Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[S:2]1(=[O:33])[CH2:7][CH2:6][CH2:5][CH2:4][N:3]1[C:8]1[N:17]=[C:16]([C:18]([O:20][CH3:21])=[O:19])[C:15]([O:22]S(C2C=CC(C)=CC=2)(=O)=O)=[C:14]2[C:9]=1[CH:10]=[CH:11][CH:12]=[N:13]2.C[O-].[Na+].C(O)(=O)C.O>CN(C=O)C>[O:33]=[S:2]1(=[O:1])[CH2:7][CH2:6][CH2:5][CH2:4][N:3]1[C:8]1[N:17]=[C:16]([C:18]([O:20][CH3:21])=[O:19])[C:15]([OH:22])=[C:14]2[C:9]=1[CH:10]=[CH:11][CH:12]=[N:13]2
Reactant: COC(=O)c1nc(N2CCCCS2(=O)=O)c2cccnc2c1OS(=O)(=O)c1ccc(C)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: COC(=O)c1nc(N2CCCCS2(=O)=O)c2cccnc2c1O
Reaction time: 1 h

Procedure:
To a solution of methyl 5-(1,1-dioxido-1,2-thiazinan-2-yl)-8-{[(4-methylphenyl)sulfonyl]oxy}-1,6-naphthyridine-7-carboxylate (6.0 g, 12.2 mmol) in DMF (50 mL) under nitrogen at zero degrees C. was added sodium methoxide (49.40 mL, 24.70 mmol, 0.5 M in Methanol). The cold solution was allowed to stir for one hour. Acetic acid (1.64 mL, 27.4 mmol) was added followed by water to precipitate the product. The mixture was allowed to stand for one hour. The crude reaction was filtered and the solids were washed with 1:1 methanol:water and dried in vacuo to afford the desired product.
Reaction SMILES: [C:1]([C:3]1[CH:12]=[CH:11][C:6]([O:7][CH2:8][CH2:9][OH:10])=[CH:5][CH:4]=1)#[CH:2].Br[C:14]1[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][N:15]=1>CCOC(C)=O>[Br:20][C:17]1[CH:18]=[CH:19][C:14]([C:2]#[C:1][C:3]2[CH:12]=[CH:11][C:6]([O:7][CH2:8][CH2:9][OH:10])=[CH:5][CH:4]=2)=[N:15][CH:16]=1
Reactant: Brc1ccc(Br)nc1
Reactant: C#Cc1ccc(OCCO)cc1
Solvent: CCOC(C)=O
Product: OCCOc1ccc(C#Cc2ccc(Br)cn2)cc1

Procedure:
The product was obtained analogously to Example 1.1d starting from 7.70 g (47.48 mmol) of 2-(4-ethynylphenoxy)ethanol and 11.37 g (48.00 mmol) of 2,5-dibromopyridine. Yield: 7.40 g (49% of theoretical); C15H12BrNO2 (M=318.165); calc.: molpeak (M+H)+: 318/320 (Br); found: molpeak (M+H)+: 318/320 (Br); Rf value: 0.20 (silica gel, PE/EtOAc 6:4).
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH2:8][CH2:7][N:6]([CH2:9][CH2:10][N:11]2[C:20]3[C:15](=[N:16][CH:17]=[C:18]([O:21][CH3:22])[CH:19]=3)[CH:14]=[CH:13][C:12]2=[O:23])[CH2:5][CH2:4]1.C[O-].[Na+].CO.[CH3:29][O:30][C:31]1[C:32]([CH3:39])=[CH:33][C:34]([CH:37]=O)=[N:35][CH:36]=1.C([BH3-])#N.[Na+].C(=O)([O-])O.[Na+]>CO.O.C(Cl)(Cl)Cl.C(O)(=O)C>[CH3:22][O:21][C:18]1[CH:19]=[C:20]2[C:15]([CH:14]=[CH:13][C:12](=[O:23])[N:11]2[CH2:10][CH2:9][N:6]2[CH2:5][CH2:4][CH:3]([NH:2][CH2:37][C:34]3[CH:33]=[C:32]([CH3:39])[C:31]([O:30][CH3:29])=[CH:36][N:35]=3)[CH2:8][CH2:7]2)=[N:16][CH:17]=1
Reactant: COc1cnc2ccc(=O)n(CCN3CCC(N)CC3)c2c1
Reactant: COc1cnc(C=O)cc1C
Agent: C[O-]
Agent: Cl
Agent: O=C([O-])O
Solvent: CO
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: COc1cnc2ccc(=O)n(CCN3CCC(NCc4cc(C)c(OC)cn4)CC3)c2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 38.8 %

