Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([NH:4][CH2:5][CH2:6][NH2:7])([CH3:3])[CH3:2].[N:8]#[C:9][Br:10]>CO>[BrH:10].[CH:1]([N:4]1[CH2:5][CH2:6][N:7]=[C:9]1[NH2:8])([CH3:3])[CH3:2]
Reactant: N#CBr
Reactant: CC(C)NCCN
Solvent: CO
Product: Br
Product: CC(C)N1CCN=C1N
Temperature: 80 °C
Yield: 51.5 %

Procedure:
A solution of N-isopropylethylenediamine (10.0 g, 0.097 mol) in methanol (10 ml) was cooled to 0° C. and treated dropwise with a solution of cyanogen bromide (10.37 g, 0.098 mol) in methanol (25 ml) while maintaining the temperature below 10° C. The reaction mixture was then heated to 80° C. for 45 min, cooled and concentrated under reduced pressure. Crystallization of the residue from cold ethanol gave 10.4 g (50% yield) of the title product as white crystals; mp 154-155° C. 1HNMR 400 MHz (CDCl3) δ (ppm): 1.27 (6H, d, J=6.6 Hz, 2×CH3), 3.57-3.75 (4H, m, 2×CH2), 4.41 (1H, m, CH).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[C:15](#[N:18])[CH:16]=[CH2:17]>[Cl-].C[N+](CCCCCCCC)(CCCCCCCC)CCCCCCCC.CC(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:14][CH2:13][N:12]([CH2:17][CH2:16][C:15]#[N:18])[CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: Clc1ccc(N2CCNCC2)cc1Cl
Reactant: C=CC#N
Agent: CCCCCCCC[N+](C)(CCCCCCCC)CCCCCCCC
Agent: [Cl-]
Solvent: CC(C)O
Product: N#CCCN1CCN(c2ccc(Cl)c(Cl)c2)CC1
Yield: 98.5 %

Procedure:
A mixture of 1-(3,4-dichlorophenyl)piperazine (0.1 mol), 2-propenenitrile (0.15 mol), and N-methyl-N,N-dioctyl octanaminiumchloride (1 ml) in 2-propanol (150 ml) was stirred and refluxed for one hour. The solvent was evaporated and the residue was purified by column chromatography over silica gel (eluent: CH2Cl2 /CH3OH 95/5). The pure fractions were collected and the solvent was evaporated. The residue was stirred in diisopropylether/acetonitrile 10/1. The solvent was evaporated, yielding 28 g (98.5%) of 4-(3,4-dichlorophenyl)-1-piperazinepropanenitrile (interm. 3).
Reaction SMILES: [C:1]([OH:8])(=O)[CH:2]=[CH:3][CH:4]=[CH:5][CH3:6].ClC(OCC)=O.C(N(CC)CC)C.[CH:22]1([NH2:25])[CH2:24][CH2:23]1.[Cl-].[Na+]>C1COCC1>[CH:22]1([NH:25][C:1](=[O:8])/[CH:2]=[CH:3]/[CH:4]=[CH:5]/[CH3:6])[CH2:24][CH2:23]1
Reactant: NC1CC1
Reactant: CC=CC=CC(=O)O
Agent: CCOC(=O)Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C/C=C/C=C/C(=O)NC1CC1
Yield: 51 %

Procedure:
2,4-Hexadienoic acid 1 eq, ethyl chloroformate 1.05 eq, triethylamine 1.2 eq, cyclopropylamine 1.3 eq as a 2.0M solution in THF, quench with 10% sodium chloride solution, yield=51%. 0.54 ppm (m, 2H), 0.79 ppm (m, 2H), 1.82 ppm (d, 3H, J=5.93 Hz), 2.80 ppm (m, 1H), 5.72 ppm (d, 1H), 6.00 ppm (br. s, 1H), 6.03-6.15 ppm (m, 2H), 7.18 ppm (d, 1H, J=14.98 Hz, of d, J=10.02 Hz).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]([NH:10][OH:11])=[NH:9])[CH:5]=[CH:4][N:3]=1.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[N:22]=[C:21]([C:29](O)=O)[N:20]=2)=[CH:15][CH:14]=1>>[Cl:12][C:13]1[CH:14]=[CH:15][C:16]([C:19]2[CH:24]=[C:23]([C:25]([F:27])([F:26])[F:28])[N:22]=[C:21]([C:29]3[O:11][N:10]=[C:8]([C:6]4[CH:5]=[CH:4][N:3]=[C:2]([NH2:1])[CH:7]=4)[N:9]=3)[N:20]=2)=[CH:17][CH:18]=1
Reactant: N=C(NO)c1ccnc(N)c1
Reactant: O=C(O)c1nc(-c2ccc(Cl)cc2)cc(C(F)(F)F)n1
Product: Nc1cc(-c2noc(-c3nc(-c4ccc(Cl)cc4)cc(C(F)(F)F)n3)n2)ccn1

Procedure:
The title compound was prepared from 2-amino-N-hydroxy-pyridine-4-carboxamidine (example C.5) (0.11 g, 0.75 mmol) and 4-(4-chloro-phenyl)-6-trifluoromethyl-pyrimidine-2-carboxylic acid (example D.1) (0.15 g, 0.5 mmol) according to the general procedure V. Obtained as an off-white solid (0.018 g, 9%). MS (ISP) 419.0 [(M+H)+]; mp 223.5° C.
