Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[CH2:5][N:6]1[CH2:11][CH2:10][N:9]([CH2:12][CH2:13][CH2:14][C:15]2[C:23]3[CH2:22][CH2:21][CH2:20][CH2:19][C:18]=3[NH:17][C:16]=2[CH:24]=O)[CH2:8][CH2:7]1)[CH3:2].[CH3:27][NH:28][S:29]([C:32]1[CH:33]=[C:34]2[C:38](=[CH:39][CH:40]=1)[NH:37][C:36](=[O:41])[CH2:35]2)(=[O:31])=[O:30]>>[CH2:1]([O:3][C:4](=[O:26])[CH2:5][N:6]1[CH2:11][CH2:10][N:9]([CH2:12][CH2:13][CH2:14][C:15]2[C:23]3[CH2:22][CH2:21][CH2:20][CH2:19][C:18]=3[NH:17][C:16]=2/[CH:24]=[C:35]2\[C:36](=[O:41])[NH:37][C:38]3[C:34]\2=[CH:33][C:32]([S:29](=[O:31])(=[O:30])[NH:28][CH3:27])=[CH:40][CH:39]=3)[CH2:8][CH2:7]1)[CH3:2]
Reactant: CCOC(=O)CN1CCN(CCCc2c(C=O)[nH]c3c2CCCC3)CC1
Reactant: CNS(=O)(=O)c1ccc2c(c1)CC(=O)N2
Product: CCOC(=O)CN1CCN(CCCc2c(/C=C3\C(=O)Nc4ccc(S(=O)(=O)NC)cc43)[nH]c3c2CCCC3)CC1

Procedure:
{(4-[3-(2-formyl-4,5,6,7-tetrahydro-1H-indol-3-yl)-propyl]-piperazin-1-yl}-acetic acid ethyl ester (60 mg, 0.1 73 mmol) was condensed with 5-methylaminosulfonyloxindole (45 mg, 0.1 9 mmol, 1.1 eq.) following the procedure used in Example 1 above. The reaction mixture was purified by flash chromatography (dichloromethane/methanol 10/1) to give the desired product.
Reaction SMILES: C([O:3][C:4](=O)[C@@:5]([NH2:24])([CH2:22][CH3:23])[CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[CH:10][CH:9]=1)C.[BH3-][C:27]#N.[Na+]>ClCCl.C(O)=O>[CH2:22]([C@@:5]([NH:24][CH3:27])([CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[CH:10][CH:9]=1)[CH2:4][OH:3])[CH3:23]
Reactant: [BH3-]C#N
Reactant: CCCCCCCOc1ccc(CC[C@](N)(CC)C(=O)OCC)cc1
Agent: [Na+]
Solvent: O=CO
Solvent: ClCCl
Product: CCCCCCCOc1ccc(CC[C@](CC)(CO)NC)cc1

Procedure:
(R)-2-amino-2-ethyl-4-(4-heptyloxy-phenyl)-butyric acid ethyl ester (175 mg; 0.5 mmol) is dissolved in dichloromethane (2) and formic acid (100 μl), p-formaldehyde (100 μl; 30% in water) and NaBH3CN are added. After 1 hour at RT the reaction mixture is extracted with saturated aqueous NaHCO3 solution and the organic layer is dried over MgSO4 and purified on silica gel using n-hexanetethyl acetate (1/1→1/9) as mobile phase.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:32][NH2:33])[CH2:14][CH2:13][CH2:12][N:11]3[C:15]([C:18]4[CH:23]=[CH:22][C:21]([C:24]5[O:28][C:27]([CH3:29])=[N:26][CH:25]=5)=[C:20]([O:30][CH3:31])[CH:19]=4)=[N:16][N:17]=[C:10]23)[CH:5]=[CH:6][C:7]=1[Cl:8].C(N(CC)CC)C.[C:41](OC(=O)C)(=[O:43])[CH3:42].O>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:32][NH:33][C:41](=[O:43])[CH3:42])[CH2:14][CH2:13][CH2:12][N:11]3[C:15]([C:18]4[CH:23]=[CH:22][C:21]([C:24]5[O:28][C:27]([CH3:29])=[N:26][CH:25]=5)=[C:20]([O:30][CH3:31])[CH:19]=4)=[N:16][N:17]=[C:10]23)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC(=O)OC(C)=O
Reactant: COc1cc(-c2nnc3n2CCCC3(CN)c2ccc(Cl)c(Cl)c2)ccc1-c1cnc(C)o1
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1cc(-c2nnc3n2CCCC3(CNC(C)=O)c2ccc(Cl)c(Cl)c2)ccc1-c1cnc(C)o1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of 1-{8-(3,4-dichlorophenyl)-3-[3-methoxy-4-(2-methyl-1,3-oxazol-5-yl)phenyl]-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyridin-8-yl}methanamine (76.7 mg) and triethylamine (26.2 μL) in THF (1 mL) was added acetic anhydride under ice-cooling, and the mixture was stirred at room temperature for 2 hr. Water was added to the reaction mixture, and the precipitated solid was collected by filtration. The solid was purified by silica gel column chromatography (methanol/ethyl acetate) to give the title compound (59.6 mg).
