Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1(S([O-])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Na+].Br[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1Br.[O-2].[Ca+2]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2C=CC=CC=2)CCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CN1CCCC1=O>[C:1]1([C:13]2[C:12]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Brc1ccccc1Br
Reactant: O=S([O-])c1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [Ca+2]
Solvent: CN1CCCC1=O
Product: c1ccc(-c2ccccc2-c2ccccc2)cc1
Yield: 45 %

Procedure:
3.28 g (20 mmol) of sodium benzenesulfinate, 2.36 g (10 mmol) of o-dibromobenzene, 0.0255 g (0.1 mmol) of palladium acetate, 0.0478 g (0.12 mmol) of 1,2-bis(diphenylphosphino)-ethane, 6.73 g (120 mmol) of calcium oxide and 60 ml of N-methyl-2-pyrrolidone were placed in a 100 ml round bottom flask and reacted at 150° C. in a nitrogen gas stream for 8 hours. After the completion of the reaction, the reaction mixture was analyzed by means of high performance liquid chromatography. The analysis showed that 4.5 mmol (yield 45%) of o-terphenyl was formed in the reaction mixture solution.
Reaction SMILES: [CH3:1][C:2]([CH3:21])([CH3:20])[CH2:3][N:4]([CH2:17][CH2:18][OH:19])[C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[C:7]([C:13]([F:16])([F:15])[F:14])[CH:6]=1.[F:22][C:23]1[CH:28]=[CH:27][C:26](O)=[CH:25][CH:24]=1>>[CH3:1][C:2]([CH3:21])([CH3:20])[CH2:3][N:4]([CH2:17][CH2:18][O:19][C:26]1[CH:27]=[CH:28][C:23]([F:22])=[CH:24][CH:25]=1)[C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[C:7]([C:13]([F:14])([F:15])[F:16])[CH:6]=1
Reactant: CC(C)(C)CN(CCO)c1ccc(C#N)c(C(F)(F)F)c1
Reactant: Oc1ccc(F)cc1
Product: CC(C)(C)CN(CCOc1ccc(F)cc1)c1ccc(C#N)c(C(F)(F)F)c1

Procedure:
Synthesized as described in Example 1C from 4-[(2,2-dimethylpropyl)(2-hydroxyethyl)amino]-2-(trifluoromethyl)benzonitrile and 4-fluorophenol: 1H NMR (400 MHz, CDCl3) δ 7.55 (d, J=8.8 Hz, 1H), 7.10 (d, J=2.4 Hz, 1H), 6.99-6.93 (m, 2H, partially overlapping 6.91), 6.91 (dd, J=8.9, 2.3 Hz, 1H), 6.80-6.73 (m, 2H), 4.07 (t, J=5.7 Hz, 2H), 3.92 (t, J=5.7 Hz, 2H), 3.40 (s, 2H), 1.01 (s, 9H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[N:5]=[C:4]([N:13]2[CH2:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[S:16](=[O:25])(=[O:24])[CH2:15][CH2:14]2)[CH:3]=1.[CH3:26][NH:27][CH3:28]>>[O:24]=[S:16]1(=[O:25])[C:17]2[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=2[CH2:19][N:13]([C:4]2[CH:3]=[C:2]([N:27]([CH3:28])[CH3:26])[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=3)[N:5]=2)[CH2:14][CH2:15]1
Reactant: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(Cl)c2c1
Reactant: CNC
Product: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(N(C)C)c2c1

Procedure:
The title compound was prepared in analogy to Example 16-1 in Scheme 5 by using 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy to the one in Example 2-1) and dimethylamine. MS obsd. (ESI+) [(M+H)+] 382, 1H NMR (400 MHz, CD3OD) δ ppm 8.07 (d, J=7.6 Hz, 1 H), 7.85-7.83 (m, 2 H), 7.73-7.70 (m, 2 H), 7.58-7.55 (m, 2 H), 6.14 (s, 1 H), 5.30 (s, 2 H), 4.51 (s, 2 H), 3.72-3.70 (m, 2 H), 3.29 (s, 6 H), 2.45 (s, 3 H).
Reaction SMILES: N[C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([N+:19]([O-:21])=[O:20])[C:10]=1[C:11](=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:5]([OH:7])=[O:6].S(=O)(=O)(O)[OH:23].N([O-])=O.[Na+]>O>[C:11]([C:10]1[C:9]([N+:19]([O-:21])=[O:20])=[CH:8][C:4]([C:5]([OH:7])=[O:6])=[CH:3][C:2]=1[OH:23])(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=S(=O)(O)O
Reactant: Nc1cc(C(=O)O)cc([N+](=O)[O-])c1C(=O)c1ccccc1
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: O=C(O)c1cc(O)c(C(=O)c2ccccc2)c([N+](=O)[O-])c1

