Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C@H:3]1[CH2:20][CH2:19][C@@:18]2([CH3:21])[C:5](=[CH:6][C:7](=[O:23])[C@@H:8]3[C@@H:17]2[CH2:16][CH2:15][C@@:13]2([CH3:14])[C@H:9]3[CH2:10][CH2:11][C@@H:12]2[OH:22])[CH2:4]1.N1C=CC=CC=1[CH2:30][C:31](OC(=O)CC1C=CC=CN=1)=[O:32]>>[CH3:1][O:2][C@H:3]1[CH2:20][CH2:19][C@@:18]2([CH3:21])[C:5](=[CH:6][C:7](=[O:23])[C@@H:8]3[C@@H:17]2[CH2:16][CH2:15][C@@:13]2([CH3:14])[C@H:9]3[CH2:10][CH2:11][C@@H:12]2[O:22][C:31](=[O:32])[CH3:30])[CH2:4]1
Reactant: O=C(Cc1ccccn1)OC(=O)Cc1ccccn1
Reactant: CO[C@H]1CC[C@@]2(C)C(=CC(=O)[C@H]3[C@@H]4CC[C@H](O)[C@@]4(C)CC[C@@H]32)C1
Product: CO[C@H]1CC[C@@]2(C)C(=CC(=O)[C@H]3[C@@H]4CC[C@H](OC(C)=O)[C@@]4(C)CC[C@@H]32)C1

Procedure:
3β-methoxy-17β-hydroxyandrost-5-ene-7-one (28) was acetylated in pyridine-acetic anhydride mixture at room temperature to obtain product 29, m.p. 168-70° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:10]=[CH:11][N:12]([CH2:14][CH2:15][N:16]([CH3:18])[CH3:17])[CH:13]=2)[CH:5]=[CH:6][C:7]=1[F:8].C([Li])CCC.[C:24]([O:28][C:29]([N:31]1[CH2:36][CH2:35][C:34](=[O:37])[CH2:33][CH2:32]1)=[O:30])([CH3:27])([CH3:26])[CH3:25]>C1COCC1>[C:24]([O:28][C:29]([N:31]1[CH2:36][CH2:35][C:34]([C:11]2[N:12]([CH2:14][CH2:15][N:16]([CH3:18])[CH3:17])[CH:13]=[C:9]([C:4]3[CH:5]=[CH:6][C:7]([F:8])=[C:2]([Cl:1])[CH:3]=3)[N:10]=2)([OH:37])[CH2:33][CH2:32]1)=[O:30])([CH3:27])([CH3:25])[CH3:26]
Reactant: CN(C)CCn1cnc(-c2ccc(F)c(Cl)c2)c1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CN(C)CCn1cc(-c2ccc(F)c(Cl)c2)nc1C1(O)CCN(C(=O)OC(C)(C)C)CC1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 41.3 %

Procedure:
Dissolve {2-[4-(3-chloro-4-fluoro-phenyl)-imidazol-1-yl]-ethyl}-dimethylamine (1.00 equiv; 4.07 mmol; 1.09 g) in anhydrous THF (15 mL; 184.33 mmol) and cool the mixture to −78° C. Slowly add n-butyl lithium (1.40 equiv; 5.70 mmol; 3.56 mL) (1.6M Aldrich), and stir at −78° C. for 30 min, then add a THF (10 mL) solution of N-t-butoxycarbonyl-4-piperidone (1.20 equiv; 4.89 mmol; 973.43 mg) dropwise over 10 min. After 20 min, warm the reaction to RT and stir 3 h. Partition between EA and water. Wash the organic layer with brine, NaCl aq (50/50) and dry over MgSO4. Filter and concentrate. Purify the residue by ISCO chromatography over a Biotage 40M column eluting with 100% DCM to 10% MeOH/DCM to give 785 mg (41%) of the title compound as a white solid. ES(MS): (m/z)=467.0 (M+H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.Br[CH2:11][CH2:12][CH2:13][CH2:14][Cl:15]>>[Cl:15][CH2:14][CH2:13][CH2:12][CH2:11][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: c1ccc2[nH]ccc2c1
Reactant: ClCCCCBr
Product: ClCCCCn1ccc2ccccc21

