Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([N:4]([CH:7]([CH3:9])[CH3:8])[CH2:5][CH3:6])(C)C.N.CN(C(O[N:19]1N=NC2[C:20]1=[CH:21][CH:22]=[CH:23]C=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN(C)C=[O:38]>O1CCOCC1>[CH3:1][N:4]1[C:7]2[C:9](=[CH:23][CH:22]=[C:21]([C:20]([NH2:19])=[O:38])[CH:8]=2)[CH:6]=[CH:5]1
Reactant: CN(C)C=O
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: CCN(C(C)C)C(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: N
Solvent: C1COCCO1
Product: Cn1ccc2ccc(C(N)=O)cc21
Temperature: 25 °C
Reaction time: 20 h

Procedure:
Sodium hydride (0.77 g of a 60% suspension in mineral oil) was washed with anhydrous hexane (2×10 mL) under a nitrogen atmosphere and then suspended in anhydrous N,N-dimethylformamide (DMF, 30 mL). A solution of indole-6-carboxylic acid (1.01 g) in DMF (20 mL) was added over 5 min and the solution stirred at room temperature for an additional 30 min. Iodomethane (1.2 mL) was added and the mixture stirred for 1 h. The solution was poured onto ice and allowed to warm up to room temperature. The resulting solid was collected by filtration, washed with water and dried under high vacuum to afford methyl 1-methylindole-6-carboxylate. A potion of this material (0.33 g) was dissolved in methanol (7 mL) and DMF (1 mL) and treated with 5N aqueous sodium hydroxide solution (2 mL). The mixture was heated at reflux for 22 h and then allowed to cool to ambient temperature. The solvent was evaporated under reduced pressure. The residue was dissolved in water (15 mL) and the solution was cooled in an ice-bath and acidified to pH 4 with concentrated HCl. The precipitated solid was collected by filtration, washed with water and dried under high vacuum to produce 1-methylindole-6-carboxylic acid. A portion of this material (0.27 g) was dissolved in DMF (4 mL), and treated with diisopropylethylamine (1.6 mL) and ammonia (12 mL of a 0.5M solution in dioxane) under a nitrogen atmosphere. O-Benzotriazol-N,N,N′, N′-tetramethyluronium hexafluorophosphate (0.64 g) was added and the mixture stirred at room temperature for 20 h. The solvent was removed under reduced pressure. The residue was dissolved in ethyl acetate (50 mL), and the solution washed with water, 1M sodium carbonate solution, and brine, and dried over magnesium sulfate. Evaporation of the solvent under reduced pressure produced 1-methylindole-6-carboxamide as an off-white solid. A portion of this material (0.04 g) was suspended in anhydrous toluene (1.0 mL) under a nitrogen atmosphere, and treated with 3,5-bis(trifluoromethylphenyl isocyanate (42 μL). The mixture was heated at reflux for 2 h and then allowed to cool to room temperature. The solid was collected by filtration, washed with petroleum ether, dichloromethane and methanol and dried under high vacuum to yield the title compound.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[S:7][C:6]([C:8]2[NH:9][C:10]3[C:15]([CH:16]=2)=[CH:14][CH:13]=[CH:12][C:11]=3[N:17]([CH3:26])[S:18]([C:21]2[S:22][CH:23]=[CH:24][CH:25]=2)(=[O:20])=[O:19])=[N:5][CH2:4]1.[C:27](OC(=O)C)(=[O:29])[CH3:28].O>CN(C)C(=O)C>[CH3:26][N:17]([S:18]([C:21]1[S:22][CH:23]=[CH:24][CH:25]=1)(=[O:20])=[O:19])[C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:10]=1[NH:9][C:8]([C:6]1[S:7][CH:3]([CH2:2][NH:1][C:27](=[O:29])[CH3:28])[CH2:4][N:5]=1)=[CH:16]2
Reactant: CN(c1cccc2cc(C3=NCC(CN)S3)[nH]c12)S(=O)(=O)c1cccs1
Reactant: CC(=O)OC(C)=O
Solvent: O
Solvent: CC(=O)N(C)C
Product: CC(=O)NCC1CN=C(c2cc3cccc(N(C)S(=O)(=O)c4cccs4)c3[nH]2)S1
Reaction time: 0.5 h
Yield: 68 %

