Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:5][C:6](=[O:53])[CH2:7][C@H:8]([NH:27][C:28]([C@@H:30]1[CH2:35][CH2:34][CH2:33][N:32]([C:36](=[O:52])[CH2:37][CH2:38][CH:39]2[CH2:44][CH2:43][N:42](C(OC(C)(C)C)=O)[CH2:41][CH2:40]2)[CH2:31]1)=[O:29])[C:9]1[CH:10]=[N:11][CH:12]=[C:13]([C:15]#[C:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH2:24][CH2:25][F:26])[CH:18]=2)[CH:14]=1)(C)(C)C>C(O)=O>[F:26][CH2:25][CH2:24][O:23][C:19]1[CH:18]=[C:17]([C:16]#[C:15][C:13]2[CH:14]=[C:9]([C@@H:8]([NH:27][C:28]([C@@H:30]3[CH2:35][CH2:34][CH2:33][N:32]([C:36](=[O:52])[CH2:37][CH2:38][CH:39]4[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]4)[CH2:31]3)=[O:29])[CH2:7][C:6]([OH:53])=[O:5])[CH:10]=[N:11][CH:12]=2)[CH:22]=[CH:21][CH:20]=1
Reactant: CC(C)(C)OC(=O)C[C@H](NC(=O)[C@@H]1CCCN(C(=O)CCC2CCN(C(=O)OC(C)(C)C)CC2)C1)c1cncc(C#Cc2cccc(OCCF)c2)c1
Solvent: O=CO
Product: O=C(O)C[C@H](NC(=O)[C@@H]1CCCN(C(=O)CCC2CCNCC2)C1)c1cncc(C#Cc2cccc(OCCF)c2)c1
Yield: 82.9 %

Procedure:
Tert-butyl 4-{3-[(3R)-3-{[(1S)-3-tert-butoxy-1-(5-{[3-(2-fluoroethoxy)phenyl]ethynyl}pyridin-3-yl)-3-oxopropyl]carbamoyl}piperidin-1-yl]-3-oxopropyl}piperidine-1-carboxylate (15.7 mg, 20 μmol) was heated to 60° C. in formic acid (1.5 mL) for 40 minutes. The solution was then concentrated in vacuum and the residue purified by preparative HPLC to yield 9.6 mg of (3S)-3-(5-{[3-(2-fluoroethoxy)phenyl]ethynyl}pyridin-3-yl)-3-[({(3R)-1-[3-(piperidin-4-yl)propanoyl]piperidin-3-yl}carbonyl)amino]propanoic acid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:13][N:12]=[C:11]([CH:14]=O)[CH:10]=2)=[CH:5][CH:4]=1.[CH3:16][O:17][C:18]1[CH:19]=[C:20]([CH:24]=[CH:25][C:26]=1[O:27][CH3:28])[CH2:21][C:22]#[N:23]>>[CH3:16][O:17][C:18]1[CH:19]=[C:20](/[C:21](=[CH:14]/[C:11]2[CH:10]=[C:9]([C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=3)[O:13][N:12]=2)/[C:22]#[N:23])[CH:24]=[CH:25][C:26]=1[O:27][CH3:28]
Reactant: COc1ccc(-c2cc(C=O)no2)cc1
Reactant: COc1ccc(CC#N)cc1OC
Product: COc1ccc(-c2cc(/C=C(\C#N)c3ccc(OC)c(OC)c3)no2)cc1
Yield: 35.7 %

Procedure:
5-(4-Methoxyphenyl)-isoxazole-3-carboxaldehyde (200 mg) was condensed with 3,4-dimethoxybenzyl cyanide (174 mg) through Method A (production step 2), to thereby yield the target product (yield: 127 mg, 36%).
Reaction SMILES: [C:1]1([C:7]2[N:11]=[C:10]([CH2:12][C:13]([OH:15])=O)[S:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:16]([O:20][C:21](=[O:25])[C@H:22]([CH3:24])[NH2:23])[CH:17]([CH3:19])[CH3:18]>>[CH2:16]([O:20][C:21](=[O:25])[C@H:22]([CH3:24])[NH:23][C:13](=[O:15])[CH2:12][C:10]1[S:9][N:8]=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:11]=1)[CH:17]([CH3:19])[CH3:18]
Reactant: CC(C)COC(=O)[C@H](C)N
Reactant: O=C(O)Cc1nc(-c2ccccc2)ns1
Product: CC(C)COC(=O)[C@H](C)NC(=O)Cc1nc(-c2ccccc2)ns1

