Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[CH2:11][C:9](=O)[C:8]2[C:3](=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:2]1.[O:12]1CCBN1.C[C@@H](N)[C@@H](O)C1C=CC=CC=1.CSC.B>C1COCC1>[CH2:1]1[CH:11]([OH:12])[CH2:9][C:8]2[C:3](=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:2]1
Reactant: O=C1CCCc2ccccc21
Reactant: B1CCON1
Agent: B
Agent: C[C@@H](N)[C@@H](O)c1ccccc1
Solvent: CSC
Solvent: C1CCOC1
Product: OC1CCc2ccccc2C1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
(1S, 2R)-(+)-Norephedrine (7.78 g, 51 mmol), toluene (150 mL), and trimethylboroxine (4.8 mL) were combined at ambient temperature and stirred for 5 days. Water, toluene and excess boroxine were distilled off until about 70 mL volume remained. The reaction was chased with toluene (3×90 mL), and the remainder of toluene removed under vacuum to afford the oxazaborolidine as a pale yellow oil (8.71 g, 98%). 1H NMR (C6D6) δ; 7.36-6.98 (m, 5H), 5.33(d, J=8 Hz, 1H), 3.43 (dq, J=8 Hz, J=6 Hz, 1H), 2.72 (bs, 1H, 0.37 (s, 3H), 0.36(d, J=6 Hz, 3H). To a solution of α-tetralone (2.92 g, 19.7 mmol), THF (80 mL), and the oxazaborolidine derived from norephedrine (218 mg, 1.2 mmol) under a nitrogen atmosphere was added borane methylsulfide complex (2M in THF, 7.0 mL, 14 mmol) over 75 min. After the addition was complete, the contents stirred for an additional 15 min, cooled to 0° C., and quenched with methanol (27 mL). After stirring the quenched reaction for 18 hrs the solvents were removed under vacuum, the residual oil was dissolved in methylene chloride (50 mL), washed with pH 4 phosphate buffer (50 mL), water (50 mL), treated with magnesium sulfate, and the solvent was removed under vacuum to give 3.16 g (80% ee) of the (S) tetralol as a colorless oil.
Reaction SMILES: Cl[C:2]1[C:3]2[CH2:11][N:10]([C:12]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:13]=3[C:14]#[N:15])[CH2:9][CH2:8][C:4]=2[N:5]=[CH:6][N:7]=1.[CH:21]1([C:24]2[CH:25]=[CH:26][C:27]([CH2:30][NH2:31])=[N:28][CH:29]=2)[CH2:23][CH2:22]1.C(N(CC)C(C)C)(C)C>C(#N)C>[CH:21]1([C:24]2[CH:25]=[CH:26][C:27]([CH2:30][NH:31][C:2]3[C:3]4[CH2:11][N:10]([C:12]5[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:13]=5[C:14]#[N:15])[CH2:9][CH2:8][C:4]=4[N:5]=[CH:6][N:7]=3)=[N:28][CH:29]=2)[CH2:23][CH2:22]1
Reactant: Cc1ccc(N2CCc3ncnc(Cl)c3C2)c(C#N)c1
Reactant: NCc1ccc(C2CC2)cn1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(N2CCc3ncnc(NCc4ccc(C5CC5)cn4)c3C2)c(C#N)c1

Procedure:
A reaction mixture of 2-(4-chloro-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)-5-methylbenzonitrile (150 mg, 0.53 mmol) and (5-cyclopropylpyridin-2-yl)methanamine (115 mg, 0.78 mmol) in acetonitrile (2 mL) and N,N-diisopropylethylamine (0.14 mL, 0.78 mmol) was subjected to microwave irradiation at 180° C. for 2 h. The mixture was concentrated and the residue was purified by preparative HPLC (100×20.2 mm, C18 column; 50-70% CH3CN-water [10 mM Et2NH]) to yield an off-white foam.
Reaction SMILES: [NH2:1][C:2]1[S:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([NH2:13])[CH:8]=2)[C:3]=1[C:14]([NH2:16])=[O:15].C(N(CC)C(C)C)(C)C.[C:26]1([N:32]=[C:33]=[O:34])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>O1CCOCC1>[NH2:1][C:2]1[S:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([NH:13][C:33]([NH:32][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[O:34])[CH:8]=2)[C:3]=1[C:14]([NH2:16])=[O:15]
Reactant: NC(=O)c1c(-c2cccc(N)c2)nsc1N
Reactant: O=C=Nc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: NC(=O)c1c(-c2cccc(NC(=O)Nc3ccccc3)c2)nsc1N
Yield: 97.5 %

