Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7]2[CH:13]=[C:12](B(O)O)[CH:11]=[CH:10][C:8]=2[N:9]=1)(=[O:3])[CH3:2].Br[C:18]1[CH:19]=[C:20]([O:24][CH2:25][CH2:26][N:27]2[CH2:31][CH2:30][CH2:29][C:28]2=[O:32])[CH:21]=[N:22][CH:23]=1.C(=O)([O-])[O-].[Na+].[Na+]>[Pd].O1CCOCC1>[O:32]=[C:28]1[CH2:29][CH2:30][CH2:31][N:27]1[CH2:26][CH2:25][O:24][C:20]1[CH:19]=[C:18]([C:12]2[CH:11]=[CH:10][C:8]3[N:9]=[C:5]([NH:4][C:1](=[O:3])[CH3:2])[S:6][C:7]=3[CH:13]=2)[CH:23]=[N:22][CH:21]=1
Reactant: CC(=O)Nc1nc2ccc(B(O)O)cc2s1
Reactant: O=C1CCCN1CCOc1cncc(Br)c1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CC(=O)Nc1nc2ccc(-c3cncc(OCCN4CCCC4=O)c3)cc2s1
Reaction time: 0.33 h

Procedure:
To a 5 ml CEM microwave tube was added 2-acetamidobenzo[d]thiazol-6-ylboronic acid (0.1 g, 0.4 mmol), 1-(2-(5-bromopyridin-3-yloxy)ethyl)pyrrolidin-2-one (0.2 g, 0.6 mmol), sodium carbonate (0.6 ml, 1 mmol), Pd FibreCat® (Anchored homogeneous catalyst, Johnson Matthey, West Deptford, N.J. (30% wt, 45 mg), and dioxane (3 mL). The vial was sealed and placed into CEM microwave for 20 min. at 100° C., with 100 watts of power via Powermax®. The reaction mixture was partitioned between EtOAc/water. The aqueous layer was extracted with EtOAc (2×10 mL). The combined organic layers were washed with water, brine, dried over MgSO4 and removed solvent. The crude product was purified using SiO2 chromatography with DCM:MeOH (95%:5%) solvent system to afford the product as white solid. Wt: 45.0 mg. MS (ESI pos. ion) m/z: 397.3. Calc'd exact mass for C20H20N4O3S: 396.46. 1H NMR (300 MHz, chloroform-d) δ ppm 1.99-2.14 (m, 2H) 2.33 (s, 3H) 2.42 (t, J=8.11 Hz, 2H) 3.62 (t, J=7.09 Hz, 2H) 3.74 (t, J=5.19 Hz, 2H) 4.25 (t, J=5.19 Hz, 2H) 7.43 (d, J=2.48 Hz, 1H) 7.62 (dd, J=8.48, 1.90 Hz, 1H) 7.81 (d, J=8.33 Hz, 1H) 7.99 (d, J=1.46 Hz, 1H) 8.27 (d, J=2.63 Hz, 1H) 8.50 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:20])=[C:4]([CH:17]=[CH:18][CH:19]=1)[CH2:5][N:6]1C(=O)C2=CC=CC=C2C1=O.O.NN.O>CO>[Cl:1][C:2]1[C:3]([CH3:20])=[C:4]([CH:17]=[CH:18][CH:19]=1)[CH2:5][NH2:6]
Reactant: Cc1c(Cl)cccc1CN1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: O
Solvent: CO
Product: Cc1c(Cl)cccc1CN
Temperature: 80 °C
Reaction time: 8 h
Yield: 100.3 %

