Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:32][CH2:31][C:11]3([CH2:15][N:14](C(OCC4C=CC=CC=4)=O)[C@H:13]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:12]3)[CH2:10][CH2:9]2)[CH:5]=[C:4]([O:33][C@H:34]([C:39]2[CH:44]=[CH:43][C:42]([C:45]3[CH2:46][CH2:47][N:48]([S:51]([CH3:54])(=[O:53])=[O:52])[CH2:49][CH:50]=3)=[CH:41][C:40]=2[N:55]2[CH:59]=[CH:58][C:57]([CH3:60])=[N:56]2)[C:35]([F:38])([F:37])[F:36])[N:3]=1>CO.[Pd]>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:32][CH2:31][C:11]3([CH2:15][NH:14][C@H:13]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:12]3)[CH2:10][CH2:9]2)[CH:5]=[C:4]([O:33][C@H:34]([C:39]2[CH:44]=[CH:43][C:42]([CH:45]3[CH2:46][CH2:47][N:48]([S:51]([CH3:54])(=[O:53])=[O:52])[CH2:49][CH2:50]3)=[CH:41][C:40]=2[N:55]2[CH:59]=[CH:58][C:57]([CH3:60])=[N:56]2)[C:35]([F:37])([F:38])[F:36])[N:3]=1
Reactant: CCOC(=O)[C@@H]1CC2(CCN(c3cc(O[C@H](c4ccc(C5=CCN(S(C)(=O)=O)CC5)cc4-n4ccc(C)n4)C(F)(F)F)nc(N)n3)CC2)CN1C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)[C@@H]1CC2(CCN(c3cc(O[C@H](c4ccc(C5CCN(S(C)(=O)=O)CC5)cc4-n4ccc(C)n4)C(F)(F)F)nc(N)n3)CC2)CN1

Procedure:
A solution of (S)-2-benzyl 3-ethyl 8-(2-amino-6-((R)-2,2,2-trifluoro-1-(2-(3-methyl-1H-pyrazol-1-yl)-4-(1-(methylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate (290 mg, 0.340 mmol, Step 1) in MeOH (10 mL) was hydrogenated in an H-Cube apparatus using a 10% (w/w) Pd/C cartridge with a flow rate of 1.0 mL/min at RT. The resulting eluent was concentrated in vacuo and The product was purified by column chromatography using an Isco Gold reversed phase silica cartridge (100% CH2Cl2 to 90:9:1 CH2Cl2:MeOH:conc. NH4OH) to provide (S)-ethyl 8-(2-amino-6-((R)-2,2,2-trifluoro-1-(2-(3-methyl-1H-pyrazol-1-yl)-4-(1-(methylsulfonyl)piperidin-4-yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate.
Reaction SMILES: Cl[C:2]1[C:3]2[N:10]=[CH:9][S:8][C:4]=2[N:5]=[CH:6][N:7]=1.[NH2:11][CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+].Cl>CN(C)C=O.O>[N:10]1[C:3]2[C:2]([NH:11][CH2:12][CH2:13][C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=3)=[N:7][CH:6]=[N:5][C:4]=2[S:8][CH:9]=1
Reactant: NCCc1ccc(O)cc1
Reactant: Clc1ncnc2scnc12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Oc1ccc(CCNc2ncnc3scnc23)cc1
Temperature: 100 °C
Reaction time: 8 h
Yield: 23.4 %

