Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:19]2[CH2:21][CH2:20]2)=[C:6]([CH:8]=[C:9]2[C:13]([CH3:15])([CH3:14])[O:12][C:11]([CH3:17])([CH3:16])[C:10]2=[O:18])[CH:7]=1.[OH-:22].[Li+].OO>CO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:19]2[CH2:21][CH2:20]2)=[C:6]([CH:8]2[C:9]3([C:10](=[O:18])[C:11]([CH3:17])([CH3:16])[O:12][C:13]3([CH3:14])[CH3:15])[O:22]2)[CH:7]=1
Reactant: CC1(C)OC(C)(C)C(=Cc2cc(Br)ccc2C2CC2)C1=O
Reactant: [OH-]
Agent: OO
Agent: [Li+]
Solvent: CO
Product: CC1(C)OC(C)(C)C2(OC2c2cc(Br)ccc2C2CC2)C1=O
Temperature: 45 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4-[1-(5-bromo-2-cyclopropylphenyl)methylidene]-2,2,5,5-tetramethyldihydrofuran-3-one (189 g, 541 mmol) in methanol (2650 ml) at 53° C. is added and 2M aqueous lithium hydroxide (27.1 ml, 54.2 mmol) then 50% aqueous hydrogen peroxide (46.1 ml, 812 mmol). After stirring for 30 minutes at this temperature the solution is cooled to 45° C. and quenched with saturated aqueous sodium thiosulfate. Distilled water (1000 ml) is added and the organic solvents are removed in vacuo. The aqueous phase is then extracted into ethyl acetate (×2) and the combined organic extracts are washed with saturated aqueous sodium hydrogen carbonate (×2), brine (500 mL), then dried over anhydrous magnesium sulfate. Volatile solvents are removed under vacuum to afford 2-(5-bromo-2-cyclopropylphenyl)-4,4,6,6-tetramethyl-1,5-dioxaspiro[2.4]heptan-7-one.
Reaction SMILES: FC1C(F)=CC=CC=1[C@@H]1CC[C@@H](CC([N:23]2[CH2:28][CH2:27][CH:26]([N:29]3[C:37]4[C:32](=[N:33][CH:34]=[CH:35][CH:36]=4)[NH:31][C:30]3=[O:38])[CH2:25][CH2:24]2)=O)C2=NC=CC=C2C1.FC1C(F)=CC=CC=1[C@H]1CC[C@H](CC(N2CCC(N3C4C(=NC=CC=4)NC3=O)CC2)=O)C2=NC=CC=C2C1.Cl>C(Cl)Cl>[NH:23]1[CH2:24][CH2:25][CH:26]([N:29]2[C:37]3[C:32](=[N:33][CH:34]=[CH:35][CH:36]=3)[NH:31][C:30]2=[O:38])[CH2:27][CH2:28]1
Reactant: O=C(C[C@@H]1CC[C@@H](c2cccc(F)c2F)Cc2cccnc21)N1CCC(n2c(=O)[nH]c3ncccc32)CC1
Agent: Cl
Agent: O=C(C[C@H]1CC[C@H](c2cccc(F)c2F)Cc2cccnc21)N1CCC(n2c(=O)[nH]c3ncccc32)CC1
Solvent: ClCCl
Product: O=c1[nH]c2ncccc2n1C1CCNCC1

