Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1]P(O)(O)=O.[O:6]=[P:7]12[O:18]P3(OP(OP(O3)([O:14]1)=O)(=O)[O:8]2)=O.P([O-])([O-])([O-])=O.[Ca+2:25].P([O-])([O-])([O-])=O.[Ca+2].[Ca+2].[S:33](=[O:37])(=[O:36])([OH:35])[OH:34]>>[OH2:1].[S:33]([O-:37])([O-:36])(=[O:35])=[O:34].[Ca+2:25].[Ca+2:25].[S:33]([O-:37])([O-:36])(=[O:35])=[O:34].[P:7](=[O:6])([OH:18])([OH:14])[OH:8]
Reactant: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Reactant: O=S(=O)(O)O
Agent: O=P(O)(O)O
Agent: O=P([O-])([O-])[O-]
Agent: [Ca+2]
Product: O
Product: O=S(=O)([O-])[O-]

Procedure:
Superphosphoric acid (SPA), which is used in the manufacture of fertilizers, is phosphoric acid containing about 68 to about 70% by weight of P2O5. It can be manufactured by dissolving calcium phosphate rock with sulfuric acid, producing a slurry of calcium sulfate hemihydrate in a solution of phosphoric acid. The slurry is filtered and the calcium sulfate hemihydrate filter cake is discarded. The filtered acid is evaporated to about 48% P2O5 for further purification.
Reaction SMILES: C(O[C:4](=[O:15])[CH:5](P(OCC)(OCC)=O)[F:6])C.C([Li])CCC.[NH2:21][C:22]1[C:27]([CH:28]=O)=[CH:26][N:25]=[C:24]([S:30][CH3:31])[N:23]=1.[Cl-].[NH4+]>O1CCCC1.O>[F:6][C:5]1[C:4](=[O:15])[NH:21][C:22]2[N:23]=[C:24]([S:30][CH3:31])[N:25]=[CH:26][C:27]=2[CH:28]=1
Reactant: CCOC(=O)C(F)P(=O)(OCC)OCC
Reactant: CSc1ncc(C=O)c(N)n1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Product: CSc1ncc2cc(F)c(=O)[nH]c2n1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 92.1 %

Procedure:
A solution of 1.74 g (10.33 mmol) of (diethoxy-phosphoryl)-fluoro-acetic acid ethyl ester in 20 mL of tetrahydrofuran is cooled to −78° C. and treated dropwise with 12.9 mL (20.65 mmol) of a 1.6 M solution of n-butyl lithium in hexanes. After stirring for 30 minutes at −78° C. the solution is treated with 1.74 g (10.33 mmol) of 4-amino-2-methylsulfanyl-pyrimidine-5-carboxaldehyde (Example 3), allowed to warm to room temperature, and stirred overnight. The reaction is treated with saturated aqueous ammonium chloride, then water. The solid is collected by filtration and washed with diethyl ether to give 2.01 g (92%) of the product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]([C:7]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=2)=O)=[CH:5][CH:4]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:30])=CC=1>ClC1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]([C:7]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=2)=[S:30])=[CH:5][CH:4]=1
Reactant: COc1ccc(C(=O)Nc2ccc([N+](=O)[O-])cc2)cc1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Clc1ccccc1
Product: COc1ccc(C(=S)Nc2ccc([N+](=O)[O-])cc2)cc1
Yield: 129.3 %