Procedure:
To a suspension of 0.20 g of 1-(2-(4-aminopiperidin-1-yl)ethyl)-7-methoxy-1,5-naphthyridin-2(1H)-one hydrochloride in 2 mL of methanol, 0.28 g of a 28% sodium methoxide/methanol solution, 73 mg of 5-methoxy-4-methylpyridine-2-carbaldehyde and 28 μL of acetic acid were added. Then, 61 mg of sodium cyanoborohydride was added thereto, and the mixture was stirred at room temperature for 1 hour 30 minutes. To the reaction mixture, chloroform, a saturated aqueous sodium hydrogen carbonate solution and water were added. The organic layer was separated, and the aqueous layer was extracted with chloroform. The organic layer and the extract were combined, the resultant solution was washed with water and a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The resultant residue was purified by basic silica gel column chromatography using gradient elution with chloroform:methanol=93:7 to 86:14 to obtain 82 mg of 7-methoxy-1-(2-(4-(((5-methoxy-4-methylpyridin-2-yl)methyl)amino)piperidin-1-yl)ethyl)-1,5-naphthyridin-2(1H)-one as a light yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C@:15]3([CH2:19][S:18][C:17]([NH2:20])=[N:16]3)[C:14]3[C:9](=[CH:10][CH:11]=[C:12](I)[CH:13]=3)[O:8][C:5]2=[N:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[F:28][C:29]1[C:34](B(O)O)=[CH:33][CH:32]=[CH:31][N:30]=1.O1CCOCC1>O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CO.CCOC(C)=O>[Br:1][C:2]1[CH:3]=[C:4]2[C@:15]3([CH2:19][S:18][C:17]([NH2:20])=[N:16]3)[C:14]3[C:9](=[CH:10][CH:11]=[C:12]([C:34]4[C:29]([F:28])=[N:30][CH:31]=[CH:32][CH:33]=4)[CH:13]=3)[O:8][C:5]2=[N:6][CH:7]=1
Reactant: OB(O)c1cccnc1F
Reactant: NC1=N[C@@]2(CS1)c1cc(I)ccc1Oc1ncc(Br)cc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1COCCO1
Product: NC1=N[C@@]2(CS1)c1cc(-c3cccnc3F)ccc1Oc1ncc(Br)cc12
Temperature: 100 °C
Yield: 46.1 %

Procedure:
A pressure reaction vessel was charged with (S)-3-bromo-7-iodo-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-thiazol]-2′-amine (1.51 g, 3.19 mmol), potassium carbonate (2.20 g, 15.95 mmol), 2-fluoropyridin-3-ylboronic acid (0.72 g, 5.10 mmol), tetrakis(triphenylphosphine)palladium(0) (0.37 g, 0.32 mmol), dioxane (21.3 mL) and water (10.6 mL). The reaction was stirred and heated at 100° C. for 1 h. After cooling to rt, the reaction was diluted with water (25 mL) and poured into a separatory funnel containing EtOAc (50 mL). The layers were separated and the aqueous layer was extracted with EtOAc (1×100 mL). The combined organic layers were washed with water, dried over sodium sulfate, filtered, and concentrated in vacuo to provide a brown foam that was purified by silica gel chromatography (Redi-Sep pre-packed silica gel column (40 g), 0-100% EtOAc in 90:10 CH2Cl2:CH3OH to provide a white solid, (S)-3-bromo-7-(2-fluoropyridin-3-yl)-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-thiazol]-2′-amine (0.65 g, 1.47 mmol). MS m/z=443.0 [M+H]+. Calc'd for C19H12BrFN4OS: 441.99.
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([N:8]2[CH2:10][CH2:9]2)=[O:7])=[CH:4][CH:3]=1.[NH2:13][C:14]1[C:30]([Cl:31])=[CH:29][C:17]([C:18]([NH:20][C@H:21]2[CH2:26][CH2:25][NH:24][CH2:23][C@H:22]2[O:27][CH3:28])=[O:19])=[C:16]([O:32][CH3:33])[CH:15]=1.C1C=CC=CC=1>CO>[NH2:13][C:14]1[C:30]([Cl:31])=[CH:29][C:17]([C:18]([NH:20][C@H:21]2[CH2:26][CH2:25][N:24]([CH2:9][CH2:10][NH:8][C:6](=[O:7])[C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:12][CH:11]=3)[CH2:23][C@H:22]2[O:27][CH3:28])=[O:19])=[C:16]([O:32][CH3:33])[CH:15]=1
Reactant: O=C(c1ccc(F)cc1)N1CC1
Reactant: COc1cc(N)c(Cl)cc1C(=O)N[C@H]1CCNC[C@H]1OC
Solvent: c1ccccc1
Solvent: CO
Product: COc1cc(N)c(Cl)cc1C(=O)N[C@H]1CCN(CCNC(=O)c2ccc(F)cc2)C[C@H]1OC

