Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:9]=C[CH:11]=1)[C:5](OO)=[O:6].[OH:12][C:13]1[CH:14]=[C:15]([S:19][C:20]2[C:28]3[C:27](=[O:29])[N:26]([CH3:30])[C:25](=[O:31])[N:24]([CH2:32][CH:33]([CH3:35])[CH3:34])[C:23]=3[S:22][C:21]=2[CH2:36][C:37]2[C:46]3[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=3)[CH:40]=[CH:39][CH:38]=2)[CH:16]=[CH:17][CH:18]=1.C(OCC)(=O)C>ClCCl>[CH3:11][CH2:2][CH2:3][CH:4]([CH3:9])[CH3:5].[OH:12][C:13]1[CH:14]=[C:15]([S:19]([C:20]2[C:28]3[C:27](=[O:29])[N:26]([CH3:30])[C:25](=[O:31])[N:24]([CH2:32][CH:33]([CH3:34])[CH3:35])[C:23]=3[S:22][C:21]=2[CH2:36][C:37]2[C:46]3[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=3)[CH:40]=[CH:39][CH:38]=2)=[O:6])[CH:16]=[CH:17][CH:18]=1
Reactant: CC(C)Cn1c(=O)n(C)c(=O)c2c(Sc3cccc(O)c3)c(Cc3cccc4ccccc34)sc21
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)Cn1c(=O)n(C)c(=O)c2c(S(=O)c3cccc(O)c3)c(Cc3cccc4ccccc34)sc21
Product: CCCC(C)C
Reaction time: 2 h
Yield: 24.2 %

Procedure:
3-Chloroperoxybenzoic acid (0.12 g) was added to a solution of 5-[(3-hydroxyphenyl)thio]-3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (Example 27, 0.20 g) in dichloromethane (5 ml). After 2 hours, ethyl acetate (50 ml) was added and the solution was washed with saturated sodium bisulfite solution (25 ml), then with saturated sodium hydrogen carbonate solution (25 ml), then with brine (25 ml). The organic layer was dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure. The residue was purified by preparative normal-phase HPLC with dichloromethane:ethanol gradient elution then recrystallised from ethyl acetate:isohexane to give the title compound (0.05 g).
Reaction SMILES: [O:1]([CH2:8][C:9]([NH:11][CH:12]1[C:23](=[O:24])[N:14]2[C:15]([C:20]([O-:22])=[O:21])=[C:16]([CH3:19])[CH2:17][S:18][C@H:13]12)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Na+].S([O-])([O-])(=O)=O.[OH-].[CH2:32]([N+](CCCC)(CCCC)CCCC)[CH2:33][CH2:34]C.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.[OH-].[Na+].C(Br)C=C>C(Cl)Cl.O>[O:1]([CH2:8][C:9]([NH:11][CH:12]1[C:23](=[O:24])[N:14]2[C:15]([C:20]([O:22][CH2:34][CH:33]=[CH2:32])=[O:21])=[C:16]([CH3:19])[CH2:17][S:18][C@H:13]12)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCC[N+](CCCC)(CCCC)CCCC
Reactant: CC1=C(C(=O)[O-])N2C(=O)C(NC(=O)COc3ccccc3)[C@H]2SC1
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C=CCBr
Solvent: ClCCl
Product: C=CCOC(=O)C1=C(C)CS[C@@H]2C(NC(=O)COc3ccccc3)C(=O)N12
Temperature: 50 °C
Reaction time: 0.08 h