Procedure:
7-Chlorothiazolo[5,4-d]pyrimidine (2.71 grams (g), 15.7 millimoles (mmol)) and tyramine (2.16 g, 15.7 mmol) were dissolved with magnetic stirring in N,N-dimethylformamide (DMF; 20 milliliters (mL)) in a 100 mL round bottom flask equipped with a reflux condenser and a dry nitrogen line at 25° C. To the solution was added potassium carbonate (K2CO3; 6.0 g, 43.4 mmol), and the mixture was heated at 100° C., then cooled to 25° C., and stirred overnight. The reaction was diluted with water (H2O; 150 mL), and then treated with 2 N hydrochloric acid (HCl) to adjust the pH to 6. The aqueous layer was washed repeatedly with EtOAc, and the pooled organic fractions were filtered and concentrated in vacuo to provide 4-[2-(thiazolo[5,4-d]pyrimidin-7-ylamino)-ethyl]-phenol (Compound 3; 1.0 g) as an amber powder: mp 161-168° C.; 1H NMR (DMSO-d6) δ 9.24 (s, 1H), 9.18 (s, 1H), 8.42 (s, 1H), 8.29 (br s, 1H), 7.04 (d, J=8.0 Hz, 2H), 6.67 (d, J=8.3 Hz, 2H), 3.65 (m, 2H), 2.81 (m, 2H); ESIMS m/z 273.1 ([M+H]+).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9](=[O:16])[NH:8][C:7]1=[O:17].[CH3:18][S:19](Cl)(=[O:21])=[O:20]>C(N(CC)CC)C>[CH3:18][S:19]([O:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9](=[O:16])[NH:8][C:7]1=[O:17])(=[O:21])=[O:20]
Reactant: O=c1[nH]c(=O)n(CCCCO)c2ccccc12
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCCCn1c(=O)[nH]c(=O)c2ccccc21
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred suspension of 1-[4-hydroxybutyl)-2,4(1H,3H)-quinazolinedione (778 mg) in chloroformtetrahydrofuran (40 ml, 1:1 V/V) was added methanesulfonyl chloride (0.57 ml), and triethylamine (1.85 ml) on an ice-bath. After stirring for 18 hours at room temperature, the reaction mixture was heated at 50° C. for 30 hours with stirring. After evaporation of the solvents the residue was diluted with ethyl acetate. The mixture was washed in turn with water and brine, dried over magnesium sulfate, and evaporated. 1-(4-Methanesulfonyloxybutyl)-2,4(1H,3H)-quinazolinedione (675 mg) as a crystal was obtained by recrystallization from methanol.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[C:13]#[C:14][C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1)=O)(C)(C)C.Cl>C(OCC)(=O)C>[N:17]1[CH:18]=[CH:19][CH:20]=[C:15]([C:14]#[C:13][C@@H:9]2[CH2:10][CH2:11][CH2:12][NH:8]2)[CH:16]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C#Cc1cccnc1
Agent: Cl
Solvent: CCOC(C)=O
Product: C(#C[C@@H]1CCCN1)c1cccnc1
Temperature: 2.5 °C
Reaction time: 0.17 h
Yield: 63.3 %

Procedure:
An ice-cold stirred solution (S)-N-(tert-butoxycarbonyl)-2-(2-(3-pyridyl)ethynyl)pyrrolidine (300 mg, 1.10 mmol) in ethyl acetate (25 mL) was treated with concentrated hydrochloric acid (1 mL). The mixture was stirred for 10 min at 0-5° C., then for 3 h at room temperature. The layers were separated and the pH of the aqueous portion was brought to 12 with 1N NaOH. The aqueous phase was extracted with ethyl acetate (2×25 mL). The combined organic phases were washed with brine (5 mL), then dried (MgSO4), filtered and concentrated by rotary evaporation. The crude product was purified by column chromatography on silica gel, eluting with chloroform/methanol (90/10, v/v). Selected fractions containing the product were concentrated via rotary evaporation to give 0.120 g of a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([O:8][CH2:9][CH:10]2[CH2:17][CH2:16][C:13]3([CH2:15][CH2:14]3)[CH2:12][CH2:11]2)[C:5]([C:18]([OH:20])=[O:19])=[CH:4][N:3]=1.C([O-])([O-])=O.[K+].[K+].[CH2:27](Br)[CH:28]=[CH2:29]>CN(C=O)C.O>[CH2:29]([O:19][C:18]([C:5]1[C:6]([O:8][CH2:9][CH:10]2[CH2:11][CH2:12][C:13]3([CH2:15][CH2:14]3)[CH2:16][CH2:17]2)=[N:7][C:2]([Cl:1])=[N:3][CH:4]=1)=[O:20])[CH:28]=[CH2:27]
Reactant: C=CCBr
Reactant: O=C(O)c1cnc(Cl)nc1OCC1CCC2(CC1)CC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C=CCOC(=O)c1cnc(Cl)nc1OCC1CCC2(CC1)CC2
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
To a solution of the 2-chloro-4-(spiro[2.5]oct-6-ylmethoxy)pyrimidine-5-carboxylic acid (490 mg) in DMF (2.9 mL) are added K2CO3 (4.4 mmol) and allyl bromide (7.4 mmol) at room temperature. After stirring at 50° C. for 0.5 h, the reaction mixture is cooling and diluted with H2O. The mixture is extracted with AcOEt. The organic extracts are washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The resulting residue is purified by silica gel column chromatography to give a crude title compound.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][C:7]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[CH:8][C:9]=1[N:10]([CH:20]1[CH2:25][CH2:24][N:23]([C:26]#[N:27])[CH2:22][CH2:21]1)[C:11]([CH:13]1[CH2:18][CH2:17][CH:16]([CH3:19])[CH2:15][CH2:14]1)=[O:12])=[O:4].O.O[Li].O>O1CCOCC1>[C:26]([N:23]1[CH2:22][CH2:21][CH:20]([N:10]([C:11]([CH:13]2[CH2:14][CH2:15][CH:16]([CH3:19])[CH2:17][CH2:18]2)=[O:12])[C:9]2[CH:8]=[C:7]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[S:6][C:5]=2[C:3]([OH:4])=[O:2])[CH2:25][CH2:24]1)#[N:27]
Reactant: COC(=O)c1sc(-c2ccccc2)cc1N(C(=O)C1CCC(C)CC1)C1CCN(C#N)CC1
Agent: [Li]O
Solvent: O
Solvent: C1COCCO1
Product: CC1CCC(C(=O)N(c2cc(-c3ccccc3)sc2C(=O)O)C2CCN(C#N)CC2)CC1
Temperature: 50 °C
Reaction time: 2 h
Yield: 79.1 %

