Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]([F:12])([F:11])[F:10])=[CH:4][CH:3]=1.[CH2:13]([OH:18])[CH2:14][CH2:15][C:16]#[CH:17]>N1CCCCC1.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>[F:10][C:9]([F:12])([F:11])[O:8][C:5]1[CH:6]=[CH:7][C:2]([C:17]#[C:16][CH2:15][CH2:14][CH2:13][OH:18])=[CH:3][CH:4]=1
Reactant: C#CCCCO
Reactant: FC(F)(F)Oc1ccc(I)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCNCC1
Product: OCCCC#Cc1ccc(OC(F)(F)F)cc1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 81.8 %

Procedure:
A mixture of 1-iodo-4-trifluoromethoxy-benzene (5 g, 17 mmol), Pd(PPh3)4 (973 mg, 1 mmol) and cuprous iodide (160 mg, 1 mmol) in piperidine (130 ml) was stirred for 30 min at 50° C. under an argon atmosphere. 4-Pentyn-1-ol (2.13 g, 25 mmol) was added within 60 min at 50° C. The temperature was raised to 80° C. and the mixture was stirred for 3 h at this temperature. The reaction mixture was cooled to ambient temperature, poured into a solution of saturated aqueous 10% KHSO4/ice water 1/1 and extracted two times with tert butyl methyl ether. The combined extracts were washed with water and brine (two times) and dried over sodium sulfate. The solvent was removed under reduced pressure and the residue purified by column chromatography (silica gel, heptane/AcOEt) to give 3.4 g (13.9 mmol, 83%) of the title compound as orange oil.
Reaction SMILES: [CH:1]1([C:4]2[O:5][C:6]3[C:7](=[C:9]([C:14]([O:16]C)=[O:15])[CH:10]=[C:11]([F:13])[CH:12]=3)[N:8]=2)[CH2:3][CH2:2]1.[OH-].[Na+].Cl>CO>[CH:1]1([C:4]2[O:5][C:6]3[C:7](=[C:9]([C:14]([OH:16])=[O:15])[CH:10]=[C:11]([F:13])[CH:12]=3)[N:8]=2)[CH2:2][CH2:3]1
Reactant: COC(=O)c1cc(F)cc2oc(C3CC3)nc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1cc(F)cc2oc(C3CC3)nc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.9 %

Procedure:
A mixture of the ester from Step E (115 mg, 0.49 mmol), 2 N NaOH (2.0 mL, 4.0 mmol), and methanol (5 mL) was stirred at room temperature under nitrogen for 2 h. The reaction mixture was acidified with 1 N HCl, extracted with methylene chloride, washed with brine, dried over sodium sulfate, filtered and concentrated to afford 2-cyclopropyl-6-fluorobenzoxazole-4-carboxylic acid (105 mg, 97%) as a white solid: 1H NMR (300 MHz, CDCl3) δ 12.90 (br s, 1H), 7.91 (dd, J=8.1, 2.4 Hz, 1H), 7.58 (dd, J=10.2, 2.4 Hz, 1H), 2.39-2.29 (m, 1H), 1.25-1.14 (m, 4H); 19F NMR (282 MHz, CDCl3) δ-116.79; MS (ESI+) m/z 222 (M+H).
Reaction SMILES: C1CO[CH:17]2[CH:3]([C@@H:4]([C@@H:15]([CH:20]=[CH:21][C:22](=[O:31])[C:23]([CH3:30])([CH3:29])[CH2:24][CH:25]=[C:26]([CH3:28])[CH3:27])[CH2:16]2)[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])[O:2]1.[BH4-].[Na+]>CO>[O:2]=[C:3]1[CH2:17][CH2:16][C@H:15]([CH:20]=[CH:21][CH:22]([OH:31])[C:23]([CH3:30])([CH3:29])[CH2:24][CH:25]=[C:26]([CH3:27])[CH3:28])[C@H:4]1[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12]
Reactant: COC(=O)CCCCCC[C@H]1C2OCCOC2C[C@@H]1C=CC(=O)C(C)(C)CC=C(C)C
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)CCCCCC[C@H]1C(=O)CC[C@@H]1C=CC(O)C(C)(C)CC=C(C)C
Reaction time: 0.5 h

