Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C@H:4]([OH:7])[CH2:5][OH:6].[CH3:8][C:9]1([CH3:33])[CH2:18][CH2:17][C:16]([CH3:20])([CH3:19])[C:15]2[CH:14]=[C:13]([C:21]3[N:22]=[C:23]([N:26]4[CH2:31][CH2:30][C:29](=O)[CH2:28][CH2:27]4)[S:24][CH:25]=3)[CH:12]=[CH:11][C:10]1=2.Cl>>[CH3:8][C:9]1([CH3:33])[CH2:18][CH2:17][C:16]([CH3:19])([CH3:20])[C:15]2[CH:14]=[C:13]([C:21]3[N:22]=[C:23]([N:26]4[CH2:31][CH2:30][CH:29]([NH:1][CH2:2][CH2:3][C@H:4]([OH:7])[CH2:5][OH:6])[CH2:28][CH2:27]4)[S:24][CH:25]=3)[CH:12]=[CH:11][C:10]1=2
Reactant: CC1(C)CCC(C)(C)c2cc(-c3csc(N4CCC(=O)CC4)n3)ccc21
Reactant: NCC[C@H](O)CO
Agent: Cl
Product: CC1(C)CCC(C)(C)c2cc(-c3csc(N4CCC(NCC[C@H](O)CO)CC4)n3)ccc21

Procedure:
The preparation is carried out analogously starting from 22 mg (0.21 mmol) of (S)-4-aminobutane-1,2-diol and 80 mg (0.21 mmol) of 1-[4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)thiazol-2-yl]piperidin-4-one. The product is in the form of the hydrochloride.
Reaction SMILES: [CH2:1]([N:8]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:17]3[CH:18]=[C:19]([CH:27]4[O:32][CH2:31][CH:30]5[CH2:33][NH:34][CH2:35][CH2:36][N:29]5[CH2:28]4)[N:20]4[C:25]=3[C:24]([NH2:26])=[N:23][CH:22]=[N:21]4)[CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:44](O)(=[O:47])[CH2:45][OH:46].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C>[NH2:26][C:24]1[C:25]2=[C:17]([C:12]3[CH:13]=[CH:14][C:15]4[C:10]([CH:11]=3)=[N:9][N:8]([CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH:16]=4)[CH:18]=[C:19]([CH:27]3[O:32][CH2:31][CH:30]4[CH2:33][N:34]([C:45](=[O:46])[CH2:44][OH:47])[CH2:35][CH2:36][N:29]4[CH2:28]3)[N:20]2[N:21]=[CH:22][N:23]=1
Reactant: Nc1ncnn2c(C3CN4CCNCC4CO3)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Reactant: O=C(O)CO
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Nc1ncnn2c(C3CN4CCN(C(=O)CO)CC4CO3)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 37.1 %

Procedure:
To a stirred solution of 5-(2-benzyl-2H-indazol-6-yl)-7-(octahydropyrazino[2,1-c][1,4]oxazin-3-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (50 mg, 0.10 mmol), triethylamine (43 μL, 0.31 mmol), and glycolic acid (8 mg, 0.10 mmol) in DMF (1 mL), benzotriazol-1-yloxytris(dimethylamino)-phosphonium hexafluorophosphate (51 mg, 0.11 mmol) was added at 0° C. The reaction was allowed to stir for 30 minutes while warming to rt. The mixture was partitioned between ethyl acetate (30 mL) and saturated aqueous K2CO3 solution (10 mL). The layers were separated and the organic phase was washed, dried (Na2SO4), and concentrated to dryness. The residue was triturated with Et2O to obtain 20 mg (36%) of the desired product. 1H-NMR (DMSO-d6) 8.53 (s, 1H), 7.91 (s, 1H), 7.78 (d, 1H), 7.57 (s, 1H), 7.35 to 7.27 (m, 5H), 7.11 (dd, 1H), 6.71 (s, 1H), 5.64 (s, 2H), 5.16-5.12 (m, 1H), 4.35-3.96 (m, 3H), 3.88-3.85 (m, 1H), 3.67-3.55 (m, 1H), 3.36-3.27 (m, 1H), 3.12-3.01 (m, 1H), 2.79-2.64 (m, 2H), 2.55-2.41 (m, 3H), 2.19-2.10 (m, 2H); LC-MS [M+H]+=539, RT=2.19 min.
Reaction SMILES: [C:1]([OH:13])(=[O:12])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]CCC(O)=O.C[OH:15]>>[OH:15][C:3]1[CH:4]=[C:5]([CH3:6])[O:12][C:1](=[O:13])[CH:2]=1
Reactant: O=C(O)CCCCCCCC(=O)O
Reactant: CO
Product: Cc1cc(O)cc(=O)o1