Procedure:
3-[(1-cyano-piperidin-4-yl)-(4-methyl cyclohexanecarbonyl)-amino]-5-phenyl-thiophene-2-carboxylic acid methyl ester (150 mg, 0.32 mmol) was dissolved in a 4:1 mixture of dioxane:H2O (3.2 ml) and treated with LiOH.H2O (20 mg, 0.48 mmol). After 2 hours of stirring at 50° C., the solvents were removed and then partitioned between 5 ml of H2O acidified to pH 4 and 5 ml of EtOAc. The organic layer was separated and the aqueous phase as washed twice with ethyl acetate (2×5 mL). The combined ethyl acetate layer was dried (Na2SO4) and concentrated. The residue was purified by silica gel column chromatography using (5% MeOH/CH2Cl2) to provide 3-[(1-Cyano-piperidin-4-yl)-(4-methyl-cyclohexanecarbonyl)-amino]-5-phenyl-thiophene-2-carboxylic acid (114.3 mg, 78% yield) as pale green foam. 1H NMR (DMSO-d6, 400 MHz): 7.80 (m, 2H), 7.45 (m, 4H), 4.44 (m, 1H), 3.35 (m, 2H), 3.13 (m, 2H), 1.96 (t, 1H), 1.88 (d, 1H), 1.75 (m, 1H), 1.70-1.40 (m, 6H), 1.20 (m, 3H), 0.70 (d, 3H), 0.60 (m, 2H).
Reaction SMILES: Cl[C:2]1[C:11]([CH2:12][S:13][C:14]2[N:19]=[C:18]([OH:20])[CH:17]=[C:16]([CH3:21])[N:15]=2)=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[NH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1.O>CS(C)=O>[CH3:21][C:16]1[N:15]=[C:14]([S:13][CH2:12][C:11]2[C:2]([N:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)=[N:3][C:4]3[C:9]([CH:10]=2)=[CH:8][CH:7]=[CH:6][CH:5]=3)[N:19]=[C:18]([OH:20])[CH:17]=1
Reactant: Cc1cc(O)nc(SCc2cc3ccccc3nc2Cl)n1
Reactant: C1CCNCC1
Solvent: CS(C)=O
Solvent: O
Product: Cc1cc(O)nc(SCc2cc3ccccc3nc2N2CCCCC2)n1
Temperature: 90 °C
Yield: 60.8 %

