Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([S:5][NH:6][CH3:7])([CH3:4])([CH3:3])[CH3:2].[Cl:8][C:9]1[CH:10]=[C:11]([N:16]=[C:17]=[O:18])[CH:12]=[CH:13][C:14]=1[Cl:15]>C(N(CC)CC)C.O1CCCC1>[CH3:7][N:6]([S:5][C:1]([CH3:4])([CH3:3])[CH3:2])[C:17]([NH:16][C:11]1[CH:12]=[CH:13][C:14]([Cl:15])=[C:9]([Cl:8])[CH:10]=1)=[O:18]
Reactant: O=C=Nc1ccc(Cl)c(Cl)c1
Reactant: CNSC(C)(C)C
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CN(SC(C)(C)C)C(=O)Nc1ccc(Cl)c(Cl)c1
Reaction time: 0.5 h
Yield: 82.8 %

Procedure:
12 g of tert.-butylmercapto monomethylamine, 20 g of 3,4-dichlorophenyl isocyanate and 3 drops of triethylamine were added to 120 ml of tetrahydrofuran and after stirring the mixture for 30 minutes, the solvent was distilled off under reduced pressure. The residue was crystallized from ethanol to obtain 25.6 g of N-methyl-N-tert.-butylthio-N'-(3,4-dichlorophenyl)-urea melting at 127° C.
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH2:17][CH3:18])=[CH:11][C:10]=1[NH2:19])=[S:7])=[O:4].[CH:20](O)=[O:21]>O>[CH3:1][O:2][C:3]([NH:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH2:17][CH3:18])=[CH:11][C:10]=1[NH:19][CH:20]=[O:21])=[S:7])=[O:4]
Reactant: O=CO
Reactant: CCCCc1ccc(NC(=S)NC(=O)OC)c(N)c1
Solvent: O
Product: CCCCc1ccc(NC(=S)NC(=O)OC)c(NC=O)c1
Yield: 73.2 %

Procedure:
1-Methoxycarbonyl-3-(2-amino-4-n-butylphenyl)thiourea (15.0 g; 0.053 mole) and formic acid (18.4 g; 0.4 mole) were mixed together at laboratory temperature and the mixture was refluxed for forty minutes. The hot clear solution was then poured into water, and the solid which separated was filtered off, washed with water, dried and crystallised from 2-ethoxyethanol to give 1-methoxycarbonyl-3-(4-n-butyl-2-formamidophenyl)thiourea (12.0 g), m.p. 182°-183° C. (with decomposition).
Reaction SMILES: Cl[CH:2]([O:4][C:5]([NH:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH3:19])[CH:11]=1)=[O:6])[CH3:3].[C:20]([OH:23])(=[O:22])[CH3:21]>>[C:20]([O:23][CH:2]([O:4][C:5]([NH:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH3:19])[CH:11]=1)=[O:6])[CH3:3])(=[O:22])[CH3:21]
Reactant: CC(=O)O
Reactant: COc1ccc(CCNC(=O)OC(C)Cl)cc1OC
Product: COc1ccc(CCNC(=O)OC(C)OC(C)=O)cc1OC
Temperature: 25 °C
Reaction time: 3 h