Procedure:
Similar to Example 150, 6.81 g (21.9 mmol, 73%) of a methyl ester compound was obtained as orange crystals from 6.08 g (0.0 mmol recrystallized from 3 methanol) of monomethyl ester of azelaic acid and 3.78 g (30.0 mmol) of 4-hydroxy-6-methyl-2-pyrone by recrystallization from methanol.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[C:6]2=[C:9]([C:23]3[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=3)[C:26]([OH:28])=[O:27])[N:10]([CH2:12][C:13]3[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[CH:16]=[CH:15][CH:14]=3)[N:11]=[C:5]2[NH:4][C:3]1=[O:32].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl:52][C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][C:54]=1[CH2:59]O>C1COCC1>[Cl:52][C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][C:54]=1[CH2:59][N:4]1[C:5]2=[N:11][N:10]([CH2:12][C:13]3[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[CH:16]=[CH:15][CH:14]=3)[C:9]([C:23]3[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=3)[C:26]([OH:28])=[O:27])=[C:6]2[C:7](=[O:8])[N:2]([CH3:1])[C:3]1=[O:32]
Reactant: OCc1ccccc1Cl
Reactant: Cn1c(=O)[nH]c2nn(Cc3cccc4ccccc34)c(-c3cccc(C(=O)O)c3)c2c1=O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cn1c(=O)c2c(-c3cccc(C(=O)O)c3)n(Cc3cccc4ccccc34)nc2n(Cc2ccccc2Cl)c1=O
Reaction time: 20 h

Procedure:
Diisipropylazodicarboxylate (0.157 g) was added to a mixture of resin bound 3-[5-methyl-2-(1-naphthylmethyl)-4,6-dioxo-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-d]pyrimidin-3-yl]benzoic acid (0.120 g), triphenylphosphine (0.204 g), and 2-chlorophenylmethanol in dry THF (2 mL) at −15° C. Reaction temperature was allowed to come to room temperature and shaken for 20 h. The resin was filtered, washed (3 times) DMF, CH2Cl2, MeOH, CH2Cl2, and dried in vacuum. The dry resin was treated with 15% TFA in dichloromethane (1 mL) for 2 h, and filtered and washed (2 times) with dichloromethane. Combined filtrates were concentrated, and dried in vacuum to give the title compound (0.062 g). Mass 548.80 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][CH2:7][NH:8][C:9]([C:11]2[CH:30]=[CH:29][C:14]([O:15][C:16]3[CH:21]=[CH:20][C:19]([CH2:22][C:23]([O:25]C)=[O:24])=[CH:18][C:17]=3[O:27][CH3:28])=[CH:13][CH:12]=2)=[O:10])=[CH:4][CH:3]=1.[OH-].[Na+]>CO.C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH2:7][NH:8][C:9]([C:11]2[CH:12]=[CH:13][C:14]([O:15][C:16]3[CH:21]=[CH:20][C:19]([CH2:22][C:23]([OH:25])=[O:24])=[CH:18][C:17]=3[O:27][CH3:28])=[CH:29][CH:30]=2)=[O:10])=[CH:31][CH:32]=1
Reactant: COC(=O)Cc1ccc(Oc2ccc(C(=O)NCCc3ccc(Cl)cc3)cc2)c(OC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COc1cc(CC(=O)O)ccc1Oc1ccc(C(=O)NCCc2ccc(Cl)cc2)cc1
Reaction time: 0.08 h
Yield: 65.2 %

