Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([C:9]3[CH:14]=[CH:13][C:12]([O:15][CH2:16][C@@H:17]4[CH2:19][O:18]4)=[CH:11][CH:10]=3)=[N:7][O:8][C:4]=2[CH:3]=1.[C:22]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1)#[N:23]>CN(C)C=O.C(O)C>[F:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([C:9]3[CH:14]=[CH:13][C:12]([O:15][CH2:16][C@@H:17]([OH:18])[CH2:19][N:33]4[CH2:32][CH2:31][N:30]([C:25]5[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=5[C:22]#[N:23])[CH2:35][CH2:34]4)=[CH:11][CH:10]=3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: N#Cc1ccccc1N1CCNCC1
Reactant: Fc1ccc2c(-c3ccc(OC[C@@H]4CO4)cc3)noc2c1
Solvent: CCO
Solvent: CN(C)C=O
Product: N#Cc1ccccc1N1CCN(C[C@H](O)COc2ccc(-c3noc4cc(F)ccc34)cc2)CC1

Procedure:
The title compound is prepared from a mixture of (S)-6-fluoro-3-(4-oxiranylmethoxy-phenyl)-benzo[d]isoxazole in dimethylformamide and 1-(2-cyanophenyl)piperazine in ethanol essentially as described above in Example 21. Purity by LC/MS=100%, [M+H]+=473.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11](O)=[O:12])=[CH:10][C:5]=2[N:4]=[C:3]1[NH:14][C:15]1[S:16][C:17]2[CH:23]=[C:22]([O:24][C:25]([F:28])([F:27])[F:26])[CH:21]=[CH:20][C:18]=2[N:19]=1.[C:29]([O:33][C:34](=[O:39])[NH:35][CH2:36][CH2:37][NH2:38])([CH3:32])([CH3:31])[CH3:30].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>>[C:29]([O:33][C:34](=[O:39])[NH:35][CH2:36][CH2:37][NH:38][C:11]([C:9]1[CH:8]=[CH:7][C:6]2[N:2]([CH3:1])[C:3]([NH:14][C:15]3[S:16][C:17]4[CH:23]=[C:22]([O:24][C:25]([F:28])([F:26])[F:27])[CH:21]=[CH:20][C:18]=4[N:19]=3)=[N:4][C:5]=2[CH:10]=1)=[O:12])([CH3:32])([CH3:30])[CH3:31]
Reactant: Cn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)O)ccc21
Reactant: CC(C)(C)OC(=O)NCCN
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: Cn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)NCCNC(=O)OC(C)(C)C)ccc21
Yield: 83.2 %

Procedure:
(2-{[1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carbonyl]-amino}-ethyl)-carbamic acid tert-butyl ester (92 mg) was prepared by following General Procedure F using 1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzimidazole-5-carboxylic acid (82 mg), (2-amino-ethyl)-carbamic acid tert-butyl ester (64 mg), HBTU (76 mg), and DIEA (0.2 ml). LC/MS: m/z 552. 1H NMR (DMSO-d6, 400 MHz): δ 8.40 (br, 1H), 8.06 (s, 1H), 7.91 (s, 1H), 7.73 (m, 2H), 7.46 (d, 1H), 7.34 (d, 1H), 6.91 (t, 1H), 4.24 (t, 2H), 3.64 (s, 3H), 3.14-3.09 (q, 2H), and 1.36 (s, 9H), —NH proton signal was not observed.
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[C:9]([Cl:10])=[CH:8][N:7]=[CH:6][C:5]=1[Cl:11].[CH3:12][O:13][C:14]1[CH:15]=[C:16]([CH:32]=[CH:33][CH:34]=1)[CH2:17][N:18]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][N:25]=2)[C:20]([C:27](=[O:31])[C:28](Cl)=[O:29])=[CH:19]1>C1COCC1>[Cl:11][C:5]1[CH:6]=[N:7][CH:8]=[C:9]([Cl:10])[C:4]=1[NH:3][C:28](=[O:29])[C:27]([C:20]1[C:21]2[C:26](=[N:25][CH:24]=[CH:23][CH:22]=2)[N:18]([CH2:17][C:16]2[CH:32]=[CH:33][CH:34]=[C:14]([O:13][CH3:12])[CH:15]=2)[CH:19]=1)=[O:31]
Reactant: Nc1c(Cl)cncc1Cl
Reactant: COc1cccc(Cn2cc(C(=O)C(=O)Cl)c3cccnc32)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cccc(Cn2cc(C(=O)C(=O)Nc3c(Cl)cncc3Cl)c3cccnc32)c1
Reaction time: 1 h

