Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8](=[O:11])[C:7]12[C:23]2[C:14](=[CH:15][C:16]3[O:21][CH2:20][CH2:19][O:18][C:17]=3[CH:22]=2)[O:13][CH2:12]1.N1C2C(=CC=CC=2)C2(C3=CC4OCOC=4C=C3OC2)C1=O.Cl.Cl[CH2:47][C:48]1[C:53]([C:54]([F:57])([F:56])[F:55])=[CH:52][CH:51]=[CH:50][N:49]=1.CC1C=CC(S(OC[C@H]2COCCO2)(=O)=O)=CC=1>>[F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([CH2:47][C:48]1[C:53]([C:54]([F:56])([F:55])[F:57])=[CH:52][CH:51]=[CH:50][N:49]=1)[C:8](=[O:11])[C:7]12[C:23]2=[CH:22][C:17]3[O:18][CH2:19][CH2:20][O:21][C:16]=3[CH:15]=[C:14]2[O:13][CH2:12]1
Reactant: O=C1Nc2c(F)cccc2C12COc1cc3c(cc12)OCCO3
Reactant: FC(F)(F)c1cccnc1CCl
Agent: Cc1ccc(S(=O)(=O)OC[C@H]2COCCO2)cc1
Agent: Cl
Agent: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCO3
Product: O=C1N(Cc2ncccc2C(F)(F)F)c2c(F)cccc2C12COc1cc3c(cc12)OCCO3

Procedure:
Following the procedure as described in EXAMPLE 8 and making non-critical variations using 7′-fluoro-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one to replace spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one, and 2-(chloromethyl)-3-(trifluoromethyl)pyridine hydrochloride to replace (R)-(1,4-dioxan-2-yl)methyl 4-methylbenzenesulfonate, 7′-fluoro-1′-((3-(trifluoromethyl)pyridin-2-yl)methyl)-3,7-dihydro-2H-spiro[benzofuro[5,6-b][1,4]dioxine-8,3′-indolin]-2′-one was obtained (40%) as a colorless solid: mp 241-243° C. (dichloromethane); 1H NMR (300 MHz, CDCl3) δ8.62 (d, J=4.7 Hz, 1H), 7.97 (d, J=7.8 Hz, 1H), 7.34-7.30 (m, 1H), 7.00-6.86 (m, 3H), 6.68 (s, 1H), 6.50 (s, 1H), 5.54 (d, J=17.1 Hz, 1H), 5.37 (d, J=17.1 Hz, 1H), 4.99 (d, J=9.0 Hz, 1H), 4.73 (d, J=9.0 Hz, 1H), 4.21-4.19 (m, 2H), 4.15-4.14 (m, 2H); 13C NMR (75 MHz, CDCl3) δ177.9, 155.1, 153.0, 151.9, 149.2, 145.9, 144.7, 138.3, 135.5, 134.3, 129.2, 123.9, 121.9, 121.3, 119.6, 116.4, 116.2, 112.5, 99.2, 80.2, 64.6, 63.9, 58.5, 44.2; MS (ES+) m/z 473.0 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:12][C:11](=O)[CH2:10][CH2:9][S:8](=[O:15])(=[O:14])[CH:7]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[F:22])[C:6]=2[CH:23]=1.COC1C=CC([SH:32]2(=S)PP(=S)(C3C=CC(OC)=CC=3)S2)=CC=1.O>CN(C)P(=O)(N(C)C)N(C)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:12][C:11](=[S:32])[CH2:10][CH2:9][S:8](=[O:15])(=[O:14])[CH:7]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[F:22])[C:6]=2[CH:23]=1
Reactant: COc1ccc(P2(=S)P[SH](=S)(c3ccc(OC)cc3)S2)cc1
Reactant: O=C1CCS(=O)(=O)C(c2ccccc2F)c2cc(Cl)ccc2N1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: O
Product: O=S1(=O)CCC(=S)Nc2ccc(Cl)cc2C1c1ccccc1F
Temperature: 25 °C

