Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[OH:11][CH2:12][C@H:13]1[CH2:18][CH2:17][C@H:16]([CH2:19][CH2:20][C:21]2[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[CH:23][CH:22]=2)[CH2:15][CH2:14]1.C(N(CC)CC)C>C(Cl)Cl.O>[C:25]([C:24]1[CH:27]=[CH:28][C:21]([CH2:20][CH2:19][C@H:16]2[CH2:17][CH2:18][C@H:13]([CH:12]=[O:11])[CH2:14][CH2:15]2)=[CH:22][CH:23]=1)#[N:26]
Reactant: N#Cc1ccc(CC[C@H]2CC[C@H](CO)CC2)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: ClCCl
Product: N#Cc1ccc(CC[C@H]2CC[C@H](C=O)CC2)cc1
Temperature: 25 °C

Procedure:
A mixture of 9.3 g of oxalyl chloride and 166 ml of methylene chloride was treated dropwise with 10 minutes with a solution of 11.4 g of dimethyl sulphoxide in 33 ml of methylene chloride while stirring and gassing with nitrogen at -60° C. Thereafter, the mixture was treated dropwise within 15 minutes at -60° C. with a solution of 16.2 g of p-[2-(trans-4-hydroxymethylcyclohexyl)ethyl]benzonitrile in 66 ml of methylene chloride and the resulting mixture was stirred for a further 15 minutes at -60° C. Subsequently, the reaction mixture was treated dropwise within 15 minutes at -60° C. with 46.6 ml of triethylamine, the mixture was then warmed to room temperature within 30 minutes, poured into 330 ml of water and extracted three times with 200 ml of methylene chloride each time. The organic phases were washed twice with 200 ml of water each time, dried over sodium sulphate and concentrated at 50° C. in vacuo. Low-pressure chromatography (0.3 bar) of the resulting, brownish crystals (16.5 g) on silica gel with methylene chloride gave 14.4 g (89.6%) of pure trans-4-[2-(p-cyanophenyl)ethyl]cyclohexanecarboxaldehyde as colourless crystals with m.p. 90.0°-91.2° C.
Reaction SMILES: [NH2:1][C:2]1([C:5]2[CH:14]=[CH:13][C:8]([C:9]([O:11]C)=[O:10])=[CH:7][CH:6]=2)[CH2:4][CH2:3]1.Cl[CH2:16][CH2:17][CH2:18][S:19](Cl)(=[O:21])=[O:20]>>[O:20]=[S:19]1(=[O:21])[CH2:18][CH2:17][CH2:16][N:1]1[C:2]1([C:5]2[CH:14]=[CH:13][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=2)[CH2:4][CH2:3]1
Reactant: O=S(=O)(Cl)CCCCl
Reactant: COC(=O)c1ccc(C2(N)CC2)cc1
Product: O=C(O)c1ccc(C2(N3CCCS3(=O)=O)CC2)cc1

Procedure:
Using methyl 4-(1-aminocyclopropyl)benzoate (532 mg) and 3-chloropropane-1-sulfonyl chloride (0.44 mL) and by the reaction and treatment in the same manner as in Preparation Example 16, the title compound (559 mg) was obtained.
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][C:35]([C:37]1[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[C:39]([F:45])[CH:38]=1)=[O:36]>>[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:13][CH2:14][N:15]([CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][C:35]([C:37]3[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[C:39]([F:45])[CH:38]=3)=[O:36])[CH2:16][CH2:17]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1
Reactant: COc1ccc(C(=O)CCCCCBr)cc1F
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1ccc(C(=O)CCCCCN2CCC(CNC(=O)c3cc(Cl)c(N)cc3OC)CC2)cc1F
Yield: 64.2 %