Procedure:
Following General Procedure BI above, and using (3-phenyl-1,2,4-thiadiazol-5-yl)acetic acid (CAS# 90771-06-5) and alanine iso-butyl ester (prepared following General Procedure BJ above), the title compound was prepared. The reaction was monitored by tlc on silica gel and purification was by filtration as described in the general procedure.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:11]=[CH:12][CH:13]=1)[O:5][CH2:6][CH2:7][C:8]([OH:10])=O.C(Cl)(=O)C(Cl)=O.[Cl-].[Cl-].[Cl-].[Al+3].Cl>ClCCl.CN(C)C=O>[F:1][C:2]1[CH:3]=[C:4]2[C:11]([C:8](=[O:10])[CH2:7][CH2:6][O:5]2)=[CH:12][CH:13]=1
Reactant: O=C(O)CCOc1cccc(F)c1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Agent: [Al+3]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C1CCOc2cc(F)ccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 40.2 %

Procedure:
To a solution of 3-(3-fluorophenoxy)-propionic acid (4.94 g, 26.8 mmol) in dichloromethane (135 mL) is added several drops of anhydrous dimethylformamide, followed by oxalyl chloride (4.68 mL, 53.6 mmol). The reaction is stirred at room temperature until gas evolution ceases (˜30 min), then evaporated under reduced pressure and reconstituted in dichloromethane (135 mL). Following the addition of aluminum trichloride (4.28 g, 32.1 mmol), the reaction is stirred for 1 h, then 2 M aqueous hydrochloric acid (100 mL) and dichloromethane (100 mL) are added. The layers are separated, and the aqueous layer extracted with dichloromethane (2×100 mL). The combined organic-layers are washed with brine (2×100 mL), dried over magnesium sulfate, filtered and evaporated under reduced pressure. The crude residue is recrystallized twice from 2-propanol to afford slightly impure title compound (1.79 g, 40%), and the mother liquor subjected to flash chromatography (silica gel, 3:1 pentane/Et2O) to afford pure title compound (1.15 g, 26%): Rf 0.45 (1:1 ethyl acetate/hexanes); mp 53-56 ° C.; 1 H NMR (300 MHz, CDCl3), δ2.75 (t, J=6.4 Hz, 2H), 4.51 (t, J=6.4 Hz, 2H), 6.61 (dd, J=2.3, 9.9 Hz, 1H), 6.65-6.72 (m, 1H), 7.87 (dd, J=6.7, 8.8 Hz, 1H); 19F NMR (282 MHz, CDCl3), δ-101.06; APCI MS m/z 167 [C9H7FO2+H]+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[C:10]3[N:15]([CH3:16])[CH2:14][CH2:13][CH2:12][C:11]=13)[N:8]=[CH:7][N:6]([C@H:17]1[CH2:22][CH2:21][CH2:20][CH2:19][C@@H:18]1[OH:23])[C:5]2=[O:24].[Cl-].[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([CH2:33][Zn+])=[CH:29][N:28]=1>C1COCC1.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[Cl:26][C:27]1[N:28]=[CH:29][C:30]([CH2:33][C:2]2[CH:3]=[C:4]3[C:9](=[C:10]4[N:15]([CH3:16])[CH2:14][CH2:13][CH2:12][C:11]=24)[N:8]=[CH:7][N:6]([C@H:17]2[CH2:22][CH2:21][CH2:20][CH2:19][C@@H:18]2[OH:23])[C:5]3=[O:24])=[CH:31][CH:32]=1
Reactant: CN1CCCc2c(Br)cc3c(=O)n([C@H]4CCCC[C@@H]4O)cnc3c21
Reactant: Clc1ccc(C[Zn+])cn1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: [Cl-]
Solvent: C1CCOC1
Product: CN1CCCc2c(Cc3ccc(Cl)nc3)cc3c(=O)n([C@H]4CCCC[C@@H]4O)cnc3c21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 6-bromo-3-[(1S,2S)-2-hydroxycyclohexyl]-10-methyl-7,8,9,10-tetrahydropyrido[3,2-h]quinazolin-4(3H)-one (40 mg, 0.10 mmol) in THF (0.4 mL) at 0° C. was added (2-chloro-5-pyridyl)methylzinc chloride (0.5 M in THF, 408 μL, 0.20 mmol) and Pd(PtBu3)2. The mixture was warmed to rt and stirred for 30 min. The resulting solution was quenched with water and extracted with CH2Cl2. The combined extracts were dried (Na2SO4) and concentrated. Purification by silica gel chromatography (0-5% MeOH/CH2Cl2) afforded 6-[(6-chloropyridin-3-yl)methyl]-3-[(1S,2S)-2-hydroxycyclohexyl]-10-methyl-7,8,9,10-tetrahydropyrido[3,2-h]quinazolin-4(3H)-one in pure form: 1H NMR (400 MHz, CD3OD); 1H NMR (400 MHz, CDCl3) 8.20 (d, J=2.3 Hz, 1H), 8.03 (s, 1H), 7.59 (s, 1H), 7.33 (dd, J=2.3, 8.2 Hz, 1H), 7.17 (d, J=8.2 Hz, 1H), 4.51 (m, 1H), 3.96 (s, 2H), 3.90 (m, 1H), 3.12 (t, J=5.2 Hz, 2H), 3.08 (s, 3H), 2.56 (t, J=6.5 Hz, 2H), 2.24-2.15 (m, 2H), 2.00-1.92 (m, 2H), 1.89-1.75 (m, 4H), 1.55-1.37 (m, 2H); HRMS (MH+) calcd for C24H28ClN4O2 439.1895. found 439.1894.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([C:16]3[C:17]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[O:28]C)=[N:18][O:19][C:20]=3[CH3:21])=[O:15])[CH2:10][CH2:9]2)=[CH:6][C:5]([NH:30][C:31](=[O:41])[C:32]2[CH:37]=[CH:36][C:35]([N:38]([CH3:40])[CH3:39])=[CH:34][CH:33]=2)=[C:4]([N+:42]([O-:44])=[O:43])[CH:3]=1.B(Br)(Br)Br>C(Cl)Cl>[Cl:1][C:2]1[C:7]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([C:16]3[C:17]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[OH:28])=[N:18][O:19][C:20]=3[CH3:21])=[O:15])[CH2:10][CH2:9]2)=[CH:6][C:5]([NH:30][C:31](=[O:41])[C:32]2[CH:37]=[CH:36][C:35]([N:38]([CH3:39])[CH3:40])=[CH:34][CH:33]=2)=[C:4]([N+:42]([O-:44])=[O:43])[CH:3]=1
Reactant: COc1ccccc1-c1noc(C)c1C(=O)N1CCN(c2cc(NC(=O)c3ccc(N(C)C)cc3)c([N+](=O)[O-])cc2Cl)CC1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cc1onc(-c2ccccc2O)c1C(=O)N1CCN(c2cc(NC(=O)c3ccc(N(C)C)cc3)c([N+](=O)[O-])cc2Cl)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 85.7 %