Procedure:
A mixture of 5-amino-3-(3-aminophenyl)isothiazole-4-carboxamide (21 mg, 0.090 mmol), N,N-diisopropylethylamine (0.039 mL, 0.23 mmol), and phenyl isocyanate (0.014 mL, 0.13 mmol) in 1.0 mL dioxane was reacted at rt for 1 hour. The precipitant was filtered and rinsed with 30% EtOAc/hexane to give the title compound as a white solid (31 mg, 96%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9]([NH:10][CH:11]3[C:15]([CH3:17])([CH3:16])[CH2:14][N:13]([S:18]([CH3:21])(=[O:20])=[O:19])[CH2:12]3)=[C:8]([C:22]([NH2:24])=[O:23])[CH:7]=[N:6][N:5]2[CH:25]=1.[CH3:26][N:27]1[CH:31]=[C:30](B2OC(C)(C)C(C)(C)O2)[CH:29]=[N:28]1>>[CH3:16][C:15]1([CH3:17])[CH2:14][N:13]([S:18]([CH3:21])(=[O:20])=[O:19])[CH2:12][CH:11]1[NH:10][C:9]1[C:4]2[N:5]([CH:25]=[C:2]([C:30]3[CH:29]=[N:28][N:27]([CH3:26])[CH:31]=3)[CH:3]=2)[N:6]=[CH:7][C:8]=1[C:22]([NH2:24])=[O:23]
Reactant: CC1(C)CN(S(C)(=O)=O)CC1Nc1c(C(N)=O)cnn2cc(Br)cc12
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Product: Cn1cc(-c2cc3c(NC4CN(S(C)(=O)=O)CC4(C)C)c(C(N)=O)cnn3c2)cn1

Procedure:
The title compound was prepared according to the procedure described for Example 297 by Suzuki coupling with (+/−)-6-bromo-4-(4,4-dimethyl-1-(methylsulfonyl)pyrrolidin-3-ylamino)pyrrolo[1,2-b]pyridazine-3-carboxamide (from Step 1 of Example 297) with 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)(=[O:12])=[O:11])=[CH:6][CH:5]=1)([O-])=O.C1C(=O)N([Br:26])C(=O)C1>CO.C(Cl)Cl.[Pd]>[Br:26][C:5]1[CH:6]=[C:7]([S:10]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)(=[O:12])=[O:11])[CH:8]=[CH:9][C:4]=1[NH2:1]
Reactant: O=C1CCC(=O)N1Br
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)N2CCOCC2)cc1
Agent: [Pd]
Solvent: CO
Solvent: ClCCl
Product: Nc1ccc(S(=O)(=O)N2CCOCC2)cc1Br
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 22.3 %