Procedure:
A mixture of 11 parts of 1-(4-fluorobenzoyl)aziridine, 6.28 parts of cis-4-amino-5-chloro-2-methoxy-N-(3-methoxy-4-piperidinyl)benzamide, 45 parts of benzene and 20 parts of methanol was stirred and refluxed for 6 hours. The reaction mixture was evaporated and the residue was purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (90:10 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from acetonitrile, yielding 5.09 parts of cis-4-amino-5-chloro-N-[1-[2-[(4 -fluorobenzoyl)amino]ethyl]-3-methoxy-4-piperidinyl]-2-methoxybenzamide; mp. 208.7° C. (compound 131).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=O.[NH2:14][C@@H:15]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:16][OH:17]>>[CH3:1][C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4]([NH:14][CH:15]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:16][OH:17])=[O:6]
Reactant: Cc1ccc([N+](=O)[O-])cc1C(=O)O
Reactant: N[C@H](CO)Cc1ccccc1
Product: Cc1ccc([N+](=O)[O-])cc1C(=O)NC(CO)Cc1ccccc1
Yield: 87 %

Procedure:
5 g (27.6 mmol) of 2-methyl-5-nitrobenzoic acid were reacted with (S)-2-amino-3-phenyl-1-propanol by the method of procedure 3c. 7.5 g (87%) of the product were obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[C:19]([I:21])[CH:18]=[CH:17][C:3]=1[C:4]([CH:6](C(OCC)=O)[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5].C1(C)C=CC(S(O)(=O)=O)=CC=1>O>[Cl:1][C:2]1[CH:20]=[C:19]([I:21])[CH:18]=[CH:17][C:3]=1[C:4](=[O:5])[CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: CCOC(=O)C(C(=O)OCC)C(=O)c1ccc(I)cc1Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: CCOC(=O)CC(=O)c1ccc(I)cc1Cl
Temperature: 25 °C
Yield: 92 %

Procedure:
mc) 70.3 g of diethyl 2-(2-chloro-4-iodo-benzoyl)-malonate are heated to boiling under reflux for 6 hrs. while stirring vigorously with 750 ml of water and 0.75 g of p-toluenesulphonic acid. The reaction mixture is cooled to room temperature and extracted three times with 200 ml of diethyl ether each time. The ether phases are washed twice with 200 ml of saturated, aqueous sodium chloride solution each time, dried over magnesium sulphate and concentrated. 53.7 g (92%) of ethyl 3-(2-chloro-4-iodo-phenyl)-3-oxo-propionate are obtained as a yellowish oil. Mass spectrum: peaks inter alia at 352 (M+, 3%), 317 (73%), 289 (19%), 265 (100%).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]([CH2:22][C:23](O)=[O:24])[C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:26]([NH:28][CH2:29][C:30]1[CH:37]=[CH:36][C:33]([C:34]#[N:35])=[CH:32][CH:31]=1)[CH3:27]>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]([C:15]2[CH:16]=[CH:17][C:18]([CH3:21])=[CH:19][CH:20]=2)[CH2:22][C:23]([N:28]([CH2:29][C:30]2[CH:31]=[CH:32][C:33]([C:34]#[N:35])=[CH:36][CH:37]=2)[CH2:26][CH3:27])=[O:24])(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: CCNCc1ccc(C#N)cc1
Reactant: Cc1ccc(N(CC(=O)O)S(=O)(=O)c2ccc(C(C)(C)C)cc2)cc1
Product: CCN(Cc1ccc(C#N)cc1)C(=O)CN(c1ccc(C)cc1)S(=O)(=O)c1ccc(C(C)(C)C)cc1