Procedure:
Prepared by Procedure AH, and Scheme P using 1H-indole and 1-bromo-4-chlorobutane: 1NMR (400 MHz, CDCl3) δ 7.72–7.02 (m, 5H), 6.49 (d, 1H, J=2.8 Hz), 4.13 (t, 2H, J=6.8 Hz), 3.48 (t, 2H, J=6.8 Hz), 2.06–1.92 (m, 2H), 1.80–1.70 (m, 2H).
Reaction SMILES: C(OC(=O)[N:7]([CH2:12][C:13]1[CH:14]=[N:15][C:16]([C:19]2[S:27][C:26]3[C:21](=[N:22][CH:23]=[CH:24][C:25]=3[O:28][C:29]3[CH:34]=[CH:33][C:32]([NH:35][C:36]([NH:38][C:39](=[O:48])[CH2:40][C:41]4[CH:46]=[CH:45][C:44]([F:47])=[CH:43][CH:42]=4)=[S:37])=[CH:31][C:30]=3[F:49])[CH:20]=2)=[CH:17][CH:18]=1)[CH2:8][CH2:9][O:10][CH3:11])(C)(C)C.Cl.O>CC(O)=O>[F:49][C:30]1[CH:31]=[C:32]([NH:35][C:36]([NH:38][C:39](=[O:48])[CH2:40][C:41]2[CH:42]=[CH:43][C:44]([F:47])=[CH:45][CH:46]=2)=[S:37])[CH:33]=[CH:34][C:29]=1[O:28][C:25]1[CH:24]=[CH:23][N:22]=[C:21]2[CH:20]=[C:19]([C:16]3[CH:17]=[CH:18][C:13]([CH2:12][NH:7][CH2:8][CH2:9][O:10][CH3:11])=[CH:14][N:15]=3)[S:27][C:26]=12
Reactant: COCCN(Cc1ccc(-c2cc3nccc(Oc4ccc(NC(=S)NC(=O)Cc5ccc(F)cc5)cc4F)c3s2)nc1)C(=O)OC(C)(C)C
Agent: Cl
Solvent: O
Solvent: CC(=O)O
Product: COCCNCc1ccc(-c2cc3nccc(Oc4ccc(NC(=S)NC(=O)Cc5ccc(F)cc5)cc4F)c3s2)nc1
Temperature: 40 °C
Reaction time: 0.25 h

Procedure:
To a suspension of 14 (45.06 g, 62.6 mmol, 1 eq.) in AcOH (338 mL) was added 1N HCl (188 mL) over 1 min. The reaction mixture was heated at 40° C. for 2 h. After cooling down to r.t., water (676 mL) was added. The reaction mixture turned into a suspension and was stirred at r.t. for 15 min. The solid was collected by filtration and the product cake was washed with water (2×100 mL) then dried in vacuum for 30 min to afford a crude hydrochloride salt of 15 as a white solid.
Reaction SMILES: [CH:1]1([CH:7]([NH:27][C:28]2[CH:33]=[CH:32][C:31]([C:34]([NH:36][CH2:37][CH2:38][C:39]([O:41]CC)=[O:40])=[O:35])=[CH:30][CH:29]=2)[C:8]2[O:9][C:10]3[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]4[CH:25]=[CH:24][N:23]=[C:22]([F:26])[CH:21]=4)=[CH:14][C:11]=3[C:12]=2[CH3:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+]>C(O)C>[CH:1]1([CH:7]([NH:27][C:28]2[CH:33]=[CH:32][C:31]([C:34]([NH:36][CH2:37][CH2:38][C:39]([OH:41])=[O:40])=[O:35])=[CH:30][CH:29]=2)[C:8]2[O:9][C:10]3[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]4[CH:25]=[CH:24][N:23]=[C:22]([F:26])[CH:21]=4)=[CH:14][C:11]=3[C:12]=2[CH3:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)CCNC(=O)c1ccc(NC(c2oc3ccc(OCc4ccnc(F)c4)cc3c2C)C2CCCCC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1c(C(Nc2ccc(C(=O)NCCC(=O)O)cc2)C2CCCCC2)oc2ccc(OCc3ccnc(F)c3)cc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 74.4 %