Procedure:
A solution of 250 mg (0.918 mmol) of 4-(4-nitro-benzenesulfonyl)-morpholine in MeOH (15 mL) was treated with 20 mg of 10% Pd/C (Degussa type E101-NE/W, Aldrich, 50% by weight water) under H2 (1 atm). The mixture was stirred at RT for 1.5 h and filtered through Celite. The filter cake was washed with MeOH, and the filtrate was concentrated in vacuo. The residue was taken up in CH2Cl2 (10 mL), cooled to 0° C., and treated with 124 mg (0.698 mmol) of NBS at that temperature for 25 min. The mixture was diluted with CH2Cl2 (15 mL) and washed with saturated aqueous NaHCO3 (1×10 mL). The organic layer was dried (MgSO4) and concentrated in vacuo. Silica gel chromatography of the residue on a 50-g Varian MegaBond Elut SPE column with 40-50% EtOAc-hexane afforded 50.0 mg (17%) of the title compound as a pale tan solid: Mass spectrum (ESI, m/z): Calcd. for C10H13N2O3SBr, 321.0 (M+H), found 320.9/322.8.
Reaction SMILES: N[C@@](C1C=CC2C(=CC=C(O[C@H]3CC[C@H](C(C)(C)C)CC3)C=2C2C=CC(OC(F)(F)F)=CC=2)C=1)(C)CO.[C:38]([C@H:42]1[CH2:47][CH2:46][C@H:45]([O:48][C:49]2[C:50]([C:66]3[CH:71]=[CH:70][C:69]([Cl:72])=[CH:68][CH:67]=3)=[C:51]3[C:56](=[CH:57][CH:58]=2)[CH:55]=[C:54]([C@:59]2([CH3:65])[CH2:63][O:62]C(=O)[NH:60]2)[CH:53]=[CH:52]3)[CH2:44][CH2:43]1)([CH3:41])([CH3:40])[CH3:39]>>[NH2:60][C@@:59]([C:54]1[CH:53]=[CH:52][C:51]2[C:56](=[CH:57][CH:58]=[C:49]([O:48][C@H:45]3[CH2:44][CH2:43][C@H:42]([C:38]([CH3:41])([CH3:40])[CH3:39])[CH2:47][CH2:46]3)[C:50]=2[C:66]2[CH:71]=[CH:70][C:69]([Cl:72])=[CH:68][CH:67]=2)[CH:55]=1)([CH3:65])[CH2:63][OH:62]
Reactant: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3cc([C@]4(C)COC(=O)N4)ccc3c2-c2ccc(Cl)cc2)CC1
Agent: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3cc([C@@](C)(N)CO)ccc3c2-c2ccc(OC(F)(F)F)cc2)CC1
Product: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3cc([C@@](C)(N)CO)ccc3c2-c2ccc(Cl)cc2)CC1

Procedure:
(R)-2-amino-2-(6-(trans-4-tert-butylcyclohexyloxy)-5-(4-chlorophenyl)naphthalen-2-yl)propan-1-ol was synthesized as per (R)-2-amino-2-(6-(trans-4-tert-butylcyclohexyloxy)-5-(4-(trifluoromethoxy)phenyl)naphthalen-2-yl)propan-1-ol (Example 221) in 81% yield using (R)-4-(6-(trans-4-tert-butylcyclohexyloxy)-5-(4-chlorophenyl)naphthalen-2-yl)-4-methyloxazolidin-2-one as starting material. MS: m/z=449.41 [M-16]+. 1H NMR (MeOD) δ: 7.94 (d, J=1.8 Hz, 1H), 7.90 (d, J=8.8 Hz, 1H), 7.46-7.52 (m, 3H), 7.42 (d, J=9.3 Hz, 2H), 7.29 (d, J=8.0 Hz, 2H), 4.07-4.17 (m, 1H), 3.66-3.75 (m, 2H), 2.00-2.08 (m, 2H), 1.77-1.84 (m, 2H), 1.52 (s, 3H), 0.92-1.25 (m, 5H), 0.84-0.89 (m, 9H)
Reaction SMILES: F[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][CH2:6][CH2:5]2.[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1)=[O:19])([CH3:16])([CH3:15])[CH3:14].O>CS(C)=O>[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][N:23]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[C:8](=[O:12])[NH:7][CH2:6][CH2:5]3)[CH2:22][CH2:21]1)=[O:19])([CH3:16])([CH3:14])[CH3:15]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=C1NCCc2cc(F)ccc21
Solvent: CS(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(c2ccc3c(c2)CCNC3=O)CC1
Temperature: 120 °C
Reaction time: 8 h
Yield: 24.9 %

Procedure:
6-Fluoro-3,4-dihydro-2H-isoquinolin-1-one (0.99 g) prepared according to the method described in J. Med. Chem., Vol. 39, 4583–4591 (1996) was dissolved in dimethyl sulfoxide (2.5 ml). N-t-Butoxycarbonylpiperazine (3.4 g) was added to the solution, and the mixture was stirred at 120° C. overnight. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was then removed by distillation under the reduced pressure. The residue was purified by column chromatography on silica gel (n-hexane:ethyl acetate=1:3) to give 6-[4-(t-butoxycarbonyl)piperazin-1-yl]-3,4-dihydro-2H-isoquinolin-1-one (0.495 g, 24.9%).
Reaction SMILES: [N:1]([C:4]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:5]=1[C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=O)=[N+:2]=[N-:3].Cl.[NH2:20][OH:21]>N1C=CC=CC=1.C(O)C>[N:1]([C:4]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:5]=1[C:6](=[N:20][OH:21])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=Nc1ccc(Cl)cc1C(=O)c1ccccc1
Reactant: NO
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Product: [N-]=[N+]=Nc1ccc(Cl)cc1C(=NO)c1ccccc1
Reaction time: 5 h

