Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[N:6]([CH3:7])[N:5]=[CH:4][C:3]=1[CH:8]=[O:9].[Cl:10][C:11]1[C:16](C(C2C=NN(C)C=2C2C=CC(C)=CC=2)O)=[C:15]([Cl:32])[N:14]=[CH:13][N:12]=1>>[Br:1][C:2]1[N:6]([CH3:7])[N:5]=[CH:4][C:3]=1[CH:8]([C:16]1[C:11]([Cl:10])=[N:12][CH:13]=[N:14][C:15]=1[Cl:32])[OH:9]
Reactant: Cn1ncc(C=O)c1Br
Reactant: Cc1ccc(-c2c(C(O)c3c(Cl)ncnc3Cl)cnn2C)cc1
Product: Cn1ncc(C(O)c2c(Cl)ncnc2Cl)c1Br

Procedure:
5-Bromo-1-methyl-1H-pyrazole-4-carbaldehyde (C24) was converted to the product using a procedure analogous to that described for the synthesis of (4,6-dichloropyrimidin-5-yl)[1-methyl-5-(4-methylphenyl)-1H-pyrazol-4-yl]methanol (C4) in Example 1, step 4. In this case the product was purified not by recrystallization, but using silica gel chromatography (Eluent: 10:1 heptane/ethyl acetate, then 2:1 heptane/ethyl acetate). Yield: 1.26 g, 3.73 mmol, 70%. LCMS m/z 339.1 (M+1). 1H NMR (400 MHz, CDCl3) δ 2.4-3.0 (v br s, 1H), 3.88 (s, 3H), 6.36 (s, 1H), 7.56 (s, 1H), 8.74 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=3)=[CH:12][C:11]([C:22](O)=[O:23])=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8].ClC1C=C(N2C(C3C=CC=C(OCCO)C=3)=CC(C([N:49]3[CH2:53][C:52](=[O:54])[NH:51][CH2:50]3)=O)=N2)C=CC=1>>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=3)=[CH:12][C:11]([C:22]([N:49]3[CH2:53][C:52](=[O:54])[NH:51][CH2:50]3)=[O:23])=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: O=C1CN(C(=O)c2cc(-c3cccc(OCCO)c3)n(-c3cccc(Cl)c3)n2)CN1
Reactant: COc1cccc(-c2cc(C(=O)O)nn2-c2ccc(F)c(Cl)c2)c1
Product: COc1cccc(-c2cc(C(=O)N3CNC(=O)C3)nn2-c2ccc(F)c(Cl)c2)c1

Procedure:
The preparation of the title compound takes place starting from the compound of Example 102A in analogy to the synthesis of the compound of Example 23. 7 mg (12% of theory) of the title compound are obtained.
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[S:25][C:11]2[N:12]=[C:13]([S:23][CH3:24])[N:14]=[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([OH:22])[CH:17]=3)[C:10]=2[C:9]=1[NH2:26])=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.Cl[C:37]([O:39][CH3:40])=[O:38]>C(Cl)Cl>[C:1]([NH:5][C:6]([C:8]1[S:25][C:11]2[N:12]=[C:13]([S:23][CH3:24])[N:14]=[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([O:22][C:37]([O:39][CH3:40])=[O:38])[CH:17]=3)[C:10]=2[C:9]=1[NH2:26])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)Cl
Reactant: CSc1nc(-c2cccc(O)c2)c2c(N)c(C(=O)NC(C)(C)C)sc2n1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)Oc1cccc(-c2nc(SC)nc3sc(C(=O)NC(C)(C)C)c(N)c23)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
tert-Butyl 5-amino-2-methylthio-4-(3-hydroxyphenyl)-thieno[2,3-d]pyrimidine-6-carboxamide (example 1f, 100 mg) was dissolved in dry CH2Cl2 (5 ml). DIPEA (500 μl ) and methyl chloroformate (199 μl ) were added and the reaction mixture was stirred at room temperature overnight. The reaction mixture was washed with H2O. The organic layer was dried (MgSO4) and concentrated under reduced pressure. The title compound was purified by HPLC using a Luna C-18 column with the following gradient: CH3CN/H2O=10/90 to 90/10 (v/v) in 30 min. The title compound was then lyophilized from a mixture of 1,4-dioxane and H2O.
Reaction SMILES: Br[CH2:2][C:3]1[CH:19]=[CH:18][C:6]([C:7]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[O:8])=[CH:5][CH:4]=1.[OH:20][C@H:21]1[CH2:27][CH2:26][C@@H:25]([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[O:24][C:22]1=[O:23].C(OCC)C>CN(C)C=O.[Ag]=O>[CH2:10]([O:9][C:7]([C:6]1[CH:18]=[CH:19][C:3]([CH2:2][O:20][C@H:21]2[CH2:27][CH2:26][C@H:25]([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[O:24][C:22]2=[O:23])=[CH:4][CH:5]=1)=[O:8])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: CCCCCCCCOC(=O)c1ccc(CBr)cc1
Reactant: CCCCCC[C@@H]1CC[C@H](O)C(=O)O1
Agent: O=[Ag]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CCCCCCCCOC(=O)c1ccc(CO[C@H]2CC[C@H](CCCCCC)OC2=O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 2.2 %