Procedure:
To a solution of 9-ethylenedioxy-15-keto-16,16,19-trimethyl-prosta-13,18-dienoic acid, methyl ester, (5.2 g.) in methanol (40 ml.), 0.89 g of sodium borohydride are gradually added, while the temperature is kept under 35° C. The mixture is stirred for 30 minutes, then diluted with 300 ml. of water and extracted with ethyl acetate (3×100 ml). The organic layer is washed with water to neutrality, dried over Na2SO4 and the solvent is evaporated in vacuo, to obtain a residue (4.9 g) which is suspended in acetic acid 65% (60 ml.) and stirred at room temperature for 60 minutes. The so obtained solution is diluted with water (200 ml.) and extracted with diethyl ether (3×100 ml). The organic phase is washed with an aqueous, saturated solution of NaHCO3, then with water to neutrality, dried over Na2SO4, and the solvent is evaporated in vacuo. The oily residue (4.2 g. is purified by chromatography on SiO2 (400 g.); the eluent is benzene/ethyl acetate (4:1). One gram of 9-keto-15β-hydroxy-16,16,19-trimethyl-prosta-13,18-dienoic acid, methyl ester, 0.5 g. of 9-keto-15α-hydroxy-16,16,19-trimethyl-prosta-13,18-dienoic acid, methyl ester, and 2.1 g. of a mixture of 15α- and 15β-isomers are obtained.
Reaction SMILES: O[CH2:2][C:3]1[N:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]2=[N:5][C:4]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13].S(Cl)([Cl:19])=O>C(Cl)(Cl)Cl>[ClH:19].[Cl:19][CH2:2][C:3]1[N:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]2=[N:5][C:4]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: O=S(Cl)Cl
Reactant: CCOC(=O)c1nc2ccccn2c1CO
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1nc2ccccn2c1CCl
Product: Cl
Temperature: 25 °C

Procedure:
To a solution of ethyl 3-(hydroxymethyl)imidazo[1,2-a]pyridine-2-carboxylate (2.85 g) in chloroform (40 ml) was added thionyl chloride (8.0 ml) at room temperature, and the mixture was heated under reflux for 12 hr. The reaction solution was cooled to room temperature, and concentrated under reduced pressure. The precipitated crystals were collected by filtration, washed with diethyl ether to give the object product (3.50 g).
Reaction SMILES: [NH:1]([C:3]1[CH:4]=[C:5]([CH2:9][C:10]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[O:11])[CH:6]=[CH:7][CH:8]=1)[NH2:2].[CH3:18][C:19]([CH3:26])([CH3:25])[C:20](=O)[CH2:21][C:22]#[N:23].C(=O)([O-])O.[Na+]>C(O)C.Cl>[C:19]([C:20]1[CH:21]=[C:22]([NH2:23])[N:1]([C:3]2[CH:4]=[C:5]([CH2:9][C:10]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)=[O:11])[CH:6]=[CH:7][CH:8]=2)[N:2]=1)([CH3:26])([CH3:25])[CH3:18]
Reactant: CC(C)(C)C(=O)CC#N
Reactant: NNc1cccc(CC(=O)N2CCOCC2)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C)c1cc(N)n(-c2cccc(CC(=O)N3CCOCC3)c2)n1
Temperature: 25 °C
Yield: 91.6 %

