Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][C@@H:8]([C@@H:16]1[CH2:18][O:17]1)[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2].[OH:20][CH2:21][C@@H:22]1[CH2:26][CH2:25][CH2:24][NH:23]1>>[C:1]([O:5][C:6](=[O:19])[NH:7][C@H:8]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C@@H:16]([OH:17])[CH2:18][N:23]1[CH2:24][CH2:25][CH2:26][C@H:22]1[CH2:21][OH:20])([CH3:4])([CH3:3])[CH3:2]
Reactant: OC[C@@H]1CCCN1
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccccc1)[C@@H]1CO1
Product: CC(C)(C)OC(=O)N[C@H](Cc1ccccc1)[C@@H](O)CN1CCC[C@H]1CO

Procedure:
Using general procedure 1 and purification method D with [(1R)-1-{(2R)-oxiran-2-yl}-2-phenyl-ethyl]carbamic acid tert-butylester (0.10 g, 0.38 mmol) and (2S)-2-hydroxymethyl-pyrrolidine (0.077 g, 0.76 mmol) gives the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]2[C:6]3[C:7](=[CH:18][NH:19][CH:20]=3)[CH2:8][N:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[F:17])[C:4]=2[CH:3]=1.CC(C)([O-])C.[K+].Br[CH2:30][C:31]([O:33][CH3:34])=[O:32]>CN(C)C=O.O>[CH3:34][O:33][C:31](=[O:32])[CH2:30][N:19]1[CH:20]=[C:6]2[C:7]([CH2:8][N:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[F:17])[C:4]3[CH:3]=[C:2]([Cl:1])[CH:22]=[CH:21][C:5]=32)=[CH:18]1
Reactant: Fc1ccccc1C1=NCc2c[nH]cc2-c2ccc(Cl)cc21
Reactant: COC(=O)CBr
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)Cn1cc2c(c1)-c1ccc(Cl)cc1C(c1ccccc1F)=NC2
Reaction time: 0.25 h

Procedure:
In one portion 2.0 g (6.4 mmol) of 8-chloro-6-(2-fluorophenyl)-2H,4H-pyrrolo[3,4-d][2]benzazepine was added to a solution of 0.9 g (8 mmol) of potassium t-butoxide in 30 ml of dimethylformamide which was cooled to 0°. After stirring for 15 min, 0.7 ml (7.5 mmol) of methyl bromoacetate was added. The mixture was stirred for 5 min, diluted with water and extracted with ether. The ether solution was washed with water, dried over anhydrous sodium sulfate and concentrated at reduced pressure to dryness. Purification of the residue by column chromatography gave a pale yellow oil.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:6][CH2:5][N:4]([C:7]2[C:15]([C:16]3[CH:17]=[N:18][CH:19]=[N:20][CH:21]=3)=[CH:14][C:10]([C:11]([OH:13])=O)=[CH:9][N:8]=2)[CH2:3]1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.CCN(C(C)C)C(C)C.[F:55][CH:56]([S:58][C:59]1[CH:65]=[CH:64][C:62]([NH2:63])=[CH:61][CH:60]=1)[F:57]>CN(C=O)C.CCOC(C)=O>[F:57][CH:56]([F:55])[S:58][C:59]1[CH:60]=[CH:61][C:62]([NH:63][C:11](=[O:13])[C:10]2[CH:14]=[C:15]([C:16]3[CH:21]=[N:20][CH:19]=[N:18][CH:17]=3)[C:7]([N:4]3[CH2:5][CH2:6][C@@H:2]([OH:1])[CH2:3]3)=[N:8][CH:9]=2)=[CH:64][CH:65]=1
Reactant: O=C(O)c1cnc(N2CC[C@@H](O)C2)c(-c2cncnc2)c1
Reactant: Nc1ccc(SC(F)F)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccc(SC(F)F)cc1)c1cnc(N2CC[C@@H](O)C2)c(-c2cncnc2)c1
Reaction time: 48 h