Procedure:
To a solution of N-{2-[5-(aminomethyl)-4,5-dihydro-1,3-thiazol-2-yl]-1H-indol-7-yl}-N-methylthiophene-2-sulfonamide (0.27 g) in N,N-dimethylacetamide (6 mL) was added acetic anhydride (0.10 mL) at 0° C., and the mixture was stirred for 30 min. Water was added to the reaction mixture, and the precipitated solid was collected by filtration, washed with water, and dried. The obtained solid was subjected to silica gel column chromatography to give the title compound (0.20 g, yield 68%) as pale-yellow crystals from a fraction eluted with ethyl acetate-hexane (95:5, volume ratio). melting point 212-213° C.
Reaction SMILES: [Cl:1][CH2:2][C:3]1[N:8]=[C:7]([CH2:9][C:10]#[N:11])[CH:6]=[CH:5][CH:4]=1.[NH2:12][C:13]([NH2:15])=[S:14]>CO>[ClH:1].[C:10]([CH2:9][C:7]1[N:8]=[C:3]([CH2:2][S:14][C:13](=[NH:12])[NH2:15])[CH:4]=[CH:5][CH:6]=1)#[N:11]
Reactant: N#CCc1cccc(CCl)n1
Reactant: NC(N)=S
Solvent: CO
Product: Cl
Product: N#CCc1cccc(CSC(=N)N)n1
Reaction time: 1 h
Yield: 74.2 %

Procedure:
The 6-chloromethyl-2-pyridylacetonitrile (200 mg, 1.20 mmol) and thiourea (101 mg, 1.32 mmol) were mixed in 1 ml of methanol. The mixture was heated to reflux for 3 to 4 hours. The reaction mixture was evaporated. After that, 1 ml of methanol and 4 ml of acetone were added and the mixture was stirred for one hour. The crystalline material was filtered and the product was dried under high vacuum overnight to yield 216 mg (0.89 mmol, yield 74%) of product as off white crystals, with purity greater than 95%. 1H NMR (300 MHz, d6-DMSO) δ 4.29 (s, 2H), 4.64 (s, 2H), 7.41 (d, 1H, J=7.78), 7.51 (d, 1H, J=7.78), 7.91 (t, 1H, J=7.78), 9.46 (s, 4H). (M+H) 207.00
Reaction SMILES: Br[C:2]1[C:3]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:4][N:5]2[C:10]([N:11]3[CH2:15][CH2:14][CH2:13][CH2:12]3)=[CH:9][CH:8]=[N:7][C:6]=12.[F:22][C:23]1[CH:28]=[C:27](B(O)O)[CH:26]=[CH:25][N:24]=1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O.O.ClCCl.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>[F:22][C:23]1[CH:28]=[C:27]([C:2]2[C:3]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[N:4][N:5]3[C:10]([N:11]4[CH2:15][CH2:14][CH2:13][CH2:12]4)=[CH:9][CH:8]=[N:7][C:6]=23)[CH:26]=[CH:25][N:24]=1
Reactant: Brc1c(-c2ccccc2)nn2c(N3CCCC3)ccnc12
Reactant: OB(O)c1ccnc(F)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: O
Product: Fc1cc(-c2c(-c3ccccc3)nn3c(N4CCCC4)ccnc23)ccn1
Temperature: 110 °C
Yield: 31.6 %

