Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@:2]12[CH2:37][CH2:36][C@@H:35]([C:38]([CH3:40])=[CH2:39])[C@@H:3]1[C@@H:4]1[C@@:17]([CH3:20])([CH2:18][CH2:19]2)[C@@:16]2([CH3:21])[C@@H:7]([C@:8]3([CH3:34])[C@@H:13]([CH2:14][CH2:15]2)[C:12]([CH3:23])([CH3:22])[C:11]([C:24]2[CH:33]=[CH:32][C:27]([C:28]([O:30]C)=[O:29])=[CH:26][CH:25]=2)=[CH:10][CH2:9]3)[CH2:6][CH2:5]1.CN(C)CCC(N[C@]12CC[C@@H](C(C)=C)[C@@H]1[C@@H]1[C@@](C)(CC2)[C@@]2(C)[C@@H]([C@]3(C)[C@@H](CC2)C(C)(C)C(C2C=CC(C(O)=O)=CC=2)=CC3)CC1)=O.[CH3:87][C@H:88]1[O:93][C@@H:92]([CH3:94])[CH2:91][N:90]([CH2:95][C:96]([OH:98])=O)[CH2:89]1>>[CH3:94][C@H:92]1[CH2:91][N:90]([CH2:95][C:96]([NH:1][C@:2]23[CH2:37][CH2:36][C@@H:35]([C:38]([CH3:40])=[CH2:39])[C@@H:3]2[C@@H:4]2[C@@:17]([CH3:20])([CH2:18][CH2:19]3)[C@@:16]3([CH3:21])[C@@H:7]([C@:8]4([CH3:34])[C@@H:13]([CH2:14][CH2:15]3)[C:12]([CH3:23])([CH3:22])[C:11]([C:24]3[CH:25]=[CH:26][C:27]([C:28]([OH:30])=[O:29])=[CH:32][CH:33]=3)=[CH:10][CH2:9]4)[CH2:6][CH2:5]2)=[O:98])[CH2:89][C@@H:88]([CH3:87])[O:93]1
Reactant: C[C@@H]1CN(CC(=O)O)C[C@H](C)O1
Reactant: C=C(C)[C@@H]1CC[C@]2(N)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: C=C(C)[C@@H]1CC[C@]2(NC(=O)CCN(C)C)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
Product: C=C(C)[C@@H]1CC[C@]2(NC(=O)CN3C[C@@H](C)O[C@@H](C)C3)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
Yield: 43 %

Procedure:
The title compound was prepared in 43% yield from methyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-amino-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)benzoate following the same procedure as described for the preparation of 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(3-(dimethylamino)propanamido)-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, except [(2R,6S)-2,6-dimethylmorpholin-4-yl]acetic acid was used instead of 3-(dimethylamino)propionic acid hydrochloride in Step 1. LCMS: m/e 685.6 (M+H)+, 2.48 min (method 6). 1H NMR (500 MHz, 1:1 CDCl3:MeOD) δ=7.92 (d, J=8.2 Hz, 2H), 7.20 (d, J=8.2 Hz, 2H), 5.29 (dd, J=1.5, 6.1 Hz, 1H), 4.75 (d, J=1.2 Hz, 1H), 3.89 (dd, J=6.3, 9.0 Hz, 2H), 3.64 (br. s., 1H), 3.24 (br. s., 2H), 2.69-2.49 (m, 4H), 2.39 (dd, J=8.1, 12.4 Hz, 1H), 2.13 (dd, J=6.4, 17.1 Hz, 1H), 1.93-1.76 (m, 3H), 1.74 (br. s., 1H), 1.72 (s, 3H), 1.70-1.66 (m, 1H), 1.60-1.42 (m, 8H), 1.42-1.30 (m, 3H), 1.25 (d, J=3.1 Hz, 3H), 1.24 (d, J=2.7 Hz, 3H), 1.18-1.11 (m, 2H), 1.08 (s, 3H), 1.03 (s, 3H), 1.01 (s, 3H), 0.95 (s, 3H), 0.94 (s, 3H).
Reaction SMILES: C([O:5][C:6](=O)[NH:7][C:8]([C:11](=[O:31])[NH:12][C:13]1[S:14][C:15]([N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)=[C:16]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)[N:17]=1)([CH3:10])[CH3:9])(C)(C)C.Cl.CCO[C:37]([CH3:39])=O>>[CH:37]1([CH2:39][C:6]([NH:7][C:8]([CH3:10])([CH3:9])[C:11]([NH:12][C:13]2[S:14][C:15]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)=[C:16]([C:18]3[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=3)[N:17]=2)=[O:31])=[O:5])[CH2:19][CH2:18][CH2:16][CH2:15]1
Reactant: CC(C)(C)OC(=O)NC(C)(C)C(=O)Nc1nc(-c2ccc(F)cc2)c(N2CCOCC2)s1
Reactant: CCOC(C)=O
Agent: Cl
Product: CC(C)(NC(=O)CC1CCCC1)C(=O)Nc1nc(-c2ccc(F)cc2)c(N2CCOCC2)s1

