Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([C:4]1[C:9]([O:10][CH3:11])=[CH:8][C:7]([O:12][CH3:13])=[CH:6][C:5]=1[OH:14])=[O:3].O1CCOCC1.[H-].[Na+].C(O)(=O)C.C([O:29][C:30](=O)[C:31]([CH3:35])([CH3:34])[C:32]#[N:33])C>>[CH3:34][C:31]([CH3:35])([C:30](=[O:29])[CH2:1][C:2](=[O:3])[C:4]1[C:9]([O:10][CH3:11])=[CH:8][C:7]([O:12][CH3:13])=[CH:6][C:5]=1[OH:14])[C:32]#[N:33]
Reactant: COc1cc(O)c(C(C)=O)c(OC)c1
Reactant: CCOC(=O)C(C)(C)C#N
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CC(=O)O
Product: COc1cc(O)c(C(=O)CC(=O)C(C)(C)C#N)c(OC)c1
Temperature: 0 °C

Procedure:
A mixture of 73.5 g of 2-hydroxy-4,6-dimethoxyacetophenone, 260 g of dimethylcyanoacetic acid ethyl ester and 375 ml of absolute dioxane is introduced into a suspension of 28.6 g of NaH in 7.3 g of dimethylcyanoacetic acid ethyl ester at 0°-10°, while stirring. The mixture is heated for 1 hour at 80°, cooled and poured into acetic acid and the resulting solution is stirred into ice water to give 2,2-dimethyl-3,5-dioxo-5-(2-hydroxy-4,6-dimethoxyphenyl)-pentanonitrile; m.p. 112°-113°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[N:5]=[CH:4][N:3]=1.[F:9][C:10]([F:21])([F:20])[C:11]1[CH:16]=[CH:15][C:14](B(O)O)=[CH:13][CH:12]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].N#N>C(COC)OC.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>[Cl:1][C:2]1[CH:7]=[C:6]([C:14]2[CH:15]=[CH:16][C:11]([C:10]([F:21])([F:20])[F:9])=[CH:12][CH:13]=2)[N:5]=[CH:4][N:3]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: N#N
Agent: O=P([O-])([O-])[O-]
Solvent: COCCOC
Solvent: O
Product: FC(F)(F)c1ccc(-c2cc(Cl)ncn2)cc1
Temperature: 90 °C
Yield: 47.9 %

Procedure:
In a screw top flask, 4,6-dichloropyrimidine (3.1 g, 21 mmol), 4-trifluoromethyl-phenyl boronic acid (3.9 g, 21 mmol) and potassium phosphate (8.8 g, 42 mmol) were combined in dimethoxyethane (60 mL) and water (12 mL). The flask was flushed with N2 and tetrakis(triphenylphosphine)palladium (1.2 g, 1.0 mmol) was added. The flask was sealed and heated to 90° C. for 12 hours. The reaction mixture was cooled to rt and H2O (50 mL) was added and resulting mixture was extracted with EtOAc (3×50 mL). The organic phases were combined, washed with brine (50 mL), dried with Na2SO4, filtered, and concentrated. The resulting residue was purified by flash column chromatography using ethyl acetate-hexanes (0%-20%) to provide a clear oil (2.6 g, 48%). MS (ESI): mass calcd. for C11H6ClF3N2, 258.0; m/z found 259.1 [M+H]+.
Reaction SMILES: [C:1]([C:3]1[C:11]2[C:6](=[N:7][C:8]([CH3:13])=[CH:9][C:10]=2[CH3:12])[N:5]([CH:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:17][CH2:16][CH2:15]2)[C:4]=1/[CH:24]=[CH:25]/[C:26]([O:28]CC)=[O:27])#[N:2].C1(C)C=CC=CC=1.[OH-].[Na+].Cl>O1CCCC1.O>[C:1]([C:3]1[C:11]2[C:6](=[N:7][C:8]([CH3:13])=[CH:9][C:10]=2[CH3:12])[N:5]([CH:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:17][CH2:16][CH2:15]2)[C:4]=1/[CH:24]=[CH:25]/[C:26]([OH:28])=[O:27])#[N:2]
Reactant: CCOC(=O)/C=C/c1c(C#N)c2c(C)cc(C)nc2n1C1CCCc2ccccc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1cc(C)c2c(C#N)c(/C=C/C(=O)O)n(C3CCCc4ccccc43)c2n1
Temperature: 50 °C
Reaction time: 0.33 h
Yield: 89.7 %