Procedure:
4-Amino-5-chloro-2-methoxy-N-(piperidin-4-ylmethyl)benzamide dihydrochloride (1.0 g) as starting compound, potassium carbonate (1.5 g) and 6-bromo-1-(3-fluoro-4-methoxyphenyl)-1-hexanone (0.94 g) were reacted and treated in the same manner as in Example 172 to give 0.90 g of 4-amino-5-chloro-N-((1-(6-(3-fluoro-4-methoxyphenyl)-6-oxohexyl)-piperidin-4-yl)methyl)-2-methoxybenzamide.
Reaction SMILES: [C:1]1([C@@H:7]2[CH2:9][O:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCOCC.[Mg+2].[Br-].[Br-].[CH2:18]([NH:21][CH2:22][CH:23]=[CH2:24])[CH:19]=[CH2:20].[Cl-].[NH4+]>O1CCCC1>[CH2:18]([N:21]([C@@H:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH2:9][OH:8])[CH2:22][CH:23]=[CH2:24])[CH:19]=[CH2:20]
Reactant: c1ccc([C@@H]2CO2)cc1
Reactant: C=CCNCC=C
Agent: [Br-]
Agent: [Cl-]
Agent: [Mg+2]
Solvent: C1CCOC1
Solvent: CCOCC
Product: C=CCN(CC=C)[C@H](CO)c1ccccc1
Temperature: 25 °C
Yield: 97 %

Procedure:
In a 100 ml 2-necked flask equipped with a reflux condenser, a thermometer, a magnetic stirrer and an inert gas supply, 20 ml tetrahydrofuran were added to 2.3 ml (R)-phenyloxirane (20 mmol) and 1.03 g magnesium bromide ethyl etherate (4 mmol) were dissolved therein. The yellowish solution was mixed with 4.9 ml diallylamine and refluxed for 2 h. The orange-brown solution was cooled to room temperature, stirred for 15 min with 20 ml 5M ammonium chloride solution and the aqueous phase was separated. The organic phase was dried with 8.5 g sodium sulfate, filtered and washed with 10 ml tetrahydrofuran. The solvent was concentrated and the orange-brown oil was dried during 1 h to yield 4.2 g (97%) of (S)-2-(N,N-diallylamino)-2-phenylethanol and (R)-2-(N,N-diallylamino)-1-phenylethanol.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4](/[CH:9]=[CH:10]/[C:11]2[CH:19]=[CH:18][C:14]([C:15]([OH:17])=[O:16])=[C:13]([NH:20][C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)[CH:12]=2)[CH:5]=[CH:6][C:7]=1[CH3:8].C(OCC)(=O)C>[C].[Pd].CO>[CH3:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][C:11]2[CH:19]=[CH:18][C:14]([C:15]([OH:17])=[O:16])=[C:13]([NH:20][C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)[CH:12]=2)[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: Cc1ccc(/C=C/c2ccc(C(=O)O)c(Nc3ccc(F)cc3)c2)cc1C
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: Cc1ccc(CCc2ccc(C(=O)O)c(Nc3ccc(F)cc3)c2)cc1C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To the obtained 4-((E)-2-(3,4-dimethylphenyl)vinyl)-2-(4-fluoroanilino)benzoic acid were added ethyl acetate 1.0 mL, methanol 1.0 mL and 10% palladium-carbon 10 mg sequentially, and it was stirred under hydrogen atmosphere at room temperature for 2 hours. The solvent was removed under reduced pressure after insoluble matter was filtrated to give 4-(2-(3,4-dimethylphenyl)ethyl)-2-(4-fluoroanilino)benzoic acid 2.5 mg of a white solid.
Reaction SMILES: [C:1]([O:5][C@@H:6]1[CH2:11][NH:10][C@H:9]([C:12]([N:14]2[CH2:19][CH2:18][N:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:16][CH2:15]2)=[O:13])[C@@H:8]([C:26]([O:28][CH3:29])=[O:27])[CH2:7]1)([CH3:4])([CH3:3])[CH3:2].C(Cl)Cl.Cl[C:34]([O:36][CH3:37])=[O:35]>CN(C)C1C=CN=CC=1>[C:1]([O:5][C@@H:6]1[CH2:11][N:10]([C:34]([O:36][CH3:37])=[O:35])[C@H:9]([C:12]([N:14]2[CH2:19][CH2:18][N:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:16][CH2:15]2)=[O:13])[C@@H:8]([C:26]([O:28][CH3:29])=[O:27])[CH2:7]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)Cl
Reactant: COC(=O)[C@H]1C[C@H](OC(C)(C)C)CN[C@@H]1C(=O)N1CCN(c2ccccc2)CC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: COC(=O)[C@H]1C[C@H](OC(C)(C)C)CN(C(=O)OC)[C@@H]1C(=O)N1CCN(c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of methyl (2S,3S,5S)-5-tert-butoxy-2-[(4-phenylpiperazin-1-yl)carbonyl]piperidine-3-carboxylate (0.03345 g, 8.290E-5 mol) and 4-dimethylaminopyridine (0.0152 g, 0.000124 mol) in methylene chloride (1.50 mL, 0.0234 mol) was added methyl chloroformate (0.00833 mL, 0.000108 mol). The reaction was stirred at rt overnight. After quenched with aq. sodium bicaronate, the reaction was extracted with ethyl acetate. The combined organic layers were washed with brine, dried, concentrated to dry. The resulting residue was used directly in next step. MS (ESI): (M+H)+=462.2.
Reaction SMILES: [O:1]([C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[CH2:11][CH2:12][C:13]2=O)[Si](C(C)(C)C)(C)C.[BH4-].[Na+].Cl.C(O)(=O)C(O)=O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.[NH4+].[Cl-]>CO.C1COCC1>[OH:1][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[CH:11]=[CH:12][CH2:13]2
Reactant: CC(C)(C)[Si](C)(C)Oc1cccc2c1CCC2=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: O=C(O)C(=O)O
Solvent: CO
Solvent: C1CCOC1
Product: Oc1cccc2c1C=CC2
Reaction time: 8 h
Yield: 65.1 %