Procedure:
To N-(4-chloro-5-(4-(3-(2-methoxyphenyl)-5-methylisoxazole-4-carbonyl)piperazin-1-yl)-2-nitrophenyl)-4-(dimethylamino)benzamide (Example 14, 50 mg, 0.081 mmol) in 7 mL of DCM at −78° C. was added 0.24 mL of 1.0 M boron tribromide in DCM. The solution was stirred at room temperature for 16 hours. Solvent was evaporated in vacuo and the product was purified by preparative HPLC (acetonitrile/water, 10 mM NH4OAc) to give 42 mg of the title compound. 1H-NMR (CDCl3, 400 MHz): δ 11.52 (1H, s), 8.70 (1H, s), 8.30 (1H, s), 7.90 (2H, d, J=9.0 Hz), 7.45-7.33 (2H, m), 7.15-7.07 (1H, m), 7.04-6.95 (1H, m), 6.88 (2H, d, J=8.8 Hz), 4.07-4.00 (2H, m), 3.38 (4H, s), 3.12 (6H, s), 2.99 (2H, s), 2.57 (3H, s). HPLC/MS (Method G): (ES+) m/z (M+H)+=605; Rt=2.29 min.
Reaction SMILES: [N+:1]([O-:4])([O-])=[O:2].[K+].[N+]([O-])(O)=O.C(O)(=O)C.[N+]([O-])(O)=O.[C:18]1([C:24]([F:27])([F:26])[F:25])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>S(=O)(=O)(O)O>[N+:1]([C:20]1[CH:19]=[C:18]([C:24]([F:27])([F:26])[F:25])[CH:23]=[CH:22][CH:21]=1)([O-:4])=[O:2]
Reactant: O=[N+]([O-])[O-]
Reactant: FC(F)(F)c1ccccc1
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: CC(=O)O
Solvent: O=[N+]([O-])O
Product: O=[N+]([O-])c1cccc(C(F)(F)F)c1
Reaction time: 1 h