Procedure:
1-(1-(2-((6R,9S)-6-(2,3-Difluorophenyl)-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-yl)acetyl)piperidin-4-yl)-1H-imidazo[4,5-b]pyridin-2(3H)-one and 1-(1-(2-((6S,9R)-6-(2,3-difluorophenyl)-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-yl)acetyl)piperidin-4-yl)-1H-imidazo[4,5-b]pyridin-2(3H)-one. In a 100 mL round-bottomed flask was 2-((6,9-trans)-6-(2,3-difluorophenyl)-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-yl)acetic acid (46.0 mg, 0.145 mmol) and 1-(piperidin-4-yl)-1H-imidazo[4,5-b]pyridin-2(3H)-one (95 mg, 0.435 mmol) (bis-HCl salt) in CH2Cl2 (4 ml) to give a colorless suspension. Hunig'sBase (0.127 ml, 0.725 mmol) and 3-(DIETHOXYPHOSPHORYLOXY)-1,2,3-BENZO-TRIAZIN-4(3H)-ONE (87 mg, 0.290 mmol) were added. The reaction mixture was diluted with DMF (1 ml). Most solids were dissolved. It was stirred at rt overnight. 44 h: LCMS indicated complete conversion. It was diluted with EtOAc and washed with water. The layers were separated. The organic layer was washed with brine, dried with Na2SO4, and concentrated to a tan oil/gel. Purification by FCC (ISCO) up to 8% MeOH in CH2Cl2 afforded the desired product as a tan foam (68 mg, 86% for 2 steps). MS(ESI)[M+H+]=518.27; 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 11.44 (br.s., 1 H) 8.25-8.42 (m, 1 H) 8.05 (d, J=5.29 Hz, 1 H) 7.38 (t, J=8.44 Hz, 1 H) 7.20-7.31 (m, 1 H) 6.83-7.10 (m, 5 H) 4.87 (d, J=12.34 Hz, 1 H) 4.53-4.73 (m, 1 H) 4.43 (t, J=15.36 Hz, 1 H) 3.81-4.00 (m, 1 H) 3.36-3.60 (m, 2 H) 3.24 (t, J=12.97 Hz, 1 H) 2.94 (t, J=11.21 Hz, 1 H) 2.33-2.80 (m, 4 H) 2.05-2.31 (m, 3 H) 1.80-2.05 (m, 3 H) 1.38-1.63 (m, 1 H). The racemic product was resolved by chiral HPLC (Chiralpak AD-H analytical column, 4.6×250 mm, 5 μm; Mobile Phase: 40% MeOH in CO2; Temp: 35° C.; Flow rate: 2.0 mL/min. for 26 min; Injection: 5 uL of ˜2 mg/mL in MeOH). Compound (6R, 9S) was the first peak with tR=13.88 min while compound (6S, 9R) was the second peak with tR=19.19 min).
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[N:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]2=[N:6][C:5]=1[C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=1.[CH3:20][C:21]1[CH:26]=[CH:25][NH:24][C:23](=[O:27])[N:22]=1>>[Cl:19][C:16]1[CH:17]=[CH:18][C:13]([C:5]2[N:6]=[C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][N:8]3[C:4]=2[CH2:3][N:24]2[CH:25]=[CH:26][C:21]([CH3:20])=[N:22][C:23]2=[O:27])=[CH:14][CH:15]=1
Reactant: ClCc1c(-c2ccc(Cl)cc2)nc2ccccn12
Reactant: Cc1cc[nH]c(=O)n1
Agent: Cc1ccnc(O)n1
Agent: Cl
Product: Cc1ccn(Cc2c(-c3ccc(Cl)cc3)nc3ccccn23)c(=O)n1

Procedure:
The title compound was prepared according to Method B and the experimentals described for compound 91 from 3-(chloromethyl)-2-(4-chlorophenyl)imidazo[1,2-a]pyridine hydrochloride and 4-methylpyrimidin-2(1H)-one or 4-methylpyrimidin-2-ol. m/e+ 351 for C19H16ClN40 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]3[O:17][CH2:16][CH2:15][C:14]([C:18]([NH:20][C:21]4[CH:26]=[CH:25][C:24]([CH2:27][S:28][C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=5)=[CH:23][CH:22]=4)=[O:19])=[CH:13][C:12]=3[CH:35]=2)=[CH:4][CH:3]=1.ClC1C=CC=C(C(OO)=[O:44])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[CH:10][C:11]3[O:17][CH2:16][CH2:15][C:14]([C:18]([NH:20][C:21]4[CH:26]=[CH:25][C:24]([CH2:27][S:28]([C:29]5[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=5)=[O:44])=[CH:23][CH:22]=4)=[O:19])=[CH:13][C:12]=3[CH:35]=2)=[CH:6][CH:7]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CSc4ccccc4)cc2)CCO3)cc1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CS(=O)c4ccccc4)cc2)CCO3)cc1
Reaction time: 0.5 h
Yield: 106.4 %