Procedure:
A solution of 13.4 g of 8-chloro-6-(2-fluorophenyl)-1,3,4,6-tetrahydro-2-oxo-2H-5,1-benzothiazocine 5,5-dioxide in 380 ml of hexamethylphosphoric acid triamide is treated with 7.7 g of 2,4-bis-(4-methoxyphenyl)-1,2,3,4-dithiadiphosphetane-2,4-disulphide, the mixture is heated to 100° for 2 hours, again cooled to room temperature and then poured into 8.3 l of water. The mixture is extracted twice with ethyl acetate and the organic extracts are washed with water and with saturated sodium chloride solution. The ethyl acetate solutions are evaporated and the residue is chromatographed on 500 g of silica gel. By elution with chloroform which contains 0.5% ethanol and crystallization from ether there is obtained 8-chloro-6-(2-fluorophenyl)-1,3,4,6-tetrahydro-2-thiono-2H-5,1-benzothiazocine 5,5-dioxide of melting point 226°.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:27]=[CH:26][C:16]([CH2:17][P:18](=[O:25])([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21])=[CH:15][C:14]=2[O:28][CH3:29])[N:3]=1.[C:30]([OH:39])(=[O:38])[C:31]1[C:32](=[CH:34][CH:35]=[CH:36][CH:37]=1)[NH2:33]>>[CH2:20]([O:19][P:18]([CH2:17][C:16]1[CH:26]=[CH:27][C:13]([NH:12][C:4]2[N:3]=[C:2]([NH:33][C:32]3[CH:34]=[CH:35][CH:36]=[CH:37][C:31]=3[C:30]([OH:39])=[O:38])[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=2)=[C:14]([O:28][CH3:29])[CH:15]=1)([O:22][CH2:23][CH3:24])=[O:25])[CH3:21]
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)c(OC)c1)OCC
Reactant: Nc1ccccc1C(=O)O
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccccc3C(=O)O)n2)c(OC)c1)OCC

Procedure:
The title compound was prepared according to the procedure for example 102 using diethyl (4-{[4-chloro-5-(trifluoromethyl)pyrimidin-2-yl]amino}-3-methoxybenzyl)phosphonate (50.0 mg, 0.110 mmol) and anthranilic acid (15.1 mg, 0.110 mmol). The reaction mixture concentrated under reduced pressure and purified on an ISCO Combiflash system (DCM/MeOH 100:0→95:5) twice. 1H NMR (400 MHz, CHLOROFORM-d) δ 11.65 (br. s., 1H), 9.74 (s, 1H), 8.48 (d, J=8.84 Hz, 1H), 8.25 (s, 1H), 8.08 (dd, J=1.39, 7.96 Hz, 1H), 7.81 (br. s., 1H), 7.47 (t, J=7.71 Hz, 1H), 7.12 (t, J=7.58 Hz, 1H), 6.94 (s, 1H), 6.88 (dd, J=2.02, 8.08 Hz, 1H), 4.06-4.17 (m, 4H), 3.85 (s, 3H), 3.18-3.29 (m, 2H), 1.30 (t, J=7.07 Hz, 6H). MS (ES+): m/z 555.1432 (MH+). HPLC: tR=1.47 min (UPLC TOF, polar—3 min).
Reaction SMILES: S(Cl)(Cl)=O.[CH:5]1[C:10]([CH2:11][C@H:12]([NH2:16])[C:13]([OH:15])=O)=[CH:9][CH:8]=[C:7]([I:17])[CH:6]=1.CN1CCOCC1.[C:25](=O)([O:31]C(C)(C)C)[O:26][C:27]([CH3:30])([CH3:29])[CH3:28].[BH4-].[Na+].Cl>O.ClCCl.CO>[OH:15][CH2:13][C@@H:12]([NH:16][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[CH2:11][C:10]1[CH:5]=[CH:6][C:7]([I:17])=[CH:8][CH:9]=1
Reactant: N[C@@H](Cc1ccc(I)cc1)C(=O)O
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CN1CCOCC1
Solvent: O
Product: CC(C)(C)OC(=O)N[C@H](CO)Cc1ccc(I)cc1
Reaction time: 19 h

