Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][CH2:11][OH:12])[CH:6]=[CH:7][CH:8]=1.CCN(CC)CC.[CH3:22][S:23](Cl)(=[O:25])=[O:24]>>[F:1][C:2]([F:13])([F:14])[C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][CH2:11][O:12][S:23]([CH3:22])(=[O:25])=[O:24])[CH:6]=[CH:7][CH:8]=1
Reactant: OCCCc1cccc(C(F)(F)F)c1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCCc1cccc(C(F)(F)F)c1

Procedure:
In a manner analogous to the preparation of Example 83(a), 3-(3-trifluoromethyl-phenyl)-propan-1-ol (0.94 g, 4.61 mmol), Et3N (1.28 mL, 9.22 mmol) and MsCl (0.44 mL, 5.53 mmol) gave the desired compound as a light brown oil. 1H NMR (300 MHz, CDCl3) δ 2.10-2.16 (m, 2H), 2.82-2.86 (t, 2H) 3.02 (s, 3H), 4.24-4.28 (t, 2H), 7.38-7.52 (m, 4H).
Reaction SMILES: Br[CH:2]([C:4]1([C:12]2[CH:17]=[CH:16][C:15]([CH2:18][CH:19]([CH3:21])[CH3:20])=[CH:14][CH:13]=2)OCC(C)(C)CO1)C.[C:22]([O-:25])(=[O:24])C.[K+]>C(N)=O>[CH2:18]([C:15]1[CH:14]=[CH:13][C:12]([CH:4]([CH3:2])[C:22]([OH:25])=[O:24])=[CH:17][CH:16]=1)[CH:19]([CH3:20])[CH3:21]
Reactant: CC(C)Cc1ccc(C2(C(C)Br)OCC(C)(C)CO2)cc1
Reactant: CC(=O)[O-]
Agent: [K+]
Solvent: NC=O
Product: CC(C)Cc1ccc(C(C)C(=O)O)cc1
Temperature: 170 °C
Reaction time: 2.5 h
Yield: 25 %

Procedure:
A mixture of 2-(1-bromoethyl)-5,5-dimethyl-2-(4-isobutylphenyl)-1,3-dioxane (3.55 g; 10 mmol), potassium acetate (1.2 g; 12 mmol), formamide (50 ml) is heated at 170° C. under stirring for 2.5 h. The reaction mixture is worked up as described in Example 1a to give 2-(4-isobutylphenyl)-propionic acid (2.5 mmol; yield 25%), m.p. 74°-76° C.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[C:5]2[S:10][C:9]3[N:11]=[C:12]([C:16]4[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH3:25])[CH:17]=4)[CH:13]=[C:14]([CH3:15])[C:8]=3[C:6]=2[N:7]=1.[CH3:32][CH2:33][O-:34].[K+]>O1CCOCC1>[CH2:33]([O:34][C:2]1[N:3]=[C:4]([N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[C:5]2[S:10][C:9]3[N:11]=[C:12]([C:16]4[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH3:25])[CH:17]=4)[CH:13]=[C:14]([CH3:15])[C:8]=3[C:6]=2[N:7]=1)[CH3:32]
Reactant: COc1ccc(-c2cc(C)c3c(n2)sc2c(N4CCNCC4)nc(Cl)nc23)cc1OC
Reactant: CC[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: CCOc1nc(N2CCNCC2)c2sc3nc(-c4ccc(OC)c(OC)c4)cc(C)c3c2n1

Procedure:
0.1 g (0.22 mmol) 2-chloro-7-(3,4-dimethoxyphenyl)-9-methyl-4-piperazin-1-yl-pyrido-[3′,2′:4,5]thieno[3,2-d]pyrimidine and 0.22 ml (0.44 mmol) potassium ethylate (2M THF) are refluxed in 10 ml absolute dioxane for 3 h. Then, the solvent is removed and the residue is suspended in some water. The aqueous suspension is extracted with dichloromethane, the organic phase is dried on sodium sulfate and the solvent is removed. 50 mg (49%) of the title substance is obtained.
Reaction SMILES: [CH:1](/[P:4](=[O:11])([O:8][CH2:9][CH3:10])[O:5][CH2:6][CH3:7])=[CH:2]\[CH3:3].[Br:12]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:12][CH2:3]/[CH:2]=[CH:1]/[P:4](=[O:11])([O:5][CH2:6][CH3:7])[O:8][CH2:9][CH3:10]
Reactant: O=C1CCC(=O)N1Br
Reactant: C/C=C/P(=O)(OCC)OCC
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCOP(=O)(/C=C/CBr)OCC
Reaction time: 0.5 h
Yield: 58.5 %