Procedure:
To a solution of 3-amino-4-benzoyl-5--nitrobenzoic acid (100 g) in a mixture of conc. sulfuric acid (875 ml) and water (280 ml) is dropwise added a solution of sodium nitrite (45.0 g) in water (280 ml), while stirring at -5° C to 0° C. After additional stirring at -5° C to 0° C for about 15 minutes, the resulting diazoniumsolution is heated on a steam bath for 2-3 hours until the nitrogen evolution has ceased. After cooling, the resulting precipitate is collected by filtration and washed with water. After drying and recrystallization twice from aqueous ethanol, 4-benzoyl-3-hydroxy-5-nitrobenzoic acid is obtained as a monohydrate with a melting point of 264° -266° C.
Reaction SMILES: S(Cl)(Cl)=O.[Cl:5][C:6]1[C:7]([O:18][CH3:19])=[C:8]([C:12]([O:16][CH3:17])=[C:13]([Cl:15])[CH:14]=1)[C:9]([OH:11])=O.C1(C)C=CC=CC=1.[NH2:27][CH2:28][CH:29]1[CH2:33][CH2:32][CH2:31][N:30]1[CH2:34][CH3:35]>C(OCC)C.O>[CH2:34]([N:30]1[CH2:31][CH2:32][CH2:33][CH:29]1[CH2:28][NH:27][C:9](=[O:11])[C:8]1[C:12]([O:16][CH3:17])=[C:13]([Cl:15])[CH:14]=[C:6]([Cl:5])[C:7]=1[O:18][CH3:19])[CH3:35]
Reactant: CCN1CCCC1CN
Reactant: COc1c(Cl)cc(Cl)c(OC)c1C(=O)O
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: CCN1CCCC1CNC(=O)c1c(OC)c(Cl)cc(Cl)c1OC

Procedure:
20 ml of thionyl chloride is added to 11.9 g (0.047 mol) of 3,5-dichloro-2,6-dimethoxybenzoic acid. The mixture is heated on a steam bath for 30 minutes. To the solution is added 50 ml of toluene. The solvent and excess thionyl chloride is evaporated at reduced pressure. The residue is dissolved in 50 ml of dry ethyl ether. To the obtained solution is added dropwise while stirring 6.0 g (0.047 mol) of 2-(aminomethyl)-1-ethylpyrrolidine in 50 ml of ethyl ether. After 30 minutes at room temperature 300 ml of water is added while stirring. The water layer is separated and alkalized with sodium hydroxide solution which is added dropwise while stirring and cooling in ice. The precipitate is collected and washed with water. Yield: 9.0 g, m.p. 120°-21° C.
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:54])[CH2:13][NH:14][CH2:15][C@:16]23[CH2:50][CH2:49][C@@H:48]([C:51]([CH3:53])=[CH2:52])[C@@H:17]2[C@@H:18]2[C@@:31]([CH3:34])([CH2:32][CH2:33]3)[C@@:30]3([CH3:35])[C@@H:21]([C@:22]4([CH3:47])[C@@H:27]([CH2:28][CH2:29]3)[C:26]([CH3:37])([CH3:36])[C:25]([C:38]3[CH:46]=[CH:45][C:41]([C:42]([OH:44])=[O:43])=[CH:40][CH:39]=3)=[CH:24][CH2:23]4)[CH2:20][CH2:19]2)[CH2:8][CH2:7]1)=[O:5])C.[OH-].[Na+].O>CO.O1CCOCC1>[C:42]([C:41]1[CH:45]=[CH:46][C:38]([C:25]2[C:26]([CH3:37])([CH3:36])[C@H:27]3[C@:22]([CH3:47])([CH2:23][CH:24]=2)[C@@H:21]2[C@:30]([CH3:35])([C@@:31]4([CH3:34])[C@H:18]([CH2:19][CH2:20]2)[C@H:17]2[C@H:48]([C:51]([CH3:53])=[CH2:52])[CH2:49][CH2:50][C@:16]2([CH2:15][NH:14][CH2:13][C:12]([N:9]2[CH2:10][CH2:11][CH:6]([C:4]([OH:5])=[O:3])[CH2:7][CH2:8]2)=[O:54])[CH2:33][CH2:32]4)[CH2:29][CH2:28]3)=[CH:39][CH:40]=1)([OH:44])=[O:43]
Reactant: C=C(C)[C@@H]1CC[C@]2(CNCC(=O)N3CCC(C(=O)OCC)CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CO
Solvent: O
Product: C=C(C)[C@@H]1CC[C@]2(CNCC(=O)N3CCC(C(=O)O)CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 25 °C
Reaction time: 4 h