Procedure:
To a suspension of 2 g of sodium hydride in 20 mL of THF, 2.4 g of 4-amino-3,5-dichloropyridine (15 mmoles) in 30 mL of THF are added dropwise at −5° C. The mixture is then kept for one hour at 20° C. with stirring. Subsequently, the previously prepared suspension of 1-(3-methoxybenzyl)-7-azaindole-3-yl-glyoxylic acid chloride is added dropwise at about 0° C. Finally, the reaction mixture is refluxed for 4 hours, after which the solvent is removed under vacuum. The residue is stirred with 50 mL of ethyl acetate and 50 mL of water. The phases are separated and the organic phase is washed with water. The solvent is distilled off under vacuum and the residue recrystallized from ispropanol.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([NH2:14])[CH:11]=[N:10][C:9]=2[O:15][CH2:16][C:17]([F:20])([F:19])[F:18])=[CH:4][CH:3]=1.Cl.[C:22](Cl)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[N:25][CH:24]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([NH:14][C:22](=[O:29])[C:23]3[CH:28]=[CH:27][CH:26]=[N:25][CH:24]=3)[CH:11]=[N:10][C:9]=2[O:15][CH2:16][C:17]([F:18])([F:20])[F:19])=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1cccnc1
Reactant: Nc1cnc(OCC(F)(F)F)c(-c2ccc(Cl)cc2)n1
Agent: Cl
Product: O=C(Nc1cnc(OCC(F)(F)F)c(-c2ccc(Cl)cc2)n1)c1cccnc1

Procedure:
The title compound was synthesized in analogy to Example 48e, using 6-(4-chloro-phenyl)-5-(2,2,2-trifluoro-ethoxy)-pyrazin-2-ylamine (example 49d) and nicotinoyl chloride hydrochloride as starting materials; LC-MS (UV peak area/ESI) 95.7%, 407.0532 (M−H)−.
Reaction SMILES: [CH:1]([O:4][C:5](=[O:43])[C@H:6]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]2[C:34](=[O:35])[C:33]3[C:28](=[CH:29][CH:30]=[C:31]([CH2:36][N:37](C=O)[CH3:38])[CH:32]=3)[N:27]([CH3:41])[C:26]2=[O:42])=[CH:21][CH:20]=1)[NH:7][C:8](=[O:17])[C:9]1[C:14]([Cl:15])=[CH:13][CH:12]=[CH:11][C:10]=1[Cl:16])([CH3:3])[CH3:2].C(Cl)(=O)C.C(OC(C)C)(=O)C>CC(O)C>[ClH:15].[CH:1]([O:4][C:5](=[O:43])[C@H:6]([CH2:18][C:19]1[CH:20]=[CH:21][C:22]([N:25]2[C:34](=[O:35])[C:33]3[C:28](=[CH:29][CH:30]=[C:31]([CH2:36][NH:37][CH3:38])[CH:32]=3)[N:27]([CH3:41])[C:26]2=[O:42])=[CH:23][CH:24]=1)[NH:7][C:8](=[O:17])[C:9]1[C:14]([Cl:15])=[CH:13][CH:12]=[CH:11][C:10]=1[Cl:16])([CH3:3])[CH3:2]
Reactant: CC(C)OC(=O)[C@H](Cc1ccc(-n2c(=O)c3cc(CN(C)C=O)ccc3n(C)c2=O)cc1)NC(=O)c1c(Cl)cccc1Cl
Solvent: CC(=O)Cl
Solvent: CC(C)O
Solvent: CC(=O)OC(C)C
Product: CNCc1ccc2c(c1)c(=O)n(-c1ccc(C[C@H](NC(=O)c3c(Cl)cccc3Cl)C(=O)OC(C)C)cc1)c(=O)n2C
Product: Cl
Temperature: 10 °C
Yield: 194.8 %

