Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:18])[CH2:15][CH2:16][CH3:17])[C:11]([CH3:19])=[CH:10][C:9]=1[NH2:20])(C)(C)C.C(O[C:27](=[O:50])[CH2:28][C:29](=O)[C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]2[O:37][CH:38]=[C:39]([CH2:41][O:42]C3CCCCO3)[N:40]=2)[CH:31]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[OH:42][CH2:41][C:39]1[N:40]=[C:36]([C:32]2[CH:31]=[C:30]([C:29]3[CH2:28][C:27](=[O:50])[NH:20][C:9]4[CH:10]=[C:11]([CH3:19])[C:12]([N:14]([CH3:18])[CH2:15][CH2:16][CH3:17])=[CH:13][C:8]=4[N:7]=3)[CH:35]=[CH:34][CH:33]=2)[O:37][CH:38]=1
Reactant: CCCN(C)c1cc(NC(=O)OC(C)(C)C)c(N)cc1C
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2nc(COC3CCCCO3)co2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCN(C)c1cc2c(cc1C)NC(=O)CC(c1cccc(-c3nc(CO)co3)c1)=N2

Procedure:
The title compound was prepared from [2-amino-4-methyl-5-(methyl-propyl-amino)-phenyl]-carbamic acid tert-butyl ester (0.21 g) (Example J24) and 3-oxo-3-[3-[4-(tetrahydro-pyran-2-yloxymethyl)-oxazol-2-yl]-phenyl]-propionic acid tert-butyl ester (Example K11) (0.31 g) according to the general procedure M. The obtained material was deprotected and cyclized by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a yellow solid (0.16 g).
Reaction SMILES: [C:1]([C:5]1[CH:23]=[CH:22][C:8]([O:9][C@@H:10]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=2)[C:11]([OH:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(Cl)(=O)C(Cl)=O.[CH3:30][Si:31]([CH3:36])([CH3:35])[CH2:32][CH2:33]O>>[C:1]([C:5]1[CH:23]=[CH:22][C:8]([O:9][C@@H:10]([CH2:14][C:15]2[CH:16]=[CH:17][C:18]([OH:21])=[CH:19][CH:20]=2)[C:11]([O:13][CH2:33][CH2:32][Si:31]([CH3:36])([CH3:35])[CH3:30])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: C[Si](C)(C)CCO
Reactant: CC(C)(C)c1ccc(O[C@@H](Cc2ccc(O)cc2)C(=O)O)cc1
Agent: O=C(Cl)C(=O)Cl
Product: CC(C)(C)c1ccc(O[C@@H](Cc2ccc(O)cc2)C(=O)OCC[Si](C)(C)C)cc1

Procedure:
The target compound (16.0 g) was obtained as colorless crystals by carrying out the reaction and the post-treatment according to Reference example 20(e) using the above carboxylic acid (13.3 g), oxalyl chloride (18.45 ml) and 2-trimethylsilylethanol (30.3 ml).
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH3:5])[CH3:2].[CH3:6][N:7]([CH3:12])[C:8](=[O:11])[CH:9]=[CH2:10]>[Hg]>[CH2:1]([N:3]([CH2:4][CH3:5])[CH2:10][CH2:9][C:8]([N:7]([CH3:12])[CH3:6])=[O:11])[CH3:2]
Reactant: C=CC(=O)N(C)C
Reactant: CCNCC
Agent: [Hg]
Product: CCN(CC)CCC(=O)N(C)C

Procedure:
In accordance with this example, anhydrous diethylamine (44 grams) and N,N-dimethylacrylamide (60 grams) were heated at reflux temperature (about 56°-60° C.) for 48 hours. After this period of time, the reaction mixture was subjected to distillation to separate unreacted amine and amide followed by recovery of product in 86 per cent yield at 70° C. and 2 mm. mercury pressure. The liquid product (purity = about 95 per cent) is designated herein as Amine Catalyst V, and has the formula, (C2H5)2N-CH2CH2C(0)N(CH3)2. The structure of this novel product was confirmed by infrared functional analysis and purity by gas-liquid chromatographic analysis.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[NH:10][C:9](=[O:12])[O:8][CH2:7][C:6]=2[CH:5]=[C:4]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][S:18][C:19]2[CH:24]=[CH:23][C:22]([NH:25][C:26](=[O:28])[CH3:27])=[CH:21][CH:20]=2)[CH:3]=1.[OH:29]O>>[Cl:1][C:2]1[C:11]2[NH:10][C:9](=[O:12])[O:8][CH2:7][C:6]=2[CH:5]=[C:4]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][S:18]([C:19]2[CH:24]=[CH:23][C:22]([NH:25][C:26](=[O:28])[CH3:27])=[CH:21][CH:20]=2)=[O:29])[CH:3]=1
Reactant: CC(=O)Nc1ccc(SCCCCOc2cc(Cl)c3c(c2)COC(=O)N3)cc1
Reactant: OO
Product: CC(=O)Nc1ccc(S(=O)CCCCOc2cc(Cl)c3c(c2)COC(=O)N3)cc1