Procedure:
1.15 g of N-(3-chloro-2-methylbenzyl)phthalimide was dissolved in 20 mL of methanol, and 5 mL of hydrazine monohydrate was added thereto at room temperature. Thereafter, it was warmed to 80° C., followed by continuously reacting overnight. After completion of the reaction, the reaction liquid was left to be cooled, and water was added thereto, followed by extraction with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and then concentrated under reduced pressure to obtain 628 mg (yield 100%) of a title compound as a colorless clear oily substance.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH2:15]Cl)=[N:13][N:14]=[C:10]3[CH2:9][N:8]=[C:7]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[F:23])[C:6]=2[CH:24]=1.[I-].[K+].[CH2:27]([CH:29]=[CH:30][CH2:31][NH2:32])[CH3:28]>O1CCCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH2:15][NH:32][CH2:31][CH2:30][CH2:29][CH:27]=[CH2:28])=[N:13][N:14]=[C:10]3[CH2:9][N:8]=[C:7]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[F:23])[C:6]=2[CH:24]=1
Reactant: CCC=CCN
Reactant: Fc1ccc2c(c1)C(c1ccccc1F)=NCc1nnc(CCl)n1-2
Agent: [I-]
Agent: [K+]
Solvent: C1CCOC1
Product: C=CCCCNCc1nnc2n1-c1ccc(F)cc1C(c1ccccc1F)=NC2

Procedure:
In the manner given in Preparation 39, 8-fluoro-1-(chloromethyl)-6-(o-fluorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine, potassium iodide and ethylallylamine in tetrahydrofuran are reacted to give 8-fluoro-1-[(allylethylamino)methyl]-6-(o-fluorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine. Preparation 47 9-(Trifluoromethyl)-1-[(allylmethylamino)methyl]-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine
Reaction SMILES: Cl[CH2:2][N:3]([C:7]1[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][C:8]=1[F:14])[C:4](Cl)=[O:5].[F:15][C:16]([F:35])([F:34])[O:17][C:18]1[CH:33]=[CH:32][C:21]([CH2:22][NH:23][C:24]([NH:26][CH2:27][C:28]([F:31])([F:30])[F:29])=[S:25])=[CH:20][CH:19]=1>C1(C)C=CC=CC=1>[F:29][C:28]([F:30])([F:31])[CH2:27][N:26]=[C:24]1[N:23]([CH2:22][C:21]2[CH:20]=[CH:19][C:18]([O:17][C:16]([F:35])([F:15])[F:34])=[CH:33][CH:32]=2)[C:4](=[O:5])[N:3]([C:7]2[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][C:8]=2[F:14])[CH2:2][S:25]1
Reactant: Cc1ccc(N(CCl)C(=O)Cl)c(F)c1
Reactant: FC(F)(F)CNC(=S)NCc1ccc(OC(F)(F)F)cc1
Solvent: Cc1ccccc1
Product: Cc1ccc(N2CSC(=NCC(F)(F)F)N(Cc3ccc(OC(F)(F)F)cc3)C2=O)c(F)c1
Yield: 54.3 %

Procedure:
0.60 g of N-chloromethyl-N-(2-fluoro-4-methylphenyl)carbamoyl chloride and 0.84 g of 1-(4-trifluoromethoxybenzyl)-3-(2,2,2-trifluoroethyl)thiourea were dissolved in 50 ml of toluene, and the solution was heated under reflux for 5 hours. After the reaction, toluene was evaporated under reduced pressure. The resulting oily product was purified by column chromatography silica gel; developing solvent hexane/ethyl acetate (9:1)) to give 0.68 g of the captioned compound.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]([C:11]2[S:12][CH:13]=[CH:14][CH:15]=2)[CH:8]=[CH:9][CH:10]=1)=[O:4].[OH-].[Na+].Cl>CO.O1CCCC1>[C:3]([C:5]1[CH:6]=[C:7]([C:11]2[S:12][CH:13]=[CH:14][CH:15]=2)[CH:8]=[CH:9][CH:10]=1)([OH:4])=[O:2]
Reactant: COC(=O)c1cccc(-c2cccs2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1cccc(-c2cccs2)c1
Temperature: 60 °C
Reaction time: 2 h
Yield: 93.6 %