Procedure:
The solution of sodium 7-phenoxyacetylamino-3-methyl-3-cephem-4-carboxylate was added to a solution of 71.3 g (210 mmole) of tetra-n-butylammonium hydroxide sulfate in 700 ml of methylene chloride and 700 ml of water which had been readjusted to pH 7.5 with 2N sodium hydroxide. The mixture was stirred for about 5 minutes and the methylene chloride layer was separated. The aqueous phase was extracted twice with methylene chloride and the extracts were combined with the organic layer. The organic layer was dried over magnesium sulfate and evaporated to a brown oil. The oil was dissolved in 250 ml of chloroform and 34.6 ml (400 mmole) of allyl bromide (previously filtered through activated alumina) were added with stirring. The mixture was stirred for about 19 hours at room temperature and when thin layer chromatography indicated some remaining starting material, 17 ml of allyl bromide were added and the mixture was heated to 50° C. with stirring for about 2 hours. The reaction mixture was evaporated on a rotary evaporator to remove chloroform and the concentrate was dissolved in 3:1, v:v of diethyl ether:methylene chloride and the solution extracted twice with pH 7 buffer, once with brine and was dried over magnesium sulfate. The solution was evaporated under vacuum to provide allyl 7-phenoxyacetylamino-3-methyl-3-cephem-4-carboxylate as a crude yellow solid.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([NH:11][C:12]3[CH:17]=[C:16]([C:18]4[CH2:19][CH2:20][NH:21][CH2:22][CH:23]=4)[N:15]=[CH:14][N:13]=3)[CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C=O.[C:26](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CC#N>[CH3:26][N:21]1[CH2:20][CH:19]=[C:18]([C:16]2[N:15]=[CH:14][N:13]=[C:12]([NH:11][C:8]3[CH:9]=[C:10]4[C:5]([CH:4]=[CH:3][CH:2]=[N:1]4)=[CH:6][CH:7]=3)[CH:17]=2)[CH2:23][CH2:22]1
Reactant: C1=C(c2cc(Nc3ccc4cccnc4c3)ncn2)CCNC1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: [Na+]
Solvent: CC#N
Product: CN1CC=C(c2cc(Nc3ccc4cccnc4c3)ncn2)CC1

Procedure:
This compound could be prepared from quinolin-7-yl-[6-(1,2,3,6-tetrahydro-pyridin-4-yl)-pyrimidin-4-yl]-amine and formaldehyde in the presence of sodium triacetoxyborohydride and MeCN.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6].Cl[C:14](Cl)([O:16]C(=O)OC(Cl)(Cl)Cl)Cl.C(N(CC)CC)C.[C:32]1([CH3:62])[C:33]([C:38]([CH2:40][N:41]2[C:47]3[CH:48]=[C:49]([CH3:52])[CH:50]=[CH:51][C:46]=3[N:45]([C:53]([C:55]3[O:56][CH:57]=[CH:58][CH:59]=3)=[O:54])[CH2:44][CH:43]([NH2:60])[C:42]2=[O:61])=[O:39])=[CH:34][CH:35]=[CH:36][CH:37]=1>O1CCCC1>[C:32]1([CH3:62])[C:33]([C:38]([CH2:40][N:41]2[C:47]3[CH:48]=[C:49]([CH3:52])[CH:50]=[CH:51][C:46]=3[N:45]([C:53]([C:55]3[O:56][CH:57]=[CH:58][CH:59]=3)=[O:54])[CH2:44][CH:43]([NH:60][C:14]([NH:1][C:2]3[CH:12]=[CH:11][CH:10]=[C:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH:3]=3)=[O:16])[C:42]2=[O:61])=[O:39])=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CCOC(=O)c1cccc(N)c1
Reactant: Cc1ccc2c(c1)N(CC(=O)c1ccccc1C)C(=O)C(N)CN2C(=O)c1ccco1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cccc(NC(=O)NC2CN(C(=O)c3ccco3)c3ccc(C)cc3N(CC(=O)c3ccccc3C)C2=O)c1
Reaction time: 8 h
Yield: 96.9 %

Procedure:
Ethyl 3-aminobenzoate (373 mg) was dissolved in tetrahydrofuran (60 ml), under ice-cooling triphosgene (225 mg) was added, triethylamine (194 μl) was added thereto five times every 3 minutes, a solution of 1-(2-toluoylmethyl)-2-oxo-3-amino-5-(furan-2-ylcarbonyl)-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine (856 mg) in tetrahydrofuran (15 ml) was added thereto, the mixture was allowed to come to room temperature and stirred overnight. The reaction mixture was concentrated under reduced pressure, water (50 ml) was added to the residue, extracted with methylene chloride. The organic layer was dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography(chloroform:ethyl acetate=10:1), to thereby obtain 447 mg of the titled compound.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[C:3]=1[O:4][C:5]1[C:18](=[O:19])[N:17]([CH3:20])[C:8]2[N:9]=[C:10](S(C)(=O)=O)[N:11]=[CH:12][C:7]=2[CH:6]=1.[F:26][C:27]1[CH:33]=[CH:32][C:30]([NH2:31])=[CH:29][CH:28]=1.CO>CN1CCCC1=O>[Cl:1][C:2]1[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[C:3]=1[O:4][C:5]1[C:18](=[O:19])[N:17]([CH3:20])[C:8]2[N:9]=[C:10]([NH:31][C:30]3[CH:32]=[CH:33][C:27]([F:26])=[CH:28][CH:29]=3)[N:11]=[CH:12][C:7]=2[CH:6]=1
Reactant: Cn1c(=O)c(Oc2c(Cl)cccc2Cl)cc2cnc(S(C)(=O)=O)nc21
Reactant: Nc1ccc(F)cc1
Solvent: CN1CCCC1=O
Solvent: CO
Product: Cn1c(=O)c(Oc2c(Cl)cccc2Cl)cc2cnc(Nc3ccc(F)cc3)nc21
Temperature: 110 °C
Reaction time: 12 h