Procedure:
A mixture of 2-{[(2-chloroquinolin-3-yl)methyl]sulfanyl}-6-methylpyrimidin-4-ol (0.5 g, 1.57 mmol) and piperidine (1.33 g, 15.7 mmol) in DMSO was heated overnight at 90° C. Water was then added, and the product was extracted in dichloromethane and back washed with water. The organic layer was separated, dried, and evaporated to provide the titled product as a beige solid (0.35 g, 61% yield); 1H NMR (400 MHz, DMSO-d6): δ 2.09 (s, 3H), 2.31 (s, 3H), 4.95 (s, 2H), 6.04 (bs, 1H), 7.87 (t, J=7.8, 15.0 Hz, 1H), 8.08 9 m, 2H), 8.26 (d, J=8.1 Hz, 1H), 8.48 (d, J=8.2 Hz, 1H), 9.00 (d, J=8.2 Hz, 1H); M+ 366.5.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:6]=1[Cl:12].[OH:13][C:14]1[CH:15]=[C:16]([CH2:22][CH:23]([CH3:29])[C:24]([O:26]CC)=[O:25])[CH:17]=[CH:18][C:19]=1OC>>[Cl:12][C:6]1[CH:7]=[C:8]([Cl:11])[CH:9]=[CH:10][C:5]=1[O:4][CH2:3][CH2:2][O:13][C:14]1[CH:15]=[C:16]([CH2:22][CH:23]([CH3:29])[C:24]([OH:26])=[O:25])[CH:17]=[CH:18][CH:19]=1
Reactant: CCOC(=O)C(C)Cc1ccc(OC)c(O)c1
Reactant: Clc1ccc(OCCBr)c(Cl)c1
Product: CC(Cc1cccc(OCCOc2ccc(Cl)cc2Cl)c1)C(=O)O

Procedure:
Using 1-(2-bromoethoxy)-2,4-dichlorobenzene and ethyl 3-(3-hydroxy-4-methoxyphenyl)-2-methylpropanoate, the title compound was obtained in the same manner as described in Example 33c).
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3](=O)[CH2:4][C:5]([C:7]1[S:8][C:9]2[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:10]=2[N:11]=1)=O.Cl.[S:22]([C:26]1[CH:31]=[CH:30][C:29]([NH:32][NH2:33])=[CH:28][CH:27]=1)(=[O:25])(=[O:24])[NH2:23]>>[CH3:17][O:16][C:14]1[CH:13]=[CH:12][C:10]2[N:11]=[C:7]([C:5]3[N:32]([C:29]4[CH:28]=[CH:27][C:26]([S:22]([NH2:23])(=[O:25])=[O:24])=[CH:31][CH:30]=4)[N:33]=[C:3]([C:2]([F:20])([F:19])[F:1])[CH:4]=3)[S:8][C:9]=2[CH:15]=1
Reactant: COc1ccc2nc(C(=O)CC(=O)C(F)(F)F)sc2c1
Reactant: NNc1ccc(S(N)(=O)=O)cc1
Agent: Cl
Product: COc1ccc2nc(-c3cc(C(F)(F)F)nn3-c3ccc(S(N)(=O)=O)cc3)sc2c1

Procedure:
The procedure of Example 9 was repeated using 4,4,4-trifluoro-1-(6-methoxybenzothiazol-2-yl)butane-1,3-dione and 4-sulfamoylphenylhydrazine hydrochloride as the starting materials to obtain 4-[5-(6-methoxybenzothiazol-2-yl)-3-trifluoromethyl-1H-pyrazol-1-yl]benzenesulfonamide. NMR(CDCl3) δ: 3.88 (3H, s), 5.03 (2H, bs), 7.11 (1H, dd, J=2.3 Hz, 8.9 Hz), 7.20 (1H, s), 7.31 (2H, d, J=2.3 Hz), 7.68 (2H, d, J=8.6 Hz), 7.83 (1H, d, J=8.9 Hz), 8.01 (2H, d, J=8.6 Hz); mp 236-237° C. (ethyl acetate-isooctane)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:14]=[C:13](F)[N:12]=[CH:11][N:10]=2)[C:5](=[O:16])[N:4]2[C:17]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=3)([CH3:21])[NH:18][C:19](=[O:20])[C:3]=12.[C:29]([NH-:31])#[N:30].[Na+].O.Cl>CN1CCCC1=O>[Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[N:10]=[CH:11][N:12]=[C:13]([NH:31][C:29]#[N:30])[CH:14]=2)[C:5](=[O:16])[N:4]2[C:17]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=3)([CH3:21])[NH:18][C:19](=[O:20])[C:3]=12
Reactant: N#C[NH-]
Reactant: CC1(c2cccc(Cl)c2)NC(=O)c2c(Cl)cc(Nc3cc(F)ncn3)c(=O)n21
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CN1CCCC1=O
Product: CC1(c2cccc(Cl)c2)NC(=O)c2c(Cl)cc(Nc3cc(NC#N)ncn3)c(=O)n21
Temperature: 50 °C
Reaction time: 2 h

