Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[CH:24][C:4]=1[CH2:5][N:6]1[C:9](=[O:10])[C@@H:8]([NH:11][C:12](=[O:21])[O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C@H:7]1[CH2:22]O.[Si:30]([O:37][CH2:38][C:39]1[N:40]=[N:41][NH:42][CH:43]=1)([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[Si:30]([O:37][CH2:38][C:39]1[CH:43]=[N:42][N:41]([CH2:22][C@@H:7]2[C@H:8]([NH:11][C:12](=[O:21])[O:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:9](=[O:10])[N:6]2[CH2:5][C:4]2[CH:24]=[CH:25][C:26]([O:28][CH3:29])=[CH:27][C:3]=2[O:2][CH3:1])[N:40]=1)([C:33]([CH3:36])([CH3:34])[CH3:35])([CH3:32])[CH3:31]
Reactant: CC(C)(C)[Si](C)(C)OCc1c[nH]nn1
Reactant: COc1ccc(CN2C(=O)[C@@H](NC(=O)OCc3ccccc3)[C@H]2CO)c(OC)c1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1ccc(CN2C(=O)[C@@H](NC(=O)OCc3ccccc3)[C@H]2Cn2ncc(CO[Si](C)(C)C(C)(C)C)n2)c(OC)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 89.7 %

Procedure:
To a solution of benzyl ((2S,3S)-1-(2,4-dimethoxybenzyl)-2-(hydroxymethyl)-4-oxoazetidin-3-yl)carbamate (0.94 g, 2.34 mmol), 4-(((tert-butyldimethylsilyl)oxy)methyl)-1H-1,2,3-triazole (0.5 g, 2.34 mmol), and PPh3 (0.74 g, 2.81 mmol) in THF (20 mL) at 0° C. was added DIAD (0.57 g, 2.81 mmol) slowly. After stirring at rt for 16 h, the reaction mixture was concentrated in vacuo. The crude residue was purified via silica gel chromatography (EtOAc-hexanes, 20-30%) to afford the title compound (1.25 g, 89%) as a pale yellow solid. LCMS: m/z=594.3 (M−1).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:29])[C:15]2[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[C:17]([C:25]([F:28])([F:27])[F:26])[CH:16]=2)[C@H:10]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=2)[CH2:9]1)C1C=CC=CC=1.C([O-])=O.[NH4+].C(O)C>[Pd].O>[F:27][C:25]([F:26])([F:28])[C:17]1[CH:16]=[C:15]([CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=1)[C:14]([N:11]1[CH2:12][CH2:13][NH:8][CH2:9][C@H:10]1[CH2:30][C:31]1[CH:32]=[CH:33][C:34]([F:37])=[CH:35][CH:36]=1)=[O:29]
Reactant: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCN(Cc2ccccc2)C[C@H]1Cc1ccc(F)cc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCNC[C@H]1Cc1ccc(F)cc1
Temperature: 60 °C
Reaction time: 1.5 h
Yield: 92.1 %

Procedure:
A mixture of (2R)-4-benzyl-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(4-fluorobenzyl)piperazine (7.92 g), ammonium formate (2.38 g) and 10% palladium charcoal (0.79 g) in a mixed solvent of ethanol (80 ml) and water (8 ml) was stirred for 1.5 hours at 60° C. under nitrogen atmosphere. The reaction mixture was cooled to room temperature and filtered through Celite® pad. The filtrate was concentrated under reduced pressure and the residue was dissolved into ethyl acetate. The solution was washed with water and brine successively, dried over magnesium sulfate, and evaporated under reduced pressure to give (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(4-fluorobenzyl)piperazine (6.04 g) as an oil.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][C@@H:9]1[CH2:14][NH:13][CH2:12][CH2:11][N:10]1[C:15]1[N:16]=[N:17][C:18]([C:25]2[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=2)=[C:19]2[CH:24]=[CH:23][N:22]=[CH:21][C:20]=12.[C:35](Cl)(=[O:42])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH3:8][C@H:9]1[N:10]([C:15]2[N:16]=[N:17][C:18]([C:25]3[CH:26]=[CH:27][C:28]([C:31]([F:34])([F:32])[F:33])=[CH:29][CH:30]=3)=[C:19]3[CH:24]=[CH:23][N:22]=[CH:21][C:20]=23)[CH2:11][CH2:12][N:13]([C:35]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[O:42])[CH2:14]1
Reactant: O=C(Cl)c1ccccc1
Reactant: C[C@@H]1CNCCN1c1nnc(-c2ccc(C(F)(F)F)cc2)c2ccncc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@@H]1CN(C(=O)c2ccccc2)CCN1c1nnc(-c2ccc(C(F)(F)F)cc2)c2ccncc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 77 %

