Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:3]=1[C:4]#[N:5].N[C:12]1[CH:17]=[CH:16][C:15]([N:18]2[C:22]([CH2:23][CH3:24])=[CH:21][C:20]([C:25]3[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=3)=[N:19]2)=[CH:14][CH:13]=1>C(O)(=O)C.[Ni]>[CH2:23]([C:22]1[N:18]([C:15]2[CH:16]=[CH:17][C:12]([NH:5][CH2:4][C:3]3[C:6]([CH3:10])=[CH:7][CH:8]=[CH:9][C:2]=3[F:1])=[CH:13][CH:14]=2)[N:19]=[C:20]([C:25]2[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=2)[CH:21]=1)[CH3:24]
Reactant: CCc1cc(-c2cccnc2)nn1-c1ccc(N)cc1
Reactant: Cc1cccc(F)c1C#N
Agent: [Ni]
Solvent: CC(=O)O
Product: CCc1cc(-c2cccnc2)nn1-c1ccc(NCc2c(C)cccc2F)cc1
Reaction time: 7 h
Yield: 49.7 %

Procedure:
A mixture of 2-chloro-6-methylbenzonitrile (5 g, 33.0 mmol) and CsF (14 g, 92.2 mmol) in DMSO (30 ml) was heated at 140° C. for 15 hr and then allowed to cool to room temperature. It was diluted with water, extracted with dichloromethane, washed with brine, dried (Na2SO4) and concentrated to give 2-fluoro-6-methylbenzonitrile (2.93 g, 66%). A mixture of the above nitrile (250 mg), 1-(4-aminophenyl)-3-(3-pyridyl)-5-ethylpyrazole (200 mg, 0.76 mmol) and Raney Ni (50% in water, 100 mg) in glacial acetic acid (15 ml) was shaken in a Parr apparatus under H2 (40 psi) for 7 hr. The catalyst was removed by filtration and the solvent was evaporated. Chromatography on silica gel (hexane/ethyl acetate=2:1) afforded the title compound (146 mg). 1H-NMR (CDCl3): 1.30 (t, J=7.5 Hz, 3H), 2.46 (s, 3H), 2.67 (q, J=7.5 Hz, 2H), 3.92 (bs, 1H), 4.38 (s, 2H), 6.58 (s, 1H), 6.78 (d, J=8.6 Hz, 2H), 6.99 (t, J=6.8Hz, 1H), 7.05 (d, J=7.8 Hz, 1H), 7.19-7.38 (m, 4 H), 8.20 (d, J=7.8 Hz, 1H), 8.56 (d, J=3.7Hz, 1H), 9.10 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH3:9])[CH:5]=[CH:6][C:7]=1[Br:8].[N+:10]([O-])([OH:12])=[O:11]>O>[Br:8][C:7]1[CH:6]=[C:5]([N+:10]([O-:12])=[O:11])[C:4]([CH3:9])=[CH:3][C:2]=1[Br:1]
Reactant: Cc1ccc(Br)c(Br)c1
Reactant: O=[N+]([O-])O
Solvent: O
Product: Cc1cc(Br)c(Br)cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 1 h
Yield: 76.7 %

Procedure:
3,4-dibromotoluene (108.11 mL, 800 mmol) was added dropwise over 4 hours to nitric acid (90%, 280 mL, 6000 mmol) that was cooled to 0° C. under a nitrogen atmosphere with mechanical stirring. The internal temperature of the mixture was maintained below 10° C. during the addition and was stirred for 1 hour at 0° C. after completion of addition. Water (840 mL) was added drop-wise to the mixture maintaining the internal temperature below 10° C. The crude product was collected by filtration and was washed with water (5×500 mL) to remove the excess nitric acid. The solids were dried under high vacuum and purified by recrystallization from ethanol (800 mL) to produce 180.9 g (77% yield) of the desired product as a solid. 1H NMR (400 mHz, CDCl3) δ 8.24 (s, 1H), 7.64 (s, 1H), 2.55 (s, 3H)
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9](=O)[CH3:10].[C:12]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])#[N:13].C([O-])(=O)C.[NH4+]>C(OCC)(=O)C.C(O)(=O)C.C1C=CC=CC=1>[CH2:18]([O:17][C:15](=[O:16])[C:14]([C:12]#[N:13])=[C:9]([C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([Cl:8])[C:2]=1[Cl:1])[CH3:10])[CH3:19]
Reactant: CCOC(=O)CC#N
Reactant: CC(=O)c1cccc(Cl)c1Cl
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: c1ccccc1
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CCOC(=O)C(C#N)=C(C)c1cccc(Cl)c1Cl
Temperature: 25 °C
Reaction time: 10 h

