Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS(Cl)(=O)=O.[CH:6]1([CH2:9]O)[CH2:8][CH2:7]1.[Br-].[Li+].[O:13]1[C@@H:25]2[C@@:26]34[CH2:28][CH2:29][NH:30][C@@H:20]([C@:21]3([OH:32])[CH2:22][CH2:23][C:24]2=[O:31])[CH2:19][C:18]2=[C:27]4[C:14]1=[C:15]([OH:33])[CH:16]=[CH:17]2>CN(C=O)C.C(N(CC)CC)C>[CH2:7]1[CH:6]([CH2:9][N:30]2[C@@H:20]3[CH2:19][C:18]4[CH:17]=[CH:16][C:15]([OH:33])=[C:14]5[O:13][CH:25]6[C:24]([CH2:23][CH2:22][C@:21]3([OH:32])[C@:26]6([C:27]=45)[CH2:28][CH2:29]2)=[O:31])[CH2:8]1
Reactant: O=C1CC[C@@]2(O)[C@H]3Cc4ccc(O)c5c4[C@@]2(CCN3)[C@H]1O5
Reactant: OCC1CC1
Agent: CS(=O)(=O)Cl
Agent: [Br-]
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C1CC[C@@]2(O)[C@H]3Cc4ccc(O)c5c4[C@@]2(CCN3CC2CC2)C1O5
Temperature: 2.5 °C

Procedure:
Methanesulphonyl chloride (76 kg) was added to the mixture of cyclopropyl methanol (50 kg) and triethylamine (192 L) in DMF (400 L) maintained at 0-5° C., the reaction mixture was maintained at 0-5° C. for 3.0 hrs. Lithium bromide (60 Kg) was added to reaction mixture at 0-15° C. and maintained for 10-15 minutes. Noroxymorphone (40 Kg) was added to above reaction mixture at 0-5° C. and temperature raised to 65-70° C. over 1.0 hr period and maintained for 14-15 hrs. After completion of reaction it was quenched in ice-water below 20° C. and the product was extracted with ethylacetate, The ethylacetate layer was concentrated and the product was isolated with MDC and cyclohexane mixture at 10-15° C. Yield=35.3 Kg.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:8]([C:11]([CH:14]2[S:18][CH2:17][CH2:16][S:15]2)([CH3:13])[CH3:12])=[CH:7][C:4]=1[CH:5]=O.[NH2:19][C@H:20]1[CH2:25][CH2:24][CH2:23][N:22]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[C@H:21]1[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.C(OC(N1CCC[C@H](NCC2C=C(C(C#N)C)C=CC=2OC)[C@@H]1C1C=CC=CC=1)=O)(C)(C)C>>[C:29]([O:28][C:26]([N:22]1[CH2:23][CH2:24][CH2:25][C@H:20]([NH:19][CH2:5][C:4]2[CH:7]=[C:8]([C:11]([CH:14]3[S:18][CH2:17][CH2:16][S:15]3)([CH3:13])[CH3:12])[CH:9]=[CH:10][C:3]=2[O:2][CH3:1])[C@@H:21]1[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:27])([CH3:32])([CH3:30])[CH3:31]
Reactant: COc1ccc(C(C)(C)C2SCCS2)cc1C=O
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](N)[C@@H]1c1ccccc1
Agent: COc1ccc(C(C)C#N)cc1CN[C@H]1CCCN(C(=O)OC(C)(C)C)[C@H]1c1ccccc1
Product: COc1ccc(C(C)(C)C2SCCS2)cc1CN[C@H]1CCCN(C(=O)OC(C)(C)C)[C@H]1c1ccccc1

Procedure:
This compound was prepared from Compound 81 and Compound 17 in the same manner of Compound 18.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[C:12]([NH2:19])[CH:11]=2)[CH:7]=[CH:8][CH:9]=1)=[O:4].CC1(C)[O:26][C:25]([C:27]2[CH:28]=[C:29]([CH:32]=[CH:33][CH:34]=2)[C:30]#[N:31])=[CH:24][C:23](=O)[O:22]1>>[CH3:1][O:2][C:3]([C:5]1[N:6]([C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[C:12]([NH:19][C:23](=[O:22])[CH2:24][C:25]([C:27]3[CH:34]=[CH:33][CH:32]=[C:29]([C:30]#[N:31])[CH:28]=3)=[O:26])[CH:11]=2)[CH:7]=[CH:8][CH:9]=1)=[O:4]
Reactant: CC1(C)OC(=O)C=C(c2cccc(C#N)c2)O1
Reactant: COC(=O)c1cccn1-c1ccc([N+](=O)[O-])c(N)c1
Product: COC(=O)c1cccn1-c1ccc([N+](=O)[O-])c(NC(=O)CC(=O)c2cccc(C#N)c2)c1

