Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH2:20][CH2:21][CH2:22][NH:23][CH2:24][C:25]3[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=3)[C:9]=2[C:10]=1[CH2:11][N:12]=[N+]=[N-])=[O:5])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>C1COCC1.C(OCC)(=O)C>[CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH2:20][CH2:21][CH2:22][NH:23][CH2:24][C:25]3[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=3)[C:9]=2[C:10]=1[CH2:11][NH2:12])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1oc2cccc(OCCCNCc3cccnc3)c2c1CN=[N+]=[N-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)c1oc2cccc(OCCCNCc3cccnc3)c2c1CN
Temperature: 70 °C
Yield: 32.7 %

Procedure:
3-Azidomethyl-4-{3-[(pyridin-3-ylmethyl)-amino]-propoxy}-benzofuran-2-carboxylic acid ethyl ester (49 mg) and triphenylphosphine (50 mg) were dissolved in THF (2.5 ml). To the solution was added water (0.3 ml) and the mixture was heated to 70° C. overnight. The reaction mixture was diluted with ethyl acetate (5 ml) and washed with brine (5 ml), then dried over anhydrous sodium sulfate. The filtrate was concentrated in vacuo and the residue was purified by silica gel chromatography developed by dichloromethane-methanol giving 3-aminomethyl-4-{3-[(pyridin-3-ylmethyl)-amino]-propoxy}-benzofuran-2-carboxylic acid ethyl ester as a colorless oil (15 mg). FAB-MS: m/z 384 (MH+); 1H-NMR (CDCl3): δ 1.45 (3H, t, J=7.3 Hz), 2.12 (2H, quintet, J=6.3 Hz), 2.90 (2H, t, J=6.6 Hz),3.85 (2H, s), 4.24 (2H, t, J=6.3 Hz), 4.31 (2H, s), 4.45 (2H, q, J=7.3 Hz), 6.68 (1H, d, J=8.3 Hz), 7.16 (1H, d, J=8.3 Hz), 7.21 (1H, dd, J=4.9 Hz, 7.9 Hz), 7.35 (1H, t, J=8.3 Hz), 7.68 (1H, d, J=7.9 Hz), 8.48 (1H, dd, J=1.7 Hz, 4.9 Hz), 8.56 (1H, d, J=1.7 Hz).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:4](Cl)[N:3]=1.[Cl:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[NH:24][NH2:25]>C(N(CC)CC)C>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:4]([NH:25][NH:24][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[Cl:17])[N:3]=1
Reactant: NNc1ccccc1Cl
Reactant: Clc1nc(Cl)c2ncn(C3CCCC3)c2n1
Solvent: CCN(CC)CC
Product: Clc1nc(NNc2ccccc2Cl)c2ncn(C3CCCC3)c2n1

Procedure:
2-Chloro-6-(2-chlorophenylhydrazino)-9-cyclopentylpurine is prepared from 2,6-dichloro-9-cyclopentylpurine, 2-chlorophenylhydrazine, and triethylamine essentially as described above in Example 1, Scheme A, step b.
Reaction SMILES: P(OCC)(OCC)(O[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][CH:6]=1)=O.[CH:18]([C:20]1[C:21](B(O)O)=[CH:22][S:23][CH:24]=1)=[O:19].ClC1C=CC(CC2SC(C=O)=CC=2)=CC=1>>[Cl:11][C:8]1[CH:7]=[CH:6][C:5]([CH2:4][C:21]2[C:20]([CH:18]=[O:19])=[CH:24][S:23][CH:22]=2)=[CH:10][CH:9]=1
Reactant: O=Cc1cscc1B(O)O
Reactant: CCOP(=O)(OCC)OCc1ccc(Cl)cc1
Agent: O=Cc1ccc(Cc2ccc(Cl)cc2)s1
Product: O=Cc1cscc1Cc1ccc(Cl)cc1
Yield: 58 %