Procedure:
{1-[4-(4-Fluoro-phenyl)-5-morpholin-4-yl-thiazol-2-ylcarbamoyl]-1-methyl-ethyl}-carbamic acid tert-butyl ester was stirred overnight in freshly prepared HCl (g)/EtOAc solution. Evaporation to dryness afforded the desired product as the hydrochloride salt. 1H NMR (400 MHz, DMSO-D6) 1.63 (s, 6H) 2.81-2.89 (m, 4H) 3.70-3.78 (m, 4H) 7.23-7.29 (m, 2H) 8.10-8.16 (m, 2H) 8.62 (s, 3H) 12.46 (s, 1H).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[Li+].CC([N-]C(C)C)C.[F:21][C:22]1[CH:27]=[C:26]([F:28])[C:25]([F:29])=[CH:24][C:23]=1[C:30]1[O:31][CH2:32][C:33]([CH3:36])([CH3:35])[N:34]=1.Cl[Si:38]([CH3:41])([CH3:40])[CH3:39]>C1COCC1.O>[F:21][C:22]1[C:27]([Si:38]([CH3:41])([CH3:40])[CH3:39])=[C:26]([F:28])[C:25]([F:29])=[CH:24][C:23]=1[C:30]1[O:31][CH2:32][C:33]([CH3:36])([CH3:35])[N:34]=1
Reactant: CC1(C)COC(c2cc(F)c(F)cc2F)=N1
Reactant: C[Si](C)(C)Cl
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Solvent: CC(C)NC(C)C
Product: CC1(C)COC(c2cc(F)c(F)c([Si](C)(C)C)c2F)=N1
Temperature: -78 °C
Reaction time: 1 h
Yield: 83.1 %

Procedure:
A solution of 8.7 ml (62.1 mmol) of diisopropylamine in 100 ml of dry THF under argon was cooled to -78° C. and treated with 28.3 ml (56.6 mmol) of 2.0M n-butyllithium. The LDA solution was stirred at -78° C. for 15 minutes. To this solution was added a solution of 11.8 g (51.5 mmol) of 2-(2,4,5-trifluorophenyl)-4,4-dimethyl-2-oxazoline in 50 ml of THF, and the reaction mixture was stirred for one hour at -78° C. To the reaction mixture was added 13 ml (102.5 mmol) of chlorotrimethylsilane, and the solution was warmed to room temperature. Water was added; the organic layer was dried over magnesium sulfate and concentrated. The crude product was chromatographed on silica gel (E. Merck 230-400 Mesh), eluting with 80:20 chloroform:ethyl acetate to give 12.9 g of the title compound, mp 71°-72° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9][C:10]2[N:14]([CH:15]([CH3:17])[CH3:16])[N:13]=[C:12]([CH3:18])[C:11]=2[C:19]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:20])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[BH4-].[Na+].O>CO>[Cl:8][C:6]1[CH:5]=[C:4]([S:9][C:10]2[N:14]([CH:15]([CH3:17])[CH3:16])[N:13]=[C:12]([CH3:18])[C:11]=2[CH:19]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[OH:20])[CH:3]=[C:2]([Cl:1])[CH:7]=1
Reactant: Cc1nn(C(C)C)c(Sc2cc(Cl)cc(Cl)c2)c1C(=O)c1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: Cc1nn(C(C)C)c(Sc2cc(Cl)cc(Cl)c2)c1C(O)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.3 %

