Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([CH2:12][CH2:13][CH2:14][CH3:15])=[N:8][O:9][C:10]=1[CH3:11])=O)C.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[CH2:12]([C:7]1[C:6]([CH2:4][OH:3])=[C:10]([CH3:11])[O:9][N:8]=1)[CH2:13][CH2:14][CH3:15]
Reactant: CCCCc1noc(C)c1C(=O)OCC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCCc1noc(C)c1CO
Yield: 95.7 %

Procedure:
To a stirred solution of 3-butyl-5-methyl-isoxazole-4-carboxylic acid ethyl ester (9.8 g, 46.3 mmol) in THF (100 mL) under argon and at 0° C. was added lithium aluminium hydride (2.03 g, 53.4 mmol) in five portions. After 1 h the reaction mixture was quenched dropwise with Seignette salt solution. The reaction mixture was filtered and the filtrate extracted with ethyl acetate. The combined organic extracts were washed with Seignette salt solution then dried, filtered and concentrated. Purification by chromatography (silica, heptane:ethyl acetate=100:0 to 4:6) afforded the title compound (7.5 g, 95%) as a yellow liquid. MS: m/e=170.3 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]([OH:12])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].C(=O)([O-])[O-].[K+].[K+].[CH2:19](Cl)[CH:20]=[C:21]([CH2:23][CH2:24][CH:25]=[C:26]([CH2:28][CH2:29][CH:30]=[C:31]([CH3:33])[CH3:32])[CH3:27])[CH3:22].Cl>C(OCC)(=O)C.CN(C=O)C>[CH3:22]/[C:21](/[CH2:23][CH2:24]/[CH:25]=[C:26](\[CH3:27])/[CH2:28][CH2:29][CH:30]=[C:31]([CH3:33])[CH3:32])=[CH:20]\[CH2:19][O:12][C:10]1[CH:9]=[CH:8][C:3]([C:4]([O:6][CH3:7])=[O:5])=[C:2]([OH:1])[CH:11]=1
Reactant: COC(=O)c1ccc(O)cc1O
Reactant: CC(C)=CCCC(C)=CCCC(C)=CCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OC/C=C(\C)CC/C=C(\C)CCC=C(C)C)cc1O
Temperature: 60 °C
Reaction time: 3 h
Yield: 70.6 %

Procedure:
In 10 m of DMF were poured 1.28 g (7.6 mmol) of methyl 2,4-dihydroxybenzoate and 1.05 g (7.6 mmol) of potassium carbonate, and 1.84 g (7.6 mmol) of farnesyl chloride was added thereto dropwise at room temperature. After the addition, the mixture was stirred at 60° C. for 3 hours and then poured into a 12% hydrochloric acid aqueous solution. Ethyl acetate was poured thereinto to conduct extraction. The resulting extract was washed with water and a saturated sodium chloride aqueous solution, dried over sodium sulfate, and concentrated. The resulting crude product was purified by column chromatography on silica gel to obtain 2.0 g (yield: 71%) of methyl 4-{(2E,6E)-3,7,11-trimethyl-2,6,10-dodecatrienyloxy}-2-hydroxybenzoate represeted by the following structural formula (hereinafter referred to as compound 37) as a colorless, clear and oily substance. The analytical results are shown below. ##STR58##
Reaction SMILES: Cl[C:2]1[N:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[F:10][C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][C:12]=1B1OC(C)(C)C(C)(C)O1>>[F:10][C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][C:12]=1[C:2]1[N:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: N#Cc1cccnc1Cl
Reactant: CC1(C)OB(c2cc([N+](=O)[O-])ccc2F)OC1(C)C
Product: N#Cc1cccnc1-c1cc([N+](=O)[O-])ccc1F