Procedure:
The title compound was prepared following the procedure described below: To the solution of 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(4-(ethoxycarbonyl)piperidin-1-yl)-2-oxoethylamino)methyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoic acid (12 mg, 0.016 mmol) in MeOH (3.00 ml) and dioxane (3 ml), sodium hydroxide (10 mg, 0.250 mmol) was added followed by 0.5 ml of water. The resulting suspension was stirred at 25° C. for 4 h. The solvent was removed in vacuo, the product was isolated by prep. HPLC as a white solid (5 mg, 41.4%). LCMS: m/e 713.5 (MH+), 2.37 min (method 3). 1H NMR (400 MHz, MeOD) δ ppm 7.95 (m, 2H), 7.27 (m, 2H), 5.32 (d, J=4.5 Hz, 1H), 4.76 (d, J=1.8 Hz, 1H), 4.66 (s, 1H), 4.29-4.46 (m, 1H), 4.09-4.25 (m, 2H), 3.64-3.85 (m, 1H), 3.17-3.32 (m, 2H), 3.05 (m, 1H), 2.87 (dd, J=12.8, 4.8 Hz, 1H), 2.67 (tt, J=10.8, 4.0 Hz, 1H), 2.49 (dt, J=10.9, 5.5 Hz, 1H), 2.07-2.29 (m, 2H), 1.85-2.07 (m, 4H), 1.67-1.85 (m, 8H), 1.43-1.67 (m, 9H), 1.36 (br. s., 2H), 1.32 (d, J=6.5 Hz, 2H), 1.24 (d, J=14.8 Hz, 1H), 1.13-1.20 (m, 4H), 1.11 (s, 3H), 1.04 (s, 3H), 0.99 (s, 3H), 0.98 (s, 3H).
Reaction SMILES: C1C2C(=CC=CC=2)C[N:2]1[CH2:10][CH2:11][C:12]1[CH:13]=[C:14]([NH:22][C:23]([CH:25]2[CH2:34][C:33]3[CH:32]=[C:31]([O:35][C:36]4[CH:41]=[CH:40][N:39]=[C:38]([C:42]([NH:44][CH3:45])=[O:43])[CH:37]=4)[CH:30]=[CH:29][C:28]=3[CH2:27][CH2:26]2)=[O:24])[CH:15]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:17]=1.C(N)CN>CCOC(C)=O.O>[NH2:2][CH2:10][CH2:11][C:12]1[CH:13]=[C:14]([NH:22][C:23]([CH:25]2[CH2:34][C:33]3[CH:32]=[C:31]([O:35][C:36]4[CH:41]=[CH:40][N:39]=[C:38]([C:42]([NH:44][CH3:45])=[O:43])[CH:37]=4)[CH:30]=[CH:29][C:28]=3[CH2:27][CH2:26]2)=[O:24])[CH:15]=[C:16]([C:18]([F:21])([F:19])[F:20])[CH:17]=1
Reactant: CNC(=O)c1cc(Oc2ccc3c(c2)CC(C(=O)Nc2cc(CCN4Cc5ccccc5C4)cc(C(F)(F)F)c2)CC3)ccn1
Solvent: NCCN
Solvent: CCOC(C)=O
Solvent: O
Product: CNC(=O)c1cc(Oc2ccc3c(c2)CC(C(=O)Nc2cc(CCN)cc(C(F)(F)F)c2)CC3)ccn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 106.9 %