Procedure:
To a solution of methyl 2-(4-(4-((4-chlorophenethyl)carbamoyl)phenoxy)-3-methoxyphenyl)acetate (0.065 g, 0.143 mmol) in methanol/THF (1:1, 3 ml) was added NaOH (0.100 ml, 0.500 mmol). After 5 minutes, reaction was quenched with 10 ml of 2N HCl and the product was extracted into ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and concentrated. The crude material was purified by silica gel chromatography, eluting with a gradient of 0.5% methanol/dichloromethane (containing 0.5% AcOH) to 7.5% methanol/dichloromethane containing (0.5% AcOH) to provide 2-(4-(4-((4-chlorophenethyl)carbamoyl)phenoxy)-3-methoxyphenyl)acetic acid (0.041 g, 65.1% yield) as a white solid. 1H NMR (400 MHz, CD3OD) δ 8.37-8.41 (bt, NH), 7.70 (d, J=8.7 Hz, 2H), 7.28 (d, J=8.6 Hz, 2H), 7.23 (d, J=8.5 Hz, 2H), 7.08 (s, 1H), 7.02 (d, J=8.6 Hz, 1H), 6.91 (d, J=8.6 Hz, 2H), 3.64 (s, 2H), 3.56 (t, J=6.8 Hz, 2H), 2.88 (t, J=7.4 Hz, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[C:6]2[C:7]([O:9][C:10](=[O:12])[NH:11][C:5]2=[CH:4][CH:3]=1)=O.[NH:14]1[CH2:17][CH2:16][C@H:15]1C(O)=O>CN(C)C=O.C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[C@@H:15]3[CH2:16][CH2:17][N:14]3[C:7](=[O:9])[C:6]=2[CH:13]=1
Reactant: O=C(O)[C@@H]1CCN1
Reactant: O=c1[nH]c2ccc(Cl)cc2c(=O)o1
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: O=C1Nc2ccc(Cl)cc2C(=O)N2CC[C@@H]12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 86.3 %

Procedure:
59.3 g (0.3 mol) of 5-chloro-isatoic anhydride and 30.3 g (0.3 mol) of (S)-azetidine-2-carboxylic acid were suspended in 400 ml of N,N-dimethylformamide/acetic acid 5:1 and heated to 87°-90° in an oil bath under argon for 64 hrs. The solvent was removed in a vacuum and the residue was taken up in 500 ml of methanol, whereupon the mixture was stirred at room temperature for 30 min. The white, pure crystals were filtered off under suction. The solvent was removed in a vacuum and the semi-crystalline residue was recrystallized from 60 ml of methanol (hot filtration). The products were combined and dried in a vacuum. There were obtained 61.3 g (86%) of (S)-6-chloro-1,2,4,9,10,10a-hexahydro-azeto[2,1-c][1,4]benzodiazepine-4,10-dione of m.p. 229°-231° (dec.).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N+:9]([O-])=[CH:8][CH:7]=[CH:6]2.ClC(OC)=O.[CH3:19][O:20][C:21]1[CH:22]=[C:23]([Mg]Br)[CH:24]=[CH:25][CH:26]=1>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8]([C:25]1[CH:24]=[CH:23][CH:22]=[C:21]([O:20][CH3:19])[CH:26]=1)[CH:7]=[CH:6]2
Reactant: COc1cccc([Mg]Br)c1
Reactant: COc1ccc2c(ccc[n+]2[O-])c1
Agent: COC(=O)Cl
Solvent: C1CCOC1
Product: COc1cccc(-c2ccc3cc(OC)ccc3n2)c1
Temperature: 0 °C
Reaction time: 16 h
Yield: 46.4 %