Procedure:
A mixture of 6-(2,6-dichlorophenoxy)-8-methyl-2-(methylsulfonyl)pyrido[2,3-d]pyrimidin-7(8H)-one (see Example 12—Step A-B, (replacing methyl 2-fluorophenoxyacetate with methyl 2,6-dichlorophenoxyacetate) 0.35 g, 1 mmol) and 4-fluoroaniline (0.284 mL, 3 mmol) in 0.5 mL 1-methyl-2-pyrrolidinone was stirred at 110° C. for 12 hours and then cooled to room temperature. Methanol (2 mL) was added and the suspension was stirred for 30 minutes. Filtration and washing of the precipitate thoroughly with methanol followed by drying provided the crude product which was purified by column chromatography (SiO2, CH2Cl2/MeOH—95/5). The column fractions were combined and concentrated under reduced pressure to provide the free amine. This was suspended in ethyl acetate (1-2 mL) and hydrochloric acid in ether (1M, 1.2 eq) was added. Isolation of the solid via filtration and drying provided 0.131 g of the hydrochloride salt (Mass spec. M+1=430, MP=248.2-249.1° C.).
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[CH:22][C:5]([C:6]([N:8]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[CH2:12][N:11]3[CH:19]=[CH:20][CH:21]=[C:10]3[CH2:9]2)=[O:7])=[C:4]([Cl:24])[CH:3]=1.C(N(CC)C(C)C)(C)C.[CH3:34][C:35]1[C:40]([C:41](Cl)=[O:42])=[CH:39][CH:38]=[CH:37][N:36]=1>C(Cl)Cl>[CH:21]1[CH:20]=[CH:19][N:11]2[CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[N:8]([C:6]([C:5]3[CH:22]=[CH:23][C:2]([NH:1][C:41]([C:40]4[C:35]([CH3:34])=[N:36][CH:37]=[CH:38][CH:39]=4)=[O:42])=[CH:3][C:4]=3[Cl:24])=[O:7])[CH2:9][C:10]=12
Reactant: Nc1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)c(Cl)c1
Reactant: Cc1ncccc1C(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ncccc1C(=O)Nc1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)c(Cl)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 1.1 g of 10,11-dihydro-10-(4-amino-2-chlorobenzoyl)-5H-pyrrolo[2,1-c][1,4]benzodiazepine and 3 ml of N,N-diisopropylethylamine in 100 ml of methylene chloride is stirred while a solution of 600 mg of 2-methylpyridine-3-carbonyl chloride in 15 ml of methylene chloride is added slowly. The reaction mixture is stirred at room temperature for 2 hours. The reaction mixture is quenched with water and the organic layer washed with water, dried(MgSO4), filtered and evaporated in vacuo to a residue. The product is purified by column chromatography on silica gel by elution with 1:1 ethyl acetate:hexane to give the desired product as a pale yellow residue. M+ =456.
Reaction SMILES: [S:1]([N:11]1[C:15]2=[N:16][CH:17]=[C:18]([CH:20]=[N:21]O)[N:19]=[C:14]2[CH:13]=[CH:12]1)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].CC(O)=O.C(Cl)[Cl:28]>C1COCC1.[Zn]>[ClH:28].[S:1]([N:11]1[C:15]2=[N:16][CH:17]=[C:18]([CH2:20][NH2:21])[N:19]=[C:14]2[CH:13]=[CH:12]1)([C:4]1[CH:5]=[CH:6][C:7]([CH3:8])=[CH:9][CH:10]=1)(=[O:2])=[O:3]
Reactant: ClCCl
Reactant: Cc1ccc(S(=O)(=O)n2ccc3nc(C=NO)cnc32)cc1
Agent: [Zn]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: Cc1ccc(S(=O)(=O)n2ccc3nc(CN)cnc32)cc1
Product: Cl
Reaction time: 2 h