Procedure:
To a solution of diethyl trans-1-propenylphosphonate (32.04 g.) in carbon tetrachloride (320 ml.) were added N-bromosuccinimide (41.65 g.) and dibenzoylperoxide (2.8 g.). The reaction mixture was heated to reflux for 1.5 hours and stirred for 30 minutes under ice-cooling. Insoluble materials were removed off by filtration and the filtrate was concentrated under reduced pressure to give an oily residue (63.09 g.), which was subjected to a column chromatography on silicagel and eluted with chloroform. The eluates were evaporated to dryness under reduced pressure to give an oily diethyl 3-bromo-trans-1-propenylphosphonate (27.04 g.).
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[C@@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1[S:12]([CH:15]=[CH2:16])(=[O:14])=[O:13])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[S:25]1C=CC=C1CC(O)=O.[CH3:34][CH2:35][O:36]CC>>[C:1]([O:5][C:6](=[O:17])[C@@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1[S:12]([CH2:15][CH2:16][S:25][C:35](=[O:36])[CH3:34])(=[O:13])=[O:14])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOCC
Reactant: C=CS(=O)(=O)N1CCC[C@H]1C(=O)OC(C)(C)C
Reactant: O=C(O)Cc1cccs1
Solvent: CCN(CC)CC
Product: CC(=O)SCCS(=O)(=O)N1CCC[C@H]1C(=O)OC(C)(C)C
Reaction time: 8 h

Procedure:
N-(Vinylsulfonyl)-L-proline t-butyl ester (5.0 g., 0.0192 mol.), triethylamine (2.8 ml., 0.02 mol.) and thiolacetic acid (1.43 ml., 0.02 mol.) are mixed in 100 ml. of ether and allowed to stand overnight. The mixture is washed with 5% potassium bisulfate solution, saturated sodium bicarbonate solution and brine, then evaporated in vacuo to a yellow oil. The procedure is repeated using half of the above quantities of triethylamine and thiolacetic acid. Workup as in part (a) affords the crude product, N-[[2-(acetylthio)ethyl]sulfonyl]-L-proline t-butyl ester, which is filtered through a short silica gel column and crystallized from ether/hexane, m.p. 46°-50° (2.9 g., 45%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[O:23][C:17]3=[CH:18][N:19]=[C:20](Cl)[CH:21]=[C:16]3[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:24][S:25]([CH2:28][C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1)(=[O:27])=[O:26]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[O:23][C:17]3=[CH:18][N:19]=[C:20]([C:32]4[CH:31]=[CH:30][C:29]([CH2:28][S:25]([CH3:24])(=[O:27])=[O:26])=[CH:34][CH:33]=4)[CH:21]=[C:16]3[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CS(=O)(=O)Cc1ccc(B(O)O)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(c2cc3cc(Cl)ncc3o2)CC1
Product: CC(C)(C)OC(=O)N1CCC(c2cc3cc(-c4ccc(CS(C)(=O)=O)cc4)ncc3o2)CC1

Procedure:
The title compound is prepared from 4-(5-chloro-furo[2,3-c]pyridin-2-yl)-piperidine-1-carboxylic acid tert-butyl ester and 4-methylsulfonylmethyl-phenylboronic acid following a procedure analogous to that described for Example 1; the reaction is conducted at 150° C. LC (method 1): tR=1.26 min; Mass spectrum (ESI+): m/z=471 [M+H]+.
Reaction SMILES: F[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8]C)=[O:7])=[CH:4][C:3]=1[O:12][CH3:13].[Br:14][C:15]1[N:16]=[CH:17][NH:18][CH:19]=1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C=O)C.O>[Br:14][C:15]1[N:16]=[CH:17][N:18]([C:2]2[CH:11]=[CH:10][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=2[O:12][CH3:13])[CH:19]=1
Reactant: Brc1c[nH]cn1
Reactant: COC(=O)c1ccc(F)c(OC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(C(=O)O)ccc1-n1cnc(Br)c1
Temperature: 100 °C
Reaction time: 8 h
Yield: 55.9 %

