Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:4]([CH2:15][CH:16]=[CH2:17])(C(OCC)=O)[C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH:2]=[CH2:3].[C-]#N.[Na+].CS(C)=O>O>[C:5]([CH:4]([CH2:1][CH:2]=[CH2:3])[CH2:15][CH:16]=[CH2:17])([O:7][CH2:8][CH3:9])=[O:6]
Reactant: C=CCC(CC=C)(C(=O)OCC)C(=O)OCC
Agent: [C-]#N
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: C=CCC(CC=C)C(=O)OCC
Temperature: 160 °C
Yield: 78.1 %

Procedure:
A mixture of diethyl diallylmalonate (701; 50 g, 208 mmol), sodium cyanide (20.7 g, 422 mmol) and DMSO (166 mL) was heated at 160° C. for 6 h. After being cooled to r.t., the mixture was added to 400 mL of water and the product was extracted into hexane (4×100 mL). After evaporation of the solvent at reduced pressure, the residue was distilled (42-43° C./1 Torr) to give 27.34 g (78%) of 702 as a colorless liquid. 1H NMR (400 MHz, CDCl3) δ 5.80-5.70 (m, 2H, 2 CH═CH2), 5.10-5.02 (m, 4H, 2 CH═CH2), 4.14 (q, 2H, J=7.2 Hz, OCH2), 2.54-2.48 (m, 1H, CH), 2.41-2.34, 2.29-2.23 (2m, 4H, 2CH2), 1.25 (t, J=7.2 Hz, 3H, CH3).
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[CH2:3][N:4]=[C:5]([NH2:19])[NH:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([S:13][CH2:14][CH2:15][CH2:16][C:17]#[N:18])[N:8]=1.[OH:22]S(O)(=O)=O.[OH-].[Na+]>O>[F:21][C:2]([F:1])([F:20])[CH2:3][N:4]=[C:5]([NH2:19])[NH:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([S:13][CH2:14][CH2:15][CH2:16][C:17]([NH2:18])=[O:22])[N:8]=1
Reactant: N#CCCCSc1nccc(NC(N)=NCC(F)(F)F)n1
Reactant: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: NC(=O)CCCSc1nccc(NC(N)=NCC(F)(F)F)n1
Reaction time: 3 h

Procedure:
A mixture of 4-[4-(2-[2,2,2-trifluoroethyl]guanidino)pyrimid-2-ylthio]butyronitrile (0.14 g.) and concentrated H2SO4 was left at room temperature for 3 hours and then diluted with crushed ice and water. The solution was basified with 10 N aqueous NaOH and the mixture extracted three times with EtOAc. The combined extracts were dried and evaporated to dryness to give 4-[4-(2-[2,2,2-trifluoroethyl]guanidino)pyrimid-2-ylthio]butyramide (0.13 g.) which was characterised as the hydrogen maleate, m.p. 202°-203° on recrystallisation from aqueous EtOH.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=O)=[C:4]([Cl:11])[CH:3]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.Cl.Cl.[NH2:26][C:27]1[C:35]([NH2:36])=[CH:34][CH:33]=[CH:32][C:28]=1[C:29]([NH2:31])=[O:30]>N1C=CC=CC=1.CN(C=O)C>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]2[NH:36][C:35]3[CH:34]=[CH:33][CH:32]=[C:28]([C:29]([NH2:31])=[O:30])[C:27]=3[N:26]=2)=[C:4]([Cl:11])[CH:3]=1
Reactant: O=C(O)c1ccc(Br)cc1Cl
Reactant: NC(=O)c1cccc(N)c1N
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: NC(=O)c1cccc2[nH]c(-c3ccc(Br)cc3Cl)nc12
Temperature: 45 °C
Reaction time: 2 h