Procedure:
25.8 G (0.100 mol) of 2-azido-5-chlorobenzophenone [compare Example 1a] are dissolved in 500 ml of pyridine/ethanol (1:1). 14.0 G (0.200 mol) of hydroxylamine hydrochloride are added to the solution and the mixture is boiled for 5 hours under reflux and evaporated in vacuo at 60°C. The residue is taken up in 250 ml of methanol and the solution is poured into 250 ml of 2 N hydrochloric acid. The crude product which precipitates is filtered off, suspended in 250 ml of 75% strength methanol, again filtered off and dried in vacuo. 2-Azido-5-chloro-benzophenone-oxime of melting point 125°-132°C is obtained. A sample of the crude product is recrystallised from benzene/cyclohexane, after which the pure compound melts at 135°-137°C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:22]=[CH:21][C:6]([CH2:7][N:8]2[CH:12]=[C:11]([C:13]3[CH:18]=[CH:17][N:16]=[C:15](SC)[N:14]=3)[CH:10]=[N:9]2)=[CH:5][CH:4]=1.C1C=C(Cl)C=C(C(OO)=O)C=1.[NH2:34][C:35]1[CH:36]=[C:37]([OH:42])[CH:38]=[CH:39][C:40]=1[F:41].C([O-])([O-])=O.[K+].[K+]>ClCCl.CN(C=O)C.O>[CH3:1][O:2][C:3]1[CH:22]=[CH:21][C:6]([CH2:7][N:8]2[CH:12]=[C:11]([C:13]3[CH:18]=[CH:17][N:16]=[C:15]([O:42][C:37]4[CH:38]=[CH:39][C:40]([F:41])=[C:35]([NH2:34])[CH:36]=4)[N:14]=3)[CH:10]=[N:9]2)=[CH:5][CH:4]=1
Reactant: Nc1cc(O)ccc1F
Reactant: COc1ccc(Cn2cc(-c3ccnc(SC)n3)cn2)cc1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1ccc(Cn2cc(-c3ccnc(Oc4ccc(F)c(N)c4)n3)cn2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 83.8 %

Procedure:
To a solution of 4-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)-2-(methylthio)pyrimidine (200 mg, 0.64 mmol) in dichloromethane was added m-CPBA (220 mg, 1.28 mmol). The reaction was stirred for 2 hour at RT. Water was added, the organic layer was separated and the aqueous layer was extracted with dichloromethane. The combined organics were washed with brine and concentrated in vacuo. The residue was combined with 3-amino-4-fluorophenol (165 mg, 1.28 mmol) and K2CO3 (176 mg, 1.28 mmol) in DMF (5 mL) and the resultant mixture was heated at 90° C. overnight. After filtration and concentration, the residue was purified by silica gel column chromatography to give 5-(4-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)pyrimidin-2-yloxy)-2-fluorobenzenamine (210 mg, 84% yield). 1H NMR (300 MHz, DMSO-d6) δ 8.50 (s, 1H), 8.44, (d, J=5.4 Hz, 1H), 8.10 (s, 1H), 7.42 (d, J=5.4 Hz, 1H), 7.25 (d, J=8.4 Hz, 2H), 6.98 (t, J=9.6 Hz, 1H), 6.91 (d, J=8.4 Hz, 2H), 6.52 (dd, J=2.7, 8.7 Hz, 1H), 6.28 (m, 1H), 5.30 (br s, 2H), 5.26 (s, 2H), 3.72 (s, 3H); MS (ESI) m/z: 392.2 (M+H+).
Reaction SMILES: [CH2:1]([N:8]([CH3:12])[C:9]([Cl:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:13](NCC)C1C=CC=CC=1.CC#N.O.CC#N>O>[CH2:1]([N:8]([CH2:12][CH3:13])[C:9]([Cl:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(Cc1ccccc1)C(=O)Cl
Reactant: CCNCc1ccccc1
Solvent: O
Solvent: CC#N
Product: CCN(Cc1ccccc1)C(=O)Cl