Procedure:
The title compound was synthesized from 4-chlorobenzyl diethyl phosphate and 4-formylthiophen-3-ylboronic acid using the conditions to synthesize 5-(4-chlorobenzyl)thiophene-2-carbaldehyde (Example 1.1.a). Purification by prep-TLC (50% heptane/DCM, double elution) yielded 266 mg of 4-(4-chlorobenzyl)thiophene-3-carbaldehyde (58%). 1H NMR (400 MHz, CDCl3) δ ppm 4.25 (s, 2H), 6.84-6.88 (m, 1H), 7.14-7.19 (m, 2H), 7.25-7.30 (m, 2H), 8.12 (d, J=3.17 Hz, 1H), 9.96 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 185.52, 140.84, 140.28, 140.02, 138.06, 132.10, 130.31, 128.58, 124.75, 34.70; LCMS-MS (ESI+) 236.68 (M+H).
Reaction SMILES: [NH:1](C(OCC1C2C(=CC=CC=2)C2C1=CC=CC=2)=O)[C@H:2]([C:24]([O:26][CH3:27])=[O:25])[CH2:3][S:4][C:5]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C(NCC)C>C(#N)C>[NH2:1][C@H:2]([C:24]([O:26][CH3:27])=[O:25])[CH2:3][S:4][C:5]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: COC(=O)[C@H](CSC(c1ccccc1)(c1ccccc1)c1ccccc1)NC(=O)OCC1c2ccccc2-c2ccccc21
Solvent: CCNCC
Solvent: CC#N
Product: COC(=O)[C@@H](N)CSC(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 0.5 h

Procedure:
To a solution of Fmoc-L-Cys(Trt)-OMe (2.58 g, 4.30 mmol) in acetonitrile (20.0 mL) was added diethylamine (20.0 mL). After 30 minutes, the mixture was concentrated in vacuo. The residue was dissolved in acetonitrile (3×10 mL) and concentrated in vacuo to afford L-Cys(Trt)-OMe as crude product which was used without purification.
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][CH2:11][N:12]1[C:17](=[O:18])[C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:15][N:14]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:13]1=[O:32])=O)(C)(C)C.Cl>C(OCC)(=O)C>[NH2:8][CH2:9][CH2:10][CH2:11][N:12]1[C:17](=[O:18])[C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:15][N:14]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:13]1=[O:32]
Reactant: CC(C)(C)OC(=O)NCCCn1c(=O)c(-c2ccccc2)cn(Cc2ccccc2)c1=O
Agent: Cl
Solvent: CCOC(C)=O
Product: NCCCn1c(=O)c(-c2ccccc2)cn(Cc2ccccc2)c1=O
Temperature: 25 °C

Procedure:
To a solution of 3-(3-tert-butoxycarbonylaminopropyl)-1-benzyl-5-phenyl-1H-pyrimidine-2,4-dione (160 mg, 0.37 mmol) in ethyl acetate (20 mL) at −78° C. was added HCl (g) for 5 min. The reaction was warmed to ambient temperature, the excess HCl removed by bubbling through nitrogen gas and then the reaction concentrated to provide the hydrochloride salt of 3-(3-aminopropyl)-1-benzyl-5-phenyl-1H-pyrimidine-2,4-dione as a white solid.
Reaction SMILES: [O:1]1[C:5]([CH2:6][C:7]([OH:9])=O)=[CH:4][CH:3]=[N:2]1.C1C=NC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[CH3:29][O:30][C:31](=[O:45])[C:32]1[CH:37]=[CH:36][C:35]([NH:38][CH:39]([CH2:42][CH3:43])[CH2:40][CH3:41])=[C:34]([NH2:44])[CH:33]=1>CN(C=O)C.O.C(Cl)CCl>[CH3:29][O:30][C:31](=[O:45])[C:32]1[CH:37]=[CH:36][C:35]([NH:38][CH:39]([CH2:40][CH3:41])[CH2:42][CH3:43])=[C:34]([NH:44][C:7](=[O:9])[CH2:6][C:5]2[O:1][N:2]=[CH:3][CH:4]=2)[CH:33]=1
Reactant: O=C(O)Cc1ccno1
Reactant: CCC(CC)Nc1ccc(C(=O)OC)cc1N
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CCC(CC)Nc1ccc(C(=O)OC)cc1NC(=O)Cc1ccno1
Reaction time: 16 h
Yield: 54.9 %