Procedure:
To 4-bromo-2-chlorobenzoic acid (2.48 g) in pyridine (12 mL) and DMF (12 mL) was added CDI (1.88 g). The solution was stirred at 45° C. for 2 hours, cooled, treated with 2,3-diaminobenzamide dihydrochloride (2.36 g), stirred at ambient temperature for 18 hours, and concentrated. The concentrate was partitioned between ethyl acetate (70 mL) and water (100 mL) and filtered. The filtrant was washed with water and ethyl acetate and dried. This solid was suspended in acetic acid (40 mL) and the mixture was heated at 125° C. for 4 hours and filtered. The filtrate was cooled to ambient temperature and filtered. The filtrant was washed with methanol and dried to give the first batch of product. The mother liquor was concentrated and the concentrate was treated with dichloromethane and filtered to provide a second batch of solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C@@H:8]1[C:14](=[O:15])[NH:13][C:12]2[CH:16]=[C:17]([F:20])[CH:18]=[CH:19][C:11]=2[O:10][C@@H:9]1[CH3:21])([CH3:4])([CH3:3])[CH3:2].O([CH2:31][C:32]([F:35])([F:34])[F:33])S(C(F)(F)F)(=O)=O.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[C:1]([O:5][C:6](=[O:22])[NH:7][C@@H:8]1[C:14](=[O:15])[N:13]([CH2:31][C:32]([F:35])([F:34])[F:33])[C:12]2[CH:16]=[C:17]([F:20])[CH:18]=[CH:19][C:11]=2[O:10][C@@H:9]1[CH3:21])([CH3:4])([CH3:2])[CH3:3]
Reactant: C[C@H]1Oc2ccc(F)cc2NC(=O)[C@H]1NC(=O)OC(C)(C)C
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: C[C@H]1Oc2ccc(F)cc2N(CC(F)(F)F)C(=O)[C@H]1NC(=O)OC(C)(C)C
Yield: 96.6 %

Procedure:
A solution of 3.00 g (10.0 mmol) ((6R,7S)-2-fluoro-6-methyl-8-oxo-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocyclohepten-7-yl)-carbamic acid tert-butyl ester and 3.37 g (15.0 mmol) 2,2,2-trifluoroethyl triflate in 30 ml dimethylformamide were treated with 4.73 g (15.0 mmol) cesium carbonate for 6 hours. The solvent was distilled off at low pressure and the residue was extracted with water/ethylacetate. Chromatography on silicagel with heptane/ethylacetate 100:0 to 0:100 yielded 3.79 g (99%) [(6R,7S)-2-fluoro-6-methyl-8-oxo-9-(2,2,2-trifluoro-ethyl)-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocyclohepten-7-yl]-carbamic acid tert-butyl ester, MS m/e (%): 393.3 (M+H+, 100).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[N:14]=[C:13]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)[CH:12]=[C:11]([C:21]([NH2:23])=[O:22])[C:7]=3[NH:8][C:9]=2[CH:10]=1.O[CH:25]1[CH2:30][CH2:29][N:28](C(OC(C)(C)C)=O)[CH2:27][CH2:26]1>>[C:15]1([C:13]2[CH:12]=[C:11]([C:21]([NH2:23])=[O:22])[C:7]3[NH:8][C:9]4[CH:10]=[C:2]([O:1][CH:25]5[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]5)[CH:3]=[CH:4][C:5]=4[C:6]=3[N:14]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: NC(=O)c1cc(-c2ccccc2)nc2c1[nH]c1cc(O)ccc12
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Product: NC(=O)c1cc(-c2ccccc2)nc2c1[nH]c1cc(OC3CCNCC3)ccc12

Procedure:
This was similarly prepared from 7-hydroxy-2-phenyl-5H-pyrido[3,2-b]indole-4-carboxamide and tert-butyl 4-hydroxypiperidine-1-carboxylate. MS (ESI) m/z 387.1 (M+H). 1H NMR (500 MHz, DMSO-d6) δ ppm 11.35 (1H, br. s.), 8.57 (1H, s), 8.36 (1H, s), 8.28 (2H, d, J=7.02 Hz), 8.12 (1H, d, J=8.55 Hz), 7.84 (1H, s), 7.54 (2H, t, J=7.63 Hz), 7.42 (1H, t, J=7.32 Hz), 7.32 (1H, d, J=2.14 Hz), 6.91 (1H, dd, J=8.85, 2.14 Hz), 4.43-4.57 (1H, m), 3.05 (2H, ddd, J=12.67, 4.27, 4.12 Hz), 2.61-2.74 (2H, m), 1.98-2.11 (2H, m), 1.91 (3H, s), 1.50-1.68 (2H, m).
Reaction SMILES: [C:1]([C:3]1[C:8]2[N:9]=[C:10]([C:12]([N:14]([CH3:16])[CH3:15])=[O:13])[O:11][C:7]=2[C:6](F)=[C:5]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=2)[C:4]=1[CH3:25])#[N:2].C(N(CC)CC)C.[CH3:33][N:34](C)[C@H:35]1[CH2:39][CH2:38][NH:37][CH2:36]1>CS(C)=O>[C:1]([C:3]1[C:8]2[N:9]=[C:10]([C:12]([N:14]([CH3:16])[CH3:15])=[O:13])[O:11][C:7]=2[C:6]([N:37]2[CH2:38][CH2:39][C@H:35]([NH:34][CH3:33])[CH2:36]2)=[C:5]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=2)[C:4]=1[CH3:25])#[N:2]
Reactant: CN(C)[C@H]1CCNC1
Reactant: Cc1c(-c2cccc(F)c2)c(F)c2oc(C(=O)N(C)C)nc2c1C#N
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CN[C@H]1CCN(c2c(-c3cccc(F)c3)c(C)c(C#N)c3nc(C(=O)N(C)C)oc23)C1
Temperature: 150 °C
Reaction time: 1 h