Procedure:
2-Chloronicotinonitrile (0.80 g, 5.8 mmol) was coupled to 2-(2-fluoro-5-nitrophenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (2 g, 7.49 mmol) using the method in Example 48. Purification by chromatography on silica gel eluting with dichloromethane gave 2-(2-fluoro-5-nitrophenyl)nicotinonitrile as a yellow solid: δH (360 MHz, CDCl3) 8.97 (1H, dd, J 5 and 2), 8.56 (1H, dd, J 6 and 3), 8.40-8.45 (1H, m), 8.15 (1H, dd, J 8 and 2), 7.55 (1H, dd, J 8 and 5), 7.43 (1H, dd, J 9 and 9); m/z (ES+) 244 (M++H).
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.C([O-])([O-])=O.[K+].[K+].[C:23]([OH:30])(=[O:29])/[CH:24]=[CH:25]/[C:26]([OH:28])=[O:27].[C:31](#N)[CH3:32]>C(O)C>[C:23]([OH:30])(=[O:29])/[CH:24]=[CH:25]/[C:26]([OH:28])=[O:27].[C:26]([O:28][CH2:31][CH2:32][N:12]1[CH2:11][CH2:10][CH:9]([C:6]2[C:5]3[CH:15]=[CH:16][C:2]([F:1])=[CH:3][C:4]=3[O:8][N:7]=2)[CH2:14][CH2:13]1)(=[O:27])[CH3:25]
Reactant: CC#N
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Agent: O=C(O)/C=C/C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CC(=O)OCCN1CCC(c2noc3cc(F)ccc23)CC1
Temperature: 25 °C

Procedure:
A mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (3.0 g, 13.6 mmol), K2CO3 (3.5 g, 25 mmol) 2-bromoethyl acetate (4 g, 26.5 mmol) in acetonitrile (50 ml) was heated at reflux for 4 hours. After cooling to room temperature, the inorganic salts were filtered and washed with DCM (dichloromethane 50 ml). The organic solvent was removed on a rotary evaporator to give an oil. The oily product was purified on a flash chromatography column (60 g of SiO2; eluted with MeOH 2%-4% in DCM). The pure product thus obtained weighed 4.43 g. This oil was dissolved in ethanol and treated with a solution of fumaric acid (1.2 g) in ethanol. The sale crystallized out at room temperature to yield 3.44 g (57%) m.p.=154°-155° C. ANALYSIS: Calculated for C10H19FN2O3.C4H4O4: 56.86%C 5.49%H 6.63%N Found: 56.75%C 5.41%H 6.54%N
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][N:3]=1.C([Sn](CCCC)(CCCC)[C:16]1[O:20][C:19]([CH:21]2[O:25][CH2:24][CH2:23][O:22]2)=[CH:18][CH:17]=1)CCC>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[O:22]1[CH2:23][CH2:24][O:25][CH:21]1[C:19]1[O:20][C:16]([N:3]2[CH:2]=[C:10]3[C:5]([CH:6]=[CH:7][CH:8]=[CH:9]3)=[N:4]2)=[CH:17][CH:18]=1
Reactant: Ic1n[nH]c2ccccc12
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc(C2OCCO2)o1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: c1ccc2nn(-c3ccc(C4OCCO4)o3)cc2c1
Reaction time: 0.25 h

Procedure:
10 g (41 mmol) of 3-iodoindazole (U. Wrzeciono et al., Pharmazie 1978, 34, 20) are dissolved in 125 ml of DMF under argon, 0.7 g of Pd(PPh3)4 is added and the mixture is stirred for 15 minutes. 19.4 g (43.9 mmol) of 2-(5-tributylstannyl-2-furanyl)-1,3-dioxolane are added and the mixture is stirred at 100° C. for 2 hours. The solvent is evaporated off in vacuo and the residue is chromatographed over silica gel using toluene and toluene/ethyl acetate mixtures as the eluent. 10 g (90.3% of theory) of 3-(2-(5-(1,3-dioxolan-2-yl)furyl)indazole are obtained.
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([NH:7][C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)[C:3]=1[C:14]([NH2:16])=[O:15].[F:17][C:18]1[CH:25]=[CH:24][C:21]([CH:22]=O)=[CH:20][C:19]=1[O:26][CH3:27]>CCO.N1CCCCC1>[F:17][C:18]1[CH:25]=[CH:24][C:21]([CH:22]=[N:1][C:2]2[NH:6][N:5]=[C:4]([NH:7][C:8]3[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=3)[C:3]=2[C:14]([NH2:16])=[O:15])=[CH:20][C:19]=1[O:26][CH3:27]
Reactant: NC(=O)c1c(Nc2cccnc2)n[nH]c1N
Reactant: COc1cc(C=O)ccc1F
Solvent: C1CCNCC1
Solvent: CCO
Product: COc1cc(C=Nc2[nH]nc(Nc3cccnc3)c2C(N)=O)ccc1F