Procedure:
0.56 ml (7.73 mmol) of thionyl chloride was added to 3 ml of methanol under cooling with ice. 450 mg (1.56 mmol) of L-4-iodophenylalanine was added to the resultant mixture, and they were heated under reflux for 2 hours. The solvent was evaporated. 0.52 ml (4.68 mmol) of N-methylmorpholine, 443 mg (2.03 mmol) of di-t-butyl carbonate and 10 ml of dichloromethane were added to the residue, and they were stirred for 19 hours. The reaction liquid was diluted with water. After the extraction with dichloromethane, the organic layer was washed with saturated aqueous sodium hydrogencarbonate solution and then with saturated aqueous NaCl solution, and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. 3 ml of methanol and 3 ml of tetrahydrofuran were added to the residue. 143 mg (3.78 mmol) of sodium borohydride was added to the resultant mixture, and they were stirred for 17 hours. The reaction liquid was slowly poured into 1 N hydrochloric acid. After the extraction with ethyl acetate, the organic layer was successively washed with water. 1 N hydrochloric acid, 1 N sodium hydroxide and saturated aqueous NaCl solution, and dried over anhydrous magnesium sulfate. The solvent was evaporated. The residue was purified by the silica gel column chromatography to obtain the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[N:10][N:11]([CH3:18])[C:12]=2[C:13]2[N:14]=[CH:15][NH:16][CH:17]=2)=[CH:4][CH:3]=1.Cl[C:20]1[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][N:21]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[N:10][N:11]([CH3:18])[C:12]=2[C:13]2[N:14]=[CH:15][N:16]([C:20]3[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][N:21]=3)[CH:17]=2)=[CH:4][CH:3]=1
Reactant: FC(F)(F)c1ccc(Cl)nc1
Reactant: Cn1nnc(-c2ccc(F)cc2)c1-c1c[nH]cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1nnc(-c2ccc(F)cc2)c1-c1cn(-c2ccc(C(F)(F)F)cn2)cn1
Temperature: 120 °C
Yield: 82.4 %

Procedure:
A mixture of 4-(4-fluoro-phenyl)-5-(1H-imidazol-4-yl)-1-methyl-1H-[1,2,3]triazole (36 mg, 0.15 mmol), 2-chloro-5(trifluoromethyl)pyridine (27 mg, 0.15 mmol) and potassium carbonate (41 mg, 0.3 mmol) in DMF (0.6 mL) was stirred under Ar in a sealed flask and heated at 120° C. for 16 h. After cooling to room temperature the mixture was poured into water and extracted with ethyl acetate and the combined extracts washed with water, brine, dried over sodium sulphate, filtered and evaporated. Purification by chromatography (silica, 0 to 100% ethyl acetate in heptane) afforded the title compound (48 mg, 84%) as a white solid. MS: m/e=389.2 [M+H]+.
Reaction SMILES: [C:1]([NH:4][C:5]1[N:10]=[CH:9][C:8]([NH:11][CH:12]2[CH2:17][CH2:16][N:15]([C@H:18]([CH3:32])[CH2:19][CH2:20][NH:21][C:22]([C:24]3[C:25]([CH3:31])=[N:26][CH:27]=[N:28][C:29]=3[CH3:30])=[O:23])[CH2:14][CH2:13]2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].Br[CH2:34][C:35]1[CH:39]=[CH:38][S:37][CH:36]=1>>[C:1]([NH:4][C:5]1[N:10]=[CH:9][C:8]([N:11]([CH2:34][C:35]2[CH:39]=[CH:38][S:37][CH:36]=2)[CH:12]2[CH2:13][CH2:14][N:15]([C@H:18]([CH3:32])[CH2:19][CH2:20][NH:21][C:22]([C:24]3[C:25]([CH3:31])=[N:26][CH:27]=[N:28][C:29]=3[CH3:30])=[O:23])[CH2:16][CH2:17]2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc(NC2CCN([C@H](C)CCNC(=O)c3c(C)ncnc3C)CC2)cn1
Reactant: BrCc1ccsc1
Product: CC(=O)Nc1ccc(N(Cc2ccsc2)C2CCN([C@H](C)CCNC(=O)c3c(C)ncnc3C)CC2)cn1
Yield: 20.6 %