Procedure:
Ethyl 3-[({4-[(cyclohexyl{5-[(2-fluoropyridin-4-yl)methoxy]-3-methyl-1-benzofuran-2-yl}methyl)amino]phenyl}carbonyl)amino]propanoate (0.24 g) synthesized in the above-mentioned (2) was dissolved in ethanol (3 mL), 1N aqueous sodium hydroxide solution (1.0 mL) was added to the solution at room temperature, and the mixture was stirred at room temperature for 0.5 hr. Ethanol was evaporated under reduced pressure, and 1N hydrochloric acid (1.0 mL) was added to the residue. The precipitate was washed with water to give the title object compound (0.17 g, 75%) as a colorless solid.
Reaction SMILES: [NH2:1][C@@H:2]1[C:8](=[O:9])[N:7]([CH2:10][CH:11]2[CH2:13][CH2:12]2)[C:6]2[CH:14]=[CH:15][CH:16]=[CH:17][C:5]=2[C:4]2[CH:18]=[CH:19][CH:20]=[CH:21][C:3]1=2.[CH3:22][C:23]([CH3:39])([C:27]([NH:29][CH2:30][CH2:31][C:32]([F:38])([F:37])[C:33]([F:36])([F:35])[F:34])=[O:28])[C:24](O)=[O:25]>C(Cl)(Cl)Cl>[CH:11]1([CH2:10][N:7]2[C:8](=[O:9])[C@@H:2]([NH:1][C:24](=[O:25])[C:23]([CH3:22])([CH3:39])[C:27]([NH:29][CH2:30][CH2:31][C:32]([F:37])([F:38])[C:33]([F:36])([F:34])[F:35])=[O:28])[C:3]3[CH:21]=[CH:20][CH:19]=[CH:18][C:4]=3[C:5]3[CH:17]=[CH:16][CH:15]=[CH:14][C:6]2=3)[CH2:13][CH2:12]1
Reactant: CC(C)(C(=O)O)C(=O)NCCC(F)(F)C(F)(F)F
Reactant: N[C@@H]1C(=O)N(CC2CC2)c2ccccc2-c2ccccc21
Solvent: ClC(Cl)Cl
Product: CC(C)(C(=O)NCCC(F)(F)C(F)(F)F)C(=O)N[C@@H]1C(=O)N(CC2CC2)c2ccccc2-c2ccccc21

Procedure:
(S)-7-amino-5-cyclopropylmethyl-5H,7H-dibenzo[b,d]azepin-6-one was coupled with 2,2-dimethyl-N-(3,3,4,4,4-pentafluoro-butyl)-malonamic acid in analogy to the description in example 73 to yield N-((S)-5-cyclopropylmethyl-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl)-2,2-dimethyl-N′-(3,3,4,4,4-pentafluoro-butyl)-malonamide (epimers) as white solid, [α] 589=−64.9° (1% in CHCl3), MS m/e (%): 538.3 (M+H+, 100).
Reaction SMILES: Br[C:2]1[C:10]2[C:6](=[CH:7][N:8]([CH3:11])[N:9]=2)[C:5]([CH3:12])=[CH:4][CH:3]=1.[C:13]([Cu])#[N:14].O>CN1C(=O)CCC1>[CH3:11][N:8]1[CH:7]=[C:6]2[C:10]([C:2]([C:13]#[N:14])=[CH:3][CH:4]=[C:5]2[CH3:12])=[N:9]1
Reactant: N#C[Cu]
Reactant: Cc1ccc(Br)c2nn(C)cc12
Solvent: CN1CCCC1=O
Solvent: O
Product: Cc1ccc(C#N)c2nn(C)cc12
Yield: 40 %