Procedure:
The title compound was prepared from 1-(3-amino-4-nitro-phenyl)-1H-pyrrole-2-carboxylic acid methyl ester (Example F9) and 3-(2,2-dimethyl-6-oxo-6H-[1,3]dioxin-4-yl)-benzonitrile (Example L1) according to the general procedure M. Obtained as a yellow solid (840 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:11][C:12]2[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=2[C:14](O)=[O:15])[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.[BH4-].[Na+].B(F)(F)F.CCOCC>O1CCCC1>[CH3:10][O:9][C:7]1[CH:6]=[C:5]([S:11][C:12]2[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=2[CH2:14][OH:15])[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=1
Reactant: COc1cc(OC)cc(Sc2ccccc2C(=O)O)c1
Agent: FB(F)F
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: COc1cc(OC)cc(Sc2ccccc2CO)c1
Reaction time: 0.5 h
Yield: 70.9 %

Procedure:
To a stirred solution of 12.3 g of the 2-(3,5-dimethoxyphenylthio)benzoic acid, prepared in Example 1, in 50 ml of anhydrous tetrahydrofuran was added 1.8 g of sodium borohydride portionwise at 0° C. After 30 minutes, the resulting solution was treated with 6.3 ml of BF3. Et2O at the same temperature and then the mixture was stirred at room temperature for 1 hour. The reaction mixture was partitioned between ethyl acetate and dilute hydrochloric acid, and the ethyl acetate layer was successively washed with water and brine. The organic layer was dried over anhydrous sodium sulfate and concentrated. The concentrate was purified by silica gel column chromatography (eluting solvent; hexane:ethyl acetate=3:1) to give 8.3 g (71%) of a compound of the indicated formula (11).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[C:16]([C:22]([F:25])([F:24])[F:23])[CH:15]=2)[CH:10]([CH2:26][CH3:27])[CH2:9]1)C1C=CC=CC=1.[H][H]>CO.[C].[Pd]>[CH2:26]([CH:10]1[CH2:9][NH:8][CH2:13][CH2:12][N:11]1[C:14]1[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[C:16]([C:22]([F:25])([F:24])[F:23])[CH:15]=1)[CH3:27]
Reactant: CCC1CN(Cc2ccccc2)CCN1c1ccc(C#N)c(C(F)(F)F)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CCC1CNCCN1c1ccc(C#N)c(C(F)(F)F)c1

Procedure:
A 0.65 g portion of 4-(4-benzyl-2-ethylpiperazin-1-yl)-2-trifluoromethylbenzonitrile synthesized in Reference Example 6-1 and 65 mg of 10% palladium-carbon were stirred in methanol at room temperature for 6 hours at atmospheric pressure in an atmosphere of hydrogen. The insoluble matter was removed by filtration through celite, the filtrate was concentrated under reduced pressure, the resulting residue was purified by a silica gel column chromatography, and 0.46 g of the title compound was obtained from chloroform-methanol-29% aqueous ammonia (10:1:0.1, v/v/v) eluate as a yellow oily substance.
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1[N:5]=[C:6]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[S:7][CH:8]=1.[CH3:17][C:18]1[C:19]([C:24](O)=[O:25])=[N:20][CH:21]=[CH:22][N:23]=1.C1CCC(N=C=NC2CCCCC2)CC1>C(Cl)Cl>[CH3:1][N:2]([CH2:3][C:4]1[N:5]=[C:6]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:13])([CH3:15])[CH3:14])[S:7][CH:8]=1)[C:24]([C:19]1[C:18]([CH3:17])=[N:23][CH:22]=[CH:21][N:20]=1)=[O:25]
Reactant: Cc1nccnc1C(=O)O
Reactant: CNCc1csc(NC(=O)OC(C)(C)C)n1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: Cc1nccnc1C(=O)N(C)Cc1csc(NC(=O)OC(C)(C)C)n1
Reaction time: 2 h
Yield: 67.9 %