Procedure:
To a solution of 5-tosyl-5H-pyrrolo[2,3-b]pyrazine-2-carbaldehyde (0.150 g, 0.498 mmol) in MeOH (10 mL) was added hydroxylamine (50% solution in water, 0.061 mL, 1.0 mmol). The reaction mixture was heated to about 45° C. After about 2 h, the reaction mixture was cooled to ambient temperature and concentrated under reduced pressure to provide the crude 5-tosyl-5H-pyrrolo[2,3-b]pyrazine-2-carbaldehyde oxime as a tan solid. LC/MS (Table 2, Method a) Rt=2.15 min; MS m/z: 317 (M+H)+. To a solution of the crude oxime in THF (20 mL) was added AcOH (0.285 mL, 4.98 mmol) followed by zinc dust (<10 micron, 0.130 g, 1.99 mmol). After a further 2 h, additional AcOH (0.285 mL, 4.98 mmol) and zinc dust (<10 micron, 0.130 g, 1.99 mmol) were added to the reaction mixture. After about an additional 2 h, additional AcOH (0.285 mL, 4.98 mmol) and zinc dust (<10 micron, 0.130 g, 1.99 mmol) were added to the reaction mixture. After about 15 h, the reaction mixture was diluted with DCM (about 5 mL) and filtered. The filtrate was washed with saturated aqueous NaHCO3 and brine. The organic layer was dried over anhydrous Na2SO4, filtered, treated with HCl (4 M in 1,4-dioxane, 1 mL) and concentrated under reduced pressure to provide (5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)methanamine hydrochloride: LC/MS (Table 2, Method a) Rt=1.64 min; MS m/z: 303 (M+H)+. To a suspension of the crude amine hydrochloride in DCM (10 mL) was added TEA (0.208 mL, 1.49 mmol) followed by cyclohexanecarbonyl chloride (0.101 mL, 0.747 mmol). After about 30 min, the reaction mixture was diluted with DCM and washed with saturated aqueous NaHCO3 (25 mL) and brine (25 mL). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude amide was purified by silica gel chromatography eluting with a gradient of 40-80% EtOAc in DCM to provide N-((5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)methyl)cyclohexanecarboxamide as a tan solid (0.081 g, 39% over 2 steps). LC/MS (Table 2, Method a) Rt=2.40 min; MS m/z: 413 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:3]=1[O:4][CH2:5][C:6](Cl)=[O:7].CN1C=CN=C1.[N+:20]([CH:23]=[C:24]1[NH:29][CH2:28][CH2:27][CH2:26][S:25]1)([O-:22])=[O:21].[O-][Si]([O-])=O.[Mg+2]>O1CCCC1.C(Cl)Cl.O>[Cl:1][C:2]1[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:3]=1[O:4][CH2:5][C:6](=[O:7])[C:23]([N+:20]([O-:22])=[O:21])=[C:24]1[NH:29][CH2:28][CH2:27][CH2:26][S:25]1
Reactant: O=[N+]([O-])C=C1NCCCS1
Reactant: O=C(Cl)COc1ccc(Cl)cc1Cl
Agent: Cn1ccnc1
Agent: O=[Si]([O-])[O-]
Agent: [Mg+2]
Solvent: O
Solvent: ClCCl
Solvent: C1CCOC1
Product: O=C(COc1ccc(Cl)cc1Cl)C(=C1NCCCS1)[N+](=O)[O-]
Reaction time: 0.5 h