Procedure:
To a solution of 6-methoxyquinoline-N-oxide (175 mg, 1.0 mmol) in THF (3 mL) at room temperature is added methyl chloroformate (77 uL, 1.0 mmol). The mixture is cooled to 0° C. and 3-methoxyphenylmagnesium bromide (2 mL of 1M, 2 mmol) is added dropwise. The mixture is stirred for 16 h while warming to room temperature. The solvent is removed in vacuo and the resulting residue is partitioned between water and CH2Cl2. The organic phase is washed with water and brine, dried over MgSO4, filtered and concentrated. Flash chromotography (0–20% EtOAc/hexanes) yields 6-methoxy-2-(3-methoxy-phenyl)-quinoline (123 mg, 46% yield).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH2:5]C1C=C2C(C=CN2)=CC=1)[CH3:2].C(O[C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[N:25]([C:29]([NH2:31])=[O:30])[CH:24]=[C:23]2[N:32]=[C:33]=[O:34])C=C>>[CH2:1]([O:3][C:4](=[O:15])[CH2:5][C:28]1[CH:27]=[C:26]2[C:22]([C:23]([N:32]=[C:33]=[O:34])=[CH:24][N:25]2[C:29](=[O:30])[NH2:31])=[CH:21][CH:20]=1)[CH3:2]
Reactant: CCOC(=O)Cc1ccc2cc[nH]c2c1
Reactant: C=CCOc1ccc2c(c1)c(N=C=O)cn2C(N)=O
Product: CCOC(=O)Cc1ccc2c(N=C=O)cn(C(N)=O)c2c1

Procedure:
was prepared from (1H-indol-6-yl)-acetic acid ethyl ester using the protocol described for steps B-E in scheme A4 for the preparation of 5-allyloxy-3-isocyanato-indole-1-carboxylic acid amide.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:25]=[CH:24][C:20]([C:21]([OH:23])=[O:22])=[CH:19][CH:18]=2)=[CH:13][CH:12]=1.O.C(OCC)(=O)C.[ClH:33].[CH3:34][CH:35]1[O:40][CH:39]([CH3:41])[CH2:38][NH:37][CH2:36]1>>[ClH:33].[CH3:41][CH:39]1[O:40][CH:35]([CH3:34])[CH2:36][N:37]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][O:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:25]=[CH:24][C:20]([C:21]([OH:23])=[O:22])=[CH:19][CH:18]=3)=[CH:13][CH:12]=2)[CH2:38]1
Reactant: O=C(O)c1ccc(-c2ccc(OCCCCCCCCBr)cc2)cc1
Reactant: CC1CNCC(C)O1
Agent: Cl
Solvent: O
Solvent: CCOC(C)=O
Product: CC1CN(CCCCCCCCOc2ccc(-c3ccc(C(=O)O)cc3)cc2)CC(C)O1

Procedure:
A suspension of 4-[4-(8-bromooctyloxy)phenyl]benzoic acid (1 g) in 2,6-dimethylmorpholine (3.06 ml) was refluxed for 30 minutes. The reaction mixture was added to a mixture of water and ethyl acetate and adjusted to pH 2.0 with conc. HCl. The organic layer was taken and dried over magnesium sulfate. The magnesium sulfate was filtered off, and the filtrate was evaporated under reduced pressure to give 4-[4-[8-(2,6-dimethylmorpholin-4-yl)octyloxy]phenyl]benzoic acid hydrochloride (0.95 g).
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[C:11]2[C:6](=[CH:7][C:8]([NH2:13])=[C:9]([NH2:12])[CH:10]=2)[NH:5][C:4](=[O:14])[CH2:3]1.[N:16]1([C:21]2[CH:28]=[CH:27][C:24]([CH:25]=O)=[CH:23][CH:22]=2)[CH:20]=[CH:19][N:18]=[CH:17]1.C1(C)C=CC(S(O)(=O)=O)=CC=1.N>O.C(O)C>[CH3:1][C:2]1([CH3:15])[C:11]2[CH:10]=[C:9]3[NH:12][C:25]([C:24]4[CH:23]=[CH:22][C:21]([N:16]5[CH:20]=[CH:19][N:18]=[CH:17]5)=[CH:28][CH:27]=4)=[N:13][C:8]3=[CH:7][C:6]=2[NH:5][C:4](=[O:14])[CH2:3]1
Reactant: O=Cc1ccc(-n2ccnc2)cc1
Reactant: CC1(C)CC(=O)Nc2cc(N)c(N)cc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: N
Solvent: O
Solvent: CCO
Product: CC1(C)CC(=O)Nc2cc3nc(-c4ccc(-n5ccnc5)cc4)[nH]c3cc21