Reaction SMILES: N1CCCC(C(OCC)=O)C1.[N:12]1[CH:17]=[CH:16][C:15]([CH:18]2[CH2:23][NH:22][CH2:21][CH2:20][N:19]2[C:24]2[CH:42]=[CH:41][C:27]([C:28]([N:30]3[CH2:40][CH2:39][CH2:38][CH:32]([C:33]([O:35]CC)=[O:34])[CH2:31]3)=[O:29])=[CH:26][CH:25]=2)=[CH:14][CH:13]=1>>[N:12]1[CH:17]=[CH:16][C:15]([CH:18]2[CH2:23][NH:22][CH2:21][CH2:20][N:19]2[C:24]2[CH:25]=[CH:26][C:27]([C:28]([N:30]3[CH2:40][CH2:39][CH2:38][CH:32]([C:33]([OH:35])=[O:34])[CH2:31]3)=[O:29])=[CH:41][CH:42]=2)=[CH:14][CH:13]=1
Reactant: CCOC(=O)C1CCCN(C(=O)c2ccc(N3CCNCC3c3ccncc3)cc2)C1
Agent: CCOC(=O)C1CCCNC1
Product: O=C(O)C1CCCN(C(=O)c2ccc(N3CCNCC3c3ccncc3)cc2)C1
Yield: 35 %

Procedure:
In a similar manner to Example 56 but using ethyl nipecotate, was prepared ethyl 4-[(4-pyridyl)piperazin-1-yl]benzoylnipecotate in 35% yield as a solid; NMR (d6DMSO) δ1.15 (3H,t), 1.35-1.75 (3H,m), 1.9-2.05 (1H,m), 2.3-2.5(1H,m), 3.0-3.3 (4H,m), 3.3-3.4 (4H,m), 3.4-3.5 (4H,m), 4.05 (2H,q), 6.85 (2H,d), 6.95 (2H,d), 7.25 (2H,d), 8.15 (2H,d); m/e 423 (M+H)+ ; calculated for C24H30N4O3.0.5H2O: C, 66.8; H, 7.2; N, 13.0. Found C, 66.4; H, 7.3; N, 13.1%.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH3:9])=[CH:4][CH:3]=1.CC[O:20][CH2:21]C.C[Li].C([Li])CCC.C1C[O:33]CC1>>[C:13]([O:12][C:11]([NH:10][C@H:8]([C:5]1[CH:6]=[CH:7][C:2]([C:21]([OH:20])=[O:33])=[CH:3][CH:4]=1)[CH3:9])=[O:17])([CH3:16])([CH3:15])[CH3:14]
Reactant: CCOCC
Reactant: C[C@H](NC(=O)OC(C)(C)C)c1ccc(Br)cc1
Reactant: C1CCOC1
Agent: [Li]C
Agent: [Li]CCCC
Product: C[C@H](NC(=O)OC(C)(C)C)c1ccc(C(=O)O)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of tert-butyl [(1S)-1-(4-bromophenyl)ethyl]carbamate from Example 1, Step 7 (91.7 g, 305 mmol) in THF (1.5 L)/ether (300 mL) at −20° C. was added methyllithium (1.6M in ether, 229 mL, 366 mmol) and the mixture was slowly warmed to 0° C. and stirred for 30 min. and then cooled to −72° C. (internal temperature). n-Butyllithium (2.5M in hexanes, 146 mL, 366 mmol) was added dropwise and the mixture was stirred at −72° C. for 30 min. Excess CO2 gas was bubbled into the reaction mixture (white solid formation) and the suspension was allowed to warm in air for 30 min. and then to it was added 18 mL of acetic acid. The slurry was stirred at r.t. for 1 h and then filtered. The solid was collected and redissolved in acetic acid (50 mL), ethyl acetate and water and extracted with ethyl acetate. The organic layers were washed with water, dried over Na2SO4 and filtered. The crude product was washed with ether and dried under vacuum to give the desired product.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([SH:9])[N:3]=1.C1COCC1.C(N(CC)CC)C.[N+:22]([C:25]1[CH:32]=[CH:31][C:28]([CH2:29]Br)=[CH:27][CH:26]=1)([O-:24])=[O:23]>O>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([S:9][CH2:29][C:28]2[CH:31]=[CH:32][C:25]([N+:22]([O-:24])=[O:23])=[CH:26][CH:27]=2)[N:3]=1