Procedure:
A mixture of 2′,3′-dichloroacetophenone (50 mmol), ethyl cyanoacetate (50 mmol), acetic acid (1.14 mL) ammonium acetate (400 mg), and benzene (50 mL) is heated to reflux in a Dean-Stark apparatus. After approximately 10 hours, additional ethyl cyanoacetate (50 mmol), acetic acid (1.14 mL), and ammonium acetate (400 mg) are added. After an additional 10 hours, the reaction is cooled to room temperature, diluted with ethyl acetate (30 mL), washed with water (240 mL), brine (40 mL), and dried (Na2SO4). After filtering, the extract is concentrated in vacuo and the desired product, as a mixture of E and Z-isomers, is isolated by column chromatography on silica gel, eluting with 5% ethyl acetate in petroleum ether.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]([N:17]2[C:25](=[O:26])[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][C:23]=3[NH2:27])[C:18]2=[O:28])[CH2:12][S:13]([CH3:16])(=[O:15])=[O:14])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[CH:29]1([C:32](Cl)=[O:33])[CH2:31][CH2:30]1.C(O)C>CCOCC>[CH:29]1([C:32]([NH:27][C:23]2[CH:22]=[CH:21][CH:20]=[C:19]3[C:24]=2[C:25](=[O:26])[N:17]([CH:11]([C:5]2[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=2)[CH2:12][S:13]([CH3:16])(=[O:14])=[O:15])[C:18]3=[O:28])=[O:33])[CH2:31][CH2:30]1
Reactant: COc1ccc(C(CS(C)(=O)=O)N2C(=O)c3cccc(N)c3C2=O)cc1OC
Reactant: O=C(Cl)C1CC1
Solvent: CCOCC
Solvent: CCO
Product: COc1ccc(C(CS(C)(=O)=O)N2C(=O)c3cccc(NC(=O)C4CC4)c3C2=O)cc1OC
Reaction time: 0.5 h
Yield: 42 %

Procedure:
A stirred mixture of 2-[1-(3,4-dimethoxyphenyl)-2-(methylsulfonyl)ethyl]-4-aminoisoindoline-1,3-dione (0.68 g, 1.7 mmol) and cyclopropane carbonyl chloride (1.3 mL) was heated to reflux for 25 min. To the mixture was added ethanol (10 mL) at 0° C. and kept for 30 min. The solvent was removed in vacuo to give a oil. The oil was stirred in ether (20 mL) for 30 min to give a suspension. The suspension was filtered and the solid washed with ether to give a white solid. The solid was purified by column chromatography (Silica Gel, 10% ethyl acetate in methylene chloride) to give cyclopropyl-N-{2-[1-(3,4-dimethoxyphenyl)-2-(methylsulfonyl)ethyl]-1,3-dioxoisoindolin-4-yl}carboxamide as a white solid (330 mg, 42% yield); mp, 130-132° C.; 1H NMR (CDCl3) δ 0.92-0.98 (m, 2H, 2CHH), 1.09-1.14 (m, 2H, 2CHH), 1.61-1.64 (m, 1H, CH), 2.88 (s, 3H, CH3), 3.73 (dd, J=4.4, 14.3 Hz, 1H, CHH), 3.86 (s, 3H, CH3), 3.90 (s, 3H, CH3), 4.58 (dd, J=10.4, 14.3 Hz, 1H, CHH), 5.90 (dd, J=4.4, 10.3 Hz, 1H, NCH), 6.84 (d, J=8 Hz, 1H, Ar), 7.09-7.14 (m, 2H, Ar), 7.47 (d, J=7.2 Hz, 1H, Ar), 7.65 (t, J=7.6 Hz, 1H, Ar), 8.75 (d, J=8.4 Hz, 1H, Ar), 9.68 (s, 1H, NH); 13C NMR (CDCl3) δ 6.75, 16.13, 41.54, 48.43, 54.36, 55.81, 55.94, 110.98, 111.11, 114.78, 117.88, 120.27, 124.93, 129.30, 130.94, 136.00, 137.68, 149.19, 149.35, 167.45, 169.48, 172.79; Anal Calcd for C23H24N2O7S: C, 58.46; H, 5.12; N, 5.93. Found: C, 58.10; H, 5.16; N, 5.78.
Reaction SMILES: CO[C:3]1[CH2:4][CH:5]([CH3:11])[CH2:6][CH:7]([CH3:10])[CH2:8][N:9]=1.[Cl-:12].[NH4+:13]>CO>[ClH:12].[CH3:11][CH:5]1[CH2:6][CH:7]([CH3:10])[CH2:8][NH:9][C:3](=[NH:13])[CH2:4]1
Reactant: COC1=NCC(C)CC(C)C1
Reactant: [Cl-]
Reactant: [NH4+]
Solvent: CO
Product: CC1CNC(=N)CC(C)C1
Product: Cl
Yield: 92.1 %