Procedure:
3-Bromo-2-phenyl-7-pyrrolidin-1-ylpyrazolo[1,5-α]pyrimidine (150 mg, 0.44 mmol) was dissolved in N,N-dimethylformamide (4 mL). To this solution was added dichlorobis(tripenylphosphine)palladium (II) (60 mg, 0.09 mmol), 2-fluoropyridin-4-ylboronic acid (92 mg, 0.66 mmol), sodium carbonate (185 mg, 1.76 mmol) and a few drops of water. The resulting solution was heated at 110° C. for 24 hours. The resulting mixture was diluted with dichloromethane and washed with water. The organic phase was dried over magnesium sulfate, filtered and concentrated. The resulting black residue was purified by silica gel chromatography (ethyl acetate:hexane 1:1) to give 50 mg (32%) of the title compound as a white solid. 1H NMR (CDCl3):δ 8.17 (d, 1H), 8.08 (d, 1H), 7.60 (m, 2H), 7.41 (m, 4H), 7.24 (broad s, 1H), 5.87 (d, 1H), 4.06 (broad s, 4H), 2.07 (broad s, 4H); 19F NMR (CDCl3):δ −-69.34; MS m/z 360 (M+1).
Reaction SMILES: [CH3:1][Si:2]([CH3:9])([CH3:8])[C:3]#[C:4][CH2:5][CH2:6]O.[C:10]1(=[O:20])[NH:14][C:13](=[O:15])[C:12]2=[CH:16][CH:17]=[CH:18][CH:19]=[C:11]12>>[CH3:1][Si:2]([CH3:9])([CH3:8])[C:3]#[C:4][CH2:5][CH2:6][N:14]1[C:10](=[O:20])[C:11]2[C:12](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:13]1=[O:15]
Reactant: C[Si](C)(C)C#CCCO
Reactant: O=C1NC(=O)c2ccccc21
Product: C[Si](C)(C)C#CCCN1C(=O)c2ccccc2C1=O

Procedure:
The title compound was prepared in accordance with the general method of Example 109(D), from 4-(trimethylsilyl)but-3-yn-1-ol (3.20 g, 22.5 mmol) and phthalimide (3.50 g, 23.8 mmol).
Reaction SMILES: [C:1]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH:15][C@@H:16]([CH2:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([N:35]([CH3:46])[C:36]([NH:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45])=[O:37])[CH:30]=2)=[CH:25][CH:24]=1)[C:17]([O:19]CC)=[O:18])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Li+].Cl>O1CCCC1.CO.O>[C:1]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH:15][C@@H:16]([CH2:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([N:35]([CH3:46])[C:36]([NH:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45])=[O:37])[CH:30]=2)=[CH:25][CH:24]=1)[C:17]([OH:19])=[O:18])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCCCCCNC(=O)N(C)c1cccc(-c2ccc(C[C@H](Nc3ccccc3C(=O)c3ccccc3)C(=O)OCC)cc2)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CCCCCCCNC(=O)N(C)c1cccc(-c2ccc(C[C@H](Nc3ccccc3C(=O)c3ccccc3)C(=O)O)cc2)c1
Reaction time: 6 h
Yield: 77.5 %

Procedure:
0.75 g (1.2 mmol) of ethyl (S)-2-(2-benzoylphenylamino)-3-[3′-(3-heptyl-1-methylureido)biphenyl-4-yl]propionate (Example 1H) is dissolved in a mixture of 10 ml of tetrahydrofuran, 1 ml of methanol and a few drops of water. 86 mg (2 mmol) of lithium hydroxide are added. The medium is stirred for 6 h and then treated with an aqueous 1N hydrochloric acid solution, extracted with ethyl acetate, dried over magnesium sulfate, and concentrated. The residue obtained is purified by chromatography on a column of silica and eluted with a 1/1 heptane/ethyl acetate mixture. 0.55 g of (S)-2-(2-benzoylphenylamino)-3-[3′-(3-heptyl-1-methylureido)biphenyl-4-yl)propionic acid is obtained with a 77% yield.
Reaction SMILES: [BH4-].[Na+].[O:3]([C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][CH:17]=1)[CH:13]=O)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:18]([OH:21])(=O)[CH3:19].[CH3:22]O>>[O:3]([C:10]1[CH:11]=[C:12]([CH2:13][CH2:22][CH2:19][CH2:18][OH:21])[CH:15]=[CH:16][CH:17]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CC(=O)O
Reactant: CO
Reactant: O=Cc1cccc(Oc2ccccc2)c1
Agent: [BH4-]
Agent: [Na+]
Product: OCCCCc1cccc(Oc2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 100 %

