Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:15])[NH:10][CH2:11][C:12]([OH:14])=O)[CH:5]=[CH:6][CH:7]=1.[NH:16]([CH:23]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.S(Cl)(Cl)=O>>[CH3:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:15])[NH:10][CH2:11][C:12]([N:16]([CH:23]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[O:14])[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)CC(Nc1ccccc1)c1ccccc1
Reactant: Cc1cccc(NC(=O)NCC(=O)O)c1
Solvent: O=S(Cl)Cl
Product: CCOC(=O)CC(c1ccccc1)N(C(=O)CNC(=O)Nc1cccc(C)c1)c1ccccc1
Yield: 17.6 %

Procedure:
The procedure is as in Example 1, but using 11.6 g of 2-[3-(3-methylphenyl)ureido]acetic acid, 15 g of ethyl (RS)-3-anilino-3-phenylpropionate and 4 cm3 of thionyl chloride as starting materials. The product obtained is purified by chromatography on 250 g of silica (0.04-0.063 mm) contained in a column 5 cm in diameter [eluent: methanol/dichloromethane (2/98 by volume)], using an excess pressure of 40 kPa of nitrogen and collecting 75-cm3 fractions. Fractions 19 to 21 are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 40° C. and the residue obtained is recrystallized from ethyl acetate. 4.5 g of ethyl (RS)-3-{2-[3-(3-methylphenyl)ureido]-N-phenylacetamido}-3-phenylpropionate melting at 146° C. are then obtained.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:13]2[CH:18]=[CH:17][N:16]=[C:15]([NH:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26](OC)=[O:27])[CH:21]=3)[N:14]=2)=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:6]=1.[Cl-].[NH4+]>O1CCCC1.C1(C)C=CC=CC=1>[NH2:1][C:2]1[S:3][C:4]([C:13]2[CH:18]=[CH:17][N:16]=[C:15]([NH:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([CH2:26][OH:27])[CH:21]=3)[N:14]=2)=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:6]=1
Reactant: COC(=O)c1cccc(Nc2nccc(-c3sc(N)nc3-c3ccccc3)n2)c1
Agent: [Cl-]
Agent: [NH4+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: Nc1nc(-c2ccccc2)c(-c2ccnc(Nc3cccc(CO)c3)n2)s1

Procedure:
To a suspension of N-[4-(2-amino-4-phenyl-thiazol-5-yl)-pyrimidin-2-yl]-N-(3-methoxycarbonyl-phenyl)-amine (800 mg, 2.0 mmol) in tetrahydrofuran (25 ml) is added a solution of sodium dihydro-bis(2-methoxyethoxy)aluminate in toluene (3 ml of a 3.5M solution) without cooling. The temperature of the reaction mixture rises to about +40° C. and the starting material dissolves immediately yielding a yellow clear solution. After an additional hour the solution is poured onto crushed ice and ammonium chloride. The colorless precipitate is filtered and washed with ethyl acetate and tetrahydrofuran. The organic phases are pooled, dried and concentrated under reduced pressure. Chromatography of the resulting solid gives the N-[4-(2-amino-4-phenyl-thiazol-5-yl)-pyrimidin-2-yl]-N-(3-hydroxymethyl-phenyl)-amine, m.p. 214–215° C.
Reaction SMILES: [CH:1]1([C:4]2[C:5]([O:14][CH2:15][C:16]3([C:22]([F:25])([F:24])[F:23])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)=[CH:6][C:7]([F:13])=[C:8]([CH:12]=2)[C:9](O)=[O:10])[CH2:3][CH2:2]1.Cl.C(N=C=NCCCN(C)C)C.[CH3:38][S:39]([NH2:42])(=[O:41])=[O:40].Cl>ClCCl.CN(C)C1C=CN=CC=1.C(OCC)(=O)C>[CH:1]1([C:4]2[C:5]([O:14][CH2:15][C:16]3([C:22]([F:25])([F:24])[F:23])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)=[CH:6][C:7]([F:13])=[C:8]([CH:12]=2)[C:9]([NH:42][S:39]([CH3:38])(=[O:41])=[O:40])=[O:10])[CH2:3][CH2:2]1
Reactant: O=C(O)c1cc(C2CC2)c(OCC2(C(F)(F)F)CCCCC2)cc1F
Reactant: CS(N)(=O)=O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CS(=O)(=O)NC(=O)c1cc(C2CC2)c(OCC2(C(F)(F)F)CCCCC2)cc1F
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 61.7 %