Procedure:
Prepared analogously to Example 2 from 8-chloro-6-[4-(4-acetamido-phenylmercapto)-butoxy]-4H-3,1-benzoxazin-2-one and hydrogen peroxide.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][C:13]=1[O:14][CH3:15])[CH2:6][NH:7][CH:8]([CH3:10])[CH3:9].COC1C=C(C=CC=1OC)C=O.C(N)(C)C.[OH-].[Na+].[Cl:34][CH:35]([Cl:39])[C:36](Cl)=[O:37]>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][C:13]=1[O:14][CH3:15])[CH2:6][N:7]([CH:8]([CH3:10])[CH3:9])[C:36](=[O:37])[CH:35]([Cl:39])[Cl:34]
Reactant: COc1ccc(CNC(C)C)cc1OC
Reactant: O=C(Cl)C(Cl)Cl
Agent: COc1ccc(C=O)cc1OC
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)N
Solvent: Cc1ccccc1
Product: COc1ccc(CN(C(=O)C(Cl)Cl)C(C)C)cc1OC
Temperature: 0 °C

Procedure:
A mixture of 126 g N-(3,4-dimethoxybenzyl)-N-isopropyl amine (prepared by condensing 3,4-dimethoxybenzaldehyde and isopropylamine and hydrogenating the conversation product b.p. 77.5°-77.8°/0.03 mbar) and 250 ml of toluene is stirred in a 750 ml 4-neckflask until the amine is dissolved. Then 120 g of 20% sodium hydroxide is added thereto and the reaction-mixture is cooled in a CO2 /alcohol bath to a temperature of -10°/-15°. A mixture of 89 g of dichloroacetic acid chloride in 100 ml of toluene is then added dropwise while stirring to the cold reaction mixture. A white precipitate forms immediately. When everything is added, what takes about 11/2hours, the cooling bath is removed and the reaction mixtured is stirred until room temperature has been reached. Then it is poured into an ice-water mixture. The phases are separated and the water-phase is extracted with toluene. The organic layer is then washed twice with 1N hydrochloric acid and twice with water, dried and concentrated. There remain 176 g (91.7% of the theory) or a clear sticky oil with a refraction index of nD22 1.5495 which eventually crystallizes m.p. 69°-72°.
Reaction SMILES: [Cl:1][C:2]([Cl:10])([Cl:9])[C:3]([C:5](Cl)([Cl:7])[Cl:6])=[O:4].[Sb](F)(F)[F:12]>[Sb](Cl)(Cl)(Cl)(Cl)Cl>[Cl:1][C:2]([Cl:10])([Cl:9])[C:3]([C:5]([Cl:7])([Cl:6])[F:12])=[O:4]
Reactant: F[Sb](F)F
Reactant: O=C(C(Cl)(Cl)Cl)C(Cl)(Cl)Cl
Agent: Cl[Sb](Cl)(Cl)(Cl)Cl
Product: O=C(C(F)(Cl)Cl)C(Cl)(Cl)Cl
Temperature: 140 °C
Yield: 128.1 %