Procedure:
To 61.67 L of 2-propanol, there was added 5.226 kg of Nα-(2,6-dichlorobenzoyl)-4-{1-methyl-6-(N-formyl-N-methylamino-methyl)-quinazoline-2,4[1H,3H]-dion-3-yl}-L-phenylalanine isopropyl ester to thus form a suspension and the resulting suspension was cooled to 10° C. and stirred in a nitrogen gas stream. Acetyl chloride (10.00 kg) was dropwise added to this suspension over one hour while taking care to prevent any excess generation of heat, then 37.67 L of isopropyl acetate was added to the suspension and the resulting mixture was heated with stirring at 70° C. for 24 hours. After the confirmation of the progress of the reaction by HPLC, the slurry was cooled to 25° C. and stirred over 19 hours. The resulting precipitates were recovered by the filtration using a centrifuge and the resulting cake was washed with 20.90 L of 2-propanol. The resulting wet crystals were dried under reduced pressure at 75° C. to thus give 5.159 kg of the title compound as a white crystalline solid (yield: 95%).
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH2:16][C@H:17]4[CH2:19][O:18]4)[CH:10]=3)=[N:7][O:8][C:4]=2[CH:3]=1.[S:22]1[CH:26]=[CH:25][CH:24]=[C:23]1[CH2:27][NH2:28]>ClC(Cl)C.C(O)C>[F:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([C:9]3[CH:10]=[C:11]([CH:12]=[CH:13][CH:14]=3)[O:15][CH2:16][C@H:17]([OH:18])[CH2:19][NH:28][CH2:27][C:23]3[S:22][CH:26]=[CH:25][CH:24]=3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: Fc1ccc2c(-c3cccc(OC[C@H]4CO4)c3)noc2c1
Reactant: NCc1cccs1
Solvent: CC(Cl)Cl
Solvent: CCO
Product: O[C@H](CNCc1cccs1)COc1cccc(-c2noc3cc(F)ccc23)c1

Procedure:
The title compound is prepared from a mixture of (R)-6-fluoro-3-(3-oxiranylmethoxy-phenyl)-benzo[d]isoxazole in dichloroethane, 2-thiophenemethylamine and ethanol, essentially as described above in Example 57. Purity by LC/MS=100%, [M+H]+=399.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][C:10]=2[C:16]([F:19])([F:18])[F:17])[CH:7]=1.[Cl:20][C:21]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:22]=1[S:28](Cl)(=[O:30])=[O:29]>CCCCCC.CCOCC>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][S:28]([C:22]3[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:21]=3[Cl:20])(=[O:30])=[O:29])=[CH:11][C:10]=2[C:16]([F:17])([F:19])[F:18])[CH:7]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1Cl
Reactant: Nc1ccc(Oc2cncc(Cl)c2)c(C(F)(F)F)c1
Solvent: CCCCCC
Solvent: CCOCC
Product: O=S(=O)(Nc1ccc(Oc2cncc(Cl)c2)c(C(F)(F)F)c1)c1ccc(Cl)cc1Cl
Yield: 21.5 %

Procedure:
Using the method of Example 17.4, 2-(3-chloro-5-pyridyloxy)-5-aminobenzotrifluoride (0.394 g) and 2,4-dichlorobenzenesulfonyl chloride (0.34 g) were combined to provide, after flash chromatography and trituration with hexane/ether the title compound as a crystalline solid (0.146 g). mp 129-130° C.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[C:11]([CH3:12])=[CH:10][CH:9]=[CH:8][C:7]=1[CH3:13])=[O:4].[CH3:14][CH:15]1[CH2:20][NH:19][CH2:18][CH2:17][NH:16]1>>[CH3:13][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]([CH3:12])[C:6]=1[NH:5][C:3](=[O:4])[CH2:2][N:19]1[CH2:18][CH2:17][NH:16][CH:15]([CH3:14])[CH2:20]1
Reactant: Cc1cccc(C)c1NC(=O)CCl
Reactant: CC1CNCCN1
Product: Cc1cccc(C)c1NC(=O)CN1CCNC(C)C1