Procedure:
Sodium borohydride (961 mg, 25.3 mmol) was added in one portion to a solution of 3-phenoxybenzaldehyde (10.0 g, 50.5 mmol) in methanol (150 mL) at RT under argon. Once the bubbling ceased, the reaction was stirred at RT for 5 min, then adjusted to pH 6 with glacial acetic acid (about 1 mL). The reaction was concentrated in vacuo to give a residue, which was partitioned between EtOAc (200 mL) and saturated NaHCO3 (50 mL). The organic layer was washed with water and brine (50 mL each), then dried over MgSO4. Evaporation gave title compound (10.1 g, 100%) as a tan oil.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.Cl[CH2:18][CH2:19][CH2:20][CH:21]([C:29]1[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=1)[C:22]1[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[ClH:1].[Cl:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:10][CH2:11][N:12]([CH2:18][CH2:19][CH2:20][CH:21]([C:22]4[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=4)[C:29]4[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=4)[CH2:13][CH2:14]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: Fc1ccc(C(CCCCl)c2ccc(F)cc2)cc1
Reactant: Clc1ccc2c(C3CCNCC3)noc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cl
Product: Fc1ccc(C(CCCN2CCC(c3noc4cc(Cl)ccc34)CC2)c2ccc(F)cc2)cc1
Yield: 62.7 %

Procedure:
A mixture of 16.5 g of 6-chloro-3-(4-piperidyl)-1,2-benzisoxazole, 22.4 g of 4-chloro-1,1-bis(4-fluorophenyl)butane, 22.0 g of potassium carbonate and 200 ml of dimethylformamide was stirred and heated at 75° for 5 hrs. The reaction mixture was allowed to cool and was filtered. The filtrate was concentrated in vacuo to an oil, which was taken up in 300 ml ether and washed with an equal portion of brine. The ether layer was dried over anhydrous sodium sulfate and concentrated in vacuo to an oil. The oil was dissolved in 65 ml of ethanol, the solution was cooled, and 20 ml of ether saturated with hydrogen chloride was added dropwise. Ether (400 ml) was added causing turbidity. The mixture was seeded and then stirred for 1/2 hour to produce the salt. Recrystallization from 800 l of 3:5 ethanol-ether gave 11.3 g (13% yield) of product, mp 205°-207°.
Reaction SMILES: Cl.[F:2][C:3]1[CH:16]=[CH:15][C:6]([C:7]([CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[O:8])=[CH:5][CH:4]=1.[C:17]([O:25][C:26]1[CH:31]=[C:30]([O:32][C:33](=O)[C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH:29]=[CH:28][C:27]=1[CH2:41][C:42](O)=[O:43])(=O)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(N(CC)CC)C.P(C#N)(OCC)(OCC)=O>CN(C)C=O.O>[CH2:17]([O:25][C:26]1[CH:31]=[C:30]([O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH:29]=[CH:28][C:27]=1[CH2:41][C:42]([N:12]1[CH2:13][CH2:14][CH:9]([C:7](=[O:8])[C:6]2[CH:5]=[CH:4][C:3]([F:2])=[CH:16][CH:15]=2)[CH2:10][CH2:11]1)=[O:43])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: O=C(O)Cc1ccc(OC(=O)c2ccccc2)cc1OC(=O)c1ccccc1
Reactant: O=C(c1ccc(F)cc1)C1CCNCC1
Agent: CCOP(=O)(C#N)OCC
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: O=C(c1ccc(F)cc1)C1CCN(C(=O)Cc2ccc(OCc3ccccc3)cc2OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 87.5 %