Procedure:
A mixture of methyl 4-fluoro-3-methoxybenzoate (2.13 g), 4-bromo-1H-imidazole (3.74 g) and potassium carbonate (4.80 g) in DMF (20 mL) was stirred at 100° C. overnight, and allowed to cool to room temperature, and ethyl acetate and water were added. The aqueous layer was separated, and acidified with 6N hydrochloric acid (pH=3-4), and the resultant precipitate was collected by filtration to give the title compound (1.92 g).
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14]([C@@H:16]([CH2:21][CH:22]=[CH2:23])[CH2:17][C:18]([OH:20])=O)=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[Cl:47][C:48]1[CH:55]=[CH:54][C:51]([CH2:52][NH2:53])=[CH:50][CH:49]=1>ClCCl.CN(C1C=CN=CC=1)C>[CH2:1]([C@@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14]([C@@H:16]([CH2:21][CH:22]=[CH2:23])[CH2:17][C:18]([NH:53][CH2:52][C:51]1[CH:54]=[CH:55][C:48]([Cl:47])=[CH:49][CH:50]=1)=[O:20])=[O:15])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NCc1ccc(Cl)cc1
Reactant: C=CC[C@@H](CC(=O)O)C(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Agent: CN(C)c1ccncc1
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: ClCCCl
Product: C=CC[C@@H](CC(=O)NCc1ccc(Cl)cc1)C(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Yield: 77.3 %

Procedure:
A solution of compound 3a (0.402 g, 1.3 mmol), EDC (0.364 g, 1.9 mmol), HOBT (0.256 g, 1.9 mmol), and Hunig's base (0.662 mL, 3.8 mmol) in dichloromethane (17 mL) was cooled to 0° C. and stirred for half an hour. To this solution 4-chlorobenzylamine (0.174 mL, 1.43 mmol) and a catalytic amount of DMAP were added. The reaction was stirred overnight and the reaction progress was monitored by TLC. The dichloromethane was removed in vacuo and the reaction mixture quenched with aqueous NH4Cl. The solution was washed with water and brine, dried over Na2SO4, and concentrated under reduced pressure to give well formed white crystals of 4a (0.443 g, 79%). 1H NMR (500 MHz, CDCl3): δ ppm 7.31-7.36 (m, 2H) 7.21-7.29 (m, 5H) 7.17-7.21 (m, 2H) 6.09 (t, J=5.6 Hz, 1H) 5.73-5.82 (m, 1H) 5.04-5.10 (m, 2H) 4.65 (ddd, J=13.3, 6.7, 3.4 Hz 1H) 4.41 (dd, J=15.2, 5.9 Hz, 1H) 4.34 (dd, J=14.9, 5.9 Hz, 1H) 4.23-4.30 (m, 1H) 4.23-4.30 (m, 1H) 4.14-4.18 (m, 2H) 3.28 (dd, J=13.7, 2.9 Hz, 1H) 2.66-2.80 (m, 2H) 2.41-2.51 (m, 2H) 2.22-2.29 (m, 1H); 13C NMR (126 MHz, CDCl3): δ 175.1, 171.0, 153.4, 137.1, 135.7, 134.8, 133.4, 129.7, 129.3, 129.1, 129.0, 127.5, 118.1, 66.3, 55.7, 43.1, 40.1, 38.0, 37.8, 36.3. HRMS calcd. for C24H25ClN2O4 (M+H) m/z 441.1581, found 441.1581.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([O:10][CH3:11])[CH:3]=1.[H-].[Na+].Br[CH2:15][CH2:16][OH:17]>CN(C=O)C.O>[OH:17][CH2:16][CH2:15][O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([O:10][CH3:11])[CH:3]=1
Reactant: COc1cc(O)ccc1C=O
Reactant: OCCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(OCCO)ccc1C=O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of 4-hydroxy-2-methoxybenzaldehyde (1.217 g, 8.00 mmol) in dry DMF (8.88 mL) was added to a stirred suspension of sodium hydride (60% dispersion in mineral oil) (0.267 mL, 8.00 mmol) in dry DMF (2.22 mL) via cannula at 0° C. under N2. The reaction mixture was stirred at 0° C. for 30 min and warmed to room temperature. 2-bromoethanol (0.851 mL, 12.00 mmol) was added dropwise and the reaction mixture was stirred at 50° C. overnight. The reaction was diluted with water (50 mL) and extracted with EtOAc (3×50 mL). The combined extracts were washed with 1N aq. NaOH (50 mL), dried (MgSO4) and concentrated in vacuo to afford the crude product. This was purified by flash chromatography (Biotage Horizon, 40M, Si, ˜30 mL/min, 100% hexanes for 360 mL, gradient to 60% EtOAc in hexanes over 4536 mL) to afford 4-(2-hydroxyethoxy)-2-methoxybenzaidehyde, as a colorless solid. Rf=0.29 (50% EtOAc/hexanes). LCMS calc.=197.1; found=197.0 (M+H)+. 1H NMR (500 MHz, CHCl3): δ 10.16 (s, 1 H); 7.68 (d, J=8.7 Hz, 1 H); 6.46 (dd, J=8.7, 2.2 Hz, 1 H); 6.40 (d, J=2.2 Hz, 1 H); 4.09 (t, J=4,6 Hz, 2 H); 3.94 (t, J=4.4 Hz, 2 H); 3.79 (s, 3 H); 3.20 (s, 1 H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]2[N:16]=[N:17][C:18]([S:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)(=[O:21])=[O:20])=[C:4]2[N:3]=1.[CH2:28]([NH:30][CH2:31][CH3:32])[CH3:29]>CN(C=O)C>[CH2:28]([N:30]([CH2:31][CH3:32])[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]2[N:16]=[N:17][C:18]([S:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)(=[O:21])=[O:20])=[C:4]2[N:3]=1)[CH3:29]
Reactant: COc1cc2c(Cl)nc3c(S(=O)(=O)c4ccccc4)nnn3c2cc1OC
Reactant: CCNCC
Solvent: CN(C)C=O
Product: CCN(CC)c1nc2c(S(=O)(=O)c3ccccc3)nnn2c2cc(OC)c(OC)cc12
Temperature: 40 °C
Yield: 80.4 %