Procedure:
To a solution of 2-(3-methoxycarbonylphenyl)thiophene (1.29 g) in methanol (15 ml) and tetrahydrofuran (5 ml) was added an aqueous solution of sodium hydroxide (1N, 8.87 ml) followed by stirring for 2 hours at 60° C. To the mixture was added hydrochloric acid (1N, 10 ml). The resulting precipitate was collected by filtration and dried to give 2-(3-carboxyphenyl)thiophene (1.13 g, 93.4%).
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[C:3]=1[C:4]([N:6]=[C:7]=[O:8])=[O:5].[F:14][C:15]1[CH:21]=[C:20]([O:22][CH2:23][C:24]([F:27])([F:26])[F:25])[C:19]([Cl:28])=[CH:18][C:16]=1[NH2:17]>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[C:3]=1[C:4]([NH:6][C:7]([NH:17][C:16]1[CH:18]=[C:19]([Cl:28])[C:20]([O:22][CH2:23][C:24]([F:27])([F:25])[F:26])=[CH:21][C:15]=1[F:14])=[O:8])=[O:5]
Reactant: O=C=NC(=O)c1c(F)cccc1F
Reactant: Nc1cc(Cl)c(OCC(F)(F)F)cc1F
Solvent: Cc1ccccc1
Product: O=C(NC(=O)c1c(F)cccc1F)Nc1cc(Cl)c(OCC(F)(F)F)cc1F
Reaction time: 10 h

Procedure:
A solution of 3.0 g of 2,6-difluorobenzoylisocyanate in 10 ml of dry toluene is added at room temperature to a solution of 4 g of 2-fluoro-4-(2,2,2-trifluoroethoxy)-5-chloroaniline in 50 ml of dry toluene, and the batch is stirred for 10 hours. Subsequently, about 75% of the solvent is removed by rotary evaporation. The resultant precipitate is isolated by suction filtration, washed with a small amount of cold toluene and hexane and dried in vacuo, affording the title compound of the formula ##STR15## in the form of a white, crystalline powder; m.p.: 201°-202° C.
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([CH:7]([OH:13])[CH:8]([NH2:12])[C:9]([OH:11])=[O:10])=[CH:3][CH:2]=1.[C:14]1([CH2:20][C:21](O)=O)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[CH2:20]([C:21]1[O:13][C:7]([C:4]2[CH:3]=[CH:2][CH:1]=[CH:6][CH:5]=2)=[C:8]([C:9]([OH:11])=[O:10])[N:12]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C(O)Cc1ccccc1
Reactant: NC(C(=O)O)C(O)c1ccccc1
Product: O=C(O)c1nc(Cc2ccccc2)oc1-c1ccccc1

Procedure:
Prepared starting from DL-3-phenylserine hydrate following sequentially general procedures W, X with phenyl-acetic acid, Y and Z. LC-MS-conditions 02: tR=0.95 min; [M+H]+=220.18.
Reaction SMILES: [CH2:1]([OH:7])[CH2:2][CH2:3][CH2:4][CH2:5][OH:6].[C:8]1([CH2:14]Br)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[OH-].[K+].C(OCC)C>O>[C:8]1([CH2:14][O:6][CH2:5][CH2:4][CH2:3][CH2:2][CH2:1][OH:7])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: BrCc1ccccc1
Reactant: OCCCCCO
Agent: [K+]
Agent: [OH-]
Solvent: CCOCC
Solvent: O
Product: OCCCCCOCc1ccccc1
Yield: 56.8 %

Procedure:
A stirred solution of 107.0 grams (1.0 mole) of 1,5-pentanediol, 30 ml (0.25 mole) of phenylmethyl bromide and 33.0 grams of 85% potassium hydroxide in 40 ml of xylenes was heated at 110° C. for 18 hours. After this time the reaction mixture was cooled and shaken with diethyl ether and water. The organic layer was washed in turn with water, aqueous 5% hydrochloric acid, water, and with an aqueous solution saturated with sodium chloride. The organic layer was dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to a residual oil. The oil was subjected to column chromatography on silica gel. Elution was accomplished using 0.5-50% diethyl ether in hexanes. The appropriate fractions were combined and concentrated under reduced pressure yielding 27.6 grams of 7-phenyl-6-oxaheptan-1-ol. The nmr spectrum was consistent with the proposed structure.
Reaction SMILES: [CH3:1][CH2:2][O:3][CH2:4][C:5](Cl)=[O:6].[Cl:8][C:9]1[CH:18]=[CH:17][C:12]([C:13]([NH:15][NH2:16])=[O:14])=[CH:11][N:10]=1.CN1CCOCC1>ClCCl>[CH2:2]([O:3][CH2:4][C:5]([NH:16][NH:15][C:13](=[O:14])[C:12]1[CH:17]=[CH:18][C:9]([Cl:8])=[N:10][CH:11]=1)=[O:6])[CH3:1]
Reactant: CCOCC(=O)Cl
Reactant: NNC(=O)c1ccc(Cl)nc1
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CCOCC(=O)NNC(=O)c1ccc(Cl)nc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 83 %