Procedure:
A solution of ethyl (E)-3-[3-cyano-4,6-dimethyl-1-(1,2,3,4-tetrahydro-1-naphthalenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl]-2-propenoate (1.2 g, 3 mmol) in tetrahydrofuran (6 ml)-toluene (6 ml) was heated to 50° C. To the resultant solution was added a 2 N aqueous sodium hydroxide solution (4 ml, 8 mmol) and the mixture was stirred at 50° C. for 20 minutes. Then, water (100 ml) was added to the reaction mixture, which was adjusted to pH 3 to 4 with 12 N hydrochloric acid, and then the product was extracted using ethyl acetate-tetrahydrofuran (3:1, v/v). The organic extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was removed under vacuum. Hexane was added to the residue on a solid material and the residue was finely crushed using a spatula. The solid was collected by filtration using Kiriyama Roht and was washed with hexane to give the title compound (yield (amount) 1.0 g, yield (rate) 92%).
Reaction SMILES: [Br-].[Li+].[BH4-].[Na+].[C:5]([O:9][C:10]([C@@H:12]1[CH2:16][S:15][C@@H:14]([C:17](OCC)=[O:18])[CH2:13]1)=[O:11])([CH3:8])([CH3:7])[CH3:6].[Cl-].[NH4+].[Cl-].[Na+]>C(O)C>[C:5]([O:9][C:10]([C@@H:12]1[CH2:16][S:15][C@@H:14]([CH2:17][OH:18])[CH2:13]1)=[O:11])([CH3:8])([CH3:7])[CH3:6]
Reactant: CCOC(=O)[C@H]1C[C@H](C(=O)OC(C)(C)C)CS1
Agent: [BH4-]
Agent: [Br-]
Agent: [Cl-]
Solvent: CCO
Product: CC(C)(C)OC(=O)[C@@H]1CS[C@@H](CO)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99 %

Procedure:
Lithium bromide (686 mg) and sodium borohydride (165 mg) were dissolved in ethanol (6 ml) and under nitrogen atmosphere the mixture was stirred for 1 hour at room temperature. To the mixture, trans-4-tert-butoxycarbonyl-2-ethoxycarbonyltetrahydrothiophene (ref. compound No. 1, 567 mg) dissolved in ethanol (2 ml) was added at room temperature and the mixture was stirred for 18 hours. Aqueous ammonium chloride solution and saturated sodium chloride solution were added to the mixture and extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate and concentrated in vacuo. The oily residue was purified by a silica gel column chromatography to give 436 mg (99%) of the titled compound (compound No. 1-1).
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][NH:11][C:12]1[C:13]([C:31]([OH:33])=[O:32])=[N:14][N:15]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[Cl:30])[C:16]=1[C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=1)=O)(C)(C)C.Cl.CCO>>[NH2:8][CH2:9][CH2:10][NH:11][C:12]1[C:13]([C:31]([OH:33])=[O:32])=[N:14][N:15]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[Cl:30])[C:16]=1[C:17]1[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=1
Reactant: CC(C)(C)OC(=O)NCCNc1c(C(=O)O)nn(-c2ccccc2Cl)c1-c1ccc(Cl)cc1
Agent: Cl
Solvent: CCO
Product: NCCNc1c(C(=O)O)nn(-c2ccccc2Cl)c1-c1ccc(Cl)cc1
Reaction time: 17 h