Procedure:
To a solution of 0.71 g of Isoxazol-5-yl-acetic acid in 15 ml of dry DMF 0.38 g of HOAT, 1.29 g of EDC and 3 ml of DIPEA were added at 0° C. After 30 min 1.32 g of 3-amino-4-(1-ethyl-propylamino)-benzoic acid methyl ester were added and the reaction was stirred at it for 16 h. The reaction was then poured into water and extracted with ethyl acetate three times. The combined organic phases were washed with saturated aqueous sodium bicarbonate solution and brine, dried over magnesium sulphate and concentrated. The crude product was purified by precipitation from diisoprpylether to yield 1.06 g (55%) of 4-(1-Ethyl-propylamino)-3-(2-isoxazol-5-yl-acetylamino)-benzoic acid methyl ester.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([N:10]3[C:14]4=[N:15][C:16]([CH:19]=[CH2:20])=[CH:17][CH:18]=[C:13]4[N:12]=[CH:11]3)=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[C:21](O)(=[O:23])[CH3:22].Cl.C(N=C=NCCCN(C)C)C>CN(C)C1C=CN=CC=1.ClCCl>[C:21]([N:1]1[C:9]2[C:4](=[CH:5][C:6]([N:10]3[C:14]4=[N:15][C:16]([CH:19]=[CH2:20])=[CH:17][CH:18]=[C:13]4[N:12]=[CH:11]3)=[CH:7][CH:8]=2)[CH2:3][CH2:2]1)(=[O:23])[CH3:22]
Reactant: C=Cc1ccc2ncn(-c3ccc4c(c3)CCN4)c2n1
Reactant: CC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: C=Cc1ccc2ncn(-c3ccc4c(c3)CCN4C(C)=O)c2n1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of 3-(2,3-dihydro-1H-indol-5-yl)-5-vinyl-3H-imidazo[4,5-b]pyridine (Intermediate 10.1) (150.0 mg, 0.57 mmol), glacial acetic acid (39.3 μl, 0.69 mmol), N-ethyl-N′-(3-dimethylaminopropyl)carbodiimide hydrochloride (175.4 mg, 0.91 mmol), 4-dimethylaminopyridine (419.2 mg, 3.43 mmol), and dichloromethane (10 ml) is stirred for 24 h at ambient temperature. The mixture is successively extracted with saturated aqueous ammonium chloride and saturated aqueous sodium bicarbonate. The organic layer is dried over sodium sulfate and concentrated in vacuo to render 139.1 mg (80%) of the respective amide. HPLC (over 10 min 10-85% MeCN/100 mM aq. NaOAc): 99% purity, tR 6.43 min (tR(SM) 6.64 min). GC/MS: 96% purity, tR 13.98 min, m/z 304 (M, 58), 262 (100), 207 (62) Finnegan LCQ.
Reaction SMILES: C1(CO[C:9]2[CH:10]=[CH:11][C:12](C(=O)CCl)=[C:13]3[C:18]=2[NH:17][C:16](=[O:19])[CH:15]=[CH:14]3)C=CC=CC=1.CB1N2CCC[C@@H]2C(C2C=CC=CC=2)(C2C=CC=CC=2)O1>C1(C)C=CC=CC=1.C1COCC1>[NH:17]1[C:18]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:14]=[CH:15][C:16]1=[O:19]
Reactant: O=C(CCl)c1ccc(OCc2ccccc2)c2[nH]c(=O)ccc12
Agent: CB1OC(c2ccccc2)(c2ccccc2)[C@H]2CCCN12
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: O=c1ccc2ccccc2[nH]1
Temperature: 1 °C