Procedure:
The product of EXAMPLE 34 (1.75 g, 8.6 mmol) in 25 mL of MeOH was reacted with ammonium chloride (0.48 g, 9.0 mmol) by the method of EXAMPLE 27 to yield 1.4 g (83%) of the title material.
Reaction SMILES: [NH2:1][C:2]1[CH2:6][CH2:5][N:4]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:8]=2)[N:3]=1.C(O[CH2:21][CH3:22])(=O)C>CO.C(O)C>[N:4]1[CH:7]=[CH:8][CH:9]=[CH:10][C:21]=1[CH:22]=[N:1][C:2]1[CH2:6][CH2:5][N:4]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:14])([F:16])[F:15])[CH:8]=2)[N:3]=1
Reactant: NC1=NN(c2cccc(C(F)(F)F)c2)CC1
Reactant: CCOC(C)=O
Solvent: CCO
Solvent: CO
Product: FC(F)(F)c1cccc(N2CCC(N=Cc3ccccn3)=N2)c1
Reaction time: 8 h

Procedure:
3-Amino-1-(3-trifluoromethylphenyl)-2-pyrazoline in methanol (23 ml) was stirred together with 2-pyridylaldehyde at room temperature for 2 hours and then under reflux for a further 2 hours. Thin layer chromatography (SiO2, ethyl acetate) indicated that the reaction was substantially complete. After standing overnight, additional 2-pyridylaldehyde (0.5 g) was added and heating was continued for 2 hours. TLC again indicated that no further reaction had occurred. The reaction mixture was evaporated in vacuo to yield an orange-coloured solid which was stirred for 45 minutes in aqueous ethanol (3:1) and 3-(2-pyridylmethyleneamino)-1-(3-trifluoromethylphenyl)-2-pyrazoline was collected, m.p. 155.6°.
Reaction SMILES: O1CCC[CH2:2]1.[CH3:6][O:7][N:8]=[C:9]1[CH2:15][C:14]([CH3:17])([CH3:16])[CH:13]([OH:18])[CH:12]([N:19]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:20](=[O:22])[CH3:21])[CH:11]=[C:10]1[CH3:30].[H-].[Na+].CI>C(O)(=O)C>[CH3:6][O:7][N:8]=[C:9]1[CH2:15][C:14]([CH3:16])([CH3:17])[CH:13]([O:18][CH3:2])[CH:12]([N:19]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:20](=[O:22])[CH3:21])[CH:11]=[C:10]1[CH3:30]
Reactant: C1CCOC1
Reactant: CON=C1CC(C)(C)C(O)C(N(Cc2ccccc2)C(C)=O)C=C1C
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: CC(=O)O
Product: CON=C1CC(C)(C)C(OC)C(N(Cc2ccccc2)C(C)=O)C=C1C
Temperature: 0 °C
Reaction time: 1 h
Yield: 86 %