Procedure:
To a solution of tert-butyl 4-((methylamino)methyl)thiazol-2-ylcarbamate (Intermediate 17, 1.30 g, 5.3 mmol) and 3-methylpyrazine-2-carboxylic acid (1.1 g, 8 mmol) in CH2Cl2 (25 mL) was added DCC (1.64 g, 8 mmol). The mixture was stirred for 2 hours and the solids were removed by filtration. The filtrate was concentrated in vacuo and purified by column chromatography (2% MeOH in CH2Cl2, Rf=0.15) to afford tert-butyl 4-((N,2-dimethylpyrazine-3-carboxamido)methyl)thiazol-2-ylcarbamate (1.30 g, 3.6 mmol) as an off-white solid in 68% yield.
Reaction SMILES: C[C:2]([CH3:5])([O-:4])C.[K+].[C:7]([OH:12])(=[O:11])[C:8]([CH3:10])=[CH2:9].C1OCCOCCOCCOCCOCC[O:15][CH2:14]1>CN(C=O)C>[C:2]([O:15][CH2:14][O:11][C:7](=[O:12])[C:8]([CH3:10])=[CH2:9])(=[O:4])[CH3:5]
Reactant: C=C(C)C(=O)O
Reactant: CC(C)(C)[O-]
Reactant: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Solvent: CN(C)C=O
Product: C=C(C)C(=O)OCOC(C)=O
Temperature: 25 °C
Reaction time: 96 h
Yield: 951.2 %

Procedure:
Potassium tert. butoxide (5.0 g, 0.045 mol ) was added to a solution of methacrylic acid (3.87 g, 0.045 mol) in DMF (150 ml). Chloromethyl acetate3 (4.86 g, 0.045 mol) was added to the resulting suspension. 18crown-6 (0.9 g, 3.45 mmol) was then added and the reaction mixture was left with stirring at room temperature for 4 days. The reaction mixture was filtered end the solvent was removed under reduced pressure. The residue was dissolved in chloroform (100 ml) and washed with saturated aqueous sodium hydrogen carbonate (50 ml) and water (50 ml). The organic phase was dried (MgSO4) and the solvent removed under reduced pressure. Flash chromatography gave 5.19 g (75 %) of the title product.
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:11]=1[CH2:12][CH2:13][CH2:14][CH:15]2[C:20]([N:22]([C:29]1[CH:30]=[N:31][C:32]([CH:35]([CH3:37])[CH3:36])=[CH:33][CH:34]=1)[CH2:23][C:24]1[CH:25]=[N:26][NH:27][CH:28]=1)=[O:21])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[CH2:39][C:40]1[CH:45]=[CH:44][C:43]([CH2:46][CH3:47])=[CH:42][N:41]=1>>[CH2:2]([O:9][C:10]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:11]=1[CH2:12][CH2:13][CH2:14][CH:15]2[C:20]([N:22]([CH2:23][C:24]1[CH:25]=[N:26][N:27]([CH2:39][C:40]2[CH:45]=[CH:44][C:43]([CH2:46][CH3:47])=[CH:42][N:41]=2)[CH:28]=1)[C:29]1[CH:30]=[N:31][C:32]([CH:35]([CH3:37])[CH3:36])=[CH:33][CH:34]=1)=[O:21])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CC(C)c1ccc(N(Cc2cn[nH]c2)C(=O)C2CCCc3c(OCc4ccccc4)cccc32)cn1
Reactant: CCc1ccc(CCl)nc1
Agent: Cl
Product: CCc1ccc(Cn2cc(CN(C(=O)C3CCCc4c(OCc5ccccc5)cccc43)c3ccc(C(C)C)nc3)cn2)nc1
Yield: 82.9 %

Procedure:
By the reaction and treatment in the same manner as in Example 271 using 5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-[(pyrazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide hydrochloride (0.78 g) and 2-chloromethyl-5-ethylpyridine (0.58 g) as starting materials, 5-benzyloxy-N-({1-[(5-ethylpyridin-2-yl)methyl]pyrazol-4-yl}methyl)-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.75 g) was obtained.
Reaction SMILES: CO[C:3](=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10]Br.[CH3:13][CH:14]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:15][NH2:16].C([O-])([O-])=O.[K+].[K+].C(OCC)(=O)C>C1(C)C=CC=CC=1.CCCCCC>[CH3:13][CH:14]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:15][N:16]1[CH2:10][C:5]2[C:4](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:3]1=[O:12]
Reactant: CC(CN)Cc1ccccc1
Reactant: COC(=O)c1ccccc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: CC(Cc1ccccc1)CN1Cc2ccccc2C1=O
Temperature: 100 °C
Reaction time: 2 h
Yield: 49.9 %