Procedure:
A mixture of (R)-6-(3-hydroxypyrrolidin-1-yl)-5-(pyrimidin-5-yl)nicotinic acid (Stage 170.1, 60 mg, 0.21 mmol), O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU, 88 mg, 0.231 mmol) and DIPEA (73.2 μL, 0.419 mmol), in DMF (419 μL), was stirred at RT for 10 min. 4-Difluoromethylsulfanyl-aniline (60 mg, 0.21 mmol) was added and the RM was stirred for 2 days. The RM was diluted with EtOAc and washed with brine. The organic phase was dried over MgSO4 and evaporated to dryness under reduced pressure. The crude product was purified by preparative SFC (Column 2-EP, from 20% to 25% in 6 min) to obtain the title compound as a solid. UPLC-MS (Condition 3), tR=0.86 min, m/z=444.3 [M+H]+; 1H-NMR (400 MHz, DMSO-d6), δ ppm (TFA), 1.82 (br. s, 1H) 1.90 (d, J=8.60 Hz, 1H) 2.97 (d, J=10.95 Hz, 1H) 3.28 (d, J=7.04 Hz, 2H) 3.35-3.47 (m, 1H) 4.26 (br. s, 1H) 7.49-7.63 (m, 2H) 7.79-7.90 (m, 2H) 8.25 (br. s, 1H) 8.74 (br. s, 1H) 8.89-8.98 (m, 2H) 9.20-9.28 (m, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([N:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)=[N:10][CH:11]=[CH:12][N:13]=2)=[CH:4][CH:3]=1.[CH3:20][N:21]1[C:25]([CH3:26])=[C:24]([CH2:27][CH2:28][CH:29]=O)[C:23]([CH3:31])=[N:22]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[Cl:46]CCCl>>[ClH:46].[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([N:14]3[CH2:15][CH2:16][N:17]([CH2:29][CH2:28][CH2:27][C:24]4[C:23]([CH3:31])=[N:22][N:21]([CH3:20])[C:25]=4[CH3:26])[CH2:18][CH2:19]3)=[N:10][CH:11]=[CH:12][N:13]=2)=[CH:4][CH:3]=1
Reactant: Fc1ccc(-c2nccnc2N2CCNCC2)cc1
Reactant: Cc1nn(C)c(C)c1CCC=O
Reactant: ClCCCl
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: Cc1nn(C)c(C)c1CCCN1CCN(c2nccnc2-c2ccc(F)cc2)CC1
Product: Cl
Yield: 78 %

Procedure:
Dissolve 3′-(4-fluorophenyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl (0.300 g, 1.16 mmol) in DCE (15 mL). Add 3-(1,3,5-trimethyl-1H-pyrazol-4-yl)-propionaldehyde (0.232 g, 1.39 mmol), and stir at room temperature for 10 min. Add sodium triacetoxyborohydride (0.369 g, 1.74 mmol) and stir at room temperature for 18 hr. Purify by SCX chromatography, followed by silica gel chromatography, eluting with 45:45:10 DCM:hexanes:ethanol, to give the free base of the title compound (368 mg, 78%). Dissolve the free base (0.362 g, 0.888 mmol) in methanol and add a solution of ammonium chloride (0.047 g, 0.888 mmol) in a minimal volume of methanol. Shake for 3 hr. at room temperature and concentrate to give the title compound (395 mg, 100%). MS (ES): m/z=409 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4](Cl)[N:3]=1.[NH3:12].CO>>[NH2:12][C:4]1[N:3]=[C:2]([Cl:1])[N:10]=[C:9]2[C:5]=1[NH:6][CH:7]=[N:8]2
Reactant: N
Reactant: Clc1nc(Cl)c2[nH]cnc2n1
Solvent: CO
Product: Nc1nc(Cl)nc2nc[nH]c12
Temperature: 100 °C
Yield: 60 %