Procedure:
A solution containing 32 mg of [5-(3,5-dichlorophenylthio)-1-isopropyl-3-methyl-1H-pyrazol-4-yl]-phenyl-methanone in 2 ml of methanol was treated with 6 mg of sodium borohydride at rt under nitrogen. The mixture was then stirred at rt overnight. To the mixture was added 2 ml of water and then extracted with diethyl ether three times. Combined extracts were washed with brine then dried over anhydrous magnesium sulphate, filtered and evaporated to give 30 mg of [5-(3,5-dichlorophenylthio)-1-isopropyl-3-methyl-1H-pyrazol-4-yl]-phenyl-methanol as a white solid which was used without further purification. Mass spectrum (ES) m/z 407[M+H]+.
Reaction SMILES: [CH:1]1[N:5]=[CH:4][N:3]([CH2:6][C:7]([P:13]([OH:16])([OH:15])=[O:14])([P:9]([OH:12])([OH:11])=[O:10])[OH:8])[CH:2]=1.[OH-].[Na+:18].O>C(O)C>[CH:1]1[N:5]=[CH:4][N:3]([CH2:6][C:7]([P:9]([O-:12])([O-:11])=[O:10])([P:13]([O-:15])([OH:16])=[O:14])[OH:8])[CH:2]=1.[Na+:18].[Na+:18].[Na+:18]
Reactant: O=P(O)(O)C(O)(Cn1ccnc1)P(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=P([O-])([O-])C(O)(Cn1ccnc1)P(=O)([O-])O
Temperature: 25 °C
Yield: 86 %

Procedure:
A 250 ml flask was loaded with Zoledronic acid form XII (5.0 g), Sodium hydroxide (1.4 g), absolute Ethanol (50 ml) and water (2.5 ml) [=5% v/v water in Ethanol]. The reaction mixture was heated to reflux temperature for 20 hours. Then the reaction mixture was cooled to room temperature. Further cooling was performed using an ice-bath. The precipitate was then filtered, washed with absolute Ethanol (2×25 ml) and dried in a vacuum oven at 50° C. for 24 hours to give 5.4 g (86%) of Zoledronate trisodium crystal form XI (LOD by TGA=8.9%).
Reaction SMILES: C([O:5][C:6](=[O:45])[C@@H:7]([NH:34][C:35]([O:37][CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)=[O:36])[CH2:8][N:9]1[CH:17]=[N:16][C:15]2[C:10]1=[N:11][CH:12]=[N:13][C:14]=2[N:18]1[CH2:23][CH2:22][CH:21]([C:24]2[CH:33]=[CH:32][C:31]3[CH2:30][CH2:29][CH2:28][NH:27][C:26]=3[N:25]=2)[CH2:20][CH2:19]1)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH2:38]([O:37][C:35]([NH:34][C@@H:7]([CH2:8][N:9]1[CH:17]=[N:16][C:15]2[C:10]1=[N:11][CH:12]=[N:13][C:14]=2[N:18]1[CH2:19][CH2:20][CH:21]([C:24]2[CH:33]=[CH:32][C:31]3[CH2:30][CH2:29][CH2:28][NH:27][C:26]=3[N:25]=2)[CH2:22][CH2:23]1)[C:6]([OH:45])=[O:5])=[O:36])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: CC(C)(C)OC(=O)[C@H](Cn1cnc2c(N3CCC(c4ccc5c(n4)NCCC5)CC3)ncnc21)NC(=O)OCc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(N[C@@H](Cn1cnc2c(N3CCC(c4ccc5c(n4)NCCC5)CC3)ncnc21)C(=O)O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
219 mg of the compound of step d) were dissolved in 12 ml of dichloromethane and 2 ml trifluoroacetic acid were added under stirring at ambient temperature. After 6 hours the reaction was complete. The solvents were removed in vacuo. The residue was mixed with toluene and this mixture was again evaporated. The resulting resin was triturated with diethylether. After filtration 210 mg of a faint yellow solid were isolated. MS (ES+): m/e=557.2 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[C:12]([Cl:14])[C:11]([O:15][CH2:16][CH2:17][OH:18])=[C:10]([Cl:19])[CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[C:21](OC(=O)C)(=[O:23])[CH3:22]>N1C=CC=CC=1>[C:1]([O:5][C:6]([NH:7][C:8]1[CH:13]=[C:12]([Cl:14])[C:11]([O:15][CH2:16][CH2:17][O:18][C:21](=[O:23])[CH3:22])=[C:10]([Cl:19])[CH:9]=1)=[O:20])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)(C)OC(=O)Nc1cc(Cl)c(OCCO)c(Cl)c1
Solvent: c1ccncc1
Product: CC(=O)OCCOc1c(Cl)cc(NC(=O)OC(C)(C)C)cc1Cl
Temperature: 25 °C
Reaction time: 15 h