Procedure:
prepared by reaction of [(4-tert-butyl-benzenesulfonyl)-p-tolyl-amino]-acetic acid with 4-ethylaminomethyl-benzonitrile
Reaction SMILES: C([C@H]1COC(C)(C)N1C(=O)C(C1C=CN(C2C=CC(C3C=CC=CC=3)=CC=2)C=1)O)C1C=CC=CC=1.[CH2:36]([C@H:43]1[CH2:47][O:46][C:45]([CH3:49])([CH3:48])[N:44]1[C:50](=[O:70])[C:51]([C:53]1[O:57][C:56]([C:58]2[CH:63]=[CH:62][C:61]([C:64]3[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=3)=[CH:60][CH:59]=2)=[CH:55][CH:54]=1)=[O:52])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.[BH4-].[Na+]>>[CH2:36]([C@H:43]1[CH2:47][O:46][C:45]([CH3:49])([CH3:48])[N:44]1[C:50](=[O:70])[CH:51]([C:53]1[O:57][C:56]([C:58]2[CH:59]=[CH:60][C:61]([C:64]3[CH:65]=[CH:66][CH:67]=[CH:68][CH:69]=3)=[CH:62][CH:63]=2)=[CH:55][CH:54]=1)[OH:52])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: CC1(C)OC[C@H](Cc2ccccc2)N1C(=O)C(=O)c1ccc(-c2ccc(-c3ccccc3)cc2)o1
Agent: CC1(C)OC[C@H](Cc2ccccc2)N1C(=O)C(O)c1ccn(-c2ccc(-c3ccccc3)cc2)c1
Agent: [BH4-]
Agent: [Na+]
Product: CC1(C)OC[C@H](Cc2ccccc2)N1C(=O)C(O)c1ccc(-c2ccc(-c3ccccc3)cc2)o1

Procedure:
According to the procdure described in Example 13 for the preparation of 1-(4(S)-benzyl-2,2-dimethyl-oxazolidin-3-yl)-2-(biphenyl-4-yl-1H-pyrrol-3-yl)-2-hydroxy-ethanone, 1-(4(S)-benzyl-2,2-dimethyl-oxazolidin-3-yl)-2-(2-biphenyl-4-yl-furan-5-yl)ethane-1,2-dione was reduced with NaBH4 to give in quantitative yield 1-(4(S)-benzyl-2,2-dimethyl-oxazolidin-3-yl)-2-(2-biphenyl-4-yl-furan-5-yl)-2-hydroxy-ethanone. 1H NMR: δ 7.70 (d, 2H, J=7.7 Hz), 7.61 (d, 4H, J=8.5 Hz), 7.45 (t, 2H, J=7.4 Hz), 7.38-7.19 (m, 6H), 6.64 (d, 1H, J=2.9 Hz), 6.43 (d, 1H, J=3.3 Hz), 5.08 (d, 1H, J=6.6 Hz), 4.45 (d, 1H, J=7.0 Hz), 3.88-3.85 (m, 1H), 3.78 (d, 1H, J=8.8 Hz), 3.63 (dd, 1H, J=5.2, 8.8 Hz), 3.03 (dd, 1H, J=4.2, 13.1 Hz), 2.89 (dd, 1H, J=9.8, 13.4 Hz), 1.83 (s, 3H), 1.58 (s, 3H). Anal. Calculated for C30H29NO4•0.5 H2O: C, 75.6 1; H, 6.34; N, 2.94. Found: C, 75.62; H, 6.32; N, 2.88.
Reaction SMILES: CN1CCOCC1.[NH:8]([C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24])[C@H:9]([C:20](O)=[O:21])[CH2:10][C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[NH:13][CH:12]=1.[NH2:33][CH2:34][C:35]([O:37][CH3:38])=[O:36].CP(OP(CC)(C)=O)(CC)=O.C([O-])(O)=O.[Na+]>>[NH:8]([C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24])[C@H:9]([C:20]([NH:33][CH2:34][C:35]([O:37][CH3:38])=[O:36])=[O:21])[CH2:10][C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[NH:13][CH:12]=1
Reactant: O=C(N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O)OCc1ccccc1
Reactant: COC(=O)CN
Agent: CCP(C)(=O)OP(C)(=O)CC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCOCC1
Product: COC(=O)CNC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)OCc1ccccc1
Reaction time: 10 h