Reaction SMILES: [ClH:1].Cl.[F:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2([CH2:15][CH2:16][CH2:17][N:18]([CH2:20][CH2:21][N:22]3[CH2:27][CH2:26][CH:25](OC4C=CC(F)=CC=4)[CH2:24][CH2:23]3)[CH3:19])[O:14]CCO2)=[CH:6][CH:5]=1.Cl.[C:37]1(N)[C:42]([F:43])=[C:41](F)[C:40](F)=[C:39](N)[C:38]=1F.Cl.Cl>CO>[ClH:1].[ClH:1].[F:3][C:4]1[CH:5]=[CH:6][C:7]([C:10](=[O:14])[CH2:15][CH2:16][CH2:17][N:18]([CH2:20][CH2:21][N:22]2[CH2:23][CH2:24][CH:25]([C:39]3[CH:38]=[CH:37][C:42]([F:43])=[CH:41][CH:40]=3)[CH2:26][CH2:27]2)[CH3:19])=[CH:8][CH:9]=1
Reactant: Nc1c(F)c(N)c(F)c(F)c1F
Reactant: CN(CCCC1(c2ccc(F)cc2)OCCO1)CCN1CCC(Oc2ccc(F)cc2)CC1
Agent: Cl
Solvent: CO
Product: CN(CCCC(=O)c1ccc(F)cc1)CCN1CCC(c2ccc(F)cc2)CC1
Temperature: 25 °C

Procedure:
A suspension of 11.4 g (21.4 mmol) of 1-{2-{N-{3-[2-(4-fluorophenyl)-1,3-dioxolan-2-yl]propyl}-N-methylamino}ethyl}-4-(4-fluorophenoxy)piperidine dihydrochloride, 260 ml of methanol and 130 ml of 3N HCl was heated at reflux for 3 hours under nitrogen. The mixture was allowed to cool to room temperature and the methanol evaporated. The mixture was made basic with saturated sodium carbonate, extracted twice with ether, washed with saturated sodium chloride and dried over potassium carbonate. Evaporation of the solvent provided an oil. The yield of the dihydrochloride was 8.38 g (79.9%). Recrystallization from ethanol/methanol provided analytically pure material.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([C:14]([OH:16])=O)[CH2:10][CH2:9]2)=[CH:4][C:3]=1[O:17][CH3:18].Cl.[CH3:20][NH:21][O:22][CH3:23].Cl.C(N=C=NCCCN(C)C)C.C(N(CC)C(C)C)(C)C>CN(C)C1C=CN=CC=1.C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:9][CH2:10][CH:11]([C:14]([N:21]([O:22][CH3:23])[CH3:20])=[O:16])[CH2:12][CH2:13]2)=[CH:4][C:3]=1[O:17][CH3:18]
Reactant: CNOC
Reactant: COc1cc(N2CCC(C(=O)O)CC2)ccc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(N2CCC(C(=O)N(C)OC)CC2)ccc1Cl
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A mixture of 1-(4-chloro-3-methoxyphenyl)piperidine-4-carboxylic acid (9.0 g, 33.4 mmol), N,O-dimethylhydroxylamine hydrochloride (4.88 g, 50.1 mmol) and DCM (15 mL) was treated with 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (9.59 g, 50.1 mmol) and 4-(dimethylamino)pyridine (0.408 g, 3.34 mmol). The mixture was cooled in an ice bath and treated with N,N-diisopropylethylamine (11.62 mL, 66.7 mmol) over 3 min. After 10 min, the cooling bath was removed and the mixture was stirred at RT overnight (ca. 14 h). At the conclusion of this period, the mixture was diluted with DCM (50 mL), and then washed successively with saturated NaHCO3 (3×25 mL), 1 M HCl (2×50 mL) and brine. The organic phase was dried (MgSO4) and concentrated in vacuo. The resultant residue was purified by flash chromatography using a 120 g silica gel cartridge and 10:1 Hex/EtOAc to elute the product. The fractions containing the product were pooled and concentrated on a rotary evaporator to give 1-(4-chloro-3-methoxyphenyl)-N-methoxy-N-methylpiperidine-4-carboxamide as pale yellow oil.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1.[CH2:12]([CH:14]([NH2:17])[CH2:15][CH3:16])[CH3:13].CCN(C(C)C)C(C)C>CCO>[Cl:1][C:2]1[N:7]=[C:6]([NH:17][CH:14]([CH2:15][CH3:16])[CH2:12][CH3:13])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1