Procedure:
To a solution of tetrahydrofuran (40 ml) containing the 4-(N-acetylbenzylamino)-5-hydroxy-2,6,6-trimethyl-2-cyclohepten-1-one methyloxime obtained in step 2 (9.5 g, 27.6 millimoles) there was gradually added 55% sodium hydride (3.6 g) while cooling on ice. After then adding methyl iodide (7.8 g, 55.2 millimoles) and stirring for 30 minutes, the mixture was returned to room temperature and stirring was continued for one hour. The reaction solution was poured into ice water (100 ml) containing acetic acid (1 ml), and subjected to extraction with benzene. After washing the benzene solution with water, it was dried over anhydrous magnesium sulfate. The benzene was distilled off, and the resulting residue was subjected to silica gel column chromatography with benzene-ethyl acetate (9:1) as the eluent, to obtain 8.51 g (86%) of 4-(N-acetylbenzylamino)-5-methoxy-2,6,6-trimethyl-2-cyclohepten-1-one methyloxime as a colorless oil.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][C:13]([C:15]2[S:22][C:21]([CH3:23])=[C:20]3[C:16]=2[CH2:17][C@H:18]2[C:24]([CH3:26])([CH3:25])[C@H:19]23)=[O:14])=[CH:7][CH:6]=1.CCN(C(C)C)C(C)C.[CH3:36][S:37](Cl)(=[O:39])=[O:38]>C(Cl)Cl>[O:14]=[C:13]([C:15]1[S:22][C:21]([CH3:23])=[C:20]2[C:16]=1[CH2:17][C@H:18]1[C:24]([CH3:26])([CH3:25])[C@H:19]12)[CH2:12][CH2:11][C:8]1[CH:9]=[CH:10][C:5]([CH2:4][CH2:3][CH2:2][O:1][S:37]([CH3:36])(=[O:39])=[O:38])=[CH:6][CH:7]=1
Reactant: Cc1sc(C(=O)CCc2ccc(CCCO)cc2)c2c1[C@H]1[C@@H](C2)C1(C)C
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1sc(C(=O)CCc2ccc(CCCOS(C)(=O)=O)cc2)c2c1[C@H]1[C@@H](C2)C1(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 98.5 %

Procedure:
A solution of 3-[4-(3-hydroxy-propyl)-phenyl]-1-((1aS,5aR)-1,1,2-trimethyl-1,1a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalen-4-yl)-propan-1-one (147 mg, 0.40 mmol), DIPEA (0.11 mL, 0.642 mmol) in DCM (5 mL) is treated with methane sulfonylchloride (40 μL, 0.481 mmol) at 0° C. The solution is stirred at 0° C. for 30 min, then at rt for 1 h before it is diluted with DCM and washed with 0.1 N aq. NaOH solution, followed by 10% aq. citric acid solution. The organic layer is separated, dried over Na2SO4 and evaporated to give methanesulfonic acid 3-{4-[3-oxo-3-((1aS,5aR)-1,1,2-trimethyl-1,1a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalen-4-yl)-propyl]-phenyl}-propyl ester (176 mg) as a colourless oil; LC-MS: tR=1.14 min, [M+1]+=447.25.
Reaction SMILES: Br[C:2]1[CH:13]=[CH:12][C:5]([CH2:6][N:7]2[CH2:11][CH2:10][CH2:9][CH2:8]2)=[CH:4][CH:3]=1.CC(C)=O.C(=O)=O.[Li]CCCC.[N:26]1([C:32]([CH:34]2[CH2:37][C:36](=[O:38])[CH2:35]2)=[O:33])[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1>C1COCC1>[OH:38][C:36]1([C:2]2[CH:13]=[CH:12][C:5]([CH2:6][N:7]3[CH2:11][CH2:10][CH2:9][CH2:8]3)=[CH:4][CH:3]=2)[CH2:37][CH:34]([C:32]([N:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)=[O:33])[CH2:35]1
Reactant: O=C1CC(C(=O)N2CCOCC2)C1
Reactant: Brc1ccc(CN2CCCC2)cc1
Agent: O=C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)=O
Product: O=C(C1CC(O)(c2ccc(CN3CCCC3)cc2)C1)N1CCOCC1
Yield: 20.4 %