Procedure:
In 1.5 ml of dry dimethylformamide were dissolved 180 mg of octyl p-bromomethylbenzoate and 100 mg of (2S,5R)-2-hydroxy-5-hexyl-δ-valerolactone, and 300 mg of silver oxide was added to the solution and the mixture was stirred overnight at room temperature to effect reaction. After the reaction, diethyl ether was added to the reacted solution to extract the reaction product. The extract was washed with a saturated aqueous solution of sodium chloride and dried on anhydrous magnesium sulfate. Diethyl ether was removed by distillation under a reduced pressure. The obtained crude product was purified by the silica gel column chromatography to obtain 5 mg of (2S,5S)-2-(4'-octyloxycarbonylbenzyloxy)-5-hexyl-δ-valerolactone.
Reaction SMILES: C([O:3][C:4](=O)[NH:5][N:6]=[CH:7][C:8]1[N:9]=[C:10]([CH2:14][CH2:15][CH3:16])[NH:11][C:12]=1[CH3:13])C.C1(OC2C=CC=CC=2)C=CC=CC=1>>[CH3:13][C:12]1[N:11]=[C:10]([CH2:14][CH2:15][CH3:16])[N:9]2[C:8]=1[CH:7]=[N:6][NH:5][C:4]2=[O:3]
Reactant: CCCc1nc(C=NNC(=O)OCC)c(C)[nH]1
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CCCc1nc(C)c2cn[nH]c(=O)n12

Procedure:
A 14.50 gm. portion of 3-[(5-methyl-2-n-propyl-4-imidazolyl)methylene]carbazic acid ethyl ester and 100 ml. of diphenyl ether are reacted as described in Example 70 giving the desired product, m.p. 129.5°-131.5° C.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:17]=[CH:18][C:19]([CH2:33][OH:34])=[C:20]([C:22]5[CH:27]=[CH:26][C:25]([C:28]([N:30]([CH3:32])[CH3:31])=[O:29])=[CH:24][CH:23]=5)[CH:21]=4)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.[C:35]1(C)[CH:40]=CC(S(O)(=O)=O)=C[CH:36]=1>C(O)(C)C>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:17]=[CH:18][C:19]([CH2:33][O:34][CH:35]([CH3:40])[CH3:36])=[C:20]([C:22]5[CH:27]=[CH:26][C:25]([C:28]([N:30]([CH3:31])[CH3:32])=[O:29])=[CH:24][CH:23]=5)[CH:21]=4)=[O:14])[CH2:11][CH2:12]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CN(C)C(=O)c1ccc(-c2cc(NC(=O)C3(c4ccc5c(c4)OCO5)CC3)ccc2CO)cc1
Solvent: CC(C)O
Product: CC(C)OCc1ccc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)cc1-c1ccc(C(=O)N(C)C)cc1
Yield: 43.9 %