Procedure:
The chloroethyl carbamate from Example 11 (0.25 g) was dissolved in acetic acid (25 ml) and mercuric acetate (1.0 g) was added to it. The reaction mixture was stirred at room temperature for 3 hours. It was filtered and the filtrate was evaporated in vacuum at room temperature. The residue was dissolved in ether and filtered. Evaporation of ether gave a thick oil weighing 0.21 g as a practically pure compound. An analytical sample was prepared by filtering through silica gel in chloroform. NMR (CDCl3) δ1.45 (3H, d, J=7 Hz, CH3CH), 2.06 (3H, s, OAc), 2.76 (2H, t, J=7 Hz), ArCH2), 3.38 (2H, t, J=7 Hz, NHCH2), 3.9 (6H, s, OMe), 5.06 (1H, broad t, NH) and 6.6-7.0 (4H, CHCH3 and aromatic). IR (film) ν3345, 1742, 1723, 1515, 1262, 1238 cm-1. m/e 311 (M+), 207, 164, 151, etc.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:10]=[N:9][N:8]([C@@H:11]3[O:17][C@H:16]([CH2:18][OH:19])[C@@H:14]([OH:15])[C@H:12]3[OH:13])[C:4]=2[N:5]=[CH:6][N:7]=1.C[Si](Cl)(C)C.[C:25](Cl)(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.N>N1C=CC=CC=1.O>[C:25]([NH:1][C:2]1[C:3]2[N:10]=[N:9][N:8]([C@@H:11]3[O:17][C@H:16]([CH2:18][OH:19])[C@@H:14]([OH:15])[C@H:12]3[OH:13])[C:4]=2[N:5]=[CH:6][N:7]=1)(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Nc1ncnc2c1nnn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Agent: C[Si](C)(C)Cl
Agent: N
Solvent: c1ccncc1
Solvent: O
Product: O=C(Nc1ncnc2c1nnn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O)c1ccccc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
100 mg (0.37 mmol) of 7-amino-3-β-D-ribofuranosyl-3H-1,2,3-triazolo[4,5-d]pyrimidine are initially introduced in 5 ml of dry pyridine. 0.47 ml (3.7 mmol) of trimethylsilyl chloride is added dropwise to this solution under an argon atmosphere. After the mixture has been stirred at room temperature for half an hour (monitoring by TLC), 0.25 ml (2.0 mmol) of benzoyl chloride is added dropwise, and this reaction mixture is stirred at room temperature for 4 hours. It is then cooled down to 0-5° C. and 1 ml of water is added followed, 5 min later, by 2 ml of aqueous ammonia (25%); this mixture is then stirred for a further 30 min. The solvent is stripped off and the residue is then evaporated with toluene. The residue is taken up in 15 ml of a saturated solution of NaHCO3, and this mixture is extracted one with 25 ml of methylene chloride and several times with ethyl acetate. The combined organic phases are dried using Na2SO4.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:16]1[CH:21]=[N:20][CH:19]=[CH:18][N:17]=1)C(OC(C)(C)C)=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].O.C(=O)=O>CO>[C:1]([O:5][C:6]([NH:8][C:16]1[CH:21]=[N:20][CH:19]=[CH:18][N:17]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1cnccn1
Agent: O=C=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)Nc1cnccn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 74.2 %

Procedure:
Di-(t-butoxycarbonyl)aminopyrazine (2.1 g, 7.1 mM) in methanol (50 ml) under nitrogen, was treated with aqueous sodium hydroxide (2.5 M, 2.84 ml, 7.1 mM), and stirred at ambient temperature for 2 hours. The mixture was neutralised by the addition of water (25 ml) and solid carbon dioxide, then methanol evaporated. The residual aqueous solution was extracted with dichloromethane (2×20 ml), the extracts washed with brine (20 ml) and evaporated. The resulting solid was triturated with isohexane (50 ml) to give the title product as a white solid (1.03 g). NMR (DMSO-d6) δ: 1.47 (s, 9H); 8.25 (d, 1H); 8.30 (d, 1H); 9.03 (s, 1H); 10.14 (s, 1H). MS (ESP): 196 (MH+) for C9H13N13O2
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]([C@H:7]2[O:9][C@@H:8]2[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[CH:5][CH:6]=1.[CH2:16]([NH2:22])[CH:17]1[O:21][CH2:20][CH2:19][CH2:18]1>O>[C:10]1([CH:8]([OH:9])[CH:7]([NH:22][CH2:16][CH:17]2[CH2:18][CH2:19][CH2:20][O:21]2)[C:4]2[CH:3]=[CH:2][CH:1]=[CH:6][CH:5]=2)[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: c1ccc([C@H]2O[C@@H]2c2ccccc2)cc1
Reactant: NCC1CCCO1
Solvent: O
Product: OC(c1ccccc1)C(NCC1CCCO1)c1ccccc1
Temperature: 140 °C
Reaction time: 18 h
Yield: 76.7 %