Procedure:
To a solution of 8-chloro-3-(3-chlorophenyl)-6-((6-fluoropyrimidin-4-yl)amino)-3-methyl-2,3-dihydroimidazo[1,5-a]pyridine-1,5-dione (3, 100 mg, 0.24 mmol) in N-methyl-2-pyrrolidinone (4 mL) was added sodium hydrogencyanamide (46 mg, 0.72 mmol). The reaction was stirred at 50° C. for 2 h. The resulting mixture was cooled to room temperature, poured into water and acidified to pH=5.5 with concentrated hydrochloric acid. The mixture was filtered. The solid crude was purified via HPLC to afford N-(6-((8-chloro-3-(3-chlorophenyl)-3-methyl-1,5-dioxo-1,2,3,5-tetrahydroimidazo[1,5-a]pyridin-6-yl)amino)pyrimidin-4-yl)cyanamide (Cpd. No. 184).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7](=O)[CH2:8][C:9]([O:11]CC)=O)=[CH:3][CH:2]=1.Cl.Cl.[NH2:17][C:18]1[NH:23][CH2:22][CH2:21][CH2:20][N:19]=1.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[N:1]1[CH:2]=[CH:3][C:4]([C:7]2[N:17]=[C:18]3[NH:23][CH2:22][CH2:21][CH2:20][N:19]3[C:9](=[O:11])[CH:8]=2)=[CH:5][CH:6]=1
Reactant: NC1=NCCCN1
Reactant: CCOC(=O)CC(=O)c1ccncc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: O=c1cc(-c2ccncc2)nc2n1CCCN2
Yield: 75.4 %

Procedure:
A mixture of 8.98 g (46.5 mmol) of ethyl 3-(4-pyridyl)-3-oxopropionate and 8.0 g (46.5 mmol) of 2-amino-3,4,5,6-tetrahydropyrimidine dihydrochloride (prepared according to J. Org. Chem. 1955, 20, 829.) and 19.3 g (139.5 mmol) of potassium carbonate in 60 ml of ethanol was heated at reflux temperature during 18 h. The solution cooled, was evaporated to remove solvent. The residue was treated with water and extracted with dichloromethane. The extracts were dried and evaporated to give 8.0 g (75%) of product as a white powder. Mp: 219° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([CH3:13])[CH2:10][C@@H:9]1[C:14]([OH:16])=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].CI.[C:19](=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([CH3:13])[CH2:10][C@@H:9]1[C:14]([O:16][CH3:19])=[O:15])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: C[C@H]1C[C@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC#N
Product: COC(=O)[C@H]1C[C@H](C)CN1C(=O)OC(C)(C)C