Procedure:
A solution of 4-(2-tert-butoxycarbonylaminoethylamino)-1-(2-chlorophenyl)-5-(4-chlorophenyl)-1H-pyrazole-3-carboxylic acid (I-4c, 879 mg) in 2:1 conc HCl/EtOH (12 ml) was allowed to stand at room temperature for 17 hours. The reaction mixture was concentrated under vacuum to give the desired product I-4d: +ES MS (M+1) 391.4.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:10][C:11]3[CH:26]=[C:25]([O:27][CH3:28])[CH:24]=[CH:23][C:12]=3[C:13]=2[C:14](=[O:22])[C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=2)=[CH:5][CH:4]=1.[CH:29]([N:32]([CH2:36][CH2:37]Cl)[CH:33]([CH3:35])[CH3:34])([CH3:31])[CH3:30].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:10][C:11]3[CH:26]=[C:25]([O:27][CH3:28])[CH:24]=[CH:23][C:12]=3[C:13]=2[C:14](=[O:22])[C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:37][CH2:36][N:32]([CH:33]([CH3:35])[CH3:34])[CH:29]([CH3:31])[CH3:30])=[CH:17][CH:16]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(-c2oc3cc(OC)ccc3c2C(=O)c2ccc(O)cc2)cc1
Reactant: CC(C)N(CCCl)C(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(-c2oc3cc(OC)ccc3c2C(=O)c2ccc(OCCN(C(C)C)C(C)C)cc2)cc1
Temperature: 100 °C

Procedure:
The title compound was prepared by reacting the compound of Preparation 4a supra, 2-(4-methoxyphenyl)-3-(4-hydroxybenzoyl)-6-methoxybenzofuran (10 g, 26.7 mmol) which is dissolved in 200 ml of N,N-dimethylformamide with 2-(N,N-diisopropylamino)ethyl chloride (6.4 g, 32 mmol) and potassium carbonate (11.06 g, 80.2 mmol). The mixture was heated to 100° C. and was maintained at that temperature for about two hours. The reaction mixture was then cooled to room temperature and maintained at this temperature overnight while stirring.
Reaction SMILES: C(=O)(O)[O-].[K+].[CH3:6][O:7][C:8]1[CH:20]=[CH:19][C:11]([O:12][CH2:13][CH:14]2[NH:18][CH2:17][CH2:16][S:15]2)=[CH:10][CH:9]=1.[Cl:21][CH2:22][C:23](Cl)=[O:24]>O.C(OCC)(=O)C>[CH3:6][O:7][C:8]1[CH:9]=[CH:10][C:11]([O:12][CH2:13][CH:14]2[N:18]([C:23](=[O:24])[CH2:22][Cl:21])[CH2:17][CH2:16][S:15]2)=[CH:19][CH:20]=1
Reactant: O=C(Cl)CCl
Reactant: COc1ccc(OCC2NCCS2)cc1
Agent: O=C([O-])O
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Product: COc1ccc(OCC2SCCN2C(=O)CCl)cc1