Procedure:
Using general procedure H, 4,6-dimethyl-pyrimidine-5-carboxylic acid {(R)-3-[4-(6-acetylamino-pyridin-3-ylamino)-piperidin-1-yl]-butyl}-amide (see EXAMPLE 246) (343 mg, 0.780 mmol) and 3-(bromomethyl)thiophene (207 mg) gave COMPOUND 328 as a yellow foam (86 mg, 21%). 1H NMR (CDCl3) δ 0.94-1.22 (m, 2H), 1.01 (d, 3H, J=6.6 Hz), 1.55 (m, 1H), 1.75 (m, 3H), 2.10 (s, 3H), 2.19 (m, 1H), 2.51 (s, 6H), 2.55 (m, 1H), 2.73-2.89 (m, 3H), 3.32 (m, 1H), 3.48 (m, 1H), 3.84 (s, 2H), 3.87 (m, 1H), 7.49 (m, 3H), 7.27 (m, 1H), 7.65 (d, 1H, J=3.0 Hz), 7.93 (d, 1H, J=9.3 Hz), 8.06 (s, 1H), 8.63 (m, 1H), 8.83 (s, 1H). 13C NMR (CDCl3) δ 13.82, 22.33, 24.81, 29.56, 30.68, 31.10, 40.51, 53.91, 45.47, 52.40, 56.77, 60.75, 114.94, 121.30, 123.84, 126.63, 126.71, 131.23, 133.74, 140.77, 142.05, 143.02, 158.01, 163.43, 166.72, 168.47. ES-MS m/z 536 (M+H). Anal. Calcd. for C28H37N7SO2.1.1CH2Cl2: C, 55.56; H, 6.28; N, 15.58; S, 5.10. Found: C, 55.76; H, 6.30; N, 15.63; S, 5.27.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:19])[C@@H:10]([O:12]C1CCCCO1)[CH3:11].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>C(O)C>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:19])[C@@H:10]([OH:12])[CH3:11]
Reactant: C[C@H](OC1CCCCO1)C(=O)c1ccc(F)cc1F
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CCO
Product: C[C@H](O)C(=O)c1ccc(F)cc1F
Temperature: 55 °C
Reaction time: 1 h
Yield: 61.1 %

Procedure:
In ethanol (3 ml) was dissolved (2S)-2',4'-difluoro-2-(3,4,5,6-tetrahydro-2H-pyran-2-yloxy)propiophenone (95 mg), to which was added pyridinium p-toluenesulfonate (21 mg), followed by stirring for one hour at 55° C. The solvent was distilled off under reduced pressure, and the residue was dissolved in ethyl acetate (20 ml), which was dried over anhydrous magnesium sulfate, followed by distilling off the solvent. The residue was purified by means of a silica gel chromatography (eluent, hexane:ethyl acetate=5:1) to give (2S)-2',4'-difluoro-2-hydroxypropiophenone (40 mg) as a pale yellow oily product.
Reaction SMILES: C([N:5]1[CH2:9][CH2:8][CH:7]([C:10](=O)[C:11]2[CH:16]=[CH:15][CH:14]=[N:13][CH:12]=2)C1=O)=CCC.Cl>O>[CH:15]1[CH:14]=[N:13][CH:12]=[C:11]([C:10]2[CH2:7][CH2:8][CH2:9][N:5]=2)[CH:16]=1
Reactant: CCC=CN1CCC(C(=O)c2cccnc2)C1=O
Agent: Cl
Solvent: O
Product: c1cncc(C2=NCCC2)c1
Temperature: 25 °C
Yield: 69.9 %