Procedure:
4-Cyano-7-fluoro-6-(3-fluorophenyl)-N,N,5-trimethyl-1,3-benzoxazole-2-carboxamide (I-184) (75 mg, 0.22 mmol) was dissolved in dimethyl sulfoxide (3.5 ml), then at room temperature, triethylamine (40 μl, 0.29 mmol) was added. The solution was heated at 150° C., a solution of (3S)-3-(dimethylamino)pyrrolidine (30 μl, 0.29 mmol) dissolved in dimethyl sulfoxide (1 ml) was added all at a time. The solution was stirred under nitrogen atmosphere at the same temperature for 1 hour. After cooling to room temperature, the solvent was evaporated away under reduced pressure. The residue was fractionated with chloroform and an aft aqueous saturated sodium hydrogencarbonate solution. The aqueous layer was further extracted twice with chloroform. The organic layers were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The insoluble matter was separated by filtration, the solvent was evaporated away under reduced pressure, and the resulting residue was purified first by preparative TLC (eluent, chloroform:methanol=9:1) to obtain a roughly-purified form (54 mg). This was further purified by preparative TLC (eluent, chloroform:7 N ammonia-containing methanol solution=95:5), then recrystallized from diisopropyl ether to obtain the entitled compound (12 tag, 13%) as a white solid.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([OH:8])[CH2:4][CH2:3]1.C(N(CC)CC)C.[C:16](Cl)([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C([O-])(O)=O.[Na+]>C(Cl)Cl>[C:16]([NH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([OH:8])[CH2:4][CH2:3]1)([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)([C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: N[C@H]1CC[C@H](O)CC1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O[C@H]1CC[C@H](NC(c2ccccc2)(c2ccccc2)c2ccccc2)CC1
Reaction time: 8 h

Procedure:
Trans-4-aminocyclohexanol (2.6 g, 22.6 mmol) was suspended in 60 mL DCM, then 4 mL (28.7 mmol) triethylamine was added. The mixture was cooled in ice bath, and trityl chloride (6.3 g, 22.6 mmol) was added. The mixture was stirred overnight, allowing it to slowly warm up. Saturated NaHCO3 was added to quench the chloride, and product was extracted with EtOAc three times. The combined organic layer was washed with brine, and dried over Na2SO4. Column chromatography with 20-40% EtOAc in hexanes provided 5.3 g (66%) white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[C:5]([CH3:17])[CH:4]=1.C([Li])(CC)C.[CH3:23][C:24]([CH3:28])([CH3:27])[CH:25]=[O:26].Cl>O1CCCC1.O>[C:12]([O:11][C:10](=[O:16])[NH:9][C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][C:5]=1[CH2:17][CH:25]([OH:26])[C:24]([CH3:28])([CH3:27])[CH3:23])([CH3:13])([CH3:14])[CH3:15]
Reactant: CC(C)(C)C=O
Reactant: COc1ccc(NC(=O)OC(C)(C)C)c(C)c1
Agent: Cl
Agent: [Li]C(C)CC
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(NC(=O)OC(C)(C)C)c(CC(O)C(C)(C)C)c1
Reaction time: 0.25 h