Procedure:
A mixture of trans-stilbene oxide (1.96 g, 0.010 mol) and tetrahydrofurfurylamine (3.03 g, 0.030 mol) was heated at 140° C. for 2 hours. After standing at ambient temperature for 18 hours the mixture was diluted with water (150 mL). An oil separated from the solution but solidified on standing for an hour. NMR and mass spectral analyses showed stilbene oxide remaining. The solid was treated with another 3.03 g of tetrahydrofurfurylamine and the mixture heated at 150° C. for another 3 hours. The reaction mixture was treated with water (150 mL) as before to obtain 2.28 g (77%) of an off-white solid after drying under ambient conditions for 18 hours. The solid was recrystallized form toluene; mp 167°-168° C.
Reaction SMILES: [OH:1][CH:2]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1)[C:3]1[CH:4]=[C:5]([C:16]([OH:18])=O)[CH:6]=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=2)[CH:8]=1.[CH3:25][C:26]1[N:31]=[CH:30][C:29]([CH2:32][NH2:33])=[CH:28][CH:27]=1.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[OH:1][CH:2]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1)[C:3]1[CH:4]=[C:5]([C:16]([NH:33][CH2:32][C:29]2[CH:30]=[N:31][C:26]([CH3:25])=[CH:27][CH:28]=2)=[O:18])[CH:6]=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=2)[CH:8]=1
Reactant: Cc1ccc(-c2cc(C(=O)O)cc(C(O)c3ccccn3)c2)cc1
Reactant: Cc1ccc(CN)cn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(-c2cc(C(=O)NCc3ccc(C)nc3)cc(C(O)c3ccccn3)c2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 5-(hydroxy-pyridin-2-yl-methyl)-4′-methyl-biphenyl-3-carboxylic acid (35 mg, 0.11 mmol) in N,N-dimethylformamide (1 mL) were added (6-methylpyridin-3-yl)methanamine (40 mg, 0.33 mmol), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (100 mg, 0.26 mmol), and N,N-diisopropylethylamine (100 μL, 0.57 mmol). The reaction mixture was stirred for 16 hours at 25° C. The reaction mixture was purified by preparative HPLC (100×21.2 mm C18 column, CH3CN/water[10 mM Et2NH]) to afford a light color solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:18]=[C:19]([Cl:21])[CH:20]=1)[CH2:5][C:6]1[C:7]([CH2:16][CH3:17])=[N:8][N:9]([CH2:13][CH2:14][NH2:15])[C:10]=1[CH2:11][CH3:12].[CH3:22][N:23]1[CH:27]=[C:26]([S:28](Cl)(=[O:30])=[O:29])[N:25]=[CH:24]1.C(N(CC)CC)C>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:18]=[C:19]([Cl:21])[CH:20]=1)[CH2:5][C:6]1[C:7]([CH2:16][CH3:17])=[N:8][N:9]([CH2:13][CH2:14][NH:15][S:28]([C:26]2[N:25]=[CH:24][N:23]([CH3:22])[CH:27]=2)(=[O:30])=[O:29])[C:10]=1[CH2:11][CH3:12]
Reactant: CCc1nn(CCN)c(CC)c1Cc1cc(Cl)cc(Cl)c1
Reactant: Cn1cnc(S(=O)(=O)Cl)c1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCc1nn(CCNS(=O)(=O)c2cn(C)cn2)c(CC)c1Cc1cc(Cl)cc(Cl)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 39 %

Procedure:
A solution of the amine of Example 43 (98 mg, 0.30 mmol) in dimethylformamide (3.75 ml) was treated with 1-methylimidazole-4-sulphonyl chloride (60 mg, 0.33 mmol) and triethylamine (46 μL, 0.33 mmol) and the resulting mixture was stirred at room temperature for 18 hours. The solution was concentrated under reduced pressure. The residue was partitioned between dichloromethane and saturated aqueous sodium hydrogencarbonate solution. The organic extract was dried over anhydrous magnesium sulphate, filtered and concentrated under reduced pressure. The crude material was purified by flash chromatography on silica gel eluting with dichloromethane:methanol (95:5, by volume) to afford the title compound (55 mg) as a white solid, m.p. 172-174° C.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:20][CH2:19][C:18]3[C:13](=[CH:14][CH:15]=[C:16]([O:21]C)[CH:17]=3)[CH:12]2[CH2:23][C:24]2[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].B(Br)(Br)Br>C(Cl)Cl>[C:1]([NH:4][C:5]1[CH:6]=[CH:7][C:8]([N:11]2[CH2:20][CH2:19][C:18]3[C:13](=[CH:14][CH:15]=[C:16]([OH:21])[CH:17]=3)[CH:12]2[CH2:23][C:24]2[CH:25]=[CH:26][C:27]([OH:30])=[CH:28][CH:29]=2)=[CH:9][CH:10]=1)(=[O:3])[CH3:2]
Reactant: COc1ccc2c(c1)CCN(c1ccc(NC(C)=O)cc1)C2Cc1ccc(O)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CC(=O)Nc1ccc(N2CCc3cc(O)ccc3C2Cc2ccc(O)cc2)cc1
Yield: 74.7 %