Procedure:
The subtitle compound was prepared from 2-chloro-N-(2,6-dimethylphenyl)acetamide (7 g) and (±)-2-methyl-piperazine (3.55 g) by the method of Example 15 step (ii) as a white solid. Yield 7 g.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[CH:4](/[CH:5]=[C:6](\[Cl:11])/[C:7](=[O:10])[O:8][CH3:9])[CH:3]1[C:12]([OH:14])=[O:13].[C:16]([C@@H:18](O)[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([O:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:20]=1)#[N:17]>C1C=CC=CC=1>[CH3:1][C:2]1([CH3:15])[C@@H:4](/[CH:5]=[C:6](\[Cl:11])/[C:7](=[O:10])[O:8][CH3:9])[C@H:3]1[C:12]([O:14][C@H:18]([C:16]#[N:17])[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([O:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:20]=1)=[O:13]
Reactant: COC(=O)/C(Cl)=C/C1C(C(=O)O)C1(C)C
Reactant: N#C[C@@H](O)c1cccc(Oc2ccccc2)c1
Solvent: c1ccccc1
Product: COC(=O)/C(Cl)=C/[C@H]1[C@@H](C(=O)O[C@H](C#N)c2cccc(Oc3ccccc3)c2)C1(C)C

Procedure:
Using the procedure of Example 1, (1R, cis) 2,2-dimethyl-3(Z)-[2-chloro-3-oxo-3-methoxy-propenyl]-cyclopropane-1-carboxylic acid and (S)α-cyano-3-phenoxy-benzyl alcohol were reacted to obtain (S)α-cyano-3-phenoxy-benzyl (1R,cis) 2,2-dimethyl-3(Z)-[2-chloro-3-oxo-3-methoxy-propenyl]-cyclopropane-1-carboxylate with a specific rotation of [α]D20 =+62.5°±1.5° (c=1% in benzene).
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]1[CH:18]=[C:17]([O:19][CH2:20][O:21][CH3:22])[CH:16]=[C:15]([O:23][CH2:24][O:25][CH3:26])[C:11]=1[C:12](O)=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>O1CCCC1.ClCCl>[CH2:1]([O:8][CH2:9][C:10]1[CH:18]=[C:17]([O:19][CH2:20][O:21][CH3:22])[CH:16]=[C:15]([O:23][CH2:24][O:25][CH3:26])[C:11]=1[C:12]([NH:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:13])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ccccc1
Reactant: COCOc1cc(COCc2ccccc2)c(C(=O)O)c(OCOC)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Solvent: C1CCOC1
Product: COCOc1cc(COCc2ccccc2)c(C(=O)Nc2ccccc2)c(OCOC)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 476.2 %

Procedure:
2-(Benzyloxymethyl)-4,6-bis(methoxymethoxy)benzoic acid (35 mg, 0.0096 mmol) obtained in Step 6 of Example 22 was dissolved in tetrahydrofuran (4 mL) and dichloromethane (1 mL), and aniline (0.030 mL, 0.33 mmol), 1-hydroxybenzotriazole monohydrate (56 mg, 0.37 mmol) and 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (0.13 g, 0.68 mmol) were added to the obtained solution followed by stirring at a room temperature for 20 hours. The reaction mixture was concentrated under reduced pressure and the obtained residue was purified by preparative thin-layer chromatography (chloroform/methanol=100/1) to obtain 2-(benzyloxymethyl)-4,6-bis(methoxymethoxy)-N-phenylbenzamide (20 mg, 49%).
Reaction SMILES: [NH2:1][CH:2]1[CH2:6][CH2:5][NH:4][C:3]1=[O:7].C(N(CC)CC)C.[CH2:15]([O:22][C:23](ON1C(=O)CCC1=O)=[O:24])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>O.CC#N>[O:7]=[C:3]1[CH:2]([NH:1][C:23](=[O:24])[O:22][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:6][CH2:5][NH:4]1
Reactant: NC1CCNC1=O
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: O
Product: O=C(NC1CCNC1=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 22 h
Yield: 69.6 %