Procedure:
A mixture of 2-bromomethyl-benzoic acid methyl ester (0.460 g, 2.0 mmol), 2-methyl-3-phenyl-propylamine (0.298 g, 2.0 mmol), and K2CO3 (0.500 g, 3.6 mmol) in toluene (10 mL) was heated with stirring at 100° C. for 2 h. Workup and silica gel column chromatography using 30% ethyl acetate in hexane afforded 2-(2-methyl-3-phenyl-propyl)-2,3-dihydro-isoindol-1-one (0.265 g, 50%). 1H NMR (300 MHz, CDCl3): δ (ppm) 0.93 (d, 3H), 2.19 (m, 1H), 2.46 (m, 1H), 2.73 (m, 1H) 3.56 (d, 2H), 4.36 (dd, 2H), 7.14-7.56 (m, 8H), 7.86 (d, 1H). GC-MS: m/z 265 (M)+.
Reaction SMILES: [N+](C1C=NSC=1OC1CCN(C(OC(C)(C)C)=O)CC1)([O-])=O.[N+:23]([C:26]1[CH:27]=[N:28][S:29][C:30]=1[N:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1)([O-])=O>>[O:34]1[CH2:35][CH2:36][N:31]([C:30]2[S:29][N:28]=[CH:27][C:26]=2[NH2:23])[CH2:32][CH2:33]1
Reactant: O=[N+]([O-])c1cnsc1N1CCOCC1
Agent: CC(C)(C)OC(=O)N1CCC(Oc2sncc2[N+](=O)[O-])CC1
Product: Nc1cnsc1N1CCOCC1

Procedure:
Following the procedure described in Example 1, and substituting Compound 1C3 in Step (3) with 4-(4-nitroisothiazol-5-yl)morpholine (6C6) (500 mg, 2.32 mmol) the compound 6D8 (300 mg, 1.62 mmol) was obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([N:14]3[CH2:19][CH2:18][CH2:17][CH2:16][C:15]3=[O:20])[CH:11]=[C:10]([C:21]([OH:23])=O)[CH:9]=2)=[CH:4][CH:3]=1.Cl.[CH3:25]N(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.[CH3:47][C:48]1[N:53]=[CH:52][C:51]([CH2:54][NH2:55])=[CH:50][N:49]=1.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([N:14]3[CH2:19][CH2:18][CH2:17][CH2:16][C:15]3=[O:20])[CH:11]=[C:10]([C:21]([NH:55][CH2:54][C:51]3[CH:50]=[N:49][C:48]([CH2:47][CH3:25])=[N:53][CH:52]=3)=[O:23])[CH:9]=2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(-c2cc(C(=O)O)cc(N3CCCCC3=O)c2)cc1
Reactant: Cc1ncc(CN)cn1
Reactant: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CCc1ncc(CNC(=O)c2cc(-c3ccc(C)cc3)cc(N3CCCCC3=O)c2)cn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 4′-methyl-5-(2-oxopiperidin-1-yl)biphenyl-3-carboxylic acid (45 mg, 0.14 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (56 mg, 0.29 mmol), 1-hydroxybenzotriazole hydrate (22 mg, 0.14 mmol), and CH2Cl2 (3 mL) were added (2-methylpyrimidin-5-yl)methanamine (27 mg, 0.22 mmol) and N,N-diisopropylethylamine (51 μL, 0.29 mmol). The mixture was stirred at room temperature overnight and then concentrated. The residue was purified by preparative HPLC (100×20.2 mm, C18 column; 30-80% CH3CN-water [10 mM Et2NH]) to afford a white foam.
Reaction SMILES: [C:1](#[N:7])[CH:2]([CH2:4][C:5]#[N:6])[OH:3].[C:8]([O-:11])(=O)C.[K+].[CH2:13]=[O:14]>C(O)(=O)C>[CH2:13]([C:4]([CH2:8][OH:11])([C:5]#[N:6])[CH:2]([OH:3])[C:1]#[N:7])[OH:14]
Reactant: CC(=O)[O-]
Reactant: C=O
Reactant: N#CCC(O)C#N
Agent: [K+]
Solvent: CC(=O)O
Product: N#CC(O)C(C#N)(CO)CO