Procedure:
(2-Ethoxy)-acetyl chloride [(1.72 g, 13.99 mmol), Tett. Lett., 35, (39), 7269; 1994)] was added to an ice-cold solution of 6-chloronicotinic acid hydrazide (2 g, 11.66 mmol) and N-methylmorpholine (1.92 mL, 17.49 mmol) in dichloromethane (60 mL) and the mixture was stirred at room temperature for 18 hours. The mixture was then washed with citric acid, sodium hydrogen carbonate solution and brine and the solvent was evaporated under reduced pressure to yield some title product as a white solid, 880 mg. The combined aqueous washings were extracted with ethyl acetate (×2) and the combined organic solutions were dried over sodium sulfate and concentrated in vacuo to afford a further crop of title compound as a pale yellow solid, 1.6 g (total yield of 83%).
Reaction SMILES: [CH2:1]([N:3]1[C:8]2[N:9]=[C:10](S(C)=O)[N:11]=[CH:12][C:7]=2[CH:6]=[CH:5][C:4]1=[O:16])[CH3:2].[O:17]1[CH2:22][CH2:21][N:20]([C:23]2[CH:29]=[CH:28][C:26]([NH2:27])=[CH:25][CH:24]=2)[CH2:19][CH2:18]1>C(OCC)(=O)C>[CH2:1]([N:3]1[C:8]2[N:9]=[C:10]([NH:27][C:26]3[CH:25]=[CH:24][C:23]([N:20]4[CH2:21][CH2:22][O:17][CH2:18][CH2:19]4)=[CH:29][CH:28]=3)[N:11]=[CH:12][C:7]=2[CH:6]=[CH:5][C:4]1=[O:16])[CH3:2]
Reactant: Nc1ccc(N2CCOCC2)cc1
Reactant: CCn1c(=O)ccc2cnc(S(C)=O)nc21
Solvent: CCOC(C)=O
Product: CCn1c(=O)ccc2cnc(Nc3ccc(N4CCOCC4)cc3)nc21
Temperature: 175 °C

Procedure:
A mixture of 8-ethyl-2-methanesulfinyl-8H-pyrido[2,3-d]pyrimidin-7-one (136 mg, 0.57 mmol) and 4-morpholinoaniline (205 mg, 1.15 mmol) was heated at 175° C. for 10 minutes then cooled to room temperature, and ethyl acetate was added. The precipitate was collected by filtration and purified by flash chromatography eluting with ethyl acetate. The fractions containing product were concentrated, and ethyl acetate and hexane were added to the residue. The resultant precipitate was collected by filtration to give 114 mg (57%) yield of 8-ethyl-2-(4-morpholin-4-yl-phenylamino)-8H-pyrido[2,3-d]pyrimidin-7-one, mp 227-228° C.
Reaction SMILES: [Cl:1][C:2]1[CH:29]=[CH:28][C:5]2[N:6]=[C:7]([NH:9][C:10]3[N:14]([CH3:15])[C:13]4[CH:16]=[CH:17][C:18]([C:20]([NH:22][C@H:23]([CH3:27])[C:24](O)=[O:25])=[O:21])=[CH:19][C:12]=4[N:11]=3)[S:8][C:4]=2[CH:3]=1.[CH3:30][N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:27][C@@H:23]([NH:22][C:20]([C:18]1[CH:17]=[CH:16][C:13]2[N:14]([CH3:15])[C:10]([NH:9][C:7]3[S:8][C:4]4[CH:3]=[C:2]([Cl:1])[CH:29]=[CH:28][C:5]=4[N:6]=3)=[N:11][C:12]=2[CH:19]=1)=[O:21])[C:24]([N:34]1[CH2:35][CH2:36][N:31]([CH3:30])[CH2:32][CH2:33]1)=[O:25]
Reactant: CN1CCNCC1
Reactant: C[C@@H](NC(=O)c1ccc2c(c1)nc(Nc1nc3ccc(Cl)cc3s1)n2C)C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C[C@@H](NC(=O)c1ccc2c(c1)nc(Nc1nc3ccc(Cl)cc3s1)n2C)C(=O)N1CCN(C)CC1
Yield: 33.6 %