Procedure:
The nitration step (a) may be effected by using various nitrating agents such as concentrated nitric-sulfuric acid, potassium nitrate--sulfuric acid and nitric acid-acetic acid. The preferred nitrating agent is connected nitric-sulfuric acid. The reaction is carried out by slowly adding fuming nitric acid to a mixture of benzotrifluoride in concentrated sulfuric acid while maintaining the temperature of the reaction between 0° to 40° C., preferably 20°-30° C. When the addition is complete, the reaction is allowed to continue for 1 to 2 hours, preferably 1 hour at room temperature. 3-Nitrobenzotrifluoride is isolated from the reaction mixture by conventional techniques.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)([C:14](O)=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH3:23]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)([C:14]([NH2:23])=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)(c2cccnc2)CC1
Reactant: N
Product: CC(C)(C)OC(=O)N1CCC(C(N)=O)(c2cccnc2)CC1

Procedure:
Prepare by the method of example 20.8 using 1-tert-butoxycarbonyl-4-(pyridin-3-yl)-piperidine-4-carboxylic acid (4.0 mmol) and NH3 (gas). Purify to give the title compound.
Reaction SMILES: [NH2:1][CH2:2][C:3]([OH:5])=[O:4].[C:6]1(=O)[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.C(O)C>O.[Pd]>[CH:6]1([NH:1][CH2:2][C:3]([OH:5])=[O:4])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: O=C1CCCCC1
Reactant: NCC(=O)O
Agent: [Pd]
Solvent: O
Solvent: CCO
Product: O=C(O)CNC1CCCCC1

Procedure:
338 g of glycine (4.5 mols) is dissolved in 1.5 liters of deionized water. The solution is put into a 1-gallon autoclave. 25 g of 10% Pd on C, 551 g of cyclohexanone (5.6 mols) and 500 ml of ethanol are added. Hydrogenation is carried out at 60° C. between 56.2 and 70.3 kg/cm2. In the course of three hours a pressure drop corresponding to 98.4 kg/cm2 is observed.
Reaction SMILES: [CH3:1][CH:2]([CH2:4][CH:5]1[C:18](=O)[CH2:17][CH:16]2[N:7]([CH2:8][CH2:9][C:10]3[C:15]2=[CH:14][C:13]([O:20][CH3:21])=[C:12]([O:22][CH3:23])[CH:11]=3)[CH2:6]1)[CH3:3].Cl.NO.[N:27]1C=CC=CC=1>C(O)C>[CH2:4]([CH:5]1[CH2:6][N:7]2[CH2:8][CH2:9][C:10]3[C:15]([CH:16]2[CH2:17][CH:18]1[NH2:27])=[CH:14][C:13]([O:20][CH3:21])=[C:12]([O:22][CH3:23])[CH:11]=3)[CH:2]([CH3:3])[CH3:1]
Reactant: c1ccncc1
Reactant: COc1cc2c(cc1OC)C1CC(=O)C(CC(C)C)CN1CC2
Agent: Cl
Agent: NO
Solvent: CCO
Product: COc1cc2c(cc1OC)C1CC(N)C(CC(C)C)CN1CC2
Temperature: 25 °C
Reaction time: 24 h