Procedure:
It is also known that malonitrile can be reacted in glacial acetic acid, in the presence of potassium acetate, with gaseous formaldehyde at 100° C. to produce bis(methylol) malonitrile (Ardis, A. E.; Averill, S. J.; Gilbert, H.; Miller, F. F.; Schmidt, R. F.; Stewart, F. D.; and Trumbull, H. L.; J. Am. Chem. Soc., 72 (1950), 1305), although the yield is only 24% of the theoretical yield.
Reaction SMILES: C1(C)C=CC=CC=1.C[Si]([N-][Si](C)(C)C)(C)C.[K+].COCCOC.[CH3:24][O:25][C:26](=[O:46])/[CH:27]=[C:28](\[CH3:45])/[CH2:29][CH2:30][S:31]([C:34]1[N:38]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[N:37]=[N:36][N:35]=1)(=O)=O.C[C@H]([C@@H](O[Si](CC)(CC)CC)CC)C=O>C1COCC1>[CH3:24][O:25][C:26](=[O:46])/[CH:27]=[C:28](\[CH3:45])/[CH2:29][CH2:30][S:31][C:34]1[N:38]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[N:37]=[N:36][N:35]=1
Reactant: COC(=O)/C=C(\C)CCS(=O)(=O)c1nnnn1-c1ccccc1
Agent: CC[C@H](O[Si](CC)(CC)CC)[C@@H](C)C=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Solvent: COCCOC
Product: COC(=O)/C=C(\C)CCSc1nnnn1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 108.9 %

Procedure:
0.5M Potassium bis(trimethylsilyl)amide toluene solution (8.48 ml, 4.24 mmol) was added dropwise to a DME (40 ml) solution of methyl-(2E)-3-methyl-5-[(1-phenyl-1-H-tetrazol-5-yl)sulfonyl]pent-2-enoate (1.19 g, 3.53 mmol) at −60° C. and the reaction solution was stirred at the same temperature for 30 minutes. Subsequently a THF (5 ml) solution of (2R,3S)-2-methyl-3-[(triethylsilyl)oxy]pentanal (1.63 g, 7.06 mmol) was added dropwise at −78° C. and the reaction solution was stirred for two hours. After the reaction solution was warmed to room temperature, distilled water was added. The reaction solution was diluted with ethyl acetate and washed with brine. After the organic layer was dried over anhydrous sodium sulfate and the drying agent was filtered off, the organic layer was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (Merck, commercial name Silica Gel 60, 230-400 mesh; hexane:diethyl ether=50:1) to obtain the title compound (1.17 g) as a colorless oil. The title compound was determined to be a mixture of E:Z 17:1 by 1H-NMR.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([CH:7]2[CH2:11][CH2:10][N:9](C(OC(C)(C)C)=O)[CH2:8]2)[S:5][CH:6]=1>C(O)(C(F)(F)F)=O.C(Cl)Cl>[CH3:1][C:2]1[N:3]=[C:4]([CH:7]2[CH2:11][CH2:10][NH:9][CH2:8]2)[S:5][CH:6]=1
Reactant: Cc1csc(C2CCN(C(=O)OC(C)(C)C)C2)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1csc(C2CCNC2)n1
Yield: 96.1 %

Procedure:
To a solution of tert-butyl 3-(4-methylthiazol-2-yl)pyrrolidine-1-carboxylate (90 mg, 0.34 mmol) in TFA/CH2Cl2 (20%, 2 mL) was stirred at rt for 1 h and concentrated to give 4-methyl-2-(pyrrolidin-3-yl)thiazole (55 mg, 98%) as a yellow oil.
Reaction SMILES: [C:1]1([S:11]([C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([O:23][CH2:24][CH2:25][CH2:26]OS(C4C=CC(C)=CC=4)(=O)=O)[CH:21]=3)[NH:16][N:15]=2)(=[O:13])=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[NH:38]1[CH2:43][CH2:42][O:41][CH2:40][CH2:39]1>C1COCC1>[N:38]1([CH2:26][CH2:25][CH2:24][O:23][C:20]2[CH:21]=[C:22]3[C:17](=[CH:18][CH:19]=2)[NH:16][N:15]=[C:14]3[S:11]([C:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:4]=[CH:3][CH:2]=2)(=[O:12])=[O:13])[CH2:43][CH2:42][O:41][CH2:40][CH2:39]1
Reactant: Cc1ccc(S(=O)(=O)OCCCOc2ccc3[nH]nc(S(=O)(=O)c4cccc5ccccc45)c3c2)cc1
Reactant: C1COCCN1
Solvent: C1CCOC1
Product: O=S(=O)(c1cccc2ccccc12)c1n[nH]c2ccc(OCCCN3CCOCC3)cc12
Temperature: 25 °C
Yield: 100 %