Procedure:
5-amino-3-(pyridin-3-ylamino)-1H-pyrazole-4-carboxamide (100 mg) was suspended in EtOH (3 mL) and 4-Fluoro-3-methoxybenzaldehyde (1 eq.) and piperidine (1 drop) were added. Stirred at reflux until intermediate was absent (HPLC). After reaction was complete (18 hrs) it was brought to room temperature and filtered to obtain 5-((4-fluoro-3-methoxybenzylidene)amino)-3-(pyridin-3-ylamino)-1H-pyrazole-4-carboxamide as a yellow powder. Powder was washed with EtOH. Product was allowed to dry under vacuum for 1 hr.
Reaction SMILES: [F:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[C@@H:12]([CH3:13])[CH2:11][N:10]([C:14](=[O:25])[CH2:15][CH2:16][C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][C:18]=3[OH:24])[C@H:9]([CH3:26])[CH2:8]2)=[CH:4][CH:3]=1.[H-].[Na+].[CH3:31][O:32][C:33](=[O:36])[CH2:34]Br>O1CCCC1>[CH3:31][O:32][C:33](=[O:36])[CH2:34][O:24][C:18]1[CH:19]=[C:20]([CH3:23])[CH:21]=[CH:22][C:17]=1[CH2:16][CH2:15][C:14]([N:10]1[CH2:11][C@H:12]([CH3:13])[N:7]([CH2:6][C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:28][CH:27]=2)[CH2:8][C@H:9]1[CH3:26])=[O:25]
Reactant: Cc1ccc(CCC(=O)N2C[C@H](C)N(Cc3ccc(F)cc3)C[C@H]2C)c(O)c1
Reactant: COC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)COc1cc(C)ccc1CCC(=O)N1C[C@H](C)N(Cc2ccc(F)cc2)C[C@H]1C
Reaction time: 0.08 h
Yield: 103.8 %

Procedure:
To a solution of 1-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazin-1-yl]-3-(2-hydroxy-4-methyl-phenyl)-propan-1-one, (0.15 g, 0.38 mmol) in tetrahydrofuran (2 mL) at 0° C. was added sodium hydride (0.023 g, 0.57 mmol). The reaction was stirred for 5 minutes, then bromoacetic acid methyl ester (0.043 mL, 0.45 mmol) was added and the reaction was stirred at ambient temperature overnight. The reaction was quenched by the addition of water and the mixture was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and concentrated in vacuo to give the title compound (0.18 g).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][C@H:12]([CH3:14])[CH2:11][C@@H:10]([N:15]([CH3:23])[C:16](=[O:22])[CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:9]2)[CH:5]=[C:4]([C:24]2[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[C:26](F)[CH:25]=2)[N:3]=1.O.[NH2:34][NH2:35]>C(O)C>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][C@H:12]([CH3:14])[CH2:11][C@@H:10]([N:15]([CH3:23])[C:16](=[O:22])[CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:9]2)[CH:5]=[C:4]([C:24]2[CH:25]=[C:26]3[C:27]([C:30]([NH2:31])=[N:34][NH:35]3)=[CH:28][CH:29]=2)[N:3]=1
Reactant: C[C@@H]1C[C@@H](N(C)C(=O)CC(C)(C)C)CN(c2cc(-c3ccc(C#N)c(F)c3)nc(N)n2)C1
Reactant: NN
Solvent: CCO
Solvent: O
Product: C[C@@H]1C[C@@H](N(C)C(=O)CC(C)(C)C)CN(c2cc(-c3ccc4c(N)n[nH]c4c3)nc(N)n2)C1
Temperature: 120 °C
Reaction time: 4 h
Yield: 42.7 %