Procedure:
HG-6 was also synthesized using the following alternative method: tetrabenazine (317 mg, 1 mmol) was dissolved in ethanol (EtOH, 10 ml) and hydroxylamine hydrochloride (70 mg, 1 mmol) was added, followed by the addition of pyridine (1 ml). The reaction was refluxed for 2 hours. After removing solvent, the residue was redissolved in methanol (MeOH, 10 ml). To this solution, MoO3 (80 mg) and sodium borohydride (80 mg) were slowly added. The reaction was stirred at room temperature for 24 hours and quenched with water. The aqueous solution was extracted with methylene chloride (10 ml) twice. The combined organic phase was washed with brine and dried with sodium sulfate. After removing solvent, the residue was purified by chromatography. Two hundred and fifty milligrams of HG-6 (3-isobutyl-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1-a]isoquinolin-2-amine) was obtained as white solid (yield: 78%).
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[F:23][C:24]([F:64])([F:63])[C:25]1[CH:26]=[C:27]([C@H:35]([O:37][C@@H:38]2[C@@H:43]([C:44]3[CH:49]=[CH:48][C:47]([F:50])=[CH:46][CH:45]=3)[C@H:42]([CH2:51][N:52]3[CH2:62][CH2:61][C:55]4([CH2:59][O:58][CH2:57][C@H:56]4[OH:60])[CH2:54][CH2:53]3)[CH2:41][CH2:40][O:39]2)[CH3:36])[CH:28]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:30]=1>ClCCl>[F:64][C:24]([F:23])([F:63])[C:25]1[CH:26]=[C:27]([C@H:35]([O:37][C@@H:38]2[C@@H:43]([C:44]3[CH:49]=[CH:48][C:47]([F:50])=[CH:46][CH:45]=3)[C@H:42]([CH2:51][N:52]3[CH2:53][CH2:54][C:55]4([CH2:59][O:58][CH2:57][C:56]4=[O:60])[CH2:61][CH2:62]3)[CH2:41][CH2:40][O:39]2)[CH3:36])[CH:28]=[C:29]([C:31]([F:32])([F:33])[F:34])[CH:30]=1
Reactant: C[C@@H](O[C@H]1OCC[C@@H](CN2CCC3(CC2)COC[C@H]3O)[C@@H]1c1ccc(F)cc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: C[C@@H](O[C@H]1OCC[C@@H](CN2CCC3(CC2)COCC3=O)[C@@H]1c1ccc(F)cc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 60.4 %

Procedure:
Dess-Martin periodinane (0.6 g, 1.4 mmol) was added to a solution of (4S)-8-[(2R,3R,4R)-2-[(1R)-1-(3,5-bis(trifluoromethyl)phenyl)ethoxy]-3-(4-fluorophenyl)-tetrahydropyran-4-yl]methyl-2-oxa-8-aza-spiro[4.5]decan-4-ol (Example 3; 0.85 g, 1.4 mmol) in dichloromethane (20 ml). The mixture was stirred at room temperature for 4 hours then quenched by addition of saturated sodium hydrogen carbonate. After 30 minutes the mixture was partitioned between water and dichloromethane. The organic extracts were dried and concentrated. The residue was chromatographed on silica gel eluting with 2% methanol/dichloromethane to give the title compound (510 mg, 60%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][CH2:9][C:10]1[N:14]=[CH:13][O:12][N:11]=1.[BH4-].[Na+]>CO>[NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][CH2:9][C:10]1[NH:14][CH2:13][O:12][N:11]=1
Reactant: Nc1ccccc1SCc1ncon1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Nc1ccccc1SCC1=NOCN1
Reaction time: 8 h

Procedure:
To a solution of 3-(2-aminophenylthiomethyl)1,2,4-oxadiazole (3.1 g, 0.015 mol) in dry methanol was added sodium borohydride (1.72 g) at 0° in aliquots over 2 hours, with stirring. After standing at 0° overnight a white precipitate had formed. The crude product was recovered by filtration and re-crystallised from ethanol to give 3-(2-aminophenylthiomethyl)-4,5-dihydro-1,2,4-oxadiazole, m.p. 108°.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH:11]([C:26]1[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=1)[C:12]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][N:23]([CH3:25])[CH3:24])=[CH:16][CH:15]=1)=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.[Cl-].[NH4+]>O1CCCC1>[CH2:1]([O:8][CH2:9][CH2:10][CH:11]([C:26]1[CH:27]=[CH:28][C:29]([Cl:32])=[CH:30][CH:31]=1)[C:12]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][N:23]([CH3:24])[CH3:25])=[CH:16][CH:15]=1)([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[OH:13])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Brc1ccccc1
Reactant: CN(C)CCOc1ccc(C(=O)C(CCOCc2ccccc2)c2ccc(Cl)cc2)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CN(C)CCOc1ccc(C(O)(c2ccccc2)C(CCOCc2ccccc2)c2ccc(Cl)cc2)cc1