Procedure:
2 g. (9.7 mmole) 4,4-dimethyl-6,7-diamino-1,2,3,4-tetrahydroquinolin-2-one (see Example 13 a)), 1.67 g. (9.7 mmole) 4-(1H-imidazol-1-yl)-benzaldehyde, 0.17 g. p-toluenesulphonic acid and 120 ml. ethanol were mixed together and heated under reflux for 3 hours while passing through air. The evaporation residue was suspended in water, neutralized with 2N aqueous ammonia and recrystallized from methanol to give 1.7 g. (49% of theory) of the title compound; m.p. >300° C.
Reaction SMILES: [C:1]([O:9][C@H:10]([CH3:13])[CH2:11]Br)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([N+](CCCC)(CCCC)CCCC)CCC.[OH:31][C:32]1[CH:33]=[C:34]([CH2:39][C@H:40]([NH:44][C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])[C:41]([O-:43])=[O:42])[CH:35]=[CH:36][C:37]=1[OH:38].C(=O)(O)[O-].[Cs+]>CN(C)C(=O)C>[C:48]([O:47][C:45]([NH:44][C@@H:40]([CH2:39][C:34]1[CH:35]=[CH:36][C:37]([OH:38])=[C:32]([OH:31])[CH:33]=1)[C:41]([O:43][CH2:11][C@H:10]([O:9][C:1]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:8])[CH3:13])=[O:42])=[O:46])([CH3:51])([CH3:49])[CH3:50]
Reactant: C[C@H](CBr)OC(=O)c1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(O)c(O)c1)C(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])O
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Product: C[C@H](COC(=O)[C@H](Cc1ccc(O)c(O)c1)NC(=O)OC(C)(C)C)OC(=O)c1ccccc1
Temperature: 55 °C
Reaction time: 16 h
Yield: 66.6 %

Procedure:
A suspension of (1R)-2-bromo-1-methylethyl benzoate 1b (4.98 g, 20.6 mmol), (2S)-3-(3,4-dihydroxyphenyl)-2-[(tert-butoxycarbonyl)amino]propanoic acid, tetrabutylammonium salt 1a (7.3 g, 25 mmol), and cesium bicarbonate (4.85 g, 25 mmol) in N,N-dimethylacetamide (100 mL) was stirred at 55° C. for 16 h. The solvent was evaporated under vacuum. Ethyl acetate was added to the residue and the resulting solution was washed with water, then 5% NaHCO3 and brine, and dried over Na2SO4. After removing the solvent under reduced pressure, chromatography (silica gel, 30% ethyl acetate in hexane) of the residue gave 6.3 g (68% yield) of the title compound 1c as a white solid. 1H NMR (400 MHz, CD3OD): δ 1.25 (s, 9H), 1.40 (d, J=6.4 Hz, 3H), 2.99 (dd, J=7.6, 14.4 Hz, 1H), 3.10 (dd, J=5.6, 14.4 Hz, 1H), 4.24 (dd, J=5.6, 7.4 Hz, 1H), 4.38 (dd, J=6.8, 11.6 Hz, 1H), 4.52 (dd, J=3.2, 11.6 Hz, 1H), 5.40 (m, 1H), 6.53 (dd, J=2.2, 8.4 Hz, 1H), 6.66 (d, J=2.2 Hz, 1H), 6.69 (d, J=8.4 Hz, 1H), 7.47 (t, J=7.6 Hz, 2H), 7.60 (t, J=7.6 Hz, 1H), 8.02 (d, J=7.6 Hz, 2H). MS (ESI) m/z 360.15 (M+H)+ and 358.09 (M−H)−.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[O:22][CH3:23])[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:10][CH:9]=1)=[O:6].[O:24]1[C:28]2[CH:29]=[CH:30][C:31](B(O)O)=[CH:32][C:27]=2[O:26][CH2:25]1.C([O-])([O-])=O.[Na+].[Na+].COCCOC>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.O>[O:24]1[C:28]2[CH:29]=[CH:30][C:31]([C:2]3[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=3[O:22][CH3:23])[C:5]([NH:7][C:8]3[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:10][CH:9]=3)=[O:6])=[CH:32][C:27]=2[O:26][CH2:25]1
Reactant: COc1ccc(C(=O)Nc2ccc(OC(F)(F)F)cc2)cc1Br
Reactant: OB(O)c1ccc2c(c1)OCO2
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: [Na+]
Solvent: O
Solvent: COCCOC
Product: COc1ccc(C(=O)Nc2ccc(OC(F)(F)F)cc2)cc1-c1ccc2c(c1)OCO2