Reactant: O=[N+]([O-])c1cnc(Cl)nc1Cl
Reactant: CCC(N)CC
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: CCC(CC)Nc1nc(Cl)ncc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2,4-dichloro-5-nitro-pyrimidine (2 g, 10.31 mmol) in anhydrous EtOH (20 ml) is added 1-ethylpropylamine (1.322 ml, 11.341 mmol) at 0 C (ice bath) under inert atmosphere. To this is added neat DIPEA (2.694 ml, 15.465 mmol). The reaction is stirred at r.t. for 8 hrs. The reaction mixture was concentrated in vacuo and the residue is dissolved with EtOAc. The organic layer is washed with sat. NaHCO3 and brine, dried over Na2SO4, and concentrated in vacuo. Purification with column chromatography (SiO2, 1:3 EtOAC/Hexane) gives the desired product.
Reaction SMILES: [CH3:1][C:2]1[C:3]([OH:11])=[C:4]([CH3:10])[C:5]([CH3:9])=[C:6]([CH:8]=1)O.Cl.[CH3:13][CH:14]([CH2:16][CH2:17][CH2:18][CH:19]([CH2:21][CH2:22][CH2:23][CH:24]([CH2:26][CH2:27][CH2:28][C:29]([OH:33])([CH:31]=[CH2:32])[CH3:30])[CH3:25])[CH3:20])[CH3:15]>C1(C)C=CC=CC=1.[Cl-].[Zn+2].[Cl-]>[CH3:10][C:4]1[C:5]([CH3:9])=[C:6]2[C:8]([CH2:32][CH2:31][C:29]([CH2:28][CH2:27][CH2:26][CH:24]([CH2:23][CH2:22][CH2:21][CH:19]([CH2:18][CH2:17][CH2:16][CH:14]([CH3:13])[CH3:15])[CH3:20])[CH3:25])([CH3:30])[O:33]2)=[C:2]([CH3:1])[C:3]=1[OH:11]
Reactant: Cc1cc(O)c(C)c(C)c1O
Reactant: C=CC(C)(O)CCCC(C)CCCC(C)CCCC(C)C
Agent: Cl
Agent: [Cl-]
Agent: [Zn+2]
Solvent: Cc1ccccc1
Product: Cc1c(C)c2c(c(C)c1O)CCC(C)(CCCC(C)CCCC(C)CCCC(C)C)O2
Temperature: 85 °C
Reaction time: 4 h
Yield: 99.7 %

Procedure:
13.5 g of trimethyl hydroquinone are dissolved in 100 ml of toluene, and 13.5 g of silica-alumina, 6.0 g of zinc chloride and 0.5 g of concentrated hydrochloric acid (35% hydrochloric acid) are added thereto under nitrogen flow. The reaction system is warmed to 85° C. and then 25.0 g of isophytol are added dropwise over about 20 minutes. After completion of the addition, stirring is continued for about 4 hours at the same temperature and then the reaction system is allowed to cool. Then, 100 ml of toluene are added to the reaction mixture and the insoluble material is filtered off. The filtrate is washed in succession with 3% caustic soda, 1% sodium hydrosulfite, water and saturated aqueous salt solution and dehydrated with anhydrous magnesium sulfate. The solvent is then distilled off under reduced pressure to give 36.2 g of dl-α-tocopherol (yield 99.8%). 25.0 g of dl-α-tocopherol thus obtained are dissolved in 50 ml of acetic anhydride and 12.5 g of sodium acetate and 1.25 g of metallic zinc powder are added thereto. The reaction mixture is acetylated by stirring at 95°-100° C. for about 3.5 hours and then extracted with 200 ml of n-hexane. The extract is washed in succession with 1% caustic soda, water and saturated aqueous salt solution and dried over magnesium sulfate. Thereafter, n-hexane is distilled off under reduced pressure to give 26.2 g of crude dl-α-tocopherol acetate. The crude dl-α-tocopherol acetate thus obtained is subjected to vacuum distillation to give 20.5 g of the main fraction of 165°-175° C./8×10-3 mmHg. The purity of this product is 97.3% and the distillation yield is 78.0%.