Procedure:
(2R,4S)-4-Methylpyrrolidine-2-carboxylic acid described in J. Chem. Soc. C, pp. 514–522 (1971) is reacted with di-tert-butyl dicarbonate to give (2R,4S)-1-tert-butoxycarbonyl-4-methylpyrrolidine-2-carboxylic acid. (2R,4S)-1-tert-Butoxycarbonyl-4-methylpyrrolidine-2-carboxylic acid is reacted with methyl iodide in the presence of potassium carbonate in acetonitrile solvent to give methyl (2R,4S)-1-tert-butoxycarbonyl-4-methylpyrrolidine-2-carboxylate. Methyl (2R,4S)-1-tert-butoxycarbonyl-4-methylpyrrolidine-2-carboxylate is reduced with lithium borohydride to give (2R,4S)-1-tert-butoxycarbonyl-2-hydroxymethyl-4-methylpyrrolidine. (2R,4S)-1-tert-Butoxycarbonyl-2-hydroxymethyl-4-methylpyrrolidine is reacted with 4N hydrogen chloride-dioxane to give (2R,4S)-2-hydroxymethyl-4-methylpyrrolidine hydrochloride. (2R,4S)-2-Hydroxymethyl-4-methylpyrrolidine hydrochloride is reacted with acrylonitrile to give 3-[(2R,4S)-2-hydroxymethyl-4-methylpyrrolidin-1-yl]propionitrile. In the same manner as in Example 1b (e) and using 3-[(2R,4S)-2-hydroxymethyl-4-methylpyrrolidin-1-yl]propionitrile and N,N-diethyl-2,3-dimethylbenzamide, 3-(2-[(2R,4S)-2-hydroxymethyl-4-methylpyrrolidin-1-yl]ethyl)-5-methyl-2H-isoquinolin-1-one is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C@@H:12]2[CH2:17][CH2:16][CH2:15][CH2:14][C@H:13]2[C:18]([NH2:20])=[O:19])(=[O:10])=[O:9])=[CH:4][CH:3]=1.Br[CH2:22][C:23]1[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[CH:25][CH:24]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH2:22][C:23]2[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[CH:25][CH:24]=2)[C@@H:12]2[CH2:17][CH2:16][CH2:15][CH2:14][C@H:13]2[C:18]([NH2:20])=[O:19])(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: N#Cc1ccc(CBr)cc1
Reactant: NC(=O)[C@@H]1CCCC[C@H]1NS(=O)(=O)c1ccc(Cl)cc1
Product: N#Cc1ccc(CN([C@@H]2CCCC[C@H]2C(N)=O)S(=O)(=O)c2ccc(Cl)cc2)cc1
Yield: 43 %

Procedure:
The titled compound was prepared in 43% yield from trans-2-(4-chlorobenzenesulfonylamino)-cyclohexanecarboxylic acid amide and 4-bromomethyl-benzonitrile according to the procedure described in Example 11: 1H NMR (DMSO-d6) δ 7.71(m, 4 H), 7.53 (m, 4 H), 7.29 (s, 1 H), 6.76 (s, 1 H), 4.44 (AB2,2 H,Δv=16,Jab=84 Hz), 3.96 (m, 1 H), 1.80 (m, 1 H), 1.57 (m, 3 H), 1.17 (m, 5 H); MS m/e 432.01 (M+H)+.
Reaction SMILES: C(O)CO.[Br:5][C:6]1[N:10]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[C:9]([CH:19]=O)=[C:8]([C:21]([O:23]CC)=O)[CH:7]=1.O.[NH2:27][NH2:28]>O>[Br:5][C:6]1[N:10]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[C:9]2[CH:19]=[N:27][NH:28][C:21](=[O:23])[C:8]=2[CH:7]=1
Reactant: CCOC(=O)c1cc(Br)n(COCC[Si](C)(C)C)c1C=O
Reactant: NN
Solvent: O
Solvent: OCCO
Product: C[Si](C)(C)CCOCn1c(Br)cc2c(=O)[nH]ncc21
Temperature: 125 °C
Reaction time: 2 h
Yield: 73.6 %

Procedure:
To 2.1 L of ethylene glycol solution containing 430 g (1.14 mol) of ethyl 5-bromo-2-formyl-1-(2-trimethylsilylethoxymethyl)-1H-pyrrol-3-carboxylate obtained in Reference example 15-(f) was added 290 ml (5.98 mol) of hydrazine monohydrate at 60° C., and the mixture was stirred at 125° C. for 2 hours. After completion of the reaction, the reaction mixture was poured into water, and precipitated solid was collected by filtration and washed with water. The obtained crude solid was recrystallized from 3 L of a mixed solvent (toluene/cyclohexane=1/1 (V/V)) to obtain 289 g of the title compound as a beige solid. (Yield: 74%)
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:10]([Br:11])=[C:9]([Br:12])[N:8]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:7]=1[CH2:19]Br)=[O:5])[CH3:2].[CH2:21]([O:23][C:24](=[O:34])[CH2:25][NH:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH3:22]>>[CH2:1]([O:3][C:4]([C:6]1[C:10]([Br:11])=[C:9]([Br:12])[N:8]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:7]=1[CH2:19][N:26]([C:27]([O:29][C:30]([CH3:31])([CH3:33])[CH3:32])=[O:28])[CH2:25][C:24]([O:23][CH2:21][CH3:22])=[O:34])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(Br)c(Br)n(-c2ccccc2)c1CBr
Reactant: CCOC(=O)CNC(=O)OC(C)(C)C
Product: CCOC(=O)CN(Cc1c(C(=O)OCC)c(Br)c(Br)n1-c1ccccc1)C(=O)OC(C)(C)C