Procedure:
A solution of 26 g of potassium bicarbonate in 55 ml of water was added under storing stirring to a solution of 2-(4-methoxy-phenoxymethyl)thiazolidine (54,5 g) in 550 ml of ethyl acetate cooled at 0°-5° C. The mixture was added with a solution of α-chloro-acetylchloride (19,2 ml) in ethyl acetate (50 ml) for 1 hour, under strong stirring and external cooling. Stirring was continued for 2 more hours, then the phases were separated. After washing of the organic phase with water, 5% aqueous NaHCO3 and water, and drying over Na2SO4, the mixture was evaporated to dryness to give 54,5 g of 2-(4-methoxy-phenoxymethyl)-3-α-chloroacetyl-thiazolidine, m.p. 51°-53° C. (from isopropyl alcohol).
Reaction SMILES: [CH3:1][C@H:2]1[C:20](=[O:21])[O:19][C@@H:18]([CH2:22][CH:23]([CH3:25])[CH3:24])[C:16](=[O:17])[O:15][C@H:14]([C@@H:26]([C@@H:28]2[O:30][C@H:29]2[C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH3:27])[CH2:13][CH:12]=[CH:11][C:9](=[O:10])[NH:8][C@H:7]([CH2:37][C:38]2[CH:39]=[CH:40][C:41]([O:45][CH3:46])=[C:42]([Cl:44])[CH:43]=2)[C:5](=[O:6])[NH:4][CH2:3]1.Cl.C(=O)([O-])[O-].[K+].[K+]>CC#N.O>[CH3:1][CH:2]1[C:20](=[O:21])[O:19][CH:18]([CH2:22][CH:23]([CH3:24])[CH3:25])[C:16](=[O:17])[O:15][CH:14]([CH:26]([CH:28]2[O:30][CH:29]2[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH3:27])[CH2:13][CH:12]=[CH:11][C:9](=[O:10])[NH:8][CH:7]([CH2:37][C:38]2[CH:39]=[CH:40][C:41]([O:45][CH3:46])=[C:42]([Cl:44])[CH:43]=2)[C:5](=[O:6])[NH:4][CH2:3]1
Reactant: COc1ccc(C[C@H]2NC(=O)C=CC[C@@H]([C@H](C)[C@@H]3O[C@H]3c3ccccc3)OC(=O)[C@H](CC(C)C)OC(=O)[C@H](C)CNC2=O)cc1Cl
Agent: COc1ccc(CC2NC(=O)/C=C/CC(C(C)C3OC3c3ccccc3)OC(=O)C(CC(C)C)OC(=O)C(C)CNC2=O)cc1Cl
Agent: COc1ccc(C[C@H]2NC(=O)/C=C/C[C@@H]([C@H](C)[C@@H]3O[C@H]3c3ccccc3)OC(=O)[C@H](CC(C)C)OC(=O)[C@H](C)CNC2=O)cc1Cl
Agent: Cl
Solvent: O
Solvent: CC#N
Product: COc1ccc(CC2NC(=O)C=CCC(C(C)C3OC3c3ccccc3)OC(=O)C(CC(C)C)OC(=O)C(C)CNC2=O)cc1Cl
Reaction time: 12 h

Procedure:
A solution of 6.0 mg of Cryptophycin 38 in 0.5 mL of dimethoxythane was treated with 2 μL concentrated HCl at room temperature. After 12 hours the excess acid was neutralized by stirring with 20 mg of solid potassium carbonate. The reaction mixture was filtered and the solvent evaporated to obtain a residue which was subjected to reversed-phase HPLC (C18, 10 μm, 22×250 mm column, 3:1 CH3CN/H2O, 3 mL/min flow rate) to give 4.3 mg of Cryptophycin 69 (tR 25.6 min) and 1.1 mg of Cryptophycin 70 (tR 24 min).
Reaction SMILES: C([O:4][CH2:5][CH:6]1[O:11][CH:10]([CH2:12][O:13][CH2:14][C:15]([N:17]([CH2:21][CH2:22][CH3:23])[CH2:18][CH2:19][CH3:20])=[O:16])[CH2:9][O:8][CH2:7]1)C=C.N1CCCCC1.[Mn]([O-])(=O)(=O)=O.[K+].Cl.S(=O)(O)[O-].[Na+].[C:42]([OH:45])(=[O:44])[CH3:43]>CC(C)=O.O.C(Cl)(Cl)Cl>[CH2:21]([N:17]([CH2:18][CH2:19][CH3:20])[C:15](=[O:16])[CH2:14][O:13][CH2:12][CH:10]1[O:11][CH:6]([CH2:5][O:4][CH2:43][C:42]([OH:45])=[O:44])[CH2:7][O:8][CH2:9]1)[CH2:22][CH3:23]
Reactant: CC(=O)O
Reactant: C=CCOCC1COCC(COCC(=O)N(CCC)CCC)O1
Agent: O=[Mn](=O)(=O)[O-]
Agent: Cl
Agent: O=S([O-])O
Solvent: O
Solvent: C1CCNCC1
Solvent: ClC(Cl)Cl
Product: CCCN(CCC)C(=O)COCC1COCC(COCC(=O)O)O1
Reaction time: 0.5 h