Procedure:
A 2-liter round bottom flask equipped with a condenser and mechanical stirrer was charged with 1 liter (6.6 moles) of hexachloroacetone, 411.2 g (2.2 moles) of anhydrous antimony trifluoride and 30 ml of antimony pentachloride. The mixture was heated to 140° C. for a period of one hour then cooled to 0° C. The liquid portion of the reaction was decanted from the salts of the reaction and washed with 5×200 ml portions of 12N HCl dried over MgSO4 and distilled. The fraction boiling at 160°-167° C. afforded 700 g of product as a 3:1 mixture of pentachlorofluoro and tetrachlorodifluoro acetones, respectively, and was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[N:7]2[N:8]=[C:9]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)[C:10]([C:11](=O)[C:12]#[CH:13])=[C:6]2[CH:5]=[CH:4][CH:3]=1.Cl.[CH:23]1([NH:28][C:29]([NH2:31])=[NH:30])[CH2:27][CH2:26][CH2:25][CH2:24]1.C(=O)([O-])[O-].[K+].[K+]>CN1CCCC1=O>[Cl:1][C:2]1[N:7]2[N:8]=[C:9]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)[C:10]([C:11]3[CH:12]=[CH:13][N:31]=[C:29]([NH:28][CH:23]4[CH2:27][CH2:26][CH2:25][CH2:24]4)[N:30]=3)=[C:6]2[CH:5]=[CH:4][CH:3]=1
Reactant: C#CC(=O)c1c(-c2ccc(F)cc2)nn2c(Cl)cccc12
Reactant: N=C(N)NC1CCCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: Fc1ccc(-c2nn3c(Cl)cccc3c2-c2ccnc(NC3CCCC3)n2)cc1
Yield: 43.8 %

Procedure:
In a similar manner as described in Example 7 1-[7-chloro-2-(4-fluorophenyl)pyrazolo[1,5-α]pyridin-3-yl]-2-propyn-1-one (210 mg, 0.70 mmol), cyclopentylguanidine hydrochloride (291 mg, 2.1 mmol), and potassium carbonate (345 mg, 2.1 mmol) were heated at 120° C. for 1.5 hours in 1-methyl-2-pyrrolidinone (8 mL) to form 4-[7-chloro-2-(4-fluorophenyl)pyrazolo[1,5-α]pyridin-3-yl]-N-cyclopentyl-2-pyrimidinamine (125 mg, 44%) as a white foam. 1H NMR (CDCl3) δ 8.42 (d, 1H), 8.09 (d, 1H), 7.67 (dd, 2H), 7.30 (m, 1H), 7.17 (t, 2H), 7.06 (d, 1H), 6.33 (d, 1H), 5.30 (d, 1H), 4.35 (m, 1H), 2.18–2.05 (m, 2H), 1.84–1.52 (m, 6H); 19F NMR (CDCl3) δ −112.78; MS m/z 408 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][NH2:10].[Br:11][C:12]1[CH:13]=[CH:14][C:15]2[N:16]([CH:18]=[C:19]([C:21](OCC)=[O:22])[N:20]=2)[CH:17]=1>>[Br:11][C:12]1[CH:13]=[CH:14][C:15]2[N:16]([CH:18]=[C:19]([C:21]([NH:10][CH2:9][C:3]3[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=3[Cl:8])=[O:22])[N:20]=2)[CH:17]=1
Reactant: CCOC(=O)c1cn2cc(Br)ccc2n1
Reactant: NCc1c(Cl)cccc1Cl
Product: O=C(NCc1c(Cl)cccc1Cl)c1cn2cc(Br)ccc2n1