Procedure:
To a stirred solution of 5-cyclopropyl-2-fluoro-4-((1-(trifluoromethyl)-cyclohexyl)methoxy)benzoic acid (0.36 g, 1.00 mmol) in dichloromethane (20 mL) were added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.29 g, 1.50 mmol) and 4-dimethylaminopyridine (0.28 g, 2.30 mmol). The reaction was stirred at ambient temperature for 10 minutes, methanesulfonamide (0.15 g, 1.56 mmol) was added and the stirring was continued at ambient temperature for 17 hours. 5% aqueous hydrochloric acid solution (10 mL) were added and diluted with ethyl acetate (100 mL), washed with water and brine; dried over anhydrous sodium sulfate and concentrated in vacuo. Purification of the residue by column chromatography (30% ethyl acetate in hexanes) afforded the title compound (0.27 g, 62%) as a colorless solid: 1H NMR (300 MHz, CDCl3) δ 8.70 (br s, 1H), 7.59 (d, J=9.0 Hz, 1H), 6.59 (d, J=14.1 Hz, 1H), 4.12 (s, 2H), 3.39 (s, 3H), 2.03-1.88 (m, 3H), 1.76-1.63 (m, 5H), 1.48-1.23 (m, 3H), 0.94-0.87 (m, 2H), 0.64-0.58 (m, 2H); MS (ES−) m/z 436.2 (M−1).
Reaction SMILES: [CH:1]1([S:4][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH2:3][CH2:2]1.C([Li])CCC.[I:16]N1C(=O)CCC1=O.C(=O)([O-])O.[Na+]>O1CCCC1>[I:16][C:1]1([S:4][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH2:3][CH2:2]1
Reactant: c1ccc(SC2CC2)cc1
Reactant: O=C1CCC(=O)N1I
Agent: O=C([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Product: IC1(Sc2ccccc2)CC1
Temperature: 25 °C

Procedure:
Cyclopropylphenyl thioether (5.0 g, 33.3 mmol) was dissolved in tetrahydrofuran (50 mL), and n-butyllithium (25.1 mL, 39.9 mmol) was dropwisely added at 0° C. for 5 minutes under an argon atmosphere. Then, a solution of N-iodosuccinimide (8.99 g, 39.9 mmol) in tetrahydrofuran (100 mL) was dropwisely added at −78° C. The resultant mixture was stirred overnight, and gradually warmed to room temperature. The reaction solution was added with a saturated aqueous solution of sodium hydrogen carbonate, and extracted with hexane. The organic layer was washed with brine, dried over anhydrous sodium sulfate, concentrated in vacuo, and purified using silica-gel column chromatography (hexane), to obtain a crude product ((1-iodocyclopropyl)(phenyl)sulfane:cyclopropylphenylthioether (=2.4:1) (5.64 g). Next, 5-hydroxy-2-methylpyridine (1.82 g, 16.7 mmol) was dissolved in toluene (150 mL). The resultant mixture was added with silver carbonate (9.19 g, 33.3 mmol) and 1-iodocyclopropyl)(phenypsulfane:cyclopropylphenylthioether (=2.4:1) mixture (5.64 g, 16.7 mmol (*converted in terms of 1-iodocyclopropyl)(phenyl)sulfane), and stirred overnight at room temperature. Then, acetic acid (200 mL) was added thereto, and stirred for 10 minutes. The reaction solution was filtered using celite and concentrated in vacuo. The obtained residue was purified using silica-gel column chromatography (hexane/ethyl acetate), and 2-methyl-5-(1-(phenylthio)cyclopropoxy)pyridine (1.88 g, yield 44%) was obtained as a yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH3:20])[NH:12][C:11]([C:21]2[S:22][C:23]([O:26][CH3:27])=[CH:24][N:25]=2)=[N:10]1.C1C(=O)N([Br:35])C(=O)C1>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH2:20][Br:35])[NH:12][C:11]([C:21]2[S:22][C:23]([O:26][CH3:27])=[CH:24][N:25]=2)=[N:10]1
Reactant: CCOC(=O)C1=C(C)NC(c2ncc(OC)s2)=NC1c1ccc(F)cc1Br
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Product: CCOC(=O)C1=C(CBr)NC(c2ncc(OC)s2)=NC1c1ccc(F)cc1Br
Yield: 34.1 %