Procedure:
A mixture of 5-chloro-7,8-dimethoxy-3-(phenylsulfonyl)-[1,2,3]triazolo[1,5-a]quinazoline (25 mg, 0.062 mmol) and diethylamine (32 uL, 0.31 mmol) in DMF (2 mL) was heated at 40° C. for 1.5 hrs. After removal of the solvent, the residue was purified by column chromatography on silica gel eluting with 40% ethyl acetate in hexane to yield the desired product (22 mg, 82%). 1H NMR (CDCl3, 600 MHz) δ 8.23 (d, 2H, J=7.2 Hz), 7.93 (s, 1H), 7.55-7.52 (m, 1H), 7.49-7.57 (m, 2H), 7.32 (s, 1H), 4.10 (s, 3H), 3.99 (s, 3H), 3.76 (q, 4H, J=7.2 Hz), 1.46 (t, 6H, J=7.2 Hz); MS (ES+) m/z 442.1 (M+H)+
Reaction SMILES: C1N2CN3[CH2:10][N:4](C2)CN1C3.[CH2:11]([O:18][C:19]1[CH:24]=[CH:23][C:22]([C:25](=[O:28])CBr)=[CH:21][CH:20]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.CCOCC.C(Cl)(Cl)[Cl:35]>>[ClH:35].[NH2:4][CH2:10][C:25]([C:22]1[CH:23]=[CH:24][C:19]([O:18][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:20][CH:21]=1)=[O:28]
Reactant: C1N2CN3CN1CN(C2)C3
Reactant: ClC(Cl)Cl
Reactant: O=C(CBr)c1ccc(OCc2ccccc2)cc1
Solvent: CCOCC
Product: Cl
Product: NCC(=O)c1ccc(OCc2ccccc2)cc1
Reaction time: 3 h