Procedure:
3-Bromo-4-methoxy-N-(4-(trifluoromethoxy)phenyl)benzamide (Stage 30.1, 60 mg, 0.154 mmol), benzo[d][1,3]dioxol-5-ylboronic acid (33.2 mg, 0.200 mmol), (Ph3P)4Pd (9 mg, 6.94 μmol), 2 M Na2CO3 (0.115 mL, 0.231 mmol), DME (2.4 mL) and water (0.8 mL) were subjected to MW irradiation at 150° C. for 10 min. The RM was filtered through a PL-Thiol MP SPE cartridge (StratoSpheres™, 6 mL), the cartridge was washed with MeOH (10 mL) and the combined filtrates were evaporated under reduced pressure to give the crude product was purified by preparative HPLC to afford the title compound. UPLC-MS (Condition 6) tR=2.37 min, m/z=432.3 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[C:3]([CH2:18][NH:19]CC1C=CC=CC=1)([OH:17])[CH2:4][C:5]([C:8]1[CH:13]=[C:12]([F:14])[CH:11]=[CH:10][C:9]=1[O:15][CH3:16])([CH3:7])[CH3:6].[H][H]>C(O)C.[Pd]>[NH2:19][CH2:18][C:3]([OH:17])([CH2:4][C:5]([C:8]1[CH:13]=[C:12]([F:14])[CH:11]=[CH:10][C:9]=1[O:15][CH3:16])([CH3:7])[CH3:6])[C:2]([F:28])([F:27])[F:1]
Reactant: [H][H]
Reactant: COc1ccc(F)cc1C(C)(C)CC(O)(CNCc1ccccc1)C(F)(F)F
Agent: [Pd]
Solvent: CCO
Product: COc1ccc(F)cc1C(C)(C)CC(O)(CN)C(F)(F)F
Yield: 97.2 %

Procedure:
1,1,1-Trifluoro-4-[5-fluoro-2-(methyloxy)phenyl]-4-methyl-2-{[(phenylmethyl)amino]methyl}-2-pentanol (Intermediate 17, 63 g, 0.158 mol) was added to a stirred solution of 10% Pd/C (12.6 g, 50% wet) in ethanol (1.07 L) at 20° C. in a nitrogen purged vessel. The mixture was hydrogenated at 20° C. and atmospheric pressure until there was no further hydrogen uptake. The suspension was then filtered through Celite and glass fibre filter paper to remove the catalyst, and the cake washed with ethanol (120 mL). The combined filtrate and washings were evaporated under reduced pressure to give the title compound as a light grey solid (47.5 g).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[N:11]1[C:20]2[C:15](=[CH:16][C:17]([CH2:21][C:22]([O:24][CH3:25])=[O:23])=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1.[CH3:26]I>C1COCC1>[N:11]1[C:20]2[C:15](=[CH:16][C:17]([CH:21]([CH3:26])[C:22]([O:24][CH3:25])=[O:23])=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1
Reactant: COC(=O)Cc1ccc2ncccc2c1
Reactant: CI
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)C(C)c1ccc2ncccc2c1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 84.5 %