Procedure:
A mixture of 4-methoxy-4′-nitrothiobenzaniline 3 (1.0 g, 3.7 mmol) and Lawesson's reagent (0.89 g, 2.2 mmol, 0.6 equiv.) in chlorobenzene (15 mL) was heated to reflux for 4 hrs. The solvent was evaporated and the residue was purified with flush column (hexane:ethyl acetate=4:1) to give 820 mg (77.4%) of the product 4 as orange color solid. 1HNMR (300 MHz, DMSO-d6) δ: 8.29 (d, 2H, H-3′,5′), 8.00 (d, J=8.5 Hz, 2H, H-2′,6′), 7.76 (d, 2H), 7.03 (d, J=8.4 Hz, 2H), 3.808.37 (d, J=5.5 Hz, 2H, H-3′,5′), 8.17 (d, J=6.3 Hz, 2H, H-2′,6′), 7.48 (d, J=6.6 Hz, 2H), 6.97 (d, J=6.5 Hz, 2H), 3.75 (s, 3H, MeO). (s, 3H, MeO).
Reaction SMILES: [F:1][C:2]([F:8])([F:7])[S:3](Cl)(=[O:5])=[O:4].[Cl:9][C:10]1[C:18]([Cl:19])=[C:17]2[C:13]([CH2:14][C:15]([CH3:27])([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:16]2=[O:20])=[CH:12][C:11]=1CC(O)=O.CC(C)=[O:34]>>[Cl:9][C:10]1[C:18]([Cl:19])=[C:17]2[C:13]([CH2:14][C:15]([CH3:27])([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:16]2=[O:20])=[CH:12][C:11]=1[O:4][S:3]([C:2]([F:8])([F:7])[F:1])(=[O:34])=[O:5]
Reactant: CC1(c2ccccc2)Cc2cc(CC(=O)O)c(Cl)c(Cl)c2C1=O
Reactant: CC(C)=O
Reactant: O=S(=O)(Cl)C(F)(F)F
Product: CC1(c2ccccc2)Cc2cc(OS(=O)(=O)C(F)(F)F)c(Cl)c(Cl)c2C1=O
Reaction time: 0.25 h

Procedure:
After ten minutes a solution of trifluoromethanesulfonyl chloride (11.84 g., 0.07 mole) in acetone (150 ml.) is added over 10 minutes. After 15 minutes of stirring the precipitated salts are filtered and the acetone is evaporated at reduced pressure to leave an oil which upon trituration with hexane gives 15 g. of (6,7-dichloro-1-oxo-2-methyl-2-phenyl-5-indanyl)acetic acid which melts at 105°-107° C.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][CH:5]=[C:6]([Cl:9])[C:7]=1Cl.[NH4+:10].[OH-]>CCO>[Cl:1][C:2]1[N:3]=[N:4][CH:5]=[C:6]([Cl:9])[C:7]=1[NH2:10]
Reactant: Clc1cnnc(Cl)c1Cl
Reactant: [NH4+]
Agent: [OH-]
Solvent: CCO
Product: Nc1c(Cl)cnnc1Cl
Temperature: 120 °C
Yield: 36 %

Procedure:
A mixture of 3,4,5-trichloropyridazine (Preparation 3, 500 mg, 2.73 mmole) in EtOH (5.5 mL) and NH4OH (5.5 mL) was heated under microwave irradiation 120° C. for 25 minutes. Concentration under reduced pressure and purification via silica gel column chromatography eluting with acetone:dichloromethane (0-15% acetone), provided the title product in 36% yield, 163 mg.
Reaction SMILES: [CH:1]1([C@@:6]([OH:16])([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:7]([OH:9])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[N:17]1(C(OC(C)(C)C)=O)[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1.CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>C(Cl)Cl>[CH:1]1([C@@:6]([OH:16])([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:7]([N:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=C(O)[C@](O)(c1ccccc1)C1CCCC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(N1CCNCC1)[C@](O)(c1ccccc1)C1CCCC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 68.7 %