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Reactant: Cc1cc(C)nc(S)n1
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1cc(C)nc(SCc2ccc([N+](=O)[O-])cc2)n1
Temperature: 25 °C
Yield: 56.5 %

Procedure:
To 4,6-dimethylpyrimidine-2-thiol (9.1 g) was added THF (70 ml), and to this solution was added triethylamine (21.5 ml) and then, 4-nitrobenzyl bromide (10 g), and the mixture was stirred for 5 hours at 50° C. After cooling to room temperature, the mixture was added to water, and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure and the obtained residue was washed with hexane/ethyl acetate, to give 4,6-dimethyl-2-[(4-nitrobenzyl)sulfanyl]pyrimidine (7.2 g).
Reaction SMILES: [CH3:1][C:2]1([C:15]2[CH:16]=[CH:17][C:18]3[O:22][C:21]4([CH3:29])[CH:23]5[CH2:27][C:26]([CH3:28])([C:20]4([CH3:30])[C:19]=3[CH:31]=2)[CH2:25][CH2:24]5)[C:6]2[CH:7]=[CH:8][C:9]([C:11]([O:13]C)=[O:12])=[CH:10][C:5]=2[O:4][CH2:3]1.[OH-].[Na+].[OH-].[Li+].CO>C1COCC1.O>[CH3:1][C:2]1([C:15]2[CH:16]=[CH:17][C:18]3[O:22][C:21]4([CH3:29])[CH:23]5[CH2:27][C:26]([CH3:28])([C:20]4([CH3:30])[C:19]=3[CH:31]=2)[CH2:25][CH2:24]5)[C:6]2[CH:7]=[CH:8][C:9]([C:11]([OH:13])=[O:12])=[CH:10][C:5]=2[O:4][CH2:3]1
Reactant: COC(=O)c1ccc2c(c1)OCC2(C)c1ccc2c(c1)C1(C)C3(C)CCC(C3)C1(C)O2
Agent: [Li+]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CC1(c2ccc3c(c2)C2(C)C4(C)CCC(C4)C2(C)O3)COc2cc(C(=O)O)ccc21
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of methyl 3-methyl-3-(1,2,3,4-tetrahydro-1,4a,9b-trimethyl-1,4-methanodibenzofur-8-yl)-2H-1-benzofuran-6-carboxylate (0.41 g, 0.98 mmol), sodium hydroxide (0.1 g, 2.5 mmol), lithium hydroxide (0.1 g, 2.5 mmol), methanol and water in THF is stirred for 48 h at room temperature.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1.CCN(C(C)C)C(C)C.[N:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[CH2:24][NH2:25].O>CC(O)C>[Cl:8][C:6]1[N:5]=[CH:4][N:3]=[C:2]([NH:25][CH2:24][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][N:18]=2)[CH:7]=1
Reactant: NCc1ccccn1
Reactant: Clc1cc(Cl)ncn1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: Clc1cc(NCc2ccccn2)ncn1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 77.7 %

Procedure:
To a solution of 4,6-dichloro-pyrimidine (1 g, 7 mmol) in iPrOH (40 mL) and DIPEA (1.16 g, 9 mmol) was added a solution of 2-pyridinylmethanamine (970 g, 9 mmol) at room temperature. The resulting mixture was stirred at room temperature for 2.5 hours. Water was added and the mixture was extracted with DCM. The combined extracts were washed with brine, dried over anhydrous sodium sulfate and concentrated to give a crude product, which was purified by flash chromatography on silica to obtain the title compound (1.2 g, yield: 78%). MS (ESI): 221 [M+H]+.