Procedure:
The title compound is prepared analogously as described for benzyl-methyl-carbamoyl chloride from benzyl ethylamine. MS (LC-MS): [M+H]+=198.1. tR (HPLC, Waters Symmetry C18 column, 20-95% CH3CN/H2O/3.5 min, 95% CH3CN/H2O, 2 min, CH3CN and H2O containing 0.1% TFA, flow: 0.6 mL/min): 4.12 min.
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[NH:7][CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:16]=[CH:17][N:18]3[C:23]=2[C:22](SC)=[N:21][CH:20]=[N:19]3)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[Cl:27][C:28]1[CH:29]=[C:30]([NH2:42])[CH:31]=[CH:32][C:33]=1[O:34][CH2:35][C:36]1[CH:37]=[N:38][CH:39]=[CH:40][CH:41]=1>>[C:1]([O:5][C:6](=[O:26])[NH:7][CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:16]=[CH:17][N:18]3[C:23]=2[C:22]([NH:42][C:30]2[CH:31]=[CH:32][C:33]([O:34][CH2:35][C:36]4[CH:37]=[N:38][CH:39]=[CH:40][CH:41]=4)=[C:28]([Cl:27])[CH:29]=2)=[N:21][CH:20]=[N:19]3)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CSc1ncnn2ccc(CN3CCC(NC(=O)OC(C)(C)C)CC3)c12
Reactant: Nc1ccc(OCc2cccnc2)c(Cl)c1
Product: CC(C)(C)OC(=O)NC1CCN(Cc2ccn3ncnc(Nc4ccc(OCc5cccnc5)c(Cl)c4)c23)CC1
Yield: 60.1 %

Procedure:
Compound 2B (78 mg, 61%) was prepared from 1B (86 mg, 0.23 mmol) and 2A (86 mg, 0.37 mmol) by a route analogous to that used for the preparation of 1F (method one).
Reaction SMILES: C1C=CC=CC=1.N1C=CC=CC=1.[CH:13]1[C:18]([CH2:19][C:20]2[CH:25]=[CH:24][C:23](N=C=O)=[CH:22][CH:21]=2)=[CH:17][CH:16]=[C:15](N=C=O)[CH:14]=1>C(Cl)(Cl)Cl>[C:18]1([CH2:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=C=Nc1ccc(Cc2ccc(N=C=O)cc2)cc1
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Solvent: c1ccccc1
Product: c1ccc(Cc2ccccc2)cc1
Temperature: 40 °C