Procedure:
2,6-Dichloro-purine, 1 (30 g, 0.159 mol) was dissolved in a NH3/MeOH solution (300 ml, 30 wt % NH3 in MeOH). The reaction mixture was stirred in an autoclave and heated to 100° C. for 48 h. After cooling, the mixture was filtered and the solid was washed with methanol. Then it was dried in vacuum to afford 2 as a pale yellow powder (16 g, yield 60%).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[CH2:9][CH2:8][CH2:7][C:6]1=[O:10].[Cl:11][C:12]1[CH:13]=[C:14]([N:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[CH:15]=[CH:16][CH:17]=1.C([O-])([O-])=O.[Na+].[Na+].N[C@H](C(O)=O)CC1C=C2C(C=CC=C2)=CC=1>C1(C)C=CC=CC=1>[Cl:11][C:12]1[CH:13]=[C:14]([N:18]2[CH2:23][CH2:22][N:21]([CH2:2][CH2:3][CH2:4][N:5]3[CH2:9][CH2:8][CH2:7][C:6]3=[O:10])[CH2:20][CH2:19]2)[CH:15]=[CH:16][CH:17]=1
Reactant: Clc1cccc(N2CCNCC2)c1
Reactant: O=C1CCCN1CCCCl
Agent: N[C@@H](Cc1ccc2ccccc2c1)C(=O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: O=C1CCCN1CCCN1CCN(c2cccc(Cl)c2)CC1
Temperature: 110 °C
Reaction time: 12 h

Procedure:
A mixture of 1-chloro-3-[2-oxopyrrolidin-1-yl]propane (1.0 g, 6.2 mmol), 1-(3-chlorophenyl)piperazine (1.22 g, 6.2 minol), anhydrous Na2CO3 (0.33 g, 3.1 mmol) and Nal (0.093 g, 0.6 mmcl) in dry toluene (10 ml) was stirred at 110° C. for 12 hrs. The solvent was removed at reduced pressure and residue was poured on water (20 ml). The separated residue was extracted with ethylacetate (3×20 ml), dried over Na2SO4 and concentrated under reduced pressure to give 1-[4-(3-chlorophenyl)piperazin-1-yl]-3-[2-oxopyrrolidin-1-yl]propane as an oil which was purified by flash column chromatography over silica gel using chloroform as eluent, yield 0.60 g (30.0%).
Reaction SMILES: COCCOC.[H-].[Na+].[O:9]=[C:10]([CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH2:11]P(=O)(OC)OC.[CH:23](=O)[C:24]1[CH:33]=[CH:32][C:29]([O:30][CH3:31])=[C:26]([O:27][CH3:28])[CH:25]=1>O>[CH3:28][O:27][C:26]1[CH:25]=[C:24]([CH:23]=[CH:11][C:10](=[O:9])[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH:33]=[CH:32][C:29]=1[O:30][CH3:31]
Reactant: CCCCCC(=O)CP(=O)(OC)OC
Reactant: COc1ccc(C=O)cc1OC
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CCCCCC(=O)C=Cc1ccc(OC)c(OC)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Under cooling with ice, to 70 ml of dry 1,2-dimethoxyethane containing 0.87 g of sodium hydride (50% mineral oil) was added dropwise 30 ml of dry 1,2-dimethoxyethane containing 4.0 g of dimethyl 2-oxoheptylphosphonate. Then, the mixture was stirred at room temperature for 1 hour and, after that, cooled at -30° C. Then, 3 ml of dry 1,2-dimethoxyethane containing 3.0 g of veratraldehyde was added dropwise. After dropping, the temperature was restored slowly to room temperature. Then, the reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with water and dried with magnesium sulfate. The solvent was removed by distillation to obtain crude product. After purification of the crude product by means of column chromatography (silica gel/hexane:ethyl acetate=3:1), 1.3 g of the above caption compound was obtained.
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:10]([O:11]C(=O)C)[C@H:9]([O:15]C(=O)C)[C@@H:8]([CH2:19][O:20]C(=O)C)[O:7][C@H:6]1[O:24][C:25]1[C:29]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH2:38][CH2:39][CH2:40][NH2:41])=[CH:33][C:32]=2[CH3:42])=[C:28]([CH:43]([CH3:45])[CH3:44])[NH:27][N:26]=1)(=O)C.[NH2:46][CH2:47][CH2:48][OH:49].NCCN1CC[O:56][CH2:55]C1>>[C@@H:6]1([O:24][C:25]2[C:29]([CH2:30][C:31]3[CH:36]=[CH:35][C:34]([O:37][CH2:38][CH2:39][CH2:40][NH:41][C:55]([NH:46][CH2:47][CH2:48][OH:49])=[O:56])=[CH:33][C:32]=3[CH3:42])=[C:28]([CH:43]([CH3:45])[CH3:44])[NH:27][N:26]=2)[O:7][C@H:8]([CH2:19][OH:20])[C@@H:9]([OH:15])[C@H:10]([OH:11])[C@H:5]1[OH:4]
Reactant: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(C)C)c2Cc2ccc(OCCCN)cc2C)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: NCCO
Reactant: NCCN1CCOCC1
Product: Cc1cc(OCCCNC(=O)NCCO)ccc1Cc1c(O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)n[nH]c1C(C)C