Procedure:
To triethylamine (0.315 ml, 2.26 mmol) and (R)-4-(2-methylpiperazin-1-yl)-1-(4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyridazine 21 (0.352 g, 0.943 mmol), in CH2Cl2 (3.1 ml) was added benzoyl chloride (0.120 ml, 1.04 mmol). The reaction was stirred at 25° C. After 2 h, the reaction contents were poured into saturated sodium bicarbonate (10 mL) and extracted with dichloromethane (3×15 mL). The combined organics were dried with Na2SO4 and concentrated in vacuo. Silica gel chromatography (gradient elution 20 to 90% EtOAc in CH2Cl2) afforded 347 mg of desired product (R)-(3-methyl-4-(1-(4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyridazin-4-yl)piperazin-1-yl)(phenyl)methanone 22 (77% yield). 1H NMR (500 MHz, CDCl3) δ ppm 9.57 (s, 1H) 8.96 (d, J=6.1 Hz, 1H) 7.81-7.97 (m, 4H) 7.77 (d, J=5.5 Hz, 1H) 7.47 (s, 5H) 3.30-4.82 (m, 7H) 1.29-1.53 (m, 3H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([C:13]3([CH3:26])[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]3)=[N:10][C:9]=2[C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([NH:33][S:34]([C:37]3[C:42]([F:43])=[CH:41][CH:40]=[CH:39][C:38]=3[F:44])(=[O:36])=[O:35])[C:28]=2[F:45])[CH:5]=[CH:4][N:3]=1.[OH-].[NH4+:47]>>[NH2:47][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([C:13]3([CH3:26])[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]3)=[N:10][C:9]=2[C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([NH:33][S:34]([C:37]3[C:42]([F:43])=[CH:41][CH:40]=[CH:39][C:38]=3[F:44])(=[O:36])=[O:35])[C:28]=2[F:45])[CH:5]=[CH:4][N:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(C)(c2nc(-c3cccc(NS(=O)(=O)c4c(F)cccc4F)c3F)c(-c3ccnc(Cl)n3)s2)CC1
Reactant: [NH4+]
Agent: [OH-]
Product: CC(C)(C)OC(=O)N1CCC(C)(c2nc(-c3cccc(NS(=O)(=O)c4c(F)cccc4F)c3F)c(-c3ccnc(N)n3)s2)CC1
Temperature: 90 °C
Yield: 106.2 %

Procedure:
A suspension of 1,1-dimethylethyl 4-[5-(2-chloro-4-pyrimidinyl)-4-(3-{[(2,6-difluorophenyl)sulfonyl]amino}-2-fluorophenyl)-1,3-thiazol-2-yl]-4-methyl-1-piperidinecarboxylate (39 mg, 0.057 mmol) in ammonium hydroxide solution (28%, 2 mL, 51.4 mmol) sealed in a 5-mL microwave tube was heated at 90° C. for 3 h under the microwave conditions. The mixture was concentrated and dried under high vacuum to obtain the title compound (40 mg). MS (ESI): 661.4 [M+1]+.
Reaction SMILES: [C:1]1(=[O:7])O[C:4](=[O:5])[CH:3]=[CH:2]1.[Br:8][C:9]1[CH:10]=[C:11]([NH2:15])[CH:12]=[CH:13][CH:14]=1.C([O-])(=O)C.[Na+].C(OC(=O)C)(=O)C>CCOCC.O>[Br:8][C:9]1[CH:10]=[C:11]([N:15]2[C:4](=[O:5])[CH:3]=[CH:2][C:1]2=[O:7])[CH:12]=[CH:13][CH:14]=1
Reactant: O=C1C=CC(=O)O1
Reactant: Nc1cccc(Br)c1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Solvent: CC(=O)OC(C)=O
Product: O=C1C=CC(=O)N1c1cccc(Br)c1
Temperature: 100 °C
Yield: 64.8 %