Procedure:
To N-{(3R,5R)-1-[2-amino-6-(4-cyano-3-fluorophenyl)-4-pyrimidinyl]-5-methyl-3-piperidinyl}-N,3,3-trimethylbutanamide (82 mg, 0.187 mmol) in ethanol (4 mL) was added hydrazine monohydrate (1 mL, 20.4 mmol), and the reaction mixture was stirred for 4 hours at 120° C. into a sealed vessel. The reaction was allowed to cool down to room temperature, and poured onto water (˜120 mL). The resulting aqueous mixture was extracted with EtOAc (2×20 mL). The combined organic layers were washed with brine, dried (MgSO4), filtered and concentrated to afford the title compound (36 mg) as an off-white solid as a 3:2 mixture of rotamers. LC-MS (ES) m/z=451 [M+H]+. 1H NMR (400 MHz, DMSO-d6+1 drop D2O): δ 0.98 (m, 12H), 1.41 and 1.52 (m, 1H), 1.87-2.41 (m, 4H), 2.76 and 2.90 (s, 3H), 2.99-3.25 (m, 2H), 3.84-3.99 (m, 1H), 4.01-4.26 (m, 1H), 4.39-4.66 (m, 1H), 6.57-6.62 (s, 1H), 7.50-7.60 (m, 1H), 7.70 (m, 1H), 7.92 (s, 1H).
Reaction SMILES: [CH2:1]([C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[C:5]#[N:6])[CH3:2].[Br:11]Br>>[Br:11][C:8]1[CH:9]=[CH:10][C:3]([CH2:1][CH3:2])=[C:4]([CH:7]=1)[C:5]#[N:6]
Reactant: BrBr
Reactant: CCc1ccccc1C#N
Product: CCc1ccc(Br)cc1C#N

Procedure:
9.74 ml of 2-ethylbenzonitrile are added dropwise to 100 g of Na-X zeolite (Linde 13X, STREM) with vigorous stirring. After the exothermic reaction, 5.6 ml of bromine are added dropwise at 55° C., add vigorous stirring of the mixture is continued. The temperature is kept at 45-50° C., by means of an ice bath. After the addition is complete, the ice bath is removed, and the mixture is stirred at 50° C. for 20 hours. 300 ml of methanol are added to the reaction mixture while stirring and the suspension is clarified by filtration through Hyflow. The filtrate is evaporated and the residue is partitioned between 100 ml of ethyl acetate and 50 ml of saturated sodium bicarbonate solution. The organic phase is dried with sodium sulphate, filtered and evaporated. The title compound is obtained as a beige crystalline solid from the residue by flash chromatography. Rt=4.87.
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[C:25]([O:29][C:30]([N:32]1[CH2:37][CH:36]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[CH2:35][CH:34]([C:44](O)=[O:45])[CH2:33]1)=[O:31])([CH3:28])([CH3:27])[CH3:26].[N:47]1[CH:52]=[CH:51][C:50]([C:53]2[C:61]3[C:56](=[CH:57][CH:58]=[C:59]([NH2:62])[CH:60]=3)[N:55]([C:63]([C:76]3[CH:81]=[CH:80][CH:79]=[CH:78][CH:77]=3)([C:70]3[CH:75]=[CH:74][CH:73]=[CH:72][CH:71]=3)[C:64]3[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=3)[N:54]=2)=[CH:49][CH:48]=1.C(N(C(C)C)CC)(C)C>CN(C=O)C>[C:38]1([CH:36]2[CH2:35][CH:34]([C:44](=[O:45])[NH:62][C:59]3[CH:60]=[C:61]4[C:56](=[CH:57][CH:58]=3)[N:55]([C:63]([C:70]3[CH:71]=[CH:72][CH:73]=[CH:74][CH:75]=3)([C:76]3[CH:77]=[CH:78][CH:79]=[CH:80][CH:81]=3)[C:64]3[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=3)[N:54]=[C:53]4[C:50]3[CH:51]=[CH:52][N:47]=[CH:48][CH:49]=3)[CH2:33][N:32]([C:30]([O:29][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:31])[CH2:37]2)[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1
Reactant: Nc1ccc2c(c1)c(-c1ccncc1)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CC(C(=O)O)CC(c2ccccc2)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC(C(=O)Nc2ccc3c(c2)c(-c2ccncc2)nn3C(c2ccccc2)(c2ccccc2)c2ccccc2)CC(c2ccccc2)C1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
2-(7-Aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU) (49 mg, 0.129 mmol) was added to a suspension of 1-(tert-butoxycarbonyl)-5-phenylpiperidine-3-carboxylic acid (36 mg, 0.117 mmol) in DMF (0.5 mL) and was stirred at room temperature for 15 minutes. A solution of 3-(pyridin-4-yl)-1-trityl-1H-indazol-5-amine (0.117 mmol) in DMF (0.5 mL) was added to the reaction and followed by diisopropyl ethyl amine (DIEA) (0.1 mL). The mixture was stirred at room temperature for an additional 30 minutes. The reaction was quenched with water (5 mL) and extracted with ethyl acetate (3×10 mL). The extracts were combined, dried using anhydrous sodium sulfate, filtered, and concentrated in vacuo. The crude product was progressed to the next step without purification.
Reaction SMILES: [CH:1]1([CH:4]([N:11]([CH2:15][CH2:16][CH3:17])[C:12]([NH2:14])=[S:13])[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH2:3][CH2:2]1.Br[CH:19]([CH3:30])[C:20]([C:22]1[CH:27]=[CH:26][C:25]([I:28])=[CH:24][C:23]=1[Cl:29])=O>>[Cl:29][C:23]1[CH:24]=[C:25]([I:28])[CH:26]=[CH:27][C:22]=1[C:20]1[N:14]=[C:12]([N:11]([CH:4]([CH:1]2[CH2:2][CH2:3]2)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:15][CH2:16][CH3:17])[S:13][C:19]=1[CH3:30]
Reactant: CCCN(C(N)=S)C(c1ccccc1)C1CC1
Reactant: CC(Br)C(=O)c1ccc(I)cc1Cl
Product: CCCN(c1nc(-c2ccc(I)cc2Cl)c(C)s1)C(c1ccccc1)C1CC1