Reaction SMILES: N#N.[N+:3]([C:6]1[CH:7]=[N:8][N:9]([CH2:11][C:12]2[O:16][C:15]([CH2:17][OH:18])=[CH:14][CH:13]=2)[CH:10]=1)([O-:5])=[O:4]>C(C#N)(C)=O.O=[Mn]=O>[N+:3]([C:6]1[CH:7]=[N:8][N:9]([CH2:11][C:12]2[O:16][C:15]([CH:17]=[O:18])=[CH:14][CH:13]=2)[CH:10]=1)([O-:5])=[O:4]
Reactant: O=[N+]([O-])c1cnn(Cc2ccc(CO)o2)c1
Agent: O=[Mn]=O
Agent: CC(=O)C#N
Agent: N#N
Product: O=Cc1ccc(Cn2cc([N+](=O)[O-])cn2)o1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of [5-(4-nitro-pyrazol-1-ylmethyl)-furan-2-yl]-methanol (7.0 g, 15.68 mmol) in AcCN (320.0 mL) was treated at rt with MnO2 (18.2 g, 188.18 mmol). The reaction mixture was stirred at rt overnight before being filtered through Celite and the solvent was removed under reduced pressure. Purification of the residue by FC (60:40 hept-EA) gave the title compound. TLC: rf (60:40 hept-EA)=0.16. LC-MS-conditions 02: tR=0.80 min. 1H NMR (400 MHz, CDCl3) δ 5.44 (s, 2H), 6.66 (d, J=3.5 Hz, 1H), 7.25 (d, J=3.5 Hz, 1H), 8.10 (s, 1H), 8.28 (s, 1H), 9.65 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:20][C:21]([OH:23])=O)[CH:6]=[CH:7][C:8]=1[NH:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:19])=[O:11].[CH2:24]([O:26][C:27]([C:29]1[CH:34]=[CH:33][C:32]([C:35]#[C:36][CH:37]2[CH2:41][CH2:40][CH2:39][NH:38]2)=[CH:31][CH:30]=1)=[O:28])[CH3:25].C(Cl)CCl.Cl>CN(C1C=CN=CC=1)C.CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:20][C:21]([N:38]2[CH2:39][CH2:40][CH2:41][CH:37]2[C:36]#[C:35][C:32]2[CH:33]=[CH:34][C:29]([C:27]([O:26][CH2:24][CH3:25])=[O:28])=[CH:30][CH:31]=2)=[O:23])[CH:6]=[CH:7][C:8]=1[NH:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:19])=[O:11]
Reactant: COc1cc(CC(=O)O)ccc1NC(=O)Nc1ccccc1C
Reactant: CCOC(=O)c1ccc(C#CC2CCCN2)cc1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(C#CC2CCCN2C(=O)Cc2ccc(NC(=O)Nc3ccccc3C)c(OC)c2)cc1
Reaction time: 8 h
Yield: 88.6 %

Procedure:
A mixture of 3-methoxy-4-[N′-(2-methylphenyl)ureido]phenylacetic acid (1.45 g, 4.6 mmol), 2-(2-(4-ethoxycarbonylphenyl)ethynyl)pyrrolidine (1.12 g, 4.6 mmol), EDC 1.32 g (6.9 mmol), DMAP (562 mg, 4.6 mmol) in DMF (20 mL) was stirred overnight. The mixture was poured into 1 N HCl and the solid was collected with suction. The solid was dissolved in CHCl3 and died over MgSO4. After removal of the solvent, the residue was chromatographed on silica-gel with CHCl3—MeOH (100:1, v/v) as eluent to give 2.20 g (89%) ethyl 4-[2-[1-[3-methoxy-4-(N′-(2-methylphenyl)ureido]phenylacetyl]-2-pyrrolidinyl]ethynyl]benzoate as a white amorphous solid. 1H-NMR (CDCl3) δ1.37-1.41 (3 H, m), 1.94-2.22 (4 H, m), 2.29 (3 H, s), 3.41-3.89 (2 H, m), 3.62 (3 H, s), 3.69 (2 H, s), 4.34-4.40 (2 H, m), 4.72-5.01 (1 H, m), 6.33 (1 H, br s), 6.80-8.06 (12 H, m).