Procedure:
To a solution of maleic anhydride (1.71 g, 17.4 mmol) in dry ether (25 ml) was added a solution of 3-bromo-phenylamine (3.0 g, 17.4 mmol) in ether (5 ml), via slow drop-wise addition. The material was stirred for 1 hour at ambient Sodium acetate (721 mg, 8.8 mmol) and then acetic anhydride (6 ml, 63 mmol) were added and the mixture was heated for 2 hours (oil bath, 100° C.). The material was cooled to ambient and then in an ice bath. Water (50 ml) was added with vigorous stirring and the resultant precipitate was collected by filtration. The precipitate was washed with several volumes of water and finally with hexane (30 ml). The material was dried over night in the vacuum oven to afford 2.84 g of 1-(3-bromo-phenyl)-pyrrole-2,5-dione as a light yellow-white powder.
Reaction SMILES: [NH2:1][N:2]1[C:7](=[O:8])[C:6]([C:9]2[NH:14][C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[S:11](=[O:20])(=[O:19])[N:10]=2)=[C:5]([OH:21])[C:4]2[S:22][CH:23]=[CH:24][C:3]1=2.[S:25]1[C:29]([CH:30]=O)=[CH:28][N:27]=[CH:26]1>CN(C)C(=O)C>[O:19]=[S:11]1(=[O:20])[C:12]2[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=2[NH:14][C:9]([C:6]2[C:7](=[O:8])[N:2]([N:1]=[CH:30][C:29]3[S:25][CH:26]=[N:27][CH:28]=3)[C:3]3[CH:24]=[CH:23][S:22][C:4]=3[C:5]=2[OH:21])=[N:10]1
Reactant: O=Cc1cncs1
Reactant: Nn1c(=O)c(C2=NS(=O)(=O)c3ccccc3N2)c(O)c2sccc21
Solvent: CC(=O)N(C)C
Product: O=c1c(C2=NS(=O)(=O)c3ccccc3N2)c(O)c2sccc2n1N=Cc1cncs1
Temperature: 25 °C

Procedure:
The product of Example 268D (0.115 g, 0.30 mmol) was reacted with 1,3-thiazole-5-carbaldehyde (0.35 g, 3.0 mmol) in N,N-dimethylacetamide (3 mL) in a sealed tube at 140° C. for 80 minutes in a microwave reactor. The reaction was cooled to 25° C. and concentrated under vacuum. The resulting residue was triturated with 0.1 M HCl (20 mL) and filtered to give the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:28]=[CH:29][CH:30]=1)[CH2:5][N:6]1[C:10]([CH3:11])=[N:9][C:8]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:22]=[CH:21][C:20]([O:23][C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=3)[N:13]=2)=[N:7]1.[CH3:31][S:32]([CH:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1)(=[O:34])=[O:33].C([O-])([O-])=O.[Cs+].[Cs+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:31][S:32]([CH:35]1[CH2:40][CH2:39][N:38]([C:2]2[CH:30]=[CH:29][CH:28]=[C:4]([CH2:5][N:6]3[C:10]([CH3:11])=[N:9][C:8]([C:12]4[O:16][N:15]=[C:14]([C:17]5[CH:22]=[CH:21][C:20]([O:23][C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=5)[N:13]=4)=[N:7]3)[CH:3]=2)[CH2:37][CH2:36]1)(=[O:34])=[O:33]
Reactant: CS(=O)(=O)C1CCNCC1
Reactant: Cc1nc(-c2nc(-c3ccc(OC(F)(F)F)cc3)no2)nn1Cc1cccc(Br)c1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: Cc1nc(-c2nc(-c3ccc(OC(F)(F)F)cc3)no2)nn1Cc1cccc(N2CCC(S(C)(=O)=O)CC2)c1
Temperature: 140 °C
Reaction time: 0.2 h