Procedure:
To a solution of 3-aminopyrrolidin-2-one (2.70 g, 27 mmol) in water (36 mL) at ambient temperature was added triethylamine (4.12 mL, 29.7 mmol, 1.1 equivalent) followed by the dropwise addition over 15 minutes of a solution of N-(benzyloxycarbonyloxy)succinimide (7.4 g, 29.7 mmol, 1.1 equivalent) in MeCN (20 mL). The mixture was stirred at room temperature for 22 hours. The mixture was evaporated and the residue was partitioned between 0.5 M aqueous NaOH (500 mL) and DCM (600 mL). The aqueous fraction was further extracted with DCM (2×250 mL) and the combined organic extracts were back-washed with water (300 mL), dried (MgSO4) and evaporated to a cream solid which was filtered, dried and evaporated then triturated with ether (50 mL) for 0.5 hours, before being dried at room temperature for 2 hours to give benzyl N-(2-oxopyrrolidin-3-yl)carbamate (D39) 4.4 g (70%);
Reaction SMILES: CS[C:3]1[NH:4][CH:5]=[C:6]([CH2:10][C:11]2[CH:12]=[N:13][CH:14]=[N:15][CH:16]=2)[C:7](=[O:9])[N:8]=1.[CH3:17][NH:18][CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:37])([F:36])[F:35])[CH:29]=2)=[CH:23][CH:22]=1>C(O)C>[CH3:17][N:18]([CH2:19][CH2:20][C:21]1[CH:22]=[CH:23][C:24]([O:27][C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:35])([F:37])[F:36])[CH:29]=2)=[CH:25][CH:26]=1)[C:3]1[NH:4][CH:5]=[C:6]([CH2:10][C:11]2[CH:12]=[N:13][CH:14]=[N:15][CH:16]=2)[C:7](=[O:9])[N:8]=1
Reactant: CSc1nc(=O)c(Cc2cncnc2)c[nH]1
Reactant: CNCCc1ccc(Oc2cccc(C(F)(F)F)c2)cc1
Solvent: CCO
Product: CN(CCc1ccc(Oc2cccc(C(F)(F)F)c2)cc1)c1nc(=O)c(Cc2cncnc2)c[nH]1
Temperature: 125 °C
Reaction time: 8 h
Yield: 53.9 %