Procedure:
To a solution of tert-butyl (4-methoxy-2-methylphenyl)carbamate (475 mg) in tetrahydrofuran (7 mL) was added dropwise sec-butyllithium (1.04 mol/L hexane-cyclohexane solution, 4.3 mL) at −40° C. under an argon atmosphere, and the mixture was stirred for 15 minutes. Then a solution of trimethylacetaldehyde (0.287 mL) in tetrahydrofuran (1 mL) was added dropwise, and the mixture was stirred at −40° C. for 15 minutes and at room temperature for additional one hour. Water and μmol/L hydrochloric acid were added to the reaction mixture and this resulting mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate-hexane) to obtain the title compound (234 mg).
Reaction SMILES: Cl[C:2]1[C:3]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][C@H:9]2[CH3:14])=[N:4][CH:5]=[CH:6][N:7]=1.C.[CH3:16][N:17]([CH3:31])[CH2:18][CH2:19][O:20][C:21]1[C:26]([O:27][CH2:28][CH2:29][OH:30])=[CH:25][CH:24]=[CH:23][N:22]=1.C1COCC1.CC(C)([O-])C.[K+]>C1(C)C=CC=CC=1>[CH3:16][N:17]([CH3:31])[CH2:18][CH2:19][O:20][C:21]1[C:26]([O:27][CH2:28][CH2:29][O:30][C:2]2[C:3]([N:8]3[CH2:13][CH2:12][NH:11][CH2:10][C@H:9]3[CH3:14])=[N:4][CH:5]=[CH:6][N:7]=2)=[CH:25][CH:24]=[CH:23][N:22]=1
Reactant: CN(C)CCOc1ncccc1OCCO
Reactant: C[C@@H]1CNCCN1c1nccnc1Cl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: C[C@@H]1CNCCN1c1nccnc1OCCOc1cccnc1OCCN(C)C
Temperature: 100 °C
Reaction time: 0.42 h

Procedure:
(2R)-1-(3-chloro-2-pyrazinyl)-2-methylpiperazine (20 L in toluene solution; see Example 8 for preparation) and active charcoal (201 g) was added to the 328 L-reactor containing 2-{[2-(2-dimethylaminoethoxy)-3-pyridinyl]oxy} ethanol (Example 1C) in toluene solution. The mixture was stirred for 25 minutes before transferred to a through a GAF-filter (containing a Teflon filter bag) to a 250 L-stainless steel reactor. The mixture was heated to 100° C. before the prepared “THF/potassium tert-butoxide-solution” was added to the reactor using a 50 L addition bowl. After 10 L “THF/potassium tert-butoxide-solution” was added, an IP-HPLC was taken to ensure that the title compound had started to form. The total addition of THF/potassium tert-butoxide-solution was made during 2 h and 15 minutes. Water (21 L) and sodium chloride (1 kg) was added to a 198 L-glasslined reactor. The salt was dissolved before the reaction mixture was transferred from the 328 L-reactor and quenched into the 198 L-reactor. Toluene (10 L) was also transferred to make sure that no reaction-mixture was left in the hoses used for the transfer. The mixture was then heated to 70° C. before the mechanical stirrer was turned off. The phases were allowed to separate for 30 minutes before the water phase (25 L) was discharged. The mixture was heated to reflux and toluene (10 L) was distilled off. Water (100 L) was added and the mixture was heated to reflux again and 60 L of water was distilled off. The remaining solution was then cooled to RT. The title compound was never isolated; it was directly used in the next step (Example 3C). IP sample (HPLC) of the toluene mixture confirmed the retention time for the desired product (tret=2.2 minutes).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[CH:4][N:3]=1.O.[NH2:15][NH2:16]>C(O)C>[CH3:11][C:10]([CH3:13])([CH3:12])[CH2:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([NH:15][NH2:16])=[N:3][CH:4]=1
Reactant: NN
Reactant: CC(C)(C)COc1ccc(Cl)nc1
Solvent: CCO
Solvent: O
Product: CC(C)(C)COc1ccc(NN)nc1