Procedure:
A mixture of 5-(1-(3-bromobenzyl)-5-methyl-1H-1,2,4-triazol-3-yl)-3-(4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazole (Example 11, Step 1; 165 mg, 0.34 mmol), 4-(methylsulfonyl)piperidine (62 mg, 0.38 mmol), and Cs2CO3 (224 mg, 0.69 mmol) in toluene (2 mL) was degassed with argon for 5 min. Pd2(dba)3 (0.15 mg, 0.017 mmol) and dicyclohexyl(2′,4′,6′-triisopropyl-[1,1′-biphenyl]-2-yl)phosphine (33 mg, 069 mmol) were added and the reaction mixture was degassed a second time with argon for 5 min, then heated to 140° C. for 18 h. The mixture was then cooled to RT, diluted with EtOAc (15 mL), filtered through a pad of Celite, and concentrated under reduced pressure. The crude product was purified by prep-HPLC (Mobile phase: A=0.1% TFA/H2O, B=0.1% TFA/MeCN; Gradient: B=40%-80% in 12 min; Column: C18) to give the title compound as a white solid; MS (ES+) C25H25F3N6O4S requires: 562. found: 563 [M+H]+; 1H NMR (600 MHz, DMSO-d6) δ 8.22 (d, J=8.8 Hz, 2H), 7.61 (d, J=8.2 Hz, 2H), 7.21 (t, J=7.9 Hz, 1H), 6.97 (bs, 1H), 6.94 (dd, J=8.3, 2.4 Hz, 1H), 6.64 (d, J=7.5 Hz, 1H), 5.48 (s, 2H), 3.86 (bd, J=13.4 Hz, 2H), 3.28 (m, 1H), 2.94 (s, 3H), 2.76 (m, 2H), 2.57 (s, 3H), 2.06 (bd, J=13.4 Hz, 2H), 1.68 (ddd, J=16.5, 12.5, 4.1 Hz, 2H); 19F NMR (282 MHz, DMSO-d6) δ −56.6.
Reaction SMILES: [CH2:1]([O:4][C:5]1([CH3:46])[CH2:10][CH2:9][N:8]([C:11]2[N:16]3[N:17]=[C:18]([CH2:20][O:21][CH2:22][C:23]4[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=4[CH2:30][CH2:31]C=C)[CH:19]=[C:15]3[N:14]=[C:13]([CH3:34])[C:12]=2[C@H:35]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])[C:36]([O:38][CH2:39][CH3:40])=[O:37])[CH2:7][CH2:6]1)[CH:2]=[CH2:3].[BH4-].[Na+]>C(Cl)Cl.O>[C:42]([O:41][C@@H:35]([C:12]1[C:13]([CH3:34])=[N:14][C:15]2=[CH:19][C:18]3=[N:17][N:16]2[C:11]=1[N:8]1[CH2:9][CH2:10][C:5]([CH3:46])([O:4][CH2:1][CH2:2][CH2:3][CH2:31][CH2:30][C:24]2[CH:25]=[C:26]([F:29])[CH:27]=[CH:28][C:23]=2[CH2:22][O:21][CH2:20]3)[CH2:6][CH2:7]1)[C:36]([O:38][CH2:39][CH3:40])=[O:37])([CH3:44])([CH3:45])[CH3:43]
Reactant: C=CCCc1cc(F)ccc1COCc1cc2nc(C)c([C@H](OC(C)(C)C)C(=O)OCC)c(N3CCC(C)(OCC=C)CC3)n2n1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)nc2cc3nn2c1N1CCC(C)(CC1)OCCCCCc1cc(F)ccc1COC3
Temperature: 25 °C
Reaction time: 1 h
Yield: 74.7 %