Procedure:
2-Methylsulfanyl-5-pyrimidin-5-ylmethyl-1H-pyrimidin-4-one (30 mg, 0.128 mmol, 1 eq) and methyl-{2-[4-(3-trifluoromethyl-phenoxy)-phenyl]ethyl}-amine (56.7 mg, 0.192 mmol, 1.5 eq) were dissolved in dry ethanol (300 μl) and stirred at 125° C. for overnight. Reaction mixture was evaporated and crude residue was sent to HPLC/MS Purification. After HPLC/MS purification combined fractions of desired product were collected and put on lyophilisation to obtain 2-(methyl-{2-[4-(3-trifluoromethyl-phenoxy)-phenyl]-ethyl}-amino)-5-pyrimidin-5-ylmethyl-1H-pyrimidin-4-one (0.069 mmol; yield: 54%, HPLC-MS/UV: [M+H]+=482.48; rt: 11.27 min; purity: 96%). 1H NMR (300 MHz; DMSO-d6) δ/ppm 2.80 (t, J=6.68 Hz, 2H), 2.94 (s, 3H), 3.52 (s, 2H), 3.69 (t, J=7.09 Hz, 2H), 7.00 (d, J=8.76 Hz, 2H), 7.19 (d, J=8.10 Hz, 1H), 7.24 (s, 1H), 7.30 (d, J=8.45 Hz, 2H), 7.44 (d, J=7.75 Hz, 1H), 7.58 (t, J=8.10 Hz, 1H), 7.66 (s, 1H), 8.66 (s, 2H), 8.95 (s, 1H)
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:15]=[N:16][N:17]([CH2:19][CH2:20][N:21](C)[C:22](=O)OC(C)(C)C)[CH:18]=3)=[CH:11][CH:12]=2)[C@H:7]([NH:30][C:31]2[CH:36]=[N:35][CH:34]=[CH:33][N:32]=2)[CH2:6][C@@H:5]1[CH3:37])(=[O:3])[CH3:2].FC(F)(F)C(O)=O.[ClH:45].CCOCC>ClCCl>[ClH:45].[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:15]=[N:16][N:17]([CH2:19][CH2:20][NH:21][CH3:22])[CH:18]=3)=[CH:11][CH:12]=2)[C@H:7]([NH:30][C:31]2[CH:36]=[N:35][CH:34]=[CH:33][N:32]=2)[CH2:6][C@@H:5]1[CH3:37])(=[O:3])[CH3:2]
Reactant: CC(=O)N1c2ccc(-c3cnn(CCN(C)C(=O)OC(C)(C)C)c3)cc2[C@H](Nc2cnccn2)C[C@@H]1C
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Solvent: O=C(O)C(F)(F)F
Product: CNCCn1cc(-c2ccc3c(c2)[C@H](Nc2cnccn2)C[C@H](C)N3C(C)=O)cn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 39.3 %

Procedure:
A solution 1,1-dimethylethyl (2-{4-[(2S,4R)-1-acetyl-2-methyl-4-(2-pyrazinylamino)-1,2,3,4-tetrahydro-6-quinolinyl]-1H-pyrazol-1-yl}ethyl)methylcarbamate (for a preparation see Intermediate 74) (204 mg, 0.403 mmol) in dichloromethane (DCM) (4 mL) was treated with trifluoroacetic acid (TFA) (1 mL, 12.98 mmol) and the resulting mixture was stirred at room temperature for 30 min then concentrated in vacuo. The residue was loaded on a 5 g SCX cartridge then eluted with MeOH (20 mL) followed by 2M NH3 in MeOH (20 mL). The ammonia fractions were combined to give a residue. Purification of this residue on SP4 using a 25 G silica cartridge (gradient:1 to 10% (2M NH3 in MeOH) in DCM) gave a second residue which was purified by MDAP (modifier: formic acid) to give a third residue which was loaded on a 5 g SCX cartridge then eluted with MeOH (20 mL) followed by 2M NH3 in MeOH (20 mL). The ammonia fractions were combined to give a residue which was dissolved in DCM (5 mL). The resulting solution was treated with HCl (1M in Et2O, 0.2 mL, 0.2 mmol) then concentrated in vacuo. Trituration of the residue with Et2O gave (2S,4R)-1-acetyl-2-methyl-6-{1-[2-(methylamino)ethyl]-1H-pyrazol-4-yl}-N-2-pyrazinyl-1,2,3,4-tetrahydro-4-quinolinamine hydrochloride (77 mg, 0.159 mmol, 39.3% yield) as a cream solid.
Reaction SMILES: [NH2:1][N:2]1[C:7](=[O:8])[C:6]([CH3:9])=[N:5][N:4]=[C:3]1[SH:10].[OH-].[Na+].[CH2:13](Cl)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>O.C(O)C>[NH2:1][N:2]1[C:7](=[O:8])[C:6]([CH3:9])=[N:5][N:4]=[C:3]1[S:10][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: ClCc1ccccc1
Reactant: Cc1nnc(S)n(N)c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1nnc(SCc2ccccc2)n(N)c1=O
Temperature: 80 °C