Procedure:
To a stirred suspension of (3-nitro-phenyl)-acetic acid (2 g) in CH2Cl2 (40 ml, with a catalytic amount of DMF) at 0° C. under N2 was added oxalyl chloride (1.1 ml) drop wise. The reaction mixture was stirred for 40 min morpholine (2.5 g) was added. After stirring for 20 min, the reaction mixture was filtered. The filtrate was concentrated in vacuo to yield 1-morpholin-4-yl-2-(3-nitro-phenyl)-ethanone as a solid (2 g). A mixture of 1-morpholin-4-yl-2-(3-nitro-phenyl)-ethanone (2 g) and 10% Pd on activated carbon (0.2 g) in ethanol (30 ml) was hydrogenated at 30 psi for 3 h and filtered over Celite. Removal of the volatiles in vacuo provided 2-(3-amino-phenyl)-1-morpholin-4-yl-ethanone (1.7 g). A solution of 2-(3-amino-phenyl)-1-morpholin-4-yl-ethanone (1.7 g, 7.7 mmol) was dissolved in 6 N HCl (15 ml), cooled to 0° C., and vigorously stirred. Sodium nitrite (0.54 g) in water (8 ml) was added. After 30 min, tin (II) chloride dihydrate (10 g) in 6 N HCl (30 ml) was added. The reaction mixture was stirred at 0° C. for 3 h. The pH was adjusted to pH 14 with solid potassium hydroxide and extracted with EtOAc. The combined organic extracts were concentrated in vacuo provided 2-(3-hydrazin-phenyl)-1-morpholin-4-yl-ethanone (1.5 g). 2-(3-Hydrazinophenyl)-1-morpholin-4-yl-ethanone (3 g) and 4,4-dimethyl-3-oxopentanenitrile (1.9 g, 15 mmol) in ethanol (60 ml) and 6 N HCl (1 ml) were refluxed for 1 h and cooled to RT. The reaction mixture was neutralized by adding solid sodium hydrogen carbonate. The slurry was filtered and removal of the volatiles in vacuo provided a residue that was extracted with ethyl acetate. The volatiles were removed in vacuo to provide 2-[3-(3-tert-butyl-5-amino-1H-pyrazol-1-yl)phenyl]-1-morpholinoethanone (4 g), which was used without further purification.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH:12]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)[CH2:13][CH2:14][NH2:15])=[CH:7][CH:6]=1.C(N(CC)CC)C.Cl[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[S:36](Cl)(=[O:38])=[O:37].[ClH:40]>C(Cl)Cl.O>[CH3:1][O:2][CH2:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([CH2:11][CH:12]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)[CH2:13][CH2:14][NH:15][S:36]([C:31]2[CH:32]=[CH:33][C:34]([Cl:40])=[CH:35][CH:30]=2)(=[O:38])=[O:37])=[CH:9][CH:10]=1
Reactant: O=S(=O)(Cl)c1ccccc1Cl
Reactant: COCOc1ccc(CC(CCN)c2cccnc2)cc1
Reactant: Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COCOc1ccc(CC(CCNS(=O)(=O)c2ccc(Cl)cc2)c2cccnc2)cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To the solution of 0.72 g of 4-(4-methoxymethyloxyphenyl)-3-(3-pyridyl)butylamine and 0.27 g of triethylamine in methylene chloride, after cooling at 0° C., was added 0.51 g of chlorobenzene sulfonylchloride, and stirred at room temperature for five hours. To the reaction mixture was added water which was then adjusted to weak acidity with 2N hydrogen chloride, and the organic phase was separated which was then extracted from aqueous phase with methylene chloride. The combined organic phases were washed in saturated aqueous sodium chloride solution, and dried over magnesium sulfate, to distill off the solvent. The obtained residue was subjected to chromatography on a silica gel column, and from a fraction eluted with methanol-methylene chloride (5:95 v/v) was obtained 1.02 g of N-[4- (4-methoxymethyloxyphenyl)-3-(3-pyridyl)butyl]-4-chlorobenzenesulfonamide.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][N:3]1[C:8]1[CH:13]=[CH:12][C:11]([C:14]2[O:18][N:17]=[C:16]([C:19]3[CH:20]=[C:21]4[C:26](=[CH:27][CH:28]=3)[CH2:25][N:24](C(OC(C)(C)C)=O)[CH2:23][CH2:22]4)[N:15]=2)=[CH:10][C:9]=1[C:36]([F:39])([F:38])[F:37].C(Cl)[Cl:41]>C(O)(C(F)(F)F)=O>[ClH:41].[CH3:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][N:3]1[C:8]1[CH:13]=[CH:12][C:11]([C:14]2[O:18][N:17]=[C:16]([C:19]3[CH:20]=[C:21]4[C:26](=[CH:27][CH:28]=3)[CH2:25][NH:24][CH2:23][CH2:22]4)[N:15]=2)=[CH:10][C:9]=1[C:36]([F:39])([F:37])[F:38]
Reactant: ClCCl
Reactant: CC1CCCCN1c1ccc(-c2nc(-c3ccc4c(c3)CCN(C(=O)OC(C)(C)C)C4)no2)cc1C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Product: CC1CCCCN1c1ccc(-c2nc(-c3ccc4c(c3)CCNC4)no2)cc1C(F)(F)F
Product: Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
tert-butyl 6-{5-[4-(2-methylpiperidin-1-yl)-3-(trifluoromethyl)phenyl]-1,2,4-oxadiazol-3-yl}-3,4-dihydroisoquinoline-2(1H)-carboxylate obtained from step 1 was dissolved in DCM (3 mL) and TFA (1 mL). The resulting solution was stirred at RT for 1 hour and the solvent was evaporated in vacuo to give a light yellow oil. The latter was filtered through a short plug of alumina (c-hexane/EtOAc, 80/20 then 50/50) to give a light yellow oil that was triturated in a Et2O/HCl (1 M) mixture (1:1, 2 mL), filtered and washed with Et2O to the title compound as an off-white solid. 1H NMR (DMSO-d6) δ 9.30 (bs, 2H), 8.45-8.41 (m, 1H), 8.38 (m, 1H), 8.01-7.98 (m, 2H), 7.86 (d, J=8.5 Hz, 1H), 7.46 (d, J=8.0 Hz, 1H), 4.41 (m, 2H), 3.54-3.42 (m, 3H), 3.18-3.08 (m, 3H), 2.97-2.93 (m, 1H), 2.65-2.59 (m, 1H), 1.80-1.77 (m, 2H), 1.63-1.30 (m, 4H), 0.78 (d, J=6 Hz, 3H). HPLC (Method A) Rt 4.61 min (Purity: 100.0%). LC/MS (method B): 443.2 (M+H)+.
Reaction SMILES: [CH:1]1([O:7][N:8]2[C:13]([CH3:15])([CH3:14])[CH2:12][CH:11]([OH:16])[CH2:10][C:9]2([CH3:18])[CH3:17])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH:19]([C:25]([O:27]C)=O)[NH:20][C:21]([O:23][CH3:24])=[O:22]>CCCC[O-].CCCC[O-].CCCC[O-].CCCC[O-].[Ti+4]>[NH:20]([C:21]([O:23][CH:24]1[CH2:15][C:13]([CH3:12])([CH3:14])[N:8]([O:7][CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[C:9]([CH3:18])([CH3:17])[CH2:10]1)=[O:22])[NH:19][C:25]([O:16][CH:11]1[CH2:10][C:9]([CH3:18])([CH3:17])[N:8]([O:7][CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)[C:13]([CH3:14])([CH3:15])[CH2:12]1)=[O:27]
Reactant: COC(=O)NNC(=O)OC
Reactant: CC1(C)CC(O)CC(C)(C)N1OC1CCCCC1
Agent: [Ti+4]
Agent: CCCC[O-]
Product: CC1(C)CC(OC(=O)NNC(=O)OC2CC(C)(C)N(OC3CCCCC3)C(C)(C)C2)CC(C)(C)N1OC1CCCCC1
Yield: 54.5 %