Procedure:
A mixture of (S)-ethyl 2-(7-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-(((2-(but-3-en-1-yl)-4-fluorobenzyl)oxy)methyl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate (50 mg, 0.079 mmol) and Grubb's II catalyst (66.7 mg, 0.079 mmol) in DCM (50 mL) was refluxed for 2 h. It was then concentrated and the residue was dissolved in MeOH (2 mL). NaBH4 (2.97 mg, 0.079 mmol) was added and the reaction mixture was stirred at rt for 1 h. It was then diluted with water, extracted with EtOAc. The organic layer was dried over MgSO4, filtered and concentrated to obtain an oil, which was then purified by biotage, eluting with 20% EtOAc/hexane to obtain ethyl (2S)-2-(tert-butoxy)-2-{16-fluoro-4,25-dimethyl-11,24-dioxa-1,5,7,8-tetraazapentacyclo[23.2.2.16,9.02,7.013,18]triaconta-2,4,6(30),8,13(18),14,16-heptaen-3-yl}acetate (36 mg, 0.059 mmol, 75% yield) as a white solid. 1H NMR (400 MHz, CDCl3) δ 7.33-7.27 (m, 1H), 6.95 (dd, J=10.3, 2.7 Hz, 1H), 6.85 (td, J=8.3, 2.7 Hz, 1H), 6.56 (s, 1H), 6.07 (s, 1H), 4.78-4.64 (m, 4H), 4.58 (t, J=11.2 Hz, 1H), 4.18-4.11 (m, 2H), 3.90 (t, J=11.0 Hz, 1H), 3.44 (d, J=5.1 Hz, 2H), 3.05 (d, J=11.5 Hz, 1H), 2.95-2.85 (m, 1H), 2.83-2.72 (m, 2H), 2.63 (s, 3H), 2.03-1.88 (m, 2H), 1.84-1.62 (m, 8H), 1.31-1.24 (m, 15H). LCMS (M+1)=611.4.
Reaction SMILES: [OH-].[Na+].C([O:6][C:7]1[C:17]2[C:16](=[O:18])[C:13]3([CH2:15][CH2:14]3)[O:12][C:11]=2[CH:10]=[CH:9][CH:8]=1)(=O)C.Cl>>[OH:6][C:7]1[C:17]2[C:16](=[O:18])[C:13]3([CH2:14][CH2:15]3)[O:12][C:11]=2[CH:10]=[CH:9][CH:8]=1
Reactant: CC(=O)Oc1cccc2c1C(=O)C1(CC1)O2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C1c2c(O)cccc2OC12CC2
Temperature: 25 °C

Procedure:
A 10% aqueous solution of sodium hydroxide was added to 4-acetoxyspiro[benzo[b]furan-2(3H),1'-cyclopropane]-3-one and the mixture was stirred at room temperature. The reaction mixture was made acidic with hydrochloric acid and extracted with ethyl acetate. The extract was washed with water, dried and distilled to remove the solvent. The residue was recrystallized from petroleum ether. By the above procedure there was obtained 4-hydroxyspiro[benzo[b]furan-2(3H),1'-cyclopropane]-3-one as yellow needles, m.p. 100°-109° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C@H:4]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1)[NH:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7].[H-].[Na+].[Cl:24][C:25]1[CH:33]=[N:32][CH:31]=[C:30]([Cl:34])[C:26]=1[C:27](Cl)=[O:28].[NH4+].[Cl-]>C1COCC1>[CH3:1][O:2][C:3](=[O:21])[C@H:4]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][C:27](=[O:28])[C:26]2[C:25]([Cl:24])=[CH:33][N:32]=[CH:31][C:30]=2[Cl:34])=[CH:16][CH:15]=1)[NH:5][C:6]([O:8][C:9]([CH3:12])([CH3:10])[CH3:11])=[O:7]
Reactant: O=C(Cl)c1c(Cl)cncc1Cl
Reactant: COC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COC(=O)[C@H](Cc1ccc(OC(=O)c2c(Cl)cncc2Cl)cc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 76.9 %