Procedure:
This compound was prepared from N-(α-cyclopropylbenzyl)-N-propylthiourea (Compound 75) and 2-bromo-1-(2-chloro-4-iodophenyl)-1-propanone (Compound 18) according to the process described in Example 1.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].O=S(Cl)Cl.[CH3:15]O>>[I:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([O:7][CH3:15])=[O:6]
Reactant: O=C(O)c1cccc(I)c1
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cccc(I)c1
Reaction time: 16 h
Yield: 93 %

Procedure:
3-iodobenzoic acid (7.44 g, 30 mmol) was suspended in dry MeOH (40 mL) under nitrogen at 0° C. SOCl2 (3.3 mL) was added over 5 minutes. Stirring continued at room temperature for 16 hours, after which the reaction mixture was concentrated. The residue was dissolved in EtOAc and was washed twice with NaHCO3 (conc.). The organic solution was dried over MgSO4, filtered and concentrated to yield a white crystalline solid (7.32 g, 93%). NMR 1H (ppm, CDCl3): 8.36 (t, J4=1.6 Hz, 1H), 7.98 (d, J3=7.8 Hz, 1H), 7.86 (d, J3=7.9 Hz, 1H), 7.16 (t, J3=7.8 Hz, 1H), 3.90 (s, 3H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([F:15])=[C:11]([F:16])[C:10]=1[F:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li+].CC([N-]C(C)C)C.[Li]CCCC.[C:31](=[O:33])=[O:32]>>[CH2:1]([O:8][C:9]1[C:10]([F:17])=[C:11]([F:16])[C:12]([F:15])=[C:13]([CH:14]=1)[C:31]([OH:33])=[O:32])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Fc1ccc(OCc2ccccc2)c(F)c1F
Reactant: O=C=O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Product: O=C(O)c1cc(OCc2ccccc2)c(F)c(F)c1F
Reaction time: 7.5 h

Procedure:
To a solution of 1-benzyloxy-2,3,4-trifluorobenzene in appropriate inert solvent is added strong base (such as LDA, n-BuLi, LiHDMS) at low temperature (−50-−80° C., prefer −78° C.) under nitrogen atmosphere. The stirring is maintained at this temperature for several hours (0.5-12 h, prefer 0.5-2 h). The mixture is transferred to a bottle with dry ice and the resulting mixture is stirred for some time (such as 3-12 h, prefer 5-10 h). 5-Benzoxy-2,3,4-trifluorobenzoic acid is obtained after conventional workup.
Reaction SMILES: N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O.[Cl:17][C:18]1[C:27]2[C:22](=[CH:23][C:24]([O:29][CH3:30])=[C:25]([OH:28])[CH:26]=2)[N:21]=[CH:20][N:19]=1.[N:31]1([CH2:37][CH2:38][CH2:39]O)[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[Cl:17][C:18]1[C:27]2[C:22](=[CH:23][C:24]([O:29][CH3:30])=[C:25]([O:28][CH2:39][CH2:38][CH2:37][N:31]3[CH2:36][CH2:35][O:34][CH2:33][CH2:32]3)[CH:26]=2)[N:21]=[CH:20][N:19]=1
Reactant: OCCCN1CCOCC1
Reactant: COc1cc2ncnc(Cl)c2cc1O
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1cc2ncnc(Cl)c2cc1OCCCN1CCOCC1
Reaction time: 2 h
Yield: 66.5 %