Procedure:
Prepared in analogy to that of Example 1(c) from 4,5-dibromo-2-bromomethyl-1-phenyl-1H-pyrrole-3-carboxylic acid ethyl ester and tert-butoxycarbonylamino-acetic acid ethyl ester. The title compound, ESI MS (m/z): 609 (M+Na+).
Reaction SMILES: [C:1]([O:4][C:5]1[C:10]2[CH2:11][CH2:12][CH2:13][C:14](=[S:16])[NH:15][C:9]=2[CH:8]=[CH:7][CH:6]=1)(=[O:3])[CH3:2].F[B-](F)(F)F.[CH3:22][O+](C)C.O>C(Cl)Cl>[C:1]([O:4][C:5]1[C:10]2[CH2:11][CH2:12][CH2:13][C:14]([S:16][CH3:22])=[N:15][C:9]=2[CH:8]=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: C[O+](C)C
Reactant: CC(=O)Oc1cccc2c1CCCC(=S)N2
Agent: F[B-](F)(F)F
Solvent: O
Solvent: ClCCl
Product: CSC1=Nc2cccc(OC(C)=O)c2CCC1
Yield: 91.8 %

Procedure:
To a solution of 1,3,4,5-tetrahydro-6-acetoxy-2H-1-benzazepin-2-thione (235 mg, 1.0 mmol) in 25 mL of CH2Cl2 was added at 0° 295 mg (2.0 mmol) of trimethyloxonium tetrafluoroborate. After stirring at room temperature for about 30 min. water was added and the CH2Cl2 layer was separated. Drying over Na2SO4 and removal of the solvent gave 229 mg of 4,5-dihydro-6-acetoxy-2-methylthio-3H-benzazepine.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([C:15]2[S:16][CH:17]=[C:18]([CH2:20][O:21]S(C)(=O)=O)[N:19]=2)([CH3:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:26][S:27]([C:30]1[CH:35]=[CH:34][C:33](O)=[CH:32][CH:31]=1)(=[O:29])=[O:28].C([O-])([O-])=O.[Cs+].[Cs+]>C(#N)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([C:15]2[S:16][CH:17]=[C:18]([CH2:20][O:21][C:33]3[CH:34]=[CH:35][C:30]([S:27]([CH3:26])(=[O:29])=[O:28])=[CH:31][CH:32]=3)[N:19]=2)([CH3:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CS(=O)(=O)c1ccc(O)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(C)(c2nc(COS(C)(=O)=O)cs2)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCC(C)(c2nc(COc3ccc(S(C)(=O)=O)cc3)cs2)CC1
Temperature: 40 °C

Procedure:
A mixture of 4-(4-methanesulfonyloxymethyl-thiazol-2-yl)-4-methyl-piperidine-1-carboxylic acid tert-butyl ester (0.2 g, 0.5 mmol), 4-methanesulfonyl-phenol (86 mg, 0.5 mmol) and Cs2CO3 (170 mg, 0.52 mmol) in acetonitrile (4 mL) was heated at 40° C. overnight. After cooling, the solid was filtered through a pad of celite. The filtrate was concentrated in vacuo. The residue was purified on silica gel (EtOAc-hexanes, 1:1) to afford the desired product. 1H NMR (CDCl3): δ 7.83 (2H, m), 7.23 (1H, s), 7.09 (2H, m), 5.2 (2H, s), 3.64-3.54 (2H, m), 3.3˜3.24 (2H, m), 2.99 (3H, s), 2.2˜2.1 (2H, m), 1.72-1.64(2H, m), 1.41 (9H, s), 1.36 (3H, s).
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][C:5]([N+]([O-])=O)=[CH:4][C:3]=1[S:11]([OH:14])(=[O:13])=[O:12].OC1C2C(=C(S(O)(=O)=O)C([NH2:26])=CC=2)C=C(S(O)(=O)=O)C=1>O>[S:11]([OH:14])(=[O:13])([C:3]1[CH:4]=[CH:5][C:6]([NH2:26])=[CH:7][CH:2]=1)=[O:12]
Reactant: Nc1ccc2c(O)cc(S(=O)(=O)O)cc2c1S(=O)(=O)O
Reactant: Nc1ccc([N+](=O)[O-])cc1S(=O)(=O)O
Solvent: O
Product: Nc1ccc(S(=O)(=O)O)cc1
Reaction time: 1 h

