:8][C:9]1[CH:10]=[C:11]([CH:17]2[C:21]3[CH:22]=[C:23]([C:30]([CH3:33])([CH3:32])[CH3:31])[CH:24]=[C:25]([C:26]([CH3:29])([CH3:28])[CH3:27])[C:20]=3[O:19][C:18]2=[O:34])[CH:12]=[C:13]([CH3:16])[C:14]=1[OH:15].CS(O)(=O)=O>C1(C)C(C)=CC=CC=1>[CH3:8][C:9]1[CH:10]=[C:11]([CH:17]2[C:21]3[CH:22]=[C:23]([C:30]([CH3:33])([CH3:32])[CH3:31])[CH:24]=[C:25]([C:26]([CH3:27])([CH3:28])[CH3:29])[C:20]=3[O:19][C:18]2=[O:34])[CH:12]=[C:13]([CH3:16])[C:14]=1[O:15][C:1](=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3]
Reactant: CC(C)(C)C(=O)Cl
Reactant: Cc1cc(C2C(=O)Oc3c2cc(C(C)(C)C)cc3C(C)(C)C)cc(C)c1O
Agent: CS(=O)(=O)O
Solvent: Cc1ccccc1C
Product: Cc1cc(C2C(=O)Oc3c2cc(C(C)(C)C)cc3C(C)(C)C)cc(C)c1OC(=O)C(C)(C)C
Yield: 92.3 %

Procedure:
180.1 g (1.49 mol) of pivaloyl chloride are added dropwise over a period of 25 minutes to a suspension of 274.5 g (0.75 mol) of 3-(3,5-dimethyl-4-hydroxyphenyl)-5,7-di-tert-butylbenzofuran-2-one, (compound (107), Table 1, Example 2) in 600 ml of xylene and 7.5 ml (115.7 mmol) of methanesulfonic acid which is stirred at 95° C. under a nitrogen atmosphere. The clear, homogeneous reaction mixture is then refluxed for another 2.5 hours and then concentrated under a slight vacuum. 50 ml of 1-butanol and 600 ml of methanol are carefully poured into the liquid, hot residue at about 170° C. through the condenser and the mixture is cooled with ice/water. The precipitated product is filtered and washed with 350 ml of cold methanol. Drying gives 311.9 g (92%) of 3-(3,5-dimethyl-4-pivaloyloxyphenyl)-5,7-di-tert-butylbenzofuran-2-one, melting point 140°-142° C. (compound (110 ), Table 1).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8].[C:10]([O:14][CH2:15][CH:16](O)[CH3:17])(=[O:13])[CH:11]=[CH2:12].C(Cl)CCl>C(Cl)Cl>[C:10]([O:14][CH2:15][CH:16]([O:8][C:7](=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][Br:1])[CH3:17])(=[O:13])[CH:11]=[CH2:12]
Reactant: O=C(O)CCCCCBr
Reactant: C=CC(=O)OCC(C)O
Solvent: ClCCCl
Solvent: ClCCl
Product: C=CC(=O)OCC(C)OC(=O)CCCCCBr
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a 0° C. cooled mixture of 6-bromohexanoic acid (9.89 g), 2-hydroxypropyl acrylate (6 g), in CH2Cl2 (30 ml), EDC (7.89 g) was added. After being stirred for 30 min the reaction mixture was diluted with additional 20 ml of CH2Cl2 and stirring was continued for 16 h at room temperature. It was then filtered over celite and the filtrate was evaporated to dryness. The obtained beige-yellow residue was purified by silica column chromatography to give nearly pure material as transparent oil.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[C:9]([I:10])=[CH:8][N:7]=[C:6]2[NH:11][CH:12]=[CH:13][C:5]=12.[C:14]1([S:20](Cl)(=[O:22])=[O:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.O>CN(C)C=O>[Cl:3][C:4]1[C:9]([I:10])=[CH:8][N:7]=[C:6]2[N:11]([S:20]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)(=[O:22])=[O:21])[CH:12]=[CH:13][C:5]=12
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Clc1c(I)cnc2[nH]ccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=S(=O)(c1ccccc1)n1ccc2c(Cl)c(I)cnc21
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 97.9 %

Procedure:
NaH (0.960 g, 24.0 mmol, 60% dispersion in mineral oil) at 0° C. was added to 4-chloro-5-iodo-1H-pyrrolo[2,3-b]pyridine (5.57 g, 20.0 mmol) in dimethylformamide (“DMF”; 40 mL) and stirred at 0° C. for 20 minutes. Benzenesulfonyl chloride (2.82 mL, 22.0 mmol) was added, and the reaction was stirred at room temperature for 2 hours. Water (200 mL) was added and stirred for 10 minutes. The solid formed was collected by filtration, washed with ether, and dried to give 4-chloro-5-iodo-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine (8.20 g, 98% yield).