Procedure:
The title compound was prepared by essentially following the same procedures described for Intermediate I, using (2,6-dichlorophenyl)methanamine and ethyl 6-bromoimidazo[1,2-a]pyridine-2-carboxylate as starting materials.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][CH2:15][CH2:16][NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(C)C=CC=CC=1.[OH-].[K+].[C:33](Cl)(Cl)=[O:34]>CO>[CH2:1]([N:8]1[CH2:9][CH2:10][CH:11]([N:14]2[CH2:15][CH2:16][N:17]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:33]2=[O:34])[CH2:12][CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(CN2CCC(NCCNc3ccccc3)CC2)cc1
Reactant: O=C(Cl)Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: Cc1ccccc1
Product: O=C1N(c2ccccc2)CCN1C1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
200 g of 1-benzyl-4-(2-anilino-ethylamino)-piperidine and 2000 ml of toluene and 1940 ml of potassium hydroxide solution are charged into a reaction vessel. The temperature is kept between 5° and 10° C. with a mixture of ice and methanol while 300 g of phosgene are introduced in the course of 3 hours. Thereafter the reaction mixture is stirred for 2 hours at room temperature. During the dropwise addition of 860 ml of potassium hydroxide, the temperature is kept below 25° C. with an ice-bath. The batch is then stirred for 14 hours. The precipitated crystals are collected with suction and dried. The two-phase filtrate is separated in a separating funnel. The toluene phase is dried over 200 g of sodium sulphate, filtered and concentrated. The residue is recrystallised from 400 ml of ethanol to give the 1-(1-benzyl-4-piperidyl)-3-phenyl-imidazolidin-2-one with a melting point of 173°-174° C. A mixture of 151 g of 1-(1-benzyl-4-piperidyl)-3-phenylimidazolidin-2-one, 1100 ml of methanol, 45 g of hydrochloric acid (chemically pure), 500 ml of water and 15 g of palladium on charcoal catalyst is hydrogenated at 30°-35° C. and under normal pressure until the theoretical amount of hydrogen has been taken up. The catalyst is removed by suction filtration and the filtrate is concentrated by rotary evaporation. The residue is dissolved in 200 ml of water, the solution is made alkaline with 100 ml of conc. ammonia (minimum pH 12) and extracted with five 300 ml portions of methylene chloride. The purified extracts are dried over Na2SO4 and concentrated. The residual colourless oil crystallises after some time. The 103 g of crystalline substance are dissolved in 600 ml of ethyl acetate under reflux, insoluble material is filtered off hot and the filtrate is concentrated by rotary evaporation to a volume of approx. 500 ml and allowed to crystallise. White crystals of 1-(4-piperidyl)-2-phenyl-imidazolidin-2-one with a melding point of 123°-125° C. are obtained.
Reaction SMILES: [C:1]1([C:7]2[CH:31]=[CH:30][C:10]([C:11]([N:13]3[C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=4[CH2:17][N:16]4[C:24]([C:27](O)=[O:28])=[CH:25][CH:26]=[C:15]4[CH2:14]3)=[O:12])=[CH:9][C:8]=2[CH3:32])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.Cl.[CH3:34][O:35][C:36](=[O:41])[C@H:37]([CH2:39][OH:40])[NH2:38].ON1C2C=CC=CC=2N=N1.Cl.C(N=C=N)C.C(N(CC)C(C)C)(C)C>C(OCC)(=O)C>[CH3:34][O:35][C:36](=[O:41])[C@@H:37]([NH:38][C:27]([C:24]1[N:16]2[C:15]([CH2:14][N:13]([C:11](=[O:12])[C:10]3[CH:30]=[CH:31][C:7]([C:1]4[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=4)=[C:8]([CH3:32])[CH:9]=3)[C:19]3[CH:18]=[CH:23][CH:22]=[CH:21][C:20]=3[CH2:17]2)=[CH:26][CH:25]=1)=[O:28])[CH2:39][OH:40]
Reactant: COC(=O)[C@@H](N)CO
Reactant: Cc1cc(C(=O)N2Cc3ccc(C(=O)O)n3Cc3ccccc32)ccc1C1=CCCCC1
Agent: CCN=C=N
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@H](CO)NC(=O)c1ccc2n1Cc1ccccc1N(C(=O)c1ccc(C3=CCCCC3)c(C)c1)C2
Temperature: 25 °C
Reaction time: 12 h
Yield: 89 %

Procedure:
10-(4-Cyclohex-1-en-1-yl-3-methyl-benzoyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxylic acid of Example 5, Step E (0.300 g, 0.703 mmol), L-serine methyl ester hydrochloride (0.131 g, 0.844 mmol), 1-hydroxy benzotriazole (0.104 g, 0.773 mmol) and 1-[3-dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (0.148 g, 0.773 mmol) were combined in amine-free N,N-dimethylformamide (2.8 mL), followed by addition of N,N-diisopropylethylamine (0.307 mL, 1.76 mmol). The reaction was stirred at room temperature for 12 hours, then diluted with ethyl acetate and washed with water, 1 N hydrochloric acid, 1 N sodium hydroxide and brine. The combined aqueous washings were saturated with sodium chloride and extracted with ethyl acetate. The combined, organic phases were dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by flash column chromatography on silica gel eluting with 10% methanol in chloroform, to afford 0.330 g of the title compound as a pale yellow solid.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[F:9][C:10]1([C:23]([O:25]C)=O)[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]1.[Cl:27][CH2:28]I>>[Cl:27][CH2:28][C:23]([C:10]1([F:9])[CH2:11][CH2:12][N:13]([C:16]([O:18][C:19]([CH3:20])([CH3:21])[CH3:22])=[O:17])[CH2:14][CH2:15]1)=[O:25]
Reactant: ClCI
Reactant: COC(=O)C1(F)CCN(C(=O)OC(C)(C)C)CC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Product: CC(C)(C)OC(=O)N1CCC(F)(C(=O)CCl)CC1
Yield: 78.1 %