Procedure:
Ethyl 4-(2-bromo-4-fluorophenyl)-2-(5-methoxythiazol-2-yl)-6-methyl-1,4-dihydropyrimidine-5-carboxylate (2 g, 4.4 mmol) was reacted with NBS (0.78 g, 4.4 mmol) in DCM (50 mL) according to the procedure as described in Example 1, Step B to give the title compound as a yellow solid (0.80 g, 34%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [CH:1]([NH2:4])([CH3:3])[CH3:2].Cl[C:6]1[C:7]2[N:8]([C:16]([CH2:19][CH3:20])=[N:17][N:18]=2)[C:9]2[C:14]([N:15]=1)=[CH:13][CH:12]=[CH:11][CH:10]=2>CN(C)C=O>[CH:1]([NH:4][C:6]1[C:7]2[N:8]([C:16]([CH2:19][CH3:20])=[N:17][N:18]=2)[C:9]2[C:14]([N:15]=1)=[CH:13][CH:12]=[CH:11][CH:10]=2)([CH3:3])[CH3:2]
Reactant: CCc1nnc2c(Cl)nc3ccccc3n12
Reactant: CC(C)N
Solvent: CN(C)C=O
Product: CCc1nnc2c(NC(C)C)nc3ccccc3n12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 63 %

Procedure:
Isopropylamine (1.77 g., 0.03 mole) was added to a solution of 4-chloro-1-ethyl-[1,2,4]triazolo-[4,3-a]quinoxaline (2.3 g., 0.01 mole), the product of Example 4, in N,N-dimethylformamide (30 ml.). Within 30 minutes, a precipitate formed. The reaction mixture was then stirred overnight at room temperature. The precipitate was separated by filtration and washed with N,N-dimethylformamide. Recrystallization from ethanol then gave 1.6 g. (63% yield) of 4-isopropylamino-1-ethyl[1,2,4]triazolo[4,3-a]quinoxaline, m.p. 222°-4° C.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)(O)[CH2:4][CH2:3]1.[OH-].[Na+]>C(O)=O.CS(C)=O.O>[CH3:1][N:2]1[CH2:3][CH:4]=[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:6][CH2:7]1
Reactant: CN1CCC(O)(c2ccccc2Cc2ccccc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: O=CO
Solvent: CS(C)=O
Product: CN1CC=C(c2ccccc2Cc2ccccc2)CC1
Reaction time: 16 h

Procedure:
A solution of 8.0 g of 1-methyl-4-(α-phenyl-2-tolyl)-4-piperidinol, Example 1, in 100 ml of 97% formic acid is refluxed with stirring for 16 hours. The solution is poured into 300 ml of water, made strongly basic with a 50% sodium hydroxide solution and the basic mixture extracted thrice with 100 ml of portions of chloroform. The combined chloroform extracts are dried and the chloroform removed leaving an oil. The oil is dissolved in 20 ml of dimethylsulfoxide. The solution is diluted with 250 ml of water leaving a cream colored solid which is recrystallized from dimethylsulfoxide to give colorless crystals, mp 55°-57° C. of 1-methyl-4-(α-phenyl-2-tolyl)-1,2,3,6-tetrahydropyridine.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]([CH3:13])=[N:10][C:9]=2[C:14]([N:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH:17]2[CH2:22][C:23](O)=O)=[O:15])=[CH:4][CH:3]=1.[CH3:26][O:27][C:28]1[CH:29]=[C:30]([NH2:35])[C:31]([NH2:34])=[CH:32][CH:33]=1>C(OCC)(=O)C>[CH3:26][O:27][C:28]1[CH:33]=[CH:32][C:31]2[NH:34][C:23]([CH2:22][CH:17]3[CH2:18][CH2:19][CH2:20][CH2:21][N:16]3[C:14]([C:9]3[N:10]=[C:11]([CH3:13])[S:12][C:8]=3[C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)=[O:15])=[N:35][C:30]=2[CH:29]=1
Reactant: COc1ccc(N)c(N)c1
Reactant: Cc1nc(C(=O)N2CCCCC2CC(=O)O)c(-c2ccc(F)cc2)s1
Solvent: CCOC(C)=O
Product: COc1ccc2[nH]c(CC3CCCCN3C(=O)c3nc(C)sc3-c3ccc(F)cc3)nc2c1
Yield: 13 %