Procedure:
A solution of [3,5-dichloro-4-(2-hydroxy-ethoxy)-phenyl]-carbamic acid tert-butyl ester (0.85 g) in pyridine (14 mL) is treated with acetic anhydride (1.24 mL) and the mixture is stirred at room temperature for 15 hours. The solvent is removed under reduced pressure and the residue dissolved in ethyl acetate. This solution is then washed twice with 5% aqueous hydrochloric acid, once with saturated aqueous sodium bicarbonate, and then with saturated aqueous sodium chloride. The solution is dried over anhydrous magnesium sulfate and the solvent is removed under reduced pressure to provide the desired product as a colorless oil.
Reaction SMILES: CS(C1C=CC(N)=CC=1)(=O)=O.[CH3:12][S:13]([C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][C:20](=[O:25])[C:19]2=[O:26])(=[O:15])=[O:14].[CH:27]1[C:32]([NH:33][NH2:34])=[CH:31][CH:30]=[C:29]([S:35]([NH2:38])(=[O:37])=[O:36])[CH:28]=1.Cl>>[CH3:12][S:13]([C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][C:20](=[O:25])[C:19]2=[O:26])(=[O:15])=[O:14].[CH3:12][S:13]([C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][C:20](=[O:25])[C:19]2=[N:34][NH:33][C:32]1[CH:31]=[CH:30][C:29]([S:35]([NH2:38])(=[O:36])=[O:37])=[CH:28][CH:27]=1)(=[O:15])=[O:14]
Reactant: NNc1ccc(S(N)(=O)=O)cc1
Agent: CS(=O)(=O)c1ccc(N)cc1
Agent: CS(=O)(=O)c1ccc2c(c1)C(=O)C(=O)N2
Agent: Cl
Product: CS(=O)(=O)c1ccc2c(c1)C(=NNc1ccc(S(N)(=O)=O)cc1)C(=O)N2