Reaction SMILES: C(OC(=O)[N:7]([C:30]1[CH:35]=[CH:34][C:33]([N:36]2[CH2:41][CH2:40][N:39]([CH3:42])[CH2:38][CH2:37]2)=[CH:32][CH:31]=1)[C:8]1[C:9]2[N:10]([CH:27]=[CH:28][N:29]=2)[C:11]([Sn](CCCC)(CCCC)CCCC)=[CH:12][N:13]=1)(C)(C)C.Br[C:45]1[S:49][CH:48]=[C:47]([C:50]([NH2:52])=[O:51])[CH:46]=1>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH3:7].[CH3:42][N:39]1[CH2:40][CH2:41][N:36]([C:33]2[CH:34]=[CH:35][C:30]([NH:7][C:8]3[C:9]4[N:10]([CH:27]=[CH:28][N:29]=4)[C:11]([C:45]4[S:49][CH:48]=[C:47]([C:50]([NH2:52])=[O:51])[CH:46]=4)=[CH:12][N:13]=3)=[CH:31][CH:32]=2)[CH2:37][CH2:38]1
Reactant: NC(=O)c1csc(Br)c1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnc(N(C(=O)OC(C)(C)C)c2ccc(N3CCN(C)CC3)cc2)c2nccn12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: CN1CCN(c2ccc(Nc3ncc(-c4cc(C(N)=O)cs4)n4ccnc34)cc2)CC1
Product: N
Temperature: 85 °C
Reaction time: 2 h
Yield: 40 %

Procedure:
To a solution of [4-(4-methyl-piperazin-1-yl)-phenyl]-(5-tributylstannanyl-imidazo[1,2-a]pyrazin-8-yl)-carbamic acid tert-butyl ester (0.106 g, 0.15 mmol) in DMF (3 mL) is added 5-bromo-thiophene-3-carboxylic acid amide (0.062 g, 0.3 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.018 g, 0.015 mmol). The solution is degassed and heated at 85° C. for 18 hours. The reaction mixture is diluted with ethyl acetate and washed with water (3×) and brine. The aqueous layers are backwashed with ethyl acetate and the organic layers are combined, dried (MgSO4), and concentrated. The crude mixture is then stirred in (1:1) TFA: dichloromethane (3 mL) for 2 hours at room temperature. The resulting solution is diluted with ethyl acetate and washed with water, sat. NaHCO3 and brine. The aqueous layers are backwashed with ethyl acetate and the organic layers are combined, dried (MgSO4), and concentrated. The crude material is purified by flash column chromatography using 99:1 and 95:5 DCM:NH3 (7M in MeOH), to give 5-{8-[4-(4-methyl-piperazin-1-yl)-phenylamino]-imidazo[1,2-a]pyrazin-5-yl}-thiophene-3-carboxylic acid amide (0.013 g, 20%) as a yellow solid. LCMS: Rt 2.79 min, (93.3%), m/z (APCI) 434 (M+H)+; 1H-NMR (400 MHz, d6-DMSO) δ (ppm). 2.26 (3H, s), 2.48-2.53 (4H, m), 3.14 (4H, m), 6.96 (2H, d), 7.42 (1H, br s), 7.61 (1H, s), 7.78 (1H, s), 7.82 (2H, d), 7.92 (1H, s), 7.99 (1H, br s), 8.21 (1H, s), 8.31 (1H, s), 9.61 (1H, s).