Procedure:
Prepared according to the method of Example 60, Step A, using lithium diisopropylamide (12.8 mL, 19.1 mmol), 1-tert-butyl 4-methyl 4-fluoropiperidine-1,4-dicarboxylate (1.0 g, 3.83 mmol) and chloroiodomethane (2.70 g, 15.3 mmol). Obtained 0.837 g (78.2% yield) of the desired compound.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([CH2:14][NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:10][CH:9]=1.Br[CH2:24][CH2:25][CH2:26][CH3:27]>>[CH2:24]([O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([CH2:14][NH:15][C:16](=[O:22])[O:17][C:18]([CH3:19])([CH3:21])[CH3:20])=[CH:10][CH:9]=1)[CH2:25][CH2:26][CH3:27]
Reactant: CC(C)(C)OC(=O)NCc1ccc(-c2ccccc2O)cc1
Reactant: CCCCBr
Product: CCCCOc1ccccc1-c1ccc(CNC(=O)OC(C)(C)C)cc1

Procedure:
The title compound was prepared in a similar manner to that described in Reference Example 20 using tert-butyl N-(2′-hydroxybiphenyl-4-ylmethyl)carbamate instead of tert-butyl N-(3′-hydroxybiphenyl-4-ylmethyl)carbamate and 1-bromobutane instead of 1-bromopropane.
Reaction SMILES: [Br:1][C:2]1[CH:19]=[CH:18][C:5]2[N:6]3[CH2:17][CH2:16][C:15]4[C:7]3=[C:8]([CH:12]=[CH:13][CH:14]=4)[C:9](=O)[NH:10][C:4]=2[CH:3]=1.[CH2:20]([N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)[CH2:21][CH3:22].[OH-].[Na+]>[Ti](Cl)(Cl)(Cl)Cl.C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:19]=[CH:18][C:5]2[N:6]3[CH2:17][CH2:16][C:15]4[C:7]3=[C:8]([CH:12]=[CH:13][CH:14]=4)[C:9]([N:26]3[CH2:27][CH2:28][N:23]([CH2:20][CH2:21][CH3:22])[CH2:24][CH2:25]3)=[N:10][C:4]=2[CH:3]=1
Reactant: O=C1Nc2cc(Br)ccc2N2CCc3cccc1c32
Reactant: CCCN1CCNCC1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: CCCN1CCN(C2=Nc3cc(Br)ccc3N3CCc4cccc2c43)CC1
Temperature: 25 °C
Yield: 30.1 %

Procedure:
A stirred mixture of 7.88 g (0.0250 mole) of 9-bromo-1,2dihydrobenzo[b]pyrrolo[3,2,1-jk][1,4]benzodiazepin-6-one and 1200 ml of toluene was heated until a solution resulted. Then there was added 32.1 g (0.25 mole) of N-propylpiperazine, followed by 14.2 g (0.075 mole) of titanium tetrachloride. The mixture was refluxed for 3 hours, and then cooled to room temperature. The mixture was stirred with 500 ml of 2N sodium hydroxide solution for 15 minutes and the layers were separated. The aqueous phase was extracted with 300 ml of toluene. The toluene layers were combined, filtered, washed once with 2N sodium hydroxide solution, twice with water, dried over anhydrous sodium sulfate, and concentrated to an oily solid. The oily solid was dissolved in 25 ml of hot ethyl acetate, filtered, and allowed to crystallize first at room temperature, then at 0° C. to yield 3.20 g (30%) of product, mp 134°14 136° C.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[CH:6]2)=[O:2].[C:12]([O:16][C:17](=O)[O:18]C(C)(C)C)([CH3:15])([CH3:14])[CH3:13]>CN(C)C1C=CN=CC=1.C(#N)C.CCOC(C)=O>[C:12]([O:16][C:17]([N:8]1[C:9]2[C:5](=[CH:4][C:3]([CH:1]=[O:2])=[CH:11][CH:10]=2)[CH:6]=[CH:7]1)=[O:18])([CH3:15])([CH3:14])[CH3:13]
Reactant: O=Cc1ccc2[nH]ccc2c1
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CC(C)(C)OC(=O)n1ccc2cc(C=O)ccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.9 %