Procedure:
0.272 g of 4-amino-3-mercapto-6-methyl-4H-1,2,4-triazin-5-one (which can be prepared by the method of A. Dornow, H. Menzel, P. Marx, Chem. Ber. 97, 2173 (1964)) was suspended in 0.86 ml of a 2N solution of sodium hydroxide in water. A solution of 0.218 g of benzyl chloride in ethanol was subsequently added dropwise, and the mixture was heated at 80° C. for 30 minutes. The resultant precipitate was filtered off with suction, giving 4-amino-3-benzylsulfanyl-6-methyl-4H-1,2,4-triazin-5-one.
Reaction SMILES: [Na].C(O[C:5](=O)[C:6]([O:8][CH2:9][CH3:10])=[O:7])C.[CH:12]1([C:17](=[O:19])C)[CH2:16][CH2:15][CH2:14][CH2:13]1>C(O)C>[CH2:9]([O:8][C:6](=[O:7])[CH2:5][C:17]([CH:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1)=[O:19])[CH3:10]
Reactant: CCOC(=O)C(=O)OCC
Reactant: CC(=O)C1CCCC1
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)CC(=O)C1CCCC1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
Sodium pellets (3.1 g, 135 mmol) were dissolved in ethanol (100 ml) under nitrogen at room temperature and a solution of diethyloxalate (18.4 ml, 135 mmol) and 1-cyclopentylethanone (16.7 g, 149 mmol) was added dropwise at room temperature over 30 minutes. The reaction was diluted with ethanol (100 ml), heated to 60° C. and stirred at this temperature for 2 hours. After cooling to room temperature the reaction was poured onto ice-cold 2N HCl (200 ml) and extracted with diethylether (300 ml) and ethyl acetate (300 ml). The combined organic extracts were dried over MgSO4, concentrated under reduced pressure and the residue was purified by flash column chromatography on silica gel eluting with pentane:ethyl acetate (6:1, by volume) to give 3-cyclopentyl-3-oxo-propionc acid ethyl ester (23.8 g) as an orange oil. 1H NMR (400 MHz, CDCl3): δ=14.38-14.65 (1H, brs), 6.83 (1H, s), 4.30-4.39 (2H, quart), 2.82-2.92 (1H, quin), 1.83-1.96 (2H, m), 1.57-1.83 (6H, 2×m), 1.33-1.40 (3H, t) ppm. LRMS (electrospray): m/z [M−H]+ 211.
Reaction SMILES: [S:1]([O:5][CH2:6][C@H:7]1[O:14][C@@H:11]([O:12][CH3:13])[C@H:10]([NH:15][C:16]([NH:18][CH3:19])=[O:17])[C@@H:9]([OH:20])[C@@H:8]1[OH:21])([CH3:4])(=[O:3])=[O:2].C(O)(=O)C.[N:26]([O-])=[O:27].[Na+]>O>[S:1]([O:5][CH2:6][C@H:7]1[O:14][C@@H:11]([O:12][CH3:13])[C@H:10]([NH:15][C:16]([N:18]([CH3:19])[N:26]=[O:27])=[O:17])[C@@H:9]([OH:20])[C@@H:8]1[OH:21])([CH3:4])(=[O:3])=[O:2]
Reactant: CNC(=O)N[C@H]1[C@H](OC)O[C@H](COS(C)(=O)=O)[C@@H](O)[C@@H]1O
Reactant: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CO[C@@H]1O[C@H](COS(C)(=O)=O)[C@@H](O)[C@H](O)[C@H]1NC(=O)N(C)N=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.4 %