Procedure:
The procedure of Example 1 is repeated using 24.1 g of 1-cyclohexyloxy-2,2,6,6-tetramethylpiperidin-4-ol, 6.67 g of dimethyl hydrazine-1,2-dicarboxylate and 1.5 g of tetrabutyl titanate to afford 14.6 g of the title compound as a white solid; mp 150°-152° C.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:19]([NH:22][CH2:23][CH2:24]Cl)=[CH:18][C:3]=1[C:4]([NH:6][CH2:7][C:8]12[CH2:17][CH:12]3[CH2:13][CH:14]([CH2:16][CH:10]([CH2:11]3)[CH2:9]1)[CH2:15]2)=[O:5].[CH2:26](CN)O.C([N:32]([CH2:35][CH3:36])[CH2:33][CH3:34])C>O1CCCC1>[Cl:1][C:2]1[CH:21]=[CH:20][C:19]([NH:22][CH2:23][CH2:24][N:32]2[CH2:33][CH2:34][CH2:26][CH2:36][CH2:35]2)=[CH:18][C:3]=1[C:4]([NH:6][CH2:7][C:8]12[CH2:17][CH:12]3[CH2:11][CH:10]([CH2:16][CH:14]([CH2:13]3)[CH2:15]1)[CH2:9]2)=[O:5]
Reactant: NCCO
Reactant: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cc(NCCCl)ccc1Cl
Reactant: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cc(NCCN2CCCCC2)ccc1Cl