Procedure:
A mixture of 1-(but-1-enyl)-3-nicotinoylpyrrolidin-2-one (II), (40 g, 0.1639 mol), 50 ml water and 85 ml HCl were refluxed together for 12 hrs. The reaction mixture was cooled to room temperature, washed with 50 ml×2 ethyl acetate, further cooled to 0° C. and pH adjusted to >13 using NaOH. The reaction mixture was extracted with 100 ml×3 of dichloromethane and the extract dried over Na2SO4. After removing the solvent under reduced pressure, the crude solid obtained was purified by high vacuum distillation to give colorless solid myosmine (16.75 g, 70%). 1H NMR (CDCl3): δ 2.05 (2H, m), 2.94 (2H, t), 4.06 (2H, t), 7.34 (1H, dd), 8.18 (1H, dt), 8.64 (1H, dd), and 8.99 (1H, d). 13C-NMR (CDCl3): δ 170.56, 151.1, 149.1, 134.6, 130.0, 123.3, 61.5, 34.7, and 22.5. IR: 2961, 1620, and 1590 Cm−1.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[N:17]([C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=3)[N:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl.O1CCOCC1>CCOC(C)=O>[ClH:30].[Cl:30][C:27]1[CH:28]=[CH:29][C:24]([N:17]2[C:18]3[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:15]([O:14][CH:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)=[N:16]2)=[CH:25][CH:26]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2nn(-c3ccc(Cl)cc3)c3ccccc23)CC1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: Clc1ccc(-n2nc(OC3CCNCC3)c3ccccc32)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 171.9 %

Procedure:
Intermediate 42 (212 mg, 0.495 mmol) was dissolved in EtOAc (2 ml), treated with 4M HCl in dioxane (1.61 ml, 6.44 mmol) and stirred overnight at room temperature. The mixture was concentrated in vacuo, treated with EtOAc and concentrated again. This process was repeated 5 times. The resulting white solid was triturated with Et2O, filtered, rinsed with Et2O and dried in a vacuum oven at 50° C. to afford 155 mg (86%) of the title product—1-(4-chloro-phenyl)-3-(piperidin-4-yloxy)-1H-indazole hydrochloride as a white solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[NH:7][C@H:8]([C:25](=[O:28])[NH:26][CH3:27])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[C:12]([OH:24])[CH:11]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:30]([N:32]=[C:33]=[O:34])[CH3:31]>ClCCl.CN(C1C=CN=CC=1)C.C(OCC)(=O)C>[C:1]([O:5][C:6](=[O:29])[NH:7][C@H:8]([C:25](=[O:28])[NH:26][CH3:27])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[C:12]([O:24][C:33](=[O:34])[NH:32][CH2:30][CH3:31])[CH:11]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: CNC(=O)[C@H](Cc1ccc(OCc2ccccc2)c(O)c1)NC(=O)OC(C)(C)C
Reactant: CCN=C=O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCNC(=O)Oc1cc(C[C@H](NC(=O)OC(C)(C)C)C(=O)NC)ccc1OCc1ccccc1
Temperature: 50 °C