Procedure:
5′-(1-(Benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-2′-(hydroxymethyl)-N,N-dimethylbiphenyl-4-carboxamide (46 mg, 0.10 mmol) and para-toluenesulfonic acid (38 mg, 0.2 mmol) were dissolved in isopropanol (1.0 mL) and irradiated in the microwave at 140° C. for 10 minutes. Volatiles were removed in vacuo and crude product was purified by reverse phase HPLC to afford the pure product (22 mg, 44%). ESI-MS m/z calc. 500.2, found 501.3 (M+1)+; retention time 3.30 minutes.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]([Br:12])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].Cl[S:14]([C:17]1[C:25]2[C:21](=[N:22][S:23][N:24]=2)[CH:20]=[CH:19][CH:18]=1)(=[O:16])=[O:15]>>[CH3:7][O:6][C:4](=[O:5])[C:3]1[CH:8]=[CH:9][C:10]([Br:12])=[CH:11][C:2]=1[NH:1][S:14]([C:17]1[C:25]2=[N:24][S:23][N:22]=[C:21]2[CH:20]=[CH:19][CH:18]=1)(=[O:16])=[O:15]
Reactant: COC(=O)c1ccc(Br)cc1N
Reactant: O=S(=O)(Cl)c1cccc2nsnc12
Product: COC(=O)c1ccc(Br)cc1NS(=O)(=O)c1cccc2nsnc12
Yield: 75 %

Procedure:
The title compound (3.95 g, 75%) was prepared from methyl 2-amino-4-bromobenzoate and 4-chlorosulfonyl-2,1,3-benzothiadiazole as in Example 1, Part A. MS (ESI−): mass calcd. for C14H10BrN3O4S2, 426.9; m/z found, 426 [M−H]−. 1H NMR (400 MHz, CDCl3): 11.34 (br s, 1H), 8.40 (dd, J=7.0, 0.9, 1H), 8.24 (dd, J=8.8, 0.9, 1H), 7.92 (d, J=1.8, 1H), 7.74 (dd, J=8.8, 7.0, 1H), 7.72 (d, J=8.5, 1H), 7.10 (dd, J=8.5, 1.8, 1H), 3.92 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.Cl.[F:13][C:14]1[CH:15]=[N:16][CH:17]=[CH:18][C:19]=1[N:20]1[CH2:25][CH2:24][CH:23]([C:26]([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)=[O:27])[CH2:22][CH2:21]1.C(N(CC)CC)C>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:31]2[CH2:32][CH2:33][N:28]([C:26]([CH:23]3[CH2:24][CH2:25][N:20]([C:19]4[CH:18]=[CH:17][N:16]=[CH:15][C:14]=4[F:13])[CH2:21][CH2:22]3)=[O:27])[CH2:29][CH2:30]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=C(C1CCN(c2ccncc2F)CC1)N1CCNCC1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(C1CCN(c2ccncc2F)CC1)N1CCN(S(=O)(=O)c2ccc(Br)cc2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 65.3 %

Procedure:
4-Bromophenylsulphonyl chloride (1.02 g) was added to a mixture of 1-[1-(3-fluoro-4-pyridyl)-piperidin-4-ylcarbonyl]piperazine hydrochloride (1.22 g) and triethylamine (3.70 ml) in dichloromethane (45 ml) at 0° C. The solution was stirred at ambient temperature for 18 hours. The solution was diluted with dichloromethane and washed with water, dried (Na2SO4) and evaporated. The residue was purified by chromatography eluting with 2% methanol in dichloromethane. Recrystallisation from ethyl acetate/hexane gave 1-(4-bromophenylsulphonyl)-4-[1-(3-fluoro-4-pyridyl)piperidin-4-ylcarbonyl]piperazine (1.24 g) as a solid.
Reaction SMILES: [F:1][C:2]1[C:6]([C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)=[N:5][N:4]2[CH:13]=[CH:14][N:15]([C:16]3[CH:17]=[C:18]([CH:20]=[CH:21][C:22]=3[CH3:23])[NH2:19])[C:3]=12.[F:24][S:25]([F:38])([F:37])([F:36])([F:35])[C:26]1[CH:27]=[C:28]([CH:32]=[CH:33][CH:34]=1)[C:29](O)=[O:30]>>[F:1][C:2]1[C:6]([C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)=[N:5][N:4]2[CH:13]=[CH:14][N:15]([C:16]3[CH:17]=[C:18]([NH:19][C:29](=[O:30])[C:28]4[CH:32]=[CH:33][CH:34]=[C:26]([S:25]([F:38])([F:24])([F:35])([F:36])[F:37])[CH:27]=4)[CH:20]=[CH:21][C:22]=3[CH3:23])[C:3]=12
Reactant: Cc1ccc(N)cc1-n1ccn2nc(-c3cccnc3)c(F)c12
Reactant: O=C(O)c1cccc(S(F)(F)(F)(F)F)c1
Product: Cc1ccc(NC(=O)c2cccc(S(F)(F)(F)(F)F)c2)cc1-n1ccn2nc(-c3cccnc3)c(F)c12