Procedure:
The title compound was prepared in a similar manner to that described in Example 19 using 3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(3-aminopropoxy)-2-methylphenyl]methyl}-5-isopropyl-1H-pyrazole and 2-aminoethanol instead of 3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(3-aminopropoxy)phenyl]methyl}-5-isopropyl-1H-pyrazole and 4-(2-aminoethyl)morpholine, respectively.
Reaction SMILES: O[C:2]([C:5]1[CH:10]=[C:9]([O:11][CH3:12])[C:8]([N:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)=[CH:7][C:6]=1[OH:19])([CH3:4])[CH3:3].FC(F)(F)C(O)=O.C([SiH](CC)CC)C>ClCCl>[CH:2]([C:5]1[CH:10]=[C:9]([O:11][CH3:12])[C:8]([N:13]2[CH2:14][CH2:15][NH:16][CH2:17][CH2:18]2)=[CH:7][C:6]=1[OH:19])([CH3:4])[CH3:3]
Reactant: COc1cc(C(C)(C)O)c(O)cc1N1CCNCC1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(C(C)C)c(O)cc1N1CCNCC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 98.8 %

Procedure:
To a stirred suspension of 2-(1-Hydroxy-1-methyl-ethyl)-4-methoxy-5-piperazin-1-yl-phenol (0.5 g, 1.9 mmol) in dichloromethane under nitrogen at room temperature was added trifluoroacetic acid (7.2 mL, 93.86 mmol) followed by triethyl silane (3.0 mL, 18.8 mmol). The reaction mixture was stirred for 18 hours at room temperature, and then was evaporated under reduced pressure. The residue was partitioned between dichloromethane and saturated aqueous potassium carbonate. The organic layer was separated, washed with water, dried (MgSO4), filtered, and evaporated under reduced pressure to afford 0.47 g (99%) of 2-Isopropyl-4-methoxy-5-piperazin-1-yl-phenol as an oil.
Reaction SMILES: NCC#N.Br[C:6]1[C:7]([NH:11][C@H:12]([C:17]([NH:19][CH2:20][C:21]#[N:22])=[O:18])[CH2:13][CH:14]([CH3:16])[CH3:15])=[N:8][S:9][CH:10]=1.C(OC([N:30]1[CH2:35][CH2:34][N:33]([C:36]2[CH:41]=[CH:40][C:39](B(O)O)=[CH:38][CH:37]=2)[CH2:32][CH2:31]1)=O)(C)(C)C>>[C:21]([CH2:20][NH:19][C:17](=[O:18])[C@H:12]([CH2:13][CH:14]([CH3:16])[CH3:15])[NH:11][C:7]1[C:6]([C:39]2[CH:38]=[CH:37][C:36]([N:33]3[CH2:32][CH2:31][NH:30][CH2:35][CH2:34]3)=[CH:41][CH:40]=2)=[CH:10][S:9][N:8]=1)#[N:22]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(B(O)O)cc2)CC1
Reactant: CC(C)C[C@H](Nc1nscc1Br)C(=O)NCC#N
Agent: N#CCN
Product: CC(C)C[C@H](Nc1nscc1-c1ccc(N2CCNCC2)cc1)C(=O)NCC#N