Procedure:
To solution (20 ml) of 4-(4-fluorobenzoyl) piperidine. hydrochloride (670 mg) and 2,4-dibenzoyloxyphenylacetic acid (1.0 g) in N,N-dimethylformamide are added triethylamine (1.2 ml) and diethyl cyanophosphate (561 mg) and the mixture is stirred at room temperature for 10 minutes. To the reaction solution is added water and the mixture stirred for 20 minutes. The product is extracted with dichloromethane. The dichloromethane layer is washed with water and dried over anhydrous sodium sulfate, and then the solvent is distilled off. The residue is purified by silica gel column chromatography. The crude product is obtained from a fraction eluted with dichloromethane-ethyl acetate mixture (2:1). Recrystallization of the product from dichloromethane-diethyl ether mixture yields 1-(2,4-dibenzyloxyphenylacetyl)-4-(4-fluorobenzoyl)piperidine (1.25 g) in the colorless columnar crystal form. Melting point 158°-159° C.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([NH2:11])[CH:8]=[C:4]([C:5]([O-:7])=O)[C:3]=1[C:12]([O-:14])=[O:13].[Na+].[Na+].[CH3:17][C:18]1=[C:19]([CH3:25])[C:20]([O:22][C:23]1=[O:24])=O>O.C1(C)C=CC=CC=1>[CH3:25][C:19]1[C:20](=[O:22])[N:1]([C:2]2[CH:10]=[C:9]([N:11]3[C:5](=[O:7])[C:4]([CH3:8])=[C:3]([CH3:2])[C:12]3=[O:13])[CH:8]=[C:4]3[C:5]([O:14][C:12](=[O:13])[C:3]=23)=[O:7])[C:23](=[O:24])[C:18]=1[CH3:17]
Reactant: CC1=C(C)C(=O)OC1=O
Reactant: Nc1cc(N)c(C(=O)[O-])c(C(=O)[O-])c1
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: CC1=C(C)C(=O)N(c2cc3c(c(N4C(=O)C(C)=C(C)C4=O)c2)C(=O)OC3=O)C1=O
Temperature: 100 °C
Yield: 115.7 %

Procedure:
7.20 g (0.039 mol) of disodium 3,5-diaminophthalate, dissolved in 200 ml of water, are added to a solution of 8.82 g (0.078 mol) of dimethylmaleic anhydride in 80 ml of toluene. This mixture is boiled under reflux for 1 hour. It is then evaporated to dryness in a rotary evaporator, the residue is dissolved, at 90° C., in 100 ml of N,N-dimethylacetamide and 50 ml of water and the solution is rendered acid to Congo Blue with 10% strength hydrochloric acid. After cooling, the slurry-like mixture is filtered and the residue is rinsed with acetone and then dried in vacuo at 80° C. The dry residue is then suspended in 100 ml of acetic anhydride and this mixture is warmed to about 100° C. for 1 hour. It is then evaporated to dryness and the residue is recrystallized from 1,2-dichlorobenzene. 8.9 g (69% of theory) of 3,5-bis-(dimethylmaleimidyl)-phthalic anhydride are obtained; colour: light brownish; melting point 298° C. (decomposition).
Reaction SMILES: [C:1]([CH2:4][CH2:5][N:6]1[C:10](=[O:11])[CH:9]([CH2:12][C:13](O)=[O:14])[S:8][CH:7]1[C:16]1[S:17][C:18]([C:21]#[C:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:19][CH:20]=1)(=[O:3])[NH2:2].[NH:29]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:31]([CH2:38][CH2:39][NH2:40])=[CH:30]1.C(P(=O)(OCC)OCC)#N.C(N(C(C)C)CC)(C)C>CN(C=O)C.O>[NH:29]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:31]([CH2:38][CH2:39][NH:40][C:13]([CH2:12][C@H:9]2[S:8][C@@H:7]([C:16]3[S:17][C:18]([C:21]#[C:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[CH:19][CH:20]=3)[N:6]([CH2:5][CH2:4][C:1]([NH2:2])=[O:3])[C:10]2=[O:11])=[O:14])=[CH:30]1
Reactant: NCCc1c[nH]c2ccccc12
Reactant: NC(=O)CCN1C(=O)C(CC(=O)O)SC1c1ccc(C#Cc2ccccc2)s1
Agent: CCOP(=O)(C#N)OCC
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: NC(=O)CCN1C(=O)[C@@H](CC(=O)NCCc2c[nH]c3ccccc23)S[C@H]1c1ccc(C#Cc2ccccc2)s1
Yield: 16.4 %