Procedure:
6.2 g (30.8 mmol) 2-chloro-5-(2,2-dimethylpropoxy)pyridine together with 60 ml (1.2 mol) hydrazine hydrate are divided into four portions of equal size and 10 ml ethanol are added to each portion. Each portion is reacted in a single mode microwave (CEM Explorer) at 170° C. (200 watt) for in each case 12 h. Thereafter, the four mixtures are combined and the solvent is removed. The residue is taken up in ethyl acetate and the mixture is washed in each case once with saturated sodium bicarbonate solution and saturated sodium chloride solution. The mixture is dried over magnesium sulfate and the solvent is removed in vacuo.
Reaction SMILES: C([O:3][C:4](=[O:26])[CH:5]([N:11]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH:6]([CH:8]1[CH2:10][CH2:9]1)[OH:7])C.O.[OH-].[Li+]>O1CCCC1.O>[CH:8]1([CH:6]([OH:7])[CH:5]([N:11]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:4]([OH:26])=[O:3])[CH2:10][CH2:9]1
Reactant: CCOC(=O)C(C(O)C1CC1)N(Cc1ccccc1)Cc1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)C(C(O)C1CC1)N(Cc1ccccc1)Cc1ccccc1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
To 17.1 g (48.5 mmol) racemic (2R,3S and 2S,3R)-3-cyclopropyl-2-dibenzylamino-3-hydroxy-propionic acid ethyl ester in 446 ml tetrahydrofurane were added 8.22 g (194 mmol) lithium hydroxide monohydrate dissolved in 74 ml water. The mixture was stirred at 60° C. overnight. The organic solvent was removed by distillation. Sodium dihydrogenphosphate was added followed by extraction with ethyl acetate. Chromatography on silicagel with diethylether/heptane (1:1 to 1:0) yielded 9.03 g (57%) racemic (2R,3S and 2S,3R)-3-cyclopropyl-2-dibenzylamino-3-hydroxy-propionic acid, MS m/e (%): 326.1 (M+H+, 100).
Reaction SMILES: [NH2:1][C:2]1[N:14]=[C:13]([C:15]2[C:20]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=3)=[CH:19][CH:18]=[CH:17][C:16]=2[O:31][CH2:32][CH:33]2[CH2:35][CH2:34]2)[CH:12]=[C:11]([S:36][CH3:37])[C:3]=1[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5].C1C=C(Cl)C=C(C(OO)=[O:46])C=1>C(Cl)Cl>[NH2:1][C:2]1[N:14]=[C:13]([C:15]2[C:20]([O:21][CH2:22][C:23]3[CH:24]=[CH:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=3)=[CH:19][CH:18]=[CH:17][C:16]=2[O:31][CH2:32][CH:33]2[CH2:34][CH2:35]2)[CH:12]=[C:11]([S:36]([CH3:37])=[O:46])[C:3]=1[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5]
Reactant: COc1ccc(COc2cccc(OCC3CC3)c2-c2cc(SC)c(C(=O)OC(C)(C)C)c(N)n2)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: COc1ccc(COc2cccc(OCC3CC3)c2-c2cc(S(C)=O)c(C(=O)OC(C)(C)C)c(N)n2)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 62.6 %

Procedure:
To a cold (0° C.) solution of tert-butyl 2-amino-6-{2-(cyclopropylmethoxy)-6-[(4-methoxybenzyl)oxy]phenyl}-4-(methylsulfanyl)nicotinate (1.72 g, 3.30 mmol) in CH2Cl2 (20 mL) was added m-CPBA (69%, 0.82 g, 3.30 mmol). The reaction mixture was stirred at 0° C. for 15 min, quenched with saturated aqueous NaHCO3 solution (20 mL) containing Na2S2O3 (1 g). The organic phase was separated, dried over Na2SO4, filtered, and concentrated under reduced pressure. Purification by column chromatography on silica gel (hexane/ethyl acetate=3:2 to 1:1) gave solid, which was triturated with ethyl acetate and diisoproyl ether to give tert-butyl 2-amino-6-{2-(cyclopropylmethoxy)-6-[(4-methoxybenzyl)oxy]phenyl}-4-(methylsul-finyl)nicotinate as a white powder (1.112 g, yield; 63%).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH:12]=O)[N:8]2[CH3:11])=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[N:3]=1.[O:20]1[CH2:25][CH2:24][CH:23]([N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[CH2:22][CH2:21]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH2:12][N:29]3[CH2:28][CH2:27][N:26]([CH:23]4[CH2:24][CH2:25][O:20][CH2:21][CH2:22]4)[CH2:31][CH2:30]3)[N:8]2[CH3:11])=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[N:3]=1
Reactant: Cn1c(C=O)nc2c(N3CCOCC3)nc(Cl)nc21
Reactant: C1CN(C2CCOCC2)CCN1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: Cn1c(CN2CCN(C3CCOCC3)CC2)nc2c(N3CCOCC3)nc(Cl)nc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 97.2 %