Procedure:
To a solution of 7-(4-methylphenyl)-N-(4-(phenylthiomethyl)phenyl)-2,3-dihydro-1-benzoxepine-4-carboxamide (0.1 g) in dichloromethane (30 ml) was added 70% m-chloroperbenzoic acid (0.046 g) at the temperature ranging from −20 to −10° C., and the mixture was stirred for 30 minutes. To the mixture was added sodium thiosulfate solution, and the mixture was concentrated and extracted with ethyl acetate. The organic layer was washed with sodium hydrogen carbonate solution, water and saturated sodium chloride solution, and dried with anhydrous magnesium sulfate. Under reduced pressure, the solvent was evaporated to give crude crystals, which were recrystallized from ethyl acetate-hexane to give 7-(4-methylphenyl)-N-(4-(phenylsulfinylmethyl)phenyl)-2,3-dihydro-1-benzoxepine-4-carboxamide (Compound 108) (0.11 g) as colorless crystals.
Reaction SMILES: [C:1]([CH:3]([C:5]1[CH:10]=[CH:9][C:8]([S:11][C:12]2[C:17]([CH2:18][C:19]([OH:21])=O)=[CH:16][CH:15]=[CH:14][N:13]=2)=[CH:7][CH:6]=1)[CH3:4])#[N:2].[OH-:22].[Na+]>>[O:21]=[C:19]1[CH2:18][C:17]2[CH:16]=[CH:15][CH:14]=[N:13][C:12]=2[S:11][C:8]2[CH:9]=[CH:10][C:5]([CH:3]([CH3:4])[C:1]([NH2:2])=[O:22])=[CH:6][C:7]1=2
Reactant: CC(C#N)c1ccc(Sc2ncccc2CC(=O)O)cc1
Reactant: [OH-]
Agent: [Na+]
Product: CC(C(N)=O)c1ccc2c(c1)C(=O)Cc1cccnc1S2
Temperature: 150 °C
Reaction time: 1.08 h

Procedure:
The mixture of 101 mg of 2-[4'-(α-cyanoethyl)-phenylthio]-3-pyridylacetic acid and 2 g of polyphosphoric acid was stirred at 150° C. for 65 minutes. After cooling, to this was added ice-water and the mixture was neutralized with conc. sodium hydroxide solution and 3% sodium hydroxide solution, then was made alkaline therewith. The resulting mixture was extracted with ethyl acetate and the extract was washed with 3% sodium hydroxide solution and dried over anhydrous sodium sulfate. The solvent was distilled off to obtain 36 mg of yellow glutinous substance, which was chromatographed over silica gel, eluted with n-hexane/acetone (2/1) and there was obtained 25 mg of 2-(5,6-dihydro-6-oxo benzo[b]pyrido[3,2-f]-thiepin-8-yl)-propionamide as colorless glutinous substance. This was solidified with ethanol to give crystals having a melting point of 175°-180° C. These were recrystallized from ethanol to give crystals having a melting point of 190°-192.5° C.
Reaction SMILES: [CH2:1]([C:3]1([NH2:9])[CH2:8][O:7][CH2:6][O:5][CH2:4]1)[CH3:2].[OH-].[Na+].O.[Br:13][CH:14]([CH2:18][Cl:19])[C:15](Cl)=[O:16]>C(Cl)Cl>[Br:13][CH:14]([CH2:18][Cl:19])[C:15]([NH:9][C:3]1([CH2:1][CH3:2])[CH2:8][O:7][CH2:6][O:5][CH2:4]1)=[O:16]
Reactant: CCC1(N)COCOC1
Reactant: O=C(Cl)C(Br)CCl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: CCC1(NC(=O)C(Br)CCl)COCOC1
Reaction time: 0.5 h