Procedure:
A solution of 4-{[7-({[3-[2-(1,3-dihydro-2H-isoindol-2-yl)ethyl]-5-(trifluoromethyl)phenyl]amino}carbonyl)-5,6,7,8-tetrahydronaphthalen-2-yl]oxy}-N-methylpyridine-2-carboxamide (0.158 g, 0.25 mmol) and ethane-1,2-diamine (2 mL) was allowed to stir at rt overnight. The reaction mixture was diluted with EtOAc and water. The solution was extracted with EtOAc. The combined organic solutions were washed with brine and concentrated to give a white solid. The residue was purified by column chromatography to give 4-{[7-({[3-(2-aminoethyl)-5-(trifluoromethyl)phenyl]-amino}carbonyl)-5,6,7,8-tetrahydronaphthalen-2-yl]oxy}-N-methylpyridine-2-carboxamide (I-47, 137 mg, 29%) as the formate salt. 1H NMR (300 MHz, CD3OD): δ 8.44 (d, 1H), 8.42 (s, 1H), 7.91 (s, 1H), 7.78 (s, 1H), 7.51 (s, 1H), 7.34 (s, 1H), 7.24-7.21 (m, 1H), 7.07-7.04 (m, 1H), 6.92-6.89 (m, 1H), 3.24-3.19 (m, 2H), 3.10-2.78 (m, 9H), 2.56-2.13 (m, 1H), and 2.03-1.84 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:14]=[C:13]([NH:15][C:16]3[NH:20][N:19]=[C:18]([CH:21]4[CH2:23][CH2:22]4)[CH:17]=3)[CH:12]=[CH:11][N:10]=2)=[CH:4][CH:3]=1.[F:24][C:25]([F:36])([F:35])[C:26]1[CH:27]=[C:28]([CH:32]=[CH:33][CH:34]=1)[C:29](Cl)=[O:30]>C(Cl)Cl>[CH:21]1([C:18]2[CH:17]=[C:16]([NH:15][C:13]3[CH:12]=[CH:11][N:10]=[C:9]([NH:8][C:5]4[CH:6]=[CH:7][C:2]([NH:1][C:29](=[O:30])[C:28]5[CH:32]=[CH:33][CH:34]=[C:26]([C:25]([F:24])([F:35])[F:36])[CH:27]=5)=[CH:3][CH:4]=4)[N:14]=3)[NH:20][N:19]=2)[CH2:23][CH2:22]1
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1
Reactant: Nc1ccc(Nc2nccc(Nc3cc(C4CC4)n[nH]3)n2)cc1
Solvent: ClCCl
Product: O=C(Nc1ccc(Nc2nccc(Nc3cc(C4CC4)n[nH]3)n2)cc1)c1cccc(C(F)(F)F)c1
Reaction time: 1 h