Procedure:
A dry 3 L, 4-necked flask equipped with a mechanical stirrer, thermometer, addition funnel and refluxing condenser is charged with 50 g 8-(phenylmethoxy)-5-(α-chloroacetyl)-(1H)-quinolin-2-one and 600 mL dry THF under N2. Then 15 mL of a 1 molar solution of (R)-tetrahydro-1-methyl-3,3-diphenyl-(1H,3H)-pyrrolo[1,2-c][1,3,2]-oxazaborole in toluene was added. The mixture was cooled to an internal temperature of 0-2° C. and while maintaining an internal temperature of 0-2° C., 153 mL of a 1 molar solution of BH3 in THF was added over 1-2 hours. The reaction was stirred for another hour at an internal temperature of 0-2° C. and then quenched by addition of 65 mL methanol. The resulting solution was warmed to 25° C. and concentrated to a volume of 250 mL (50° C./200 mbar). To this concentrate was added a mixture of 713 mL water and 37 g HCl 37%. During the addition 8-(phenylmethoxy)-5-((R)-2-chloro-1-hydroxy-ethyl)-(1H)-quinolin-2-one precipitated as a nearly colourless precipitation. The resulting suspension was stirred for 30 minutes at 25° C., filtrated and washed with 220 mL water in several portions. Drying in a vacuum drier at 50° C. for 12 hours resulted in 47.41 g of 8-(phenylmethoxy)-5-((R)-2-chloro-1-hydroxy-ethyl)-(1H-quinolin-2-one as a slightly yellowish powder.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][CH2:11][CH2:12][OH:13])[CH:5]=[CH:6][C:7]=1[Cl:8].[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][CH2:11][CH:12]=[O:13])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: OCCCCc1ccc(Cl)c(Cl)c1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: O=CCCCc1ccc(Cl)c(Cl)c1
Reaction time: 1 h
Yield: 66.2 %

Procedure:
To a solution of Intermediate 20A (3.5 g, 16 mmol) in DCM (100 mL) was added silica gel (2.5 g) followed by pyridinium chlorochromate (4.13 g, 19.2 mmol). After stirring for 1 h, the reaction mixture was filtered and the filtrate was diluted with water and the layers were separated. The aqueous layer was further extracted with dichloromethane twice. The combined organic layers were washed with 1N HCl twice, water twice, brine twice, dried over MgSO4, filtered and concentrated. The residue was purified by ISCO chromatography (EtOAc/Hexanes 0-70%, column 40 g) to give Intermediate 20B (2.3 g, 66%) as an oil. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.80-1.92 (2H, m), 2.36-2.43 (2H, m), 2.50-2.60 (2H, m), 6.94 (1H, dd, J=8.3, 2.0 Hz), 7.25-7.32 (1H, m), 7.28 (1H, d, J=8.3 Hz), 9.70 (1H, s).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([C:12]2[CH:49]=[CH:48][C:15]([CH2:16][O:17][C:18]3[C:23]([C:24]([F:27])([F:26])[F:25])=[CH:22][CH:21]=[CH:20][C:19]=3[C:28]3[N:33]=[C:32]([N:34]4[C:38]([C:39]([F:42])([F:41])[F:40])=[C:37]([C:43]([O:45]CC)=[O:44])[CH:36]=[N:35]4)[CH:31]=[CH:30][CH:29]=3)=[CH:14][CH:13]=2)[CH2:9]1)=[O:7])(C)(C)C.[C:50]([OH:56])([C:52]([F:55])([F:54])[F:53])=[O:51].CCN(C(C)C)C(C)C.ClC(OC)=O.C(=O)([O-])N.[OH-].[Li+].Cl>C(Cl)Cl.O1CCOCC1.C(#N)C>[C:50]([OH:56])([C:52]([F:55])([F:54])[F:53])=[O:51].[CH3:1][O:5][C:6]([N:8]1[CH2:9][CH:10]([C:12]2[CH:13]=[CH:14][C:15]([CH2:16][O:17][C:18]3[C:23]([C:24]([F:25])([F:26])[F:27])=[CH:22][CH:21]=[CH:20][C:19]=3[C:28]3[N:33]=[C:32]([N:34]4[C:38]([C:39]([F:41])([F:42])[F:40])=[C:37]([C:43]([OH:45])=[O:44])[CH:36]=[N:35]4)[CH:31]=[CH:30][CH:29]=3)=[CH:48][CH:49]=2)[CH2:11]1)=[O:7]
Reactant: CCOC(=O)c1cnn(-c2cccc(-c3cccc(C(F)(F)F)c3OCc3ccc(C4CN(C(=O)OC(C)(C)C)C4)cc3)n2)c1C(F)(F)F
Agent: COC(=O)Cl
Agent: Cl
Agent: NC(=O)[O-]
Solvent: C1COCCO1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)N1CC(c2ccc(COc3c(-c4cccc(-n5ncc(C(=O)O)c5C(F)(F)F)n4)cccc3C(F)(F)F)cc2)C1
Temperature: 50 °C
Reaction time: 0.05 h