Procedure:
To a stirred solution of (R)-cyclopentylhydroxyphenyl acetic acid (10.0 g, 45.4 mmol) in DCM (200 mL) was added t-butyl 1-piperazinecarboxylate (8.5 g, 45.4 mmol). Into the reaction was added DIPEA (23.7 mL, 13.6 mmol), HOBt (10.4 g, 68.1 mmol), and then EDCI (10.4 g, 54.5 mmol). The mixture was stirred at room temperature for 12 hours. The mixture was then washed with 1N NaOH (300 mL), 1N HCl (300 mL) then saturated aqueous NaCl (300 mL). The organic layer was then removed, dried over MgSO4 and then filtered. The solvent was removed under reduced pressure. A solution of 20% TFA/DCM was added to the crude material, and the resulting mixture was stirred for 2 hours at room temperature. The solvent was removed under reduced pressure. DCM (300 mL) was added and the mixture was washed with saturated sodium bicarbonate (300 mL). The organic layer was then removed, dried over MgSO4 and filtered. The crude material was purified via silica gel chromatography (10% MeOH/DCM w/1% NH3 (aq)) to afford the title compound as a white powder (9.0 g, 31.2 mmol).
Reaction SMILES: Cl.Cl.Cl.[N:4]1[CH:9]=[CH:8][C:7]([CH2:10][C@H:11]([C:13]([N:15]2[CH2:20][CH2:19][CH:18]([CH:21]3[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]3)[CH2:17][CH2:16]2)=[O:14])[NH2:12])=[CH:6][CH:5]=1.[NH:28]1[C:36]2[C:31](=[CH:32][CH:33]=[C:34]([C:37](O)=[O:38])[CH:35]=2)[CH:30]=[CH:29]1>>[NH:28]1[C:36]2[C:31](=[CH:32][CH:33]=[C:34]([C:37]([NH:12][C@@H:11]([C:13]([N:15]3[CH2:16][CH2:17][CH:18]([CH:21]4[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]4)[CH2:19][CH2:20]3)=[O:14])[CH2:10][C:7]3[CH:6]=[CH:5][N:4]=[CH:9][CH:8]=3)=[O:38])[CH:35]=2)[CH:30]=[CH:29]1
Reactant: CN1CCC(C2CCN(C(=O)[C@H](N)Cc3ccncc3)CC2)CC1
Reactant: O=C(O)c1ccc2cc[nH]c2c1
Agent: Cl
Product: CN1CCC(C2CCN(C(=O)[C@@H](Cc3ccncc3)NC(=O)c3ccc4cc[nH]c4c3)CC2)CC1

Procedure:
Using methods substantially equivalent to those described in Method D-1, the titled compound was prepared from 1-[β-(4-pyridinyl)-D-alanyl]-4-(1-methylpiperidin-4-yl)piperidine trihydrochloride and indole-6-carboxylic acid (23%).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:13]([CH2:14][CH:15]([CH3:17])[CH3:16])[CH2:12][CH2:11][CH2:10][CH2:9][C:8]([C:18]([O:20][CH3:21])=[O:19])=[CH:7][C:6]=2[CH:22]=1.[CH2:23]([O:27][CH2:28][CH2:29][O:30][C:31]1[CH:36]=[CH:35][C:34](OB(O)O)=[CH:33][CH:32]=1)[CH2:24][CH2:25][CH3:26].C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.C(O)C.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:23]([O:27][CH2:28][CH2:29][O:30][C:31]1[CH:32]=[CH:33][C:34]([C:2]2[CH:3]=[CH:4][C:5]3[N:13]([CH2:14][CH:15]([CH3:17])[CH3:16])[CH2:12][CH2:11][CH2:10][CH2:9][C:8]([C:18]([O:20][CH3:21])=[O:19])=[CH:7][C:6]=3[CH:22]=2)=[CH:35][CH:36]=1)[CH2:24][CH2:25][CH3:26]
Reactant: COC(=O)C1=Cc2cc(Br)ccc2N(CC(C)C)CCCC1
Reactant: CCCCOCCOc1ccc(OB(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: O
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCCCN3CC(C)C)cc1
Reaction time: 1 h
Yield: 98.2 %