Procedure:
To a stirring solution of 1-(4-bromo-benzyl-pyrrolidine (1.6 g, 6.5 mmol) in THF (20 mL) at −78° C. (acetone/dry ice bath) was added slowly down the side of the flask a solution of nBuLi (2.6 mL, 6.5 mmol, 2.5 M THF). After 15 minutes a solution of Intermediate 7, 3-(morpholin-4-ylcarbonyl)cyclobutanone (1.0 g, 5.4 mmol, in 7 mL of THF) precooled to −78° C. was added slowly. After 30 minutes the reaction was quenched cold with 1N HCl (20 mL). This mixture was diluted with EtOAc and then the layers were separated and the organic layer was discarded. The aqueous layer was basified with 1 N NaOH and extracted with CHCl3/iPrOH (3:1). The organic layer was dried over MgSO4, filtered and concentrated to give a yellow oil. This material was purified by flash column chromatography using a 40 g ISCO™ column, eluting with a gradient of 3%, 5%, 10%, 20%, 30% MeOH/CHCl3 with 0.1% NH4OH. The product containing fraction were collected and concentrated under reduced pressure to give the title compound (379 mg, 20% yield): Rf=0.3 (30% MeOH/CH2Cl2); LRMS m/z Calcd for C20H28N2O3, 344.4, found, 345 (M+1) APCI: 400 MHz 1H NMR (CDCl3) δ 7.42 (d, J=8.3 Hz, 2H), 7.29 (d, J=8.3 Hz, 2H), 4.58 (brs, 1H), 3.62-3.55 (m, 8H), 3.34-3.32 (m, 2H), 2.87 (dddd, J=8.3, 8.3, 8.3, 8.3 Hz, 1H), 2.77-2.71 (m, 2H), 2.64-2.59 (m, 2H), 2.48-2.45 (m, 4H), 1.75-1.70 (m, 4H); 100 MHz 13C NMR (CDCl3) δ 173.8, 144.4, 137.8, 129.3, 125.3, 72.9, 67.0, 66.9, 60.3, 54.2, 46.0, 42.6, 40.9, 28.1, 23.5.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:8]2[C@@H:12]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=3)[NH:11][C:10](=[S:20])[NH:9]2)[CH:5]=[CH:6][CH:7]=1.[CH3:21][I:22]>CCO>[IH:22].[F:19][C:15]1[CH:14]=[C:13]([C@H:12]2[C@@H:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=3)[NH:9][C:10]([S:20][CH3:21])=[N:11]2)[CH:18]=[CH:17][CH:16]=1
Reactant: Fc1cccc([C@H]2NC(=S)N[C@H]2c2cccc(F)c2)c1
Reactant: CI
Solvent: CCO
Product: CSC1=N[C@@H](c2cccc(F)c2)[C@@H](c2cccc(F)c2)N1
Product: I
Temperature: 25 °C
Yield: 75.1 %

Procedure:
A mixture of cis-4,5-bis-(3-fluorophenyl)imidazolidine-2-thione (27) (4.5 g, 0.0188 mol) and methyl iodide (1.45 mL, 0.0232 mol) in abs. EtOH (50 mL) is heated at 95° C. overnight. The reaction mixture is cooled to RT, concentrated in vacuo, and the residue suspended in abs EtOH/Et2O. The insoluble material is filtered to give 6.10 g of the product 44. 1H NMR (DMSO-d6) δ 10.78 (s, 2 H), 7.30-7.15 (m, 2 H), 7.05-6.90 (m, 6 H); 5.87 (s, 2 H), 2.87 (s, 3 H); MS: m/z 305 (M++1).
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([Cl:8])[N:3]=1.[F:9][C@H:10]1[C@@H:15]([OH:16])[CH2:14][CH2:13][N:12]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:11]1.ClC1N=C(OC2CCN(C(OC(C)(C)C)=O)CC2)C=NC=1>>[Cl:8][C:4]1[N:3]=[C:2]([O:16][C@H:15]2[CH2:14][CH2:13][N:12]([C:17]([O:19][C:20]([CH3:22])([CH3:21])[CH3:23])=[O:18])[CH2:11][C@H:10]2[F:9])[CH:7]=[N:6][CH:5]=1
Reactant: Clc1cncc(Cl)n1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](O)[C@H](F)C1
Agent: CC(C)(C)OC(=O)N1CCC(Oc2cncc(Cl)n2)CC1
Product: CC(C)(C)OC(=O)N1CC[C@H](Oc2cncc(Cl)n2)[C@H](F)C1