Procedure:
Prepared according to the method described in Example 69 from 2-chloro-5-(2-chloroethyl)amino-N-(tricyclo[3.3.1.13,7]dec-1-ylmethyl)-benzamide (0.1 g), ethanolamine (0.24 g), triethylamine (0.5 ml) and tetrahydrofuran (3 ml). Purification by flash column chromatography eluting with 10% methanol and 1% triethylamine in dichloromethane gave 2-chloro-5-(2-(piperidin-1-yl)ethylamino)-N-(tricyclo[3.3.1.13,7]dec-1-ylmethyl)-benzamide as a glass. Conversion to the hydrochloride salt upon treatment with excess ethereal hydrochloric acid (2M) gave the title compound as a cream solid (0.056 g).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[CH:9][C:8]([C:14]#[N:15])=[C:7]2[NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[CH:18]=1)([O-])=O.NN>[Pd].C(O)C>[NH2:1][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[CH:9][C:8]([C:14]#[N:15])=[C:7]2[NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[CH:18]=1
Reactant: Cc1cccc(Nc2c(C#N)cnc3ccc([N+](=O)[O-])cc23)c1
Agent: [Pd]
Agent: NN
Solvent: CCO
Product: Cc1cccc(Nc2c(C#N)cnc3ccc(N)cc23)c1
Yield: 109.4 %

Procedure:
Added 253 mg 10% palladium on carbon to a round bottom flask under N2 and covered catalyst with 140 ml ethanol. To this added 2.49 g (8.18 mmol) 6-nitro-4-[(3-methylphenyl)amino]-quinoline-3-carbonitrile and 640 μl (20.4 mmol) anhydrous hydrazine. The mixture was heated to reflux for 2 hours 15 minutes and filtered hot through celite. Stripped solvent and dried in vacuo, giving 2.455 g of yellow solid: mass spectrum (electrospray m/e): M+H=275.2.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]3[N:14]=[CH:15][N:16]([C:18]4[CH:26]=[CH:25][C:21]([C:22](O)=[O:23])=[CH:20][N:19]=4)[CH:17]=3)=[C:11]([CH3:27])[N:10]=[N:9]2)=[CH:4][CH:3]=1.[CH3:28][C:29]1([NH2:33])[CH2:32][O:31][CH2:30]1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]3[N:14]=[CH:15][N:16]([C:18]4[CH:26]=[CH:25][C:21]([C:22]([NH:33][C:29]5([CH3:28])[CH2:32][O:31][CH2:30]5)=[O:23])=[CH:20][N:19]=4)[CH:17]=3)=[C:11]([CH3:27])[N:10]=[N:9]2)=[CH:4][CH:3]=1
Reactant: CC1(N)COC1
Reactant: Cc1nnn(-c2ccc(F)cc2)c1-c1cn(-c2ccc(C(=O)O)cn2)cn1
Product: Cc1nnn(-c2ccc(F)cc2)c1-c1cn(-c2ccc(C(=O)NC3(C)COC3)cn2)cn1
Yield: 86 %