Procedure:
5-Formylindole (1.45 g, 10.0 mmol) and 4-dimethylaminopyridine (1.47 g, 12.0 mmol) were dissolved in acetonitrile (20 mL) with stirring at ambient temperature. Once dissolution was complete, the reaction mixture was cooled to −10° C. with stirring. Di-t-butylcarbonate (2.18 g, 10.0 mmol) was added in one portion. Stirring was continued for 2 h. The reaction mixture was diluted with EtOAc (50 mL) and the organic solution was washed successively with water (20 mL), a 1N HCl solution (10 mL), a saturated NaHCO3 solution (20 mL) and brine (20 mL). The organic solution was dried over MgSO4 and filtered. Solvent was removed in vacuo from the filtrate to provide a pale yellow oil (2.45 g, 100% yield): 1H NMR (CDCl3, 300 MHz): 10.1 (s, 1H), 8.31 (d, 1H, J=8), 8.12 (s, 1H), 7.87 (dd, 1H, J=8, 1), 7.70 (d, 1H, J=4), 6.71 (d, 1H, J=4), 1.71 (s, 9H).
Reaction SMILES: CN(CCN(C)C)C.[NH:9]1[CH:16]=[CH:15][C:13]([NH2:14])=[N:12][C:10]1=[O:11].[F:17][C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1>CO.O.O.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[NH2:14][C:13]1[CH:15]=[CH:16][N:9]([C:21]2[CH:22]=[CH:23][C:18]([F:17])=[CH:19][CH:20]=2)[C:10](=[O:11])[N:12]=1
Reactant: Nc1cc[nH]c(=O)n1
Reactant: OB(O)c1ccc(F)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: CN(C)CCN(C)C
Solvent: CO
Solvent: O
Product: Nc1ccn(-c2ccc(F)cc2)c(=O)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 321.7 %

Procedure:
TMEDA (8 mL, 54 mmol) was added to a stirred suspension of cytosine (3 g, 27 mmol), 4-fluorophenylboronic acid (7.55 g, 5 mmol) and copper(II)acetate monohydrate (5.44 g, 27 mmol) in a mixture of MeOH (960 mL) and H2O (240 mL). The mixture was stirred at RT for 16 hours. The solvents were evaporated in vacuo and the crude product purified by open column chromatography (silica; MeOH in DCM with a gradient of 0/100 to 100/0). The desired fractions were collected and the solvents evaporated in vacuo. The product was triturated with MeOH and DCM and the solid formed filtered and dried in vacuo to yield 4-amino-1-(4-fluoro-phenyl)-1H-pyrimidin-2-one (3.3 g, 60% yield) as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[C:5](=O)[CH:6]([C:14](=[O:16])[CH3:15])[C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH3:2].C([N:21](CC)CC)C.Cl.NO.Cl>C(Cl)(Cl)Cl>[CH2:1]([O:3][C:4]([C:5]1[C:6]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])=[C:14]([CH3:15])[O:16][N:21]=1)=[O:18])[CH3:2]
Reactant: CCN(CC)CC
Reactant: CCOC(=O)C(=O)C(C(C)=O)C(=O)OC(C)(C)C
Agent: Cl
Agent: NO
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1noc(C)c1C(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 77.8 %

Procedure:
The 1,3-diketone obtained in Step 1 (34.7 mmol, 8.9 g) was dissolved in chloroform (50 ml). 4.91 g of triethylamine (1.4 eq, 48.6 mmol) and hydroxylamine-HCl salt (1.3 eq, 45.1 mmol, 3.13 g) were added and the mixture was refluxed for 3 h. The reaction was cooled to room temperature and 1N aq. HCl (100 ml) was added followed by extraction with DCM (3×100 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated. Column purification by silica gel yielded (6.89 g, 77% yield) of tert-butyl 3-(ethoxycarbonyl)-5-methylisoxazole-4-carboxylate. 1H NMR (300 MHz, CDCl3), δ 4.42 (q, 2H), 2.66 (s, 3H), 1.53 (s, 15H), 1.39 (t, 3H).
Reaction SMILES: C1(C)C=CC(S(O[CH2:11][C@H:12]2[C@@H:17]([CH2:18][O:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:16][CH:15]=[CH:14][CH2:13]2)(=O)=O)=CC=1.[C-:28]#[N:29].[K+].O>CS(C)=O>[C:28]([CH2:11][C@H:12]1[C@@H:17]([CH2:18][O:19][CH2:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:16][CH:15]=[CH:14][CH2:13]1)#[N:29]
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H]2CC=CC[C@@H]2COCc2ccccc2)cc1
Reactant: [C-]#N
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: N#CC[C@@H]1CC=CC[C@@H]1COCc1ccccc1
Temperature: 100 °C
Yield: 86.8 %