Procedure:
A solution of 2-(4-acetamidophenyl)-1-(4-hydroxybenzyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline (0.025 g, 0.062 mmol) in 1 mL of CH2Cl2 was demethylated with BBr3 as described in Example 30.G to provide the title compound (0.018 g, 75% yield). ES-MS, (m/z) 389 [M+H]+.
Reaction SMILES: [OH:1][C@:2]1([C:22]#[N:23])[CH2:7][CH2:6][C@H:5]2[C@H:8]3[C@H:18]([CH2:19][CH2:20][C@:3]12[CH3:4])[C@:16]1([CH3:17])[C:11](=[CH:12][C:13](=[O:21])[CH2:14][CH2:15]1)[CH2:10][CH2:9]3.Cl(O)(=O)(=O)=[O:25]>C(O)(=O)C.C(OC(=O)C)(=O)C>[OH:1][C@:2]1([C:22]([NH2:23])=[O:25])[CH2:7][CH2:6][C@H:5]2[C@H:8]3[C@H:18]([CH2:19][CH2:20][C@:3]12[CH3:4])[C@:16]1([CH3:17])[C:11](=[CH:12][C:13](=[O:21])[CH2:14][CH2:15]1)[CH2:10][CH2:9]3
Reactant: C[C@]12CCC(=O)C=C1CC[C@@H]1[C@@H]2CC[C@@]2(C)[C@H]1CC[C@]2(O)C#N
Reactant: [O-][Cl+3]([O-])([O-])O
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: C[C@]12CCC(=O)C=C1CC[C@@H]1[C@@H]2CC[C@@]2(C)[C@H]1CC[C@]2(O)C(N)=O
Temperature: 20 °C
Reaction time: 1 h

Procedure:
A solution of 6.26 g of 17α-hydroxy-17-cyano-4-androsten-3-one in 50 ml of glacial acetic acid and 50 ml of acetic anhydride is combined with 0.5 ml of 70% perchloric acid, and the mixture is allowed to stand for 1 hour at 20° C. The product is precipitated into ice water, filtered off, and then dissolved in 570 ml of methanol. This solution is combined with 61 ml of a 1 N potassium hydroxide solution, and the mixture is stirred overnight at 20° C. The methanolic solution is diluted with 500 g of ice water, the precipitated product is vacuum-filtered and dried. Repeated crystallization from ethyl acetate--methylene chloride yields 5.62 g of 17α-hydroxy-3-oxo-4-androstene-17-carboxylic acid amide, mp 271°-273.5° C.
Reaction SMILES: C([BH3-])#N.[Na+].[CH2:5]([CH:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:15][CH2:14][C:13]1=O)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[CH3:23][O:24][C:25]1[CH:32]=[CH:31][CH:30]=[CH:29][C:26]=1[CH2:27][NH2:28].C(O)(=O)C.C(=O)([O-])[O-].[Na+].[Na+]>CO>[CH2:5]([CH:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:15][CH2:14][CH:13]1[NH:28][CH2:27][C:26]1[CH:29]=[CH:30][CH:31]=[CH:32][C:25]=1[O:24][CH3:23])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: COc1ccccc1CN
Reactant: O=C1CCc2ccccc2C1Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: COc1ccccc1CNC1CCc2ccccc2C1Cc1ccccc1
Reaction time: 48 h
Yield: 76.8 %

Procedure:
Sodium cyanoborohydride (0.46 g, 7.28 mmol) was added to a solution of 1-benzyl-2-tetralone (0.86 g, 3.64 mmol), 2-methoxybenzylamine (0.50 g, 3.64 mmol), and acetic acid (0.22 g, 3.64 mmol) in methanol (10 mL) under nitrogen. After 48 h of stirring, the reaction mixture was concentrated in vacuo to provide a brown oil. Saturated aqueous sodium carbonate solution (25 mL) was added to this residue and the resulting mixture was extracted with chloroform. The chloroform extracts were combined, dried (Na2SO4), and concentrated to provide a brown oil which was purified on flash silica gel (1% methanol-chloroform to 5% methanol-chloroform) to provide 1.0 g of 1-benzyl-2-(2-methoxybenzylamino)tetralin as a brown oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:24]=[C:23]([OH:25])[CH:22]=[CH:21][C:16]=2[C:17]([O:19][CH3:20])=[O:18])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH3:32][O:33][CH2:34]Cl>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:24]=[C:23]([O:25][CH2:32][O:33][CH3:34])[CH:22]=[CH:21][C:16]=2[C:17]([O:19][CH3:20])=[O:18])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1ccc(O)cc1OC1CCN(C(=O)OC(C)(C)C)CC1
Reactant: COCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COCOc1ccc(C(=O)OC)c(OC2CCN(C(=O)OC(C)(C)C)CC2)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 96.4 %