Procedure:
A solution of N-BOC-L-tyrosine methyl ester (2.95 g, 10 mmol) in THF (10 ml) was added to a suspension of NaH (60% in oil, 11 mmol, 440 mg) in THF (30 ml) at 0°. After 10 min, a solution of 3,5-dichloroisonicotinoyl chloride (11 mml, 2.32 g) in THF (10 ml) was added and the mixture stirred at RT for 4 h. NH4Cl (aq) was added and the mixture extracted with DCM. The DCM extracts were dried (Na2SO4) and concentrated in vacuo. Recrystallisation (EtOAc/hexane) gave the title compound as white crystals (3.61 g, 77%). δH (DMSO d6) 8.89 (2H, s), 7.39 (2H, d, J 8.5 Hz), 7.32 (1H, d, J 8.2 Hz), 7.23 (2H, d, J 8.5 Hz), 4.21 (1H, m), 3.62 (3H, s), 3.05 (1H, dd, J 13.8, 4.9 Hz), 2.89 (1H, dd, J 13.8, 10.5 Hz), 1.31 (9H). m/z (ES+, 70V) 410 (M++Na).
Reaction SMILES: C[O:2][C:3]([C@@H:5]1[CH2:9][C@H:8]([NH:10][C:11]([C:13]2[CH:22]=[CH:21][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]=2[OH:23])=[O:12])[CH2:7][N:6]1[CH2:24][CH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1)=O.[NH:31]1[CH2:35][CH2:34][CH2:33][CH2:32]1>>[CH:25]1([CH2:24][N:6]2[C@H:5]([C:3]([N:31]3[CH2:35][CH2:34][CH2:33][CH2:32]3)=[O:2])[CH2:9][C@H:8]([NH:10][C:11]([C:13]3[CH:22]=[CH:21][C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[C:14]=3[OH:23])=[O:12])[CH2:7]2)[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]1
Reactant: COC(=O)[C@@H]1C[C@H](NC(=O)c2ccc3ccccc3c2O)CN1CC1CCCCC1
Reactant: C1CCNC1
Product: O=C(N[C@H]1C[C@@H](C(=O)N2CCCC2)N(CC2CCCCC2)C1)c1ccc2ccccc2c1O

Procedure:
Hydroxy-naphthalene-2-carboxylic acid [(3S,5S)-1-cyclohexylmethyl-5-(pyrrolidine-1-carbonyl)-pyrrolidin-3-yl]-amide was prepared from (2S,4S)-1-cyclohexylmethyl-4-[(1-hydroxy-naphthalene-2-carbonyl)-amino]-pyrrolidine-2-carboxylic acid methyl ester and pyrrolidine in an analogous manner to example 12. MS calcd. for C27H36N3O3 [(M+H)+] 450.0, obsd. 450.2.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([CH2:13][S:14][C:15]2[NH:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[N:16]=2)[C:8]=1[CH3:24].[OH-:25].[Na+].O>ClCCl>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([CH2:13][S:14]([C:15]2[NH:16][C:17]3[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=3[N:19]=2)=[O:25])[C:8]=1[CH3:24]
Reactant: COCCCOc1ccnc(CSc2nc3ccccc3[nH]2)c1C
Reactant: [OH-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: COCCCOc1ccnc(CS(=O)c2nc3ccccc3[nH]2)c1C
Yield: 23.5 %