Procedure:
A mixture of [3-(2-carbamoyl-ethyl)-4-oxo-2-(5-phenylethynyl-thiophen-2-yl)-thiazolidin-5-yl]-acetic acid (1.36 g,3.28 mmol), 3-indolylethylamine (0.77 g, 4.8 mmol), diethyl cyanophosphonate (0.781 g, 4.8 mmol) and diisopropylethylamine (0.62 g, 4.8 mmol) was stirred in DMF (50 mL) for three hours at room temperature. The mixture was poured into water (100 mL). The product was extracted into ethyl acetate (2×100 mL). The extract was washed successively with sat. NaHCO3, H2O, brine, and then dried (MgSO4). The solvent was evaporated to a brown gum, which was washed twice with methanol to remove the dark color to provide the title compound as an off-white solid (0.3 g, 16.8%). 1H NMR (DMSO-d6) δ 10.8 (s, 1H), 8.19-8.23 (t, 1H), 7.51-7.55 (m, 3H), 7.33-7.46 (m, 4H), 7.27-7.31 (m, 3H), 7.14-7.15 (d, 1H, J=2.2 Hz), 7.02-7.07 (t, 1H), 6.91-6.98 (m, 2H), 6.13 (s, 1H ), 4.15-4.20 (dd, 1H, J=3.1 Hz ), 3.55-3.64 (m, 1H), 3.27-3.41 (m, 2H), 2.97-3.07 (m, 2H), 2.79-2.84 (t, 2H), 2.60 (s, 1H), 2.55-2.56 (d, 1H, J=4.7 Hz), 2.35-2.45 (m,1H), 2.08-2.18 (m, 1H), 95% cis based on peaks at δ 6.13 and 4.15-4.20); MS(ESI)557[M+H]+.FTIR(ATR) 1620, 1660 cm−1.Anal.(C30H28N4O3S2) calc. C, 64.72; H, 5.07; N, 10.06. Obs. C, 64.55; H, 4.98; N, 9.93.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:9]=[C:8]([Br:10])[N:7]([CH:11]([CH3:13])[CH3:12])[C:6]=1[CH:14]([C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=1)O)=[O:4].[CH3:23][N:24]1[C:28]([NH2:29])=[CH:27][C:26]([CH3:30])=[N:25]1.C(OC(C1C=CN(C(C)C)C=1C(C1C=CC(Cl)=CC=1)O)=O)C.NC1C(=O)N(C)C=C(Cl)C=1>>[CH3:1][O:2][C:3]([C:5]1[CH:9]=[C:8]([Br:10])[N:7]([CH:11]([CH3:13])[CH3:12])[C:6]=1[CH:14]([C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=1)[NH:29][C:28]1[N:24]([CH3:23])[N:25]=[C:26]([CH3:30])[CH:27]=1)=[O:4]
Reactant: COC(=O)c1cc(Br)n(C(C)C)c1C(O)c1ccc(Cl)cc1
Reactant: Cc1cc(N)n(C)n1
Agent: CCOC(=O)c1ccn(C(C)C)c1C(O)c1ccc(Cl)cc1
Agent: Cn1cc(Cl)cc(N)c1=O
Product: COC(=O)c1cc(Br)n(C(C)C)c1C(Nc1cc(C)nn1C)c1ccc(Cl)cc1