Procedure:
Five and two-tenths g (0.04 mole) of 5-ethyl-5-amino-1,3-dioxane, 3.2 g (0.04 mole) of 50% sodium hydroxide, 10 ml of water, and 90 ml of methylene chloride were combined in a reaction flask. The mixture was cooled to below 35° C. Eight and two-tenths g (0.04 mole) of 2-bromo-3chloropropionyl chloride were added dropwise. The mixture was stirred for 1/2 hour, filtered, dried over magnesium sulfate, and vacuum stripped. Yield was 10.8 g of 5-(2'-bromo-3'-chloropropionyl) amino-5-ethyl-1,3-dioxane. m.p.=95°-109° C. Structure was confirmed by NMR.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:11]2[CH2:13][O:12]2)[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].[NH2:14][CH2:15][CH2:16][OH:17].CCOC(C)=O.C1COCC1>C1COCC1>[OH:17][CH2:16][CH2:15][NH:14][CH2:13][CH:11]([C:4]1[CH:5]=[CH:6][C:7]([N+:8]([O-:10])=[O:9])=[C:2]([CH3:1])[CH:3]=1)[OH:12]
Reactant: NCCO
Reactant: Cc1cc(C2CO2)ccc1[N+](=O)[O-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1cc(C(O)CNCCO)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of (RS)-2-(3-methyl-4-nitrophenyl)oxirane (4.63 g) in THF (15 ml) was added 2-aminoethanol (15.5 ml) and the mixture was stirred at room temperature overnight. The reaction mixture was then poured into EtOAc/THF (1:1) and extracted with saturated brine. The organic layer was dried over Na2SO4 and concentrated in vacuo to afford (RS)-2-(2-hydroxyethylamino)-1-(3-methyl-4-nitrophenyl)ethanol (6.84 g, quant.) as a brown oil which was used in the next step without further purification. MS (ISP): 241.1 ([M+H]+).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:12])=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1.[NH:13]1[CH2:18][CH2:17][CH:16]([CH2:19][CH2:20][OH:21])[CH2:15][CH2:14]1>>[F:12][C:8]1[CH:7]=[C:6]2[C:11](=[CH:10][CH:9]=1)[C:2]([N:13]1[CH2:18][CH2:17][CH:16]([CH2:19][CH2:20][OH:21])[CH2:15][CH2:14]1)=[N:3][CH:4]=[CH:5]2
Reactant: OCCC1CCNCC1
Reactant: Fc1ccc2c(Cl)nccc2c1
Product: OCCC1CCN(c2nccc3cc(F)ccc23)CC1
Yield: 39.1 %