Procedure:
To a solution of 4-(tert-butyldimethylsiloxy)-1-indanone (35.0 g, 133 mmol) in methanol/THF (100 ml:200 ml) was NaBH4 (7.57 g, 200 mmol) added in portions at 0° C. The reaction mixture is stirred overnight. The resulting solution is poured on ice, acidified with concentrated hydrochloric acid to pH=1 and extracted with diethyl eter (2×200 ml). The organic fractions were combined and washed with brine, water and dried over sodiumsulfate. The solvents were evaporated and the remaining oil (siloxyindanol) was dissolved in toluene (300 ml). To this solution was oxalic acid (24.0 g, 267 mmol) added. The mixture was heated under reflux for 3 hours, whereafter the reaction mixture was washed with a 10% aqueous solution of NaHCO3 and dried over sodiumsulfate. The solvent was removed by evaporation. The remaining yellow oil was dissolved in THF (300 ml) and treated with tetra-n-butylammonium fluoride (69.6 g, 266 mmol) at 0° C. and stirred for 30 min at room temperature. The reaction solution was treated with a saturated NH4Cl solution (200 ml) and extracted with diethyl ether (2×200 ml) The organic phase was collected, evaporation of solvent left a solid which was recrystallized from methanol to give a pale yellow solid (11.45 g, 86.6 mmol, 65.10%).
Reaction SMILES: CC([N:5]([C@H:9]1[CH2:14][CH2:13][C@@H:12]([CH3:15])[N:11]([C:16]2[CH:21]=[C:20]([C:22]3[CH:27]=[CH:26][C:25]([C:28]#[N:29])=[C:24]([F:30])[CH:23]=3)[N:19]=[C:18]([NH2:31])[N:17]=2)[CH2:10]1)C(=O)[O-])(C)C.[ClH:32]>O1CCOCC1>[ClH:32].[NH2:31][C:18]1[N:19]=[C:20]([C:22]2[CH:27]=[CH:26][C:25]([C:28]#[N:29])=[C:24]([F:30])[CH:23]=2)[CH:21]=[C:16]([N:11]2[CH2:10][C@@H:9]([NH2:5])[CH2:14][CH2:13][C@H:12]2[CH3:15])[N:17]=1
Reactant: C[C@@H]1CC[C@H](N(C(=O)[O-])C(C)(C)C)CN1c1cc(-c2ccc(C#N)c(F)c2)nc(N)n1
Agent: Cl
Solvent: C1COCCO1
Product: C[C@@H]1CC[C@H](N)CN1c1cc(-c2ccc(C#N)c(F)c2)nc(N)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1,1-dimethylethyl{(3S,6R)-1-[2-amino-6-(4-cyano-3-fluorophenyl)-4-pyrimidinyl]-6-methyl-3-piperidinyl}carbamate (985 mg, 2.310 mmol) in 1,4-dioxane (5 mL) was added 4M HCl in 1,4-dioxane (10 mL, 40.0 mmol) into a 40 mL vial. A solid formed, and the mixture was stirred at room temperature for 30 minutes, then concentrated to afford an HCl salt of the title compound (1.15 g) as a white solid. LC-MS (ES) m/z=327 [M+H]+.
Reaction SMILES: [N:1]([C:4]1[CH:13]=[CH:12][C:7]([C:8](=O)[CH2:9]Br)=[CH:6][CH:5]=1)=[N+:2]=[N-:3].[NH2:14][C:15]1[CH:20]=[CH:19][C:18]([I:21])=[CH:17][N:16]=1>C(#N)C>[N:1]([C:4]1[CH:13]=[CH:12][C:7]([C:8]2[N:14]=[C:15]3[CH:20]=[CH:19][C:18]([I:21])=[CH:17][N:16]3[CH:9]=2)=[CH:6][CH:5]=1)=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=Nc1ccc(C(=O)CBr)cc1
Reactant: Nc1ccc(I)cn1
Solvent: CC#N
Product: [N-]=[N+]=Nc1ccc(-c2cn3cc(I)ccc3n2)cc1
Temperature: 80 °C
Yield: 65.2 %