Procedure:
A solution of 8.23 g (0.025 mole) of 2-[[6-[(2-propenyloxy)methyl]-1,4-dioxan-2-yl]methoxy]-N,N-dipropylacetamide in 350 ml of dry acetone is stirred at -20°, treated with 12.0 ml (0.12 mole) of piperidine and 9.53 g of potassium permanganate (0.06 mole). The mixture is stirred for 30 minutes, and treated below -20° with 2 ml of acetic acid in 25 ml of acetone. After 4 hours at -20°, 250 ml of chloroform is added (-20°), followed by careful addition of 30 ml of concentrated hydrochloric acid in 150 ml of water and 14 g of sodium bisulfite in 100 ml of water. Extraction with chloroform, evaporation and vacuum distillation of the resulting yellow oil, yields 4.3 g (54%), b.p. 131°-135° @ 0.1 mm, of the above compound.
Reaction SMILES: [OH:1][C:2]1[C:3]([C:8]([OH:10])=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=1.S(=O)(=O)(O)O.O.[CH2:17](O)[CH3:18]>C1C=CC=CC=1>[OH:1][C:2]1[C:3]([C:8]([O:10][CH2:17][CH3:18])=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1ncccc1O
Reactant: CCO
Agent: O=S(=O)(O)O
Solvent: c1ccccc1
Solvent: O
Product: CCOC(=O)c1ncccc1O

Procedure:
3-Hydroxypicolinic acid (12.5 g, 900 mmol) was suspended in a mixture of ethanol (300 ml) and benzene (100 ml). Sulfuric acid (5 ml) was added and the reaction mixture was heated at reflux with azeotropic removal of water via Dean Stark trap. After the reaction was complete, the organics were removed in vacuo. The residue was dissolved in water, basified with sodium carbonate and extracted with ethyl acetate. The ethyl acetate layer was dried over magnesium sulfate, concentrated in vacuo to give ethyl 3-hydroxypicolinate (15 g).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[N:16]=[C:15]2[N:23]2[CH2:28][CH2:27][N:26]([CH3:29])[CH2:25][CH2:24]2)[CH2:10][CH2:9]1)C1C=CC=CC=1>CO.[OH-].[OH-].[Pd+2]>[CH3:29][N:26]1[CH2:25][CH2:24][N:23]([C:15]2[N:14]([CH:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[N:16]=2)[CH2:28][CH2:27]1
Reactant: CN1CCN(c2nc3ccccc3n2C2CCN(Cc3ccccc3)CC2)CC1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CN1CCN(c2nc3ccccc3n2C2CCNCC2)CC1
Temperature: 25 °C
Reaction time: 23 h
Yield: 87.3 %

Procedure:
A suspension mixture of 1-(1-benzyl-4-piperidinyl)-2-(4-methylpiperazinyl)-1H-benzimidazole (4.62 g, 11.86 mmol) and Pd(OH)2/C (2.35 g) in MeOH(100 ml) was stirred under hydrogen atmosphere at room temperature for 23 h. The catalyst was removed by filtration and the filtrate was concentrated to give 3.10 g (87%) of title compound as white solid.
Reaction SMILES: FC(F)(F)C(O)=O.[C:8]([C:10]1[CH:22]=[C:21]([O:23][CH:24]([CH3:26])[CH3:25])[CH:20]=[CH:19][C:11]=1[C:12]([O:14]C(C)(C)C)=[O:13])#[N:9]>ClCCl>[C:8]([C:10]1[CH:22]=[C:21]([O:23][CH:24]([CH3:26])[CH3:25])[CH:20]=[CH:19][C:11]=1[C:12]([OH:14])=[O:13])#[N:9]
Reactant: CC(C)Oc1ccc(C(=O)OC(C)(C)C)c(C#N)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)Oc1ccc(C(=O)O)c(C#N)c1
Reaction time: 2 h