Procedure:
A solution of N2-(4-aminophenyl)-N4-(3-cyclopropyl-1H-pyrazol-5-yl)pyrimidine-2,4-diamine (0.011 g, 0.035 mmol; Shokat Lab: A. Statsyuk) in CH2Cl2 (10 mL) was cooled in an ice-water bath. To this 3-(trifluoromethyl)benzoyl chloride (0.005 mL, 0.036 mmol) diluted in CH2Cl2 (5 mL) was added drop wise. The reaction was allowed to warm and was left stirring for 1 hour. The reaction proceeded until completion as judged by TLC and LC-MS. The reaction mixture was concentrated in vacuo, resuspended in 50:50 H2O—CH3CN, and purified on a C18 column in CH3CN/H20/0.1% TFA (1-100% gradient) to afford AD74. ESI-MS m/z [M+H]+ found 480.5, calculated 480.2.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[S:10][C:9]([C:11]3[N:12]=[N:13][N:14]([CH2:16][Si](C)(C)C)[CH:15]=3)=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1.O>[Cl:1][C:2]1[C:3]2[S:10][C:9]([C:11]3[N:12]=[N:13][N:14]([CH3:16])[CH:15]=3)=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: C[Si](C)(C)Cn1cc(-c2cc3ncnc(Cl)c3s2)nn1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: Cn1cc(-c2cc3ncnc(Cl)c3s2)nn1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a solution of compound 48.3 (0.5 mmol) in THF (10.0 mL) was added several drops of water and TBAF (0.55 mmol; 1.0 M in THF) at 0° C. The resulting mixture was stirred at 0° C. for 15 minutes, concentrated and washed with hexanes. The white solid that formed was suspended in ice water (10 mL), filtered, washed with ice water and dried in vacuo to provide 4-chloro-6-(1-methyl-1H-[1,2,3]triazol-4-yl)-thieno[3,2-d]pyrimidine (compound 48.4) in 95% yield. EIMS (m/z): calcd. for C9H6ClN5S (M+)+H 252.00. found 252.00.
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]1[CH:16]=[CH:15][C:13]([NH2:14])=[CH:12][CH:11]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl.[OH:18][C:19]1[C:20]([C:27](O)=[O:28])=[N:21][CH:22]=[CH:23][C:24]=1[O:25][CH3:26].ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C.CCN=C=NCCCN(C)C.Cl>C(Cl)(Cl)Cl>[OH:18][C:19]1[C:20]([C:27]([NH:14][C:13]2[CH:12]=[CH:11][C:10]([O:9][CH2:2][C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=3)=[CH:16][CH:15]=2)=[O:28])=[N:21][CH:22]=[CH:23][C:24]=1[O:25][CH3:26]
Reactant: COc1ccnc(C(=O)O)c1O
Reactant: Nc1ccc(OCc2ccccc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COc1ccnc(C(=O)Nc2ccc(OCc3ccccc3)cc2)c1O
Reaction time: 8 h
Yield: 58.6 %

Procedure:
4-Benzyloxyaniline hydrochloride (0.21 g, 0.87 mmol), 0.15 g (0.73 mmol) of 3-hydroxy-4-methoxypicolinic acid hydrochloride, 0.15 g (1.10 mmol) of 1-hydroxybenzotriazole, and 0.16 g (1.10 mmol) of triethylamine were mixed into chloroform to prepare a suspension (2 ml). A chloroform solution (2 ml) of WSCI.HCl (0.21 g, 1.10 mmol) and 0.11 g (1.10 mmol) of triethylamine were added dropwise at −20° C. to this suspension, and a reaction was then allowed to proceed at room temperature overnight. The reaction mixture was concentrated under the reduced pressure. The concentrate was redissolved in chloroform. The solution was washed with saturated brine, and was then dried over anhydrous sodium sulfate. The dried solution was concentrated under the reduced pressure. The residue was purified by column chromatography on silica gel (chloroform) to give 0.15 g (yield 59%) of title compound.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][NH:11][C:12]([C:14]1[C:24]2[O:23][CH2:22][CH2:21][C:20]([C:25](OC)=[O:26])=[CH:19][C:18]=2[CH:17]=[CH:16][CH:15]=1)=[O:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[NH2:30][C:31]([NH2:33])=[NH:32].C[O-].[Na+].C(OCC)(=O)C>CN(C)C=O.CO.O>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][NH:11][C:12]([C:14]1[C:24]2[O:23][CH2:22][CH2:21][C:20]([C:25]([NH:32][C:31]([NH2:33])=[NH:30])=[O:26])=[CH:19][C:18]=2[CH:17]=[CH:16][CH:15]=1)=[O:13])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)C1=Cc2cccc(C(=O)NCCNC(=O)OC(C)(C)C)c2OCC1
Reactant: N=C(N)N
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)NCCNC(=O)c1cccc2c1OCCC(C(=O)NC(=N)N)=C2
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.5 %