Procedure:
A stirring mixture of (1-{1-[5-(4-Fluoro-phenyl)-2-methyl-thiazol-4-yl]-methanoyl}-piperidin-2-yl)-acetic acid, D17 (150 mg, 0.42 mmol) and 4-methoxy-benzene-1,2-diamine (58 mg, 0.42 mmol) was heated at 120° C. for 4 h. The cooled reaction mixture was dissolved in ethyl acetate, washed with sodium hydrogen carbonate (2×) then brine. The solvent was removed in vacuo and the residue was chromatographed (silica gel, ethyl acetate) to afford the title compound as a brown gum (25 mg, 13%).
Reaction SMILES: [C:1]([C:4]([CH:17]1[CH2:22][CH2:21][CH2:20][NH:19][CH2:18]1)([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)(=[O:3])[NH2:2].[OH:23][C:24]1[CH:32]=[CH:31][C:27]([CH2:28][CH2:29]Br)=[CH:26][CH:25]=1.C(=O)(O)[O-].[Na+]>C(#N)C>[C:1]([C:4]([CH:17]1[CH2:22][CH2:21][CH2:20][N:19]([CH2:29][CH2:28][C:27]2[CH:31]=[CH:32][C:24]([OH:23])=[CH:25][CH:26]=2)[CH2:18]1)([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)(=[O:3])[NH2:2]
Reactant: NC(=O)C(c1ccccc1)(c1ccccc1)C1CCCNC1
Reactant: Oc1ccc(CCBr)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: NC(=O)C(c1ccccc1)(c1ccccc1)C1CCCN(CCc2ccc(O)cc2)C1

Procedure:
A mixture containing 3-(R,S)-(1-carbamoyl-1,1-diphenylmethyl)piperidine (0.3 g), 4-hydroxyphenethyl bromide (0.21 g), sodium bicarbonate (0.3 g) and acetonitrile (15 ml) was heated under reflux for 5 hours. The mixture was partitioned between dichloromethane (30 ml) and 10% aqueous sodium carbonate (30 ml), the layers separated, and the aqueous layer extracted with dichloromethane (2×50 ml). The combined dichloromethane extracts were dried (MgSO4) and concentrated in vacuo to give a gum which was purified by column chromatography, firstly on silica eluting with dichlorometbane containing methanol (0% up to 6%), and then on alumina eluting with dichloromethane containing methanol (0% up to 10%). The product-containing fractions were combined and concentrated in vacuo to give the title compound as colourless microcrystals, yield 0.042 g, m.p. 135°-140° C.
Reaction SMILES: [N:1]1[CH:2]=[C:3]([CH2:10][C:11]([OH:13])=O)[N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.[P:14]([OH:17])([OH:16])[OH:15].P(Cl)(Cl)Cl>O1CCOCC1>[CH:7]1[CH:8]=[CH:9][N:4]2[C:3]([CH2:10][C:11]([P:14]([OH:17])([OH:16])=[O:15])([P:14]([OH:17])([OH:16])=[O:15])[OH:13])=[CH:2][N:1]=[C:5]2[CH:6]=1
Reactant: O=C(O)Cc1cnc2ccccn12
Reactant: OP(O)O
Solvent: ClP(Cl)Cl
Solvent: C1COCCO1
Product: O=P(O)(O)C(O)(Cc1cnc2ccccn12)P(=O)(O)O
Temperature: 92.5 °C
Yield: 52.3 %