Procedure:
As described for example 36b, 6-(4-(1-(4-fluorophenyl)-4-methyl-1H-1,2,3-triazol-5-yl)-1H-imidazol-1-yl)nicotinic acid (56 mg, 0.154 mmol) was converted, using 3-methyloxetan-3-amine instead of isopropylamine, to the title compound (57 mg, 86%) which was obtained as an off white solid. MS: m/e=434.3 [M+H]+.
Reaction SMILES: [CH2:1]([N:19]=[C:20]=[O:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[C:22]([CH2:47][CH2:48][SH:49])([C:25]([C:28]([C:31]([C:34]([C:37]([C:40]([C:43]([F:46])([F:45])[F:44])([F:42])[F:41])([F:39])[F:38])([F:36])[F:35])([F:33])[F:32])([F:30])[F:29])([F:27])[F:26])([F:24])[F:23].N1(C2CCCCCCC2)CCCCCCN1>>[CH2:1]([NH:19][C:20]([S:49][CH2:48][CH2:47][C:22]([C:25]([C:28]([C:31]([C:34]([C:37]([C:40]([C:43]([F:44])([F:45])[F:46])([F:41])[F:42])([F:38])[F:39])([F:35])[F:36])([F:33])[F:32])([F:30])[F:29])([F:27])[F:26])([F:24])[F:23])=[O:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCCCCCCCCCCCCN=C=O
Reactant: FC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)CCS
Agent: C1CCCC(N2CCCCCCN2)CCC1
Product: CCCCCCCCCCCCCCCCCCNC(=O)SCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Temperature: 100 °C
Reaction time: 6 h

Procedure:
Octadecyl isocyanate (29.5 g, 0.1 mole), C8F17CH2CH2SH (48 g, 0.1 moles) and 2.2.2 diazabicyclooctane (0.1 g) were mixed under nitrogen and heated to 100° C. with stirring for 6 hours. An infrared spectrum showed no --NCO absorption, indicating completion of the reaction. The product is a white wax, melting at 85°-89° C. NMR showed proton resonances at 4.7 ppm (1 proton NH), 3.2 ppm (2 protons CH2CH2NH), 3.1 ppm (2 protons CH2SCO), 2.5 ppm (2 protons C8F17CH2), 1.3 ppm (32 protons CH3 (CH2)16) and 0.8 ppm (3 protons CH3 (CH2)16).
Reaction SMILES: [CH3:1][C:2]1([C:7]2[N:8]=[C:9]([CH2:12][N:13]3[CH:17]=[C:16]([NH2:18])[CH:15]=[N:14]3)[S:10][CH:11]=2)[O:6]CCO1.[F:19][C:20]([F:33])([F:32])[C:21]1[CH:26]=[CH:25][C:24](/[CH:27]=[CH:28]/[C:29](O)=[O:30])=[CH:23][CH:22]=1>>[C:2]([C:7]1[N:8]=[C:9]([CH2:12][N:13]2[CH:17]=[C:16]([NH:18][C:29](=[O:30])/[CH:28]=[CH:27]/[C:24]3[CH:23]=[CH:22][C:21]([C:20]([F:32])([F:33])[F:19])=[CH:26][CH:25]=3)[CH:15]=[N:14]2)[S:10][CH:11]=1)(=[O:6])[CH3:1]
Reactant: O=C(O)/C=C/c1ccc(C(F)(F)F)cc1
Reactant: CC1(c2csc(Cn3cc(N)cn3)n2)OCCO1
Product: CC(=O)c1csc(Cn2cc(NC(=O)/C=C/c3ccc(C(F)(F)F)cc3)cn2)n1

Procedure:
Following general procedure B followed by C starting from 1-[4-(2-methyl-[1,3]dioxolan-2-yl)-thiazol-2-ylmethyl]-1H-pyrazol-4-ylamine and (E)-3-(4-trifluoromethyl-phenyl)-acrylic acid. LC-MS-conditions 02: tR=0.98 min; [M+H]+=421.22.
Reaction SMILES: [OH:1][C:2]([C:30]1[CH:35]=[CH:34][C:33]([C:36]2[CH:41]=[C:40]([CH3:42])[CH:39]=[C:38]([NH:43][C:44](=[O:46])[CH3:45])[CH:37]=2)=[CH:32][CH:31]=1)([C:6]1[N:7]=[CH:8][N:9](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:10]=1)[CH:3]([CH3:5])[CH3:4].Cl.N1C=CC=CC=1>>[OH:1][C:2]([C:30]1[CH:31]=[CH:32][C:33]([C:36]2[CH:41]=[C:40]([CH3:42])[CH:39]=[C:38]([NH:43][C:44](=[O:46])[CH3:45])[CH:37]=2)=[CH:34][CH:35]=1)([C:6]1[N:7]=[CH:8][NH:9][CH:10]=1)[CH:3]([CH3:5])[CH3:4]
Reactant: CC(=O)Nc1cc(C)cc(-c2ccc(C(O)(c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)C(C)C)cc2)c1
Agent: Cl
Solvent: c1ccncc1
Product: CC(=O)Nc1cc(C)cc(-c2ccc(C(O)(c3c[nH]cn3)C(C)C)cc2)c1
Yield: 67 %