Procedure:
tert-butyl cis-4-[(6-chloropyrazin-2-yl)oxy]-3-fluoropiperidine-1-carboxylate was prepared from 2,6-dichloropyrazine and tert-butyl cis-3-fluoro-4-hydroxypiperidine-1-carboxylate using the conditions described for the preparation of tert-butyl 4-[(6-chloropyrazin-2-yl)oxy]piperidine-1-carboxylate (Compound 1, Step 3). LRMS (ESI) calculated for C14H19ClFN3O3[M+Na]+, 354.1; found 354.1.
Reaction SMILES: [CH2:1]([O:8][C@@H:9]([C@H:12]([OH:15])[CH2:13][OH:14])[CH2:10][OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:16]1(O[Si](C)(C)C)[CH2:21][CH2:20][CH2:19][CH2:18][CH:17]=1>C(OCC)C.Cl>[CH2:1]([O:8][C@@H:9]([C@H:12]1[CH2:13][O:14][C:16]2([CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[O:15]1)[CH2:10][OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)OC1=CCCCC1
Reactant: OC[C@@H](O)[C@@H](CO)OCc1ccccc1
Agent: Cl
Solvent: CCOCC
Product: OC[C@@H](OCc1ccccc1)[C@H]1COC2(CCCCC2)O1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96624.1 %

Procedure:
4.34 g (0.02 mol) of (2R,3R)-2-benzyloxybutane-1,3,4-triol were suspended in a mixture of 3.4 g (0.02 mmol) of 1-cyclohexenyloxytrimethylsilane and 40 ml of diethyl ether. Two drops of concentrated hydrochloric acid were added and the mixture was stirred at room temperature for 30 minutes. The mixture was then evaporated to give 5.65 g of β(R)-benzyloxy-1,4-dioxaspiro[4,5]decane-2(R)-ethanol in the form of a colourless viscous oil; MS: m/e 292 [M]+.
Reaction SMILES: C([Li])CCC.[C:6]([N:25]1[CH:29]=[CH:28][N:27]=[CH:26]1)([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH2:30]([O:37][CH2:38][C@H:39]1[CH2:41][O:40]1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.O>C1COCC1>[CH2:30]([O:37][CH2:38][C@H:39]([OH:40])[CH2:41][C:26]1[N:25]([C:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH:29]=[CH:28][N:27]=1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: c1ccc(COC[C@H]2CO2)cc1
Reactant: c1ccc(C(c2ccccc2)(c2ccccc2)n2ccnc2)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: O[C@@H](COCc1ccccc1)Cc1nccn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 0.5 h

Procedure:
In an argon atmosphere, n-butyllithium (1.6 M solution in hexane, 6.9 ml) was added drop by drop to a solution of 1-tritylimidazole (3.10 g) in THF (80 ml) under ice cooling. After stirring at the same temperature for 30 minutes, (R)-2-[(benzyloxy)methyl]oxirane (1.52 ml) was added. After stirring under ice cooling for 1.5 hours and at room temperature for 1 hour, water was added and the reaction mixture was extracted with ethyl acetate. The extract was washed with water and saline and dried over magnesium sulfate, after which it was concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluent: ethyl acetate-hexane 1:1) to yield the titled compound (1.402 g) as a pale-yellow oily substance.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][CH2:10][O:11][CH2:12][CH3:13])=[CH:4][CH:3]=1.[NH:14]([C:18]1[CH:26]=[CH:25][C:21]([C:22](Cl)=[O:23])=[CH:20][CH:19]=1)[C:15]([NH2:17])=[NH:16].[C:27]([O-:30])([OH:29])=[O:28].[Na+]>N1C=CC=CC=1>[C:27](=[O:28])([OH:30])[OH:29].[NH:14]([C:18]1[CH:26]=[CH:25][C:21]([C:22]([O:1][C:2]2[CH:3]=[CH:4][C:5]([S:8][CH2:9][CH2:10][O:11][CH2:12][CH3:13])=[CH:6][CH:7]=2)=[O:23])=[CH:20][CH:19]=1)[C:15]([NH2:17])=[NH:16]
Reactant: O=C([O-])O
Reactant: CCOCCSc1ccc(O)cc1
Reactant: N=C(N)Nc1ccc(C(=O)Cl)cc1
Agent: [Na+]
Solvent: c1ccncc1
Product: CCOCCSc1ccc(OC(=O)c2ccc(NC(=N)N)cc2)cc1
Product: O=C(O)O
Temperature: 25 °C
Reaction time: 27 h
Yield: 40 %