Procedure:
Imidazo[1,2-a]pyridin-3-yl acetic acid (46 gm), phosphorous acid (75 gm) and 1,4-Dioxane (900 mL) was taken in a four necked round bottom flask fitted with an addition funnel, mechanical stirrer, condenser and thermometer pocket and allowed to stir at 90-95° C. Phosphorus trichloride (130 gm) was then added to reaction mixture and allowed to heat at 90-95° C. The reaction mixture was cooled and distilled water (450 mL) was added to it. The reaction mixture was further heated to 90-95° C. It was then cooled and acetone (1400 mL) was added to it. The solution was further cooled to 0-5° C. and stirred for 4-5 hrs. The precipitated solid was filtered and dried under vacuum to give 44 gm of product.
Reaction SMILES: Cl[C:2]1[N:7]([CH3:8])[C:6](=[O:9])[N:5]([CH3:10])[C:4](=[O:11])[C:3]=1[CH:12]=[O:13].C(N(CC)CC)C.[CH3:21][NH:22][CH2:23][CH:24]=[CH2:25]>C(O)C>[CH2:23]([N:22]([CH3:21])[C:2]1[N:7]([CH3:8])[C:6](=[O:9])[N:5]([CH3:10])[C:4](=[O:11])[C:3]=1[CH:12]=[O:13])[CH:24]=[CH2:25]
Reactant: Cn1c(Cl)c(C=O)c(=O)n(C)c1=O
Reactant: C=CCNC
Solvent: CCN(CC)CC
Solvent: CCO
Product: C=CCN(C)c1c(C=O)c(=O)n(C)c(=O)n1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 6-chloro-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carbaldehyde (0.500 g, 2.47 mmol) and triethyl-amine (0.52 ml, 3.71 mmol) in dry ethanol (10 ml), N-methylprop-2-en-1-amine (0.36 ml, 3.71 mmol) was added under argon. The resulting mixture was stirred at room temperature under argon overnight. After evaporation of the solvent in vacuo, water (15 ml) was added to the yellow oily residue, and the mixture was extracted with dichloromethane (4×15 ml). The combined organic phases were dried over anhydrous MgSO4. The solvent was evaporated in vacuo, and the crude product was purified by crystallization from a mixture of cyclohexane:isopropyl alcohol (4:1).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[OH:9].C(=O)([O-])[O-].[K+].[K+].Br[CH2:17][C:18]#[CH:19].[I-].[K+]>C(C(C)=O)C.C1(C)C=CC=CC=1>[CH2:19]([O:9][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[CH2:2][OH:1])[C:18]#[CH:17]
Reactant: OCc1ccccc1O
Reactant: C#CCBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: Cc1ccccc1
Product: C#CCOc1ccccc1CO

Procedure:
To 2-(hydroxymethyl)phenol (10.0 g, 80.6 mmol) slurried in 300 ml of methyl ethyl ketone was added 1.2 equivalents of potassium carbonate. Then 3-bromopropyne (121 mmol, 18 g of an 80% solution in toluene) and potassium iodide (0.5 g) were added and the reaction was refluxed overnight. After cooling the salts were filtered off. The filtrate was concentrated and the residue was dissolved in water and extracted twice with ether. After washing with water and brine, the organic layer was dried over MgSO4 and concentrated to afford the subtitle compound.
Reaction SMILES: [H-].[Na+].[C:3]([C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:19]=1[NH:18][CH2:17][CH2:16]2)(=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:20]I>CN(C)C=O>[CH3:20][N:18]1[C:19]2[C:15](=[CH:14][CH:13]=[CH:12][C:11]=2[C:3](=[O:10])[C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:16][CH2:17]1
Reactant: CI
Reactant: O=C(c1ccccc1)c1cccc2c1NCC2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1CCc2cccc(C(=O)c3ccccc3)c21
Temperature: 50 °C
Reaction time: 4 h

Procedure:
To a stirred slurry of 4.8 grams (0.1 mole) of 50% sodium hydride/oil in 100 ml. of dimethylformamide is added dropwise a solution of 22.3 grams (0.1 mole) of 7-benzoylindoline in 50 ml of dimethylformamide. After addition is complete, the mixture is warmed at 50° C. until all solids dissolve. While maintaining the mixture at 50° C., 9.5 grams (0.1 mole) of methyl iodide is added dropwise to the mixture. The mixture is stirred for 4 hours. The mixture is poured into 2 liters of ice water and extracted with 3 portions of 300 ml of benzene. The benzene extracts are combined, washed with water, dried over sodium sulfate and concentrated to give 1-methyl-7-benzoylindoline as a residue.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:26]=[C:27]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:28]=1)[CH2:12][N:13]1[CH:17]=[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:15]([CH2:24][OH:25])=[CH:14]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>[O-2].[O-2].[Mn+4].O1CCCC1>[CH2:30]([O:29][C:27]1[CH:26]=[C:11]([CH:10]=[C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:28]=1)[CH2:12][N:13]1[CH:17]=[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:15]([CH:24]=[O:25])=[CH:14]1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: OCc1cn(Cc2cc(OCc3ccccc3)cc(OCc3ccccc3)c2)cc1-c1ccccc1
Agent: [Mn+4]
Agent: [O-2]
Solvent: C1CCOC1
Product: O=Cc1cn(Cc2cc(OCc3ccccc3)cc(OCc3ccccc3)c2)cc1-c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.5 %