Procedure:
Analogously to the process described in Example 126, 60 mg (0.195 mmol) of the compound of Example 83A and 48 mg (0.195 mmol) of 3-(pentafluoro-λ6-sulphanyl)benzoic acid gave 35 mg (33% of theory) of the title compound. The product obtained from the preparative HPLC purification was dissolved in a little methanol and passed through a bicarbonate cartridge (from Polymerlabs, Stratospheres SPE, PL-HCO3 MP SPE, capacity 0.9 mmol). After concentration of the eluate, the residue was dried under high vacuum.
Reaction SMILES: [ClH:1].[CH:2]1([N:12]2[CH2:28][CH2:27][C:15]3([N:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[CH2:18][NH:17][C:16]3=[O:26])[CH2:14][CH2:13]2)[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.Br[CH2:30][C:31]#[N:32]>>[ClH:1].[CH:2]1([N:12]2[CH2:28][CH2:27][C:15]3([N:19]([C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=4)[CH2:18][N:17]([CH2:30][C:31]#[N:32])[C:16]3=[O:26])[CH2:14][CH2:13]2)[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: N#CCBr
Reactant: O=C1NCN(c2ccccc2)C12CCN(C1CCCCCCCCC1)CC2
Agent: Cl
Product: N#CCN1CN(c2ccccc2)C2(CCN(C3CCCCCCCCC3)CC2)C1=O

Procedure:
The title compound, white solid, m. p. 240° C. and MS: m/e=409.3 (M+H+) was prepared in accordance with the general method of example 24 from 8-cyclodecyl-1-phenyl-1,3,8-triaza-spiro[4,5]decan-4-one hydrochloride and bromoacetonitrile.
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:9](=O)C1C=CC=CC=1>CC(C)=O>[C:1]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)(=[O:8])[CH3:9]
Reactant: O=Cc1ccccc1
Reactant: OCc1ccccc1
Solvent: CC(C)=O
Product: CC(=O)c1ccccc1

Procedure:
A method according to claim 1 wherein the ketone is acetone and the carboxylic acid precursor is selected from the group consisting of benzyl alcohol and benzaldehyde to yield acetophenone.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:12][C:13](=[O:33])[C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)=[CH:16][C:15]=2[O:25][CH:26]2[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]2)=[C:6]([CH:11]=1)[C:7]([O:9]C)=[O:8].[OH-].[K+]>CCO.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:12][C:13](=[O:33])[C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)=[CH:16][C:15]=2[O:25][CH:26]2[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]2)=[C:6]([CH:11]=1)[C:7]([OH:9])=[O:8]
Reactant: COC(=O)c1cc(F)ccc1NC(=O)c1ccc(N2CCCC2)cc1OC1CCN(C)CC1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CN1CCC(Oc2cc(N3CCCC3)ccc2C(=O)Nc2ccc(F)cc2C(=O)O)CC1
Temperature: 70 °C
Reaction time: 1 h