Procedure:
To 111 parts of 2-amino-4-(m,m'-di-t-butyl-p-hydroxyphenyl)-butane, 500 parts by volume of benzene and 2 parts by volume of pyridine there are added, slowly, 55 parts of diphenylmethane-4,4'-diisocyanate in 500 parts by volume of chloroform at 25° to 30° C. The mixture is then heated at 40° C for 1 hour and filtered. There are obtained 77 parts (48% of theory) of 4,4'-di-4"' -(m,m'-di-t-butyl-p-hydroxyphenyl)-butyl-2"' -ureido]-diphenylmethane, m.p. 183° to 186° C after recrystallization from 1:1 benzene/methanol.
Reaction SMILES: [C:1]1([CH:7]([CH2:11][CH3:12])[C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Al+3].[Cl-].[Cl-].[Cl-].O.[C:18]1([O:24][CH3:25])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[CH3:25][O:24][C:18]1[CH:23]=[CH:22][C:21]([C:8](=[O:9])[CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:11][CH3:12])=[CH:20][CH:19]=1
Reactant: COc1ccccc1
Reactant: CCC(C(=O)Cl)c1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Product: CCC(C(=O)c1ccc(OC)cc1)c1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
2-Phenylbutyryl chloride (50.0 mL, 299 mmol) was dissolved in anisole (75 mL) and cooled to 0° C. AlCl3 (40.377 g, 303 mmol) was added portionwise and the resulting mixture allowed to warm to RT then stirred for 2 h. Ice was added portionwise followed by H2O (100 mL). The mixture was extracted with CH2Cl2 (3×100 mL) and the combined organics dried (MgSO4) and concentrated. The residue was distilled to remove the remaining anisole (1 mm Hg, 40-55° C.) to provide 2 (77.27 g, 100%) as a tan oil. 1H NMR (400 MHz, CDCl3): δ 0.90 (t, J=7.5 Hz, 3H), 1.85 (dq, 1H), 2.18 (dq, 1H), 3.81 (s, 3H), 4.40 (t, J=7.2 Hz, 1H), 6.85 (d, J=5.0 Hz, 2H), 7.19 (m, 1H), 7.28 (m, 4H), 7.95 (d, J=5.0 Hz, 2H).
Reaction SMILES: O1[C:5]2([CH2:10][CH2:9][CH:8]([N:11]3[CH2:15][CH2:14][CH2:13][O:12]3)[CH2:7][CH2:6]2)[O:4]CC1.Cl>C(#N)C>[O:12]1[CH2:13][CH2:14][CH2:15][N:11]1[CH:8]1[CH2:9][CH2:10][C:5](=[O:4])[CH2:6][CH2:7]1
Reactant: C1CON(C2CCC3(CC2)OCCO3)C1
Agent: Cl
Solvent: CC#N
Product: O=C1CCC(N2CCCO2)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
2-(1,4-dioxaspiro[4.5]decan-8-yl)isoxazolidine (350 mg, 1.64 mmol) from above step A, was dissolved in acetonitrile, treated with 6N HCl, and stirred at room temperature for 18 h. reaction mixture was concentrated in vacuo, treated with saturated NaHCO3 to pH 6. The solvents were removed under vacuum and the residue treated with saturated NaCl (2 mL) and extracted with 4:1 EtOAc/iPrOH (×4). The organic fractions were combined, filtered and evaporated to give the title compound.
Reaction SMILES: Cl[C:2]1[C:3]([NH2:8])=[CH:4][N:5]=[N:6][CH:7]=1.[F:9][C:10]1[CH:15]=[CH:14][C:13](B(O)O)=[C:12]([O:19][CH3:20])[CH:11]=1>CCCCCCC.C(OCC)(=O)C.CO>[F:9][C:10]1[CH:15]=[CH:14][C:13]([C:2]2[C:3]([NH2:8])=[CH:4][N:5]=[N:6][CH:7]=2)=[C:12]([O:19][CH3:20])[CH:11]=1
Reactant: Nc1cnncc1Cl
Reactant: COc1cc(F)ccc1B(O)O
Solvent: CCOC(C)=O
Solvent: CO
Solvent: CCCCCCC
Product: COc1cc(F)ccc1-c1cnncc1N

Procedure:
The title compound was prepared in analogy to example 1, intermediate b, from 5-chloro-pyridazin-4-ylamine (CAS RN 53180-92-0) and 4-fluoro-2-methoxyphenylboronic acid (CAS RN 179899-07-1) and using a gradient of n-heptane:ethyl acetate:methanol (100:0:0 to 0:100:0 to 0:50:50) for the chromatographic purification. Light yellow solid (37%). MS (ESI+): m/z=220.089 ([M+H]+).
Reaction SMILES: C(OC(=O)[NH:7][CH:8]([C:29]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[N:31]([C:38](=[O:40])[CH3:39])[CH:30]=1)[C:9]([N:11]1[CH2:15][C@H:14]([F:16])[CH2:13][C@H:12]1[C:17](=[O:28])[NH:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[C:21]=1[F:27])=[O:10])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:26][C:22]1[C:21]([F:27])=[C:20]([CH:25]=[CH:24][CH:23]=1)[CH2:19][NH:18][C:17]([C@@H:12]1[CH2:13][C@@H:14]([F:16])[CH2:15][N:11]1[C:9](=[O:10])[CH:8]([C:29]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[N:31]([C:38](=[O:40])[CH3:39])[CH:30]=1)[NH2:7])=[O:28]
Reactant: CC(=O)n1cc(C(NC(=O)OC(C)(C)C)C(=O)N2C[C@H](F)C[C@H]2C(=O)NCc2cccc(Cl)c2F)c2ccccc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(=O)n1cc(C(N)C(=O)N2C[C@H](F)C[C@H]2C(=O)NCc2cccc(Cl)c2F)c2ccccc21
Temperature: 23 °C
Reaction time: 4 h