Procedure:
To a solution of 7-bromo-2,4-dimethyl-2H-indazole (1 eq.) in NMP, was added CuCN (2 equiv.) and heated at 130 oC for 16 h. On completion, water was added to quench the reaction, solid precipitated was filtered and purified by column chromatography to afford the title compound (40-60% yield)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[Cl:15][C:16]1[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[C:17]=1[C:18]([N:20]=[C:21]=[O:22])=[O:19]>C(#N)C>[Cl:15][C:16]1[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[C:17]=1[C:18]([NH:20][C:21]([NH:14][C:11]1[CH:12]=[N:13][C:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)=[CH:9][CH:10]=1)=[O:22])=[O:19]
Reactant: O=C=NC(=O)c1c(Cl)cccc1Cl
Reactant: Nc1ccc(-c2ccc(Cl)cc2)nc1
Solvent: CC#N
Product: O=C(NC(=O)c1c(Cl)cccc1Cl)Nc1ccc(-c2ccc(Cl)cc2)nc1

Procedure:
6-(4-Chlorophenyl)-3-pyridylamine (70 mg) was dissolved in 45 ml acetonitrile and treated with 2,6-dichlorobenzoyl isocyanate (0.25 gram) under nitrogen at room temperature. A precipitate formed almost immediately and after about 2 hours stirring, the solid was collected and recrystallized from ethanol, yield, 200 mg, m.p. 225°-229° C. The identity of the product was confirmed by NMR.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:17]=[C:16]3[N:10]([CH2:11][CH2:12][C:13]4[CH:29]=[CH:28][CH:27]=[CH:26][C:14]=4[CH:15]3[O:18][CH:19]3[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]3)[C:9]=2[CH3:30])=[CH:4][CH:3]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[C:50]([O:54][C:55](=[O:58])[CH:56]=[CH2:57])([CH3:53])([CH3:52])[CH3:51].C(N(CC)CC)C.N>CN(C=O)C.CC([O-])=O.CC([O-])=O.[Pd+2].O>[C:50]([O:54][C:55](=[O:58])[CH:56]=[CH:57][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:17]=[C:16]3[N:10]([CH2:11][CH2:12][C:13]4[CH:29]=[CH:28][CH:27]=[CH:26][C:14]=4[CH:15]3[O:18][CH:19]3[CH2:20][CH2:21][N:22]([CH3:25])[CH2:23][CH2:24]3)[C:9]=2[CH3:30])=[CH:6][CH:7]=1)([CH3:53])([CH3:52])[CH3:51]
Reactant: C=CC(=O)OC(C)(C)C
Reactant: Cc1c(-c2ccc(Br)cc2)nc2n1CCc1ccccc1C2OC1CCN(C)CC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: N
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1c(-c2ccc(C=CC(=O)OC(C)(C)C)cc2)nc2n1CCc1ccccc1C2OC1CCN(C)CC1
Temperature: 100 °C

Procedure:
To a solution of 2-(4-bromophenyl)-1-methyl-4-(1-methylpiperidin-4-yloxy)-9,10-dihydro-4H-3,10a-diaza-benzo[f]azulene (example 122A) (100 mg, 0.214 mmoles) in DMF (2.5 mL) in a screw-capped vial under argon are added Pd(OAc)2 (5 mg, 10.7 μmole), PPh3 (14 mg, 53.5 μmole), tert-butylacrylate (196 μL, 1.07 mmole) and triethylamine (115 μL, 0.856 mmole). The reaction mixture is heated at 100° C. overnight. Water is added to the reaction mixture and pH adjusted to 9-10 by adding concentrated ammonia solution. The aqueous phase is extracted three times with CH2Cl2. The organic phase is dried over magnesium sulphate, filtered and the solvent is removed under reduced pressure. The residue is pre-purified by silica gel chromatography using (CH2Cl2:MeOH:NH4OH) as eluent with a gradient from (98:2:0.1) to (96.5:3.5:0.35) and the residue is submitted to a preparative thin-layer chromatography eluting with (CH2Cl2:MeOH:NH4OH) (9:1:1) to afford 3-{4-[1-methyl-4-(1-methylpiperidin-4-yloxy)-9,10-dihydro-4H-3,10a-diaza-benzo[f]azulen-2-yl]-phenyl}-acrylic acid tert-butyl ester melting at 185° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])/[CH:5]=[C:6](/[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[O:15][CH:16]([CH3:18])[CH3:17])\[CH3:7])[CH3:2].[Br:20]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[CH2:1]([O:3][C:4](=[O:19])/[CH:5]=[C:6](/[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[O:15][CH:16]([CH3:18])[CH3:17])\[CH2:7][Br:20])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)/C=C(\C)Oc1ccccc1OC(C)C
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)/C=C(\CBr)Oc1ccccc1OC(C)C
Yield: 62.9 %