Procedure:
A solution of methyl 5-fluoro-2-[2-(1-methylpiperidin-4-yloxy)-4-(pyrrolidin-1-yl)benzoylamino]benzoate (7.8 g, 17 mmol) in EtOH (100 mL) and water (100 mL) was treated with KOH (4.8 g, 85 mmol) and stirred at 70° C. for 1 hour. The reaction was concentrated under vacuum, quenched with glacial acetic acid (5.1 g), and allowed to stand at ambient temperature for crystallization. The solid was filtered to recover 7.4 g (98%).
Reaction SMILES: Br[C:2]([Br:5])(Br)Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:25][Si:26]([CH3:36])([C:32]([CH3:35])([CH3:34])[CH3:33])[O:27][CH2:28][CH2:29]CO>C(Cl)Cl>[Br:5][CH2:2][CH2:29][CH2:28][O:27][Si:26]([CH3:36])([CH3:25])[C:32]([CH3:35])([CH3:34])[CH3:33]
Reactant: CC(C)(C)[Si](C)(C)OCCCO
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCCCBr
Temperature: -25 °C
Reaction time: 1.5 h
Yield: 86.7 %

Procedure:
5.44 g of tetrabromomethane and 4.30 g of triphenyl-phosphine were added to a solution of 2.5 g of the product of Step A in 27 ml of methylene chloride cooled down to -25° C. The reaction solution was stirred for 90 minutes at 0° C. and then was chromatographed on silica (eluant: ethyl acetate-cyclohexane 1-9) to obtain 2.885 g of the expected product.
Reaction SMILES: [C:1](Cl)(=[O:4])[CH:2]=[CH2:3].Cl.[CH3:7][O:8][CH:9]([O:12][CH3:13])[CH2:10][NH2:11]>>[CH3:7][O:8][CH:9]([O:12][CH3:13])[CH2:10][NH:11][C:1](=[O:4])[CH:2]=[CH2:3]
Reactant: C=CC(=O)Cl
Reactant: COC(CN)OC
Agent: Cl
Product: C=CC(=O)NCC(OC)OC
Yield: 92 %

Procedure:
The round bottom flask was suspended in a dry ice-isopropanol bath. When the contents reached 0° C., the acryloylchloride solution was allowed to slowly drip into the flask. Temperature was maintained at 0° to 3° C. over a 40 minute period during which all the acryloylchloride solution had been added. Voluminous white crystals of aminoacetaldehyde dimethylacetal hydrochloride were present in the product. These crystals were removed via filtration. Methoxyhydroquinone (0.1 gram) was added and the filtrate was concentrated by evaporation of the ethyl ether to yield 189 grams of N-(2,2 dimethoxyethyl)acrylamide (92% yield).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH3:11])[CH:9]=2)[C:4]([C:12]2[N:17]=[C:16]3[C:18]([C:21](O)=[O:22])=[CH:19][NH:20][C:15]3=[N:14][CH:13]=2)=[N:3]1.[NH2:24][C:25]1([CH2:28][OH:29])[CH2:27][CH2:26]1.CCN=C=NCCCN(C)C.O>CN(C=O)C.CN(C1C=CN=CC=1)C>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH3:11])[CH:9]=2)[C:4]([C:12]2[N:17]=[C:16]3[C:18]([C:21]([NH:24][C:25]4([CH2:28][OH:29])[CH2:27][CH2:26]4)=[O:22])=[CH:19][NH:20][C:15]3=[N:14][CH:13]=2)=[N:3]1
Reactant: Cc1ccc2c(-c3cnc4[nH]cc(C(=O)O)c4n3)nn(C)c2c1
Reactant: NC1(CO)CC1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc2c(-c3cnc4[nH]cc(C(=O)NC5(CO)CC5)c4n3)nn(C)c2c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 35.8 %