Procedure:
218 mg (corresponding to 0.909 mmol) of 4-azidophenacylbromide and 200 mg (corresponding to 0.909 mmol) of 2-amino-5-iodopyridine were dissolved in 1.0 mL of acetonitrile. The resulting solution was heated in an oil bath at 80° C. for 3 hours. After the completion of the reaction, the reaction solution was cooled down to room temperature, and precipitates were filtered. Then, the precipitates were washed with acetonitrile and dried under reduced pressure. The resulting crude crystals were suspended in a mixed solution of 3 mL of water and 3 mL of methanol. Then, about 4 mL of a saturated sodium hydrogencarbonate solution was added thereto, and the mixture was sonicated for 5 minutes using an ultrasonic washing machine. Precipitates were filtered and recovered from the resulting mixture, sufficiently washed with water, and dried under reduced pressure, to obtain 214 mg (corresponding to 0.593 mmol) of 2-(4-azidophenyl)-6-iodoimidazo[1,2-a]pyridine (FIG. 1, step 1).
Reaction SMILES: [N:1]([CH2:4][CH:5]1[CH2:9][C:8]2[CH:10]=[C:11]([Cl:19])[CH:12]=[C:13]([C:14]3[CH:18]=[CH:17][S:16][CH:15]=3)[C:7]=2[O:6]1)=[N+]=[N-]>[Pt]>[Cl:19][C:11]1[CH:12]=[C:13]([C:14]2[CH:18]=[CH:17][S:16][CH:15]=2)[C:7]2[O:6][CH:5]([CH2:4][NH2:1])[CH2:9][C:8]=2[CH:10]=1
Reactant: [N-]=[N+]=NCC1Cc2cc(Cl)cc(-c3ccsc3)c2O1
Agent: [Pt]
Product: NCC1Cc2cc(Cl)cc(-c3ccsc3)c2O1
Yield: 85 %

Procedure:
Treatment of (±)-(5-chloro-7-thien-3-yl-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (0.18 g, 0.43 mmol) with sodium azide (0.11 g, 1.72 mmol) generally according to the procedure described for Intermediate 98 provided 0.13 g of (±)-2-(azidomethyl)-5-chloro-7-thien-3-yl-2,3-dihydro-1-benzofuran. Treatment of the azide with sulfided platinum on carbon (120 mg, 5 wt. %) generally according to the procedure described for Example 1 gave 0.11 g (85%) of (±)-(5-chloro-7-thien-3-yl-2,3-dihydro-1-benzofuran-2-yl)methylamine as a light yellow solid, hydrochloride salt. mp 230° C. (dec); Anal. calcd. for C13H12ClNOSHCl: C, 51.66; H, 4.34; N, 4.63. Found: C, 45.27; H, 4.19; N, 3.93.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[C:20]([F:21])=[CH:19][C:18]([C:22](=O)[CH2:23][CH2:24][C:25](OCC)=[O:26])=[CH:17][C:16]=2[F:31])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O.[NH2:33][NH2:34]>C(O)(C)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[C:20]([F:21])=[CH:19][C:18]([C:22]3[CH2:23][CH2:24][C:25](=[O:26])[NH:34][N:33]=3)=[CH:17][C:16]=2[F:31])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)CCC(=O)c1cc(F)c(OC2CCN(C(=O)OC(C)(C)C)CC2)c(F)c1
Reactant: NN
Solvent: CC(C)O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(Oc2c(F)cc(C3=NNC(=O)CC3)cc2F)CC1
Yield: 14.1 %