Procedure:
To a 250 ml round-bottomed flask was added lithium bis(trimethylsilyl)amide (2.0 g, 12 mmol) and tetrahydrofuran (75 ml). The mixture was cooled to −78° C. and methyl 2-(quinolin-6-yl)acetate (2.0 g, 9.9 mmol) was added as a solution in 1 ml THF. This was stirred at −78° C. for 30 min and then methyl iodide (0.75 ml, 12 mmol) was added. This was stirred for 30 min at −78° C. and then allowed to warm to rt. The mixture was quenched with sat NH4Cl (40 mL) and diluted with water (200 mL). The mixture was concentrated in vacuo to remove the THF and then was extracted with EtOAc (2×100 ml). The combined extracts were washed with brine (50 ml), dried (Na2SO4) and concentrated onto silica. Purification by silica gel chromatography (20 to 60% EtOAc/hexane) afforded the title compound as a brown oil (1.8 g, 85%). MS (ESI, pos. ion) m/z: 216 (M+1).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[CH2:7][CH2:8][C:9](=O)[CH2:10]2)(=[O:3])[CH3:2].[ClH:16].[CH2:17]([NH2:23])[C:18]1[O:22][CH:21]=[CH:20][CH:19]=1>>[ClH:16].[C:1]([NH:4][C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[CH2:7][CH2:8][CH:9]([NH:23][CH2:17][C:18]1[O:22][CH:21]=[CH:20][CH:19]=1)[CH2:10]2)(=[O:3])[CH3:2]
Reactant: NCc1ccco1
Reactant: CC(=O)Nc1cccc2c1CCC(=O)C2
Agent: Cl
Product: CC(=O)Nc1cccc2c1CCC(NCc1ccco1)C2

Procedure:
Starting from 2.03 g (0.01 mol) of 5-acetylamino-2-tetralone and 4.0 g (0.03 mol) of furfurylaminehydrochloride the title compound is obtained analogously to Example 4.1.11 in a yield of 2.1 g (65.4% of theory) and with a melting point of 296° C., which does not change after recrystallisation from methanol/ether.
Reaction SMILES: [O:1]=[C:2]1[C:8]2[C:9]([C:13]([F:16])([F:15])[F:14])=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]2[CH:17]=[N:18][C:19]([C:20]([O:22]CC)=[O:21])=[C:5]2[C@@H:4]2[CH2:25][CH2:26][N:3]12.[OH-].[Na+].C(O)C.Cl>O>[O:1]=[C:2]1[C:8]2[C:9]([C:13]([F:16])([F:14])[F:15])=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]2[CH:17]=[N:18][C:19]([C:20]([OH:22])=[O:21])=[C:5]2[C@@H:4]2[CH2:25][CH2:26][N:3]12
Reactant: CCOC(=O)c1ncn2c1[C@@H]1CCN1C(=O)c1c-2cccc1C(F)(F)F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)c1ncn2c1[C@@H]1CCN1C(=O)c1c-2cccc1C(F)(F)F

Procedure:
A mixture of 4.44 g (12.2 mmol) of ethyl (S)-12,12a-dihydro-9-oxo-8-(trifluoromethyl)-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepine-1-carboxylate, 0.556 g (13.9 mmol) of sodium hydroxide, 18 ml of ethanol and 9 ml of water is heated to boiling under reflux for 1 hour. The ethanol is then distilled off in vacuo and the residue is diluted with 25 ml of water. The mixture is neutralized by the addition of 13.9 ml (13.9 mmol) of 1N hydrochloric acid, the mixture is cooled to about 0°, the product is filtered off under suction, rinsed with water and dried at 90° in a high vacuum. There is obtained (S)-12,12a-dihydro-9-oxo-8-(trifluoromethyl)-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepine-1-carboxylic acid of decomposition point 227°-228°.
Reaction SMILES: [C:1]([NH:8][CH2:9][CH2:10][C:11]1[CH:17]=[CH:16][C:14]([NH2:15])=[CH:13][CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].O[CH:19](O)[C:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:21].[BH3-]C#N.[Na+]>CO>[C:22]1([CH:20]([OH:21])[CH2:19][NH:15][C:14]2[CH:16]=[CH:17][C:11]([CH2:10][CH2:9][NH:8][C:1]([O:3][C:4]([CH3:6])([CH3:7])[CH3:5])=[O:2])=[CH:12][CH:13]=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CC(C)(C)OC(=O)NCCc1ccc(N)cc1
Reactant: O=C(c1ccccc1)C(O)O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)OC(=O)NCCc1ccc(NCC(O)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.9 %