Procedure:
Ester hydrolysis and coupling with aminoacetonitrile as described in example 4 provided N2-(4-bromoisothiazol-3-yl)-N1-(cyanomethyl)-L-leucinamide. N2-(4-bromoisothiazol-3-yl)-N1-(cyanomethyl)-L-leucinamide was then treated with 4-[4-(tert-butoxycarbonyl)-1-piperazinyl]phenylboronic acid (prepared as described in Example 1) as described in Example 1 to afford, after BOC removal with methanesulfonic acid as described in Example 10, N1-(cyanomethyl)-N2-[4-(4-piperazin-1-ylphenyl)isothiazol-3-yl]-L-leucinamide. MS (+ESI): 413.2 [M+1]+.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]([C:12]2[C:21]([NH2:22])=[C:20]3[C:15]([CH:16]=[CH:17][CH:18]=[N:19]3)=[CH:14][CH:13]=2)=O)=[CH:6][CH:5]=1.[CH3:25][NH:26][S:27](Cl)(=[O:29])=[O:28].[BH4-].[Na+]>N1C=CC=CC=1>[CH3:25][N:26]1[S:27](=[O:29])(=[O:28])[NH:22][C:21]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][N:19]=3)[CH:14]=[CH:13][C:12]=2[CH:10]1[C:7]1[CH:8]=[CH:9][C:4]([O:3][C:2]([F:24])([F:23])[F:1])=[CH:5][CH:6]=1
Reactant: Nc1c(C(=O)c2ccc(OC(F)(F)F)cc2)ccc2cccnc12
Reactant: CNS(=O)(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: c1ccncc1
Product: CN1C(c2ccc(OC(F)(F)F)cc2)c2ccc3cccnc3c2NS1(=O)=O
Yield: 55.2 %

Procedure:
In a similar fashion using route 27 general procedure 70, 7[(4-trifluoromethoxyphenyl)carbonyl]-8-aminoquinoline (Intermediate 378) (100 mg, 0.31 mmol), N-methylsulfamoyl chloride (Intermediate 213) (105 mg, 1.0 mmol) and NaBH4 (14 mg, 0.34 mmol) in pyridine (4 ml) gave the title compound (70 mg, 56%) after purification by preparative HPLC (acidic conditions 1).
Reaction SMILES: [H-].[Na+].[I:3][C:4]1[C:9]([CH3:10])=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:11][OH:12].Br[CH2:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16].CCOC(C)=O>CN(C=O)C.O>[C:18]([O:17][C:15](=[O:16])[CH2:14][O:12][CH2:11][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]([CH3:10])[C:4]=1[I:3])([CH3:21])([CH3:20])[CH3:19]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: Cc1cccc(CO)c1I
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1cccc(COCC(=O)OC(C)(C)C)c1I
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 79 %

Procedure:
Sodium hydride (53 mg, 2.2 mmol) was added to a 0° C. solution of 2-iodo-3-methyl-phenyl-methanol ((Example 5: step a) 492 mg, 2 mmol) in DMF (20 mL). The solution was stirred at 0° C. for 30 min and tert-butyl bromoacetate (0.4 mL, 2.5 mmol) was added. The solution was warmed to rt over 15 min and stirred for 3 h at rt. EtOAc (80 mL) and water (40 mL) were added, the layers were separated, and the organic layer was washed with water (6×20 mL), brine (30 mL), and was dried over sodium sulfate. Concentration of the solution followed by SiO2 flash column chromatography (5–10% EtOAc in hexanes) yielded the title compound (0.571 g, 79%) as an oil. 1H-NMR (CDCl3): δ 7.36 (dd, 1H, J=1.4, 7.4 Hz), 7.30 (t, 1H, 7.4 Hz), 7.24 (dd, 1H, J=1.4, 7.4 Hz), 4.72 (s, 2H), 4.15 (s, 2H), 2.53 (s, 3H), 1.56 (s, 9H).
Reaction SMILES: [S:1]([Li])[Li:2].[P:4]12([S:16][P:14]3([S:17][P:7]([S:9][P:10]([S:13]3)([S:12]1)=[S:11])(=[S:8])[S:6]2)=[S:15])=[S:5].[O:18]=[P:19]12[O:30][P:28]3([O:31][P:21]([O:23][P:24]([O:27]3)([O:26]1)=[O:25])(=[O:22])[O:20]2)=[O:29]>>[S-2:1].[Li+:2].[Li+:2].[P:4]12([S:6][P:7]3([S:9][P:10]([S:13][P:14]([S:17]3)([S:16]1)=[S:15])(=[S:11])[S:12]2)=[S:8])=[S:5].[O:22]=[P:21]12[O:20][P:19]3([O:26][P:24]([O:27][P:28]([O:30]3)([O:31]1)=[O:29])(=[O:25])[O:23]2)=[O:18]
Reactant: [Li]S[Li]
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Agent: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Product: [Li+]
Product: [S-2]
Reaction time: 20 h