Procedure:
The process is performed as described in Example 4 (step 4.1). Starting with 1.52 g (8.39 mmol) of 1-chloro-6-fluoroisoquinoline and 1.20 g (9.23 mmol) of 2-(4-piperidyl)ethanol, and after chromatography on silica gel, eluting with a 95/5/0.5 mixture of dichloromethane, methanol and 28% aqueous ammonia, 0.90 g of pure product is obtained in the form of a yellow paste.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]([C:10]2[C:15]([NH:16][S:17]([C:20]3[CH:25]=[CH:24][C:23]([C:26]([CH3:29])([CH3:28])[CH3:27])=[CH:22][CH:21]=3)(=[O:19])=[O:18])=[CH:14][C:13]([Cl:30])=[CH:12][N:11]=2)=[O:9])[CH:5]=[CH:4][CH:3]=1.[Si](N=C=O)(C)(C)C.[CH3:38][C:39](O)=[O:40]>C1COCC1.C(#N)C>[C:26]([C:23]1[CH:22]=[CH:21][C:20]([S:17]([NH:16][C:15]2[C:10]([C:8]([C:6]3[N:7]=[C:2]([NH:1][C:39](=[O:40])[CH3:38])[CH:3]=[CH:4][CH:5]=3)=[O:9])=[N:11][CH:12]=[C:13]([Cl:30])[CH:14]=2)(=[O:18])=[O:19])=[CH:25][CH:24]=1)([CH3:27])([CH3:29])[CH3:28]
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Nc2cc(Cl)cnc2C(=O)c2cccc(N)n2)cc1
Reactant: CC(=O)O
Agent: C[Si](C)(C)N=C=O
Solvent: C1CCOC1
Solvent: CC#N
Product: CC(=O)Nc1cccc(C(=O)c2ncc(Cl)cc2NS(=O)(=O)c2ccc(C(C)(C)C)cc2)n1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
N-[2-(6-Amino-pyridine-2-carbonyl)-5-chloro-pyridin-3-yl]-4-tert-butyl-benzenesulfonamide (26 mg, 0.05 mmol) in THF (2 mL) was treated with TMS-isocyanate (100 mg) and AcOH (0.5 mL), and then stirred at 80° C. for 2 h. The mixture was subsequently diluted with acetonitrile (1 mL) and purified via HPLC to afford the title compound: 1H NMR (400 MHz, CDCl3) δ 11.1 (s, 1 H), 8.48 (d, 1 H), 8.32 (d, 1 H), 8.24 (m, 2H), 7.86 (m, 3H), 7.55 (d, 2H), 5.30 (s, 2H), 4.75 (s, 2H), 1.22 (s, 9H); ESMS m/z (relative intensity): 488.1 (M+H)+ (100).
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[O:7][CH2:6][CH:5]([NH:8][C:9]2[C:14]([NH2:15])=[CH:13][CH:12]=[C:11]([O:16][CH3:17])[N:10]=2)[CH2:4][O:3]1.C([O-])([O-])=O.[K+].[K+].Br[CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28].C(Cl)Cl>CN(C=O)C>[CH3:1][C:2]1([CH3:18])[O:7][CH2:6][CH:5]([NH:8][C:9]2[C:14]([NH:15][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:13][CH:12]=[C:11]([O:16][CH3:17])[N:10]=2)[CH2:4][O:3]1
Reactant: COc1ccc(N)c(NC2COC(C)(C)OC2)n1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCOC(=O)CNc1ccc(OC)nc1NC1COC(C)(C)OC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84 %

Procedure:
Crude N2-(2,2-dimethyl-1,3-dioxan-5-yl)-6-(methyloxy)-2,3-pyridinediamine (123.6 mmol) was dissolved in anhydrous DMF (500 ml) under argon and anhydrous K2CO3 (37.56 g) was added, followed by ethyl bromoacetate (12.31 ml). The mixture was stirred at room temperature overnight. The solvent was removed under reduced pressure and the resulting reddish-brown slurry was partitioned between DCM (1.2 L) and water (300 ml). The organic phase was separated and washed with water (300 ml), dried over Na2SO4, filtered and evaporated under reduced pressure to give a dark red oil, this was taken up in a minimum of DCM and purified by column chromatography on silica (eluted with 5%-60% EtOAc in petroleum ether (40-60°)). Appropriate fractions were combined and evaporated under reduced pressure to give the title compound as a dark orange oil (35.42 g, 84%).
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]([O:12][CH3:13])[C:5]2[O:6][CH2:7][CH2:8][O:9][C:4]=2[C:3]=1[F:14].C([Li])CCC.[CH:20](N1CCOCC1)=[O:21].[Cl-].[NH4+]>C1COCC1.C(OCC)(=O)C>[F:14][C:3]1[C:4]2[O:9][CH2:8][CH2:7][O:6][C:5]=2[C:10]([O:12][CH3:13])=[CH:11][C:2]=1[CH:20]=[O:21]
Reactant: O=CN1CCOCC1
Reactant: COc1cc(Br)c(F)c2c1OCCO2
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1cc(C=O)c(F)c2c1OCCO2
Temperature: -72 °C
Reaction time: 0.5 h