Procedure:
By the reaction in the same manner as in Example 4-(iii) using N-[4′-[1-hydroxy-2-methyl-1-(1-trityl-1H-imidazol-4-yl)propyl]-5-methyl[1,1′-biphenyl]-3-yl]acetamide (1.02 g) and pyridine hydrochloride (350 mg), the colorless amorphous title compound (410 mg) was obtained.
Reaction SMILES: C([Li])CCC.[CH3:6][O:7][C:8]1[C@@H:9]([CH:16]([CH3:18])[CH3:17])[N:10]=[C:11]([O:14][CH3:15])[CH2:12][N:13]=1.Cl[CH2:20][C:21]1[O:22][CH:23]=[CH:24][CH:25]=1>CCCCCC.C1COCC1>[CH3:6][O:7][C:8]1[C@@H:9]([CH:16]([CH3:18])[CH3:17])[N:10]=[C:11]([O:14][CH3:15])[C@H:12]([CH2:20][C:21]2[O:22][CH:23]=[CH:24][CH:25]=2)[N:13]=1
Reactant: COC1=N[C@H](C(C)C)C(OC)=NC1
Reactant: ClCc1ccco1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COC1=N[C@H](C(C)C)C(OC)=N[C@H]1Cc1ccco1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
A 1.55M solution of butyllithium (6.45 ml, 10 mmol) in hexane was added by syringe to a stirred solution of (2R)-2,5-dihydro-3,6-dimethoxy-2-isopropylpyrazine (1.84 g, 10 mmol) in THF (50 ml) at -78° C. and the solution stirred for 1 hour at -78° C. A solution of 2-chloromethylfuran (1.3 g, 11 mmol) in THF (10 ml) was added gradually and the stirring continued overnight. The solvent was removed under reduced pressure, the residue dissolved in ethyl acetate (50 ml) and extracted with phosphate buffer (pH 7). The water phase was extracted twice with ethyl acetate (2×20 ml ). The organic layer was dried (MgSO4), solvent evaporated under reduced pressure and the residue purified by flash chromatography (diethyl ether/hexane 15/1, silica gel).
Reaction SMILES: Cl.Cl.[CH3:3][O:4][C:5]1[CH:6]=[C:7]([N:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[CH:8]=[CH:9][CH:10]=1.Cl[CH2:18][CH2:19][CH2:20][C:21]1[C:25]2[CH:26]=[CH:27][C:28]([F:30])=[CH:29][C:24]=2[O:23][N:22]=1.[C:31](=[O:34])([O-:33])[O-].[K+].[K+]>[I-].[K+].CN(C)C=O>[C:5]([OH:4])(=[O:23])[C:31]([OH:33])=[O:34].[F:30][C:28]1[CH:27]=[CH:26][C:25]2[C:21]([CH2:20][CH2:19][CH2:18][N:14]3[CH2:15][CH2:16][N:11]([C:7]4[CH:8]=[CH:9][CH:10]=[C:5]([O:4][CH3:3])[CH:6]=4)[CH2:12][CH2:13]3)=[N:22][O:23][C:24]=2[CH:29]=1
Reactant: Fc1ccc2c(CCCCl)noc2c1
Reactant: O=C([O-])[O-]
Reactant: COc1cccc(N2CCNCC2)c1
Agent: Cl
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cccc(N2CCN(CCCc3noc4cc(F)ccc34)CC2)c1
Product: O=C(O)C(=O)O
Temperature: 90 °C
Reaction time: 2 h
Yield: 82.8 %