Reaction SMILES: O=[C:2]([C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([C:37]([F:40])([F:39])[F:38])[CH:32]=1)[CH2:3][C@@H:4]1[CH2:8][CH2:7][N:6]([C@H:9]2[CH2:14][CH2:13][C@@H:12]([N:15]([CH:17]([CH3:19])[CH3:18])[CH3:16])[CH2:11][C@H:10]2[CH2:20][S:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)(=[O:23])=[O:22])[C:5]1=[O:30].[O:41]([NH2:43])[CH3:42].Cl.CC([O-])=[O:47].[Na+]>CO>[F:38][C:37]([F:40])([F:39])[C:42]([OH:41])=[O:47].[CH:17]([N:15]([CH3:16])[C@@H:12]1[CH2:13][CH2:14][C@H:9]([N:6]2[CH2:7][CH2:8][C@@H:4]([CH2:3][C:2](=[N:43][O:41][CH3:42])[C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([C:37]([F:38])([F:40])[F:39])[CH:32]=3)[C:5]2=[O:30])[C@H:10]([CH2:20][S:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)(=[O:23])=[O:22])[CH2:11]1)([CH3:18])[CH3:19]
Reactant: CC(C)N(C)[C@@H]1CC[C@H](N2CC[C@@H](CC(=O)c3cccc(C(F)(F)F)c3)C2=O)[C@H](CS(=O)(=O)c2ccccc2)C1
Reactant: CON
Reactant: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CON=C(C[C@@H]1CCN([C@H]2CC[C@@H](N(C)C(C)C)C[C@H]2CS(=O)(=O)c2ccccc2)C1=O)c1cccc(C(F)(F)F)c1
Product: O=C(O)C(F)(F)F

Procedure:
A stirred mixture of Example 41 (19.7 mg, 34 μmol), methoxylamine.HCl (17 mg, 204 μmol), NaOAc (17 mg, 204 μmol), and MeOH (2 mL) was heated at 50° C. for 24 h. The solvent was removed under vacuum and the residue was dissolved in EtOAc (500 mL). The organic mixture was washed with satd NaHCO3 (3×100 mL), water (200 mL), and brine (200 mL), dried over Na2SO4, filtered, and evaporated. The residue was lyophilized from CH3CN/H2O/TFA give the title compound as a mixture of (E) and (Z) isomers (26.9 mg, 95%): 1H NMR (500 MHz, CDCl3) δ 11.03 (s, 1H), 7.97–7.86 (m, 3H), 7.83–7.76 (m, 1H), 7.70–7.63 (m, 1H), 7.62–7.53 (m, 3H), 7.50–7.41 (m, 1H), 4.32–4.20 (m, 1H), 3.99 (s, 3H), 3.95–3.85 (m, 1H), 3.60–3.43 (m, 2H), 3.32–3.20 (m, 1H), 3.15–2.94 (m, 2H), 2.91–2.77 (m, 2H), 2.75–2.65 (m, 3H), 2.63–2.50 (m, 2H), 2.20–1.68 (m, 7H), 1.50–1.40 (m, 3H), 1.35–1.24 (m, 5H); 19F NMR (282 MHz, CDCl3) δ −63.1, −76.3; ESI MS m/z 608 [C31H40F3N3O4S+H]+.1.
Reaction SMILES: [CH3:1][N:2]1[C:8](=[O:9])[C:7]2[C:10]([CH3:14])=[CH:11][CH:12]=[CH:13][C:6]=2[N:5]2[CH:15]=[N:16][CH:17]=[C:4]2[CH2:3]1.[I:18]I.S([O-])([O-])(=O)=S.[Na+].[Na+].C(=O)(O)[O-].[Na+]>CN(C)C=O.C(Cl)Cl.O>[I:18][C:17]1[N:16]=[CH:15][N:5]2[C:6]3[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[C:7]=3[C:8](=[O:9])[N:2]([CH3:1])[CH2:3][C:4]=12
Reactant: Cc1cccc2c1C(=O)N(C)Cc1cncn1-2
Reactant: II
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cccc2c1C(=O)N(C)Cc1c(I)ncn1-2

Procedure:
15.85 g (69.7 mmol) of 4,5-dihydro-5,7-dimethyl-6H-imidazo[1,5-a][1,4]benzodiazepin-6-one was heated to 95° for 2.5 hours with 67 g (264 mmol) of iodine in 100 ml of N,N-dimethylformamide. The reaction mixture was then poured into 450 ml of water, treated with methylene chloride, decolorized with sodium thiosulphate and neutralized with sodium bicarbonate. The aqueous phase was separated and extracted six times with methylene chloride. The combined organic phases were washed three times with water, dried over magnesium sulphate and evaporated. By chromatography of the residue on silica gel while eluting with ethyl acetate and recrystallization from ethyl acetate and hexane there was obtained 4,5-dihydro-3-iodo-5,7-dimethyl-6H-imidazo[1,5-a][1,4]benzodiazepin-6-one of melting point 106°-108°.