Procedure:
Lithium sulfide crystal (Li2S), phosphorus pentasulfide (P2S5), and diphosphorus pentoxide (P2O5) were prepared as a starting material. These powders were weighed at a ratio of Li2S:P2S5: P2O5=70:26:4 (molar basis) in a glove box under an argon atmosphere, and projected into a pot made of zirconia. In addition, six grinding balls made of zirconia with 4=15 mm were projected into the pot made of zirconia with a capacity of 45 cc, and sealed completely. Next, the pot made of zirconia was fitted up in a planetary ball mill machine and subjected to the mechanical milling at a rotational speed of 370 rpm for 20 hours to obtain powdery sulfide glass. As a result of measuring the obtained sulfide glass by an X-ray diffraction (XRD) method, it was confirmed that the peak of Li2S disappeared and vitrification progressed. Next, the obtained sulfide glass was subjected to burning treatment on the conditions of 280° C. and 1 hour while flowing Ar gas to obtain a sulfide solid electrolyte composed of sulfide glass ceramics.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH3:15])=[C:5]([CH2:12][C:13]#[N:14])[CH:6]=[CH:7][C:8]=1[N+:9]([O-])=O>C(O)C.[Pd]>[NH2:9][C:8]1[CH:7]=[CH:6][C:5]([CH2:12][C:13]#[N:14])=[C:4]([CH3:15])[C:3]=1[O:2][CH3:1]
Reactant: COc1c([N+](=O)[O-])ccc(CC#N)c1C
Agent: [Pd]
Solvent: CCO
Product: COc1c(N)ccc(CC#N)c1C
Reaction time: 3.5 h
Yield: 103.5 %

Procedure:
To a solution of (3-methoxy-2-methyl-4-nitro-phenyl)-acetonitnle (1.03 g, 5.0 mmole) in ethanol (100 mL) was added a small amount of 10% palladium on charcoal catalyst and the mixture hydrogenated on the Parr hydrogenator at 45 psi for 3.5 hours. The reaction mixture was filtered through celite and evaporated under reduced pressure to give the (4-amino-3-methoxy-2-methyl-phenyl)acetonitrile as a solid (0.912 g, 100%). 1H NMR (CDCl3) δ: 2.25 (s, 3H), 3.56 (s, 2H), 3.72 (s, 3H), 3.85 (br, 2H), 6.60 (d, 1H, J=8.1 Hz), 6.90 (d, 1H, J=8.1 Hz).
Reaction SMILES: [CH3:1][C:2]([CH3:11])([CH3:10])[C:3](=O)[C:4]([O:6]CC)=O.[C:12]1([C@H:18]([NH2:20])[CH3:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C(Cl)(Cl)Cl>[CH3:11][C:2]([CH3:1])([CH3:10])[C:3](=[N:20][C@@H:18]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH3:19])[C:4]([NH:20][C@@H:18]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH3:19])=[O:6]
Reactant: C[C@@H](N)c1ccccc1
Reactant: CCOC(=O)C(=O)C(C)(C)C
Solvent: ClC(Cl)Cl
Product: C[C@@H](N=C(C(=O)N[C@H](C)c1ccccc1)C(C)(C)C)c1ccccc1
Yield: 46.7 %