Procedure:
To a mixture of methyl 2,3-dihydro-9-[2-(tert-butoxycarbonylamino)ethylaminocarbonyl]-1-benzoxepin-4-carboxylate (1.1 g) and guanidine hydrochloride (1.3 g) in N,N-dimethylformamide (11 ml) was added 28% sodium methoxide in methanol (2.6 ml). The reaction mixture was stirred for 8 hours at ambient temperature, and the mixture was poured into a mixture of ethyl acetate and water. The separated organic layer was washed with water, dried over magnesium sulfate and evaporated in vacuo to give {2,3-dihydro-9-[2-(tert-butoxycarbonylamino)ethylaminocarbonyl]-1-benzoxepin-4-carbonyl}guanidine (0.9 g) as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:13]=[C:12]2[C:8]([C:9]([CH3:14])=[N:10][NH:11]2)=[CH:7][CH:6]=1)=[O:4].[Cl:15][C:16]1[CH:23]=[C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:21]=[CH:20][C:17]=1[CH2:18]Br.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>O.CCCCCC>[Cl:15][C:16]1[CH:23]=[C:22]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:21]=[CH:20][C:17]=1[CH2:18][N:10]1[C:9]([CH3:14])=[C:8]2[C:12]([CH:13]=[C:5]([C:3]([O:2][CH3:1])=[O:4])[CH:6]=[CH:7]2)=[N:11]1
Reactant: Clc1cc(-c2ccccc2)ccc1CBr
Reactant: COC(=O)c1ccc2c(C)n[nH]c2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)c1ccc2c(C)n(Cc3ccc(-c4ccccc4)cc3Cl)nc2c1
Temperature: 70 °C
Reaction time: 14 h
Yield: 26.1 %

Procedure:
A mixture of 6-(methoxycarbonyl)-3-methyl-1H-indazole (1.90 g), 2-chloro-4-phenylbenzyl bromide (3.37 g), potassium carbonate (2.76 g), ethyl acetate(10 ml) and water (5 ml) was stirred for 14 hr at 70° C. Hexane and water were added, and the precipitated solid was collected by filtration and washed with a mixed solvent of ethyl acetate and hexane (2/3). This was dried under reduced pressure to give the objective compound (1.02 g).
Reaction SMILES: C[Al](C)C.C[Si]([N:9]=[N+:10]=[N-:11])(C)C.[NH2:12][C:13]1[C:18]2[C:19](=[O:39])[N:20]([C:24]3[CH:29]=[CH:28][C:27]([C@H:30]4[CH2:35][CH2:34][C@H:33]([CH2:36][C:37]#[N:38])[CH2:32][CH2:31]4)=[CH:26][CH:25]=3)[CH2:21][CH2:22][O:23][C:17]=2[N:16]=[CH:15][N:14]=1>C1(C)C=CC=CC=1>[NH2:12][C:13]1[C:18]2[C:19](=[O:39])[N:20]([C:24]3[CH:25]=[CH:26][C:27]([CH:30]4[CH2:31][CH2:32][CH:33]([CH2:36][C:37]5[NH:38][N:11]=[N:10][N:9]=5)[CH2:34][CH2:35]4)=[CH:28][CH:29]=3)[CH2:21][CH2:22][O:23][C:17]=2[N:16]=[CH:15][N:14]=1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: N#CC[C@H]1CC[C@H](c2ccc(N3CCOc4ncnc(N)c4C3=O)cc2)CC1
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: Nc1ncnc2c1C(=O)N(c1ccc(C3CCC(Cc4nnn[nH]4)CC3)cc1)CCO2
Temperature: 80 °C