Procedure:
To a solution of 549 mg of 6-bromo-5-fluoro-8-methoxy-2,3-dihydrobenzo[1,4]dioxine in 15 ml of THF there was added dropwise 0.86 ml of n-butyllithium (2.55 M, hexane solution) at −70° C. under a nitrogen atmosphere. After stirring at −72° C. for 30 minutes, 0.3 ml of N-formylmorpholine was added and the temperature was raised from −78° C. to 0° C. over a period of 30 minutes. Saturated aqueous ammonium chloride was added to the reaction mixture, and extraction was performed with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The desiccating agent was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-heptane) to give the title compound (247 mg) as a solid.
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@@H:2]([C:13]([NH:15][C@H:16]([C:21]([N:23]([CH3:32])[C@H:24]([C:29]([NH2:31])=[O:30])[CH2:25][CH2:26][CH2:27][CH3:28])=[O:22])[CH2:17][CH:18]([CH3:20])[CH3:19])=[O:14])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.FC(F)(F)C(O)=O>CSC.C(S)(S)C>[NH2:1][C@@H:2]([C:13]([NH:15][C@H:16]([C:21]([N:23]([CH3:32])[C@H:24]([C:29]([NH2:31])=[O:30])[CH2:25][CH2:26][CH2:27][CH3:28])=[O:22])[CH2:17][CH:18]([CH3:19])[CH3:20])=[O:14])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1
Reactant: CCCC[C@@H](C(N)=O)N(C)C(=O)[C@H](CC(C)C)NC(=O)[C@@H](Cc1c[nH]c2ccccc12)NC(=O)OC(C)(C)C
Agent: CC(S)S
Solvent: CSC
Solvent: O=C(O)C(F)(F)F
Product: CCCC[C@@H](C(N)=O)N(C)C(=O)[C@H](CC(C)C)NC(=O)[C@H](N)Cc1c[nH]c2ccccc12
Yield: 37 %

Procedure:
Condensation of BocDTrp-LeuOH (Example 38, 2.09 g.) and MeNleNH2 (1.00 g.) using dicyclohexylcarbodiimide and 1-hydroxybenzotriazole gave BocDTrp-Leu-MeNleNH2 in 99% yield. De-t-butoxycarbonylation of BocDTrp-Leu-MeNleNH2 (2.50 g.) using trifluoroacetic acid in dimethyl sulfide and ethanedithiol gave HDTrp-Leu-MeNleNH2 in 37% yield.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([N:23]([CH3:25])[CH3:24])([CH2:21][CH3:22])[C:12]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)=[O:13])=[CH:6][CH:5]=1)([O-])=O.[H][H]>[Pd].C(O)C>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([N:23]([CH3:25])[CH3:24])([CH2:21][CH3:22])[C:12]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)=[O:13])=[CH:6][CH:5]=1
Reactant: [H][H]
Reactant: CCC(Cc1ccc([N+](=O)[O-])cc1)(C(=O)c1ccc(F)cc1)N(C)C
Agent: [Pd]
Solvent: CCO
Product: CCC(Cc1ccc(N)cc1)(C(=O)c1ccc(F)cc1)N(C)C

Procedure:
7.0 g Palladium on charcoal (5%) are added to solution of 69.5 g (0.178 mol) 2-[(4-nitro-phenyl)methyl]-1-(4-fluorophenyl)-2-dimethylamino-1-butanone in 700 ml ethanol in an hydrogenation autoclave. Hydrogen is entered with a continuous increase of pressure to 5 bar at temperature between room temperature and 40° C. After 25 hours no further hydrogen uptake is observed. The catalyst is filtered off and the crude product obtained as yellowish oil after evaporation of the solvent. Thin film chromatography shows a main product and some minor by-products. The crude material is used without further purification in the next reaction step.
Reaction SMILES: [NH2:1][C@H:2]([C:4]1[N:13]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH2:21][C:22]([F:28])([F:27])[C:23]([F:26])([F:25])[F:24])[CH:15]=2)[C:12](=[O:29])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[F:30])[N:5]=1)[CH3:3].Cl[C:32]1[C:33]2[CH:40]=[CH:39][NH:38][C:34]=2[N:35]=[CH:36][N:37]=1.C(N(C(C)C)CC)(C)C>CC(O)(C)C>[N:35]1[C:34]2[NH:38][CH:39]=[CH:40][C:33]=2[C:32]([NH:1][C@H:2]([C:4]2[N:13]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH2:21][C:22]([F:28])([F:27])[C:23]([F:24])([F:25])[F:26])[CH:15]=3)[C:12](=[O:29])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][C:10]=3[F:30])[N:5]=2)[CH3:3])=[N:37][CH:36]=1
Reactant: C[C@H](N)c1nc2cccc(F)c2c(=O)n1-c1cccc(OCC(F)(F)C(F)(F)F)c1
Reactant: Clc1ncnc2[nH]ccc12
Solvent: CC(C)(C)O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](Nc1ncnc2[nH]ccc12)c1nc2cccc(F)c2c(=O)n1-c1cccc(OCC(F)(F)C(F)(F)F)c1
Temperature: 120 °C
Reaction time: 36 h
Yield: 10.9 %