Procedure:
The p-toluene sulphonyl ester/benzyl ether (3) (12 g) in dimethylsulphoxide (DMSO) (15 ml) is added with stirring to potassium cyanide (3 g) in DMSO (20 ml). The mixture is heated at 100° C. under nitrogen for 6 hours and is then cooled, poured into water and the product extracted with ether. The solvent is removed and the residue purified on a Florisil column, eluting with petroleum ether-benzene (1:1) to give the title compound as an oil (6.5 g, ca. 80%) νmax (film) 2220 and 1600 cm-1.
Reaction SMILES: C([Li])CCC.[C:6]([C:8]1[CH:13]=[CH:12][C:11]([C@H:14]2[CH2:19][CH2:18][C@H:17]([CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:16][CH2:15]2)=[CH:10][CH:9]=1)#[CH:7].CN(C)[CH:27]=[O:28].Cl>CCCCCC.O1CCCC1>[CH:27]([C:7]#[C:6][C:8]1[CH:13]=[CH:12][C:11]([C@H:14]2[CH2:19][CH2:18][C@H:17]([CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:16][CH2:15]2)=[CH:10][CH:9]=1)=[O:28]
Reactant: CN(C)C=O
Reactant: C#Cc1ccc([C@H]2CC[C@H](CCCCC)CC2)cc1
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCCCC[C@H]1CC[C@H](c2ccc(C#CC=O)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
6.75 ml (0.80 mmol) of 1.6 molar n-butyllithium solution in n-hexane are added dropwise at 0° C. to 2.48 g (9.80 mmol) of 1-ethynyl-4-(trans-4-pentylcyclohexyl)benzene in 25 ml of tetrahydrofuran. After 1 hour, this solution is added dropwise to 0.83 ml of dimethylformamide in 20 ml of tetrahydrofuran, the mixture is stirred at room temperature for 1 hour, acidifed by means of aqueous hydrochloric acid and partitioned between ether and water, and the organic phase is dried and evaporated. Chromatography on silica gel using n-hexane/dichloromethane (1:1) gives 1.75 g of 1-(formylethynyl)-4-(trans-4-pentylcyclohexyl)benzene, ##STR39## which is stirred for 2 hours at room temperature with 1.05 g (6.49 mmol) of diethylaminosulfur trifluoride in 10 ml of dichloromethane. After partitioning between water and dichloromethane, the organic phase is dried over sodium sulfate, evaporated and chromatographed on silica gel using n-heptane, giving 0.89 g of product ##STR40## having the phase sequence
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:11][CH:10]([OH:12])[CH2:9]2)=[C:4]([F:13])[CH:3]=1.N1C=CC=CC=1.Cl[C:21]([O:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:22]>CC(C)=O>[F:13][C:4]1[CH:3]=[C:2]([NH:1][C:21](=[O:22])[O:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:7]=[CH:6][C:5]=1[N:8]1[CH2:9][CH:10]([OH:12])[CH2:11]1
Reactant: Nc1ccc(N2CC(O)C2)c(F)c1
Reactant: O=C(Cl)Oc1ccccc1
Solvent: CC(C)=O
Solvent: c1ccncc1
Product: O=C(Nc1ccc(N2CC(O)C2)c(F)c1)Oc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 76.5 %

Procedure:
To a stirred solution of 1-(4-amino-2-fluorophenyl)azetidin-3-ol (1.8 g, 9.94 mmol, 1.0 eq) in acetone (50 mL) was added pyridine (1.57 g, 19.87 mmol, 2.0 eq) and phenyl chloroformate (1.71 g, 10.89 mmol, 1.1 eq) and stirred at RT for 2 h. The reaction mixture was evaporated, diluted with EtOAc (100 mL), washed with water (100 mL) followed by brine and evaporated. The residue obtained was purified by CC (eluent: EtOAc/PE (1:4)) to obtain phenyl 3-fluoro-4-(3-hydroxyazetidin-1-yl)phenylcarbamate (2.3 g, 76%, brown solid) (TLC: EtOAc/PE (1:1), Rf: 0.45).