Procedure:
The title compound was prepared in analogy to the procedure described for Step L3 but 5-bromo-2-[(4-chloro-phenyl)-hydroxy-methyl]-1-isopropyl-1H-pyrrole-3-carboxylic acid methyl ester (step D3) and 2,5-dimethyl-2H-pyrazol-3-ylamine [3524-32-1] were used instead of 2-[(4-chloro-phenyl)-hydroxy-methyl]-1-isopropyl-1H-pyrrole-3-carboxylic acid ethyl ester and 3-amino-5-chloro-1-methyl-1H-pyridin-2-one respectively. The title compound was obtained as a foam. ESI-MS: tR=1.29 min, [M+H]+ 479/481/483 (LC-MS 1); TLC: Rf=0.31 (1:1 CH2Cl2/EtOAc).
Reaction SMILES: [CH:1]1([CH:7]([C:19]2[CH:23]=[C:22]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=3)[O:21][C:20]=2[CH2:34][O:35][CH2:36][CH3:37])[O:8][C:9]2[CH:18]=[CH:17][C:12]([C:13]([O:15]C)=[O:14])=[CH:11][CH:10]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Li+].O.Cl>CO.O1CCCC1>[CH:1]1([CH:7]([C:19]2[CH:23]=[C:22]([C:24]3[CH:25]=[CH:26][C:27]([C:30]([F:31])([F:32])[F:33])=[CH:28][CH:29]=3)[O:21][C:20]=2[CH2:34][O:35][CH2:36][CH3:37])[O:8][C:9]2[CH:10]=[CH:11][C:12]([C:13]([OH:15])=[O:14])=[CH:17][CH:18]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOCc1oc(-c2ccc(C(F)(F)F)cc2)cc1C(Oc1ccc(C(=O)OC)cc1)C1CCCCC1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CCOCc1oc(-c2ccc(C(F)(F)F)cc2)cc1C(Oc1ccc(C(=O)O)cc1)C1CCCCC1
Temperature: 60 °C
Reaction time: 2 h
Yield: 38 %

Procedure:
To a solution of cyclohexyl{2-(methoxymethyl)-5-[4-(trifluoromethyl)phenyl]furan-3-yl}methanol (574 mg) obtained by the above-mentioned reaction and methyl 4-hydroxybenzoate (274 mg) in tetrahydrofuran (20 mL) were added tributylphosphine (0.7 mL) and 1,1′-(azodicarbonyl)dipiperidine (757 mg), and the mixture was stirred at room temperature overnight. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column (0% ethyl acetate/hexane to 15% ethyl acetate/hexane) to give methyl 4-(cyclohexyl{2-(ethoxymethyl)-5-[4-(trifluoromethyl)phenyl]furan-3-yl}methoxy)benzoate as an amorphous compound. The obtained methyl 4-(cyclohexyl{2-(ethoxymethyl)-5-[4-(trifluoromethyl)phenyl]furan-3-yl}methoxy)benzoate was dissolved in methanol (2 mL) and tetrahydrofuran (2 mL). 2N Lithium hydroxide (1.0 mL) was added, and the mixture was stirred at 60° C. for 2 hr. The reaction mixture was poured into water, and the mixture was acidified with 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure to give the title compound (289 mg, 38%) as an amorphous compound.
Reaction SMILES: [F:1][CH:2]([F:13])[O:3][C:4]1[CH:9]=[C:8]([OH:10])[N:7]=[C:6]([S:11][CH3:12])[N:5]=1.O.O1CCOCC1.Cl[CH:22]([F:24])[F:23]>[OH-].[K+].C1OCCOCCOCCOCCOCCOC1>[F:13][CH:2]([F:1])[O:3][C:4]1[CH:9]=[C:8]([O:10][CH:22]([F:24])[F:23])[N:7]=[C:6]([S:11][CH3:12])[N:5]=1
Reactant: FC(F)Cl
Reactant: CSc1nc(O)cc(OC(F)F)n1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CSc1nc(OC(F)F)cc(OC(F)F)n1
Temperature: 40 °C
Yield: 86.7 %