Procedure:
A solution of toluene-4-sulfonic acid 3-[3-(naphthalene-1-sulfonyl)-1H-indazol-5-yloxy]-propyl ester (0.080 mg, 0.15 mmol) and morpholine (0.45-0.75 mmol) in THF (10 mL) was stirred at 90° C. for about 2 hours in a sealed tube. After cooling to ambient temperature the reaction mixture was solvent evaporated. It was dissolved in ethyl acetate and washed twice with aqueous sodium bicarbonate. The organic phase was dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by flash chromatography using 0.5% ammonium hydroxide/5.0% methanol in chloroform. 5-(3-Morpholin-4-yl-propoxy)-3-(naphthalene-1-sulfonyl)-1H-indazole as a light yellow solid (74.4 mg, 100%) was obtained. This product was dissolved in methanol, and ethereal hydrochloride was added. Concentrating and drying in vacuo 83° C. for 24 hours yielded the hydrochloride as a yellow foam (74.5 mg, 100%); Mass Spectrum (+EI, [M+H]+) m/z 452. 1HNMR (500 MHz, DMSO-d6): δ14.15 (s, 1H), 10.56-10.62 (br, 1H), 8.75 (d, 1H, J=8.66 Hz), 8.52 (dd, 1H, J=7.44 Hz and 1.22 Hz), 8.27 (d, 1H, J=8.30 Hz), 8.02-8.05 (m, 1H), 7.71-7.75 (m, 1H), 7.54-7.65 (m, 3H), 7.29 (d, 1H, J=2.32 Hz), 7.07-7.10 (m, 1H), 4.10 (t, 2H, J=5.86 Hz), 3.93-3.96 (m, 2H), 3.71-3.77 (m, 2H), 3.43-3.46 (m, 2H), 2.99-3.15 (m, 2H), 2.14-2.22 ppm (m, 2H). Elemental Analysis for C24H25N3O5S.1.00 mol HCl.1.30 mol H2O: Calcd: C, 56.36; H, 5.36; N, 8.22; Found: C, 56.05; H, 5.65; N, 8.09.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[C:11]([O:13][CH3:14])[CH:12]=1)[C:9](O)=[N:8][C:7]([NH:16][C:17]1[CH:21]=[C:20]([CH3:22])[NH:19][N:18]=1)=[CH:6]2.O=P(Cl)(Cl)[Cl:25]>>[Cl:25][C:9]1[C:10]2[C:5](=[CH:4][C:3]([O:2][CH3:1])=[CH:12][C:11]=2[O:13][CH3:14])[CH:6]=[C:7]([NH:16][C:17]2[CH:21]=[C:20]([CH3:22])[NH:19][N:18]=2)[N:8]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1cc(OC)c2c(O)nc(Nc3cc(C)[nH]n3)cc2c1
Product: COc1cc(OC)c2c(Cl)nc(Nc3cc(C)[nH]n3)cc2c1
Temperature: 140 °C
Yield: 47.28 %

Procedure:
A mixture of 6,8-Dimethoxy-3-(5-methyl-1H-pyrazol-3-ylamino)-isoquinolin-1-ol (0.4 g, 1.33 mmol) in POCl3 (4 ml), were sealed in microwave process vials (5 ml). The mixture was heated at 140° C. for 75 minutes under microwave irradiation. The mixture was concentrated, and the residue was treated with 1 ml MeOH. The solid was collected and dried to give desired product (0.2 g, 47.28%). LC-MS: m/e 319 (MH+).
Reaction SMILES: [NH:1]([C:15]([O:17][C:18]([C:21]1[CH:30]=[C:27]([O:28][CH3:29])[CH:26]=[C:23]([O:24][CH3:25])[CH:22]=1)([CH3:20])[CH3:19])=[O:16])[CH2:2][C:3]([NH:5][C@H:6]([C:11]([O:13]C)=[O:12])[C@H:7]([CH2:9][CH3:10])[CH3:8])=[O:4].[OH-].[Na+].CC1C(C2(C3C(C)=CC(O)=C(C(C)C)C=3)OC(=O)C3C2=CC=CC=3)=CC(C(C)C)=C(O)C=1>O1CCOCC1.O>[NH:1]([C:15]([O:17][C:18]([C:21]1[CH:22]=[C:23]([O:24][CH3:25])[CH:26]=[C:27]([O:28][CH3:29])[CH:30]=1)([CH3:19])[CH3:20])=[O:16])[CH2:2][C:3]([NH:5][C@H:6]([C:11]([OH:13])=[O:12])[C@H:7]([CH2:9][CH3:10])[CH3:8])=[O:4]
Reactant: CC[C@H](C)[C@H](NC(=O)CNC(=O)OC(C)(C)c1cc(OC)cc(OC)c1)C(=O)OC
Agent: Cc1cc(O)c(C(C)C)cc1C1(c2cc(C(C)C)c(O)cc2C)OC(=O)c2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CC[C@H](C)[C@H](NC(=O)CNC(=O)OC(C)(C)c1cc(OC)cc(OC)c1)C(=O)O