Procedure:
4-(N-Boc-2-aminoethyl)aniline 28 (1.25 g, 5.29 mmole) was dissolved in methanol (30 mL), followed by addition of phenyl glyoxal 24 (0.708 g, 5.28 mmole). The reaction mixture was stirred for 1 h at rt, prior to addition of NaCNBH3 (0.665 g, 10.6 mmole). The final mixture was stirred for 12 h at rt, concentrated, and purified by flash silica column chromatography (2 to 5% MeOH/CH2Cl2) to give N-(2-phenyl-2-hydroxyethyl)-4-(N-Boc-2-aminoethyl)-aniline as a pale yellow oil (1.71 g, 91%): Rf=0.18 in 5% MeOH/CH2Cl2. 1H-NMR (CD3OD, 299.96 MHz): δ (ppm) 7.4–7.25 (m, 5H), 7.0–6.95 (d, 2H), 6.63–6.60 (d, 2H), 4.85–4.79 (dd, 1H), 3.3–3.21 (t, 2H),3.2–3.15 (m, 2H), 2.64–2.5 (t, 2H), 1.42 (s, 9H).
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[N:7]([CH3:8])[C:6](=[O:9])[CH2:5][CH2:4]1.CC(C)([O-])C.[Na+].[C:16]([C:20]1[S:24]/[C:23](=[N:25]\[C:26](=[O:38])[C:27]2[CH:32]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:30]=[CH:29][C:28]=2F)/[N:22]([CH2:39][C@H:40]2[CH2:44][CH2:43][CH2:42][O:41]2)[CH:21]=1)([CH3:19])([CH3:18])[CH3:17]>C1COCC1>[C:16]([C:20]1[S:24]/[C:23](=[N:25]\[C:26](=[O:38])[C:27]2[CH:32]=[C:31]([C:33]([F:35])([F:34])[F:36])[CH:30]=[CH:29][C:28]=2[O:1][CH2:2][C@@H:3]2[CH2:4][CH2:5][C:6](=[O:9])[N:7]2[CH3:8])/[N:22]([CH2:39][C@H:40]2[CH2:44][CH2:43][CH2:42][O:41]2)[CH:21]=1)([CH3:19])([CH3:17])[CH3:18]
Reactant: CC(C)(C)c1cn(C[C@H]2CCCO2)/c(=N/C(=O)c2cc(C(F)(F)F)ccc2F)s1
Reactant: CN1C(=O)CC[C@H]1CO
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN1C(=O)CC[C@H]1COc1ccc(C(F)(F)F)cc1C(=O)/N=c1\sc(C(C)(C)C)cn1C[C@H]1CCCO1
Temperature: 22 °C
Reaction time: 0.33 h

Procedure:
To a solution of (S)-5-(hydroxymethyl)-1-methylpyrrolidin-2-one (108 mg, 0.84 mmol) (Williams, P. D. et al. Journal of Medicinal Chemistry 1991, 34, 887-900) in 5 mL of THF was added sodium tert-butoxide (100 mg, 1.05 mmol). The mixture was stirred at 22° C. for 20 minutes. The mixture was cooled to 5° C. and a solution of Example 1A (180 mg, 0.42 mmol) in 2 mL of THF was added. The mixture was stirred at 5° C. for 2 hours, then at 22° C. for 1 hour. The solvent was evaporated under reduced pressure. The residue was dissolved in methylene chloride, washed with water, dried over MgSO4 and concentrated. The residue was purified by flash chromatography on SiO2 using an Analogix® Intelliflash280™ (eluted with CH2Cl2:10% MeOH and 3N NH3 in CH2Cl2: 0 to 100%) to afford the title compound; 1H NMR (300 MHz, CDCl3) δ ppm 1.36 (s, 9 H), 1.58-1.73 (m, 1 H), 1.74-2.14 (m, 4 H), 2.14-2.42 (m, 2 H), 2.44-2.64 (m, 1 H), 2.91 (s, 3 H), 3.72-3.91 (m, 2 H), 3.93-4.03 (m, 1H), 4.07 (dd, J=12.0, 4.8 Hz, 1 H), 4.14-4.32 (m, 3 H), 4.39 (dd, J=13.3, 2.6 Hz, 1 H), 6.88 (s, 1 H), 6.99 (d, J=8.7 Hz, 1 H), 7.60 (dd, J=8.7, 2.4 Hz, 1 H), 8.11 (d, J=2.4 Hz, 1 H); MS (ESI) m/z 540 (M+H)+.