Procedure:
3.4 g of 2-ethoxyethyl 4-hydroxyphenyl sulfide was dissolved in 50 ml of pyridine. 4-Guanidinobenzoyl chloride was added to the solution under cooling with ice and the mixture was stirred at room temperature for 27 h. A saturated aqueous solution of sodium hydrocarbonate was added thereto under cooling with ice. A precipitate thus formed was recovered by filtration, washed with water and then with acetone, and dried to obtain 2.86 g (yield: 40 %) of 4-(2-ethoxyethylthio)phenyl 4-guanidinobenzoate carbonate.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8]1[S:9][C:10]([CH:13]=O)=[CH:11][N:12]=1.[NH2:15][C:16]1[CH:17]=[C:18]([CH:22]=[CH:23][C:24]=1[F:25])[C:19]([OH:21])=[O:20].C([SiH](CC)CC)C>C(Cl)Cl>[F:25][C:24]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=[O:20])=[CH:17][C:16]=1[NH:15][CH2:13][C:10]1[S:9][C:8]([NH:7][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)=[N:12][CH:11]=1
Reactant: Nc1cc(C(=O)O)ccc1F
Reactant: O=Cc1cnc(Nc2ccccn2)s1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Product: O=C(O)c1ccc(F)c(NCc2cnc(Nc3ccccn3)s2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 91.3 %

Procedure:
To a suspension of 2-(pyridin-2-ylamino)-thiazole-5-carbaldehyde (1.0 g, 4.90 mmol, compound 1A) in methylene chloride (20 mL) at RT 3-amino-4-fluorobenzoic acid (0.95 g, 4.90 mmol) TFA (5 mL) and triethylsilane (1.71 mg, 14.7 mmol) were added. The above reaction mixture was stirred at RT for 4 h, then concentrated in vacuo and the resulting slurry was triturated with methanol to afford 4-fluoro-3-{[2-(pyridin-2-ylamino)-thiazol-5-ylmethyl]-amino}-benzoic acid as light yellow solid (1.54 g, 91%) (M+H)+=345.
Reaction SMILES: N1CCOCC1.C([O:10][C:11](=[O:38])[C@:12]([S:25]([C:28]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:31]=[CH:30][CH:29]=1)(=[O:27])=[O:26])([CH:14]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:15]([OH:17])=[O:16])[NH2:13])C=C>C1COCC1.C(Cl)Cl.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:28]1([S:25]([C@@:12]([C:11]([OH:38])=[O:10])([CH:14]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:15]([OH:17])=[O:16])[NH2:13])(=[O:26])=[O:27])[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:31]=[CH:30][CH:29]=1
Reactant: C=CCOC(=O)[C@@](N)(C(Cc1ccccc1)C(=O)O)S(=O)(=O)c1cccc2ccccc12
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCN1
Solvent: C1CCOC1
Solvent: ClCCl
Product: N[C@](C(=O)O)(C(Cc1ccccc1)C(=O)O)S(=O)(=O)c1cccc2ccccc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Morpholine (3.3 ml; 38 mmol) was added to a solution of 2-Naphthalenesulphonyl β-benzyl-L-aspartic acid allyl ester (3--3) (1.73 g; 3.8 mmol) and tetrakis (triphenylphosphine) palladium (0.42 g; 0.37 mmol) in dry THF (40 ml) under an atmosphere of argon. The reaction mixture was stirred at room temperature for 2 h and then evaporated to dryness. The resultant yellow oil was triturated with ethyl acetate followed by filtration of the white solid obtained. The crude product was dissolved in DCM (30 ml) and then washed successively with 2N HCl (30 ml) and brine (30 ml×3). The solution was dried (sodium sulphate). Filtration and evaporation of the solvent gave the product as a white solid.
Reaction SMILES: [CH:1]1([N:6]2[C:11]3[N:12]=[C:13]([S:16][CH3:17])[N:14]=[CH:15][C:10]=3[CH:9]=[C:8]([CH2:18][O:19][CH2:20][CH3:21])[C:7]2=[O:22])[CH2:5][CH2:4][CH2:3][CH2:2]1.C1(S(N2C(C3C=CC=CC=3)O2)(=O)=[O:30])C=CC=CC=1>ClCCl>[CH:1]1([N:6]2[C:11]3[N:12]=[C:13]([S:16]([CH3:17])=[O:30])[N:14]=[CH:15][C:10]=3[CH:9]=[C:8]([CH2:18][O:19][CH2:20][CH3:21])[C:7]2=[O:22])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CCOCc1cc2cnc(SC)nc2n(C2CCCC2)c1=O
Reactant: O=S(=O)(c1ccccc1)N1OC1c1ccccc1
Solvent: ClCCl
Product: CCOCc1cc2cnc(S(C)=O)nc2n(C2CCCC2)c1=O
Temperature: 25 °C
Reaction time: 12 h