Procedure:
To a stirred mixture of 2-(1,6-dimethyl-1H-indazol-3-yl)-5H-pyrrolo[3,2-b]pyrazine-7-carboxylic acid (80 mg, 0.26 mmol) and (1-aminocyclopropyl)methanol (34 mg, 0.39 mmol) in DMF (3 mL), was added EDCI (100 mg, 0.52 mmol) followed by DMAP (63 mg, 0.52 mmol). The mixture was stirred at room temperature for 16 hours. Then the mixture was poured into water (5 mL) and filtered. The crude product was purified by preparative-HPLC (Gemini 5u C18 150×21.2 mm; inject volume: 3 mL/inj, flow rate: 20 mL/min; wavelength: 214 nm and 254 nm; the gradient conditions were: 35% acetonitrile/65% water (0.1% trifluoroacetic acid, v/v) initially, proceeding to 45% acetonitrile/55% water (0.1% trifluoroacetic acid, v/v) in a linear fashion over 9 min.) to give 2-(1,6-dimethyl-1H-indazol-3-yl)-N-(1-(hydroxymethyl)cyclopropyl)-5H-pyrrolo[3,2-b]pyrazine-7-carboxamide (35 mg, 36%) as a white solid. MS: (M+H)+=377; 1H NMR (300 MHz, DMSO): δ 13.84 (s, 1H), 9.12 (s, 1H), 8.74 (s, 1H), 8.43-8.40 (m, 2H), 7.56 (s, 1H), 7.21 (d, 1H, J=8.4 Hz), 4.89 (brs, 1H), 4.16 (s, 3H), 3.62 (s, 2H), 2.55 (s, 3H), 0.97-0.86 (m, 4H).
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][CH:6]([CH2:10][C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]([N+:21]([O-:23])=[O:22])=[CH:13][CH:12]=1)[C:7]([OH:9])=[O:8])=[O:4].N1C=CC=CC=1.[CH3:30][Si:31]([CH3:36])([CH3:35])[CH2:32][CH2:33]O.C1(N=C=NC2CCCCC2)CCCCC1>C(#N)C>[CH3:30][Si:31]([CH3:36])([CH3:35])[CH2:32][CH2:33][O:8][C:7](=[O:9])[CH:6]([NH:5][C:3]([O:2][CH3:1])=[O:4])[CH2:10][C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]([N+:21]([O-:23])=[O:22])=[CH:13][CH:12]=1
Reactant: C[Si](C)(C)CCO
Reactant: COC(=O)NC(Cc1ccc([N+](=O)[O-])c2ccccc12)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CC#N
Solvent: c1ccncc1
Product: COC(=O)NC(Cc1ccc([N+](=O)[O-])c2ccccc12)C(=O)OCC[Si](C)(C)C
Reaction time: 1 h

Procedure:
To a mixture of 2-methoxycarbonylamino-3-(4-nitro-naphthalen-1-yl)-propionic acid (0.35 g, 1.1 mmol), pyridine (0.78 mL) and 2-trimethylsilylethanol (0.18 mL, 1.25 mmol, 1.1 eq) in acetonitrile (1.1 mL) cooled in an ice bath was added dicyclohexylcarbodiimide (0.25 g, 1.21 mmol). The mixture was stirred cold for 1 hour, placed in the refrigerator for 14 hours. The reaction mixture was filtered, concentrated under reduced pressure and purified on silica gel eluting with heptane/ethyl acetate (4:1) to provide the titled compound. MS ESI(−)) m/e 417 (M−H)−.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:16][CH2:15][N:14]([C:17]([C:19]2[CH:24]=[CH:23][C:22]([N:25]3[CH2:29][CH2:28][NH:27][C:26]3=[O:30])=[CH:21][CH:20]=2)=[O:18])[CH2:13][CH2:12]1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Br[CH2:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36].O>CN(C)C=O>[C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:12][CH2:13][N:14]([C:17]([C:19]2[CH:24]=[CH:23][C:22]([N:25]3[CH2:29][CH2:28][N:27]([CH2:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[C:26]3=[O:30])=[CH:21][CH:20]=2)=[O:18])[CH2:15][CH2:16]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccccc1N1CCN(C(=O)c2ccc(N3CCNC3=O)cc2)CC1
Reactant: CC(C)(C)OC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CN1CCN(c2ccc(C(=O)N3CCN(c4ccccc4C(C)(C)C)CC3)cc2)C1=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 1-(4-{[4-(2-tert-butylphenyl)piperazin-1-yl]carbonyl}phenyl)imidazolidin-2-one (1.0 g, 2.46 mmol) and sodium hydride (0.16 g, 4.0 mmol) in N,N-dimethylformamide (20 mL) was stirred at 0° C. for 1 h. tert-Butyl bromoacetate was added to the reaction mixture and the mixture was stirred at room temperature for 3 h. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give a solid (1.3 g, quant.).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([CH:29]=[CH:30][CH:31]=1)[CH2:6][NH:7][C:8]([C:10]1[NH:11][C:12]2[C:17]([C:18]=1[S:19]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)(=[O:21])=[O:20])=[CH:16][C:15]([Cl:28])=[CH:14][CH:13]=2)=[O:9].B(Br)(Br)Br.CCCCCC.C([O-])(O)=O.[Na+]>C(Cl)Cl>[OH:2][C:3]1[CH:4]=[C:5]([CH:29]=[CH:30][CH:31]=1)[CH2:6][NH:7][C:8]([C:10]1[NH:11][C:12]2[C:17]([C:18]=1[S:19]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)(=[O:20])=[O:21])=[CH:16][C:15]([Cl:28])=[CH:14][CH:13]=2)=[O:9]
Reactant: COc1cccc(CNC(=O)c2[nH]c3ccc(Cl)cc3c2S(=O)(=O)c2ccccc2)c1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCCCCC
Product: O=C(NCc1cccc(O)c1)c1[nH]c2ccc(Cl)cc2c1S(=O)(=O)c1ccccc1
Reaction time: 16 h