Procedure:
Trifluoroacetic acid (0.6 mL, 7.8 mmol) was added drop-wise to a solution of tert-butyl 2-cyano-4-isopropoxybenzoate (82 mg, 0.31 mmol) in dichloromethane (0.6 mL) at 0° C. under N2 atmosphere. After the addition was complete, the cooling bath was removed and stirring was continued for an additional 2 h at 25° C. The solvent was removed under reduced pressure to yield 2-cyano-4-isopropoxybenzoic acid that was used directly in the next step without further purification.
Reaction SMILES: [CH3:1][N:2]([CH3:32])[C:3]1[C:4]2[S:31][CH:30]=[CH:29][C:5]=2[N:6]=[C:7]([NH:9][C@H:10]2[CH2:14][CH2:13][N:12]([C:15](=O)[CH2:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=3)[CH2:11]2)[N:8]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:42])=CC=1>C1(C)C=CC=CC=1>[CH3:1][N:2]([CH3:32])[C:3]1[C:4]2[S:31][CH:30]=[CH:29][C:5]=2[N:6]=[C:7]([NH:9][C@H:10]2[CH2:14][CH2:13][N:12]([C:15](=[S:42])[CH2:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=3)[CH2:11]2)[N:8]=1
Reactant: CN(C)c1nc(N[C@H]2CCN(C(=O)Cc3ccc(OC(F)(F)F)cc3)C2)nc2ccsc12
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: CN(C)c1nc(N[C@H]2CCN(C(=S)Cc3ccc(OC(F)(F)F)cc3)C2)nc2ccsc12
Temperature: 110 °C
Yield: 26.1 %

Procedure:
A mixture of (S)-1-(3-(4-dimethylaminothieno[3,2-d]pyrimidin-2-ylamino)pyrrolidin-1-yl)-2-(4-trifluoromethoxyphenyl)ethanone (0.10 g), Lawesson's reagent (0.087 g), and toluene (10 mL) was heated at 110° C. for 5 h with stirring. After left stand for cooling, the reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (silica gel, chloroform/methanol=50:1) to obtain light yellow solid (S)-1-(3-(4-dimethylaminothieno[3,2-d]pyrimidin-2-ylamino)pyrrolidin-1-yl)-2-(4-trifluoromethoxyphenyl)ethanethione (0.027 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17](/[CH:18]=[CH:19]/[CH:20]=[O:21])=[C:16]([CH:22]([CH3:24])[CH3:23])[N:15]=[C:14]3[C:9]=2[CH:10]=[CH:11][C:12](=O)[NH:13]3)=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:28])=O>>[Cl:28][C:12]1[CH:11]=[CH:10][C:9]2[C:14](=[N:15][C:16]([CH:22]([CH3:24])[CH3:23])=[C:17](/[CH:18]=[CH:19]/[CH:20]=[O:21])[C:8]=2[C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[N:13]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CC(C)c1nc2[nH]c(=O)ccc2c(-c2ccc(F)cc2)c1/C=C/C=O
Product: CC(C)c1nc2nc(Cl)ccc2c(-c2ccc(F)cc2)c1/C=C/C=O