Procedure:
A suspension of methyl 9-bromo-1-isobutyl-2,3,4,5-tetrahydro-1H-1-benzoazonin-6-carboxylate (2.1 g) and 4-(2-butoxyethoxy)phenyl boric acid (1.77 g) and potassium carbonate (2.06 g) in toluene (25 ml), ethanol (2.5 ml) and water (2.5 ml) was stirred under argon atmosphere for 1 hour, and then tetrakis(triphenylphosphine)palladium (332 mg) was added. The mixture was refluxed for 5 hours. After returning to room temperature, water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried with magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=19:1→hexane:ethyl acetate=9:1) to give methyl 9-(4-(2-butoxyethoxy)phenyl)-1-isobutyl-2,3,4,5-tetrahydro-1H-1-benzoazonin-6-carboxylate (2.7 g) as a yellow oily material.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[N:11]=[C:10](O)[N:9]=[CH:8]2.O=P(Cl)(Cl)[Cl:16]>>[Cl:16][C:10]1[N:9]=[CH:8][C:7]2[C:12](=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][CH:6]=2)[N:11]=1
Reactant: COc1cccc2cnc(O)nc12
Reactant: O=P(Cl)(Cl)Cl
Product: COc1cccc2cnc(Cl)nc12
Temperature: 142.5 °C
Reaction time: 0.02 h
Yield: 89 %

Procedure:
Neat POCl3 (400 mL) was added to 8-methoxyquinazolin-2-ol (5.0 g, 28.4 mmole) with stirring and cooling over an ice bath under argon. After ca. 1 minute, the reaction was removed from the ice bath and stirred at RT for ca. 20 minutes until a fine yellow suspension was formed. The reaction, fitted with a reflux condenser, was heated in an oil bath at 140-145° C. After about 1 hour, the reaction turned clear and colorless. LCMS showed that the reaction was complete. The POCl3 was evaporated under reduced pressure, and dried in vacuo. After 12 hours, the residue was partitioned between EtOAc (300 mL) and sat. NaHCO3 (200 mL). The mixture was stirred cautiously watching gas evolution until the pH reached ˜8. The layers were separated and the organic layer was washed with NaHCO3 (2×100 mL), water with 5% brine (2×100 mL), brine (100 mL), dried (Na2SO4), filtered and evaporated to a yellow solid. The crude product was purified by flash chromatography eluting with 50% EtOAc/Hexane and finishing with 100% EtOAc to produce a white solid after evaporating the correct fractions. The pure 2-chloro-8-methoxyquinazoline was isolated in 89% yield (4.9 g, 25.3 mmole).
Reaction SMILES: C(O[C:4]([C:6]1[C:7](=[O:39])[C:8]2[CH:13]=[N:12][C:11]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([N:21]4[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]4)=[CH:17][CH:16]=3)=[N:10][C:9]=2[N:28]([C:30]2[CH:31]=[C:32]3[C:36](=[CH:37][CH:38]=2)[CH2:35][CH2:34][CH2:33]3)[CH:29]=1)=[O:5])C.[CH3:40][NH2:41]>CO>[CH3:40][NH:41][C:4]([C:6]1[C:7](=[O:39])[C:8]2[CH:13]=[N:12][C:11]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([N:21]4[CH2:22][CH2:23][N:24]([CH3:27])[CH2:25][CH2:26]4)=[CH:17][CH:16]=3)=[N:10][C:9]=2[N:28]([C:30]2[CH:31]=[C:32]3[C:36](=[CH:37][CH:38]=2)[CH2:35][CH2:34][CH2:33]3)[CH:29]=1)=[O:5]
Reactant: CN
Reactant: CCOC(=O)c1cn(-c2ccc3c(c2)CCC3)c2nc(Nc3ccc(N4CCN(C)CC4)cc3)ncc2c1=O
Solvent: CO
Product: CNC(=O)c1cn(-c2ccc3c(c2)CCC3)c2nc(Nc3ccc(N4CCN(C)CC4)cc3)ncc2c1=O
Temperature: 70 °C
Reaction time: 0.5 h