Procedure:
To a solution of the title compound from Example 148 Step C (170 mg, 0.246 mmol) in DCM (3 mL) was added TFA (1 mL). After 3 min, the reaction mixture was concentrated in vacuo to provide the crude TFA-salt, which was used without further purification: LCMS m/z 590.9 [M+1-1]+. A portion of the unpurified TFA salt (0.08 mmol) was dissolved in DCM (1 mL), and DIEA (130 μL, 0.74 mmol) was added, followed by methyl chloroformate (19 μL, 0.25 mmol). After 20 min, the reaction mixture was quenched by addition of sat aq NaHCO3 and the aqueous phase was extracted with DCM. The organic phase was separated and concentrated in vacuo to provide the unpurified carbamate, which was used without further purification: LCMS m/z 648.9 [M+H]+. To a solution of the carbamate in dioxane (2 mL) was added lithium hydroxide (1 mL, 2N aqueous, 2 mmol), and the mixture was stirred at 50° C. for 1 h, then at ambient temperature. After 15 h, the reaction mixture was rendered acidic by addition of HCl (2N aqueous), then was diluted with acetonitrile and purified by reverse phase HPLC (30 to 100% acetonitrile/water, both 0.1% v/v TFA) to provide the title compound: LCMS m/z 620.9 [M+H]+; 1H NMR (500 MHz, d6-DMSO) δ 8.34 (s, 1H), 8.22 (t, J=8.0 Hz, 1H), 8.07 (d, J=8.0 Hz, 1H), 7.95 (d, J=8.0 Hz, 1H), 7.88-7.86 (m, 2H), 7.54 (t, J=8.0 Hz, 1H), 7.32 (d, J=8.0 Hz, 2H), 7.13 (d, J=8.0 Hz, 2H), 4.54 (s, 2H), 4.33-4.26 (m, 2H), 3.90-3.81 (m, 3H), 3.59 (s, 3H).
Reaction SMILES: S(Br)(C)(=O)=O.[Li]C(C)(C)C.[CH3:11][O:12][C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]=1.[C:23]([O:27][C:28](=[O:37])[NH:29][CH2:30][C:31](N(OC)C)=[O:32])([CH3:26])([CH3:25])[CH3:24]>C1COCC1.C(Cl)Cl>[C:23]([O:27][C:28](=[O:37])[NH:29][CH2:30][C:31]([C:22]1[C:13]([O:12][CH3:11])=[N:14][C:15]2[C:20]([CH:21]=1)=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:32])([CH3:26])([CH3:24])[CH3:25]
Reactant: COc1ccc2ccccc2n1
Reactant: CON(C)C(=O)CNC(=O)OC(C)(C)C
Agent: CS(=O)(=O)Br
Agent: [Li]C(C)(C)C
Solvent: ClCCl
Solvent: C1CCOC1
Product: COc1nc2ccccc2cc1C(=O)CNC(=O)OC(C)(C)C
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of mesyl bromide (17.23 mmol) in 10 mL of THF cooled to −78° C. was added a 1.7 M THF solution of tBuLi (34.5 mmol) dropwise. The mixture was left stirring at −78° C. for 1 h. The mixture was then allowed to reach 0° C. and a solution of 2-methoxyquinoline (12.9 mmol) in THF (40 mL) was added dropwise over 10 min. The resulting mixture was aged at 0° C. for 1 h, cooled to −78° C. and added dropwise with a solution of tert-butyl(2-(methoxy(methyl)amino)-2-oxoethyl)carbamate (4.31 mmol) in 20 mL of THF. The mixture was stirred at −78° C. for 30 min then left at room temperature over night. The mixture was diluted with DCM and washed with sat. aq. NaHCO3, dried (Na2SO4), concentrated under reduced pressure and the crude product was purified by flash chromatography (SiO2, Petroleum ether/EtOAc, from 5% to 40% EtOAc). Pooled fractions were concentrated under vacuum to title product (1.01 g). MS (ES) C17H20N2O4 requires: 316.35, found: 317.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[C:5]([CH2:16][N:17]([CH3:25])[C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:6][NH:7][C:8]=1[C:9]1[C:10]([F:15])=[N:11][CH:12]=[CH:13][CH:14]=1.C1OCCOCCOCCOCCOC1.[CH3:41][S:42]([C:45]1[CH:46]=[C:47]([S:51](Cl)(=[O:53])=[O:52])[CH:48]=[CH:49][CH:50]=1)(=[O:44])=[O:43]>O1CCCC1.O>[F:3][C:4]1[C:5]([CH2:16][N:17]([CH3:25])[C:18](=[O:24])[O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[CH:6][N:7]([S:51]([C:47]2[CH:48]=[CH:49][CH:50]=[C:45]([S:42]([CH3:41])(=[O:44])=[O:43])[CH:46]=2)(=[O:53])=[O:52])[C:8]=1[C:9]1[C:10]([F:15])=[N:11][CH:12]=[CH:13][CH:14]=1
Reactant: CS(=O)(=O)c1cccc(S(=O)(=O)Cl)c1
Reactant: CN(Cc1c[nH]c(-c2cccnc2F)c1F)C(=O)OC(C)(C)C
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CN(Cc1cn(S(=O)(=O)c2cccc(S(C)(=O)=O)c2)c(-c2cccnc2F)c1F)C(=O)OC(C)(C)C
Reaction time: 1 h
Yield: 93.2 %