Procedure:
[(S)-2-(4-Benzyloxy-3-hydroxy-phenyl)-1-methylcarbamoyl-ethyl]-carbamic acid tert-butyl ester (348 mg) was dissolved in dry dichloromethane (2 ml) and ethyl isocyanate (0.31 ml) added followed by a catalytic amount of DMAP. The solution was heated at 50° C. for 5 hours and a white solid formed. The mixture was diluted with ethyl acetate and the crude product was filtered off and washed with ethyl acetate. Recrystallisation from methanol afforded [(S)-2-(4-benzyloxy-3-ethylcarbamoyloxy-phenyl)-1-methylcarbamoyl-ethyl]-carbamic acid tert-butyl ester, 253 mg; HPLC/MS Retention time 5.49 min, m/z 472 (MH+).
Reaction SMILES: [CH3:1][N:2]([CH3:43])[C:3]1[CH:8]=[CH:7][C:6]([P:9]([C:34]2[CH:39]=[CH:38][C:37]([N:40]([CH3:42])[CH3:41])=[CH:36][CH:35]=2)([CH2:11][CH2:12][CH2:13][P:14]([C:25]2[CH:30]=[CH:29][C:28]([N:31]([CH3:33])[CH3:32])=[CH:27][CH:26]=2)([C:16]2[CH:21]=[CH:20][C:19]([N:22]([CH3:24])[CH3:23])=[CH:18][CH:17]=2)=O)=O)=[CH:5][CH:4]=1.C(N(CCCC)CCCC)CCC.C1([SiH](Cl)Cl)C=CC=CC=1>CC1C=CC=CC=1C>[CH3:33][N:31]([CH3:32])[C:28]1[CH:29]=[CH:30][C:25]([P:14]([C:16]2[CH:17]=[CH:18][C:19]([N:22]([CH3:24])[CH3:23])=[CH:20][CH:21]=2)[CH2:13][CH2:12][CH2:11][P:9]([C:6]2[CH:7]=[CH:8][C:3]([N:2]([CH3:1])[CH3:43])=[CH:4][CH:5]=2)[C:34]2[CH:39]=[CH:38][C:37]([N:40]([CH3:41])[CH3:42])=[CH:36][CH:35]=2)=[CH:26][CH:27]=1
Reactant: CN(C)c1ccc(P(=O)(CCCP(=O)(c2ccc(N(C)C)cc2)c2ccc(N(C)C)cc2)c2ccc(N(C)C)cc2)cc1
Agent: Cl[SiH](Cl)c1ccccc1
Solvent: CCCCN(CCCC)CCCC
Solvent: Cc1ccccc1C
Product: CN(C)c1ccc(P(CCCP(c2ccc(N(C)C)cc2)c2ccc(N(C)C)cc2)c2ccc(N(C)C)cc2)cc1
Temperature: 145 °C
Yield: 95 %

Procedure:
12.0 g (19.5 mmol) of 1,3-bis[bis(4-dimethylaminophenyl)phosphinyl]propane and 24 ml (100 mmol) of tri-n-butylamine are initially charged in 80 ml of o-xylene in an argon atmosphere while stirring. 14.4 ml (100 mmol) of phenyldichlorosilane are slowly added dropwise. The mixture is heated to 145° C., stirred for 6 hours and the solvent is distilled off under reduced pressure. Cooling the clear solution results in formation of colorless crystals which are filtered off. The crystals obtained are suspended in 100 ml of degassed o-xylene and extracted with 20 ml of 2N sodium hydroxide solution. The organic phase is separated off, dried with sodium sulphate and evaporated under reduced pressure. This gives 10.8 g of colorless solid, corresponding to a yield of 95%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[O:10][N:9]=2)=[CH:4][CH:3]=1.C1(C2[C:27](C3N=CN(C4C=CC=CC=4)C=3)=[C:26](C(F)(F)F)[O:25]N=2)C=CC=CC=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]([C:26](=[O:25])[CH3:27])=[C:11]([C:13]([F:14])([F:16])[F:15])[O:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: Fc1ccc(-c2cc(C(F)(F)F)on2)cc1
Reactant: FC(F)(F)c1onc(-c2ccccc2)c1-c1cn(-c2ccccc2)cn1
Product: CC(=O)c1c(-c2ccc(F)cc2)noc1C(F)(F)F
Yield: 85 %