Procedure:
To a stirred mixture of (E)-3-(2-isopropoxy-phenoxy)-but-2-enoic acid ethyl ester (4.90 g, 0.019 mol) in carbon tetrachloride (35 mL) under a nitrogen atmosphere was added N-bromosuccinimide (4.95 g, 0.028 mol) and benzoyl peroxide (450 mg, 0.002 mol). Nitrogen gas was bubbled through the mixture for 5 min, and the resulting mixture was heated to reflux for 4 h. The reaction mixture was then placed in the refrigerator overnight. The solids formed were removed by filtration and the filtrate concentrated in vacuo. The crude product obtained was purified using flash column chromatography (silica gel (100-200 mesh), ethyl acetate/hexanes) to afford (E)-4-bromo-3-(2-isopropoxy-phenoxy)-but-2-enoic acid ethyl ester (4.10 g, 64%) as a yellow oil.
Reaction SMILES: [C:1]([Si:5]([CH3:35])([CH3:34])[O:6][C@H:7]1[C@H:11]2[O:12][CH2:13][C@@H:14]([O:15][C:16]3[N:24]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])[C:23]4[C:18](=[N:19][C:20](Cl)=[N:21][CH:22]=4)[N:17]=3)[C@H:10]2[O:9][CH2:8]1)([CH3:4])([CH3:3])[CH3:2].[C:36]1([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[CH:41]=[CH:40][C:39](B(O)O)=[CH:38][CH:37]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].CCOC(C)=O>O.O1CCOCC1.[Au].CCOC(C)=O.CCCCCC>[C:36]1([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[CH:41]=[CH:40][C:39]([C:20]2[N:19]=[C:18]3[C:23]([N:24]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:30])([CH3:31])[CH3:32])[C:16]([O:15][C@@H:14]4[CH2:13][O:12][C@@H:11]5[C@H:7]([O:6][Si:5]([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:34])[CH3:35])[CH2:8][O:9][C@H:10]45)=[N:17]3)=[CH:22][N:21]=2)=[CH:38][CH:37]=1
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1CO[C@H]2[C@@H]1OC[C@H]2Oc1nc2nc(Cl)ncc2n1COCC[Si](C)(C)C
Reactant: OB(O)c1ccc(-c2ccccc2)cc1
Agent: [Au]
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: O
Product: CC(C)(C)[Si](C)(C)O[C@@H]1CO[C@H]2[C@@H]1OC[C@H]2Oc1nc2nc(-c3ccc(-c4ccccc4)cc3)ncc2n1COCC[Si](C)(C)C
Temperature: 85 °C
Reaction time: 2.5 h

Procedure:
Palladium tetrakistriphenylphosphine (21.3 mg, 0.018 mmol) was added to a stirred suspension of 8-(((3R,3aR,6R,6aS)-6-((tert-butyldimethyl-silyl)oxy)hexahydrofuro[3,2-b]furan-3-yl)oxy)-2-chloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-purine (Intermediate 47, 50.0 mg, 0.092 mmol), 4-biphenylboronic acid (27.3 mg, 0.138 mmol), and potassium phosphate tribasic (58.6 mg, 0.276 mmol) in degassed 20% water in dioxane (0.72 mL). The reaction mixture stirred under N2 at 85° C. for 2.5 h, then additional more palladium tetrakistriphenylphosphine (21.3 mg, 0.018 mmol) was added. The reaction mixture heated under N2 at 85° C. for another 3.5 h and then cooled to room temperature. The lower aqueous layer was drawn off and discarded. The remaining reaction mixture was added to EtOAc (25 mL), and filtered. The resulting solids were washed with EtOAc (2×10 mL). The filtrate was evaporated under reduced pressure to give a residue. Flash chromatography of the resulting residue utilizing a 12 g silica RediSep Rf® Gold column and employing a 0-80% EtOAc/hexane gradient afforded the title compound. LC-MS: calculated for C35H48N4O5Si2 660.32 observed m/e: 661.61 (M+H)+ (Rt 1.85/2.0 min).
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]([F:24])([F:23])[F:22])[CH:15]=2)[N:8]=1)=O.[NH:26]([C:28]1[CH:33]=[CH:32][N:31]=[C:30]([CH3:34])[CH:29]=1)N>>[CH3:34][C:30]1[CH:29]=[C:28]([N:26]2[C:5]([C:7]3[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]4[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]([F:24])([F:23])[F:22])[CH:15]=4)[N:8]=3)=[CH:4][CH:3]=[N:2]2)[CH:33]=[CH:32][N:31]=1
Reactant: CN(C)/C=C/C(=O)c1nn(-c2cccc(OC(F)(F)F)c2)ccc1=O
Reactant: Cc1cc(NN)ccn1
Product: Cc1cc(-n2nccc2-c2nn(-c3cccc(OC(F)(F)F)c3)ccc2=O)ccn1