Procedure:
2-[{4-(3-Methoxypropoxy)-3-methylpyridin-2-yl}methylthio]-1H-benzimidazole (25.0 g (72.8 mmol)) was dissolved in dichloromethane and cooled. Then, mcpba (70.2% purity; 5.37 g (21.8 mmol)) was added gradually so that the internal temperature did not exceed −15° C. 10% Aqueous sodium hydroxide solution (70.8 ml) was then added, and after stirring and still standing the water layer was separated. The separated water layer was washed with dichloromethane (48 ml) twice. After addition of a 2N-ammonium acetate aqueous solution, the water layer was extracted with dichloromethane (48 ml) twice. The dichloromethane layer was washed with water (48 ml) twice, concentrated under a reduced pressure, crystallized with ethyl acetate (66 ml) and filtered to obtain 2-[{4-(3-methoxypropoxy)-3-methylpyridin-2-yl}methylsulfinyl]-1H-benzimidazole (6.15 g) (HPLC purity 99.8%, yield 23.5%).
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8]Cl)[CH:3]=1.[OH:10][C:11]1[CH:34]=[CH:33][C:14]([CH2:15][N:16]2[CH:20]=[C:19]([CH2:21][CH2:22][C:23]([O:25]C)=[O:24])[C:18]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[N:17]2)=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+].O.[OH-].[Li+].Cl>CO.O.O1CCCC1.CN(C)C=O>[C:27]1([C:18]2[C:19]([CH2:21][CH2:22][C:23]([OH:25])=[O:24])=[CH:20][N:16]([CH2:15][C:14]3[CH:13]=[CH:12][C:11]([O:10][CH2:8][C:4]4[CH:3]=[N:2][CH:7]=[CH:6][CH:5]=4)=[CH:34][CH:33]=3)[N:17]=2)[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: ClCc1cccnc1
Reactant: COC(=O)CCc1cn(Cc2ccc(O)cc2)nc1-c1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CN(C)C=O
Solvent: O
Product: O=C(O)CCc1cn(Cc2ccc(OCc3cccnc3)cc2)nc1-c1ccccc1
Temperature: 50 °C
Reaction time: 3 h
Yield: 75.7 %

Procedure:
A mixture of 3-picolyl chloride hydrochloride (148 mg), methyl 3-[1-(4-hydroxybenzyl)-3-phenyl-1H-pyrazol-4-yl]propionate (300 mg), potassium carbonate (357 mg) and N,N-dimethylformamide (5 ml) was stirred at 50° C. for 3 hours. The reaction mixture was poured into water, which was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), then concentrated. The residue was subjected to silica gel column chromatography, and a colorless oily substance was obtained from the fraction eluted with ethyl acetate. A mixture of the oily substance obtained, lithium hydroxide monohydrate (108 mg), tetrahydrofuran (6 ml), water (4 ml), and methanol (4 ml) was stirred at room temperature for 2 hours, and 1N hydrochloric acid (2.6 ml) was added to the mixture, which was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), then concentrated. The colorless crystals obtained were collected by filtration to yield 3-[3-phenyl-1-[4-(3-pyridylmethoxy)benzyl]-1H-pyrazol-4-yl]propionic acid (279 mg, yield: 78%). This was recrystallized from acetone-hexane. Melting point: 112–113° C.
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:6]=[C:7]([CH:12]=[C:13]([CH2:15][N:16]=[N+]=[N-])[CH:14]=1)[C:8]([O:10][CH3:11])=[O:9])=[N+]=[N-]>CO.[Pd]>[NH2:1][CH2:4][C:5]1[CH:6]=[C:7]([CH:12]=[C:13]([CH2:15][NH2:16])[CH:14]=1)[C:8]([O:10][CH3:11])=[O:9]
Reactant: COC(=O)c1cc(CN=[N+]=[N-])cc(CN=[N+]=[N-])c1
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1cc(CN)cc(CN)c1
Reaction time: 12 h
Yield: 98.8 %