Procedure:
Methyl 2-deoxy-6-O-mesyl-2-(N'-methylureido)-β-D-glucopyranoside (400 mg) of the formula ##STR36## was dissolved in 50 ml of water, and the resulting aqueous solution was adjusted to pH 3 by addition of 2 ml of acetic acid. The acidified aqueous solution was admixed with 120 mg of sodium nitrite and the mixture was agitated at ambient temperature overnight to effect the nitrosation. The reaction mixture was treated with Amberlite IR-120 (H+ form) to remove the sodium ion therefrom. The reaction mixture was then evaporated under a reduced pressure at a temperature below 25° C. The residue was crystallized from ethanol to give 350 mg of the titled compound. mp. 131°-132° C. (with decomposition). [α]D20 -14° (c 0.5, dimethylsulfoxide).
Reaction SMILES: [CH3:1][CH:2]([CH3:6])[CH2:3][CH2:4]N.[OH:7][CH2:8][C@@H:9]1[CH2:13][CH2:12][CH2:11][N:10]1[CH2:14][CH:15]([N:17]1[C:30]2[CH:29]=[C:28]([C:31](=S)[NH2:32])[CH:27]=[CH:26][C:25]=2[S:24][C:23]2[C:18]1=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH3:16].C([OH:36])C>>[OH:7][CH2:8][C@@H:9]1[CH2:13][CH2:12][CH2:11][N:10]1[CH2:14][CH:15]([N:17]1[C:30]2[CH:29]=[C:28]([C:31]([NH:32][CH2:4][CH2:3][CH:2]([CH3:6])[CH3:1])=[O:36])[CH:27]=[CH:26][C:25]=2[S:24][C:23]2[C:18]1=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH3:16]
Reactant: CC(CN1CCC[C@H]1CO)N1c2ccccc2Sc2ccc(C(N)=S)cc21
Reactant: CC(C)CCN
Reactant: CCO
Product: CC(C)CCNC(=O)c1ccc2c(c1)N(C(C)CN1CCC[C@H]1CO)c1ccccc1S2
Reaction time: 16 h

Procedure:
3-Methylbutylamine (1.74 cc) is added to a solution of 10-{1-[(2S)-2-hydroxymethyl-1-pyrrolidinyl]-2-propyl}-2-phenothiazinecarbothioamide, L series (1.20 g) in absolute ethanol (20 cc). The mixture is brought to 150° C. for 16 hours and then concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 50° C. The residue is diluted with ethyl acetate (100 cc), washed with distilled water (2×50 cc), dried over magnesium sulphate and then concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 50° C., before being purified by chromatography on a column (height: 14.5 cm; diameter: 2.8 cm) of silica gel (0.04-0.06 mm) with a slight excess pressure of nitrogen (40 kPa), eluting with mixtures of cyclohexane and ethyl acetate in proportions (by volume) of 65:35 (1200 cc) and 35:65 (1.2 liters), collecting 60-cc fractions. Fractions 16 to 33 are combined and concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 50° C. to give 10-{1-[(2S)-2-hydroxymethyl-1-pyrrolidinyl]-2-propyl}-N-(3-methylbutyl)-2-phenothiazinecarboxamide, L series (0.34 g) in the form of a yellow resin.
Reaction SMILES: [OH-].[Na+].C([O:6][C:7]1[CH:8]=[CH:9][C:10]([O:35][CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[C:11]([CH:34]=1)[C:12]([NH:14][C:15]1[CH:27]=[C:26]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:25]=[CH:24][C:16]=1[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[O:13])(=O)C>CO.O1CCOCC1>[CH2:36]([O:35][C:10]1[CH:9]=[CH:8][C:7]([OH:6])=[CH:34][C:11]=1[C:12]([NH:14][C:15]1[CH:27]=[C:26]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:25]=[CH:24][C:16]=1[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[O:13])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: CC(=O)Oc1ccc(OCc2ccccc2)c(C(=O)Nc2cc(-c3ccccc3)ccc2C(=O)OC(C)(C)C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CO
Product: CC(C)(C)OC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1cc(O)ccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97.3 %

Procedure:
A 2.0 mol/L aqueous solution of sodium hydroxide (1.6 mL) was added to a solution mixture of tert-butyl 2-(5-acetoxy-2-(benzyloxy)benzamido)-4-phenylbenzoate (0.58 g) in methanol (3.0 mL) and dioxane (2.0 mL), followed by stirring at room temperature for 30 minutes. The solvent was evaporated under reduced pressure, and water and chloroform were added to the residue, followed by adjusting the pH to 4.0 with 2.0 mol/L hydrochloric acid. The organic layer was separated, washed with a saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to obtain 0.52 g of tert-butyl 2-(2-(benzyloxy)-5-hydroxybenzamido)-4-phenylbenzoate as a white solid.