Procedure:
2-(6-Chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carboxylic acid [(R)-1-methyl-2-(4-methyl-piperazin-1-yl)-2-oxo-ethyl]amide (20 mg) was prepared by following General Procedure F starting from (R)-2-{[2-(6-chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carbonyl]-amino}-propionic acid (50 mg), 1-methyl-piperazine (50 mg), HBTU (150 mg), and DIEA (100 uL) in DMF (1 mL). LC/MS: m/z 511.7. 1H NMR (DMSO-d6, 400 MHz): δ 8.82-8.67 (m, 1H), 8.12 (m, 1H), 7.97 (s, 1H), 7.85-7.83 (m, 1H), 7.56-7.52 (m, 2H), 7.44-7.41 (m, 1H), 5.02-4.96 (m, 1H), 4.50-4.43 (m, 1H), 4.35-4.19 (m, 1H), 3.69 (s, 3H), 3.62-3.51 (m, 2H), 3.45 (m, 1H), 3.28 (m, 1H), 3.10 (m, 1H), 2.78-2.77 (d, 3H), 1.44-1.35 (m, 3H)—NH proton signal was not observed.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[N:4][C:5](I)=[CH:6][CH:7]=1.[C:14]([Cu])#[N:15].O>N1C=CC=CC=1>[Cl:1][C:2]1[C:3]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[N:4][C:5]([C:14]#[N:15])=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1nc(I)ccc1Cl
Reactant: N#C[Cu]
Solvent: c1ccncc1
Solvent: O
Product: CCOC(=O)c1nc(C#N)ccc1Cl
Temperature: 80 °C
Yield: 75.3 %

Procedure:
To a solution of ethyl 3-chloro-6-iodopicolinate (1.6 g, 5.38 mmol) in pyridine (40 mL) was added CuCN (480 mg, 5.36 mmol). The reaction mass was heated at 80° C. for 6 h. Then water was added to the reaction mass and it was extracted with EtOAc. The organic layer was separated, dried, filtered and concentrated to afford 850 mg of the title product. 1H NMR (300 MHz, DMSO-d6): δ 8.44 (d, J=8.1 Hz, 1H), 8.28 (d, J=8.4 Hz, 1H), 4.42 (q, J=7.2 Hz, 2H), 1.33 (t, J=7.2 Hz, 3H).
Reaction SMILES: C(O)C.[Cl:4][C:5]1[CH:13]=[C:12]2[C:8]([C:9]([C:14]3[CH2:15][CH2:16][NH:17][CH2:18][CH:19]=3)=[CH:10][NH:11]2)=[CH:7][CH:6]=1.[O:20]1[CH2:22][C@H:21]1[CH2:23][O:24][C:25]1[CH:33]=[CH:32][CH:31]=[C:30]2[C:26]=1[CH:27]=[CH:28][NH:29]2>CS(C)=O>[Cl:4][C:5]1[CH:13]=[C:12]2[C:8]([C:9]([C:14]3[CH2:15][CH2:16][N:17]([CH2:22][C@H:21]([OH:20])[CH2:23][O:24][C:25]4[CH:33]=[CH:32][CH:31]=[C:30]5[C:26]=4[CH:27]=[CH:28][NH:29]5)[CH2:18][CH:19]=3)=[CH:10][NH:11]2)=[CH:7][CH:6]=1
Reactant: Clc1ccc2c(C3=CCNCC3)c[nH]c2c1
Reactant: c1cc(OC[C@@H]2CO2)c2cc[nH]c2c1
Solvent: CCO
Solvent: CS(C)=O
Product: O[C@H](COc1cccc2[nH]ccc12)CN1CC=C(c2c[nH]c3cc(Cl)ccc23)CC1