Procedure:
A solution of 7.2 g of 2,4-dichlorophenoxyacetyl chloride in 20 ml of tetrahydrofuran was added dropwise to a solution of 2.5 g of 1-methylimidazole in 80 ml of tetrahydrofuran at 0.5°. The resulting slurry was stirred for 30 minutes at 5°, then 4.8 g of 5B was added all at once. The mixture was stirred overnight. Then 0.5 equivalent mole of the imidazole complex in 50 ml of tetrahydrofuran was prepared and added at 5°. The stirred mixture was allowed to rise slowly to room temperature, and stirred overnight. The solvent was stripped; the residue was treated with 1:1 volume mixture of water and methylene chloride. The phases were separated, the water phase was extracted with methylene chloride, the methylene chloride solutions were combined, washed with water and saturated salt solution, dried (MgSO4) and the solvent was stripped to give an oil. The oil was passed through Florisil to give a mush, which was triturated with pentane to give 3-(2,4-dichlorophenoxy)- 1-nitro-1-(tetrahydro-2H-1,3-thiazin-2-ylidene)-2-propanone (5C), as a pale yellow solid, m.p.: 164°-164.5°.
Reaction SMILES: [NH2:1][C:2]1[C:11]([F:12])=[C:10]([F:13])[C:9]2[O:14][CH2:15][C@H:16]([CH3:17])[N:7]3[C:8]=2[C:3]=1[C:4](=[O:21])[C:5]([C:18]([NH2:20])=O)=[CH:6]3.C(N(CC)CC)C.O=P(Cl)(Cl)Cl.N#N>C(Cl)Cl>[NH2:1][C:2]1[C:11]([F:12])=[C:10]([F:13])[C:9]2[O:14][CH2:15][C@H:16]([CH3:17])[N:7]3[C:8]=2[C:3]=1[C:4](=[O:21])[C:5]([C:18]#[N:20])=[CH:6]3
Reactant: C[C@H]1COc2c(F)c(F)c(N)c3c(=O)c(C(N)=O)cn1c23
Agent: N#N
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@H]1COc2c(F)c(F)c(N)c3c(=O)c(C#N)cn1c23
Reaction time: 5 h
Yield: 82.2 %

Procedure:
To a solution of 4 (500 mg, 1.69 mmol) and triethylamine (1.2 mL, 8.5 mmol.) in DCM (20 mL) was added POCl3 (431 μL, 3.2 mmol.) dropwise under Ar (or N2) at 0° C. Stirring was continued for an additional 5 h. A dark colored mixture was formed. Upon completion of the reaction, DCM was removed under vacuo and the residue was washed several times with water. The solid was dried under vacuum to give 5 (385 mg, 82% yield). This product was not very soluble except in DMF or DMSO and was used in the next step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:35]=[CH:34][C:33](I)=[CH:32][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[CH:9][C:8]=1[N:17]1[CH2:22][CH2:21][CH2:20][C@H:19]([N:23]([CH3:31])[C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH2:18]1)=[O:5].[C:37]([C:39]1[CH:40]=[N:41][C:42]([NH2:45])=[N:43][CH:44]=1)#[CH:38].C(N(CC)CC)C>CC#N.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.[Cu]I>[NH2:45][C:42]1[N:43]=[CH:44][C:39]([C:37]#[C:38][C:33]2[CH:34]=[CH:35][C:2]([F:1])=[C:3]([CH:32]=2)[C:4]([NH:6][C:7]2[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[CH:9][C:8]=2[N:17]2[CH2:22][CH2:21][CH2:20][C@H:19]([N:23]([CH3:31])[C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH2:18]2)=[O:5])=[CH:40][N:41]=1
Reactant: C#Cc1cnc(N)nc1
Reactant: CN(C(=O)OC(C)(C)C)[C@H]1CCCN(c2ccc(C(F)(F)F)cc2NC(=O)c2cc(I)ccc2F)C1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CN(C(=O)OC(C)(C)C)[C@H]1CCCN(c2ccc(C(F)(F)F)cc2NC(=O)c2cc(C#Cc3cnc(N)nc3)ccc2F)C1
Reaction time: 16 h