Procedure:
5-Methylsulfonyl-1H-indole-2,3-dione was prepared from 4-methylsulfonylaniline according to Procedure A: 1H NMR (DMSO-d6): δ3.21 (s, 3H), 7.07(d, J=8.3 Hz, 1H), 7.92 (d, J=1.7 Hz, 1H), 8.05 (dd, J=8.2, 2.0 Hz, 1H), 11.46 (s, 1H); APCI−MS m/z 225 (M)−. The title compound was prepared from 5-methylsulfonyl-1H-indole-2,3-dione and 4-sulfonamidophenylhydrazine hydrochloride according to Procedure G: mp>250° C.; 1H NMR (DMSO-d6): δ3.20 (s, 3H), 7.11 (d, J=8.3 Hz, 1H), 7.26 (s, 2H), 7.65 (d, J=8.9 Hz, 2H), 7.78 (d, J=8.7 Hz, 2H), 7.79 (dd, J=8.2, 1.9 Hz, 1H), 8.06 (d, J=1.6 Hz, 1H), 11.54 (s, 1H), 12.75 (s, 1H); APCI−MS m/z 394 (M)−. Anal. Calcd for C15H14N4O5S2.0.9H2O: C, 43.87; H, 3.88; N, 13.64; S, 15.62. Found: C, 43.96; H, 3.80; N, 13.58; S, 15.67.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][C:12]#[C:13][C:14]1[CH2:31][C@@:29]2([CH3:30])[C@@H:25]([CH2:26][CH2:27][C@@H:28]2[O:32][CH:33]2[CH2:38][CH2:37][CH2:36][CH2:35][O:34]2)[C@@:24]2([C:39]#[N:40])[C:15]=1[C:16]1[CH:17]=[CH:18][C:19]([O:41][CH3:42])=[CH:20][C:21]=1[CH2:22][CH2:23]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>O1CCCC1.CO.[Pd]>[CH2:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]1[CH2:31][C@@:29]2([CH3:30])[C@@H:25]([CH2:26][CH2:27][C@@H:28]2[O:32][CH:33]2[CH2:38][CH2:37][CH2:36][CH2:35][O:34]2)[C@@:24]2([C:39]#[N:40])[C:15]=1[C:16]1[CH:17]=[CH:18][C:19]([O:41][CH3:42])=[CH:20][C:21]=1[CH2:22][CH2:23]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc2c(c1)CC[C@]1(C#N)C2=C(C#CCCCOCc2ccccc2)C[C@]2(C)[C@@H](OC3CCCCO3)CC[C@H]21
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc2c(c1)CC[C@]1(C#N)C2=C(CCCCCOCc2ccccc2)C[C@]2(C)[C@@H](OC3CCCCO3)CC[C@H]21
Temperature: 25 °C
Yield: 100.2 %

Procedure:
A solution of 15.26 g of alkyne 3 in 300 ml of tetrahydrofuran/methanol (3:1) is mixed with 2.7 g of palladium (10% on magnesium carbonate) and stirred at room temperature under a hydrogen atmosphere (1 bar) until the reaction is completed. For working-up, it is filtered on Celite and concentrated by evaporation in a vacuum. 15.4 g of a colorless foam 4 is obtained, which is used without further purification in the next stage (GC-MS: m/z theor.: 569, pract.: 569).
Reaction SMILES: [CH2:1]([NH2:11])[C:2]1[CH:10]=[CH:9][C:8]2[O:7][CH2:6][O:5][C:4]=2[CH:3]=1.[O:12]=[C:13]1[NH:21][CH:20]=[N:19][C:18]2[N:17]([CH2:22][CH2:23][C:24](OCC)=[O:25])[CH:16]=[N:15][C:14]1=2>C(#N)C>[O:12]=[C:13]1[NH:21][CH:20]=[N:19][C:18]2[N:17]([CH2:22][CH2:23][C:24]([NH:11][CH2:1][C:2]3[CH:10]=[CH:9][C:8]4[O:7][CH2:6][O:5][C:4]=4[CH:3]=3)=[O:25])[CH:16]=[N:15][C:14]1=2
Reactant: NCc1ccc2c(c1)OCO2
Reactant: CCOC(=O)CCn1cnc2c(=O)[nH]cnc21
Solvent: CC#N
Product: O=C(CCn1cnc2c(=O)[nH]cnc21)NCc1ccc2c(c1)OCO2
Temperature: 110 °C
Reaction time: 0.33 h
Yield: 68 %