Procedure:
To a solution of 8-indan-5-yl-2-[4-(4-methyl-piperazine-1-yl)-phenylamino]-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester Cpd 1 (Example 1(g), 5 mg) in 1 mL of methanol was added 1 mL of methylamine (40 wt. % in water). The solution was stirred at 70° C. for 30 minutes. The solvent was evaporated and the product was purified by preparative HPLC. 1.7 mg of 8-indan-5-yl-2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid methylamide
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:17][C:18]([C:20]2[N:21]=[C:22]([CH3:25])[S:23][CH:24]=2)=[O:19])[C:5]2[C:9]([CH:10]=1)=[N:8][N:7](C1CCCCO1)[CH:6]=2.P([O-])([O-])([O-])=O.[K+].[K+].[K+].CC1(C)C(C)(C)OB([C:42]2[CH:50]=[CH:49][CH:48]=[C:47]3[C:43]=2[CH:44]=[N:45][NH:46]3)O1.O1CCOCC1>CO.O>[NH:46]1[C:47]2[CH:48]=[CH:49][CH:50]=[C:42]([C:2]3[CH:10]=[C:9]4[C:5]([CH:6]=[N:7][NH:8]4)=[C:4]([NH:17][C:18]([C:20]4[N:21]=[C:22]([CH3:25])[S:23][CH:24]=4)=[O:19])[CH:3]=3)[C:43]=2[CH:44]=[N:45]1
Reactant: CC1(C)OB(c2cccc3[nH]ncc23)OC1(C)C
Reactant: Cc1nc(C(=O)Nc2cc(Br)cc3nn(C4CCCCO4)cc23)cs1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: CO
Solvent: O
Product: Cc1nc(C(=O)Nc2cc(-c3cccc4[nH]ncc34)cc3[nH]ncc23)cs1
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
A microwave vial was charged with N-[6-bromo-2-(tetrahydro-2H-pyran-2-yl)-2H-indazol-4-yl]-2-methyl-1,3-thiazole-4-carboxamide (50 mg), Solvias catalyst (7 mg), tripotassium phosphate (101 mg), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole (available from J&W Pharmlab, 29 mg), 1,4-dioxane (0.5 ml) and water (0.1 ml). The reaction was heated under microwave irradiation for a total of 60 min at 80° C., then 30 min at 120° C. The reaction was passed through a silica cartridge preconditioned with methanol, washing with methanol, then dried in vacuo. The residue was subjected to a DCM/water wash, dried through a hydrophobic frit and dried in vacuo. The residue was dissolved in DMSO:methanol (1 ml, 1:1, v/v) and purified by MDAP (Method D). Appropriate fractions were evaporated under a stream of nitrogen. The residue was dissolved in methanol and a few drops of 2M HCl (aq) were added and the reaction was stirred for 30 min. The reaction was diluted with methanol and passed through an aminopropyl cartridge, pre-conditioned with methanol, washing with methanol, then dried to give title compound, 11 mg.
Reaction SMILES: [CH3:1][C:2]1[C@@H:19]([O:20][C:21]([C@H:23]([OH:39])[C@@H:24]([NH:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)=[O:22])[CH2:18][C@:14]2([OH:40])[C:15]([CH3:17])([CH3:16])[C:3]=1[C@@H:4]([OH:58])[C:5]([C@@:7]1([CH3:57])[C@H:12]([C@@H:13]2[O:41][C:42]([C:44]2[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=2)=[O:43])[C@:11]2([O:52][C:53]([CH3:55])=[O:54])[CH2:50][O:51][C@@H:10]2[CH2:9][C@@H:8]1[OH:56])=[O:6].C1CCCCC1.O.C(OCC)(=[O:68])C.S([O-])([O-])(=O)=[O:73].[Al+3].[K+].S([O-])([O-])(=O)=[O:80]>C(O)C>[CH3:1][C:2]1[C@@H:19]([O:20][C:21]([C@H:23]([OH:39])[C@@H:24]([NH:31][C:32]([O:34][C:35]([CH3:36])([CH3:37])[CH3:38])=[O:33])[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:22])[CH2:18][C@@:14]2([OH:40])[C:15]([CH3:16])([CH3:17])[C:3]=1[C@@H:4]([OH:58])[C:5]([C@@:7]1([CH3:57])[C@H:12]([C@@H:13]2[O:41][C:42]([C:44]2[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=2)=[O:43])[C@:11]2([O:52][C:53]([CH3:55])=[O:54])[CH2:50][O:51][C@@H:10]2[CH2:9][C@@H:8]1[OH:56])=[O:6].[OH2:68].[OH2:73].[OH2:80]
Reactant: CCOC(C)=O
Reactant: CC(=O)O[C@@]12CO[C@@H]1C[C@H](O)[C@@]1(C)C(=O)[C@H](O)C3=C(C)[C@@H](OC(=O)[C@H](O)[C@@H](NC(=O)OC(C)(C)C)c4ccccc4)C[C@@](O)([C@@H](OC(=O)c4ccccc4)[C@H]21)C3(C)C
Reactant: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [K+]
Solvent: CCO
Solvent: C1CCCCC1
Solvent: O
Product: CC(=O)O[C@@]12CO[C@@H]1C[C@H](O)[C@@]1(C)C(=O)[C@H](O)C3=C(C)[C@@H](OC(=O)[C@H](O)[C@@H](NC(=O)OC(C)(C)C)c4ccccc4)C[C@](O)([C@@H](OC(=O)c4ccccc4)[C@H]21)C3(C)C
Temperature: 7.5 °C
Reaction time: 0.46 h
Yield: 70 %