Procedure:
To a suspension of sodium hydride (60% in oil, 60 mg) in tetrahydrofuran (5 mL) were added dropwise a solution (3 mL) of tert-butyl {[4-fluoro-5-(2-fluoropyridin-3-yl)-1H-pyrrol-3-yl]methyl}methylcarbamate (323 mg) in tetrahydrofuran, 15-crown-5 (330 mg) and 3-(methylsulfonyl)benzenesulfonyl chloride (307 mg) under ice-cooling and the mixture was stirred for 1 hr. The reaction mixture was diluted with water, and extracted with ethyl acetate. The separated aqueous layer was extracted again with ethyl acetate. The combined organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=6:1→1:1) to give the title compound as a pale-yellow oil (yield 504 mg, 96%).
Reaction SMILES: C([NH:5][C:6]([NH:8][C@H:9]([CH2:12][CH2:13][C:14]1[CH:18]=[CH:17][S:16][CH:15]=1)[CH2:10]O)=[S:7])(C)(C)C.Cl>C(O)C>[S:16]1[CH:17]=[CH:18][C:14]([CH2:13][CH2:12][C@@H:9]2[CH2:10][S:7][C:6]([NH2:5])=[N:8]2)=[CH:15]1
Reactant: CC(C)(C)NC(=S)N[C@@H](CO)CCc1ccsc1
Agent: Cl
Solvent: CCO
Product: NC1=N[C@H](CCc2ccsc2)CS1
Temperature: 100 °C
Reaction time: 18 h
Yield: 52.5 %

Procedure:
A mixture of 0.72 g of N-(tert-butyl)-N′-[(1R)-2-hydroxy-1-(2-thien-3-yl-ethyl)ethyl]-thiourea in 20 mL of aqueous solution of 5N hydrochloric acid is heated under magnetic stirring at a temperature of about 100° C. for 18 hours. The reaction medium is then evaporated under reduced pressure (2 kPa) at a temperature of about 40° C. and the residue obtained is taken up in 20 mL of ethanol and concentrated again according to the conditions described above. The evaporating residue is taken up in 5 mL of ethanol, filtered, washed with 2 times 2 mL of ethanol and with 2 times 5 mL of ethyl ether. The product is dried in an oven under vacuum (10 Pa) at a temperature of about 20° C. About 0.28 g of (4R)-4-(2-thien-3-ylethyl)-4,5-dihydro-1,3-thiazol-2-ylamine, chlorhydrateare are obtained in the form of a colored-beige solid melting at 150° C. [1H NMR spectrum (300 MHz, (CD3)2SO d6, δ in ppm): from 1.85 to 2.10 (mt, 2H); 2.70 (mt, 2H); from 3.30 to 3.45 (mt, 1H); 3.69 (dd, J=11 and 7.5 Hz, 1H); 4.21 (mt, 1H); 7.05 (dd, J=5 and 1.5 Hz, 1H); 7.26 (mt, 1H); 7.50 (dd, J=5 and 3 Hz, 1H); 9.10 (mf, 1H); 9.61 (mf, 1H); 10.27 (s large, 1H)].
Reaction SMILES: B(F)(F)F.C([N:12]1[C:21](=[O:22])[C:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[C:15]2[S:16][CH:17]=[CH:18][CH2:19][N:14]2[C:13]1=[O:29])C1C=CC=CC=1.CO>C1(C)C=CC=CC=1>[C:23]1([C:20]2[C:21](=[O:22])[NH:12][C:13](=[O:29])[N:14]3[CH2:19][CH:18]=[CH:17][S:16][C:15]=23)[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: O=c1c(-c2ccccc2)c2n(c(=O)n1Cc1ccccc1)CC=CS2
Agent: FB(F)F
Solvent: Cc1ccccc1
Solvent: CO
Product: O=c1[nH]c(=O)n2c(c1-c1ccccc1)SC=CC2
Reaction time: 0.5 h
Yield: 17.5 %