Procedure:
The procedure described under h) was carried out using 15 g of ethyl trimethyl-pyruvate and 50 g of (R)-1-phenylethylamine. There were isolated 14.9 g of (47%) of (R)-3,3-dimethyl-N-[(R)-1-phenylethyl]-2-(1-phenylethylimino)-butyramide of melting point 95°-96° C. [α]=+59.6 (c=1.0, CHCl3).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]([CH3:13])[C:10]2[N:9](COCC[Si](C)(C)C)[C:8](=[O:22])[C:7]3[S:23][C:24]([CH3:26])=[CH:25][C:6]=3[C:5]=2[C:4]=1[C:27]1[CH:32]=[CH:31][C:30]([C@@H:33]([CH3:43])[CH2:34][NH:35]C(=O)OC(C)(C)C)=[CH:29][CH:28]=1.FC(F)(F)C(O)=O.C(Cl)[Cl:52]>>[ClH:52].[NH2:35][CH2:34][C@@H:33]([C:30]1[CH:29]=[CH:28][C:27]([C:4]2[C:5]3[C:6]4[CH:25]=[C:24]([CH3:26])[S:23][C:7]=4[C:8](=[O:22])[NH:9][C:10]=3[C:11]([CH3:13])=[CH:12][C:3]=2[O:2][CH3:1])=[CH:32][CH:31]=1)[CH3:43]
Reactant: ClCCl
Reactant: COc1cc(C)c2c(c1-c1ccc([C@@H](C)CNC(=O)OC(C)(C)C)cc1)c1cc(C)sc1c(=O)n2COCC[Si](C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(C)c2[nH]c(=O)c3sc(C)cc3c2c1-c1ccc([C@@H](C)CN)cc1
Product: Cl
Reaction time: 2 h
Yield: 30 %

Procedure:
To a solution of (R)-tert-butyl 2-(4-(8-methoxy-2,6-dimethyl-4-oxo-5-((2-(trimethylsilyl)ethoxy)methyl)-4,5-dihydrothieno[2,3-c]quinolin-9-yl)phenyl)propylcarbamate (24 mg, 0.039 mmol) in CH2Cl2 (1 mL) at rt was added trifluoroacetic acid (1.0 mL) and the reaction was stirred at that temperature for 2 h. The mixture was concentrated and the residue was dissolved methanol (2 mL) and treated with NH4OH (2 mL). The resulting mixture was stirred at rt for 2 h and purified by preparatory HPLC (C18 silica, acetonitrile/water (with 0.05% TFA) gradient). The desired fractions were combined, concentrated and the residue was dissolved in aqueous HCl, concentrated and dried under high vacuum to afford the desired product (5 mg, 30%) as a hydrochloride salt: 1H NMR (500 MHz, CD3OD) δ 7.52 (dd, J=7.8, 1.5 Hz, 1H), 7.47 (dd, J=7.7, 1.5 Hz, 1H), 7.32 (s, 1H), 7.31-7.22 (m, 2H), 5.30 (d, J=2.7 Hz, 1.1H), 3.29-3.18 (m, 3H), 2.63 (s, 3H), 1.47 (d, J=6.1 Hz, 3H): ESI MS m/z 392 [C23H24N2O4S+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH2:11][N:12]2[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][CH:13]2[CH3:25])[C:5]2[O:9][CH:8]=[CH:7][C:6]=2[CH:10]=1.[Cl:26][C:27]1[S:28][C:29]([Cl:36])=[CH:30][C:31]=1[S:32](Cl)(=[O:34])=[O:33]>>[ClH:26].[ClH:26].[Cl:26][C:27]1[S:28][C:29]([Cl:36])=[CH:30][C:31]=1[S:32]([NH:1][C:2]1[CH:3]=[C:4]([CH2:11][N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH:13]2[CH3:25])[C:5]2[O:9][CH:8]=[CH:7][C:6]=2[CH:10]=1)(=[O:34])=[O:33]
Reactant: O=S(=O)(Cl)c1cc(Cl)sc1Cl
Reactant: CC1CN(C(=O)OC(C)(C)C)CCN1Cc1cc(N)cc2ccoc12
Product: CC1CNCCN1Cc1cc(NS(=O)(=O)c2cc(Cl)sc2Cl)cc2ccoc12
Product: Cl
Yield: 86.3 %