Procedure:
At 0° C. there were added while stirring 6.5 ml of N-methyl morpholine to a mixture of 3.35 g (0.05 mol) of Z-Trp-OH and 1.25 g of H-Gly-OMe. Into the solution obtained there were added dropwise at the temperature specified, while stirring, 4 g of methylethylphosphinic acid anhydride. The mixture was allowed to stand at room temperature for 10 hours and the solvent was separated by distillation in vacuo at room temperature. The residue was taken up by a mixture of 25 ml of water and 70 ml of ethyl acetate, the ethyl acetate extract was separated and the aqueous solution was extracted twice using each time 10 ml of ethyl acetate. The combined ethyl acetate extracts were washed twice using each time 7 ml of water, a 5% potassium sulfate solution (until an acid reaction took place) and a saturated NaHCO3 solution until a slightly alkaline reaction took place. Upon drying over magnesium sulfate and clearing with active carbon, the solvent was largely separated by distillation in vacuo and the residue was digested with diisopropyl ether.
Reaction SMILES: C([Li])CCC.Br[C:7]1[S:8][CH:9]=[CH:10][N:11]=1.C([Mg]Cl)(C)C.CON(C)[C:20](=[O:34])[C@@H:21]([NH:23][C:24](=[O:33])[O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH3:22].[Li]C1SC=CN=1.[NH4+].[Cl-]>C1COCC1.O>[CH3:22][C@H:21]([NH:23][C:24](=[O:33])[O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:20](=[O:34])[C:7]1[S:8][CH:9]=[CH:10][N:11]=1
Reactant: Brc1nccs1
Reactant: CON(C)C(=O)[C@H](C)NC(=O)OCc1ccccc1
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: C[C@H](NC(=O)OCc1ccccc1)C(=O)c1nccs1
Temperature: -78 °C
Reaction time: 0.75 h

Procedure:
n-Butyllithium (1.6M in hexanes, 1.76 mL, 2.83 mmol) was added dropwise to a stirred solution of 2-bromothiazole (462 mg, 251 μL, 2.82 mmol) in dry THF (13 mL) at −78° C. under N2 and the reaction was stirred at −78° C. for 45 min. Separately, isopropylmagnesium chloride (2M in THF, 0.94 mL, 1.99 mmol) was added to a stirred solution of benzyl {(1S)-2-[methoxy(methyl)amino]-1-methyl-2-oxoethyl}carbamate (500 mg, 1.88 mmol) in dry THF (4 mL) at −15° C. under N2. This solution was stirred for 15 min at −15° C. and was added dropwise to the above 2-lithiothiazole solution at −78° C. The reaction was allowed to warm to room temperature overnight and saturated NH4Cl (20 mL) and water (10 mL) were added and the mixture was extracted with EtOAc (3×30 mL). The combined extracts were washed with brine, dried (Na2SO4) and concentrated in vacuo to give the crude product. This was purified by flash chromatography (Si, 25×160 mm, 0-50% EtOAc in hexanes gradient) to afford benzyl [(1S)-1-methyl-2-oxo-2-(1,3-thiazol-2-yl)ethyl]carbamate. Rf=0.28 (20% EtOAc in hexanes). LCMS calc.=291.1; found=291.3 (M+1)+. 1H NMR (600 MHz, CDCl3) δ 8.03 (s, 1H), 7.70 (d, J=3.1 Hz, 1H), 7.34-7.29 (m, 5H), 5.79 (d, J=6.6 Hz, 1H), 5.53-5.49 (m, 1H), 5.14-5.08 (m, 2H), 1.55 (d, J=6.4 Hz, 3H).
Reaction SMILES: [N:1]1([S:5]([NH2:8])(=[O:7])=[O:6])[CH2:4][CH2:3][CH2:2]1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl[C:50]1[CH:55]=[C:54]([O:56][CH:57]([CH3:59])[CH3:58])[N:53]=[C:52]([S:60][CH2:61][C:62]2[CH:67]=[CH:66][CH:65]=[C:64]([F:68])[C:63]=2[F:69])[N:51]=1>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:69][C:63]1[C:64]([F:68])=[CH:65][CH:66]=[CH:67][C:62]=1[CH2:61][S:60][C:52]1[N:51]=[C:50]([NH:8][S:5]([N:1]2[CH2:4][CH2:3][CH2:2]2)(=[O:7])=[O:6])[CH:55]=[C:54]([O:56][CH:57]([CH3:59])[CH3:58])[N:53]=1
Reactant: NS(=O)(=O)N1CCC1
Reactant: CC(C)Oc1cc(Cl)nc(SCc2cccc(F)c2F)n1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CC(C)Oc1cc(NS(=O)(=O)N2CCC2)nc(SCc2cccc(F)c2F)n1
Temperature: 100 °C