Procedure:
Methyl 2-(1-tert-butoxycarbonylpiperidin-4-yloxy)-4-hydroxybenzoate (9.13 g, 26.0 mmol) was dissolved in DMF. Potassium carbonate (7.19 g, 52.0 mmol) was added, followed by methoxymethyl chloride (2.51 g, 31.2 mmol), and the reaction was stirred at room temperature under a drying tube for 24 h. An additional 1.2 eq of methoxymethyl chloride was added and the reaction stirred an additional 48 h. The DMF was removed in vacuo. The residue was dissolved in ethyl acetate, washed with water, dried, and the solvent was removed in vacuo to give 9.91 g (96.2%) of a viscous oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13]([C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=O)=[CH:16][CH:15]=2)=[CH:12][CH:11]=[N:10]1.[F:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30]C#N)=[CH:26][CH:25]=1>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13]([C:14]2[CH:19]=[CH:18][C:17]3=[N:20][O:22][C:30]([C:27]4[CH:28]=[CH:29][C:24]([F:23])=[CH:25][CH:26]=4)=[C:16]3[CH:15]=2)=[CH:12][CH:11]=[N:10]1
Reactant: N#CCc1ccc(F)cc1
Reactant: O=[N+]([O-])c1ccc(-c2ccnn2-c2ccc(F)cc2F)cc1
Product: Fc1ccc(-c2onc3ccc(-c4ccnn4-c4ccc(F)cc4F)cc23)cc1

Procedure:
The title compound, light grey solid (22 mg, 17%), MS (ISP) m/z=392.2 [(M+H)+], mp 149° C., was prepared in accordance with the general method of example 1 from 1-(2,4-difluoro-phenyl)-5-(4-nitro-phenyl)-1H-pyrazole (intermediate I) (100 mg, 353 μmol) and commercially available 2-(4-fluoro-phenyl)-acetonitrile.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH2:17][CH2:16][CH2:15]2)[CH:10]([C:18](=[O:20])[NH2:19])[CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[N:14]1([C@@H:11]2[CH2:12][CH2:13][NH:8][CH2:9][C@H:10]2[C:18]([NH2:19])=[O:20])[CH2:17][CH2:16][CH2:15]1
Reactant: CC(C)(C)OC(=O)N1CCC(N2CCC2)C(C(N)=O)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC(=O)[C@@H]1CNCC[C@H]1N1CCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 69 %

Procedure:
To a solution of 4-azetidin-1-yl-piperidine-1,3-dicarboxylic acid 1-tert-butyl ester 3-methyl ester (0.66 g. 2.21 mmol) in anhydrous DMF (13 mL) was added formamide (370 μL, 9.32 mmol). The mixture was heated to 100° C. and a solution of sodium methoxide in MeOH (25 w/w. 330 μL, 1.44 mmol) was added with heating being continued for 2 h. The reaction mixture was cooled to RT, then loaded onto an Isolute® SCX-2 cartridge. The cartridge was washed with MeOH then eluted with 2 M NH3 in MeOH to give 4-azetidin-1-yl-3-carbamoyl-piperidine-1-carboxylic acid tert-butyl ester. To a solution of 4-azetidin-1-yl-3-carbamoyl-piperidine-1-carboxylic acid tert-butyl ester in DCM (40 mL) was added TFA (5 mL) and the resulting mixture was stirred at RT for 1 h. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge, washed with MeOH then eluted with 2 M NH3 in MeOH to give a 1:1 cis:trans mixture of the title compound as a colourless oil (280 mg, 69%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([N:10]2[C:15]3[N:16]=[CH:17][CH:18]=[CH:19][C:14]=3[C:13](=[O:20])[NH:12][C:11]2=[O:21])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].CN(C)C=O.[H-].[Na+].C1(=O)O[CH2:32][CH2:31][O:30]1>O>[N+:1]([C:4]1[CH:5]=[C:6]([N:10]2[C:15]3[N:16]=[CH:17][CH:18]=[CH:19][C:14]=3[C:13](=[O:20])[N:12]([CH2:32][CH2:31][OH:30])[C:11]2=[O:21])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=C1OCCO1
Reactant: O=c1[nH]c(=O)n(-c2cccc([N+](=O)[O-])c2)c2ncccc12
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=c1c2cccnc2n(-c2cccc([N+](=O)[O-])c2)c(=O)n1CCO
Temperature: 150 °C
Yield: 86.6 %