Procedure:
A solution of {1-(1-acetyl-1H-indol-3-yl)-2-[(2S,4R)-2-(3-chloro-2-fluoro-benzylcarbamoyl)-4-fluoro-pyrrolidin-1-yl]-2-oxo-ethyl}-carbamic acid tert-butyl ester (102 mg, 0.173 mmol) and TFA (66.7 μL, 0.866 mmol) in CH2Cl2 (0.58 mL) was stirred at 23° C. overnight. TFA (66.7 μL, 0.866 mmol) was again added and the reaction mixture was stirred at 23° C. for an additional 4 h to complete the reaction. Solvents were removed in vacuo and the crude residue was purified by preparative HPLC (Waters SunFire C180 DB, 5 μm, 19×50, eluent: 5% CH3CN/95% H2O to 100% CH3CN in 17 min, CH3CN and H2O containing 0.1% of TFA, flow 20 mL/min) to give after lyophilization of the purified fractions the desired material. MS (LC-MS): 487.1 [M−H]−; tR (HPLC conditions b): 3.19 min.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11].[CH3:15][C:16]1[N:24]([C:25]([C:27]2[CH:28]=[CH:29][C:30]([Cl:33])=[CH:31][CH:32]=2)=[O:26])[C:23]2[CH:22]=[CH:21][C:20]([O:34][CH3:35])=[CH:19][C:18]=2[C:17]=1[CH2:36][C:37](O)=[O:38].CCN=C=NCCCN(C)C>CC#N.CCOC(C)=O>[Cl:33][C:30]1[CH:29]=[CH:28][C:27]([C:25]([N:24]2[C:23]3[C:18](=[CH:19][C:20]([O:34][CH3:35])=[CH:21][CH:22]=3)[C:17]([CH2:36][C:37]([NH:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][NH:7][C:8](=[O:14])[O:9][C:10]([CH3:11])([CH3:13])[CH3:12])=[O:38])=[C:16]2[CH3:15])=[O:26])=[CH:32][CH:31]=1
Reactant: CC(C)(C)OC(=O)NCCOCCN
Reactant: COc1ccc2c(c1)c(CC(=O)O)c(C)n2C(=O)c1ccc(Cl)cc1
Agent: CCN=C=NCCCN(C)C
Solvent: CC#N
Solvent: CCOC(C)=O
Product: COc1ccc2c(c1)c(CC(=O)NCCOCCNC(=O)OC(C)(C)C)c(C)n2C(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 77.5 %