Procedure:
Under nitrogen, to (S)-2-(1-aminoethyl)-5-fluoro-3-(3-(2,2,3,3,3-pentafluoropropoxy)phenyl)quinazolin-4(3H)-one (86 mg, 0.20 mmol, 1.0 equiv) in t-BuOH (0.2 mL) at 23° C. was added 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (34 mg, 0.22 mmol, 1.1 equiv) and diisopropylethylamine (70 μL, 0.40 mmol, 2.0 equiv). After stirring for 36 hr at 120° C. in a sealed tube, the reaction mixture was concentrated in vacuo and the residue was purified by preparative TLC eluting with CH2Cl2/MeOH to afford 12 mg of the title compound (11% yield).
Reaction SMILES: Cl.[S:2]([N:12]1[C:16]2=[N:17][CH:18]=[C:19]([CH2:21][NH2:22])[N:20]=[C:15]2[CH:14]=[CH:13]1)([C:5]1[CH:11]=[CH:10][C:8]([CH3:9])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[CH:23]1([C:29](Cl)=[O:30])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1.CCN(C(C)C)C(C)C.C([O-])(O)=O.[Na+]>C(Cl)Cl>[S:2]([N:12]1[C:16]2=[N:17][CH:18]=[C:19]([CH2:21][NH:22][C:29]([CH:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)=[O:30])[N:20]=[C:15]2[CH:14]=[CH:13]1)([C:5]1[CH:6]=[CH:7][C:8]([CH3:9])=[CH:10][CH:11]=1)(=[O:3])=[O:4]
Reactant: O=C(Cl)C1CCCCC1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3nc(CN)cnc32)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(S(=O)(=O)n2ccc3nc(CNC(=O)C4CCCCC4)cnc32)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 80.5 %

Procedure:
To a slurry of (5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)methanamine hydrochloride (0.50 g, 1.476 mmol, Example #5, Step C) in DCM (10 mL) was added cyclohexanecarbonyl chloride (0.221 mL, 1.623 mmol) followed by DIEA (0.644 mL, 3.69 mmol). The reaction mixture was stirred for about 4 h at ambient temperature and then saturated aqueous NaHCO3 (20 mL) and DCM (20 mL) were added to the reaction mixture. The organic layer was separated, concd in vacuo, and purified by chromatography on silica gel (40 g) eluting with 20-80% EtOAc in DCM to provide N-((5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)methyl)cyclohexanecarboxamide (0.49 g, 80%) as a colorless solid: LC/MS (Table 1, Method a) Rt=2.40 min; MS m/z: 413 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:14]1[CH2:19][CH2:18][C:17](=[O:20])[CH2:16][CH:15]=1)[CH3:13])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH2:31](Br)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>C1COCC1.C(OCC)(=O)C>[CH2:31]([CH:18]1[CH:19]=[C:14]([C@@H:12]([NH:11][C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:10])[CH3:13])[CH2:15][CH2:16][C:17]1=[O:20])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: BrCc1ccccc1
Reactant: C[C@H](NC(=O)OCc1ccccc1)C1=CCC(=O)CC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C[C@H](NC(=O)OCc1ccccc1)C1=CC(Cc2ccccc2)C(=O)CC1
Temperature: -78 °C
Reaction time: 6 h