Procedure:
In a 25-mL RBF (S)-tert-butyl 1-(2-(2-fluoro-5-iodobenzamido)-4-(trifluoromethyl)phenyl)piperidin-3-yl(methyl)carbamate (0.496 g, 0.80 mmol), 5-ethynylpyrimidin-2-amine (0.19 g, 1.6 mmol), Bis(triphenylphosphine)palladium(II) dichloride (0.028 g, 0.040 mmol), and Copper(I) iodide (0.0076 g, 0.040 mmol) were taken up in CH3CN and Triethylamine (1.7 ml, 12 mmol) was added, and the tube was flushed with nitrogen. The tube was sealed and the reaction heated to 70 deg. C. for 16 h. The reaction was cooled and transfered to a larger flask with EtOAc and concentrated in vacuo. The solid was adsorbed onto 4 g silica gel from 10% MeOH/MC purified by Isco {Redi-Sep® pre-packed silica gel column (80 g); eluent 0-75% EtOAc/hexanes over 30 min}. Product-containing fractions were concentrated to afford (S)-tert-butyl 1-(2-(5-(2-(2-aminopyrimidin-5-yl)ethynyl)-2-fluorobenzamido)-4-(trifluoromethyl)phenyl)piperidin-3-yl(methyl)carbamate as a orange foam. MS m/z=613 [M+H]+. Calc'd for C31H32F4N6O3: 612.
Reaction SMILES: [Br:1][C:2]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:3]=1[O:4][CH:5]1[CH2:8][N:7]([C:9]2[N:10]=[CH:11][C:12]([C:15]([NH2:17])=O)=[N:13][CH:14]=2)[CH2:6]1.C(N(CC)CC)C.C(OC(C(F)(F)F)=O)(C(F)(F)F)=O>C1COCC1>[Br:1][C:2]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:3]=1[O:4][CH:5]1[CH2:8][N:7]([C:9]2[N:10]=[CH:11][C:12]([C:15]#[N:17])=[N:13][CH:14]=2)[CH2:6]1
Reactant: NC(=O)c1cnc(N2CC(Oc3cc(F)ccc3Br)C2)cn1
Solvent: CCN(CC)CC
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: C1CCOC1
Product: N#Cc1cnc(N2CC(Oc3cc(F)ccc3Br)C2)cn1
Reaction time: 0.25 h

Procedure:
To 5-[3-(2-bromo-5-fluorophenoxy)azetidin-1-yl]pyrazine-2-carboxamide (0.66 g, 1.8 mmol) in THF (30 mL) at 0° C. was added triethylamine (0.46 g, 4.5 mmol) followed by TFAA (0.57 g, 2.7 mmol). After 15 min at room temperature, the reaction mixture was partitioned between ethyl acetate and saturated sodium bicarbonate. The organic phase was separated, dried over sodium sulfate and filtered. The residue was purified by flash chromatography to provide the title compound as a white solid.
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][N:17]3C(=O)C4=CC=CC=C4C3=O)[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.O.NN>C(O)C>[F:29][C:2]([F:1])([F:28])[C:3]1[CH:4]=[CH:5][C:6]([N:9]2[CH2:10][CH2:11][N:12]([CH2:15][CH2:16][NH2:17])[CH2:13][CH2:14]2)=[CH:7][CH:8]=1
Reactant: O=C1c2ccccc2C(=O)N1CCN1CCN(c2ccc(C(F)(F)F)cc2)CC1
Agent: NN
Solvent: CCO
Solvent: O
Product: NCCN1CCN(c2ccc(C(F)(F)F)cc2)CC1
Yield: 105.9 %

Procedure:
N-{2-[4-(4-trifluoromethylphenyl)piperazin-1-yl]ethyl}phthalimide (4 g, 9.92 mmol) prepared in Reference Example 153 was suspended in ethanol (30 ml), to which hydrazine monohydrate (0.53 ml, 10.91 mmol) was added, and the mixture was heated under reflux for 5 hours. The reaction mixture was allowed to return to room temperature, and the resulting precipitates were collected by filtration. This was purified by silica gel column chromatography (methylene chloride/ethyl acetate=100/1) to afford 2-[4-(4-trifluoromethylphenyl)piperazin-1-yl]ethylamine (2.87 g, yield 100%) as a colorless crystalline powder.
Reaction SMILES: [Cl:1][C:2]1[C:9]([Cl:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[I-].[CH3:12][S+](C)C.[OH-].[K+].O>C(#N)C.C(OCC)(=O)C>[Cl:1][C:2]1[C:9]([Cl:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]1[CH2:12][O:5]1
Reactant: C[S+](C)C
Reactant: O=Cc1cccc(Cl)c1Cl
Agent: [I-]
Agent: [K+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC#N
Product: Clc1cccc(C2CO2)c1Cl
Temperature: 60 °C