Procedure:
tert-Butyl 2-(2-aminoethoxy)ethylcarbamate (150 mg, 0.735 mmol) was then taken up in CH3CN (10 mL) along with indomethacin (263 mg, 0.735 mmol) and EDCI (155 mg, 0.81 mmol). The resulting reaction mixture was stirred at room temperature for 18 h. It was then diluted with EtOAc (20 mL), washed with saturated aqueous NaHCO3, brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (9:1 CH2Cl2/MeOH) to afford 310 mg of tert-butyl 2-(2-(2-(1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl)acetamido)ethoxy)ethylcarbamate (78%).
Reaction SMILES: Cl([O-])(=O)(=O)=O.[CH2:6]([C:9]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[S:11][C:10]=1[C:18]1[C:30]2[C:22](=[CH:23][C:24]3[NH:25][C:26](=[O:31])[O:27][C:28]=3[CH:29]=2)[CH:21]=[C:20]([CH3:32])[O+]=1)[CH2:7][CH3:8].C(C1C2C=CC=CC=2SC=1C=O)CC.O.[NH2:48][NH2:49]>CC(O)C>[CH3:32][C:20]1[CH2:21][C:22]2[CH:23]=[C:24]3[NH:25][C:26](=[O:31])[O:27][C:28]3=[CH:29][C:30]=2[C:18]([C:10]2[S:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[C:9]=2[CH2:6][CH2:7][CH3:8])=[N:49][N:48]=1
Reactant: CCCc1c(-c2[o+]c(C)cc3cc4[nH]c(=O)oc4cc23)sc2ccccc12
Reactant: NN
Agent: CCCc1c(C=O)sc2ccccc12
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: CC(C)O
Solvent: O
Product: CCCc1c(C2=NN=C(C)Cc3cc4[nH]c(=O)oc4cc32)sc2ccccc12
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a suspension of 5-(3-propyl-1-benzothien-2-yl)-7-methyl-2-oxo-1H,2H-isochromeno[6,7-d][1,3]oxazol-6-ium perchlorate (51 mmol) (obtained according to Steps A and B described in Example 1 using 3-propyl-1-benzothiophene-2-carbaldehyde instead of 2-naphthaldehyde) in 2-propanol (468 mL) there is added hydrazine hydrate (6.68 mL; 133 mmol), with vigorous stirring, at ambient temperature. The reaction mixture is stirred for 20 hours at ambient temperature. The crystals obtained are then filtered off and then stirred in warm water (1900 mL) for 30 minutes. After filtration and drying, the solid is purified by chromatography over a silica gel column (eluant: dichloromethane/ethyl acetate) to yield the title product.
Reaction SMILES: C(OC(=O)[NH:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH:13]([C:17]2[N:18]([CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=3[C:39]#[N:40])[C:19]3[C:28](=[O:29])[N:27]([CH3:30])[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][N:25]=4)[C:20]=3[N:31]=2)[CH2:12]1)C1C=CC=CC=1>[Pd].CCO.C1COCC1>[NH2:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH:13]([C:17]2[N:18]([CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=3[C:39]#[N:40])[C:19]3[C:28](=[O:29])[N:27]([CH3:30])[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][N:25]=4)[C:20]=3[N:31]=2)[CH2:12]1
Reactant: Cn1c(=O)c2c(nc(C3CCCC(NC(=O)OCc4ccccc4)C3)n2Cc2ccccc2C#N)c2cccnc21
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: Cn1c(=O)c2c(nc(C3CCCC(N)C3)n2Cc2ccccc2C#N)c2cccnc21
Reaction time: 1.5 h
Yield: 72.7 %

Procedure:
A solution of {3-[3-(2-cyano-benzyl)-5-methyl-4-oxo-4,5-dihydro-3H-1,3,5,6-tetraaza-cyclopenta[a]naphthalen-2-yl]-cyclohexyl}-carbamic acid benzyl ester (55 mg, 0.10 mmol) in 1:1 EtOH/THF (8 mL) was hydrogenated at 1 atm over 10% Pd/C (54 mg, 0.05 mmol) at room temperature. After 90 min, the reaction vessel was purged with nitrogen, and the catalyst was removed by filtration, rinsing with MeOH to provide 2-[2-(3-amino-cyclohexyl)-5-methyl-4-oxo-4,5-dihydro-1,3,5,6-tetraaza-cyclopenta[a]naphthalen-3-ylmethyl]-benzonitrile (30 mg, 72% yield). The crude amine was taken up in 2 mL of EtOAc and a minimum amount of EtOH, and was treated with 0.2 mL of 1N HCl in diethyl ether. The solvent was removed to give the corresponding HCl salt as a white solid. 1H-NMR (DMSO): δ 8.65 (m, 1H), 8.53 (dd, 1H, J=7.6, 1.6 Hz), 8.11 (m, 2H), 7.95 (m, 1H), 7.59 (t, 1H, J=7.6 Hz), 7.49 (m, 1H), 7.42 (m, 1H), 6.68 (d, 1H, J=7.6 Hz), 6.04 (m, 2H), 4.61 (m, 1H), 3.70 (s, 3H), 3.17 (m, 1H), 2.18 (m, 1H), 1.97 (m, 2H), 1.82 (m, 1H), 1.71 (m, 2H), 1.51 (m, 1H), 1.41 (m, 1H). MS: calculated for C24H24N6O+H. 413.2; found: 413.3.