Procedure:
Hexamine (5.6 g; 40 mmol) was added to a solution of 1-(4-benzyloxy-phenyl)-2-bromo-ethanone (12.2 g; 40 mmol) in chloroform (80 ml), and stirred for 3 h. Dry ether (80 ml) was added and the solid that separated was filtered, washed with ether, dried then suspended in methanol (100 ml) and con. HCl (20 ml) and allowed to stir for 16 h. The reaction mixture was concentrated, and treated with water (20 ml). The solid obtained was filtered, washed with cold water (2×10 ml) and dried to obtain the title compound. Yield, 10 g (89.9%); mp, 228-29° C.; MS (EI): 241, 211, 91; analysis: C15H16ClNO2 requires: C, 64.87; H, 5.81; N, 5.04. found: C, 64.86; H, 6.11; N, 5.16%.
Reaction SMILES: Br[C:2]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:3]=1[O:4][CH2:5][C:6]([N:8]([CH:18]([CH3:20])[CH3:19])[NH:9][C:10](=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:7].C([O-])([O-])=O.[Na+].[Na+].[O:32]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1B(O)O)[CH:33]([CH3:35])[CH3:34]>COCCOC>[F:25][C:23]1[CH:22]=[CH:21][C:3]([O:4][CH2:5][C:6]([N:8]([CH:18]([CH3:20])[CH3:19])[NH:9][C:10](=[O:17])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:7])=[C:2]([C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][C:36]=2[O:32][CH:33]([CH3:35])[CH3:34])[CH:24]=1
Reactant: CC(C)Oc1ccccc1B(O)O
Reactant: CC(C)N(NC(=O)c1ccccc1)C(=O)COc1ccc(F)cc1Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CC(C)Oc1ccccc1-c1cc(F)ccc1OCC(=O)N(NC(=O)c1ccccc1)C(C)C
Yield: 38.8 %

Procedure:
A solution of benzoic acid N′-[2-(2-bromo-4-fluoro-phenoxy)-acetyl]-N′-isopropyl-hydrazide (50 mg, 0.122 mmol) in DME (3 ml)/2M Na2CO3 (0.215 ml, 0.427 mmol) was treated with 2-isopropoxylphenylboronic acid (32 mg, 0.183 mmol) and Pd[PPh3]4 (27 mg, 0.0244 mmol) for 12 hours at 90° C. The reaction mixture was partitioned between water and ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated. The crude was purified first on a silica gel column with 30% ethyl acetate/hexanes then by RP HPLC to afford the product as a white solid (22 mg, 38%). MS m/e 465.27 (M+H+)
Reaction SMILES: Cl.[CH:2]1([CH2:6][NH2:7])[CH2:5][CH2:4][CH2:3]1.[C:8](Cl)(Cl)=[O:9]>>[CH:2]1([CH2:6][NH:7][C:8]([NH:7][CH2:6][CH:2]2[CH2:5][CH2:4][CH2:3]2)=[O:9])[CH2:5][CH2:4][CH2:3]1
Reactant: NCC1CCC1
Reactant: O=C(Cl)Cl
Agent: Cl
Product: O=C(NCC1CCC1)NCC1CCC1
Yield: 37 %

Procedure:
In the manner of step (a) of Example 1, cyclobutanemethylamine hydrochloride (Buchman and Howton, J. Amer. Chem. Soc. 1948, 70:2517; 7.96 g, 80.5 mmol) was reacted with phosgene to give 1,3-bis(cyclobutylmethyl)urea as white powder (5.20 g, 37%), m.p. 153°-155° C.; 1H-NMR (DMSO-d6) consistent with structure.
Reaction SMILES: [CH3:1][N:2]1[C:6]([O:7][C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([OH:16])=O)[N:9]=2)=[CH:5][C:4]([CH3:17])=[N:3]1.C(N1C=CN=C1)(N1C=CN=C1)=O.[F:30][C:31]1[CH:32]=[C:33]([CH:35]=[CH:36][CH:37]=1)[NH2:34].O>O1CCCC1>[F:30][C:31]1[CH:32]=[C:33]([NH:34][C:14]([C:10]2[N:9]=[C:8]([O:7][C:6]3[N:2]([CH3:1])[N:3]=[C:4]([CH3:17])[CH:5]=3)[CH:13]=[CH:12][CH:11]=2)=[O:16])[CH:35]=[CH:36][CH:37]=1
Reactant: Cc1cc(Oc2cccc(C(=O)O)n2)n(C)n1
Reactant: Nc1cccc(F)c1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(Oc2cccc(C(=O)Nc3cccc(F)c3)n2)n(C)n1
Temperature: 40 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-(1',3'-dimethyl-pyrazol-5-yloxy)-pyridine-6-carboxylic acid (2.2 g, 9.6 mmol) (from Example 53) in anhydrous tetrahydrofuran (20 ml) was added carbonyldiimidazole (1.6 g, 10.6 mmol) and stirred for 30 minutes, maintaining the temperature up to 40° C. 3-fluoroaniline (1.1 ml, 10.6 mmol) was added and the reaction mixture heated to 50° C. After 2 hours, the clear mixture was poured into water (100 ml) and extracted three times with ethyl acetate (50 ml each). The combined extracts were dried with anhydrous magnesium sulphate and the solvent was removed in vacuo. The crude product was purified by flash silica gel column chromatography using hexane/ethyl acetate 1/1. The title compound was obtained as a white solid (1.7 g, 54%), mp 110° C.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:11][CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:9]=2)[N:4]([NH2:19])[CH:3]=1.Cl.Cl[C:22]1[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=1.C(=O)(O)[O-].[Na+]>CN1CCCC1=O>[CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:11][CH2:12][C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:9]=2)[N:4]([NH:19][C:22]2[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=2)[CH:3]=1
Reactant: Cc1cn(N)c2ccc(OCc3ccccc3)cc12
Reactant: Clc1ccncc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: Cc1cn(Nc2ccncc2)c2ccc(OCc3ccccc3)cc12
Temperature: 80 °C
Yield: 91.7 %