Procedure:
To a solution of 2.8 g of 1-(m-nitrophenyl)pyrido[2,3-d]pyrimidine-2,4 (1H,3H)-dione and 30 ml of dimethylformamide was added 0.53 g of 55 % sodium hydride, and the solution was heated up to 150°C. To this was added 0.97 g of ethylene carbonate, and the mixture was reacted for one hour at 150°C. After the reaction was complete, the solvent was distilled off from the resulting mixture under reduced pressure. To the residue obtained was added water to precipitate a crude product. This product was recrystallized from methanol to yield 2.8 g of 1-(m-nitrophenyl)-3-(2-hydroxyethyl)pyrido[2,3-d] pyrimidine-2,4(1H,3H)-dione as pale yellow prisms, melting at 212°-213°C.
Reaction SMILES: [C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1)#[N:2].[CH3:11][C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13].[OH-].[Na+].O>C(O)C>[CH:14]1([C:12]([CH:11]=[CH:7][C:6]2[CH:9]=[CH:10][C:3]([C:1]#[N:2])=[CH:4][CH:5]=2)=[O:13])[CH2:16][CH2:15]1
Reactant: CC(=O)C1CC1
Reactant: N#Cc1ccc(C=O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: N#Cc1ccc(C=CC(=O)C2CC2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.2 %

Procedure:
To a solution of 39.3 g of 4-cyanobenzaldehyde and 25.2 g of cyclopropyl methyl ketone in 60 ml of absolute ethanol was added 21 ml of 20% sodium hydroxide solution over a 25 minute period. The mixture was stirred for one hour at room temperature, cooled to 1° C. and 40 ml of cold water added. The solid material was collected by filtration and triturated with 450 ml of methylene dichloride and 150 ml of water at room temperature. The aqueous phase was extracted with methylene dichloride and the combined organic layers dried and concentrated in vacuo. The residue was recrystallized from absolute ethanol to give 45.0 g of 4-cyanophenylvinyl cyclopropyl ketone, m.p. 104° C.
Reaction SMILES: [NH2:1][C:2]1([CH2:6][NH:7][C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([CH3:18])[CH:16]=3)[N:11]=[C:10]([N:19]3[CH2:25][C:24]4[CH:26]=[CH:27][CH:28]=[C:29](F)[C:23]=4[S:22](=[O:32])(=[O:31])[CH2:21][CH2:20]3)[CH:9]=2)[CH2:5][O:4][CH2:3]1.[CH3:33][O-:34].[Na+]>CO>[NH2:1][C:2]1([CH2:6][NH:7][C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([CH3:18])[CH:16]=3)[N:11]=[C:10]([N:19]3[CH2:25][C:24]4[CH:26]=[CH:27][CH:28]=[C:29]([O:34][CH3:33])[C:23]=4[S:22](=[O:32])(=[O:31])[CH2:21][CH2:20]3)[CH:9]=2)[CH2:5][O:4][CH2:3]1
Reactant: Cc1ccc2nc(N3CCS(=O)(=O)c4c(F)cccc4C3)cc(NCC3(N)COC3)c2c1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1cccc2c1S(=O)(=O)CCN(c1cc(NCC3(N)COC3)c3cc(C)ccc3n1)C2
Temperature: 100 °C
Reaction time: 0.33 h
Yield: 29.1 %