Procedure:
Boron trifluoride (0.7 ml) was added to a solution of 7-benzyl-9-phenyl-4H,6H-pyrimido[6,1-b][1,3]thiazine-6,8(7H)-dione (1 g) in toluene (25 ml) and the mixture was refluxed for 15 hours. Methanol (7.5 ml) was added to the reaction solution at room temperature and the solution was stirred for 30 minutes. The reaction solution was concentrated to dryness, and acetone was added to the resulting residue to obtain the presipitate by filtration. The resulting crude crystals were washed and recrystallized from DMF-water to give yellow needles (0.13 g, 18%).
Reaction SMILES: Cl[C:2]1[C:3](=[O:15])[N:4]([C@@H:9]([CH:12]2[CH2:14][CH2:13]2)[CH2:10][CH3:11])[CH:5]=[C:6]([Cl:8])[N:7]=1.[Br:16][C:17]1[CH:18]=[C:19]2[C:23](=[C:24]([Br:26])[CH:25]=1)[NH:22][CH2:21][CH2:20]2>>[Cl:8][C:6]1[N:7]=[C:2]([N:22]2[C:23]3[C:19](=[CH:18][C:17]([Br:16])=[CH:25][C:24]=3[Br:26])[CH2:20][CH2:21]2)[C:3](=[O:15])[N:4]([C@@H:9]([CH:12]2[CH2:14][CH2:13]2)[CH2:10][CH3:11])[CH:5]=1
Reactant: Brc1cc(Br)c2c(c1)CCN2
Reactant: CC[C@H](C1CC1)n1cc(Cl)nc(Cl)c1=O
Product: CC[C@H](C1CC1)n1cc(Cl)nc(N2CCc3cc(Br)cc(Br)c32)c1=O

Procedure:
Part B: Prepared in a similar fashion as described for Example 413 using 3,5-dichloro-1-[(1R)-1-cyclopropylpropyl]-2(1H)-pyrazinone and 5,7-dibromoindoline as the starting materials. mp 164-165° C.; 1H NMR (300 MHz, CDCl3): δ 7.42 (d, J=1.8 Hz, 1 H), 7.22 (d, J=1.5 Hz, 1 H), 6.96 (s, 1 H), 4.26 (t, J=8.1 Hz, 2 H), 3.99 (app. q, J=8.3 Hz, 1 H), 3.08 (t, J=7.9 Hz, 2 H), 1.94-1.69 (m, 2 H), 1.02-0.92 (m, 1 H), 0.87 (t, J=7.5 Hz, 3 H), 0.78-0.68 (m, 1 H), 0.50-0.39 (m, 2 H), 0.29-0.22 (m, 1 H); HRMS (ESI) calcd for C18H19N3OBr2Cl (M+H)+: 485.9583; found m/z 485.9592.
Reaction SMILES: C([N:8]1[CH2:14][CH2:13][C:12]([CH:15]=[O:16])=[C:11]([Cl:17])[CH2:10][CH2:9]1)C1C=CC=CC=1.Cl[C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20]>>[CH2:22]([O:21][C:19]([N:8]1[CH2:14][CH2:13][C:12]([CH:15]=[O:16])=[C:11]([Cl:17])[CH2:10][CH2:9]1)=[O:20])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: O=CC1=C(Cl)CCN(Cc2ccccc2)CC1
Product: O=CC1=C(Cl)CCN(C(=O)OCc2ccccc2)CC1