Reaction SMILES: [CH3:1][O:2][CH:3]=[CH2:4].[C:5]1([OH:11])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[Cl:12]OC(C)(C)C>O1CCCC1>[CH3:1][O:2][CH:3]([O:11][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH2:4][Cl:12]
Reactant: CC(C)(C)OCl
Reactant: C=COC
Reactant: Oc1ccccc1
Solvent: C1CCOC1
Product: COC(CCl)Oc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
At -20° C., 10 parts by weight of vinyl methyl ether is added all at once to 4.5 parts by weight of phenol in 50 parts by weight of tetrahydrofuran. Over a period of 30 minutes and at -20° C., 10 parts of tert.-butyl hypochlorite (Org. Synthesis, Coll. Vol. IV, 125, John Wiley & Sons, Inc., New York/London, 1963) is dripped into this mixture. The resultant mixture is allowed to come to room temperature. After stirring for 2 hours at room temperature, the solvent is removed, and distillation gives 5 parts by weight of 1-methoxy-1-phenoxy-2-chloroethane, b.p. 89°-91° C./4mm Hg.
Reaction SMILES: C([O:4][CH:5]([C:13]1[CH:21]=[C:20]2[C:16]([CH:17]=[CH:18][CH2:19]2)=[CH:15][CH:14]=1)[CH2:6][O:7][CH2:8][CH2:9][N:10]([CH3:12])[CH3:11])(=O)C.C[O-].[Na+].CO.[ClH:27].C(O)C>CO.C(O)C>[ClH:27].[CH2:19]1[C:20]2[C:16](=[CH:15][CH:14]=[C:13]([CH:5]([OH:4])[CH2:6][O:7][CH2:8][CH2:9][N:10]([CH3:11])[CH3:12])[CH:21]=2)[CH:17]=[CH:18]1
Reactant: CC(=O)OC(COCCN(C)C)c1ccc2c(c1)CC=C2
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: CCO
Product: CN(C)CCOCC(O)c1ccc2c(c1)CC=C2
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
In 0.5 ml of methanol was dissolved 80 mg of 1-acetoxy-1-(1H-inden-6-yl)-2-[2-(N,N-dimethylamino)ethoxy]ethane. To the solution was added 80 mg of a 28% sodium methoxide-methanol solution with ice cooling. The resulting mixture was stirred at room temperature for 20 minutes. The solvent was removed by distillation under reduced pressure. The residue thus obtained was purified by column chromatography (eluant: chloroform/methanol=20/1) to obtain a yellow oily product. The oily product was dissolved in 0.1 ml of ethanol. To the solution was added 0.1 ml of a 5.9N dry hydrogen chloride-ethanol solution at room temperature. The resulting crystals were collected by filtration to obtain 20 mg of 1-(1H-inden-6-yl)-2-[2-(N,N-dimethylamino)ethoxy]ethanol hydrochloride (compound No. 298).
Reaction SMILES: [CH3:1][CH:2]([CH3:6])[C:3](=[S:5])[NH2:4].[Cl:7][CH2:8][C:9](=O)[CH2:10]Cl>C(O)C>[Cl:7][CH2:8][C:9]1[N:4]=[C:3]([CH:2]([CH3:6])[CH3:1])[S:5][CH:10]=1
Reactant: O=C(CCl)CCl
Reactant: CC(C)C(N)=S
Solvent: CCO
Product: CC(C)c1nc(CCl)cs1
Yield: 71.5 %

Procedure:
A mixture of 2-methylpropanethioamide (5.20 g), 1,3-dichloro-2-propanone (7.03 g) and ethanol (100 mL) was heated under reflux for 2 hrs. The reaction mixture was concentrated and ethyl acetate was added to the residue. The ethyl acetate layer was washed successively with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give 4-chloromethyl-2-isopropyl-1,3-thiazole as a colorless oil (6.33 g, yield 72%) from a fraction eluted with ethyl acetate-hexane (1:20, v/v).