Procedure:
A mixture of 4-[4-(3-ethoxycarbonyl-propionyl)-2,6-difluoro-phenoxy]-piperidine-1-carboxylic acid tert-butyl ester (3.21 g, 7.27 mmol) and hydrazine monohydrate (0.7 mL, 14.1 mmol) in isopropanol (20 mL) was stirred at reflux overnight. Isopropanol was concentrated at reduced pressure and partitioned between saturated aqueous sodium bicarbonate solution and methylene chloride. The aqueous layer was extracted twice with methylene chloride and the combined organics was washed with brine, dried (Na2SO4), filtered, and concentrated to provide a crude material. The crude material was purified by ISCO (80 g silica gel column) chromatography using 15 to 60% EtOAc in hexane to obtain 4-[2,6-difluoro-4-(6-oxo-1,4,5,6-tetrahydro-pyridazin-3-yl)-phenoxy]-piperidine-1-carboxylic acid tert-butyl ester (0.42 g, 14%).
Reaction SMILES: [O:1]=[Si]=O.[OH-].[Na+:5].[O-:6][Si:7]([O-:9])=[O:8].[Na+].[Na+]>>[Si:7]([O-:1])([O-:9])([O-:6])[O-:8].[Na+:5].[Na+:5].[Na+:5].[Na+:5]
Reactant: O=[Si]=O
Reactant: O=[Si]([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Product: [O-][Si]([O-])([O-])[O-]

Procedure:
EP 0 425 428 B1 likewise describes a process for the preparation of crystalline sodium silicates having a sheet structure and the aforementioned molar ratio and also a water content of less than 0.3% by weight from a water glass solution having at least 20% by weight of solids, which comprises obtaining the water glass solution by reacting quartz sand with sodium hydroxide solution, treating the water glass solution in a spray-drying zone at 200 to 300° C. and for a residence time of from 10 to 25 seconds, the temperature of the waste gas leaving the spray-drying zone being from 90 to 130° C., to form a pulverulent sodium silicate, which is then introduced into an inclined rotary kiln fitted with a solids agitation device and treated countercurrently with flue gas at temperatures of from 500 to 850° C. for a period of up to 60 minutes to form crystalline sodium silicate.
Reaction SMILES: N1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O=O>[Ni].C([O-])(=O)C.[Cu+2].C([O-])(=O)C.CCCCCCC>[CH3:2][CH:3]([CH2:4][CH2:5][CH2:6][CH:3]([CH2:4][CH2:5][CH2:6][CH:3]([CH2:4][CH2:5][CH2:6][CH2:2][CH:3]([CH2:4][CH2:5][CH2:6][CH:3]([CH2:4][CH2:5][CH2:6][CH:3]([CH3:4])[CH3:2])[CH3:2])[CH3:6])[CH3:2])[CH3:2])[CH3:5]
Reactant: c1ccncc1
Agent: [Cu+2]
Agent: [Ni]
Agent: CC(=O)[O-]
Solvent: CCCCCCC
Product: CC(C)CCCC(C)CCCC(C)CCCCC(C)CCCC(C)CCCC(C)C
Reaction time: 5 h

Procedure:
In a 2-l. three-necked and round-bottomed flask were placed 220 g of 3,7,11-trimethyl-6,10-dien-1-in-3-ol, 1 g of copper acetate, 20.2 ml of pyridine and 440 ml of n-heptane. The mixture was stirred at temperatures of 60°~70°C for 5 hours by passing oxygen. The reaction mixture was washed with a 3N-H2SO4 -solution and then with a 10 % aqueous sodium chloride solution respectively three times and the n-heptane was distilled off to give 348 g of a crude product. A 100 g portion of this crude product was placed in a 500 ml autoclave and 200 ml of n-heptane, 1.8 g of nickel catalyst supported on diatomaceous earth which is roughly the same amount as that of nickel and 3.6 g of silica-alumina (alumina: 28~30 %) were added thereto. The mixture was subjected to hydrogenolysis at a temperature of 200°C under a hydrogen pressure of 100~20 kg/cm2 with stirring for 16 hours. After filtering off the catalyst and distilling off the n-heptane, the residue was distilled off at 202° - 208°C under reduced pressure of 0.3 - 0.4 mmHg to give 45.0 g of squalane.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([CH2:11][CH3:12])=[CH:7]2.C[Mg]I.[Cl:16][C:17]1[C:18]([Cl:26])=[C:19]([CH:23]=[CH:24][CH:25]=1)[C:20](Cl)=[O:21].[NH4+].[Cl-]>CCOCC.C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([CH2:11][CH3:12])=[C:7]2[C:20]([C:19]1[CH:23]=[CH:24][CH:25]=[C:17]([Cl:16])[C:18]=1[Cl:26])=[O:21]
Reactant: O=C(Cl)c1cccc(Cl)c1Cl
Reactant: CCc1cc2cccc(Br)c2[nH]1
Agent: C[Mg]I
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCc1[nH]c2c(Br)cccc2c1C(=O)c1cccc(Cl)c1Cl
Reaction time: 3 h
Yield: 35.7 %