Procedure:
The title product was prepared according to the procedure of Example 112, Step 3, starting from tert-butyl 4-[(5-amino-1-benzofuran-7-yl)methyl]-3-methylpiperazine-1-carboxylate (45 mg crude material, 0.10 mmol; obtained in Example 112, Step 2) and 2,5-dichlorothiophene-3-sulphonyl chloride (38 mg, 0.15 mmol). The title compound (23 mg, 43%) was obtained as an off-white solid. HPLC 98%, RT=1.61 min (System A; 10-97% MeCN over 3 min), 100%, RT=1.43 min (System B; 10-100% MeCN over 3 min). 1H NMR (400 MHz, methanol-d4) δ ppm 1.53 (d, J=6.27 Hz, 3H) 2.87-3.02 (m, 1H) 3.14-3.27 (m, 2H) 3.39-3.47 (m, 1H) 3.47-3.54 (m, 1H) 4.12-4.24 (m, 1H) 4.62-4.71 (m, 1H) 6.89 (d, J=2.26 Hz, 1H) 7.13 (s, 1H) 7.30-7.32 (m, J=1.76 Hz, 1H) 7.45 (d, J=2.26 Hz, 1H) 7.85 (d, J=2.26 Hz, 1H). *Two hydrogens are not visible in the spectrum. Probably “hidden” behind the H2O— and the MeOH signals. MS (ESI+) for C18H19Cl2N3O3S2 m/z 460 (M+H)+.
Reaction SMILES: [N:1](=[C:3]1[N:7]=[C:6]([CH3:8])[C:5]([CH3:13])([CH2:9][CH:10]([CH3:12])[CH3:11])[S:4]1)[OH:2].[CH3:14][N:15]=[C:16]=[O:17]>>[CH3:14][NH:15][C:16]([O:2][N:1]=[C:3]1[N:7]=[C:6]([CH3:8])[C:5]([CH3:13])([CH2:9][CH:10]([CH3:11])[CH3:12])[S:4]1)=[O:17]
Reactant: CN=C=O
Reactant: CC1=NC(=NO)SC1(C)CC(C)C
Product: CNC(=O)ON=C1N=C(C)C(C)(CC(C)C)S1

Procedure:
2-oxo-4,5-dimethyl-5-isobutyl-3-thiazoline-oxime was reacted with methyl isocyanate as described in Example 4 to yield 2-oxo-4,5-dimethyl-5-isobutyl-3-thiazoline-O-(methylcarbamoyl)-oxime, m.p. 99°-101° C. The 2-oxo-4,5-dimethyl-5-isobuty-3-thiazoline-oxime starting material melts at 105°-107° C.
Reaction SMILES: [Br:1][CH2:2][C:3](Br)=[O:4].[CH2:6]([NH:8][CH2:9][CH2:10][OH:11])[CH3:7].C(C1C=CC(S(NC2C=CC(C)=CC=2)(=O)=O)=CC=1)(C)(C)C>>[Br:1][CH2:2][C:3]([N:8]([CH2:6][CH3:7])[CH2:9][CH2:10][OH:11])=[O:4]
Reactant: CCNCCO
Reactant: O=C(Br)CBr
Agent: Cc1ccc(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)cc1
Product: CCN(CCO)C(=O)CBr

Procedure:
prepared by reaction of 2-bromoacetyl bromide with N-ethyl-N-(2-hydroxy-ethyl)-amine and 4-tert-butyl-N-p-tolyl-benzenesulfonamide; in contrast to the general procedure the intermediate 2-bromo-N-ethyl-N-(2-hydroxy-ethyl)-acetamide was isolated before being used in the coupling with the potassium N-tolylsulfonamide.