Procedure:
A mixture of azetidine-1-sulfonamide (0.327 g), tris(dibenzylideneacetone)dipalladium (0) (50 mg), 2-dicyclohexylphosphino-2′,4′,6′-tri-isopropyl-1,1′-biphenyl (XPHOS) (50 mg), cesium carbonate (0.585 g) and 4-chloro-2-[(2,3-difluorobenzyl)thio]-6-isopropoxypyrimidine (the product from step i), 0.400 g) in dioxane (20 ml) was heated at reflux in a microwave at 100° C., 300 W, open vessel with cooling for 30 mins. The reaction mixture was then reduced in vacuo and the residue separated between DCM (150 ml) and H2O (150 ml). The organics were separated and the aqueous layer was re-extracted with DCM (2×150 ml). Organics were combined, dried (MgSO4) and reduced in vacuo and the resulting residue purified by prep HPLC to give the title compound as a white solid. Yield: 0.18 g
Reaction SMILES: [ClH:1].[C:2]12([CH2:12][CH2:13][N:14]([CH2:27][CH2:28][C:29]([O:31]C(C)(C)C)=O)[C:15]([NH:17][CH2:18][CH2:19][CH2:20][C:21]3[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=3)=[O:16])[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([CH2:5]3)[CH2:3]1)[CH2:9]2.C(OCC)(=O)C>O1CCOCC1>[ClH:1].[C:2]12([CH2:12][CH2:13][N:14]3[CH2:27][CH2:28][C:29](=[O:31])[N:17]([CH2:18][CH2:19][CH2:20][C:21]4[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=4)[C:15]3=[O:16])[CH2:9][CH:8]3[CH2:7][CH:6]([CH2:5][CH:4]([CH2:10]3)[CH2:3]1)[CH2:11]2
Reactant: CC(C)(C)OC(=O)CCN(CCC12CC3CC(CC(C3)C1)C2)C(=O)NCCCc1ccncc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: O=C1CCN(CCC23CC4CC(CC(C4)C2)C3)C(=O)N1CCCc1ccncc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79 %

Procedure:
A 4 N solution of hydrogen chloride in 1,4-dioxane (2.5 ml) was added to 1-[2-(1-adamantyl)ethyl]-1-[2-(t-Butoxycarbonyl)ethyl]-3-[3-(4-pyridyl)propyl]urea (Compound No. 1-69) (0.23 g, 0.49 mmol), and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, a 1 N aqueous sodium hydroxide solution (20 ml) and ethyl acetate (30 ml) were added to the residue, and layers were separated. The ethyl acetate layer was washed with water (20 ml) and a saturated aqueous sodium chloride solution (20 ml) successively and dried over anhydrous magnesium sulfate. The ethyl acetate layer was concentrated under reduced pressure, and the resulting oily matter was dissolved in diethyl ether (20 ml). A 4 N solution of hydrogen chloride in ethyl acetate (0.50 ml, 2.00 mol) was added thereto under ice-cooling, the mixture was concentrated under reduced pressure, and the precipitated solid was filtered off with ethyl acetate to give 0.17 g (79%) of the titled compound.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[C:24]([CH:26]([F:28])[F:27])[CH:23]=[CH:22][C:21]=4[O:29][CH2:30][CH:31]4[CH2:33][CH2:32]4)[C:14]=3[NH:13][C:12]=2[CH3:34])=[O:10])[C@H:4]([F:35])[CH2:3]1.[CH3:36][O:37][CH2:38][C:39](Cl)=[O:40]>>[CH:31]1([CH2:30][O:29][C:21]2[CH:22]=[CH:23][C:24]([CH:26]([F:28])[F:27])=[CH:25][C:20]=2[C:19]2[C:14]3[NH:13][C:12]([CH3:34])=[C:11]([C:9]([NH:8][C@H:5]4[CH2:6][CH2:7][C@H:2]([NH:1][C:39](=[O:40])[CH2:38][O:37][CH3:36])[CH2:3][C@H:4]4[F:35])=[O:10])[C:15]=3[N:16]=[CH:17][N:18]=2)[CH2:32][CH2:33]1
Reactant: Cc1[nH]c2c(-c3cc(C(F)F)ccc3OCC3CC3)ncnc2c1C(=O)N[C@H]1CC[C@H](N)C[C@H]1F
Reactant: COCC(=O)Cl
Product: COCC(=O)N[C@H]1CC[C@H](NC(=O)c2c(C)[nH]c3c(-c4cc(C(F)F)ccc4OCC4CC4)ncnc23)[C@H](F)C1