Procedure:
3.45 g of 7-bromo-2-ethyl-1H-indole are placed under nitrogen in 30 ml of ether and the mixture is cooled to +3° C.; 5.1 ml of methylmagnesium iodide in 20 ml of ether and then 5.9 g of dichlorobenzoyl chloride in 30 ml of ether are added. 10 ml of THF are added and the mixture is allowed to return to AT and is stirred for 3 hours. The medium is poured onto a saturated NH4Cl solution and is then extracted with ether. The organic phase is washed with a 10% HCl solution, a 10% NaOH solution, water and an NaCl solution. It is dried and evaporated and then the residue is chromatographed on silica while eluting with an AcOEt/cyclohexane (3/7, v/v) mixture. 2.18 g of the expected compound are obtained.
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([CH:6](P(OCC)(OCC)=O)[F:7])=[O:5].C([Li])CCC.[C:21]([NH:28][CH2:29][CH:30]=O)([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22].O>C1COCC1>[C:24]([O:23][C:21]([NH:28][CH2:29]/[CH:30]=[C:6](/[F:7])\[C:4]([O:3][CH2:2][CH3:1])=[O:5])=[O:22])([CH3:27])([CH3:26])[CH3:25]
Reactant: CCOC(=O)C(F)P(=O)(OCC)OCC
Reactant: CC(C)(C)OC(=O)NCC=O
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)/C(F)=C\CNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 84.9 %

Procedure:
To a stirred solution of triethyl 2-fluoro-2-phosphonoacetate (0.61 mL, 3 mmol) in dry THF (40 mL) at −10° C. under nitrogen was added n-butyllithium (2.5 M solution in hexanes; 1.16 mL, 2.9 mmol) dropwise. The contents of the vessel were allowed to stir for 5 mins at −10° C. before addition of N-Boc-aminoacetaldehyde (0.378 g, 2.5 mmol, in 5 mL THF). The reaction mixture was then allowed to warm to room temperature and stirred for 16 hours. Water (50 mL) was added to the mixture and the organic layer extracted with diethyl ether (50 mL) and washed with brine (20 mL), dried over MgSO4, filtered and the solvent removed under reduced pressure to afford the crude product as a clear oil (0.850 g). Purification by flash chromatography (silica, ˜4 g) eluting in 5-15% EtOAc in n-hexane afforded (E)-ethyl 4-(tert-butoxycarbonylamino)-2-fluorobut-2-enoate (0.525 g, 85%) as a clear oil and a mixture of 10:1 E:Z; E(major)-isomer 1H-NMR (200 MHz, CDCl3): δppm: 1.36 (3H, t, J 7.0 Hz), 1.45 (9H, s), 4.17 (2H, m), 4.32 (2H, q, J 7.0 Hz), 4.88 (1H, br s), 6.01 (1H, dt, J 19.5, 7.2).
Reaction SMILES: [C:1]1(C)C=CC(S(O)(=O)=O)=CC=1.[OH:12][C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[CH:18]([C:22]([OH:24])=[O:23])[CH2:17][CH2:16]2>CO>[OH:12][C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[CH:18]([C:22]([O:24][CH3:1])=[O:23])[CH2:17][CH2:16]2
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: O=C(O)C1CCc2cc(O)ccc21
Solvent: CO
Product: COC(=O)C1CCc2cc(O)ccc21
Temperature: 90 °C
Yield: 10949.9 %