Procedure:
4-Benzyloxy-2-(4-chlorophenyl)-1-[4-(2-dimethylaminoethoxy)phenyl]butan-1-one (9.4 g, 0.021 mol) is added to Grignard reagent prepared from bromobenzene (13.1 g, 0.083 mol) and Mg turnings (2.0 g, 0.083 mol) in dry tetrahydrofuran. The mixture is refluxed for 3 h. Saturated ammonium chloride solution is added to the cooled reaction mixture, the THF layer is separated and the aqueous phase is extracted with toluene. The combined organic phases are washed with water and the solvents are evaporated. The residual product (10.7 g) is used in the next reaction step without further purification.
Reaction SMILES: [H-].[Na+].[C:3]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])(=[O:15])[CH2:4][C:5]([O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:6].Cl[CH2:22][CH2:23][S:24][CH3:25].O>CN(C)C=O>[CH2:8]([O:7][C:5](=[O:6])[CH:4]([C:3]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:22][CH2:23][S:24][CH3:25])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CSCCCl
Reactant: CC(C)(C)OC(=O)CC(=O)OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CSCCC(C(=O)OCc1ccccc1)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 98.7 %

Procedure:
Sodium hydride (0.96 g, 50% suspension in mineral oil) was added to a stirred solution of t-butyl benzyl malonate (5 g) in dry dimethylformamide (50 ml), maintained at 0° C. under an atmosphere of nitrogen. After stirring for 15 minutes, 2-chloroethyl-methyl sulphide (2.21 g) in dimethylformamide (10 ml) was added dropwise, while the temperature of the reaction was maintained below 10° C. The reaction was allowed to warm to room temperature and stirred for 15 hours when water was cautiously added. The reaction mixture was extracted with ethyl acetate (2×100 ml), the ethyl acetate extracts were washed with water (4×), dried (Na2SO4) and evaporated to give 4-methylthio-2-t-butyloxycarbonyl-butanoic acid benzyl ester as an oil (6.4 g). This product was dissolved in trifluoroacetic acid (50 ml) with vigorous stirring at 0° C. under nitrogen. After stirring for 45 minutes, the trifluoroacetic acid was evaporated under reduced pressure at below 35° C. Final traces of trifuoroacetic acid were removed by azeotroping with carbon tetrachloride (3×20 ml), to leave an oily residue, which was dissolved in pyridine (20 ml). To this solution were added piperidine (0.44 ml) and paraformaldehyde (1.47 g), and the mixture heated at 60° C. under nitrogen for 2 hours. The reaction mixture was cautiously poured onto iced water, and the pH adjusted to 1 using concentrated suphuric acid. The mixture was extracted with ether (2×100 ml), and the ether extracts dried (Na2SO4) and evaporated under reduced pressure to yield the crude product (5.4 g) as an oil. This was chromatographed over silica gel, eluting with a mixture of hexane and ethyl acetate, to yield the title ester as a colourless oil (1.22 g). Found: C,64.69; H,6.55. C13H16O2S (0.25 H2O) requires C,64.85; H,6.91%.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([O:10][CH3:11])[C:5]([O:8][CH3:9])=[CH:6][CH:7]=1.[CH3:12][O:13]C(Cl)Cl>C(Cl)Cl.[Ti](Cl)(Cl)(Cl)Cl>[CH3:11][O:10][C:4]1[C:5]([O:8][CH3:9])=[CH:6][C:7]([CH:12]=[O:13])=[C:2]([F:1])[CH:3]=1
Reactant: COC(Cl)Cl
Reactant: COc1ccc(F)cc1OC
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: COc1cc(F)c(C=O)cc1OC
Temperature: 0 °C