Procedure:
Di-tert-butyl azodicarboxylate (1.44 g, 6.26 mmol) was added portionwise at room temperature to a stirred suspension of 4-chloro-7-methoxyquinazolin-6-ol (1.20 g, 5.70 mmol), 3-morpholin-4-ylpropan-1-ol (0.91 g, 6.27 mmol) and triphenylphosphine (1.8 g, 6.87 mmol) in dichloromethane (25 ml). The reaction mixture was stirred for 2 hours and then the resulting orange solution was purified directly by silica gel chromatography eluting with a mixture of 5% methanol in dichloromethane to give 4-chloro-7-methoxy-6-(3-morpholin-4-ylpropoxy)quinazoline (1.28 g, 67% yield) as a pale yellow solid:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:15][CH3:16])=[C:6]([N:8]2[CH2:13][CH2:12][NH:11][CH:10]([CH3:14])[CH2:9]2)[CH:7]=1.[CH:17]12[CH2:23][CH:20]([CH:21]=[CH:22]1)[CH2:19][CH:18]2[CH:24]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH:17]12[CH2:23][CH:20]([CH:21]=[CH:22]1)[CH2:19][CH:18]2[CH2:24][N:11]1[CH2:12][CH2:13][N:8]([C:6]2[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=2[O:15][CH3:16])[CH2:9][CH:10]1[CH3:14]
Reactant: COc1ccc(Cl)cc1N1CCNC(C)C1
Reactant: O=CC1CC2C=CC1C2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: COc1ccc(Cl)cc1N1CCN(CC2CC3C=CC2C3)C(C)C1
Reaction time: 8 h

Procedure:
48 mg (0.2 mmol) of 1-(5-Chloro-2-methoxy-phenyl)-3-methyl-piperazine was dissolved in 1.5 mL anhydrous 1,2-dichloroethane. 5-Norbornene-2-carboxaldehyde (25 mg, 0.2 mmol) was added, followed by followed by 63 mg (0.3 mmol) sodium triacetoxyborohydride [NaBH(OAc)3]. The reaction was stirred overnight, then quenched with 1.0 mL DMSO:methanol (1:1). The reaction mixture was filtered and purified by reverse-phase HPLC (2-99CH3CN in 0.085% TFA (aq), 50 mL/min, 2.0 mL injected), and the product 1-bicyclo[2.2.1]hept-5-en-2-ylmethyl-4-(5-chloro-2-methoxy-phenyl)-2-methyl-piperazine isolated as the mono-TFA salt. Theoretical (M+H)+ m/z=347.9; Found 348.0.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:10]=[C:9]([O:11][CH2:12][O:13][CH3:14])[CH:8]=[CH:7][C:6]=1[C:15]1[NH:16][C:17]2[C:22]([C:23]=1[CH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1)=[CH:21][CH:20]=[C:19]([C:30]([O:32][CH3:33])=[O:31])[CH:18]=2.[H-].[Na+].Br[CH2:37][CH2:38][O:39][CH:40]1[CH2:45][CH2:44][CH2:43][CH2:42][O:41]1.C(=O)([O-])O.[Na+]>CN(C)C=O>[CH3:1][O:2][CH2:3][O:4][C:5]1[CH:10]=[C:9]([O:11][CH2:12][O:13][CH3:14])[CH:8]=[CH:7][C:6]=1[C:15]1[N:16]([CH2:37][CH2:38][O:39][CH:40]2[CH2:45][CH2:44][CH2:43][CH2:42][O:41]2)[C:17]2[C:22]([C:23]=1[CH:24]1[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]1)=[CH:21][CH:20]=[C:19]([C:30]([O:32][CH3:33])=[O:31])[CH:18]=2
Reactant: BrCCOC1CCCCO1
Reactant: COCOc1ccc(-c2[nH]c3cc(C(=O)OC)ccc3c2C2CCCCC2)c(OCOC)c1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCOc1ccc(-c2c(C3CCCCC3)c3ccc(C(=O)OC)cc3n2CCOC2CCCCO2)c(OCOC)c1
Reaction time: 0.33 h