Procedure:
2-Amino-5-nitro-benzenesulfonic acid is diazotized and coupled neutrally to I acid. 43 mmol of this dye are dissolved in 200 ml water and indirectly diazotized. After stirring for 1 hour, the excess nitrous acid is removed with amidosulfonic acid and a solution of 43 mmol 4-hy-droxy-7-aminonaphthalene-2,8-disulfonic acid in 200 ml water is added. Coupling is completed overnight at pH 8-9, the dye is filtered under suction and the sulfo group is split off by boiling for 12 h in a 1:1 mixture of water and N-methyl pyrrolidone containing 60 ml concentrated hydrochloric acid. This dye is diazdtized and added dropwise to a solution in 100 ml water of 7.2 mmol of a dye obtained by acidic coupling of p-sulfanilic acid onto 4-amino-5-hydroxynaphthalene-1,3-disulfonic acid. After stirring overnight, the dye is precipitated by addition of acetone, optionally dissolved and allowed to crystallize once more and then washed with aqueous acetone. 0.1 g dye are dissolved in 9.9 g polyvinyl alcohol (PVAL) (Mowiol®28-99, a product of Hoechst AG) and 190 ml water and a 500μ thick layer is cast from this solution. After evaporation of the water, an approx. 50μ thick dark-blue film is obtained. The film is stretched by 500% at 130° C. The value is 15.3 at 650 nm. If the following acids are used instead of 4-amino-5-hydroxynaphthalene-,1, 3-disulfonic acid, the following results are obtained:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[CH:4]([C:9]1[NH:10][C:11]2[C:16]([C:17]=1[CH2:18][CH2:19][N:20]=[N+:21]=[N-:22])=[CH:15][CH:14]=[C:13]([F:23])[CH:12]=2)[C:5]([O:7][CH3:8])=[O:6].[CH3:25][O-].[Na+]>CO>[CH3:1][O:2][C:3](=[O:24])[C:4]([C:9]1[NH:10][C:11]2[C:16]([C:17]=1[CH2:18][CH2:19][N:20]=[N+:21]=[N-:22])=[CH:15][CH:14]=[C:13]([F:23])[CH:12]=2)([CH3:25])[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)C(C(=O)OC)c1[nH]c2cc(F)ccc2c1CCN=[N+]=[N-]
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)C(C)(C(=O)OC)c1[nH]c2cc(F)ccc2c1CCN=[N+]=[N-]
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-[3-(2-azidoethyl)-6-fluoro-1H-indol-2-yl]-propanedioic acid dimethyl ester (37 mmol) in dry MeOH (0.25 L) at 0° C. under argon was added a solution of 25% NaOMe in MeOH (8.56 mL, 37.4 mmol). The mixture was stirred for 30 min at 0° C. Mel (3.56 mL, 56.6 mmol) was added. The mixture was refluxed for 42 h, cooled, and concentrated. The residue was partitioned between H2O and Et2O. The Et2O extracts were washed with H2O , dried, and concentrated to an oil. This oil was purified by silica chromatography to give the title compound: TLC Rf=0.50 (CH2Cl2); MS (ESI+) m/z 371.1; 1H NMR (CDCl3, 300 MHz) δ 9.63 (1H), 7.44 (1H), 7.05 (1H), 6.97 (1H), 3.82 (6H), 3.44 (2H), 2.94 (2H), 1.93 (3H).