Procedure:
To 40 ml of dimethylformamide was added 5.3 g of 4-(3-methoxyphenyl)piperazine dihydrochloride, 6.4 g of 3-(3-chloropropyl)-6-fluoro-1,2-benzisoxazole, 10.0 g of milled potassium carbonate, and 0.01 g of potassium iodide. The mixture was stirred at 90° C. for two hrs, cooled, filtered, and evaporated to an oil. The oil was stirred with 100 ml water for ten mins, and extracted with ether. The ether extract was washed with water (2×), saturated sodium chloride solution and dried over anhydrous magnesium sulfate. After filtering, ethereal oxalic acid was added and the resulting precipitate was collected and dried to give 3.8 g (41%) of product. Two recrystallizations from ethyl acetate/methanol/ether (10:1:5), gave the analytical sample, mp 168° C. (dec).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@H:9]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[CH3:10])[N:5]=[C:4]([N:18]2[CH2:23][CH2:22][C:21]([CH2:25][OH:26])([OH:24])[CH2:20][CH2:19]2)[CH:3]=1.[NH2:27][C:28]1[CH:33]=[N:32][CH:31]=[CH:30][N:29]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.CC(C)([O-])C.[Na+]>C(OCC)(=O)C.O1CCOCC1.C1(C)C=CC=CC=1>[F:17][C:14]1[CH:15]=[CH:16][C:11]([C@@H:9]([NH:8][C:6]2[N:5]=[C:4]([N:18]3[CH2:23][CH2:22][C:21]([CH2:25][OH:26])([OH:24])[CH2:20][CH2:19]3)[CH:3]=[C:2]([NH:27][C:28]3[CH:33]=[N:32][CH:31]=[CH:30][N:29]=3)[N:7]=2)[CH3:10])=[CH:12][CH:13]=1
Reactant: C[C@H](Nc1nc(Cl)cc(N2CCC(O)(CO)CC2)n1)c1ccc(F)cc1
Reactant: Nc1cnccn1
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: C[C@H](Nc1nc(Nc2cnccn2)cc(N2CCC(O)(CO)CC2)n1)c1ccc(F)cc1
Temperature: 100 °C
Reaction time: 1 h
Yield: 69.3 %

Procedure:
100 mg of (S)-1-{6-chloro-2-[1-(4-fluorophenyl)ethylamino]pyrimidin-4-yl}-4-(hydroxymethyl)piperidin-4-ol, 32 mg of 2-aminopyrazine, mg of 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl, 38 mg of sodium t-butoxide and 27 mg of tris(dibenzylideneacetone)(chloroform)palladium were added in turn to a degassed mixed solution of 3 ml of toluene and 2 ml of 1,4-dioxane, and the mixture was stirred at 100° C. for 1 hour under argon atmosphere. The reaction solution was diluted with ethyl acetate. The solution was washed in turn with water and brine and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and then the obtained residue was purified by silica gel column chromatography to obtain 80 mg of the objective compound as brown powder.
Reaction SMILES: N[C:2]1(CO)[CH2:7][O:6][C:5]([CH3:9])([CH3:8])[O:4][CH2:3]1.[OH:12]P([O-])(O)=O.[K+]>O>[CH3:9][C:5]1([CH3:8])[O:4][CH2:3][C:2](=[O:12])[CH2:7][O:6]1
Reactant: CC1(C)OCC(N)(CO)CO1
Reactant: O=P([O-])(O)O
Agent: [K+]
Solvent: O
Product: CC1(C)OCC(=O)CO1
Temperature: 0 °C
Reaction time: 8 h
Yield: 74.9 %

Procedure:
To a water (1.5 L) solution of (5-amino-2,2-dimethyl-1,3-dioxan-5-yl)methanol (251 g, 1.57 mol) and KH2PO4 (213 g, 1.57 mol) at 0° C., a water solution (1.8 L) of NaIO4 (336 g, 1.57 mol) was added dropwise. The reaction mixture was stirred at 0° C. for 2 hours and room temperature overnight. The product was extracted by CH2Cl2 (5×300 mL), dried over MgSO4 and distilled, yielding 2,2-Dimethyl-1,3-dioxan-5-one (153 g, 75%) as a colorless liquid, by 102° C./40 torr. 1H NMR (300 MHz, CDCl3) δ1.26 (s, 6H), 3.96 (s, 4H).