Procedure:
A stirred suspension of crude 10 (0.77 g) and 10% Pd on carbon (0.07 g) in methanol (5 mL) was degassed at room temperature and then subjected to 1 atm of hydrogen gas via inflated balloon for 12 h. Excess hydrogen was removed under vacuum and the reaction vessel was purged with argon. The reaction mixture was filtered through filter agent Celatom FW-14 with methanol washings to remove catalyst. The filtrate was concentrated under reduced pressure to provide 0.60 g of methyl 3,5-bis(aminomethyl)benzoate (11) as a pale yellow oil. The crude product was used without further purification; IR(thin film): 3357, 3296, 2951, 1721, 1651, 1602, 1544, 1435, 1307, 1224 cm-1 ; PMR (DMSO-d6) δ7.76 (s, 2 H), 7.56 (s, 1 H), 3.85 (s, 4 H), 3.79 (s, 3 H).
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH:12]1([CH2:15][C:16]([CH3:29])([C:19]2[CH:20]=[N:21][C:22]([C:25]([F:28])([F:27])[F:26])=[N:23][CH:24]=2)[CH2:17][NH2:18])[CH2:14][CH2:13]1>>[Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:18][CH2:17][C:16]([CH3:29])([C:19]1[CH:20]=[N:21][C:22]([C:25]([F:28])([F:27])[F:26])=[N:23][CH:24]=1)[CH2:15][CH:12]1[CH2:14][CH2:13]1)=[O:6]
Reactant: O=C(O)c1cccc(Cl)c1Cl
Reactant: CC(CN)(CC1CC1)c1cnc(C(F)(F)F)nc1
Product: CC(CNC(=O)c1cccc(Cl)c1Cl)(CC1CC1)c1cnc(C(F)(F)F)nc1

Procedure:
From 2,3-dichlorobenzoic acid and 3-cyclopropyl-2-methyl-2-(2-(trifluoromethyl)pyrimidin-5-yl)propan-1-amine. LCMS (MH+): m/z=432.1, tR (minutes, Method G)=2.58
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:18]3[C:17](=[O:19])[CH2:16][CH2:15][CH2:14][C:13]=3[N:12]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=3)[C:11](=[O:30])[N:10]2[S:31]([CH2:34][CH2:35][CH2:36][C:37]([OH:39])=[O:38])(=[O:33])=[O:32])=[CH:5][CH:4]=1)#[N:2].C(C1C=CC(C2C(C#N)=C(C3C4C(=O)CCCC=4N(C4C=CC=C(C(F)(F)F)C=4)C(=O)N3[S:76]([C:79]3C=C(C(OC)=O)SC=3)(=O)=O)C=CC=2)=CC=1)#N>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:18]3[C:17](=[O:19])[CH2:16][CH2:15][CH2:14][C:13]=3[N:12]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:27])([F:29])[F:28])[CH:21]=3)[C:11](=[O:30])[N:10]2[S:31]([C:34]2[CH:35]=[C:36]([C:37]([OH:39])=[O:38])[S:76][CH:79]=2)(=[O:32])=[O:33])=[CH:5][CH:4]=1)#[N:2]
Reactant: COC(=O)c1cc(S(=O)(=O)N2C(=O)N(c3cccc(C(F)(F)F)c3)C3=C(C(=O)CCC3)C2c2cccc(-c3ccc(C#N)cc3)c2C#N)cs1
Reactant: N#Cc1ccc(C2C3=C(CCCC3=O)N(c3cccc(C(F)(F)F)c3)C(=O)N2S(=O)(=O)CCCC(=O)O)cc1
Product: N#Cc1ccc(C2C3=C(CCCC3=O)N(c3cccc(C(F)(F)F)c3)C(=O)N2S(=O)(=O)c2csc(C(=O)O)c2)cc1

Procedure:
The title compound is prepared in analogy to 4-(4-(4-cyanophenyl)-2,5-dioxo-1-(3-(tri-fluoromethyl)phenyl)-1,2,5,6,7,8-hexahydroquinazolin-3(4H)-ylsulfonyl)butanoic acid example 45), using methyl 4-(4-(4-cyanophenyl)-2,5-dioxo-1-(3-(trifluoromethyl)phenyl)-1,2,5,6,7,8-hexahydroquinazolin-3(4H)-ylsulfonyl)thiophene-2-carboxylate (example 44, 22 mg, 36 μmol) as starting material. Yield: 9 mg; ESI mass spectrum [M+H]+=602; Retention time HPLC: 0.94 min (Z018_S04).