Procedure:
7.8 g (23 mmol) of the compound from Example 5 are heated to 75° C. in 20 ml of phosphorus oxychloride. After a clear solution has formed, the mixture is concentrated in vacuo, the residue is dissolved in ethyl acetate, and the solution is poured into ice water and stirred vigorously. The aqueous phase is extracted twice with ethyl acetate, the combined organic phases are dried and the solvent is stripped off. 5.78 g (71%) of colorless crystals of m.p.: 142° C. crystallize from ether.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@H:8]([O:10][C:11](=[O:26])[NH:12][C:13]1[C:14]([C:19]2[CH:24]=[CH:23][C:22](Br)=[CH:21][CH:20]=2)=[N:15][O:16][C:17]=1[CH3:18])[CH3:9].C([O:29][C:30]([CH2:32][C:33]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1)=[O:31])C.C(=O)([O-])[O-].[K+].[K+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.COCCOC>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@H:8]([O:10][C:11]([NH:12][C:13]1[C:14]([C:19]2[CH:24]=[CH:23][C:22]([C:36]3[CH:37]=[CH:38][C:33]([CH2:32][C:30]([OH:31])=[O:29])=[CH:34][CH:35]=3)=[CH:21][CH:20]=2)=[N:15][O:16][C:17]=1[CH3:18])=[O:26])[CH3:9]
Reactant: CCOC(=O)Cc1ccc(B(O)O)cc1
Reactant: Cc1onc(-c2ccc(Br)cc2)c1NC(=O)O[C@H](C)c1ccccc1F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Product: Cc1onc(-c2ccc(-c3ccc(CC(=O)O)cc3)cc2)c1NC(=O)O[C@H](C)c1ccccc1F
Temperature: 90 °C
Reaction time: 3 h

Procedure:
[3-(4-Bromo-phenyl)-5-methyl-isoxazol-4-yl]-carbamic acid (R)-1-(2-fluoro-phenyl)-ethyl ester (0.080 g, 0.16 mmol), (4-ethoxycarbonylmethylphenyl)boronic acid, pinacol ester (0.055 g, 0.19 mmol), potassium carbonate (0.055 g, 0.40 mmol), and bis(triphenylphosphine)palladium(II) dichloride (0.011 g, 0.016 mmol) were combined in 2:1 DME:H2O and degassed with N2 for 5 minutes. The reaction was stirred at 90° C. for 3 hours, until no starting material was seen by analytical LCMS. 1N Aqueous LiOH (0.5 mL) was added, and the reaction was stirred at room temperature until no ester starting material was seen by analytical LCMS. After acidic work-up, the crude material was purified by preparative HPLC to give the title compound. Mass spectometric data [M+H]=475.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:10]=[C:11]([C:19]2[O:23][N:22]=[C:21]([C:24]3[C:25]([CH3:34])=[C:26]4[C:31](=[CH:32][CH:33]=3)[CH2:30][NH:29][CH2:28][CH2:27]4)[N:20]=2)[CH:12]=[CH:13][C:14]=1[O:15][CH:16]([CH3:18])[CH3:17].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:42][C:43]([O:45][CH2:46][CH3:47])=[O:44]>CN(C=O)C.C(OCC)(=O)C>[CH2:46]([O:45][C:43](=[O:44])[CH2:42][N:29]1[CH2:28][CH2:27][C:26]2[C:31](=[CH:32][CH:33]=[C:24]([C:21]3[N:20]=[C:19]([C:11]4[CH:12]=[CH:13][C:14]([O:15][CH:16]([CH3:18])[CH3:17])=[C:9]([Cl:8])[CH:10]=4)[O:23][N:22]=3)[C:25]=2[CH3:34])[CH2:30]1)[CH3:47]
Reactant: CCOC(=O)CBr
Reactant: Cc1c(-c2noc(-c3ccc(OC(C)C)c(Cl)c3)n2)ccc2c1CCNC2
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: CCOC(=O)CN1CCc2c(ccc(-c3noc(-c4ccc(OC(C)C)c(Cl)c4)n3)c2C)C1
Reaction time: 0.58 h
Yield: 88.7 %