Procedure:
To 5 mL of dry ethanol were added 6-chloro-3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole (1.54 g, 6.61 mmol) and (S)-(+)-4-(oxiranylmethoxy)-1H-indole (1.25 g, 6.61 mmol). The mixture was heated at the reflux temperature for about 6 hours, and was then cooled and concentrated. The residue was purified by silica gel chromatography with 95/5 chloroform/methanol. The product was isolated as a yellow foam. Yield 1.52 g (55%). mp 200°-202° C. FDMS m/e=421 (M+ of free base). α[D]589 =+4.39 (c=1.00, dimethylsulfoxide)
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][CH2:7][C:8](=[O:14])[C:9]([CH3:13])([CH3:12])[CH2:10]O)=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)(Cl)(Cl)[Cl:37]>>[Cl:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][CH2:7][C:8](=[O:14])[C:9]([CH3:13])([CH3:12])[CH2:10][Cl:37])=[CH:4][CH:3]=1
Reactant: CC(C)(CO)C(=O)COc1ccc(Cl)cc1
Reactant: ClC(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CC(C)(CCl)C(=O)COc1ccc(Cl)cc1

Procedure:
Into a 100-ml egg plant type flask were placed 2.4 g of 1-(p-chlorophenoxy)-3,3-dimethyl-4-hydroxy-2-butanone, 2.6 g of triphenylphosphine and 50 ml of carbon tetrachloride, which were then refluxed for 18 hours. The reaction mixture was cooled, the crystals separating out were filtered off, and the filtrate was concentrated in a vacuum. The residue obtained was purified by silica gel column chromatography, giving 1.8 g of the above-identified desired compound.
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3=[N:17][CH:18]=[CH:19][C:20]([C:21]4[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][C:22]=4[O:29][CH2:30][CH:31]4[CH2:33][CH2:32]4)=[C:15]3[NH:14][C:13]=2[CH3:34])=[O:11])[CH2:5][CH2:4]1.[C:35](Cl)(=[O:38])[CH2:36][CH3:37]>>[CH:31]1([CH2:30][O:29][C:22]2[CH:23]=[C:24]([O:27][CH3:28])[CH:25]=[CH:26][C:21]=2[C:20]2[CH:19]=[CH:18][N:17]=[C:16]3[C:12]([C:10]([NH:9][C@H:6]4[CH2:7][CH2:8][C@@H:3]([NH:2][C:35](=[O:38])[CH2:36][CH3:37])[CH2:4][CH2:5]4)=[O:11])=[C:13]([CH3:34])[NH:14][C:15]=23)[CH2:32][CH2:33]1
Reactant: COc1ccc(-c2ccnc3c(C(=O)N[C@H]4CC[C@@H](N)CC4)c(C)[nH]c23)c(OCC2CC2)c1
Reactant: CCC(=O)Cl
Agent: Cl
Product: CCC(=O)N[C@H]1CC[C@@H](NC(=O)c2c(C)[nH]c3c(-c4ccc(OC)cc4OCC4CC4)ccnc23)CC1

Procedure:
Starting from N-(cis-4-aminocyclohexyl)-7-[2-(cyclopropylmethoxy)-4-methoxyphenyl]-2-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide hydrochloride (example D.f13) and commercially propionyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:20]=[C:21]([F:23])[CH:22]=1)[O:5][C:6]1[C:11]2[CH2:12][C:13]([CH3:16])([CH3:15])[O:14][C:10]=2[CH:9]=[C:8]([C:17]([OH:19])=O)[CH:7]=1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1.[CH3:53][N:54]1[CH:58]=[CH:57][C:56]([NH2:59])=[N:55]1>C(Cl)Cl>[CH3:53][N:54]1[CH:58]=[CH:57][C:56]([NH:59][C:17]([C:8]2[CH:7]=[C:6]([O:5][C:4]3[CH:20]=[C:21]([F:23])[CH:22]=[C:2]([F:1])[CH:3]=3)[C:11]3[CH2:12][C:13]([CH3:15])([CH3:16])[O:14][C:10]=3[CH:9]=2)=[O:19])=[N:55]1
Reactant: Cn1ccc(N)n1
Reactant: CC1(C)Cc2c(Oc3cc(F)cc(F)c3)cc(C(=O)O)cc2O1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: Cn1ccc(NC(=O)c2cc(Oc3cc(F)cc(F)c3)c3c(c2)OC(C)(C)C3)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 24.8 %