Reaction SMILES: [Br:1][N:2]1[C:6](=O)[CH2:5][CH2:4][C:3]1=[O:8].[O:9]1C2N=CCC(=O)[C:12]=2[CH:11]=[CH:10]1.CO>C(#N)C>[Br:1][N:2]1[C:6]2[O:8][CH:3]=[CH:4][C:5]=2[C:10](=[O:9])[CH2:11][CH2:12]1
Reactant: O=C1CC=Nc2occc21
Reactant: O=C1CCC(=O)N1Br
Solvent: CO
Solvent: CC#N
Product: O=C1CCN(Br)c2occc21
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Add N-bromosuccinimide (63.16 g, 354.9 mmol) as a solution in anhydrous acetonitrile (480 mL) to a suspension of 5H-furo[3,2]pyridin-4-one (36.9 g, 273 mmol) in anhydrous acetonitrile (740 mL) at 0° C. over 1 hour. Warm to room temperature, add anhydrous methyl alcohol (1.5 L) and stir at room temperature for 18 hours. Quench with water (20 ml) and saturated sodium bicarbonate (20 mL), concentrate to a volume of 1.3 liters, and pour into water (1.3 L). Collection of the precipitate by filtration and drying (vacuum oven 2 days 40-60° C.) gives the title compound as an off-white solid.
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[CH:13]1([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:15][CH2:14]1.[Cl:23][C:24]1[CH:31]=[CH:30][C:27]([CH:28]=[O:29])=[CH:26][C:25]=1[N+:32]([O-:34])=[O:33].[Cl-].[NH4+]>CCCCCC.C1COCC1>[Cl:23][C:24]1[CH:31]=[CH:30][C:27]([CH:28]([OH:29])[C:13]2([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:15][CH2:14]2)=[CH:26][C:25]=1[N+:32]([O-:34])=[O:33]
Reactant: CC(C)(C)OC(=O)C1CC1
Reactant: O=Cc1ccc(Cl)c([N+](=O)[O-])c1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CC(C)NC(C)C
Product: CC(C)(C)OC(=O)C1(C(O)c2ccc(Cl)c([N+](=O)[O-])c2)CC1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
9.7 ml (24.3 mmol) of a 2.5 M solution of n-butyllithium in hexane were added dropwise to a solution, cooled to from −20° C. to −30° C., of 3.4 ml (24.3 mmol) of diisopropylamine in 20 ml of abs. THF. After the addition had ended, the mixture was stirred at from −20° C. to −30° C. for another 30 min. The mixture was then cooled to −78° C., and a solution of 2.53 g (17.8 mmol) of tert-butyl cyclopropanecarboxylate in 15 ml of abs. THF was added dropwise at this temperature. After 4 h at −78° C., a solution of 3 g (16.2 mmol) of 4-chloro-3-nitrobenzaldehyde in 15 ml of abs. THF was then added. The reaction mixture was slowly warmed to RT overnight and then allowed to stand at RT for three days, and saturated aqueous ammonium chloride solution was then added. The mixture was extracted with ethyl acetate and the organic phase was dried over magnesium sulphate and concentrated under reduced pressure. The crude product was purified by chromatography on silica gel (mobile phase cyclohexane/ethyl acetate 50:1→20:1). This gave 3.21 g of the target compound (60.6% of theory).