Procedure:
To a saturated solution of N-(3-methoxybenzyl) 3-phenylsulfonyl-5-chloroindole-2-carboxamide (1.37 g, 3.0 mmol) in dry methylene chloride (140 mL) under an inert atmosphere was added boron tribromide in hexane (1M, 10 mL, 10 mmol). After stirring for 12-20 hours, the reaction was neutralized by addition of aq. NaHCO3. After two hours, the solution was made weakly acidic by addition of dilute HC1. The precipitated product was collected by filtration and then the aqueous filtrate extracted with ethyl acetate. The organic layer was dried (Na2SO4), filtered, and the solvent evaporated. The residue was triturated with diethyl ether to give additional product. The solids were combined and crystallized from hot methanol/ethyl acetate to give analytically pure product, mp 73.5°-274.5° C.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[CH:9][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:6]2[N:5]=[CH:4][C:3]=1[C:16]([N:18]1[CH2:23][CH2:22][CH:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:20][CH2:19]1)=[O:17].[F:30][C:31]1[CH:37]=[CH:36][C:34]([NH2:35])=[CH:33][C:32]=1[CH3:38]>>[CH2:14]([O:13][C:11]([C:10]1[CH:9]=[N:8][N:7]2[C:2]([NH:35][C:34]3[CH:36]=[CH:37][C:31]([F:30])=[C:32]([CH3:38])[CH:33]=3)=[C:3]([C:16]([N:18]3[CH2:23][CH2:22][CH:21]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH2:20][CH2:19]3)=[O:17])[CH:4]=[N:5][C:6]=12)=[O:12])[CH3:15]
Reactant: CCOC(=O)c1cnn2c(Cl)c(C(=O)N3CCC(c4ccccc4)CC3)cnc12
Reactant: Cc1cc(N)ccc1F
Product: CCOC(=O)c1cnn2c(Nc3ccc(F)c(C)c3)c(C(=O)N3CCC(c4ccccc4)CC3)cnc12
Yield: 99.7 %