Procedure:
To a mixture of 4-(3,5-difluoro-phenoxy)-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid (113b) (0.308 g, 0.00096 mol), EDCl (0.28 g, 0.0015 mol), HOBt (0.21 g, 0.0015 mol) and NMM (0.49 g, 0.0048 mol) in CH2Cl2 (15 mL) was added 1-methyl-1H-pyrazol-3-amine (0.11 g, 0.001 mol) in one portion. The mixture was stirred at room temperature overnight. The reaction mixture was washed with water, aq. citric acid and then sat. NaHCO3. The organic phase was dried over Na2SO4 and concentrated to give a brown oil. The crude oil was purified by prep. HPLC to give the title compound (95 mg, 51% yield) as a white solid. 1H NMR (400 MHz, CDCl3): δ 8.82 (s, 1H), 7.20 (m, 2H), 7.03 (d, 2H), 6.73 (s, 1H), 6.42 (m, 3H), 3.72 (s, 3H), 2.84 (s, 2H), 1.42 (s, 6H);
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:16](=O)[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:7]([C:12]([O:14]C)=O)[N:8]2[CH3:11])=[CH:4][CH:3]=1.[N:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[NH:29][NH2:30]>C(O)(=O)C.C(O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[N:30][N:29]([C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][N:23]=4)[C:12](=[O:14])[C:7]=3[N:8]([CH3:11])[C:9]=2[CH:10]=1
Reactant: NNc1ccccn1
Reactant: CCOC(=O)C(=O)c1c(C(=O)OC)n(C)c2cc(F)ccc12
Solvent: CC(=O)O
Solvent: CCO
Product: CCOC(=O)c1nn(-c2ccccn2)c(=O)c2c1c1ccc(F)cc1n2C

Procedure:
A solution of 0.40 g (1.36 mmol) of ethyl 6-fluoro-2-(methoxycarbonyl)-1-methyl-α-oxo-1H-indole-3-acetate (obtained in stage 1.4.), of 30 ml of absolute ethanol, of a few drops of glacial acetic acid and of 0.60 g (5.5 mmol) of 2-pyridinylhydrazine is brought to reflux for 17 h.
Reaction SMILES: FC(F)(F)C(O)=O.[Br:8][C:9]1[CH:57]=[CH:56][C:12]2[NH:13][C:14]([CH2:16][CH2:17][CH:18]3[CH2:21][CH:20]([N:22]([CH2:24][C@@H:25]4[C@H:29]5[O:30]C(C)(C)[O:32][C@H:28]5[C@H:27]([N:35]5[C:39]6[N:40]=[CH:41][N:42]=[C:43]([NH:44]CC7C=CC(OC)=CC=7OC)[C:38]=6[CH:37]=[CH:36]5)[CH2:26]4)[CH3:23])[CH2:19]3)=[N:15][C:11]=2[CH:10]=1.C([SiH](CC)CC)C>O>[NH2:44][C:43]1[C:38]2[CH:37]=[CH:36][N:35]([C@@H:27]3[CH2:26][C@H:25]([CH2:24][N:22]([CH:20]4[CH2:19][CH:18]([CH2:17][CH2:16][C:14]5[NH:13][C:12]6[CH:56]=[CH:57][C:9]([Br:8])=[CH:10][C:11]=6[N:15]=5)[CH2:21]4)[CH3:23])[C@@H:29]([OH:30])[C@H:28]3[OH:32])[C:39]=2[N:40]=[CH:41][N:42]=1
Reactant: COc1ccc(CNc2ncnc3c2ccn3[C@@H]2C[C@H](CN(C)C3CC(CCc4nc5cc(Br)ccc5[nH]4)C3)[C@H]3OC(C)(C)O[C@H]32)c(OC)c1
Agent: CC[SiH](CC)CC
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CN(C[C@H]1C[C@@H](n2ccc3c(N)ncnc32)[C@H](O)[C@@H]1O)C1CC(CCc2nc3cc(Br)ccc3[nH]2)C1
Reaction time: 1 h
Yield: 27.1 %