Reaction SMILES: [CH2:1]([C:5]1[CH:6]=[C:7]([C:11]([OH:13])=O)[S:8][C:9]=1[CH3:10])[CH:2]([CH3:4])[CH3:3].[CH2:14]([O:17][C:18]1[CH:27]=[CH:26][C:21]([C:22]([NH:24]O)=[NH:23])=[C:20]([O:28][CH3:29])[CH:19]=1)[CH:15]=[CH2:16].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C.C(OCC)C>[CH2:14]([O:17][C:18]1[CH:27]=[CH:26][C:21]([C:22]2[N:23]=[C:11]([C:7]3[S:8][C:9]([CH3:10])=[C:5]([CH2:1][CH:2]([CH3:3])[CH3:4])[CH:6]=3)[O:13][N:24]=2)=[C:20]([O:28][CH3:29])[CH:19]=1)[CH:15]=[CH2:16]
Reactant: C=CCOc1ccc(C(=N)NO)c(OC)c1
Reactant: Cc1sc(C(=O)O)cc1CC(C)C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCOCC
Solvent: CCN(C(C)C)C(C)C
Product: C=CCOc1ccc(-c2noc(-c3cc(CC(C)C)c(C)s3)n2)c(OC)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 62.1 %

Procedure:
To a mixture of 4-isobutyl-5-methyl-thiophene-2-carboxylic acid (505 mg, 2.55 mmol), 4-allyloxy-N-hydroxy-2-methoxy-benzamidine (611 mg, 2.75 mmol) and DIPEA (377 mg, 2.92 mmol) in DMF (10 mL) is added TBTU (882 mg, 2.75 mmol). The mixture is stirred at rt for 15 h before it is diluted with diethyl ether (100 mL) and washed with 1 N aq. NaOH (2×30 mL), 1 M aq. KHSO4 (30 mL) and brine (30 mL). The organic extract is dried (Na2SO4), filtered and evaporated. The yellow oily residue is dissolved in dry toluene (10 mL) and heated at 150° C. for 20 min in a microwave oven. The mixture is poured into diethyl ether (100 mL) and washed with brine (75 mL). The organic extract is dried (Na2SO4), filtered and evaporated to give 3-(4-allyloxy-2-methoxy-phenyl)-5-(4-isobutyl-5-methyl-thiophen-2-yl)-[1,2,4]oxadiazole (609 mg) as a yellow solid; LC-MS: tR=1.19 min, [M+1]=385.23.
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[CH:6][C:7]([C:15]([OH:17])=O)=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:14][CH2:13]2)[CH2:3][CH2:2]1.Cl.[NH2:19][C:20]1([CH2:26][OH:27])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1>>[OH:27][CH2:26][C:20]1([NH:19][C:15]([C:7]2[CH:6]=[N:5][C:4]([CH:1]3[CH2:2][CH2:3]3)=[C:9]([O:10][CH2:11][CH:12]3[CH2:13][CH2:14]3)[N:8]=2)=[O:17])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: NC1(CO)CCCCC1
Reactant: O=C(O)c1cnc(C2CC2)c(OCC2CC2)n1
Agent: Cl
Product: O=C(NC1(CO)CCCCC1)c1cnc(C2CC2)c(OCC2CC2)n1

Procedure:
The title compound was synthesized in analogy to Example 69, using 5-cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid (Example 10 g, 50 mg, 0.214 mmol) and (1-amino-cyclohexyl)-methanol hydrochloride (CAN 5460-68-4, 22.8 mg, 0.17 mmol) as starting materials and isolated (46 mg, 62.32%) as white solid; LC-MS (UV peak area, ESI) 96.49%, 346.0 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:26]=[CH:25][C:5]2[C:6]3[N:10]([CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1)[CH:9]=[C:8]([C:14]1[N:15]([CH2:20][C:21]([F:24])([F:23])[F:22])[N:16]=[C:17]([CH3:19])[N:18]=1)[N:7]=3.[CH3:27][C:28]1[CH:39]=[CH:38][CH:37]=[CH:36][C:29]=1[CH2:30][CH:31]1[CH2:35][CH2:34][CH2:33][NH:32]1.CN1C(=O)CCC1>C(N(CC)CC)C>[CH3:19][C:17]1[N:18]=[C:14]([C:8]2[N:7]=[C:6]3[C:5]4[CH:25]=[N:26][C:2]([N:32]5[CH2:33][CH2:34][CH2:35][CH:31]5[CH2:30][C:29]5[CH:36]=[CH:37][CH:38]=[CH:39][C:28]=5[CH3:27])=[CH:3][C:4]=4[O:13][CH2:12][CH2:11][N:10]3[CH:9]=2)[N:15]([CH2:20][C:21]([F:24])([F:22])[F:23])[N:16]=1