Procedure:
Crude docetaxel (1.0 g) was dissolved in a mixture of ethanol:cyclohexane:demineralised water:ethyl acetate (20:2:10:0.8) containing 0.02 g potassium aluminum sulfate at 25-30° C. under constant stirring. The clear biphasic reaction was then concentrated to 20 ml and cooled to 5-10° C. The precipitated solid was stirred for 25-30 minutes at 5-10° C., then filtered, washed with demineralised water (1 ml) and dried under vacuum under a humid atmosphere (until the moisture content was between 5-7% by Karl Fischer method) to afford Docetaxel trihydrate in 70-90% yield.
Reaction SMILES: [CH:1]1([C:4]2[N:22]=[C:7]3[C:8]([O:20][CH3:21])=[CH:9][CH:10]=[C:11]([C:12](=O)[CH:13]([CH3:18])[CH2:14][C:15](O)=[O:16])[N:6]3[N:5]=2)[CH2:3][CH2:2]1.CC(O)=O.[NH2:27][NH2:28]>CCO>[CH:1]1([C:4]2[N:22]=[C:7]3[C:8]([O:20][CH3:21])=[CH:9][CH:10]=[C:11]([C:12]4[CH:13]([CH3:18])[CH2:14][C:15](=[O:16])[NH:27][N:28]=4)[N:6]3[N:5]=2)[CH2:3][CH2:2]1
Reactant: NN
Reactant: COc1ccc(C(=O)C(C)CC(=O)O)n2nc(C3CC3)nc12
Solvent: CC(=O)O
Solvent: CCO
Product: COc1ccc(C2=NNC(=O)CC2C)n2nc(C3CC3)nc12