Procedure:
A mixture of [1-(3,5-dibenzyloxybenzyl)-4-phenyl-3-pyrrolyl]methanol (23.8 g), activated manganese dioxide (50.00 g), and tetrahydrofuran (200 ml) was stirred at room temperature for two hours. After the manganese dioxide was removed by filtration, the filtrate was concentrated. The colorless crystals obtained were collected by filtration to yield 1-(3,5-dibenzyloxybenzyl)-4-phenylpyrrole-3-carbaldehyde (23.10 g, yield: 97%). This was recrystallized from tetrahydrofuran-hexane. Melting point: 117–118° C.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[CH3:9].Cl[CH2:11][CH2:12][N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.C([O-])([O-])=O.[K+].[K+].[Na+].[I-]>CS(C)=O.CCOC(C)=O>[Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[CH:4][C:3]=1[CH3:9]
Reactant: ClCCN1CCOCC1
Reactant: Cc1cc(N)ccc1Br
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: Cc1cc(NCCN2CCOCC2)ccc1Br
Yield: 32.5 %

Procedure:
4-Bromo-3-methylaniline (0.96 gm, 5.14 mmol), 4-(2-chloro-ethyl)-morpholine (1 gm, 5.4 mmol), K2CO3 (1.5 gm, 10.8 mmol), and NaI (0.81 gm, 5.4 mmol) were suspended in DMSO (10 mL) and the mixture was stirred vigorously at reflux for 12 h. The mixture was cooled, diluted with EtOAc, and washed with saturated NaHCO3. The organic layer was washed with another portion of NaHCO3, brine (50 mL), and was dried over MgSO4. Removal of the solvents in vacuo followed by flash chromatography of the residue (Biotage Flash System—40 M SiO2 column, 10% EtOAc in hexanes to 100% EtOAc) yielded the product (500 mg, 31%) as a tan oil. 1H-NMR (CDCl3; 400 MHz): δ 7.36 (d, 1H, J=8.6 Hz), 6.61 (d, 1H, J=2.8 Hz), 6.43 (dd, 1H, d, 8.6, 2.8 Hz), 4.36 (br s, 1H), 3.80 (t, 4H, J=4.6 Hz), 3.20 (t, 2H, J=5.8 Hz), 2.69 (t, 2H, J=6.0 Hz), 2.54 (t, 4H, J=4.4 Hz), 2.40 (s, 3H). ESI-MS (m/z): Calcd. for C13H19BrN2O: 299.2; found: 299.1, 301.1.
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@H:2]([C:11]([N:13]([CH3:42])[C@H:14]([C:18]([N:20]([CH3:41])[C@H:21]([C:34]([NH:36][S:37]([CH3:40])(=[O:39])=[O:38])=[O:35])[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([OH:29])=[C:25]([C:30]([CH3:33])([CH3:32])[CH3:31])[CH:24]=1)=[O:19])[CH:15]([CH3:17])[CH3:16])=[O:12])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][CH:5]=1.[C:50]([OH:56])([C:52]([F:55])([F:54])[F:53])=[O:51]>C(Cl)Cl>[NH2:1][C@H:2]([C:11]([N:13]([CH3:42])[C@H:14]([C:18]([N:20]([CH3:41])[C@H:21]([C:34]([NH:36][S:37]([CH3:40])(=[O:39])=[O:38])=[O:35])[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([OH:29])=[C:25]([C:30]([CH3:33])([CH3:31])[CH3:32])[CH:24]=1)=[O:19])[CH:15]([CH3:16])[CH3:17])=[O:12])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][CH:5]=1.[F:53][C:52]([C:50]([OH:56])=[O:51])([F:55])[F:54]
Reactant: CC(C)[C@@H](C(=O)N(C)[C@@H](Cc1ccc(O)c(C(C)(C)C)c1)C(=O)NS(C)(=O)=O)N(C)C(=O)[C@H](Cc1ccc(F)cc1)NC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)[C@@H](C(=O)N(C)[C@@H](Cc1ccc(O)c(C(C)(C)C)c1)C(=O)NS(C)(=O)=O)N(C)C(=O)[C@@H](N)Cc1ccc(F)cc1
Reaction time: 1.5 h
Yield: 94 %