Procedure:
0.500 g (3.31 mmol) of piperonylamine was placed into a 10 ml round bottom flask with a magnetic stirring bar and heated to 110° C. and 0.250 g (1.06 mmol) of 3-(1,6-dihydro-6-oxo-9H-purin-9-yl)propionic acid, ethyl ester (AIT-0027) was added to the stirring amine. The solution was heated for 40 minutes at which time the reaction mixture had solidified. 10 ml of acetonitrile was added to the residue and the solution was stirred for about 20 min. The white precipitate was collected by Buchner vacuum filtration and was washed with acetonitrile and then with ether. This yielded 245 mg of (AIT-0066) as a white solid. Yield: 68%.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]([N:8]([C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=1)[C@H:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[NH:12][C@@H:11]([CH3:19])[CH2:10]1)=[O:7])(=[O:3])[CH3:2].C(N(C(C)C)CC)(C)C.Cl[C:37]([C:39]1[CH:44]=[CH:43][C:42]([CH2:45][CH2:46][CH2:47][C:48]([CH3:54])([CH3:53])[C:49]([O:51][CH3:52])=[O:50])=[CH:41][CH:40]=1)=[O:38]>C(Cl)Cl>[C:1]([O:4][CH2:5][C:6]([N:8]([C:20]1[CH:21]=[CH:22][C:23]([Cl:26])=[CH:24][CH:25]=1)[C@H:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]([C:37]([C:39]2[CH:44]=[CH:43][C:42]([CH2:45][CH2:46][CH2:47][C:48]([CH3:54])([CH3:53])[C:49]([O:51][CH3:52])=[O:50])=[CH:41][CH:40]=2)=[O:38])[C@@H:11]([CH3:19])[CH2:10]1)=[O:7])(=[O:3])[CH3:2]
Reactant: COC(=O)C(C)(C)CCCc1ccc(C(=O)Cl)cc1
Reactant: CC(=O)OCC(=O)N(c1ccc(Cl)cc1)[C@@H]1C[C@H](C)Nc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)C(C)(C)CCCc1ccc(C(=O)N2c3ccccc3[C@H](N(C(=O)COC(C)=O)c3ccc(Cl)cc3)C[C@@H]2C)cc1
Temperature: 25 °C
Yield: 39.5 %

Procedure:
To a solution of 2-{(4-chlorophenyl)[(2S,4R)-2-methyl-1,2,3,4-tetrahydroquinolin-4-yl]amino}-2-oxoethyl acetate (170 mg, 0.45 mmol, 1 equ.) in methylene chloride (2.0 mL) at room temperature was added diisopropylethylamine (127 uL, 0.73 mmol, 1.60 equ.) followed by methyl 5-[4-(chlorocarbonyl)phenyl]-2,2-dimethylpentanoate (196 mg, 0.73 mmol, 1.60 equ.). The reaction was stirred over night at room temperature. The mixture was concentrated, then poured into water and extracted with ethyl acetate. The extracts were washed with brine, dried over magnesium sulfate, filtered dried and concentrated. The crude residue was purified by silica gel chromatography (ethyl acetate/hexane 25/75 to 1:1 gradient) to afford the pure methyl 5-(4-{[(2S,4R)-4-[[(acetyloxy)acetyl](4-chlorophenyl)amino]-2-methyl-3,4-dihydroquinolin-1(2H)-yl]carbonyl}phenyl)-2,2-dimethylpentanoate (110 mg, 40%).
Reaction SMILES: [C:1]([OH:10])(=O)/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].C(Cl)(=O)C(Cl)=O.[CH3:17][C:18]1[CH:27]=[C:26]([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[N:19]=1.C(N(CC)CC)C>ClCCl.CN(C=O)C>[CH3:17][C:18]1[CH:27]=[C:26]([N:28]2[CH2:33][CH2:32][N:31]([C:1](=[O:10])/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[CH2:30][CH2:29]2)[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[N:19]=1
Reactant: Cc1cc(N2CCNCC2)c2ccccc2n1
Reactant: CCCCC/C=C/C(=O)O
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCCCC/C=C/C(=O)N1CCN(c2cc(C)nc3ccccc23)CC1
Yield: 75.6 %