Procedure:
To a cooled 0° C., stirred solution of trimethylaluminum (2M in toluene, 0.33 mL) in toluene (0.66 mL) were added trimethylsilylazide (0.86 mL) and {trans-4-[4-(4-amino-5-oxo-7,8-dihydropyrimido[5,4-f][1,4]oxazepin-6(5H)-yl)phenyl]cyclohexyl}acetonitrile (25 mg). This mixture was heated at 80° C. for 40 hours, cooled, concentrated in vacuo and chromatographed (4 g silica gel column, 0-10% methanol:chloroform) to afford the title compound as a white solid, 2.8 mg. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.96-1.28 (m, 2 H) 1.25-1.45 (m, 2H) 1.62-1.80 (m, 5H) 2.31-2.50 (m, 1H) 2.62-2.76 (m, 2H) 3.85-3.95 (m, 2H) 4.45-4.57 (m, 2H) 7.13-7.29 (m, 4H) 7.55 (br. s., 2H) 8.10 (s, 1H) m/z=421.3 (M+1). IC50 76.2 nM (range 47.5-163 nM).
Reaction SMILES: [OH:1][C:2]1[CH:15]=[C:14]([O:16][CH2:17][CH:18]2[O:20][CH2:19]2)[CH:13]=[CH:12][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5].[CH:21]1([O:27][N:28]2[C:33]([CH3:35])([CH3:34])[CH2:32][CH:31]([OH:36])[CH2:30][C:29]2([CH3:38])[CH3:37])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1.P(O)(O)O>C(OCC)(=O)C>[OH:1][C:2]1[CH:15]=[C:14]([O:16][CH2:17][CH:18]([OH:20])[CH2:19][O:36][CH:31]2[CH2:32][C:33]([CH3:34])([CH3:35])[N:28]([O:27][CH:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)[C:29]([CH3:38])([CH3:37])[CH2:30]2)[CH:13]=[CH:12][C:3]=1[C:4]([C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)=[O:5]
Reactant: CC1(C)CC(O)CC(C)(C)N1OC1CCCCC1
Reactant: O=C(c1ccccc1)c1ccc(OCC2CO2)cc1O
Agent: OP(O)O
Solvent: CCOC(C)=O
Product: CC1(C)CC(OCC(O)COc2ccc(C(=O)c3ccccc3)c(O)c2)CC(C)(C)N1OC1CCCCC1
Yield: 2.1 %

Procedure:
A mixture of 5.0 g (18.5 mmol) of 2-hydroxy-4-(2,3-epoxypropoxy)benzophenone and 15.0 g (58.7 mmol) of 1-cyclohexyloxy-4-hydroxy-2,2,6,6-tetramethylpiperidine is heated to 80° and then treated with 0.5 g of phosphorous acid (99%). The reaction mixture is heated at 80°-90° C. for 6 hours, then cooled and dissolved in ethyl acetate (200 ml). The organic solution is washed with saturated sodium bicarbonate solution (100 ml), dried over magnesium sulfate, and evaporated to a yellow oil. Purification by flash chromatography on silica gel to obtain the least polar material formed in the reaction mixture affords approximately 200 mg of the title compound, a yellow glass.
Reaction SMILES: C([Li])CCC.[CH2:6]([C:8]([C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[C:22]([CH3:27])[CH:21]=1)([C:11]1[CH:16]=[CH:15][C:14]([C:17]#[CH:18])=[C:13]([CH3:19])[CH:12]=1)[CH2:9][CH3:10])[CH3:7].[O:28]1[CH2:33][CH2:32][C:31](=[O:34])[CH2:30][CH2:29]1.[Cl-].[NH4+]>O1CCCC1>[CH2:6]([C:8]([C:11]1[CH:16]=[CH:15][C:14]([C:17]#[C:18][C:31]2([OH:34])[CH2:32][CH2:33][O:28][CH2:29][CH2:30]2)=[C:13]([CH3:19])[CH:12]=1)([C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[C:22]([CH3:27])[CH:21]=1)[CH2:9][CH3:10])[CH3:7]
Reactant: C#Cc1ccc(C(CC)(CC)c2ccc(O)c(C)c2)cc1C
Reactant: O=C1CCOCC1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCC(CC)(c1ccc(O)c(C)c1)c1ccc(C#CC2(O)CCOCC2)c(C)c1
Reaction time: 0.25 h
Yield: 72.3 %