Procedure:
As described for Example 1e, 3-(4-fluoro-phenyl)-5-trifluoromethyl-isoxazole (50.0 mg, 216 mmol), instead of 3-phenyl-4-(1-phenyl-1H-imidazol-4-yl)-5-trifluoromethyl-isoxazole, was converted to the title compound (50.2 mg, 85%) which was obtained as a light yellow oil. MS: m/e=272.1 [M−H]−.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:8][CH2:7][C:6]2[C:9]3[C:14]([NH:15][C:16]4[CH:25]=[CH:24][C:19]5[NH:20][C:21](=[O:23])[S:22][C:18]=5[CH:17]=4)=[N:13][CH:12]=[N:11][C:10]=3[S:26][C:5]=2[CH2:4]1.[CH3:27][CH:28]([S:30](Cl)(=[O:32])=[O:31])[CH3:29]>>[O:23]=[C:21]1[NH:20][C:19]2[CH:24]=[CH:25][C:16]([NH:15][C:14]3[C:9]4[C:6]5[CH2:7][CH2:8][CH:3]([CH2:2][NH:1][S:30]([CH:28]([CH3:29])[CH3:27])(=[O:32])=[O:31])[CH2:4][C:5]=5[S:26][C:10]=4[N:11]=[CH:12][N:13]=3)=[CH:17][C:18]=2[S:22]1
Reactant: CC(C)S(=O)(=O)Cl
Reactant: NCC1CCc2c(sc3ncnc(Nc4ccc5[nH]c(=O)sc5c4)c23)C1
Product: CC(C)S(=O)(=O)NCC1CCc2c(sc3ncnc(Nc4ccc5[nH]c(=O)sc5c4)c23)C1

Procedure:
75 mg (196 μmol) (RS)-6-{[7-(aminomethyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-4-yl]amino}-1,3-benzothiazol-2(3H)-one (prepared according to example 20), were transformed in analogy to example 21 using propane-2-sulfonyl chloride to give after working up and purification 5.7 mg (6%) of the title compound.
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([C@H:7]([NH2:11])[C:8]([OH:10])=[O:9])=[CH:3][CH:2]=1.[N+:12]([O-])([OH:14])=[O:13].[OH-].[Na+]>S(=O)(=O)(O)O.O>[NH2:11][C@@H:7]([C:4]1[CH:3]=[CH:2][CH:1]=[C:6]([N+:12]([O-:14])=[O:13])[CH:5]=1)[C:8]([OH:10])=[O:9]
Reactant: N[C@H](C(=O)O)c1ccccc1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: N[C@H](C(=O)O)c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of L-phenylglycine (10 g) in 40 mL of conc. sulfuric acid was cooled in an ice water/acetone bath. 90% Nitric acid (3.72 mL) was added dropwise over a 30 minute period at such a rate as to keep the internal temperature below 10° C. After addition was complete, stirring was continued for 1 hour at 0° C. and then the reaction mixture was allowed to warm to room temperature over 1.5 hours. The reaction mixture was poured onto 200 g of crushed ice and the resulting mixture was neutralized with sodium hydroxide to pH 7. The reaction mixture was diluted with 600 mL of water, Celite was added and the resulting suspension was filtered and concentrated to give the crude product D contaminated with sodium sulfate. This material was taken to the next step without further purification.
Reaction SMILES: [CH:1]1([CH:7]([O:20][CH3:21])[C:8]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][C:9]=2[CH:10]=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[F:22][C:23]([F:37])([F:36])[C:24]1[CH:25]=[C:26]([CH:29]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:31]=1)[CH2:27][NH2:28].[BH4-].[Na+]>C(O)C>[CH:1]1([CH:7]([O:20][CH3:21])[C:8]2[CH:15]=[CH:14][C:13]([C:16]([F:17])([F:19])[F:18])=[CH:12][C:9]=2[CH2:10][NH:28][CH2:27][C:26]2[CH:29]=[C:30]([C:32]([F:33])([F:34])[F:35])[CH:31]=[C:24]([C:23]([F:22])([F:36])[F:37])[CH:25]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COC(c1ccc(C(F)(F)F)cc1C=O)C1CCCCC1
Reactant: NCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: COC(c1ccc(C(F)(F)F)cc1CNCc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C1CCCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79 %