Procedure:
In a flame-dried, round-bottomed flask fitted with a magnetic stirrer and N2 inlet was placed 4-fluoroveratrole (0.78 g, 5.0 mmol, Aldrich Chemical Co.) in 20 ml of anhydrous CH2Cl2. After cooling to 0° C., titanium (IV) chloride (0.91 ml, 1.57 g, 8.3 mmol) was added, followed after 10 min. by a,a-dichloromethyl methyl ether (0.45 ml, 0.575 g, 5.0 mmol). The mixture was allowed to warm to room temperature and after 2 hr it was quenched with an excess of aqueous saturated NaHCO3. The suspension was filtered through a pad of d.e. (diatomaceous earth), the aqueous phase was extracted with additional amounts of CH2Cl2 and the organic phases were combined and washed with water followed by saturated aqueous NaCl. After drying with MgSO4, the organic solvent was removed in vacuo to give the title compound as a white solid, 910 mg.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([CH:18]([CH3:20])[CH3:19])=[CH:14][N:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:21][CH:22]([CH3:26])[CH:23](O)[CH3:24].C(#N)C>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([N:11]([C:12]2[CH:17]=[CH:16][C:15]([CH:18]([CH3:20])[CH3:19])=[CH:14][N:13]=2)[CH:23]([CH:22]([CH3:26])[CH3:21])[CH3:24])(=[O:10])=[O:9])=[CH:6][CH:7]=1
Reactant: CC(C)c1ccc(NS(=O)(=O)c2ccc(F)cc2)nc1
Reactant: CC(C)C(C)O
Solvent: Cc1ccccc1
Solvent: CC#N
Product: CC(C)c1ccc(N(C(C)C(C)C)S(=O)(=O)c2ccc(F)cc2)nc1
Temperature: 150 °C
Yield: 12.7 %

Procedure:
To a solution of 4-fluoro-N-(5-isopropylpyridin-2-yl)benzenesulfonamide (203 mg, 0.690 mmol) and 3-methylbutan-2-ol (60.8 mg, 0.690 mmol) in toluene (3 mL) stirred in air at room temperature was added a solution of 2-tributylphosphoranylidene)acetonitrile (166 mg, 0.690 mmol) in toluene (0.5 mL). The reaction vessel was sealed and heated by microwaves to 150° C. for 30 minutes. After cooling, the solvent was evaporated in vacuo and the crude purified by mass directed autoprep (formic acid modifier) to give the title product (32 mg) as a colourless oil. LCMS (2 min, formic) Rt 1.41 min, m/z (ES+) 365 (M+H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([O:16][CH2:17][CH:18]([CH3:21])[CH2:19][CH3:20])=[O:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][OH:35].[I-].[K+]>CC(C)=O>[OH:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([O:16][CH2:17][CH:18]([CH3:21])[CH2:19][CH3:20])=[O:15])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: OCCCCCCCl
Reactant: CCC(C)COC(=O)c1ccc(-c2ccc(O)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCC(C)COC(=O)c1ccc(-c2ccc(OCCCCCCO)cc2)cc1
Yield: 34.1 %

Procedure:
2.84 g of 2-methylbutyl 4'-hydroxybiphenyl-4-carboxylate, 4.14 g of potassium carbonate, 4.10 g of 6-chloro-1-hexanol and 4.28 g of potassium iodide were heat-refluxed for 48 hours in acetone. The mixture was subjected to filtration, condensation and purification by column chromatography to obtain 1.31 g of the objective product (yield: 34%).
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[N:14]([NH2:18])[CH:13]=[CH:12]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.Cl[C:21]1[CH:26]=[CH:25][N:24]=[CH:23][C:22]=1[F:27].C([O-])([O-])=O.[K+].[K+]>CN1CCCC1=O>[F:27][C:22]1[CH:23]=[N:24][CH:25]=[CH:26][C:21]=1[NH:18][N:14]1[C:15]2[C:11](=[CH:10][C:9]([O:8][CH2:7][C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[CH:17][CH:16]=2)[CH:12]=[CH:13]1
Reactant: Fc1cnccc1Cl
Reactant: Nn1ccc2cc(OCc3ccccc3)ccc21
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: Fc1cnccc1Nn1ccc2cc(OCc3ccccc3)ccc21
Temperature: 80 °C
Reaction time: 0.08 h

Procedure:
To 250 ml 1-methyl-2-pyrrolidinone was added 5-phenylmethoxy-1H-indol-1-amine (27.3 g), and the mixture was heated to 80° C. Then, 4-chloro-3-fluoropyridine hydrochloride (22 g) was added, and the mixture was heated at 80° C. for two hours. After cooling, the mixture was poured into 1 liter of ice-water, stirred for five minutes, and adjusted to pH 9 with milled K2CO3. The product was extracted with ethyl acetate (3×). The organic layer was washed with water (2×) and dried (saturated NaCl, anhydrous MgSO4). After filtration, the filtrate was concentrated to give an oil, 46 g of which was eluted on a silica gel column with ethyl acetate/dichloromethane (1:1) via HPLC. The desired fractions were combined and concentrated to give an oil, which solidified on cooling, 32.2 g, m.p. 140° C. A sample of this material was recrystallized from ether, m.p. 157°-159° C.