Procedure:
14.0 g (0.067 mole) of 4-difluoromethoxy-6-hydroxy-2-methylthiopyrimidine are suspended in 18 ml of 50% potassium hydroxide solution, 10 ml of water and 160 ml of dioxane. After the addition of 0.5 g of 18-crown-6, the reaction mixture is heated to 40° C., and 20 g of chlorodifluoromethane are subsequently introduced over 5 hours. The aqueous phase is then separated and the organic phase is distilled under a high vacuum, affording 15.0 g (86.4% of theory) of 4,6-bis-difluoromethoxy-2-methylthiopyrimidine with a boiling point of 63° C./0.06 mbar. The substance melts at 46°-48° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[C:18]4[CH2:19][CH2:20][C:21](=O)[C:22](=[CH:23][N:24](C)C)[C:17]=4[S:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[F:8].[NH2:28]N>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[N:15]=[CH:14][N:13]=[C:12]3[S:16][C:17]4[C:22]5[C:21]([CH2:20][CH2:19][C:18]=4[C:11]=23)=[N:28][NH:24][CH:23]=5)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: NN
Reactant: CN(C)C=C1C(=O)CCc2c1sc1ncnc(Nc3ccc(F)c(Cl)c3)c21
Solvent: CCO
Product: Fc1ccc(Nc2ncnc3sc4c(c23)CCc2n[nH]cc2-4)cc1Cl
Temperature: 25 °C
Reaction time: 5 h
Yield: 55.9 %

Procedure:
To a solution of 4-(3-Chloro-4-fluoro-phenylamino)-8-dimethylaminomethylene-5,8-dihydro-6H-benzo[4,5]thieno[2,3-d]pyrimidin-7-one (100 mg, 0.25 mmol) in anhydrous ethanol (2 mL) was added hydrazine (12 mg, 0.37 mmol). The resulting mixture was stirred at rt for 5 h. The solid was filtered and washed with EtOAc and then with water. It yielded N-(3-chloro-4-fluorophenyl)-4,5-dihydro-2H-pyrimido[5′,4′:4,5]thieno[2,3-e]indazol-6-amine as a red solid (52 mg, 56%). 1H-NMR (DMSO-d6) δ 12.73 (s, 1H), 8.58 (s, 1H), 8.39 (s, 1H), 7.99 (s, 1H), 7.88 (s, 1H), 7.61 (m, 1H), 7.40 (t, 1H), 3.40 (t, 2H), 2.96 (t, 2H); LCMS RT=2.98 min; [M+H]+=372.3.
Reaction SMILES: [CH:1]1([NH:7][C:8]2[N:13]=[CH:12][N:11]=[C:10]([C:14]([OH:16])=O)[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:17][C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][C:19]=1[F:25]>ClCCl>[CH:1]1([NH:7][C:8]2[N:13]=[CH:12][N:11]=[C:10]([C:14]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][C:19]=3[F:25])=[O:16])[CH:9]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(O)c1cc(NC2CCCCC2)ncn1
Reactant: Nc1ccc(O)cc1F
Solvent: ClCCl
Product: O=C(Nc1ccc(O)cc1F)c1cc(NC2CCCCC2)ncn1

Procedure:
Following the general method as outlined in Example 1, starting from 6-(cyclohexylamino)pyrimidine-4-carboxylic acid (Intermediate 4) and 4-amino-3-fluorophenol (Apollo), the title compound was obtained as a white solid after trituration in dichloromethane.