Procedure:
n-Butyllithium (2.71 M solution in hexane, 3.15 mL, 8.55 mmol) was added to a solution of 4-[1-ethyl-1-(4-ethynyl-3-methyl-phenyl)-propyl]-2-methyl-phenol (Example 1-(3); 1.0 g, 3.42 mmol) in tetrahydrofuran (30 mL) in a nitrogen atmosphere at 0° C., and the mixture was stirred for 15 minutes. Then, tetrahydropyran-4-one (685 mg, 6.84 mmol) was added to the reaction mixture, which was further stirred at 0° C. for 30 minutes. The reaction mixture was then poured into a saturated aqueous ammonium chloride solution, followed by extraction with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (hexane:ethyl acetate=100:0 to 30:70) to give the target compound as a colorless oil (0.97 g, 72%).
Reaction SMILES: [CH3:1][N:2]([S:20]([C:23]1[CH:28]=[CH:27][C:26]([C:29]2[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=2)=[CH:25][CH:24]=1)(=[O:22])=[O:21])[CH:3]1[CH2:7][CH:6]([CH2:8][S:9][C:10]2[S:11][C:12]3[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=3[N:14]=2)[O:5][C:4]1=[O:19].[OH-:37].[Li+]>O.C1COCC1>[CH3:1][N:2]([S:20]([C:23]1[CH:28]=[CH:27][C:26]([C:29]2[CH:30]=[CH:31][C:32]([O:35][CH3:36])=[CH:33][CH:34]=2)=[CH:25][CH:24]=1)(=[O:22])=[O:21])[CH:3]([CH2:7][CH:6]([OH:5])[CH2:8][S:9][C:10]1[S:11][C:12]2[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=2[N:14]=1)[C:4]([OH:19])=[O:37]
Reactant: COc1ccc(-c2ccc(S(=O)(=O)N(C)C3CC(CSc4nc5ccccc5s4)OC3=O)cc2)cc1
Reactant: [OH-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(-c2ccc(S(=O)(=O)N(C)C(CC(O)CSc3nc4ccccc4s3)C(=O)O)cc2)cc1
Reaction time: 4 h

Procedure:
To a solution of N-methyl 3-[(4′-Methoxy[1,1′-biphenyl]-4-yl)sulfonyl]amino-2-oxo-5-[[(2-benzothiazolyl)thio]methyl]-tetrahydrofuran 62c (1.00 g, 2.05 mmol) in water (5 mL) and THF (5 mL) is slowly added lithium hydroxide (0.49 g, 20.5 mmol). The reaction is stirred for 4 hr, then concentrated to dryness. The reaction mixture is diluted with water and then the mixture is extracted with ethy ether (2×25 mL) The ethyl ether layer is discarded and the aqueous layer is slowly acidified with 1N HCl to pH 5, and then extracted 3 times with ethyl acetate. The combined ethyl acetate layers are washed with water and brine, dried over MgSO4, filtered and concentrated under reduced pressure. The white solid is then recrystallized with ethyl acetate/hexanes to give the desired product as a white solid.
Reaction SMILES: [C:1]([CH2:3][CH2:4][C:5]1([C:18]([O:20]CC)=O)[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]1)#[N:2]>N.[Ni]>[O:20]=[C:18]1[C:5]2([CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:1][NH:2]1
Reactant: CCOC(=O)C1(CCC#N)CCN(C(=O)OC(C)(C)C)CC1
Agent: [Ni]
Agent: N
Product: CC(C)(C)OC(=O)N1CCC2(CCCNC2=O)CC1
Reaction time: 48 h
Yield: 40.8 %

Procedure:
A heterogeneous mixture of Raney Ni (5.0 g) in ethanolic ammonia (˜20% v/v) and 1-tert-butyl 4-ethyl 4-(2-cyanoethyl)piperidine-1,4-dicarboxylate (8.5 g, 27.42 mmol) was hydrogenated at 100 psi for 48 h at rt in an autoclave. After completion of the reaction, the catalyst was filtered off and washed with ethanol. The combined filtrate was concentrated under reduced pressure and triturated with n-pentane to yield a solid which was purified by column chromatography (eluent=6% methanol in chloroform) to furnish the title compound as a white solid (3.0 g, 41%). [1H-NMR (DMSO-d6, 300 MHz): δ 7.38 (s, 1H), 3.68-3.60 (m, 2H), 3.18-2.95 (m, 4H), 1.89-1.58 (m, 4H), 1.45-1.22 (m, 13H); HPLC RtA=3.835 min (96%); LCMS RtA=1.630, [M+H-Boc]+=169.1].