Procedure:
To a solution consisting of 3-methyl-5-(phenylmethoxy)-1H-indol-1-amine (6.31 g) and 1-methyl-2-pyrrolidinone (109 ml) was added 4-chloropyridine hydrochloride (3.94 g). The resulting mixture was heated at 80° C. for 4-5 hours. Another batch of reaction was also carried out with the amine (2.94 g) and 4-chloropyridine hydrochloride (1.84 g) in nmp (50 ml) at 80° C. for 4 hours. The above reaction mixtures were poured together into dilute aqueous sodium bicarbonate and extracted with EtOAc (4×) and ether (1×). The combined organic layers were washed with water and brine followed by drying (K2CO3). Filtration, concentration and purification via flash column chromatography (silica gel, 2% Et3N/ether/0-5% MeOH) afforded 7.55 g of the desired product. Recrystallization from EtOAc gave a solid, m.p. 167.5°-169.5° C.
Reaction SMILES: C([Li])CCC.C(OP([CH2:14][C:15]([OH:17])=[O:16])(OCC)=O)C.[Cl:18][C:19](=[CH:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH:20]=O.Cl>O1CCCC1>[Cl:18][C:19](=[CH:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH:20]=[CH:14][C:15]([OH:17])=[O:16]
Reactant: CCOP(=O)(CC(=O)O)OCC
Reactant: O=CC(Cl)=Cc1ccccc1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=C(O)C=CC(Cl)=Cc1ccccc1
Temperature: -65 °C
Reaction time: 0.67 h
Yield: 75.9 %

Procedure:
Butyllithium (50 mL of 2.5 N solution) was added to 250 mL of anhydrous tetrahydrofuran (THF) at −65° C. A solution of diethylphosphonoacetic acid (11.4 g) in 90 mL of anhydrous THF was added dropwise to the stirred solution at −65° C. The resulting solution was stirred at −65° C. for an additional 40 minutes and then a solution of α-chloro-cinnamaldehyde (10.0 g) in 60 mL of anhydrous THF was added to the reaction at −65° C. over a period of 95 minutes. The reaction was stirred for one hour, allowed to warm to room temperature and then stirred overnight. The reaction was then acidified with 5% hydrochloric acid (48 mL) to a pH of 3.9. The aqueous layer was extracted with 50 mL of ether twice and with 50 mL of ethyl acetate once. The combined organic extract was dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The crude material was dissolved in 30 mL of hot methanol and then refrigerated overnight. The crystals formed were filtered and dried under vacuum to afford 9.2 g of the desired 4-chloro-5-phenyl-2,4-pentadienoic acid. 1H NMR (acetone-d6, 300 MHz), δ(ppm) 7.86 (d, 2H), 7.60 (d, 1H), 7.45 (m, 3H), 7.36 (broad s, 1H), 6.32 (d, 1H).
Reaction SMILES: [C:1]([OH:10])(=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4].[C:11](OC(=O)C)(=[O:13])[CH3:12]>>[C:11]([C:1]1[O:10][N:4]=[C:3]2[C:2]=1[CH:8]=[CH:7][CH:6]=[CH:5]2)(=[O:13])[CH3:12]
Reactant: Nc1ccccc1C(=O)O
Reactant: CC(=O)OC(C)=O
Product: CC(=O)c1onc2ccccc12