Reactant: Cc1nc(-c2cn3c(n2)-c2cnc(Cl)cc2OCC3)n(CC(F)(F)F)n1
Reactant: Cc1ccccc1CC1CCCN1
Solvent: CN1CCCC1=O
Solvent: CCN(CC)CC
Product: Cc1nc(-c2cn3c(n2)-c2cnc(N4CCCC4Cc4ccccc4C)cc2OCC3)n(CC(F)(F)F)n1
Temperature: 160 °C
Yield: 25.2 %

Procedure:
A 10 mL microwave vial was charged with 8-Chloro-2-[5-methyl-2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1,3a,9-triaza-benzo[e]azulene (85 mg, 0.22 mmol) and 2-(2-Methyl-benzyl)-pyrrolidine (231 mg, 6 eq). 0.5 mL of NMP and 0.5 mL of triethylamine was added. The vial was sealed and heated at 160° C. for 24 h. After cooling to room temperature, the solution was purified directly by reverse phase HPLC (0.1% NH4OH/ACN). The isolated solid was further purified by chiral SFC (AD column, 35% MeOH isocratic) to give 27 mg of one enantiomer and 29 mg of 420 (48% total yield). LCMS: 524.2. 1H NMR (400 MHz, DMSO) δ 9.08 (s, 1H), 9.08 (s, 1H), 7.92 (s, 1H), 7.27-7.06 (m, 4H), 5.99 (s, 1H), 5.80 (q, J=8.9 Hz, 2H), 4.50 (m, 4H), 4.38 (br s, 1H), 3.49 (t, J=8.6 Hz, 1H), 3.15 (d, J=10.0 Hz, 1H), 2.60-2.53 (m, 1H), 2.42 (s, 3H), 2.28 (s, 3H), 2.10-1.89 (m, 2H), 1.81-1.71 (m, 2H)
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3](=[O:17])[CH2:4][C:5]([C:7]1[CH:12]=[C:11]([CH3:13])[C:10]([O:14][CH3:15])=[CH:9][C:8]=1[CH3:16])=O.[CH3:20][NH:21][NH2:22]>C(O)C>[CH3:15][O:14][C:10]1[C:11]([CH3:13])=[CH:12][C:7]([C:5]2[CH2:4][C:3]([C:2]([F:19])([F:18])[F:1])([OH:17])[N:21]([CH3:20])[N:22]=2)=[C:8]([CH3:16])[CH:9]=1.[CH3:15][O:14][C:10]1[C:11]([CH3:13])=[CH:12][C:7]([C:5]2[N:21]([CH3:20])[N:22]=[C:3]([C:2]([F:19])([F:18])[F:1])[CH:4]=2)=[C:8]([CH3:16])[CH:9]=1
Reactant: COc1cc(C)c(C(=O)CC(=O)C(F)(F)F)cc1C
Reactant: CNN
Solvent: CCO
Product: COc1cc(C)c(-c2cc(C(F)(F)F)nn2C)cc1C
Product: COc1cc(C)c(C2=NN(C)C(O)(C(F)(F)F)C2)cc1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
At 0° C., to a mixture of 4,4,4-trifluoro-1-(4-methoxy-2,5-dimethyl-phenyl)-butane-1,3-dione (described in Reference Preparation example 83) 6.8 g and ethanol 100 ml was added methyl hydrazine 1.7 g. The resulting mixture was raised to room temperature and was stirred for one hour. The reaction mixture was concentrated under reduced pressure and the resulting residue was subjected to a silica gel column chromatography to give 5-(4-methoxy-2,5-dimethyl-phenyl)-2-methyl-3-trifluoromethyl-3,4-dihydro-2H-pyrazole-3-ol 3.2 g and 5-(4-methoxy-2,5-dimethyl-phenyl)-1-methyl-3-trifluoromethyl-1H-pyrazole 3 g.