Procedure:
To a solution of 2,3-dichlorobenzaldehyde (0.314 mmol) in acetonitrile (1 ml) was added solid trimethylsulfonium iodide (0.314 mmol, 64 mg), potassium hydroxide (0.628 mmol, 35 mg), and water (0.079 mmol, 1.4 μl). The heterogeneous mixture were heated in a capped test tube at 60° C. for 3 h. The suspension was then diluted with ethyl acetate (1 ml) and washed with saturated sodium bicarbonate (1×1 ml) and water (3×0.5 ml). The tube was concentrated by vacuum centrifuge over 1 hour and the resulting 2,3-dichlorophenyloxirane used without further purification
Reaction SMILES: C(OC(N1CCN(C([C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([C:25]#[N:26])[CH:23]=3)[N:18]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:17]=2[O:33][C:34]2[CH:39]=[C:38]([F:40])[CH:37]=[CH:36][C:35]=2[CH3:41])=O)CC1)=O)(C)(C)C.[C:42]([NH2:45])(=[O:44])C.[OH2:46]>C1COCC1.[Pd](Cl)Cl>[F:40][C:38]1[CH:37]=[CH:36][C:35]([CH3:41])=[C:34]([CH:39]=1)[O:33][C:17]1[N:18]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:19]2[C:24]([C:16]=1[C:42]([N:45]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1)=[O:44])=[CH:23][C:22]([C:25]([NH2:26])=[O:46])=[CH:21][CH:20]=2
Reactant: Cc1ccc(F)cc1Oc1c(C(=O)N2CCN(C(=O)OC(C)(C)C)CC2)c2cc(C#N)ccc2n1-c1ccccc1
Reactant: O
Reactant: CC(N)=O
Agent: Cl[Pd]Cl
Solvent: C1CCOC1
Product: Cc1ccc(F)cc1Oc1c(C(=O)N2CCNCC2)c2cc(C(N)=O)ccc2n1-c1ccccc1
Temperature: 25 °C
Reaction time: 30 h

Procedure:
A mixture of 4-[5-cyano-2-(5-fluoro-2-methyl-phenoxy)-1-phenyl-1H-indole-3-carbonyl]-piperazine-1-carboxylic acid tert-butyl ester (70 mg, 0.126 mmol), acetamide (31.5 mg, 0.53 mmol) and palladium(II) chloride (2.2 mg, 13 μmol) in THF (4 ml) and water (1.4 ml) was stirred at room temperature for 30 h. After addition of water, the mixture was extracted with EA. The combined organic layers were dried over sodium sulfate and concentrated. The residue was dissolved in DCM (1 ml), TFA (0.3 ml) was added, and the mixture was stirred at room temperature for 1 h. The solvents were evaporated and the obtained solid was purified by preparative HPLC. The eluate was lyophilized overnight. The residue was dissolved in a small quantity of MOH, mixed with hydrochloric acid (0.1 M) and lyophilized overnight. 13.5 mg of the title compound were obtained in the form of the 2-(5-fluoro-2-methyl-phenoxy)-1-phenyl-3-(piperazine-1-carbonyl)-1H-indole-5-carboxylic acid amide hydrochloride.
Reaction SMILES: [C:1]([C:9]1[CH:17]=[CH:16][C:12]([C:13](Cl)=[O:14])=[CH:11][CH:10]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:18]1[CH:19]=[CH:20][N:21]2[CH2:27][C:26]3[CH:28]=[CH:29][CH:30]=[CH:31][C:25]=3[NH:24][CH2:23][C:22]=12.C(N(CC)CC)C>C(Cl)Cl.C(Cl)(Cl)Cl>[C:1]([C:9]1[CH:17]=[CH:16][C:12]([C:13]([N:24]2[C:25]3[CH:31]=[CH:30][CH:29]=[CH:28][C:26]=3[CH2:27][N:21]3[CH:20]=[CH:19][CH:18]=[C:22]3[CH2:23]2)=[O:14])=[CH:11][CH:10]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccc(C(=O)c2ccccc2)cc1
Reactant: c1ccc2c(c1)Cn1cccc1CN2
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: O=C(c1ccccc1)c1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1
Reaction time: 16 h
Yield: 84.5 %

Procedure:
A mixture of 2.16 g of 4-(benzoyl)benzoyl chloride (Reference Example 36) and 1.0 g of 10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine in 30 ml of methylene chloride containing 7 ml of triethylamine is stirred under nitrogen atmosphere for 16 hours. The reaction mixture is diluted with 50 ml of chloroform and washed with 2N HCl, water, saturated NaHCO3 and water. The organic layer is dried (Na2SO4) and columned on silica gel by elution with 7:1 to 3:1 ethyl acetate:hexane to give 1.8 g of the desired product as a solid. M+H 393.2; M+Na 415.2.