Procedure:
To a stirred solution of the above ketone (33) (14.93 g) in dry THF (200 mL) at -78° C. under Ar was added a solution of lithium bis-trimethylsilylamide (55 mL, 1N in THF). After stirring for 20 min benzylbromide (35 mL) was added and the reaction stirred for an additional 6 h at -78° C. then allowed to slowly warm to room temperature. The reaction was taken up in ethyl acetate, washed with 1N HCl, saturated NaCl, dried over MgSO4 and evaporated. The product (34) was obtained by flash chromatography on silica gel eluted with 20 to 25% ethyl acetate in n-hexane (6.09 g, 31%): TLC Rf 0.17 (20% ethyl acetate, n-hexane); 1H NMR (CDCl3) δ1.12 (3H, d, J=7 Hz), 2.0-3.2 (7H, m), 4.18(1H, q), 5.1(2H, s), 5.33(1 H, dd), 5.55(1H, br s), 7.22 (5H, m), 7.32 (5H, s).
Reaction SMILES: [C:1]([CH2:3][CH:4]([C:10]1[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=1)[C:5](OCC)=[O:6])#[N:2].N>CO.[Ni].O>[F:17][C:16]([F:19])([F:18])[C:13]1[CH:14]=[CH:15][C:10]([CH:4]2[CH2:3][CH2:1][NH:2][C:5]2=[O:6])=[CH:11][CH:12]=1
Reactant: CCOC(=O)C(CC#N)c1ccc(C(F)(F)F)cc1
Agent: [Ni]
Agent: N
Solvent: CO
Solvent: O
Product: O=C1NCCC1c1ccc(C(F)(F)F)cc1

Procedure:
A solution of the product from Example 266B (4.1 g, 15.12 mmol) in methanol (10 mL) was added to 7 M ammonia in methanol (5.00 mL) and Raney® nickel, water wet, A-7000 (12.30 g, 210 mmol) in a 250 mL stainless steel pressure bottle and stirred for 16 hours under hydrogen (30 psi) at room temperature. The mixture was filtered through a nylon membrane and then concentrated to obtain solid. The solid was slurried in 5% ethyl acetate/hexanes, filtered and dried to give the title compound. MS (DCI+) m/z 247 (M+NH4)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](/[C:9](/[CH:16]([CH3:18])[CH3:17])=[CH:10]\[CH:11]=[CH:12]\[C:13]([OH:15])=[O:14])=[CH:5][CH:4]=1.[N+:19]([C:22]1[CH:27]=[CH:26][C:25](O)=[CH:24][CH:23]=1)([O-:21])=[O:20].C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[N+:19]([C:22]1[CH:27]=[CH:26][C:25]([O:14][C:13](=[O:15])/[CH:12]=[CH:11]/[CH:10]=[C:9](\[C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)/[CH:16]([CH3:18])[CH3:17])=[CH:24][CH:23]=1)([O-:21])=[O:20]
Reactant: COc1ccc(/C(=C\C=C\C(=O)O)C(C)C)cc1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: COc1ccc(/C(=C\C=C\C(=O)Oc2ccc([N+](=O)[O-])cc2)C(C)C)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 74.4 %

Procedure:
As in Example 115, (2E,4Z)-5-(4-methoxyphenyl)-6-methyl-2,4-heptadienoic acid (3.2 g) and 4-nitrophenol (2.2 g) in 20 mL of dichloromethane was treated with 1,3-dicyclohexylcarbodiimide (2.7 g) and the mixture was stirred at room temperature for 18 hours. After the usual work up. crystallization of the crude product from 2-propanol-hexane yielded 3.55 g of (2E,4Z)-5-(4-methoxyphenyl)-6-methyl-2,4-heptadienoic acid 4-nitrophenyl ester, mp 111.5°-113° C.