Procedure:
To a suspension of 6-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-5-methyl-1,2,3,4-tetrahydroisoquinoline trifluoroacetate (Example 10; 90 mg; 0.18 mmol) in DMF (3 ml) under nitrogen at room temperature was added caesium carbonate (177 mg; 0.54 mmol) followed by ethyl bromoacetate (0.026 ml; 0.23 mmol). After 35 min, the mixture was diluted with ethyl acetate and the precipitate removed. The solution was washed with water and the aqueous layer further extracted with ethyl acetate. The organic layer was washed with brine, dried over MgSO4 and concentrated in vacuo to give the title compound (75 mg).
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.[Br:8][C:9]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][C:10]=1[NH2:11].O>C(O)(=O)C>[Br:8][C:9]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][C:10]=1[NH:11][C:5](=[O:7])[CH3:6]
Reactant: Nc1cc([N+](=O)[O-])ccc1Br
Reactant: CC(=O)OC(C)=O
Solvent: CC(=O)O
Solvent: O
Product: CC(=O)Nc1cc([N+](=O)[O-])ccc1Br
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Acetic anhydride (1.4 mL, 13.8 mmol) was added dropwise to a stirring solution of 2-bromo-5-nitroaniline (3 g, 13.8 mmol) in glacial acetic acid (30 mL) at 25° C. The reaction mixture was stirred at room temperature overnight, and then poured into water. The precipitate was collected via filtration, washed with water and dried under vacuum to provide N-(2-bromo-5-nitrophenyl)acetamide as an off white solid (3.6 g, 90%).
Reaction SMILES: [Cl-].[NH4+].[CH:3]1([O:9][C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-])=O)=[CH:12][C:11]=2[NH:19][S:20]([CH3:23])(=[O:22])=[O:21])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.C(OCC)(=O)C>[Fe].O>[NH2:16][C:13]1[CH:14]=[CH:15][C:10]([O:9][CH:3]2[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]2)=[C:11]([NH:19][S:20]([CH3:23])(=[O:22])=[O:21])[CH:12]=1
Reactant: CS(=O)(=O)Nc1cc([N+](=O)[O-])ccc1OC1CCCCC1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCOC(C)=O
Product: CS(=O)(=O)Nc1cc(N)ccc1OC1CCCCC1
Temperature: 80 °C
Yield: 80.9 %

Procedure:
To 100 ml of an aqueous solution containing 5.0 g of ammonium chloride were added 98.0 g of N-(2-cyclohexyloxy-5-nitrophenyl)methanesulfonamide and 78.0 g of an iron powder with heating at 80° C. with stirring, followed by stirring for 2 hours. The reaction solution was cooled back to room temperature, and then ethyl acetate and water were added thereto. After extraction, the organic layer was successively washed with water and a saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. After evaporation of the solvent, the residue was recrystallized from ethanol to give 71.7 g of N-(5-amino-2-cyclohexyloxyphenyl)methanesulfonamide as colorless prisms.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4]Cl.[C:10](OCC)(=[O:16])[C:11]([O:13][CH2:14][CH3:15])=[O:12]>C(OCC)C>[F:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][C:10](=[O:16])[C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: Fc1ccccc1CCl
Reactant: CCOC(=O)C(=O)OCC
Solvent: CCOCC
Product: CCOC(=O)C(=O)Cc1ccccc1F
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 70 %

Procedure:
To a suspension of Mg turnings (0.231 g, 9.51 mmol) in diethyl ether (1.5 mL) was added a solution of 2-fluorobenzyl chloride (1.25 g, 8.65 mmol) in diethyl ether (9 mL) dropwise to the refluxing reaction mixture. The mixture was stirred for 10 min, cooled to room temperature and added dropwise to a solution of diethyl oxalate (2.53 g, 17.29 mmol) in diethyl ether (17 mL) at 0° C. The reaction mixture was stirred at room temperature for 2 hours, quenched with 1M aqueous hydrochloric acid and extracted with diethyl ether. The combined extracts were washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. The excess of diethyl oxalate was removed by bulb to bulb distillation at room temperature and the residue was purified by flash chromatography (SiO2, 15-20% ethyl acetate in petroleum ether) to give the resulting compound B4 as colorless oil in 70% yield which was used instantly in next step.