Procedure:
A mixture of 2-chloro-9-methyl-6-morpholin-4-yl-9H-purine-8-carbaldehyde (165 mg, 0.59 mmol), 1-(tetrahydropyran-4-yl)piperazine (110 mg, 0.65 mmol) and molecular sieves (4 Å, powdered, 750 mg) in DCE (10 mL) was stirred at ambient temperature for 4 h. Sodium triacetoxyborohydride (170 mg, 0.80 mmol) was added and the mixture stirred for 18 h, then loaded onto an Isolute® SCX-2 cartridge (10 g). The cartridge was then washed with methanol and the desired product was subsequently eluted using 2 M NH3 in MeOH. The product was collected and concentrated in vacuo. The resultant residue was purified by flash chromatography (Si—PPC, DCM:MeOH, 100:0 to 98:2 to 95:5 to 90:10) to afford 2-Chloro-9-methyl-6-morpholin-4-yl-8-[4-(tetrahydropyran-4-yl)piperazin-1-ylmethyl]-9H-purine as a white solid (250 mg, 98%). 1H NMR (CDCl3, 400 MHz) δ 4.27 (m, 4 H), 4.01 (dd, J=11.5, 4.2 Hz, 2 H), 3.81 (m, 7 H), 3.69 (s, 2 H), 3.36 (dd, J=12.5, 10.9 Hz, 2 H), 2.55 (m, 8 H), 2.40 (m, 1 H), 1.75 (d, J=12.5 Hz, 2 H) and 1.56 (m, 2 H)
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:8]2[CH:9]=[N:10][N:11]([CH3:13])[CH:12]=2)=[CH:6][CH:7]=1.[F:14][C:15]([F:30])([C:20]1[CH:21]=[C:22]2[C:27](=[CH:28][CH:29]=1)[N:26]=[CH:25][CH:24]=[CH:23]2)[C:16]([NH:18][NH2:19])=O.CS(O)(=O)=O>COCC(O)C>[F:30][C:15]([F:14])([C:16]1[N:3]2[N:4]=[C:5]([C:8]3[CH:9]=[N:10][N:11]([CH3:13])[CH:12]=3)[CH:6]=[CH:7][C:2]2=[N:19][N:18]=1)[C:20]1[CH:21]=[C:22]2[C:27](=[CH:28][CH:29]=1)[N:26]=[CH:25][CH:24]=[CH:23]2
Reactant: NNC(=O)C(F)(F)c1ccc2ncccc2c1
Reactant: Cn1cc(-c2ccc(Cl)nn2)cn1
Agent: CS(=O)(=O)O
Solvent: COCC(C)O
Product: Cn1cc(-c2ccc3nnc(C(F)(F)c4ccc5ncccc5c4)n3n2)cn1
Temperature: 80 °C

Procedure:
To a reactor under inert atmosphere was added 73.84 g (0.38 mol) 3-chloro-6-(1-methyl-1H-pyrazol-4-yl)pyridazine, 90 g (0.38 mol) 2,2-difluoro-2-quinolin-6-ylacetohydrazide and 1200 mL 1-methoxy-2-propanol. Then 29.85 mL (0.455 mol) methane sulphonic acid was added and the reaction mixture was heated at 80° C. for 8 hours. After cooling to ambient temperature the mesylate salt of the title compound was filtered off from the reaction mixture. This salt was dissolved in a mixture of 400 mL ethanol and 300 mL water, after alkalisation at 80° C. with 50 mL ammonia (0.65 mol) in 200 mL water the free base of the title compound precipitates and was filtered off. This precipitate was dried at 50° C. and was subsequently re-crystallized from 2-propanol (1.8 L/mol) to yield the title compound in 75% yield.
Reaction SMILES: [Br-].[O:2]1[CH2:6][CH2:5][O:4][CH:3]1[CH2:7][CH2:8][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CCCCCC.C([Li])CCC.[CH3:39][O:40][C:41]1[CH:42]=[C:43]([CH2:61][CH2:62][CH:63]=O)[CH:44]=[CH:45][C:46]=1[O:47][CH2:48][C:49]1[N:50]=[C:51]([C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)[O:52][C:53]=1[CH3:54]>O1CCCC1>[CH3:39][O:40][C:41]1[CH:42]=[C:43]([CH2:61][CH:62]=[CH:63][CH2:8][CH2:7][CH:3]2[O:2][CH2:6][CH2:5][O:4]2)[CH:44]=[CH:45][C:46]=1[O:47][CH2:48][C:49]1[N:50]=[C:51]([C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)[O:52][C:53]=1[CH3:54]
Reactant: COc1cc(CCC=O)ccc1OCc1nc(-c2ccccc2)oc1C
Reactant: c1ccc([P+](CCC2OCCO2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COc1cc(CC=CCCC2OCCO2)ccc1OCc1nc(-c2ccccc2)oc1C
Reaction time: 1 h