Procedure:
Under an argon atmosphere 4-(2-Cyclopropyl-8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-5-yl)-3-methyl-4-oxo-butyric acid (0.1 g, ca. 0.33 mmol) was dissolved in EtOH (1.5 mL). AcOH (0.11 mL, 1.98 mmol) and NH2NH2*H2O (0.048 mL, 0.99 mmol) were added. The solution was heated at reflux for 17 h after which it was concentrated in vacuo and co-concentrated with toluene. Aq. NaHCO3 was added and the aqueous phase was extracted with ÉtOAc (×2). The combined organic phases were dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by flash chromatography using EtOAc as the eluent to afford the title compound as a solid.
Reaction SMILES: [CH2:1]([CH:8]1[NH:13][CH2:12][CH2:11][N:10]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[C:25]([CH3:27])[CH:24]=[CH:23][C:22]=3[Cl:28])=[CH:17][CH:16]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4]C=1.[CH:29](N(CC)C(C)C)(C)C.IC>C(#N)C.ClCCl>[CH3:29][N:13]1[CH2:12][CH2:11][N:10]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[C:25]([CH3:27])[CH:24]=[CH:23][C:22]=3[Cl:28])=[CH:17][CH:16]=2)[CH2:9][CH:8]1[C:1]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:2]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: Cc1ccc(Cl)c(-c2ccc(CN3CCNC(Cc4ccccc4)C3)cc2)c1
Solvent: CI
Solvent: CC#N
Solvent: ClCCl
Product: Cc1ccc(Cl)c(-c2ccc(CN3CCN(C)C(c4ccccc4)C3)cc2)c1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
This compound could be made the following manner: 100 mg of 3-benzyl-1-(2′-chloro-5′-methyl-biphenyl-4-ylmethyl)-piperazine would be dissolved in acetonitrile, 3 equiv. of N,N-diisopropylethylamine would be added followed by 1.1 equiv. of iodomethane. The reaction would be stirred at 80° C. overnight. The reaction would be diluted with dichloromethane and washed with 1N aqueous NaOH solution. The organic layer would be dried over Na2SO4, filtered and concentrated in vacuo. The crude residue would be purified by column chromatography to afford 1-methyl-2-phenyl-4-(2′-chloro-5′-methyl-biphenyl-4-ylmethyl)-piperazine.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][N:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[C:7]([C:12]([O:14]CC)=[O:13])[C:6]2=[O:17].C(OC([NH:25][CH:26]1[CH2:30][CH2:29][NH:28][CH2:27]1)=O)(C)(C)C>N1C=CC=CC=1>[ClH:1].[NH2:25][CH:26]1[CH2:30][CH2:29][N:28]([C:2]2[CH:3]=[CH:4][N:5]3[C:10]([CH:11]=2)=[CH:9][CH:8]=[C:7]([C:12]([OH:14])=[O:13])[C:6]3=[O:17])[CH2:27]1
Reactant: CC(C)(C)OC(=O)NC1CCNC1
Reactant: CCOC(=O)c1ccc2cc(Cl)ccn2c1=O
Solvent: c1ccncc1
Product: Cl
Product: NC1CCN(c2ccn3c(=O)c(C(=O)O)ccc3c2)C1
Temperature: 70 °C
Yield: 72.3 %

Procedure:
Ethyl 8-chloro-4H-quinolizin-4-one-3-carboxylate (1.0 g, 3.97 mmol), from Step 3, was dissolved in 20 mL of dry pyridine under a nitrogen atmosphere. To the resultant solution was added a solution of 1.85 g (9.92 mmol) of 3-(N-t-butoxycarbonylamino)pyrrolidine in 5 mL of dry pyridine and the reaction mixture was heated at 70° C. for 4.5 hours. The reaction mixture was then concentrated in vacuo in order to remove all of the pyridine. The dry residue (3.124 g) was purified by chromatography on silica gel eluted with 2% methanol in methylene chloride to afford 0.889 g (56% yield) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[N:5][C:6](Cl)=[CH:7][CH:8]=2)[N:3]=1.[CH3:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[C:15]=1[OH:21].[OH-].[K+]>>[NH2:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[N:5][C:6]([O:21][C:15]3[C:16]([CH3:20])=[CH:17][CH:18]=[CH:19][C:14]=3[CH3:13])=[CH:7][CH:8]=2)[N:3]=1
Reactant: Nc1ccc2ccc(Cl)nc2n1
Reactant: Cc1cccc(C)c1O
Agent: [K+]
Agent: [OH-]
Product: Cc1cccc(C)c1Oc1ccc2ccc(N)nc2n1
Yield: 80 %