Procedure:
To a solution of methyl 2-(2,4-bismethoxymethoxyphenyl)-3-cyclohexyl-1H-indole-6-carboxylate (16.9 g, 37.3 mmol) in N,N-dimethylformamide (120 ml) was added sodium hydride (2.1 g, 52.2 mmol) under ice-cooling, and the mixture was stirred for 20 min. To the reaction mixture was added 2-(2-bromoethoxy)tetrahydro-2H-pyran (8.5 ml, 55.9 mmol), and the mixture was stirred at room temperature for 4 hr. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate solution and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure to give methyl 2-(2,4-bismethoxymethoxyphenyl)-3-cyclohexyl-1-[2-(tetrahydropyran-2-yloxy)ethyl]-1H-indole-6-carboxylate as a crude product. The obtained compound was used in Step 5 without further purification.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:24])[CH:10]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)C(OCC)=O)=[C:5]([CH3:25])[CH:4]=1)#[N:2]>CS(C)=O.[Cl-].[Na+].O>[CH3:23][O:22][C:19]1[CH:18]=[CH:17][C:16]([CH2:10][C:9]([C:6]2[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][C:5]=2[CH3:25])=[O:24])=[CH:21][CH:20]=1
Reactant: CCOC(=O)C(C(=O)c1ccc(C#N)cc1C)c1ccc(OC)cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: COc1ccc(CC(=O)c2ccc(C#N)cc2C)cc1
Temperature: 150 °C
Yield: 60.4 %

Procedure:
To a mixture of ethyl 3-(4-cyano-2-methylphenyl)-2-(4-methoxyphenyl)-3-oxopropanoate (9F) (40 g, 0.1186 mol) in dimethyl sulfoxide (75 mL) was added catalytic amount of brine (2.5 mL), and the reaction mixture was heated at 150° C. for 2.5 h. When TLC showed the starting material was consumed, the reaction mixture was cooled down to room temperature, and partitioned between water (150 mL) and ethyl acetate (150 mL). The aqueous layer was extracted with ethyl acetate (100 mL×2). The combined organic layer was washed with brine (200 mL), dried over anhydrous sodium sulfate (15 g), evaporated, and purified by chromatography on silica gel (petroleum ether/ethyl acetate=25:1) to give 4-(2-(4-methoxyphenyl)acetyl)-3-methylbenzonitrile (9G) (19 g, yield 60.4%).
Reaction SMILES: [C:1]1(=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[CH:3]=[CH:2]1.[CH2:13]([N:29]1[CH:33]=[CH:32][CH:31]=[CH:30]1)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28].C1(C)C=CC(S(O)(=O)=O)=CC=1>C(Cl)(Cl)Cl>[CH2:13]([N:29]1[CH:30]=[CH:31][CH:32]=[C:33]1[C:3]1[C:4](=[O:11])[C:5]2[C:10]([C:1](=[O:12])[CH:2]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: CCCCCCCCCCCCCCCCn1cccc1
Reactant: O=C1C=CC(=O)c2ccccc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCCCCCCCn1cccc1C1=CC(=O)c2ccccc2C1=O
Yield: 41 %

Procedure:
6.32 millimol of 1,4-naphthoquinone and 3.16 millimol of N-hexadecylpyrrole were stirred in 50 ml of chloroform in a round-bottomed flask for 5 hours at room temperature, the reaction being catalysed by addition of a few milligrams of para-toluenesulphonic acid. The reaction medium was diluted with 50 ml of chloroform and then washed four times with 50 ml of water and finally with saturated aqueous NaCl solution. The resulting organic phase was dried over Na2SO4 and then concentrated under vacuum. The product 2-(1-hexadecyl-1H-pyrrol-2-yl)-[1,4]-naphthoquinone was thus isolated in a yield of 41% after purification by chromatography on a column of silica.