Procedure:
The product was obtained starting from 3-((E)-3-Dimethylamino-acryloyl)-1-(3-trifluoromethoxy-phenyl)-1H-pyridazin-4-one (A-6) and 4-hydrazino-2-methylpyridine according to the method described for example 43. MS: M=414.2 (M+H)+
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[C:10](=[O:12])[CH3:11].[CH3:13]C([O-])(C)C.[Na+].C(OCC)=O.Cl>O1CCOCC1.O>[CH3:9][O:8][C:6]1[CH:7]=[C:2]2[C:3]([C:10]([OH:12])=[CH:11][CH:13]=[N:1]2)=[CH:4][CH:5]=1
Reactant: COc1ccc(C(C)=O)c(N)c1
Reactant: CC(C)(C)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCOC=O
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc2c(O)ccnc2c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1-(2-amino-4-methoxyphenyl)ethanone [J Med Chem, 32(4):807-826 (1989)] (7.32 g, 44.3 mmol) in dioxane (150 mL), NaOt-Bu (9.8 g, 102 mmol) was added and stirred at RT for 30 min. The color changed from lime green to dark green. Ethyl formate (23.64 mL, 292 mmol) was added with an additional 20 mL dioxane. The reaction mixture was stirred at RT 18 h after which the mixture was poured into water (20 mL) and the pH adjusted to 7 with 2N HCl. The solution was evaporated a little. The red solid was filtered and rinsed with water. The solid was triturated with 1:1 EtOAc:hexanes and then filtered to give the title compound as a brown solid.
Reaction SMILES: OC(C(F)(F)F)=O.[NH:8]1[CH2:11][CH:10]([NH:12][C:13](=[O:30])[CH2:14][NH:15][C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([C:25]([F:28])([F:27])[F:26])[CH:23]=3)[N:18]([CH3:29])[N:17]=2)[CH2:9]1.[OH:31][C:32]1([C:39]2[O:40][CH:41]=[CH:42][N:43]=2)[CH2:37][CH2:36][C:35](=O)[CH2:34][CH2:33]1>>[OH:31][C:32]1([C:39]2[O:40][CH:41]=[CH:42][N:43]=2)[CH2:33][CH2:34][CH:35]([N:8]2[CH2:9][CH:10]([NH:12][C:13](=[O:30])[CH2:14][NH:15][C:16]3[C:24]4[C:19](=[CH:20][CH:21]=[C:22]([C:25]([F:27])([F:26])[F:28])[CH:23]=4)[N:18]([CH3:29])[N:17]=3)[CH2:11]2)[CH2:36][CH2:37]1
Reactant: Cn1nc(NCC(=O)NC2CNC2)c2cc(C(F)(F)F)ccc21
Reactant: O=C1CCC(O)(c2ncco2)CC1
Solvent: O=C(O)C(F)(F)F
Product: Cn1nc(NCC(=O)NC2CN(C3CCC(O)(c4ncco4)CC3)C2)c2cc(C(F)(F)F)ccc21