Procedure:
The procedure is similar to that described in Example 4, but starting with 2-amino-7-chloro-1,8-naphthyridine (17.95 g), 2,6-dimethylphenol (48.6 g) and potassium hydroxide pellets (13.2 g; 85% purity). After treatment with caustic soda and washing, the product produced (24.8 g; m.p. 204° C.) is purified by chromatography on a column 45 mm in diameter containing silica (360 g; 0.040-0.063 mm), eluting with pure methylene chloride and collecting 100-cc fractions. After concentration to dryness of fractions 1 to 48 at 40° C. under reduced pressure (4 kPa), 2-amino-7-(2,6-dimethylphenoxy)-1,8 naphthyridine (21.2 g) is produced, m.p. 218° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[NH:9][C:10]([C:12]1[CH:17]=[CH:16][C:15]([CH:18]([CH3:22])[C:19]([OH:21])=[O:20])=[CH:14][CH:13]=1)=[O:11].[CH2:23](O)[CH:24]([CH3:26])[CH3:25].O>O1CCCC1>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[NH:9][C:10]([C:12]1[CH:17]=[CH:16][C:15]([CH:18]([CH3:22])[C:19]([O:21][CH2:23][CH:24]([CH3:26])[CH3:25])=[O:20])=[CH:14][CH:13]=1)=[O:11]
Reactant: CC(C(=O)O)c1ccc(C(=O)Nc2cccc(Cl)c2Cl)cc1
Reactant: CC(C)CO
Solvent: C1CCOC1
Solvent: O
Product: CC(C)COC(=O)C(C)c1ccc(C(=O)Nc2cccc(Cl)c2Cl)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 80 %

Procedure:
3.38 g of 2-[4 (2,3-dichlorophenylcarbamoyl)-phenyl]-propionic acid was dissolved in 30 ml of anhydrous tetrahydrofuran. While cooling the solution with ice water, 2.43 g of N,N'-carbonyldiimidazole was added thereto, and the mixture was stirred for 30 minutes. Thereafter, 0.74 g of isobutyl alcohol was added thereto. The mixture was returned to room temperature and stirred for 5 hours. After completion of the reaction, the reaction solution was poured into 300 ml of water, and the resulting crystals were collected by filtration, washed with water and dried, and then recrystallized from toluene-hexane to obtain 3.15 g of desired isobutyl 2-[4-(2,3-dichloropheylcarbamoyl)-phenyl]-propionate. The yield was 80%, and the melting point of this compound was from 70° to 72° C.
Reaction SMILES: Br[C:2]1[CH:35]=[CH:34][C:5]([CH2:6][C:7]2[N:8]([C:20]3[CH:25]=[CH:24][C:23]([N:26]4[S:30](=[O:32])(=[O:31])[NH:29][C:28](=[O:33])[CH2:27]4)=[CH:22][CH:21]=3)[CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=3[Cl:19])[N:11]=2)=[CH:4][CH:3]=1.[Cl:36][C:37]1[CH:42]=[CH:41][C:40](B(O)O)=[CH:39][N:38]=1>>[Cl:36][C:37]1[N:38]=[CH:39][C:40]([C:2]2[CH:35]=[CH:34][C:5]([CH2:6][C:7]3[N:8]([C:20]4[CH:25]=[CH:24][C:23]([N:26]5[S:30](=[O:32])(=[O:31])[NH:29][C:28](=[O:33])[CH2:27]5)=[CH:22][CH:21]=4)[CH:9]=[C:10]([C:12]4[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=4[Cl:19])[N:11]=3)=[CH:4][CH:3]=2)=[CH:41][CH:42]=1
Reactant: OB(O)c1ccc(Cl)nc1
Reactant: O=C1CN(c2ccc(-n3cc(-c4ccc(Cl)cc4Cl)nc3Cc3ccc(Br)cc3)cc2)S(=O)(=O)N1
Product: O=C1CN(c2ccc(-n3cc(-c4ccc(Cl)cc4Cl)nc3Cc3ccc(-c4ccc(Cl)nc4)cc3)cc2)S(=O)(=O)N1

Procedure:
5-{-4-[2-(4-Bromo-benzyl)-4-(2,4-dichloro-phenyl)-imidazol-1-yl]-phenyl}-1,2,5-thiadiazolidine-3-one-1,1-dioxide (592 mg, 1 mmol) was treated as described in general procedure G using 2-chloro-5-pyridine-boronic acid (315 mg, 2 mmol) to give 5-{-4-[2-[4-(6-chloro-pyridin-3-yl)-benzyl]-4-(2,4-dichloro-phenyl)-imidazol-1-yl]-phenyl}-1,2,5-thiadiazolidine-3-one-1,1-dioxide.