Procedure:
A mixture of 2-(cyclohexyl(methoxy)methyl)-5-(trifluoromethyl)benzaldehyde (107 my, 0.36 mmol) and 3,5-bistrifluoromethylbenzylamine (113.8 mg, 0.37 mmol) in ethanol was stirred at room temperature overnight. Sodium borohydride (16.5 mg, 0.44 mmol) was added and the mixture was stirred at room temperature overnight. Solvent was removed and the residue was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by chromatography over 25+S Biotage silica column (eluted with 0-15% ethyl acetate in heptane) to afford the title compound (150 mg, 80%). 1H NMR (400 MHz, CDCl3) δ ppm 0.94-1.23 (m, 6H) 1.51-1.59 (m, 1H) 1.62 (d, J=7.05 Hz, 2H) 1.69-1.78 (m, 1H) 1.99 (d, J=12.45 Hz, 1H) 3.17 (s, 3H) 3.83 (d, J=12.86 Hz, 1H) 3.92 (d, J=12.86 Hz, 1H) 4.00 (d, J=6.64 Hz, 2H) 4.22 (d, J=7.05 Hz, 1H) 7.50 (d, J=8.30 Hz, 1H) 7.55 (d, J=7.88 Hz, 1H) 7.63 (s, 1H) 7.80 (s, 1H) 7.86 (s, 2H). MS (ES30) Calc: 527.2, Found: 528.5 (M+1).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([O:8][CH3:9])[N:5]=[C:4]([NH:10][NH2:11])[CH:3]=1.[CH3:12][C:13]([C:15]1[CH:20]=[CH:19][C:18]([N:21]([CH3:23])[CH3:22])=[CH:17][CH:16]=1)=O>C(O)C>[Cl:1][C:2]1[N:7]=[C:6]([O:8][CH3:9])[N:5]=[C:4]([NH:10][N:11]=[C:13]([C:15]2[CH:20]=[CH:19][C:18]([N:21]([CH3:23])[CH3:22])=[CH:17][CH:16]=2)[CH3:12])[CH:3]=1
Reactant: COc1nc(Cl)cc(NN)n1
Reactant: CC(=O)c1ccc(N(C)C)cc1
Solvent: CCO
Product: COc1nc(Cl)cc(NN=C(C)c2ccc(N(C)C)cc2)n1

Procedure:
The title compound was prepared from (6-chloro-2-methoxy-pyrimidin-4-yl)hydrazine (414 mg, 2.4 mmol) and 4-dimethylaminoacetophenone (387 mg, 2.4 mmol) in ethanol (10 mL) by a procedure similar to Example 1, step 4 yielding 305 mg (40%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]([OH:11])=O)=[N:7][CH:8]=1.[NH2:12][C:13]1[CH:14]=[C:15]([C@:20]2([CH2:31][F:32])[CH2:25][C@@H:24]([C:26]([F:29])([F:28])[F:27])[O:23][C:22]([NH2:30])=[N:21]2)[C:16]([F:19])=[N:17][CH:18]=1>>[NH2:30][C:22]1[O:23][C@H:24]([C:26]([F:27])([F:29])[F:28])[CH2:25][C@:20]([C:15]2[CH:14]=[C:13]([NH:12][C:9](=[O:11])[C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][N:7]=3)[CH:18]=[N:17][C:16]=2[F:19])([CH2:31][F:32])[N:21]=1
Reactant: NC1=N[C@](CF)(c2cc(N)cnc2F)C[C@@H](C(F)(F)F)O1
Reactant: COc1ccc(C(=O)O)nc1
Product: COc1ccc(C(=O)Nc2cnc(F)c([C@]3(CF)C[C@@H](C(F)(F)F)OC(N)=N3)c2)nc1

Procedure:
The title compound was synthesized using procedures analogous to those described in Method H Step 2 (Example 66) above, but using 5-methoxy-picolinic acid and (4S,6S)-4-(5-amino-2-fluoropyridin-3-yl)-4-(fluoromethyl)-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-amine (as described in Example 138, method S). MS m/z=446.0 [M+H]+. Calculated for C18H16F5N5O3: 445.3