Procedure:
(E)-Oct-2-enoic acid (71.1 mg, 0.5 mmol) was dissolved in dichloromethane (1 ml) and a 2M solution of oxalyl chloride in dichloromethane was added (0.3 ml, 0.6 mmol). The solution was stirred at room temperature for one hour after which a drop of DMF was added. Stirring was continued for another hour, the mixture was evaporated to dryness under reduced pressure. The residue was dissolved in dichloromethane (1 ml), the resulting solution was added to a solution of 2-methyl-4-piperazin-1-yl-quinoline (103 mg, 0.45 mmol) and triethylamine (90 μl, 0.64 mmol) in dichloromethane (1 ml). The resulting mixture was stirred at room temperature overnight, diluted with dichloromethane (1 ml), washed with water and 2M NaOH (2 ml each) and evaporated to dryness under reduced pressure. The residue was purified by preparative HPLC (gradient of water containing 0.1% ammonia and acetonitrile) to yield 121.3 mg of a solid (0.34 mmol, 77%).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([CH:17]([CH3:37])[C:18]([C:24]3[CH:25]=[CH:26][C:27]4[O:32][CH2:31][C:30](=[O:33])[N:29]([CH2:34][CH3:35])[C:28]=4[CH:36]=3)([OH:23])[C:19]([F:22])([F:21])[F:20])=[C:13]([Cl:38])[CH:12]=2)=[CH:7][C:6]=1[F:39])=[O:4]>CCCCCCC>[Cl:38][C:13]1[CH:12]=[C:11]([C:8]2[CH:9]=[CH:10][C:5]([C:3]([OH:4])=[O:2])=[C:6]([F:39])[CH:7]=2)[CH:16]=[CH:15][C:14]=1[CH:17]([CH3:37])[C:18]([C:24]1[CH:25]=[CH:26][C:27]2[O:32][CH2:31][C:30](=[O:33])[N:29]([CH2:34][CH3:35])[C:28]=2[CH:36]=1)([OH:23])[C:19]([F:22])([F:21])[F:20]
Reactant: CCN1C(=O)COc2ccc(C(O)(C(C)c3ccc(-c4ccc(C(=O)OC)c(F)c4)cc3Cl)C(F)(F)F)cc21
Solvent: CCCCCCC
Product: CCN1C(=O)COc2ccc(C(O)(C(C)c3ccc(-c4ccc(C(=O)O)c(F)c4)cc3Cl)C(F)(F)F)cc21

Procedure:
In analogy to Example 56, step 6, 3′-chloro-4′-[2-(4-ethyl-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-6-yl)-3,3,3-trifluoro-2-hydroxy-1-methyl-propyl]-3-fluoro-biphenyl-4-carboxylic acid methyl ester was hydrolyzed (3 h, 65° C.). The product was treated with heptane for 17 h, filtered and dried to give the title compound as a white solid. MS (m/e, ISP neg. ion)=550.2 [M−H+].
Reaction SMILES: [S:1]1[CH2:5][CH2:4][N:3]=[C:2]1[NH:6][C:7]1(O)[C:12](=[CH:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:11][S:10][CH2:9][C:8]1=[CH:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C1(C)C=CC=CC=1.Cl[Ti](Cl)(Cl)Cl>[C:21]1([CH:20]2[N:3]3[CH2:4][CH2:5][S:1][C:2]3=[N:6][C:7]3[C:12](=[CH:13][C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[CH2:11][S:10][CH2:9][C:8]2=3)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: OC1(NC2=NCCS2)C(=Cc2ccccc2)CSCC1=Cc1ccccc1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: C(=C1CSCC2=C1N=C1SCCN1C2c1ccccc1)c1ccccc1
Temperature: 25 °C
Yield: 78.1 %