Procedure:
The title compound was prepared as a white solid from reaction of N-azetidin-3-yl-2-(1-methyl-5-trifluoromethyl-1H-indazol-3-ylamino)-acetamide TFA salt (as prepared in Example 18, Step D) and 4-hydroxy-4-oxazol-2-yl-cyclohexanone using the procedure described in Step E of Example 1.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([O:8][CH3:9])[CH:3]=1.[C:10]1(/[CH:16]=[CH:17]/B(O)O)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C([O-])([O-])=O.[K+].[K+]>CS(C)=O>[CH3:9][O:8][C:4]1[CH:3]=[C:2](/[CH:17]=[CH:16]/[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:7]=[CH:6][N:5]=1
Reactant: COc1cc(Br)ccn1
Reactant: OB(O)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: COc1cc(/C=C/c2ccccc2)ccn1
Temperature: 90 °C
Yield: 92.8 %

Procedure:
4-Bromo-2-methoxypyridine (1.85 g, 9.84 mmol), (E)-phenylvinylboronic acid (4.3 g, 30 mmol), K2CO3 (4.0 g, 30 mmol) and [1,1′-Bis-(diphosphenylphosphino)ferrocene]dichloropalladium(II) (PdCl2dppf) (400 mg, 0.5 mmol) were stirred in DMSO (15 mL) under vacuum for 30 min. The flask was flushed with nitrogen and the mixture was heated at 90° C. for 30 min. Upon cooling, the mixture was diluted with methylene chloride and washed with 5% lithium chloride solution (5×), dried, concentrated, and the residue was purified by column chromatography (silica gel, hexanes/ethyl acetate, 97:3 to 75:25) to provide the title compound (1.93 g, 93%) as an orange oil: 1H NMR (300 MHz, CDCl3) δ 8.12 (d, J=5.2 Hz, 1H), 7.51 (m, 2H), 7.40-7.22 (m, 4H), 7.02-6.94 (m, 2H), 6.78 (s, 1H), 3.95 (s, 3H).
Reaction SMILES: [CH3:1][Si:2]([CH3:9])([CH3:8])[C:3]1[S:4][CH:5]=[CH:6][N:7]=1.[O:10]1[C:14]2([CH2:19][CH2:18][C:17](=[O:20])[CH2:16][CH2:15]2)[O:13][CH2:12][CH2:11]1>>[CH3:1][Si:2]([CH3:9])([CH3:8])[C:3]1[S:4][C:5]([C:17]2([OH:20])[CH2:18][CH2:19][C:14]3([O:13][CH2:12][CH2:11][O:10]3)[CH2:15][CH2:16]2)=[CH:6][N:7]=1
Reactant: O=C1CCC2(CC1)OCCO2
Reactant: C[Si](C)(C)c1nccs1
Product: C[Si](C)(C)c1ncc(C2(O)CCC3(CC2)OCCO3)s1

Procedure:
The title compound was prepared as a white solid from 2-trimethylsilanyl-thiazole (Fluka) and 1,4-dioxa-spiro[4.5]decan-8-one using the procedure described in Step A of Example 33.
Reaction SMILES: [CH:1]([C:3]1[S:7][C:6]([C:8]2[S:9][C:10]([C:13]3[S:14][CH:15]=[CH:16][C:17]=3[CH2:18][OH:19])=[CH:11][CH:12]=2)=[CH:5][CH:4]=1)=[O:2].[BH4-].[Na+]>O1CCCC1>[OH:2][CH2:1][C:3]1[S:7][C:6]([C:8]2[S:9][C:10]([C:13]3[S:14][CH:15]=[CH:16][C:17]=3[CH2:18][OH:19])=[CH:11][CH:12]=2)=[CH:5][CH:4]=1
Reactant: O=Cc1ccc(-c2ccc(-c3sccc3CO)s2)s1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: OCc1ccc(-c2ccc(-c3sccc3CO)s2)s1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 99.3 %