Procedure:
In the same manner as in Example 19, step 5 and using 7-chloro-3-ethoxycarbonyl-6-(4-phenylpiperidine-1-carbonyl)pyrazolo[1,5-a]pyrimidine (100 mg, 0.24 mmol) obtained in Example 19, step 4 and 4-fluoro-3-methylaniline (46 mg, 0.36 mmol), the title compound (120 mg, 99%) was obtained.
Reaction SMILES: C[Si]([C:5]#[C:6][C:7]1[CH:8]=[CH:9][C:10]([OH:17])=[C:11]([CH:16]=1)[C:12]([O:14][CH3:15])=[O:13])(C)C.O.O.[F-].[K+]>CN(C=O)C>[C:6]([C:7]1[CH:8]=[CH:9][C:10]([OH:17])=[C:11]([CH:16]=1)[C:12]([O:14][CH3:15])=[O:13])#[CH:5]
Reactant: COC(=O)c1cc(C#C[Si](C)(C)C)ccc1O
Agent: [F-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C#Cc1ccc(O)c(C(=O)OC)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of methyl 5-[(trimethylsilyl)ethynyl]-2-hydroxybenzoate (100 g, 0.57 mol) and potassium fluoride dihydrate (150 g, 1.59 mol) in DMF (600 ml) was stirred for 4 h at room temperature. The solution was extracted with ether (3×400 ml) and the combined ether extracts were washed with 1M HCl (2×200 ml) and water (2×100 ml). The ether layer was dried with Na2SO4 and evaporated to dryness. Yield 66.5 g (93%).
Reaction SMILES: [C:1]([Si:5]([CH3:28])([CH3:27])[O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]([C:18]2[S:22][C:21]([CH2:23][OH:24])=[C:20]([CH3:25])[CH:19]=2)([CH2:16][CH3:17])[CH2:14][CH3:15])=[CH:9][C:8]=1[CH3:26])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:36]1([CH3:46])[CH:41]=[CH:40][C:39]([S:42](Cl)(=[O:44])=[O:43])=[CH:38][CH:37]=1>CCOCC>[C:1]([Si:5]([CH3:28])([CH3:27])[O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]([C:18]2[S:22][C:21]([CH2:23][O:24][S:42]([C:39]3[CH:40]=[CH:41][C:36]([CH3:46])=[CH:37][CH:38]=3)(=[O:44])=[O:43])=[C:20]([CH3:25])[CH:19]=2)([CH2:16][CH3:17])[CH2:14][CH3:15])=[CH:9][C:8]=1[CH3:26])([CH3:2])([CH3:4])[CH3:3]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCC(CC)(c1ccc(O[Si](C)(C)C(C)(C)C)c(C)c1)c1cc(C)c(CO)s1
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CCC(CC)(c1ccc(O[Si](C)(C)C(C)(C)C)c(C)c1)c1cc(C)c(COS(=O)(=O)c2ccc(C)cc2)s1
Reaction time: 8 h
Yield: 54 %

Procedure:
To a solution of (5-{1-[4-(tert-butyl-dimethyl-silanyloxy)-3-methyl-phenyl]-1-ethyl-propyl}-3-methyl-thiophen-2-yl)-methanol (1.0 g, 2.39 mmol) in Et2O (5 ml) is added triethyl amine (666 μl, 4.78 mmol). The mixture is added to a solution of p-toluenesulfonyl chloride (501 mg, 2.62 mmol) in Et2O (5 ml) and stirred overnight. The reaction is filtered, concentrated and chromatographed (12 g SiO2, 5% EtOAc/Hex) to yield the title compound (740 mg, 55%).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]2[NH:15][C:14](=[O:16])[O:13][CH2:12][C:11]=2[CH:17]=1.[CH3:18][C:19]1[CH:24]=[CH:23][C:22]([SH:25])=[CH:21][CH:20]=1>>[CH3:18][C:19]1[CH:24]=[CH:23][C:22]([S:25][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]2[CH:8]=[CH:9][C:10]3[NH:15][C:14](=[O:16])[O:13][CH2:12][C:11]=3[CH:17]=2)=[CH:21][CH:20]=1
Reactant: O=C1Nc2ccc(OCCCCCl)cc2CO1
Reactant: Cc1ccc(S)cc1
Product: Cc1ccc(SCCCCOc2ccc3c(c2)COC(=O)N3)cc1

Procedure:
Prepared analogously to Example 1 from 6-(4-chlorobutoxy)-4H-3,1-benzoxazin-2-one and 4-methyl-thiophenol.