Reaction SMILES: C([O:3][C:4](=[O:39])[CH2:5][N:6]([CH2:28][C:29]1[N:34]=[CH:33][C:32]2[O:35][CH2:36][CH2:37][O:38][C:31]=2[CH:30]=1)[CH:7]1[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][N:15]2[C:24]3[C:19](=[N:20][CH:21]=[C:22]([O:25][CH3:26])[CH:23]=3)[CH:18]=[CH:17][C:16]2=[O:27])[CH2:9][CH2:8]1)C.[OH-].[Na+].Cl>CO.O1CCCC1>[O:38]1[C:31]2[CH:30]=[C:29]([CH2:28][N:6]([CH2:5][C:4]([OH:39])=[O:3])[CH:7]3[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][N:15]4[C:24]5[C:19](=[N:20][CH:21]=[C:22]([O:25][CH3:26])[CH:23]=5)[CH:18]=[CH:17][C:16]4=[O:27])[CH2:9][CH2:8]3)[N:34]=[CH:33][C:32]=2[O:35][CH2:36][CH2:37]1
Reactant: CCOC(=O)CN(Cc1cc2c(cn1)OCCO2)C1CCN(CCn2c(=O)ccc3ncc(OC)cc32)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1cnc2ccc(=O)n(CCN3CCC(N(CC(=O)O)Cc4cc5c(cn4)OCCO5)CC3)c2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 63.3 %

Procedure:
A solution of 90 mg of ethyl((2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)(1-(2-(7-methoxy-2-oxo-1,5-naphthyridin-1(2H)-yl)ethyl)piperidin-4-yl)amino)acetate in 0.2 mL of methanol and 1 mL of tetrahydrofuran, 0.2 mL of a 10% aqueous sodium hydroxide solution was added, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was added with a 1 mol/L aqueous hydrochloric acid solution and neutralized, and the solvent was distilled off under reduced pressure. The resultant residue was purified by a resin; HP-20, made by Mitsubishi Chemical Corporation and an eluent of acetone to obtain 54 mg of ((2,3-dihydro(1,4)dioxino(2,3-c) pyridin-7-ylmethyl)(1-(2-(7-methoxy-2-oxo-1,5-naphthyridin-1(2H)-yl)ethyl)piperidin-4-yl)amino)acetic acid as a light yellow solid.
Reaction SMILES: [CH2:1]([Si:4]([CH3:7])([CH3:6])[CH3:5])[C:2]#[CH:3].[Li]CCCC.[Al](Cl)(C)C.[CH2:17]([C@@H:19]1[O:21][CH2:20]1)[Cl:18]>C1(C)C=CC=CC=1>[Cl:18][CH2:17][C@H:19]([OH:21])[CH2:20][C:3]#[C:2][CH2:1][Si:4]([CH3:7])([CH3:6])[CH3:5]
Reactant: ClC[C@H]1CO1
Reactant: C#CC[Si](C)(C)C
Agent: C[Al](C)Cl
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Product: C[Si](C)(C)CC#CC[C@@H](O)CCl
Reaction time: 24 h
Yield: 66.6 %

Procedure:
14.11 g (126 mmol) of propargyltrimethylsilane was dissolved in 125 ml of abs. toluene and cooled to -17°. 81.1 ml of nBuLi (1.55 M, hexane) was slowly added while keeping the temperature below -5°. 5 Minutes later, 126 ml of Me2AlCl (1 M, hexane) was added to this solution of the Li-acetylide. The temperature was then lowered to -45° and 6.90 ml of (R)-epichlorohydrine (88 mmol), dissolved in 50 ml of toluene, was added. The cooling bath was then removed and the reaction mixture allowed to reach ambient temperature during 24h. After careful quenching with icecold water and filtration, the product was extracted with ether, washed with NH4Cl, dried over sodium sulfate and the solvents removed i. V. Flash chromatography (SiO2, hexane/AcOEt=86/14) yielded 12.01 g of (R)-1-chloro-6-trimethylsilanyl-hex-4-yn-2-ol as colorless oil, 97% pure according to GC.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[F:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][CH:7]=1.[CH2:14]([O:16][C:17](=[O:28])[C:18]([OH:27])([C:23]([F:26])([F:25])[F:24])[CH2:19][C:20](=[CH2:22])[CH3:21])[CH3:15].Cl>>[CH2:14]([O:16][C:17](=[O:28])[C:18]([OH:27])([C:23]([F:26])([F:25])[F:24])[CH2:19][C:20]([C:10]1[CH:11]=[C:6]([F:5])[CH:7]=[CH:8][C:9]=1[O:12][CH3:13])([CH3:22])[CH3:21])[CH3:15]