Procedure:
A slurry of the 4-[(4,5-dihydro-2-thiazolyl)amino]tetrahydro-3,5-bis(phenylmethylene)-2H-thiopyran-4-ol (2.0 g, 5.1 mmole) from part A in 20 ml dry toluene under nitrogen at room temperature is treated with 12 ml of a solution of TiCl4 in toluene (1.29 g, TiCl4 in 25 ml). The resulting mixture is heated at reflux temperature for 2 hours. Upon cooling, the solid mass is pulverized and collected by filtration. The solids are partitioned between CHCl3 and aqueous NaHCO3. The aqueous layer is extracted with additional CHCl3. The extracts are washed (H2O), combined, dried (CaCl2) and concentrated on a steam bath; a volume of 75-100 ml is maintained by periodic addition of MeOH. When precipitation commences, the flask is cooled to room temperature. The product is collected, washed (MeOH) and dried in vacuo (80°) for several hours to give 1.5 g (79%) of product, m.p. 195°-196° d.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9]([O:13][C:14]3[C:19]4=[N:20][S:21](=[O:25])(=[O:24])[CH2:22][CH2:23][N:18]4[CH:17]=[CH:16][CH:15]=3)=[CH:10]2)=[CH:5][CH:4]=1>[Pt](=O)=O.C(O)(=O)C>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9]([O:13][CH:14]3[C:19]4=[N:20][S:21](=[O:25])(=[O:24])[CH2:22][CH2:23][N:18]4[CH2:17][CH2:16][CH2:15]3)=[CH:10]2)=[CH:5][CH:4]=1
Reactant: COc1ccc2ccc(OC3=CC=CN4CCS(=O)(=O)N=C34)cc2c1
Agent: O=[Pt]=O
Solvent: CC(=O)O
Product: COc1ccc2ccc(OC3CCCN4CCS(=O)(=O)N=C34)cc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 22.6 %

Procedure:
A mixture of 9-[(7-methoxynaphthalen-2-yl)oxy]-3,4-dihydropyrido[2,1-c][1,2,4]thiadiazine 2,2-dioxide (120 mg), platinum (IV) oxide (76 mg) and acetic acid (10 ml) was stirred under a hydrogen atmosphere at room temperature overnight. The reaction mixture was filtered, and concentrated under reduced pressure. To the residue was added a saturated aqueous sodium hydrogen carbonate solution and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was crystallized from ethyl acetate and hexane to give the title compound (27.4 mg) as a gray white solid.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([C:12]2[C:16]3[S:17][CH:18]=[CH:19][C:15]=3[O:14][N:13]=2)[CH:9]=[CH:10][CH:11]=1.C(=O)([O-])[O-].[K+].[K+].[NH2:26][CH:27]1[CH2:35][C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH2:28]1>C(#N)C>[CH2:28]1[C:29]2[C:34](=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:35][CH:27]1[NH:26][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]2[C:16]3[S:17][CH:18]=[CH:19][C:15]=3[O:14][N:13]=2)[CH:7]=1
Reactant: NC1Cc2ccccc2C1
Reactant: BrCCCOc1cccc(-c2noc3ccsc23)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: c1cc(OCCCNC2Cc3ccccc3C2)cc(-c2noc3ccsc23)c1

Procedure:
The title compound is prepared from 3-[3-(3-bromo-propoxy)-phenyl]-thieno[2,3-d]isoxazole, potassium carbonate, 2-aminoindan, and acetonitrile essentially as described above in example 48. Purity by LC/MS (APCI)=99%, [M+H]+=391.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:13])[CH:10]([CH3:12])[CH3:11].IC.[C:16]([O-])([O-])=O.[Cs+].[Cs+]>C(#N)C>[OH:1][C:2]1[CH:7]=[C:6]([O:8][CH3:16])[CH:5]=[CH:4][C:3]=1[C:9](=[O:13])[CH:10]([CH3:11])[CH3:12]
Reactant: CC(C)C(=O)c1ccc(O)cc1O
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CI
Solvent: CC#N
Product: COc1ccc(C(=O)C(C)C)c(O)c1
Temperature: 25 °C

Procedure:
The above prepared 1-(2,4-dihydroxy-phenyl)-2-methyl-propan-1-one (1.13 g, 5.55 mmol, corrected for purity) was dissolved in 22 mL of acetonitrile and treated successively at 0° C. with iodomethane (0.36 mL, 1.05 eq.) and Cs2CO3 (1.998 g, 1.1 eq.), and the mixture then stirred over night at ambient temperature. Pouring onto crashed ice/NH4Cl, twofold extraction with AcOEt, washing with water, drying over sodium sulfate, and evaporation of the solvents, followed by flash chromatography (SiO2, hexane/AcOEt=95/5), delivered 0.740 g of the title compound as colorless oil.