Procedure:
Trifluoroacetic Acid (20 ml) added to a mixture of Water (2 ml) and 7-((3aS,4R,6R,6aR)-6-(((3-(2-(5-bromo-1H-benzo[d]imidazol-2-yl)ethyl)cyclobutyl)(methyl)amino)methyl)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)-N-(2,4-dimethoxybenzyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (0.9 g, 1 mmol) at RT. The reaction mixture was stirred for one hour, Triethylsilane (0.39 ml, 2.4 mmol) was added. The volatiles were removed in vacuo and resulting residue was purified twice by flash chromatography (DCM/7N NH3 in MeOH 87:13). The residue was taken up in MeOH/H2O (5:0.5 ml) and K2CO3 (100 mg) added. The mixture was stirred for 1 hour, then concentrated and purified by flash chromatography (DCM/7N NH3 in MeOH 87:13) to give the desired product (0.15 g) as an off-white foam/gum. cyclobutyl)(methyl)amino)methyl)cyclopentane-1,2-diol (0.15 g; 20%) as an off-white foam/gum. MS (ESI+) for C26H32BrN7O2 m/z 554.1 [M+H]+; MS (ESI−) for C26H32BrN7O2 m/z 552.1 [M−H]−; HPLC purity >90% (ret. time, 2.298 min.) 1HNMR (400 MHz, d4-MeOH) δH 8.080 (s, 1H), 7.652 (s, 1H), 7.425-7.403 (m, 1H), 7.342-7.7.312 (m, 1H), 7.232-7.217 (m, 1H), 6.620-6.611 (d, J=3.6 Hz, 1H), 4.358-4.318 (m, 1H), 3.928-3.888 (m, 1H), 3.099-3.039 (m, 0.5H (methine of trans isomer)), 2.898-2.829 (m, 2H), 2.777-2.726 (m, 0.5H (methine of cis isomer)), 2.580-2.529 (m, 1H), 2.453-2.397 (m, 2H), 2.307-2.141 (7H), 2.068-2.017 (m, 1H), 1.955-1.891 (m, 3H), 1.695-1.506 (m, 2H).
Reaction SMILES: CC1C=CC(S([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([OH:18])[C:13]=2[N:19]2[C:23]([CH3:24])=[CH:22][C:21]([CH3:25])=[N:20]2)(=O)=O)=CC=1.[OH-].[K+]>C(O)C.O>[CH3:25][C:21]1[CH:22]=[C:23]([CH3:24])[N:19]([C:13]2[C:14]([OH:18])=[CH:15][CH:16]=[CH:17][C:12]=2[OH:11])[N:20]=1
Reactant: Cc1ccc(S(=O)(=O)Oc2cccc(O)c2-n2nc(C)cc2C)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1cc(C)n(-c2c(O)cccc2O)n1
Yield: 58.9 %

Procedure:
To 62 mg of 2-(3,5-dimethyl-1H-pyrazol-1-yl)-3-hydroxyphenyl 4-methylbenzene sulfonate was added a solution in which 97 mg of potassium hydroxide was dissolved in 1.5 ml of ethanol and 1.5 ml of water, and heated at reflux for 3.5 hours. To the reaction mixture, 20 ml of water was added, and extracted with 20 ml of ethyl acetate. After the organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and purified using preparative thin-layer silica gel column chromatography (hexane:ethyl acetate=1:1) to yield 20.8 mg of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[O:9][N:10]=[C:11]3[CH:16]=[CH:15][C:14]([C:17]([C:19]4[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=4)=[O:18])=[CH:13][C:12]=23)[CH:5]=[CH:6][CH:7]=1.C1COCC1>O>[NH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17](=[O:18])[C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)=[CH:13][C:12]=1[C:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=1)=[O:9]
Reactant: COc1ccc(C(=O)c2ccc3noc(-c4cccc(Cl)c4)c3c2)cc1
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(C(=O)c2ccc(N)c(C(=O)c3cccc(Cl)c3)c2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 104.6 %

Procedure:
Intermediate 10 (0.0536 mol) was added at room temperature to THF (200 ml). TiCl3 15% in water (120 ml) was added dropwise at room temperature. The mixture was stirred at room temperature for 3 hours, poured out into ice water and extracted with DCM. The organic layer was separated, washed with K2CO3 10% then with water, dried (MgSO4), filtered and the solvent was evaporated, yielding 20.5 g (quantitative) of [2-amino-5(4-methoxybenzoyl)phenyl](3-chlorophenyl)-methanone (intermediate 11).