Reactant: C=C(C)CC(O)(C(=O)OCC)C(F)(F)F
Reactant: COc1ccc(F)cc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Product: CCOC(=O)C(O)(CC(C)(C)c1cc(F)ccc1OC)C(F)(F)F
Temperature: 25 °C
Reaction time: 40 h

Procedure:
0.8 g of anhydrous aluminum chloride is added to 5 ml of 4-fluoranisole and 0.9 g of 2-hydroxy-4-methylene-2-trifluoromethyl-valeric acid ethyl ester. After 40 hours of stirring at room temperature, it is added to ice-cooled 2N hydrochloric acid and extracted with ethyl acetate. The ethyl acetate phase is washed with 1N hydrochloric acid and water, dried (Na2SO4) and concentrated by evaporation. After chromatography on silica gel with hexane/ethyl acetate (1:1), 1 g of 4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-valeric acid ethyl ester, melting point 38-39° C., is obtained.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[Cl:15])[N:3]=1.[CH:16]1([C:19]2[NH:23][N:22]=[C:21]([NH2:24])[CH:20]=2)[CH2:18][CH2:17]1>C(O)C>[Cl:1][C:2]1[N:7]=[C:6]([NH:24][C:21]2[CH:20]=[C:19]([CH:16]3[CH2:18][CH2:17]3)[NH:23][N:22]=2)[CH:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[Cl:15])[N:3]=1
Reactant: Clc1cc(-c2ccccc2Cl)nc(Cl)n1
Reactant: Nc1cc(C2CC2)[nH]n1
Solvent: CCO
Product: Clc1nc(Nc2cc(C3CC3)[nH]n2)cc(-c2ccccc2Cl)n1
Temperature: 25 °C
Reaction time: 96 h
Yield: 38.7 %

Procedure:
2,4-Dichloro-6-(2-chloro-phenyl)-pyrimidine (180 mg, 0.694 mmol) and 5-cyclopropyl-1H-pyrazol-3-ylamine (128 mg, 1.04 mmol) was taken into 3 ml of ethanol. The reaction was stirred at room temperature for 4 days. The reaction was evaporated in vacuo and the crude product purified by flash chromatography (SiO2) eluting with ethyl acetate/hexane (1:1) to afford 93 mg of the desired product. HPLC (C18 column) Rt 6.23 mins.; MS m/z 346.1 (M+H) 344.1 (M-H)
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([N:13]3[C@H:17]([CH2:18]O)[CH2:16][O:15][C:14]3=[O:20])[S:11][CH:12]=2)=[CH:4][CH:3]=1.C(N(S(F)(F)F)CC)C.C(Cl)[Cl:31]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([N:13]3[C@H:17]([CH2:18][Cl:31])[CH2:16][O:15][C:14]3=[O:20])[S:11][CH:12]=2)=[CH:4][CH:3]=1
Reactant: ClCCl
Reactant: O=C1OC[C@@H](CO)N1c1nc(-c2ccc(Br)cc2)cs1
Agent: CCN(CC)S(F)(F)F
Product: O=C1OC[C@@H](CCl)N1c1nc(-c2ccc(Br)cc2)cs1
Temperature: -78 °C
Reaction time: 1 h
Yield: 14 %

Procedure:
(4R)-3-[4-(4-Bromophenyl)-1,3-thiazol-2-yl]-4-(hydroxymethyl)-1,3-oxazolidin-2-one (80 mg, 0.23 mmol), prepared in Example 71, was dissolved in 5 mL methylene chloride and cooled to −78° C. A solution of (diethylamino)sulfur trifluoride (0.034 mL, 0.25 mmol) in 5 mL of methylene chloride was added dropwise. The mixture was stirred at −78° C. for 1 h then warmed to 25° C. The reaction was quenched by pouring over ice and was then diluted with water and methylene chloride. The layers were separated and the aqueous layer was extracted with methylene chloride. The organics were combined and washed with water, brine, dried over anhydrous MgSO4, filtered and concentrated under reduced pressure. Flash chromatography (gradient 10% acetone/hexane to 20% acetone/hexane) afforded the title compound (12 mg, 14%) as a white solid. HRMS: calcd for C13H10BrClN2O2S+H+, 372.94076; found (ESI, [M+H]+), 372.9406. Analytical HPLC: retention time 10.6 min, 210-370 nm the Xterra® RP18 column, 3.5μ, 150×4.6 mm 40° C. 85/15-5/95 (Ammon. Form. Buff. pH=3.5/ACN+MeOH) for 10 min, hold 4 min, 1.2 mL/min 5 μL injection.