Procedure:
To a solution of Boc-Phe(4-F)-N-Me-Val-N-Me-Tyr(3-t-Bu)-NHSO2Me (208 mg, 0.294 mmol) in methylene chloride (6 ml), TFA (3 ml) was added and stirred for 1.5 hours. The reaction mixture was evaporated under reduced pressure; the thus obtained residue was dissolved in a mixture of acetonitrile/water (1:10) (80 ml), which mixture containing 0.1% TFA, and lyophilized to give the titled compound (0.20 g, 94%).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:10]#[C:11][C:12]2[CH:22]=[CH:21][C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:14][C:13]=2[CH3:23])[CH:5]=[N:6][C:7]=1[C:8]#[N:9].[CH3:24][C:25]1[CH:26]=[CH:27][C:28](B2OC(C)(C)C(C)(C)O2)=[C:29]([NH:31]C(=O)OC(C)(C)C)[CH:30]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.C(O)C.CO.C(Cl)Cl.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:9][C:8]1[C:7]2[N:6]=[CH:5][C:4]([C:10]#[C:11][C:12]3[CH:22]=[CH:21][C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:14][C:13]=3[CH3:23])=[CH:3][C:2]=2[C:28]2[CH:27]=[CH:26][C:25]([CH3:24])=[CH:30][C:29]=2[N:31]=1
Reactant: Cc1ccc(B2OC(C)(C)C(C)(C)O2)c(NC(=O)OC(C)(C)C)c1
Reactant: CCOC(=O)c1ccc(C#Cc2cnc(C#N)c(Cl)c2)c(C)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCOC(=O)c1ccc(C#Cc2cnc3c(N)nc4cc(C)ccc4c3c2)c(C)c1
Temperature: 25 °C

Procedure:
A solution of ethyl 4-((5-chloro-6-cyanopyridin-3-yl)ethynyl)-3-methylbenzoate (from the previous step) (1.0 eq.), tert-butyl 5-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenylcarbamate (from Example 5/Step 2) (1.1 eq.), tetrakis(triphenylphosphine)palladium (8 mol %), and potassium carbonate (3.0 eq.) in toluene/ethanol (9:1, 0.2 M) was stirred at 100° C. overnight. After cooling to ambient temperature, the reaction mixture was diluted with 2% MeOH in DCM. The two phases were separated. The combined organic layers were washed with brine, dried over anhydrous MgSO4, and concentrated en vaccuo. The crude material was purified by flash chromatography on a COMBIFLASH® system (ISCO) using 0-40% ethyl acetate in toluene to give ethyl 4-((5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethynyl)-3-methylbenzoate.
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:14]=[CH:13][C:12]([C:15]3([C:19]#[N:20])[CH2:18][CH2:17][CH2:16]3)=[CH:11][CH:10]=2)[O:3]1.B.C1COCC1>>[CH3:7][C:6]1([CH3:8])[C:2]([CH3:1])([CH3:21])[O:3][B:4]([C:9]2[CH:10]=[CH:11][C:12]([C:15]3([CH2:19][NH2:20])[CH2:16][CH2:17][CH2:18]3)=[CH:13][CH:14]=2)[O:5]1
Reactant: CC1(C)OB(c2ccc(C3(C#N)CCC3)cc2)OC1(C)C
Agent: B
Solvent: C1CCOC1
Product: CC1(C)OB(c2ccc(C3(CN)CCC3)cc2)OC1(C)C
Yield: 92 %

Procedure:
Following the procedure outlined for Example 666, 1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)cyclobutane carbonitrile (4.0 g, 14 mmol) was reacted with BH3.THF (1.0 M in THF, 60 mL, 60 mmol) to afford the desired product (3.7 g, 91%) as a yellow oil: ESI MS m/z 288 [C11H2BNO2+H]+.