Procedure:
In a 20-liter reactor with a mechanical stirrer, 1.6 kg of 2,3-dihydro-5-hydroxy-1H-inden-1-carboxylic acid were dissolved with 7.2 l of absolute methanol, 9 g of p-toluenesulphonic acid were added and then refluxed under stirring in oil bath heated at 90° C. for 24 hours. The mixture was allowed to cool, the excess of methanol was evaporated at vacuum, the residue was diluted with 1.5 l of water, 1.5 l of sodium bicarbonate saturated solution and 5 l of toluene and then stirred for 30 minutes. The insoluble material was filtered, washed twice with 1 l of toluene; the aqueous phase was extracted with 2 l of toluene, and the organic phases were filtered using a filter paper and washed with water. The toluene phase was concentrated at vacuum to give a blackish, viscous liquid residue weighing 1.391 kg (88%), which was distilled at vacuum to give 1.1 kg (70%) of colourless liquid at 124°-137° C./0.03-0.025 tors, nD20 =1.5533, IR and 1H-NMR spectra were consistent with structure.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:35])=[C:4]([CH3:34])[C:5]2[O:9][C:8]([CH2:11][N:12]3[CH2:17][CH2:16][CH:15]([NH:18][CH:19]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[CH2:14][CH2:13]3)([CH3:10])[CH2:7][C:6]=2[C:32]=1[CH3:33]>CCCCCC.CC(O)C>[NH2:1][C:2]1[C:3]([CH3:35])=[C:4]([CH3:34])[C:5]2[O:9][C@@:8]([CH2:11][N:12]3[CH2:17][CH2:16][CH:15]([NH:18][CH:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=4)[CH2:14][CH2:13]3)([CH3:10])[CH2:7][C:6]=2[C:32]=1[CH3:33]
Reactant: Cc1c(C)c2c(c(C)c1N)CC(C)(CN1CCC(NC(c3ccccc3)c3ccccc3)CC1)O2
Solvent: CC(C)O
Solvent: CCCCCC
Product: Cc1c(C)c2c(c(C)c1N)C[C@@](C)(CN1CCC(NC(c3ccccc3)c3ccccc3)CC1)O2

Procedure:
1-[(5-Amino-2,3-dihydro-2,4,6,7-tetramethylbenzofuran-2-yl)methyl]-N-(diphenylmethyl)-4-piperidinamine was subjected to preparative high-performance liquid chromatography (column: CHIRALCEL OD (20×250 mm, Daicel Chemical Industry, Ltd.), mobile phase: hexane-2-propanol=95:5); flow rate: 80 mL/min., column temperature: 30° C.) to provide the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([S:15][C:16]2[CH:24]=[CH:23][C:19]([C:20]([OH:22])=O)=[CH:18][C:17]=2[NH:25][C:26]2[C:27]3[CH:35]=[CH:34][C:33]([CH:36]([CH3:38])[CH3:37])=[N:32][C:28]=3[N:29]=[CH:30][N:31]=2)=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:39]1([CH3:48])[CH:44]=[CH:43][CH:42]=[C:41]([CH2:45][CH2:46][NH2:47])[CH:40]=1>>[C:1]([O:5][C:6](=[O:7])[NH:8][C:9]1[CH:10]=[CH:11][C:12]([S:15][C:16]2[CH:24]=[CH:23][C:19]([C:20](=[O:22])[NH:47][CH2:46][CH2:45][C:41]3[CH:40]=[C:39]([CH3:48])[CH:44]=[CH:43][CH:42]=3)=[CH:18][C:17]=2[NH:25][C:26]2[C:27]3[CH:35]=[CH:34][C:33]([CH:36]([CH3:37])[CH3:38])=[N:32][C:28]=3[N:29]=[CH:30][N:31]=2)=[CH:13][CH:14]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: Cc1cccc(CCN)c1
Reactant: CC(C)c1ccc2c(Nc3cc(C(=O)O)ccc3Sc3ccc(NC(=O)OC(C)(C)C)cc3)ncnc2n1
Product: Cc1cccc(CCNC(=O)c2ccc(Sc3ccc(NC(=O)OC(C)(C)C)cc3)c(Nc3ncnc4nc(C(C)C)ccc34)c2)c1

Procedure:
According to the procedure in Example 385F, the title compound was prepared using 4-(4-tert-butoxycarbonylamino-phenylsulfanyl)-3-(7-isopropyl-pyrido[2,3-d]pyrimidin-4-ylamino)-benzoic acid (prepared in Example 385E) and 2-(m-tolyl)ethylamine.