Procedure:
To a solution of 5-formyl-3"-hydroxymethyl-2,2 ':5',2"-terthiophene (60 mg) in tetrahydrofuran (5 ml) was added sodium borohydride (15 mg). The reaction mixture was stirred at room temperature for 40 minutes. Methanol was removed and water was added. The solution was extracted with ethyl acetate, washed with brine, dried over anhydrous magnesium sulfate and concentrated to give yellowish solid product (60 mg), melting point 93°-95° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[N:5]([CH3:9])[CH:6]=[CH:7][CH:8]=1.[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=1[S:18](Cl)(=[O:20])=[O:19]>>[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=1[S:18]([NH:1][CH2:2][CH2:3][C:4]1[N:5]([CH3:9])[CH:6]=[CH:7][CH:8]=1)(=[O:20])=[O:19]
Reactant: O=S(=O)(Cl)c1cc(Cl)ccc1Cl
Reactant: Cn1cccc1CCN
Product: Cn1cccc1CCNS(=O)(=O)c1cc(Cl)ccc1Cl

Procedure:
Prepared from 2-(2-aminoethyl)-1-methylpyrrole and 2,5-dichlorobenzenesulphonylchloride analogously to Example A.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([CH:11](OS(C2C=CC(C)=CC=2)(=O)=O)[CH3:12])[CH2:10][O:9][CH2:8][CH2:7][O:6]1)=[O:4].Cl.C(OCC)C>N1(C2CCCCCCCCCC2)CCCN=CCCCCC1>[CH3:1][O:2][C:3]([C:5]1([CH:11]=[CH2:12])[CH2:10][O:9][CH2:8][CH2:7][O:6]1)=[O:4]
Reactant: COC(=O)C1(C(C)OS(=O)(=O)c2ccc(C)cc2)COCCO1
Agent: C1=NCCCN(C2CCCCCCCCCC2)CCCCC1
Agent: Cl
Solvent: CCOCC
Product: C=CC1(C(=O)OC)COCCO1
Temperature: 25 °C
Yield: 36.5 %

Procedure:
A solution of 2-[1-(toluene-4-sulfonyloxy)-ethyl]-[1,4]dioxane-2-carboxylic acid methyl ester (1.68 g, 4.9 mmol) in 1,8-diazabicycloundec-7-ene (3 mL) was heated in a sealed tube at 130° C. for 2 h. The reaction mixture was cooled to room temperature and 2 M hydrochloric acid and diethyl ether were added. The mixture was extracted with diethyl ether and the organic extracts were combined and washed with brine. The organic solution was filtered through a hydrophobic frit and the filtrate was evaporated. The residue was purified by silica gel chromatography using a gradient of pentane/diethyl ether 3:1 to 1:1 to afford the title compound (308 mg, 36%) as a volatile, colorless oil. 1H NMR (300 MHz, CDCl3) δ 3.47 (d, J=11.6 Hz, 1H), 3.62-3.78 (m, 2H), 3.81-3.86 (m, 1H), 3.84 (s, 3H), 3.99-4.07 (m, 1H), 4.33 (d, J=11.6 Hz, 1H), 5.34 (dd, J=10.7, 1.1 Hz, 1H), 5.52 (dd, J=17.4, 1.1 Hz, 1H), 5.79 (dd, J=17.4, 10.7 Hz, 1H). LCMS (m/z) 195.1 [M+Na], Tr=1.23 min.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])[CH:5]=[CH:6][CH:7]=1.[C:14]1([CH2:20][O:21][C:22]([NH:24][C@H:25]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:26][CH2:27]O)=[O:23])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C[N+](CC(O)=O)(C)C>>[CH3:35][C:32]([CH3:33])([O:31][C:29](=[O:30])[CH:25]([NH:24][C:22]([O:21][CH2:20][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:23])[CH2:26][CH2:27][O:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])[CH:5]=[CH:6][CH:7]=1)[CH3:34]
Reactant: CC(C)(C)OC(=O)[C@H](CCO)NC(=O)OCc1ccccc1
Reactant: COC(=O)CCc1cccc(O)c1
Agent: C[N+](C)(C)CC(=O)O
Product: COC(=O)CCc1cccc(OCCC(NC(=O)OCc2ccccc2)C(=O)OC(C)(C)C)c1
Yield: 67.9 %

Procedure:
The operation is carried out as in Preparation 1 (Method 2) starting from 270 mg of the phenol prepared in Stage A, 309 mg of 1,1-dimethyl-ethyl N-[(phenylmethoxy)carbonyl]-L-homoserinate and 616 mg of betaine. 320 mg of expected product is obtained.