Procedure:
A mixture of N-[(3-aminooxetan-3-yl)methyl]-2-(9-fluoro-1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-amine (20 mg, 0.044 mmol, prepared in analogy to Example 1-4) and sodium methoxide (24 mg, 0.44 mmol) in methanol (2 mL) was heated with stirring in a sealed 5 mL of microwave process via for 20 minutes at 100° C. under microwave irradiation. The resulting mixture was concentrated in vacuo. The residue was purified by preparative HPLC to afford 6 mg of the product (yield was 29%). MS obsd. (ESI+) [(M+H)+] 469, 1H NMR (400 MHz, CD3OD) δ ppm 7.67 (s, 1 H), 7.62-7.52 (m, 1 H), 7.47 (d, J=8.59 Hz, 1 H), 7.41 (d, J=7.07 Hz, 1 H), 7.31 (dd, J=8.46, 1.89 Hz, 1 H), 7.16 (d, J=7.83 Hz, 1 H), 5.99 (s, 1 H), 5.08 (s, 2 H), 4.63-4.49 (m, 4 H), 4.31 (t, J=5.56 Hz, 2 H), 3.98-3.81 (m, 5 H), 3.54 (s, 2 H), 2.43 (s, 3 H).
Reaction SMILES: [C:1]([C:3]1[CH:19]=[CH:18][C:6]([CH2:7][N:8]([CH3:17])[CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=[C:5]([Cl:20])[CH:4]=1)#[N:2].[NH2:21][OH:22]>C(O)C>[Cl:20][C:5]1[CH:4]=[C:3]([C:1](=[N:21][OH:22])[NH2:2])[CH:19]=[CH:18][C:6]=1[CH2:7][N:8]([CH3:17])[CH2:9][C:10]([O:12][C:13]([CH3:15])([CH3:14])[CH3:16])=[O:11]
Reactant: NO
Reactant: CN(CC(=O)OC(C)(C)C)Cc1ccc(C#N)cc1Cl
Solvent: CCO
Product: CN(CC(=O)OC(C)(C)C)Cc1ccc(C(N)=NO)cc1Cl
Yield: 76 %

Procedure:
A solution of tert-butyl 2-((4-cyano-2-chlorobenzyl)(methyl)amino)acetate (1.25 g, 4.25 mmol) and 50% aqueous hydroxylamine (1.30 mL) in ethanol (10 mL) was heated at 80° C. for 5 hours. The solvent was evaporated under vacuum. The residue was partitioned between DCM and water. The organic phase was passed through a hydrophobic frit and concentrated under vacuum to afford the title compound (1.34 g, 76%). 1H NMR (CDCl3, 400 MHz) δ 7.63 (1H, d, J=1.8 Hz), 7.59 (1H, d, J=8.0 Hz), 7.50 (1H, dd, J=8.0, 1.8 Hz), 4.84 (2H, s), 3.83 (2H, s), 3.25 (2H, s), 2.42 (3H, s), 1.48 (9H, s).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:7](Cl)=[N:8][OH:9])=[N:4][O:5][N:6]=1.Cl.Cl.[NH2:13][CH2:14][CH2:15][NH:16][S:17]([CH3:20])(=[O:19])=[O:18].C(N(CC)CC)C>C(O)C>[NH2:1][C:2]1[C:3]([C:7](=[N:8][OH:9])[NH:13][CH2:14][CH2:15][NH:16][S:17]([CH3:20])(=[O:19])=[O:18])=[N:4][O:5][N:6]=1
Reactant: CS(=O)(=O)NCCN
Reactant: Nc1nonc1C(Cl)=NO
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CS(=O)(=O)NCCNC(=NO)c1nonc1N
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 100.9 %

Procedure:
4-Amino-N-hydroxy-1,2,5-oxadiazole-3-carboximidoyl chloride (9.7 g, 60 mmol) was stirred in ethanol (460 mL) and N-(2-aminoethyl)methanesulfonamide dihydrochloride (19 g, 109 mmol) was added slowly in portions and the temperature rose to 25° C. After cooling back to 0° C., triethylamine (53 mL, 380 mmol) was added dropwise over 15 minutes and the reaction was stirred for an additional 15 minutes. The solution was washed with water (300 mL) and brine (300 mL). The organic layer was dried over sodium sulfate and concentrated in vacuo to give the desired product (16 g, 100%). LCMS calculated for C6H13N6O4S (M+H)+: m/z=265.1. 1H NMR (400 MHz, DMSO-d6): δ 10.16 (s, 1H), 9.07 (m, 1H), 7.18 (m, 1H), 6.37 (s, 2H), 3.36 (m, 2H), 3.15 (m, 2H), 2.87 (s, 3H).