Procedure:
8-Cyclopentyl-6-ethoxymethyl-2-methylsulfanyl-8H-pyrido[2,3-d]pyrimidin-7-one (4.60 g, 14.40 mmol) and 2-benzenesulfonyl-3-phenyl-oxaziridine (4.89 g, 18.72 mmol) were dissolved in dichloromethane (30 mL) and stirred at ambient temperature for 12 hours. The crude product was then purified by silica gel chromatography to give 8-cyclopentyl-6-ethoxymethyl-2-methanesulfinyl-8H-pyrido[2,3-d]pyrimidin-7-one as a white waxy solid (2.67 g, 55.3%). 1H NMR δ (400 MHz, CDCl3) 8.94 (s, 1H), 7.81 (t, J=1.7 Hz, 1H), 5.98 (m, 1H), 4.50 (d, J=1.7 Hz, 1H), 3.68 (q, J=7.1 Hz, 2H), 2.96 (s, 3H), 2.22 (m, 2H), 2.12 (m, 2H), 1.94 (m, 2H), 1.69 (m, 2H), 1.31 (t, J=7.1 Hz, 3H).
Reaction SMILES: [CH3:1][C@@:2]12[C:8]([CH3:10])([CH3:9])[C@@H:5]([CH2:6][CH2:7]1)[C:4](=O)[C:3]2=O.COP([CH2:19][C:20]([C:22]1[C:23]([CH3:34])=[N:24][N:25]([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:26]=1)=O)(=O)OC.O.[NH2:36][NH2:37]>>[CH2:27]([N:25]1[CH:26]=[C:22]([C:20]2[CH:19]=[C:4]3[C:3]([C@:2]4([CH3:1])[C:8]([CH3:10])([CH3:9])[C@H:5]3[CH2:6][CH2:7]4)=[N:37][N:36]=2)[C:23]([CH3:34])=[N:24]1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: NN
Reactant: CC1(C)[C@H]2CC[C@]1(C)C(=O)C2=O
Reactant: COP(=O)(CC(=O)c1cn(Cc2ccccc2)nc1C)OC
Solvent: O
Product: Cc1nn(Cc2ccccc2)cc1-c1cc2c(nn1)[C@@]1(C)CC[C@@H]2C1(C)C

Procedure:
yellow solid. MS (ESI): 359.1 (MH+). Prepared from (1S,4R)-1,7,7-trimethyl-bicyclo[2.2.1]heptane-2,3-dione, [2-(1-Benzyl-3-methyl-1H-pyrazol-4-yl)-2-oxo-ethyl]-phosphonic acid dimethyl ester, hydrazine monohydrate.