Procedure:
To a suspension of [2-(1,3-dioxolan-2-yl)ethyl] triphenylphosphonium bromide (6.7 g) in tetrahydrofuran (THF) (60 ml) was added dropwise, at -30° C. in nitrogen streams, a hexane solution of n-butyl lithium (1.6M, 9.4 ml). The mixture was stirred for one hour at the same temperature, to which was then added dropwise, at -30° C., a solution of 3-[3-methoxy-4-(5-methyl-2-phenyl-4-oxazolylmethoxy)phenyl]propionaldehyde (4.1 g) in tetrahydrofuran (THF) (10 ml). The cooling bath was removed, and the reaction mixture was stirred for further one hour at room temperature. The reaction mixture was poured into water, which was subjected to extraction with ethyl acetate. The ethyl acetate layer was washed with water and dried (MgSO4), followed by distilling off the solvent under reduced pressure. The residue was subjected to column chromatography on silica gel. From the fraction eluted with ethyl acetate-hexane (1:2), was obtained 2-[5-[3-methoxy-4-(5-methyl-2-phenyl-4-oxazolylmethoxy) phenyl]-3-pentenyl]-1,3-dioxolan as an oily product (4.5 g). This oily product was dissolved in methanol (50 ml)--tetrahydrofuran (THF) (30 ml). To the solution was added palladium-carbon (5%, 0.5 g), which was subjected to catalytic hydrogenation at room temperature under 1 atmospheric pressure. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure to give 2-[5-[3-methoxy-4-(5-methyl-2-phenyl-4-oxazolylmethoxy)phenyl]pentyl]-1,3-dioxolan (3.8 g, 75%), which was recrystallized from ethyl acetate-hexane to give colorless needles, m.p.81-82° C.
Reaction SMILES: O=O.[F:3][C:4]1[CH:5]=[C:6]([S:10][C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][CH:20]=2)[C:17]([C:21]([NH2:23])=[O:22])=[CH:16][CH2:15][CH2:14]3)[CH:7]=[CH:8][CH:9]=1.[H][H]>CO>[F:3][C:4]1[CH:5]=[C:6]([S:10][C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][CH:20]=2)[C@H:17]([C:21]([NH2:23])=[O:22])[CH2:16][CH2:15][CH2:14]3)[CH:7]=[CH:8][CH:9]=1
Reactant: NC(=O)C1=CCCc2cc(Sc3cccc(F)c3)ccc21
Reactant: [H][H]
Agent: O=O
Solvent: CO
Product: NC(=O)[C@@H]1CCCc2cc(Sc3cccc(F)c3)ccc21
Temperature: 25 °C

Procedure:
In a glove box (O2 content≦2 ppm) a 50 ml autoclave equipped with a mechanical stirrer was charged with 4.00 g (13.36 mmol) of 6-(3-Fluoro-phenylsulfanyl)-3,4-dihydro-naphthalene-1-carboxylic acid amide, 1.07 mg (0.00134 mmol) of [Ru(OAc)2((S)-MeOBIPHEP)] (S/C 10000) and 28 ml of methanol. The asymmetric hydrogenation was run for 18 h at 40° C. under 9 bar of hydrogen. After cooling to room temperature the pressure was released from the autoclave, the methanol solution was evaporated in vacuo. Isolation as described in example 4 afforded after drying (R)-6-(3-Fluoro-phenylsulfanyl)-1,2,3,4-tetrahydro-naphthalene-1-carboxylic acid amide in quantitative yield as an off-white solid with an enantiomeric ratio of 99:1. The conversion was >=99.8%.