Procedure:
Starting from N-[(1S*,2R*,4S*)-4-amino-2-fluorocyclohexyl]-4-[2-(cyclopropylmethoxy)-5-(difluoromethyl)phenyl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide (example D.f73) and commercially available methoxy-acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:19]3[C:9]([CH2:10][C@@H:11]4[C@@H:16]([C:17]=3[CH:18]=1)[CH2:15][C@H:14]([NH:20][C:21](=[O:27])[N:22]([CH2:25][CH3:26])[CH2:23][CH3:24])[CH2:13][N:12]4[CH3:28])=[CH:8][NH:7]2)([O-:3])=[O:2].[C:29](Cl)(=[O:31])[CH3:30].[OH-].[K+]>C(Cl)Cl.S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.C(=O)(O)[O-].[Na+]>[C:29]([N:7]1[C:6]2[C:19]3[C:9]([CH2:10][C@@H:11]4[C@@H:16]([C:17]=3[CH:18]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[CH2:15][C@H:14]([NH:20][C:21](=[O:27])[N:22]([CH2:25][CH3:26])[CH2:23][CH3:24])[CH2:13][N:12]4[CH3:28])=[CH:8]1)(=[O:31])[CH3:30]
Reactant: CC(=O)Cl
Reactant: CCN(CC)C(=O)N[C@H]1C[C@@H]2c3cc([N+](=O)[O-])cc4[nH]cc(c34)C[C@H]2N(C)C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])O
Agent: O=S(=O)([O-])O
Solvent: ClCCl
Product: CCN(CC)C(=O)N[C@H]1C[C@@H]2c3cc([N+](=O)[O-])cc4c3c(cn4C(C)=O)C[C@H]2N(C)C1
Reaction time: 1.5 h

Procedure:
A solution is prepared from 410 mg of 3-(13-nitro-6-methyl-8α-ergolinyl)-1,1-diethylurea in 10 ml of methylene chloride, 40 mg of tetrabutylammonium hydrogen sulfate and 0.8 ml of acetyl chloride are added, and this mixture is poured on 1 g of pulverized potassium hydroxide. After 1.5 hours of agitation at room temperature, the mixture is diluted with sodium bicarbonate solution, the organic phase is separated and dried with sodium sulfate. After evaporation and chromatography as indicated in Example 9, 375 mg of 3-(1-acetyl-6-methyl-13-nitro-8α-ergolinyl)-1,1-diethylurea is obtained.
Reaction SMILES: C[Si](C)(C(C)(C)C)[O:3][CH2:4][C:5]1[CH:10]=[C:9]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][C@@H:12]2[CH3:17])[N:8]=[C:7]([C:18]2[CH:23]=[CH:22][C:21]([NH:24][C:25]([NH:27][CH2:28][CH3:29])=[O:26])=[CH:20][CH:19]=2)[N:6]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[CH2:28]([NH:27][C:25]([NH:24][C:21]1[CH:20]=[CH:19][C:18]([C:7]2[N:6]=[C:5]([CH2:4][OH:3])[CH:10]=[C:9]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][C@@H:12]3[CH3:17])[N:8]=2)=[CH:23][CH:22]=1)=[O:26])[CH3:29]
Reactant: CCNC(=O)Nc1ccc(-c2nc(CO[Si](C)(C)C(C)(C)C)cc(N3CCOC[C@@H]3C)n2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CCNC(=O)Nc1ccc(-c2nc(CO)cc(N3CCOC[C@@H]3C)n2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.6 %

Procedure:
1-[4-[4-[(Dimethyl-tert-butyl-silyl)oxymethyl]-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2-yl]phenyl]-3-ethyl-urea (104 mg) was dissolved in THF (10 mL) and TBAF (1.0 M solution, 0.22 mL) was added. The reaction was allowed to stir for 1 hour at room temperature and then passed down a SCX-2 column. The column was washed with methanol and the desired material eluted with 7N ammonia in methanol. The fractions were concentrated in vacuo to give the desired compound (76 mg) as a white solid.