Procedure:
10 g (23.56 mmols) of Ddz-Gly-Ile-OMe were dissolved in a mixture of 24 ml of dioxane and 8 ml of water and titrated with 1 N NaOH against thymolphthalein as indicator. Over 23 ml were consumed depending on the acetic acid content. After neutralization with citric acid, the dioxane was distilled off. The residue was taken up in water and a pH of 3 was adjusted at 0° C. with 2 N citric acid. If necessary, the aqueous phase was again acidified to pH 3 and extracted with ethyl acetate. The combined ethyl acetate extracts were shaken once with water, dried over Na2SO4, concentrated and dried again in a high vacuum. An amorphous substance was obtained. Yield 8.9 g (92%), m.p. 80°-90° C.
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]1[CH:4]=[CH:5][C:6]2[N:12]3[C:13]([CH3:16])=[N:14][N:15]=[C:11]3[CH2:10][N:9]=[C:8]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[C:7]=2[CH:23]=1.[C:26](Cl)(=O)[CH3:27]>CN(C)C=O>[F:25][C:2]([F:1])([F:24])[C:3]1[CH:4]=[CH:5][C:6]2[N:12]3[C:13]([CH2:16][CH2:11][N:12]([CH2:13][CH2:26][CH3:27])[CH2:6][CH2:5][CH3:4])=[N:14][N:15]=[C:11]3[CH2:10][N:9]=[C:8]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[C:7]=2[CH:23]=1
Reactant: CC(=O)Cl
Reactant: Cc1nnc2n1-c1ccc(C(F)(F)F)cc1C(c1ccccn1)=NC2
Solvent: CN(C)C=O
Product: CCCN(CCC)CCc1nnc2n1-c1ccc(C(F)(F)F)cc1C(c1ccccn1)=NC2

Procedure:
In the manner given in Example 1, a solution of 8-trifluoromethyl-1-methyl-6-(2-pyridyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine in dimethylformamide, N,N,N',N'-tetrapropyldiaminomethane and acetyl chloride (in 0.1 molar excess compared to the N,N,N',N'-tetrapropyldiaminomethane) are reacted together to give 8-trifluoromethyl-1-[2-(dipropylamino)ethyl]-6-(2-pyridyl)-4H-s-triazolo[4,3-a][1,4-]benzodiazepine.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]4[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]4)[CH2:23][CH2:22][C:21]([C:32]([O:34]C)=[O:33])=[CH:20][C:19]=3[CH:36]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].[OH-].[Na+]>CO.C1COCC1>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]4[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]4)[CH2:23][CH2:22][C:21]([C:32]([OH:34])=[O:33])=[CH:20][C:19]=3[CH:36]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCN3CC2CCCCC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCN3CC2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89 %

Procedure:
In methanol (25 ml) and THF (25 ml) was dissolved methyl 7-[4-(2-butoxyethoxy)phenyl]-1-cyclohexylmethyl-2,3-dihydro-1H-1-benzazepine-4-carboxylate (0.37 g). To the solution was added 1N sodium hydroxide solution (7.5 ml), and the mixture was stirred at room temperature overnight and concentrated, which was neutralized with 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried with anhydrous magnesium sulfate. The solvent was evaporated to give 7-[4-(2-butoxyethoxy)phenyl]-1-cyclohexylmethyl-2,3-dihydro-1H-1-benzazepine-4-carboxylic acid (0.32 g) as yellow crystals.