Procedure:
This compound was prepared from 40 gm (0.16 mol) of 1-benzyl-4-chloro-5-formyl-2,3,6,7-tetrahydro-1H-azepine and 34.2 gm (0.20 mol) of benzyl chloroformate analogous to Example G.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:18]2[C@@H:17]3[C@H:8]([C@@H:9]4[C@@:13]([CH2:15][CH2:16]3)([CH3:14])[C@H:12]([CH2:21][OH:22])[CH2:11][CH2:10]4)[CH2:7][CH2:6][C:5]=2[CH:4]=1.CC(O)C.O>CS(C)=O.C(N(CC)CC)C>[CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:18]2[C@@H:17]3[C@H:8]([C@@H:9]4[C@@:13]([CH2:15][CH2:16]3)([CH3:14])[C@H:12]([CH:21]=[O:22])[CH2:11][CH2:10]4)[CH2:7][CH2:6][C:5]=2[CH:4]=1
Reactant: COc1ccc2c(c1)CC[C@@H]1[C@@H]2CC[C@]2(C)[C@H](CO)CC[C@H]12
Solvent: CS(C)=O
Solvent: O
Solvent: CC(C)O
Product: COc1ccc2c(c1)CC[C@@H]1[C@@H]2CC[C@]2(C)[C@H](C=O)CC[C@H]12
Reaction time: 0.33 h
Yield: 80.2 %

Procedure:
i)—A solution of sulfur trioxide pyridine complex (50.0 g) in dimethyl sulfoxide (250 ml) was added in 15 min. to a solution of (14β,17α)-3-methoxyestra-1,3,5(10)-triene-17-methanol (Example 1, step ii; 23.6 g) in a mixture of dimethyl sulfoxide (425 ml) and triethylamine (70 ml). After 20 min. stirring, 2-propanol (88 ml) was added and stirring was continued for 15 min. The reaction mixture was poured into water (1300 ml) and the product was extracted into dichloromethane. The combined organic phases were washed with water and brine, dried over magnesium sulfate and concentrated under reduced pressure. Trituration (water/ethanol, first 3:2, then 1:1) afforded (14β,17α)-3-methoxyestra-1,3,5(10)-triene-17-carboxaldehyde (18.8 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][C:25]=1[O:26][CH3:27])[CH2:5][N:6]1[C:10]2[CH:11]=[C:12]([C:15]#[N:16])[CH:13]=[CH:14][C:9]=2[N:8]([C@H:17]2[CH2:21][CH2:20][NH:19][CH2:18]2)[C:7]1=[O:22].[CH:28](OCC)=[O:29]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][C:25]=1[O:26][CH3:27])[CH2:5][N:6]1[C:10]2[CH:11]=[C:12]([C:15]#[N:16])[CH:13]=[CH:14][C:9]=2[N:8]([C@H:17]2[CH2:21][CH2:20][N:19]([CH:28]=[O:29])[CH2:18]2)[C:7]1=[O:22]
Reactant: COc1ccc(Cn2c(=O)n([C@H]3CCNC3)c3ccc(C#N)cc32)cc1Cl
Reactant: CCOC=O
Product: COc1ccc(Cn2c(=O)n([C@H]3CCN(C=O)C3)c3ccc(C#N)cc32)cc1Cl

Procedure:
A solution of 3-(3-chloro-4-methoxybenzyl)-5-cyano-1-[(S)-pyrrolidin-3-yl]-2,3-dihydro-1H-benzimidazol-2-one (80 mg) in ethyl formate (2 mL) was heated under reflux for 10 hours. After evaporation of the solvent, the residue was subjected to a preparative thin-layer chromatography eluting with a mixture of chloroform and methanol (15:1) to give 3-(3-chloro-4-methoxybenzyl)-5-cyano-1-[(S)-1-formylpyrrolidin-3-yl]-2,3-dihydro-1H-benzimidazol-2-one (52 mg) as amorphous powders.