Procedure:
reacting the anthranilic acid compound of step (3) with acetic anhydride to form an acetylanthranil compound of the formula ##STR44##
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([F:21])[C:5]([O:8][C:9]2[CH:20]=[CH:19][C:12]([O:13][CH:14]([CH3:18])[C:15](Cl)=[O:16])=[CH:11][CH:10]=2)=[N:6][CH:7]=1.C(N(CC)CC)C.[CH2:29]([NH:33][C:34]#[N:35])[CH2:30][CH2:31][CH3:32]>C1(C)C=CC=CC=1>[CH2:29]([N:33]([C:34]#[N:35])[C:15](=[O:16])[CH:14]([O:13][C:12]1[CH:19]=[CH:20][C:9]([O:8][C:5]2[C:4]([F:21])=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=2)=[CH:10][CH:11]=1)[CH3:18])[CH2:30][CH2:31][CH3:32]
Reactant: CCCCNC#N
Reactant: CC(Oc1ccc(Oc2ncc(Cl)cc2F)cc1)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCCCN(C#N)C(=O)C(C)Oc1ccc(Oc2ncc(Cl)cc2F)cc1
Reaction time: 5 h

Procedure:
While cooling with ice, a solution of 9.9 g (0.030 mole) of 2-[4-(5-chloro-3-fluoropyridin-2-yloxy)phenoxy]propionyl chloride in 30 ml of toluene is added dropwise to a solution of 3.5 g (0.035 mole) of triethylamine and 3.2 g (0.033 mole) of n-butylcyanamine in 40 m of toluene. After 5 hours, the precipitate is removed by filtrate and the filtrate is purified by chromatography through silica gel. The eluate is concentrated by evaporation, affording 2-[4-(5-chloro-3-fluoropyridin-2-yloxy)phenoxy]propionic acid N-n-butyl-N-cyanamide as a yellowish oil, nD25 : 1.5482.
Reaction SMILES: Br[CH2:2][Si:3]([CH3:8])([O:6][CH3:7])[O:4][CH3:5].CN[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[CH3:18][N:19](C)C>CCCCCC>[CH2:11]([CH2:18][NH:19][CH2:2][Si:3]([CH3:8])([O:6][CH3:7])[O:4][CH3:5])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CO[Si](C)(CBr)OC
Reactant: CN(C)C
Reactant: CNCc1ccccc1
Solvent: CCCCCC
Product: CO[Si](C)(CNCCc1ccccc1)OC
Temperature: 100 °C
Reaction time: 3 h

Procedure:
To 0.25 moles of bromomethylmethyldimethoxysilane is added 0.25 moles of methylbenzylamine, and the mixture is heated to 100° C. for 12 hours. At the end of that time, 300 ml of hexane is added and excess trimethylamine is added. This mixture is allowed to stir for 3 hours, filtered, and the hexane is removed under reduced pressure, leaving benzylmethylaminomethylmethyldimethoxysilane.
Reaction SMILES: [Cl:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[CH:11]=[O:12])=[CH:8][C:7]([N+:13]([O-:15])=[O:14])=[CH:6][CH:5]=2.[H-].[Na+].[CH3:18]I>C1COCC1>[Cl:1][C:2]1[N:3]([CH3:18])[C:4]2[C:9]([C:10]=1[CH:11]=[O:12])=[CH:8][C:7]([N+:13]([O-:15])=[O:14])=[CH:6][CH:5]=2
Reactant: O=Cc1c(Cl)[nH]c2ccc([N+](=O)[O-])cc12
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cn1c(Cl)c(C=O)c2cc([N+](=O)[O-])ccc21
Reaction time: 8 h

Procedure:
To 5 g of (65) in 100 ml THF was added 550 mg NaH and 2.5 ml methyliodide. The reaction was left with stirring overnight. Most of the THF was evaporated off, water was added, and the water phase extracted with EtOAc. The water phase was then acidified with acetic acid, which precipitated the pure product. Filtration and drying gave 770 mg of (66).